CN117683037A - Spiro compounds and uses - Google Patents
Spiro compounds and uses Download PDFInfo
- Publication number
- CN117683037A CN117683037A CN202311134920.8A CN202311134920A CN117683037A CN 117683037 A CN117683037 A CN 117683037A CN 202311134920 A CN202311134920 A CN 202311134920A CN 117683037 A CN117683037 A CN 117683037A
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- Prior art keywords
- alkylene
- halogen
- substituted
- alkyl
- alkynyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003413 spiro compounds Chemical class 0.000 title abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 230000002159 abnormal effect Effects 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 230000035755 proliferation Effects 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims description 98
- 229910052736 halogen Inorganic materials 0.000 claims description 91
- 150000002367 halogens Chemical group 0.000 claims description 91
- 125000003342 alkenyl group Chemical group 0.000 claims description 69
- 125000000304 alkynyl group Chemical group 0.000 claims description 69
- 125000003118 aryl group Chemical group 0.000 claims description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 47
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 45
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 44
- 125000002947 alkylene group Chemical group 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 238000006467 substitution reaction Methods 0.000 claims description 27
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- 230000017854 proteolysis Effects 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
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- 125000004432 carbon atom Chemical group C* 0.000 description 15
- -1 methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene Chemical group 0.000 description 14
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 229910052717 sulfur Chemical group 0.000 description 8
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 7
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
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- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
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- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
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- 230000034512 ubiquitination Effects 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Abstract
The invention provides a spiro compound with a binding effect with E3 ligase protein CRBN shown in a formula I and application thereof in preparing medicines for treating cell abnormal proliferation diseases.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a novel ligand compound for combining spiro cerebellar protein (cereblon) E3 ubiquitin ligase protein.
Background
Protein degradation is a highly regulated and necessary process to maintain cellular homeostasis. Selective identification and removal of damaged, misfolded or excess proteins is achieved by the Ubiquitin-proteasome pathway (UPP). UPP is responsible for the clearance of defective proteins and has ATP-dependent, highly efficient, highly selective characteristics, with the catalytic moiety being ubiquitinated E3 ligase, but needs to be first recruited to the protein that needs to be degraded. The PROTACs technology is designed based on the UPP principle, and the ligand of the target protein and the ligand of the E3 ligase are connected by a proper chemical bond, so that the target protein can be identified, the binding capacity of the ligase E3 and the target protein is enhanced, the target protein is further subjected to targeted ubiquitination and forced degradation, and the method has the characteristics of catalyst quantity, high efficiency, high selectivity and the like.
A number of ubiquitin molecules label proteins for proteasome degradation by covalent attachment of the E3 ubiquitin ligase to terminal lysine residues, wherein the protein is digested into small peptides and eventually into its constituent amino acids, which serve as building blocks for new proteins. Defective proteasome degradation is associated with a variety of clinical conditions including alzheimer's disease, parkinson's disease, huntington's disease, muscular dystrophy, cardiovascular disease, cancer, and the like.
Cerebellin (Cereblon), a binding protein for thalidomide, is part of the E3 ubiquitin ligase protein complex, which acts selectively as a substrate receptor for ubiquitinated proteins. Cereblon is a protein encoded by the human CRBN gene, and forms the E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDBl), cullin-4A (CUL 4A) and Cullin-1 modulator (ROCI), which ubiquitinates a range of proteins, but the specific mechanism is not known. Cereblon is a commonly used E3 ligase currently known to be applied to PROTACs technology.
The present invention discloses a novel class of spiro compounds which can be used as potent CRBN ligands, and further can synthesize corresponding protas bifunctional compounds which can target protein degradation to chimeras, which are useful in the treatment of a variety of medical conditions, particularly abnormal cell proliferation.
