Pyrazolone-fused pyrimidine compounds, their preparation and use

Abstract

The present invention provides pyrazolone-fused pyrimidine compounds as shown in formula (II), which have excellent inhibitory activity against WEE1 kinase. [Formula 1] TIFF2022538901000260.tif41170

Description

Detailed Description of the Invention

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority from Chinese Patent Application No. 201910579671.0, filed on June 28, 2019. The entire text of the Chinese patent application is incorporated herein by reference. [Technical field]

[0002] The present invention relates to pyrazolone-fused pyrimidine compounds, their preparation and use. [Background technology]

[0003] The cell cycle is closely linked to the process of DNA damage repair. The cell cycle, which encompasses the entire cell division process, is divided into two phases: interphase and mitotic phase (M). Cell cycle checkpoints are key points that regulate the cell cycle. Their main role is to ensure that each event in the cycle occurs at the correct time and in the correct order, and to adjust the cell's state to adapt to the external environment. The main cellular checkpoints are: 1) the G1 / S checkpoint, also known as the R (restriction) point in mammals, which controls the cell's transition from the resting G1 phase to the DNA synthesis phase; 2) the S phase checkpoint, which indicates whether DNA replication is complete; 3) the G2 / M checkpoint, which controls the cell's transition to the mitotic phase; and 4) the metaphase-anaphase checkpoint, also known as the spindle assembly checkpoint, which interrupts the cell cycle when the centromere is not properly attached to the spindle. If there is an abnormality, such as DNA damage, in a specific process of the cell division cycle, the checkpoints immediately detect it and initiate repair. The p53 protein is a key regulator of the G1 checkpoint. Upon DNA damage, it prevents cells from entering S phase and activates DNA repair mechanisms, which is crucial for maintaining the integrity of the cellular genome. However, tumor cells often harbor p53 mutations, resulting in defective G1 checkpoints. Therefore, cell division in these cells depends on the G2 / M checkpoint. WEE1 kinase, a cell cycle regulator, regulates the phosphorylation status of cyclin-dependent kinase 1 (CDK1), thereby regulating the activity of the CDK1-cyclin B complex, thereby regulating the cell cycle. It also plays a crucial role in regulating the DNA damage checkpoint. WEE1 is a key gene for G2 / M phase arrest, plays an important role in monitoring, and is overexpressed in some cancers.Since both inhibition or downregulation of WEE1 kinase disrupts mitosis, WEE1 kinase inhibitors have become a hotspot in anti-cancer drug research and development as they play an important role in anti-cancer therapy.

[0004] Although several small molecule WEE1 kinase inhibitors have been disclosed in international patent applications WO2019037678, WO2019028008, WO2018133829, WO2010098367, WO2010067886, WO2008115742, WO2008115738, WO2007126122, WO2007126128, and WO2004007499, among others, no small molecule WEE1 kinase inhibitors have yet been approved for marketing. Therefore, there is a need in this field to develop WEE1 kinase inhibitors that have excellent anticancer activity and are highly safe. [DISCLOSURE OF THE INVENTION] [Problem to be solved by the invention]

[0005] The technical problem to be solved by the present invention is as follows: Therefore, the present invention provides pyrazolone-fused pyrimidine compounds, their preparation and use, which have excellent inhibitory activity against WEE1 kinase.

[0006] The present invention provides a pyrazolone-fused pyrimidine compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, or a prodrug thereof:

[0007] [ka] In the formula, A is one or two R 1 C3 to C substituted by 20 is a cycloalkyl group, X is CH or N; R 1 are independently halogen, -OR 1-1 , -SR 1-2 , -CN, -NR 1-3R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7 , =NOR 1-9 (where "=" means that two hydrogen atoms of a methylene group in a cycloalkyl group are replaced), or optionally one, two, or three R 1-8 C2-C7 alkenyl group, C2-C8 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-1 independently optionally one, two or three R 1-1-1 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-1-1 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-1-1-1 is an amino group substituted by R 1-1-1-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-2 are independently hydrogen, optionally one, two or three R 1-2-1 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10an aryl group or a C1-C7 heteroaryl group, R 1-2-1 are independently hydrogen, halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-2-1-1 is an amino group substituted by R 1-2-1-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 , -S(=O)2NR 1-3-7 R 1-3-8 , -C(=O)NR 1-3-9 R 1-3-10 or optionally one, two or three R 1-3-11 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, Or R 1-3 , R 1-4 and the nitrogen atom connected thereto are both optionally bound to one, two or three R 1-3-12 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-3-13)- and R 1-3-13 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-1 , R 1-3-2 independently optionally one or two R 1-3-1-1 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl group or C6-C 10 is an aryl group, and R 1-3-1-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-3 are independently hydrogen, —CN, a C1 to C7 alkyl group, a C2 to C7 alkenyl group, a C2 to C7 alkynyl group, or a C3 to C 14 is a cycloalkyl group, R 1-3-5 , R 1-3-6 , R 1-3-7 , R 1-3-8 , R 1-3-9 , R 1-3-10 are independently hydrogen, a C1 to C7 alkyl group, a C2 to C7 alkenyl group, a C2 to C7 alkynyl group, or a C3 to C 14 is a cycloalkyl group, Or R 1-3-5 , R 1-3-6 and the nitrogen atom connected thereto are both optionally bound to one, two or three R 1-3-5-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-3-5-2 )- and R 1-3-5-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, and R 1-3-5-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, Or R 1-3-7 , R 1-3-8 and the nitrogen atom connected thereto are both optionally bound to one, two or three R 1-3-7-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-3-7-2 )- and R 1-3-7-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, and R 1-3-7-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, Or R 1-3-9 , R 1-3-10 and the nitrogen atom connected thereto are both optionally bound to one, two or three R 1-3-9-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-3-9-2 )- and R 1-3-9-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, and R 1-3-9-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-11 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-3-11-1is an amino group substituted by R 1-3-11-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-12 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-3-12-1 is an amino group substituted by R 1-3-12-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-5 are independently hydrogen, -NR 1-5-1 R 1-5-2 , -OR 1-5-3 or optionally one, two or three R 1-5-4 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, a C2 to C7 alkenyl group, a C2 to C7 alkynyl group, or a C3 to C 14 is a cycloalkyl group, Or R 1-5-1 , R 1-5-2 and the nitrogen atom connected thereto are both optionally bound to one, two or three R 1-5-1-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-5-1-2 )- and R 1-5-1-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, and R 1-5-1-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-5-3 are independently hydrogen, a C1-C7 alkyl group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-4 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-5-4-1 is an amino group substituted by R 1-5-4-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-6 are independently hydrogen, —CN, —OH, or optionally one, two, or three R 1-6-1 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-6-1are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-6-1-1 is an amino group substituted by R 1-6-1-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-7 are independently hydrogen, -OR 1-7-1 , -NR 1-7-2 R 1-7-3 or optionally one, two or three R 1-7-4 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-7-1 are independently hydrogen, a C1-C7 alkyl group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkane group, C6~C 10 an aryl group or a C1-C7 heteroaryl group, R 1-7-2 , R 1-7-3 are independently a C1 to C7 alkyl group, a C2 to C7 alkenyl group, a C2 to C7 alkynyl group, or a C3 to C 14 is a cycloalkyl group, Or R 1-7-2 , R 1-7-3 and the nitrogen atom connected thereto are both optionally bound to one, two or three R 1-7-2-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-7-2-2 )- and R 1-7-2-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, and R 1-7-2-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-7-4 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-7-4-1 is an amino group substituted by R 1-7-4-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-8 are independently oxo, halogen, -OH, amino group, mercapto group, cyano group, C1-C7 alkyl group, C1-C7 alkoxy group, C1-C7 alkylthio group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-8-1 is an amino group substituted by R 1-8-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-9 are independently hydrogen or a C1 to C7 alkyl group, R 2 HA-OR 2-1 , a cyano group, a carboxy group, or optionally one, two or three R 2-2C2-C7 alkyl groups, C3-C 14 Cycloalkyl group or C3-C 14 is a heterocycloalkyl group, R 2-1 is a C1-C7 alkyl group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 2-2 are independently halogen, hydroxy group, amino group, C1-C7 alkyl group, C1-C7 alkoxy group, C3-C 14 Cycloalkyl group or C3-C 14 is a heterocycloalkyl group, In any of the above cases, the above C3 to C 14 The heteroatoms in the heterocycloalkyl group and the C1-C7 heteroaryl group are independently selected from one or more of boron, silicon, oxygen, sulfur, serine, nitrogen, and phosphorus, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0008] In one aspect, some substituents in the pyrazolone-fused pyrimidine compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, or a prodrug thereof are further defined as follows, and substituents not mentioned below are defined as defined in any of the above aspects (hereinafter abbreviated as "in one aspect"). R with one or two A 1 C3 to C substituted by 20 When the cycloalkyl group is a cycloalkyl group, the C3 to C 20 The cycloalkyl group is, for example, a C to C 20 Monocyclic cycloalkyl groups, C3-C 20 Spirocyclic cycloalkyl groups, C3-C 20 Fused ring cycloalkyl group or C3-C 20 It is a bridged ring cycloalkyl group.

