Borate derivatives and their use

Abstract

Provided are compounds represented by formula I, or a pharma- ceutically acceptable salt thereof, and the use of the compounds in the preparation of a medicament for preventing and / or treating a PDE-related disorder. JPEG2024500982000094.jpg32170

Description

[Technical Field]

[0001] This disclosure pertains to the field of pharmaceuticals and relates to borate derivatives and their use. [Background technology]

[0002] Phosphodiesterases (PDEs) are a class of intracellular enzymes that cleave phosphodiester bonds on the second messenger molecules 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP). The cyclic nucleotides cAMP and cGMP act as second messengers in various cellular pathways. Of these, PDE4 is highly specific to cAMP and has four subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4 is involved in promoting monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, vasodilation and myocardial contraction, and other related physiological and pathological processes, and has effects on central nervous system function, cardiovascular function, inflammation / immune system, cell adhesion, etc. PDE4 plays a crucial regulatory role in the expression of pro-inflammatory and anti-inflammatory signaling molecules, and PDE4 inhibitors can inhibit the release of harmful signaling molecules by inflammatory cells. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] CN102014927A [Patent Document 2] WO2020070651 [Overview of the project] [Problems that the invention aims to solve]

[0004] Many PDE4 inhibitors have been identified in recent years. For example, roflumilast is approved for reducing the frequency of sudden onsets or preventing exacerbations of COPD in severe chronic obstructive pulmonary disease (COPD), and apremilast is approved for the treatment of adults with active psoriatic arthritis. While PDE4 inhibitors exhibit good pharmacological activity, these PDE inhibitors have side effects, such as induced gastrointestinal symptoms, including vomiting and diarrhea. There remains a need to develop selective PDE4 inhibitors, particularly those with affinity for PDE4B and PDE4D.

[0005] The boron(B)-containing drug crisabolol was approved by the FDA on December 14, 2016, as a topical treatment for mild to moderate atopic dermatitis. The boron atom promotes skin penetration and binds to the bimetallic center of phosphodiesterase 4 (PDE4). Furthermore, other boron-containing PDE inhibitor small molecules have been reported, such as CN102014927A and WO2020070651. However, the compound of this disclosure has not been disclosed in any literature, and such compounds exhibit a specific PDE4 inhibitory effect. [Means for solving the problem]

[0006] This disclosure relates to Formula I [ka]

[0007] (In the formula, ring A is selected from the group consisting of 5-6 membered aryl rings and heteroaryl rings, and the aryl ring or heteroaryl ring may optionally consist of one or more R A1 It is further replaced by, R A1 These are halogens, deuterium, hydroxy, nitro, cyano, amino, and C. 1~6 Alkyl, C 3~6 Cycloalkyl, 3-6 membered ring heterocyclyl, C 1~6 Alkoxyl, C 3~6Selected from the group consisting of cycloalkyloxyl and 3- to 6-membered heterocycloalkyloxyl, C 1~6 alkyl, C 1~6 alkoxyl, C 3~6 cycloalkyloxyl or 3- to 6-membered heterocycloalkyloxyl is optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxy, nitro, cyano, amino and C 1~6 alkoxyl, B is a boron atom, Z is selected from a carbon atom and a nitrogen atom, R 1 is each independently hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1~6 alkyl, C 3~6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1~6 alkoxyl, C 3~6 cycloalkyloxyl and 3- to 6-membered heterocycloalkyloxyl, independently selected from the group consisting of C 1~6 alkyl, C 3~6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1~6 alkoxyl, C 3~6 cycloalkyloxyl or 3- to 6-membered heterocycloalkyloxyl is optionally further substituted with one or more R A2 , R A2 is halogen, deuterium, hydroxy, nitro, cyano, amino, C 1~6 alkyl, C 3~6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1~6 alkoxyl, C 3~6 cycloalkyloxyl and 3- to 6-membered heterocycloalkyloxyl, selected from the group consisting of C 1~6 alkyl, C 1~6 alkoxyl, C 3~6 cycloalkyloxyl or 3- to 6-membered heterocycloalkyloxyl is optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxy, nitro, cyano, amino and C 1~6 alkoxyl, R2 R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally selected as one or more R A3 It is further replaced by, R A3 It is selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, and amino. R 3 , R 4 and R 5 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyl, C 3~6 Independently selected from the group consisting of cycloalkyl, 3-6 membered heterocyclyl, and 3-6 membered heterocycloalkoxyl, wherein alkyl, alkoxyl, cycloalkoxyl, cycloalkyl, heterocyclyl, or heterocycloalkoxyl are optionally one or more R A4 It is further replaced by, R A4 It is selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, and amino. R 6 and R 7 These, together with the carbon atoms attached to them, form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring may optionally have one or more R A5 It is further replaced by, R A5 These are halogens, deuterium, hydroxyl, oxo, nitro, cyano, and C. 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Selected from the group consisting of cycloalkoxyls, 3-6 membered heterocycloalkoxyls, phenyls, and 5-6 membered heteroaryls, C 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyl, 3-6 membered ring heterocycloalkoxyl, C 3~8Cycloalkenyloxyl, phenyl, or 5-6 membered ring heteroaryl is optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, and cyano. m is an integer from 0 to 5. n is an integer from 1 to 3, for example, 1 or 2. and

[0008] [ka]

[0009] It is at the meta position on ring A, "

[0010] [ka]

[0011] This provides compounds (which have single bonds or none) or pharmaceutically acceptable salts thereof.

[0012] In some embodiments, in a compound of formula I, or a pharmaceutically acceptable salt thereof, R 3 and R 4 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally one or more R A4 It is further replaced with R A4 This is as defined above.

[0013] In some embodiments, in a compound of formula I, or a pharmaceutically acceptable salt thereof, R 3 and R 4 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 3~6 Cycloalkoxyl, C 3~6Independently selected from the group consisting of cycloalkyls, 3-6 membered heterocyclyls, and 3-6 membered heterocycloalkoxyls, the cycloalkoxyl, cycloalkyl, heterocyclyl, or heterocycloalkoxyl is optionally one or more R A4 It is further replaced with R A4 This is as defined above.

[0014] In some other embodiments, in a compound of formula I, or a pharmaceutically acceptable salt thereof, R 5 Hydrogen, deuterium, halogen, amino, hydroxyl, C 1~6 Alkyl and C 1~6 Selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally one or more R A4 It is further replaced by [this].

[0015] In some other embodiments, in a compound of formula I, or a pharmaceutically acceptable salt thereof, R 5 Hydrogen, deuterium, halogen, amino, hydroxyl, C 3~6 Cycloalkoxyl, C 3~6 Selected from the group consisting of cycloalkyls, 3-6 membered heterocyclines, and 3-6 membered heterocycloalkoxyls, the cycloalkoxyl, cycloalkyl, heterocycline, or heterocycloalkoxyl may optionally be one or more R A4 It is further replaced by [this].

[0016] Furthermore, in the compounds of formula I shown in some embodiments, or pharmaceutically acceptable salts thereof, R 3 and R 4 Each is independently selected from hydrogen, and R 5 C 1~6 Alkyl and C 1~6 Selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally selected from 1 to 3 R A4 It has been replaced with.

[0017] In some embodiments, in a compound of formula I, or a pharmaceutically acceptable salt thereof, RA4 is selected from halogen, for example fluorine.

[0018] In some embodiments, in the compound of formula I, or a pharmaceutically acceptable salt thereof, R A4 is selected from the group consisting of hydroxy, nitro, cyano and amino.

[0019] In another aspect, the compound of formula I shown in some embodiments is

[0020]

Chemical formula

[0021] (wherein X 1 is selected from the group consisting of -O-, -N(R 16a )- and -CR 16a R 16b -, X 2 is selected from the group consisting of -O- and -CR 17a R 17b -, X 3 is selected from the group consisting of a bond, -CR 18a R 18b - and -CR 18a R 18b CR 18c R 18d -, R 16a and R 16b are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, C 1~6 alkyl and C 1~6 alkoxyl, and the alkyl or alkoxyl is optionally substituted with halogen, nitro, cyano or C <00OO099>alkoxyl, R 17a and R 17b are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, C 1~6 alkyl and C 1~6Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally halogen, nitro, cyano, or C 1~6 Substituted with alkoxyl, R 18a , R 18b , R 18c and R 18d These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally halogen, nitro, cyano, or C 1~6 Substituted with alkoxyl, R 8 and R 9 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyl, C 3~6 Independently selected from the group consisting of cycloalkyl, 3-6 membered heterocyclyl, and 3-6 membered heterocycloalkoxyl, the alkyl, alkoxyl, cycloalkoxyl, cycloalkyl, or heterocyclyl may be optionally selected as one or more R A6 It is further replaced by, or R 8 and R 9 These, together with the carbon atoms attached to them, form a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring may optionally have one or more R A6 It is further replaced by, or R 8 and R 9 Together they form oxo (=O), R A6 These are halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, and C. 1~6 Alkyl and C 1~6 Selected from the group consisting of alkoxyls, Ring A, R 1 ~R 5 , B, m, n and "

[0022] [ka]

[0023] (This is defined as in the compound of formula I.)

[0024] In some embodiments, in a compound of formula IA, or a pharmaceutically acceptable salt thereof, X 1 It is selected from -O-.

[0025] In some embodiments, in a compound of formula IA, or a pharmaceutically acceptable salt thereof, X 1 is selected from -O-, X 2 -O- and -CR 17a R 17b - Selected from, R 17a and R 17b These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 It is independently selected from the group consisting of alkoxyls.

[0026] In some embodiments, in a compound of formula IA, or a pharmaceutically acceptable salt thereof, X 3 This involves bonding and -CR 18a R 18b - Selected from, R 18a and R 18b These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 It is independently selected from the group consisting of alkoxyls.

[0027] In some embodiments, in a compound of formula IA, or a pharmaceutically acceptable salt thereof, X 1 is selected from -O-, X 2 -O- and -CR 17a R 17b - Selected from, R 17a and R 17b These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively.1~6 Alkyl and C 1~6 Independently selected from the group consisting of alkoxyls, X 3 It is selected from the combination.

[0028] In some embodiments, in a compound of formula IA, or a pharmaceutically acceptable salt thereof, X 1 is selected from -O-, X 2 -O- and -CR 17a R 17b - Selected from, R 17a and R 17b These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 Independently selected from the group consisting of alkoxyls, X 3 -CR 18a R 18b - Selected from, R 18a and R 18b These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 It is independently selected from the group consisting of alkoxyls.

[0029] In another embodiment, the compounds of formula IA shown in some embodiments are

[0030] [ka]

[0031] That is the case.

[0032] In some embodiments, in a compound of formula I or formula IA, or a pharmaceutically acceptable salt thereof, R 8 and R 9 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally one or more R A6 It is further replaced with R A6These are halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, and C. 1~6 Alkyl and C 1~6 Selected from the group consisting of alkoxyls.

[0033] In some embodiments, in a compound of formula IA, or a pharmaceutically acceptable salt thereof, R 8 and R 9 The 3-6 membered carbocyclic rings or 4-6 membered heterocyclic rings formed by the carbon atoms attached to them are

[0034] [ka]

[0035] The group is selected from the following. Furthermore, the carbocyclic or heterocyclic ring can be optionally selected from 1 to 3 R A6 It is replaced with R A6 These are halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, and C. 1~6 Alkyl and C 1~6 Selected from the group consisting of alkoxyls.

[0036] In some embodiments, in a compound of formula IA, or a pharmaceutically acceptable salt thereof, R A6 R is selected from deuterium and oxo. In some embodiments, in a compound of formula IA, or a pharmaceutically acceptable salt thereof, R A6 is halogen, C 1~6 Alkyl and C 1~6 Selected from the group consisting of alkoxyls. In some embodiments, in a compound of formula IA, or a pharmaceutically acceptable salt thereof, R A6 The element is selected from the group consisting of fluorine, chlorine, methyl, ethyl, methoxyl, and ethoxyl.

