Imidazo [4, 5-d] pyridazine compounds and conjugates thereof, their preparation and their therapeutic use

Abstract

The present invention relates to a compound of formula (I) A-L1-RCG1 (I) wherein A has formula (A), R1 is H, optionally substituted alkyl, alkenyl, alkynyl; r2 is halogen; alkyl; an alkenyl group; an alkynyl group; an alkylthio group; an alkylthioalkyl group; alkyl-S (O)-; alkyl-S (O2)-; alkyl-S (O)-alkyl-; alkyl-S (O2)-alkyl-; an alkoxy group; an alkoxyalkyl group; a halogenated alkoxy alkyl group; a cycloalkyl-O-alkyl group; an alkyl group-NH-alkyl group; (alkyl) 2-N-alkyl; alkyl-NH; and (alkyl) 2N; r3 is deuterium; h; alkyl; an alkenyl group; an alkynyl group; an alkylthio group; -OR < 6 >; -NR7R8,-NR7R8; heterocycloalkyl groups; a heteroaryl group; an aryl group; cycloalkyl; l1 is a linker, and RCG1 is a reactive chemical group. The invention also relates to a compound of formula A-L1-G-BA (II) wherein G is the product of the reaction between RCG1 and the reactive group RCG2, and BA is a binding agent; a pharmaceutical composition comprising the compound; and therapeutic uses of the compounds, for example in the treatment of cancer.

Description

Technical Field

[0001] This disclosure relates to novel imidazo[4,5-d]pyridazine (also known as payloads), novel imidazo[4,5-d]pyridazine conjugates, pharmaceutical compositions comprising these conjugates, and their therapeutic uses, such as as TLR7 and / or 8 agonists. This disclosure also relates to methods for preparing these payloads and conjugates. Background Technology

[0002] Over the past decade, immunotherapy, primarily immune checkpoint inhibitors (ICIs), has produced impressive clinical responses in patients. However, the percentage of patients responding to ICIs remains low. Notably, the efficacy of ICIs is associated with an "inflammatory" tumor microenvironment (TME), and patients with "non-inflammatory" tumors tend to respond poorly to ICIs.

[0003] Therapeutic activation of TLRs (Toll-like receptors) such as TLR7 and / or 8 has shown potential for immunotherapy by transforming non-inflammatory or malignant inflammatory tumors into immunoinflammatory tumors and (re)initiating T cell-mediated anti-tumor immune responses. The innate immune system contains several germline-encoded families of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). These receptors recognize danger signals from released internal cellular components called damage-associated molecular patterns (DAMPs) or microbial components called pathogen-associated molecular patterns (PAMPs). PAMPs are highly conserved molecular structures on a wide range of pathogens, such as viruses, fungi, bacteria, and parasites. Both TLR7 and TLR8 are located within lysosomes and play important roles in immune responses during viral infection through their ability to recognize single-stranded RNA PAMPs and synthesize small molecules. Their stimulation leads to intracellular signaling and downstream activation of genes encoding co-stimulatory molecules, pro-inflammatory cytokines, and type I interferons, among others. Agonist activation of TLRs (such as TLR7 and / or TLR8) can induce the secretion of type I interferons (such as IFNα and IFNβ), tumor necrosis factor (TNFα), and interleukins (such as IL6 and IL12), which are key factors in initiating innate and adaptive immunity. For example, TLR7 activation preferentially stimulates the release of immunostimulatory cytokines such as IFNα and IP10, while TLR8 activation preferentially stimulates the release of pro-inflammatory cytokines such as IL6 and TNFα. The secretion of these cytokines (associated with the expression of co-stimulatory molecules) is known to induce the maturation of dendritic cells, monocytes, and macrophages, promoting antigen presentation and stimulation of adaptive immune responses.

[0004] Various small molecule agonists of TLR7 (commonly referred to as TLR7 agonists) and / or agonists of TLR8 (commonly referred to as TLR8 agonists) have been described as potent antitumor compounds. For example, due to tolerability issues with systemic administration, imidazoquinoline compounds, such as imiquimod (R-837, a TLR7 agonist) and remiquimod (R-848, also known as R848, a TLR7 and 8 agonist, as referred to as a TLR7 / 8 agonist), have been developed for local administration (local and / or intratumoral). Current intratumoral delivery methods exhibit poor tumor retention, limiting antitumor benefits and contributing to treatment-related adverse events. For example, Seven and Eight's BDB-001 (a combination of an intravenously administered TLR7 / 8 agonist and pembrolizumab in advanced solid tumors) showed activity in approximately 78% of recruited patients as monotherapy, and also demonstrated treatment-related adverse events (Journal of Clinical Oncology 2021 39:15_Supplement, 2512-2512).

[0005] Recently, antibody-conjugated TLR7 and / or 8 agonists for intravenous tumor-targeted delivery have been described. Several conjugates have been developed but discontinued primarily due to unfavorable therapeutic indices or toxicities.

[0006] WO 2018 / 009916 discloses imidazoquinoline or imidazopyrimidine compounds as TLR7 and / or 8 agonists as immunoconjugates. BDC-1001 (an imidazoquinoline TLR7 / 8 agonist conjugated with an anti-Her2 antibody using an uncleavable linker) showed a safety profile with biomarkers consistent with its mechanism of action in Phase 1, but was discontinued in Phase 2 due to low efficacy.

[0007] WO 2023 / 057564 discloses an imidazoquinoline R848 conjugate with an uncleavable linker. All disclosed ADCs (antibody-drug conjugates), particularly the R848 agonist conjugated with an anti-CEACAM5 antibody using a PEG24 linker (Tusamitamab-R848 ADC, also named Tusa-R848 in this disclosure), have been discontinued in the preclinical stage due to their narrow therapeutic index. The formula for Tusa-R848 is as follows:

[0008]

[0009] WO 2017 / 072662 discloses pyrrolopyrimidine compounds as TLR7 agonists in immunoconjugates. NJH395 (a TLR7 agonist conjugated with an anti-HER2 antibody) was discontinued in Phase 1 due to toxicity reasons (low-grade CRS, meningitis / pseudomeningitis, hepatotoxicity).

[0010] SBT-6050 (a TLR8 agonist conjugated with an anti-HER2 antibody) and SBT-6290 (a TLR8 agonist conjugated with an anti-connector protein 4 antibody) were also discontinued in Phase 1 due to toxicity (low-grade CRS, hypotension).

[0011] Therefore, there remains a need for novel immunotherapies based on TLR7 and / or 8 agonists with fewer adverse events and / or better therapeutic indices to treat diseases, particularly cancer.

[0012] The purpose of this disclosure is to provide novel immunostimulatory compounds that are suitable for systemic delivery, well-tolerated, and exhibit fewer adverse reactions.

[0013] This disclosure describes novel TLR7 and / or 8 payload compounds suitable for conjugation with antibodies, as well as their immunostimulant-conjugates.

[0014] This disclosure also describes immunostimulant conjugates with specific cytokine profiles. Summary of the Invention

[0015] This disclosure relates to a compound of formula (I) (also referred to in the text of this invention as a payload or compound / payload) or a pharmaceutically acceptable salt thereof:

[0016] A-L1-RCG1 (I)

[0017] in:

[0018] - A is the drug unit of formula (A)

[0019] (A)

[0020] in:

[0021] R1 means:

[0022] - Hydrogen atom, or

[0023] - Selected from the following groups:

[0024] a)

[0025] - (C1-C6)alkyl-group;

[0026] - Hydroxyl-(C1-C6)alkyl- group;

[0027] - NH2-(C1-C6)alkyl-group;

[0028] - NH-(C1-C6)alkyl-(C1-C6)alkyl- group;

[0029] - N((C1-C6)alkyl)2-(C1-C6)alkyl-group;

[0030] - (C2-C6) alkenyl-group;

[0031] - (C2-C6) ynyl group;

[0032] b)

[0033] - A phenyl (C1-C6)alkyl group, which is either unsubstituted or substituted by at least one substituent selected from the following:

[0034] b1) - (C1-C6)alkoxy-group;

[0035] b2) - Hydroxyl group;

[0036] b3) -C(O)-H group; and

[0037] b4) - (C1-C6) alkyl group, which is either unsubstituted or substituted by at least one substituent selected from the following:

[0038] b4.1) - Hydroxyl group; and

[0039] b4.2) - -NR4R5 group, wherein R4 and R5 are independently selected from:

[0040] b4.2.1) - Hydrogen atom;

[0041] b4.2.2) - (C1-C 16 )alkyl-group;

[0042] b4.2.3) - CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30; (C1-C6)alkoxy(C1-C6)alkyl- group; or (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl- group;

[0043] b4.2.4) - (C1-C6)alkyl-S(O2)- group;

[0044] b4.2.5) - (C1-C6)alkyl-NH-C(O)- group;

[0045] b4.2.6) - (C1-C16 )alkyl-C(O)- group;

[0046] b4.2.7) - (C1-C 16 )alkyl-OC(O)- group;

[0047] b4.2.8) - CH3-[O-(CH2)2] n -C(O)- group, where n is an integer from 1 to 30;

[0048] b4.2.9) - (C3-C 10 ) Cycloalkyl-groups, which are either unsubstituted or substituted by at least one substituent selected from the following:

[0049] -hydroxyl group; and

[0050] -(C1-C6)alkyl-group; or

[0051] b4.2.10) - (C3-C 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2-;

[0052] b4.2.11) - Phenyl-C(O)- group;

[0053] b4.2.12) - (C1-C6)alkoxy-phenyl-(C1-C6)alkyl-OC(O)- group;

[0054] b4.2.13) - (C1-C 16 )alkyl-C(O)-NH-phenyl-(C1-C6)alkyl-OC(O)- group;

[0055] b4.2.14) - (C1-C 16 )alkyl-OC(O)-(C1-C6)alkyl-group;

[0056] Alternatively, R4 and R5, together with the nitrogen atom to which they are attached, form a (C3-C) group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heterocyclic alkyl-group, the (C3-C 10 The heterocyclic alkyl group is either unsubstituted or substituted by at least one substituent selected from the following: (C1-C6) alkyl group and CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30;

[0057] c) - (C3-C 10)cycloalkyl (C1-C6)alkyl-group, which is unsubstituted or substituted by at least one substituent selected from the following: -NH2 and NH2-(C1-C6)alkyl-group;

[0058] d) - (C3-C 10 A heterocyclic alkyl (C1-C6) alkyl group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0059] The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the following: (C1-C6) alkyl-groups and CH3-[O-(CH2)2] n -A group, where n is an integer from 1 to 30; and

[0060] e) - (C5-C 10 A heteroaryl (C1-C6) alkyl group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0061] The heteroaryl group is either unsubstituted or substituted by at least one substituent selected from the following:

[0062] -(C1-C6)alkyl-group;

[0063] -NH2-(C1-C6)alkyl-groups and

[0064] -Cyano;

[0065] f) - (C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 ) alkyl-group, wherein the heterocyclic alkyl group comprises one to four heteroatoms selected from oxygen, nitrogen, S(O), SO2 and sulfur;

[0066] g) - (C3-C 10 )Hypercyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 ) alkyl-group, wherein the heterocyclic alkyl group comprises one to four heteroatoms selected from oxygen, nitrogen, S(O), SO2 and sulfur;

[0067] R2 represents a halogen atom,

[0068] Or selected from the following groups:

[0069] -(C1-C6)alkyl-group;

[0070] -(C2-C6)alkenyl-group;

[0071] -(C2-C6) ynyl group;

[0072] -(C1-C6)alkylthio- group;

[0073] -(C1-C6)alkylthio(C1-C6)alkyl-group;

[0074] -(C1-C6)alkyl-S(O) group;

[0075] -(C1-C6)alkyl-S(O2-) group;

[0076] -(C1-C6)alkyl-S(O)-(C1-C6)alkyl-group;

[0077] -(C1-C6)alkyl-S(O2)-(C1-C6)alkyl-group;

[0078] -(C1-C6)alkoxy- group;

[0079] -(C1-C6)alkoxy(C1-C6)alkyl-group;

[0080] -(C1-C6)haloalkoxy(C1-C6)alkyl-group;

[0081] -(C3-C5)cycloalkyl-O-(C1-C6)alkyl-group;

[0082] -(C1-C6)alkyl-NH-(C1-C6)alkyl-group;

[0083] -((C1-C6)alkyl)2-N-(C1-C6)alkyl-group;

[0084] -(C1-C6)alkyl-NH- group; and

[0085] -((C1-C6)alkyl)2N-group;

[0086] R3 means:

[0087] - Deuterium atom;

[0088] - Hydrogen atom

[0089] Or selected from the following groups:

[0090] a)

[0091] - (C1-C6)alkyl-group;

[0092] - (C2-C6) alkenyl-group;

[0093] - (C2-C6) ynyl group; and

[0094] - (C1-C6) alkylthio- group;

[0095] b)

[0096] - OR6 group, wherein R6 is selected from:

[0097] - Hydrogen atom;

[0098] -(C1-C6)alkyl-group;

[0099] -CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30;

[0100] -(C2-C6)alkenyl-group;

[0101] -(C2-C6) ynyl group;

[0102] -(C3-C 10 )cycloalkyl-group;

[0103] -Phenyl;

[0104] -Phenyl (C1-C6)alkyl-group; and

[0105] -(C3-C 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(=O)- and -S(=O)2-;

[0106] c)

[0107] - -NR7R8 groups, wherein R7 and R8 are independently selected from:

[0108] - Hydrogen atom;

[0109] - CH3-[O-(CH2)2] n -, where n is an integer from 1 to 30;

[0110] - (C1-C6)alkyl-group, which is either unsubstituted or substituted with the following:

[0111] - (C5-C 10 ) heteroaryl groups, comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur; or

[0112] - Phenyl, which is either unsubstituted or substituted with at least one substituent selected from the following:

[0113] - Cyano and

[0114] - NR9R 10 -(C1-C6)alkyl-group, wherein:

[0115] R9 and R 10 Selected independently from:

[0116] - Hydrogen atom;

[0117] - (C1-C6)alkyl-group;

[0118] - CH3-[O-(CH2)2] n -, where n is an integer from 1 to 30, or

[0119] R9 and R 10 Together with the nitrogen atoms to which they are attached, they form (C 3- C 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0120] The (C3-C) 10 The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the following: (C1-C6) alkyl-groups and CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30;

[0121] Alternatively, R7 and R8 together with the nitrogen atoms they are attached to form (C3-C). 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0122] The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the following:

[0123] - Phenyl and

[0124] - Hydroxyl (C1-C6)alkyl-phenyl group;

[0125] d)

[0126] - (C3-C 10 (a) heterocyclic alkyl group containing one to four heteroatoms selected from oxygen, nitrogen and sulfur;

[0127] e)

[0128] - (C5-C 10 A heteroaryl group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0129] The (C5-C) 10 The heteroaryl group is either unsubstituted or substituted by at least one (C1-C6) alkyl group;

[0130] f)

[0131] - (C6-C 10 ) aryl-group; and

[0132] g)

[0133] - (C3-C 10 )cycloalkyl-group;

[0134] - L1 indicates the connector; and

[0135] - RCG1 indicates a reactive chemical group that is reactive to chemical groups present on binders, such as proteins, polypeptides, ligands, peptides, oligonucleotides or oligosaccharides, such as on targets, such as on cell binders, such as antibodies, such as monoclonal antibodies or VHH antibodies.

[0136] This disclosure further relates to a compound of formula (II) (also referred to in the text of this invention as a conjugate or compound / conjugate) or a pharmaceutically acceptable salt thereof:

[0137] A-L1-G-BA (II)

[0138] in:

[0139] A and L1 are as defined in this disclosure;

[0140] BA stands for binding agent, such as protein, polypeptide, ligand, peptide, oligonucleotide or oligosaccharide. For example, BA is a targeting agent, such as a cell binding agent, such as an antibody, such as a monoclonal antibody or VHH antibody.

[0141] G represents the product of the reaction between RCG1 as defined in this disclosure and the reactive group RCG2 present on the binder, for example, G is selected from the group consisting of:

[0142] ; ; ; ; ; ; ; ; ; ;and ,

[0143] For example, the left side of the G group is linked to a binding agent (e.g., protein, polypeptide, ligand, peptide, oligonucleotide, or oligosaccharide, such as a target agent, cell binding agent, such as an antibody (Ab), such as a monoclonal antibody or VHH antibody, such as an antibody (Ab)), and the right side of the G group is linked to L1, for example, G represents the following groups: ; ; ; , or Such as ; ; or .

[0144] Compounds of formulas (I) and (II) may also exist in tautomer form. Indeed, it should be understood that this disclosure covers all isomers of formulas (I) and (II) and their pharmaceutically acceptable derivatives, including all geometric isomers, tautomers, and mixtures thereof.

[0145] In the context of this disclosure, compounds of formula (I) include compounds of formulas (I1) and (I2) as defined in this disclosure.

[0146] In the context of this disclosure, compounds of formula (II) include compounds of formulas (II1) and (II2) as defined in this disclosure.

[0147] The compound / load of formula (I) may exist in the form of a base or an addition salt of an acid or base, particularly a pharmaceutically acceptable salt.

[0148] Pharmaceutically acceptable salts of the compounds / loads of formula (I) do indeed form part of this disclosure.

[0149] Compounds / loads of formula (I) may exist as bases, acids, zwitterions, or addition salts of acids or bases. Such addition salts, bases, acids, and zwitterions form part of this disclosure. Therefore, this disclosure relates particularly to compounds / loads of formula (I) or to their pharmaceutically acceptable salts.

[0150] These salts can be prepared with pharmaceutically acceptable acids or bases, but salts of other acids or bases that can be used, for example, to purify or isolate compounds / loads of formula (I) also form part of this disclosure.

[0151] This disclosure also relates to methods for preparing compounds / conjugates according to formula (II) of this disclosure.

[0152] Therefore, according to a specific embodiment, this disclosure relates to a method for preparing compounds / conjugates of formula (II) as defined in this disclosure, the method comprising at least the following steps:

[0153] (i) Make the following come into contact and react:

[0154] - An optional buffered aqueous solution of a binder, such as a protein, polypeptide, ligand, peptide, oligonucleotide, or oligosaccharide, for example a targeting agent, such as a cell binding agent, such as an antibody (Ab), such as a monoclonal antibody or VHH antibody, comprising a reactive RCG2 group optionally modified by a modifying agent.

[0155] as well as

[0156] - A solution of a compound / load as defined in formula (I) in this disclosure, wherein the compound / load

[0157] Contains a reactive RCG1 group.

[0158] The RCG1 group of the compound / load of formula (I) is reactive to the RCG2 group of the binder (e.g., protein, polypeptide, ligand, peptide, oligonucleotide or oligosaccharide, such as a target agent, such as a cell binder, such as an antibody (Ab), such as a monoclonal antibody or VHH antibody) to form a G group by covalent bond and form a compound / conjugate of formula (II).

[0159] (ii) and then optionally separate the compound / conjugate of formula (II) formed in step (i) from the unreacted compound / load of formula (I); and / or from the unreacted binder (e.g., protein, polypeptide, ligand, peptide, oligonucleotide or oligosaccharide, such as a target agent, such as a cell binder, such as an antibody (Ab), such as a monoclonal antibody or VHH antibody); and or from any aggregates that may have formed.

[0160] Another subject of this disclosure is compounds / conjugates selected from the above and below definitions / lists according to formula (II) of this disclosure, or pharmaceutically acceptable salts thereof, used as medicines.

[0161] Another subject of this disclosure is compounds / conjugates selected from the above and below definitions / lists according to formula (II) of this disclosure, or pharmaceutically acceptable salts thereof, for therapeutic use, particularly as TLR7 and / or 8 agonists.

[0162] Another subject of this disclosure is compounds / conjugates selected from the above and below definitions / lists according to formula (II) of this disclosure, or pharmaceutically acceptable salts thereof, for inducing large amounts of immunostimulatory cytokines with low or no induction of pro-inflammatory cytokines, for stimulating cytokine induction of IFNα and IP10 with low or no stimulation of IL6 and TNFα, particularly wherein the IFNα / TNFα ratio is greater than 1.

[0163] Another subject of this disclosure is compounds / conjugates selected from the above and below definitions / lists according to formula (II) of this disclosure, or pharmaceutically acceptable salts thereof, for the prevention and / or treatment of diseases or disorders that may benefit from activation of the immune system, such as for the prevention and / or treatment of proliferative disorders; cancer; chronic myelogenous diseases; hairy cell leukemia; skin diseases such as skin lesions or skin cancers (e.g., genital and perianal warts / condyloma acuminata, genital herpes, actinic keratosis, basal cell carcinoma, cutaneous T-cell lymphoma); autoimmune diseases; inflammatory diseases; respiratory diseases; sepsis; allergic reactions (e.g., allergic rhinitis or respiratory allergies); asthma; graft rejection; graft-versus-host disease and immunodeficiency, such as for the prevention and / or treatment of cancer.

[0164] Another subject of this disclosure is compounds / conjugates selected from the above and below definitions / lists according to formula (II) of this disclosure, or pharmaceutically acceptable salts thereof, for the prevention and / or treatment of cancer.

[0165] Another subject of this disclosure is compounds / conjugates selected from the above and below definitions / lists according to formula (II) of this disclosure, or pharmaceutically acceptable salts thereof, used as anticancer agents.

[0166] Another subject of this disclosure is compounds / conjugates selected from the above and below definitions / lists according to formula (II) of this disclosure, or pharmaceutically acceptable salts thereof, for use in antitumor vaccines.

[0167] Another subject of this disclosure is the prevention and / or treatment of diseases or disorders that may benefit from activation of the immune system, such as the prevention and / or treatment of proliferative disorders; cancer; chronic myeloid diseases; hairy cell leukemia; skin diseases such as skin lesions or skin cancer (e.g., genital and perianal warts / condyloma acuminata, genital herpes, actinic keratosis, basal cell carcinoma, cutaneous T-cell lymphoma); autoimmune diseases; inflammatory diseases; respiratory diseases; sepsis; allergic reactions (e.g., allergic rhinitis or respiratory allergies); asthma; graft rejection; graft-versus-host disease; and immunodeficiency, the method comprising administering to a subject in need, such as a human, a therapeutically effective amount of a compound / conjugate selected from the above and below definitions / lists according to formula (II) of this disclosure, or a pharmaceutically acceptable salt thereof.

[0168] In another aspect, this disclosure also relates to methods for preventing diseases or disorders in patients in need, such as those who may benefit from activation of the immune system, such as proliferative diseases; cancer; chronic myeloid diseases; hairy cell leukemia; skin diseases such as skin lesions or skin cancer (e.g., genital and perianal warts / condyloma acuminata, genital herpes, actinic keratosis, basal cell carcinoma, cutaneous T-cell lymphoma); autoimmune diseases; inflammatory diseases; respiratory diseases; sepsis; allergic reactions (e.g., allergic rhinitis or respiratory allergies); asthma; graft rejection; graft-versus-host disease; and immunodeficiency, the method comprising immunizing said patient with a vaccine comprising a compound / conjugate selected from the above and below definitions / lists according to formula (II) of this disclosure or a pharmaceutically acceptable salt thereof.

[0169] In another aspect, this disclosure also relates to anti-tumor vaccines.

[0170] This disclosure further relates to the use of compounds / conjugates or pharmaceutically acceptable salts thereof selected from the above and below definitions / lists according to formula (II) of this disclosure for the manufacture of antitumor vaccines and / or pharmaceutical agents for the prevention and / or treatment of diseases or disorders that may benefit from activation of the immune system, such as for the prevention and / or treatment of proliferative disorders; cancer; chronic myeloid diseases; hairy cell leukemia; skin diseases such as skin lesions or skin cancer (e.g., genital and perianal warts / condyloma acuminata, genital herpes, actinic keratosis, basal cell carcinoma, cutaneous T-cell lymphoma); autoimmune diseases; inflammatory diseases; respiratory diseases; sepsis; allergic reactions (e.g., allergic rhinitis or respiratory allergies); asthma; graft rejection; graft-versus-host disease and immunodeficiency, such as cancer.

[0171] Another subject of this disclosure is a pharmaceutical preparation comprising, as an active ingredient, an effective dose of a compound / conjugate selected from the above and below definitions / lists according to formula (II) of this disclosure, or a pharmaceutically acceptable salt thereof.

[0172] Another subject of this disclosure is a pharmaceutical preparation comprising a compound / conjugate selected from the above and below definitions / lists according to formula (II) of this disclosure, or a pharmaceutically acceptable salt thereof.

[0173] Another subject of this disclosure is a pharmaceutical composition comprising, as an effective dose of an active ingredient, a compound / conjugate selected from the above and below definitions / lists of formula (II) according to this disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0174] Another subject of this disclosure is a pharmaceutical composition comprising a compound / conjugate selected from the above and below definitions / lists of formula (II) according to this disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0175] definition

[0176] In the context of this disclosure, unless otherwise stated throughout this specification, the following terms shall have the following definitions:

[0177] - "Halogen atom": a fluorine, chlorine, bromine, or iodine atom, and for example, fluorine and chlorine atoms;

[0178] - "hydroxyl group": "-OH" group;

[0179] - "Oxide group": "=O" group;

[0180] - Nitro group: "-NO2" group;

[0181] - "Cyano": "-C≡N" group;

[0182] - “(C x -C y Alkyl group: A straight-chain or branched aliphatic group based on a saturated hydrocarbon containing x to y carbon atoms (e.g., 1 to 6 carbon atoms or 1 to 16 carbon atoms). Examples may include, but are not limited to: methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, octyl, nonyl, decyl, etc.

[0183] - “(C x -C y "Alkenyl" group: A straight-chain or branched aliphatic group based on a hydrocarbon that contains at least one unsaturated (double bond) and contains x to y carbon atoms (x is an integer of at least 2), for example, 2 to 6 carbon atoms. Examples may include, but are not limited to: vinyl, propenyl, butenyl, pentenyl, hexenyl, etc.

[0184] - “(C x -C y "Alynyl" group: A straight-chain or branched aliphatic group based on a hydrocarbon that contains at least one triple bond and contains x to y carbon atoms (x is an integer of at least 2), for example, from 2 to 6 carbon atoms. Examples, but not limited to, may include: ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc.

[0185] - “(C x -C y"Alkoxy" group: -O-alkyl, wherein the alkyl group is as previously defined. For example, (C1-C6)alkoxy. Examples may include, but are not limited to: methoxy; ethoxy; propoxy; isopropoxy; straight-chain butoxy, sec-butoxy, or tert-butoxy; isobutoxy; pentoxy; hexoxy; heptoxy; octoxy; nonoxy; decoxy, etc.

[0186] - “(C x -C y The "haloalkoxy" group is an -O-alkyl group, wherein the alkyl group is as previously defined and is further substituted with at least one halogen atom as previously defined. For example, (C1-C6) haloalkoxy. Examples, but not limited to, include: chloromethoxy, fluoromethoxy, dichloromethoxy, 2-fluoropropoxy, etc.

[0187] - “(C x -C y "alkylthio" group: -S-alkyl, wherein the alkyl group is as previously defined. For example, (C1-C6)alkylthio. Examples may include, but are not limited to: methylthio; ethylthio; propylthio; isopropylthio; linear butylthio, sec-butylthio, or tert-butylthio; isobutylthio; pentylthio; hexylthio; heptylthio; octylthio; nonylthio; decanthio, etc.

[0188] - “(C3-C 10 "(C3-C5)cycloalkyl" group: Cycloalkyl group, unless otherwise specified, contains 3 to 10 carbon atoms (note: "(C3-C5)cycloalkyl" group). 10 (C3-C5)cycloalkyl groups, or groups with 3 to 5 carbon atoms (note: "(C3-C5)cycloalkyl groups"), are saturated or partially unsaturated and unsubstituted or substituted. Examples, but not limited to, may include: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, etc.

[0189] - “(C3-C 10 "Heterocyclic alkyl" group: A monocyclic alkyl group that, unless otherwise specified, contains 3 to 10 carbon atoms (C3-C4). 10A heterocyclic alkyl group is defined as a alkyl group consisting of 1 to 4 heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)-, and -SO2- (in other words, one heteroatom replaces one carbon atom). Such a heterocyclic alkyl group may be saturated or partially saturated and may be unsubstituted or substituted. Examples of heterocyclic alkyl groups include, but are not limited to: piperazine; morpholino; pyrrolidine; tetrahydropyran; thiocyclic butane dioxide; piperidine; thiocyclic pentane; thiocyclic pentane oxide; thiocyclic pentane dioxide; Dihydrofuran; tetrahydrofuran; aziridine; oxadiazole; thioheterobutane; 2H-pyrrole; 1H-, 2H- or 3H-pyrroleline; tetrahydrothiophene; oxadiazole and, for example, 1,3,4-oxadiazole or 1,3,5-oxadiazole; thiadiazole and, for example, 1,3,4-thiadiazole; isoxazoline; 2- or 3-pyrazoline; pyrroleline; pyrazolidine; imidazoline; imidazoline; thiazoline; isoxazoline; isoxazoline; dioxopentane; oxthiazolidine; dioxazole group, etc.

[0190] - "(C5-C 10 "Heteroaryl" refers to a cyclic aromatic group containing 5 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur (C5-C6). 10 (In other words, a heteroatom replaces a carbon atom). This heteroaryl group can be unsubstituted or substituted. Taking 5 to 10-membered heteroaryl groups as examples, but not limited to: pyridine, furan, pyrrole, thiophene, pyrazole, oxazole, isoxazole, triazole, tetraazole, oxadiazole, furazon, thiazole, isothiazole, thiadiazole, imidazole, pyrimidine, pyridazine, triazine group, etc.

[0191] - “(C6-C 10 "Aryl" group: A cyclic aromatic group containing 6 to 10 carbon atoms (Note: "(C6-C10") 10 (6- to 10-membered aryl groups). This aryl group can be unsubstituted or substituted. Examples of 6- to 10-membered aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0192] - "Deuterium atom" (D or 2 H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144;

[0193] - "Hydroxy protecting group" refers to: ethers, silyl ethers, esters, carbonates, carbamates, etc., such as acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl ether (MEM), dimethoxytriphenylmethyl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT), methoxymethyl ether (MOM), methoxytriphenylmethyl [(4-methoxyphenyl)diphenylmethyl] (MMT), p-methoxybenzyl ether (PMB), p-methoxyphenyl ether (PMP), methylthiomethyl ether, neopentanoyl (Piv), tetrahydropyranyl (THP), tetrahydrofuran (THF), triphenylmethyl (triphenylmethyl, Tr) Silyl ethers (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), methyl ethers, ethoxyethyl ethers (EE), such as acetyl (Ac), benzyl (Bn), β-methoxyethoxymethyl ether (MEM), dimethoxytriphenylmethyl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT), p-methoxybenzyl ether (PMB), tetrahydropyranyl (THP), triphenylmethyl (triphenylmethyl, Tr), trimethylsilyl (TMS), and tert-butyldimethylsilyl (TBDMS). (See Greene's Handbook on Protective Groups in Inorganic Synthesis, PGMWUTS and TWGREENE, 4th Edition, 1807 Wiley 207, Wiley Interscience)

[0194] - "Amino protecting group" refers to: urethane esters, amides, alkyl groups, enamines, imides, imides, etc., such as benzyloxycarbonyl (Cbz) groups, p-methoxybenzylcarbonyl (Moz or MeOZ) groups, tert-butyloxycarbonyl (BOC) groups, 9-fluorenylmethyloxycarbonyl (Fmoc) groups, acetyl (Ac) groups, benzoyl (Bz) groups, benzyl (Bn) groups, urethane ester groups, p-methoxyphenyl (PMP) groups, p-toluenesulfonyl (Ts) groups. Groups, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), Troc (trichloroethyl chloroformate) groups, other sulfonamides such as benzyloxycarbonyl (Cbz) groups, tert-butyloxycarbonyl (BOC) groups, 9-fluorenylmethyloxycarbonyl (Fmoc) groups, acetyl (Ac) groups, benzoyl (Bz) groups, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), Troc (trichloroethyl chloroformate) groups. (See Greene's Protective Groups in Organic Synthesis, PGMWUTS and TWGREENE, 4th Edition, 1807 Wiley 207, Wiley Interscience).

[0195] - "Carboxylic acid protecting group" refers to: esters, silyl esters, amides, hydrazides, etc., such as methyl esters, benzyl esters, tert-butyl esters, allyl esters, esters of 2,6-disubstituted phenols (e.g., 2,6-dimethylphenol, 2,6-diisopropylphenol, 2,6-ditert-butylphenol), silyl esters, orthoesters, oxazolines, such as methyl esters and benzyl esters. (See Greene's Protective Groups in Organic Synthesis, PGMWUTS and TWGREENE, 4th Edition, 1807 Wiley 207, Wiley Interscience).

[0196] - "Aldehyde protecting group" or "ketone protecting group" (also known as "carbonyl protecting group") refers to: acetals and ketals, dithioacetals and ketals, substituted hydrazones, oximes, etc., such as acetals and ketals, carbonyl esters, and dithianes. (See Greene's Protective Groups in Organic Synthesis, PGMUTS and TWGREENE, 4th Edition, 1807 Wiley 207, Wiley Interscience).

[0197] - "Leaving group" means: an atom or group of atoms that detaches from the main or residual part of the substrate during a reaction or a basic step of a reaction;

[0198] - "Amphoteric ion" refers to a molecule that is neutral in nature and has both positive and negative charges as well as acidic and basic groups;

[0199] - In this disclosure, "room temperature" (also referred to as rt) means a range from 18°C ​​to 30°C, such as a temperature from 18°C ​​to 25°C;

[0200] - A “self-destructive joint” or “self-destructive spacer” is a covalent assembly tailored to link the cleavage of two chemical bonds upon activation of a protective moiety in the precursor (AGGavriel et al., Polym. Chem. 2022, 13, 3188; A. Alouane et al., Angew. Chem. Int. Ed. 2015, 54, 7492-7509). Examples of self-destructive joints suitable for this disclosure include, for instance. -C(O)-O-(CR 14 R 15 )-Aryl-NR 16 - Groups, -C(O)-O-(CR 14 R 15 )-Heteroaryl-NR 16 - Groups, -C(O)-NR 17 -(C2-C6)alkyl-NR 18 - , -C(O)-NR 17- (C2-C6)alkyl-NR18 -C(O)-O-CR 15 R 14 -Aryl-NR 16 - Groups, -C(O)-NR 17- (C2-C6)alkyl-NR 18 -C(O)-O-CR 15 R 14 -heteroaryl-NR 16 - Groups, -CR 15 R 14 -Aryl-NR 16 - Group or -CR 15 R 14 -heteroaryl-NR 16 - Group, aryl is (C6-C 10 ) aryl and heteroaryl are C5-C6 groups containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heteroaryl compounds, for example -C(O)-O-CH2-phenyl-NH- Group, single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site of covalent attachment to the (AA)w group; R 14 R 15 R 16 R 17 and R 18 It is a hydrogen atom or a (C1-C6) alkyl group;

[0201] - "PEG": Polyethylene glycol, PEGn means -(CH2-CH2-O) n The part, where n represents an integer from 1 to 30, such as from 2 to 29, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28 and 29;

[0202] - "TLR": The terms "Toll-like receptor" and "TLR" refer to any member of a highly conserved family of mammalian proteins that recognize pathogen-associated molecular patterns and act as key signaling elements in innate immunity. TLR peptides share a characteristic structure comprising an extracellular domain with leucine-rich repetitive sequences, a transmembrane domain, and an intracellular domain involved in TLR signaling.