Disclosure of Invention
The invention provides a compound shown in a formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:
wherein,
R 1 selected from hydrogen, -C 1-6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 1~4 alkylene-OR 11 、-C 1~4 alkylene-NR 11 R 12 、-C 1~4 Alkylene- (3-10 membered cycloalkyl), -C 1~4 Alkylene- (4-10 membered heterocycloalkyl);
R 11 、R 12 independently selected from hydrogen, -C 1-6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl;
ring A is selected fromWherein the A ring may be further optionally substituted with one, two, three or four independent R A1 Substitution;
each R A1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr A2 R A3 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR A2 、-C 0~4 alkylene-OC (O) R A2 、-C 0~4 alkylene-SR A2 、-C 0~4 alkylene-S (O) 2 R A2 、-C 0~4 alkylene-S (O) R A2 、-C 0~4 alkylene-S (O) 2 NR A2 R A3 、-C 0~4 alkylene-S (O) NR A2 R A3 、-C 0~4 alkylene-C (O) R A2 、-C 0~4 alkylene-C (O) OR A2 、-C 0~4 alkylene-C (O) NR A2 R A3 、-C 0~4 alkylene-NR A2 R A3 、-C 0~4 alkylene-NR A2 C(O)R A3 、-C 0~4 alkylene-NR A2 S(O) 2 R A3 、-C 0~4 alkylene-NR A2 S(O)R A3 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R A4 Substitution;
each R A4 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr A2 R A3 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR A2 、-C 0~4 alkylene-OC (O) R A2 、-C 0~4 alkylene-SR A2 、-C 0~4 alkylene-S (O) 2 R A2 、-C 0~4 alkylene-S (O) R A2 、-C 0~4 alkylene-S (O) 2 NR A2 R A3 、-C 0~4 alkylene-S (O) NR A2 R A3 、-C 0~4 alkylene-C (O) R A2 、-C 0~4 alkylene-C (O) OR A2 、-C 0~4 alkylene-C (O) NR A2 R A3 、-C 0~4 alkylene-NR A2 R A3 、-C 0~4 alkylene-NR A2 C(O)R A3 、-C 0~4 alkylene-NR A2 S(O) 2 R A3 、-C 0~4 alkylene-NR A2 S(O)R A3 ;
R A2 、R A3 Are respectively and independently selected from hydrogen and C 1-6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl;
R 2 independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr 21 R 22 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 21 、-C 0~4 alkylene-OC (O) R 21 、-C 0~4 alkylene-SR 21 、-C 0~4 alkylene-S (O) 2 R 21 、-C 0~4 alkylene-S (O) R 21 、-C 0~4 alkylene-S (O) 2 NR 21 R 22 、-C 0~4 alkylene-S (O) NR 21 R 22 、-C 0~4 alkylene-C (O) R 21 、-C 0~4 alkylene-C (O) OR 21 、-C 0~4 alkylene-C (O) NR 21 R 22 、-C 0~4 alkylene-NR 21 R 22 、-C 0~4 alkylene-NR 21 C(O)R 22 、-C 0~4 alkylene-NR 21 S(O) 2 R 22 、-C 0~4 alkylene-NR 21 S(O)R 22 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 23 Substitution;
each R 23 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =CR 21 R 22 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 21 、-C 0~4 alkylene-OC (O) R 21 、-C 0~4 alkylene-SR 21 、-C 0~4 alkylene-S (O) 2 R 21 、-C 0~4 alkylene-S (O) R 21 、-C 0~4 alkylene-S (O) 2 NR 21 R 22 、-C 0~4 alkylene-S (O) NR 21 R 22 、-C 0~4 alkylene-C (O) R 21 、-C 0~4 alkylene-C (O) OR 21 、-C 0~4 alkylene-C (O) NR 21 R 22 、-C 0~4 alkylene-NR 21 R 22 、-C 0~4 alkylene-NR 21 C(O)R 22 、-C 0~4 alkylene-NR 21 S(O) 2 R 22 、-C 0~4 alkylene-NR 21 S(O)R 22 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 26 Substitution;
R 21 、R 22 are respectively and independently selected from hydrogen and C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 1~4 alkylene-OR 24 、-C 1~4 alkylene-OC (O) R 24 、-C 1~4 alkylene-SR 24 、-C 1~4 alkylene-S (O) 2 R 24 、-C 1~4 alkylene-S (O) R 24 、-C 1~4 alkylene-S (O) 2 NR 24 R 25 、-C 1~4 alkylene-S (O) NR 24 R 25 、-C 1~4 alkylene-C (O) R 24 、-C 1~4 alkylene-C (O) OR 24 、-C 1~4 alkylene-C (O) NR 24 R 25 、-C 1~4 alkylene-NR 24 R 25 、-C 1~4 alkylene-NR 24 C(O)R 25 、-C 1~4 alkylene-NR 24 S(O) 2 R 25 、-C 1~4 alkylene-NR 24 S(O)R 25 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 26 Substitution;
each R 26 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr 24 R 25 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 24 、-C 0~4 alkylene-OC (O) R 24 、-C 0~4 alkylene-SR 24 、-C 0~4 alkylene-S (O) 2 R 24 、-C 0~4 alkylene-S (O) R 24 、-C 0~4 alkylene-S (O) 2 NR 24 R 25 、-C 0~4 alkylene-S (O) NR 24 R 25 、-C 0~4 alkylene-C (O) R 24 、-C 0~4 alkylene-C (O) OR 24 、-C 0~4 alkylene-C (O) NR 24 R 25 、-C 0~4 alkylene-NR 24 R 25 、-C 0~4 alkylene-NR 24 C(O)R 25 、-C 0~4 alkylene-NR 24 S(O) 2 R 25 、-C 0~4 alkylene-NR 24 S(O)R 25 、-C 0~4 Alkylene group- (3-to 10-membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 27 Substitution;
R 24 、R 25 are respectively and independently selected from hydrogen and C 1-6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl;
each R 27 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl;
R 3 selected from hydrogen, -C 1-6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl groups.
