Exonucleotide pyrophosphatase / phosphodiesterase 1 inhibitor as well as preparation method and application thereof

Abstract

The invention relates to an exonucleotide pyrophosphatase / phosphodiesterase 1 inhibitor as well as a preparation method and application thereof. Specifically, the compound disclosed by the invention has a structure as shown in a formula I, and the definitions of all groups and substituent groups are described in the specification. The invention also discloses a preparation method of the compound and application of the compound in preventing and / or treating diseases such as cancers. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicines, and in particular to an ectonucleotide pyrophosphatase / phosphodiesterase 1 inhibitor and a preparation method and use thereof. Background Art

[0002] Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) activates the stimulator of interferon genes (STING) pathway, which is an important anti-cancer innate immune pathway. The cGAS-cGAMP-STING pathway can be activated by cytoplasmic DNA under microbial infection or pathophysiological conditions including cancer and autoimmune diseases. Cyclic GMP-AMP synthase (cGAS) belongs to the nucleotidyl transferase family and is an important cytoplasmic DNA sensor in the innate immune pathway. It is activated after binding to cytoplasmic dsDNA and catalyzes GMP and AMP to produce the signaling molecule (2'-5', 3'-5') cyclic GMP-AMP (or 2',3'-cGAMP or cGAMP). 2',3'-cGAMP acts as a second messenger during microbial infection, binds to and activates STING on the endoplasmic reticulum membrane, thereby inducing the production of type I interferon (IFN) and inflammatory cytokines, regulating downstream protein expression, inducing cell growth arrest and apoptosis, and producing anti-infective effects. In addition to its role in microbial infection, the STING pathway can also regulate the innate immune recognition of immunogenic tumors through cGAMP and type I interferon, enhance anti-tumor immune responses, and thus inhibit the occurrence and development of cancer. The STING pathway has become a therapeutic target for tumors and autoimmune diseases.

[0003] cGAMP is a key stimulator of the innate immune response and an endogenous activator of STING, which has anti-tumor immune effects. Ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) is the main hydrolase that degrades cGAMP. ENPP1 is a member of the ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family and is a type II transmembrane glycoprotein containing two identical disulfide-bonded subunits. ENPP1 protein has a wide range of specificity and can cut a variety of substrates including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. ENPP1 can hydrolyze nucleoside 5' triphosphates into their corresponding monophosphates, and can also hydrolyze polyphosphate diadenosine. cGAMP produced by tumor cells is rapidly hydrolyzed by ENPP1 after being transported to the extracellular space, producing immunosuppressive adenosine molecules, thereby promoting tumor immune escape. Inhibiting ENPP1 activity to increase cGAMP levels in the tumor microenvironment has become a potential strategy for tumor immunotherapy.

[0004] Since the function of ENPP1 as a regulator of the cGAS-STING pathway was confirmed, some research has been conducted on ENPP1 selective inhibitors, but the development of ENPP1 inhibitors with drug-like properties faces great difficulties. Currently, no such drugs are on the market, and only a few molecules are undergoing early clinical and preclinical studies to study their role as immunomodulators in tumor immunotherapy. In 2022, the oral ENPP1 small molecule inhibitor RBS2418 entered Phase I clinical trials (NCT05270213) to be administered in combination with Keytruda or as a monotherapy for the treatment of advanced unresectable, recurrent or metastatic tumors. Unfortunately, its structure has not yet been made public, so its precise structural information is still unclear.

[0005] QS-1 is a PC-1 inhibitor developed by Pfizer (Bioorganic & Medicinal Chemistry Letters 2009, 19, 3339-3343). In 2020, researchers from Stanford University reported that the compound showed a strong affinity for ENPP1 (K i =1600 nM). Furthermore, researchers at Stanford developed a series of ENPP1 inhibitors containing phosphate groups, and its representative compound 1 showed a very high affinity for ENPP1 (K i <2nM), and the results of in vivo pharmacodynamic studies showed that compound 1 could inhibit the growth of breast cancer in E0771 mice.