[0203] - "TLR7": The terms "Toll-like receptor 7" and "TLR7" refer to a nucleic acid or polypeptide that has at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater sequence identity with a publicly available TLR7 sequence (e.g., GenBank accession number AAZ99026 for the human TLR7 polypeptide or GenBank accession number AAK62676 for the mouse TLR7 polypeptide);

[0204] - "TLR8": The terms "Toll-like receptor 8" and "TLR8" refer to a nucleic acid or polypeptide that has at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or greater sequence identity with a publicly available TLR8 sequence (e.g., GenBank accession number AAZ95441 for the human TLR8 polypeptide or GenBank accession number AAK62677 for the mouse TLR8 polypeptide);

[0205] - "TLR agonists": These are substances that bind directly or indirectly to TLRs (e.g., TLR7 and / or TLR8) to induce TLR signaling. Any detectable difference in TLR signaling can indicate agonist stimulation or activation of the TLR. Differences in signaling can manifest as, for example, changes in target gene expression, changes in phosphorylation of signal transduction components, changes in the intracellular localization of downstream elements (such as NF-κB), changes in the association of certain components (such as IRAK) with other proteins or intracellular structures, or changes in the biochemical activity of components such as kinases (such as MAPK). TLR7 agonists more effectively induce IFNα and IFN-regulated immunostimulatory cytokines, such as IP10. TLR8 agonists more effectively induce pro-inflammatory cytokines associated with the NF-κB pathway, such as TNFα and IL6;

[0206] - "Immune response": As used in this article, an "immunological response" or "immune reaction" to an antigen or component refers to a humoral immune response and / or cellular immune response to that antigen or component in a subject;

[0207] Immune responses include innate and adaptive immune responses. Innate immune responses are rapid, acting responses that provide the first line of defense for the immune system. In contrast, adaptive immunity utilizes the selection and clonal expansion of immune cells with somatically rearranged receptor genes (e.g., T-cell receptors and B-cell receptors) that recognize antigens from a given pathogen or barrier (e.g., a tumor), thus providing specificity and immune memory. Innate immune responses (in their many functions) lead to a rapid burst of inflammatory cytokines and activation of antigen-presenting cells (APCs) such as macrophages and dendritic cells. To distinguish pathogens from their own components, the innate immune system uses a variety of relatively invariant receptors (called pathogen-associated molecular patterns, or PAMPs) that detect the characteristics of pathogens. The mechanism behind this enhanced immune response has been reported to involve pattern recognition receptors (PRRs), which are differentially expressed on a variety of immune cells, including neutrophils, monocytes, macrophages, dendritic cells, natural killer cells, B cells, and some non-immune cells such as epithelial and endothelial cells. The involvement of dendritic receptors (PRRs) leads to the activation of some cells within these cells and the secretion of their cytokines and chemokines, as well as the maturation and migration of others. This, in turn, creates an inflammatory environment that leads to the establishment of adaptive immune responses. PRRs include non-phagocytic receptors (such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) proteins), as well as receptors that induce phagocytosis (such as scavenger receptors, mannose receptors, and β-glucan receptors). Dendritic cells are thought to be responsible for initiating naïve CD4+ phagocytosis. + Auxiliary T (T) H Cell initiation and induction of CD8 + T cells are among the most important cell types that differentiate into killer cells. TLR signaling has been reported to play a crucial role in determining the quality of these helper T cell responses; for example, the nature of TLR signaling identifies the specific type of TH response observed (e.g., T...). H 1. Reaction and T H 2. Reaction). The combination of antibodies (humoral) and cellular immunity acts as T... H A portion of the type 1 reaction is produced, while T... H Type 2 reactions are primarily antibody reactions;

[0208] Humoral immunity refers to immune responses mediated by antibody molecules, while cellular immunity refers to immune responses mediated by T lymphocytes and / or other leukocytes. An important aspect of cellular immunity involves the antigen-specific response of cytolytic T cells (“CTLs”). CTLs are specific for peptide antigens that are presented by association with proteins encoded by the major histocompatibility complex (MHC) and expressed on the cell surface. CTLs help induce and promote the destruction of intracellular microbes or the lysis of cells infected by such microbes. Another aspect of cellular immunity involves the antigen-specific response of helper T cells. Helper T cells help stimulate the function of nonspecific effector cells against cells that display peptide antigens associated with MHC molecules on their surface and focus their activity. Cellular immunity also refers to the production of cytokines, chemokines, and other such molecules (including those derived from CD4+) by activated T cells and / or other leukocytes. + T cells and CD8 + The production of these molecules in T cells;

[0209] - An “immune response” associated with TLR7 and / or TLR8 is an immune response involving the activation of TLR7 and / or TLR8 receptors. Activation of TLR7 and / or TLR8 receptors can be determined in vitro using methods such as those described in the examples;

[0210] - "Induction": "Induction" and its variations refer to any measurable increase in cellular activity. Induction of an immune response can include, for example, an increase in cytokine production; activation, proliferation, or maturation of immune cell populations; and / or other indicators of increased immune function.

[0211] - "Binding agent": A molecule with affinity for biological targets (such as ligands, proteins, peptides, antibodies (such as monoclonal antibodies or VHH antibodies), peptides, oligonucleotides, oligosaccharides (e.g., targeting agents, such as cell binders)). The function of a binding agent is to direct biologically active compounds (such as TLR7 and / or 8 agonist compounds) to biological targets;

[0212] - "Cell binding agents": Cell binding agents can be any type currently known or becoming known, and include both peptides and non-peptides. Cell binding agents can be any compound that can bind to cells in a specific or non-specific manner. Typically, these can be antibodies (especially monoclonal antibodies), lymphokines, hormones, growth factors, vitamins, nutrient transport molecules (such as transferrin), or any other cell-binding molecule or substance.

[0213] More specific examples of cell-binding agents that can be used include:

[0214] (a) Polyclonal antibodies;

[0215] (b) Monoclonal antibodies;

[0216] (c) Antibody fragments, such as Fab, Fab1, and F(ab')2, Fv (Parham, J. Immunol. [Journal of Immunology] 131:2895-2902 (1983); Spring et al. J. Immunol. [Journal of Immunology] 113:470-478 (1974); Nisonoff et al. Arch. Biochem. Biophys. [Archives of Biochemistry and Biophysics] 89:230-244 (1960));

[0217] (d) Interferons (e.g., α, β, γ);

[0218] (e) Lymphokines, such as IL2, IL3, IL4, and IL6;

[0219] (f) Hormones, such as insulin, TRH (thyrotropin-releasing hormone), MSH (melanocyte-stimulating hormone), and steroid hormones (such as androgens and estrogens).

[0220] (g) Growth factors and colony-stimulating factors, such as EGF, TGFα, FGF, VEGF, G-CSF, M-CSF, and GM-CSF (Burgess, Immunology Today 5:155-158 (1984)); or

[0221] (h) transferrin (O'Keefe et al. J. Biol. Chem. [Journal of Biochemistry] 260:932-937(1985)); and (i) vitamins, such as folic acid;

[0222] - "Cell-permeable" compounds: Membrane permeability of compounds was evaluated using an in vitro model of passive transcellular permeation called PAMPA (for parallel artificial membrane permeability assay). This PAMPA assay allows evaluation of permeability across a pH range from pH 6.5 to pH 7.4. Compounds were considered to be: below 25, "poorly permeable or lowly permeable"; between 26 and 300, "moderately permeable"; and above 300, "highly permeable". "Non-cell-permeable compounds" were defined by a PAMPA level below 25 and by the differential activity between the free drug and the drug conjugated to a mAb in the THP1 DUAL reporter cell assay: non-cell-permeable drugs were inactive as free drugs at 500 nM and active when conjugated to a mAb in the nM range.

[0223] - "Targeted agents": Targeted agents are structures that have a selective affinity for target molecules relative to other non-target molecules. The targeting moiety binds to the target molecule. The targeting moiety can include, for example, antibodies, peptides, ligands, receptors, or their binding portions. The target biomolecule can be a biological receptor or other cellular structure, such as a tumor antigen. The targeting moiety is typically specific to a particular cell surface antigen, enabling immunostimulatory compounds to target target cells or disease sites.

[0224] - "Antibody": An antibody with affinity for a biological target, such as a monoclonal antibody. The function of an antibody is to direct a biologically active compound (such as a TLR7 and / or 8 agonist compound) toward the biological target. Antibodies can be monoclonal, polyclonal, or multispecific; they can also be antibody fragments; they can also be mouse antibodies, chimeric antibodies, humanized antibodies, or human antibodies. An "antibody" can be a natural or conventional antibody in which two heavy chains are linked to each other by disulfide bonds, and each heavy chain is linked to a light chain by a disulfide bond (also known as a "full-length antibody"). The term "conventional (or full-length) antibody" refers both to an antibody containing a signal peptide (or propeptide, if present) and to the mature form obtained after secretion and proteolytic processing of one or more chains. There are two types of light chains, λ (l) and κ (k). There are five main heavy chain classes (or isotypes) that determine the functional activity of the antibody molecule: IgM, IgD, IgG, IgA, and IgE. Each chain contains different sequence domains. The light chain contains two domains or regions: a variable domain (VL) and a constant domain (CL). The heavy chain contains four domains: one variable domain (VH) and three constant domains (CH1, CH2, and CH3, collectively referred to as CH). The variable regions of both the light chain (VL) and heavy chain (VH) determine the binding recognition and specificity of antigens. The constant domains (CL) of the light chain and the constant domains (CH) of the heavy chain confer important biological properties, such as antibody chain association, secretion, transplacental mobility, complement binding, and binding to the Fc receptor (FcR). The Fv fragment is the N-terminal portion of the immunoglobulin Fab fragment and consists of a variable portion of one light chain and one heavy chain. Antibody specificity lies in the structural complementarity between the antibody binding site and the antigenic determinant. The antibody binding site is composed primarily of residues from the hypervariable region or complementarity-determining region (CDR). Sometimes, residues from the non-hypervariable region or frame region (FR) can affect the overall domain structure, thereby affecting the binding site. CDRs are amino acid sequences that collectively define the binding affinity and specificity of the native Fv region of the immunoglobulin binding site. The light and heavy chains of immunoglobulins each have three CDRs, designated CDR1-L, CDR2-L, CDR3-L and CDR1-H, CDR2-H, CDR3-H, respectively. Therefore, a typical antibody-antigen binding site contains six CDRs, comprising a set of CDRs from the respective heavy chain V region and light chain V region.

[0225] As used herein, the term "antibody" refers to both conventional (full-length) antibodies and their fragments, as well as single-domain antibodies and their fragments (such as the variable heavy chain of a single-domain antibody). Fragments of (conventional) antibodies typically contain a portion of the complete antibody (such as the antigen-binding region or variable region of the complete antibody) and retain the biological function of the conventional antibody. Examples of such fragments include Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, VHH, and biantibodies;

[0226] By convention, the numbering of variable constant region domains increases as they move further away from the antigen-binding site or N-terminus of the immunoglobulin or antibody. The N-terminus of each heavy and light immunoglobulin chain is a variable region, and the C-terminus is a constant region; C... H 3 and C L The domains actually contain the carboxyl terminus of the heavy chain and the carboxyl terminus of the light chain, respectively. Therefore, the domains of light chain immunoglobulins are denoted by V. L -C L The orientation is arranged, and the heavy chain structural domain is VH-CHl-hinge-C H 2-C H Arranged in 3 directions.

[0227] The amino acid positions in the heavy chain constant region, including C H 1. Hinges, C H 2. C H 3 and C L The amino acid positions within the domain can be numbered according to the Kabat indexing system (see Kabat et al., "Sequences of Proteins of Immunological Interest", US Dept. Health and Human Services, 5th edition, 1991), EU numbers (see Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969). PMID:5257969), or according to IMGT (see Lefranc, M.-P. et al., Dev. Comp. Immunol., 29, 185-203 (2005) PMID: 15572068). As used herein, the term "V" is... H The term "domain" includes the N-terminal variable domain of the immunoglobulin heavy chain, and the term "V" LThe "domains" include the N-terminal variable domain of the immunoglobulin light chain.

[0228] As used in this article, the term "C" H The "1 domain" includes the first (most amino-terminal) constant region domain of the immunoglobulin heavy chain, which extends, for example, from approximately positions 114-223 (EU positions 118-215) in the Kabat numbering system. H 1. Domain V of immunoglobulin heavy chain molecules H The amino groups at the ends of the domain and hinge region are adjacent and do not form part of the Fc region of the immunoglobulin heavy chain.

[0229] As used herein, the term "hinge region" includes the C-linked region of the heavy chain molecule. H 1. Structural Domains and C H 2. The hinge region. This hinge region contains approximately 25 residues and is flexible, thus allowing the two N-terminal antigen-binding regions to move independently. The hinge region can be subdivided into three distinct domains: the upper hinge domain, the middle hinge domain, and the lower hinge domain (Roux et al. J. Immunol. [Journal of Immunology] 1998, 161:4083).

[0230] As used in this article, the term "C" H The "2-domain" includes a portion of the heavy chain immunoglobulin molecule that extends, for example, from approximately positions 244-360 (EU positions 231-340) in the Kabat numbering system. H The 2-domain is unique because it does not pair tightly with the other domain. Instead, two N-linked branched sugar chains insert into the two C-linked domains of the intact natural IgG molecule. H 2. Between the structural domains. In one embodiment, the antigen-binding protein disclosed herein comprises a C-terminus derived from an IgG1 molecule (e.g., a human IgG1 molecule). H 2. Structural domain.

[0231] As used in this article, the term "C" H The "3-domain" includes a portion of the heavy chain immunoglobulin molecule, which originates from C... H The N-terminus of the 2-domain extends by approximately 110 residues, for example, from approximately positions 361-476 (EU positions 341-445) in the Kabat numbering system. H The 3-domain typically forms the C-terminal portion of an antibody. However, in some immunoglobulins, additional domains can be derived from the C-terminal region. H3 The structural domain extends to form the C-terminal portion of the molecule (e.g., the C-terminal portion of the μ chain of IgM and the ε chain of IgE). H 4 domains). In one embodiment, the antigen-binding protein disclosed herein includes a C domain derived from an IgG1 molecule (e.g., a human IgG1 molecule).H 3. Structural Domains. As used in this paper, the term "C" refers to a structural domain. L "Domains" include, for example, the constant region domain of the immunoglobulin light chain extending from approximately Kabat position 107A-216. L Domain and V L The domains are adjacent. In one embodiment, the antigen-binding protein disclosed herein comprises a C domain derived from the κ light chain (e.g., the human κ light chain). L Structural domain.

[0232] As used in this article, the location is defined according to the EU number.

[0233] For example: A118 is located at position 118 according to the EU number, position 114 according to the Kabat number, and position 1 according to the IMGT number; E152 is located at position 152 according to the EU number, position 150 according to the Kabat number, and position 35 according to the IMGT number; K274 is located at position 274 according to the EU number, position 187 according to the Kabat number, and position 44 according to the IMGT number; K414 is located at position 414 according to the EU number, position 145 according to the Kabat number, and position 74 according to the IMGT number; and K360 is located at position 360 according to the EU number, position 383 according to the Kabat number, and position 20 according to the IMGT number.

[0234] - "Biological target": an antigen (or antigen set), such as one located on the surface of cancer cells or stromal cells associated with the tumor; these antigens may be, for example, growth factor receptors, oncogene products or mutated "tumor suppressor" gene products, angiogenesis-related molecules or adhesion molecules or receptors that are increased in the tumor microenvironment.

[0235] - "Conjugate": Antibody-drug conjugate or ADC, i.e., polypeptide, such as an antibody covalently attached to at least one TLR7 and / or 8 agonist molecule via a linker (as defined above). In the context of this disclosure, it means compounds of formulas (II), (II1), and (II2);

[0236] - "DAR" (Drug-to-Antibody Ratio): The number of TLR7 and / or 8 agonists attached to antibodies via linkers. DAR can be an average or exact number, depending on the conjugation technique used. DAR can be an average or exact DAR between 2 and 10. Preferably, DAR can be 2, 4, or 8;

[0237] - "Fc receptor": A protein on the surface of certain immune cells (such as B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, monocytes, neutrophils, eosinophils, basophils, human platelets, and mast cells) that contributes to the protective function of the immune system. It can recognize the Fc (crystallizable fragment) region of antibodies;

[0238] - "Connector": A group of atoms or a single bond that can covalently attach the compound / load of formula (I) to a binding agent (e.g., a protein, polypeptide, ligand, peptide, oligonucleotide or oligosaccharide, such as a target agent, such as a cell binding agent, such as an antibody, such as a monoclonal antibody or VHH antibody) to form the compound / conjugate of formula (II).

[0239] - "Peptide linker": a linker containing amino acids;

[0240] - "PEGylated connector": A connector containing PEG as defined above;

[0241] - "Payload": The TLR7 and / or 8 agonist compound covalently linked to the connector. In the context of this disclosure, it refers to compounds of formulas (I), (I1), and (I2).

[0242] - "Modifier": A chemical agent used to modify the amino acid side chain of an antibody to introduce a reactive group;

[0243] - "Reactive group": A group of atoms that can promote or undergo a chemical reaction;

[0244] - "Activated disulfide": A group containing at least one disulfide group that is prone to undergoing thiol-disulfide exchange, as described in Greg T. Hermanson's *Bioconjugate techniques*, 2nd edition (ISBN 978-0-12-370501-3). Using activated disulfides as an example, it is possible to mention, but is not limited to, groups containing at least one disulfide group that is prone to undergoing thiol-disulfide exchange. ;

[0245] - "Activated C≡C": A group containing at least one cycloalkyne C≡C bond, as described in Greg T. Hermanson's *Bioconjugate techniques*, 2nd edition (ISBN 978-0-12-370501-3). Using activated C≡C as an example, cyclooctyne moieties may be mentioned, but are not limited to, those in DBCO-amines. or BCN or MFCO ;

[0246] - "Cycloalkynes": monocyclic or polycyclic, containing at least one C≡C bond and 3 to 16 carbon atoms, and may be unsubstituted or substituted;

[0247] - "Heterocyclic alkyne": a cyclic alkyne group as defined above that contains at least one to six heteroatoms selected from oxygen, nitrogen and sulfur. Attached Figure Description

[0248] Figure 1a This graph illustrates a comparison of IFNα production among three examples (i.e., Example 75, Example 103, and Example 105) according to this disclosure; and a comparative assay of what is called unconjugated mAb (monoclonal antibody) (also referred to as naked mAb in this text) (reference). Therefore, this graph comprises four columns, corresponding from left to right to Example 75, Example 103, Example 105, and unconjugated mAb, respectively. The x-axis corresponds to the concentration of ADC in nanomoles (nM), and the y-axis corresponds to the concentration of IFNα in pg / ml (see Example C below).

[0249] Figure 1b This graph illustrates a comparison of IP10 production among three examples (i.e., Example 75, Example 103, and Example 105) according to this disclosure; and a comparative assay of what is called unconjugated mAb (monoclonal antibody) (also referred to as naked mAb in this text) (reference). Therefore, this graph comprises four columns, corresponding from left to right to Example 75, Example 103, Example 105, and the unconjugated mAb, respectively. The x-axis corresponds to the concentration of ADC in nM, and the y-axis corresponds to the concentration of IP10 in pg / ml (see Example C below).

[0250] Figure 1c This graph illustrates a comparison of TNFα production among three examples (i.e., Example 75, Example 103, and Example 105) according to this disclosure; and a comparative assay of what is called unconjugated mAb (monoclonal antibody) (also referred to as naked mAb in this text) (reference). Therefore, this graph comprises four columns, corresponding from left to right to Example 75, Example 103, Example 105, and unconjugated mAb, respectively. The x-axis corresponds to the concentration of ADC in nM, and the y-axis corresponds to the concentration of TNFα in pg / ml (see Example C below).

[0251] Figure 1dThis graph illustrates a comparison of IL6 production among three examples (i.e., Example 75, Example 103, and Example 105) according to this disclosure; and a comparative assay of what is called unconjugated mAb (monoclonal antibody) (also referred to as naked mAb in this text) (reference). Therefore, this graph comprises four columns, corresponding from left to right to Example 75, Example 103, Example 105, and the unconjugated mAb, respectively. The x-axis corresponds to the concentration of ADC in nM, and the y-axis corresponds to the concentration of IL6 in pg / ml (see Example C below).

[0252] Figure 2 This graph illustrates the evaluation of antitumor activity. It comprises 11 curves: 10 curves from the 10 examples disclosed herein, plus one curve from a comparative assay named teretrazoliumab-R848 ADC. The x-axis corresponds to the concentration of the conjugate in nM, and the y-axis corresponds to the AUC (area under the curve) data at 138 h (see Example D below). The 11 different curves are detailed below:

[0253] With symbols The curve corresponds to tsa-r848 ADC (also named Tusa-R848 in this disclosure).

[0254] With symbols The curve corresponds to Example 91.

[0255] With symbols The curve corresponds to Example 99.

[0256] With symbols The curve corresponds to Example 19.

[0257] With symbols The curve corresponds to Example 64.

[0258] With symbols The curve corresponds to Example 15.

[0259] With symbols The curve corresponds to Example 97.

[0260] With symbols The curve corresponds to Example 21.

[0261] With symbols The curve corresponds to Example 107.

[0262] With symbols The curve corresponds to Example 27.

[0263] With symbols The curve corresponds to Example 31.

[0264] abbreviation

[0265] Ab: Antibody; ACN, MeCN, or CH3CN: Acetonitrile; AcOH: Acetic acid; ADC: Antibody-drug conjugate; ADIBO: Azadibenzocyclooctylene; Ala: Alanine; AP-1: Activator protein-1; AUC: Area under the curve; CDCl3: Deuterated chloroform; CEACAM5: Carcinoembryonic antigen cell adhesion molecule 5; CHCl3: Chloroform; Cit: Citrulline; CO2: Carbon dioxide; conc.: Concentrated; Cs2CO3: Cesium carbonate; D2O: Deuterium oxide; DAR: Drug to antibody ratio; DBCO Dibenzylcyclooctyne; DC: Dendritic cells; DCC: N,N'-dicyclohexylcarbodiimide; DCM: Dichloromethane; DHAA: Dehydroascorbic acid; DIEA or DIPEA: N,N-diisopropylethylamine; DIC: N,N'-diisopropylcarbodiimide; DMA: Dimethylacetamide; DMAP: 4-Dimethylaminopyridine; DMF: N,N-dimethylformamide; DMSO: Dimethyl sulfoxide; DPBS: Durbecco's phosphate-buffered saline. saline); DSC: N,N'-disuccinimidyl carbonate; DTT: dithiothreitol; EC50: effective concentration 50; EDC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDTA: ethylenediaminetetraacetic acid; ELSD: evaporative light scattering detector; ES: electrospray ionization; Et2O: diethyl ether; EtOAc: ethyl acetate; EtOH: ethanol; FBS: fetal bovine serum; Glu: glutamic acid; H2O: water; H2SO4: sulfuric acid; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexaoxide Fluorophosphate; HBTU: (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate; HCl: hydrochloric acid; HEK: human embryonic kidney; HEPES: 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid; HIC: hydrophobic interaction chromatography; HOAt: 1-hydroxy-7-azabenzotriazole; HOBt: hydroxybenzotriazole; HPLC: high-performance liquid chromatography; HRMS: high-resolution mass spectrometry; IEC: ion exchange chromatography; IFN: interferon; ie: "that is", meaning; IL: interleukin; IP10: interferon-γ-induced protein 10; iPr2O: diisopropyl ether; iPrOH: isopropanol; ISG: interferon-stimulated gene; KCl: potassium chloride; K DDissociation constant; K₂HPO₄: dipotassium hydrogen phosphate; KH₂PO₄: potassium dihydrogen phosphate; LAR: linker to antibody ratio; LCMS: liquid chromatography-mass spectrometry; LiOH: sodium hydroxide; mAb or MAb: monoclonal antibody; mCPBA: m-chloroperoxybenzoic acid; MeOH: methanol; Me-THF or MeTHF: methyltetrahydrofuran; MgSO₄: magnesium sulfate; MS: mass spectrometry; MSD: Mesoscale. Discovery; MTBE: Methyl tert-butyl ether; N2: Nitrogen; NaCl: Sodium chloride; NaH: Sodium hydride; NaHCO3: Sodium bicarbonate; Na2HPO4: Disodium hydrogen phosphate; NaOH: Sodium hydroxide; NaPi: Sodium phosphate; Na2SO4: Sodium sulfate; NBS: N-bromosuccinimide; nBuLi: n-Butyllithium; NF-κB: Nuclear factor-activated B cell κ light chain enhancer; NH2NH2.H2O: Hydrazine hydrate; NH3: Ammonia; NH4Cl: Ammonium chloride; NH4OH: Ammonium hydroxide; NHS: N-hydroxysuccinimide; NMP N-Methyl-2-pyrrolidone; NMR: Nuclear Magnetic Resonance; NT: Not Detected; OD: Optical Density; PBMC: Peripheral Blood Mononuclear Cells; PBS: Phosphate-Buffered Saline; PDL1: Programmed Death Ligand 1; PEG: Polyethylene Glycol; PEGn: Polyethylene Glycol containing n (integer) ethylene glycol units; PES: Polyethersulfone; POCl3: Phosphoryl Chloride; PODS: Phenylene Oxadiazolyl Methyl Sulfone; PS: Polysorbate; PTFE: Polytetrafluoroethylene; PVDF: Polyvinylidene Fluoride; RP: Reverse Phase; RPMI: Roswell Memorial Institute Park Memorial Institute); rt or RT: room temperature; sat.: saturated; SCX: strong cation exchange; SEAP: secretory embryonic alkaline phosphatase; SEC: size exclusion chromatography; SFC: supercritical fluid chromatography; SOCl2: thionyl chloride; T: temperature; TAA: tumor-associated antigen; TCEP: tris(2-carboxyethyl)phosphine; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin-layer chromatography; TLR: Toll-like receptor; TMS: tetramethylsilane; t R : Retention time; UPLC: Ultra-high performance liquid chromatography; UV: Ultraviolet light; Val: Valine; ~: Approximately. Detailed Implementation

[0266] This disclosure relates to compounds / loads of formula (I) or pharmaceutically acceptable salts thereof:

[0267] A-L1-RCG1 (I)

[0268] in:

[0269] - A is the drug unit of formula (A)

[0270] (A)

[0271] in:

[0272] R1 means:

[0273] - Hydrogen atom, or

[0274] - Selected from the following groups:

[0275] a)

[0276] - (C1-C6)alkyl-group;

[0277] - Hydroxyl-(C1-C6)alkyl- group;

[0278] - NH2-(C1-C6)alkyl-group;

[0279] - NH-(C1-C6)alkyl-(C1-C6)alkyl- group;

[0280] - N((C1-C6)alkyl)2-(C1-C6)alkyl-group;

[0281] - (C2-C6) alkenyl-group;

[0282] - (C2-C6) ynyl group;

[0283] b)

[0284] - A phenyl (C1-C6)alkyl group, which is either unsubstituted or substituted by at least one substituent selected from the following:

[0285] b1) - (C1-C6)alkoxy-group;

[0286] b2) - Hydroxyl group;

[0287] b3) -C(O)-H group; and

[0288] b4) - (C1-C6) alkyl group, which is either unsubstituted or substituted by at least one substituent selected from the following:

[0289] b4.1) - Hydroxyl group; and

[0290] b4.2) - -NR4R5 group, wherein R4 and R5 are independently selected from:

[0291] b4.2.1) - Hydrogen atom;

[0292] b4.2.2) - (C1-C 16 )alkyl-group;

[0293] b4.2.3) - CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30; (C1-C6)alkoxy(C1-C6)alkyl- group; or (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl- group;

[0294] b4.2.4) - (C1-C6)alkyl-S(O2)- group;

[0295] b4.2.5) - (C1-C6)alkyl-NH-C(O)- group;

[0296] b4.2.6) - (C1-C 16 )alkyl-C(O)- group;

[0297] b4.2.7) - (C1-C 16 )alkyl-OC(O)- group;

[0298] b4.2.8) - CH3-[O-(CH2)2] n -C(O)- group, where n is an integer from 1 to 30;

[0299] b4.2.9) - (C3-C 10 ) Cycloalkyl-groups, which are either unsubstituted or substituted by at least one substituent selected from the following:

[0300] -hydroxyl group; and

[0301] -(C1-C6)alkyl-group; or

[0302] b4.2.10) - (C3-C 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2-;

[0303] b4.2.11) - Phenyl-C(O)- group;

[0304] b4.2.12) - (C1-C6)alkoxy-phenyl-(C1-C6)alkyl-OC(O)- group;

[0305] b4.2.13) - (C1-C 16 )alkyl-C(O)-NH-phenyl-(C1-C6)alkyl-OC(O)- group;

[0306] b4.2.14) - (C1-C 16)alkyl-OC(O)-(C1-C6)alkyl-group;

[0307] Alternatively, R4 and R5, together with the nitrogen atom to which they are attached, form a (C3-C) group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heterocyclic alkyl-group, the (C3-C 10 The heterocyclic alkyl group is either unsubstituted or substituted by at least one substituent selected from the following: (C1-C6) alkyl group and CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30;

[0308] c) - (C3-C 10 )cycloalkyl (C1-C6)alkyl-group, which is unsubstituted or substituted by at least one substituent selected from the following: -NH2 and NH2-(C1-C6)alkyl-group;

[0309] d) - (C3-C 10 A heterocyclic alkyl (C1-C6) alkyl group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0310] The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the following: (C1-C6) alkyl-groups and CH3-[O-(CH2)2] n -A group, where n is an integer from 1 to 30; and

[0311] e) - (C5-C 10 A heteroaryl (C1-C6) alkyl group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0312] The heteroaryl group is either unsubstituted or substituted by at least one substituent selected from the following:

[0313] -(C1-C6)alkyl-group;

[0314] -NH2-(C1-C6)alkyl-groups and

[0315] -Cyano;

[0316] f) - (C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 ) alkyl-group, wherein the heterocyclic alkyl group comprises one to four heteroatoms selected from oxygen, nitrogen, S(O), SO2 and sulfur;

[0317] g) - (C3-C 10 )Hypercyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16) alkyl-group, wherein the heterocyclic alkyl group comprises one to four heteroatoms selected from oxygen, nitrogen, S(O), SO2 and sulfur;

[0318] R2 represents a halogen atom,

[0319] Or selected from the following groups:

[0320] -(C1-C6)alkyl-group;

[0321] -(C2-C6)alkenyl-group;

[0322] -(C2-C6) ynyl group;

[0323] -(C1-C6)alkylthio- group;

[0324] -(C1-C6)alkylthio(C1-C6)alkyl-group;

[0325] -(C1-C6)alkyl-S(O) group;

[0326] -(C1-C6)alkyl-S(O2-) group;

[0327] -(C1-C6)alkyl-S(O)-(C1-C6)alkyl-group;

[0328] -(C1-C6)alkyl-S(O2)-(C1-C6)alkyl-group;

[0329] -(C1-C6)alkoxy- group;

[0330] -(C1-C6)alkoxy(C1-C6)alkyl-group;

[0331] -(C1-C6)haloalkoxy(C1-C6)alkyl-group;

[0332] -(C3-C5)cycloalkyl-O-(C1-C6)alkyl-group;

[0333] -(C1-C6)alkyl-NH-(C1-C6)alkyl-group;

[0334] -((C1-C6)alkyl)2-N-(C1-C6)alkyl-group;

[0335] -(C1-C6)alkyl-NH- group; and

[0336] -((C1-C6)alkyl)2N-group;

[0337] R3 means:

[0338] - Deuterium atom;

[0339] - Hydrogen atom

[0340] Or selected from the following groups:

[0341] a)

[0342] - (C1-C6)alkyl-group;

[0343] - (C2-C6) alkenyl-group;

[0344] - (C2-C6) ynyl group; and

[0345] - (C1-C6) alkylthio- group;

[0346] b)

[0347] - OR6 group, wherein R6 is selected from:

[0348] - Hydrogen atom;

[0349] -(C1-C6)alkyl-group;

[0350] -CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30;

[0351] -(C2-C6)alkenyl-group;

[0352] -(C2-C6) ynyl group;

[0353] -(C3-C 10 )cycloalkyl-group;

[0354] -Phenyl;

[0355] -Phenyl (C1-C6)alkyl-group; and

[0356] -(C3-C 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(=O)- and -S(=O)2-;

[0357] c)

[0358] - -NR7R8 groups, wherein R7 and R8 are independently selected from:

[0359] - Hydrogen atom;

[0360] - CH3-[O-(CH2)2] n -, where n is an integer from 1 to 30;

[0361] - (C1-C6)alkyl-group, which is either unsubstituted or substituted with the following:

[0362] - (C5-C 10 ) heteroaryl groups, comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur; or

[0363] - Phenyl, which is either unsubstituted or substituted with at least one substituent selected from the following:

[0364] - Cyano and

[0365] - NR9R 10 -(C1-C6)alkyl-group, wherein:

[0366] R9 and R 10 Selected independently from:

[0367] - Hydrogen atom;

[0368] - (C1-C6)alkyl-group;

[0369] - CH3-[O-(CH2)2] n -, where n is an integer from 1 to 30, or

[0370] R9 and R 10 Together with the nitrogen atoms to which they are attached, they form (C 3- C 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0371] The (C3-C) 10 The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the following: (C1-C6) alkyl-groups and CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30;

[0372] Alternatively, R7 and R8 together with the nitrogen atoms they are attached to form (C3-C). 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0373] The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the following:

[0374] - Phenyl and

[0375] - Hydroxyl (C1-C6)alkyl-phenyl group;

[0376] d)

[0377] - (C3-C 10 (a) heterocyclic alkyl group containing one to four heteroatoms selected from oxygen, nitrogen and sulfur;

[0378] e)

[0379] - (C5-C 10 A heteroaryl group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0380] The (C5-C) 10 The heteroaryl group is either unsubstituted or substituted by at least one (C1-C6) alkyl group;

[0381] f)

[0382] - (C6-C 10 ) aryl-group; and

[0383] g)

[0384] - (C3-C 10 )cycloalkyl-group;

[0385] - L1 indicates the connector; and

[0386] - RCG1 indicates a reactive chemical group that is reactive to chemical groups present on binders, such as proteins, polypeptides, ligands, peptides, oligonucleotides or oligosaccharides, such as on targets, such as on cell binders, such as antibodies, such as monoclonal antibodies or VHH antibodies.

[0387] According to a specific embodiment, L1 represents a cuttable joint or a non-cuttable joint.

[0388] According to one particular embodiment, L1 is a cuttable connector, which is a peptide connector.

[0389] According to another specific embodiment, L1 is an uncuttable connector, which is a PEGylated connector.

[0390] RCG1 is a reactive chemical group well known to those skilled in the art. RCG1 is a tool for conjugation and, because it is not a limiting group, its list is neither limited nor restricted.

[0391] Examples of RCG1 that can be mentioned include:

[0392] (i) R a Z a -C(=O)- reactive group, wherein:

[0393] Z a This indicates a single bond, -O-, or -NH, such as -O-, and

[0394] R aRepresents hydrogen atoms, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C6)alkenyl, -(C6-C 10 )aryl, comprising 4 to 9 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur -(C5-C 10 ( ) heteroaryl, or -(C3-C7) heterocyclic alkyl comprising 2 to 6 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2-, wherein -(C6-C 10 )Aryl, -(C5-C 10 The heteroaryl group and / or -(C3-C7) heterocyclic alkyl group are optionally substituted by 1 to 5 atoms / groups selected from the following: halogen atoms such as fluorine atoms, -(C1-C6)alkyl groups, -(C1-C6)alkoxy groups, hydroxyl groups, oxo groups, nitro groups, and cyano groups; or

[0395] (ii) One of the following reactive groups: maleimide group Group; substituted maleimide group, such as ; Haloacetamide group Group, wherein R 21 Indicates a hydrogen atom or -(C1-C6)alkyl group, such as methyl; Cl-; N3-; HO-; HS-; activated disulfide, such as ;H2N-;HC≡C- or activated C≡C, such as cyclooctyne moieties, for example, DBCO-amines or BCN or MFCO ; Phenylacetazole methyl sulfone group (PODS), such as ; Group; Groups; -O-alkylhydroxylamine or Pictet-Spengler reaction substrates, such as those described in Agarwal P. et al., Bioconjugate Chem 2013, 24, 846-851. For example, RCG1 is an N3-, maleimide group. Substituted maleimide group -COOH group, phenyloxadiazolylmethyl sulfone group ; Group; or Groups, such as N3-, -COOH groups and maleimide groups .

[0396] For example, R a Z a - can represent HO-, CH3O-, CH2=CH-CH2O-, (O-NHS), The cation is represented by, for example, sodium, potassium, or cesium. , , , , Groups, wherein GI represents at least one inductive group, such as -NO2 or a halogen atom (such as a fluorine atom (F)). For example, they can be the following groups: or .

[0397] Another type of R a Z a The -C(=O)- group is as follows: .

[0398] Specifically, RCG1 is an N3-, -COOH, or maleimide group. .

