Pyrimidine-pyridazinone compounds as Toll-like receptor agonists

Abstract

This invention provides a class of Toll-like receptor agonists, their preparation, and applications. Specifically, this invention provides a compound of Formula I, its preparation method, and its use as a TLR7 and / or TLR8 agonist. The compound can be used to prepare pharmaceutical compositions for treating or preventing tumors or viral infections.

Description

Technical Field

[0001] This invention belongs to the field of chemical medicine, and in particular relates to pyrimidine pyridazinone compounds as TLR7 / 8 agonists, their preparation methods and applications. Background Technology

[0002] Toll-like receptors (TLRs) are a class of structurally conserved proteins that form the first line of defense in the innate immune response. By recognizing various conserved pathogen-associated molecular patterns (PAMPs), TLRs can identify endogenous molecules released after invasive microorganisms, tissue damage, or non-physiological cell death, and activate signaling cascades, leading to the production of pro-inflammatory cytokines. Inflammation is crucial for the development and progression of many diseases, such as type 1 diabetes, sepsis, cancer, and viral infections. Therefore, strategies to manipulate inflammatory responses and treat related diseases using small-molecule TLR modulators are promising.

[0003] The human TLR family has 10 known members. These are type I transmembrane proteins characterized by a leucine-rich extracellular domain and a cytoplasmic tail containing a conserved Toll / interleukin (IL)-1 receptor (TIR) ​​domain. Within this family, TLR3, TLR7, TLR8, and TLR9 are located in endosome compartments.

[0004] Both TLR7 and TLR8 recognize RNA molecules (ssRNA) from single-stranded RNA viruses. TLR7 is mainly expressed in plasmacytoid dendritic cells and B cells. TLR8 is mainly distributed in mDCs, macrophages, and monocytes, and is also expressed on T cells. TLR7 stimulation mainly induces the production of type I interferons, including interferon-α (IFN-α), and causes transcription of interferon-stimulating genes (ISGs). Interferon-α is one of the main drugs for treating chronic hepatitis B or C. TLR8 is mainly distributed in mDCs, macrophages, and monocytes, and is also expressed on T cells. TLR8 activation mainly produces a pro-inflammatory response, stimulating immune cells to secrete pro-inflammatory cytokines, including tumor necrosis factor- (TNF-α) and IL-6. The distribution and downstream signaling pathways of TLR7 / 8 overlap, thus exhibiting functional similarities. Once activated, TLR7 / 8 cells can exert direct antiviral activity through type I interferon responses. They can also regulate innate immunity by pro-inflammatory responses, promoting the activation of NK and NKT cells, inducing adaptive immunity, improving antigen presentation, and activating dendritic cells, thereby enhancing T cell responses and promoting antibody-producing B cell differentiation. The development of TLR7 / 8 agonists has significant clinical value in antiviral and antitumor therapy and can also be used in antibody-drug conjugates and vaccine adjuvants.

[0005] Several patent applications for related TLR7 / 8 agonists are currently pending, but there is still a need to continue developing highly active, safer, and more therapeutically effective TLR7 / 8 agonists. Summary of the Invention

[0006] The purpose of this invention is to provide a highly active, safer, and therapeutically effective TLR7 / 8 agonist.

[0007] In a first aspect, the present invention provides a compound, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof, as shown in Formula I.

[0008]

[0009] in:

[0010] L1 is selected from the following group: -O-, -NH-, -S-, -S(=O)- or -S(=O)2-;

[0011] R1 is selected from the following groups: H, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl; wherein, the R1 may be further divided by one or more R a The substituent is replaced, and the R is said to be substituent. aSelected from the following groups: hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -NR a1 R a2 -NHC(=O)-R a3 One or more R a4 Substituted 5-6 aryl groups;

[0012] The R a1 R a2 R a3 or R a4 Selected from the following group: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl;

[0013] The R2 is independently selected from the group consisting of: hydrogen, halogen, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl; wherein, the R2 may be further substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, or amino.

[0014] m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0015] B does not exist, or B is selected from the following group: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-12 aryl, 5-12 heteroaryl or Each A atom is independently selected from C, CH, or N, and R6 and R7 together form C with their adjacent carbon atoms. 4-7 Cycloalkyl or C 4-7 Heterocyclic alkyl groups, the C 4-7 One or more methylene groups in the cycloalkyl or 4-7 membered heteroalkyl group may be independently replaced by a carbonyl group or S(=O)2; in the 4-7 membered heteroalkyl group, the heteroatom is selected from N, O, S, and the number of heteroatoms is 1 to 3;

[0016] L2 is selected from the following group: None, -(CR) b R c ) p -(NR d ) q -、-O-、-S-、-(CR b R c ) p -C(=O)-、-(CR b R c ) p-C(=O)NH-、-(CR b R c ) p -NHC(=O)-, -S(=O)-, or -S(=O)2-; where R b R c Selected from the following groups: hydrogen, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl or C 1-6 Haloalkyl, R d Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 1-6 Halogenated alkyl or hydroxy-substituted C 1-6 Alkyl group, p is 0, 1, 2, 3, 4, 5 or 6, q is 0 or 1;

[0017] R4 is selected from the following group: hydrogen, halogen, cyano, amino, hydroxyl, C 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-12 Aryl or 5-12 heteroaryl; and the R4 may optionally be replaced by one or more R e Substituent substitution, where R e Selected from the following groups: hydrogen, halogen, hydroxyl, carboxylic acid, amino, C 1-6 Alkyl, one or more R e1 Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-12 Cycloalkyl, 4-12 heterocycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, -N(R) e2 R e3 -C(=O)OR e2 -C(=O)NH-R e2 -S(=O)2-R e2 ;

[0018] And when L2 is non-existent and R 4 When the answer is H, B is selected from the following group: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-12 aryl, 5-12 heteroaryl or Each A atom is independently selected from C, CH, or N, and R6 and R7 together form C with their adjacent carbon atoms. 4-7 Cycloalkyl or C 4-7Heterocyclic alkyl groups;

[0019] R e1 Selected from the following group: halogens, hydroxyl groups;

[0020] R e2 R e3 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl or hydroxy-substituted C 1-6 alkyl;

[0021] R5 is selected from the following group: halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -C(=O)OR f -C(=O)NH-R f -S(=O)2-R f ;where R f Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Halogenated alkyl groups;

[0022] n is 1, 2, 3, 4, 5 or 6;

[0023] Wherein, each of the heterocyclic groups can be saturated or partially unsaturated (but without an aromatic structure), and in the heterocyclic group, the heteroatom is selected from N, O, S, and the number of heteroatoms is 1, 2, 3 or 4 (preferably 1 or 2); in the heteroaryl group, the heteroatom is selected from N, O, S, and the number of heteroatoms is 1, 2 or 3.

[0024] In another preferred embodiment, L1 is selected from the group consisting of -O-, -NH-, or -S-.

[0025] In another preferred embodiment, L1 is -NH-.

[0026] In another preferred embodiment, m is 1 or 2.

[0027] In another preferred embodiment, R1 is selected from the following group: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl or 4-12 membered heterocyclic alkyl; and said R1 can be further divided by one or more R a The substituent is replaced, and the R is said to be substituent. a Selected from the following groups: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl.

[0028] In another preferred embodiment, R1 is selected from the group C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 Alkyne group; and the R1 can be further divided by one or more R groups. a The substituent is replaced, and the R is said to be substituent. a Selected from the following groups: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl.

[0029] In another preferred embodiment, R1 is selected from the following group: H, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl or 4-8 membered heterocyclic alkyl; wherein, the R1 may be further divided by one or more R a The substituent is replaced, and the R is said to be substituent. a Selected from the following groups: hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkyl group.

[0030] In another preferred embodiment, R1 is selected from the group C. 1-8 Alkyl; and the R1 can be further divided by one or more R a The substituent is replaced, and the R is said to be substituent. a Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0031] In another preferred embodiment, B does not exist, or B is selected from the following group: C 3-8 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl, or

[0032] In another preferred embodiment, B is absent, or B is selected from the group consisting of phenyl and pyridyl.

[0033] In another preferred embodiment, L2 is selected from the following group: -(CR b R c ) p -(NR d ) q -、-O-、-S-、-(CR b R c ) p -C(=O)-、-(CR b Rc ) p -C(=O)NH-、-(CR b R c ) p -NHC(=O)-, -S(=O)-, or -S(=O)2-; where R b R c Selected from the following groups: hydrogen, halogens, C 1-6 Alkyl; R d It is hydrogen or C 1-6 Alkyl; p is 0, 1, 2 or 3, q ​​is 0 or 1.

[0034] In another preferred embodiment, L2 is selected from the group consisting of: -(CH2) p -、-(CH2) p -NR d -、-O-、-S-、-(CH2) p -C(=O)-、-(CH2) p -C(=O)NH-、-(CH2) p -NHC(=O)-; where R d It is hydrogen or C 1-6 Alkyl group; p is 0, 1, 2 or 3.

[0035] In another preferred embodiment, R4 is selected from the group consisting of: hydrogen, halogen, amino, hydroxyl, C. 1-12 Alkyl, C 1-12 Alkoxy, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 Aryl, or 5-12 heteroaryl; and the R4 may optionally be replaced by one or more R e Substituents; where R e Selected from the following groups: hydrogen, halogen, hydroxyl, carboxylic acid, amino, C 1-6 Alkyl, one or more R e1 Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-7 membered heteroaryl, -N(R) e2 R e3 ), where R e1 Selected from the following group: halogens, hydroxyl groups; R e2 R e3 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 C1-6 alkyl groups substituted with haloalkyl or hydroxyl groups.

[0036] In another preferred embodiment, R4 is selected from the group consisting of hydrogen, C 1-12 Alkyl, C 1-12 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a group formed by losing a hydrogen atom from a ring selected from the following groups: Furthermore, R4 can optionally be replaced by one or more R e Substituent substitution.

[0037] In another preferred embodiment, R5 is selected from the group consisting of: halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl.

[0038] In another preferred embodiment, R5 is selected from the group consisting of halogens, C 1-4 Alkyl, C1-4 alkoxy.

[0039] In another preferred embodiment, the compound of formula I is compound I-1 to I-71.

[0040] A second aspect of the present invention provides a pharmaceutical composition comprising: one or more of a compound of formula I as described in the first aspect of the present invention, a pharmaceutically acceptable salt thereof, a racemic mixture thereof, an R-isomer, an S-isomer thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients, and / or diluents.

[0041] A third aspect of the invention provides the use of a compound of formula I as described in the first aspect of the invention, a pharmaceutically usable salt, racemic mixture, R-isomer, S-isomer, or mixture thereof, characterized in that it is used to prepare a pharmaceutical composition for treating or preventing tumors or infections caused by viruses.

[0042] In another aspect, the present invention provides a conjugate obtained by chemically linking a compound as described in the present invention with a small biological molecule or monoclonal antibody.

[0043] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0044] Through long-term and in-depth research, the inventors have discovered a class of small molecule compounds with TLR7 and / or TLR8 agonist activity. These compounds possess novel structures and exhibit agonist activity comparable to or superior to that of similar compounds in the prior art. Based on these findings, the inventors have completed this invention.

[0045] the term

[0046] In this invention, the halogen is F, Cl, Br or I.

[0047] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0048] In this invention, the term "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0049] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0050] In this invention, the term "C3-C7 cycloalkyl" refers to a cyclic alkyl group having 3 to 7 carbon atoms on a ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The terms "C5-C6 cycloalkyl" and "C3-C6 cycloalkyl" have similar meanings.

[0051] In this invention, the terms "aromatic ring" and "aryl" have the same meaning, and preferably "aryl" means "C6-C". 12 "Aromatic" or "C6-C" 10 Aryl group. The term "C6-C" is also mentioned. 12 "Aryl" refers to an aromatic cyclic group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring, such as phenyl and naphthyl. The term "C6-C" is also used. 10 "Aromatic" has a similar meaning.

[0052] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaryl group containing one or more heteroatoms. Heteroatoms referred to herein include oxygen, sulfur, and nitrogen. Examples include furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0053] In this invention, the term "3-9 membered carbon cyclic group" refers to a 3-9 membered cyclic group that is saturated or unsaturated (non-aromatic ring, including monocyclic, fused, spirocyclic, bridged ring, etc.) and whose ring skeleton structure includes only carbon atoms, such as cyclopentyl, cyclohexyl, etc.

[0054] In this invention, the term "3-9 membered heterocyclic group" refers to a 3-9 membered cyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, and is either saturated or unsaturated (non-aromatic ring, including monocyclic, fused, spirocyclic, bridged, etc.) of a ring, such as dioxanepentyl. The term "3-7 membered heterocyclic group" has a similar meaning.