[0037] In another embodiment, the compound of formula I in some embodiments is

[0038] [ka]

[0039] (In the formula, X 4 These are selected from nitrogen atoms and carbon atoms. R 10 and R 11 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyl, C 3~6 Independently selected from the group consisting of cycloalkyl, 3-6 membered heterocyclyl, and 3-6 membered heterocycloalkoxyl, wherein alkyl, alkoxyl, cycloalkoxyl, cycloalkyl, or heterocyclyl is optionally selected as one or more R A7 It is further replaced by, R A7 These are halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, and C. 1~6 Alkyl and C 1~6 Selected from the group consisting of alkoxyls, Rings A, Z, R 1 ~R 5 , B, m, n and "

[0040] [ka]

[0041] (This is defined as in the compound of formula I.)

[0042] In some embodiments, in a compound of formula IB, or a pharmaceutically acceptable salt thereof, R 10 and R 11 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally selected from 1 to 3 R A7 It is further substituted with. In some embodiments, in a compound of formula IB, or a pharmaceutically acceptable salt thereof, RA7 is halogen, C 1~6 Alkyl and C 1~6 Selected from the group consisting of alkoxyls. In some embodiments, a compound of formula IB, or a pharmaceutically acceptable salt thereof, R A7 The element is selected from the group consisting of fluorine, chlorine, methyl, ethyl, methoxyl, and ethoxyl.

[0043] In other embodiments, in some examples, a compound of formula IB, or a pharmaceutically acceptable salt thereof, X 4 A is selected from nitrogen atoms, and Z is selected from nitrogen atoms.

[0044] In some embodiments, the compound of formula I is

[0045] [ka]

[0046] (In the formula, X 5 These are selected from nitrogen atoms and carbon atoms. R 12 , R 13 and R 14 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyl, C 3~6 Independently selected from the group consisting of cycloalkyl, 3-6 membered heterocyclyl, and 3-6 membered heterocycloalkoxyl, wherein alkyl, alkoxyl, cycloalkoxyl, cycloalkyl, or heterocyclyl is optionally selected as one or more R A8 It is further replaced by, R A8 These are halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, and C. 1~6 Alkyl and C 1~6 Selected from the group consisting of alkoxyls, Rings A, Z, R 1 ~R 5 , B, m, n and "

[0047] [ka]

[0048] (This is defined as in the compound of formula I.)

[0049] In some embodiments, in a compound of formula IC, or a pharmaceutically acceptable salt thereof, R 12 , R 13 and R 14 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally selected from 1 to 3 R A8 It is further substituted with. In some embodiments, in a compound of formula IC, or a pharmaceutically acceptable salt thereof, R A8 is halogen, C 1~6 Alkyl and C 1~6 Selected from the group consisting of alkoxyls. In some embodiments, a compound of formula IC, or a pharmaceutically acceptable salt thereof, R A8 The element is selected from the group consisting of fluorine, chlorine, methyl, ethyl, methoxyl, and ethoxyl.

[0050] In other embodiments, in some examples, a compound of formula IC, or a pharmaceutically acceptable salt thereof, X 5 Z is selected from nitrogen atoms, and Z is selected from carbon atoms.

[0051] In other embodiments, in some examples, in a compound of formula I, or a pharmaceutically acceptable salt thereof, ring A is

[0052] [ka]

[0053] (In the formula, R 15a , R 15b , R15c and R 15d These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 A group consisting of alkoxyls is independently selected from the group consisting of alkyl or alkoxyls, which are optionally further substituted with one or more halogens, deuterium, hydroxyl, nitro, cyano, or amino compounds.

[0054] In some embodiments, in a compound of formula I, or a pharmaceutically acceptable salt thereof, R 15a , R 15b , R 15c and R 15d These are hydrogen, deuterium, halogen, and C, respectively. 1~6 R is independently selected from the group consisting of alkyl groups. In some embodiments, in a compound of formula I, or a pharmaceutically acceptable salt thereof, R 15a , R 15b , R 15c and R 15d Each of these is independently selected from the group consisting of fluorine, chlorine, methyl, and ethyl.

[0055] In the compounds of formula I shown in some other embodiments, or pharmaceutically acceptable salts thereof, ring A is

[0056] [ka]

[0057] It is selected from the group consisting of the following.

[0058] In some embodiments, in a compound of formula I, or a pharmaceutically acceptable salt thereof, n is selected from 1 and 2.

[0059] In some embodiments, compounds of formula I or formula IA are

[0060] [ka]

[0061] It is selected from the group consisting of the following.

[0062] In some embodiments, compounds of formula I or formula IA are

[0063] [ka]

[0064] It is selected from the group consisting of the following.

[0065] In some embodiments, compounds of formula I or formula IB are

[0066] [ka]

[0067] Selected from.

[0068] In some embodiments, the compound of formula I or formula IC is

[0069] [ka]

[0070] Selected from.

[0071] In some embodiments, the compound of formula I is

[0072] [ka]

[0073] Selected from.

[0074] In another embodiment, in a compound of formula I, formula IA, formula IB, or formula IC as shown in some embodiments, or a pharmaceutically acceptable salt thereof, R 2is hydrogen and C 1~6 Selected from the group consisting of alkyl groups. In some embodiments, a compound of formula I, formula IA, formula IB, or formula IC, or a pharmaceutically acceptable salt thereof, R 2 R is selected from the group consisting of hydrogen, methyl, and ethyl. In some embodiments, a compound of formula I, formula IA, formula IB, or formula IC, or a pharmaceutically acceptable salt thereof, is used. 2 It is selected from hydrogen.

[0075] In another embodiment, in a compound of formula I, formula IA, formula IB, or formula IC as shown in some embodiments, or a pharmaceutically acceptable salt thereof, R 1 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1~6 Alkyl and C 1~6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally further substituted with one or more groups consisting of halogen, deuterium, hydroxy, nitro, cyano, and amino. In some embodiments, in compounds of formula I, IA, IB, or IC, or pharmaceutically acceptable salts thereof, R 1 Each of these is independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, methoxyl, and ethoxyl.

[0076] The compounds of formula I shown in some other embodiments are:

[0077] [ka]

[0078] That is the case.

[0079] In some embodiments, the compound of formula I is

[0080] [ka]

[0081] That is the case.

[0082] The compounds of formula I shown in some other embodiments are:

[0083] [ka]

[0084] It is selected from the group consisting of the following.

[0085] In some embodiments, the compound of formula I is

[0086] [ka]

[0087] It is selected from the group consisting of the following.

[0088] Typical compounds of formula I, or pharmaceutically acceptable salts thereof,

[0089] [ka]

[0090] [ka]

[0091] [ka]

[0092] This includes, but is not limited to, those listed above.

[0093] Typical compounds of formula I, or pharmaceutically acceptable salts thereof,

[0094] [ka]

[0095]

Chem.

[0096]

Chem.

[0097] including, but not limited to, those.

[0098] In another aspect, the present disclosure provides a compound of formula (1)

[0099]

Chem.

[0100] (wherein R 19a and R 19b are each independently selected from the group consisting of hydrogen and C 1~6 alkyl, and the alkyl is optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, and C 1~6 alkoxyl, or R 19a and R 19b together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring, and the heterocyclic ring is optionally further substituted with one or more R A9 ; R A9 is selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1~6 alkyl, and C 1~6 alkoxyl; ring A, R 1 ~R 7 , B, n, and Z are as defined for the compounds of formula I), or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the compound of formula (1) is

[0102] [ka]

[0103] (In the formula, rings A, R 1 , R 3 ~R 5 B and n are defined as in the compound of formula I, and R 8 ~R 9 , X 1 , X 2 , X 3 (This is as defined for compounds of formula IA.)

[0104] In some embodiments, the compound of formula (1), or a pharmaceutically acceptable salt thereof,

[0105] [ka]

[0106] (In the formula, rings A, R 1 , R 3 ~R 5 B, n, and Z are defined as in the compound of formula I, and R 10 ~R 11 , X 4 (This is as defined for compounds of formula IB.)

[0107] In some embodiments, the compound of formula (1) is

[0108] [ka]

[0109] (In the formula, rings A, R 1 , R 3 ~R 5 B, n, and Z are defined as in the compound of formula I, and R 12 ~R 14 , X 5 (This is as defined for compounds of formula IB.)

[0110] In another aspect, in some embodiments, the compound of formula (1) is

[0111]

Chemical formula

[0112] (wherein R A9 is selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1~6 alkyl and C 1~6 alkoxyl, o is an integer from 0 to 4, and ring A, R 1 ~R 7 , B, n, Z are as defined for the compound of formula I).

[0113] In another aspect, in some embodiments, the compound of formula (1) is

[0114]

Chemical formula

[0115] (wherein R A9 is selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1~6 alkyl and C 1~6 alkoxyl, p is an integer from 0 to 6, and ring A, R 1 ~R 7 , B, n, Z are as defined for the compound of formula I).

[0116] The present disclosure is a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising the step of converting a compound of formula (1) into a compound of formula I or a pharmaceutically acceptable salt thereof

[0117]

Chemical formula

[0118] (In the formula, R 19a and R 19b These are hydrogen and C, respectively. 1~6 Independently selected from the group consisting of alkyls, the alkyl is optionally halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, and C 1~6 It is further substituted with one or more groups selected from the group consisting of alkoxyls, or R 19a and R 19b These, together with the atoms attached to them, form a 5-membered ring or a 6-membered heterocyclic ring, and the heterocyclic ring may optionally contain one or more R atoms. A9 It is further replaced with R A9 These are halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, and C. 1~6 Alkyl and C 1~6 We also provide a method that includes (selected from the group consisting of alkoxyls).

[0119] In another aspect, this disclosure relates to formula (2)

[0120] [ka]

[0121] (In the formula, R 20a and R 20b These are hydrogen and C, respectively. 1~6 Independently selected from the group consisting of alkyls, the alkyl is optionally halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, and C 1~6 It is further substituted with one or more groups selected from the group consisting of alkoxyls, or R 20a and R 20b These, together with the atoms attached to them, form a 5-membered ring or a 6-membered heterocyclic ring, and the heterocyclic ring may optionally contain one or more R atoms. A10 It is further replaced with R A10 These are halogens, deuterium, hydroxy, oxo, nitro, cyano, amino, and C. 1~6 Alkyl and C 1~6The invention also provides compounds (selected from the group consisting of alkoxyls) or pharmaceutically acceptable salts thereof.

[0122] The compound of formula (2) shown in some embodiments is

[0123] [ka]

[0124] That is the case.

[0125] The compound of formula (2) shown in some embodiments is

[0126] [ka]

[0127] That is the case.

[0128] In some embodiments, the compound of formula (2), or a pharmaceutically acceptable salt thereof,

[0129] [ka]

[0130] It is selected from the group consisting of the following.

[0131] The disclosure also provides a pharmaceutical composition comprising at least one compound of the aforementioned formula I, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount, and a pharmaceutically acceptable excipient.

[0132] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0133] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the aforementioned compound, or a pharmaceutically acceptable salt thereof, based on the total mass of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the aforementioned compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound, or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of pharmaceutically acceptable excipients based on the total mass of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% of pharmaceutically acceptable excipients.

[0135] This disclosure also provides a method for preventing and / or treating PDE-related disorders by administering to a patient a therapeutically effective amount of the aforementioned compound of formula I or formula IA, or a pharmaceutically acceptable salt thereof, or a compound prepared by the aforementioned method, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0136] In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes mellitus, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

[0137] The Disclosure also provides a method for preventing and / or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes mellitus, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism by administering to a patient a therapeutically effective amount of the aforementioned compound of formula I or formula IA, or a pharmaceutically acceptable salt thereof, or a compound prepared by the aforementioned method, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0138] This disclosure also provides the use of the compounds of formula I or formula IA described above, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions in the preparation of pharmaceuticals for preventing and / or treating PDE-related disorders. In some embodiments, the PDE-related disorders are preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes mellitus, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

[0139] This disclosure also provides the use of the aforementioned compounds of formula I or formula IA, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions in the preparation of pharmaceuticals for the prevention and / or treatment of asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes mellitus, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

[0140] In another embodiment, pharmaceutically acceptable salts of the compounds described herein are selected from inorganic salts and organic salts.

