Deuterated heterocyclic compound as PDE4B inhibitor and application thereof

Abstract

The invention belongs to the field of medicines, and particularly relates to a deuterated heterocyclic compound serving as a PDE4B inhibitor and application of the deuterated heterocyclic compound. The invention specifically relates to a compound as shown in a formula I, or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The compound has a relatively good PDE4B inhibition effect. # imgabs0 #

Description

[0001] Priority Information

[0002] This application claims the priority and benefits of patent applications 202311744747.3 filed with the China National Intellectual Property Administration on December 15, 2023, 202410070286.4 filed with the China National Intellectual Property Administration on January 17, 2024, 202410658874.X filed with the China National Intellectual Property Administration on May 24, 2024, 202411247213.4 filed with the China National Intellectual Property Administration on September 5, 2024, and 202411758940.7 filed with the China National Intellectual Property Administration on December 2, 2024, and incorporates the entire text thereof herein by reference. Technical Field

[0003] The present invention belongs to the field of medicine. Specifically, the present invention relates to a class of deuterated heterocyclic compounds as PDE4B inhibitors and their applications. Specifically, it relates to the compounds shown in Formula I, or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; the compounds have good PDE4B inhibitory effects. Background Art

[0004] PDE4 is a cyclic nucleotide phosphodiesterase that is abundantly expressed in most cells and hydrolyzes cAMP with a micromolar Km value. The PDE4 molecule is involved in a variety of physiological processes, including brain function, mononuclear macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, and myocardial contraction. It has been reported that PDE4 is a target for various inflammatory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis. PDE4 is composed of four subtypes, namely PDE4A, PDE4B, PDE4C, and PDE4D, which are located on chromosomes 19p13.2, 1p31, 19p13.11, and 5q12, respectively. The PDE4 molecule exists in long, short, and ultra-short forms according to its molecular size. The X-ray structure of the PDE4 molecule shows that the active center can be divided into three sub-pockets: a divalent metal pocket that interacts with the phosphate moiety of cAMP; two Q pockets that form hydrogen bonds and hydrophobic interactions with inhibitors; and a solvation pocket (S pocket). PDE4 inhibitors occupy the active site through a variety of interactions, including hydrophobic interactions with conserved phenylalanine and isoleucine, and hydrogen bond interactions with invariant glutamine. The high conservation and structural homology of the PDE4 catalytic domain make the discovery of PDE4 subtype-selective inhibitors challenging.

[0005] Clinical studies of PDE4 inhibitors are limited by side effects, including nausea and vomiting, which are thought to be caused by inhibition of the PDE4D subtype. Similarly, side effects also limit the therapeutic index of the second-generation PDE4 inhibitors cilomilast and roflumilast. Selective inhibition of the PDE4B subtype may provide a way to achieve efficacy while potentially reducing these adverse events.

[0006] Currently, there are no drugs on the market that use the PDE4B inhibitor inhibition pathway to treat numerous diseases including fibrosis. Therefore, the development of new compounds that can inhibit PDE4B activity is of positive significance for the treatment of diseases. SUMMARY OF THE INVENTION

[0007] The object of the present invention is to provide a new compound for use as an inhibitor of PDE4B.

[0008] In a first aspect of the present invention, there is provided a compound which is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula I:

[0009]

[0010] Wherein,

[0011] Ring A is a 5- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring;

[0012] Each R T is independently H, halogen, hydroxy, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 deuterated cycloalkyl, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy, and the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 deuterated cycloalkyl, C 1-6 deuterated alkyl and C 1-6 deuterated alkoxy are optionally substituted by one or more of the following substituents: halogen, hydroxy, amino, nitro, cyano or carbonyl, and when there are multiple substituents, the substituents are the same or different;

[0013] B is a 3- to 10-membered heteroalkyl, 3- to 10-membered heteroalkenyl or 3- to 10-membered cycloalkyl;

[0014] R a and R b are each independently H, deuterium, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxy, C1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 halocycloalkyl, C 1-6 alkylhydroxy, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, 3- to 10-membered heterocycloalkyl; the C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 halocycloalkyl, C 1-6 alkylhydroxy, C 1-6 alkylcarbonyl, C 1-6 alkoxy and C 1-6 haloalkoxy is optionally substituted by one or more R c substituents; the R c is the following substituent: deuterium, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkylhydroxy, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 haloalkoxy; when the substituent R c is plural, the R c are the same or different;

[0015] Y is NR 1 、O, S or C(R 1 )2;

[0016] each R 1 is independently Η, deuterium, C 1-10 alkyl, C 2-6 alkenyl, the C 1-10 alkyl and C 2-6 alkenyl is optionally substituted by one or more R d substituents; the R d is the following substituent: deuterium, halogen, C 1-3 haloalkyl, C 1-6 alkoxy, C 1-6Halogenated alkoxy, -COO-C 1-6 alkyl, -C(O)NR f R f , 5-8 membered aromatic ring, -het 1 , monocyclic- or bicyclic-C 5-8- cycloalkyl; wherein, said R f is hydrogen, C 1-6 alkyl; said het 1 represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O each other;

[0017] Q is the following group:

[0018] R 2 and R 3 pair, R 5 and R 6 each pair of pairs can independently form a saturated or partially saturated 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring with the carbon atoms to which they are attached respectively; wherein said 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring contains 0, 1, 2 or 3 heteroatoms, said heteroatoms being N, O or S, and further, wherein said 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted by g R 23 substituents, said R 23 is at least one of the following: Η, deuterium, halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkyl hydroxyl, C 1-6 alkyl carbonyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 halogenated alkoxy, -COO-C 1-6 alkyl, -C(O)NR f R f ; wherein, said R f is hydrogen, C 1-6 alkyl;

[0019] Or, R 5 and R 6 are each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, said C 1-6 alkyl, C1-6 Deuterated alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy and C 1-6 Deuterated alkoxy is optionally substituted with one or more R d ; said R d Is a substituent selected from the following: deuterium, halogen, C 1-3 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -COO-C 1-6 Alkyl, -C(O)NR f R f , -OC(O)NR f R f , 5- to 8-membered aromatic ring, -het 2 , mono- or bicyclic -C 5-8- Cycloalkyl; wherein, said R f Is hydrogen, C 1-6 Alkyl; said het 2 Represents a 5- to 8-membered monocyclic or bicyclic, saturated or unsaturated heterocycle containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O;

[0020] R 4 Is H, deuterium, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, 3- to 10-membered heterocycloalkyl; said C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, 3- to 10-membered heterocycloalkyl is optionally substituted with one or more R g ; said Rg Substituents for at least one of the following: deuterium, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 haloalkoxy; when there are multiple substituents R g are, the said R g are the same or different;

[0021] x is 1, 2, 3 or 4;

[0022] m and n are each 1, 2, 3, 4, 5, 6, 7 or 8;

[0023] g is 1, 2, 3, 4, 5, 6, 7 or 8;

[0024] Among them, the compound represented by formula I needs to meet the following conditions:

[0025] At least one of R T , R a , R b , R 1 , R 2 , R 3 , R 23 , R 4 , R 5 , or R 6 is deuterium, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy.

[0026] According to an embodiment of the present invention, the present invention discloses a compound, which is a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula I or the compound represented by formula I:

[0027]

[0028] Among them,

[0029] Ring A is a 5- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring;

[0030] Each R T is independently H, halogen, hydroxyl, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 deuterated cycloalkyl, C 1-6 deuterated alkyl or C1-6 Deuterated alkoxy group;

[0031] B is a 3- to 10-membered heteroalkyl group, a 3- to 10-membered heteroalkenyl group, or a 3- to 10-membered cycloalkyl group;

[0032] R a and R b are each independently H, deuterium, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 halocycloalkyl, C 1-6 alkylhydroxy, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, 3- to 10-membered heteroalkyl; the C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 halocycloalkyl, C 1-6 alkylhydroxy, C 1-6 alkylcarbonyl, C 1-6 alkoxy and C 1-6 haloalkoxy are optionally substituted by one or more R c substituents; the R c is a substituent selected from the following: deuterium, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkylhydroxy, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 haloalkoxy; when the substituent R c is plural, the R c are the same or different;

[0033] Y is NR 1 、O、S or C(R 1 )2;

[0034] Each R 1 is independently Η, deuterium, C 1-10 alkyl, C 2-6An alkenyl group, wherein the C 1-10 alkyl group, C 2-6 alkenyl group is optionally substituted by one or more R d groups; the R d groups are substituents selected from the following: deuterium, halogen, C 1-3 fluoroalkyl group, C 1-6 alkoxy group, C 1-6 haloalkoxy group, -COO-C 1-6 alkyl group, -C(O)NR f R f group, a 5- to 8-membered aromatic ring, -het 1 group, a monocyclic- or bicyclic-C 5-8- cycloalkyl group; wherein the R f group is hydrogen or C 1-6 alkyl group; the het 1 group represents a 5- to 8-membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O;

[0035] Q is a group as follows:

[0036] R 2 and R 3 for each pair of R 5 and R 6 can independently form a saturated or partially saturated 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring with their respective attached carbon atoms; wherein the 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms that are O or S, and further, wherein the 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring is substituted by g R 23 groups, the R 23 groups being at least one of the following: Η, deuterium, halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuterated alkyl group, C 1-4 haloalkyl group, C 1-6 alkyl hydroxy group, C 1-6 alkyl carbonyl group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, -COO-C 1-6 alkyl group, -C(O)NR f R f group; wherein the R f group is hydrogen or C 1-6 alkyl group;

[0037] Alternatively, R5 and R 6 each independently is H, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, wherein the C 1-6 alkyl, C 2-6 alkenyl is optionally substituted by one or more R d ; the R d is a substituent selected from the following: deuterium, halogen, C 1-3 fluoroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -COO-C 1-6 alkyl, -C(O)NR f R f , a 5- to 8-membered aromatic ring, -het 2 , a mono- or bicyclic C 5-8- cycloalkyl; wherein the R f is hydrogen, C 1-6 alkyl; the het 2 represents a 5- to 8-membered monocyclic or bicyclic, saturated or unsaturated heterocycle containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O;

[0038] R 4 is H, deuterium, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxy, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 halocycloalkyl, C 1-6 alkylhydroxy, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, 3- to 10-membered heterocycloalkyl; the C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 halocycloalkyl, C 1-6 alkylhydroxy, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6Halogenated alkoxy, 3- to 10-membered heteroalkyl optionally substituted by one or more R g ; said R g is a substituent selected from at least one of the following: deuterium, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkylhydroxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy; when there are multiple substituents R g , said R g are the same or different;

[0039] x is 1, 2, 3 or 4;

[0040] m and n are each 1, 2, 3, 4, 5, 6, 7 or 8;

[0041] g is 1, 2, 3, 4, 5, 6, 7 or 8;

[0042] Among them, the compound shown in formula I needs to meet the following conditions:

[0043] At least one of R T , R a , R b , R 1 , R 23 , R 4 , R 5 or R 6 is deuterium, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy.

[0044] In some embodiments of the present invention, ring A is selected from 5- to 9-membered heteroaryl rings.

[0045] In some embodiments of the present invention, the heteroaryl ring has 1 or 2 heteroatoms.

[0046] In some embodiments of the present invention, the heteroatoms are selected from N or O.

[0047] In some embodiments of the present invention, ring A is a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or a benzoxazolyl group.

[0048] In some embodiments of the present invention, ring A is In some embodiments of the present invention, the structural unit is In some embodiments of the present invention, the R ais H, deuterium, F, Cl, C 1-3 alkyl, C 1-3 deuterated alkyl or C 1-3 haloalkyl.

[0049] In some embodiments of the present invention, the R a is H, deuterium, F, Cl, C 1-3 deuterated alkyl or C substituted with a halogen 1-3 alkyl.

[0050] In some embodiments of the present invention, the R a is H, deuterium, F, Cl, CH3, CD3 or CH3 substituted with a halogen.

[0051] In some embodiments of the present invention, the R a is H, deuterium, F, Cl, CH3, CD3 or CH3 substituted with F.

[0052] In some embodiments of the present invention, the R a is H, deuterium, CD3, F, Cl or CHF2.

[0053] In some embodiments of the present invention, the structural unit is In some embodiments of the present invention, when Y is NR 1 or CHR 1 R 1 is selected from H, deuterium, or C 1-6 alkyl.

[0054] In some embodiments of the present invention, when Y is NR 1 or CHR 1 R 1 is selected from H or C 1-6 alkyl.

[0055] In some embodiments of the present invention, Y is -NH-.

[0056] In some embodiments of the present invention, B is selected from 3- to 10-membered heteroalkyl, or 3- to 10-membered heteroalkenyl.

[0057] In some embodiments of the present invention, B is 3- to 10-membered heteroalkyl.