[0055] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic alkyl groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, for example, where the two rings share a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. The substituents include, for example (but are not limited to): C 1-8 Alkyl, C 2-8 alkenyl, C2-8 ynyl, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C 2-10 Acyl group, C 2-10 Ester group, amino group, alkoxy group, C 1-10 Sulfonyl groups, etc.

[0056] Compounds of Formula I with TLR7 and / or TLR8 modulating activity

[0057] This invention provides a compound of Formula I, its solvate, its prodrug, its metabolite, or a pharmaceutically acceptable salt thereof.

[0058]

[0059] The definitions of each group are as described above.

[0060] Preparation method of compound I

[0061] The present invention also provides a method for preparing the compound shown in Formula I above. Specifically, the compound of the present invention is prepared using the following process 1 or 2:

[0062] Process 1

[0063]

[0064] In process 1, starting compound II-1 undergoes a substitution reaction to obtain compound II; compound II undergoes another substitution reaction to obtain compound III; compound III undergoes an oxidation reaction and a ring-closure reaction to obtain compound IV; compound IV undergoes a substitution reaction or a copper-catalyzed reaction to obtain compound V; compound V undergoes a reduction reaction and ring closure to obtain compound VI; compound VI undergoes a substitution reaction to obtain compound VII; compound VII undergoes a substitution reaction with different amines to obtain compound VIII; compound VIII undergoes deprotection to obtain compound I.

[0065]

[0066] In process 2, compound V undergoes hydrolysis to obtain compound VI-a; compound VI-a undergoes condensation to obtain compound VIII-a; and compound VIII-a undergoes deprotection to obtain compound I.

[0067] Pharmaceutical compositions containing active ingredients

[0068] Because the compounds of the present invention possess excellent agonistic activity against Toll-like receptors, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) diseases or conditions related to the abnormal expression or activation of Toll-like receptors (especially TLR7, 8), such as tumors or viral infections; preferably, the virus is one or more of HBV, HCV, HIV and influenza virus, and the tumor is preferably lung cancer, pancreatic cancer, kidney cancer, head and neck cancer, breast cancer, lymphoma, skin cancer, urothelial carcinoma, gastric cancer, hepatocellular carcinoma and colorectal cancer, etc.

[0069] The pharmaceutical compositions of the present invention comprise the compound of the present invention within a safe and effective range and a pharmaceutically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 0.01-99.99% by weight of the compound of the present invention per dose, more preferably, 0.1-99.9% by weight of the compound of the present invention per dose. Preferably, "one dose" is a capsule or tablet.

[0070] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0071] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous, intramuscular, or subcutaneous).

[0072] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0073] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0074] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0075] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0076] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0077] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0078] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).

[0079] When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable compounds. One or more (two, three, four, or more) of these other pharmaceutically acceptable compounds may be used simultaneously, separately, or sequentially with the compounds of the present invention for the prevention and / or treatment of diseases or conditions associated with the aberration or activation of Toll-like receptors (particularly TLR7, 8).

[0080] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is the pharmaceutically considered effective dose. Of course, the specific dose should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0081] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0082] In the following examples, the structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD) as solvents, and tetramethylsilane (TMS) as an internal standard.

[0083] SHIMADZU LC system (column: CSHTM Prep-C18, 19*150mm, Liquid Handling Unit LH-40, Pump LC-20AP, Detector SPD-20A, System Controller CBM-20A, Solvent System: Acetonitrile and 0.05% Trifluoroacetic Acid Aqueous Solution).

[0084] The LC / MS spectra of the compounds were obtained using LC / MS (Agilent Technologies 1200 Series). The LC / MS conditions were as follows (run time: 10 minutes):

[0085] Acidic conditions: A: 0.05% aqueous solution of trifluoroacetic acid; B: 0.05% acetonitrile solution of trifluoroacetic acid;

[0086] Alkaline conditions: A: 0.05% aqueous solution of NH3·H2O; B: acetonitrile

[0087] Neutral conditions: A: 10mM aqueous solution of NH4OAC; B: acetonitrile

[0088] Unless otherwise specified, in the following examples, intermediates and final compounds were purified using silica gel column chromatography or by using... Purification was performed by preparative HPLC on a CSH™ Prep-C18 (5μm, OBD™ 19*150mm) column or on a reversed-phase column using an XBridge™ Prep Phenyl (5μm, OBD™ 30*100mm) column.

[0089] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0090] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0091] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for TLC detection products have a diameter of 0.15mm to 0.2mm, while those used for TLC separation and purification products have a diameter of 0.4mm to 0.5mm.

[0092] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0093] Abbreviations: MeOH: Methanol; DIEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DCM: Dichloromethane; Dioxane: 1,4-dioxane; EA: Ethyl acetate; Conc.HCl: Concentrated hydrochloric acid; DMF: Dimethylformamide; AcOH: Acetic acid; DMA: Dimethylacetamide; Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene; DCE: 1,2-dichloroethane; BH3: Borane; Boc2O: tert-butoxycarbonyl tert-butyl carbonate; t-BuLi: tert-butyllithium; DMF-DMA: 1,1-dimethoxy-N,N-dimethyl-methylamine; PPA: Polyphosphoric acid; NaHMDS: Sodium bis(trimethylsilyl)aminobis(sodium)aminobis(trimethylsilyl)aminobis(sodium)aminobis(trimethyl)aminobis(sodium)chloride; POCl3: Phosphorus oxychloride; Pd / C: Palladium on carbon; ACN: Acetonitrile; EtOH: Ethanol; t-butyl nitrite: tert-butyl nitrite; Pyrrolidine: pyrrolidine; Toluene: toluene; TsOH: p-toluenesulfonic acid; Acrylamide: propylene-2-enamide; THF: tetrahydrofuran; LDA: lithium diisopropylamino; LAH: lithium aluminum hydride; Pd2(dba)3: tris(dibenzylacetone)dipalladium; PMB: p-methoxybenzyl; Xphos: 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl; H2: hydrogen; Pd(dppf)Cl2: [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride; t-B uOK: Potassium tert-butoxide; K2CO3: Potassium carbonate; HCOONH4: Ammonium formate; LiHMDS: Lithium bis(trimethylsilyl)amino; Urea: Urea; n-BuLi: n-Butyllithium; MsCl: Methanesulfonyl chloride; Dppf: Bisdiphenylphosphine ferrocene; Et3N: Triethylamine; AcCl: Acetyl chloride; NaH: Sodium hydride; TFA: Trifluoroacetic acid; SOCl2: Thionyl chloride; NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide; 1,4-Dioxane: 1,4-dioxane; K3PO4: Potassium phosphate; RuPhos Pd G2: Chloro(2-dicyclohexylphosphino-2,6-di-isopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II).

[0094] Intermediate Int.A

[0095] 2-(bis(4-methoxybenzyl)amino)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0096]

[0097] Step 1: Preparation of methyl 2-chloro-4-methyl-6-(pentan-2-ylamino)pyrimidine-5-carboxylic acid (Int. A-1)

[0098] Methyl 2,4-dichloro-6-methylpyrimidin-5-carboxylic acid (500 mg, 2.262 mmol) and pentane-2-amine (237 mg, 2.71 mmol) were dissolved in DCM (10 mL), and DIEA (351 mg, 2.71 mmol) was added with stirring at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into 10% potassium bicarbonate ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid methyl 2-chloro-4-methyl-6-(pentane-2-ylamino)pyrimidin-5-carboxylic acid (560 mg, 91%). MS: 272.1 [M+H] +

[0099] Step 2: Preparation of methyl 2-(bis(4-methoxybenzyl)amino)-4-methyl-6-(pentan-2-ylamino)pyrimidine-5-carboxylic acid (Int. A-2)

[0100] Methyl 2-chloro-4-methyl-6-(pentan-2-ylamino)pyrimidine-5-carboxylic acid (560 mg, 2.061 mmol) and bis(4-methoxybenzyl)amine (636 mg, 2.473 mmol) were dissolved in DMSO (10 mL), and DIEA (400 mg, 3.09 mmol) was added with stirring at 0 °C. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid methyl 2-(bis(4-methoxybenzyl)amino)-4-methyl-6-(pentan-2-ylamino)pyrimidine-5-carboxylic acid (800 mg, 78.8%). MS: 493.3 [M+H] +

[0101] Step 3: Preparation of methyl 2-(bis(4-methoxybenzyl)amino)-4-formyl-6-(pentan-2-ylamino)pyrimidine-5-carboxylic acid (Int. A-3)

[0102] Methyl 2-(bis(4-methoxybenzyl)amino)-4-methyl-6-(pentan-2-ylamino)pyrimidine-5-carboxylic acid (800 mg, 1.624 mmol) was dissolved in 1,4-Dioxane (5 mL), and selenium dioxide (216 mg, 1.949 mmol) was added with stirring. The reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid, methyl 2-(bis(4-methoxybenzyl)amino)-4-formyl-6-(pentan-2-ylamino)pyrimidine-5-carboxylic acid (360 mg, 43.8%). MS: 507.2 [M+H] +

[0103] Step 4: Preparation of 2-(bis(4-methoxybenzyl)amino)-4-(pentan-2-ylamino)pyrimidine[4,5-d]pyridazine-5(6H)-one (Int. A)

[0104] Methyl 2-(bis(4-methoxybenzyl)amino)-4-formyl-6-(pentan-2-ylamino)pyrimidine-5-carboxylic acid (360 mg, 0.711 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (45.5 mg, 1.421 mmol) was added with stirring at 0°C. The reaction mixture was stirred at 85°C for 1 hour. The reaction mixture was concentrated, filtered, and washed with petroleum ether / ethyl acetate to give a white solid 2-(bis(4-methoxybenzyl)amino)-4-(pentan-2-ylamino)pyrimidine[4,5-d]pyridazine-5(6H)-one (230 mg, 66.2%). MS: 489.2 [M+H] +

[0105] intermediate Int.B

[0106] 2-(bis(4-methoxybenzyl)amino)-4-((2-methoxyethyl)amino)pyrimidine[4,5-d]pyridazine-5(6H)-one

[0107]

[0108] The synthesis of intermediate Int.B was based on intermediate Int.A, but was prepared by replacing pentane-2-amine with 2-methoxyethane-1-amine. MS: 477.2 [M+H] +

[0109] Intermediate Int.C

[0110] 2-(bis(4-methoxybenzyl)amino)-4-(butylamino)pyrimidine[4,5-d]pyridazine-5(6H)-one

[0111]

[0112] The synthesis of intermediate Int.C was based on intermediate Int.A, but was prepared by replacing pentane-2-amine with n-butylamine. MS: 475.2 [M+H] +

[0113] Intermediate Int.D

[0114] (R)-2-(bis(4-methoxybenzyl)amino)-4-(pentan-2-ylamino)pyrimidin[4,5.d]pyridazine-5(6H)-one

[0115]

[0116] The synthesis of intermediate Int.D was based on intermediate Int.A, and intermediate Int.D was prepared by replacing pentane-2-amine with intermediate Int.E. MS: 489.2 [M+H] +

[0117] Intermediate Int.E

[0118] (R)-Pentane-2-amine hydrochloride

[0119]

[0120] Step 1: Preparation of (R,E)-2-methyl-N-(2-pentylene)propane-2-sulfonamide (intermediate Int.E-1)

[0121] 10 g (116 mmol) of pentane-2-one was dissolved in 200 mL of EtOAc. (R)-2-methylpropane-2-sulfonamide (14 g, 116 mmol) and tetraisopropyl titanate (66 g, 233 mmol) were added sequentially to the reaction mixture under stirring at 10°C. The reaction mixture was then stirred at 10°C for 15 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to give a colorless oily intermediate, Int.E-1 (7.0 g, 32%). MS: 190.2 [M+H] +

[0122] Step 2: Preparation of (R)-2-methyl-N-((R)-pentan-2-yl)propane-2-sulfonamide (intermediate Int.E-2)

[0123] Intermediate Int.E-1 (7.0 g, 37 mmol) was dissolved in THF (100 mL). Sodium borohydride (2.1 g, 55.6 mmol) was added to the reaction mixture under stirring at -70°C, and the reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a colorless oily intermediate Int.E-2 (3.5 g, 49%). MS: 192.2 [M+H] +

[0124] Step 3: Preparation of (R)-pentane-2-amine hydrochloride (intermediate Int.E)

[0125] The intermediate Int.E-2 (3.5 g, 18.3 mmol) was reacted in a 20 mL solution of 4N 1,4-dioxane hydrochloric acid at 20°C with stirring for 12 hours. The reaction mixture was concentrated and evaporated to dryness to give a crude product, which was washed with diethyl ether to give a white solid intermediate Int.E (2.0 g, 90%).

