Heteroaryl-containing compounds

Abstract

The present application belongs to the technical field of medicine, and relates to a compound containing a heteroaryl ring, a preparation method of the compound, a pharmaceutical composition containing the compound, and use of the compound in treating related diseases (for example, cancer).

Description

Technical Field

[0001] This application relates to compounds containing heteroaryl cyclic rings, methods for their preparation, pharmaceutical compositions containing such compounds, and their use in treating related diseases (e.g., cancer). Background Technology

[0002] Bruton's tyrosine kinase (BTK) is primarily expressed in B cells and distributed throughout the lymphatic, hematopoietic, and blood systems. It is a member of the Tec family of non-receptor tyrosine kinases, which also includes TEC, ITK / TSK / EMT, TXK, and BMX, sharing high structural homology. Recent studies on B cells, particularly B-cell non-Hodgkin's lymphoma and rheumatoid arthritis, have revealed aberrant BTK expression. Due to its primary expression in B cells and myeloid cells, BTK is a target with good targeting potential and safety.

[0003] Protac (proteolysis targeting chimera) molecules are bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds induce the target protein to be recognized by the cell's proteasome, causing its degradation and effectively reducing its concentration in cells. By introducing ligands that bind to different target proteins into Protac molecules, Protac technology has become possible for the treatment of various diseases, and this technology has received widespread attention in recent years. Invention Details

[0005] This application relates to compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0006]

[0007] in,

[0008] Ring A does not exist, or it is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl;

[0009] Ring B is selected from phenyl or 6-membered heteroaryl;

[0010] The ring C is selected from isoxazolyl or furanyl;

[0011] Each R 1 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;

[0012] n is selected from 0, 1, 2, or 3;

[0013] X 2 Selected from CH or N;

[0014] L 1 Selected from -O- or -NHCO-;

[0015] Each R is independently selected from halogen, -CN, C 1-4 Alkoxy, or C substituted with one or more halogens 1-4 alkyl;

[0016] Each R 2 Each is independently selected from halogen or C 1-4 alkyl;

[0017] p and q are independently selected from 0, 1, 2, or 3, respectively;

[0018] X is selected from CH or N;

[0019] The ring E is selected from 7-12-membered spirocycloalkyl, 7-12-membered heterospirocycloalkyl, 6-12-membered fused cycloalkyl, or 6-12-membered heterofused cycloalkyl;

[0020] Each R 3 Each is independently selected from -OH, -NH2, halogen, -CN, =O, C 1-4 Alkyl or C 1-4 Alkoxy;

[0021] m is selected from 0, 1, 2, or 3;

[0022] L is selected from the linking group.

[0023] On the other hand, this application relates to compounds of formula II, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0024]

[0025] Among them, rings A, B, C, and R 1 , n, X 2 L 1 , R, R 2 p, q, X, ring E, R 3 The definitions of m and L are as described in this application.

[0026] In some implementations, L is connected to ring B. In some implementations, X... 2 Connected to ring B. In some implementations, when ring A exists, L can be directly covalently connected to ring B; similarly, It can also be directly covalently connected to ring B.

[0027] In some implementations, ring A is absent, or is selected from C. 5-7 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0028] In some implementations, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0029] In some implementations, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, or oxazolyl.

[0030] In some embodiments, ring A is absent, or is selected from C5-cycloalkenyl, C6-cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl or oxazolyl.

[0031] In some embodiments, ring A is absent, or is selected from cyclopentenyl, dicyclohexenyl, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyridine. The group can be phenyl, dihydrooxazinyl, azirospirooctenyl, azirospirononenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, or oxazolyl.

[0032] In some implementations, ring B is selected from phenyl.

[0033] In some implementation schemes, the structural part (moiety) Selected from In some implementation schemes, the structural portion Selected from Among them, the key connected to ring A The asterisk (*) indicates that the bond is connected to an atom on ring A; the bond connected to ring C is... The asterisk (*) indicates that the bond is connected to an atom on the carbon ring. Similar asterisks in this article have the same or similar meanings. The asterisk (*) indicates that the bond is connected to an atom on the ring to which it is attached.

[0034] In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from (For example (For example The definition of * is the same as or similar to that above.

[0035] In some implementation schemes, the structural portion Selected from

[0036] In some implementation schemes, the structural portion Selected from

[0037] In some implementation schemes, the structural portion Selected from

[0038] In some implementation schemes, the structural portion Selected from

[0039] In some implementation schemes, the structural portion Selected from

[0040] In some implementations, each R 1 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl.

[0041] In some implementations, each R 1 Each is independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN.

[0042] In some implementation schemes, R 1 Selected from fluorine.

[0043] In some implementations, n is selected from 0, 1, or 2.

[0044] In some implementation schemes, the structural portion Selected from

[0045] In some implementation schemes, X 2 Selected from CH; in some implementations, X 2 Selected from N.

[0046] In some implementations, L 1 Selected from -O-.

[0047] In some implementations, each R is independently selected from fluorine, chlorine, -CN, C 1-3 alkoxy groups, or C groups optionally substituted with one or more fluorine, chlorine, bromine, or iodine groups. 1-3 alkyl.

[0048] In some embodiments, each R is independently selected from fluorine, chlorine, -CN, methoxy, ethoxy, or a methyl group optionally substituted with one or more fluorine or chlorine molecules.

[0049] In some implementations, each R is independently selected from chlorine or -CF3.

[0050] In some implementations, each R 2 Each is independently selected from fluorine, chlorine, bromine, iodine, or C. 1-3 alkyl.

[0051] In some implementations, each R 2 Each is independently selected from fluorine, chlorine, methyl, or ethyl.

[0052] In some implementation schemes, R 2 Selected from fluorine.

[0053] In some implementations, q is selected from 0, 1, or 2. In some implementations, q is selected from 0 or 1. In some implementations, q is selected from 0.

[0054] In some implementations, p is selected from 0, 1, or 2. In some implementations, p is selected from 0 or 1. In some implementations, p is selected from 0.

[0055] In some implementations, X is selected from CH.

[0056] In some embodiments, ring E is selected from 7-12-membered spirobicycloalkyl, 7-12-membered heterospirobicycloalkyl, 6-12-membered anabolic cycloalkyl, or 6-12-membered heteroabolic cycloalkyl.

[0057] In some embodiments, ring E is selected from 7-12-membered spirobicycloalkyl, 7-12-membered heterospirobicycloalkyl, 7-10-membered anabolic cycloalkyl, or 6-10-membered heteroabolic cycloalkyl.

[0058] In some embodiments, ring E is selected from 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered heterospirobicycloalkyl, or 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterobicycloalkyl.

[0059] In some embodiments, the heterospirobicycloalkyl or heterobionic bicycloalkyl contains one, two, or three heteroatoms selected from N, O, or S. In some embodiments, the heterospirobicycloalkyl or heterobionic bicycloalkyl contains one or two heteroatoms selected from N or O. In some embodiments, the heterospirobicycloalkyl or heterobionic bicycloalkyl contains one or two N atoms, or contains one N atom and one O atom. In some embodiments, the heterospirobicycloalkyl or heterobionic bicycloalkyl contains one or two N atoms.

[0060] In some embodiments, ring E is selected from 7-11 heterospirobicycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, or 6-10 heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S.

[0061] In some embodiments, cycloE is selected from diazaspiro[3.5]nonane, azaspiro[3.5]nonane, azaspiro[5.5]undecane, azaspiro[3.3]heptane, azaspiro[3.4]octane, diazaspiro[3.3]heptane, azaspiro[4.5]decane, diazaspiro[4.5]decane, azaspiro[5.5]undecane, octahydrocyclopent[c]pyrrole, furan[3,4-b]pyrrole, azabicyclo[3.1.0]hexane, azabicyclo[3.2.0]heptane, octahydro-1H-isoindole, decahydroisoquinoline, or octahydro-1H-cyclopent[c]pyridine.