[0058] In some embodiments of the present invention, the 3- to 10-membered heteroalkyl is monocyclic, fused bicyclic, bridged or spiro bicyclic.

[0059] In some embodiments of the present invention, the 3- to 10-membered heteroalkyl further has 1 to 3 heteroatoms selected from N, O, S.

[0060] In some embodiments of the present invention, B is a 3- to 10-membered heteroalkenyl group.

[0061] In some embodiments of the present invention, the 3- to 10-membered heteroalkenyl group is selected from monocyclic or fused bicyclic groups.

[0062] In some embodiments of the present invention, the 3- to 10-membered heteroalkenyl group further has 1 to 3 heteroatoms selected from N, O, and S.

[0063] In some embodiments of the present invention, B is the following group:

[0064]

[0065] Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 、Z 7 、Z 8 and Z 9 are each independently N, NH, CH2, CH, C, -NH-CH2-, or -CH2-CH2-; p is 0, 1, or 2.

[0066] In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the is In some embodiments of the present invention, the fragment is

[0067]

[0068] In some embodiments of the present invention, the fragment is

[0069] In some embodiments of the present invention, each R b is independently H, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, halogen, C 3-8 cycloalkyl or oxo.

[0070] In some embodiments of the present invention, each R b is independently H, deuterium, methyl, F, C 1-3 deuterated alkyl, cyclohexyl or oxo.

[0071] In some embodiments of the present invention, each R b is independently H, deuterium, methyl, F, cyclohexyl or oxo.

[0072] In some embodiments of the present invention, each R b is independently H or deuterium.

[0073] In some embodiments of the present invention, the R c is 0, 1, 2 or 3.

[0074] In some embodiments of the present invention, each R c is independently deuterium, halogen, oxo, C 1-6 deuterated alkyl, C 1-6 alkyl or C 1-6 haloalkyl.

[0075] In some embodiments of the present invention, the R g is 0, 1, 2 or 3.

[0076] In some embodiments of the present invention, each R g is independently deuterium, halogen, hydroxy, cyano, C 1-6 deuterated alkyl, C 1-6 alkyl or C1-6 Halogenated alkyl

[0077] In some embodiments of the present invention, each R g is independently deuterium, halogen, oxo, C 1-3 deuterated alkyl, C 1-3 alkyl or C 1-3 halogenated alkyl

[0078] In some embodiments of the present invention, each R T is independently H, deuterium, C 1-3 deuterated alkyl or C 1-3 deuterated alkoxy

[0079] In some embodiments of the present invention, each R T is independently H or deuterium

[0080] In some embodiments of the present invention, each R 4 is independently H, deuterium, halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkyl hydroxy, C 1-6 alkyl carbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, C 1-6 deuterated alkoxy, 3- to 10-membered heterocycloalkyl; the C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 3-8 halogenated cycloalkyl, C 1-6 alkyl hydroxy, C 1-6 alkyl carbonyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, C 1-6 deuterated alkoxy, 3- to 10-membered heterocycloalkyl is optionally substituted by one or more R g ; the R g is a substituent of at least one of the following: deuterium, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 1-6 alkyl hydroxy, C 1-6 alkyl carbonyl, C 1-6 alkoxy, C1-6 Halogenated alkoxy group; when the substituent R g is plural, the R g are the same or different.

[0081] In some embodiments of the present invention, each R 4 is independently H, deuterium, hydroxyl group, C 1-6 alkyl group, C 3-8 cycloalkyl group, C 1-6 deuterated alkyl group, C 1-6 halogenated alkyl group, C 3-8 halogenated cycloalkyl group, C 1-6 alkyl hydroxyl group.

[0082] In some embodiments of the present invention, each R 4 is independently H, deuterium or hydroxyl group.

[0083] In some embodiments of the present invention, the R 5 and R 6 are each independently H, deuterium, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 2-6 alkenyl group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, the C 1-6 alkyl group, and C 2-6 alkenyl group are optionally substituted by one or more R d ; the R d is a substituent selected from the following: deuterium, halogen, C 1-3 fluoroalkyl group, C 1-6 alkoxy group, C 1-6 halogenated alkoxy group, -COO-C 1-6 alkyl group.

[0084] In some embodiments of the present invention, the R 5 and R 6 are each independently H, deuterium, C 1-6 alkyl group, C 1-6 deuterated alkyl group.

[0085] In some embodiments of the present invention, the R 5 and R 6 are each independently H or deuterium.

[0086] In some embodiments of the present invention, the Q is R 4 is a hydroxyl group.

[0087] In some embodiments of the present invention, the Q is a group as follows:

[0088] In some embodiments of the present invention, Q is a group as follows:

[0089] In some embodiments of the present invention, the is a group as follows:

[0090] In some embodiments of the present invention, the compound has a structure represented by Formula I-A or Formula I-B:

[0091]

[0092] wherein, Ring A, B, R a , R b , R T , Y, Q, m, n and x are defined as defined in the present invention.

[0093] In some embodiments of the present invention, the compound has a structure represented by Formula I-1:

[0094]

[0095] wherein, Z 1 , Z 4 are each independently CH or N;

[0096] Ring A, R a , R b , R T , Y, Q, m, n and x are defined as defined in the present invention.

[0097] In some embodiments of the present invention, the compound has a structure represented by Formula I-1A:

[0098]

[0099] wherein, Z 1 , Z 2 are each independently CH or N;

[0100] Ring A, R a , R b , R T , R 1 , R 23 , R 4 , R 5 , R 6 , m, n and x are defined as defined in the present invention.

[0101] In some embodiments of the present invention, the compound has a structure represented by Formula I-1B:

[0102]

[0103] Wherein, X 1 and X 2 are each independently CH or N; Z 1 and Z 4 are each independently N or CH;

[0104] R a and R b and R T and R 1 and R 23 and R 4 and R 5 and R 6 m, n, g and x are as defined in the present invention.

[0105] In some embodiments of the present invention, in the structures represented by Formula I-1, Formula I-1A and Formula I-1B, Z 1 is N, Z 4 is CH. In some embodiments of the present invention, the compound has a structure represented by Formula I-1B1, I-1B2 or I-1B3:

[0106]

[0107]

[0108] Wherein, X 1 and X 2 are each independently CH or N;

[0109] Each R a is independently H, halogen, hydroxyl, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy; Each R T is independently H, halogen, hydroxyl, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy; Each R 23 is independently H, halogen, hydroxyl, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy; R 5 and R 6 are each independently H, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C1-6 Alkoxy, C 1-6 Deuterated alkoxy;

[0110] Each R b Is independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy; wherein at least one of R T , R a , R b , R 23 , R 5 Or R 6 Is deuterium, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy.

[0111] In some embodiments of the present invention, in the structures represented by Formula I-1B, I-1B1, I-1B2, and I-1B3, X 1 And X 2 Are both N.

[0112] In some embodiments of the present invention, the compound has the structure represented by Formula I-1B4’ or I-1B5’:

[0113]

[0114] Each R a Is independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy; each R T Is independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy; each R 23 Is independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy; R 5 And R 6 Are independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy;

[0115] Each Rb Each is independently H, a halogen, a hydroxyl group, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy; wherein at least one of R T , R a , R b , R 23 , R 5 or R 6 is deuterium, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy.

[0116] In some embodiments of the present invention, the compound has the structure shown in Formula I-1B4:

[0117]

[0118] R 5 and R 6 are each independently H, deuterium, a halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy;

[0119] Each R b is independently H, a halogen, a hydroxyl group, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy; wherein at least one of R b , R 5 and R 6 is deuterium, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy.

[0120] In some embodiments of the present invention, the compound has the structure shown in Formula I-1B5:

[0121]

[0122] wherein R 5 and R 6 are each independently H, deuterium, a halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy; each R b is independently H, a halogen, a hydroxyl group, deuterium, C 1-6 alkyl, C1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy; wherein at least one R b , R 5 and R 6 is deuterium, C 1-6 deuterated alkyl or C 1-6 deuterated alkoxy.

[0123] In some embodiments of the present invention, each R T is independently H or deuterium.

[0124] In some embodiments of the present invention, at least one of each R T is deuterium, and the remaining R T are all H.

[0125] In some embodiments of the present invention, each R 23 is independently H or deuterium.

[0126] In some embodiments of the present invention, at least one of each R 23 is deuterium, and the remaining R 23 are all H.

[0127] In some embodiments of the present invention, R 5 and R 6 are independently H or deuterium.

[0128] In some embodiments of the present invention, R 5 and R 6 at least one is deuterium, and the other is H or deuterium.

[0129] In some embodiments of the present invention, R 5 is H.

[0130] In some embodiments of the present invention, R 5 is deuterium.

[0131] In some embodiments of the present invention, R 6 is H.

[0132] In some embodiments of the present invention, R 6 is deuterium.

[0133] In some embodiments of the present invention, each R b is independently H or deuterium.

[0134] In some embodiments of the present invention, at least one of each R b is deuterium, and the remaining R b are all H.

[0135] In some embodiments of the present invention, each R a is independently H, deuterium, Cl or F.

[0136] In some embodiments of the present invention, each R a at least one of which is deuterium, and the remaining Rs a are all H, Cl or F.

[0137] In some embodiments of the present invention, the compound has the following structure:

[0138]

[0139]

[0140] In some embodiments of the present invention, the compound has the following structure:

[0141]

[0142]

[0143]

[0144] In some embodiments of the present invention, the compound represented by Formula I may not be one of Compounds 1 to 26.

[0145] In a second aspect of the present invention, there is provided a pharmaceutical composition, which comprises: the compound as described in the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

[0146] In a preferred embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0147] In a second aspect of the present invention, there is provided a pharmaceutical composition, which comprises: the compound represented by Formula I as described in the first aspect of the present invention, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier.

[0148] In a third aspect of the present invention, there is provided the use of the compound as described in the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition as described in the second aspect, in inhibiting PDE4B, and / or preventing and / or treating PDE4B-related diseases, and / or avoiding or reducing gastrointestinal side effects during the treatment of PDE4B-related diseases.

[0149] In the fourth aspect of the present invention, there is provided the use of the compound as described in the first aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect, in the preparation of a drug or preparation for inhibiting PDE4B and / or preventing and / or treating a disease related to PDE4B.

[0150] In the fifth aspect of the present invention, there is provided the use of the compound as described in the first aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect, in the preparation of a drug or preparation for avoiding or reducing gastrointestinal side effects when treating a disease related to PDE4B.

[0151] In the sixth aspect of the present invention, there is provided the use of the compound represented by formula I as described in the first aspect of the present invention, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect of the present invention, and the uses include: inhibiting PDE4B; and / or, preventing and / or treating a disease related to PDE4B; and / or, preparing a drug, pharmaceutical composition or preparation for inhibiting PDE4B and / or preventing and / or treating a disease related to PDE4B.

[0152] In the seventh aspect of the present invention, there is provided the compound as described in the first aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the second aspect, for inhibiting PDE4B, and / or preventing and / or treating a disease related to PDE4B, and / or avoiding or reducing gastrointestinal side effects when treating a disease related to PDE4B.

[0153] In the eighth aspect of the present invention, there is provided a method for inhibiting PDE4B or preventing and / or treating a disease related to PDE4B, comprising the step of administering to a subject in need the compound represented by formula I as described in the first aspect of the present invention, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

[0154] In the ninth aspect of the present invention, there is provided a method for inhibiting PDE4B, and / or preventing and / or treating a disease related to PDE4B, and / or avoiding or reducing gastrointestinal side effects when treating a disease related to PDE4B, comprising the step of administering to a subject in need the compound represented by formula I as described in the first aspect of the present invention, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

[0155] In accordance with embodiments of the present invention, in the uses or methods described in the above third, fourth, fifth, sixth, seventh, eighth, and ninth aspects, the PDE4B-related diseases include: respiratory diseases, gastrointestinal diseases, inflammatory diseases of joints, skin or eyes, cancers, and peripheral or central nervous system diseases, autoimmune diseases (such as diffuse connective tissue diseases like systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis, and sicca syndrome), transplant rejection reactions, and diseases related to smooth muscle contractility.

[0156] Preferably, the respiratory disease is a respiratory or pulmonary disease accompanied by increased mucus production, airway inflammation, and / or obstructive diseases.

[0157] Preferably, the respiratory disease is COPD, idiopathic pulmonary fibrosis, interstitial lung disease, α1-antitrypsin deficiency, chronic rhinosinusitis, asthma, and chronic bronchitis.

[0158] Preferably, the gastrointestinal disease is regional enteritis, ulcerative colitis, or Crohn's disease.

[0159] Preferably, the inflammatory diseases of joints, skin or eyes are rheumatoid arthritis, sarcoidosis, dry eye syndrome, and glaucoma.

