Method for producing and using dihydrothienopyrimidine derivatives

Abstract

This invention provides compounds having a novel structure as PDE4B inhibitors, a method for producing these compounds, and their use in the treatment of PDE4B-mediated diseases. These compounds exhibit potent inhibitory effects against the PDE4B enzyme and have been experimentally confirmed to be promising compounds for the treatment of PDE4B-mediated diseases.

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical technology, and more particularly to compounds as PDE4B inhibitors, especially substituted dihydrothienoazaaryl derivatives, and methods and uses for producing their prodrugs. [Background technology]

[0002] Phosphodiesterases (PDEs) hydrolyze intracellular second messengers (cAMP, adenosine cyclic phosphate, or cGMP, guanosine cyclic phosphate), thereby degrading intracellular cAMP or cGMP and terminating the biochemical effects transmitted by these second messengers. cAMP and cGMP have important regulatory effects on cellular activity, and their concentration is regulated primarily by the balance between nucleotide cyclase synthesis and phosphodiesterase (PDE) hydrolysis. PDEs are widely distributed in the human body, and their physiological effects are involved in many research fields. Human PDE4 isozymes are classified into four subtypes: PDE4A, 4B, 4C, and 4D. PDE4 is involved in the hydrolysis of cAMP in various inflammatory cells; therefore, inhibition of PDE4 can inhibit immune and inflammatory cells.

[0003] Furthermore, literature has reported that PDE4 acts to regulate the calcium-induced calcium release process, and preferential inhibition of PDE4B maintains the therapeutic effect of pulmonary fibrosis.

[0004] Therefore, selective inhibitors of PDE4B are expected to be effective drugs for treating idiopathic pulmonary fibrosis and progressive fibrotic interstitial lung disease due to their dual inhibitory effects on inflammation and fibrosis. [Overview of the project] [Problems that the invention aims to solve]

[0005] The object of the present invention is to provide a novel PDE4B inhibitor compound, a method for producing the compound, and use in the treatment of PDE4B-mediated diseases. The novel compound is biochemically effective, has biological activity, and has good pharmacokinetic properties and low toxicity properties.

Means for Solving the Problems

[0006] The first aspect of the present invention provides a compound represented by the following formula (I), a stereoisomer, a tautomer or a mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound:

[0007]

Chemical formula

[0008] In the formula, X is selected from S, SO or SO2; Y is NR Y ; R Y is hydrogen or deuterium; Ring Q is: C 3-8 cycloalkyl, C 4-8 cycloalkenyl, 3- to 10-membered heterocyclyl, 5- to 6-membered heteroaryl, C 6-12 aryl; Each R Q is halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, phosphate group, carboxyl, -CN, -OH, -SH, -NO2, -NH2, -CONH2,

[0009]

Chemical formula

[0010] -L Y -OH, -L Y -SH, -L Y -C(O)OH, -L Y -NH-C(O)H, -L Y -C(O)NH2, -L Y-NHC(O)OH, -L Y -C(O)H,

[0011] [ka]

[0012] C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-6 cycloalkyl, C4-6 cycloalkenyl, 3-6 membered heterocyclyl, halo C1-3 alkyl, -L Y -OC(O)R d , -L Y -OC(O)OR d Selected from; preferably, each R Q Halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, phosphate group, carboxyl, -CN, -OH, -SH, -NO2, -NH2, -CONH2,

[0013] [ka]

[0014] -L Y -OH, -L Y -SH, -L Y -C(O)OH, -L Y -NH-C(O)H, -L Y -C(O)NH2, -L Y -NHC(O)OH, -L Y -C(O)H,

[0015] [ka]

[0016] C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-6 cycloalkyl, C4-6 cycloalkenyl, 3-6 membered heterocyclyl, halo C1-3 alkyl, -L Y-OC(O)R d Selected from; more preferably, each R Q Halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, phosphate group, carboxyl, -CN, -OH, -SH, -NO2, -NH2, -CONH2,

[0017] [ka]

[0018] -L Y -OH, -L Y -SH, -L Y -C(O)OH, -L Y -NH-C(O)H, -L Y -C(O)NH2, -L Y -NHC(O)OH, -L Y -C(O)H,

[0019] [ka]

[0020] Selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-6 cycloalkyl, C4-6 cycloalkenyl, 3-6 membered heterocyclyl, and halo-C1-3 alkyl;

[0021] L Y is optionally substituted C1-4 alkylene, C2-6 alkenylene, C2-6 alkylylene, or C1-4 alkylene oxy, where the optional substitution is optionally substituted with one or more substituents selected from halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, or halo-C1-3 alkyl;

[0022] L is a bond, or optionally substituted, C1-4 alkylene, C2-4 alkenylene, C2-4 alkylylene, or C1-4 alkylene oxy, where the optional substitution is one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, or halo-C1-6 alkyl;

[0023] Ring W is C 4-16 Cycloalkyl, C 4-16 Cycloalkenyls, saturated or partially unsaturated 4-18 member heterocyclyls, 5-16 member heteroaryls, C 6-18 It is an allele;

[0024] Each R w These are, independently, halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, acetamide, -CN, -OH, -SH, -NO2, -NH2, -CONH2, -Z-(R Z ) m , -NR b R c , -C(O)OR d , optionally substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, where the optional substitution is deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, -C(O)OR d , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12 Optionally substituted with one or more substituents selected from aryl, halo-C1-6 alkyl, halo-C1-6 alkoxy, halophenyl, and -O-C3-6 cycloalkyl; preferably, each R wThese are, independently, halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, -CN, -OH, -SH, -NO2, -NH2, -CONH2, -Z-(R Z ) m , optionally substituted, selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, where the optional substitutions are halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12 Optionally substituted with one or more substituents selected from aryl, halo-C1-6 alkyl, halo-C1-6 alkoxy, halophenyl, and -O-C3-6 cycloalkyl;

[0025] R b and R c Each is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C1-6 hydroxyalkyl, and halo-C1-6 alkyl;

[0026] R d H, C1-6 alkyl, C1-6 hydroxyalkyl, halo C1-6 alkyl, C 1-6 Selected from alkylaminos; preferably, R d This is selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, and halo-C1-6 alkyl;

[0027] Z is C 4-16 Cycloalkyl, C 4-16 Cycloalkenyls, saturated or partially unsaturated 4-18 member heterocyclyls, 5-16 member heteroaryls, C 6-12 It is an allele;

[0028] R ZThese are, independently, halogens, -CN, -OH, -SH, -NO2, -NH2, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, halo-C1-6 alkyl, halo-C1-6 alkoxy, saturated or partially unsaturated 4-6 membered heterocyclyl, and -OR Z1 , -NR Z2 R Z3 Selected from; R Z1 C 1-6 Alkyl, Halo C 1-6 Selected from alkyl; R Z2 , R Z3 These are H and C, respectively, independently. 1-6 Selected from alkyl groups; preferably, R Z Each is independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, halo-C1-6 alkyl, halo-C1-6 alkoxy; more preferably, R Z Each is independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 hydroxyalkyl, halo-C1-6 alkyl, and halo-C1-6 alkoxy;

[0029] n is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, 4, or 5;

[0030] however, (1) If L is a bond,

[0031] [ka]

[0032] Not; (2) L is a bond,

[0033] [ka]

[0034] If R w is a substituted phenyl or

[0035] [ka]

[0036] Not; (3) When X is SO and L is a bond,

[0037] [ka]

[0038] Not either of the following; or (3')X is SO and L is a bond,

[0039] [ka]

[0040] Not either of the following; (4) If X is S or SO2 and L is a bond, then ring Q and ring W are not substituted phenyl at the same time; or if X is S and L is a bond and ring Q is phenyl, then ring W is

[0041] [ka]

[0042] Not; and (5) If X is S or SO2 and L is a bond, then ring Q is

[0043] [ka]

[0044] Not; The heteroatoms in the heterocyclyl and heteroaryl are independently selected from O, N, or S, and the number of heteroatoms is preferably 1, 2, or 3.

[0045] In a preferred embodiment of the present invention, R Y It is deuterium; In a preferred embodiment of the present invention, R Y is hydrogen; In a preferred embodiment of the present invention, Y is NH; In a preferred embodiment of the present invention, X is S; In a preferred embodiment of the present invention, X is SO; In a preferred embodiment of the present invention, X is SO2; In a preferred embodiment of the present invention, ring Q is C 4-6 Cycloalkyl, C 4-6 Cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, and phenyl; In a preferred embodiment of the present invention, ring Q is C 4-6 It is a cycloalkyl, 3-6 membered heterocyclyl, or phenyl; In preferred embodiments of the present invention, ring Q is cyclobutyl, cyclohexenyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, phenyl, or tetrahydropyranyl;

[0046] In a preferred embodiment of the present invention, each R Q These are, independently, halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, phosphate group, carboxyl, -CN, -OH, -SH, -NO2, -NH2, -CONH2,

[0047] [ka]

[0048] C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 alkylthio, C3-6 cycloalkyl, C3-6 cycloalkenyl, 3-6 member heterocyclyl, halo C1-3 alkyl, -L Y -OC(O)R d , -L Y -OC(O)OR d and;

[0049] In a preferred embodiment of the present invention, each R Q is independently halogen, oxo, acetyl,

[0050]

Chemical formula

[0051] -L Y -OH, -L Y -C(O)OH, C1-3 alkyl, C3-6 cycloalkyl, 3-6 member heterocyclyl, -L Y -OC(O)R d , -L Y -OC(O)OR d and;

[0052] In a preferred embodiment of the present invention, each R Q is independently halogen, oxo, acetyl,

[0053]

Chemical formula

[0054] -L Y -OH, -L Y -C(O)OH, C1-3 alkyl, C3-6 cycloalkyl, -L Y -OC(O)R d , -L Y -OC(O)OR d and;

[0055] In a preferred embodiment of the present invention, each R QThese are hydroxymethyl, carboxymethyl, and acetyl, respectively, independently.

[0056] [ka]

[0057] and; In a preferred embodiment of the present invention, L Y is an optionally substituted C1-4 alkylene, where the optionally substituted is one or more substituents selected from halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, and halo-C1-3 alkyl;

[0058] In a preferred embodiment of the present invention, L Y A C1-2 alkylene is optionally substituted, where the optionally substituted substituent is optionally substituted with one or more substituents selected from halogens, -OH, -SH, -NH2, C1-3 alkyl, and halo-C1-3 alkyl;

[0059] In a preferred embodiment of the present invention, L Y is optionally substituted methylene, ethylene, where the optionally substituted is optionally substituted with one or more substituents selected from halogen, -OH, -SH, methyl, and ethyl;

[0060] In a preferred embodiment of the present invention,

[0061] [ka]

[0062] In a preferred embodiment of the present invention,

[0063] [ka]

[0064] In a preferred embodiment of the present invention,

[0065] [ka]

[0066] In preferred embodiments of the present invention, L is a bond or optionally substituted C1-3 alkylene, C2-4 alkenylene, or C2-4 alkynylene, where the optional substitution is optionally substituted with one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -SH, -NH2, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 alkylthio, C3-8 cycloalkyl, or halo-C1-3 alkyl;

[0067] In a preferred embodiment of the present invention, L is a bond or optionally substituted C2-4 alkenylene, C2-4 alkynylene, where the optional substitution is optionally substituted with one or more substituents selected from deuterium, -CN, -OH, -SH, -NH2, and C1-3 alkyl;

[0068] In a preferred embodiment of the present invention, L is a bond or optionally substituted vinyl, propenyl, ethynyl, or propynyl, where the optionally substituted is optionally substituted with one or more substituents selected from deuterium, -CN, -OH, -SH, -NH2, and C1-3 alkyl;

[0069] In a preferred embodiment of the present invention, L is a bond; In a preferred embodiment of the present invention, L is ethynyl;

[0070] In a preferred embodiment of the present invention, L is optionally substituted propynyl, where the optional substitution is optionally substituted with one or more substituents selected from deuterium, -CN, -OH, -SH, -NH2, and C1-3 alkyl;

[0071] In a preferred embodiment of the present invention, ring W is C 4-12Cycloalkyl, C 4-12 Cycloalkenyls, saturated or partially unsaturated 4-12 member heterocyclyls, 5-16 member heteroaryls, C 6-12 It is an allele;

[0072] In a preferred embodiment of the present invention, ring W is C 4-10 Monocyclic cycloalkyl, C 5-12 Bicyclic cycloalkyl, C 9-12 Tricyclic cycloalkyl, C 4-10 Monocyclic cycloalkenyl, C 7-12 Bicyclic cycloalkenyl, C 9-12 These include tricyclic cycloalkenyls, saturated or partially unsaturated 4-12 member monocyclic heterocyclyls, saturated or partially unsaturated 7-12 member bicyclic heterocyclyls, saturated or partially unsaturated 9-12 member tricyclic heterocyclyls, 5-8 member monocyclic heteroaryls, 9-16 member bicyclic heteroaryls, 9-16 member tricyclic heteroaryls, phenyls, and naphthyls;

[0073] In a preferred embodiment of the present invention, ring W is C 4-5 Monocyclic cycloalkyl, C 5-10 Bicyclic cycloalkyl, C 4-8 Monocyclic cycloalkenyl, C 7-10 These include bicyclic cycloalkenyls, saturated or partially unsaturated 4-8 membered monocyclic heterocyclyls, saturated or partially unsaturated 7-12 membered bicyclic heterocyclyls, 5-6 membered monocyclic heteroaryls, 9-16 membered bicyclic heteroaryls, phenyls, and naphthyls;

[0074] In a preferred embodiment of the present invention, ring W is

[0075] [ka]

[0076] In a preferred embodiment of the present invention, ring W is

[0077] [ka]

[0078] In a preferred embodiment of the present invention, ring W is

[0079] [ka]

[0080] In a preferred embodiment of the present invention, ring W is

[0081] [ka]

[0082] In a preferred embodiment of the present invention, ring W is

[0083] [ka]

[0084] In a preferred embodiment of the present invention, ring W is

[0085] [ka]

[0086] In a preferred embodiment of the present invention, ring W is [ka]

[0087] In a preferred embodiment of the present invention, ring W is [ka]

[0088] In a preferred embodiment of the present invention, ring W is

[0089] [ka]

[0090] In a preferred embodiment of the present invention, ring W is [Chemical formula]

[0091] In a preferred embodiment of the present invention,

[0092] [Chemical formula]

[0093] In a preferred embodiment of the present invention, [Chemical formula]

[0094] In a preferred embodiment of the present invention, [Chemical formula]

[0095] In a preferred embodiment of the present invention, each R w is independently halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, acetamide, -CN, -OH, -SH, -NO2, -CONH2, -Z-(R Z ) m , -NR b R c , -C(O)OR d, optionally substituted, C1-6 alkyl, C1-6 alkoxy selected, where optionally substituted are deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12 Optionally substituted with one or more substituents selected from aryl, halo-C1-6 alkyl, halo-C1-6 alkoxy, halophenyl, and -O-C3-6 cycloalkyl;

[0096] R b and R c Each is independently selected from H, C1-3 alkyl, C1-3 hydroxyalkyl, and halo-C1-3 alkyl;

[0097] R d This is selected from H, C1-3 alkyl, C1-3 hydroxyalkyl, and halo-C1-3 alkyl;

[0098] In a preferred embodiment of the present invention, each R w These are, independently, halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, -CN, -OH, -SH, -NO2, -NH2, -CONH2, -Z-(R Z ) m , optionally substituted, selected from C1-6 alkyl, C1-6 alkoxy, where the optional substitutions are halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12 Optionally substituted with one or more substituents selected from aryl, halo-C1-6 alkyl, halo-C1-6 alkoxy, halophenyl, and -O-C3-6 cycloalkyl;

[0099] Z is C 4-10 Cycloalkyl, C 4-10 Cycloalkenyls, saturated or partially unsaturated 4-12 member heterocyclyls, 5-12 member heteroaryls, C 6-12 It is an allele;

[0100] R Z These are, independently, halogens, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 alkoxy, C1-3 hydroxyalkyl, halo-C1-3 alkyl, halo-C1-3 alkoxy, saturated or partially unsaturated 4-6 membered heterocyclyl, and -OR Z1 , -NR Z2 R Z3 Selected from;

[0101] R Z1 C 1-3 Alkyl, Halo C 1-3 Selected from alkyl groups;

[0102] R Z2 , R Z3 These are H and C, respectively, independently. 1-3 Selected from alkyl groups;

[0103] In a preferred embodiment of the present invention, each R w These are, independently, halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, -CN, -OH, -SH, -NO2, -NH2, -CONH2, -Z-(R Z ) m , optionally substituted, selected from C1-6 alkyl, C1-6 alkoxy, where the optional substitutions are halogen, -CN, -OH, -SH, -NO2, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12Optionally substituted with one or more substituents selected from aryl, halo-C1-6 alkyl, halo-C1-6 alkoxy, halophenyl, and -O-C3-6 cycloalkyl;

[0104] Z is a saturated or partially unsaturated 4-12 member heterocyclyl, 5-12 member heteroaryl, C 6-12 It is a member;

[0105] R Z These are, independently, halogens, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 alkoxy, C1-3 hydroxyalkyl, halo-C1-3 alkyl, halo-C1-3 alkoxy, saturated or partially unsaturated 4-6 membered heterocyclyl, and -OR Z1 , -NR Z2 R Z3 Selected from;

[0106] R Z1 C 1-3 Alkyl, Halo C 1-3 Selected from alkyl groups;

[0107] R Z2 , R Z3 These are H and C, respectively, independently. 1-3 Selected from alkyl groups;

[0108] In a preferred embodiment of the present invention, each R w These are, independently, halogen, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, -CN, -OH, -SH, -NH2, -Z-(R Z ) m , or optionally substituted, selected from C1-4 alkyl, C1-4 alkoxy, where the optional substitutions are halogen, -CN, -OH, -SH, -NO2, -NH2, -CONH2, C1-3 alkyl, C1-3 alkoxy, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12Optionally substituted with one or more substituents selected from aryl, halo C1-3 alkyl, halo C1-3 alkoxy, halophenyl;

[0109] Z is 5-6 member heteroaryl, phenyl;

[0110] R Z is each independently halogen, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, halo C1-3 alkyl, halo C1-3 alkoxy, saturated or partially unsaturated 4-6 member heterocyclyl, -OR Z1 -NR Z2 R Z3 selected from;

[0111] R Z1 is C 1-3 alkyl, halo C 1-3 alkyl selected from;

[0112] R Z2 R Z3 are each independently H, C 1-3 alkyl selected from;

[0113] In a preferred embodiment of the present invention, each R w is each independently halogen, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, -CN, -OH, -SH, -NH2, -Z-(R Z ) m optionally substituted, selected from C1-4 alkyl, C1-4 alkoxy, where optionally substituted is with one or more substituents selected from halogen, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, 3-8 member heterocyclyl, 5-6 member heteroaryl, C 6-12 aryl, halo C1-3 alkyl, halo C1-3 alkoxy, halophenyl;

[0114] Z is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, or phenyl;

[0115] R Z These are, independently, halogens, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, halo-C1-3 alkyl, halo-C1-3 alkoxy, saturated or partially unsaturated 4-6 membered heterocyclyl, and -OR Z1 , -NR Z2 R Z3 Selected from;

[0116] R Z1 C 1-3 Alkyl, Halo C 1-3 Selected from alkyl groups;

[0117] R Z2 , R Z3 These are H and C, respectively, independently. 1-3 Selected from alkyl groups;

[0118] In a preferred embodiment of the present invention, each R w These are independently methanesulfonamide, ethanesulfonamide, F, Cl, -CN, -OH, -SH, -NH2, -Z-(R Z ) m , or optionally substituted, selected from methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, where optionally the substitution is optionally substituted with one or more substituents selected from halogen, -CN, -OH, -NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy;

[0119] In a preferred embodiment of the present invention, -Z-(R Z ) m teeth,

[0120] [ka]

[0121] In a preferred embodiment of the present invention, each R w Each is independently selected from methylsulfonyl, methanesulfonamide, -F, -Cl, -CN, -OH, -SH, -NH2, -CF3, and -CH3;

[0122] In a preferred embodiment of the present invention, each R w Each is independent of the others.

[0123] [ka]

[0124] In a preferred embodiment of the present invention, each R w Each is independent of the others.

[0125] [ka]

[0126] In a preferred embodiment of the present invention, m is 1, 2, or 3; In a preferred embodiment of the present invention, m is 1 or 2; In a preferred embodiment of the present invention, n is 0, 1, 2, or 3; In a preferred embodiment of the present invention, n is 0, 1, or 2; In a preferred embodiment of the present invention, n is 1 or 2; In a preferred embodiment of the present invention, q is 0, 1, 2, or 3; In a preferred embodiment of the present invention, q is 0, 1, or 2; In a preferred embodiment of the present invention, q is 1 or 2;

[0127] The present invention further provides compounds represented by formulas (IA), (IB), and (IC), stereoisomers, tautomers, or mixtures thereof of said compounds, or pharmaceutically acceptable salts thereof:

[0128] [ka]

[0129] In the formula, X, q, R Q , ring Q, n, R W The ring W is as shown in compound (I);

[0130] The present invention further provides compounds represented by formulas (II-A) to (II-E), stereoisomers, tautomers, or mixtures thereof of said compounds, or pharmaceutically acceptable salts of said compounds:

[0131] [ka]

[0132] In the formula, X, n, R W , Ring W, R Q q is as in the compound of formula (I);

[0133] The present invention further provides compounds represented by formulas (III-A) to (III-H), stereoisomers, tautomers, or mixtures thereof of the said compounds, or pharmaceutically acceptable salts thereof:

[0134] [ka]

[0135] In the formula, n, R W , Ring W, R Q q is as follows:

[0136] S* is a chiral sulfur atom;

[0137] In a preferred embodiment of the present invention, S* is a chiral sulfur atom having an R / S-enantiomer; In a preferred embodiment of the present invention, S* is a chiral sulfur atom having an R-enantiomer. In a preferred embodiment of the present invention, S* is a chiral sulfur atom having an S-enantiomer;

[0138] The present invention further provides compounds represented by formulas (IV-A) to (IV-E), stereoisomers, tautomers, or mixtures thereof of the said compounds, or pharmaceutically acceptable salts thereof:

[0139] [ka]

[0140] In the formula, n, R W Ring W is as in the compounds of formula (I), (II-A)~(II-E), and (III-A)~(III-H);

[0141] In a preferred embodiment of the present invention, in formula (IV-A) or formula (IV-E),

[0142] [ka]

[0143] In a preferred embodiment of the present invention, in formula (IV-A) or formula (IV-E),

[0144] [ka]

[0145] And; moreover, Rw is Z-(R Z ) m and;

[0146] In a preferred embodiment of the present invention, in formula (IV-A) or formula (IV-E),

[0147] [ka]

[0148] Preferred embodiments of the present invention can be obtained by arbitrarily combining the above preferred conditions based on the ordinary knowledge of the art.

[0149] Preferably, the present invention provides compounds having the following structures, or stereoisomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts of said compounds:

[0150] [ka]

[0151] [ka]

[0152] [ka]

[0153] [ka]

[0154] [ka]

[0155] The object of the present invention further includes providing a method for producing a compound represented by the above general formula, stereoisomers, tautomers, or mixtures thereof of the compound, or a pharmaceutically acceptable salt of the compound.

[0156] Compounds of the general formula can be prepared by a variety of methods, including, but not limited to, the following methods.

[0157] Scheme 1:

[0158] [ka]

[0159] However, M is ligand-containing boron or metal.

[0160] Z is a leaving group such as a halogen, sulfonic acid ester, alkylthio, alkylthioacyl, or alkylsulfinyl.

[0161] Scheme 2:

[0162] [ka]

[0163] Here, Z is a leaving group such as a halogen, sulfonic acid ester, alkylthio, alkylthioacyl, or alkylsulfinyl.

[0164] The present invention also provides pharmaceutical compositions comprising the compound of the present invention, stereoisomers, tautomers, or mixtures thereof of the compound, or pharmaceutically acceptable salts thereof.

[0165] The present invention also provides a pharmaceutical composition comprising the compound of the present invention, stereoisomers, tautomers, or mixtures thereof of the compound, or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable excipient.

[0166] The object of the present invention further includes providing the use of the compound of the present invention, stereoisomers, tautomers, or mixtures thereof of the compound, or pharmaceutically acceptable salts of the compound, in the manufacture of a pharmacopoeia for the treatment or prevention of PDE4B-mediated diseases.

[0167] In some embodiments, the PDE4B-mediated disease is a fibrosis-related disease or an immune-inflammatory disease.

[0168] In some embodiments, PDE4B-mediated diseases include respiratory diseases, gastrointestinal diseases, inflammatory diseases, allergic diseases, autoimmune diseases, or cancer.

[0169] Preferably, the respiratory disease is selected from respiratory or pulmonary diseases involving increased mucus production, respiratory inflammation, and / or obstructive disease; more preferably, the respiratory disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, interstitial pneumonia, chronic obstructive pulmonary disease (COPD), alpha-antitrypsin deficiency, chronic sinusitis, asthma, or chronic bronchitis;

[0170] Preferably, the gastrointestinal disorder is selected from ileitis, ulcerative colitis, or Crohn's disease;

[0171] Preferably, the inflammatory disease is selected from dry eye syndrome or glaucoma;

[0172] Preferably, the autoimmune disease is selected from systemic lupus erythematosus, atopic dermatitis, seborrheic dermatitis, psoriasis, urticaria, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis, or diffuse connective tissue diseases such as xerosis.

[0173] More preferably, in some embodiments, the PDE4B-mediated disease is chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, asthma, or interstitial lung disease.

[0174] An object of the present invention is to provide a method for the prevention and / or treatment of PDE4B-mediated diseases, the method comprising administering to a patient a therapeutically effective amount of the compound of the present invention, a stereoisomer, a tautomer or mixture thereof of said compound, or a pharmaceutically acceptable salt of said compound, or a pharmaceutical composition of the present invention.

[0175] The compounds of the present invention, stereoisomers, tautomers, or mixtures thereof of said compounds, or pharmaceutically acceptable salts of said compounds are administered in combination with other fibrotic agents or immunoinflammatory inhibitors for the treatment or prevention of PDE4B-mediated diseases.

[0176] When the compound of the present invention, a stereoisomer, tautomer, or mixture thereof of said compound, or a pharmaceutically acceptable salt of said compound is administered in combination with other inhibitory agents for the treatment of fibrosis or immunoinflammation, the compound of the present invention or a pharmaceutically acceptable salt thereof may provide an enhancement of the therapeutic effect of PDE4B-mediated diseases, such as the therapeutic effect of antifibrosis or anti-immunoinflammation.

[0177] definition The term "alkyl," unless otherwise specified, refers to a monovalent saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C1-10 alkyl), more preferably containing 1 to 8 carbon atoms (C1-8 alkyl), and more preferably containing 1 to 6 carbon atoms (i.e., C1-6 alkyl). For example, "C1-6 alkyl" refers to an alkyl group in which the number of carbon atoms on the carbon chain is between 1 and 6 (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, and n-octyl.

[0178] The term "alkenyl," unless otherwise specified, refers to an unsaturated aliphatic hydrocarbon group having at least one double bond in a straight or branched chain consisting of carbon atoms and hydrogen atoms. Alkenyls may include 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C2-10 alkenyls), more preferably 2 to 8 carbon atoms (C2-8 alkenyls), more preferably 2 to 6 carbon atoms (i.e., C2-6 alkenyls), 2 to 5 carbon atoms (i.e., C2-5 alkenyls), 2 to 4 carbon atoms (i.e., C2-4 alkenyls), 2 to 3 carbon atoms (i.e., C2-3 alkenyls), and 2 carbon atoms (i.e., C2 alkenyls). For example, "C2-6 alkenyl" means that the group is an alkenyl group and the number of carbon atoms on the carbon chain is 2 to 6 (specifically, 2, 3, 4, 5, or 6). Non-exclusive examples of alkenyls include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0179] The term "alkynyl," unless otherwise specified, refers to an unsaturated aliphatic hydrocarbon group having at least one triple bond in a straight or branched chain consisting of carbon atoms and hydrogen atoms. An alkynyl group may include 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C2-10 alkynyl), more preferably 2 to 8 carbon atoms (C2-8 alkynyl), more preferably 2 to 6 carbon atoms (i.e., C2-6 alkynyl), 2 to 5 carbon atoms (i.e., C2-5 alkynyl), 2 to 4 carbon atoms (i.e., C2-4 alkynyl), 2 to 3 carbon atoms (i.e., C2-3 alkynyl), or 2 carbon atoms (i.e., C2 alkynyl). For example, "C2-6 alkynyl" means that the group is an alkynyl and has 2 to 6 carbon atoms on the carbon chain (specifically 2, 3, 4, 5, or 6). Non-exclusive examples of alkynyls include, but are not limited to, ethynnyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0180] The term "cycloalkyl" refers, unless otherwise specified, to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic groups (e.g., bicyclic and tricyclic groups), and includes condensed cycloalkyl groups, crosslinked cycloalkyl groups, or spirocycloalkyl groups.

[0181] For example, a cycloalkyl group may contain 3 to 16 carbon atoms (e.g., 3 to 10, further e.g., 3 to 8, further e.g., 3 to 6, 3 to 5, or 3 to 4). Further examples include monocyclic groups containing 3 to 12 carbon atoms (e.g., 3 to 10, further e.g., 3 to 8, or 3 to 6). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Specifically, examples of saturated monocyclic cycloalkyl groups (e.g., C3-8 cycloalkyl groups) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In preferred embodiments, the cycloalkyl is a monocyclic ring (abbreviated as C3-6 cycloalkyl) containing 3 to 6 carbon atoms, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyls include those arranged as condensed bicyclic rings selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or those arranged as bridging bicyclic rings selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane, having 5 to 12, further 7 to 12, or 5 to 10 ring atoms. Further examples of bicyclic cycloalkyls include those arranged as bicyclic rings selected from the [5,6] and [6,6] ring systems. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but not fully conjugated and not aromatic (aromatic is as defined herein).