[0399] Among the compounds of formula (I) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which A has formula (A1) or formula (A2).

[0400] (A1) (A2)

[0401] in:

[0402] R1, R2 and R3 are as defined in this disclosure;

[0403] single asterisk ( ) indicates the site covalently attached to -L1-RCG1;

[0404] R1 express:

[0405] - Single bond, which means that -L1-RCG1 is directly connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring.

[0406] - or a divalent group formed by R1 as defined in this disclosure, which means that -L1-RCG1 is connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring via R1;

[0407] R3 express:

[0408] - Single bond, which means that -L1-RCG1 is directly connected to the carbon atom of the imidazo[4,5-d]pyridazine ring.

[0409] - or a divalent group formed by R3 as defined in this disclosure, meaning that -L1-RCG1 is connected to the carbon atom of the imidazo[4,5-d]pyridazine ring via R3.

[0410] According to a particular embodiment, A has formula (A1).

[0411] According to another embodiment, A has formula (A2).

[0412] Therefore, according to a specific embodiment, when R1 When representing a single bond, compounds of formula (I) according to this disclosure or pharmaceutically acceptable salts thereof have the following formula (Ia):

[0413] (Ia)

[0414] R2, R3, L1, and RCG1 are as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is a hydrogen atom.

[0415] According to another specific embodiment, when R1 When representing a divalent group formed by R1 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (I) of this disclosure has the following formula (Iaa):

[0416] (Iaa)

[0417] R2, R3, L1, and RCG1 are as defined in this disclosure, and R1 It is divalent R1 as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is not a hydrogen atom.

[0418] According to another specific embodiment, when R3 When representing a single bond, compounds of formula (I) according to this disclosure or pharmaceutically acceptable salts thereof have the following formula (Ib):

[0419] (Ib)

[0420] R1, R2, L1, and RCG1 are as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is a hydrogen atom.

[0421] According to another specific embodiment, when R3 When representing a divalent group formed by R3 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (I) of this disclosure has the following formula (Ibb):

[0422] (Ibb)

[0423] R1, R2, L1, and RCG1 are as defined in this disclosure, and R3 It is divalent R3 as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is not a hydrogen atom.

[0424] In this disclosure, the key The symbol represents a covalent attachment site.

[0425] The pharmaceutical A or its pharmaceutically acceptable salts contained in Formulas (I) and (II) of this disclosure, as well as their preparation methods and their therapeutic uses (e.g., as Toll-like receptor 7 agonists and / or Toll-like receptor 8 agonists), are described in PCT / EP2022 / 052387 (WO 2022167438).

[0426] As described in PCT / EP2022 / 052387 (WO 2022167438), according to a specific embodiment, in the formula of drug A or a pharmaceutically acceptable salt thereof, at least one of R1 and R3 may not be a hydrogen atom.

[0427] As described in PCT / EP2022 / 052387 (WO 2022167438), according to another specific embodiment, in the formula of drug A or its pharmaceutically acceptable salt, R1 and R3 may not be hydrogen atoms at the same time.

[0428] Among the compounds of formula (A) described in PCT / EP2022 / 052387 (WO 2022167438) and / or covered by claim 1 of PCT / EP2022 / 052387 (WO2022167438), the following compounds may be mentioned, for example:

[0429] (1) 2-Butyl-7-isopropoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0430] (2) 2-Butyl-N7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0431] (3) 2-Butyl-7-(isopropylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0432] (4) 2-Butyl-1-(4-methoxybenzyl)-7-(2-methoxyethoxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0433] (5) 2-Butyl-1-(4-methoxybenzyl)-7-propoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0434] (6) 7-(allyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0435] (7) 7-(sec-butoxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0436] (8) 7-Butoxy-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0437] (9) 2-Butyl-7-(cyclopentyloxy)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0438] (10) 2-Butyl-1-(4-methoxybenzyl)-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0439] (11) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-3-yl)-1H-imidazo[4,5d]pyridazine-4-amine;

[0440] (12)(E)-2-Butyl-1-(4-methoxybenzyl)-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0441] (13) 2-Butyl-7-isopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0442] (14) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0443] (15) 2-Butyl-7-(cyclopent-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0444] (16) 2-Butyl-7-cyclopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0445] (17) 2-Butyl-1-(4-methoxybenzyl)-7-(prop-1-en-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0446] (18) 2-Butyl-7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0447] (19) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0448] (20) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0449] (21) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0450] (22) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0451] (23) 1-(((1S,3R)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (and its enantiomers);

[0452] (24) 1-(4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)-2-methylprop-2-ol;

[0453] (25) trans-1-(4-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0454] (26) 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0455] (27)6-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)nicotinonitrile;

[0456] (28)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5d]pyridazin-1-yl)methyl)benzyl)acetamide;

[0457] (29)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)undecanoamide;

[0458] (30)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)pentanamide;

[0459] (31)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-(2-methoxyethoxy)propionamide;

[0460] (32) 1-(((1S,3S)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-]pyridazine-4-amine (and its enantiomers);

[0461] (33) 1-(3-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0462] (34) 4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde;

[0463] (35)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)phenyl)methanol;

[0464] (36) 2-Butyl-1-(4-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0465] (37) 3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazinyl)methyl)benzyl)amino)thionecyclobutane 1,1-dioxide;

[0466] (38)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-N-(1,1-sulfur dioxide heterocyclic butyl-3-yl)acetamide;

[0467] (39) 2-Butyl-7-isopropoxy-1-(4-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0468] (40) 2-Butyl-7-isopropoxy-1-(4-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0469] (41) 2-Butyl-N7,N7,1-trimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0470] (42) 2-Butyl-1-methyl-7-(pyrrolid-1-yl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0471] (43) 2-Butyl-N7-(4-((dimethylamino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0472] (44) 2-Butyl-N7,1-Dimethyl-N7-(4-(morpholinomethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0473] (45) 4-(((4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazin-7-yl)(methyl)amino)methyl)benzonitrile;

[0474] (46)N7-(4-(aminomethyl)benzyl)-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0475] (47) 2-Butyl-N7-(4-(((2-methoxyethyl)(methyl)amino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0476] (48) 2-Butyl-7-ethoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0477] (49) 2-Butyl-1-(4-methoxybenzyl)-N7-(2-methoxyethyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0478] (50) 2-Butyl-7-methoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0479] (51) 2-Butyl-7-cyclohexyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0480] (52) 7-(benzyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0481] (53) 2-Butyl-1-(4-methoxybenzyl)-N7-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0482] (54)(S)-2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0483] (55) 2-Butyl-7-(furan-2-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0484] (56) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0485] (57) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydro-2H-pyran-4-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0486] (58) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrothiophen-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0487] (59) 2-Butyl-1-(4-methoxybenzyl)-7-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0488] (60) 2-Butyl-1-(4-methoxybenzyl)-7-(2-methylprop-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0489] (61) 2-Butyl-7-isobutyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0490] (62) 2-Butyl-1-(4-methoxybenzyl)-7-(thiophen-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0491] (63) 2-Butyl-1-(4-methoxybenzyl)-7-(thiophen-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0492] (64) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0493] (65) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1-oxide isomer A;

[0494] (66) 2-Butyl-7-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0495] (67) 2-Butyl-7-(furan-3-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0496] (68) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1,1-dioxide;

[0497] (69)3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1-oxide isomer B;

[0498] (70) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0499] (71) 2-Butyl-1-(4-methoxybenzyl)-N7,N7-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0500] (72) 2-Butyl-1-(4-methoxybenzyl)-7-phenoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0501] (73) 2-Butyl-7-(2,5-dihydrofuran-3-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0502] (74) 2-Butyl-7-isopropoxy-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0503] (75) 2-Butyl-7-isopropoxy-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0504] (76) 2-Butyl-7-isopropoxy-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0505] (77) 1-(5-aminopentyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0506] (78) 2-Butyl-7-isopropoxy-1-(2-(piperidin-4-yl)ethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0507] (79) 2-Butyl-7-isopropoxy-1-(2-(piperazin-1-yl)ethyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0508] (80) 1-Benzyl-2-Butyl-7-Isopropoxy-1H-Imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0509] (81) 2-Butyl-1-(cyclohexylmethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0510] (82) 2-Butyl-7-isopropoxy-1-(4-(((tetrahydro-2H-pyran-4-yl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0511] (83) 2-Butyl-7-isopropoxy-1-(4-((isopropylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0512] (84)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)heptamide;

[0513] (85)(4-(1-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridine-7-yl)pyrrolidine-3-yl)phenyl)methanol hydrochloride;

[0514] (86) 2-Butyl-7-isopropoxy-1-methyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0515] (87)N7-(4-(aminomethyl)benzyl)-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0516] (88) 2-Butyl-N7-isopropyl-1-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0517] (89) 2-Butyl-1-methyl-7-(3-phenylpyrrolidin-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0518] (90) N7-benzyl-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0519] (91) 2-Butyl-1-methyl-N7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0520] (92) 2-Butyl-1-(4-methoxybenzyl)-7-phenyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0521] (93) 4-Amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-ol;

[0522] (94) 2-Butyl-N7-(3-(furan-2-yl)propyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0523] (95) 2-Butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0524] (96) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0525] (97) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0526] (98) 2-Butyl-N7-isopropyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0527] (99) 2-Butyl-7-(isopropylthio)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0528] (100) (1R,3R)-3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)cyclobut-1-ol dihydrochloride;

[0529] (101) 2-Butyl-7-isopropoxy-1-(4-(pyrrolidone-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0530] (102) 2-Butyl-7-isopropoxy-1-(4-(morpholinomethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0531] (103) N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)propionamide;

[0532] (104) 2-Butyl-7-isopropoxy-1-(4-(((2-methoxyethyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0533] (105) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]methyl]imidazo[4,5-d]pyridazine-7-amine;

[0534] (106) N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)benzamide;

[0535] (107) N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-methoxypropionamide;

[0536] (108) 2-Butyl-7-isopropoxy-1-(4-(((2-(2-methoxyethoxy)ethyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0537] (109) 2-Butyl-1-(4-((hexylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0538] (110) 2-Butyl-1-(4-((decylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0539] (111) (4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate;

[0540] (112) (4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate 4-methoxybenzyl ester;

[0541] (113) 1-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-ethylurea;

[0542] (114) (4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate 4-acetamidobenzyl ester;

[0543] (115) N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)methanesulfonamide;

[0544] (116) 2-Butyl-1-(4-((dimethylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0545] (117) (4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)glycine tert-butyl ester;

[0546] (118) 2-Butyl-7-isopropoxy-1-(4-((methylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0547] (119) 3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)tert-butyl propionate;

[0548] (120) 1-(4-(5,8,11-trioxa-2-azadecyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0549] (121) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethylamino]methyl]phenyl]methyl]imidazo[4,5-d]pyridazine-7-amine;

[0550] (122) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]methyl]imidazo[4,5-d]pyridazine-7-aminedi-2,2,2-trifluoroacetate;

[0551] (123) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy] ...

[0552] (124) 2-Butyl-7-isopropoxy-1-(3-((methylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0553] (125) 2-Butyl-1-(3-((dimethylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0554] (126) 2-Butyl-1-(3-((cyclobutylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0555] (127) 2-Butyl-1-(3-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0556] (128) 2-Butyl-7-isopropoxy-1-(3-((isopropylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0557] (129) 3-((3-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)thionecyclobutane 1,1-dioxide;

[0558] (130) 2-Butyl-7-isopropoxy-1-(3-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0559] (131) 2-Butyl-7-isopropoxy-1-(3-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0560] (132) (E)-1-(4-(aminomethyl)benzyl)-2-butyl-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0561] (133) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0562] (134) 1-(4-(aminomethyl)benzyl)-2-butyl-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0563] (135) 1-(4-(aminomethyl)benzyl)-2-butyl-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0564] (137) 1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-((E)-3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine

[0565] (138) 1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0566] (139) 1-(((1R,4R)-4-aminocyclohexyl)methyl)-2-butyl-7-((E)-3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0567] (140) 1-(((1R,4R)-4-aminocyclohexyl)methyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0568] (141) 1-(((1R,4R)-4-aminocyclohexyl)methyl)-2-butyl-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0569] (142) 1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0570] (143) 3-[(4-aminocyclohexyl)methyl]-2-butyl-4-pyrrolidine-1-yl-imidazo[4,5-d]pyridazine-7-amine;

[0571] (144) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-(2,5-dihydro-1H-pyrrolo-3-yl)imidazo[4,5-d]pyridazin-4-amine;

[0572] (145) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-pyrrolidine-3-yl-imidazo[4,5-d]pyridazine-4-amine;

[0573] (146) 3-(6-aminohexyl)-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine dihydrochloride;

[0574] (147) 2-Butyl-4-isopropoxy-3-[6-(tetrahydropyran-4-ylamino)hexyl]imidazo[4,5-d]pyridazine-7-amine dihydrochloride;

[0575] (148) N-[6-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)hexyl]-N-tetrahydropyran-4-yl-acetamide;

[0576] (149) 3-(4-aminobutyl)-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine dihydrochloride;

[0577] (150) 2-Butyl-4-isopropoxy-3-[4-(tetrahydropyran-4-ylamino)butyl]imidazo[4,5-d]pyridazine-7-amine hydrochloride;

[0578] (151) N-[4-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)butyl]-N-tetrahydropyran-4-yl-acetamide;

[0579] (152) 2-Butyl-3-[4-[(1,1-dioxothioheterobutyl-3-yl)amino]butyl]-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine;

[0580] (153) N-[4-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)butyl]-N-(1,1-dioxothioneheterobutyl-3-yl)acetamide;

[0581] (154) 2-Butyl-3-[6-[(1,1-dioxothione-3-yl)amino]hexyl]-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine;

[0582] (155) N-[6-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)hexyl]-N-(1,1-dioxothione-3-yl)acetamide hydrochloride;

[0583] (156) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]-2-methyl-propane-1,3-diol hydrochloride;

[0584] (157) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]propane-1,3-diol hydrochloride;

[0585] (158) 1-(4-(aminomethyl)benzyl)-7-isopropoxy-2-propyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0586] (159) 1-(4-(aminomethyl)benzyl)-2-(ethoxymethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0587] (160) 1-(4-(aminomethyl)benzyl)-7-isopropoxy-2-methyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0588] (161) 3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylthioalkyl-imidazo[4,5-d]pyridazine-7-amine;

[0589] (162) 3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylsulfinyl-imidazo[4,5-d]pyridazine-7-amine;

[0590] (163) 3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-N2-propyl-imidazo[4,5-d]pyridazine-2,7-diamine;

[0591] (164) 3-[[4-(aminomethyl)phenyl]methyl]-2-(ethylaminomethyl)-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine;

[0592] (165) 2-Butyl-7-isopropoxy-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0593] (166) 3-[[4-(1-amino-1-methyl-ethyl)phenyl]methyl]-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine;

[0594] (167) 2-Butyl-7-(2,5-dihydro-1H-pyrrolo-3-yl)-1-methyl-imidazo[4,5-d]pyridazin-4-amine;

[0595] (168) 2-Butyl-3-methyl-4-piperazin-1-yl-imidazo[4,5-d]pyridazin-7-amine; or

[0596] Its pharmaceutically acceptable salt.

[0597] In the compounds of formula (A), formula (A1) or formula (A2) that are the subject of this disclosure, a group of compounds consists of the following compounds, wherein:

[0598] R1 means:

[0599] - (C1-C6) alkyl-groups, especially methyl groups;

[0600] - NH2-(C1-C6)alkyl-groups, especially NH2-(CH2)5-groups;

[0601] - A phenyl (C1-C6)alkyl- group, particularly a phenyl-CH2- group, which is unsubstituted or substituted with at least one substituent, especially substituted on the benzene ring with at least one substituent, for example, substituted with a substituent selected from the following:

[0602] - (C1-C6)alkyl-group, particularly methyl (or -CH2-group, if substituted) or isopropyl (or -CH(CH3)2-group, if substituted), which is unsubstituted or substituted with at least one substituent, particularly substituted with a substituent selected from:

[0603] - -NR4R5 group, wherein R4 and R5 are independently selected from: hydrogen atoms and (C1-C2) 16 Alkyl groups, particularly methyl groups, such as -NR4R5 being -NH2 or -NH(CH3); or R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted (C3-C) group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heterocyclic alkyl groups, especially unsubstituted (C3-C) groups containing two nitrogen atoms 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[0604] - (C3-C 10Cycloalkyl (C1-C6) alkyl- groups, especially cyclohexyl-CH2- groups, which are unsubstituted or substituted, particularly in (C3-C6) alkyl groups. 10 The cycloalkyl group is substituted by at least one substituent, particularly by a substituent selected from the following: -NH2 and NH2-(C1-C6)alkyl groups, such as NH2-CH2- groups;

[0605] R2 means:

[0606] -(C1-C6)alkyl-groups, especially -(CH2)3-CH3 groups;

[0607] -(C1-C6) alkylthio-groups, especially -S-(CH2)2-CH3 groups; or

[0608] -(C1-C6)alkyl-NH- groups, especially -NH-(CH2)2-CH3 groups; and

[0609] R3 means:

[0610] - -OR6 group, where R6 is a (C1-C6) alkyl-group, especially -O-isopropyl (that is, -O-CH(CH3)2 group);

[0611] - -NR7R8 groups, wherein R7 and R8, together with the nitrogen atom to which they are attached, form a heteroatom comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur, particularly a (C3-C) group comprising two nitrogen atoms. 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[0612] - (C3-C 10 A heterocyclic alkyl group containing one to four heteroatoms selected from oxygen, nitrogen and sulfur, particularly one or two nitrogen atoms, such as dihydropyrrole, such as 2,5-dihydro-1H-pyrrole or piperazine.

[0613] In the compounds of formula (A), formula (A1) or formula (A2) that are the subject of this disclosure, a group of compounds consists of compounds in which the drug (drug unit) A is a TLR7 agonist and is specifically selected from the group consisting of:

[0614] (1) 2-Butyl-7-isopropoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0615] (2) 2-Butyl-N7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0616] (3) 2-Butyl-7-(isopropylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0617] (4) 2-Butyl-1-(4-methoxybenzyl)-7-(2-methoxyethoxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0618] (5) 2-Butyl-1-(4-methoxybenzyl)-7-propoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0619] (6) 7-(allyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0620] (7) 7-(sec-butoxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0621] (8) 7-Butoxy-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0622] (9) 2-Butyl-7-(cyclopentyloxy)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0623] (10) 2-Butyl-1-(4-methoxybenzyl)-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0624] (11) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-3-yl)-1H-imidazo[4,5d]pyridazine-4-amine;

[0625] (12) (E)-2-Butyl-1-(4-methoxybenzyl)-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0626] (13) 2-Butyl-7-isopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0627] (14) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0628] (15) 2-Butyl-7-(cyclopent-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0629] (16) 2-Butyl-7-cyclopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0630] (17) 2-Butyl-1-(4-methoxybenzyl)-7-(prop-1-en-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0631] (18) 2-Butyl-7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0632] (19) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0633] (20) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0634] (25) trans-1-(4-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0635] (26) 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0636] (27) 6-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)nicotinonitrile;

[0637] (28) N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5d]pyridazin-1-yl)methyl)benzyl)acetamide;

[0638] (29) N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)undecanoamide;

[0639] (30) N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)pentanamide;

[0640] (31) N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-(2-methoxyethoxy)acrylamide;

[0641] (34) 4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde;

[0642] (35) (4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)phenyl)methanol;

[0643] (37) 3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazinyl)methyl)benzyl)amino)thionecyclobutane 1,1-dioxide;

[0644] (48) 2-Butyl-7-ethoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0645] (49) 2-Butyl-1-(4-methoxybenzyl)-N7-(2-methoxyethyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0646] (50) 2-Butyl-7-methoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0647] (51) 2-Butyl-7-cyclohexyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0648] (52) 7-(benzyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0649] (53) 2-Butyl-1-(4-methoxybenzyl)-N7-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0650] (54) (S)-2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0651] (55) 2-Butyl-7-(furan-2-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0652] (56) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0653] (57) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydro-2H-pyran-4-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0654] (58) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrothiophene-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0655] (59) 2-Butyl-1-(4-methoxybenzyl)-7-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0656] (60) 2-Butyl-1-(4-methoxybenzyl)-7-(2-methylprop-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0657] (61) 2-Butyl-7-isobutyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0658] (62) 2-Butyl-1-(4-methoxybenzyl)-7-(thiophen-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0659] (63) 2-Butyl-1-(4-methoxybenzyl)-7-(thiophen-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0660] (64) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0661] (65) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1-oxide isomer A;

[0662] (66) 2-Butyl-7-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0663] (67) 2-Butyl-7-(furan-3-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0664] (68) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazin-7-yl)oxy)tetrahydrothiophene 1,1-dioxide;

[0665] (69) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1-oxide isomer B;

[0666] (70) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0667] (71) 2-Butyl-1-(4-methoxybenzyl)-N7,N7-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0668] (72) 2-Butyl-1-(4-methoxybenzyl)-7-phenoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0669] (73) 2-Butyl-7-(2,5-dihydrofuran-3-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0670] (75) 2-Butyl-7-isopropoxy-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0671] (76) 2-Butyl-7-isopropoxy-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0672] (77) 1-(5-aminopentyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0673] (78) 2-Butyl-7-isopropoxy-1-(2-(piperidin-4-yl)ethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0674] (79) 2-Butyl-7-isopropoxy-1-(2-(piperazin-1-yl)ethyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0675] (80) 1-Benzyl-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0676] (81) 2-Butyl-1-(cyclohexylmethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0677] (87) N7-(4-(aminomethyl)benzyl)-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0678] (92) 2-Butyl-1-(4-methoxybenzyl)-7-phenyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0679] (94) 2-Butyl-N7-(3-(furan-2-yl)propyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0680] (97) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-d]pyridazin-4-amine; and

[0681] Its pharmaceutically acceptable salt.

[0682] In the compounds of formula (A), formula (A1) or formula (A2) that are the subject of this disclosure, a group of compounds consists of compounds in which the drug (drug unit) A is a TLR7 / 8 agonist and is specifically selected from the group consisting of:

[0683] (21) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0684] (22) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0685] (23) 1-(((1S,3R)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (and enantiomers);

[0686] (24) 1-(4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)-2-methylprop-2-ol;

[0687] (32) 1-(((1S,3S)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-]pyridazine-4-amine (and enantiomers);

[0688] (33) 1-(3-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0689] (36) 2-Butyl-1-(4-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0690] (39) 2-Butyl-7-isopropoxy-1-(4-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0691] (40) 2-Butyl-7-isopropoxy-1-(4-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0692] (41) 2-Butyl-N7,N7,1-trimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0693] (42) 2-Butyl-1-methyl-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0694] (43) 2-Butyl-N7-(4-((dimethylamino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0695] (44) 2-Butyl-N7,1-dimethyl-N7-(4-(morpholinomethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0696] (45) 4-(((4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazin-7-yl)(methyl)amino)methyl)benzonitrile;

[0697] (46) N7-(4-(aminomethyl)benzyl)-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0698] (47) 2-Butyl-N7-(4-(((2-methoxyethyl)(methyl)amino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0699] (74) 2-Butyl-7-isopropoxy-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0700] (82) 2-Butyl-7-isopropoxy-1-(4-(((tetrahydro-2H-pyran-4-yl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0701] (83) 2-Butyl-7-isopropoxy-1-(4-((isopropylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0702] (84) N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)heptamide;

[0703] (85) (4-(1-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridine-7-yl)pyrrolidine-3-yl)phenyl)methanol hydrochloride;

[0704] (86) 2-Butyl-7-isopropoxy-1-methyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0705] (88) 2-Butyl-N7-isopropyl-1-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0706] (89) 2-Butyl-1-methyl-7-(3-phenylpyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0707] (90) N7-benzyl-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0708] (91) 2-Butyl-1-methyl-N7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0709] (95) 2-Butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0710] (98) 2-Butyl-N7-isopropyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0711] (99) 2-Butyl-7-(isopropylthio)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0712] (118) 2-Butyl-7-isopropoxy-1-(4-((methylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0713] (161) 3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylthioalkyl-imidazo[4,5-d]pyridazine-7-amine;

[0714] (163) 3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-N2-propyl-imidazo[4,5-d]pyridazine-2,7-diamine;

[0715] (166) 3-[[4-(1-amino-1-methyl-ethyl)phenyl]methyl]-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine;

[0716] (167) 2-Butyl-7-(2,5-dihydro-1H-pyrrolo-3-yl)-1-methyl-imidazo[4,5-d]pyridazin-4-amine;

[0717] (168) 2-Butyl-3-methyl-4-piperazin-1-yl-imidazo[4,5-d]pyridazin-7-amine; and

[0718] Its pharmaceutically acceptable salt.

[0719] In the compounds of formula (A), formula (A1) or formula (A2) that are the subject of this disclosure, a group of compounds consists of compounds in which the drug (drug unit) A is selected from the group consisting of:

[0720] ;

[0721] ;

[0722] ;

[0723] ;

[0724] ;

[0725] ;

[0726] ;

[0727] ;

[0728] ;

[0729] ;as well as

[0730] .

[0731] In the compounds of formula (A), formula (A1) or formula (A2) that are the subject of this disclosure, a group of compounds consists of compounds in which A is selected from the group consisting of:

[0732] ;

[0733] ;

[0734] ;

[0735] ;as well as

[0736] ;

[0737] In the compounds of formula (A), formula (A1) or formula (A2) that are the subject of this disclosure, a group of compounds consists of compounds in which A is selected from the group consisting of:

[0738]

[0739] ;as well as

[0740] .

[0741] In the compounds of formula (A), formula (A1) or formula (A2) which are the subject of this disclosure, a group of compounds consists of such compounds, wherein the drug (or drug unit) A is further low in cell permeability or non-cell permeability, and in particular, low in cell permeability or non-cell permeability drug unit A is defined by less than 25 PAMPA.

[0742] In the compounds of formula (A), formula (A1) or formula (A2) that are the subject of this disclosure, a group of compounds consists of compounds in which A is selected from the group consisting of:

[0743] ;

[0744] ;

[0745] ;as well as

[0746] .

[0747] In the compounds of formula (I) that are the subject of this disclosure, a group of compounds consists of compounds in which:

[0748] A has the formula (A), where:

[0749] R1 means:

[0750] - (C1-C6) alkyl-groups, especially methyl groups;

[0751] - NH2-(C1-C6)alkyl-groups, especially NH2-(CH2)5-groups;

[0752] - A phenyl (C1-C6)alkyl- group, particularly a phenyl-CH2- group, which is unsubstituted or substituted with at least one substituent, especially substituted on the benzene ring with at least one substituent, for example, substituted with a substituent selected from the following:

[0753] - (C1-C6)alkyl-group, particularly methyl (or -CH2-group, if substituted) or isopropyl (or -CH(CH3)2-group, if substituted), which is unsubstituted or substituted with at least one substituent, particularly substituted with a substituent selected from:

[0754] - -NR4R5 group, wherein R4 and R5 are independently selected from: hydrogen atoms and (C1-C2) 16 Alkyl groups, particularly methyl groups, such as -NR4R5 being -NH2 or -NH(CH3); or R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted (C3-C) group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heterocyclic alkyl groups, especially unsubstituted (C3-C) groups containing two nitrogen atoms 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[0755] - (C3-C 10 Cycloalkyl (C1-C6) alkyl- groups, especially cyclohexyl-CH2- groups, which are unsubstituted or substituted, particularly in (C3-C6) alkyl groups. 10 The cycloalkyl group is substituted by at least one substituent, particularly by a substituent selected from the following: -NH2 and NH2-(C1-C6)alkyl groups, such as NH2-CH2- groups;

[0756] R2 means:

[0757] -(C1-C6)alkyl-groups, especially -(CH2)3-CH3 groups;

[0758] -(C1-C6) alkylthio-groups, especially -S-(CH2)2-CH3 groups; or

[0759] -(C1-C6)alkyl-NH- groups, especially -NH-(CH2)2-CH3 groups; and

[0760] R3 means:

[0761] - -OR6 group, where R6 is a (C1-C6) alkyl-group, especially -O-isopropyl (that is, -O-CH(CH3)2 group);

[0762] - -NR7R8 groups, wherein R7 and R8, together with the nitrogen atom to which they are attached, form a heteroatom comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur, particularly a (C3-C) group comprising two nitrogen atoms. 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[0763] - (C3-C 10 () A heterocyclic alkyl group containing one to four heteroatoms selected from oxygen, nitrogen and sulfur, particularly one or two nitrogen atoms, such as dihydropyrrole, such as 2,5-dihydro-1H-pyrrole or piperazine;

[0764] L1 means:

[0765] -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0766] -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0767] -Cit-Val-C(O)-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[0768] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0769] -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0770] -C(O)-O-CH2-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[0771] -C(O)-O-CH2-phenyl-NH-Ala-Val-Glu--C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[0772] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[0773] <00第2541号-Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ,

[0774] -C(O)-(CH2-CH2-O) 24 -CH2-CH2- ;

[0775] -(CH2-CH2-O) 23 -CH2-CH2- ;

[0776] -C(O)-(CH2-CH2-O) 20 -CH2-CH2- ;

[0777] It should be noted that in the above translation, "对苯基" is translated as "phenyl" which is a common abbreviation in chemical terms. Also, some of the tags like " " etc. are kept as they are as per the requirement. And the commas and semicolons are translated accurately to maintain the original punctuation. -C(O)-(CH2-CH2-O) 16 -CH2-CH2- ;

[0778] -C(O)-(CH2-CH2-O) 12 -CH2-CH2- ;

[0779] -C(O)-(CH2-CH2-O)8-CH2-CH2- ;

[0780] -C(O)-C(CH3)2-CH2-O-(CH2-CH2-O) 20 -CH2-CH2- ;

[0781] -C(O)-O-(CH2-CH2-O) 20 -CH2-CH2- ;

[0782] -C(O)-NH-(CH2-CH2-O) 20 -CH2-CH2- ;

[0783] ;

[0784] ;

[0785] -C(O)-(CH2-CH2-O) 24 -CH2-CH2-NH-C(O)-CH2-CH2- ;

[0786] -C(O)-(CH2-CH2-O) 20 -CH2-CH2-NH-C(O)-CH2-CH2- ; or <​​​-CH2-CH2-NH-C(O)-CH2-CH2- ;

[0788] single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site of covalent attachment to the -RCG1 group; and

[0789] RCG1 is an N3-, -COOH group or a maleimide group. .

[0790] According to specific embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof are selected from the compounds of formula (I1) and formula (I2):

[0791] A-(La)m-(AA)w-(Lb)p-Lc-Ld'-RCG1 (I1)

[0792] in:

[0793] - A is as defined in equation (I);

[0794] - La indicates a self-extinguishing connector, for example -C(O)-O-(CR 14 R 15 )-Aryl-NR 16 - Groups, -C(O)-O-(CR 14 R 15 )-Heteroaryl-NR 16 - Groups, -C(O)-NR 17 -(C2-C6)alkyl-NR 18 - , -C(O)-NR 17- (C2-C6)alkyl-NR 18 -C(O)-O-CR 15 R 14 -Aryl-NR 16 - Groups, -C(O)-NR 17- (C2-C6)alkyl-NR 18 -C(O)-O-CR 15R 14 -heteroaryl-NR 16 - Groups, -CR 15 R 14 -Aryl-NR 16 - Group or -CR 15 R 14 -heteroaryl-NR 16 - Group, aryl is (C6-C 10 ) aryl and heteroaryl are C5-C6 groups containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heteroaryl compounds, for example -C(O)-O-CH2-phenyl-NH- Group, single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site of covalent attachment to the (AA)w group;

[0795] R 14 R 15 R 16 R 17 and R 18 It is a hydrogen atom or a (C1-C6) alkyl group;

[0796] Group;

[0797] - m represents an integer from 0 to 1;

[0798] - (AA)w represents a sequence of w amino acids AA linked together by peptide bonds;

[0799] w represents an integer from 1 to 12, such as from 1 to 6, like 2 and 3;

[0800] AA represents a natural or non-natural amino acid with configuration D or L, selected from: alanine (Ala), β-alanine, γ-aminobutyric acid, 2-amino-2-cyclohexylacetic acid, 2-amino-2-phenylacetic acid, arginine (Arg), asparagine (Asn), aspartic acid (Asp), citrulline (Cit), cysteine ​​(Cys), α,α-dimethyl-γ-aminobutyric acid, β,β-dimethyl-γ-aminobutyric acid, glutamine (Gln), glutamic acid (Glu), glycine (Gln). y), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), ε-acetyl-lysine (AcLys), methionine (Met), ornithine (Orn), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val), such as valine (Val), citrulline (Cit), alanine (Ala), and glutamic acid (Glu);

[0801] - Lb represents the spacer, for example -C(O)-(C1-C6)alkyl-C(O)-NH- Group or -C(O)- Groups, such as -C(O)-(CH2)3-C(O)-NH- Group or -C(O)- Group, single asterisk ( ) indicates the site covalently attached to the (AA)w group, and the double asterisk ( ) indicates the site of covalent attachment to the Lc group;

[0802] - p represents an integer from 0 to 1;

[0803] - Lc represents the spacer, for example -(CH2-CH2-O)n- Group, where n represents an integer from 2 to 12, such as from 3 to 7, like 3 and 4, if Lb exists (that is, if p is 1), single asterisk ( The asterisk () indicates the site covalently attached to the Lb group, or if Lb is absent (i.e., if p is 0), the asterisk ( ) indicates the site directly covalently attached to the (AA)w group, and the double asterisk ( ) indicates the site of covalent attachment to the Ld' group;

[0804] - Ld' represents the spacer, for example -(C2-C6)alkyl- Groups, -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group or -(C2-C6)alkyl-C(O)-NH-(C2-C6)alkyl- Groups, such as -(CH2)2- Groups, -(CH2)2-NH-C(O)-(CH2)2- Group or -(CH2)2-C(O)-NH-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the Lc group, and the double asterisk ( ) indicates the site of covalent attachment to the RCG1 group; and

[0805] - RCG1 indicates a reactive chemical group that is reactive to chemical groups present on binders, such as proteins, polypeptides, ligands, peptides, oligonucleotides or oligosaccharides, such as on targets, such as on cell binders, such as antibodies, such as monoclonal antibodies or VHH antibodies.

[0806] - For example, RCG1 means:

[0807] (i) R a Z a -C(=O)- reactive group, wherein:

[0808] Z a This indicates a single bond, -O-, or -NH, such as -O-, and

[0809] R a Represents hydrogen atoms, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C6)alkenyl, -(C6-C 10 )aryl, comprising 4 to 9 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur -(C5-C 10( ) heteroaryl, or -(C3-C7) heterocyclic alkyl comprising 2 to 6 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2-, wherein -(C6-C 10 )Aryl, -(C5-C 10 The heteroaryl group and / or -(C3-C7) heterocyclic alkyl group are optionally substituted by 1 to 5 atoms / groups selected from the following: halogen atoms such as fluorine atoms, -(C1-C6)alkyl groups, -(C1-C6)alkoxy groups, hydroxyl groups, oxo groups, nitro groups, and cyano groups; or

[0810] (ii) One of the following reactive groups: maleimide group Group; substituted maleimide group, such as ; Haloacetamide group Group, wherein R 21 Indicates a hydrogen atom or (C1-C6) alkyl group, such as methyl; Cl-; N3-; HO-; HS-; activated disulfide, such as ;H2N-;HC≡C- or activated C≡C, such as cyclooctyne moieties, for example, DBCO-amines or BCN or MFCO ; Phenylacetazole methyl sulfone group (PODS), such as ; Group; Group; O-alkyl hydroxylamine or Pickett-Spengler reaction substrate, such as ,

[0811] For example, RCG1 is an N3-, maleimide group. Substituted maleimide group COOH group, phenyloxadiazolylmethyl sulfone group ; Group; or Groups, such as N3- and maleimide groups ;

[0812] A-(P)oL-Ld-RCG1 (I2)

[0813] in

[0814] - A is as defined in equation (I);

[0815] - P represents the -C(O)- group, -C(O)-O- group, -S(O2)- group, -C(O)-C(CH3)2-CH2-O- group, -C(O)-NH- group, Group or Group;

[0816] - o represents an integer from 0 to 1;

[0817] - L indicates -(CH2-CH2-O)n- Groups, where n represents an integer from 1 to 30, such as from 8 to 25, like 8, 12, 16, 20, 23, and 24, if P exists (that is, if o is 1), single asterisk ( The asterisk () indicates the site covalently attached to the P group, or if P is absent (i.e., if o is 0), the asterisk ( ) indicates the site directly covalently attached to group A, and the double asterisk ( This indicates the site where the Ld group is covalently attached;

[0818] - Ld represents the spacer, for example -(C2-C6)alkyl- Groups, -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group or -(C2-C6)alkyl-C(O)-NH-(C2-C6)alkyl- Groups, such as -(CH2)2- Groups, -(CH2)2-NH-C(O)-(CH2)2- Group or -(CH2)2-C(O)-NH-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( ) indicates the site of covalent attachment to the RCG1 group; and

[0819] - RCG1 indicates a reactive chemical group that is reactive to chemical groups present on binders, such as proteins, polypeptides, ligands, peptides, oligonucleotides or oligosaccharides, such as on targets, such as on cell binders, such as antibodies, such as monoclonal antibodies or VHH antibodies.