[0009] Said C3~C 20 The monocyclic cycloalkyl group is, for example, a C3 to C6 monocyclic cycloalkyl group, and also, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclopropyl group. and, for example, a cyclohexyl group.

[0010] Said C3~C 20 The bridged ring cycloalkyl group is, for example, a C5 to C8 bridged ring cycloalkyl group, and also, for example,

[0011] [ka] is.

[0012] In one embodiment, R with one or two A 1 C3 to C substituted by 20 When the cycloalkyl group is a cycloalkyl group, the C3 to C 20 The cycloalkyl group is, for example, a C to C 20 It is a saturated cycloalkyl group.

[0013] In one embodiment, A is one R 1 C3 to C substituted by 20 When A is a cycloalkyl group, it can be, for example,

[0014] [ka] is.

[0015] The aforementioned

[0016] [ka] For example,

[0017] [ka] Also, for example,

[0018] [ka] in,

[0019] [ka] The ratio is 1:1."

[0020] The aforementioned

[0021] [ka] For example,

[0022] [ka] And, for example,

[0023] [ka] in,

[0024] [ka] The ratio is 1:1."

[0025] In one embodiment, R 1 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14 The heterocycloalkyl group is, for example, a C to C 14 Monocyclic heterocycloalkyl groups, C3-C 14 Spirocyclic heterocycloalkyl groups, C3-C 14 Fused ring heterocycloalkyl group or C3-C 14 It is a bridged ring heterocycloalkyl group.

[0026] Said C3~C 14Examples of monocyclic heterocycloalkyl groups include "C3-C9 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," "C3-C5 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," and "C3-C5 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," which are connected to a benzene ring via a nitrogen atom, and further examples of monocyclic heterocycloalkyl groups include azetidinyl, morpholinyl, piperidinyl, and piperazinyl groups.

[0027] The azetidinyl group is, for example,

[0028] [ka] The morpholinyl group is, for example,

[0029] [ka] The piperidinyl group is, for example,

[0030] [ka] The piperazinyl group is, for example,

[0031] [ka] is.

[0032] In one embodiment, R 1 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14 The heteroatoms of a heterocycloalkyl group may be unsubstituted.

[0033] In one embodiment, R 1 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14 The methylene groups in the heterocycloalkyl group may be unaltered.

[0034] In one embodiment, R 1 are independently one R 1-8 C3 to C substituted by 14 When the heterocycloalkyl group is a C3 to C 14 The heterocycloalkyl group is, for example, a C to C 14 Monocyclic heterocycloalkyl groups, C3-C 14 Spirocyclic heterocycloalkyl groups, C3-C 14 Fused ring heterocycloalkyl group or C3-C 14 It is a bridged ring heterocycloalkyl group.

[0035] Said C3~C 14 The monocyclic heterocycloalkyl group is, for example, "a C3-C9 monocyclic heterocycloalkyl group having one or two heteroatoms selected from one or two of N, O, and S," or, for example, "a C3-C5 monocyclic heterocycloalkyl group having one or two heteroatoms selected from one or two of N, O, and S," or, further, for example, "a C3-C5 monocyclic heterocycloalkyl group having one or two heteroatoms selected from one or two of N, O, and S," which is connected to a benzene ring via a nitrogen atom, or, further, for example, an azetidinyl group,

[0036] [ka] , a morpholinyl group, a piperidinyl group, or a piperazinyl group.

[0037] The azetidinyl group is, for example,

[0038] [ka] The morpholinyl group is, for example,

[0039] [ka] The piperidinyl group is, for example,

[0040] [ka] The piperazinyl group is, for example,

[0041] [ka] is.