[0126] intermediate Int.F

[0127] 2-(bis(4-methoxybenzyl)amino)-4-(1-hydroxyhexane-3-yl)amino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0128]

[0129] The synthesis of intermediate Int.F was based on intermediate Int.A, but was prepared by replacing pentane-2-amine with 3-aminohexane-1-ol. MS: 519.2 [M+H] +

[0130] intermediate Int.G

[0131] (S)-Pentane-2-amine hydrochloride

[0132]

[0133] The synthesis of intermediate Int.G is based on intermediate Int.E, which is prepared by replacing (R)-2-methylpropane-2-sulfonamide with (S)-2-methylpropane-2-sulfonamide.

[0134] intermediate Int.H

[0135] (S)-2-(bis(4-methoxybenzyl)amino)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0136]

[0137] The synthesis of intermediate Int.H was based on intermediate Int.A, and was prepared by replacing pentane-2-amine with intermediate Int.G. MS: 489.2 [M+H] +

[0138] Intermediate Int.J

[0139] 2-(bis(4-methoxybenzyl)amino)-4-(butylamino)-8-methylpyrimidin[4,5-d]pyridazine-5(6H)-one

[0140]

[0141] Step 1: Preparation of intermediate Int.J-1

[0142] Intermediate Int.J-001 (10 g, 44 mmol) and n-pentylamine (3.2 g, 44 mmol) were dissolved in DCM (200 mL), and DIEA (4.5 g, 44 mmol) was added with stirring at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into 10% potassium bicarbonate ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid intermediate Int.J-1 (9.5 g, 82%). MS: 264.1 [M+H] +

[0143] Step 2: Preparation of intermediate Int.J-2

[0144] A reaction mixture of intermediate Int.J-1 (9 g, 34.1 mmol), potassium carbonate (7.1 g, 51.1 mmol), and methyl iodide (5.8 g, 40.9 mmol) in DMF (100 mL) was stirred at 20°C for 12 h. The reaction mixture was poured into 10% potassium bicarbonate ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid intermediate Int.J-2 (8 g, 84%). MS: 278.1 [M+H] +

[0145] Step 3: Preparation of intermediate Int.J-3

[0146] A reaction mixture of intermediate Int.J-2 (1.7 g, 6.11 mmol), tributyl(1-ethoxyvinyl)tin (2.65 g, 7.33 mmol), and Pd(PPh3)2Cl2 (0.215 g, 0.306 mmol) in dioxane (20 mL) was stirred at 100 °C for 2 h. The reaction mixture was poured into 10% potassium bicarbonate ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid intermediate Int.J-3 (1.3 g, 67.8%). MS: 314.1 [M+H] +

[0147] Step 4: Preparation of intermediate Int.J-4

[0148] The synthesis of intermediate Int.J-4 referenced intermediate Int.A-2, and intermediate Int.J-4 was prepared by replacing Int.A-1 with intermediate Int.J-3. MS: 535.2 [M+H] +

[0149] Step 5: Preparation of intermediate Int.J-5

[0150] The reaction mixture of intermediate Int.J-4 (1.7 g, 6.11 mmol) and TsOH (0.854 g, 4.49 mmol) in tetrahydrofuran (15 mL) was stirred at 50 °C for 2 h. The reaction mixture was poured into 10% potassium bicarbonate ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid intermediate Int.J-5 (1.3 g, 86%). MS: 507.1 [M+H] +

[0151] Step 6: Preparation of intermediate Int.J

[0152] The synthesis of intermediate Int.J referenced intermediate Int.A, and was prepared by replacing intermediate Int.A-3 with intermediate Int.J-5. MS: 489.2 [M+H] +

[0153] intermediate Int.K

[0154] (S)-2-(bis(4-methoxybenzyl)amino)-4-(1-hydroxypentan-2-yl)amino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0155]

[0156] The synthesis of intermediate Int.K was based on intermediate Int.A, but was prepared by replacing pentane-2-amine with (S)-2-aminopentan-1-ol. MS: 505.2 [M+H] +

[0157] intermediate Int.K1

[0158] (R)-2-(bis(4-methoxybenzyl)amino)-4-(hexane-3-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0159]

[0160] The synthesis of intermediate Int.K1 was based on intermediate Int.A, and was prepared by replacing pentane-2-amine with (R)-n-hexane-3-amine. MS: 50 3.2 [M+H] +

[0161] intermediate Int.K2

[0162] (S)-2-(bis(4-methoxybenzyl)amino)-4-(1-hydroxyhexane-2-yl)amino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0163]

[0164] The synthesis of intermediate Int.K2 was based on intermediate Int.A, but was prepared by replacing pentane-2-amine with (S)-2-aminohexane-1-ol. MS: 519.2 [M+H] +

[0165] intermediate Int.K3

[0166] (R)-2-(bis(4-methoxybenzyl)amino)-4-(1-hydroxypentan-2-yl)amino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0167] The synthesis of intermediate Int.K3 was based on intermediate Int.A, and was prepared by replacing pentane-2-amine with (R)-2-aminopentan-1-ol. MS: 50 5.2 [M+H] +

[0168] Compound I-1

[0169] 2-Amino-4-(pentan-2-ylamino)-6-(4-(pyrrolidone-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0170]

[0171] Step 1: Preparation of methyl 4-(2-(bis(4-methoxybenzyl)amino)-5-oxy-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-6(5H)-yl)methyl)benzoate (Intermediate I-1-1)

[0172] Intermediate Int.A (230 mg, 0.471 mmol), methyl 4-(bromomethyl)benzoate (162 mg, 0.706 mmol), and Cs₂CO₃ (306 mg, 0.941 mmol) were dissolved in DMF (4 mL). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid intermediate I-1-1 (270 mg, 90%). MS: 637.2 [M+H] +

[0173] Step 2: Preparation of 2-(bis(4-methoxybenzyl)amino)-6-(4-(hydroxymethyl)benzyl)-4-(pentan-2-ylamino)pyrimidine[4,5-d]pyridazine-5(6H)-one (Intermediate I-1-2)

[0174] Intermediate I-1-1 (270 mg, 0.424 mmol) was dissolved in THF (5 mL), and a 1.0 M LAH (0.5 mL, 0.5 mmol) tetrahydrofuran solution was added with stirring at 0 °C. The reaction mixture was heated to 20 °C and stirred for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a white solid intermediate I-1-2 (198 mg, 77%). MS: 609.2 [M+H] +

[0175] Step 3: Preparation of 2-(bis(4-methoxybenzyl)amino)-6-(4-(chloromethyl)benzyl)-4-(pentan-2-ylamino)pyrimidine[4,5-d]pyridazine-5(6H)-one (Intermediate I-1-3)

[0176] Intermediate I-1-2 (198 mg, 0.326 mmol) was dissolved in DCM (1 mL), and thionyl chloride (48.6 mg, 0.408 mmol) was added with stirring at 0 °C. The reaction mixture was then stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give intermediate I-1-3 (245 mg, 95%) as a yellow solid. MS: 628.2 [M+H]+

[0177] Step 4: Preparation of 2-(bis(4-methoxybenzyl)amino)-4-(pentan-2-ylamino)-6-(4-(pyrrolidone-1-ylmethyl)benzyl)pyrimidine[4,5-d]pyridazine-5(6H)-one (Intermediate I-1-4)

[0178] Intermediate I-1-3 (163 mg, 0.259 mmol) and pyrrolidine (36.9 mg, 0.518 mmol) were dissolved in EtOH (1 mL), and K₂CO₃ (71.6 mg, 0.518 mmol) was added with stirring at 20 °C. The reaction mixture was stirred at 85 °C for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a white solid intermediate I-1-4 (140 mg, 80.2%). MS: 662.2 [M+H] + .

[0179] Step 5: Preparation of 2-amino-4-(pentan-2-ylamino)-6-(4-(pyrrolidone-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one (Compound I-1)

[0180] Intermediate I-1-4 (140 mg, 0.212 mmol) was dissolved in trifluoroacetic acid (20 mL), and the reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was concentrated to dryness and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC to give compound I-1 (78 mg, 87%) as a white solid. MS: 422.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.90 (d, J=8.3Hz, 1H), 7.83 (s, 1H), 7.28-7.19 (m, 4H), 7.02 (br, 2H), 5.24-5.07 (m, 2H), 4.25-4.16 (m, 1H), 3 .54 (s, 2H), 2.43-2.38 (m, 4H), 1.68-1.64 (m, 4H), 1.54-1.46 (m, 2H), 1.37-1.27 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0181] Compound I-1a and Compound I-1b

[0182] (R)-2-amino-4-(pentan-2-ylamino)-6-(4-(pyrrolidin-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one and (S)-2-amino-4-(pentan-2-ylamino)-6-(4-(pyrrolidin-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0183]

[0184] Compound I-1 was chirally separated by SFC (column type: CHIRALPAKIG, 2cm×25cm, 5μm column, mobile phase: 20% ethanol in carbon dioxide) to obtain the first component peak, compound I-1a (retention time 4.65 min), and the second component peak, compound I-1b (retention time 5.39 min), both of which are white solids.

[0185] Compound I-1a: MS: 422.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=8.3Hz, 1H), 7.82 (s, 1H), 7.28-7.16 (m, 4H), 7.02 (br, 2H), 5.24-5.04 (m, 2H), 4.19 (q, J=7.0Hz, 1H) , 3.50 (s, 2H), 2.42-2.31 (m, 4H), 1.70-1.60 (m, 4H), 1.55-1.44 (m, 2H), 1.37-1.26 (m, 2H), 1.15 (d, J=6.5Hz, 3H), 0.87 (t, J=7.3Hz, 3H)

[0186] Compound I-1b: MS: 422.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=8.3Hz, 1H), 7.82 (s, 1H), 7.28-7.16 (m, 4H), 7.02 (br, 2H), 5.24-5.04 (m, 2H), 4.19 (q, J=7.0Hz, 1H) , 3.50 (s, 2H), 2.42-2.31 (m, 4H), 1.70-1.60 (m, 4H), 1.55-1.44 (m, 2H), 1.37-1.26 (m, 2H), 1.15 (d, J=6.5Hz, 3H), 0.87 (t, J=7.3Hz, 3H)

[0187] Compound I-2

[0188] 2-Amino-4-(Butamino)-6-(4-(piperazin-1-carbonyl)benzyl)pyrimidine[4,5-d]pyridazin-5(6H)-one

[0189]

[0190] Step 1: Preparation of methyl 4-((2-(bis(4-methoxybenzyl)amino)-4-(butylamino)-5-oxopyridyl[4,5-d]pyridazine-6(5H)-yl)methyl)benzoate (Intermediate I-2-1)

[0191] The synthesis of intermediate I-2-1 referenced intermediate I-1-1, and intermediate I-2-1 was prepared by replacing intermediate Int.A with intermediate Int.C. MS: 623.3 [M+H] + .

[0192] Step 2: Preparation of 4-((2-(bis(4-methoxybenzyl)amino)-4-(butylamino)-5-oxopyridyl[4,5-d]pyridazine-6(5H)-yl)methyl)benzoic acid (intermediate I-2-2)

[0193] Intermediate I-2-1 (500 mg, 0.803 mmol) was dissolved in THF (5 mL) and H₂O (5 mL), and lithium hydroxide (160 mg, 4.01 mmol) was added with stirring at 0 °C. The reaction mixture was stirred at 20 °C for 1 hour. The pH of the reaction mixture was adjusted to 5 with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid intermediate I-2-2 (400 mg, 82%). MS: 609.3 [M+H] +

[0194] Step 3: Preparation of tert-butyl 4-(4-((2-(bis(4-methoxybenzyl)amino)-4-(butylamino)-5-oxopyridyl[4,5-d]pyridazine-6(5H)-yl)methyl)benzoyl)piperazine-1-carboxylic acid (intermediate I-2-3)

[0195] A mixture of intermediate I-2-2 (80 mg, 0.131 mmol), HATU (75.0 mg, 0.197 mmol), DIEA (34.0 mg, 0.263 mmol), and piperazine-1-carboxylic acid tert-butyl ester (49.0 mg, 0.263 mmol) in DMF (2 mL) was stirred at 20°C for 2 hours. The reaction mixture was then poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid intermediate I-2-3 (80 mg, 78%). MS: 777.4 [M+H] +

[0196] Step 4: Preparation of 2-amino-4-(butylamino)-6-(4-(piperazin-1-carbonyl)benzyl)pyrimidine[4,5-d]pyridazin-5(6H)-one (Compound I-2)

[0197] The synthesis of compound I-2 was based on compound I-1, but was prepared as a white solid by using intermediate I-2-3 instead of intermediate I-1-4. MS: 437.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.97 (t, J=5.7Hz, 1H), 7.85 (s, 1H), 7.37-7.31 (m, 4H), 7.05 (s, 2H), 5.22 (s, 2H), 3.62-3.52 (m, 2H), 3.45-3.40 (m, 2H), 3.30-3.20 (m, 2H), 2.82-2.67 (m, 4H), 1.54 (q, J=7.2Hz, 2H), 1.34 (q, J=7.4Hz, 2H), 0.90 (t, J=7.3Hz, 3H).

