Deuterated heterocyclic compound acting as pde4b inhibitor and use thereof

Abstract

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Description

Deuterated heterocyclic compounds as PDE4B inhibitors and their applications

[0001] Priority information

[0002] This application claims priority to and the benefits of patent application 202311744747.3 filed with the State Intellectual Property Office of China on December 15, 2023, patent application 202410070286.4 filed with the State Intellectual Property Office of China on January 17, 2024, patent application 202410658874.X filed with the State Intellectual Property Office of China on May 24, 2024, patent application 202411247213.4 filed with the State Intellectual Property Office of China on September 5, 2024, and patent application 202411758940.7 filed with the State Intellectual Property Office of China on December 2, 2024, and the entire text of which is incorporated 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, the present invention relates to a compound represented by Formula I, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof; the compound exhibits potent PDE4B inhibitory activity. Background Art

[0004] PDE4 is a cyclic nucleotide phosphodiesterase (CAMP) that is abundantly expressed in most cells and hydrolyzes cAMP with a micromolar Km. PDE4 molecules are involved in a variety of physiological processes, including brain function, monocyte-macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, and cardiac contraction. PDE4 has been reported as a target for various inflammatory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis. PDE4 consists of four isoforms: PDE4A, PDE4B, PDE4C, and PDE4D, located on chromosomes 19p13.2, 1p31, 19p13.11, and 5q12, respectively. PDE4 molecules exist in long, short, and ultrashort forms depending on their molecular size. The X-ray structure of PDE4 reveals that the active center can be divided into three subpockets: 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 multiple interactions, including hydrophobic interactions with conserved phenylalanine and isoleucine, and hydrogen bonding with the invariant glutamine. The high degree of conservation and structural homology of the PDE4 catalytic domain makes the discovery of PDE4 isoform-selective inhibitors challenging.

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

[0006] Currently, there are no drugs on the market that inhibit PDE4B pathways to treat a variety of diseases, including fibrosis. Therefore, the development of new compounds that can inhibit PDE4B activity has positive significance for the treatment of diseases. Summary of the Invention

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

[0008] In a first aspect, the present invention provides 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] in,

[0010] Ring A is a 5-10 membered aromatic ring or a 5-10 membered heteroaromatic ring;

[0011] 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 with one or more of the following substituents: halogen, hydroxy, amino, nitro, cyano or carbonyl. When there are multiple substituents, the substituents may be the same or different.

[0012] B is a 3-10 membered heterocycloalkyl, a 3-10 membered heterocycloalkenyl or a 3-10 membered cycloalkyl;

[0013] R a and R b are independently H, deuterium, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C3- 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 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 Halogenated alkyl, 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 Substituted; said R c 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 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R c When there are multiple R c Same or different;

[0014] Y is NR 1 , O, S or C(R 1 )2;

[0015] 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 Substituted; said R d is the following substituent: deuterium, halogen, C 1-3 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -COO-C1-6 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 heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O;

[0016] Q is the following group:

[0017] R 2 and R 3 Yes, R 5 and R 6 Each of the pairs can independently form a saturated or partially saturated 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring with the carbon atoms to which they are attached; wherein the 3-membered, 4-membered, 5-membered, 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-membered, 4-membered, 5-membered, or 6-membered monocyclic ring is surrounded by g R 23 Substituted, 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 Halogenated alkyl, 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, the R f For hydrogen, C 1-6 alkyl;

[0018] 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 1-6Deuterated alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy and C 1-6 Deuterated alkoxy is optionally substituted by one or more R d Substituted; said R d is the following substituent: deuterium, halogen, C 1-3 Halogenated alkyl, 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 heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O;

[0019] 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 Halogenated alkyl, 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 Halogenated alkyl, 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 Halogenated alkoxy, 3-10 membered heterocycloalkyl, optionally substituted with one or more R g Substituted; said R gis 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 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R g When there are multiple R g Same or different;

[0020] x is 1, 2, 3, or 4;

[0021] m and n are 1, 2, 3, 4, 5, 6, 7 or 8 respectively;

[0022] g is 1, 2, 3, 4, 5, 6, 7 or 8;

[0023] Wherein, the compound represented by formula I must meet the following conditions:

[0024] 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.

[0025] According to an embodiment of the present invention, the present invention discloses 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:

[0026] in,

[0027] Ring A is a 5-10 membered aromatic ring or a 5-10 membered heteroaromatic ring;

[0028] 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;

[0029] B is a 3-10 membered heterocycloalkyl, a 3-10 membered heterocycloalkenyl or a 3-10 membered cycloalkyl;

[0030] R a and R b Each is 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 Halogenated alkyl, 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 Alkynyl, C 1-6 Halogenated alkyl, 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 Substituted; said R c 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 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R c When there are multiple R c Same or different;

[0031] Y is NR 1 , O, S or C(R 1 )2;

[0032] Each R 1 are independently H, deuterium, C 1-10 Alkyl, C 2-6 Alkenyl, the C 1-10 Alkyl, C2-6 The alkenyl group is optionally substituted with one or more R d Substituted; said R d is the following substituent: deuterium, halogen, C 1-3 Fluorinated alkyl, 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 heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O;

[0033] Q is the following group:

[0034] R 2 and R 3 Yes, R 5 and R 6 Each of the pairs can independently form a saturated or partially saturated 3-membered, 4-membered, 5-membered, or 6-membered monocyclic ring with the carbon atoms to which they are attached; 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 surrounded by g R 23 Substituted, 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 1-4 Halogenated alkyl, 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, the R f For hydrogen, C 1-6 alkyl;

[0035] Or, R 5 and R 6are independently 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, C 2-6 The alkenyl group is optionally substituted with one or more R d Substituted; said R d is the following substituent: deuterium, halogen, C 1-3 Fluorinated alkyl, 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 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 heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O;

[0036] 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 Halogenated alkyl, 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 Alkynyl, C 1-6 Halogenated alkyl, 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 Halogenated alkoxy, 3-10 membered heterocycloalkyl, optionally substituted with one or more Rg Substituted; 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 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R g When there are multiple R g Same or different;

[0037] x is 1, 2, 3, or 4;

[0038] m and n are 1, 2, 3, 4, 5, 6, 7 or 8 respectively;

[0039] g is 1, 2, 3, 4, 5, 6, 7 or 8;

[0040] Wherein, the compound represented by formula I must meet the following conditions:

[0041] At least one R T 、R a 、R b 、R 1 、R 23 、R 4 、R 5 or R 6 Deuterium, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy.

[0042] In some embodiments of the present invention, the ring A is selected from a 5-9 membered heteroaromatic ring.

[0043] In some embodiments of the invention, the heteroaryl ring has 1 or 2 heteroatoms.

[0044] In some embodiments of the present invention, the heteroatom is selected from N or O.

[0045] In some embodiments of the present invention, the ring A is a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or a benzoxazolyl ring.

[0046] In some embodiments of the present invention, the ring A is

[0047] In some embodiments of the present invention, the structural unit for

[0048] In some embodiments of the present invention, the R a H, deuterium, F, Cl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl.

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

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

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

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

[0055] In some embodiments of the present invention, Y is NR 1 or CHR 1 When R 1 Selected from H or C 1-6 alkyl.

[0056] In some embodiments of the present invention, said Y is -NH-.

[0057] In some embodiments of the present invention, B is selected from 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl.

[0058] In some embodiments of the present invention, B is a 3-10 membered heterocycloalkyl group.

[0059] In some embodiments of the present invention, the 3-10 membered heterocycloalkyl group is a monocyclic, fused bicyclic, bridged or spirocyclic bicyclic ring.

[0060] In some embodiments of the present invention, the 3-10 membered heterocycloalkyl group further has 1 to 3 heteroatoms selected from N, O, and S.

[0061] In some embodiments of the present invention, B is a 3-10 membered heterocycloalkenyl group.

[0062] In some embodiments of the present invention, the 3-10 membered heterocycloalkenyl is selected from a monocyclic or a fused bicyclic ring.

[0063] In some embodiments of the present invention, the 3-10 membered heterocycloalkenyl further has 1 to 3 heteroatoms selected from N, O, and S.

