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JP-2026076165-A - Cleavable conjugates of TLR7/8 agonist compounds, methods for preparing the same, and use.

JP2026076165AJP 2026076165 AJP2026076165 AJP 2026076165AJP-2026076165-A

Abstract

[Problem] To provide a Toll-like receptor 7/8 agonist compound that facilitates the local release and/or retention of the bioactive form of TLR7/8 agonists, and reduces undesirable systemic pro-inflammatory cytokine responses. [Solution] A compound of formula (I): F-[W- L3 - L2 - L1 -D]x(I) [wherein D is a TLR7/8 agonist moiety, L1 is a binding or self-leaving linker, L2 is a cleavable linker, L3 is a conjugation linker, W is O, S or NR10 , R10 is H or C1 - C8 alkyl, x is an integer from 1 to 500, F is a conjugation moiety, and the TLR7/8 agonist moiety is a 1H-imidazo[4,5-c]quinoline derivative] is provided. [Selection Diagram] None

Inventors

  • コッフマン， ロバート エル．
  • チップマン， スチュワート ディー．
  • キワン， ラドワン
  • ザリプスキー， サミュエル
  • オット， ゲイリー エス．

Assignees

  • ダイナヴァックス テクノロジーズ コーポレイション

Dates

Publication Date
20260511
Application Date
20251225
Priority Date
20171114

Claims (20)