[0182] The term "spirocycloalkyl group" includes cyclic structures that contain carbon atoms and are formed by at least two rings sharing one atom. For example, the term "7-12 member spirocycloalkyl group" refers to a cyclic structure that contains 7 to 12 carbon atoms and is formed by at least two rings sharing one atom.

[0183] The term "condensed cycloalkyl group" refers to a condensed ring formed by two or more rings containing carbon atoms and sharing two adjacent atoms. For example, the term "5-10 membered condensed cycloalkyl group" refers to a condensed ring formed by two or more rings containing 5 to 10 ring carbon atoms and sharing two adjacent atoms.

[0184] Examples include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo-3 to 8-membered cycloalkyls, benzo-C4-6 cycloalkenyls, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, and 1,4-dihydronaphthyl. Preferred embodiments are 8 to 9-membered fused rings, referring to cyclic structures containing 8 to 9 ring atoms in the examples above.

[0185] The term "crosslinked cycloalkyl group" includes a cyclic structure formed by two rings containing carbon atoms and sharing two non-adjacent atoms. The term "7-10 membered crosslinked cycloalkyl group" includes a cyclic structure formed by two rings containing 7 to 12 carbon atoms and sharing two non-adjacent atoms.

[0186] The term "cycloalkenyl group" refers to a non-aromatic cyclic alkyl group having one or more rings and at least one double bond, preferably one to two double bonds, and having 4 to 16, for example, 4 to 12 carbon atoms. In one embodiment, the cycloalkenyl is cyclopentenyl (1-cyclopente-1-enyl, 1-cyclopente-2-enyl, 1-cyclopente-3-enyl) or cyclohexenyl (1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl), preferably cyclohexenyl.

[0187] The term "oxaalkyl," unless otherwise specified, refers to alkyl residues in which one or more carbon atoms (and their associated hydrogen atoms) are substituted with oxygen, such as "alkoxy" and "alkoxyalkyl." Examples include methoxy, ethoxy, propoxy, and methoxypropyl groups. The term oxaalkyl is understood in the context of the art and refers to compounds in which oxygen is bonded to an adjacent atom by a single bond (forming an ether bond), as is the case in "Naming and Indexing of Chemical Substances for Chemical Abstracts (American Chemical Society), 196, not limited to 127(a)"; this does not refer to double-bonded oxygen found in carbonyl groups.

[0188] The term "alkoxy" refers to an -O-alkyl group unless otherwise specified, and the alkyl group is as defined above, i.e., it contains 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6 carbon atoms). Typical examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, and 1-ethylpropoxy groups.

[0189] The terms "thiaalkyl" and "oxaalkyl" mean, unless otherwise specified, the conversion of oxygen in the above-mentioned "oxaalkyl" to sulfur or nitrogen.

[0190] The term "halogen" or "halo" refers to F, Cl, Br, and I unless otherwise specified. The term "haloalkyl" means that one, two, or more hydrogen atoms, or all of the hydrogen atoms in the alkyl group defined above, are substituted with halogens. Typical examples of haloalkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0191] The term "heterocyclic group," unless otherwise specified, refers to a saturated or partially unsaturated monocyclic, dicyclic, or polycyclic hydrocarbon substituent, which has a non-aromatic structure and contains 3 to 20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O, or S, and the other ring atoms are C. Preferably, it contains 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The heteroatoms are preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidyl, imidazolidinyl, tetrahydrofuran, dihydropyrrole, piperidinyl, piperazinyl, and pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused, and bridged fused heterocyclic groups.

[0192] The term “heterocyclyl” or “heterocyclic” refers, unless otherwise specified, to a non-aromatic heterocyclyl having one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and including monocyclic rings, fused rings, bridging rings, and spirocyclic rings, i.e., containing monocyclic heterocyclyls, bridging heterocyclyls, spiroheterocyclyls, and fused heterocyclic groups.

[0193] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. Heterocyclic groups can be saturated or partially saturated.

[0194] Examples of exemplary monocyclic 4- to 18-membered heterocyclyl groups include (numbered from the bond position assigned priority 1) pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpho Phosphate-2-yl, Morpholin-3-yl, Oxyranil, Aziridin-1-yl, Aziridin-2-yl, Azocan-1-yl, Azocan-2-yl, Azocan-3-yl, Azocan-4-yl, Azocan-5-yl, Tiranil, Azethidine-1-yl, Azethidine-2-yl, Azethidine-3-yl, Oxetanil, Thietanil, 1,2-Dithietanil, 1,3-Dithietanil, Dihydropyridinyl, Tetrahydropyridinyl, Thiomorpholinil, Thioxanil, Piperazinil, Homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathianyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathanyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl Examples include, but are not limited to, dihydrofuranil, tetrahydrofuranil, tetrahydrothienyl, tetrahydropyranil, tetrahydrothiopyranil, 1-pyrrolinil, 2-pyrrolinil, 3-pyrrolinil, indolinil, 2H-pyranil, 4H-pyranil, 1,4-dioxanil, 1,3-dioxolanil, pyrazolinil, pyrazolidinil, dithianil, dithiolanil, pyrazolidinil, imidazolinil, pyrimidinol, or 1,1-dioxo-thiomorpholinil.

[0195] The term “spiroheterocyclyl” refers to a 5- to 20-membered polycyclic heterocycline having rings bonded via a common carbon atom (called a spiro atom), with one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members being carbon. One or more rings of a spiroheterocyclyl may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, spiroheterocyclyls are 6- to 14 members, more preferably 7- to 12 members. Depending on the typical number of spiro atoms, spiroheterocyclyls can be monospiroheterocyclyls, disspiroheterocyclyls, or polyspiroheterocyclyls, preferably monospiroheterocyclyls or disspiroheterocyclyls, and more preferably 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyls. Typical examples of spiroheterocyclils include 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-1,2'-pyrrolidine]-1'-yl), 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro[indene-2,2'-pyrrolidine]-1'-yl), azaspiro[2.4]heptane (e.g., 5-azaspiro[2.4]heptane-5-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), and 2-oxa-6-azaspiro[3.4]octane (e.g., 2-oxa-6- This includes, but is not limited to, azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), 1,7-dioxaspiro[4.5]decane, 2-oxa-7-azaspiro[4.4]nonane (e.g., 2-oxa-7-azaspiro[4.4]non-7-yl), 7-oxaspiro[3.5]nonyl, and 5-oxaspiro[2.4]heptyl.

[0196] The term "condensed heterocyclyl" refers to a polycyclic heterocyclic group with 5 to 18 members, where each ring in the system shares an adjacent atom pair (carbon and carbon, or carbon and nitrogen) with another ring, and contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a condensed heterocyclyl may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Condensed heterocyclyls have 6 to 14 members, preferably 7 to 12 members, more preferably 7 to 10 members. Depending on the number of rings, condensed heterocyclyl groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclyls, preferably bicyclic or tricyclic condensed heterocyclyls, more preferably 5-membered / 5-membered, 5-membered / 6-membered, or 6-membered / 7-membered bicyclic condensed heterocyclyls. Representative examples of condensed heterocyclyls include octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrole-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindoline (e.g., isoindoline-2-yl or isoindoline-5-yl), octahydrobenzo[b][1,4]dioxin, dihydropyridozinyl (e.g., 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl), or dihydrobenzoxazepinyl (e.g., 5-oxo-3,4-dihydrobenzo[f][1,4]oxazepinyl), and benzoaze Examples include, but are not limited to, pinyl (e.g., 2,3,4,5-tetrahydro-1-oxo-2-benzoazepinyl-6-yl), benzoxazepinyl (e.g., 5-oxo-2,3,4,5-tetrahydro-1,4-benzoazepinyl-8-yl), dihydroisoquinolinyl (e.g., 1-oxo-2-methyl-3,4-dihydroisoquinolin-6-yl), tetrahydroisoquinolinyl (e.g., 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl), and dihydrobenzoxazine (e.g., 3,4-dihydro-2H-1,4-benzoxazine-6-yl).

[0197] The term "bridged heterocyclyl" refers to a 5- to 18-membered polycyclic heterocycloalkyl group in which two rings in the system each share two unconnected atoms containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring member is carbon. One or more rings of a bridged heterocyclyl may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, bridged heterocyclyls are 6- to 14 members, more preferably 7- to 10 members. Depending on the number of rings, bridged heterocyclyls are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyls, preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclyls, more preferably bicyclic or tricyclic bridged heterocyclyls. Representative examples of cross-linked heterocyclils include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0198] The term "heterocycloalkyl," unless otherwise specified, means a monocyclic saturated "heterocyclyl" or "heterocyclic" as defined above, the ring atoms being as defined above, namely, containing 3 to 20 ring atoms ("3 to 20 membered heterocycloalkyl"), the number of heteroatoms being 1, 2, 3, or 4 (1 to 4), preferably 1, 2, or 3 (1 to 3), where each heteroatom is independently selected from N, O, and S. It is preferable to contain 3 to 12 ring atoms ("3 to 12-membered heterocycloalkyl"), more preferably 3 to 10 ring atoms ("3 to 10-membered heterocycloalkyl"), even more preferably 3 to 8 ring atoms ("3 to 8-membered heterocycloalkyl"), even more preferably 4 to 7 ring atoms ("4 to 7-membered heterocycloalkyl"), even more preferably 5 to 10 ring atoms ("5 to 10-membered heterocycloalkyl"), and even more preferably 5 to 6 ring atoms ("5 to 6-membered heterocycloalkyl"). In some embodiments, each example of heterocycloalkyl may be independently and optionally substituted, for example, unsubstituted (unsubstituted heterocycloalkyl) or substituted with one or more substituents (substituted heterocycloalkyl). In the above-mentioned "heterocyclyl" or "heterocycle," examples of partially exemplary "heterocycloalkyl" include, but are not limited to, oxacyclohexyl, thiomorpholinyl, oxathiocyclohexyl, oxazolidinylthiazolidinyl, pyrazolidinyl, and imidazolidinyl.

[0199] The term "heterocycloalkenyl" means, unless otherwise specified, a monocyclic unsaturated "heterocyclyl" or "heterocyclic" as defined above, wherein the ring atoms are as defined above, namely, 4 to 12 ring atoms ("4 to 12-membered heterocycloalkenyl"), the number of heteroatoms being 1, 2, 3, or 4 (1 to 4), preferably 1, 2, or 3 (1 to 3), where each heteroatom is independently selected from N, O, and S. Preferably, it contains 4 to 10 ring atoms ("4 to 10-membered heterocycloalkenyl"), more preferably 4 to 8 ring atoms ("4 to 8-membered heterocycloalkenyl"), even more preferably 4 to 6 ring atoms ("4 to 6-membered heterocycloalkenyl"), and even more preferably 5 to 6 ring atoms ("5 to 6-membered heterocycloalkenyl"). In one embodiment, each example of a heterocycloalkenyl may be independently and optionally substituted, for example, unsubstituted (unsubstituted heterocycloalkenyl) or substituted with one or more substituents (substituted heterocycloalkenyl).

[0200] The term "aryl" refers, unless otherwise specified, to monocyclic, bicyclic, and tricyclic aromatic carbocyclic rings containing 6 to 16 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenantrenyl, or pyrenyl.

[0201] The term "heteroaryl," unless otherwise specified, refers to an aromatic monocyclic, bicyclic, or polycyclic ring system containing a 5-16 member structure, or a 5-14 member structure, a 5-12 member structure, a 5-10 member structure, a 5-8 member structure, or a 5-6 member structure, where one, two, three or more ring atoms are heteroatoms, the remaining atoms are carbon, the heteroatoms are independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, or three. Examples of heteroaryl groups include furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridinyl, ben Examples include, but are not limited to, zopyrimidinil, benzopyradinil, benzimidazolyl, benzophthalazinil, pyrro[2,3-b]pyridinil, imidazolyl[1,2-a]pyridinil, pyrazolyl[1,5-a]pyridinil, pyrazolyl[1,5-a]pyridinil, imidazolyl[1,2-b]pyridadinil, [1,2,4]triazolyl[4,3-b]pyridadinil, [1,2,4]triazolyl[1,5-a]pyridinil, and [1,2,4]triazolyl[1,5-a]pyridinil.

[0202] The term "alkylene" refers to the divalent alkyl group as defined above. The term "alkenylene" refers to the divalent alkenyl group as defined above. The term "alkynylene" refers to the divalent alkynyl group as defined above. The term "cycloalkylene" refers to the divalent cycloalkyl group as defined above. The term "heterocyclylene" refers to the divalent heterocyclyl group as defined above. The term "arylene" refers to the divalent aryl group as defined above. The term "heteroarylene" refers to the divalent heteroaryl group as defined above.

[0203] The term “pharmaceutically acceptable salt” or “medicinal salt” means, unless otherwise specified, a salt that is suitable for contact with mammalian tissues, particularly human tissues, within reasonable medical judgment, without excessive toxicity, irritation, or allergic reactions, and that has an appropriate benefit-risk ratio. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other compounds are well known to those skilled in the art. Such salts can be prepared in situ during the final separation and purification of the compounds of the present invention, or by reacting a free base or free acid alone with a suitable reagent.

[0204] The compounds of the present invention also include their "isotope derivatives." Unless otherwise specified, the term "isotope derivative" means that the compounds of the present invention may exist in isotopic tracer or enriched form and contain one or more atoms having an atomic weight or mass number different from the maximum atomic weight or mass number found in nature. The isotopes may be radioactive or non-radioactive. Commonly used isotopes for isotopic labeling include hydrogen isotopes: 2 H and 3 H, carbon isotope: 13 C and 14 C, chlorine isotope: 35 Cl and 37 Cl, fluorine isotope: 18 F, iodine isotope: 123 I and 125 I. Nitrogen Isotopes: 13 N and 15 N, oxygen isotope: 15 O, 17 O, and 18 O, and sulfur isotopes 35 It is S. These isotope-labeled compounds can be used to study the distribution of medicinal molecules in tissues. In particular 3 H and 13 C is more widely used because it is easy to label and detect. Deuterium ( 2Substitution with specific heavier isotopes, such as H), improves metabolic stability and extends the half-life, leading to reduced dosages and therapeutic benefits. Isotope-labeled compounds are generally synthesized starting from labeled raw materials using known synthetic techniques, similar to unisotopically labeled compounds.

[0205] The compounds of the present invention also include their “solvates.” Unless otherwise specified, the term “solvate” means the physical association of the compounds of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. Solvates can be isolated if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvent molecules in a solvate may exist in regular and / or disordered arrangements. A solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. “Solvate” includes both the solution phase and the separable solvate. Solvation methods are well known in the art.

[0206] The term "stereoisomer," unless otherwise specified, refers to a compound that has the same chemical structure but differs in the arrangement of atoms or groups in space. Stereoiomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atrop isomers, and others. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0207] The term "tautomer" refers, unless otherwise specified, to structural isomers with different energies that can be interconverted over a low energy barrier. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through the rearrangement of some of the bonded electrons.

[0208] The term "optional substitution," unless otherwise specified, refers to the fact that the hydrogen atoms of the substituted sites of the group are either unsubstituted or substituted with one or more substituents. Preferably, they are substituted with one, two, or three substituents. The substituents are halogens, hydroxyl groups, mercapto groups, cyano groups, nitro groups, amino groups, azide groups, oxo groups, carboxyl groups, and C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkylsulfonyl group, 3-10 membered heterocycloalkyl group, C 6-14 It is preferable to select from the group consisting of an aryl group or a 5-10 membered heteroaryl ring group. However, the C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkylsulfonyl group, 3-10 membered heterocycloalkyl group, C 6-14 The aryl group, or the 5-10 membered heteroaryl ring group, is a halogen, hydroxyl group, amino group, cyano group, C 1-6 Alkyl alkyl group, or C 1-6 The alkoxy group may be optionally substituted with one or more selected alkoxy groups. The oxo group refers to a double bond formed when two hydrogen atoms at the same substitution site are substituted with the same oxygen atom.

[0209] The term “therapeutic dose” means a non-toxic but sufficient amount of drug or agent to achieve the desired effect. In embodiments of the present invention, when treating a patient according to the present invention, the predetermined amount of drug to be administered depends on many factors such as a specific administration protocol, the type and severity of the disease or condition, and the specificity of the patient or host requiring treatment (e.g., body weight). However, the dose can be routinely determined by methods known in the art, depending on specific surrounding circumstances, including the specific drug employed, the route of administration, the condition being treated, and the patient or host being treated. In the case of a pharmaceutical composition of the present invention, it comprises a therapeutic dose of the compound of the present invention and a pharmaceutically acceptable carrier, where “therapeutic dose” means that, based on the weight of the pharmaceutical composition, the compound of the present invention constitutes 1 to 99%, e.g., 20 to 80%, 30 to 70%, or 45 to 55%, and the weight of the pharmaceutically acceptable carrier constitutes 99 to 1%, e.g., 80 to 20%, 70 to 30%, or 55 to 45%. Pharmaceutically acceptable carriers are well known in the art and will not be further described herein. [Effects of the Invention]

[0210] The present invention exhibits the following advantageous effects.

[0211] This invention designs novel structural compounds for the development of PDE4B inhibitory drugs, offering a new direction. In vitro biochemical enzyme activity studies demonstrated that these compounds exhibited potent inhibitory effects and better selectivity against the PDE4B enzyme. Pharmacokinetic studies in mice showed good bioavailability and exposure levels, demonstrating excellent metabolic properties. Therefore, these compounds are useful as promising candidates for the treatment of PDE4B-mediated diseases. [Modes for carrying out the invention]

[0212] The present invention will be further described below with reference to specific examples. It should be understood that these examples are merely illustrative and do not limit the scope of the present invention. Experimental methods in the following examples that do not specify concrete conditions are generally carried out under normal conditions or conditions recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Any other methods and materials similar or equivalent to those described may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are merely illustrative.

[0213] The compound structures of the present invention are identified by nuclear magnetic resonance (NMR) and / or liquid chromatography-nuclear magnetic resonance (LC-MS) and / or liquid chromatography (HPLC). The instruments used for NMR measurements were a Bruker 400 MHz and / or Varian 400 MHz; the instruments used for LC-MS were an Agilent 1260 Infinity II-6120 / 6125MSD; and the instruments used for HPLC were Waters UPCC (CA-352).

[0214] The starting materials in the embodiments of the present invention are known, commercially available, or can be synthesized using or in accordance with methods known in the art.

[0215] The present invention provides a method for producing the compound. The compound of the present invention can be produced by the following steps.

[0216] Manufacturing Example 1 Preparation of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0217] [ka]

[0218] Step 1: Preparation of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methanol:

[0219] [ka]

[0220] 2,4-Dichloro-6,7-Dihydrothieno[3,2-d]pyrimidine (6.3 g), (1-aminocyclobutyl)methanol hydrochloride (4.6 g), and N,N-diisopropylethylamine (DIEA) (15.6 g) were dissolved in acetonitrile (ACN) (30 mL) and reacted overnight at 85°C. Then, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2) and washed with water (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and dried in a rotary evaporator to obtain the crude product. The crude product was separated and purified by flash chromatography (100-200 mesh silica gel, petroleum ether:ethyl acetate = 0-50%) to obtain a white solid. Then, acetonitrile (20 mL) and water (40 mL) were added and the mixture was stirred overnight at room temperature. The solid was filtered by suction, washed with acetonitrile / water (1:2, 20 mL), and the cake was dried in a rotary evaporator to obtain the target compound (4.2 g). LC-MS(ESI)[M+H] + = 272.10.

[0221] Step 2: Preparation of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0222] [ka]

[0223] (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methanol (1g), Ti(O iPr)4 (52.4 mg) and (S)-(-)-1,1'-bi-2-naphthol ((S)-BINOL) (105.6 mg) were dissolved in dichloromethane (DCM) (5 mL) and water (0.5 mL), and then stirred under a nitrogen atmosphere for 0.5 hours. Subsequently, tert-butyl hydroperoxide (t-BuOOH) (522 mg, 70% aqueous solution) was added under an ice bath, and the mixture was stirred at room temperature for 1 hour. Monitoring by LC-MS showed the main peak of the product. The solution was then dried using a rotary evaporator, isopropyl acetate (15 mL) was added, and after ultrasonic washing for 1 minute, it was filtered, washed with isopropyl acetate (2 mL), and dried to obtain the target compound (1 g). LC-MS(ESI)[M+H] + = 288.08.

[0224] Manufacturing Example 2 Step 1: Preparation of tert-butyl 3-(4-chlorophenyl)-3-(methoxy-d3)azetidine-1-carboxylate:

[0225] [ka]

[0226] 0.50 g of tert-butyl 3-(4-chlorophenyl)-3-hydroxyazetidine-1-carboxylate was dissolved in 5 mL of DMF, substituted with nitrogen three times, and 141 mg of 60% sodium hydride was added under ice bath. The mixture was stirred under ice bath for 10 minutes, and 0.51 g of deuterated methyl iodide was added, after which stirring was continued under ice bath for 30 minutes. Saturated aqueous NH4Cl solution was added to quench the mixture, and the mixture was added to water and extracted with methyl t-butyl ether. The organic layers were washed together with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and dried using a rotary evaporator to obtain the target compound (700 mg, crude).

[0227] Step 2: Preparation of 3-(4-chlorophenyl)-3-(methoxy-d3)azetidine hydrochloride:

[0228] [ka]

[0229] 650 mg of tert-butyl 3-(4-chlorophenyl)-3-(methoxy-d3)azetidine-1-carboxylate was added to 5 mL of 4 M hydrogen chloride / ethyl acetate solution and stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. Petroleum ether was added to the crude product to form a slurry and obtain the target compound (500 mg). LCMS(ESI)[M+H] + =201.1.

[0230] Manufacturing Example 3 Step 1: Preparation of tert-butyl 3-(4-(difluoromethoxy)phenyl)-3-hydroxyazetidine-1-carboxylate:

[0231] [ka]

[0232] Under a nitrogen gas atmosphere, 1-bromo-4-(difluoromethoxy)benzene (5.08 g) was dissolved in anhydrous tetrahydrofuran (40 mL). 2.5 M n-butyllithium / hexane solution (9.8 mL) was added dropwise at -78°C, and the mixture was reacted at -78°C for 0.5 hours to obtain a pseudo-white turbidity. tert-butyl 3-oxoazetidine-1-carboxylate (3.00 g) was dissolved in anhydrous tetrahydrofuran (10 mL), and slowly added to the solution at -78°C, reacting with stirring for 1 hour. The reaction mixture was raised to 0°C, saturated ammonium chloride solution (20 mL) was added to quench the reaction, water (200 mL) was added, and the mixture was extracted with methyl t-butyl ether. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column (PE:EA=3:1) to obtain the target compound (4.10 g). LCMS(ESI)[M+H-56] + = 260.2.

[0233] Step 2: Preparation of tert-butyl 3-(4-(difluoromethoxy)phenyl)-3-methoxyazetidine-1-carboxylate:

[0234] [ka]

[0235] 4.00 g of tert-butyl 3-(4-(difluoromethoxy)phenyl)-3-hydroxyazetidine-1-carboxylate was dissolved in 40 mL of DMF, substituted three times with nitrogen, and 0.61 g of 60% sodium hydride was added under ice bath conditions. The mixture was stirred for 10 minutes under ice bath conditions, and 2.70 g of methyl iodide was added. Stirring was continued under ice bath conditions for 1 hour. Saturated aqueous NH4Cl solution was added to the reaction mixture to quench the reaction, and the mixture was added to 200 mL of water. Extraction was performed with methyl t-butyl ether, and the organic phases were combined. The mixture was washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (4.46 g).

[0236] Step 3: Preparation of 3-(4-(difluoromethoxy)phenyl)-3-methoxyazetidine hydrochloride:

[0237] [ka]

[0238] 4.00 g of tert-butyl 3-(4-(difluoromethoxy)phenyl)-3-methoxyazetidine-1-carboxylate was added to 20 mL of 4 M hydrogen chloride / ethyl acetate solution and stirred at room temperature for 0.5 hours. LC-MS monitoring indicated completion of raw material consumption. The reaction mixture was concentrated under reduced pressure to obtain the target compound (3.23 g, crude). LC-MS(ESI)[M+H] + = 230.1.

[0239] Manufacturing Example 4 In the same manner as in Production Example 3, 1-bromo-4-(difluoromethoxy)benzene was replaced with 1-bromo-4-(cyclopropylmethoxy)benzene to obtain 3-(4-(cyclopropylmethoxy)phenyl)-3-methoxyazetidine hydrochloride LCMS(ESI)[M+H] + = 234.2.

[0240] Manufacturing Example 5 In the same manner as in Production Example 3, 1-bromo-4-(difluoromethoxy)benzene was replaced with 1-(4-bromophenyl)pyrrolidine to obtain 1-(4-(3-methoxyazetidine-3-yl)phenyl)pyrrolidine hydrochloride LCMS(ESI)[M+H-MeO] + =201.3.

[0241] Manufacturing Example 6 4-(3-methoxyazetidine-3-yl)-N,N-dimethylaniline hydrochloride is produced by replacing 1-bromo-4-(difluoromethoxy)benzene with 4-bromo-N,N-dimethylaniline using the same method as in Production Example 3.

[0242] Manufacturing example 7 Using the same method as in Production Example 3, 1-bromo-4-(difluoromethoxy)benzene is replaced with 3-bromo-N,N-dimethylaniline to produce 3-(3-methoxyazetidine-3-yl)-N,N-dimethylaniline hydrochloride.

[0243] Manufacturing Example 8 In the same manner as in Production Example 3, 1-bromo-4-(difluoromethoxy)benzene was replaced with 5-bromobenzo(d)[1,3]dioxolane to obtain 3-(benzo(d)[1,3]dioxol-5-yl)-3-methoxyazetidine hydrochloride LCMS(ESI)[M+H] + = 208.1.

[0244] Manufacturing Example 9 In the same manner as in Production Example 3, 1-bromo-4-(difluoromethoxy)benzene was replaced with tert-butyl(4-bromophenyl)(methyl)carbamate to obtain 4-(3-methoxyazetidine-3-yl)-N-methylaniline dihydrochloride LCMS(ESI)LCMS(ESI)[M+H] + = 193.1.

[0245] Example 1 (Compound 1) Synthesis of (R / S)-2-(3-(4-chlorophenyl)-3-hydroxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0246] [ka]

[0247] Step 1: Preparation of tert-butyl 3-(4-chlorophenyl)-3-hydroxyazetidine-1-carboxylate:

[0248] [ka]

[0249] 2 g of p-chloroiodobenzene was dissolved in 20 mL of anhydrous tetrahydrofuran (THF), and n-butyllithium (n-BuLi) (5.25 mL, 1.6 M n-hexane solution) was added under a nitrogen atmosphere at -78°C. The mixture was stirred at -78°C for 10 minutes. Next, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (0.95 g) in 5 mL of tetrahydrofuran was added dropwise to the reaction system, and the reaction mixture was stirred at -78°C for 1 hour. Monitoring by LC-MS showed the main peak of the product. Next, the reaction was quenched by adding an aqueous solution of saturated ammonium chloride (20 mL), and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Separation and purification were performed by flash chromatography (silica gel, petroleum ether:ethyl acetate = 5:1-2:1) to obtain the target compound (1.2 g). LC-MS (ESI) [M-55] + = 228.14.

[0250] Step 2: Preparation of 3-(4-chlorophenyl)azetidine-3-ol trifluoroacetate:

[0251] [ka]

[0252] 200 mg of tert-butyl 3-(4-chlorophenyl)-3-hydroxyazetidine-1-carboxylate was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid (TFA) was added. The mixture was stirred at room temperature for 1 hour. LC-MS monitoring indicated completion of the reaction, and the solution was then dried using a rotary evaporator to obtain the crude product of the target compound. LC-MS(ESI)[M+H] + = 184.14.

[0253] Step 3: Preparation of (R / S)-2-(3-(4-chlorophenyl)-3-hydroxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0254] [ka]

[0255] 3-(4-chlorophenyl)azetidine-3-ol trifluoroacetate (200 mg, crude product, obtained from the previous reaction) was dissolved in dioxane (4 mL), N,N-diisopropylethylamine (1 mL) was added, and the reaction system was homogenized and stirred. Then (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (70 mg) was added. The reaction was carried out at 120°C for 20 minutes using microwaves. Monitoring by LC-MS indicated completion of the reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of the target compound. The crude product of the target compound was added to ethyl acetate (15 mL), stirred overnight at 85°C, the reaction system was cooled, and the mixture was filtered to obtain the target compound (63.3 mg).

[0256] LCMS(ESI)[M+H] + =435.28;Chiral HPLC: ee%=100%; 1 H NMR(400 MHz, DMSO-d6 )δ 7.54(d, J=8.4 Hz, 2H), 7.44(d, J=8.8 Hz, 3H), 6.48(s, 1H), 4.85(t, J=5.5 Hz, 1H), 4.19(s, 4H), 3.70(d, J=5.5 Hz, 2H), 3.51-3.36(m, 1H), 3.26 - 3.15(m, 1H), 2.92(ddd, J=20.7, 15.4, 7.4 Hz, 2H), 2.41 - 2.25(m, 2H), 2.12(t, J=9.4 Hz, 2H), 1.73(dt, J=19.7, 10.2 Hz (2H).

[0257] Example 2 (Compound 2) Synthesis of (R / S)-2-(3-hydroxy-3-(4-methoxyphenyl)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0258] [ka]

[0259] Step 1: tert-butyl 3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate:

[0260] [ka]

[0261] 1-Bromo-4-methoxybenzene (2g) was dissolved in tetrahydrofuran (40mL), and under a nitrogen atmosphere, n-butyllithium (4.3mL, 2.5M n-hexane solution) was added dropwise at -78°C, and the mixture was incubated and stirred for 0.5 hours. tert-butyl3-oxoazetidine-1-carboxylate (2.75g) was dissolved in tetrahydrofuran (10mL), and this solution was added dropwise to the above n-butyllithium solution at -78°C, and the mixture was incubated and stirred for 0.5 hours. LCMS monitoring revealed a novel product. The reaction mixture was poured into water (100mL), extracted with ethyl acetate (30mL x 3), the organic phase was dried over sodium sulfate, and the crude product was dried using a rotary evaporator. The crude product was purified using a silica gel column (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound (1.9g). LCMS: (ESI)[M-Boc-OH+H] + = 162.1.

