6-aryl substituted pyrazolo[1,5-a]pyrimidines and preparation and use thereof

Abstract

The application provides a 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compound and preparation and application thereof. The compound structure is shown as formula (I). The compound of the application shows better anti-MTB activity than DMH-1. Meanwhile, compared with DMH-1, the compound of the application shows higher in-vitro safety. (I).

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically, to a 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compound, its preparation, and its application. Background Technology

[0002] Pyrazolo[1,5-a]pyrimidine scaffolds are among the unique heterocyclic compounds in drug discovery. Their application as building blocks for developing drug candidates has demonstrated broad pharmaceutical properties, such as anticancer, anti-infective, and anti-inflammatory effects, making them a key focus in drug development. This invention utilizes a compound library for anti-tuberculosis mycobacterium (...) Mycobacterium tuberculosis , M. tuberculosis Through MTB activity screening, the pyrazolo[1,5-a]pyrimidin-3-yl)quinoline compound DMH-1 (structure shown below) was first discovered to possess certain anti-MTB activity. Based on this, to further enhance its anti-tuberculosis activity, a series of derivatives with modified 3-quinoline and 6-aryl groups of pyrazolo[1,5-A]pyrimidin compounds were designed and synthesized, exhibiting anti-MTB activity comparable to or improved upon that of DMH-1. More importantly, all compounds showed good in vitro safety.

[0003] As is well known, tuberculosis (TB) caused by MTB remains one of the top ten causes of death worldwide. Therefore, it is of great significance to develop new anti-MTB drugs with novel mechanisms of action to achieve effective treatment and control of MTB.

[0004] . Summary of the Invention

[0005] One object of the present invention is to provide a 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compound.

[0006] Another object of the present invention is to provide a method for preparing the 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compound.

[0007] Another object of the present invention is to provide pharmaceutical compositions containing the 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compounds.

[0008] Another object of the present invention is to provide the use of the 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compounds.

[0009] To achieve the above objectives, in one respect, the present invention provides a 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compound, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the structure of the compound is shown in formula (I):

[0010]

[0011] (I)

[0012] in,

[0013] R 1 The aryl group is selected from 4- to 14-membered aryl groups or 5- to 14-membered heteroaryl groups; optionally, the aryl or heteroaryl group is substituted by 0, 1 or more substituents selected from H, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, hydroxyl, carboxyl, =O, nitro, amino, cyano; the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by 0, 1 or more substituents selected from H, F, Cl, Br or I; the heteroaryl group contains 1, 2, 3, 4 or 5 heteroatoms selected from N, O or S;

[0014] R 2 Selected from H, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, hydroxyl, carboxyl, nitro, amino, cyano, -C(O)OR 21 -C(O)R 22 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, or -O-(CH2) m -R 23 Optionally, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocyclic alkyl groups are substituted with 0, 1, or more substituents selected from H, F, Cl, Br, I, C1-5 alkyl, or C1-5 alkoxy groups; the heterocyclic alkyl groups contain 1, 2, or 3 heteroatoms selected from N, O, or S.

[0015] R 21 R 22 Each is independently selected from H or C1-10 alkyl groups;

[0016] R 23 The alkyl group is selected from 3- to 10-membered cycloalkyl or 3- to 10-membered heterocycloalkyl; the heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S; optionally, the cycloalkyl and heterocycloalkyl are substituted by 0, 1 or more substituents selected from H, F, Cl, Br or I;

[0017] R 3 The group is selected from H, halogens, C1-10 alkyl or C1-10 alkoxy groups; optionally, the alkyl or alkoxy group is substituted with a substituent selected from H, F, Cl, Br or I.

[0018] Ring A is selected from benzene rings or 4- to 8-membered unsaturated non-aromatic carbon rings;

[0019] n is 0, 1, 2 or 3; m is 0, 1, 2, 3, 4 or 5.

[0020] According to some specific embodiments of the present invention, wherein,

[0021] R 1 The aryl group is selected from 6- to 10-membered aryl groups or 5- to 10-membered heteroaryl groups; optionally, the aryl or heteroaryl group is substituted by 0, 1 or more substituents selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-5 alkoxy, hydroxyl, =O, carboxyl, nitro, amino, cyano; the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I; the heteroaryl group contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0022] R 2 Selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-5 alkoxy, hydroxyl, carboxyl, nitro, amino, cyano, -C(O)OR 21 -C(O)R 22 5- to 8-membered cycloalkyl, 5- to 8-membered heterocycloalkyl, or -O-(CH2) m -R 23 Optionally, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocyclic alkyl groups are substituted with 0, 1, 2, or 3 substituents selected from H, F, Cl, Br, I, C1-3 alkyl, or C1-3 alkoxy groups; the heterocyclic alkyl groups contain 1, 2, or 3 heteroatoms selected from N, O, or S.

[0023] R 21 R 22 Each is independently selected from H or C1-5 alkyl groups;

[0024] R 23 The alkyl group is selected from 5- to 8-membered cycloalkyl or 5- to 8-membered heterocycloalkyl; the heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S; optionally, the cycloalkyl and heterocycloalkyl are substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I;

[0025] R 3 The alkyl or alkoxy group is selected from H, halogen, C1-5 alkyl or C1-5 alkoxy; optionally, the alkyl or alkoxy group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I.

[0026] Ring A is selected from a benzene ring or a 5-, 6-, 7-, or 8-membered unsaturated non-aromatic carbon ring;

[0027] n is 0, 1, 2 or 3; m is 0, 1, 2, 3, 4 or 5.

[0028] According to some specific embodiments of the present invention, wherein,

[0029] R 1 The aryl group is selected from 6- to 10-membered aryl groups or 5- to 10-membered heteroaryl groups; optionally, the aryl or heteroaryl group is substituted by 0, 1, 2 or 3 substituents selected from H, halogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, hydroxyl, =O, carboxyl, nitro, amino, cyano; the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I; the heteroaryl group contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0030] R 2 Selected from H, halogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, hydroxyl, carboxyl, nitro, amino, cyano, -C(O)OR 21 -C(O)R 22 5- or 6-membered cycloalkyl, 5- or 6-membered heterocycloalkyl, or -O-(CH2) m -R 23 Optionally, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocyclic alkyl groups are substituted with 0, 1, 2, or 3 substituents selected from H, F, Cl, Br, I, C1-3 alkyl, or C1-3 alkoxy groups; the heterocyclic alkyl groups contain 1, 2, or 3 heteroatoms selected from N, O, or S.

[0031] R 21 R 22 Each is independently selected from H or C1-3 alkyl groups;

[0032] R 23 Selected from 5- or 6-membered cycloalkyl or 5- or 6-membered heterocycloalkyl; the heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S; optionally, the cycloalkyl and heterocycloalkyl are substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I;

[0033] R 3 The alkyl or alkoxy group is selected from H, halogen, C1-3 alkyl or C1-3 alkoxy; optionally, the alkyl or alkoxy group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I.

[0034] Ring A is selected from a benzene ring or a 5-, 6-, 7-, or 8-membered unsaturated non-aromatic carbon ring;

[0035] n is 0, 1, or 2; m is 0, 1, 2, or 3.

[0036] According to some specific embodiments of the present invention, wherein,

[0037] R 1The substituents are selected from phenyl, five- or six-membered heteroaryl, saturated or unsaturated five- or six-membered non-aromatic heterocyclic groups, benzo-six-membered saturated or unsaturated heterocyclic groups, benzo-six-membered cycloalkyl groups, naphthyl, benzo-five-membered saturated or unsaturated heterocyclic groups, or benzo-five-membered cycloalkyl groups; optionally, the above substituents are replaced by 0, 1, 2, or 3 substituents selected from H, halogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, hydroxyl, =O, carboxyl, nitro, amino, and cyano; the alkyl, alkenyl, alkynyl, and alkoxy groups are optionally replaced by 0, 1, 2, or 3 substituents selected from H, F, Cl, Br, or I; the heteroaryl and heterocyclic groups contain 1 or 2 heteroatoms selected from N, O, or S;

[0038] R 2 Selected from H, F, Cl, Br, I, C1-3 alkyl, C1-3 alkoxy, hydroxyl, carboxyl, nitro, amino, cyano, -C(O)OR 21 -C(O)R 22 5- or 6-membered heterocyclic alkyl groups or -O-(CH2) m -R 23 Optionally, the alkyl and heterocyclic alkyl groups are substituted with 0, 1, 2 or 3 substituents selected from H, F, Cl, Br, I, or C1-3 alkyl groups; optionally, the alkoxy group is substituted with 0, 1, 2 or 3 substituents selected from H, F, Cl, Br, I, C1-3 alkyl groups or C1-3 alkoxy groups; the heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S.

