CN116375717A - Spiro compounds and their bifunctional compounds and uses - Google Patents
Spiro compounds and their bifunctional compounds and uses Download PDFInfo
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- CN116375717A CN116375717A CN202211680416.3A CN202211680416A CN116375717A CN 116375717 A CN116375717 A CN 116375717A CN 202211680416 A CN202211680416 A CN 202211680416A CN 116375717 A CN116375717 A CN 116375717A
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- alkylene
- halogen
- substituted
- alkyl
- membered
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- 125000003342 alkenyl group Chemical group 0.000 claims description 247
- 125000000304 alkynyl group Chemical group 0.000 claims description 247
- 125000003118 aryl group Chemical group 0.000 claims description 165
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 164
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 143
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides a novel spiro compound with a binding effect with E3 ligase protein CRBN and application thereof in preparing medicaments for treating cell abnormal proliferation diseases. The invention also provides a bifunctional compound targeting protein degradation, and an intermediate compound in the synthesis process of the bifunctional compound.
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 and a protein degradation targeting chimeric (PROTACs) bifunctional compound containing the ligand compound.
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, the liquid crystal display device comprises a liquid crystal display device,
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;
the A ring is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring and 5-10 membered heteroaromatic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic 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 group- (6-to 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, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring,The heteroaromatic ring may further optionally be 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 groups.
Further, the structure shown in formula I is shown in formula IIa or IIb:
wherein the substituents are as defined above.
Still further, the method further comprises the steps of,
Wherein the ring selected from ring A may be further optionally substituted with one, two, three or four independent R A1 And (3) substitution.
As preferable: each R A1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, -C 1~3 Alkyl, halogen substituted-C 1~3 An alkyl group.
As preferable: r is R 1 Selected from hydrogen, methyl, ethyl, propyl.
As preferable: 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.
Further: 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 heteroaromatic ring), - (4-6 membered)Heterocycloalkyl), - (3-6 membered cycloalkyl) wherein the aromatic, heteroaromatic, 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.
Further specifically, the compound is represented by formula III:
wherein, the liquid crystal display device comprises a liquid crystal display device,
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;
R 21 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 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 22 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.
In some embodiments of the invention, the compounds are specifically:
the invention also provides a compound shown in a formula V, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
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;
the A ring is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring and 5-10 membered heteroaromatic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic 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 groupradical-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;
X 1 are independently selected from chemical bond, =cr 21 -、C 1~6 Alkylene-, C 2~6 Alkenylene, C 2~6 Alkynylene, halogen substituted C 1~6 Alkylene, halogen substituted C 2~6 Alkenylene, halogen substituted C 2~6 Alkynylene radicals, -C 0~4 alkylene-O-, -C 0~4 alkylene-OC (O) -, -C 0~4 alkylene-S-, -C 0~4 alkylene-S (O) 2 -、-C 0~4 alkylene-S (O) -, -C 0~4 alkylene-S (O) 2 NR 21 -、-C 0~4 alkylene-S (O) NR 21 -、-C 0~4 alkylene-C (O) -, -C 0~4 alkylene-C (O) O-, -C 0~4 alkylene-C (O) NR 21 -、-C 0~4 alkylene-NR 21 -、-C 0~4 alkylene-NR 21 C(O)-、-C 0~4 alkylene-NR 21 S(O) 2 -、-C 0~4 alkylene-NR 21 S(O)-、-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 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 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;
t is selected from- (L) T ) q -;
q is an integer from 1 to 50;
each L T Are respectively and independently selected from CR T2 R T3 、C(O)、-C(S)-、O、S、S(O)、S(O) 2 、NR T2 、-CR T2 =CR T3 -, -C.ident.C-, 3-to 12-membered cycloalkane, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-membered heteroaromatic ring, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocyclic ring; wherein the cycloalkane, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three R T1 Substitution;
each R T1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr T2 R T3 、-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, -C 0~4 alkylene-OC (O) R T2 、-C 0~4 alkylene-SR T2 、-C 0~4 alkylene-S (O) 2 R T2 、-C 0~4 alkylene-S (O) R T2 、-C 0~4 alkylene-S (O) 2 NR T2 R T3 、-C 0~4 alkylene-S (O) NR T2 R T3 、-C 0~4 alkylene-C (O) R T2 、-C 0~4 alkylene-C (O) OR T2 、-C 0~4 alkylene-C (O) NR T2 R T3 、-C 0~4 alkylene-NR T2 R T3 、-C 0~4 alkylene-NR T2 C(O)R T3 、-C 0~4 alkylene-NR T2 S(O) 2 R T3 、-C 0~4 alkylene-NR T2 S(O)R T3 、-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 T1 Substitution;
each R T1 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- (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);
X 2 selected from the group consisting of-NH 2 、-NHR X21 -OH, -SH, ethynyl, vinyl, -C (O) H, -C (O) OH-;
R X21 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.
Further, the compound of formula V is represented by formula VIa or formula VIb:
wherein the substituents are as defined above.