[0006] However, under the test conditions of the present invention, compound 1, despite its IC 50 The inhibitory IC of ENPP1 in MDA-MB-231 breast cancer cells was 0.6 nM. 50 The activity of this compound is 50nM, which is more than 80 times lower. In addition, this type of compound has a cell membrane-impermeable phosphate group. The effective dose of this compound in the in vivo efficacy test is as high as 300mg / kg, and it can only be administered subcutaneously, which seriously limits the further development of this type of drug as a candidate new drug.

[0007] Summary of the invention

[0008] The object of the present invention is to provide a compound represented by formula I and a method for preparing the compound and use thereof in preventing and / or treating diseases such as cancer.

[0009] In a first aspect of the present invention, a compound is provided, wherein the compound is a compound represented by Formula I, or a pharmaceutically acceptable salt, racemate, R-isomer, or S-isomer thereof,

[0010]

[0011] in,

[0012] R1, R2, R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, hydroxyl;

[0013] R5 is selected from the group consisting of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, cyano, hydroxyl;

[0014] R6 is selected from the following group: substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, NR8R9; the substitution refers to substitution by 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy;

[0015] R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C2-C4 alkenyl, halogenated C2-C4 alkenyl, C2-C4 alkynyl, halogenated C2-C4 alkynyl, C1-C4 alkoxy, cyano, and hydroxyl;

[0016] X is selected from the following group: N, CR a ;

[0017] R a Selected from the group consisting of hydrogen, cyano;

[0018] R7 is hydrogen;

[0019] or R a Together with R7 and the C to which they are respectively connected, they form a substituted or unsubstituted group selected from the following group: phenyl, a 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, a 5-7 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, a C4-C8 monocyclic cycloalkyl, a C4-C8 bridged ring cycloalkyl, a C4-C8 spirocyclic cycloalkyl; the substitution refers to substitution by 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, oxo.

[0020] In another preferred embodiment, R1, R2, and R3 are hydrogen;

[0021] R4 is a C1-C4 alkoxy group.

[0022] In another preferred embodiment, R4 is selected from the following group: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy.

[0023] In another preferred embodiment, R5 is selected from the following group: halogen, C1-C4 alkyl, cyano, hydroxyl.

[0024] In another preferred embodiment, the halogen is selected from the following group: F, Cl, Br, I.

[0025] In another preferred embodiment, the C1-C4 alkyl group is selected from the following group: methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.

[0026] In another preferred embodiment, R5 is cyano.

[0027] In another preferred embodiment, R6 is selected from the following group: substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, NR8R9; the substitution refers to substitution by 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy;

[0028] R8 and R9 are each independently selected from the following group: hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, cyano, and hydroxyl.

[0029] In another preferred embodiment, R a Selected from the group consisting of hydrogen, cyano;

[0030] R7 is hydrogen.

[0031] In another preferred embodiment, the compound is selected from the following group:

[0032]

[0033]

[0034]

[0035] The second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds described in the first aspect of the present invention.

[0036] In another preferred embodiment, the pharmaceutical composition further comprises a second active ingredient selected from the following group: immune checkpoint inhibitors, tyrosine kinase inhibitors, PARP inhibitors, and steroid drugs.

[0037] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing a drug for preventing and / or treating diseases related to ectonucleotide pyrophosphatase / phosphodiesterase 1.

[0038] In another preferred embodiment, the ectonucleotide pyrophosphatase / phosphodiesterase 1 related disease is an ectonucleotide pyrophosphatase / phosphodiesterase 1 high expression disease.

[0039] In another preferred embodiment, the drug is an ectonucleotide pyrophosphatase / phosphodiesterase 1 inhibitor.

[0040] In another preferred embodiment, the ectonucleotide pyrophosphatase / phosphodiesterase 1 related disease is selected from the following group: cancer, autoimmune disease, inflammatory disease, neurodegenerative disease.

[0041] In another preferred embodiment, the cancer is selected from the group consisting of breast cancer, pancreatic cancer, colon cancer, and lung cancer.

[0042] In another preferred embodiment, the cancer is advanced cancer.

[0043] In another preferred embodiment, the cancer is recurrent and / or metastatic cancer.

[0044] In another preferred embodiment, the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, psoriasis, and arthritis.

