PDE4 inhibitors for the treatment of diseases

Abstract

Disclosed herein are novel compounds, geometric isomers thereof, or pharmaceutically acceptable salts thereof, which are selective PDE4 inhibitors. Also disclosed are methods of treating diseases or conditions associated with mis-regulation of PDE4.

Description

PDE4 INHIBITORS FOR THE TREATMENT OF DISEASESTECHNICAL FIELD

[0001] Disclosed herein are dihydrothienopyrimidine sulfoxide compounds of Formula (I), as well as those of sub-Formulae (I-a), (I-b), (I-c), and (I-d) which are inhibitors of PDE4 isozymes, and the use of such compounds in methods for treating, e.g., metabolic, autoimmune, inflammatory, dermatological and fibrotic diseases or disorders.BACKGROUND

[0002] Phosphodiesterases (PDEs) are a group of intracellular enzymes that break the phosphodiester bond in adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP), converting them to 5-AMP and 5-GMP, respectively.

[0003] Among the 11 identified phosphodiesterases, PDE4, PDE7, and PDE8 are selective for cAMP. PDE4 is particularly significant as a modulator of cAMP in immune and inflammatory cells, including neutrophils, macrophages, and T-lymphocytes. Since cAMP plays a crucial role as a second messenger in regulating inflammatory responses, PDE4 influences these responses by modulating pro- inflammatory cytokines such as TNF-a, IL-2, IFN-y, GM-CSF, and LTB4. Consequently, inhibiting PDE4 has emerged as a promising therapeutic target for various inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, and inflammatory bowel diseases like Crohn's disease.

[0004] Several PDE4 inhibitors have shown success in clinical trials for various conditions. For example, Roflumilast (DALIRESP®) is approved for severe chronic obstructive pulmonary disease (COPD) to help reduce flare-ups and prevent symptom exacerbations. Apremilast (OTEZLA®) has also received approval from the U.S. FDA for the treatment of adults with active psoriatic arthritis. More recently, Ensifentrine (OHTUVAYRE®) is granted marketing authorization for the maintenance treatment of moderate to severe COPD in adults.

[0005] While PDE4 inhibitors have demonstrated beneficial pharmacological effects, side effects such as nausea, vomiting, and diarrhea commonly occur. The beneficial effects are thought to be associated with the inhibition of the PDE4B isoform, while the undesirable effects are attributed to the inhibition of the PDE4D isoform. More selective PDE4 inhibitors like BI-1015550 (Ensifentrine) have shown improved tolerability, supporting this hypothesis. Achieving selectivity between PDE4B and PDE4D has historically been challenging due to the highly conserved sequences. There is a need for the development of selective PDE4 inhibitors, particularly those distinguishing between PDE4B and PDE4D. Compounds selectively targeting PDE4B are expected to be beneficial for treating various diseases and disorders while reducing gastrointestinal side effects. The discovery of specific compounds in this context addresses this ongoing need and offers new therapeutic options for a range of metabolic, autoimmune, inflammatory, fibrotic, and dermatological conditions.

[0006] The present disclosure relates to compounds inhibiting the PDE4 activity of PDEs family, and in particular, a higher activity of inhibiting PDE4B than PDE4D isoforms.SUMMARY

[0007] The compounds of this patent document address the need. Disclosed herein are novel PDE4 inhibitors that represent a potential new treatment for diseases or conditions modulated by PDE4B including, for example, COPD, psoriasis and any other diseases. The compounds can also be combined with other therapeutic agents.

[0008] An aspect of the patent document provides a compound of formula I, a geometric isomer thereof, or a pharmaceutically acceptable salt thereof,whereinA iswhich could be linked to Cy and dihydrothienopyrimidine sulfoxide core in head-to-tail or tail-to-head direction.Cy is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0009] Another aspect of the patent document provides a pharmaceutical composition comprising the compound of formula 1, geometric isomer thereof, or pharmaceutically acceptable salt thereof disclosed herein, and a pharmaceutically acceptable carrier.

[0010] Another aspect provides a method of treating a disease associated with PDE enzymes, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I, geometric isomer thereof, or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof disclosed herein, wherein the disease is selected from the group consisting of metabolic, autoimmune, inflammatory, fibrotic, and dermatological conditions.

[0011] Another aspect provides a method of inhibiting PDE4 enzymes, comprising contacting a cell with an effective amount of the compound of formula (I) or the pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof disclosed herein.DETAILED DESCRIPTION

[0012] This patent document discloses selective PDE4 inhibitors and use of thereof for treating various diseases.

[0013] While the following text may reference or exemplify specific embodiments of a compound, substituent, or use thereof, it is not intended to limit the scope of the compound, substituent or its use tosuch particular references or examples. Various modifications may be made by those skilled in the art, in view of scientific and practical considerations, such as replacement of a substituent or treatment of other diseases.

[0014] The articles "a" and "an" as used herein refer to "one or more" or "at least one," unless otherwise indicated. That is, reference to any element or component of an embodiment by the indefinite article "a" or "an" does not exclude the possibility that more than one element or component is present.

[0015] The term "acyl” refers to -C(O)CH3, -C(O)CH2CH3, -C(O)CH2CH2CH3, - C(O)CH2CH2CH2CH3and groups alike.

[0016] The term "alkyl" refers to a hydrocarbon or a hydrocarbon chain which may be either straight-chained or branched. The term "Ci-6 alkyl" refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Non-limiting examples include groups such as CH3, (CH2)2CH3, CH2CH(CH3)CH3, and the like. Similarly, the term "C2-5 alkyl" refers to alkyl groups having 2, 3, 4 or 5 carbon atoms. In some embodiments, an alkyl is used interchangely with alkylene and one of ordinary skill in the art could readily recognize the meaning of the term in the context of a chemical structure.

[0017] The term “alkylene” refers to a divalent hydrocarbon or a hydrocarbon chain which may be either straight-chained or branched. Non-limiting examples include groups such as CH2, (CH2)2CH2, CH2CH(CH3)CH2, and the like. A Ci-3alkylene includes alkylenes with 1, 2 or 3 carbons such as CH2, (CH2)2, CHCH3,(CH2)3, and CH(CH3)CH2.

[0018] The term "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 ring carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0019] The term "aryl" group refers to a Cs-i4 aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. The term “aromatic ring” can also encompasses heteroaryl.

[0020] The term “alkeny” refers to a carbon chain containing a carbon-carbon double bond moiety.Non-limiting examples of alkenyl groups include ethylenyl, 1 -propenyl, allyl and 2-butenyl.

[0021] The term "alkynyl" group refers to a caron chain containing a carbon-carbon triple bond moiety. Non-limiting examples of alkynyl groups include ethynyl, 1-propanyl, propargyl and 2-butynyl.

[0022] The term “haloalkyl” refers to a Ce-ioalkyl chain, straight or branched, in which one or more hydrogen has been replaced by a halogen. Non-limiting examples of haloalkyls include CHF2, CFH2, CF3, CH2CHF2, CH2CH2C1, CH2CF3, and CH2CH2F. In some embodiments, the alkyl in haloalkyl has 1, 2, 3 or 4 carbons.

[0023] The term “heteroalkyl” refers to a Ce-ioalkyl group, straight or branched, wherein one or more carbon atoms in the chain are replaced by one or more heteroatoms selected from the group consisting of O, S, N and NRm. In some embodiments, the alkyl in heteroalkyl has 1 to 10 carbons. In some embodiments, the alkyl in heteroalkyl has 2, 3, 4 or more than 2 carbons.

[0024] The term “geometric isomer” refers to an isomer which has the same molecular formula and sequence of bonded atoms (constitution) of a reference compound, but differ in the spatial arrangement of atoms or groups around a rigid double bond structure. A geometric isomer is also known as a cis or trans isomer, sometimes as an E or Z isomer.

