Preparation method and application of dihydrothienopyrimidine derivative

Abstract

The invention relates to a preparation method and application of a dihydrothienopyrimidine derivative. The invention provides a compound which is used as a PDE4B inhibitor and has a brand-new structure, a preparation method of the compound and application of the compound in the aspect of treating PDE4B-mediated diseases. Experiments prove that the compounds have a relatively strong inhibition effect on PDE4B enzyme, and can be used as promising compounds for treating PDE4B-mediated diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to compounds as PDE4B inhibitors, particularly substituted dihydrothiophenezaazaaryl derivatives and their prodrugs, and methods for their preparation and use. Background Technology

[0002] Phosphodiesterases (PDEs) hydrolyze intracellular second messengers (cAMP, cyclic adenosine monophosphate or cGMP, cyclic guanosine monophosphate), degrading intracellular cAMP or cGMP and thus terminating the biochemical processes mediated by these second messengers. cAMP and cGMP play crucial regulatory roles in cellular activity, and their concentrations are primarily determined by the balance between the synthesis of nucleotide cyclases and the hydrolytic activity of phosphodiesterases (PDEs). PDEs are widely distributed in the human body, and their physiological functions are studied in multiple fields. Human PDE4 isoenzymes are classified into four subtypes: PDE4A, 4B, 4C, and 4D. PDE4 is involved in the hydrolysis of cAMP in various inflammatory cells; therefore, inhibiting PDE4 can suppress immune and inflammatory cells.

[0003] In addition, according to literature reports, PDE4 plays a role in controlling calcium-induced calcium release, and preferential inhibition of PDE4B can maintain the efficacy of treatment for pulmonary fibrosis.

[0004] Therefore, selective inhibitors of PDE4B are expected to become effective drugs for the treatment of idiopathic pulmonary fibrosis and progressive fibrotic interstitial lung disease through their dual inhibitory effects on inflammation and fibrosis. Summary of the Invention

[0005] The present invention aims to provide a novel PDE4B inhibitor compound, a method for preparing the compound, and its use in treating PDE4B-mediated diseases. The compound is biochemically effective and physiologically active, exhibiting strong inhibitory activity against the PDE4B enzyme with good selectivity.

[0006] In a first aspect, the present invention provides a compound of formula (I), a stereoisomer, tautomer, or mixture thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] R represents hydrogen, C represents... 1-6 Alkyl group, -C(O)R2;

[0010] R1 is C 1-6 Alkyl, C 3-6 cycloalkyl, deuterated C1-6 Alkyl, deuterated C 3-6 cycloalkyl;

[0011] R2 is -NR a R b ;

[0012] R a R b H (independently) and C (optionally substituted) 1-6 Alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 4-8 Cycloalkenyl, 3-8 membered heterocyclic groups; wherein optional substitution refers to being replaced by one or more groups selected from oxo, OH, NH2, C 1-3 Substituents of alkyl groups;

[0013] X1 and X2 can be independently CH or N;

[0014] The heteroatoms in the heterocyclic group are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3.

[0015] In a preferred embodiment of the present invention, R is hydrogen or -C(O)R2;

[0016] In a preferred embodiment of the present invention, R1 is C. 1-3 Alkyl, C 3-4 cycloalkyl, deuterated C 1-3 Alkyl, deuterated C 3-4 cycloalkyl;

[0017] In a preferred embodiment of the present invention, R2 is -NR. a R b ;

[0018] R a R b H (independently) and C (optionally substituted) 1-4 Alkyl, C 3-4 cycloalkyl; wherein optional substitution means being substituted by one or more elements selected from OH, NH2, C 1-3 Alkyl substituents;

[0019] In a preferred embodiment of the present invention, R1 is methyl or CD3;

[0020] In a preferred embodiment of the present invention, R2 is -NHR b ;

[0021] R b H, optional substitution: C 1-4 Alkyl, C 3-4cycloalkyl; wherein optional substitution means being substituted by one or more elements selected from OH, NH2, C 1-3 Alkyl substituents;

[0022] S* is a chiral sulfur atom;

[0023] In a preferred embodiment of the present invention, S* is a chiral sulfur atom having an R / S-enantiomer;

[0024] In a preferred embodiment of the present invention, S* is a chiral sulfur atom having an R-enantiomer;

[0025] In a preferred embodiment of the invention, S* is a chiral sulfur atom having an S-enantiomer.

[0026] The present invention further provides compounds represented by formulas (II-1) and (II-2) below, wherein the stereoisomers, tautomers, or mixtures thereof, isotopic derivatives, or pharmaceutically acceptable salts of the compounds are:

[0027]

[0028] Wherein, R1, R2, X1, and X2 are as described in compound (I);

[0029] The present invention further provides compounds represented by formula (Ⅲ), stereoisomers, tautomers, or mixtures thereof, isotopic derivatives thereof, or pharmaceutically acceptable salts of said compounds:

[0030]

[0031] Among them, R1, R a R b As described in compound (I);

[0032] In a preferred embodiment of the present invention, R1 is methyl or CD3;

[0033] In a preferred embodiment of the present invention, R a For H;

[0034] In a preferred embodiment of the present invention, R b H, methyl, cyclopropyl;

[0035] The present invention also provides a compound of formula (A) below, a stereoisomer, tautomer, or mixture thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof:

[0036]

[0037] Wherein, R, R1, X1, and X2 are as described in the compound shown in formula (Ⅰ).

[0038] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0039] Preferably, the compound provided by the present invention, or its stereoisomers, tautomers, mixtures thereof, isotopic derivatives, or pharmaceutically acceptable salts of the compound, wherein the compound has the following structure:

[0040]

[0041]

[0042] The present invention also aims to provide a method for preparing compounds represented by the above general formula, stereoisomers, tautomers or mixtures thereof, isotopic derivatives of the compounds, or pharmaceutically acceptable salts of the compounds.

[0043] The compound of the general formula can be prepared by a variety of methods, including but not limited to the following:

[0044] Option 1:

[0045]

[0046] Where M is hydrogen, a metal with or without ligands, or boron, etc.;

[0047] Z1 and Z2 are leaving groups such as halogen, sulfonate, alkylthio, alkylthioyl, and alkylthionyl.

[0048] Z3 represents groups such as esters, amides, aldehydes, acetals, acyloxymethyl groups, and alkoxymethyl groups that can be converted into hydroxymethyl groups.

[0049] Option 2:

[0050]

[0051] Where M is hydrogen, a metal with or without ligands, or boron, etc.;

[0052] Z1 and Z2 are leaving groups such as halogen, sulfonate, alkylthio, alkylthioyl, and alkylthionyl.

[0053] Option 3:

[0054]

[0055] Where M is hydrogen, a metal with or without ligands, or boron, etc.

[0056] Z1 and Z2 are leaving groups such as halogen, sulfonate, alkylthio, alkylthioyl, and alkylthionyl.

[0057] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, a stereoisomer, tautomer or mixture thereof, an isotope derivative thereof, or a pharmaceutically acceptable salt thereof.