[0820] - For example, RCG1 means:

[0821] (i) R a Z a -C(=O)- reactive group, wherein:

[0822] Z a This indicates a single bond, -O-, or -NH, such as -O-, and

[0823] R a Represents hydrogen atoms, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C6)alkenyl, -(C6-C 10 )aryl, comprising 4 to 9 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur -(C5-C 10 ( ) heteroaryl, or -(C3-C7) heterocyclic alkyl comprising 2 to 6 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2-, wherein -(C6-C 10 )Aryl, -(C5-C 10 The heteroaryl group and / or -(C3-C7) heterocyclic alkyl group are optionally substituted by 1 to 5 atoms / groups selected from the following: halogen atoms such as fluorine atoms, -(C1-C6)alkyl groups, -(C1-C6)alkoxy groups, hydroxyl groups, oxo groups, nitro groups, and cyano groups; or

[0824] (ii) One of the following reactive groups: maleimide group Group; substituted maleimide group, such as ; Haloacetamide group Group, wherein R 21 Indicates a hydrogen atom or (C1-C6) alkyl group, such as methyl; Cl-; N3-; HO-; HS-; activated disulfide, such as ;H2N-;HC≡C- or activated C≡C, such as cyclooctyne moieties, for example, DBCO-amines or BCN or MFCO ; Phenylacetazole methyl sulfone group (PODS), such as ; Group; Group; O-alkyl hydroxylamine or Pickett-Spengler reaction substrate, such as ,

[0825] For example, RCG1 is an N3-, maleimide group. Substituted maleimide group COOH group, phenyloxadiazolylmethyl sulfone group ; Group; or Groups, such as N3-, -COOH groups and maleimide groups .

[0826] Among the compounds of formula (I1) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which A has formula (A1) or formula (A2).

[0827] (A1) (A2)

[0828] in:

[0829] R1, R2 and R3 are as defined in this disclosure;

[0830] single asterisk ( ) indicates the site covalently attached to -(La)m-(AA)w-(Lb)p-Lc-Ld'-RCG1;

[0831] R1 express:

[0832] - Single bond, which means that -(La)m-(AA)w-(Lb)p-Lc-Ld'-RCG1 is directly connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring.

[0833] - or a divalent group formed by R1 as defined in this disclosure, which means that -(La)m-(AA)w-(Lb)p-Lc-Ld'-RCG1 is linked to the nitrogen atom of the imidazo[4,5-d]pyridazine ring via R1;

[0834] R3 express:

[0835] - Single bond, which means that -(La)m-(AA)w-(Lb)p-Lc-Ld'-RCG1 is directly connected to the carbon atom of the imidazo[4,5-d]pyridazine ring.

[0836] - or a divalent group formed by R3 as defined in this disclosure, which means that -(La)m-(AA)w-(Lb)p-Lc-Ld'-RCG1 is linked to a carbon atom of an imidazo[4,5-d]pyridazine ring via R3.

[0837] According to a particular embodiment, A has formula (A1).

[0838] According to another embodiment, A has formula (A2).

[0839] Therefore, according to a specific embodiment, when R1 When representing a single bond, a compound or a pharmaceutically acceptable salt thereof according to formula (I1) of this disclosure has the following formula (Ia1):

[0840] (Ia1)

[0841] Wherein R2, R3, La, m, AA, w, Lb, p, Lc, Ld', and RCG1 are as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is a hydrogen atom.

[0842] According to another specific embodiment, when R1 When representing a divalent group formed by R1 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (I1) of this disclosure has the following formula (Iaa1):

[0843] (Iaa1)

[0844] Wherein R2, R3, La, m, AA, w, Lb, p, Lc, Ld', and RCG1 are as defined in this disclosure, and R1 It is divalent R1 as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is not a hydrogen atom.

[0845] According to another specific embodiment, when R3 When representing a single bond, the compound or its pharmaceutically acceptable salt according to formula (I1) of this disclosure has the following formula (Ib1):

[0846] (Ib1)

[0847] Wherein R1, R2, La, m, AA, w, Lb, p, Lc, Ld', and RCG1 are as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is a hydrogen atom.

[0848] According to another specific embodiment, when R3 When representing a divalent group formed by R3 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (I1) of this disclosure has the following formula (Ibb1):

[0849] (Ibb1)

[0850] Where R1, R2, La, m, AA, w, Lb, p, Lc, Ld', and RCG1 are as defined in this disclosure, and R3 It is divalent R3 as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is not a hydrogen atom.

[0851] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds is composed of compounds such that A is selected from the group consisting of:

[0852] ;

[0853] ;

[0854] ;

[0855] ;

[0856] ;

[0857] ;

[0858] ;

[0859] ;

[0860] ;

[0861] ;as well as

[0862] .

[0863] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds is composed of compounds such that A is selected from the group consisting of:

[0864] ;

[0865] ;as well as

[0866] .

[0867] Among the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which La is a self-canceling linker. Self-canceling linkers are well known to those skilled in the art. La is a covalent assembly tailored to associate the cleavage of two chemical bonds following the protection moiety in the activated precursor. Therefore, the list is neither limited nor restricted.

[0868] For example, La represents -C(O)-O-(CR 14 R 15 )-Aryl-NR 16 - Groups, -C(O)-O-(CR 14 R 15 )-Heteroaryl-NR 16 - Groups, -C(O)-NR 17 -(C2-C6)alkyl-NR 18 - , -C(O)-NR 17- (C2-C6)alkyl-NR 18 -C(O)-O-CR 15 R 14 -Aryl-NR 16 - Groups, -C(O)-NR 17- (C2-C6)alkyl-NR 18 -C(O)-O-CR 15 R 14 -heteroaryl-NR 16 - Groups, -CR 15 R 14 -Aryl-NR 16 - Group or -CR 15 R 14 -heteroaryl-NR 16 - Group, aryl is (C6-C 10 ) aryl and heteroaryl are C5-C6 groups containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) Yuanhe aryl, single star ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site covalently attached to the (AA)w group, R 14 R 15 R 16 R 17 and R 18 It is a hydrogen atom or a (C1-C6) alkyl group.

[0869] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which La represents -C(O)-O-CH2-phenyl-NH- Group, single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site covalently attached to the (AA)w group.

[0870] In the compounds of formula (I1) which are the subject of this disclosure, a group of compounds consists of compounds in which (AA)w, w represents an integer from 1 to 6, and AA is selected from valine, citrulline, alanine and glutamic acid.

[0871] In the compounds of formula (I1) which are the subject of this disclosure, a group of compounds consists of compounds in which (AA)w, w represents an integer 2 or 3, and AA is selected from valine (Val), citrulline (Cit), alanine (Ala), and glutamic acid (Glu).

[0872] For example, the amino acid sequence (AA)w contains citrulline (Cit).

[0873] For example, the amino acid sequence (AA)w is selected from Glu-Val-Cit; Glu-Val-Ala; Val-Cit or Val-Ala.

[0874] For example, when the amino acid sequence (AA)w is Glu-Val-Cit, citrulline (Cit) is linked to La or A (if La is not present, that is, if m is 0), and glutamic acid (Glu) is linked to Lb or Lc (if Lb is not present, that is, if p is 0).

[0875] For example, when the amino acid sequence (AA)w is Glu-Val-Ala, alanine (Ala) is linked to La or A (if La is not present, that is, if m is 0), and glutamic acid (Glu) is linked to Lb or Lc (if Lb is not present, that is, if p is 0).

[0876] For example, when the amino acid sequence (AA)w is Val-Cit, citrulline (Cit) is linked to La or A (if La is not present, that is, if m is 0), and valine (Val) is linked to Lb or Lc (if Lb is not present, that is, if p is 0).

[0877] For example, when the amino acid sequence (AA)w is Val-Ala, alanine (Ala) is linked to La or A (if La is not present, that is, if m is 0), and valine (Val) is linked to Lb or Lc (if Lb is not present, that is, if p is 0).

[0878] For example, the amino acid sequence (AA)w is Val-Cit.

[0879] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Lb represents -C(O)-(C1-C6)alkyl-C(O)-NH- Group or -C(O)- Group, single asterisk ( ) indicates the site covalently attached to the (AA)w group, and the double asterisk ( ) indicates the site covalently attached to the Lc group.

[0880] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Lb represents -C(O)-(CH2)3-C(O)-NH- Group or -C(O)- Group, single asterisk ( ) indicates the site covalently attached to the (AA)w group, and the double asterisk ( ) indicates the site covalently attached to the Lc group.

[0881] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Lc represents -(CH2-CH2-O)n- Group, where n represents an integer from 2 to 12, if Lb exists (that is, if p is 1), single asterisk ( The asterisk () indicates the site covalently attached to the Lb group, or if Lb is absent (i.e., if p is 0), the asterisk ( ) indicates the site directly attached to the (AA)w group, and the double asterisk ( ) indicates the site covalently attached to the Ld' group.

[0882] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Lc represents -(CH2-CH2-O)n- Group, where n represents an integer from 3 to 7, if Lb exists (that is, if p is 1), single asterisk ( The asterisk () indicates the site covalently attached to the Lb group, or if Lb is absent (i.e., if p is 0), the asterisk ( ) indicates the site directly attached to the (AA)w group, and the double asterisk ( ) indicates the site covalently attached to the Ld' group.

[0883] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Lc represents -(CH2-CH2-O)n- Group, where n represents an integer 3 or 4, if Lb exists (that is, if p is 1), single asterisk ( ) indicates the site of covalent attachment, or if Lb does not exist (that is, if p is 0), a single asterisk ( ) indicates the site directly attached to the (AA)w group, and the double asterisk ( ) indicates the site covalently attached to the Ld' group.

[0884] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(C2-C6)alkyl- Groups, -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group or -(C2-C6)alkyl-C(O)-NH-(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the Lc group, and the double asterisk ( ) indicates the site covalently attached to the RCG1 group.

[0885] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(CH2)2- Groups, -(CH2)2-NH-C(O)-(CH2)2- Group or -(CH2)2-C(O)-NH-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the Lc group, and the double asterisk ( ) indicates the site covalently attached to the RCG1 group.

[0886] In the compounds of formula (I1) which are the subject of this disclosure, a group of compounds consists of such compounds, where m represents the integer 1.

[0887] In the compounds of formula (I1) which are the subject of this disclosure, a group of compounds consists of such compounds, where m represents 0.

[0888] In the compounds of formula (I1) which are the subject of this disclosure, a group of compounds consists of such compounds, where p represents the integer 1.

[0889] In the compounds of formula (I1) which are the subject of this disclosure, a group of compounds consists of such compounds, where p represents 0.

[0890] Among the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which RCG1 represents N3- or maleimide group. .

[0891] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the Lc group and the double asterisk ( When the symbol indicates the site covalently attached to the RCG1 group, then RCG1 represents N3-.

[0892] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(C2- C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the Lc group and the double asterisk ( When the site is indicated as a covalent attachment site to the RCG1 group, then RCG1 represents a maleimide group. .

[0893] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the Lc group and the double asterisk ( When the symbol indicates the site covalently attached to the RCG1 group, then RCG1 represents N3-.

[0894] In the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(CH2)2-NH-C(O)-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the Lc group and the double asterisk ( When the site is indicated as a covalent attachment site to the RCG1 group, then RCG1 represents a maleimide group. .

[0895] All of these subgroups, whether used individually or in combination, are part of this disclosure.

[0896] According to specific embodiments, this disclosure relates to compounds / loads of formula (I1) or pharmaceutically acceptable salts thereof, wherein A and RCG1 are as defined in this disclosure, and

[0897] La is -C(O)-O-CH2-p-phenyl-NH ;

[0898] m is 1;

[0899] AA is selected from Ala, Val, Cit, and Glu;

[0900] w is 2 or 3;

[0901] Lb is -C(O)-(CH2)3-C(O)-NH- ;

[0902] p is 1;

[0903] Lc is -(CH2-CH2-O)3- ;and

[0904] Ld' is -(CH2)2- or -(CH2)2-NH-C(O)-(CH2)2- .

[0905] According to another specific embodiment, this disclosure relates to compounds / loads of formula (I1) or pharmaceutically acceptable salts thereof, wherein

[0906] A and RCG1 are as defined in this disclosure;

[0907] m is 0;

[0908] AA is selected from Ala, Val, and Cit;

[0909] w is 2;

[0910] Lb is -C(O)-(CH2)3-C(O)-NH- or -C(O)- ;

[0911] p is 1;

[0912] Lc is -(CH2-CH2-O)3- ;and

[0913] Ld' is -(CH2)2- or -(CH2)2-NH-C(O)-(CH2)2- .

[0914] According to another specific embodiment, this disclosure relates to compounds / loads of formula (I1) or pharmaceutically acceptable salts thereof, wherein the -(La)m-(AA)w-(Lb)p-Lc-Ld'- portion is selected from the group consisting of:

[0915] -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0916] -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0917] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0918] -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0919] -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[0920] -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu--C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[0921] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[0922] -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;and

[0923] -Cit-Val-C(O)-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ,

[0924] single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site covalently attached to the RCG1 group.

[0925] Among the compounds of formula (I1) that are the subject of this disclosure, a group of compounds consists of compounds in which:

[0926] A has the formula (A), where:

[0927] R1 means:

[0928] - (C1-C6) alkyl-groups, especially methyl groups;

[0929] - NH2-(C1-C6)alkyl-groups, especially NH2-(CH2)5-groups;

[0930] - A phenyl (C1-C6)alkyl- group, particularly a phenyl-CH2- group, which is unsubstituted or substituted with at least one substituent, especially substituted on the benzene ring with at least one substituent, for example, substituted with a substituent selected from the following:

[0931] - (C1-C6)alkyl-group, particularly methyl (or -CH2-group, if substituted) or isopropyl (or -CH(CH3)2-group, if substituted), which is unsubstituted or substituted with at least one substituent, particularly substituted with a substituent selected from:

[0932] - -NR4R5 group, wherein R4 and R5 are independently selected from: hydrogen atoms and (C1-C2) 16Alkyl groups, particularly methyl groups, such as -NR4R5 being -NH2 or -NH(CH3); or R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted (C3-C) group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heterocyclic alkyl groups, especially unsubstituted (C3-C) groups containing two nitrogen atoms 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[0933] - (C3-C 10 Cycloalkyl (C1-C6) alkyl- groups, especially cyclohexyl-CH2- groups, which are unsubstituted or substituted, particularly in (C3-C6) alkyl groups. 10 The cycloalkyl group is substituted by at least one substituent, particularly by a substituent selected from the following: -NH2 and NH2-(C1-C6)alkyl groups, such as NH2-CH2- groups;

[0934] R2 means:

[0935] -(C1-C6)alkyl-groups, especially -(CH2)3-CH3 groups;

[0936] -(C1-C6) alkylthio-groups, especially -S-(CH2)2-CH3 groups; or

[0937] -(C1-C6)alkyl-NH- groups, especially -NH-(CH2)2-CH3 groups; and

[0938] R3 means:

[0939] - -OR6 group, where R6 is a (C1-C6) alkyl-group, especially -O-isopropyl (that is, -O-CH(CH3)2 group);

[0940] - -NR7R8 groups, wherein R7 and R8, together with the nitrogen atom to which they are attached, form a heteroatom comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur, particularly a (C3-C) group comprising two nitrogen atoms. 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[0941] - (C3-C 10 () A heterocyclic alkyl group containing one to four heteroatoms selected from oxygen, nitrogen and sulfur, particularly one or two nitrogen atoms, such as dihydropyrrole, such as 2,5-dihydro-1H-pyrrole or piperazine;

[0942] -(La)m-(AA)w-(Lb)p-Lc-Ld'- express:

[0943] -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0944] -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0945] -Cit-Val-C(O)-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[0946] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0947] -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[0948] -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[0949] -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu--C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[0950] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;or

[0951] -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ,

[0952] single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site of covalent attachment to the -RCG1 group; and

[0953] RCG1 is an N3- or maleimide group. .

[0954] Among the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which A has formula (A1) or formula (A2):

[0955] (A1) (A2)

[0956] in:

[0957] R1, R2 and R3 are as defined in this disclosure;

[0958] single asterisk ( ) indicates the site covalently attached to -(P)oL-Ld-RCG1;

[0959] R1 express:

[0960] - Single bond, which means that -(P)oL-Ld-RCG1 is directly connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring.

[0961] - Or a divalent group is formed by R1 as defined in this disclosure, which means that -(P)oL-Ld-RCG1 is connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring via R1;

[0962] R3 express:

[0963] - Single bond, which means that -(P)oL-Ld-RCG1 is directly connected to the carbon atom of the imidazo[4,5-d]pyridazine ring.

[0964] - Or a divalent group is formed by R3 as defined in this disclosure, which means that -(P)oL-Ld-RCG1 is connected to the carbon atom of the imidazo[4,5-d]pyridazine ring via R3.

[0965] According to a particular embodiment, A has formula (A1).

[0966] According to another embodiment, A has formula (A2).

[0967] Therefore, according to a specific embodiment, when R1 When representing a single bond, compounds of formula (I2) disclosed herein or pharmaceutically acceptable salts thereof have the following formula (Ia2):

[0968] (Ia2)

[0969] R2, R3, P, o, L, Ld, and RCG1 are as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is a hydrogen atom.

[0970] According to another specific embodiment, when R1 When representing a divalent group formed by R1 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (I2) of this disclosure has the following formula (Iaa2):

[0971] (Iaa2)

[0972] Wherein R2, R3, P, o, L, Ld, and RCG1 are as defined in this disclosure, and R1 It is divalent R1 as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is not a hydrogen atom.

[0973] According to another specific embodiment, when R3 When representing a single bond, the compound or its pharmaceutically acceptable salt according to formula (I2) of this disclosure has the following formula (Ib2):

[0974] (Ib2)

[0975] R1, R2, P, o, L, Ld, and RCG1 are as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is a hydrogen atom.

[0976] According to another specific embodiment, when R3 When representing a divalent group formed by R3 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (I2) of this disclosure has the following formula (Ibb2):

[0977] (Ibb2)

[0978] Where R1, R2, P, o, L, Ld, and RCG1 are as defined in this disclosure, and R3 It is divalent R3 as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is not a hydrogen atom.

[0979] In the compounds of formula (I2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which A is selected from the group consisting of:

[0980] ;

[0981] ;

[0982] ;

[0983] ;

[0984] ;

[0985] ;

[0986] ;

[0987] ;

[0988] ;

[0989] ;as well as

[0990] .

[0991] In the compounds of formula (I2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which A is selected from the group consisting of:

[0992] ;

[0993] ;as well as

[0994] .

[0995] Among the compounds of formula (I2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which P is a -C(O)- group.

[0996] Among the compounds of formula (I2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which P is a -C(O)-O- group.

[0997] Among the compounds of formula (I2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which P is a -S(O2)- group.

[0998] Among the compounds of formula (I2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which P is a -C(O)-C(CH3)2-CH2-O- group.

[0999] Among the compounds of formula (I2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which P is a -C(O)-NH- group.

[1000] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which P is Group.

[1001] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which P is Group.

[1002] In the compounds of formula (I2) which are the subject of this disclosure, there is a group of compounds consisting of such compounds, where o is 0.

[1003] In the compounds of formula (I2) that are the subject of this disclosure, there is a group of compounds consisting of such compounds, where o is 1.

[1004] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which L represents -(CH2-CH2-O)n- Group, where n represents an integer from 8 to 25, if P exists (that is, if o is 1), single asterisk ( The asterisk () indicates the site covalently attached to the P group, or if P is absent (i.e., if o is 0), the asterisk ( ) indicates the site where the A group is directly attached, and the double asterisk ( ) indicates the site where it is covalently attached to the Ld group.

[1005] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which L represents -(CH2-CH2-O)n- Group, where n represents 8, 12, 16, 20, 23, or 24, if P is present (that is, if o is 1), single asterisk ( The asterisk () indicates the site covalently attached to the P group, or if P is absent (i.e., if o is 0), the asterisk ( ) indicates the site where the A group is directly attached, and the double asterisk ( ) indicates the site where it is covalently attached to the Ld group.

[1006] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(C2-C6)alkyl- Groups, -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group or -(C2-C6)alkyl-C(O)-NH-(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( ) indicates the site covalently attached to the RCG1 group.

[1007] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(CH2)2- Groups, -(CH2)2-NH-C(O)-(CH2)2- Group or -(CH2)2-C(O)-NH-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( ) indicates the site covalently attached to the RCG1 group.

[1008] Among the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which RCG1 represents an N3-, -COOH group or a maleimide group. .

[1009] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the symbol indicates the site covalently attached to the RCG1 group, then RCG1 represents N3-.

[1010] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the symbol indicates the site covalently attached to the RCG1 group, then RCG1 represents -COOH.

[1011] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the site is indicated as a covalent attachment site to the RCG1 group, then RCG1 represents a maleimide group. .

[1012] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the symbol indicates the site covalently attached to the RCG1 group, then RCG1 represents N3-.

[1013] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the symbol indicates the site covalently attached to the RCG1 group, then RCG1 represents -COOH.

[1014] In the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(CH2)2-NH-C(O)-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the site is indicated as a covalent attachment site to the RCG1 group, then RCG1 represents a maleimide group. .

[1015] All of these subgroups, whether used individually or in combination, are part of this disclosure.

[1016] According to specific embodiments, this disclosure relates to compounds / loads of formula (I2) or pharmaceutically acceptable salts thereof, wherein the -(P)oL-Ld- portion is selected from the group consisting of:

[1017] -C(O)-(CH2-CH2-O) 24 -CH2-CH2- ;

[1018] -(CH2-CH2-O) 23 -CH2-CH2- ;

[1019] -C(O)-(CH2-CH2-O) 20 -CH2-CH2- ;

[1020] -C(O)-(CH2-CH2-O) 16 -CH2-CH2- ;

[1021] -C(O)-(CH2-CH2-O) 12 -CH2-CH2- ;

[1022] -C(O)-(CH2-CH2-O)8-CH2-CH2- ;

[1023] -C(O)-C(CH3)2-CH2-O-(CH2-CH2-O) 20 -CH2-CH2- ;

[1024] -C(O)-O-(CH2-CH2-O) 20 -CH2-CH2- ;

[1025] -C(O)-NH-(CH2-CH2-O) 20 -CH2-CH2- ;

[1026] ;

[1027] ;

[1028] -C(O)-(CH2-CH2-O) 24 … -CH2-CH2-NH-C(O)-CH2-CH2- ;

[1029] -C(O)-(CH2-CH2-O) 20 -CH2-CH2-NH-C(O)-CH2-CH2- ; and

[1030] -C(O)-(CH2-CH2-O) 12 -CH2-CH2-NH-C(O)-CH2-CH2- ;

[1031] single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site covalently attached to the RCG1 group.

[1032] Among the compounds of formula (I2) that are the subject of this disclosure, a group of compounds consists of compounds in which:

[1033] A has the formula (A), where:

[1034] R1 means:

[1035] - (C1-C6) alkyl-groups, especially methyl groups;

[1036] - NH2-(C1-C6)alkyl-groups, especially NH2-(CH2)5-groups;

[1037] - A phenyl (C1-C6)alkyl- group, particularly a phenyl-CH2- group, which is unsubstituted or substituted with at least one substituent, especially substituted on the benzene ring with at least one substituent, for example, substituted with a substituent selected from the following:

[1038] - (C1-C6)alkyl-group, particularly methyl (or -CH2-group, if substituted) or isopropyl (or -CH(CH3)2-group, if substituted), which is unsubstituted or substituted with at least one substituent, particularly substituted with a substituent selected from:

[1039] - -NR4R5 group, wherein R4 and R5 are independently selected from: hydrogen atoms and (C1-C2) 16 Alkyl groups, particularly methyl groups, such as -NR4R5 being -NH2 or -NH(CH3); or R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted (C3-C) group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heterocyclic alkyl groups, especially unsubstituted (C3-C) groups containing two nitrogen atoms 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[1040] - (C3-C 10 Cycloalkyl (C1-C6) alkyl- groups, especially cyclohexyl-CH2- groups, which are unsubstituted or substituted, particularly in (C3-C6) alkyl groups. 10 The cycloalkyl group is substituted by at least one substituent, particularly by a substituent selected from the following: -NH2 and NH2-(C1-C6)alkyl groups, such as NH2-CH2- groups;

[1041] R2 means:

[1042] -(C1-C6)alkyl-groups, especially -(CH2)3-CH3 groups;

[1043] -(C1-C6) alkylthio-groups, especially -S-(CH2)2-CH3 groups; or

[1044] -(C1-C6)alkyl-NH- groups, especially -NH-(CH2)2-CH3 groups; and

[1045] R3 means:

[1046] - -OR6 group, where R6 is a (C1-C6) alkyl-group, especially -O-isopropyl (that is, -O-CH(CH3)2 group);

[1047] - -NR7R8 groups, wherein R7 and R8, together with the nitrogen atom to which they are attached, form a heteroatom comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur, particularly a (C3-C) group comprising two nitrogen atoms. 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[1048] - (C3-C 10 () A heterocyclic alkyl group containing one to four heteroatoms selected from oxygen, nitrogen and sulfur, particularly one or two nitrogen atoms, such as dihydropyrrole, such as 2,5-dihydro-1H-pyrrole or piperazine;

[1049] -(P)oL-Ld- express:

[1050] -C(O)-(CH2-CH2-O) 24 -CH2-CH2- ;

[1051] -(CH2-CH2-O) 23 -CH2-CH2- ;

[1052] -C(O)-(CH2-CH2-O) 20 -CH2-CH2- ;

[1053] -C(O)-(CH2-CH2-O)16 -CH2-CH2- ;

[1054] -C(O)-(CH2-CH2-O) 12 -CH2-CH2- ;

[1055] -C(O)-(CH2-CH2-O)8-CH2-CH2- ;[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ ;

[1064] single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site of covalent attachment to the -RCG1 group; and

[1065] RCG1 is an N3-, -COOH group or a maleimide group. .

[1066] In the compounds / loads having formula (I), (I1) or (I2) or their pharmaceutically acceptable salts that are the subject of this disclosure, the following compounds may be mentioned, for example:

[1067] ;

[1068] ;

[1069] ;

[1070] ;

[1071] ;

[1072] ;

[1073] ;

[1074] ;

[1075] ;

[1076] ;

[1077] ;

[1078] ;

[1079] ;

[1080] ;

[1081] ;

[1082] ;

[1083] ;

[1084] ；

[1085] ；

[1086] ；

[1087] ；

[1088] ；

[1089] ；

[1090] ；

[1091] ；

[1092] ；

[1093] ；

[1094] ；

[1095] ；

[1096] ；

[1097] ；

[1098] ；

[1099] ；

[1100] ；

[1101] ；

[1102] ；

[1103] ；

[1104] ；

[1105] ；

[1106] ；

[1107] ；

[1108] ；

[1109] ;

[1110] ;

[1111] ;

[1112] ;

[1113] ;

[1114] ;

[1115] ;

[1116] ;

[1117] ;

[1118] ;

[1119] ;

[1120] ;

[1121] ;

[1122] ;as well as

[1123] .

[1124] In the compounds / loads having formula (I), (I1) or (I2) or their pharmaceutically acceptable salts that are the subject of this disclosure, the following compounds may be mentioned, for example:

[1125] (P1) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-carbonyl]oxymethyl]aniline]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentyl]amino]-5-oxopentanoic acid;

[1126] (P2) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylcarbamoyloxymethyl]aniline]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentyl]amino]-5-oxopentanoic acid;

[1127] (P3) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-carbonyl]oxymethyl]aniline]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentanoyl]amino]-5-oxopentanoic acid;

[1128] (P4) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylcarbamoyloxymethyl]aniline]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentanoyl]amino]-5-oxopentanoic acid;

[1129] (P5) N'-[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-yl]-1-oxoprop-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide;

[1130] (P6) N'-[(2S)-1-[[(2S)-1-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide;

[1131] (P7) N'-[(2S)-1-[[(2S)-1-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-1-oxoprop-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide;

[1132] (P8) N'-[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-yl]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide;

[1133] (P9) N'-[(2S)-1-[[(2S)-1-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide;

[1134] (P10) N'-[(2S)-1-[[(2S)-1-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide, 2,2,2-trifluoroacetic acid;

[1135] (P11) 1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-yl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]prop-1-one;

[1136] (P12) N-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1137] (P13) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-yl]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethyl]-3-(2,5-dioxopyrrole-1-yl)propionamide, 2,2,2-trifluoroacetic acid;

[1138] (P14) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-(2,5-dioxopyrrolo-1-yl)propionamide, 2,2,2-trifluoroacetic acid;

[1139] (P15) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-(2,5-dioxopyrrole-1-yl)propionamide, 2,2,2-trifluoroacetic acid;

[1140] (P16) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] 3-(2,5-dioxopyrrole-1-yl)propionamide, 2,2,2-trifluoroacetic acid;

[1141] (P17) 3-[[4-[[4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1142] (P18) 3-[[trans-4-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1143] (P19) N-[[trans-4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1144] (P20) N-[[trans-4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1145] (P21) N-[[trans-4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acrylamide;

[1146] (P22) 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[trans-4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid;

[1147] (P23) N-[[trans-4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acrylamide;

[1148] (P24) ((4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylcarbamoyloxymethyl]aniline]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentyl]amino]-5-oxopentanoic acid;

[1149] (P25) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]carbamoyloxymethyl]aniline]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentyl]amino]-5-oxopentanoic acid;

[1150] (P26) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylcarbamoyloxymethyl]aniline]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentanoyl]amino]-5-oxopentanoic acid;

[1151] (P27) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]carbamoyloxymethyl]aniline]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentanoyl]amino]-5-oxopentanoic acid;

[1152] (P28) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide;

[1153] (P29) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]amino]-1-oxoprop-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide;

[1154] (P30) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-1-oxoprop-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide;

[1155] (P31) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide;

[1156] (P32) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]amino]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide; 2,2,2-trifluoroacetate;

[1157] (P33) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide; 2,2,2-trifluoroacetate;

[1158] (P34) N'-[(1S)-1-[[(1S)-1-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]carbamoyl]-4-ureo-butyl]carbamoyl]-2-methyl-propyl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide; 2,2,2-trifluoroacetic acid;

[1159] (P35) (2S)-N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-2-[[(2S)-2-[3-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]propionylamino]-3-methyl-butyryl]amino]-5-ureo-pentanoamide; 2,2,2-trifluoroacetic acid;

[1160] (P36) (2S)-N-[[4-[[7-amino-4-isopropoxy-2-(propylamino)imidazo[4,5-d]pyridazin-3-yl]methyl]phenyl]methyl]-2-[[(2S)-2-[3-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]propionylamino]-3-methyl-butyryl]amino]-5-ureo-pentanamide; 2,2,2-trifluoroacetic acid;

[1161] (P37) N'-[(1S)-1-[[(1S)-1-[3-(4-amino-2-butyl-1-methyl-imidazo[4,5-d]pyridazin-7-yl)-2,5-dihydropyrrolo-1-carbonyl]-4-ureo-butyl]carbamoyl]-2-methyl-propyl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide; 2,2,2-trifluoroacetic acid;

[1162] (P38) N'-[(1S)-1-[[(1S)-1-[4-(7-amino-2-butyl-3-methyl-imidazo[4,5-d]pyridazin-4-yl)piperazin-1-carbonyl]-4-ureo-butyl]carbamoyl]-2-methyl-propyl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide; 2,2,2-trifluoroacetic acid;

[1163] (P39) (2S)-N-[5-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)pentyl]-2-[[(2S)-2-[3-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]propionylamino]-3-methyl-butyryl]amino]-5-ureo-pentanamide, 2,2,2-trifluoroacetic acid;

[1164] (P40) (2S)-N-[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]-2-[[(2S)-2-[3-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]propionylamino]-3-methyl-butyryl]amino]-5-ureo-pentanamide, 2,2,2-trifluoroacetic acid;

[1165] (P41) N-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1166] (P42) N-[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1167] (P43) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethyl]-3-(2,5-dioxopyrrole-1-yl)acrylamide; 2,2,2-trifluoroacetate;

[1168] (P44) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[4-[(7-amino-4-isopropoxy-2-propylthioalkyl-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethyl]-3-(2,5-dioxopyrrole-1-yl)propionamide;

[1169] (P45) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] 3-(2,5-dioxopyrrole-1-yl)acrylamide, 2,2,2-trifluoroacetic acid;

[1170] (P46) 3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1171] (P47) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1172] (P48) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1173] (P49) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1174] (P50) 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-3-oxo-propoxy]eth ...

[1175] (P51) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionamide;

[1176] (P52) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-(2,5-dioxopyrrolo-1-yl)propionamide;

[1177] (P53) N-[1-[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]-1-methyl-ethyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1178] (P54) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...N-methyl-propionamide;

[1179] (P55) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1180] (P56) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1181] (P57) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1182] (P58) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]carbamate 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1183] (P59) 1-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

[1184] Or its pharmaceutically acceptable salt.

[1185] The compounds / loads of formula (I), (I1) or (I2) according to this disclosure, or their pharmaceutically acceptable salts, may be prepared by any method known to a person skilled in the art, and for example by the following methods.

[1186] Synthesis of compounds / payloads of formulas (I) and (I1):

[1187] -Connector assembly

[1188] a) A combination scheme for Type 1 and Type 2 connectors

[1189]

[1190] Option 1

[1191] In Scheme 1, PG represents a carboxylic acid protecting group as defined in this disclosure; n is as defined in this disclosure; and R11 and R12 independently represent the side chains of AA as defined in this disclosure.

[1192] b) Combination scheme of type 3 and type 4 connectors

[1193]

[1194] Option 2

[1195] In scheme 2, R11 and R12 independently represent the side chains of AA as defined in this disclosure; and n is as defined in this disclosure.

[1196] c) Composite scheme of type 5, type 6 and type 7 connectors

[1197]

[1198] Option 2a

[1199] In scheme 2a, R13 and R14 independently represent -(C1-C6)alkyl, or alternatively R13 and R14 together with the carbon atoms to which they are attached form -(C3-C6)cycloalkyl or (C3-C6) heterocycloalkyl as defined in this disclosure; and n is as defined in this disclosure.

[1200] d) Composite scheme for type 8 connector

[1201]

[1202] Option 2b

[1203] In scheme 2b, n is as defined in this disclosure.

[1204] e) Synthesis scheme for type 9 connector

[1205]

[1206] Option 2c

[1207] In scheme 2c, R11 and R12 independently represent the side chains of AA as defined in this disclosure; and n is as defined in this disclosure.

[1208] - Payload synthesis

[1209] Synthesis of compounds / payloads of formulas (I) and (I1)

[1210] a) A combined scheme for the effective load of type 1 and type 2 CL (cuttable) joints

[1211]

[1212] Option 3

[1213] In scheme 3, -R1 -NH2 corresponds to -R1 as defined in this disclosure, provided that R1 contains an NH2 group; R2 and R3 are as defined in this disclosure; n is as defined in this disclosure; R11 and R12 independently represent side chains of AA as defined in this disclosure; and PG represents a carboxylic acid protecting group as defined in this disclosure.