[0039] R 21 R 22 Each is independently selected from H or C1-3 alkyl groups;

[0040] R 23 The heterocyclic alkyl group is selected from 5-membered or 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S; optionally, the heterocyclic alkyl group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I;

[0041] R 3 The alkyl or alkoxy group is selected from H, halogen, C1-3 alkyl or C1-3 alkoxy; optionally, the alkyl or alkoxy group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I.

[0042] Ring A is selected from a benzene ring or a 5- or 6-membered unsaturated non-aromatic carbon ring;

[0043] n is 0, 1, or 2; m is 1, 2, or 3.

[0044] According to some specific embodiments of the present invention, wherein,

[0045] R 1The aryl or heteroaryl group is selected from 6-membered to 10-membered heteroaryl groups; optionally, the aryl or heteroaryl group is substituted by 0, 1, 2 or 3 substituents selected from H, halogen, C1-3 alkyl, C1-3 alkoxy, hydroxyl, =O, carboxyl, nitro, amino, cyano; the alkyl and alkoxy groups are optionally substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I; the heteroaryl group contains 1 or 2 heteroatoms selected from N, O or S;

[0046] R 2 The alkoxy group is selected from F, Cl, Br, I or C1-3 alkoxy; optionally, the alkoxy group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br, I, C1-3 alkyl or C1-3 alkoxy.

[0047] R 3 Selected from H or halogen;

[0048] Ring A is selected from the benzene ring.

[0049] According to some specific embodiments of the present invention, wherein,

[0050] R 1 The substituents are selected from five- or six-membered heteroaryl groups or benzo-six-membered saturated or unsaturated heterocyclic groups; optionally, the above substituents are replaced by 0, 1, 2 or 3 substituents selected from H, halogen, C1-3 alkyl, C1-3 alkoxy, hydroxyl, =O, carboxyl, nitro, amino, cyano; the alkyl and alkoxy groups are optionally replaced by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I; the heteroaryl and heterocyclic groups contain 1 or 2 heteroatoms selected from N, O or S;

[0051] R 2 The alkoxy group is selected from F, Cl, Br, I or C1-3 alkoxy; optionally, the alkoxy group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br, I, C1-3 alkyl or C1-3 alkoxy.

[0052] R 3 Selected from H or halogen;

[0053] Ring A is selected from the benzene ring.

[0054] According to some specific embodiments of the present invention, wherein,

[0055] R 1 The heteroaryl group is selected from one of the following structures:

[0056]

[0057] According to some specific embodiments of the present invention, wherein,

[0058] The unsaturated nonaromatic carbon ring of ring A is selected from one of the following structures:

[0059] .

[0060] According to some specific embodiments of the present invention, wherein,

[0061] R 1 Selected from ;

[0062] R 2 Selected from H, F, Cl, Br, I, C1-3 alkyl, C1-3 alkoxy, hydroxyl, carboxyl, nitro, amino, cyano, -C(O)OR 21 -C(O)R 22 5- or 6-membered heterocyclic alkyl groups or -O-(CH2) m -R 23 Optionally, the alkyl and heterocyclic alkyl groups are substituted with 0, 1, 2 or 3 substituents selected from H, F, Cl, Br, I, or C1-3 alkyl groups; optionally, the alkoxy group is substituted with 0, 1, 2 or 3 substituents selected from H, F, Cl, Br, I, C1-3 alkyl groups or C1-3 alkoxy groups; the heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S.

[0063] R 21 R 22 Each is independently selected from H or C1-3 alkyl groups;

[0064] R 23 The heterocyclic alkyl group is selected from 5-membered or 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S; optionally, the heterocyclic alkyl group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I;

[0065] R 3 The alkyl or alkoxy group is selected from H, halogen, C1-3 alkyl or C1-3 alkoxy; optionally, the alkyl or alkoxy group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I.

[0066] Ring A is selected from a 5- or 6-membered unsaturated non-aromatic carbon ring;

[0067] n is 0, 1, or 2; m is 1, 2, or 3;

[0068] or

[0069] R 1 Selected from ;

[0070] R 2Selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, hydroxy, carboxyl, nitro, amino, cyano, -C(O)OR 21 -C(O)R 22 5- or 6-membered heterocyclic alkyl groups or -O-(CH2) m -R 23 Optionally, the alkyl and heterocyclic alkyl groups are substituted with 0, 1, 2 or 3 substituents selected from H, F, Cl, Br, I, or C1-3 alkyl groups; optionally, the alkoxy group is substituted with 0, 1, 2 or 3 substituents selected from H, F, Cl, Br, I, C1-3 alkyl groups or C1-3 alkoxy groups; the heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S.

[0071] R 21 R 22 Each is independently selected from H or C1-3 alkyl groups;

[0072] R 23 The heterocyclic alkyl group is selected from 5-membered or 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S; optionally, the heterocyclic alkyl group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I;

[0073] R 3 The alkyl or alkoxy group is selected from H, halogen, C1-3 alkyl or C1-3 alkoxy; optionally, the alkyl or alkoxy group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I.

[0074] Ring A is selected from the benzene ring;

[0075] n is 0, 1, or 2; m is 1, 2, or 3;

[0076] or

[0077] R 1 The heteroaryl group is selected from one of the following structures:

[0078]

[0079] R 2 Selected from H, F, Cl, Br, I, C1-3 alkyl, C1-3 alkoxy, hydroxyl, carboxyl, nitro, amino, cyano, -C(O)OR 21 -C(O)R 22 5- or 6-membered heterocyclic alkyl groups or -O-(CH2) m -R 23Optionally, the alkyl and heterocyclic alkyl groups are substituted with 0, 1, 2 or 3 substituents selected from H, F, Cl, Br, I, or C1-3 alkyl groups; optionally, the alkoxy group is substituted with 0, 1, 2 or 3 substituents selected from H, F, Cl, Br, I, C1-3 alkyl groups or C1-3 alkoxy groups; the heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S.

[0080] R 21 R 22 Each is independently selected from H or C1-3 alkyl groups;

[0081] R 23 The heterocyclic alkyl group is selected from 5-membered or 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains 1, 2 or 3 heteroatoms selected from N, O or S; optionally, the heterocyclic alkyl group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I;

[0082] R 3 The alkyl or alkoxy group is selected from H, halogen, C1-3 alkyl or C1-3 alkoxy; optionally, the alkyl or alkoxy group is substituted by 0, 1, 2 or 3 substituents selected from H, F, Cl, Br or I.

[0083] Ring A is selected from a benzene ring or a 5- or 6-membered unsaturated non-aromatic carbon ring;

[0084] n is 0, 1, or 2; m is 1, 2, or 3.

[0085] According to some specific embodiments of the present invention, the compound is selected from one of the following structures:

[0086]

[0087]

[0088] On the other hand, the present invention also provides a method for preparing the 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compounds, their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the method comprises:

[0089] Method 1

[0090] When R 1 Selected from substituted or unsubstituted 5- to 10-membered heteroaryl groups, ring A is selected from an unsaturated non-aromatic carbon ring, and the method includes:

[0091] Prepare 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compounds of formula (I) using compounds of formula (II-1) and (III-1) as starting materials:

[0092] .

[0093] According to some specific embodiments of the present invention, the compounds of formula (II-1) and (III-1) are reacted at 80-100°C; preferably at 90-100°C.

[0094] According to some specific embodiments of the present invention, the reaction time of the compound of formula (II-1) and the compound of formula (III-1) is 2-5 h; preferably 3-5 h.

[0095] According to some specific embodiments of the present invention, the molar ratio of compound (II-1) to compound (III-1) is 1:(2-4).

[0096] According to some specific embodiments of the present invention, the compounds of formula (II-1) and (III-1) are reacted in the presence of Pd(PPh3)4 and K2CO3.

[0097] According to some specific embodiments of the present invention, the molar ratio of compound of formula (II-1) to Pd(PPh3)4 and K2CO3 is 1:(0.05-0.1):(2-5).

[0098] According to some specific embodiments of the present invention, the method further includes preparing a compound of formula (II-1) using a compound of formula (IV-1) as a starting material:

[0099] .

[0100] According to some specific embodiments of the present invention, the compound of formula (IV-1) is prepared by reacting at 20-30°C to prepare the compound of formula (II-1); preferably, the reaction is carried out at room temperature.

[0101] According to some specific embodiments of the present invention, the reaction time of the compound of formula (IV-1) is 3-5 h.

[0102] According to some specific embodiments of the present invention, the compound of formula (IV-1) is reacted in the presence of NBS.