Still further, the compound is represented by formula VII:
Wherein, the liquid crystal display device comprises a liquid crystal display device,
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;
R 21 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 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, halogenPlain 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;
t is selected from- (L) T ) q -;
q is an integer from 1 to 30;
each L T Are respectively and independently selected from CR T2 R T3 、C(O)、-C(S)-、O、S、S(O)、S(O) 2 、NR T2 、-CR T2 =CR T3 -, -C.ident.C-, 3-to 12-membered cycloalkane, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-membered heteroaromatic ring, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocyclic ring; wherein the cycloalkane, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three R T1 Substitution;
each R T1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr T2 R T3 、-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, -C 0~4 alkylene-OC (O) R T2 、-C 0~4 alkylene-SR T2 、-C 0~4 alkylene-S (O) 2 R T2 、-C 0~4 alkylene-S (O) R T2 、-C 0~4 alkylene-S (O) 2 NR T2 R T3 、-C 0~4 alkylene-S (O) NR T2 R T3 、-C 0~4 alkylene-C (O) R T2 、-C 0~4 alkylene-C (O) OR T2 、-C 0~4 alkylene-C (O) NR T2 R T3 、-C 0~4 alkylene-NR T2 R T3 、-C 0~4 alkylene-NR T2 C(O)R T3 、-C 0~4 alkylene-NR T2 S(O) 2 R T3 、-C 0~4 alkylene-NR T2 S(O)R T3 、-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 groupsR of (2) T1 Substitution;
each R T1 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- (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);
X 2 Selected from the group consisting of-NH 2 、-NHR X21 -OH, -SH, ethynyl, vinyl, -C (O) H, -C (O) OH-;
R X21 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.
Further specifically, the method comprises the steps of,
In some embodiments of the present invention, the compound of formula V is 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.
Further, there is provided the use of said compound, 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 medicament.
Still further, the targeted protein degradation drug is a drug that relies on the E3 ligase CRBN for protein degradation.
The invention also provides a bifunctional compound shown in the formula X, or a deuterated compound or a stereoisomer or a pharmaceutically acceptable salt thereof:
Wherein, the liquid crystal display device comprises a liquid crystal display device,
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 extractionsubstituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl;
the A ring is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring and 5-10 membered heteroaromatic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic 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;
X 1 are independently selected from chemical bond, =cr 21 -、C 1~6 Alkylene-, C 2~6 Alkenylene, C 2~6 Alkynylene, halogen substituted C 1~6 Alkylene, halogen substituted C 2~6 Alkenylene, halogen substituted C 2~6 Alkynylene radicals, -C 0~4 alkylene-O-, -C 0~4 alkylene-OC (O) -, -C 0~4 alkylene-S-, -C 0~4 alkylene-S (O) 2 -、-C 0~4 alkylene-S (O) -, -C 0~4 alkylene-S (O) 2 NR 21 -、-C 0~4 alkylene-S (O) NR 21 -、-C 0~4 alkylene-C (O) -, -C 0~4 alkylene-C (O) O-, -C 0~4 alkylene-C (O) NR 21 -、-C 0~4 alkylene-NR 21 -、-C 0~4 alkylene-NR 21 C(O)-、-C 0~4 alkylene-NR 21 S(O) 2 -、-C 0~4 alkylene-NR 21 S(O)-、-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 and heteroaromatic rings may further be Optionally by one, two, three or four independent R 26 Substitution;
R 21 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 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 group-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;
t is selected from- (L) T ) q -;
q is an integer from 1 to 50;
each L T Are respectively and independently selected from CR T2 R T3 、C(O)、-C(S)-、O、S、S(O)、S(O) 2 、NR T2 、-CR T2 =CR T3 -, -C.ident.C-, 3-to 12-membered cycloalkane, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aromatic ring5-10 membered heteroaromatic ring, 5-12 membered spiro heterocycle, 5-12 membered bridged ring, 5-12 membered bridged heterocycle; wherein the cycloalkane, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three R T1 Substitution;
each R T1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr T2 R T3 、-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, -C 0~4 alkylene-OC (O) R T2 、-C 0~4 alkylene-SR T2 、-C 0~4 alkylene-S (O) 2 R T2 、-C 0~4 alkylene-S (O) R T2 、-C 0~4 alkylene-S (O) 2 NR T2 R T3 、-C 0~4 alkylene-S (O) NR T2 R T3 、-C 0~4 alkylene-C (O) R T2 、-C 0~4 alkylene-C (O) OR T2 、-C 0~4 alkylene-C (O) NR T2 R T3 、-C 0~4 alkylene-NR T2 R T3 、-C 0~4 alkylene-NR T2 C(O)R T3 、-C 0~4 alkylene-NR T2 S(O) 2 R T3 、-C 0~4 alkylene-NR T2 S(O)R T3 、-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 T1 Substitution;
each R T1 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- (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);
Z is a group having a binding effect to a target protein.
Further, the compound of formula X is represented by formula XIa or formula XIb:
wherein the substituents are as defined above.