[0045] In another preferred embodiment, the inflammatory disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, psoriasis, and arthritis.

[0046] In another preferred embodiment, the neurodegenerative disease is selected from the group consisting of Parkinson's disease and Alzheimer's disease.

[0047] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0048] After long-term and in-depth research, the inventors obtained a compound with excellent ENPP1 inhibitory activity at the cellular level through structural optimization (such as introducing a substituent at the para position of the nitrogen atom of the piperidine ring). On this basis, the inventors completed the present invention.

[0049] the term

[0050] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0051] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0052] In the present invention, "C1-C6 alkyl" refers to a straight or branched alkyl group including 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like. The terms "C1-C4 alkyl" and "C1-C3 alkyl" have similar meanings.

[0053] In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to vinyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl, etc. The term "C2-C4 alkenyl" has a similar meaning.

[0054] In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched alkynyl group having 2-6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl, etc. The term "C2-C4 alkynyl" has a similar meaning.

[0055] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3-8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C3-C6 cycloalkyl" has a similar meaning.

[0056] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is C1-C4 alkoxy, more preferably C1-C3 alkoxy.

[0057] In the present invention, the term "heterocyclyl" or "heterocycloalkyl" refers to a 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, including (but not limited to) the following groups:

[0058] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6-10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0059] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0060] In the present invention, the term "halo" means substituted with halogen.

[0061] In the present invention, the term "deuterated" means substituted with deuterium.

[0062] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically feasible combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic radical, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, etc.

[0063] In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings. The term "plurality" refers to 2-6, such as 2, 3, 4, 5 or 6.

[0064] It should be understood that when a group is present in multiple different positions of a compound at the same time, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the following group:" has the same meaning as the term "each independently selected from the following group:".

[0065] Compound

[0066] The present invention obtains a new type of piperidine ENPP1 inhibitor containing quaternary carbon. The compounds maintain high inhibitory activity on ENPP1 molecular level and significantly improve the inhibitory activity on cellular ENPP1. Under the same batch test conditions as compound 1, most of the compounds IC 50The value is less than 10nM.

[0067] Specifically, the present invention provides a compound, which is a compound represented by Formula I, or a pharmaceutically acceptable salt, racemate, R-isomer, or S-isomer thereof,

[0068]

[0069] wherein each group is as defined above.

[0070] In another preferred embodiment, in the compound, any one of R1, R2, R3, R4, R5, R6, R7, and X is independently a corresponding group in the specific compound of the present invention.

[0071] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0072] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0073] The present invention's various embodiments specifically describe the preparation methods of the compounds of formula I of the present invention, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

[0074] Typically, the raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased through commercial channels unless otherwise specified.

[0075] Pharmaceutical compositions and methods of administration

[0076] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compounds.

[0077] Since the compounds of the present invention have excellent anti-tumor activity, 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 treat, prevent and alleviate tumor-related diseases.

[0078] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0079] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which 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 the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0080] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0081] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0082] 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 ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0083] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0084] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0085] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0086] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0087] Compositions for parenteral injection may include 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.

[0088] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0089] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0090] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0091] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0092] Compared with the prior art, the present invention has the following main advantages:

[0093] (1) The compound has excellent ENPP1 inhibitory activity at the cellular level;

[0094] (2) The compound has better metabolic stability in animals and has better anti-tumor effect when used in combination with other therapies such as radiotherapy.

[0095] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0096] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0097] Example 1

[0098] Synthesis of compound S1:

[0099]

[0100] Synthesis of compound 1-3:

[0101] Dissolve tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate (200 mg, 0.861 mmol) and (tert-butyloxycarbonyl)((4-(dimethylamino)pyridin-1-bromo-1-yl)sulfonyl)amide (337 mg, 1.12 mmol) in 6 ml of dichloromethane, add N,N-diisopropylethylamine (450 μl, 2.58 mmol), and react at room temperature until the reaction is complete. The reaction solution is directly spin-dried and then mixed with silica gel and loaded onto a column, DCM:CH3OH=100:1 to obtain 291 mg of product 1-3.

