CN117229263A - Compound for inhibiting or degrading Bcl6 and application of compound in medicine - Google Patents
Compound for inhibiting or degrading Bcl6 and application of compound in medicine Download PDFInfo
- Publication number
- CN117229263A CN117229263A CN202310680011.8A CN202310680011A CN117229263A CN 117229263 A CN117229263 A CN 117229263A CN 202310680011 A CN202310680011 A CN 202310680011A CN 117229263 A CN117229263 A CN 117229263A
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- China
- Prior art keywords
- alkyl
- substituted
- membered
- cyano
- alkoxy
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 86
- 101100381525 Mus musculus Bcl6 gene Proteins 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims description 13
- 230000000593 degrading effect Effects 0.000 title description 3
- 230000002401 inhibitory effect Effects 0.000 title description 3
- 239000013078 crystal Substances 0.000 claims abstract description 43
- 239000000651 prodrug Substances 0.000 claims abstract description 42
- 229940002612 prodrug Drugs 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 239000012453 solvate Substances 0.000 claims abstract description 39
- 239000002207 metabolite Substances 0.000 claims abstract description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 558
- -1 methoxy, ethoxy, cyclopropyl Chemical group 0.000 claims description 294
- 125000000623 heterocyclic group Chemical group 0.000 claims description 285
- 125000003545 alkoxy group Chemical group 0.000 claims description 226
- 229910052736 halogen Inorganic materials 0.000 claims description 226
- 229910052760 oxygen Inorganic materials 0.000 claims description 222
- 229910052717 sulfur Inorganic materials 0.000 claims description 200
- 150000002367 halogens Chemical class 0.000 claims description 188
- 125000001424 substituent group Chemical group 0.000 claims description 177
- 125000005842 heteroatom Chemical group 0.000 claims description 174
- 229910052757 nitrogen Inorganic materials 0.000 claims description 167
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 153
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 152
- 229910052731 fluorine Inorganic materials 0.000 claims description 149
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 142
- 229910052740 iodine Inorganic materials 0.000 claims description 138
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 121
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 91
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 90
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 89
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 87
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 86
- 229910052739 hydrogen Inorganic materials 0.000 claims description 79
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 78
- 125000002393 azetidinyl group Chemical group 0.000 claims description 75
- 229910052799 carbon Inorganic materials 0.000 claims description 75
- 125000001072 heteroaryl group Chemical group 0.000 claims description 74
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 69
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 68
- 125000003386 piperidinyl group Chemical group 0.000 claims description 68
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 52
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 49
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 48
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 46
- 125000002883 imidazolyl group Chemical group 0.000 claims description 43
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 42
- 125000005843 halogen group Chemical group 0.000 claims description 41
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 41
- 125000004076 pyridyl group Chemical group 0.000 claims description 41
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 41
- 125000004429 atom Chemical group 0.000 claims description 40
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 35
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 34
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 32
- 125000004193 piperazinyl group Chemical group 0.000 claims description 31
- 125000000304 alkynyl group Chemical group 0.000 claims description 28
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 27
- 125000002947 alkylene group Chemical group 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
- 125000002837 carbocyclic group Chemical group 0.000 claims description 17
- 239000012634 fragment Substances 0.000 claims description 17
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 125000002541 furyl group Chemical group 0.000 claims description 13
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 13
- 125000001544 thienyl group Chemical group 0.000 claims description 13
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 12
- 125000002971 oxazolyl group Chemical group 0.000 claims description 12
- 125000003003 spiro group Chemical group 0.000 claims description 12
- 125000000335 thiazolyl group Chemical group 0.000 claims description 12
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 11
- 125000002757 morpholinyl group Chemical group 0.000 claims description 11
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 10
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 10
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 10
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 9
- 125000003566 oxetanyl group Chemical group 0.000 claims description 9
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 8
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 229910052805 deuterium Inorganic materials 0.000 claims description 7
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 125000003725 azepanyl group Chemical group 0.000 claims description 6
- 230000015556 catabolic process Effects 0.000 claims description 6
- 238000006731 degradation reaction Methods 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 6
- 125000004306 triazinyl group Chemical group 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 125000001620 monocyclic carbocycle group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
- WRJQAQIVNJHDRJ-UHFFFAOYSA-N 2H-furo[3,2-b]indole Chemical compound O1CC=C2C1=C1C=CC=CC1=N2 WRJQAQIVNJHDRJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000006450 cyclopropyl cyclopropyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000005561 phenanthryl group Chemical group 0.000 claims description 3
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 35
- 238000004519 manufacturing process Methods 0.000 claims 2
- SXYMXKBSJPLGAM-UHFFFAOYSA-N 1-(azetidin-1-yl)pyrrolidine Chemical class C1CCN1N1CCCC1 SXYMXKBSJPLGAM-UHFFFAOYSA-N 0.000 claims 1
- QGRRJTQMMXJUNP-UHFFFAOYSA-N 1-pyrrolidin-1-ylpyrrolidine Chemical class C1CCCN1N1CCCC1 QGRRJTQMMXJUNP-UHFFFAOYSA-N 0.000 claims 1
- FOGGMWDTLLXUTO-UHFFFAOYSA-N 4,7-diazabicyclo[3.2.0]heptane Chemical class C1CNC2CNC21 FOGGMWDTLLXUTO-UHFFFAOYSA-N 0.000 claims 1
- KNLOUXALILBKPY-UHFFFAOYSA-N 5,8-diazabicyclo[4.2.0]octane Chemical class C1CCNC2CNC21 KNLOUXALILBKPY-UHFFFAOYSA-N 0.000 claims 1
- HONIICLYMWZJFZ-UHFFFAOYSA-O azetidin-1-ium Chemical compound C1C[NH2+]C1 HONIICLYMWZJFZ-UHFFFAOYSA-O 0.000 claims 1
- 230000005496 eutectics Effects 0.000 abstract description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 70
- 238000006243 chemical reaction Methods 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 238000002360 preparation method Methods 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 15
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- 125000004452 carbocyclyl group Chemical group 0.000 description 9
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 9
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- 125000006413 ring segment Chemical group 0.000 description 5
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- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
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- 108010026668 snake venom protein C activator Proteins 0.000 description 4
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a pharmaceutical composition thereof, and application thereof in Bcl6 related diseases such as cancers. B-L-K (I).
Description
Technical Field
The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a pharmaceutical composition thereof, and application thereof in Bcl6 related diseases such as cancers.
Background
Bcl6 is a transcriptional repressor that can regulate germinal center B cell development and function. The high expression of Bcl6 protein caused by various influencing factors such as exon mutation, regulation and control channel mutation, somatic Bcl6 translocation, promoter mutation and the like can lead the B cells of the hair-growing center to proliferate rapidly, thereby promoting the generation of B cell lymphomas. Meanwhile, bcl6 can inhibit cell cycle check points and differentiation related genes and DNA damage reaction, and preclinical researches show that the deletion of Bcl6 in lymphoma cells can cause the stagnation of tumor development. Thus, bcl6 is a suitable target with potential treatment of a variety of lymphomas.
PROTAC (proteolysis targeting chimera) is a double-function compound capable of simultaneously combining target protein and E3 ubiquitin ligase, and the compound can be recognized by a proteasome of a cell to cause degradation of the target protein, so that the content of the target protein in the cell can be effectively reduced. By introducing ligands capable of binding different targeting proteins into the PROTAC molecule, the application of the PROTAC technology to the treatment of various diseases has become possible, and this technology has received a great deal of attention in recent years.
Therefore, there is a need to develop novel PROTAC drugs targeting Bcl6 protein and E3 ubiquitin ligase for the treatment of Bcl6 related tumor diseases.
Disclosure of Invention
The invention aims to provide a compound which has novel structure, good drug effect, high bioavailability, safer property and can inhibit and degrade Bcl6, and is used for treating Bcl6 related diseases such as cancers.
The invention provides a compound or stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),
B-L-K(I)；
in certain embodiments, the compound of formula (I) is selected from compounds of formula (II-1) or (II-2),
In certain embodiments, L is selected from a bond or-C 1-50 Hydrocarbyl-, having from 0 to 20 methylene units in said hydrocarbyl optionally further replaced by-Ak-, -Cy-;
in certain embodiments, L is selected from a bond or-C 1-20 Hydrocarbyl-, having from 0 to 20 methylene units in said hydrocarbyl optionally further replaced by-Ak-, -Cy-;
in certain embodiments, L is selected from a bond or-C 1-10 Hydrocarbyl-, having from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) methylene units in the hydrocarbyl group optionally further replaced by-Ak-, -Cy-;
in certain embodiments, each-Ak-is independently selected from Ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, or Ak9;
in certain embodiments, each-Ak-is independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-NR L (CH 2 ) q C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -、-CH＝CH-、-Si(R L ) 2 -、-Si(OH)(R L )-、-Si(OH) 2 -、-P(＝O)(OR L )-、-P(＝O)(R L )-、-S-、-S(＝O)-、-S(＝O) 2 -or a bond, said-CH 2 Optionally substituted with 1 to 2 groups selected from halogen, OH, CN, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Substituted by alkyl;
in certain embodiments, ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally substituted with 1 to 2 groups selected from halogen, OH, CN, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Substituted by alkyl;
in certain embodiments, ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally 1 to 2 are selected from F, cl, br, I, OH, CN, NH 2 、CF 3 Hydroxymethyl, C 1-4 Alkyl, C 1-4 Substituted with alkoxy;
in certain embodiments, ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally 1 to 2 are selected from F, cl, br, I, OH, CN, NH 2 、CF 3 A hydroxymethyl, methyl, ethyl, methoxy or ethoxy substituent;
in certain embodiments, ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from the group consisting of a bond, -O-, -OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-C≡C-、-C(CH 3 ) 2 -、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-N(CH 3 )-、-NH-、-CH 2 N(CH 3 )-、-CH 2 NH-、-NHCH 2 -、-CH 2 CH 2 N(CH 3 )-、-CH 2 CH 2 NH-、-NHCH 2 CH 2 -、-C(＝O)-、-C(＝O)CH 2 NH-、-CH 2 C (=o) NH-, -C (=o) NH-or-NHC (=o) -;
in certain embodiments, R L Each independently selected from H, C 1-6 An alkyl group, a 3-7 membered heterocyclyl group, a 3-7 membered cycloalkyl group, a phenyl group or a 5-6 membered heteroaryl group, said heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R L Each independently selected from H or C 1-6 An alkyl group;
in certain embodiments, R L Each independently selected from H or C 1-4 An alkyl group;
in certain embodiments, R L Selected from H, methyl or ethyl;
in certain embodiments, q is each independently selected from 0, 1, 2, 3, 4, 5, or 6;
in certain embodiments, q is each independently selected from 0, 1, 2, 3, or 4;
in certain embodiments, q is each independently selected from 0, 1, 2, or 3;
in certain embodiments, each-Cy-is independently selected from Cy1, cy2, cy3, cy4, or Cy5;
in certain embodiments, each-Cy-is independently selected from the group consisting of a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heterobicyclic ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro or bridged ring optionally being substituted with 1 to 2 groups selected from halogen, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatom is selected from S;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heteroacene, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, and C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Meta spirocycloalkyl, C 7-10 A bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro or bridged ring optionally being selected from 1 to 2 of F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Substituted by substituents of alkoxy groups, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro or bridged ring containing 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally being substituted1 or 2 = O substitutions;
in certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered nitrogen containing heteromonocyclic ring, a 4-10 membered nitrogen containing heterobicyclic ring, a 5-12 membered nitrogen containing heterospiro ring, a 7-10 membered nitrogen containing heterobridged ring, C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said heteromonocyclic, heterobicyclic, heterobridged, heterospiro, cycloalkyl, aryl or heteroaryl optionally being selected from 1 to 2 of F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteromonocyclic, heterobicyclic, heterobridged, heterospiro or heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatoms are selected from S;
in certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazepinyl, phenyl, pyridine, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirocyclobutyl, cyclopropyl-spirocyclopentyl cyclopropyl spirohexyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentyl spiropentyl, cyclopentyl spirohexyl, cyclohexyl spirohexyl, cyclopropyl azetidinyl, cyclopropyl pyrrolidyl, cyclopropyl piperidyl cyclobutyl azetidine, cyclobutyl pyrrolidyl, cyclobutyl azetidinyl, cyclopentyl pyrrolidyl cyclopentyl-piperidinyl, cyclohexyl-azetidinyl, cyclohexyl-pyrrolidinyl, cyclohexyl-piperidyl, azetidino-aza Cyclobutyl, azetidinopyrrolidinyl, pyrrolidinoazetidinyl, pyrrolidinopyrrolidinyl, piperidinyloazetidinyl, piperidinylopyrrolidinyl, cyclopropylpiropiridyl, cyclopropylpiropiperidyl, cyclopropylpiropiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidinyl, cyclobutylspiropiperidinyl, cyclopentylpiropiperidyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, azetidinyl, azetidinone spiropyrrolidinyl, azetidinyl spiropiperidinyl, pyrrolidinylpiropiperidyl, piperidinylspiroazetidinyl, piperidinylspiropyrrolidinyl, piperidinylspiropyrrolidinylpiropiperidyl, piperidinylspiropyrrolidinyl, piperidinylspiropiperidinyl, piperidinylspiropyrrolidinyl, when substituted, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2 、COOH、CN、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups:
when substituted, is selected from the group consisting of F, CF by 1 to 4 3 OH, methyl, =O, hydroxymethyl, COOH, CN or NH 2 Is substituted by a substituent of (2);
in some embodiments of the present invention, in some embodiments, L is selected from the group consisting of-Cy 1-Cy2-Ak2-Cy3-Cy4-Ak 4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak 5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak 1-2-Ak 2-Ak3-Cy3-Cy4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy 1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5- -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak 2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy 3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy 4-Ak4-Ak5-, -1-Cy 2-Cy3-Ak2-Ak 3-Cy4-Ak4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak 4-Ak5-Cy1-Cy2-Cy3-Cy 2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5- -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy 4-; -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy 4-; -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy 3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy 4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4- -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Ak 5-; ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9;
In some embodiments of the present invention, in some embodiments, L is selected from the group consisting of bond, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-Ak 1-; -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, cy1-Ak1-Ak2-, cy3-Ak 4-, cy1-Cy2-Ak2-, cy1-Cy2-, cy1-Ak 2-, cy1-Cy2-, cy2-Cy 1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3- -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak 2-Cy3-Ak3-, -Cy1-Cy 3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Cy2-Cy3-Cy 4-; -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak 4-Ak5- -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;
