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

Abstract

This invention relates to a compound of formula (I), wherein R1 represents H, (C1-C6)alkyl-; hydroxy-(C1-C6)alkyl-; NH2-(C1-C6)alkyl-; NH-(C1-C6)alkyl-(C1-C6)alkyl-; N((C1-C6)alkyl)2-(C1-C6)alkyl-; (C2-C6)alkenyl-; (C2-C6)alkynyl-; phenyl(C1-C6)alkyl-; (C3-C 10 )cycloalkyl (C1-C6)alkyl-; (C3-C 10 ) heterocyclic alkyl (C1-C6) alkyl-; (C5-C 10 ) heteroaryl (C1-C6) alkyl-; (C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 )alkyl-; and (C3-C 10 ) heterocyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 R2 represents a halogen atom, a (C1-C6)alkyl group, or other well-defined group; and R3 represents a deuterium atom; H, (C1-C6)alkyl; (C2-C6)alkenyl; (C2-C6)ynyl; (C1-C6)alkylthio; -OR6; -NR7R8; (C3-C 10 ) heterocyclic alkyl-; (C5-C 10 ) Aromatic compounds -; -(C6-C 10 ) Yuanfangji; and (C3-C 10 )cycloalkyl-. The present invention further relates to intermediates of these compounds, methods of their preparation, pharmaceutical preparations and pharmaceutical compositions comprising them, and their therapeutic uses, particularly as TLR7 and / or TLR8 agonists, and their use in vaccines.

Description

[0001] This invention relates to novel imidazo[4,5-d]pyridazine compounds, their preparation methods, novel intermediates, and their therapeutic uses, such as as Toll-like receptor 7 agonists and / or Toll-like receptor 8 agonists. Background Technology

[0002] The innate immune system contains several families of germline-encoded pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). These receptors recognize microbial components known as pathogen-associated molecular patterns (PAMPs), which are highly conserved molecular structures on a wide variety of pathogens, such as viruses, fungi, bacteria, and parasites.

[0003] TLRs are known to be promising targets for the development of novel and effective therapeutics. More specifically, both TLR7 and TLR8 are located within lysosomes and play important roles in the immune response during viral infection through their ability to recognize single-stranded RNA PAMPs and synthesize small molecules. Their stimulation leads to the activation of intracellular signaling and downstream gene encoding, particularly targeting co-stimulatory molecules, pro-inflammatory cytokines, and type I interferons.

[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, such as imiquimod (R-837), resiquimod (R-848), and gardiquimod.

[0005] For example, retinomod can act as both a TLR7 and TLR8 agonist. Some other synthetic small molecules (such as imiquimod) preferentially activate TLR7.

[0006] 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 players in initiating innate and adaptive immunity. 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, thereby promoting antigen presentation and stimulation of adaptive immune responses.

[0007] TLR7 agonists and / or TLR8 agonists have been reported as vaccine adjuvants and for the treatment of infections and diseases, such as skin cancer and bladder cancer, renal cell carcinoma, autoimmune diseases, inflammatory diseases, and allergic diseases.

[0008] However, there is still a need to provide novel compounds that can be used as TLR7 agonists and / or TLR8 agonists.

[0009] Therefore, the purpose of this disclosure is to provide novel compounds that can act as TLR7 agonists and / or TLR8 agonists. Summary of the Invention

[0010] This disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] in:

[0013] R1 means:

[0014] -hydrogen atom, or

[0015] - Selected from the following groups:

[0016] a)

[0017] -(C1-C6)alkyl- groups;

[0018] -hydroxy-(C1-C6)alkyl- groups;

[0019] -NH2-(C1-C6)alkyl- groups;

[0020] -NH-(C1-C6)alkyl-(C1-C6)alkyl- groups;

[0021] -N((C1-C6)alkyl)2-(C1-C6)alkyl- groups;

[0022] -(C2-C6)alkenyl- groups;

[0023] -(C2-C6) ynyl group;

[0024] b)

[0025] - A phenyl (C1-C6) alkyl group that is unsubstituted or substituted with at least one of the following substituents:

[0026] b1)-(C1-C6)alkoxy- group;

[0027] b2)-hydroxyl group;

[0028] b3)-C(O)-H group; and

[0029] b4) - A (C1-C6) alkyl group that is unsubstituted or substituted by at least one of the following substituents:

[0030] b4.1)-hydroxyl; and

[0031] b4.2)--NR4R5 group, wherein R4 and R5 are independently selected from:

[0032] b4.2.1) - Hydrogen atom;

[0033] b4.2.2)-(C1-C 16 )alkyl- groups;

[0034] b4.2.3) - where n is an integer from 1 to 30 CH3-[O-(CH2)2] n - group, (C1-C6)alkoxy(C1-C6)alkyl- group, or (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl- group;

[0035] b4.2.4)-(C1-C6)alkyl-S(O2)- groups;

[0036] b4.2.5)-(C1-C6)alkyl-NH-C(O)- groups;

[0037] b4.2.6)-(C1-C 16 )alkyl-C(O)- groups;

[0038] b4.2.7)-(C1-C 16 )alkyl-OC(O)- groups;

[0039] b4.2.8) - where n is an integer from 1 to 30 CH3-[O-(CH2)2] n -C(O)- groups;

[0040] b4.2.9) - unsubstituted or substituted by at least one of the following substituents (C3-C 10 Cycloalkyl groups:

[0041] -hydroxyl group; and

[0042] -(C1-C6)alkyl- groups; or

[0043] b4.2.10) - Contains one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2- (C3-C 10 ) heterocyclic alkyl groups;

[0044] b4.2.11)-phenyl-C(O)- group;

[0045] b4.2.12)-(C1-C6)alkoxy-phenyl-(C1-C6)alkyl-OC(O)- groups;

[0046] b4.2.13)-(C1-C16 )alkyl-C(O)-NH-phenyl-(C1-C6)alkyl-OC(O)- groups;

[0047] b4.2.14)-(C1-C 16 )alkyl-OC(O)-(C1-C6)alkyl- groups;

[0048] Or R4 and R5 together with the nitrogen atoms to which they are attached form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one to four heteroatoms selected from oxygen, nitrogen, and sulfur, wherein 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] where n is an integer from 1 to 30. n - group;

[0049] c) - Unsubstituted or substituted by at least one of the following substituents (C3-C 10 Cycloalkyl (C1-C6)alkyl- groups: -NH2 and NH2-(C1-C6)alkyl- groups;

[0050] d) - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C3-C 10 ) heterocyclic alkyl (C1-C6) alkyl- groups,

[0051] The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the group consisting of (C1-C6) alkyl groups and CH3-[O-(CH2)2] where n is an integer from 1 to 30. n - groups; and

[0052] e) - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 A heteroaryl (C1-C6)alkyl group, wherein the heteroaryl group is unsubstituted or substituted by at least one substituent selected from the following:

[0053] -(C1-C6)alkyl- groups;

[0054] -NH2-(C1-C6)alkyl- groups, and

[0055] -Cyano;

[0056] f)-(C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 The heterocyclic alkyl group comprises one to four heteroatoms selected from the following: oxygen, nitrogen, S(O), SO2 and sulfur;

[0057] g)-(C3-C 10 )Hypercyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 The heterocyclic alkyl group comprises one to four heteroatoms selected from the following: oxygen, nitrogen, S(O), SO2 and sulfur;

[0058] R2 represents a halogen atom.

[0059] Or selected from the following groups:

[0060] -(C1-C6)alkyl- groups;

[0061] -(C2-C6)alkenyl- groups;

[0062] -(C2-C6) ynyl group;

[0063] -(C1-C6)alkylthio- groups;

[0064] -(C1-C6)alkylthio(C1-C6)alkyl- groups;

[0065] -(C1-C6)alkyl-S(O)- groups;

[0066] -(C1-C6)alkyl-S(O2)- groups;

[0067] -(C1-C6)alkyl-S(O)-(C1-C6)alkyl- groups;

[0068] -(C1-C6)alkyl-S(O2)-(C1-C6)alkyl- groups;

[0069] -(C1-C6)alkoxy- groups;

[0070] -(C1-C6)alkoxy(C1-C6)alkyl- groups;

[0071] -(C1-C6)haloalkoxy(C1-C6)alkyl- groups;

[0072] -(C3-C5)cycloalkyl-O-(C1-C6)alkyl- groups;

[0073] -(C1-C6)alkyl-NH-(C1-C6)alkyl- groups;

[0074] -((C1-C6)alkyl)2-N-(C1-C6)alkyl- groups;

[0075] -(C1-C6)alkyl-NH- groups; and

[0076] -((C1-C6)alkyl)2N- groups;

[0077] R3 indicates:

[0078] -Deuterium atom;

[0079] - Hydrogen atom

[0080] Or selected from the following groups:

[0081] a)

[0082] -(C1-C6)alkyl- groups;

[0083] -(C2-C6)alkenyl- groups;

[0084] -(C2-C6)ynyl- groups; and

[0085] -(C1-C6)alkylthio- groups;

[0086] b)

[0087] --OR6 group, where R6 is selected from:

[0088] - Hydrogen atom;

[0089] -(C1-C6)alkyl- groups;

[0090] -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n - group;

[0091] -(C2-C6)alkenyl- groups;

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

[0093] -(C3-C 10 )cycloalkyl- groups;

[0094] -Phenyl;

[0095] -phenyl (C1-C6)alkyl- groups; and

[0096] - Contains one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(=O)- and -S(=O)2- (C3-C 10 ) heterocyclic alkyl groups;

[0097] c)

[0098] --NR7R8 group, wherein R7 and R8 are independently selected from:

[0099] - Hydrogen atom;

[0100] -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -;

[0101] - Unsubstituted or (C1-C6) alkyl groups:

[0102] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) Aromatic compounds; or

[0103] - Phenyl groups that are unsubstituted or substituted with at least one of the following substituents:

[0104] -Cyano, and

[0105] -NR9R 10 -(C1-C6)alkyl- groups, wherein:

[0106] R9 and R 10 Selected independently from:

[0107] - Hydrogen atom;

[0108] -(C1-C6)alkyl- groups;

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

[0110] R9 and R 10 Together with the nitrogen atoms to which they are attached, they form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0111] 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] where n is an integer from 1 to 30. n - groups; or R7 and R8 together with the nitrogen atoms to which they are attached to form (C3-C 10 A heterocyclic alkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the heterocyclic alkyl group is unsubstituted or substituted by at least one substituent selected from:

[0112] -phenyl, and

[0113] -hydroxy(C1-C6)alkyl-phenyl- groups;

[0114] d)

[0115] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C3-C10 ) heterocyclic alkyl groups;

[0116] e)

[0117] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) heteroaryl- group,

[0118] The (C5-C) 10 The heteroaryl group is either unsubstituted or substituted by at least one (C1-C6) alkyl group;

[0119] f)

[0120] --(C6-C 10 Yuan Fangji; and

[0121] g)

[0122] -(C3-C 10 ) Cycloalkyl- groups.

[0123] This disclosure further relates to a method for preparing compounds according to formula (I) of this disclosure.

[0124] Therefore, according to a specific embodiment, this disclosure relates to a first method for preparing a compound of formula (I) according to this disclosure or a pharmaceutically acceptable salt thereof, as shown in Scheme 1 below (also referred to in this disclosure as SynMethod 1) and detailed below.

[0125] According to another specific embodiment, this disclosure relates to a second method for preparing a compound of formula (I) according to this disclosure or a pharmaceutically acceptable salt thereof, as shown in Scheme 2 below (also referred to in this disclosure as SynMethod 2, SynMethod 2a and SynMethod 2b) and detailed below.

[0126] According to another specific embodiment, this disclosure relates to a third method for preparing a compound of formula (I) according to this disclosure or a pharmaceutically acceptable salt thereof, as shown in Scheme 3 below (also referred to in this disclosure as SynMethod 3) and detailed below.

[0127] According to another specific embodiment, this disclosure relates to a fourth method for preparing a compound of formula (I) according to this disclosure or a pharmaceutically acceptable salt thereof, as shown in Scheme 4 below (also referred to in this disclosure as SynMethod 4, SynMethod 4a and SynMethod 4b) and detailed below.

[0128] This disclosure also relates to intermediate compounds of the following formula or pharmaceutically acceptable salts thereof:

[0129]

[0130] in

[0131] -R1、R 1a R2, R 3a HAL and G1 are as defined in this disclosure.

[0132] This disclosure further relates to specific intermediate compounds selected from the following, or pharmaceutically acceptable salts thereof:

[0133]

[0134]

[0135] in:

[0136] - Compounds (H) and (J) or their pharmaceutically acceptable salts belong to formula (VIIa) as defined in this disclosure.

[0137] - Compounds (Ia) and (K) or pharmaceutically acceptable salts thereof belong to formula (VIIIa) as defined in this disclosure.

[0138] - Compounds (L) and (N) or pharmaceutically acceptable salts thereof belong to formula (VIII) as defined in this disclosure, and

[0139] - Compounds (M) and (R) or pharmaceutically acceptable salts thereof belong to formula (IX) as defined in this disclosure.

[0140] Compounds of formula (I) may contain one or more asymmetric carbon atoms. They may therefore exist as enantiomers, preferably pure enantiomers, or diastereomers and mixtures thereof.

[0141] Compounds of formula (I) may also exist as tautomers. Indeed, it should be understood that this disclosure covers all isomers of formulas (I), (Ia), (VIIa), (VIII), (VIIIa), (IX), and (X) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric, and optical forms and mixtures thereof (e.g., racemic or non-racemic mixtures). It should be understood that in this disclosure, isomers may be limited to geometric isomers, optical isomers, and tautomers.

[0142] Compounds of formulas (I), (Ia), (VIIa), (VIII), (VIIIa), (IX), and (X) may exist as bases, acids, zwitterions, or addition salts of acids or bases, particularly pharmaceutically acceptable salts. Such addition salts, bases, acids, and zwitterions form part of this disclosure. Therefore, this disclosure particularly relates to compounds of formulas (I), (Ia), (VIIa), (VIII), (VIIIa), (IX), and (X), or pharmaceutically acceptable salts thereof.

[0143] These salts can be prepared from pharmaceutically acceptable acids or bases, although salts of other acids or bases that can be used, for example, to purify or isolate compounds of formulas (I), (Ia), (VIIa), (VIII), (VIIIa), (IX), and (X) also form part of this disclosure.

[0144] Among suitable salts that form part of this disclosure, the following salts may be referenced: hydrochloride salts and trifluoroacetate salts.

[0145] Another subject of this disclosure is compounds of formula (I) according to this disclosure, selected from the above and below lists, which are used as medicines.

[0146] Another subject of this disclosure is compounds of formula (I) according to this disclosure, selected from the above and below lists, or pharmaceutically acceptable salts thereof, used in therapy, particularly as TLR7 agonists and / or as TLR8 agonists.

[0147] Another subject of this disclosure is compounds of formula (I) according to this disclosure, selected from the above and below lists, or pharmaceutically acceptable salts thereof, for the prevention and / or treatment of diseases or disorders associated with TLR7 and / or TLR8 activity, such as proliferative disorders, cancer, chronic myeloid leukemia, 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, allergies (e.g., allergic rhinitis or respiratory allergies), asthma, graft rejection, graft-versus-host disease, and immunodeficiency.

[0148] Another subject of this disclosure is compounds of formula (I) according to this disclosure, selected from the above and below lists, which are pharmaceutically acceptable salts thereof for the prevention and / or treatment of cancer.

[0149] Another subject of this disclosure is compounds of formula (I) according to this disclosure, selected from the above and below lists, or pharmaceutically acceptable salts thereof, for use in vaccines. For example, compounds of formula (I) according to this disclosure may be used as vaccine adjuvants or the vaccine may be a self-adjuvanting vaccine.

[0150] Another subject of this disclosure is a method for treating diseases or disorders associated with TLR7 and / or TLR7 / 8 activity, such as proliferative disorders, cancer, chronic myeloid leukemia, 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, allergies (e.g., allergic rhinitis or respiratory allergies), asthma, graft rejection, graft-versus-host disease, immunodeficiency, the method comprising administering to a subject in need, such as a human, a therapeutically effective amount of a compound selected from the above and below lists according to formula (I) of this disclosure or a pharmaceutically acceptable salt thereof.

[0151] On the other hand, this disclosure also relates to a method for preventing and / or treating diseases or disorders associated with TLR7 and / or TLR7 / 8 activity in patients, such as humans, who require treatment of diseases or disorders such as proliferative disorders, cancer, chronic myeloid leukemia, 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, allergies (e.g., allergic rhinitis or respiratory allergies), asthma, graft rejection, graft-versus-host disease, and immunodeficiency, the method comprising immunizing the patient with a vaccine comprising a compound of formula (I) selected from the above and below lists of this disclosure or a pharmaceutically acceptable salt thereof.

[0152] On the other hand, this disclosure also relates to adjuvants used in vaccines.

[0153] This disclosure further relates to the use of compounds of formula (I) of this disclosure selected from the above and below lists, or pharmaceutically acceptable salts thereof, for the manufacture of vaccines and / or pharmaceutical agents for the prevention and / or treatment of diseases or disorders associated with TLR7 and / or TLR7 / 8 activity, such diseases or disorders as proliferative disorders, cancer, chronic myeloid leukemia, 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, allergies (e.g., allergic rhinitis or respiratory allergies), asthma, graft rejection, graft-versus-host disease, and immunodeficiency.

[0154] Another subject of this disclosure is a pharmaceutical preparation comprising, as an active ingredient, an effective dose of a compound of formula (I) of this disclosure selected from the above and below lists, or a pharmaceutically acceptable salt thereof.

[0155] Another subject of this disclosure is a pharmaceutical composition comprising, as an effective dose of a compound of formula (I) of this disclosure selected from the above and below lists, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0156] definition

[0157] In the context of this disclosure, unless otherwise stated throughout the specification, the following terms shall have the following definitions:

[0158] - "Halogen atom": a fluorine, chlorine, bromine, or iodine atom, and for example, fluorine and chlorine atoms;

[0159] - "hydroxyl group": "-OH" group;

[0160] - "Oxide group": "=O" group;

[0161] - "Cyano": "-C≡N" group;

[0162] -“(C x -C y Alkyl group: A straight-chain or branched aliphatic group based on hydrocarbons containing x to y carbon atoms, for example, from 1 to 6 carbon atoms or from 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.

[0163] -“(C x -C y"Alkenyl" group: A straight-chain or branched aliphatic group based on a hydrocarbon that contains at least one degree of unsaturation (double 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 may include, but are not limited to: vinyl, propenyl, butenyl, pentenyl, hexenyl, etc.

[0164] -“(C x -C y "Alynyl" group: A straight-chain or branched aliphatic group based on hydrocarbons 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.

[0165] -“(C x -C y "Alkoxy" group: -O-alkyl, wherein the alkyl group is as defined above. For example, (C1-C6)alkoxy. Examples may include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, straight-chain, secondary or tert-butoxy, isobutoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, etc.

[0166] -“(C x -C y "Haloalkoxy" group: -O-alkyl, wherein the alkyl group is as defined above and further substituted with at least one halogen atom as defined above. For example, (C1-C6)haloalkoxy. Examples include, but are not limited to: chloromethoxy, fluoromethoxy, dichloromethoxy, 2-fluoropropoxy, etc.

[0167] -“(C x -C y "alkylthio" group: -S-alkyl, wherein the alkyl group is as defined above. For example, (C1-C6)alkylthio. Examples may include, but are not limited to: methylthio, ethylthio, propylthio, isopropylthio, straight-chain, secondary or tert-butylthio, isobutylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio, etc.

[0168] -“(C3-C 10 "(C3-C5)cycloalkyl" group: Cycloalkyl group, unless otherwise mentioned, contains 3 to 10 carbon atoms (referred to as "(C3-C5)cycloalkyl" group). 10 Cycloalkyl or cycloalkyl groups of 3 to 5 carbon atoms (referred to as "(C3-C5)cycloalkyl") 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.

[0169] -“(C3-C 10 Heterocyclic alkyl groups: Monocyclic alkyl groups, unless otherwise specified, which contain 3 to 10 carbon atoms (referred to as "(C3-C10") 10 A heterocyclic alkyl group is defined as a alkyl group containing 1 to 4 heteroatoms selected from the following: 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 unsubstituted or substituted. Examples of heterocyclic alkyl groups include, but are not limited to: piperazine, morpholino, pyrrolidine, tetrahydropyran, thiocyclic butane dioxide, piperidine, tetrahydrothiophene, tetrahydrothiophene oxide, tetrahydrothiophene dioxide, and dihydrothiophene. Hydrogen furan, tetrahydrofuran, aziridine, oxadiazole, thioheterocyclic butane, 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, dioxazoline, oxazoline, dioxazoline, dioxazolidine, dioxazole group, etc.

[0170] -“(C5-C 10 "Heteroaryl" groups refer to cyclic aromatic groups consisting of 5 to 10 carbon atoms and containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur (called "C5-C"). 10 (5- to 10-membered heteroaryl groups) (in other words, one heteroatom replaces one carbon atom). Such heteroaryl groups can be unsubstituted or substituted. Examples of 5- to 10-membered heteroaryl groups include, but are not limited to: pyridine, furan, pyrrole, thiophene, pyrazole, oxazole, isoxazole, triazole, tetraazole, oxadiazole, furazon, thiazole, isothiazole, thiadiazole, imidazole, pyrimidine, pyridazine, triazine group, etc.

[0171] -“(C6-C 10 aryl group: A cyclic aromatic group containing 6 to 10 carbon atoms (called "(C6-C7)"). 10 (6- to 10-membered aryl groups). These aryl groups can be unsubstituted or substituted. Examples of 6- to 10-membered aryl groups include, but are not limited to: phenyl, naphthyl, etc.

[0172] - "Deuterium atom" (D or 2 H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144;

[0173] - "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), triisopropylsiloxymethyl (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: Greene's Protective Groups Inorganic Synthesis, PGMUTS and TWGREENE, 4th Edition, 1807 Wiley 207, Wiley Interscience);

[0174] - "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-butoxycarbonyl (BOC) groups, 9-fluorenylmethoxycarbonyl (Fmoc) groups, acetyl (Ac) groups, benzoyl (Bz) groups, benzyl (Bn) groups, urethane ester groups, p-methoxyphenyl (PMP) groups, toluenesulfonyl (Ts) groups. Groups including p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), Troc (trichloroethyl chloroformate) groups, and other sulfonamides such as benzyloxycarbonyl (Cbz) groups, tert-butoxycarbonyl (BOC) groups, 9-fluorenylmethoxycarbonyl (Fmoc) groups, acetyl (Ac) groups, benzoyl (Bz) groups, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), and Troc (trichloroethyl chloroformate) groups. (See Greene's Protective Groups in Organic Synthesis, PGMUTS and TWGREENE, 4th Edition, 1807 Wiley 207, Wiley Interscience.)

[0175] - "Carboxylic acid protecting group" refers to: esters, silyl esters, amides, hydrazides, etc., such as methyl esters, benzyl esters, tert-butyl 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 Handbook "Protective Groups Inorganic Synthesis", PGMUTS and TWGREENE, 4th Edition, 1807 Wiley 207, Wiley Interscience);

[0176] - "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, acyl acetals and dithianes. (See Greene's Protective Groups in Organic Synthesis, PGMUTS and TWGREENE, 4th Edition, 1807 Wiley 207, Wiley Interscience);

[0177] - "Amphoteric ions" refers to: a generally neutral molecule that has both positive and negative charges and both acidic and basic groups.

[0178] - In this publication, "room temperature" (also referred to as rt) means a temperature in the range of 18°C ​​to 30°C, for example, 18°C ​​to 25°C;

[0179] - "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 repeat sequences, a transmembrane domain, and an intracellular domain involved in TLR signaling;

[0180] - "TLR7": The terms "Toll-like receptor 7" and "TLR7" refer to a nucleic acid or polypeptide that shares 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., the human TLR7 polypeptide with GenBank accession number AAZ99026 or the mouse TLR7 polypeptide with GenBank accession number AAK62676).

[0181] - "TLR8": The terms "Toll-like receptor 8" and "TLR8" refer to a nucleic acid or polypeptide that shares 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., the human TLR8 polypeptide with GenBank accession number AAZ95441 or the mouse TLR8 polypeptide with GenBank accession number AAK62677).

[0182] - "TLR agonist": This is a substance that binds directly or indirectly to a TLR (e.g., TLR7 and / or TLR8) to induce TLR signaling. Any detectable difference in TLR signaling can indicate that an agonist stimulates or activates the TLR. Differences in signaling can manifest as, for example, changes in target gene expression, phosphorylation of signal transduction components, intracellular localization of downstream elements (such as NF-κB), 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).

[0183] - "Immune response": As used herein, "immunological response" or "immune response" to an antigen or composition means the development of a humoral and / or cellular immune response to an antigen or composition in a subject;

[0184] Immune responses include innate and adaptive immune responses. Innate immune responses are rapid-acting reactions 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 somatic rearranged receptor genes (e.g., T-cell and B-cell receptors) that recognize antigens from a given pathogen or barrier (e.g., tumor), thus providing specificity and immunological memory. Among its many roles, innate immune responses 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 its own components, the innate immune system uses a variety of relatively invariable receptors that detect the signature of pathogens, known as pathogen-associated molecular patterns or PAMPs. The mechanism behind this enhancement of the 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 conjugation of dendritic receptors (PRRs) leads to the activation of some cells and the secretion of their cytokines and chemokines, as well as the maturation and migration of others. In tandem, this creates an inflammatory environment that leads to the establishment of an adaptive immune response. PRRs include non-phagocytic receptors such as Toll-like receptors (TLRs) and nucleotide-binding oligomeric 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+ phosphatidylcholine receptors (CD4+). + Auxiliary T(T) H Primary immune response of cells and their use in inducing CD8 + T cells differentiate into some of the most important cell types of 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 determines 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.

[0185] "Humoral immune response" refers to an immune response mediated by antibody molecules, while "cellular immune response" refers to an immune response 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 presented 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 and focus their activity against cells displaying peptide antigens associated with MHC molecules on their surface. "Cellular immune response" also refers to the production of cytokines, chemokines, and other such molecules produced by activated T cells and / or other leukocytes, including those derived from CD4+. + and CD8 + Those T cells.

[0186] - 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.

[0187] - "Induction": "Induction" and its variations refer to any measurable increase in cellular activity. For example, the induction of an immune response may include, for instance, an increase in cytokine production, activation, proliferation, or maturation of immune cell populations, and / or other indicators of increased immune function. Detailed Implementation

[0188] This disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0189]

[0190] in:

[0191] R1 means:

[0192] -hydrogen atom, or

[0193] - Selected from the following groups:

[0194] a)

[0195] -(C1-C6)alkyl- groups;

[0196] -hydroxy-(C1-C6)alkyl- groups;

[0197] -NH2-(C1-C6)alkyl- groups;

[0198] -NH-(C1-C6)alkyl-(C1-C6)alkyl- groups;

[0199] -N((C1-C6)alkyl)2-(C1-C6)alkyl- groups;

[0200] -(C2-C6)alkenyl- groups;

[0201] -(C2-C6) ynyl group;

[0202] b)

[0203] - A phenyl (C1-C6) alkyl group that is unsubstituted or substituted with at least one of the following substituents:

[0204] b1)-(C1-C6)alkoxy- group;

[0205] b2)-hydroxyl group;

[0206] b3)-C(O)-H group; and

[0207] b4) - A (C1-C6) alkyl group that is unsubstituted or substituted by at least one of the following substituents:

[0208] b4.1)-hydroxyl; and

[0209] b4.2)--NR4R5 group, wherein R4 and R5 are independently selected from:

[0210] b4.2.1) - Hydrogen atom;

[0211] b4.2.2)-(C1-C 16 )alkyl- groups;

[0212] b4.2.3) - where n is an integer from 1 to 30 CH3-[O-(CH2)2] n - group, (C1-C6)alkoxy(C1-C6)alkyl- group, or (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl- group;

[0213] b4.2.4)-(C1-C6)alkyl-S(O2)- groups;

[0214] b4.2.5)-(C1-C6)alkyl-NH-C(O)- groups;

[0215] b4.2.6)-(C1-C 16 )alkyl-C(O)- groups;

[0216] b4.2.7)-(C1-C 16)alkyl-OC(O)- groups;

[0217] b4.2.8) - where n is an integer from 1 to 30 CH3-[O-(CH2)2] n -C(O)- groups;

[0218] b4.2.9) - unsubstituted or substituted by at least one of the following substituents (C3-C 10 Cycloalkyl groups:

[0219] -hydroxyl group; and

[0220] -(C1-C6)alkyl- groups; or

[0221] b4.2.10) - Contains one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2- (C3-C 10 ) heterocyclic alkyl groups;

[0222] b4.2.11)-phenyl-C(O)- group;

[0223] b4.2.12)-(C1-C6)alkoxy-phenyl-(C1-C6)alkyl-OC(O)- groups;

[0224] b4.2.13)-(C1-C 16 )alkyl-C(O)-NH-phenyl-(C1-C6)alkyl-OC(O)- groups;

[0225] b4.2.14)-(C1-C 16 )alkyl-OC(O)-(C1-C6)alkyl- groups;

[0226] Or R4 and R5 together with the nitrogen atoms to which they are attached form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one to four heteroatoms selected from oxygen, nitrogen, and sulfur, wherein 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] where n is an integer from 1 to 30. n - group;

[0227] c) - Unsubstituted or substituted by at least one of the following substituents (C3-C 10 Cycloalkyl (C1-C6)alkyl- groups: -NH2 and NH2-(C1-C6)alkyl- groups;

[0228] d) - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C3-C 10 ) heterocyclic alkyl (C1-C6) alkyl- groups,

[0229] The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the group consisting of (C1-C6) alkyl groups and CH3-[O-(CH2)2] where n is an integer from 1 to 30. n - groups; and

[0230] e) - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) heteroaryl (C1-C6) alkyl- groups,

[0231] The heteroaryl group is either unsubstituted or substituted by at least one substituent selected from the following:

[0232] -(C1-C6)alkyl- groups;

[0233] -NH2-(C1-C6)alkyl- groups, and

[0234] -Cyano;

[0235] f)-(C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 The heterocyclic alkyl group comprises one to four heteroatoms selected from the following: oxygen, nitrogen, S(O), SO2 and sulfur;

[0236] g)-(C3-C 10 )Hypercyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 The heterocyclic alkyl group comprises one to four heteroatoms selected from the following: oxygen, nitrogen, S(O), SO2 and sulfur;

[0237] R2 represents a halogen atom.

[0238] Or selected from the following groups:

[0239] -(C1-C6)alkyl- groups;

[0240] -(C2-C6)alkenyl- groups;

[0241] -(C2-C6) ynyl group;

[0242] -(C1-C6)alkylthio- groups;

[0243] -(C1-C6)alkylthio(C1-C6)alkyl- groups;

[0244] -(C1-C6)alkyl-S(O)- groups;

[0245] -(C1-C6)alkyl-S(O2)- groups;

[0246] -(C1-C6)alkyl-S(O)-(C1-C6)alkyl- groups;

[0247] -(C1-C6)alkyl-S(O2)-(C1-C6)alkyl- groups;

[0248] -(C1-C6)alkoxy- groups;

[0249] -(C1-C6)alkoxy(C1-C6)alkyl- groups;

[0250] -(C1-C6)haloalkoxy(C1-C6)alkyl- groups;

[0251] -(C3-C5)cycloalkyl-O-(C1-C6)alkyl- groups;

[0252] -(C1-C6)alkyl-NH-(C1-C6)alkyl- groups;

[0253] -((C1-C6)alkyl)2-N-(C1-C6)alkyl- groups;

[0254] -(C1-C6)alkyl-NH- groups; and

[0255] -((C1-C6)alkyl)2N- groups;

[0256] R3 indicates:

[0257] -Deuterium atom;

[0258] - Hydrogen atom

[0259] Or selected from the following groups:

[0260] a)

[0261] -(C1-C6)alkyl- groups;

[0262] -(C2-C6)alkenyl- groups;

[0263] -(C2-C6)ynyl- groups; and

[0264] -(C1-C6)alkylthio- groups;

[0265] b)

[0266] --OR6 group, where R6 is selected from:

[0267] - Hydrogen atom;

[0268] -(C1-C6)alkyl- groups;

[0269] -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n - group;

[0270] -(C2-C6)alkenyl- groups;

[0271] -(C2-C6) ynyl group;

[0272] -(C3-C 10 )cycloalkyl- groups;

[0273] -Phenyl;

[0274] -phenyl (C1-C6)alkyl- groups; and

[0275] - Contains one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(=O)- and -S(=O)2- (C3-C 10 ) heterocyclic alkyl groups;

[0276] c)

[0277] --NR7R8 group, wherein R7 and R8 are independently selected from:

[0278] - Hydrogen atom;

[0279] -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -;

[0280] - Unsubstituted or (C1-C6) alkyl groups:

[0281] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) Aromatic compounds; or

[0282] - Phenyl groups that are unsubstituted or substituted with at least one of the following substituents:

[0283] -Cyano, and

[0284] -NR9R 10 -(C1-C6)alkyl- groups, wherein:

[0285] R9 and R 10 Selected independently from:

[0286] - Hydrogen atom;

[0287] -(C1-C6)alkyl- groups;

[0288] -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -,or

[0289] R9 and R 10 Together with the nitrogen atoms to which they are attached, they form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0290] 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] where n is an integer from 1 to 30. n - group;

[0291] Or R7 and R8 together with the nitrogen atoms they are attached to form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one to four heteroatoms selected from oxygen, nitrogen, and sulfur.

[0292] The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the following:

[0293] -phenyl, and

[0294] -hydroxy(C1-C6)alkyl-phenyl- groups;

[0295] d)

[0296] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C3-C 10 ) heterocyclic alkyl groups;

[0297] e)

[0298] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) heteroaryl- group,

[0299] The (C5-C) 10 The heteroaryl group is either unsubstituted or substituted by at least one (C1-C6) alkyl group;

[0300] f)

[0301] --(C6-C 10 Yuan Fangji; and

[0302] g)

[0303] -(C3-C 10 ) Cycloalkyl- groups.

[0304] Among the compounds of formula (I) which are the subject of this disclosure, there is a group of compounds consisting of such compounds, wherein R1 represents...

[0305] -hydrogen atom, or

[0306] - Selected from the following groups:

[0307] a)

[0308] -(C1-C6)alkyl- groups;

[0309] -hydroxy-(C1-C6)alkyl- groups, or

[0310] -NH2-(C1-C6)alkyl- groups;

[0311] b)

[0312] -A phenyl (C1-C6) alkyl group that is either unsubstituted or substituted with a substituent selected from the following:

[0313] b1)-(C1-C6)-alkoxy- group;

[0314] b3)--C(O)-H group, and

[0315] b4) - A (C1-C6) alkyl group substituted with at least one of the following substituents:

[0316] b4.1)-hydroxyl group;

[0317] b4.2)--NR4R5 group, wherein R4 and R5 are independently selected from:

[0318] b4.2.1) - Hydrogen atom;

[0319] b4.2.2)-(C1-C 16 )alkyl- groups;

[0320] b4.2.3) - where n is an integer from 1 to 30 CH3-[O-(CH2)2] n - group, (C1C6)alkoxy(C1-C6)alkyl- group, or (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl- group;

[0321] b4.2.4)-(C1-C6)alkyl-S(O2)- groups;

[0322] b4.2.5)-(C1-C6)alkyl-NH-C(O)- groups;

[0323] b4.2.6)-(C1-C16 )alkyl-C(O)- groups;

[0324] b4.2.7)-(C1-C 16 )alkyl-OC(O)- groups;

[0325] b4.2.8) - where n is an integer from 1 to 30 CH3-[O-(CH2)2] n -C(O)- groups;

[0326] b4.2.9) - Unsubstituted or substituted with at least one (C1-C6) alkyl or hydroxyl group (C3-C4) 10 )cycloalkyl- groups;

[0327] b4.2.10) - Contains one to four heteroatoms selected from the following (C3-C 10 Groups of heterocyclic alkyl groups: oxygen, nitrogen, and -SO2-;

[0328] b4.2.11)-phenyl-C(O)- group;

[0329] b4.2.12)-(C1-C6)alkoxy-phenyl-(C1-C6)alkyl-OC(O)- groups;

[0330] b4.2.13)-(C1-C 16 )alkyl-C(O)-NH-phenyl-(C1-C6)alkyl-OC(O)- groups;

[0331] b4.2.14)-(C1-C 16 )alkyl-OC(O)-(C1-C6)alkyl- groups;

[0332] Or R4 and R5 together with the nitrogen atoms they are attached to form (C3C) 10 A heterocyclic alkyl group, wherein the group comprises one or two heteroatoms selected from oxygen and nitrogen;

[0333] c) - Unsubstituted or substituted by a substituent selected from the following (C3-C 10 Cycloalkyl (C1-C6)alkyl- groups: -NH2 and NH2-(C1-C6)alkyl- groups;

[0334] d) - Unsubstituted (C3-C) compounds containing one or two nitrogen heteroatoms 10 )Hypercyclic alkyl (C1-C6) alkyl- groups;

[0335] e) - Contains a nitrogen atom (C5-C) 10 ) heteroaryl (C1-C6) alkyl- groups,

[0336] The heteroaryl group is either unsubstituted or substituted by at least one substituent selected from the following:

[0337] -NH2-(C1-C6)alkyl- groups, and

[0338] -Cyano;

[0339] f)-(C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 The heterocyclic alkyl group contains a heteroatom selected from oxygen, nitrogen, S(O), SO2 and sulfur;

[0340] g)-(C3-C 10 )Hypercyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 The heterocyclic alkyl group contains a heteroatom selected from oxygen, nitrogen, S(O), SO2 and sulfur.

[0341] Among the compounds of formula (I) which are the subject of this disclosure, there is a group of compounds consisting of compounds in which R1 represents:

[0342] -hydrogen atom, or

[0343] - Selected from the following groups:

[0344] a)

[0345] -methyl;

[0346] -C(OH)(CH3)2-CH2- groups, C(CH3)(CH2OH)2-CH2- groups, CH(CH2OH)2-CH2- groups;

[0347] -NH2-(CH2)4- groups, NH2-(CH2)5- groups, or NH2-(CH2)6- groups;

[0348] b)-Phenylenemethyl (i.e., benzyl),

[0349] The phenyl group is either unsubstituted or substituted with at least one substituent selected from the following:

[0350] b1)-Methoxy, such as methoxy at the para position of a phenyl group;

[0351] b3)--C(O)-H group, such as -C(O)-H at the para position of the phenyl group;

[0352] b4) - A methyl group substituted with at least one of the following substituents:

[0353] b4.1)-hydroxyl group;

[0354] b4.2)--NR4R5 group, wherein R4 and R5 are independently selected from:

[0355] b4.2.1) - Hydrogen atom;

[0356] b4.2.2)-Methyl, isopropyl, pentyl, hexyl, nonyl, decyl;

[0357] b4.2.3)-CH3-O-(CH2)2- groups, CH3-O-((CH2)2-O) 11 -(CH2)2- groups, CH3-O-((CH2)2-O)7-(CH2)2- groups, CH3-O-((CH2)2-O)5-(CH2)2- groups, CH3-O-((CH2)2-O)3-(CH2)2- groups, CH3-O-((CH2)2-O)2-(CH2)2- groups, or CH3-O-(CH2)2-O-(CH2)2- groups;

[0358] The group b4.2.4)-CH3-S(O2)-;

[0359] (b4.2.5)-CH3-CH2-NH-C(O)- groups;

[0360] b4.2.6) Groups of CH3-C(O)-, CH3-CH2-C(O)-, CH3-(CH2)5-C(O)-, CH3-(CH2)9-C(O)-, or CH3-(CH2)3-C(O)-;

[0361] b4.2.7)-CH3-CH2-OC(O)- group;

[0362] b4.2.8)-CH3-[O-(CH2)2]2-C(O)- or CH3-O-(CH2)2-C(O)-;

[0363] b4.2.9)-Cyclopropyl or cyclobutyl,

[0364] The cyclopropyl or cyclobutyl group is unsubstituted or substituted by at least one substituent selected from the group consisting of hydroxyl or methyl.