[0262] Step 2: Preparation of 3-(4-methoxyphenyl)azetidine-3-ol trifluoroacetate:

[0263] [ka]

[0264] 145 mg of tert-butyl 3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added at room temperature. The mixture was stirred at room temperature for 1 hour. Monitoring by LC-MS showed the disappearance of the starting material, and the reaction mixture was dried in a rotary evaporator to obtain the target compound (150 mg).

[0265] Step 3: Preparation of (R / S)-2-(3-hydroxy-3-(4-methoxyphenyl)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0266] [ka]

[0267] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 3-(4-methoxyphenyl)azetidine-3-ol trifluoroacetate (153.95 mg), and N,N-diisopropylethylamine (226.17 mg) were dissolved in dioxane (2 mL) and reacted at 120°C for 1.5 hours using microwaves. The reaction was completed by monitoring with LC-MS. The reaction solution was directly separated and purified by Prep-HPLC (C18, 10 mmol / L, aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (40.3 mg).

[0268] LCMS:(ESI)[M+H]+=431.33; 1H NMR(400 MHz, DMSO-d6+D2O)δ 7.38(d, J=8.4 Hz, 2H), 6.92(d, J=8.5 Hz, 2H), 4.30 - 4.05(m, 4H), 3.75 - 3.63(m, 5H), 3.47 - 3.35(m, 1H), 3.30 - 3.19(m, 1H), 3.01 - 2.85(m, 2H), 2.34 - 2.19(m, 2H), 2.17 - 2.00(m, 2H), 1.84 - 1.64(m, 2H).

[0269] Example 3 (Compound 3) Synthesis of (R / S)-2-(3-(4-chloro-3-methoxyphenyl)-3-hydroxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0270] [ka]

[0271] Step 1: tert-butyl 3-hydroxy-3-(4-chloro-3-methoxyphenyl)azetidine-1-carboxylate:

[0272] [ka]

[0273] 4-Bromo-1-chloro-2-methoxybenzene (2 g) was dissolved in tetrahydrofuran (40 mL), and n-butyllithium (3.6 mL, 2.5 M n-hexane solution) was added dropwise at -78°C under a nitrogen atmosphere, and the mixture was stirred for 0.5 hours. Tert-butyl 3-oxoazetidine-1-carboxylate (2.32 g) was dissolved in tetrahydrofuran (15 mL), and this was added dropwise to the above n-butyllithium solution at -78°C, and the mixture was stirred for 0.5 hours. Monitoring by LCMS showed product formation, and water (10 mL) was added dropwise to the reaction mixture at -78°C to quench it. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was washed with water (200 mL x 3), dried over anhydrous sodium sulfate, and dried in a rotary evaporator to obtain the crude product. The crude product was purified using silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound (1.3 g). LC-MS: (ESI)[M-OH+H] + = 196.17.

[0274] Step 2: Preparation of 3-(4-chloro-3-methoxyphenyl)azetidine-3-ol trifluoroacetate:

[0275] [ka]

[0276] 145 mg of tert-butyl 3-hydroxy-3-(4-chloro-3-methoxyphenyl)azetidine-1-carboxylate was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added at room temperature. The mixture was stirred at room temperature for 1 hour. Monitoring by LC-MS showed the disappearance of the starting material, and the reaction mixture was dried in a rotary evaporator to obtain the target compound (160 mg).

[0277] Step 3: Preparation of (R / S)-2-(3-(4-chloro-3-methoxyphenyl)-3-hydroxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0278] [ka]

[0279] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 3-(4-chloro-3-methoxyphenyl)azetidine-3-ol trifluoroacetate (153.95 mg), and N,N-diisopropylethylamine (DIEA) (226.17 mg) were dissolved in dioxane (2 mL) and reacted at 120°C for 1.5 hours using microwave. Monitoring by LC-MS showed the disappearance of the starting materials, and separation and purification were performed to obtain the product (31.9 mg).

[0280] LCMS:(ESI)[M+H] + =465.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.52 - 7.37(m, 2H), 7.25(d, J=1.9 Hz, 1H), 7.08(d, J=8.3 Hz, 1H), 6.50(s, 1H), 4.85(t, J=5.6 Hz, 1H), 4.40 - 4.15(m, 4H), 3.86(s, 3H), 3.70(d, J=5.8 Hz, 2H), 3.48 - 3.37(m, 1H), 3.25 - 3.15(m, 1H), 3.10 - 2.85(m, 2H), 2.43 - 2.26(m, 2H), 2.20 - 2.15(m, 2H), 1.85 - 1.65 (m, 2H).

[0281] Example 4 (Compound 4) Synthesis of (R / S)-2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0282] [ka]

[0283] Step 1: Preparation of tert-butyl 3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-carboxylate:

[0284] [ka]

[0285] 4-bromo-2-chloro-1-methoxybenzene (2.5 g) was dissolved in anhydrous tetrahydrofuran (20 mL), and the reaction system was cooled to -78°C under a nitrogen atmosphere. Then, n-butyllithium (7 mL, 1.6 M n-hexane solution) was added, and the reaction system was reacted at -78°C for 0.5 hours. Next, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.28 g) in tetrahydrofuran (2 mL) was slowly added dropwise to the above reaction system solution, and the mixture was stirred at -78°C for 1 hour. Monitoring by LC-MS showed the main peak of the product. Subsequently, the reaction was quenched by adding aqueous ammonium chloride (10 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and then dried using a rotary evaporator. The crude product was separated and purified by flash chromatography (Silica gel, petroleum ether:ethyl acetate = 3:1-2:1) to obtain the target compound (1.57 g). LC-MS (ESI) [M+H] + = 258.12.

[0286] Step 2: Preparation of 3-(3-chloro-4-methoxyphenyl)azetidine-3-ol trifluoroacetate:

[0287] [ka]

[0288] 120 mg of tert-butyl 3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-carboxylate was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction system was stirred at room temperature for 1 hour. LC-MS monitoring showed the main peak of the product. The solvent was then dried using a rotary evaporator, and the crude target compound was used directly in the next step without purification. LC-MS(ESI)[M+H] + = 214.17.

[0289] Step 3: Preparation of (R / S)-2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0290] [ka]

[0291] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg), 3-(3-chloro-4-methoxyphenyl)azetidine-3-ol trifluoroacetate (80 mg, crude) and N,N-diisopropylethylamine (0.5 mL) were dissolved in dioxane (3 mL), and the reaction system was reacted at 120 °C for 1 hour. Monitoring by LC-MS showed the main peak of the product. The solvent was then dried using a rotary evaporator to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (62.66 mg).

[0292] LCMS(ESI)[M+H] + =465.34; 1H NMR(400 MHz, DMSO-d6)δ 7.52(d, J=2.0 Hz, 1H), 7.43(dd, J=7.5, 3.2 Hz, 2H), 7.16(d, J=8.7 Hz, 1H), 6.42(s, 1H), 4.85(t, J=5.7 Hz, 1H), 4.16(s, 4H), 3.85(s, 3H), 3.70(d, J=5.8 Hz, 2H), 3.49-3.36(m, 1H), 3.26-3.16(m, 1H), 3.04-2.80(m, 2H), 2.34(td, J=21.4, 9.7 Hz, 2H), 2.12(t, J=9.4 Hz, 2H), 1.85-1.62(m, 2H).

[0293] Example 5 (Compound 5) Synthesis of (R / S)-2-(3-hydroxy-3-(3-methoxyphenyl)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0294] [ka]

[0295] Step 1: Preparation of tert-butyl 3-hydroxy-3-(3-methoxyphenyl)azetidine-1-carboxylate:

[0296] [ka]

[0297] Under a nitrogen atmosphere, M-bromoanisole (1.87 g) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled in an external dry ice-ethanol bath, and while maintaining the internal temperature below -65°C, n-butyllithium (1.6 M n-hexane solution, 6.6 mL) was added dropwise with stirring. After the addition was complete, the mixture was kept warm for 30 minutes. Tert-butyl 3-oxoazetidine-1-carboxylate (1.88 g) was dissolved in tetrahydrofuran (8 mL) and added to the reaction mixture while maintaining the internal temperature below -60°C. After 30 minutes of reaction, LC-MS monitoring indicated the completion of raw material consumption. The cold bath was removed, water (50 mL) was added, the mixture was allowed to rise naturally to room temperature, and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (silica gel, petroleum ether:tetrahydrofuran = 100:0 to 50:50 gradient elution) to obtain the target compound (1.20 g). LC-MS (ESI) [2M+H] + = 559.4.

[0298] Step 2: Preparation of 3-(3-methoxyphenyl)azetidine-3-ol hydrochloride:

[0299] [ka]

[0300] Under a nitrogen gas atmosphere, tert-butyl 3-hydroxy-3-(3-methoxyphenyl)azetidine-1-carboxylate (1.20 g) was dissolved in dichloromethane (20 mL), stirred in an ice bath for 10 minutes, and at 0°C, 4 M hydrogen chloride solution in ethyl acetate (EA) (3.23 mL) was added to the reaction mixture. The ice bath was removed, and the temperature was raised to room temperature for 1 hour. Monitoring by LC-MS indicated that the starting material had been consumed and converted to the product. The mixture was filtered, the cake was washed with dichloromethane (5 mL), and the cake was concentrated to dryness to obtain the target compound (0.83 g). LC-MS(ESI)[M+H] + = 216.1.

[0301] Step 3: Preparation of (R / S)-2-(3-hydroxy-3-(3-methoxyphenyl)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0302] [ka]

[0303] Under a nitrogen gas atmosphere, (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg) and 3-(3-methoxyphenyl)azetidine-3-ol hydrochloride (90 mg) were added to dioxane (5 mL). N,N-diisopropylethylamine (114 mg) was then added, and after three nitrogen substitutions, the reaction mixture was heated to 110°C and reacted for 1 hour. Monitoring by LCMS showed that the starting materials were consumed and converted to the product. Heating was stopped, the reaction mixture was concentrated to dryness, and the residue was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (118.5 mg).

[0304] LCMS(ESI)[M+H] + =431; 1H NMR(400 MHz, DMSO-d6)δ 7.43(s, 1H), 7.31(t, J=7.9 Hz, 1H), 7.07(t, J=5.1 Hz, 2H), 6.89 - 6.82(m, 1H), 6.37(s, 1H), 4.86(t, J=5.7 Hz, 1H), 4.17(s, 4H), 3.76(s, 3H), 3.70(d, J=5.7 Hz, 2H), 3.48 - 3.36(m, 1H), 3.23(dt, J=13.5, 8.3 Hz, 1H), 3.02 - 2.83(m, 2H), 2.34(td, J=21.4, 9.7 Hz, 2H), 2.12(t, J=9.3 Hz, 2H), 1.87 - 1.63(m, 2H).

[0305] Example 6 (Compound 11) Synthesis of (R / S)-2-(3-(4-chlorophenyl)-3-hydroxypyrrolidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0306] [ka]

[0307] Step 1: Preparation of tert-butyl 3-(4-chlorophenyl)-3-hydroxypyrrolidine-1-carboxylate

[0308] [ka]

[0309] Under a nitrogen gas atmosphere, 2.38 g of parachloroiodobenzene was dissolved in 30 mL of anhydrous tetrahydrofuran. The mixture was cooled in an external dry ice-ethanol bath, and while maintaining the internal temperature below -65°C, 6.6 mL of n-butyllithium (1.6 M n-hexane solution) was added dropwise with stirring. After the addition was complete, the mixture was kept warm for 30 minutes. 2.03 g of tert-butyl 3-oxopyrrolidine-1-carboxylate was dissolved in 8 mL of tetrahydrofuran and added to the reaction mixture, ensuring the internal temperature did not exceed -60°C. After 30 minutes of reaction, LC-MS monitoring indicated the completion of raw material consumption. The cold bath was removed, 50 mL of water was added, and the mixture was allowed to rise naturally to room temperature. Extraction was performed with ethyl acetate (100 mL x 3). The mixture was separated, the organic phases were combined, the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (silica gel, petroleum ether:tetrahydrofuran = 100:0 to 50:50 gradient elution) to obtain the target compound (1.34 g). LCMS(ESI)[2M+Na] + ] + = 617.3.

[0310] Step 2: Preparation of 3-(4-chlorophenyl)pyrrolidine-3-ol hydrochloride:

[0311] [ka]

[0312] Under a nitrogen gas atmosphere, tert-butyl 3-(4-chlorophenyl)-3-hydroxypyrrolidine-1-carboxylate (1.34 g) was dissolved in dichloromethane (20 mL), stirred in an ice bath for 10 minutes, and ethyl acetate solution of 4 M hydrogen chloride (3.38 mL) was added to the reaction mixture at 0°C. The ice bath was removed, and the temperature was raised to 20°C for 1 hour. Monitoring by LC-MS indicated that the starting material had been consumed and converted to the product, and a white solid precipitated. The mixture was filtered, the cake was washed with dichloromethane (5 mL), and the cake was concentrated to dryness to obtain the target product (0.90 g). LC-MS(ESI)[M+H] += 198.1.

[0313] Step 3: Preparation of (5R / S)-2-(3-(4-chlorophenyl)-3-hydroxypyrrolidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0314] [ka]

[0315] Under a nitrogen gas atmosphere, (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg) and 3-(4-chlorophenyl)pyrrolidine-3-ol hydrochloride (98 mg) were added to dioxane (5 mL), followed by the addition of N,N-diisopropylethylamine (114 mg). After three nitrogen substitutions, the reaction mixture was heated to 110°C and reacted for 1 hour. Monitoring by LC-MS indicated that the starting materials were consumed and converted to the product. Heating was stopped, the reaction mixture was concentrated to dryness, and the residue was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (83 mg).

[0316] LCMS(ESI)[M+H] + =449 / 451; 1H NMR(400 MHz, DMSO-d6)δ 7.56(d, J=8.5 Hz, 2H), 7.46 - 7.37(m, 2H), 7.32 - 7.20(m, 1H), 5.55(dd, J=19.9, 11.6 Hz, 1H), 4.86(dt, J=18.9, 5.6 Hz, 1H), 3.91 - 3.70(m, 3H), 3.70 - 3.55(m, 3H), 3.49 - 3.35(m, 1H), 3.28 - 3.15(m, 1H), 3.01 - 2.80(m, 2H), 2.47 - 2.25(m, 3H), 2.23 - 2.02(m, 3H), 1.87 - 1.61(m, 2H).

[0317] Example 7 (Compound 12) Synthesis of (5R / S)-2-(3-(5-chloropyrimidine-2-yl)pyrrolidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0318] [ka]

[0319] Step 1: Preparation of pyrrolidine-3-carbonilicate hydrochloride:

[0320] [ka]

[0321] 5 g of tert-butyl 3-cyanopyrrolidine-1-carboxylate was dissolved in 20 mL of dioxane, and a 50 mL solution of 4 M hydrochloric acid / dioxane was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was dried using a rotary evaporator to obtain the target compound (3.38 g).

[0322] Step 2: Preparation of pyrrolidine-3-carboxymidohydrochloride:

[0323] [ka]

[0324] Pyrrolidine-3-carbonitride hydrochloride (2.4 g) was dissolved in hydrochloric acid / dioxane (10 mL), and methanol (MeOH) (1.74 g) was added in an ice bath while maintaining the temperature below 10°C. The mixture was stirred at room temperature for 1 hour. Sodium methoxide (NaOMe) (1.96 g) was dissolved in anhydrous methanol (8 mL) to prepare a sodium methoxide solution. The sodium methoxide solution was slowly added to the above solution, and the mixture was stirred at a temperature below 15°C for 1 hour. Finally, 7 M ammonia / methanol solution (8 mL) was added to the above solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain the crude target compound, which was used directly in the next reaction without purification.

[0325] Step 3: Preparation of 5-chloro-2-(pyrrolidin-3-yl)pyrimidine 4-methylbenzenesulfonate:

[0326] [ka]

[0327] To the dioxane solution of pyrrolidine-3-carboxymidamide hydrochloride obtained in the above process, a solution of sodium methoxide (2.39 g) in anhydrous methanol (40 mL) was added and the mixture was stirred at room temperature for 30 minutes. (Z)-N-[2-chloro-3-(dimethylamino)allyl]-N-methylmethylammonium hexafluorophosphate (4.34 g) was added and stirring was continued at room temperature for 3.5 hours. The mixture was concentrated under reduced pressure to approximately 60 mL. 2-methyltetrahydrofuran (80 mL) was added and the mixture was further concentrated to approximately 100 mL. Another 2-methyltetrahydrofuran (80 mL) was added, the mixture was cooled to 20°C, water (150 mL) was added, and the mixture was stirred for 5 minutes. The mixture was allowed to stand and separate into layers. The organic layers were collected, washed with 30% sodium hydroxide (120 mL) aqueous solution, and the organic layers were combined. The above organic layers were concentrated to 50 mL and n-propanol (20 mL) was added. A solution of 4-methylbenzenesulfonic acid (TsOH) (2.43 g) in n-butanol (20 mL) was slowly added dropwise at 65°C for 10 minutes. The reaction mixture was concentrated to 50 mL under reduced pressure. After cooling to room temperature and filtering, the crude product of the target compound (6.6 g) was obtained. LC-MS: (ESI)[M+H] + = 184.17.

[0328] Step 4: Preparation of (R / S)-2-(3-(5-chloropyrimidine-2-yl)pyrrolidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0329] [ka]

[0330] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg), 5-chloro-2-(pyrrolidine-3-yl)pyrimidine 4-methylbenzenesulfonate (74.19 mg), and N,N-diisopropylethylamine (65.91 mg) were dissolved in dioxane (2 mL) and heated at 120 °C for 2 hours using microwave (MW). Monitoring by LC-MS showed that the starting materials had disappeared. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (30 mL x 3), and the organic phase was dried over sodium sulfate and dried in a rotary evaporator to obtain the crude product. The crude product was separated and purified using preparative purification Prep-HPLC (C18, 10 mmol / L, NH4HCO3 / water, MeCN) to obtain the target compound (4.15 mg).

[0331] LCMS:(ESI)[M+H] + =435.29; 1 HNMR(400 MHz, DMSO-d6)δ 8.90(s, 2H), 7.23(s, 1H), 4.84(s, 1H), 4.00 - 3.55(m, 7H), 3.46 - 3.35(m, 1H), 3.25 - 3.15(m, 1H), 3.00 - 2.80(m, 2H), 2.42 - 2.10(m, 6H), 1.88 - 1.64(m, 2H).

[0332] Example 8 (Compound 13 and Compound 14) Synthesis of (R / S)-2-(3-(4-(difluoromethoxy)phenyl)-3-hydroxypyrrolidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (compound 13) and (R / S)-2-(3-(4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (compound 14):

[0333] [ka]

[0334] Step 1: Preparation of tert-butyl 3-(4-(difluoromethoxy)phenyl)-3-hydroxypyrrolidine-1-carboxylate:

[0335] [ka]

[0336] Under a nitrogen gas atmosphere, 1-(difluoromethoxy)-4-iodobenzene (2.7 g) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled in an external dry ice-ethanol bath, and while maintaining the internal temperature so as not to exceed -65°C, isopropylmagnesium chloride-lithium chloride (1.3 M, 8 mL) was added dropwise with stirring. After the addition was complete, the reaction was allowed to proceed for 30 minutes while maintaining the temperature at -65°C. t-butyl 3-oxopyrrolidine-1-carboxylate (2.03 g) was dissolved in tetrahydrofuran (8 mL) and added to the reaction mixture, ensuring the internal temperature did not exceed -60°C. After 30 minutes of reaction, LC-MS monitoring indicated the completion of raw material consumption. The cold bath was removed, 100 mL of water was added, and the mixture was allowed to rise naturally to room temperature. Extraction was performed with ethyl acetate (100 mL x 3). The organic phases were separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (silica gel, petroleum ether:tetrahydrofuran = 100:0 to 50:50 gradient elution) to obtain the target compound (0.8 g). LC-MS (ESI) [2M + Na] + = 681.5.

[0337] Step 2: Preparation of 3-(4-(difluoromethoxy)phenyl)pyrrolidine-3-ol hydrochloride and 3-(4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole hydrochloride:

[0338] [ka]

[0339] Under a nitrogen gas atmosphere, tert-butyl 3-(4-(difluoromethoxy)phenyl)-3-hydroxypyrrolidine-1-carboxylate (0.8 g) was dissolved in dichloromethane (20 mL), stirred in an ice bath for 10 minutes, and 4 M ethyl hydrogen chloride solution (3 mL) was added to the reaction mixture at 0°C. The ice bath was removed, and the mixture was heated to room temperature and reacted for 1 hour. Monitoring by LC-MS showed that the starting material had been consumed and converted into the product and dehydrated by-products. The reaction mixture was concentrated to dryness to obtain the crude product of the target compound (400 mg). LC-MS(ESI)[M+H] + =230.

[0340] Step 3: Preparation of (R / S)-2-(3-(4-(difluoromethoxy)phenyl)-3-hydroxypyrrolidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (compound 13) and (R / S)-2-(3-(4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (compound 14):

[0341] [ka]

[0342] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 3-(4-(difluoromethoxy)phenyl)pyrrolidine-3-ol hydrochloride and 3-(4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole hydrochloride (148 mg, crude mixture, obtained in the previous reaction) were added to dioxane (5 mL) under a nitrogen gas atmosphere. Then, N,N-diisopropylethylamine (137 mg) was added, and after three nitrogen substitutions, the reaction mixture was heated to 110°C and reacted for 1 hour. Monitoring by LCMS showed that the consumption of the starting materials was complete and that the target compound had been converted. The reaction mixture was concentrated to dryness, and the residue was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (5R / S)-2-(3-(4-(difluoromethoxy)phenyl)-3-hydroxypyrrolidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (compound 13) (47 mg).

[0343] LCMS(ESI)[M+H] + =481; 1 H NMR(400 MHz, DMSO-d6)δ7.63 - 7.55(m, 2H), 7.41 -7.04(td, J=72 Hz, 1H), 7.26-7.24(m, 1H), 7.19 - 7.15(m, 2H), 7.04(d, J=2.2 Hz, 1H), 5.51(dd, J=21.0, 11.8 Hz, 1H), 4.86(dt, J=18.8, 5.5 Hz, 1H), 3.94 - 3.56(m, 6H), 3.48 - 3.36(m, 1H), 3.22(dd, J=8.4, 5.2 Hz, 1H), 3.01 - 2.80(m, 2H), 2.35(tt, J=20.3, 10.0 Hz, 3H), 2.23 - 2.02(m, 3H), 1.75(pd, J=20.0, 10.6 Hz, 2H).

[0344] The target compound, (R / S)-2-(3-(4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (compound 14) (45 mg), was obtained.

[0345] LCMS(ESI)[M+H] + =463; 1 H NMR(400 MHz, DMSO-d6)δ 7.61(d, J=8.7 Hz, 1H), 7.56(d, J=8.6 Hz, 1H), 7.46-7.06(td, J=72 Hz, 1H), 7.35(d, J=5.9 Hz, 1H), 7.21(dd, J=15.7, 8.6 Hz, 2H), 7.09(d, J=4.0 Hz, 1H), 6.49(s, 1H), 4.88(dt, J=11.5, 5.6 Hz, 1H), 4.61(d, J=11.0 Hz, 2H), 4.42(s, 2H), 3.77(dd, J=9.0, 5.8 Hz, 2H), 3.45(dq, J=14.2, 7.2 Hz, 1H), 3.29 - 3.18(m, 1H), 2.98(dt, J=16.4, 8.2 Hz, 1H), 2.88(dd, J=13.4, 7.5 Hz, 1H), 2.47 - 2.31(m, 2H), 2.20(dd, J=23.1, 10.3Hz, 2H), 1.89 - 1.69(m, 2H).

[0346] Example 9 (Compound 15) Synthesis of (R / S)-2-(3-(5-chloropyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0347] [ka]

[0348] Step 1: Preparation of tert-butyl 3-(5-chloropyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate:

[0349] [ka]

[0350] 500 mg of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate, 447 mg of 5-chloro-2-iodopyrimidine, 247 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2) and 700 mg of potassium carbonate were dissolved in 5 mL of dioxane and 0.5 mL of water. The reaction system was carried out at 110°C for 16 hours under a nitrogen atmosphere. Monitoring by LC-MS showed a major peak of the product, and the reaction system was then cooled to room temperature. The solid was filtered, and the filtrate was dried using a rotary evaporator. The filtrate was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 3:1~2:1) to obtain the target compound (550 mg, crude). LCMS(ESI)[M-55] + = 226.12.

[0351] Step 2: 5-Chloro-2-(2,5-dihydro-1H-pyrrole-3-yl)pyrimidine:

[0352] [ka]

[0353] 200 mg of tert-butyl 3-(5-chloropyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate was dissolved in 2 mL of dichloromethane, and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. After TLC indicated the completion of the reaction, the crude target compound was obtained by drying in a rotary evaporator and used directly in the next step. LCMS(ESI)[M+H]+ = 182.13.

[0354] Step 3: Preparation of (R / S)-2-(3-(5-chloropyrimidine-2-yl)-2,5-dihydro-1H-pyrrole-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0355] [ka]

[0356] 5-Chloro-2-(2,5-dihydro-1H-pyrrole-3-yl)pyrimidine (200 mg, crude, obtained in the previous reaction) was dissolved in dioxane (4 mL), then N,N-diisopropylethylamine (2 mL) was added and the mixture was stirred homogeneously. Then (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (70 mg) was added, and the mixture was reacted at 110°C for 20 minutes using microwaves. LC-MS monitoring indicated completion of the reaction. The mixture was cooled to room temperature, stirred overnight, filtered, and the cake was washed with ethyl acetate. The cake was then concentrated to dryness to obtain the target compound (50.63 mg).

[0357] LCMS(ESI)[M+H] + =433.27; 1H NMR(400 MHz, DMSO-d6)δ 8.96(d, J=8.4 Hz, 2H), 7.36(s, 1H), 7.06(s, 1H), 4.87(dt, J=11.4, 5.6 Hz, 1H), 4.65(s, 2H), 4.51(s, 2H), 3.77(t, J=5.6 Hz, 2H), 3.52-3.39(m, 1H), 3.23(dd, J=14.7, 7.0 Hz, 1H), 2.93(ddd, J=20.5, 14.3, 6.8 Hz, 2H), 2.38(dd, J=33.3, 12.6 Hz, 2H), 2.19(t, J=9.3 Hz, 2H), 1.88-1.71(m, 2H).

[0358] Example 10 (Compound 16) Synthesis of (R / S)-2-(1-(5-chloropyrimidine-2-yl)-1,2,3,6-tetrahydropyridine-4-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0359] [ka]

[0360] Step 1: tert-butyl(R / S)-4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0361] [ka]

[0362] Under a nitrogen gas atmosphere, (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg) and t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (130 mg) were added to dioxane (5 mL). 2 mL of water was added to the reaction mixture, and while stirring, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (25 mg) and potassium carbonate (121 mg) were added. After substituting with nitrogen three times, the reaction mixture was heated to 90°C and reacted for 1 hour. Monitoring by LCMS showed that the starting materials were consumed and converted to the product. After cooling the reaction mixture to room temperature, 20 mL each of water and ethyl acetate were added, and the mixture was extracted and separated. The resulting organic phase was concentrated to dryness, and the residue was separated by column chromatography (petroleum ether / ethyl acetate = 5:1 to 3:1) to obtain the target compound (90 mg). LCMS: (ESI)[M+H] + = 435.2.

[0363] Step 2: Preparation of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(1,2,3,6-tetrahydropyridine-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide hydrochloride:

[0364] [ka]

[0365] (R / S)-tert-butyl 4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (90 mg) was dissolved in 4 mL of dichloromethane under a nitrogen atmosphere and stirred in an ice bath for approximately 10 minutes. A 4 M hydrogen chloride dioxane solution (1 mL) was added to the reaction mixture at 0°C, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour. Monitoring by LC-MS showed that the starting material had been consumed and converted to the product. The reaction mixture was concentrated to obtain the crude product of the target compound (97 mg). LC-MS: (ESI)[M+H] + = 335.2.

[0366] Preparation of the third step (R / S)-2-(1-(5-chloropyrimidine-2-yl)-1,2,3,6-tetrahydropyridine-4-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0367] [ka]

[0368] (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(1,2,3,6-tetrahydropyridine-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide hydrochloride (37 mg, crude, obtained from the reaction in the above step) was dissolved in 2 mL of dimethyl sulfoxide under a nitrogen gas atmosphere. 5-chloro-2-iodopyrimidine (36 mg) and N,N-diisopropylethylamine (39 mg) were weighed in, and the mixture was heated to 120°C and stirred for 1 hour. Monitoring by LC-MS showed that the starting materials were consumed and converted to the product. The reaction mixture was separated directly by preparative high-performance liquid chromatography (0.5% ammonium bicarbonate / water / acetonitrile) to obtain the target compound (9 mg).

[0369] LCMS:(ESI)[M+H] + =447.1; 1H NMR(400 MHz, DMSO-d6)δ 8.46(s, 2H), 7.88(s, 1H), 7.23(s, 1H), 4.86(t, J=5.7 Hz, 1H), 4.39(d, J=2.8 Hz, 2H), 3.95(t, J=5.8 Hz, 2H), 3.83 - 3.68(m, 2H), 3.62 - 3.49(m, 1H), 3.29(d, J=8.1 Hz, 1H), 3.18 - 3.07(m, 1H), 3.05 - 2.94(m, 1H), 2.61(s, 2H), 2.41 - 2.19(m, 4H), 1.78(dt, J=19.9, 9.8 Hz, 2H).

[0370] Example 11 (Compound 17) Synthesis of (R / S)-2-(4-(5-chloropyrimidine-2-yl)phenyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0371] [ka]

[0372] Step 1: Synthesis of 4-(5-chloropyrimidine-2-yl)phenol:

[0373] [ka]

[0374] Under a nitrogen gas atmosphere, tetrakis(triphenylphosphine)palladium (Pd(Ph3P)4) (2.52 g) was added to a mixture of (4-hydroxyphenyl)boronic acid (3.00 g), 2,5-dichloropyrimidine (3.24 g), and potassium carbonate (9.02 g) in dioxane (90 mL) and water (15 mL), and the mixture was heated at 100 °C for 14 hours. LC-MS monitoring indicated completion of the reaction. The reaction mixture was then diluted with water (100 mL), extracted with ethyl acetate (300 mL), separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and separated and purified by flash chromatography (silica gel, ethyl acetate:petroleum ether = 1:5) to obtain the target compound (2.50 g). LC-MS(ESI)[M+H] + = 207.1.