[0042] In one embodiment, R 1 are independently one R 1-8 C3 to C substituted by 14 When R is a heterocycloalkyl group, 1-8 Excluding the above C3 to C 14 The heteroatoms of a heterocycloalkyl group may be unsubstituted.

[0043] In one embodiment, R 1 are independently one R 1-8 C3 to C substituted by 14 When the heterocycloalkyl group is a C3 to C 14 The methylene groups in the heterocycloalkyl group may be unaltered.

[0044] In one embodiment, R 1 are independently one R 1-8 C3 to C substituted by 14 When the R is a heterocycloalkyl group, 1-8 C3 to C substituted by 14 Heterocycloalkyl groups are

[0045] [ka] may be.

[0046] In one embodiment, R 1-3 , R 1-4 are independently a C1 to C7 alkyl group, the C1 to C7 alkyl group is, for example, a C1 to C3 alkyl group, and is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0047] In one embodiment, R 1-3-1 are independently a C1 to C7 alkyl group, the C1 to C7 alkyl group is, for example, a C1 to C3 alkyl group, and is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0048] In one embodiment, R 1-3-2 C3~C 14 When the cycloalkyl group is a cycloalkyl group, the C3 to C 14 Cyclo The alkyl group may be, for example, a C3 to C 14 It is a monocyclic cycloalkyl group, for example, a C3 to C6 monocyclic cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, for example, a cyclopropyl group.

[0049] In one embodiment, R 1-3-2 C3~C 14 When the cycloalkyl group is a cycloalkyl group, the C3 to C 14 The cycloalkyl group is, for example, a C to C 14 It is a saturated cycloalkyl group.

[0050] In one embodiment, R 1-5 independently C3~C 14When the heterocycloalkyl group is a C3 to C 14 The heterocycloalkyl group is, for example, a C to C 14 Monocyclic heterocycloalkyl groups, C3-C 14 Spirocyclic heterocycloalkyl groups, C3-C 14 Fused ring heterocycloalkyl group or C3-C 14 It is a bridged ring heterocycloalkyl group.

[0051] Said C3~C 14 The monocyclic heterocycloalkyl group is, for example, a "C3-C9 monocyclic heterocycloalkyl group having one or two heteroatoms selected from one or two of N, O, and S," or, for example, a "C3-C5 monocyclic heterocycloalkyl group having one or two heteroatoms selected from one or two of N, O, and S," or, for example, a "C3-C5 monocyclic heterocycloalkyl group having one or two heteroatoms selected from one or two of N, O, and S," which is connected to a benzene ring via a nitrogen atom, or, for example, an azetidinyl group.

[0052] The azetidinyl group is, for example,

[0053] [ka] is.

[0054] In one embodiment, R 1-5 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14 The heteroatoms of a heterocycloalkyl group may be unsubstituted.

[0055] In one embodiment, R 1-5 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14The methylene groups in the heterocycloalkyl group may be unaltered.

[0056] In one embodiment, R 1-5-1 , R 1-5-2 are independently a C1 to C7 alkyl group, the C1 to C7 alkyl group is, for example, a C1 to C3 alkyl group, and is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0057] In one embodiment, R 1-5-1 , R 1-5-2 independently C3~C 14 When the cycloalkyl group is a cycloalkyl group, the C3 to C 14 The cycloalkyl group is, for example, a C to C 14 Monocyclic cycloalkyl groups, C3-C 14 Spirocyclic cycloalkyl groups, C3-C 14 Fused ring cycloalkyl group or C3-C 14 It is a bridged ring cycloalkyl group.

[0058] Said C3~C 14 The monocyclic cycloalkyl group is, for example, a C3 to C6 monocyclic cycloalkyl group, and is, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and is, for example, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0059] Said C3~C 14 The bridged ring cycloalkyl group is, for example, a C5 to C8 bridged ring cycloalkyl group, and also, for example,

[0060] [ka] is.

[0061] In one embodiment, R 1-5-1 , R 1-5-2 independently C3~C 14 When the cycloalkyl group is a cycloalkyl group, the C3 to C14 The cycloalkyl group is, for example, a C to C 14 It is a saturated cycloalkyl group.

[0062] In one embodiment, R 1-5-3 are independently a C1 to C7 alkyl group, the C1 to C7 alkyl group is, for example, a C1 to C3 alkyl group, and is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0063] In one embodiment, R 1-9 are independently a C1 to C7 alkyl group, the C1 to C7 alkyl group is, for example, a C1 to C3 alkyl group, and is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0064] In one embodiment, R 2 optionally one, two or three R 2-2 In the case where the C2 to C7 alkyl group is a C2 to C4 alkyl group substituted by, for example, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, and further for example an isopropyl group.

[0065] In one embodiment, R 2 is one R 2-2 C2-C7 alkyl group substituted by R 2-2 is a hydroxy group, 2-2 The C2-C7 alkyl group substituted by

[0066] [ka] is.

[0067] In one embodiment, R 2optionally one, two or three R 2-2 C3 to C substituted by 14 Haitai When the alkyl group is a cycloalkyl group, the C3 to C 14 The heterocycloalkyl group is, for example, a C to C 14 Monocyclic heterocycloalkyl groups, C3-C 14 Spirocyclic heterocycloalkyl groups, C3-C 14 Fused ring heterocycloalkyl group or C3-C 14 It is a bridged ring heterocycloalkyl group.

[0068] Said C3~C 14 Examples of monocyclic heterocycloalkyl groups include "C3-C9 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," "C3-C5 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," and "C3-C5 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," which are connected to a benzene ring via a nitrogen atom, and further examples include oxetanyl groups.

[0069] The morpholinyloxetanyl group is, for example, oxetan-3-yl.

[0070] In one embodiment, R 2 optionally one, two or three R 2-2 C3 to C substituted by 14 When R is a heterocycloalkyl group, 2-2 Excluding the above C3 to C 14 The heteroatoms of a heterocycloalkyl group may be unsubstituted.

[0071] In one embodiment, R 2 optionally one, two or three R 2-2 C3 to C substituted by14 When the heterocycloalkyl group is a C3 to C 14 The methylene groups in the heterocycloalkyl group may be unaltered.