[0365] b4.2.10)-Tetrahydropyranyl or thionylbutane dioxide group;

[0366] b4.2.11)-phenyl-C(O)- group;

[0367] b4.2.12)-CH3-O-phenyl-CH2-OC(O)- group;

[0368] b4.2.13)-CH3-C(O)-NH-phenyl-CH2-OC(O)- group;

[0369] b4.2.14)-C(CH3)3-OC(O)-CH2- or C(CH3)3-OC(O)-(CH2)2-;

[0370] or

[0371] R4 and R5 together with the nitrogen atoms to which they are attached form piperazine, morpholino, or pyrrolidinyl groups;

[0372] c) - Cyclohexyl-CH2- groups that are unsubstituted or substituted by at least one of the following substituents: -NH2 groups and NH2-CH2- groups;

[0373] d) A group consisting of piperazinyl-(CH2)2-, piperidinyl-CH2-, or piperidinyl-(CH2)2-; and

[0374] e) - A pyridyl-CH2- group that is unsubstituted or substituted by at least one of the following substituents: NH2-CH2- groups and cyano groups;

[0375] f) A group consisting of tetrahydropyranyl-NH-(CH2)4-, a group consisting of tetrahydropyranyl-NH-(CH2)6-, a group consisting of dioxothioheterocyclic butyl-NH-(CH2)4-, or a group consisting of dioxothioheterocyclic butyl-NH-(CH2)6-.

[0376] g)-Tetrahydropyranyl-N(C(O)-CH3)-(CH2)4-, tetrahydropyranyl-N(C(O)-CH3)-(CH2)6-, dioxothioheterocyclic butyl-N(C(O)-CH3)-(CH2)4-, or dioxothioheterocyclic butyl-N(C(O)-CH3)-(CH2)6-.

[0377] Among the compounds of formula (I) which are the subject of this disclosure, there is a group of compounds consisting of compounds in which R2 represents a group selected from:

[0378] -(C1-C6)alkyl- groups;

[0379] -(C1-C6)alkylthio- groups;

[0380] -(C1-C6)alkyl-S(O)- groups;

[0381] -(C1-C6)alkyl-NH-(C1-C6)alkyl- groups;

[0382] -(C1-C6)alkyl-NH- groups; and

[0383] -(C1-C6)alkoxy(C1-C6)alkyl- groups.

[0384] Among the compounds of formula (I) which are the subject of this disclosure, there is a group of compounds consisting of compounds in which R2 represents a group selected from:

[0385] -Methyl, ethyl, n-propyl, n-butyl;

[0386] -CH3-(CH2)2-S- groups;

[0387] -CH3-(CH2)2-S(O)- groups;

[0388] -CH3-S-(CH2)2- groups;

[0389] -CH3-CH2-O-CH2- groups;

[0390] -CH3-O-(CH2)2- groups;

[0391] -CH3-CH2-NH-CH2- groups; and

[0392] -CH3-(CH2)2-NH- group.

[0393] Among the compounds of formula (I) which are the subject of this disclosure, there is a group of compounds consisting of compounds in which R2 represents (C1-C6) alkyl, such as butyl such as n-butyl, methyl, or propyl such as n-propyl.

[0394] Among the compounds of formula (I) which are the subject of this disclosure, there is a group of compounds consisting of compounds in which R3 represents:

[0395] -hydrogen atom, or

[0396] - Selected from the following groups:

[0397] a)-(C1-C6)alkyl- groups;

[0398] -(C2-C6)alkenyl- groups;

[0399] -(C1-C6)alkylthio- groups;

[0400] b)

[0401] --OR6 group, where R6 is selected from:

[0402] - Hydrogen atom;

[0403] -(C1-C6)alkyl- groups;

[0404] -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n - group;

[0405] -(C2-C6)alkenyl;

[0406] -(C3-C 10 )cycloalkyl;

[0407] -Phenyl;

[0408] -phenyl (C1-C6 alkyl)- groups; and

[0409] - Contains a heteroatom selected from oxygen, sulfur, -S(O)- and -SO2- (C3-C 10 ) heterocyclic alkyl groups;

[0410] c)

[0411] --NR7R8 group, wherein R7 and R8 are independently selected from:

[0412] - Hydrogen atom;

[0413] -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -;

[0414] - Unsubstituted or (C1-C6) alkyl groups:

[0415] - Contains one oxygen atom (C5-C) 10 ) heteroaryl- groups; or

[0416] - Phenyl groups that are unsubstituted or substituted with at least one of the following substituents:

[0417] -Cyano, and

[0418] -NR9R 10 -(C1-C6)alkyl- groups, wherein R9 and R... 10 Selected independently from:

[0419] - Hydrogen atom;

[0420] --(C1-C6)alkyl, or

[0421] -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -;

[0422] Or R9 and R 10 Together with the nitrogen atoms attached to them, they form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one or two heteroatoms selected from oxygen and nitrogen.

[0423] The (C3-C) 10 The heterocyclic alkyl group is replaced by at least one (C1-C6) alkyl group, such as one to three (C1-C6) alkyl groups, such as one (C1-C6) alkyl group;

[0424] Or R7 and R8 together with the nitrogen atoms they are attached to form (C3C) 10 A heterocyclic alkyl group, wherein the group contains a nitrogen atom,

[0425] The heterocyclic alkyl group is unsubstituted or substituted with at least one substituent, such as one to three substituents, including a substituent selected from:

[0426] -phenyl, and

[0427] -hydroxy(C1-C6)alkyl-phenyl- groups;

[0428] d)

[0429] -(C3-C 10 A heterocyclic alkyl group, wherein the group comprises a heteroatom selected from oxygen and nitrogen;

[0430] e)

[0431] - Contains one or two heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) heteroaryl- group,

[0432] The (C5-C) 10 The heteroaryl group is unsubstituted or substituted by at least one (C1-C6) alkyl group, such as one to three (C1-C6) alkyl groups, such as one (C1-C6) alkyl group.

[0433] f)

[0434] -(C6-C 10 ) aryl- groups, and

[0435] g)

[0436] -(C3-C 10 ) Cycloalkyl- groups.

[0437] Among the compounds of formula (I) which are the subject of this disclosure, there is a group of compounds consisting of compounds in which R3 represents:

[0438] -hydrogen atom, or

[0439] - Selected from the following groups:

[0440] a)

[0441] -Isopropyl, isobutyl, isopentyl;

[0442] -C-(CH3)(=CH2)- groups, (CH3)2C=CH- groups, (CH3)2CH-CH=CH- groups;

[0443] -isopropylthio- group;

[0444] b)

[0445] --OR6 group, where R6 represents:

[0446] - Hydrogen atom;

[0447] -Methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl;

[0448] -CH3-O-(CH2)2- groups;

[0449] -Propylene group;

[0450] -cyclopentyl;

[0451] - Unsubstituted phenyl groups, phenyl-CH2- groups;

[0452] -Tetrahydropyranyl, tetrahydrothiophene group, tetrahydrothiophene oxide group, tetrahydrothiophene dioxide group or tetrahydrofuranyl;

[0453] c)

[0454] -NR7R8 group, wherein R7 and R8 are independently selected from:

[0455] - Hydrogen atom;

[0456] -CH3-O-(CH2)2- groups;

[0457] -Methyl, isopropyl;

[0458] -furanyl-(CH2)3- group;

[0459] -phenyl-(CH2)- group, wherein the phenyl group is unsubstituted or substituted with at least one substituent, for example, one to five substituents, such as one substituent, said substituent being selected from:

[0460] -Cyano, and

[0461] -NR9R 10 -CH2- groups, in which

[0462] R9 and R 10 Selected independently from:

[0463] - Hydrogen atom;

[0464] -methyl, or

[0465] -CH3-O-(CH2)2- groups;

[0466] Or R9 and R 10 Together with the nitrogen atoms to which they are attached, they form morpholino groups or piperazine groups, which are either unsubstituted or substituted with at least one methyl group.

[0467] Alternatively, R7 and R8, together with the nitrogen atoms they are attached to, form pyrroloalkyl groups.

[0468] The pyrrolidinium is unsubstituted or substituted with at least one substituent, such as one to three substituents, including a substituent selected from:

[0469] -phenyl, or

[0470] -OH-CH2-phenyl- groups, for example, OH-CH2- groups at the para position of the phenyl group;

[0471] d)

[0472] -Tetrahydrofuranyl, dihydropyrrolidinyl or dihydrofuranyl;

[0473] e)

[0474] -Thiophene, furanyl, pyrrole, pyrazolyl

[0475] The thiophene, furanyl, pyrroleyl or pyrazolyl groups are unsubstituted or substituted by at least one methyl group, for example one to three methyl groups, such as one methyl group;

[0476] f)

[0477] -Phenyl;

[0478] g)

[0479] -Cyclopentenyl, cyclopentyl, cyclohexenyl, and cyclohexyl.

[0480] All of these subgroups, individually or in combination, are part of this public text.

[0481] According to one specific embodiment, this disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, provided that at least one of R1 and R3 is not a hydrogen atom.

[0482] According to another specific embodiment, this disclosure relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, provided that R1 and R3 are not hydrogen atoms at the same time.

[0483] According to another embodiment, this disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0484]

[0485] in:

[0486] R1 represents a group selected from the following:

[0487] a)

[0488] -(C1-C6)alkyl, such as methyl;

[0489] -NH2-(C1-C6)alkyl- groups, such as NH2-(CH2)4- groups, NH2-(CH2)5- groups, and NH2-(CH2)6- groups;

[0490] b) A phenyl (C1-C6)alkyl group, such as benzyl, wherein the phenyl group is unsubstituted or substituted with at least one substituent, for example, one to five substituents, such as one substituent, said substituent being selected from:

[0491] b1)-(C1-C6)alkoxy, such as methoxy, such as methoxy at the para position of a phenyl group;

[0492] b3)--C(O)-H, such as -C(O)-H at the para position of the phenyl group, and

[0493] b4)-(C1-C6)alkyl, such as methyl, such as methyl at the para and / or one or more meta positions of a phenyl group, wherein the alkyl group itself is unsubstituted or substituted by at least one substituent, such as one substituent selected from:

[0494] b4.1)-hydroxyl group;

[0495] b4.2)--NR4R5 group, where R4 and R5 are independent of each other:

[0496] b4.2.1) - Hydrogen atom;

[0497] b4.2.2)-(C1-C 16 )alkyl- groups, such as isopropyl;

[0498] b4.2.3) - where n is an integer from 1 to 30 (e.g., n is 6 or 8) of CH3-[O-(CH2)2] n - group;

[0499] b4.2.5)-(C1-C6)alkyl-NH-C(O)- groups, such as CH3-CH2-NH-C(O)- groups;

[0500] b4.2.6)-(C1-C 16 )alkyl-C(O)- groups, such as CH3-C(O)-;

[0501] b4.2.7)-(C1-C 16 )alkyl-OC(O)- groups, such as CH3-CH2-OC(O)- groups;

[0502] b4.2.8) - where n is an integer from 1 to 30 (e.g., n is 1) of CH3-[O-(CH2)2] n -C(O)- groups;

[0503] b4.2.9)-(C3-C 10 ) A cycloalkyl group, such as cyclobutyl, wherein the cycloalkyl group is unsubstituted or substituted by at least one substituent, such as one to five substituents, such as a (C1-C6) alkyl group, such as methyl;

[0504] b4.2.10) - Contains a heteroatom (C3-C 10 A heterocyclic alkyl group, wherein the heteroatom is -SO2-, for example, a thioheterocyclic butane dioxide group;

[0505] b4.2.12)-(C1-C6)alkoxy-phenyl-(C1-C6)alkyl-OC(O)-, such as CH3-O-p-phenyl-CH2-OC(O)-.

[0506] Or R4 and R5 together with the nitrogen atoms to which they are attached form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one to four heteroatoms selected from oxygen, nitrogen, and sulfur, wherein 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] where n is an integer from 1 to 30. n- Groups, such as R4 and R5, together with the nitrogen atoms to which they are attached, form piperazine groups;

[0507] c)-(C3-C 10 ) A cycloalkyl (C1-C6)alkyl- group, such as a cyclohexyl-CH2- group, wherein the cycloalkyl group is unsubstituted or substituted by: at least one substituent, such as one to five substituents, such as a substituent selected from NH2 and NH2-(C1-C6)alkyl- groups, such as NH2-CH2- groups;

[0508] d)-(C3-C 10 A heterocyclic alkyl (C1-C6) alkyl group, such as a piperazine-(CH2)2- group or a piperidinyl-(CH2)2- group, wherein the heterocyclic alkyl group contains one or two nitrogen atoms, such as piperazine or piperidinyl;

[0509] e)-(C5-C 10 A heteroaryl (C1-C6) alkyl- group, such as a pyridyl-CH2- group, wherein the heteroaryl contains a nitrogen atom, such as a pyridyl, and the heteroaryl is unsubstituted or substituted by at least one substituent, such as one to three substituents, such as a cyano group;

[0510] f)-(C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 The heterocyclic alkyl group comprises one to four heteroatoms, for example, one heteroatom selected from oxygen, nitrogen, S(O), SO2 and sulfur, such as a dioxothioheterocyclic butyl group -NH-(CH2)4-.

[0511] g)-(C3-C 10 )Hypercyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 The heterocyclic alkyl group comprises one to four heteroatoms, such as one heteroatom selected from oxygen, nitrogen, S(O), SO2 and sulfur, such as tetrahydropyranyl-N(C(O)-(CH3))-(CH2)4-, tetrahydropyranyl-N(C(O)-(CH3))-(CH2)6-, dioxothioheterocyclic butyl-N(C(O)-(CH3))-(CH2)4- or dioxothioheterocyclic butyl-N(C(O)-(CH3))-(CH2)6-.

[0512] R2 represents a group selected from the following:

[0513] -(C1-C6)alkyl, such as n-butyl or n-propyl;

[0514] -(C1-C6)alkoxy(C1-C6)alkyl- groups, such as CH3CH2-O-CH2- groups, and

[0515] -(C1-C6)alkyl-S(O)- groups, such as CH3CH2CH2-S(O)- groups;

[0516] R3 indicates a group selected from the following:

[0517] a)-(C1-C6)alkyl- groups, such as isopropyl, isobutyl or isopentyl;

[0518] -(C2-C6)alkenyl- groups, such as propenyl such as C(CH3)(=CH2)-, butenyl such as (CH3)2C=CH-, or pentenyl such as (CH3)2CH-CH=CH-;

[0519] -(C1-C6)alkylthio- groups, such as isopropylthio- groups;

[0520] b) --OR6 group,

[0521] R6 is:

[0522] -(C1-C6)alkyl- groups, such as methyl, isopropyl, n-propyl, n-butyl or sec-butyl;

[0523] -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n - groups, such as CH3-O-(CH2)2-;

[0524] -(C2-C6)alkenyl- groups, such as propenyl groups, such as -CH2-CH=CH2;

[0525] -(C3-C 10 )cycloalkyl groups, such as cyclopentyl;

[0526] -Phenyl;

[0527] -phenyl(C1-C6)alkyl)- groups, such as benzyl; or

[0528] - Contains a heteroatom selected from oxygen, sulfur, -S(O)- and -SO2- (C3-C 10 Groups of heterocyclic alkyl groups, such as tetrahydropyranyl, tetrahydrothiophene dioxide group, tetrahydrothiophene group, tetrahydrothiophene oxide group, and tetrahydrofuranyl;

[0529] c)--NR7R8 group,

[0530] R7 and R8 are selected independently from:

[0531] - Hydrogen atom;

[0532] -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n - groups, such as CH3-O-(CH2)2-;

[0533] -(C1-C6)alkyl, such as methyl or isopropyl, wherein the (C1-C6)alkyl is unsubstituted or substituted with a phenyl group (to form, for example, benzyl), wherein the phenyl group is unsubstituted or substituted with at least one NH2-(C1-C6)alkyl-, such as one to five NH2-(C1-C6)alkyl-, such as one NH2-(C1-C6)alkyl-, such as NH2-CH2-:

[0534] Alternatively, R7 and R8, together with the nitrogen atoms to which they are attached, form a (C3-C) group containing a nitrogen heteroatom. 10 ) heterocyclic alkyl groups, such as pyrrolidinyl groups;

[0535] d) - Contains one oxygen heteroatom (C3-C 10 ) A heterocyclic alkyl group, such as tetrahydrofuranyl or dihydrofuranyl;

[0536] e) - Contains one or two heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) heteroaryl- groups, such as thienyl, furanyl or pyrroleyl, said (C5-C 10 The heteroaryl group is either unsubstituted or substituted by: at least one (C1-C6) alkyl group, such as one to three (C1-C6) alkyl groups, such as one (C1-C6) alkyl group, for example, methyl, and

[0537] g)-(C3-C 10 )Cycloalkyl, such as cyclopentenyl, cyclopentyl, cyclohexenyl or cyclohexyl.

[0538] According to another embodiment, this disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0539]

[0540] in:

[0541] R1 represents a hydrogen atom or a group selected from the following:

[0542] a)

[0543] -(C1-C6)alkyl- groups, such as methyl groups;

[0544] -hydroxy-(C1-C6)alkyl- groups, such as C(OH)(CH3)2-CH2- groups, C(CH3)(CH2OH)2-CH2- groups or CH(CH2OH)2-CH2- groups;

[0545] b)

[0546] -Phenyl (C1-C6)alkyl- groups, such as benzyl, wherein the phenyl group is unsubstituted or substituted by: at least one (C1-C6)alkyl- group, such as one to five (C1-C6)alkyl- groups, such as one (C1-C6)alkyl- group, such as methyl, such as methyl at the para-position and / or one or more meta-positions of the phenyl group, which may replace the alkyl group of the phenyl group itself. The alkyl group itself is unsubstituted or substituted by: at least one -NR4R5 group, such as one -NR4R5 group, wherein R4 and R5 are independently of each other:

[0547] -b4.2.1) Hydrogen atom;

[0548] -b4.2.2)(C1-C 16 )alkyl- groups, such as methyl, hexyl or decyl;

[0549] -b4.2.3) where n is an integer from 1 to 30 (e.g., n is 1, 2, 3, 4, or 12) of CH3-[O-(CH2)2] n - group;

[0550] -b4.2.4)(C1-C6)alkyl-S(O2)- groups, such as CH3-S(O2)- groups;

[0551] -b4.2.6)(C1-C 16 )alkyl-C(O)- groups, such as CH3-CH2C(O)- groups;

[0552] -b4.2.9)(C3-C 10 The cycloalkyl group, such as cyclopropyl or cyclobutyl, is unsubstituted or substituted by at least one (C1-C6) alkyl group, such as one to five (C1-C6) alkyl groups, such as one (C1-C6) alkyl group, such as a methyl group, or substituted by at least one hydroxyl group.

[0553] -b4.2.10) contains one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -SO2 (C3-C 10 ) Groups of heterocyclic alkyl groups, such as thioheterocyclic butane dioxide groups;

[0554] -b4.2.11)-phenyl-C(O)- group;

[0555] -b4.2.13)(C1-C 16 )alkyl-C(O)-NH-phenyl-(C1-C6)alkyl-OC(O)- groups, such as CH3-C(O)-NH-phenyl-CH2-OC(O)- groups;

[0556] -b4.2.14)(C1-C 16 )alkyl-OC(O)-(C1-C6)alkyl- groups, such as C(CH3)3-OC(O)-CH2- groups or C(CH3)3-OC(O)-(CH2)2- groups;

[0557] Or R4 and R5 together with the nitrogen atoms to which they are attached form (C3-C) 10 The (C3-C) group comprises one to four heteroatoms selected from oxygen, nitrogen, and sulfur, for example, one to two heteroatoms selected from nitrogen and oxygen. 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] where n is an integer from 1 to 30. n - Groups, such as R4 and R5, together with the nitrogen atoms to which they are attached, form pyrrolidinyl or morpholino groups;

[0558] c)

[0559] -(C3-C 10 ) A cycloalkyl (C1-C6) alkyl- group, such as a cyclohexyl-CH2- group, wherein the cycloalkyl group is unsubstituted or substituted by at least one NH2 group, such as one to five NH2 groups, including one NH2 group;

[0560] e)

[0561] -(C5-C 10 A heteroaryl (C1-C6)alkyl group, such as a pyridyl-CH2- group, wherein the heteroaryl group contains a nitrogen atom, such as a pyridyl group, and the heteroaryl group is unsubstituted or substituted by: at least one NH2-(C1-C6)alkyl group, such as NH2-CH2-, such as one to three NH2-(C1-C6)alkyl groups, such as one to three NH2-CH2-, such as one NH2-(C1-C6)alkyl group, such as one NH2-CH2-, and

[0562] f)

[0563] -(C3-C 10 ) heterocyclic alkyl-NH-(C1-C16 The heterocyclic alkyl group comprises one to four heteroatoms, such as one heteroatom selected from oxygen, nitrogen, S(O), SO2 and sulfur, such as tetrahydropyranyl-NH-(CH2)4-, tetrahydropyranyl-NH-(CH2)6- or dioxothioheterocyclic butyl-NH-(CH2)6-.

[0564] R2 represents a group selected from the following:

[0565] -(C1-C6)alkyl- groups, such as methyl, n-butyl;

[0566] -(C1-C6) alkylthio- groups, such as CH3CH2CH2S- groups;

[0567] -(C1-C6)alkyl-NH-(C1-C6)alkyl- groups, such as CH3CH2-NH-CH2- groups;

[0568] -(C1-C6)alkyl-NH- groups, such as CH3CH2CH2-NH- groups;

[0569] R3 indicates a group selected from the following:

[0570] a)

[0571] -(C1-C6)alkyl- groups, such as isopentyl;

[0572] -(C2-C6)alkenyl- groups, such as (CH3)2-CH-CH=CH- groups;

[0573] -(C1-C6) alkylthio- groups, such as isopropylthio- groups.

[0574] b)

[0575] --OR6 group, where R6 is a (C1-C6) alkyl group, such as isopropyl, and

[0576] c)

[0577] --NR7R8 group,

[0578] R7 and R8 are independently selected from hydrogen atoms; (C1-C6)alkyl- groups, such as methyl or isopropyl; (C1-C6)alkyl- groups substituted with phenyl groups, such as benzyl, wherein the phenyl group is unsubstituted or substituted with at least one NR9R 10 -(C1-C6)alkyl- groups, such as one to five NR9R groups. 10 -(C1-C6)alkyl- groups, such as an NR9R 10-(C1-C6)alkyl- groups, such as NR9R 10 -CH2- groups,

[0579] R9 and R 10 The groups are (C1-C6)alkyl- groups, such as methyl, or CH3-[O-(CH2)2] where n is an integer from 1 to 30. n - groups, such as CH3-O-(CH2)2- groups,

[0580] Or R9 and R 10 Together with the nitrogen atoms to which they are attached, they form (C3-C) heteroatoms containing one or two heteroatoms selected from oxygen and nitrogen. 10 ) heterocyclic alkyl groups, such as morpholino groups

[0581] Or R7 and R8 together with the nitrogen atoms they are attached to form (C3-C) 10 A heterocyclic alkyl group containing a nitrogen atom, such as a pyrrolidinyl group, wherein the heterocyclic alkyl group is unsubstituted or substituted by at least one substituent, such as one to three substituents, such as a substituent selected from phenyl and hydroxy (C1-C6) alkyl-phenyl groups, such as OH-CH2-phenyl, such as p-OH-CH2-phenyl;

[0582] d)

[0583] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C3-C 10 ) A heterocyclic alkyl group, such as dihydropyrrole or pyrrolealkyl, or

[0584] e)

[0585] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) heteroaryl- group, said (C5-C 10 The heteroaryl group is either unsubstituted or substituted with at least one (C1-C6) alkyl group, such as pyrrole.

[0586] According to another embodiment, this disclosure relates to compounds or pharmaceutically acceptable salts of formula (I):

[0587]

[0588] in:

[0589] R1 represents a group selected from the following:

[0590] a)

[0591] -(C1-C6)alkyl- groups, such as methyl groups;

[0592] -hydroxy-(C1-C6)alkyl- groups, such as C(OH)(CH3)2-CH2- groups, CH(CH2OH)2-CH2- groups or C(CH2OH)2(CH3)-CH2- groups;

[0593] b)

[0594] -Phenyl (C1-C6)alkyl- groups, such as benzyl, wherein the phenyl group is unsubstituted or substituted by: at least one (C1-C6)alkyl- group, such as one to five (C1-C6)alkyl- groups, such as one (C1-C6)alkyl, such as methyl, such as methyl at the para-position and / or one or more meta-positions of the phenyl group, wherein the alkyl group itself is unsubstituted or substituted by: at least one substituent, such as one substituent selected from:

[0595] b4.1)-hydroxyl group;

[0596] b4.2)--NR4R5 group,

[0597] R4 and R5 are independent of each other:

[0598] b4.2.1) - Hydrogen atom;

[0599] b4.2.6)-(C1-C 16 Alkyl-C(O)- groups, such as CH3-C(O)- groups;

[0600] b4.2.9)-(C3-C 10 ) cycloalkyl, such as cyclopropyl or cyclobutyl, wherein the cycloalkyl is unsubstituted or substituted by at least one (C1-C6) alkyl- group, such as one to five (C1-C6) alkyl- groups, such as one (C1-C6) alkyl- group, such as methyl;

[0601] Or R4 and R5 together with the nitrogen atoms to which they are attached form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one to four heteroatoms selected from oxygen, nitrogen, and sulfur, such as a nitrogen atom;

[0602] c)

[0603] -(C3-C 10 A cycloalkyl (C1-C6)alkyl- group, such as a cyclohexyl-CH2- group, wherein the cycloalkyl group is unsubstituted or substituted by at least one substituent, such as one to five substituents, including a substituent selected from NH2 and NH2-(C1-C6)alkyl- groups, such as NH2-CH2- groups; and

[0604] e)

[0605] -(C5-C 10 A heteroaryl (C1-C6)alkyl- group, such as a pyridyl-CH2- group, wherein the heteroaryl contains a nitrogen atom, such as a pyridyl group, and the heteroaryl is unsubstituted or substituted by at least one NH2-(C1-C6)alkyl- group, such as one to three NH2-(C1-C6)alkyl- groups, such as an NH2-(C1-C6)alkyl- group, such as an NH2-CH2- group;

[0606] R2 represents a group selected from the following:

[0607] -(C1-C6)alkyl- groups, such as n-butyl;

[0608] -(C1-C6)alkoxy(C1-C6)alkyl- groups, such as CH3CH2-O-CH2- groups;

[0609] -(C1-C6) alkylthio- groups, such as CH3CH2CH2-S- groups;

[0610] -(C1-C6)alkyl-NH-(C1-C6)alkyl- groups, such as CH3CH2-NH-CH2- groups;

[0611] -(C1-C6)alkyl-NH- groups, such as CH3CH2CH2-NH- groups;

[0612] R3 indicates a group selected from the following:

[0613] b)

[0614] --OR6 group,

[0615] R6 is a (C1-C6) alkyl group, such as isopropyl, and

[0616] c)

[0617] --NR7R8 group,

[0618] R7 and R8 are independently selected from (C1-C6) alkyl- groups, such as methyl; and (C1-C6) alkyl- groups substituted with phenyl groups, such as benzyl, wherein the phenyl group is unsubstituted or substituted with at least one NR9R 10 -(C1-C6)alkyl- groups, such as one to five NR9R groups. 10 -(C1-C6)alkyl- groups, such as an NR9R 10 -(C1-C6)alkyl- groups, such as NR9R 10-CH2- groups, R9 and R 10 Each is independently (C1-C6) alkyl, such as methyl or CH3-[O-(CH2)2] where n is an integer from 1 to 30. n -, for example, the -(CH2)2-OCH3 group, or

[0619] d)

[0620] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C3-C 10 () A heterocyclic alkyl group, such as dihydropyrrole.

[0621] According to another embodiment, this disclosure relates to compounds or pharmaceutically acceptable salts of formula (I):

[0622]

[0623] in:

[0624] R1 means:

[0625] -hydrogen atom, or

[0626] - Selected from the following groups:

[0627] a)

[0628] -(C1-C6)alkyl- groups, such as methyl groups;

[0629] b)

[0630] The -phenyl (C1-C6)alkyl- group, such as the phenylmethyl- group (i.e., benzyl), is either unsubstituted or substituted by at least one substituent selected from the following:

[0631] b1)-(C1-C6)alkoxy- groups, such as methoxy groups; and

[0632] b4)-(C1-C6)alkyl- groups, such as methyl, which are unsubstituted or substituted by at least one of the following:

[0633] b4.2)--NR4R5 group, wherein R4 and R5 are independently selected from:

[0634] b4.2.1) - Hydrogen atom; and

[0635] b4.2.3) - where n is an integer from 1 to 30 (e.g., n is 12) of CH3-[O-(CH2)2] n - groups; and

[0636] c)-(C3-C 10) Cycloalkyl (C1-C6)alkyl- groups, such as cyclohexylmethyl- groups, which are unsubstituted or substituted by at least one -NH2 group;

[0637] R2 represents a group selected from the following:

[0638] -(C1-C6)alkyl- groups, such as methyl or n-butyl;

[0639] -(C1-C6)alkyl-NH-(C1-C6)alkyl- groups, such as CH3CH2-NH-CH2- groups; and

[0640] -(C1-C6)alkyl-NH- groups, such as CH3CH2CH2-NH- groups;

[0641] R3 indicates:

[0642] - Hydrogen atom

[0643] Or selected from the following groups:

[0644] b)

[0645] --OR6 group, where R6 is selected from:

[0646] -hydrogen atom; and

[0647] -(C1-C6)alkyl- groups, such as isopropyl;

[0648] c)

[0649] --NR7R8 group, wherein R7 and R8 are independently selected from:

[0650] - Hydrogen atom;

[0651] -(C1-C6)alkyl- groups, such as methyl or isopropyl, which are unsubstituted or substituted with the following:

[0652] - Phenyl groups that are unsubstituted or substituted with at least one of the following:

[0653] -NR9R 10 -(C1-C6)alkyl- groups, wherein:

[0654] R9 and R 10 Together with the nitrogen atoms to which they are attached, they form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one to four heteroatoms selected from oxygen, nitrogen, and sulfur, such as piperazine group.

[0655] The (C3-C) 10The heterocyclic alkyl group is unsubstituted or substituted by at least one substituent selected from the following: (C1-C6) alkyl- groups, such as methyl;

[0656] d)

[0657] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C3-C 10 Groups consisting of heterocyclic alkyl groups, such as dihydropyrrolidinyl or pyrrolidinyl; and

[0658] e)

[0659] - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 A heteroaryl group, such as pyrazolyl or pyrroleyl,

[0660] The (C5-C) 10 The heteroaryl group is either unsubstituted or substituted by at least one (C1-C6) alkyl group, such as methyl.

[0661] In this public text, the key The symbol represents a covalent attachment site.

[0662] When R1 represents a (C1-C6) alkyl- group, suitable examples of R1 groups that can be mentioned include methyl, ethyl, propyl, butyl, pentyl, or hexyl, such as methyl, ethyl, propyl, or butyl, like methyl.

[0663] When R1 represents a hydroxyl-(C1-C6)alkyl- group, suitable examples of R1 groups include hydroxymethyl, dihydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxybutyl, trihydroxybutyl, hydroxypentyl, dihydroxypentyl, and hydroxyhexyl, such as hydroxybutyl as C(OH)(CH3)2-CH2-, dihydroxybutyl as CH(CH2OH)2-CH2-, or dihydroxypentyl as C(CH3)(CH2OH)2-CH2-. In other words, at least one hydroxyl group replaces a hydrogen atom belonging to the alkyl moiety.

[0664] When R1 represents an NH2-(C1-C6)alkyl- group, suitable examples of R1 groups that may be mentioned include NH2-methyl- groups, NH2-ethyl- groups, NH2-propyl- groups, NH2-butyl- groups, NH2-pentyl- groups, or NH2-hexyl- groups, such as NH2-butyl- groups like NH2-(CH2)4-, NH2-pentyl- groups like NH2-(CH2)5-, or NH2-hexyl- groups like NH2-(CH2)6-.

[0665] When R1 represents an NH-(C1-C6)alkyl-(C1-C6)alkyl- group, suitable examples of R1 groups that can be mentioned include NH(CH3)-CH2- groups, NH(C2H5)-CH2- groups, NH(CH3)-(CH2)3- groups, or NH(C3H7)-(CH2)6- groups.

[0666] When R1 represents a group of N((C1-C6)alkyl)2-(C1-C6)alkyl-, suitable examples of R1 groups that can be mentioned include groups of N(CH3)2-CH2-, N(CH3)(C2H5)-CH2-, N(C3H7)(CH3)-(CH2)3-, or NH(C4H9)-(CH2)6-.

[0667] When R1 represents a (C2-C6) alkenyl- group, suitable examples of R1 groups that may be mentioned include ethenyl (or vinyl), propenyl, butenyl, pentenyl, or hexenyl, such as vinyl or propenyl.

[0668] When R1 represents a (C2-C6) ynyl- group, suitable examples of R1 groups that may be mentioned include ethynyl, propynyl, butynyl, pentylyl, or hexynyl, such as ethynyl or propynyl.

[0669] When R1 represents a phenyl (C1-C6)alkyl group, suitable examples of R1 groups that may be mentioned include benzyl, phenylpropyl, phenylbutyl, phenylpentyl, or phenylhexyl, such as benzyl.

[0670] When R1 represents a phenyl (C1-C6)alkyl group, the phenyl is substituted by a (C1-C6)alkyl group (e.g., methyl, such as methyl at the para and / or one or more meta positions of the phenyl) and the (C1-C6)alkyl group itself is substituted by a -NR4R5 group, for which suitable (C3-C5) groups may be mentioned. 10 Examples of heterocyclic alkyl groups include: piperazine, morpholino, pyrrolidine, tetrahydropyran, thiocyclic butane dioxide, piperidine, tetrahydrothiophene, tetrahydrothiophene oxide, tetrahydrothiophene dioxide, dihydrofuran, tetrahydrofuran, azacyclic butane, oxacyclic butane, thiocyclic butane, 2H-pyrrole, 1H-, 2H- or 3H-pyrroleline, tetrahydrothiophene, oxadiazole, 1,3,4-oxadiazole, 1,3,5-oxadiazole, thiadiazole, 1,3,4-thiadiazole, isoxazoline, 2- or 3-pyrazoline, pyrrolidine, pyrazolidine, imidazoline, imidazoline, thiazoline, isoxazoline, isoxazoline, dioxazoline, oxazoline, and dioxazole groups, such as tetrahydropyran or thiocyclic butane dioxide, such as...

[0671]

[0672] When R1 represents a phenyl (C1-C6)alkyl group, the phenyl is substituted by a (C1-C6)alkyl group (e.g., methyl, such as methyl at the para and / or one or more meta positions of the phenyl) and the (C1-C6)alkyl group itself is substituted by a -NR4R5 group, for which suitable unsubstituted or substituted (C3-C6) groups may be mentioned. 10 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, such as cyclopropyl or cyclobutyl, etc.

[0673]

[0674] When R1 represents a phenyl (C1-C6)alkyl group, the phenyl is substituted with a (C1-C6)alkyl group (e.g., methyl, such as methyl at the para and / or one or more meta positions of the phenyl) and the (C1-C6)alkyl group itself is substituted with a -NR4R5 group, wherein R4 and R5 together with the nitrogen atom to which they are attached form a (C3-C6)alkyl group. 10 The group consisting of a heterocyclic alkyl group, and suitable examples of NR4R5 groups that may be mentioned include unsubstituted or substituted (C3-C4R5) groups. 10 Groups consisting of heterocyclic alkyl groups, such as unsubstituted or substituted piperazine groups, unsubstituted or substituted morpholino groups, or unsubstituted or substituted pyrrolidinyl groups, such as...

[0675]

[0676] When R1 represents unsubstituted or substituted (C5-C) 10 When referring to a heteroaryl (C1-C6)alkyl group, suitable examples of the R1 group include pyridyl-CH2- groups, pyridyl-(CH2)2- groups, pyridyl-(CH2)3- groups, pyridyl-(CH2)4- groups, pyridyl-(CH2)5- groups, pyridyl-(CH2)6- groups, and pyridyl-(C(CH3)2)- groups, such as pyridyl-CH2- groups, wherein the pyridyl group is unsubstituted or substituted and, for example, as follows:

[0677]

[0678] When R1 represents (C3-C 10When referring to a heterocyclic alkyl (C1-C6)alkyl group, suitable examples of suitable R1 groups include piperazine (C1-C6)alkyl groups, piperidinyl (C1-C6)alkyl groups, morpholino (C1-C6)alkyl groups, tetrahydrofuran (C1-C6)alkyl groups, or tetrahydropyran (C1-C6)alkyl groups, such as piperazine-(CH2)2- groups, piperazine-CH2- groups, piperazine-(CH2)3- groups, piperazine-(CH2)4- groups, piperidinyl-(CH2)- groups, or piperidinyl-(CH2)2- groups, such as...

[0679]

[0680] When R1 represents unsubstituted or substituted (C3-C) 10 When referring to cycloalkyl (C1-C6)alkyl groups, suitable examples of suitable R1 groups include cyclopropyl (C1-C6)alkyl groups, cyclopropenyl (C1-C6)alkyl groups, cyclobutyl (C1-C6)alkyl groups, cyclobutenyl (C1-C6)alkyl groups, cyclopentyl (C1-C6)alkyl groups, cyclopentenyl (C1-C6)alkyl groups, cyclohexyl (C1-C6)alkyl groups, cyclooctyl (C1-C6)alkyl groups, cyclononyl (C1-C6)alkyl groups, or cyclodecyl (C1-C6)alkyl groups, such as cyclohexyl-CH2- groups, where the cyclohexyl group is unsubstituted or substituted, such as:

[0681]

[0682] When R1 represents (C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 When referring to alkyl groups, suitable examples of R1 groups that can be mentioned include dioxothioheterocyclic butyl-NH-(C1-C) 16 )alkyl- groups, piperazine-NH- (C1-C 16 )alkyl- groups, piperidinyl-NH- (C1-C 16 )alkyl- groups, morpholino-NH- (C1-C 16 )alkyl- groups, tetrahydrofuranyl-NH-(C1-C 16 ) alkyl- groups, or tetrahydropyranyl-NH- (C1-C 16 )alkyl- groups, such as tetrahydropyranyl-NH-(CH2)4- groups, tetrahydropyranyl-NH-(CH2)6- groups, dioxothioheterocyclic butyl-NH-(CH2)4- groups, dioxothioheterocyclic butyl-NH-(CH2)6- groups, such as

[0683]

[0684] When R1 represents (C3-C 10 )Hypercyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 When referring to alkyl groups, suitable examples of R1 groups that can be mentioned include dioxothioheterocyclic butyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 )alkyl- groups, piperazine-N(C(O)-(C1-C6)alkyl)-(C1-C 16 )alkyl- groups, piperidinyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 )alkyl- groups, morpholino-N(C(O)-(C1-C6)alkyl)-(C1-C 16 )alkyl- groups, tetrahydrofuranyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 )alkyl- groups, or tetrahydropyranyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 Alkyl groups, such as tetrahydropyranyl-N(C(O)CH3)-(CH2)4-, tetrahydropyranyl-N(C(O)CH3)-(CH2)6-, dioxothioheterocyclic butyl-N(C(O)CH3)-(CH2)4-, dioxothioheterocyclic butyl-N(C(O)CH3)-(CH2)6-, and so on.

[0685]

[0686] When R2 represents a (C1-C6) alkyl- group, suitable examples of R2 groups that can be mentioned include: methyl, ethyl, propyl, butyl, pentyl, or hexyl, such as methyl, ethyl, propyl such as n-propyl, and butyl such as n-butyl.

[0687] When R2 represents a (C2-C6) alkenyl- group, suitable examples of R2 groups that can be mentioned include ethenyl (or vinyl), propenyl, butenyl, pentenyl, or hexenyl, such as vinyl or propenyl.

[0688] When R2 represents a (C2-C6) ynyl- group, suitable examples of R2 groups that can be mentioned include ethynyl, propynyl, butynyl, pentylyl, or hexynyl, such as ethynyl or propynyl.

[0689] When R2 represents a (C1-C6) alkylthio- group, suitable examples of R2 groups that can be mentioned include methylthio, ethylthio, propylthio, butylthio, pentylthio, or hexylthio, such as propylthio such as CH3-(CH2)2-S-.

[0690] When R2 represents a (C1-C6)alkylthio(C1-C6)alkyl- group, suitable examples of R2 groups that can be mentioned include methylthiomethyl, methylthioethyl, ethylthiopropyl, butylthioethyl, pentylthiohexyl, for example CH3-S-(CH2)2-.

[0691] When R2 represents a (C1-C6)alkyl-S(O)- group, suitable examples of R2 groups that can be mentioned include groups of methyl-S(O)-, ethyl-S(O)-, propyl-S(O)-, butyl-S(O)-, pentyl-S(O)-, and hexyl-S(O)-, such as groups of methyl-S(O)-, ethyl-S(O)-, or propyl-S(O)-.