[0103] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (IV-1) to NBS is 1:(1-2).

[0104] According to some specific embodiments of the present invention, the method further includes preparing compound (IV-1) using compounds of formula (V-1) and formula (VI-1) as raw materials:

[0105] .

[0106] According to some specific embodiments of the present invention, the compounds of formula (V-1) and (VI-1) are reacted at 80-100°C; preferably at 90-100°C.

[0107] According to some specific embodiments of the present invention, the reaction time of the compound of formula (V-1) and the compound of formula (VI-1) is 2-5 h; preferably 3-5 h.

[0108] According to some specific embodiments of the present invention, the molar ratio of compound (VI-1) to compound (V-1) is 1:(1-2).

[0109] According to some specific embodiments of the present invention, the compounds of formula (II-1) and (III-1) are reacted in the presence of Pd(PPh3)4 and K2CO3.

[0110] According to some specific embodiments of the present invention, the molar ratio of compound of formula (II-1) to Pd(PPh3)4 and K2CO3 is 1:(0.05-1):(2-5).

[0111] According to some specific embodiments of the present invention, the method further includes preparing compound (VI-1) using compounds of formula (VII-1) and (VIII-1) as raw materials:

[0112] .

[0113] According to some specific embodiments of the present invention, the compounds of formula (VII-1) and (VIII-1) are reacted at 40-60°C; preferably at 50-60°C.

[0114] According to some specific embodiments of the present invention, the reaction time of the compound of formula (VII-1) and the compound of formula (VIII-1) is 10-16 h; preferably 12-15 h.

[0115] According to some specific embodiments of the present invention, the molar ratio of compound (VII-1) to compound (VIII-1) is 1:(2-3).

[0116] According to some specific embodiments of the present invention, the compounds of formula (VII-1) and (VIII-1) are reacted in the presence of TEA.

[0117] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (VII-1) to TEA is 1:(1.5-4).

[0118] According to some specific embodiments of the present invention, in method one,

[0119] R 1 Selected from substituted or unsubstituted Ring A is selected from R 2 Selected from substituted or unsubstituted C1-3 alkoxy groups.

[0120] Method 2

[0121] When R 1 Selected from substituted or unsubstituted 6- to 10-membered aryl or 5- to 10-membered heteroaryl groups, ring A is selected from a benzene ring, and the method includes:

[0122] Prepare 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compounds of formula (I) using compounds of formula (II-1) and (III-1) as starting materials:

[0123] .

[0124] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (II-1) and the compound of formula (III-1) is 90-100°C.

[0125] According to some specific embodiments of the present invention, the reaction time of the compound of formula (II-1) and the compound of formula (III-1) is 2-5 h; preferably 3-5 h.

[0126] According to some specific embodiments of the present invention, the molar ratio of compound (II-1) to compound (III-1) is 1:(2-4).

[0127] According to some specific embodiments of the present invention, the compounds of formula (II-1) and (III-1) are reacted in the presence of Pd(PPh3)4 and K2CO3.

[0128] According to some specific embodiments of the present invention, the molar ratio of compound of formula (II-1) to Pd(PPh3)4 and K2CO3 is 1:(0.05-1):(2-5).

[0129] According to some specific embodiments of the present invention, the method further includes preparing a compound of formula (II-1) using a compound of formula (IV-1) as a starting material:

[0130] .

[0131] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (IV-1) is 0-30°C.

[0132] According to some specific embodiments of the present invention, the reaction time of the compound of formula (IV-1) is 2-5 h; preferably 3-5 h.

[0133] According to some specific embodiments of the present invention, the compound of formula (IV-1) is reacted in the presence of NBS.

[0134] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (IV-1) to NBS is 1:(1-2).

[0135] According to some specific embodiments of the present invention, the method further includes preparing compound (IV-1) using compounds of formula (V-2) and formula (VI-2) as raw materials:

[0136] .

[0137] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (V-2) and the compound of formula (VI-2) is 90-100°C.

[0138] According to some specific embodiments of the present invention, the reaction time of the compound of formula (V-2) and the compound of formula (VI-2) is 2-5 h; preferably 3-5 h.

[0139] According to some specific embodiments of the present invention, the compounds of formula (V-2) and (VI-2) are reacted in the presence of Pd(PPh3)4 and K2CO3.

[0140] According to some specific embodiments of the present invention, the molar ratio of compound of formula (V-2) to Pd(PPh3)4 and K2CO3 is 1:(0.05-1):(2-5).

[0141] According to some specific embodiments of the present invention, in method two,

[0142] R 1 Selected from phenyl, five- or six-membered heteroaryl, benzo-six-membered saturated or unsaturated heterocyclic group, naphthyl or benzo-five-membered saturated or unsaturated heterocyclic group; ring A is selected from benzene ring, R 2 Selected from H, F, Cl, Br, I, substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C1-3 alkoxy, hydroxyl, carboxyl, nitro, amino, cyano, -C(O)OR 21 -C(O)R 22 5- or 6-membered heterocyclic alkyl groups.

[0143] According to some specific embodiments of the present invention, in method two,

[0144] R 1The heteroaryl group is selected from one of the following structures:

[0145] .

[0146] Method 3

[0147] When R 1 Selected from substituted or unsubstituted benzohexa-unsaturated heterocyclic groups, where ring A is selected from a benzene ring, the method includes:

[0148] Prepare 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compounds of formula (I) using compounds of formula (II-3) and (III-3) as starting materials:

[0149] .

[0150] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (II-3) and the compound of formula (III-3) is 80-100°C; preferably 90-100°C.

[0151] According to some specific embodiments of the present invention, the reaction time of the compound of formula (II-3) and the compound of formula (III-3) is 2-5 h; preferably 3-5 h.

[0152] According to some specific embodiments of the present invention, the molar ratio of compound (II-3) to compound (III-3) is 1:(0.5-1).

[0153] According to some specific embodiments of the present invention, the compounds of formula (II-3) and (III-3) are reacted in the presence of Pd(PPh3)4 and K2CO3.

[0154] According to some specific embodiments of the present invention, the molar ratio of compound of formula (II-3) to Pd(PPh3)4 and K2CO3 is 1:(0.05-1):(2-5).

[0155] According to some specific embodiments of the present invention, the method further includes preparing compound (III-3) using compounds of formula (IV-3) and formula (VIII-1) as raw materials:

[0156]

[0157] R 1’ For R 1 Remove one H from the remaining structure.

[0158] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (IV-3) and the compound of formula (V-3) is 40-60°C; preferably 50-60°C.

[0159] According to some specific embodiments of the present invention, the reaction time of the compound of formula (IV-3) and the compound of formula (V-3) is 10-15 h; preferably 12-15 h.

[0160] According to some specific embodiments of the present invention, the molar ratio of compound (IV-3) to compound (V-3) is 1:(1-2).

[0161] According to some specific embodiments of the present invention, the compounds of formula (IV-3) and (V-3) are reacted in the presence of TEA.

[0162] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (IV-3) to TEA is 1:(1.5-4).

[0163] According to some specific embodiments of the present invention, in method three,

[0164] When R 1 Selected from substituted or unsubstituted It is preferred to be replaced by =O; ring A is selected from benzene ring.

[0165] Compounds of formula (III-3) have substituted or unsubstituted structures as follows:

[0166] .

[0167] Method 4:

[0168] When R 1 The group is selected from substituted or unsubstituted benzohexa-saturated heterocyclic groups or benzohexa-cycloalkyl groups, wherein ring A is selected from a benzene ring, and the method comprises:

[0169] Prepare 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compounds of formula (I) from compounds of formula (II-4):

[0170]

[0171] R 1 '' is a benzohexa-saturated heterocyclic group or benzohexa-unsaturated carbocyclic group formed by removing two H atoms from the saturated ring of a benzohexa-saturated heterocyclic group or benzohexa-saturated carbocyclic group of R1.

[0172] According to some specific embodiments of the present invention, the compound of formula (II-4) is reacted at 20-30°C.

[0173] According to some specific embodiments of the present invention, the compound of formula (II-4) is reacted in the presence of Pd / C.

[0174] According to some specific embodiments of the present invention, the molar ratio of compound of formula (II-4) to Pd / C is 1:(4-6).

[0175] According to some specific embodiments of the present invention, the method further includes preparing compound (II-4) from compounds of formula (II-3) and formula (III-3):

[0176] .

[0177] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (II-3) and the compound of formula (III-3) is 80-100°C; preferably 90-100°C.

[0178] According to some specific embodiments of the present invention, the reaction time of the compound of formula (II-3) and the compound of formula (III-3) is 2-5 h; preferably 3-5 h.