[1214] b) Combined load scheme with type 3 and type 4 CL joints

[1215]

[1216] Option 4

[1217] In scheme 4, -R1 -NH2 corresponds to -R1 as defined in this disclosure, provided that R1 contains an NH2 group; n is as defined in this disclosure; R2 and R3 are as defined in this disclosure; and R11 and R12 independently represent side chains of AA as defined in this disclosure.

[1218] c) Composite scheme with effective load of type 9 CL connector

[1219]

[1220] Option 4a

[1221] In scheme 4a, -R1 -NH2 corresponds to -R1 as defined in this disclosure, provided that R1 contains an NH2 group; n is as defined in this disclosure; R2 and R3 are as defined in this disclosure; and R11 and R12 independently represent side chains of AA as defined in this disclosure.

[1222]

[1223] Option 4b

[1224] In scheme 4b, -R3 -NH - R4 corresponds to -R3 as defined in this disclosure, provided that R3 contains a -NH-R4 group, R4 is as defined in this disclosure; n is as defined in this disclosure; R1 and R2 are as defined in this disclosure; and R11 and R12 independently represent side chains of AA as defined in this disclosure.

[1225] Synthesis of compounds / payloads of formulas (I) and (I2):

[1226] a) Synthetic scheme with effective load of NCL (non-cuttable) amide joint

[1227]

[1228] Option 1'

[1229] In scheme 1', -R1 -NH-R4 corresponds to -R1 as defined in this disclosure, provided that -R1 contains the -NH-R4 group, R4 is as defined in this disclosure; n is as defined in this disclosure; and R2 and R3 are as defined in this disclosure.

[1230]

[1231] Option 1'a

[1232] In scheme 1'a, -R1 -NH-R4 corresponds to -R1 as defined in this disclosure, provided that -R1 contains the -NH-R4 group, R4 is as defined in this disclosure; n is as defined in this disclosure; and R2 and R3 are as defined in this disclosure.

[1233] b) Synthetic schemes with effective loading of NCL (non-cuttable) alkyl links

[1234]

[1235] Option 2'

[1236] In scheme 2', -R1 -NH- corresponds to -R1, provided that R1 contains an NH2 group as defined in this disclosure; n is as defined in this disclosure; R2 and R3 are as defined in this disclosure; LG represents a leaving group as defined in this disclosure; and PG represents an amino protecting group as defined in this disclosure.

[1237]

[1238] Option 2''

[1239] In scheme 2'', -R1 -NH- corresponds to -R1 as defined in this disclosure, provided that R1 contains an NH2 group; n is as defined in this disclosure; R2 and R3 are as defined in this disclosure; and LG represents a leaving group as defined in this disclosure.

[1240] c) Synthetic schemes with effective loads of NCL (non-cuttable) urethane joints

[1241]

[1242] Option 2''a

[1243] In scheme 2''a, -R1 -NH2 corresponds to -R1 as defined in this disclosure, provided that -R1 contains the -NH2 group; n is as defined in this disclosure; and R2 and R3 are as defined in this disclosure.

[1244] d) Synthetic scheme with effective load of type 8 NCL (non-cuttable) urea connector

[1245]

[1246] Option 2''b

[1247] In scheme 2''b, -R1 -NH2 corresponds to -R1 as defined in this disclosure, provided that -R1 contains the -NH2 group; n is as defined in this disclosure; and R2 and R3 are as defined in this disclosure.

[1248] Compounds / loads of specific formulas (I), (I1), and (I2) as defined in this disclosure are indicated in Tables 1 and 1' (numbers and formulas) and are further detailed below. Tables 2 and 2' also indicate… 1 H NMR and liquid chromatography / mass spectrometry.

[1249] Table 2 and Table 2' 1 H NMR is as defined in the experimental section. 1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6 or CDCl3).

[1250] The liquid chromatography / mass spectrometry (LC / MS) results for Tables 2 and 2' were obtained using one of the four methods described in the experimental section.

[1251] Table 1 :

[1252]

[1253] Table 1':

[1254]

[1255] Table 2:

[1256]

[1257] Table 2':

[1258]

[1259] This disclosure further relates to compounds / conjugates of formula (II) or pharmaceutically acceptable salts thereof:

[1260] A-L1-G-BA (II)

[1261] in:

[1262] A and L1 are as defined in this disclosure;

[1263] BA stands for binding agent, such as protein, polypeptide, ligand, peptide, oligonucleotide or oligosaccharide. For example, BA is a targeting agent, such as a cell binding agent, such as an antibody, such as a monoclonal antibody or VHH antibody.

[1264] G represents the product of the reaction between RCG1 as defined in this disclosure and the reactive group RCG2 present on the binder, for example, G is selected from the group consisting of:

[1265] ; ; ; ; ; ; ; ; ; ;and ,

[1266] For example, the left side of the G group is connected to BA (e.g., antibody (Ab)), and the right side of the G group is connected to L1. For example, G represents the following groups:

[1267] ; ; ; ; or Such as ; ; or .

[1268] According to a specific embodiment, L1 represents a cuttable joint or a non-cuttable joint.

[1269] According to one particular embodiment, L1 is a cuttable connector, which is a peptide connector.

[1270] According to another specific embodiment, L1 is an uncuttable connector, which is a PEGylated connector.

[1271] In the compounds of formula (II), which are the subject of this disclosure, a group of compounds consists of compounds in which A has formula (A1) or formula (A2).

[1272] (A1) (A2)

[1273] in:

[1274] R1, R2 and R3 are as defined in this disclosure;

[1275] single asterisk ( ) indicates the site covalently attached to -L1-G-BA;

[1276] R1 express:

[1277] - Single bond, which means that -L1-G-BA is directly connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring.

[1278] - Or a divalent group formed by R1 as defined in this disclosure, which means that -L1-G-BA is connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring via R1;

[1279] R3 express:

[1280] - Single bond, which means that -L1-G-BA is directly connected to the carbon atom of the imidazo[4,5-d]pyridazine ring.

[1281] - or a divalent group formed by R3 as defined in this disclosure, which means that -L1-G-BA is connected to the carbon atom of the imidazo[4,5-d]pyridazine ring via R3.

[1282] According to a particular embodiment, A has formula (A1).

[1283] According to another embodiment, A has formula (A2).

[1284] Therefore, according to a specific embodiment, when R1 When representing a single bond, compounds of formula (II) according to this disclosure or pharmaceutically acceptable salts thereof have the following formula (IIa):

[1285] (IIa)

[1286] R2, R3, L1, G, and BA are as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is a hydrogen atom.

[1287] According to another specific embodiment, when R1 When representing a divalent group formed by R1 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (II) of this disclosure has the following formula (IIaa):

[1288] (IIaa)

[1289] R2, R3, L1, G, and BA are as defined in this disclosure, and R1 It is divalent R1 as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is not a hydrogen atom.

[1290] According to another specific embodiment, when R3 When representing a single bond, compounds of formula (II) according to this disclosure or pharmaceutically acceptable salts thereof have the following formula (IIb):

[1291] (IIb)

[1292] R1, R2, L1, G, and BA are as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is a hydrogen atom.

[1293] According to another specific embodiment, when R3 When representing a divalent group formed by R3 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (II) of this disclosure has the following formula (IIbb):

[1294] (IIbb)

[1295] R1, R2, L1, G, and BA are as defined in this disclosure, and R3 It is divalent R3 as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is not a hydrogen atom.

[1296] According to specific embodiments, the binder BA represents the antibody Ab, such as a monoclonal antibody or a VHH antibody.

[1297] Among the compounds of formula (II) that are the subject of this disclosure, a group of compounds consists of compounds in which:

[1298] A has the formula (A), where:

[1299] R1 means:

[1300] - (C1-C6) alkyl-groups, especially methyl groups;

[1301] - NH2-(C1-C6)alkyl-groups, especially NH2-(CH2)5-groups;

[1302] - A phenyl (C1-C6)alkyl- group, particularly a phenyl-CH2- group, which is unsubstituted or substituted with at least one substituent, especially substituted on the benzene ring with at least one substituent, for example, substituted with a substituent selected from the following:

[1303] - (C1-C6)alkyl-group, particularly methyl (or -CH2-group, if substituted) or isopropyl (or -CH(CH3)2-group, if substituted), which is unsubstituted or substituted with at least one substituent, particularly substituted with a substituent selected from:

[1304] - -NR4R5 group, wherein R4 and R5 are independently selected from: hydrogen atoms and (C1-C2) 16 Alkyl groups, particularly methyl groups, such as -NR4R5 being -NH2 or -NH(CH3); or R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted (C3-C) group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heterocyclic alkyl groups, especially unsubstituted (C3-C) groups containing two nitrogen atoms 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[1305] - (C3-C 10 Cycloalkyl (C1-C6) alkyl- groups, especially cyclohexyl-CH2- groups, which are unsubstituted or substituted, particularly in (C3-C6) alkyl groups. 10 The cycloalkyl group is substituted by at least one substituent, particularly by a substituent selected from the following: -NH2 and NH2-(C1-C6)alkyl groups, such as NH2-CH2- groups;

[1306] R2 means:

[1307] -(C1-C6)alkyl-groups, especially -(CH2)3-CH3 groups;

[1308] -(C1-C6) alkylthio-groups, especially -S-(CH2)2-CH3 groups; or

[1309] -(C1-C6)alkyl-NH- groups, especially -NH-(CH2)2-CH3 groups; and

[1310] R3 means:

[1311] - -OR6 group, where R6 is a (C1-C6) alkyl-group, especially -O-isopropyl (that is, -O-CH(CH3)2 group);

[1312] - -NR7R8 groups, wherein R7 and R8, together with the nitrogen atom to which they are attached, form a heteroatom comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur, particularly a (C3-C) group comprising two nitrogen atoms. 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[1313] - (C3-C 10 () A heterocyclic alkyl group containing one to four heteroatoms selected from oxygen, nitrogen and sulfur, particularly one or two nitrogen atoms, such as dihydropyrrole, such as 2,5-dihydro-1H-pyrrole or piperazine;

[1314] L1 means:

[1315] -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1316] -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1317] -Cit-Val-C(O)-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[1318] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1319] -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1320] -C(O)-O-CH2-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[1321] -C(O)-O-CH2-phenyl-NH-Ala-Val-Glu--C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[1322] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[1323] -Ala-Val-C(O)-(CH)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ,<{

[1324] -C(O)-(CH2-CH2-O) 24 -CH2-CH2- [[ID=3)) ;

[1325] -(CH2-CH2-O) 23 -CH2-CH2- ;

[1326] -C(O)-(CH2-CH2-O) 20 -CH2-CH2- ;

[1327] -C(O)-(CH2-CH2-O) 16 -CH2-CH2- ;

[1328] -C(O)-(CH2-CH2-O)12 -CH2-CH2- ;

[1329] -C(O)-(CH2-CH2-O)8-CH2-CH2- ;

[1330] -C(O)-C(CH3)2-CH2-O-(CH2-CH2-O) 20 -CH2-CH2- ;

[1331] -C(O)-O-(CH2-CH2-O) 20 -CH2-CH2- ;

[1332] -C(O)-NH-(CH2-CH2-O) 20 -CH2-CH2- ;

[1333] ;

[1334] ;

[1335] -C(O)-(CH2-CH2-O) 24 -CH2-CH2-NH-C(O)-CH2-CH2- ;

[1336] -C(O)-(CH2-CH2-O) 20 -CH2-CH2-NH-C(O)-CH2-CH2- ;or

[1337] -C(O)-(CH2-CH2-O) 12 -CH2-CH2-NH-C(O)-CH2-CH2- ;

[1338] single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( This indicates the site where a G group belonging to the -G-BA group is covalently attached;

[1339] G indicates , , or ;and

[1340] BA stands for antibody, such as monoclonal antibody or VHH antibody.

[1341] According to specific embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from the compounds of formula (II1) or (II2):

[1342] A-(La)m-(AA)w-(Lb)p-Lc-Ld'-G-BA (II1)

[1343] in:

[1344] A, La, m, (AA)w, AA, w, Lb, p, Lc, Ld', and BA are as defined in this disclosure;

[1345] G represents the product of the reaction between RCG1 as defined in this disclosure and the reactive group RCG2 present on the binder, for example, G is selected from the group consisting of:

[1346] ; ; ; ; ; ; ; ; ; ;and ,

[1347] For example, these G groups are connected to BA on the left and to Ld' on the right, where G represents the following groups:

[1348] ; ; or Such as or ,

[1349] A-(P)oL-Ld-G-BA (II2)

[1350] in:

[1351] A, P, o, L, Ld, and BA are as defined in this disclosure;

[1352] G represents the product of the reaction between RCG1 as defined in this disclosure and the reactive group RCG2 present on the binder, for example, G is selected from the group consisting of:

[1353] ; ; ; ; ; ; ; ; ; ;and ,

[1354] For example, these G groups are connected to BA on the left and to Ld on the right, such as G representing the following groups:

[1355] ; ; ; ; or Such as , , or .

[1356] According to specific embodiments, the binding agent BA is an antibody Ab, such as a monoclonal antibody or a VHH antibody.

[1357] Among the compounds of formula (II1) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which A has formula (A1) or formula (A2).

[1358] (A1) (A2)

[1359] in:

[1360] R1, R2 and R3 are as defined in this disclosure;

[1361] single asterisk ( ) indicates the site covalently attached to -(La)m-(AA)w-(Lb)p-Lc-Ld'-G-BA;

[1362] R1 express:

[1363] - Single bond, which means that -(La)m-(AA)w-(Lb)p-Lc-Ld'-G-BA is directly connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring.

[1364] - Or a divalent group formed by R1 as defined in this disclosure, which means that -(La)m-(AA)w-(Lb)p-Lc-Ld'-G-BA is linked to the nitrogen atom of the imidazo[4,5-d]pyridazine ring via R1;

[1365] R3 express:

[1366] - Single bond, which means that -(La)m-(AA)w-(Lb)p-Lc-Ld'-G-BA is directly connected to the carbon atom of the imidazo[4,5-d]pyridazine ring.

[1367] - Or a divalent group formed by R3 as defined in this disclosure, which means that -(La)m-(AA)w-(Lb)p-Lc-Ld'-G-BA is linked to a carbon atom of an imidazo[4,5-d]pyridazine ring via R3.

[1368] According to a particular embodiment, A has formula (A1).

[1369] According to another embodiment, A has formula (A2).

[1370] Therefore, according to a specific embodiment, when R1 When representing a single bond, compounds of formula (II1) according to this disclosure or pharmaceutically acceptable salts thereof have the following formula (IIa1):

[1371] (IIa1)

[1372] Wherein R2, R3, La, m, AA, w, Lb, p, Lc, Ld', G, and BA are as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is a hydrogen atom.

[1373] According to another specific embodiment, when R1 When representing a divalent group formed by R1 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (II1) of this disclosure has the following formula (IIaa1):

[1374] (IIaa1)

[1375] Where R2, R3, La, m, AA, w, Lb, p, Lc, Ld', G, and BA are as defined in this disclosure, and R1 It is divalent R1 as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is not a hydrogen atom.

[1376] According to another specific embodiment, when R3 When representing a single bond, compounds of formula (II1) according to this disclosure or pharmaceutically acceptable salts thereof have the following formula (IIb1):

[1377] (IIb1)

[1378] Wherein R1, R2, La, m, AA, w, Lb, p, Lc, Ld', G, and BA are as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is a hydrogen atom.

[1379] According to another specific embodiment, when R3 When representing a divalent group formed by R3 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (II1) of this disclosure has the following formula (IIbb1):

[1380] (IIbb1)

[1381] Where R1, R2, La, m, AA, w, Lb, p, Lc, Ld', G, and BA are as defined in this disclosure, and R3 It is divalent R3 as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is not a hydrogen atom.

[1382] In the compounds of formula (II1) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which A is selected from the group consisting of:

[1383] ;

[1384] ;

[1385] ;

[1386] ;

[1387] ;

[1388] ;

[1389] ;

[1390] ;

[1391] ;

[1392] ;as well as

[1393] .

[1394] In the compounds of formula (II1) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which A is selected from the group consisting of:

[1395] ;

[1396] ;as well as

[1397] .

[1398] Among the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which La is a self-canceling linker. Self-canceling linkers are well known to those skilled in the art. La is a covalent assembly tailored to associate the cleavage of two chemical bonds following the protection moiety in the activated precursor. Therefore, the list is neither limited nor restricted.

[1399] For example, La represents -C(O)-O-(CR 14 R 15 )-Aryl-NR 16 - Groups, -C(O)-O-(CR 14 R 15 )-Heteroaryl-NR 16 - Groups, -C(O)-NR 17 -(C2-C6)alkyl-NR 18 - , -C(O)-NR 17- (C2-C6)alkyl-NR 18 -C(O)-O-CR 15 R 14 -Aryl-NR 16 - Groups, -C(O)-NR 17- (C2-C6)alkyl-NR 18 -C(O)-O-CR 15 R 14 -heteroaryl-NR 16 - Groups, -CR 15 R 14 -Aryl-NR 16 - Group or -CR 15 R 14 -heteroaryl-NR 16 - Group, aryl is (C6-C 10 ) aryl and heteroaryl are C5-C6 groups containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) Yuanhe aryl, single star ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site covalently attached to the (AA)w group, R 14 R 15 R 16 R 17 and R 18 It is a hydrogen atom or a (C1-C6) alkyl group.

[1400] Among the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which La represents -C(O)-O-CH2-phenyl-NH- Group, single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site covalently attached to the (AA)w group.

[1401] In the compounds of formula (II1) which are the subject of this disclosure, a group of compounds consists of compounds in which (AA)w, w represents an integer from 1 to 6, and AA is selected from valine, citrulline, alanine and glutamic acid.

[1402] In the compounds of formula (II1) which are the subject of this disclosure, a group of compounds consists of compounds in which (AA)w, w represents an integer 2 or 3, and AA is selected from valine (Val), citrulline (Cit), alanine (Ala) and glutamic acid (Glu).

[1403] For example, (AA)w contains citrulline (Cit).

[1404] For example, (AA)w is selected from Glu-Val-Cit; Glu-Val-Ala; Val-Cit or Val-Ala.

[1405] For example, when the amino acid sequence (AA)w is Glu-Val-Cit, citrulline (Cit) is linked to La or A (if La is not present, that is, if m is 0), and glutamic acid (Glu) is linked to Lb or Lc (if Lb is not present, that is, if p is 0).

[1406] For example, when the amino acid sequence (AA)w is Glu-Val-Ala, alanine (Ala) is linked to La or A (if La is not present, that is, if m is 0), and glutamic acid (Glu) is linked to Lb or Lc (if Lb is not present, that is, if p is 0).

[1407] For example, when the amino acid sequence (AA)w is Val-Cit, citrulline (Cit) is linked to La or A (if La is not present, that is, if m is 0), and valine (Val) is linked to Lb or Lc (if Lb is not present, that is, if p is 0).

[1408] For example, when the amino acid sequence (AA)w is Val-Ala, alanine (Ala) is linked to La or A (if La is not present, that is, if m is 0), and valine (Val) is linked to Lb or Lc (if Lb is not present, that is, if p is 0).

[1409] For example, (AA)w is Val-Cit.

[1410] Among the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Lb represents -C(O)-(C1-C6)alkyl-C(O)-NH- Group or -C(O)- Group, single asterisk ( ) indicates the site covalently attached to the (AA)w group, and the double asterisk ( ) indicates the site covalently attached to the Lc group.

[1411] Among the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Lb represents -C(O)-(CH2)3-C(O)-NH- Group or -C(O)- Group, single asterisk ( ) indicates the site covalently attached to the (AA)w group, and the double asterisk ( ) indicates the site covalently attached to the Lc group.

[1412] Among the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Lc represents -(CH2-CH2-O)n- Group, where n represents an integer from 2 to 12, if Lb exists (that is, if p is 1), single asterisk ( The asterisk () indicates the site covalently attached to the Lb group, or if Lb is absent (i.e., if p is 0), the asterisk ( ) indicates the site directly attached to the (AA)w group, and the double asterisk ( ) indicates the site covalently attached to the Ld' group.

[1413] Among the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Lc represents -(CH2-CH2-O)n- Group, where n represents an integer from 3 to 7, if Lb exists (that is, if p is 1), single asterisk ( The asterisk () indicates the site covalently attached to the Lb group, or if Lb is absent (i.e., if p is 0), the asterisk ( ) indicates the site directly attached to the (AA)w group, and the double asterisk ( ) indicates the site covalently attached to the Ld' group.

[1414] Among the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Lc represents -(CH2-CH2-O)n- Group, where n represents an integer 3 or 4, if Lb exists (that is, if p is 1), single asterisk ( ) indicates the site of covalent attachment, or if Lb does not exist (that is, if p is 0), a single asterisk ( ) indicates the site directly attached to the (AA)w group, and the double asterisk ( ) indicates the site covalently attached to the Ld' group.

[1415] Among the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(C2-C6)alkyl- Groups, -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group or -(C2-C6)alkyl-C(O)-NH-(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the Lc group, and the double asterisk ( () indicates the site where a G group belonging to the -G-BA group is covalently attached.

[1416] Among the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(CH2)2- Groups, -(CH2)2-NH-C(O)-(CH2)2- Group or -(CH2)2-C(O)-NH-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the Lc group, and the double asterisk ( () indicates the site where a G group belonging to the -G-BA group is covalently attached.

[1417] In the compounds of formula (II1), which is the subject of this disclosure, a group of compounds consists of such compounds, where m represents the integer 1.

[1418] In the compounds of formula (II1) which are the subject of this disclosure, a group of compounds consists of such compounds, where m represents 0.

[1419] In the compounds of formula (II1), which is the subject of this disclosure, a group of compounds consists of such compounds, where p represents the integer 1.

[1420] In the compounds of formula (II1) which are the subject of this disclosure, there is a group of compounds consisting of such compounds, where p represents 0.

[1421] In the compounds of formula (II1) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which G is selected from the group consisting of:

[1422] ; ; ; ; ; ; ; ; ; ;and ,

[1423] The left side of the G group is connected to BA, and the right side of the G group is connected to Ld'.

[1424] In the compounds of formula (II1) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which G is selected from the group consisting of:

[1425] ; ; and The left side of the G group is connected to BA, and the right side of the G group is connected to Ld'.

[1426] In the compounds of formula (II1) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which G is selected from the group consisting of:

[1427] and The left side of the G group is connected to BA, and the right side of the G group is connected to Ld'.

[1428] In the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the Lc group, and the double asterisk ( When the ) indicates the site of covalent attachment to a G group belonging to the -G-BA group, then G is The left side of the G group is connected to BA, and the right side of the G group is connected to Ld'.

[1429] In the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the Lc group, and the double asterisk ( When the ) indicates the site of covalent attachment to a G group belonging to the -G-BA group, then G is The left side of the G group is connected to BA, and the right side of the G group is connected to Ld'.

[1430] In the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the Lc group, and the double asterisk ( When the ) indicates the site of covalent attachment to a G group belonging to the -G-BA group, then G is The left side of the G group is connected to BA, and the right side of the G group is connected to Ld'.

[1431] In the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which Ld' represents -(CH2)2-NH-C(O)-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the Lc group, and the double asterisk ( When the ) indicates the site of covalent attachment to a G group belonging to the -G-BA group, then G is The left side of the G group is connected to BA, and the right side of the G group is connected to Ld'.

[1432] Among the compounds of formula (II1) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which BA is an antibody Ab.

[1433] Among the compounds of formula (II1) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which Ab is a monoclonal antibody, such as teretetumab and avelumab variants.

[1434] Among the compounds of formula (II1) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which Ab is a VHH antibody.

[1435] All of these subgroups, whether used individually or in combination, are part of this disclosure.

[1436] According to specific embodiments, this disclosure relates to compounds / conjugates of formula (II1) or pharmaceutically acceptable salts thereof, wherein A, G, and BA are as defined in this disclosure, and

[1437] La is -C(O)-O-CH2-p-phenyl-NH ;

[1438] m is 1;

[1439] AA is selected from Ala, Val, Cit, and Glu;

[1440] w is 2 or 3;

[1441] Lb is -C(O)-(CH2)3-C(O)-NH- ;

[1442] p is 1;

[1443] Lc is -(CH2-CH2-O)3- ;and

[1444] Ld' is -(CH2)2- or -(CH2)2-NH-C(O)-(CH2)2- .

[1445] According to another specific embodiment, this disclosure relates to compounds / conjugates of formula (II1) or pharmaceutically acceptable salts thereof, wherein:

[1446] A, G and BA are as defined in this disclosure;

[1447] m is 0;

[1448] AA is selected from Ala, Val, and Cit;

[1449] w is 2;

[1450] Lb is -C(O)-(CH2)3-C(O)-NH- or -C(O)- ;

[1451] p is 1;

[1452] Lc is -(CH2-CH2-O)3- ;and

[1453] Ld' is -(CH2)2- or -(CH2)2-NH-C(O)-(CH2)2- .

[1454] According to another specific embodiment, this disclosure relates to compounds / conjugates of formula (II1) or pharmaceutically acceptable salts thereof, wherein the -(La)m-(AA)w-(Lb)p-Lc-Ld'- portion is selected from the group consisting of:

[1455] -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1456] -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1457] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1458] -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1459] -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[1460] -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[1461] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ; -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;as well as

[1462] -Cit-Val-C(O)-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ,

[1463] single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( This indicates the site where the G group, which belongs to the -G-BA group, is covalently attached.

[1464] Among the compounds of formula (II1) that are the subject of this disclosure, a group of compounds consists of compounds in which:

[1465] A has the formula (A), where:

[1466] R1 means:

[1467] - (C1-C6) alkyl-groups, especially methyl groups;

[1468] - NH2-(C1-C6)alkyl-groups, especially NH2-(CH2)5-groups;

[1469] - A phenyl (C1-C6)alkyl- group, particularly a phenyl-CH2- group, which is unsubstituted or substituted with at least one substituent, especially substituted on the benzene ring with at least one substituent, for example, substituted with a substituent selected from the following:

[1470] - (C1-C6)alkyl-group, particularly methyl (or -CH2-group, if substituted) or isopropyl (or -CH(CH3)2-group, if substituted), which is unsubstituted or substituted with at least one substituent, particularly substituted with a substituent selected from:

[1471] - -NR4R5 group, wherein R4 and R5 are independently selected from: hydrogen atoms and (C1-C2) 16 Alkyl groups, particularly methyl groups, such as -NR4R5 being -NH2 or -NH(CH3); or R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted (C3-C) group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heterocyclic alkyl groups, especially unsubstituted (C3-C) groups containing two nitrogen atoms 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[1472] - (C3-C 10 Cycloalkyl (C1-C6) alkyl- groups, especially cyclohexyl-CH2- groups, which are unsubstituted or substituted, particularly in (C3-C6) alkyl groups. 10 The cycloalkyl group is substituted by at least one substituent, particularly by a substituent selected from the following: -NH2 and NH2-(C1-C6)alkyl groups, such as NH2-CH2- groups;

[1473] R2 means:

[1474] -(C1-C6)alkyl-groups, especially -(CH2)3-CH3 groups;

[1475] -(C1-C6) alkylthio-groups, especially -S-(CH2)2-CH3 groups; or

[1476] -(C1-C6)alkyl-NH- groups, especially -NH-(CH2)2-CH3 groups; and

[1477] R3 means:

[1478] - -OR6 group, where R6 is a (C1-C6) alkyl-group, especially -O-isopropyl (that is, -O-CH(CH3)2 group);

[1479] - -NR7R8 groups, wherein R7 and R8, together with the nitrogen atom to which they are attached, form a heteroatom comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur, particularly a (C3-C) group comprising two nitrogen atoms. 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[1480] - (C3-C 10 () A heterocyclic alkyl group containing one to four heteroatoms selected from oxygen, nitrogen and sulfur, particularly one or two nitrogen atoms, such as dihydropyrrole, such as 2,5-dihydro-1H-pyrrole or piperazine;

[1481] -(La)m-(AA)w-(Lb)p-Lc-Ld'- express:

[1482] -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1483] -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1484] -Cit-Val-C(O)-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[1485] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1486] -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ;

[1487] -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[1488] -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu--C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;

[1489] -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ;or

[1490] -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ,

[1491] single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( This indicates the site where a G group belonging to the -G-BA group is covalently attached;

[1492] G indicates or ;and

[1493] BA stands for antibody, such as monoclonal antibody or VHH antibody.

[1494] Among the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which A has formula (A1) or formula (A2).

[1495] (A1) (A2)

[1496] in:

[1497] R1, R2 and R3 are as defined in this disclosure;

[1498] single asterisk ( ) indicates the site covalently attached to -(P)oL-Ld-G-BA;

[1499] R1 express:

[1500] - Single bond, which means that -(P)oL-Ld-G-BA is directly connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring.

[1501] - Or a divalent group is formed by R1 as defined in this disclosure, which means that -(P)oL-Ld-G-BA is connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring via R1;

[1502] R3 express:

[1503] - Single bond, which means that -(P)oL-Ld-G-BA is directly connected to the carbon atom of the imidazo[4,5-d]pyridazine ring.

[1504] - Or a divalent group is formed by R3 as defined in this disclosure, which means that -(P)oL-Ld-G-BA is connected to the carbon atom of the imidazo[4,5-d]pyridazine ring via R3.

[1505] According to a particular embodiment, A has formula (A1).

[1506] According to another embodiment, A has formula (A2).

[1507] Therefore, according to a specific embodiment, when R1 When representing a single bond, compounds of formula (II2) according to this disclosure or pharmaceutically acceptable salts thereof have the following formula (IIa2):

[1508] (IIa2)

[1509] R2, R3, P, o, L, Ld, G, and BA are as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is a hydrogen atom.

[1510] According to another specific embodiment, when R1 When representing a divalent group formed by R1 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (II2) of this disclosure has the following formula (IIaa2):

[1511] (IIaa2)

[1512] Where R2, R3, P, o, L, Ld, G, and BA are as defined in this disclosure, and R1 It is divalent R1 as defined in this disclosure. This means that in this particular embodiment, in drug A, R1 is not a hydrogen atom.

[1513] According to another specific embodiment, when R3 When representing a single bond, compounds of formula (II2) according to this disclosure or pharmaceutically acceptable salts thereof have the following formula (IIb2):

[1514] (IIb2)

[1515] R1, R2, P, o, L, Ld, G, and BA are as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is a hydrogen atom.

[1516] According to another specific embodiment, when R3 When representing a divalent group formed by R3 as defined in this disclosure, a compound or a pharmaceutically acceptable salt thereof according to formula (II2) of this disclosure has the following formula (IIbb2):

[1517] (IIbb2)

[1518] Where R1, R2, P, o, L, Ld, G, and BA are as defined in this disclosure, and R3 It is divalent R3 as defined in this disclosure. This means that in this particular embodiment, in drug A, R3 is not a hydrogen atom.

[1519] In the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which A is selected from the group consisting of:

[1520] ;

[1521] ;

[1522] ;

[1523] ;

[1524] ;

[1525] ;

[1526] ;

[1527] ;

[1528] ;

[1529] ;as well as

[1530] .

[1531] In the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which A is selected from the group consisting of:

[1532] ;

[1533] ;as well as

[1534] .

[1535] Among the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which P is a -C(O)- group.

[1536] Among the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which P is a -C(O)-O- group.

[1537] Among the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which P is a -S(O2)- group.

[1538] Among the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which P is a -C(O)-C(CH3)2-CH2-O- group.

[1539] Among the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which P is a -C(O)-NH- group.

[1540] In the compounds of formula (II2), which are the subject of this disclosure, a group of compounds consists of compounds in which P is Group.

[1541] In the compounds of formula (II2), which are the subject of this disclosure, a group of compounds consists of compounds in which P is Group.

[1542] In the compounds of formula (II2) which are the subject of this disclosure, there is a group of compounds consisting of such compounds, where o is 0.

[1543] In the compounds of formula (II2), which are the subject of this disclosure, there is a group of compounds consisting of such compounds, where o is 1.

[1544] Among the compounds of formula (II2) that are the subject of this disclosure, a group of compounds consists of compounds in which L represents -(CH2-CH2-O)n- Group, where n represents an integer from 8 to 25, if P exists (that is, if o is 1), single asterisk ( The asterisk () indicates the site covalently attached to the P group, or if P is absent (i.e., if o is 0), the asterisk ( ) indicates the site where the A group is directly attached, and the double asterisk ( ) indicates the site where it is covalently attached to the Ld group.

[1545] Among the compounds of formula (II2) that are the subject of this disclosure, a group of compounds consists of compounds in which L represents -(CH2-CH2-O)n- Group, where n represents 8, 12, 16, 20, 23, or 24, if P is present (that is, if o is 1), single asterisk ( The asterisk () indicates the site covalently attached to the P group, or if P is absent (i.e., if o is 0), the asterisk ( ) indicates the site where the A group is directly attached, and the double asterisk ( ) indicates the site where it is covalently attached to the Ld group.

[1546] In the compounds of formula (II2), which are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(C2-C6)alkyl- Groups, -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group or -(C2-C6)alkyl-C(O)-NH-(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( () indicates the site where a G group belonging to the -G-BA group is covalently attached.

[1547] In the compounds of formula (II2), which are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(CH2)2- Groups, -(CH2)2-NH-C(O)-(CH2)2- Group or -(CH2)2-C(O)-NH-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( () indicates the site where a G group belonging to the -G-BA group is covalently attached.

[1548] In the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which G is selected from the group consisting of:

[1549] ; ; ; ; ; ; ; ; ; ;and ,

[1550] The left side of the G group is connected to BA, and the right side of the G group is connected to Ld.

[1551] In the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which G is selected from the group consisting of:

[1552] ; ; ; ; and .

[1553] In the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which G is selected from the group consisting of:

[1554] ; ; ;and .

[1555] In the compounds of formula (II2), which are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the ) indicates the site of covalent attachment to a G group belonging to the -G-BA group, then G is The left side of the G group is connected to BA, and the right side of the G group is connected to Ld.

[1556] In the compounds of formula (II2), which are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the ) indicates the site of covalent attachment to a G group belonging to the -G-BA group, then G is The right side of the G group is connected to BA, and the left side of the G group is connected to Ld.

[1557] In the compounds of formula (II2), which are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the ) indicates the site of covalent attachment to a G group belonging to the -G-BA group, then G is The left side of the G group is connected to BA, and the right side of the G group is connected to Ld.

[1558] In the compounds of formula (II2), which are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the ) indicates the site of covalent attachment to a G group belonging to the -G-BA group, then G is The left side of the G group is connected to BA, and the right side of the G group is connected to Ld.

[1559] In the compounds of formula (II2), which are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the ) indicates the site of covalent attachment to a G group belonging to the -G-BA group, then G is The right side of the G group is connected to BA, and the left side of the G group is connected to Ld.

[1560] In the compounds of formula (II2), which are the subject of this disclosure, a group of compounds consists of compounds in which Ld represents -(CH2)2-NH-C(O)-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( When the ) indicates the site of covalent attachment to a G group belonging to the -G-BA group, then G is The left side of the G group is connected to BA, and the right side of the G group is connected to Ld.

[1561] In the compounds of formula (II2) which are the subject of this disclosure, there is a group of compounds consisting of compounds in which BA is an antibody Ab.

[1562] In the compounds of formula (II2) which are the subject of this disclosure, a group of compounds consists of compounds in which BA is a monoclonal antibody, such as teretetumab (CAS [2349294-95-5]) and a variant of avirumab.

[1563] Among the compounds of formula (II2) that are the subject of this disclosure, there is a group of compounds consisting of compounds in which BA is a VHH antibody.

[1564] All of these subgroups, whether used individually or in combination, are part of this disclosure.