[0102] Synthesis of compound 1-4:

[0103] 291 mg of compound 1-3 (0.708 mmol) was dissolved in 13 ml of dichloromethane, and 2.5 ml of trifluoroacetic acid was added under stirring. The mixture was reacted at room temperature for about two hours. The reaction solvent was evaporated under reduced pressure to obtain a crude product which was directly used for the next step.

[0104] Synthesis of compound S1:

[0105] Compound 1-4 (75 mg, 0.355 mmol) and 4-chloro-8-methoxyquinoline-3-carbonitrile 1-5 (60 mg, 0.274 mmol) were dissolved in 3 ml of N,N-dimethylformamide, and N,N-diisopropylethylamine (143 μl, 0.823 mmol) was added, and heated to 80°C until the reaction was complete. The reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The sample was mixed with silica gel and loaded onto a column, and DCM:CH3OH=20:1 was used to obtain a crude product, which was slurried with ethyl acetate and filtered to obtain 44 mg of compound S1. 1H NMR (400MHz, DMSO-d6) δ8.61(s,1H),7.52–7.44(m,2H),7.29(dd,J=7.1,1.9Hz,1H),6.88(t,J=6.9Hz,1H),6.58(s,2H),4 .12–4.04(m,2H),3.93(s,3H),3.44–3.35(m,2H),3.16(dd,J=10.0,6.1Hz,1H),3.10(d,J=6.9Hz,1H),2.04–1.85(m,4H).

[0106] Example 2

[0107] Synthesis of compound S2:

[0108]

[0109] Synthesis of compound 2-3:

[0110] The synthesis of compound 2-3 was the same as that of compound 1-3, except that compound 2-1 was used to replace 1-1.

[0111] Synthesis of compound 2-4:

[0112] The synthesis of compound 2-4 was the same as that of compound 1-4, except that compound 2-3 was used to replace 1-3.

[0113] Synthesis of compound S2:

[0114] The synthesis of compound S2 was the same as that of compound S1, except that compound 2-4 was used to replace 1-4, and compound 2-5 was used to replace 1-5.

[0115] 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),7.50–7.41(m,2H),7.27(d,J=7.3Hz,1H),6.55(s,2H),6.38(t,J=6.7Hz,1H),4.61(s,1H),4 .01(d,J=12.9Hz,2H),3.92(s,3H),3.45(t,J=12.3Hz,2H),2.90(d,J=6.8Hz,2H),1.80(t,J=12.6Hz,2H),1.56(d,J=13.3Hz,2H).

[0116] Example 3

[0117] Synthesis of compound S3:

[0118]

[0119] Synthesis of compound 2-3:

[0120] The synthesis of compound 2-3 was the same as that of compound 1-3, except that compound 2-1 was used to replace 1-1.

[0121] Synthesis of compound 2-4:

[0122] The synthesis of compound 2-4 was the same as that of compound 1-4, except that compound 2-3 was used to replace 1-3.

[0123] Synthesis of compound S3:

[0124] The synthesis of compound S3 was the same as that of compound S1, except that compound 2-4 was used to replace 1-4.

[0125] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=4.2Hz,1H),7.56(d,J=4.7Hz,2H),7.35–7.25(m,1H),6.58(s,2H),6.41(d,J=7.0Hz,1H),4.6 8(s,1H),3.94(d,J=3.6Hz,3H),3.66(d,J=11.8Hz,2H),3.59(s,2H),2.96(d,J=6.8Hz,2H),1.91(s,2H),1.64(d,J=12.8Hz,2H).

[0126] Example 4

[0127] Synthesis of compound S4:

[0128]

[0129] Synthesis of compound 4-2:

[0130] 4-Chloro-8-methoxyquinoline-3-carbonitrile 1-5 (150 mg, 0.686 mmol) and 4-methyl-4-(BOC-aminomethyl)piperidine 4-1 (204 mg, 0.892 mmol) were dissolved in 9 ml of n-butanol, and N,N-diisopropylethylamine (358 μl, 2.06 mmol) was added. The mixture was protected by nitrogen and heated to 100°C until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The sample was mixed with silica gel and loaded onto a column. DCM:CH3OH=50:1 to obtain 251 mg of product 4-2.