  1. Equation (I): F-[W-L 3 -L 2 -L 1 -D] x (I) [In the formula, D is the TLR7/8 agonist section, L1 is a binding or self-deactivating linker, L2 is a severable linker, L3 is a conjugation linker, W is O, S, or NR 10 . R10 is H or C1 - C8 alkyl, x is an integer between 1 and 500. F is the conjugation part, The TLR7/8 agonist moiety is a 1H-imidazo[4,5-c]quinoline derivative. A compound of [unclear].
  2. D is given by equation (D-1): [In the formula, R1A is a C1 - C8 alkyl, C1 - C8 hydroxyalkyl, or C3 - C8 cycloalkyl. R 2 is NHR 2a , and R 2a is H or C1 - C8 alkyl. Each of R 35 is independently a halogen or a C1 - C8 alkyl. R4a and R4b are independently H or C1 - C8 alkyl groups. Each of R5 is independently a halogen or a C1 - C8 alkyl. p and q are independently 0, 1, 2, 3, or 4. The wavy line indicates the connection point of D in equation (I). The compound according to claim 1, having the following characteristics.
  3. D is equation (D-2): [In the formula, n is an integer between 4 and 21. X is -NH- or -NH(C=O)-, R1 is a C3 - C6 alkyl, -( CH2 ) p OR 1a , -( CH2 ) p NHR 1b , or -( CH2 ) p R1c , where R1a and R1b are independently C1 - C3 alkyl, R1c is a C3 - C4 cycloalkyl, and p is 1 or 2. R3 is independently a halogen, a C1 - C8 alkyl, a -( C1 - C7 alkylene) -NH2 , or a -CH2 -phenylene- CH2NH2 . q is 0, 1, 2, 3, or 4. R4a and R4b are independently H or C1 - C8 alkyl groups. The wavy line indicates the connection point of D in equation (I). The compound according to claim 1, having the following characteristics.
  4. D is given by equation (D-2a) or (D-2b): [In the formula, n is an integer between 4 and 21. R1 is a C3 - C6 alkyl, -( CH2 ) p OR 1a , -( CH2 ) p NHR 1b , or -( CH2 ) p R1c , where R1a and R1b are independently C1 - C3 alkyl, R1c is a C3 - C4 cycloalkyl, and p is 1 or 2. R 20 is NHR 20a , and R 20a is H, OH, NH 2 , or methyl. R3 is independently a halogen, a C1 - C8 alkyl, a -( C1 - C7 alkylene) -NH2 , or a -CH2 -phenylene- CH2NH2 . q is 0, 1, 2, 3, or 4. R4a and R4b are independently H or C1 - C8 alkyl groups. The wavy line indicates the connection point of D in equation (I). The compound according to claim 1, having the following characteristics.
  5. The compound according to claim 3, wherein X is -NH-.
  6. The compound according to any one of claims 3 to 5, wherein n is an integer from 4 to 15.
  7. The compound according to any one of claims 3 to 6, wherein n is 4, 5, 6, or 7.
  8. The compound according to claim 3, wherein X is -NH(C=O)-.
  9. The compound according to claim 4 or 8, wherein n is 11, 12, 13, or 14.
  10. The compound according to any one of claims 3 to 9, wherein R1 is a C3 - C6 alkyl group.
  11. The compound according to claim 10, wherein R1 is n-butyl.
  12. The compound according to any one of claims 3 to 9, wherein R1 is -( CH2 ) p OR 1a .
  13. The compound according to any one of claims 3 to 9, wherein R 1 is -(CH 2 ) p NHR 1b .
  14. The compound according to any one of claims 3 to 9, wherein R1 is -( CH2 ) pR1c .
  15. The compound according to any one of claims 3 to 14, wherein q is 0.
  16. The compound according to any one of claims 3 to 14, wherein q is 1 and R3 is a C1 - C8 alkyl group.
  17. The compound according to any one of claims 3 to 16, wherein R 4a and R 4b are each H.
  18. D is equation (D-3): [In the formula, R0 is a C4 - C21 hydrocarbyl which is optionally substituted with 1-4 halogen atoms. X is -NH- or -NH(C=O)-, R1 is a C3 - C6 alkyl, -( CH2 ) p OR 1a , -( CH2 ) p NHR 1b , or -( CH2 ) p R1c , where R1a and R1b are independently C1 - C3 alkyl, R1c is a C3 - C4 cycloalkyl, and p is 1 or 2. R3 is independently a halogen, a C1 - C8 alkyl, a -( C1 - C7 alkylene) -NH2 , or a -CH2 -phenylene- CH2NH2 . q is 0, 1, 2, 3, or 4. R4a and R4b are independently H or C1 - C8 alkyl groups. The wavy line indicates the connection point of D in equation (I). The compound according to claim 1, having the following characteristics.
  19. D is given by equation (D-3a) or (D-3b): [In the formula, R0 is a C4 - C21 hydrocarbyl which is optionally substituted with 1-4 halogen atoms. R1 is a C3 - C6 alkyl, -( CH2 ) p OR 1a , -( CH2 ) p NHR 1b , or -( CH2 ) p R1c , where R1a and R1b are independently C1 - C3 alkyl, R1c is a C3 - C4 cycloalkyl, and p is 1 or 2. R 20 is NHR 20a , and R 20a is H, OH, NH 2 , or methyl. R3 is independently a halogen, a C1 - C8 alkyl, a -( C1 - C7 alkylene) -NH2 , or a -CH2 -phenylene- CH2NH2 . q is 0, 1, 2, 3, or 4. R4a and R4b are independently H or C1 - C8 alkyl groups. The wavy line indicates the connection point of D in equation (I). The compound according to claim 1, having the following characteristics.
  20. The compound according to claim 18, wherein X is -NH(C=O)-.