[0058] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, a stereoisomer, tautomer or mixture thereof, an isotope derivative thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

[0059] The object of the present invention also includes the use of the compounds shown in the present invention, stereoisomers, tautomers or mixtures thereof, isotopic derivatives thereof, or pharmaceutically acceptable salts of the compounds, or pharmaceutical compositions comprising the compounds shown in the present invention in the preparation of medicaments for treating or preventing diseases mediated by PDE4B.

[0060] In some embodiments, the PDE4B-mediated disease is a fibrosis-related disease or an immune-inflammatory-related disease.

[0061] In some embodiments, the PDE4B-mediated diseases include respiratory diseases, gastrointestinal diseases, inflammatory diseases, allergic diseases, autoimmune diseases, and cancer.

[0062] Preferably, the respiratory disease is selected from respiratory or pulmonary diseases accompanied by increased mucus production, respiratory inflammation and / or obstructive diseases; more preferably, the respiratory disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, interstitial pneumonia, chronic obstructive pulmonary disease (COPD), α-antitrypsin deficiency, chronic sinusitis, asthma or chronic bronchitis.

[0063] Preferably, the gastrointestinal disease is selected from segmental ileitis, ulcerative colitis, or Crohn's disease;

[0064] Preferably, the inflammatory disease is selected from dry eye syndrome or glaucoma;

[0065] Preferably, the autoimmune disease is selected from diffuse connective tissue diseases such as systemic lupus erythematosus, atopic dermatitis, seborrheic dermatitis, psoriasis, urticaria, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis, or Sjögren's syndrome.

[0066] More preferably, in some embodiments, the PDE4B-mediated disease is chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, asthma, or interstitial lung disease.

[0067] The object of the present invention also includes providing a method for preventing and / or treating diseases mediated by PDE4B, comprising administering to a patient a therapeutically effective dose of a compound shown in the present invention, a stereoisomer, tautomer, or mixture thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0068] The compounds shown in this invention, stereoisomers, tautomers or mixtures thereof, isotopic derivatives, or pharmaceutically acceptable salts of the compounds may be administered in combination with other inhibitors for the treatment or prevention of PDE4B-mediated diseases, such as fibrosis or immune-inflammatory disorders.

[0069] When the compounds of the present invention, stereoisomers, tautomers, or mixtures thereof, isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, are administered in combination with other inhibitors for the treatment of diseases such as fibrosis or immune inflammation, the compounds of the present invention or pharmaceutically acceptable salts thereof may provide enhanced therapeutic effects for PDE4B-mediated diseases, such as antifibrotic or anti-immunoinflammatory effects.

[0070] definition

[0071] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0072] Unless otherwise specified, the term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl.

[0073] For example, a cycloalkyl group may contain 3 to 16 carbon atoms (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4). Even further, for example, the cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms (such as 3 to 10, further such as 3 to 8, 3 to 6). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Specifically, examples of saturated monocyclic cycloalkyl groups (e.g., C3-8 cycloalkyl groups) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, the cycloalkyl group is a monocyclic group containing 3 to 6 carbon atoms (abbreviated as C3-6 cycloalkyl), which includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 5 to 12, more such as 7 to 12 or 5 to 10 ring atoms arranged in a fused bicyclic arrangement selected from the [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, or a bridging bicyclic arrangement selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include rings arranged in a bicyclic arrangement selected from the [5,6] and [6,6] ring systems. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and is not aromatic, as aromatic is defined herein.

[0074] The term "spirocycloalkyl" refers to a cyclic structure containing a carbon atom and consisting of at least two rings sharing a common atom. For example, the term "7- to 12-membered spirocycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and consisting of at least two rings sharing a common atom.

[0075] The term "fused cycloalkyl" refers to a fused ring containing carbon atoms and formed by two or more rings sharing two adjacent atoms. For example, the term "5- to 10-membered fused cycloalkyl" refers to a fused ring containing 5 to 10 ring carbon atoms and formed by two or more rings sharing two adjacent atoms.

[0076] Examples include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decahydronaphthalene, as well as benzo3- to 8-membered cycloalkyl, benzoC4-6 cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrazolyl, 1,4-dihydronaphthyl, etc. A preferred embodiment is an 8- to 9-membered fused ring, where the fused ring refers to a cyclic structure containing 8 to 9 ring atoms in the above examples.

[0077] The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and consisting of two rings sharing two non-adjacent atoms. The term "7- to 12-membered bridged cycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and consisting of two rings sharing two non-adjacent atoms.

[0078] Unless otherwise specified, the term "heterocyclic group" or "heterocycle" refers to a non-aromatic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members and the remaining ring members being carbon, including monocyclic rings, fused rings, bridging rings, and spirocyclic groups, i.e., containing monocyclic heterocyclic groups, bridging heterocyclic groups, spirocyclic groups, and fused heterocyclic groups.

[0079] The term "monocyclic heterocyclic group" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle can be saturated or partially saturated.

[0080] Exemplary monocyclic 4- to 18-membered heterocyclic groups include, but are not limited to (as numbered from the connection position specified as priority 1), pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, ethylene oxide, aziridine-1-yl, aziridine-2-yl, aziridine-3-yl, etc. Cyclopropane-2-yl, azircyclooctane-1-yl, azircyclooctane-2-yl, azircyclooctane-3-yl, azircyclooctane-4-yl, azircyclooctane-5-yl, thiocyclopropane, azircyclobutane-1-yl, azircyclobutane-2-yl, azircyclobutane-3-yl, oxetane, thiocyclobutane, 1,2-dithiocyclobutane, 1,3-dithiocyclobutane, dihydropyridyl, tetrahydropyridyl, thiomorpholinyl, oxetanethionylhexyl, piperazine, homopiperazine, homopiperidinyl 1-yl azirheptan-2-yl azirheptan-3-yl azirheptan-4-yl oxacycloheptyl thiocycloheptyl 1,4-oxathiocyclohexyl 1,4-dioxacycloheptyl 1,4-oxathiocycloheptyl 1,4-oxaazacycloheptyl 1,4-dithiocycloheptyl 1,4-thioazacycloheptyl and 1,4-diazacycloheptyl 1,4-dithiocyclohexyl 1,4-azathiocyclohexyl oxacyclohexyl , diazaphenyl, thiazaphenyl, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, pyrazolylalkyl, dithiaalkyl, dithiacyclopentyl, pyrazolylalkyl, imidazolinyl, pyrimidinoneyl, or 1,1-dioxo-thiomorpholinyl.

