C 3 - carbon-linked glutarimide degradation determinants

CN122167340APending Publication Date: 2026-06-09C4 THERAPEUTICS INC

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Patent Information

Authority / Receiving Office: CN · China
Patent Type: Applications(China)
Current Assignee / Owner: C4 THERAPEUTICS INC
Filing Date: 2017-05-10
Publication Date: 2026-06-09

Application Information

Patent Timeline

10 May 2017

Application

09 Jun 2026

Publication

CN122167340A

IPC: C07D211/88; C07D221/20; C07D221/22; C07D401/12; C07D471/04; C07D471/18; C07D413/12; C07D487/04; C07D491/048; C07D495/04; A61P35/00; A61P37/06; A61P29/00; A61P19/02; A61P3/10; A61P9/00; A61P31/12; A61P31/14; A61P31/20; A61P31/16; A61P31/10; A61P31/04; A61P33/00; A61P33/02; A61P33/14; A61P35/02; A61K31/4418; A61K31/438; A61K31/439; A61K31/4439; A61K31/444; A61K31/519; A61K31/553; A61K31/4545; A61K31/5517

CPC: C07D401/14; C07K14/72; C07K14/47; C07D405/14; C07D413/14; C07D221/22; C07D401/04; C07D401/06

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Application Domain

Antibacterial agents Antimycotics

Technology Topics

Moiety In vivo

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AI Technical Summary

Technical Problem

Existing technologies struggle to effectively regulate protein degradation in vivo, particularly in therapeutic applications, where there is a lack of compounds and methods capable of efficiently targeting specific proteins.

Method used

A C3-carbon linked glutarimide degradation determinant was developed, which binds nonvalently to target proteins via E3 ubiquitin ligases (such as cereblon) and utilizes the ubiquitin-proteasome pathway (UPP) for selective protein degradation.

Benefits of technology

It achieves efficient in vivo degradation of specific proteins, with potential therapeutic applications, such as the treatment of cancer, inflammation, and infectious diseases, providing a new therapeutic intervention.

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Abstract

The present invention provides degron bodies with carbon-linked E3 ubiquitin ligase targeting moieties (degrons) that can be linked to targeting ligands for proteins selected for degradation in vivo, methods and compositions for their use, and methods for their preparation.

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Claims

1. Compounds of formula I or II: (AND) (II) Or its pharmaceutically acceptable salts, N-oxides, or isotopic derivatives. in: W 1 It is CR 1 R 2 C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; W 2 It is CR 3 R 4 C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; X is independently selected from NH and NR. 12 CH2, CHR 12 C(R) 12 2. O or S; N is 0, 1, 2, or 3; Is it a single bond or a double bond? R 6 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and And when R 10 When Y is bonded to carbon, then Y is CR. 10 And when R 10 Bonded to nitrogen Z or Z 2 When, then Z or Z 2 It is NR 10 ; R 1 R 2 R 3 R 4 R 7 R 8 and R 15 Independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, carbocyclic, aryl, heteroaryl, hydroxyl, halogen, azide, CN-, alkoxy, amine, -NHalkyl and -Nalkyl2, -NH (aliphatic) and -N (independently aliphatic)2, or R 1 and R 2 Together with the carbon atoms they are attached to, they form 3-, 4-, 5- or 6-membered spirocarbocycles, or 4-, 5- or 6-membered spiroheterocycles containing one or two heteroatoms selected from N and O; Or R 3 and R 4 Together with the carbon atoms they are attached to, they form 3-, 4-, 5- or 6-membered spirocarbocycles, or 4-, 5- or 6-membered spiroheterocycles containing one or two heteroatoms selected from N and O; Or R 7 and R 8 Together with the carbon atoms they are attached to, they form 3-, 4-, 5- or 6-membered spirocarbocycles, or 4-, 5- or 6-membered spiroheterocycles containing one or two heteroatoms selected from N and O; Or R 1 and R 3 Forming 1 or 2 carbon bridged rings; Or R 1 and R 7 Forming 1 or 2 carbon bridged rings; Or R 3 and R 7 Forming 1 or 2 carbon bridged rings; Or R 15 and R 1 Forming 3, 4, 5, or 6 carbon fused rings; Or R 15 and R 7 Forming 3, 4, 5, or 6 carbon fused rings; Or R 15 and R 3 Forming 1 or 2 carbon bridged rings; Or R 15 and R 5 Forming 3, 4, 5 or 6 carbon fused rings, where R 5 In R 15 On the α carbon, or a 1, 2, 3, or 4 carbon bridge ring, where R 5 Not in R 15 On the α-carbon; R 5 In each case, it is selected from: alkyl, olefin, alkyne, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, halogen, hydroxyl, alkoxy, azide, amino, -NH (alkyl or aliphatic), -N (independently alkyl or aliphatic)2, -NHSO2 (aliphatic), -N (alkyl or aliphatic)SO 2( Alkyl or aliphatic group), -NHSO2 aryl, -N(alkyl or aliphatic)SO2 aryl, -NHSO2 alkenyl, -N(alkyl or aliphatic)SO2 alkenyl, -NHSO2 ynyl, -N(alkyl or aliphatic)SO2 ynyl and halogenated (alkyl or aliphatic group), Or two Rs 5 Substituents, together with the carbon atoms they are bonded to, can form 3, 4, 5, or 6-membered rings; R 10 It is a linker-targeting ligand; R 11 In each case, the radical is selected from: hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyl, heterocyclic, heteroalkyl, carbocyclic, heteroaliphatic, aliphatic, alkoxy, aryl, heteroaryl, alkylamino, alkylhydroxy, -NHalkyl, -Nalkyl2, -NH (aliphatic), -N (independent aliphatic)2, amino, cyano, nitro, nitroso, sulfone, sulfoxide, thioalkyl, mercapto, and haloalkyl. R 12 In each case, the hydrocarbons are selected from: hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, heteroaryl, aryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic, aryl or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, aryl or heteroaryl), alkenes and alkynes. R 13 and R 14 Independently selected from hydrogen, alkyl, alkenyl, alkoxy, haloalkoxy, hydroxyl, amino, -NHalkyl, and -N(alkyl)2, Or R 13 and R 14 Together with the carbon atoms they are attached to, they form C(O), C(S), C=CH2, 3-, 4-, 5- or 6-membered spirocarbocycles, or 4-, 5- or 6-membered spiroheterocycles containing one or two heteroatoms selected from N and O; Linkers are chemical groups that connect degradation determinants to target ligands; Y is independently selected from N, CH and CR 11 Instances of 0, 1, 2, 3, or 4 Ys (as the context allows) are selected as N and are selected to produce stable rings and pharmaceutically acceptable degradation determinants. When Y is in a six-membered ring (unfused or fused), in a non-limiting embodiment as the context allows, the ring may be pyridine, diazine, triazine, pyrimidine, pyridazine, pyrazine, triazine, or tetraazine; Z is NH, O, S, or NR. 12 ; Furthermore, the target ligands are selected from those target ligands in Figures 1A to 8PPPPP.