[0131] Synthesis of compound 4-3:

[0132] The synthesis of compound 4-3 was the same as that of compound 1-4, except that compound 4-2 was used to replace 1-3.

[0133] Synthesis of compound 4-4:

[0134] The synthesis of compound 4-4 was the same as that of compound 1-3, except that compound 4-3 was used to replace 1-1.

[0135] Synthesis of compound S4:

[0136] Compound 4-4 (180 mg, 0.368 mmol) was dissolved in 2 ml of DCM, and a 4 M hydrochloric acid solution in 1,4-dioxane (1 ml) was added at 0°C, and the mixture was reacted overnight at room temperature. After the reaction was completed, the mixture was filtered, and the filter cake was dissolved in methanol, and the sample was mixed with silica gel and loaded onto a column, and DCM:CH3OH=50:1 to obtain 18 mg of product S4. 1 H NMR (400MHz, Methanol-d4) δ8.59(s,1H),7.64(d,J=8.6Hz,1H),7.55(t,J=8.2Hz,1H),7.29(d,J=7.8Hz,1H ),4.03(s,3H),3.81–3.62(m,4H),3.03(s,2H),1.86(d,J=13.3Hz,2H),1.63(d,J=13.5Hz,2H),1.14(s,3H).

[0137] Example 5

[0138] Synthesis of compound S5:

[0139]

[0140] Synthesis of compound 5-3:

[0141] Dissolve p-toluenesulfonyl chloride 5-2 (397 mg, 2.08 mmol) in 5.7 ml of anhydrous DCM, and add anhydrous DCM solution (0.7 ml) containing tert-butyl 4-cyano-4-(hydroxymethyl)-1-piperidincarboxylate 5-1 (500 mg, 2.08 mmol), triethylamine (578 mg, 4.16 mmol) and 4-dimethylaminopyridine (25 mg, 0.208 mmol) at 0°C. The mixture is reacted overnight at room temperature. After the reaction, water is added, and the mixture is extracted with DCM. The mixture is washed with 3M aqueous hydrochloric acid solution, saturated sodium bicarbonate solution and water respectively. After drying with anhydrous sodium sulfate, the mixture is mixed with silica gel and loaded onto a column. PE:EA=5:1 to obtain 311 mg of product 5-3.

[0142] Synthesis of compound 5-4:

[0143] Compound 5-3 (311 mg, 0.789 mmol) was dissolved in 2.5 ml N,N-dimethylformamide, sodium azide (103 mg, 1.58 mmol) was added, and the mixture was heated to 100°C until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was mixed with silica gel and loaded onto a column. PE:EA=8:1 to obtain 167 mg of product 5-4.

[0144] Synthesis of compound 5-5:

[0145] Compound 5-4 (167 mg, 0.630 mmol) was dissolved in 4 ml of ethanol, and 10% palladium carbon (68 mg, 0.0630 mmol) was added, and the reaction was completed under a hydrogen atmosphere. After the reaction was completed, the diatomaceous earth was filtered, and the filtrate was mixed with silica gel and loaded on a column, and DCM:CH3OH=50:1 was used to obtain 90 mg of product 5-5.

[0146] Synthesis of compound 5-6:

[0147] The synthesis of compound 5-6 was the same as that of compound 1-3, except that compound 5-5 was used to replace 1-1.

[0148] Synthesis of compound 5-7:

[0149] The synthesis of compound 5-7 was the same as that of compound 1-4, except that compound 5-6 was used to replace 1-3.

[0150] Synthesis of compound S5:

[0151] The synthesis of compound S5 was the same as that of compound S1, except that compound 5-7 was used to replace 1-4. 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=1.0Hz,1H),7.66–7.49(m,2H),7.33(dd,J=7.4,1.6Hz,1H),7.23(t,J=7.1Hz,1H),6.73(s,2H ),3.95(s,3H),3.82(d,J=13.1Hz,2H),3.54(t,J=12.4Hz,2H),3.23(d,J=7.2Hz,2H),2.11(d,J=13.4Hz,2H),2.01–1.91(m,2H).