[1565] According to specific embodiments, this disclosure relates to compounds / conjugates of formula (II2) or pharmaceutically acceptable salts thereof, wherein the -(P)ol-Ld- portion is selected from the group consisting of:

[1566] -C(O)-(CH2-CH2-O) 24 -CH2-CH2- ;

[1567] -(CH2-CH2-O) 23 -CH2-CH2- ;

[1568] -C(O)-(CH2-CH2-O) 20 -CH2-CH2- ;

[1569] -C(O)-(CH2-CH2-O) 16 -CH2-CH2- ;

[1570] -C(O)-(CH2-CH2-O) 12 -CH2-CH2- ;

[1571] -C(O)-(CH2-CH2-O)8-CH2-CH2- ;

[1572] -C(O)-C(CH3)2-CH2-O-(CH2-CH2-O) 20 -CH2-CH2- ;

[1573] -C(O)-O-(CH2-CH2-O) 20 -CH2-CH2- ;

[1574] -C(O)-NH-(CH2-CH2-O) 20 -CH2-CH2- ;

[1575] ;

[1576] ;

[1577] -C(O)-(CH2-CH2-O) 24 -CH2-CH2-NH-C(O)-CH2-CH2- ;

[1578] -C(O)-(CH2-CH2-O) 20 -CH2-CH2-NH-C(O)-CH2-CH2- ;as well as

[1579] -C(O)-(CH2-CH2-O) 12 -CH2-CH2-NH-C(O)-CH2-CH2- ;

[1580] single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( This indicates the site where the G group, which belongs to the -G-BA group, is covalently attached.

[1581] Among the compounds of formula (II2) that are the subject of this disclosure, a group of compounds consists of compounds in which:

[1582] A has the formula (A), where:

[1583] R1 means:

[1584] - (C1-C6) alkyl-groups, especially methyl groups;

[1585] - NH2-(C1-C6)alkyl-groups, especially NH2-(CH2)5-groups;

[1586] - A phenyl (C1-C6)alkyl- group, particularly a phenyl-CH2- group, which is unsubstituted or substituted with at least one substituent, especially substituted on the benzene ring with at least one substituent, for example, substituted with a substituent selected from the following:

[1587] - (C1-C6)alkyl-group, particularly methyl (or -CH2-group, if substituted) or isopropyl (or -CH(CH3)2-group, if substituted), which is unsubstituted or substituted with at least one substituent, particularly substituted with a substituent selected from:

[1588] - -NR4R5 group, wherein R4 and R5 are independently selected from: hydrogen atoms and (C1-C2) 16 Alkyl groups, particularly methyl groups, such as -NR4R5 being -NH2 or -NH(CH3); or R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted (C3-C) group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heterocyclic alkyl groups, especially unsubstituted (C3-C) groups containing two nitrogen atoms 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[1589] - (C3-C 10 Cycloalkyl (C1-C6) alkyl- groups, especially cyclohexyl-CH2- groups, which are unsubstituted or substituted, particularly in (C3-C6) alkyl groups. 10 The cycloalkyl group is substituted by at least one substituent, particularly by a substituent selected from the following: -NH2 and NH2-(C1-C6)alkyl groups, such as NH2-CH2- groups;

[1590] R2 means:

[1591] -(C1-C6)alkyl-groups, especially -(CH2)3-CH3 groups;

[1592] -(C1-C6) alkylthio-groups, especially -S-(CH2)2-CH3 groups; or

[1593] -(C1-C6)alkyl-NH- groups, especially -NH-(CH2)2-CH3 groups; and

[1594] R3 means:

[1595] - -OR6 group, where R6 is a (C1-C6) alkyl-group, especially -O-isopropyl (that is, -O-CH(CH3)2 group);

[1596] - -NR7R8 groups, wherein R7 and R8, together with the nitrogen atom to which they are attached, form a heteroatom comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur, particularly a (C3-C) group comprising two nitrogen atoms. 10 ) heterocyclic alkyl-groups, such as piperazine-groups; or

[1597] - (C3-C10 () A heterocyclic alkyl group containing one to four heteroatoms selected from oxygen, nitrogen and sulfur, particularly one or two nitrogen atoms, such as dihydropyrrole, such as 2,5-dihydro-1H-pyrrole or piperazine;

[1598] -(P)oL-Ld- express:

[1599] -C(O)-(CH2-CH2-O) 24 -CH2-CH2- ;

[1600] -(CH2-CH2-O) 23 -CH2-CH2- ;

[1601] -C(O)-(CH2-CH2-O) 20 -CH2-CH2- ;

[1602] -C(O)-(CH2-CH2-O) 16 -CH2-CH2- ;

[1603] -C(O)-(CH2-CH2-O) 12 -CH2-CH2- ;

[1604] -C(O)-(CH2-CH2-O)8-CH2-CH2- ;

[1605] -C(O)-C(CH3)2-CH2-O-(CH2-CH2-O) 20 -CH2-CH2- ;

[1606] -C(O)-O-(CH2-CH2-O) 20 -CH2-CH2- ;

[1607] -C(O)-NH-(CH2-CH2-O) 20 -CH2-CH2- ;

[1608] ;

[1609] ;

[1610] -C(O)-(CH2-CH2-O) 24 -CH2-CH2-NH-C(O)-CH2-CH2- ;

[1611] -C(O)-(CH2-CH2-O) 20 -CH2-CH2-NH-C(O)-CH2-CH2- ;or

[1612] -C(O)-(CH2-CH2-O) 12 -CH2-CH2-NH-C(O)-CH2-CH2- ;

[1613] single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( This indicates the site where a G group belonging to the -G-BA group is covalently attached;

[1614] G indicates , , or ;and

[1615] BA stands for antibody, such as monoclonal antibody or VHH antibody.

[1616] In the compounds / conjugates of formulas (II), (II1), or (II2) that are the subject of this disclosure, the following compounds may be mentioned, for example:

[1617]

[1618]

[1619]

[1620]

[1621]

[1622]

[1623]

[1624]

[1625]

[1626]

[1627] ；

[1628] ；

[1629] ；

[1630] ；

[1631] ；

[1632] ；

[1633] ；

[1634] ；

[1635] ；

[1636] ；

[1637] ；

[1638] ；

[1639] ；

[1640] ；

[1641] ；

[1642] ；

[1643] ；

[1644] ;

[1645] ;

[1646] ;

[1647] ;

[1648] ;

[1649] ;

[1650] ;

[1651] ;

[1652] ;

[1653] ;

[1654] ;

[1655] ;

[1656] ;

[1657] ;

[1658] ;

[1659] ;

[1660] ;

[1661] ;

[1662] and

[1663] ,

[1664] Ab represents antibody, such as monoclonal antibody or VHH antibody.

[1665] Among the compounds of formulas (II), (II1), and (II2) that are the subject of this disclosure, a group of compounds consists of compounds in which BA is a monoclonal antibody, for example:

[1666] Tseretidone (CAS [2349294-95-5]),

[1667] Avelumab_K76R-K100R,

[1668] Avelumab_K360C,

[1669] Avelumab_LALA-K360C

[1670] 769_VarB_VH7 / VL2、

[1671] p01_CEA_1_07、

[1672] p01_CEA_1_07_A118C、

[1673] p01_CEA_1_07_E152C、

[1674] p01_CEA_1_07_K360C、

[1675] p01_CEA_1_07_K414C、

[1676] p07_CEA_3_50_VH1_A118C、

[1677] p07_CEA_3_50_VH1_K360C、

[1678] p07_CEA_3_50_VH1_K414C、

[1679] p01_CEA_1_07_A118C_K360C、

[1680] p01_CEA_1_07_E152C_K360C、

[1681] p01_CEA_1_07_K274C_K414C、

[1682] p07_CEA_3_50_VH1_A118C_K360C,

[1683] p07_CEA_3_50_VH1_K274C_K414C,

[1684] In particular, in the compounds / conjugates of formulas (II), (II1), or (II2) that are the subject of this disclosure, references may be made to, for example, the following compounds:

[1685] (c1) CEACAM5_Texatumab-P5 ADC (Example 13)

[1686] (c2) PDL1_Averumab_K76R-K100R-P5 ADC (Example 14)

[1687] (c3) CEACAM5_Texatumab-P8 ADC (Example 15)

[1688] (c4) PDL1_Averumab_K76R-K100R-P8 ADC (Example 16)

[1689] (c5) CEACAM5_Texatumab-P3 ADC (Example 17)

[1690] (c6) PDL1_Averumab_K76R_K100R-P3 ADC (Example 18)

[1691] (c7) CEACAM5_Texatumab-Example 3 ADC (Example 19)

[1692] (c8) PDL1_Averumab_K76R_K100R - Example 3 ADC (Example 20)

[1693] (c9) CEACAM5_Texatumab-Example 5 ADC (Example 21)

[1694] (c10) PDL1_Averumab_K76R_K100R - Example 5 ADC (Example 22)

[1695] (c11) PDL1_Averumab_K360C-Example 6 ADC (Example 23)

[1696] (c12) PDL1_Averumab_LALA_K360C - Example 6 ADC (Example 24)

[1697] (c13) CEACAM5_Texatumab-Example 2 ADC (Example 25)

[1698] (c14) PDL1_Averrucumab_K76R_K100R-Example 2 ADC (Example 26))

[1699] (c15) CEACAM5_Texatumab-Example 7 ADC (Example 27)

[1700] (c16) PDL1_Averumab_K76R_K100R - Example 7 ADC (Example 28)

[1701] (c17) CEACAM5_Texatumab-Example 11b ADC (Example 29)

[1702] (c18) PDL1_Averumab_K76R_K100R - Example 11b ADC (Example 30)

[1703] (c19) CEACAM5_Texatumab-Example 8 ADC (Example 31)

[1704] (c20) PDL1_Averumab_K76R_K100R - Example 8 ADC (Example 32)

[1705] (c21) PDL1_Averumab_K360C-P16 ADC (Example 33)

[1706] (c22) PDL1_Averumab_K360C-Example 10 ADC (Example 34)

[1707] (c23) PDL1_Averumab_LALA_K360C-Example 10 ADC (Example 35)

[1708] (c24) PDL1_Averumab_K360C-P14 ADC (Example 36)

[1709] (c25) PDL1_Averumab_LALA_K360C-P14 ADC (Example 37)

[1710] (c26) PDL1_Averumab_K76R_K100R - Example 12 ADC (Example 38)

[1711] (c27) CEACAM5_Texatumab-Example 11a ADC (Example 39)

[1712] (c28) PDL1_Averumab_K76R_K100R-Example 11a ADC (Example 40)

[1713] (c29) CEACAM5_Texatumab-Example 43 ADC (Example 62)

[1714] (c30) PDL1_Averumab_K76R_K100R-Example 43 ADC (Example 63)

[1715] (c31) CEACAM5_Texatumab-Example 45 ADC (Example 64)

[1716] (c32) CEACAM5_769_VarB_VH7 / VL2 - Example 45 ADC (Example 65)

[1717] (c33) CEACAM5_p01_CEA_1_07-Example 45 ADC (Example 66)

[1718] (c34) PDL1_Averumab_K76R_K100R - Example 45 ADC (Example 67)

[1719] (c35) CEACAM5_p01_CEA_1_07-Example 46 ADC (DAR4) (Example 68)

[1720] (c36) CEACAM5_p01_CEA_1_07-Example 46 ADC (DAR8) (Example 69)

[1721] (c37) CEACAM5_p01_CEA_1_07_A118C - Example 46 ADC (Example 70)

[1722] (c38) CEACAM5_p01_CEA_1_07_E152C - Example 46 ADC (Example 71)

[1723] (c39) CEACAM5_p01_CEA_1_07_K360C - Example 46 ADC (Example 72)

[1724] (c40) CEACAM5_p01_CEA_1_07_K414C - Example 46 ADC (Example 73)

[1725] (c41) CEACAM5_p07_CEA_3_50_VH1_A118C - Example 46 ADC (Example 74)

[1726] (c42) CEACAM5_p07_CEA_3_50_VH1_K360C - Example 46 ADC (Example 75)

[1727] (c43) CEACAM5_p07_CEA_3_50_VH1_K414C - Example 46 ADC (Example 76)

[1728] (c44) CEACAM5_p01_CEA_1_07_A118C_K360C - Example 46 ADC (Example 77)

[1729] (c45) CEACAM5_p01_CEA_1_07_E152C_K360C - Example 46 ADC (Example 78)

[1730] (c46) CEACAM5_p01_CEA_1_07_K274C_K414C - Example 46 ADC (Example 79)

[1731] (c47) CEACAM5_p07_CEA_3_50_VH1_A118C_K360C - Example 46 ADC (Example 80)

[1732] (c48) CEACAM5_p07_CEA_3_50_VH1_K274C_K414C - Example 46 ADC (Example 81)

[1733] (c49) PDL1_Averumab_K360C-Example 46 ADC (Example 82)

[1734] (c50) PDL1_Averumab_LALA_K360C-Example 46 ADC (Example 83)

[1735] (c51) CEACAM5_p01_CEA_1_07_K360C - Example 47 ADC (Example 84)

[1736] (c52) CEACAM5_p01_CEA_1_07_K360C-P36 ADC (Example 85)

[1737] (c53) PDL1_Averumab_K360C-P36 ADC (Example 86)

[1738] (c54) CEACAM5_p01_CEA_1_07_K360C - Example 48 ADC (Example 87)

[1739] (c55) PDL1_Averumab_K360C-Example 48 ADC (Example 88)

[1740] (c56) CEACAM5_p01_CEA_1_07_K360C-Example 49 ADC (Example 89)

[1741] (c57) PDL1_Averumab_K360C-Example 49 ADC (Example 90)

[1742] (c58) CEACAM5_Texatumab-Example 42 ADC (Example 91)

[1743] (c59) PDL1_Averumab_K76R_K100R-Example 42 ADC (Example 92)

[1744] (c60) CEACAM5_Texatumab-Example 41 ADC (Example 93)

[1745] (c61) PDL1_Averumab_K76R_K100R-Example 41 ADC (Example 94)

[1746] (c62) CEACAM5_Texatumab-P29 ADC (Example 95)

[1747] (c63) PDL1_Averumab_K76R_K100R-P29 ADC (Example 96)

[1748] (c64) CEACAM5_Texatumab-P32 ADC (Example 97)

[1749] (c65) PDL1_Averumab_K76R_K100R-P32 ADC (Example 98)

[1750] (c66) CEACAM5_Texatumab-P27 ADC (Example 99)

[1751] (c67) PDL1_Averumab_K76R_K100R-P27 ADC (Example 100)

[1752] (c68) CEACAM5_Texatumab-P25 ADC (Example 101)

[1753] (c69) PDL1_Averumab_K76R_K100R-P25ADC (Example 102)

[1754] (c70) CEACAM5_p07_CEA_3_50_VH1_K360C-P39 ADC (Example 103)

[1755] (c71) CEACAM5_p07_CEA_3_50_VH1_A118C_K360C-P39 ADC (Example 104)

[1756] (c72) CEACAM5_p07_CEA_3_50_VH1_K360C-P40 ADC (Example 105)

[1757] (c73) CEACAM5_p07_CEA_3_50_VH1_A118C_K360C-P40 ADC (Example 106)

[1758] (c74) CEACAM5_Texatumab-Example 50 ADC (Example 107)

[1759] (c75) PDL1_Averumab_K76R_K100R-Example 50 ADC (Example 108)

[1760] (c76) PDL1_Averumab_K360C-P45 ADC (Example 109)

[1761] (c77) CEACAM5_769_VarB_VH7 / VL2-P47 ADC (Example 110)

[1762] (c78) CEACAM5_p01_CEA_1_07-P47 ADC (Example 111)

[1763] (c79) CEACAM5_p01_CEA_1_07-Example 51 ADC (DAR4) (Example 112)

[1764] (c80) CEACAM5_p01_CEA_1_07-Example 51 ADC (DAR8) (Example 113)

[1765] (c81) PDL1_Averumab_K360C-Example 51 ADC (Example 114)

[1766] (c82) PDL1_Averumab_LALA_K360C-Example 51 ADC (Example 115)

[1767] (c83) CEACAM5_p01_CEA_1_07_A118C - Example 51 ADC (Example 116)

[1768] (c84) CEACAM5_p01_CEA_1_07_E152C - Example 51 ADC (Example 117)

[1769] (c85) CEACAM5_p01_CEA_1_07_K360C - Example 51 ADC (Example 118)

[1770] (c86) CEACAM5_p01_CEA_1_07_K414C - Example 51 ADC (Example 119)

[1771] (c87) CEACAM5_p01_CEA_1_07_A118C_K360C - Example 51 ADC (Example 120)

[1772] (c88) CEACAM5_p01_CEA_1_07_E152C_K360C - Example 51 ADC (Example 121)

[1773] (c89) CEACAM5_p01_CEA_1_07_K274C_K414C - Example 51 ADC (Example 122)

[1774] (c90) CEACAM5_Texatumab-Example 57 ADC (Example 123)

[1775] (c91) CEACAM5_Texatumab-Example 58 ADC (Example 124)

[1776] (c92) CEACAM5_Texartumab-Example 59 ADC (Example 125)

[1777] (c93) CEACAM5_Texartumab-Example 60 ADC (Example 126)

[1778] (c94) CEACAM5_Texartumab-Example 61 ADC (Example 127)

[1779] (c95) PDL1_Averumab_K360C-P52 ADC (Example 128)

[1780] (c96) PDL1_Averumab_LALA_K360C-P52 ADC (Example 129)

[1781] (c97) PDL1_Averumab_K76R_K100R-Example 54 ADC (Example 130)

[1782] (c98) CEACAM5_Texatumab-Example 53 ADC (Example 131)

[1783] (c99) PDL1_Averumab_K76R_K100R-Example 53 ADC (Example 132)

[1784] (c100) CEACAM5_Texatumab-Example 55 ADC (Example 133)

[1785] (c101) CEACAM5_Texatumab-Example 56 ADC (Example 134)

[1786] (c102) PDL1_Averumab_K360C-Example 52 ADC (Example 135)

[1787] (c103) CEACAM5_Texatumab-P42 ADC (Example 136)

[1788] (c104) PDL1_Averumab_K76R_K100R-P42 ADC (Example 137)

[1789] The compounds / conjugates of formulas (II), (II1), and (II2) according to this disclosure, or their pharmaceutically acceptable salts, can be prepared by any method known to those skilled in the art, and for example by the following method. The method is also detailed in the experimental section of this disclosure.

[1790] Compounds / conjugates of formulas (II), (II1), and (II2) can also be prepared by the following methods

[1791] (i) Make the following come into contact and react:

[1792] - An optional buffered aqueous solution of a binder (e.g., an antibody Ab) as defined in this disclosure, the binder comprising a reactive RCG2 group optionally modified by a modifier.

[1793] as well as

[1794] - Solutions of compounds / loads of formula (I), (I1) or (I2) as defined in this disclosure, wherein the compound / load contains a reactive RCG1 group;

[1795] The RCG1 group of the compound / load of formula (I), (I1) or (I2) is reactive to the RCG2 group of the binder (e.g., antibody) as defined in this disclosure to form a G group by covalent bond and form a compound / conjugate of formula (II), (II1) or (II2).

[1796] (ii) and then optionally, the compounds of formula (II), (II1) or (II2) formed in step (i) are separated from unreacted compounds of formula (I), (I1) or (I2); and / or from unreacted antibodies; and / or from any aggregates that may have formed.

[1797] Examples of RCG2 present on binders (e.g., antibodies) as defined in this disclosure may be mentioned (Garnett MC et al., Advanced Drug Delivery Reviews, 2001, 53, 171-216):

[1798] (i) An ε-amino group (ε-NH2 group) carried by a side chain of a lysine residue present on the surface of a binder (e.g., an antibody) as defined in this disclosure.

[1799] (ii) The α-amino group (α-NH2 group) of the N-terminal amino acid of the heavy or light chain of the binder (e.g., antibody) as defined in this disclosure.

[1800] (iii) Sugar groups in the hinge region;

[1801] (iv) The thiol group (-SH group) of cysteine ​​residues generated by reducing the intrachain disulfide bond of a binder (e.g., antibody) as defined in this disclosure, or the -SH group of engineered cysteine ​​residues of a binder (e.g., antibody) as defined in this disclosure.

[1802] (v) An amide group (-C(O)NH2 group) carried by a side chain of a glutamine residue present on the surface of a binder (e.g., an antibody) as defined in this disclosure.

[1803] (vi) The use of formicylglycine synthase to introduce aldehyde groups (-C(O)H groups); and

[1804] (vii) RCG2 groups introduced optionally by means of a modifier.

[1805] According to specific embodiments, in compounds of formula (II), (II1) or (II2) as defined in this disclosure, RCG2 is a reactive group of the cysteine-engineered amino acid residue of the antibody.

[1806] For example, in compounds of formulas (II), (II1), or (II2) as defined in this disclosure, the cysteine-engineered amino acid residue is located at at least one position according to an EU number index, the at least one position being selected from heavy chain constant (C H The interchain cysteine ​​residues 118, 152, 360, 274, and 414 of the ) domain, particularly the engineered cysteine ​​amino acid residues in the heavy chain constant (C) according to the EU number index. H The location of the structural domain is at position 360.

[1807] Recently, other site-specific conjugation approaches have been considered, such as introducing cysteine ​​through mutation (Junutula J.R. et al., Nature Biotechnology 2008, 26, 925-932), introducing non-natural amino acids to allow for other types of chemistry (Axup JY et al., PNAS 2012, 109, 40, 16101-16106), or conjugating on antibody-glycans (Zhou Q. et al., Bioconjugate Chem. 2014, 25, 510-520). The use of cysteine ​​bridging dibromomaleimide (Behrens C.R. et al., Mol. Pharmaceutics 2015, 3986-3998) and disulfone reagents (Bryant P. et al., Mol. Pharmaceutics 2015, 1872-1879) to crosslink antibodies has also been described and may be applicable to this disclosure.

[1808] Another approach to site-specific modification of antibodies is based on enzymatic conjugation, using, for example, bacterial transglutaminase (Jeger S. et al., Angew. Chem. Int. Ed. [Applied Chemistry International Edition] 2010, 49, 9995-9997; Strop P. et al., Chem. Biol. [Chemical Biology] 2013, 20, 161-167) or formylglycine synthase (Hudak JE et al., Angew. Chem. Int. Ed. [Applied Chemistry International Edition] 2012, 51, 4161-4165). For a review of site-specific conjugation strategies, see Agarwal P. and Bertozzi CR, Bioconjugate Chem [Bioconjugate Chemistry] 2015, 26, 176-192. These conjugation techniques can also be applied to compounds / payloads of formulas (I), (I1), or (I2) as described in this disclosure.

[1809] Binders (e.g., antibodies) as defined in this disclosure can also be chemically modified to introduce novel RCG2 reactive groups. Therefore, those skilled in the art are well aware of how binders (e.g., antibodies) as defined in this disclosure can be modified by introducing modifiers such as activated disulfides, thiols, maleimides, haloacetamides, azides, alkynes, or cycloalkynes (see, in particular, page 14 of WO 2005 / 077090 and WO 2011 / 001052). Modification allows for improved conjugation reactions and the use of a wider variety of RCG1 groups present on compounds / loads of formula (I), (I1), or (I2).

[1810] For example, in the case where RCG1 is of type (ii) as defined above, that is, one of the following reactive groups: maleimide group Group; substituted maleimide group, such as ; Haloacetamide group Group, wherein R 21 Indicates a hydrogen atom or (C1-C6) alkyl group, such as methyl; Cl-; N3-; HO-; HS-; activated disulfide, such as ;H2N-;HC≡C- or activated C≡C, such as cyclooctyne moieties, for example, DBCO-amines or BCN or MFCO ; Phenylacetazole methyl sulfone group (PODS), such as ; Group; Groups; -O-alkylhydroxylamine or Pickett-Spengler reaction substrates, such as For example, RCG1 is an N3-, maleimide group. Substituted maleimide group phenyloxadiazole methyl sulfone group ; Group; or Group,

[1811] Antibodies can be chemically modified using appropriate modifiers or by introducing one or more non-natural amino acids to introduce a suitable RCG2 group. For example:

[1812] - When RCG1 represents N-hydroxysuccinimide ester, RCG2 represents -NH2 group;

[1813] - When RCG1 represents a maleimide functional group, a haloacetamide functional group, a chlorine atom, or an activated disulfide functional group, RCG2 can be a -SH group;

[1814] - When RCG1 represents the -N3 group, RCG2 can be a -C=CH functional group or an activated C=C functional group, such as a cyclooctyne moiety;

[1815] - When RCG1 represents a -OH group or a -NH2 group, RCG2 can be a carboxylic acid or amide functional group;

[1816] - When RCG1 represents a -SH group, RCG2 can be a maleimide functional group, a haloacetamide functional group, or an activated disulfide functional group.

[1817] - When RCG1 represents a -C=CH functional group or an activated -C=C functional group, RCG2 can be a -N3 group;

[1818] - When RCG1 represents an O-alkylhydroxylamine functional group or a Pickett-Spengler reaction substrate, RCG2 can be an aldehyde or ketone functional group.

[1819] As indicated above, instances of G that may be mentioned include:

[1820] ; ; ; ; ; ; ; ; ; ;and ,

[1821] For example, the left side of the G group is connected to BA, and the right side of the G group is connected to L1.

[1822] For example, G represents the following groups:

[1823] ; ; or Such as or .

[1824] • Synthesis of Modifiers

[1825]

[1826] Option 5

[1827] Step (i): Coupling of dibenzocyclooctyne-amine with glutaric anhydride;

[1828] Step (ii): Activate the carboxylic acid to an activated ester by the following method:

[1829] • Treat with DSC in the presence of a base (such as DIEA); or

[1830] • Treat with sodium N-hydroxysuccinimide sulfonate in the presence of a coupling agent (such as DCC); or

[1831] • Treat with 4-hydroxyphenyl dimethyl sulfonate in the presence of a coupling agent (such as DIC); or

[1832] • Treat with sodium 2,3,5,6-tetrafluoro-4-hydroxybenzenesulfonate in the presence of a coupling agent (such as DIC).

[1833] Scheme 5 describes a synthesis starting with dibenzocyclooctyne-amine (CAS No. [1255942-06-3]), but it is also applicable to other commercially available cyclooctyne-amines. It describes a synthesis using glutaric anhydride, but it is also applicable to commercially available succinic anhydride or alkyl diacid with an n range of 3 to 10.

[1834] Preparation of compounds / conjugates of formulas (II), (II1), and (II2):

[1835] The compounds / conjugates of formula (II), (II1), or (II2) disclosed herein, or their pharmaceutically acceptable salts, can be obtained via a method comprising at least the following steps:

[1836] (i) Make the following come into contact and react:

[1837] - An optional buffered aqueous solution of a binder (e.g., an antibody Ab) as defined in this disclosure, the binder comprising a reactive RCG2 group optionally modified by a modifier.

[1838] as well as

[1839] - Solutions of compounds / loads of formula (I), (I1), or (I2) as defined in this disclosure, wherein the compound / load contains a reactive RCG1 group,

[1840] The RCG1 group of the compound / load of formula (I), (I1) or (I2) is reactive to the RCG2 group of the binder (e.g., antibody) as defined in this disclosure to form a G group by covalent bond and to form a compound / conjugate of formula (II), (II1) or (II2).

[1841] According to a variant of step (ii), for example, the compound / conjugate of formula (II), (II1) or (II2) from step (i) is separated from the unreacted compound / load of formula (I), (I1) or (I2); separated from any aggregates formed; and / or separated from any unreacted binder as defined in this disclosure (e.g., any unreacted antibody).

[1842] The function of the contact is to react the RCG1 group with the RCG2 group to ensure that the compound / load of formula (I), (I1), or (I2) is attached to a binder (e.g., an antibody) as defined in this disclosure by forming a covalent bond; such as:

[1843] • When RCG1 represents a chlorine atom, a maleimide group, or a haloacetamide group, a binder (e.g., an antibody) as defined in this disclosure may contain a thiol group;

[1844] • When RCG1 represents an azide group, a binder (e.g., an antibody) as defined in this disclosure may contain a -C=CH moiety or an activated C≡C, such as a cyclooctyne group;

[1845] • When RCG1 represents the -NH2 group, enzyme catalysis can be used to react on the amide functional group of the antibody, such as the amide group carried by the side chain of the glutamine (Gln) residue of the binder (e.g., antibody) as defined in this disclosure.

[1846] • When RCG1 represents HC≡C- or an activated C≡C group (such as a cyclooctyne moiety), the binder (e.g., an antibody) as defined in this disclosure may contain an azide group.

[1847] The term “aggregate” refers to an association that can be formed between two or more binders (e.g., two or more antibodies) as defined in this disclosure, which may have been modified by conjugation. Aggregates are readily formed under the influence of a variety of parameters, such as high concentrations of binders (e.g., antibodies) in solution as defined in this disclosure, pH of the solution, high shear stress, amount of transplanted drug and its hydrophobic properties, and temperature (see references cited in the introduction to J. Membrane Sci. 2008, 318, 311-316), however, some of which have not been clearly elucidated. In the case of proteins or antibodies, see AAPS Journal, “Protein Aggregation and Bioprocessing” 2006, 8(3), E572-E579. The aggregate content can be determined by known techniques such as SEC (see Analytical Biochemistry 1993, 212(2), 469-480 for this purpose).

[1848] Aqueous solutions of binders (e.g., antibodies) as defined in this disclosure may be buffered with buffers (e.g., potassium phosphate or HEPES, or mixtures of buffers such as buffers A, B, C, D, and E as described below). The buffer depends on the properties of the binder (e.g., antibody) as defined in this disclosure. Compounds / loads of formula (I), (I1), or (I2) may be dissolved in a polar organic solvent such as DMSO or DMA.

[1849] The reaction occurs generally at temperatures ranging from 20°C to 40°C. Reaction times can range from 1 to 24 hours. The reaction between a binder (e.g., an antibody) as defined in this disclosure and a compound / load of formula (I), (I1), or (I2) can be monitored by SEC using refractive indexing and / or a UV detector and / or HRMS to determine its progression. If the degree of substitution is insufficient, the reaction can be prolonged and / or a compound / load of formula (I), (I1), or (I2) can be added. Further details regarding specific conditions can be found in the Examples section. Specific examples are described in Examples 9 through 40.

[1850] Those skilled in the art are familiar with various chromatographic techniques available for use in the separation of step (ii): the compounds / conjugates of formula (II), (II1), or (II2) can be purified, for example, by size exclusion chromatography (SEC), adsorption chromatography (e.g., ion exchange, IEC), hydrophobic interaction chromatography (HIC), affinity chromatography, chromatography on a mixed support (such as ceramic hydroxyapatite), or HPLC. Purification by dialysis or percolation may also be used.

[1851] Following step (i) or (ii), the solution of the compound / conjugate of formula (II), (II1), or (II2) may undergo ultrafiltration and / or percolation steps (iii). After these steps, the compound / conjugate of formula (II), (II1), or (II2) is thus obtained in aqueous solution.

[1852] This disclosure also relates to compounds of formula (II), (II1) or (II2) that can be obtained by one or more methods according to this disclosure.

[1853] binder

[1854] As mentioned above, a "binding agent" refers to a molecule that has an affinity for a biological target, such as ligands, proteins, peptides, antibodies (such as monoclonal antibodies or VHH antibodies), peptides, oligonucleotides, or oligosaccharides (e.g., targeting agents, such as cell binders). The function of a binding agent is to direct biologically active compounds (such as TLR7 and / or 8 agonist compounds) to the biological target.

[1855] Cell binding agents

[1856] As mentioned above, cell binders can be of any type currently known or becoming known, and include both peptides and non-peptides. Cell binders can be any compound that can bind to cells in a specific or non-specific manner. Typically, these can be antibodies (especially monoclonal antibodies), lymphokines, hormones, growth factors, vitamins, nutrient transport molecules (such as transferrin), or any other cell-binding molecule or substance.

[1857] More specific examples of cell-binding agents that can be used include:

[1858] (a) Polyclonal antibodies;

[1859] (b) Monoclonal antibodies;

[1860] (c) Antibody fragments, such as Fab, Fab1, and F(ab')2, Fv (Parham, J. Immunol. [Journal of Immunology] 131:2895-2902 (1983); Spring et al. J. Immunol. [Journal of Immunology] 113:470-478 (1974); Nisonoff et al. Arch. Biochem. Biophys. [Archives of Biochemistry and Biophysics] 89:230-244 (1960));

[1861] (d) Interferons (e.g., α, β, γ);

[1862] (e) Lymphokines, such as IL-2, IL-3, IL-4, and IL-6;

[1863] (f) Hormones, such as insulin, TRH (thyrotropin-releasing hormone), MSH (melanocyte-stimulating hormone), and steroid hormones (such as androgens and estrogens).

[1864] (g) Growth factors and colony-stimulating factors, such as EGF, TGF-α, FGF, VEGF, G-CSF, M-CSF, and GM-CSF (Burgess, Immunology Today 5:155-158 (1984)); or

[1865] (h) transferrin (O'Keefe et al. J. Biol. Chem. [Journal of Biochemistry] 260:932-937(1985)); and (i) vitamins, such as folic acid.

[1866] According to specific embodiments, the binder (also referred to as BA in this text) may be an antibody (also referred to as Ab in this text), such as a monoclonal antibody or a VHH antibody.

[1867] Antibody

[1868] Antibodies can be monoclonal antibodies selected from groups consisting of mouse antibodies, chimeric antibodies, humanized antibodies, and human antibodies.

[1869] In one embodiment, the antibody is a monospecific antibody, that is, an antibody that specifically binds to a single target. Alternatively, it can be a multispecific antibody.

[1870] In one embodiment, the antibody is an IgG antibody, such as an IgG1, IgG2, IgG3, or IgG4 antibody.

[1871] According to this disclosure, antibodies specifically bind to targets, thereby directing compounds / conjugates of formula (II), (II1), or (II2) toward the targets. As used herein, "specific binding," "specifically binding with," or "binding with" means that the antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Specific binding can occur through at least about 1 x 10- -8 M or smaller (e.g., K) D The smaller the value, the tighter the bond (K). D Characterization is performed using methods well known in the art for determining whether two molecules specifically bind, including, for example, equilibrium dialysis, surface plasmon resonance, etc. As described herein, antibodies have been characterized, for example, by using surface plasmon resonance (e.g., BIACORE™) to demonstrate the specific binding of antibodies to targets and / or target antigens.

[1872] Targets typically correspond to proteins expressed on the cell surface, such as proteins expressed on the surface of tumor cells.

[1873] In one embodiment, the target is the CEACAM5 receptor. The CEACAM5 receptor is a member of the carcinoembryonic antigen-associated cell adhesion molecule (CEACAM) receptor family and is also referred to as "CEA cell adhesion molecule 5" or "CD66e". Antibodies that specifically bind to the CEACAM5 receptor may, for example, correspond to one of the antibodies described in WO 2014 / 079886 (US 9617345B2).

[1874] In one embodiment, the target is programmed cell death ligand 1 (PDL1). PDL1 is a transmembrane protein considered a co-inhibitory factor of the immune response. An antibody that specifically binds to PDL1 may, for example, correspond to one of the antibodies described in WO2013 / 079174A1.

[1875] Antibodies may optionally be modified with a modifier to facilitate the attachment of compounds / payloads of formulas (I), (I1), or (I2) as described above. Antibodies may be, in particular, monoclonal, polyclonal, or multispecific. They may also be antibody fragments. They may also be mouse antibodies, human antibodies, humanized antibodies, or chimeric antibodies. The antibodies used in the examples disclosed herein are:

[1876] • Teretazomab (CAS [2349294-95-5]), an antibody targeting the CEACAM5 receptor. Following the procedure described in WO 2014 / 079886 (US 9617345B2), the sequence of teretazomab (CAS [2349294-95-5]) is represented by SEQ ID NO: 88 (light chain of antibody teretazomab (CAS [2349294-95-5])) and by SEQ ID NO: 87 (heavy chain of antibody teretazomab (CAS [2349294-95-5])). For the amino acid sequence of teretazomab, it can also be referenced to SEQ ID NO. 1 (light chain) and SEQ ID NO. 2 (heavy chain) disclosed below.

[1877] • Avirumab_K76R-K100R, an antibody targeting PDL1. It corresponds to the antibody avirumab (CAS [1537032-82-8]), where Lys 76 and Lys 100 have been replaced by Arg. For the amino acid sequence of avirumab_K76R-K100R, refer to SEQ ID NO.7 (light chain) and SEQ ID NO.8 (heavy chain) disclosed below.

[1878] • Avirumab_K360C, an antibody targeting PDL1. It corresponds to the antibody avirumab (CAS [1537032-82-8]), where Lys 360 has been replaced by Cys. For the amino acid sequence of avirumab_K360C, refer to SEQ ID NO.5 (light chain) and SEQ ID NO.6 (heavy chain) disclosed below.