In some embodiments of the present invention, in some embodiments, L is selected from the group consisting of-Cy 1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-Cy2-;
in certain embodiments, L is selected from the group consisting of-Cy 1-Ak1-Cy2-;
in certain embodiments, L is selected from a bond or a group shown in Table L-1, wherein the left side of the group is attached to B;
in certain embodiments, L is selected from a bond or a group as shown in Table L-2, wherein the left side of the group is attached to B;
in certain embodiments, L is selected from the group shown in Table L-3, wherein the left side of the group is attached to B;
in certain embodiments, -Cy1-Ak1-Cy 2-is selected from the group shown in Table L-3, wherein the left side of the group is attached to B;
TABLE L-1L group
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TABLE L-2L groups
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TABLE L-3
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In certain embodiments, B is selected from
In certain embodiments, B is selected from
In certain embodiments, X is selected from O, S or CH 2 ；
In certain embodiments, X is selected from O or S;
in certain embodiments, Y1 is selected from NR Y Or O;
in certain embodiments, Y1 is selected from NH or O;
in certain embodiments, Y2 is selected from NR Y S or O;
in certain embodiments, Y2 is selected from NH, S, or O;
In certain embodiments, Y2 is selected from S;
in certain embodiments, Z is selected from O, -ch=, S, S (=o), S (=o) 2 、N(R Z )C(＝O)、C(＝O)N(R Z )、S(＝O) 2 N(R Z )、N(R Z )、C 1-4 Alkylene, -OC 1-3 Alkylene-, -C 1-3 Alkylene group O-, -C 1-3 Alkylene group S-, -C 1-3 Alkylene S (=o) -, C 1-3 Alkylene group S (=o) 2 -、-N(R Z )C 1-3 alkylene-or-C 1-3 Alkylene N (R) Z ) -said alkylene group optionally being 1 to 4 groups selected from halogen, =o, = S, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, Z is selected from O, S, -ch=, N (R Z )、-N(R Z )C(＝O)-、-C(＝O)N(R Z )-、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-CH 2 S-、-CH 2 CH 2 S-、-CH 2 S(＝O) 2 -、-CH 2 CH 2 S(＝O) 2 -、-N(R Z )CH 2 -、-N(R Z )CH 2 CH 2 -、-CH 2 N(R Z )-、-CH 2 CH 2 N(R Z )-、-N(R Z )C(＝O)CH 2 -or-CH 2 C(＝O)N(R Z ) -, the CH 2 Optionally further 0 to 2 are selected from H, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, Z is selected from-NHC (=o) -, -C (=o) NH-, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-NHCH 2 -、-NHCH 2 CH 2 -、-CH 2 NH-、-CH 2 CH 2 NH-、-NHC(＝O)CH 2 -、-CH 2 C(＝O)NH-、O、S、NH、-CH＝、-N(CH 3 )C(＝O)-、-C(＝O)N(CH 3 )-、-CH 2 C(＝O)NH-、-CH 2 C(＝O)N(CH 3 )-、-N(CH 2 CH 3 )C(＝O)-、-N(CH(CH 3 ) 2 )C(＝O)-、-N(CH 2 CH(CH 3 ) 2 ) C (=o) -, -N (cyclopropyl) C (=o) -, -N (CH) 2 -cyclopropyl) C (=o) -, -N (CH) 2 -ethynyl) C (=o) -, -C (=o) N (CH) 2 CH 3 )-、-C(＝O)N(CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 ) 2 ) -, -C (=O) N (cyclopropyl) -or-C (=O) N (CH) 2 -cyclopropyl) -;
in certain embodiments, R Z Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl being optionally substituted with 1 to 4 groups selected from deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 Alkynyl, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S or N;
in certain embodiments, R Z Each independently selected from H, methyl,Ethyl, propyl, isopropyl or cyclopropyl, optionally substituted with 1 to 4 groups selected from deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, 3-to 6-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S or N;
in certain embodiments, R Z Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl,
-CH 2 -cyclopropyl, -CH 2 -ethynyl;
in certain embodiments, ring W is selected from C 3-10 Carbocycles or 3-to 10-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, ring W is selected from C 3-7 Carbocycles or 3-to 8-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, ring W is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1, 4-diazepinyl, azepinyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1, 4-diazepinyl, azepinyl optionally substituted with 1 to 3 substituents selected from F,Cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
in certain embodiments, R t1 、R t2 Or R is t3 Each independently selected from H, halogen, cyano, NH 2 、NO 2 、OH、C 1-6 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3 to 10 membered heterocycle, said alkyl, alkoxy, alkenyl, alkynyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R t1 、R t2 Or R is t3 Each independently selected from H, F, cl, br, I, cyano, NH 2 、NO 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R t1 、R t2 Or R is t3 Each independently selected from H, F, cl, br, I, cyano, NH 2 、NO 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl optionally being 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
in certain embodiments, two R' s t1 Two R t2 Two R t3 Respectively with atoms directly connected thereto to form C 3-10 Carbocycles or 3-to 10-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, two R' s t1 Two R t2 Two R t3 Respectively and directly connected with atoms to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl and piperidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl and piperidinyl are optionally substituted by 1 to 3 atoms selected from halogen, OH, cyano and NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, two R' s t1 And the atoms directly attached thereto form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted by 1 to 3 atoms selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
in certain embodiments, R Y Selected from H, C 1-6 Alkyl, C 3-10 Carbocycle or 3-to 10-membered heterocycle, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R Y Selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, optionally substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R A Selected from C 3-12 Carbocycle or- (CH) 2 ) t4 NR A1 R A2 The carbocycle or heterocycle is optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R A Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or- (CH) 2 ) t4 NR A1 R A2 The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl are optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R A Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or- (CH) 2 ) t4 NR A1 R A2 The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
in certain embodiments, R B Selected from H, OH, - (CH) 2 ) t4 NR B1 R B2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Carbocycles, 4-12 membered heterocycles, optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R B Selected from H, OH, - (CH) 2 ) t4 NR B1 R B2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R B Selected from H, OH, - (CH) 2 ) t4 NR B1 R B2 Methyl, ethylA group selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl being optionally substituted with 1 to 4 groups selected from the group consisting of F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl, ethyl and cyclopropyl;
in certain embodiments, R C Selected from 5-6 membered heteroaryl,The heteroaryl group is optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a 3 to 8 membered heterocyclic ring substituted with a substituent, said heterocyclic ring or heteroaryl containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R C Selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and, The pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl are optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a 3 to 8 membered heterocyclic ring substituted with a substituent, said heterocyclic ring or heteroaryl containing 1 to 3 heteroatoms selected from O, S, N; />
In certain embodiments, R C Selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and,
The pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl are optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl, ethyl and cyclopropyl;
in certain embodiments, R C And R is R 3b And the atoms to which they are directly attached form a 4-12 membered heterocyclic ring, said heterocyclic ring optionally being substituted with 1 to 4 atoms selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R C And R is R 3b And the atoms to which they are directly attached form a 5-8 membered heterocyclic ring, said heterocyclic ring optionally being substituted with 1 to 4 atoms selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R C And R is R 3b And atoms directly attached thereto formSaid->Optionally from 1 to 4 are selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl, ethyl and cyclopropyl;
in certain embodiments, R A1 、R B1 、R B2 Each independently selected from H, OH, NH 2 、NH(C 1-6 Alkyl group), NH (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Carbocycle or 4-12 membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R A1 、R B1 、R B2 Each independently selected from H, OH, NH 2 、NH(C 1-4 Alkyl group), NH (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 Carbocycle or 4-8 membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R A1 、R B1 、R B2 Each independently selected from H, OH, NH 2 NH (methyl), NH (ethyl), NH (propyl), NH (isopropyl), NH (methyl) 2 NH (ethyl) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentylOptionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH, by methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl 2 、CF 3 Substituted by methyl, ethyl, methoxy, ethyl, cyclopropyl;
in certain embodiments, R A2 Selected from C 2-6 Alkenyl, C 2-6 Alkynyl, NH (C) 1-6 Alkyl group), NH (C) 1-6 Alkyl group 2 、C 3-12 Carbocycle or 4-12 membered heterocycle, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R A2 Selected from C 2-4 Alkenyl, C 2-4 Alkynyl, NH (C) 1-4 Alkyl group), NH (C) 1-4 Alkyl group 2 4-7 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, 5-to 10-membered heteroaryl or 6-to 10-membered aryl, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Carbocycles or 3-to 8-membered heterogeniesA ring substituted with a substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
In certain embodiments, R A2 Selected from one of the following substituted or unsubstituted: vinyl, ethynyl, propargyl, propynyl, NH (methyl), NH (ethyl), NH (propyl), NH (isopropyl), NH (methyl) 2 NH (ethyl) 2 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, triazolyl, oxazolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, when substituted, optionally substituted with 1 to 4 groups F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituted by methyl, ethyl, methoxy, ethyl, cyclopropyl;
in certain embodiments, R C1 Each independently selected from H, C 1-6 Alkyl, C 3-12 Carbocycle or 4-12 membered heterocycle, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
In certain embodiments, R C1 Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R C1 Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl optionally being selected from F, cl, br, I, OH, cyano, NH 1 to 4 2 、CF 3 Substituted by methyl, ethyl, methoxy, ethyl, cyclopropyl;
in certain embodiments, R 3a Or R is 4 Each independently selected from H, OH, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3-to 10-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, N (CH) 3 )、N(CH 3 ) 2 、N(CH 2 CH 3 )、N(CH 2 CH 3 ) 2 、NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 3a Or R is 4 Each independently selected from H, OH, NH 2 、C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle or 3-to 6-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, N (CH) 3 )、N(CH 3 ) 2 、N(CH 2 CH 3 )、N(CH 2 CH 3 ) 2 、NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by carbocyclic rings or substituents of 3-to 6-membered heterocyclic rings containingFrom 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 3a Or R is 4 Each independently selected from H, OH, NH 2 Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl optionally being substituted with 1 to 3 substituents selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 3a Selected from H, OH, NH 2 Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl optionally being substituted with 1 to 3 substituents selected from F, cl, br, I, OH, cyano, NH 2 Substituents such as methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
in certain embodiments, R 4 Each independently selected from H, methyl, ethyl, cyclopropyl;
in certain embodiments, R 3b Or R is 5 Each independently selected from H, halogen, cyano, NH 2 、NO 2 、OH、C 1-6 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3-to 10-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 3b Or R is 5 Each independently selected from H, halogen, cyano, NH 2 、NO 2 、OH、C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocycle or 3-to 6-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 3b Or R is 5 Each independently selected from H, F, cl, br, I, cyano, NH 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 3b Each independently selected from H, F, cl, br, I, OH, methyl, ethyl, cyclopropyl;
in certain embodiments, R 5 Each independently selected from H,F. Cl, br, I, cyano, NH 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl optionally being substituted with 1 to 3 groups selected from F, cl, br, I, OH, cyano, NH 2 Methyl, ethyl, cyclopropyl;
in certain embodiments, t1, t2, or t3 is selected from 1, 2, 3, 4, or 5;
in certain embodiments, t1, t2, or t3 is selected from 1, 2, or 3;
in certain embodiments, t1, t2, or t3 is selected from 1 or 2;
in certain embodiments, t4 is selected from 0, 1, 2, 3, 4, or 5;
in certain embodiments, t4 is selected from 0, 1, 2, 3, or 4;
in certain embodiments, t4 is selected from 0, 1, or 2;
In certain embodiments, m is selected from 0, 1, 2, 3, or 4;
in certain embodiments, m is selected from 0, 1, 2, or 3;
in certain embodiments, m is selected from 0 or 1;
in certain embodiments, n is selected from 0, 1, or 2;
in certain embodiments, n is selected from 0 or 1;
in certain embodiments, B is selected from one of the structural fragments shown in Table B-1;
in certain embodiments, B is selected from one of the structural fragments shown in Table B-2;
table B-1
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Table B-2
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In certain embodiments, K is selected from K1, K2, K3, K4;
in certain embodiments, K1 is selected from
In certain embodiments, K1 is selected from />
In certain embodiments, K2 is selected from
In certain embodiments, K2 is selected from
In certain embodiments, K3 is selected from/>
In certain embodiments, K3 is selected from
In certain embodiments, K4 is selected from
In certain embodiments, K4 is selected from
In certain embodiments, E is each independently selected from C 3-10 Carbocycle, C 6-10 An aromatic ring, a 3-12 membered heterocyclic ring, or a 5-12 membered heteroaromatic ring containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, E is each independently selected from C 3-10 A carbocycle, a benzene ring, a 4-12 membered heterocycle, a 5-12 membered heteroaryl ring containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, each E is independently selected from a benzene ring, a 5-6 membered heteroaryl ring, the heterocycle or heteroaryl ring containing 1 to 3 (e.g., 1,2, 3) heteroatoms selected from O, S, N;
in certain embodiments, each E is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, an oxazole ring, an indoline ring, an isoindoline ring, a 1,2,3, 4-tetrahydroquinoline ring, or a 1,2,3, 4-tetrahydroisoquinoline ring;
in certain embodiments, each E is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxazole ring;
in certain embodiments, each E is independently selected from the group consisting of a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring;
in certain embodiments, each E is independently selected from a benzene ring or a pyridine ring;
in certain embodiments, A is selected from C 3-10 Carbocycle, C 6-10 An aromatic ring, a 3-10 membered heterocyclic ring, or a 5-10 membered heteroaromatic ring containing 1 to 4 (e.g., 1,2,3, or 4) heteroatoms selected from O, S, N;
in certain embodiments, A is selected from C 3-8 A carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring, or a 5-6 membered heteroaromatic ring containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from O, S, N;
in certain embodiments, a is selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxazole ring;
in certain embodiments, a is selected from a benzene ring or a pyridine ring;
in certain embodiments, F is each independently selected from C 3-20 Carbocyclyl, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl ring containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, F is each independently selected from C 3-7 Monocyclic carbocycle, C 4-10 Carbocyclic ring, C 5-12 Spiro carbocycles, C 5-10 Bridged ring carbocycle, 4-7 membered heteromonocyclic ring, 4-10 membered heterofused ring, 8-15 membered heterofused ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 Aryl, 5-10 membered heteroaryl, said heteromonocyclic, heterobicyclic, heterospiro, heterobridged, or heteroaromatic ring containing from 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, F is each independently selected from C 3-7 Monocyclic carbocycle, C 4-10 Carbocyclic ring, C 5-12 Spiro carbocycles, C 5-10 Bridged ring carbocycle, 4-7 membered heteromonocyclic ring, 4-10 membered heterofused ring, 8-15 membered heterofused ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 Aryl, 5-10 membered heteroaryl,The heteromonocyclic, heterobicyclic, heterospiro, heterobridged or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S or N;
in certain embodiments, each F is independently selected from the group consisting of a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrimidine ring, and a pyrimidine ring,
In certain embodiments, each F is independently selected from the group consisting of a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrimidine ring, and a pyrimidine ring,
