Tricyclic fused heterocyclic pde3 / 4 dual inhibitor and use thereof

Abstract

Disclosed are tricyclic fused heterocyclic compounds with PDE3 / 4 dual inhibition effect shown in formula (I), and stereoisomers, solvates, or pharmaceutically acceptable salts thereof, and use thereof in the preparation of drugs for treating / preventing PDE3 / 4 mediated diseases, wherein the groups in formula (I) are as defined in the specification.

Description

Technical Field

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

[0002] COPD (chronic obstructive pulmonary disease) is a group of lung diseases characterized by airflow limitation that is not fully reversible and progresses, primarily affecting the lungs. It is the most common chronic killer of lung health. The high incidence and mortality rates of COPD are due to two main factors: firstly, early diagnosis is extremely difficult, as 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; secondly, COPD is currently incurable, and medications primarily rely on bronchodilators that modulate airway smooth muscle. These drugs only relieve symptoms and delay disease progression, treating the symptoms but not the root cause. COPD has a long course, often requiring frequent medical visits, hospitalizations for acute exacerbations, and long-term care, consuming significant medical resources and becoming a serious global disease burden. Therefore, for COPD, it is necessary to develop new drugs 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 transductions and regulating various physiological processes. Studies have found that PDE3 is associated with the contraction of respiratory smooth muscle, while PDE4 plays a crucial role in inflammatory responses 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 suggests 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; however, this drug has poor solubility and high plasma clearance, making it suitable for inhalation administration. Bioactivity data show that its PDE4 inhibitory activity is unsatisfactory, potentially leading to less than ideal anti-inflammatory effects. Therefore, dual PDE3 / 4 inhibitors 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 such as good activity, easy formulation with physicochemical properties, high bioavailability, and low toxicity.

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

[0006]

[0007] Among them, R1, R2, R a and R b Independently, it can be H, deuterium, halogen, CN, OH, NH2, or -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -OC 1-4 Alkyl group, -O(CH2) m C 3-6 Cycloalkyl groups, -O(CH2) m Phenyl, -O(CH2) m - Contains 1-3 4-7 membered heterocyclic alkyl groups selected from N, S, and O heteroatoms, and -O(CH2). m - Contains 1-3 5-6 membered heteroaryl groups selected from N, S, and O heteroatoms, C 1-4 Alkyl group, -(CH2) m C 3-6 Cycloalkyl, -(CH2) m Phenyl, -(CH2) m - Contains 1-3 4-7 membered heterocyclic alkyl groups selected from N, S, and O heteroatoms, or -(CH2) m - Contains 1-3 5-6-membered heteroaryl groups selected from N, S, and O heteroatoms, wherein the alkyl, phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected from 1-3 deuterium, halogen, C... 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, CN, NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Substitution of alkyl groups (2) and OH groups;

[0008] In some implementation schemes, R1, R2, R a and R b Independently, it can be H, deuterium, halogen, CN, OH, NH2, or -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -OC 1-4 Alkyl group, -O(CH2) m C 3-6 Cycloalkyl groups, -O(CH2) m- Contains 1-3 4-7 membered heterocyclic alkyl groups selected from N, S, and O heteroatoms, C 1-4 Alkyl group, -(CH2) m C 3-6 Cycloalkyl, or -(CH2) m - Contains 1-3 4-7 membered heterocyclic alkyl groups selected from N, S, and O heteroatoms, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups are optionally further composed of 1-3 groups selected from deuterium, halogen, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0009] In some implementation schemes, R1, R2, R a and R b Independently, H, deuterium, halogen, CN, OH, -OC 1-4 Alkyl group, -O(CH2) m C 3-6 cycloalkyl, C 1-4 Alkyl group, or -(CH2) m C 3-6 Cycloalkyl groups, wherein the alkyl and cycloalkyl groups are optionally further selected from 1-3 elements selected from deuterium, halogen, C. 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0010] In some implementation schemes, R1, R2, R a and R b Independently, it can be H, methoxy, ethoxy, propoxy, isopropoxy, or -O(CH2). m Cyclopropyl, methyl, ethyl, propyl, isopropyl, or -(CH2) m Cyclopropyl, wherein the methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, methyl, ethyl, propyl, isopropyl and cyclopropyl are optionally further substituted 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;

[0011] Optionally, R1 and R2, together with the atoms they are attached to, form a 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, or a C-type heterocycle. 4-7The heterocyclic ring and the carbon ring are optionally composed of 1-3 elements selected from deuterium, halogens, and carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0012] In some embodiments, R1 and R2, together with the atoms they are connected to, form a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, or C. 5-6 The heterocyclic ring and the carbon ring are optionally composed of 1-3 elements selected from deuterium, halogens, and carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0013] In some embodiments, R1 and R2, together with the atoms they are connected to, form a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, or C. 5-6 The heterocyclic ring and the carbon ring are optionally composed of 1-3 elements selected from deuterium, halogens, and carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl and C 1-4 Alkoxy group substitution;

[0014] In some implementations, R1 and R2, along with the atoms they are connected to, form a single structure. It is optionally substituted with 1-2 groups selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, halomethyl, haloethyl and halopropyl;

[0015] R3, R4, R5, and R6 are independently H, deuterium, halogen, and C, respectively. 1-4 Alkyl group, -(CH2) m C 3-6 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from deuterium, halogens, CN and NH2;

[0016] In some implementations, R3, R4, R5, and R6 are independently H, deuterium, halogen, and C. 1-4 Alkyl group, wherein the alkyl group is optionally substituted with 1 to 3 groups selected from deuterium, halogen, CN and NH2;

[0017] In some implementations, R3 and R4 are independently H, deuterium, halogen, and C. 1-4Alkyl group, wherein the alkyl group is optionally substituted with 1-3 groups selected from deuterium, F, Cl, Br and I, and R5 and R6 are independently H;

[0018] In some embodiments, R3 and R4 are independently H, deuterium, F, Cl, Br, I, methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl group is optionally substituted by 1 to 3 groups selected from deuterium, F, Cl, Br, and I, and R5 and R6 are independently H.