[0160] Preferably, the cancer is mesothelioma, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis, and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, fibroid, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0161] Preferably, the peripheral or central nervous system diseases are depression, bipolar depression or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis, or acute and chronic pain and brain damage caused by stroke, hypoxia, or cranio-cerebral trauma.

[0162] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be learned through the practice of the present invention.

[0163] Terms and Definitions

[0164] Unless otherwise specified, the definitions of groups and terms recited in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, etc., may be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination shall fall within the scope described in the specification of this application.

[0165] Unless otherwise defined, all scientific and technical terms used herein have the same meanings as those commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and published materials cited herein in their entirety are incorporated herein by reference. If there are multiple definitions of a term in this document, the definitions in this chapter shall prevail.

[0166] Unless otherwise specified or there is an obvious conflict in the context, the articles "a", "one (kind)", and "the" used herein are intended to include "at least one" or "one or more". Therefore, these articles used herein refer to articles for one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, that is, there may be more than one component considered to be adopted or used in the implementation of the described embodiment.

[0167] It should be understood that the above summary and the following detailed description are exemplary and for explanatory purposes only, and do not impose any limitation on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that unless otherwise stated, the terms "or", "or" mean "and / or". In addition, the term "comprising" and other forms, such as "including", "containing", and "having", are not restrictive.

[0168] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED.", Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy and pharmacological methods. Unless a specific definition is provided, the terms used herein in the descriptions related to analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and the treatment of patients. For example, the instructions provided by the manufacturer for the kits can be utilized, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in a number of general and more specific documents cited and discussed in this specification, in accordance with the conventional methods well-known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0169] Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, a substituted group can have one substituent replacing at each substitutable position of the group. When more than one position in the given structural formula can be replaced by one or more substituents of a specific group, then the substituents can replace at each substitutable position either identically or differently. Generally, the term "substituted ring" means that the hydrogen atoms on each ring atom of the ring can be replaced, for example can be

[0170] The term "unsubstituted" means that the specified group bears no substituents.

[0171] As described in the present invention, the compounds of the present invention can optionally be substituted by one or more substituents, such as the compounds of the general formula above, or as the specific examples, subclasses, and a class of compounds included in the present invention in the examples. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". Generally, the term "optionally", whether located before the term "substituted" or not, means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, an optional substituent group can have one substituent replacing at each substitutable position of the group. When more than one position in the given structural formula can be replaced by one or more substituents of a specific group, then the substituents can replace at each position either identically or differently.

[0172] In addition, it should be noted that, unless otherwise explicitly indicated, in the present invention, the description methods "each... independently is", "... each independently is", and "... independently is" can be interchanged, and should all be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0173] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when writing the structural formula from right to left. For example, CH2O is equivalent to OCH2. As used herein, represents the bonding site of the group. As used herein, "R1", "R1", and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R2, the similarly defined meanings are the same.

[0174] The chapter headings used herein are only for the purpose of organizing the article and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and theses, are incorporated herein by reference in their entirety.

[0175] Except as described above, when used in the specification and claims of this application, unless otherwise specifically indicated, the following terms have the meanings shown below.

[0176] For the numerical ranges recited in the specification and claims of this application, when the numerical range is understood as "integers", it should be understood that the two endpoints of the range and each integer within the range are recited. For example, "integers from 1 to 6" should be understood as reciting each of 0, 1, 2, 3, 4, 5, and 6. When the numerical range is understood as "numbers", it should be understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "numbers from 1 to 10" should be understood as not only reciting each of the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least reciting the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively.

[0177] In this application, "saturated, partially saturated or unsaturated" includes saturated substituents, substituents completely unsaturated with hydrogen, and substituents partially saturated with hydrogen.

[0178] In this application, when alone or as part of other substituents, the term "halogen" refers to fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.

[0179] As used herein, when alone or as part of other substituents, the term "cyano" means -CN.

[0180] As used herein, when alone or as part of other substituents, the term "amino" means -NH2.

[0181] In this application, when alone or as part of other substituents, the term "hydroxyl" means -OH.

[0182] In this application, when alone or as part of other substituents, the term "deuterium" means an isotope of hydrogen, also known as heavy hydrogen, with the chemical symbol D or 2 H.

[0183] When alone or as part of other substituents, the term "alkyl" means a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. The alkyl group can be unsubstituted or substituted with one or more suitable substituents. The alkyl group can also be an isotopologue of a natural abundance alkyl group enriched in carbon and / or hydrogen isotopes (i.e., deuterium or tritium).

[0184] Unless otherwise specified, the absolute configuration of a stereocenter is represented by a solid wedge bond and a dashed wedge bond and the relative configuration of a stereocenter is represented by a solid straight bond and a dashed straight bond For example: is represented as one of the configurations in, and is represented as the remaining other configuration; is represented as one of the configurations in, and is represented as the remaining other configuration.

[0185] The term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group having 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention, and the substituents include, but are not limited to, deuterium, amino group, hydroxyl group, cyano group, F, Cl, Br, I, mercapto group, nitro group, oxo (=O), and the like. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), and the like. The term "alkyl" and its prefix "alk" as used herein both include straight-chain and branched-chain saturated carbon chains.

[0186] When used alone or as part of other substituents, the term "deuterated alkyl" refers to an alkyl group substituted by one or more deuteriums, that is, the hydrogen on the alkyl group is replaced by deuterium.

[0187] When used alone or as part of other substituents, the term "deuterated alkoxy" refers to an alkoxy group substituted by one or more deuteriums, that is, the hydrogen on the alkoxy group is replaced by deuterium.

[0188] When used alone or as part of other substituents, the term "alkylene" should be understood to represent a straight-chain or branched-chain saturated, unsaturated or partially saturated divalent hydrocarbon group. For example, "C 1-6 alkylene" or "C 1- 6 alkylene" represents a straight-chain or branched-chain divalent hydrocarbon group having 1 to 6 carbon atoms, including but not limited to methylene, ethylene, propylene, 1-methylpropylene, butylene.

[0189] The "benzene group" alone or in combination refers to the divalent group C4H4=, one of which represents -CH=CH-CH=CH-, and forms a benzene-like ring when attached to another ring in the ortho position, such as tetralin, indole, etc.

[0190] When used alone or as part of other substituents, the term "C α-β haloalkyl" refers to an alkyl group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by fluorine, chlorine, bromine or iodine.

[0191] When alone or as part of another substituent, the term "cycloalkyl" refers to a cyclic alkyl group. The term "m-n cycloalkyl" or "C m-n cycloalkyl" is understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having from m to n atoms. For example, "3-15 cycloalkyl" or "C3-C 15 cycloalkyl" refers to a cyclic alkyl group containing from 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which may contain 1 to 4 rings. "3-10 cycloalkyl" contains 3-10 carbon atoms. It includes monocyclic, bicyclic, tricyclic, spiro or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or bicyclic hydrocarbon groups such as decahydronaphthalene rings. The cycloalkyl group may be substituted by one or more substituents. In some embodiments, the cycloalkyl group may be a cycloalkyl group fused to an aryl or heteroaryl ring. The term "cycloalkyl" may be used interchangeably with the term "carbocyclic group".

[0192] When alone or as part of another substituent, the term "heterocycloalkyl" refers to a cycloalkyl group in which one or more (in some embodiments 1 to 3) carbon atoms are replaced by heteroatoms such as, but not limited to, N, O, S and P. The term "m-n heterocycloalkyl" or "C m-n heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having from m to n atoms, wherein the heteroatoms are N, O, S, P, preferably N, O or S. For example, the term "4-8 heterocycloalkyl" or "C4-C8 heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having from 4 to 8 atoms, wherein 1, 2, 3, or 4 ring atoms are N, O, S, P, preferably N, O or S. "4-10 heterocyclic group" means a saturated, unsaturated or partially saturated ring having from 4 to 10 atoms. In some embodiments, the heterocycloalkyl group may be a heterocycloalkyl group fused to an aromatic ring or a heteroaromatic ring. When a prefix such as 4-8 or 4-10 is used to denote a heterocycloalkyl group, the number of carbons also means including the heteroatoms. It includes monocyclic, bicyclic, tricyclic, spiro or bridged rings. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, etc. The term "heterocycloalkyl" may be used interchangeably with the term "heteroalkane ring".

[0193] When used alone or as part of other substituents, the term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group having from two to forty carbon atoms with at least one carbon-carbon sp2 double bond (e.g., C2-C6 alkenyl, such as C2-C4 alkenyl), and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples of alkenyl include, but are not limited to, vinyl and allyl.

[0194] When used alone or as part of other substituents, the term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group having from two to forty carbon atoms with at least one carbon-carbon sp triple bond (e.g., C2-C6 alkynyl, such as C2-C4 alkynyl). Examples of alkynyl include, but are not limited to, ethynyl and propargyl.

[0195] When used alone or as part of other substituents, the term "alkoxy" refers to the group -O-R Q , where R Q is "alkyl" as defined above.

[0196] When used alone or as part of other substituents, the term "oxo" means that two hydrogens on the methylene group are replaced by oxygen, i.e., the methylene group is replaced by a carbonyl group, representing =O.

[0197] When used alone or as part of other substituents, the term "thioxo" means that two hydrogens on the methylene group are replaced by sulfur, representing =S.

[0198] When used alone or as part of other substituents, the term "aromatic ring" refers to a monocyclic or polycyclic carbocyclic ring having from 6 to 20 carbon atoms, where at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the group can be linked through the aromatic ring or through the non-aromatic ring. Examples of aryl include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthryl, and acenaphthylenyl. The term "aromatic ring" can be used interchangeably with the term "aryl".

[0199] When alone or as part of other substituents, the term "heteroaryl ring" refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are C, and at least one ring is an aromatic ring. The group can be a carbon group or a heteroatom group (i.e., it can be C-linked or N-linked, as long as it is possible). When one of the rings is a non-aromatic ring, the group can be linked through the aromatic ring or through the non-aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothienyl, benzofuryl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl, and tetrahydroquinoline. The term "heteroaryl ring" can be used interchangeably with the terms "heteroaromatic ring", "heteroaryl group", or "heteroaryl moiety".

[0200] When alone or as part of other substituents, the term "bicyclic" refers to a group having two linked rings. The bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2, or 3 heteroatoms such as N, O, or S). Both of these rings can be aliphatic (such as decalin and norbornane), or can be aromatic (such as naphthalene), or a combination of aliphatic and aromatic (such as tetrahydronaphthalene).

[0201] Unless otherwise specified, the term "3-10 membered heteroalkenyl" alone or in combination with other terms respectively represents a partially unsaturated cyclic group consisting of 3 to 10 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms can be optionally oxidized (i.e., C(=O), NO, and S(O)p, where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocycles, fused rings, and bridged rings, and any ring of this system is non-aromatic. In addition, with respect to this "3-10 membered heteroalkenyl", the heteroatom can occupy the connection position of the heteroalkenyl to the rest of the molecule. The 3-10 membered heteroalkenyl includes 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, and 10-membered heteroalkenyls, etc.

[0202] Bicyclic rings include (a) spiro compounds in which the two rings share only one single atom (the spiro atom, which is usually a quaternary carbon). Examples of spiro compounds include, but are not limited to:

[0203]

[0204] It also includes spiroalkyl groups in which a monospiroalkyl group shares a spiro atom with a heteroalkyl group. Non-limiting examples include:

[0205]

[0206] (b) fused rings, i.e., fused bicyclic compounds, where two rings share two adjacent atoms. In other words, the rings share a covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thujene and decalin). Examples of fused bicyclics include, but are not limited to:

[0207]

[0208] and (c) bridged bicyclic compounds, where two rings share three or more atoms and the two bridgehead atoms are separated by a bridge containing at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered a pair of cyclopentane rings, each sharing three of their five carbon atoms. Examples of bridged bicyclics include, but are not limited to:

[0209]

[0210] When alone or as part of other substituents, the NR f R f group can exist in the form, or it can also include cases where two R f groups together form a ring, which optionally contains N, O, or S atoms, and can also include the following groups, for example:

[0211] When alone or as part of other substituents, the group N(C α-β alkyl)C α-β alkyl (where α and β are defined as above) includes substituents where two C α-β alkyl groups together form a ring (optionally containing N, O, or S atoms), and includes the following groups, for example:

[0212] The compounds provided herein, including intermediates useful for preparing the compounds provided herein, which contain reactive functional groups (e.g., but not limited to carboxyl, hydroxyl, and amino moieties), also include their protected derivatives. "Protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also known as protecting groups). Suitable protecting groups for carboxyl moieties include benzyl, tert-butyl, etc., as well as isotopes, etc. Suitable protecting groups for amino and amido groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for hydroxyl groups include benzyl, etc. Other suitable protecting groups are well known to those of ordinary skill in the art.

[0213] In the present application, "optional" or "optionally" means that the subsequent described event or condition may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl is either substituted or unsubstituted, and the description includes both the substituted aryl and the unsubstituted aryl.