[0025] The term “hydroxyalkyl” refers to a Ce-ioalkyl chain, straight or branched, wherein a carbon is substituted with a hydroxyl group. The carbon the hydroxyl is attached to is a primary carbon or secondary carbon. In some embodiments, the alkyl in hydroxylalkyl has 2, 3, 4 or more than 2 carbons.

[0026] The term “dihydroxyalkyl” refers to a C2-ioalkyl chain, straight or branched, wherein two carbons are each substituted with a hydroxyl group. In some embodiments, the alkyl in dihydroxylalkyl has 2, 3, 4 or more than 2 carbons.

[0027] The term “heterocyclyl” or “heterocyclic” group is a ring structure having from about 3 to about 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S, the remainder of the ring atoms being carbon. The heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, azocanyl, azepanyl, diazepanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiooxazepanyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, oxazepanyl, azabicyclohexanes, azabicycloheptanes and oxa azabiocycloheptanes. Specifically excluded from the scope of this term are compounds having adj acent annular O and / or S atoms.

[0028] The term “heteroaryl” refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0029] The term “halogen” refers to F, Cl, Br or I.

[0030] The term “subject” refers to humans or animals including for example sheep, horses, cattle, pigs, dogs, cats, rats, mice, birds, and reptiles. Preferably, the subject is a human or other mammal.

[0031] The term “effective amount” or “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit activity. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0032] The term “hydrogen bond donor” refers to a group containing a hydrogen, which can be form a hydrogen bond with another electronegative atom such as F, N or O. Non-limiting examples of hydrogen bond donor include OH and NH2, which can share its hydrogen with electron rich atoms to form a hydrogen bond.

[0033] The term “hydrogen bond acceptor” refers to a group or atom rich in electrons, which can form a hydrogen bond with a hydrogen bond donor. Non-limiting examples of hydrogen bond acceptor include O, N and F.

[0034] The term “oxo” refers to an oxygen which is bonded to a carbon via a doule bond. For example, a carbon atom substituted with an oxo is a carbonyl group (C=O).

[0035] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0036] The term “pharmaceutically acceptable carrier” refers to a chemical compound that facilitates the delivery or incorporation of a compound or therapeutic agent into cells or tissues.

[0037] The term “pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Non-limiting examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy- 2-ene- 1 -carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-l -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid,hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, / >-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, tertiaiybutylacetic acid, and trimethylacetic acid. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, ethylenediamine, triethanolamine, tromethamine, and V-methylglucamine. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0038] The term “pharmaceutical composition” refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or additional carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a pharmaceutical composition exist in the art including, but not limited to, oral, injection, aerosol, parenteral, intranasal, sublingual, inhalational, and topical administration. In some embodiments, pharmaceutically acceptable salts of the compounds disclosed herein are provided.

[0039] The term "treating" or "treatment" of any disease or condition refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical signs and symptoms thereof). In some embodiments "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In some embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In some embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder, or even preventing the same. “Prophylactic treatment” is to be construed as any mode of treatment that is used to prevent progression of the disease or is used for precautionary purpose for persons at risk of developing the condition.

[0040] Phosphodiesterase 4 (PDE4) regulate inflammatory and immune response. Oral selective phosphodiesterase 4 (PDE4) inhibitors are useful to treat chronic obstructive pulmonary disease and psoriasis / psoriatic arthritis, respectively. The antifibrotic potential of PDE4 inhibitors is being explored clinically. PDE4 inhibitors having high level isoform selectivity would provide a safer and more effective treatment for various metabolic, autoimmune, inflammatory, fibrotic, and dermatological conditions such as COPD.

[0041] Compounds

[0042] An aspect of the disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, which are inhibitors of PDE4 enzymes.Formula IWhich could be linked to Cy and dihydrothienopyrimidine sulfoxide core in head-to-tail or tail-to-head direction.Cy is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0043] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula I-aWhereinCy is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0044] In some embodiments, the compound is represented by Formula I-bWhereinCy is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0045] In some embodiments, the compound is represented by Formula I-c,Zi and Z2 is independently selected from N or CH;Rxis independently selected from the group consisting of alkyl, substituted alkyl, halo, hydroxyl, alkoxyl; m = 0, 1,2 and 3

[0046] In some embodiments, the compound is represented by Formula I-d,whereinZi and Z2 is independently selected from N or CH;Rxis independently selected from the group consisting of alkyl, substituted alkyl, halo, hydroxyl, alkoxyl; m = 0, 1,2 and 3

[0047] In any embodiments disclosed herein where a stereocenter is present, the configuration can be R or S. The patent document also encompasses geometric isomers of the compounds disclosed herein. In some embodiments, one or more hydrogens of the compound of Formula I can be replaced with deuterium. Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar.

[0048] The invention also includes any or all metabolites of any of the compounds described. The metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.

[0049] In some embodiments, the compound is one of the following:

[0050] Pharmaceutical Composition and Kit

[0051] Another aspect of the patent specification provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof disclosed herein and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds described in this patent specification may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, peroral, sublingual, buccal, intrathecal, transdermal, topical, subcutaneous, intramuscular, intraperitoneal, intranasal, intratracheal, or intrarectal.

[0052] Nonlimiting examples of pharmaceutically acceptable carriers include physiologically acceptable surface active agents, glidants, plasticizers, diluents, excipients, smoothing agents, suspension agents, complexing agents, film forming substances, and coating assistants. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents. Suitable exemplary binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like. Suitable exemplary disintegrants include starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, and the like. Suitable exemplary solvents or dispersion media include water, alcohol (for example, ethanol), polyols (for example, glycerol, propylene glycol, and polyethylene glycol, sesame oil, com oil, and the like), and suitable mixtures thereof that are physiologically compatible. Suitable exemplary solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzylbenzoate, cyclodextrins, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Suitable exemplary suspending agents include surfactants such as stearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, coconut oil, olive oil, sesame oil, peanut oil, soya and the like; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like. Suitable exemplary isotonic agent includes sodium chloride, glycerin, D-mannose, and the like. Suitable exemplary buffer agents include buffer solutions of salts, such as phosphate, acetates, carbonates, and citrates. Suitable exemplary soothing agents include benzyl alcohol, and the like. Suitable exemplary antiseptic substances include para-oxybenzoic acid esters, benzethonium chloride, benzalkonium chloride,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Suitable exemplary antioxidants include sulfite salts, ascorbic acid, and the like. Suitable exemplary sealers include, but are not limited to HPMC (or hypromellose), HPC, PEG and combinations thereof. Suitable exemplary lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, hardened oil and the like.

[0053] In further exemplary embodiments for solid preparations, carriers or excipients include diluents, lubricants, binders, and disintegrants. In exemplary embodiments for liquid preparations, carriers include solvents, solubilizing agents, suspending agents, isotonic agents, buffer agents, soothing agents, and the like. Acceptable additional carriers or diluents for therapeutic use and the general procedures for the preparation of pharmaceutical compositions are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety.

[0054] The compound of Formula I may also be in a pharmaceutically acceptable salt form. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt, wherein the counterion includes, for example, chloride, bromide, iodide, - O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0055] A related aspect provides a kit, which includes a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and an instruction for treating or preventing certain diseases or conditions. In some embodiments, the kit further includes other therapeutic agent.Method of Treating Diseases

[0056] Another aspect of the patent specification provides for methods for treating a disease or condition mediated by PDE4. The method includes administering to a subject in need thereof the compound of formula I, a geometrical isomer thereof, a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition disclosed herein.

[0057] In some embodiments, the disease treatable with the methods disclosed herein is an inflammatory and autoimmune disease. Examples include COPD, rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis.

[0058] In some embodiments, the disease treatable with the methods disclosed herein is a neurodegenerative disease selected from for example Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, traumatic brain injury, prion diseases, Huntington’s disease, Parkinson’s disease,chronic traumatic encephalopathy, amyotrophic lateral sclerosis, mixed dementias, vascular dementia, hydrocephalus, and amyotrophic lateral sclerosis.

