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WO2025031294A1 - Agent de dégradation irak4 et composition pharmaceutique et son utilisation pharmaceutique - Google Patents

Agent de dégradation irak4 et composition pharmaceutique et son utilisation pharmaceutique Download PDF

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Publication number
WO2025031294A1
WO2025031294A1 PCT/CN2024/109554 CN2024109554W WO2025031294A1 WO 2025031294 A1 WO2025031294 A1 WO 2025031294A1 CN 2024109554 W CN2024109554 W CN 2024109554W WO 2025031294 A1 WO2025031294 A1 WO 2025031294A1
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substituted
unsubstituted
alkyl
halogen
cyano
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段文虎
丁健
陈智伟
谢华
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Zhongshan Institute For Drug Discovery Shanghai Institute Of Materia Medica Chinese Academy Of Sciences
Shanghai Institute of Materia Medica of CAS
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Zhongshan Institute For Drug Discovery Shanghai Institute Of Materia Medica Chinese Academy Of Sciences
Shanghai Institute of Materia Medica of CAS
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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.
  • PROTAC Proteolysis targeting chimeras
  • 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.
  • 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.
  • Ring T is selected from a 5-9 membered heteroaromatic ring
  • L' is -CONH- or -NHCO-, with the left side connected to the ring T and the right side connected to the parent nucleus;
  • E is CH or N
  • Rx 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 substitution by one or more R j ;
  • R b and 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 one or more of halogen, hydroxyl, amino, carbonyl, cyano, -CONH 2 , -SO 2 NH 2 , 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 form a 4-8 membered heterocyclic ring, which is optionally substituted by one or more R j ;
  • 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, -CONH 2 , -SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;
  • Each Ra 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 substitution by one or more Rj ;
  • Each Rj is independently selected from halogen, carbonyl, -L2-CN, -L2- ORk , -L2- COORk , -L2- NRkRm , -L2- CONRkRm , -L2-S(O) 2NRkRm , 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, -CONH2 , -SO2NH2
  • 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 and R m are 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, -CONH 2 , -SO 2 NH 2 ;
  • Each R y 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 one or more of halogen, hydroxyl, amino, -CONH 2 , -SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;
  • n 1 or 2;
  • Each R z 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;
  • n is selected from 1, 2, 3, 4;
  • 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;
  • Each R n 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 R1 ; each R1 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
  • L3 is selected from a chemical bond or a divalent saturated or unsaturated straight or branched C1-C6 alkyl chain; and one or more hydrogens on L3 are optionally substituted by halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 , -SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;
  • two R1 groups on the same atom optionally form a saturated or partially saturated C3-C12 carbocycle, a saturated or partially saturated 4-12 membered heterocycle together with their intermediate atom; the heterocycle is optionally substituted by one or more Rp ;
  • Each R p 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.
  • ring T is a 5-9 membered nitrogen-containing heteroaromatic ring.
  • ring T is a 5-membered heteroaromatic ring or a 9-membered condensed heteroaromatic ring.
  • the 9-membered fused heteroaromatic ring is a 6-membered aromatic ring or a heteroaromatic ring fused with a 5-membered heteroaromatic ring.
  • 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.
  • ring T is selected from the following structures:
  • each R y 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.
  • each R y 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.
  • each R y 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.
  • each R y 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.
  • L' is selected from in, indicates the site of attachment to loop T, Indicates the site of connection with the mother nucleus, preferably
  • Rx 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 substitution by one or more R j ;
  • R b and 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 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 form a 4-8 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by one or more R j ;
  • L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C6 alkyl chain; and any one of L1 One or more hydrogens are optionally substituted by halogen, hydroxy, amino, cyano, carbonyl, -CONH 2 , -SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;
  • Each Ra 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 substitution by one or more Rj ;
  • Each Rj is independently selected from halogen, carbonyl, -L2-CN, -L2- ORk , -L2- COORk , -L2- NRkRm , -L2- CONRkRm , -L2-S(O) 2NRkRm , 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, -CONH2 , -SO2NH2
  • 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 and R m are 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 of halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 , and -SO 2 NH 2 .
  • Rx 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 substitution by one or more R j .
  • R b and 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 one or more of halogen, hydroxyl, amino, cyano, and -CONH 2 ; or R b and R c optionally form a 5-6 membered heterocyclic ring together with the nitrogen atom to which they are connected, and the heterocyclic ring is optionally substituted by one or more R j .