2. Compounds of formula VII: (VII) in: R 17 Selected from: , , , ,and Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein other variables are as described in claim 1.

3. Compounds of formula III or IV that provide the following structures: (III) (IV) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; R 16 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , and ; And the variables and definitions therein are provided as in claim 1.

4. The compound according to claim 1, 2 or 3, wherein W 1 It is C=O, W 2 It is C=O and X is NH.

5. The compound of claim 1, 2, 3 or 4, wherein the linker has a chain of 2 to 20 carbon atoms, wherein one or more carbon atoms may be replaced by heteroatoms such as O, N, S or P or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.

6. The compound of claim 1, 2, 3 or 4, wherein the linker is selected from the fractions of formulas L1, L1I, LIII, LIV, LLV, LVI and LVII: in: X 1 and X 2 Independently selected from bonds, NH, NR 25 CH2, CHR 25 C(R) 25 2. O and S; R 20 R 21 R 22 R 23 and R 24 Independently selected from bonds, alkyl groups, -C(O)-, -C(O)O-, -OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO2-, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, -N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-OR) 26 )-、-CH(-NHR 25 -CH(-NH2)-, -CH(-NR) 25 2) -、-C(-OR 26 )alkyl, -C(-NHR) 25 )alkyl-, -C(-NH2)alkyl-, -C(-NR 25 2) Alkyl-, -C(R) 4 R 4 )-, -alkyl (R 27 )-alkyl(R 28 )-、-C(R 27 R 28 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 -NHC(O)NH- -N(R) 25 )C(O)N(R 25 )-、-N(H)C(O)N(R 25 ), polyethylene glycol, poly(lactic acid-co-glycolic acid), olefin, haloalkyl, alkoxy, alkyne, heteroarylalkyl, aryl, arylalkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocyclic, or -O-(CH2). 1-12 -O-, -NH-(CH2) 1-12 -NH-, -NH-(CH2) 1-12 -O-, or -O-(CH2) 1-12 -NH-, -S-(CH2) 1-12 -O-, -O-(CH2) 1-12 -S-、-S-(CH2) 1-12 -S-、-S-(CH2) 1-12 -NH- or -NH-(CH2) 1-12 -S-; R 25 In each case, it is selected from: alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl, or alkynyl, or may be aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclic; R 26 It is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, olefin, and alkyne; or, in addition to these, may be selected from aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic groups; and R 27 and R 28 It is independently selected from hydrogen, alkyl, amine, or together with the carbon atoms to which they are attached, to form C(O), C(S), C=CH2, C3-C6 spirocarbocycles, or 4-, 5-, or 6-membered spiroheterocycles containing one or two heteroatoms selected from N and O, or to form one or two carbon-bridged rings.