[0064] In some embodiments of the present invention, said B is the following group:

[0065] Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 、Z 7 、Z 8 and Z 9 each independently represents 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 for

[0067] In some embodiments of the present invention, the for

[0068] In some embodiments of the present invention, the for

[0069] In some embodiments of the present invention, the for

[0070] In some embodiments of the present invention, the for

[0071] In some embodiments of the present invention, the for

[0072] In some embodiments of the present invention, the for

[0073] In some embodiments of the present invention, the for

[0074] In some embodiments of the present invention, the for

[0075] In some embodiments of the present invention, the for

[0076] In some embodiments of the present invention, the for

[0077] In some embodiments of the present invention, the for

[0078] In some embodiments of the present invention, the for

[0079] In some embodiments of the present invention, the for

[0080] In some embodiments of the present invention, the fragment for

[0081] In some embodiments of the present invention, the fragment for

[0082] In some embodiments of the present invention, each R b are independently H, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, halogen, C 3-8 Cycloalkyl or oxo.

[0083] In some embodiments of the present invention, each R b are independently H, deuterium, methyl, F, C 1-3 deuterated alkyl, cycloethyl or oxo.

[0084] In some embodiments of the present invention, each R b are each independently H, deuterium, methyl, F, cycloethyl or oxo.

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

[0086] In some embodiments of the present invention, the R c 0, 1, 2 or 3.

[0087] In some embodiments of the present invention, each R c are independently deuterium, halogen, oxo, C 1-6 Deuterated alkyl, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0088] In some embodiments of the present invention, the R g 0, 1, 2 or 3.

[0089] In some embodiments of the present invention, each R g are independently deuterium, halogen, hydroxyl, cyano, C 1-6 Deuterated alkyl, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0090] In some embodiments of the present invention, each R g are independently deuterium, halogen, oxo, C 1-3 Deuterated alkyl, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0091] In some embodiments of the present invention, each R T are independently H, deuterium, C 1-3 Deuterated alkyl or C 1-3 Deuterated alkoxy.

[0092] In some embodiments of the present invention, each R T are each independently H or deuterium.

[0093] In some embodiments of the present invention, 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 Halogenated alkyl, 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 C1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl 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 Substituted; 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 Halogenated alkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy; when the substituent R g When there are multiple R g Same or different.

[0094] In some embodiments of the present invention, each R 4 are independently H, deuterium, hydroxyl, 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 hydroxyl groups.

[0095] In some embodiments of the present invention, each R 4 are each independently H, deuterium or hydroxyl.

[0096] In some embodiments of the present invention, the R 5 and R 6 are independently 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 Substituted; said R d is the following substituent: deuterium, halogen, C 1-3 Fluorinated alkyl, C1-6 Alkoxy, C 1-6 Haloalkoxy, -COO-C 1-6 alkyl.

[0097] In some embodiments of the present invention, the R 5 and R 6 are independently H, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl.

[0098] In some embodiments of the present invention, the R 5 and R 6 are each independently H or deuterium.

[0099] In some embodiments of the present invention, Q is R 4 It is a hydroxyl group.

[0100] In some embodiments of the present invention, Q is the following group:

[0101] In some embodiments of the present invention, Q is the following group:

[0102] In some embodiments of the present invention, the For the following groups:

[0103] In some embodiments of the present invention, the compound has the structure shown in Formula IA or Formula IB:

[0104] Among them, ring A, B, R a 、R b 、R T , Y, Q, m, n and x are as defined in the present invention.

[0105] In some embodiments of the present invention, the compound has the structure shown in Formula I-1:

[0106] Among them, Z 1 , Z 4 are independently CH or N;

[0107] Ring A, R a 、R b 、R T , Y, Q, m, n and x are as defined in the present invention.

[0108] In some embodiments of the present invention, the compound has the structure shown in Formula I-1A:

[0109] Among them, Z 1 、Z 2 are independently CH or N;

[0110] Ring A, R a 、R b 、R T 、R 1 、R 23 、R 4 、R 5 、R 6 The definitions of m, n and x are as defined in the present invention.

[0111] In some embodiments of the present invention, the compound has the structure shown in Formula I-1B:

[0112] Among them, X 1 、X 2 are independently CH or N; Z 1 and Z 4 are each independently N or CH;

[0113] R a 、R b 、R T 、R 1 、R 23 、R 4 、R 5 、R 6 The definitions of m, n, g and x are as defined in the present invention.

[0114] In some embodiments of the present invention, in the structures shown in Formula I-1, Formula I-1A and Formula I-1B, Z 1 N, Z 4 For CH.

[0115] In some embodiments of the present invention, the compound has a structure shown in Formula I-1B1, I-1B2 or I-1B3:

[0116] Among them, X 1 、X 2 are independently CH or N;

[0117] 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;

[0118] 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;

[0119] 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;

[0120] 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;

[0121] 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;

[0122] 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.

[0123] In some embodiments of the present invention, in the structures shown in Formulas I-1B, I-1B1, I-1B2, and I-1B3, X 1 and X 2 All are N.

[0124] In some embodiments of the present invention, the compound has a structure shown in Formula I-1B4' or I-1B5':

[0125] Each R a are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6deuterated alkoxy;

[0126] 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;

[0127] 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;

[0128] 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;

[0129] 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;

[0130] 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.

[0131] In some embodiments of the present invention, the compound has the structure shown in Formula I-1B4:

[0132] 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;

[0133] Each R b are independently H, halogen, hydroxyl, deuterium, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Deuterated alkyl or C 1-6 deuterated alkoxy;

[0134] Among them, at least one R b 、R 5 and R 6 Deuterium, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy.

[0135] In some embodiments of the present invention, the compound has the structure shown in Formula I-1B5:

[0136] Among them, 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;

[0137] 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;

[0138] Among them, at least one R b 、R 5 and R 6 Deuterium, C 1-6 Deuterated alkyl or C 1-6 Deuterated alkoxy.

[0139] In some embodiments of the present invention, each R T are each independently H or deuterium.

[0140] In some embodiments of the present invention, each R T At least one of them is deuterium, and the rest are R T Both are H.

[0141] In some embodiments of the present invention, each R 23 are each independently H or deuterium.

[0142] In some embodiments of the present invention, each R 23 At least one of them is deuterium, and the rest are R 23 Both are H.

[0143] In some embodiments of the present invention, the R 5 and R6 are each independently H or deuterium.

[0144] In some embodiments of the present invention, R 5 and R 6 At least one of them is deuterium and the other is H or deuterium.

[0145] In some embodiments of the present invention, the R 5 For H.

[0146] In some embodiments of the present invention, the R 5 For deuterium.

[0147] In some embodiments of the present invention, the R 6 For H.

[0148] In some embodiments of the present invention, the R 6 For deuterium.

[0149] In some embodiments of the present invention, each R b are each independently H or deuterium.

[0150] In some embodiments of the present invention, each R b At least one of them is deuterium, and the rest are R b Both are H.

[0151] In some embodiments of the present invention, each R a are independently H, deuterium, Cl or F.

[0152] In some embodiments of the present invention, each R a At least one of them is deuterium, and the rest are R a All are H, Cl or F.

[0153] In some embodiments of the present invention, the compound has the following structure:

[0154] In some embodiments of the present invention, the compound has the following structure:

[0155] In some embodiments of the present invention, the compound represented by Formula I may not be one of Compounds 1 to 26.

[0156] In a second aspect, the present invention provides a pharmaceutical composition comprising: the compound as described in the first aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

[0157] In a preferred embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0158] In a second aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and a pharmaceutically acceptable carrier.

[0159] In a third aspect, the present invention provides the use of the compound according to the first aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to the second aspect for inhibiting PDE4B, and / or preventing and / or treating PDE4B-related diseases, and / or avoiding or reducing gastrointestinal side effects when treating PDE4B-related diseases.

[0160] In a fourth aspect, the present invention provides use of the compound according to the first aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to the second aspect in the preparation of a medicament or preparation for inhibiting PDE4B, and / or preventing and / or treating PDE4B-related diseases.

[0161] In a fifth aspect, the present invention provides the use of the compound described in the first aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the second aspect in the preparation of a drug or preparation for avoiding or reducing gastrointestinal side effects when treating PDE4B-related diseases.