  • R b and R c are each 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 group, and halogenated or unhalogenated C1-C6 alkoxy group.
  • 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, or -CONH2 .
  • 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.
  • each Ra 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 substitution by one or more Rj .
  • each Ra 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 a 4-8 membered heterocyclyl, a substituted or unsubstituted 5-8 membered heteroaryl; the substitution refers to substitution by one or more R j .
  • each R j 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.
  • each R j 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.
  • 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 and R m are independently selected from hydrogen, C1-C6 alkyl, and C2-C6 acyl.
  • Rx 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-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 substitution by one or more R j ;
  • R b and 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 form a 5-6 membered heterocyclic ring, which is optionally substituted by one or more R j ;
  • 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;
  • Each Ra 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 substitution by one or more Rj ;
  • Each Rj is independently selected from halogen, -L2- CN , -L2- ORk , -L2- COORk , -L2- NRkRm , -L2- CONRkRm , -L2-S(O) 2NRkRm , halogenated or unhalogenated C1 - C4 alkyl ;
  • R k and R m are independently selected from hydrogen, C1-C6 alkyl, and C2-C6 acyl.
  • Rx is 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, -NRbRc ; the substitution refers to substitution by one or more Rj .
  • R b and 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 connected form a 4-8 membered heterocycle, wherein the heterocycle is optionally substituted by one or more R j .
  • each R j 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
  • Rx 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-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, -NRbRc ; the substitution refers to substitution by one or more Rj ;
  • R b and 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 form a 5-6 membered heterocyclic ring, which is optionally substituted by one or more R j ;
  • L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain;
  • Each Ra 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 substitution by one or more Rj ;
  • Each R j 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;
  • R k and R m are independently selected from hydrogen, C1-C6 alkyl, and C2-C6 acyl.
  • 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 4-8 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substitution refers to substitution by one or more R j ;
  • L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain;
  • Each Ra 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;
  • Each R j 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.
  • Rx is 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:
  • R x is preferably halogen, such as fluorine, chlorine, or bromine.
  • Rz is preferably hydrogen, halogen, C1-C6 alkyl, more preferably hydrogen, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, more preferably hydrogen.
  • 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-,
  • 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.
  • 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.
  • each Cy is independently selected from the following rings: cyclobutane, cyclopentane, cyclohexane, Benzene ring, naphthalene ring,
  • each R 1 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 carbocycle (including monocyclic, bridged, condensed, spirocyclic), -L3-substituted or unsubstituted saturated or partially saturated 4-8 membered heterocycle (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 or un
  • L3 is selected from a chemical bond or a divalent saturated or unsaturated straight or branched C1-C4 alkyl chain; and one or more hydrogens on L3 are optionally substituted by halogen, hydroxyl, amino, cyano, carbonyl, -CONH 2 , -SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.
  • each R 1 is independently selected from halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 haloalkyl alkyl, C1-C4 alkoxy, NR d R e , wherein R d , Re are each independently selected from C1-C3 alkyl.
  • 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-,
  • 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.
  • the compound has a structure shown in Formula II:
  • R x and L are as described herein;
  • R y1 is selected from halogen, hydroxy, amino, -CONH 2 , -SO 2 NH 2 , halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;
  • R y1 is selected from hydrogen, NH 2 ;
  • Rx 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;
  • L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain;
  • Each Ra 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 with alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted with alkyl;
  • L is selected from the following structures:
  • LBM is a cereblon E3 ubiquitin ligase binding portion and has a structure shown in Formula I-aa:
  • Q 1 , Q 2 , Q 3 , Q 4 are each independently selected from C (when connected to L), CR 21 or N;
  • Each R 21 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 ;
  • 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;
  • Each Rf 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.
  • one of Q 1 , Q 2 , Q 3 and Q 4 is C (when connected to L), and the others are CH.
  • one of Q 1 , Q 2 , Q 3 and Q 4 is C (when connected to L), one of them is CR 21 , and the others are CH, wherein R 21 is selected from hydrogen, halogen, halogenated or unhalogenated C1-C3 alkyl, C1-C3 alkoxy.
  • R 3 is selected from hydrogen, halogenated or unhalogenated C1-C3 alkyl.