[0019] Alternatively, R3 and R4, or R5 and R6, together with the carbon atoms they are bonded to, form C. 3-6 cycloalkyl;

[0020] X is either CO or SO2; in some implementations, X is CO.

[0021] Ring A is phenyl, C 9-10 It has a fused carbocyclic ring or contains 1-3 5-6 membered heteroaryl groups selected from N, S, and O heteroatoms;

[0022] In some implementations, ring A is phenyl, (The linking site is any ring atom on the ring that conforms to the rules of chemical bonding), pyridinyl, pyrimidinyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl;

[0023] In some implementations, ring A is phenyl, (The linking site is any ring atom on the ring that conforms to the rules of chemical bonding), thiophene group, thiazolyl group, isothiazolyl group, oxazolyl group or isoxazolyl group;

[0024] In some implementations, ring A is phenyl, (The linking site is any ring atom on the ring that conforms to the rules of chemical bonding), thiophene group or thiazolyl group;

[0025] L1 is C 1-6 Alkylene, wherein the alkylene is optionally surrounded by 1-3 elements selected from deuterium, halogen, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0026] In some implementations, L1 is C 2-4 Alkylene, wherein the alkylene is optionally surrounded by 1-3 elements selected from deuterium, halogen, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0027] In some implementations, L1 is C2-4 Alkylene;

[0028] R7 represents H and C. 1-4 Alkyl or -(CH2) m C 3-6 Cycloalkyl groups, wherein the alkyl and cycloalkyl groups are optionally composed of 1-3 elements selected from deuterium, halogen, C. 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0029] In some implementations, R7 is H or C. 1-4 Alkyl groups, wherein the alkyl groups are optionally surrounded by 1-3 elements selected from deuterium, halogens, and C. 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0030] In some implementations, R7 is H or C. 1-3 Alkyl groups, wherein the alkyl groups are optionally surrounded by 1-3 elements selected from deuterium, halogens, and C. 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0031] In some embodiments, R7 is H, methyl, ethyl, propyl, or isopropyl, wherein the methyl, ethyl, propyl, or isopropyl group is optionally 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.

[0032] R8 and R9 are independently H and C. 1-4 Alkyl and C 3-6 cycloalkyl;

[0033] In some implementations, R8 and R9 are independently H;

[0034] Optionally, R8 and R9, together with the N atom they are attached to, form a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle is optionally surrounded by 1-3 heteroatoms selected from O, deuterium, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0035] In some embodiments, R8 and R9, together with the N atom they are attached to, form a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle is optionally surrounded by 1-3 heteroatoms selected from O, deuterium, halogens, and C. 1-4 Alkyl and C 1-4 Alkoxy group substitution;

[0036] Each R 10 Independently, it can be H, halogen, CN, NH2, or -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl)2, OH, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, -(CH2) m -C 3-6 cycloalkyl, -OC 3-6 cycloalkyl or C 1-4 Alkoxy groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxy groups are optionally surrounded by 1-3 elements selected from deuterium, halogen, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, CN, NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Substitution of alkyl groups (2) and OH groups;

[0037] In some implementations, each R 10 Independently, H, halogen, CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl or C 1-4 Alkoxy groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxy groups are optionally surrounded by 1-3 elements selected from deuterium, halogen, C. 1-4 Alkyl and CN groups are substituted;

[0038] In some implementations, each R 10 Independently, H, halogen, CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-4 cycloalkyl or C 1-4 Alkoxy groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxy groups are optionally surrounded by 1-3 elements selected from deuterium, halogen, C. 1-4 Alkyl and CN groups are substituted;

[0039] In some implementations, each R 10Independently, 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 optionally substituted by 1 to 3 groups selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, and CN;

[0040] n can be 0, 1, 2, 3, or 4;

[0041] In some implementations, n is 0, 1, 2, or 3;

[0042] Each m is independently 0, 1, 2, 3 or 4;

[0043] In some implementations, each m is independently 0, 1, 2, or 3;

[0044] q is 2 or 3;

[0045] The condition is that when for At that time, R 10 '、R 10 "、R 10 "Like R" 10 By definition, a compound satisfies:

[0046] (iv) R1 and R2 are not both methoxy groups; or

[0047] (v) R3, R4, R5, and R6 are not all H at the same time; or

[0048] (vi)R 10 "Not H or methyl."

[0049] 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.

[0050]

[0051] Among them, R1, R2, R a and R b Independently, it can be H, deuterium, halogen, CN, OH, NH2, or -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -OC 1-4 Alkyl group, -O(CH2) m C 3-6 Cycloalkyl groups, -O(CH2) mPhenyl, -O(CH2) m - Contains 1-3 4-7 membered heterocyclic alkyl groups selected from N, S, and O heteroatoms, and -O(CH2). m - Contains 1-3 5-6 membered heteroaryl groups selected from N, S, and O heteroatoms, C 1-4 Alkyl group, -(CH2) m C 3-6 Cycloalkyl, -(CH2) m Phenyl, -(CH2) m - Contains 1-3 4-7 membered heterocyclic alkyl groups selected from N, S, and O heteroatoms, or -(CH2) m - Contains 1-3 5-6-membered heteroaryl groups selected from N, S, and O heteroatoms, wherein the alkyl, phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups are optionally further selected from 1-3 deuterium, halogen, C... 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, CN, NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Substitution of alkyl groups (2) and OH groups;