[0214] In the present application, the terms "salt" or "pharmaceutically acceptable salt" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0215] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic acids or organic acids that can retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic bases or organic bases that can maintain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization, or purification of the compounds of the present invention.

[0216] The term "amine salt" refers to the product obtained by neutralizing a primary, secondary, or tertiary alkylamine with an acid. The acids include the inorganic acids or organic acids described in the present application.

[0217] The term "stereoisomer" refers to isomers produced by different arrangements of atoms in space within a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers.

[0218] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in the form of one or a mixture of possible isomers, such as as pure enantiomers, or as a mixture of isomers, such as as a racemic and diastereoisomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center(s) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0219] When depicting the bonds to the chiral carbon in the formulas of the present invention as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and, thus, both the enantiomerically pure compounds and mixtures thereof resulting therefrom are included within the scope of the general formula. The graphical representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114 - 120. The absolute configuration of a stereocenter is represented by wedge and dashed bonds.

[0220] The term "tautomer" refers to functional group isomers resulting from the rapid migration of an atom within a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Prototropic tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium form, and attempting to isolate a single tautomer usually results in a mixture whose physical and chemical properties are identical to those of a mixture of compounds. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0221] The term "solvate" refers to a stoichiometric or non - stoichiometric solvent in which a compound of the present invention or its salt is included by non - covalent intermolecular forces, and when the solvent is water, it is a hydrate.

[0222] The term "prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound of the present invention. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and such modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by attaching a hydroxyl or amino group in the compound of the present invention to any group, and when the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0223] In the present application, a "pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium commonly accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient, and thereby exert its biological activity.

[0224] In the present application, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the relevant government regulatory authorities for use in humans or livestock.

[0225] The term "adjuvant" refers to pharmaceutically inert ingredients. Non-limiting examples of the types of "excipients" include binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of pharmaceutical formulations, that is, make the formulations more suitable for direct compression by increasing fluidity and / or adhesiveness.

[0226] The term "treatment" refers to therapeutic treatment. When referring to a specific disease or disorder, treatment means: (1) alleviating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade that causes or gives rise to the disorder or (b) one or more biological manifestations of the disorder, (3) improving one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.

[0227] The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0228] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has received administration of the compound or composition according to an embodiment of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.

[0229] The term "therapeutically effective amount" refers to the amount of a compound that, when administered to a patient, is sufficient to effectively treat the diseases or disorders described herein. The "therapeutically effective amount" will vary depending on the compound, the disorder and its severity, and the age of the patient to be treated, and can be adjusted by those skilled in the art as needed.

[0230] For the reactions of each step, the reaction temperature can be appropriately selected according to the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, etc. After the reaction of each step is completed, the target compound can be separated, purified, etc. from the reaction system by common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. Without affecting the next reaction, the target compound can also directly enter the next reaction without separation and purification.

[0231] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0232] Beneficial effects

[0233] After extensive and in-depth research, the present inventor unexpectedly developed a class of deuterated heterocyclic compounds and their preparation methods and uses. The present invention provides a compound represented by Formula I, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. The compound of Formula I and its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug have a significant inhibitory effect on PDE4B, can be used as a selective inhibitor of PDE4B, and have good permeability; have excellent pharmacokinetic properties and good drug-forming properties; further, the compound of the present invention has an excellent inhibitory effect on TNF-α secreted by LPS-stimulated human PBMCs; compared with the control compound 1, the area under the curve AUC0-t and Cmax of the compound of the present invention are significantly improved, the clearance rate is lower, and it has more excellent pharmacokinetic properties; the compound of the present invention has lower toxicity to human hepatocytes, and it is expected to have better safety during long-term medication; the compound of the present invention has a lower gastrointestinal distribution in mice, and the tissue / plasma area under the curve ratio is significantly reduced, and it is expected to have fewer gastrointestinal side effects such as vomiting and diarrhea during long-term medication, and has high safety; in addition, the compound of the present invention also has advantages such as high solubility, excellent oral absorption, and good clearance rate. Detailed Embodiments

[0234] The following further illustrates the present invention with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as a limitation on the protection scope of the present invention. On the basis of fully understanding the present invention, for the experimental methods without specific conditions noted in the following examples, they are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be regarded as being included in the protection scope of the present invention.

[0235] The present application has the following definitions:

[0236] Symbol or unit:

[0237] IC 50 : Half maximal inhibitory concentration, referring to the concentration when the maximum inhibitory effect reaches half.

[0238] M: mol / L. For example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) represents an n-hexane solution of n-butyllithium with a molar concentration of 2.5 mol / L.

[0239] N: Normality. For example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution.

[0240] Reagent:

[0241] DCM: Dichloromethane

[0242] DIPEA: N,N - Diisopropylethylamine

[0243] DMF: N,N - Dimethylformamide

[0244] TFA: Trifluoroacetic acid

[0245] THF: Tetrahydrofuran

[0246] S - (-)-BINOL: S - 1,1'-Bi - 2 - naphthol

[0247] Ti(OiPr)4: Titanium(IV) isopropoxide

[0248] Intermediate A1: Preparation of (5R)-2 - chloro - 4 - ((1 - (hydroxymethyl)cyclobutyl)amino)-5 - oxo - 6,7 - dihydrothieno[3,2 - d]pyrimidine. The synthetic route of intermediate A1 is as follows:

[0249]

[0250] The first step: Synthesis of (1 - aminocyclobutyl)methanol (Intermediate A1 - 2)

[0251]

[0252] At room temperature, dissolve 1 - aminocyclobutane carboxylic acid (15 g, 130.3 mmol) in tetrahydrofuran (300 ml). Under the conditions of 0 °C, argon protection and stirring, slowly add lithium aluminum hydride (2.5 M tetrahydrofuran solution, 104 mL, 260 mmol). After the addition is complete, slowly raise the reaction mixture to room temperature and stir for 16 h under argon protection. Quench the reaction with solid sodium sulfate decahydrate under ice bath, then dry with anhydrous sodium sulfate and filter. Wash the filter cake with ethyl acetate. Concentrate the combined filtrate at room temperature to obtain (1 - aminocyclobutyl)methanol (Intermediate A1 - 2) (12 g, yield 90%).

[0253] The second step: Synthesis of (1 - ((2 - chloro - 6,7 - dihydrothieno[3,2 - d]pyrimidin - 4 - yl)amino)cyclobutyl)methanol (Intermediate A1 - 4)

[0254]

[0255] Intermediate A1-2 (3 g, 29.7 mmol), A1-3 (2.1 g, 29.7 mmol) and triethylamine (9 g, 100 mmol) were added to acetonitrile (100 mL), and the mixture was stirred at 75 °C for 12 h. The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1 - 1:1, gradient elution) to obtain (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (Intermediate A1-4) (3.5 g, yield 43%).

[0256] Step 3: Synthesis of (5R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidine (Intermediate A1)

[0257]

[0258] Under nitrogen at 21 °C, Intermediate A1-4 (2.7 g, 10 mmol), S-(-)-BINOL (0.28 g, 1 mmol), dichloromethane (80 mL), Ti(OiPr)4 (1.4 mL, 0.5 mmol) and water (0.18 mL, 10 mmol) were added to a flask and stirred for 1 h. At 21 °C, tert-butyl hydroperoxide (70% in water, 1.5 mL, 11 mmol) was added, and the mixture was stirred at room temperature for 1.5 h. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane: methanol (V / V) = 10:1, gradient elution) to obtain (5R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidine (Intermediate A1) (2.5 g, yield 87%).

[0259] Intermediate 2: 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (Intermediate B1)

[0260]

[0261] The synthetic route is as follows:

[0262]

[0263] Step 1: Synthesis of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Intermediate B-2)

[0264]

[0265] Dissolve tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (Compound 16-1) (5.00 g, 23.7 mmol) in tetrahydrofuran (80 mL), then dropwise add lithium bis(trimethylsilyl)amide (4.75 g, 28.4 mmol) at -70 °C. React at 25 °C for 1 hour. Dissolve N-phenylbis(trifluoromethanesulfonyl)imide (9.30 g, 26.0 mmol) in tetrahydrofuran (10 mL) and dropwise add it to the reaction solution at -78 °C, then warm up to 25 °C and mix for reaction for 2 hours. Quench the reaction solution with ammonium chloride (100 mL), then extract it three times with ethyl acetate (300 mL), wash the organic phase with saturated brine (200 mL), dry it over anhydrous sodium sulfate, filter, concentrate, and purify it by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:0 - 20:1) to obtain tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Intermediate B-2) (4.20 g, yield 43.1%).

[0266] Step 2: Synthesis of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Intermediate B-3)

[0267]

[0268] Dissolve tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Compound 16-2) (700 mg, 2.04 mmol), bis(pinacolato)diboron (569 mg, 2.24 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (47.6 mg, 102 μmol), and potassium acetate (600 mg, 6.12 mmol) in 1,4-dioxane (10 mL), then react under nitrogen protection at 100 °C for 10 hours. Filter the reaction solution through diatomaceous earth and concentrate to obtain tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Intermediate B-3) (1.00 g, crude product).

[0269] LC-MS, M / Z (ESI): 266.2 [M - 56 + H]

[0270] Step 3: Synthesis of tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Intermediate B-4)

[0271]

[0272] tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Compound 16-3) (800 mg,

[0273] 2.49 mmol), 5-chloro-2-iodopyrimidine (718 mg, 2.99 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), potassium carbonate

[0274] (860 mg, 6.23 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (182 mg, 249 μmol) were added, and the reaction was carried out at 90 °C for 5 h under nitrogen protection. The reaction solution was diluted with water (50 mL), then extracted three times with ethyl acetate (150 mL), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0 - 5:1) to obtain tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Intermediate B-4) (312 mg, yield 41.7%). LC-MS, M / Z

[0275] (ESI): 252.2 [M - 55] + 。 1 H NMR (400 MHz, CDCl3) δ = 8.65 (s, 2H), 6.92 (s, 1H), 4.15 (d, 4H), 3.07 (s, 2H), 1.46

[0276] (s, 9H).

[0277] Step 4: Synthesis of tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate B-5)

[0278]

[0279] Dissolve tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Compound 16-4) (400 mg, 1.30 mmol) in methanol (10 mL). Under nitrogen protection, add tris(triphenylphosphine)rhodium(III) chloride (120 mg, 130 μmol). The suspension is purged with nitrogen and hydrogen three times respectively, and then reacted at 50 psi of hydrogen pressure and 50 °C for 16 hours. The reaction solution is filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:0 - 5:1) to obtain tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate B-5) (360 mg, 94.0%). LC-MS, M / Z (ESI): 209.2 [M - 100] + 。

[0280] Step 5: Synthesis of 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (Intermediate B1)

[0281]

[0282] Dissolve tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (16-5) (360 mg, 1.16 mmol) in methanol (10 mL), and add hydrogen chloride / methanol solution (4 M, 5 mL). React at 25 °C for 5 hours. Concentrate the reaction solution to obtain 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (Intermediate B1) (172 mg, yield 54.1%). LC-MS, M / Z (ESI): 210.2 [M + H] + 。

[0283] Synthesis Route 1:

[0284]

[0285] Example 1: Preparation of Target Compound 1

[0286] (5R)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-2-yl-5,6-d2)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (Target Compound 1)

[0287]

[0288] The synthesis route of Target Compound 1 is as follows:

[0289]

[0290] Step 1: Synthesis of tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate-5,6-d2 (1-5)

[0291]

[0292] Dissolve tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (B-4) (6.80 g, 20.7 mmol) in deuterated methanol-d4 (50.0 mL), add tris(triphenylphosphine)rhodium(III) chloride (3.84 g, 4.15 mmol), displace with inert gas and deuterium three times respectively, and react under a deuterium atmosphere of 50 psi at 50 °C with stirring for 20 hours. After the reaction is completed, filter and concentrate the reaction solution, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:0 - 5:1) to obtain compound tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate-5,6-d2 (1-5) (5.16 g, yield 79.5%). LC-MS, M / Z (ESI): 312.3 [M+H] + 。

[0293] Step 2: Synthesis of 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-5,6-d2 (1-6)

[0294]

[0295] Dissolve tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate-5,6-d2 (5) (1.01 g, 3.24 mmol) in dichloromethane (8.00 mL), then add trifluoroacetic acid (2.00 mL) at 0 °C, and react with stirring at 25 °C for 1 hour. After the reaction is completed, concentrate the reaction solution to dryness by rotary evaporation to obtain compound 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-5,6-d2 (1-6) (1.00 g, crude product). Directly use it for the next step. LC-MS, M / Z (ESI): 212.2 [M+H] + 。

[0296] Step 3: Synthesis of (5R)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-2-yl-5,6-d2)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (Target Compound 1)

[0297]