[0141] The compounds of this disclosure may exist in specific geometric or stereoisomeric forms. This disclosure considers all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, all of which are within the scope of this disclosure. Additional chiral carbon atoms may be present in substituents, such as alkyl groups. All of these isomers and mixtures thereof are within the scope of this disclosure. Compounds containing chiral carbon atoms of this disclosure may be isolated in optically pure form or in racemic form. The optically pure form may be isolated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0142] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. If a certain type of enantiomer of a compound in this disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral additives, the resulting enantiomer mixture is separated, and the auxiliary groups are cleaved to obtain the pure, desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), the diastereoisomer salt is formed with a suitable optically active acid or base. The diastereoisomer is then separated by conventional methods well known in the art, and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereoisomers is typically performed using chromatography, which is used with a chiral stationary phase and optionally combined with chemical derivatization (e.g., production of carbamates from amines).

[0143] In the chemical structure of the compound disclosed herein, the bond "

[0144] [ka]

[0145] " means an unspecified configuration, that is, when chiral isomers are present in the chemical structure, the bond "

[0146] [ka]

[0147] "teeth,"

[0148] [ka]

[0149] " or "

[0150] [ka]

[0151] It could be " or two arrangements "

[0152] [ka]

[0153] " and "

[0154] [ka]

[0155] This includes both " and ". Combined "

[0156] [ka]

[0157] " means an unspecified configuration, including cis-(E) and trans-(Z) configurations.

[0158] The compounds and intermediates of this disclosure may also exist in different tautomer forms, all of which are included within the scope of this disclosure. The terms “tautomer” or “tautomer form” refer to structural isomers of different energies that can be interconverted across low-energy barriers. For example, proton tautomers (also known as prototropic tautomers) include tautomerism via proton transfer, such as ketone-enol and imine-enamine, and lactam-lactim tautomerism. An example of lactam-lactim equilibrium is between A and B, as shown below.

[0159] [ka]

[0160] All compounds in this disclosure can be described as either Type A or Type B. All forms of tautomerism are within the scope of this disclosure. The nomenclature of the compounds does not exclude any tautomers.

[0161] This disclosure also includes certain isotope-labeled compounds, which are identical to those described herein but in which one or more atoms are replaced by atoms with atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, respectively. 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Includes Cl.

[0162] Unless otherwise specified, when a position is specifically designated as deuterium (D), this position should be understood to have a deuterium abundance at least 1,000 times greater than the natural deuterium abundance (0.015%) (i.e., at least 10% deuterium incorporation). For example, a compound with a deuterium abundance greater than the natural deuterium abundance may have a deuterium abundance at least 1,000 times, at least 2,000 times, at least 3,000 times, at least 4,000 times, at least 5,000 times, at least 6,000 times greater than the natural deuterium abundance, or a high deuterium abundance. This disclosure also includes various deuterated forms of the compound of formula (I). Each available hydrogen atom bonded to the carbon atom may be independently substituted with a deuterium atom. Those skilled in the art can synthesize the deuterated forms of the compound of formula (I) by referring to relevant literature. The deuterated form of the compound of formula (I) can be prepared using commercially available deuterated starting materials, or it can be synthesized by conventional techniques using deuterated reagents, including but not limited to deuterated borane, trihydroborane solution in tetrahydrofuran, lithium aluminum deuteride, deuterated iodoethane, and deuterated iodomethane.

[0163] "Optionally" or "optionally" means that the described event or environment may occur later, but does not have to occur, and such description includes the circumstances under which the event or environment may or may not occur. For example, "C 1~6 The statement "The alkyl is optionally substituted with a halogen or cyano" means that while a halogen or cyano may be present, it is not required, and such a statement includes situations where the alkyl is substituted with a halogen or cyano, and situations where the alkyl is not substituted with a halogen or cyano.

[0164] "Pharmaceutical composition" means a mixture containing one or more compounds described herein, or physiologically pharmaceutically acceptable salts thereof, or prodrugs thereof, and other chemical components, as well as other components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate drug delivery to an organism and to aid in the absorption of the active ingredient in order to exert its biological activity.

[0165] "Pharmacovigilantly acceptable excipients" or "acceptable excipients" include, but are not limited to, any adjuvants, carriers, flow enhancers, sweeteners, diluents, preservatives, colorants, flavorings, surfactants, humectants, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock animals.

[0166] As used in this disclosure, “effective dose” or “therapeutic effective dose” includes an amount sufficient to alleviate or prevent the symptoms or condition of a medical disease. An effective dose also includes an amount sufficient to enable or facilitate a diagnosis. The effective dose for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the patient’s general health, the method, route and dosage of drug administration, and the severity of adverse reactions. The effective dose may be the maximum dose or dosage that avoids significant adverse reactions or toxic effects.

[0167] "Alkyl" refers to a saturated aliphatic hydrocarbon group that is a linear or branched group containing 1 to 20 carbon atoms. Alkyl groups contain 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. Alkyl groups may be substituted or unsubstituted. If substituted, substituents may be substituted at any available connection point. Substituents may include halogens, deuterium, hydroxyl, nitro, cyano, amino, and C. 1~6 Alkyl, C 3~6 Cycloalkyl, 3-6 membered ring heterocyclyl, C 1~6Alkoxyl, C 3~6 Preferably one or more groups independently selected from the group consisting of cycloalkoxyls and 3- to 6-membered heterocycloalkoxyls, C 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyls or 3-6 membered heterocycloalkoxyls may optionally be halogens, deuterium, hydroxyl, nitro, cyano, amino, and C 1~6 It is further substituted with one or more groups selected from the group consisting of alkoxyls.

[0168] The terms "cycloalkyl" or "carbocyclic ring" refer to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents. Cycloalkyl rings contain 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl. Polycyclic cycloalkyls include cycloalkyls having a spiro ring, a fused ring, or a crosslinked ring. Cycloalkyls may be substituted or unsubstituted. If substituted, substituents may be substituted at any available connection point. Substituents are preferably halogens, deuterium, hydroxyl, nitro, cyano, amino, and C. 1~6 Alkyl, C 3~6 Cycloalkyl, 3-6 membered ring heterocyclyl, C 1~6 Alkoxyl, C 3~6 One or more groups independently selected from the group consisting of cycloalkoxyls and 3- to 6-membered heterocycloalkoxyls, C 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyls or 3-6 membered heterocycloalkoxyls may optionally be halogens, deuterium, hydroxyl, nitro, cyano, amino, and C 1~6The cycloalkyl ring may be condensed with an aryl or heteroaryl ring, and the ring attached to the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl may be optionally substituted or unsubstituted. If substituted, the substituents are preferably halogen, deuterium, hydroxy, nitro, cyano, amino, or C 1~6 Alkyl, C 3~6 Cycloalkyl, 3-6 membered ring heterocycloalkyl, C 1~6 Alkoxyl, C 3~6 One or more groups independently selected from the group consisting of cycloalkoxyls and 3- to 6-membered heterocycloalkoxyls, C 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyls or 3-6 membered heterocycloalkoxyls may optionally be halogens, deuterium, hydroxyl, nitro, cyano, amino, and C 1~6 It is further substituted with one or more groups selected from the group consisting of alkoxyls.

[0169] The term "heterocyclyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents containing 3 to 6 ring atoms. Non-exclusive examples of "heterocyclyl" are:

[0170] [ka]

[0171] Includes, etc.

[0172] Heterocyclyls may be optionally substituted or unsubstituted. If substituted, the substituents are preferably halogen, deuterium, hydroxyl, oxo, nitro, cyano, or C. 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6One or more groups independently selected from the group consisting of cycloalkoxyl, 3-6 membered heterocycloalkoxyl, phenyl, and 5-6 membered heteroaryl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyl, 3-6 membered ring heterocycloalkoxyl, C 3~8 The cycloalkenyloxyl, phenyl, or 5-6 membered heteroaryl ring is optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0173] The term "heteroaryl" refers to a heteroaromatic system having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, and 5 to 14 ring atoms. Heteroaryls are preferably 5-membered or 6-membered rings. For example, non-limiting examples include:

[0174] [ka]

[0175] Includes, etc.

[0176] Heteroaryls may be optionally substituted or unsubstituted. If substituted, the substituents are preferably halogen, deuterium, hydroxyl, oxo, nitro, cyano, or C. 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 One or more groups independently selected from the group consisting of cycloalkoxyl, 3-6 membered heterocycloalkoxyl, phenyl, and 5-6 membered heteroaryl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyl, 3-6 membered ring heterocycloalkoxyl, C 3~8 The cycloalkenyloxyl, phenyl, or 5-6 membered heteroaryl ring is optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0177] The term "alkoxyl" refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples of alkoxyls include methoxyl, ethoxyl, propoxyl, and butoxyl. Alkoxyls may optionally be substituted or unsubstituted. If substituted, the substituents are preferably halogen, deuterium, hydroxyl, oxo, nitro, cyano, or C. 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 One or more groups independently selected from the group consisting of cycloalkoxyl, 3-6 membered heterocycloalkoxyl, phenyl, and 5-6 membered heteroaryl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 3~6 Cycloalkoxyl, 3-6 membered ring heterocycloalkoxyl, C 3~8 The cycloalkenyloxyl, phenyl, or 5-6 membered heteroaryl ring is optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

[0178] The term "cycloalkoxyl" refers to -O-(cycloalkyl), and cycloalkyl is as defined above, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.

[0179] The term "heterocyclic ring" means that the atoms forming the ring include other atoms in addition to carbon atoms, and the term includes heterocyclyl and heteroaryl rings.

[0180] The term "hydroxyl" refers to the -OH group.

[0181] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0182] The term "cyano" refers to the -CN group.

[0183] The term "amino" refers to the -NH2 group.

[0184] The term "nitro" refers to the -NO2 group.

[0185] The term "oxo" refers to a substituent, or oxygen group.

[0186] "Substitutable" means that one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, are independently substituted by a corresponding number of substituents. Needless to say, the substituents are only in their possible chemical positions. Those skilled in the art can determine (experimentally or theoretically) whether substitutions are possible or impossible without excessive effort. [Brief explanation of the drawing]

[0187] [Figure 1] This is a comparison of the clinical scores of each group of compounds in relation to a disease model. [Figure 2] This is a comparison of the clinical scores of each compound in an erythematous disease model. [Figure 3] This is a comparison of the clinical scores of each compound in a psoriasis disease model. [Figure 4] This study compares the inhibitory effects of each compound on the increase in skin thickness. [Figure 5] This is a comparison of the effects of each group of compounds on the ratio of spleen mass to body weight. [Modes for carrying out the invention]

[0188] Examples are incorporated below for further explanation of the present disclosure, but these examples do not limit the scope of the present disclosure.

[0189] The experimental methods using unspecified conditions in the examples of this disclosure generally follow conventional conditions or conditions recommended by the raw material or product manufacturer. Reagents without a specific source are conventional reagents purchased on the market.

[0190] The structure of the compound is identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift is 10 -6 The concentration is expressed in ppm. NMR is determined using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer. The solvents used for determination are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (methanol-d4), with tetramethylsilane (TMS) as the internal standard.

[0191] HPLC results are obtained using an Agilent 1100 high-pressure liquid chromatograph equipped with a GAS15B DAD UV detector and a Waters Xbridge C18 150×4.6 mm, 5 μm column.

[0192] MS is determined using an Agilent 6120 triple quadrupole mass spectrometer equipped with a G1315D DAD detector and a Waters Xbridge C18 4.6×50mm, 5μm column, scanning in positive / negative ion mode within a mass scan range of 80 to 1200.

[0193] Preparative HPLC conditions: Waters HPLC; Column: Sunfire (Prep C18 OBD 19×250mm, 10μm); Chiral column splitting conditions: Column: Chiralpak IG 5 μm, 30 × 250 mm; Mobile phase: Hex:EtOH = 35:65, 15 mL / min; Temp: 30 °C; Wavelength: 254 nm.