Description

Cross-reference of related applications This application claims priority and interest to U.S. Provisional Patent Application No. 62/586,110, filed November 14, 2017, the entirety of which is incorporated herein by reference. Field of Invention This disclosure relates to Toll-like receptor 7/8 agonist compounds that are covalently conjugated to a drug, such as a tumor-specific targeting agent or polymer nanoparticle agent, via a cleavable linker moiety, thereby facilitating local release and/or retention of the bioactive form of the TLR7/8 agonist and reducing undesirable systemic pro-inflammatory cytokine responses. This disclosure also relates to methods for preparing the cleavable conjugate, its use for stimulating an effective immune response, and its use for the treatment of cancer. Background of the Invention Toll-like receptors (TLRs) are a family of transmembrane proteins that recognize structurally conserved molecules derived from pathogens, known as pathogen-associated molecular patterns. Therefore, TLRs function as frontline sensors of pathogen-associated molecular patterns in the mammalian immune system to detect the presence of invading pathogens (Takeuchi and Akira 2010, Cell 140:805-820). The human genome contains 10 known TLRs. Of these, TLR7 and TLR8 sense single-stranded RNA ligands and their (oligo)nucleotide degradation products. The distribution of TLR7 and TLR8 is restricted to the endolysosome compartment, and these receptors are preferentially expressed in antigen-presenting cells (APCs), which are a key cell type that modulates immune system activation. In progenitor immune cells, TLRs are involved in key molecular mechanisms that activate innate and adaptive immune responses, including the biosynthesis of selected cytokines (e.g., interferon type I), induction of co-stimulatory molecules, and increased antigen-presenting ability via APCs. In plasmacytoid dendritic cells, TLR7 is involved in the induction of IFN-α/β, which plays an essential role in regulating adaptive immunity. TLR8 is expressed in bone marrow dendritic cells, monocytes, and monocyte-induced dendritic cells, and the involvement of TLR8 agonists induces a prominent pro-inflammatory cytokine profile characterized by increased production of tumor necrosis factor α (TNF-α), interleukin-12 (IL-12), and IL-18. Therefore, virtually all major types of monocytic and dendritic cells can be activated by either a TLR7 or TLR8 agonist to become highly effective antigen-presenting cells. Since most antigen-presenting cell types express only one of these two receptors, agonists that can stimulate both receptors are potentially more effective adjuvants than agonists that are specific to only one of these TLRs (Wille-Reece, et al. Proc. Nat'l Acad. Sci. 2005, 102:15190-15194). Furthermore, TLR7 and TLR7/8 agonists may also be effective in stimulating antitumor immune responses in cancer, based on studies in animal models (Singh, et al. J Immunol 2014, 193:4722-4731). Therefore, TLR agonists have been extensively studied as stimulants of innate and adaptive immune responses, including for use as cancer treatment agents and vaccine adjuvants (Sabado et al. 2015, Ca Immunol Res 3:278-287; Vasilakos and Tomai 2013, Exp Rev Vaccines 12:809-819). Several classes of small molecules are known to interact at the guanosine/uridine ligand binding site and possess varying levels of TLR7 and/or TLR8 agonist bioactivity, many of which are derivatives of the 1H-imidazo[4,5-c]quinoline-1H-imidazo[4,5-c]quinoline-4-amine (imiquimod), a moderately effective TLR7 agonist approved in 1997 as a topical formulation for actinic keratosis, superficial basal cell carcinoma, and genital warts. Subsequent efforts in medicinal chemistry have led to the creation of several derivatives with significant improvements in dual TLR7/8 agonist activity, most notably 1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-1-yl)-2-methylpropan-2-ol (R848, Resiquimod), as well as 1-(4-aminomethylbenzyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (IMDQ, Figure 1) and 1-(3-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (meth-IMDQ, Figure 1; for example, incorporated herein by reference, Beesu, M. et al. 2015, J Med Chem See 50:7833-7849; U.S. Patents 8,728,486 and 9,441,005. However, rapid systemic diffusion of these small molecule compounds after topical administration of pharmacologically relevant doses (e.g., subcutaneous [SC], intratumor [IT], or intramuscular [IM]) leads to an increased risk in humans of systemic induction of pro-inflammatory cytokine responses and adverse events (e.g., fever, discomfort, lymphopenia). See, for example, Vasilakos and Tomai 2013, Exp Rev Vaccines 12:809-819; Smirnov, D. et al. 2011, Vaccine 29:5434-5442. Therefore, there is still a need for an immunotherapeutic agent that: 1) possesses potent biological activity against both TLR7/8 agonist receptors and has potent immunostimulatory activity that activates a larger subse