[0375] Step 2: Synthesis of 4-(5-chloropyrimidine-2-yl)phenyl trifluoromethanesulfonic acid:

[0376] [ka]

[0377] To a solution of 4-(5-chloropyrimidine-2-yl)phenol (1.00 g) in dichloromethane (20 mL) in an ice bath, trifluoromethanesulfonic anhydride (Tf2O) (2.05 g) was added, and triethylamine (TEA) (1.47 g) was added dropwise. After the addition was complete, the mixture was stirred in an ice bath for 2 hours, and then reacted at room temperature for 12 hours. After the reaction was completed by TLC detection, saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then separated and purified by flash chromatography (silica gel, ethyl acetate:petroleum ether = 1:10) to obtain the target compound (1.00 g). LCMS(ESI)[M+H] + =339.0.

[0378] Step 3: 5-Chloro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidine:

[0379] [ka]

[0380] Under a nitrogen gas atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (108 mg) was added to a solution of 4-(5-chloropyrimidine-2-yl)phenyl trifluoromethanesulfonic acid (500 mg), bis(pinacolate)diboron ((Bpin)2) (562 mg), and potassium acetate (435 mg) in dioxane (3 mL). The mixture was heated to 100 °C and reacted for 4 hours. After TLC detection confirmed the reaction was complete, the reaction solution was diluted with water (100 mL) and ethyl acetate (300 mL), separated, and the organic phase was washed three times with saturated brine (100 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then separated and purified by flash chromatography (silica gel, ethyl acetate:petroleum ether = 1:20) to obtain the target compound (300 mg). LCMS(ESI)LCMS(ESI)[M+H] + = 317.1.

[0381] Step 4: Synthesis of (R / S)-2-(4-(5-chloropyrimidine-2-yl)phenyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0382] [ka]

[0383] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (13 mg) was added to a mixed solution of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg), 5-chloro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidine (55 mg), and potassium carbonate (60 mg) in a mixture of dioxane (2 mL) and water (0.5 mL). The mixture was heated to 100°C and reacted for 2 hours. After monitoring by LC-MS, the reaction mixture was diluted with water (10 mL) and ethyl acetate (50 mL), separated, and the organic phase was washed three times with saturated brine (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was then separated and purified by Prep-HPLC (C18, 10 mmol / L HCOOH / water, MeCN) to obtain the target compound (20 mg). LC-MS(ESI)[M+H] + =442.2; 1 H NMR(400 MHz, DMSO-d6)δ 9.07(s, 2H), 8.48(s, 4H), 8.11(s, 1H), 4.94(t, J=5.7 Hz, 1H), 3.85(d, J=4.0 Hz, 2H), 3.74 - 3.59(m, 1H), 3.40(dd, J=14.8, 6.6 Hz, 1H), 3.27 - 3.21(m, 1H), 3.05(dd, J=13.5, 6.2 Hz, 1H), 2.47 - 2.39(m, 2H), 2.36(d, J=9.7 Hz, 2H), 1.94 - 1.78(m, 2H).

[0384] Example 12 (Compound 22) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(isoindolin-2-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0385] [ka]

[0386] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), isoindoline (45.55 mg), and N,N-diisopropylethylamine (134.73 mg) were added to dioxane (2 mL) and reacted at 120°C for 20 minutes using microwaves. Monitoring by LC-MS showed that the starting materials had disappeared. The reaction solution was added to 15 mL of water and stirred for 30 minutes, resulting in the appearance of a large amount of insoluble matter, which was then filtered. The insoluble matter was added to ethyl acetate (20 mL) and stirred at 65°C for 1 hour. The temperature was lowered to room temperature, and the mixture was filtered to obtain the target compound (56.79 mg).

[0387] LCMS:(ESI)[M+H] + =371.1; 1 H NMR(400 MHz, DMSO-d6)δ 7.49 - 7.35(m, 3H), 7.34 - 7.27(m, 2H), 4.90 - 4.72(m, 5H), 3.85 - 3.75(m, 2H), 3.51 - 3.40(m, 1H), 3.30 - 3.18(m, 1H), 3.04 - 2.94(m, 1H), 2.93 - 2.84(m, 1H), 2.45 - 2.32(m, 2H), 2.28 - 2.15(m, 2H), 1.85 - 1.60(m, 2H).

[0388] Example 13 (Compound 23) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(indoline-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0389] [ka]

[0390] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg) and indoline (83.3 mg) were added to ethanol (5 mL), 2 mL of water was added, and 1 M dilute hydrochloric acid (0.3 mL) was added under stirring. The mixture was heated to 65 °C and stirred for 1 hour. Monitoring by LC-MS showed that the starting materials had substantially disappeared and the product had been formed. 3 mL of saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8. 20 mL of water and 20 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated. The organic phase was washed with water and concentrated. The residue was separated and purified by preparative chromatography using acetonitrile / water (0.5% ammonium bicarbonate system), and freeze-dried to obtain the target compound (32 mg).

[0391] LCMS:(ESI)[M+H] + =371.2;ee%=100%. 1 H NMR(400 MHz, DMSO-d6)δ 8.35(d, J=8.0 Hz, 1H), 7.56(s, 1H), 7.27 - 7.11(m, 2H), 6.91(td, J=7.4, 0.9 Hz, 1H), 4.87(t, J=5.7 Hz, 1H), 4.14(t, J=8.7 Hz, 2H), 3.79(d, J=5.7 Hz, 2H), 3.60 - 3.47(m, 1H), 3.28(dd, J=10.9, 5.8 Hz, 1H), 3.17 - 3.10(m, 2H), 3.10 - 3.04(m, 1H), 2.93(ddd, J=13.4, 7.3, 1.7 Hz, 1H), 2.39(td, J=22.0, 9.7 Hz, 2H), 2.25(s, 2H), 1.89 - 1.70(m, 2H).

[0392] Example 14 (Compound 24) Synthesis of (R / S)-2-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0393] [ka]

[0394] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg), 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine hydrochloride (49.23 mg), and N,N-diisopropylethylamine (87.88 mg) were added to dioxane (1.5 mL) and heated at 120°C for 2 hours using a microwave. Monitoring by LC-MS showed the disappearance of the starting materials, and the reaction product was separated and purified directly by Prep-HPLC (C18, 10 mmol / L, NH4HCO3 / water, MeCN) to obtain the target compound (16.88 mg).

[0395] LCMS(ESI)[M+H] + =372.2; 1 H NMR(400 MHz, DMSO-d6)δ 8.64(d, J=16.4 Hz, 1H), 8.49(d, J=5.0 Hz, 1H), 7.54 - 7.37(m, 2H), 4.95 - 4.75(m, 5H), 3.79(d, J=5.2 Hz, 2H), 3.53 - 3.40(m, 1H), 3.28 - 3.18(m, 1H), 3.05 - 2.96(m, 1H), 2.93 - 2.82(m, 1H), 2.45 - 2.31(m, 2H), 2.30 - 2.18(m, 2H), 1.95 - 1.71(m, 2H).

[0396] Example 15 (Compound 25) Synthesis of (R / S)-2-(5-chloroisoindolin-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0397] [ka]

[0398] 66 mg of 5-chloro-2,3-dihydro-1H-isoindoline hydrochloride was added to a mixed solution of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg) and N,N-diisopropylethylamine (67 mg) in tetrahydrofuran (5 mL) and water (1 mL). The mixture was heated to 70°C and stirred for 12 hours. After monitoring by LC-MS, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (30 mL), separated, and the organic phases were combined. The organic phase was concentrated under reduced pressure and then separated and purified by Prep-HPLC (C18, 10 mmol / LHCOOH / water, MeCN) to obtain the target compound (35 mg).

[0399] LCMS(ESI)[M+H] + =405.1; 1 H NMR(400 MHz, DMSO-d6)δ 7.50(d, J=18.1 Hz, 1H), 7.43(dd, J=16.8, 8.5 Hz, 2H), 7.36(dd, J=8.2, 1.8 Hz, 1H), 4.86(t, J=5.6 Hz, 1H), 4.77(t, J=8.7 Hz, 4H), 3.83 - 3.74(m, 2H), 3.52 - 3.40(m, 1H), 3.24(dt, J=13.4, 8.3 Hz, 1H), 3.04 - 2.94(m, 1H), 2.93 - 2.84(m, 1H), 2.38(dt, J=21.1, 10.6 Hz, 2H), 2.23(dd, J=11.1, 7.4 Hz, 2H), 1.90 - 1.70(m, 2H).

[0400] Example 16 (Compound 26) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(5-methoxyisoindolin-2-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0401] [ka]

[0402] 65 mg of 5-methoxy-2,3-dihydro-1H-isoindoline hydrochloride was added to a mixed solution of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide and 16 mg of N,N-diisopropylethylamine in 5 mL of tetrahydrofuran and 1 mL of water. The mixture was heated to 70°C and stirred for 12 hours. After monitoring by LC-MS, the reaction was completed, and the reaction solution was diluted with water (10 mL). The solution was extracted with ethyl acetate (50 mL) and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was then separated and purified by Prep-HPLC (C18, 10 mmol / LHCOOH / water, MeCN) to obtain the target compound (30 mg).

[0403] LCMS(ESI)[M+H] + =401.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.39(s, 1H), 7.29(dd, J=17.7, 8.4 Hz, 1H), 6.99(d, J=23.6 Hz, 1H), 6.87(d, J=8.3 Hz, 1H), 4.87(s, 1H), 4.73(dd, J=17.4, 7.7 Hz, 4H), 3.79(s, 2H), 3.76(s, 3H), 3.51 - 3.41(m, 1H), 3.24(dt, J=13.4, 8.4 Hz, 1H), 2.98(dd, J=17.0, 8.1Hz, 1H), 2.88(dd, J=14.0, 6.4 Hz, 1H), 2.47 - 2.31(m, 2H), 2.22(d, J=8.9 Hz, 2H), 1.92 - 1.70(m, 2H).

[0404] Example 17 (Compound 27) Synthesis of (R / S)-2-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)isoindoline-5-carbonitrile:

[0405] [ka]

[0406] 63 mg of 2,3-dihydro-1H-isoindoline-5-carbonitride hydrochloride was added to a mixed solution of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg) and N,N-diisopropylethylamine (67 mg) in tetrahydrofuran (5 mL) and water (1 mL). The mixture was heated to 70°C and stirred for 12 hours. After monitoring by LC-MS, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (30 mL), separated, and the organic phase was dried over anhydrous sodium sulfate. After concentration, the solution was separated and purified by Prep-HPLC (C18, HCOOH / water 10 mmol / L, MeCN) to obtain the target compound (35 mg).

[0407] LCMS(ESI)[M+H] + =396.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.89(d, J=16.4 Hz, 1H), 7.77(d, J=7.9 Hz, 1H), 7.62(dd, J=19.2, 7.9 Hz, 1H), 7.45(s, 1H), 4.94 - 4.72(m, 5H), 3.86 - 3.75(m, 2H), 3.53 - 3.40(m, 1H), 3.24(dt, J=13.5, 8.3 Hz, 1H), 2.98(dd, J=17.0, 8.1 Hz, 1H), 2.93 - 2.85(m, 1H), 2.39(td, J=20.4, 10.0 Hz, 2H), 2.23(t, J=9.3 Hz, 2H), 1.80(dt, J=28.2, 9.5 Hz, 2H).

[0408] Example 18 (Compound 28) Synthesis of (R / S)-2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0409] [ka]

[0410] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (100.64 mg), and N,N-diisopropylethylamine (179.64 mg) were added to dioxane (2 mL) and stirred at 120°C with microwaves for 2 hours. Monitoring by LC-MS showed the disappearance of the starting materials. The reaction product was directly separated and purified by Prep-HPLC (C18, 10 mmol / L, NH4HCO3 / water, MeCN) to obtain the target compound (53.14 mg).

[0411] LCMS:(ESI)[M+H] + =372.30; 1 H NMR(400 MHz, DMSO-d6)δ 8.55 - 8.42(m, 1H), 7.83(dd, J=19.4, 7.5 Hz, 1H), 7.44(s, 1H), 7.33(dd, J=7.7, 4.9 Hz, 1H), 4.94 - 4.72(m, 5H), 3.79(d, J=5.5 Hz, 2H), 3.52 - 3.40(m, 1H), 3.30 - 3.19(m, 1H), 3.02 - 2.88(m, 1H), 2.94 - 2.85(m, 1H), 2.49 - 2.33(m, 2H), 2.25 - 2.21(m, 2H), 1.90 - 1.70 (m, 2H).

[0412] Example 19 (Compound 29) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(5-(2-hydroxypropan-2-yl)isoindorin-2-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0413] [ka]

[0414] Step 1: Methyl 2-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)isoindoline-5-carboxylate:

[0415] [ka]

[0416] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (120 mg), methyl-isoindoline-5-carboxylate hydrochloride (106.8 mg), and N,N-diisopropylethylamine (1 mL) were dissolved in dioxane (3 mL), and the reaction system was reacted at 120 °C for 1 hour. Monitoring by LC-MS showed the main peak of the product, and the solvent was then dried using a rotary evaporator. The crude product was added to ethyl acetate (5 mL) and sonicated for 1 minute. The solid was then filtered by suction, and the cake was washed with ethyl acetate. The cake was then concentrated to dryness to obtain the target compound (200 mg). LC-MS(ESI)[M+H] + = 429.31.

[0417] Step 2: Preparation of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(5-(2-hydroxypropan-2-yl)isoindorin-2-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0418] [ka]

[0419] Methyl(R / S)-2-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)isoindoline-5-carboxylate (150 mg) was dissolved in anhydrous tetrahydrofuran (10 mL), and methylmagnesium bromide (2 mL, 3 M, in 2-methyltetrahydrofuran) was added under ice bath. The reaction system was then stirred at room temperature for 2 hours. Monitoring by LC-MS showed a major peak of the product, and the reaction was then quenched by adding saturated ammonium chloride aqueous solution (5 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (41.24 mg).

[0420] LCMS(ESI)[M+H] + =429.32; 1 H NMR(400 MHz, DMSO-d6)δ 7.50(s, 1H), 7.45-7.36(m, 2H), 7.31(dd, J=13.9, 8.0 Hz, 1H), 5.02(d, J=8.7 Hz, 1H), 4.87(t, J=5.5 Hz, 1H), 4.76(d, J=10.1 Hz, 4H), 3.80(d, J=5.5 Hz, 2H), 3.51-3.41(m, 1H), 3.24(dt, J=13.3, 8.3 Hz, 1H), 3.03-2.85(m, 2H), 2.40(dd, J=21.4, 9.7Hz, 2H), 2.23(s, 2H), 1.90-1.72(m, 2H), 1.43(s, 6H).

[0421] Example 20 (Compound 30) Synthesis of (R / S)-2-(benzo[b]thiophen-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0422] [ka]

[0423] Under a nitrogen gas atmosphere, (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg) and benzo[b]thiophene-2-ylboronic acid (75 mg) were added to dioxane (8 mL). Water (2 mL) was added to the reaction mixture, and while stirring, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (25 mg) and potassium carbonate (121 mg) were added. After submerging the mixture with nitrogen gas three times, the reaction mixture was heated to 85°C and allowed to react for 1 hour, consuming the starting materials and converting them to the product. After stopping the heating and cooling to room temperature, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3) to separate the organic phase. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (22 mg).

[0424] LCMS(ESI)[M+H] + =386; 1H NMR(400 MHz, DMSO-d6)δ 8.24(s, 1H), 8.20(s, 1H), 8.05 - 7.94(m, 2H), 7.47 - 7.39(m, 2H), 4.91(t, J=5.6 Hz, 1H), 3.92 - 3.81(m, 2H), 3.72 - 3.59(m, 1H), 3.42 - 3.34(m, 1H), 3.22(dd, J=17.1, 7.9 Hz, 1H), 3.04(dd, J=13.7, 6.2 Hz, 1H), 2.39(dt, J=16.2, 9.7 Hz, 4H), 1.84(dd, J=18.1, 9.2 Hz (2H).

[0425] Example 21 (Compound 31) Synthesis of (R / S)-N-(2-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)isoindorin-5-yl)methanesulfonamide:

[0426] [ka]

[0427] Step 1: Preparation of tert-butyl 5-(methylsulfonamide)isoindoline-2-carboxylate:

[0428] [ka]

[0429] Under a nitrogen gas atmosphere, tert-butyl 5-bromoisoindoline-2-carboxylate (1.2 g), N,N-dimethylglycine (41.3 mg), methylsulfonamide (457 mg), copper iodide (76 mg), and anhydrous potassium phosphate (1.7 g) were added to anhydrous dimethyl sulfoxide (DMSO) (30 mL), the temperature was raised to 150 °C, and the reaction was allowed to proceed for 48 hours. Monitoring by LC-MS confirmed that the product was partially converted. After lowering the reaction mixture to room temperature, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (silica gel, petroleum ether:tetrahydrofuran = 100:0 to 50:50 gradient elution) to obtain the target compound (400 mg). LCMS(ESI)[2M+Na] + = 647.3.

[0430] Step 2: Production of N-(isoindolin-5-yl)methanesulfonamide hydrochloride;

[0431] [ka]

[0432] Under a nitrogen gas atmosphere, tert-butyl 5-(methylsulfonamide)isoindoline-2-carboxylate (400 mg) was dissolved in dichloromethane (20 mL), stirred in an ice bath for 10 minutes, and 0.96 mL of ethyl acetate solution of 4 M hydrogen chloride at 0°C was added to the reaction mixture. The ice bath was removed, and the temperature was raised to room temperature for 1 hour until the starting materials were consumed and the product was obtained. The mixture was filtered, the cake was washed with 5 mL of dichloromethane, and the cake was concentrated to dryness to obtain the target compound (230 mg). LCMS(ESI)[M+H] + =213.

[0433] Step 3: (R / S)-N-(2-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)isoindorin-5-yl)methanesulfonamide;

[0434] [ka]

[0435] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg) and N-(isoindorin-5-yl)methanesulfonamide hydrochloride (104 mg) were added to dioxane (5 mL) under a nitrogen atmosphere. Then, N,N-diisopropylethylamine (114 mg) was added, and after three nitrogen substitutions, the reaction mixture was heated to 110°C and reacted for 1 hour. Monitoring by LC-MS showed that the starting materials were consumed and converted to the product. Heating was stopped, the reaction mixture was concentrated to dryness, and the residue was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (25.5 mg).

[0436] LCMS(ESI)[M+H] + =464.1; 1H NMR(400 MHz, DMSO-d6)δ 9.72(s, 1H), 7.40(s, 1H), 7.35(dd, J=18.7, 8.3 Hz, 1H), 7.24(d, J=13.0 Hz, 1H), 7.14(dd, J=13.8, 5.7 Hz, 1H), 4.86(t, J=5.7 Hz, 1H), 4.76(t, J=10.5 Hz, 4H), 3.79(d, J=5.5 Hz, 2H), 3.46(dt, J=16.3, 8.0 Hz, 1H), 3.23(dt, J=13.4, 8.3 Hz, 1H), 3.04 - 2.93(m, 4H), 2.92 - 2.84(m, 1H), 2.47 - 2.30(m, 2H), 2.23(d, J=7.8 Hz, 2H), 1.90 - 1.70(m, 2H).

[0437] Example 22 (Compound 40) Synthesis of (1-((2-(4-(5-chloropyrimidine-2-yl)piperidine-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methanol:

[0438] [ka]

[0439] (1-((2-chloro-6H,7H-thieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methanol (50 mg), 5-chloro-2-(piperidine-4-yl)pyrimidine p-toluenesulfonate (102.07 mg), and potassium carbonate (74.63 mg) were added to N,N-dimethylformamide (DMF) (1 mL), and the mixture was reacted at 150°C under microwave conditions for 0.5 hours. Monitoring by LC-MS showed that the starting materials were almost completely consumed and the product had been formed. The reaction mixture was filtered, and the filtrate was directly separated and purified by Prep-HPLC (C18, 10 mmol / L, NH4HCO3 / water, MeCN) to obtain the target compound (22.49 mg).

[0440] LCMS(ESI)[M+H]+ =433.30; 1 H NMR(400 MHz, DMSO-d6)δ 8.85(s, 2H), 5.97(s, 1H), 4.80(t, J=5.6 Hz, 1H), 4.65 - 4.50(m, 2H), 3.68(d, J=5.6 Hz, 1H), 3.21(t, J=8.1 Hz, 2H), 3.17 - 3.07(m, 1H), 3.00 - 2.85(m, 4H), 2.36 - 2.25(m, 2H), 2.17 - 2.05(m, 2H), 1.85 - 1.85(m, 2H), 1.81 - 1.57(m, 4H).

[0441] Example 23 (Compound 7) Synthesis of (R / S)-2-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0442] [ka]

[0443] Step 1: Preparation of tert-butyl 3-hydroxy-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylate:

[0444] [ka]

[0445] 1-iodo-4-(trifluoromethyl)benzene (2.00 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (40 mL), and n-butyllithium (2.5 M, 1.0 eq in hexane) was added dropwise at -78°C under a nitrogen atmosphere, and the mixture was stirred for 0.5 hours while maintaining temperature. tert-butyl3-oxoazetidine-1-carboxylate (1.5 eq) was dissolved in anhydrous tetrahydrofuran (15 mL), and this was added dropwise to the above n-butyllithium solution at -78°C, and the mixture was stirred for 0.5 hours while maintaining temperature. Monitoring by LCMS showed that the starting materials had disappeared and the main peak of the product was observed. The reaction mixture was quenched by adding water (10 mL) dropwise at -78°C, the reaction mixture was poured into water (300 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was washed with water (200 mL x 3), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound (1.30 g). LC-MS: (ESI) [M-56] + = 262.

[0446] Step 2: Preparation of 3-(4-(trifluoromethyl)phenyl)azetidine-3-ol 2,2,2-trifluoroacetate:

[0447] [ka]

[0448] 165 mg, 1 eq of tert-butyl 3-hydroxy-3-(4-(trifluoromethyl)phenyl)azetidine-1-carboxylate was dissolved in 2 mL of dichloromethane, and trifluoroacetic acid (1 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour. Monitoring by LC-MS showed that the starting material had disappeared and the product had a major peak. The reaction mixture was dried using a rotary evaporator to obtain the target compound (170 mg).

[0449] Step 3: Preparation of (R / S)-2-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0450] [ka]

[0451] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 1 eq), 3-[4-(trifluoromethyl)phenyl]azetidine-3-ol 2,2,2-trifluoroacetate (1.5 eq), and DIEA (5 eq) were dissolved in dioxane (2 mL) and reacted at 120°C for 1 hour using microwave. Monitoring by LC-MS showed that the starting materials disappeared and the product had a major peak. The reaction mixture was directly separated and purified by Prep-HPLC (C18, 10 mmol / L, aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (42 mg).

[0452] LCMS:(ESI)[M+H] + =469.2; 1 H NMR(400 MHz, DMSO-d6+ D2O)δ 7.80 - 7.68(m, 4H), 4.35 - 4.10(m, 4H), 3.75 - 3.71(m, 1H), 3.69 - 3.64(m, 1H), 3.48 - 3.34(m, 1H), 3.31 - 3.20(m, 1H), 3.02 - 2.84(m, 2H), 2.38 - 2.20(m, 2H), 2.15 - 2.05(m, 2H), 1.85 - 1.62(m, 2H).

[0453] Example 24 (Compound 8) Synthesis of (R / S)-2-(4-((2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)phenyl)acetic acid:

[0454] [ka]

[0455] Step 1: Preparation of ethyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)aminophenyl)acetate:

[0456] [ka]

[0457] 2,4-Dichloro-6,7-Dihydrothieno[3,2-d]pyrimidine (1.5 g, 1.0 eq), ethyl 2-(4-aminophenyl) acetate (1.2 eq), and N,N-diisopropylethylamine (3.0 eq) were dissolved in dimethyl sulfoxide (20 mL), and the reaction system was reacted at 145 °C for 16 hours. Monitoring by LC-MS showed the main peak of the product. The reaction system was lowered to room temperature, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with water (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to obtain the target compound (1.98 g). LC-MS(ESI)[M+H] + =350.1.

[0458] Step 2: Preparation of (R / S)-ethyl 2-(4-((2-chloro-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)aminophenyl)acetate:

[0459] [ka]

[0460] Ethyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)phenyl) acetate (600 mg, 1.0 eq) and (S)-(-)-1,1'-bi-2-naphthol (0.1 eq) were dissolved in dichloromethane (5 mL) and stirred for 5 minutes under a nitrogen gas atmosphere. Next, tetraisopropyl titanate (Ti(O)) was added. i Pr)4) (0.1 eq) and water (1.0 eq) were added and the mixture was stirred at room temperature for 1 hour. Under an ice bath, tert-butyl hydroperoxide (70% / water, 1.5 eq) was added and the mixture was stirred at room temperature for 16 hours. Monitoring by LC-MS mainly showed the product. The solution was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by flash chromatography (silica gel, dichloromethane:methanol = 20:1) to obtain the target compound (230 mg). LC-MS(ESI)[M+H] + = 366.2.

[0461] Step 3: (R / S)-Ethyl 2-(4-((2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)phenyl)acetate:

[0462] [ka]

[0463] (R / S)-ethyl 2-(4-((2-chloro-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)phenyl)acetate (230 mg, 1.0 eq), 3-(3-chloro-4-methoxyphenyl)azetidine-3-oltrifluoroacetate (1.3 eq), and N,N-diisopropylethylamine (3.0 eq) were dissolved in 1,4-dioxane (4 mL) and reacted at 120 °C for 2 hours. Monitoring by LC-MS showed the main peak of the product. The reaction system was lowered to room temperature, water (30 mL) was added, and the mixture was stirred for 0.5 hours. The solid was filtered, and the cake was washed twice with water to obtain the target compound (200 mg). LC-MS(ESI)[M+H] + = 543.4.

[0464] Step 4: (R / S)-2-(4-((2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)phenyl)acetic acid

[0465] [ka]

[0466] (R / S)-ethyl 2-(4-((2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)phenyl)acetate (200 mg, 1.0 eq) and lithium hydroxide monohydrate (10 eq) were dissolved in tetrahydrofuran (3 mL), MeOH (3 mL), and water (1.5 mL), and the reaction system was stirred at 25°C for 2 hours. Monitoring by LC-MS showed the main peak of the product, and then aqueous citric acid solution was added to adjust the pH to 5-6. The aqueous phase was extracted with ethyl acetate (30 mL x 2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L formic acid aqueous solution, acetonitrile) to obtain the target compound (42 mg).

[0467] LCMS(ESI)[M+H] + =515.2; 1 H NMR(400 MHz, DMSO-d6)δ 9.55(s, 1H), 7.73(d, J=8.6 Hz, 2H), 7.55(s, 1H), 7.46(d, J=8.3 Hz, 1H), 7.17(dd, J=13.7, 8.6 Hz, 3H), 6.48(s, 1H), 4.26(t, J=8.9 Hz, 4H), 3.85(s, 3H), 3.57 - 3.51(m, 1H), 3.50(s, 1H), 3.31 - 3.23(m, 3H), 3.07(dd, J=17.1, 8.0 Hz, 1H), 2.98(dd, J=14.1, 6.6 Hz, 1H).

[0468] Example 25 (Compound 10) Synthesis of (R / S)-2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-4-((3-(2-hydroxypropan-2-yl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0469] [ka]

[0470] Step 1: Preparation of methyl 3-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)aminobenzoate:

[0471] [ka]

[0472] 2,4-Dichloro-6,7-Dihydrothieno[3,2-d]pyrimidine (1.2 g, 1.0 eq), methyl 3-aminobenzoate (1.2 eq), and N,N-diisopropylethylamine (3.0 eq) were dissolved in dimethyl sulfoxide (20 mL). The reaction system was then reacted at 120 °C for 16 hours, and the main peak of the product was observed by monitoring with LC-MS. The reaction system was then cooled, water was added, the aqueous phase was extracted with ethyl acetate (100 mL x 2), and the organic phase was washed with water (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by flash chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to obtain the target compound (550 mg). LC-MS(ESI)[M+H] + =322.1.

[0473] Step 2: Preparation of (R / S)-methyl 3-((2-chloro-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)benzoate:

[0474] [ka]

[0475] Methyl 3-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)benzoate (340 mg, 1.0 eq) and (S)-(-)-1,1'-bi-2-naphthol (0.1 eq) were dissolved in dichloromethane (3 mL), and water (1.0 eq) and tetraisopropyl titanate (1.0 eq) were added under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. Next, tert-butyl hydroperoxide (1.5 eq) was added, and the mixture was stirred overnight at room temperature. Monitoring by LC-MS showed the main peak of the product. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by flash chromatography (silica gel, dichloromethane:methanol = 20:1) to obtain the target compound (120 mg). LC-MS(ESI)[M+H] + = 338.1.

[0476] Step 3: Preparation of methyl(R / S)-3-((2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)benzoate:

[0477] [ka]

[0478] Methyl(R / S)-3-((2-chloro-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)benzoate (120 mg, 1.0 eq), 3-(3-chloro-4-methoxyphenyl)azetidine-3-oltrifluoroacetate (2.0 eq), and N,N-diisopropylethylamine (10 eq) were dissolved in 1,4-dioxane (4 mL), and the reaction system was reacted at 120 °C for 2 hours. Monitoring by LC-MS indicated completion of the reaction. The reaction system was then lowered to room temperature, water (30 mL) was added, and the mixture was stirred overnight. The mixture was filtered, and the cake was sequentially washed with water (10 mL x 2) and acetone (5 mL) to obtain the target compound (164 mg). LC-MS(ESI)[M+H] + = 515.3.