[0081] The term "spiroheterocyclic group" refers to a 5- to 18-membered polycyclic heterocyclic group having a ring linked by a shared carbon atom (called a spiro atom), comprising one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of the spiroheterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the spiroheterocyclic group is 6- to 14-membered, and more preferably 7- to 12-membered. Depending on the number of shared spiro atoms, spiroheterocyclic groups are classified as monospirocyclic, dispirocyclic, or polyspirocyclic, and preferably refer to monospirocyclic or dispirocyclic groups, and more preferably 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic groups. Representative examples of spirochetal groups include, but are not limited to, the following groups: 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-1,2'-pyrrolidine]-1'-yl), 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro[indene-2,2'-pyrrolidine]-1'-yl), azaspiro[2,4]heptane (e.g., 5-azaspiro[2,4]heptane-5-yl), azaspiro[3,4]octane (e.g., 6-azaspiro[3,4]octane-6-yl), 2-oxa-6 -azaspiro[3.4]octane (e.g., 2-oxa-6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]oct-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]oct-6-yl), 1,7-dioxaspiro[4.5]decane, 2-oxa-7-azaspiro[4.4]nonane (e.g., 2-oxa-7-azaspiro[4.4]non-7-yl), 7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

[0082] The term "fused heterocyclic group" refers to a 5- to 18-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms (carbon and carbon or carbon and nitrogen) with another ring, containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a fused heterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the fused heterocyclic group is 6- to 14-membered, more preferably 7- to 12-membered, and even more preferably 7- to 10-membered. Depending on the number of member rings, fused heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, and even more preferably 5-membered / 5-membered, 5-membered / 6-membered, or 6-membered / 7-membered bicyclic fused heterocyclic groups. Representative examples of fused heterocycles include, but are not limited to, the following groups: octahydrocyclopentadienzo[c]pyrrole (e.g., octahydrocyclopentadienzo[c]pyrrole-2-yl), octahydropyrrolo[3,4-c]pyrroleyl, octahydroisoindolyl, isoindololinyl (e.g., isoindololin-2-yl or isoindololin-5-yl), octahydro-benzo[b][1,4]dioxin, dihydropyridooxazinyl (e.g., 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl) or dihydrobenzooxazonyl (e.g., 5-oxo-3,4-dihydrobenzo[f][1,4]... [Oxazonyl), benzozazafonyl (e.g., 2,3,4,5-tetrahydro-1-oxo-2-benzozazafon-6-yl), benzooxazonyl (e.g., 5-oxo-2,3,4,5-tetrahydro-1,4-benzooxazon-8-yl), dihydroisoquinolinyl (e.g., 1-oxo-2-methyl-3,4-dihydroisoquinolin-6-yl), tetrahydroisoquinolinyl (e.g., 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl), dihydrobenzoxazine (e.g., 3,4-dihydro-2H-1,4-benzoxazine-6-yl).

[0083] The term "bridging heterocyclic group" refers to a 5- to 18-membered polycyclic heterocyclic alkyl group in which each pair of rings shares two unconnected atoms, comprising one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of the bridging heterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the bridging heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, bridging heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclic groups, and preferably refer to bicyclic, tricyclic, or tetracyclic bridging heterocyclic groups, and more preferably bicyclic or tricyclic bridging heterocyclic groups. Representative examples of bridging heterocyclic groups include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0084] Unless otherwise specified, the term "heterocyclic alkyl" refers to a monocyclic, saturated "heterocyclic group" or "heterocycle" as defined above, with the same definition of ring atoms, i.e., containing 3-20 ring atoms ("3-20-membered heterocyclic alkyl"), the number of heteroatoms being 1, 2, 3 or 4 (1-4), preferably 1, 2 or 3 (1-3), wherein each heteroatom is independently selected from N, O or S. Preferably containing 3-12 ring atoms ("3-12-membered heterocyclic alkyl"), more preferably containing 3-10 ring atoms ("3-10-membered heterocyclic alkyl"), even more preferably containing 3-8 ring atoms ("3-8-membered heterocyclic alkyl"), even more preferably containing 4-7 ring atoms ("4-7-membered heterocyclic alkyl"), even more preferably containing 5-10 ring atoms ("5-10-membered heterocyclic alkyl"), and even more preferably containing 5-6 ring atoms ("5-6-membered heterocyclic alkyl"). In some embodiments, each example of a heterocyclic alkyl group is independently optionally substituted, for example, unsubstituted (an “unsubstituted heterocyclic alkyl”) or substituted with one or more substituents (an “substituted heterocyclic alkyl”). The “heterocyclic group” or “heterocyclic” section above has given some exemplary “heterocyclic alkyl”, and also includes, but is not limited to, oxacyclohexyl, thiomorpholino, oxathiohexyl, oxazolidinyl, thiazolyl, pyrazolyl, imidazolinidine, etc.

[0085] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within reasonable medical judgment, is suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0086] The compounds of this invention also include their "isotope derivatives." Unless otherwise specified, the term "isotope derivative" refers to compounds of this invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive isotopes. Commonly used isotopes for isotopic labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0087] The compounds of this invention also include their solvates. Unless otherwise specified, the terms "solvate" or "solvent" refer to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Solventization methods are well known in the art.

[0088] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0089] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0090] Unless otherwise specified, the term "optional substitution" means that the hydrogen at the substituted site of the group is not substituted, or is substituted by one or more substituents. "Multiple optional substitutions" refers to 2, 3, 4, 5, 6, 7, or 8 substituents. Preferably, the substituent is substituted by one, two, or three substituents, preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C. 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 One or more substituents in the alkoxy group are substituted, wherein the oxo group refers to two H atoms at the same substitution position being replaced by the same O atom to form a double bond.

[0091] The term "therapeuticly effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. In embodiments of the invention, when treating a patient according to the invention, the amount of a given drug depends on many factors, such as the specific dosing regimen, the type and severity of the disease or condition, and the unique characteristics (e.g., weight) of the patient or host requiring treatment. However, depending on the specific surrounding circumstances, including, for example, the specific drug used, the route of administration, the condition being treated, and the patient or host being treated, the dosage can be conventionally determined by methods known in the art. For the pharmaceutical compositions of the invention, which comprise a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier, wherein "therapeuticly effective amount" refers to, based on the weight of the pharmaceutical composition, the compound of the invention comprises 1-99% by weight, for example 20-80%, 30-70%, or 45-55%, and the pharmaceutically acceptable carrier comprises 99-1% by weight, for example 80-20%, 70-30%, or 55-45%. Pharmaceutically acceptable carriers are those well known in the art and will not be described further here.

[0092] The beneficial effects of this invention are as follows:

[0093] This invention designs a class of novel compounds, providing a new direction for the development of PDE4B inhibitors. In vitro biochemical enzyme activity studies show that these compounds have strong inhibitory effects on PDE4B enzymes and exhibit good selectivity. Detailed Implementation

[0094] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0095] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The NMR measurements were performed using a Bruker 400MHz and / or Varian 400MHz instrument; the LC-MS instrument used was an Agilent 1260 Infinity II-6120 / 6125MSD; and the HPLC instrument used was a Waters UPCC (CA-352).

[0096] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0097] This invention provides a method for preparing the compound. The compound can be prepared by the following steps.