[0692] When R2 represents a (C1-C6)alkyl-SO2- group, suitable examples of R2 groups that can be mentioned include methyl-SO2- groups, ethyl-SO2- groups, propyl-SO2- groups, butyl-SO2- groups, pentyl-SO2- groups, hexyl-SO2- groups, such as methyl-SO2- groups or ethyl-SO2- groups.

[0693] When R2 represents a (C1-C6)alkyl-S(O)-(C1-C6)alkyl- group, suitable examples of R2 groups that can be mentioned include methyl-S(O)-methyl, ethyl-S(O)-propyl, or pentyl-S(O)-hexyl.

[0694] When R2 represents a (C1-C6)alkyl-SO2-(C1-C6)alkyl- group, suitable examples of R2 groups that can be mentioned include methyl-SO2-methyl- groups, ethyl-SO2-propyl- groups, and hexyl-SO2-butyl- groups.

[0695] When R2 represents a (C1-C6)alkoxy- group, suitable examples of R2 groups that may be mentioned include methoxy, ethoxy, propoxy such as n-propoxy or isopropoxy, butoxy such as n-butoxy, sec-butoxy, tert-butoxy or isobutoxy, pentoxy such as n-pentoxy, isopentoxy or tert-pentoxy, or hexoxy such as n-hexoxy, isopentoxy or tert-hexoxy.

[0696] When R2 represents a (C1-C6)alkoxy(C1-C6)alkyl- group, suitable examples of R2 groups that can be mentioned include methoxymethyl, methoxyethyl, ethoxypropyl, butoxyethyl, such as CH3-CH2-O-CH2- or CH3-O-(CH2)2-.

[0697] When R2 represents a (C1-C6)haloalkoxy (C1-C6)alkyl group, suitable examples of R2 groups that can be mentioned include trifluoromethoxymethyl or difluoromethoxyethyl.

[0698] When R2 represents a (C3-C5)cycloalkyl-O-(C1-C6)alkyl- group, suitable examples of R2 groups that may be mentioned include cyclopropyl-O-methyl, cyclopropyl-O-ethyl, cyclopropyl-O-hexyl, cyclopropenyl-O-ethyl, cyclobutyl-O-methyl, cyclobutyl-O-propyl, cyclobutenyl-O-butyl, cyclopentyl-O-methyl, cyclopentyl-O-ethyl, or cyclopentenyl-O-ethyl, such as cyclobutyl-O-methyl or cyclopentyl-O-ethyl.

[0699] When R2 represents a (C1-C6) alkyl-NH- group, suitable examples of R2 groups that may be mentioned include methyl-NH- groups, ethyl-NH- groups, propyl-NH- groups, butyl-NH- groups, pentyl-NH- groups, or hexyl-NH- groups, such as CH3NH-, CH3CH2NH-, or CH3CH2CH2NH-.

[0700] When R2 represents a ((C1-C6)alkyl)2-N- group, suitable examples of R2 groups that can be mentioned include (CH3)2-N- groups, (C2H5)2-N- groups, (CH3)(C2H5)N- groups, or (C3H7)2-N- groups.

[0701] When R2 represents a (C1-C6)alkyl-NH-(C1-C6)alkyl- group, suitable examples of R2 groups that can be mentioned include groups of CH3-NH-CH2-, CH3-CH2-NH-CH2-, CH3-NH-C2H5-, or C3H7-NH-CH2-.

[0702] When R2 represents a ((C1-C6)alkyl)2-N-(C1-C6)alkyl- group, suitable examples of R2 groups that can be mentioned include (CH3)2-N-CH2- groups, (CH3)(C2H5)N-CH2- groups, or (CH3)(C2H5)N-C3H7- groups.

[0703] When R3 represents a (C1-C6) alkyl- group, suitable examples of R3 groups that can be mentioned include: methyl, ethyl, propyl, butyl, pentyl or hexyl, such as propyl, butyl, and pentyl such as isopropyl, isobutyl or isopentyl.

[0704] When R3 represents a (C2-C6) alkenyl- group, suitable examples of R3 groups that can be mentioned include: ethenyl (or vinyl), propenyl, butenyl, pentenyl, or hexenyl, such as propenyl as C(CH3)(=CH2)-, butenyl as (CH3)2C=CH-, or pentenyl as (CH3)2CH-CH=CH-.

[0705] When R3 represents a (C2-C6) ynyl- group, suitable examples of R3 groups that may be mentioned include ethynyl, propynyl, butynyl, pentylyl, or hexynyl, such as ethynyl or propynyl.

[0706] When R3 represents a (C1-C6) alkylthio- group, suitable examples of R3 groups that can be mentioned include: methylthio- groups, ethylthio- groups, propylthio- groups, butylthio- groups, pentylthio- groups, or hexylthio- groups, such as propylthio- groups, such as isopropylthio- groups.

[0707] When R3 represents an -OR6 group and R6 is a (C1-C6)alkyl- group, suitable examples of R6 groups that can be mentioned include: methyl, ethyl, propyl, butyl, pentyl or hexyl, such as methyl, ethyl, propyl or butyl, such as methyl, ethyl, isopropyl, n-propyl, n-butyl or sec-butyl.

[0708] When R3 represents the -OR6 group and R6 is CH3-[O-(CH2)2] where n is an integer from 1 to 30. n Suitable examples of R6 groups that can be mentioned include: CH3-O-(CH2)2-, CH3-[O-(CH2)2]2-, CH3-[O-(CH2)2]3-, CH3-[O-(CH2)2]4-, CH3-[O-(CH2)2]5-, CH3-[O-(CH2)2]6-, CH3-[O-(CH2)2]7-, CH3-[O-(CH2)2]8-, CH3-[O-(CH2)2]9-, CH3-[O-(CH2)2] 10 - CH3-[O-(CH2)2] 11 - CH3-[O-(CH2)2] 12 - CH3-[O-(CH2)2] 13 - CH3-[O-(CH2)2] 14- CH3-[O-(CH2)2] 15 - CH3-[O-(CH2)2] 16 - CH3-[O-(CH2)2] 17 - CH3-[O-(CH2)2] 18 - CH3-[O-(CH2)2] 19 - CH3-[O-(CH2)2] 20 - CH3-[O-(CH2)2] 21 - CH3-[O-(CH2)2] 22 - CH3-[O-(CH2)2] 23 - CH3-[O-(CH2)2] 24 - CH3-[O-(CH2)2] 25 - CH3-[O-(CH2)2] 26 - CH3-[O-(CH2)2] 27 - CH3-[O-(CH2)2] 28 - CH3-[O-(CH2)2] 29 - CH3-[O-(CH2)2] 30 -, such as CH3-[O-(CH2)2] 24 - and CH3-O-(CH2)2-.

[0709] When R3 represents an -OR6 group and R6 is a (C2-C6)alkenyl- group, suitable examples of R6 groups that can be mentioned include vinyl, propenyl, butenyl, pentenyl, or hexenyl, such as propenyl such as CH=CH-CH2-.

[0710] When R3 represents an -OR6 group and R6 is a (C2-C6) ynyl- group, suitable examples of R6 groups that can be mentioned include: ethynyl, propynyl, butynyl, pentylyl, or hexynyl, such as ethynyl or propynyl.

[0711] When R3 represents the -OR6 group and R6 is (C3-C... 10 When referring to cycloalkyl- groups, suitable examples of R6 groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, such as cyclopentyl.

[0712] When R3 represents an -OR6 group and R6 is a phenyl ((C1-C6)alkyl)- group, suitable examples of R6 groups that can be mentioned include benzyl (i.e., phenylmethyl), phenylpropyl, phenylbutyl, phenylpentyl, or phenylhexyl, such as benzyl.

[0713] When R3 represents the -OR6 group and R6 is (C3-C... 10 When referring to heterocyclic alkyl groups, suitable examples of R6 groups include piperazine, morpholino, pyrrolidine, tetrahydropyran, thiocyclic butane dioxide, piperidine, tetrahydrothiophene, tetrahydrothiophene oxide, tetrahydrothiophene dioxide, dihydrofuran, tetrahydrofuran, azacyclic butane, oxacyclic butane, thiocyclic butane, 2H-pyrrole, 1H-, 2H- or 3H-pyrrolidine, tetrahydrothiophene, oxadiazole, 1,3,4-oxadiazole, 1,3,5-oxadiazole, thiadiazole, 1,3,4-thiadiazole, isoxazoline, 2- or 3-pyrazoline, pyrrololine, pyrazolidine, imidazoline, imidazoline, thiazoline, isoxazoline, isoxazoline, dioxopentane, oxathiazole, oxathiidine, and dioxazole groups, such as piperazine, morpholino, pyrrolidine, tetrahydropyran, thiohexacyclic butane dioxide, piperidine, tetrahydrothiophene, tetrahydrothiophene oxide, tetrahydrothiophene dioxide, dihydrofuran, and tetrahydrofuran groups, such as tetrahydropyran group, tetrahydrothiophene dioxide group, tetrahydrothiophene group, tetrahydrothiophene oxide group, and tetrahydrofuran group, for example

[0714]

[0715] When R3 represents a -NR7R8 group and R7 and R8 together with the nitrogen to which they are attached form an unsubstituted or substituted 3-10 membered heterocyclic alkyl group, suitable examples of -NR7R8 groups that can be mentioned include unsubstituted or substituted piperazines, morpholinos, or pyrrolidines, such as unsubstituted or substituted pyrrolidines, such as...

[0716]

[0717] When R3 represents a -NR7R8 group and R7 and / or R8 represents a 5-10 member heteroaryl (C1-C6)alkyl group, suitable examples of R7 and / or R8 groups that may be mentioned include pyridine (C1-C6)alkyl groups, furan (C1-C6)alkyl groups, pyrrole (C1-C6)alkyl groups, thiophene (C1-C6)alkyl groups, pyrazole (C1-C6)alkyl groups, oxazole (C1-C6)alkyl groups, isoxazole (C1-C6)alkyl groups, triazole (C1-C6)alkyl groups, tetraazole (C1-C6)alkyl groups, and oxadiazole (C1-C6)alkyl groups. - groups, furazon (C1-C6)alkyl- groups, thiazole (C1-C6)alkyl- groups, isothiazole (C1-C6)alkyl- groups, thiadiazole (C1-C6)alkyl- groups, imidazole (C1-C6)alkyl- groups, pyrimidine (C1-C6)alkyl- groups, pyridazine (C1-C6)alkyl- groups, and triazine (C1-C6)alkyl- groups, such as furanyl-CH2- groups, furanyl-(CH2)2- groups, furanyl-(CH2)3- groups, furanyl-(CH2)4- groups, furanyl-(CH2)5- groups, furanyl-(CH2)6- groups, such as

[0718]

[0719] When R3 represents the -NR7R8 group, R7 and / or R8 represent a phenyl (C1-C6)alkyl group, such as benzyl, and the phenyl group is said to be substituented by at least one group such as an NR9R. 10 When -(C1-C6)alkyl- groups are substituted, suitable NR9Rs can be mentioned. 10 Examples of -(C1-C6)alkyl- groups include:

[0720]

[0721] For R3, when R9 and R 10 Together with the nitrogen atoms attached to them, they form unsubstituted or substituted (C3-C) atoms. 10 When referring to heterocyclic alkyl groups, suitable NR9R can be mentioned. 10Examples of groups include: piperazine, morpholino, pyrrolidine, tetrahydropyran, thiohexacyclic butane dioxide, piperidine, tetrahydrothiophene, tetrahydrothiophene oxide, tetrahydrothiophene dioxide, dihydrofuran, tetrahydrofuran, azacyclic butane, oxacyclic butane, thiohexacyclic butane, 2H-pyrrole, 1H-, 2H- or 3H-pyrroleline, tetrahydrothiophene, oxadiazole, 1,3,4-oxadiazole, 1,3,5-oxadiazole, thiadiazole, 1,3,4-thiadiazole, isoxazoline, 2- or 3-pyrazoline, pyrrolidine, pyrazolidine, imidazoline, imidazoline, thiazoline, isoxazoline, isoxazoline, dioxazoline, oxazodiazole, and dioxazole groups, such as morpholino or piperazine groups, such as...

[0722]

[0723] When R3 represents (C3-C 10 When referring to the alkyl-membered heterocyclic group, suitable examples of 3-10 membered heterocyclic alkyl groups include piperazine, morpholino, pyrrolidine, tetrahydropyran, dihydropyrrole, thiocyclic butane dioxide, piperidine, tetrahydrothiophene, tetrahydrothiophene oxide, tetrahydrothiophene dioxide, dihydrofuran, tetrahydrofuran, aziridine, oxacyclobutane, thiocyclic butane, 2H-pyrrole, 1H-, 2H- or 3H-pyrrole. -Pyrrolidone, tetrahydrothiophene, oxadiazole, 1,3,4-oxadiazole, 1,3,5-oxadiazole, thiadiazole, 1,3,4-thiadiazole, isoxazoline, 2- or 3-pyrrolidone, pyrrolidone, pyrazolidine, imidazoline, imidazoline, thiazoline, isoxazoline, isoxazoline, dioxazoline, dioxazoline, and dioxazole groups, such as tetrahydrofuranyl, dihydropyrrolyl, or dihydrofuranyl, etc.

[0724]

[0725] When R3 represents (C3-C 10 When referring to cycloalkyl groups, suitable (C3-C) groups can be mentioned. 10 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, such as cyclopentenyl, cyclopentyl, cyclohexenyl, or cyclohexyl, etc.

[0726]

[0727] When R3 represents unsubstituted or substituted (C5-C) 10 When referring to a heteroaryl group, suitable examples of such groups include pyridine, furan, pyrrole, thiophene, pyrazole, oxazole, isoxazole, triazole, tetraazole, oxadiazole, furazon, thiazole, isothiazole, thiadiazole, imidazole, pyrimidine, pyridazine, and triazine groups, such as thiophene, furanyl, pyrrole, or pyrazolyl, etc.

[0728]

[0729] When R3 represents (C6-C) 10 When referring to aryl- groups, suitable (C6-C) groups can be mentioned. 10 Examples of aryl- groups include naphthyl and phenyl.

[0730] According to another implementation scheme, R3 means:

[0731]

[0732] In the context of this publication, appropriate references may be made to CH3-[O-(CH2)2], where n is an integer from 1 to 30. n Examples of groups containing - include: CH3-O-(CH2)2-, CH3-[O-(CH2)2]2-, CH3-[O-(CH2)2]3-, CH3-[O-(CH2)2]4-, CH3-[O-(CH2)2]5-, CH3-[O-(CH2)2]6-, CH3-[O-(CH2)2]7-, CH3-[O-(CH2)2]8-, CH3-[O-(CH2)2]9-, CH3-[O-(CH2)2] 10 - CH3-[O-(CH2)2] 11 - CH3-[O-(CH2)2] 12 - CH3-[O-(CH2)2] 13 - CH3-[O-(CH2)2] 14 - CH3-[O-(CH2)2] 15 - CH3-[O-(CH2)2] 16 - CH3-[O-(CH2)2] 17 - CH3-[O-(CH2)2] 18 - CH3-[O-(CH2)2] 19 - CH3-[O-(CH2)2] 20 - CH3-[O-(CH2)2] 21 - CH3-[O-(CH2)2] 22 - CH3-[O-(CH2)2] 23 - CH3-[O-(CH2)2] 24 - CH3-[O-(CH2)2] 25 - CH3-[O-(CH2)2] 26 - CH3-[O-(CH2)2] 27 - CH3-[O-(CH2)2] 28- CH3-[O-(CH2)2] 29 - CH3-[O-(CH2)2] 30 -, such as CH3-[O-(CH2)2] 24 - and CH3-O-(CH2)2.

[0733] In the compounds of formula (I), which are the subject of this disclosure, the following compounds may be mentioned, for example:

[0734] (1) 2-Butyl-7-isopropoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0735] (2) 2-Butyl-N7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0736] (3) 2-Butyl-7-(isopropylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0737] (4) 2-Butyl-1-(4-methoxybenzyl)-7-(2-methoxyethoxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0738] (5) 2-Butyl-1-(4-methoxybenzyl)-7-propoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0739] (6) 7-(allyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0740] (7) 7-(sec-butoxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0741] (8) 7-Butoxy-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0742] (9) 2-Butyl-7-(cyclopentoxy)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0743] (10) 2-Butyl-1-(4-methoxybenzyl)-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0744] (11) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-3-yl)-1H-imidazo[4,5d]pyridazine-4-amine;

[0745] (12)(E)-2-Butyl-1-(4-methoxybenzyl)-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0746] (13) 2-Butyl-7-isopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0747] (14) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0748] (15) 2-Butyl-7-(cyclopent-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0749] (16) 2-Butyl-7-cyclopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0750] (17) 2-Butyl-1-(4-methoxybenzyl)-7-(prop-1-en-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0751] (18) 2-Butyl-7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0752] (19) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0753] (20) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0754] (21) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0755] (22) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0756] (23) 1-(((1S,3R)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (and enantiomers);

[0757] (24) 1-(4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)-2-methylprop-2-ol;

[0758] (25) trans-1-(4-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0759] (26) 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0760] (27)6-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)nicotinonitrile;

[0761] (28)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5d]pyridazin-1-yl)methyl)benzyl)acetamide;

[0762] (29)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)undecanoamide;

[0763] (30)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)pentanamide;

[0764] (31)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-(2-methoxyethoxy)propionamide;

[0765] (32) 1-(((1S,3S)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-]pyridazine-4-amine (and enantiomers);

[0766] (33) 1-(3-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0767] (34) 4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde;

[0768] (35)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)phenyl)methanol;

[0769] (36) 2-Butyl-1-(4-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0770] (37) 3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazinyl)methyl)benzyl)amino)thionecyclobutane 1,1-dioxide;

[0771] (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 butane-3-yl)acetamide;

[0772] (39) 2-Butyl-7-isopropoxy-1-(4-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0773] (40) 2-Butyl-7-isopropoxy-1-(4-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0774] (41) 2-Butyl-N7,N7,1-trimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0775] (42) 2-Butyl-1-methyl-7-(pyrrolid-1-yl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0776] (43) 2-Butyl-N7-(4-((dimethylamino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0777] (44) 2-Butyl-N7,1-Dimethyl-N7-(4-(morpholinomethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0778] (45) 4-(((4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazine-7-yl)(methyl)amino)methyl)benzylnitrile;

[0779] (46)N7-(4-(aminomethyl)benzyl)-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0780] (47) 2-Butyl-N7-(4-(((2-methoxyethyl)(methyl)amino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0781] (48) 2-Butyl-7-ethoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0782] (49) 2-Butyl-1-(4-methoxybenzyl)-N7-(2-methoxyethyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0783] (50) 2-Butyl-7-methoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0784] (51) 2-Butyl-7-cyclohexyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0785] (52) 7-(benzyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0786] (53) 2-Butyl-1-(4-methoxybenzyl)-N7-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0787] (54)(S)-2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0788] (55) 2-Butyl-7-(furan-2-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0789] (56) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0790] (57) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydro-2H-pyran-4-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0791] (58) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrothiophen-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0792] (59) 2-Butyl-1-(4-methoxybenzyl)-7-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0793] (60) 2-Butyl-1-(4-methoxybenzyl)-7-(2-methylprop-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0794] (61) 2-Butyl-7-isobutyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0795] (62) 2-Butyl-1-(4-methoxybenzyl)-7-(thiophen-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0796] (63) 2-Butyl-1-(4-methoxybenzyl)-7-(thiophen-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0797] (64) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0798] (65) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1-oxide isomer A;

[0799] (66) 2-Butyl-7-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0800] (67) 2-Butyl-7-(furan-3-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0801] (68) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1,1-dioxide;

[0802] (69)3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1-oxide isomer B;

[0803] (70) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0804] (71) 2-Butyl-1-(4-methoxybenzyl)-N7,N7-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0805] (72) 2-Butyl-1-(4-methoxybenzyl)-7-phenoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0806] (73) 2-Butyl-7-(2,5-dihydrofuran-3-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0807] (74) 2-Butyl-7-isopropoxy-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0808] (75) 2-Butyl-7-isopropoxy-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0809] (76) 2-Butyl-7-isopropoxy-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0810] (77) 1-(5-aminopentyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0811] (78) 2-Butyl-7-isopropoxy-1-(2-(piperidin-4-yl)ethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0812] (79) 2-Butyl-7-isopropoxy-1-(2-(piperazin-1-yl)ethyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0813] (80) 1-Benzyl-2-Butyl-7-Isopropoxy-1H-Imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0814] (81) 2-Butyl-1-(cyclohexylmethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0815] (82) 2-Butyl-7-isopropoxy-1-(4-(((tetrahydro-2H-pyran-4-yl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0816] (83) 2-Butyl-7-isopropoxy-1-(4-((isopropylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0817] (84)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)heptamide;

[0818] (85)(4-(1-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridine-7-yl)pyrrolidine-3-yl)phenyl)methanol hydrochloride;

[0819] (86) 2-Butyl-7-isopropoxy-1-methyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0820] (87)N7-(4-(aminomethyl)benzyl)-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0821] (88) 2-Butyl-N7-isopropyl-1-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0822] (89) 2-Butyl-1-methyl-7-(3-phenylpyrrolidin-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0823] (90) N7-benzyl-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0824] (91) 2-Butyl-1-methyl-N7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0825] (92) 2-Butyl-1-(4-methoxybenzyl)-7-phenyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0826] (93) 4-Amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-ol;

[0827] (94) 2-Butyl-N7-(3-(furan-2-yl)propyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0828] (95) 2-Butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0829] (96) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0830] (97) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0831] (98) 2-Butyl-N7-isopropyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0832] (99) 2-Butyl-7-(isopropylthio)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0833] (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;

[0834] (101)2-Butyl-7-isopropoxy-1-(4-(pyrrolidone-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0835] (102) 2-Butyl-7-isopropoxy-1-(4-(morpholinomethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0836] (103)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)propionamide;

[0837] (104) 2-Butyl-7-isopropoxy-1-(4-(((2-methoxyethyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0838] (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;

[0839] (106)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)benzamide;

[0840] (107)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-methoxypropionamide;

[0841] (108)2-Butyl-7-isopropoxy-1-(4-(((2-(2-methoxyethoxy)ethyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0842] (109)2-Butyl-1-(4-((hexylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0843] (110)2-Butyl-1-(4-((decylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0844] (111)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate;

[0845] (112)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate-4-methoxybenzyl ester;

[0846] (113)1-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-ethylurea;

[0847] (114)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate 4-acetamidobenzyl ester;

[0848] (115)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)methanesulfonamide;

[0849] (116)2-Butyl-1-(4-((dimethylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0850] (117)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)glycine tert-butyl ester;

[0851] (118)2-Butyl-7-isopropoxy-1-(4-((methylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0852] (119)3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)tert-butyl propionate;

[0853] (120)1-(4-(5,8,11-trioxa-2-azadodecyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0854] (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;

[0855] (122) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]methyl]imidazo[4,5-d]pyridazine-7-aminedi-2,2,2-trifluoroacetate;

[0856] (123) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy] ...

[0857] (124) 2-Butyl-7-isopropoxy-1-(3-((methylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0858] (125) 2-Butyl-1-(3-((dimethylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0859] (126) 2-Butyl-1-(3-((cyclobutylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0860] (127) 2-Butyl-1-(3-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0861] (128) 2-Butyl-7-isopropoxy-1-(3-((isopropylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0862] (129)3-((3-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)thionecyclobutane 1,1-dioxide;

[0863] (130) 2-Butyl-7-isopropoxy-1-(3-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0864] (131) 2-Butyl-7-isopropoxy-1-(3-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0865] (132)(E)-1-(4-(aminomethyl)benzyl)-2-butyl-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0866] (133) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0867] (134) 1-(4-(aminomethyl)benzyl)-2-butyl-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0868] (135) 1-(4-(aminomethyl)benzyl)-2-butyl-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0869] (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

[0870] (138) 1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0871] (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;

[0872] (140)1-(((1R,4R)-4-aminocyclohexyl)methyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0873] (141) 1-(((1R,4R)-4-aminocyclohexyl)methyl)-2-butyl-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0874] (142) 1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0875] (143) 3-[(4-aminocyclohexyl)methyl]-2-butyl-4-pyrrolidine-1-yl-imidazo[4,5-d]pyridazine-7-amine;

[0876] (144) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-(2,5-dihydro-1H-pyrrolo-3-yl)imidazo[4,5-d]pyridazine-4-amine;

[0877] (145) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-pyrrolidine-3-yl-imidazo[4,5-d]pyridazine-4-amine;

[0878] (146) 3-(6-aminohexyl)-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine dihydrochloride;

[0879] (147) 2-Butyl-4-isopropoxy-3-[6-(tetrahydropyran-4-ylamino)hexyl]imidazo[4,5-d]pyridazine-7-amine dihydrochloride;

[0880] (148)N-[6-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)hexyl]-N-tetrahydropyran-4-yl-acetamide;

[0881] (149) 3-(4-aminobutyl)-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine dihydrochloride;

[0882] (150) 2-Butyl-4-isopropoxy-3-[4-(tetrahydropyran-4-ylamino)butyl]imidazo[4,5-d]pyridazine-7-amine hydrochloride;

[0883] (151)N-[4-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)butyl]-N-tetrahydropyran-4-yl-acetamide;

[0884] (152) 2-Butyl-3-[4-[(1,1-dioxothione-3-yl)amino]butyl]-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine;

[0885] (153)N-[4-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)butyl]-N-(1,1-dioxothione-butane-3-yl)acetamide;

[0886] (154) 2-Butyl-3-[6-[(1,1-dioxothione-3-yl)amino]hexyl]-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine;

[0887] (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;

[0888] (156) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]-2-methyl-prop-1,3-diol hydrochloride;

[0889] (157) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]prop-1,3-diol hydrochloride;

[0890] (158) 1-(4-(aminomethyl)benzyl)-7-isopropoxy-2-propyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0891] (159) 1-(4-(aminomethyl)benzyl)-2-(ethoxymethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0892] (160) 1-(4-(aminomethyl)benzyl)-7-isopropoxy-2-methyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0893] (161)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylthioalkyl-imidazo[4,5-d]pyridazine-7-amine;

[0894] (162)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylsulfinyl-imidazo[4,5-d]pyridazine-7-amine;

[0895] (163)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-N2-propyl-imidazo[4,5-d]pyridazine-2,7-diamine;

[0896] (164)3-[[4-(aminomethyl)phenyl]methyl]-2-(ethylaminomethyl)-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine;

[0897] (165) 2-Butyl-7-isopropoxy-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine; or

[0898] Its pharmaceutically acceptable salt.

[0899] Among the compounds listed above, the following compounds of interest may be cited, for example:

[0900] (1) 2-Butyl-7-isopropoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0901] (2) 2-Butyl-N7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0902] (3) 2-Butyl-7-(isopropylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0903] (4) 2-Butyl-1-(4-methoxybenzyl)-7-(2-methoxyethoxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0904] (5) 2-Butyl-1-(4-methoxybenzyl)-7-propoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0905] (6) 7-(allyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0906] (7) 7-(sec-butoxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0907] (8) 7-Butoxy-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0908] (9) 2-Butyl-7-(cyclopentoxy)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0909] (10) 2-Butyl-1-(4-methoxybenzyl)-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0910] (11) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-3-yl)-1H-imidazo[4,5d]pyridazine-4-amine;

[0911] (12)(E)-2-Butyl-1-(4-methoxybenzyl)-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0912] (13) 2-Butyl-7-isopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0913] (14) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0914] (15) 2-Butyl-7-(cyclopent-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0915] (16) 2-Butyl-7-cyclopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0916] (17) 2-Butyl-1-(4-methoxybenzyl)-7-(prop-1-en-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0917] (18) 2-Butyl-7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0918] (19) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0919] (20) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0920] (25) trans-1-(4-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0921] (26) 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0922] (27)6-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)nicotinonitrile;

[0923] (28)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5d]pyridazin-1-yl)methyl)benzyl)acetamide;

[0924] (29)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)undecanoamide;

[0925] (30)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)pentanamide;

[0926] (31)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-(2-methoxyethoxy)propionamide;

[0927] (34) 4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde;

[0928] (35)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)phenyl)methanol;

[0929] (37) 3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazinyl)methyl)benzyl)amino)thionecyclobutane 1,1-dioxide;

[0930] (48) 2-Butyl-7-ethoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0931] (49) 2-Butyl-1-(4-methoxybenzyl)-N7-(2-methoxyethyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0932] (50) 2-Butyl-7-methoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0933] (51) 2-Butyl-7-cyclohexyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0934] (52) 7-(benzyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0935] (53) 2-Butyl-1-(4-methoxybenzyl)-N7-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0936] (54)(S)-2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0937] (55) 2-Butyl-7-(furan-2-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0938] (56) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0939] (57) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydro-2H-pyran-4-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0940] (58) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrothiophen-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0941] (59) 2-Butyl-1-(4-methoxybenzyl)-7-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0942] (60) 2-Butyl-1-(4-methoxybenzyl)-7-(2-methylprop-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0943] (61) 2-Butyl-7-isobutyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0944] (62) 2-Butyl-1-(4-methoxybenzyl)-7-(thiophen-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0945] (63) 2-Butyl-1-(4-methoxybenzyl)-7-(thiophen-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0946] (64) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0947] (65) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1-oxide isomer A;

[0948] (66) 2-Butyl-7-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0949] (67) 2-Butyl-7-(furan-3-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0950] (68) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1,1-dioxide;

[0951] (69)3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1-oxide isomer B;

[0952] (70) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0953] (71) 2-Butyl-1-(4-methoxybenzyl)-N7,N7-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0954] (72) 2-Butyl-1-(4-methoxybenzyl)-7-phenoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0955] (73) 2-Butyl-7-(2,5-dihydrofuran-3-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0956] (75) 2-Butyl-7-isopropoxy-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0957] (76) 2-Butyl-7-isopropoxy-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0958] (77) 1-(5-aminopentyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0959] (78) 2-Butyl-7-isopropoxy-1-(2-(piperidin-4-yl)ethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0960] (79) 2-Butyl-7-isopropoxy-1-(2-(piperazin-1-yl)ethyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0961] (80) 1-Benzyl-2-Butyl-7-Isopropoxy-1H-Imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0962] (81) 2-Butyl-1-(cyclohexylmethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[0963] (87)N7-(4-(aminomethyl)benzyl)-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0964] (92) 2-Butyl-1-(4-methoxybenzyl)-7-phenyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0965] (94) 2-Butyl-N7-(3-(furan-2-yl)propyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[0966] (97) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0967] (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;

[0968] (107)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-methoxypropionamide;

[0969] (111)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate;

[0970] (112)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate-4-methoxybenzyl ester;

[0971] (113)1-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-ethylurea;

[0972] (122) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]methyl]imidazo[4,5-d]pyridazine-7-aminedi-2,2,2-trifluoroacetate;

[0973] (128) 2-Butyl-7-isopropoxy-1-(3-((isopropylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[0974] (131) 2-Butyl-7-isopropoxy-1-(3-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[0975] (134) 1-(4-(aminomethyl)benzyl)-2-butyl-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0976] (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;

[0977] (138) 1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0978] (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;

[0979] (140)1-(((1R,4R)-4-aminocyclohexyl)methyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0980] (142) 1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[0981] (143) 3-[(4-aminocyclohexyl)methyl]-2-butyl-4-pyrrolidine-1-yl-imidazo[4,5-d]pyridazine-7-amine;

[0982] (146) 3-(6-aminohexyl)-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine dihydrochloride;

[0983] (148)N-[6-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)hexyl]-N-tetrahydropyran-4-yl-acetamide;

[0984] (149) 3-(4-aminobutyl)-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine dihydrochloride;

[0985] (151)N-[4-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)butyl]-N-tetrahydropyran-4-yl-acetamide;

[0986] (152) 2-Butyl-3-[4-[(1,1-dioxothione-3-yl)amino]butyl]-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine;

[0987] (153)N-[4-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)butyl]-N-(1,1-dioxothione-butane-3-yl)acetamide;

[0988] (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;

[0989] (158) 1-(4-(aminomethyl)benzyl)-7-isopropoxy-2-propyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[0990] (159) 1-(4-(aminomethyl)benzyl)-2-(ethoxymethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0991] (162)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylsulfinyl-imidazo[4,5-d]pyridazine-7-amine;

[0992] (165) 2-Butyl-7-isopropoxy-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine; or

[0993] Its pharmaceutically acceptable salt. Among the compounds listed above, the following compounds of interest may be cited, for example:

[0994] (21) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[0995] (22) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[0996] (23) 1-(((1S,3R)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (and enantiomers);

[0997] (24) 1-(4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)-2-methylprop-2-ol;

[0998] (32) 1-(((1S,3S)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-]pyridazine-4-amine (and enantiomers);

[0999] (33) 1-(3-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[1000] (36) 2-Butyl-1-(4-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1001] (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 butane-3-yl)acetamide;

[1002] (39) 2-Butyl-7-isopropoxy-1-(4-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1003] (40) 2-Butyl-7-isopropoxy-1-(4-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[1004] (41) 2-Butyl-N7,N7,1-trimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1005] (42) 2-Butyl-1-methyl-7-(pyrrolid-1-yl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[1006] (43) 2-Butyl-N7-(4-((dimethylamino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1007] (44) 2-Butyl-N7,1-Dimethyl-N7-(4-(morpholinomethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1008] (45) 4-(((4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazine-7-yl)(methyl)amino)methyl)benzylnitrile;

[1009] (46)N7-(4-(aminomethyl)benzyl)-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1010] (47) 2-Butyl-N7-(4-(((2-methoxyethyl)(methyl)amino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1011] (74) 2-Butyl-7-isopropoxy-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1012] (82) 2-Butyl-7-isopropoxy-1-(4-(((tetrahydro-2H-pyran-4-yl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride;

[1013] (83) 2-Butyl-7-isopropoxy-1-(4-((isopropylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[1014] (84)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)heptamide;

[1015] (85)(4-(1-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridine-7-yl)pyrrolidine-3-yl)phenyl)methanol hydrochloride;

[1016] (86) 2-Butyl-7-isopropoxy-1-methyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[1017] (88) 2-Butyl-N7-isopropyl-1-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1018] (89) 2-Butyl-1-methyl-7-(3-phenylpyrrolidin-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1019] (90) N7-benzyl-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1020] (91) 2-Butyl-1-methyl-N7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1021] (95) 2-Butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1022] (98) 2-Butyl-N7-isopropyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; and

[1023] (99) 2-Butyl-7-(isopropylthio)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1024] (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;

[1025] (101)2-Butyl-7-isopropoxy-1-(4-(pyrrolidone-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1026] (102) 2-Butyl-7-isopropoxy-1-(4-(morpholinomethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1027] (103)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)propionamide;

[1028] (104) 2-Butyl-7-isopropoxy-1-(4-(((2-methoxyethyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1029] (106)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)benzamide;

[1030] (108)2-Butyl-7-isopropoxy-1-(4-(((2-(2-methoxyethoxy)ethyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1031] (109)2-Butyl-1-(4-((hexylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1032] (110)2-Butyl-1-(4-((decylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1033] (114)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate 4-acetamidobenzyl ester;

[1034] (115)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)methanesulfonamide;

[1035] (116)2-Butyl-1-(4-((dimethylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1036] (117)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)glycine tert-butyl ester;

[1037] (118)2-Butyl-7-isopropoxy-1-(4-((methylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1038] (119)3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)tert-butyl propionate;

[1039] (120)1-(4-(5,8,11-trioxa-2-azadodecyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1040] (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;

[1041] (123) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy] ...

[1042] (124) 2-Butyl-7-isopropoxy-1-(3-((methylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1043] (125) 2-Butyl-1-(3-((dimethylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1044] (126) 2-Butyl-1-(3-((cyclobutylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[1045] (127) 2-Butyl-1-(3-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[1046] (129)3-((3-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)thionecyclobutane 1,1-dioxide;

[1047] (130) 2-Butyl-7-isopropoxy-1-(3-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[1048] (132)(E)-1-(4-(aminomethyl)benzyl)-2-butyl-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1049] (133) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[1050] (135) 1-(4-(aminomethyl)benzyl)-2-butyl-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[1051] (141) 1-(((1R,4R)-4-aminocyclohexyl)methyl)-2-butyl-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1052] (144) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-(2,5-dihydro-1H-pyrrolo-3-yl)imidazo[4,5-d]pyridazine-4-amine;

[1053] (145) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-pyrrolidine-3-yl-imidazo[4,5-d]pyridazine-4-amine;

[1054] (147) 2-Butyl-4-isopropoxy-3-[6-(tetrahydropyran-4-ylamino)hexyl]imidazo[4,5-d]pyridazine-7-amine dihydrochloride;

[1055] (150) 2-Butyl-4-isopropoxy-3-[4-(tetrahydropyran-4-ylamino)butyl]imidazo[4,5-d]pyridazine-7-amine hydrochloride;

[1056] (154) 2-Butyl-3-[6-[(1,1-dioxothione-3-yl)amino]hexyl]-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine;

[1057] (156) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]-2-methyl-prop-1,3-diol hydrochloride;

[1058] (157) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]prop-1,3-diol hydrochloride;

[1059] (160) 1-(4-(aminomethyl)benzyl)-7-isopropoxy-2-methyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[1060] (161)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylthioalkyl-imidazo[4,5-d]pyridazine-7-amine;

[1061] (163)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-N2-propyl-imidazo[4,5-d]pyridazine-2,7-diamine;

[1062] (164) 3-[[4-(aminomethyl)phenyl]methyl]-2-(ethylaminomethyl)-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine or a pharmaceutically acceptable salt thereof.

[1063] Among the compounds listed above, the following compounds of interest may be cited, for example:

[1064] (19) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride;

[1065] (20) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[1066] (21) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1067] (22) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[1068] (23) 1-(((1S,3R)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (and enantiomers);

[1069] (24) 1-(4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)-2-methylprop-2-ol;

[1070] (25) trans-1-(4-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1071] (26) 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1072] (28)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5d]pyridazin-1-yl)methyl)benzyl)acetamide;

[1073] (33) 1-(3-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate;

[1074] (35)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)phenyl)methanol;

[1075] (36) 2-Butyl-1-(4-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1076] (39) 2-Butyl-7-isopropoxy-1-(4-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1077] (40) 2-Butyl-7-isopropoxy-1-(4-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine;

[1078] (43) 2-Butyl-N7-(4-((dimethylamino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1079] (47) 2-Butyl-N7-(4-(((2-methoxyethyl)(methyl)amino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1080] (144) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-(2,5-dihydro-1H-pyrrolo-3-yl)imidazo[4,5-d]pyridazine-4-amine;

[1081] (156) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]-2-methyl-prop-1,3-diol hydrochloride;

[1082] (157) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]prop-1,3-diol hydrochloride;

[1083] (159) 1-(4-(aminomethyl)benzyl)-2-(ethoxymethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine;

[1084] (161)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylthioalkyl-imidazo[4,5-d]pyridazine-7-amine;

[1085] (163)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-N2-propyl-imidazo[4,5-d]pyridazine-2,7-diamine;

[1086] (164) 3-[[4-(aminomethyl)phenyl]methyl]-2-(ethylaminomethyl)-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine or

[1087] Its pharmaceutically acceptable salt. Among the compounds listed above, the following compounds of interest may be cited, for example:

[1088] (91) 2-Butyl-1-methyl-N7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1089] (93) 4-Amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-ol;

[1090] (95) 2-Butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1091] (96) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1092] (97) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1093] (98) 2-Butyl-N7-isopropyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine;

[1094] (123) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy] ...

[1095] (141) 1-(((1R,4R)-4-aminocyclohexyl)methyl)-2-butyl-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine;

[1096] (144) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-(2,5-dihydro-1H-pyrrolo-3-yl)imidazo[4,5-d]pyridazine-4-amine;

[1097] (145) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-pyrrolidine-3-yl-imidazo[4,5-d]pyridazine-4-amine;

[1098] (160) 1-(4-(aminomethyl)benzyl)-7-isopropoxy-2-methyl-1H-imidazo[4,5-d]pyridazine-4-amine;

[1099] (163)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-N2-propyl-imidazo[4,5-d]pyridazine-2,7-diamine;

[1100] (164) 3-[[4-(aminomethyl)phenyl]methyl]-2-(ethylaminomethyl)-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine or

[1101] Its pharmaceutically acceptable salt.