[0072] In one embodiment, R 2 is one R 2-2 C3 to C substituted by 14 Heterocycloalkyl group, R 2-2 is a halogen or hydroxy group, 2-2 C3 to C substituted by 14 Heterocycloalkyl groups include, for example:

[0073] [ka] is.

[0074] In one embodiment, The pyrazolone-fused pyrimidine compound represented by the formula II may have an equal ratio of each isomer, for example, a racemate.

[0075] In one embodiment, The atoms in the pyrazolone-fused pyrimidine compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, or a prodrug thereof may all be present in their natural abundance form.

[0076] In one embodiment, A is one R 1 C3 to C substituted by 20 It is a cycloalkyl group.

[0077] In one embodiment, A is one or two R 1 replaced by

[0078] [ka] is.

[0079] In one embodiment, A is

[0080] [ka] is.

[0081] In one embodiment, R 1 are independently halogen, -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7 , =NOR 1-9 or optionally one, two or three R 1-8 C3 to C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 , -S(=O)2NR 1-3-7 R 1-3-8 , -C(=O)NR 1-3-9 R 1-3-10 or optionally one, two or three R 1-3-11 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-3-1 , R 1-3-2 independently optionally one or two R 1-3-1-1 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14Heterocycloalkyl group or C6-C 10 is an aryl group, and R 1-3-1-1 are independently a C1 to C7 alkyl group, R 1-3-3 are independently hydrogen, R 1-3-5 , R 1-3-6 , R 1-3-7 , R 1-3-8 , R 1-3-9 , R 1-3-10 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, R 1-3-11 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-3-11-1 is an amino group substituted by R 1-3-11-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-5 are independently hydrogen, -NR 1-5-1 R 1-5-2 , -OR 1-5-3 or optionally one, two or three R 1-5-4 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, R 1-5-3 are independently hydrogen, C1-C7 alkyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C10 an aryl group or a C1-C7 heteroaryl group, R 1-5-4 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-5-4-1 is an amino group substituted by R 1-5-4-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-6 are independently hydrogen, -CN, or -OH, R 1-7 are independently hydrogen, -NR 1-7-2 R 1-7-3 and R 1-7-2 , R 1-7-3 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, Or R 1-7-2 , R 1-7-3 and the nitrogen atom connected thereto are both optionally bound to one, two or three R 1-7-2-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently replaced by an oxygen atom or a sulfur atom, and R 1-7-2-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-8 are independently oxo, halogen, -OH, amino group, mercapto group, cyano group, C1-C7 alkyl group, C1-C7 alkoxy group, C1-C7 alkylthio group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10an aryl group, a C1-C7 heteroaryl group, or one or two R 1-8-1 is an amino group substituted by R 1-8-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-9 are independently hydrogen or a C1 to C7 alkyl group.

[0082] In one embodiment, R 1 are independently halogen, -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7 or optionally one, two or three R 1-8 C3 to C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 , -S(=O)2NR 1-3-7 R 1-3-8 , -C(=O)NR 1-3-9 R 1-3-10 or optionally one, two or three R 1-3-11 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-3-1 , R 1-3-2 independently optionally one or two R 1-3-1-1 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14Heterocycloalkyl group or C6-C 10 is an aryl group, and R 1-3-1-1 are independently a C1 to C7 alkyl group, R 1-3-3 are independently hydrogen, R 1-3-5 , R 1-3-6 , R 1-3-7 , R 1-3-8 , R 1-3-9 , R 1-3-10 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-11 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-3-11-1 is an amino group substituted by R 1-3-11-1 are independently C1 to C7 alkyl groups or is C3~C 14 is a cycloalkyl group, R 1-5 are independently hydrogen, -NR 1-5-1 R 1-5-2 , -OR 1-5-3 or optionally one, two or three R 1-5-4 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, R 1-5-3 are independently hydrogen, C1-C7 alkyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C10 an aryl group or a C1-C7 heteroaryl group, R 1-5-4 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-5-4-1 is an amino group substituted by R 1-5-4-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-6 are independently hydrogen, -CN, or -OH, R 1-7 are independently hydrogen, -NR 1-7-2 R 1-7-3 and R 1-7-2 , R 1-7-3 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, Or R 1-7-2 , R 1-7-3 and the nitrogen atom connected thereto are both optionally bound to one, two or three R 1-7-2-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently replaced by an oxygen atom or a sulfur atom, and R 1-7-2-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-8 are independently halogen, -OH, amino group, mercapto group, cyano group, C1-C7 alkyl group, C1-C7 alkoxy group, C1-C7 alkylthio group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R1-8-1 is an amino group substituted by R 1-8-1 are independently a C1 to C7 alkyl group or a C3 to C 14 It is a cycloalkyl group.

[0083] In one embodiment, R 1 are independently a cyano group, a halogen, or -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7 , =NOR 1-9 , a C1-C7 heteroaryl group or optionally one R 1-8 C3 to C substituted by 14 It is a heterocycloalkyl group.

[0084] In one embodiment, R 1 are independently a cyano group, a halogen, or -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7 , C1 to C7 heteroaryl group or C3 to C 14 It is a heterocycloalkyl group.

[0085] In one embodiment, R 1 -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , =NOR 1-9 or optionally one R 1-8 C3 to C substituted by 14 It is a heterocycloalkyl group.

[0086] In one embodiment, R 1 is independently -NR 1-3 R 1-4 , -C(=O)R 1-5 Or C3~C 14 Hetero It is a cycloalkyl group.

[0087] In one embodiment, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 or a C1 to C7 alkyl group, R 1-3-1 , R 1-3-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-3 is hydrogen, R 1-3-5 , R 1-3-6 is hydrogen.

[0088] In one embodiment, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 or a C1 to C7 alkyl group, and R 1-3-1 are independently a C1 to C7 alkyl group.

[0089] In one embodiment, R 1-5 is independently -NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 are independently hydrogen or a C1 to C7 alkyl group.

[0090] In one embodiment, R 1-5 is independently -NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 is hydrogen.

[0091] In one embodiment, R 1-8 are independently oxo.

[0092] In one embodiment, R 1-9 are independently hydrogen or a C1 to C7 alkyl group.

[0093] In one embodiment, R 2 optionally one, two or three R 2-2 C2-C7 alkyl groups, C3-C 14 Cycloalkyl group or C3-C 14 is a heterocycloalkyl group, R 2-2 are independently a halogen or a hydroxy group.