[0098] Preparation Example 1

[0099] Preparation of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide:

[0100]

[0101] Step 1: Preparation of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol:

[0102]

[0103] 2,4-Dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (6.3 g), (1-aminocyclobutyl)methanol hydrochloride (4.6 g), and N,N-diisopropylethylamine (DIEA) (15.6 g) were dissolved in acetonitrile (ACN) (30 mL) and reacted overnight at 85 °C. Water (100 mL) was then added, and the mixture was extracted with ethyl acetate (100 mL × 2) and washed with water (100 mL × 3). The organic phase was then dried over anhydrous sodium sulfate. The mixture was filtered and evaporated to dryness to obtain the crude product. The crude product was purified by rapid chromatography (100-200 mesh silica gel, petroleum ether:ethyl acetate = 0-50%) to give a white solid. Acetonitrile (20 mL) and water (40 mL) were then added, and the mixture was stirred overnight at room temperature. The solid was filtered and washed with acetonitrile / water (1:2, 20 mL), and the filter cake was evaporated to dryness to give the target compound (4.2 g). LCMS(ESI)[M+H] + =272.10

[0104] Step 2: Preparation of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide:

[0105]

[0106] 1 g of (1-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol, Ti(O) i Pr)4 (52.4 mg) and S-binaphthol ((S)-BINOL) (105.6 mg) were dissolved in dichloromethane (DCM) (5 mL) and water (0.5 mL), and then stirred for half an hour under nitrogen protection. Then, tert-butanol peroxide (t-BuOOH) (522 mg, 70% aqueous solution) was added under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. LCMS monitoring showed the product as the main peak. The solution was then evaporated to dryness, and isopropyl acetate (15 mL) was added. The mixture was sonicated for 1 minute, filtered, washed with isopropyl acetate (2 mL), and dried to obtain the target compound (1 g). LCMS (ESI) [M+H] + =288.08

[0107] Example 1

[0108] Synthesis of (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate:

[0109]

[0110] Step 1: Preparation of (4-chlorophenyl)lithium:

[0111]

[0112] Under nitrogen protection, 1-chloro-4-iodobenzene (4.18 g, 1 eq) was dissolved in anhydrous THF (50 mL) and stirred until dissolved. A 2.5 M n-butyllithium solution in hexane (1 eq) was added dropwise at -78 °C, and the reaction was continued at -78 °C with stirring for 0.5 hours to obtain the crude target compound. This was used directly in the next step.

[0113] Step 2: Preparation of tert-butyl 3-(4-chlorophenyl)-3-hydroxyazacyclobutane-1-carboxylate:

[0114]

[0115] Under nitrogen protection, tert-butyl 3-oxoazacyclobutane-1-carboxylate (2 g, 1 eq) was dissolved in anhydrous THF (10 mL) and slowly added to the previous reaction solution at -78 °C. The mixture was stirred at -78 °C for 1 hour and detected by TLC. The reaction was quenched by adding saturated ammonium chloride solution (10 mL) to the reaction solution at 0 °C, and the crude product was purified. The crude product was added to petroleum ether (30 mL) and stirred at room temperature for 1 hour. After filtration, the filter cake was washed with petroleum ether (20 mL) to obtain the target compound (2.56 g). LCMS (ESI) [M+H-56] + =228.1.

[0116] Step 3: Preparation of tert-butyl 3-(4-chlorophenyl)-3-methoxyazacyclobutane-1-carboxylate:

[0117]

[0118] Under nitrogen protection, tert-butyl 3-(4-chlorophenyl)-3-hydroxyazacyclobutane-1-carboxylate (500 mg, 1 eq) was dissolved in anhydrous DMF (5 mL). 60 wt% sodium hydride (2.05 eq) was added in an ice-water bath, and the mixture was stirred for 10 minutes. Iodomethane (5 eq) was then added, and stirring continued for 30 minutes. LC-MS analysis confirmed complete consumption of the reactants. The reaction was quenched by adding saturated NH4Cl aqueous solution. The mixture was then added to water and extracted with methyl tert-butyl ether. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude target compound (585 mg, which was used directly in the next step).

[0119] Step 4: Preparation of 3-(4-chlorophenyl)-3-methoxyazacyclobutane hydrochloride:

[0120]

[0121] 585 mg of tert-butyl 3-(4-chlorophenyl)-3-methoxyazacyclobutane-1-carboxylate (the crude product from the previous step) was added to a 4M solution of ethyl acetate (5 mL) and stirred at room temperature for 0.5 hours. LCMS analysis confirmed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure, and 20 mL of methyl tert-butyl ether was added to the residue. The mixture was stirred at room temperature for 30 minutes, filtered, and the filter cake was washed with 10 mL of methyl tert-butyl ether to obtain the target compound (380 mg). LCMS (ESI) [M+H] + =198.1.

[0122] Step 5: Preparation of (R / S)-2-(3-(4-chlorophenyl)-3-methoxyazacyclobutane-1-yl)-4-((1-hydroxymethylcyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine-5-oxide:

[0123]

[0124] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (100 mg, 1 eq), 3-(4-chlorophenyl)-3-methoxyazacyclobutane hydrochloride (1.22 eq), and N,N-diisopropylethylamine (3.98 eq) were added to a mixture of water (0.5 mL) and THF (2.5 mL), and the mixture was stirred at 70 °C for 2 hours. LCMS analysis confirmed complete consumption of the reactants. The reaction mixture was then added to water (20 mL), filtered, and purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (82 mg). LCMS (ESI) [M+H] + =449.3; 1 H NMR (400MHz, DMSO-d6) δ7.49 (s, 5H), 4.84 (t, J = 5.7Hz, 1H), 4.22 (s, 3H), 3.77-3.65 (m, 2H), 3.41 (dt, J = 16.6, 8.0Hz, 2H), 3.27-3.1 5(m,2H),2.99-2.82(m,3H),2.34(d,J=10.5Hz,2H),2.26(d,J=10.0Hz,1H),2.14(t,J=10.2Hz,2H),1.74(dq,J=19.6,10.3Hz,2H).

[0125] Step 6: Preparation of (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl 1H-imidazolium-1-carboxylate:

[0126]

[0127] (R / S)-2-(3-(4-chlorophenyl)-3-methoxyazacyclobutane-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (200 mg, 1 eq) was added to DCM (3 mL), followed by N,N-diisopropylethylamine (87 mg, 1.5 eq) and CDI (87 mg, 1.2 eq). The reaction was carried out at room temperature for 1 hour. LCMS analysis confirmed complete consumption of the starting materials. The reaction solution was concentrated under reduced pressure to obtain the target compound (400 mg). LCMS (ESI) [M+H] + =543.2.

[0128] Step 7: Preparation of (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate:

[0129]

[0130] (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl-1H-imidazolium-1-carboxylate (200 mg, 1 eq) was added to a methanolic solution of ammonia (0.21 mL, 7 M), and stirred overnight at room temperature. LC-MS analysis showed product formation. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (77 mg). LC-MS (ESI) [M+H] + =492.0; 1H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.49(s,4H),6.47(s,2H),4.37(s,2H),4.23(s,4H),3.45–3.37(m,1H), 3.25–3.17(m,1H),3.04(s,3H),2.98–2.84(m,2H),2.38–2.27(m,2H),2.23–2.13(m,2H),1.88–1.74(m,2H).