In certain embodiments, each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1]Pentanyl, 6, 7-dihydro-5H-cyclopenta [ c ]]Pyridyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthryl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazineA group, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridyl imidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyridinyl, benzofuranyl, benzopyrrolidinyl, benzopyridazinyl, pyrrolopyridinyl, and the like pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyridopyridinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyridines, indolothiothiophenes, indolofurans, The left side of the connecting rod is directly connected with L;
in certain embodiments, each Q is independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 3-12 membered heterocycle, optionally substituted with 1 to 4 (e.g. 1, 2, 3, 4) selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each Q is independently selected from the group consisting of-O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 4-7 membered heterocycle, said heterocycleThe rings are optionally selected from F, cl, br, I, OH, = O, NH by 1 to 4 (e.g. 1, 2, 3, 4) 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each Q is independently selected from a bond, C (=o), Q1, or Q2;
in certain embodiments, Q1 is selected from a bond, CH 2 、NH、N(CH 3 )、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH 3 )C(＝O)、C(＝O)N(CH 3 )、/>
In certain embodiments, Q2 is selected from a bond, CH 2 、O、S、C(＝O)、NHC(＝O)、N(CH 3 )C(＝O)；
In certain embodiments, R q Selected from H or C 1-6 An alkyl group;
in certain embodiments, R q Selected from H or C 1-4 An alkyl group;
in certain embodiments, R q Selected from H, methyl, ethyl;
in certain embodiments, R k2 Each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-or-C (R) k3 ) 2 -；
In certain embodiments, R k2 Each independently selected from-CO-, -SO 2 -or-C (R) k3 ) 2 -；
In certain embodiments, R k1 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, R k7a Said alkyl, alkoxy, cycloalkyl is optionally selected from F, cl, br, I, OH, = O, NH by 1 to 4 (e.g. 1, 2, 3, 4) groups 2 、CN、COOH、CONH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
in certain embodiments, R k1 Selected from R k7a ；
In certain embodiments, R k3 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being selected from F, cl, br, I, OH, = O, NH by 1 to 4 (e.g. 1, 2, 3, 4) 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, R k1 、R k3 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being selected from F, cl, br, I, OH, NH by 1 to 4 (e.g. 1, 2, 3 or 4) 2 Is substituted by a substituent of (2);
in certain embodiments, R k1 、R k3 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 Methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, optionally from 1 to 4 (e.g. 1, 2, 3 or 4) of which are selected from F, cl, br, I, OH, NH 2 Is substituted by a substituent of (2);
in certain embodiments, two R' s k3 And carbon atoms or ring skeletons directly attached to both form C 3-8 Carbocycle or 3-8 membered heterocycle, two R k1 And carbon atoms or ring skeletons directly attached to both form C 3-8 Carbocycles or 3-8 membered heterocycles, optionally substituted with 1 to 4 (e.g. 1, 2, 3, 4) selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, two R' s k3 And carbon atoms or ring skeletons directly attached to both form C 3-6 Carbocycle or 3-7 membered heterocycle, two R k1 And carbon atoms or ring skeletons directly attached to both form C 3-6 Carbocycles or 3-7 membered heterocycles, optionally substituted with 1 to 4 (e.g. 1, 2, 3, 4) selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, R k4 Each independently selected from H, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being selected from F, cl, br, I, OH, = O, NH by 1 to 4 (e.g. 1, 2, 3, 4) 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, R k4 Each independently selected from H, OH, NH 2 、CF 3 、CN、C 1-4 An alkyl group;
in certain embodiments, R k5 Each independently selected fromC(CH 3 ) 2 、CO、CH 2 、CH 2 CH 2 、SO 2 、/>
In certain embodiments, R k5 Each independently selected from CO, CH 2 、SO 2 Or (b)
In certain embodiments, R k6 Each independently selected from CO, CH, SO, SO 2 、CH 2 N or NR k7a ；
In certain embodiments, R k7 Each independently selected fromC(CH 3 ) 2 、CO、CH、N、CH 2 、O、S、NR k7a ；
In certain embodiments, R k7 Each independently selected fromC(CH 3 ) 2 、CO、CH、N、CH 2 、O、S、N(CH 3 )、N(CH 2 CH 3 ) N (cyclopropyl) or NH;
in certain embodiments, R k7 Each independently selected from CO, CH, N, CH 2 、O、S、N(CH 3 ) Or NH;
in certain embodiments, R k7 Each independently selected from CH 2 、O、N(CH 3 ) Or NH;
in certain embodiments, R k7a Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted by 1 to 4 members selected from F, cl, br, I, OH, NH 2 、CN、CF 3 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substituted cycloalkyl;
in certain embodiments, R k7a Selected from H, C 1-4 Alkyl group、C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted by 1 to 4 members selected from F, cl, br, I, OH, NH 2 、CN、CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Substituted cycloalkyl;
in certain embodiments, R k7a Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl or cycloalkyl, heterocycloalkyl optionally being substituted by 1 to 4 groups selected from halogen, OH, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
in certain embodiments, R k7a Selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, CN, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 Substituted cycloalkyl;
in certain embodiments, R k7a Selected from H, CF 3 Methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH 2 CF 3 、-CH(CH 3 )CF 3 、-CH(CH 3 ) -cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -vinyl, -CH 2 -ethynyl, -CH 2 CH 2 -methoxy;
in certain embodiments, R k7a Selected from H, CF 3 Methyl, ethyl, cyclopropyl, -CH 2 -ringA propyl group;
in certain embodiments, R k7a Selected from H, CH 3 、CH 2 CH 3 Cyclopropyl;
in certain embodiments, R k8 Each independently selected from C, N or CH;
in certain embodiments, R k9 Each independently selected from the group consisting of a bond,C(CH 3 ) 2 、CO、CH 2 、CH 2 CH 2 Or SO 2 ；
In certain embodiments, R k9 Each independently selected from CO, SO 2 Or CH (CH) 2 ；
In certain embodiments, M 1 Selected from bond, -CH 2 -C (=o) NH-or-C (=o) CH 2 NH-；
In certain embodiments, M 2 Selected from-NHC (=o) -C 1-6 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being selected from F, cl, br, I, =o, OH, NH by 1 to 4 (e.g. 1, 2, 3, 4) 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, M 3 Selected from-NH-or-O-;
in certain embodiments, R k10 Selected from C 1-6 Alkyl optionally selected from F, cl, br, I, =o, OH, C by 1 to 4 (e.g. 1, 2, 3, 4) 1-6 Alkyl or C 3-6 Substituted cycloalkyl;
in certain embodiments, G is selected from C 6-10 An aromatic or 5-10 membered heteroaromatic ring optionally substituted with 1 to 4 (e.g. 1, 2, 3, 4) selected from F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, the heteroaryl ring containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, S;
in certain embodiments, R k11 Each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or-O-C (=o) -C 1-6 Alkyl, said alkyl, alkoxy or alkylthio being optionally selected from F, cl, br, I, OH, C by 1 to 4 (e.g. 1, 2, 3, 4) 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k12 、R k13 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being selected from F, cl, br, I, =o, OH, NH by 1 to 4 (e.g. 1, 2, 3, 4) 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k14 Selected from 5-6 membered heteroaryl optionally substituted with 1 to 4 (e.g. 1, 2, 3, 4) selected from F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl group substituted with a substituent, the heteroaryl group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, S;
in certain embodiments, R k14 Selected from the group consisting of
In certain embodiments, K is selected from one of the structural fragments shown in Table K-1;
in certain embodiments, K is selected from one of the structural fragments shown in Table K-2;
table K-1
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Table K-2
/>
/>
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Optionally, when Y2 is selected from NR Y Or O, at least one R t1 Is halogen or two R t1 And atoms directly attached thereto form C 3-10 Carbocycles or 3-to 10-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Carbocycles or 3-to 8-membered heterocycles containing 1 to 3 heteroatoms selected from O, S, N.
As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
L is selected from a bond or-C 1-50 Hydrocarbyl-, having from 1 to 20 methylene units in said hydrocarbyl optionally replaced by-Ak-, -Cy-;
each-Ak-is independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-NR L (CH 2 ) q C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -、-CH＝CH-、-Si(R L ) 2 -、-Si(OH)(R L )-、-Si(OH) 2 -、-P(＝O)(OR L )-、-P(＝O)(R L )-、-S-、-S(＝O)-、-S(＝O) 2 -or a bond, said-CH 2 Optionally substituted with 1 to 2 groups selected from halogen, OH, CN, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Substituted by alkyl;
q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;
R L each independently selected from H, C 1-6 An alkyl group, a 3-7 membered heterocyclyl group, a 3-7 membered cycloalkyl group, a phenyl group or a 5-6 membered heteroaryl group, said heterocyclyl or heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N;
each-Cy-is independently selected from the group consisting of a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heteroacene ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, and C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 7-10 Bridged cycloalkyl, 5-to 10-membered heteroaryl or 6-to 10-membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonoThe ring, hetero-spiro or hetero-bridged ring being optionally substituted by 1 to 2 groups selected from halogen, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatom is selected from S;
B is selected from
X is selected from O, S or CH 2 ；
Y1 is selected from NR Y Or O;
y2 is selected from NR Y S or O;
z is selected from O, -CH=, S, S (=O), S (=O) 2 、N(R Z )C(＝O)、C(＝O)N(R Z )、S(＝O) 2 N(R Z )、N(R Z )、C 1-4 Alkylene, -OC 1-3 Alkylene-, -C 1-3 Alkylene group O-, -C 1-3 Alkylene group S-, -C 1-3 Alkylene S (=o) -, C 1-3 Alkylene group S (=o) 2 -、-N(R Z )C 1-3 alkylene-or-C 1-3 Alkylene N (R) Z ) -said alkylene group optionally being 1 to 4 groups selected from halogen, =o, = S, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
R Z each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl being optionally substituted with 1 to 4 groups selected from deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 Alkynyl, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S or N;
ring W is selected from C 3-10 Carbocycles or 3-to 10-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R t1 、R t2 Or R is t3 Each independently selected from H, halogen, cyano, NH 2 、NO 2 、OH、C 1-6 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3 to 10 membered heterocycle, said alkyl, alkoxy, alkenyl, alkynyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
or two R t1 Two R t2 Two R t3 Respectively with atoms directly connected thereto to form C 3-10 Carbocycles or 3-to 10-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
provided that when Y2 is selected from NR Y Or O, at least one R t1 Is halogen or two R t1 And atoms directly attached thereto form C 3-10 Carbocycles or 3-to 10-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R Y selected from H, C 1-6 Alkyl, C 3-10 Carbocycle or 3-to 10-membered heterocycle, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A selected from C 3-12 Carbocycle or- (CH) 2 ) t4 NR A1 R A2 The carbocycle or heterocycle is optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R B selected from H, OH, - (CH) 2 ) t4 NR B1 R B2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Carbocycles, 4-12 membered heterocycles, optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R C selected from 5-6 membered heteroaryl,The heteroaryl group is optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a 3 to 8 membered heterocyclic ring substituted with a substituent, said heterocyclic ring or heteroaryl containing 1 to 3 heteroatoms selected from O, S, N;
or R is C And R is R 3b And the atoms to which they are directly attached form a 4-12 membered heterocyclic ring, said heterocyclic ring optionally being substituted with 1 to 4 atoms selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A1 、R B1 、R B2 each independently selected from H, OH, NH 2 、NH(C 1-6 Alkyl group), NH (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Carbocycle or 4-12 membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A2 selected from C 2-6 Alkenyl, C 2-6 Alkynyl, NH (C) 1-6 Alkyl group), NH (C) 1-6 Alkyl group 2 、C 3-12 Carbocycle or 4-12 membered heterocycle, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R C1 each independently selected from H, C 1-6 Alkyl, C 3-12 Carbocycle or 4-12 membered heterocycle, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R 3a or R is 4 Each independently selected from H, OH, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3-to 10-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, N (CH) 3 )、N(CH 3 ) 2 、N(CH 2 CH 3 )、N(CH 2 CH 3 ) 2 、NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R 3b or R is 5 Each independently selected from H, halogen, cyano, NH 2 、NO 2 、OH、C 1-6 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3 to 10 membered heterocycle, said alkyl, alkoxy, alkenyl, alkynyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
t1, t2 or t3 is selected from 1, 2, 3, 4 or 5;
t4 is selected from 0, 1, 2, 3, 4 or 5;
m is selected from 0, 1, 2, 3 or 4;
n is selected from 0, 1 or 2;
k is selected from K1, K2, K3 and K4;
k1 is selected from/>
K2 is selected from
K3 is selected from
K4 is selected from
Q is each independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 3-12 membered heterocycle, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R q Selected from H or C 1-6 An alkyl group;
a is selected from C 3-10 Carbocycle, C 6-10 An aromatic ring, a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S or N;
f are each independently selected from C 3-20 Carbocycle, C 6-20 An aromatic ring, a 3-20 membered heterocyclic ring, or a 5-20 membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S or N;
R k2 each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-or-C (R) k3 ) 2 -；
R k1 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, R k7a Said alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
R k7a selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted by 1 to 4 members selected from F, cl, br, I, OH, NH 2 、CN、CF 3 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substituted cycloalkyl;
R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S or N;
or two R k3 And carbon atoms or ring skeletons directly attached to both form C 3-8 Carbocycle or 3-8 membered heterocycle, two R k1 And carbon atoms or ring skeletons directly attached to both form C 3-8 Carbocycles or 3-8 membered heterocycles, optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R k4 each independently selected from H, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S or N;
M 1 selected from bond, -CH 2 -C (=o) NH-or-C (=o) CH 2 NH-；
M 2 Selected from-NHC (=o) -C 1-6 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S or N;
M 3 Selected from-NH-or-O-;
R k10 selected from C 1-6 Alkyl optionally substituted with 1 to 4 groups selected from F, cl, br, I, =o, OH, C 1-6 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or-O-C (=o) -C 1-6 Alkyl, said alkyl, alkoxy or alkylthio being optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k14 selected from 5-6 membered heteroaryl, optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl containing 1 to 4 heteroatoms selected from N, O or S;
g is selected from C 6-10 An aromatic or 5-10 membered heteroaromatic ring optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl ring containing 1 to 4 heteroatoms selected from N, O or S;
n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
l is selected from the group consisting of-Cy 1-Cy2-Ak2-Cy3-Cy4-Ak 4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak 5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak 1-2-Ak 2-Ak3-Cy3-Cy4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak 5-; -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5- -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak 5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak 5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak2-Ak 3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -1-Ak 2-Ak3-Ak4-Ak 2-Cy3-Cy4-Ak 5-; -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak 2-Cy 5-Cy1-Cy 2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5- -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy 4-; -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy 4-; -Ak1-Ak2-Ak3-Ak 1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4- Ak1-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak 6-; -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9;
Ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally substituted with 1 to 2 groups selected from halogen, OH, CN, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy group,Halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Substituted by alkyl;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heteroacene ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Meta spirocycloalkyl, C 7-10 A bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro or bridged ring optionally being selected from 1 to 2 of F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatom is selected from S;
q is each independently selected from 0, 1, 2, 3 or 4;
R L each independently selected from H or C 1-6 An alkyl group;
the remaining definitions are the same as in the first embodiment of the invention.