  • R f is hydrogen
  • LBM is a cereblon E3 ubiquitin ligase binding portion and has a structure shown in Formula I-aa-1:
  • R 21 is selected from hydrogen, halogen, halogenated or unhalogenated C1-C3 alkyl, C1-C3 alkoxy, preferably hydrogen.
  • LBM is a cereblon E3 ubiquitin ligase binding portion and has a structure shown in Formula I-bb:
  • X is selected from CH or N;
  • V is selected from C or N;
  • U is selected from CR 4 , NR 5 or O;
  • P 1 , P 2 , P 3 , P 4 are each independently selected from C (when linked to L), CR 22 or N;
  • R 22 , R 4 , R 5 are each 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;
  • Each Rg 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.
  • one of P 1 , P 2 , P 3 and P 4 is C (when connected to L), and the others are CH.
  • R 22 and R g are both hydrogen, and R 4 and R 5 are each independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C3 alkyl, and C1-C3 alkoxy.
  • LBM is a cereblon E3 ubiquitin ligase binding portion and has formula I-bb-1, formula I-bb-2 or The structure shown in formula I-bb-3:
  • Each R 22 is independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.
  • LBM is a celeblon E3 ubiquitin ligase binding portion and has a structure of formula I-cc:
  • W is CH or N
  • Y is a covalent bond, -N(R 6 )-, -C(O)-N(R 6 )-, or -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 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 ;
  • R6 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 is independently selected from hydrogen, halogen, hydroxy, 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.
  • ring B is selected from a benzene ring and a pyridine ring.
  • each R 23 is independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C3 alkyl, halogen Halogenated or unhalogenated C1-C3 alkoxy.
  • R 6 is selected from hydrogen and C1-C3 alkyl.
  • R h is hydrogen
  • LBM is a celeblon E3 ubiquitin ligase binding portion and has a structure of Formula I-cc-1 or Formula I-cc-2:
  • Y is a covalent bond, -N(R 6 )-, or -C(O)-N(R 6 )-, wherein the left side of the above divalent group is connected to ring B;
  • W is CH or N
  • Each R 23 is independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.
  • LBM is a celeblon E3 ubiquitin ligase binding portion and has a structure of formula I-dd:
  • D is selected from -CH 2 -, -C(O)-; and the H atom is optionally substituted 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 are each independently selected from C (when linked to L), CR 24 , N;
  • Each R 24 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 ;
  • Each R i is independently selected from hydrogen, halogen, hydroxy, amino, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;
  • n4 is selected from 0, 1 or 2.
  • one of A 1 , A 2 , A 3 and A 4 is C (when connected to L), and the others are CH.
  • one of A 1 , A 2 , A 3 , A 4 is C (when connected to L), one of them is CR 24 , and the others are CH, wherein R 24 is selected from halogen, halogenated or unhalogenated C1-C3 alkyl, C1-C3 alkoxy.
  • R i is hydrogen
  • LBM is a celeblon E3 ubiquitin ligase binding portion and has a structure of formula I-dd-1 or formula I-dd-2. Structure:
  • Each R 24 is independently selected from hydrogen, halogen, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.
  • LBM is a VHL E3 ubiquitin ligase binding part and has a structure of formula I-ee:
  • G is selected from S, O;
  • H 1 , H 2 , H 3 , H 4 are each 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 and Z 2 are each independently selected from H, halogen, hydroxy, amino, cyano, carbonyl, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy;
  • I 1 , I 2 , I 3 , I 4 , and I 5 are each independently selected from H, halogen, hydroxy, 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 and R 9 are each 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 ;
  • 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 substitution by one or more of halogen, hydroxyl, amino, mercapto, cyano, -CONH 2 , and -SO 2 NH 2 .
  • H 1 , H 2 , H 3 , and H 4 are all CH.
  • Z 1 and Z 2 are each independently selected from H and C1-C3 alkyl.
  • I 1 , I 2 , I 3 , I 4 , and I 5 are all H.
  • R 7 is selected from substituted or unsubstituted C1-C6 alkyl.
  • R 8 and R 9 are each independently selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to substitution with halogen, hydroxyl, amino or mercapto.
  • the LBM is connected to L via -NH-, R 8 , R 9 , and R 10 .