[0062] In some implementations, ring E is selected from

[0063] In some implementations, ring E is selected from

[0064] In some implementations, each R 3 Each is independently selected from -OH, -NH2, halogen, -CN, =O, methyl, ethyl, or methoxy.

[0065] In some implementations, each R 3 Each is independently selected from -OH, -NH2, halogen, -CN, and =O.

[0066] In some implementations, m is selected from 0 or 1. In some implementations, m is selected from 0.

[0067] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-50 Alkylene, C 2-50 imide or C 2-50 Alkyne group, optionally, the C 1-50 Alkylene, C 2-50 imide or C 2-50 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-15 Cycloalkyl, 3-15 membered heterocyclic alkyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl, 5-15 quinone heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0068] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C1-30 Alkylene, C 2-30 imide or C 2-30 Alkyne group, optionally, the C 1-30 Alkylene, C 2-30 imide or C 2-30 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0069] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-20 Alkylene, C 2-20 imide or C 2-20 Alkyne group, optionally, the C 1-20 Alkylene, C 2-20 imide or C 2-20 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-10 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl, 5-10 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0070] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-15 Alkylene, C 2-15 imide or C 2-15 Alkyne group, optionally, the C 1-15 Alkylene, C 2-15 imide or C 2-15 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, C 6-8 Aryl, 5-8 quinone heteroaryl, -NH-, -N(C 1-4 Alkyl)- or -S- substitution.

[0071] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-10 Alkylene, C 2-10 imide or C 2-10 Alkyne group, optionally, the C 1-10 Alkylene, C 2-10 imide or C 2-10One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S- substitution.

[0072] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-6 Alkylene, C 2-6 imide or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene, C 2-6 imide or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S- substitution.

[0073] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-4 Alkylene, C 2-4 imide or C 2-4 Alkyne group, optionally, the C 1-4 Alkylene, C 2-4 imide or C 2-4 One or more (e.g., one or two, one or three, etc.) of the ethynyl group are independently and optionally separated by -O-, C 4-6 Cycloalkyl, 4-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S- substitution.

[0074] In some embodiments, in the definition of L, the substituent is selected from deuterium, halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl.

[0075] In some embodiments, in the definition of L, the substituent is selected from deuterium, halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-4 alkyl)NH-, (C 1-4 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl.

[0076] In some embodiments, in the definition of L, the substituent is selected from =O, hydroxyl C. 1-3 Alkyl, -NH2, -CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, (C 1-3 alkyl)NH- or (C 1-3 Alkyl)2N-.

[0077] In some embodiments, in the definition of L, the substituent is selected from =O or hydroxyC. 1-3 Alkyl group. In some embodiments, in the definition of L, the substituent is =O or HOCH2-.

[0078] In some implementations, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -,in,

[0079] Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-12 Aryl, 5-12-membered heteroaryl, or 4-12-membered heterocyclic alkenyl;

[0080] LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-12 Alkylene, C 2-12 imidene group, C 2-12 Ethyne or C 1-12 Heteroalkylene;

[0081] Each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl.

[0082] In some implementations, Cy 1 Cy 2 and Cy 3 They are not both keys. In some implementations, Cy 1 Cy 2 and Cy 3 As a key. In some implementations, Cy 2 and Cy 3 As a key. In some implementations, LNK 1 and LNK 2 Selected from key.

[0083] In some implementations, the L is selected from -Cy 1 -、-Cy 2 -、-LNK 1 -、-Cy 1 -LNK-、-Cy 1 -Cy 2 -、-LNK 1 -Cy 1 -LNK-、-LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、-LNK 1 -Cy 1 -Cy 2 -、-Cy 1 -LNK-Cy 2 -、-LNK 1 -Cy 1 -Cy 2 -LNK 2 -、-LNK 1 -Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -Cy 3 -or-Cy 1 -Cy 2 -LNK2 -Cy 3 - In some implementations, the L is selected from -Cy 1 -、-Cy 2 -、-LNK 1 -、-Cy 1 -LNK-、-LNK 1 -Cy 1 -LNK- or -LNK-Cy 2 -LNK 2 -

[0084] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne or C 1-10 Heteroalkylene.

[0085] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne or C 1-6 Heteroalkylene.

[0086] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-3 Alkylene, C 2-3 Ethyne or C 1-3 Heteroalkylene.

[0087] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-2 alkylene, C2-alkynyl or C 1-2 Heteroalkylene.

[0088] In some implementation schemes, LNK, LNK 1 and LNK2 Each group is independently selected from the following groups: bond, -NH-, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, ethynyl group, -C(O)-, or -C(O)CH2-.

[0089] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the key, or selected from those optionally controlled by one or more R. c The following groups are substituted: C 1-6 Alkylene or C 1-6 Heteroalkylene.

[0090] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the key, or selected from those optionally controlled by one or more R. c Replacement C 1-3 Alkylene.

[0091] In some implementation schemes, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -CH2-, -C(O)-, or -C(O)CH2-. In some embodiments, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, or -CH2-.

[0092] In some implementations, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-11 Cycloalkyl, 4-12-membered heterocycloalkyl, 4-11-membered heterocycloalkenyl or 5-11-membered heteroaryl.

[0093] In some implementations, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0094] In some implementations, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C4-6 (e.g., C4, C5, or C6) cycloalkyl, 4-9 quinary (e.g., 4, 5, 6, 7, 8, or 9) heterocycloalkyl, or 5-6 heteroaryl. In some embodiments, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, azircyclobutyl, pyrrolyl, piperidinyl, tetrahydropyridyl, piperazine, azirspiroheptyl, azirspiroctyl, azirspironyl, diazirspironyl, azirspirodealkyl, diazirspirodealkyl, azirspiroundecyl, diazirspiroundecyl, azirbicyclohexane, octahydrocyclopentylpyrrole, diazirbicyclooctyl, azirbicyclononyl, azirbicycloheptyl, or pyrazine.

[0095] In some implementations, Cy 1 Cy 2 or Cy 3 Selected independently from keys,

[0096] In some implementations, Cy 1 Cy 2 or Cy 3 Selected independently from keys,

[0097] In some implementations, Cy 1 Cy 2 or Cy 3 Selected independently from keys,

[0098] In some implementations, Cy 1 Cy 2 or Cy 3 Selected independently from keys,

[0099] In some implementations, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl.

[0100] In some implementations, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-.

[0101] In some implementations, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-4 alkyl)NH-, or (C 1-4 Alkyl)2N-.

[0102] In some implementations, each R b and R c Each is independently selected from C-terminals that are =O or hydroxyl-substituted. 1-3 alkyl.

[0103] In some implementations, each R b and R c Each is independently selected from =O or HOCH2-.

[0104] In some implementations, L or -LNK 1 - Selected from -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, ethynyl group, -C(O)- or -C(O)CH2-.

[0105] In some implementations, L or -LNK 1 -Selected from -CH2- or -C(O)CH2-.

[0106] In some implementations, the L or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 - Selected from -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-,

[0107]

[0108] In some implementations, the L or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -Selected from

[0109] In some embodiments, the heterocyclic alkenyl or heterocyclic alkyl group contains heteroatoms selected from N, NH, O, or S. In some embodiments, the heterocyclic alkenyl or heterocyclic alkyl group contains heteroatoms selected from N, O, or S. In some embodiments, the heteroaryl group contains heteroatoms selected from N, O, or S. In some embodiments, the heteroalkylene group contains heteroatoms selected from N, NH, O, S, S(O), or S(O)₂.