[0052] Optionally, R1 and R2, together with the atoms they are attached to, form a 5-7 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, or a C-type heterocycle. 4-7 The heterocyclic ring and the carbon ring are optionally composed of 1-3 elements selected from deuterium, halogens, and carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0053] R3, R4, R5, and R6 are independently H, deuterium, halogen, and C, respectively. 1-4 Alkyl group, -(CH2) m C 3-6 Cycloalkyl groups, wherein the alkyl groups and cycloalkyl groups are optionally substituted with 1 to 3 groups selected from deuterium, halogens, CN and NH2;

[0054] Alternatively, R3 and R4, or R5 and R6, together with the carbon atoms they are bonded to, form C. 3-6 cycloalkyl;

[0055] X is either CO or SO2;

[0056] Ring A is phenyl, C 9-10 It has a fused carbocyclic ring or contains 1-3 5-6 membered heteroaryl groups selected from N, S, and O heteroatoms;

[0057] L1 is C 1-6 Alkylene, wherein the alkylene is optionally surrounded by 1-3 elements selected from deuterium, halogen, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0058] R7 represents H and C. 1-4 Alkyl or -(CH2) m C 3-6 Cycloalkyl groups, wherein the alkyl and cycloalkyl groups are optionally composed of 1-3 elements selected from deuterium, halogen, C. 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0059] R8 and R9 are independently H and C. 1-4 Alkyl and C 3-6 cycloalkyl;

[0060] Optionally, R8 and R9, together with the N atom they are attached to, form a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle is optionally surrounded by 1-3 heteroatoms selected from O, deuterium, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0061] Each R 10 Independently, it can be H, halogen, CN, NH2, or -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl)2, OH, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, -(CH2) m -C 3-6 cycloalkyl, -OC 3-6 cycloalkyl or C 1-4 Alkoxy groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxy groups are optionally surrounded by 1-3 elements selected from deuterium, halogen, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, CN, NH2, -NHC 1-4Alkyl, -N(C) 1-4 Substitution of alkyl groups (2) and OH groups;

[0062] n can be 0, 1, 2, 3, or 4;

[0063] Each m is independently 0, 1, 2, 3 or 4;

[0064] The condition is that when for At that time, R 10 '、R 10 "、R 10 "Like R" 10 By definition, a compound satisfies:

[0065] (vii) R1 and R2 are not both methoxy groups; or

[0066] (viii) R3, R4, R5, and R6 are not all H at the same time; or

[0067] (ix)R 10 "Not H or methyl."

[0068] 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, R... a and R b Independently, it can be H, deuterium, halogen, CN, OH, NH2, or -NHC. 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -OC 1-4 Alkyl group, -O(CH2) m C 3-6 Cycloalkyl groups, -O(CH2) m - Contains 1-3 4-7 membered heterocyclic alkyl groups selected from N, S, and O heteroatoms, C 1-4 Alkyl group, -(CH2) m C 3-6 Cycloalkyl, or -(CH2) m - Contains 1-3 4-7 membered heterocyclic alkyl groups selected from N, S, and O heteroatoms, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups are optionally further composed of 1-3 groups selected from deuterium, halogen, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0069] Optionally, R1 and R2, together with the atoms they are attached to, form a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, or a C-type heterocycle. 5-6 The heterocyclic ring and the carbon ring are optionally composed of 1-3 elements selected from deuterium, halogens, and carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0070] R3, R4, R5, and R6 are independently H, deuterium, halogen, and C. 1-4 Alkyl group, wherein the alkyl group is optionally substituted with 1 to 3 groups selected from deuterium, halogen, CN and NH2;

[0071] Ring A is phenyl, Pyridyl, pyrimidinyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl;

[0072] L1 is C 2-4 Alkylene, wherein the alkylene is optionally surrounded by 1-3 elements selected from deuterium, halogen, C 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0073] R7 is H or C 1-4 Alkyl groups, wherein the alkyl groups are optionally surrounded by 1-3 elements selected from deuterium, halogens, and C. 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0074] R8 and R9 are independently H and C. 1-4 Alkyl and C 3-6 cycloalkyl;

[0075] Optionally, R8 and R9, together with the N atom they are attached to, form a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycle is optionally surrounded by 1-3 heteroatoms selected from O, deuterium, halogens, and C. 1-4 Alkyl and C 1-4 Alkoxy group substitution;

[0076] Each R 10 Independently, H, halogen, CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl or C 1-4 Alkoxy groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxy groups are optionally surrounded by 1-3 elements selected from deuterium, halogen, C.1-4 Alkyl and CN groups are substituted;

[0077] p is 1 or 2;

[0078] The rest is as described in the first technical solution.

[0079] 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:

[0080]

[0081] Among them, R1, R2, R a and R b Independently, H, deuterium, halogen, CN, OH, -OC 1-4 Alkyl group, -O(CH2) m C 3-6 cycloalkyl, C 1-4 Alkyl group, or -(CH2) m C 3-6 Cycloalkyl groups, wherein the alkyl and cycloalkyl groups are optionally further selected from 1-3 elements selected from deuterium, halogen, C. 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0082] Optionally, R1 and R2, together with the atoms they are attached to, form a 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, or a C-type heterocycle. 5-6 The heterocyclic ring and the carbon ring are optionally composed of 1-3 elements selected from deuterium, halogens, and carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl and C 1-4 Alkoxy group substitution;

[0083] R3 and R4 are independently H, deuterium, halogen, and C. 1-4 Alkyl group, wherein the alkyl group is optionally substituted with 1 to 3 groups selected from deuterium, F, Cl, Br and I;

[0084] Ring A is phenyl, Thiophene group, thiazolyl group, isothiazolyl group, oxazolyl group, or isoxazolyl group;

[0085] R7 is H or C 1-3 Alkyl groups, wherein the alkyl groups are optionally surrounded by 1-3 elements selected from deuterium, halogens, and C. 1-4 Alkoxy, deuterated C 1-4 Alkoxy and halogenated C 1-4 Alkoxy group substitution;

[0086] Each R 10 Independently, H, halogen, CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-4 cycloalkyl or C 1-4 Alkoxy groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxy groups are optionally surrounded by 1-3 elements selected from deuterium, halogen, C. 1-4 Alkyl and CN groups are substituted;

[0087] q is 1, 2, or 3;

[0088] The rest is as described in the second technical solution.