  • the LBM is connected to L by replacing one hydrogen in -NH-, R 8 , R 9 , and R 10 .
  • Z 1 is a C1-C3 alkyl group
  • Z 2 is hydrogen
  • R 7 is a C1-C3 alkyl group
  • the compound is selected from the structure shown in the following formula:
  • R x , R y , T, E, L, L' are as defined above; and R 2 is selected from hydrogen, halogen, cyano, halogenated or unhalogenated C1-C6 alkyl, halogenated or unhalogenated C1-C6 alkoxy.
  • the compound is selected from the structure shown in the following formula:
  • R x , R y , T, L are as defined above;
  • R 2 is selected from hydrogen, halogen, halogenated C1-C3 alkane C1-C3 alkoxy, halogenated C1-C3 alkoxy;
  • Rx 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;
  • L1 is selected from a chemical bond or a divalent saturated or unsaturated linear or branched C1-C4 alkyl chain;
  • Each Ra 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 with alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryl substituted with alkyl;
  • L is selected from the following structures:
  • R x , R y , R z , E, L, L′, m, n, and LBM are each independently a corresponding group of compound 1-102.
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises the following components:
  • 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.
  • 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.
  • 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:
  • 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.
  • a protein kinase selected from the following group: RET, VEGFR, ErbB2, FLT3, FLT3-ITD or other FLT3 mutations, or a combination thereof.
  • 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.
  • cancer 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.
  • the cancer or proliferative disease is selected from the following group: 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, prostate hyperplasia, epithelial cell cancer , adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, pancreatic ductal carcinoma, breast cancer, follicular carcinoma,
  • 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.
  • 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 cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, arthritis, polychondritis, scleroderma, dermatomyositis, polymyositis, chronic hepatitis, myasthenia gravis, Stevens-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
  • eye diseases
  • a method for preventing and/or treating an IRAK4-mediated disease comprising the steps of:
  • the compound as described in the first aspect of the present invention or its deuterated product, stereoisomer, geometric isomer, tautomer The isomer, solvate, hydrate, prodrug, pharmaceutically acceptable salt or co-crystal, or the pharmaceutical composition according to the second aspect of the present invention is administered to a subject in need thereof.
  • the subject is a human or non-human mammal.
  • a method for degrading IRAK4 protein 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.
  • the inventors 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.
  • linking 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.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • 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 accordingly with the number of connected chemical bonds to become a group with a corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bonds in the figure represent the bonds between the two ends of the nitrogen atom in the group and Other groups are connected;
  • 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.
  • this bond can be a single bond or a double bond, as long as the structure of the formed compound is stable.
  • spiro ring refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between monocyclic rings. They may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system. Spirocyclic radicals are divided into single spirocyclic radicals, double spirocyclic radicals or multiple spirocyclic radicals according to the number of spiro atoms shared between 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).
  • "Spirocyclic ring” or “spirocyclic radical” may be monovalent, divalent, trivalent or tetravalent.
  • Non-limiting examples of spirocyclic rings include:
  • condensed ring or “condensed ring radical” 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 ⁇ electron system.
  • Each ring of the condensed 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). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl.
  • Condensed ring or “condensed ring radical” can be monovalent, divalent, trivalent or tetravalent.
  • Non-limiting examples of condensed rings include:
  • 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 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S (O) n or O, wherein n is 0, 1, 2).
  • Bridged ring or “bridged ring group” can be monovalent, divalent, trivalent or tetravalent.
  • Non-limiting examples of bridged rings include:
  • 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.
  • the "C0 alkyl” mentioned in the claims of the present invention refers to the case where the group is a chemical bond.
  • 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.
  • the alkyl is unsubstituted or substituted.
  • 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.
  • alkoxy refers to a substituted or unsubstituted straight or branched "-O-alkyl”.
  • C1-C6 alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.
  • alkylamino refers to substituted or unsubstituted straight or branched "-NH-alkyl” or “-N(alkyl) 2 ".
  • C1-C6 alkylamino refers to substituted or unsubstituted straight or branched "-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.
  • C2-C6 acyl includes, but is not limited to, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, sec-butyryl, tert-butyryl, Hexanoyl.
  • halogen refers to F, Cl, Br or I.
  • halo means that one or more hydrogens are replaced by F, Cl, Br or I.