[0059] Also disclosed in this patent document is the use of a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to treat a disease or condition. This patent document further provides a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition. The disease or condition, the means of administration, the dosage form and formulation, and the additional agents are the same as in the methods described herein.Administration Regimen

[0060] The compound of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutically composition thereof for the methods or kit described herein described herein may be administered to the subject by any suitable means. Non-limiting examples of methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through nonoral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrastemally, or the like, including infusion pump delivery; as well as (d) administration topically; as deemed appropriate by those of skill in the art for bringing the active compound into contact with living tissue.

[0061] Advantageously, the compound of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutically composition thereof for administrations described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0062] In exemplary embodiments of the pharmaceutical composition of the compound of Formula I, or a pharmaceutically acceptable salt thereof for oral administration, the composition can be a tablet, coated tablet, capsule, caplet, cachet, lozenges, gel capsule, hard gelatin capsule, soft gelatin capsule, troche, dragee, dispersion, powder, granule, pill, liquid, an aqueous or non-aqueous liquid suspension, an oil-in-liquid or oil-in-water emulsion, including sustained release formulations that are known in the art. For pediatric and geriatric applications, suspensions, syrups and chewable tablets are especially suitable.

[0063] The therapeutically effective amount (dosage) of the compound of Formula I, or a pharmaceutically acceptable salt thereof required will depend on the route of administration, the species (human or animal), and the physical characteristics of the particular subject or patient being treated. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the patient or animal being treated. Determination of atherapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0064] In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved or adverse side effects disappear. The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Typically, dosages may be about 10 pg / kg to about 100 mg / kg body weight, preferably about 100 pg / g to about 10 mg / kg body weight. Alternatively, dosages may be based and calculated upon the surface area of the animal, as understood by those of skill in the art.

[0065] The exact formulation, route of administration and dosage for the pharmaceutical compositions can be chosen by the individual physician in view of the patient’s condition, (see e.g., Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics”, which is hereby incorporated herein by reference in its entirety, with particular reference to Ch. 1, p. 1). In some embodiments, the dose range of the compound of Formula I or a pharmaceutically acceptable salt thereof administered to the subject or patient can be from about 0.5 to about 1000 mg / kg of their body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. In instances where human dosages for compounds have been established for at least some conditions, those same dosages, or dosages that are about 0.1% to about 500%, more preferably about 25% to about 250% of the established human dosage may be used.

[0066] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to side-effects, toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response was not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may also be used in veterinary medicine.

[0067] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, a peroral dose of about 0.01 mg to 2000 mg of the active ingredient, preferably from about 0.01 mg to about 500 mg. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of the active ingredient of about 0.01 mg to about 100 mg, preferably about 0.01 mg to about 60 mg is used. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the freebase. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively, a compound of Formula I or a pharmaceutically acceptable salt thereof may be administered by continuous intravenous infusion, preferably at a dose of up to about 1000 mg per day. As will be understood by those of skill in the art, in certain situations it may be necessary to administer a compound of Formula I or a pharmaceutically acceptable salt thereof disclosed herein in amounts that exceed, or even far exceed, theabove-stated, preferred dosage range in order to effectively and aggressively treat particularly intractable diseases or conditions. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0068] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof is formulated into a dosage form for release for a period of 1 to 12, typically 3 to 12 hours, more typically 6-12 hours after administration. In some embodiments, the oral pharmaceutical compositions described herein may be administered in single or divided doses, from one to four times a day. The oral dosage forms may be conveniently presented in unit dosage forms and prepared by any methods well known to those skilled in the art of pharmacy.

[0069] A compound of Formula I or a pharmaceutically acceptable salt thereof can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of the compound may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity may be determined in an animal model (such as mice, rats, rabbits, or monkeys) using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every class of condition. Similarly, acceptable animal models may be used to establish the efficacy of chemicals to treat such conditions. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, and route of administration, and dosing regime. Of course, human clinical trials can also be used to determine the efficacy of a compound of Formula I or a pharmaceutically acceptable salt thereof in humans.

[0070] A compound of Formula I or a pharmaceutically acceptable salt thereof may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0071] The following non-limiting examples serve to further illustrate the embodiments of the present disclosure.