[0089] 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, R... a and R b Independently, it can be H, methoxy, ethoxy, propoxy, isopropoxy, or -O(CH2). m Cyclopropyl, methyl, ethyl, propyl, isopropyl, or -(CH2) m Cyclopropyl, wherein the methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, methyl, ethyl, propyl, isopropyl and cyclopropyl are optionally further substituted 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;

[0090] Alternatively, R1 and R2, along with the atoms they are connected to, form a single structure. It is optionally substituted with 1-2 groups selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, halomethyl, haloethyl and halopropyl;

[0091] R3 and R4 are independently H, deuterium, F, Cl, Br, I, methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl group is optionally substituted by 1 to 3 groups selected from deuterium, F, Cl, Br, and I;

[0092] Ring A is phenyl, Thiophene group or thiazolyl group;

[0093] R7 is H, methyl, ethyl, propyl, or isopropyl, wherein the methyl, ethyl, propyl, or isopropyl group is optionally substituted by 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.

[0094] Each R 10 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 optionally substituted by 1 to 3 groups selected from deuterium, F, Cl, Br, I, methyl, ethyl, propyl, and CN;

[0095] q is 2 or 3;

[0096] The rest is as described in the third technical solution.

[0097] 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:

[0098]

[0099]

[0100] As a more specific sixth technical solution of the present invention, a pharmaceutical composition is provided, comprising 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.

[0101] As a more specific seventh technical solution of the present invention, a use is provided, namely, the use of the compound described in any of the first to fifth technical solutions, its stereoisomer, solvate, or pharmaceutically acceptable salt, or the composition described in the sixth technical solution, in the preparation of a medicament for treating / preventing PDE3 / 4 mediated diseases.

[0102] Furthermore, the PDE3 / 4-mediated diseases are selected from COPD and asthma.

[0103] Synthetic route

[0104] Those skilled in the art can prepare the compounds of this invention using known organic synthesis techniques, with starting materials being commercially available chemicals and / or compounds described in chemical literature. "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, among others.

[0105] References and monographs in this field provide detailed descriptions of the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing such preparation methods for reference. These 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”4thEdition(1992)John Wiley & Sons,ISBN:0-471-60180-2;Otera,J.(editor)“ModernCarbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.“Patai’s 1992Guide 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)JohnWiley & 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”JohnWiley & Sons,in 73 volumes.

[0106] 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. Chemicals known but not commercially available in the catalogue can optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services (e.g., those listed above). A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PHStahl & CGWermuth, “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002.

[0107] the term

[0108] Unless otherwise specified in this invention, the terminology used in this invention has the following meanings:

[0109] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0110] In this article, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0111] "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 hydrogen atoms that can be substituted in the substituted group. Unless otherwise specified, the number of halogen substituents can be any integer between 1 and this upper limit. When the number of halogen substituents is greater than 1, the substitution can be with the same or different halogens. Common cases include 1-5 halogen substitutions, 1-4 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

[0112] "Deuterium" refers to the hydrogen (H) isotope deuterium, which is synonymous with "D".

[0113] "Deuteration" or "deuterated product" refers to the substitution of at least one deuterium atom for a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, or alkynyl group. The upper limit for the number of deuterations is equal to the sum of the number of hydrogen atoms that can be substituted in the substituted group. Unless otherwise specified, the number of deuterations is any integer between 1 and this 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.

[0114] “C x-y A "group" refers to a group containing x to y carbon atoms, such as "C". 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0115] "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, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc., and the alkyl group may be further substituted with substituents.

[0116] "Alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, etc.

[0117] "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 substituted in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and this upper limit. Typically, alkyl groups are substituted 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.

[0118] "Alkoxy" or "alkyloxy" refers to -O-alkyl. For example, -OC 1-8 Alkyl, -OC 1-6 Alkyl, -OC 1-4 Alkyl or -OC 1-2 Alkyl groups. Specific, non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy, etc.; the alkoxy groups may optionally be substituted with substituents.

[0119] "Haloalkoxy" refers to -O-haloalkyl. For example, -O-haloC 1-8 Alkyl, -O-halogenated C 1-6 Alkyl, -O-halogenated C 1-4 Alkyl or -O-halogenated C 1-2 Alkyl groups; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be replaced 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, the same or different halogens can be used for substitution. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0120] "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, 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 group may optionally be further substituted with substituents.

[0121] "Alkenyl" refers to a straight-chain 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 optionally be substituted with substituents.

[0122] "Alynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (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, ethynyl, 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-octyynyl, 3-nonynyl, and 4-decynyl; the alkynyl group may optionally be substituted with substituents.

[0123] "Imyynyl" refers to a straight-chain or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), typically containing 2-6 carbon atoms, and more commonly 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, and butynyl, and the ethynyl group may optionally be substituted with substituents.

[0124] "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain cyclic heteroatoms. Cycloalkyl groups can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic groups can be fused, spirocyclic, bridged, or combinations thereof. A bicyclic or polycyclic group may include one or more aromatic rings, but the ring system as a whole is not aromatic. The linkage 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 it is a monocyclic cycloalkyl group, it contains 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms. When it is a bicyclic or polycyclic cycloalkyl group, it contains 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, and cyclohexenyl. In addition, cycloalkyl groups may optionally be substituted with substituents.

[0125] "Cycloalkylene" refers to the divalent group of a cycloalkyl group.