[0198] Compound I-3

[0199] 2-Amino-4-(Butamino)-6-(4-(4-methylpiperazine-1-carbonyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0200]

[0201] The synthesis of compound I-3 was based on compound I-2, but was prepared as a white solid by replacing piperazine-1-carboxylic acid tert-butyl ester with 1-methylpiperazine. MS: 451.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.97 (t, J=5.7Hz, 1H), 7.85 (s, 1H), 7.36-7.30 (m, 4H), 7.05 (s, 2H), 5.22 (s, 2H), 3.45-3.40 (m , 2H), 3.35-3.25(m, 4H), 2.40-2.20(m, 4H), 2.18(s, 3H), 1.57-1.51(m, 2H), 1.39-1.29(m, 2H), 0.90(t, J=7.3Hz, 3H).

[0202] Compound I-4

[0203] 2-Amino-4-((2-methoxyethyl)amino)-6-(4-(pyrrolidone-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0204]

[0205] The synthesis of compound I-4 was based on compound I-1, but was prepared as a white solid by substituting intermediate Int.B for intermediate Int.A. MS: 410.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.07 (t, J=5.5Hz, 1H), 7.84 (s, 1H), 7.24 (q, J=8.3Hz, 4H), 7.06 (br, 2H), 5.17 (s, 2 H), 3.62-3.58(m, 2H), 3.55(s, 2H), 3.52-3.48(m, 2H), 3.28(s, 3H), 2.44-2.39(m, 4H), 1.69-1.65(m, 4H).

[0206] Compound I-5

[0207] 2-Amino-4-(Butamino)-6-(4-(pyrrolidone-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0208]

[0209] The synthesis of compound I-5 was based on compound I-1, but was prepared as a white solid by using intermediate I-2-1 instead of intermediate I-1-1. MS: 408.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.84 (s, 1H), 7.24 (q, J=8.0Hz, 4H), 7.03 (s, 2H), 5.17 (s, 2H), 3.56 (s, 3H), 3.43 (q, J= 6.6Hz, 2H), 2.46-2.39(m, 4H), 1.71-1.66(m, 4H), 1.58-1.51(m, 2H), 1.37-1.32(m, 2H), 0.91(t, J=7.4Hz, 3H).

[0210] Compound I-6

[0211] 2-Amino-4-(Butamino)-6-(4-(morpholinomethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0212]

[0213] The synthesis of compound I-6 was based on compound I-5, but was prepared as a white solid by using morpholine instead of pyrrolidine. MS: 424.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.99 (t, J=5.7Hz, 1H), 7.83 (s, 1H), 7.28-7.20 (m, 4H), 7.00 (br, 2H), 5.16 (s, 2H), 3.56- 3.51 (m, 4H), 3.45-3.39 (m, 4H), 2.32-2.27 (m, 4H), 1.56-1.49 (m, 2H), 1.38-1.28 (m, 2H), 0.90 (t, J=7.4Hz, 3H).

[0214] Compound I-7

[0215] 2-Amino-4-(Butamino)-6-(4-((dimethylamino)methyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0216]

[0217] The synthesis of compound I-7 was based on compound I-5, but was prepared as a white solid by using dimethylamine hydrochloride instead of pyrrolidine. MS: 382.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.99 (t, J=5.7Hz, 1H), 7.83 (s, 1H), 7.24-7.20 (m, 4H), 7.04 (br, 2H), 5.16 (s, 2H), 3.45-3.38 (m, 2H), 2.32 (s, 2H), 2.09 (s, 6H), 1.58-1.49 (m, 2H), 1.38-1.28 (m, 2H), 0.90 (t, J=7.3Hz, 3H).

[0218] Compound I-8

[0219] 2-Amino-4-(butylamino)-6-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0220]

[0221] The synthesis of compound I-8 was based on compound I-2, and was prepared as a white solid by using tert-butyl 6-(bromomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid instead of methyl 4-(bromomethyl)benzoate. MS: 380.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.98 (t, J=5.6Hz, 1H), 8.25 (s, 1H), 7.82 (s, 1H), 7.09-7.02 (m, 5H), 5.12 (s, 2H), 4.00 (s, 2H), 3.42 (q, J=6.8Hz, 2H), 3.10 (t, J=6.1Hz, 2H), 2.77 (t, J=6.1Hz, 2H), 1.58-1.50 (m, 2H), 1.39-1.28 (m, 2H), 0.90 (t, J=7.3Hz, 3H).

[0222] Compound I-9

[0223] 2-Amino-4-(Butamino)-6-(4-(piperazin-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazin-5(6H)-one

[0224]

[0225] The synthesis of compound I-9 was based on compound I-5, but was prepared as a white solid by using piperazine-1-carboxylic acid tert-butyl ester instead of pyrrolidine. MS: 423.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.98 (t, J=5.6Hz, 1H), 8.32 (s, 1H), 7.83 (s, 1H), 7.26-7.20 (m, 4H), 7.04 (br, 2H), 5.16 (s, 2H) , 3.45-3.39(m, 4H), 2.84-2.79(m, 4H), 2.40-2.35(m, 4H), 1.58-1.49(m, 2H), 1.39-1.28(m, 2H), 0.90(t, J=7.4Hz, 3H).

[0226] Compound I-10

[0227] 2-Amino-4-(butylamino)-6-(4-((cyclopropylamino)methyl)benzyl)pyrimidine[4,5-d]pyridazine-5(6H)-one

[0228]

[0229] The synthesis of compound I-10 referenced compound I-5, and was prepared as a white solid by using cyclopropylamine instead of pyrrolidine. MS: 394.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.99 (t, J=5.6Hz, 1H), 7.82 (s, 1H), 7.28-7.16 (m, 4H), 7.00 (br, 2H), 5.15 (s, 2H), 3.66 (s, 2H), 3.45-3. 40 (m, 2H), 2.02-1.98 (m, 1H), 1.58-1.50 (m, 2H), 1.38-1.28 (m, 2H), 0.90 (t, J=7.3Hz, 3H), 0.34-0.28 (m, 2H), 0.24-0.19 (m, 2H).

[0230] Compound I-11

[0231] 6-(4-((3,6-diazacyclic[3.1.1]heptane-3-yl)methyl)benzyl)-2-amino-4-(butylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0232]

[0233] The synthesis of compound I-11 was based on compound I-5, and was prepared as a white solid by using tert-butyl 3,6-diazacyclic [3.1.1]heptane-6-carboxylic acid instead of pyrrolidine. MS: 435.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.99 (t, J=5.6Hz, 1H), 8.37 (s, 1H), 7.83 (s, 1H), 7.31- 7.21 (m, 4H), 7.03 (br, 2H), 5.17 (s, 2H), 3.81 (d, J=5.7Hz, 2H), 3.68 (s, 2H), 3. 45-3.40 (m, 2H), 3.04-2.98 (m, 2H), 2.78-2.74 (m, 2H), 2.44-2.39 (m, 1H), 1.97 (d, J=8.4Hz, 1H), 1.58-1.50 (m, 2H), 1.39-1.28 (m, 2H), 0.90 (t, J=7.3Hz, 3H).

[0234] Compound I-12

[0235] 6-(4-((2,6-diazaspirocyclic[3,4]octane-6-yl)methyl)benzyl)-2-amino-4-(butylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0236]

[0237] The synthesis of compound I-12 was based on compound I-5, and was prepared as a white solid by using tert-butyl 2,6-diazaspirocyclic [3,4]octane-2-carboxylate instead of pyrrolidine. MS: 449.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.98 (t, J=5.6Hz, 1H) 8.60 (br, 1H), 7.85 (s, 1H), 7 .30-7.22(m, 4H), 7.05(br, 2H), 5.18(s, 2H), 3.92-3.87(m, 2H), 3.85-3.79 (m, 2H), 3.70-3.58 (m, 2H), 3.43 (q, J=6.6Hz, 2H), 2.80-2.55 (m, 4H), 2.08 -2.02(m, 2H), 1.59-1.50(m, 2H), 1.39-1.29(m, 2H), 0.90(t, J=7.3Hz, 3H).

[0238] Compound I-13

[0239] 2-Amino-4-(Butamino)-6-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0240] The synthesis of compound I-13 was based on compound I-2, and was prepared as a white solid by replacing methyl 4-(bromomethyl)benzoate with 6-(bromomethyl)-2-isopropyl-1,2,3,4-tetrahydroisoquinoline. MS: 422.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.99 (t, J=5.7Hz, 1H), 7.80 (s, 1H), 7.05-6.95 (m, 5H), 5.10 (s, 2H), 3.61 (s, 2H), 3.45-3.39 (m, 2H), 2.90-2 .81 (m, 1H), 2.76-1.71 (m, 2H), 2.70-2.65 (m, 2H), 1.58-1.50 (m, 2H), 1.39-1.29 (m, 2H), 1.03 (d, J=6.5Hz, 6H), 0.90 (t, J=7.3Hz, 3H).

[0241] Compound I-14

[0242] 2-Amino-4-(Butamino)-6-(2-Methoxy-4-(pyrrolidine-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0243] The synthesis of compound I-14 was based on compound I-1, prepared by substituting intermediate Int.C for intermediate Int.A and methyl 4-(bromomethyl)-3-methoxybenzoate for methyl 4-(bromomethyl)benzoate, yielding a white solid compound I-14. MS: 438.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.00 (t, J=5.7Hz, 1H), 7.83 (s, 1H), 7.04 (br, 2H), 6.94 (s, 1H), 6.82-6.73 (m, 2H), 5.13 (s, 2H), 3.79 (s, 3H), 3.54 (s, 2H), 3.43 (t, J=7.1Hz, 2H), 2.46-2.38 (m, 4H), 1.71-1.65 (m, 4H), 1.58-1.50 (m, 2H), 1.39-1.28 (m, 2H), 0.90 (t, J=7.3Hz, 3H)

[0244] Compound I-15

[0245] 2-Amino-4-(Butamino)-6-(2-fluoro-4-(pyrrolidone-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0246]

[0247] The synthesis of compound I-15 was based on compound I-14, but was prepared as a white solid by substituting methyl 4-(bromomethyl)-3-fluorobenzoate for methyl 4-(bromomethyl)-3-methoxybenzoate. MS: 426.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.95 (t, J=5.6Hz, 1H), 7.83 (s, lH), 7.20-6.98 (m, 5H), 5.21 (s, 2H), 3.54 (s, 2H), 3.45- 3.39 (m, 2H), 2.43-2.36 (m, 4H), 1.72-1.62 (m, 4H), 1.58-1.49 (m, 2H), 1.39-1.28 (m, 2H), 0.90 (t, J=7.3Hz, 3H).

[0248] Compound I-16

[0249] 2-Amino-4-(Butamino)-6-((2-methoxy-6-(pyrrolidone-1-ylmethyl)pyridin-3-yl)methyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0250]

[0251] The synthesis of compound I-16 referenced compound I-14, and was prepared as a white solid by substituting methyl 5-(bromomethyl)-6-methoxypyridinecarboxylate for methyl 4-(bromomethyl)-3-methoxybenzoate. MS: 439.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.96 (t, J=5.7Hz, 1H), 7.84 (s, 1H), 7.26 (d, J=7.5Hz, 1H), 7.06 (br, 2H), 6.93 (d, J=7.5Hz, 1H), 5.10 (s, 2H), 3.87 (s, 3H), 3.62 (s, 2H), 3.46-3.37 (m, 1H), 2.54-2.50 (m, 4H), 1.72-1.66 (m, 4H), 1.57-1.49 (m, 2H), 1.39-1.27 (m, 2H), 0.89 (t, J=7.3Hz, 3H)

[0252] Compound I-17

[0253] 2-Amino-4-(Butamino)-6-(3-methoxy-4-(pyrrolidine-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0254]

[0255] The synthesis of compound I-17 was based on compound I-14, and was prepared as a white solid by using methyl 4-(bromomethyl)-2-methoxybenzoate instead of methyl 4-(bromomethyl)-3-methoxybenzoate. MS: 438.2 [M+H]+. 1HNMR (400MHz, DMSO-d6) δ9.00 (t, J=5.7Hz, 1H), 7.84 (s, 1H), 7.23 (d, J=7.7 Hz, 1H), 7.05 (br, 1H), 6.92 (d, J=1.6Hz, 1H), 6.77 (dd, J=7.6, 1.5Hz, 1H), 5. 16(s, 2H), 3.74(s, 3H), 3.56(s, 2H), 3.46-3.39(m, 2H), 2.48-2.43(m, 4H), 1 .71-1.63(m, 4H), 1.58-1.50(m, 2H), 1.39-1.28(m, 2H), 0.90(t, J=7.3Hz, 3H)

[0256] Compound I-18

[0257] 2-Amino-4-(Butamino)-6-(3-fluoro-4-(pyrrolidone-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0258]

[0259] The synthesis of compound I-18 was based on compound I-14, and was prepared as a white solid by substituting methyl 4-(bromomethyl)-2-fluorobenzoate for methyl 4-(bromomethyl)-3-methoxybenzoate. MS: 426.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.96 (t, J=5.7Hz, 1H), 7.84 (s, 1H), 7.35 (t, J=7.9Hz, 1H), 7.14-6.96 (m, 4H), 5.17 (s, 2H), 3.55 (s, 2 H), 3.42 (q, J=6.6Hz, 2H), 2.43-2.37 (m, 4H), 1.67-1.63 (m, 4H), 1.57-1.50 (m, 2H), 1.39-1.28 (m, 2H), 0.90 (t, J=7.3Hz, 3H).