[0298] 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-5,6-d2 (1-6) (960 mg, 2.95 mmol) was dissolved in 1,4-dioxane (30.0 mL), then diisopropylethylamine (1.90 g, 14.7 mmol, 2.57 mL) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Intermediate A1) (805 mg, 2.80 mmol) were added, and the reaction was slowly heated to 100 °C and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated to dryness by rotary evaporation. The crude product was first separated and purified by silica gel column chromatography (methylene chloride:methanol (V / V) = 1:0 - 10:1), and then further separated and purified by high performance liquid chromatography. The separation method was (column: Waters Xbridge 150*25 mm*5 μm; solvents: A = water + ammonia water (0.5%), B = acetonitrile; gradient: 20% - 50%, 11 minutes), to obtain compound (5R)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-2-yl-5,6-d2)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 1) (500 mg, yield 36.4%). LC-MS, M / Z (ESI): 463.3 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 2H), 5.89 (s, 1H), 5.20 - 5.71 (m, 1H), 4.08 - 4.30 (m, 4H), 3.85 (s, 2H), 3.55 - 3.65 (m, 1H), 3.36 - 3.47 (m, 1H), 2.96 - 3.09 (m, 2H), 2.58 - 2.69 (m, 3H), 2.34 (br d, 2H), 2.10 - 2.23 (m, 2H), 1.88 - 2.03 (m, 2H)

[0299] Example 2: Synthesis of Compound 2

[0300] 2-(6-(5-chloropyrimidin-2-yl)-6-deuterio-2-azaspiro[3.3]hept-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (Target Compound 2)

[0301]

[0302] The synthetic route of Compound 2 is as follows:

[0303]

[0304] Step 1: tert-Butyl 6-deutero-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (Compound 2-2)

[0305]

[0306] Add tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g, 47.3 mmol) dissolved in methanol (10 mL) to a 100 mL single-necked flask. Slowly add sodium borodeuteride (397 mg, 94.6 mmol) in batches at room temperature. Stir the reaction system at room temperature for 1 hour. Remove the reaction device, slowly add NH4Cl (aq. 10 mL) aqueous solution, extract twice with ethyl acetate (10 mL * 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and rotary evaporate the obtained mother liquor to obtain the target compound tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (Compound 2-2) (1.0 g, yield 99.6%).

[0307] Step 2: tert-Butyl 6-deutero-6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (Compound 2-3)

[0308]

[0309] Add Compound 2-2 (1.0 g, 47.1 mmol) dissolved in Toluene (10.0 mL) to a 100 mL single-necked flask. Then slowly add triphenylphosphine (1.83 g, 70.7 mmol), imidazole (477 mg, 70.7 mmol), and elemental iodine (1.43 g, 56.5 mmol) to the reaction solution. Heat and stir the reaction system at 120 °C for 1 hour. After the reaction solution cools, filter it through diatomaceous earth, wash it with ethyl acetate (20.0 mL), rotary evaporate the mother liquor and mix the sample, and purify it by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:0 - 20:1) to obtain the target compound tert-butyl 6-deutero-6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (Compound 2-3) (1.0 g, yield 65.8%).

[0310] Step 3: tert-Butyl 6-(5-chloropyrimidin-2-yl)-6-deutero-2-azaspiro[3.3]heptane-2-carboxylate (Compound 2-4)

[0311]

[0312] In a 250.0 mL three-necked flask, compound 2-3 (6.0 g, 186 mmol) and zinc powder (1.2 g, 372 mmol) were dissolved in a mixed solvent of DMAC (30.0 mL) and THF (30.0 mL). The system was purged with N2 atmosphere three times. Subsequently, trimethylchlorosilane (200 mg, 37.2 mmol) was slowly added to the reaction solution. The reaction system was stirred at room temperature for half an hour. 5-Chloro-2-iodopyrimidine (2.23 g, 186 mmol) and Pd(dppf)Cl2 (336 mg, 9.3 mmol) dissolved in DMAC (30.0 mL) and THF (300.0 mL) were added to the reaction solution. After the addition was completed, the system was heated to 90 °C and stirred overnight. After the reaction solution was cooled, it was filtered through diatomaceous earth. Saturated NH4Cl solution (aq. 50.0 mL) was added to the mother liquor, and the mixture was extracted with ethyl acetate (50.0 mL). The organic phase was washed with saturated brine (50.0 mL). The obtained organic phase was dried over anhydrous sodium sulfate and then filtered. The mother liquor was evaporated to dryness and mixed with samples, and then separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 30:1 - 10:1) to obtain the target compound tert-butyl 6-(5-chloropyrimidin-2-yl)-6-deuterio-2-azaspiro[3.3]heptane-2-carboxylate (compound 2-4) (3.7 g, yield 65%).

[0313] Step 4: 6-(5-Chloropyrimidin-2-yl)-6-deuterio-2-azaspiro[3.3]heptane hydrobromide (compound 2-5)

[0314]

[0315] Compound 2-4 (1.7 g, 54.8 mmol) was dissolved in DCM (20.0 mL) in a 10.0 mL single-necked flask. Boron tribromide (1.6 g, 65.7 mmol) was slowly added to the reaction solution. The reaction system was stirred at room temperature for 2 hours. The reaction solution was directly evaporated to dryness to obtain the target compound 6-(5-chloropyrimidin

[0316] -2-yl)-6-deuterio-2-azaspiro[3.3]heptane hydrobromide (compound 2-5).

[0317] Step 5: 2-(6-(5-Chloropyrimidin-2-yl)-6-deuterio-2-azaspiro[3.3]hept-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide

[0318]

[0319] In a 10 mL single-necked flask, compound 2-5 (1.15 g, 55.3 mmol) was dissolved in a mixed solvent of THF (20.0 mL) and H2O (10.0 mL). Subsequently, DIEA (2.56 g, 276.5 mmol) was added to the reaction solution. After stirring for ten minutes, (5R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide 6A (683 mg, 33.2 mmol) was added to the reaction solution. The system was heated to 85 °C and stirred overnight. After the reaction solution was cooled, H2O (20.0 mL) was added to the reaction solution, and the mixture was extracted twice with DCM (20.0 mL). The combined organic phases were dried over anhydrous sodium sulfate (20.0 g), filtered, and the mother liquor was evaporated to dryness and mixed with samples. The mixture was separated and purified by silica gel column chromatography to obtain the target compound (R)-2-(6-(5-chloropyrimidin-2-yl)-6-deuterio-2-azaspiro[3.3]hept-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (target compound 2) (604 mg, yield 55%).

[0320] LC-MS, M / Z (ESI): 462.39 (M+1).

[0321] 1 H NMR (400 MHz, CDCl3) δ 8.61 (s, 2H), 5.86 (s, 1H), 5.46 (d, 1H), 4.17 (d, 4H), 3.83 (s, 2H), 3.64–3.52 (m, 1H), 3.45–3.35 (m, 1H), 3.01 (dt, 2H), 2.63 (q, 4H), 2.33 (d, 2H), 2.23–2.10 (m, 2H), 2.05–1.84 (m, 2H).

[0322] Example 3: Preparation of Target Compound 3

[0323] (R)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptan-2-yl)-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (Target Compound 3)

[0324]

[0325] The synthetic route of the target compound 3 is as follows:

[0326]

[0327] The first step: Synthesis of (1-aminocyclobutyl)methane-d2-ol (Compound 3-2)

[0328]

[0329] Dissolve 1-aminocyclobutanecarboxylic acid (Compound 3-1) (15.0 g, 130 mmol) in anhydrous tetrahydrofuran (500 mL), cool to 0 °C in an ice-water bath, carefully add lithium aluminum deuteride (9.89 g, 260 mmol), and react at 25 °C for 10 hours. Cool the reaction solution to 0 °C, carefully and slowly add sodium sulfate decahydrate (20.0 g, 65.1 mmol) to quench it under a nitrogen stream, dry with anhydrous sodium sulfate, filter, concentrate by rotary evaporation to obtain the yellow oily compound (1-aminocyclobutyl)methane-d2-ol (Compound 3-2) (14.5 g, crude product, directly used for the next step).

[0330] Second step: Synthesis of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methane-d2-ol (Compound 3-3)

[0331]

[0332] Dissolve 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (Compound A1-3) (22.0 g, 104 mmol) and (1-aminocyclobutyl)methane-d2-ol (12.9 g, 125 mmol) in acetonitrile (400 mL), add triethylamine (31.7 g, 313 mmol, 43.6 mL), and react at 80 °C for 10 hours. Add the reaction solution to saturated sodium bicarbonate solution (400 ml), extract with ethyl acetate (900 mL) 3 times, wash with saturated brine (1000 ml), dry with sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1 - 1:1) to obtain the target compound (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methane-d2-ol (Compound 3-3) (6.00 g, yield 21.4%).

[0333] Third step: (R)-2-chloro-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Compound 3-4)

[0334]

[0335] (1 - ((2 - chloro - 6,7 - dihydrothieno[3,2 - d]pyrimidin - 4 - yl)amino)cyclobutyl)methane - d2 - ol (3 - 3) (5.00 g, 18.0 mmol), S - (-)-1,1'-Bi - 2 - naphthol (515 mg, 1.80 mmol) were dissolved in dichloromethane (50 mL). Titanium(IV) isopropoxide (255 mg, 900 μmol, 265 μL) and water (324 mg, 18.0 mmol, 324 μL) were added, and the reaction was carried out at 20 °C for 1 hour. After cooling to 0 °C, 70% aqueous tert - butyl hydroperoxide (2.43 g, 18.9 mmol, 2.59 mL, 70%) was added, and the reaction was carried out at 25 °C for 1.5 hours. The solid product precipitated from the reaction solution was filtered, and the filter cake was washed twice with ethyl acetate (10 mL), dried to obtain the target compound (R)-2 - chloro - 4 - ((1 - (hydroxymethyl - d2)cyclobutyl)amino)-6,7 - dihydrothieno[3,2 - d]pyrimidine 5 - oxide (target compound 3 - 4) (4.60 g, yield 88.5%).

[0336] Step 4: Synthesis of (R)-2-(6-(5 - chloropyrimidin - 2 - yl)-2 - azaspiro[3.3]heptan - 2 - yl)-4 - ((1 - (hydroxymethyl - d2)cyclobutyl)amino)-6,7 - dihydrothieno[3,2 - d]pyrimidine - 5 - oxide (target compound 3)

[0337]

[0338] 6-(5 - Chloropyrimidin - 2 - yl)-2 - azaspiro[3.3]heptane hydrobromide (intermediate B1) (1.20 g, 4.13 mmol) and diisopropylethylamine (2.23 g, 17.2 mmol, 3.00 mL) were added to a solution of (R)-2 - chloro - 4 - ((1 - (hydroxymethyl - d2)cyclobutyl)amino)-6,7 - dihydrothieno[3,2 - d]pyrimidine 5 - oxide (64.4 mg, 219 μmol) in 1,4 - dioxane (30 mL). The temperature was slowly raised to 100 °C and the reaction was carried out for 3 hours. The reaction solution was concentrated to dryness by rotary evaporation, and the crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (V / V)=1:0 - 10:1) to obtain the target compound (R)-2-(6-(5 - chloropyrimidin - 2 - yl)-2 - azaspiro[3.3]heptan - 2 - yl)-4 - ((1 - (hydroxymethyl - d2)cyclobutyl)amino)-6,7 - dihydrothieno[3,2 - d]pyrimidine - 5 - oxide (compound 3) (1.00 g, yield 60.8%).

[0339] LC - MS, M / Z(ESI): 463.2[M + H] +

[0340] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.62 (s, 2H), 6.25 (br s, 1H), 4.95 - 5.82 (m, 1H), 3.99 - 4.39 (m, 4H), 3.57 - 3.75 (m, 2H), 3.33 - 3.44 (m, 1H), 2.94 - 3.12 (m, 2H), 2.65 (br m, 4H), 2.15 - 2.34 (m, 4H), 1.82 - 1.97 (m, 2H).

[0341] Example 4: Synthesis of Compound 4

[0342] 2-[6-(5-Chloropyrimidin-2-yl)-6-deuterio-2-azaspiro[3.3]hept-2-yl]-4-(((dideuteriohydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (Compound 4)

[0343]

[0344] The synthesis route is as follows:

[0345]

[0346] Add the bromide of Compound 2-5 (700 mg, 3.35 mmol) to a 100 mL single-necked flask dissolved in a mixed solvent of THF (5.0 mL) and H2O (5.0 mL). Subsequently, add DIEA (2.14 g, 16.75 mmol) to the reaction solution. After stirring for ten minutes, add Compound 3-4 (574 mg, 2.1 mmol) to the reaction solution. Heat the system to 85 °C and stir overnight. After the reaction solution is cooled, add H2O (10.0 mL) to the reaction solution, extract twice with DCM (10.0 mL), combine the organic phases, add anhydrous sodium sulfate (10.0 g) for drying and filtration. Rotate the mother liquor to dryness and mix the sample, and purify by silica gel column chromatography to obtain the target compound (R)-2-[6-(5-Chloropyrimidin-2-yl)-6-deuterio-2-azaspiro[3.3]hept-2-yl]-4-(((dideuteriohydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (Compound 4) (740 mg, yield 80%).