[0126] "Aryl" refers to an aromatic carbon ring that does not contain heteroatoms, including monocyclic aryl and fused-ring aryl. It typically contains 6 to 13 carbon atoms, more commonly 6 to 9 carbon atoms, and is further preferably phenyl. Non-limiting examples include phenyl, naphthyl, anthraceneyl, and phenanthrene. The aryl group may optionally be substituted with substituents.

[0127] "Carbocyclic" 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. Carbon rings typically have 3 to 12 carbon atoms, or 3 to 10 carbon atoms, or 3 to 6 carbon atoms. In non-limiting embodiments, monocyclic carbon rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, etc., and bicyclic bridged rings include... Etc., double-ring parallel rings include etc., double-ring spiral rings include In addition, the carbon ring can be optionally replaced by substituents.

[0128] "Heterocyclic alkyl" refers to a non-aromatic carbon ring containing 1, 2, 3, or 4 heteroatoms selected from N, S, and O, either saturated or partially unsaturated. Heterocyclic alkyl groups can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic groups can be bridged rings, fused rings, spirocyclic rings, or combinations thereof. A bicyclic or polycyclic group may include one or more aromatic or heteroaromatic rings, but the ring system as a whole is not aromatic. Linking sites can be on aromatic or non-aromatic rings. Typically, heterocyclic alkyl groups are 3 to 20-membered rings. When monocyclic, they are typically 3 to 15-membered, or 3-10-membered, or 3-8-membered, or 3-6-membered rings. When bicyclic or polycyclic heterocyclic alkyl groups, they are typically 5-12-membered, or 5-11-membered, or 6-9-membered rings. The heteroatoms N and S include their oxidation states. Non-limiting examples of heterocyclic alkyl groups include azirrobutyl, morpholino, piperazinyl, piperidinyl, tetrahydropyranyl, oxacyclobutyl, pyranyl, azirropentenyl, azirrohexenyl, oxacyclopentenyl, oxacyclohexenyl, etc., and the heterocyclic alkyl groups may optionally be substituted with substituents.

[0129] Unless otherwise specified, "heteroaromatic ring" or "heteroaryl" 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, pyridazinyl, indoleyl, purine, etc. The heteroaryl group can be optionally substituted with a substituent.

[0130] "Heterocycle" or "heterocyclic group" refers to a saturated or unsaturated, aromatic or non-aromatic ring containing one to four heteroatoms selected from N, O, or S and their oxidation states. It includes 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-dioxhexane, piperazinyl, azirroheptyl, pyridinyl, furanyl, thiopheneyl, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazoleyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, and di... Hydrofuranyl, dihydropyranyl, dithiapentylyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, 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, In addition, heterocyclic rings can be optionally substituted by substituents.

[0131] "Hypo-heterocyclic group" refers to a divalent heterocyclic group that is substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic. Non-limiting examples include... wait.

[0132] A "spirocyclic ring" is a polycyclic group that shares a single carbon atom (called a spiro atom) between rings. It can contain 0 or more double or triple bonds and 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. Common spirocyclic rings include tri-spirotri- (representing a three-membered ring followed by a spirotri-membered ring), tri-spirotetra-, tri-spiropenta-, tri-spirohexa-, tetra-spirotetra-, tetra-spiropenta-, tetra-spirohexa-, tetra-spiropenta-, tetra-spirohexa-, penta-spiropenta-, or penta-spirohexa-. Non-limiting examples of spirocyclic rings include... The spiroring can be optionally replaced by a substituent.

[0133] "Built rings" refer to polycyclic groups that share two adjacent ring atoms and a chemical bond. They can contain one or more double or triple bonds and can contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Typically, fused rings are 5 to 20-membered, 5 to 14-membered, 5 to 12-membered, or 5 to 10-membered rings. Common fused ring types include trifused tetracyclic rings (representing fused rings formed by a three-membered and a four-membered ring; according to IUPC nomenclature, this could be a fused ring with either a three-membered or a four-membered ring as the base ring, and the same applies below), trifused pentacyclic rings, trifused hexacyclic rings, tetrafused tetracyclic rings, tetrafused pentacyclic rings, tetrafused hexacyclic rings, pentafused pentacyclic rings, pentafused hexacyclic rings, and hexafused hexacyclic rings. Non-limiting examples of fused rings include purines, quinolines, isoquinolines, benzopyrans, benzofurans, and benzothiophenes. The cyclic ring can be optionally replaced by a substituent.

[0134] A "bridged ring" refers to two rings sharing two non-adjacent ring atoms and may contain one or more double or triple bonds. Bridged rings can contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Typically, bridged rings have 5 to 20, 5 to 14, 5 to 12, or 5 to 10 ring atoms. Non-limiting examples of bridged rings include adamantane, etc. The bridge ring can be optionally replaced by a substituent.

[0135] 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 bonding. Exemplary substituents include, but are not limited to: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Heteroalkyl, C 5-12 Aryl, 5-12 heteroaryl, hydroxyl, C 1-6 Alkoxy, C 5-12 aryloxy groups, thiol groups, C 1-6 Alkylthio, cyano, halogen, C 1-6 alkylthiocarbonyl, C 1-6 Alkyl carbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, phosphonic acid, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2,-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C1-6 Alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2,-HC(=O)NH(C 1-6 Alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 alkyl)2,-SO2NH(C 1-6 Alkyl group, -SO2NH2, -SO2C 1-6 Alkyl groups, etc.

[0136] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0137] "Pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, wherein the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0138] "Pharmaceutical composition" means one or more of the compounds described herein or their stereoisomers, solvates, pharmaceutically acceptable salts or eutectics, mixed with other components, wherein the other components contain physiologically / pharmaceuticalally acceptable carriers and / or excipients.

[0139] "Carrier" refers to a system that does not cause significant stimulation to the organism and does not eliminate the biological activity and properties of the given compound, and can change the way the drug enters the human body and its distribution in the 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.