Still further, the compound is represented by formula XII:
wherein, the liquid crystal display device comprises a liquid crystal display device,
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;
R 21 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 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;
t is selected from- (L) T ) q -;
q is an integer from 1 to 30;
each L T Are respectively and independently selected from CR T2 R T3 、C(O)、-C(S)-、O、S、S(O)、S(O) 2 、NR T2 、-CR T2 =CR T3 -, -C.ident.C-, 3-to 12-membered cycloalkane, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-membered heteroaromatic ring, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocyclic ring; wherein the cycloalkane, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three R T1 Substitution;
each R T1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr T2 R T3 、-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, -C 0~4 alkylene-OC (O) R T2 、-C 0~4 alkylene-SR T2 、-C 0~4 alkylene-S (O) 2 R T2 、-C 0~4 alkylene-S (O) R T2 、-C 0~4 alkylene-S (O) 2 NR T2 R T3 、-C 0~4 alkylene-S (O) NR T2 R T3 、-C 0~4 alkylene-C (O) R T2 、-C 0~4 alkylene-C (O) OR T2 、-C 0~4 alkylene-C (O) NR T2 R T3 、-C 0~4 alkylene-NR T2 R T3 、-C 0~4 alkylene-NR T2 C(O)R T3 、-C 0~4 alkylene-NR T2 S(O) 2 R T3 、-C 0~4 alkylene-NR T2 S(O)R T3 、-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 T1 Substitution;
each R T1 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- (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);
Z is a group having a binding effect to a target protein.
Further specifically, the method comprises the steps of,
In some embodiments of the present invention, the compound of formula X is specifically:
the invention also provides the application of any one of the bifunctional compounds, or stereoisomers thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof in preparing medicines.
Further, the drug is a targeted protein degradation drug.
Still further, the drug is a protein degradation drug targeted by the E3 ligase CRBN.
The compounds of formula I, formula V or formula X of the present invention do not comprise the following compounds:
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.
"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 of the groups "a" to "bAlkyl groups of 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. Representative branched alkyl groups 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" may 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.
The invention is that"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 that do not contain ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. 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, & I>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: pd (dppf) Cl 2 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride;
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-MS 2020 (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 A-3
To a 50mL reaction flask, compound A-2 (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 A-1 (190.00 mg,0.65 mmol) was added, the reaction was stirred under ice bath conditions for 0.5 hours and 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 concentrated under reduced pressure to give Compound A-3 (crude product).
Step two, preparation of Compound A-4
A50 mL reaction flask was successively charged with Compound A-3 (crude product), sodium hydroxide (44.00 mg,1.10 mmol), tetrahydrofuran (4 mL) and water (2 mL), the reaction was quenched after stirring at room temperature for 8 hours (LC-MS monitoring), the pH of the system was adjusted to 6-7 with 1N hydrochloric acid solution, and the reaction solution was concentrated to give Compound A-4 (crude product) which was directly used for the next reaction.
Step three, preparation of Compound A-6
To a 50mL reaction flask, DIPEA (132.25 mg,1.00mmol, 178.06. Mu.L), HATU (250.96 mg,0.66 mmol) and DCM (2 mL) were added sequentially, after the reaction system temperature had fallen to 0deg.C, compound A-4 (91.71 mg,0.65 mmol) was added, the reaction was quenched (monitored by LC-MS) after stirring under ice bath conditions for 0.5 hours, saturated NaCl solution (10 mL) and ethyl acetate (3X 20 mL) were extracted, the organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, the solvent was evaporated, and concentrated under reduced pressure to give Compound A-6 (80.00 mg, 126.52. Mu. Mol,19.46% yield).
Step four, synthesis of compound A1
Compound A-6 (80.00 mg, 126.52. Mu. Mol) was dissolved in a mixed solution of 6N HCl and ethyl acetate (2 mL) in a 25mL reaction flask, the reaction was stirred at room temperature for 0.5 hour, quenched (LC-MS monitoring), extracted with saturated NaCl solution (10 mL) and ethyl acetate (3X 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, the column was chromatographed using an eluent in a volume ratio of petroleum ether/ethyl acetate=100:1 to 3:1, and the solvent was removed by concentration under reduced pressure to give compound A1 (25.20 mg, 47.35. Mu. Mol,37.42% yield, 99.4% purity), LCMS: C 28 H 33 N 6 O 3 S,[M+H] + :533.2,found 533.3。 1 H NMR(600MHz,Methonal-d 4 )δ8.12-7.83(m,2H),7.55-7.44(m,2H),7.39-7.04(m,4H),4.96-4.93(m,1H),4.79-4.72(m,1H),4.50-4.29(m,3H),4.20-3.89(m,3H),3.57-3.54(m,2H),3.31-3.12(m,6H),3.03-2.89(m,2H),2.80-2.45(m,4H).
Referring to the synthesis method of the compound A-6, the following raw materials of Table 1 were used instead of the compounds A-1, A-2 and A-5, and the other raw materials and the operation methods were unchanged, to obtain the compounds A2-A16.
TABLE 1 Compounds A2-A16
Example 2 preparation of bifunctional Compounds
Preparation of the bifunctional compound BRD 4-linker-CRBN:
step 1: synthesis of Compound 3
At 25A0 mL reaction flask was charged with Compound 1 (1.00 g,4.67 mol), compound 2 (1.50 g,6.25 mol), K 2 CO 3 (3.86 g,2.80 mol) and ACN (50 mL), the temperature is raised to 70 ℃ and stirred, and after the reaction is complete, water is added to quench the reaction (monitored by LC-MS). Saturated NaCl solution (50 mL) and ethyl acetate (3X 50 mL) are extracted, the organic phases are combined, the organic phases are dried with anhydrous sodium sulfate, the solvent is evaporated, and the solvent is removed by vacuum concentration to obtain the compound 3 (crude product), LCMS (ESI) [ M+H)]:373.0。
Characterization of the compound obtained: MS (ESI) M/z=373.0 (m+1) + 。
Step 2: preparation of Compound 4
A150 mL reaction bottle is sequentially added with compound 3 (crude product), sodium hydroxide (3.39 g,84.75 mmol), ethanol (10 mL) and water (15 mL), stirring and reacting for 8 hours at normal temperature, quenching reaction (LC-MS monitoring), adjusting the pH value of the system to 6-7 by using 1N hydrochloric acid solution, concentrating the reaction solution to obtain compound 4 (crude product), directly used for the next reaction, and LCMS (ESI) [ M+H ]:255.0.