[0479] Step 4: Preparation of (R / S)-2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-4-((3-(2-hydroxypropan-2-yl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0480] [ka]

[0481] Methyl(R / S)-3-((2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)benzoate (100 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (5 mL), and then methylmagnesium bromide (3 M diethyl ether solution, 10.0 eq) was added under ice bath. The reaction system was stirred at room temperature for 16 hours. Monitoring by LC-MS indicated that the reaction was complete, and then saturated ammonium chloride aqueous solution (10 mL) was added to quench the reaction. The aqueous solution was extracted with ethyl acetate (30 mL x 2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (4 mg).

[0482] LCMS(ESI)[M+H] + =515.2; 1 H NMR(400 MHz, DMSO-d6)δ 9.52(s, 1H), 8.00(s, 1H), 7.62 - 7.51(m, 2H), 7.45(d, J=8.4 Hz, 1H), 7.22(t, J=7.9 Hz, 1H), 7.15(t, J=6.2 Hz, 2H), 6.48(s, 1H), 4.94(s, 1H), 4.25(d, J=8.5 Hz, 4H), 3.85(s, 3H), 3.51(dd, J=16.8, 8.2 Hz, 1H), 3.26(d, J=8.4 Hz, 1H), 3.07(dd, J=17.1, 7.8 Hz, 1H), 2.97(dd, J=13.7, 6.7 Hz, 1H), 1.41(s, 6H).

[0483] Example 26 (Compound 18) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0484] [ka]

[0485] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), [4-(2-hydroxypropan-2-yl)phenyl]boronic acid (1.5 eq), Pd(dppf)Cl2 (0.1 eq), and potassium carbonate (2.5 eq) were added to dioxane (3 mL) and water (1 mL), purged three times with nitrogen, and stirred at 110°C for 3 hours under a nitrogen gas atmosphere. Monitoring by LCMS showed that most of the starting materials had disappeared and the product had been formed. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (8 mg).

[0486] LCMS:(ESI)[M+1] + =388.28; 1 H NMR(400 MHz, DMSO-d6)δ 8.25(d, J=8.4 Hz, 2H), 7.97(s, 1H), 7.58(d, J=8.4 Hz, 2H), 5.09(s, 1H), 4.92(t, J=5.7 Hz, 1H), 3.87 - 3.77(m, 2H), 3.69 - 3.57(m, 1H), 3.42 - 3.33(m, 1H), 3.25 - 3.15(m, 1H), 3.10 - 2.95(m, 1H), 2.49 - 2.10(m, 4H), 1.93 - 1.76(m, 2H), 1.45(s, 6H).

[0487] Example 27 (Compound 19) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(trifluoromethyl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0488] [ka]

[0489] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), [4-(trifluoromethyl)phenyl]boronic acid (1.5 eq), Pd(dppf)Cl2 (0.1 eq), and potassium carbonate (2.5 eq) were added to dioxane (3 mL) and water (1 mL), purged three times with nitrogen, and stirred at 110 °C for 3 hours under a nitrogen gas atmosphere. Monitoring by LC-MS showed that the starting materials had disappeared and the main peak of the product was observed. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (1 mg).

[0490] LCMS:(ESI)[M+1] + =398.1; 1 H NMR(400 MHz, DMSO-d6)δ 8.50(d, J=8.1 Hz, 2H), 8.20(s, 1H), 7.88(d, J=8.3 Hz, 2H), 4.93(t, J=5.7 Hz, 1H), 3.90 - 3.76(m, 2H), 3.75 -3.60(m, 1H), 3.44 - 3.36(m, 1H), 3.30 - 3.20(m, 1H), 3.10 - 3.00(m, 1H), 2.44 - 2.30(m, 4H), 1.93 - 1.75(m, 2H).

[0491] Example 28 (Compound 20) Synthesis of (R / S)-2-(4-chlorophenyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0492] [ka]

[0493] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 eq) was added to a solution of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), (4-chlorophenyl)boronic acid (1.2 eq), and potassium carbonate (2.5 eq) in dioxane (3 mL) and water (0.6 mL). The resulting mixture was heated to 110°C and reacted for 2 hours. LC-MS monitoring indicated completion of the reaction. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (50 mL), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was then separated and purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (16 mg).

[0494] LCMS(ESI)[M+H] + =364.2; 1 H NMR(400 MHz, DMSO-d6)δ 8.31(d, J=8.7 Hz, 2H), 8.11(s, 1H), 7.57(d, J=8.6 Hz, 2H), 4.92(t, J=5.7 Hz, 1H), 3.90 - 3.76(m, 2H), 3.70 - 3.57(m, 1H), 3.41 - 3.35(m, 1H), 3.21(ddd, J=17.1, 8.1, 1.8 Hz, 1H), 3.11 - 2.97(m, 1H), 2.40(d, J=12.1 Hz, 1H), 2.34(dd, J=15.4, 6.3Hz, 3H), 1.82(dd, J=17.9, 9.2Hz, 2H).

[0495] Example 29 (Compound 21) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(trifluoromethoxy)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0496] [ka]

[0497] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), (4-(trifluoromethoxy)phenyl)boronic acid (1.5 eq), Pd(dppf)Cl2 (0.1 eq), and potassium carbonate (2.5 eq) were added to dioxane (3 mL) and water (0.6 mL). After purging with nitrogen, the mixture was heated and stirred at 110 °C for 3 hours. Monitoring by LC-MS showed that the starting materials disappeared and the main peak of the product was observed. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (3 mg).

[0498] LCMS:(ESI)[M+H] + =414.2; 1 H NMR(400 MHz, DMSO-d6)δ 8.42(d, J=8.8 Hz, 2H), 8.12(s, 1H), 7.49(d, J=8.5 Hz, 2H), 4.91(t, J=5.7 Hz, 1H), 3.87 - 3.75(m, 2H), 3.70 - 3.58(m, 1H), 3.44 - 3.34(m, 1H), 3.24 - 3.18(m, 1H), 3.10 - 2.98(m, 1H), 2.50 - 2.10(m, 4H), 1.90 - 1.72(m, 2H).

[0499] Example 30 (Compound 35) Synthesis of (R / S)-2-(4-chloro-5-methoxyisoindolin-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0500] [ka]

[0501] Step 1: Preparation of tert-butyl 5-methoxyisoindoline-2-carboxylate:

[0502] [ka]

[0503] Under a nitrogen gas atmosphere, 5-methoxyisoindoline (300 mg, 1.0 eq) was added to dichloromethane (10 mL). Triethylamine (2.0 eq) and di-tert-butyl dicarbonate (1.5 eq) were added to the reaction mixture, and the reaction was allowed to proceed at room temperature for 16 hours. Monitoring by LC-MS confirmed that the starting materials were consumed and converted to the product. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 300 mg of the target compound. LC-MS (ESI) [M+H] + = 250.2.

[0504] Step 2: Production of tert-butyl 4-chloro-5-methoxyisoindoline-2-carboxylate:

[0505] [ka]

[0506] Under a nitrogen gas atmosphere, tert-butyl 5-methoxyisoindoline-2-carboxylate (300 mg, 1.0 eq) was added to acetonitrile (5 mL) and tetrahydrofuran (5 mL). N-chlorosuccinimide (1.5 eq) was added to the reaction mixture, and the reaction was allowed to proceed at room temperature for 16 hours. Monitoring by LC-MS confirmed that the starting materials were consumed and converted to the product. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (60 mg). LC-MS (ESI) [M+H] + = 284.2.

[0507] Step 3: Preparation of 4-chloro-5-methoxyisoindoline hydrochloride:

[0508] [ka]

[0509] Under a nitrogen gas atmosphere, tert-butyl 4-chloro-5-methoxyisoindoline-2-carboxylate (60 mg, 1.0 eq) was added to 1,4-dioxane (5 mL), and the mixture was stirred in an external ice bath for 20 minutes. 4 M hydrogen chloride / 1,4-dioxane (19.0 eq) was added to the reaction mixture, and the mixture was stirred in an ice bath for 10 minutes. The ice bath was removed, and the reaction was allowed to proceed at room temperature for 2 hours. LC-MS monitoring indicated that the starting materials were consumed and converted to the product. The reaction mixture was concentrated to obtain the target compound (46 mg). LC-MS(ESI)[M+H] + = 184.1.

[0510] Step 4: Preparation of (R / S)-2-(4-chloro-5-methoxyisoindolin-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0511] [ka]

[0512] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 1.0 eq) and 4-chloro-5-methoxyisoindoline hydrochloride (1.0 eq) were added to 1,4-dioxane (5 mL) under a nitrogen atmosphere. N,N-diisopropylethylamine (3 eq) was added to the reaction mixture, and the mixture was reacted at 100°C for 6 hours. Monitoring by LC-MS showed that the starting materials were consumed and converted to the product. After cooling to room temperature, water (30 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (42 mg).

[0513] LCMS(ESI)[M+H] + =435.1; 1 H NMR(400 MHz, DMSO-d6)δ 7.48(d, J=20.9 Hz, 2H), 7.23(d, J=32.6 Hz, 1H), 4.84(d, J=29.1 Hz, 1H), 4.75(s, 2H), 4.71(d, J=7.1 Hz, 2H), 3.86(s, 3H), 3.79(s, 2H), 3.53 - 3.40(m, 1H), 3.23(dt, J=13.5, 8.3 Hz, 1H), 3.05 - 2.93(m, 1H), 2.89(dd, J=13.5, 6.5 Hz, 1H), 2.47 - 2.31(m, 2H), 2.19(d, J=28.1 Hz, 2H), 1.91 - 1.69(m, 2H).

[0514] Example 31 (Compound 65) Synthesis of (R / S)-1-(3-((2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)phenyl)ethane-1-one:

[0515] [ka]

[0516] Methyl(R / S)-3-((2-(3-(3-chloro-4-methoxyphenyl)-3-hydroxyazetidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)benzoate (100 mg, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (5 mL), and then methylmagnesium bromide (3 M diethyl ether solution, 10.0 eq) was added under ice bath. The reaction system was stirred at room temperature for 16 hours. Monitoring by LC-MS indicated completion of the reaction, and then the reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL). The aqueous solution was extracted with ethyl acetate (30 mL x 2), and the organic phase was dried over anhydrous sodium sulfate and dried in a rotary evaporator to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (2 mg).

[0517] LCMS(ESI)[M+H] + =499.2; 1H NMR(400 MHz, DMSO-d6)δ 9.81(s, 1H), 8.63(s, 1H), 8.04(d, J=8.5 Hz, 1H), 7.65(d, J=8.1 Hz, 1H), 7.55(s, 1H), 7.47(t, J=7.8 Hz, 2H), 7.17(s, 1H), 6.52(d, J=11.7 Hz, 1H), 4.29(d, J=14.5 Hz, 4H), 3.85(s, 3H), 3.54(d, J=8.8 Hz, 1H), 3.26(d, J=7.2 Hz, 1H), 3.14 - 3.07(m, 1H), 3.05 - 2.97 (m, 1H), 2.56 (s, 3H)

[0518] Example 32 (Compound 66) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(3-methoxyazetidine-1-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0519] [ka]

[0520] Step 1: Preparation of 1-(4-bromophenyl)-3-methoxyazetidine:

[0521] [ka]

[0522] Under a nitrogen gas atmosphere, 1-bromo-4-iodobenzene (565 mg, 1.0 eq) and 3-methoxyazetidine hydrochloride (1.0 eq) were added to 1,4-dioxane (10 mL). Pd2(dba)3 (0.05 eq), 4,5-bis-diphenylphosphino-9,9-dimethylxanthene (0.05 eq), and cesium carbonate (2.5 eq) were added to the reaction mixture. The reaction mixture was heated to 100°C and reacted for 2 hours. Monitoring by LC-MS showed that the starting materials were consumed and converted to the product. Heating was stopped, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether:ethyl acetate = 20:1) to obtain the target compound (370 mg). LC-MS(ESI)[M+H] + = 242.1.

[0523] Step 2: Preparation of 3-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine:

[0524] [ka]

[0525] Under a nitrogen gas atmosphere, 1-(4-bromophenyl)-3-methoxyazetidine (370 mg, 1.0 eq) and bis(pinacolate)diborone (1.2 eq) were added to 1,4-dioxane (15 mL). Pd(dppf)Cl2 (0.1 eq) and potassium acetate (2.5 eq) were added to the reaction mixture, and the reaction mixture was heated to 90°C and allowed to react for 2 hours. Monitoring by LC-MS indicated that the starting materials were consumed and converted to the product. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1~10:1) to obtain 350 mg of the target compound. LC-MS(ESI)[M+H] + = 290.2.

[0526] Step 3: Preparation of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(3-methoxyazetidine-1-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0527] [ka]

[0528] Under a nitrogen gas atmosphere, (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 1.0 eq) and 3-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine (1.2 eq) were added to 1,4-dioxane (8 mL). Water (2 mL) was added to the reaction mixture, and while stirring, Pd(PPh3)4 (0.1 eq) and sodium carbonate (2.5 eq) were added. The reaction mixture was heated to 80°C and reacted for 2 hours. Monitoring by LCMS showed that the starting materials were consumed and converted to the product. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 663). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (23 mg).

[0529] LCMS(ESI)[M+H] + =415.3; 1H NMR(400 MHz, DMSO-d6)δ 8.17(d, J=8.7 Hz, 2H), 7.80(s, 1H), 6.49(d, J=8.8 Hz, 2H), 4.92(t, J=5.3 Hz, 1H), 4.39 - 4.30(m, 1H), 4.18 - 4.07(m, 2H), 3.80(d, J=4.9 Hz, 2H), 3.71(dd, J=8.5, 4.0 Hz, 2H), 3.65 - 3.52(m, 1H), 3.32 - 3.28(m, 1H), 3.26(s, 3H), 3.14(dd, J=17.0, 8.1Hz, 1H), 2.98(dd, J=13.7, 5.7 Hz, 1H), 2.46 - 2.33(m, 2H), 2.30(dd, J=8.2, 4.7 Hz, 2H), 1.82(dt, J=18.0, 9.1 Hz, 2H).

[0530] Example 33 (Compound 67) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(4-methylpiperazin-1-yl)phenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0531] [ka]

[0532] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (13 mg, 0.1 eq) was added to a mixture of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (1 eq), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (1 eq), potassium carbonate (2.5 eq), dioxane (1 mL), and water (0.2 mL). The mixture was heated to 110°C and reacted for 2 hours. TLC detection indicated completion of the reaction. The reaction solution was diluted with ethyl acetate (100 mL), activated carbon (0.05 g) was added to the diluted solution and stirred for 4 hours, filtered through a diatomaceous earth (2.00 g) cake, concentrated the filtrate, and then separated and purified it by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (30 mg).

[0533] LCMS(ESI)[M+H] + =428.4; 1 H NMR(400 MHz, DMSO-d6)δ 8.17(d, J=8.9 Hz, 2H), 7.82(s, 1H), 7.00(d, J=9.0 Hz, 2H), 4.92(t, J=5.6 Hz, 1H), 3.81(d, J=5.4 Hz, 2H), 3.65 - 3.53(m, 1H), 3.38 - 3.34(m, 1H), 3.30 - 3.24(m, 4H), 3.15(dd, J=17.1, 8.2 Hz, 1H), 2.99(dd, J=13.7, 5.7 Hz, 1H), 2.47 - 2.42(m, 4H), 2.41 - 2.33(m, 2H), 2.33 - 2.24(m, 2H), 2.22(s, 3H), 1.84(dd, J=16.6, 8.4 Hz, 2H).

[0534] Example 34 (Compound 68) Synthesis of (R / S)-1-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)pyrrolidine-2-one:

[0535] [ka]

[0536] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (13 mg, 0.1 eq) was added to a mixture of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (1 eq), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-one (1.2 eq), potassium carbonate (2.5 eq), dioxane (2 mL), and water (0.5 mL). The mixture was heated to 110°C and reacted for 2 hours. TLC detection confirmed the completion of the reaction. The reaction solution was diluted with ethyl acetate (100 mL), activated carbon (0.1 g) was added to the diluted solution and stirred for 4 hours, filtered through a diatomaceous earth (2 g) cake, concentrated the filtrate, and then separated and purified it by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (30 mg).

[0537] LCMS(ESI)[M+H] + =413.1; 1H NMR(400 MHz, DMSO-d6)δ 8.32(d, J=8.8 Hz, 2H), 8.00(s, 1H), 7.81(d, J=8.9 Hz, 2H), 4.93(t, J=5.6 Hz, 1H), 3.89(t, J=7.0 Hz, 2H), 3.82(d, J=4.7 Hz, 2H), 3.70 - 3.52(m, 1H), 3.37(t, J=6.9 Hz, 1H), 3.20(dd, J=17.1, 8.1 Hz, 1H), 3.08 - 2.97(m, 1H), 2.54(t, J=8.1 Hz, 2H), 2.46 - 2.39(m, 1H), 2.38 - 2.25(m, 3H), 2.15 - 2.01(m, 2H), 1.93 - 1.74(m, 2H).

[0538] Example 35 (Compound 69) Synthesis of (R / S)-2-(4-(dimethylamino)phenyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0539] [ka]

[0540] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 eq) was added to a mixture of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.5 eq), potassium carbonate (2.5 eq), dioxane (2 mL), and water (0.5 mL). The mixture was heated to 110°C and reacted for 2 hours. TLC detection indicated completion of the reaction. The reaction mixture was diluted with water (10 mL) and ethyl acetate (30 mL), separated, and the organic phase was concentrated. The organic phase was then separated and purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (10 mg).

[0541] LCMS(ESI)[M+H] + =373.1; 1 H NMR(400 MHz, DMSO-d6)δ 8.17(d, J=9.0 Hz, 2H), 7.74(s, 1H), 6.77(d, J=9.0 Hz, 2H), 4.91(d, J=5.5 Hz, 1H), 3.81(d, J=5.1 Hz, 2H), 3.63 - 3.53(m, 1H), 3.31 - 3.28(m, 1H), 3.14(dd, J=17.5, 6.8 Hz, 1H), 3.00(s, 6H), 2.96(s, 1H), 2.39(dd, J=22.3, 12.3 Hz, 2H), 2.29(s, 2H), 1.91 - 1.75 (m, 2H).

[0542] Example 36 (Compound 70) Synthesis of (R / S)-4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)benzonitrile:

[0543] [ka]

[0544] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 eq) was added to a mixture of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), (4-cyanophenyl)boronic acid (1.5 eq), potassium carbonate (2.5 eq), dioxane (2 mL), and water (0.5 mL). The mixture was heated to 110°C and reacted for 2 hours. The reaction was completed by detection with LC-MS. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (30 mL), separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (50 mg).

[0545] LCMS(ESI)[M+H] + =355.2; 1 H NMR(400 MHz, DMSO-d6)δ 8.45(d, J=8.5 Hz, 2H), 8.25(s, 1H), 7.98(d, J=8.5 Hz, 2H), 4.94(t, J=5.7 Hz, 1H), 3.82(dd, J=5.7, 2.7 Hz, 2H), 3.72 - 3.60(m, 1H), 3.43 - 3.34(m, 1H), 3.24(dd, J=17.3, 8.3 Hz, 1H), 3.05(dd, J=13.7, 5.6 Hz, 1H), 2.45 - 2.38(m, 1H), 2.33(t, J=8.3 Hz, 3H), 1.85(dd, J=17.1, 8.7Hz, 2H).

[0546] Example 37 (Compound 71) Synthesis of (R / S)-N-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)acetamide:

[0547] [ka]

[0548] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 eq) was added to a mixture of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (1.5 eq), potassium carbonate (2.5 eq), dioxane (2 mL), and water (0.5 mL). The mixture was heated to 110°C and reacted for 2 hours. LC-MS detection indicated completion of the reaction. The reaction mixture was diluted with water (10 mL) and ethyl acetate (30 mL), separated, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (10 mg).

[0549] LCMS(ESI)[M+H] + =387.1; 1 H NMR(400 MHz, DMSO-d6)δ 10.18(s, 1H), 8.25(d, J=8.8 Hz, 2H), 7.96(s, 1H), 7.70(d, J=8.8 Hz, 2H), 4.92(t, J=5.7 Hz, 1H), 3.82(d, J=5.7 Hz, 2H), 3.62(dt, J=15.8, 7.7 Hz, 1H), 3.38(d, J=8.2 Hz, 1H), 3.19(dd, J=16.3, 7.4 Hz, 1H), 3.01(dd, J=13.6, 5.6 Hz, 1H), 2.42(dd, J=11.9, 9.7 Hz, 1H), 2.37 - 2.27(m, 3H), 2.08(s, 3H), 1.88 - 1.77(m, 2H).

[0550] Example 38 (Compound 72) Synthesis of (R / S)-N-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)methanesulfonamide:

[0551] [ka]

[0552] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 eq) was added to a mixture of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (1.5 eq), potassium carbonate (2.5 eq), dioxane (2 mL), and water (0.5 mL). The mixture was heated to 110°C and reacted for 2 hours. The reaction was completed by detection using LC-MS. The reaction mixture was diluted with water (10 mL) and ethyl acetate (30 mL), separated, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (15 mg).

[0553] LCMS(ESI)[M+H] + =423.1; 1H NMR(400 MHz, DMSO-d6)δ 9.93(s, 1H), 8.27(d, J=8.7 Hz, 2H), 8.01(s, 1H), 7.29(d, J=8.7 Hz, 2H), 4.93(t, J=5.7 Hz, 1H), 3.81(d, J=5.6 Hz, 2H), 3.61(dd, J=16.7, 8.5 Hz, 1H), 3.36(s, 1H), 3.19(dd, J=16.9, 7.9 Hz, 1H), 3.08(s, 3H), 3.01(dd, J=13.8, 5.9 Hz, 1H), 2.40(d, J=12.3Hz, 1H), 2.33(s, 3H), 1.89 - 1.76(m, 2H).

[0554] Example 39 (Compound 73) Synthesis of (R / S)-2-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)-2-methylpropanenitrile:

[0555] [ka]

[0556] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 eq) was added to a mixture of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), (4-(2-cyanopropan-2-yl)phenyl)boronic acid (1.5 eq), potassium carbonate (2.5 eq), dioxane (2 mL), and water (0.5 mL). The mixture was heated to 110°C and reacted for 2 hours. The reaction was completed by LC-MS detection. The reaction mixture was diluted with water (10 mL) and ethyl acetate (30 mL), separated, and the organic phase was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (25 mg).

[0557] .LCMS(ESI)[M+H] + =397.1; 1 H NMR(400 MHz, DMSO-d6)δ 8.35(d, J=8.5 Hz, 2H), 8.10(s, 1H), 7.66(d, J=8.6 Hz, 2H), 4.93(t, J=5.7 Hz, 1H), 3.82(d, J=4.1 Hz, 2H), 3.71 - 3.59(m, 1H), 3.41 - 3.35(m, 1H), 3.22(dd, J=17.2, 8.2 Hz, 1H), 3.04(dd, J=13.7, 5.6 Hz, 1H), 2.39(dd, J=17.5, 7.9 Hz, 1H), 2.36 - 2.27(m, 3H), 1.89 - 1.78(m, 2H), 1.73(s, 6H).

[0558] Example 40 (Compound 74) Synthesis of (R / S)-methyl 2-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)-2-methylpropanoate:

[0559] [ka]

[0560] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 eq) was added to a mixture of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 1 eq), methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.5 eq), potassium carbonate (2.5 eq), dioxane (2 mL), and water (0.5 mL). The mixture was heated to 110°C and reacted for 2 hours. The reaction was completed by detection using LC-MS. The reaction solution was diluted with ethyl acetate (100 mL), activated carbon (0.10 g) was added to the diluted solution and stirred for 4 hours, filtered through a diatomaceous earth (3.00 g) cake, concentrated the filtrate, and then separated and purified it by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (100 mg).

[0561] .LCMS(ESI)[M+H] + =430.3; 1 H NMR(400 MHz, DMSO-d6)δ 8.28(d, J=8.5 Hz, 2H), 8.04(s, 1H), 7.44(d, J=8.5 Hz, 2H), 4.92(t, J=5.6 Hz, 1H), 3.81(d, J=5.0 Hz, 2H), 3.65(dd, J=15.7, 6.5 Hz, 1H), 3.59(s, 3H), 3.43 - 3.35(m, 1H), 3.21(dd, J=16.4, 7.5 Hz, 1H), 3.03(dd, J=13.8, 5.8 Hz, 1H), 2.46 - 2.39(m, 1H), 2.38 - 2.25(m, 3H), 1.92 - 1.77(m, 2H), 1.54(s, 6H).

[0562] Example 41 (Compound 75) Synthesis of (R / S)-2-(4-(2-aminopropan-2-yl)phenyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0563] [ka]

[0564] Step 1: Preparation of (R / S)-tert-butyl2-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)propan-2-yl)carbamate:

[0565] [ka]

[0566] Under a nitrogen gas atmosphere, tert-butyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)carbamate (1.2 eq) and (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 1 eq) were dissolved in potassium carbonate (2.5 eq), to which [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 eq) was added, and the mixture was heated to 110°C and reacted for 2 hours. The reaction was completed by TLC detection. The reaction mixture was diluted with ethyl acetate (100 mL), activated carbon (0.50 g) was added, and the mixture was stirred for 6 hours. The mixture was filtered through a diatomaceous earth cake (3.00 g), and the filtrate was concentrated. The filtrate was then purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to obtain the target compound (100 mg). LCMS(ESI)[M+H] + = 487.1.

[0567] Step 2: Preparation of (R / S)-2-(4-(2-aminopropan-2-yl)phenyl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0568] [ka]

[0569] To a solution of tert-butyl(2-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)propan-2-yl)carbamate (60 mg, 1 eq) in dichloromethane (2 mL), 4 M hydrogen chloride / dioxane (20 eq) was added dropwise, and the mixture was allowed to react at room temperature for 6 hours. The reaction was completed by TLC detection. Saturated sodium bicarbonate solution was added to the reaction mixture to quench it and adjust the pH to 9-10. The mixture was extracted with dichloromethane (50 mL), separated, and the organic phase was concentrated under reduced pressure. The target compound (30 mg) was separated and purified by Prep-HPLC (C18, 10 mmol / L sodium bicarbonate aqueous solution, acetonitrile).

[0570] .LCMS(ESI)[M+H] + =387.1; 1 H NMR(400 MHz, DMSO-d6)δ 8.24(d, J=8.4 Hz, 2H), 7.99(s, 1H), 7.65(d, J=8.4 Hz, 2H), 4.93(t, J=5.6 Hz, 1H), 3.82(d, J=4.7 Hz, 2H), 3.69 - 3.57(m, 1H), 3.41 - 3.35(m, 1H), 3.21(dd, J=16.4, 7.4 Hz, 1H), 3.02(dd, J=13.6, 5.8 Hz, 1H), 2.44 - 2.37(m, 1H), 2.36 - 2.25(m, 3H), 2.08(s, 2H), 1.89 - 1.77(m, 2H), 1.40(s, 6H).

[0571] Example 42 (Compound 76) Synthesis of (R / S)-2-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)-2-methylpropanoic acid:

[0572] [ka]

[0573] To a solution of methyl(R / S)-2-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)-2-methylpropanoate (50 mg, 1 eq) in acetic acid (1 mL), concentrated hydrochloric acid (0.5 mL, 37 wt%, 30 eq) was added, and the mixture was heated to 75°C and reacted for 6 hours. The reaction was completed by detection with LC-MS. The reaction mixture was quenched with concentrated ammonia water to adjust the pH to 6-7, and then separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (10 mg).

[0574] LCMS(ESI)[M+H] + =416.2; 1 H NMR(400 MHz, DMSO-d6)δ 12.14(s, 1H), 8.27(d, J=8.4 Hz, 2H), 8.03(s, 1H), 7.47(d, J=8.4 Hz, 2H), 4.93(s, 1H), 3.81(s, 2H), 3.68 - 3.58(m, 1H), 3.39(d, J=8.2 Hz, 1H), 3.21(dd, J=16.7, 7.5 Hz, 1H), 3.02(dd, J=13.6, 5.8 Hz, 1H), 2.41(d, J=11.7 Hz, 1H), 2.34(dd, J=13.1, 6.2 Hz, 3H), 1.90 - 1.77(m, 2H), 1.51(s, 6H).

[0575] Example 43 (Compound 77) (R / S)-2-(4-(4-((1-(acetyloxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)-2-methylpropanoic acid:

[0576] [ka]

[0577] To a solution of methyl(R / S)-2-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)phenyl)-2-methylpropanoate (50 mg, 1 eq) in acetic acid (1 mL), concentrated hydrochloric acid (0.5 mL, 37 wt%, 30 eq) was added, and the mixture was heated to 75°C and reacted for 6 hours. The reaction was completed by detection with LC-MS. The reaction mixture was quenched with concentrated ammonia water to adjust the pH to 6-7, and then separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (10 mg).

[0578] LCMS(ESI)[M+H] + =458.2; 1 H NMR(400 MHz, DMSO-d6)δ 12.42(s, 1H), 8.40(s, 1H), 8.28(d, J=8.4 Hz, 2H), 7.48(d, J=8.4 Hz, 2H), 4.56(q, J=11.1 Hz, 2H), 3.71 - 3.58(m, 1H), 3.42 - 3.37(m, 1H), 3.23(dd, J=16.8, 7.8 Hz, 1H), 3.02(dd, J=13.7, 6.1 Hz, 1H), 2.46 - 2.40(m, 1H), 2.36(t, J=7.6 Hz, 3H), 2.00(s, 3H), 1.94 - 1.82(m, 2H), 1.51(s, 6H).

[0579] Example 44 (Compound 78) Synthesis of (R / S,E)-2-(4-chlorostyryl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0580] [ka]

[0581] Under a nitrogen gas atmosphere, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 eq) was added to a mixture of (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), (E)-(4-chlorostyryl)boronic acid (1.2 eq), potassium carbonate (2.5 eq), dioxane (2 mL), and water (0.4 mL). The mixture was heated to 110°C and reacted for 2 hours. TLC detection confirmed the completion of the reaction. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (50 mL), separated, and the organic phase was concentrated. The organic phase was then separated and purified by Prep-HPLC (C18, 10 mmol / L formic acid aqueous solution, acetonitrile) to obtain the target compound (30 mg).