[0140] "Excipient" refers to an agent that is not itself a therapeutic agent but is used as a diluent, excipient, binder, and / or medium to be added 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 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 waxes; (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.

[0141] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0142] 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 substituted with OH, the right-hand tautomer compound is also included.

[0143]

[0144] "Solvate" refers to a substance formed by the combination of the compound of the present invention or its salt with a stoichiometric or non-stoichiometric solvent through intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0145] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate. Detailed Implementation

[0146] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0147] Example 1:

[0148] (E)-1-(2-(2-(2,4,6-trimethylbenzimino)-10-methoxy-9-(methoxy-d3)-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 1)

[0149] (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

[0150]

[0151] first step:

[0152] 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%).

[0153] LC-MS (ESI): m / z = 301.2 [M+H] + .

[0154] Step Two:

[0155] 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 give the target compound 1C (42 g, yield 65.9%).

[0156] LC-MS (ESI): m / z = 369.1 [M+H] +

[0157] Step 3:

[0158] 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 separated by silica gel column chromatography (DCM:MeOH (v / v) = 40:1) to give the target compound (12.7 g, yield 30%).

[0159] LC-MS (ESI): m / z = 369.1 [M+H] + .

[0160] 1 H NMR (400MHz, CDCl3) δ7.48-7.32 (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).

[0161] Step 4:

[0162] 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, the mixture 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 separated by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to give compound 1E (8.3 g, yield 80%).

[0163] LC-MS (ESI): m / z = 468.2 [M+H] + .

[0164] Step 5:

[0165] 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 reacted under nitrogen protection at 95 °C for 48 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 residue obtained after concentration under reduced pressure was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0 to 1:1) to give the target compound 1F (0.92 g, yield 24%).

[0166] LC-MS (ESI): m / z = 641.2 [M+H] + .

[0167] Step 6:

[0168] 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, 73% yield).

[0169] LC-MS (ESI): m / z = 551.2 [M+H] + .

[0170] Step 7:

[0171] 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. Deuterated iodomethane (0.30 g, 2.1 mmol) was then added dropwise, and the reaction was allowed to proceed completely at room temperature for 1 hour. After the reaction was complete, 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 separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0–1:1) to give compound 1H (0.52 g, yield 87%).

[0172] LC-MS (ESI): m / z = 568.2 [M+H] + .

[0173] Step 8:

[0174] 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 separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 5:1) to give compound 1I (0.35 g, yield 87%).

[0175] LC-MS (ESI): m / z = 438.1 [M+H] +

[0176] Step 9:

[0177] 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 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 reaction. After the addition was complete, the reaction was continued at 80 °C for 2 h. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate (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 separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 10:1) to give compound 1 (0.12 g, yield 50%).

[0178] LC-MS (ESI): m / z = 481.3 [M+H] +

[0179] 1H NMR (400MHz, CDCl3) δ6.91 (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).

[0180] Example 2:

[0181] (E)-1-(2-(2-((2,6-dimethyl-4-(trifluoromethyl)phenyl)imino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 2)

[0182] (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

[0183]

[0184] first step:

[0185] 2A (50 g, 0.28 mol) was dissolved in water (150 mL), and KCNO (8.1 g, 0.10 mol) was added. 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 resulting filter cake was dried to give the title compound 2B (51 g, 82.3%).

[0186] LC-MS (ESI): m / z = 225.2 [M+H] + .

[0187] Step Two:

[0188] 2B (51 g, 0.22 mol) was dissolved in anhydrous ethanol (300 mL), followed by the addition of diethyl malonate (50 g, 0.34 mol) and sodium ethoxide (47 g, 0.69 mol). The reaction mixture was heated to reflux and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove most of the ethanol. Water (150 mL) was added to the residue, and the pH was adjusted to 6.0 with dilute hydrochloric acid (5 M). The mixture was 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%).

[0189] LC-MS (ESI): m / z = 293.3 [M+H] + .

[0190] Step 3:

[0191] 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 5 N 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%).

[0192] 1 H NMR (400MHz, DMSO-d6) δ7.50 (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).

[0193] LC-MS (ESI): m / z = 293.3 [M+H] + .

[0194] Step 4:

[0195] 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, it was stopped and cooled to room temperature. The mixture was then concentrated under reduced pressure to remove most of the reaction solution. DCM (20 mL) 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 give the title compound 2F (0.42 g, 25%).

[0196] LC-MS (ESI): m / z = 190.2 [M+H] + .

[0197] Step 5:

[0198] 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 mixture was reacted at 90 °C for 24 hours. After the reaction was complete, the reaction was stopped, and the mixture was cooled to room temperature. The solvent was concentrated under reduced pressure to remove most of the reaction solvent. A saturated sodium bicarbonate aqueous solution (20 mL) was added to the residue, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with a saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to give compound 2G (0.65 g, yield 85%).

[0199] LC-MS (ESI): m / z = 446.3 [M+H] + .

[0200] Step 6:

[0201] 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 separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0 to 1:1) to give the target compound 2H (0.25 g, yield 45%).

[0202] LC-MS (ESI): m / z = 619.3 [M+H] + .

[0203] Step 7:

[0204] 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 separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 5:1) to give compound 2I (0.17 g, yield 89%).

[0205] LC-MS (ESI): m / z = 489.1 [M+H] + .

[0206] Step 8:

[0207] Compound 2I (0.17 g, 0.36 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. 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 aqueous solution of sodium bicarbonate (10 mL) was added. The mixture was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 10:1) to give compound 2 (0.08 g, yield 41%).

[0208] 1 H NMR (400MHz, Methanol-d4) δ7.36(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).

[0209] LC-MS (ESI): m / z = 532.3 [M+H] + .