[0131] Example 2

[0132] Synthesis of (R / S)-(1-((2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutane-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate:

[0133]

[0134] Step 1: Preparation of methyl (R / S)-(1-((2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutane-1-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)1H-imidazolium-1-carboxylate:

[0135]

[0136] (R / S)-2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutane-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (100 mg, 1 eq) was added to DCM (1 mL), followed by N,N-diisopropylethylamine (43 mg, 1.5 eq) and N,N'-carbonyldiimidazole (43 mg, 1.2 eq). The reaction was carried out at room temperature for 1 hour. LCMS analysis showed complete consumption of the starting materials. The reaction solution was concentrated under reduced pressure to obtain the target compound (150 mg). LCMS (ESI) [M+H] + =546.2.

[0137] Step 2: Preparation of (R / S)-(1-((2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutane-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate:

[0138]

[0139] Methyl (R / S)-(1-((2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutane-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)1H-imidazolium-1-carboxylate (200 mg, 1 eq) was added to a methanolic solution of ammonia (0.15 mL, 7 M) and stirred overnight at room temperature. LC-MS analysis showed product formation. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (31 mg). LC-MS (ESI) [M+H] + =495.0; 1 H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.49(s,4H),6.47(s,2H),4.37(s,1H),4.23(s,4H),3.71(s,1H),3.48–3.37(m,1 H),3.21(qd,J=8.4,4.2Hz,1H),3.02–2.80(m,2H),2.38–2.24(m,2H),2.23–2.09(m,2H),1.77(dt,J=30.8,9.3Hz,2H).

[0140] Example 3

[0141] Synthesis of (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate:

[0142]

[0143] Step 1: Preparation of (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate:

[0144]

[0145] (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl 1H-imidazolium-1-carboxylate (100 mg, 1 eq) was added to DCM (2 mL), followed by methylamine hydrochloride (37 mg, 2.98 eq) and N,N-diisopropylethylamine (119 mg, 5 eq). The mixture was stirred at room temperature for 5 hours, and LCMS analysis showed product formation. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (31 mg). LCMS (ESI) [M+H] + =505.9; 1 HNMR(400MHz, DMSO-d6)δ7.69(s,1H),7.49(s,4H),6.93(d,J=4.8Hz,1H),4.40(s,2H),4.22(s,4H),3.42(dt,J=16.4,7.8Hz,1H),3.26–3.17( m,1H),3.04(s,3H),2.91(ddd,J=25.8,15.2,7.5Hz,2H),2.54(d,J=4.6Hz,3H),2.31(dt,J=21.6,11.3Hz,2H),2.19(s,2H),1.86–1.76(m,2H).

[0146] Example 4

[0147] Synthesis of (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcyclopropylcarbamate:

[0148]

[0149] Step 1: Preparation of (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcyclopropylcarbamate:

[0150]

[0151] (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl 1H-imidazolium-1-carboxylate (100 mg, 1 eq) was added to DCM (2 mL), followed by cyclopropylamine (20 mg, 1.9 eq). The mixture was stirred at room temperature for 2 hours, and LCMS analysis showed product formation. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (29 mg). LCMS (ESI) [M+H] + =532.0; 1 H NMR (400MHz, DMSO-d6) δ7.65(s,1H),7.49(s,4H),7.28(s,1H),4.40(s,2H),4.23(s,4H),3.41(dd,J=17.1,8.3Hz,1H),3.21(dt,J=16.5,8.5Hz,1H) ,3.04(s,3H),2.91(ddd,J=25.2,15.3,7.5Hz,2H),2.31(d,J=19.5Hz,3H) ,2.19(s,2H),1.81(s,2H),0.53(dt,J=6.8,3.3Hz,2H),0.40–0.34(m,2H).

[0152] Example 5

[0153] Synthesis of (R / S)-2-(3-(5-chloropyrimidin-2-yl)-3-methoxyazacyclobutane-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide:

[0154]

[0155] Step 1: Preparation of tert-butyl 3-(5-chloropyrimidin-2-yl)-3-hydroxyazine-1-carboxylate:

[0156]

[0157] Under nitrogen protection, 5-chloro-2-iodopyrimidine (4.63 g, 1.1 eq) was added to anhydrous tetrahydrofuran (60 mL), and a 2.5 M n-butyllithium solution in hexane (8.41 mL, 1.2 eq) was added dropwise at -78 °C. The reaction was continued at -78 °C for 0.5 h, followed by the slow addition of anhydrous tetrahydrofuran (3 mL) of tert-butyl 3-oxoazacyclobutane-1-carboxylate (3.00 g, 1 eq). Stirring was continued at -78 °C for 1 h, and LC-MS detected product formation. The reaction was quenched by adding saturated ammonium chloride solution to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 elution) to obtain the target compound (1.30 g).

[0158] LCMS(ESI)[M+H-100] + =186.1.

[0159] Step 2: Preparation of tert-butyl 3-(5-chloropyrimidin-2-yl)-3-methoxyazine-1-carboxylate:

[0160]

[0161] Under nitrogen protection, tert-butyl 3-(5-chloropyrimidin-2-yl)-3-hydroxyazacyclobutane-1-carboxylate (1.30 g, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). 60% sodium hydride (2 eq) was added in portions under ice bath conditions, and the mixture was stirred for 10 minutes under ice bath conditions. Iodomethane (1.5 eq) was then added, and stirring continued for another 60 minutes under ice bath conditions. LC-MS analysis confirmed complete consumption of the reactants. The reaction was quenched by adding saturated ammonium chloride aqueous solution, then added to water, and extracted with methyl tert-butyl ether. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 elution) to obtain the target compound (0.30 g). LC-MS (ESI) [M+H-100] + =199.9.

[0162] Step 3: Preparation of 5-chloro-2-(3-methoxyazacyclobut-3-yl)pyrimidine hydrochloride:

[0163]

[0164] 3-(5-chloropyrimidin-2-yl)-3-methoxyazacyclobutane-1-carboxylic acid tert-butyl ester (300 mg, 1 eq) was added to 4M ethyl hydrochloride solution (5 mL) and methanol (5 mL), and stirred at room temperature for 1 hour. LCMS analysis confirmed complete consumption of the starting material. The reaction solution was concentrated under reduced pressure to obtain the target compound (320 mg, crude product). LCMS (ESI) [M+H] + =200.1.

[0165] Step 4: Preparation of (R / S)-2-(3-(5-chloropyrimidin-2-yl)-3-methoxyazacyclobutane-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide:

[0166]

[0167] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (400 mg, 1 eq), 5-chloro-2-(3-methoxyazacyclobutyl-3-yl)pyrimidine hydrochloride (0.98 eq), and N,N-diisopropylethylamine (4.04 eq) were added to a mixed solution of tetrahydrofuran (5 mL) and water (1 mL), and the mixture was stirred at 70 °C for 2 hours. LCMS analysis confirmed complete consumption of the reactants. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (21 mg). LCMS (ESI) [M+H] + =450.9; 1 H NMR (400MHz, DMSO-d6) δ9.03(s,2H),7.46(s,1H),4.91–4.80(m,1H),4.52–4.38(m,2H),4.20(d,J=9.8Hz,2H),3.70(d,J =4.8Hz,2H),3.46–3.34(m,1H),3.17(s,4H),3.01–2.79(m,2H),2.41–2.22(m,2H),2.19–2.05(m,2H),1.86–1.65(m,2H).