[0162] In a sixth aspect, the present invention provides uses of the compound of formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or uses of the pharmaceutical composition described in the second aspect of the present invention, the uses comprising: inhibiting PDE4B; and / or, preventing and / or treating PDE4B-related diseases; and / or, preparing drugs, pharmaceutical compositions or preparations for inhibiting PDE4B, and / or preventing and / or treating PDE4B-related diseases.

[0163] In a seventh aspect, the present invention provides a compound as described in the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition as described in the second aspect, for inhibiting PDE4B, and / or preventing and / or treating PDE4B-related diseases, and / or avoiding or reducing gastrointestinal side effects when treating PDE4B-related diseases.

[0164] In an eighth aspect of the present invention, a method for inhibiting PDE4B, or preventing and / or treating PDE4B-related diseases is provided, comprising the steps of administering to a subject in need thereof the compound of formula I described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.

[0165] In a ninth aspect of the present invention, a method for inhibiting PDE4B, and / or preventing and / or treating PDE4B-related diseases, and / or avoiding or reducing gastrointestinal side effects when treating PDE4B-related diseases is provided, comprising the steps of administering to a subject in need thereof a compound of formula I according to the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.

[0166] According to an embodiment of the present invention, in the uses or methods described in the third, fourth, fifth, sixth, seventh, eighth and ninth aspects above, the PDE4B-related diseases include: respiratory diseases, gastrointestinal diseases, inflammatory diseases of the joints, skin or eyes, cancer and peripheral or central nervous system diseases, autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis and Sjögren's disease and other diffuse connective tissue diseases), transplant rejection reactions and diseases related to smooth muscle contractility.

[0167] Preferably, the respiratory disease is a respiratory or pulmonary disease associated with increased mucus production, airway inflammation and / or obstructive disease.

[0168] Preferably, the respiratory disease is COPD, idiopathic pulmonary fibrosis, interstitial lung disease, α1-antitrypsin deficiency, chronic sinusitis, asthma and chronic bronchitis.

[0169] Preferably, the gastrointestinal disease is endocrine disease, ulcerative colitis or Crohn's disease.

[0170] Preferably, the inflammatory disease of the joints, skin or eyes is rheumatoid arthritis, sarcoidosis, dry eye syndrome and glaucoma.

[0171] Preferably, 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, gastric 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 Pigmentoma, brain tumor, lymphoma, head and neck cancer, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder cancer, bronchogenic carcinoma, 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.

[0172] Preferably, 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.

[0173] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0174] Terms and Definitions

[0175] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0176] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0177] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiments.

[0178] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions 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 use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "comprising", "including" and "containing" are not restrictive.

[0179] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0180] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted by one or more substituents of a specified group, the substituents may be the same or different at each substitutable position. In general, the term "substituted ring" means that each hydrogen atom in the ring can be replaced, for example Can be

[0181] The term "unsubstituted" means that the designated group bears no substituents.

[0182] As described herein, the compounds of the present invention may optionally be substituted with one or more substituents, as described above for the general formula compounds, or as specifically exemplified in the Examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with the specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents of a specified group, the substituents may be the same or different at each position.

[0183] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention such as "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0184] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result from writing the formula from right to left. For example, CHO is equivalent to OCH. As used herein, As used herein, "R1", "R2" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R2, similar definitions have the same meaning.

[0185] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0186] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0187] When the numerical ranges described in the specification and claims of this application are understood as “integers”, they should be understood as recording the two endpoints of the range and each integer within the range. For example, “an integer from 1 to 6” should be understood as recording each integer of 0, 1, 2, 3, 4, 5, and 6. When the numerical range is understood as a “number”, it should be understood as recording the two endpoints of the range and each integer within the range and each decimal within the range. For example, “a number from 1 to 10” should be understood as recording not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively.

[0188] In the present application, "saturated, partially saturated or unsaturated" includes saturated substituents, substituents completely unsaturated with hydrogen and substituents partially saturated with hydrogen.

[0189] As used herein, the term "halogen" alone or as part of another substituent refers to fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.

[0190] As used herein, the term "cyano" by itself or as part of another substituent refers to -CN.

[0191] As used herein, the term "amino" by itself or as part of another substituent refers to -NH2.

[0192] As used herein, the term "hydroxy" by itself or as part of another substituent refers to -OH.

[0193] In this application, the term "deuterium" when used alone or as part of other substituents refers to an isotope of hydrogen, also known as heavy hydrogen, with the chemical symbol D or 2 H.

[0194] The term "alkyl" when used alone or as part of another substituent means a straight or branched hydrocarbon chain radical consisting solely 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. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopomers of naturally abundant alkyl groups enriched in isotopes of carbon and / or hydrogen (i.e., deuterium or tritium).

[0195] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter, for example: Expressed as One of the configurations, and Then it is represented by the remaining another configuration; Expressed as One of the configurations, and It represents the remaining configuration.

[0196] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group of 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, wherein the alkyl group may be independently and optionally substituted with one or more substituents described herein, including but not limited to deuterium, amino, hydroxyl, cyano, F, Cl, Br, I, mercapto, nitro, 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 "alkane" as used herein include both straight and branched saturated carbon chains.

[0197] The term "deuterated alkyl" when used alone or as part of another substituent refers to an alkyl group substituted with one or more deuterium groups, ie, a hydrogen atom on the alkyl group is replaced with a deuterium atom.

[0198] The term "deuterated alkoxy" when used alone or as part of another substituent refers to an alkoxy group substituted with one or more deuterium groups, ie, a hydrogen atom on the alkoxy group is replaced with a deuterium atom.

[0199] The term "alkylene" when used alone or as part of another substituent is understood to mean a straight-chain or branched saturated, unsaturated or partially saturated divalent hydrocarbon radical. For example, "C 1-6 "Alkylene" or "C 1- The term "C6 alkylene" refers to a straight or branched divalent hydrocarbon group having 1 to 6 carbon atoms, including but not limited to methylene, ethylene, propylene, 1-methylpropylene, and butylene.

[0200] "Benzo" alone or in combination refers to a divalent group C4H4=, one of which represents -CH=CH-CH=CH-, which forms a benzene-like ring when attached ortho to another ring, such as tetralin, indole, etc.

[0201] When used alone or as part of another substituent, 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.

[0202] The term "cycloalkyl" when used alone or as part of another substituent refers to a cyclic alkyl group. The term "mn-membered cycloalkyl" or "C m- n "Cycloalkyl" is understood to mean a saturated, unsaturated or partially saturated carbon ring having m to n atoms. For example, "3-15 membered cycloalkyl" or "C3-C 15 "Cycloalkyl" refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which may contain 1 to 4 rings. "3-10 membered cycloalkyl" contains 3-10 carbon atoms. It includes monocyclic, bicyclic, tricyclic, spirocyclic or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring. The cycloalkyl group may be substituted with one or more substituents. In some embodiments, the cycloalkyl group may be a cycloalkyl group fused to an aryl or heteroaryl ring group. The term "cycloalkyl" can be used interchangeably with the term "carbocyclyl".

[0203] The term "heterocycloalkyl" when used alone or as part of another substituent 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 "mn-membered heterocycloalkyl" or "C m-n"Heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms, wherein the heteroatoms are N, O, S, P, preferably N, O or S. For example, the term "4-8 membered heterocycloalkyl" or "C4-C8 heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 8 atoms, wherein 1, 2, 3 or 4 ring atoms are N, O, S, P, preferably N, O or S. "4-10 membered heterocyclyl" means a saturated, unsaturated or partially saturated ring having 4 to 10 atoms. In some embodiments, heterocycloalkyl can be A heterocycloalkyl group is a fused aromatic or heteroaromatic ring group. When a prefix such as 4-8 or 4-10 members is used to represent a heterocycloalkyl group, the number of carbon atoms is also meant to include heteroatoms. This includes monocyclic, bicyclic, tricyclic, spirocyclic, or bridged rings. Examples of heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, and oxazepanyl. The term "heterocycloalkyl" can be used interchangeably with the term "heteroalkane ring."

[0204] The term "alkenyl" when used alone or as part of another substituent refers to a linear or branched monovalent hydrocarbon radical of two to forty carbon atoms (e.g., C2-C6 alkenyl, for example, C2-C4 alkenyl) having at least one carbon-carbon sp2 double bond, and includes groups with "cis" and "trans" orientations or "E" and "Z" orientations. Examples of alkenyl groups include, but are not limited to, vinyl and allyl.