[0152] Example 6

[0153] Synthesis of compound S9:

[0154]

[0155] Synthesis of compound 9-2:

[0156] Compound 5-5 (64 mg, 0.268 mmol) was dissolved in 1 ml of anhydrous DCM, triethylamine (75 μl, 0.536 mmol) was added, and 4-morpholinesulfonyl chloride 9-1 (75 mg, 0.402 mmol) was added at 0°C, and the reaction was carried out at room temperature until the reaction was complete. The reaction solution was diluted with DCM, washed with 10% sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, mixed with silica gel and loaded on a column, DCM:CH3OH=100:1 to obtain 45 mg of product 9-2.

[0157] Synthesis of compound 9-3:

[0158] The synthesis of compound 9-3 was the same as that of compound 1-4, except that compound 9-2 was used to replace 1-3.

[0159] Synthesis of compound S9:

[0160] The synthesis of compound S9 was the same as that of compound S1, except that compound 9-3 was used to replace 1-4.

[0161] 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),7.92(t,J=6.8Hz,1H),7.58–7.49(m,2H),7.29(dd,J=7.3,1.6Hz,1H),3.92(s,3H),3.80(d,J=13. 0Hz, 2H), 3.62 (t, J = 4.7Hz, 4H), 3.49 (t, J = 12.5Hz, 2H), 3.29 (s, 2H), 3.04 (t, J = 4.8Hz, 4H), 2.08 (d, J = 13.3Hz, 2H), 1.96–1.85 (m, 2H).

[0162] Example 7

[0163] Synthesis of compound S12:

[0164]

[0165] Synthesis of compound 12-2:

[0166] Compound 5-5 (90 mg, 0.375 mmol) was dissolved in 1.2 ml of anhydrous acetonitrile, and 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate 12-1 (123 mg, 0.375 mmol) was added at 0°C, and the reaction was carried out at room temperature until the reaction was complete. Water was added to the reaction solution, and ethyl acetate was extracted. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The sample was mixed with silica gel and loaded onto a column, and DCM:CH3OH=100:1 to obtain 75 mg of product 12-2.

[0167] Synthesis of compound 12-4:

[0168] Compound 12-2 (75 mg, 0.234 mmol), N-methylpropargylamine 12-3 (21 μl, 0.234 mmol) and DBU (36 μl, 0.234 mmol) were dissolved in 600 μl acetonitrile and reacted at 50°C until the reaction was complete. The reaction solution was directly spin-dried and then mixed with silica gel and loaded onto a column, DCM:CH3OH=100:1 to obtain 48 mg of product 12-4.

[0169] Synthesis of compound 12-5:

[0170] The synthesis of compound 12-5 was the same as that of compound 1-4, except that compound 12-4 was used to replace 1-3.

[0171] Synthesis of compound S12:

[0172] The synthesis of compound S12 was the same as that of compound S1, except that compound 12-5 was used to replace 1-4.

[0173] 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),7.99(t,J=6.7Hz,1H),7.63–7.52(m,2H),7.33(d,J=7.3Hz,1H),3.98(d,J=2.5Hz,2H),3.95(s,3H),3.83(d, J=13.2Hz,2H),3.53(t,J=12.4Hz,2H),3.40(t,J=2.4Hz,1H),3.26(d,J=6.8Hz,2H),2.80(s,3H),2.12(d,J=13.3Hz,2H),1.93(t,J=12.3Hz,2H).

[0174] Example 8

[0175] Synthesis of compound S31:

[0176]

[0177] Synthesis of compound 31-3:

[0178] Compound 31-1 (100 mg, 0.466 mmol) and compound 31-2 (52 μl, 0.466 mmol) were dissolved in 4 ml of anhydrous 1,4-dioxane, palladium acetate (7.8 mg, 0.0466 mmol), Xanphos (26 mg, 0.0466 mmol) and cesium carbonate (304 mg, 0.932 mmol) were added, and heated to 100°C under nitrogen protection until the reaction was complete. The reaction solution was filtered through diatomaceous earth and washed with DCM. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The sample was mixed with silica gel and loaded onto a column, and DCM:CH3OH=100:1 to obtain 90 mg of product 31-3.