[0110] In some embodiments, the heterocyclic alkenyl, heterocyclic alkyl, heteroalkylene, or heteroaryl group is wherein the number of heteroatoms is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the heterocyclic alkenyl, heterocyclic alkyl, heteroalkylene, or heteroaryl group is wherein the number of heteroatoms is selected from 1, 2, 3, or 4. In some embodiments, the heterocyclic alkenyl, heterocyclic alkyl, heteroalkylene, or heteroaryl group is wherein the number of heteroatoms is selected from 1, 2, or 3.

[0111] This application also relates to compounds of formula III or IV, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0112]

[0113] Among them, rings A and R 1 , n, X 2 , R, R 2 p, q, ring E, R 3 The definitions of m and L are as described in this application;

[0114] X 3 Selected from CH or N.

[0115] This application relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0116]

[0117]

[0118] On the other hand, this application relates to a pharmaceutical composition containing the compounds described above, their stereoisomers, or pharmaceutically acceptable salts thereof, and the pharmaceutical composition of this application further includes pharmaceutically acceptable excipients.

[0119] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of diseases by degrading target proteins that bind to target ligands.

[0120] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of diseases by binding to cerebellar proteins in vivo.

[0121] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of BTK-related diseases.

[0122] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of autoimmune diseases, inflammatory diseases or cancer.

[0123] This application relates to a method for treating or preventing diseases in mammals by degrading target proteins that bind to target ligands, including administering a therapeutically effective amount of the aforementioned compound of this application, its stereoisomers, its derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, to mammals, preferably humans, in the treatment of such mammals.

[0124] This application relates to methods for treating or preventing diseases by binding to cerebellar proteins in vivo, including administering a therapeutically effective amount of the aforementioned compound, its stereoisomers, its derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, to a mammal, preferably a human, in need of such treatment.

[0125] On the other hand, this application relates to a method for treating BTK-related diseases in mammals, including administering a therapeutically effective amount of the above-mentioned compound of this application, its stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof to a mammal, preferably a human, that requires such treatment.

[0126] On the other hand, this application relates to methods for treating autoimmune diseases, inflammatory diseases, or cancer in mammals, including administering a therapeutically effective amount of the aforementioned compound of this application, its stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, to a mammal, preferably a human, in the treatment of which such treatment is required.

[0127] On the other hand, this application relates to the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of diseases by means of the degradation of target proteins that bind to target ligands.

[0128] On the other hand, this application relates to the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of diseases that are treated by binding to cerebellar proteins in vivo.

[0129] On the other hand, this application relates to the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the prevention or treatment of BTK-related diseases.

[0130] On the other hand, this application relates to the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of autoimmune diseases, inflammatory diseases, or cancer.

[0131] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the prevention or treatment of diseases by means of degradation of target proteins bound to target ligands.

[0132] On the other hand, this application relates to the use of the aforementioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of diseases that are treated by binding to cerebellar proteins in vivo.

[0133] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the prevention or treatment of BTK-related diseases.

[0134] On the other hand, this application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the prevention or treatment of autoimmune diseases, inflammatory diseases or cancer.

[0135] In some specific embodiments, the aforementioned BTK-related diseases are selected from diseases treated by degrading proteins that bind to BTK target protein ligands; in some specific embodiments, the aforementioned BTK-related diseases are selected from diseases treated by binding to cerebellar proteins in vivo; in some specific embodiments, the aforementioned diseases are selected from autoimmune diseases, inflammatory diseases, or cancer.

[0136] In some specific implementations, the conditions treated by binding to cerebellar proteins in vivo and / or the conditions treated by binding to cerebellar proteins in vivo are selected from BTK-related diseases; in some specific implementations, the BTK-related diseases are selected from autoimmune diseases, inflammatory diseases, or cancer.

[0137] In some implementations, this application includes the variables defined above, their implementations, and any combination thereof.

[0138] Technical effect

[0139] The compound of this application exhibits a degradation effect on BTK in OCI-LY10 cells; in vitro, it can inhibit the degradation of BTK in cells (OCI-LY10 cells, TMD8-BTK). C481S Cells or OCI-LY10-BTK C481S Cell proliferation; compared to EGFR and TEC kinases, targeting BTK and / or BTK C481S The kinase is selective; it is metabolically stable in vitro and has good in vivo pharmacokinetic properties; it has an inhibitory effect on mouse TMD-8 xenografts in vivo.

[0140] definition

[0141] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0142] The term "one or more" as used in this application is selected from one, two, three, four, five, or six. In some embodiments, "one or more" is selected from one, two, or three. In some embodiments, "one or more" is selected from one or two.

[0143] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0144] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. The phrase “optionally substituted” indicates that the group is substituted or unsubstituted. For example, the ethyl group being “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or synthetically undesirable is introduced.

[0145] C in this article m-nThis part has an integer number of carbon atoms within a given range (mn). For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0146] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group contains two Rs, then each R has an independent option.

[0147] When a bond cross-bonds two atoms in a ring (including monocyclic, fused, or spirocyclic rings), this bond can bond with any atom in the ring (including monocyclic, fused, or spirocyclic rings). For example, structural units. This indicates that the bonds on both sides can be connected to any two different atoms in ring A, ring B, or ring C; for example... This indicates that the bonds on both sides can be connected to any two different atoms on ring A, the middle benzene ring, or ring C; further for example... This indicates that the bonds on both sides can be connected to any two different atoms in the four rings of the system.

[0148] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0149] The term "hydroxyl group" refers to the -OH group.

[0150] The term "amino" refers to the -NH2 group.

[0151] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group. This alkyl group can be straight-chain or branched. For example, the term "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0152] The term "alkylene" is an alkyl group that has lost one hydrogen atom.

[0153] The term "heteroalkylene" refers to an alkylene group in which one or more carbon atoms are replaced by heteroatoms, and at least one carbon atom is present. Specific heteroatoms can be selected from N, NH, O, S, S(O), or S(O)₂. The number of heteroatoms is selected from 1, 2, 3, 4, 5, or 6. For example, C 1-12A heteroalkylene group indicates that the heteroalkylene group contains 1 to 12 carbon atoms and one or more heteroatoms (e.g., 1-6, 1-3, 1, 2, or 3 heteroatoms). For example, C 1-6 A heteroalkylene group indicates that the heteroalkylene group contains 1 to 6 carbon atoms and one or more heteroatoms.

[0154] The term "alkoxy" refers to -O-alkyl.

[0155] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0156] The term "cycloalkenyl" refers to a non-aromatic carbon ring that is not fully saturated and may exist as a monocyclic, (e.g., bicyclic) bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 4- to 12-membered, 4- to 10-membered, or 4- to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl.

[0157] Non-limiting examples of “benzocycloalkenyl” include benzo4- to 12-membered cycloalkenyl, benzo4- to 10-membered cycloalkenyl, or benzo4- to 8-membered (e.g., 4-, 5-, 6-, 7-, or 8-membered) cycloalkenyl.

[0158] The term "cycloalkyl" refers to a fully saturated carbon ring that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring (e.g., a 5- to 8-membered ring). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0159] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered ring, a 3- to 10-membered ring, a 3- to 8-membered ring, a 3- to 7-membered ring, a 3- to 6-membered ring, or a 3- to 5-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred.

[0160] The term "heterocyclic alkenyl" includes cycloalkenyl groups in which one or more carbon atoms are replaced by heteroatoms, specifically, for example, cycloalkenyl groups in which up to three carbon atoms, in one embodiment up to two carbon atoms, or in another embodiment one carbon atom is independently replaced by O, S(O), NH, or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. Cyclic groups can exist as monocyclic, bridged, or spirocyclic rings, and can be 3 to 12-membered rings (e.g., 5 to 8-membered rings). Examples of heterocyclic alkenyl groups include, but are not limited to, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyryl. Benzyl or azirrospirocyclooctene.