[0205] When alone or as part of other substituents, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of two to forty carbon atoms (e.g., C2-C6 alkynyl, and also C2-C4 alkynyl) having at least one carbon-carbon sp triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl and propynyl.

[0206] The term "alkoxy" when used alone or as part of another substituent refers to the group -OR Q , where R Q is an "alkyl" group as defined above.

[0207] The term "oxo" when used alone or as part of another substituent refers to the replacement of two hydrogen atoms on a methylene group by oxygen atoms, ie, the methylene group is replaced by a carbonyl group, representing =0.

[0208] The term "thio" by itself or as part of another substituent refers to the replacement of two hydrogen atoms on a methylene group with sulfur, representing =S.

[0209] The term "aromatic ring," when used alone or as part of another substituent, refers to a monocyclic or polycyclic carbocyclic ring having from 6 to 20 carbon atoms, at least one of which is aromatic. When one of the rings is non-aromatic, the group may be attached through either the aromatic ring or the non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthenyl. The term "aromatic ring" may be used interchangeably with the term "aryl group."

[0210] When used alone or as part of another substituent, the term "heteroaryl ring" refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is independently a heteroatom selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are C, wherein at least one ring is aromatic. The group may be a carbon group or a heteroatom group (i.e., it may be C-attached or N-attached, as long as it is possible). When one of the rings is non-aromatic, the group may be attached via either an aromatic ring or a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl, and tetrahydroquinoline. The term "heteroaromatic ring" may be used interchangeably with the terms "heteroaromatic ring," "heteroaryl," or "heteroaromatic ring group."

[0211] The term "bicyclic," when used alone or as part of another substituent, 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 rings can be aliphatic (e.g., decalin and norbornane), or aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic rings (e.g., tetralin).

[0212] Unless otherwise specified, the term "3-10 membered heterocycloalkenyl" by itself or in combination with other terms refers to 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 of the 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 may be optionally oxidized (i.e., C(=O), NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings, and any ring of this system is non-aromatic. In addition, with respect to the "3-10 membered heterocycloalkenyl", a heteroatom may occupy the position at which the heterocycloalkenyl is connected to the rest of the molecule. The 3-10 membered heterocycloalkenyl includes 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered and 10-membered heterocycloalkenyls, etc.

[0213] Bicyclic rings include (a) spirocyclic compounds, in which the two rings share only one single atom (the spiro atom, which is usually a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to:

[0214] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0215] (b) Fused rings, i.e., fused bicyclic compounds, wherein the 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 bicyclic rings include, but are not limited to:

[0216] and (c) bridged bicyclic compounds in which the two rings share three or more atoms and the two bridgehead atoms are separated by a bridge comprising 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 bicyclic rings include, but are not limited to:

[0217] When alone or as part of another substituent, NR f R f The group can be It may exist in the form of, or may include two R f The groups together form a ring which optionally contains N, O or S atoms and may also include groups such as:

[0218] When alone or as part of another substituent, the group N(C α-β Alkyl)C α-β Alkyl groups (wherein α and β are as defined above) include groups wherein two C α-β The alkyl groups together form a substituent of a ring (optionally containing N, O or S atoms) and include groups such as:

[0219] Compounds provided herein include intermediates that can be used to prepare compounds provided herein, which contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof."Protected derivatives" are compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as blocking groups). Suitable carboxyl moiety protecting groups include benzyl, tert-butyl, etc., and isotopes, etc. Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable hydroxyl protecting groups include benzyl, etc. Other suitable blocking groups are well known to those of ordinary skill in the art.

[0220] In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0221] In this application, the term "salt" or "pharmaceutically acceptable salt" includes 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 are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0222] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. These salts may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used in the identification, characterization, or purification of the compounds of the present invention.

[0223] The term "amine salt" refers to the product obtained by neutralizing an alkyl primary amine, secondary amine or tertiary amine with an acid, wherein the acid includes an inorganic acid or an organic acid as described in the present application.

[0224] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0225] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in one of the possible isomers or in a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric 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 (or centers) in the molecule. The prefixes D and L or (+) and (–) are used to designate the signs for the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0226] When bonds to chiral carbon atoms in the present formulae are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formula. The diagrammatic representation of racemates or enantiomerically pure compounds herein is adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0227] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties 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.

[0228] The term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.

[0229] The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl group or an amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or a free amino group, respectively.

[0230] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0231] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0232] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or cohesiveness, making the formulation more suitable for direct compression.

[0233] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0234] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0235] The term "patient" refers to any animal, preferably a mammal, that is about to be or has been administered a compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.

[0236] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art.

[0237] The reaction temperature and reaction time for each step can be appropriately selected based on the solvent, starting materials, reagents, and other factors. After the completion of each step, the target compound can be isolated and purified from the reaction system using conventional methods, such as filtration, extraction, recrystallization, washing, and silica gel column chromatography. The target compound can also be directly used in the next step without isolation or purification, provided this does not affect the next step.

[0238] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention. Beneficial effects

[0239] After extensive and in-depth research, the present inventors unexpectedly developed a class of deuterated heterocyclic compounds and their preparation methods and uses. The present invention provides a compound of 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 drugability; furthermore, the compound of the present invention has an excellent inhibitory effect on TNF-α secretion by human PBMCs stimulated by LPS; 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 the pharmacokinetic properties are more excellent; the compound of the present invention has lower toxicity to human hepatocytes and is expected to have better safety with long-term use; the compound of the present invention has lower gastrointestinal distribution in mice, with a significantly reduced tissue / plasma area under the curve ratio, and is expected to have less gastrointestinal side effects such as vomiting and diarrhea with long-term use, and is highly safe; in addition, the compound of the present invention has advantages such as high solubility, excellent oral absorption, and good clearance rate. DETAILED DESCRIPTION

[0240] The present invention will be further described below in conjunction 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 limiting the scope of protection of the present invention. Based on a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of protection of the present invention.

[0241] This application has the following definitions:

[0242] Symbol or unit:

[0243] IC50 : Half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0244] M: mol / L, for example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol / L

[0245] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0246] Reagents:

[0247] DCM: dichloromethane

[0248] DIPEA: N,N-diisopropylethylamine

[0249] DMF: N,N-dimethylformamide

[0250] TFA: trifluoroacetic acid

[0251] THF: Tetrahydrofuran

[0252] S-(-)-BINOL:S-1,1'-bino-2-naphthol

[0253] Ti(OiPr)4: Tetraisopropoxytitanium

[0254] Intermediate A1: Preparation of (5R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidine

[0255] The synthetic route of intermediate A1 is as follows:

[0256] Step 1: Synthesis of (1-aminocyclobutyl)methanol (Intermediate A1-2)

[0257] 1-Aminocyclobutanecarboxylic acid (15 g, 130.3 mmol) was dissolved in tetrahydrofuran (300 ml) at room temperature. Lithium aluminum hydride (2.5 M solution in tetrahydrofuran, 104 mL, 260 mmol) was added dropwise at 0°C under argon with stirring. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred under argon for 16 h. The reaction was quenched with solid sodium sulfate decahydrate in an ice bath, dried over anhydrous sodium sulfate, and filtered. The filter cake was rinsed with ethyl acetate. The combined filtrates were concentrated at room temperature to yield (1-aminocyclobutyl)methanol (Intermediate A1-2) (12 g, 90% yield).

[0258] Step 2: Synthesis of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (Intermediate A1-4)

[0259] Intermediates A1-2 (3 g, 29.7 mmol) and 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 on a silica gel column (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, 43% yield).

[0260] Step 3: Synthesis of (5R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidine (Intermediate A1)

[0261] 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. Tert-butyl peroxide (70% in water, 1.5 mL, 11 mmol) was added at 21°C and 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 give (5R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidine (Intermediate A1) (2.5 g, 87% yield).