[0260] Compound I-19

[0261] 2-Amino-4-(Butamino)-6-(4-(2-(methylamino)ethoxy)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0262]

[0263] The synthesis of compound I-19 referenced compound I-14, and was prepared as a white solid by replacing methyl 4-(bromomethyl)-3-methoxybenzoate with 2-(4-(bromomethyl)phenoxy)-N-methylethane-1-amine. MS: 398.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.00 (t, J=5.7Hz, 1H), 8.27 (d, J=1.1Hz, 1H), 7.81 (s, 1H), 7.28-7.18 (m, 2H), 7.03 (br, 2H), 6.94-6.86 (m, 2H), 5.11 (s, 2H), 4.06 (t, J=5.4Hz, 2H), 3.45-3.39 (m, 2H), 3.01 (t, J=5.4Hz, 2H), 2. 43(s, 3H), 1.58-1.50(m, 2H), 1.39-1.29(m, 2H), 0.90(t, J=7.4Hz, 3H).

[0264] Compound I-20

[0265] 2-Amino-4-(Butamino)-6-(5-(pyrrolidone-1-yl)pentyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0266]

[0267] The synthesis of compound I-20 was based on compound I-14, and was prepared as a white solid by substituting methyl 5-bromopentanoate for methyl 4-(bromomethyl)-3-methoxybenzoate. MS: 374.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.48 (s, 1H), 9.28 (s, 1H), 7.90 (s, 1H), 7.41 (br, 2H), 4.04 (t, J = 7.0Hz, 2H), 3.53-3.42 (m, 4H), 3.11-3.05 (m, 2H) , 2.99-2.90 (m, 2H), 2.01-1.94 (m, 2H), 1.87-1.80 (m, 2H), 1.75-1.68 (m, 2H), 1.65-1.52 (m, 4H), 1.39-1.26 (m, 4H), 0.91 (t, J=7.3Hz, 3H)

[0268] Compound I-21

[0269] 2-Amino-4-(Butamino)-6-(4-((2-hydroxyethyl)(propyl)amino)methyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0270]

[0271] The synthesis of compound I-21 was based on compound I-5, but was prepared as a white solid by using 2-(propylamino)ethane-1-ol instead of pyrrolidine. MS: 440.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.99 (t, J=5.6Hz, 1H), 7.83 (s, 1H), 7.29-7.17 (m, 4H), 7.03 (br, 2H), 5.16 (s, 2H), 3.52 (s, 2H), 3.45-3.39 ( m, 4H), 2.44 (t, J=6.7Hz, 2H), 2.37-2.32 (m, 2H), 1.57-1.50 (m, 2H), 1.44-1.27 (m, 4H), 0.90 (t, J=7.3Hz, 3H), 0.79 (t, J=7.3Hz, 3H)

[0272] Compound I-22

[0273] 2-Amino-4-(Butamino)-6-(5-oxo-5-(piperazin-1-yl)pentyl)pyrimidin[4,5-d]pyridazin-5(6H)-one

[0274]

[0275] The synthesis of compound I-22 referenced compound I-2, and was prepared as a white solid by using intermediate I-20-1 instead of intermediate I-2-1. MS: 403.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.06 (t, J=5.6Hz, 1H), 8.21 (d, J=1.3Hz, 1H), 7.80 (s, 1H), 7.00 (br, 2H), 4.00 (t, J=7.0Hz, 2H), 3.46-3.37 (m, 6H), 2.79-2.68 (m, 4H), 2.32 (t, J=7.4Hz, 2H), 1.73-1.65 (m, 2H), 1.59-1.43 (m, 4H), 1.40-1.30 (m, 2H), 0.91 (t, J=7.3Hz, 3H).

[0276] Compound I-23

[0277] 2-Amino-6-(4-((bis(2-hydroxyethyl)amino)methyl)benzyl)-4-(butylamino)pyrimidine[4,5-d]pyridazine-5(6H)-one

[0278]

[0279] The synthesis of compound I-23 referenced compound I-5, and was prepared as a white solid by using dihydroxyethylamine instead of pyrrolidine. MS: 442.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.99 (t, J=5.7Hz, 1H), 7.83 (s, 1H), 7.31-7.18 (m, 4H), 7.03 (br, 2H), 5.16 (s, 2H), 4.33 (br, 2H), 3.58 (s, 2H), 3.45-3.38 (m, 6H), 2.52-2.46 (m, 4H), 1.57-1.50 (m, 2H), 1.40-1.27 (m, 2H), 0.90 (t, J=7.3Hz, 3H).

[0280] Compound I-24

[0281] (R)-2-amino-6-(2-methoxy-4-(piperazin-1-carbonyl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazin-5(6H)-one

[0282]

[0283] The synthesis of compound I-24 referenced compound I-2, and was prepared as a white solid by using intermediate Int.D instead of intermediate Int.C. MS: 481.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.88 (d, J=8.3Hz, 1H), 7.85 (s, 1H), 7.12-7.98 (m, 3H), 6.89-6.84 (m, 2H), 5.22-5.09 (m, 2H), 4.20 (p, J=6.7Hz, 1H), 3.60-3.48(m, 2H), 3.90-3.20(m, 2H), 2.80-2.64(m, 4H), 1.53-1.43(m , 2H), 1.37-1.25 (m, 2H), 1.15 (d, J=6.5Hz, 3H), 0.87 (t, J=7.3Hz, 3H).

[0284] Compound I-25

[0285] (R)-2-amino-6-(2-methoxy-4-(pyrrolidone-1-ylmethyl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0286]

[0287] The synthesis of compound I-25 referenced compound I-1, and was prepared as a white solid by using intermediate I-24-1 instead of intermediate I-1-1. MS: 452.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.91 (d, J=8.3Hz, 1H), 7.83 (s, 1H), 7.05 (br, 2H), 6.94 (s, 1H), 6.82-6.74 (m, 2H), 5.20-5.06 (m, 2H), 4.20 (p, J=6.7Hz, 1H), 3.79(s, 3H), 3.55(s, 2H), 2.46-2.40(m, 4H), 1.71-1.64(m, 4H), 1.54-1.4 4 (m, 2H), 1.36-1.26 (m, 2H), 1.15 (d, J = 6.4Hz, 3H), 0.87 (t, J = 7.3Hz, 3H).

[0288] Compound I-26

[0289] (R)-2-amino-6-(4-((2-hydroxyethyl)(propyl)amino)methyl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0290]

[0291] The synthesis of compound I-26 was based on compound I-1, prepared by replacing intermediate Int.A with intermediate Int.D and pyrrolidine with 2-(propylamino)ethane-1-ol to obtain a white solid, I-26. MS: 454.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.91 (d, J=8.3Hz, 1H), 7.83 (s, 1H), 7.10-6.95 (m, 3H), 6.81-6.7 3(m, 2H), 5.20-5.05(m, 2H), 4.33(br, 1H), 4.20(p, J=6.9Hz, 1H), 3.79(s, 3H), 3.53(s, 2 H), 3.44 (t, J=6.7Hz, 2H), 2.46 (t, J=6.6Hz, 2H), 2.37 (t, J=7.3Hz, 2H), 1.53-1.36 (m, 4H ), 1.35-1.27 (m, 2H), 1.15 (d, J = 6.6Hz, 3H), 0.87 (t, J = 7.3Hz, 3H), 0.81 (t, J = 7.3Hz, 3H)

[0292] Compound I-27

[0293] (R)-2-amino-6-(4-((bis(2-hydroxyethyl)amino)methyl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0294]

[0295] The synthesis of compound I-27 was based on compound I-26, but was prepared as a white solid by using diethanolamine instead of 2-(propylamino)ethane-1-ol. MS: 456.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.91 (d, J=8.3Hz, 1H), 7.11-6.95 (m, 3H), 7.01 (s, 3H), 6.83-6.72 (m, 2H), 5.19-5.06 (m, 2H), 4.20 (p, J=6.9Hz, 1H), 3.79 ( s, 3H), 3.59 (s, 2H), 3.43 (t, J=6.3Hz, 4H), 2.54-2.50 (m, 4H), 1.53-1.42 (m, 2H), 1.37-1.25 (m, 2H), 1.15 (d, J=6.5Hz, 3H), 0.87 (t, J=7.2Hz, 3H).

[0296] Compound I-28

[0297] 2-Amino-4-(Butamino)-8-methyl-6-(4-(piperazin-1-carbonyl)benzyl)pyrimidin[4,5-d]pyridazin-5(6H)-one

[0298]

[0299] The synthesis of compound I-28 referenced compound I-2, and was prepared as a white solid by using intermediate Int.J instead of intermediate Int.C. MS: 451.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=8.3Hz, 1H), 7.36-7.28 (m, 4H), 7.04 (br, 2H), 5.19 (s, 2H), 3.63-3.48 (m, 2H), 3.43 (q, J= 6.6Hz, 2H), 3.33-3.20 (m, 2H), 2.86-2.64 (m, 4H), 2.28 (s, 3H), 1.58-1.49 (m, 2H), 1.38-1.28 (m, 2H), 0.89 (t, J=7.3Hz, 3H).

[0300] Compound I-29

[0301] 2-Amino-4-(Butamino)-8-methyl-6-(4-(pyrrolidone-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0302]

[0303] The synthesis of compound I-29 referenced compound I-1, and was prepared as a white solid by using intermediate I-28-1 instead of intermediate I-1-1. MS: 422.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.16 (t, J=5.6Hz, 1H), 7.29-7.16 (m, 4H), 7.04 (br, 2H), 5.13 (s, 2H), 3.57 (s, 2H), 3.42 (q, J=6.6 Hz, 2H), 2.47-2.41 (m, 4H), 2.27 (s, 3H), 1.70-1.63 (m, 4H), 1.57-1.49 (m, 2H), 1.38-1.28 (m, 2H), 0.89 (t, J=7.3Hz, 3H).

[0304] Compound I-30

[0305] 2-Amino-4-((1-hydroxyhexane-3-yl)amino)-6-(4-(piperazine-1-carbonyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0306]

[0307] The synthesis of compound I-30 referenced compound I-2, and was prepared as a white solid by using intermediate Int.F instead of intermediate Int.C. MS: 481.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.90 (d, J=8.8Hz, 1H), 8.22 (s, 1H), 7.84 (s, 1H), 7.39-7.26 (m, 4H), 7.05 (br, 2H), 5.26-5.15 (m, 2H), 4.35-4.25 (m, 1 H), 3.60-3.49(m, 2H), 3.45-3.40(m, 2H), 3.31-3.19(m, 2H), 2.85-2.6 0 (m, 4H), 1.77-1.42 (m, 4H), 1.35-1.21 (m, 2H), 0.86 (t, J=7.3Hz, 3H).

[0308] Compound I-31

[0309] 2-Amino-4-((1-hydroxyhexane-3-yl)amino)-6-(4-(pyrrolidine-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0310]

[0311] The synthesis of compound I-31 referenced compound I-1, and was prepared as a white solid by using intermediate I-30-1 instead of intermediate I-1-1. MS: 452.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.92 (d, J=8.8Hz, 1H), 7.83 (s, 1H), 7.28-7.20 (m, 4H), 7.02 (br, 2H), 5.19-5.11 (m, 2H), 4.35-4.2 5 (m, 1H), 3.57 (s, 2H), 3.45-3.39 (m, 2H), 2.46-2.40 (M, 4H), 1.76-1.45 (m, 8H), 1.35-2.23 (m, 2H), 0.86 (t, J=7.3Hz, 3H).