[0179] Synthesis of compound 31-4:

[0180] Compound 31-3 (90 mg, 0.348 mmol) was dissolved in 1.4 ml methanol and 400 μl water, sodium hydroxide (28 mg, 0.696 mmol) was added, and the mixture was reacted at 60°C until the reaction was complete. The reaction solution was evaporated to dryness, diluted with water, adjusted to pH 6-7 with 1 M hydrochloric acid, extracted with 10% MeOH / DCM, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated acid was used to obtain 86 mg of product 31-4.

[0181] Synthesis of compound 31-5:

[0182] Compound 31-4 (75 mg, 0.306 mmol) was dissolved in 1 ml of phosphorus oxychloride and heated to 100°C under nitrogen protection until the reaction was complete. The reaction solution was spin-dried, diluted with DCM, and mixed with neutral alumina and loaded on a column, DCM:CH3OH=200:1 to obtain 36 mg of product 31-5.

[0183] Synthesis of compound S31:

[0184] The synthesis of compound S31 was the same as that of compound S2, except that compound 31-5 was used to replace 1-5.

[0185] 1H NMR (400MHz, DMSO-d6) δ8.90 (dd, J=7.5, 1.5Hz, 1H), 8.17 (dd, J=7.5, 1.5Hz, 1H ),7.73(dd,J=7.5,1.5Hz,1H),7.64(t,J=7.4Hz,1H),7.55(t,J=7.5Hz,1H),7. 43(t,J=10.3Hz,1H),7.05(dd,J=7.5,1.5Hz,1H),5.34(s,2H),4.67(s,1H),3. 88(s,3H),3.63(q,J=7.2Hz,4H),3.08(d,J=10.4Hz,2H),1.91(d,J=7.2Hz,4H).

[0186] The following target compounds were prepared by referring to the synthesis method of the above examples:

[0187]

[0188]

[0189]

[0190]

[0191] Biological activity test

[0192] ENPP1 enzyme activity detection at the molecular level

[0193] 1. Experimental Materials

[0194] AMP-Glo TM Assay Kit (Promega, V5011), 2'3'-cGAMP sodium salt (Sigma, SML1229), recombinant human ENPP1 protein (expressed and purified in the laboratory), 384-well plate (Perkin Elmer, 6008289).

[0195] 2. Experimental Methods

[0196] The ENPP1 enzyme activity reaction system includes reaction buffer (50mM Tris, 250mM NaCl, 0.5mM CaCl2, 1mM ZnCl2, pH 7.5), 5μM cGAMP, 20ng recombinant human ENPP1 protein and different concentration gradients of the test compound. After reacting at room temperature for 3.5h, the reaction solution was incubated at 90℃ for 10min to terminate the enzyme reaction. 5μL of reaction solution and 5μL of AMP-Glo ​​were added to the 384-well plate. TMReagent I, shake for 1 min, react at room temperature for 1 h, add 10 μL AMP Detection Solution (AMP-Glo TM Reagent II: One Solution = 1:100). After shaking for 1 min, react at room temperature for 1 h, and measure the luminescence reading using a multifunctional microwell analysis system (PerkinElmer ENVISION). GraphPad was used to calculate the inhibition rate and IC of the compound on ENPP1 enzyme activity. 50 value.

[0197] The compounds of the present invention have significant inhibitory activity against ENPP1. The IC values ​​of some compounds of the present invention for inhibiting ENPP1 enzyme activity are 50 See Table 1.

[0198] Table 1 represents the inhibitory activity of compounds on ENPP1 enzyme at the molecular level

[0199] Compound <![CDATA[IC 50 (nM)]]> Compound 1 0.6 S1 3.7 S2 7.3 S3 13.8 S4 3.9 S5 7.0 S6 12.0 S7 10.2

[0200] Detection of ENPP1 activity at the cellular level

[0201] 1. Experimental Materials

[0202] MDA-MB-231 cells (ATCC), L-15 medium (BasalMedia, L620KJ), p-Nph-5V-TMP (Sigma, T4510), 96-well plates (Corning, 3599).