[0168] Example 6

[0169] Synthesis of (R / S)-(1-((2-(3-(5-chloropyrimidin-2-yl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate:

[0170]

[0171] Step 1: Preparation of methyl (R / S)-(1-((2-(3-(5-chloropyrimidin-2-yl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)1H-imidazol-1-carboxylic acid:

[0172]

[0173] (R / S)-2-(3-(5-chloropyrimidin-2-yl)-3-methoxyazacyclobutane-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (600 mg, 1 eq) was added to dichloromethane (5 mL), followed by N,N-diisopropylethylamine (3 eq) and N,N'-carbonyldiimidazole (1.85 eq). The reaction was carried out at room temperature for 2 hours. LCMS analysis confirmed complete consumption of the starting materials. The reaction solution was concentrated under reduced pressure to obtain the target compound (700 mg). LCMS (ESI) [M+H] + =545.2.

[0174] Step 2: Preparation of (R / S)-(1-((2-(3-(5-chloropyrimidin-2-yl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate:

[0175]

[0176] Methyl (R / S)-(1-((2-(3-(5-chloropyrimidin-2-yl)-3-methoxyazacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)1H-imidazolium-1-carboxylate (500 mg, 1 eq) was added to a 7M ammonia-methanol solution (1 mL). The mixture was stirred at room temperature for 2 hours, and LC-MS analysis confirmed product formation. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to yield the target compound (169 mg). LC-MS (ESI) [M+H] + =493.9; 1 H NMR(400MHz,DMSO-d6)δ9.03(s,2H),7.70(s,1H),6.47(s,2H),4.51–4.30(m,4H),4.21(d,J=9.9Hz,2H), 3.49–3.36(m,1H),3.17(s,4H),3.02–2.82(m,2H),2.42–2.24(m,2H),2.19(s,2H),1.81(p,J=8.9Hz,2H).

[0177] Example 7

[0178] Synthesis of (R / S)-2-(3-(5-chloropyrimidin-2-yl)-3-(methoxy-d3)azacyclobutane-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide:

[0179]

[0180] Step 1: Preparation of tert-butyl 3-(5-chloropyrimidin-2-yl)-3-(methoxy-d3)azacyclobutane-1-carboxylate:

[0181]

[0182] Under nitrogen protection, tert-butyl 3-(5-chloropyrimidin-2-yl)-3-hydroxyazacyclobutane-1-carboxylate (450 mg, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). 60% sodium hydride (1.5 eq) was added in portions under ice bath conditions, and the mixture was stirred for 10 minutes under ice bath conditions. Deuterated iodomethane (2 eq) was then added, and stirring was continued for another 60 minutes under ice bath conditions. LC-MS analysis confirmed complete consumption of the reactants. The reaction was quenched by adding saturated ammonium chloride aqueous solution, extracted with methyl tert-butyl ether, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 elution) to obtain the target compound (170 mg). LC-MS (ESI) [M+H-100] + =203.1.

[0183] Step 2: Preparation of 5-chloro-2-(3-(methoxy-d3)azacyclobutane-3-yl)pyrimidine hydrochloride:

[0184]

[0185] 170 mg (1 eq) of 3-(5-chloropyrimidin-2-yl)-3-(methoxy-d3)azacyclobutane-1-carboxylic acid tert-butyl ester was added to 5 mL of 4 M ethyl hydrochloride solution and 5 mL of methanol, and stirred at room temperature for 1 hour. LC-MS analysis confirmed complete consumption of the starting material. The reaction solution was concentrated under reduced pressure to obtain the target compound (100 mg). LC-MS (ESI) [M+H] + =203.1.

[0186] Step 3: Preparation of (R / S)-2-(3-(5-chloropyrimidin-2-yl)-3-(methoxy-d3)azacyclobutane-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide:

[0187]

[0188] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 1 eq), 5-chloro-2-(3-(methoxy-d3)azacyclobutane-3-yl)pyrimidine hydrochloride (1.04 eq), and N,N-diisopropylethylamine (4.04 eq) were added to a mixed solution of water (0.4 mL) and tetrahydrofuran (2 mL), and the mixture was stirred at 70 °C for 2 hours. LCMS analysis confirmed complete consumption of the starting materials. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (14 mg). LCMS (ESI) [M+H] + =454.; 1 H NMR (400MHz, DMSO-d6) δ9.03(s,2H),7.46(s,1H),4.85(s,1H),4.48–4.40(m,2H),4.20(d,J=9.9Hz,2H),3.70(d,J=5.8Hz,2H),3.47–3.34(m,1 H),3.21(dt,J=13.4,8.3Hz,1H),2.99–2.83(m,2H),2.31(dt,J=20.8,10.4Hz,2H),2.14(t,J=10.5Hz,2H),1.74(ddd,J=19.6,13.3,7.9Hz,2H).

[0189] Example 8

[0190] Synthesis of (R / S)-(1-((2-(3-(5-chloropyrimidin-2-yl)-3-(methoxy-d3)azacyclobutane-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate:

[0191]

[0192] Step 1: Preparation of methyl (R / S)-(1-((2-(3-(5-chloropyrimidin-2-yl)-3-(methoxy-d3)azacyclobutane-1-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)1H-imidazolium-1-carboxylate:

[0193]

[0194] (R / S)-2-(3-(5-chloropyrimidin-2-yl)-3-(methoxy-d3)azacyclobutan-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (120 mg, 1 eq) was added to dichloromethane (5 mL), followed by N,N-diisopropylethylamine (3 eq) and N,N'-carbonyldiimidazole (1.87 eq). The reaction was carried out at room temperature for 2 hours. LCMS analysis confirmed complete consumption of the starting materials. The reaction solution was concentrated under reduced pressure to obtain the target compound (200 mg, crude product). LCMS (ESI) [M+H] + =548.3.

[0195] Step 2: Preparation of (R / S)-(1-((2-(3-(5-chloropyrimidin-2-yl)-3-(methoxy-d3)azacyclobutane-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate:

[0196]

[0197] Methyl (R / S)-(1-((2-(3-(5-chloropyrimidin-2-yl)-3-(methoxy-d3)azacyclobutane-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)1H-imidazolium-1-carboxylate (200 mg, 1 eq) was added to a 7M ammonia-methanol solution (1 mL). The mixture was stirred at room temperature for 2 hours, and LC-MS analysis confirmed product formation. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (10 mg). LC-MS (ESI) [M+H] + =497.0; 1 H NMR (400MHz, DMSO-d6) δ9.03 (s, 2H), 7.70 (s, 1H), 6.47 (s, 2H), 4.51–4.30 (m, 4H), 4.21 (d, J = 9.8Hz, 2H), 3.48–3. 36(m,1H),3.20(dt,J=16.0,8.3Hz,1H),3.01–2.83(m,2H),2.39–2.25(m,2H),2.18(s,2H),1.81(t,J=8.1Hz,2H).