[0179] According to some specific embodiments of the present invention, the molar ratio of compound (II-3) to compound (III-3) is 1:(0.5-1).

[0180] According to some specific embodiments of the present invention, the compounds of formula (II-3) and (III-3) are reacted in the presence of Pd(PPh3)4 and K2CO3.

[0181] According to some specific embodiments of the present invention, the molar ratio of compound of formula (II-3) to Pd(PPh3)4 and K2CO3 is 1:(0.05-1):(2-5).

[0182] According to some specific embodiments of the present invention, the method further includes preparing compound (III-3) using compounds of formula (IV-3) and formula (VIII-1) as raw materials:

[0183]

[0184] R 1’ For R 1 Remove one H from the remaining structure.

[0185] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (IV-3) and the compound of formula (VIII-1) is 40-60°C; preferably 50-60°C.

[0186] According to some specific embodiments of the present invention, the reaction time of the compound of formula (IV-3) and the compound of formula (VIII-1) is 10-15 h; preferably 12-15 h.

[0187] According to some specific embodiments of the present invention, the molar ratio of compound (IV-3) to compound (VIII-1) is 1:(1-2).

[0188] According to some specific embodiments of the present invention, the compounds of formula (IV-3) and (VIII-1) are reacted in the presence of TEA.

[0189] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (IV-3) to TEA is 1:(1.5-4).

[0190] According to some specific embodiments of the present invention, in method four,

[0191] When R 1 Selected from substituted or unsubstituted Ring A is selected from the benzene ring.

[0192] Compounds of formula (III-3) have substituted or unsubstituted structures as follows:

[0193] .

[0194] Method 5

[0195] When R 2 Selected from -O-(CH2) m -R 23 Ring A is selected from benzene rings, and the method includes:

[0196] Prepare 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compounds of formula (I) from compounds of formula (II-5):

[0197]

[0198] R 23’ For R 23 Remove one H from the remaining structure.

[0199] According to some specific embodiments of the present invention, the compound of formula (II-5) is reacted at 20-30°C; preferably 2-30°C.

[0200] According to some specific embodiments of the present invention, the reaction time of the compound of formula (II-5) is 2-5 h.

[0201] According to some specific embodiments of the present invention, the compound of formula (II-5) is reacted under conditions of pH 4-5.5.

[0202] According to some specific embodiments of the present invention, the method further includes preparing compound (II-5) using compounds of formula (III-5) and formula (IV-5) as raw materials:

[0203] .

[0204] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (III-5) and the compound of formula (IV-5) is 80-100°C; preferably 90-100°C.

[0205] According to some specific embodiments of the present invention, the reaction time of the compound of formula (III-5) and the compound of formula (IV-5) is 10-13 h; preferably 11-12 h.

[0206] According to some specific embodiments of the present invention, the molar ratio of compound (III-5) to compound (IV-5) is 1:(1.5-3).

[0207] According to some specific embodiments of the present invention, the compounds of formula (III-5) and (IV-5) are reacted in the presence of potassium carbonate.

[0208] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (III-5) and potassium carbonate is 1:(2-5).

[0209] According to some specific embodiments of the present invention, in method five,

[0210] R 1 Selected from .

[0211] Method Six:

[0212] When R 2 Selected from substituted or unsubstituted C1-3 alkoxy groups, ring A is selected from a benzene ring, and the method comprises:

[0213] Prepare 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compounds of formula (I) using compounds of formula (II-6) and (III-6) as starting materials:

[0214]

[0215] R 2 'Selected from R' 2 The remaining structure after removing the O from the alkoxy group; X is selected from F, Cl, Br or I.

[0216] According to some specific embodiments of the present invention, the reaction temperature of the compound of formula (II-6) and the compound of formula (III-6) is 80-100°C; preferably 90-100°C.

[0217] According to some specific embodiments of the present invention, the reaction time of the compound of formula (II-6) and the compound of formula (III-6) is 10-13 h; preferably 11-12 h.

[0218] According to some specific embodiments of the present invention, the molar ratio of compound (II-6) to compound (III-6) is 1:(1.5-3).

[0219] According to some specific embodiments of the present invention, the compounds of formula (II-6) and (III-6) are reacted in the presence of potassium carbonate.

[0220] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (II-6) and potassium carbonate is 1:(2-5).

[0221] According to some specific embodiments of the present invention, in method six,

[0222] R 1 Selected from .

[0223] Without contradiction, the structures of each substituent in the preparation method can be arbitrarily combined with the specific implementation schemes of the substituents defined in the previous compound definition.

[0224] In another aspect, the present invention also provides a pharmaceutical composition comprising, in any one of the present invention, a 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compound, its stereoisomer, deuterated form or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or diluent.

[0225] According to some specific embodiments of the present invention, the 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compound, its stereoisomer, deuterated product or pharmaceutically acceptable salt thereof, constitutes 0.1%-99.9% by weight in the composition.

[0226] The pharmaceutical compositions of the present invention can be prepared into any pharmaceutically acceptable dosage form. Preferably, the pharmaceutically acceptable formulations are tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, capsules, hard capsules, soft capsules, sustained-release capsules, and powders.

[0227] According to some specific embodiments of the present invention, the pharmaceutical composition is a tablet, powder, capsule, or tablet.

[0228] When the pharmaceutical composition of the present invention is in solid form, the pharmaceutically acceptable carrier is selected from one or more of diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, swelling agents, etc.

[0229] When the pharmaceutical composition of the present invention is in an encapsulated form, the pharmaceutically acceptable carrier is selected from one or more of magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, and cocoa butter.

[0230] For ease of administration and uniform dosage, it is particularly advantageous to formulate the above-mentioned pharmaceutical preparations in unit dosage form. Unit dosage form refers to a physically separated unit suitable for single-dose administration, each unit containing a calculated, predetermined amount of active ingredient to produce the desired therapeutic effect. This unit dosage form can be in package form, such as tablets, capsules, or powder packaged in tubes or vials.

[0231] The pharmaceutical composition of the present invention, as a formulation, contains an effective amount of the compound of the present invention in each dose of 0.1 to 1000 mg.

[0232] Although the amount of active ingredient contained in the dosage unit can vary, it is generally adjusted within the range of 1 to 800 mg, depending on the potency of the selected active ingredient.

[0233] Each dose refers to each unit of preparation, such as each tablet or each capsule, or it can refer to the dosage taken each time, such as 100mg per dose.

[0234] In another aspect, the present invention also provides the use of the 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compounds, their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for treating mycobacterial infections.

[0235] According to some specific embodiments of the present invention, the mycobacterium is Mycobacterium tuberculosis.

[0236] According to some specific embodiments of the present invention, when the active compound of formula (I) of the present invention is used as a drug for treating Mycobacterium tuberculosis infection, it is preferred to administer an amount of 6 to 14 mg / kg body weight in the first stage.

[0237] In some cases, those skilled in the art can determine the preferred dosage suitable for a particular situation using conventional methods. Generally, the initial treatment dose is lower than the optimal dose of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved. For convenience, the total daily dose may be divided into several portions and administered in multiple doses.

[0238] It is understood that, without contradiction, the various specific embodiments of the present invention can be combined with each other.

[0239] Definition of Invention Terms

[0240] Unless otherwise defined, all terms used herein have the meanings commonly understood by one of ordinary skill in the art. In case of any discrepancy, the definitions provided in this application shall prevail.

[0241] "Substitution" refers to the replacement of a hydrogen atom on a carbon atom or heteroatom by one or more defined substituents. The upper limit of the number of substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Generally, the number of substituents is any integer between 1 and this upper limit. When the number of halogen substituents is greater than 1, the same or different substituents can be used for substitution.

[0242] "Optional" is a selective expression, meaning that the subsequent event may or may not occur. For example, "optionally, the aryl and alkyl groups are separated by 1, 2, or 3 elements selected from F, Cl, Br, I, or C." 1-6 "Substituted by straight-chain or branched alkyl groups" means that substitution may or may not occur. Specifically, it means that the aryl and alkyl groups mentioned above may or may not be substituted by the substituents mentioned above.

[0243] "Deuterated product" refers to a group containing hydrogen atoms in which at least one deuterium atom is replaced. The upper limit of the number of deuterated atoms is equal to the sum of the number of hydrogen atoms that can be replaced in the substituted group. Generally, the number of deuterated atoms is any integer between 1 and the upper limit. Preferably, 1-20 deuterium atoms are substituted, more preferably 1-10 deuterium atoms are substituted, even more preferably 1-5 deuterium atoms are substituted, and even more preferably 1-3 deuterium atoms are substituted.