Wherein R in formula I is attached to ring A 2 And carbonyl groups may be attached at any of the substitutable positions of the A ring described above.
Preferably, R 1 Selected from hydrogen, -C 1-3 Alkyl, -C 2~4 Alkenyl, -C 2~4 Alkynyl, halogen substituted-C 1~3 An alkyl group.
Still further, the method further comprises the steps of,
ring A is selected fromWherein the A ring may be further optionally substituted with one, two, three or four independent R A1 And (3) substitution.
Preferably, each R A1 Are respectively and independently selected from hydrogen and C 1~3 Alkyl, halogen substituted-C 1~3 An alkyl group.
Preferably, R 3 Selected from hydrogen, -C 1~3 Alkyl, halogen substituted-C 1~3 An alkyl group.
As a preferred alternative to this,
the R is 2 Selected from hydrogen, halogen, cyano, nitro, =o, =s, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 21 、-C 0~4 alkylene-OC (O) R 21 、-C 0~4 alkylene-C (O) R 21 、-C 0~4 alkylene-C (O) OR 21 、-C 0~4 alkylene-C (O) NR 21 R 22 、-C 0~4 alkylene-NR 21 R 22 ;-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 23 Substitution;
each R 23 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 21 、-C 0~4 alkylene-OC (O) R 21 、-C 0~4 alkylene-C (O) R 21 ;-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 26 Substitution;
R 21 、R 22 are respectively and independently selected from hydrogen and C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 1~4 alkylene-OR 24 、-C 1~4 alkylene-OC (O) R 24 、-C 1~4 alkylene-C (O) R 24 、-C 1~4 alkylene-C (O) OR 24 、-C 1~4 alkylene-C (O) NR 24 R 25 、-C 1~4 alkylene-NR 24 R 25 、-C 1~4 alkylene-NR 24 C(O)R 25 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 26 Substitution;
each R 26 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr 24 R 25 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 24 、-C 0~4 alkylene-OC (O) R 24 、-C 0~4 alkylene-C (O) R 24 、-C 0~4 alkylene-C (O) OR 24 、-C 0~4 alkylene-C (O) NR 24 R 25 、-C 0~4 alkylene-NR 24 R 25 、-C 0~4 alkylene-NR 24 C(O)R 25 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring);
R 24 、R 25 respectively and independently selectFrom hydrogen, -C 1-3 Is substituted by alkyl, halogen, -C 1~3 An alkyl group.
Further, the method comprises the steps of,
R 2 selected from-C (O) NR 21 R 22 、-C(O)R 21 、-C 0~2 alkylene-NR 21 R 22 、-C(O)OR 21 ;
R 21 、R 22 Are respectively and independently selected from hydrogen and C 1~3 Alkyl, -C 0~1 Alkylene- (6-membered aromatic ring), -C 0~1 Alkylene- (10 membered heteroaryl ring), - (4-6 membered heterocycloalkyl), - (3-6 membered cycloalkyl), wherein the aryl, heteroaryl, heterocycloalkyl, cycloalkyl may be further optionally substituted with one, two, three or four independent R 26 Substitution;
each R 26 Are respectively and independently selected from hydrogen and C 1~3 Alkyl, - (4-to 6-membered heterocycloalkyl), -C (O) R 24 、-C(O)OR 24 、-OC(O)R 24 ;
R 24 Selected from hydrogen, methyl, ethyl, propyl.
More specifically, the process is carried out,
R 2 selected from hydrogen,
In some embodiments of the invention, the compounds of formula I are specifically:
the invention also provides the application of any one of the compounds, or stereoisomers thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof in preparing medicaments for treating diseases related to abnormal cell proliferation.
Further, the disease is cancer.
The invention also provides the application of any one of the compounds, or stereoisomers thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof in preparing targeted protein degradation medicaments.
The invention also provides the application of any one of the compounds, or stereoisomers thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof as intermediates in preparing targeted protein degradation medicaments.