[0194] Yantai Huanghai's HSGF254 silica gel plates are used as gel plates for thin-layer chromatography. The specifications are 0.2 mm ± 0.03 mm for thin-layer chromatography (TLC) and 0.4 mm to 0.5 mm for the separation and purification of products by thin-layer chromatography.

[0195] The Combiflash Rf150 (TELEDYNE ISCO) or Isolera one (Biotage) are used as rapid column purification systems.

[0196] In normal-phase column chromatography, 200-300 mesh silica gel from Yantai Huanghai or 300-400 mesh silica gel are commonly used as supports, or pre-packed ultra-high purity normal-phase silica gel columns from Changzhou Santai (40-63 μm, 60 g, 24 g, 40 g, 120 g, or other specifications) are used.

[0197] The known starting materials of this disclosure can be synthesized by or in accordance with methods known in the industry, or can be purchased from Shanghai Titan, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Bide Pharm, and other companies.

[0198] Unless otherwise specified in the examples, all reactions may be carried out under a nitrogen atmosphere.

[0199] A nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of approximately 1 liter.

[0200] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of approximately 1 liter.

[0201] Hydrogen is produced by a QPH-1L hydrogen generator from Shanghai Quan Pu Scientific Instruments.

[0202] A nitrogen or hydrogen atmosphere is generally created by three repetitions of vacuuming and filling with nitrogen or hydrogen.

[0203] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0204] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is between 20°C and 30°C.

[0205] Thin-layer chromatography (TLC) is used to monitor the reaction process in the examples. The volume ratios of the developing agent used in the reaction, the eluent system for column chromatography and the developing agent system for thin-layer chromatography used for compound purification, and the solvent are adjusted according to the polarity of the compound. Small amounts of basic or acidic reagents, such as triethylamine and acetic acid, may also be added for adjustment. [Examples]

[0206] [ka]

[0207] Step 1) Compound 1a (2.0 g, 14.6 mmol) and triethylamine (1.8 g, 17.8 mmol) were dissolved in N,N-dimethylformamide (30 mL), and the solution was cooled to 0°C. Tert-butyldiphenylchlorosilane (4.0 g, 14.6 mmol) was added dropwise to the reaction system under a nitrogen atmosphere. The reaction system was warmed to room temperature and continuously stirred until the reaction was complete as detected by TLC. The reaction solution was poured into water and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with water (50 mL x 2), dehydrated with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (ethyl acetate / petroleum ether) to obtain compound 1b (5.1 g), which was used directly in the next reaction.

[0208] Step 2) A mixture of compound 1b (5.1 g, 13.6 mmol), bis(pinacolato)diborone (4.2 g, 16.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (512 mg, 0.7 mmol), and potassium acetate (2.0 g, 20.4 mmol) in dioxane (100 mL) was heated to 80°C and stirred overnight under a nitrogen atmosphere. The reaction solution was poured into water and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with water (30 mL x 2), dehydrated with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain compound 1c (2.0 g). LCMS: m / z 423.2 (M+H) + .

[0209] Step 3) Trimethylsulfur iodide (20.93 g, 95.10 mmol) and anhydrous tetrahydrofuran (100 mL) were added successively to a 250 mL three-necked flask, and the mixture was stirred until dissolved. The solution was cooled to -10°C, and a solution of n-butyllithium in tetrahydrofuran (35.19 mL, 2.5 M, 87.97 mmol) was slowly added. The mixture was stirred at -10°C for 1 hour. Then, a solution of 6-oxabicyclo[3.1.0]hexane (2.00 g, 23.78 mmol) in tetrahydrofuran was slowly added dropwise. After the addition, the reaction solution was warmed to room temperature and continuously stirred until the reaction was complete, as detected by TLC. The reaction solution was slowly poured into water to quench the reaction, and extracted with ethyl acetate (100 mL x 3). The organic phase was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 1d (400 mg concentrate), which was used directly in the next step.

[0210] Step 4) Compound 5 (100.00 mg, 1.02 mmol), 5-bromo-2-methoxyphenol (206.87 mg, 1.02 mmol), and triphenylphosphine (801.12 mg, 3.06 mmol) were successively added to anhydrous tetrahydrofuran (10 mL) in a 25 mL neck flask. The reaction solution was thoroughly stirred, purged three times with nitrogen, and cooled to 0°C. Diisopropyl azodicarboxylic acid (618.02 mg, 3.06 mmol) was slowly added dropwise. After the addition, the reaction solution was warmed to room temperature and stirred until the reaction was complete as detected by TLC. 50 mL of water was added to the reaction solution to quench the reaction. The reaction solution was extracted with ethyl acetate (100 mL x 3), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1e (60 mg). 1 H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 8.6, 2.3 Hz, 1H), 6.92 (dd, J = 8.6, 4.2 Hz, 1H), 5.05 (d, J = 1.5 Hz, 2H), 5.01 (t, J = 4.3 Hz, 1H), 3.74 (s, 3H), 2.47-2.36 (m, 1H), 2.35-2.21 (m, 1H), 2.05-1.90 (m, 1H), 1.86-1.59 (m, 3H).

[0211] Step 5) Compound 1e (60.00 mg, 1.02 mmol) was added to a 25 mL neck flask, heated to 180°C, and stirred until the reaction was complete as detected by TLC. 10 mL of water was added to the reaction solution to quench the reaction. The reaction solution was extracted with ethyl acetate (20 mL x 3), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1f (45 mg). 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 5.19 (s, 1H), 3.87 (s, 3H), 3.55 (s, 2H), 2.33-2.28 (m, 4H), 1.9-1.79 (m, 2H).

[0212] Step 6) Compound 1f (45.00 mg, 0.16 mmol) and Amberlyst® 15 ion exchange resin (41.80 mg, 0.64 mmol) were added to toluene (5 mL) in a 25 mL neck flask at room temperature. The reaction system was thoroughly stirred, purged three times with nitrogen, heated to 90°C, and stirred until the reaction was complete as detected by TLC. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain 1 g (30 mg) of compound. 1 H NMR (400 MHz, DMSO-d6) δ 6.93 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 3.74 (s, 3H), 3.16 (s, 2H), 2.04-1.90 (m, 2H), 1.86-1.66 (m, 6H).

[0213] Step 7) 1 g (100.00 mg, 0.35 mmol) of compound, compound bis(pinacolato)diborone (179.36 mg, 0.71 mmol), potassium acetate (104.00 mg, 1.06 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (25.80 mg, 0.035 mmol) were successively added to 50 mL of 1,4-dioxane in a 25 mL neck flask at room temperature. The reaction system was purged three times with nitrogen, heated to 90°C, stirred until the reaction was complete as detected by TLC, and then filtered. 30 mL of water was added, and the reaction solution was extracted with ethyl acetate (50 mL x 3), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain 1 h (45 mg) of compound. 1 H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 2.9 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 3.86 (s, 3H), 3.34 (s, 2H), 2.17-2.10 (m, 2H), 1.97-1.85 (m, 2H), 1.80-1.66 (m, 4H), 1.30 (s, 12H).

[0214] Step 8) Compound 1h (45.00 mg, 0.14 mmol), compound 3-bromo-5-iodopyridine (38.69 mg, 0.14 mmol), potassium acetate (153.50 mg, 0.27 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (41.00 mg, 0.014 mmol) were successively added at room temperature to 1,4-dioxane and water (3:1, 8 mL) in a 25 mL neck flask. The reaction system was purged three times with nitrogen, heated to 90°C, stirred until the reaction was complete as detected by TLC, and then filtered. Water (20 mL) was added, the reaction solution was extracted with ethyl acetate (20 mL x 3), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 1i (30 mg). LCMS: m / z 360.0 (M+H) + .

[0215] Step 9) Compound 1i (100 mg, 0.28 mmol), Compound 1c (176.02 mg, 0.42 mmol), potassium carbonate (76.75 mg, 0.56 mmol), potassium acetate (40.87 mg, 0.42 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20.05 mg, 0.023 mmol) were successively added to 1,4-dioxane and water (3:1, 8 mL) in a 25 mL neck flask at room temperature. The reaction system was purged three times with nitrogen, heated to 90°C, and stirred until the reaction was complete as detected by LC-MS. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain Compound 1k (60 mg). LCMS: m / z 576.2 (M+H) + .

[0216] Step 10) 1k of compound (60 mg, 0.10 mmol), followed by a solution of hydrochloric acid (1:1, 4 mL) in tetrahydrofuran, was added to a 25 mL neck flask at room temperature and stirred at 25°C. TLC detection indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate / petroleum ether) to obtain 1 liter (40 mg) of compound. LCMS: m / z 338.0 (M+H) + .

[0217] Step 11) 1 liter of compound (40 mg, 0.12 mmol), followed by tetrahydrofuran (5 mL), was added to a 25 mL three-necked flask at room temperature and cooled to 0°C. A solution of borane in tetrahydrofuran (0.47 mL, 1 M, 0.48 mmol) was added dropwise. After the addition, the reaction solution was allowed to warm naturally to room temperature and stirred overnight. Water (0.5 mL) was added and the mixture was stirred continuously for 0.5 hours. LC-MS detection indicated that the reaction was complete. The reaction solution was purified by preparative liquid chromatography to obtain compound 1 (1.31 mg). LCMS: m / z 366.1 (M+H) + . 1 H NMR (400 MHz, MeOD) δ 8.40 (d, J = 26.6 Hz, 2H), 7.79 (s, 1H), 6.91 (q, J = 8.4 Hz, 2H), 4.58 (s, 3H), 4.17-3.95 (m, 1H), 3.89-3.85 (m, 3H), 3.83-3.78 (m, 1H), 2.16-2.01 (m, 2H), 1.93-1.88 (m, 2H), 1.84-1.68 (m, 5H), 1.37-1.22 (m, 1H), 1.19-1.09 (m, 1H).

[0218] Product に, キラル division (カラム: Chiralpak IG 5μm, 30×250mm; mobile phase: Hex:EtOH=35:65, 15mL / min; Temp: 30℃; wavelength: 254nm), compound 1-1 (short holding time) and compound 1-2 (long holding time). Compound 1-1 LCMS: m / z 366.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 1.9 Hz, 1H), 7.77 (s, 1H), 6.96-6.89 (m, 2H), 4.27 (t, J = 8.2 Hz, 1H), 3.83 (t, J = 8.9 Hz, 1H), 3.79 (s, 3H), 3.55-3.43 (m, 1H), 3.30 (s, 2H), 2.03-1.89 (m, 2H), 1.76-1.69 (m, 6H), 1.31 (dd, J = 16.2, 8.2 Hz, 1H), 1.11 (dd, J = 16.2, 10.2 Hz, 1H). Compounds 1-2 LCMS: m / z 366.1 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.41 (d, J = 1.7 Hz, 1H), 7.75 (s, 1H), 6.97-6.81 (m, 2H), 4.25 (t, J = 8.2 Hz, 1H), 3.81 (t, J = 8.9 Hz, 1H), 3.77 (s, 3H), 3.55-3.40 (m, 1H), 3.29-3.23 (m, 2H), 1.95-1.91 (m, 2H), 1.74-1.67 (m, 6H), 1.29 (dd, J = 16.1, 8.1 Hz, 1H), 1.09 (dd, J = 16.2, 10.2 Hz, 1H).

Example

[0219]

change

[0220] Compound 2 was synthesized according to the method of Example 1. LCMS: m / z 326.1 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 8.77 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 7.06-7.01 (m, 2H), 5.02 (d, J = 6.4 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 2H), 3.47 (d, J = 8.5 Hz, 1H), 3.32 (s, 1H), 3.01 (dd, J = 15.4, 8.2 Hz, 1H), 1.48 (d, J = 6.2 Hz, 3H), 1.36 (m, 2H).