  • haloalkyl means that one or more hydrogens of an alkyl group are replaced by halogen, including monohaloalkyl, dihaloalkyl and polyhaloalkyl.
  • C1-C3 haloalkyl means a monohaloalkyl, dihaloalkyl and polyhaloalkyl group comprising 1 to 3 carbon atoms.
  • C1-C3 haloalkyl examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, difluoropropyl, dichloroethyl and dichloropropyl etc.
  • haloalkoxy means that one or more hydrogens of an alkoxy group are replaced by halogen, specifically including monohaloalkoxy, dihaloalkoxy and polyhaloalkoxy.
  • 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.
  • 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).
  • 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.
  • alkylene refers to a divalent alkyl group.
  • An "alkylene chain” is a polymethylene group, ie, -(CH 2 ) n -, where n is a positive integer.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by an optional substituent.
  • 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.
  • 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.
  • aryl refers to a 6-14-membered monocyclic, bicyclic or polycyclic aromatic hydrocarbon group, wherein at least one ring is aromatic.
  • 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.
  • 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.
  • 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.
  • heteroaryl also includes groups in which a heteroaromatic ring is fused to one or more aromatic rings, carbocyclic rings or heterocyclic rings, wherein the radical or point of attachment is on the heteroaromatic 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, tetrazinyl, 1,4-oxazin-3(4H)-one.
  • 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.
  • heterocycle 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.
  • 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.
  • substituents 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.
  • substituted all mean that one or more hydrogens of the specified part are replaced by suitable substituents.
  • substituted 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.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • 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.
  • alkaline earth metal salts e.g. magnesium salts or calcium salts
  • ammonium salts such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts
  • 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.
  • 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.
  • 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, amino, It can be in the form of compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.
  • 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.
  • structures depicted herein also encompass compounds that differ only in the presence of one or more isotopic atoms.
  • compounds having substitutions including replacement of hydrogen by deuterium or tritium, or replacement of carbon by 13 C or 14 C are useful as analytical tools (e.g., as probes in biological assays) or as therapeutic agents according to the present invention.
  • tautomer means that structural isomers of different energies can interconvert over a low energy barrier.
  • proton tautomers i.e., prototropic tautomers
  • valence tautomers include interconversions via reorganization of some of the bonding electrons.
  • inhibitor is defined as a compound that binds to and inhibits the function of IRAK kinase.
  • degradation is defined as a compound that can bind to IRAK kinase and E3 ligase and cause the ubiquitination and degradation of IRAK kinase.
  • 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.
  • 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:
  • the compound is selected from the structure shown in the following formula:
  • R x , R y , T, L are as defined in claim 1;
  • R 2 is selected from hydrogen, halogen, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy.
  • L is selected from the following table:
  • 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.
  • LBM is selected from the following table:
  • the compound is selected from the compounds listed in the following table:
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid
  • Another preferred salt is a salt of the compound of the present invention with 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), such as 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 morpholine, piperazine, lysine, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt,
  • 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.
  • Reaction Scheme I The general synthesis method of the IRAK binding part of the present invention is shown in Reaction Scheme I. It comprises the following steps:
  • Compound 1a is reduced under palladium carbon/hydrogen or iron powder/ammonium chloride conditions to obtain compound 1b;
  • Compound 4c reacts with 4d in the presence of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole condensation agent to obtain compound 4e.
  • compositions containing compounds of formula I are provided.
  • 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.
  • a pharmaceutical composition can be prepared in various forms according to different administration routes.
  • 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.
  • safe and effective amount means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • 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.
  • the "one dose” is a capsule or tablet.
  • “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.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • compositions of the present invention there is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention.
  • Representative administration methods include (but are not limited to) Limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • 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, cetylene glyco
  • 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.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • 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.
  • 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 cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • 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.
  • 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.
  • 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 ingredient can be used to treat, prevent and alleviate diseases related to the activity or expression of IRAK4, such as preventing and/or Treatment of diseases related to abnormal expression of IRAK4 signaling pathway.
  • the compounds of the present invention can be used to treat the following diseases: cancer, autoimmune diseases, inflammatory diseases and thromboembolic diseases.
  • 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.
  • 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,
  • 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.
  • 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.
  • the present invention has the following main advantages:
  • the degrading agent prepared by using the compound has a significant inhibitory effect on IRAK4 enzyme activity.