[0210] Example 3:

[0211] (E)-1-(2-(2-((4-cyclopropyl-2,6-dimethylphenyl)imino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 3)

[0212] (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

[0213]

[0214] first step:

[0215] Compound 3A (3 g, 15.07 mmol) and cyclopropylboronic acid (1.94 g, 22.67 mmol) were dissolved in toluene (20 mL) and water (5 mL). Palladium acetate (0.34 g, 1.51 mmol), tricyclohexylphosphine (0.47 g, 28.38 mmol), and potassium phosphate (6.40 g, 30.14 mmol) 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. The reaction was allowed to cool to room temperature, and the mixture was concentrated under reduced pressure to remove most of the reaction solution. DCM (20 mL) 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 give the title compound 3B (0.70 g, 29%).

[0216] LC-MS (ESI): m / z = 162.2 [M+H] + .

[0217] Step Two:

[0218] 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 separated by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to give compound 3C (0.50 g, yield 70%).

[0219] LC-MS (ESI): m / z = 418.3 [M+H] + .

[0220] Step 3:

[0221] 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 a nitrogen atmosphere at 120 °C for 2 hours using 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 separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0 to 1:1) to give the target compound 3D (0.33 g, yield 47%).

[0222] LC-MS (ESI): m / z = 591.3 [M+H] + .

[0223] Step 4:

[0224] 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 separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 5:1) to give compound 3E (0.18 g, yield 70%).

[0225] LC-MS (ESI): m / z = 461.2 [M+H] + .

[0226] Step 5:

[0227] Compound 3E (0.18 g, 0.39 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. An aqueous solution of potassium cyanate (81 mg, 1 mmol) (1 mL) was added dropwise to the system. After the addition was complete, stirring was continued for 2 h. The mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (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 separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 10:1) to give compound 3 (0.07 g, yield 36%).

[0228] 1H NMR (400MHz, Methanol-d4) δ7.03-6.98 (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).

[0229] LC-MS (ESI): m / z = 504.3 [M+H] + .

[0230] Example 4:

[0231] (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)

[0232] (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

[0233]

[0234] first step:

[0235] Compound 4A (77 mg, 0.17 mmol) (synthesis of compound 4A is described in patent WO2021143843) was dissolved in water (5 mL), and potassium cyanate (48.3 mg, 0.6 mmol, 3.5 eq) was added. Dilute hydrochloric acid (concentrated HCl (43 μL, 0.51 mmol, 3 eq) diluted with water (5 mL) was added) was then 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, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to give compound 4 (81 mg, 0.16 mmol, 97% yield).

[0236] LC-MS (ESI): m / z = 492.2 [M+H] + .

[0237] 1 H NMR (400MHz, Chloroform-d) δ6.94 (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).

[0238] Example 5: (E)-1-(2-(2-((4-fluoro-2,6-dimethylphenyl)imino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 5)

[0239] (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

[0240]

[0241] first step:

[0242] 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 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 separated by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to give compound 5A (0.57 g, yield 85%).

[0243] LC-MS (ESI): m / z = 396.2 [M+H] + .

[0244] Step Two:

[0245] 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 separated by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0 to 1:1) to give the target compound 5B (0.34 g, yield 40%).

[0246] LC-MS (ESI): m / z = 569.2 [M+H] + .

[0247] Step 3:

[0248] 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 separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 5:1) to give compound 5C (0.17 g, yield 89%).

[0249] LC-MS (ESI): m / z = 439.1 [M+H] + .

[0250] Step 4:

[0251] 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. After the addition was complete, the mixture was stirred under these conditions for 2 h. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate (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 separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 10:1) to give compound 5 (0.09 g, yield 93%).

[0252] 1H NMR (400MHz, CD3OD) δ6.78 (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).

[0253] LC-MS (ESI): m / z = 482.3 [M+H] + .

[0254] Example 6: (E)-1-(2-(9-(benzyloxy)-2-(trimethylmethylimino)-10-methoxy-4-oxo-6,7-dihydro-2H-pyrimidinone[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 6)

[0255] (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

[0256]

[0257] first step:

[0258] 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 a 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%).

[0259] Step Two:

[0260] Compound 6A (63 mg, 0.12 mmol) was dissolved in water (5 mL), and potassium cyanate (34 mg, 0.42 mmol, 3.5 eq) was added. Concentrated hydrochloric acid (0.03 mL, 0.36 mmol, 3 eq) was diluted with water (5 mL) and then 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).

[0261] LC-MS (ESI): m / z = 554.3 [M+H] + .

[0262] 1 H NMR (400MHz, CDCl3) δ7.41-7.33 (m, 5H), 6.92 (s, 2H), 6.72 (s, 2H), 5.48 (s, 1H), 5.18 (s, 2H) , 4.44(m, 2H), 4.06(m, 2H), 3.76(s, 3H), 3.56(m, 2H), 2.89(m, 2H), 2.30(s, 3H), 2.08(s, 6H).

[0263] Example 7: (E)-1-(2-(2-(2,4,6-trimethylbenzimino)-9-methoxy-10-(methoxy-D3-deuterated)-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (compound 7)

[0264] (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

[0265]

[0266] first step:

[0267] 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%).

[0268] LC-MS (ESI): m / z = 301.2 [M+H] + .

[0269] Step Two:

[0270] 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 5 N hydrochloric acid. The mixture was then filtered, and the filter cake was washed with water (150 mL) and dried to obtain the target compound 7C (42 g, 90% yield).

[0271] LC-MS (ESI): m / z = 369.1 [M+H] + .

[0272] Step 3:

[0273] 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 separated by silica gel column chromatography (DCM:MeOH (v / v) = 40:1) to give the target compound 7D (12.7 g, yield 30%).

[0274] LC-MS (ESI): m / z = 369.1 [M+H] + .

[0275] Step 4:

[0276] 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 separated by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to give compound 7E (0.53 g, yield 55%).

[0277] LC-MS (ESI): m / z = 468.2 [M+H] + .