Example

[0221]

change

[0222] Compound 3 was synthesized according to the method of Example 1. LCMS: m / z 365.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.37-7.26 (m, 3H), 7.21 (d, J = 7.4 Hz, 1H), 6.87 (dd, J = 19.4, 8.4 Hz, 2H), 4.28-4.20 (m, 1H), 3.82-3.74 (m, 4H), 3.51 -3.40 (m, 1H), 3.28 (s, 2H), 2.03-1.89 (m, 2H), 1.84-1.63 (m, 6H), 1.28 (dd, J = 16.2, 8.1 Hz, 1H), 1.05 (dd, J = 16.2, 9.8 Hz, 1H). [Examples]

[0223] [ka]

[0224] Compound 4 was synthesized according to the method of Example 1. LCMS: m / z 367 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 4.31 (t, J = 10.8 Hz, 1H), 4.03-3.94 (m, 1H), 3.82 (s, 3H), 3.77-3.65 (m, 1H), 3.53 (d, J = 6.4 Hz, 2H), 1.97 (s, 2H), 1.78-1.75 (m, 6H), 1.32-1.30 (m, 1H), 1.22-1.12 (m, 1H). [Examples]

[0225] [ka]

[0226] Compound 5 was synthesized according to the method of Example 1. LCMS: m / z 367.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.33-4.27 (m, 1H), 3.89 (t, J = 8.9 Hz, 1H), 3.83 (s, 3H), 3.57-3.46 (m, 3H), 2.01-1.94 (m, 2H), 1.84-1.68 (m, 6H), 1.34 (dd, J = 16.3, 8.3 Hz, 1H), 1.16 (dd, J = 16.4, 10.4 Hz, 1H). [Examples]

[0227] [ka]

[0228] Compound 6 was synthesized according to the method of Example 1. LCMS: m / z 340.1 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.77 (t, J = 2.0 Hz, 1H), 6.98-6.90 (m, 2H), 4.37-4.21 (m, 1H), 3.86-3.82 (m, 1H), 3.80 (s, 3H), 3.57-3.42 (m, 1H), 3.15 (s, 2H), 1.42 (s, 6H), 1.34-1.28 (m, 1H), 1.14-1.08 (m, 1H). [Examples]

[0229] [ka]

[0230] Step 1) Compound 1a (15.00 g, 109.51 mmol) and imidazole (6.71 g, 98.555 mmol) were dissolved in N,N-dimethyl sulfoxide (100 mL). Tert-butyldimethylchlorosilane (14.03 g, 93.08 mmol) was added at 30°C for a reaction at room temperature for 3 hours. TLC detection indicated that the reaction was complete. The reaction solution was added to water (100 mL) to quench the reaction, then extracted with methyl tert-butyl ether (100 mL x 3), and dehydrated with anhydrous sodium sulfate to obtain compound 7a (25.00 g). 1 H NMR (400 MHz, CDCl3) δ 5.98 (dd, J = 3.5, 1.7 Hz, 1H), 5.55 (dd, J = 3.1, 1.5 Hz, 1H), 4.23 (t, J = 1.7 Hz, 2H), 0.95 (s, 9H), 0.12 (s, 6H).

[0231] Step 2) Compound 7a (25.00 g, 99.51 mmol), bis(pinacolato)diborone (27.80 g, 109.46 mmol), potassium acetate (19.53 g, 199.01 mmol), and bis(triphenylphosphinopalladium dichloride (1.55 g, 1.99 mmol)) were dissolved in 1,4-dioxane (90 mL) at room temperature. The reaction system was purged three times with nitrogen and then stirred at 80°C for 16 hours. LC-MS detection indicated that the reaction was complete. Water (200 mL) and ethyl acetate (100 mL x 3) were added to the reaction solution for extraction. The organic phase was dehydrated with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain product 7b (11.00 g). 1 H NMR (400 MHz, DMSO-d6) δ 5.85-5.80 (m, 1H), 5.73-5.71 (m, 1H), 4.17 (t, J = 1.9 Hz, 2H), 1.20 (s, 12H), 0.87 (s, 9H), 0.03 (s, 6H).

[0232] Step 3) Compound 7c (10.0 g, 35.04 mmol) was dissolved in 1,4-dioxane (14 mL) and cooled to 0°C. Perchloric acid (5.14 mL, 59.57 mmol, 70 wt.%) was added dropwise and the mixture was stirred at 0°C for 0.5 hours. Ice water (140 mL) was added to precipitate the white solid, which was then filtered. The white solid was dissolved in dichloromethane (200 mL) and the aqueous phase was separated. The organic phase was dehydrated with anhydrous sodium sulfate and filtered. The filtrate was added dropwise at 0°C to a solution of compound 2-methoxypyridine (5.93 g, 54.32 mmol) in dichloromethane (100 mL). After addition, the reaction was carried out at room temperature for 1 hour. TLC detection indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure. The residue was added to anhydrous ether, a white solid precipitated, and filtered to obtain the target compound 7d (9.5 g). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (dd, J = 6.5, 1.5 Hz, 1H), 8.28-8.24 (m, 1H), 7.72 (dd, J = 6.6, 3.1 Hz, 1H), 7.53-7.45 (m, 1H), 6.74 (s, 2H), 4.26 (s, 3H), 2.50 (dd, J = 4.0, 2.1 Hz, 6H), 2.17 (s, 3H).

[0233] Step 4) Compound 7d (9.0 g, 27.74 mmol) and ethyl 4,4,4-trifluoro-2-butinoate (4.61 g, 27.74 mmol) were dissolved in N,N-dimethylformamide (20 mL). Potassium carbonate (7.7 g, 55.48 mmol) was added, and the mixture was stirred at room temperature for 16 hours. LC-MS detection indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 7e (3.05 g). LCMS: m / z 289.0 (M+H) + .

[0234] Step 5) Compound 7e (2.9 g, 10.06 mmol) was dissolved in acetonitrile (20 mL) at room temperature. N-bromosuccinimide (2.7 g, 15.09 mmol) was added. The reaction solution was purged three times with nitrogen and heated at 70°C for 5 hours for the reaction. LC-MS detection indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 7f (1.5 g). LCMS: m / z 366.9 (M+1) + .

[0235] Step 6) Compound 7f (1.5 g, 4.09 mmol) was dissolved in methanol (10 mL). A solution of potassium hydroxide (917 mg, 16.34 mmol) in water (5 mL) was added dropwise at room temperature for 16 hours for the reaction. LC-MS detection indicated that the reaction was complete. 1N hydrochloric acid was added to adjust the pH to approximately 7. The reaction solution was concentrated under reduced pressure to remove methanol, and then 1N hydrochloric acid was added to adjust the pH to approximately 2. The solution was extracted with ethyl acetate (50 mL x 3) and washed with water (25 mL x 3) and saturated sodium chloride aqueous solution. The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7 g (1.3 g). LCMS: m / z 339.9 (M+H) + .

[0236] Step 7) 7 g (1.3 g, 3.83 mmol) of compound was dissolved in ethanol (20 mL). Concentrated sulfuric acid (1 mL) was added. The reaction solution was heated at 90°C for 16 hours for the reaction to proceed. LC-MS detection indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure. A saturated solution of sodium bicarbonate was added to adjust the pH to approximately 9. The reaction solution was extracted with ethyl acetate (50 mL x 3) and washed with water (25 mL x 3) and saturated sodium chloride aqueous solution (25 mL x 3). The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7h (749 mg). LCMS: m / z 356.2 (M+H) + .

[0237] Step 8) Compound 7h (300 mg, 1.02 mmol), bis(pinacolato)diborone (387 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (75 mg, 0.102 mmol), and potassium acetate (19.53 g, 199.01 mmol) were mixed in 1,4-dioxane (5 mL). The reaction solution was purged three times with nitrogen and heated at 100°C for 16 hours for the reaction. LC-MS detection indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 7i (300 mg). LCMS: m / z 343.1 (M+H) + .

[0238] Step 9) Compound 7i (0.9 g, 2.63 mmol), 3,5-dibromopyridine (0.612 mL, 5.26 mmol), potassium carbonate (0.55 g, 3.95 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.10 g, 0.13 mmol) were mixed in 1,4-dioxane / water (10 mL / 0.2 mL). The reaction solution was purged three times with nitrogen and stirred at 90°C for 16 hours. LC-MS detection indicated that the reaction was complete. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 7j (850 mg). LCMS: m / z 374 (M+H) + .

[0239] Step 10) Compound 7j (800 mg, 2.15 mmol), compound 6b (833.67 mg, 2.79 mmol), potassium acetate (316.46 mg, 3.23 mmol), potassium carbonate (594.23 mg, 4.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (78.65 mg, 0.11 mmol) were mixed in 1,4-dioxane / water (10 mL / 0.02 mL) at room temperature. The reaction solution was purged three times with nitrogen and stirred at 90°C for 16 hours. LC-MS detection indicated that the reaction was complete. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain compound 7k (430 mg). LCMS: m / z 464 (M+H) + .

[0240] Step 11) 1,2-Bis(diphenylphosphin)ethane (32.67 mg, 0.082 mmol) and (1,5-cyclooctadinyl)methoxyiridium(I) dimer (27.17 mg, 0.041 mmol) were added to 1,2-dichloroethane (3 mL) in a thoroughly dried 100 mL three-necked flask equipped with a thermometer, under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 15 minutes. Compound 7k (190 mg, 0.410 mmol) was added and the mixture was stirred at room temperature for 15 minutes. The mixed solution was stirred and heated in an oil bath to 95°C. When the thermometer reading reached 70°C, pinacolborane (0.416 mL, 2.87 mmol) was added dropwise. The reaction solution was stirred for 0.5 hours. LC-MS detection indicated that the reaction was complete. The reaction solution was allowed to cool to room temperature, and the reaction was quenched by adding 5 mL of methanol. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 7 L (120 mg) of the compound. LCMS: m / z 592 (M+H) + .

[0241] Step 12) 7 L (100 mg, 0.17 mmol) of compound was dissolved in tetrahydrofuran (1 mL) at room temperature. 1 mL of 1 N hydrochloric acid was slowly added dropwise at room temperature for 0.5 hours under stirring to initiate the reaction. LC-MS detection indicated that the reaction was complete. The reaction solution was concentrated and diluted with ethyl acetate (5 mL). Saturated potassium phosphate aqueous solution was added to adjust the pH to approximately 8. The reaction solution was extracted with ethyl acetate (10 mL x 3). The organic phase was dehydrated with anhydrous sodium sulfate, concentrated, and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain compound 7 (5.54 mg). LCMS: m / z 378 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.57 (m, 1H), 7.99 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.34-4.28 (t, J = 8.6 Hz, 1H), 4.20 (s, 3H), 3.89 (t, J = 8.8 Hz, 1H), 3.62-3.51 (m, 1H), 1.34 (m, 1H), 1.19-1.12 (m, 1H). [Examples]

[0242] [ka]

[0243] Step 1) Compound 8a (25.00 g, 178.39 mmol) and N-bromosuccinimide (31.75 g, 178.39 mmol) were added to acetonitrile (200 mL) in a 500 mL neck flask at room temperature and stirred until dissolved. The reaction system was purged three times with nitrogen and stirred at room temperature for 16 hours. TLC detection indicated that the reaction was complete. The reaction solution was concentrated, diluted with ethyl acetate (100 mL), and poured into aqueous sodium bisulfite solution (500 mL). The pH was adjusted to approximately 3. The reaction solution was extracted with ethyl acetate (200 mL). The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 8b (24.00 g). 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.94 (s, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.45 (d, J = 8.9 Hz, 1H), 3.76 (s, 3H).

[0244] Step 2) Compound 8b (100.00 mg, 0.46 mmol), 3-bromo-2-methylpropene (61.64 mg, 0.46 mmol), and potassium carbonate (94.65 mg, 0.69 mmol) were added to 10 mL of N,N-dimethylformamide in a 100 mL neck flask at room temperature. The reaction system was purged three times with nitrogen and stirred at room temperature for 16 hours. TLC detection indicated that the reaction was complete. The reaction solution was filtered and concentrated under reduced pressure. Saturated sodium chloride aqueous solution (100 mL) was added. The reaction solution was extracted with ethyl acetate (100 mL). The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 8c (25.00 mg). 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 5.07 (s, 1H), 4.91 (s, 1H), 4.36 (s, 2H), 3.76 (s, 3H), 1.82 (s, 3H).