Still further, the targeted protein degradation drug is a drug that relies on the E3 ligase CRBN for protein degradation.
The compounds and derivatives provided in the present invention may be named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule. "substitution" may also refer to the substitution of a lone pair of electrons of an atom in a molecule by "=o", "=s", etc.
"optionally further substituted" means that "substitution" may, but need not, occur, and that the description includes situations that may or may not occur.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a~b Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1~4 Alkyl "refers to an alkyl group containing 1 to 4 carbon atoms.
"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. For example, C 1 ~ 6 Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group may be linear or branched. Substitution ofThe branched alkyl groups shown have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of another group, such as C 1 ~ 6 An alkoxy group.
"alkylene" as used herein refers to a divalent saturated aliphatic hydrocarbon group having the indicated number of carbon atoms. "C a ~ b Alkylene "refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbyl groups. For example, "C 1~6 Alkylene "is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene" may be exemplified by the following structure:likewise, the term
"dimethylbutylene" can be exemplified, for example, by any of the following structures:furthermore, the term "(C) 1 ~ 6 ) Alkylene "is intended to include such branched chain hydrocarbon groups, such as cyclopropylmethylene, which may be exemplified by the following structures: />Also e.g. -C 0 ~ 4 The alkylene group may be C 0 Alkylene, C 1 Alkylene (e.g. -CH 2 -)、C 2 Alkylene (e.g. -CH 2 CH 2 -etc., C 3 Alkylene or C 4 An alkylene group; c (C) 0 Alkylene means that the radicals are not present here and are attached in the form of chemical bonds, e.g.A-C 0 alkylene-B refers to A-B, i.e., the A group is directly linked to the B group by a chemical bond.
"alkenyl" means having the specified number of carbon atoms and in some embodiments from 2 to 6 carbon atoms or from 2 to 4 carbon atoms and having at least 1 site of ethylenic unsaturation>C=C<) A linear or branched hydrocarbyl group of (a). For example, C a-b Alkenyl refers to alkenyl groups having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1, 3-butadienyl, and the like.
"alkenylene" as used herein refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond, and two unsaturated valences. For example, (C) 3 -C 6 ) Alkenylene group includes>C=CH-CH 2 -、-CH-CH=CH-CH 2 -and the like.
"alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C) 2 -C 6 ) Alkynyl is intended to include ethynyl, propynyl, and the like.
"halogen" is fluorine, chlorine, bromine or iodine.
"haloalkyl" means that a hydrogen atom in an alkyl group may be substituted with one or more halogen atoms. For example C 1~4 Halogen alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which a hydrogen atom is substituted with one or more halogen atoms.
As used herein, "OR", "-NRR", etc. means that the R group is attached to the oxygen OR nitrogen atom by a single bond.
In the present invention, "-C (O) R", "-S (O) 2 The oxygen atom in R' and the like is doubly bonded to a carbon atom or a sulfur atom, and the R group is singly bonded to the oxygen atom or the sulfur atom.
"cycloalkyl", "cycloalkane" as used herein refers to a saturated or partially saturated cyclic group having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, spiro, and adamantane systems). For polycyclic systems having aromatic and non-aromatic rings containing no ring heteroatoms, the term "cycloalkane" applies when the point of attachment is at a non-aromatic carbon atomA group "(e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl). The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups comprising a multicycloalkyl ring system are dicyclohexyl, dicyclopentyl, bicyclooctyl, and the like. For exampleAdamantyl groups include, but are not limited to, the following structures: />
"heterocycle", "heterocycloalkyl", "heterocycloalkane" as used herein refers to a saturated or non-aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. Typically a monovalent saturated or partially unsaturated mono-or bicyclic ring system of a plurality of ring atoms, preferably a monovalent saturated or partially unsaturated mono-or bicyclic ring system of 3 to 9 ring atoms, comprising 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings sharing two ring atoms, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl,thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepayl, homopiperazinyl or oxaazepanyl. An example of a bicyclic saturated heterocycloalkyl group is 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl group,Examples of partially unsaturated heterocycloalkyl groups are dihydrofuryl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.
"spiroheterocyclyl" and "spiroheterocycle" are used interchangeably and refer to a non-aromatic saturated or non-aromatic unsaturated ring system having two monocyclic rings sharing one carbon atom, which is composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus. For example, "5-to 12-membered spiroheterocycle" refers to a spiroheterocycle having 5 to 12 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms.