[0094] In one embodiment, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a halogen or a hydroxy group.

[0095] In one embodiment, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a hydroxy group.

[0096] In one embodiment, R 2 teeth

[0097] [ka] is.

[0098] In one embodiment, X is N.

[0099] In one embodiment, R 1 is = NOR 1-9 and R 1-9 are independently hydrogen or a C1 to C7 alkyl group.

[0100] In one embodiment, R 1-3-5 , R 1-3-6 , R 1-3-7 , R 1-3-8 , R 1-3-9 , R 1-3-10 is hydrogen.

[0101] In one embodiment, A is one or two R 1 replaced by

[0102] [ka] and X is CH or N; R 1 are independently halogen, -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7 , =NOR 1-9 or optionally one, two or three R 1-8 C3 to C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R1-3-6 , -S(=O)2NR 1-3-7 R 1-3-8 , -C(=O)NR 1-3-9 R 1-3-10 or optionally one, two or three R 1-3-11 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-3-1 , R 1-3-2 independently optionally one or two R 1-3-1-1 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl group or C6-C 10 is an aryl group, and R 1-3-1-1 are independently a C1 to C7 alkyl group, R 1-3-3 are independently hydrogen, R 1-3-5 , R 1-3-6 , R 1-3-7 , R 1-3-8 , R 1-3-9 , R 1-3-10 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, R 1-3-11 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-3-11-1 By is an amino group substituted with R 1-3-11-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-5 are independently hydrogen, -NR 1-5-1 R1-5-2 , -OR 1-5-3 or optionally one, two or three R 1-5-4 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, R 1-5-3 are independently hydrogen, C1-C7 alkyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-4 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-5-4-1 is an amino group substituted by R 1-5-4-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-6 are independently hydrogen, -CN, or -OH, R 1-7 are independently hydrogen, -NR 1-7-2 R 1-7-3 and R 1-7-2 , R 1-7-3 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, Or R 1-7-2 , R 1-7-3 and the nitrogen atom connected thereto are both optionally bound to one, two or three R1-7-2-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently replaced by an oxygen atom or a sulfur atom, and R 1-7-2-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-8 are independently oxo, halogen, -OH, amino group, mercapto group, cyano group, C1-C7 alkyl group, C1-C7 alkoxy group, C1-C7 alkylthio group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-8-1 is an amino group substituted by R 1-8-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-9 are independently hydrogen or a C1 to C7 alkyl group, R 2 optionally one, two or three R 2-2 C2-C7 alkyl groups, C3-C 14 Cycloalkyl group or C3-C 14 is a heterocycloalkyl group, R 2-2 are independently a halogen or a hydroxy group; In any of the above cases, the above C3 to C 14 The heteroatoms in the heterocycloalkyl group and the C1-C7 heteroaryl group are independently selected from one or more of boron, silicon, oxygen, sulfur, serine, nitrogen, and phosphorus, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0103] In one embodiment, A is one or two R 1 C3 to C substituted by 20 is a cycloalkyl group, X is CH or N; R 1 are independently a cyano group, a halogen, or -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7 , =NOR 1-9 , a C1-C7 heteroaryl group or optionally one R 1-8 C3 to C substituted by 14 is a heterocycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1 -3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 or a C1 to C7 alkyl group, R 1-3-1 , R 1-3-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-3 is hydrogen, R 1-3-5 , R 1-3-6 is hydrogen, R 1-5 is independently -NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 are independently hydrogen or a C1 to C7 alkyl group, R 1-8 are independently oxo, R 1-9 are independently hydrogen or a C1 to C7 alkyl group, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14is a heterocycloalkyl group, and R 2-2 is a halogen or a hydroxy group.

[0104] In one embodiment, A is one R 1 C3 to C substituted by 20 is a cycloalkyl group, X is CH or N; R 1 -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , =NOR 1-9 or optionally one R 1-8 C3 to C substituted by 14 is a heterocycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 or a C1 to C7 alkyl group, R 1-3-1 , R 1-3-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-3 is hydrogen, R 1-3-5 , R 1-3-6 is hydrogen, R 1-5 Ha-NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, R 1-5-3 is hydrogen or a C1-C7 alkyl group, R 1-8 are independently oxo, R 1-9are independently hydrogen or a C1 to C7 alkyl group, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a hydroxy group.

[0105] In one embodiment, A is one R 1 C3 to C substituted by 20 is a cycloalkyl group, X is CH or N; R 1 -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , =NOR 1-9 or optionally one R 1-8 C3 to C substituted by 14 is a heterocycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 or a C1 to C7 alkyl group, R 1-3-1 , R 1-3-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-3 is hydrogen, R 1-3-5 , R 1-3-6 is hydrogen, R 1-5 Ha-NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, R 1-5-3 is hydrogen, R 1-8 are independently oxo, R 1-9 are independently hydrogen or a C1 to C7 alkyl group, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a hydroxy group.

[0106] In one embodiment, A is

[0107] [ka] and X is CH or N; R 1 -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , =NOR 1-9 or optionally one R 1-8 C3 to C substituted by 14 is a heterocycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 or a C1 to C7 alkyl group, R 1-3-1 , R 1-3-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-3 is hydrogen, R 1-3-5 , R 1-3-6 is hydrogen, R 1-5 Ha-NR 1-5-1 R 1-5-2 , -OR 1-5-3Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 is hydrogen or a C1-C7 alkyl group, R 1-8 are independently oxo, R 1-9 are independently hydrogen or a C1 to C7 alkyl group, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a hydroxy group.

[0108] In one embodiment, A is

[0109] [ka] and X is CH or N; R 1 are independently -CN and -NR 1-3 R 1-4 , -C(=O)R 1-5 , =NOR 1-9 or optionally one R 1-8 C3 to C substituted by 14 is a heterocycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 or a C1 to C7 alkyl group, R 1-3-1 , R 1-3-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-3 is hydrogen, R 1-3-5 , R 1-3-6 is hydrogen, R 1-5 is independently -NR 1-5-1 R 1-5-2 , -OR 1-5-3 , or C3~C 14 is a heterocycloalkyl group, R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, R 1-5-3 are independently hydrogen or a C1 to C7 alkyl group, R 1-8 are independently oxo, R 1-9 are independently hydrogen or a C1 to C7 alkyl group, R 2 teeth

[0110] [ka] is.