[0347] LC-MS, M / Z (ESI): 464.2 (M+1).

[0348] 11H NMR (400 MHz, CDCl3) δ 8.61 (s, 2H), 5.87 (s, 1H), 5.42 (s, 1H), 4.17 (d, 4H), 3.64 - 3.53 (m, 1H), 3.44–3.35 (m, 1H), 3.07–2.94 (m, 2H), 2.63 (q, 4H), 2.32 (d, 2H), 2.23–2.10 (m, 2H), 2.03–1.82 (m, 2H).

[0349] Example 5: Synthesis of Compound 7

[0350] (R)-2-(6-(5-Chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-2-yl)-4-((1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Target Compound 7)

[0351]

[0352] The synthetic route of the target compound 7 is as follows:

[0353]

[0354] The First Step: Synthesis of Diethyl cyclobutane-1,1-dicarboxylate-d6 (7-2)

[0355]

[0356] Dissolve diethyl malonate (7-1) (1.54 g, 9.62 mmol, 1.46 mL) and 1,3-dibromopropane-1,1,2,2,3,3-d6 (1A) (2.00 g, 9.62 mmol) in anhydrous tert-butanol (10.0 mL), cool to 0 °C in an ice-water bath, then add sodium tert-butoxide (1.00 M, 21.1 mL, 2.20 eq), and stir the reaction at 90 °C for 4 hours. After the reaction is completed, concentrate the reaction solution by rotary evaporation, then dilute with water (10.0 mL), extract with dichloromethane (10.0 mL), combine the organic phases, wash with saturated brine (10.0 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1 / 0 - 10 / 1) to obtain diethyl cyclobutane-1,1-dicarboxylate-d6 (7-2) (950 mg, yield 47.8%). 1 1H NMR (400 MHz, CDCl3) δ 4.10 - 4.28 (m, 4H), 1.24 (t, 6H).

[0357] Step 2: Synthesis of 1-(Ethoxycarbonyl)cyclobutane-1-carboxylic acid-2,2,3,3,4,4-d6 acid (7-3)

[0358]

[0359] Dissolve diethyl cyclobutane-1,1-dicarboxylate-d6 (7-2) (950 mg, 4.61 mmol) in ethanol (6.00 mL), cool to 0 °C in an ice-water bath, carefully add aqueous potassium hydroxide solution (1.80 M, 2.81 mL), stir the reaction at 0 °C for 5 hours, and then stir at 25 °C for 35 hours. After the reaction is complete, concentrate the reaction solution by rotary evaporation, dilute with water (5.00 mL), then adjust the pH to 2 with 1.00 M dilute hydrochloric acid, extract three times with ethyl acetate (30.0 mL), combine the organic phases, wash with saturated brine (10.0 mL), dry over anhydrous sodium sulfate, filter, concentrate by rotary evaporation, and obtain compound 1-(Ethoxycarbonyl)cyclobutane-1-carboxylic acid-2,2,3,3,4,4-d6 acid (7-3) (470 mg, yield 57.2%).

[0360] Step 3: Synthesis of 1-((tert-Butoxycarbonyl)amino)ethyl cyclobutane-1-carboxylate-2,2,3,3,4,4-d6 (7-4)

[0361]

[0362] Dissolve 1-(Ethoxycarbonyl)cyclobutane-1-carboxylic acid-2,2,3,3,4,4-d6 acid (7-3) (470 mg, 2.64 mmol) in anhydrous tert-butanol (10.0 mL), add diphenylphosphoryl azide (762 mg, 2.77 mmol, 597 μL) and triethylamine (374 mg, 2.90 mmol, 505 μL), stir the reaction at 25 °C for 0.5 hour, and then stir at 100 °C for 4 hours. After the reaction is complete, dilute the reaction solution with water (10.0 mL), then extract three times with ethyl acetate (30.0 mL), combine the organic phases, wash with 5% aqueous citric acid solution (20.0 mL), saturated sodium bicarbonate (20.0 mL), and brine (30.0 mL) respectively, dry over anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel plate separation (petroleum ether:ethyl acetate (V / V) = 10:1) to obtain compound 1-((tert-Butoxycarbonyl)amino)ethyl cyclobutane-1-carboxylate-2,2,3,3,4,4-d6 (7-4) (200 mg, yield 30.4%).

[0363] Step 4: Synthesis of tert-Butyl (1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)carbamate (7-5)

[0364]

[0365] Ethyl 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate-2,2,3,3,4,4-d6 (7-4) (200 mg, 802 μmol) was dissolved in anhydrous tetrahydrofuran (10.0 mL), cooled to 0 °C in an ice-water bath, and lithium borohydride solution (2.00 M, 1.60 mL) was carefully added. The reaction was stirred at 0 °C for 0.5 h and then at 25 °C for 1.5 h. After completion of the reaction, the reaction mixture was cooled to 10 °C, and 1 M citric acid (5.00 mL) was carefully and slowly added under a nitrogen stream to quench the reaction. Then it was extracted three times with ethyl acetate (30.0 mL). The combined organic phases were washed with saturated sodium bicarbonate (20.0 mL) and brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and the residue was dried under reduced pressure to obtain tert-butyl (1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)carbamate (7-5) (200 mg, crude product), which was directly used in the next step.

[0366] Step 5: Synthesis of (1-aminocyclobutyl-2,2,3,3,4,4-d6)methanol hydrochloride (7-6)

[0367]

[0368] tert-Butyl (1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)carbamate (7-5) (200 mg, 964 μmol) was dissolved in anhydrous dioxane (10.0 mL), and hydrochloric acid dioxane solution (2.00 M, 9.65 mL) was carefully added. The reaction was stirred at 25 °C for 1 h. After completion of the reaction, the reaction mixture was concentrated by rotary evaporation to obtain (1-aminocyclobutyl-2,2,3,3,4,4-d6)methanol hydrochloride (7-6) (200 mg, crude product), which was directly used in the next step.

[0369] Step 6: Synthesis of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl-2,2,3,3,4,4-d6)methanol (7-7)

[0370]

[0371] (1-Aminocyclobutyl-2,2,3,3,4,4-d6)methanol hydrochloride (7-6) (200 mg, 1.39 mmol, HCl) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (A1-3) (288 mg, 1.39 mmol) were dissolved in acetonitrile (10.0 mL), triethylamine (704 mg, 6.96 mmol, 968 μL) was added, and the reaction was stirred at 80 °C for 2 h. After completion of the reaction, the reaction solution was diluted with water (10.0 mL), then extracted with ethyl acetate (30.0 mL) three times. The combined organic phases were washed with saturated brine (30.0 mL), dried over sodium sulfate, concentrated, and the crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1 - 1:1) to give compound (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl-2,2,3,3,4,4-d6)methanol (7-7) (70.0 mg, yield 16.2%). LC-MS, M / Z (ESI): 278.0 [M+H] + .

[0372] Step 7: Synthesis of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (7-8)

[0373]

[0374] (1-((2-Chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl-2,2,3,3,4,4-d6)methanol (7-7) (60.0 mg, 194 μmol) and (S)-(-)-1,1'-bi-2-naphthol (11.1 mg, 38.8 μmol) were dissolved in dichloromethane (10.0 mL), then titanium(IV) isopropoxide (5.52 mg, 19.4 μmol, 5.74 μL) and water (3.50 mg, 194 μmol, 3.50 μL) were added. The reaction was stirred at 20 °C for 1 h, then cooled to 0 °C, and 70% aqueous tert-butyl hydroperoxide (26.2 mg, 204 μmol, 27.9 μL, 70.0%) was added. The reaction was stirred at 25 °C for 1.5 h. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium sulfite (10.0 mL), then concentrated in vacuo and the crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 1:0 - 10:1) to give compound (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (7-8) (40.0 mg, yield 70.0%). LC-MS, M / Z (ESI): 294.0 [M+H] + 。

[0375] Step 8: Synthesis of (R)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-2-yl)-4-((1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (Target Compound 7)

[0376]

[0377] (R)-2-Chloro-4-((1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (7-8) (40.0 mg, 136 μmol) was dissolved in 1,4-dioxane (5.00 mL), then 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane hydrobromide (B1) (47.4 mg, 163 μmol, HBr) and diisopropylethylamine (87.9 mg, 680 μmol, 118 μL) were added, and the reaction was stirred at 100 °C for 2 h. After completion of the reaction, the reaction solution was concentrated to dryness by rotary evaporation, and the crude product was separated and purified by high performance liquid chromatography (column: Boston Green ODS 150*30 mm*5 μm; solvent: A = water + 0.05 volume of formic acid (99%), B = acetonitrile; gradient: 15%-45%, 11 min) to obtain compound (R)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-2-yl)-4-((1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (Compound 7) (17.0 mg, yield 27.6%).

[0378] LC-MS, M / Z (ESI): 467.3 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 2H), 5.81 (s, 1H), 4.01 - 4.37 (m, 4H), 3.85 (s, 2H), 3.54 - 3.74 (m, 2H), 3.35 - 3.54 (m, 1H), 2.88 - 3.17 (m, 2H), 2.55 - 2.77 (m, 4H)

[0379] Example 6: The preparation methods of the following compounds refer to the preparation method of Example 1:

[0380]

[0381]

[0382]

[0383] Synthesis of Control Compound 1:

[0384]

[0385] The synthetic route is as follows:

[0386]

[0387] Step 1: Synthesis of (R)-2-(6-(5-chloropyrimidin-2-yl)spiro[3.3]heptan-2-yl)-5-oxo-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Control Compound 1)

[0388]

[0389] 6-(5-Chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (Intermediate B1) (60.0 mg, 219 μmol) and diisopropylethylamine (141 mg, 1.10 mmol) were added to a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (64.4 mg, 219 μmol) in 1,4-dioxane (10 mL). The temperature was slowly raised to 100 °C and the reaction was carried out for 3 hours. The mixture was extracted three times with dichloromethane (60 mL), dried over sodium sulfate, concentrated, and the crude product was purified by reverse-phase high performance liquid chromatography (Column: Waters Xbridge 150*25 mm*5 μm; Solvent: A = water + 0.05% ammonia, B = acetonitrile; Gradient (acetonitrile): 18% - 48%, 9 minutes) to obtain the compound (R)-2-(6-(5-chloropyrimidin-2-yl)spiro[3.3]heptan-2-yl)-5-oxo-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (Control Compound 1). LC-MS, M / Z (ESI): 461.3 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ = 8.87 (s, 2H), 7.33 (s, 1H), 4.87 (m, 1H), 4.12 (s, 2H), 3.95 (s, 2H), 3.64 - 3.72 (m, 3H), 3.36 - 3.42 (m, 1H), 3.16 - 3.23 (m, 1H), 2.82 - 2.94 (m, 2H), 2.58 - 2.65 (m, 3H), 2.37 (br d, 2H), 2.30 (br s, 1H), 2.10 - 2.15 (m, 2H), 1.71 - 1.82 (m, 2H).

[0390] Synthesis of Control Compound 2:

[0391]

[0392] The synthetic route is as follows:

[0393]

[0394] Step 1: Synthesis of tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

[0395]

[0396] tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (10 g, 30.9 mmol), 4-chlorophenylmagnesium bromide (25.8 mL, 62.0 mmol, 2.4 M in THF), and Pd(dppf)Cl2 (2.2 g, 3.1 mmol) were successively added to 100 mL of anhydrous THF. The reaction was carried out at 50 °C for 16 h under nitrogen protection. After the reaction system was cooled to room temperature, it was concentrated. The obtained crude product was purified by silica gel column (PE / EA = 6 / 1) to obtain tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (8.1 g, yellow oil).

[0397] Step 2: Synthesis of 6-(4-chlorophenyl)-2-azaspiro[3.3]heptane

[0398]

[0399] tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (4.5 g, 14.6 mmol) and BBr3 (5.5 g, 22 mmol) were successively added to 100 mL of dry DCM. The reaction was carried out at room temperature for 4 h. The reaction system was concentrated to obtain 6.1 g of a crude product as a pale yellow oil, which was directly used for the next purification step.