[0198] Example 9

[0199] Synthesis of (R / S)-2-((2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropylcarbamate:

[0200]

[0201] Step 1: Preparation of tert-butyl 3-(4-chlorophenyl)-3-hydroxyazacyclobutane-1-carboxylate:

[0202]

[0203] Under nitrogen protection, 1-bromo-4-chlorobenzene (15.66 g, 1.4 eq) was dissolved in anhydrous THF (200 mL). A 2.5 M hexane solution of n-butyllithium (5.61 g, 1.5 eq) was added dropwise to the reaction flask at -78 °C. The reaction was stirred at -78 °C for 0.5 h, yielding a white turbid liquid. An anhydrous THF solution of tert-butyl 3-oxoazacyclobutane-1-carboxylate (10 g, 1 eq) was slowly added to the solution, and the reaction was continued at -78 °C for 1 h, followed by TLC analysis. The reaction was quenched by adding saturated ammonium chloride solution to the reaction solution at 0 °C. Water was added to the mixture, and the solution was extracted with methyl tert-butyl ether (300 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried with petroleum ether to obtain the target compound (13 g).

[0204] Step 2: Preparation of tert-butyl 3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutane-1-carboxylate:

[0205]

[0206] Under nitrogen protection, tert-butyl 3-(4-chlorophenyl)-3-hydroxyazacyclobutane-1-carboxylate (2 g, 1 eq) was added to anhydrous DMF (20 mL). Sodium hydride (0.19 g, 1.2 eq) was added in portions under ice bath conditions, and the mixture was stirred for 10 minutes. Deuterated iodomethane (1.53 g, 1.5 eq) was then added, followed by stirring under ice bath conditions for another 60 minutes. LC-MS analysis confirmed complete consumption of the reactants. The reaction was quenched by adding saturated NH4Cl aqueous solution. The mixture was then added to water, extracted with methyl tert-butyl ether, and concentrated under reduced pressure to obtain the crude product. The crude product was then slurried with petroleum ether to obtain the target compound (2.34 g).

[0207] Step 3: Preparation of 3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutane hydrochloride:

[0208]

[0209] 2.34 g (1 eq) of tert-butyl 3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutane-1-carboxylic acid was added to hydrochloric acid solution (15 mL, 4 M, 52.9 eq) and stirred at room temperature for 1 hour. The reaction mixture was analyzed by LC-MS to confirm complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was then slurried with petroleum ether to obtain the target compound (1.58 g). LC-MS (ESI) [M+H] + =200.9.

[0210] Step 4: Preparation of 2-((2-chloro-6,7-dihydrothieno[3,2-d-pyrimidin-4-yl)amino)-2-methyl-1-propanol:

[0211]

[0212] 2,4-Dichloro-6,7-dihydrothiophene[3,2-D]pyrimidine (4.5 g, 1 eq), 2-amino-2-methyl-1-propanol (2.13 g, 1.1 eq), and N,N-diisopropylethylamine (8.43 g, 3 eq) were added to anhydrous acetonitrile (45 mL). The mixture was stirred at 85 °C for 16 hours. LCMS analysis showed product formation. The reaction mixture was evaporated to dryness, and the crude product was purified by silica gel column chromatography (PE:EA = 0:1) to obtain the target compound (3.8 g). LCMS (ESI) [M+Na] + =282.2.

[0213] Step 5: Preparation of (R / S)-2-chloro-4-((1-hydroxy-2-methylpropyl-2-yl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine-5-oxide:

[0214]

[0215] R-1,1'-bi-2-naphthol (728 mg, 0.2 eq) was dissolved in anhydrous dichloromethane (20 mL), and tetraisopropyl titanate (IV) (0.72 g, 0.2 eq) was added. The reaction was carried out at 25 °C under nitrogen protection for 1 hour. Water (0.25 g, 1.1 eq) was added, and the reaction was continued for 0.5 hours. Then 2-((2-chloro-6,7-dihydrothieno[3,2-dpyrimidin-4-yl)amino)-2-methyl-1-propanol (3.3 g, 1 eq) was added, and the reaction was carried out for 1 hour. Then tert-butyl hydroperoxide (1.8 g, 1.1 eq) was added. The reaction was monitored by LCMS to ensure complete reaction. The reaction solution was added to water (30 mL), extracted with DCM:MeOH = 10:1, and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the target compound (3.85 g, crude product). LCMS(ESI)[M+H] +=276.1.

[0216] Step 6: Preparation of (R / S)-2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutane-1-yl)-4-((1-hydroxy-2-methylpropyl-2-yl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide:

[0217]

[0218] (R / S)-2-chloro-4-((1-hydroxy-2-methylpropyl-2-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (0.9 g), 3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutane hydrochloride (1.42 g), and N,N-diisopropylethylamine (1.7 g) were added to a mixed solution of THF (9 mL) and H₂O (1.8 mL), and the mixture was stirred at 70 °C for 2 hours. LCMS analysis confirmed complete consumption of the starting materials. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the target compound (1.56 g). LCMS (ESI) [M+H] + =440.0.

[0219] Step 7: Preparation of (R / S)-2-((2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobut-1-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl 1H-imidazolium-1-carboxylate:

[0220]

[0221] (R / S)-2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobutan-1-yl)-4-((1-hydroxy-2-methylpropyl-2-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (0.5 g, 1 eq) was added to anhydrous dichloromethane (1 ml), followed by N,N-diisopropylethylamine (0.22 g, 1.51 eq) and N,N'-carbonyldiimidazole (0.2 g, 1.1 eq). The reaction was carried out at room temperature for 1 hour. LCMS analysis confirmed complete consumption of the starting materials. The reaction solution was concentrated under reduced pressure to obtain the target compound (0.5 g). LCMS (ESI) [M+H] + =534.3.

[0222] Step 8: Preparation of (R / S)-2-((2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropylcarbamate:

[0223]

[0224] (R / S)-2-((2-(3-(4-chlorophenyl)-3-(methoxy-d3)azacyclobut-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl 1H-imidazolium-1-carboxylate (500 mg) was added to a methanol solution of ammonia (25.17 mL), and stirred at room temperature for 1 hour. Product formation was detected by LCMS. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by Prep-HPLC (C18, 10 mmol / L NH4HCO3 in water, MeCN) to obtain the target compound (232.97 mg). LCMS (ESI) [M+H] + =483.0.

[0225] Biological testing evaluation

[0226] Experiment 1: In vitro evaluation of the inhibitory activity of the compound against PDE4B2 and PDE4D2 enzymes

[0227] 1. Experimental materials and instruments:

[0228]

[0229]

[0230] 2. Experimental steps:

[0231] 2.1 Preparation and treatment of compounds

[0232] 2.1.1 Preparation of DMSO stock solution for compound: Dissolve the compound powder in 100% DMSO to prepare a 10 mM stock solution, and shake with a shaker to completely dissolve the compound.

