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CN-116457344-B - Low molecular weight protein degradation agent and application thereof

CN116457344BCN 116457344 BCN116457344 BCN 116457344BCN-116457344-B

Abstract

The present invention relates to compounds of formula (Ia), (Ib), (Ic) and (II) and their use in methods of treating cancer. These compounds can be used in combination with existing anti-cancer therapies to improve their efficacy.

Inventors

  • S. Ketang
  • N. Dickinson
  • K. Kazanovska
  • K. Oddsville
  • R. Pluta
  • M. Warzac

Assignees

  • 凯普托尔治疗学股份有限公司

Dates

Publication Date
20260512
Application Date
20210803
Priority Date
20200803

Claims (20)

  1. 1. A compound of formula (Ia): Or a pharmaceutically acceptable salt thereof, Wherein the method comprises the steps of L is hydrogen, alkyl, benzyl, -CH 2 OC (O) Me or-CH 2 OC(O) t Bu; each R 14 is independently selected from deuterium and hydrogen; R 15 is selected from hydrogen, deuterium, and C 1 -C 4 alkyl; r g is a group consisting of CR a R b R c , R h is selected from H and C 1 -C 4 alkyl; R a and R b are each H, or R a and R b are each deuterium, or R a is H and R b is methyl; r c is selected from NR 1 R 2 and OH; Each R d 、R e and R f is independently selected from H, deuterium, X, C 1 -C 4 alkyl, and NH 2 ; n is 1; X is selected from F, cl, br and I; r 1 is selected from H and C 1 -C 3 alkyl, R 2 is selected from H, C 1 -C 3 alkyl, -COR 3 and-COOR 3 , R 3 is selected from: unsubstituted C 1 -C 4 alkyl; C 1 -C 10 alkyl substituted with one or more R 4 , wherein each R 4 is independently selected from NH 2 、NHC(NH)NH 2 、NHCOOR 5 、-OH、OCOR 5 , substituted or unsubstituted dioxolyl, 5 membered heteroaryl, indole, and 6 membered aryl substituted with-OH or-OCO (C 1 -C 4 alkyl), and wherein R 4 is not X; A 6-membered aryl group substituted with one or more substituents independently selected from CH 2 -OH or CH 2 OCO(C 1 -C 4 alkyl, and R 5 is unsubstituted C 1 -C 6 alkyl.
  2. 2. The compound of claim 1, wherein when C 1 -C 10 alkyl is substituted with indole, C 1 -C 10 alkyl is also substituted with at least one additional R 4 .
  3. 3. The compound according to claim 1 or 2, wherein R h is H.
  4. 4. The compound according to claim 1 or 2, wherein R h is methyl.
  5. 5. The compound according to claim 1 or 2, wherein R c is selected from NHR 2 .
  6. 6. The compound of claim 1, wherein the compound is selected from the group consisting of: And pharmaceutically acceptable salts thereof.
  7. 7. The compound according to claim 1 or 2, wherein R 2 is selected from H, -COR 3 and-COOR 3 .
  8. 8. The compound of claim 1 or 2, wherein R 3 is C 1 -C 10 alkyl substituted with one or more R 4 .
  9. 9. The compound of claim 1 or 2, wherein each R 4 is independently selected from NH 2 、OCOR 5 , substituted or unsubstituted dioxolyl, indole, and 6 membered aryl substituted with one or more-OCO (C 1 -C 4 alkyl), wherein R 4 is not X.
  10. 10. The compound of claim 1, wherein the compound is selected from the group consisting of compounds 51, 2, 22, 3, 24, 6, 23, 52, and 37: And pharmaceutically acceptable salts thereof.
  11. 11. Compound 43: Or a pharmaceutically acceptable salt thereof.
  12. 12. A pharmaceutical composition comprising a compound of claim 1 or 11.
  13. 13. Use of a compound in the manufacture of a medicament for treating cancer, the treatment comprising administering the compound to a subject in need thereof, and wherein the compound is: (i) A compound of formula (Ia): Or a pharmaceutically acceptable salt thereof, Wherein the method comprises the steps of L is hydrogen, alkyl, benzyl, -CH 2 OC (O) Me or-CH 2 OC(O) t Bu; each R 14 is independently selected from deuterium and hydrogen; R 15 is selected from hydrogen, deuterium, and C 1 -C 4 alkyl; R g is selected from the group consisting of-COOH and CR a R b R c , R h is selected from H and C 1 -C 4 alkyl; R a and R b are each H, R a and R b are each deuterium, or R a is H and R b is methyl; r c is selected from NR 1 R 2 and OH; Each R d 、R e and R f is independently selected from H, deuterium, X, C 1 -C 4 alkyl, and NH 2 ; n is 1; X is selected from F, cl, br and I; R 1 is selected from H and C 1 -C 4 alkyl, R 2 is selected from H, C 1 -C 4 alkyl, -COR 3 and-COOR 3 , R 3 is selected from: unsubstituted C 1 -C 4 alkyl; C 1 -C 10 alkyl substituted with one or more R 4 , wherein each R 4 is independently selected from NH 2 、NHC(NH)NH 2 、NHCOOR 5 、-OH、OCOR 5 , substituted or unsubstituted dioxolyl, 5 membered heteroaryl, indole, and 6 membered aryl substituted with OH or-OCO (C 1 -C 4 alkyl), and wherein R 4 is not X; A 6-membered aryl group substituted with one or more substituents independently selected from CH 2 -OH or CH 2 OCO(C 1 -C 4 alkyl, and R 5 is unsubstituted C 1 -C 6 alkyl; Or (b) (Ii) A compound of formula (II): Or a pharmaceutically acceptable salt thereof, Wherein: Each R 1 is independently selected from H and C 1 -C 4 alkyl; r 11 is OH OR OR 5a , and R 5a is unsubstituted C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with one or more substituents independently selected from the group consisting of 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl; Or (b) (Iii) Compound 43: Or a pharmaceutically acceptable salt thereof.
  14. 14. The use of claim 13, wherein when C 1 -C 10 alkyl is substituted with indole, C 1 -C 10 alkyl is also substituted with at least one additional R 4 .
  15. 15. The use according to claim 13, wherein R 11 is OH.
  16. 16. The use according to claim 13, wherein NR 1 R 1 is NH 2 .
  17. 17. The use of claim 13, wherein R h is H.
  18. 18. The use according to claim 13, wherein R c is selected from NHR 2 and OH.
  19. 19. The use according to claim 13, wherein the compound is selected from the group consisting of: And pharmaceutically acceptable salts thereof.
  20. 20. The use of claim 13, wherein R c is NHR 2 .