[0244] As used in this invention, the term "alkyl" refers to a monovalent saturated hydrocarbon group formed by removing a hydrogen atom from a straight-chain or branched saturated hydrocarbon. The alkyl group can be straight-chain (i.e., "n-alkyl") or branched. The range of carbon atoms in an alkyl group is indicated by the prefix "Cx-y", for example, "C1-5 alkyl" represents an alkyl group containing 1, 2, 3, 4, or 5 carbon atoms. It should be understood that such ranges include all integers and subranges within this range, such as C1-C4, C2-C6, etc. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc.

[0245] As used in this invention, the term "alkoxy" refers to a group represented by the formula -OR, where R is an alkyl group as defined in this invention. Therefore, an alkoxy group inherits all the characteristics of the alkyl group to which it is attached, including but not limited to its range of carbon atoms, straight-chain or branched structure, and optional substitution. For example, "C1-5 alkoxy" refers to a straight-chain or branched alkyl group having 1 to 5 carbon atoms linked by an oxygen atom, non-limiting examples of which include methoxy, ethoxy, n-propoxy, isopropoxy, etc. When described as "optionally substituted alkoxy," it means that one or more hydrogen atoms of its alkyl portion R can be independently substituted by one or more substituents as described in this invention.

[0246] As used in this invention, the term "aryl" refers to an aromatic carbocyclic group consisting of a single aromatic ring or a fused plurality of aromatic rings, which is a monovalent group formed by removing a hydrogen atom from the system. The aryl group typically has 6 to 14 ring carbon atoms ("C6-C14 aryl"), preferably 6 to 10 ring carbon atoms ("C6-C10 aryl"). Non-limiting examples include phenyl, naphthyl, anthracene, and phenanthrene. Particularly preferred aryl groups are phenyl and naphthyl. When described as "optionally substituted aryl," it means that one or more, preferably 1, 2, or 3 hydrogen atoms of the aryl group can be independently substituted by one or more substituents described in this invention, or remain unsubstituted.

[0247] As used in this invention, "heteroaryl" refers to a 5- to 14-membered monocyclic or fused-ring aromatic group comprising 1, 2, 3, 4, or 5 heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S) as ring atoms. The heteroaryl group is formed by removing a hydrogen atom from an atom of the ring system to form a monovalent group. The total number of ring atoms (the sum of carbon atoms and heteroatoms) is preferably 5 to 10-membered, more preferably 5- or 6-membered. The heteroaryl group can be an aromatic ring consisting only of heteroatoms and carbon atoms (e.g., furanyl, thiophene, pyrrole, oxazolyl, imidazolyl, pyridinyl, pyrimidinyl), or a fused-ring system formed by fusion with one or more aryl rings (e.g., benzofuranyl, indolyl, quinolinyl), with the connecting point located on an aromatic ring atom or a non-aromatic ring atom. When described as "optionally substituted heteroaryl," it means that one or more hydrogen atoms of the heteroaryl group can be independently substituted by one or more substituents as described in this invention.

[0248] As used in this invention, the term "cycloalkyl" refers to a monovalent group having 3 to 10 ring carbon atoms, derived from a saturated or partially unsaturated (i.e., containing one or more double or triple bonds but not aromatic) carbocyclic system. The cycloalkyl includes monocyclic systems (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl), spirocyclic systems (e.g., spiro[3.3]heptyl), bridged ring systems (e.g., norbornyl (bicyclo[2.2.1]heptyl), adamantyl), and fused polycyclic systems (e.g., decahydronaphthyl). Preferably, the cycloalkyl has 5 to 8 ring carbon atoms ("C5-8 cycloalkyl"), more preferably 5 to 6 ring carbon atoms. When described as "optionally substituted cycloalkyl," it means that one or more hydrogen atoms of the cycloalkyl can be independently substituted by one or more substituents as described in this invention, or remain unsubstituted.

[0249] As used in this invention, the term "heterocyclic alkyl" (also referred to as "non-aromatic heterocyclic group") refers to a monovalent group having 3 to 10 ring atoms derived from a non-aromatic saturated or partially unsaturated (i.e., containing one or more double or triple bonds but not aromatic) monocyclic or polycyclic system, wherein one, two, or three ring atoms are heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), and the remaining ring atoms are carbon. The heterocyclic alkyl includes monocyclic systems (e.g., azirrobutyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazineyl, morpholinyl, tetrahydropyranyl, dioxaneyl, dioxane), spirocyclic systems, bridged ring systems, and fused polycyclic systems. Preferably, the heterocyclic alkyl is a 5- to 8-membered monocyclic ring. When described as "optionally substituted heterocyclic alkyl," it means that one or more hydrogen atoms (including hydrogen atoms attached to carbon or nitrogen atoms) of the heterocyclic alkyl can be independently substituted by one or more substituents as described in this invention.

[0250] As used in this invention, the term "unsaturated non-aromatic carbocyclic ring" refers to a cyclic structure composed of carbon and hydrogen atoms with non-aromatic unsaturated bonds. This term encompasses carbocyclic rings containing one or more carbon-carbon double bonds (C=C) and / or carbon-carbon triple bonds (C≡C), but which do not conform to Hückel's aromaticity rule. The ring can be a monocyclic ring (e.g., cyclohexene, cyclopentadiene) or a polycyclic system consisting of multiple rings connected in a spirocyclic, bridged, or fused manner (e.g., norbornene, norcarene, dihydronaphthalene, tetrahydronaphthalene). It should be understood that this term explicitly excludes fully saturated cycloalkyl groups and fully aromatic aryl groups.

[0251] In summary, this invention provides a 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compound, its preparation, and its applications. The compounds of this invention have the following advantages:

[0252] The compounds of this invention exhibit superior anti-MTB activity compared to DMH-1. Furthermore, compared to DMH-1, the compounds of this invention demonstrate higher in vitro safety. Detailed Implementation

[0253] The following detailed embodiments illustrate the implementation process and beneficial effects of the present invention, aiming to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of this case.

[0254] Example 1: 3-(chroman-4-yl)-6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidine

[0255]

[0256] TEA (6.88 g, 67.4 mmol, 2.00 eq) was added to a solution of chromone-4-one (5.00 g, 33.7 mmol, 1.00 eq) in DCM (50.0 mL) at 25 °C. Trifluoromethanesulfonic anhydride (19.0 g, 67.4 mmol, 2.00 eq) was added at 0 °C. The mixture was stirred at 50 °C for 12 hours. Post-treatment: The reaction mixture was concentrated to obtain a residue. The residue was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate = 10:1, 4%) to give a pale yellow oily 2H-chromone-4-yltrifluoromethanesulfonate (yield: 30.6%).

[0257] At 25 °C, 6-(4-isopropoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrazolo[1,5-A]pyrimidine (185 mg, 0.48 mmol, 1.00 eq), K₂CO₃ (134 mg, 0.96 mmol, 2.00 eq), and Pd(PPh₃)₄ (28.2 mg, 0.024 mmol, 0.05 eq) were added to a dioxane:H₂O = 5:1 (3.60 mL) solution of the above compound (136 mg, 0.48 mmol, 1.00 eq), and Pd(PPh₃)₄ (28.2 mg, 0.024 mmol, 0.05 eq). The mixture was stirred at 90 °C under N₂ for 3 hours. Post-treatment: The reaction mixture was concentrated to remove the solvent. The residue was purified by rapid silica gel chromatography (PE:EtOAc=5:1, 18%) to give a yellow solid 3-(2H-methyl-4-yl)-6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidine (yield: 48.3%).

[0258] Pd / C (100 mg) was added to a methanol (10.0 mL) solution of the above compound (90.0 mg, 0.23 mmol, 1.00 eq) at 25 °C. The mixture was stirred in H2 at 25 °C for 3 hours. The reaction mixture was concentrated to remove the solvent. Post-treatment: The residue was purified by preparative TLC (PE:EtOAc = 5:1, 18%) to give a white solid final product 3-(chroman-4-yl)-6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidine (yield: 48.3%).

[0259] 1 H NMR (400 MHz, DMSO- d 6) δ 9.35 (d, 1H), 8.89 (d, 1H), 7.96 (s, 1H), 7.79 - 7.74 (m, 2H), 7.13 - 7.06 (m, 3H), 6.91 -6.74 (m, 3H), 4.72 (m, 1H), 4.59 (dd, 1H), 4.33 - 4.24 (m, 2H), 2.47- 2.35 (m, 1H), 2.31 - 2.22 (m, 1H), 1.32 (d, 6H). MS-ESI (m / z): 386.1 (M + H) + .