As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally 1 to 2 are selected from F, cl, br, I, OH, CN、NH 2 、CF 3 Hydroxymethyl, C 1-4 Alkyl, C 1-4 Substituted with alkoxy;
R L each independently selected from H or C 1-4 An alkyl group;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered nitrogen containing heteromonocyclic ring, a 4-10 membered nitrogen containing heterobicyclic ring, a 5-12 membered nitrogen containing heterospiro ring, a 7-10 membered nitrogen containing heterobridged ring, and C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said heteromonocyclic, heterobicyclic, heterobridged, heterospiro, cycloalkyl, aryl or heteroaryl optionally being selected from 1 to 2 of F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteromonocyclic, heterobicyclic, heterobridged, heterospiro or heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatoms are selected from S;
Z is selected from O, S, -CH=, N (R) Z )、-N(R Z )C(＝O)-、-C(＝O)N(R Z )-、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-CH 2 S-、-CH 2 CH 2 S-、-CH 2 S(＝O) 2 -、-CH 2 CH 2 S(＝O) 2 -、-N(R Z )CH 2 -、-N(R Z )CH 2 CH 2 -、-CH 2 N(R Z )-、-CH 2 CH 2 N(R Z )-、-N(R Z )C(＝O)CH 2 -or-CH 2 C(＝O)N(R Z ) -, the CH 2 Optionally further 0 to 2 are selected from H, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
R Z each independently selected from H, methyl, ethyl, propyl, isopropyl or cyclopropyl, said methyl, ethyl, propyl, isopropyl or cyclopropyl optionally being substituted with 1 to 4 groups selected from deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, 3-to 6-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S or N;
ring W is selected from C 3-7 Carbocycles or 3-to 8-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R t1 、R t2 or R is t3 Each independently selected from H, F, cl, br, I, cyano, NH 2 、NO 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
or two R t1 Two R t2 Two R t3 Respectively and directly connected with atoms to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl and piperidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl and piperidinyl are optionally substituted by 1 to 3 atoms selected from halogen, OH, cyano and NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R Y selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, optionally substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or- (CH) 2 ) t4 NR A1 R A2 The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl are optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R B selected from H, OH, - (CH) 2 ) t4 NR B1 R B2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinylOptionally from 1 to 4 are selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R C selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and,The pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl are optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a 3 to 8 membered heterocyclic ring substituted with a substituent, said heterocyclic ring or heteroaryl containing 1 to 3 heteroatoms selected from O, S, N;
or R is C And R is R 3b And the atoms to which they are directly attached form a 5-8 membered heterocyclic ring, said heterocyclic ring optionally being substituted with 1 to 4 atoms selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A1 、R B1 、R B2 each independently selected from H, OH, NH 2 、NH(C 1-4 Alkyl group), NH (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 Carbocycle or 4-8 membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A2 selected from C 2-4 Alkenyl, C 2-4 Alkynyl, NH (C) 1-4 Alkyl group), NH (C) 1-4 Alkyl group 2 4-7 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, 5-to 10-membered heteroaryl or 6-to 10-membered aryl, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R C1 each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R 3a or R is 4 Each independently selected from H, OH, NH 2 Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl optionally being substituted with 1 to 3 substituents selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl group,Hydroxy-substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R 3b or R is 5 Each independently selected from H, F, cl, br, I, cyano, NH 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
k1 is selected from
K2 is selected from
K3 is selected from
A is selected from C 3-8 A carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S or N;
f are each independently selected from C 3-7 Monocyclic carbocycle, C 4-10 Carbocyclic ring, C 5-12 Spiro carbocycles, C 5-10 Bridged ring carbocycle, 4-7 membered heteromonocyclic ring, 4-10 membered heterofused ring, 8-15 membered heterofused ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 Aryl, 5-10 membered heteroaryl, The heteromonocyclic, heterobicyclic, heterospiro, heterobridged or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S or N;
represents a ring selected from aromatic or non-aromatic rings;
e is each independently selected from C 3-10 A carbocycle, a benzene ring, a 4-12 membered heterocycle, a 5-12 membered heteroaryl ring containing 1 to 4 heteroatoms selected from O, S or N;
q is each independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 4-7 membered heterocycle, said heterocycle optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R q selected from H or C 1-4 An alkyl group;
R k1 、R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 4 groups selected from F, cl, br, I, OH or NH 2 Is substituted by a substituent of (2);
or two R k3 And carbon atoms or ring skeletons directly attached to both form C 3-6 Carbocycle or 3-7 membered heterocycle, two R k1 And twoDirectly linked to a carbon atom or ring skeleton to form C 3-6 Carbocycles or 3-7 membered heterocycles, optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R k4 each independently selected from H, OH, NH 2 、CF 3 CN or C 1-4 An alkyl group;
R k5 each independently selected fromC(CH 3 ) 2 、CO、CH 2 、CH 2 CH 2 、SO 2 、
R k6 Each independently selected from CO, CH, SO, SO 2 、CH 2 N or NR k7a ；
R k7 Each independently selected fromC(CH 3 ) 2 、CO、CH、N、CH 2 、O、S、NR k7a ；
R k8 Each independently selected from C, N or CH;
R k9 each independently selected from the group consisting of a bond,C(CH 3 ) 2 、CO、CH 2 、CH 2 CH 2 Or SO 2 ；
R ka Selected from O, S or NH;
R k7a selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally beingIs selected from F, cl, br, I, OH, NH by 1 to 4 2 、CN、CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Substituted cycloalkyl;
R k14 selected from the group consisting of
The remaining definitions are the same as in the first or second embodiment of the invention.
As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally 1 to 2 are selected from F, cl, br, I, OH, CN, NH 2 、CF 3 A hydroxymethyl, methyl, ethyl, methoxy or ethoxy substituent;
R L selected from H, methyl or ethyl;
q is each independently selected from 0, 1, 2 or 3;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azepinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazepinyl, phenyl, pyridine, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl A group, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirocyclopentyl, cyclopropyl-spirocyclohexyl, cyclobutyl-spirobutyl, cyclobutyl-spiropentyl, cyclobutyl-spirohexyl, cyclopentyl-spirocyclopentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl, cyclopropyl-azetidinyl cyclopropyl-pyrrolidinyl, cyclopropyl-piperidinyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidinyl, cyclobutyl-piperidinyl, cyclopentyl-azetidinyl, cyclopentyl-pyrrolidinyl cyclopentyl, cyclohexyl and azetidinyl, cyclohexyl and pyrrolidinyl, cyclohexyl and piperidinyl, azetidinyl and azetidinyl, azetidinopyrrolidinyl, azetidinopiperidyl, and combinations thereof pyrrolidinyl azetidinyl, pyrrolidinyl pyrrolidyl, pyrrolidinyl piperidyl, piperidinyl azetidinyl, piperidinyl pyrrolidinyl, piperidinyl piperidyl, cyclopropylpyrimidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidinyl, cyclobutylspiropiperidinyl, cyclopentylpyrispiroazetidinyl, cyclopentylpyristyl, cyclopentylpyrimidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, azetidinyl spiroazetidinyl, azetidinyl spiropyrrolidinyl, azetidinyl spiropiperidinyl, pyrrolidinyl spiropyrrolidinyl, pyrrolidinyl spiropiperidinyl, piperidinylspiroazetidine, piperidinylspiropyrrolidinyl spiropyrrolidinyl, piperidinyl spiro
When substituted, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2 、COOH、CN、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy radical extractionSubstituted C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
x is selected from O or S;
y1 is selected from NH or O;
y2 is selected from NH, O or S;
z is selected from-NHC (=O) -, -C (=O) NH-, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-NHCH 2 -、-NHCH 2 CH 2 -、-CH 2 NH-、-CH 2 CH 2 NH-、-NHC(＝O)CH 2 -、-CH 2 C(＝O)NH-、O、S、NH、-CH＝、-N(CH 3 )C(＝O)-、-C(＝O)N(CH 3 )-、-CH 2 C(＝O)NH-、-CH 2 C(＝O)N(CH 3 )-、-N(CH 2 CH 3 )C(＝O)-、-N(CH(CH 3 ) 2 )C(＝O)-、-N(CH 2 CH(CH 3 ) 2 ) C (=o) -, -N (cyclopropyl) C (=o) -, -N (CH) 2 -cyclopropyl) C (=o) -, -N (CH) 2 -ethynyl) C (=o) -, -C (=o) N (CH) 2 CH 3 )-、-C(＝O)N(CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 ) 2 ) -, -C (=O) N (cyclopropyl) -or-C (=O) N (CH) 2 -cyclopropyl) -;
the ring W is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1, 4-diazaheptanyl, and azepanyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1, 4-diazaheptanyl, and azepanyl being optionally substituted with 1 to 3 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
R t1 、R t2 or R is t3 Each independently selected from H, F, cl, br, I, cyano, NH 2 、NO 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropylSaid methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
or two R t1 And the atoms directly attached thereto form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted by 1 to 3 atoms selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
R A selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or- (CH) 2 ) t4 NR A1 R A2 The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
R B selected from H, OH, - (CH) 2 ) t4 NR B1 R B2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl optionally being selected from 1 to 4 of F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl, ethyl and cyclopropyl;
R C selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and,The pyrrolyl, pyrazolyl, imidazolyl and pyridylOptionally 1 to 4 of pyrimidinyl, pyrazinyl, pyridazinyl, and/or pyridinyl, selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl, ethyl and cyclopropyl;
or R is C And R is R 3b And atoms directly attached thereto formSaid->Optionally from 1 to 4 are selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl, ethyl and cyclopropyl;
R A1 、R B1 、R B2 each independently selected from H, OH, NH 2 NH (methyl), NH (ethyl), NH (propyl), NH (isopropyl), NH (methyl) 2 NH (ethyl) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituted by methyl, ethyl, methoxy, ethyl, cyclopropyl;
R A2 selected from one of the following substituted or unsubstituted: vinyl, ethynyl, propargyl, propynyl, NH (methyl), NH (ethyl), NH (propyl), NH (isopropyl), NH (methyl) 2 NH (ethyl) 2 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,Adamantyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, triazolyl, oxazolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, and, When substituted, optionally substituted with 1 to 4 groups F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituted by methyl, ethyl, methoxy, ethyl, cyclopropyl;
R C1 each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl optionally being selected from F, cl, br, I, OH, cyano, NH 1 to 4 2 、CF 3 Substituted by methyl, ethyl, methoxy, ethyl, cyclopropyl;
R 3a selected from H, OH, NH 2 Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl optionally being substituted with 1 to 3 substituents selected from F, cl, br, I, OH, cyano, NH 2 Substituents such as methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
R 4 each independently selected from H, methyl, ethyl, cyclopropyl;
R 3b each independently selected from H, F, cl, br, I, OH, methyl, ethyl, cyclopropyl;
R 5 each independently selected from H, F, cl, br, I, cyano, NH 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, said methyl, ethyl, propylOptionally 1 to 3 radicals selected from F, cl, br, I, OH, cyano, NH, and isopropyl, methoxy, ethoxy, propoxy, isopropoxy, and cyclopropyl 2 Methyl, ethyl, cyclopropyl;
k1 is selected from
K4 is selected from
Q is selected from a bond, C (=o);
q1 is selected from bond, CH 2 、NH、N(CH 3 )、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH 3 )C(＝O)、C(＝O)N(CH 3 )、
Q2 is selected from bond, CH 2 、O、S、C(＝O)、NHC(＝O)、N(CH 3 )C(＝O)；
E. Each a is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxazole ring;
f is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1]Pentanyl, 6, 7-dihydro-5H-cyclopenta [ c ]]Pyridyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridoimidazolyl, benzoimidazolyl, and the like Imidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, and imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidinopyridinyl, pyrimidinopyrazinyl, pyrimidinopyridazinyl, pyrimidinopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyridines, indolothiophenes, indolofurans, The left side of the connecting rod is directly connected with L;
R ka selected from O, S or NH;
R k7 each independently selected fromC(CH 3 ) 2 、CH 2 、O、N(CH 3 )、N(CH 2 CH 3 ) N (cyclopropyl) or NH;
R k7a selected from H, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl Optionally from 1 to 4, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are selected from F, cl, br, I, OH, CN, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 Substituted cycloalkyl;
p1 or p2 are each independently selected from 0, 1, 2 or 3;
the remaining definitions are the same as in the first, second or third embodiments of the invention.