[0262] Intermediate 2: 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (Intermediate B1)

[0263] The synthetic route is as follows:

[0264] Step 1: Synthesis of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Intermediate B-2)

[0265] 6-Oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (Compound 16-1) (5.00 g, 23.7 mmol) was dissolved in tetrahydrofuran (80 mL), and then lithium bis(trimethylsilyl)amide (4.75 g, 28.4 mmol) was added dropwise at -70 ° C. and reacted at 25 ° C for 1 hour. N-phenylbis(trifluoromethanesulfonyl)imide (9.30 g, 26.0 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to the reaction solution at -78 ° C., and then the temperature was raised to 25 ° C. and mixed for 2 hours. The reaction solution was quenched with ammonium chloride (100 mL), then extracted three times with ethyl acetate (300 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified on a silica gel column (petroleum ether: ethyl acetate (V / V) = 1:0-20:1) to obtain compound 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tert-butyl ester (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] tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Compound 16-2) (700 mg, 2.04 mmol), bis-pinacol boronate (569 mg, 2.24 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (47.6 mg, 102 umol), and potassium acetate (600 mg, 6.12 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 100°C under nitrogen for 10 hours. The reaction solution was filtered through celite and concentrated to give 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).

[0268] LC-MS, M / Z(ESI):266.2[M-56+H]

[0269] Step 3: Synthesis of tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (Intermediate B-4)

[0270] 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tert-butyl ester (Compound 16-3) (800 mg, 2.49 mmol) and 5-chloro-2-iodopyrimidine (718 mg, 2.99 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), and potassium carbonate (860 mg, 6.23 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (182 mg, 249 μmol) were added, and the reaction was carried out at 90 ° C under nitrogen protection for 5 hours. 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 on a silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-5:1) to obtain compound 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tert-butyl ester (Intermediate B-4) (312 mg, yield 41.7%). LC-MS, M / Z (ESI): 252.2 [M-55] + . 1 H NMR (400MHz, CDCl3) δ = 8.65 (s, 2H), 6.92 (s, 1H), 4.15 (d, 4H), 3.07 (s, 2H), 1.46 (s, 9H).

[0271] Step 4: Synthesis of tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate B-5)

[0272] 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tert-butyl ester (Compound 16-4) (400 mg, 1.30 mmol) was dissolved in methanol (10 mL). Tris(triphenylphosphine)rhodium chloride (120 mg, 130 umol) was added under nitrogen. The suspension was replaced with nitrogen and hydrogen three times, and then reacted at 50°C under a hydrogen pressure of 50 psi for 16 hours. The reaction solution was filtered, concentrated, and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:0-5:1) to obtain compound 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (Intermediate B-5) (360 mg, 94.0%). LC-MS, M / Z (ESI): 209.2 [M-100] + .

[0273] Step 5: Synthesis of 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (Intermediate B1)

[0274] 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (16-5) (360 mg, 1.16 mmol) was dissolved in methanol (10 mL), and a hydrochloric acid gas / methanol solution (4 M, 5 mL) was added. The mixture was reacted at 25°C for 5 hours. The reaction solution was concentrated to obtain compound 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] + .

[0275] Synthesis Route 1:

[0276] Example 1: Preparation of target compound 1

[0277] (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 (target compound 1)

[0278] The synthetic route of target compound 1 is as follows:

[0279] Tert-butyl 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (B-4) (6.80 g, 20.7 mmol) was dissolved in deuterated methanol-d4 (50.0 mL), and tris(triphenylphosphine)rhodium chloride (3.84 g, 4.15 mmol) was added. The atmosphere was replaced with inert gas and deuterium three times, respectively. The reaction was stirred at 50°C under a deuterium atmosphere of 50 psi for 20 hours. After completion of the reaction, the reaction solution was filtered and concentrated, and the crude product was purified 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, 79.5% yield). LC-MS, M / Z(ESI):312.3[M+H] + .

[0280] Step 2: Synthesis of 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-5,6-d2(1-6)

[0281] 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester-5,6-d2(5) (1.01 g, 3.24 mmol) was dissolved in dichloromethane (8.00 mL), and trifluoroacetic acid (2.00 mL) was added at 0°C. The reaction was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated and dried to give compound 6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-5,6-d2(1-6) (1.00 g, crude product). It was used directly in the next step. LC-MS, M / Z(ESI): 212.2[M+H] + .

[0282] 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]pyrimidine-5-oxide (target compound 1)

[0283] 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) solution, and 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. The reaction temperature was slowly raised to 100 ° C and stirred for 1 hour. After completion of the reaction, the reaction solution was concentrated and dried. The crude product was first separated and purified using a silica gel column (dichloromethane:methanol (V / V) = 1:0-10:1) and then separated and purified using high performance liquid chromatography (HPLC) using a Waters Xbridge 150*25mm*5μm column; solvent: A = water + ammonia (0.5%), B = acetonitrile; gradient: 20%-50% over 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, 36.4% yield). LC-MS, M / Z (ESI): 463.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.63(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)

[0284] Example 2: Synthesis of Compound 2

[0285] 2-(6-(5-chloropyrimidin-2-yl)-6-deuterated-2-azaspiro[3.3]hept-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine-5-oxide (target compound 2)

[0286] The synthetic route of compound 2 is as follows:

[0287] Step 1: 6-deuterated-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (Compound 2-2)

[0288] In a 100 mL single-necked bottle, tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g, 47.3 mmol) was dissolved in methanol (10 mL). Sodium deuterated borohydride (397 mg, 94.6 mmol) was slowly added in batches at room temperature. The reaction system was stirred at room temperature for 1 hour. The reaction apparatus was removed, and NH4Cl (aq. 10 mL) aqueous solution was slowly added. The mixture was extracted twice with ethyl acetate (10 mL * 2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the resulting mother liquor was spin-dried 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%).

[0289] Step 2: 6-deuterated 6-iodo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (Compound 2-3)

[0290] Compound 2-2 (1.0 g, 47.1 mmol) was added to a 100 mL single-necked flask and dissolved in Toluene (10.0 mL). Triphenylphosphine (1.83 g, 70.7 mmol), imidazole (477 mg, 70.7 mmol), and iodine (1.43 g, 56.5 mmol) were then slowly added to the reaction solution. The reaction system was heated to 120°C and stirred for 1 hour. After cooling, the reaction solution was filtered through celite and rinsed with ethyl acetate (20.0 mL). The mother liquor was spin-dried and the sample was then purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 1:0-20:1) to obtain the target compound, tert-butyl 6-deuterated-6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (compound 2-3) (1.0 g, yield 65.8%).

[0291] Step 3: 6-(5-chloropyrimidin-2-yl)-6-deuterated-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (Compound 2-4)

[0292] Compound 2-3 (6.0 g, 186 mmol) and zinc powder (1.2 g, 372 mmol) were added to a 250.0 mL three-necked flask and dissolved in a mixed solvent of DMAC (30.0 mL) and THF (30.0 mL). The system was replaced with N2 atmosphere three times, and then trimethylsilyl chloride (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 mmole) dissolved in DMAC (30.0 mL) and THF (300.0 mL) were added to the reaction solution. ol), after the addition was completed, the system was heated to 90 ° C and heated with stirring overnight. After the reaction solution was cooled, the reaction solution was filtered through diatomaceous earth, saturated NH4Cl solution (aq. 50.0 mL) was added to the mother liquor, extracted with ethyl acetate (50.0 mL), and the organic phase was washed and extracted with saturated brine (50.0 mL). The obtained organic phase was dried over anhydrous sodium sulfate and filtered, the mother liquor was spin-dried and mixed with the sample, and separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 30: 1-10: 1) to obtain the target compound 6- (5-chloropyrimidin-2-yl) -6- deuterated -2- azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (Compound 2-4) (3.7 g yield 65%).

[0293] Step 4: 6-(5-chloropyrimidin-2-yl)-6-deuterated-2-azaspiro[3.3]heptane hydrobromide (Compound 2-5)

[0294] Compound 2-4 (1.7 g, 54.8 mmol) was dissolved in DCM (20.0 mL) in a 10.0 mL single-necked vial. Boron tribromide (1.6 g, 65.7 mmol) was slowly added to the reaction solution, and the reaction system was stirred at room temperature for 2 hours. The reaction solution was directly spin-dried to dryness to obtain the target compound, 6-(5-chloropyrimidin-2-yl)-6-deuterated-2-azaspiro[3.3]heptane hydrobromide (Compound 2-5).