[0072] Examples

[0073] Example 1: compound synthesis

[0074] Compounds disclosed herein can be prepared via chemistry known in the organic synthesis.The scheme below illustrates a synthesis route to a compound under Formula I. Isomers can be separated via procedures including chromatography column, recrystallization and other methods known in the field of organic synthesis.Synthesis of INTIINT1To a stirred solution of [l-({2-chloro-6H,7H-thieno[3,2-d]pyrimidin-4-yl}amino)cyclobutyl]methanol (6.00 g, 22.078 mmol, 1 equiv) in DCM (120 mL) was added m-CPBA (3.81 g, 22.078 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction was quenched with water (300 mL) at 0 °C and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford 2-chloro-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (5.00 g, 78.70% yield) as a white solid.LCMS-INT1 :(ES,m / z):288[M+l]+Synthetic Route to 05-1-0A and 05-1-0B1a 1b 1c-1 "lc-2To a stirred solution of tert-butyl 3-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) methylidene] pyrrolidine- 1 -carboxylate (500 mg, 1.617 mmol, 1 equiv) in Dioxane (5 mL) and Water (1 mL) was added bromochlorobenzene (la, 464 mg, 2.425 mmol, 1.5 equiv), Pd(dtbpf)C12(105 mg, 0.162 mmol, 0.1 equiv) and K3PO4 (686 mg, 3.234 mmol, 2 equiv) at 25°C and stirred at 60°C for 2 h. And then the reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:4) to afford tert-butyl 3-(4- chlorobenzylidene)pyrrolidine-l -carboxylate (lb, 460 mg) as a yellow solid. The Z / E mixture compound, tert-butyl 3-(4-chlorobenzylidene) pyrrolidine- 1 -carboxylate (460 mg) was separated by chiral HPLC separation under the condition (Column: CHIRALPAK IK 3*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 40 mL / min; gradient ; Wave Length: 215 / 257 nm; RTl(min): 10.112; RT2(min): 1.998; Sample Solvent: EtOH--HPLC; Injection Volume: 1.5 mL) to afford tert-butyl (3E)-3-[(4-chlorophenyl)methylidene]pyrrolidine-l-carboxylate (200 mg, 42.10%yield, 95%purity) as a white solid and tert-butyl (3Z)-3-[(4-chlorophenyl)methylidene]pyrrolidine- 1 -carboxylate (200 mg, 42.10% yield, 95% purity) as a white solid.Compound lc-1LCMS:(ES,m / z): 278.95[M-56+41]+ 1H_NMR-PH-PTRG-MC-2024-05-l-l:(400 MHz, Chloroform-d) 8 7.34 - 7.26 (m, 2H), 7.23 - 7.15 (m, 2H), 6.37 (p, J= 2.2 Hz, 1H), 4.13 (q, J= 1.7 Hz, 2H), 3.55 (t, J= 7.3 Hz, 2H), 2.84 - 2.75 (m, 2H), 1.48 (s, 9H).NOESY :(400 MHz, Chloroform-d): the proton at 6.39 ppm has correlation with the proton at 4.14 ppm.Compound lc-2LCMS:(ES,m / z): 278.90[M-56+41]+1H_NMR: (400 MHz, Chloroform-d) 87.34 - 7.24 (m, 2H), 7.15 - 7.07 (m, 2H), 6.35 (p, J= 2.3 Hz, 1H), 4.18 (s, 2H), 3.45 (t, J= 7.3 Hz, 2H), 2.80 - 2.70 (m, 2H), 1.48 (s, 9H).NOESY :(400 MHz, Chloroform-d): the proton at 6.35 ppm has correlation with the proton at 2.75 ppm.Synthesis of IdTo a stirred solution of tert-butyl (3E)-3-[(4-chlorophenyl) methylidene] pyrrolidine- 1 -carboxylate (200 mg, 0.681 mmol, 1 equiv) in DCM (2 mL) was added TFA (0.4 mL) at 25°C and stirred for 2 h. And then the reaction was concentrated under reduced pressure to afford (3E)-3-[(4-chlorophenyl) methylidene] pyrrolidine (200 mg crude) as a yellow oil. The crude product was used in the next step directly without further purification.LCMS-ld:(ES,m / z): 193.90[M+l]+Synthesis of leTo a stirred solution of (3E)-3-[(4-chlorophenyl) methylidene] pyrrolidine (200 mg crude TFA salt, 0.68 mmol, 1 equiv) in DMF (2.4 mL) was added 2-chloro-4-([l-(hydroxymethyl)cyclobutyl]amino-6H,7H- 51ambda4-thieno[3,2-d]pyrimidin-5-one (142 mg, 0.496 mmol, 0.8 equiv) and K2CO3 (256 mg, 1.860 mmol, 3 equiv) at 25°C and stirred at 80°C for 2 h. And then the reaction mixture was precipitated by the addition of water (5 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 5mL). The residue was purified by trituration with DMF (0.4 mL), MeOH (1.2 mL), MTBE (0.4 mL) and DCM (0.4 mL). The precipitated solids were collected by filtration and washed with MeOH (2 x 5 mL) to afford 2-[(3E)-3-[(4-chlorophenyl) methylidene] pyrrolidin-l-yl] -4-([l-(hydroxymethyl) cyclobutyl] amino-6H,7H-51ambda4-thieno[3,2-d] pyrimidin-5-one (63.4 mg, 22.99% yield, 98.45% purity) as a white solid.LCMS-le:(ES,m / z): 445.10[M+l]+1H NMR-le: (400 MHz, DMSO-d«) 8 7.53 - 7.19 (m, 5H), 6.55 (s, 1H), 4.82 (t, J= 5.6 Hz, 1H), 4.30 (s,2H), 3.78 - 3.67 (m, 4H), 3.43 (dt, J= 16.4, 7.8 Hz, 1H), 3.29 - 3.17 (m, 1H), 3.02 - 2.80 (m, 4H), 2.45 - 2.33 (m, 2H), 2.29 - 2.10 (m, 2H), 1.94 - 1.64 (m, 2H).Synthesis of O5-1-OA / O5-1-0BThe racemic compound 2-[(3E)-3-[(4-chlorophenyl)methylidene]pyrrolidin-l-yl]-4-([l-(hydroxymethyl) cyclobutyl]amino-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (60 mg, 0.135 mmol, 1 equiv) was separated into constituent enantiomers by chiral HPLC separation under the condition (Column: Cellulose SZ; Mobile Phase A: HEX(0.1%DEA): EtOH=50: 50; Flow rate: 1.67ml / min mL / min; Gradient (B%): isocratic ; Injection Volume: 2 mL) to afford assumed (5S)-2-[(3E)-3-[(4- chlorophenyl)methylidene]pyrrolidin-l-yl]-4-([l-(hydroxymethyl)cyclobutyl]amino-6H,7H-51ambda4- thieno[3,2-d]pyrimidin-5-one (19.9 mg, 33.17%yield, 98.8%purity) as a white solid and assumed (5R)-2- [(3E)-3-[(4-chlorophenyl)methylidene]pyrrolidin-l-yl]-4-([l-(hydroxymethyl)cyclobutyl]amino-6H,7H- 51ambda4-thieno[3,2-d]pyrimidin-5-one (19.3 mg, 32.17%yield, 98.7%purity) as a white solid.LCMS-05-l-0A:(ES,m / z): 445.10[M+l]+'H NMR-PH-PTRG-MC-2024-05-1-0A: (400 MHz, DMSO-dtf) 8 7.46 - 7.40 (m, 2H), 7.37 (d, J= 8.4 Hz, 2H), 7.32 (s, 1H), 6.56 (s, 1H), 4.85 (t, J= 5.6 Hz, 1H), 4.30 (s, 2H), 3.78 - 3.68 (m, 4H), 3.43 (dt, J = 16.3, 7.8 Hz, 1H), 3.22 (dt, J= 13.5, 8.3 Hz, 1H), 3.00 - 2.82 (m, 4H), 2.38 (dd, J= 21.8, 11.6 Hz, 2H), 2.18 (s, 2H), 1.79 (s, 2H).Chiral HPLC-05-1-0A: Column: CHIRALPAK IM-3 0.46*5cm.3u; Mobile Phase: Hex(0.1%DEA):EtOH=50:50; Flow rate: 1.67ml / min; Temperature :35°C; RT [min]: 1.269.LCMS-05-l-0B:(ES,m / z): 445.10[M+l]+'H NMR-05-1-0B: (400 MHz, DMSO-d«) 6 7.46 - 7.40 (m, 2H), 7.37 (d, J= 8.5 Hz, 2H), 7.32 (s, 1H), 6.56 (s, 1H), 4.85 (t, J= 5.5 Hz, 1H), 4.30 (s, 2H), 3.78 - 3.68 (m, 4H), 3.43 (dt, J= 16.3, 7.9 Hz, 1H), 3.22 (dt, J= 13.5, 8.4 Hz, 1H), 2.92 (td, J= 