[0400] Step 3: (R)-2-(6-(4-chlorophenyl)-2-azaspiro[3.3]heptan-2-yl)-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (Control Compound 2)

[0401]

[0402] Intermediate A1 (3.7 g, 13.1 mmol), 6-(4-chlorophenyl)-2-azaspiro[3.3]heptane (6.1 g crude, 14.6 mmol), and DIPEA (9.4 g, 73 mmol) were successively added to a mixed system of THF / water (40 / 20 mL). The reaction system was reacted at 85 °C for 2 hours, cooled to room temperature and concentrated. The crude product was first purified rapidly by silica gel column to obtain the crude product of the product, and then separated and purified by Pre-HPLC and freeze-dried to obtain (R)-2-(6-(4-chlorophenyl-2-yl)-2-azaspiro[3.3]heptan-2-yl)-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (Control Compound 2) (1.2 g, two-step yield 17.9%). LC-MS, M / Z (ESI): 459 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.25 (t, 2H), 7.09 (d, 2H), 6.08 (s, 1H), 5.55 (t, 1H), 4.25 (s, 2H), 4.04 (s, 2H), 3.81 (d, 2H), 3.65–3.53 (m, 1H), 3.39 (dt, 2H), 3.09–2.94 (m, 2H), 2.62 (t, J = 9.8 Hz, 2H), 2.30 (t, 4H), 2.24–2.09 (m, 2H), 2.03–1.81 (m, 2H).

[0403] Test Example 1: Enzyme Activity Inhibition Experiments of Compounds to be Tested against PDE4B2 and PDE4D2

[0404] The inhibitory activities of the compounds of the present invention against PDE4B2 and PDE4D2 can be determined using AMP-Glo TMAssay kit (Promega, V5011). First, all compounds were prepared into 20 or 25mM stock solutions with DMSO, and then the compounds to be tested were diluted 3 times with DMSO in the compound plate to 200X working solution. At the same time, 200X Rolipram (2mM) was prepared as a positive control, and 100% DMSO was used as a blank control. The compound plate was centrifuged at 1000rpm for 1 minute, and 20nL of the compound working solution was transferred to a 384 experimental test plate (Greiner, 784075) using Echo 550, and the plate was sealed and centrifuged at 1000rpm for 1 minute. Use ice-cold PDE assay buffer to dilute PDE4B2 enzyme (BPS bioscience, 60042) and PDE4D2 enzyme (BPS bioscience, 60048) to 2X working solution; add 2μL of 2X PDE4B2 (6.4pg / μL) or 2X PDE4D2 (4pg / μL) working solution to each well of the 384 assay plate, seal the plate and equilibrate at room temperature for 10 minutes. Use PDE assay buffer to dilute Cyclic-3',5'-AMP (sigma, A6882) to 2X working solution; add 2μL of 2X Cyclic-3',5'-AMP (2μM) working solution to each well of the 384 assay plate and incubate at room temperature for 60 minutes. Use AMP-Glo TM Assay kit (Promega, V5011) was used to detect AMP. 4 μL of AMP-Glo ​​reagent I was added to each well of the 384 experimental test plate and incubated at room temperature for 60 minutes. Then 8 μL of AMP detection reagent was added to each well and incubated at room temperature for 60 minutes. The RLU signal was read using the Envision2105 instrument to calculate the inhibition rate of the test compound at different concentrations: Inhibition (%) = (1-(RLU compound-RLU positive control) / (RLU blank control-RLU positive control)) × 100%. The experimental results were input into GraphPad Prism software, and the IC of each compound was obtained by fitting calculation. 50 The results show that the PDE4B2 IC 50 The values ​​are all lower than the IC of PDE4D2 50 This example shows the data of some compounds, as shown in Table 1.

[0405] Table 1. IC values ​​of compounds 50 value

[0406] Compound number <![CDATA[PDE4B2 IC 50 (nM)]]> <![CDATA[PDE4D2 IC 50 (nM)]]> Compound 2 23.9 50.2 Compound 3 14.5 45.1 Compound 4 17.5 42.7

[0407] The experimental results show that the compound of the present invention has a significant inhibitory effect on PDE4B and can be used as a selective inhibitor of PDE4B.

[0408] Test Example 2: Pharmacokinetic Experiment

[0409] For the pharmacokinetic experiment of minipigs, male minipigs weighing 10 - 12 kg were used. Three minipigs were selected for each group, fasted, and administered 10 mg / kg by oral gavage. Blood samples were collected before dosing and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing; for another three minipigs in each group, 3 mg / kg was administered by intravenous injection, and blood samples were collected before dosing and at 5, 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing. After the whole blood samples were anticoagulated in EDTA-K2 tubes, they were centrifuged at 4°C (1500 - 1600 g) for 10 minutes to separate plasma. Before analysis and detection, all samples were stored at -80°C. 20 μL of plasma at each time point was taken, added to 400 μL of acetonitrile-methanol aqueous solution containing internal standard, vortex-mixed, centrifuged at 3700 rpm for 10 minutes, 50 μL of the supernatant was taken, added to 100 μL of water, vortex-mixed, and an appropriate amount of the mixed solution was taken for LC-MS / MS analysis. Non-compartmental models were used to calculate the main pharmacokinetic parameters of plasma.

[0410] The experimental results showed that the compounds of the present invention exhibited excellent pharmacokinetic properties.

[0411] Test Example 3: Caco-2 Cell Permeability Experiment

[0412] Caco-2 cells were seeded onto 96-well Transwell plates at a density of 1×10 5 cells / cm 2 , and the culture medium was renewed every 4 - 5 days until a confluent monolayer membrane was formed on the 28th day. The integrity of the Caco-2 cell membrane layer was verified using HBSS solution containing 100 μM fluorescein. Then, the following experiments were carried out in the presence and absence of Elacridar (10 μM): In the A-to-B group, the test compound was added to the dosing side of the 96-well Transwell plate at a final concentration of 2 μM, and buffer was added to the receiving side. Then, the plate was incubated in a CO2 incubator at 37°C and 5% CO2 under saturated humidity conditions for 2 hours; after incubation, samples were taken simultaneously from the dosing side and the receiving side. After all samples were mixed with acetonitrile containing internal standard, they were centrifuged at 3200 g for 10 minutes, the supernatant was taken, and then the compound concentration was detected by LC-MS / MS. The B-to-A group was detected under the same conditions. Finally, the apparent permeability coefficient (Papp, 10 -6 cm / sec) and efflux ratio were calculated according to the following formula.

[0413] Apparent permeability coefficient (Papp) = (volume of the receiving side) / (membrane area × incubation time) × (drug concentration in the receiving side at the end of incubation) / (drug concentration in the dosing side at the start of incubation)

[0414] Efflux rate (ER) = Papp (B-A) / Papp (A-B) .

[0415] The test results show that the compound of the present invention has good permeability.

[0416] Test Example 4: Inhibition experiment of the test compound on TNF-α secretion by human PBMC stimulated by LPS

[0417] Use fresh blood samples and add the same volume of PBS (BI, 02-024-01ACS) to dilute for later use. Take a 50mL centrifuge tube, add 15mL lymphocyte separation solution Lymphoprep (stem cell, 7851), and slowly add 30mL of diluted blood sample on top of Lymphoprep, taking care not to damage the interface. Centrifuge at 1000g for 25min at room temperature without braking. Collect the white blood cell layer containing PBMC into a new 50mL centrifuge tube, add 50mL DPBS to wash twice, centrifuge at 350g for 10min, discard the supernatant, resuspend the cells with 1640 complete medium, and adjust the concentration to 1.5×10 6 cells / mL. Take a 96-well cell culture plate and add 100 μL PBMC cells to each well. Use 1640 complete medium to prepare the test compound into a series of 4× working solutions, add 50 μL of the compound working solution to the corresponding cell culture plate, and set up the LPS group (without compound) and the DMSO group (without LPS and compound) at the same time. After incubation in a 37°C CO2 incubator for 1 hour, add 50 μL of LPS (final concentration 0.1 μg / mL) to the corresponding cell culture plate and incubate in an incubator for 4 hours. After incubation, centrifuge and collect the supernatant, and detect TNF-α expression according to the Human TNF-α ELISA kit (Cat: 555212) of BD Biosciences. Calculate the inhibitory rate of the test compound on the secretion of TNF-α by human PBMC stimulated by LPS. According to the inhibition rate of different concentrations of the compound, use GraphPad Prism8 software to fit the IC of the compound on the secretion of TNF-α by human PBMC stimulated by LPS. 50 This example shows the data of some compounds, as shown in Table 2.

[0418] Inhibition rate=100%-(test compound-DMSO group) / (LPS group-DMSO group)*100%.

[0419] Table 2 Inhibition results of compounds on TNF-α secretion by human PBMC stimulated by LPS

[0420] Compound number <![CDATA[IC 50 (nM)]]> Compound 3 41.4 Compound 2 57.8 Control compound 1 63.4

[0421] The test results show that: compared with the control compound 1, the compounds of the present invention have a better inhibitory effect on TNF-α secreted by LPS-stimulated human PBMCs; the compounds 2 and 3 of the present invention have a better inhibitory effect on TNF-α secreted by LPS-stimulated human PBMCs. In particular, compound 3 has greatly improved the effect on TNF-α secreted by LPS-stimulated human PBMCs and has a stronger anti-inflammatory effect.

[0422] Test Example 5: Pharmacokinetic Test

[0423] For the pharmacokinetic test of monkey PK, male cynomolgus monkeys weighing 5 - 7 kg were used and fasted overnight. Three cynomolgus monkeys were taken and orally gavaged with 10 mg / kg. Blood samples were collected before dosing and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing. After anticoagulating the whole blood samples in EDTA-K2 tubes, the plasma was separated by centrifugation (1500 - 1600 g) at 4°C for 10 minutes. Before analysis and detection, all samples were stored at -80°C. 20 μL of plasma at each time point was taken, added to 400 μL of a mixed solution of acetonitrile, methanol, and water containing an internal standard, vortex-mixed, centrifuged at 3700 rpm for 10 minutes, 50 μL of the supernatant was taken, 100 μL of water was added, vortex-mixed, and an appropriate amount of the mixed solution was taken for LC-MS / MS analysis. Non-compartmental models were used to calculate the main pharmacokinetic parameters of the plasma.

[0424] Table 3 Pharmacokinetic Results of Oral Gavage in Cynomolgus Monkeys

[0425]

[0426] Using monkeys with a metabolic profile closer to that of humans to investigate PK, the results show that the area under the curve AUC0-t and Cmax of the compounds of the present invention have been significantly improved, the clearance rate is lower, and they have more excellent pharmacokinetic properties; the area under the curve AUC of compound 3 of the present invention 0-t is twice that of the control compound 1, the Cmax has also increased significantly, the oral absorption is better, the clearance rate is lower, compound 3 of the present invention has more excellent pharmacokinetic properties, and it is expected that the dosing dose will be smaller and the side effects will be lower.

[0427] Test Example 6: In Vitro Toxicity Evaluation of Compounds on Human HepG2 Cells

[0428] HepG2 cells in the logarithmic growth phase were digested with trypsin and resuspended in MEM complete medium containing 10% FBS. 10000 cells were seeded in each well of a 96-well plate (the blank control group did not seed cells), and the seeding volume was 100 μL / well. The plate was placed in a 37°C CO2 incubator and incubated for 24 h.

[0429] Prepare a 50 mM stock solution of the test compound in DMSO solvent, dilute it to an appropriate concentration using a DMSO gradient, and then dilute it 3-fold with cell culture medium to a 2X concentration as the compound working solution. Add 100 μL of the test compound working solution to the corresponding wells of a 96-well plate (n = 2). At the same time, set up a blank control group (cell culture medium containing 0.5% DMSO) and a DMSO group (cell culture medium containing 0.5% DMSO). After incubating in a 37°C CO2 incubator for 72 h, aspirate 100 μL of the supernatant from each well and discard it. Then add 50 μL of CTG (Promega, G9243) to each well, shake on a microplate shaker for 5 min, let it stand for 10 min, and then read the luminescence value using a microplate reader to calculate the inhibition rate of the test compound on human HepG2 cells. Fit the inhibition rate of the compound at different concentrations to obtain the inhibition IC 50 value.

[0430] Inhibition rate = 100% - (test compound - blank control group) / (DMSO group - blank control group) * 100%

[0431] Table 4 Results of in vitro toxicity evaluation of the compound on HepG2 cells

[0432] Test compound <![CDATA[IC 50 (μM)]]> Test compound <![CDATA[IC 50 (μM)]]> Compound 1 >200 Compound 11 >200 Compound 2 >200 Compound 13 >200 Compound 3 >200 Compound 14 >200 Compound 4 >200 Compound 17 >200 Compound 5 >200 Compound 18 >200 Compound 6 >200 Compound 19 >200 Compound 7 >200 Compound 23 >200 Compound 9 >200 Compound 22 >200 Compound 10 >200 Control compound 2 31.2

[0433] The test results show that the inhibitory effect of Compound 3 of the present invention on human HepG2 cells is significantly weaker than that of Control Compound 2. Thus, it can be seen that the compounds of the present invention have lower toxicity to human hepatocytes and are expected to have better safety for long-term drug use.