[0295] Step 5: 2-(6-(5-chloropyrimidin-2-yl)-6-deuterated-2-azaspiro[3.3]hept-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiophene[3,2-d]pyrimidine-5-oxide

[0296] Compound 2-5 (1.15 g, 55.3 mmol) was added to a 10 mL single-necked flask and dissolved in a mixed solvent of THF (20.0 mL) and H2O (10.0 mL). DIEA (2.56 g, 276.5 mmol) was then 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 organic phases were combined, anhydrous sodium sulfate (20.0 g) was added, dried and filtered, and the mother liquor was spin-dried and mixed with the sample. The mixture was separated and purified on a silica gel column to obtain the target compound (R)-2-(6-(5-chloropyrimidin-2-yl)-6-deuterated-2-azaspiro[3.3]hept-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiophene[3,2-d]pyrimidine-5-oxide (target compound 2) (604 mg, yield 55%).

[0297] LC-MS, M / Z (ESI): 462.39 (M+1).

[0298] 1 H NMR(400MHz, CDCl3)δ8.61(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).

[0299] Example 3: Preparation of target compound 3

[0300] (R)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-yl)-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (target compound 3)

[0301] The synthetic route of target compound 3 is as follows:

[0302] Step 1: Synthesis of (1-aminocyclobutyl)methane-d2-ol (Compound 3-2)

[0303] 1-Aminocyclobutanecarboxylic acid (Compound 3-1) (15.0 g, 130 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL) and cooled to 0°C in an ice-water bath. Deuterated lithium aluminum hydride (9.89 g, 260 mmol) was carefully added and allowed to react at 25°C for 10 hours. The reaction solution was cooled to 0°C and quenched by the careful addition of sodium sulfate decahydrate (20.0 g, 65.1 mmol) under a nitrogen stream. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to dryness to obtain (1-aminocyclobutyl)methane-d2-ol (Compound 3-2) as a yellow oil (14.5 g, crude product, used directly in the next step).

[0304] Step 2: Synthesis of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methane-d2-ol (Compound 3-3)

[0305] 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. The reaction solution was added to a saturated sodium bicarbonate solution (400 ml), extracted three times with ethyl acetate (900 mL), washed with saturated brine (1000 ml), dried over sodium sulfate, and concentrated. The crude product was separated and purified by silica gel column (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%).

[0306] Step 3: (R)-2-chloro-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxidation (Compound 3-4)

[0307] (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) and S-(-)-1,1'-Bi-2-naphthol (515 mg, 1.80 mmol) were dissolved in dichloromethane (50 mL). Titanium tetraisopropoxide (255 mg, 900 μmol, 265 μL) and water (324 mg, 18.0 mmol, 324 μL) were added and reacted at 20°C for 1 hour. The mixture was cooled to 0°C and then a 70% aqueous solution of tert-butyl peroxide (2.43 g, 18.9 mmol, 2.59 mL, 70%) was added. The reaction was continued at 25°C for 1.5 hours. The product solid precipitated from the reaction solution was filtered, and the filter cake was washed twice with ethyl acetate (10 mL) and 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%).

[0308] Step 4: Synthesis of (R)-2-(6-(5-chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane-2-yl)-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (target compound 3)

[0309] 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 1,4-dioxane (30 mL) solution containing (R)-2-chloro-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (64.4 mg, 219 umol), and the temperature was slowly raised to 100 ° C for 3 hours. The reaction solution was concentrated to dryness, 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]heptane-2-yl)-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (Compound 3) (1.00 g, yield 60.8%).

[0310] LC-MS, M / Z(ESI):463.2[M+H] +

[0311] 1 H NMR (400MHz, 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).

[0312] Example 4: Synthesis of Compound 4

[0313] 2-[6-(5-chloropyrimidin-2-yl)-6-deutero-2-azaspiro[3.3]hept-2-yl]-4-(((dideuterohydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (Compound 4)

[0314] The synthetic route is as follows:

[0315] In a 100 mL single-necked flask, the bromine compound of compound 2-5 (700 mg, 3.35 mmol) was dissolved in a mixed solvent of THF (5.0 mL) and H2O (5.0 mL). DIEA (2.14 g, 16.75 mmol) was then added to the reaction solution. After stirring for ten minutes, compound 3-4 (574 mg, 2.1 mmol) was added to the reaction solution, and the system was heated to 85 ° C and stirred overnight. After the reaction solution was cooled, H2O (10.0 mL) was added to the reaction solution, and the mixture was extracted twice with DCM (10.0 mL). The organic phases were combined, anhydrous sodium sulfate (10.0 g) was added, dried and filtered, and the mother liquor was spin-dried and mixed with the sample. The mixture was separated and purified on a silica gel column to obtain the target compound (R)-2-[6-(5-chloropyrimidin-2-yl)-6-deutero-2-azaspiro[3.3]hept-2-yl]-4-(((dideuterohydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (Compound 4) (740 mg, yield 80%).

[0316] LC-MS, M / Z (ESI): 464.2 (M+1).

[0317] 1H NMR(400MHz, CDCl3)δ8.61(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).

[0318] Example 5: Synthesis of Compound 7

[0319] (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)

[0320] The synthetic route of target compound 7 is as follows:

[0321] Step 1: Synthesis of diethyl cyclobutane-1,1-dicarboxylate-d6(7-2)

[0322] 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) were dissolved in anhydrous tert-butanol (10.0 mL), cooled to 0°C in an ice-water bath, and then sodium tert-butoxide (1.00 M, 21.1 mL, 2.20 eq) was added and the reaction was stirred at 90°C for 4 hours. After the reaction is completed, the reaction solution is concentrated and dried, then diluted with water (10.0 mL), extracted with dichloromethane (10.0 mL), and the organic phases are combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 1 / 0-10 / 1) to obtain compound cyclobutane-1,1-dicarboxylic acid diethyl ester-d6(7-2) (950 mg, yield 47.8%). 1 H NMR (400MHz, CDCl3) δ4.10-4.28(m,4H),1.24(t,6H).

[0323] Step 2: Synthesis of 1-(ethoxycarbonyl)cyclobutane-1-carboxylic acid-2,2,3,3,4,4-d6 acid (7-3)

[0324] Cyclobutane-1,1-dicarboxylic acid diethyl ester-d6 (7-2) (950 mg, 4.61 mmol) was dissolved in ethanol (6.00 mL) and cooled to 0°C in an ice-water bath. Aqueous potassium hydroxide solution (1.80 M, 2.81 mL) was carefully added and the reaction was stirred at 0°C for 5 hours and then at 25°C for 35 hours. After completion of the reaction, the reaction solution was concentrated to dryness, diluted with water (5.00 mL), and then adjusted to pH 2 with 1.00 M dilute hydrochloric acid. The solution was then extracted three times with ethyl acetate (30.0 mL). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give compound 1-(ethoxycarbonyl)cyclobutane-1-carboxylic acid-2,2,3,3,4,4-d6 acid (7-3) (470 mg, 57.2% yield).

[0325] Step 3: Synthesis of ethyl 1-((tert-butyloxycarbonyl)amino)cyclobutane-1-carboxylate-2,2,3,3,4,4-d6(7-4)

[0326] 1-(Ethoxycarbonyl)cyclobutane-1-carboxylic acid-2,2,3,3,4,4-d6 acid (7-3) (470 mg, 2.64 mmol) was dissolved in anhydrous tert-butanol (10.0 mL), and diphenylphosphoryl azide (762 mg, 2.77 mmol, 597 μL) and triethylamine (374 mg, 2.90 mmol, 505 μL) were added. The reaction was stirred at 25 ° C for 0.5 hours and then at 100 ° C for 4 hours. After completion of the reaction, the reaction solution was diluted with water (10.0 mL), and then extracted three times with ethyl acetate (30.0 mL). The organic phases were combined, washed with 5% aqueous citric acid solution (20.0 mL), saturated sodium bicarbonate (20.0 mL), and brine (30.0 mL), respectively, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified on a silica gel plate (petroleum ether: ethyl acetate (V / V) = 10:1) to give compound 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid ethyl ester-2,2,3,3,4,4-d6(7-4) (200 mg, yield 30.4%).