18.4, 17.8, 11.5 Hz, 4H), 2.44 - 2.34 (m, 2H), 2.18 (s, 2H), 1.79 (s, 2H).Chiral HPLC-05-1-0B: Column: CHIRALPAK IM-3 0.46*5cm.3u; Mobile Phase: Hex(0.1%DEA):EtOH=50:50; Flow rate: 1.67ml / min; Temperature :35°C; RT [min]: 2.195.Synthesis of 05-2-0A / 05-2-GB05-2-0A and 05-2-0B were obtained in a similar manner from lc-2The racemic compound 2-[(3Z)-3-[(4-chlorophenyl)methylidene]pyrrolidin-l-yl]-4-{[l-(hydroxymethyl) cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (2e, 58 mg, 0.130 mmol, 1 equiv) was separated into constituent enantiomers by chiral HPLC separation under the condition (Column: Cellulose SZ; Mobile Phase A: HEX(0.1%DEA): EtOH=50: 50; Flow rate: 1.67ml / min mL / min; Gradient (B%): isocratic ; Injection Volume: 2 mL) to afford assumed (5S)-2-[(3Z)-3-[(4- chlorophenyl)methylidene]pyrrolidin-l-yl]-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4- thieno[3,2-d]pyrimidin-5-one (19.4 mg, 33.45%yield, 98.5%purity) as a white solid and assumed (5R)-2- [(3Z)-3-[(4-chlorophenyl)methylidene]pyrrolidin-l-yl]-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H- 51ambda4-thieno[3,2-d]pyrimidin-5-one (18.3 mg, 31.55%yield, 99.2%purity) as a white solid.LCMS-05-2-0A:(ES,m / z): 445.10[M+l]+‘H NMR-05-2-0A: (400 MHz, DMSO-<76) 6 7.50 - 7.40 (m, 2H), 7.33 - 7.19 (m, 3H), 6.52 (d, J = 3.0 Hz, 1H), 4.87 -4.83 (m, 1H), 4.34 (s, 2H), 3.75 (s, 2H), 3.61 (s, 2H), 3.48 - 3.39 (m, 1H), 3.20 (t, J= 10.7 Hz, 1H), 3.00- 2.91 (m, 1H), 2.91 - 2.81 (m, 3H), 2.43 - 2.33 (m, 2H), 2.16 (s, 2H), 1.95 - 1.61 (m, 2H).Chiral HPLC-PH-05-2-0A: Column: Lux 3u Cellulose-2 0.46*5cm.3u; Mobile Phase: Hex(0.1%DEA):EtOH=50:50; Flow rate: 1.67ml / min; Temperature :35°C; RT [min]: 1.055.LCMS-05-2-0B:(ES,m / z): 445.15[M+1]+1H NMR-05-2-0B: (400 MHz, DMSO-dtf) 6 7.45 (t, J= 11.5 Hz, 2H), 7.32 - 7.26 (m, 2H), 6.52 (s, 1H), 4.85 (s, 1H), 4.34 (s, 2H), 3.75 (s, 2H), 3.61 (s, 2H), 3.48 - 3.39 (m, 1H), 3.22 (q, J= 9.9 Hz, 1H), 2.97 (s, 1H), 2.86 (td, J= 1. , 4.2 Hz, 3H), 2.43 - 2.33 (m, 1H), 2.18 - 2.14 (m, 2H), 1.85 - 1.80 (m, 2H).Chiral HPLC-05-2-0B: Column: CHIRALPAK IM-3 0.46*5cm.3u; Mobile Phase: Hex(0.1%DEA):EtOH=50:50; Flow rate: 1.67ml / min; Temperature :35°C; RT [min]: 1.814.Synthesis of O5-3-OA / O5-3-0B5- -O5-3-0A / O5-3-OB were obtained from 3e which was prepared similarly starting from 3aThe racemic compound 2-[(3E)-3- [(5-chloropyrimidin-2-yl) methylidene] pyrrolidin-l-yl] -4-{[l- (hydroxymethyl) cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (compound 3e, 63 mg, 0.141 mmol, 1 equiv) was separated by chiral HPLC separation under the condition (Column: Cellulose SZ; Mobile Phase A: HEX(0.1%DEA): EtOH=50: 50; Flow rate: 1.67ml / min mL / min; Gradient (B%): isocratic ; Injection Volume: 2 mL) to afford assumed (5S)-2-[(3E)-3-[(5-chloropyrimidin-2- yl)methylidene]pyrrolidin-l-yl]-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2- d]pyrimidin-5-one (21.3 mg, 33.81%yield, 99.0%purity) as a white solid and assumed (5R)-2-[(3E)-3-[(5- chloropyrimidin-2-yl)methylidene]pyrrolidin- 1 -yl] -4- { [ 1 -(hy droxymethyl)cyclobutyl] amino } -6H,7H- 51ambda4-thieno[3,2-d]pyrimidin-5-one (27.1 mg, 43.02%yield, 97.7%purity) as a white solid.LCMS-05-3-0A:(ES,m / z): 447.10[M+l]+’H NMR-05-3-0A: (400 MHz, DMSO-dtf) 6 8.91 (s, 2H), 7.33 (s, 1H), 6.65 (t, J= 2.3 Hz, 1H), 4.85 (s, 1H), 4.41 (s, 2H), 3.85 - 3.65 (m, 4H), 3.50 - 3.37 (m, 1H), 3.35 -3.18 (m, 3H), 3.02 -2.79 (m, 2H), 2.38 (dd, J= 21.6, 11.5 Hz, 2H), 2.21 - 2.17 (m, 2H), 1.83 - 1.72 (m, 2H).Chiral HPLC-05-3-0A: Column: Lux 3u Cellulose-2 0.46*5cm.3u; Mobile Phase: Hex(0.1%DEA):EtOH_50:50; Flow rate: 1.67ml / min; Temperature :35°C; RT [min]: 1.280.LCMS-O5-3-OB:(ES,m / z): 447.10[M+l]+'HNMR-O5-3-0B: (400 MHz, DMSO-d«) 5 8.91 (s, 2H), 7.33 (s, 1H), 6.65 (t, J= 2.3 Hz, 1H), 4.85 (s,1H), 4.41 (s, 2H), 3.75 (s, 4H), 3.50 - 3.37 (m, 1H), 3.36 - 3.17 (m, 3H), 3.01 - 2.82 (m, 2H), 2.47 - 2.31 (m, 2H), 2.19 (s, 2H), 1.78 (d, J= 26.5 Hz, 2H).Chiral HPLC-05-3-0B: Column: Lux 3u Cellulose-2 0.46*5cm.3u; Mobile Phase: Hex(0.1%DEA):EtOH=50:50; Flow rate: 1.67ml / min; Temperature :35°C; RT [min]: 1.918.Synthesis of O5-4-OA / O5-4-0B05-4-0A 05-4-0BO5-4-0A / O5-4-OB were prepared accordingly.4e 05-4-0A 05-4-0BThe racemic compound 2-[(3Z)-3-[(5-chloropyrimidin-2-yl)methylidene]pyrrolidin-l-yl]-4-{[l- (hydroxymethyl) cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (4e, 63 mg, 0.141 mmol, 1 equiv) was separated into constituent enantiomers by chiral HPLC separation under the condition (Column: Cellulose SZ; Mobile Phase A: HEX(0.1%DEA): EtOH=50: 50; Flow rate: 1.67ml / min mL / min; Gradient (B%): isocratic; Injection Volume: 3.000 mL) to afford assumed ((5S)-2-[(3Z)-3-[(5- chloropyrimidin-2-yl)methylidene] pyrrolidin-l-yl]-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H- 51ambda4-thieno[3,2-d]pyrimidin-5-one (25.3 mg, 40.16%yield, 99.3%purity) as a white solid and assumed (5R)-2-[(3Z)-3-[(5-chloropyrimidin-2-yl) methylidene]pyrrolidin-l-yl]-4-{[l- (hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (19.5 mg, 30.95%yield, 99.4%purity) as a white solid.LCMS-05-4-0A:(ES,m / z): 447.10[M+l]+'HNMR-05-4-0A: (400 MHz, DMSO-d6) 3 8.95 (s, 1H), 8.84 (s, 1H), 7.25 (d, J= 43.5 Hz, 1H), 6.60 (t, J = 2.3 Hz, 1H), 4.85 (t, J= 5.6 Hz, 1H), 4.75 - 4.53 (m, 2H), 3.86 - 3.72 (m, 2H), 3.68 (t, J= 7.5 Hz, 2H), 3.55 - 3.37 (m, 1H), 3.29 - 3.18 (m, 1H), 3.00 (t, J= 7.6 Hz, 3H), 2.92 - 2.82 (m, 1H), 2.44 -2.33 (m, 2H), 2.27 -2.12 (m, 2H), 2.02 - 1.67 (m, 2H).Chiral HPLC-05-4-0A: Column: CHIRALPAK IM-3 0.46*5cm.3u; Mobile Phase: MtBE(0.1%DEA):MeOH=70:30; Flow rate: 1.67ml / min; Temperature :35°C; RT [min]: 1.100.LCMS-05-4-0B :(ES,m / z): 447.15 [M+l ]+'H NMR (400 MHz, DMSO-d«) 8 8.95 (s, 1H), 8.84 (s, 1H), 7.25 (d, J= 43.4 Hz, 1H), 6.60 (q, J= 2.3 Hz, 1H), 4.85 (t, J= 5.6 Hz, 1H), 4.66 (d, J = 10.6 Hz, 2H), 3.84 - 3.72 (m, 2H), 3.71 - 3.64 (m, 2H), 3.55 - 3.36 (m, 1H), 3.29 - 3.18 (m, 1H), 3.06 - 2.95 (m, 3H), 2.92 - 2.82 (m, 1H), 2.45 - 2.35 (m, 2H), 2.22 - 2.17 (m, 2H), 2.03 - 1.70 (m, 2H).Chiral HPLC-05-4-0B: Column: CHIRALPAK IM-3 0.46*5cm.3u; Mobile Phase:MtBE(0.1%DEA):MeQH=70:30; Flow rate: 1.67ml / min; Temperature :35°C; RT [min]: 