[0312] Compound I-32

[0313] 2-Amino-4-((1-hydroxyhexane-3-yl)amino)-6-(4-(4-methylpiperazine-1-carbonyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0314]

[0315] The synthesis of compound I-32 was based on compound I-30, and was prepared as a white solid by replacing piperazine-1-carboxylic acid tert-butyl ester with 1-methylpiperazine. MS: 495.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.90 (d, J=8.8Hz, 1H), 7.84 (s, 1H), 7.36-7.30 (m, 4H), 7.06 (br, 2H), 5.28-5.15 (m, 2H), 4.35-4.26 (m, 1H), 3.63-3.5 3(m, 2H), 3.46-3.40(m, 2H), 3.32-3.24(m, 2H), 2.38-2.22(m, 4H), 2.1 6(s, 3H), 1.76-1.43(m, 4H), 1.35-1.21(m, 2H), 0.86(t, J=7.3Hz, 3H).

[0316] Compound I-33

[0317] (S)-2-amino-6-(2-methoxy-4-(pyrrolidone-1-ylmethyl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0318]

[0319] The synthesis of compound I-33 was based on compound I-25, and was prepared as a white solid by substituting intermediate H for intermediate D. MS: 452.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.91 (d, J=8.3Hz, 1H), 7.83 (s, 1H), 7.05 (br, 2H), 6.94 (s, 1H), 6.82-6.74 (m, 2H), 5.20-5.06 (m, 2H), 4.20 (p, J=6.7Hz, 1H), 3.79(s, 3H), 3.55(s, 2H), 2.46-2.40(m, 4H), 1.71-1.64(m, 4H), 1.54-1.4 4 (m, 2H), 1.36-1.26 (m, 2H), 1.15 (d, J = 6.4Hz, 3H), 0.87 (t, J = 7.3Hz, 3H).

[0320] Compound I-34

[0321] (S)-2-amino-6-(4-((bis(2-hydroxyethyl)amino)methyl)-2-methoxybenzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0322]

[0323] The synthesis of compound I-34 referenced compound I-33, and was prepared as a white solid by using diethanolamine instead of pyrrolidine. MS: 486.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.91 (d, J=8.3Hz, 1H), 7.11-6.95 (m, 3H), 7.01 (s, 3H), 6.83-6.71 (m, 2H), 5.20-5.06 (m, 2H), 4.20 (p, J=6.9Hz, 1H), 3.79 ( s, 3H), 3.59 (s, 2H), 3.43 (t, J=6.3Hz, 4H), 2.55-2.50 (m, 4H), 1.53-1.43 (m, 2H), 1.37-1.25 (m, 2H), 1.15 (d, J=6.5Hz, 3H), 0.87 (t, J=7.2Hz, 3H).

[0324] Compound I-35

[0325] (S)-2-amino-6-(2-methoxy-4-(piperazin-1-carbonyl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazin-5(6H)-one

[0326]

[0327] The synthesis of compound I-35 referenced compound I-24, and was prepared as a white solid by using intermediate I-33-1 instead of intermediate I-24-1. MS: 481.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.11 (d, J=8.3Hz, 1H), 7.95 (s, 1H), 7.48 (br, 2H) 7.08 (s, 1H), 6.94 (s, 2H), 5.29-5.14 (m, 2H), 4.27-4.20 (m, 1H) , 3.85 (s, 3H), 3.65-3.48 (m, 4H), 3.20-3.07 (m, 4H), 1.55-1.48 (m, 2H), 1.38-1.26 (m, 2H), 1.18 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0328] Compound I-36

[0329] (R)-2-amino-6-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)-2-methoxybenzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0330]

[0331] The synthesis of compound I-36 referenced compound I-24, and was prepared as a white solid by replacing tert-butyl piperazine-1-carboxylic acid with 2-(piperazin-1-yl)ethane-1-ol. MS: 525.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.24 (d, J=8.3Hz, 1H), 8.00 (s, 1H), 7.75 (br, 2H), 7.07 (d, J=1.2Hz, 1H), 7.00-6.93 (m, 2H), 5.31-5.17 (m, 2H), 4.30-4.15 ( m, 4H), 3.75-3.70 (m, 2H), 3.50-3.35 (m, 2H), 3.26-3.07 (m, 4H), 1.59-1.4 8 (m, 2H), 1.38-1.26 (m, 2H), 1.19 (d, J = 6.4Hz, 3H), 0.88 (t, J = 7.3Hz, 3H).

[0332] Compound I-37

[0333] (S)-2-amino-6-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)-2-methoxybenzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0334]

[0335] The synthesis of compound I-37 was based on compound I-35, and was prepared as a white solid by replacing tert-butyl piperazine-1-carboxylic acid with 2-(piperazin-1-yl)ethane-1-ol. MS: 525.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.24 (d, J=8.3Hz, 1H), 8.00 (s, 1H), 7.75 (br, 2H), 7.07 (d, J=1.2Hz, 1H), 7.00-6.93 (m, 2H), 5.31-5.17 (m, 2H), 4.30-4.15 ( m, 4H), 3.75-3.70 (m, 2H), 3.50-3.35 (m, 2H), 3.26-3.07 (m, 4H), 1.59-1.4 8 (m, 2H), 1.38-1.26 (m, 2H), 1.19 (d, J = 6.4Hz, 3H), 0.88 (t, J = 7.3Hz, 3H).

[0336] Compound I-38

[0337] (S)-2-amino-6-(4-((2-hydroxyethyl)(propyl)amino)methyl)-2-methoxybenzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0338]

[0339] The synthesis of compound I-38 was based on compound I-33, but was prepared as a white solid by using 2-(propylamino)ethane-1-ol instead of pyrrolidine. MS: 484.2 [M+H] + .

[0340] Compound I-39

[0341] (R)-2-amino-6-(4-(2-(methylamino)ethoxy)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0342]

[0343] The synthesis of compound I-39 was based on compound I-25, and was prepared as a white solid by replacing methyl 4-(bromomethyl)-3-methoxybenzoate with 2-(4-(bromomethyl)phenoxy)-N-methylethane-1-amine. MS: 412.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.17 (s, 1H), 8.65 (s, 1H), 7.93 (s, 1H), 7.52 (br, 2 H), 7.32-7.22(m, 2H), 7.00-6.90(m, 2H), 5.24-5.06(m, 2H), 4.27-4.20(m, 1H), 4.19-4.15(m, 2H), 3.36-3.27(m, 2H), 2.62(t, J=5.4Hz, 3H), 1.57-1. 48 (m, 2H), 1.36-1.26 (m, 2H), 1.18 (d, J = 6.5Hz, 3H), 0.88 (t, J = 7.3Hz, 3H).

[0344] Compound I-40

[0345] (R)-2-amino-4-(pentan-2-ylamino)-6-(4-(pyrrolidin-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0346]

[0347] The synthesis of compound I-40 referenced compound I-26, and was prepared as a white solid by replacing 2-(propylamino)ethane-1-ol with pyrrolidine. MS: 422.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.90 (d, J=8.3Hz, 1H), 7.83 (s, 1H), 7.28-7.20 (m, 4H), 7.02 (br, 2H), 5.23-5.08 (m, 2H), 4.25-4.15 (m, 1H), 3 .56 (s, 2H), 2.47-2.38 (m, 4H), 1.70-1.63 (m, 4H), 1.55-1.42 (m, 2H), 1.37-1.24 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.87 (t, J=7.3Hz, 3H).

[0348] Compound I-41

[0349] (R)-6-(4-((2-oxo-6-azaspirocyclic[3.3]heptane-6-yl)methyl)benzyl)-2-amino-4-(pentane-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0350]

[0351] The synthesis of compound I-41 was based on compound I-26, and was prepared as a white solid by replacing 2-(propylamino)ethane-1-ol with 2-oxo-6-azaspirocyclic [3.3]heptane. MS: 450.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=8.3Hz, 1H), 7.83 (s, 1H), 7.23-7.16 (m, 4H), 7.03 (br, 2H), 5.21-5.08 (m, 2H), 4.57 (s, 4H), 4 .25-4.15 (m, 1H), 3.44 (s, 2H), 3.25 (s, 4H), 1.55-1.45 (m, 2H), 1.37-1.26 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0352] Compounds 1-42

[0353] (R)-2-amino-6-(4-((2-hydroxyethyl)amino)methyl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0354]

[0355] The synthesis of compound I-42 referenced compound I-26, and was prepared as a white solid by using ethanolamine instead of 2-(propylamino)ethane-1-ol. MS: 412.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.83 (s, 1H), 7.92 (s, 1H), 7.46 (d, J=7 .9Hz, 2H), 7.39 (br, 2H), 7.33 (d, J=7.9Hz, 2H), 5.30-5.18 (m2H), 4.27-4.1 7(m, 1H), 4.15-4.08(m, 2H), 3.65-3.60(m, 2H), 2.98-2.90(m, 2H), 1.56-1. 45 (m, 2H), 1.35-1.25 (m, 2H), 1.17 (d, J = 6.6Hz, 3H), 0.88 (t, J = 7.3Hz, 3H).

[0356] Compound I-43

[0357] (R)-6-(4-((2-oxo-6-azaspirocyclic 13.3]heptane-6-yl)methyl)-2-methoxybenzyl)-2-amino-4-(pentane-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0358]

[0359] The synthesis of compound I-43 was based on compound I-25, but was prepared as a white solid by replacing pyrrolidine with 2-oxo-6-azaspirocyclic [3.3]heptane. MS: 480.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 9.16 (d, J=8.4Hz, 1H), 7.95 (s, 1H), 7.59 (br, 2H), 7.08 (s, 1H), 6.92 (s, 2H), 5.24-5.12 (m, 2H), 4.6 8 (s, 2H), 4.60 (s, 2H), 4.30-4.15 (m, 7H), 3.83 (s, 3H), 1.55-1.47 (m, 2H), 1.36-1.26 (m, 2H), 1.17 (d, J=6.5Hz, 3H), 0.87 (t, J=7.3Hz, 3H).

[0360] Compound I-44

[0361] (R)-2-amino-6-(4-((2-hydroxyethyl)amino)methyl)-2-methoxybenzyl)-4-(pentyl-2-amino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0362]

[0363] The synthesis of compound I-44 referenced compound I-25, and was prepared as a white solid by using ethanolamine instead of pyrrolidine. MS: 442.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.12 (d, J=8.3Hz, 1H), 8.86 (s, 1H), 7.93 (s, 1H), 7.50 ( br, 2H), 7.21 (s, 1H), 6.98 (d, J = 7.8Hz, 1H), 6.92 (d, J = 7.8Hz, 1H), 5.23-5.11 (m , 2H), 4.26-1.18(m, 1H), 4.15-4.09(m, 2H), 3.83(s, 3H), 2.98-2.90(m, 2H), 1.5 5-1.45 (m, 2H), 1.35-1.28 (m, 2H), 1.17 (d, J=6.5Hz, 3H), 0.87 (t, J=7.3Hz, 3H).

[0364] Compound I-45

[0365] 2-Amino-4-(Butamino)-6-((5-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0366]

[0367] The synthesis of compound I-45 referenced compound I-2, and was prepared as a white solid by using tert-butyl 7-(bromomethyl)-5-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylic acid instead of methyl 4-(bromomethyl)benzoate. MS: 410.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.14 (s, 1H), 8.91 (s, 2H), 7.90 (s, 1H), 7.32 (br, 2H), 6.89 (s, 1H), 6.64 (s, 1H), 5.18 (s, 2H), 4.21-4.16 (m, 2H ), 3.78 (s, 3H), 3.49-3.41 (m, 2H), 3.38-3.30 (m, 2H), 2.77-2.72 (m, 2H), 1.61-1.52 (m, 2H), 1.38-1.31 (m, 2H), 0.90 (t, J=7.3Hz, 3H).