[0260] Example 2, 4-(6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-2H-chromen-2-one

[0261]

[0262] The preparation method was the same as in Example 1. The compound benzodihydropyran-2,4-dione was reacted with trifluoromethanesulfonic anhydride and 6-(4-isopropoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazolo[1,5-A]pyrimidine to obtain a yellow solid (yield: 57.7%).

[0263] 1 H NMR: (400 MHz, DMSO- d6) δ 9.60 (d, 1H), 9.13 (d, 1H), 8.78 (s,1H), 7.99 (dd, 1H), 7.85 - 7.81 (m, 2H), 7.69 (m, 1H), 7.51 (dd, 1H), 7.40(m, 1H), 7.12 - 7.06 (m, 2H), 6.85 (s, 1H), 4.72 (m, 1H), 1.31 (d, 6H). MS-ESI (m / z): 398.1 (M + H) + .

[0264] Example 3: 6-(4-isopropoxyphenyl)-3-(1,2,3,4-tetrahydronaphth-1-yl)pyrazolo[1,5-a]pyrimidine

[0265]

[0266] The preparation method was the same as in Example 1. Compound 3,4-dihydronaphth-1(2H)-one was reacted with trifluoromethanesulfonic anhydride and 6-(4-isopropoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazolo[1,5-A]pyrimidine to obtain a yellow solid (yield: 33.3%).

[0267] 1 H NMR: (400 MHz, DMSO- d6 ) 9.32 (d, 1H), 8.87 (d, 1H), 7.85 (s, 1H),7.79 - 7.74 (m, 2H), 7.18 - 7.10 (m, 2H), 7.10 - 7.05 (m, 2H), 7.02 (t, 1H),6.88 (d, 1H), 4.72 (m, 1H), 4.51 (t, 1H), 3.02 - 2.78 (m, 2H), 2.15 (m, 2H), 2.00 - 1.76 (m, 2H), 1.32 (d, 6H). MS-ESI (m / z): 384.2 (M + H) + .

[0268] Example 4, 6-(4-isopropoxyphenyl)-3-(thiaran-4-yl)pyrazolo[1,5-a]pyrimidine

[0269]

[0270] The preparation method was the same as in Example 1. The compound thiaran-4-one was reacted with trifluoromethanesulfonic anhydride and 6-(4-isopropoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazolo[1,5-A]pyrimidine to obtain a yellow solid (yield: 10.1%).

[0271] 1 H NMR: (400 MHz, DMSO- d6 ) δ 9.35 (d, 1H), 8.90 (d, 1H), 7.77 (d,3H), 7.19 - 7.15 (m, 1H), 7.13 (m, 1H), 7.10 - 7.04 (m, 2H), 6.99 - 6.92 (m,2H), 4.72 (m, 1H), 4.60 (dd, 1H), 3.09 (m, 1H), 2.97 (m, 1H), 2.60 (m, 1H), 2.26 (m, 1H), 1.32 (d, 6H). MS-ESI (m / z): 402.2 (M + H) + .

[0272] Example 5: 4-(6-(4-methoxycyclohexyl-1-en-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0273]

[0274] The preparation method is the same as in Example 1. Compound 4-methoxycyclohexane-1-one is reacted with pyrazolo[1,5-a]pyrimidin-6-ylboronic acid and quinoline-4-ylboronic acid to obtain a yellow solid (yield: 8.03%).

[0275] 1 H NMR: (400 MHz, DMSO- d6 ) δ δ 9.19 (d, 1H), 8.94 (dd, 2H), 8.66 (s,1H), 8.17 (dd, 1H), 8.10 (dd, 1H), 7.84 - 7.70 (m, 2H), 7.61 (m, 1H), 6.40(t, 1H), 3.57 - 3.50 (m, 1H), 3.31 (s, 3H), 2.61 (d, 3H), 2.21 (s, 1H), 2.07- 1.97 (m, 1H), 1.75 (m, 1H). MS-ESI (m / z): 357.3 (M + H) + .

[0276] Example 6: 4-(6-phenylpyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0277]

[0278] At 25 °C, phenylboronic acid (738 mg, 6.08 mmol, 1.20 eq), K₂CO₃ (2.09 g, 15.2 mmol, 3.00 eq), and Pd(PPh₃)₄ (291 mg, 0.25 mmol, 0.05 eq) were added to a solution of 6-bromopyrazolo[1,5-A]pyrimidine (1.00 g, 5.07 mmol, 1.00 eq) in dioxane:H₂O = 10:1 (20.0 mL). The mixture was stirred at 100 °C for 3 h under nitrogen. Post-treatment: The reaction mixture was concentrated to remove the solvent. The residue was purified by rapid silica gel chromatography (PE:EtOAc = 10:1, 8%) to give 6-phenylpyrazolo[1,5-A]pyrimidine as a white solid (yield: 91.0%).

[0279] NBS (821 mg, 5.52 mmol, 1.00 eq) was added to a 15.0 mL DMF solution of the above compound (900 mg, 5.53 mmol, 1.00 eq) at 0 °C. The mixture was stirred at 25 °C for 3 h. Post-treatment: The reaction mixture was concentrated to remove the solvent. The residue was purified by rapid silica gel chromatography (PE:EtOAc = 5:1, 15%) to give a yellow solid of 3-bromo-6-phenylpyrazolo[1,5-a]pyrimidine (yield: 44.3%).

[0280] At 25 °C, quinoline-4-ylboronic acid (252 mg, 1.46 mmol, 2.00 eq), K₂CO₃ (302 mg, 2.19 mmol, 3.00 eq), and Pd(PPh₃)₄ (42.1 mg, 0.036 mmol, 0.05 eq) were added to a dioxane:H₂O = 8:1 (3.60 mL) solution of the above compound (200 mg, 0.73 mmol, 1.00 eq). The mixture was stirred at 100 °C for 3 hours under nitrogen. Post-treatment: The reaction mixture was concentrated to remove the solvent. The residue was purified by rapid silica gel chromatography (PE:EtOAc = 3:1, 20%) to give a white solid final product (yield: 63.8%).

[0281] 1 H NMR: (400 MHz, DMSO- d6) δ 9.68 (d, 1H), 9.11 (d, 1H), 8.99 (d,1H), 8.77 (s, 1H), 8.22 (d, 1H), 8.13 (d, 1H), 7.96 - 7.91 (m, 2H), 7.83 (td,2H), 7.64 (m, 1H), 7.58 (dd, 2H), 7.50 (t, 1H). MS-ESI (m / z): 323.1 (M + H) + .

[0282] Example 7, 6-(4-isopropoxyphenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine

[0283]

[0284] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (4-isopropoxyphenyl)boronic acid and pyridin-4-ylboronic acid to obtain a yellow solid (yield: 23.85%).

[0285] 1H NMR (400 MHz, DMSO-d6) 9.65 (d, 1H), 9.29 - 9.19 (m, 2H), 8.81 (d,2H), 8.67 - 8.61 (m, 2H), 7.89 - 7.81 (m, 2H), 7.14 - 7.06 (m, 2H), 4.73(hept, 1H), 1.31 (d, 6H). ESI (m / z): 331.1 (M + H) + .

[0286] Example 8, 6-(4-isopropoxyphenyl)-3-phenylpyrazolo[1,5-a]pyrimidine

[0287]

[0288] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (4-isopropoxyphenyl)boronic acid and phenylboronic acid to obtain a yellow solid (yield: 25.53%).

[0289] 1 H NMR: (400 MHz, DMSO- d6) δ 9.42 (d, 1H), 9.02 (d,1H), 8.77 (s, 1H), 8.17 (dt, 2H), 7.83 - 7.76 (m, 2H), 7.46 (t, 2H), 7.30 - 7.22 (m, 1H), 7.12- 7.04 (m, 2H), 4.72 (p, 1H), 1.31 (d, 6H). MS-ESI (m / z): 330.1 (M + H) + .

[0290] Example 9, 6-(4-isopropoxyphenyl)-3-(naphth-1-yl)pyrazolo[1,5-a]pyrimidine

[0291]

[0292] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (4-isopropoxyphenyl)boronic acid and naphth-1-ylboronic acid to obtain a yellow solid (yield: 87.68%).

[0293] 1 H NMR (400 MHz, DMSO-d6) 9.50 (d, 1H), 8.93 (d,1H), 8.53 (s, 1H), 8.05 - 7.99 (m, 2H), 7.97 (d, 1H), 7.84 - 7.76 (m, 2H), 7.71 (dd,1H), 7.66 -7.60 (m, 1H), 7.60 – 7.53 (m, 1H), 7.50 (m,1H), 7.12 – 7.03 (m, 2H), 4.71 (m,1H), 1.31 (d, 6H). MS-ESI (m / z): 380.1 (M + H) + .