[0203] 2. Experimental Methods

[0204] MDA-MB-231 cells were inoculated in 96-well plates. After 24 h of culture, the culture medium was replaced with reaction buffer (50 mM Tris, 250 mM NaCl, pH 9.5). The substrate p-Nph-5V-TMP was added to a concentration of 1 mM, and the test compound with different concentration gradients was added at the same time. The reaction was placed in an air incubator at 37 ° C for 1 h. The OD value was read at a wavelength of 405 nm using a microplate reader (Spectra Max190). GraphPad calculated the inhibition rate and IC of the compound on ENPP1 activity 50 value.

[0205] It has been determined that the compounds of the present invention have good inhibitory activity against ENPP1 at the cellular level, and the activity of some of the compounds is better than that of the control compound 1. The results are shown in Table 2.

[0206] Table 2 represents the inhibitory activity of compounds against ENPP1 at the cellular level

[0207] Compound <![CDATA[IC 50 (nM)]]> Compound 1 50.10±0.97 S1 1.23±0.62 S2 1.53±0.28 S3 1.84±0.30 S4 1.07±0.55 S5 0.97±0.16 S6 2.88±0.13 S7 4.41±0.02

[0208] Conclusion: Based on the sulfonylurea ENPP1 inhibitor QS-1 and the phosphate inhibitor compound 1, the present invention introduces a substituent at the position of the nitrogen atom of the piperidine ring in the structure center, further optimizes the structure of the sulfonylurea group and the aromatic heterocyclic tail chain, and designs and synthesizes a series of ENPP1 inhibitors with quaternary carbon centers. The introduction of the quaternary carbon center restricts the rotation of the sulfonylurea group, significantly improving the inhibitory activity of the compound against ENPP1 at the cellular level. The representative compound S5 has an inhibitory IC of ENPP1 on cells. 50 <1nM, which is more than fifty times higher than the positive control compound 1.

[0209] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound, characterized in that The compound is a compound represented by formula I, or a pharmaceutically acceptable salt, racemate, R-isomer, or S-isomer thereof, in, R1, R2, R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, hydroxyl; R5 is selected from the group consisting of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, cyano, hydroxyl; R6 is selected from the following group: substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, NR8R9; the substitution refers to substitution by 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy; R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C2-C4 alkenyl, halogenated C2-C4 alkenyl, C2-C4 alkynyl, halogenated C2-C4 alkynyl, C1-C4 alkoxy, cyano, and hydroxyl; X is selected from the following group: N, CR a ; R a Selected from the group consisting of hydrogen, cyano; R7 is hydrogen; or R a Together with R7 and the C to which they are respectively connected, they form a substituted or unsubstituted group selected from the following group: phenyl, a 5-7 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, a 5-7 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, a C4-C8 monocyclic cycloalkyl, a C4-C8 bridged ring cycloalkyl, a C4-C8 spirocyclic cycloalkyl; the substitution refers to substitution by 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, oxo.

2. The compound according to claim 1, characterized in that R1, R2, and R3 are hydrogen; R4 is a C1-C4 alkoxy group.

3. The compound according to claim 1, characterized in that R5 is selected from the group consisting of halogen, C1-C4 alkyl, cyano, and hydroxy.

4. The compound according to claim 1, characterized in that R6 is selected from the following group: substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, NR8R9; the substitution refers to substitution by 1, 2 or 3 substituents selected from the following group: halogen, hydroxyl, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy; R8 and R9 are each independently selected from the following group: hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, cyano, and hydroxyl.

5. The compound according to claim 1, characterized in that R a Selected from the group consisting of hydrogen, cyano; R7 is hydrogen.

6. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

7. A pharmaceutical composition, characterized in that The invention comprises a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound according to claim 1.

8. A use of the compound according to claim 1, characterized in that: Used for preparing medicines for preventing and / or treating diseases related to ectonucleotide pyrophosphatase / phosphodiesterase 1.

9. The use according to claim 8, characterized in that The ectonucleotide pyrophosphatase / phosphodiesterase 1 related disease is selected from the group consisting of cancer, autoimmune disease, inflammatory disease, and neurodegenerative disease.

10. The use according to claim 9, characterized in that The cancer is selected from the group consisting of breast cancer, pancreatic cancer, colon cancer, and lung cancer.

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