"bridged ring or bridged ring radical" means a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms with each other, specific examples of which include, but are not limited to:
"bridged heterocyclyl" and "bridged heterocyclic ring" are used interchangeably and refer to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms with each other, consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus. Specific embodiments thereof include, but are not limited to:
as used herein, "aromatic ring", "aryl" refers to aromatic hydrocarbon groups having multiple carbon atoms. Aryl is typically a monocyclic, bicyclic or tricyclic aryl group having 5 to 20 carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.
"heteroaryl ring", "heteroaryl ring radical" as used herein refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. An aromatic mono-or bicyclic hydrocarbon typically comprising a plurality of ring atoms, wherein one or more of the ring atoms is selected from heteroatoms of O, N, S. Preferably one to three heteroatoms. Heteroaryl represents, for example: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.
"stereoisomers" include enantiomers and diastereomers;
"deuterated compound" in the present invention refers to a molecule or group in which 1 or more hydrogen atoms are replaced with deuterium atoms, wherein the ratio of deuterium atoms is greater than the abundance of deuterium in nature.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
The terms "salts" and "pharmaceutically acceptable salts" refer to the acidic and/or basic salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base as appropriate (for example, equivalent). These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium. The salts of the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salts of the compounds.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Detailed Description
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
The known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from An Naiji chemical, chengkoulochemical, shaoshan chemical technology, carbofuran technology, and the like.
The reagents described in the examples are abbreviated as follows: DIPEA: N, N-diisopropylethylamine; HATU 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate.
The reaction was carried out under nitrogen atmosphere without specific explanation in examples. The examples are not specifically described, and the solution refers to an aqueous solution. The temperature of the reaction was room temperature, unless otherwise specified in the examples. The room temperature is the most suitable reaction temperature and is 20-30 ℃. In the examples, M is mol/liter unless otherwise specified.
The structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR was performed using a nuclear magnetic resonance apparatus (Bruker Avance III 400 and Bruker Avance 600) with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (method-d) 4 ) The internal standard is Tetramethylsilane (TMS). LC-MS was measured using Shimadzu LC-MS2020 (ESI). HPLC was performed using a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) uses Gilson GX-281 reverse phase preparative chromatograph. The specification of the thin layer chromatography separation and purification product adopted by the smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
Example 1 preparation of Compound A1
Step one, preparation of Compound 3
To a 50mL reaction flask, compound 1 (177.00 mg,0.75 mmol), DIPEA (132.25 mg,1.00mmol, 178.06. Mu.L), HATU (250.96 mg,0.66 mmol) and dichloromethane (2 mL) were sequentially added, after the reaction system temperature was lowered to 0deg.C, compound 2 (29.30 mg,0.65 mmol) was added, the reaction was stirred under ice bath conditions for 0.5 hour, quenched (LC-MS monitoring), saturated NaCl solution (10 mL) and ethyl acetate (3X 20 mL) were extracted, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the solvent was removed by concentration under reduced pressure to give compound 3 (crude product).
Step two, preparation of Compound 4
A50 mL reaction bottle is sequentially added with a compound 3 (crude product), lithium hydroxide (26.34 mg,1.10 mmol), tetrahydrofuran (4 mL) and water (2 mL), stirring and reacting for 8 hours at normal temperature, quenching reaction (LC-MS monitoring), adjusting the pH value of the system to 6.0-7.0 by using a 1M hydrochloric acid solution, and concentrating the reaction solution to obtain a compound 4 (crude product) which is directly used for the next reaction.
Step three, synthesis of Compound A1
A50 mL reaction flask was charged with Compound 4 (6.69 mg, 26.82. Mu. Mol), DIPEA (14.80 mg, 107.27. Mu. Mol), HATU (20.38 mg, 53.64. Mu. Mol) and dichloromethane (2 mL) in this order, and after the temperature of the reaction system had fallen to 0℃Compound 5 (4.13 mg, 26.82. Mu. Mol) was addedmol), stirring the reaction under ice bath for 0.5 hours, quenching the reaction (monitored by LC-MS), extracting the saturated NaCl solution (10 mL) with ethyl acetate (3X 20 mL), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, purifying the organic phases by MPLC, evaporating the solvent, concentrating under reduced pressure to remove the solvent to obtain the compound A1 (5.10 mg, 13.24. Mu. Mol,.45.64% yield, purity 96.5%). LC-MS: c (C) 19 H 20 N 3 O 4 S,[M+H] + 386.1;found 386.1. 1 H NMR(400MHz,Methanol-d 4 )δ7.97(m,1H),7.90-7.75(m,1H),7.51(m 2H),4.07-3.89(m,1H),3.77(d,J=12.4Hz,1H),3.70-3.40(m,2H),3.12(s,6H),2.98-2.64(m,2H),2.43-2.28(m,1H),2.20-2.00(m,1H).