  • the compound can achieve significant degradation of IRAK4 enzyme at the nM level.
  • the compound also has a significant inhibitory effect on the proliferation of various cancer cells mediated by IRAK4 at the cellular level.
  • the compound has excellent inhibitory selectivity for normal cells/tumor cells.
  • 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.
  • 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.
  • Example 2 can be prepared by the same method as Example 1.
  • Example 3 can be prepared by the same method as Example 1.
  • 1 H NMR 600 MHz, Chloroform-d
  • Example 5 can be prepared by the same method as Example 6.
  • 1 H NMR 600 MHz, Chloroform-d
  • intermediate I-6-2 The preparation of intermediate I-6-2 is the same as that of intermediate I-1-10.
  • 1 H NMR (400 MHz, Chloroform-d) ⁇ 8.71-8.60 (m, 2H), 7.46-7.35 (m, 2H), 6.64 (s, 1H), 6.57 (s, 1H), 3.85-3.65 (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).
  • intermediate I-6-3 is the same as intermediate I-1-11.
  • 1 H NMR 400MHz, Chloroform-d
  • intermediate I-6-5 is the same as intermediate I-1-13.
  • Example 6 The preparation method of Example 6 is the same as step 15 in Example 1.
  • 1 H NMR 600 MHz, Chloroform-d
  • ⁇ 9.26 s, 1H
  • 8.79 s, 1H
  • 8.28 s, 1H
  • 8.19 s, 1H
  • Example 7 can be prepared by the same method as Example 8.
  • 1 H NMR 600 MHz, Chloroform-d
  • Example 12 can be prepared by the same method as Example 4.
  • Example 14 can be prepared by the same method as Example 4.
  • Example 52 can be prepared by the same method as Example 55.
  • 1 H NMR 600 MHz, Chloroform-d
  • Example 53 can be prepared by the same method as Example 55.
  • Example 67 can be prepared by the same method as Example 61.
  • Embodiment 84 is a diagrammatic representation of Embodiment 84.
  • intermediate I-88-2 The preparation of intermediate I-88-2 is the same as that of intermediate I-87-2.
  • intermediate I-90-1 The preparation of intermediate I-90-1 is the same as intermediate I-87-1.
  • intermediate I-90-2 is the same as that of intermediate I-87-2.
  • 1 H NMR 400 MHz, Chloroform-d
  • intermediate I-92-1 is the same as intermediate I-87-1.
  • Example 92 The preparation method of Example 92 is the same as step 5 of the preparation method of Example 91.
  • intermediate I-93-1 The preparation of intermediate I-93-1 is the same as that of intermediate I-87-1.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 94 was the same as step 5 of the preparation of Example 91.
  • Example 95 was the same as step 5 of the preparation of Example 91.
  • Example 96 was the same as step 5 of the preparation of Example 91.
  • Example 97 was the same as step 5 of the preparation of Example 91.
  • intermediate II-100-1 The preparation of intermediate II-100-1 is the same as that of intermediate I-55-2.
  • 1 H NMR 400 MHz, Chloroform-d
  • ⁇ 7.77 (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 6.0 Hz, 6H).
  • intermediate II-101-1 The preparation of intermediate II-101-1 is the same as that of intermediate II-98-5.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 101 The preparation method of Example 101 is the same as step 2 of the preparation method of Example 99.
  • intermediate II-102-2 is the same as intermediate I-1-2.
  • intermediate II-102-3 The preparation of intermediate II-102-3 is the same as intermediate I-55-4.
  • Example 102 was the same as step 2 of the preparation of Example 4.
  • 1 H NMR 400 MHz, Chloroform-d
  • ⁇ 9.34 s, 1H
  • 8.56 s, 1H
  • 8.42 s, 1H
  • 8.27 s, 2H
  • 6.72 (t, J 55.3 Hz, 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),3.4
  • 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.
  • D (%) refers to the degradation rate of IRAK4 protein in OCI-LY10 cells detected by Western Blot method at 10 nM by the compound of the present invention.
  • A represents D (%)>75%;
  • B represents 50% ⁇ D (%) ⁇ 75%;
  • C represents 35% ⁇ D (%) ⁇ 50%;
  • D represents D (%) ⁇ 35%.
  • the experimental results are the average of two independent repeated experiments.
  • KT-474 This is Example I-417 in patent WO2020113233.