[0434] Test Example 7: Detection of mouse tissue distribution

[0435] For the mouse tissue distribution experiment, use ICR mice, 20 - 25 g, fast overnight. Take 8 male mice and 4 female mice, and administer the drug orally by gavage at a dose of 10 mg / kg. Collect tissues such as blood, stomach, small intestine, and large intestine at 30 minutes, 1, 4, and 8 hours after drug administration. At each time point, use 2 male mice and 1 female mouse. After anticoagulating the whole blood samples in EDTA-K2 tubes, centrifuge them at 4°C (1500 - 1600 g) for 10 minutes to separate the plasma. Before analysis and detection, all plasma and tissue samples are stored at -80°C. Use the LC-MS / MS method to detect the compound concentration in mouse plasma, stomach, small intestine, and large intestine homogenate samples, and calculate the area under the concentration-time curve and the area ratio of tissue / plasma under the curve according to the compound concentration at different time points.

[0436] Table 5 Results of mouse tissue distribution detection

[0437]

[0438]

[0439] The test results show that the compound of the present invention has a lower gastrointestinal distribution in mice, and the ratio of the area under the curve of tissue / plasma is significantly reduced. It is expected that there will be fewer gastrointestinal side effects such as vomiting and diarrhea during long-term medication, and the safety is high.

[0440] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound of formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula I: in, Ring A is a 5-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; Each R T are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Deuterated cycloalkyl, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Deuterated cycloalkyl, C 1-6 Deuterated alkyl and C 1-6 The deuterated alkoxy group is optionally substituted by one or more of the following substituents: halogen, hydroxy, amino, nitro, cyano or carbonyl. When there are multiple substituents, the substituents are the same or different. B is a 3-10 membered heterocycloalkyl, a 3-10 membered heterocycloalkenyl or a 3-10 membered cycloalkyl; R a and R b are each independently H, deuterium, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 deuterated alkoxy, 3-10 membered heterocycloalkyl; the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy and C 1-6 The haloalkoxy group is optionally substituted with one or more R c Substitution; said R c The following substituents are: deuterium, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R c When it is multiple, the R c Same or different; Y is NR 1 , O, S or C (R 1 )2; Each R 1 are independently H, deuterium, C 1-10 Alkyl, C 2-6 Alkenyl, the C 1-10 Alkyl and C 2-6 The alkenyl group is optionally substituted with one or more R d Substitution; said R d is a substituent of: deuterium, halogen, C 1-3 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -COO-C 1-6 Alkyl, -C(O)NR f R f , 5-8 membered aromatic ring, -het 1 , monocyclic- or bicyclic-C 5-8- Cycloalkyl; wherein said R f For hydrogen, C 1-6 Alkyl; the het 1 represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O; Q is the following group: R 2 and R 3 Yes, R 5 and R 6 Each of the pairs can independently form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 heteroatoms, wherein the heteroatoms are N, O, or S, and further wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is surrounded by g R 23 Substitute, the R 23 is at least one of the following: H, deuterium, halogen, hydroxyl, amino, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -COO-C 1-6 Alkyl, -C(O)NR f R f ; wherein said R f For hydrogen, C 1-6 alkyl; Or, R 5 and R 6 are independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy and C 1-6 The deuterated alkoxy group is optionally substituted with one or more R d Substitution; said R d is a substituent of: deuterium, halogen, C 1-3 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -COO-C 1-6 Alkyl, -C(O)NR f R f 、-OC(O)NR f R f , 5-8 membered aromatic ring, -het 2 , mono- or bicyclic-C 5-8- Cycloalkyl; wherein said R f For hydrogen, C 1-6 Alkyl; the het 2 represents a 5-8 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O; R 4 H, deuterium, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 deuterated alkoxy, 3-10 membered heterocycloalkyl; the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 The halogenated alkoxy group and the 3- to 10-membered heterocycloalkyl group are optionally substituted with one or more R g Substitution; said R g is at least one of the following substituents: deuterium, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R g When it is multiple, the R g Same or different; x is 1, 2, 3, or 4; m and n are 1, 2, 3, 4, 5, 6, 7 or 8 respectively; g is 1, 2, 3, 4, 5, 6, 7 or 8; Wherein, the compound represented by formula I must meet the following conditions: At least one R T , R a , R b , R 1 , R 2 , R 3 , R 23 , R 4 , R 5 or R 6 Deuterium, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy.

2. The compound according to claim 1, characterized in that Ring A is selected from 5-9 membered heteroaromatic rings; and / or, the heteroaromatic ring has 1 or 2 heteroatoms; and / or, the heteroatom is selected from N or O; and / or, the ring A is a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or a benzoxazolyl ring; And / or, the ring A is and / or, structural unit for and / or, the R a H, deuterium, F, Cl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl; and / or, the R a is H, deuterium, F, Cl, CH3, CD3 or CH3 substituted by halogen; and / or, the R a is H, deuterium, F, Cl, CH3, CD3 or CH3 substituted by F; and / or, the R a is H, deuterium, CD3, F, Cl or CHF2; and / or, structural unit for And / or, said Y is NR 1 or CHR 1 When R 1 Selected from H, deuterium or C 1-6 alkyl; And / or, said Y is -NH-.

3. The compound according to claim 1, characterized in that B is selected from 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl; and / or, the 3-10 membered heterocycloalkyl is a monocyclic, fused bicyclic, bridged or spirocyclic bicyclic; and / or, the 3-10 membered heterocycloalkyl further has 1 to 3 heteroatoms selected from N, O, and S; and / or, the 3-10 membered heterocycloalkenyl is selected from a monocyclic or fused bicyclic; and / or, the 3-10 membered heterocycloalkenyl further has 1 to 3 heteroatoms selected from N, O, and S; And / or, B is the following group: Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 Each is independently N, NH, CH2, CH, C, -NH-CH2- or -CH2-CH2-; p is 0, 1 or 2; and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, fragment for and / or, fragment for 4. The compound according to claim 1, characterized in that The R b are independently H, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, halogen, C 3-8 Cycloalkyl or oxo; and / or, each R b are independently H, deuterium, methyl, F, C 1-3 deuterated alkyl, cycloethyl or oxo; and / or, each R b are each independently H, deuterium, methyl, F, cycloethyl or oxo; and / or, each R b are independently H or deuterium; and / or, the R c 0, 1, 2 or 3; and / or, each R c are independently deuterium, halogen, oxo, C 1-6 Deuterated alkyl, C 1-6 Alkyl or C 1-6 Haloalkyl; and / or, each R c are independently deuterium, halogen, oxo, C 1-3 Deuterated alkyl, C 1-3 Alkyl or C 1-3 Haloalkyl; and / or, the R g 0, 1, 2 or 3; and / or, each R g are independently deuterium, halogen, hydroxyl, cyano, C 1-6 Deuterated alkyl, C 1-6 Alkyl or C 1-6 Haloalkyl; and / or, each R g are independently deuterium, halogen, oxo, C 1-3 Deuterated alkyl, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

5. The compound according to claim 1, characterized in that Each R T are independently H, deuterium, and C 1-3 Deuterated alkyl or C 1-3 deuterated alkoxy; and / or, each R T are independently H or deuterium; and / or, each R 4 are independently H, deuterium, halogen, hydroxyl, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 deuterated alkoxy, 3-10 membered heterocycloalkyl; the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, 3-10 membered heterocycloalkyl, optionally substituted with one or more R g Substitution; said R g is at least one of the following substituents: deuterium, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R g When it is multiple, the R g Same or different; and / or, each R 4 are independently H, deuterium, hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl; and / or, each R 4 are independently H, deuterium or hydroxyl; and / or, R 5 and R 6 Each independently is H, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, the C 1-6 Alkyl and C 2-6 The alkenyl group is optionally substituted with one or more R d Substitution; said R d is a substituent of: deuterium, halogen, C 1-3 Fluorinated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -COO-C 1-6 alkyl; and / or, R 5 and R 6 Each independently is H, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl; and / or, R 5 and R 6 Each independently is H or deuterium; And / or, Q is R 4 is hydroxyl group; And / or, Q is the following group: And / or, Q is the following group: and / or, For the following groups:

6. The compound according to claim 1, characterized in that The compound has a structure shown in Formula IA or Formula IB: Among them, ring A, B, R a , R b , R T , Y, Q, m, n and x are as defined in claim 1.

7. The compound according to claim 1, characterized in that The compound has the structure shown in Formula I-1: Among them, Z 1 , Z 4 are independently CH or N; Ring A, R a , R b , R T , Y, Q, m, n and x are as defined in claim 1.

8. The compound according to claim 1, characterized in that The compound has the structure shown in Formula I-1A: Among them, Z 1 , Z 2 are independently CH or N; Ring A, R a , R b , R T , R 1 , R 23 , R 4 , R 5 , R 6 , m, n and x are as defined in claim 1.

9. The compound according to claim 1, characterized in that The compound has the structure shown in Formula I-1B: Among them, X 1 , X 2 are independently CH or N; Z 1 and Z 4 are each independently N or CH; R a , R b , R T , R 1 , R 23 , R 4 , R 5 , R 6 , m, n, g and x are as defined in claim 1.

10. The compound according to claim 1, characterized in that The compound has a structure shown in Formula I-1B1, I-1B2 or I-1B3: Among them, X 1 , X 2 are independently CH or N; Each R a are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 deuterated alkoxy; Each R T are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 deuterated alkoxy; Each R 23 are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 deuterated alkoxy; R 5 and R 6 are independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 deuterated alkoxy; Each R b are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 deuterated alkoxy; Among them, at least one R T , R a , R b , R 23 , R 5 or R 6 Deuterium, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy.

11. The compound according to claim 10, characterized in that The compound has a structure shown in formula I-1B4' or I-1B5': Each R a are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 deuterated alkoxy; Each R T are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 deuterated alkoxy; Each R 23 are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 deuterated alkoxy; R 5 and R 6 are independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 deuterated alkoxy; Each R b are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 deuterated alkoxy; Among them, at least one R T , R a , R b , R 23 , R 5 or R 6 Deuterium, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy.

12. The compound according to claim 11, characterized in that The compound has a structure shown in formula I-1B4 or I-1B5: R 5 and R 6 are independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 deuterated alkoxy; Each R b are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 deuterated alkoxy; Among them, at least one R b , R 5 and R 6 Deuterium, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy.

13. The compound according to claim 10, characterized in that Each R T are independently H or deuterium; and / or, each R T At least one of them is deuterium, and the rest are R T All are H; and / or, each R 23 are independently H or deuterium; and / or, each R 23 At least one of them is deuterium, and the rest are R 23 All are H; and / or, R 5 and R 6 are independently H or deuterium; and / or, R 5 and R 6 At least one of them is deuterium and the other is H or deuterium; and / or, each R b are independently H or deuterium; and / or, each R b At least one of them is deuterium, and the rest are R b All are H; and / or, each R a are independently H, deuterium, Cl or F; and / or, each R a At least one of them is deuterium, and the rest are R a All are H, Cl or F.

14. The compound according to claim 1, characterized in that The compound has the following structure:

15. The compound according to claim 14, characterized in that The compound has the following structure:

16. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a compound as claimed in any one of claims 1 to 15, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; And / or, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

17. Use of the compound according to any one of claims 1 to 15, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 16 for inhibiting PDE4B.

18. Use of the compound according to any one of claims 1 to 15, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 16 in the preparation of a drug or preparation, wherein the drug or preparation is used for: Inhibits PDE4B, and / or Prevention and / or treatment of PDE4B-related diseases, and / or Avoid or reduce gastrointestinal side effects when treating PDE4B-related diseases.

19. The use according to claim 18, characterized in that The PDE4B-related diseases include: respiratory diseases, gastrointestinal diseases, inflammatory diseases of joints, skin or eyes, cancer and peripheral or central nervous system diseases, autoimmune diseases, transplant rejection or diseases related to smooth muscle contractility; Optionally, the respiratory disease is a respiratory or pulmonary disease associated with increased mucus production, airway inflammation and / or obstructive disease; Optionally, the respiratory disease is COPD, idiopathic pulmonary fibrosis, interstitial lung disease, alpha 1-antitrypsin deficiency, chronic sinusitis, asthma or chronic bronchitis; Optionally, the autoimmune disease is a diffuse connective tissue disease such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis or Sjögren's disease; Optionally, the gastrointestinal disease is enteritis, ulcerative colitis or Crohn's disease; Optionally, the inflammatory disease of the joints, skin or eyes is rheumatoid arthritis, sarcoidosis, dry eye syndrome or glaucoma; Optionally, the cancer is mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma Pigmented tumors, brain tumors, lymphomas, head and neck cancers, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma; Optionally, the peripheral or central nervous system disease is depression, bipolar depression or manic depression, acute and chronic anxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain and brain damage caused by stroke, hypoxia or craniocerebral trauma.

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