The invention has the technical effects that the invention is illustrated by the following test examples:
test example 1 detection of inhibition of CRBN/DDB1 Activity by Compounds (FRET)
1. Experimental materials and reagents
Microplate reader (BMG PHERAstar FSX), ECHO (LABCYLE ECHO 665), microplate thermostatted shaker (RehengJim instruments Inc. of Hangzhou), disodium hydrogen phosphate (Sigma), sodium dihydrogen phosphate (Sigma), bovine serum albumin (Sigma), anti-6His-Tb crypad Gold (CISBIO), CRBN/DDB1 protein (HitGen), 384 well plate (Grenier Bio-one).
2. Experimental method
Compound dry powder was dissolved in DMSO, diluted with ECHO gradient and added to 384 well reaction plates to give a final DMSO concentration of 1.0% in the whole reaction system (10.0 μl) and an equivalent amount of DMSO was added as a control.
CRBN/DDB1 protein was diluted to 2 times the desired final concentration (5.0 nM) using 20mM disodium hydrogen phosphate, 20mM sodium dihydrogen phosphate, 0.08% bovine serum albumin, pH7.0 buffer, 5.0. Mu.L of the diluted CRBN/DDB1 protein was pipetted into 384 well reaction plates to which the compound had been added, centrifuged at 1000rpm for 1 minute, and then placed on a microplate thermostatted shaker at 25℃at 250rpm for 15 minutes. The Anti-6His-Tb crypad Gold and FITC-labeled thalidomide analogs were diluted to 2 times the desired final concentration with 20mM disodium hydrogen phosphate, 20mM sodium dihydrogen phosphate, 0.08% bovine serum albumin, pH7.0 buffer, the final concentration of Anti-6His-Tb crypad Gold was 0.2nM, the final concentration of FITC-labeled thalidomide analogs was 50.0nM, a mixed solution of Anti-6His-Tb crypad Gold/FITC-labeled thalidomide analogs was obtained, 5.0. Mu.L of the mixed solution of Anti-6His-Tb crypad Gold/FITC-labeled thalidomide analogs was pipetted into 384-well reaction plates, centrifuged at 1000rpm for 1 minute, and then placed on a microplate thermostated shaker at 25℃at 250rpm for 30 minutes. After the reaction, the microplate reader reads the fluorescence signal values in 384 well reaction plates (ex=337 nm em=520/490 nm).
3. Data analysis
The vehicle group (containing 5.0nM CRBN/DDB1,0.2nM Anti-6His-Tb crypad Gold,50.0nM FITC-labeled thalidomide analog and 1.0% DMSO) was used as a negative control, and the reaction buffer group (containing 0.2nM Anti-6His-Tb crypad Gold,50.0nM FITC-labeled thalidomide analog and 1.0% DMSO) was used as a blank control;
the percent viability remaining for each concentration was calculated as follows:
residual viability (%) =100% × (Flu) Group of compounds -Flu Blank control )/(Flu Negative control -Flu Blank control )
IC was then calculated using GraphPad 6.0 fit effect curve 50 Values.
Table 1: CRBN/DDB1 protein inhibition assay
Numbering device | IC 50 |
A1 | 13.70μM |
The above experiments show that the compounds of the examples of the present invention have good CRBN inhibitory effect and may be useful in the treatment of diseases associated with abnormal CRBN activity.