[0245] Step 3) Compound 8c (50.00 mg, 0.18 mmol) and iodine (9.29 mg, 0.037 mmol) were added to dichloromethane (2 mL) in a 100 mL neck flask at room temperature and stirred until dissolved. The reaction system was purged three times with nitrogen and stirred at room temperature for 16 hours. TLC detection indicated that the reaction was complete. The reaction solution was added to a saturated sodium thiosulfate solution (25 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dehydrated with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 8d (20.0 mg). 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 4.80 (s, 2H), 4.53 (s, 3H), 2.08 (s, 6H).

[0246] Step 4) Compound 8d (400.00 mg, 1.46 mmol), biboric acid (557.84 mg, 2.2 mmol), potassium acetate (431.18 mg, 4.39 mmol), and 1,1-bis(diphenyl)ferrocene palladium dichloride (53.60 mg, 0.073 mmol) were added to 1,4-dioxane (10 mL) in a 50 mL neck flask at room temperature and stirred until dissolved. The reaction system was purged three times with nitrogen and stirred at 110 °C for 16 hours. LC-MS detection indicated that the reaction was complete. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dehydrated with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 8e (0.26 g). LCMS: m / z 321.1 (M+H) + .

[0247] Step 5) Compound 8e (240.00 mg, 0.750 mmol), 3,5-dibromopyridine (355.12 mg, 1.5 mmol), potassium carbonate (207.18 mg, 1.5 mmol), and 1,1-bis(diphenyl)ferrocene palladium dichloride (54.87 mg, 0.075 mmol) were added at room temperature to a mixed solvent of 1,4-dioxane (6 mL) and water (2 mL) in a 25 mL neck flask, and stirred until dissolved. The reaction system was purged three times with nitrogen and stirred at 90°C for 16 hours. LC-MS detection indicated that the reaction was complete. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried and then concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain compound 8f (150.00 mg). LCMS: m / z 351.9 (M+H+2) + .

[0248] Step 6) Compound 8f (130.00 mg, 0.37 mmol), Compound 7b (143.95 mg, 0.48 mmol), potassium carbonate (102.60 mg, 0.74 mmol), potassium acetate (54.65 mg, 0.56 mmol), and 1,1-bis(diphenyl)ferrocene palladium dichloride (13.59 mg, 0.019 mmol) were added at room temperature to a 100 mL single-neck flask containing a mixed solvent of 1,4-dioxane (6 mL) and water (0.12 mL), and stirred until dissolved. The reaction system was purged three times with nitrogen and stirred at 110 °C for 16 hours. LC-MS detection indicated that the reaction was complete. The reaction solution was added to 100 mL of water and extracted with ethyl acetate (200 mL x 3). The organic phase was dried and then concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain 8 g (150.00 mg) of the compound. LCMS: m / z 442.1 (M+H) + .

[0249] Step 7) 1,2-Bis(diphenylphosphin)ethane (23.46 mg, 0.059 mmol) and (1,5-cyclooctadinyl)methoxyiridium(I) dimer (19.51 mg, 0.029 mmol) were added to a 50 mL three-necked flask at room temperature. Then, anhydrous 1,2-dichloroethane (15 mL) was added. 8 g of the compound (130.00 mg, 0.294 mmol, dissolved in 5 mL of 1,2-dichloroethane) was slowly added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was then warmed to 70°C, and pinacolborane (263.70 mg, 2.061 mmol) was added dropwise. After the addition, the reaction solution was stirred at 70°C for 1 hour. LC-MS detection indicated that the reaction was complete. The reaction solution was cooled to 0°C. The reaction was quenched by adding 20 mL of methanol dropwise. The reaction solution was then concentrated and subjected to column chromatography (ethyl acetate / petroleum ether) to obtain compound 8H (120.00 mg). LCMS: m / z 570.1 (M+H) + .

[0250] Step 8) The reaction product 8h (100.00 mg, 0.17 mmol) and the solvent tetrahydrofuran (2 mL) were added to a 25 mL round-bottom flask at room temperature and cooled to 0°C. 1N hydrochloric acid (2 mL) was added dropwise. After the addition, the reaction solution was stirred at room temperature for 1 hour. LC-MS detection indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure and extracted with ethyl acetate (100 mL x 3). A saturated aqueous solution of potassium phosphate was added to the aqueous phase to adjust the pH to 8.0. The reaction solution was extracted with ethyl acetate (100 mL x 3). The organic phase was pooled and washed with water (100 mL x 3) and saturated physiological saline (100 mL x 3). The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative liquid chromatography (Pre-HPLC) to obtain compound 8 (5.46 mg). LCMS: m / z 356.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.53 (s, 1H), 8.39 (s, 1H), 7.75 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 4.27 (t, J = 8.1 Hz, 1H), 3.92 (s, 2H), 3.82 (t, J = 8.9 Hz, 1H), 3.78 (s, 3H), 3.51-3.46 (m, 1H), 1.34-1.28 (m, 7H), 1.14-1.07(m, 1H). [Examples]

[0251] [ka]

[0252] Compound 9 was synthesized according to the method of Example 8. LCMS: m / z 354.2 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 7.69 (s, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 4.27 (t, J = 8.2 Hz, 1H), 3.82 (t, J = 8.9 Hz, 1H), 3.75 (s, 3H), 3.55-3.42 (m, 1H), 2.54-2.50 (m, 2H), 1.66 (t, J = 6.5 Hz, 2H), 1.38-1.23 (m, 7H), 1.17–0.97 (m, 1H).

Example

[0253]

change

[0254] Compound 10 was synthesized according to the method of Example 8. LCMS: m / z 389.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.61 (d, J = 1.5 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.87-7.84 (m, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 4.31 (t, J = 8.3 Hz, 1H), 4.08 (s, 3H), 3.88 (t, J = 8.9 Hz, 1H), 3.58-3.55 (m, 1H), 1.34 (dd, J = 16.2, 8.1 Hz, 1H), 1.15 (dd, J = 16.2, 10.4 Hz, 1H).

Example

[0255] [ka]

[0256] Compound 11 was synthesized according to the method of Example 9, and chiral resolution was performed to obtain compound 11-1 (short retention time) and compound 11-2 (long retention time). Compound 11-1 LCMS: m / z 357.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.34-4.26 (m, 1H), 4.07-3.97 (m, 3H), 3.80 (s, 3H), 3.73-3.62 (m, 1H), 1.36-1.27 (m, 7H), 1.25-1.14 (m, 1H). Compound 11-2 LCMS: m / z 357.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.39-4.23 (m, 1H), 4.06-3.93 (m, 3H), 3.80 (s, 3H), 3.73-3.62 (m, 1H), 1.33-1.23 (m, 7H), 1.21-1.15 (m, 1H). [Examples]

[0257] [ka]

[0258] Step 1) Compound 12a (100 g, 492 mmol), DMF (1000 mL), potassium iodide (92.6 g, 837 mmol), cuprous iodide (3.13 g, 9.85 mmol), and potassium carbonate (136 g, 985 mmol) were successively added to a 2000 mL necked flask at room temperature. Compound 3-chloro-3-methyl-1-butyne (100 mL, 886 mmol) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at 70°C for 16 hours. The reaction solution was cooled to room temperature, added to water (1000 mL), and then extracted with petroleum ether (1000 mL x 3). The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 12b (50 g). 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 2.4 Hz, 1H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 3.79 (s, 3H), 2.58 (s, 1H), 1.65 (s, 6H).

[0259] Step 2) Compound 12b (20.0 g, 74.4 mmol), n-hexane (200 mL), and calcium palladium carbonate (1.95 g, 18.8 mmol) were successively added to a 500 mL necked flask at room temperature. The reaction solution was stirred under a hydrogen atmosphere at room temperature for 16 hours, filtered, and concentrated under reduced pressure to obtain compound 12c (19 g). 1 H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.8, 2.4 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.12 (dd, J = 17.6, 10.8 Hz, 1H), 5.14 (dd, J = 20.0, 9.2 Hz, 2H), 3.79 (s, 3H), 1.46 (s, 6H).

[0260] Step 3) Compound 12c (10.0 g, 36.9 mmol) and diethylaniline (10 mL, 62.5 mmol) were added successively to a 50 mL neck flask at room temperature. The reaction solution was stirred at 210 °C for 1 hour and then cooled to room temperature. 1 M HCl was added to adjust the pH to neutral. The reaction solution was extracted with ethyl acetate (200 mL x 3), washed with water (200 mL x 3), and concentrated under reduced pressure to obtain compound 12d (9.1 g). 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 5.14-5.01 (m, 1H), 3.78 (s, 3H), 3.40 (d, J = 6.8 Hz, 2H), 1.74 (s, 3H), 1.63 (s, 3H).

[0261] Step 4) Compound 12d (5.00 g, 18.5 mmol), toluene (25 mL), and Amberlyst® 15 (5.00 g, 15.9 mmol) were successively added to a 100 mL necked flask at room temperature. The reaction solution was stirred at 100 °C for 2 hours under a nitrogen atmosphere, and then cooled to room temperature. The reaction mixture was filtered and concentrated under reduced pressure to obtain compound 12e (3.89 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.04 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 3.71 (s, 3H), 2.63 (t, J = 6.8 Hz, 2H), 1.78 (t, J = 6.8 Hz, 2H), 1.26 (s, 6H).

[0262] Step 5) Compound 12e (28.4 g, 105 mmol), dioxane (300 mL), bis(pinacolato)diborone (31.9 g, 126 mmol), potassium acetate (20.6 g, 209 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.66 g, 10.5 mmol) were successively added to a 500 mL neck flask at room temperature. The reaction solution was stirred at 105 °C for 16 hours under a nitrogen atmosphere, and then cooled to room temperature. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 12f (28.4 g). LCMS: m / z 319 (M+H) + .

[0263] Step 6) Compound 12f (6.20 g, 19.5 mmol), 1,4-dioxane (80 mL), water (16 mL), 2,6-dichloropyrazine (2.90 g, 39.0 mmol), potassium carbonate (5.39 g, 39.0 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.43 g, 1.95 mmol) were continuously added to a 250 mL neck flask at room temperature. The reaction solution was stirred at 110 °C for 16 hours under a nitrogen atmosphere, and then cooled to room temperature. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 12 g (5.7 g). LCMS: m / z 305 (M+H) + .

[0264] Step 7) 12 g (35.0 g, 115 mmol) of compound 1c (44.5 g, 149 mmol), potassium carbonate (23.8 g, 172 mmol), potassium acetate (16.9 g, 172 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (8.41 g, 11.5 mmol) were added at room temperature to a mixed solvent of 1,4-dioxane (250 mL) and water (5 mL) in a 500 mL neck flask, and stirred until dissolved. The reaction system was purged three times with nitrogen and stirred at 110 °C for 16 hours. The reaction solution was cooled to room temperature. Water (500 mL) was added, and the reaction solution was extracted with ethyl acetate (300 mL x 3), dehydrated with anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 12h (37 g). LCMS: m / z 441.1 (M+H) + .

[0265] Step 8) 1,2-Bis(diphenylphosphin)ethane (1.81 g, 4.54 mmol), (1,5-cyclooctadinyl)methoxyiridium(I) dimer (1.50 g, 2.27 mmol), and anhydrous 1,2-dichloroethane (100 mL) were added to a 250 mL three-necked flask at room temperature and stirred at room temperature for 10 minutes. Compound 12h (10.0 g, 22.7 mmol) was added. The reaction solution was warmed to 70°C and pinacolborane (20.3 g, 159 mmol) was added dropwise. The reaction was carried out at 95°C for 4 hours. The reaction solution was cooled to 0°C. Methanol (50 mL) was added dropwise to quench the reaction. The reaction solution was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 12i (1.4 g). LCMS: m / z 569.3 (M+H) + .