[0161] Non-limiting embodiments of "benzo[a]heterocyclic alkenyl]" include benzo[4- to 12-membered heterocyclic alkenyl (e.g., 5-, 6-, 10-, or 11-membered), benzo[5- to 11-membered heterocyclic alkenyl, or benzo[5- to 8-membered (e.g., 4-, 5-, 6-, 7-, or 8-membered) heterocyclic alkenyl. Specific examples include...

[0162] Unless otherwise indicated, the carbon ring is typically a 4- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl.

[0163] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring, or multiple fused rings containing 6 to 14, particularly 6 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc.

[0164] The term "spirocyclic" refers to a fully saturated or partially unsaturated polycyclic system in which the individual rings share a single carbon atom (called a spiro atom), including carbon rings and heterocyclic rings. Unless otherwise indicated, the spirocyclic ring is 5 to 20 rings, preferably 6 to 14 rings, and more preferably 9 to 14 rings. When the spirocyclic ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from N, O, and S(O). n (where n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0165] In this application, wavy lines are used ( ) represents one of the absolute configurations of a solid center (e.g. one, specific express ) or one of the relative configurations (e.g. express When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, they include E and Z geometric isomers, unless otherwise specified. Similarly, all tautomer forms are included within the scope of this application.

[0166] Groups or structural motifs in this application, such as L, LNK, Cy, etc. 1 Cy 2 -Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, which can optionally be read from left to right, corresponding to the group or part of the left-hand and right-hand groups in the general formula, for example, when L is selected from Following the reading order from left to right, The left side and the part corresponding to the left side in the general formula Connection, right side and right side part The connection forms a structure as follows: Optionally, the groups or structural moiety in this application such as L, LNK, Cy 1 Cy2 -Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, can be read from right to left, corresponding to the group or part of the left and right groups in the general formula, for example, when L is selected from Following the reading order from right to left, The right side corresponds to the left side of the general formula. Connect the left side to the corresponding right side of the general formula. The part formed by the connection is The other groups are the same as described above.

[0167] Unless otherwise specified, Hydrogen atoms at any position within the brackets [] can be replaced by groups connected by "—".

[0168] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0169] (i) Suppress the disease or disease state, that is, curb its development;

[0170] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0171] The term “prevention” means administering the compound or formulation described in this application to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0172] The term "therapeutic effective amount" means the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0173] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0174] As pharmaceutically acceptable salts, examples include metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids.

[0175] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0176] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0177] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0178] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0179] In this document, unless the context clearly indicates otherwise, singular terms encompass plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" is intended to include "and".

[0180] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0181] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0182] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium.

[0183] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents.

[0184] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0185] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0186] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0187] In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0188] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0189] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0190] In all methods of administration of the compounds of general formula I described herein, the daily dose is 0.01 to 200 mg / kg body weight, administered in single or separate doses.

[0191] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0192] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0193] An important consideration in synthetic route planning in this field is selecting appropriate protecting groups for reactive functional groups (such as amino groups in this application). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0194] In some embodiments, the compounds of formula I of this application can be prepared by those skilled in the art of organic synthesis via the following route:

[0195]

[0196] Among them, rings A, B, C, and R 1 , n, X 2 L 1 , R, R 2 p, q, X, ring E, R 3 The definitions of m and L are as described in this application.

[0197] This application uses the following abbreviations:

[0198] Boc stands for tert-butyloxycarbonyl.

[0199] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0200] For clarity, this application is further illustrated with examples, but these examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. Detailed Implementation

[0201] Example 1: Synthesis of Compound 1

[0202]

[0203] Intermediate 1a (80 mg, synthesis reference patent WO2022253250 Example 46), intermediate 1b (103 mg, synthesis reference patent WO2023088406 Example 14), and methanol (5 mL) were added to a reaction flask. One drop of acetic acid was added, followed by sodium cyanoborohydride (35 mg). The reaction was carried out at room temperature. After the reaction was complete, dichloromethane and water were added to the system for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by column chromatography to obtain compound 1 (42 mg).

[0204] HRMS(ESI,[M+H] + m / z: 776.3676

[0205] 1 H NMR (500MHz, DMSO-d6) δ11.54(s,1H),11.18(s,1H),8.23(s,1H),7.71–7.61(m,2H),7.53(d,J=8.2 Hz,1H),7.50–7.40(m,3H),7.22–7.09(m,6H),6.49(t,J=2.4Hz,1H),4.67(dd,J=11.8,5.1Hz,2H),3 .77(s,1H),3.48(s,1H),2.86(ddd,J=22.1,11.1,4.9Hz,2H),2.64(dt,J=16.8,4.0Hz,2H),2.42(d t,J=12.4,6.1Hz,2H),2.35–2.04(m,6H),2.02–1.92(m,5H),1.87(s,4H),1.66(s,2H),1.56(s,2H).

[0206] Example 2: Synthesis of Compound 2

[0207]

[0208] Intermediate 1a (80 mg), intermediate 2a (69 mg, synthesis reference: Example 13, patent WO2023088406), and methanol (5 mL) were added to a reaction flask. One drop of acetic acid was added, followed by sodium cyanoborohydride (24 mg). The reaction was carried out at room temperature. After the reaction was complete, dichloromethane and water were added to the system for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by column chromatography to obtain compound 2 (44 mg).

[0209] HRMS(ESI,[M+H] + m / z: 776.3692

[0210] 1 H NMR (500MHz, DMSO-d6) δ11.74(d,J=32.8Hz,1H),11.17(s,1H),8.24(s,1H),7.67–7.62(m,2H),7.54(q,J=2.8Hz,1H),7.47–7.41(m,2H),7.37(d ,J=18.5Hz,1H),7.35-7.30(m,5H),7.21–7.17(m,1H),7.17–7.10(m,4H) ,6.56(dd,J=3.0,1.8Hz,1H),4.65(dd,J=11.6,5.1Hz,2H),4.14(d,J=17 .4Hz,1H),3.95(d,J=17.9Hz,2H),3.92–3.75(m,2H),3.68(d,J=9.5Hz,1H),2.85(ddd,J=17.2,12.0,5.4Hz,1H),2.66–2.59(m,1H),2.43(dd,J= 12.4,8.3Hz,2H),2.34(s,1H),2.25–2.16(m,2H),1.98(d,J=9.9Hz,1H), 1.91(s,3H),1.73(d,J=13.0Hz,3H),1.62(s,2H),1.47(d,J=9.7Hz,1H).

[0211] Example 3: Synthesis of Compound 3

[0212]

[0213] Intermediate 1a (80 mg), intermediate 3a (96 mg, synthesis reference: Example 15, patent WO2023088406), and methanol (5 mL) were added to a reaction flask. One drop of acetic acid was added, followed by sodium cyanoborohydride (24 mg). The reaction was carried out at room temperature. After the reaction was complete, dichloromethane and water were added to the system for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by column chromatography to obtain compound 3 (45 mg).

[0214] HRMS(ESI,[M+H] + m / z: 776.3703

[0215] 1 H NMR (500MHz, DMSO-d6) δ11.18(d,J=1.9Hz,1H),8.23(s,1H),7.91(dd,J=9.2,3.6Hz,1H),7.71(dd,J=21.3,3.2Hz,1H),7.66–7.61(m,2H),7.49( dd,J=9.1,3.3Hz,1H),7.44(ddd,J=8.7,7.3,1.7Hz,2H),7.21–7.10(m,5H),6.58(dd,J=7.0,3.1Hz,1H),5.09(d,J=38.9Hz,1H),4.73–4.61(m,2 H),4.02-3.82(m,2H),3.42-3.35(m,2H),3.18–2.92(m,2H),2.85(ddd, J=17.3,12.1,5.3Hz,1H),2.63(dt,J=17.2,4.2Hz,1H),2.55-2.51(m,1H ),2.50-2.45(m,1H),2.43(tt,J=12.5,6.3Hz,2H),2.23(dq,J=13.8,4.8 Hz,3H),2.22-1.95(m,3H),1.99–1.91(m,3H),1.87(s,3H),1.66(s,3H).