[1102] According to this disclosure, the compound of formula (I) can be prepared, for example, by the following methods, corresponding to scheme 1 (SynMethod 1), 2 (including SynMethod 2, 2a and 2b), 3 (SynMethod 3) and 4 (SynMethod 4).

[1103] These methods also form part of this disclosure and are detailed below.

[1104] Compounds of formula (I) with different substituents, as well as other related compounds, can be synthesized using the techniques and materials described below or other techniques and materials known to those skilled in the art. Furthermore, the solvents, temperatures, and other reaction conditions given below may be varied as deemed appropriate by those skilled in the art.

[1105] The general methods for preparing the compounds described below may optionally be modified by using appropriate reagents and conditions to introduce the portions found in formula (I) as described below.

[1106] Scheme 1: Preparation of compounds of formula (I) - General method (SynMethod 1)

[1107]

[1108] According to Option 1, the method according to this disclosure includes at least the following steps:

[1109] (iB) provides compounds of formula (II),

[1110]

[1111] (iiB) The compound of formula (II) provided in step (iB) is cyclized by reaction with R2-C(OCH3)3 or R2-COCl to obtain the compound of formula (III), wherein R2 is as defined in this disclosure.

[1112]

[1113] R2 is as defined in this disclosure;

[1114] (iiiB) Hydrolyze the nitrile group of the compound of formula (III) obtained in step (iiB) to obtain the compound of formula (IV).

[1115]

[1116] R2 is as defined in this disclosure;

[1117] (ivB) Esterification of the carboxylic acid functional group of the compound of formula (IV) obtained from step (iiiB) to obtain the compound of formula (V),

[1118]

[1119] Wherein R is a (C1-C4) alkyl- group, such as methyl, ethyl, propyl or butyl, such as methyl, and R2 is as defined in this disclosure;

[1120] (vB) Optionally, the compound of formula (V) obtained from step (ivB) is reacted with R1-X to obtain the compound of formula (Vb), wherein R1 is as defined in this disclosure and X represents a halogen atom, such as a chlorine, iodine, or bromine atom.

[1121]

[1122] Wherein R is (C1-C4) alkyl, such as methyl, ethyl, propyl or butyl, such as methyl, and R1 and R2 are as defined in this disclosure;

[1123] (viB) Cyclate the compound of formula (Vb) obtained from step (vB) or the compound of formula (V) obtained from step (ivB) (where R1 is a hydrogen atom) to obtain the compound of formula (VIb).

[1124]

[1125] R1 and R2 are as defined in this disclosure;

[1126] (viiB) The compound of formula (VIb) obtained in step (viB) is dihalogenated to obtain the compound of formula (VIIa).

[1127]

[1128] Wherein R1 and R2 are as defined in this disclosure, and HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, for example, two HALs are identical and are chlorine atoms;

[1129] (viiiB) The compound of formula (VIIa) obtained from step (viiB) is subjected to nucleophilic aromatic substitution to obtain the compound of formula (VIIIa).

[1130]

[1131] Wherein R1 and R2 are as defined in this disclosure, and HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, such as a chlorine atom;

[1132] (ixB) Substitute and / or couple the compound of formula (VIIIa) obtained from step (viiiB) to obtain the compound of formula (Ia).

[1133]

[1134] Where R1 and R2 are as defined in this disclosure, and R 3a R3 as defined in this disclosure may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group.

[1135] (xB) when R 3a If it is not R3 as defined in this disclosure, then the compound of formula (Ia) obtained from step (ixB) is reacted with any suitable reagent under any suitable conditions to obtain a compound of formula (I) as defined in this disclosure.

[1136] The described pathway allows for the preparation of compounds, for example, those of the following formula (I) according to this disclosure: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 86, 92, 93, 94, 95, 96, 97, 98, and 99.

[1137] Scheme 2: Preparation of compounds of formula (I) - general methods (SynMethod 2, 2a and 2b)

[1138]

[1139] According to Option 2, the method according to this disclosure includes at least the following steps:

[1140] (i) Provide compounds of formula (II),

[1141]

[1142] (ii) Cycling the compound of formula (II) provided in step (i) by reacting it with R2-C(OCH3)3 or R2-COCl to obtain the compound of formula (III), wherein R2 is a hydrogen atom as defined in this disclosure.

[1143]

[1144] Where R2, as defined in this disclosure, is a hydrogen atom;

[1145] (iii) Hydrolyze the nitrile group of the compound of formula (III) obtained in step (ii) to obtain the compound of formula (IV).

[1146]

[1147] Where R2, as defined in this disclosure, is a hydrogen atom;

[1148] (iv) Esterify the carboxylic acid functional group of the compound of formula (IV) obtained in step (iii) to obtain the compound of formula (V).

[1149]

[1150] Wherein R is a (C1-C4) alkyl- group, such as methyl, ethyl, propyl or butyl, such as methyl, and R2 is a hydrogen atom as defined in this disclosure.

[1151] (v) Cyclate the compound of formula (V) obtained from step (iv) to obtain the compound of formula (VI).

[1152]

[1153] Where R2, as defined in this disclosure, is a hydrogen atom;

[1154] (vi) The compound of formula (VI) obtained in step (v) is dihalogenated to obtain the compound of formula (VII).

[1155]

[1156] Where R2 is a hydrogen atom as defined in this disclosure, and HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, for example, two HALs are the same and are chlorine atoms;

[1157] (vii) The compound of formula (VII) obtained from step (vi) is subjected to nucleophilic aromatic substitution with the compound of formula (AA).

[1158]

[1159] The two G1s independently represent either hydrogen atoms or methoxy groups; for example, if the two G1s are methoxy groups,

[1160] In order to obtain the compound of formula (VIII),

[1161]

[1162] Where R2 is a hydrogen atom as defined in this disclosure, HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, such as a chlorine atom, and the two G1s independently represent a hydrogen atom or a methoxy group, for example, the two G1s are methoxy groups;

[1163] (viii) The compound of formula (VIII) obtained from step (vii) is subjected to substitution and / or coupling reactions to obtain the compound of formula (IX).

[1164]

[1165] Where R2, as defined in this disclosure, is a hydrogen atom, R 3a R3 as defined in this disclosure may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and both G1s independently represent a hydrogen atom or a methoxy group, for example, both G1s are methoxy groups;

[1166] Then (ixAlpha, also known as ixα) the compound of formula (IX) obtained from step (viii) is reacted with R. 1a -X reaction to obtain a compound of formula (X), where R 1a R1 is as defined in this disclosure, and may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and X represents a halogen atom, a toluene sulfonate, or a methanesulfonate.

[1167]

[1168] Where R2, as defined in this disclosure, is a hydrogen atom, R 3a R3, as defined in this disclosure, may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and the two G1s independently represent a hydrogen atom or a methoxy group, for example, the two G1s are methoxy groups, and R 1a As defined in the above step (ixAlpha);

[1169] Or (ixBeta, also known as ixβ) make the compound of formula (IX) obtained from step (viii) with formula The epoxide reaction is used to obtain a compound of formula (X), wherein R' and R" are independently hydrogen atoms or (C1-C6) alkyl groups, such as methyl.

[1170]

[1171] Where R2, as defined in this disclosure, is a hydrogen atom, R 3a R3, as defined in this disclosure, may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and the two G1s independently represent a hydrogen atom or a methoxy group, for example, the two G1s are methoxy groups, and R 1a As defined in the steps above (ixAlpha);

[1172] as well as

[1173] (x) The compound of formula (X) obtained from step (ixAlpha) or (ixBeta) is deprotected to obtain a compound of formula (I) as defined in this disclosure; and when R2 in the compound of formula (X) prior to deprotection is a hydrogen atom, the hydrogen is converted to R2 as defined in formula (I) by chemical modification such as metallization, followed by reaction, for example, with an alkyl disulfide or dimethylformamide or N-bromosuccinimide, which, if desired, undergoes further chemical reactions such as oxidative or reductive amination or nucleophilic substitution to obtain the desired R2;

[1174] Or (x) deprotects the compound of formula (X) obtained from step (ixAlpha) or (ixBeta) to obtain the compound of formula (XI).

[1175]

[1176] Where R 3a R3, as defined in this disclosure, may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group; R2, as defined in this disclosure; and R... 1b R is as defined in this disclosure text. 1a Or R with functional groups such as amino, alcohol and aldehyde 1a ; and then (xi) reduction, reductive amination, nucleophilic substitution and / or oxidation of the compound of formula (XI) obtained from step (x) in order to obtain a compound of formula (I) as defined in this disclosure;

[1177] Or (Gamma, also known as γ) reduction, reductive amination, nucleophilic substitution and / or oxidation of the compound of formula (X) obtained from step (ixAlpha) or (ixBeta) to obtain the compound of formula (XII).

[1178]

[1179] Where R 3a R3, as defined in this disclosure, may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group; R2, as defined in this disclosure, has two G1s that independently represent a hydrogen atom or a methoxy group, for example, both G1s are methoxy groups; and R... 1b R as defined in this disclosure is obtained through reductive amination, reduction, substitution, and / or oxidation. 1a The derivative; and then (x) deprotecting the compound of formula (XII) obtained from step (Gamma) to obtain a compound of formula (I) as defined in this disclosure.

[1180] As shown in Scheme 2, there are three options for the compound of formula (X).

[1181] The first option is referred to in this disclosure as SynMethod 2. It only includes step (x) of obtaining a compound of formula (I) as defined in this disclosure from a compound of formula (X) as defined in this disclosure.

[1182] The second option is referred to in this disclosure as SynMethod 2a. It includes step (x) obtaining a compound of formula (xi) as defined in this disclosure from a compound of formula (X) as defined in this disclosure, and then step (xi) obtaining a compound of formula (I) as defined in this disclosure from a compound of formula (xi) as defined in this disclosure.

[1183] The third option is referred to in this disclosure as SynMethod 2b. It includes step (Gamma) (also called step γ) obtaining a compound of formula (XII) as defined in this disclosure from a compound of formula (X) as defined in this disclosure, and then step (x) obtaining a compound of formula (I) as defined in this disclosure from a compound of formula (XII) as defined in this disclosure.

[1184] The SynMethod 2 pathway allows the preparation of compounds, for example, those of the following formula (I) according to this disclosure: 19, 20, 21, 22, 23, 24, 25, 27, 32, 33, 34, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 and 165.

[1185] The SynMethod 2a pathway allows the preparation of compounds, for example, those of the following formula (I) according to this disclosure: 38, 39, 40, 84, 103, 104, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 119, 148, 151, 153, and 155.

[1186] The SynMethod 2b route allows the preparation of compounds, for example, those of the following formula (I) according to this disclosure: 26, 28, 29, 30, 31, 35, 36, 37, 100 to 102, 105, 120 to 131, 146, 147, 149, 150, 152, 154, and 156 to 160.

[1187] Scheme 3: Preparation of compounds of formula (I) - General method (SynMethod 3)

[1188]

[1189] According to Option 3, the method according to this disclosure includes at least the following steps:

[1190] (iA) provides compounds of formula (II).

[1191]

[1192] (iiA) The compound of formula (II) provided in step (iA) is cyclized by reaction with R2-C(OCH3)3 or R2-COCl to obtain the compound of formula (III), wherein R2 is as defined in this disclosure.

[1193]

[1194] R2 is as defined in this disclosure;

[1195] (iiiA) Hydrolyze the nitrile group of the compound of formula (III) obtained in step (iiA) to obtain the compound of formula (IV).

[1196]

[1197] R2 is as defined in this disclosure;

[1198] (ivA) Esterification of the carboxylic acid functional group of the compound of formula (IV) obtained in step (iiiA) to obtain the compound of formula (V),

[1199]

[1200] Wherein R is a (C1-C4) alkyl- group, such as methyl, ethyl, propyl or butyl, such as methyl, and R2 is as defined in this disclosure;

[1201] (vA) Cyclate the compound of formula (V) obtained from step (ivA) to obtain the compound of formula (VI).

[1202]

[1203] R2 is as defined in this disclosure;

[1204] (viA) Dihalogenate the compound of formula (VI) obtained from step (vA) to obtain the compound of formula (VII);

[1205]

[1206] Wherein R2 is as defined in this disclosure, and HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, for example, two HALs are identical and are chlorine atoms;

[1207] (viiA) Optionally, the compound of formula (VII) obtained from step (viA) is reacted with R1-X to obtain the compound of formula (VIIa), wherein R1 is as defined in this disclosure and X represents a halogen atom, such as a chlorine atom, an iodine atom or a bromine atom;

[1208]

[1209] Wherein R1 and R2 are as defined in this disclosure, and HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, for example, two HALs are identical and are chlorine atoms;

[1210] (viiiA) A nucleophilic aromatic substitution is performed on the compound of formula (VIIa) obtained from step (viiA) or the compound of formula (VII) obtained from step (viA) (where R1 is a hydrogen atom) to obtain the compound of formula (VIIIa).

[1211]

[1212] Wherein R1 and R2 are as defined in this disclosure, and HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, such as a chlorine atom;

[1213] (ixA) Substitute and / or couple the compound of formula (VIIIa) obtained from step (viiiA) to obtain the compound of formula (Ia).

[1214]

[1215] Where R 3a R3 as defined in this disclosure may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and R1 and R2 are as defined in this disclosure;

[1216] (xA) When R 3a If it is not R3 as defined in this disclosure, then the compound of formula (Ia) obtained from step (ixA) is reacted with any suitable reagent under any suitable conditions to obtain a compound of formula (I) as defined in this disclosure.

[1217] The SynMethod 3 pathway allows the preparation of compounds, for example, those of the following formula (I) according to this disclosure: 41, 42, 43, 44, 45, 46, 47, 85, 87, 88, 89, 90 and 91.

[1218] Scheme 4: Preparation of compounds of formula (I) - General method (SynMethod 4)

[1219]

[1220] According to Option 4, the method according to this disclosure includes at least the following steps:

[1221] (i) Provide compounds of formula (II),

[1222]

[1223] (ii) Cycling the compound of formula (II) provided in step (i) by reacting it with R2-C(OCH3)3 or R2-COCl to obtain the compound of formula (III), wherein R2 is as defined in this disclosure.

[1224]

[1225] R2 is as defined in this disclosure;

[1226] (iii) Hydrolyze the nitrile group of the compound of formula (III) obtained in step (ii) to obtain the compound of formula (IV).

[1227]

[1228] R2 is as defined in this disclosure;

[1229] (iv) Esterify the carboxylic acid functional group of the compound of formula (IV) obtained in step (iii) to obtain the compound of formula (V).

[1230]

[1231] Wherein R is a (C1-C4) alkyl- group, such as methyl, ethyl, propyl or butyl, such as methyl, and R2 is as defined in this disclosure;

[1232] (v) Cyclate the compound of formula (V) obtained from step (iv) to obtain the compound of formula (VI).

[1233]

[1234] R2 is as defined in this disclosure;

[1235] (vi) The compound of formula (VI) obtained in step (v) is dihalogenated to obtain the compound of formula (VII).

[1236]

[1237] Wherein R2 is as defined in this disclosure, and HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, for example, two HALs are identical and are chlorine atoms;

[1238] Then (viialpha, also known as viiα) the compound of formula (VII) obtained from step (vi) is reacted with R. 1a -X reaction to obtain a compound of formula (VIIIaa), where R 1a R1 is as defined in this disclosure, and may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and X represents a halogen atom, a toluene sulfonate, or a methanesulfonate.

[1239]

[1240] Where R2 is as defined in this disclosure, HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, for example, two identical HAL atoms are chlorine atoms, and R 1a As defined in the above step (viialpha);

[1241] Or (viiBeta, also known as viiβ) make the compound of formula (VII) obtained from step (vi) with formula The epoxide reaction is carried out to obtain a compound of formula (VIIIaa), wherein R' and R" are independently hydrogen atoms or (C1-C6) alkyl groups, such as methyl.

[1242]

[1243] Where R2 is as defined in this disclosure, HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, for example, two identical HAL atoms are chlorine atoms, and R 1a As defined in the steps above (viialpha);

[1244] (viiiAA) The compound of formula (VIIIaa) obtained from step (viialpha) or step (viibeta) is subjected to nucleophilic aromatic substitution with the compound of formula (AA).

[1245]

[1246] The two G1s independently represent either hydrogen atoms or methoxy groups; for example, if the two G1s are methoxy groups,

[1247] In order to obtain a compound of formula (IXaa),

[1248]

[1249] Where R2 is as defined in this disclosure, HAL is a halogen atom, such as a chlorine atom, a fluorine atom, an iodine atom, or a bromine atom, such as a chlorine atom, R 1aAs defined in the steps above (viialpha), and the two G1s independently represent either a hydrogen atom or a methoxy group, for example, the two G1s are methoxy groups;

[1250] (ixAA) Substitution and / or coupling reactions are carried out on the compound of formula (IXaa) obtained from step (viiiAA) to obtain the compound of formula (X).

[1251]

[1252] Where R2 is as defined in this disclosure, R 1a As defined in the steps above (viialpha), R 3a R3 as defined in this disclosure may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and both G1s independently represent a hydrogen atom or a methoxy group, for example, both G1s are methoxy groups;

[1253] as well as

[1254] (x) Deprotect the compound of formula (X) obtained from step (ixAA) to obtain a compound of formula (I) as defined in this disclosure;

[1255] Or (x) deprotects the compound of formula (X) obtained in step (ixAA) to obtain the compound of formula (XI).

[1256]

[1257] Where R 3a R3, as defined in this disclosure, may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group; R2, as defined in this disclosure; and R... 1b It is R1a or R1a having a functional group such as amino, alcohol and aldehyde; and then (xi) reduction, reductive amination, nucleophilic substitution and / or oxidation of the compound of formula (XI) obtained from step (x) in order to obtain the compound of formula (I) as defined in this disclosure.

[1258] Or (Gamma, also known as γ) reduction, reductive amination, nucleophilic substitution and / or oxidation of the compound of formula (X) obtained from step (ixAA) to obtain the compound of formula (XII).

[1259]

[1260] Where R 3aR3, as defined in this disclosure, may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group; R2, as defined in this disclosure, has two G1s that independently represent a hydrogen atom or a methoxy group, for example, both G1s are methoxy groups; and R... 1b R is obtained through reductive amination, reduction, substitution, and / or oxidation. 1a The derivative; and then (x) deprotecting the compound of formula (XII) obtained from step (Gamma) to obtain a compound of formula (I) as defined in this disclosure.

[1261] As shown in Scheme 4, there are three options for the compound of formula (X).

[1262] The first option is referred to in this disclosure as SynMethod 4. It only includes step (x) obtaining a compound of formula (I) as defined in this disclosure from a compound of formula (X) as defined in this disclosure.

[1263] The second option is referred to in this disclosure as SynMethod 4a. It includes step (x) obtaining a compound of formula (xi) as defined in this disclosure from a compound of formula (X) as defined in this disclosure, and then step (xi) obtaining a compound of formula (I) as defined in this disclosure from a compound of formula (xi) as defined in this disclosure.

[1264] The third option is referred to in this disclosure as SynMethod 4b. It includes step (Gamma) (also called step γ) obtaining a compound of formula (XII) as defined in this disclosure from a compound of formula (X) as defined in this disclosure, and then step (x) obtaining a compound of formula (I) as defined in this disclosure from a compound of formula (XII) as defined in this disclosure.

[1265] The SynMethod 4 pathway allows for the preparation of compounds, for example, those of the following formula (I) according to this disclosure: 132 to 135, 137 to 145.

[1266] Regarding steps (i), (iA), and (iB) (not shown in schemes 1, 2, 3, and 4):

[1267] The compounds of formula (II) are commercially available compounds, for example from Fisher or Merck-Sigma, or can be prepared by any method known to a person skilled in the art.

[1268] Regarding steps (ii), (iiA), and (iiB) (which are schemes 2 (or 4), 3, and 1, respectively):

[1269] Cyclization steps (ii), (iiA) and (iiB) of compound (II) as defined in this disclosure allow for obtaining a compound of formula (III) as defined in this disclosure.

[1270] For example, the cyclization steps (ii), (iiA) and (iiB) of compound (II) can be carried out using R2-C(OCH3)3 (where R2 is as defined in this disclosure (steps (ii), (iiA) and (iiB))) or a hydrogen atom (step (ii))) as a reagent and further carried out in the presence of a solvent such as xylene, acetonitrile, dioxane, toluene or mixtures thereof (e.g., a mixture of xylene and acetonitrile) under heat (i.e. at a temperature in the range of 25°C to 200°C, for example from 85°C to 150°C).

[1271] The cyclization steps (ii), (iiA) and (iiB) of compound (II) can also be carried out by using R2-COCl (where R2 is as defined in this disclosure (steps (ii), (iiA) and (iiB))) or a hydrogen atom (step (ii))) as a reagent in ethyl acetate (EtOAc) at room temperature and then treating with sodium hydride (NaH) in dimethylformamide (DMF) followed by heating under reflux.

[1272] Regarding steps (iii), (iiiA), and (iiiB) (which are schemes 2 (or 4), 3, and 1, respectively):

[1273] Hydrolysis steps (iii), (iiiA), and (iiiB) of the nitrile group present on the compound of formula (III) as defined in this disclosure allow for the production of the compound of formula (IV) as defined in this disclosure.

[1274] For example, the hydrolysis steps (iii), (iiiA) and (iiiB) of the nitrile group of the compound of formula (III) can be carried out in the presence of an acid such as sulfuric acid, hydrochloric acid or a mixture thereof, in the presence of water (water reflux) or in the presence of water and other organic solvents (such as dioxane), for example in the presence of sulfuric acid in water, under heat (i.e., at a temperature in the range of 25°C to 150°C, for example at 100°C).

[1275] The hydrolysis steps (iii), (iiiA) and (iiiB) of the nitrile group of the compound of formula (III) can also be carried out in refluxed sodium hydroxide, followed by acidification with hydrochloric acid.

[1276] Regarding steps (iv), (ivA), and (ivB) (which are respectively scheme 2 (or 4), 3, and 1):

[1277] Esterification steps (iv), (ivA), and (ivB) on compounds of formula (IV) as defined in this disclosure allow for the production of compounds of formula (V) as defined in this disclosure.

[1278] For example, the esterification steps (iv), (ivA) and (ivB) of the carboxylic acid functional group present on the compound of formula (IV) can be carried out in the presence of a chlorinating agent such as thionyl chloride (SOCl2), phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), oxalyl chloride or mixtures thereof, such as SOCl2, and in the presence of a primary alcohol R-OH (where R is a C1-C4 alkyl group (e.g., methyl, ethyl, propyl or butyl, such as methyl), such as methanol, ethanol, propanol or butanol, such as methanol), for example in SOCl2 and methanol, at a temperature in the range of 25°C to 100°C, for example at 60°C.

[1279] The esterification steps (iv), (ivA) and (ivB) of the carboxylic acid functional groups present on the compound of formula (IV) can also be carried out at 100°C in the presence of H2SO4, H2O, or MeOH (methanol).

[1280] Regarding steps (vB) (Option 1):

[1281] Step (vB) allows obtaining a compound of formula (Vb) as defined in this disclosure from a compound of formula (V) as defined in this disclosure.

[1282] Step (vB) is optional and can be performed if a compound of formula (Vb) in which R1 is as defined in this disclosure (i.e., R1 is not just a hydrogen atom) is required.

[1283] In other words, the compound of formula (V) (corresponding to R1 being a hydrogen atom):

[1284] - It can directly undergo step (viB) to provide a compound of formula (VIb), wherein R1 and R2 are as defined in this disclosure.

[1285] or

[1286] - The compound of formula (Vb) may be subjected to step (vB) to provide a compound of formula (Vb), wherein R1 and R2 are as defined in this disclosure, and then the compound of formula (Vb) thus obtained may be subjected to step (viB) to provide a compound of formula (VIb), wherein R1 and R2 are as defined in this disclosure.

[1287] Depending on the desired compound, the technician will choose to perform the more appropriate steps.

[1288] For example, step (vB) may be carried out in the presence of R1-X (where R1 and X are as defined in this disclosure) and further in the presence of a base such as potassium carbonate, cesium carbonate or sodium hydride, for example in potassium carbonate, in a solvent such as dimethylformamide, acetone, acetonitrile, 1,4-dioxane, tetrahydrofuran (THF) or mixtures thereof, for example in dimethylformamide, such as in the presence of potassium carbonate and dimethylformamide at a temperature from 0°C to 150°C, for example from 25°C to 130°C.

[1289] Regarding steps (v), (vA), and (viB) (which are schemes 2 (or 4), 3, and 1, respectively):

[1290] The cyclization steps (v), (vA) and (viB) respectively allow the production of compounds of formula (V), (V) or (Vb) as defined in this disclosure.

[1291] For example, cyclization steps (v), (vA) and (viB) can be carried out in the presence of a reagent such as hydrazine hydrate, in the presence of a solvent such as methanol, ethanol or a mixture thereof (e.g., methanol), such as in the presence of hydrazine, water and methanol, or at a temperature in the range of 25°C to 150°C, for example from 60°C to 85°C.

[1292] Regarding steps (vi), (viA), and (viiB) (which are schemes 2 (or 4), 3, and 1, respectively):

[1293] The dihalogenation steps (vi), (viA) and (viiB) respectively allow the production of compounds of formula (VI), (VI) or (VIb) as defined in this disclosure, respectively, from compounds of formula (VII), (VII) and (VIIa) as defined in this disclosure.

[1294] For example, the dihalogenation steps (vi), (viA) and (viiB) can be carried out in the presence of reagents such as phosphorus oxychloride (POCl3), phosphorus pentachloride (PCl5) or mixtures thereof (e.g., POCl3), in the presence of solvents such as N,N-dimethylaniline, such as in the presence of phosphorus oxychloride and N,N-dimethylaniline, at a temperature in the range of 80°C to 160°C, for example, from 100°C to 110°C.

[1295] The dihalogenation steps (vi), (viA) and (viiB) can also be carried out at reflux temperature in the presence of a mixture of phosphorus oxychloride and phosphorus pentachloride.

[1296] Regarding step (vii) (Solution 2):

[1297] Step (vii) allows obtaining compounds of formula (VIII) as defined in this disclosure from compounds of formula (VII) as defined in this disclosure.

[1298] Step (vii) is nucleophilic aromatic substitution, which is carried out, for example, in the presence of solvents such as butanol, isoamyl alcohol, isopropanol, or mixtures thereof (e.g., butanol), in the presence of bases such as N,N-diisopropylethylamine (DIEA), triethylamine (TEA), 1,8-diazabicyclo[5.4.0]undec-7-ene DBU (e.g., N,N-diisopropylethylamine), such as in the presence of N,N-diisopropylethylamine and butanol, at a temperature ranging from 80°C to 200°C, for example from 120°C to 130°C, or also at 130°C in the presence of N-methylpyrrolidone, or from room temperature to 50°C in the presence of TEA, dimethylacetamide, and in the presence of compounds of formula (AA).

[1299]

[1300] In this formula, G1 represents either a hydrogen atom or a methoxy group. Advantageously, to increase the reaction rate, each of the two G1 groups in formula (AA) is a methoxy group.

[1301] Regarding step (viiA) (Solution 3):

[1302] Step (viiA) allows obtaining a compound of formula (VIIa) as defined in this disclosure from a compound of formula (VII) as defined in this disclosure.

[1303] Step (viiA) is an optional step, which may be performed if a compound of formula (VIIa) in which R1 is as defined in this disclosure (i.e., R1 is not just a hydrogen atom) is required.

[1304] In other words, the compound of formula (VII) (corresponding to R1 being a hydrogen atom):

[1305] - It can directly undergo step (ViiiA) to provide a compound of formula (VIIIa), wherein R1, R2, and HAL are as defined in this disclosure, or

[1306] - The compound of formula (VIIa) may be subjected to step (viiA) to provide a compound of formula (VIIa), wherein R1, R2 and HAL are as defined in this disclosure, and then the compound of formula (VIIa) obtained therefrom may be subjected to step (viiiA) to provide a compound of formula (VIIIa), wherein R1, R2 and HAL are as defined in this disclosure.

[1307] Depending on the desired compound, the technician will choose to perform the more appropriate steps.

[1308] Step (viiA) may be carried out in the presence of R1-X (wherein R1 and X are as defined in this disclosure), such as in the presence of methyl iodine (MeI), in the presence of acetone and K2CO3, at room temperature (25°C), or in the presence of R1-X as defined in this disclosure, in Cs2CO3, 1,4-dioxane, from room temperature (25°C) to 120°C.

[1309] Regarding steps (viialpha, also known as viiα) and (viibeta, also known as viiβ) (Scheme 4):

[1310] step( viialpha The steps (viibeta) from the compound of formula (VII) as defined in this disclosure allow the preparation of the compound of formula (VIIIaa) as defined in this disclosure.

[1311] Step (viialpha) can be found in R 1a The process is performed in the presence of -X, where R 1a R1 is as defined in this disclosure, which may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and X represents a halogen atom, a toluene sulfonate, or a methanesulfonate.

[1312] The step (viibeta) can be found in formula The process is carried out in the presence of an epoxide, wherein R' and R" are independently hydrogen atoms or (C1-C6) alkyl groups, such as methyl.

[1313] Regarding steps (viiiAA) (Solution 4):

[1314] Step (viiiAA) allows obtaining compounds of formula (IXaa) as defined in this disclosure from compounds of formula (VIIIaa) as defined in this disclosure.

[1315] Step (viiiAA) is nucleophilic aromatic substitution, which is carried out, for example, in the presence of solvents such as butanol, isoamyl alcohol, isopropanol, or mixtures thereof (e.g., butanol), in the presence of bases such as N,N-diisopropylethylamine (DIEA), triethylamine (TEA), 1,8-diazabicyclo[5.4.0]undec-7-ene DBU (e.g., N,N-diisopropylethylamine), such as in the presence of N,N-diisopropylethylamine and butanol, at a temperature ranging from 80°C to 200°C, for example from 120°C to 130°C, or also at 130°C in the presence of N-methylpyrrolidone, or from room temperature to 50°C in the presence of TEA, dimethylacetamide, and in the presence of compounds of formula (AA).

[1316]

[1317] In this formula, G1 represents either a hydrogen atom or a methoxy group. Advantageously, to increase the reaction rate, each of the two G1 groups in formula (AA) is a methoxy group.

[1318] Pay attention to steps (viiiA) and (viiiB) (which are schemes 3 and 1 respectively):

[1319] In scheme 1, step (viiiB) is applied to the compound of formula (VIIa) as defined in this disclosure to obtain the compound of formula (VIIIa) as defined in this disclosure.

[1320] In scheme 3, depending on the desired compound, step (viiiA) may be applied to a compound of formula (VIIa) obtained from step (viiA) as defined in this disclosure, wherein HAL, R1, and R2 are as defined in this disclosure, or applied to a compound of formula (VII) obtained from step (viA) as defined in this disclosure, wherein HAL and R2 are as defined in this disclosure, in order to obtain a compound of formula (VIIIa) as defined in this disclosure.

[1321] For example, nucleophilic aromatic substitution steps (viiiA) and (ViiiB) are carried out in the presence of a base such as ammonia (NH3), or in the presence of water, alcohol, dioxane or mixtures thereof, such as in the presence of ammonia and water, under heat (i.e. at a temperature in the range of 25°C to 200°C, for example at 150°C).

[1322] Regarding step (viii) (Option 2):

[1323] Step (viii) allows obtaining compounds of formula (IX) as defined in this disclosure from compounds of formula (VIII) as defined in this disclosure.

[1324] For example, step (viii) can be carried out in the presence of a solvent such as isopropanol and a reagent such as an alcohol (e.g., sodium propionyl 2-olide (iPrONa, for example, sodium propionyl 2-olide), for example in sodium propionyl 2-olide / isopropanol, under heat, i.e. at a temperature in the range of 50°C to 200°C, for example from 150°C to 170°C.

[1325] Regarding steps (ixAA) (Option 4):

[1326] Step (ixAA) allows obtaining a compound of formula (X) as defined in this disclosure from a compound of formula (IXaa) as defined in this disclosure.

[1327] For example, step (ixAA) can be carried out in the presence of a solvent such as isopropanol and a reagent such as an alcohol (e.g., sodium propionyl 2-olide (iPrONa, e.g., sodium propionyl 2-olide), e.g., in sodium propionyl 2-olide / isopropanol, under heat, i.e. at a temperature in the range of 50°C to 200°C, e.g., from 150°C to 170°C.

[1328] Focus on steps (ixA) and (ixB) (which are schemes 3 and 1 respectively):

[1329] Substitution and / or coupling steps (ixA) and (ixB) from compounds of formula (VIIIa) as defined in this disclosure allow the preparation of compounds of formula (Ia) as defined in this disclosure.

[1330] The substitution and / or coupling steps (ixA) and (ixB) can be any suitable chemical reaction involving the dehalogenation of the molecule, such as alkylation, nucleophilic aromatic substitution, and / or coupling such as Suzuki coupling, for example in R 3a The reaction occurs in the presence of -Y, where R 3a R3 represents a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde or a ketone protecting group, as defined in formula (I) of this disclosure, and Y represents a hydroxyl group, an amine, or a boric acid.

[1331] Focus on steps (xA) and (xB): (representing schemes 3 and 1 respectively):

[1332] Steps (xA) and (xB) allow the preparation of compounds of formula (Ia) as defined in this disclosure. It should be understood that if R is present in the compounds of formula (Ia) obtained by steps (xA) and (xB) respectively... 3a If it is R3, then there is no need to perform steps (xA) or (xB) separately.

[1333] Therefore, compounds of formula (Ia) (where R) can be made... 3a The reaction of R3 (not as defined in this disclosure) with any suitable reagent under suitable conditions to obtain a compound of formula (I) as defined in this disclosure. For example, these steps may be selected from reduction steps, deprotection steps, hydrolysis steps, oxidation steps, and combinations thereof, and it should be understood that these steps may be performed only once or several times if desired. All of these steps are well known to those skilled in the art.

[1334] Regarding steps (ixAlpha, also known as ixα) and (ixBeta, also known as ixβ) (Scheme 2):

[1335] Step (ixAlpha) or step (ixBeta) from a compound of formula (IX) as defined in this disclosure allows the preparation of a compound of formula (X) as defined in this disclosure.

[1336] Step (ixAlpha) can be found in R 1a The process is performed in the presence of -X, where R 1a R1 is as defined in this disclosure, which may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and X represents a halogen atom, a toluene sulfonate, or a methanesulfonate.

[1337] Step (ixBeta) can be found in formula The process is carried out in the presence of an epoxide, wherein R' and R" are independently hydrogen atoms or (C1-C6) alkyl groups, such as methyl.

[1338] Regarding the steps (Gamma, also known as γ) (Solution 2, SynMethod 2b, or Solution 4, SynMethod 4b):

[1339] Step (Gamma) allows obtaining compounds of formula (XII) as defined in this disclosure from compounds of formula (X) as defined in this disclosure.

[1340] The step (Gamma) can be reduction, reductive amination, nucleophilic substitution, and / or oxidation.

[1341] Regarding step (x) (Option 2 or Option 4):

[1342] A deprotection step (x) can be performed to deprotect the amino group attached to the pyridazine moiety of the imidazopyridazine ring, and optionally, if applicable, the amino group corresponding to R. 1a and / or R 3a The protected group.

[1343] In other words, step (x) can be performed from a compound of formula (X) as defined in this disclosure or from a compound of formula (XII) as defined in this disclosure to obtain a compound of formula (I) as defined in this disclosure, or from a compound of formula (X) as defined in this disclosure to obtain a compound of formula (XI) as defined in this disclosure.

[1344] For example, step (x) can be carried out in the presence of an acid such as trifluoroacetic acid (TFA), hydrochloric acid or a mixture thereof (e.g., TFA), or in a solvent such as dichloromethane (DCM), dioxane, tetrahydrofuran (THF) or a mixture thereof (e.g., DCM), for example in the presence of TFA and DCM.

[1345] Regarding step (xi) (Solution 2, SynMethod2a, or Solution 4, SynMethod4a):

[1346] Step (xi) allows obtaining a compound of formula (I) as defined in this disclosure from a compound of formula (XI) as defined in this disclosure.

[1347] Step (xi) can be reduction, reductive amination, nucleophilic substitution, and / or oxidation. Compounds of specific formula (I) as defined in this disclosure are indicated in Table 1 (number, chemical name, and formula) and are further detailed below. Table 2 also indicates… 1 H NMR, retention time, and liquid chromatography / mass spectrometry.

[1348] Table 2 1 H NMR is as defined in the experimental section. 1 H NMR spectrum (400 MHz, δ in ppm, DMSO-d6).

[1349] The liquid chromatography / mass spectrometry (LC / MS) data in Table 2 were obtained according to one of the seven methods described in the experimental section.

[1350] The retention time (RT) in Table 2 is defined in minutes.

[1351] Table 1:

[1352]

[1353]

[1354]

[1355]

[1356]

[1357]

[1358]

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365]

[1366]

[1367]

[1368]

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387]

[1388]

[1389]

[1390]

[1391]

[1392]

[1393]

[1394]

[1395]

[1396] Table 2

[1397]

[1398]

[1399]

[1400]

[1401]

[1402]

[1403]

[1404]

[1405]

[1406]

[1407]

[1408]

[1409]

[1410]

[1411]

[1412]

[1413]

[1414]

[1415]

[1416]

[1417]

[1418]

[1419]

[1420]

[1421]

[1422]

[1423]

[1424]

[1425]

[1426]

[1427]

[1428]

[1429]

[1430]

[1431]

[1432]

[1433]

[1434]

[1435]

[1436]

[1437] Among the intermediate compounds of formulas (VIIa), (VIII), (VIIIa) and (IX) that are the subject of this disclosure, the following compounds, for example, shown in Table 3 below, may be mentioned:

[1438] Table 3:

[1439]

[1440]

[1441]

[1442] Table 4 below also indicates 1H NMR, retention time, and liquid chromatography / mass spectrometry.

[1443] Table 4 1 H NMR is as defined in the experimental section. 1 H NMR spectrum (400 MHz, δ in ppm, DMSO-d6).

[1444] The liquid chromatography / mass spectrometry (LC / MS) data in Table 4 were obtained according to one of the seven methods described in the experimental section.

[1445] The retention time (RT) in Table 4 is defined in minutes.

[1446] Table 4:

[1447]

[1448] The following examples describe the preparation of some compounds according to this disclosure. The quantities of compounds in the following examples correspond to those given in Tables 1 and 3 above. Unless otherwise stated, all reactions were carried out under an inert atmosphere.

[1449] In the following embodiments, when the source of the starting product is not specified, it should be understood that the product is a known compound.

[1450] Example

[1451] In the preparation and examples, the following abbreviations are used: ACN, MeCN, or CH3CN: acetonitrile.

[1452] CDCl3: deuterated chloroform

[1453] DCM: Dichloromethane

[1454] DIPEA: Diisopropylethylamine

[1455] DMF: N,N-dimethylformamide

[1456] DMSO: Dimethyl sulfoxide

[1457] EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[1458] Et2O: Diethyl ether

[1459] EtOAc: Ethyl acetate

[1460] EtOH: Ethanol

[1461] HBTU: (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon hexafluorophosphate

[1462] HOBt: Hydroxybenzotriazole

[1463] iPrOH: Isopropanol

[1464] mCPBA: m-chloroperoxybenzoic acid

[1465] MeOH: Methanol

[1466] Me-THF: Methyltetrahydrofuran

[1467] MgSO4: Magnesium sulfate

[1468] MS: Mass spectrometry

[1469] MTBE: Methyl tert-butyl ether

[1470] NaCl: Sodium chloride

[1471] NBS: N-bromosuccinimide

[1472] nBuLi: n-Butyllithium

[1473] rt: room temperature

[1474] RT: Retention Time

[1475] NMR: Nuclear Magnetic Resonance

[1476] NMP: N-methyl-2-pyrrolidone

[1477] TEA: Triethylamine

[1478] TFA: Trifluoroacetic acid

[1479] THF: Tetrahydrofuran

[1480] Ti(iPrO)4: Titanium isopropoxide (IV)

[1481] TLC: Thin-layer chromatography

[1482] TMS: Tetramethylsilane

[1483] h or hr: hours

[1484] Materials and methods

[1485] The progress of the synthesis reaction was monitored by TLC. The plates were made of glass and coated with Merck 60F254 silica gel. After elution, the plates were observed under UV light at 254 nm.