[0368] Compound I-46

[0369] (R)-2-amino-6-(2-methoxy-4-(2-(methylamino)ethoxy)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0370]

[0371] The synthesis of compound I-46 referenced compound I-25, and was prepared as a white solid by replacing methyl 4-(bromomethyl)-3-methoxyphenoxy)-N-methylethane-1-amine. MS: 442.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.93 (d, J=8.3Hz, 1H), 7.81 (s, 1H), 7.01 (br, 2H), 6.83 (d , J=8.4Hz, 1H), 6.59 (d, J=2.4Hz, 1H), 6.47 (dd, J=8.4, 2.4Hz, 1H), 5.15-5.01 (m, 2H), 4.25-4.17(m, 1H), 4.10-4.05(t, J=5.3Hz, 2H), 3.02(s, 2H), 2.44(s, 3H), 1. 55-1.44 (m, 2H), 1.37-1.27 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0372] Compound I-47

[0373] (R)-2-amino-6-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0374]

[0375] The synthesis of compound I-47 was based on compound I-25, and was prepared as a white solid by replacing methyl 4-(bromomethyl)pyridin-2-yl)oxy)-N-methylethane-1-amine. MS: 413.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.88 (d, J=8.3Hz, 1H), 8.28 (s, 1H), 8.14 (d, J=2.5Hz, 1H), 7 .82 (s, 1H), 7.66 (dd, J=8.6, 2.5Hz, 1H), 7.03 (br, 2H), 6.79 (d, J=8.6Hz, 1H), 5.21- 5.06(m, 2H), 4.36-4.30(m, 2H), 4.25-4.17(m, 1H), 3.00-2.94(m, 2H), 2.40(s, 3H), 1.57-1.45 (m, 2H), 1.39-1.27 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0376] Compound I-48

[0377] (R)-2-amino-6-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazin-5(6H)-one

[0378]

[0379] The synthesis of compound I-48 referenced compound I-26, and was prepared as a white solid by replacing 2-(propylamino)ethane-1-ol with 4-methylpiperazine. MS: 451.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=8.3Hz, 1H), 7.84 (s, 1H), 7.30-7.22 (m, 4H), 7.03 (br, 2H), 5.26-5.09 (m, 2H), 4.26-4.17 (m, 1H), 3.54-3.49 (m, 2H), 3.36-3.29 (m, 4H), 2.75-2.70 (m, 2H), 2.53 (s, 3H), 1.55-1.44 ( m, 2H), 1.36-1.26 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0380] Compound I-49

[0381] (R)-2-amino-6-(4-((2-hydroxyethyl)(methyl)amino)methyl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0382]

[0383] The synthesis of compound I-49 referenced compound I-26, and was prepared as a white solid by substituting 2-(methylamino)ethane-1-ol for 2-(propylamino)ethane-1-ol. MS: 426.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=8.3Hz, 1H), 7.84 (s, 1H), 7.33 (d, J=7.9Hz , 2H), 7.27 (d, J=7.9Hz, 2H), 7.03 (br, 2H), 5.26-5.07 (m, 2H), 4.25-4.17 (m, 1 H), 3.75 (s, 2H), 3.56 (t, J=6.0Hz, 2H), 2.68-2.60 (m, 2H), 2.33 (s, 3H), 1.56- 1.45 (m, 2H), 1.36-1.25 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0384] Compound I-50

[0385] (R)-2-amino-4-(pentan-2-ylamino)-6-(4-(piperazin-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazin-5(6H)-one

[0386]

[0387] The synthesis of compound I-50 referenced compound I-26, and was prepared as a white solid by replacing 2-(propylamino)ethane-1-ol with piperazine-1-carboxylic acid tert-butyl ester. MS: 437.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=8.3Hz, 1H), 7.83 (s, 1H), 7.27-7.21 (m, 4H), 7.05 (br, 2H), 5.23-5.08 (m, 2H), 4.21 (p, J=6.8Hz, 1H), 3.45 (s, 2H), 2.93-2.87 (m, 4H), 2.44-2.38 (m, 4H), 1.55-1.44 (m, 2H), 1.37-1.25 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0388] Compound I-51

[0389] 2-Amino-4-(((R)-pentan-2-yl)amino)-6-(4-((R)-1-(propylamino)ethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0390]

[0391] The synthesis of compound I-51 was based on compound I-26, and was prepared as a white solid by substituting (R)-(1-(4-(chloromethyl)phenyl)ethyl)(propyl)carbamate tert-butyl ester for methyl 4-(bromomethyl)benzoate. MS: 424.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=8.3Hz, 1H), 7.83 (s, 1H), 7.35 (d, J=8.1Hz, 2H) , 7.27 (d, J=7.9Hz, 2H), 7.05 (br, 2H), 5.25-5.08 (m, 2H), 4.21 (p, J=6.7Hz, 1H), 3 .96-3.89(m,1H),2.53-2.46(m,1H),2.38-2.29(m,1H),1.54-1.38(m,4H),1.35- 1.27 (m, 5H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H), 0.81 (t, J=7.4Hz, 3H).

[0392] Compound I-52

[0393] 2-Amino-4-(((R)-pentan-2-yl)amino)-6-(4-((S)-1-(propylamino)ethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0394]

[0395] The synthesis of compound I-52 was based on compound I-26, and was prepared as a white solid by substituting (S)-(1-(4-(chloromethyl)phenyl)ethyl)(propyl)carbamate tert-butyl ester for methyl 4-(bromomethyl)benzoate. MS: 424.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.88 (d, J=8.3Hz, 1H), 7.84 (s, 1H), 7.42 (d, J=8.1Hz, 2H) , 7.32 (d, J=8.0Hz, 2H), 7.04 (br, 2H), 5.27-5.11 (m, 2H), 4.21 (t, J=7.0Hz, 2H), 3 .40-3.22(m, 2H), 2.73-2.65(m, 1H), 2.49-2.43(m, 1H), 1.58-1.42(m, 7H), 1.36- 1.25 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H), 0.83 (t, J=7.4Hz, 3H).

[0396] Compound I-53

[0397] (R)-2-amino-6-((2-methoxy-6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0398]

[0399] The synthesis of compound I-53 was based on compound I-52, prepared by substituting (S)-(1-(4-(chloromethyl)phenyl)ethyl)(propyl)carbamate with 2-((5-(bromomethyl)-6-methoxypyridin-2-yl)oxy)-N-methylethane-1-amine to give a white solid, I-53. MS: 443.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.89 (d, J=8.3Hz, 1H), 7.80 (s, 1H), 7.34 (d, J=8.1Hz, 1H), 7.02 (br, 2H), 6.31 (d, J=8.1Hz, 1H), 5.12-4.98 (m, 2H), 4.30 -4.17(m, 3H), 3.86(s, 3H), 2.87-2.78(m, 2H), 2.33(s, 3H), 1.53-1.45( m, 2H), 1.37-1.27 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0400] Compound I-54

[0401] (R)-4-(4-((2-amino-5-oxo-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-6(5H)-yl)methyl)benzyl)piperazine-1-carboxylic acid butyl ester

[0402]

[0403] The synthesis of compound I-54 referenced compound I-26, and was prepared as a white solid by replacing 2-(propylamino)ethane-1-ol with piperazine-1-carboxylate. MS: 537.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.90 (d, J=8.3Hz, 1H), 7.83 (s, 1H), 7.27-7.21 (m, 4H), 7.03 (br, 2H), 5.23-5.06 (m, 2H), 4.25-4.16 (m, 1H), 3.96 (t, J= 6.5Hz, 2H), 3.43 (s, 2H), 3.35-3.32 (m, 4H), 2.30-2.25 (m, 4H), 1.55-1. 45(m, 4H), 1.35-1.25(m, 4H), 1.16(d, J=6.5Hz, 3H), 0.90-1.83(m, 6H).

[0404] Compound I-55

[0405] (R)-2-amino-4-(pentan-2-ylamino)-6-(4-(piperidin-4-yl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0406]

[0407] The synthesis of compound I-55 was based on compound I-26, and was prepared as a white solid by replacing methyl 4-(bromomethyl)benzoate with tert-butyl 4-(4-bromomethyl)phenylpiperidine-1-carboxylic acid. MS: 422.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.90 (d, J=8.3Hz, 1H), 7.83 (d, J=2.0Hz, 1H), 7.42-7.14 (m, 4 H), 7.04 (br, 2H), 5.24-5.03 (m, 2H), 4.21 (p, J=6.8Hz, 1H), 3.38-3.33 (m, 1H), 3.10-3 .03(m, 1H), 2.93-2.87(m, 1H), 2.68-2.56(m, 1H), 2.34-2.28(m, 1H), 1.88-1.85(m, 3H ), 1.71-1.45 (m, 3H), 1.36-1.24 (m, 2H), 1.16 (d, J = 6.5Hz, 3H), 0.88 (t, J = 7.3Hz, 3H).

[0408] Compound I-56

[0409] (R)-2-amino-4-(pentan-2-ylamino)-6-(4-(piperazin-1-carbonyl)benzyl)pyrimidin[4,5-d]pyridazin-5(6H)-one

[0410]

[0411] The synthesis of compound I-56 referenced compound I-24, and was prepared as a white solid by using intermediate I-26-1 instead of intermediate I-24-1. MS: 451.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.07 (d, J=8.1Hz, 1H), 8.84 (br, 2H), 7.94 (s, 1H), 7.46-7.33 (m, 6H), 5.34-5.18 (m, 2H), 4.23 (p, J=7.0H z, 1H), 3.75-3.50 (m, 4H), 3.19-3.06 (m, 4H), 1.56-1.48 (m, 2H), 1.37-1.27 (m, 2H), 1.18 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0412] Compound I-57

[0413] (R)-2-amino-6-(4-(1-methylpiperidin-4-yl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0414]

[0415] The synthesis of compound I-57 was based on compound I-26, and was prepared as a white solid by replacing methyl 4-(bromomethyl)benzoate with 4-(4-(bromomethyl)phenyl)-1-methylpiperidine. MS: 436.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.90 (d, J=8.3Hz, 1H), 7.83 (d, J=2.4Hz, 1H), 7.25-7.17 (m, 4H ), 7.03 (br, 2H), 5.21-5.03 (m, 2H), 4.20 (p, J=6.8Hz, 1H), 3.00-2.98 (m, 2H), 2.58-2.5 2(m, 1H), 2.45-2.38(m, 1H), 2.24(d, J=21.7Hz, 3H), 2.05-1.95(m, 1H), 1.72-1.57(m, 3 H), 1.54-1.44 (m, 2H), 1.37-1.26 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0416] Compound I-58

[0417] (S)-2-amino-4-((1-hydroxypentan-2-yl)amino)-6-(4-(piperazine-1-carbonyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0418]

[0419] The synthesis of compound I-58 referenced compound I-2, and was prepared as a white solid by using intermediate Int.K instead of intermediate Int.C. MS: 467.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.00 (d, J=8.7Hz, 1H), 8.21 (s, 1H), 7.84 (s, 1H), 7. 40-7.29(m, 4H), 7.04(br, 2H), 5.30-5.12(m, 2H), 4.23-4.13(m, 1H), 3.65- 3.53 (m, 2H), 3.50-3.42 (m, 2H), 3.35-3.20 (m, 2H), 2.84-2.66 (m, 4H), 1.63 -1.53(m, 1H), 1.52-1.43(m, 1H), 1.35-1.24(m, 2H), 0.88(t, J=7.3Hz, 3H).

[0420] Compound I-59

[0421] (S)-2-amino-4-((1-hydroxypentan-2-yl)amino)-6-(4-(pyrrolid-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0422]

[0423] The synthesis of compound I-59 referenced compound I-1, and was prepared as a white solid by using intermediate I-58-1 instead of intermediate I-1-1. MS: 438.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, J=8.7Hz, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.3 2-7.20(m, 4H), 7.00(br, 2H), 5.25-5.06(m, 2H), 4.84(br, 1H), 4.23-4.14(m, 1H), 3.65(s, 2H), 3.51-3.42(m, 2H), 2.55-2.50(m, 4H), 1.72-1.66(m, 4H), 1. 63-1.53(m, 1H), 1.53-1.41(m, 1H), 1.36-1.24(m, 2H), 0.88(t, J=7.3Hz, 3H).

[0424] Compound I-60

[0425] (R)-2-amino-6-(4-(4-methylpiperazine-1-carbonyl)benzyl)-4-(pentan-2-ylamino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0426]

[0427] The synthesis of compound I-60 referenced compound I-24, and was prepared as a white solid by replacing intermediate I-24-1 with intermediate I-26-1 and replacing piperazine-1-carboxylic acid tert-butyl ester with 1-methylpiperazine. MS: 465.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.88 (d, J=8.3Hz, 1H), 7.85 (s, 1H), 7.37-7.30 (m, 4H), 7.04 (br, 2H), 5.3 0-5.13(m, 2H), 4.25-4.16(m, 1H), 2.34-2.30(m, 4H), 2.40-2.25(m, 4H), 2.20(s, 3H), 1.54-1.45(m 2H), 1.37-1.26 (m, 2H), 1.16 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3Hz, 3H).

[0428] Compound I-61

[0429] 2-Amino-4-(Butamino)-6-((4-(pyrrolidone-1-ylmethyl)thiazolyl-2-yl)methyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0430]

[0431] The synthesis of compound I-61 was based on compound I-1, prepared as a white solid by substituting intermediate Int.C for intermediate Int.A and methyl 2-(chloromethyl)thiazol-4-carboxylic acid for methyl 4-(bromomethyl)benzoate. MS: 415.2 [M+H] + .