[0266] Step 9) Reactant 12i (9.00 g, 15.8 mmol) and tetrahydrofuran (30 mL) were added to a 50 mL neck flask at room temperature and cooled to 0°C. 2 M hydrochloric acid (50 mL) was added and the mixture was stirred at 50°C for 16 hours. The reaction solution was concentrated under reduced pressure and extracted with ethyl acetate (300 mL x 3). The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (acetonitrile / water / trifluoroacetic acid) to obtain compound 12 (3.82 g).

[0267] The product was subjected to chiral resolution (column: Chiralpak IG 5 μm, 30 × 250 mm; mobile phase: Hex:EtOH=35:65, 15 mL / min; Temp: 30 °C; wavelength: 254 nm) to obtain compound 12-1 (short retention time) and compound 12-2 (long retention time). Compound 12-1 LCMS: m / z 355.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.48 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.29 (dd, J = 8.8, 7.6 Hz, 1H), 3.96 (dd, J = 8.8, 6.8 Hz, 1H), 3.77 (s, 3H), 3.74-3.62 (m, 1H), 2.93-2.67 (m, 2H), 1.68 (t, J = 6.8 Hz, 2H), 1.38-1.24 (m, 7H), 1.21-1.08 (m, 1H). Compound 12-2 LCMS: m / z 355.0 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.48 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.29 (dd, J = 8.8, 7.6 Hz, 1H), 3.96 (dd, J = 8.8, 6.8 Hz, 1H), 3.77 (s, 3H), 3.74-3.60 (m, 1H), 2.89-2.67 (m, 2H), 1.68 (t, J = 6.8 Hz, 2H), 1.36-1.25 (m, 7H), 1.21-1.07 (m, 1H). [Examples]

[0268] [ka]

[0269] Compound 12h (400 mg, 0.91 mmol) was dissolved in anhydrous THF (4 mL) at room temperature. The reaction solution was cooled to -10°C under an N2 atmosphere. 1,5-Cyclooctadiene iridium chloride dimer (21 mg, 0.041 mmol, 4.5% mol) and (S)-1-(diphenylphosphino)-2-[(S)-4-isopropyloxazolin-2-yl]ferrocene (52 mg, 0.11 mmol, 12% mol) were added. The reaction solution was stirred at room temperature for 15 minutes. A solution of catecholborane in THF (1 M, 7.2 mL, 7.2 mmol) was added, and the reaction was continued at room temperature for 3 hours. Concentrated hydrochloric acid (0.2 mL) was added, and the reaction was continued for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (acetonitrile / water / trifluoroacetic acid) to obtain a compound (105 mg), which was identified by chiral HPLC to obtain a compound identical to compound 12-1 obtained by resection. LCMS: m / z 355.0 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.48 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.29 (dd, J = 8.8, 7.6 Hz, 1H), 3.96 (dd, J = 8.8, 6.8 Hz, 1H), 3.77 (s, 3H), 3.74-3.62 (m, 1H), 2.93-2.67 (m, 2H), 1.68 (t, J = 6.8 Hz, 2H), 1.38-1.24 (m, 7H), 1.21-1.08 (m, 1H).

[0270] Biological evaluation This disclosure is further described and explained below by reference to test examples, but these test examples are not intended to limit the scope of this disclosure.

[0271] The structure of compound A is,

[0272] [ka]

[0273] Compound A was prepared by the method disclosed in Example 4 on page 181 of the specification of patent application WO2020070651A.

[0274] Test Example 1: In vitro PDE4B enzyme activity detection test 1. Experimental materials

[0275] [Table 1]

[0276] 2. Experimental Steps First, a stock solution of the compound was prepared at a concentration of 10 mM in a test tube containing 90% DMSO (10% water). This was then used to prepare serial dilutions at a dilution ratio of 1:5, starting from 100 μM and going down to a final concentration of 0.05 nM.

[0277] 0.2 μl of the compound solution was transferred to a 384-well reaction plate, and 0.2 μl of 100% DMSO was added to both the negative and positive control wells. Next, 10 μl of 2× PDE4B1 enzyme solution (to a final concentration of 0.04 nM) was added to each well, and 10 μl of 1× reaction buffer was added to the control well with zero enzyme activity instead of the enzyme solution. The plate was centrifuged at 1,000 rpm for 1 min and incubated at room temperature for 15 min. Next, 10 μl of 2× FAM-cAMP substrate solution (to a final substrate concentration of 0.1 μM) was added to each well of the 384-well reaction plate. The plate was centrifuged at 1,000 rpm for 1 min, and the reaction was carried out at 25°C for 30 min. After the reaction was complete, 60 μl of reaction stop solution was added to each well of the 384-well reaction plate to terminate the reaction. The plate was then incubated in the dark at room temperature, shaking with a shaker at 600 rpm for 60 minutes.

[0278] After incubation, RLU data was read and the inhibition rate was calculated. 50 The values ​​are calculated from the fitted concentration-inhibition curve, with the maximum value representing the reading for the DMSO control and the minimum value representing the reading for the control with zero enzyme activity.

[0279] The in vitro inhibition of PDE4B1 enzyme activity by the embodiments of this disclosure was determined and measured by the above test and IC. 50 The values ​​are shown in Table 1 (Table 2).

[0280] [Table 2]

[0281] Test Example 2: Inhibitory effect of compounds on the release of pro-inflammatory cytokines from peripheral blood mononuclear cells (PBMCs). Frozen PBMCs were thawed, and cell viability and number were detected by trypan blue staining. The thawed PBMCs were washed with RPMI1640 complete medium (RPMI1640 + 10% FBS + 1% PS), centrifuged, and the supernatant was discarded. The PBMCs were resuspended in RPMI1640 complete medium, and the cell density was measured to 2 × 10⁶. 6 Prepared to cells / mL. 2 × 10 5 PBMC cells were seeded in a 96-well cell culture plate, and the compounds to be tested were added at different concentrations as nine 1:5 serial dilutions, each in a double-decker system, starting from a maximum compound concentration of 100 μM. LPS was added to a final concentration of 0.1 ng / mL, bringing the total volume to 200 μL. For negative and positive controls, only LPS and DMSO were added to the negative control wells, while 1 μg / mL of dexamethasone was added to the positive control wells in addition to the cells and LPS. The cells were incubated in an incubator at 37°C for 24 hours. After incubation was complete, 100 μL of the cell culture supernatant was collected and TNF-α levels were detected by ELISA. 100 μL of CellTiter-Glo was added to the remaining cells in each well to detect cell viability levels. IC50 was performed to detect the inhibition of TNF-α release by the compounds. 50 The value was calculated.

[0282] The in vitro inhibition of pro-inflammatory cytokine release by PBMCs according to the embodiments of this disclosure was determined by the above test, and the determined IC 50 The values ​​are shown in Table 2 (Table 3).

[0283] [Table 3]

[0284] Test Example 3: Experiment on in vitro inhibition of IL-23 secretion by DC cells differentiated from human mononuclear cells using a compound. Day 0: Mononuclear cells were isolated from fresh human peripheral blood, purified, and then resuspended in RPMI-1640 complete medium (RPMI-1640 + 10% FBS + 1% PS + 55 μM 2-mercaptoethanol). For differentiation into DC cells, IL-4 was added to the medium at a concentration of 50 ng / ml and GM-CSF at 100 ng / ml. The cells were placed in a 100 mm diameter culture dish and incubated at 37°C with a carbon dioxide concentration of 5% for differentiation, at a rate of 1 × 10⁶ cells. 6 Cells were cultured at a density of cells / mL. Day 3: Half the volume of RPMI complete medium was replaced with fresh RPMI complete medium while maintaining concentrations of IL-4 at 50 ng / ml and GM-CSF at 100 ng / ml. Day 6: Non-adherent cells (DC cells) were collected from the culture dish and washed with PBS. The washed DC cells were incubated in RPMI complete medium at a rate of 1 × 10⁶ 6 The cells were then resuspended at a density of 1 × 10⁻⁶ cells / mL. 5 DC cells were added to each well of a 96-well cell culture plate and pre-incubated for 1 hour with various dilutions of the compound to be tested (or equivalent concentrations of DMSO blank negative control). Subsequently, 200 μg / ml of the TLR2 agonist zymosan was added to stimulate the DC cells for 24 hours. Day 7: 24 hours after zymosan stimulation of the DC cells, the supernatant was collected from each well of the 96-well plate and the concentration of IL-23 was detected by ELISA.

[0285] The inhibition of IL-23 secretion by the compounds disclosed herein in DC cells differentiated from human mononuclear cells was determined by the above test, and the determined IC 50 The values ​​are shown in Table 3 (Table 4).

[0286] [Table 4]

[0287] Test Example 4: Experiment on the suppression of imiquimod-induced psoriasis An appropriate amount of compound 12-1 was added to an ointment containing the following ingredients: 0.1% compound 12-1, 9% hexanediol, 78.8% white petrolatum, 5% paraffin, 7% mono- and distearate glyceryl, and 0.1% dihydroxybutyltoluene, which was then mechanically stirred until an ointment was formed.

[0288] 1) Model establishment and drug administration Seven-week-old Balb / c female mice were used, and the dorsal hair of a 2cm x 3cm area was shaved the day before the experiment. On days 1-7 of the experiment, the test compound was applied to the skin for 6 hours, and then imiquimod (IMQ) ointment (Aldara (5%)) was continuously applied to the dorsal skin of the mice for 7 days to establish a mouse model of psoriasis, while the control group was given the same dose of petrolatum ointment. On days 3, 5, and 7, the severity of dermatitis was assessed, including measurement of skin thickness, crusting, and erythema, which were scored on a 5-point scale (0-4), respectively. The overall score was used to assess the severity of dermatitis. On day 7 of the experiment, the spleen was collected, weighed, and the ratio of the spleen to body weight was calculated to evaluate the immunosuppressive effect of the drug.

[0289] In this experiment, we prepared a normal control group, a model control group, low, medium, and high dose groups of compound 12-1 (0.01%, 0.03%, and 0.1%), a 0.03% compound 1-1 group, and a 0.03% reference compound A group.

[0290] 2) Evaluation indicators The overall score for the severity of dermatitis was a clinical score, and its indicator was relatively subjective; a higher score indicated a more severe disease. The degree of skin thickness increase was an objective evaluation indicator; an increase in thickness indicated a more severe disease. The ratio of spleen mass to body weight was an objective evaluation indicator; a smaller ratio indicated a stronger immunosuppressive effect of the drug.

[0291] 3) Experimental results 3.1) Clinical scores Compound A, Compound 1-1, and Compound 12-1 at each dose significantly reduced clinical scores at the endpoint (Figures 1-4). As can be seen from the single-item scores, Compound 1-1 and Compound 12-1 at each dose group primarily improved scab formation and reduced skin thickness in the psoriasis model. Of the skin thickness scores, Compound 12-1 at both the low and high dose groups significantly inhibited the increase in skin thickness, while Compound A showed no significant effect. Compound 12-1 at 0.03% had a significantly higher inhibitory effect on the increase in skin thickness than Compound A at the same dose (Figure 4). The results indicate that Compound 12-1 is significantly superior to reference compound A in improving psoriasis symptoms. Specific score data are shown in Table 4 (Table 5).

[0292] [Table 5]

[0293] 3.2) Ratio of spleen mass to body weight Under the influence of IMQ, there was no significant difference in animal body weight between the model group and each treatment group, but the ratio of spleen mass to total body weight in the model group increased significantly (Figure 5), indicating splenomegaly. Compound A did not have a significant effect on the ratio of spleen mass to body weight, but compound 1-1 and compound 12-1 in the three dose groups significantly reduced the ratio of spleen mass to body weight, indicating that these compounds have immunosuppressive effects and that compound 12-1 exhibits a dose-response relationship. At the same dose (0.03%), the effect of compound 1-1 and compound 12-1 on the ratio of spleen mass to body weight differed significantly from that of compound A, indicating that the immunosuppressive effects of compound 1-1 and compound 12-1 are stronger than those of compound A. Specific data are shown in Table 5 (Table 6).

