Tricyclic fused heterocyclic pde3 / 4 dual inhibitor and preparation and use therefor

Abstract

Provided in the invention are a phosphodiesterase inhibitor compound, and a preparation method and use therefor. In particular, provided is a compound of structural formula (I) or a pharmaceutically acceptable form thereof, wherein each substituent is as defined in the description, respectively. The compound in the invention or the pharmaceutically acceptable form thereof can be used as a phosphodiesterase inhibitor and has high activity.

Description

Tricyclic fused heterocyclic PDE3 / 4 dual inhibitors and their preparation method and application Technical Field

[0001] The present invention relates to a tricyclic fused heterocyclic compound and a preparation method and application thereof, and in particular to a tricyclic fused heterocyclic compound and a preparation method thereof and application thereof as a phosphodiesterase PDE3 / 4 dual inhibitor. Background Art

[0002] Phosphodiesterases (PDEs) belong to a superfamily of enzymes encompassing at least 11 families and 22 subtypes. They are involved in intracellular and extracellular information transmission and functional regulation. PDEs catalyze the hydrolysis of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to generate AMP and GMP, respectively.

[0003] The PDE3 family consists of two genes, PDE3A and PDE3B. PDE3 activity in the respiratory system is primarily concentrated in alveolar macrophages, endothelial cells, and platelets. PDE3 is involved in regulating numerous physiological activities in the body, such as vasodilation of vascular smooth muscle, antiplatelet aggregation, antithrombotic, cardiotonic, and anti-cell proliferation. Excessive use of PDE3 inhibitors can cause adverse reactions such as hypotension and tachycardia, significantly limiting their clinical application.

[0004] PDE4 is an enzyme that specifically hydrolyzes cAMP. Its family consists of four subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. Each subtype is encoded by a corresponding gene and has distinct cellular distribution and roles. PDE4 is primarily distributed in airway smooth muscle cells, inflammatory cells, and immune cells, regulating intracellular cAMP levels. Currently, most PDE4 inhibitors used in clinical practice have some degree of side effects, such as gastrointestinal reactions like nausea and vomiting, and even depression.

[0005] Given the limitations of using either PDE3 or PDE4 inhibitors alone and the side effects of PDE inhibitors, dual inhibition of inhaled PDE3 / 4 appears to be a more attractive approach to target the key pathological features of COPD and asthma. Evidence has shown that inhaled dual-target PDE3 / 4 inhibitors have synergistic inhibitory effects, including synergistic anti-inflammatory and bronchodilatory effects.

[0006] CN100415743C discloses a pyrimido[6,1a]isoquinolin-4-one derivative:

[0007] The compound of the general formula is used as a PDE inhibitor for treating respiratory diseases such as asthma, has a longer duration of action than troquinecin, and does not have the very bitter taste of troquinecin.

[0008] There is still an urgent need in the art for new PDE3 / PDE4 inhibitors, especially PDE3 / PDE4 inhibitors with high activity and good drugability. Summary of the Invention

[0009] An object of the present invention is to provide a novel compound as a PDE inhibitor.

[0010] Another object of the present invention is to provide a method for preparing the compound.

[0011] Another object of the present invention is to provide the use of the compound.

[0012] Another object of the present invention is to provide a pharmaceutical composition comprising the compound and use thereof.

[0013] Another object of the present invention is to provide an intermediate for preparing the compound.

[0014] Another object of the present invention is to provide a method for preparing the intermediate.

[0015] <First Aspect>

[0016] The present invention provides a compound having structural formula I or a pharmaceutically acceptable form thereof,

[0017] in:

[0018] R1 and R2 are each independently selected from H, C 1-6 Straight chain alkyl, C 3-6 Branched alkyl and C 3-6 Cycloalkyl; the linear alkyl, branched alkyl or cycloalkyl is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0019] R3 and R4 are each independently selected from H, halogen, CN, C 1-6 Alkoxy, C 1-6 Straight chain alkyl, C 3-6 Branched alkyl and C 3- 6 cycloalkyl; the alkoxy, linear alkyl, branched alkyl or cycloalkyl is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0020] X is selected from C, N, O and S;

[0021] R5 is selected from H, halogen, CN, C 1-6 Alkoxy, C 1-6 Straight chain alkyl, C 3-6 Branched alkyl and C 3-6 Cycloalkyl;

[0022] R6 is Wherein, Y is O or S, R8 is selected from amino, C 1-6 Alkoxy, C 3-12 Cycloalkyl, C 6-10 Aryl, C 5-10 Heterocyclic group, the heterocyclic group contains 1-3 heteroatoms selected from N, O and S, the amino, alkoxy, cycloalkyl, aryl, heteroaryl are optionally further substituted by 0 to 4 atoms selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent;

[0023] R7 is selected from H, =O, NH2, CN, C 1-6 Straight chain alkyl, C 3-6 Branched alkyl, C 3-6 Cycloalkyl and The H in R7 is optionally further replaced by 0 to 4 selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0024] n is 0, 1, or 2;

[0025] k is 0, 1, or 2;

[0026] Optionally, H of the compound of formula I is optionally further substituted with 0 to 6 Ds.

[0027] According to some specific embodiments of the present invention, in the compound of formula I of the present invention or a pharmaceutically acceptable form thereof, R1 and R2 are each independently selected from H, CH3, CHF2, and CD3.

[0028] According to some specific embodiments of the present invention, in the compound of formula I of the present invention or a pharmaceutically acceptable form thereof, R1 and R2 respectively correspond to the groups or values ​​shown in any one of Compounds 1 to 34.

[0029] According to some specific embodiments of the present invention, in the compound of formula I of the present invention or a pharmaceutically acceptable form thereof, R3, R4, and R5 are each independently selected from H, CH3, i-Pr, OMe, CN, CD3 or halogen.

[0030] According to some specific embodiments of the present invention, in the compound of formula I of the present invention or a pharmaceutically acceptable form thereof, R3, R4, and R5 respectively correspond to the groups or values ​​shown in any one of Compounds 1 to 34.

[0031] According to some specific embodiments of the present invention, in the compound of formula I or its pharmaceutically acceptable form, R6 is wherein R8 is selected from amino, and the amino group is optionally further replaced by 0 or 1 selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent.

[0032] According to some specific embodiments of the present invention, in the compound of formula I or its pharmaceutically acceptable form, R6 is Wherein, R8 is selected from C 1-6 Alkoxy, the alkoxy optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent.

[0033] According to some specific embodiments of the present invention, in the compound of formula I or its pharmaceutically acceptable form, R6 is Wherein, R8 is selected from C 3-12 Cycloalkyl, the cycloalkyl optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent.

[0034] According to some specific embodiments of the present invention, in the compound of formula I or its pharmaceutically acceptable form, R6 is Wherein, R8 is selected from C 6-10 Aryl, which is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent.

[0035] According to some specific embodiments of the present invention, in the compound of formula I or its pharmaceutically acceptable form, R6 is Wherein, R8 is selected from C 5-10 Heterocyclic group, the heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, the heteroaryl group is optionally further substituted by 0 to 4 heteroatoms selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent.

[0036] According to some specific embodiments of the present invention, in the compound of formula I or its pharmaceutically acceptable form, X is selected from C and O; R5 is selected from H and C 1-6 alkyl.

[0037] According to some specific embodiments of the present invention, in the compound of formula I or a pharmaceutically acceptable form thereof, R7 is H.

[0038] According to some specific embodiments of the present invention, in the compound of formula I of the present invention or a pharmaceutically acceptable form thereof, n is 0 or 1, and k is 1 or 2.

[0039] According to some specific embodiments of the present invention, in the compound of formula I or a pharmaceutically acceptable form thereof, R6 corresponds to the group or value shown in any one of Compounds 1 to 34.

[0040] According to some specific embodiments of the present invention, the compound of formula I or a pharmaceutically acceptable form thereof of the present invention has a structure shown in formula Ia:

[0041] in:

[0042] R8 is selected from amino,

[0043] k is 1 or 2.

[0044] According to some specific embodiments of the present invention, in Formula Ia of the present invention:

[0045] R8 is selected from amino,

[0046] k is 1.

[0047] According to some specific embodiments of the present invention, in the compound of formula I of the present invention or a pharmaceutically acceptable form thereof, R1, R2, R3, R4, R5, R6, R7, X, n, and k respectively correspond to the groups or values ​​shown in any one of Compounds 1 to 34.

[0048] According to some specific embodiments of the present invention, the compound of formula I or a pharmaceutically acceptable form thereof of the present invention is selected from one or more of the compounds shown in Table 1:

[0049] Table 1

[0050] According to some specific embodiments of the present invention, the compound of formula I of the present invention or a pharmaceutically acceptable form thereof, the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt or cocrystal, stereoisomer, tautomer, deuterated form, solvate, chelate, non-covalent complex or prodrug.

[0051] <Second Aspect>

[0052] The present invention also provides an intermediate compound having a structure shown in Formula II:

[0053] Wherein, R1, R2, R3, R4, R5, R7, X, n, k are as defined in any of the embodiments of the compound of formula I or its pharmaceutically acceptable form according to the <first aspect> of the present invention. 10 Each independently represents H, Boc, Cbz, SEM, Fmoc, Alloc, Pht, OTs, PMB, Bn, and Trt.

[0054] <Third Aspect>

[0055] The present invention also provides a method for preparing the compound of the first aspect of the present invention or a pharmaceutically acceptable form thereof. A synthetic route for preparing the compound of Formula I or a pharmaceutically acceptable form thereof can be designed based on the chemical structure of the compound of Formula I or a pharmaceutically acceptable form thereof, with reference to methods known in the art.

[0056] According to some specific embodiments of the present invention, the method of the present invention for preparing the compound of the first aspect of the present invention or a pharmaceutically acceptable form thereof comprises:

[0057] The intermediate compound of formula II described in the second aspect of the present invention has R9, R 10 The end of the reaction is modified to prepare a compound having structural formula I.

[0058] According to some specific embodiments of the present invention, the method of preparing the compound described in the <first aspect> of the present invention or a pharmaceutically acceptable form thereof also includes a process for preparing the intermediate compound described in the <second aspect> of the present invention.

[0059] According to some specific embodiments of the present invention, the method of preparing the compound of the first aspect of the present invention or a pharmaceutically acceptable form thereof comprises the steps shown in any reaction scheme in the examples.

[0060] <Fourth Aspect>

[0061] The present invention also provides a pharmaceutical composition comprising: the compound described in the <First Aspect> of the present invention or a pharmaceutically acceptable form thereof (preferably a pharmaceutically acceptable salt), and a pharmaceutically acceptable carrier, excipient and / or one or more other therapeutic agents.

[0062] <Fifth Aspect>

[0063] The present invention also provides the use of the compound described in the first aspect of the present invention or a pharmaceutically acceptable form thereof (preferably a pharmaceutically acceptable salt) or the pharmaceutical composition described in the fourth aspect of the present invention in the preparation of a formulation for inhibiting phosphodiesterase. Preferably, the phosphodiesterase includes PDE3 and / or PDE4.

[0064] <Sixth Aspect>

[0065] The present invention also provides the use of the compound described in the <first aspect> of the present invention or a pharmaceutically acceptable form thereof (preferably a pharmaceutically acceptable salt) or the pharmaceutical composition described in the <fourth aspect> of the present invention in the preparation of a drug for treating phosphodiesterase-related diseases.

[0066] The present invention also provides a method for treating phosphodiesterase-related diseases, which comprises administering to a subject an effective amount of the compound described in the <first aspect> of the present invention or a pharmaceutically acceptable form thereof (preferably a pharmaceutically acceptable salt) or the pharmaceutical composition described in the <fourth aspect> of the present invention.

[0067] According to some specific embodiments of the present invention, the phosphodiesterase comprises PDE3 and / or PDE4.

[0068] According to some specific embodiments of the present invention, the phosphodiesterase-related disease includes a respiratory disease such as asthma.

[0069] According to some specific embodiments of the present invention, the subject is a mammal or a human, preferably, the subject is a human.

[0070] The compound of the present invention having structural formula I or a pharmaceutically acceptable form thereof can be used as a phosphodiesterase inhibitor, has a highly effective inhibitory activity against phosphodiesterase, particularly PDE3 and / or PDE4, and has practical value.

[0071] Definition and Description

[0072] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0073] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed bond

[0074] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0075] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salts thereof" refers to salts of the compounds of the present invention prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases, as discovered herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, dihydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0076] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0077] The term "eutectic" refers to a crystalline material comprising two or more distinct solids at room temperature, each solid having different physical properties, such as structure, melting point, and heat of fusion.

[0078] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular asymmetric plane due to at least one chiral factor (including a chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane-polarized light. Because the compounds of the present invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Because the compounds of the present invention and their salts may include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, enantiomers, and mixtures of diastereomers. Typically, these compounds can be prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in a single stereoisomer (purity ≥98%, purity ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, or ≥80%). A single stereoisomer of a compound is synthesized from an optically active starting material containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, for example, by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatography, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds with a specific stereochemistry are either commercially available or prepared as described herein and resolved by methods well known in the art. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the compounds of the present invention.

[0079] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include (but are not limited to) interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the compounds of the present invention.

[0080] Unless otherwise indicated, the compounds represented by the structural formulae of the present invention may be in the form of a purified single stereoisomer or tautomer, or in the form of a mixture containing a plurality of stereoisomers or tautomers.

[0081] The term "solvate" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates, ethanolates, acetonides, etc.

[0082] The term "chelate" refers to a complex having a cyclic structure, which is obtained by the chelation of two or more ligands with the same metal ion to form a chelate ring.

[0083] The term "non-covalent complex" is formed by the interaction of a compound with another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also known as ionic bonding).

[0084] The term "prodrug" refers to a derivative compound that, upon application to a patient, is capable of providing, directly or indirectly, a compound of the invention. Particularly preferred derivative compounds or prodrugs are compounds that, when administered to a patient, can increase the bioavailability of the compound of the invention (e.g., more readily absorbed into the bloodstream) or compounds that facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the invention are within the scope of the invention, and various prodrug forms are well known in the art.

[0085] The term "each independently" means that at least two groups (or ring systems) present in a structure with the same or similar value ranges may have the same or different meanings in specific circumstances. For example, if substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y may be either hydrogen, or halogen, hydroxyl, cyano, alkyl, or aryl. Similarly, when substituent Y is hydrogen, substituent X may be either hydrogen, or halogen, hydroxyl, cyano, alkyl, or aryl.

[0086] The terms "including" and "comprising" are used in their open, non-limiting sense.

[0087] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0088] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0089] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0090] When a variable in a structural formula is selected as missing, it means that it does not exist. For example, when R in CR is selected as missing, it means that the structure is actually C.

[0091] When a variable connecting two groups in a structural formula is selected from a bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond or does not exist, it means that the structure is actually AZ.

[0092] When the substituents listed do not specify through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof. For example, a phenyl substituent can be connected to the substituted group through any carbon atom on the benzene ring.

[0093] Unless otherwise specified, the term "alkyl" is used to refer to a straight or branched saturated hydrocarbon group, which may be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3), and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0094] Unless otherwise specified, the term "alkylene" refers to a divalent straight or branched chain alkane group consisting only of carbon atoms and hydrogen atoms, containing no saturation, and connected to other fragments by two single bonds, including (but not limited to) methylene, 1,1-ethylene and 1,2-ethylene. For example, "C 1-3 "Alkylene" refers to a saturated divalent straight or branched chain alkyl group containing from 1 to 3 carbon atoms.

[0095] Unless otherwise specified, "cycloalkyl" includes any stable cyclic or polycyclic hydrocarbon radical, any carbon atom of which is saturated, which may be monosubstituted or polysubstituted, and which may be monovalent, divalent, or polyvalent. Examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like.

[0096] Unless otherwise specified, the term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. 1-5 Alkoxy groups include C1, C2, C3, C4, and C5 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S-pentoxy. The alkoxy group may be optionally substituted with one or more substituents described herein.

[0097] Unless otherwise specified, the term "3-6 membered ring" means a saturated or unsaturated monocyclic ring with or without heteroatoms, which contains 3, 4, 5 or 6 C, O, S, N atoms in the ring; the "3-6 membered ring" can be connected to the rest of the structural formula through any carbon atom or, if present, a nitrogen atom.

[0098] Unless otherwise specified, the term "amino" refers to -NH2, -NH(alkyl), or -N(alkyl)(alkyl).

[0099] Unless otherwise specified, the term "aromatic ring" means a polyunsaturated aromatic alkane monocyclic ring which may be mono- or polysubstituted.

[0100] Unless otherwise specified, the term "4-6 membered heterocycloalkyl" refers to a saturated monovalent monocyclic hydrocarbon ring containing 3, 4 or 5 carbon atoms and one or more radicals selected from O, NR a heteroatom group, wherein R a Represents hydrogen atom or C 1-6 Alkyl; the "4-6 membered heterocycloalkyl" may be attached to the rest of the molecule via any carbon atom or, if present, a nitrogen atom.

[0101] Unless otherwise specified, the term "heteroaromatic ring" refers to an aromatic ring containing one to four heteroatoms selected from one or more of N, O and S.

[0102] Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, for example, fused, bridged or spiro) non-aromatic group, the ring atoms of which are composed of carbon atoms and at least one heteroatom selected from N, O and S, wherein the S atom is optionally substituted to form S(=O), S(=O)2 or S(=O)(=NR x ), R x Independently selected from H or C 1-4Alkyl. If the valence bond requirements are met, the heterocyclic group can be attached to the rest of the molecule through any one of the ring atoms. For example, the term "3-8 membered heterocyclic group" as used in the present invention refers to a heterocyclic group having 3 to 8 ring atoms. For example, the heterocyclic group can be an oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl or trithianyl.

[0103] Unless otherwise specified, the term "aryl" refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π electron system. For example, the term "C 6-10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms. For example, the aromatic group may be phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthenyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like.

[0104] Unless otherwise specified, the term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic group having a conjugated π electron system, the ring atoms of which are composed of carbon atoms and at least one heteroatom selected from N, O and S. If the valence bond requirements are met, the heteroaryl group can be connected to the rest of the molecule through any one of the ring atoms. For example, the term "5-10 membered heteroaryl" as used in the present invention refers to a heteroaryl group having 5 to 10 ring atoms. For example, the heteroaryl group can be thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and benzo derivatives thereof, pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, purinyl, etc.

[0105] Unless otherwise specified, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). The term "hydroxy" refers to -OH. The term "cyano" refers to -CN. The term "amino" refers to -NH2.

[0106] Unless otherwise specified, the term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or a pharmaceutically acceptable form thereof with other chemical components, wherein "other chemical components" refers to a pharmaceutically acceptable carrier, excipient and / or one or more other therapeutic agents. "Carrier" refers to a material that does not significantly irritate the organism and does not eliminate the biological activity and properties of the administered compound. "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders and disintegrants.

[0107] The compound of the present invention has good PDE inhibitory activity and has potential application value in treating diseases related to PDE, especially diseases related to PDE3 / PDE4. DETAILED DESCRIPTION

[0108] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all commercially available conventional products.

[0109] The structures of the compounds were determined by nuclear magnetic resonance or mass spectrometry. Nuclear magnetic resonance was measured using a BRUKER 400M nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts (δ) were measured in 10 -6 The unit is ppm. Mass spectra were measured using a Waters ACQUITY Arc / ACQUITY QDa or a Thermo U3000-ISQ EC LC / MS instrument.

[0110] High-performance liquid chromatography (HPLC) analysis was performed using a Thermo U3000 HPLC, and preparative HPLC was performed using a Hanbon DAC-50 or Shimadzu LC-20AP preparative chromatograph.

[0111] Reaction monitoring was performed using thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvents used for TLC included dichloromethane and methanol, or petroleum ether and ethyl acetate. The solvent volume ratio was adjusted based on the polarity of the compound or by adding a small amount of triethylamine. LC-MS was performed using a Waters ACQUITY Arc / ACQUITY QDa or Thermo Fisher Scientific U3000-ISQ EC LC / MS instrument.

[0112] Column chromatography generally uses 200-300 mesh silica gel as a carrier. Eluent systems include: dichloromethane and methanol system, petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, or a small amount of triethylamine can be added to adjust the ratio.

[0113] Unless otherwise specified in the following examples, the reaction temperature was room temperature (20° C. to 30° C.), and the solvents were dried and purified according to standard methods.

[0114] Comparative Example Compound 1

[0115] Comparative Example Compound 2

[0116] Compounds of formula I according to the embodiments of the present invention

[0117] [R1, R2=CH3, CHF2, CD3]:

[0118] [R3,R4,R5=H,CH3,i-Pr,OMe,Halogen]:

[0119] [n=1,k=2,X=CH2]:

[0120] [n=0,k=1,X=CH2]:

[0121] [n=1,k=1,X=O]:

[0122] R6 is Wherein, R8=-NH-R 11 ,R 11 =H or C1-C6 alkyl:

[0123] R6 is Where R8 = -OR 11 ,R 11 =H or C1-C6 alkyl:

[0124] R6 is Wherein, R8=Cy represents a cyclic structure, preferably a five-membered aromatic ring:

[0125] R6 is Wherein, R8=Cy represents a cyclic structure, preferably a six-membered aromatic ring:

[0126] Example 1, Compound 6

[0127] Reaction route:

[0128] Experimental operation:

[0129] 1.

[0130] Under nitrogen, triethylamine (26.4 g, 260.2 mmol, 20.0 equiv), 1,3-bis(diphenylphosphino)propane (1.1 g, 2.6 mmol, 0.2 equiv), and palladium acetate (0.6 g, 2.6 mmol, 0.2 equiv) were added portionwise to a solution of 2-chloro-6,8-dimethylquinoline (2.5 g, 13.1 mmol, 1.0 equiv) and methyl acrylate (11.2 g, 130.1 mmol, 10.0 equiv) in N,N-dimethylformamide (20 mL) at room temperature. The resulting residue was stirred and reacted overnight at 100°C under nitrogen. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were backwashed with saturated sodium chloride solution (2 x 30 mL) and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give methyl (2E)-3-(6,8-dimethylquinolin-2-yl)prop-2-enoate (1.5 g, yield 43%) as a solid.

[0131] LCMS (ESI, m / z): [M+H] + =242.11

[0132] 2.

[0133] To the autoclave was added 50 ml of a methanol solution of methyl (2E)-3-(6,8-dimethylquinolin-2-yl)prop-2-enoate (1.5 g, 6.2 mmol, 1.0 equiv), followed by palladium on carbon (10%, 0.66 g). The atmosphere was replaced with nitrogen, and hydrogen was introduced at 20 bar, allowing the reaction to proceed overnight at room temperature. Celite was then added for filtration, and the filtrate was concentrated under reduced pressure. This afforded methyl 3-(6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)propanoate (1.5 g crude product).

[0134] LCMS (ESI, m / z): [M+H] + =248.16

[0135] 3.

[0136] Under nitrogen protection, to a solution of methyl 3-(6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)propanoate (350 mg, 1.4 mmol, 1.0 eq) and cesium carbonate (922 mg, 2.8 mmol, 2.0 eq) in 1,4-dioxane (5 ml) was added portionwise 2-chloro-9,10-dimethoxy-6H,7H-pyrimido[4,3-a] ] isoquinolin-4-one (828 mg, 2.8 mmol, 2.0 eq) and methanesulfonic acid {[4-(N,N-(dimethylamino)phenyl]di-tert-butylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (180 mg, 0.3 mmol, 0.2 eq). The resulting residue was stirred and reacted overnight at 100 degrees Celsius under nitrogen protection. The filter cake was washed with ethyl acetate (3x The reaction mixture was washed with 50 mL of water (50 mL), and the filtrate was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were backwashed with saturated sodium chloride solution (2 x 30 mL), and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography using the following conditions: a C18 column, a mobile phase of water and acetonitrile, a gradient from 10% to 90% over 60 minutes, and a UV detector at 254 nm. This afforded 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one as a solid (120 mg, 15% yield).

[0137] LCMS (ESI, m / z): [M+H] + =504.24

[0138] 4.

[0139] Under nitrogen, a solution of 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one (240 mg, 0.5 mmol, 1.0 equiv) and lithium hydroxide (23 mg, 1.0 mmol, 2.0 equiv) in methanol (2 mL) and H₂O (2 mL) was stirred overnight at room temperature. The reaction mixture was acidified to pH 4 with hydrochloric acid. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were backwashed with saturated sodium chloride solution (2 x 50 mL) and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. 3-(1-(9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrimidin[6,1-a]isoquinolin-2-yl)-6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)propanoic acid (180 mg, yield 69%) was obtained.

[0140] LCMS (ESI, m / z): [M+H]+=490.23

[0141] 5.

[0142] Under nitrogen, to a solution of 3-(1-(9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrimidin[6,1-a]isoquinolin-2-yl)-6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)propanoic acid (250 mg, 0.5 mmol, 1.0 equiv) and triethylamine (155 mg, 1.5 mmol, 3.0 equiv) in 1,4-dioxane (2 mL) was added diphenylphosphoryl azide (281 mg, 1.0 mmol, 2.0 equiv) portionwise at room temperature. The resulting residue was stirred at room temperature under nitrogen for 2 hours, then heated to 100°C and stirred for 1 hour. The mixture was cooled to room temperature, and a methanolic ammonia solution (5 mL) was added. The resulting residue was stirred at room temperature under nitrogen for 1 hour. The resulting residue was purified by reverse-phase column chromatography using the following conditions: column specifications, mobile phase: water and acetonitrile, gradient from 10% to 90% over 30 minutes, UV detector at 254 nm. This yielded 3-(1-(9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrimidin[6,1-a]isoquinolin-2-yl)-6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)ethylurea (200 mg, 70% yield).

[0143] LCMS (ESI, m / z): [M+H]+=504.25

[0144] 6.

[0145] Under nitrogen, a solution of 3-(1-(9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrimidin[6,1-a]isoquinolin-2-yl)-6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)ethylurea (250 mg, 0.5 mmol, 1.0 equiv) and sodium hydroxide (397 mg, 10.0 mmol, 20.0 equiv) in dimethyl sulfoxide (10 mL) and water (0.5 mL) was stirred overnight at 120°C. The resulting residue was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography using the following conditions: column specifications, mobile phase: water (0.1% formic acid) and acetonitrile, gradient from 10% to 90% over 30 minutes, UV detection at 254 nm. 3-(1-(9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrimidin[6,1-a]isoquinolin-2-yl)6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)ethylamine (90 mg, yield 35%) was obtained.

[0146] LCMS (ESI, m / z): [M+H]+=461.25

[0147] 7.

[0148] Under nitrogen protection, to a solution of 3-(1-(9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrimidin[6,1-a]isoquinolin-2-yl)-6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)ethylamine (40 mg, 0.09 mmol, 1.0 equiv) and 1H-imidazole-2-carboxylic acid (12 mg, 0.1 mmol, 1.2 equiv) in N,N-dimethylformamide (1 ml) were added portionwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 0.13 mmol, 1.5 equiv) and 1-hydroxybenzotriazole (18 mg, 0.13 mmol, 1.5 equiv) at room temperature. The resulting residue was stirred under nitrogen protection at room temperature for 1 hour. The crude product was purified by HPLC to give N-[2-(1-(9,10-dimethoxy-4-oxo-6H,7H-pyrimidin[4,3-a]isoquinolin-2-yl-6,8-dimethyl-3,4-dihydro-2H-quinolin-2-yl)ethyl]-1H-imidazole-2-carboxamide (10.61 mg, 22% yield) under the following conditions (column: XBridge BEH Shield RP18 5 μm, 30 mm × 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient (B%): 34% B to 54% B in 8 minutes; wavelength: 254 / 220 nm; RT1 (min): 7.35).

[0149] LCMS (ESI, m / z): [M+H] + =555.26

[0150] 1 H NMR(400MHz,Methanol-d4)δ7.25–7.01(m,4H),6.96(s,1H),6.82(s,1H),5.79 (s,1H),5.34–5.27(m,1H),4.32–4.24(m,1H),4.08–4.00(m,1H),3.91(s,3H),3 .73(s,4H),3.38(d,J=9.3Hz,1H),3.00(t,J=6.8Hz,2H),2.63–2.50(m,2H),2.3 8(s,4H),2.20(s,3H),1.81–1.71(m,1H),1.65–1.56(m,1H),1.39–1.29(m,1H).

[0151] Example 2, Compound 24

[0152] Reaction route:

[0153] Experimental operation:

[0154] Under nitrogen protection, to a solution of 3-(1-(9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrimidin[6,1-a]isoquinolin-2-yl)-6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)ethylamine (40 mg, 0.09 mmol, 1.0 equiv) and 2-pyridinecarboxylic acid (13 mg, 0.1 mmol, 1.2 equiv) in N,N-dimethylformamide (1 ml) were added portionwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 0.13 mmol, 1.5 equiv) and 1-hydroxybenzotriazole (17 mg, 0.13 mmol, 1.5 equiv) at room temperature. The resulting residue was stirred under nitrogen protection at room temperature for 1 hour. The crude product was purified by HPLC to give N-(2-(1-(9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-2-yl)-6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)ethyl)picolinamide (10.82 mg, 21.4% yield) under the following conditions (column: XBridge BEH C18 OBD Prep Column, 5 μm, 30 mm x 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: ACN; flow rate: 60 mL / min; gradient (B%): 35% B to 60% B in 10 min; wavelength: 254 / 220 nm; RT1 (min): 8.02).

[0155] LCMS (ESI, m / z): [M+H] + =566.27

[0156] 1H NMR(400MHz, Methanol-d4)δ8.60(d,J=4.5Hz,1H),8.07(d,J=7.8Hz,1H),7.98–7.92(m,1H),7 .55–7.50(m,1H),7.15–7.01(m,2H),6.96(s,1H),6.81(s,1H),5.76(s,1H),5.46–5.37(m,1H), 4.31–4.24(m,1H),4.06–3.98(m,1H),3.91(s,3H),3.72(s,4H),3.61–3.53(m,1H),3.01(d,J= 6.0Hz,2H),2.63–2.51(m,2H),2.37(s,4H),2.15(s,3H),1.75–1.67(m,2H),1.39–1.30(m,1H).

[0157] Other Example Compounds

[0158] The compound of formula I of the present invention was synthesized, and the MS data are shown in Table 2. Among them, for [M+H] + , H uses a value of 1.01.

[0159] Table 2

[0160] PDE enzyme activity inhibition assay

[0161] The compounds of each example were tested for inhibition of PDE enzyme activity using the FP method, and comparative example compound 1 (compound RPL-554 of Example 1 of CN100415743C) and comparative example compound 2 were used as positive controls.

[0162] Prepare PDE enzyme and substrate (FAM-cyclic AMP / cyclic AMP) solutions in reaction buffer (1× IMAP Reaction Buffer containing 0.1% BSA supplemented with 1 mM DTT). The positive control has a starting concentration of 1 / 10 μM in PDE, with 3-fold dilutions and a 10+0 dose. 0.05 μL of compound in 100% DMSO was delivered to a 384-well plate (Corning 4514) using acoustic liquid delivery technology (Echo 655) and centrifuged at 1000 rpm for 1 minute. 2.5 μL of PDE enzyme solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 10 minutes. 2.5 μL of Sub solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 60 minutes. 15 μL of binder mixture was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 60 minutes. FP signals were read using a BMG (PHERAstar FSX). IC50 values ​​and nonlinear regression curve fitting were obtained using GraphPad Prism software.

[0163] Measurement of enzyme activity of each compound in comparative example and example IC 50 IC 50 The smaller the value, the less amount of compound is needed to achieve half inhibition of the different PDE enzymes, indicating that the inhibitory activity is stronger. The results are shown in Table 3.

[0164] Table 3

[0165] The results show that the compound of the present invention has a highly effective inhibitory activity on PDE3 / 4 and has practical value.

[0166] The above description is only a specific embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable form thereof, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt or cocrystal, stereoisomer, tautomer, deuterated form, solvate, chelate, non-covalent complex or prodrug: in: R1 and R2 are each independently selected from H, C 1-6 Straight chain alkyl, C 3-6 Branched alkyl and C 3-6 Cycloalkyl; the linear alkyl, branched alkyl or cycloalkyl is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R3 and R4 are each independently selected from H, halogen, CN, C 1-6 Alkoxy, C 1-6 Straight chain alkyl, C 3-6 Branched alkyl and C 3-6 Cycloalkyl; the alkoxy, linear alkyl, branched alkyl or cycloalkyl may be further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; X is selected from C, N, O and S; R5 is selected from H, halogen, CN, C 1-6 Alkoxy, C 1-6 Straight chain alkyl, C 3-6 Branched alkyl and C 3-6 Cycloalkyl; R6 is Wherein, Y is O or S, R8 is selected from amino, C 1-6 Alkoxy, C 3-12 Cycloalkyl, C 6-10 Aryl, C 5-10 A heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O and S, and the amino, alkoxy, cycloalkyl, aryl, heteroaryl are optionally further substituted by 0 to 4 atoms selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1- 4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent; R7 is selected from H, =O, NH2, CN, C 1-6 Straight chain alkyl, C 3-6 Branched alkyl, C 3-6 Cycloalkyl and The H in R7 is optionally further replaced by 0 to 4 selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; n is 0, 1 or 2; k is 0, 1, or 2; Optionally, H of the compound of formula I is optionally further substituted with 0 to 6 Ds.

2. The compound according to claim 1 or a pharmaceutically acceptable form thereof, wherein: R1 and R2 are each independently selected from H, CH3, CHF2, and CD3.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein: R3, R4, and R5 are each independently selected from H, CH3, i-Pr, OMe, CN, CD3 or halogen.

4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable form thereof, wherein: R6 is wherein R8 is selected from amino, and the amino group is optionally further substituted by 0 or 1 selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent; or R6 is Wherein R8 is selected from C 1-6 Alkoxy, the alkoxy optionally further substituted by 0 to 4 selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent; or R6 is Wherein R8 is selected from C 3-12 Cycloalkyl, the cycloalkyl optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent; or R6 is Wherein R8 is selected from C 6-10 Aryl, which is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent; or R6 is Wherein R8 is selected from C 5-10 A heterocyclic group, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, and the heteroaryl group is optionally further substituted by 0 to 4 heteroatoms selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable form thereof, wherein: X is selected from C and O; R5 is selected from H and C 1-6 alkyl.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable form thereof, wherein: R7 is H; n is 0 or 1, and k is 1 or 2.

7. The compound according to claim 1 or a pharmaceutically acceptable form thereof, wherein: The compound has the structure shown in Formula Ia: in: R8 is selected from amino, k is 1 or 2.

8. The compound according to claim 7 or a pharmaceutically acceptable form thereof, wherein: R8 is selected from amino, k is 1.

9. The compound according to claim 1 or a pharmaceutically acceptable form thereof, wherein: The compound is selected from one or more of the following compounds:

10. An intermediate compound having a structure shown in Formula II: in, R1, R2, R3, R4, R5, R7, X, n, k are as defined in any one of claims 1 to 9; R9, R 10 Each independently represents H, Boc, Cbz, SEM, Fmoc, Alloc, Pht, OTs, PMB, Bn, and Trt.

11. A method for preparing a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable form thereof, the method comprising: For the intermediate compound of claim 10, R9, R 10 The end is subjected to modification reaction to prepare a compound having structural formula I.

12. The method according to claim 11, further comprising a process for preparing the intermediate compound according to claim 10.

13. A pharmaceutical composition comprising: A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient and / or one or more other therapeutic agents.

14. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable form thereof or the pharmaceutical composition according to claim 13 in the preparation of a preparation for inhibiting phosphodiesterase.

15. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable form thereof or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a phosphodiesterase-related disease; Preferably, the phosphodiesterase-related disease comprises a respiratory disease such as asthma.

Images