[0582] LCMS(ESI)[M+H] + =390.1; 1 H NMR(400 MHz, DMSO-d6)δ 7.92(s, 1H), 7.82(d, J=8.7 Hz, 1H), 7.78 - 7.72(m, 2H), 7.47(d, J=8.5 Hz, 2H), 7.06(d, J=16.0 Hz, 1H), 4.90(t, J=5.7 Hz, 1H), 3.79(d, J=5.7 Hz, 2H), 3.58(dt, J=15.9, 7.8 Hz, 1H), 3.37(d, J=8.3 Hz, 1H), 3.15(dd, J=16.3, 7.3 Hz, 1H), 3.00(dd, J=13.9, 5.7 Hz, 1H), 2.39(d, J=11.1 Hz, 1H), 2.36 - 2.23(m, 3H), 1.90 - 1.75(m, 2H).

[0583] Example 45 (Compound 79) Synthesis of (R / S)-2-(3-(4-chloro-3-methoxyphenyl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0584] [ka]

[0585] Step 1: Preparation of tert-butyl 3-(4-chloro-3-methoxyphenyl)-3-methoxyazetidine-1-carboxylate:

[0586] [ka]

[0587] 500 mg (1 eq) of tert-butyl 3-(4-chloro-3-methoxyphenyl)-3-hydroxyazetidine-1-carboxylate was dissolved in 5 mL of N,N-dimethylformamide, substituted with nitrogen three times, and 2.05 eq of 60% sodium hydride was added in an ice bath. The mixture was stirred in the ice bath for 10 minutes, 5 eq of methyl iodide was added, and stirring was continued in the ice bath for 30 minutes. Monitoring by LC-MS indicated completion of raw material consumption. A saturated NH4Cl solution was added to the reaction mixture to quench the reaction. The mixture was added to 30 mL of water, extracted with ethyl acetate (20 mL x 2), the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target compound (417 mg).

[0588] Step 2: Production of 3-(4-chloro-3-methoxyphenyl)-3-methoxyazetidine-trifluoroacetate:

[0589] [ka]

[0590] 1 eq of tert-butyl 3-(4-chloro-3-methoxyphenyl)-3-methoxyazetidine-1-carboxylate was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (2 mL) was added under ice bath conditions. The mixture was stirred at room temperature for 0.5 hours. LC-MS monitoring indicated completion of raw material consumption. The reaction mixture was concentrated under reduced pressure to obtain the crude product of the target compound (800 mg, used directly in the next step). LC-MS(ESI)[M+H] + = 228.1.

[0591] Step 3: Preparation of (R / S)-2-(3-(4-chloro-3-methoxyphenyl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0592] [ka]

[0593] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (150 mg, crude product obtained from the previous step), 3-(4-chloro-3-methoxyphenyl)-3-methoxyazetidine (231 mg), and N,N-diisopropylethylamine (538 mg) were dissolved in dioxane (5 mL) and heated and stirred at 100°C for 1 hour. Monitoring by LC-MS indicated the completion of raw material consumption. The reaction mixture was added to water (50 mL), filtered, and separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (110 mg).

[0594] LCMS(ESI)[M+H] + =479.3; 1H NMR(400 MHz, DMSO-d6)δ 7.53(s, 1H), 7.47(d, J=8.2 Hz, 1H), 7.14(d, J=2.0 Hz, 1H), 7.05(dd, J=8.1, 1.9 Hz, 1H), 4.85(t, J=5.6 Hz, 1H), 4.21(s, 4H), 3.90(s, 3H), 3.72(dd, J=5.8, 2.4 Hz, 2H), 3.42(dt, J=16.9, 8.3 Hz, 4H), 3.21(dt, J=13.6, 8.4 Hz, 1H), 3.00 - 2.83(m, 2H), 2.37 - 2.22(m, 2H), 2.20 - 2.10(m, 2H), 1.75(dq, J=19.4, 9.9 Hz, 2H).

[0595] Example 46 (Compound 80) Synthesis of (R / S)-2-(3-(4-chloro-3-fluorophenyl)-3-hydroxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0596] [ka]

[0597] Step 1: Preparation of magnesium 4-chloro-3-fluorophenylbromide:

[0598] Under a nitrogen gas atmosphere, magnesium scrap (696 mg, 1.2 eq) with the oxide layer removed, elemental iodine (0.01 eq), and 4-bromo-1-chloro-2-fluorobenzene (0.6 eq) were added to anhydrous THF (3 mL). The mixture was heated until the brown color disappeared, and then a solution of 4-bromo-1-chloro-2-fluorobenzene (0.4 eq) in anhydrous THF (17 mL) was slowly added. The mixture was reacted at room temperature for 2 hours, consuming a large amount of magnesium scrap to obtain the crude compound of the target compound, which was then used directly in the next step.

[0599] Step 2: Preparation of tert-butyl 3-(4-chloro-3-fluorophenyl)-3-hydroxyazetidine-1-carboxylate:

[0600] [ka]

[0601] Under a nitrogen gas atmosphere, tert-butyl 3-oxoazetidine-1-carboxylate (3.00 g, 1 eq) was added to anhydrous THF (20 mL). At 0°C, the reaction solution from the previous step (5.32 g) was slowly added, and the mixture was stirred at 0°C for 1 hour. New spots were observed by TLC detection. Saturated ammonium chloride solution was added to the reaction solution to quench it, followed by the addition of water (150 mL). Extraction was performed with MTBE (100 mL x 2), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target compound (4.70 g). LCMS (ESI) [M+H-56] + = 246.1.

[0602] Step 3: Preparation of 3-(4-chloro-3-fluorophenyl)-3-hydroxyazetidine trifluoroacetate:

[0603] [ka]

[0604] 200 mg (1 eq) of tert-butyl 3-(4-chloro-3-fluorophenyl)-3-hydroxyazetidine-1-carboxylate was dissolved in 1 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes. LC-MS monitoring indicated completion of raw material consumption. The reaction mixture was concentrated under reduced pressure to obtain 240 mg of the target product, which was used directly in the next step. LC-MS(ESI)[M+H] + =202.1.

[0605] Step 4: Preparation of (R / S)-2-(3-(4-chloro-3-fluorophenyl)-3-hydroxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0606] [ka]

[0607] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 1 eq), 3-(4-chloro-3-fluorophenyl)-3-hydroxyazetidine trifluoroacetate (160 mg, the crude product was used directly in the next step), and N,N-diisopropylethylamine (4 eq) were dissolved in a mixed solution of tetrahydrofuran (2.5 mL) and water (0.5 mL), and heated and stirred at 70°C for 2 hours. Monitoring by LC-MS indicated the completion of raw material consumption. The reaction mixture was added to water (20 mL), filtered, and separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (100 mg).

[0608] LCMS(ESI)[M+H] + =453.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.61(t, J=8.1 Hz, 1H), 7.55 - 7.47(m, 2H), 7.38(dd, J=8.5, 2.1 Hz, 1H), 6.64(s, 1H), 4.87(t, J=5.7 Hz, 1H), 4.18(s, 4H), 3.70(dd, J=5.9, 1.5 Hz, 2H), 3.42(d, J=8.7 Hz, 1H), 3.27 - 3.17(m, 1H), 3.01 - 2.82(m, 2H), 2.42 - 2.24(m, 2H), 2.20 - 2.05(m, 2H), 1.87 - 1.64 (m, 2H).

[0609] Example 47 (Compound 81) Synthesis of (R / S)-2-(3-(4-chloro-3-methoxyphenyl)-3-hydroxyazetidine-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0610] Step 1: Preparation of 2-chloro-N-(tetrahydro-2H-pyran-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-4-amine:

[0611] [ka]

[0612] 2,4-Dichloro-6,7-Dihydrothieno[3,2-d]pyrimidine (5.00 g, 1 eq), 4-aminotetrahydropyran (1.1 eq), and N,N-diisopropylethylamine (3 eq) were dissolved in acetonitrile (50 mL) and stirred at 85°C for 4 hours. LC-MS monitoring indicated completion of raw material consumption. The reaction mixture was concentrated under reduced pressure, and the resulting solid was sludged with MTBE (50 mL). After filtration, it was washed with MTBE (20 mL) and dried to obtain the target compound (5.43 g). LC-MS(ESI)[M+H] + = 272.1.

[0613] Step 2: Preparation of (R / S)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide:

[0614] [ka]

[0615] 2-Chloro-N-(tetrahydro-2H-pyran-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-4-amine (0.50g, 1eq), (S)-(-)-1,1'-bi-2-naphthol (0.1eq), Ti(O) iPr)4 (0.05 eq) was added to DCM (5 mL) and water (0.5 mL), purged three times with nitrogen gas, stirred at room temperature for 1 hour, and 70% t-butyl hydroperoxide (1.1 eq) was added under an ice bath, and stirred at room temperature for 3 hours. Monitoring by LCMS showed that only a small amount of starting material remained. The reaction was quenched by adding water (20 mL) under an ice bath, extracted with DCM (20 mL x 2), and after combining the organic phases, washed sequentially with water (10 mL) and saturated saline (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain the target compound (187 mg). LCMS(ESI)[M+H] + = 288.1.

[0616] Step 3: Preparation of (R / S)-2-(3-(4-chloro-3-methoxyphenyl)-3-hydroxyazetidine-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0617] [ka]

[0618] (R / S)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 1 eq), 3-(4-chloro-3-methoxyphenyl)-3-hydroxyazetidine hydrochloride (1.3 eq), and N,N-diisopropylethylamine (5 eq) were dissolved in a mixed solution of THF (1.5 mL) and water (0.3 mL) and heated and stirred at 70°C for 1 hour. Monitoring by LCMS indicated completion of raw material consumption. The reaction mixture was added to water (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined and washed with water (10 mL) and saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain the target compound (55 mg).

[0619] LCMS(ESI)[M+H] + =465.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.68(d, J=7.5 Hz, 1H), 7.43(d, J=8.3 Hz, 1H), 7.25(d, J=2.0 Hz, 1H), 7.09(d, J=8.2 Hz, 1H), 6.50(s, 1H), 4.22(t, J=13.5 Hz, 5H), 3.87(s, 4H), 3.43(dd, J=17.1, 8.5 Hz, 1H), 3.30 - 3.11(m, 4H), 2.94(ddd, J=26.1, 15.5, 7.6 Hz, 2H), 1.69(d, J=60.2 Hz, 4H).

[0620] Example 48 (Compound 82) Synthesis of (R / S)-2-(3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0621] [ka]

[0622] Step 1: Preparation of tert-butyl 3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine-1-carboxylate:

[0623] [ka]

[0624] 300 mg (1 eq) of tert-butyl 3-(4-chloro-3-fluorophenyl)-3-hydroxyazetidine-1-carboxylate was dissolved in 3 mL of DMF, substituted with nitrogen three times, and 2 eq of 60 wt% sodium hydride was added under ice bath conditions. The mixture was stirred for 5 minutes in the ice bath, 2 eq of methyl iodide was added, and stirring continued for 4 hours. Monitoring by LC-MS indicated the completion of raw material consumption. Under ice cooling, saturated ammonium chloride aqueous solution was added to the reaction mixture to quench it, and the mixture was added to 30 mL of water. Extraction was performed with MTBE (20 mL x 2), and after combining the organic phases, the mixture was washed with 10 mL of water and 10 mL x 2 of saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target compound (260 mg).

[0625] Step 2: Preparation of 3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine trifluoroacetate:

[0626] [ka]

[0627] 260 mg, 1 eq of tert-butyl 3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine-1-carboxylate was added to a mixed solution of TFA (2 mL) and DCM (3 mL), and the mixture was stirred at room temperature for 0.5 hours. LC-MS monitoring indicated completion of raw material consumption. The reaction mixture was concentrated under reduced pressure, and the resulting 350 mg, crude 3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine-trifluoroacetate was used directly in the next step. LC-MS(ESI)[M+H] + = 216.1.

[0628] Step 4: Preparation of (R / S)-2-(3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0629] [ka]

[0630] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (200 mg, 1 eq), 3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine trifluoroacetic acid (343 mg, crude product obtained from the previous step), and N,N-diisopropylethylamine (5 eq) were added to a mixed solution of water (1 mL) and THF (5 mL) and stirred at 70°C for 2 hours. Monitoring by LC-MS indicated completion of raw material consumption. The reaction mixture was added to water (20 mL), filtered, and separated and purified by Prep-HPLC (C18, 0.1% formic acid aqueous solution, acetonitrile) to obtain the target compound (209 mg, yield 64%).

[0631] LCMS(ESI)[M+H] + =467.3; 1H NMR(400 MHz, DMSO-d6)δ 7.66(t, J=8.0 Hz, 1H), 7.58 - 7.48(m, 2H), 7.35(dd, J=8.3, 2.1 Hz, 1H), 4.84(t, J=5.6 Hz, 1H), 4.20(d, J=8.9 Hz, 4H), 3.76 - 3.64(m, 2H), 3.43(dd, J=17.0, 8.3 Hz, 1H), 3.22(dt, J=13.5, 8.3 Hz, 1H), 3.06(s, 3H), 2.98 - 2.84(m, 2H), 2.30(dt, J=21.0, 10.3 Hz, 2H), 2.19 - 2.10(m, 2H), 1.85 - 1.65(m, 2H).

[0632] Example 49 (Compound 83) Synthesis of (R / S)-2-(3-(4-chlorophenyl)-3-methoxyazetidine-1-yl)-4-((1-hydroxymethylcyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0633] [ka]

[0634] Step 1: Preparation of (4-chlorophenyl)lithium:

[0635] Under a nitrogen gas atmosphere, 1-chloro-4-iodobenzene (4.18 g, 1 eq) was dissolved in anhydrous THF (50 mL) and stirred until dissolved. A hexane solution of 2.5 Mn-butyllithium (1 eq) was added dropwise at -78°C, and the reaction was continued with stirring at -78°C for 0.5 hours to obtain the crude product of the target compound. This was used directly in the next step.

[0636] Step 2: Preparation of tert-butyl 3-(4-chlorophenyl)-3-hydroxyazetidine-1-carboxylate:

[0637] [ka]

[0638] Under a nitrogen gas atmosphere, tert-butyl 3-oxoazetidine-1-carboxylate (2 g, 1 eq) was dissolved in anhydrous THF (10 mL) and slowly added to the reaction mixture from the previous step at -78°C. The mixture was stirred at -78°C for 1 hour and monitored by TLC. At 0°C, saturated ammonium chloride solution (10 mL) was added to the reaction mixture to quench the reaction, and the product was purified to obtain the crude product. The crude product was added to petroleum ether (30 mL), stirred at room temperature for 1 hour, filtered, and the cake was washed with petroleum ether (20 mL) to obtain the target compound (2.56 g). LCMS(ESI)[M+H-56] + = 228.1.

[0639] Step 3: Preparation of tert-butyl 3-(4-chlorophenyl)-3-methoxyazetidine-1-carboxylate:

[0640] [ka]

[0641] Under a nitrogen gas atmosphere, tert-butyl 3-(4-chlorophenyl)-3-hydroxyazetidine-1-carboxylate (500 mg, 1 eq) was dissolved in anhydrous DMF (5 mL), and 60 wt% sodium hydride (2.05 eq) was added in an ice bath. The mixture was stirred for 10 minutes, methyl iodide (5 eq) was added, and stirring was continued for another 30 minutes. Monitoring by LCMS indicated the completion of raw material consumption. Saturated NH4Cl aqueous solution was added to the reaction mixture to quench the reaction, and the mixture was added to water (30 mL). Extraction was performed with methyl t-butyl ether (20 mL x 2), and after combining the organic phases, the mixture was washed sequentially with water (20 mL) and saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of the target compound (585 mg; the crude product was used directly in the next step).

[0642] Step 4: Preparation of 3-(4-chlorophenyl)-3-methoxyazetidine hydrochloride:

[0643] [ka]

[0644] 585 mg of tert-butyl 3-(4-chlorophenyl)-3-methoxyazetidine-1-carboxylate (crude product from the previous step) was added to a 5 mL solution of 4 M hydrogen chloride in ethyl acetate and stirred at room temperature for 0.5 hours. LC-MS monitoring indicated completion of raw material consumption. The reaction mixture was concentrated under reduced pressure, 20 mL of methyl t-butyl ether was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered, and the cake was washed with 10 mL of methyl t-butyl ether to obtain the target compound (380 mg). LC-MS(ESI)[M+H] + = 198.1.

[0645] Step 5: Preparation of (R / S)-2-(3-(4-chlorophenyl)-3-methoxyazetidine-1-yl)-4-((1-hydroxymethylcyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0646] [ka]

[0647] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 1 eq), 3-(4-chlorophenyl)-3-methoxyazetidine hydrochloride (1.22 eq), and N,N-diisopropylethylamine (3.98 eq) were added to a mixed solution of water (0.5 mL) and THF (2.5 mL) and stirred at 70°C for 2 hours. Monitoring by LCMS indicated completion of raw material consumption. The reaction mixture was added to water (20 mL), filtered, and separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (82 mg, yield 52%).

[0648] LCMS(ESI)[M+H]+ =449.3; 1 H NMR(400 MHz, DMSO-d6)δ 7.49(s, 5H), 4.84(t, J=5.7 Hz, 1H), 4.22(s, 3H), 3.77 - 3.65(m, 2H), 3.41(dt, J=16.6, 8.0 Hz, 2H), 3.27 - 3.15(m, 2H), 2.99 - 2.82(m, 3H), 2.34(d, J=10.5 Hz, 2H), 2.26(d, J=10.0 Hz, 1H), 2.14(t, J=10.2 Hz, 2H), 1.74(dq, J=19.6, 10.3Hz, 2H).

[0649] Example 50 (Compound 84) Synthesis of (R / S)-2-(5-(2-hydroxypropan-2-yl)isoindorin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0650] [ka]

[0651] Step 1: Preparation of methyl 2-(5-oxide-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)isoindoline-5-carboxylate:

[0652] [ka]

[0653] (R / S)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (130 mg, 1 eq), methyl-isoindoline 5-carboxylate hydrochloride (1.2 eq), and N,N-diisopropylethylamine (5 eq) were dissolved in water (0.3 mL) and THF (1.5 mL) and heated and stirred at 70°C for 1 hour. LC-MS monitoring indicated completion of raw material consumption. The reaction mixture was added to water (20 mL), filtered, the cake was washed with water (20 mL), the cake was collected, ethyl acetate (30 mL) was added, and the mixture was concentrated under reduced pressure to obtain the target compound (170 mg). LC-MS(ESI)[M+H] + = 429.3.

[0654] Step 2: (R / S)-2-(5-(2-hydroxypropan-2-yl)isoindorin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0655] [ka]

[0656] Under a nitrogen gas atmosphere, (R / S)-methyl 2-(5-oxide-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-2-yl)isoindoline-5-carboxylate (120 mg, 1 eq) was dissolved in THF (2 mL), stirred for 10 minutes under an ice bath, and 3 M methylmagnesium bromide / 2-methyltetrahydrofuran solution (10.7 eq) was added dropwise, and stirring was continued for 1 hour. LC-MS monitoring indicated completion of the reaction. Saturated ammonium chloride aqueous solution was added to the ice-cooled reaction mixture to quench the reaction, the mixture was added to water (30 mL), extracted with MTBE (20 mL x 2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by pre-HPLC (C18 in aqueous ammonium bicarbonate, 10 mmol / L, acetonitrile) to obtain the target compound (27 mg).

[0657] LCMS(ESI)[M+H] + =429.3; 1 H NMR(400 MHz, DMSO-d6)δ 7.61(t, J=6.3 Hz, 1H), 7.50(s, 1H), 7.40(t, J=8.3 Hz, 1H), 7.31(dd, J=12.9, 8.0 Hz, 1H), 5.04(d, J=5.1 Hz, 1H), 4.81(d, J=8.2 Hz, 3H), 4.30(s, 1H), 3.92(s, 2H), 3.44(q, J=14.4 Hz, 3H), 3.23(dt, J=13.4, 8.5 Hz, 2H), 3.03(d, J=7.2 Hz, 1H), 2.90(dd, J=13.6, 7.1 Hz, 1H), 1.84(d, J=12.9 Hz, 2H), 1.64(dd, J=17.6, 9.3 Hz, 2H), 1.44(s, 6H).

[0658] Example 51 (Compound 85) Synthesis of (R / S)-2-(5-chloroisoindolin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0659] [ka]

[0660] Step 1: Preparation of (R / S)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide:

[0661] [ka]

[0662] (S)-(-)-1,1'-bi-2-naphthol (0.2 eq) is dissolved in DCM (10 mL) and Ti(O i Pr)4 (0.2 eq) was added and the reaction was carried out at 25°C for 1 hour under a nitrogen gas atmosphere. Water (0.14 mL) was added and the reaction was continued for 0.5 hours. Next, 2-chloro-N-(tetrahydro-2H-pyran-4-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-4-amine (2.00 g, 1 eq) was added and the reaction was carried out for 1 hour, after which 70 wt% tert-butyl hydroperoxide (1.1 eq) was added. LC-MS monitoring indicated completion of the reaction. The reaction mixture was added to water (30 mL), extracted with DCM:MeOH = 10:1 (20 mL x 2), the organic phases were combined, washed with water (20 mL) and saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound (1.50 g). LC-MS(ESI)[M+H] + = 288.1.

[0663] Step 2: (R / S)-2-(5-chloroisoindolin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0664] [ka]

[0665] (R / S)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 1 eq) and 5-chloroisoindoline hydrochloride (0.91 eq) were added to a mixed solution of THF (2 mL) and H2O (0.4 mL), and N,N-diisopropylethylamine (4.95 eq) was added. The mixture was stirred at 70°C for 1 hour. The product was detected by monitoring with LC-MS. The reaction mixture was added to water (30 mL), extracted with DCM:MeOH = 10:1 (20 mL x 2), and after combining the organic phases, it was washed with water (20 mL) and saturated saline (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / L aqueous ammonium bicarbonate solution, acetonitrile) to obtain the target compound (60 mg).

[0666] LCMS(ESI)[M+H] + =405.3; 1 H NMR(400 MHz, DMSO-d6)δ 7.64(d, J=7.6 Hz, 1H), 7.55 - 7.31(m, 3H), 4.81(d, J=7.9 Hz, 4H), 4.29(s, 1H), 3.91(s, 2H), 3.53 - 3.35(m, 3H), 3.24(dt, J=13.4, 8.5 Hz, 1H), 3.00(dd, J=17.0, 8.1 Hz, 1H), 2.91(dd, J=13.4, 7.1 Hz, 1H), 1.83(d, J=12.6 Hz, 2H), 1.74 - 1.57(m, 2H).

[0667] Example 52 (Compound 86) Synthesis of (R / S)-2-(3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0668] [ka]

[0669] (R / S)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (150 mg) and 3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine hydrochloride (150 mg) were added to a mixed solution of tetrahydrofuran (2.5 mL) and H2O (0.5 mL). N,N-diisopropylethylamine (336 mg) was added, and the mixture was stirred at 70°C for 1 hour. The reaction product was added to water (20 mL), extracted with DCM:MeOH = 10:1 (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (70 mg).

[0670] LCMS(ESI)[M+H] + =467.3; 1 H NMR(400 MHz, DMSO-d6)δ 7.71 - 7.62(m, 2H), 7.55(dd, J=10.4, 2.1 Hz, 1H), 7.35(dd, J=8.4, 2.1 Hz, 1H), 4.26(q, J=10.0 Hz, 5H), 3.89(d, J=8.8 Hz, 2H), 3.42(dq, J=15.1, 7.3 Hz, 2H), 3.22(dt, J=13.7, 8.4 Hz, 2H), 3.07(s, 3H), 2.93(ddd, J=21.7, 15.4, 7.7 Hz, 2H), 1.77(d, J=12.6 Hz, 2H), 1.61(qt, J=11.6, 5.8 Hz, 2H).

[0671] Example 53 (Compound 87) Synthesis of (R / S)-2-(5-(difluoromethoxy)isoindolin-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0672] [ka]

[0673] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 5-(difluoromethoxy)isoindoline hydrochloride (100 mg), and N,N-diisopropylethylamine (180 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (111 mg).

[0674] LCMS(ESI)[M+H] + =437.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.52 - 7.38(m, 2H), 7.33 - 6.99(m, 3H), 4.91 - 4.71(m, 5H), 3.79(d, J=5.8 Hz, 2H), 3.46(dt, J=16.4, 7.9 Hz, 1H), 3.24(dt, J=13.3, 8.2 Hz, 1H), 2.94(ddd, J=35.6, 15.3, 7.6 Hz, 2H), 2.38(dt, J=20.2, 10.0 Hz, 2H), 2.28 - 2.17(m, 2H), 1.80(dd, J=19.0, 10.5 Hz, 2H).

[0675] Example 54 (Compound 88) Synthesis of (R / S)-2-(3-(4-chlorophenyl)-3-methoxyazetidine-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0676] [ka]

[0677] (R / S)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (200 mg) and 3-(4-chlorophenyl)-3-methoxyazetidine hydrochloride (200 mg) were added to a mixed solution of tetrahydrofuran (4 mL) and H2O (0.8 mL), and N,N-diisopropylethylamine (450 mg) was added. The mixture was stirred at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (270 mg).

[0678] LCMS(ESI)[M+H] + =449.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.67(d, J=7.6 Hz, 1H), 7.50(s, 4H), 4.26(s, 5H), 3.88(s, 2H), 3.41(dd, J=17.2, 8.7 Hz, 2H), 3.22(dt, J=13.7, 8.4 Hz, 2H), 3.05(s, 3H), 3.00 - 2.84(m, 2H), 1.75(s, 2H), 1.62(dt, J=13.6, 6.9 Hz, 2H).

[0679] Example 55 (Compound 89) Synthesis of (R / S)-2-(5-fluoroisoindolin-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0680] [ka]

[0681] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 5-fluoro-2,3-dihydro-1H-isoindoline hydrochloride (79 mg), and N,N-diisopropylethylamine (180 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (75 mg).

[0682] LCMS(ESI)[M+H] + =389.0; 1 H NMR(400 MHz, DMSO-d6)δ 7.49 - 7.37(m, 2H), 7.27(dd, J=23.1, 9.0 Hz, 1H), 7.18 - 7.10(m, 1H), 4.92 - 4.70(m, 5H), 3.79(d, J=5.7 Hz, 2H), 3.46(dt, J=16.4, 7.9 Hz, 1H), 3.24(dt, J=13.4, 8.3 Hz, 1H), 3.04 - 2.84(m, 2H), 2.38(dt, J=20.6, 10.4 Hz, 2H), 2.23(t, J=9.8 Hz, 2H), 1.80(dq, J=19.1, 9.8 Hz, 2H).

[0683] Example 56 (Compound 90) Synthesis of (R / S)-2-(5,6-difluoroisoindolin-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0684] [ka]

[0685] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 5,6-difluoro-2,3-dihydro-1H-isoindoline hydrochloride (87 mg), and N,N-diisopropylethylamine (180 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (119 mg).

[0686] LCMS(ESI)[M+H] + =407.0; 1 H NMR(400 MHz, DMSO-d6)δ 7.61 - 7.42(m, 3H), 4.90 - 4.67(m, 5H), 3.79(d, J=6.0 Hz, 2H), 3.45(dd, J=16.8, 8.2 Hz, 1H), 3.23(dt, J=13.4, 8.3 Hz, 1H), 3.02 - 2.85(m, 2H), 2.38(dd, J=22.1, 11.8 Hz, 2H), 2.28 - 2.14(m, 2H), 1.79(dq, J=19.3, 9.9 Hz, 2H).

[0687] Example 57 (Compound 91) Synthesis of (R / S)-2-(5-(difluoromethyl)isoindolin-2-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0688] [ka]

[0689] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 5-(difluoromethyl)isoindoline hydrochloride (110 mg), and N,N-diisopropylethylamine (180 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 L) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (93 mg). LCMS(ESI)[M+H] + =421.3; 1 H NMR(400 MHz, DMSO-d6)δ 7.69 - 7.39(m, 4H), 7.06(td, J=55.9, 5.3 Hz, 1H), 4.86(dd, J=13.2, 6.0 Hz, 5H), 3.80(d, J=5.8 Hz, 2H), 3.47(dt, J=16.4, 7.8 Hz, 1H), 3.24(dt, J=13.5, 8.3 Hz, 1H), 2.99(dd, J=17.1, 8.1 Hz, 1H), 2.89(dd, J=13.5, 7.2 Hz, 1H), 2.39(dt, J=21.6, 10.6 Hz, 2H), 2.24(t, J=9.9 Hz, 2H), 1.80(dd, J=19.0, 9.7 Hz, 2H).

[0690] Example 58 (Compound 92) Synthesis of (R / S)-2-(3-(4-chlorophenyl)-3-(methoxy--d3)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0691] [ka]

[0692] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 3-(4-chlorophenyl)-3-(methoxy-d3)azetidine hydrochloride (123 mg), and N,N-diisopropylethylamine (180 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (90 mg).

[0693] LCMS(ESI)[M+H] + =452.3; 1 H NMR(400 MHz, DMSO-d6)δ 7.49(s, 4H), 4.84(t, J=5.6 Hz, 1H), 4.22(s, 4H), 3.71(s, 2H), 3.46 - 3.37(m, 2H), 3.22(dt, J=15.4, 8.5 Hz, 1H), 3.01 - 2.83(m, 2H), 2.39 - 2.23(m, 2H), 2.16(d, J=10.2 Hz, 2H), 1.74(dq, J=18.9, 9.3 Hz, 2H).

[0694] Example 59 (Compound 94) Synthesis of (R / S)-2-(3-(4-chlorophenyl)-3-(methoxy-d3)azetidine-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0695] [ka]

[0696] (R / S)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 3-(4-chlorophenyl)-3-(methoxy-d3)azetidine hydrochloride (123 mg), and N,N-diisopropylethylamine (180 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (51 mg).

[0697] LCMS(ESI)[M+H] + =452.3; 1 H NMR(400 MHz, DMSO-d6)δ 7.66(d, J=7.6 Hz, 1H), 7.50(s, 4H), 4.25(s, 5H), 3.88(s, 2H), 3.43(dt, J=17.0, 8.1 Hz, 3H), 3.22(dt, J=13.6, 8.5 Hz, 1H), 3.02 - 2.85(m, 2H), 1.76(s, 2H), 1.69 - 1.53(m, 2H).