Claims (13)
1. A compound of formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:
wherein,
R 1 selected from hydrogen, -C 1-6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 1~4 alkylene-OR 11 、-C 1~4 alkylene-NR 11 R 12 、-C 1~4 Alkylene- (3-10 membered cycloalkyl), -C 1~4 Alkylene- (4-10 membered heterocycloalkyl);
R 11 、R 12 independently selected from hydrogen, -C 1-6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl;
ring A is selected fromWherein the A ring may be further optionally substituted with one, two, three or four independent R A1 Substitution;
each R A1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr A2 R A3 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR A2 、-C 0~4 alkylene-OC (O) R A2 、-C 0~4 alkylene-SR A2 、-C 0~4 alkylene-S (O) 2 R A2 、-C 0~4 alkylene-S (O) R A2 、-C 0~4 alkylene-S (O) 2 NR A2 R A3 、-C 0~4 alkylene-S (O) NR A2 R A3 、-C 0~4 alkylene-C (O) R A2 、-C 0~4 alkylene-C (O) OR A2 、-C 0~4 alkylene-C (O) NR A2 R A3 、-C 0~4 alkylene-NR A2 R A3 、-C 0~4 alkylene-NR A2 C(O)R A3 、-C 0~4 alkylene-NR A2 S(O) 2 R A3 、-C 0~4 alkylene-NR A2 S(O)R A3 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R A4 Substitution;
each R A4 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr A2 R A3 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR A2 、-C 0~4 alkylene-OC (O) R A2 、-C 0~4 alkylene-SR A2 、-C 0~4 alkylene-S (O) 2 R A2 、-C 0~4 alkylene-S (O) R A2 、-C 0~4 alkylene-S (O) 2 NR A2 R A3 、-C 0~4 alkylene-S (O) NR A2 R A3 、-C 0~4 alkylene-C (O) R A2 、-C 0~4 alkylene-C (O) OR A2 、-C 0~4 alkylene-C (O) NR A2 R A3 、-C 0~4 alkylene-NR A2 R A3 、-C 0~4 alkylene-NR A2 C(O)R A3 、-C 0~4 alkylene-NR A2 S(O) 2 R A3 、-C 0~4 alkylene-NR A2 S(O)R A3 ;
R A2 、R A3 Are respectively and independently selected from hydrogen and C 1-6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl;
R 2 independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr 21 R 22 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 21 、-C 0~4 alkylene-OC (O) R 21 、-C 0~4 alkylene-SR 21 、-C 0~4 alkylene-S (O) 2 R 21 、-C 0~4 alkylene-S (O) R 21 、-C 0~4 alkylene-S (O) 2 NR 21 R 22 、-C 0~4 alkylene-S (O) NR 21 R 22 、-C 0~4 alkylene-C (O) R 21 、-C 0~4 alkylene-C (O) OR 21 、-C 0~4 alkylene-C (O) NR 21 R 22 、-C 0~4 alkylene-NR 21 R 22 、-C 0~4 alkylene-NR 21 C(O)R 22 、-C 0~4 alkylene-NR 21 S(O) 2 R 22 、-C 0~4 alkylene-NR 21 S(O)R 22 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 23 Substitution;
each R 23 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr 21 R 22 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 21 、-C 0~4 alkylene-OC (O) R 21 、-C 0~4 alkylene-SR 21 、-C 0~4 alkylene-S (O) 2 R 21 、-C 0~4 alkylene-S (O) R 21 、-C 0~4 alkylene-S (O) 2 NR 21 R 22 、-C 0~4 alkylene-S (O) NR 21 R 22 、-C 0~4 alkylene-C (O) R 21 、-C 0~4 alkylene-C (O) OR 21 、-C 0~4 alkylene-C (O) NR 21 R 22 、-C 0~4 alkylene-NR 21 R 22 、-C 0~4 alkylene-NR 21 C(O)R 22 、-C 0~4 alkylene-NR 21 S(O) 2 R 22 、-C 0~4 alkylene-NR 21 S(O)R 22 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 26 Substitution;
R 21 、R 22 are respectively and independently selected from hydrogen and C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 1~4 alkylene-OR 24 、-C 1~4 alkylene-OC (O) R 24 、-C 1~4 alkylene-SR 24 、-C 1~4 alkylene-S (O) 2 R 24 、-C 1~4 alkylene-S (O) R 24 、-C 1~4 alkylene-S (O) 2 NR 24 R 25 、-C 1~4 alkylene-S (O) NR 24 R 25 、-C 1~4 alkylene-C (O) R 24 、-C 1~4 alkylene-C (O) OR 24 、-C 1~4 alkylene-C (O) NR 24 R 25 、-C 1~4 alkylene-NR 24 R 25 、-C 1~4 alkylene-NR 24 C(O)R 25 、-C 1~4 alkylene-NR 24 S(O) 2 R 25 、-C 1~4 alkylene-NR 24 S(O)R 25 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 26 Substitution;
each R 26 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr 24 R 25 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 24 、-C 0~4 alkylene-OC (O) R 24 、-C 0~4 alkylene-SR 24 、-C 0~4 alkylene-S (O) 2 R 24 、-C 0~4 alkylene-S (O) R 24 、-C 0~4 alkylene-S (O) 2 NR 24 R 25 、-C 0~4 alkylene-S (O) NR 24 R 25 、-C 0~4 alkylene-C (O) R 24 、-C 0~4 alkylene-C (O) OR 24 、-C 0~4 alkylene-C (O) NR 24 R 25 、-C 0~4 alkylene-NR 24 R 25 、-C 0~4 alkylene-NR 24 C(O)R 25 、-C 0~4 alkylene-NR 24 S(O) 2 R 25 、-C 0~4 alkylene-NR 24 S(O)R 25 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 27 Substitution;
R 24 、R 25 are respectively and independently selected from hydrogen and C 1-6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl;
each R 27 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl;
R 3 selected from hydrogen, -C 1-6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl groups.