As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from the group consisting of bond, -O-, -OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-C≡C-、-C(CH 3 ) 2 -、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-N(CH 3 )-、-NH-、-CH 2 N(CH 3 )-、-CH 2 NH-、-NHCH 2 -、-CH 2 CH 2 N(CH 3 )-、-CH 2 CH 2 NH-、-NHCH 2 CH 2 -、-C(＝O)-、-C(＝O)CH 2 NH-、-CH 2 C (=o) NH-, -C (=o) NH-or-NHC (=o) -;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups:
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when substituted, is selected from the group consisting of F, CF by 1 to 4 3 OH, methyl, =O, hydroxymethyl, COOH, CN or NH 2 Is substituted by a substituent of (2);
b is selected from one of the structural fragments shown in Table B-1;
K is selected from one of the structural fragments shown in the table K-1;
the remaining definitions are the same as in the first, second, third or fourth embodiments of the invention.
As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
-Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, and-Cy 1-Ak1-Ak2-Ak3-Ak 4-; -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-Ak4-, and-Cy 1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy 3-Ak3-Cy 1-Ak2-Cy3-, cy1-Ak 2-Cy3-Ak3- -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy 3-Cy4-Ak 1-Cy2-Ak 3-Cy 4-; -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Cy3-, -Ak1-Cy 3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy3-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy3-Ak 4-Ak5- -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak 5-; -Ak1-Cy2-Ak 3-Ak4-Ak5-, -Ak1-Cy2-Ak 3-Ak4-, -Ak1-Cy2-Ak 3-;
The remaining definitions are the same as in the first, second, third, fourth or fifth embodiments of the invention.
As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
l is selected from a bond or one of the structural fragments shown in Table L-1, wherein the left side of the group is attached to B;
the remaining definitions are the same as in the first, second, third, fourth, fifth or sixth embodiments of the invention.
As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
l is selected from a bond or one of the structural fragments shown in Table L-2, wherein the left side of the group is attached to B;
k is selected from one of the structural fragments shown in the table K-2;
the remaining definitions are the same as for the first, second, third, fourth, fifth, sixth or seventh embodiments of the invention.
As a ninth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound represented by the general formula (I) is selected from the group consisting of the compounds represented by the general formula (II-1) and the general formula (II-2),
B is selected from one of the structural fragments shown in Table B-2;
cy1 or Cy2 are each independently selected from one of the following substituted or unsubstituted groups:
when substituted, is selected from the group consisting of F, CF by 1 to 4 3 OH, methyl, =O, hydroxymethyl, COOH, CN or NH 2 Is substituted by a substituent of (2);
ak1 is selected from CH 2 、CH 2 CH 2 、O、NH、CO、N(CH 3 ) Or C (CH) 3 ) 2 ；
R k1 Selected from F, cl, br, CF 3 OH, methyl, =O, hydroxymethyl, COOH, CN or NH 2 ；
p1 is selected from 0, 1 or 2.
As a tenth embodiment of the present invention, the compound represented by the aforementioned general formula (II-1) or (II-2) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
b is selected from/>
-Cy1-AK1-Cy 2-is selected from one of the fragments shown in Table L-3, preferably
R k1 Selected from F;
p1 is selected from 0 or 1.
The present invention relates to a compound selected from one of the following structures S-1 in table:
table S-1
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The invention relates to a pharmaceutical composition comprising a compound of the invention or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
The invention relates to an application of the compound or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic thereof in preparing medicines for treating diseases related to Bcl6 activity or expression level.
The invention relates to an application of the compound or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic thereof in preparing medicines for treating and inhibiting or degrading Bcl6 related diseases.
The invention relates to the use of the above compounds of the invention or stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, characterized in that the disease is selected from cancer.
The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in unit dosage form (the amount of the main drug in a unit dosage form is also referred to as "formulation specification").
The present application also provides a method for treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the application or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition. In some embodiments, the mammal of the present application comprises a human.
By "effective amount" or "therapeutically effective amount" in the present application is meant that a sufficient amount of a compound of the present disclosure is administered that will alleviate to some extent one or more symptoms of the disease or disorder being treated (e.g., cancer). In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is that amount comprising a compound of the present disclosure that is required to provide clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 25-500mg 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;
In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500mg, 1-600mg, 20-400mg, 25-200mg, 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg of a compound of the invention or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof.
A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of the invention, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, preferably 1-1500mg, said disease being preferably cancer.
A method for treating a disease in a mammal comprising administering a pharmaceutical compound of the invention, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, to a subject in a daily dose of 1-1500 mg/day, which may be a single dose or divided doses, and in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, and in some embodiments, the daily dose includes, but is not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1500 mg/day, 2000 mg/day.
The present application relates to a kit comprising a single or multiple dose form of a composition comprising a compound of the application or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in an amount equivalent to that in the pharmaceutical composition described above.
The amount of a compound of the application or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof in the present application is in each case converted in the form of the free base.
Unless stated to the contrary, the terms used in the specification and claims of the present application have the following meanings.
"formulation specification" refers to the weight of the principal drug contained in each individual, tablet or other unit of formulation.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the application each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the application are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"halogen" means F, cl, br or I.
"halo substituted" means F, cl, br or I substituted, including but not limited to 1 to 10 substituents selected from F, cl, br or I, 1 to 6 substituents selected from F, cl, br or I, preferably 1 to 4 substituents selected from F, cl, br or I. "halo substituted" is simply referred to as "halo".
"alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group including, but not limited to, alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; alkyl groups appearing herein are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent, or tetravalent.
"alkylene" means a substituted or unsubstituted straight and branched chain divalent saturated hydrocarbon radical, including- (CH) 2 ) v - (v is an integer of 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, butylene and the like.
"cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl groups as herein presented are defined as described above. Cycloalkyl groups may be monovalent, divalent, trivalent, or tetravalent.
"heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group including, but not limited to, 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl group being oxidizable to various oxidation states. Heterocycloalkyl groups can be attached to heteroatoms or carbon atoms, heterocycloalkyl groups can be attached to aromatic or non-aromatic rings, and heterocycloalkyl groups can be attached to bridged or spiro rings, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocyclylalkyl can be monovalent, divalent, trivalent, or tetravalent
"alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbyl groups having at least 1, typically 1, 2 or 3 carbon-carbon double bonds, the backbone including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, alkenyl examples including but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl and the like; alkenyl groups appear herein, the definition of which is consistent with the definition. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.
"alkynyl" refers to substituted or unsubstituted straight and branched monovalent unsaturated hydrocarbon radicals having at least 1, typically 1, 2 or 3 carbon triple bonds, the backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone, examples of alkynyl radicals include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 1-4-decynyl, and the like; alkynyl groups may be monovalent, divalent, trivalent or tetravalent.
"alkoxy" refers to a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy.
"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring, or a 10 to 15 membered tricyclic ring system, and carbocyclyl may be attached to an aromatic or non-aromatic ring, which may be aromatic or non-aromaticThe ring is optionally a monocyclic, bridged or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,"carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent, or tetravalent.
"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring that may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system and that contains 1 or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O or S, and C, N, S optionally substituted in the ring of the heterocyclyl can be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridged ring or a spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, pyridinyl, furanyl, thiophenyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [ 3.1.1 ] ]Octyl and azabicyclo [5.2.0]Nonylalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]Heptyl radical,
"heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent, or tetravalent.
"Spiro" or "spirocyclic group" refers to a polycyclic group having one atom (referred to as a spiro atom) shared between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spirocyclic ring system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 members selected from N, O or S (=O) n Is a heteroatom of (2). Non-limiting embodiments include:
"Spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.
"fused ring" or "fused ring group" refers to a polycyclic group wherein each ring in the system shares an adjacent pair of atoms with the other rings in the system, wherein one or more of the rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (=o) n Or O, n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:
"fused" or "fused-ring" groups may be monovalent, divalent, trivalent, or tetravalent.
"bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly attached, which may contain 0 or more double bonds, and any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S (=o) n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include
Cubane and adamantane. "bridged ring" or "bridged ring radical" can be monovalent, divalent, trivalent, or tetravalent.
"carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spiro" ring system consisting of only carbon atoms. "carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" as referred to herein are defined in accordance with spirocyclic rings.
"carbon-fused", "fused carbocyclyl" or "carbon-fused cyclic" refers to a "fused ring" in which the ring system has only carbon atoms. "carbo-cyclic", "carbocyclyl" or "carbo-cyclic" as used herein is defined as consistent with a carbo-cyclic group.
"carbon bridged ring", "bridged carbocyclyl" or "carbon bridged cyclyl" refers to a "bridged ring" in which the ring system has only carbon atoms. "carbobridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged ring radical" as used herein is defined as being identical to a bridged ring.
"heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to a "heterocyclyl" or "heterocycle" of a monocyclic system, and the heterocyclic groups, "monocyclic heterocyclyl" or "heteromonocyclic" appearing herein are defined as identical to heterocycles.
"heterobicyclic", "heterobicyclic radical", "fused-to-heterocyclic radical" or "heterobicyclic radical" refers to a "fused ring" containing a heteroatom. The "heteroacene", "heteroacenyl", "fused-ring heterocyclyl" or "heteroacenyl" as presented herein are defined in accordance with the fused ring.
"Heterospiro", "spirocyclic heterocyclyl" or "Heterospiro" refers to a "spiro" containing heteroatoms. As used herein, a heterospiro, "spiroheterocyclyl," or "heterospiro" is defined as a spiro.
"heterobridged", "bridged heterocyclyl" or "heterobridged heterocyclyl" refers to a "bridged ring" that contains a heteroatom. The term "heterobridged ring," as used herein, refers to a bridged ring, or a bridged ring.
"aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is an aryl ring, non-limiting examples of which include benzene rings, naphthalene rings,The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the aryl ring.
"heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (=o) n, n being 0, 1, 2), heteroaryl ringsThe number of ring atoms includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include Heteroaryl groups as herein appear, the definition of which is consistent with the definition. Heteroaryl groups may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment sites are located on the heteroaryl ring.
"5 membered ring and 5 membered heteroaryl ring" refers to a fused heteroaryl ring of 5 and 5 members, at least 1 of the 2 rings containing more than 1 heteroatom (including but not limited to O, S or N), the entire group having aromaticity, non-limiting examples including pyrrolopyrrole rings, pyrazolopyrrole rings, pyrazolopyrazole rings, pyrrolofuran rings, pyrazolofuran rings, pyrrolothiene rings, pyrazolothiophene rings.
"5-and 6-membered heteroaryl ring" refers to a fused 5-and 6-membered heteroaryl ring, at least 1 of the 2 fused rings containing more than 1 heteroatom (including but not limited to O, S or N), the entire group having aromaticity, non-limiting examples including benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl rings.
"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2, 3, 4, or 5) substituents including but not limited to H, F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate, - (CH) 2 ) m -C(＝O)-R a 、-O-(CH 2 ) m -C(＝O)-R a 、-(CH 2 ) m -C(＝O)-NR b R c 、-(CH 2 ) m S(＝O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d Or- (CH) 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed. R is R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring.
"containing 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
"substituted with 1 to X substituents" means substituted with 1, 2, 3 … X substituents, X being selected from any integer between 2 and 10. The term "substituted with 1 to 4 substituents" means substituted with 1, 2, 3 or 4 substituents. By "substituted with 1 to 5 substituents" is meant substituted with 1, 2, 3, 4 or 5 substituents. By "the hetero-bridge ring is optionally substituted with 1 to 4 substituents selected from H or F" is meant that the hetero-bridge ring is optionally further substituted with 1, 2, 3 or 4 substituents selected from H or F.
The X-Y membered ring (X is selected from integers less than Y and greater than 3 and Y is selected from any integer between 4 and 12) includes X, X +1, X+2, X+3, X+4 … Y membered rings. The ring includes heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means 4-, 5-, 6-or 7-membered heteromonocyclic ring, and "5-10 membered heteromonocyclic ring" means 5-, 6-, 7-, 8-, 9-or 10-membered heteromonocyclic ring.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to one or more compounds of the present invention, or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and mixtures of other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers, diastereomers, and conformational isomers.
"tautomer" refers to a functional group isomer produced by rapid movement of an atom in a molecule at two positions, such as keto-enol isomers and amide-imine alcohol isomers.