[1486] Microwave reactions were performed using a Biotage Initiator 8EXP microwave system. If necessary, the products were purified using a Biotage Isolera chromatograph or a Spot 2 chromatograph from Merck. Merck 15–40 μm silica columns (2.5 g to 800 g) were used.

[1487] analyze

[1488] Mass spectrometry (MS):

[1489] Method A:

[1490] Spectra were obtained on Waters UPLC-SQD.

[1491] Ionization: Positive and / or negative modes (ES+ / -) electrospray

[1492] -Column: ACQUITY CORTECS C18+-1.6μm-2.1x50mm

[1493] Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid)

[1494] - Column temperature: 40℃

[1495] - Flow rate: 1 mL / min

[1496] - Gradient (3 min): From 2% to 100% B within 2.0 min; 2.6 min: 100% B; 2.7 min: 2% B

[1497] Method A has been used for compounds 2, 9, 35, 65, 69, 86, 87 and 91.

[1498] Method B:

[1499] Spectra were obtained on Waters UPLC-SQD.

[1500] Ionization: Positive and / or negative modes (ES+ / -) electrospray

[1501] -Column: ACQUITY CORTECS C18+-1.6μm-2.1x50mm

[1502] -Solvent: A: H2O (0.1% TFA) B: CH3CN (0.1% TFA)

[1503] - Column temperature: 40℃

[1504] - Flow rate: 1 mL / min

[1505] - Gradient (10 min): 1 min: 2% B, increasing from 2% to 100% B over 6.5 min; 1.7 min: 100% B; decreasing from 100% B to 2% B over 0.1 min; 1.7 min: 2% B

[1506] Method B has been used for compound 68.

[1507] Method N:

[1508] Spectra were obtained on Waters UPLC-SQD2:

[1509] Ionization: Positive and / or negative mode (ES+ / -) electrospray.

[1510] -Column ACQUITY CSH C18-1.7μm-2.1x50mm

[1511] Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid)

[1512] - Column temperature: 60℃

[1513] - Flow rate: 1 mL / min

[1514] - Gradient (2.5 min): from 3% to 100% B in 2.1 min; 2.45 min: 100% B; 2.50 min: 3% B

[1515] Method N has been applied to compounds: 1, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 64, 66, 67, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 88, 89, 90, 92, 93, 94, 95, 96, 97, 101, 102, 103, 104, 105, 107 to 117, 120, 121, 124 to 135, 137 to 146, 149, 150, 152 to 161, 163 to 165; intermediates: (IA), (IB), (J), (K), (L), (M) and (N).

[1516] Method N1:

[1517] Spectra obtained on Waters UPLC-SQD2:

[1518] Ionization: Positive and / or negative mode (ES+ / -) electrospray.

[1519] -Column ACQUITY CSH C18-1.7μm-2.1x50mm

[1520] Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid)

[1521] - Column temperature: 60℃

[1522] - Flow rate: 1 mL / min

[1523] - Gradient (10 min): From 3% to 100% B in 8.6 min; 100% B in 9.6 min; 3% B in 9.8 min.

[1524] Method N1 has been used for compound: 106.

[1525] Method O:

[1526] Spectra were obtained on the Waters Quattro Premiere.

[1527] Ionization: Positive and / or negative modes (ES+ / -) electrospray

[1528] -Column: ACQUITY MSS T3-1.8μm-2.1x50mm

[1529] Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid)

[1530] - Column temperature: 55℃

[1531] - Flow rate: 0.9 ml / min

[1532] - Gradient (3.7 min): 5% to 100% B over 3 min; 3.1 min: 5% B

[1533] Method O has been used for compounds: 80, 81, 82, 83, 84, 100, 118, 119, 147 and intermediate (O).

[1534] Method P:

[1535] Spectra obtained on Waters XeVo-QTof

[1536] Ionization: Positive mode (ES+) electrospray.

[1537] -Column ACQUITY BEH C18-1.7μm-2.1x100mm

[1538] Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid)

[1539] - Column temperature: 45℃

[1540] - Flow rate: 0.6 mL / min

[1541] - Gradient (5.3 min): 0.3 min 5% B; from 5% to 100% B over 3.7 min; 0.6 min: 100% B; 0.7 min: 5% B

[1542] Method P has been used for compounds: 16, 42 and 85.

[1543] Method M:

[1544] Spectra obtained on Agilent 1200 & 6110B

[1545] Ionization: Positive mode (ES+) electrospray.

[1546] -Kinetex C18 50*2.1mm, 5μm

[1547] -Solvent: A: H2O+0.037% (v / v) TFA B: ACN+0.018% (v / v) TFA

[1548] - Column temperature: 40℃

[1549] - Flow rate: 1 mL / min

[1550] - Gradient (5 min): From 5% to 95% B over 3 min; 1 min: 95% B; 1.50 min: 5% B

[1551] Method M has been used for intermediates: (A), (B) and (E), and for compounds: 122, 123, 148, 151 and 162.

[1552] Method Z:

[1553] Spectra were obtained on the Waters Acquity UPLC system with a PDA detector.

[1554] Ionization: Positive and / or negative modes (ES+ / -) electrospray

[1555] -Acquity BEH C18 column (50mm x 2.1mm) 1.7μm

[1556] Solvents: A: H2O (0.05% formic acid) B: CH3CN (0.05% formic acid)

[1557] - Column temperature: 35℃

[1558] - Flow rate: 0.6 mL / min

[1559] - Gradient (4 min): 0.4 min: 3% B; from 3% to 98% B within 1.6 min; 1.5 min: 98% B; 0.50 min: 3% B

[1560] Method Z has been used for intermediates: (F), (G), and (H).

[1561] 1 1H nuclear magnetic resonance (NMR)

[1562] Recording in deuterated DMSO on a Brüker Avance and / or Varian G spectrometer (300 MHz, 400 MHz, 500 MHz, or 600 MHz) 1 1H 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, quintet, sext = sextet, dd = double doublet, ddd = double double doublet, m = multiplet, ax. = axial, equat. = equator.

[1563] preparation

[1564] Synthesize all of the following compounds according to the following scheme.

[1565] Preparation of intermediate (E):

[1566] Preparation 1: Intermediate (A) 2-Butyl-1H-imidazolium-4,5-dicarboxynitrile

[1567]

[1568] A suspension of (Z)-2,3-diaminobut-2-enonitrile (45.0 g, 416 mmol, 1.00 equivalent) and 1,1,1-trimethoxypentane (67.5 g, 416 mmol, 1.00 equivalent) in MeCN (90.0 mL) was stirred in an oil bath and maintained at 85 °C for 6 h. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. This compound was completely dissolved in xylene (90.0 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. The product was used for the next step without any purification. Intermediate (A) (63.0 g, 87% yield).

[1569] 1¹H NMR (400MHz, δ in ppm, CDCl₃): 2.82 (t, J = 7.6Hz, 15.2Hz, 2H), 1.72–1.80 (m, 2H), 1.36–1.45 (m, 2H), 0.93–0.97 (m, 3H).

[1570] MS method M: RT = 1.019 min, m / z 175.1(M+H) + .

[1571] Preparation 2: Intermediate (B) 2-Butyl-1H-imidazolium-4,5-dicarboxylic acid

[1572]

[1573] A solution of compound (A) (63.0 g, 362 mmol, 1.00 equivalent) 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.

[1574] 1 ¹H NMR (400MHz, 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).

[1575] MS method M: RT = 1.163 min, m / z 213.1(M+H) + .

[1576] Preparation 3: Intermediate (C) 2-butyl-1H-imidazolium-4,5-dimethyl dicarboxylate

[1577]

[1578] SOCl2 (214 g, 1.80 mol, 131 mL, 5.00 equivalent) was slowly added to a mixture of compound (B) (76.5 g, 361 mmol, 1.00 equivalent) in MeOH (230 mL), and the mixture was degassed and purged three times with N2. The mixture was then stirred at 40-45 °C under N2 atmosphere for 12 h. 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.

[1579] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d6): 3.87 (s, 6H), 2.77 (t, J = 8.0Hz, 2H), 1.68–1.76 (m, 2H), 1.30–1.40 (m, 2H), 0.90 (t, J = 7.6Hz, 3H).

[1580] Preparation 4: Intermediate (D) 2-butyl-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione

[1581]

[1582] The mixture of compound (C) (81.0 g, 337 mmol, 1.00 equivalent) and NH₂NH₂.H₂O (51.7 g, 1.01 mol, 50.2 mL, 98.0% purity, 3.00 equivalent) in MeOH (243 mL) was degassed and purged three times with N₂. The mixture was then stirred at 60 °C under N₂ atmosphere for 1 hour. 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 hours, the mixture was cooled and the white product was filtered 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.

[1583] Preparation 5: Intermediate (E) 2-butyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazine

[1584]

[1585] N,N-dimethylaniline (50.0 mL) was added to a cooled solution of compound (D) (49.5 g, 238 mmol, 1.00 equivalent) 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), the pH was adjusted to 7 with solid sodium bicarbonate, and the mixture was extracted with EtOAc (2 x 1 L). 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 in MTBE (200 mL) was stirred for 2 h. The suspension was filtered, and the filter cake was collected. An intermediate (E) (54.5 g, 92.0% yield) was given as a yellow solid.

[1586] 1 ¹H NMR (400MHz, δ in ppm, CDCl₃): 3.18 (t, J = 7.6Hz, 2H), 1.90–1.97 (m, 2H), 1.40–1.49 (m, 1H), 0.92 (t, J = 7.2Hz, 3H).

[1587] MS method M: RT = 2.161 min, m / z 245.0 (M+H) + .

[1588] Preparation of intermediate (H):

[1589] Preparation 6: Intermediate (F) 2-Butyl-1-[(4-methoxyphenyl)methyl]imidazolium-4,5-dicarboxylate dimethyl ester

[1590]

[1591] K₂CO₃ (260 g, 1.88 mol) was added to a solution of intermediate (C) (300 g, 1.25 mol) in DMF (3.5 L) and stirred at room temperature for 1 h. Then, 4-methoxybenzyl chloride (244.6 g, 1.56 mol) was added and stirred at room temperature for 16 h. The reaction mixture was poured into water (5 L) and extracted with EtOAc (2 x 3 L). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide intermediate (F) (450 g, crude product) as a pale yellow oil, which was used as is in the next step.

[1592] 1¹H NMR (400MHz, δ in ppm, CDCl₃): 6.95 (d, J = 8.8Hz, 2H) 6.84 (d, J = 8.6Hz, 2H) 5.31 (s, 2H) 3.91 (s, 3H) 3.81 (s, 3H) 3.78 (s, 3H) 2.68-2.64 (t, 2H) 1.36-1.63 (m, 2H) 1.37-1.31 (m, 2H) 0.89-0.84 (t, 3H).

[1593] MS: Method Z, TR = 1.97 min, m / z 361.1 (M+H) + .

[1594] Preparation 7: Intermediate (G) 2-Butyl-3-[(4-methoxyphenyl)methyl]-5,6-dihydroimidazo[4,5-d]pyridazine-4,7-dione.

[1595]

[1596] NH₂NH₂·H₂O (175.2 g, 3.49.8 mol) was added to a solution of intermediate (F) (450 g, 1.25 mol) in methanol (1.3 L) and the mixture was heated to 75 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with Et₂O (1 L), and the precipitated solid was filtered and dried to provide intermediate (G) (250 g, 61.7% yield) as a grayish-white solid.

[1597] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 7.17 (d, J = 8.8Hz, 2H) 6.89 (d, J = 8.4Hz, 2H) 6.87-6.64 (bs, 2H) 5.68 (s, 2H) 3.72 (s, 3H) 2.69-2.65 (t, 2H) 1.59-1.54 (m, 2H) 1.32-1.23 (m, 2H) 0.83-0.8 (t, 3H).

[1598] MS: Method Z: RT = 1.59 min, m / z 329.1 (M+H) + .

[1599] Preparation 8: Intermediate (H)2-butyl-4,7-dichloro-3-[(4-methoxyphenyl)methyl]imidazo[4,5-d]pyridazine.

[1600]

[1601] N,N-dimethylaniline (140 mL, 2 volumes) was added to a cooled solution of intermediate (G) (70 g, 213.4 mmol) in POCl3 (620 mL, 8.8 vol), and the reaction mixture was stirred at 110 °C for 4 h. The reaction mixture was cooled to room temperature, poured into cold water (5 L), and the pH was adjusted to 7 with solid Na2CO3 and extracted with EtOAc (2 x 3 L). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was milled with Et2O (200 mL) for 2 h, filtered, and dried to provide intermediate (H) (38 g, 48.5% yield) as a pale yellow solid.

[1602] 1 ¹H NMR (400MHz, δ in ppm, CDCl₃): 6.92-6.85 (m, 4H) 5.68 (s, 2H) 3.79 (s, 3H) 2.91-2.87 (t, 2H) 1.82-1.78 (m, 2H) 1.44-1.38 (m, 2H) 0.93-0.89 (t, 3H).

[1603] MS: Method Z, m / z 365.3(M+H) + .

[1604] Preparation 9: Intermediate (IA) 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine, and intermediate (IB) 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride

[1605] Intermediate (IA) 2-Butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1606]

[1607] A mixture of intermediate (H) (5 g, 13.7 mmol) and ammonia solution (10 mL, 35%) was introduced into a microwave-safe vial. The suspension was heated in a microwave at 150 °C for 6 hours. The resulting mixture was filtered and washed with water to give 5 g of crude product, which was purified by recrystallization in EtOH to provide intermediate (IA) (2.15 g, 45% yield) as a white solid.

[1608] 1¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.84 (t, J = 7.4 Hz, 3H); 1.32 (m, 2H); 1.64 (m, 2H); 2.83 (m, 2H); 3.72 (s, 3H); 5.65 (s, 2H); 6.71 (s-width, 2H); 6.91 (d, J = 8.9 Hz, 2H); 6.96 (d, J = 8.9 Hz, 2H).

[1609] MS method N: RT(min): 1.22; [M+H] + 346; ES-[MH-+HCO2H] - : m / z 390.

[1610] Intermediate (IB) 2-Butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride

[1611]

[1612] A mixture of intermediate (H) (5 g, 13.7 mmol) and ammonia solution (25 mL, 35%) was introduced into an autoclave. The suspension was heated at 150 °C and an internal pressure of 25 bar for 6 h and then kept overnight without heating. The resulting precipitate was filtered and the filter cake was dissolved in HCl dioxane (200 mL, 4 N), which was concentrated to 1 / 10 volume under reduced pressure. The fresh precipitate was filtered, washed with EtOAc, and dried under vacuum overnight at 30 °C to intermediate (IB) (3.65 g, 54% yield), which was used directly in the following steps.

[1613] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.83 (t, J = 7Hz, 3H), 1.32 (sxt, J = 7Hz, 2H), 1.63 (quin, J = 8Hz, 2H ),2.90(t,J=8Hz,2H),3.73(s,3H),5.75(s,2H),6.92(d,J=9Hz,2H),7.07(d,J=9Hz,2H),8.97(br s,2H),15.13(br s,1H).

[1614] MS method N: RT(min): 1.22; [M+H] + 346; ES-[MH-+HCO2H] - : m / z 390.

[1615] Preparation 10: Intermediate (J) 2-Butyl-4,7-dichloro-1-methyl-1H-imidazo[4,5-d]pyridazine

[1616]

[1617] Potassium carbonate (8.29 g, 60 mmol) was added to a solution of intermediate (E) (4.9 g, 20 mmol) in acetone (200 mL). The suspension was stirred at room temperature for 30 min. Then methyl iodine (1.9 mL, 30 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was filtered and washed with acetone (2 x 20 mL) and DCM (2 x 20 mL). The filtrate was concentrated under reduced pressure to give 6.75 g of yellow solid. The solid was dissolved in EtOAc (250 mL) and washed with water (150 mL) and brine (150 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 5.1 g of yellow solid. The product was purified by silica gel column chromatography on a Merck column (300 g, 15-40 μm silica) using a mixture of DCM / MeOH / CH3CN (96 / 2 / 2) as the eluent to provide the expected product (J) as a yellow solid (3.64 g, 70% yield).

[1618] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d6): 0.95 (t, J = 7.4 Hz, 3H); 1.43 (m, 2H); 1.79 (m, 2H); 3.00 (m, 2H); 4.04 (s, 3H).

[1619] MS method N: RT(min): 1.32; [M+H] + 259.

[1620] Preparation 11: Intermediate (K)2-butyl-7-chloro-1-methyl-1H-imidazo[4,5-d]pyridazine-4-amine

[1621]

[1622] A mixture of intermediate (J) (3.64 g, 14 mmol) and ammonia solution (100 mL, 35%) was introduced into an autoclave and heated at 150 °C and 35 bar for 6 h. The solid was dissolved in 100 mL of MeOH and concentrated under vacuum to give 4.16 g of crude product. The product was poured into water (100 mL) and stirred at room temperature for 1 h. The suspension was filtered, washed with water, and dried to provide the desired product (K) (1.44 g, 43% yield) as a beige solid.

[1623] 1¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.93 (t, J = 7.4 Hz, 3H); 1.41 (m, 2H); 1.74 (m, 2H); 2.90 (m, 2H); 3.95 (s, 3H); 6.63 (s-width, 2H).

[1624] MS method N: RT(min): 0.84; [M+H] + 240.

[1625] Preparation 12: Intermediate (L) 2-butyl-7-chloro-N,N-bis(2,4-dimethoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1626] 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 over 1 hour. An additional 5 g (15.8 mmol) of bis(2,4-dimethoxybenzyl)amine was added and heating was continued for 1 hour. 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 compound (L) as a pale yellow solid (12 g, 37% yield).

[1627] 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 & 8.4 Hz, 2H); 6.54 (d, J = 2.4 Hz, 2H); 6.95 (d, J = 8.4 Hz, 2H); 13.35 (s-width, 1H).

[1628] MS method N: RT(min): 1.59; [M+H] + 526.

[1629] Preparation 13: Intermediate (M) 2-Butyl-N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine.

[1630]

[1631] 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 hours. 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). Compound (M) (2.11 g, 50% yield) was given as a white solid.

[1632] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.84 (t, J = 7.4Hz, 3H); 1.26 (m, 2H); 1.37 (d, J = 6.2Hz, 6H); 1.66 (m, 2H); 2.77 (t, J = 7.6Hz, 2H); 3.70 (s, 6H); 3.71 (s, 6H); 5.00 (s-width, 4H); 5.41 (sept, J = 6.2Hz, 1H); 6.38 (dd, J = 2.4 & 8.4Hz, 2H); 6.52 (d, J = 2.4Hz, 2H); 6.94 (d, J = 8.4Hz, 2H); 13.01 (s-width, 1H).

[1633] MS method N: RT(min): 1.58; [M+H] + 550.

[1634] Preparation 14: Intermediate (N)2-butyl-7-chloro-N,N-bis(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1635]

[1636] DIPEA (3.42 mL, 19.58 mmol) and bis(4-methoxybenzyl)amine (1.68 g, 6.53 mmol) were added to a solution of intermediate (E) (1.6 g, 6.53 mmol) in n-butanol (8 mL) in a microwave-safe vial. The resulting mixture was stirred at room temperature for 5 min and then heated in a microwave-safe environment at 150 °C for 6 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under vacuum to give 3.75 g of crude product, which was purified by chromatography on a Merck column (150 g 15-40 μm silica) using heptane / EtOAc 90 / 10 to 20 / 80 as eluent to give compound (N) (1.25 g, 41% yield) as a pale yellow solid.

[1637] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.86 (t, J = 7Hz, 3H), 1.31 (sxt, J = 7Hz, 2H), 1.72 (quin, J = 8Hz, 2H), 2.86 (t, J = 7Hz, 2H), 3.72 (s, 6H), 5.08 (br s, 4H), 6.86 (d, J = 9Hz, 4H), 7.19 (d, J = 9Hz, 4H), 13.45 (br s, 1H).

[1638] MS method N: RT(min): 1.78; [M+H] + 466.

[1639] Preparation 15: Intermediate (R) 2-butyl-N,N-bis,4-methoxybenzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine.

[1640]

[1641] Sodium (418.6 mg, 18.03 mmol) was added to a solution of isopropanol (11 mL) with stirring, and the mixture was heated at 70 °C until hydrogen bubbling ceased. The hot sodium isopropoxide solution was rapidly added to a microwave-safe vial containing 1.2 g (2.58 mmol) of 2-butyl-7-chloro-N,N-bis(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (N) in dioxane (8 mL). The mixture was heated at 170 °C and 5 bar for 6 hours and maintained overnight. The reaction mixture was filtered and washed with EtOAc to give 1.94 g of crude product. The crude product was dissolved in EtOAc (100 mL) with stirring to give a suspension, which was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure to obtain 1.63 g of crude material, which was purified by chromatography on a Merck column (150 g 15-40 μm silica) using EtOAc / heptane 20 / 80 to 80 / 20 eluent. Compound (R) was given as a white solid (0.76 g, 60% yield).

[1642] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.86 (t, J = 7Hz, 3H), 1.30 (sxt, J = 7Hz, 2H), 1.39 (d, J = 6Hz, 6H), 1.71 (quin, J = 7Hz, 2H), 2. 82(t,J=7Hz,2H),3.71(s,6H),4.98(s,4H),5.44(spt,J=6Hz,1H),6.84(d,J=9Hz,4H),7.16(d,J=8Hz,4H),13.11(s,1H).

[1643] MS method O: RT(min): 2.79; [M+H] + 490.

[1644] Example

[1645] Example (1): Preparation of compound 1: 2-Butyl-7-isopropoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1646]

[1647] 2-Propanol (500 μL, 6.50 mmol) was added to a suspension of potassium hydroxide (250 mg, 3.79 mmol) in anhydrous CH3CN (2 mL). The mixture was stirred at room temperature for 5 min. Then, 2-Butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride intermediate (IB) (200 mg, 0.52 mmol) was added. The mixture was heated in a microwave oven at 150 °C for 2 h. The mixture was cooled, filtered, and washed with 2-propanol and ethyl acetate. The filtrate was concentrated under reduced pressure to give 836 mg of crude product. The residue was dissolved in EtOAc (100 mL), washed with H2O and brine, dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 242 mg of crude material. This crude material was purified by chromatography on a Merck column (10 g 15-40 μm silica) using elution with 99 / 1 to 95 / 5 EtOAc / EtOH. Example (1) (27 mg, 14% yield) was obtained as a white solid.

[1648] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.85 (t, J = 7.4 Hz, 3H); 1.25 (d, J = 6.2 Hz, 6H); 1.33 (m, 2H); 1.63 (m, 2H); 2.81 (m, 2H); 3.71 (s, 3H); 5.36 (sept, J = 6.2 Hz, 1H); 5.51 (s, 2H); 5.91 (s, 2H); 6.90 (d, J = 8.8 Hz, 2H); 7.06 (d, J = 8.8 Hz, 2H).

[1649] MS method N: RT(min): 1.2; [M+H] + 370.

[1650] The following compounds can be produced in a manner similar to that of Example 1: 48, 50, 52, 54, 56, 57, 58, 65, 68, 69, 72 and 86.

[1651] Example (2): Preparation of compound 2: 2-Butyl-N7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine

[1652]

[1653] Isopropylamine (1.8 mL, 20.85 mmol) was added to a solution of 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (200 mg, 0.58 mol) in 1,4-dioxane (10 mL). The reaction mixture was heated in a microwave oven at 230 °C for 3 h. The mixture was concentrated under reduced pressure to give 208 mg of crude product, which was purified by chromatography on a Merck column (10 g 15-40 μm silica) by elution with DCM / MeOH / NH4OH at a concentration of 98 / 2 / 0.5 to 90 / 10 / 0.5. Example (2) (8 mg, 4% yield) was obtained as a white amorphous solid.

[1654] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.87 (t, J = 7.4Hz, 3H); 1.03 (d, J = 6.3Hz, 6H); 1.36 (m, 2H); 1.67 (m, 2H); 2.87 (m, 2H); 3 .71 (s, 3H); 4.00 (m, 1H); 4.79 (d, J = 6.5Hz, 1H); 5.59 (s, 2H); 6.10 (s, 2H); 6.90 (d, J = 8.9Hz, 2H); 7.00 (d, J = 8.9Hz, 2H).

[1655] MS Method A: RT(min): 0.82; [M+H] + 369.

[1656] The following compounds, 49, 53, 71, 94, and 98, can be produced in a manner similar to that of Example 2.

[1657] Example (3): Preparation of compound 3: 2-Butyl-7-(isopropylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1658]

[1659] 2-Propanthiol (400 μl, 4.18 mmol) was added to a suspension of potassium hydroxide (150 mg, 2.27 mmol) in acetonitrile (2 mL). The mixture was stirred at room temperature for 5 min, and then 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (180 mg, 0.52 mmol) was added. The reaction mixture was heated in a microwave oven at 150 °C for 2 h. The mixture was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure to give 695 mg of crude product, which was purified by chromatography on a Merck column (20 g 15-40 μm silica) by elution with 80 / 20 to 50 / 50 DCM / DCM-MeOH (90 / 10). Example (3) (26 mg, 13% yield) was given as a white solid.

[1660] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.81 (t, J = 7.4Hz, 3H); 1.22 (d, J = 6.8Hz, 6H); 1.29 (m, 2H); 1.60 (m, 2H); 2.74 (m, 2H); 3.71 (s, 3H); 5.85 (sept, J = 6.8Hz, 1H); 5.74 (s, 2H); 6.46 (s, 2H); 6.90 (m, 4H).

[1661] MS method N: RT(min): 1.23; [M+H] + 386.

[1662] The following compound, 99, can be produced in a manner similar to that of Example 3.

[1663] Example (4): Preparation of compound 4: 2-Butyl-1-(4-methoxybenzyl)-7-(2-methoxyethoxy)-1H-imidazo[4,5-d]pyridazine-4-amine

[1664]

[1665] 2-Methoxyethanol (460.71 μL, 5.78 mmol) was added to a suspension of potassium hydroxide (90 mg, 1.36 mmol) in anhydrous acetonitrile (4 mL). The mixture was stirred at room temperature for 5 min, and then 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (200 mg, 0.58 mmol) was added. The reaction mixture was heated in a microwave oven at 170 °C for 2 h. The mixture was filtered and washed with 2-propanol and EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a Merck column (20 g 15-40 μm silica) eluted with 100 / 0 to 0 / 100 DCM / DCM-MeOH (95-5). Example (4) (46 mg, 21% yield) was obtained as a white solid.

[1666] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.85 (t, J = 7.4 Hz, 3H); 1.33 (m, 2H); 1.63 (m, 2H); 2.82 (m, 2H); 3.25 (s, 3H); 3.65 (m, 2H); 3.71 (s, 3H); 4.50 (m, 2H); 5.52 (s, 2H); 5.98 (s, 2H); 6.89 (d, J = 8.7 Hz, 2H); 7.13 (d, J = 8.7 Hz, 2H).

[1667] MS method N: RT(min): 1.13; [M+H] + 386.

[1668] Example (5): Preparation of compound 5: 2-Butyl-1-(4-methoxybenzyl)-7-propoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[1669]

[1670] Sodium (43 mg, 1.87 mmol) was added to 1-propanol (3 mL, 39.73 mmol), and the mixture was stirred until hydrogen bubbling ceased. A sodium propoxide solution was added to a mixture of 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride intermediate (IB) (200 mg, 0.52 mmol) and triethylamine (150 μL, 1.07 mmol) in a microwave reactor, and the reaction mixture was heated in a microwave oven at 150 °C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 147 mg of crude product, which was purified by chromatography on a Merck column (10 g 15-40 μm silica) by elution with 90 / 10 to 80 / 20 DCM / DCM-MeOH-MeCN (80-10-10). Example (5) (73 mg, 38% yield) was given as a white solid.

[1671] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.84 (t, J = 7.4Hz, 3H); 0.89 (t, J = 7.4Hz, 3H); 1.32 (m, 2H); 1.61 (m, 2H); 1.70 (m, 2H); 2 .79 (m, 2H); 3.71 (s, 3H); 4.32 (t, J = 6.4Hz, 2H); 5.54 (s, 2H); 5.97 (s, 2H); 6.90 (d, J = 8.8Hz, 2H); 7.06 (d, J = 8.8Hz, 2H).

[1672] MS method N: RT(min): 1.2; [M+H] + 370.

[1673] Example (6): Preparation of compound 6: 7-(allyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1674]

[1675] Sodium (43 mg, 1.87 mmol) was added to allyl alcohol (3 mL, 43.47 mmol), and the mixture was stirred at room temperature until hydrogen bubbling ceased. A solution of allyl sodium oxide was added to 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (200 mg, 0.58 mmol) in a microwave reactor, and the reaction mixture was heated in a microwave at 150 °C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 496 mg of crude product, which was purified by chromatography on a Merck column (10 g 15–40 μm silica) eluted with 80 / 20 to 0 / 100 DCM / DCM-MeOH (90–10). Example (6) (43 mg, 20% yield) yielded a white solid.

[1676] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.84 (t, J = 7.4Hz, 3H); 1.32 (m, 2H); 1.61 (m, 2H); 2.80 (m, 2H); 3.71 (s, 3H); 4.93 (td, J = 1.6&5.21Hz, 2H); 5.1 9(qd,J=1.6&10.5Hz,1H); 5.30(qd,J=1.6&17.3Hz,1H); 5.54(s,2H); 6.00(s,2H); 6.06(m,1H); 6.89(d,J=8.9Hz,2H); 7.07(d,J=8.9Hz,2H).

[1677] MS method N: RT(min): 1.17; [M+H] + 368.

[1678] Example (7): Preparation of compound 7: 7-(sec-butoxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1679]

[1680] Sodium (43 mg, 1.87 mmol) was added to 2-butanol (3 mL, 32.46 mmol), and the mixture was stirred at room temperature until hydrogen bubbling ceased. A sodium 2-butoxide solution was added to a mixture of 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride intermediate (IB) (200 mg, 0.52 mmol) and triethylamine (150 μL, 1.07 mmol) in a microwave reactor, and the reaction mixture was heated at 150 °C in a microwave oven for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 165 mg of crude product, which was then processed on a Gilson GX271 system using a CSH 50 x 250 mm, 5 μm column (Waters) operating at 150 mL / min and room temperature. TM Purification was performed using the following A / B gradient: t = 0 min: 18% solution B, t = 5 min: 18% solution B, t = 25 min: 38% solution B, and A: water / formic acid 0.1% (v / v) and B: acetonitrile / formic acid 0.1% (v / v). Example (7) (82 mg, 41% yield) was obtained as a white amorphous solid.

[1681] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.81 (t, J = 7.4 Hz, 3H); 0.85 (t, J = 7.4 Hz, 3H); 1.22 (d, J = 6.2 Hz, 3H); 1.33 (m, 2H); 1.55 to 1.67 (m, 4H); 2.79 (m, 2H); 3.71 (s, 3H); 5.23 (m, 1H); 5.50 (d, J = 16.2 Hz, 1H); 5.55 (d, J = 16.2 Hz, 1H); 5.97 (s, 2H); 6.78 (d, J = 8.9 Hz, 2H); 7.03 (d, J = 8.9 Hz, 2H).

[1682] MS method N: RT(min): 1.28; [M+H] + 384.

[1683] Example (8): Preparation of compound 8: 7-butoxy-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1684]

[1685] Sodium (86 mg, 3.74 mmol) was added to 1-butanol (3 mL, 32.46 mmol), and the mixture was stirred at room temperature until hydrogen bubbling ceased. A sodium butoxide solution was added to a mixture of 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride intermediate (IB) (200 mg, 0.52 mmol) and triethylamine (150 μL, 1.07 mmol) in a microwave reactor, and the reaction mixture was heated in a microwave oven at 150 °C for 2 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 156 mg of crude product, which was purified by chromatography on a Merck column (10 g 15-40 μm silica) by elution with 90 / 10 to 80 / 20 DCM / DCM80-MeOH10-MeCN10. Example (8) (59 mg, 29% yield) was given as a white solid.

[1686] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.84 (t, J = 7.4Hz, 3H); 0.85 (t, J = 7.4Hz, 3H); 1.31 (m, 4H); 1.63 (m, 4H); 2.80 (m, 2H); 3.71 (s, 3H); 4.36 (t, J = 6.5Hz, 2H); 5.53 (s, 2H); 5.96 (s, 2H); 6.90 (d, J = 8.8Hz, 2H); 7.03 (d, J = 8.8Hz, 2H).

[1687] MS method N: RT(min): 1.25; [M+H] + 384; ES-: [M-H+HCO2H] - :m / z 428.

[1688] Example (9): Preparation of compound 9: 2-Butyl-7-(cyclopentoxy)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine.

[1689]

[1690] A mixture of cyclopentanol (1.5 mL, 16.34 mmol) and sodium (93.11 mg, 4.05 mmol) was stirred at 80 °C for 1 h. Then, a solution of 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (0.2 g, 58 mmol) in 1,4-dioxane (4 mL) was added, and the mixture was heated in a microwave oven at 170 °C for 6 h. The reaction mixture was concentrated under reduced pressure to provide 310 mg of crude product, which was purified by chromatography on a Merck column (20 g 15-40 μm silica) eluted with DCM / MeOH (95 / 5) to provide 63 mg (26.5% yield) of a white solid, Example (9).

[1691] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.83 (t, J = 7.40 Hz, 3H) 1.32 (s x t, J = 7.60, 2H) 1.45-1.76 (m, 8H) 1.78-1.94 (m, 2H) 2.78 (t, J = 7.60 Hz, 2H) 3.70 (s, 3H) 5.42-5.57 (m, 3H) 5.92 (s, 2H) 6.89 (d, J = 8.78 Hz, 2H) 7.01 (d, J = 8.78 Hz, 2H).

[1692] MS Method A: RT(min): 0.96; [M+H] + 396.

[1693] Example (10): Preparation of compound 10: 2-Butyl-1-(4-methoxybenzyl)-7-(pyrrolidine-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine.

[1694]

[1695] A mixture of 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (0.2 g, 0.58 mmol) in pyrrolidine (2 mL, 23.72 mmol) and water (1 mL) was stirred in a microwave at 160 °C for 4 h. The reaction mixture was concentrated under reduced pressure to provide 347 mg of crude product, which was purified by chromatography on a Merck column (20 g 15-40 μm silica) eluted with DCM / MeOH (90 / 10) to provide 20 mg (9.1% yield) of white foam in Example (10).

[1696] 1H NMR (400MHz, δ in ppm, DMSO-d6): 0.83 (t, J = 7.5Hz, 3H); 1.31 (m, 2H); 1.63 (m, 2H); 1.82 (m, 4H); 2.70 (m, 2H); 3.15 (m, 4H); 3.71 (s, 3H); 5.62 (s, 2H); 6.11 (s, 2H); 6.88 (d, J = 8.9Hz, 2H); 6.96 (d, J = 8.9Hz, 2H).

[1697] MS method N: RT(min): 1.26; [M+H] + 381.

[1698] Example (11): Preparation of compound 11: 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-3-yl)-1H-imidazo[4,5d]pyridazine-4-amine

[1699]

[1700] A solution of 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (250 mg, 0.72 mmol) in 1,4-dioxane (5 mL) was added to a microwave-safe vial, followed by the addition of Pd(dppf)Cl2·DCM (88.55 mg, 0.11 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrole (224.55 mg, 1.08 mmol), and finally a 2M Cs2CO3 aqueous solution (1.45 mL, 2.89 mmol). The mixture was heated in a microwave-safe environment at 135 °C for 60 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in DCM and washed with a saturated aqueous solution of NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. Example (11) shows that the crude material was purified by silica gel chromatography using a mixture of CHCl3 / iPrOH (90 / 10) as the eluent to obtain 18.3 mg (6.5% yield) of a creamy solid.

[1701] 1H NMR (400MHz, δ in ppm, DMSO-d6): 0.83 (t, J = 7.4Hz, 3H); 1.31 (m, 2H); 1.63 (m, 2H); 2.71 (m, 2H); 3.60 (s, 3H); 3.68 (m, 3 H); 5.32 (s, 2H); 6.08 (dd, J = 1.9&2.5Hz, 1H); 6.28 (s, 2H); 6.68 (d, J = 8.9Hz, 2H); 6.72 (m, 2H); 6.81 (d, J = 8.3Hz, 2H).

[1702] MS method N: RT(min): 1.18; [M+H] + 391.

[1703] The following compounds can be produced in a manner similar to that of Example 11: 55, 62, 63, 64, 67, 70, 92, 93, 95, 96 and 97.

[1704] Example (12A): Preparation of compound 12: (E)-2-butyl-1-(4-methoxybenzyl)-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazin-4-amine, and

[1705] Example (12B): Preparation of compound 13: 2-Butyl-7-isopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1706] Step 1: Example (12A): Preparation of compound 12: (E)-2-butyl-1-(4-methoxybenzyl)-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1707]

[1708] Add 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (500 mg, 1.45 mmol) in 1,4-dioxane (10 mL), then add Pd(dppf)Cl2·DCM (177.10 mg, 0.22 mmol), (E)-4,4,5,5-tetramethyl-2-(3-methylbut-1-en-1-yl)-1,3,2-dioxane (567 mg, 2.89 mmol), and finally add 2M Cs2CO3 aqueous solution (2.89 mL, 5.78 mmol). Heat the mixture in a microwave-safe environment at 120 °C for 1 h 30 min. Evaporate the solvent under reduced pressure and dilute the residue with DCM and wash with a saturated aqueous solution of NaHCO3. Separate the organic layer, dry over MgSO4, filter, and evaporate under reduced pressure. The crude material was purified by silica gel chromatography using a mixture of DCM / NH3 (97 / 3) in MeOH (2N) as the eluent to obtain 70 mg (12.7% yield) as a beige solid.

[1709] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.86 (t, J = 7.5 Hz, 3H); 0.92 (d, J = 6.8 Hz, 6H); 1.35 (m, 2H); 1.68 (m, 2H); 2.34 (m, 1H); 2.87 (m, 2H); 3.7 0 (s, 3H); 5.55 (s, 2H); 6.37 (s, 2H); 6.44 (dd, J = 5.9&15.5Hz, 1H); 6.51 (d, J = 15.5Hz, 1H); 6.86 (d, J = 9.1Hz, 2H); 6.90 (d, J = 9.1Hz, 2H).

[1710] MS method N: RT(min): 1.33; [M+H] + 380.

[1711] Step 2: Preparation of Compound 13 in Example (12B): 2-Butyl-7-isopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1712]

[1713] Pd / C 10% (23 mg) was added to a solution of (E)-2-butyl-1-(4-methoxybenzyl)-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazin-4-amine in MeOH (7 mL). The mixture was kept at 30 °C for 1 h 30 min under a hydrogen atmosphere (4 bar). The mixture was filtered through a 0.2 μm filter membrane and the filtrate was evaporated under reduced pressure to give 28 mg (67% yield) of cream-colored solid in Example (12B).

[1714] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.79 (d, J = 6.6 Hz, 6H); 0.85 (t, J = 7.4 Hz, 3H); 1.29 to 1.40 (m, 4H); 1.48 (m, 1H); 1.68 (m, 2H); 2.74 to 2.84 (m, 4H); 3.70 (s, 3H); 5.52 (s, 2H); 6.20 (s, 2H); 6.79 (d, J = 8.7 Hz, 2H); 6.91 (d, J = 8.7 Hz, 2H).

[1715] MS method N:RT(min):1.41;[M+H]+382.

[1716] The following compounds, 51, 59, 60, 61, 66 and 73, can be produced in a manner similar to that of Example 12.

[1717] Example (13): Preparation of compound 14: 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1718]

[1719] A solution of 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (150 mg, 0.43 mmol) in 1,4-dioxane (3 mL) was added to a microwave-safe vial. Then, Pd(dppf)Cl2·DCM (53.13 mg, 0.065 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrole (167.47 mg, 0.87 mmol), and finally, a 2M Cs2CO3 aqueous solution (867.48 μL, 1.73 mmol) was added. The mixture was microwaved at 110 °C for 60 min and then at 130 °C for 45 min. The solvent was then evaporated under reduced pressure, and the residue was dissolved in DCM and washed with a saturated aqueous solution of NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude material was purified by silica gel chromatography using a mixture of 97 / 3DCM / NH3 in MeOH(2N) as the eluent to give 41.24 mg (25.5% yield) of a white solid, Example (13).

[1720] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.82 (t, J = 7.5 Hz, 3H); 1.29 (m, 2H); 1.61 (m, 2H); 2.69 (m, 2H); 3.68 (s, 3H); 5.31 (s, 2H); 6.16 (dt, J = 1.8 & 2.5 Hz, 1H); 6.26 (s, 2H); 6.69 (d, J = 9.0 Hz, 2H); 6.80 (m, 3H); 6.85 (td, J = 1.8 & 2.5 Hz, 1H); 11.00 (s, 1H).