1.549.Synthesis of 05-5-0A / 05-5-0B,A solution of 2-chloro-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2- d]pyrimidin-5-one (2.78 g, 9.702 mmol, 1 equiv), tert-butyl 3-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)methylidene]pyrrolidine-l -carboxylate (3.00 g, 9.702 mmol, 1 equiv), K3PO4(6.18 g, 29.106 mmol, 3 equiv) and Pd(dppf)Ch CH2CI2 (0.79 g, 0.970 mmol, 0.1 equiv) in dioxane (30 mL) and H2O (6 mL) was stirred at 100 °C for 1 h under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water (200 L) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford tert-butyl 3-[(4-{[l-(hydroxymethyl)cyclobutyl]amino}-5-oxo-6H,7H-51ambda4- thieno[3,2-d]pyrimidin-2-yl)methylidene]pyrrolidine-l-carboxylate (5a, 3.20 g, 75.90% yield) as a white solid.LCMS-5a:(ES,m / z):435[M+l]+Synthesis of 5a-l and 5a-2Tert-butyl 3-[(4-{[l-(hydroxymethyl)cyclobutyl]amino}-5-oxo-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-2-yl)methylidene]pyrrolidine-l -carboxylate (3.20 g) was purified by Prep-Achiral HPLC with thefollowing conditions (Column: NB-Viridis Silica, 4.6*100mm, 5um; Mobile Phase A: CO2, Mobile Phase B: IPA(20mM NH3.IPA); Flow rate: 100 mL / min; Gradient (B%): isocratic 30% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 / 254 nm; RTl(min): 2.73; RT2(min): 3.16; Sample Solvent: MEOH: DCM=1: 1; Injection Volume: 0.8 mL; Number Of Runs: 11) to afford tertbutyl (3E)-3-[(4-{[l-(hydroxymethyl)cyclobutyl]amino}-5-oxo-6H,7H-51ambda4-thieno[3,2-d]pyrimidin- 2-yl)methylidene]pyrrolidine-l -carboxylate (1.2 g, 37.50% yield) as a white solid and tert-butyl (3Z)-3-[(4- {[l-(hydroxymethyl)cyclobutyl]amino}-5-oxo-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-2- yl)methylidene]pyrrolidine-l -carboxylate (1.1 g, 34.38% yield) as a white solid.’H NMR- 5a-l: 'H NMR (400 MHz, DMSO-cfc) 5 7.61 (s, 1H), 6.35 - 6.23 (m, 1H), 4.83 (t, J= 5.6 Hz, 1H), 4.30 (d, J= 4.2 Hz, 1H), 4.12 (s, 2H), 3.82 - 3.70 (m, 3H), 3.60 - 3.43 (m, 3H), 3.39 - 3.29 (m, 1H), 3.17 - 3.04 (m, 2H), 3.02 - 2.91 (m, 1H), 2.40 - 2.29 (m, 1H), 2.29 - 2.19 (m, 2H), 1.87 - 1.69 (m, 2H), 1.42 (s, 9H).NOESY- 5a-l (400 MHz, DMSO-cfc): the proton at 6.31 ppm has correlation with the proton at 4.12 ppm.‘H NMR- 5a-2: 'H NMR (400 MHz, DMSO-<76) 5 7.61 (s, 1H), 6.29 (s, 1H), 4.78 (t, J= 5.7 Hz, 1H), 4.30 (d, J= 4.2 Hz, 1H), 3.82-3.70 (m, 3H), 3.62 -3.46 (m, 1H), 3.44 - 3.30 (m, 3H), 3.18 - 2.91 (m, 2H), 2.41 - 2.21 (m, 5H), 1.91 - 1.67 (m, 2H), 1.43 (s, 9H).NOESY- 5a-2 (400 MHz, DMSO- e): the proton at 6.30 ppm has correlation with the proton at 2.81 ppm.Synthesis of Sb5A solution of tert-butyl (3E)-3-[(4-{[l-(hydroxymethyl)cyclobutyl]amino}-5-oxo-6H,7H-51ambda4- thieno[3,2-d]pyrimidin-2-yl)methylidene]pyrrolidine-l-carboxylate (150 mg, 0.345 mmol, 1 equiv) in DCM (1.5 mL) and TFA (1.5 mL) was stirred at 25 °C for 1 h. The resulting mixture was concentrated under vacuum to afford 4-{[l-(hydroxymethyl)cyclobutyl]amino}-2-[(3E)-pyrrolidin-3-ylidenemethyl]- 6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (5b, 150 mg crude) as a crude yellow oil. The crude product was used in the next step directly without further purification.LCMS-5b:(ES,m / z):335[M+l]+Synthesis of 5c5b 5cA solution of 4-{[l-(hydroxymethyl)cyclobutyl]amino]-2-[(3E)-pyrrolidin-3-ylidenemethyl]-6H,7H- 51ambda4-thieno[3,2-d]pyrimidin-5-one (150 mg crude TFA salt, 0.345 mmol, 1 equiv), 2,5- dichloropyrimidine (66 mg, 0.449 mmol, 1.3 equiv) and K2CO3 (123 mg, 0.898 mmol, 2.5 equiv) in DMF (5 mL) was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was purified by trituration with H2O (50 mL) and MeOH (30 mL) to afford 2-{[(3E)-l-(5-chloropyrimidin-2- yl)pyrrolidin-3-ylidene]methyl }-4- { [ 1 -(hydroxymethyl)cyclobutyl]amino } -6H,7H-51ambda4-thieno[3 ,2- d]pyrimidin-5-one (5c, 56.0 mg, 27.94% yield, 97.4%purity) as a white solid.LCMS-5c:(ES,m / z):447[M+l]+Synthesis of 05-5-0A / 05-5-0B2-{[(3E)-l-(5-chloropyrimidin-2-yl)pyrrolidin-3-ylidene]methyl}-4-{[l- (hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (56.0 mg) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IM 3*25 cm, 5 pm; Mobile Phase A: Hex(10mMNH3)-HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 40 mL / min; Gradient (B%): isocratic 50% B; Wave Length: 259 / 202 nm; RTl(min): 13.598; RT2(min): 17.811; Sample Solvent: FA DCM EtOH-HPLC; Injection Volume: 0.45 mL; Number Of Runs: 5) to afford assumed (5S)-2-{ [(3E)- 1 -(5 -chloropyrimidin-2-y l)pyrrolidin-3 -ylidene]methyl } -4- { [ 1 -(hydroxymethy l)cyclobuty 1] amino } - 6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (22.8 mg, 42.86% yield, 98.0% purity) as a white solid and assumed (5R)-2-{[(3E)-l-(5-chloropyrimidin-2-yl)pyrrolidin-3-ylidene]methyl}-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (15.7 mg, 29.51% yield, 99.1% purity) as a white solid.LCMS-05-5-0A:(ES,m / z):447[M+l]+HNMR-05-5-0A: ‘H NMR (400 MHz, DMSO-<4) 3 8.46 (s, 2H), 7.71 (s, 1H), 6.40 (p, J = 2.3 Hz, 1H), 4.88 (t, J= 5.6 Hz, 1H), 4.37 (d, J = 2.2 Hz, 2H), 3.74 (t, J= 7.3 Hz, 4H), 3.55 (dt, J= 17.2, 7.7 Hz, 1H), 3.40 - 3.27 (m, 2H), 3.12 (ddd, J= 17.1, 8.2, 2.3 Hz, 1H), 2.98 (ddd, J= 13.5, 7.5, 2.3 Hz, 1H), 2.41 -2.19 (m,5H), 1.86 - 1.70 (m, 2H).ChiralHPLC- 05-5-0A: Column: CHIRALPAK IM-3; Column Size: 4.6*50mm,3um; Mobile Phase: Hex(0.1%DEA):EtOH=70:30; Flow: 1.67 mL / min; Temperature: Ambient; RT=2.199 minLCMS-05-5-0B:(ES,m / z):447[M+l]+HNMR-05-5-0B: ’H NMR (400 MHz, DMSO-A) 88.46 (s, 2H), 7.71 (s, 1H), 6.40 (t, J= 2.3 Hz, 1H), 4.88 (t, J= 5.6 Hz, 1H), 4.37 (d, J= 2.1 Hz, 2H), 3.74 (t, J= 7.3 Hz, 4H), 3.55 (dt, J= 17.2, 7.7 Hz, 1H), 3.40 - 3.27 (m, 2H), 3.12 (ddd, J= 17.2, 8.2, 2.3 Hz, 1H), 2.98 (ddd, J= 13.5, 7.5, 2.3 Hz, 1H), 2.35-2.25 (m, 5H), 1.87 - 1.70 (m, 2H).ChiralHPLC-05-5-0B: Column: CHIRALPAK IM-3; Column Size: 4.6*50mm,3um; Mobile Phase: Hex(0.1%DEA):EtOH=70:30; Flow: 1.67 mL / min; Temperature: Ambient; RT=2.973 minSynthesis of 05-6-0A / 05-6-0B2-{[(3Z)-l-(5-chloropyrimidin-2-yl)pyrrolidin-3-ylidene]methyl}-4-{[l- (hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (compound 6c, prepared from 5a-2, 93.60 mg) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IM 3*25 cm, 5 pm; Mobile Phase A: Hex(10mMNH3)-HPLC, Mobile