[0216] Example 4 Synthesis of compounds 4-1 and 4-2

[0217]

[0218] Intermediate 1a (100 mg), intermediate 4a (99 mg, synthesis reference patent WO2023088406, Example 98), and methanol (5 mL) were added to a reaction flask, followed by 1 drop of acetic acid and sodium cyanoborohydride (29 mg). The reaction was carried out at room temperature. After the reaction was complete, dichloromethane and water were added to the system for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was then separated by high performance liquid chromatography to obtain the leading peak compound 4-1 (45 mg) and the trailing peak compound 4-2 (30 mg).

[0219] The preparation conditions are as follows:

[0220] Instrumentation and Preparative Column: A Shimadzu LC-20AD high-performance liquid chromatograph was used. The preparative column model was Polar-RP, 5μm, 21*250mm. Mobile Phase System: Acetonitrile / 10mM ammonium acetate, with isogradient elution: acetonitrile / 10mM ammonium acetate = 50 / 50.

[0221] Compound 4-1 (front peak):

[0222] HRMS(ESI,[M+H] + m / z: 762.3527

[0223] 1 H NMR (500MHz, DMSO-d6) δ11.19(s,1H),8.23(s,1H),7.89–7.78(m,2H),7.65(d,J=8.1Hz,2H),7.51–7.39(m,3H),7.16(ddd,J=23.3,14.9,7 .6Hz,5H),6.60(d,J=3.1Hz,1H),5.24(p,J=8.2Hz,1H),4.73–4.61(m,2H),3.41-3.35(m,2H),3.32-3.30(m,1H),3.10(s,2H),2.98(s,2H) ,2.85(ddd,J=17.4,12.0,5.4Hz,1H),2.72(d,J=7.2Hz,2H),2.63(dt,J=17.3,4.2Hz,1H),2.61-2.58(m,2H),2.44(dd,J=12.5,4.2Hz,1H) ,2.35(d,J=8.9Hz,2H),2.23(dq,J=13.9,4.8Hz,1H),2.04(d,J=13.2Hz,2H),1.96(t,J=12.8Hz,2H),1.90–1.81(m,2H),1.72–1.57(m,2H).

[0224] Compound 4-2 (back peak):

[0225] HRMS(ESI,[M+H] + m / z: 762.3543

[0226] 1 H NMR (500MHz, DMSO-d6) δ11.18(s,1H),8.22(s,1H),7.84(d,J=9.1Hz,1H),7.78(d,J=3.2Hz,1H),7.67–7.61(m,2H),7.48(d,J=9. 1Hz,1H),7.43(t,J=7.9Hz,2H),7.21–7.10(m,5H),6.60(d,J=3.1Hz,1H),4.98(p,J=8.7Hz,1H),4.72–4.61(m,2H),3.33(s,4H), 2.85(ddd,J=17.3,12.1,5.4Hz,2H),2.74–2.57(m,4H),2.59-2.51(m,2H),2.43(tt,J=12.3,6.2Hz,1H),2.23(dq,J=13.5,5.1,4 .5Hz,2H),2.19–2.10(m,2H),2.07(d,J=9.5Hz,2H),1.96(q,J=12.7,12.0Hz,2H),1.85(d,J=12.2Hz,2H),1.65(t,J=12.7Hz,2H).

[0227] Example 5: Synthesis of compounds 5-1 and 5-2

[0228]

[0229] Intermediate 1a (100 mg), intermediate 5a (79 mg, synthesis reference patent WO2023088406 Example 100), and methanol (5 mL) were added to a reaction flask. One drop of acetic acid was added, followed by sodium cyanoborohydride (29 mg). The reaction was carried out at room temperature. After the reaction was complete, dichloromethane and water were added to the system for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was then separated by high-performance liquid chromatography (HPLC) to obtain the leading peak compound 5-1 (26 mg) and the trailing peak compound 5-2 (17 mg). The preparation conditions were as follows:

[0230] Instrumentation and Preparative Column: A Shimadzu LC-20AD high-performance liquid chromatograph was used. The preparative column model was Polar-RP, 5μm, 21*250mm. Mobile phase system: acetonitrile / 10mM ammonium acetate, with isogradient elution: acetonitrile / 10mM ammonium acetate = 48 / 52.

[0231] Compound 5-1 (front peak):

[0232] HRMS(ESI, [M+H] + ) m / z: 748.3361

[0233] 1 H NMR (500 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.23 (s, 1H), 7.87–7.78 (m, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 9.0 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.15 (ddt, J = 23.1, 15.9, 7.6 Hz, 5H), 6.61 (d, J = 3.1 Hz, 1H), 4.84 (s, 1H), 4.68 (ddd, J = 20.3, 11.5, 6.0 Hz, 2H), 3.65–3.57 (m, 1H), 3.41 - 3.35 (m, 2H), 3.13 (s, 2H), 3.00 (s, 2H), 2.85 (ddd, J = 17.2, 12.0, 5.3 Hz, 1H), 2.72 (d, J = 15.2 Hz, 2H), 2.63 (dt, J = 17.2, 4.2 Hz, 1H), 2.43 (td, J = 12.5, 4.3 Hz, 1H), 2.28–2.20 (m, 2H), 2.09–2.01 (m, 2H), 2.01–1.92 (m, 2H), 1.86 (d, J = 12.1 Hz, 2H), 1.80–1.73 (m, 1H), 1.65 (t, J = 12.0 Hz, 2H).

[0234] Compound 5-2 (rear peak):

[0235] HRMS(ESI, [M+H] + ) m / z: 748.3365

[0236] 1H NMR (500MHz, DMSO-d6) δ11.17(s,1H),8.25(s,1H),7.85–7.78(m,2H),7.63(d,J=8.3Hz,2H),7.51(d,J=9.0Hz,1H),7.43(t,J=7.8Hz,2H), 7.16(ddt,J=23.1,15.9,7.6Hz,5H),6.63(d,J=3.1Hz,1H),4.83(s,1H),4.66(ddd,J=20.3,11.5,6.0Hz,2H),3.66–3.55(m,1H),3.42-3.36 (m,2H),3.14(s,2H),3.01(s,2H),2.82(ddd,J=17.2,12.0,5.3Hz,1H),2.75(d,J=15.2Hz,2H),2.65(dt,J=17.2,4.2Hz,1H),2.42(td,J=12 .5,4.3Hz,1H),2.25–2.18(m,2H),2.10–2.02(m,2H),2.04–1.93(m,2H),1.85(d,J=12.1Hz,2H),1.82–1.75(m,1H),1.66(t,J=12.0Hz,2H).

[0237] Example 6 Synthesis of compounds 6-1 and 6-2

[0238]

[0239] Intermediate 1a (100 mg), intermediate 6a (103 mg, synthesis reference patent WO2023088406 Example 102), and methanol (5 mL) were added to a reaction flask, followed by 1 drop of acetic acid and sodium cyanoborohydride (29 mg). The reaction was carried out at room temperature. After the reaction was complete, dichloromethane and water were added to the system for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was then separated by high performance liquid chromatography to obtain the leading peak compound 6-1 (47 mg) and the trailing peak compound 6-2 (20 mg).

[0240] The preparation conditions are as follows:

[0241] Instrumentation and Preparative Column: A Shimadzu LC-20AD high-performance liquid chromatograph was used. The preparative column model was Polar-RP, 5μm, 21*250mm. Mobile phase system: acetonitrile / 10mM ammonium acetate, with isogradient elution: acetonitrile / 10mM ammonium acetate = 52 / 48.