[1721] MS method N: RT(min): 1.15; [M+H]+377; ES-: [M-H+HCO2H]-: m / z 421.

[1722] Example (14A): Preparation of compound 15: 2-Butyl-7-(cyclopent-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride, and

[1723] Example (14B): Preparation of compound 16: 2-Butyl-7-cyclopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1724] Step 1: Example (14A): Preparation of compound 15: 2-Butyl-7-(cyclopent-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride

[1725]

[1726] A solution of 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (250 mg, 0.72 mmol) in a Me-THF / DMF (8 / 2, 4 mL) mixture was added to a microwave-safe vial, followed by the addition of Pd(dppf)Cl2·DCM (88.55 mg, 0.11 mmol), cyclopent-1-en-1-ylboronic acid (121.38 mg, 1.08 mmol), and finally a 2M Cs2CO3 aqueous solution (1.45 mL, 2.89 mmol). The mixture was heated in a microwave-safe environment at 100 °C for 2 h. It was then diluted with Me-THF, washed with H2O, and washed with a saturated aqueous solution of NaCl. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude material was purified by silica gel chromatography using the mixture DCM / MeOH 98 / 2 as the eluent. The first fraction containing the desired compound was evaporated to dryness and then dissolved in Et₂O, with 2M HCl added to the Et₂O solution at 0°C. The resulting solid was filtered and dried under vacuum to give 37 mg (12.4% yield) of Example (14A). The second fraction containing the desired compound was evaporated to dryness to give 70 mg of free base, and the next step was performed as is.

[1727] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.86 (t, J = 7.5 Hz, 3H); 1.36 (m, 2H); 1.70 (m, 2H); 1.80 (m, 2H); 2.31 (m, 2H); 2.47 (m, 2H); 2.91 (m, 2H); 3.71 (s, 3H); 5.51 (s, 2H); 6.00 (m, 1H); 6.81 (d, J = 8.9 Hz, 2H); 6.89 (d, J = 8.9 Hz, 2H); 8.82 (m width, 2H); 14.60 (s width, 1H).

[1728] MS method N: RT(min): 1.27; [M+H] + 378.

[1729] Step 2: Example (14B): Preparation of compound 16: 2-Butyl-7-cyclopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1730]

[1731] Platinum oxide (IV) hydrate (13 mg) was added to a solution of 2-butyl-7-(cyclopent-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine (70 mg, 0.19 mmol) from step 1 in MeOH (6 mL). The mixture was kept at 25 °C for 1 h 50 min under a hydrogen atmosphere (2 bar). The mixture was filtered through a 0.2 μm filter membrane and the filtrate was evaporated under reduced pressure. The obtained crude material was purified by silica gel chromatography using a mixture of DCM / MeOH (98 / 2) as eluent to give 46 mg (63.8% yield) of a white solid, Example (14B).

[1732] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.85 (t, J = 7.5 Hz, 3H); 1.35 (m, 2H); 1.52 (m, 2H); 1.61 to 1.83 (m, 8H); 2.88 (m, 2H); 3.45 (m, 1H); 3.72 (s, 3H); 5.66 (s, 2H); 6.92 (s, 4H); 8.15 (m, 2H).

[1733] MS method P: RT(min): 2.36; [M+H]+380.

[1734] Example (15A): Preparation of compound 17: 2-Butyl-1-(4-methoxybenzyl)-7-(prop-1-en-2-yl)-1H-imidazo[4,5-d]pyridazin-4-amine, and

[1735] Example (15B): Preparation of compound 18: 2-Butyl-7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1736] Step 1: Example (15A): Preparation of compound 17: 2-Butyl-1-(4-methoxybenzyl)-7-(prop-1-en-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1737]

[1738] To a suspension of 2-butyl-7-chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (IA) (200 mg, 0.58 mmol) in 1,4-dioxane (6 mL), Pd(dppf)Cl2·DCM (47.3 mg, 0.58 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxane (228.85 μL, 1.16 mmol), and finally a 2M aqueous solution of Cs2CO3 (809.64 μL, 1.62 mmol) was added. The mixture was heated under reflux for 6 h, then diluted with EtOAc and washed with H2O. The organic layer was separated and washed with a saturated aqueous solution of NaCl. The separated organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The crude material was purified by silica gel chromatography using a mixture of DCM / MeOH (97 / 3) as the eluent to obtain 88 mg of a creamy foam. The obtained product was ground together with Et2O, filtered, and dried to obtain 71.2 mg (35% yield) Example (15A).

[1739] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.86 (t, J = 7.5 Hz, 3H); 1.35 (m, 2H); 1.69 (m, 2H); 1.83 (s broad, 3H); 2.82 (m, 2H); 3.69 (s, 3H); 4.94 (s broad, 1H); 5.36 (s broad, 1H); 5.48 (s, 2H); 6.42 (s, 2H); 6.72 (d, J = 8.9 Hz, 2H); 6.86 (d, J = 8.9 Hz, 2H).

[1740] MS method N: RT(min): 1.22; [M+H] + 352.

[1741] Step 2: Example (15B), Preparation of Compound 18: 2-Butyl-7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1742]

[1743] Example (15A) added platinum(IV) hydrate (7 mg) to a solution of 2-butyl-1-(4-methoxybenzyl)-7-(prop-1-en-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine (55 mg, 0.16 mmol) in MeOH (6 mL). The mixture was kept at 25 °C for 2 h under a hydrogen atmosphere (2 bar). Then, platinum(IV) hydrate (7 mg) was added and the mixture was kept at 25 °C for 4 h 30 min under a hydrogen atmosphere (2 bar). The mixture was filtered through a 0.2 μm filter membrane and the filtrate was evaporated under reduced pressure to give 65 mg of crude product, which was purified by silica gel chromatography using a mixture of CHCl3 / iPrOH (94 / 6) as eluent to give 25 mg (44.2% yield) of white solid in Example (15B).

[1744] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.85 (t, J = 7.5Hz, 3H); 1.11 (d, J = 6.7Hz, 6H); 1.35 (m, 2H); 1.68 (m, 2H); 2.83 (m, 2 H); 3.26 (sept, J = 6.7Hz, 1H); 3.70 (s, 3H); 5.53 (s, 2H); 6.19 (s, 2H); 6.82 (d, J = 9.0Hz, 2H); 6.91 (d, J = 9.0Hz, 2H).

[1745] MS method N: RT(min): 1.23; [M+H] + 354.

[1746] The following compound, 159, can be produced in a manner similar to that of Example 15.

[1747] Example (16A): Preparation of compound 19: 1-(((1r,4r)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride

[1748] Step 1: (4-(4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)cyclohexyl)methyl)tert-butyl carbamate

[1749]

[1750] Cs₂CO₃ (1.78 g, 5.46 mmol) was added to a suspension of 2-butyl-N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (M) (1 g, 1.82 mmol) in Me-THF (20 mL). The mixture was stirred at room temperature for 30 min. Then, n-([(1r,4r)-4(bromomethyl)cyclohexyl]methyl)carbamate tert-butyl ester (879 mg, 2.73 mmol) was added to Me-THF (12 mL). The mixture was stirred at room temperature for 5 min and then refluxed for 24 h. The reaction mixture was then diluted with EtOAc (150 mL), washed with water and brine, and concentrated under reduced pressure to give 1.73 g of crude product, which was purified by chromatography on a Merck column (70 g 15–40 μm silica) using 0 / 100 to 50 / 50 EtOAc / heptane elution. The expected product (1.03 g, 73% yield) was given as a white solid.

[1751] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.75 (m. 2H); 0.83 (tJ = 7 Hz. 3H); 1.08 (m. 2H); 1.24 to 1.40 (m. 18H); 1.48 (dJ = 12 Hz. 2H); 1.58 to 1.81 (m. 5H); 2.73 (tJ = 6 Hz. 2H); 2.77 (tJ = 7 Hz). Hz.2H); 3.66 to 3.76 (m.12H); 4.10 (dJ=6Hz.2H); 5.00 (s width.4H); 5.37 (spt.J=6Hz.1H) ; 6.39 (dd.J=2&8Hz.2H); 6.52 (dJ=2Hz.2H); 6.78 (tJ=6Hz.1H); 6,96 (d,J=8Hz,2H).

[1752] MS method N: RT(min): 1.87; [M+H] + 775.

[1753] Step 2: Example (16A): Preparation of compound 19: 1-(((1r,4r)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride

[1754]

[1755] To the solution of (4-((4-(bis(4-methoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)cyclohexyl)methyl)carbamate tert-butyl ester (1.03 g, 1.33 mmol) in DCM (6 mL), 2,2,2-trifluoroacetic acid (6 mL, 77.9 mmol) and 1,3-dimethoxybenzene (522 μL, 3.99 mmol) were added. The mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with DCM (50 mL) and H2O (10 mL). The pH of the mixture was adjusted to pH 10–12 with stirring in an ice bath using 30% NaOH. The product was extracted with DCM (4 x 50 mL), the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 3.1 g of crude product. The residue was purified by chromatography on a Macherey-Nagel column (40 g 15-40 μm diol) using 100 / / 0 to 50 / / 50 DCM-DCM / MeOH / H2O (80 / 10 / 1) to obtain an oil. The oil was treated with iPr2O (10 mL), the white solid was filtered and washed with iPr2O (3 x 5 mL), and dried under vacuum to give 617 mg of powder. 500 mg of this product was purified by elution with a C18 19 x 150 mm 5 μm column using 10 mM ammonium bicarbonate (pH 10) / acetonitrile to provide 188 mg of material, which was dissolved in HCl in MeOH (1.25 N) and the mixture was evaporated under reduced pressure. The residue was then dissolved in water, filtered through a 0.22 μm membrane, and the filtrate was freeze-dried to give 190 mg (39.5% yield) of hydrochloric acid (2HCl) as in Example 16A.

[1756] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.87 (qJ = 13 Hz, 2H); 0.94 (tJ = 7 Hz, 3H); 1.12 (qJ = 13 Hz, 2H); 1.33 to 1.48 (m, 8H); 1.51 to 1.63 (m, 3H); 1.66 to 1.92 (m, 5H); 2.63 (t, J = 6 Hz, 2H); 2.93 (t, J = 8 Hz, 2H); 4.21 (d, J = 7 Hz, 2H); 5.24 (quin, J = 6 Hz, 1H); 7.90 (s-width, 3H); 8.57 (s-width, 2H); 13.89 (s, 1H).

[1757] MS method N: RT(min): 0.83; [M+H] + 375.

[1758] Example (16B): Preparation of compound 20: trans-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate.

[1759] Step 1: (4-(4-(bis(4-methoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)cyclohexyl)methyl)tert-butyl carbamate

[1760]

[1761] Cs₂CO₃ (827 mg, 2.54 mmol) was added to a suspension of 2-butyl-7-isopropoxy-N,N-bis(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (R) (414 mg, 0.85 mmol) in THF (23 mL). The mixture was stirred at room temperature for 30 min. Then, N-([(1r,4r)-4(bromomethyl)cyclohexyl]methyl)carbamate tert-butyl ester (545 mg, 1.69 mmol) and DMF (6 mL) were added. The mixture was stirred at room temperature for 5 min, and then heated in a microwave oven at 100 °C for 1 h. The reaction mixture was filtered, the filtrate was diluted with EtOAc (200 mL), washed with water and brine, and concentrated under reduced pressure to give 820 mg of crude product. The residue was purified by chromatography on a Merck column (50 g 15-40 μm silica) eluted with 10 / 90 to 80 / 20 EtOAc / heptane. The expected product (233 mg, 39% yield) was given as a white solid.

[1762] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.78 (m, 2H); 0.86 (t, J = 7.5 Hz, 3H); 1.08 (m, 2H); 1.23 to 1.41 (m, 3H); 1.36 (s, 9H); 1.37 (d, J = 6.2 Hz, 6H); 1.49 (m, 2H); 1.63 to 1.82 (m, 5H); 2.73 (t, J) =6.1Hz,2H);2.83(t,J=7.6Hz,2H);3.71(s,6H);4.14(d,J=7.2Hz,2H);4.97(s,4H);5.41 (sept, J=6.2Hz, 1H); 6.78 (t, J=6.1Hz, 1H); 6.84 (d, J=8.8Hz, 4H); 7.17 (d, J=8.8Hz, 4H).

[1763] MS method N: RT(min): 1.82; [M+H]+ 715; ES - [MH - +HCO2H] - :m / z 759.

[1764] Step 2: Example (16B): Preparation of Compound 20: 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate

[1765]

[1766] Add 2,2,2-trifluoroacetic acid (4 mL, 0.32 mmol) to a solution of (4-((4-(bis(4-methoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)cyclohexyl)methyl)carbamate tert-butyl ester (230 mg, 0.32 mmol) in DCM (4 mL). Stir the mixture at room temperature for 6 days. Dilute the reaction with EtOAc (120 mL) and extract with H2O (100 mL). Freeze-dry the aqueous phase to give 123 mg of crude product. Pour the residue into a saturated solution of NaHCO3 and extract with EtOAc (3 x 50 mL), dry to anhydrous MgSO4, filter, and concentrate the filtrate under reduced pressure. Give Example (16B) (50 mg, 37% yield) as a white solid.

[1767] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.80 (m, 2H); 0.93 (t, J = 7.5 Hz, 3H); 1.10 (m, 2H); 1.30 (m, 1H); 1.36 (d, J = 6.2 Hz, 6H); 1.41 (m, 2H); 1.50 (m, 2H); 1.71 to 1.82 (m, 5H); 2.46 (d, J = 6.9 Hz, 2H); 2.83 (m, 2H); 4.13 (d, J = 7.4 Hz, 2H); 4.74 (m, 3H); 5.39 (sept, J = 6.2 Hz, 1H); 5.87 (s, 2H).

[1768] MS method N: RT(min): 0.80; [M+H]+375; ES+[M+2H-iPr]2+: m / z 167.

[1769] Example (17A): Preparation of compound 21: 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[1770] Step 1: (4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)tert-butyl carbamate

[1771]

[1772] Cs₂CO₃ (1.78 g, 5.46 mmol) was added to a suspension of 2-butyl-N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (M) (1 g, 1.82 mmol) in Me-THF (30 mL). The mixture was stirred at room temperature for 30 min, and then tert-butyl 4-(bromomethyl)benzylcarbamate (819 mg, 2.73 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with 150 mL of Me-THF and washed with water and brine, dried over anhydrous MgSO₄, filtered, and the filtrate was concentrated under reduced pressure to give 1.73 g of crude product. The residue was purified by chromatography on a Merck column (50 g 15–40 μm silica) using 100 / 0 to 50 / 50 DCM-DCM / MeOH (90 / 10). The desired product (1.34 g, 96% yield) was obtained as a white foam.

[1773] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.76 (t, J = 7 Hz, 3H); 1.21 (m, 8H); 1.37 (s, 9H); 1.55 (quin, J = 7 Hz, 2H); 2.74 (t, J = 7 Hz, 2H); 3.71 (s, 12H); 4.07 (d, J = 6 Hz, 2H); 5.01 (s, 4H). H); 5.31 (quin, J = 6Hz, 1H); 5.55 (s, 2H); 6.39 (dd, J = 2et & 8Hz, 2H); 6.52 (d, J = 2Hz, 2 H); 6.97 (d, J = 8Hz, 2H); 7.03 (d, J = 8Hz, 2H); 7.19 (d, J = 8Hz, 2H); 7.34 (t, J = 6Hz, 1H).

[1774] MS method N: RT(min): 1.87; [M+H] + 769.

[1775] Step 2: Example (17A): Preparation of compound 21: 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[1776]

[1777] To the solution of (4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate tert-butyl ester (684 mg, 0.889 mmol) in DCM (10 mL) from step 1, which was cooled in an ice bath, 1,3-dimethoxybenzene (349 μL, 2.67 mmol) and 2,2,2-trifluoroacetic acid (10 mL, 129.8 mmol) were added. After 15 minutes, the ice bath was removed and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (100 mL) and H2O (50 mL), and the aqueous phase was washed with DCM (2 x 50 mL). The pH of the aqueous layer was adjusted to pH 11 with 30% NaOH in an ice bath with stirring. The product was extracted with DCM (4 x 50 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 306 mg of crude product, which was purified by chromatography on a Macherey Nagel column (26 g 15-40 μm diol) with 100 / 0 to 0 / 100 DCM-DCM / MeOH (90 / 10) to give 91 mg of purified compound, which was further purified by elution with a C18 19 x 150 mm 5 μm column with 10 mM ammonium bicarbonate (pH 10) / acetonitrile to provide 64 mg (19.5% yield) Example (17A).

[1778] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.84 (t, J = 7Hz, 3H); 1.21 (s, 3H); 1.23 (s, 3H); 1.33 (m, 2H); 1.63 (m, 2H); 1.97 (m, 2H); 2. 79(d,J=15Hz,2H); 3.66(s,2H); 5.33(spt,J=6Hz,1H); 5.54(s,2H); 5.91(s,2H); 7.01(d,J=8Hz,2H); 7.28(d,J=8Hz,2H).

[1779] MS method N: RT(min): 0.76; [M+H] + 369.

[1780] The following compounds, 158 and 160, can be produced in a manner similar to that of Example 17a.

[1781] Example (17B): Preparation of compound 22: 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate

[1782] Step 1: (4-((4-(bis(4-methoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)tert-butyl carbamate

[1783]

[1784] Cs₂CO₃ (266 mg, 0.81 mmol) was added to a suspension of 2-butyl-7-isopropoxy-N,N-bis(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine intermediate (R) (133 mg, 0.27 mmol) in THF (7 mL). The mixture was stirred at room temperature for 15 min, and then tert-butyl 4-(bromomethyl)benzylcarbamate (163 mg, 0.52 mmol) was added. The mixture was stirred at room temperature for 20 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 269 mg of crude product, which was purified by chromatography on a Merck column (20 g 15–40 μm silica) eluted with 10 / 90 to 60 / 40 EtOAc / heptane. The desired product (83 mg, 43% yield) was given as a white solid.

[1785] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.78 (t, J = 7.4Hz, 3H); 1.21 (d, J = 6.2Hz, 6H); 1.28 (m, 2H); 1.36 (s, 9H); 1.60 (m, 2H); 2.79 (t, J = 7.6Hz, 2H); 3.71 (s, 6H); 4.07 (d, J = 6.2Hz, 3H); δ in ppm, DMSO-d⁶: 0.78 (t, J = 7.4Hz, 3H); 1.21 (d, J = 6.2Hz, 6H); δ in ppm, DMSO-d⁶: 1.28 (m, 2H); δ in ppm, DMSO-d⁶: 1.36 (s, 9 ... 2H); 4.98 (s, 4H); 5.34 (sept, J = 6.2Hz, 1H); 5.59 (s, 2H); 6.85 (d, J = 8.8Hz, 4H); 7.04 (d, J=8.2Hz, 2H); 7.18 (d, J=8.8Hz, 4H); 7.20 (d, J=8.2Hz, 2H); 7.35 (t, J=6.2Hz, 1H).

[1786] MS method N: RT(min): 1.67; [M+H] + 709; ES - [2MH - +HCO2H]-: m / z 1462; ES-[MH-+HCO2H]-: m / z 753.

[1787] Step 2: Example (17B), Preparation of Compound 22: 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate

[1788]

[1789] Add 2,2,2-trifluoroacetic acid (1.2 mL, 15.51 mmol) to the solution of (4-((4-(bis(4-methoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate tert-butyl ester (70 mg, 0.099 mmol) in DCM (1.2 mL). Stir the mixture at room temperature for 8 days. Dilute the reaction mixture with DCM (80 mL) and extract with H2O (200 mL). Wash the aqueous phase with EtOAc (2 x 50 mL). Freeze-dry the aqueous phase overnight. Example (17B) (75 mg, 93% yield) was obtained as a freeze-dried product.

[1790] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.85 (t, J = 7.4Hz, 3H); 1.22 (d, J = 6.2Hz, 6H); 1.33 (m, 2H); 1.66 (m, 2H); 2.87 (m, 2 H); 4.02 (m, 2H); 5.16 (m, 1H); 5.67 (s, 2H); 7.18 (d, J = 8.5Hz, 2H); 7.42 (d, J = 8.5Hz, 2H); 8.13 (s, 3H); 8.47 (m, 2H).

[1791] MS method N: RT(min): 0.68; [M+H] + 369.

[1792] Example (18): Preparation of compound 23: 1-(((1S,3R)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (and enantiomers)

[1793] Step 1: ((1R,3S)-3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)cyclohexyl)tert-butyl carbamate (and enantiomers)

[1794]

[1795] Cs₂CO₃ (449.05 mg, 1.36 mmol) was added to a suspension of intermediate (M) (500 mg, 0.91 mmol) in Me-THF (15 mL). The mixture was stirred at room temperature for 30 min. Then, tert-butyl [cis-3-(bromomethyl)cyclohexyl]carbamate (419.70 mg, 1.36 mmol) was added, and the mixture was stirred at room temperature for 20 h and then heated at 60 °C for 5 days. The mixture was diluted with Me-THF (250 mL), washed with H₂O (2 x 80 mL), brine (80 mL), dried over anhydrous MgSO₄, and filtered. The filtrate was concentrated under reduced pressure to give 940 mg of crude product, which was purified by chromatography on a Merck column (50 g 15-40 μm silica) eluted with 10 / 90 to 80 / 20 EtOAc / heptane. The desired compound was obtained as a white solid (490 mg, 71% yield).

[1796] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.80 to 1.44 (m, 7H); 0.83 (t, J = 7.5 Hz, 3H); 1.34 (s, 9H); 1.35 (d, J = 6.2 Hz, 3H); 1.38 (d, J = 6.2 Hz, 3H); 1.57 (m, 1H); 1.61 to 1.76 (m, 4H); 1.85 (m, 1H); 2.78 (t, J = 7.4 Hz) ,2H);3.12(m,1H);3.70(s,6H);3.71(s,6H);4.12(m,2H);5.00(s,4H);5.38(sept,J=6.2Hz,1H) ; 6.38 (dd, J = 2.4&8.4Hz, 2H); 6.52 (d, J = 2.4Hz, 2H); 6.76 (d, J = 7.9Hz, 1H); 6.95 (d, J = 8; 4Hz, 2H).

[1797] MS method N: RT(min): 1.83; [M+H] + 761.

[1798] Step 2: Example (18), Preparation of compound 23: 1-(((1S,3R)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (and enantiomers)

[1799]

[1800] Add 2,2,2-trifluoroacetic acid (2.5 mL, 32.65 mmol) to the solution of ((1R,3S)-3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)cyclohexyl)carbamate (and its enantiomer) (480 mg, 0.63 mmol) in DCM (2.5 mL). Stir the mixture at room temperature for 24 hours. Pour the reaction mixture into DCM (100 mL) and wash with H2O (2 x 80 mL). Neutralize the aqueous phase by adding 5 M sodium hydroxide and extract with EtOAc (3 x 75 mL). The organic phase was washed with H2O and brine, dried with anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 115 mg (50.7% yield) of white powder in Example (18).

[1801] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.75 to 1.00 (m, 2H); 0.93 (t, J = 7.4 Hz, 3H); 1.15 (m, 1H); 1.33 to 1.54 (m, 9H); 1.63 to 1.89 (m, 5H); 2.07 (m, 2H); 2.45 (m, 3H); 2.83 (m, 2H); 4.11 (m, 2H); 5.38 (sept, J = 6.2 Hz, 1H); 5.85 (s, 2H).

[1802] MS method N: RT(min): 0.85; [M+H] + 361; ES+[M+2H] 2+ :m / z 181.

[1803] Example (19): Preparation of compound 24: 1-(4-amino-2-butyl-7-isopropoxy-1H-imidazo[4.5-d]pyridazin-1-yl)-2-methylprop-2-ol

[1804] Step 1: 1-(4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)-2-methylprop-2-ol

[1805]

[1806] Cs₂CO₃ (900 mg, 2.73 mmol) was added to the suspension of intermediate (M) (500 mg, 91 mmol) in Me-THF (15 mL). The mixture was stirred at room temperature for 30 min. Then, 2,2-dimethylethylene oxide (125 μL, 1.37 mmol) was added. The mixture was heated in a microwave oven at 60 °C for 20 h, and then concentrated under reduced pressure. The residue was diluted in MeCN (15 mL), 2,2-dimethylethylene oxide (250 μL, 2.74 mmol) was added, and the mixture was heated in a microwave oven at 90 °C for 48 h. The reaction mixture was then diluted with Me-THF (250 mL), washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 533 mg of crude product, which was purified by chromatography on a Merck column (40 g 15–40 μm silica) eluting with 10 / 90 to 60 / 40 EtOAc / heptane. The expected product (236 mg, 42% yield) was given as a white amorphous solid.

[1807] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.83 (t, J = 7.4Hz, 3H); 1.09 (s-width, 6H); 1.29 (m, 2H); 1.36 (d, J = 6.2Hz, 6H); 1.64 (m, 2H); 2.95 (t, J = 7.6Hz, 2H); 3.70 (s, 6H); 3.71 (s, 6H); 4.29 (s-width, 2H); 4.76 (s, 1H); 5.01 (s, 4H); 5.38 (sept, J = 6.2Hz, 1H); 6.39 (dd, J = 2.4 & 8.4Hz, 2H); 6.52 (d, J = 2.4Hz, 2H); 6.96 (d, J = 8.4Hz, 2H).

[1808] MS method N: RT(min): 1.59; [M+H] + 622; ES-[M-H+HCO2H]-: m / z 666.

[1809] Step 2: Example (19): Preparation of compound 24: 1-(4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)-2-methylprop-2-ol

[1810]

[1811] Add 2,2,2-trifluoroacetic acid (1.5 mL, 20.19 mmol) to a solution of 1-(4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)-2-methylprop-2-ol (230 mg, 0.37 mol) in DCM (2 mL). Stir the mixture at room temperature for 5 h. Dilute the reaction mixture with DCM (100 mL) and extract with H2O (2 x 80 mL). Neutralize the aqueous phase with NaOH (5 M) until pH 10, extract with EtOAc (3 x 75 mL), wash the organic phase with water and brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Give Example (19) (37 mg, 31% yield) as a white solid.

[1812] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.92 (t, J = 7.3Hz, 3H); 1.09 (s-width, 6H); 1.36 (d, J = 6.2Hz, 6H); 1.39 (m, 2H); 1.75 (m, 2H); 3.01 (m, 2H); 4.28 (s, 2H); 4.78 (s, 1H); 5.36 (sept, J = 6.2Hz, 1H); 6.24 (s, 2H).

[1813] MS method N: RT(min): 1.1; [M+H] + 322.

[1814] The following compounds, 74, 75, 76, 80, and 81, can be produced in a manner similar to that of Example 19.

[1815] Example (20): Preparation of compound 25: trans-1-(4-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[1816] Step 1: 4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)cyclohexyl)tert-butyl carbamate

[1817]

[1818] Cs₂CO₃ (720 mg, 2.19 mmol) was added to a suspension of intermediate (M) (400 mg, 0.73 mmol) in Me-THF (15 mL). The mixture was stirred at room temperature for 30 min. Then, tert-butyl 4-(bromomethyl)cyclohexyl)carbamate (320 mg, 1.10 mmol) was added. The mixture was stirred at room temperature for 24 h, and then heated in a microwave at 90 °C for 18 h. Afterward, the reaction mixture was diluted with Me-THF (methyltetrahydrofuran) (250 mL), washed with water and brine, dried over MgSO₄, filtered, and concentrated under reduced pressure to give 692 mg of crude product, which was purified by chromatography on a Merck column (40 g 15-40 μm silica) eluted with 10 / 90 to 100 / 00 EtOAc / heptane. The expected product (357 mg, 64% yield) was given as a white solid.

[1819] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.83 (t, J = 7.5 Hz, 3H); 1.04 (m, 2H); 1.14 (m, 2H); 1.09 (m, 2H); 1.36 (s, 9H); 1.37 (d, J = 6.2 Hz, 6H); 1.47 (m, 2H); 1.60 to 1.79 (m, 5H); 2.77 (t, J = 7.4 Hz, 2H); 3.17 ( m,1H);3.70(s,6H);3.71(s,6H);4.10(d,J=7.2Hz,2H);5.00(s,4H);5.38(sept,J=6.2Hz,1H); 6.39(dd,J=2.5&8.4Hz,2H); 6.52(d,J=2.5Hz,2H); 6.68(d,J=7.9Hz,1H); 6.96(d,J=8.4Hz,2H).

[1820] MS method N: RT(min): 1.79; [M+H] + 761.

[1821] Step 2: Example (20): Preparation of compound 25: trans-1-(4-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[1822]

[1823] Add 2,2,2-trifluoroacetic acid (2 mL, 26.66 mmol) to a solution of 4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)cyclohexyl)carbamate tert-butyl ester (345 mg, 0.45 mmol) in DCM (2 mL). Stir the mixture at room temperature for 24 hours. Dilute the reaction mixture with DCM (100 mL) and extract with H2O (2 x 80 mL). Neutralize the aqueous phase with NaOH (5 M) until pH 10, extract with EtOAc (3 x 75 mL), wash the organic phase with water and brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Give Example (20) (142 mg, 87% yield) as a white solid.

[1824] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.92 (t, J = 7.3Hz, 3H); 0.94 (m, 2H); 1.12 (m, 2H); 1.34 to 1.48 (m, 5H); 1.36 (d, J = 6.2Hz, 6H); 1.65 to 1.81 (m, 5H); 2.82 (m, 2H); 2.95 (m width, 2H); 4.10 (d, J = 7.5Hz, 2H); 5.39 (sept, J = 6.2Hz, 1H); 5.85 (s, 2H).

[1825] MS method N: RT(min): 0.78; [M+H] + 361; ES+[M+2H] 2+ :m / z 181).

[1826] The following compounds can be produced in a manner similar to that of Example 20: 77, 78, 79, 146, 149, 165.

[1827] Example (21A): Preparation of compound 26: 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-4-amine, and

[1828] Example (21B): Preparation of compound 27: -((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)nicotinonitrile

[1829] Step 1: 6-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)nicotinonitrile

[1830]

[1831] Cs₂CO₃ (898 mg, 2.73 mmol) was added to a suspension of intermediate (M) (500 mg, 0.91 mmol) in Me-THF (15 mL). The mixture was stirred at room temperature for 30 min, and then 6-(bromomethyl)nicotinonitrile (285 mg, 1.37 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with Me-THF, washed with water and brine, dried over MgSO₄, filtered, and concentrated under reduced pressure to give 661 mg of crude product, which was purified by chromatography on a Merck column (50 g 15–40 μm silica) eluting with 10 / 90 to 80 / 20 EtOAc / heptane. The desired product (467 mg, 77% yield) was given as a white solid.

[1832] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.80 (t, J = 7.5Hz, 3H); 1.06 (d, J = 6.2Hz, 6H); 1.28 (m, 2H); 1.61 (m, 2H); 2.81 (t, J = 7.6Hz, 2H); 3.71 (s, 6H); 3.72 (s, 6H); 5.02 (s, 4H); 5.18 (sept, J = 6. 2Hz, 1H); 5.75 (s, 2H); 6.40 (dd, J=2.4&8.4Hz, 2H); 6.53 (d, J=2.4Hz, 2H); 6.98 (d, J=8.4Hz ,2H); 7.49(dd,J=0.9&8.3Hz,1H); 8.33(dd,J=2.2&8.3Hz,1H); 8.90(dd,J=0.9&2.2Hz,1H).

[1833] MS method O: RT(min): 2.96; [M+H] + 666.

[1834] Step 2: 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[1835]

[1836] Add 10% Pd / C (46 mg, 0.43 mmol) to a solution of 6-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)nicotinonitrile (460 mg, 0.69 mmol) in EtOH (10 mL). Hydrogenate the mixture at 17 bar and 25 °C for 6 h and filter. Concentrate the filtrate under vacuum to give 413 mg of crude product, which is purified by chromatography on a Merck column (20 g 15-40 μm silica) eluted with 99 / 1 / 0.1 to 93 / 7 / 0.1 DCM / MeOH / NH4OH. The desired product (178 mg, 38% yield) is given as a white solid.

[1837] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.79 (t, J = 7.4 Hz, 3H); 1.17 (d, J = 6.2 Hz, 6H); 1.27 (m, 2H); 1.61 (m, 2H); 1.95 (m width, 2H); 2.83 (t, J = 7.6 Hz, 2H); 3.67 (s, 2H); 3.71 (s, 6H); 3.72 (s, 6H); 5.01 (s, 4H); 5. 24(sept,J=6.2Hz,1H);5.61(s,2H);6.39(dd,J=2.4&8.4Hz,2H);6.52(d,J=2.4Hz,2H);6.97(d,J =8.4Hz,2H);7.16(dd,J=0.8&8.1Hz,1H);7.73(dd,J=2.3&8.1Hz,1H);8.37(dd,J=0.8&2.3Hz,1H).

[1838] MS method N: RT(min): 1.32; [M+H] + 670; ES + [M+2H] 2+ : m / z 335.7.

[1839] Step 3(I): Example (21A): Preparation of compound 26: 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[1840]

[1841] Add 2,2,2-trifluoroacetic acid (1.20 mL, 15.68 mmol) to the solution of 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (175 mg, 0.26 mmol) in DCM (1.2 mL). Stir the mixture at room temperature for 24 h. Dilute the reaction mixture with DCM (100 mL) and extract with H2O (2 x 80 mL). Adjust the aqueous phase to pH 10 with 5N sodium hydroxide solution, extract with EtOAc (3 x 75 mL), wash the organic phase with water and brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Give Example (21A) (79 mg, 82% yield) as a white solid.

[1842] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.86 (t, J = 7.4Hz, 3H); 1.16 (d, J = 6.2Hz, 6H); 1.35 (m, 2H); 1.68 (m, 2H); 2.67 (m, 2H); 2.87 (m, 2H); 3.70 (s, 2H); 5.25 (sept, J = 6.2Hz, 1H); 5.61 (s, 2H); 5.89 (s, 2H); 7.12 (d, J = 8.1Hz, 1H); 7.73 (dd, J = 2.3&8.1Hz, 1H); 8.38 (d, J = 2.3Hz, 1H).

[1843] MS method N: RT(min): 0.46; [M+H] + 370.

[1844] Step 3 (II): Example (21-B): Preparation of compound 27: 6-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)nicotinonitrile

[1845]

[1846] Add 2,2,2-trifluoroacetic acid (1.50 mL, 19.59 mmol) to the solution of 6-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)nicotinonitrile (225 mg, 0.34 mmol) in DCM (1.5 mL). Stir the mixture at room temperature for 24 h. Dilute the reaction mixture with DCM (100 mL) and extract with H2O (2 x 80 mL). Adjust the aqueous phase to pH 12 with 5N sodium hydroxide solution, saturate with NaCl, extract with EtOAc (3 x 75 mL), wash the organic phase with water and brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Give Example (21B) (110 mg, 89% yield) as a white solid.

[1847] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.86 (t, J = 7Hz, 3H); 1.05 (d, J = 6Hz, 6H); 1.35 (dq, J = 7&15Hz, 2H); 1.68 (dt, J = 8 & 15Hz, 2H); 2.87 (t, J=8Hz, 2H); 5.19 (spt, J=6Hz, 1H); 5.75 (s, 2H); 5.92 (s, 2H); 7.45 (dd, J=1&8Hz, 1H); 8.33 (dd, J=2&8Hz, 1H); 8.90 (dd, J=1&2Hz, 1H).

[1848] MS method N: RT(min): 1.10; [M+H] + m:z 366.

[1849] Example (22): Preparation of compound 28: N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5d]pyridazin-1-yl)methyl)benzyl)acetamide

[1850]

[1851] DIPEA (95 μL, 0.54 mmol) and acetic anhydride (61 μL, 0.65 mmol) were added to a solution of 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (Example (17A)) (200 mg, 0.54 mmol) in DMF (6 mL). The solution was stirred at room temperature for 2 h and then poured into a mixture of water (30 mL) and ice (30 g), and stirred at room temperature for 30 min. Solid NaHCO3 was then added until pH 8. The solution was extracted with EtOAc (3 x 40 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 139 mg of white solid, which was dissolved in MeOH (10 mL). Potassium carbonate (108 mg) was added and the suspension was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum, dissolved in DCM (10 mL), and washed with water (5 mL) and brine (5 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give a crude product, which was stirred in diisopropyl ether (2 mL) at room temperature for 15 min. The suspension was filtered. The solid was washed with diisopropyl ether (2 x 1 mL) and dried under vacuum. Example (22) (70 mg, 65% yield) was obtained as a white solid.

[1852] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.84 (t, J = 7.5Hz, 3H); 1.21 (d, J = 6.2Hz, 6H); 1.32 (m, 2H); 1.63 (m, 2H); 1.83 (s, 3H); 2.79 (m, 2H); 4.19 ( d, J = 6.0Hz, 2H); 5.32 (sept, J = 6.2Hz, 1H); 5.55 (s, 2H); 5.91 (s, 2H); 7.03 (d, J = 8.4Hz, 2H); 7.20 (d, J = 8.4Hz, 2H); 8.29 (t, J = 6.0Hz, 1H).

[1853] MS method N: RT(min): 1.09; [M+H] + 411.

[1854] Example (23): Preparation of compound 29: N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)undecanoamide

[1855]

[1856] To a solution of 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (Example (17A)) (127 mg, 0.35 mmol) in DMF (3 mL), undecanoic acid (65 μL, 0.35 mmol) and TEA (345 μL, 0.35 mmol) were added. The solution was stirred at room temperature for 5 min. Then HBTU (167 mg, 0.43 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into a mixture of water (30 mL) and ice (30 g) and stirred at room temperature for 30 min, then extracted with EtOAc (3 x 30 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain 200 mg of crude product. This crude product was purified by chromatography on a Merck column (10 g 15-40 μm silica) using DCM / MeOH (93 / 7) elution to obtain a colorless gel. This gel was dissolved in MeOH (2.5 mL) and filtered through an Amberlist A-26OH column. The MeOH filtrate was concentrated under vacuum to obtain a gel (48 mg), which was stirred with diisopropyl ether at room temperature for 15 min. The supernatant was removed, and the gel was dried under vacuum. Example (23) (31 mg, 15% yield) was obtained as a colorless gel.

[1857] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.84 (t, J = 7.4 Hz, 3H); 0.85 (t, J = 6.9 Hz, 3H); 1.21 (d, J = 6.2 Hz, 6H); 1.22 (s-width, 14H); 1.32 (m, 2H); 1.48 (m, 2H); 1.62 (m, 2H); 2.08 (t, J = 7.4 Hz, 3H); 0.85 (t, J = 6.9 Hz, 3H); 0.85 (t, J = 6.9 Hz, 3H); 0.85 (t, J = 6.9 Hz, 3H); 0.85 (t, J = 6.9 Hz, 3H); 0.85 (t, J = 6.9 Hz, 3H); 0.85 (t, J = 6.9 Hz, 3H); 0.85 (d ... .4Hz,2H);2.79(m,2H);4.20(d,J=6.1Hz,2H);5.32(sept,J=6.2Hz,1H);5.54(s,2H ); 5.91 (s, 2H); 7.02 (d, J = 8.4Hz, 2H); 7.19 (d, J = 8.4Hz, 2H); 8.24 (t, J = 6.1Hz, 1H).

[1858] MS method N: RT(min): 1.59; [M+H] + 537; ES - [M-H+HCO2H] - :m / z 581.

[1859] The following compounds, 84, 103, 106, and 107, can be produced in a manner similar to that of Example 23.

[1860] Example (24): Preparation of compound 30: N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)pentanamide

[1861]

[1862] To a solution of 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (Example (17A)) (200 mg, 0.42 mmol) in THF (5 mL), valeric acid (51 μL, 0.46 mmol), EDCI (238 mg, 1.24 mmol), HOBt (95 mg, 1.5 equivalents) was added dropwise, followed by the dropwise addition of DIPEA (290 μL, 4 equivalents). The solution was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL), a saturated sodium bicarbonate aqueous solution (25 mL), and water (2 x 25 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain 156 mg of crude product, which was purified by chromatography on a Merck column (10 g 15-40 μm silica) by elution with DCM / MeOH / CH3CN (90 / 5 / 5) to obtain Example (24) (94 mg, 50% yield) as a white solid.