Phase B: EtOH-- HPLC; Flow rate: 40 mL / min; Gradient (B%): isocratic 50% B; Wave Length: 259 / 202 nm; RTl(min): 13.598; RT2(min): 17.811; Sample Solvent: FA DCM EtOH-HPLC; Injection Volume: 0.45 mL; Number Of Runs: 5) to afford assumed (5S)-2-{[(3Z)-l-(5-chloropyrimidin-2-yl)pyrrolidin-3-ylidene]methyl}-4- {[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5-one (24.8 mg, 26.50% yield, 99.8% purity) as a white solid and assumed (5R)-2-{[(3Z)-l-(5-chloropyrimidin-2- yl)pyrrolidin-3-ylidene]methyl}-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2- d]pyrimidin-5-one (39.9 mg, 42.63% yield, 98.5% purity) as a white solid.LCMS-05-6-0A:(ES,m / z):447[M+l]+HNMR-05-6-0A: *H NMR (400 MHz, DMSO-6) 8 8.45 (s, 2H), 7.72 (s, 1H), 6.36 (q, J= 2.3 Hz, 1H), 4.80 (t, J= 5.6 Hz, 1H), 4.65 (s, 2H), 3.85 (d, J= 5.7 Hz, 2H), 3.65 (t, J= TA Hz, 2H), 3.57 (dt, J= 17.2, 7.7 Hz, 1H), 3.41 - 3.26 (m, 1H), 3.12 (ddd, J= 17.2, 8.1, 2.3 Hz, 1H), 3.04 - 2.93 (m, 3H), 2.43 - 2.34 (m, 2H), 2.33 - 2.20 (m, 2H), 1.89 - 1.76 (m, 2H).ChiralHPLC-05-6-0A: Column: CH1RALPAK IM-3; Column Size: 4.6*50mm,3um; Mobile Phase:Hex(0.1%DEA):EtOH=50:50; Flow: 1.67 mL / min; Temperature: Ambient; RT=1.499 minLCMS-05-6-0B:(ES,m / z):447[M+l]+HNMR-05-6-0B: ‘II NMR (400 MHz, DMSO- d6) 8 8.45 (s, 2H), 7.72 (s, 1H), 6.36 (q, J= 2.3 Hz, 1H), 4.81 (t, J= 5.4 Hz, 1H), 4.65 (s, 2H), 3.85 (d, J= 4.8 Hz, 2H), 3.65 (t, J= 1A Hz, 2H), 3.57 (dt, J= 17.1, 7.7 Hz, 1H), 3.40 - 3.28 (m, 1H), 3.12 (ddd, J- 17.2, 8.2, 2.3 Hz, 1H), 2.99-2.96 (m, 3H), 2.47 - 2.34 (m, 2H), 2.31-2.25 (m, 2H), 1.92 - 1.76 (m, 2H).ChiralHPLC-05-6-0B: Column: CHIRALPAK IM-3; Column Size: 4.6*50mm,3um; Mobile Phase: Hex(0.1%DEA):EtOH=50:50; Flow: 1.67 mL / min; Temperature: Ambient; RT=1.984 minCompounds 05-7-0A / 05-7-0B2-{[l-(4-chlorophenyl)pyrrolidin-3-ylidene]methyl}-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H- 51ambda4-thieno[3,2-d]pyrimidin-5-one (160 mg) was purified by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK ID, 3*25 cm, 5 pm; Mobile Phase A: MTBE(10mMNH3)— HPLC, Mobile Phase B: MeOH--HPLC; Flow rate: 40 mL / min; Gradient (B%): isocratic 10% B; Wave Length: 254 / 220 nm; RTl(min): 8.8; RT2(min): 12.73; Sample Solvent: FA HFIP MeOH DCM-HPLC; Injection Volume: 0.8 mL; Number Of Runs: 10) to afford assumed (5S)-2-{[(3E)-l-(4-chlorophenyl)pyrrolidin-3- ylidene]methyl}-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5- one (19.4 mg, 12.76% yield, 96.1% purity) as a white solid and assumed (5R)-2-{[(3E)-l-(4- chlorophenyl)pyrrolidin-3-ylidene]methyl}-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4- thieno[3,2-d]pyrimidin-5-one (19.2 mg, 12.63% yield, 98.2% purity) as a white solid.LCMS-05-7-0A:(ESI, m / z):445[M+l]+HNMR-05-7-0A:1HNMR (400 MHz, DMSO-6) 8 7.72 (s, 1H), 7.27 - 7.19 (m, 2H), 6.71 - 6.62 (m, 2H), 6.38 (t, J= 2.3 Hz, 1H), 4.90 (t, J= 5.6 Hz, 1H), 4.12 (d, J= 2.2 Hz, 2H), 3.76 (d, J= 5.6 Hz, 2H), 3.62 - 3.49 (m, 1H), 3.45 (t, J= 7.1 Hz, 2H), 3.39-3.23(m, 3H), 3.18 - 3.06 (m, 1H), 2.99-2.95 (m, 1H), 2.42 - 2.20 (m, 4H), 1.86 - 1.70 (m, 2H).NOESY- 05-7-0A (400 MHz, DMSO- s): the proton at 6.38 ppm has correlation with the proton at 4.12 ppm.ChiralHPLC-05-7-0A: Column: CHIRALPAK ID-3; Column Size: 4.6*50mm,3um; Mobile Phase:MtBE(0.1%DEA):MeOH=90:10; Flow: 1.67 mL / min; Temperature: Ambient; RT=1.445 minLCMS-05-7-0B:(ESI, m / z):445[M+l]+HNMR-05-7-0B: ‘HNMR (400 MHz, DMSO-ofc) 8 7.72 (s, 1H), 7.27 - 7.19 (m, 2H), 6.71 - 6.62 (m, 2H), 6.38 (t, J= 2.3 Hz, 1H), 4.90 (t, J= 5.6 Hz, 1H), 4.12 (d, J= 2.0 Hz, 2H), 3.76 (d, J= 5.7 Hz, 2H), 3.62 - 3.51 (m, 1H), 3.45 (t, J= 7.1 Hz, 2H),3.40-3.25(m, 3 H), 3.18 - 3.05 (m, 1H), 2.99-2.95 (m, 1H), 2.42 - 2.20 (m, 4H), 1.89-1.68 (m, 2H).NOESY- 05-7-0B (400 MHz, DMSO- s): the proton at 6.38 ppm has correlation with the proton at 4.12 ppm.ChiralHPLC-05-7-0B: Column: CHIRALPAK ID-3; Column Size: 4.6*50mm,3um; Mobile Phase: MtBE(0.1%DEA):MeOH=90:10; Flow: 1.67 mL / min; Temperature: Ambient; RT=2.662 minCompounds 05-8-0A / 05-8-0B2-{[l-(4-chlorophenyl)pyrrolidin-3-ylidene]methyl}-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H- 51ambda4-thieno[3,2-d]pyrimidin-5-one (160 mg) was purified by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK ID, 3*25 cm, 5 pm; Mobile Phase A: MTBE(10mMNH3)--HPLC, Mobile Phase B: MeOH--HPLC; Flow rate: 40 mL / min; Gradient (B%): isocratic 10% B; Wave Length: 254 / 220 nm; RTl(min): 8.8; RT2(min): 12.73; Sample Solvent: FA HFIP MeOH DCM-HPLC; Injection Volume: 0.8 mL; Number Of Runs: 10) to afford assumed 2-{[(3Z)-l-(4-chlorophenyl)pyrrolidin-3- ylidene]methyl}-4-{[l-(hydroxymethyl)cyclobutyl]amino}-6H,7H-51ambda4-thieno[3,2-d]pyrimidin-5- one (38.8 mg, 25.53% yield, 98.6% purity) as a white solid and assumed 2-{[(3Z)-l-(4- chlorophenyl)pyrrolidin-3-ylidene]methyl}-4-{[l-(hydroxymethyl)cyclobutyl]ammo}-6H,7H-51ambda4- thieno[3,2-d]pyrimidin-5-one (37.8 mg, 24.87% yield, 95.3% purity) as a white solid.LCMS-05-8-0A:(ESI, m / z):445[M+l]+HNMR-05-8-0A: 'H NMR (400 MHz, DMSO-6) 8 7.78 (s, 1H), 7.29-7.20 (m, 2H), 6.75-6.67 (m, 2H), 6.36 (q, J = 2.3 Hz, 1H), 4.96 (t, J= 5.5 Hz, 1H), 4.36 (s, 2H), 3.88-3.76 (m, 2H), 3.58 (dt, J= VIA, 1.1 Hz, 1H), 3.41-3.27 (m, 3H), 3.15-3.12 (m, 1H), 3.04- 2.94 (m, 3H), 2.38-2.21 (m, 4H), 1.94-1.74 (m, 2H).NOESY- 05-8-0A (400 MHz, DMSO- e): the proton at 6.36 ppm has correlation with the proton at 2.98 ppm.ChiralHPLC-05-8-0A: Column: CHIRALPAK ID-3; Column Size: 4.6*50mm,3um; Mobile Phase:MtBE(0.1%DEA):MeOH=90:10; Flow: 1.67 mL / min; Temperature: Ambient; RT=1.001 minLCMS-05-8-0B:(ESI, m / z):445[M+l]+HNMR-05-8-0B: *H NMR (400 MHz, DMSO-< ) 8 7.78 (s, 1H), 7.25 (d, J= 8.7 Hz, 2H), 6.74-6.67 (m, 2H), 6.36 (t, J= 2.3 Hz, 1H), 4.96 (t, J= 5.4 Hz, 1H), 4.36 (s, 2H), 3.82 (d, J= 5.3 Hz, 2H), 3.58 (dt, J=17.1, 7.7 Hz, 1H), 3.42-3.27 (m, 3H), 3.15-3.12 (m, 1H), 2.99-2.95 (m, 3H), 2.31 (dt, J= 21.8, 8.4 Hz, 4H), 1.90-1.71 (m, 2H).NOESY- 05-8-0A (400 MHz, DMSO- e): the proton at 6.36 ppm has correlation with the proton at 2.99 ppm.ChiralHPLC-05-8-0B: Column: CHIRALPAK ID-3; Column Size: 4.6*50mm,3um; Mobile Phase: MtBE(0.1%DEA):MeOH-90:10; Flow: 1.67 mL / min; Temperature: Ambient; RT-1.715 min