Characterization of the compound obtained: MS (ESI) M/z= 254.8 (m+1) + 。
Step 3: preparation of Compound 6
To a 50mL reaction flask under nitrogen was added in order Compound 4 (255.06 mg,1.00 mmol), compound 5 (166.97 mg,1.00 mmol), K 2 CO 3 (202.39 mg,2.00 mmol), 1, 4-dioxane and water (4 mL/1 mL) and Pd (dppf) Cl 2 (0.25 mol%). The reaction was sealed and quenched after stirring at 80℃for 2 hours (LC-MS monitoring). Saturated NaCl solution (20 mL) and ethyl acetate (3X 20 mL) are used for extraction, organic phases are combined, the organic phases are dried by anhydrous sodium sulfate, the solvent is evaporated, column chromatography is carried out, the volume ratio of eluent used is petroleum ether/ethyl acetate=1:100-1:5,after concentrating under reduced pressure to remove the solvent, compound 6 (200.00 mg, 672.71. Mu. Mol,67.27% yield) was obtained, LCMS (ESI) [ M+H)]:298.1。
Characterization of the compound obtained: MS (ESI) M/z= 298.2 (m+1) + 。
Step 4: preparation of Compound 7
To a 50mL reaction flask, compound 6 (70.00 mg, 235.45. Mu. Mol), DIPEA (91.29 mg, 706.35. Mu. Mol, 123.03. Mu. L), HATU (89.30 mg, 235.45. Mu. Mol) and DMF (5 mL) were added sequentially, after the reaction system temperature had dropped to 0deg.C, compound Linker 1 (50.93 mg, 235.45. Mu. Mol) was added, the reaction was stirred under ice bath conditions for 0.5 hour and 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, purified by MPLC, the solvent was evaporated, and concentrated under reduced pressure to give Compound 7 (100.00 mg, 201.77. Mu. Mol,85.70% yield) LCMS (ESI) [ M+H ]:496 3.
Characterization of the compound obtained: MS (ESI) M/z= 496.4 (m+1) + 。
Step 5: synthesis of Compound 8
In a 25mL reaction flask, compound 7 (80.00 mg, 161.42. Mu. Mol), trifluoroacetic acid (18.41 mg, 161.42. Mu. Mol,2 mL) and DCM (5 mL) were sequentially added, the reaction was stirred at room temperature for 0.5 hour, quenched (monitored by LC-MS), saturated NaCl solution (10 mL) and ethyl acetate (3X 10 mL) were extracted, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, the solvent was evaporated, and the column was chromatographed using an eluent in a volume ratio of petroleum ether/ethyl acetate=100:1 to 3:1, and after removal of the solvent by concentration under reduced pressure, compound 8 (crude) was obtained, LCMS (ESI) [ M+H ]:396.2.
Characterization of the compound obtained: MS (ESI) M/z= 396.4 (m+1) + 。
Step 6: synthesis of Compound 10
A50 mL reaction flask was charged with Compound 8 (crude), compound A-1 (44.05 mg, 151.71. Mu. Mol), naBH3CN (47.67 mg, 758.55. Mu. Mol) and tetrahydrofuran (5 mL) in this order. The reaction was stirred at ambient temperature for 2 hours, quenched (monitored by LC-MS), evaporated to dryness, purified by MPLC, and concentrated under reduced pressure to give compound 10 (80.00 mg, 119.43. Mu. Mol,78.72% yield), LCMS (ESI) [ M+H ]:670.4.
Characterization of the compound obtained: MS (ESI) M/z= 670.5 (m+1) + 。
Step 7: synthesis of Compound 11
To a 50mL reaction flask, compound A-3 (21.16 mg, 89.57. Mu. Mol), DIPEA (34.73 mg, 268.72. Mu. Mol, 46.81. Mu. L), HATU (34.04 mg, 89.57. Mu. Mol) and DMF (5 mL) were added sequentially, after the reaction system temperature was lowered to 0deg.C, compound 10 (60.00 mg, 89.57. Mu. Mol) was added, the reaction was stirred under ice bath conditions for 0.5 hour and 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, purified by MPLC, the solvent was evaporated, and concentrated under reduced pressure to give compound 11 (60.00 mg, 67.56. Mu. Mol,75.43% yield) LCMS (ESI) [ M+H ]:888.4.
Characterization of the compound obtained: MS (ESI) M/z= 888.3 (m+1) + 。
Step 8: synthesis of Compound 12
A50 mL reaction flask was charged with 11 (60.00 mg, 67.56. Mu. Mol), sodium hydroxide (18.02 mg, 450.41. Mu. Mol), tetrahydrofuran (5 mL) and water (1 mL), stirred at room temperature for 8 hours, quenched (monitored by LC-MS), adjusted to pH 6-7 with 1N hydrochloric acid solution, and concentrated to give 12 (crude product), which was used directly in the next reaction, LCMS (ESI) [ M+H ]:847.4.