[1863] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.83 (t, J = 7.4Hz, 6H); 1.21 (d, J = 6.2Hz, 6H) ;1.23(m,2H);1.32(m,2H);1.47(m,2H);1.62(m,2H);2.09(t,J=7.5Hz,2H);2 .79(m,2H);4.20(d,J=6.0Hz,2H);5.31(sept,J=6.2Hz,1H);5.55(s,2H);5.9 6 (s, 2H); 7.02 (d, J = 8.3Hz, 2H); 7.19 (d, J = 8.3Hz, 2H); 8.25 (t, J = 6.0Hz, 1H).

[1864] MS method N: RT(min): 1.23; [M+H] + 453; ES - [M-H+HCO2H] - :m / z 497.

[1865] Example (25): Preparation of compound 31: N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-(2-methoxyethoxy)propionamide

[1866]

[1867] To a solution of 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (Example (17A)) (200 mg, 0.42 mmol) in THF (5 mL), 3-(2-methoxyethoxy)propionic acid (65 mg, 0.41 mmol), EDCI (238 mg, 1.24 mmol), HOBT (95 mg, 1.5 equivalents), and DIPEA (290 μl, 4 equivalents) were added dropwise. The solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL), saturated sodium bicarbonate aqueous solution (25 mL), and water (2 x 25 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain 182 mg of crude product, which was purified by chromatography on a Merck column (10 g 15-40 μm silica) by elution with DCM / methanol / acetonitrile (85 / 7.5 / 7.5) to obtain Example (25) (58.5 mg, 28% yield) as a colorless gel.

[1868] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.85 (t, J = 7.4 Hz, 3H); 1.21 (d, J = 6.2 Hz, 6H); 1.32 (m, 2H); 1.63 (m, 2H); 2.34 (t, J = 6.5 Hz, 2H); 2.78 (t, J = 7.6 Hz, 2H); 3.16 (s, 3H); 3.37 (m, 2H); 3 .46(m,2H); 3.60(t,J=6.5Hz,2H); 4.23(d,J=6.1Hz,2H); 5.32(sept,J=6.2Hz,1H); 5.55 (s, 2H); 5.91 (s, 2H); 7.02 (d, J = 8.3Hz, 2H); 7.20 (d, J = 8.3Hz, 2H); 8.31 (t, J = 6.1Hz, 1H).

[1869] MS method N: RT(min): 1.11; [M+H] + 499.

[1870] Example (26): Preparation of compound 32: 1-(((1S,3S)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-]pyridazine-4-amine (and enantiomers).

[1871] Step 1: N-[(1S,3S)-3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)cyclohexyl)tert-butyl carbamate (and enantiomers)

[1872]

[1873] Cs₂CO₃ (898 mg, 2.73 mmol) was added to a suspension of intermediate (M) (500 mg, 0.91 mmol) in Me-THF (15 mL). The mixture was stirred at room temperature for 30 min. Then, tert-butyl [trans-3-(bromomethyl)cyclohexyl]carbamate (410 mg, 1.36 mmol) was added. The mixture was stirred at room temperature for 4 days, then heated in a microwave at 90 °C for 9 hours. The reaction mixture was diluted with Me-THF (250 mL), washed with water and brine, dried over MgSO₄, filtered, and concentrated under reduced pressure to give 1.23 g of crude product, which was purified by chromatography on a Merck column (70 g 15–40 μm silica) eluted with 50 / 50 to 100 / 0 EtOAc / heptane. The desired product (434 mg, 63% yield) was given as a white solid.

[1874] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.84 (t, J = 7.5 Hz, 3H); 1.08 (m, 1H); 1.20 to 1.55 (m, 9H); 1.32 (s, 9H); 1.36 (d, J = 6.2 Hz, 3H); 1.38 (d, J = 6.2 Hz, 3H); 1.66 (m, 2H); 2.11 (m, 1H); 2.78 (t, J = 7.5 Hz, 2H); 3.6 8 (m partially hidden, 1H); 3.70 (s, 6H); 3.71 (s, 6H); 4.11 (d, J = 7.2Hz, 2H); 5.00 (s, 4H); 5.36 (sept, J = 6.2Hz, 1H); 6.38 (dd, J = 2.4 & 8.4Hz, 2H); 6.52 (d, J = 2.4Hz, 2H); 6.73 (d, J = 7.2Hz, 1H); 6.95 (d, J = 8.4Hz, 2H).

[1875] MS method N: RT(min): 1.82; [M+H]+ 761.

[1876] Step 2: Example (26): Preparation of compound 32: 1-(((1S,3S)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-]pyridazine-4-amine (and enantiomers)

[1877]

[1878] Add 2,2,2-trifluoroacetic acid (2.5 mL, 32.65 mmol) to a solution of tert-butyl 3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)cyclohexyl)carbamate (435 mg, 0.57 mmol) in DCM (2.5 mL). Stir the mixture at room temperature for 24 hours. Dilute the reaction mixture with DCM (100 mL) and extract with H2O (2 x 80 mL). Adjust the aqueous phase to pH 10 with 5N sodium hydroxide solution and extract with EtOAc (3 x 75 mL). Wash the organic phase with water and brine, dry to MgSO4, filter, and evaporate under reduced pressure. Give Example (26) (136 mg, 66% yield) as a white solid.

[1879] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.93 (t, J = 7.4 Hz, 3H); 1.07 (m, 1H); 1.26 to 1.62 (m, 15H); 1.78 (m, 2H); 1.90 (m wide, 2H); 2.22 (m, 1H); 2.82 (m, 2H); 3.09 (m, 1H); 4.11 (m, 2H); 5.38 (sept, J = 6.2 Hz, 1H); 5.84 (s, 2H).

[1880] MS method N: RT(min): 0.90; [M+H] + 361; ES+[M+2H] 2+ :m / z 181.

[1881] Example (27): Preparation of compound 33: 1-(3-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate

[1882]

[1883] Step 1: (3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)tert-butyl carbamate

[1884]

[1885] Cs₂CO₃ (356 mg, 1.09 mmol) was added to a suspension of intermediate (M) (200 mg, 0.36 mmol) in THF (11 mL). The mixture was stirred at room temperature for 30 min. Then, tert-butyl 3-bromomethylbenzylcarbamate (230 mg, 0.73 mmol) was added. The mixture was stirred at room temperature for 20 h, then filtered, and the filtrate was concentrated under reduced pressure to give 526 mg of crude product. The residue was dissolved in EtOAc, washed with water and brine, and concentrated under reduced pressure to give 428 mg of crude product, which was purified by chromatography on a Merck column (30 g 15–40 μm silica) eluted with 10 / 90 to 80 / 20 EtOAc / heptane. The expected product (61 mg, 22% yield) was given as a white solid.

[1886] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.77 (t, J = 7.5 Hz, 3H); 1.22 (d, J = 6.2 Hz, 6H); 1.24 (m, 2H); 1.34 (s, 9H); 1.56 (m, 2H); 2.75 (t, J = 7.6 Hz, 2H); 3.71 (s, 12H); 4.06 (d, J = 6.4 Hz, 2H); 5.01 (s, 4H); 5.32 (sept, J = 6… 5.56(s, 2H); 6.39(dd, J = 2.5 & 8.4 Hz, 2H); 6.52(d, J = 2.5 Hz, 2H); 6.94(d width, J = 7.9 Hz, 1H); 6.98(d, J = 8.4 Hz, 2H); 7.03(s width, 1H); 7.14(d width, J = 7.9 Hz, 1H); 7.28(t, J = 7.9 Hz, 1H); 7.32(t, J = 6.4 Hz, 1H).

[1887] MS method O: RT(min): 3.22; [M+H] + 769.

[1888] Step 2: Example (27): Preparation of compound 33: 1-(3-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate

[1889]

[1890] Add 2,2,2-trifluoroacetic acid (1 mL, 13 mmol) to the solution of (3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate tert-butyl ester (60 mg, 0.08 mmol) in DCM (1 mL). Stir the mixture at room temperature for 8 hours. Dilute the reaction mixture with DCM (100 mL) and extract with H2O (2 x 50 mL). Neutralize the aqueous phase with saturated K2CO3 solution until pH 8 and extract with EtOAc (3 x 75 mL). Dry the organic phase over anhydrous MgSO4, filter, and concentrate the filtrate under reduced pressure. Give Example (27) (24 mg, 83% yield) as a white solid.

[1891] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.86 (t, J = 7.4Hz, 3H); 1.22 (d, J = 6.2Hz, 6H); 1.34 (m, 2H); 1.67 (m, 2H); 2.80 (m ,2H);3.94(s,2H);5.32(sept,J=6.2Hz,1H);5.59(s,2H);5.98(s,2H);7.11(t,J=2.0Hz,1H);7.14(td,J=2.0et 7.8Hz, 1H); 7.36 (td, J=2.0et7.8Hz, 1H); 7.41 (t, J=7.8Hz, 1H); 7.86 (m, 3H).

[1892] MS method N: RT(min): 0.81; [M+H] + 369.

[1893] Example (28): Preparation of compound 34: 4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde

[1894]

[1895] Step 1: 4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde

[1896]

[1897] 4-(bromomethyl)benzaldehyde (847 mg, 4.26 mmol) and Cs₂CO₃ (1.32 g, 4.11 mmol) were added to a suspension of intermediate (M) (2.2 g, 3.12 mmol) in Me-THF (21 mL). The mixture was stirred at room temperature for 24 h. The mixture was poured into Me-THF (15 mL), washed with H₂O (15 mL), dried over anhydrous MgSO₄, filtered, and the filtrate was concentrated under reduced pressure to give 3 g of crude product, which was purified by chromatography on a Merck column (150 g 15-40 μm silica) eluting with EtOAc / heptane (38 / 62). The expected product (1.5 g, 71% yield) was given as a white solid.

[1898] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.76 (t, J = 7.4 Hz, 3H); 1.13 (d, J = 6.2 Hz, 6H); 1.24 (m, 2H); 1.56 (m, 2H); 2.77 (t, J = 7.5 Hz, 2H); 3.71 (s, 12H); 5.02 (s, 4H); 5.26 (se) pt,J=6.2Hz,1H);5.69(s,2H);6.40(dd,J=2.5&8.4Hz,2H);6.53(d,J=2.5Hz,2H) ; 6.99 (d, J = 8.4Hz, 2H); 7.25 (d, J = 8.3Hz, 2H); 7.89 (d, J = 8.3Hz, 2H); 9.97 (s, 1H).

[1899] MS method N: RT(min): 1.66; [M+H] + 668; ES - [2M-H+HCO2H] - :m / z 1379.

[1900] Step 2: Example (28), Preparation of compound 34: 4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde

[1901]

[1902] Add 2,2,2-trifluoroacetic acid (1.6 mL, 21 mmol) to a solution of 4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde (110 mg, 0.17 mmol) in DCM (1.6 mL). Stir the mixture at room temperature for 24 h. Pour the reaction mixture into DCM (10 mL) and wash with 1 M sodium hydroxide. Dry the organic layer with anhydrous MgSO4, filter, and concentrate under vacuum to give 96 mg of crude product. Purify the crude product by chromatography on a Merck column (5 g 15-40 μm silica) eluted with DCM / MeOH (96 / 4). Example (28) (23 mg, 36.8% yield) was obtained as a solid.

[1903] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.84 (t, J = 7.5Hz, 3H); 1.12 (d, J = 6.2Hz, 6H); 1.33 (m, 2H); 1.64 (m, 2H); 2.83 (m, 2H); 5.26 (m, 1H); 5.69 (s, 2H); 5.97 (s, 2H); 7.23 (d, J = 8.2Hz, 2H); 7.89 (d, J = 8.2Hz, 2H); 9.98 (s, 1H)

[1904] MS method N: RT(min): 1.21; [M+H] + 368.

[1905] Example (29): Preparation of compound 35: (4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)phenyl)methanol.

[1906]

[1907] To a solution of compound 4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde (200 mg, 0.30 mmol) in DCM (3 mL), 2,2,2-trifluoroacetic acid (1.6 mL, 21 mmol) and triethylsilane (145 μL, 0.90 mmol) were added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into DCM and washed with 1 M sodium hydroxide. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 200 mg of crude product, which was then subjected to preparative HPLC at room temperature using a 250 x 50 mm, 5 μm CSH column (WATERS). TM The compound was purified using a water / acetonitrile gradient containing 0.1% formic acid (t = 0 min: 10% acetonitrile; t = 5 min: 10% and t = 25 min: 30%). The compound was eluted at 18.8 min and lyophilized to provide 22 mg (19.8% yield) of the white foam in Example (29).

[1908] 1 H NMR (400MHz, δ in ppm, DMSO-d6): 0.84 (t, J = 7.28Hz, 3H) 1.21 (d, J = 6.27Hz, 6H) 1.32 (sx t,J=7.65Hz,2H)1.63(quin,J=7.59Hz,2H)2.79(t,J=7.81Hz,2H)4.45(s,2H)5.13(br s,1H)5.32(spt,J=6.15Hz,1H)5.56(s,2H)5.92(s,2H)7.02(d,J=8.28Hz,2H)7.27(d,J=8.28Hz,2H).

[1909] MS Method A: RT(min): 0.73; [M+H] + 370.

[1910] Example (30): Preparation of compound 36: 2-Butyl-1-(4-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[1911]

[1912] Step 1: 2-Butyl-1-(4-((cyclopropylamino)methyl)benzyl)-N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[1913]

[1914] Cyclopropylamine (25.41 μL, 0.36 mmol) and acetic acid (34.29 μL, 0.60 mmol) were added to a solution of 4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde (200 mg, 0.30 mmol) in MeOH (2 mL). The mixture was stirred at room temperature for 10 min and then sodium cyanoborohydride (29.72 mg, 0.45 mmol) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was poured into H2O and the pH was adjusted to 8 by adding ammonia solution (35%). The mixture was then extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 0.25 g of oil. The product was purified by chromatography on a Merck column (20 g 15-40 μm silica) by elution with [(EtOAc / EtOH 3 / 1) 40% - heptane 60%]. The expected product was obtained as a solid (154 mg, 72.4% yield).

[1915] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.19 (m, 2H); 0.29 (m, 2H); 0.76 (t, J = 7.4 Hz, 3H); 1.21 (d, J = 6.2 Hz, 6H); 1.24 (m, 2H); 1.54 (m, 2H); 1.97 (m, 1H); 2.56 (m, 1H); 2.75 (t, J = 7.6 Hz, 2H); 3.65 (d, J = 5.4 Hz, 6H). Hz,2H);3.71(s,12H);5.01(s,4H);5.31(sept,J=6.2Hz,1H);5.56(s,2H);6.39(dd,J=2.5&8.5H z, 2H); 6.52 (d, J = 2.5Hz, 2H); 6.97 (d, J = 8.5Hz, 2H); 7.02 (d, J = 8.3Hz, 2H); 7; 27 (d, J = 8.3Hz, 2H).

[1916] MS method N: RT(min): 1.57; [M+H] + 709; ES + [M+2H] 2+ : m / z 355.

[1917] Step 2: Example (30), Preparation of compound 36: 2-Butyl-1-(4-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine

[1918]

[1919] 2,2,2-trifluoroacetic acid (910 μL, 11.81 mmol) was added to a solution of 2-butyl-1-(4-((cyclopropylamino)methyl)benzyl)-N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (140 mg, 0.20 mol) in DCM (2 mL). The mixture was stirred at room temperature for 24 h. The reaction mixture was poured into DCM (10 mL) and washed with 1 M sodium hydroxide. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 90 mg of crude product. The crude product was purified by chromatography on a Merck column (10 g 15-40 μm silica) eluted with DCM / MeOH / NH4OH (95 / 5 / 0.2) to provide Example (30) (40 mg, 49% yield) as a solid.

[1920] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.17 to 0.32 (m, 4H); 0.83 (t, J = 7.3 Hz, 3H); 1.20 (d, J = 6.2 Hz, 6H); 1.31 (m, 2H); 1.61 (m, 2H); 1.97 (m, 1H); 2.60 (m, 1H); 2.80 (m, 2H); 3.66 (s, 2H); 5.32 (sept, J = 6.2 Hz, 1H); 5.55 (s, 2H); 5.92 (m, 2H); 7.00 (d, J = 8.3 Hz, 2H); 7.27 (d, J = 8.3 Hz, 2H).

[1921] MS method N: RT(min): 0.83; [M+H] + 409; ES+[M+2H-iPr] 2+ :m / z 184.

[1922] The following compounds, 82, 83, 100, 101, and 102, can be produced in a manner similar to that of Example 30.

[1923] Example (31): Preparation of compound 37: 3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazinyl)methyl)benzyl)amino)thionylbutane 1,1-dioxide.

[1924]

[1925] Step 1: 3-((4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-]pyridazinyl)methyl)benzyl)amino)thionecyclobutane 1,1-dioxide.

[1926]

[1927] To a solution of 4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde (810 mg, 1.21 mmol) in MeOH (10 mL) from step 1 of Example (28), 3-aminothiohexacyclic butane 1,1-dioxide hydrochloride (301.85 mg, 1.82 mmol), triethylamine (338.13 μL, 2.43 mmol), and acetic acid (208.31 μL, 3.64 mmol) were added. The mixture was stirred at room temperature for 10 min and then sodium cyanoborohydride (114.33 mg, 1.82 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction mixture was poured into water and the pH was adjusted to 8 by adding ammonia solution (35%). The mixture was then extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to provide 1g of crude product, which was used in the next step without further purification.

[1928] Step 2: Example (31), preparation of compound 37: 3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazinyl-yl)methyl)benzyl)amino)thionylbutane 1,1-dioxide.

[1929]

[1930] Add 2,2,2-trifluoroacetic acid (897.05 μl, 11.64 mmol) to the solution of 3-((4-((bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)thionylbutane 1,1-dioxide (150 mg, 0.19 mmol) in DCM (5 mL). Stir the mixture at room temperature for 24 hours. Pour the reaction mixture into DCM and wash with 1 M sodium hydroxide. Dry the organic layer with anhydrous MgSO4, filter, and concentrate under vacuum to give 99 mg of white foam. The crude product was purified by chromatography on a Merck column (10 g 15-40 μm silica) by elution with DCM / MeOH / NH4OH (95 / 5 / 0.2) to provide Example (31) (61 mg, 66% yield) as a white solid.

[1931] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.84 (t, J = 7.4 Hz, 3H); 1.20 (d, J = 6.2 Hz, 6H); 1.32 (m, 2H); 1.62 (m, 2H); 2.80 (m, 2H); 2.91 (m, 1H); 3.44 (m, 1H); 3.59 (s, 2H); 3.84 to 3.91 (m, 2H); 4.17 to 4.25 (m, 2H); 5.32 (sept, J = 6.2 Hz, 1H); 5.56 (s, 2H); 5.94 (s, 2H); 7.02 (d, J = 8.2 Hz, 2H); 7.28 (d, J = 8.2 Hz, 2H).

[1932] MS method N: RT(min): 0.99; [M+H] + 473.

[1933] Example (32): Preparation of compound 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 butane-3-yl)acetamide.

[1934]

[1935] Step 1: N-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-N-(1,1-sulfur dioxide heterocyclic butane-3-yl)acetamide

[1936]

[1937] Acetic anhydride (109.86 μL, 1.16 mmol) was added to a solution of 3-((4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)thionylbutane 1,1-dioxide (300 mg, 0.39 mmol) in pyridine (3 mL). The mixture was stirred at room temperature for 48 h. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The residue was poured into EtOAc and washed with water. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 308 mg of white foam. The crude product was purified by chromatography on a Merck column (20 g 15-40 μm silica) eluted with DCM / MeOH (95 / 5) to provide 275 mg of the desired product as white foam. The compound is used in the next step without further purification.

[1938] Step 2: Example (32), Preparation of compound 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 butane-3-yl)acetamide.

[1939]

[1940] Add 2,2,2-trifluoroacetic acid (1 mL, 12.98 mmol) to the solution of N-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-N-(1,1-sulfur dioxide heterocyclic butane-3-yl)acetamide (270 mg, 0.33 mol) in DCM (7 mL). Stir the mixture at room temperature for 24 h. Pour the reaction mixture into DCM and wash with 1 M sodium hydroxide. Dry the organic layer with anhydrous MgSO4, filter, and concentrate under vacuum to give 220 mg of white foam. The crude product was purified by chromatography on a Merck column (20 g 15-40 μm silica) by elution with CH2Cl2 / MeOH / NH4OH (93 / 7 / 0.2) to provide 110 mg (64.5% yield) as white foam (Example 32).

[1941] 1¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.82 (t, J = 7 Hz, 3 H); 1.17 (d, J = 6 Hz, 6 H); 1.30 (dq, J = 7 & 15 Hz, 2 H); 1.59 (quin, J = 8 Hz, 2 H); 1.96 (s, 2 H); 2.19 (s-width, 1 H); 2.81 (t, J = 8 Hz, 2 H); 4.06 to 4.79 (m, 6 H); 5.05 (m, 1 H); 5.30 (quin, J = 6 Hz, 1 H); 5.57 (s-width, 2 H); 5.92 (s, 2 H); 6.94 to 7.26 (m, 4 H).

[1942] MS method N: RT(min): 1.08; [M+H] + m / z 515,ES-[M-H+HCO2H]-: m / z 559.

[1943] Example (33): Preparation of compound 39: 2-Butyl-7-isopropoxy-1-(4-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine.

[1944]

[1945] Step 1: 2-Butyl-N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1-(4-(((1-methylcyclobutyl))

[1946] Amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine.

[1947]

[1948] To a solution of 4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde (300 mg, 0.45 mmol) in methanol (2 mL) of Example (28), 1-methylcyclohydrochloride (86.26 mg, 0.67 mmol), triethylamine (125.23 μL, 0.90 mmol), and acetic acid (77.15 μL, 1.35 mmol) were added. The mixture was stirred at room temperature for 10 min and then sodium cyanoborohydride (43.21 mg, 0.67 mmol) was added. The mixture was stirred at room temperature for 5 h. The reaction mixture was poured into water and the pH was adjusted to 8 by adding ammonia solution (35%). The mixture was then extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 0.45 g of oil. The crude product was purified by chromatography on a Merck column (30 g 15-40 μm silica) by elution with [(EtOAc / EtOH 3 / 1) 50% - heptane 50%] to provide the desired product as a solid (146 mg, 44.1% yield).

[1949] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.76 (t, J = 7.5 Hz, 3H); 1.18 (s, 3H); 1.23 (d, J = 6.2 Hz, 6H); 1.25 (m, 2H); 1.55 (m, 2H); 1.58 to 1.72 (m, 4H); 1.85 to 2.01 (m, 3H); 2.74 (t, J = 7.6 Hz, 2H); 3.56 (d, J = 6.4H) z,2H);3.71(s,12H);5;01(s,4H);5.33(sept,J=6.2Hz,1H);5.55(s,2H);6.39(dd,J=2.4&8.4Hz , 2H); 6.52 (d, J = 2.4Hz, 2H); 6.97 (d, J = 8.4Hz, 2H); 7.02 (d, J = 8.3Hz, 2H); 7.30 (d, J = 8.3Hz, 2H).

[1950] MS method N: RT(min): 1.32; [M+H] + 737;ES + [M+2H] 2+ :m / z 369.

[1951] Step 2: Example (33): Preparation of compound 39: 2-Butyl-7-isopropoxy-1-(4-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine.

[1952]

[1953] Add 2,2,2-trifluoroacetic acid (878 μL, 11.40 mmol) to the solution of 2-butyl-N,N-bis(2,4-dimethoxybenzyl)-7-isopropoxy-1-(4-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine (140 mg, 0.19 mmol) in DCM (4 mL). Stir the mixture at room temperature for 24 hours. Pour the reaction mixture into DCM and wash with 1 M sodium hydroxide. Dry the organic layer with anhydrous MgSO4, filter, and concentrate under vacuum to give 83 mg of white solid. The crude product was purified by chromatography on a Merck column (10 g 15-40 μm silica) by elution with CH2Cl2 / MeOH / NH4OH (94 / 6 / 0.2) to provide Example (33) as a white solid (66 mg, 79.7% yield).

[1954] 1 H RMN (400MHz, δ in ppm, DMSO-d6): 0.85 (t, J = 7.4Hz, 3H); 1.19 (s, 3H); 1.22 (d, J = 6.2Hz, 6H); 1.33 (m, 2H); 1.58 to 1.73 (m, 6H); 1.93 (m, 2H); 2.09 (m width, 1H); 2.80 (m, 2H); 3.58 (s, 2H); 5.33 (sept, J = 6.2Hz, 1H); 5.56 (s, 2H); 5.92 (s, 2H); 7.01 (d, J = 8.3Hz, 2H); 7.31 (d, J = 8.3Hz, 2H).

[1955] MS method N: RT(min): 0.9; [M+H] + 437; ES + [M+C5H8] + :m / z 369.

[1956] The following compounds, 85, 87, 88, 89, 90, and 91, can be produced in a manner similar to that of Example 33.

[1957] Example (34): Preparation of compound 40: 2-Butyl-7-isopropoxy-1-(4-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine

[1958]

[1959] Step 1: 4-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)piperazine-1-carboxylic acid tert-butyl ester

[1960]

[1961] To a solution of 4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde (200 mg, 0.30 mmol) in methanol (2.5 mL) of Example (28), 1-Boc-piperazine (85.38 mg, 0.45 mmol) and acetic acid (34.29 μL, 0.60 mmol) were added. The mixture was stirred at room temperature for 10 min and then sodium cyanoborohydride (28.23 mg, 0.45 mmol) was added. Stirring was continued at room temperature for 4.5 h. The reaction mixture was poured into water and the pH was adjusted to 9 by adding ammonia solution (35%). The mixture was then extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 0.45 g of oil. The crude product (289 mg), which is a white gel-like substance, is used directly in the next step.

[1962] Step 2: Example (34), Preparation of compound 40: 2-Butyl-7-isopropoxy-1-(4-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine

[1963]

[1964] Add 2,2,2-trifluoroacetic acid (919.29 μL, 11.93 mmol) to the solution of 4-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.3 mmol) in DCM (6.3 mL). Stir the mixture at room temperature for 24 hours. Pour the mixture into DCM and wash with 1 M sodium hydroxide. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 145 mg of crude product, which was purified by chromatography on a Merck column (20 g 15-40 μm silica) with CH2Cl2 / MeOH / NH4OH (90 / 10 / 0.2) to provide Example (34) (45 mg, 35% yield) as a white solid.

[1965] 1H NMR (400MHz, delta in ppm, DMSO-d6): 0.81 (t, J = 7Hz, 3H); 1.17 (d, J = 6Hz, 6H); 1.29 (dq, J = 7 & 15Hz, 2H); 1.59 (quin, J = 8Hz, 2H); 2.22 (s width, 4H); 2.6 3 (t, J = 5Hz, 4H); 2.81 (t, J = 7Hz, 2H); 3.36 (s, 2H); 5.30 (spt, J = 6Hz, 1H); 5.55 (s, 2H); 5.94 (s, 2H); 7.00 (d, J = 8Hz, 2H); 7.24 (d, J = 8Hz, 2H).

[1966] MS method N: RT(min): 0.80; [M+H] + 438

[1967] Example (35): Preparation of compound 41: 2-Butyl-N7,N7,1-trimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine

[1968]

[1969] The intermediate (K) (95 mg, 0.40 mmol) in a mixture of DMF (1 mL) and dimethylamine (7 mL, 40% in water) was introduced into an autoclave and heated at 160 °C for 6 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was collected and dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 40 mg of crude product, which was purified by chromatography on a Merck column (2.5 g, 15-40 μm silica) eluting with DCM / methanol (93 / 7) to provide Example (34) (13 mg, 14% yield) as a white solid.

[1970] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.94 (t, J = 7.4 Hz, 3H); 1.43 (m, 2H); 1.77 (m, 2H); 2.77 (s, 6H); 2.86 (m, 2H); 3.95 (s, 3H); 6.06 (s, 2H).

[1971] MS method N: RT(min): 0.88; [M+H] + 249.

[1972] Example (36): Preparation of compound 42: 2-Butyl-1-methyl-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine

[1973]

[1974] A mixture of intermediate (K) (50 mg, 0.21 mmol), water (1 mL), and pyrrolidine (1 mL) was introduced into a microwave-safe vial. The suspension was heated in a microwave-safe environment at 160 °C for 7 hours. The reaction mixture was concentrated under vacuum to give 100 mg of crude product, which was purified by chromatography on a Merck column (10 g 15–40 μm silica) eluted with DCM / MeOH / MeCN (85 / 7.5 / 7.5) to provide Example (36) (32 mg, 55% yield) as a yellow amorphous solid.

[1975] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.94 (t, J = 7.4 Hz, 3H); 1.43 (m, 2H); 1.77 (m, 2H); 1.89 (m, 4H); 2.88 (m, 2H); 3.30 (m, 4H); 3.96 (s, 3H); 6.88 (s, 2H).

[1976] MS method P: RT(min): 1.85; [M+H]+275.

[1977] Example (37): Preparation of compound 43: 2-Butyl-N7-(4-((dimethylamino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine

[1978]

[1979] A mixture of intermediate (K) (200 mg, 0.83 mmol), dimethyl((4-[(methylamino)methyl]phenyl)methyl)amine (783 mg, 4.17 mmol), 1-butanol (2 mL), and 3-chloropyridine hydrochloride (413 mg, 2.75 mmol) was introduced into a microwave-safe vial. The suspension was heated in a microwave oven at 160 °C for 3 hours. The reaction mixture was concentrated under vacuum to give 1.2 g of crude product. This material was dissolved in EtOAc (25 mL) and washed with water (20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 381 mg of crude compound, which was purified by chromatography on a Merck column (20 g 15–40 μm silica) eluted with DCM / methanol (8 / 2) to provide Example (37) (83 mg, 26% yield) as a yellow solid.

[1980] 1¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.94 (t, J = 7.4 Hz, 3H); 1.42 (m, 2H); 1.76 (m, 2H); 2.12 (s, 6H); 2.67 (s, 3H); 2.86 (m, 2H); 3.34 (s, 2H); 4.01 (s, 3H); 4.31 (s, 2H); 6.05 (s, 2H); 7.22 (d, J = 8.2 Hz, 2H); 7.29 (d, J = 8.2 Hz, 2H).

[1981] MS method N: RT(min): 0.84; [M+H] + 382; ES+[M+2H] 2+ : m / z 191.5.

[1982] Example (38): Preparation of compound 44: 2-Butyl-N7,1-dimethyl-N7-(4-(morpholinomethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine

[1983]

[1984] A mixture of intermediate (K) (100 mg, 0.42 mmol), methyl-(4-morpholino-4-ylmethyl-benzyl)-amine (484 mg, 2.09 mmol), 1-butanol (2 mL), and 3-chloropyridine hydrochloride (206.5 mg, 1.38 mmol) was introduced into a microwave-safe vial. The suspension was heated in a microwave at 160 °C for 6 hours. The reaction mixture was concentrated under vacuum to give 604 mg of crude product. This material was dissolved in EtOAc (50 mL) and washed with water (50 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 221 mg of a yellow solid, which was purified by chromatography on a Merck column (15 g 15-40 μm silica) eluted with DCM / MeOH (9 / 1) to provide 75 mg of a beige solid, which was stirred with isopropyl ether (2 mL) for 1 hour. After filtration and drying, Example (38) (55 mg, 35% yield) was obtained as a white solid.

[1985] 1H NMR (400MHz, δ in ppm, DMSO-d6): 0.94 (t, J = 7.3Hz, 3H); 1.42 (m, 2H); 1.76 (m, 2H); 2.32 (m, 4H); 2.66 (s, 3H); 2.86 (m, 2H); 3.41 (s, 2H); 3.56 (m, 4H); 4.00 (s, 3H); 4.30 (s, 2H); 6.02 (s, 2H); 7.23 (d, J = 8.3Hz, 2H); 7.29 (d, J = 8.3Hz, 2H).

[1986] MS method N: RT(min): 0.73; [M+H] + 424; ES+[M+2H] 2+ : m / z 212.5.

[1987] Example (39A): Preparation of compound 45: 4-(((4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazin-7-yl)(methyl)amino)methyl)benzylnitrile, and

[1988] Example (39B): Preparation of compound 46: N7-(4-(aminomethyl)benzyl)-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine

[1989] Step 1: Example (39A): Preparation of compound 45: 4-(((4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazin-7-yl)(methyl)amino)methyl)benzylnitrile

[1990]

[1991] A mixture of intermediate (K) (400 mg, 1.67 mmol), 4-(methylaminomethyl)benzyl nitrile (1.28 g, 8.34 mmol), 1-butanol (10 mL), and 3-chloropyridine hydrochloride (826 mg, 5.51 mmol) was introduced into a microwave-safe vial. The suspension was heated in a microwave-safe environment at 160 °C for 5 hours. The reaction mixture was concentrated under vacuum to give 1.9 g of crude product. This material was dissolved in EtOAc (100 mL) and washed with water (100 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 703 mg of a yellow solid, which was purified by chromatography on a Merck column (40 g 15-40 μm silica) eluted with DCM / methanol / acetonitrile (96 / 2 / 2) to provide Example (39A) (124 mg, 21% yield) as a white solid.

[1992] 1¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.94 (t, J = 7.4 Hz, 3H); 1.42 (m, 2H); 1.76 (m, 2H); 2.71 (s, 3H); 2.86 (m, 2H); 4.00 (s, 3H); 4.45 (s, 2H); 6.03 (s, 2H); 7.55 (d, J = 8.5 Hz, 2H); 7.76 (d, J = 8.5 Hz, 2H).

[1993] MS method N: RT(min): 1.12; [M+H] + 350.

[1994] Step 2: Example (39B), Preparation of Compound 46: N7-(4-(aminomethyl)benzyl)-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine

[1995]

[1996] BH3-THF 1M (893 μL, 0.89 mmol) was added dropwise to a solution of 4-(((4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazin-7-yl)(methyl)amino)methyl)benzyl nitrile (104 mg, 0.30 mmol) in THF (4 mL). The solution was heated under reflux for 18 hours. Then, methanol-HCl 1M (3 mL) was added and the mixture was heated under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure to give 414 mg of white solid. The residue was dissolved in DCM (10 mL) and washed with water (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 114 mg of white solid, which was purified by chromatography on a Macherey Nagel Chromabond Sorbenz NH2 column (16.4 g) with DCM / methanol (95 / 5) to give Example (39B) (13 mg, 12% yield) as a white solid.

[1997] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.94 (t, J = 7.5 Hz, 3H); 1.42 (m, 2H); 1.76 (m, 2H); 2.09 (m, 2H); 2.66 (s, 3H); 2.85 (m, 2H); 3.66 (s, 2H); 4.00 (s, 3H); 4.29 (s, 2H); 6.00 (s, 2H); 7.14 to 7.30 (m, 4H).

[1998] MS method N: RT(min): 0.73; [M+H] + 354; ES + [M+2H-NH3] 2+ :m / z 169.

[1999] Example (40): Preparation of compound 47: 2-Butyl-N7-(4-(((2-methoxyethyl)(methyl)amino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine

[2000]

[2001] A mixture of intermediate (K) (100 mg, 0.42 mmol), 2-methoxy-N-methyl-N-(4-((methylamino)methyl)benzyl)ethyl-1-amine (464 mg, 2.09 mmol), 1-butanol (2 mL), and 3-chloropyridine hydrochloride (206.5 mg, 1.38 mmol) was introduced into a microwave-safe vial. The suspension was heated in a microwave-safe environment at 160 °C for 3 hours. The reaction mixture was concentrated under vacuum to give 731 mg of crude product. This material was dissolved in EtOAc (25 mL) and washed with water (20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 244 mg of crude compound, which was purified by chromatography on a Merck column (20 g 15–40 μm silica) eluted with DCM / MeOH (9 / 1) to provide Example (40) (32 mg, 18% yield) as a white solid.

[2002] 1 ¹H NMR (400 MHz, δ in ppm, DMSO-d⁶): 0.94 (t, J = 7.4 Hz, 3H); 1.41 (m, 2H); 1.75 (m, 2H); 2.12 (s, 3H); 2.50 (m hidden, 2H); 2.66 (s, 3H); 2.85 (m, 2H); 3.21 (s, 3H); 3.43 (t, J = 6.0 Hz, 2H); 3.45 (s, 2H); 4.00 (s, 3H); 4.30 (s, 2H); 6.01 (s, 2H); 7.21 (d, J = 8.2 Hz, 2H); 7.28 (d, J = 8.2 Hz, 2H).

[2003] MS method N: RT(min): 0.72; [M+H] + 426; ES + [M+2H] 2+ : m / z 213.5.

[2004] Example (41): Preparation of compound 104: 2-Butyl-7-isopropoxy-1-(4-(((2-methoxyethyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine

[2005]

[2006] Under argon atmosphere, Cs₂CO₃ (531 mg, 1.63 mmol) was added to a solution of 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine (200 mg, 0.54 mmol (Example (17A))) in 3 mL of DMF, and the mixture was stirred for 30 min. Then 2-bromomethyl methyl ether (80.00 μl, 0.80 mmol) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was poured into 50 mL of ice water. The aqueous solution was extracted with EtOAc (3 x 25 mL), the organic layers were combined, and washed with brine. The organic layers were dried over anhydrous MgSO₄, filtered, and concentrated under vacuum to give 244 mg of crude compound, which was then subjected to chromatography on a Merck column (20 g). Purification was carried out on 15-40 μm silica using DCM / DCM-MeOH(8-2) / NH3·H2O (90 / 10 / 0.015 to 80 / 20 0.015) to provide Example (41) (72 mg, 31% yield) as a white solid.

[2007] 1 ¹H NMR (400MHz, δ in ppm, DMSO-d⁶): 0.83 (t, J = 7Hz, 3H), 1.20 (d, J = 6Hz, 6H), 1.24–1.41 (m, 2H), 1.55–1.67 (m, 2H), 2.59 (t, J = 6Hz, 2H), 2.75–2.86 (m, 2H), 3.20 (s, 3H), 3.33–3.41 (m partially hidden, 2H), 3.67 (s, 2H), 5.32 (spt, J = 6Hz, 1H), 5.55 (s, 2H), 5.93 (s, 2H), 7.01 (d, J = 8Hz, 2H), 7.27 (d, J = 8Hz, 2H).

[2008] MS method N: RT(min): 0.80; [M+H] + 427.

[2009] The following compounds can be produced in a manner similar to that of Example 41: 108, 109, 110, 116, 117, and 119.

[2010] Example (42): Preparation of compound 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

[2011]

[2012] Step 1: N-[[4-[[7-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-butyl-4-prop-2-yloxyimidazo[4,5-d]pyridazin-3-yl]methyl]phenyl]methyl]-N-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]tert-butyl carbamate

[2013]

[2014] Under argon atmosphere, sodium hydride (31 mg, 0.78 mmol) was added to a solution of (200 mg, 0.26 mmol) tert-butyl carbamate in DMF (3 mL) in step 1 of Example (17A) at room temperature. The mixture was stirred until gas bubbling ceased. M-PEG6-bromide (123 μl, 0.39 mmol) was then added and the mixture was stirred overnight at room temperature. A second portion of sodium hydride (31 mg, 0.78 mmol) was added and the mixture was stirred again for 24 h. The reaction mixture was poured into 100 mL of ice water. The aqueous solution was extracted with DCM (100 mL) and MeTHF (100 mL), the organic layers were combined, and concentrated under vacuum to give 65 mg of crude compound. The aqueous phase was concentrated under vacuum to give 404 mg of crude compound, which was treated with a mixture of EtOAc / EtOH. After filtering out the insoluble residue, the filtrate was concentrated under vacuum and combined with 65 mg of crude compound from the organic phase. The crude material was then purified by chromatography on a Merck column (10 g 15–40 μm silica) with EtOAc / EtOH elution from 98 / 2 to 90 / 10 to provide the desired compound (54 mg, 20% yield) as a white solid.

[2015] 1H NMR (400MHz, δ in ppm, DMSO-d6): 0.75 (t, J = 7.4Hz, 3H) 1.12-1.47 (m, 17H) 1 .55(m,2H)2.77(m,2H)3.21(m,3H)3.38-3.55(m,24H)3.71(s,12H)4.38(s ,2H)5.01(s,4H)5.31(m,1H)5.57(s,2H)6.39(m,J=8.3Hz,2H)6.53(d,J=2 .3Hz, 2H) 6.97 (m, J = 8.3Hz, 2H) 7.05 (d, J = 8.3Hz, 2H) 7.19 (d, J = 8.3Hz, 2H).