[0327] Step 4: Synthesis of tert-butyl (1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)carbamate (7-5)

[0328] 1-((tert-Butyloxycarbonyl)amino)cyclobutane-1-carboxylic acid ethyl ester-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 hours and then at 25°C for 1.5 hours. After the reaction was complete, the reaction solution was cooled to 10°C and quenched by the careful and slow addition of 1M citric acid (5.00 mL) under a nitrogen stream. The mixture was then extracted three times with ethyl acetate (30.0 mL). The organic phases were combined, washed with saturated sodium bicarbonate (20.0 mL) and brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and spin-dried to obtain tert-butyl (1-(hydroxymethyl)cyclobutyl-2,2,3,3,4,4-d6)carbamate (7-5) (200 mg, crude product). This was used directly in the next step.

[0329] Step 5: Synthesis of (1-aminocyclobutyl-2,2,3,3,4,4-d6)methanol hydrochloride (7-6)

[0330] 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). A 2.00 M dioxane hydrochloride solution (9.65 mL) was carefully added and the reaction was stirred at 25°C for 1 hour. After completion of the reaction, the reaction solution was concentrated and dried to give (1-aminocyclobutyl-2,2,3,3,4,4-d6) methanol hydrochloride (7-6) (200 mg, crude product). This was used directly in the next step.

[0331] 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)

[0332] (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 hours. After the reaction was completed, the reaction solution was diluted with water (10.0 ml) and then extracted three times with ethyl acetate (30.0 mL). The organic phases were combined, washed with saturated brine (30.0 ml), dried over sodium sulfate, and concentrated. The crude product was separated and purified on a silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1-1:1) to obtain the 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] + .

[0333] 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)

[0334] (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), and titanium tetraisopropoxide (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 hour, then cooled to 0°C, and 70% aqueous tert-butyl peroxide (26.2 mg, 204 μmol, 27.9 μL, 70.0%) was added. The reaction was stirred at 25°C for 1.5 hours. After the reaction was completed, a saturated aqueous sodium sulfite solution (10.0 mL) was added to the reaction solution to quench the reaction, which was then concentrated and dried. The crude product was separated and purified using a silica gel column (dichloromethane:methanol (V / V) = 1:0-10:1) to obtain 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, 70.0% yield). LC-MS, M / Z (ESI): 294.0 [M+H]+ .

[0335] 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)

[0336] (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, 136 μmol) was dissolved in 1,4-dioxane (5.00 mL) solution, followed by 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), and the reaction was stirred at 100 ° C for 2 hours. After the reaction was completed, the reaction solution was concentrated and dried, and the crude product was separated and purified by high performance liquid chromatography (column: Boston Green ODS150*30mm*5μm; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 15%-45%, 11 minutes) 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]pyrimidine-5-oxide (Compound 7) (17.0 mg, yield 27.6%).

[0337] LC-MS, M / Z(ESI):467.3[M+H] + . 1 H NMR(400MHz, CDCl3)δ8.63(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)

[0338] Example 6: Synthesis of the following compounds with reference to the preparation method of Example 1:

[0339] Synthesis of control compound 1:

[0340] The synthetic route is as follows:

[0341] Step 1: Synthesis of (R)-2-(6-(5-chloropyrimidin-2-yl)spiro[3.3]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (reference compound 1)

[0342] 6-(5-Chloropyrimidin-2-yl)-2-azaspiro[3.3]heptane (Intermediate B1) (60.0 mg, 219 umol) and diisopropylethylamine (141 mg, 1.10 mmol) were added to a 1,4-dioxane (10 mL) solution containing (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (64.4 mg, 219 umol) and the temperature was slowly raised to 100°C for 3 hours. The mixture was extracted three times with dichloromethane (60 mL), dried over sodium sulfate, and concentrated. 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 water, B = acetonitrile; gradient (acetonitrile): 18%-48%, 9 minutes) to obtain compound (R)-2-(6-(5-chloropyrimidin-2-yl)spiro[3.3]heptane-2-yl)-5-oxido-(6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino-cyclobutyl-methanol (reference compound 1). LC-MS, M / Z (ESI): 461.3 [M+H]. + . 1 H NMR(400MHz, 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).

[0343] Synthesis of control compound 2:

[0344] The synthetic route is as follows:

[0345] Step 1: Synthesis of tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

[0346] 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 Min THF) and Pd(dppf)Cl2 (2.2 g, 3.1 mmol) were added sequentially to 100 mL of anhydrous THF. The mixture was reacted at 50 ° C. under nitrogen protection for 16 h. The reaction system was cooled to room temperature and concentrated. The crude product was purified by silica gel column (PE / EA=6 / 1) to give tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (8.1 g, yellow oil).

[0347] Step 2: Synthesis of 6-(4-chlorophenyl)-2-azaspiro[3.3]heptane

[0348] 6-iodo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (4.5 g, 14.6 mmol) and BBr3 (5.5 g, 22 mmol) were added sequentially to 100 mL of dry DCM and reacted at room temperature for 4 hours. The reaction system was concentrated to obtain 6.1 g of a crude product as a light yellow oil, which was directly used for the next purification step.

[0349] Step 3: (R)-2-(6-(4-chlorophenyl-2-yl)-2-azaspiro[3.3]heptane-2-yl)-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxidation (reference compound 2)

[0350] 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 added sequentially to a mixture of THF / water (40 / 20 mL). The reaction system was incubated at 85°C for 2 hours, cooled to room temperature, and concentrated. The crude product was first purified by silica gel column chromatography to obtain the crude product, which was then separated and purified by Pre-HPLC and lyophilized to obtain (R)-2-(6-(4-chlorophenyl-2-yl)-2-azaspiro[3.3]heptane-2-yl)-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (reference compound 2) (1.2 g, 17.9% yield over two steps). LC-MS, M / Z (ESI): 459 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.25(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=9.8Hz,2H),2.30(t,4H),2.24–2.09(m,2H),2.03–1.81(m,2H).

[0351] Test Example 1: Inhibition of PDE4B2 and PDE4D2 Enzyme Activity by the Test Compound

[0352] The inhibitory activity of the compounds of the present invention on PDE4B2 and PDE4D2 can be detected by AMP-Glo TM Assay kit (Promega, V5011) was used for testing. All compounds were prepared in DMSO to a 20 or 25 mM stock solution. The test compounds were then serially diluted three-fold in DMSO to a 200X working solution in a compound plate. A 200X solution of Rolipram (2 mM) was prepared as a positive control, and 100% DMSO was used as a blank control. The compound plate was centrifuged at 1000 rpm for 1 minute. Using an Echo 550, 20 nL of the compound working solution was transferred to a 384 assay plate (Greiner, 784075). The plate was sealed and centrifuged at 1000 rpm for 1 minute. PDE4B2 enzyme (BPS bioscience, 60042) and PDE4D2 enzyme (BPS bioscience, 60048) were diluted to 2X working solution using ice-cold PDE assay buffer; 2 μL of 2X PDE4B2 (6.4 pg / μL) or 2X PDE4D2 (4 pg / μL) working solution was added to each well of the 384 assay plate, and the plate was sealed and equilibrated at room temperature for 10 minutes. Cyclic-3', 5'-AMP (sigma, A6882) was diluted to 2X working solution using PDE assay buffer; 2 μL of 2X Cyclic-3', 5'-AMP (2 μM) working solution was added to each well of the 384 assay plate and incubated at room temperature for 60 minutes. AMP-Glo ​​was used. TMAMP was detected using an assay kit (Promega, V5011). 4 μL of AMP-Glo ​​reagent I was added to each well of a 384-well 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 an Envision 2105 instrument, and the inhibition rate at different concentrations of the test compound was calculated as follows: Inhibition (%) = (1 – (RLU compound – RLU positive control) / (RLU blank control – RLU positive control)) × 100%. The experimental results were entered into GraphPad Prism software, and the IC values ​​of each compound were calculated by fitting. 50 The results show that the PDE4B2IC of each compound in the present invention 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.

[0353] Table 1. IC values ​​of compounds 50 value

[0354] 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.