Characterization of the compound obtained: MS (ESI) M/z=847.5 (m+1) + 。
Step 9: synthesis of Compound 13
To a 50mL reaction flask, DIPEA (22.18 mg, 171.61. Mu. Mol, 29.89. Mu.L), HATU (21.66 mg, 57.20. Mu. Mol) and DMF (5 mL) were added sequentially, after the reaction system temperature had fallen to 0deg.C, compound A-6 (8.08 mg, 57.20. Mu. Mol) was added, the reaction was quenched by stirring under ice bath conditions for 0.5 hour (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, purified by MPLC, the solvent was evaporated, and after concentrating under reduced pressure to remove the solvent, compound 13 (40.00 mg, 40.11. Mu. Mol,70.12% yield) S (ESI) [ M+H ]:998.5 was obtained.
Characterization of the compound obtained: MS (ESI) M/z= 998.5 (m+1) + 。
Step 10: synthesis of HGC01
Compound 13 (40.00 mg, 40.11. Mu. Mol) was dissolved in a mixed solution of 6N HCl and 1, 4-dioxane (5 mL) in a 25mL reaction flask, the reaction was quenched after stirring at room temperature for 0.5 hours (LC-MS monitoring), extraction was completed with saturated NaCl solution (10 mL) and ethyl acetate (3X 10 mL), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, the solvent was evaporated, and the column chromatography was carried out using an eluent in a volume ratio of petroleum ether/ethyl acetate=100:1 to 3:1, and after removal of the solvent by concentration under reduced pressure, compound HGC01 (15.50 mg, 15.67. Mu. Mol,39.07% yield) was obtained, LCMS (ESI) [ M+H ]:897.41.
Characterization of the compound obtained: MS (ESI) M/z= 897.7 (m+1) + 。
1 H NMR(600MHz,Methanol-d 4 )δ7.98-7.80(m,4H),7.67(s,1H),7.52-7.44(m,5H),7.34-7.21(m,3H),4.86(s,1H),4.72-4.54(m,2H),4.48-4.25(m,4H),4.12(s,1H),3.69(s,3H),3.47-3.46(m,5H),3.36-3.14(m,5H),2.88-2.85(m,3H),2.75(s,1H),2.74-2.61(m,4H),2.22(s,3H),1.81-1.63(m,3H),1.52(s,3H),1.21(s,2H).HPLC purity>90%.
According to the synthesis route of HGC01, the compound Linker 1 was replaced with the compound shown by Linker(s) in the following table, and the remaining operations were unchanged, so as to prepare bifunctional compounds HGC02 and HGC03.
Bifunctional compound HGC02
For C 52 H 61 N 8 O 6 S,[M+H] + 925.4;found 925.7. 1 H NMR(600MHz,Methanol-d 4 )δ7.99-7.83(m,4H),7.66(s,1H),7.50-7.44(m,5H),7.35-7.23(m,3H),4.86(s,1H),4.68-4.57(m,1H),4.39-4.28(m,4H),4.18-4.16(m,1H),4.00-3.98(m,1H),3.67-3.58(m,4H),3.47-3.44(m,4H),3.31-3.14(m,5H),2.73-2.69(m,1H),2.62-2.60(m,7H),2.21(s,3H),1.78-1.69(m,3H),1.60-1.59(m,3H),1.21-1.12(m,2H),0.99-0.96(m,2H),0.90-0.88(m,2H).HPLC purity>95%.
Bifunctional compound HGC03
For C 54 H 64 N 8 O 6 S,[M/2+H] + 477.2;found 477.8. 1 H NMR(600MHz,Methanol-d 4 )δ8.00-7.80(m,4H),7.66(s,1H),7.35-7.22(m,8H),4.93(s,2H),4.87-4.45(m,5H),4.18(s,1H),3.71(s,3H),3.46-3.30(m,6H),3.25-3.11(m,4H),3.01-2.95(m,2H),2.73-2.61(m,5H),2.23(s,3H),1.67-1.58(m,4H),1.40–1.30(m,6H),129–1.28(m,2H),1.21-1.09(m,4H).HPLC purity>80%.
The invention has the technical effects that the invention is illustrated by the following test examples:
test example 1 detection of the binding of Compounds to CRBN/DDB1 TRIC (temperature dependent method of fluorescence intensity Change)
1. Experimental materials and reagents
Disodium hydrogen phosphate (Sigma), sodium dihydrogen phosphate (Sigma), pluronic F-127 (Sigma), his-Tag Labeling Kit-RED-tris-NTA (NanoTemper), dianthus 384well plates (nanosampler), CRBN/DDB1 protein (HitGen).
2. Experimental method
6.43. Mu.L of 2.8. Mu.M dye was mixed with 443.57. Mu.L of 20mM disodium hydrogen phosphate, 20mM sodium dihydrogen phosphate, 0.1% Pluronic F-127, pH7.0 buffer to give 450.0. Mu.L of 40.0nM dye; the histidine-tagged CRBN/DDB1 protein was diluted to 400.0nM, 445.0. Mu.L of 400.0nM histidine-tagged CRBN/DDB1 protein was mixed with 445.0. Mu.L of 40.0nM dye and incubated for 30 minutes at room temperature. Centrifuge at 15000g for 10 min at 4℃and take the supernatant into a new centrifuge tube for further use.