2. A compound according to claim 1, characterized in that: r is R 1 Selected from hydrogen, -C 1-3 Alkyl, -C 2~4 Alkenyl, -C 2~4 Alkynyl, halogen substituted-C 1~3 An alkyl group.
3. A compound according to claim 1, characterized in that:
ring A is selected fromWherein the A ring may be further optionally substituted with one, two, three or four independent R A1 And (3) substitution.
4. A compound according to claim 3, characterized in that: each R A1 Are respectively and independently selected from hydrogen and C 1~3 Alkyl, halogen substituted-C 1~3 An alkyl group.
5. A compound according to claim 3, characterized in that: r is R 3 Selected from hydrogen, -C 1~3 Alkyl, halogen substituted-C 1~3 An alkyl group.
6. A compound according to claim 1, characterized in that: r is R 2 Selected from hydrogen, halogen, cyano, nitro, =o, =s, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 21 、-C 0~4 alkylene-OC (O) R 21 、-C 0~4 alkylene-C (O) R 21 、-C 0~4 alkylene-C (O) OR 21 、-C 0~4 alkylene-C (O) NR 21 R 22 、-C 0~4 alkylene-NR 21 R 22 ;-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 23 Substitution;
each R 23 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 21 、-C 0~4 alkylene-OC (O) R 21 、-C 0~4 alkylene-C (O) R 21 ;-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 26 Substitution;
R 21 、R 22 are respectively and independently selected from hydrogen and C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 1~4 alkylene-OR 24 、-C 1~4 alkylene-OC (O) R 24 、-C 1~4 alkylene-C (O) R 24 、-C 1~4 alkylene-C (O) OR 24 、-C 1~4 alkylene-C (O) NR 24 R 25 、-C 1~4 alkylene-NR 24 R 25 、-C 1~4 alkylene-NR 24 C(O)R 25 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic ring may be further optionally substituted with one, two, three or four independent R 26 Substitution;
each R 26 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr 24 R 25 、-C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, halogen substituted-C 1~6 Alkyl, halogen substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl, -C 0~4 alkylene-OR 24 、-C 0~4 alkylene-OC (O) R 24 、-C 0~4 alkylene-C (O) R 24 、-C 0~4 alkylene-C (O) OR 24 、-C 0~4 alkylene-C (O) NR 24 R 25 、-C 0~4 alkylene-NR 24 R 25 、-C 0~4 alkylene-NR 24 C(O)R 25 、-C 0~4 Alkylene- (3-10 membered cycloalkyl), -C 0~4 Alkylene- (4-10 membered heterocycloalkyl), -C 0~4 Alkylene- (6-10 membered aromatic ring), -C 0~4 Alkylene- (5-10 membered heteroaryl ring);
R 24 、R 25 are respectively and independently selected from hydrogen and C 1-3 Is substituted by alkyl, halogen, -C 1~3 An alkyl group.
7. A compound according to claim 6, characterized in that:
the R is 2 Selected from-C (O) NR 21 R 22 、-C(O)R 21 、-C 0~2 alkylene-NR 21 R 22 、-C(O)OR 21 ;
R 21 、R 22 Are respectively and independently selected from hydrogen and C 1~3 Alkyl, -C 0~1 Alkylene- (6-membered aromatic ring), -C 0~1 Alkylene- (10 membered heteroaryl ring), - (4-6 membered heterocycloalkyl), - (3-6 membered cycloalkyl), wherein the aryl, heteroaryl, heterocycloalkyl, cycloalkyl may be further optionally substituted with one, two, three or four independent R 26 Substitution;
each R 26 Are respectively and independently selected from hydrogen and C 1~3 Alkyl, - (4-to 6-membered heterocycloalkyl), -C (O) R 24 、-C(O)OR 24 、-OC(O)R 24 ;
R 24 Selected from hydrogen, methyl, ethyl, propyl.
8. A compound according to claim 7, characterized in that:
R 2 selected from hydrogen,
9. A compound according to any one of claims 1 to 8, characterized in that: the compound is specifically as follows:
10. use of a compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease associated with abnormal proliferation of cells.
11. Use according to claim 10, characterized in that: the disease is cancer.
12. Use of a compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a targeted protein degradation medicament.
13. Use of a compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, as an intermediate in the preparation of a targeted protein degradation drug.
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