[0698] Examples 60 and 61 (Compounds 95 and 96) Synthesis of (R / S)-2-(3-(2-fluorophenyl)-3-(methoxy-d3)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0699] Step 1: Preparation of tert-butyl 3-(4-fluorophenyl)-3-hydroxyazetidine-1-carboxylate:

[0700] [ka]

[0701] Under a nitrogen gas atmosphere, 1-bromo-4-fluorobenzene (5.00 g) was dissolved in anhydrous tetrahydrofuran (50 mL), and 2.5 M n-butyllithium / hexane solution (13.7 mL) was added dropwise at -78°C, and the reaction was continued at -78°C for 0.5 hours. Tert-butyl 3-oxoazetidine-1-carboxylate (4.50 g) was dissolved in anhydrous tetrahydrofuran (20 mL), and slowly added to the reaction mixture at -78°C, and stirring was continued at -78°C for 1 hour. The reaction mixture was raised to 0°C, and the reaction was quenched by adding saturated ammonium chloride solution (10 mL). Water (100 mL) was added, and the mixture was extracted twice with methyl tert-butyl ether (100 mL). After combining the organic phases, the mixture was washed once with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and dried in a rotary evaporator to obtain the crude product. The crude product was purified using silica gel column chromatography (PE:EA=5:1) to obtain the target compound (6.37 g). LC-MS (ESI) [M+H-56] + = 212.1.

[0702] Step 2: Preparation of tert-butyl 3-(4-fluorophenyl)-3-(methoxy-d3)azetidine-1-carboxylate:

[0703] [ka]

[0704] The mixture of compounds obtained in the first step (2 g) was dissolved in DMF (5 mL), purged with nitrogen three times, sodium hydride (0.57 g) was added under ice bath conditions, stirred in an ice bath for 10 minutes, methyl deuterated iodide (2.17 g) was added, and stirring continued in an ice bath for 30 minutes. Monitoring by LC-MS indicated completion of raw material consumption. The reaction was quenched by adding saturated NH4Cl aqueous solution to the reaction mixture, the mixture was added to water (100 mL), extracted twice with methyl tert-butyl ether (80 mL), the organic phases were combined, washed once with water (50 mL) and twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried in a rotary evaporator to obtain the target compound (2.13 g). This crude product was used directly in the next step.

[0705] Step 3: Preparation of 3-(4-fluorophenyl)-3-(methoxy-d3)azetidine hydrochloride:

[0706] [ka]

[0707] The mixture of compounds obtained in the second step (2.10 g) was added to a 4 M hydrogen chloride / ethyl acetate solution (15 mL) and stirred at room temperature for 0.5 hours. LC-MS monitoring indicated the completion of raw material consumption. The reaction solution was directly concentrated under reduced pressure to obtain the crude product of the target compound (1.94 g). This crude product was used directly in the next step. LC-MS(ESI)[M+H] + = 185.1.

[0708] Step 4: Preparation of (R / S)-2-(3-(2-fluorophenyl)-3-(methoxy-d3)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide and (R / S)-2-(3-(4-fluorophenyl)-3-(methoxy-d3)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0709] [ka]

[0710] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), a mixture of compounds obtained in step 3 (115 mg), and N,N-diisopropylethylamine (180.49 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL), and the mixture was stirred at 70°C for 2 hours to allow it to react. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain (R / S)-2-(3-(2-fluorophenyl)-3-(methoxy-d3)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (7.4 mg, P1) and (R / S)-2-(3-(4-fluorophenyl)-3-(methoxy-d3)azetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (61 mg, P2).

[0711] P1: LCMS(ESI)[M+H] + =436.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.59 - 7.40(m, 3H), 7.31 - 7.21(m, 2H), 4.85(t, J=5.7 Hz, 1H), 4.37(s, 2H), 4.26(d, J=10.1 Hz, 2H), 3.72(dd, J=5.8, 3.1 Hz, 2H), 3.46 - 3.36(m, 1H), 3.21(dt, J=16.4, 8.3 Hz, 1H), 2.99 - 2.82(m, 2H), 2.30(dq, J=21.0, 9.2 Hz, 2H), 2.19 - 2.11(m, 2H), 1.76(dq, J=19.4, 9.9 Hz, 2H).

[0712] P2: LCMS(ESI)[M+H] + =436.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.61 - 7.43(m, 3H), 7.26(t, J=8.9 Hz, 2H), 4.84(t, J=5.6 Hz, 1H), 4.22(s, 4H), 3.71(dd, J=5.7, 2.8 Hz, 2H), 3.41(dt, J=16.3, 7.8 Hz, 1H), 3.26 - 3.16(m, 1H), 2.90(ddd, J=21.8, 15.3, 7.7 Hz, 2H), 2.31(dq, J=21.0, 10.3 Hz, 2H), 2.15(d, J=7.9 Hz, 2H), 1.75(dq, J=18.8, 9.8 Hz, 2H).

[0713] Examples 62 and 63 (Compounds 97 and 98) Synthesis of (R / S)-2-(3-(2-fluorophenyl)-3-(methoxy-d3)azetidine-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0714] [ka]

[0715] (R / S)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (150 mg), a mixture of compounds obtained in the third step of Examples 60 and 61 (172 mg), and N,N-diisopropylethylamine (267 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL), and the mixture was stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain (R / S)-2-(3-(2-fluorophenyl)-3-(methoxy-d3)azetidine-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (8.4 mg, P1) and (R / S)-2-(3-(4-fluorophenyl)-3-(methoxy-d3)azetidine-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (66 mg, P2).

[0716] P1: LCMS(ESI)[M+H] + =436.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.75(s, 1H), 7.49(dt, J=33.9, 7.0 Hz, 2H), 7.31 - 7.22(m, 2H), 4.43(d, J=10.2 Hz, 2H), 4.32(d, J=10.3 Hz, 2H), 4.22(s, 1H), 3.89(s, 2H), 3.23(d, J=13.2 Hz, 4H), 3.03 - 2.86(m, 2H), 1.83 - 1.55(m, 4H).

[0717] P2: LCMS(ESI)[M+H] + =436.2; 1H NMR(400 MHz, DMSO-d6)δ 7.67(d, J=7.6 Hz, 1H), 7.57 - 7.44(m, 2H), 7.33 - 7.19(m, 2H), 4.24(h, J=10.8 Hz, 5H), 3.87(d, J=7.1 Hz, 2H), 3.48 - 3.37(m, 2H), 3.22(dt, J=13.6, 8.3 Hz, 2H), 2.93(ddd, J=22.0, 15.4, 7.6 Hz, 2H), 1.84 - 1.53(m, 4H).

[0718] Example 64 (Compound 99) Synthesis of (R / S)-4-((1-(aminomethyl)cyclobutyl)amino)-2-(4-(5-chloropyrimidine-2-yl)piperidine-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0719] Step 1: Preparation of tert-butyl((1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl)carbamate:

[0720] [ka]

[0721] 2,4-Dichloro-6,7-Dihydrothieno[3,2-d]pyrimidine (1.00 g), tert-butyl((1-aminocyclobutyl)methyl)carbamate (1.00 g), and N,N-diisopropylethylamine (1.87 g) were added to acetonitrile (50 mL). The mixture was stirred at 85°C for 24 hours. The mixture was concentrated under reduced pressure, dissolved in methyl t-butyl ether (50 mL), washed twice with water (30 mL) and once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and dried in a rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA=3:1) to obtain the target compound (0.85 g). LCMS(ESI)[M+H] + = 371.3.

[0722] Step 2: Preparation of tert-butyl(R / S)-((1-((2-chloro-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl)carbamate:

[0723] [ka]

[0724] 78 mg of (S)-(-)-1,1'-bi-2-naphthol was dissolved in 10 mL of DCM, and 77 mg of tetraisopropyl titanate was added. The mixture was reacted under a nitrogen atmosphere at 25°C for 1 hour. 0.14 mL of water was added, and the reaction was continued for 0.5 hours. Next, 500 mg of tert-butyl((1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl)carbamate was added and the mixture was reacted for 1 hour, after which 200 mg of tert-butyl hydroperoxide was added. The reaction mixture was added to 30 mL of water, extracted twice with DCM:MeOH = 10:1 (20 mL), the organic phases were combined, washed once with 20 mL of water and twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and dried in a rotary evaporator to obtain the crude product. The crude product was purified using silica gel column chromatography (PE:EA = 0.1:1) to obtain the target compound (340 mg). LC-MS (ESI) [M+H] + = 387.1.

[0725] Step 3: Preparation of tert-butyl(R / S)-((1-((2-(4-(5-chloropyrimidine-2-yl)piperidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl)carbamate:

[0726] [ka]

[0727] 200 mg of tert-butyl(R / S)-((1-((2-chloro-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl)carbamate, 5-chloro-2-(piperidine-4-yl)pyrimidine p-toluenesulfonate, and 267 mg of N,N-diisopropylethylamine were added to a mixed solution of H2O (1 mL) and tetrahydrofuran (5 mL) and reacted by stirring at 70°C for 2 hours. After diluting the reaction mixture with water (20 mL), it was extracted twice with DCM:MeOH = 10:1 (20 mL), the organic phases were combined, washed twice with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (380 mg). LCMS(ESI)[M+H] + = 548.2.

[0728] Step 4: Preparation of (R / S)-4-((1-(aminomethyl)cyclobutyl)amino)-2-(4-(5-chloropyrimidine-2-yl)piperidine-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0729] [ka]

[0730] 370 mg of tert-butyl(R / S)-((1-((2-(4-(5-chloropyrimidine-2-yl)piperidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl)carbamate was added to a mixture of TFA (3 mL) and DCM (3 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and separated and purified by Pre-HPLC (C18, 10 mmol / L NH4HCO3 / water, MeCN) to obtain the target compound (107 mg).

[0731] LCMS(ESI)[M+H] + =448.2; 1H NMR(400 MHz, DMSO-d6)δ 8.86(d, J=0.8 Hz, 2H), 7.49(d, J=44.5 Hz, 1H), 4.72(t, J=14.1 Hz, 2H), 3.44 - 3.38(m, 2H), 3.29 - 3.12(m, 4H), 3.11 - 2.82(m, 5H), 2.32(p, J=9.9 Hz, 2H), 2.11(t, J=10.4 Hz, 2H), 1.97(d, J=13.1 Hz, 2H), 1.70(dd, J=49.0, 11.9 Hz, 4H).

[0732] Example 65 (Compound 100) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-methoxy-3-(4-methoxyphenyl)azetidine-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0733] [ka]

[0734] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (200 mg), 3-methoxy-3-(4-methoxyphenyl)azetidine hydrochloride (200 mg), and N,N-diisopropylethylamine (360 mg) were added to a mixed solution of H2O (1 mL) and tetrahydrofuran (5 mL) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (101 mg).

[0735] LCMS(ESI)[M+H] + =445.2; 1H NMR(400 MHz, DMSO-d6)δ 7.48(s, 1H), 7.41 - 7.30(m, 2H), 7.03 - 6.92(m, 2H), 4.85(t, J=5.6 Hz, 1H), 4.19(s, 4H), 3.81 - 3.66(m, 4H), 3.46 - 3.33(m, 2H), 3.21(dt, J=16.5, 8.3 Hz, 1H), 2.98(s, 5H), 2.31(dq, J=20.9, 10.3 Hz, 2H), 2.14(t, J=10.2 Hz, 2H), 1.86 - 1.64(m, 2H).

[0736] Example 66 (Compound 101) Synthesis of (R / S)-(1-((2-(3-(4-chlorophenyl)-3-methoxyazetidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl(2-(dimethylamino)ethyl)carbonate:

[0737] [ka]

[0738] (R / S)-2-(3-(4-chlorophenyl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (120 mg) was added to DCM (3 mL), followed by the addition of N,N'-carbonyldiimidazole (48 mg), and the mixture was reacted at room temperature for 1 hour. Monitoring by LC-MS indicated the completion of raw material consumption. 175 mg of cesium carbonate and 65 mg of 2-(dimethylamino)ethane-1-ol were added to the reaction mixture and the mixture was reacted at room temperature for 2 hours. The reaction product was purified by silica gel column (DCM:MeOH = 20:1) to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 0.1% TFA / water, MeCN) to obtain the target compound (4.1 mg).

[0739] LCMS(ESI)[M+H]+ =564.2; 1 H NMR(400 MHz, DMSO-d6)δ 9.52(s, 1H), 7.98(s, 1H), 7.50(s, 3H), 4.72(s, 2H), 4.51(d, J=11.1 Hz, 1H), 4.37(d, J=5.6 Hz, 2H), 4.22(s, 2H), 3.38(d, J=4.9 Hz, 3H), 3.23(d, J=13.6 Hz, 2H), 3.03(s, 2H), 2.91(dd, J=14.1, 7.2 Hz, 2H), 2.79(d, J=4.6 Hz, 4H), 2.67(d, J=2.1 Hz, 1H), 2.39 - 2.31(m, 2H), 2.25(s, 2H), 1.84(s, 2H), 1.25(d, J=7.2 Hz, 2H).

[0740] Example 67 (Compound 102) Synthesis of (R / S)-(1-((2-(3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl(2-(dimethylamino)ethyl)carbonate:

[0741] [ka]

[0742] (R / S)-2-(3-(4-chloro-3-fluorophenyl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (500 mg) was added to DCM (5 mL), and N,N'-carbonyldiimidazole (262 mg) was added, followed by reaction at room temperature for 1 hour. 712 mg of cesium carbonate and 200 mg of 2-(dimethylamino)ethane-1-ol were added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. The reaction product was purified by silica gel column (DCM:MeOH = 20:1) to obtain the crude product. The crude product was separated and purified by Prep-HPLC (C18, 0.1% TFA / water, MeCN) to obtain the target compound (21 mg).

[0743] LCMS(ESI)[M+H] + =582.2; 1 H NMR(400 MHz, DMSO-d6)δ 9.51(s, 1H), 8.01(s, 1H), 7.67(t, J=8.0 Hz, 1H), 7.55(d, J=10.4 Hz, 1H), 7.35(d, J=8.1 Hz, 1H), 4.71(s, 2H), 4.51(d, J=10.8 Hz, 1H), 4.36(t, J=5.2 Hz, 2H), 4.22(s, 2H), 3.38(d, J=5.1 Hz, 2H), 3.27 - 3.19(m, 2H), 3.08 - 2.87(m, 6H), 2.80(d, J=4.7Hz, 4H), 2.69 - 2.65(m, 1H), 2.33(d, J=2.6 Hz, 2H), 2.22(d, J=19.1 Hz, 2H), 1.85(d, J=8.5 Hz, 2H).

[0744] Example 68 (Compound 103) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-methoxy-3-(3-methoxyphenyl)azetidine-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0745] [ka]

[0746] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (200 mg), 3-methoxy-3-(3-methoxyphenyl)azetidine hydrochloride (320 mg), and N,N-diisopropylethylamine (360 mg) were added to a mixed solution of H2O (1 mL) and tetrahydrofuran (5 mL) and stirred at 70°C for 2 hours. Monitoring by LCMS indicated completion of raw material consumption. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (132 mg).

[0747] LCMS(ESI)[M+H] + =445.3; 1 H NMR(400 MHz, DMSO-d6)δ 7.49(s, 1H), 7.36(t, J=7.9 Hz, 1H), 7.08 - 6.88(m, 3H), 4.85(t, J=5.7 Hz, 1H), 4.19(d, J=7.9 Hz, 4H), 3.82 - 3.64(m, 5H), 3.41(dt, J=16.4, 7.8 Hz, 1H), 3.21(dt, J=13.4, 8.3 Hz, 1H), 3.03(s, 3H), 2.99 - 2.83(m, 2H), 2.31(dq, J=21.1, 10.2 Hz, 2H), 2.20 - 2.07(m, 2H), 1.76(dt, J=18.8, 10.0 Hz, 2H).

[0748] Example 69 (Compound 104) Synthesis of (R / S)-4-((1-(aminomethyl-d2)cyclobutyl)amino)-2-(4-(5-chloropyrimidine-2-yl)piperidine-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0749] Step 1: Preparation of 1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutan-1-carboxamide:

[0750] [ka]

[0751] Methyl 1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutan-1-carboxylate (1.00 g) was added to 10 mL of 7 M ammonia / methanol solution and stirred at 60°C for 48 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 0.1:1) to obtain the target compound (477 mg). LC-MS (ESI) [M+H] + = 285.1.

[0752] Step 2: Preparation of N-(1-(aminomethyl-d2)cyclobutyl)-2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-amine:

[0753] [ka]

[0754] 1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutan-1-carboxamide (927 mg) was added to tetrahydrofuran (30 mL), purged with nitrogen three times, cooled in an ice bath for 5 minutes, and lithium aluminum deuteride (440 mg) was added batch by batch under nitrogen gas, and the mixture was stirred at 70°C for 2 hours. After drying the reaction mixture in an ice bath with 15% aqueous sodium hydroxide solution (0.5 mL), water (0.5 mL), and anhydrous sodium sulfate, it was filtered, the cake was washed with DCM:MeOH=10:1 (50 mL), the filtrate was collected, and concentrated under reduced pressure to obtain the target compound (1.10 g). LCMS(ESI)[M+H] + = 273.1.

[0755] Step 3: Preparation of tert-butyl((1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl-d2)carbamate:

[0756] [ka]

[0757] N-(1-(aminomethyl-d2)cyclobutyl)-2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-amine (1.10 g) and di-tert-butyl dicarbonate (0.90 g) were added to MeOH (5 mL) and stirred at room temperature for 2 hours. LC-MS detection revealed the formation of the product. The reaction mixture was diluted with methyl t-butyl ether (50 mL), washed twice with water (20 mL) and twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column (PE:EA=3:1) to obtain the target compound (257 mg). LC-MS(ESI)[M+H] + = 373.3.

[0758] Step 4: Preparation of tert-butyl(R / S)-((1-((2-chloro-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl-d2)carbamate:

[0759] [ka]

[0760] 40 mg of (S)-(-)-1,1'-bi-2-naphthol was dissolved in 10 mL of DCM, and 40 mg of tetraisopropyl titanate was added. The mixture was reacted under a nitrogen atmosphere at 25°C for 1 hour. 0.02 mL of water was added, and the reaction was continued for 0.5 hours. Next, 257 mg of tert-butyl((1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl-d2)carbamate was added and the mixture was reacted for 1 hour, after which 98 mg of tert-butyl hydroperoxide was added. The reaction mixture was added to 30 mL of water, extracted twice with DCM:MeOH = 10:1 (20 mL), and after combining the organic phases, the mixture was washed once with 20 mL of water and once with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using a silica gel column (DCM:MeOH=20:1) to obtain the target compound (135 mg). LC-MS(ESI)[M+H] + =389.1.

[0761] Step 5: Preparation of tert-butyl(R / S)-((1-((2-(4-(5-chloropyrimidine-2-yl)piperidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl-d2)carbamate:

[0762] [ka]

[0763] 135 mg of tert-butyl(R / S)-((1-((2-chloro-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl-d2)carbamate, 256 mg of 5-chloro-2-(piperidine-4-yl)pyrimidine p-toluenesulfonate, and 181 mg of N,N-diisopropylethylamine were added to a mixed solution of tetrahydrofuran (2 mL) and H2O (0.4 mL) and stirred at 70°C for 1 hour. 20 mL of water was added to the reaction mixture, and the mixture was extracted twice with methyl t-butyl ether (10 mL). The organic phases were combined, washed once with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (330 mg). LCMS(ESI)[M+H] + = 550.2.

[0764] Step 6: Preparation of (R / S)-4-((1-(aminomethyl-d2)cyclobutyl)amino)-2-(4-(5-chloropyrimidine-2-yl)piperidine-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0765] [ka]

[0766] 330 mg of tert-butyl(R / S)-((1-((2-(4-(5-chloropyrimidine-2-yl)piperidine-1-yl)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl)amino)cyclobutyl)methyl-d2)carbamate was added to a mixed solution of DCM (1 mL) and TFA (1 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (49 mg).

[0767] LCMS(ESI)[M+H] + =450.1; 1H NMR(400 MHz, DMSO-d6)δ 8.86(s, 2H), 7.43(s, 1H), 4.70(d, J=13.4 Hz, 2H), 3.48 - 3.38(m, 2H), 3.26 - 3.14(m, 3H), 3.06(t, J=12.4 Hz, 2H), 2.98 - 2.82(m, 2H), 2.39 - 2.25(m, 2H), 2.10(t, J=9.8 Hz, 2H), 1.97(d, J=12.9 Hz, 2H), 1.83 - 1.54(m, 4H).

[0768] Example 70 (Compound 105) Synthesis of (R / S)-2-(3-(4-(difluoromethoxy)phenyl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0769] [ka]

[0770] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (200 mg), 3-(4-(difluoromethoxy)phenyl)-3-methoxyazetidine hydrochloride (370 mg), and N,N-diisopropylethylamine (360 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (128 mg).

[0771] LCMS(ESI)[M+H] + =481.1; 1H NMR(400 MHz, DMSO-d6)δ 7.58 - 7.44(m, 3H), 7.31 - 7.07(m, 3H), 4.84(t, J=5.7 Hz, 1H), 4.22(d, J=8.5 Hz, 1H), 3.72(dd, J=5.7, 2.7 Hz, 2H), 3.41(dd, J=16.9, 8.3 Hz, 1H), 3.31(s, 1H), 3.22(dt, J=13.6, 8.3 Hz, 1H), 3.03(s, 3H), 2.99 - 2.84(m, 2H), 2.40 - 2.25(m, 2H), 2.20 - 2.09(m, 2H), 1.75(dq, J=18.9, 10.2Hz, 2H), 1.24(s, 2H).

[0772] Example 71 (Compound 106) Synthesis of (R / S)-2-(3-(4-(cyclopropylmethoxy)phenyl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0773] [ka]

[0774] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (150 mg), 3-(4-(cyclopropylmethoxy)phenyl)-3-methoxyazetidine hydrochloride (240 mg), and N,N-diisopropylethylamine (272 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (36 mg).

[0775] LCMS(ESI)[M+H] + =485.2;1 H NMR(400 MHz, DMSO-d6)δ 7.45(s, 1H), 7.38 - 7.30(m, 2H), 7.00 - 6.92(m, 2H), 4.85(t, J=5.6 Hz, 1H), 4.19(s, 2H), 3.83(d, J=7.0 Hz, 2H), 3.72(dd, J=5.5, 2.8 Hz, 2H), 3.47 - 3.38(m, 1H), 3.27 - 3.16(m, 1H), 2.99(s, 5H), 2.39 - 2.24(m, 2H), 2.20 - 2.10(m, 2H), 1.75(dq, J=19.3, 10.0 Hz, 2H), 1.24(s, 3H), 0.61 - 0.50(m, 2H), 0.38 - 0.27(m, 2H).

[0776] Example 72 (Compound 107) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-methoxy-3-(4-(pyrrolidine-1-yl)phenyl)azetidine-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0777] [ka]

[0778] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (71 mg), 1-(4-(3-methoxyazetidine-3-yl)phenyl)pyrrolidine hydrochloride (80 mg), and N,N-diisopropylethylamine (129 mg) were added to a mixture of water (0.5 mL) and tetrahydrofuran (2 mL) and stirred at 70°C for 2 hours. The reaction mixture was added to water (10 mL), ethyl acetate (10 mL) was added to the reaction system and separated, the aqueous phase was extracted twice with ethyl acetate (5 mL), the organic phase was combined, the organic phase was washed with saturated saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness under reduced pressure to obtain the crude product. The target compound (27 mg) was obtained by separation and purification using Prep-HPLC (C18, 10 mmol / LNH4HCO3 / / water, MeCN).

[0779] LCMS(ESI)[M+H] + =484.4; 1 H NMR(400 MHz, DMSO-d6)δ 7.42(s, 1H), 7.29 - 7.15(m, 2H), 6.56(d, J=8.6 Hz, 2H), 4.84(t, J=5.6 Hz, 1H), 4.15(d, J=8.9 Hz, 4H), 3.80 - 3.64(m, 2H), 3.44 - 3.36(m, 1H), 3.25 - 3.16(m, 5H), 2.95(s, 3H), 2.93 - 2.81(m, 2H), 2.28(d, J=11.2 Hz, 2H), 2.15(s, 2H), 2.00 - 1.89(m, 4H), 1.75(dq, J=19.6, 10.4, 9.5 Hz, 2H).

[0780] Example 73 (Compound 108) Synthesis of (R / S)-2-(3-methoxy-3-(4-methoxyphenyl)azetidine-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0781] [ka]

[0782] (R / S)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 3-methoxy-3-(4-methoxyphenyl)azetidine hydrochloride (100 mg), and N,N-diisopropylethylamine (180 mg) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL) and stirred at 70°C for 2 hours. Monitoring by LCMS indicated completion of raw material consumption. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (20 mg).

[0783] LCMS(ESI)[M+H] + =445.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.62(d, J=7.6 Hz, 1H), 7.43 - 7.31(m, 2H), 7.04 - 6.91(m, 2H), 4.23(t, J=10.0 Hz, 4H), 3.93 - 3.83(m, 2H), 3.77(s, 3H), 3.47 - 3.36(m, 2H), 3.31 - 3.16(m, 3H), 3.00(s, 3H), 2.97 - 2.85(m, 2H), 1.77(d, J=12.4 Hz, 2H), 1.61(td, J=11.7, 4.4Hz, 2H).

[0784] Example 74 (Compound 109) Synthesis of (R / S)-2-(3-(4-(dimethylamino)phenyl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0785] [ka]

[0786] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 4-(3-methoxyazetidine-3-yl)-N,N-dimethylaniline hydrochloride (130 mg), and N,N-diisopropylethylamine (0.18 g) were added to a mixed solution of H2O (0.4 mL) and tetrahydrofuran (2 mL) and stirred at 70°C for 1 hour. Monitoring by LCMS indicated completion of raw material consumption. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (82 mg).

[0787] LCMS(ESI)[M+H] + =458.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.43(s, 1H), 7.31 - 7.15(m, 2H), 6.81 - 6.66(m, 2H), 4.85(t, J=5.6 Hz, 1H), 4.16(d, J=8.7 Hz, 4H), 3.71(dd, J=5.8, 2.5 Hz, 2H), 3.40(dt, J=16.2, 7.8 Hz, 1H), 3.21(dt, J=13.5, 8.2 Hz, 1H), 2.93(d, J=22.5 Hz, 11H), 2.31(dq, J=21.1, 10.3 Hz, 2H), 2.20 - 2.09(m, 2H), 1.75(dq, J=19.9, 10.0 Hz, 2H).

[0788] Example 75 (Compound 110) Synthesis of (R / S)-2-(3-(3-(dimethylamino)phenyl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0789] [ka]

[0790] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 3-(3-methoxyazetidine-3-yl)-N,N-dimethylaniline hydrochloride (211 mg), and N,N-diisopropylethylamine (0.18 g) were added to a mixed solution of H2O (0.4 mL) and tetrahydrofuran (2 mL) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (87 mg).

[0791] LCMS(ESI)[M+H] + =458.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.45(s, 1H), 7.23(dd, J=8.9, 7.4 Hz, 1H), 6.71(qd, J=4.2, 1.6 Hz, 3H), 4.84(t, J=5.6 Hz, 1H), 4.18(d, J=8.7 Hz, 4H), 3.71(dd, J=5.7, 2.4 Hz, 2H), 3.41(dt, J=16.4, 7.8 Hz, 1H), 3.21(dt, J=13.4, 8.3 Hz, 1H), 3.02(s, 3H), 2.91(s, 8H), 2.31(dq, J=21.6, 10.0 Hz, 2H), 2.20 - 2.11(m, 2H), 1.75(dq, J=19.9, 10.4 Hz, 2H).

[0792] Example 76 (Compound 111) Synthesis of (R / S)-2-(3-(benzo(d)[1,3]dioxol-5-yl)-3-methoxyazetidine-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0793] [ka]

[0794] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg), 3-(benzo(d)[1,3]dioxol-5-yl)-3-methoxyazetidine hydrochloride (130 mg), and N,N-diisopropylethylamine (0.18 g) were added to a mixed solution of H2O (0.5 mL) and tetrahydrofuran (2.5 mL) and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (40 mg).

[0795] LCMS(ESI)[M+H] + =459.1; 1 H NMR(400 MHz, DMSO-d6)δ 7.45(s, 1H), 6.97(dd, J=21.6, 1.1 Hz, 3H), 6.04(s, 2H), 4.83(t, J=5.6 Hz, 1H), 4.15(d, J=9.4 Hz, 4H), 3.71(dd, J=5.7, 2.5 Hz, 2H), 3.41(dt, J=16.5, 7.9 Hz, 1H), 3.21(dt, J=13.4, 8.3 Hz, 1H), 3.03 - 2.83(m, 5H), 2.30(dt, J=20.9, 10.4Hz, 2H), 2.20 - 2.09(m, 2H), 1.75(dq, J=29.0, 10.2Hz, 2H).

[0796] Example 77 (Compound 112) Synthesis of (R / S)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-methoxy-3-(4-(methylamino)phenyl)azetidine-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide:

[0797] [ka]

[0798] (R / S)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (40 mg), 4-(3-methoxyazetidine-3-yl)-N-methylaniline dihydrochloride (80 mg), and N,N-diisopropylethylamine (0.07 g) were added to a mixed solution of H2O (0.2 mL) and tetrahydrofuran (1 mL) and stirred at 70°C for 2 hours. Monitoring by LCMS indicated completion of raw material consumption. The reaction mixture was concentrated under reduced pressure to obtain the crude product, and the crude product was separated and purified by Prep-HPLC (C18, 10 mmol / LNH4HCO3 / water, MeCN) to obtain the target compound (35 mg).