Dry powders of the compounds were dissolved in DMSO, the compounds were diluted in a gradient with 20mM disodium hydrogen phosphate, 20mM sodium dihydrogen phosphate, 0.1% Pluronic F-127, pH7.0 buffer for a total of 12 concentration gradients, 10.0. Mu.L of each compound was mixed with 10.0. Mu.L of the labeled protein and thoroughly mixed, the final concentration of DMSO in the whole reaction system (20.0. Mu.L) was 1.0%, incubated at room temperature for 20 minutes, readings were taken with DI, and Kd was calculated by DI.SA.
3. Data analysis
Table 1: binding strength of Compounds to CRBN/DDB1 protein
Numbering device | Kd | Numbering device | Kd | Numbering device | Kd |
A1 | ++ | A3 | +++ | A7 | + |
A2 | + | A6 | ++ | A8 | +++ |
Wherein +represents 200. Mu.M > Kd > 100. Mu.M, ++ represents 100. Mu.M > Kd > 10. Mu.M, +++ represents 10 mu M > Kd > 1. Mu.M, M > Kd ] 1. Mu.M of the total amount of the components.
Test example 2 detection of CRBN/DDB1 Activity inhibition 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 2: compounds and CRBN/DDB1 protein inhibition tables
Numbering device | IC 50 | Numbering device | IC 50 | Numbering device | IC 50 |
A1 | +++ | A4 | ++ | A7 | ++ |
A2 | + | A5 | + | A8 | ++ |
A3 | ++ | A6 | ++ | A9 | + |
Wherein +represents200μM>IC 50 >100. Mu.M, ++represents 100. Mu.M>IC 50 >The concentration of the solution was 10. Mu.M, ++ represents 10 mu M>IC 50 >1. Mu.M of the total amount of the components, ++ + + and representative IC 50 <1μM。
The above experiments show that the compounds of the embodiments of the present invention have good CRBN binding ability and inhibition, and can be effectively used for the treatment of diseases associated with abnormal CRBN activity.
Test example 3 evaluation of Compounds by Western blot method for BRD4 protein degradation experiments in MV-4-11 cells
1. Experimental instrument and reagents:
SDS-PAGE gel(4-12%)(Genscript)、PMSF 100mM(Biyotime)、Cocktail 100×(Biyotime)、P/S、IMDM modified medium with L-glutamine,HEPES(Hyclone)、FBS(Corning)、4×loading buffer(Thermo)、BRD4 rabbit mAb(Abcam)、c-Myc Rabbit mAb(CST)、CRBN Rb mAb(SIGMA)、Anti-rabbit IgG-HRP(CST)、Anti-β-actin-HRP(Abcam)、RIPA(Biyotime)、Tween-20、MV-4-11cell(ATCC)、BCA Protein Assay Kit(TIANGEN)、Immobilon Western Chemilunescent HRP Substrate(Millipore)。
2. experimental method
1) Incubation of compounds with cells: 1mL of 2X 10 6 MV-4-11 cells (medium 89% IMDM,10% FBS,1% P/S) were seeded in 6-well cell culture plates, compounds were diluted with DMSO at three concentration points, then compounds diluted in DMSO were re-diluted into MV-4-11 medium, and 1mL of the diluted compounds were directly added to six well plates for cell culture and incubated for 24 hours.
2) Protein extraction: after 24h incubation of the compounds with cells, the cells were collected in 1.5mL centrifuge tubes, washed 2 times with ice PBS, the supernatant removed and lysed on ice for 60min with 70 μl RIPA lysate added; centrifuging the cell lysate with a low-temperature centrifuge for 10min at 15000rpm, and collecting supernatant; the protein was quantified using BCA Protein Assay Kit from the cell lysate supernatant obtained. The sample was obtained by adding 4×loading buffer to the supernatant of the cell lysate and incubating at 95℃for 10 min. The resulting sample was stored in a-80 ℃ refrigerator for the next day.
3) Werstern blot: samples of 20. Mu.g were taken for SDS-PAGE and transfer, membranes were blocked with 5% skim milk at room temperature for 1h, then incubated with BRD4 rabit mAb, c-Myc rabit mAb, CRBN Rb mAb, anti- β -actin-HRP antibody overnight at 4℃and after three TBST washes with Anti-rabit IgG-HRP secondary antibody for 1h at room temperature, after three TBST washes, developed with Immobilon Western Chemiluminescent HRP Substrate and analyzed using a gum-making instrument.
3. Data analysis
And (3) analyzing by using gray analysis software, and analyzing the degradation condition of the BRD4 protein after correcting the BRD4 protein by the beta-actin.
The compounds prepared in the examples were subjected to BRD4 protein degradation assay according to the methods described above, the test results are shown in Table 3, in which DCs of the respective compounds were determined 50 By way of illustration, in table 3:
"+" indicates DC 50 A value between 0.5 and 3. Mu.M;
TABLE 3 degradation of BRD4 protein in MV-4-11 cells by Compounds
Compounds of formula (I) | BRD4 | c-Myc |
HGC01 | + | + |
Experiments show that the compound HGC01 provided by the embodiment of the invention has good BRD4 protein degradation activity and can be effectively used for treating diseases related to BRD4 activity abnormality.