[0075] Example A: PDE selectivity assessment (FP method)

[0076] The PDE4B2 and PDE4D2 assays were performed at Pharmaron using BPS Bioscience FP kits and methods.

[0077] According to BPS Bioscience manufacturer’s instructions, FAM-Cyclic-3’,5’-AMP, PDE4B2 or PDE4D2, serial diluted test compounds mixed thoroughly on the assay plate. After reaction at rt for 1 hr, biding agent diluent (cAMP) was added and incubated at room temperature. FP signals were then detected using Envision and IC50 were calculated using GraphPad.0078] Example B: PDE selectivity assessment (SPA method)

[0079] Another selectivity assessment was performed using SPA method. The assay was developed and performed by WuXi AppTec.1) Dilute compound serially with DMSO and transfer 5 pL to assay plate.2) Prepare PDE4B2 (BPS Bioscience) and PDE4D2 (Sigma-Aldrich) enzyme with assay buffer and transfer 5 pL to assay plate.3) Dilute substrate 3H-cAMP (Rewity) with assay buffer, and transfer 10 pL to assay plate, incubate the plate at 37 C for 20 mins.4) Prepare PDE SPA Beads (Rewity) with distilled water, transfer 10 pL to assay plate and incubate at RT for 20mins5) Read the assay plate with Perkin Elmer MicroBeta2 Reader.6) Analyze the data using Microsoft Excel. % Inhibition = 100 x[l- (Sample raw value- Low control Average) / (High control Average- Low control Average)]The IC50 value is calculated by GraphPad Prism 5.0 follow Dose - response - Inhibition — log [antagonist] vs. response — Variable slope model.

[0080] Results of PDE4B2 and PDE4D2 SPA IC50

[0081] All references cited herein are incorporated by reference in their entireties.

[0082] It will be appreciated by persons skilled in the art that the invention described herein is not limited to what has been particularly shown and described. Rather, the scope of the invention is defined by the claims which follow. It should further be understood that the above description is only representative of illustrative examples of embodiments. The description has not attempted to exhaustively enumerate all possible variations. The alternate embodiments may not have been presented for a specific substituent of the compound, or a step of the method, and may result from a different combination of described substituent or step, or that other undescribed alternate embodiments may be available for a compound or method, is not to be considered a disclaimer of those alternate embodiments. It will be appreciated that many of those un-described embodiments are within the literal scope of the following claims, and others are equivalent.

Claims

CLAIMS1. A compound of formula I, a geometric isomer thereof, or a pharmaceutically acceptable salt thereof,Formula Iwhich could be linked to Cy and dihydrothienopyrimidine sulfoxide core in head-to-tail or tail-to-head direction.Cy is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

2. The compound of formula I, geometric isomer thereof, or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is represented by Formula I-aWhereinCy is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

3. The compound of formula I, geometric isomer thereof, or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is represented by Formula I-bWhereinCy is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

4. The compound of formula I, geometric isomer thereof, or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is represented by Formula I-cZi and Z2 is independently selected from N or CH;Rx is independently selected from the group consisting of alkyl, substituted alkyl, halo, hydroxyl, alkoxyl; m = 0, 1,2 and 35. The compound of formula I, geometric isomer thereof, or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is represented by Formula I-dwhereinZi and Z2 is independently selected from N or CH;Rxis independently selected from the group consisting of alkyl, substituted alkyl, halo, hydroxyl, alkoxyl; m = 0, 1,2 and 36. The compound of formula I, geometric isomer thereof, or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is selected from the group consisting of7. A pharmaceutical composition comprising the compound of formula I of any of claims 1 to 6, geometric isomer thereof, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. A method of treating a disease mediated by PDE4 in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of any of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7, wherein the disease is of metabolic, autoimmune, inflammatory, fibrotic, and dermatological conditions.

9. A method of inhibiting PDE4, comprising contacting a cell with an effective amount of the compound of formula (I) or the pharmaceutically acceptable salt thereof any one of claims 1-6, or a pharmaceutical composition thereof claim 7.