“IC 50 "is the concentration of drug or inhibitor required to inhibit half of a given biological process (or a component of the process such as an enzyme, receptor, cell, etc.).
Detailed Description
The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a (Bruker Avance III and Bruker Avance 300) magnetonuclear apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);
thin layer chromatography silica gel plate using tobacco stand yellow sea HSGF 254 Or Qingdao GF 254 The silica gel plate used in Thin Layer Chromatography (TLC) has a specification of 0.15-0.20 mm, and the thin layer chromatography separation and purification product has a specification of 0.4-0.5 mm;
column chromatography generally uses 200-300 mesh silica gel of yellow sea of tobacco stand as carrier;
boc: a tert-butoxycarbonyl group;
ts: p-toluenesulfonyl;
cbz: a benzyloxycarbonyl group;
TMS: trimethylsilyl group.
Example 1: preparation of Compound 1
The first step: 1b preparation
To the reaction flask were added 1a (0.247 g,0.89 mmol) respectively (see CN112538083 for synthesis), HATU (0.51 g,1.34 mmol) and 10mL of N, N-dimethylformamide, and after stirring at room temperature for 2min, cyclopropylamine (0.16 g,2.8 mmol) and diisopropylethylamine (0.34 g,2.63 mmol) were added and reacted at room temperature for 16h. The reaction solution was poured into 50mL of water, filtered, and the cake was collected and concentrated under reduced pressure to give crude 1b (0.20 g).
LCMS m/z＝318.1[M+1] +
And a second step of: 1c preparation
To the reaction flask were added the above crude product 1b (0.20 g), 0.2g of 10% palladium on carbon and 5mL of N, N-dimethylformamide, replaced with hydrogen three times, and reacted at room temperature under a hydrogen balloon atmosphere for 2 hours. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to give crude 1c (0.19 g).
LCMS m/z＝288.2[M+1] +
And a third step of: 1d preparation
To the reaction flask were added the crude 1c (0.19 g), 2,4, 5-trichloropyrimidine (0.14 g,0.76 mmol) and diisopropylethylamine (0.16 g,1.24 mmol), 5mL of N, N-dimethylformamide, and the mixture was heated to 70℃to react for 2 hours. The reaction solution was cooled to room temperature, poured into 50mL of water, filtered, and the filtrate was concentrated under reduced pressure to give crude 1d (0.15 g).
LCMS m/z＝434.1[M+1] +
Fourth step: preparation of Compound 1
To the reaction flask were added the crude 1d (0.15 g), 2- (2, 6-dioxopiperidin-3-yl) -4- (4- (piperazin-1-ylmethyl) piperidin-1-yl) isoindoline-1, 3-dione (0.15 g,0.34 mmol) (see WO2021077010 for synthesis), diisopropylethylamine (0.23 g,1.78 mmol) and 5mL dimethyl sulfoxide, respectively, and the mixture was reacted at 100℃for 7h. The reaction solution was cooled to room temperature, poured into 50mL of water, filtered, the cake was collected, the cake was slurried with 10mL of methanol, filtered, and the cake was subjected to Pre-HPLC (instrument and preparation column: preparation of liquid phase using GILSON, preparation column model was phenomenoxc 18,5 μm, inner diameter×length=30 mm×150 mm). The preparation method comprises the following steps: the crude product was dissolved in DMSO and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: ammonium acetate in water (5 mmol/L)/acetonitrile. The gradient elution method comprises the following steps: acetonitrile was eluted with a 20% gradient (elution time 15 min), and lyophilized to give Compound 1 (30 mg, yield: 11%).
1 H NMR(400MHz,DMSO-d 6 )δ11.02(br.s,1H),8.84(s,1H),8.18–8.09(m,1H),8.05(s,1H),7.96–7.90(m,1H),7.80–7.72(m,1H),7.71–7.62(m,1H),7.52–7.43(m,1H),7.38–7.27(m,2H),7.11(s,1H),5.13–5.02(m,1H),4.55(s,2H),3.78–3.55(m,9H),2.96–2.79(m,3H),2.75–2.65(m,1H),2.65–2.51(m,2H),2.46–2.35(m,4H),2.28–2.15(m,2H),2.10–1.95(m,1H),1.90–1.75(m,3H),1.41–1.21(m,2H),0.69–0.58(m,2H),0.51–0.43(m,2H).
LCMS m/z＝837.3[M+1] +
Example 2: preparation of the trifluoroacetate salt of Compound 2
The first step: 2a preparation
To the reaction flask were added 1a (0.30 g,1.08 mmol) (see CN112538083 for synthesis), HATU (0.62 g,1.63 mmol) and DMF (5 mL), respectively, and after stirring at room temperature for 2min, 2-difluorocyclopropylamine hydrochloride (0.42 g,3.24 mmol) and DIPEA (0.54 mL) were added and reacted at room temperature for 16h. The reaction solution was poured into 20mL of water, filtered, and the cake was dried under reduced pressure to give crude 2a (0.16 g).
LCMS m/z＝354.3[M+1] +
And a second step of: 2b preparation
To the reaction flask were added crude 2a (0.16 g), 10% palladium on carbon (0.1 g), methylene chloride (6 mL) and methanol (3 mL), respectively, replaced with hydrogen three times, and reacted at room temperature under a hydrogen balloon atmosphere for 2 hours. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to give crude 2b (0.14 g).
LCMS m/z＝324.1[M+1] +
And a third step of: 2c preparation
To the reaction flask were added crude 2b (0.14 g), 2,4, 5-trichloropyrimidine (0.29 g,1.58 mmol) and DIPEA (0.29 g,2.24 mmol), respectively, and DMF (5 mL) was added and reacted at 70℃for 2h. The reaction system was cooled to room temperature, the reaction solution was poured into water (50 mL), filtered, and the cake was dried under reduced pressure to give crude 2c (0.14 g).
LCMS m/z＝470.1[M+1] +
Fourth step: preparation of trifluoroacetate salt of Compound 2
To the reaction flask were added crude 2c (50 mg), 2- (2, 6-dioxopiperidin-3-yl) -4- (4- (piperazin-1-ylmethyl) piperidin-1-yl) isoindoline-1, 3-dione (58 mg,0.13 mmol) (see WO2021077010 for synthesis), DIPEA (0.14 g,1.08 mmol) and DMSO (5 mL), respectively, and reacted at 100℃for 7h. The reaction was cooled to room temperature and subjected to Pre-HPLC (apparatus and preparative column: preparation of liquid phase using Waters 2767, preparative column model sunfire@prep C18,5 μm, inner diameter×length=19 mm×250 mm). The preparation method comprises the following steps: the crude DMSO solution was filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid)/acetonitrile. The gradient elution method comprises the following steps: acetonitrile was eluted with a 10% gradient 50% (elution time 12 min), and lyophilized to give the trifluoroacetate salt of compound 2 (30 mg).
1 H NMR(400MHz,DMSO-d 6 )δ11.07(s,1H),9.06(s,1H),8.59(s,1H),8.16(s,1H),7.93–7.84(m,1H),7.81–7.64(m,2H),7.54–7.45(m,1H),7.40–7.30(m,2H),7.15(s,1H),5.14–5.03(m,1H),4.68(s,2H),4.60–4.42(m,2H),3.78–3.52(m,7H),3.42–3.23(m,3H),3.20–2.80(m,7H),2.70–2.50(m,2H),2.18–1.77(m,5H),1.68–1.36(m,3H).
LCMS m/z＝873.3[M+1] +
Example 3: preparation of Compound 3
The first step: preparation of 3a
To the reaction flask was added 1a (0.20 g,0.72 mmol) (see CN112538083 for synthesis), HATU (0.41 g,1.08 mmol) and DMF (5 mL), respectively, and after stirring at room temperature for 2min, trans-2-fluorocyclopropane-1-amine hydrochloride (0.24 g,2.15 mmol) and DIPEA (0.28 g,2.17 mmol) were added and reacted at room temperature for 16h. The reaction solution was poured into 20mL of water, filtered, and the cake was dried under reduced pressure to give crude 3a (0.12 g).
And a second step of: preparation of 3b
To the reaction flask were added crude 3a (0.12 g), 10% palladium on carbon (0.1 g), methylene chloride (6 mL) and methanol (3 mL), respectively, replaced with hydrogen three times, and reacted at room temperature under a hydrogen balloon atmosphere for 2 hours. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to give crude 3b (0.11 g).
LCMS m/z＝306.2[M+1] +
And a third step of: preparation of 3c
To the reaction flask were added crude 3b (0.11 g), 2,4, 5-trichloropyrimidine (0.07 g,0.38 mmol) and triethylamine (0.12 g,1.19 mmol), respectively, and DMF (5 mL) was added and reacted at 70℃for 2h. The reaction system was cooled to room temperature, the reaction solution was poured into water (50 mL), filtered, and the cake was dried under reduced pressure to give crude 3c (0.12 g).
Fourth step: preparation of Compound 3
To the reaction flask were added crude 3c (40 mg), 2- (2, 6-dioxopiperidin-3-yl) -4- (4- (piperazin-1-yl) methyl) piperidin-1-yl) isoindoline-1, 3-dione (46 mg,0.103 mmol) (see WO 2021077010), DIPEA (57 mg,0.44 mmol) and DMSO (5 mL), respectively, and reacted at 100deg.C for 7h. The reaction was cooled to room temperature and subjected to Pre-HPLC (apparatus and preparative column: preparation of liquid phase using Waters 2767, preparative column model sunfire@prep C18,5 μm, inner diameter×length=19 mm×250 mm). The preparation method comprises the following steps: the crude DMSO solution was filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: aqueous ammonium acetate (5 mmol/L)/acetonitrile. The gradient elution method comprises the following steps: acetonitrile was eluted with a gradient of 10% (elution time 15 min), and lyophilized to give compound 3 (20 mg, yield: 23%).
1 H NMR(400MHz,DMSO-d 6 )δ11.07(s,1H),8.84(s,1H),8.30–8.15(m,1H),8.05(s,1H),7.99–7.90(m,1H),7.83–7.60(m,2H),7.53–7.42(m,1H),7.38–7.25(m,2H),7.12(s,1H),5.15–5.02(m,1H),4.82–4.52(m,3H),3.77–3.57(m,9H),3.14–3.00(m,1H),2.96–2.80(m,3H),2.69–2.52(m,2H),2.46–2.34(m,4H),2.29–2.16(m,2H),2.10–1.95(m,1H),1.90–1.70(m,3H),1.40–1.20(m,3H),1.04–0.90(m,1H).
LCMS m/z＝855.3[M+1] + 。
Example 4: preparation of Compound 4 trifluoroacetate salt
The first step: preparation of 4B
4A (0.2G, 0.75 mmol) (see WO 2017197046) and tert-butyl 4- (piperidin-4-ylmethyl) piperazine-1-carboxylate (0.32G, 1.13 mmol) (see WO 2020201080), ruPhos Pd G3 (0.13G, 0.16 mmol) and RuPhos (0.07G, 0.15 mmol) were added separately to the flask under nitrogen, 5mL toluene and LiHMDS in THF (4.5 mL,1 mol/L) were added and reacted at 80℃for 1.5h. The reaction solution was cooled to 0℃and quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (30 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography over silica gel (dichloromethane/methanol (v/v) =10:1) to give 4B (0.09 g, yield: 25%).
LCMS m/z＝471.6[M+1] + 。
And a second step of: preparation of 4C trifluoroacetate salt
To the reaction flask were added 4B (0.09 g,0.19 mmol), 1.0mL trifluoroacetic acid and 2mL dichloromethane and reacted at room temperature for 2h. The reaction solution was concentrated under reduced pressure to give crude 4C trifluoroacetate salt (0.09 g).
And a third step of: 4b preparation
4a (2.0 g,7.19 mmol) (see CN112538083 for synthesis), DIPEA (2.79 g,21.59 mmol), propargylamine (0.79 g,14.34 mmol) and HATU (5.47 g,14.39 mmol) were dissolved in dichloromethane (20 mL) and reacted at room temperature for 16h. To the reaction solution were added 20mL of water and 10mL of methylene chloride, the aqueous phase was extracted with methylene chloride (10 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (methylene chloride/methanol (v/v) =10:1) to give 4b (0.4 g, yield: 18%).
LCMS m/z＝316.4[M+1] + 。
Fourth step: 4c preparation
4b (0.3 g,0.95 mmol), iron powder (0.32 g,5.71 mmol) and ammonium chloride (0.51 g,9.5 mmol) were dissolved in ethanol (10 mL) and water (1 mL) and reacted under reflux for 1h. The reaction system was cooled to room temperature, filtered through celite, 10mL of saturated aqueous sodium chloride and 20mL of methylene chloride were added to the filtrate, the aqueous phase was extracted with methylene chloride (10 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (methylene chloride/methanol (v/v) =10:1) to give 4c (0.23 g, yield: 77%).
LCMS m/z＝286.3[M+1] + 。
Fifth step: preparation of 4d
To the reaction flask was added 4c (0.23 g,0.81 mmol), 2,4, 5-trichloropyrimidine (0.18 g,0.98 mmol), triethylamine (0.16 g,1.58 mmol) and 5mL DMF and reacted at 70℃for 4h. The reaction solution was cooled to room temperature, poured into 30mL of ice water, filtered, and the cake was dried under reduced pressure to give crude 4d (0.23 g).
Sixth step: preparation of Compound 4 trifluoroacetate salt
To the reaction flask were added the above crude 4C trifluoroacetate salt (0.17 g), DIPEA (0.30 g,2.32 mmol) and 5mL DMSO, respectively, and the above crude 4d (0.20 g) was added and reacted at 100℃for 7 hours. The reaction system was cooled to room temperature and the reaction solution was subjected to Pre-HPLC (apparatus and preparative column: preparation of liquid phase using Waters 2767, preparative column model is sunfire@prep C18,5 μm, inner diameter×length=19 mm×250 mm). The preparation method comprises the following steps: the crude DMSO solution was filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: water (with 0.1% tfa)/acetonitrile. The gradient elution method comprises the following steps: acetonitrile was eluted with a 10% gradient (elution time 15 min) and lyophilized to give the trifluoroacetate salt of compound 4 (150 mg).