[0111] In one aspect, the pyrazolone-fused pyrimidine compound of formula II may be a pyrazolone-fused pyrimidine compound of formula I,

[0112] [ka] In the formula, A is one or two R 1 C3 to C substituted by 20 is a cycloalkyl group, R 1 are independently halogen, -OR 1-1 , -SR 1-2 , -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7 or optionally one, two or three R 1-8C2-C7 alkenyl group, C2-C8 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-1 independently optionally one, two or three R 1-1-1 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 aryl group or a C1-C7 heteroaryl group, R 1-1-1 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-1-1-1 is an amino group substituted by R 1-1-1-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-2 are independently hydrogen, optionally one, two or three R 1-2-1 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-2-1 are independently hydrogen, halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-2-1-1 is an amino group substituted by R 1-2-1-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 , -S(=O)2NR 1-3-7 R 1-3-8 , -C(=O)NR 1-3-9 R 1-3-10 or optionally one, two or three R 1-3-11 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, Or R 1-3 , R 1-4 and the nitrogen atom connected thereto are both optionally one, two or three R 1-3-12 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-3-13 )- and R 1-3-13 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-1 , R 1-3-2 independently optionally one or two R 1-3-1-1C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl group or C6-C 10 is an aryl group, and R 1-3-1-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-3 are independently hydrogen, —CN, a C1 to C7 alkyl group, a C2 to C7 alkenyl group, a C2 to C7 alkynyl group, or a C3 to C 14 is a cycloalkyl group, R 1-3-5 , R 1-3-6 , R 1-3-7 , R 1-3-8 , R 1-3-9 , R 1-3-10 are independently a C1 to C7 alkyl group, a C2 to C7 alkenyl group, a C2 to C7 alkynyl group, or a C3 to C 14 is a cycloalkyl group, Or R 1-3-5 , R 1-3-6 and the nitrogen atom connected thereto are both optionally one, two or three R 1-3-5-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-3-5-2 )- and R 1-3-5-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, and R 1-3-5-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, Or R 1-3-7 , R 1-3-8 and the nitrogen atom connected thereto are both optionally One, two or three R 1-3-7-1 C3 to C substituted by 14 Forming a heterocycloalkyl group,14 One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-3-7-2 )- and R 1-3-7-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, and R 1-3-7-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, Or R 1-3-9 , R 1-3-10 and the nitrogen atom connected thereto are both optionally one, two or three R 1-3-9-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-3-9-2 )- and R 1-3-9-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, and R 1-3-9-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-11 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-3-11-1 is an amino group substituted by R 1-3-11-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-12are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-3-12-1 is an amino group substituted by R 1-3-12-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-5 are independently hydrogen, -NR 1-5-1 R 1-5-2 , -OR 1-5-3 or optionally one, two or three R 1-5-4 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, a C2 to C7 alkenyl group, a C2 to C7 alkynyl group, or a C3 to C 14 is a cycloalkyl group, Or R 1-5-1 , R 1-5-2 and the nitrogen atom connected thereto are both optionally one, two or three R 1-5-1-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-5-1-2 )- and R 1-5-1-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, and R 1-5-1-2are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-5-3 are independently hydrogen, a C1-C7 alkyl group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-4 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-5-4-1 is an amino group substituted by R 1-5-4-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-6 are independently hydrogen, —CN, —OH, or optionally one, two, or three R 1-6-1 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-6-1 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-6-1-1is an amino group substituted by R 1-6-1-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-7 are independently hydrogen, -OR 1-7-1 , -NR 1-7-2 R 1-7-3 or optionally one, two or three R 1-7-4 C1-C7 alkyl group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-7-1 are independently hydrogen, a C1-C7 alkyl group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-7-2 , R 1-7-3 are independently a C1 to C7 alkyl group, a C2 to C7 alkenyl group, a C2 to C7 alkynyl group, or a C3 to C 14 is a cycloalkyl group, Or R 1-7-2 , R 1-7-3 and the nitrogen atom connected thereto are both optionally one, two or three R 1-7-2-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently selected from oxygen atoms, sulfur atoms, sulfinyl groups, sulfonyl groups, carbonyl groups, ethenylene groups, or -N(R 1-7-2-2 )- and R 1-7-2-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, and R 1-7-2-2 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-7-4 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-7-4-1 is an amino group substituted by R 1-7-4-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-8 are independently halogen, -OH, amino group, mercapto group, cyano group, C1-C7 alkyl group, C1-C7 alkoxy group, C1-C7 alkylthio group, C2-C7 alkenyl group, C2-C7 alkynyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-8-1 is an amino group substituted by R 1-8-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 2 HA-OR 2-1 , a cyano group, a carboxy group, or optionally one, two or three R 2-2 C2-C7 alkyl groups, C3-C 14 Cycloalkyl group or C3-C 14 is a heterocycloalkyl group, R 2-1 is a C1-C7 alkyl group, a C2-C7 alkenyl group, a C2-C7 alkynyl group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 2-2are independently halogen, hydroxyl group, amino group, C1 to C7 alkyl group, C1 ~C7 alkoxy group, C3~C 14 Cycloalkyl group or C3-C 14 is a heterocycloalkyl group, In any of the above cases, the above C3 to C 14 The heteroatoms in the heterocycloalkyl group and the C1-C7 heteroaryl group are independently selected from one or more of boron, silicon, oxygen, sulfur, serine, nitrogen, and phosphorus, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0113] In one aspect, some substituents in the pyrazolone-fused pyrimidine compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, or a prodrug thereof are further defined as follows, and substituents not mentioned below are defined as defined in any of the above aspects (hereinafter abbreviated as "in one aspect"). R with one or two A 1 C3 to C substituted by 20 When the cycloalkyl group is a cycloalkyl group, the C3 to C 20 The cycloalkyl group is, for example, a C to C 20 Monocyclic cycloalkyl groups, C3-C 20 Spirocyclic cycloalkyl groups, C3-C 20 Fused ring cycloalkyl group or C3-C 20 It is a bridged ring cycloalkyl group.

[0114] Said C3~C 20 The monocyclic cycloalkyl group is, for example, a C3 to C6 monocyclic cycloalkyl group, and is, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and is, for example, a cyclohexyl group.

[0115] Said C3~C 20 The bridged ring cycloalkyl group is, for example, a C5 to C8 bridged ring cycloalkyl group, and also, for example,

[0116] [ka] is.