[0294] Example 10, 3-(benzofuran-3-yl)-6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidine

[0295]

[0296] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (4-isopropoxyphenyl)boronic acid and benzofuran-3-ylboronic acid to obtain a yellow solid (yield: 35.52%).

[0297] 1 H NMR: (400 MHz, DMSO-d6 ) 9.47 (d, 1H), 9.04 (d, 1H), 8.86 (s, 1H),8.54 (s, 1H), 8.28 - 8.21 (m, 1H), 7.85 - 7.77 (m, 2H), 7.71 - 7.64 (m, 1H),7.46 - 7.34 (m, 2H), 7.12 - 7.04 (m, 2H), 4.71 (m, 1H), 1.31 (d,6H). MS-ESI(m / z): 370.1 (M + H) + .

[0298] Example 11, 2-(6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)benzo[d]thiazole

[0299]

[0300] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (4-isopropoxyphenyl)boronic acid and benzo[d]thiazol-2-ylboronic acid to obtain a yellow solid (yield: 18.61%).

[0301] 1 H NMR: (400 MHz, DMSO- d6 ) 9.60 (d, 1H), 9.24 (d, 1H), 8.94 (s, 1H),8.13 (d, 1H), 8.01 (d, 1H), 7.88 - 7.79 (m, 2H), 7.56 - 7.49 (m, 1H), 7.45 -7.37 (m, 1H), 7.13 - 7.06 (m, 2H), 4.73 (m, 1H), 1.31 (d, 6H). MS-ESI (m / z):387.1 (M + H) + .

[0302] Example 12, 4-(6-(p-tolyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0303]

[0304] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with p-tolylboronic acid and quinoline-4-ylboronic acid to obtain a white solid (yield: 87.9%).

[0305] 1 H NMR: (400 MHz, DMSO-d6 ) 9.63 (d, 1H), 9.08 (d, 1H), 8.99 (d, 1H),8.75 (s, 1H), 8.24 - 8.19 (m, 1H), 8.13 (d, 1H), 7.85 - 7.80 (m, 4H), 7.64(m, 1H), 7.38 (d, 2H), 2.40 (s, 3H). MS-ESI (m / z): 337.2 (M + H) + .

[0306] Example 13, 4-(6-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0307]

[0308] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with p-fluorophenylboronic acid and quinoline-4-ylboronic acid to obtain a white solid (yield: 25.52%).

[0309] 1 H NMR: (400 MHz, DMSO- d6 ) δ 9.66 (d, 1H), 9.07 (d, 1H), 8.98 (d,1H), 8.75 (s, 1H), 8.23 ​​- 8.16 (m, 1H), 8.15 - 8.08 (m, 1H), 8.01 - 7.93 (m,2H), 7.86 - 7.77 (m, 2H), 7.63 (m, 1H), 7.45 - 7.36 (m, 2H). MS-ESI (m / z):341.1 (M + H) + .

[0310] Example 14, 4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenol

[0311]

[0312] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with p-hydroxyphenylboronic acid and quinoline-4-ylboronic acid to obtain a yellow solid (yield: 18.61%).

[0313] 1 H NMR: (400 MHz, DMSO- d6) δ 9.79 (s, 1H), 9.51 (s, 1H), 9.06 - 8.93 (m, 2H), 8.70 (s, 1H), 8.16 (dd, 2H), 7.80 (d, 2H), 7.73 (d, 2H), 7.62 (t,1H), 6.93 (d, 2H). MS-ESI (m / z): 339.1(M + H) + .

[0314] Example 15, 4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)benzonitrile

[0315]

[0316] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with p-cyanophenylboronic acid and quinoline-4-ylboronic acid to obtain a yellow solid (yield: 28.41%).

[0317] 1 H NMR: (400 MHz, DMSO- d6 ) δ 9.82 (d, 1H), 9.14 (d, 1H), 8.98 (d,1H), 8.79 (s, 1H), 8.22 - 8.08 (m, 4H), 8.07 - 7.99 (m, 2H), 7.86 - 7.77 (m,2H), 7.63 (m, 1H). MS-ESI (m / z): 348.1 (M + H) + .

[0318] Example 16, 4-(6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0319]

[0320] The preparation method was the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine was reacted with p-methoxyphenylboronic acid and quinoline-4-ylboronic acid to obtain a yellow solid (yield: 11.51%).

[0321] 1 H NMR: (400 MHz, DMSO- d6) δ 9.58 (d, 1H), 9.06 (d,1H), 8.97 (d, 1H), 8.72 (s, 1H), 8.24 - 8.17 (m, 1H), 8.11 (d, 1H), 7.90 - 7.77 (m, 4H), 7.62(m, 1H), 7.16 - 7.07 (m, 2H), 3.84 (s, 3H). MS-ESI (m / z): 353.2 (M + H) + .

[0322] Example 17, 4-(6-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0323]

[0324] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with p-nitrophenylboronic acid and quinoline-4-ylboronic acid to obtain a white solid (yield: 27.33%).

[0325] 1 H NMR: (400 MHz, DMSO- d6 ) δ 9.87 (d, 1H), 9.17 (d, 1H), 8.99 (d 1H), 8.81 (s, 1H), 8.42 -8.34 (m, 2H), 8.27- 8.21 (m, 2H), 8.18 (dt 1H), 8.15 -8.08 (m, 1H), 7.86- 7.77 (m, 2H), 7.63 (m, 1H). MS-ESI (m / z): 368.2 (M + H) + .

[0326] Example 18, 4-(6-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0327]

[0328] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (3,4,5-trimethoxyphenyl)boronic acid and quinoline-4-ylboronic acid to obtain a white solid (yield: 25.33%).

[0329] 1 H NMR: (400 MHz, DMSO- d6) δ 9.72 (d, 1H), 9.15 (d, 1H), 8.97 (d,1H), 8.75 (s, 1H), 8.21 (dd, 1.4 Hz, 1H), 8.15 - 8.08 (m, 1H), 7.86 - 7.77(m, 2H), 7.63 (m, 1H), 7.21 (s, 2H), 3.92 (s, 6H), 3.73 (s, 3H). MS-ESI (m / z): 413.2 (M + H) + .

[0330] Example 19, 3-(1H-indol-3-yl)-6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidine

[0331]

[0332] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (4-isopropoxyphenyl)boronic acid and (1H-indol-3-yl)boronic acid to obtain a white solid (yield: 15.83%).

[0333] 1 H NMR: (400 MHz, DMSO- d6 ) δ 11.30 (s, 1H), 9.37 (d, 1H), 8.94 (d,1H), 8.71 (s, 1H), 8.08 (d, 1H), 7.99 (d,1H), 7.80 (d, 2H), 7.46 (d,1H), 7.16(t, 1H), 7.13 - 7.08 (m, 2H), 7.06 (s, 1H), 4.72 (p, 1H), 1.31 (d,6H). MS-ESI(m / z): 369.2 (M + H) + .

[0334] Example 20: 3-(benzothiophene-3-yl)-6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidine

[0335]

[0336] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (4-isopropoxyphenyl)boronic acid and benzothiophene-3-ylboronic acid to obtain a white solid (yield: 15.83%).

[0337] 1H NMR: (400 MHz, DMSO- d6 ) δ 9.49 (d, 1H), 9.02 (d, 1H), 8.74 (s,1H), 8.17 (dd, 1H), 8.12 - 8.07 (m, 2H), 7.82 (d, 2H), 7.46 (m, 2H), 7.08(d, 2H), 4.72 (p, 1H), 1.31 (d, 6H). MS-ESI (m / z): 386.2 (M + H) + .

[0338] Example 21, 4-(6-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0339]

[0340] The preparation method was the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine was reacted with p-trifluoromethylphenylboronic acid and quinoline-4-ylboronic acid to obtain a white solid (yield: 54.6%).

[0341] 1 H NMR: (400 MHz, DMSO- d6 ) δ 9.82 (d, 1H), 9.15 (d, 1H), 9.00 (d,1H), 8.80 (s, 1H), 8.23 ​​- 8.11 (m, 4H), 7.93 (d, 2H), 7.87 - 7.79 (m, 2H),7.64 (m, 1H). MS-ESI (m / z): 391.2 (M + H) + .

[0342] Example 22, Methyl 4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)benzoate

[0343]

[0344] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (4-(methoxycarbonyl)phenyl)boronic acid and quinoline-4-ylboronic acid to obtain a white solid (yield: 22.47%).