[1879] • Avirumab_LALA-K360C, an antibody targeting PDL1. It corresponds to the antibody avirumab (CAS [1537032-82-8]), where Lys 360 has been replaced by Cys, and Leu 234 and Leu 235 have been replaced by Ala. For the amino acid sequence of avirumab_LALA-K360C, please refer to SEQ ID NO.3 (light chain) and SEQ ID NO.4 (heavy chain) disclosed below.

[1880] • Anti-CEACAM5_hyb_769 graft_VHg2-7_VLg2-2, also known as anti-CEACAM5_769_VarB_VH7 / VL2, is an antibody targeting the CEACAM5 receptor. The amino acid sequence of anti-CEACAM5_hyb_769 graft_VHg2-7_VLg2-2 can be found in SEQ ID NO. 9 (light chain) and SEQ ID NO. 10 (heavy chain), disclosed below.

[1881] • Anti-CEACAM5_p01_CEA-1_07_IgG1-dK, an antibody targeting the CEACAM5 receptor. The amino acid sequence of anti-CEACAM5_p01_CEA-1_07_IgG1-dK can be found in SEQ ID NO. 11 (light chain) and SEQ ID NO. 12 (heavy chain), disclosed below.

[1882] • Anti-CEACAM5_p01_CEA-1_07_IgG1_A118C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p01_CEA-1_07_IgG1-dK, where Ala 118 has been replaced by Cys. The amino acid sequence of anti-CEACAM5_p01_CEA-1_07_IgG1_A118C_dK can be found in SEQ ID NO. 13 (light chain) and SEQ ID NO. 14 (heavy chain) disclosed below.

[1883] • Anti-CEACAM5_p01_CEA-1_07_IgG1_E152C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p01_CEA-1_07_IgG1-dK, where Glu 152 has been replaced by Cys. The amino acid sequence of anti-CEACAM5_p01_CEA-1_07_IgG1_E152C_dK can be found in SEQ ID NO. 15 (light chain) and SEQ ID NO. 16 (heavy chain) disclosed below.

[1884] • Anti-CEACAM5_p01_CEA-1_07_IgG1_K360C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p01_CEA-1_07_IgG1-dK, where Lys 360 has been replaced by Cys. The amino acid sequence of anti-CEACAM5_p01_CEA-1_07_IgG1_K360C_dK can be found in SEQ ID NO.17 (light chain) and SEQ ID NO.18 (heavy chain) disclosed below.

[1885] • Anti-CEACAM5_p01_CEA-1_07_IgG1_K414C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p01_CEA-1_07_IgG1-dK, where Lys 414 has been replaced by Cys. The amino acid sequence of anti-CEACAM5_p01_CEA-1_07_IgG1_K414C_dK can be found in SEQ ID NO.19 (light chain) and SEQ ID NO.20 (heavy chain) disclosed below.

[1886] • Anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_A1118C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_dK, where Ala 118 has been replaced by Cys. The amino acid sequence of anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_A118C_dK can be found in SEQ ID NO. 21 (light chain) and SEQ ID NO. 22 (heavy chain) disclosed below.

[1887] • Anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_K360C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to the antibody anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_dK, where Lys 360 has been replaced by Cys. The amino acid sequence of anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_K360C_dK can be found in SEQ ID NO. 23 (light chain) and SEQ ID NO. 24 (heavy chain) disclosed below.

[1888] • Anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_K414C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_dK, where Lys 414 has been replaced by Cys. The amino acid sequence of anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_K414C_dK can be found in SEQ ID NO. 25 (light chain) and SEQ ID NO. 26 (heavy chain) disclosed below.

[1889] • Anti-CEACAM5_p01_CEA-1_07_IgG1_A118C_K360C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p01_CEA-1_07_IgG1-dK, where Ala 118 and Lys 360 have been replaced by Cys. The amino acid sequence of anti-CEACAM5_p01_CEA-1_07_IgG1_A118C_K360C_dK can be found in SEQ ID NO.27 (light chain) and SEQ ID NO.28 (heavy chain) disclosed below.

[1890] • Anti-CEACAM5_p01_CEA-1_07_IgG1_E152C_K360C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p01_CEA-1_07_IgG1-dK, where Glu 152 and Lys 360 have been replaced by Cys. The amino acid sequence of anti-CEACAM5_p01_CEA-1_07_IgG1_E152C_K360C_dK can be found in SEQ ID NO. 29 (light chain) and SEQ ID NO. 30 (heavy chain) disclosed below.

[1891] • Anti-CEACAM5_p01_CEA-1_07_IgG1_K274C_K414C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p01_CEA-1_07_IgG1-dK, where Lys 274 and Lys 414 have been replaced by Cys. The amino acid sequence of anti-CEACAM5_p01_CEA-1_07_IgG1_K274C_K414C_dK can be found in SEQ ID NO. 31 (light chain) and SEQ ID NO. 32 (heavy chain) disclosed below.

[1892] • Anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_A118C_K360C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_dK, where Ala 118 and Lys 360 have been replaced by Cys. The amino acid sequence of anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_A118C_K360C_dK can be found in SEQ ID NO. 33 (light chain) and SEQ ID NO. 34 (heavy chain) disclosed below.

[1893] • Anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_K274C_K414C_dK, an antibody targeting the CEACAM5 receptor. It corresponds to antibody anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_dK, where Lys 274 and Lys 414 have been replaced by Cys. The amino acid sequence of anti-CEACAM5_p07_CEA-3_50_IgG1_VH1_K274C_K414C_dK can be found in SEQ ID NO. 35 (light chain) and SEQ ID NO. 36 (heavy chain) disclosed below.

[1894] Compounds / conjugates (conjugates) of formula (II), (II1), or (II2):

[1895] Compounds / conjugates of formula (II), (II1), or (II2) typically comprise from about 1 to 10 compounds / loads of formula (I), (I1), or (I2) covalently attached to a binder (e.g., an antibody) as defined in this disclosure (this is the degree of grafting or the "drug-to-antibody ratio" or "DAR"). This number varies depending on the nature of the binder (e.g., an antibody) and the compounds / loads of formula (I), (I1), or (I2) as defined in this disclosure, as well as the operating conditions used in the conjugation process (e.g., the equivalent number of compounds / loads of formula (I), (I1), or (I2) relative to the binder (e.g., an antibody) as defined in this disclosure, the reaction time, the nature of the solvent, and any cosolvents). A mixture is produced by contacting a conjugate (e.g., an antibody) as defined in this disclosure with a compound / load of formula (I), (I1), or (I2), the mixture comprising several compounds / conjugates of formula (II), (II1), or (II2) that are individually distinguishable from each other by different DARs; optionally, unreacted conjugates as defined in this disclosure, such as unreacted antibodies; optionally, aggregates. Thus, the DAR determined on the final solution corresponds to the average DAR. The DAR is calculated by deconvolving the SEC-HRMS spectra of the compounds / conjugates of formula (II), (II1), or (II2). The DAR (HRMS) is, for example, greater than 0.5, such as in the range of 1 to 10, such as in the range of 2 to 5.

[1896] Compounds / conjugates of formula (II), (II1), or (II2) can be used as anticancer agents. Due to the presence of a binder (e.g., an antibody) as defined in this disclosure, compounds / conjugates of formula (II), (II1), or (II2) exhibit high selectivity for tumor cells (rather than healthy cells). This allows compounds / conjugates of formula (II), (II1), or (II2) to be directed into or directly directed into an environment similar to or in which they are located. Treatment of solid or liquid-filled cancers is possible. Compounds / conjugates of formula (II), (II1), or (II2) can be used alone or in combination with at least one other anticancer agent.

[1897] The compound / conjugate of formula (II), (II1), or (II2) is prepared as a buffered aqueous solution with a concentration typically ranging from 1 to 10 mg / mL. This solution may be injected by perfusion or may be rediluted to form a perfusion solution.

[1898] The following examples describe the preparation of some compounds according to formulas (I), (I1) or (I2) and (II), (II1) or (II2) of this disclosure. The number of compounds illustrated below matches those given above. Unless otherwise specified, all reactions were carried out under an inert atmosphere.

[1899] In the following examples, when the source of the starting product is not specified, it should be understood that the product is a known compound. Example

[1900] The following examples describe the preparation of certain compounds according to this disclosure. These examples are non-limiting and are merely illustrative of this disclosure.

[1901] Materials and methods

[1902] The progress of the synthesis reaction was monitored by TLC. The plates were made of glass and coated with Merck 60 F254 silica gel. After elution, the plates were observed under UV light at 254 nm.

[1903] Microwave reactions were performed using a Biotage Initiator 8 EXP microwave system. If necessary, the products were purified using a Biotage Isolera or Spot 2 chromatograph from Merck. Merck 15–40 μm silica columns (2.5 g to 800 g) were used.

[1904] The analytical methods used

[1905] High-performance liquid chromatography-mass spectrometry (LCMS)

[1906] Method M : Spectra were acquired on an Agilent 1200 & 6110B; Ionization: Electrospray (ES+) in positive mode.

[1907] •Kinetex C18 50 x 2.1 mm, 5 µm

[1908] •Solvent: A: H2O+0.037% (v / v) TFA, B: ACN+0.018% (v / v) TFA

[1909] • Column temperature: 40°C

[1910] • Flow rate: 1 mL / min

[1911] • Gradient (5 min): 5% to 95% B within 3 min; 1 min: 95% B; 1.50 min: 5% B

[1912] Method M1 : Spectra obtained on Waters UPLC-SQD; Ionization: Electrospray in positive and / or negative modes (ES+ / -).

[1913] •Column ACQUITY CSH C18 - 1.7 µm - 2.1 x 50 mm

[1914] • Solvents: A: H2O (0.1% formic acid), B: CH3CN (0.1% formic acid)

[1915] • Column temperature: 50°C

[1916] • Flow rate: 0.90 mL / min

[1917] • Gradient (2.5 min): 5% to 100% B within 1.8 min; 2.4 min: 100% B; 2.45 min: 5% B

[1918] Method M2 : Spectra were obtained on a Waters XEVO Q TOF; Ionization: Electrospray (ES+) in positive mode.

[1919] •Column ACQUITY CSH C18 - 1.7 µm - 2.1 x 100 mm

[1920] • Solvents: A: H2O (0.1% formic acid), B: CH3CN (0.1% formic acid)

[1921] • Column temperature: 45°C

[1922] • Flow rate: 0.50 mL / min

[1923] • Gradient (3 min): 0 to 0.3 min, 5% B - 0.3 to 4 min, 5% to 100% B - 4 to 4.6 min, 100% B - 4.6 to 5.3 min, 5% B

[1924] Method N : Spectra were acquired on Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative modes (ES+ / -).

[1925] •Column ACQUITY CSH C18 - 1.7 µm - 2.1 x 50 mm

[1926] • Solvents: A: H2O (0.1% formic acid), B: CH3CN (0.1% formic acid)

[1927] • Column temperature: 60°C

[1928] • Flow rate: 1 mL / min

[1929] • Gradient (2.5 min): 3% to 100% B within 2.1 min; 2.45 min: 100% B; 2.50 min: 3% B

[1930] Method N1 : Spectra were acquired on Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative modes (ES+ / -).

[1931] •Column ACQUITY CSH C18 - 1.7 µm - 2.1 x 50 mm

[1932] • Solvents: A: H2O (0.1% formic acid), B: CH3CN (0.1% formic acid)

[1933] • Column temperature: 60°C

[1934] • Flow rate: 1 mL / min

[1935] • Gradient (3 min): 0.1 min: 3% B; 3% to 97% B within 2 min; 2.45 min: 97% B; 2.50 min: 3% B; 3 min: 3% B

[1936] Method N2 : Spectra were acquired on Waters UPLC-SQD2; Ionization: Electrospray in positive and / or negative modes (ES+ / -).

[1937] •Column ACQUITY CSH C18 - 1.7 µm - 2.1 x 30 mm

[1938] • Solvents: A: H2O (0.1% formic acid), B: CH3CN (0.1% formic acid)

[1939] • Column temperature: 50°C

[1940] • Flow rate: 0.7 mL / min

[1941] • Gradient (6 min): 0.3 min: 3% B; 3% to 97% B within 4.7 min; 5 min: 100% B; 6 min: 3% B

[1942] Method N3: Spectra were acquired on a Waters UPLC-SQD2; ionization: electrospray in positive and / or negative modes (ES+ / -).

[1943] •Column ACQUITY CSH C18 - 1.7 µm - 2.1 x 30 mm

[1944] • Solvents: A: H2O (0.1% formic acid), B: CH3CN (0.1% formic acid)

[1945] • Column temperature: 50°C

[1946] • Flow rate: 0.8 mL / min

[1947] Gradient (5 min): 0.2 min: 5% B; 5% to 98% B within 3.4 min; 3.7 min: 98% B; 4.10 min: 5% B; 5 min: 5% B

[1948] Method N4: Spectra were obtained on Waters UPLC-SQD; ionization: electrospray in positive and / or negative modes (ES+ / -).

[1949] •Column ACQUITY CORTECS C18+ - 1,6 µm - 2,1 x 50 mm

[1950] • Solvents: A: H2O (0.1% formic acid), B: CH3CN (0.1% formic acid)

[1951] • Column temperature: 50°C

[1952] • Flow rate: 1 mL / min

[1953] Gradient (2 min): 0 to 1.5 min 5% to 99% B - 1.5 to 1.9 min 99% B - 1.9 to 1.95 min 99% to 5% B - 1.95 to 2.15

[1954] Method N5: Spectra were acquired on a Waters UPLC-SQD2; ionization: electrospray in positive and / or negative modes (ES+ / -).

[1955] •Column ACQUITY CSH C18 - 1.7 µm - 2.1 x 30 mm

[1956] • Solvents: A: H2O (0.1% formic acid), B: CH3CN (0.1% formic acid)

[1957] • Column temperature: 50°C

[1958] • Flow rate: 0.7 mL / min

[1959] Gradient (4 min): 0.18 min: 5% B; 5% to 99% B within 3.02 min; 3.4 min: 99% B; 4 min: 5% B

[1960] Method O Spectra obtained on WATERS QUATTRO PREMIER; Ionization: Electrospray in positive and / or negative modes (ES+ / -)

[1961] •Column ACQUITY MSS T3 - 1.8 µm - 2.1 x 50 mm

[1962] • Solvents: A: H2O (0.1% formic acid), B: CH3CN (0.1% formic acid)

[1963] • Column temperature: 55°C

[1964] • Flow rate: 0.9 mL / min

[1965] • Gradient (3.7 min): 5% to 100% B over 3 min; 3.1 min: 5% B

[1966] 1 H nuclear magnetic resonance (NMR)

[1967] Recorded in deuterated DMSO on a Brüker Avance and / or Varian G spectrometer (300 MHz, 400 MHz, 500 MHz, or 600 MHz). 11H NMR spectroscopy. Tetramethylsilane (TMS) was used as an internal reference, and chemical shifts are expressed in ppm. For spectral interpretation, the following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, dd = double doublet, ddd = double double doublet, m = multiplet, ax. = axial, equat. = equator.

[1968] Reversed-phase chromatography-high-resolution mass spectrometry (RP-HRMS)

[1969] Analysis was performed on UPLC-XEVO-G2-XS-QTOF (Waters), UPLC-XEVO-G2-S-QTOF (Waters), or UPLC-XEVO-G3-QTOF (Waters). Reversed-phase chromatography was performed at 80°C using an Agilent BioHPLC PLR 5 µm column (2.1 x 50 mm) at a flow rate of 0.5 mL / min and the following elution gradient: 5% B at 1 min, 50% B at 4 min, 50% B at 5 min, 5% B at 6 min, and 5% B at 7 min (solvent: A: H2O (0.1% formic acid); B: CH3CN (0.1% formic acid)). Mass spectrometry was performed using electrospray ionization (ES+) in positive mode. Mass spectra were deconvoluted using Waters MaxEnt1 software. The observed molecular weights correspond to the mass of the naked antibody (if present) and the conjugation of 1 (D1), 2 (D2), and n (Dn) drugs onto the antibody.

[1970] If necessary, preliminary ADC reduction was performed using the following conditions: the ADC was treated with 1 / 10 (by volume) of 0.5 M TCEP solution in water and incubated at room temperature for 30 min prior to RP-HRMS analysis. Under these conditions, the observed molecular weights corresponded to the masses of the bare light chain and heavy chain (LC HCs, if present) and the conjugation of 1 (LC1, HC1), 2 (LC2, HC2), ..., n (LCn, HCn) drugs onto the antibody.

[1971] Analytical size exclusion chromatography (SEC)

[1972] Analysis was performed on a Hitachi Labchrom or Thermo Vanquish LC system equipped with a photodiode array detector and a Tosoh Bioscience TSK-GEL SuperSW 4 μm (4.6 × 150 mm) column at a flow rate of 0.2 mL / min or a Tosoh Bioscience TSKgel G3000 SWXL 5 μm (7.8 × 300 mm) column at a flow rate of 0.5 mL / min, and isocratically eluted for 15 min with a pH 7 buffer containing 0.2 M KCl, 0.052 M KH2PO4, 0.107 M K2HPO4, and 20% isopropanol by volume.

[1973] buffer solution

[1974] •DPBS: Na2HPO4 (8.10mM), KH2PO4 (1.47mM), NaCl (136.9mM), KCl (2.67mM)

[1975] • Buffer A (pH 5.5): Sodium acetate (20 mM), 10% (w / v) sucrose

[1976] • Buffer B (pH 5.5): Sodium acetate (20 mM), 5% (w / v) sucrose, 0.01% PS80

[1977] • Buffer C (pH 7.4): NaPi (10 mM), NaCl (140 mM)

[1978] • Buffer D (pH 5.5): Histidine (10 mM), 8% (w / v) sucrose

[1979] • Buffer E (pH 6.5): Histidine (10 mM), 10% (w / v) sucrose

[1980] General methods (M1 to M4) for preparing compounds / conjugates of formula (II), (II1) or (II2).

[1981] • A general method (M1) for preparing mAb-DBCO using NHS esters

[1982] M1: Add 1 N HEPES (composition varying from 94:6 to 100:0, or in other words, from 0% to 6% HEPES (v / v)) to the final antibody solution diluted with DPBS in aqueous buffer. Treat the solution with an excess (4 to 10 equivalents) of 2 to 20 mM NHS ester DBCO linker in DMA or DMSO to achieve a final antibody concentration of 1–11 mg / mL and a DMA or DMSO percentage of 1%–20% in aqueous buffer. After stirring at room temperature for 45 min to 3 hours, analyze the mixture by SEC HPLC and / or HRMS to determine the linker-to-antibody ratio (LAR) for the monomeric antibody population. If insufficient LAR is found, treat the mixture with an additional excess of linker solution in DMA or DMSO at room temperature for an additional 2 hours with stirring.

[1983] • General methods (M2 and M3) for preparing compounds / conjugates of formula (II), (II1) or (II2).

[1984] M2: The mAb-DBCO solution in an aqueous buffer containing 1%–20% DMA or DMSO (finally diluted with DPBS) was treated with an excess (6 to 12 equivalents) of 10–20 mM azide payload in DMA or DMSO to achieve a final antibody concentration of 1–4 mg / mL and a DMA or DMSO percentage of 2%–20% in the aqueous buffer. After stirring overnight at room temperature, the reaction mixture was analyzed by RP-HRMS to determine the DAR for the monomeric antibody population. The mixture was then concentrated by ultrafiltration using a spinning column (Vivaspin®, PES membrane 50K, Sartorius) in DPBS buffer containing 20% ​​DMA. The mixture was then pre-equilibrated with Superdex in DPBS buffer containing up to 10%–20% DMA. TM Purification was performed using a 200 pg matrix (HiLoad® 16 / 60 or 26 / 60 desalting column, GE Healthcare) via gel filtration. Fractions containing monomeric conjugated antibodies were pooled and finally concentrated to a concentration between 2 and 5 mg / mL by ultrafiltration on a spinning column (Vivaspin®: PES membrane 50K, Sartorius, or Amicon® Ultra: Ultracel membrane 50K, Millipore,). In some cases, the conjugates were pre-equilibrated with Sephadex using a final aqueous buffer A, buffer D, or buffer E. TM G25 matrix (NAP® or Hitrap) TMThe desalting column (GE Healthcare) was prepared via gel filtration. The conjugate was then sterile filtered (Millex®-SV 0.22 µm, PVDF, Durapore®). The conjugate concentration was then measured by UV spectroscopy or SEC HPLC, monomer purity was determined by SEC HPLC, and DAR was determined by RP-HRMS from the unconvolution of the conjugate's mass spectrometry.

[1985] M3: Treat the mAb-DBCO solution in an aqueous buffer containing 1%–20% DMA or DMSO (finally diluted with DPBS) with an excess (6 to 12 equivalents) of 10–20 mM azide payload in DMA or DMSO to achieve a final antibody concentration of 1–4 mg / mL and a DMA or DMSO percentage of 2%–20% in the aqueous buffer. After overnight stirring at room temperature, analyze the mixture by RP-HRMS to determine the DAR for the monomeric antibody population. Purify the mixture by percolation using an ultrafiltration spinning column (Vivaspin®: PES membrane 50K, Sartorius or Amicon® Ultra: Ultracel membrane, 50K, Millipore), then pre-equilibrate with Sephadex using final aqueous buffer A, buffer D, or buffer E. TM G25 matrix (Hitrap) TM The conjugate was prepared using a desalting agent (GE Healthcare). Further purification was performed by percolation with the final buffer based on the residual free drug content as assessed by HRMS. The conjugate was then sterile filtered (Millex®-SV 0.22 µm (PVDF, Durapore)). The final conjugate concentration was measured by UV spectroscopy or SEC HPLC, monomer purity was determined by SEC-HPLC, and DAR was determined by unconvolution of the conjugate's mass spectrometry using RP-HRMS.

[1986] • A general method (M4) for preparing compounds / conjugates of formula (II), (II1), or (II2) using thio-mAb.

[1987] M4a: Add DTT (64 equivalents of 100-300 mM solution in H2O or DPBS) to a solution of 1-11 mg / mL thio-mAb in DPBS. Stir the mixture at 37°C for 45 min to 1 h, and then use Sephadex pre-equilibrated with DPBS buffer. TM G25 matrix (NAP® or Hiprep) TMPurification was performed using a 26 / 10 desalting column (GE Healthcare). DHAA (14–15 equivalents of 25–100 mM solution in DPBS) was added to the reduced thiodinated mAb solution, and the reaction mixture was stirred at room temperature for 3 hours.

[1988] M4b: After adding DMA (10%–20% v / v), treat the mixture with an excess of maleimide compound (1.5 to 2 equivalents of uncapped thiol in a 10 to 20 mM solution of DMA) to achieve a final antibody concentration of 1–4 mg / mL and a DMA percentage of approximately 10%–20% in aqueous buffer. After stirring overnight at room temperature, analyze the mixture by RP-HRMS to determine the DAR for the monomeric antibody population. Before or after purification using a Superdex 200 pg matrix (HiLoad® 16 / 60 or 26 / 60 desalting column, GE Healthcare) pre-equilibrated in an aqueous buffer (such as DPBS containing 5% to 20% organic solvents such as DMA or EtOH), the mixture is concentrated by percolation using an ultrafiltration spinning column (Vivaspin®: PES membrane 50K, Sartorius or Amicon® Ultra: Ultracel membrane, 50K, Millipore), and then pre-equilibrated with Sephadex using a final aqueous buffer A, buffer D, or buffer E. TM G25 matrix (NAP® or Hiprep) TM The conjugate was prepared by gel filtration using a 26 / 10 desalting column (GE Healthcare). Further purification was performed by percolation with a final buffer based on the residual free drug content as assessed by HRMS. The conjugate was then sterile filtered (Millex®-SV 0.22 µm, PVDF, Durapore). The conjugate concentration was measured by UV spectroscopy or SEC HPLC, monomer purity was determined by SEC-HPLC, and DAR was determined by unconvolution of the conjugate's mass spectra using RP-HRMS.

[1989] preparation

[1990] A) Preparation of TLR agonists

[1991] All of the following compounds were synthesized according to the scheme described below.

[1992] Synthesis of intermediates

[1993] Preparation 1: Intermediate (A) 2-Butyl-1H-imidazolium-4,5-dicarboxynitrile

[1994]

[1995] A suspension of (Z)-2,3-diaminobut-2-enonitrile (45.0 g, 416 mmol) and 1,1,1-trimethoxypentane (67.5 g, 416 mmol) in MeCN (90 mL) was stirred in an oil bath and maintained at 85°C for 6 h. The reaction mixture was then concentrated by evaporation under reduced pressure. The entire compound was dissolved in xylene (90 mL), and the resulting solution was stirred in an oil bath maintained at 150°C for 8 h. The mixture was concentrated to give a residue, which was filtered and washed with toluene. The filter cake was then dried to give the desired product. Intermediate (A) (63.0 g, 87% yield) was used for the next step without any purification.

[1996] 1 ¹H NMR (400 MHz, δ in ppm, CDCl₃): 2.82 (t, J = 7.6 Hz, 15.2 Hz, 2H); 1.72–1.80 (m, 2H); 1.36–1.45 (m, 2H); 0.93–0.97 (m, 3H)

[1997] MS method M:t R =1.019 min, m / z 175.1 (M+H) +

[1998] Preparation 2: Intermediate (B) 2-Butyl-1H-imidazolium-4,5-dicarboxylic acid

[1999]

[2000] The solution of intermediate (A) (63.0 g, 362 mmol) in H₂SO₄ (284 mL) and H₂O (126 mL) was stirred at 100°C for 8 h. A major new spot with low polarity was observed by TLC. The pH of the solution was adjusted to 9–10 using 10% sodium hydroxide solution. The mixture was filtered, and the filter cake was concentrated to give the desired product, which was used for the next step without further purification. Intermediate (B) (76.5 g, 99.7% yield) was obtained as a dark brown solid.

[2001] 1¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 2.59 (t, J = 7.6 Hz, 2H); 1.57–1.63 (m, 2H); 1.19–1.28 (m, 2H); 1.27–1.33 (m, 2H); 0.86 (t, J = 7.2 Hz, 14.8 Hz, 2H)

[2002] MS method M:t R =1.163 min, m / z 213.1 (M+H) + .

[2003] Preparation 3: Intermediate (C) 2-Butyl-1H-imidazolium-4,5-dicarboxylic acid dimethyl ester

[2004]

[2005] SOCl2 (214 g, 1.80 mol, 131 mL) was slowly added to a mixture of intermediate (B) (76.5 g, 361 mmol) in MeOH (230 mL), and the mixture was degassed and purged three times with N2. The mixture was then stirred at 40°C–45°C for 12 h under N2 atmosphere. The mixture was cooled and then slowly poured into cold water (500 mL). It was neutralized by adding 10% sodium hydroxide solution. The mixture was then extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1.00 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The crude product was used for the next step without further purification. Intermediate (C) (81.0 g, 93.5% yield) was obtained as a dark brown solid.

[2006] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 3.87 (s, 6H); 2.77 (t, J=8.0 Hz, 2H); 1.68–1.76 (m, 2H); 1.30–1.40 (m, 2H); 0.90 (t, J=7.6 Hz, 3H)

[2007] Preparation 4: Intermediate (D) 2-Butyl-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione

[2008]

[2009] The mixture of intermediate (C) (81.0 g, 337 mmol) and NH₂NH₂.H₂O (51.7 g, 1.01 mol, 50.2 mL, 98.0% purity) in MeOH (243 mL) was degassed and purged three times with N₂, and then stirred at 60°C for 1 h under N₂ atmosphere. The reaction mixture was filtered and washed with methanol. This material was suspended in water (1.00 L), heated to 85°C, and then acidified by adding concentrated HCl (100 mL). After stirring at 85°C for 12 h, the mixture was cooled and the white product was filtered by suction and washed with water. The crude product was used for the next step without further purification. Intermediate (D) (49.5 g, 70.5% yield) was given as a grayish-white solid.

[2010] Preparation 5: Intermediate (E) 2-Butyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazine

[2011]

[2012] N,N-dimethylaniline (50 mL) was added to a cooled solution of intermediate (D) (49.5 g, 238 mmol) in POCl3 (248 mL), and the reaction mixture was stirred at 110°C for 90 min. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was poured into cold water (2.00 L), and the pH was adjusted to 7 with solid sodium bicarbonate, and EtOAc (2 x 1 L) was extracted. The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was stirred in MTBE (200 mL) for 2 h. The suspension was filtered, and the filter cake was collected. Intermediate (E) (54.5 g, 92% yield) was obtained as a yellow solid.

[2013] 1 ¹H NMR (400 MHz, δ in ppm, CDCl₃): 3.18 (t, J = 7.6 Hz, 2H); 1.90–1.97 (m, 2H); 1.40–1.49 (m, 1H); 0.92 (t, J = 7.2 Hz, 3H)

[2014] MS method M:t R = 2.161 min, m / z 245.0 (M+H) + .

[2015] Preparation 6: Intermediate (L) 2-Butyl-7-chloro-N,N-bis(2,4-dimethoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[2016]

[2017] DIPEA (107 mL, 612.63 mmol) and bis(2,4-dimethoxybenzyl)amine (7 g, 22.1 mmol) were added to a solution of intermediate (E) (15 g, 61.20 mmol) in n-butanol (150 mL). The reaction mixture was refluxed for 1 h. An additional 5 g (15.8 mmol) of bis(2,4-dimethoxybenzyl)amine was added and heating was continued for 1 h. This operation was repeated twice more (2 x 5 g, 31.5 mmol). The resulting mixture was heated overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the n-butanol. The residue was diluted with DCM (500 mL), washed with H2O (250 mL) and brine (200 mL), dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give 38.8 g of crude product. The residue was purified by chromatography on a Merck column (800 g 15-40 μm silica) using DCM / acetone 96 / 4 to 90 / 10 as eluent to give an intermediate (L) as a pale yellow solid (12 g, 37% yield).

[2018] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.85 (t, J=7.4 Hz, 3H); 1.28 (m, 2H); 1.68 (m, 2H); 2.82 (t, J=7.6 Hz, 2H); 3.72 (s, 12H); 5.07 (s-width, 4H); 6.39 (dd, J=2.4 and 8.4 Hz, 2H); 6.54 (d, J=2.4 Hz, 2H); 6.95 (d, J=8.4Hz, 2H); 13.35 (s-width, 1H)

[2019] MS method N:t R (min): 1.59; [M+H] + 526

[2020] Preparation 7: Intermediate (M) 2-Butyl-N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine.

[2021]

[2022] Sodium isopropoxide (3.74 g, 45.62 mmol) and 2-propanol (30 mL, 1.05 mol) were added to a suspension of intermediate (L) (4 g, 7.60 mmol) in dioxane (30 mL). The mixture was heated at 170°C and 18 bar for 7 h. The reaction mixture was cooled and filtered, and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The crude product was dissolved in EtOAc (150 mL), washed with H2O (2 x 75 mL), brine (75 mL), dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give 4.37 g of product. The residue was purified by chromatography on a Merck column (200 g 15–40 μm silica) eluted with EtOAc / heptane (55 / 45). An intermediate (M) was obtained as a white solid (2.11 g, 50% yield).

[2023] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.84 (t, J=7.4 Hz, 3 Hz); 1.26 (m, 2 Hz); 1.37 (d, J=6.2 Hz, 6 Hz); 1.66 (m, 2 Hz); 2.77 (t, J=7.6 Hz, 2 Hz); 3.70 (s, 6 Hz); 3.71 (s, 6 Hz); 5.00 (s-width, 4 Hz); 5.41 (sept, J=6.2 Hz, 1 Hz); 6.38 (dd, J=2.4 and 8.4 Hz, 2 Hz); 6.52 (d, J=2.4 Hz, 2 Hz); 6.94 (d, J=8.4 Hz, 2 Hz); 13.01 (s-width, 1 Hz)

[2024] MS method N:t R (min): 1.58; [M+H] + 550

[2025] Preparation 8: Intermediate (N) 7-chloro-N,N-bis(2,4-dimethoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[2026]

[2027] Commercially available 4,7-dichloro-1H-imidazo[4,5-d]pyridazine (3 g, 15.87 mmol), n-butanol (30 mL), and DIPEA (27.79 mL, 158.73 mmol) were added to a 25 mL round-bottom flask equipped with a magnetic stir bar and a reflux condenser to produce a homogeneous solution. Then, bis(2,4-dimethoxybenzyl)amine (1.45 g, 4.48 mmol) was added, and the brown reaction mixture was heated under reflux for 1 h. Three additional portions of bis(2,4-dimethoxybenzyl)amine were added hourly (t0 + 2 h: 1.5 g, 4.63 mmol; t0 + 3 h: 1.5 g, 4.63 mmol; and t0 + 4 h: 1.09 g, 3.37 mmol). The mixture was heated under reflux for 92 h. It was cooled to room temperature and evaporated to dryness under vacuum. The remaining oily substance was dissolved in EtOAc (400 mL), transferred to a separatory funnel, and washed with water (3 x 100 mL). The aqueous phase was extracted with 100 mL of EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness to give 9.06 g of crude product. The crude material was purified by chromatography on a Merck column (600 g 15–40 μm silica) eluting with CHCl3 / MeOH (97 / 3) to give 1.79 g (24% yield) of the expected intermediate (N) as a yellow solid.

[2028] 1 H NMR (400 MHz, δ in ppm, DMSO-d6): 3.72 (s, 12 H); 5.07 (br s, 4 H); 6.40 (dd, J=8, 3 Hz, 2 H); 6.54 (d, J=3 Hz, 2 H); 6.95 (d, J=8 Hz, 2 H); 8.40 (s, 1 H); 13.74 (br s, 1 H)

[2029] MS method N:t R (min): 1.37, [M+H] + 470

[2030] Preparation 9: Intermediate (R) N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[2031]

[2032] Add 7-chloro-N,N-bis(2,4-dimethoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (N) (1.44 g, 3.06 mmol), dioxane (16 mL), and isopropanol (16 mL) to a round-bottom flask (50 mL). Transfer the resulting solution equally to two 10–20 mL microwave-safe tubes, and add sodium isopropoxide (755 mg, 9.2 mmol) to each tube. Heat both tubes at 170°C for 8 h. Combine the reaction mixtures and dilute with EtOAc (100 mL). Wash the organic solution with water (50 mL) and extract the aqueous phase with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to dryness to give 1.38 g of crude product. The crude product was purified by chromatography on a Merck column (150 g 15-40 μm silica) by elution with DCM / MeOH (99 / 1 to 98 / 2) to give 0.763 g (50% yield) of the expected intermediate (R) as a white foam.

[2033] 1 H NMR (400 MHz, δ in ppm, DMSO-d6): 1.38 (d, J=6.2 Hz, 6 H); 3.71 (s, 12 H); 5.02 (br s, 4 H); 5.41 (m, 1 H); 6.40 (dd, J=8.4, 2.4 Hz, 2 H); 6.53(d, J=2.4 Hz, 2 H); 6.95 (d, J=8.4 Hz, 2 H); 8.21 (br s, 1 H); 13.30-13.60(br s, 1H)

[2034] MS method N:t R (min): 1.29, [M+H] + 494

[2035] Preparation 10: Intermediate (S) 2-Butyl-N-[(2,4-dimethoxyphenyl)methyl]-4-isopropoxy-3H-imidazo[4,5-d]pyridazine-7-amine

[2036]

[2037] Step 1: 2-Butyl-4-chloro-7-isopropoxy-1H-imidazo[4,5-d]pyridazine

[2038]

[2039] Under N2, NaH (12.3 g, 307.3 mmol) was added to a mixture of i-PrOH (300 mL) at 0°C–5°C. The mixture was stirred at 0°C–5°C for 30 min, then heated to 95°C–100°C. A solution of 2-butyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazine intermediate (E) (15 g, 61.5 mmol) in dioxane (150 mL) was added dropwise to the reaction mixture, and the reaction was heated under N2 at 95°C–100°C for 12 h. The residue was poured into cold water (2 V) and extracted with EtOAc (2 V x 3). The combined organic layers were washed with brine (2 V), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 16 g (97% yield) of the desired compound.