Claims (28)
1. A compound of formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
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;
the A ring is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring and 5-10 membered heteroaromatic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic 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 ring, and heteroaromatic ring may be further optionallyIs 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 groups.
4. A compound according to any one of claims 3, wherein: each R A1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, -C 1~3 Alkyl, halogen substituted-C 1~3 An alkyl group.
6. A compound according to any one of claim 1, wherein: r is R 1 Selected from hydrogen, methyl, ethyl, propyl.
7. A compound according to any one of claim 1, wherein: 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 heterocycle)Alkyl), -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.
8. A compound according to any one of claims 7, wherein: 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 R is independently 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.
10. A compound according to any one of claims 1 to 3, characterized in that: the compound is shown in a formula III:
wherein, the liquid crystal display device comprises a liquid crystal display device,
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;
R 21 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 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 22 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.
12. a compound of formula V, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
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;
the A ring is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring and 5-10 membered heteroaromatic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic 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;
X 1 are independently selected from chemical bond, =cr 21 -、C 1~6 Alkylene-, C 2~6 Alkenylene, C 2~6 Alkynylene, halogen substituted C 1~6 Alkylene, halogen substituted C 2~6 Alkenylene, halogen substituted C 2~6 Alkynylene radicals, -C 0~4 alkylene-O-, -C 0~4 alkylene-OC (O) -, -C 0~4 alkylene-S-, -C 0~4 alkylene-S (O) 2 -、-C 0~4 alkylene-S (O) -, -C 0~4 alkylene-S (O) 2 NR 21 -、-C 0~4 alkylene-S (O) NR 21 -、-C 0~4 alkylene-C (O) -, -C 0~4 alkylene-C (O) O-, -C 0~4 alkylene-C (O) NR 21 -、-C 0~4 alkylene-NR 21 -、-C 0~4 alkylene-NR 21 C(O)-、-C 0~4 alkylene-NR 21 S(O) 2 -、-C 0~4 alkylene-NR 21 S(O)-、-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 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 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;
T is selected from- (L) T ) q -;
q is an integer from 1 to 50;
each L T Are respectively and independently selected from CR T2 R T3 、C(O)、-C(S)-、O、S、S(O)、S(O) 2 、NR T2 、-CR T2 =CR T3 -, -C.ident.C-, 3-to 12-membered cycloalkane, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-membered heteroaromatic ring, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocyclic ring; wherein the cycloalkane, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three R T1 Substitution;
each R T1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr T2 R T3 、-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, -C 0~4 alkylene-OC (O) R T2 、-C 0~4 alkylene-SR T2 、-C 0~4 alkylene-S (O) 2 R T2 、-C 0~4 alkylene-S (O) R T2 、-C 0~4 alkylene-S (O) 2 NR T2 R T3 、-C 0~4 alkylene-S (O) NR T2 R T3 、-C 0~4 alkylene-C (O) R T2 、-C 0~4 alkylene-C (O) OR T2 、-C 0~4 alkylene-C (O) NR T2 R T3 、-C 0~4 alkylene-NR T2 R T3 、-C 0~4 alkylene-NR T2 C(O)R T3 、-C 0~4 alkylene-NR T2 S(O) 2 R T3 、-C 0~4 alkylene-NR T2 S(O)R T3 、-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 T1 Substitution;
each R T1 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- (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);
X 2 selected from the group consisting of-NH 2 、-NHR X21 -OH, -SH, ethynyl, vinyl, -C (O) H, -C (O) OH-;
R X21 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.
14. A compound according to any one of claims 12 to 13, characterized in that: the compound is shown as a formula VII:
wherein, the liquid crystal display device comprises a liquid crystal display device,
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;
R 21 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 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 group- (6-to 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;
t is selected from- (L) T ) q -;
q is an integer from 1 to 30;
each L T Are respectively and independently selected from CR T2 R T3 、C(O)、-C(S)-、O、S、S(O)、S(O) 2 、NR T2 、-CR T2 =CR T3 -, -C.ident.C-, 3-to 12-membered cycloalkane, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-membered heteroaromatic ring, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocyclic ring; wherein the cycloalkane, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three R T1 Substitution;
each R T1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr T2 R T3 、-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, -C 0~4 alkylene-OC (O) R T2 、-C 0~4 alkylene-SR T2 、-C 0~4 alkylene-S (O) 2 R T2 、-C 0~4 alkylene-S (O) R T2 、-C 0~4 alkylene-S (O) 2 NR T2 R T3 、-C 0~4 alkylene-S (O) NR T2 R T3 、-C 0~4 alkylene-C (O) R T2 、-C 0~4 alkylene-C (O) OR T2 、-C 0~4 alkylene-C (O) NR T2 R T3 、-C 0~4 alkylene-NR T2 R T3 、-C 0~4 alkylene-NR T2 C(O)R T3 、-C 0~4 alkylene-NR T2 S(O) 2 R T3 、-C 0~4 alkylene-NR T2 S(O)R T3 、-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 T1 Substitution;
each R T1 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- (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);
X 2 selected from the group consisting of-NH 2 、-NHR X21 -OH, -SH, ethynyl, vinyl, -C (O) H, -C (O) OH-;
R X21 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.
17. use of a compound according to any one of claims 1 to 11, 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.