[0242] Compound 6-1 (front peak):

[0243] HRMS(ESI,[M+H]+ )m / z: 776.3683

[0244] 1 H NMR (500 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.24 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.64 (dd, J = 9.7, 7.6 Hz, 3H), 7.51–7.39 (m, 3H), 7.20–7.10 (m, 5H), 6.56 (d, J = 3.0 Hz, 1H), 4.69 (dp, J = 12.1, 3.5 Hz, 2H), 4.51 (s, 1H), 3.63–3.57 (m, 1H), 3.03 (s, 2H), 2.91 (s, 2H), 2.84 (td, J = 12.1, 6.0 Hz, 1H), 2.62 (dt, J = 17.2, 4.3 Hz, 1H), 2.62-2.58 (m, 1H), 2.48-2.45 (m, 1H), 2.42 (dt, J = 16.8, 4.4 Hz, 2H), 2.22 (dq, J = 12.9, 4.5 Hz, 1H), 2.15 (dd, J = 21.3, 9.7 Hz, 2H), 2.04 (dd, J = 22.5, 11.8 Hz, 4H), 1.88 (d, J = 11.8 Hz, 2H), 1.79 (d, J = 4.9 Hz, 1H), 1.70 (d, J = 12.0 Hz, 4H), 1.62 (d, J = 13.3 Hz, 2H).

[0245] Compound 6-2 (rear peak):

[0246] HRMS (ESI, [M+H] + )m / z: 776.3685

[0247] 1H NMR(500MHz,DMSO-d6)δ11.18(s,1H),8.25(s,1H),7.95(d,J=9.2Hz,1H),7.62(dd,J=9.7,7.6Hz,3H),7.50–7.40(m,3H),7.21–7.12(m,5H), 6.55(d,J=3.0Hz,1H),4.70(dp,J=12.1,3.5Hz,2H),4.52(s,1H),3.63–3.55(m,1H),3.02(s,2H),2.92(s,2H),2.83(td,J=12.1,6.0Hz,1H), 2.63(dt,J=17.2,4.3Hz,1H),2.61-2.57(m,1H),2.49-2.44(m,1H),2.43(dt,J=16.8,4.4Hz,2H),2.21(dq,J=12.9,4.5Hz,1H),2.16(dd,J=2 1.3,9.7Hz,2H),2.05(dd,J=22.5,11.8Hz,4H),1.87(d,J=11.8Hz,2H),1.78(d,J=4.9Hz,1H),1.71(d,J=12.0Hz,4H),1.63(d,J=13.3Hz,2H).

[0248] Experimental Example 1: Effect of Compounds on BTK Degradation in OCI-LY10 Cells

[0249] Detection was performed using the Total-BTK Kits (cisbio, 63ADK064PEH). 4X Supplemented Lysis buffer was prepared using Blockingreagent stock solution (100×) and Lysis buffer stock solution (4×). Premixed antibody solutions were prepared using Detection buffer, Total-BTK d2 antibody, and Total-BTKEu Cryptate antibody.

[0250] OCI-LY10 cells in good growth condition were collected into centrifuge tubes, and the cell density was adjusted to 4.17 × 10⁻⁶. 6Cells were seeded at a concentration of 12 μL / well in 384-well plates and cultured overnight. Compounds were added using a nanoparticle pipette to achieve a final concentration of 100 nM - 0.098 nM, with two replicates and a control. After culturing for another 24 hours, 4 μL / well of 4×Supplemented Lysis buffer was added to lyse the cells. After shaking at room temperature for 40 minutes, 4 μL / well of Premixed antibody solutions was added, and the plates were incubated overnight at room temperature. Fluorescence was detected at 665 nm / 620 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and DC was calculated. 50 (Drug concentration at which degradation rate reaches 50%) and D max (Maximum degradation rate). The experimental results are shown in Table 1.

[0251] Table 1 Results of BTK degradation activity

[0252]

[0253] Test results of the compound showed that the compound of this application has the effect of degrading BTK in OCI-LY10 cells.

[0254] Experimental Example 2: Assay of OCI-LY10 Cell Proliferation Inhibition Activity

[0255] Collect OCI-LY10 cells in good growth condition into centrifuge tubes and adjust the cell density to 1×10⁻⁶. 5 The compound was seeded at a concentration of 100 μL / well in a 96-well plate and cultured overnight. The compound was then added using a nanoparticle pipette to a final concentration of 5000 nM - 0.31 nM, with two replicates. A control was also included. After culturing for another 72 hours, 10 μL of CCK-8 (CK04, PP799) was added, and the plate was incubated for 2.5 hours. The absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The experimental results are shown in Table 2.

[0256] Table 2 Results of cell proliferation inhibition activity

[0257]

[0258]

[0259] Test results of the compound showed that the compound of this application has inhibitory activity against OCI-LY10 cell proliferation.

[0260] Experimental Example 3: In vitro kinase inhibition and selectivity

[0261] 3.1 BTK(WT) inhibitory activity

[0262] Prepare the Assay Buffer with the following composition: Hepes (Gibco, 15630): 50 mM, MgCl2: 10 mM, DTT: 2 mM, EGTA: 1 mM, Tween 20: 0.010%. Use the Assay Buffer to prepare working solutions for BTK (WT) kinase (Life, PR5442A), ATP (Sigma, A7699), and Ultra-poly GT (PE, TRF0100-M). Use Detection Buffer (PE, CR97-100) to prepare working solutions for EDTA and Eu-labeled anti-phosphotyrosine (PT66) antibody (PE, AD0069). 6 μL of the corresponding concentration of BTK(WT) kinase (final concentration 0.003 ng / μL) was added to the compound group and the control group, while 6 μL of Assay Buffer was added to the blank group. The compound was then added using a nanoparticle pipette, with the maximum concentration set at 1000 nM, 4-fold dilution, and 7 concentration gradients. The mixture was incubated at room temperature for 30 min. Next, 4 μL of ATP (final concentration 10 μM) and Ultra-poly GT mixture (final concentration 100 nM) were added, and the mixture was incubated at room temperature for 2 h. Then, 5 μL of EDTA (final concentration 10 mM) was added to terminate the reaction. Finally, 5 μL of antibody (final concentration 2 nM) was added, and the mixture was incubated at room temperature for 1 h. The signal values ​​were detected at 665 / 615 nm, and four-parameter analysis was performed. A dose-response curve was fitted, and the IC50 was calculated. 50 .

[0263] 3.2 BTK(C481S) inhibitory activity

[0264] Prepare the Assay Buffer with the following components: Hepes (Gibco, 15630): 50 mM, MgCl2: 10 mM, DTT: 2 mM, EGTA: 1 mM, Tween 20: 0.010%. Use the Assay Buffer to prepare working solutions for BTK (C481S) kinase (Carna Biosciences, 08-547), ATP (Sigma, A7699), and Ultra-poly GT (PE, TRF0100-M). Use the Detection Buffer to prepare working solutions for EDTA and Eu-labeled anti-phosphotyrosine (PT66) antibody (PE, AD0069). 6 μL of the corresponding concentration of BTK(C481S) kinase (final concentration 0.005 ng / μL) was added to the compound group and the control group, while 6 μL of Assay Buffer was added to the blank group. Then, the compound was added using a nanoparticle pipette. The compound concentration was set to a maximum of 1000 nM, with 4-fold dilution and 7 concentration gradients. The mixture was incubated at room temperature for 30 min. Then, 4 μL of ATP (final concentration 10 μM) and Ultra-poly GT mixture (final concentration 100 nM) were added. After incubation at room temperature for 2 h, 5 μL of EDTA (final concentration 10 mM) was added to terminate the reaction. Finally, 5 μL of antibody (final concentration 2 nM) was added. After incubation at room temperature for 1 h, the signal value was detected at 665 / 615 nm. Four-parameter analysis was performed, the dose-response curve was fitted, and the IC50 was calculated.