7. The compound of claim 1, 2, 3 or 4, wherein the linker is a portion selected from formula LVIII, LIX and LX: Each of these variables is defined as described in claim 6.

8. The compound of claim 1, 2, 3 or 4, wherein the linker is selected from... ，， , , , , , , , , , , , , , , , , , , ,and The variables mentioned therein are defined as in claim 6.

9. The compound of claim 1, 2, 3 or 4, wherein the linker is ，，，， , , ,and The variables mentioned therein are defined as in claim 6.

10. The compound of claim 1, 2, 3 or 4, wherein the linker is selected from: -NR 61 (CH2) n1 -(lower alkyl)-,-NR 61 (CH2) n1 -(lower alkoxy)-,-NR 61 (CH2) n1 -(lower alkoxy)-OCH2-,-NR 61 (CH2) n1 -(lower alkoxy)-(lower alkyl)-OCH2-,-NR 61 (CH2) n1 -(cycloalkyl)-(lower alkyl)-OCH2-,-NR 61 (CH2) n1 -(heterocyclic alkyl)-,-NR 61 (CH2CH2O) n1 -(lower alkyl)-O-CH2-,-NR 61 (CH2CH2O) n1 -(heterocyclic alkyl)-O-CH2-,-NR 61 (CH2CH2O) n1 -aryl-O-CH2-,-NR 61 (CH2CH2O) n1 -(heteroaryl)-O-CH2-,-NR 61 (CH2CH2O) n1 -(cycloalkyl)-O-(heteroaryl)-O-CH2-,-NR 61 (CH2CH2O) n1 -(cycloalkyl)-O-aryl-O-CH2-,-NR 61 (CH2CH2O) n1 -(lower alkyl)-NH-aryl-O-CH2-,-NR 61 (CH2CH2O) n1 -(lower alkyl)-O-aryl-CH2,-NR 61 (CH2CH2O) n1 -cycloalkyl-O-aryl-,-NR 61 (CH2CH2O) n1 -cycloalkyl-O-heteroaryl-,-NR 61 (CH2CH2) n1 -(cycloalkyl)-O-(heterocyclic)-CH2,-NR 61 (CH2CH2) n1 -(heterocyclic)-(heterocyclic)-CH2 and -NR 61 -(heterocyclic)-CH2; Where n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and R 61 It is H, methyl, or ethyl.

11. The compound of claim 1, 2, 3 or 4, wherein the linker is selected from: ，，，，，，，，，， , ，，，，，，，， , ，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，， , ，， , ，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，， , ，，， , ，，，， , ，， , ，，，，，，，， , ，，，， , ，，，，，，，，，，，，，，，，，， , ，，，，，，，，，，，， , ，，，，，，，，，，，， , ，，，，，，，，，，， , ，，，，，，，，，，，，，，，，，，，，， , ，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，，， , , , , , , , , , , , , , , , , , , ,and ; R 71 It is -O-, -NH, -NMe, -Nalkyl, N (aliphatic group), -N (heteroaliphatic group); represent and ;and m1, n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4, or 5.

12. A method for treating a patient suffering from a medical condition that can be treated by degrading a target protein that binds to a target ligand, comprising administering an effective amount of the compound of claim 1, 3, or 4-11 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

13. A method for treating a patient suffering from a medical condition that can be treated by binding to the protein cereblon in the body, comprising administering an effective amount of the compound of claim 2, 3 or 4-11 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

14. The method of claim 12 or 13, wherein the condition is selected from abnormal cell proliferation, tumors, cancer, immune disorders, autoimmune disorders, arthritis, lupus, diabetes, cardiovascular diseases, infectious diseases, or inflammatory diseases.

15. The method of claim 12 or 13, wherein the infectious disease is selected from HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, rotavirus, influenza, coronavirus, EBV, viral pneumonia, drug-resistant virus, avian influenza, RNA virus, DNA virus, adenovirus, poxvirus, microRNA virus, capsid virus, orthomyxovirus, retrovirus or hepatotropic DNA virus, Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, meningitis, gonorrhea, Chlamydia, Mycoplasma, fungi, protozoa, intestinal worms, worms, prions or parasites.

16. The method of claim 12 or 13, wherein the disease is a cancer selected from the group consisting of: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma; melanoma; myeloproliferative disorders; sarcoma, angiosarcoma, Kaposi's sarcoma, etc. Liposarcoma, sarcoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma and schwannoma; breast cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma.