Tricyclic fused heterocyclic PDE3 / 4 dual inhibitor compounds and their uses

Abstract

This invention discloses a tricyclic fused heterocyclic compound of formula (I) having dual PDE3 / 4 inhibitory activity, its stereoisomers, solvates, or pharmaceutically acceptable salts, and its use in the preparation of medicines for the treatment / prevention of PDE3 / 4 mediated diseases, wherein each group in formula (I) is as defined in the specification.

Description

[Technical Field]

[0001] This invention relates to a PDE3 / 4 dual inhibitor and its use in the preparation of medicines for treating COPD and asthma. [Previous Technology]

[0002] COPD (chronic obstructive pulmonary disease) is a group of lung diseases characterized by airflow limitation that is not completely reversible and progresses over time. It primarily affects the lungs and is the most common chronic killer of lung health. COPD has a high incidence and mortality rate. One reason is the difficulty in early diagnosis; COPD often has an insidious onset, and once clinical manifestations appear, it often indicates a gradual decline in the patient's overall health and a gradual increase in respiratory symptoms. Another reason is that COPD is currently incurable. Treatment mainly relies on bronchodilators that regulate airway smooth muscle. These drugs can only relieve symptoms and delay disease progression, treating the symptoms but not the root cause. COPD has a long course, requiring frequent medical visits, hospitalization due to acute exacerbations, and long-term care, consuming significant medical resources. It has become a serious global disease burden. Therefore, for COPD, new drugs need to be developed targeting different areas to meet diverse clinical needs.

[0003] Phosphodiesterases (PDEs) belong to a superfamily of enzymes, comprising 11 families, each involved in different signal transduction and regulating different physiological processes. Studies have found that PDE3 is associated with the contraction of respiratory smooth muscle, while PDE4 plays a key role in the inflammatory response induced by immune cells. Given the limitations of selective PDE3 or PDE4 inhibitors in clinical practice, dual PDE3 / 4 inhibitors appear to be a more attractive approach for targeting key pathological features of COPD and asthma. Current evidence shows that dual PDE3 / 4 inhibitors have synergistic inhibitory effects, including synergistic anti-inflammatory and bronchodilatory effects. WO2000058308A1 reported that compound RPL554 has long-acting bronchodilatory and anti-inflammatory effects, but this drug has poor solubility and high plasma clearance, making it suitable for inhalation administration. Bioactivity data shows that its PDE4 inhibitory activity is unsatisfactory, which may lead to less than ideal anti-inflammatory effects. Therefore, dual PDE3 / 4 inhibitors still warrant further investigation. [Summary of the Invention]

[0004] The present invention provides a compound of formula (I) or formula (II), its stereoisomer, solvate, or pharmaceutically acceptable salt, wherein the compound has excellent effects of good activity, convenient physicochemical properties for formulation, high bioavailability, and low toxicity.

[0005] The compounds of formula (I) or (II), their stereoisomers, solvates, or pharmaceutically acceptable salts,

[0005]

[0006] wherein, R1, R2, Ra and Rb are independently H, deuterium, halogen, CN, OH, NH2, -NHC1-4 alkyl, -N(C1-4 alkyl)2, -OC1-4 alkyl, -O(CH2)mC3-6 cycloalkyl, -O(CH2)m phenyl, -O(CH2)m-containing 1-3 4-7 member heterocycloalkyl selected from N, S, O heteroatoms, -O(CH2)m-containing 1-3 5-6 member heteroaryl selected from N, S, O heteroatoms, C1-4 alkyl, -(CH2)mC3-6 cycloalkyl, -(CH2)m phenyl, -(CH2)m- contains 1-3 heterocyclic alkyl groups of 4-7 members selected from N, S, and O heteroatoms, or -(CH2)m- contains 1-3 heteroaryl groups of 5-6 members selected from N, S, and O heteroatoms, wherein the alkyl, phenyl, cycloalkyl, heterocyclic alkyl, and heteroaryl groups are further substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, deuterated C1-4 alkyl, deuterated C1-4 alkoxy, halo-C1-4 alkoxy, CN, NH2, -NHC1-4 alkyl, -N(C1-4 alkyl)2, and OH groups;

[0007] In some instances, R1, R2, Ra, and Rb are independently H, deuterium, halogen, CN, OH, NH2, -NHC1-4 alkyl, -N(C1-4 alkyl)2, -OC1-4 alkyl, -O(CH2)mC3-6 cycloalkyl, -O(CH2)m-containing 1-3 4-7 heterocycloalkyl groups selected from N, S, and O heteroatoms, C1-4 alkyl, -(CH2) -(CH2)m- contains 1-3 4-7 heterocyclic alkyl groups selected from N, S, and O heteroatoms, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups are further substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, deuterated C1-4 alkyl, deuterated C1-4 alkoxy, and halo-C1-4 alkoxy groups, depending on the case.

[0008] In some instances, R1, R2, Ra and Rb are independently H, deuterium, halogen, CN, OH, -OC1-4 alkyl, -O(CH2)mC3-6 cycloalkyl, C1-4 alkyl, or -(CH2)mC3-6 cycloalkyl, wherein the alkyl and cycloalkyl groups are further substituted by 1 to 3 groups selected from deuterium, halogen, C1-4 alkyl, C1-4 alkoxy, deuterated C1-4 alkyl, deuterated C1-4 alkoxy and halo-C1-4 alkoxy;

[0009] In some instances, R1, R2, Ra and Rb are independently H, methoxy, ethoxy, propoxy, isopropoxy, -O(CH2)mcyclopropyl, methyl, ethyl, propyl, isopropyl or -(CH2)mcyclopropyl, wherein the methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, methyl, ethyl, propyl, isopropyl and cyclopropyl are further substituted, as appropriate, with 1 to 3 groups selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, halomethoxy, haloethoxy, halopropoxy;

[0010] Optionally, R1 and R2 and the atoms connected to them together form a 5-7 member heterocycle or a C4-7 carbon ring containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle and carbon ring are substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, halo-C1-4 alkyl, C2-4 alkenyl, C2-4 alkoxy, C1-4 alkoxy, deuterated C1-4 alkoxy, and halo-C1-4 alkoxy.

[0011] In some instances, R1 and R2 and the atoms they are connected to together form a 5-6 member heterocycle or C5-6 carbon ring containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle and carbon ring are, as appropriate, substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, deuterated C1-4 alkoxy, and halo-C1-4 alkoxy;

[0012] In some instances, R1 and R2 and the atoms they are connected to together form a 5-6 member heterocycle or C5-6 carbon ring containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle and carbon ring are substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, halo-C1-4 alkyl, and C1-4 alkoxy groups, depending on the situation;

[0013] In some instances, R1 and R2 and the atoms they are attached to are formed together and, depending on the case, are replaced by 1-2 groups selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, halomethyl, haloethyl and halopropyl.

[0014] R3, R4, R5, R6 are independently H, deuterium, halogen, C1-4 alkyl, -(CH2)mC3-6 cycloalkyl, wherein the alkyl and cycloalkyl are, as appropriate, substituted by 1-3 groups selected from deuterium, halogen, CN and NH2;

[0015] In some instances, R3, R4, R5, and R6 are independently H, deuterium, halogen, and C1-4 alkyl, wherein the alkyl is substituted by 1 to 3 groups selected from deuterium, halogen, CN, and NH2, depending on the situation;

[0016] In some instances, R3 and R4 are independently H, deuterium, halogen and C1-4 alkyl, said alkyl being substituted by 1 to 3 groups selected from deuterium, F, Cl, Br and I, and R5 and R6 are independently H;

[0017] In some instances, R3 and R4 are independently H, deuterium, F, Cl, Br, I, methyl, ethyl or propyl, wherein the methyl, ethyl or propyl is substituted by 1 to 3 groups selected from deuterium, F, Cl, Br and I, and R5 and R6 are independently H;

[0018] Optionally, R3 and R4, or R5 and R6 together with the carbon atoms to which they are attached, form a C3-6 cycloalkyl group;

[0019] X is CO or SO2; in some instances, X is CO;

[0020] Ring A is phenyl, C9-10 fused carbide ring, or contains 1-3 5-6 heteroaryl groups selected from N, S, and O heteroatoms;

[0021] In some instances, ring A is phenyl, (any ring atom on the point ring that conforms to the rules of chemical bonding), pyridyl, pyrimidinyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl;

[0022] In some instances, ring A is phenyl, (any ring atom on the point ring that conforms to the rules of chemical bonding), thiophene, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl;

[0023] In some instances, ring A is phenyl, (any ring atom on the point ring that conforms to the rules of chemical bonding), thiophene, or thiazolyl;

[0024] L1 is a C1-6 alkylene group, which is substituted by 1-3 groups selected from deuterium, halogen, C2-4 alkenyl, C2-4 alkoxy, C1-4 alkoxy, deuterated C1-4 alkoxy and halo-C1-4 alkoxy as appropriate;

[0025] In some instances, L1 is a C2-4 alkylene group, which is substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkoxy, deuterated C1-4 alkoxy and halo-C1-4 alkoxy as appropriate;

[0026] In some instances, L1 is a C2-4 alkylene group;

[0027] R7 is H, C1-4 alkyl or -(CH2)mC3-6 cycloalkyl, wherein the alkyl and cycloalkyl are substituted by 1 to 3 groups selected from deuterium, halogen, C2-4 alkenyl, C2-4 alkoxy, C1-4 alkoxy, deuterated C1-4 alkoxy and halo-C1-4 alkoxy;

[0028] In some instances, R7 is H or C1-4 alkyl, which is substituted by 1 to 3 groups selected from deuterium, halogen, C1-4 alkoxy, deuterated C1-4 alkoxy and halo-C1-4 alkoxy as appropriate;

[0029] In some instances, R7 is H or C1-3 alkyl, which is substituted by 1 to 3 groups selected from deuterium, halogen, C1-4 alkoxy, deuterated C1-4 alkoxy and halo-C1-4 alkoxy as appropriate;

[0030] In some instances, R7 is H, methyl, ethyl, propyl, or isopropyl, wherein the methyl, ethyl, propyl, or isopropyl group is, as appropriate, substituted with 1 to 3 groups selected from deuterium, F, Cl, Br, I, methoxy, ethoxy, propoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, halomethoxy, haloethoxy, and halopropoxy;

[0031] R8 and R9 are independently H, C1-4 alkyl and C3-6 cycloalkyl;

[0032] In some instances, R8 and R9 are independently H;

[0033] Optionally, R8 and R9 together with the N atom they are attached to form a 5-6 member heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle is substituted by 1-3 groups selected from O, deuterium, halogen, C1-4 alkyl, C1-4 alkoxy, deuterated C1-4 alkoxy, and halo-C1-4 alkoxy.

[0034] In some instances, R8 and R9 together with the N atom to which they are attached form a 5-6 member heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle is substituted by 1-3 groups selected from O, deuterium, halogen, C1-4 alkyl and C1-4 alkoxy groups, depending on the case.

[0035] Each R10 is independently H, halogen, CN, NH2, -NHC1-4 alkyl, -N(C1-4 alkyl)2, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -(CH2)m-C3-6 cycloalkyl, -O-C3-6 cycloalkyl or C1-4 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and alkoxy groups are, as appropriate, substituted by 1 to 3 groups selected from deuterium, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, CN, NH2, -NHC1-4 alkyl, -N(C1-4 alkyl)2 and OH;

[0036] In some instances, each R10 is independently H, halogen, CN, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl or C1-4 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and alkoxy are, as appropriate, substituted by 1 to 3 groups selected from deuterium, halogen, C1-4 alkyl and CN;

[0037] In some instances, each R10 is independently H, halogen, CN, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-4 cycloalkyl or C1-4 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and alkoxy are, as appropriate, substituted by 1 to 3 groups selected from deuterium, halogen, C1-4 alkyl and CN;

[0038] In some instances, each R10 is independently H, F, Cl, Br, I, CN, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, or propoxy, wherein the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, and propoxy groups are, as appropriate, substituted by 1 to 3 groups selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, and CN;

[0039] n is 0, 1, 2, 3 or 4;

[0040] In some instances, n is 0, 1, 2 or 3;

[0041] Each m is independently 0, 1, 2, 3 or 4;

[0042] In some instances, each m is independently 0, 1, 2, or 3;

[0043] q is 2 or 3;

[0044] Conditional system, when , R10', R10”, R10''' are as defined by R10, the compound satisfies:

[0045] (i) R1 and R2 are not both methoxy groups; or

[0046] (ii) R3, R4, R5, and R6 are not all H at the same time; or

[0047] (iii)R10''' is not H or methyl.

[0048] As a more specific first technical solution of the present invention, a compound of formula (I) is provided, its stereoisomer, solvate, or pharmaceutically acceptable salt.

[0048]

[0049] wherein, R1, R2, Ra and Rb are independently H, deuterium, halogen, CN, OH, NH2, -NHC1-4 alkyl, -N(C1-4 alkyl)2, -OC1-4 alkyl, -O(CH2)mC3-6 cycloalkyl, -O(CH2)m phenyl, -O(CH2)m-containing 1-3 4-7 member heterocycloalkyl selected from N, S, O heteroatoms, -O(CH2)m-containing 1-3 5-6 member heteroaryl selected from N, S, O heteroatoms, C1-4 alkyl, -(CH2)mC3-6 cycloalkyl, -(CH2)m phenyl, -(CH2)m- contains 1-3 heterocyclic alkyl groups of 4-7 members selected from N, S, and O heteroatoms, or -(CH2)m- contains 1-3 heteroaryl groups of 5-6 members selected from N, S, and O heteroatoms, wherein the alkyl, phenyl, cycloalkyl, heterocyclic alkyl, and heteroaryl groups are further substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, deuterated C1-4 alkyl, deuterated C1-4 alkoxy, halo-C1-4 alkoxy, CN, NH2, -NHC1-4 alkyl, -N(C1-4 alkyl)2, and OH groups;

[0050] Optionally, R1 and R2 and the atoms connected to them together form a 5-7 member heterocycle or a C4-7 carbon ring containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle and carbon ring are substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, halo-C1-4 alkyl, C2-4 alkenyl, C2-4 alkoxy, C1-4 alkoxy, deuterated C1-4 alkoxy, and halo-C1-4 alkoxy.

[0051] R3, R4, R5, R6 are independently H, deuterium, halogen, C1-4 alkyl, -(CH2)mC3-6 cycloalkyl, wherein the alkyl and cycloalkyl are, as appropriate, substituted by 1-3 groups selected from deuterium, halogen, CN and NH2;

[0052] Optionally, R3 and R4, or R5 and R6 together with the carbon atoms to which they are attached, form a C3-6 cycloalkyl group;

[0053] X is CO or SO2;

[0054] Ring A is phenyl, C9-10 fused carbide ring, or contains 1-3 5-6 heteroaryl groups selected from N, S, and O heteroatoms;

[0055] L1 is a C1-6 alkylene group, wherein the alkylene group is substituted by 1-3 groups selected from deuterium, halogen, C2-4 alkenyl, C2-4 alkoxy, C1-4 alkoxy, deuterated C1-4 alkoxy and halo-C1-4 alkoxy groups as appropriate;

[0056] R7 is H, C1-4 alkyl or -(CH2)mC3-6 cycloalkyl, wherein the alkyl and cycloalkyl are substituted by 1-3 groups selected from deuterium, halogen, C2-4 alkenyl, C2-4 alkoxy, C1-4 alkoxy, deuterated C1-4 alkoxy and halo-C1-4 alkoxy;

[0057] R8 and R9 are independently H, C1-4 alkyl and C3-6 cycloalkyl;

[0058] Optionally, R8 and R9 together with the N atom they are attached to form a 5-6 member heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle is substituted by 1-3 groups selected from O, deuterium, halogen, C1-4 alkyl, C1-4 alkoxy, deuterated C1-4 alkoxy, and halo-C1-4 alkoxy.

[0059] Each R10 is independently H, halogen, CN, NH2, -NHC1-4 alkyl, -N(C1-4 alkyl)2, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -(CH2)m-C3-6 cycloalkyl, -O-C3-6 cycloalkyl or C1-4 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and alkoxy groups are, as appropriate, substituted by 1 to 3 groups selected from deuterium, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, CN, NH2, -NHC1-4 alkyl, -N(C1-4 alkyl)2 and OH;

[0060] n is 0, 1, 2, 3 or 4;

[0061] Each m is independently 0, 1, 2, 3 or 4;

[0062] Conditional system, when , R10', R10”, R10''' are as defined by R10, the compound satisfies:

[0063] (iv) R1 and R2 are not both methoxy groups; or

[0064] (v) R3, R4, R5, and R6 are not simultaneously H; or

[0065] (vi)R10''' is not H or methyl.

[0066] As a more specific second technical solution of the present invention, the compound of formula I, its stereoisomer, solvate, or pharmaceutically acceptable salt, wherein R1, R2, Ra, and Rb are independently H, deuterium, halogen, CN, OH, NH2, -NHC1-4 alkyl, -N(C1-4 alkyl)2, -OC1-4 alkyl, -O(CH2)mC3-6 cycloalkyl, -O(CH2)m-containing 1-3 heteroatoms selected from N, S, and O. The 4-7 member heterocyclic alkyl, C1-4 alkyl, -(CH2)mC3-6 cycloalkyl, or -(CH2)m-containing 1-3 4-7 member heterocyclic alkyl groups selected from N, S, and O heteroatoms, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups are further substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, deuterated C1-4 alkyl, deuterated C1-4 alkoxy, and halo-C1-4 alkoxy groups, depending on the case.

[0067] Optionally, R1 and R2 and the atoms connected to them together form a 5-6 member heterocycle or C5-6 carbon ring containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle and carbon ring are substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, deuterated C1-4 alkoxy, and halo-C1-4 alkoxy.

[0068] R3, R4, R5, and R6 are independently H, deuterium, halogen, and C1-4 alkyl, wherein the alkyl is substituted by 1-3 groups selected from deuterium, halogen, CN, and NH2, depending on the situation;

[0069] Ring A is phenyl, pyridinyl, pyrimidinyl, thienyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl;

[0070] L1 is a C2-4 alkylene group, which is substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkoxy, deuterated C1-4 alkoxy and halo-C1-4 alkoxy as appropriate;

[0071] R7 is H or C1-4 alkyl, wherein the alkyl group is substituted by 1 to 3 groups selected from deuterium, halogen, C1-4 alkoxy, deuterated C1-4 alkoxy and halo-C1-4 alkoxy as appropriate;

[0072] R8 and R9 are independently H, C1-4 alkyl and C3-6 cycloalkyl;

[0073] Optionally, R8 and R9 together with the N atom they are attached to form a 5-6 member heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle is substituted by 1-3 groups selected from O, deuterium, halogen, C1-4 alkyl and C1-4 alkoxy groups as appropriate;

[0074] Each R10 is independently H, halogen, CN, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl or C1-4 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and alkoxy are, as appropriate, substituted by 1 to 3 groups selected from deuterium, halogen, C1-4 alkyl and CN;

[0075] p is 1 or 2;

[0076] The rest are as described in the first technical solution.

[0077] As a more specific third technical solution of the present invention, the compound of formula I, its stereoisomer, solvate, or pharmaceutically acceptable salt, wherein the compound has the structure of formula II:

[0077]

[0078] wherein, R1, R2, Ra and Rb are independently H, deuterium, halogen, CN, OH, -OC1-4 alkyl, -O(CH2)mC3-6 cycloalkyl, C1-4 alkyl, or -(CH2)mC3-6 cycloalkyl, wherein the alkyl and cycloalkyl are further substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, C1-4 alkoxy, deuterated C1-4 alkyl, deuterated C1-4 alkoxy and halo-C1-4 alkoxy;

[0079] Optionally, R1 and R2 and the atoms connected to them together form a 5-6 member heterocycle or C5-6 carbon ring containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle and carbon ring are substituted by 1-3 groups selected from deuterium, halogen, C1-4 alkyl, halo-C1-4 alkyl, and C1-4 alkoxy groups as appropriate;

[0080] R3 and R4 are independently H, deuterium, halogen and C1-4 alkyl, wherein the alkyl is substituted by 1 to 3 groups selected from deuterium, F, Cl, Br and I as appropriate;

[0081] Ring A is phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl;

[0082] R7 is H or C1-3 alkyl, wherein the alkyl group is substituted by 1 to 3 groups selected from deuterium, halogen, C1-4 alkoxy, deuterated C1-4 alkoxy and halo-C1-4 alkoxy as appropriate;

[0083] Each R10 is independently H, halogen, CN, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-4 cycloalkyl or C1-4 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and alkoxy are, as appropriate, replaced by 1 to 3 groups selected from deuterium, halogen, C1-4 alkyl and CN;

[0084] q is 1, 2, or 3;

[0085] The rest are as described in the second technical solution.

[0086] As a more specific fourth technical solution of the present invention, the compound of formula II, its stereoisomer, solvate, or pharmaceutically acceptable salt, wherein R1, R2, Ra and Rb are independently H, methoxy, ethoxy, propoxy, isopropoxy, -O(CH2)mcyclopropyl, methyl, ethyl, propyl, isopropyl or -(CH2)mcyclopropyl, wherein the methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, methyl, ethyl, propyl, isopropyl and cyclopropyl are further substituted by 1-3 groups selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, halomethoxy, haloethoxy, halopropoxy;

[0087] Optionally, R1 and R2 and the atoms connected to them are formed together and are replaced by 1-2 groups selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, halomethyl, haloethyl and halopropyl, depending on the situation.

[0088] R3 and R4 are independently H, deuterium, F, Cl, Br, I, methyl, ethyl or propyl, wherein the methyl, ethyl or propyl group is substituted by 1 to 3 groups selected from deuterium, F, Cl, Br and I as appropriate;

[0089] Ring A is phenyl, thiophene, or thiazolyl;

[0090] R7 is H, methyl, ethyl, propyl or isopropyl, wherein the methyl, ethyl, propyl or isopropyl group is, as appropriate, substituted with 1 to 3 groups selected from deuterium, F, Cl, Br, I, methoxy, ethoxy, propoxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated methoxy, deuterated ethoxy, deuterated propoxy, halomethoxy, haloethoxy and halopropoxy;

[0091] Each R10 is independently H, F, Cl, Br, I, CN, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, or propoxy, wherein the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, and propoxy groups are, as appropriate, substituted by 1 to 3 groups selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, and CN;

[0092] q is 2 or 3;

[0093] The rest are as described in the third technical solution.

[0094] As a more specific fifth technical solution of the present invention, the compound of Formula I, its stereoisomer, solvate, or pharmaceutically acceptable salt, wherein the compound is selected from one of the following structures:

[0094]

[0095] As a more specific sixth technical solution of the present invention, a pharmaceutical composition is provided, which contains the compound described in any of the first to fifth technical solutions, its stereoisomer, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0096] As a more specific seventh technical solution of the present invention, a use is provided, namely, the use of the compounds described in any of the first to fifth technical solutions, their stereoisomers, solvates, or pharmaceutically acceptable salts, or the composition described in the sixth technical solution, in the preparation of medicines for treating / preventing PDE3 / 4 mediated diseases.

[0097] Further, the PDE3 / 4 mediated diseases are selected from COPD and asthma.

[0098] Synthesis Route

[0099] Those skilled in this art can prepare the compounds of this invention by combining known organic synthesis techniques, using commercially available chemicals and / or compounds described in chemical literature as starting materials. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Energie Chemicals, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, etc.

[0100] Industry reference books and monographs provide detailed descriptions of the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing the preparation methods for reference. Such reference books and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HOHouse, "Modern Synthetic Reactions", 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.「Advanced Organic Chemistry:Reactions,Mechanisms,and Structure」4th Edition(1992)John Wiley & Sons,ISBN:0-471-60180-2;Otera,J.(editor)「Modern Carbonyl Chemistry」(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.「Patai’s 1992 Guide to the Chemistry of Functional Groups」(1992)Interscience ISBN:0-471-93022-9;Solomons,T.W.G.「Organic Chemistry」7th Edition(2000)John Wiley & Sons,ISBN:0-471-19095-0;Stowell,J.C.,「Intermediate Organic Chemistry」2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2;「Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia」(1999)John Wiley & Sons,ISBN:3-527-29645-X,in 8 volumes;「Organic Reactions」(1942-2000)John Wiley & Sons,in over 55 volumes;and「Chemistry of Functional Groups」John Wiley & Sons,in 73 volumes.

[0101] Specific and similar reactants can be selectively identified using indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service. These indexes are available in most public and university libraries, as well as online. Known but not commercially available chemicals may be prepared by custom chemical synthesis plants, many of which offer custom synthesis services (e.g., those listed above). References for the preparation and selection of pharmaceutical salts of the compounds described herein are from PHStahl & CGWermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0102] Terminology

[0103] Unless otherwise specified in this invention, the terminology used in this invention has the following meanings:

[0104] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention may be further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12C, 13C and 14C, the hydrogen isotopes include protium (H), deuterium (also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), the oxygen isotopes include 16O, 17O and 18O, the sulfur isotopes include 32S, 33S, 34S and 36S, the nitrogen isotopes include 14N and 15N, the fluorine isotope 19F, the chlorine isotopes include 35Cl and 37Cl, and the bromine isotopes include 79Br and 81Br.

[0105] In this document, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0106] "Halogenation" or "halogen substitution" refers to the substitution of a group by one or more halogen substituents selected from F, Cl, Br, I, or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, the same or different halogens can be used for substitution. It usually includes cases of 1-5 halogen substitutions, 1-4 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

[0107] "Deuterium" refers to the isotope of hydrogen (H), and is synonymous with "D".

[0108] “Deuterated” or “deuterated product” refers to the situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, or alkynyl group is replaced by at least one deuterium atom. The upper limit of the number of deuterations is equal to the sum of the number of hydrogen atoms that can be replaced in the substituted group. Unless otherwise specified, the number of deuterations is any integer between 1 and the upper limit. For example, 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms, or 1 deuterium atom.

[0109] "Cx-y" groups refer to groups containing x to y carbon atoms, such as "C1-6 alkyl" which refers to alkyl groups containing 1 to 6 carbon atoms.

[0110] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. It is typically an alkyl group with 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, neobutyl, tributyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc., and the alkyl group may be further substituted with substituents.

[0111] "alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene include, but are not limited to, methylene and ethylene.

[0112] "Halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. Usually, alkyl groups are replaced by 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen. When the number of halogen substituents is greater than 1, they can be the same or different halogens. Specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0113] "Alkoxy" or "alkyloxy" refers to -O-alkyl. For example, -O-C1-8 alkyl, -O-C1-6 alkyl, -O-C1-4 alkyl, or -O-C1-2 alkyl. Specific, non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, dibutoxy, tributoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy, etc.; the alkoxy group may be substituted with a substituent as appropriate.

[0114] "Haloalkoxy" refers to -O-haloalkyl. For example, -O-haloC1-8 alkyl, -O-haloC1-6 alkyl, -O-haloC1-4 alkyl or -O-haloC1-2 alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substituents, 1-3 halogen substituents, 1-2 halogen substituents, or 1 halogen substituent; when the number of halogen substituents is greater than 1, they can be the same or different halogens; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0115] "Alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and even further such as 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, and 2-methyl-1-butenyl. 2-Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl groups may be further substituted with substituents as appropriate.

[0116] "Alkenyl" refers to a straight or branched divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C). Unless otherwise specified, alkenyl contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include alkenylene. The alkenyl group may be substituted with substituents as appropriate.

[0117] "Alynyl" refers to a straight-chain hydrocarbon group or branched hydrocarbon group containing at least one carbon-carbon linkage (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms. Examples include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octylenyl, 3-nonynyl, and 4-decynyl, etc.; the alkynyl group may be substituted with substituents as appropriate.

[0118] "Idyne" refers to a straight or branched divalent unsaturated hydrocarbon group containing carbon-carbon linkages (C≡C), usually containing 2-6 carbon atoms, and further containing 2-4 carbon atoms. Non-limiting examples include ethynylene, propynylene, and butynylene. The ethynylene group may be substituted by substituents as appropriate.

[0119] "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain cyclic heteroatoms. Cycloalkyl can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic can be fused, spirocyclic, bridged, or combinations thereof. Bicyclic or polycyclic can include one or more aromatic rings, but the ring system as a whole is not aromatic. The linking site can be on an aromatic ring or a non-aromatic ring. Typically, cycloalkyl groups contain 3 to 20 carbon atoms, more commonly 3 to 8 carbon atoms, and even more commonly 3 to 6 carbon atoms; when they are monocyclic cycloalkyl groups, they contain 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms; when they are bicyclic or polycyclic cycloalkyl groups, they contain 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, etc.

[0119] 、、、、etc., cycloalkyl groups can be substituted with substituents as appropriate.

[0120] "Cycloalkylene" refers to the divalent group of cycloalkyl.

[0121] "Aryl" refers to an aromatic carbon ring that does not contain heteroatoms, including monocyclic aryl and fused-ring aryl. It usually contains 6 to 13 carbon atoms, further contains 6 to 9 carbon atoms, and is further phenyl. Non-limiting examples include phenyl, yl, anthracene, and phenanthrene. The aryl group may be substituted with substituents as appropriate.

[0122] "Carbocyclic ring" or "carbocyclic group" refers to a saturated, partially unsaturated, or aromatic carbon ring, including aryl and cycloalkyl groups. The carbon ring can be monocyclic, bicyclic, or polycyclic, including bridged rings, fused rings, and spirocyclic rings, as well as combinations thereof. The carbon ring typically has 3 to 12 carbon atoms, or 3 to 10 carbon atoms, or 3 to 6 carbon atoms. In non-limiting examples, monocyclic carbon rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, etc.; bicyclic bridged rings include , , etc.; bicyclic fused rings include , , , , and etc.; bicyclic spirocyclic rings include , , , , and etc.; and the carbon ring may be substituted with substituents as appropriate.

[0123] "Heterocyclic alkyl" refers to a non-aromatic carbon ring containing 1, 2, 3, or 4 saturated or partially unsaturated heteroatoms selected from N, S, and O. Heterocyclic alkyl can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic can be bridged, fused, spirocyclic, or combinations thereof. Bicyclic or polycyclic may include one or more aromatic or heteroaromatic rings, but the ring system as a whole is not aromatic. The linking site can be on an aromatic ring or a non-aromatic ring. Typically, heterocyclic alkyl is a 3 to 20-membered ring. When it is a monocyclic heterocyclic alkyl, it is typically a 3 to 15-membered ring, or a 3-10-membered ring, or a 3-8-membered ring, or a 3-6-membered ring. When it is a bicyclic or polycyclic heterocyclic alkyl, it is typically a 5-12-membered ring, or a 5-11-membered ring, or a 6-9-membered ring. The heteroatoms N and S include their oxidation states. Non-limiting examples of heterocyclic alkyl groups include azirrobutyl, morpholino, guanylate, guanidinyl, tetrahydroguanylate, oxacyclobutyl, guanylate, azirropentenyl, azirrohexenyl, oxacyclopentenyl, oxacyclohexenyl, etc., and heterocyclic alkyl groups may be substituted with substituents as appropriate.

[0124] Unless otherwise specified, "heteroaryl ring" or "heteroaryl group" refers to an aromatic ring containing 1 to 4 heteroatoms selected from N, O, or S and their oxidation states. It can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic rings can be bridged rings, fused rings, spirocyclic rings, and combinations thereof. When it is bicyclic or polycyclic, it can be a fusion of a heteroaryl group and an aryl group, or a fusion of two heteroaryl groups, wherein either the heteroaryl group or the aryl group can be a linking site. Non-limiting examples include furanyl, thiophene, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, dayl, pyryl, indole, purine, etc.; the heteroaryl group may be substituted with substituents as appropriate.

[0125] "Heterocycle" or "heterocyclic group" refers to a saturated or unsaturated, aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states, including heteroaryl and heterocyclic alkyl groups. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles or combinations thereof. They are typically 3 to 12-membered heterocycles, 5 to 12-membered heterocycles, or 5 to 7-membered heterocycles. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, guanylate, azirroheptyl, pyridyl, furanyl, thiophene, guanylate, N-alkylpyrroleyl, pyrimidinyl, pyrazolyl, pyrazolyl, dayl, imidazolyl, guanylate, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydroguanylate, dithiapentylene Cycloyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroguanyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl, etc., heterocycles may be substituted by substituents as appropriate.

[0126] "Hypocyclic group" refers to a divalent heterocyclic group that is substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic. Non-limiting examples include, etc.

[0127] "Spirocyclic" refers to a polycyclic group in which the rings share a single carbon atom (called a spiro atom). It may contain 0 or more double bonds or triple bonds, and may contain 0 to 5 heteroatoms selected from N, O, S, P, Si, and their oxidation states. Spirocyclic rings are typically 6 to 14-membered, 6 to 12-membered, or 6 to 10-membered. Typical spirocyclic rings are tri-spirotri- (representing a three-membered spirotri-membered ring), tri-spirotetra-, tri-spiropenta-, tri-spirohexa-, tetra-spirotetra-, tetra-spiropenta-, tetra-spirohexa-, penta-spiropenta-, or penta-spirohexa-. Non-limiting examples of spirocyclic rings include...

[0127] 、 ...

[0128] "Bulk ring" refers to a polycyclic group in which two rings share two adjacent ring atoms and a chemical bond. It may contain one or more double bonds or triple bonds, and may contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Typically, bulk rings are 5 to 20-membered, 5 to 14-membered, 5 to 12-membered, or 5 to 10-membered. Typically, bulk rings are tri-tetracyclic (representing a bulk ring formed by a three-membered and a four-membered ring; according to IUPC nomenclature rules, it may be a bulk ring with a three-membered or a four-membered ring as the base ring, and the same applies below), tri-pentancyclic, tri-hexacyclic, tetra-tetracyclic, tetra-pentancyclic, tetra-hexacyclic, penta-pentancyclic, penta-hexacyclic, and hexa-hexacyclic. Non-limiting examples of bulk rings include purines, quinolines, isoquinolines, benzo[a]pyran, benzo[a]furan, and benzo[a]thiophene.

[0128] 、、、、、、、;The cyclic rings described may be replaced by substituents as appropriate.

[0129] A "bridged ring" refers to two rings sharing two non-adjacent ring atoms and may contain one or more double bonds or triple bonds. A bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Typically, a bridged ring has 5 to 20, 5 to 14, 5 to 12, or 5 to 10 ring atoms. Non-limiting examples of bridged rings include adamantane,

[0129] 、、、;The bridge ring described herein may be replaced by substituents as appropriate.

[0130] Unless otherwise specified, "substitution" or "substituent" refers to any substitution occurring at a position permitted by chemical theory, with the number of substituents conforming to the rules of chemical bonds. Exemplary substituents include, but are not limited to: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 heteroalkyl, C5-12 aryl, 5-12 heteroaryl, hydroxyl, C1-6 alkoxy, C5-12 aryloxy, thiol, C1-6 alkylthio, cyano, halogen, C1-6 alkylthiocarbonyl, C1-6 alkylaminomethyl, N-aminomethyl, nitro, silyl, sulfinyl, sulfonyl, sulfene, halo-C1-6 alkyl, halo-C1-6 alkoxy, amino, phosphonic acid, -CO2 (C1-6 alkyl), -OC (=O) (C1-6 alkyl), -OCO2 (C1-6 alkyl). -C(=O)NH2, -C(=O)N(C1-6 alkyl)2, -OC(=O)NH(C1-6 alkyl), -NHC(=O)(C1-6 alkyl), -N(C1-6 alkyl)C(=O)(C1-6 alkyl), -NHCO2(C1-6 alkyl), -NHC(=O)N(C1-6 alkyl)2, -HC(=O)NH(C1-6 alkyl), -NHC(=O)NH2, -NHSO2(C1-6 alkyl), -SO2N(C1-6 alkyl)2, -SO2NH(C1-6 alkyl), -SO2NH2, -SO2C1-6 alkyl, etc.

[0131] "Whether" or "as the case may" means that the event or circumstances described below may or may not occur, and the description includes the situation in which the event or circumstances occur or do not occur. For example, "alkyl group substituted with F as the case may" means that the alkyl group may or may not be substituted with F, and the description includes the situation in which the alkyl group is substituted with F and the situation in which the alkyl group is not substituted with F.

[0132] "Medically acceptable salt" refers to a salt obtained by reacting the compound of the present invention with a free acid or a free base to retain the bioavailability and properties of the free acid or the free base with a non-toxic inorganic or organic base.

[0133] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or their stereoisomers, solvates, pharmaceutically acceptable salts or eutectics, and other components, wherein the other components include physiologically / pharmaceutical acceptable carriers and / or excipients.

[0134] "Carrier" refers to a system that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given, and can change the way the drug enters the human body and its distribution in the living body, control the release rate of the drug and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0135] "Excipient" means: which is not itself a therapeutic agent, but is used as a diluent, excipient, binder and / or medium, for addition to a pharmaceutical composition to improve its disposal or storage properties or to allow or promote the formation of a unit dosage form of the compound or pharmaceutical composition for administration. As is known to those skilled in the art, pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (e.g. croscarmellose sodium); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn... Oils and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyester, polycarbonate and / or polyanhydride; and (22) other non-toxic compatible substances used in pharmaceutical preparations.

[0136] "Stereoisomers" refers to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and configuration isomers.

[0137] The compounds of the present invention also include their tautomers. For example, when the present invention describes the left-hand compound in which the pyrimidine ring is replaced by OH, the right-hand tautomer compound is also included.

[0137]

[0138] "Solvate" refers to a substance formed by the combination of the compound of the present invention or its salt with a solvent of stoichiometry or non-stoichiometry bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0139] "Eutectic" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a eutectic form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure state, and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal, including both two-membered eutectic formed between two neutral solids and multi-membered eutectic formed between a neutral solid and a salt or solvate.

Implementation Method

[0140] Detailed Implementation

[0141] The present invention will be described in detail below by way of examples. Unless otherwise specified, the experimental methods under known conditions were used in the examples. The examples are provided to better illustrate the present invention, but should not be construed as limiting the scope of the invention to the examples given. Non-essential improvements and adjustments made to the examples by those skilled in the art based on the above [Summary of the Invention] are still within the scope of protection of the present invention.

[0142] Example 1:

[0143] (E)-1-(2-(2-(2,4,6-trimethylbenzimino)-10-methoxy-9-(methoxy-d3)-4-sideoxy-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 1)

[0144] (E)-1-(2-(2-(mesitylimino)-10-methoxy-9-(methoxy-d3)-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea

[0144]

[0145] Step 1:

[0146] Compound 2-(3-(benzyloxy)-4-methoxyphenyl)ethyl-1-amino (1A) (synthesized according to the method described in J. Med. Chem. 2013, 56, 23, 9673-9682) (51.5 g, 0.20 mol) was dissolved in water (300 mL), and potassium cyanate (32.4 g, 0.40 mol) was added in portions. After stirring until homogeneous, 2N hydrochloric acid (240 mL) was added dropwise. After the addition was complete, the mixture was refluxed overnight. The mixture was cooled to 0 °C, filtered, and the filter cake was washed with ice-cold ethanol and dried to give target compound 1B (38.0 g, yield 63%).

[0147] LC-MS(ESI): m / z=301.2[M+H]+.

[0148] Step Two:

[0149] Compound 1B (38 g, 0.13 mol) was dissolved in anhydrous ethanol (300 mL), and diethyl malonate (27 g, 0.17 mol) was added. After the system was stirred evenly, sodium ethoxide (133 g, 0.39 mol, 20 wt% in EtOH) was added dropwise. After the addition was complete, the mixture was refluxed overnight. The system was concentrated to 150 mL under reduced pressure, diluted with water (150 mL), and the pH was adjusted to 6.0 with 5 N hydrochloric acid. The mixture was then filtered, the filter cake was washed with water (150 mL), and dried to obtain the target compound 1C (42 g, yield 65.9%).

[0150] LC-MS(ESI): m / z=369.1[M+H]+

[0151] Step 3:

[0152] Compound 1C (42 g, 114 mmol) was dissolved in phosphorus oxychloride (300 mL) and reacted overnight at 120 °C. After the reaction cooled to room temperature, it was concentrated under reduced pressure. The residue was slowly added to ice water (300 mL), and the pH was adjusted to 6.0 by adding saturated sodium bicarbonate aqueous solution in portions. The mixture was extracted with dichloromethane (500 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was isolated by silica gel column chromatography (DCM:MeOH (v / v) = 40:1) to give the target compound (12.7 g, yield 30%).

[0153] LC-MS(ESI): m / z=369.1[M+H]+.

[0154] 1H NMR (400MHz, CDCl3) δ 7.48-7.32(m,5H),7.14(s,1H),6.80(s,1H),6.64(s,1H),5.23(s,2H),4.20(t,2H),3.96(s,3H),2.94(t,2H).

[0155] Step 4:

[0156] 1D (8.2 g, 22.2 mmol) was dissolved in isopropanol (120 mL), and 2,4,6-trimethylaniline (4.46 g, 33 mmol) was added. After the addition was complete, the mixture was reacted at 90 °C for 24 hours. After the reaction was cooled to room temperature, it was concentrated under reduced pressure. The residue was extracted with saturated sodium bicarbonate aqueous solution (100 mL) and dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to give compound 1E (8.3 g, yield 80%).

[0157] LC-MS(ESI): m / z=468.2[M+H]+.

[0158] Step 5:

[0159] Compound 1E (2.8 g, 6 mmol), 2-(2-bromoethyl)isoindoline-1,3-dione (9.15 g, 36 mmol), potassium carbonate (7.45 g, 54 mmol), and sodium iodide (5.4 g, 36 mmol) were added sequentially to dried 2-butanone (60 mL). The mixture was then reacted at 95 °C for 48 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (80 mL). The residue obtained after concentration under reduced pressure was isolated by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:0~1:1) to give the target compound 1F (0.92 g, yield 24%).

[0160] LC-MS(ESI): m / z=641.2[M+H]+.

[0161] Step Six:

[0162] Compound 1F (0.92 g, 1.44 mmol) was dissolved in ethyl acetate (20 mL), and palladium on carbon (0.5 g) was added. The reaction was carried out at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered, the filter cake was washed with methanol (30 mL), and the filtrate was concentrated under reduced pressure to give the target compound 1G (0.58 g, yield 73%).

[0163] LC-MS(ESI): m / z=551.2[M+H]+.

[0164] Step Seven:

[0165] Compound 1G (0.58 g, 1.05 mmol) was dissolved in DMF (10 mL), potassium carbonate (0.29 g, 2.1 mmol) was added, and the mixture was stirred until homogeneous. Then, deuterated iodomethane (0.30 g, 2.1 mmol) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 1 hour. After the reaction was completed, saturated brine (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was isolated by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:0~1:1) to give compound 1H (0.52 g, yield 87%).

[0166] LC-MS(ESI): m / z=568.2[M+H]+.

[0167] Step 8:

[0168] Compound 1H (0.52 g, 0.92 mmol) was dissolved in chloroform (10 mL) and ethanol (10 mL), and hydrazine hydrate (0.3 g, 80 wt%) was added. After stirring, the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0~5:1) to give compound 1I (0.35 g, yield 87%).

[0169] LC-MS(ESI): m / z=438.1[M+H]+

[0170] Step Nine:

[0171] Compound 1I (0.22 g, 0.50 mmol) was dissolved in water (10 mL), and 1 N hydrochloric acid (1 mL) was added. After stirring, the mixture was heated to 80 °C, and an aqueous solution of potassium cyanate (81 mg, 1 mmol) (1 mL) was added dropwise to the reaction. After the addition was complete, the reaction was continued at 80 °C for 2 h. After cooling to room temperature, a saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0~10:1) to give compound 1 (0.12 g, yield 50%).

[0172] LC-MS(ESI): m / z=481.3[M+H]+

[0173] 1H NMR (400MHz, CDCl3)δ 6.91(s,2H),6.68(s,2H),5.47(s,1H),5.25(br,2H),4.44(s,2H),4.08(s,2H), 3.75(s,3H),3.55(s,2H),2.94(s,2H),2.29(s,3H),2.09(s,6H),1.61(br,1H).

[0174] Example 2:

[0175] (E)-1-(2-(2-((2,6-dimethyl-4-(trifluoromethyl)phenyl)imino)-9,10-dimethoxy-4-sideoxy-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 2)

[0176] (E)-1-(2-(2-((2,6-dimethyl-4-(trifluoromethyl)phenyl)imino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea

[0176]

[0177] Step 1:

[0178] 2A (50 g, 0.28 mol) was dissolved in water (150 mL), KCNO (8.1 g, 0.10 mol) was added, and then hydrochloric acid solution (40 mL concentrated hydrochloric acid dissolved in 150 mL water) was slowly added dropwise. The reaction was heated to reflux and stirred overnight. After the reaction was complete, it was cooled to 0 °C, filtered, and the filter cake was washed with cold water (150 mL). The filter cake was dried to give the title compound 2B (51 g, 82.3%).

[0179] LC-MS(ESI): m / z=225.2[M+H]+.

[0180] Step Two:

[0181] 2B (51 g, 0.22 mol) was dissolved in anhydrous ethanol (300 mL), and diethyl malonate (50 g, 0.34 mol) and sodium ethoxide (47 g, 0.69 mol) were added sequentially. The reaction was heated to reflux and stirred overnight. After the reaction was complete, it was cooled to room temperature, concentrated under reduced pressure to remove most of the ethanol, and water (150 mL) was added to the residue. The pH was adjusted to 6.0 with dilute hydrochloric acid (5 M), filtered, and the filter cake was washed with cold water (150 mL) and dried to give the title compound 2C (45.0 g, 65.9%).

[0182] LC-MS(ESI): m / z=293.3[M+H]+.

[0183] Step 3:

[0184] 2C (20.0 g, 68.4 mmol) was dissolved in POCl3 (200 mL), heated to 100 °C, and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated to 30 mL, and slowly poured into ice water (300 mL). The pH was adjusted to 6.0 with 5N sodium hydroxide aqueous solution, and extracted with dichloromethane (300 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1-10:1) to give the title compound 2D (11.5 g, 55%).

[0185] 1H NMR (400MHz, DMSO-d6) δ 7.50 (s, 1H), 7.27 (s, 1H), 7.04 (s, 1H), 4.06-4.03 (m, 2H), 3.86-3.83 (m, 6H), 2.98-2.95 (m, 2H).

[0186] LC-MS(ESI): m / z=293.3[M+H]+.

[0187] Step 4:

[0188] 2E (3 g, 9.46 mmol) and trimethylcyclotriboroxane (1.79 g, 14.2 mmol) were dissolved in ethylene glycol dimethyl ether (12 mL). Tetra(triphenylphosphine)palladium (1.09 g, 0.95 mmol) and potassium carbonate (3.92 g, 28.38 mmol) were added sequentially under a nitrogen atmosphere at 100 °C. After the reaction was complete, the reaction was stopped. After the reaction was cooled to room temperature, the mixture was concentrated under reduced pressure to remove most of the reaction solution. DCM (20 mL) was added to the residue. The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1-10:1) to give the title compound 2F (0.42 g, 25%).

[0189] LC-MS(ESI): m / z=190.2[M+H]+.

[0190] Step 5:

[0191] 2D (0.5 g, 1.71 mmol) was dissolved in isopropanol (12 mL), and 2F (0.49 g, 2.57 mmol) was added. After the addition was complete, the reaction was carried out at 90 °C for 24 hours. After the reaction was complete, the reaction was stopped, and after the reaction was cooled to room temperature, most of the reaction solvent was removed by concentration under reduced pressure. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the residue, and the residue was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was isolated by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to give compound 2G (0.65 g, yield 85%).

[0192] LC-MS(ESI): m / z=446.3[M+H]+.

[0193] Step Six:

[0194] Compound 2G (0.4 g, 0.9 mmol), 2-(2-bromoethyl)isoindoline-1,3-dione (0.69 g, 2.7 mmol), potassium carbonate (0.37 g, 2.7 mmol), and sodium iodide (0.41 g, 2.7 mmol) were sequentially dissolved in dry acetonitrile (20 mL). The mixture was reacted under nitrogen protection and microwaved at 120 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure and isolated by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:0~1:1) to give the target compound 2H (0.25 g, yield 45%).

[0195] LC-MS(ESI): m / z=619.3[M+H]+.

[0196] Step Seven:

[0197] Compound 2H (0.25 g, 0.40 mmol) was dissolved in chloroform (10 mL) and ethanol (10 mL), and hydrazine hydrate (0.2 g, 80 wt%) was added. After stirring, the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0~5:1) to give compound 2I (0.17 g, yield 89%).

[0198] LC-MS(ESI): m / z=489.1[M+H]+.

[0199] Step 8:

[0200] Compound 2I (0.17 g, 0.36 mmol) was dissolved in water (10 mL), 1 N hydrochloric acid (1 mL) was added, and the mixture was stirred until homogeneous. The temperature was raised to 80 °C, and an aqueous solution of potassium cyanate (81 mg, 1 mmol) (1 mL) was added dropwise to the system. After the addition was complete, the reaction was continued for 2 h. The mixture was cooled to room temperature, and a saturated sodium bicarbonate aqueous solution (10 mL) was added. The mixture was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0~10:1) to give compound 2 (0.08 g, yield 41%).

[0201] 1H NMR (400MHz, Methanol-d4)δ 7.36(s,2H),6.88(s,1H),6.74(s,1H),5.38(s,1H),4.38-4.35(s,2H),4.18-3.93( m,2H),3.86(s,3H),3.66(s,3H),3.56-3.53(m,2H),2.94-2.91(m,2H),2.16(s,6H).

[0202] LC-MS(ESI): m / z=532.3[M+H]+.

[0203] Example 3:

[0204] (E)-1-(2-(2-((4-cyclopropyl-2,6-dimethylphenyl)imino)-9,10-dimethoxy-4-sideoxy-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 3)

[0205] (E)-1-(2-(2-((4-cyclopropyl-2,6-dimethylphenyl)imino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea

[0205]

[0206] Step 1:

[0207] Compound 3A (3g, 15.07mmol) and cyclopropylboronic acid (1.94g, 22.67mmol) were dissolved in toluene (20mL) and water (5mL). Palladium acetate (0.34g, 1.51mmol), tricyclohexylphosphine (0.47g, 28.38mmol), and potassium phosphate (6.40g, 30.14mmol) were added sequentially under a nitrogen atmosphere at 100°C. After the reaction was complete as monitored by TLC and LC-MS, the reaction was stopped. After the reaction was cooled to room temperature, most of the reaction solution was removed by concentration under reduced pressure. DCM (20mL) was added to the residue, and the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1-10:1) to obtain the title compound 3B (0.70g, 29%).

[0208] LC-MS(ESI): m / z=162.2[M+H]+.

[0209] Step Two:

[0210] 2D (0.5 g, 1.71 mmol) was dissolved in isopropanol (12 mL), and 3B (0.41 g, 2.57 mmol) was added. After the addition was complete, the mixture was reacted at 90 °C for 24 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (20 mL) was added. The mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to give compound 3C (0.50 g, yield 70%).

[0211] LC-MS(ESI): m / z=418.​​3[M+H]+.

[0212] Step 3:

[0213] Compound 3C (0.50 g, 1.20 mmol), 2-(2-bromoethyl)isoindoline-1,3-dione (0.92 g, 3.6 mmol), potassium carbonate (0.50 g, 3.6 mmol), and sodium iodide (0.54 g, 3.6 mmol) were mixed in dry acetonitrile (20 mL) and reacted under nitrogen atmosphere at 120 °C for 2 hours by microwave. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure and isolated by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:0~1:1) to give the target compound 3D (0.33 g, yield 47%).

[0214] LC-MS(ESI): m / z=591.3[M+H]+.

[0215] Step 4:

[0216] Compound 3D (0.33 g, 0.56 mmol) was dissolved in chloroform (10 mL) and ethanol (10 mL), and hydrazine hydrate (0.3 g, 80 wt%) was added. After stirring, the mixture was reacted at room temperature for 24 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0~5:1) to give compound 3E (0.18 g, yield 70%).

[0217] LC-MS(ESI): m / z=461.2[M+H]+.

[0218] Step 5:

[0219] Compound 3E (0.18 g, 0.39 mmol) was dissolved in water (10 mL), 1 N hydrochloric acid (1 mL) was added, and the mixture was stirred until homogeneous. The temperature was raised to 80 °C, and an aqueous solution of potassium cyanate (81 mg, 1 mmol) (1 mL) was added dropwise to the system. After the addition was complete, the mixture was stirred for 2 h. The mixture was cooled to room temperature, and a saturated aqueous solution of sodium bicarbonate (10 mL) was added. The mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0~10:1) to give compound 3 (0.07 g, yield 36%).

[0220] 1H NMR (400MHz, Methanol-d4)δ 7.03-6.98(m,3H),6.79(s,1H),5.65(s,1H),4.39-4.36(m,2H),4.19-4.16(m,2H),3.91(s,3H),3.69(s,3H) ,3.56-3.52(m,2H),3.06-3.03(m,2H),2.27(s,6H),1.94-1.91(m,1H),1.16-0.94(m,2H),0.83-0.61(m,2H).

[0221] LC-MS(ESI): m / z=504.3[M+H]+.

[0222] Example 4:

[0223] (E)-1-(2-(9-ethoxy-2-trimethylbenzimino)-10-methoxy-4-oxy-6,7-dihydro-2-hydro-pyrimidinone[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 4)

[0224] (E)-1-(2-(9-ethoxy-2-(mesitylimino)-10-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)ureaione

[0224]

[0225] Step 1:

[0226] Compound 4A (77 mg, 0.17 mmol) (synthesis of compound 4A is referenced in patent WO2021143843) was dissolved in water (5 mL), potassium cyanate (48.3 mg, 0.6 mmol, 3.5 eq) was added, and dilute hydrochloric acid (concentrated HCl (43 μL, 0.51 mmol, 3 eq) diluted with water (5 mL) was added). After the addition was complete, the temperature was raised to 100 °C and the reaction was carried out for 18 hours. TLC / LCMS showed that the starting material reacted completely. The reaction was cooled to room temperature, and the mixture was extracted three times with dichloromethane (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain compound 4 (81 mg, 0.16 mmol, 97% yield).

[0227] LC-MS(ESI): m / z=492.2[M+H]+.

[0228] 1H NMR(400MHz,Chloroform-d)δ 6.94(s,2H),6.68(m,2H),5.49(s,1H),4.47(s,2H),4.15(m,2H),4.11(m,2H), 3.74(s,3H),3.58(s,2H),2.95(s,2H),2.30(s,3H),2.13(s,6H),1.49(m,3H).

[0229] Example 5: (E)-1-(2-(2-((4-fluoro-2,6-dimethylphenyl)imino)-9,10-dimethoxy-4-sideoxy-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (Compound 5)

[0230] (E)-1-(2-(2-((4-fluoro-2,6-dimethylphenyl)imino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea

[0230]

[0231] Step 1:

[0232] 2D (0.5 g, 1.71 mmol) was dissolved in isopropanol (12 mL), and 4-fluoro-2-methylaniline (0.32 g, 2.57 mmol) was added. After the addition was complete, the mixture was reacted at 90 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (20 mL) was added to the residue. The residue was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to give compound 5A (0.57 g, yield 85%).

[0233] LC-MS(ESI): m / z=396.2[M+H]+.

[0234] Second step:

[0235] Compound 5A (0.57 g, 1.5 mmol), 2-(2-bromoethyl)isoindoline-1,3-dione (1.15 g, 4.5 mmol), potassium carbonate (0.62 g, 4.5 mmol), and sodium iodide (0.69 g, 4.5 mmol) were mixed in dry acetonitrile (20 mL) under nitrogen protection and microwaved at 120 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure and isolated by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:0~1:1) to give the target compound 5B (0.34 g, yield 40%).

[0236] LC-MS(ESI): m / z=569.2[M+H]+.

[0237] Step 3:

[0238] Compound 5B (0.34 g, 0.60 mmol) was dissolved in chloroform (10 mL) and ethanol (10 mL), and hydrazine hydrate (0.30 g, 80 wt%) was added. After stirring, the mixture was reacted at room temperature for 12 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0~5:1) to give compound 5C (0.17 g, yield 89%).

[0239] LC-MS(ESI): m / z=439.1[M+H]+.

[0240] Step 4:

[0241] Compound 5C (0.085 g, 0.2 mmol) was dissolved in water (10 mL), and 1 N hydrochloric acid (1 mL) was added. After stirring until homogeneous, the mixture was heated to 80 °C, and an aqueous solution of potassium cyanate (81 mg, 1 mmol) (1 mL) was added dropwise to the system. After the addition was complete, the mixture was stirred under these conditions for 2 h. After cooling to room temperature, a saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0~10:1) to give compound 5 (0.09 g, yield 93%).

[0242] 1H NMR(400MHz,CD3OD)δ 6.78(s,1H),6.74(s,1H),6.71(s,1H),6.64(s,1H),5.35(s,1H),4.26-4.23(m,2H),3.92- 3.89(m,2H),3.76(s,3H),3.59(s,3H),3.45-3.42(m,2H),2.84-2.81(m,2H),1.99(s,6H).

[0243] LC-MS(ESI): m / z=482.3[M+H]+.

[0244] Example 6: (E)-1-(2-(9-(benzyloxy)-2-(trimethylmethylimino)-10-methoxy-4-sideoxy-6,7-dihydro-2H-pyrimidinone[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 6)

[0245] (E)-1-(2-(9-(benzyloxy)-2-(mesitylimino)-10-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea

[0245]

[0246] Step 1:

[0247] Compound 1F (0.2 g, 0.31 mmol) was dissolved in chloroform (10 mL) and ethanol (10 mL), and hydrazine hydrate (194 mg, 3.1 mmol, 10 eq, 80% w / w) was added. The reaction was allowed to proceed overnight at room temperature. TLC / LCMS showed that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate aqueous solution (30 mL), and extracted with dichloromethane (40 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give product 6A (63 mg, 0.12 mmol, yield 40%).

[0248] Step Two:

[0249] Compound 6A (63 mg, 0.12 mmol) was dissolved in water (5 mL), potassium cyanate (34 mg, 0.42 mmol, 3.5 eq) was added, and concentrated hydrochloric acid (0.03 mL, 0.36 mmol, 3 eq) was diluted with water (5 mL) before being added. After the addition was complete, the mixture was heated to 100 °C and reacted overnight. TLC / LCMS showed that the reaction was complete. After the reaction was cooled to room temperature, it was quenched with saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (20 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain compound 6 (51 mg, 0.09 mmol, 77% yield) by silica gel column chromatography (dichloromethane:methanol = 10:1).

[0250] LC-MS(ESI): m / z=554.3[M+H]+.

[0251] 1H NMR (400MHz, CDCl3)δ 7.41-7.33(m,5H),6.92(s,2H),6.72(s,2H),5.48(s,1H),5.18(s,2H),4.44(m,2 H),4.06(m,2H),3.76(s,3H),3.56(m,2H),2.89(m,2H),2.30(s,3H),2.08(s,6H).

[0252] Example 7: (E)-1-(2-(2-(2,4,6-trimethylbenzimino)-9-methoxy-10-(methoxy-D3-deuterated)-4-sideoxy-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (Compound 7)

[0253] (E)-1-(2-(2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea

[0253]

[0254] Step 1:

[0255] Compound 2-(4-(benzyloxy)-3-methoxyphenyl)ethylamine (7A) (synthesized as described in Bioorganic & Medicinal Chemistry, 21(4), 856-868) (51.5 g, 0.20 mol) was dissolved in water (300 mL), and potassium cyanate (32.4 g, 0.40 mol) was added in portions. After stirring until homogeneous, 2N hydrochloric acid (240 mL) was added dropwise. After the addition was complete, the mixture was refluxed overnight. The mixture was cooled to 0 °C, filtered, and the filter cake was washed with ice-cold ethanol and dried to give the target compound 7B (38.0 g, yield 63%).

[0256] LC-MS(ESI): m / z=301.2[M+H]+.

[0257] Step Two:

[0258] Compound 7B (38 g, 0.13 mol) was dissolved in anhydrous ethanol (300 mL), and diethyl malonate (27 g, 0.17 mol) was added. After stirring until homogeneous, sodium ethoxide (133 g, 0.39 mol, 20 wt% in EtOH) was added dropwise. After the addition was complete, the mixture was refluxed overnight. After the reaction cooled to room temperature, it was concentrated under reduced pressure to 150 mL, diluted with water (150 mL), and the pH was adjusted to 6.0 with 5N hydrochloric acid. The mixture was then filtered, the filter cake was washed with water (150 mL), and dried to obtain the target compound 7C (42 g, 90% yield).

[0259] LC-MS(ESI): m / z=369.1[M+H]+.

[0260] Step 3:

[0261] Compound 7C (42 g, 114 mmol) was dissolved in phosphorus oxychloride (300 mL) and reacted overnight at 120 °C. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was slowly added to ice water (300 mL). The pH was adjusted to 6.0 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (500 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the crude product obtained after concentration under reduced pressure was isolated by silica gel column chromatography (DCM:MeOH (v / v) = 40:1) to give the target compound 7D (12.7 g, yield 30%).

[0262] LC-MS(ESI): m / z=369.1[M+H]+.

[0263] Step 4:

[0264] 7D (0.82 g, 2.22 mmol) was dissolved in isopropanol (120 mL), and 2,4,6-trimethylaniline (0.446 g, 3.3 mmol) was added. After the addition was complete, the mixture was reacted at 90 °C for 24 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was extracted with saturated sodium bicarbonate aqueous solution (100 mL) and dichloromethane (100 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to give compound 7E (0.53 g, yield 55%).

[0265] LC-MS(ESI): m / z=468.2[M+H]+.

[0266] Step 5:

[0267] Compound 7E (0.53 g, 1.13 mmol), bromoacetonitrile (0.54 g, 3.9 mmol), and lithium carbonate (0.69 g, 3.3 mmol) were sequentially dissolved in dry acetonitrile (10 mL). The reaction was carried out under a nitrogen atmosphere at 90 °C for 18 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (80 mL). The crude product obtained by concentrating the filtrate under reduced pressure was isolated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0~20:1) to give the target compound 7F (0.5 g, yield 42%).

[0268] LC-MS(ESI): m / z=507.3[M+H]+.

[0269] Step Six:

[0270] Compound 7F (0.5 g, 1.0 mmol) was dissolved in ethyl acetate (50 mL), and palladium on carbon (0.3 g, 10% w / w) was added. The reaction was carried out at room temperature for 3 hours under a hydrogen atmosphere. TLC / LCMS showed that the starting material reacted completely. The palladium on carbon was removed by filtration, and the filter cake was washed twice with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 7G (0.21 g, 58% yield).

[0271] LC-MS(ESI): m / z=417.3[M+H]+.

[0272] Step Seven:

[0273] Compound 7G (210 mg, 0.64 mmol) was dissolved in DMF (20 mL), and deuterated iodomethane (186 mg, 1.28 mmol) and potassium carbonate (177 mg, 1.28 mmol) were added sequentially. The mixture was stirred at room temperature for 5 hours. TLC / LCMS showed that the starting material reacted completely. The reaction was quenched with saturated brine (30 mL), and extracted with dichloromethane (40 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 7H (180 mg, 64% yield).

[0274] LC-MS(ESI): m / z=434.2[M+H]+.

[0275] Step 8:

[0276] Compound 7H (180 mg, 0.414 mmol) was added to ethanol (10 mL), Raney nickel (150 mg) was added in portions at room temperature, followed by hydrazine hydrate (1 mL), and the mixture was heated to 60 °C and reacted for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and the filtrate was concentrated under reduced pressure to obtain compound 7I (0.12 g, yield 66%), which could be used directly in the next reaction without further purification.

[0277] LC-MS(ESI): m / z=438.2[M+H]+.

[0278] Step Nine:

[0279] Compound 7I (0.12 g, 0.23 mmol) was dissolved in water (10 mL), 1 N hydrochloric acid (1 mL) was added, and the mixture was stirred until homogeneous. The temperature was raised to 80 °C, and an aqueous solution of potassium cyanate (81 mg, 1 mmol) (1 mL) was added dropwise to the system. After the addition was complete, the mixture was stirred under these conditions for 2 h. The mixture was cooled to room temperature, saturated sodium bicarbonate (10 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0~10:1) to give compound 7 (0.08 g, yield 41%).

[0280] LC-MS(ESI): m / z=481.3[M+H]+.

[0281] 1H NMR (400MHz, Methanol-d4)δ 6.80(s,2H),6.77(s,1H),6.65(s,1H),5.40(s,1H),4.25-4.22(m,2H),3.91-3.88( m,2H),3.76(s,3H),3.45-3.42(m,2H),2.83-2.81(m,1H),2.17(s,3H),1.96(s,6H).

[0282] Biological Testing:

[0283] 1. In vitro detection of the inhibitory activity of the compound on PDE 3A and PDE 4B2 enzymes.

[0284] Experimental Materials:

[0285] Envision 2104 Multilabel Reader (PerkinElmer)

[0286] Black 96-well Plate(Cat#6005540,PerkinElmer)

[0287] PDE3A Assay Kit (BPS, Cat.79736), PDE4B2 Assay Kit (BPS, Cat.60343)

[0288] ‧PDE3A recombinant enzyme

[0289] ‧PDE4B2 recombinant enzyme

[0290] ‧FAM-Cyclic-3′,5′-AMP

[0291] ‧PDE assay buffer

[0292] ‧Binding Agent

[0293] Binding Agent Diluent(cAMP)

[0294] Experimental Procedure:

[0295] 1) Prepare FAM cAMP working solution: Add 20 μL of FAM-Cyclic-3′,5′-AMP stock to 1980 μL of PDE assay buffer. Add 25 μL / well to all wells.

[0296] 2) Preparation of compound solutions: First, dissolve the compound to be tested in DMSO to prepare a 10 mM stock solution. Dilute the compound stock solution with DMSO to prepare a 100 X Top Dose diluent. Then, add 5 μL of the 100 X Top Dose diluent to 45 μL of PDE assay buffer to prepare the compound Top Dose working solution. Then, use PDE assay buffer containing 10% DMSO to serially dilute and prepare working solutions of various concentrations. Add 5 μL / well to the compound wells. Add 5 μL of PDE assay buffer containing 10% DMSO to each control well.

[0297] 3) Preparation of PDE enzyme solution: Dilute PDE3A and PDE4B2 enzyme stock solutions to 150 pg / μL and 50 pg / μL respectively with PDE assay buffer, and add 20 μL / well to all compound wells and Vehicle control wells. Add 20 μL of PDE assay buffer to the Blank control well.

[0298] 4) React at room temperature for 1 hour.

[0299] 5) Preparation of Binding Agent: Add 80 μL of binding agent to 7920 μL of binding agent diluent and mix well. Add to all wells at a rate of 100 μL / well.

[0300] 6) React at room temperature for 1 hour.

[0301] 7) Read FP on Envision.

[0302] 8) Calculation formula for raw data:

[0303] %Inhibition rate=(FPV-FPS) / (FPV-FPB)×100%

[0304] FPS = Sample FP

[0305] FPV = Vehicle vs. FP

[0306] FPB = Blank (corresponding to FP).

[0307] Calculate IC50 by performing a nonlinear regression of log[dose]-inhibition rate using GraphPad.

[0308] Experimental Results:

[0309] The compounds of the present invention exhibit excellent PDE 3 and PDE 4 inhibitory activity, with IC50 values ​​below 500 nM. Some superior compounds have IC50 < 200 nM, some even superior compounds have IC50 < 100 nM, and some even more superior compounds have IC50 < 50 nM. For example, for PDE 3, the IC50 of compound 1 is 0.15 nM, and the IC50 of compound 7 is 0.17 nM. The test results of some compounds are listed in the table below.

[0310] Table 1 Results of in vitro screening tests for compounds

[0311] A: 0nM <IC5050nM;

[0312] B: 50nM <IC50100nM;

[0313] C: 100nM <IC50200nM;

[0314] D: 200nM <IC50;

[0315] NT: Not tested.

[0316] 2. Study on the inhibitory effect of the compound on acetylcholine-induced bronchoconstriction in guinea pigs

[0317] Male guinea pigs were selected as the test animals in this study. The treatment groups were orally administered RPL554, compound 1, and compound 7 at a dose of 10 mg / kg, respectively, while the control group received the same dose of solvent. At 2, 4, and 6 hours after drug exposure, the animals were placed in the WBP instrument aerosol chamber. After acclimatization, they were nebulized with 300 μL of acetylcholine solution (0.5 mg / mL). Penh values ​​were continuously recorded for 7 minutes after the acetylcholine (Mch) exposure ended. The percentage of contractile inhibition by the compounds was calculated based on the Penh values.

[0318] The inhibition rates of each compound on bronchoconstriction at an oral dose of 10 mg / kg are shown in the table below:

[0318]

[0319] 3. Guinea pig tracheal ring experiment

[0320] Experimental method: Guinea pig tracheal rings were placed in a specific culture medium (Krebs-Henseleit) and tension-balanced with 1g of the tracheal rings for 40 minutes; a certain amount of carbacholine was added to achieve 100% contraction of the tracheal rings; 1×10^6M of medicine was added, and the change in contraction tension of the tracheal rings was detected.

[0321] Test conditions: 10μM single dose, 4 samples per group, calculate the 50% inhibition onset time and 50% inhibition recovery time at this dose.

[0321]

[0322] Conclusion: In this experiment, compound 7 had a shorter onset time and a longer duration of action than RPL554, and its inhibition rate of tracheal contraction at 6.75h was higher than that of RPL.

[0322] Note: The structure of RPL554 is as follows:

Claims

1. A compound, its stereoisomer, or a pharmaceutically acceptable salt, wherein, The compound is selected from one of the following structures:

2. A pharmaceutical composition comprising the compound described in claim 1, its stereoisomer or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

3. Use of a compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, or a composition of claim 2 in the preparation of a medicine for treating PDE3 / 4 mediated diseases.

4. As described in claim 3, the PDE3 / 4-mediated diseases are selected from COPD and asthma.