[0278] Step 5:

[0279] 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 separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 20:1) to obtain the target compound 7F (0.5 g, yield 42%).

[0280] LC-MS (ESI): m / z = 507.3 [M+H] + .

[0281] Step 6:

[0282] 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).

[0283] LC-MS (ESI): m / z = 417.3 [M+H] + .

[0284] Step 7:

[0285] 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).

[0286] LC-MS (ESI): m / z = 434.2 [M+H] + .

[0287] Step 8:

[0288] Compound 7H (180 mg, 0.414 mmol) was added to ethanol (10 mL), followed by the addition of Raney nickel (150 mg) and hydrazine hydrate (1 mL) in portions at room temperature. The mixture was then 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, 66% yield), which could be used directly in the next reaction without further purification.

[0289] LC-MS (ESI): m / z = 438.2 [M+H] + .

[0290] Step 9:

[0291] Compound 7I (0.12 g, 0.23 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. After the addition was complete, the mixture was stirred under these conditions for 2 h. After cooling 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 separated by silica gel column chromatography (dichloromethane:methanol (v / v) = 1:0 to 10:1) to give compound 7 (0.08 g, yield 41%).

[0292] LC-MS (ESI): m / z = 481.3 [M+H] + .

[0293] 1H NMR (400MHz, Methanol-d4) δ6.80 (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).

[0294] Biological testing:

[0295] 1. In vitro detection of the inhibitory activity of the compound on PDE 3A and PDE 4B2 enzymes.

[0296] Experimental materials:

[0297] Envision 2104 Multilabel Reader(PerkinElmer)

[0298] Black 96-well Plate (Cat#6005540, PerkinElmer)

[0299] PDE3A Assay Kit (BPS, Cat.79736), PDE4B2 Assay Kit (BPS, Cat.60343)

[0300] PDE3A recombinant enzyme

[0301] PDE4B2 recombinant enzyme

[0302] ·FAM-Cyclic-3′, 5′-AMP

[0303] PDE assay buffer

[0304] Binding Agent

[0305] Binding Agent Diluent (cAMP)

[0306] Experimental steps:

[0307] 1) Prepare FAM cAMP working solution: Add 20 μL of FAM-Cyclic-3′, 5′-AMP stock to 1980 μL of PDEassay buffer. Add to all wells at a rate of 25 μL / well.

[0308] 2) Preparation of compound solutions: First, dissolve the compound to be tested in DMSO to prepare a 10 mM stock solution. Dilute the stock solution with DMSO to prepare a 100X Top Dose diluent. Then, add 5 μL of the 100X Top Dose diluent to 45 μL of PDE assay buffer to prepare the compound Top Dose working solution. Next, prepare working solutions of various concentrations by serial dilution with PDE assay buffer containing 10% DMSO. Add 5 μL / well to each well of the compound solution. Add 5 μL of PDE assay buffer containing 10% DMSO to each well of the control solution.

[0309] 3) Prepare PDE enzyme solutions: 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 wells.

[0310] 4) React at room temperature for 1 hour.

[0311] 5) Prepare Binding Agent: Add 80 μL of binding agent to 7920 μL of binding agent concentrate and mix well. Add 100 μL / well to all wells.

[0312] 6) React at room temperature for 1 hour.

[0313] 7) Read FP on Envision.

[0314] 8) Formula for calculating raw data:

[0315] %Inhibition rate = (FP V -FP S ) / (FP V -FP B )×100%

[0316] FP S =Sample FP

[0317] FP V =Vehicle vs. FP

[0318] FP B =Blank vs. FP.

[0319] IC50 was calculated using a nonlinear regression of log[dose]-inhibition rate with Graphpad.

[0320] Experimental results:

[0321] The compounds of this invention exhibit excellent PDE3 and PDE4 inhibitory activity, with IC50 values ​​below 500 nM. 50 IC values ​​for some superior compounds 50 <200 nM, some better compounds IC 50 <100 nM, some better compounds IC 50 <50 nM, for example, for PDE 3, the IC50 of compound 1 50 The IC50 of compound 7 is 0.15 nM. 50 The value is 0.17 nM. The test results for some compounds are listed in the table below.

[0322] Table 1 Results of in vitro screening tests for compounds

[0323]

[0324] A: 0nM < IC 50 ≤50nM;

[0325] B: 50nM < IC 50 ≤100nM;

[0326] C: 100nM < IC 50 ≤200nM;

[0327] D: 200nM < IC 50 ;

[0328] NT: Not tested.

[0329] 2. Study on the inhibitory effect of the compound on acetylcholine-induced bronchoconstriction in guinea pigs.

[0330] 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.

[0331] The inhibition rates of bronchoconstriction of each compound at an oral dose of 10 mg / kg are shown in the table below:

[0332] Inhibition rate RPL554 Compound 1 Compound 7 6h 35％ 69％ 80％

[0333] 3. Guinea pig tracheal ring experiment

[0334] 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 the drug was added, and the changes in the contraction tension of the tracheal rings were detected.

[0335] Test conditions: 10μM single dose, 4 samples per group, calculate the 50% inhibition onset time and 50% inhibition recovery time at this dose.

[0336] Compound Name <![CDATA[OT 50 (min)]]> <![CDATA[RT 50 (h)]]> % inhibition@6.75h RPL554 25.51 ＞6.75h 56.70 Compound 7 19.97 ＞6.75h 75.94

[0337] Conclusion: Compound 7 had a shorter onset time and a longer duration of action than RPL554 in this experiment, and its inhibition rate of tracheal contraction at 6.75 h was higher than that of RPL.

[0338] Note: The structure of RPL554 is as follows:

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from one of the following structures: 。 2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2 or 3, in the preparation of a medicament for the treatment / prevention of PDE3 / 4 mediated diseases.

5. The use as described in claim 4, wherein the PDE3 / 4-mediated disease is selected from COPD and asthma.