[0355] Test Example 2: Pharmacokinetic Test

[0356] Minipig pharmacokinetic studies were conducted using male minipigs weighing 10-12 kg. Three minipigs per group were fasted and administered 10 mg / kg orally by gavage. Blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Three minipigs per group were administered intravenously at 3 mg / kg, and blood was collected before dosing and 5, 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Whole blood samples were anticoagulated in EDTA-K2 tubes and centrifuged at 1500-1600 g for 10 minutes at 4°C to separate plasma. All samples were stored at -80°C prior to analysis. Twenty microliters of plasma at each time point was added to 400 microliters of an acetonitrile-methanol solution containing an internal standard, vortexed, and centrifuged at 3700 rpm for 10 minutes. Fifty microliters of supernatant were added to 100 microliters of water, vortexed, and the appropriate amount of the mixture was used for LC-MS / MS analysis. The main plasma pharmacokinetic parameters were calculated using a non-compartmental model.

[0357] The experimental results show that the compound of the present invention exhibits excellent pharmacokinetic properties.

[0358] Test Example 3: Caco-2 cell permeability test

[0359] Caco-2 cells were cultured at a rate of 1 × 10 5 cells / cm 2 The cells were seeded onto 96-well Transwell plates and the culture medium was renewed every 4 to 5 days until the cells formed a dense monolayer membrane on the 28th day. The integrity of the Caco-2 cell membrane was verified using an HBSS solution containing 100 μM fluorescent yellow. The following test was then carried out in the presence and absence of Elacridar (10 μM): In groups A to B, the compound to be tested was added to the dosing side of the 96-well Transwel1 plate at a final concentration of 2 μM, and a buffer solution was added to the receiving side. The plate was then incubated in a CO2 incubator at 37°C and saturated humidity of 5% CO2 for 2 hours. At the end of incubation, samples were taken from both the dosing and receiving sides, all samples were mixed with acetonitrile containing the internal standard, centrifuged at 3200 g for 10 minutes, the supernatant was taken, and the compound concentration was then detected using LC-MS / MS. Groups B to A were tested using the same strips, and Papp (10 -6 cm / sec), efflux rate.

[0360] Apparent permeability coefficient (Papp) = (acceptor side volume) / (membrane area × incubation time) × (acceptor side drug concentration at the end of incubation) / (drug concentration on the administration side at the start of incubation)

[0361] Efflux rate (ER) = Papp (B-A) / Papp (A-B) .

[0362] The test results show that the compound of the present invention has good permeability.

[0363] Test Example 4: Inhibitory effect of the test compound on TNF-α secretion by LPS-stimulated human PBMC

[0364] 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 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 6cells / mL. Take a 96-well cell culture plate and add 100 μL PBMC cells to each well. Use 1640 complete medium to prepare a series of 4× working solutions of the test compound, add 50 μL of the compound working solution to the corresponding cell culture plate, and set up an LPS group (without compound) and a 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) from 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 value 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.

[0365] Inhibition rate=100%-(test compound-DMSO group) / (LPS group-DMSO group)*100%.

[0366] Table 2 Inhibitory effects of compounds on TNF-α secretion by LPS-stimulated human PBMC

[0367] The test results show that compared with the control compound 1, the compound of the present invention has a better inhibitory effect on the TNF-α secreted by human PBMC stimulated by LPS; the compounds 2 and 3 of the present invention have a better inhibitory effect on the TNF-α secreted by human PBMC stimulated by LPS, especially compound 3 has a great improvement in the effect on the TNF-α secreted by human PBMC stimulated by LPS and has a stronger anti-inflammatory effect.

[0368] Test Example 5: Pharmacokinetic Test

[0369] The pharmacokinetic study of monkey PK used male cynomolgus monkeys, 5-7 kg, fasted overnight. Three cynomolgus monkeys were taken and 10 mg / kg was orally administered by gavage. Blood was collected before administration and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. Whole blood samples were anticoagulated in EDTA-K2 test tubes and centrifuged at 4°C (1500-1600g) for 10 minutes to separate plasma. All samples were stored at -80°C before analysis and testing. 20 μL of plasma at each time point was taken, 400 μL of acetonitrile-methanol aqueous solution containing internal standard was added, mixed, vortexed, centrifuged at 3700 rpm for 10 minutes, 50 μL of supernatant was added to 100 μL of water, vortexed, and an appropriate amount of the mixture was taken for LC-MS / MS analysis. The main pharmacokinetic parameters of plasma were calculated using a non-compartmental model.

[0370] Table 3 Pharmacokinetic results of oral administration in cynomolgus monkeys

[0371] The PK test was conducted using monkeys whose metabolic characteristics are closer to those of humans. The results showed that the area under the curve (AUC0-t) and Cmax of the compound of the present invention were significantly improved, the clearance rate was lower, and it had better pharmacokinetic properties. The area under the curve (AUC) of compound 3 of the present invention was 0-t It is twice that of the control compound 1, and Cmax is also significantly increased. It has better oral absorption and lower clearance rate. The compound 3 of the present invention has better pharmacokinetic properties, and is expected to have a smaller dosage and lower side effects.

[0372] Test Example 6: In vitro toxicity evaluation of compounds on human HepG2 cells

[0373] HepG2 cells in the logarithmic growth phase were trypsinized and resuspended in MEM complete medium containing 10% FBS. 10,000 cells were seeded per well in a 96-well plate (no cells were seeded in the blank control group) with a seeding volume of 100 μL / well. The plates were incubated in a 37°C CO2 incubator for 24 h.

[0374] The test compound was prepared into a 50mM stock solution in DMSO solvent, diluted to an appropriate concentration using DMSO gradient, and then diluted 3 times using cell culture medium to a 2X concentration as the compound working solution. 100 μL of the test compound working solution was added to the corresponding wells of a 96-well plate (n=2), and a blank control group (cell culture medium with 0.5% DMSO) and a DMSO group (cell culture medium containing 0.5% DMSO) were set up at the same time. After incubation in a 37°C CO2 incubator for 72 hours, 100 μL of supernatant was aspirated from each well and discarded, and then 50 μL of CTG (Promega, G9243) was added to each well, placed on a microplate oscillator for 5 minutes, and after standing for 10 minutes, the luminescence value was read using an enzyme reader to calculate the inhibition rate of the test compound on human HepG2 cells. The inhibition IC value of the compound on human HepG2 cells was fitted based on the inhibition rate of different concentrations of the compound. 50 Inhibition rate = 100% - (test compound - blank control group) / (DMSO group - blank control group) * 100%

[0375] Table 4 In vitro toxicity evaluation results of compounds on HepG2 cells

[0376] 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. This shows that the compound of the present invention has lower toxicity to human liver cells and is expected to have better safety for long-term use.

[0377] Test Example 7: Mouse Tissue Distribution Detection

[0378] For the mouse tissue distribution test, ICR mice, 20-25 g, were fasted overnight. Eight male mice and four female mice were orally gavaged with 10 mg / kg. Blood, stomach, small intestine, large intestine and other tissues were collected 30 minutes and 1, 4, and 8 hours after administration. Two male mice and one female mouse were used at each time point. Whole blood samples were anticoagulated in EDTA-K2 test tubes and centrifuged at 4°C (1500-1600g) for 10 minutes to separate plasma. All plasma and tissue samples were stored at -80°C before analysis. The LC-MS / MS method was used to detect the concentration of compounds in mouse plasma, stomach, small intestine and large intestine homogenate samples, and the area under the concentration-time curve and the area under the curve ratio of tissue / plasma were calculated based on the compound concentration at different time points.

[0379] Table 5 Mouse tissue distribution test results

[0380] The test results show that the compound of the present invention has lower gastrointestinal distribution in mice, and the area under the curve ratio of tissue / plasma is significantly reduced. It is expected that long-term use will have less gastrointestinal side effects such as vomiting and diarrhea, and it is highly safe.

[0381] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify 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-alkylhydroxyl, 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 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, 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 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 halocycloalkyl, 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 are independently 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 are independently 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 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.

18. A compound according to any one of claims 1 to 15, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 16, for use in inhibiting PDE4B, and / or for preventing and / or treating a PDE4B-related disease, and / or for avoiding or reducing gastrointestinal side effects when treating a PDE4B-related disease.

19. A method for preventing and / or treating a PDE4B-related disease, and / or avoiding or reducing gastrointestinal side effects when treating a PDE4B-related disease, characterized in that: include: The compound of any one of claims 1 to 15, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of claim 16 is administered to a subject in need thereof.

20. The use according to any one of claims 17-18 or the method according to claim 19, 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.