[2040] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.91 (t, J = 7 Hz, 3 H); 1.35 (m, 8 H); 1.71 (m, 2 H); 2.72 (t, J = 7.6 Hz, 2 H); 3.78 (m, 1 H); 5.49 (m, 1 H)

[2041] Step 2: 2-Butyl-N-[(2,4-dimethoxyphenyl)methyl]-4-isopropoxy-3H-imidazo[4,5-d]pyridazine-7-amine

[2042]

[2043] To a solution of 2-butyl-4-chloro-7-isopropoxy-1H-imidazo[4,5-d]pyridazine (12 g, 44.75 mmol) and (2,4-dimethoxyphenyl)methylamine (7.48 g, 44.75 mmol) from step 1 in THF (240 mL), NaOtBu (10.75 g, 111.89 mmol) and tBuXPhos Pd G-3 (1 g, 1.34 mmol) were added. The reaction mixture was stirred at 60°C–65°C for 3 h, then poured into cold water (2 V) and extracted with EtOAc (2 V x 3). The combined organic layers were washed with brine (2 V), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 11.1 g (62% yield) of intermediate (S).

[2044] 1H NMR (400 MHz, δ in ppm, DMSO-d6): 0.89 (t, J=7.2 Hz, 3 H); 1.32 (m,8 H); 1.72 (m, 2 H); 2.82 (t, J=7.6 Hz, 2 H); 3.72 (s, 3 H); 3.78 (s, 3 H);4.53 (d, J=4.8 Hz, 2H); 5.38 (m, 1 H), 6.43 (d, J=7.6, 1 H); 6.53 (s, 1H));7.14 (bs, 1 H)

[2045] Preparation 11: Intermediate (T) 2-Butyl-4-chloro-3-methyl-imidazo[4,5-d]pyridazine-7-amine

[2046]

[2047] Step 1: 2-Butyl-4,7-dichloro-3-methyl-imidazo[4,5-d]pyridazine

[2048]

[2049] Potassium carbonate (8.5 g, 61.20 mmol) was added to a solution of 2-butyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazine intermediate (E) (5 g, 20.4 mmol) in acetone (65 mL). After stirring at room temperature for 30 min, methyl iodine (1.9 mL, 30.60 mmol) was added dropwise, and the reaction mixture was stirred for 4 h. The solid was removed by filtration through a glass frit filter, and the filtrate was concentrated to dryness. The residue was absorbed in DCM (50 mL) and washed with water (2 x 40 mL) and brine (40 mL). The organic phase was collected, dried over MgSO4, filtered, and concentrated to dryness to give a deep orange solid. This deep orange solid was then ground in isopropyl ether, collected by filtration, and dried. The desired product (4.5 g, 85% yield) was obtained as a light pink solid.

[2050] MS method N1: t R (min): 1.38; [M+H] + 258.9

[2051] Step 2: 2-Butyl-4-chloro-3-methyl-imidazo[4,5-d]pyridazine-7-amine

[2052]

[2053] A solution of 2-butyl-4,7-dichloro-3-methyl-imidazo[4,5-d]pyridazine (1.55 g, 5.98 mmol) from step 1 was reacted with a solution of 35% ammonia (30 mL) at 160°C (36 bar pressure) for 3 h. The resulting suspension was concentrated to dryness, absorbed in water (20 mL), stirred for 2 h, then further ground in isopropanol, filtered, and dried to give 533 mg (37% yield) of an intermediate (T) as a beige solid.

[2054] MS method N1: t R (min): 0.85; [M+H] + 239.9

[2055] Synthesis of TLR agonists

[2056] Example (TLR1): Preparati...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: A-L1-RCG1 (I) in: - A is the drug unit of formula (A) (A) in: R1 means: - Hydrogen atom, or - Selected from the following groups: a) - (C1-C6)alkyl-group; - Hydroxyl-(C1-C6)alkyl- group; - NH2-(C1-C6)alkyl-group; - NH-(C1-C6)alkyl-(C1-C6)alkyl- group; - N((C1-C6)alkyl)2-(C1-C6)alkyl-group; - (C2-C6) alkenyl-group; - (C2-C6) ynyl group; b) - A phenyl (C1-C6)alkyl group, which is either unsubstituted or substituted by at least one substituent selected from the following: b1) - (C1-C6)alkoxy-group; b2) - Hydroxyl group; b3) -C(O)-H group; and b4) - (C1-C6) alkyl group, which is either unsubstituted or substituted by at least one substituent selected from the following: b4.1) - Hydroxyl group; and b4.2) - -NR4R5 group, wherein R4 and R5 are independently selected from: b4.2.1) - Hydrogen atom; b4.2.2) - (C1-C 16 alkyl-group; b4.2.3) - CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30; (C1-C6)alkoxy(C1-C6)alkyl- group; or (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl- group; b4.2.4) - (C1-C6)alkyl-S(O2)- group; b4.2.5) - (C1-C6)alkyl-NH-C(O)- group; b4.2.6) - (C1-C 16 )alkyl-C(O)- group; b4.2.7) - (C1-C 16 )alkyl-OC(O)- group; b4.2.8) - CH3-[O-(CH2)2] n -C(O)- group, where n is an integer from 1 to 30; b4.2.9) - (C3-C 10 ) Cycloalkyl-groups, which are either unsubstituted or substituted by at least one substituent selected from the following: -hydroxyl group; and -(C1-C6)alkyl-group; or b4.2.10) - (C3-C 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2-; b4.2.11) - Phenyl-C(O)- group; b4.2.12) - (C1-C6)alkoxy-phenyl-(C1-C6)alkyl-OC(O)- group; b4.2.13) - (C1-C 16 )alkyl-C(O)-NH-phenyl-(C1-C6)alkyl-OC(O)- group; b4.2.14) - (C1-C 16 )alkyl-OC(O)-(C1-C6)alkyl-group; Alternatively, R4 and R5, together with the nitrogen atom to which they are attached, form a (C3-C) group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heterocyclic alkyl-group, the (C3-C 10 The heterocyclic alkyl group is either unsubstituted or substituted by at least one substituent selected from the following: (C1-C6) alkyl group and CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30; c) - (C3-C 10 )cycloalkyl (C1-C6)alkyl-group, which is unsubstituted or substituted by at least one substituent selected from the following: -NH2 and NH2-(C1-C6)alkyl-group; d) - (C3-C 10 A heterocyclic alkyl (C1-C6) alkyl group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the following: (C1-C6) alkyl-groups and CH3-[O-(CH2)2] n -A group, where n is an integer from 1 to 30; and e) - (C5-C 10 A heteroaryl (C1-C6) alkyl group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. The heteroaryl group is either unsubstituted or substituted by at least one substituent selected from the following: -(C1-C6)alkyl-group; -NH2-(C1-C6)alkyl-groups and -Cyano; f) - (C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 ) alkyl-group, wherein the heterocyclic alkyl group comprises one to four heteroatoms selected from oxygen, nitrogen, S(O), SO2 and sulfur; g) - (C3-C 10 )Hypercyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 ) alkyl-group, wherein the heterocyclic alkyl group comprises one to four heteroatoms selected from oxygen, nitrogen, S(O), SO2 and sulfur; R2 represents a halogen atom, Or selected from the following groups: -(C1-C6)alkyl-group; -(C2-C6)alkenyl-group; -(C2-C6) ynyl group; -(C1-C6)alkylthio- group; -(C1-C6)alkylthio(C1-C6)alkyl-group; -(C1-C6)alkyl-S(O) group; -(C1-C6)alkyl-S(O2-) group; -(C1-C6)alkyl-S(O)-(C1-C6)alkyl-group; -(C1-C6)alkyl-S(O2)-(C1-C6)alkyl-group; -(C1-C6)alkoxy- group; -(C1-C6)alkoxy(C1-C6)alkyl-group; -(C1-C6)haloalkoxy(C1-C6)alkyl-group; -(C3-C5)cycloalkyl-O-(C1-C6)alkyl-group; -(C1-C6)alkyl-NH-(C1-C6)alkyl-group; -((C1-C6)alkyl)2-N-(C1-C6)alkyl-group; -(C1-C6)alkyl-NH- group; and -((C1-C6)alkyl)2N-group; R3 indicates: - Deuterium atom; - Hydrogen atom Or selected from the following groups: a) - (C1-C6)alkyl-group; - (C2-C6) alkenyl-group; - (C2-C6) ynyl group; and - (C1-C6) alkylthio- group; b) - OR6 group, wherein R6 is selected from: - Hydrogen atom; -(C1-C6)alkyl-group; -CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30; -(C2-C6)alkenyl-group; -(C2-C6) ynyl group; -(C3-C 10 )cycloalkyl-group; -Phenyl; -Phenyl (C1-C6)alkyl-group; and -(C3-C 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(=O)- and -S(=O)2-; c) - -NR7R8 groups, wherein R7 and R8 are independently selected from: - Hydrogen atom; - CH3-[O-(CH2)2] n -, where n is an integer from 1 to 30; - (C1-C6)alkyl-group, which is either unsubstituted or substituted with the following: - (C5-C 10 ) heteroaryl groups, comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur; or - Phenyl, which is either unsubstituted or substituted with at least one substituent selected from the following: - Cyano and - NR9R 10 -(C1-C6)alkyl-group, wherein: R9 and R 10 Selected independently from: - Hydrogen atom; - (C1-C6)alkyl-group; - CH3-[O-(CH2)2] n -, where n is an integer from 1 to 30, or R9 and R 10 Together with the nitrogen atoms to which they are attached, they form (C 3- C 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur. The (C3-C) 10 The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the following: (C1-C6) alkyl-groups and CH3-[O-(CH2)2] n - group, where n is an integer from 1 to 30; Alternatively, R7 and R8 together with the nitrogen atoms they are attached to form (C3-C). 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur. The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the following: - Phenyl and - Hydroxyl (C1-C6)alkyl-phenyl group; d) - (C3-C 10 (a) heterocyclic alkyl group containing one to four heteroatoms selected from oxygen, nitrogen and sulfur; e) - (C5-C 10 A heteroaryl group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur. The (C5-C) 10 The heteroaryl group is either unsubstituted or substituted by at least one (C1-C6) alkyl group; f) - (C6-C 10 ) aryl-group; and g) - (C3-C 10 )cycloalkyl-group; - L1 indicates the connector; and - RCG1 indicates a reactive chemical group that is reactive to chemical groups present on binders, such as proteins, polypeptides, ligands, peptides, oligonucleotides or oligosaccharides, such as on targets, such as on cell binders, such as antibodies, such as monoclonal antibodies or VHH antibodies.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L1 represents a cuttable or non-cuttable joint.

3. The compound of formula (I) according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein: - When L1 is a cleavable linker, it is a peptide linker; or - When L1 is an uncuttable joint, it is a PEGylated joint.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein RCG1 represents: (i) R a Z a -C(=O)- reactive group, wherein: Z a This indicates a single bond, -O-, or -NH, such as -O-, and R a Represents hydrogen atoms, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C6)alkenyl, -(C6-C 10 )aryl, comprising 4 to 9 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur -(C5-C 10 ( ) heteroaryl, or -(C3-C7) heterocyclic alkyl comprising 2 to 6 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2-, wherein -(C6-C 10 )Aryl, -(C5-C 10 The heteroaryl group and / or -(C3-C7) heterocyclic alkyl group are optionally substituted by 1 to 5 atoms / groups selected from the following: halogen atoms such as fluorine atoms, -(C1-C6)alkyl groups, -(C1-C6)alkoxy groups, hydroxyl groups, oxo groups, nitro groups, and cyano groups; or (ii) One of the following reactive groups: maleimide group Group; substituted maleimide group, such as ; Haloacetamide group Group, wherein R 21 Indicates a hydrogen atom or (C1-C6) alkyl group, such as methyl; Cl-; N3-; HO-; HS-; activated disulfide, such as ;H2N-;HC≡C- or activated C≡C, such as cyclooctyne moieties, for example, DBCO-amines or BCN or MFCO ; Phenylacetazole methyl sulfone group (PODS), such as ; Group; Group; O-alkyl hydroxylamine or Pickett-Spengler reaction substrate, such as , For example, RCG1 is an N3-, maleimide group. Substituted maleimide group COOH group, phenyloxadiazolylmethyl sulfone group ; Group; or Groups, such as N3-, -COOH groups and maleimide groups .

5. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A has formula (A1) or formula (A2). (A1) (A2) in: R1, R2, and R3 are as defined in claim 1; single asterisk ( ) indicates the site covalently attached to -L1-RCG1; R1 express: - Single bond, which means that -L1-RCG1 is directly connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring. - or a divalent group formed by R1 as defined in this disclosure, which means that -L1-RCG1 is connected to the nitrogen atom of the imidazo[4,5-d]pyridazine ring via R1; R3 express: - Single bond, which means that -L1-RCG1 is directly connected to the carbon atom of the imidazo[4,5-d]pyridazine ring. - or a divalent group formed by R3 as defined in this disclosure, meaning that -L1-RCG1 is connected to the carbon atom of the imidazo[4,5-d]pyridazine ring via R3.

6. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from: ； ;as well as 。 7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds of formula (I1) and compounds of formula (I2): A-(La)m-(AA)w-(Lb)p-Lc-Ld'-RCG1 (I1) in: - A is as defined in any one of claims 1, 5 and 6; - La indicates a self-extinguishing connector, for example -C(O)-O-(CR 14 R 15 )-Aryl-NR 16 - Groups, -C(O)-O-(CR 14 R 15 )-Heteroaryl-NR 16 - Groups, -C(O)-NR 17 -(C2-C6)alkyl-NR 18 - , -C(O)-NR 17- (C2-C6)alkyl-NR 18 -C(O)-O-CR 15 R 14 -Aryl-NR 16 - Groups, -C(O)-NR 17- (C2-C6)alkyl-NR 18 -C(O)-O-CR 15 R 14 -heteroaryl-NR 16 - Groups, -CR 15 R 14 -Aryl-NR 16 - Group or -CR 15 R 14 -heteroaryl-NR 16 - Group, aryl is (C6-C 10 ) aryl and heteroaryl are C5-C6 groups containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur. 10 ) heteroaryl compounds, for example -C(O)-O-CH2-phenyl-NH- Group, single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site of covalent attachment to the (AA)w group; R 14 R 15 R 16 R 17 and R 18 It is a hydrogen atom or a (C1-C6) alkyl group; Group; - m represents an integer from 0 to 1; - (AA)w represents a sequence of w amino acids AA linked together by peptide bonds; w represents an integer from 1 to 12, such as from 1 to 6, like 2 and 3; AA represents a natural or non-natural amino acid with configuration D or L, selected from: alanine (Ala), β-alanine, γ-aminobutyric acid, 2-amino-2-cyclohexylacetic acid, 2-amino-2-phenylacetic acid, arginine (Arg), asparagine (Asn), aspartic acid (Asp), citrulline (Cit), cysteine ​​(Cys), α,α-dimethyl-γ-aminobutyric acid, β,β-dimethyl-γ-aminobutyric acid, glutamine (Gln), glutamic acid (Glu), glycine (Gln). y), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), ε-acetyl-lysine (AcLys), methionine (Met), ornithine (Orn), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val), such as valine (Val), citrulline (Cit), alanine (Ala), and glutamic acid (Glu); - Lb represents the spacer, for example -C(O)-(C1-C6)alkyl-C(O)-NH- Group or -C(O)- Groups, such as -C(O)-(CH2)3-C(O)-NH- Group or -C(O)- Group, single asterisk ( ) indicates the site covalently attached to the (AA)w group, and the double asterisk ( ) indicates the site of covalent attachment to the Lc group; - p represents an integer from 0 to 1; - Lc represents the spacer, for example -(CH2-CH2-O)n- Group, where n represents an integer from 2 to 12, such as from 3 to 7, like 3 and 4, if Lb exists (that is, if p is 1), single asterisk ( The asterisk () indicates the site covalently attached to the Lb group, or if Lb is absent (i.e., if p is 0), the asterisk ( ) indicates the site directly covalently attached to the (AA)w group, and the double asterisk ( ) indicates the site of covalent attachment to the Ld' group; - Ld' represents the spacer, for example -(C2-C6)alkyl- Groups, -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group or -(C2-C6)alkyl-C(O)-NH-(C2-C6)alkyl- Groups, such as -(CH2)2- Groups, -(CH2)2-NH-C(O)-(CH2)2- Group or -(CH2)2-C(O)-NH-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the Lc group, and the double asterisk ( ) indicates the site of covalent attachment to the RCG1 group; and - RCG1 is as defined in claim 1, for example, RCG1 means: (i) R a Z a -C(=O)- reactive group, wherein: Z a This indicates a single bond, -O-, or -NH, such as -O-, and R a Represents hydrogen atoms, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C6)alkenyl, -(C6-C 10 )aryl, comprising 4 to 9 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur -(C5-C 10 ( ) heteroaryl, or -(C3-C7) heterocyclic alkyl comprising 2 to 6 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2-, wherein -(C6-C 10 )Aryl, -(C5-C 10 The heteroaryl group and / or -(C3-C7) heterocyclic alkyl group are optionally substituted by 1 to 5 atoms / groups selected from the following: halogen atoms such as fluorine atoms, -(C1-C6)alkyl groups, -(C1-C6)alkoxy groups, hydroxyl groups, oxo groups, nitro groups, and cyano groups; or (ii) One of the following reactive groups: maleimide group Group; substituted maleimide group, such as ; Haloacetamide group Group, wherein R 21 Indicates a hydrogen atom or (C1-C6) alkyl group, such as methyl; Cl-; N3-; HO-; HS-; activated disulfide, such as ;H2N-;HC≡C- or activated C≡C, such as cyclooctyne moieties, for example, DBCO-amines or BCN or MFCO ; Phenylacetazole methyl sulfone group (PODS), such as ; Group; Group; O-alkyl hydroxylamine or Pickett-Spengler reaction substrate, such as , For example, RCG1 is an N3-, maleimide group. Substituted maleimide group COOH group, phenyloxadiazolylmethyl sulfone group ; Group; or Groups, such as N3- and maleimide groups ;as well as A-(P)oL-Ld-RCG1 (I2) in - A is as defined in any one of claims 1, 5 and 6; - P represents the -C(O)- group, -C(O)-O- group, -S(O2)- group, -C(O)-C(CH3)2-CH2-O- group, -C(O)-NH- group, Group or Group; - o represents an integer from 0 to 1; - L indicates -(CH2-CH2-O)n- Groups, where n represents an integer from 1 to 30, such as from 8 to 25, like 8, 12, 16, 20, 23, and 24, if P exists (that is, if o is 1), single asterisk ( The asterisk () indicates the site covalently attached to the P group, or if P is absent (i.e., if o is 0), the asterisk ( ) indicates the site directly covalently attached to group A, and the double asterisk ( This indicates the site where the Ld group is covalently attached; - Ld represents the spacer, for example -(C2-C6)alkyl- Groups, -(C2-C6)alkyl-NH-C(O)-(C2-C6)alkyl- Group or -(C2-C6)alkyl-C(O)-NH-(C2-C6)alkyl- Groups, such as -(CH2)2- Groups, -(CH2)2-NH-C(O)-(CH2)2- Group or -(CH2)2-C(O)-NH-(CH2)2- Group, single asterisk ( ) indicates the site covalently attached to the L group, and the double asterisk ( ) indicates the site of covalent attachment to the RCG1 group; and - RCG1 is as defined in claim 1, for example, RCG1 means: (i) R a Z a -C(=O)- reactive group, wherein: Z a This indicates a single bond, -O-, or -NH, such as -O-, and R a Represents hydrogen atoms, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C2-C6)alkenyl, -(C6-C 10 )aryl, comprising 4 to 9 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur -(C5-C 10 ( ) heteroaryl, or -(C3-C7) heterocyclic alkyl comprising 2 to 6 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2-, wherein -(C6-C 10 )Aryl, -(C5-C 10 The heteroaryl group and / or -(C3-C7) heterocyclic alkyl group are optionally substituted by 1 to 5 atoms / groups selected from the following: halogen atoms such as fluorine atoms, -(C1-C6)alkyl groups, -(C1-C6)alkoxy groups, hydroxyl groups, oxo groups, nitro groups, and cyano groups; or (ii) One of the following reactive groups: maleimide group Group; substituted maleimide group, such as ; Haloacetamide group Group, wherein R 21 Indicates a hydrogen atom or (C1-C6) alkyl group, such as methyl; Cl-; N3-; HO-; HS-; activated disulfide, such as ;H2N-;HC≡C- or activated C≡C, such as cyclooctyne moieties, for example, DBCO-amines or BCN or MFCO ; Phenylacetazole methyl sulfone group (PODS), such as ; Group; Group; O-alkyl hydroxylamine or Pickett-Spengler reaction substrate, such as , For example, RCG1 is an N3-, maleimide group. Substituted maleimide group COOH group, phenyloxadiazolylmethyl sulfone group ; Group; or Groups, such as N3-, -COOH groups and maleimide groups .

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ;as well as ， RCG1 is defined as in any one of claims 1, 4 and 7.

9. A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... (P1) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-carbonyl]oxymethyl]aniline]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentyl]amino]-5-oxopentanoic acid; (P2) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylcarbamoyloxymethyl]aniline]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentyl]amino]-5-oxopentanoic acid; (P3) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-carbonyl]oxymethyl]aniline]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentanoyl]amino]-5-oxopentanoic acid; (P4) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylcarbamoyloxymethyl]aniline]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentanoyl]amino]-5-oxopentanoic acid; (P5) N'-[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-yl]-1-oxoprop-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide; (P6) N'-[(2S)-1-[[(2S)-1-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide; (P7) N'-[(2S)-1-[[(2S)-1-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-1-oxoprop-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide; (P8) N'-[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-yl]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide; (P9) N'-[(2S)-1-[[(2S)-1-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide; (P10) N'-[(2S)-1-[[(2S)-1-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide, 2,2,2-trifluoroacetic acid; (P11) 1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-yl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]prop-1-one; (P12) N-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P13) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]piperazin-1-yl]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethyl]-3-(2,5-dioxopyrrole-1-yl)propionamide, 2,2,2-trifluoroacetic acid; (P14) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-(2,5-dioxopyrrolo-1-yl)propionamide, 2,2,2-trifluoroacetic acid; (P15) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-(2,5-dioxopyrrole-1-yl)propionamide, 2,2,2-trifluoroacetic acid; (P16) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[trans-4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] 3-(2,5-dioxopyrrole-1-yl)propionamide, 2,2,2-trifluoroacetic acid; (P17) 3-[[4-[[4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P18) 3-[[trans-4-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P19) N-[[trans-4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P20) N-[[trans-4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P21) N-[[trans-4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acrylamide; (P22) 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[trans-4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methylamino]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid; (P23) N-[[trans-4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acrylamide; (P24) ((4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylcarbamoyloxymethyl]aniline]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentyl]amino]-5-oxopentanoic acid; (P25) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]carbamoyloxymethyl]aniline]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentyl]amino]-5-oxopentanoic acid; (P26) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylcarbamoyloxymethyl]aniline]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentanoyl]amino]-5-oxopentanoic acid; (P27) (4S)-5-[[(2S)-1-[[(2S)-1-[4-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]carbamoyloxymethyl]aniline]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]amino]-4-[[5-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethylamino]-5-oxopentanoyl]amino]-5-oxopentanoic acid; (P28) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-1-oxopropyl-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide; (P29) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]amino]-1-oxoprop-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide; (P30) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-1-oxoprop-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide; (P31) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobut-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide; (P32) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]amino]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]glutaramide; 2,2,2-trifluoroacetate; (P33) N'-[(2S)-1-[[(2S)-1-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-5-(carbamoylamino)-1-oxopent-2-yl]amino]-3-methyl-1-oxobutyl-2-yl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide; 2,2,2-trifluoroacetate; (P34) N'-[(1S)-1-[[(1S)-1-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]carbamoyl]-4-ureo-butyl]carbamoyl]-2-methyl-propyl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide, 2,2,2-trifluoroacetic acid; (P35) (2S)-N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-2-[[(2S)-2-[3-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]propionylamino]-3-methyl-butyryl]amino]-5-ureo-pentanamide, 2,2,2-trifluoroacetic acid; (P36) (2S)-N-[[4-[[7-amino-4-isopropoxy-2-(propylamino)imidazo[4,5-d]pyridazin-3-yl]methyl]phenyl]methyl]-2-[[(2S)-2-[3-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]propionylamino]-3-methyl-butyryl]amino]-5-ureo-pentanamide, 2,2,2-trifluoroacetic acid; (P37) N'-[(1S)-1-[[(1S)-1-[3-(4-amino-2-butyl-1-methyl-imidazo[4,5-d]pyridazin-7-yl)-2,5-dihydropyrrolo-1-carbonyl]-4-ureo-butyl]carbamoyl]-2-methyl-propyl]-N-[2-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide, 2,2,2-trifluoroacetic acid; (P38) N'-[(1S)-1-[[(1S)-1-[4-(7-amino-2-butyl-3-methyl-imidazo[4,5-d]pyridazin-4-yl)piperazin-1-carbonyl]-4-ureo-butyl]carbamoyl]-2-methyl-propyl]-N-[2-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethyl]glutaramide, 2,2,2-trifluoroacetic acid; (P39) (2S)-N-[5-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)pentyl]-2-[[(2S)-2-[3-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]propionylamino]-3-methyl-butyryl]amino]-5-ureo-pentanamide, 2,2,2-trifluoroacetic acid; (P40) (2S)-N-[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]-2-[[(2S)-2-[3-[2-[2-[2-[3-(2,5-dioxopyrrolo-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]propionylamino]-3-methyl-butyryl]amino]-5-ureo-pentanamide, 2,2,2-trifluoroacetic acid; (P41) N-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P42) N-[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]cyclohexyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P43) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethyl]-3-(2,5-dioxopyrrole-1-yl)acrylamide, 2,2,2-trifluoroacetic acid; (P44) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[4-[(7-amino-4-isopropoxy-2-propylthioalkyl-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethyl]-3-(2,5-dioxopyrrole-1-yl)propionamide; (P45) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[4-[(7-amino-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] 3-(2,5-dioxopyrrole-1-yl)acrylamide, 2,2,2-trifluoroacetic acid; (P46) 3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P47) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P48) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P49) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P50) 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-3-oxo-propoxy]eth ... (P51) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionamide; (P52) N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methylamino]-3-oxo-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-(2,5-dioxopyrrolo-1-yl)propionamide; (P53) N-[1-[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]-1-methyl-ethyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P54) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...N-methyl-propionamide; (P55) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P56) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P57) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P58) N-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]carbamate 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ... (P59) 1-[[4-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]phenyl]methyl]-3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy] ...

10. A compound of formula (II) or a pharmaceutically acceptable salt thereof: A-L1-G-BA (II) in: A is as defined in any one of claims 1, 5, and 6, and L1 is as defined in any one of claims 1, 2, 3, and 5; BA stands for binding agent, such as protein, polypeptide, ligand, peptide, oligonucleotide or oligosaccharide. For example, BA is a targeting agent, such as a cell binding agent, such as an antibody, such as a monoclonal antibody or VHH antibody. G represents the product of the reaction between RCG1 as defined in any one of claims 1 and 4 and the reactive group RCG2 present on the binder, for example, G is selected from the group consisting of: ; ; ; ; ; ; ; ; ; ;and , For example, the left side of these G groups is linked to a binding agent BA, such as an antibody (Ab), and the right side of these G groups is linked to L1, for example, G represents the following groups: ; ; ; ; or Such as ; ; or .

11. A compound of formula (II) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds of formula (II1) and compounds of formula (II2): A-(La)m-(AA)w-(Lb)p-Lc-Ld'-G-BA (II1) in: A is as defined in any one of claims 1, 5 and 6, La, m, (AA)w, AA, w, Lb, p, Lc and Ld' are as defined in claim 7, and BA is as defined in claim 10; G represents the product of the reaction between RCG1 as defined in claim 1 or claim 4 and the reactive group RCG2 present on a binder such as an antibody as defined in claim 10, for example, G is selected from the group consisting of: ; ; ; ; ; ; ; ; ; ;and , For example, these G groups are connected to BA on the left and to Ld' on the right, such as G representing the following groups: ; ; or Such as or A-(P)oL-Ld-G-BA (II2) in: A is as defined in any one of claims 1, 5 and 6, and P, o, L and Ld are as defined in claim 7, and BA is as defined in claim 10; G represents the product of the reaction between RCG1 as defined in claim 1 or claim 4 and the reactive group RCG2 present on a binder such as an antibody as defined in claim 10, for example, G is selected from the group consisting of: ; ; ; ; ; ; ; ; ; ;and , For example, these G groups are connected to BA on the left and to Ld on the right, such as G representing the following groups: ; ; ; ; or Such as , , or .

12. The compound of formula (II) according to claim 10 or 11, or a pharmaceutically acceptable salt thereof, wherein the binding agent BA is an antibody Ab, such as a monoclonal antibody or a VHH antibody.

13. The compound of formula (II) according to any one of claims 10 to 12, or a pharmaceutically acceptable salt thereof, wherein: - When L1 is -(La)m-(AA)w-(Lb)p-Lc-Ld'-, L1 is selected from the group consisting of the following items: -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ; -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ; -Cit-Val-C(O)-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ; -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ; -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2- ; -C(O)-O-CH2-p-phenyl-NH-Cit-Val-Glu-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ; -C(O)-O-CH2-p-phenyl-NH-Ala-Val-Glu--C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ; -Cit-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- ; as well as -Ala-Val-C(O)-(CH2)3-C(O)-NH-(CH2-CH2-O)3-(CH2)2-NH-C(O)-(CH2)2- , single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( ) indicates the site of covalent attachment to a G group belonging to the -G-BA group; or - When L1 is -(P)oL-Ld-, L1 is selected from the group consisting of the following items: -C(O)-(CH2-CH2-O) 24 -CH2-CH2- ; -(CH2-CH2-O) 23 -CH2-CH2- ; -C(O)-(CH2-CH2-O) 20 -CH2-CH2- ; -C(O)-(CH2-CH2-O) 16 -CH2-CH2- ; -C(O)-(CH2-CH2-O) 12 -CH2-CH2- ; -C(O)-(CH2-CH2-O)8-CH2-CH2- ; -C(O)-C(CH3)2-CH2-O-(CH2-CH2-O) 20 -CH2-CH2- ; -C(O)-O-(CH2-CH2-O) 20 -CH2-CH2- ; -C(O)-NH-(CH2-CH2-O) 20 -CH2-CH2- ; ； ； -C(O)-(CH2-CH2-O) 24 -CH2-CH2-NH-C(O)-CH2-CH2- ; -C(O)-(CH2-CH2-O) 20 -CH2-CH2-NH-C(O)-CH2-CH2- ; as well as -C(O)-(CH2-CH2-O) 12 -CH2-CH2-NH-C(O)-CH2-CH2- ; single asterisk ( ) indicates the site covalently attached to the drug unit group A, and the double asterisk ( This indicates the site where the G group, which belongs to the -G-BA group, is covalently attached.

14. A compound of formula (II) according to any one of claims 10 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； and ， Ab represents antibody, such as monoclonal antibody or VHH antibody.

15. A compound of formula (II) according to any one of claims 10 to 12, or a pharmaceutically acceptable salt thereof, wherein RCG2 is selected from the group consisting of: (i) An ε-amino group (ε-NH2 group) carried by a side chain of a lysine residue present on the surface of a binding agent, such as the antibody, as defined in claim 10. (ii) The binding agent as defined in claim 10, for example, the α-amino group (α-NH2 group) of the N-terminal amino acid of the heavy or light chain of the antibody. (iii) Sugar groups in the hinge region; (iv) By reducing the thiol group (-SH group) of the cysteine ​​residue generated by the intrachain disulfide bond of the binder as defined in claim 10, such as the antibody, or the -SH group of the engineered cysteine ​​residue of the binder as defined in claim 10, such as the antibody. (v) An amide group (-C(O)NH2 group) carried by a side chain of a glutamine residue present on the surface of a binder such as the antibody as defined in claim 10. (vi) The use of formicylglycine synthase to introduce aldehyde groups (-C(O)H groups); and (vii) RCG2 groups introduced optionally by means of a modifier.

16. The compound of formula (II) according to any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, wherein - When RCG1 represents N-hydroxysuccinimide ester, RCG2 represents -NH2 group; - When RCG1 represents a maleimide functional group, a haloacetamide functional group, a chlorine atom, or an activated disulfide functional group, RCG2 represents a -SH group; - When RCG1 represents the -N3 group, RCG2 represents HC≡C- or an activated C≡C functional group, such as the cyclooctyne moiety; - When RCG1 represents a -OH or -NH2 group, RCG2 represents a carboxylic acid or amide functional group; - When RCG1 represents a -SH group, RCG2 represents a maleimide functional group, a haloacetamide functional group, or an activated disulfide functional group. - When RCG1 represents an HC≡C- functional group or an activated C≡C functional group, RCG2 represents an -N3 group; - When RCG1 represents an O-alkylhydroxylamine functional group or a Pickett-Spengler reaction substrate, RCG2 represents an aldehyde or ketone functional group.

17. A compound of formula (I) according to any one of claims 1 to 9 or a compound of formula (II) according to any one of claims 10 to 16, wherein pharmaceutical unit A of formula (A) as defined in claim 1 or claim 6, or pharmaceutical unit A of formula (A1) or formula (A2) as defined in claim 5 or claim 6, is a TLR7 agonist.

18. A compound of formula (I) according to any one of claims 1 to 9 or a compound of formula (II) according to any one of claims 10 to 16, wherein pharmaceutical unit A of formula (A) as defined in claim 1 or claim 6, or pharmaceutical unit A of formula (A1) or formula (A2) as defined in claim 5 or claim 6, is a TLR7 / 8 agonist.

19. A compound of formula (I) according to any one of claims 1 to 9, 17 and 18 or a compound of formula (II) according to any one of claims 10 to 18, wherein the pharmaceutical unit A is further of low cell permeability or non-cell permeability.

20. The compound of formula (I) or formula (II) according to claim 19, wherein the low cell permeability or non-cell permeability pharmaceutical unit A is defined by PAMPA less than 25.

21. The compound of formula (I1) according to claim 7 or the compound of formula (II1) according to claim 11, wherein the amino acid sequence (AA)w comprises citrulline.

22. The compound of formula (I1) or formula (II1) according to claim 21, wherein the amino acid sequence (AA)w is Val-Cit.

23. The compound of formula (II), (II1) or (II2) according to any one of claims 10 to 22, wherein RCG2 is a reactive group of the cysteine-engineered amino acid residue of the antibody.

24. The compound of formula (II), (II1), or (II2) according to claim 23, wherein the cysteine-engineered amino acid residue is at at least one position according to an EU number index, the at least one position being selected from heavy chain constant (C H The interchain cysteine ​​residues in the ) domain are 118, 152, 360, 274, and 414.

25. The compound of formula (II), (II1), or (II2) according to claim 24, wherein the cysteine-engineered amino acid residue is a heavy chain constant (C) according to the EU numbering index. H The location of the structural domain is at position 360.

26. A pharmaceutical composition comprising a compound of formula (II), (II1) or (II2) according to any one of claims 10 to 25 and at least one pharmaceutically acceptable excipient.

27. The compound of formula (II), (II1) or (II2) according to any one of claims 10 to 25, used as a pharmaceutical.

28. A compound of formula (II), (II1) or (II2) according to any one of claims 10 to 25, for inducing a large amount of immunostimulatory cytokines while having low or no induction of pro-inflammatory cytokines.

29. The compound of formula (II), (II1) or (II2) according to any one of claims 10 to 25, for stimulating cytokine induction of IFNα and IP10 with low or no stimulation of IL6 and TNFα.

30. The compound of formula (II), (II1) or (II2) according to claim 29, wherein the IFNα / TNFα ratio is greater than 1.

31. A compound of formula (II), (II1), or (II2) according to any one of claims 10 to 25, for the prevention and / or treatment of diseases or disorders that may benefit from activation of the immune system, such as for the prevention and / or treatment of proliferative disorders; cancer; chronic myeloid diseases; hairy cell leukemia; skin diseases, such as skin lesions or skin cancers, such as genital and perianal warts / condyloma acuminata, genital herpes, actinic keratosis, basal cell carcinoma, or cutaneous T-cell lymphoma; autoimmune diseases; Inflammatory diseases; Respiratory diseases; sepsis; allergic reactions, such as allergic rhinitis or respiratory allergies; asthma; graft rejection; graft-versus-host disease and immunodeficiency, such as prevention and / or treatment of cancer.

Images