[0233] 2.1.2 Storage of DMSO stock solution of compound: The DMSO stock solution of compound is stored in a desiccator at room temperature.

[0234] 2.1.3 Preparation of working stock solutions: a) Dilute the reference compound roflumilast in DMSO solution to 60 μM, then perform 4-fold dilutions to create 10 concentration gradients. b) Dilute the analyte compound in DMSO solution to 200 μM, then perform 3-fold dilutions. c) Prepare a 200X positive control (60 μM roflumilast) and a 200X carrier control (100% DMSO). d) Centrifuge the test plate at 1000 rpm for 1 minute.

[0235] 2.2 Compound Testing

[0236] 1) Transfer 20 nL of the compound dilution to each well of the assay plate using an Echo 550.

[0237] 2) Seal the assay plate and centrifuge the assay plate at 1000 rpm for 1 minute.

[0238] 3) Prepare 2X PDE4B2 / PDE4D2 in the refrigerated PDE assay buffer.

[0239] 4) Add 2 μL of 2X PDE4B2 / PDE4D2 to each well of the assay plate (prepared in step b).

[0240] 5) Seal the assay plate and equilibrate the assay plate at room temperature for 10 minutes.

[0241] 6) Prepare 2X Cyclic-3',5'-AMP in the PDE assay buffer.

[0242] 7) Add 2 μL of 2X Cyclic-3',5'-AMP (prepared in step f) to each well of the assay plate (prepared in step e) to start the reaction. Incubate at room temperature for 60 minutes.

[0243] 8) Add 4 μL of AMP-Glo Reagent I and incubate at room temperature for 60 minutes.

[0244] 9) Add 8 μL of the AMP detection solution. Incubate at room temperature for 60 minutes.

[0245] 10) Read the RLU signal on an Envision 2105 plate reader.

[0246] Experimental results:

[0247] Table 1 Test results of PDE4B2 enzyme inhibitory activity

[0248]

[0249]

[0250] IC of PDE4B2 enzyme inhibition 50 Value: A ≤ 1 nM; 1 nM < B ≤ 3 nM; 3 nM < C ≤ 15 nM; 15 nM < D ≤ 50 nM. PDE4D2 / PDE4B2 selectivity (= ratio of IC value of PDE4D enzyme inhibition to IC value of PDE4B2 enzyme inhibition): 5 < A ≤ 10; 2 < B ≤ 5; C ≤ 2. Control 1 is the compound 50 Value / IC value of PDE4B2 enzyme inhibition 50 Value ratio): 5 < A ≤ 10; 2 < B ≤ 5; C ≤ 2. Control 1 is the compound which is disclosed in CN103889970B.

Claims

1. A compound of formula (I), wherein the stereoisomer, tautomer, or mixture thereof, isotopic derivative thereof, or pharmaceutically acceptable salt thereof is: in, R represents hydrogen, C represents... 1-6 Alkyl group, -C(O)R2; R1 is C 1-6 Alkyl, C 3-6 cycloalkyl, deuterated C 1-6 Alkyl, deuterated C 3-6 cycloalkyl; R2 is -NR a R b ; R a R b H (independently) and C (optionally substituted) 1-6 Alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 4-8 Cycloalkenyl, 3-8 membered heterocyclic groups; wherein optional substitution refers to being replaced by one or more groups selected from oxo, OH, NH2, C 1-3 Substituents of alkyl groups; X1 and X2 can be independently CH or N; The heteroatoms in the heterocyclic group are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3.

2. The compound of claim 1, a stereoisomer, tautomer, or mixture thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: R is hydrogen or -C(O)R2.

3. The compound according to any one of claims 1-2, the stereoisomers, tautomers, or mixtures thereof, or isotopic derivatives of the compound, or a pharmaceutically acceptable salt of the compound, wherein: R1 is C 1-3 Alkyl, C 3-4 cycloalkyl, deuterated C 1-3 Alkyl, deuterated C 3-4 Cycloalkyl; preferably, R1 is methyl or CD3.

4. The compound according to any one of claims 1-3, a stereoisomer, tautomer, or mixture thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein: R2 is -NR a R b ;R a R b H (independently) and C (optionally substituted) 1-4 Alkyl, C 3-4 cycloalkyl; wherein optional substitution means being substituted by one or more elements selected from OH, NH2, C 1-3 Alkyl substituents; Preferably, R2 is -NHR b ;R b H, optional substitution: C 1-4 Alkyl, C 3-4 cycloalkyl; wherein optional substitution means being substituted by one or more elements selected from OH, NH2, C 1-3 Alkyl substituents are used; more preferably, R b It consists of H, methyl, and cyclopropyl groups.

5. The compounds shown in formulas (II-1) and (II-2), stereoisomers, tautomers, or mixtures thereof, isotopic derivatives thereof, and pharmaceutically acceptable salts of the compounds: in, R1, R2, X1, X2 are as described in compounds of formulas (I) 1-4.

6. A compound of formula (III) or (IV), a stereoisomer, tautomer, or mixture thereof, an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof: in, R1, R a R b R is as described in the compound of formula (I) as claimed in claims 1-4.

7. A pharmaceutically acceptable salt of a compound selected from the following: its stereoisomers, tautomers, mixtures thereof, or isotopic derivatives thereof, and the following compounds: 。 8. A pharmaceutical composition comprising the compound of any one of claims 1 to 7, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound.

9. The use of the compound of any one of claims 1 to 7, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt of the compound, or the use of the pharmaceutical composition of claim 8 in the preparation of a medicament for treating and / or preventing PDE4B-mediated diseases; wherein the PDE4B-mediated diseases are fibrosis-related diseases or immune-inflammatory-related diseases; preferably, the PDE4B-mediated diseases include respiratory diseases, gastrointestinal diseases, inflammatory diseases, allergic diseases, autoimmune diseases, and cancer; preferably, the respiratory diseases are selected from respiratory or pulmonary diseases accompanied by increased mucus production, respiratory inflammation, and / or obstructive diseases; more preferably, the respiratory diseases are selected from idiopathic pulmonary fibrosis. The gastrointestinal diseases are selected from: progressive pulmonary fibrosis, interstitial pneumonia, chronic obstructive pulmonary disease (COPD), α-antitrypsin deficiency, chronic sinusitis, asthma, or chronic bronchitis; preferably, the gastrointestinal diseases are selected from: segmental ileitis, ulcerative colitis, or Crohn's disease; preferably, the inflammatory diseases are selected from: dry eye syndrome or glaucoma; preferably, the autoimmune diseases are selected from: systemic lupus erythematosus, atopic dermatitis, seborrheic dermatitis, psoriasis, urticaria, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis, or Sjögren's syndrome, etc., diffuse connective tissue diseases; more preferably, the PDE4B-mediated diseases are: chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, asthma, or interstitial lung disease.

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