[0117] In one embodiment, R with one or two A 1 C3 to C substituted by 20 When the cycloalkyl group is a cycloalkyl group, the C3 to C 20 The cycloalkyl group is, for example, a C to C 20 It is a saturated cycloalkyl group.

[0118] In one embodiment, A is one R 1 C3 to C substituted by 20 When A is a cycloalkyl group, it can be, for example,

[0119] [ka] is.

[0120] The aforementioned

[0121] [ka] For example,

[0122] [ka] Also, for example,

[0123] [ka] in,

[0124] [ka] The ratio is 1:1."

[0125] The aforementioned

[0126] [ka] For example,

[0127] [ka] And, for example,

[0128] [ka] in,

[0129] [ka] The ratio is 1:1."

[0130] In one embodiment, R 1 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14 The heterocycloalkyl group is, for example, a C to C 14 Monocyclic heterocycloalkyl groups, C3-C 14 Spirocyclic heterocycloalkyl groups, C3-C 14 Fused ring heterocycloalkyl group or C3-C 14 It is a bridged ring heterocycloalkyl group.

[0131] Said C3~C 14Examples of monocyclic heterocycloalkyl groups include "C3-C9 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," "C3-C5 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," and "C3-C5 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," which are connected to a benzene ring via a nitrogen atom, and further examples of monocyclic heterocycloalkyl groups include azetidinyl, morpholinyl, piperidinyl, and piperazinyl groups.

[0132] The azetidinyl group is, for example,

[0133] [ka] The morpholinyl group is, for example,

[0134] [ka] The piperidinyl group is, for example,

[0135] [ka] The piperazinyl group is, for example,

[0136] [ka] is.

[0137] In one embodiment, R 1 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14 The heteroatoms of a heterocycloalkyl group may be unsubstituted.

[0138] In one embodiment, R 1 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14 The methylene groups in the heterocycloalkyl group may be unaltered.

[0139] In one embodiment, R 1-3 , R 1-4 are independently a C1 to C7 alkyl group, the C1 to C7 alkyl group is, for example, a C1 to C3 alkyl group, and is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0140] In one embodiment, R 1-3-1 are independently a C1 to C7 alkyl group, the C1 to C7 alkyl group is, for example, a C1 to C3 alkyl group, and is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0141] In one embodiment, R 1-5 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14 The heterocycloalkyl group is, for example, a C to C 14 Monocyclic heterocycloalkyl groups, C3-C 14 Spirocyclic heterocycloalkyl groups, C3-C 14 Fused ring heterocycloalkyl group or C3-C 14 It is a bridged ring heterocycloalkyl group.

[0142] Said C3~C 14The monocyclic heterocycloalkyl group is, for example, a "C3-C9 monocyclic heterocycloalkyl group having one or two heteroatoms selected from one or two of N, O, and S," or, for example, a "C3-C5 monocyclic heterocycloalkyl group having one or two heteroatoms selected from one or two of N, O, and S," or, for example, a "C3-C5 monocyclic heterocycloalkyl group having one or two heteroatoms selected from one or two of N, O, and S," which is connected to a benzene ring via a nitrogen atom, or, for example, an azetidinyl group.

[0143] The azetidinyl group is, for example, [ka] is.

[0144] In one embodiment, R 1-5 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14 The heteroatoms of a heterocycloalkyl group may be unsubstituted.

[0145] In one embodiment, R 1-5 independently C3~C 14 When the heterocycloalkyl group is a C3 to C 14 The methylene groups in the heterocycloalkyl group may be unaltered.

[0146] In one embodiment, R 1-5-1 , R 1-5-2 are independently a C1 to C7 alkyl group, the C1 to C7 alkyl group is, for example, a C1 to C3 alkyl group, and is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0147] In one embodiment, R 1-5-1 , R 1-5-2independently C3~C 14 When the cycloalkyl group is a cycloalkyl group, the C3 to C 14 The cycloalkyl group is, for example, a C to C 14 Monocyclic cycloalkyl groups, C3-C 14 Spirocyclic cycloalkyl groups, C3-C 14 Fused ring cycloalkyl group or C3-C 14 It is a bridged ring cycloalkyl group.

[0148] Said C3~C 14 The monocyclic cycloalkyl group is, for example, a C3 to C6 monocyclic cycloalkyl group, and is, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and is, for example, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0149] Said C3~C 14 The bridged ring cycloalkyl group is, for example, a C5 to C8 bridged ring cycloalkyl group, and also, for example,

[0150] [ka] is.

[0151] In one embodiment, R 1-5-1 , R 1-5-2 independently C3~C 14 When the cycloalkyl group is a cycloalkyl group, the C3 to C 14 The cycloalkyl group is, for example, a C to C 14 It is a saturated cycloalkyl group.

[0152] In one embodiment, R 1-5-3 are independently a C1 to C7 alkyl group, the C1 to C7 alkyl group is, for example, a C1 to C3 alkyl group, and is, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0153] In one embodiment, R 2optionally one, two or three R 2-2 In the case where the C2 to C7 alkyl group is a C2 to C4 alkyl group substituted by, for example, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, and further for example an isopropyl group.

[0154] In one embodiment, R 2 is one R 2-2 C2-C7 alkyl group substituted by R 2-2 is a hydroxy group, 2-2 The C2-C7 alkyl group substituted by

[0155] [ka] is.

[0156] In one embodiment, R 2 optionally one, two or three R 2-2 C3 to C substituted by 14 When the heterocycloalkyl group is a C3 to C 14 The heterocycloalkyl group is, for example, a C to C 14 Monocyclic heterocycloalkyl groups, C3-C 14 Spirocyclic heterocycloalkyl groups, C3-C 14 Fused ring heterocycloalkyl group or C3-C 14 It is a bridged ring heterocycloalkyl group.

[0157] Said C3~C 14Examples of monocyclic heterocycloalkyl groups include "C3-C9 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," "C3-C5 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," and "C3-C5 monocyclic heterocycloalkyl groups having one or two heteroatoms selected from one or two of N, O, and S," which are connected to a benzene ring via a nitrogen atom, and further examples include oxetanyl groups.

[0158] The morpholinyloxetanyl group is, for example, oxetan-3-yl.

[0159] In one embodiment, R 2 optionally one, two or three R 2-2 C3 to C substituted by 14 When R is a heterocycloalkyl group, 2-2 Excluding the above C3 to C 14 The heteroatoms of a heterocycloalkyl group may be unsubstituted.