[0265] 3.3 EGFR inhibitory activity

[0266] Prepare the Assay Buffer with the following composition: Hepes (Gibco, 15630): 50 mM, MgCl2: 10 mM, DTT: 2 mM, EGTA: 1 mM, Tween 20: 0.010%. Use the Assay Buffer to prepare working solutions for EGFR kinase (Carna, 08-115), ATP (Sigma, A7699), and Ultra-poly GT (PE, TRF0100-M). Use the Detection Buffer to prepare working solutions for EDTA and Eu-labeled anti-phosphotyrosine (PT66) antibody (PE, AD0069). 6 μL of the corresponding concentration of EGFR kinase (final concentration 0.006 ng / μL) was added to the compound group and the control group, while 6 μL of Assay Buffer was added to the blank group. Then, the compound was added using a nanoparticle pipette. The compound concentration was set to a maximum of 1000 nM, with 4-fold dilution and 7 concentration gradients. The mixture was incubated at room temperature for 30 min. Then, 4 μL of ATP (final concentration 5 μM) and Ultra-poly GT mixture (final concentration 100 nM) were added. After incubation at room temperature for 2 h, 5 μL of EDTA (final concentration 10 mM) was added to terminate the reaction. Finally, 5 μL of antibody (final concentration 2 nM) was added. After incubation at room temperature for 1 h, the signal value was detected at 665 / 615 nm. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated.

[0267] 3.4 TEC Inhibitory Activity

[0268] Prepare the Assay Buffer with the following composition: Hepes (Gibco, 15630): 50 mM, MgCl2: 10 mM, DTT: 2 mM, EGTA: 1 mM, Tween 20: 0.010%. Use the Assay Buffer to prepare working solutions for TEC kinase (Carna, 08-115), ATP (Sigma, A7699), and Ultra-poly GT (PE, TRF0100-M). Use the Detection Buffer to prepare working solutions for EDTA and Eu-labeled anti-phosphotyrosine (PT66) antibody (PE, AD0069). 6 μL of the corresponding concentration of TEC kinase (final concentration 0.01 ng / μL) was added to the compound group and the control group, while 6 μL of Assay Buffer was added to the blank group. The compound was then added using a nanoparticle pipette, with the maximum concentration set at 1000 nM, 4-fold dilution, and 7 concentration gradients. The mixture was incubated at room temperature for 30 min. Next, 4 μL of ATP (final concentration 10 μM) and Ultra-poly GT mixture (final concentration 100 nM) were added, and the mixture was incubated at room temperature for 2 h. Then, 5 μL of EDTA (final concentration 10 mM) was added to terminate the reaction. Finally, 5 μL of antibody (final concentration 2 nM) was added, and the mixture was incubated at room temperature for 1 h. The signal values ​​were detected at 665 / 615 nm, and four-parameter analysis was performed. A dose-response curve was fitted, and the IC50 was calculated. 50 The experimental results are shown in Table 3.

[0269] Table 3 In vitro kinase inhibitory activity

[0270]

[0271] Test results of the compound indicate that the compound of this application has selective inhibitory activity against kinases in vitro.

[0272] Experimental Example 4: In vitro liver microsite stability

[0273] Liver microsomal incubation samples were prepared by incubating liver microsomal solution (0.5 mg / mL) in mixed PBS buffer (pH 7.4), along with the test compound and NADPH + MgCl2 solution at 37°C and 300 rpm for 1 hour. Samples at 0 hours were prepared by incubating liver microsomal solution (0.5 mg / mL) in mixed PBS buffer (pH 7.4), along with the test compound. After adding acetonitrile solution containing an internal standard, protein precipitation was performed to prepare the supernatant, which was then diluted for LC / MS / MS analysis. Results are shown in Table 4.

[0274] Table 4. In vitro liver microsomal metabolic stability

[0275]

[0276] Test results of the compound indicate that the compound of this application has hepatic microsomal metabolic stability.

[0277] Experimental Example 5: Pharmacokinetics in Mice

[0278] ICR mice, weighing 18–22 g, were randomly divided into groups of 9 mice each after acclimatization for 3–5 days. Each group was administered the experimental compound solution via gavage at a dose of 10 mg / kg. Blood samples were collected from the orbital cavity at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h to prepare test plasma samples. 20 μL of the test plasma sample and the standard curve sample were added, and acetonitrile solution containing the internal standard was added. Protein precipitation was performed to obtain the supernatant, which was then diluted for LC / MS / MS analysis. A non-compartmental model was used for fitting. Pharmacokinetic parameters are shown in Table 5.

[0279] Table 5 Results of Pharmacokinetic Studies

[0280]

[0281]

[0282] Test results of the compound indicate that the compound of this application has good in vivo pharmacokinetic properties.

Claims

1. A compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof, in, Ring A does not exist, or it is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from phenyl or 6-membered heteroaryl; The ring C is selected from isoxazolyl or furanyl; Each R 1 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; n is selected from 0, 1, 2, or 3; X 2 Selected from CH or N; L 1 Selected from -O- or -NHCO-; Each R is independently selected from halogen, -CN, C 1-4 Alkoxy, or C substituted with one or more halogens 1-4 alkyl; Each R 2 Each is independently selected from halogen or C 1-4 alkyl; p and q are independently selected from 0, 1, 2, or 3, respectively; X is selected from CH or N; The ring E is selected from 7-12-membered spirocycloalkyl, 7-12-membered heterospirocycloalkyl, 6-12-membered fused cycloalkyl, or 6-12-membered heterofused cycloalkyl; Each R 3 Each is independently selected from -OH, -NH2, halogen, -CN, =O, C 1-4 Alkyl or C 1-4 Alkoxy; m is selected from 0, 1, 2, or 3; L is selected from the linking group.

2. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein ring A is absent, or is selected from C. 5-7 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl; Alternatively, ring A is absent, or is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl or oxazolyl; Alternatively, ring A is absent, or is selected from cyclopentenyl, dicyclohexenyl, dihydropyrroleyl, tetrahydropyridyl, tetrahydroazapyridine, and tetrahydroazapyridine. The following groups are used: α-hydroxyl, dihydrooxazinyl, azirospirooctenyl, azirospirononenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, or oxazolyl. Optionally, ring B is selected from phenyl; Optional, structural moiety Selected from Or, structural parts Selected from in, The key connected to ring A The asterisk (*) indicates that the bond is connected to an atom on ring A; the bond connected to ring C is... The asterisk (*) indicates that the bond is connected to an atom on the ring C. Or, structural parts Selected from Or, structural parts Selected from (For example ), (For example ), The definition of * is the same as or similar to that above; Or, structural parts Selected from Or, structural parts Selected from Or, structural parts Selected from Or, structural parts Selected from 3. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, each R 1 Each is independently selected from halogens, -OH, -NH2, -CN, and C. 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl; Or, each R 1 Each is independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN; Or, R 1 Selected from fluorine; Optionally, n is selected from 0, 1, or 2.

4. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein each R is independently selected from fluorine, chlorine, -CN, C 1-3 alkoxy groups, or C groups optionally substituted with one or more fluorine, chlorine, bromine, or iodine groups. 1-3 alkyl; Alternatively, each R is independently selected from fluorine, chlorine, -CN, methoxy, ethoxy, or a methyl group optionally substituted with one or more fluorine or chlorine groups; Alternatively, each R can be independently selected from chlorine or -CF3; Optionally, each R 2 Each is independently selected from fluorine, chlorine, bromine, iodine, or C. 1-3 alkyl; Or, each R 2 Each is independently selected from fluorine, chlorine, methyl, or ethyl; Or, R 2 Selected from fluorine; Optionally, q is selected from 0, 1, or 2; Optionally, p is selected from 0, 1, or 2.