[0432] Compound I-62

[0433] 2-Amino-4-(Butamino)-6-((5-(pyrrolidone-1-ylmethyl)pyridin-2-yl)methyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0434]

[0435] The synthesis of compound I-62 was based on compound I-1, and was prepared as a white solid by replacing intermediate Int.A with intermediate Int.C and methyl 6-(chloromethyl)nicotinic acid with methyl 4-(bromomethyl)benzoate. MS: 409.2 [M+H] + .

[0436] Compound I-63

[0437] (R)-2-amino-4-(hexane-3-ylamino)-6-(4-(pyrrolidone-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0438]

[0439] The synthesis of compound I-63 referenced compound I-1, and was prepared as a white solid by using intermediate Int.K1 instead of intermediate Int.A. MS: 436.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 7.93 (s, 1H), 7.48 (d, J = 8.0Hz, 2H), 7.44-7.32 (m, 4H), 5.26 (s, 2H), 4.32 (d, J = 5.7Hz, 2H), 4.22-4.12 (m, 1H), 3.40-3.29(m, 2H), 3.12-3.00(m, 2H), 2.05-1.95(m, 2H), 1.87-1. 75(m, 2H), 1.65-1.42(m, 4H), 1.36-1.20(m, 2H), 0.87(q, J=7.3Hz, 6H).

[0440] Compound I-64

[0441] (R)-2-amino-6-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)benzyl)-4-(pentyl-2-amino)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0442]

[0443] The synthesis of compound I-64 referenced compound 1-60, and was prepared as a white solid by using 2-(piperazin-1-yl)ethanol-1-ol instead of 1-methylpiperazine. MS: 495.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.20 (d, J=8.2Hz, 1H), 8.00 (s, 1H), 7.69 (br, 2H), 7.47-7.35 (m, 4H), 5.38-5.21 (m, 2H), 4.30-4.19 (m, 1H), 3.76-3.68 (m , 2H), 3.62-3.30 (m, 4H), 3.23-3.16 (M, 2H), 3.6-3.05 (s, 4H), 1.59-1.47 (m, 2H), 1.40-1.25 (m, 2H), 1.19 (d, J=6.5Hz, 3H), 0.89 (t, J=7.3Hz, 3H).

[0444] Compound I-66

[0445] (S)-2-amino-4-((1-hydroxypentan-2-yl)amino)-6-(4-((4-methylpiperazin-1-yl)methyl)benzyl)pyrimidin[4,5-d]pyridazin-5(6H)-one

[0446]

[0447] The synthesis of compound I-66 referenced compound I-59, and was prepared as a white solid by using 1-methylpiperazine instead of pyrrolidine. MS: 467.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, J=8.7Hz, 1H), 7.83 (s, 1H), 7.26-7.20 (m, 4H), 7.00 (br, 2H), 5.23-5.06 (m, 2H), 4.23-4.13 (m, 1H), 3.51- 3.45 (m, 2H), 3.43 (s, 2H), 2.57-2.50 (m, 4H), 2.47-2.31 (m, 4H), 2.29 (s, 3H), 1.64-1.41 (m, 2H), 1.35-1.24 (m, 2H), 0.88 (t, J=7.3Hz, 3H).

[0448] Compound I-67

[0449] (S)-2-amino-4-((1-hydroxyhexane-2-yl)amino)-6-(4-(pyrrolidone-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0450]

[0451] The synthesis of compound I-67 referenced compound I-1, and was prepared as a white solid by using intermediate Int.K2 instead of intermediate Int.A. MS: 452.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.79 (s, 1H), 9.23 (s, 1H), 7.94 (s, 1H), 7.48 (d, J = 8.0Hz, 2H), 7.44-7.34 (m, 3H), 5.26 (q, J=14.9Hz, 2H), 4.32 (d, J=5.7Hz, 2H), 4.19 (s, 2H), 3.55-3. 44(m, 2H), 3.41-3.30(m, 2H), 3.15-3.01(m, 2H), 2.11-1.94(m, 2H), 1.91-1.76(m, 2H) , 1.71-1.57(m, 1H), 1.56-1.43(m, 1H), 1.36-1.21(m, 4H), 0.89-0.80(t, J=3.2Hz, 3H).

[0452] Compound I-68

[0453] (R)-2-amino-4-((1-hydroxypentan-2-yl)amino)-6-(4-(pyrrolid-1-ylmethyl)benzyl)pyrimidin[4,5-d]pyridazine-5(6H)-one

[0454]

[0455] The synthesis of compound I-68 referenced compound I-1, and was prepared as a white solid by using intermediate Int.K3 instead of intermediate Int.A. MS: 438.2 [M+H] + .

[0456] Compound I-69

[0457] (S)-2-amino-4-((1-hydroxypentan-2-yl)amino)-6-(4-(4-methylpiperazine-1-carbonyl)benzyl)pyrimido[4,5-d]pyridazine-5(6H)-one

[0458]

[0459] The synthesis of compound I-69 was based on compound I-58, yielding a white solid, I-69. MS: 481.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.98 (s, 1H), 7.47 (d, J = 8.2Hz, 3H), 7.41 (d, J = 8.1Hz, 2H), 5.34 ( d, J=15.0Hz, 1H), 5.27 (d, J=14.9Hz, 1H), 4.24 (s, 2H), 3.52 (dq, J=10.6, 5.5, 4.2Hz, 4H), 3.43-3.31 (m, 2H), 3.10 (s, 2H), 2.84 (s, 3H), 2.54 (d, J = 2.0Hz, 2H), 2.52 (d, J = 2.4Hz, 2H ), 1.57 (ddq, J=36.0, 13.6, 7.9, 7.3Hz, 2H), 1.35 (h, J=7.3Hz, 2H), 0.92 (t, J=7.3Hz, 3H).

[0460] Compound I-70

[0461] 6-(4-(3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)benzyl)-2-amino-4-(((S)-1-hydroxypentan-2-yl)amino)pyrimidino[4,5-d]pyridazine-5(6H)-one

[0462]

[0463] The synthesis of compound I-70 was based on compound I-58, yielding a white solid, I-70. MS: 479.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.51 (s, 1H), 8.20 (s, 1H), 7.96 (d, J=1.3Hz, 1H), 7.49 (s, 1H), 7.45 (dd, J =8.3, 1.5Hz, 3H), 7.43-7.36 (m, 3H), 5.28 (q, J = 14.9Hz, 2H), 4.40 (s, 1H), 4.03 (s, 1H), 3.90 (s, 1 H), 3.81 (s, 1H), 3.73 (d, J = 12.6Hz, 2H), 3.50 (q, J = 6.4, 5.4Hz, 2H), 2.79 (d, J = 9.2Hz, 1H), 1.82 ( dd, J=10.3, 5.4Hz, 1H), 1.67-1.58 (m, 1H), 1.53 (s, 2H), 1.33 (p, J=7.3Hz, 2H), 0.92-0.86 (m, 3H).

[0464] Compound I-71

[0465] (S)-2-amino-4-((1-hydroxypentan-2-yl)amino)-6-(4-(piperazin-1-ylmethyl)benzyl)pyrimido[4,5-d]pyridazin-5(6H)-one

[0466]

[0467] The synthesis of compound I-71 was based on compound I-59, yielding a white solid, I-71. MS: 453.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.06 (d, J=8.7Hz, 1H), 8.80 (s, 2H), 7.87 (s, 1H), 7.3 0 (d, J=1.7Hz, 4H), 7.04 (s, 2H), 5.31-5.09 (m, 2H), 4.91 (s, 1H), 4.22 (tt, J=8 .6, 4.1Hz, 1H), 3.52 (d, J=12.8Hz, 4H), 3.10 (t, J=5.0Hz, 4H), 2.57 (d, J=5.3 Hz, 3H), 1.67-1.44 (m, 2H), 1.35 (p, J=8.2, 6.6Hz, 2H), 0.91 (t, J=7.3Hz, 3H).

[0468] Determination of the agonist activity of the compound against human TLR7 or TLR8

[0469] HEK-Blue uses stable expression of human TLR7 or TLR8. TM Cellular evaluation of the agonistic activity of the compounds of this invention against TLR7 or TLR8 was performed using their ability to induce SEAP reporter genes controlled by the fusion of the IFN-β minimal promoter with five NF-rB and ap-1 binding sites, as detailed below:

[0470] HEK-Blue TM hTLR7 (Invivogen, 80,000 cells per well) or HEK-Blue TM hTLR8 (Invivogen, 60,000 cells per well) was added to 96-well cell culture plates, followed by the addition of the test compound. The final concentration of the test compound in the culture medium ranged from 0.001 to 36 μM, and incubation was performed for 16 to 22 hours. SEAP levels in the cell culture medium were detected using the HEK-Blue assay kit (Quanti-blue, Invivogen) according to the manufacturer's instructions. Absorbance at 650 nm was measured using a Neo2 multi-plate reader (Bio-tek). The half-maximal effective concentration (EC50) of the drug was calculated using a GraphPad Prism. 50 .

[0471] Table 1: EC50 of the agonist effect of the compounds of this invention on human TLR7 / 8 50 value

[0472]

[0473]

[0474] Conclusion: The compounds of this invention exhibit good TLR7 / 8 agonist activity.

[0475] Mouse pharmacokinetic (PK) evaluation

[0476] Pharmacokinetic studies were conducted by Medicilon Pharmaceutical Technology (Shanghai) Co., Ltd., using ICR mice (Shanghai Xipu-Bikai Laboratory Animal Co., Ltd.). The test compound was administered to ICR mice intravenously (iv). The iv dose was 2 mg / kg, and the solvent system was 100% Saline (0.9% Saline). Animals were fasted overnight (10-14 hours) before administration and fed 4 hours after administration. Blood was collected in heparin sodium anticoagulant tubes at multiple time points (0.083, 0.25, 0.5, 1, 2, and 4 hours) after administration.

[0477] The test compound was administered to ICR mice by gavage (po). The po dose was 5 mg / kg, and the solvent system was 100% Saline (0.9% Saline). Animals were fasted overnight (10–14 hours) before administration and fed 4 hours after administration. Blood was collected in heparin sodium anticoagulant tubes at multiple time points (0.5, 1, 3, and 5 hours) after administration.

[0478] The test compound was administered subcutaneously (sc) to ICR mice. The sc dose was 5 mg / kg, and the solvent system was 100% Saline (0.9% Saline). Animals were fasted overnight (10–14 hours) before administration and fed 4 hours after administration. Blood was collected in heparin sodium anticoagulant tubes at multiple time points (0.5, 1, 3, and 5 hours) after administration. Samples were processed, and plasma drug concentrations were analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin.

[0479] The results showed that the compounds of this invention have unique pharmacokinetic properties and good drug-likeness.

[0480] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, in: L1 is -NH-; R1 is selected from the following group: C 1-8 Alkyl; wherein, the R1 may be further converted by an R a The substituent is replaced, and the R is said to be substituent. a Selected from the following group: hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy; R2 is hydrogen; m is 1; B does not exist, or B is selected from the following group: benzene ring, pyridine ring; L2 is selected from the following group: -(CH2) p -、-(CH2) p -NR d -、-O-、-C(=O)-; where R d Selected from the following group: hydrogen, C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl group, where p is 0, 1, or 2; R4 is selected from the following group: hydrogen, C 1-12 Alkyl, C 1-12 Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a group formed by losing a hydrogen atom from a ring selected from the following groups: And R4 is optionally divided by an R e Substituent substitution, where R e Selected from the following groups: halogen, hydroxyl, carboxylic acid, amino, C 1-6 Alkyl, one R e1 Replacement C 1-6 Alkyl, C 1-6 Alkoxy, -N(R) e2 R e3 -C(=O)OR e2 -C(=O)NH-R e2 ; R e1 It is a hydroxyl group; R e2 R e3 Independently selected from the following groups: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl; R5 is selected from the following group: halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(=O)OR f -C(=O)NH-R f -S(=O)2-R f ;where R f Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl; n is 1 or 2.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The R4 mentioned is selected from the group consisting of: hydrogen, C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a group formed by losing a hydrogen atom from a ring selected from the group consisting of:

3. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R5 is selected from the following group: hydrogen, halogens, C. 1-4 Alkyl, C 1-4 Alkyl group.

4. A compound, or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are selected from the following group:

5. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: the compound as described in claim 1 or 4, a pharmaceutically acceptable salt thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients, and / or diluents.

6. The use of the compound of formula I as claimed in claim 1 or 4, its pharmaceutically acceptable salts, or mixtures thereof, characterized in that, Used to prepare pharmaceutical compositions for treating or preventing tumors or infections caused by viruses.

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