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JP-7856847-B2 - Spiro compounds and their uses

JP7856847B2JP 7856847 B2JP7856847 B2JP 7856847B2JP-7856847-B2

Inventors

  • 李 進
  • 劉 川
  • 夏 帥
  • 竇 登峰
  • 瀋 建波
  • 向 四川
  • 蔡 龍英
  • 董 暁斐

Assignees

  • 成都先導薬物開発股▲ふん▼有限公司

Dates

Publication Date
20260511
Application Date
20230905
Priority Date
20220907

Claims (11)

  1. A compound represented by the following formula I, its stereoisomer, its deuterated compound, or a pharmaceutically acceptable salt thereof. Equation I (In the formula, == O represents the presence or absence of oxygen substitution, Ring A is selected from 3-12 membered cycloalkyl groups, 4-12 membered heterocycloalkyl groups, 6-10 membered aromatic rings, and 5-10 membered heteroaromatic rings, and the cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring bonded to R2 may be further substituted by one, two, three, or four independent R A1 groups . Each R A1 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR A2 R A3 , -C 1-6 alkyl group, -C 2-6 alkenyl group, -C 2-6 alkynyl group, -C 1-6 halogenated alkyl group, -C 2-6 halogenated alkenyl group, -C 2-6 halogenated alkynyl group, -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)2 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 member cycloalkyl group), -C 0-4 alkylene-(4-10 member heterocycloalkyl group), -C Selected from 0-4 alkylene-(6-10 membered aromatic ring) and -C 0-4 alkylene-(5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted with one, two, three, or four independent R A4 groups . Each R A4 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR A2 R A3 , -C 1-6 alkyl group, -C 2-6 alkenyl group, -C 2-6 alkynyl group, -C 1-6 halogenated alkyl group, -C 2-6 halogenated alkenyl group, -C 2-6 halogenated alkynyl group, -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)2 R A2 , -C 0-4 alkylene-S(O) 2 NR A2 R A3 , -C Selected from 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 and R A3 are independently selected from hydrogen, -C1-6 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, -C1-6 halogenated alkyl groups, -C2-6 halogenated alkenyl groups, and -C2-6 halogenated alkynyl groups. R 2 independently consists of hydrogen, halogen, cyano group, nitro group, =O, =S, =CR 21 R 22 , -C 1-6 alkyl group, -C 2-6 alkenyl group, -C 2-6 alkynyl group, -C 1-6 halogenated alkyl group, -C 2-6 halogenated alkenyl group, -C 2-6 halogenated alkynyl group, -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 member cycloalkyl group), -C 0-4 alkylene-(4-10 member heterocycloalkyl group), -C Selected from 0-4 alkylene-(6-10 membered aromatic ring) and -C 0-4 alkylene-(5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted with one, two, three, or four independent R23 groups . Each R 23 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR 21 R 22 , -C 1-6 alkyl group, -C 2-6 alkenyl group, -C 2-6 alkynyl group, -C 1-6 halogenated alkyl group, -C 2-6 halogenated alkenyl group, -C 2-6 halogenated alkynyl group, -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 member cycloalkyl group), -C 0-4 alkylene-(4-10 member heterocycloalkyl group), -C Selected from 0-4 alkylene-(6-10 membered aromatic ring) and -C 0-4 alkylene-(5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted with one, two, three, or four independent R26 groups . R21 and R22 are independently hydrogen, -C1-6 alkyl group, -C2-6 alkenyl group, -C2-6 alkynyl group, -C1-6 halogenated alkyl group, -C2-6 halogenated alkenyl group, -C2-6 halogenated alkynyl group, -C1-4 alkylene- OR24 , -C1-4 alkylene-OC(O) R24 , -C1-4 alkylene- SR24 , -C1-4 alkylene- S (O) 2R24 , -C1-4 alkylene-S( O ) 2R24 , -C1-4 alkylene -S(O) 2NR24R25 , -C1-4 alkylene-S(O) NR24R25 , -C 1-4 alkylene-C(O)R 24 , -C 1-4 alkylene-C(O)OR 24 , -C 1-4 alkylene-C(O)NR 24R 25 , -C 1-4 alkylene-NR 24R 25 , -C 1-4 alkylene-NR 24C (O)R 25 , -C 1-4 alkylene-NR 24S (O) 2R 25 , -C 1-4 alkylene-NR 24S (O)R 25 , -C 0-4 alkylene-(3-10 membered cycloalkyl group), -C 0-4 alkylene-(4-10 membered heterocycloalkyl group), -C 0-4 alkylene-(6-10 membered aromatic ring), -C Selected from 0-4 alkylene-(5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted with one, two, three, or four independent R26 groups . Each R 26 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR 24 R 25 , -C 1-6 alkyl group, -C 2-6 alkenyl group, -C 2-6 alkynyl group, -C 1-6 halogenated alkyl group, -C 2-6 halogenated alkenyl group, -C 2-6 halogenated alkynyl group, -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 member cycloalkyl group), -C 0-4 alkylene-(4-10 member heterocycloalkyl group), -C Selected from 0-4 alkylene-(6-10 membered aromatic ring) and -C 0-4 alkylene-(5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted with one, two, three, or four independent R27 groups . R24 and R25 are independently selected from hydrogen, -C1-6 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, -C1-6 halogenated alkyl groups, -C2-6 halogenated alkenyl groups, and -C2-6 halogenated alkynyl groups. Each R 27 is independently selected from hydrogen, halogen, cyano group, nitro group, =O, =S, -C1-6 alkyl group, -C2-6 alkenyl group, -C2-6 alkynyl group, -C1-6 halogenated alkyl group, -C2-6 halogenated alkenyl group, and -C2-6 halogenated alkynyl group.