5. The compound of claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein ring E is selected from 7-12-membered spirobicycloalkyl, 7-12-membered heterospirobicycloalkyl, 6-12-membered benzobicycloalkyl or 6-12-membered heterobenzobicycloalkyl; Alternatively, ring E is selected from 7-12-membered spirobicycloalkyl, 7-12-membered heterospirobicycloalkyl, 7-10-membered anabibiricycloalkyl or 6-10-membered heteroabibiricycloalkyl; Alternatively, ring E is selected from 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered heterospirobicycloalkyl, or 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocycloalkyl; Alternatively, ring E is selected from 7-11-membered heterospirobicycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, or 6-10-membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S; Alternatively, ring E is selected from diazaspiro[3.5]nonane, azaspiro[3.5]nonane, azaspiro[5.5]undecane, azaspiro[3.3]heptane, azaspiro[3.4]octane, diazaspiro[3.3]heptane, azaspiro[4.5]decane, diazaspiro[4.5]decane, azaspiro[5.5]undecane, octahydrocyclopent[c]pyrrole, furan[3,4-b]pyrrole, azabicyclo[3.1.0]hexane, azabicyclo[3.2.0]heptane, octahydro-1H-isoindole, decahydroisoquinoline, or octahydro-1H-cyclopent[c]pyridine; Alternatively, ring E is selected from Optionally, each R 3 Each is independently selected from -OH, -NH2, halogen, -CN, =O, methyl, ethyl, or methoxy; Or, each R 3 Each is independently selected from -OH, -NH2, halogens, -CN, and =O; Optionally, m is selected from 0 or 1.

6. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the L is selected from the following groups optionally substituted with one or more substituents: C 1-50 Alkylene, C 2-50 imide or C 2-50 Alkyne group, optionally, the C 1-50 Alkylene, C 2-50 imide or C 2-50 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-15 Cycloalkyl, 3-15 membered heterocyclic alkyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl, 5-15 quinone heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-30 Alkylene, C 2-30 imide or C 2-30 Alkyne group, optionally, the C 1-30 Alkylene, C 2-30 imide or C 2-30 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-12 Cycloalkyl, 3-12 membered heterocyclic alkyl, 4-12 membered heterocyclic alkenyl, C 6-12 Aryl, 5-12 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-20 Alkylene, C 2-20 imide or C 2-20 Alkyne group, optionally, the C 1-20 Alkylene, C 2-20 imide or C 2-20 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-10 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl, 5-10 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-15 Alkylene, C 2-15 imide or C 2-15 Alkyne group, optionally, the C 1-15 Alkylene, C 2-15 imide or C 2-15 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, C 6-8 Aryl, 5-8 quinone heteroaryl, -NH-, -N(C 1-4 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-10 Alkylene, C 2-10 imide or C 2-10 Alkyne group, optionally, the C 1-10 Alkylene, C 2-10 imide or C 2-10 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-6 Alkylene, C 2-6 imide or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene, C 2-6 imide or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-4 Alkylene, C 2-4 imide or C 2-4 Alkyne group, optionally, the C 1-4 Alkylene, C 2-4 imide or C 2-4 One or more (e.g., one or two, one or three, etc.) of the ethynyl group are independently and optionally separated by -O-, C 4-6 Cycloalkyl, 4-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 Alkyl)- or -S-replacement; Optionally, in the definition of L, the substituent is selected from deuterium, halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl; Alternatively, in the definition of L, the substituent is selected from deuterium, halogen, =O, -OH, -NH2, -CN, C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-4 alkyl)NH-, (C 1-4 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl; Alternatively, in the definition of L, the substituent is selected from =O, hydroxyl C. 1-3 Alkyl, -NH2, -CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, (C 1-3 alkyl)NH- or (C 1-3 Alkyl)2N-; Alternatively, in the definition of L, the substituent is selected from =O or hydroxy C. 1-3 alkyl; Alternatively, in the definition of L, the substituent is =O or HOCH2-.

7. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the L is selected from -LNK. 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -,in, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-12 Aryl, 5-12-membered heteroaryl, or 4-12-membered heterocyclic alkenyl; LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-12 Alkylene, C 2-12 imidene group, C 2-12 Ethyne or C 1-12 Heteroalkylene; Each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl; Optionally, L is selected from -Cy 1 -, -Cy 2 -, -LNK 1 -, -Cy 1 -LNK-, -Cy 1 -Cy 2 -, -LNK 1 -Cy 1 -LNK-, -LNK-Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 1 -Cy 2 -, -Cy 1 -LNK-Cy 2 -, -LNK 1 -Cy 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 1 -LNK-Cy 2 -, -Cy 1 -LNK-Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -Cy 3 - or -Cy 1 -Cy 2 -LNK 2 -Cy 3 -; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne or C 1-10 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R- bonds. c The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne or C 1-6 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-3 Alkylene, C 2-3 Ethyne or C 1-3 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-2 alkylene, C2-alkynyl or C 1-2 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each group is independently selected from the following groups: bond, -NH-, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, ethynyl group, -C(O)-, or -C(O)CH2-. Or, LNK, LNK 1 and LNK 2 Each is independently selected from the key, or selected from those optionally controlled by one or more R. c The following groups are substituted: C 1-6 Alkylene or C 1-6 Heteroalkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the key, or selected from those optionally controlled by one or more R. c Replacement C 1-3 Alkylene; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, -CH2-, -C(O)-, or -C(O)CH2-; Or, LNK, LNK 1 and LNK 2 Each is independently selected from the bond, or -CH2-; Optional, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-11 Cycloalkyl, 4-12-membered heterocycloalkyl, 4-11-membered heterocycloalkenyl or 5-11-membered heteroaryl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-6 Cycloalkyl, 4-9 membered heterocycloalkyl or 5-6 membered heteroaryl; Or, Cy 1 Cy 2 or Cy 3 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, azircyclobutyl, pyrrolyl, piperidinyl, tetrahydropyridyl, piperazine, azirspiroheptyl, azirspiroctyl, azirspironyl, diazirspironyl, azirspirodealkyl, diazirspirodealkyl, azirspiroundecyl, diazirspiroundecyl, azirbicyclohexane, octahydrocyclopentylpyrrole, diazirbicyclooctyl, azirbicyclononyl, azirbicycloheptyl, or pyrazine; Or, Cy 1 Cy 2 or Cy 3 Selected independently from keys, Or, Cy 1 Cy 2 or Cy 3 Selected independently from keys, Or, Cy 1 Cy 2 or Cy 3 Selected independently from keys, Or, Cy 1 Cy 2 or Cy 3 Selected independently from keys, Optionally, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl; Or, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-; Or, each R b and R c Each is independently selected from deuterium, halogens, =O, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-6 Alkyl, (C 1-4 alkyl)NH-, or (C 1-4 Alkyl)2N-; Or, each R b and R c Each is independently selected from C-terminals that are =O or hydroxyl-substituted. 1-3 alkyl; Or, each R b and R c Each is independently selected from =O or HOCH2-; Optionally, the L or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 - Selected from -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-, 8. Compounds of formula II, III or IV, their stereoisomers or pharmaceutically acceptable salts thereof, X 3 Selected from CH or N.

9. The following compounds, their stereoisomers, or pharmaceutically acceptable salts, 10. A pharmaceutical composition comprising the compounds described above, their stereoisomers, or pharmaceutically acceptable salts thereof, and further comprising pharmaceutically acceptable excipients.

11. Use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases by means of degradation of target proteins bound to target ligands.

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