Description

Low molecular weight protein degradation agent and application thereof Technical Field The present invention relates to compounds that modulate the cellular concentration of a variety of disease-related proteins (e.g., transcription factor SALL4 and translation termination factor GSPT 1) and uses thereof. Background Ubiquitin-protease system (UPS) is responsible for maintaining a healthy and well balanced proteome. During ubiquitination, ubiquitin units are covalently linked to proteins, forming polyubiquitin chains, which marks the degradation of proteins by proteasome. Ubiquitination is critical for the regulation of almost all cellular processes and is itself also tightly regulated. Ubiquitin ligases such as Cereblon (CRBN) promote ubiquitination of different proteins in the body and facilitate precise regulation of the system. After recognition, ubiquitin ligases mediate the binding of ubiquitin moieties to the target protein, which allows the target protein to be labeled so that it is degraded by the proteasome. The idea of selective Target Protein Degradation (TPD) by modulating UPS was first described in 1999 (US 2002173049 A1 (PROTEINIX INC) 11, 21, 2002). Implementation of this concept has been demonstrated in clinically approved thalidomide (thalidomide) analogs, because binding of the thalidomide analog to CRL4 CRBN E3 ligase causes recruitment of the selected target protein, resulting in its ubiquitination and subsequent proteasome degradation. Recently, faust TB et al Annu Rev Cancer biol 2021.5:181-201 reviewed recent scientific and clinical advances in TPD. Cereblon modulators in cancer treatment Cereblon (CRBN) is a protein related to DDB1 (DNA damage binding protein 1), CUL4 (Cullin-4) and RBX1 (RING-Box protein 1). These proteins together form a ubiquitin ligase complex, which belongs to the family of Cullin RING Ligase (CRL) proteins, designated CRL4 CRBN. Thalidomide is a drug approved for the treatment of multiple myeloma in the late 90 s of the 20 th century, which binds to cereblon and modulates the substrate specificity of the CRL4 CRBN ubiquitin ligase complex. This mechanism is the basis for the pleiotropic effects of thalidomide on immune and cancer cells (Lu G et al science 2014 Jan 17; 343 (6168): 305-9). The clinical applicability of cereblon modulators in many hematological malignancies such as multiple myeloma, myelodysplastic syndrome, lymphomas and leukemias has been demonstrated (Le Roy A et al Front immunol.2018; 9:977). The antitumor activity of CMA is mediated by: ● Inhibition of cancer cell proliferation and induction of apoptosis, ● Disruption of the nutritional support of the tumor stroma, ● Stimulation of immune cells results in proliferation of T cells, cytokine production and activation of NK (natural killer) cells. The success of thalidomide in cancer treatment has prompted efforts to develop analogs with higher potency and fewer deleterious side effects. Thus, a variety of drug candidates were generated, including lenalidomide (lenalidomide), pomalidomide (pomalidomide), CC-220, CC-122, CC-885, and CC-90009. These compounds are collectively referred to as Cereblon Modulators (CMA). For a discussion of these compounds, see, for example, US 5635517 (B2)、WO2008039489 (A2)、WO2017197055 (A1)、WO2018237026 (A1)、WO2017197051 (A1)、US 8518972 (B2)、EP 2057143 (B1)、WO2019014100 (A1)、WO2004103274 (A2) and Surka Ch et al blood 2021 Feb 4;137 (5): 661-677. The novel substrate degradation pattern of the cereblon modulator mediates phenotypes and clinical outcomes in an environmentally specific manner. For example, down-regulation of lymphotranscription factors IKZF1 (KAROS family zinc finger protein 1) and IKZF3 (KAROS family zinc finger protein 3) mediate the clinical efficacy of lenalidomide and pomalidomide in multiple myeloma. At the same time, down-regulation of IKZF1 and IKZ has been shown to contribute to the occurrence of side effects, which reduces the dosage of drugs that can be administered to patients with myelodysplastic syndrome. Side effects that occur during lenalidomide treatment include neutropenia, leukopenia, thrombocytopenia, anemia, and hemorrhagic disease (Stahl M et al cancer 2017 May 15;123 (10): 1703-1713). Thus, development of cereblon modulators is expected to advance to achieve the desired substrate specificity of the CRL4 CRBN ubiquitin ligase complex to achieve the desired therapeutic and safety profile depending on the clinical setting (SIEVERS QL ET al science 2018 Nov 2; 362 (6414). SALL4 targeting strategy for tumor cell eradication Expression of Sal-like protein 4 (SALL 4) transcription factors is detected primarily in Embryonic Stem Cell (ESC), adult germ cell, and blood progenitor cell populations, where it serves as a core controller to regulate cellular "stem cell" during developmental events. SALL4, however, is reactivated and deregulated in a variety of cancers, including Acute Myelogenous Leukemia (AML), B-cell acute lymphoblastic leuk