[0294] [Table 6]

Claims

1. Equation I 【Chemistry 1】 (In the formula, ring A is selected from the group consisting of 5-6 membered aryl rings and heteroaryl rings, and the aryl ring or heteroaryl ring is optionally one or more R A1 It is further replaced by, R A1 is selected from the group consisting of halogen, deuterium, hydroxy, nitro, cyano, amino, C 1～6 alkyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1～6 alkoxyl, C 3～6 cycloalkoxyl and 3- to 6-membered heterocycloalkoxyl, and C 1～6 alkyl, C 1～6 alkoxyl, C 3～6 cycloalkoxyl or 3- to 6-membered heterocycloalkoxyl is optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxy, nitro, cyano, amino and C 1～6 alkoxyl, B is a boron atom, Z is selected from the group consisting of carbon atoms and nitrogen atoms. R 1 These are hydrogen, halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, and C, respectively. 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered ring heterocyclyl, C 1～6 Alkoxyl, C 3～6 Independently selected from the group consisting of cycloalkoxyls and 3- to 6-membered heterocycloalkoxyls, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered ring heterocyclyl, C 1～6 Alkoxyl, C 3～6 Cycloalkoxyls or 3- to 6-membered heterocycloalkoxyls are optionally one or more R A2 It is further replaced by, R A2 However, halogen, deuterium, hydroxy, nitro, cyano, amino, C 1～6 Alkyl, C 3～6 Cycloalkyl, 3-6 membered ring heterocyclyl, C 1～6 Alkoxyl, C 3～6 Selected from the group consisting of cycloalkoxyls and 3- to 6-membered heterocycloalkoxyls, C 1～6 Alkyl, C 1～6 Alkoxyl, C 3～6 Cycloalkoxyls or 3- to 6-membered heterocycloalkoxyls are optionally substituted with halogens, deuterium, hydroxyl, nitro, cyano, amino, and C. 1～6 It is further substituted with one or more groups selected from the group consisting of alkoxyls, R 2 R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally selected as one or more R A3 It is further replaced by, R A3 However, it is selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, and amino, R 3 , R 4 and R 5 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1～6 Alkyl, C 1～6 Alkoxyl, C 3～6 Cycloalkoxyl, C 3～6 Independently selected from the group consisting of cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered heterocycloalkoxyl, one or more R groups are optionally selected from the group consisting of alkyl, alkoxyl, cycloalkoxyl, cycloalkyl, heterocyclyl, or heterocycloalkoxyl. A4 It is further replaced by, R A4 However, it is selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, and amino, R 6 and R 7 Together with the carbon atoms attached thereto, these form a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring optionally contains one or more R A5 It is further replaced by, R A5 These are halogens, deuterium, hydroxyl, oxo, nitro, cyano, and C. 1～6 Alkyl, C 1～6 Alkoxyl, C 3～6 Selected from the group consisting of cycloalkoxyls, 3-6 membered heterocycloalkoxyls, phenyls, and 5-6 membered heteroaryls, C 1～6 Alkyl, C 1～6 Alkoxyl, C 3～6 A cycloalkoxyl, a 3- to 6-membered heterocycloalkoxyl, a phenyl, or a 5- to 6-membered heteroaryl is further optionally substituted with one or more groups selected from the group consisting of halogens, deuterium, hydroxyl, oxo, nitro, and cyano. m is an integer from 0 to 5. n is an integer from 1 to 3. and 【Chemistry 2】 It lies on the meta level of ring A, 「 【Transformation 3】 " is a compound (with or without a single bond) or a pharmaceutically acceptable salt thereof.

2. R 3 and R 4 However, these are hydrogen, deuterium, halogen, amino, hydroxyl, and C respectively. 1～6 Alkyl and C 1～6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally one or more R A4 It is further replaced by, R 5 is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, C1-6 alkyl and C1-6 alkoxyl, and the alkyl or alkoxyl is optionally further substituted with one or more R A4, and R A4 However, as stipulated in claim 1, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R 3 and R 4 However, each is independently selected from hydrogen, R 5 However, C 1～6 Alkyl and C 1～6 Selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally selected from 1 to 3 R A4 It is replaced with R A4 However, the compound according to claim 1, or a pharmaceutically acceptable salt thereof, as specified in claim 1.

4. The compound of formula I, 【Chemistry 4】 (In the formula, X 1 is -O-, -N(R 16a )- and -CR 16a R 16b - Selected from the group consisting of, X 2 -O- and -CR 17a R 17b - Selected from the group consisting of, X 3 This is a combination, -CR 18a R 18b - and -CR 18a R 18b CR 18c R 18d - Selected from the group consisting of, R 16a and R 16b However, these are hydrogen, deuterium, halogen, amino, hydroxyl, and C respectively. 1～6 Alkyl and C 1～6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally a halogen, nitro, cyano, or C 1～6 Substituted with alkoxyl, R 17a and R 17b However, these are hydrogen, deuterium, halogen, amino, hydroxyl, and C respectively. 1～6 Alkyl and C 1～6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally halogen, nitro, cyano, or C 1～6 Substituted with alkoxyl, R 18a 、 R 18b 、 R 18c and R 18d are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, C 1～6 alkyl and C 1～6 alkoxyl, and the alkyl or alkoxyl is optionally substituted with halogen, nitro, cyano or C 1～6 alkoxyl, R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, C 1～6 alkyl, C 1～6 alkoxyl, C 3～6 cycloalkoxyl, C 3～6 cycloalkyl, 3- to 6-membered heterocyclyl and 3- to 6-membered heterocycloalkoxyl, and alkyl, alkoxyl, cycloalkoxyl, cycloalkyl or heterocyclyl is optionally further substituted with one or more R A6 ; or R 8 and R 9 However, together with the carbon atoms attached to them, they form a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring may optionally have one or more R A6 It is further replaced by, or R 8 and R 9 However, it forms an oxo (=O), R A6 However, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1～6 Alkyl and C 1～6 Selected from the group consisting of alkoxyls, Ring A, R 1 ~R 5 , B, m, n and " 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein "as specified in claim 1."

5. X 1 However, it is selected from -O-, X 2 However, -O- and -CR 17a R 17b - Selected from the group consisting of R 17a and R 17b However, these are hydrogen, deuterium, halogen, amino, hydroxyl, and C respectively. 1～6 Alkyl and C 1～6 A compound according to claim 4, independently selected from the group consisting of alkoxyls, or a pharmaceutically acceptable salt thereof.

6. The compound of formula I, 【Transformation 6】 The compound according to claim 4, or a pharmaceutically acceptable salt thereof.

7. R 8 and R 9 However, these are hydrogen, deuterium, halogen, amino, hydroxyl, and C respectively. 1～6 Alkyl and C 1～6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally one or more R A6 It is further replaced with R A6 However, as stipulated in claim 4, Alternatively, a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring formed by R8 and R9 and the carbon atoms attached to them, 【Transformation 7】 A compound according to claim 4, or a pharmaceutically acceptable salt thereof, selected from the group consisting of, further comprising a carbocyclic ring or a heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 3 R A6 molecules, and the R A6 molecules are as defined in claim 4.

8. The compound of formula I, 【Transformation 8】 (In the formula, X 4 It is selected from the group consisting of nitrogen atoms and carbon atoms, R 10 and R 11 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1～6 Alkyl, C 1～6 Alkoxyl, C 3～6 Cycloalkoxyl, C 3～6 Independently selected from the group consisting of cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered heterocycloalkoxyl, the alkyl, alkoxyl, cycloalkoxyl, cycloalkyl, or heterocyclyl is optionally one or more R A7 It is further replaced by, R A7 However, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1～6 Alkyl and C 1～6 Selected from the group consisting of alkoxyls, Rings A, Z, R 1 ~R 5 , B, m, n and " 【Chemistry 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein "as specified in claim 1."

9. R 10 and R 11 However, these are hydrogen, deuterium, halogen, amino, hydroxyl, and C respectively. 1～6 Alkyl and C 1～6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally selected from 1 to 3 R A7 It is replaced with R A7 The compound according to claim 8, selected from the group consisting of halogens, C1-6 alkyls, and C1-6 alkoxyls, or a pharmaceutically acceptable salt thereof.

10. X 4 The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein Z is selected from nitrogen atoms, and Z is selected from nitrogen atoms.

11. The compound of formula I, 【Chemistry 10】 (In the formula, X 5 It is selected from the group consisting of nitrogen atoms and carbon atoms, R 12 , R 13 and R 14 These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1～6 Alkyl, C 1～6 Alkoxyl, C 3～6 Cycloalkoxyl, C 3～6 Independently selected from the group consisting of cycloalkyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered heterocycloalkoxyl, the alkyl, alkoxyl, cycloalkoxyl, cycloalkyl, or heterocyclyl is optionally one or more R A8 It is further replaced by, R A8 However, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1～6 Alkyl and C 1～6 Selected from the group consisting of alkoxyls, Rings A, Z, R 1 ~R 5 , B, m, n and " 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein "as specified in claim 1."

12. R 12 , R 13 and R 14 However, these are hydrogen, deuterium, halogen, amino, hydroxyl, and C respectively. 1～6 Alkyl and C 1～6 Independently selected from the group consisting of alkoxyls, the alkyl or alkoxyl is optionally selected from 1 to 3 R A8 It is replaced with R A8 The compound according to claim 11, selected from the group consisting of halogens, C1-6 alkyls, and C1-6 alkoxyls, or a pharmaceutically acceptable salt thereof.

13. X 5 The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein Z is selected from nitrogen atoms and Z is selected from carbon atoms.

14. Ring A is 【Chemistry 12】 (In the formula, R 15a , R 15b , R 15c and R 15d These are hydrogen, deuterium, halogen, amino, hydroxyl, and C, respectively. 1～6 Alkyl and C 1～6 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkoxyls (independently selected from the group consisting of alkoxyls, wherein the alkyl or alkoxyl is optionally further substituted with one or more groups selected from the group consisting of halogens, deuterium, hydroxy, nitro, cyano and amino).

15. Ring A is 【Chemistry 13】 A compound according to claim 14, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

16. R 15a , R 15b , R 15c and R 15d However, these are hydrogen, deuterium, halogen and C respectively. 1～6 A compound according to claim 14, independently selected from the group consisting of alkyl groups, or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is selected from 1 and 2.

18. R 2 However, hydrogen and C 1～6 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl groups, wherein R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, C1-6 alkyl, and C1-6 alkoxyl groups, and the alkyl or alkoxyl is optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxy, nitro, cyano, and amino groups.

19. The compound of formula I, 【Chemistry 14】 (In the formula, R 1 ~R 5 , B and m are as defined in claim 1, R 8 and R 9 However, as stipulated in claim 4, R 15a , R 15b and R 15d A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (as defined in claim 14).

20. The compound of formula I is 【Chemistry 15】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (wherein R1 to R5, B and m are as defined in claim 1, R8 and R9 are as defined in claim 4, and R15a, R15b and R15d are as defined in claim 14).

21. The compound of formula I, 【Chemical Engineering 16A】 【Chemical 16B】 [Chemical 16C] A compound of formula I, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

22. The compound of formula I is 【Chemical Engineering 17A】 【Chemistry 17B】 [Chemical 17C] A compound of formula I, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

23. An isotopic substitution compound of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, which is a deuterated compound. 【Request Item 24】 【Chemistry 18】 A compound selected from the group consisting of the following.

25. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or an isotope-substituted compound according to claim 23, and a pharmaceutically acceptable excipient.

26. Use of a compound according to any one of claims 1 to 22, or an isotope substitution compound according to claim 23, or a pharmaceutical composition according to claim 25, in the preparation of a pharmaceutical for preventing and / or treating PDE-related disorders.

27. Use of a compound according to any one of claims 1 to 22, or an isotope-substituted compound according to claim 23, or a pharmaceutical composition according to claim 25, in the preparation of a pharmaceutical for the prevention and / or treatment of psoriasis, asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes mellitus, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.

Images