[2016] MS method N: RT(min): 1.79; [M+H] + 1047.

[2017] Step 2: Example (42): Preparation of compound 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

[2018]

[2019] Under argon atmosphere, at room temperature, TFA (203 μl, 2.63 mmol) was added to a solution of N-[[4-[[7-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl]methyl]phenyl]methyl]-N-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]tert-butyl carbamate (50 mg, 0.048 mmol) in DCM (0.2 mL), producing a purple solution, which was stirred for 48 h. The reaction mixture was then concentrated under vacuum and placed in MeOH (3 mL), followed by filtration of the insoluble residue and washing with MeOH. The methanol solution was concentrated and loaded onto a 5 g SCX column, eluted with 100 mL MeOH and 100 mL MeOH / NH3 (2 M). The MeOH / NH3 phase was concentrated under vacuum to obtain Example (42) (29.3 mg, 95% yield) as a white solid.

[2020] 1H NMR (400MHz, δ in ppm, DMSO-d6): 0.84 (t, J = 7Hz, 3H), 1.21 (d, J = 6Hz, 6H), 1.26-1.38 (m, 2H), 1.63 (t, J = 8Hz, 2H), 2.59 (t, J = 6Hz, 2H), 2.70-2.9 0(m,2H),3.22-3.25(m,3H),3.39-3.55(...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in: R1 means: - Hydrogen atom, or - Selected from the following groups: a) - (C1-C6)alkyl- groups; - Hydroxyl-(C1-C6)alkyl- groups; - NH2-(C1-C6)alkyl- groups; - NH-(C1-C6)alkyl-(C1-C6)alkyl- groups; - N((C1-C6)alkyl)2-(C1-C6)alkyl- groups; - (C2-C6)alkenyl- groups; - (C2-C6) ynyl group; b) - A phenyl (C1-C6) alkyl group that is unsubstituted or substituted with at least one of the following substituents: b1) - (C1-C6)alkoxy- group; b2) - Hydroxyl group; b3) -C(O)-H group; and b4) - A (C1-C6) alkyl group that is unsubstituted or substituted by at least one of the following substituents: 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- groups; b4.2.3) - where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n - group, (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)- groups; b4.2.5) - (C1-C6)alkyl-NH-C(O)- groups; b4.2.6) - (C1-C 16 )alkyl-C(O)- groups; b4.2.7) - (C1-C 16 )alkyl-OC(O)- groups; b4.2.8) - where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -C(O)- groups; b4.2.9) - Unsubstituted or substituted by at least one of the following substituents (C3-C) 10 ) Cycloalkyl- groups: -hydroxyl group; and -(C1-C6)alkyl- groups; or b4.2.10) - Contains one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -S(O2)- (C3-C 10 ) group of heterocyclic alkyl group; b4.2.11) - A group consisting of phenyl-C(O)-. 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)- groups; b4.2.14) - (C1-C 16 )alkyl-OC(O)-(C1-C6)alkyl- groups; Or R4 and R5 together with the nitrogen atoms to which they are attached form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one to four heteroatoms selected from oxygen, nitrogen, and sulfur, wherein 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] where n is an integer from 1 to 30. n - group; c) - Unsubstituted or substituted by at least one substituent selected from the following (C3-C) 10 Cycloalkyl (C1-C6)alkyl- groups: -NH2 and NH2-(C1-C6)alkyl- groups; d) - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C3-C 10 ) heterocyclic alkyl (C1-C6) alkyl- groups, The heterocyclic alkyl group is either unsubstituted or substituted with at least one substituent selected from the group consisting of (C1-C6) alkyl groups and CH3-[O-(CH2)2] where n is an integer from 1 to 30. n - groups; and e) - Containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) heteroaryl (C1-C6) alkyl- groups, The heteroaryl group is either unsubstituted or substituted by at least one substituent selected from the following: -(C1-C6)alkyl- groups; -NH2-(C1-C6)alkyl- groups, and -Cyano; f) - (C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 The heterocyclic alkyl group comprises one to four heteroatoms selected from the following: oxygen, nitrogen, -S(O)-, -S(O2)- and sulfur; g) - (C3-C 10 )Hypercyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 The heterocyclic alkyl group comprises one to four heteroatoms selected from the following: oxygen, nitrogen, -S(O)-, -S(O2)- and sulfur; R2 represents a halogen atom. Or selected from the following groups: -(C1-C6)alkyl- groups; -(C2-C6)alkenyl- groups; -(C2-C6) ynyl group; -(C1-C6)alkylthio- groups; -(C1-C6)alkylthio(C1-C6)alkyl- groups; -(C1-C6)alkyl-S(O)- groups; -(C1-C6)alkyl-S(O2)- groups; -(C1-C6)alkyl-S(O)-(C1-C6)alkyl- groups; -(C1-C6)alkyl-S(O2)-(C1-C6)alkyl- groups; -(C1-C6)alkoxy- groups; -(C1-C6)alkoxy(C1-C6)alkyl- groups; -(C1-C6)haloalkoxy(C1-C6)alkyl- groups; -(C3-C5)cycloalkyl-O-(C1-C6)alkyl- groups; -(C1-C6)alkyl-NH-(C1-C6)alkyl- groups; -((C1-C6)alkyl)2-N-(C1-C6)alkyl- groups; -(C1-C6)alkyl-NH- groups; and -((C1-C6)alkyl)2N- groups; R3 indicates: - Deuterium atom; - Hydrogen atom Or selected from the following groups: a) - (C1-C6)alkyl- groups; - (C2-C6)alkenyl- groups; - (C2-C6) ynyl- groups; and - (C1-C6) alkylthio- group; b) - OR6 group, wherein R6 is selected from: - Hydrogen atom; -(C1-C6)alkyl- groups; -where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n - group; -(C2-C6)alkenyl- groups; -(C2-C6) ynyl group; -(C3-C 10 )cycloalkyl- groups; -Phenyl; -phenyl (C1-C6)alkyl- groups; and - Contains one to four heteroatoms selected from oxygen, nitrogen, sulfur, -S(O)- and -S(O)2- (C3-C 10 ) group of heterocyclic alkyl group; c) - -NR7R8 groups, wherein R7 and R8 are independently selected from: - Hydrogen atom; - where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -; - Unsubstituted or (C1-C6) alkyl groups: - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) Aromatic compounds; or - Phenyl groups that are unsubstituted or substituted with at least one of the following substituents: - Cyano, and - NR9R 10 -(C1-C6)alkyl- groups, wherein: R9 and R 10 Selected independently from: - Hydrogen atom; - (C1-C6)alkyl- groups; - where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -,or R9 and R 10 Together with the nitrogen atoms to which they are attached, they form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises 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] where n is an integer from 1 to 30. n - group; Or R7 and R8 together with the nitrogen atoms they are attached to form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises 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) - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C3-C 10 ) group of heterocyclic alkyl group; e) - Contains one to four heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) heteroaryl- group, The (C5-C) 10 The heteroaryl group is either unsubstituted or substituted by at least one (C1-C6) alkyl group; f) - -(C6-C 10 Yuan Fangji; and g) - (C3-C 10 )cycloalkyl- groups.

2. The compound of formula (I) according to claim 1, provided that at least one of R1 and R3 is not a hydrogen atom.

3. The compound of formula (I) according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 represents: - Hydrogen atom, or - Selected from the following groups: a) - (C1-C6)alkyl- groups; - Hydroxyl-(C1-C6)alkyl- groups, or - NH2-(C1-C6)alkyl- groups; b) - A phenyl (C1-C6) alkyl group that is either unsubstituted or substituted with a substituent selected from the following: b1) - (C1-C6)-alkoxy- group; b3) - -C(O)-H group, and b4) - A (C1-C6) alkyl group substituted with at least one of the following substituents: b4.1) - Hydroxyl group; b4.2) - -NR4R5 group, wherein R4 and R5 are independently selected from: b4.2.1) - Hydrogen atom; b4.2.2) - (C1-C 16 )alkyl- groups; b4.2.3) - where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n - group, (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)- groups; b4.2.5) - (C1-C6)alkyl-NH-C(O)- groups; b4.2.6) - (C1-C 16 )alkyl-C(O)- groups; b4.2.7) - (C1-C 16 )alkyl-OC(O)- groups; b4.2.8) - where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -C(O)- groups; b4.2.9) - Unsubstituted or substituted with at least one (C1-C6) alkyl or hydroxyl group (C3-C4) 10 )cycloalkyl- groups; b4.2.10) - Contains one to four heteroatoms selected from the following (C3-C 10 Groups of heterocyclic alkyl groups: oxygen, nitrogen, and -S(O2)-; b4.2.11) - A group consisting of phenyl-C(O)-. 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)- groups; b4.2.14) - (C1-C 16 )alkyl-OC(O)-(C1-C6)alkyl- groups; Or R4 and R5 together with the nitrogen atoms to which they are attached form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one or two heteroatoms selected from oxygen and nitrogen; c) - Unsubstituted or substituted with a substituent selected from the following (C3-C) 10 Cycloalkyl (C1-C6)alkyl- groups: -NH2 and NH2-(C1-C6)alkyl- groups; d) - Unsubstituted (C3-C) compounds containing one or two nitrogen heteroatoms 10 )Hypercyclic alkyl (C1-C6) alkyl- groups; e) - Contains one nitrogen atom (C5-C) 10 ) heteroaryl (C1-C6) alkyl- groups, The heteroaryl group is either unsubstituted or substituted by at least one substituent selected from the following: - NH2-(C1-C6)alkyl- groups, and - Cyano group; f) - (C3-C 10 ) heterocyclic alkyl-NH-(C1-C 16 The heterocyclic alkyl group comprises a heteroatom selected from oxygen, nitrogen, -S(O)-, -S(O2)- and sulfur; g) - (C3-C 10 )Hypercyclic alkyl-N(C(O)-(C1-C6)alkyl)-(C1-C 16 The heterocyclic alkyl group contains a heteroatom selected from oxygen, nitrogen, -S(O)-, -S(O2)- and sulfur.

4. The compound of formula (I) according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 represents: - (C1-C6)alkyl- groups; - (C1-C6) alkylthio- group; - (C1-C6)alkyl-S(O)- groups; - (C1-C6)alkyl-NH-(C1-C6)alkyl- groups; - (C1-C6)alkyl-NH- groups; and - (C1-C6)alkoxy(C1-C6)alkyl- groups.

5. A compound of formula (I) according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R3 represents: - Hydrogen atom, or - Selected from the following groups: a) - (C1-C6)alkyl- groups; - (C2-C6)alkenyl- groups; - (C1-C6) alkylthio- group; b) - OR6 group, wherein R6 is selected from: - Hydrogen atom; - (C1-C6)alkyl- groups; - where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n - group; - (C2-C6) alkenyl; - (C3-C 10 )cycloalkyl; - Phenyl; -Phenyl (C1-C6 alkyl)- groups; and - Contains a heteroatom selected from oxygen, sulfur, -S(O)- and -S(O2)- (C3-C 10 ) group of heterocyclic alkyl group; c) - -NR7R8 groups, wherein R7 and R8 are independently selected from: - Hydrogen atom; - where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -; - Unsubstituted or (C1-C6) alkyl groups: - Contains one oxygen atom (C5-C) 10 ) heteroaryl- groups; or - Phenyl groups that are unsubstituted or substituted with at least one of the following substituents: - Cyano, and - NR9R 10 -(C1-C6)alkyl- groups, wherein R9 and R... 10 Selected independently from: - Hydrogen atom; - (C1-C6) alkyl, or - where n is an integer from 1 to 30 in CH3-[O-(CH2)2] n -; Or R9 and R 10 Together with the nitrogen atoms attached to them, they form (C3-C) 10 A heterocyclic alkyl group, wherein the group comprises one or two heteroatoms selected from oxygen and nitrogen. The (C3-C) 10 The heterocyclic alkyl group is replaced by at least one (C1-C6) alkyl group; Or R7 and R8 together with the nitrogen atoms they are attached to form (C3-C) 10 A heterocyclic alkyl group, wherein the group contains a nitrogen atom, The heterocyclic alkyl group is unsubstituted or substituted with at least one substituent selected from: - Phenyl, and - Hydroxyl (C1-C6)alkyl-phenyl- group; d) - (C3-C 10 A heterocyclic alkyl group, wherein the group comprises a heteroatom selected from oxygen and nitrogen; e) - Contains one or two heteroatoms selected from oxygen, nitrogen, and sulfur (C5-C 10 ) heteroaryl- group, The (C5-C) 10 The heteroaryl group is unsubstituted or substituted by at least one (C1-C6) alkyl group; f) - (C6-C 10 ) aryl- groups, and g) - (C3-C 10 )cycloalkyl- groups.

6. A compound of formula (I) according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (1) 2-Butyl-7-isopropoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (2) 2-Butyl-N7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (3) 2-Butyl-7-(isopropylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (4) 2-Butyl-1-(4-methoxybenzyl)-7-(2-methoxyethoxy)-1H-imidazo[4,5-d]pyridazine-4-amine; (5) 2-Butyl-1-(4-methoxybenzyl)-7-propoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (6) 7-(allyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (7) 7-(sec-butoxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (8) 7-Butoxy-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (9) 2-Butyl-7-(cyclopentoxy)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (10) 2-Butyl-1-(4-methoxybenzyl)-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (11) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-3-yl)-1H-imidazo[4,5d]pyridazine-4-amine; (12)(E)-2-Butyl-1-(4-methoxybenzyl)-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (13) 2-Butyl-7-isopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (14) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (15) 2-Butyl-7-(cyclopent-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride; (16) 2-Butyl-7-cyclopentyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (17) 2-Butyl-1-(4-methoxybenzyl)-7-(prop-1-en-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (18) 2-Butyl-7-isopropyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (19) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride; (20) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate; (21) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (22) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate; (23) 1-(((1S,3R)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine and its enantiomers; (24) 1-(4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)-2-methylprop-2-ol; (25) trans-1-(4-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (26) 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (27)6-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)nicotinonitrile; (28)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5d]pyridazin-1-yl)methyl)benzyl)acetamide; (29)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)undecanoamide; (30)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)pentanamide; (31)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-(2-methoxyethoxy)propionamide; (32) 1-(((1S,3S)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-]pyridazine-4-amine and its enantiomers; (33) 1-(3-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate; (34) 4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzaldehyde; (35)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)phenyl)methanol; (36) 2-Butyl-1-(4-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (37) 3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazinyl)methyl)benzyl)amino)thionecyclobutane 1,1-dioxide; (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 butane-3-yl)acetamide; (39) 2-Butyl-7-isopropoxy-1-(4-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (40) 2-Butyl-7-isopropoxy-1-(4-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine; (41) 2-Butyl-N7,N7,1-trimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (42) 2-Butyl-1-methyl-7-(pyrrolid-1-yl)-1H-imidazo[4,5-d]pyridazin-4-amine; (43) 2-Butyl-N7-(4-((dimethylamino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (44) 2-Butyl-N7,1-Dimethyl-N7-(4-(morpholinomethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (45) 4-(((4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazine-7-yl)(methyl)amino)methyl)benzylnitrile; (46)N7-(4-(aminomethyl)benzyl)-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (47) 2-Butyl-N7-(4-(((2-methoxyethyl)(methyl)amino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (48) 2-Butyl-7-ethoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (49) 2-Butyl-1-(4-methoxybenzyl)-N7-(2-methoxyethyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (50) 2-Butyl-7-methoxy-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (51) 2-Butyl-7-cyclohexyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (52) 7-(benzyloxy)-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (53) 2-Butyl-1-(4-methoxybenzyl)-N7-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (54)(S)-2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine; (55) 2-Butyl-7-(furan-2-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (56) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine; (57) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydro-2H-pyran-4-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine; (58) 2-Butyl-1-(4-methoxybenzyl)-7-((tetrahydrothiophen-3-yl)oxy)-1H-imidazo[4,5-d]pyridazine-4-amine; (59) 2-Butyl-1-(4-methoxybenzyl)-7-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (60) 2-Butyl-1-(4-methoxybenzyl)-7-(2-methylprop-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (61) 2-Butyl-7-isobutyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (62) 2-Butyl-1-(4-methoxybenzyl)-7-(thiophen-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (63) 2-Butyl-1-(4-methoxybenzyl)-7-(thiophen-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (64) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrrolo-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride; (65) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1-oxide isomer A; (66) 2-Butyl-7-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (67) 2-Butyl-7-(furan-3-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (68) 3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1,1-dioxide; (69)3-((4-amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-yl)oxy)tetrahydrothiophene 1-oxide isomer B; (70) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrrolo-2-yl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride; (71) 2-Butyl-1-(4-methoxybenzyl)-N7,N7-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (72) 2-Butyl-1-(4-methoxybenzyl)-7-phenoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (73) 2-Butyl-7-(2,5-dihydrofuran-3-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (74) 2-Butyl-7-isopropoxy-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (75) 2-Butyl-7-isopropoxy-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (76) 2-Butyl-7-isopropoxy-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate; (77) 1-(5-aminopentyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (78) 2-Butyl-7-isopropoxy-1-(2-(piperidin-4-yl)ethyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (79) 2-Butyl-7-isopropoxy-1-(2-(piperazin-1-yl)ethyl)-1H-imidazo[4,5-d]pyridazin-4-amine; (80) 1-Benzyl-2-Butyl-7-Isopropoxy-1H-Imidazo[4,5-d]pyridazine-4-amine hydrochloride; (81) 2-Butyl-1-(cyclohexylmethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride; (82) 2-Butyl-7-isopropoxy-1-(4-(((tetrahydro-2H-pyran-4-yl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine hydrochloride; (83) 2-Butyl-7-isopropoxy-1-(4-((isopropylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride; (84)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)heptamide; (85)(4-(1-(4-amino-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridine-7-yl)pyrrolidine-3-yl)phenyl)methanol hydrochloride; (86) 2-Butyl-7-isopropoxy-1-methyl-1H-imidazo[4,5-d]pyridazine-4-amine; (87)N7-(4-(aminomethyl)benzyl)-2-butyl-1-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (88) 2-Butyl-N7-isopropyl-1-methyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (89) 2-Butyl-1-methyl-7-(3-phenylpyrrolidin-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (90) N7-benzyl-2-butyl-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (91) 2-Butyl-1-methyl-N7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (92) 2-Butyl-1-(4-methoxybenzyl)-7-phenyl-1H-imidazo[4,5-d]pyridazine-4-amine; (93) 4-Amino-2-butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-7-ol; (94) 2-Butyl-N7-(3-(furan-2-yl)propyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (95) 2-Butyl-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (96) 2-Butyl-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (97) 2-Butyl-1-(4-methoxybenzyl)-7-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (98) 2-Butyl-N7-isopropyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (99) 2-Butyl-7-(isopropylthio)-1H-imidazo[4,5-d]pyridazine-4-amine; (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; (101)2-Butyl-7-isopropoxy-1-(4-(pyrrolidone-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (102) 2-Butyl-7-isopropoxy-1-(4-(morpholinomethyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (103)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)propionamide; (104) 2-Butyl-7-isopropoxy-1-(4-(((2-methoxyethyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (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; (106)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)benzamide; (107)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-methoxypropionamide; (108)2-Butyl-7-isopropoxy-1-(4-(((2-(2-methoxyethoxy)ethyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (109)2-Butyl-1-(4-((hexylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (110)2-Butyl-1-(4-((decylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (111)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate; (112)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate-4-methoxybenzyl ester; (113)1-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)-3-ethylurea; (114)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)carbamate 4-acetamidobenzyl ester; (115)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)methanesulfonamide; (116)2-Butyl-1-(4-((dimethylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (117)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)glycine tert-butyl ester; (118)2-Butyl-7-isopropoxy-1-(4-((methylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (119)3-((4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)tert-butyl propionate; (120)1-(4-(5,8,11-trioxa-2-azadodecyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (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; (122) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]methyl]imidazo[4,5-d]pyridazine-7-aminedi-2,2,2-trifluoroacetate; (123) 2-Butyl-4-isopropoxy-3-[[4-[[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy] ... (124) 2-Butyl-7-isopropoxy-1-(3-((methylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (125) 2-Butyl-1-(3-((dimethylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (126) 2-Butyl-1-(3-((cyclobutylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride; (127) 2-Butyl-1-(3-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride; (128) 2-Butyl-7-isopropoxy-1-(3-((isopropylamino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride; (129)3-((3-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)benzyl)amino)thionecyclobutane 1,1-dioxide; (130) 2-Butyl-7-isopropoxy-1-(3-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride; (131) 2-Butyl-7-isopropoxy-1-(3-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine; (132)(E)-1-(4-(aminomethyl)benzyl)-2-butyl-7-(3-methylbut-1-en-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (133) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine; (134) 1-(4-(aminomethyl)benzyl)-2-butyl-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (135) 1-(4-(aminomethyl)benzyl)-2-butyl-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate; (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 (138) 1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine; (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; (140)1-(((1R,4R)-4-aminocyclohexyl)methyl)-2-butyl-7-isopentyl-1H-imidazo[4,5-d]pyridazine-4-amine; (141) 1-(((1R,4R)-4-aminocyclohexyl)methyl)-2-butyl-7-(1H-pyrrolo-3-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (142) 1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-(pyrrolidone-1-yl)-1H-imidazo[4,5-d]pyridazine-4-amine; (143) 3-[(4-aminocyclohexyl)methyl]-2-butyl-4-pyrrolidine-1-yl-imidazo[4,5-d]pyridazine-7-amine; (144) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-(2,5-dihydro-1H-pyrrolo-3-yl)imidazo[4,5-d]pyridazine-4-amine; (145) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-pyrrolidine-3-yl-imidazo[4,5-d]pyridazine-4-amine; (146) 3-(6-aminohexyl)-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine dihydrochloride; (147) 2-Butyl-4-isopropoxy-3-[6-(tetrahydropyran-4-ylamino)hexyl]imidazo[4,5-d]pyridazine-7-amine dihydrochloride; (148)N-[6-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)hexyl]-N-tetrahydropyran-4-yl-acetamide; (149) 3-(4-aminobutyl)-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine dihydrochloride; (150) 2-Butyl-4-isopropoxy-3-[4-(tetrahydropyran-4-ylamino)butyl]imidazo[4,5-d]pyridazine-7-amine hydrochloride; (151)N-[4-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)butyl]-N-tetrahydropyran-4-yl-acetamide; (152) 2-Butyl-3-[4-[(1,1-dioxothione-3-yl)amino]butyl]-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine; (153)N-[4-(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)butyl]-N-(1,1-dioxothione-butane-3-yl)acetamide; (154) 2-Butyl-3-[6-[(1,1-dioxothione-3-yl)amino]hexyl]-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine; (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; (156) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]-2-methyl-prop-1,3-diol hydrochloride; (157) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]prop-1,3-diol hydrochloride; (158) 1-(4-(aminomethyl)benzyl)-7-isopropoxy-2-propyl-1H-imidazo[4,5-d]pyridazine-4-amine; (159) 1-(4-(aminomethyl)benzyl)-2-(ethoxymethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (160) 1-(4-(aminomethyl)benzyl)-7-isopropoxy-2-methyl-1H-imidazo[4,5-d]pyridazine-4-amine; (161)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylthioalkyl-imidazo[4,5-d]pyridazine-7-amine; (162)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylsulfinyl-imidazo[4,5-d]pyridazine-7-amine; (163)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-N2-propyl-imidazo[4,5-d]pyridazine-2,7-diamine; (164)3-[[4-(aminomethyl)phenyl]methyl]-2-(ethylaminomethyl)-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine; and (165)2-Butyl-7-isopropoxy-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-d]pyridazine-4-amine.

7. A compound of formula (I) according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (19) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine dihydrochloride; (20) 4-(aminomethyl)cyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate; (21) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (22) 1-(4-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate; (23) 1-(((1S,3R)-3-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine and its enantiomers; (24) 1-(4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)-2-methylprop-2-ol; (25) trans-1-(4-aminocyclohexyl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (26) 1-((5-(aminomethyl)pyridin-2-yl)methyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (28)N-(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5d]pyridazin-1-yl)methyl)benzyl)acetamide; (33) 1-(3-(aminomethyl)benzyl)-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine 2,2,2-trifluoroacetate; (35)(4-((4-amino-2-butyl-7-isopropoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl)phenyl)methanol; (36) 2-Butyl-1-(4-((cyclopropylamino)methyl)benzyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (39) 2-Butyl-7-isopropoxy-1-(4-(((1-methylcyclobutyl)amino)methyl)benzyl)-1H-imidazo[4,5-d]pyridazine-4-amine; (40) 2-Butyl-7-isopropoxy-1-(4-(piperazin-1-ylmethyl)benzyl)-1H-imidazo[4,5-d]pyridazin-4-amine; (43) 2-Butyl-N7-(4-((dimethylamino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (47) 2-Butyl-N7-(4-(((2-methoxyethyl)(methyl)amino)methyl)benzyl)-N7,1-dimethyl-1H-imidazo[4,5-d]pyridazine-4,7-diamine; (144) 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-7-(2,5-dihydro-1H-pyrrolo-3-yl)imidazo[4,5-d]pyridazine-4-amine; (156) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]-2-methyl-prop-1,3-diol hydrochloride; (157) 2-[(7-amino-2-butyl-4-isopropoxy-imidazo[4,5-d]pyridazin-3-yl)methyl]prop-1,3-diol hydrochloride; (159) 1-(4-(aminomethyl)benzyl)-2-(ethoxymethyl)-7-isopropoxy-1H-imidazo[4,5-d]pyridazine-4-amine; (161)3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-2-propylthioalkyl-imidazo[4,5-d]pyridazine-7-amine; (163) 3-[[4-(aminomethyl)phenyl]methyl]-4-isopropoxy-N2-propyl-imidazo[4,5-d]pyridazine-2,7-diamine; and (164)3-[[4-(aminomethyl)phenyl]methyl]-2-(ethylaminomethyl)-4-isopropoxy-imidazo[4,5-d]pyridazine-7-amine.

8. A method for preparing a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, said method comprising at least the following steps: (iB) provides compounds of formula (II), (II); (iiB) Cycling the compound of formula (II) provided in step (iB) by reacting it with R2-C(OCH3)3 or R2-COCl to obtain the compound of formula (III), wherein R2 is as defined in any one of claims 1 to 7. (III) Wherein R2 is as defined in any one of claims 1 to 7; (iiiB) Hydrolyze the nitrile group present on the compound of formula (III) obtained in step (iiB) to obtain the compound of formula (IV). (IV) Wherein R2 is as defined in any one of claims 1 to 7; (ivB) Esterification of the carboxylic acid functional group present on the compound of formula (IV) obtained in step (iiiB) to obtain the compound of formula (V), (V) Wherein R is a (C1-C4)alkyl- group, and R2 is as defined in any one of claims 1 to 7; (vB) Optionally, the compound of formula (V) obtained from step (ivB) is reacted with R1-X to obtain the compound of formula (Vb), wherein R1 is as defined in any one of claims 1 to 7, and X represents a halogen atom. (Vb) Wherein R is a (C1-C4) alkyl group, and R1 and R2 are as defined in any one of claims 1 to 7; (viB) Cyclate the compound of formula (Vb) obtained from step (vB) or the compound of formula (V) obtained from step (ivB) (where R1 is a hydrogen atom) to obtain the compound of formula (VIb). (VIb) Wherein R1 and R2 are as defined in any one of claims 1 to 7; (viiB) The compound of formula (VIb) obtained in step (viB) is dihalogenated to obtain the compound of formula (VIIa). (VIIa) Wherein R1 and R2 are as defined in any one of claims 1 to 7, and HAL is a halogen atom; (viiiB) The compound of formula (VIIa) obtained from step (viiB) is subjected to nucleophilic aromatic substitution to obtain the compound of formula (VIIIa). (VIIIa) Wherein R1 and R2 are as defined in any one of claims 1 to 7, and HAL is a halogen atom; (ixB) Substitute and / or couple the compound of formula (VIIIa) obtained from step (viiiB) to obtain the compound of formula (Ia). (him) Wherein R1 and R2 are as defined in any one of claims 1 to 7, and R 3a R3 as defined in any one of claims 1 to 7 may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group. (xB) when R 3a If R3 is not as defined in any one of claims 1 to 7, then the compound of formula (Ia) obtained from step (ixB) is reacted with any suitable reagent under any suitable conditions to obtain the compound of formula (I) as defined in any one of claims 1 to 7.

9. A method for preparing a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, said method comprising at least the following steps: (i) Provide compounds of formula (II), (II); (ii) Cycling the compound of formula (II) provided in step (i) by reacting it with R2-C(OCH3)3 or R2-COCl to obtain the compound of formula (III), wherein R2 is as defined in any one of claims 1 to 7 or is a hydrogen atom. (III) R2 is defined as in any one of claims 1 to 7 or is a hydrogen atom; (iii) Hydrolyze the nitrile group of the compound of formula (III) obtained in step (ii) to obtain the compound of formula (IV). (IV) R2 is defined as in any one of claims 1 to 7 or is a hydrogen atom; (iv) Esterify the carboxylic acid functional group of the compound of formula (IV) obtained in step (iii) to obtain the compound of formula (V). (V) Wherein R is a (C1-C4) alkyl group, and R2 is as defined in any one of claims 1 to 7 or a hydrogen atom; (v) Cyclate the compound of formula (V) obtained from step (iv) to obtain the compound of formula (VI). (WE) R2 is defined as in any one of claims 1 to 7 or is a hydrogen atom; (vi) The compound of formula (VI) obtained in step (v) is dihalogenated to obtain the compound of formula (VII). (VII) Wherein R2 is a hydrogen atom as defined in any one of claims 1 to 7, and HAL is a halogen atom; (vii) The compound of formula (VII) obtained from step (vi) is subjected to nucleophilic aromatic substitution with the compound of formula (AA). (AA) The two G1s independently represent either a hydrogen atom or a methoxy group. In order to obtain the compound of formula (VIII), (VIII) Wherein R2 is as defined in any one of claims 1 to 7 or a hydrogen atom, HAL is a halogen atom, and the two G1s independently represent a hydrogen atom or a methoxy group; (viii) The compound of formula (VIII) obtained from step (vii) is subjected to substitution and / or coupling reactions to obtain the compound of formula (IX). (IX) Wherein R2 is as defined in any one of claims 1 to 7 or is a hydrogen atom, R 3a R3 as defined in any one of claims 1 to 7 may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and the two G1s independently represent a hydrogen atom or a methoxy group; Then (ixAlpha, also known as ixα) the compound of formula (IX) obtained from step (viii) is reacted with R. 1a -X reaction to obtain a compound of formula (X), where R 1a It is R1 as defined in any one of claims 1 to 7, which may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and X represents a halogen atom, a toluene sulfonate, or a methanesulfonate. (X) Wherein R2 is as defined in any one of claims 1 to 7 or is a hydrogen atom, R 3a R3 as defined in any one of claims 1 to 7, comprising or excluding a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, wherein the two G1s independently represent a hydrogen atom or a methoxy group, and R 1a As defined in the above step (ixAlpha); Or (ixBeta, also known as ixβ) make the compound of formula (IX) obtained from step (viii) with formula The epoxide reaction is carried out to obtain a compound of formula (X), wherein R' and R'' are independently hydrogen atoms or (C1-C6) alkyl groups. (X) Wherein R2 is as defined in any one of claims 1 to 7 or is a hydrogen atom, R 3a R3 as defined in any one of claims 1 to 7 may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and the two G1s independently represent a hydrogen atom or a methoxy group; as well as (x) Deprotect the compound of formula (X) obtained from step (ixAlpha) or (ixBeta) to obtain the compound of formula (I) as defined in any one of claims 1 to 7; and when R2 in the compound of formula (X) prior to deprotection is a hydrogen atom, the hydrogen is converted by chemical modification to R2 as defined in formula (I), and if necessary, it undergoes further chemical reactions. Or (x) deprotects the compound of formula (X) obtained from step (ixAlpha) or (ixBeta) to obtain the compound of formula (XI). Where R 3a R3 as defined in any one of claims 1 to 7, comprising or not comprising a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group; R2 as defined in any one of claims 1 to 7; and R 1b It is R 1a or R with functional groups 1a , where R 1a It is R1 as defined in any one of claims 1 to 7; and then (xi) reduction, reductive amination, nucleophilic substitution and / or oxidation of the compound of formula (XI) obtained from step (x) in order to obtain the compound of formula (I) as defined in any one of claims 1 to 7; Or (Gamma, also known as γ) reduction, reductive amination, nucleophilic substitution and / or oxidation of the compound of formula (X) obtained from step (ixAlpha) or (ixBeta) to obtain the compound of formula (XII). Where R 3a R3 as defined in any one of claims 1 to 7, comprising or excluding a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group; R2 as defined in any one of claims 1 to 7, wherein the two G1s independently represent a hydrogen atom or a methoxy group; and R... 1b R is obtained through reductive amination, reduction, substitution, and / or oxidation. 1a Derivatives of R, in which R 1a It is R1 as defined in any one of claims 1 to 7; and then (x) the compound of formula (XII) obtained from step (Gamma) is deprotected to obtain the compound of formula (I) as defined in any one of claims 1 to 7.

10. A method for preparing a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, said method comprising at least the following steps: (iA) provides compounds of formula (II), (II); (iiA) Cycling the compound of formula (II) provided in step (iA) by reacting it with R2-C(OCH3)3 or R2-COCl to obtain the compound of formula (III), wherein R2 is as defined in any one of claims 1 to 7. (III) Wherein R2 is as defined in any one of claims 1 to 7; (iiiA) Hydrolyze the nitrile group of the compound of formula (III) obtained in step (iiA) to obtain the compound of formula (IV). (IV) Wherein R2 is as defined in any one of claims 1 to 7; (ivA) Esterification of the carboxylic acid functional group of the compound of formula (IV) obtained from step (iiiA) to obtain the compound of formula (V), (V) Wherein R is a (C1-C4)alkyl- group, and R2 is as defined in any one of claims 1 to 7; (vA) Cyclate the compound of formula (V) obtained from step (ivA) to obtain the compound of formula (VI). (WE) Wherein R2 is defined as in any one of claims 1 to 7; (viA) dihalogenating the compound of formula (VI) obtained from step (vA) to obtain the compound of formula (VII); (VII) Wherein R2 is as defined in any one of claims 1 to 7, and HAL is a halogen atom; (viiA) Optionally, the compound of formula (VII) obtained from step (viA) is reacted with R1-X to obtain the compound of formula (VIIa), wherein R1 is defined as in any one of claims 1 to 7, and X represents a halogen atom; (VIIa) Wherein R1 and R2 are as defined in any one of claims 1 to 7, and HAL is a halogen atom; (viiiA) A nucleophilic aromatic substitution is performed on the compound of formula (VIIa) obtained from step (viiA) or the compound of formula (VII) obtained from step (viA) (where R1 is a hydrogen atom) to obtain the compound of formula (VIIIa). (VIIIa) Wherein R1 and R2 are as defined in any one of claims 1 to 7, and HAL is a halogen atom; (ixA) Substitute and / or couple the compound of formula (VIIIa) obtained from step (viiiA) to obtain the compound of formula (Ia). (him) Where R 3a R3 as defined in any one of claims 1 to 7 may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and R1 and R2 are as defined in any one of claims 1 to 7; (xA) When R 3a If R3 is not as defined in any one of claims 1 to 7, then the compound of formula (Ia) obtained from step (ixA) is reacted with any suitable reagent under any suitable conditions to obtain the compound of formula (I) as defined in any one of claims 1 to 7.

11. A method for preparing a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, said method comprising at least the following steps: (i) Provide compounds of formula (II), (II); (ii) Cycling the compound of formula (II) provided in step (i) by reacting it with R2-C(OCH3)3 or R2-COCl to obtain the compound of formula (III), wherein R2 is as defined in any one of claims 1 to 7. (III) Wherein R2 is as defined in any one of claims 1 to 7; (iii) Hydrolyze the nitrile group of the compound of formula (III) obtained in step (ii) to obtain the compound of formula (IV). (IV) Wherein R2 is as defined in any one of claims 1 to 7; (iv) Esterify the carboxylic acid functional group of the compound of formula (IV) obtained in step (iii) to obtain the compound of formula (V). (V) Wherein R is a (C1-C4)alkyl- group, and R2 is as defined in any one of claims 1 to 7; (v) Cyclate the compound of formula (V) obtained from step (iv) to obtain the compound of formula (VI). (WE) Wherein R2 is as defined in any one of claims 1 to 7; (vi) The compound of formula (VI) obtained in step (v) is dihalogenated to obtain the compound of formula (VII). (VII) Wherein R2 is as defined in any one of claims 1 to 7, and HAL is a halogen atom; Then (viialpha, also known as viiα) the compound of formula (VII) obtained from step (vi) is reacted with R. 1a -X reaction to obtain a compound of formula (VIIIaa), where R 1a It is R1 as defined in any one of claims 1 to 7, which may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and X represents a halogen atom, a toluene sulfonate, or a methanesulfonate. (VIIIaa) Wherein R2 is as defined in any one of claims 1 to 7, and HAL is a halogen atom; Or (viiBeta, also known as viiβ) make the compound of formula (VII) obtained from step (vi) with formula The epoxide reaction is carried out to obtain a compound of formula (VIIIaa), wherein R' and R'' are independently hydrogen atoms or (C1-C6) alkyl groups. (VIIIaa) Wherein R2 is as defined in any one of claims 1 to 7, and HAL is a halogen atom; (viiiAA) The compound of formula (VIIIaa) obtained from step (viialpha) or step (viibeta) is subjected to nucleophilic aromatic substitution with the compound of formula (AA). (AA) The two G1s independently represent either a hydrogen atom or a methoxy group. In order to obtain a compound of formula (IXaa), (IXaa) Wherein R2 is as defined in any one of claims 1 to 7, HAL is a halogen atom, and the two G1s independently represent a hydrogen atom or a methoxy group; (ixAA) Substitution and / or coupling reactions are carried out on the compound of formula (IXaa) obtained from step (viiiAA) to obtain the compound of formula (X). (X) Wherein R2 is as defined in any one of claims 1 to 7, R 3a R3 as defined in any one of claims 1 to 7 may or may not contain a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group, and the two G1s independently represent a hydrogen atom or a methoxy group; as well as (x) Deprotect the compound of formula (X) obtained from step (ixAA) to obtain the compound of formula (I) as defined in any one of claims 1 to 7; Or (x) deprotects the compound of formula (X) obtained in step (ixAA) to obtain the compound of formula (XI). Where R 3a R3 as defined in any one of claims 1 to 7, comprising or not comprising a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group; R2 as defined in any one of claims 1 to 7; and R 1b It is R1a or R1a having a functional group; and then (xi) the compound of formula (XI) obtained from this step (x) is reduced, reduced amination, nucleophilic substitution and / or oxidized to obtain a compound of formula (I) as defined in any one of claims 1 to 7; Or (Gamma, also known as γ) reduction, reductive amination, nucleophilic substitution and / or oxidation of the compound of formula (X) obtained from step (ixAA) to obtain the compound of formula (XII). ， Where R 3a R3 as defined in any one of claims 1 to 7, comprising or excluding a hydroxyl protecting group, an amino protecting group, a carboxylic acid protecting group, an aldehyde protecting group, or a ketone protecting group; R2 as defined in any one of claims 1 to 7, wherein the two G1s independently represent a hydrogen atom or a methoxy group; and R... 1b R is obtained through reductive amination, reduction, substitution, and / or oxidation. 1a The derivative; and then (x) deprotecting the compound of formula (XII) obtained from step (Gamma) to obtain the compound of formula (I) as defined in any one of claims 1 to 7.

12. A pharmaceutical preparation comprising a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

14. Use of a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the preparation of TLR7 and / or TLR8 agonists.

15. Use of a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and / or treatment of diseases or disorders associated with TLR7 and / or TLR8 activity.

16. Use of a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the preparation of a vaccine for the prevention of diseases or disorders associated with TLR7 and / or TLR8 activity.

17. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is a cell proliferation disorder.

18. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is cancer.

19. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is chronic myeloid leukemia.

20. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is hairy cell leukemia.

21. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is a skin disease.

22. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is an autoimmune disease.

23. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is an inflammatory disease.

24. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is a respiratory disease.

25. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is sepsis.

26. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is allergy.

27. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is asthma.

28. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is graft rejection.

29. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is graft-versus-host disease.

30. The use according to claim 15 or 16, wherein the disease or disorder associated with TLR7 and / or TLR8 activity is an immunodeficiency.

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