[0345] 1 H NMR: (400 MHz, DMSO- d6) δ 9.79 (d, 1H), 9.14 (d,1H), 8.98 (d, 1H),8.78 (s, 1H), 8.22 - 8.16 (m, 1H), 8.15 - 8.06 (m, 5H), 7.86 - 7.77 (m, 2H),7.63 (m, 1H), 3.91 (s, 3H). MS-ESI (m / z): 381.2 (M + H) + .

[0346] Example 23, 4-(6-(4-(tetrahydro-2H-pyran-4-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0347]

[0348] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (4-(tetrahydro-2H-pyran-4-yl)phenyl)boronic acid and quinoline-4-ylboronic acid to obtain a white solid (yield: 23.57%).

[0349] 1 H NMR: (400 MHz, DMSO- d6 ) δ 9.62 (d, 1H), 9.07 (d,1H), 8.97 (d, 1H), 8.74 (s, 1H), 8.24 - 8.17 (m, 1H), 8.11 (dt, 1H), 7.88 - 7.77 (m, 4H), 7.63(m, 1H), 7.48 - 7.41 (m, 2H), 4.02 - 3.94 (m, 2H), 3.47 (m,2H), 2.86 (p, 1H), 1.74 (d,4H). MS-ESI (m / z): 407.3 (M + H) + .

[0350] Example 24, 4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde

[0351]

[0352] The preparation method is the same as in Example 6. Compound 6-bromopyrazolo[1,5-A]pyrimidine is reacted with (4-formylphenyl)boronic acid and quinoline-4-ylboronic acid to obtain a white solid (yield: 13.55%).

[0353] 1 H NMR: (400 MHz, DMSO-d6 ) δ 10.10 (s, 1H), 9.82 (d, 1H), 9.17 (d,1H), 8.98 (d, 1H), 8.79 (s, 1H), 8.23 ​​- 8.15 (m, 3H), 8.15 - 8.09 (m, 2H), 8.07 (d, 1H), 7.86 - 7.77 (m, 2H), 7.63 (m, 1H). MS-ESI (m / z): 351.2 (M + H) + .

[0354] Example 25, 2-Benzylamino-3H-phenoloxazine-3-one

[0355]

[0356] At 25°C, tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (346 mg, 1.18 mmol, 2.00 eq) and K₂CO₃ (163 mg, 1.18 mol, 2.00 eq) were added to a 5.00 mL solution of DMF (200 mg, 0.59 mmol, 1.00 eq). The mixture was stirred at 100°C for 12 hours. Post-treatment: The reaction mixture was concentrated to remove the solvent. The residue was purified by rapid silica gel chromatography (PE:EtOAc = 3:1, 28%) to give a white solid tert-butyl 4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)piperazine-1-carboxylate (yield: 17.2%).

[0357] The above compound (56.0 mg, 0.10 mmol, 1.00 eq) was stirred in a solution of HCl / dioxane (10.0 mL) for 2 hours at 25 °C. Post-treatment: The reaction mixture was concentrated to remove the solvent. The residue was purified by preparative HPLC (TFA conditions, ACN / H2O, 25%) to give a yellow solid final product (yield: 17.2%).

[0358] 1 H NMR: (400 MHz, DMSO- d6) δ δ 8.84 - 8.80 (m, 2H), 8.75 (d, 1H),8.62 (s, 1H), 8.29 (d, 1H), 8.12 (d, 1H), 8.03 - 7.97 (m, 2H), 7.80 (m, 1H),7.47 - 7.42 (m, 2H), 7.01 - 6.94 (m, 2H), 4.42 - 4.37 (m, 2H), 3.75 - 3.69(m, 6H), 3.64 (t, 4H). MS-ESI (m / z): 451.2 (M + H) + .

[0359] Example 26, 4-(6-(4-propoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0360]

[0361] The preparation method is the same as in Example 25. In Example 14, the compound 1-bromo-2-ethoxyethane was reacted to obtain a yellow solid (yield: 18.61%).

[0362] 1 H NMR: (400 MHz, DMSO- d6 ) δ 9.59 (d, 1H), 9.07 (d, 1H), 8.99 (d,1H), 8.73 (s, 1H), 8.26 - 8.20 (m, 1H), 8.13 (d, 1H), 7.91 - 7.80 (m, 4H),7.64 (m, 1H), 7.17 - 7.09 (m, 2H), 4.03 (t, 2H), 1.79 (m, 2H), 1.03 (t, 3H).MS-ESI (m / z): 381.2 (M + H) + .

[0363] Example 27, 4-(6-(4-(2-ethoxyethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline

[0364]

[0365] The preparation method is the same as in Example 25. In Example 14, the compound 1-iodopropane was reacted to produce a white solid (yield: 13.27%).

[0366] 1 H NMR: (400 MHz, DMSO- d6) δ 9.59 (d, 1H), 9.06 (d, 1H), 8.97 (d,1H), 8.71 (s, 1H), 8.20 (d, 1H), 8.14 - 8.08 (m, 1H), 7.89 - 7.78 (m, 4H),7.67 - 7.60 (m, 1H), 7.13 (d, 2H), 4.20 - 4.16 (m, 2H), 3.76 - 3.71 (m, 2H), 3.53 (q, 2H), 1.15 (t, 3H). MS-ESI (m / z): 411.2 (M + H) + .

[0367] Biological Example 1

[0368] In vitro anti-mycobacterial activity assay

[0369] The anti-tuberculosis activity of the compounds of this invention was determined by measuring their activity against the standard strain MTBH of Mycobacterium tuberculosis. 37 The minimum inhibitory concentration (MIC, μg / mL) of RvATCC 27294 is used as the control. In this experiment, DMH-1 was used as the control. The MIC was determined as follows: In sterile 96-well plates (micro-culture plates specifically for rapid drug susceptibility testing of Mycobacterium tuberculosis), each well was added with the drug diluted in modified Michaelis 7H9 liquid medium, according to the drug susceptibility test design. Each compound was prepared as an initial solution (8 μg / mL) of appropriate concentration, and then halved with medium. Ten gradients were made for each compound, and 100 μL was added to each well of the 96-well plate. The final concentrations of the test drug were 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125, and 0.015 μg / mL. Standard strain H... 37 Rv ATCC 27294, inoculate 100 μL per well, with a bacterial count of 4 × 10⁻⁶ per well. -3 CFU / mL. Each plate had four positive control wells without antibiotics and two negative control wells with distilled water instead of culture medium. The 96-well plates were capped and sealed with transparent tape, then incubated in a humidified chamber at 37°C. On day 3, the positive and negative control wells were observed. When a clear difference was observed, the number and morphology of bacteria in each well were observed to determine inhibition or resistance, and the results were recorded. A second observation and recording were performed on day 7 for confirmation. The lowest concentration of drug in the control wells without sterile growth is the minimum inhibitory concentration (MIC). The results are listed in Table 1.

[0370] Table 1. In vitro activity and cytotoxicity of the compounds in the examples against Mycobacterium tuberculosis.

[0371]

[0372] Table 1 shows the data indicating the effect of the compounds in the examples on the standard strain H of Mycobacterium tuberculosis. 37 The in vitro activity of Rv ATCC 27294 was comparable to or better than that of DMH-1. Among them, compounds 26-27 showed better activity than DMH-1. Vero cells were used for cytotoxicity testing, and samples were collected using the MTT assay (European Journal of Medicinal Chemistry 218 (2021) 113398).

Claims

1. The use of a 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating mycobacterial infections, wherein, The structure of the compound is shown in formula (I): （I） in, R 1 Selected from 5- to 10-yuan heteroaryl groups, R 1 The heteroaryl group is selected from one of the following structures: , , , , , , Optionally, the above substituents are replaced by one substituent selected from =O; R 2 Selected from C1-3 alkyl, C1-3 alkoxy, or -O-(CH2). m -R 23 Optionally, the alkoxy group is substituted with one substituent selected from C1-3 alkoxy groups; R 23 Selected from 6-membered heterocyclic alkyl groups; the heterocyclic alkyl group contains one or two heteroatoms selected from N, O or S; R 3 Selected from H; Ring A is selected from the benzene ring; n is 0, 1, or 2; m is 1, 2, or 3.

2. The application according to claim 1, wherein, The compound is selected from one of the following structures: 。 3. The application according to claim 1 or 2, wherein, The mycobacterium mentioned is Mycobacterium tuberculosis.

4. A pharmaceutical composition for treating mycobacterial infections, wherein, The pharmaceutical composition contains a 6-aryl-substituted pyrazolo[1,5-A]pyrimidine compound as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or diluent.

5. The pharmaceutical composition according to claim 4, wherein, The mycobacterium mentioned is Mycobacterium tuberculosis.

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