18. Use according to claim 17, characterized in that: the disease is cancer.
19. Use of a compound according to any one of claims 1 to 16, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a targeted protein degradation medicament.
20. Use according to claim 19, characterized in that: the compound, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is used as an intermediate in the preparation of targeted protein degradation medicaments.
21. Use according to claim 20, characterized in that: the targeted protein degradation drug is a drug which relies on E3 ligase CRBN for protein degradation.
22. A bifunctional compound represented by formula X, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
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;
the A ring is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring and 5-10 membered heteroaromatic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic, heteroaromatic 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;
X 1 are independently selected from chemical bond, =cr 21 -、C 1~6 Alkylene-, C 2~6 Alkenylene, C 2~6 Alkynylene, halogen substituted C 1~6 Alkylene, halogen substituted C 2~6 Alkenylene, halogen substituted C 2~6 Alkynylene radicals, -C 0~4 alkylene-O-, -C 0~4 alkylene-OC (O) -, -C 0~4 alkylene-S-, -C 0~4 alkylene-S (O) 2 -、-C 0~4 alkylene-S (O) -, -C 0~4 alkylene-S (O) 2 NR 21 -、-C 0~4 alkylene-S (O) NR 21 -、-C 0~4 alkylene-C (O) -, -C 0~4 alkylene-C (O) O-, -C 0~4 alkylene-C (O) NR 21 -、-C 0~4 alkylene-NR 21 -、-C 0~4 alkylene-NR 21 C(O)-、-C 0~4 alkylene-NR 21 S(O) 2 -、-C 0~4 alkylene-NR 21 S(O)-、-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 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 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 ring, heteroaromatic ring may be further optionally substituted with one or twoThree or four independent R' s 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;
t is selected from- (L) T ) q -;
q is an integer from 1 to 50;
each L T Are respectively and independently selected from CR T2 R T3 、C(O)、-C(S)-、O、S、S(O)、S(O) 2 、NR T2 、-CR T2 =CR T3 -, -C.ident.C-, 3-to 12-membered cycloalkane, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-membered heteroaromatic ring, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocyclic ring; wherein the cycloalkane, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three R T1 Substitution;
each R T1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr T2 R T3 、-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, -C 0~4 alkylene-OC (O) R T2 、-C 0~4 alkylene-SR T2 、-C 0~4 alkylene-S (O) 2 R T2 、-C 0~4 alkylene-S (O) R T2 、-C 0~4 alkylene-S (O) 2 NR T2 R T3 、-C 0~4 Alkylene-S(O)NR T2 R T3 、-C 0~4 alkylene-C (O) R T2 、-C 0~4 alkylene-C (O) OR T2 、-C 0~4 alkylene-C (O) NR T2 R T3 、-C 0~4 alkylene-NR T2 R T3 、-C 0~4 alkylene-NR T2 C(O)R T3 、-C 0~4 alkylene-NR T2 S(O) 2 R T3 、-C 0~4 alkylene-NR T2 S(O)R T3 、-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 T1 Substitution;
each R T1 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- (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);
Z is a group having a binding effect to a target protein.
24. The bifunctional compound of claim 23, wherein: the compound is shown as a formula XII:
wherein, the liquid crystal display device comprises a liquid crystal display device,
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;
R 21 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 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 grouphalogen-substituted-C 2~6 Alkenyl, halogen-substituted-C 2~6 Alkynyl;
T is selected from- (L) T ) q -;
q is an integer from 1 to 30;
each L T Are respectively and independently selected from CR T2 R T3 、C(O)、-C(S)-、O、S、S(O)、S(O) 2 、NR T2 、-CR T2 =CR T3 -, -C.ident.C-, 3-to 12-membered cycloalkane, 3-to 12-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-membered heteroaromatic ring, 5-to 12-membered spiro ring, 5-to 12-membered bridged heterocyclic ring; wherein the cycloalkane, heterocycloalkyl, aromatic ring, aromatic heterocycle, spirocycle, spiroheterocycle, bridged ring, bridged heterocycle may be further substituted with one, two or three R T1 Substitution;
each R T1 Independently selected from hydrogen, halogen, cyano, nitro, =o, =s, =cr T2 R T3 、-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, -C 0~4 alkylene-OC (O) R T2 、-C 0~4 alkylene-SR T2 、-C 0~4 alkylene-S (O) 2 R T2 、-C 0~4 alkylene-S (O) R T2 、-C 0~4 alkylene-S (O) 2 NR T2 R T3 、-C 0~4 alkylene-S (O) NR T2 R T3 、-C 0~4 alkylene-C (O) R T2 、-C 0~4 alkylene-C (O) OR T2 、-C 0~4 alkylene-C (O) NR T2 R T3 、-C 0~4 alkylene-NR T2 R T3 、-C 0~4 alkylene-NR T2 C(O)R T3 、-C 0~4 alkylene-NR T2 S(O) 2 R T3 、-C 0~4 alkylene-NR T2 S(O)R T3 、-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 T1 Substitution;
each R T1 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- (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);
z is a group having a binding effect to a target protein.
26. The use of the bifunctional compound of any one of claims 22-25, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament.
27. Use according to claim 26, characterized in that: the drug is a targeted protein degradation drug.
28. Use according to claim 26, characterized in that: the medicine is a medicine for degrading CRBN targeted protein by E3 ligase.
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