1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),9.07(s,1H),8.48(t,1H),8.15(s,1H),7.90(d,1H),7.73(dd,1H),7.48(d,1H),7.17(s,1H),7.14–7.06(m,2H),7.06–6.95(m,2H),4.64(s,2H),4.59–4.40(m,2H),3.98–3.89(m,2H),3.82–3.65(m,6H),3.65–3.51(m,2H),3.40–3.25(m,2H),3.15–2.95(m,5H),2.89–2.72(m,2H),2.72–2.57(m,1H),2.50–2.41(m,1H),2.24–1.95(m,3H),1.94–1.76(m,2H),1.47–1.30(m,2H).LCMS m/z＝383.8[M/2+1] + 。
Biological test case
1. SU-DHL-6 cell proliferation assay
Lymphoma SU-DHL-6 cells purchased from ATCC were placed in RPMI-1640 complete medium (containing 15% fetal bovine serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin) at 37℃with 5% CO 2 Culturing under the condition. Collecting cells in logarithmic phase, adjusting cell suspension to proper density with culture medium, adding 3000 cells/well into 96-well culture plate, adding test compound at different concentrations, and adding 5% CO at 37deg.C 2 Culturing was continued under the conditions. After 5 days, the cells were mixed with a pipette, 1/10 of the cells were removed to a new 96-well plate, and the incubation was continued for 5 days with the addition of the drug-containing medium. After the incubation, 75. Mu.L of CTG solution equilibrated to room temperature was added to each well according to the protocol of CellTiter-Glo kit (Promega, G7573), mixed well for 2 minutes with a microplate shaker, and after 10 minutes at room temperature, the fluorescence signal value was measured with a BMG multifunctional enzyme-labeled instrument (PHERAstar FSX). Calculating the cell proliferation inhibition rate according to formula (1), wherein RLU compound For drug treatment group readings, RLU control Mean value of solvent control group, RLU blank Mean cell-free wells. Analyzing data and computing IC using GraphPad Prism software 50 Values.
Inhibition ratio% compound –RLU blank )/(RLU control –RLU blank )]X 100% (1)
Conclusion: the compound has a certain inhibition effect on the proliferation of SU-DHL-6 cells.
2. Farage cell Bcl-6 protein degradation experiment
Farage cells from ATCC were placed in RPMI-1640 complete medium (containing 10% fetal bovine serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin) at 37℃with 5% CO 2 Culturing under the condition. Cells in the logarithmic growth phase were collected, the cell suspension was adjusted to an appropriate density with the medium, and added to a 6-well cell culture plate at a volume of 1 mL/well. Test compounds were formulated at 2 times final concentration, 1mL of compound at different concentrations was added to the dosing wells, medium containing 0.2% dmso was added to the control wells, and incubated at 37 ℃ for 24 hours. Cells were collected in a 1.5mL centrifuge tube, 25. Mu.L of RIPA lysate (containing 1 Xprotease inhibitor cocktail) was added, and after 15 minutes of lysis on ice, the cells were centrifuged at 12000 rpm at 4℃for 10 minutes, and the supernatant was collected and assayed for protein content by the BCA method. The protein sample to be tested is diluted to 0.8mg/mL, and Bcl6 is detected by a full-automatic protein expression quantitative analyzer (protein simple), and the internal reference protein is beta-actin (antibodies are all derived from CST). Raw data processing was performed using software from a fully automated protein expression quantitative analyzer (Compass for SW) to calculate peak area and Bcl6 expression rate relative to control. Calculation of DC using four-parameter nonlinear fitting model in Graphpad 8.3.0 software 50 Values.
The results of the degradation rate of the compounds of the present invention on Bcl-6 at a concentration of 10nM are shown in Table 1.
TABLE 1 degradation rate of 10nM to degrade Bcl6
| Sequence number | Compounds of formula (I) | Degradation rate% |
| 1 | Compound 1 | >70％ |
| 2 | Compound 3 | >70％ |
Conclusion: the compounds of the invention, such as the example compounds, have good degradation of Bcl-6 protein.
Claims (13)
1. A compound or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),
B-L-K(I)；
l is selected from a bond or-C 1-50 Hydrocarbyl-, having from 1 to 20 methylene units in said hydrocarbyl optionally replaced by-Ak-, -Cy-;
each-Ak-is independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-NR L (CH 2 ) q C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -、-CH＝CH-、-Si(R L ) 2 -、-Si(OH)(R L )-、-Si(OH) 2 -、-P(＝O)(OR L )-、-P(＝O)(R L )-、-S-、-S(＝O)-、-S(＝O) 2 -or a bond, said-CH 2 Optionally substituted with 1 to 2 groups selected from halogen, OH, CN, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Substituted by alkyl;
q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;
R L each independently selected from H, C 1-6 An alkyl group, a 3-7 membered heterocyclyl group, a 3-7 membered cycloalkyl group, a phenyl group or a 5-6 membered heteroaryl group, said heterocyclyl or heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N;
each-Cy-is independently selected from the group consisting of a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heteroacene ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, and C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro or bridged ring optionally being substituted with 1 to 2 groups selected from halogen, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatom is selected from S;
b is selected from
X is selected from O, S or CH 2 ；
Y1 is selected from NR Y Or O;
y2 is selected from NR Y S or O;
z is selected from O, -CH=, S, S (=O), S (=O) 2 、N(R Z )C(＝O)、C(＝O)N(R Z )、S(＝O) 2 N(R Z )、N(R Z )、C 1-4 Alkylene, -OC 1-3 Alkylene-, -C 1-3 Alkylene group O-, -C 1-3 Alkylene group S-, -C 1-3 Alkylene S (=o) -, C 1-3 Alkylene group S (=o) 2 -、-N(R Z )C 1-3 alkylene-or-C 1-3 Alkylene N (R) Z ) -said alkylene group optionally being 1 to 4 groups selected from halogen, =o, = S, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
R Z each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl being optionally substituted with 1 to 4 groups selected from deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 Alkynyl, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S or N;
ring W is selected from C 3-10 Carbocycles or 3-to 10-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R t1 、R t2 or R is t3 Each independently selected from H, halogen, cyano, NH 2 、NO 2 、OH、C 1-6 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3 to 10 membered heterocycle, said alkyl, alkoxy, alkenyl, alkynyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
or two R t1 Two R t2 Two R t3 Respectively with atoms directly connected thereto to form C 3-10 Carbocycles Or a 3 to 10 membered heterocycle, said carbocycle or heterocycle optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
provided that when Y2 is selected from NR Y Or O, at least one R t1 Is halogen or two R t1 And atoms directly attached thereto form C 3-10 Carbocycles or 3-to 10-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R Y selected from H, C 1-6 Alkyl, C 3-10 Carbocycle or 3-to 10-membered heterocycle, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A Selected from C 3-12 Carbocycle or- (CH) 2 ) t4 NR A1 R A2 The carbocycle or heterocycle is optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R B selected from H, OH, - (CH) 2 ) t4 NR B1 R B2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Carbocycles, 4-12 membered heterocycles, optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R C selected from 5-6 membered heteroaryl,The heteroaryl group is optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a 3 to 8 membered heterocyclic ring substituted with a substituent, said heterocyclic ring or heteroaryl containing 1 to 3 heteroatoms selected from O, S, N;
or R is C And R is R 3b And the atoms to which they are directly attached form a 4-12 membered heterocyclic ring, said heterocyclic ring optionally being substituted with 1 to 4 atoms selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A1 、R B1 、R B2 each independently selected from H, OH, NH 2 、NH(C 1-6 Alkyl group), NH (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Carbocycle or 4-12 membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A2 selected from C 2-6 Alkenyl, C 2-6 Alkynyl, NH (C) 1-6 Alkyl group), NH (C) 1-6 Alkyl group 2 、C 3-12 Carbocycle or 4-12 membered heterocycle, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R C1 each independently selected from H, C 1-6 Alkyl, C 3-12 Carbocycle or 4-12 membered heterocycle, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R 3a or R is 4 Each independently selected from H, OH, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3-to 10-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, N (CH) 3 )、N(CH 3 ) 2 、N(CH 2 CH 3 )、N(CH 2 CH 3 ) 2 、NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Carbocycles or 3-to 8-membered heterogeniesA ring substituted with a substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
R 3b or R is 5 Each independently selected from H, halogen, cyano, NH 2 、NO 2 、OH、C 1-6 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocycle or 3 to 10 membered heterocycle, said alkyl, alkoxy, alkenyl, alkynyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
t1, t2 or t3 is selected from 1, 2, 3, 4 or 5;
t4 is selected from 0, 1, 2, 3, 4 or 5;
m is selected from 0, 1, 2, 3 or 4;
n is selected from 0, 1 or 2;
k is selected from K1, K2, K3 and K4;
k1 is selected from
K2 is selected from
K3 is selected from
K4 is selected from
Q is each independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 3-12 membered heterocycle, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R q selected from H or C 1-6 An alkyl group;
a is selected from C 3-10 Carbocycle, C 6-10 An aromatic ring, a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S or N;
f are each independently selected from C 3-20 Carbocycle, C 6-20 An aromatic ring, a 3-20 membered heterocyclic ring, or a 5-20 membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S or N;
R k2 each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-or-C (R) k3 ) 2 -；
R k1 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, R k7a Said alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
R k7a selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted by 1 to 4 members selected from F, cl, br, I, OH, NH 2 、CN、CF 3 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substituted cycloalkyl;
R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S or N;
or two R k3 And carbon atoms or ring skeletons directly attached to both form C 3-8 Carbocycle or 3-8 membered heterocycle, two R k1 And carbon atoms or ring skeletons directly attached to both form C 3-8 Carbocycles or 3-8 membered heterocycles, optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R k4 each independently selected from H, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S or N;
M 1 selected from bond, -CH 2 -C (=o) NH-or-C (=o) CH 2 NH-；
M 2 Selected from-NHC (=o) -C 1-6 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted by alkoxy substituents, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or NA seed;
M 3 selected from-NH-or-O-;
R k10 selected from C 1-6 Alkyl optionally substituted with 1 to 4 groups selected from F, cl, br, I, =o, OH, C 1-6 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or-O-C (=o) -C 1-6 Alkyl, said alkyl, alkoxy or alkylthio being optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k14 selected from 5-6 membered heteroaryl, optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl containing 1 to 4 heteroatoms selected from N, O or S;
g is selected from C 6-10 An aromatic or 5-10 membered heteroaromatic ring optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl ring containing 1 to 4 heteroatoms selected from N, O or S;
n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
2. The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
l is selected from the group consisting of-Cy 1-Cy2-Ak2-Cy3-Cy4-Ak 4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak 5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak 1-2-Ak 2-Ak3-Cy3-Cy4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak 5-; -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5- -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak 5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak 5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak2-Ak 3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -1-Ak 2-Ak3-Ak4-Ak 2-Cy3-Cy4-Ak 5-; -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak 2-Cy 5-Cy1-Cy 2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5- -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy 4-; -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy 4-; -Ak1-Ak2-Ak3-Ak 1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4- Ak1-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak 6-; -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9;
Ak1、Ak2、Ak3Ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally substituted with 1 to 2 groups selected from halogen, OH, CN, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Substituted by alkyl;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heteroacene ring, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Meta spirocycloalkyl, C 7-10 A bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro or bridged ring optionally being selected from 1 to 2 of F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatom is selected from S;
q is each independently selected from 0, 1, 2, 3 or 4;
R L each independently selected from H or C 1-6 An alkyl group.