  2. Ring A is, The compound according to claim 1, characterized in that it is selected from rings represented by , and these rings may be further substituted by one, two, three, or four independent R A1 .
  3. The compound according to claim 2, characterized in that each R A1 is independently selected from hydrogen, halogen, cyano group, nitro group, =O, =S, -C1-3 alkyl group, and -C1-3 halogenated alkyl group.
  4. Ring A is, The compound according to claim 1, characterized by being selected from among.
  5. R2 is hydrogen, halogen, cyano group, nitro group, =O, =S, -C1-6 alkyl group, -C2-6 alkenyl group, -C2-6 alkynyl group, -C1-6 halogenated alkyl group, -C2-6 halogenated alkenyl group, -C2-6 halogenated alkynyl group, -C0-4 alkylene- OR21 , -C0-4 alkylene-OC(O) R21 , -C0-4 alkylene-C(O) R21 , -C0-4 alkylene-C(O) OR21 , -C0-4 alkylene-C(O) NR21R22 , -C0-4 alkylene - NR21R22 ; -C0-4 alkylene-(3-10 membered cycloalkyl group), -C Selected from 0-4 alkylene-(4-10 member heterocycloalkyl group), -C 0-4 alkylene-(6-10 member aromatic ring), and -C 0-4 alkylene-(5-10 member heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted with one, two, three, or four independent R23 groups . Each R 23 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, -C 1-6 alkyl group, -C 2-6 alkenyl group, -C 2-6 alkynyl group, -C 1-6 halogenated alkyl group, -C 2-6 halogenated alkenyl group, -C 2-6 halogenated alkynyl group, -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 group), -C 0-4 alkylene-(4-10 membered heterocycloalkyl group), -C 0-4 alkylene-(6-10 membered aromatic ring), -C Selected from 0-4 alkylene-(5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted with one, two, three, or four independent R26 groups . R21 and R22 are independently hydrogen, -C1-6 alkyl group, -C2-6 alkenyl group, -C2-6 alkynyl group, -C1-6 halogenated alkyl group, -C2-6 halogenated alkenyl group, -C2-6 halogenated alkynyl group, -C1-4 alkylene- OR24, -C1-4 alkylene -OC(O) R24 , -C1-4 alkylene-C(O) R24 , -C1-4 alkylene-C (O)OR24, -C1-4 alkylene-C(O)NR24R25, -C1-4 alkylene-NR24R25 , -C1-4 alkylene - NR24C ( O ) R25 , -C Selected from 0-4 alkylene-(3-10 membered cycloalkyl group), -C 0-4 alkylene-(4-10 membered heterocycloalkyl group), -C 0-4 alkylene-(6-10 membered aromatic ring), and -C 0-4 alkylene-(5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted with one, two, three, or four independent R26 groups . Each R 26 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR 24 R 25 , -C 1-6 alkyl group, -C 2-6 alkenyl group, -C 2-6 alkynyl group, -C 1-6 halogenated alkyl group, -C 2-6 halogenated alkenyl group, -C 2-6 halogenated alkynyl group, -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 , selected from -C0-4 alkylene-(3-10 member cycloalkyl group), -C0-4 alkylene-(4-10 member heterocycloalkyl group), -C0-4 alkylene-(6-10 member aromatic ring), -C0-4 alkylene-(5-10 member heteroaromatic ring), The compound according to claim 1 or 4, its stereoisomer, its deuterated compound, or its pharmaceutically acceptable salt, characterized in that R24 and R25 are each independently selected from hydrogen, a -C1-3 alkyl group, and a -C1-3 halogenated alkyl group.
  6. R2 is selected from -C(O) NR21 R22 , -C(O) R21 , -C0-2 alkylene- NR21 R22 , and -C(O) OR21 . R21 and R22 are independently selected from hydrogen, -C1-3 alkyl groups, -C0-1 alkylene-(6-membered aromatic ring), -C0-1 alkylene-(10-membered heteroaromatic ring), -(4-6 membered heterocycloalkyl group), and -(3-6 membered cycloalkyl group), and the aromatic ring, heteroaromatic ring, heterocycloalkyl group, and cycloalkyl group may be further substituted by one, two, three, or four independent R26 groups . Each R 26 is independently selected from hydrogen, -C1-3 alkyl groups, -(4-6 member heterocycloalkyl groups), -C(O)R 24 , -C(O)OR 24 , and -OC(O)R 24 . The compound according to claim 5, characterized in that R 24 is selected from hydrogen, a methyl group, and an ethyl group.
  7. R2 is hydrogen, The compound according to claim 6, characterized by being selected from among.
  8. The aforementioned compound, A compound according to any one of claims 1 to 7, characterized by being selected from among.
  9. Use of a compound according to any one of claims 1 to 8, its stereoisomer, its deuterated compound, or its pharmaceutically acceptable salt in the preparation of a pharmaceutical composition for treating diseases related to abnormal cell proliferation.
  10. The use according to claim 9, characterized in that the disease is cancer.
  11. Use of a compound according to any one of claims 1 to 8, a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof in the production of a targeted protein degradation agent.