  • the compounds of the present invention can effectively degrade IRAK4 kinase protein in cells.
  • 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%).
  • the Z′-LYTE TM kinase kit was used to detect the kinase inhibitory activity of the compounds.
  • the main steps are as follows: 2.5 ⁇ L/well of different concentrations of compound solution or solvent control 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 to a mixture of 1.5 ng/well and 2 ⁇ M/well with kinase buffer, and 5 ⁇ L/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 ⁇ L/well.
  • 2.5 ⁇ L of ATP (final concentration of 400 ⁇ M) 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 oven for 1 hour.
  • the secondary reaction reagent was added at 5 ⁇ L/well and reacted in an oven at 27°C for 1 h. Finally, 5 ⁇ L 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:
  • Emission signal ratio emission signal coumarin (445nm) / emission signal fluorescein (520nm)
  • Phosphorylation rate % [(emission signal ratio ⁇ F 100% ) – C 100% ] / [(C 0% – C 100% ) +
  • Inhibition rate % [1-(sample phosphorylation rate/0% phosphorylation control well phosphorylation rate)] ⁇ 100%
  • IC50 was calculated by fitting the inhibition rate curve at each concentration using the nonlinear four-parameter method in Graphpad Prism 8.0 software.
  • 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.
  • 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.
  • 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 were inoculated in a 96-well culture plate at different concentrations of 90 ⁇ L/well. After the cells were stable, different concentrations of the compound were added at 10 ⁇ L/well. Three replicate wells were set for each concentration, and corresponding solvent controls and blank control wells without cells were set.
  • Inhibition rate % (OD value of the control group - OD value of the drug group) / OD value of the control group ⁇ 100%.
  • the half-maximal inhibition dose IC 50 value was obtained by fitting the inhibition curve using the four-parameter method using the software attached to the enzyme reader. The experimental results are shown in Table 3.
  • Compound A Compound B: Compound C: They are respectively Examples I-28, I-29, and I-30 in Patent CN 112480101;
  • the compounds of the present invention 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.
  • 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.
  • tumor cell lines such as melanoma B16-F10, human colorectal cancer SW620, human pancreatic cancer PANC-1 and hematological tumor MV4-11.
  • the CCK-8 (Cell Counting Kit-8) method was used to detect the inhibitory effect of the compounds on cell proliferation.
  • the CCK-8 detection method steps are as follows: According to the cell growth rate, B16-F10, SW620, PANC-1 and MV4-11 cells in the logarithmic growth phase were inoculated in 96-well culture plates at different concentrations of 90 ⁇ L/well. After the cells stabilized, different concentrations of compounds were added at 10 ⁇ L/well. Three replicate wells were set for each concentration, and corresponding solvent controls and blank control wells without cells were set.
  • Inhibition rate % (OD value of the control group - OD value of the drug group) / OD value of the control group ⁇ 100%.
  • the half-maximal inhibition dose IC 50 value was obtained by fitting the inhibition curve using the four-parameter method using the software attached to the enzyme reader.
  • 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.
  • OCI-LY10 cells in the logarithmic growth phase were collected, resuspended by centrifugation and washed 3 times with PBS.
  • OCI-LY10 cells were inoculated subcutaneously in the right axilla of SCID mice at a system of 5 million cells/100 ⁇ L/mouse. When the average tumor volume reached about 100 mm 3 , the mice were randomly divided into groups of 6 mice each. The day of grouping was designated as Day 0. The dose of the test compound group was between 0-100 mg/kg.
  • the animal body weight and tumor volume (TV) were measured twice a week, and clinical symptoms were observed and recorded daily.
  • the tumor volume was calculated as follows:
  • TGI tumor inhibition rate
  • 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%
  • RTV relative tumor volume
  • V 0 the tumor volume measured at the time of group administration (Day 0)
  • Vt the tumor volume at a certain measurement.
  • 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.
  • 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 ⁇ g/mL LPS for 24 hours. The cell supernatant was collected and the TNF- ⁇ and IL-6 secretion levels were detected by ELISA.
  • the experimental data are expressed as Mean ⁇ SD.
  • the data were statistically analyzed using the one-way ANOVA method using Graphpad Prism 8.0 software.
  • the data between the two groups were considered to be significantly different when p ⁇ 0.05.