3. The compound of claim 2, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
Ak1、Ak2、Ak3、Ak4、Ak5、Ak6、Ak7、Ak8、Ak9 is independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally 1 to 2 are selected from F, cl, br, I, OH, CN, NH 2 、CF 3 Hydroxymethyl, C 1-4 Alkyl, C 1-4 Substituted with alkoxy;
R L each independently selected from H or C 1-4 An alkyl group;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered nitrogen containing heteromonocyclic ring, a 4-10 membered nitrogen containing heterobicyclic ring, a 5-12 membered nitrogen containing heterospiro ring, a 7-10 membered nitrogen containing heterobridged ring, and C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 7-10 Bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said heteromonocyclic, heterobicyclic, heterobridged, heterospiro, cycloalkyl, aryl or heteroaryl optionally being selected from 1 to 2 of F, cl, br, I, OH, COOH, CN, NH 2 、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteromonocyclic, heterobicyclic, heterobridged, heterospiro or heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatoms are selected from S;
z is selected from O, S, -CH=, N (R) Z )、-N(R Z )C(＝O)-、-C(＝O)N(R Z )-、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、
-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-CH 2 S-、-CH 2 CH 2 S-、-CH 2 S(＝O) 2 -、-CH 2 CH 2 S(＝O) 2 -、-N(R Z )CH 2 -、-N(R Z )CH 2 CH 2 -、-CH 2 N(R Z )-、-CH 2 CH 2 N(R Z )-、-N(R Z )C(＝O)CH 2 -or-CH 2 C(＝O)N(R Z ) -, the CH 2 Optionally further 0 to 2 are selected from H, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
R Z each independently selected from H, methyl, ethyl, propyl, isopropyl or cyclopropyl, said methyl, ethyl, propyl, isopropyl or cyclopropyl optionally being substituted with 1 to 4 groups selected from deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, 3-to 6-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S or N;
ring W is selected from C 3-7 Carbocycles or 3-to 8-membered heterocycles, said carbocycles or heterocycles optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R t1 、R t2 or R is t3 Each independently selected from H, F, cl, br, I, cyano, NH 2 、NO 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by carbocyclic or 3-to 6-membered heterocyclic substituentsThe heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N;
or two R t1 Two R t2 Two R t3 Respectively and directly connected with atoms to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl and piperidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl and piperidinyl are optionally substituted by 1 to 3 atoms selected from halogen, OH, cyano and NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R Y selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, optionally substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or- (CH) 2 ) t4 NR A1 R A2 The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl are optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R B selected from H, OH, - (CH) 2 ) t4 NR B1 R B2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,Propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R C selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and,The pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl are optionally substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a 3 to 8 membered heterocyclic ring substituted with a substituent, said heterocyclic ring or heteroaryl containing 1 to 3 heteroatoms selected from O, S, N;
or R is C And R is R 3b And the atoms to which they are directly attached form a 5-8 membered heterocyclic ring, said heterocyclic ring optionally being substituted with 1 to 4 atoms selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted by substituents of carbocyclic rings or 3-to 6-membered heterocyclic rings containing 1-to3 heteroatoms selected from O, S, N;
R A1 、R B1 、R B2 each independently selected from H, OH, NH 2 、NH(C 1-4 Alkyl group), NH (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 Carbocycle or 4-8 membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R A2 selected from C 2-4 Alkenyl, C 2-4 Alkynyl, NH (C) 1-4 Alkyl group), NH (C) 1-4 Alkyl group 2 4-7 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, C 3-7 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, 5-to 10-membered heteroaryl or 6-to 10-membered aryl, said alkyl, carbocycle or heterocycle optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 8 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R C1 each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl optionally being substituted with 1 to 4 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R 3a or R is 4 Each independently selected from H, OH, NH 2 Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl optionally being substituted with 1 to 3 substituents selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
R 3b or R is 5 Each independently selected from H, F, cl, br, I, cyano, NH 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl optionally being substituted with 1 to 3 groups selected from halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S, N;
k1 is selected from
K2 is selected from
K3 is selected from
A is selected from C 3-8 A carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S or N;
f are each independently selected from C 3-7 Monocyclic carbocycle, C 4-10 Carbocyclic ring, C 5-12 Spiro carbocycles, C 5-10 Bridged ring carbocycle, 4-7 membered heteromonocyclic ring, 4-10 membered heterofused ring, 8-15 membered heterofused ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 Aryl, 5-10 membered heteroaryl, The heteromonocyclic, heterobicyclic, heterospiro, heterobridged or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S or N;
represents a ring selected from aromatic or non-aromatic rings;
e is each independently selected from C 3-10 A carbocycle, a benzene ring, a 4-12 membered heterocycle, a 5-12 membered heteroaryl ring containing 1 to 4 heteroatoms selected from O, S or N;
q is each independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 4-7 membered heterocycle, said heterocycle optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R q selected from H or C 1-4 An alkyl group;
R k1 、R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 4 groups selected from F, cl, br, I, OH or NH 2 Is substituted by a substituent of (2);
or two R k3 And carbon atoms or ring skeletons directly attached to both form C 3-6 Carbocycle or 3-7 membered heterocycle, two R k1 And carbon atoms or ring skeletons directly attached to both form C 3-6 Carbocycles or 3-7 membered heterocycles, optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R k4 each independently selected from H, OH, NH 2 、CF 3 CN or C 1-4 An alkyl group;
R k5 each independently selected fromC(CH 3 ) 2 、CO、CH 2 、CH 2 CH 2 、SO 2 、
R k6 Each independently selected from CO, CH, SO, SO 2 、CH 2 N or NR k7a ；
R k7 Each independently selected fromC(CH 3 ) 2 、CO、CH、N、CH 2 、O、S、NR k7a ；
R k8 Each independently selectFrom C, N or CH;
R k9 each independently selected from the group consisting of a bond,C(CH 3 ) 2 、CO、CH 2 、CH 2 CH 2 Or SO 2 ；
R ka Selected from O, S or NH;
R k7a selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally being substituted by 1 to 4 members selected from F, cl, br, I, OH, NH 2 、CN、CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Substituted cycloalkyl;
R k14 selected from the group consisting of
4. The compound of claim 3, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(＝O)-、-(CH 2 ) q -C(＝O)NR L -、-C(＝O)-、-C(＝O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally 1 to 2 are selected from F, cl, br, I, OH, CN, NH 2 、CF 3 A hydroxymethyl, methyl, ethyl, methoxy or ethoxy substituent;
R L selected from H, methyl or ethyl;
q is each independently selected from 0, 1, 2 or 3;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azehexenyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazaheptanyl, phenyl, pyridine, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirocyclobutyl, cyclopropyl-spirocyclopentyl, cyclopropyl-spirocyclohexyl, cyclobutylspirocyclobutyl-spirocyclopentyl, cyclobutyl-spirocyclopentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl, cyclopropyl-azetidinyl, cyclopropyl-pyrrolyl, cyclopropyl-piperidyl, cyclobutyl-azetidinyl cyclobutyl-pyrrolidinyl, cyclobutyl-piperidinyl, cyclopentyl-azetidinyl, cyclopentyl-pyrrolidinyl, cyclopentyl-piperidinyl, cyclohexyl-azetidinyl, cyclohexyl-pyrrolidinyl, cyclohexyl-azetidinyl azetidinoazetidines, azetidinopyrrolidines, azetidinopiperidines, pyrrolidinoazetidines, pyrrolidinopyrrolidines, pyrrolidinopyrrolidinyl, azetidinium, pyrrolidinopyrrolidinyl, piperidinyl azetidinyl, piperidinyl pyrrolidyl, piperidinyl azetidinyl, cyclopropyl spiroazetidinyl, cyclopropyl spiropyrrolidinyl, cyclopropyl spiropiperidinyl, cyclopropyl spiropiperazinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidinyl, cyclobutylspiropiperidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, azetidinyl spiropyrrolidinyl, azetidinyl spiropiperidinyl, pyrrolidinyl spiroazetidinyl, pyrrolidinyl spiropyrrolidinyl, pyrrolidinyl spiropiperidinyl, piperidinyl spiroazetidine Cyclobutyl, piperidinyl spiropyrrolidinyl, piperidinyl spiropiperidinyl, When substituted, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2 、COOH、CN、＝O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
x is selected from O or S;
y1 is selected from NH or O;
y2 is selected from NH, O or S;
z is selected from-NHC (=O) -, -C (=O) NH-, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-
CH 2 CH 2 O-、-NHCH 2 -、-NHCH 2 CH 2 -、-CH 2 NH-、-CH 2 CH 2 NH-、-NHC(＝O)CH 2 -、-CH 2 C(＝O)NH-、O、S、NH、-CH＝、-N(CH 3 )C(＝O)-、-C(＝O)N(CH 3 )-、-CH 2 C(＝O)NH-、-CH 2 C(＝O)N(CH 3 )-、-N(CH 2 CH 3 )C(＝O)-、-N(CH(CH 3 ) 2 )C(＝O)-、-N(CH 2 CH(CH 3 ) 2 ) C (=o) -, -N (cyclopropyl) C (=o) -, -N (CH) 2 -cyclopropyl) C (=o) -, -N (CH) 2 -ethynyl) C (=o) -, -C (=o) N (CH) 2 CH 3 )-、-C(＝O)N(CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 ) 2 ) -, -C (=O) N (cyclopropyl) -or-C (=O) N (CH) 2 -cyclopropyl) -;
ring W is selected from cyclopropaneA group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1, 4-diazaheptanyl, azepanyl, and azepanyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1, 4-diazaheptanyl, and azepanyl being optionally substituted with 1 to 3 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
R t1 、R t2 or R is t3 Each independently selected from H, F, cl, br, I, cyano, NH 2 、NO 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl optionally being 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
or two R t1 And the atoms directly attached thereto form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl being optionally substituted by 1 to 3 atoms selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
R A selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or- (CH) 2 ) t4 NR A1 R A2 The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl and ethyl are substituted;
R B selected from H, OH, - (CH) 2 ) t4 NR B1 R B2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethylOxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl, ethyl and cyclopropyl;
R C selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and,The pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl are optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl, ethyl and cyclopropyl;
or R is C And R is R 3b And atoms directly attached thereto formSaid->Optionally from 1 to 4 are selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituents of methyl, ethyl and cyclopropyl;
R A1 、R B1 、R B2 each independently selected from H, OH, NH 2 NH (methyl), NH (ethyl), NH (propyl), NH (isopropyl), NH (methyl) 2 NH (ethyl) 2 Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethylOxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, furyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituted by methyl, ethyl, methoxy, ethyl, cyclopropyl;
R A2 selected from one of the following substituted or unsubstituted: vinyl, ethynyl, propargyl, propynyl, NH (methyl), NH (ethyl), NH (propyl), NH (isopropyl), NH (methyl) 2 NH (ethyl) 2 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, triazolyl, oxazolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, when substituted, optionally substituted with 1 to 4 groups F, cl, br, I, OH, cyano, NH 2 、CF 3 Substituted by methyl, ethyl, methoxy, ethyl, cyclopropyl;
R C1 each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl optionally being selected from F, cl, br, I, OH, cyano, NH 1 to 4 2 、CF 3 Substituted by methyl, ethyl, methoxy, ethyl, cyclopropyl;
R 3a selected from H, OH, NH 2 Methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, said methyl, ethyl, propyl, isopropyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl optionally substituted with 1 to 3 groups selected from F, cl, br, I, OH, cyano, NH 2 Substituents such as methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
R 4 each independently selected from H, methyl, ethyl, cyclopropyl;
R 3b each independently selected from H, F, cl, br, I, OH, methyl, ethyl, cyclopropyl;
R 5 each independently selected from H, F, cl, br, I, cyano, NH 2 OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, said methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl optionally being substituted with 1 to 3 groups selected from F, cl, br, I, OH, cyano, NH 2 Methyl, ethyl, cyclopropyl;
k1 is selected from
K4 is selected from
Q is selected from a bond, C (=o);
q1 is selected from bond, CH 2 、NH、N(CH 3 )、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH 3 )C(＝O)、C(＝O)N(CH 3 )、
Q2 is selected from bond, CH 2 、O、S、C(＝O)、NHC(＝O)、N(CH 3 )C(＝O)；
E. Each a is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxazole ring;
f is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1 ]Pentanyl, 6, 7-dihydro-5H-cyclopenta [ c ]]Pyridyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridone, benzoxazolyl, pyridmethylimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyrazinyl, indolopyphene, indolofuran, The left side of the connecting rod is directly connected with L;
R ka selected from O, S or NH;
R k7 each independently selected fromC(CH 3 ) 2 、CH 2 、O、N(CH 3 )、N(CH 2 CH 3 ) N (cyclopropyl) or NH;
R k7a selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, CN, CF 3 、C 1-4 Alkyl, C 1-4 Alkoxy, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 Substituted cycloalkyl;
p1 or p2 are each independently selected from 0, 1, 2 or 3.
5. The compound of claim 4, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
ak1, ak2, ak3, ak4, ak5, ak6, ak7, ak8, ak9 are each independently selected from the group consisting of bond, -O-, -OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-C≡C-、-C(CH 3 ) 2 -、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-N(CH 3 )-、-NH-、-CH 2 N(CH 3 )-、-CH 2 NH-、-NHCH 2 -、-CH 2 CH 2 N(CH 3 )-、-CH 2 CH 2 NH-、-NHCH 2 CH 2 -、-C(＝O)-、-C(＝O)CH 2 NH-、-CH 2 C (=o) NH-, -C (=o) NH-or-NHC (=o) -;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups:
when substituted, is selected from the group consisting of F, CF by 1 to 4 3 OH, methyl, =O, hydroxymethyl, COOH, CN or NH 2 Is substituted by a substituent of (2);
b is selected from one of the structural fragments shown in Table B-1;
k is selected from one of the structural fragments shown in Table K-1.
6. The compound of claim 5, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
-Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, and-Cy 1-Ak1-Ak2-Ak3-Ak 4-; -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-Ak4-, and-Cy 1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy 3-Ak3-Cy 1-Ak2-Cy3-, cy1-Ak 2-Cy3-Ak3- -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy 3-Cy4-Ak 1-Cy2-Ak 3-Cy 4-; -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Cy3-, -Ak1-Cy 3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy3-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy3-Ak 4-Ak5- -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-.
7. The compound of claim 6, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
l is selected from a bond or one of the structural fragments shown in Table L-1, wherein the left side of the group is attached to B.
8. The compound of claim 6, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
l is selected from a bond or one of the structural fragments shown in Table L-2, wherein the left side of the group is attached to B;
k is selected from one of the structural fragments shown in Table K-2.
9. The compound according to claim 1, wherein the compound represented by the general formula (I) is selected from the group consisting of compounds represented by the general formula (II-1) and (II-2),
b is selected from one of the structural fragments shown in Table B-2;
cy1 or Cy2 are each independently selected from one of the following substituted or unsubstituted groups:/>
when substituted, is selected from the group consisting of F, CF by 1 to 4 3 OH, methyl, =O, hydroxymethyl, COOH, CN or NH 2 Is substituted by a substituent of (2);
ak1 is selected from CH 2 、CH 2 CH 2 、O、NH、CO、N(CH 3 ) Or C (CH) 3 ) 2 ；
R k1 Selected from F, cl, br, CF 3 OH, methyl, =O, hydroxymethyl, COOH, CN or NH 2 ；
p1 is selected from 0, 1 or 2.
10. The compound of claim 1, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the structures of table S-1.
11. A pharmaceutical composition comprising a compound according to any one of claims 1-10, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier, said compound or stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof being preferably in an amount of from 1 to 1500mg.
12. Use of a compound according to any one of claims 1-10, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with Bcl6 activity or expression level.
13. Use of a compound according to any one of claims 1-10, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment and inhibition or degradation of Bcl6 related diseases, preferably cancer.
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| CN2022106719573 | 2022-06-15 | ||
| CN202210671957 | 2022-06-15 | ||
| CN2022109155125 | 2022-08-02 | ||
| CN202210915512 | 2022-08-02 |
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