CN-115427051-B - Therapeutic agents and conjugates thereof

Abstract

The present disclosure provides a class of conjugates of formula (X), a class of TLR9 agonist derivatives (such as formulas (I), (XX) and (XXI)), certain diastereomers of STING agonists, a class of STING agonist derivatives (such as formula (XXVIV)), a class of heterocyclic compounds having formula (II), a class of heterocyclic compounds having formula (III), as defined herein. A 1 、A 2 、T、Z 1 、Z 2 、Z 3 、b 1 and b 2 in formula (X) are defined herein. The conjugates provide unique properties based on the properties of the therapeutic agent as part of the conjugate. Also provides a synthesis method and application of the compound .[A 2 -Z 2 -T-Z 3 ] b2 -A 1 -[Z 1 -T-Z 2 -A 2 ] b1 (X).

Inventors

• LI ANRONG
• LI HUI
• LI XIANFENG
• YANG JUNBAO
• SONG YUNTAO

Assignees

• 北京轩义医药科技有限公司

Dates

Publication Date

20260508

Application Date

20210305

Priority Date

20200306

Claims (3)

1. 1. A conjugate, wherein the conjugate has the structure of formula (XXVII-B): (XXVII-B) Wherein: b is 1; CpG is 5' -T in sequence C G A A C G T T C G A A C G T T C G A A C G T T C G A A T-3 'phosphorothioate linked oligodeoxynucleotides and linked at the 5' -O of the terminal nucleotide; CDNs are cyclic dinucleotides that act as STING agonists and are covalently bound in the conjugate by the thiol group of the cyclic dinucleotide STING agonist; t is a triazole functional group, which is Or (b) ; X 1 is ; Representing the attachment point to the T, Representing an attachment point to a phenyl group; X 2 is-X 3 -NH-CO-X 4 -, wherein X 3 is C 3 -C 12 alkylene-L 1 - L 1 is-OP (S) (OH) -, Represents the attachment point of 5' -O to the terminal nucleotide of CpG, and Represents an attachment point to an amino group, and X 4 is , wherein, Represents the attachment point to T, and Represents an attachment point to a carbonyl group, Wherein the cyclic dinucleotide is: ; Wherein, the Meaning that the cyclic dinucleotide is covalently bound in the conjugate via an S atom.
2. 2. The conjugate of claim 1, wherein the conjugate has the structure: ; 。
3. 3. A pharmaceutical composition comprising the conjugate of claim 1 or 2, and one or more pharmaceutically acceptable excipients.

Description

Therapeutic agents and conjugates thereof Citation of related application The present application claims priority from U.S. provisional application No. 62/986,223, filed on 3/6/2020, and U.S. provisional application No. 63/062,503, filed on 8/7/2020, the disclosures of which are hereby incorporated herein by reference in their entireties for all purposes. Sequence listing The present application is electronically submitted via EFS-Web and includes a sequence table that is electronically submitted in txt format. The txt file includes a sequence table named "CSPL_011_02WO_SeqList_ST25.Txt" created on month 3 and 2 of 2021 and having a size of about 1.87 kilobytes. The sequence listing contained in this txt file is part of the specification and is incorporated herein by reference in its entirety. Background Cancer researchers have long recognized that phenotypic heterogeneity and progressive evolution of malignant tumors minimizes the chance that any agent targeting a single molecular pathway can effectively treat advanced cancers. Indeed, not only does a given cancer cell often disrupt additional normal growth and anti-apoptotic mechanisms to avoid death, it also employs mechanisms to avoid immune system elimination and coordinate changes in Tumor Microenvironment (TME) to ensure its survival (Nature.2017; 541:321-30). Despite recent breakthrough progress in immunotherapy of cancer, there remains a need for combination therapies that improve the efficacy of such therapies in patients whose tumors do not respond to current and emerging treatment criteria. Activation of the immune system is a key component of an effective persistent anti-tumor response. Pathogen-associated molecular patterns (PAMPs) have received considerable attention as immunotherapies because they have known mechanisms and can elicit Th1 immune responses. PAMPs consist of one or more structures sensed by Pattern Recognition Receptors (PRRs) on host cells and can activate immune responses mediated through one or more signaling pathways. Three common classes of PRRs are Toll-like receptors (TLRs), nucleotide binding oligomerization domain (NOD) like receptors (NLRs), and stimulators of the interferon gene (STING). STING agonists Detection of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMP) by Pattern Recognition Receptors (PRRs) triggers innate immunity, resulting in the production of type I and type III IFNs, pro-inflammatory cytokines and chemokines. STING (a stimulus for the interferon gene) is an Endoplasmic Reticulum (ER) membrane signaling protein that involves an innate immune response to cytoplasmic nucleic acids, including both self-derived and exogenously derived double-stranded DNA and bacterial cyclic dinucleotides. STING is activated by cyclic dinucleotides (such as 2'3' -cGAMP) produced by cGAS in response to cytoplasmic double stranded DNA. STING activation induces its relocation from the endoplasmic reticulum to the golgi apparatus. In this process STING recruits TBK1 that phosphorylates STING, thereby creating a platform for IRF3 recruitment and phosphorylation by TBK 1. STING also activates NF- κb. Phosphorylated IRF3 and NF- κb are subsequently translocated into the nucleus to induce type I IFN and inflammatory gene expression. In DCs, STING activation additionally induces expression of costimulatory molecules, resulting in cell maturation and initiation of adaptive immunity. Recent publications indicate that lower doses of STING agonists are optimal for generating systemic tumor-specific T cell responses and durable anti-tumor immunity, and that it may be beneficial to combine a low immunogenic dosing regimen of STING agonists with other immunotherapies to achieve good efficacy. TLR agonists Toll-like receptors (TLRs) include a range of highly conserved germline-encoded pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) expressed by a variety of infectious microorganisms. The ability of TLRs to trigger the innate immune system and enhance adaptive immunity to antigens expressed by pathogens and tumors is mature. At least 13 different TLRs have been identified in mammals, with TLR 7, TLR 8 and TLR 9 being similar in recognition of nucleic acid motifs and expression in endosomal compartments. Studies have shown that TLR7 is expressed predominantly by plasmacytoid dendritic cells (pDC), TLR8 is expressed by monocytes, monocyte-derived (m) DCs, macrophages and langerhans cells, and TLR9 is expressed by DCs, B cells, monocytes and mast cells. Synthetic agonist analogs (such as imiquimod (R837), requimod (R848), and loxorelbine) were designed to stimulate TLR7, often also trigger TLR8, and induce secretion of IL-12 and tnfα by mDC and/or pDC. Many TLR7/8 agonists also enhance expression of costimulatory molecules and migration of DCs, thereby facilitating induction of Th1 immune responses. Synthetic oligonucleotides expressing CpG motifs (such as P