  • the compounds of the present invention can significantly inhibit the secretion of TNF- ⁇ and IL-6, and the inhibitory activity is positively correlated with the dose.
  • mice 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.
  • the experimental data are expressed as Mean ⁇ SEM.
  • the data were statistically analyzed using the one-way ANOVA method using Graphpad Prism 8.0 software.
  • the data between the two groups were considered to be significantly different when p ⁇ 0.05.
  • the compound of the present invention has a therapeutic effect on a mouse acute peritonitis model.
  • DAI disease activity index
  • the experimental data are expressed as Mean ⁇ SEM.
  • the data were statistically analyzed using the one-way ANOVA method using Graphpad Prism 8.0 software. Data between the two groups were considered to be significantly different when p ⁇ 0.05.
  • the compound of the invention has a therapeutic effect on a mouse acute enteritis model.
  • MC903 was diluted with anhydrous ethanol to a concentration of 45 ⁇ M. From the first day to the fifth day and the eighth day to the twelfth day of the experiment, 25 ⁇ L 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.
  • 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.
  • Erythema 0 to 3, respectively: none; pink; dark red; deep red;
  • 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.
  • the experimental data are expressed as Mean ⁇ SEM.
  • the data were statistically analyzed using the one-way ANOVA method using Graphpad Prism 8.0 software.
  • the data between the two groups were considered to be significantly different when p ⁇ 0.05.
  • the compound of the invention has a therapeutic effect on atopic dermatitis model in mice.
  • mice 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.
  • 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.
  • Erythema 0 to 4, respectively, no erythema; light red; red; dark red; very dark red;
  • 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;
  • 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.
  • the experimental data are expressed as Mean ⁇ SEM.
  • the data were statistically analyzed using the one-way ANOVA method using Graphpad Prism 8.0 software.
  • the data between the two groups were considered to be significantly different when p ⁇ 0.05.
  • the compound of the present invention has a therapeutic effect on a mouse psoriasis model.
  • G1 normal control group
  • solvent model, G2
  • test compound group G3-G5
  • 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 intradermally 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.
  • CFA complete Freund’s adjuvant
  • 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.
  • the experimental data were expressed as Mean ⁇ SEM.
  • the data were statistically analyzed using Graphpad Prism 8.0.
  • the data between the two groups were considered to be significantly different when p ⁇ 0.05.
  • the compound of the invention has a therapeutic effect on a mouse rheumatoid arthritis model.
  • 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.

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Abstract

La présente invention concerne un agent de dégradation IRAK4 tel que représenté dans la formule I, son procédé de préparation et son utilisation, en particulier un composé tel que représenté dans la formule (I), et un composé deutéré, un stéréoisomère, un isomère géométrique, un tautomère, un solvate, un hydrate, un promédicament, un sel ou un co-cristal pharmaceutiquement acceptable, et une composition pharmaceutique de celui-ci, son procédé de préparation et son utilisation dans le traitement de maladies associées à IRAK4 telles que des maladies auto-immunes, des maladies inflammatoires et des cancers.
PCT/CN2024/109554 2023-08-04 2024-08-02 Agent de dégradation irak4 et composition pharmaceutique et son utilisation pharmaceutique Pending WO2025031294A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1890248A (zh) * 2003-12-05 2007-01-03 阿斯利康(瑞典)有限公司 新化合物
CN111094292A (zh) * 2017-06-21 2020-05-01 豪夫迈·罗氏有限公司 作为IRAK4调节剂的吡唑并[1,5a]嘧啶衍生物
CN112480101A (zh) * 2019-09-12 2021-03-12 中国科学院上海药物研究所 一类irak4激酶抑制剂及其制备和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1890248A (zh) * 2003-12-05 2007-01-03 阿斯利康(瑞典)有限公司 新化合物
CN111094292A (zh) * 2017-06-21 2020-05-01 豪夫迈·罗氏有限公司 作为IRAK4调节剂的吡唑并[1,5a]嘧啶衍生物
CN112480101A (zh) * 2019-09-12 2021-03-12 中国科学院上海药物研究所 一类irak4激酶抑制剂及其制备和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BRYAN, M. C. ET AL.: "Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, no. 13, 13 May 2019 (2019-05-13), pages 6223 - 6240, XP055683011, DOI: 10.1021/acs.jmedchem.9b00439 *

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