Description

This invention relates to the field of medical technology, and more specifically, to a novel ligand compound for binding to a spiroring cereblon E3 ubiquitin ligase protein. Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded, or excess proteins occurs through the ubiquitin-proteasome pathway (UPP). The UPP is characterized by its ATP-dependent, efficient, and highly selective nature in removing defective proteins. Its catalytic component is the E3 ubiquitin ligase, but it requires the initial replenishment of the protein to be degraded. PROTACs technology is designed based on the UPP principle, identifying the target protein by appropriately chemically linking the target protein's ligand to the E3 ligase's ligand, enhancing the E3 ligase's ability to bind to the target protein, and forcing the degradation of the target protein by targeting ubiquitination. It features low catalytic requirements, high efficiency, and high selectivity. Multiple ubiquitin molecules covalently bond to terminal lysine residues via E3 ubiquitin ligase, thereby labeling proteins and enabling proteasome degradation. The protein is digested into small peptides, ultimately broken down into amino acids, which then function as building blocks for new proteins. Defective proteasome degradation is associated with various clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer. Cereblon is a thalidomide-binding protein that is part of the E3 ubiquitin ligase protein complex and functions as a substrate receptor that selectively acts on ubiquitinated proteins. Cereblon is a protein encoded by the human CRBN gene and forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), karin 4A (CUL4A), and karin 1 regulator (ROCI). This complex can ubiquitinize a range of proteins, although the specific mechanism is unknown. Cereblon is a commonly used E3 ligase known to be used in PROTAC technology. This invention provides a novel spiro compound. This compound can function as an effective CRBN ligand and can also synthesize the corresponding proteolytic chimeric molecule PROTAC, a bifunctional compound applicable to the treatment of various medical conditions, particularly abnormal cell proliferation. The present invention provides a compound represented by the following formula I, its stereoisomer, its deuterated compound, or a pharmaceutically acceptable salt thereof. Equation I During the ceremony, ==O indicates the presence or absence of oxygen substitution. Ring A is selected from a 3-12 member cycloalkyl group, a 4-12 member heterocycloalkyl group, a 6-10 member aromatic ring, or a 5-10 member heteroaromatic ring, where the cycloalkyl group, heterocycloalkyl group, aromatic ring, or heteroaromatic ring may be further substituted with one, two, three, or four independent R A1 groups. Each R A1 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR A2 R A3 , -C 1-6 alkyl group, -C 2-6 alkenyl group, -C 2-6 alkynyl group, -C 1-6 halogenated alkyl group, -C 2-6 halogenated alkenyl group, -C 2-6 halogenated alkynyl group, -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)2 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 member cycloalkyl group), -C 0-4 alkylene-(4-10 member heterocycloalkyl group), -C Selected from 0-4 alkylene-(6-10 membered aromatic ring) and -C 0-4 alkylene-(5-10 membered heteroaromatic ring), where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted with one, two, three, or four independent R A4 groups. Each R A4 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR A2 R A3 , -C 1-6 alkyl group, -C 2-6 alkenyl group, -C 2-6 alkynyl group, -C 1-6 halogenated alkyl group, -C 2-6 halogenated alkenyl group, -C 2-6 halogenated alkynyl group, -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)2 R A2 , -C 0-4 alkylene-S(O) 2 NR A2 R A3 , -C Selected from 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 and R A3 are independently selected from hydrogen, -C1-6 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, -C1-6 halogenated alkyl groups, -C2-6 halogenated alkenyl groups, and -