[0799] LCMS(ESI)[M+H] + =444.2; 1 H NMR(400 MHz, DMSO-d6)δ 7.44(s, 1H), 7.24 - 7.07(m, 2H), 6.55(d, J=8.5 Hz, 2H), 5.77(d, J=5.1 Hz, 1H), 4.85(d, J=5.6 Hz, 1H), 4.13(d, J=9.3 Hz, 4H), 3.71(dd, J=5.8, 2.7 Hz, 2H), 3.40(dt, J=17.8, 8.5 Hz, 1H), 3.21(dt, J=16.2, 8.4 Hz, 1H), 2.94(s, 5H), 2.67(d, J=5.0 Hz, 3H), 2.30(dt, J=21.1, 10.3 Hz, 2H), 2.14(t, J=10.2 Hz, 2H), 1.91 - 1.64(m, 2H).

[0800] The following compounds were synthesized with reference to the relevant examples described above.

[0801] [ka]

[0802] [ka]

[0803] [ka]

[0804] Biological Test Evaluation Experiment 1: In vitro evaluation of the inhibitory activity of compounds against PDE4B2 and PDE4D2 enzymes. 1. Experimental materials and equipment:

[0805] [Table 0]

[0806] 2. Experimental procedure: 2.1 Preparation and Processing of Compounds

[0807] 2.1.1 Preparation of compound DMSO stock solution: The compound powder was dissolved in 10 mM DMSO stock solution, and the compound was completely dissolved using a shaker.

[0808] 2.1.2 Storage of Compound DMSO Stock Solution: Compound DMSO stock solution was stored in a dryer at room temperature.

[0809] 2.1.3 Preparation of the working stock: a) The DMSO solution of the reference sample roflumilast was diluted to 60 μM, and a concentration gradient of 10 steps was prepared by further diluting it fourfold. b) The DMSO solution of the test compound was diluted to 200 μM, and the concentration gradient was continued by further diluting it threefold. c) A 200X positive control (60 μM roflumilast) and a 200X carrier control (100% DMSO) were prepared. d) The detection plate was centrifuged at 1000 rpm for 1 minute.

[0810] 2.2 Testing of Compounds 1) Using an Echo550, 20 nL of compound dilution was transferred to each well of the detection plate.

[0811] 2) The detection plate was sealed and centrifuged at 1000 rpm for 1 minute.

[0812] 3) 2X PDE4B2 / PDE4D2 was prepared in refrigerated PDE detection buffer.

[0813] 4) 2 μL of 2X PDE4B2 / PDE4D2 was added to each well of the detection plate (prepared in step B).

[0814] 5) The detection plate was sealed and stored at room temperature for 10 minutes.

[0815] 6) 2X Cyclic-3',5'-AMP was prepared in PDE detection buffer.

[0816] 7) Add 2 μl of 2X Cyclic-3',5'-AMP (prepared in step f) to each well of the detection plate (prepared in step e) to initiate the reaction. Incubate at room temperature for 60 minutes.

[0817] 8) Add 4 μL of AMP-Glo ​​Reagent I and incubate at room temperature for 60 minutes.

[0818] 9) 8 μL of AMP detection solution was added. Incubated at room temperature for 60 minutes.

[0819] 10) The RLU signal is read by the Envision2105 reader.

[0820] Experimental results:

[0821] [Table 1]

[0822] Inhibition IC for the PDE4B2 enzyme 50Values: A < 2 nM; 2 nM < B < 5 nM; 5 nM < C < 20 nM; 20 nM < D < 50 nM. Here, compounds 79, 82, 83, 86, 88, 92, 94, 100, 105, 107, 108, 109 have an inhibition IC 50 value against PDE4B2 enzyme of less than 1 nM.

[0823] PDE4D2 / PDE4B2 selectivity (= inhibition IC 50 value against PDE4D2 enzyme / inhibition IC 50 value against PDE4B2 enzyme ratio): 5 < A ≦ 10; 2 < B ≦ 5; C ≦ 2.

[0824] The compound of Control 1 is

[0825] [Chemical formula] disclosed in CN103889970B.

[0826] [Table 2-1]

[0827] [Table 2-2]

[0828] In the above table, the ratio of the inhibitory activity against the PDE4B2 enzyme of the compounds in the left column and the compounds in the right column was less than 1 for all.

[0829] Experiment 2: Pharmacokinetic study by measuring the compound concentration in mouse body by LC-MS / MS Test principle: By LC-MS / MS, the drug concentration of the target drug in plasma at different time points was measured, and the pharmacokinetic profile of the target compound was plotted in vivo.

[0830] Test method: An appropriate amount of the test compound was weighed, added to 5% DMSO (INNOCHEM, INBZZHCAE), vortexed to dissolve, then 10% Solutol (BASF, 75389809T0) was added and vortexed to mix, and finally 85% Saline (Fengyuan, 220505102) was added and vortexed to mix to obtain 0.4 mg / mL and 1.0 mg / mL dosage formulations.

[0831] The mice used were C57BL / 6J male mice (JH Laboratory Animal Co. LTD). Three mice were administered either 2 mg / kg IV or 10 mg / kg PO to each group, and blood samples were collected at 5 minutes (IV group only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours (PO group only) after administration. Approximately 30 μL of blood sample was collected at each time point, placed in an anticoagulation tube containing EDTA-K2 anticoagulant, and centrifuged for 30 minutes to obtain plasma. Whole blood samples were placed on moist ice before centrifugation. Forty-two plasma samples were collected from each subject. All collected plasma samples were stored on dry ice or in a freezer until analysis. Blood cell drug concentrations were measured using a triple-quadrupole MS system (SCIEX). This included standard curve creation, quality control preparation, and sample preparation.

[0832] Preparation of standard curves and quality control: The working solution was diluted with ACN:H2O (1:1), and 3 μL of the working solution for the standard curves and quality control was added to 57 μL of blank plasma.

[0833] Sample preparation: 7 μL of plasma sample was added to 70 μL of internal standard solution (200 ng / mL each of Propranolol, Tolbutamide, Glipizide, Osalmid, and CAN), mixed for 5 minutes, centrifuged at 4000 rpm for 10 minutes, and 50 μL of supernatant was taken and transferred to a new plate (200 μL) for sample analysis.

[0834] Chromatographic conditions, including mobile phase composition, elution gradient conditions, flow rate, and retention time, were optimized for each sample. The column used was a Waters Acquity UPLC HSS T3 1.8 μm, 2.1 × 50 mm, with an injection volume of 2 μL.

[0835] Mass spectrometry was performed using an electrospray ion source. In the positive ion detection mode, the multi-channel reaction monitoring (MRM) mode was selected, and secondary mass spectrometry was performed.

[0836] Pharmacokinetic parameters were calculated using WinNonlin 8.2 software based on drug concentration-time data, following a non-compartmental model, and included peak blood concentration (Cmax), time to peak blood concentration (Tmax), area under the blood concentration-time curve (AUC), and blood concentration half-life (t). 1 / 2 It included [specific data / features]. The AUC calculation method was the linear trapezoidal method.

[0837] [Table 3]

[0838] The test results showed that the compound of the present invention exhibits good pharmacokinetics in the body and has potential as a pharmaceutical drug.

[0839] Experiment 3: Inhibitory activity test of compounds against LPS that induces TNFα secretion from human PBMCs. Frozen hPBMC cell stock solution was rapidly thawed in a 37°C water bath. Cells were transferred to complete medium (RPMI1640 + 10% FBS + 1% P / S). Centrifugation was performed at 1000 pm for 5 minutes. The supernatant was discarded, and the cells were resuspended in 1 mL of complete medium (RPMI1640 + 10% FBS + 1% P / S), then gently blown and counted using trypan blue staining. 5 × 10⁶ cells were transferred to a 96-well cell culture plate. 4 / / Well-formed cells were seeded in 100 μL / well complete medium. The compounds to be screened were prepared at four times their final concentration. 50 μL / well was added to the cells. The cells were incubated for 30 minutes prior to the test. No compounds were added to the control wells. The final stimulating concentration of LPS was 10 ng / ml, diluted fourfold, and added to the cells at 50 μL / well. Control wells were also prepared simultaneously, and no LPS was added to these wells. The cells were further incubated, and the 10% supernatant was collected and measured after 24 hours. The collected supernatant was measured according to the Human TNF-α kit (VAL105G, R&D). The inhibitory activity of the compounds of the present invention against LPS, which induces TNFα secretion, was measured according to the method described above.

[0840] [Table 4]

[0841] The test results showed that the compound of the present invention exhibits excellent inhibitory activity against TNFα secretion from human PBMCs, better suppressing TNFα secretion, an inflammatory factor in human PBMCs, and demonstrating superior anti-inflammatory effects.

Claims

1. Compounds represented by the following formula (I), stereoisomers, tautomers, or mixtures thereof of said compound, or pharmaceutically acceptable salts of said compound: 【Chemistry 1】 In the formula, X is S, SO, or SO 2 Selected from; Y is NR Y ; R Y is hydrogen or deuterium; The ring Q is C 3-8 Cycloalkyl, C 4-8 Cycloalkenyl, 3-10 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12 It is an allele; Each R Q is halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, phosphate group, carboxyl, -CN, -OH, -SH, -NO 2 , -NH 2 , -CONH 2 , 【Chemistry 2】 -L Y -OH、-L Y -SH、-L Y -C(O)OH、-L Y -NH-C(O)H、-L Y -C(O)NH 2 、-L Y -NHC(O)OH、-L Y -C(O)H、 【Transformation 3】 C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Alkylthio, C 3 - 6 Cycloalkyl, C 4 - 6 Cycloalkenyl, 3-6 member heterocyclyl, Halo C 1 - 6 Alkyl (e.g., Halo C) 1 - 3 Alkyl), -L Y -OC(O)R d , -L Y -OC(O)OR d Selected from; preferably, each R Q These include halogens, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, phosphate group, carboxyl, -CN, -OH, -SH, and -NO. 2 , -NH 2 ,-CONH 2 , 【Chemistry 4】 -L Y -OH、-L Y -SH、-L Y -C(O)OH、-L Y -NH-C(O)H、-L Y -C(O)NH 2 、-L Y -NHC(O)OH、-L Y -C(O)H、 【Transformation 5】 C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Alkylthio, C 3 - 6 Cycloalkyl, C 4 - 6 Cycloalkenyl, 3-6 member heterocyclyl, Halo C 1 - 6 Alkyl (e.g., Halo C) 1 - 3 Alkyl), -L Y -OC(O)R d Selected from; more preferably, each R Q These include halogens, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, phosphate group, carboxyl, -CN, -OH, -SH, and -NO. 2 , -NH 2 ,-CONH 2 , 【Transformation 6】 -L Y -OH、-L Y -SH、-L Y -C(O)OH、-L Y -NH-C(O)H、-L Y -C(O)NH 2 、-L Y -NHC(O)OH、-L Y -C(O)H、 【Transformation 7】 C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 1 - 6 alkoxy, C 1 - 6 alkylthio, C 3 - 6 cycloalkyl, C 4 - 6 cycloalkenyl, 3- to 6-membered heterocyclyl, halo C 1 - 6 alkyl (e.g., halo C 1 - 3 alkyl) selected from; L Y C is an arbitrarily substituted C 1 - 4 Alkilen, C 2 - 6 Alkenylene, C 2 - 6 Alkinylene, C 1 - 4 This is an alkylene oxy, where substitutions are optionally halogen, oxo, -CN, -OH, -SH, -NO 2 , -NH 2 , C 1 - 3 Alkyl, Halo C 1 - 3 Optionally substituted with one or more substituents selected from alkyl groups; L is a bond, or optionally substituted, C 1 - 4 Alkilen, C 2 - 4 Alkenylene, C 2 - 4 Alkinylene, C 1 - 4 This is an alkylene oxy, where the substitutions are optionally deuterium, halogen, oxo, -CN, -OH, -SH, -NO 2 , -NH 2 , C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Alkylthio, C 3 - 8 Cycloalkyl, Halo C 1 - 6 Optionally substituted with one or more substituents selected from alkyl groups; Ring W is C 4-16 Cycloalkyl, C 4-16 Cycloalkenyls, saturated or partially unsaturated 4-18 member heterocyclyls, 5-16 member heteroaryls, C 6-18 It is an allele; Each R w These are, independently, halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, acetamide, -CN, -OH, -SH, and -NO. 2 , -NH 2 ,-CONH 2 , -Z-(R Z ) m , -NR b R c , -C(O)OR d , arbitrarily substituted, C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Selected from alkylthio, where substitution is optional: deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO 2 , -NH 2 , -C(O)OR d , C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Alkylthio, C 3 - 8 Cycloalkyl, C 3 - 8 Cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12 Ariel, Halo C 1 - 6 Alkyl, Halo C 1 - 6 Alkoxy, halophenyl, -OC 3 - 6 Optionally substituted with one or more substituents selected from cycloalkyl groups; R b and R c These are H and C, respectively, independently. 1 - 6 Alkyl, C 2 - 6 Alkenil, C 1 - 6 Hydroxyalkyl, Halo C 1 - 6 Selected from alkyl; R d H, C 1 - 6 Alkyl, C 1 - 6 Hydroxyalkyl, Halo C 1 - 6 Alkyl, C 1-6 Selected from alkylaminos; preferably, each R w These are, independently, halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, acetamide, -CN, -OH, -SH, and -NO. 2 , -NH 2 ,-CONH 2 , -Z-(R Z ) m , -NR b R c , -C(O)OR d , arbitrarily substituted, C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Selected from alkylthio, where substitution is optional: deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO 2 , -NH 2 , -C(O)OR d , C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Alkylthio, C 3 - 8 Cycloalkyl, C 3 - 8 Cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12 Ariel, Halo C 1 - 6 Alkyl, Halo C 1 - 6 Alkoxy, halophenyl, -OC 3 - 6 Optionally substituted with one or more substituents selected from cycloalkyl groups; R b and R c These are H and C, respectively, independently. 1 - 6 Alkyl, C 2 - 6 Alkenil, C 1 - 6 Hydroxyalkyl, Halo C 1 - 6 Selected from alkyl; R d H, C 1 - 6 Alkyl, C 1 - 6 Hydroxyalkyl, Halo C 1 - 6 Selected from alkyl groups; more preferably, each R w These are, independently, halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, -CN, -OH, -SH, and -NO. 2 , -NH 2 ,-CONH 2 , -Z-(R Z ) m , arbitrarily substituted, C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Selected from alkylthio, where substitution is optionally halogen, oxo, oxime, -CN, -OH, -SH, -NO 2 , -NH 2 , C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Alkylthio, C 3 - 8 Cycloalkyl, C 3 - 8 Cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12 Ariel, Halo C 1 - 6 Alkyl, Halo C 1 - 6 Alkoxy, halophenyl, -OC 3 - 6 Optionally substituted with one or more substituents selected from cycloalkyl groups; Z is C 4-16 Cycloalkyl, C 4-16 Cycloalkenyls, saturated or partially unsaturated 4-18 member heterocyclyls, 5-16 member heteroaryls, C 6-12 It is an allele; R Z These are, independently, halogen, -CN, -OH, -SH, and -NO. 2 , -NH 2 , oxo, C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Hydroxyalkyl, Halo C 1 - 6 Alkyl, Halo C 1 - 6 Alkoxy, saturated or partially unsaturated 4-6 membered heterocyclyl, -OR Z1 , -NR Z2 R Z3 Selected from; R Z1 C 1-6 Alkyl, Halo C 1-6 Selected from alkyl; R Z2 , R Z3 These are H and C, respectively, independently. 1-6 Selected from alkyl groups; preferably, R Z These are, independently, halogen, -CN, -OH, -SH, and -NO. 2 , -NH 2 , oxo, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, Halo C 1-6 Alkyl, Halo C 1-6 Selected from alkoxy; more preferably, R Z These are, independently, halogen, -CN, -OH, -SH, and -NO. 2 , -NH 2 , C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, Halo C 1-6 Alkyl, Halo C 1-6 Selected from alkoxy; n is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, 4, or 5; however, (1) If L is a bond, 【Transformation 8】 (2) L is a bond, 【Chemistry 9】 If R w is a substituted phenyl or 【Chemistry 10】 Rather; (3) When X is SO and L is a bond, 【Chemistry 11】 Rather than any of the above; preferably, X is SO and L is a bond, 【Chemistry 12】 Not any of the following; (4) X is S or SO 2 If L is a bond, then ring Q and ring W are not simultaneously substituted phenyl; or if X is S and L is a bond and ring Q is phenyl, then ring W is 【Chemistry 13】 Rather; and (5) X is S or SO 2 If L is a bond, then the ring Q is 【Chemistry 14】 Rather; The heteroatoms in the heterocyclyl and heteroaryl are independently selected from O, N, or S, and the number of heteroatoms is preferably 1, 2, or 3.

2. The aforementioned compound is a compound represented by the following formulas (IA), (IB), and (IC): 【Chemistry 15】 In the formula, X, q, R Q , ring Q, n, R W Ring W is the same as in claim 1. A compound according to claim 1, stereoisomers, tautomers, or mixtures thereof of the compound, or a pharmaceutically acceptable salt of the compound.

3. The aforementioned compound is a compound represented by the following formulas (II-A) to (II-E): 【Chemistry 16】 In the formula, X, n, R W , Ring W, R Q q is the same as in claim 1. A compound according to claim 1, stereoisomers, tautomers, or mixtures thereof of the compound, or a pharmaceutically acceptable salt of the compound.

4. The aforementioned compound is a compound represented by the following formulas (III-A) to (III-H): 【Chemistry 17】 In the formula, n, R W , Ring W, R Q q is the same as in claim 1, and S* is a chiral sulfur atom, preferably of the R type. A compound according to claim 1, stereoisomers, tautomers, or mixtures thereof of the compound, or a pharmaceutically acceptable salt of the compound.

5. The aforementioned compound is a compound represented by the following formulas (IV-A) to (IV-E): [Chemistry 18] In the formula, n, R W Ring W is the same as in claim 1, and S* is a chiral sulfur atom, preferably of the R type. A compound according to claim 1, stereoisomers, tautomers, or mixtures thereof of the compound, or a pharmaceutically acceptable salt of the compound.

6. R Y is deuterium; or R Y is hydrogen; and / or The ring Q is C 4-6 Cycloalkyl, C 4-6 Cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, and phenyl; Preferably, ring Q is C 4-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl; More preferably, ring Q is cyclobutyl, cyclohexenyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, phenyl, or tetrahydropyranyl; Most preferably, ring Q is phenyl or tetrahydropyranyl; and / or Each R Q These are, independently, halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, phosphate group, carboxyl, -CN, -OH, -SH, -NO 2 , -NH 2 ,-CONH 2 , 【Chemistry 19】 -L Y -OH、-L Y -C(O)OH、-L Y -C(O)H、 【Chemistry 20】 C 1 - 3 Alkyl, C 2 - 4 Alkenil, C 2 - 4 Alkinyl, C 1 - 3 Alkoxy, C 1 - 3 Alkylthio, C 3 - 6 Cycloalkyl, C 3 - 6 Cycloalkenyl, 3-6 member heterocyclyl, Halo C 1 - 3 Alkyl, -L Y -OC(O)R d And; Preferably, each R Q These are, independently, halogen, oxo, and acetyl, 【Chemistry 21】 -L Y -OH, -L Y -C(O)OH, C 1 - 3 Alkyl, C 3 - 6 Cycloalkyl, 3-6 membered heterocyclyl, -L Y -OC(O)R d And; Comfortable, each R Q These are, independently, halogen, oxo, and acetyl, 【Chemistry 22】 -L Y -OH, -L Y -C(O)OH, C 1 - 3 Alkyl, C 3 - 6 Cycloalkyl, -L Y -OC(O)R d And; Most preferably, each R Q These are hydroxymethyl, carboxymethyl, and acetyl, respectively, independently. 【Chemistry 23】 Hydroxyisopropyl, Cl, oxo, cyclopropyl, 【Chemistry 24】 and / or L Y C is an arbitrarily substituted C 1 - 4 The compounds are alkylenes, where substitutions are optionally halogen, oxo, -CN, -OH, -SH, -NO 2 , -NH 2 , C 1 - 3 Alkyl, Halo C 1 - 3 Optionally substituted with one or more substituents selected from alkyl groups; Preferably, L Y C is an arbitrarily substituted C 1 - 2 The material is alkylene, where substitutions are optionally halogen, -OH, -SH, -NH 2 , C 1 - 3 Alkyl, Halo C 1 - 3 Optionally substituted with one or more substituents selected from alkyl groups; More preferably, L Y is optionally substituted methylene, ethylene, where the optionally substituted is optionally substituted with one or more substituents selected from halogen, -OH, -SH, methyl, ethyl; and / or L is a bond, or optionally substituted, C 1 - 3 Alkilen, C 2 - 4 Alkenylene, C 2 - 4 The compound is alkynylene, where the substitutions are optionally deuterium, halogen, oxo, -CN, -OH, -SH, -NH 2 , C 1 - 3 Alkyl, C 2 - 4 Alkenil, C 2 - 4 Alkinyl, C 1 - 3 Alkoxy, C 1 - 3 Alkylthio, C 3 - 8 Cycloalkyl, Halo C 1 - 3 Optionally substituted with one or more substituents selected from alkyl groups; Preferably, L is a bond, or optionally substituted, C 2 - 4 Alkenylene, C 2 - 4 The compound is alkynylene, where the substitutions are optionally deuterium, -CN, -OH, -SH, -NH 2 , C 1 - 3 Optionally substituted with one or more substituents selected from alkyl groups; More preferably, L is a bond or optionally substituted vinyl, propenyl, ethynyl, or propynyl, where the optional substitutions are deuterium, -CN, -OH, -SH, or -NH 2 , C 1 - 3 Optionally substituted with one or more substituents selected from alkyl groups; Most preferably, L is a bond, or L is ethynyl; or L is optionally substituted propynyl, where the optionally substituted is deuterium, -CN, -OH, -SH, -NH 2 , C 1 - 3 Optionally substituted with one or more substituents selected from alkyl groups; and / or Ring W is C 4-12 Cycloalkyl, C 4-12 Cycloalkenyls, saturated or partially unsaturated 4-12 member heterocyclyls, 5-16 member heteroaryls, C 6-12 It is an allele; Preferably, ring W is C 4-5 Monocyclic cycloalkyl, C 5-10 Bicyclic cycloalkyl, C 4-8 Monocyclic cycloalkenyl, C 7-10 These include bicyclic cycloalkenyls, saturated or partially unsaturated 4-8 membered monocyclic heterocyclyls, saturated or partially unsaturated 7-12 membered bicyclic heterocyclyls, 5-6 membered monocyclic heteroaryls, 9-16 membered bicyclic heteroaryls, phenyls, and naphthyls; More preferably, ring W is 【Chemistry 25】 A compound according to any one of claims 1 to 5, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound. 【Request Item 7】 【Chemistry 26】 Preferably 【Chemistry 27】 That is A compound according to any one of claims 1 to 6, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound.

8. Each R w These are, independently, halogen, oxo, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, -CN, -OH, -SH, and -NO. 2 , -NH 2 ,-CONH 2 , -Z-(R Z ) m , arbitrarily substituted, C 1 - 6 Alkyl, C 1 - 6 Selected from alkoxys, where substitution is optional: halogen, oxo, oxime, -CN, -OH, -SH, -NO 2 , -NH 2 , C 1 - 6 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 6 Alkoxy, C 1 - 6 Alkylthio, C 3 - 8 Cycloalkyl, C 3 - 8 Cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12 Ariel, Halo C 1 - 6 Alkyl, Halo C 1 - 6 Alkoxy, halophenyl, -OC 3 - 6 Optionally substituted with one or more substituents selected from cycloalkyl groups; Z is C 4-10 Cycloalkyl, C 4-10 Cycloalkenyls, saturated or partially unsaturated 4-12 member heterocyclyls, 5-12 member heteroaryls, C 6-12 It is an allele; R Z These are, independently, halogen, -CN, -OH, -SH, and -NO. 2 , -NH 2 , C 1 - 3 Alkyl, C 2 - 6 Alkenil, C 2 - 6 Alkinyl, C 1 - 3 Alkoxy, C 1 - 3 Hydroxyalkyl, Halo C 1 - 3 Alkyl, Halo C 1 - 3 Selected from alkoxy; Preferably, each R w These are, independently, halogen, formyl, acetyl, methylsulfonyl, ethylsulfonyl, methanesulfonamide, ethanesulfonamide, -CN, -OH, -SH, and -NH. 2 , -Z-(R Z ) m , arbitrarily substituted, C 1 - 4 Alkyl, C 1 - 4 Selected from alkoxys, where substitution is optional: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , C 1 - 3 Alkyl, C 1 - 3 Alkoxy, C 3 - 6 Cycloalkyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, C 6-12 Ariel, Halo C 1 - 3 Alkyl, Halo C 1 - 3 Optionally substituted with one or more substituents selected from alkoxys and halophenyls; Z is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, or phenyl; R Z These are, independently, halogen, -CN, -OH, -SH, and -NO. 2 , -NH 2 , C 1 - 3 Alkyl, C 1 - 3 Alkoxy, C 1 - 3 Hydroxyalkyl, Halo C 1 - 3 Alkyl, Halo C 1 - 3 Selected from alkoxy A compound according to any one of claims 1 to 7, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound.

9. The compound is a compound represented by the following formula (IV-A) or (IV-E), preferably a compound represented by the following formula (IV-A): 【Chemistry 28】 Each R w These are independently methylsulfonyl, methanesulfonamide, ethanesulfonamide, F, Cl, -CN, -OH, -SH, and -NH. 2 , 【Chemistry 29】 Alternatively, optionally substituted, selected from methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, and ethylthio, where the optional substitution is halogen, -CN, -OH, or -NH. 2 , C 1 - 3 Alkyl, C 1 - 3 Alkoxy, C 1 - 3 Haloalkyl, C 1 - 3 Optionally substituted with one or more substituents selected from haloalkoxys, preferably each R w These are independently methylsulfonyl, methanesulfonamide, ethanesulfonamide, F, Cl, -CN, -OH, -SH, and -NH. 2 , 【Transformation 30】 Selected from A compound according to claim 1, stereoisomers, tautomers, or mixtures thereof of the compound, or a pharmaceutically acceptable salt of the compound.

10. The compound is a compound represented by the following formula (IV-A) or (IV-E), preferably a compound represented by the following formula (IV-A): 【Chemistry 31】 Preferably 【Chemistry 32】 And; Each R w Each is independent of the others. 【Transformation 33】 Selected from; preferably, each R w Each is independent of the others. 【Transformation 34】 Selected from A compound according to claim 1, stereoisomers, tautomers, or mixtures thereof of the compound, or a pharmaceutically acceptable salt of the compound.

11. m is 0, 1, 2, or 3; Preferably, m is 1, 2, or 3; More preferably, m is 1 or 2; and / or n is 0, 1, 2, or 3; Preferably, n is 0, 1, or 2; More preferably, n is 1 or 2; and / or q is 0, 1, 2, or 3; Preferably, q is 0, 1, or 2; More preferably, q is 1 or 2. A compound according to any one of claims 1 to 9, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound.

12. The following compounds, stereoisomers, tautomers, or mixtures thereof of said compounds, and pharmaceutically acceptable salts of said compounds: 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 12, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound.

14. The use of a compound according to any one of claims 1 to 12, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a pharmaceutical composition according to claim 13 in the manufacture of a medicament for the treatment and / or prevention of PDE4B-mediated diseases, The PDE4B-mediated diseases preferably include respiratory diseases, gastrointestinal diseases, inflammatory diseases, allergic diseases, autoimmune diseases, or cancer. The respiratory disease is selected from, for example, respiratory or pulmonary diseases involving increased mucus production, respiratory inflammation, and / or obstructive disease; more preferably, the respiratory disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, interstitial pneumonia, chronic obstructive pulmonary disease (COPD), alpha-antitrypsin deficiency, chronic sinusitis, asthma, or chronic bronchitis. The aforementioned gastrointestinal disorder is selected from, for example, ileitis, ulcerative colitis, or Crohn's disease; The inflammatory disease is selected from, for example, dry eye syndrome or glaucoma; The aforementioned autoimmune diseases include, for example, systemic lupus erythematosus, atopic dermatitis, seborrheic dermatitis, psoriasis, urticaria, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis, or diffuse connective tissue disease of xerosis.

15. A compound according to any one of claims 1 to 12 for treating and / or preventing a PDE4B-mediated disease, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound, The PDE4B-mediated diseases preferably include respiratory diseases, gastrointestinal diseases, inflammatory diseases, allergic diseases, autoimmune diseases, or cancer. The respiratory disease is selected from, for example, respiratory or pulmonary diseases involving increased mucus production, respiratory inflammation, and / or obstructive disease; more preferably, the respiratory disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, interstitial pneumonia, chronic obstructive pulmonary disease (COPD), alpha-antitrypsin deficiency, chronic sinusitis, asthma, or chronic bronchitis. The aforementioned gastrointestinal disorder is selected from, for example, ileitis, ulcerative colitis, or Crohn's disease; The inflammatory disease is selected from, for example, dry eye syndrome or glaucoma; The aforementioned autoimmune diseases include, for example, systemic lupus erythematosus, atopic dermatitis, seborrheic dermatitis, psoriasis, urticaria, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis, or diffuse connective tissue disease of xerosis.

16. A method for treating and / or preventing a PDE4B-mediated disease, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 12, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt of said compound, or a pharmaceutical composition according to claim 13, to a subject in need thereof, The PDE4B-mediated diseases preferably include respiratory diseases, gastrointestinal diseases, inflammatory diseases, allergic diseases, autoimmune diseases, or cancer. The respiratory disease is selected from, for example, respiratory or pulmonary diseases involving increased mucus production, respiratory inflammation, and / or obstructive disease; more preferably, the respiratory disease is selected from idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, interstitial pneumonia, chronic obstructive pulmonary disease (COPD), alpha-antitrypsin deficiency, chronic sinusitis, asthma, or chronic bronchitis. The aforementioned gastrointestinal disorder is selected from, for example, ileitis, ulcerative colitis, or Crohn's disease; The inflammatory disease is selected from, for example, dry eye syndrome or glaucoma; The aforementioned autoimmune diseases include, for example, systemic lupus erythematosus, atopic dermatitis, seborrheic dermatitis, psoriasis, urticaria, rheumatoid arthritis, multiple sclerosis, dermatomyositis, polymyositis, vasculitis, or diffuse connective tissue disease of xerosis.

Images