[0160] In one embodiment, R 2 optionally one, two or three R 2-2 C3 to C substituted by 14 When the heterocycloalkyl group is a C3 to C 14 The methylene groups in the heterocycloalkyl group may be unaltered.

[0161] In one embodiment, R 2 is one R 2-2 C3 to C substituted by 14 Heterocycloalkyl group, R 2-2 is a halogen or hydroxy group, 2-2 C3 to C substituted by 14 Heterocycloalkyl groups include, for example:

[0162] [ka] is.

[0163] In one embodiment, The pyrazolone-fused pyrimidine compound represented by formula I may contain equal ratios of the isomers, for example, a racemate.

[0164] In one embodiment, Any atom in the pyrazolone-fused pyrimidine compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, or a prodrug thereof may be present in its natural abundance form.

[0165] In one embodiment, A is one or two R 1 replaced by

[0166] [ka] is.

[0167] In one embodiment, A is one R 1 C3 to C substituted by 20 It is a cycloalkyl group.

[0168] In one embodiment, A is

[0169] [ka] is.

[0170] In one embodiment, R 1 are independently halogen, -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR1-6 )R 1-7 or optionally one, two or three R 1-8 C3 to C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 , -S(=O)2NR 1-3-7 R 1-3-8 , -C(=O)NR 1-3-9 R 1-3-10 or optionally one, two or three R 1-3-11 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-3-1 , R 1-3-2 independently optionally one or two R 1-3-1-1 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl group or C6-C 10 is an aryl group, and R 1-3-1-1 are independently a C1 to C7 alkyl group, R 1-3-3 are independently hydrogen, R 1-3-5 , R 1-3-6 , R 1-3-7 , R 1-3-8 , R 1-3-9 , R 1-3-10 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-11are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-3-11-1 is an amino group substituted by R 1-3-11-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-5 are independently hydrogen, -NR 1-5-1 R 1-5-2 , -OR 1-5-3 or optionally one, two or three R 1-5-4 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, R 1-5-3 are independently hydrogen, C1-C7 alkyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-4 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-5-4-1 is an amino group substituted by R 1-5-4-1are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-6 are independently hydrogen, -CN, or -OH, R 1-7 are independently hydrogen, -NR 1-7-2 R 1-7-3 and R 1-7-2 , R 1-7-3 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, Or R 1-7-2 , R 1-7-3 and the nitrogen atom connected thereto are both optionally one, two or three R 1-7-2-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently replaced by an oxygen atom or a sulfur atom, and R 1-7-2-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-8 are independently halogen, -OH, amino group, mercapto group, cyano group, C1-C7 alkyl group, C1-C7 alkoxy group, C1-C7 alkylthio group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-8-1 is an amino group substituted by R 1-8-1 are independently a C1 to C7 alkyl group or a C3 to C 14 It is a cycloalkyl group.

[0171] In one embodiment, R 1 are independently a cyano group, a halogen, or -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7, C1 to C7 heteroaryl group or C3 to C 14 It is a heterocycloalkyl group.

[0172] In one embodiment, R 1 is independently -NR 1-3 R 1-4 , -C(=O)R 1-5 Or C3~C 14 It is a heterocycloalkyl group.

[0173] In one embodiment, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 or a C1 to C7 alkyl group, and R 1-3-1 are independently a C1 to C7 alkyl group.

[0174] In one embodiment, R 1-5 is independently -NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 are independently hydrogen or a C1 to C7 alkyl group.

[0175] In one embodiment, R 1-5 is independently -NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 is hydrogen.

[0176] In one embodiment, R 2optionally one, two or three R 2-2 C2-C7 alkyl groups, C3-C 14 Cycloalkyl group or C3-C 14 is a heterocycloalkyl group, R 2-2 are independently a halogen or a hydroxy group.

[0177] In one embodiment, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a halogen or a hydroxy group.

[0178] In one embodiment, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a hydroxy group.

[0179] In one embodiment, R 2 teeth

[0180] [ka] is.

[0181] In one embodiment, A is one or two R 1 replaced by

[0182] [ka] and R 1 are independently halogen, -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7or optionally one, two or three R 1-8 C3 to C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 , -C(=O)R 1-3-2 , -C(=NR 1-3-3 )NR 1-3-5 R 1-3-6 , -S(=O)2NR 1-3-7 R 1-3-8 , -C(=O)NR 1-3-9 R 1-3-10 or optionally one, two or three R 1-3-11 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-3-1 , R 1-3-2 independently optionally one or two R 1-3-1-1 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl group or C6-C 10 is an aryl group, and R 1-3-1-1 are independently a C1 to C7 alkyl group, R 1-3-3 are independently hydrogen, R 1-3-5 , R 1-3-6 , R 1-3-7 , R 1-3-8 , R 1-3-9 , R 1-3-10 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-3-11are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-3-11-1 is an amino group substituted by R 1-3-11-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-5 are independently hydrogen, -NR 1-5-1 R 1-5-2 , -OR 1-5-3 or optionally one, two or three R 1-5-4 C1-C7 alkyl groups, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, R 1-5-3 are independently hydrogen, C1-C7 alkyl group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group or a C1-C7 heteroaryl group, R 1-5-4 are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, a C1-C7 alkyl group, a C1-C7 alkoxy group, a C1-C7 alkylthio group, a C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 an aryl group, a C1-C7 heteroaryl group, or one or two R 1-5-4-1 is an amino group substituted by R 1-5-4-1are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-6 are independently hydrogen, -CN, or -OH, R 1-7 are independently hydrogen, -NR 1-7-2 R 1-7-3 and R 1-7-2 , R 1-7-3 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, Or R 1-7-2 , R 1-7-3 and the nitrogen atom connected thereto are both optionally one, two or three R 1-7-2-1 C3 to C substituted by 14 Forming a heterocycloalkyl group, 14 One or more methylene groups in the heterocycloalkyl group are optionally independently replaced by an oxygen atom or a sulfur atom, and R 1-7-2-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 1-8 are independently halogen, -OH, amino group, mercapto group, cyano group, C1-C7 alkyl group, C1-C7 alkoxy group, C1-C7 alkylthio group, C3-C 14 Cycloalkyl groups, C3-C 14 Heterocycloalkyl groups, C6-C 10 Aryl groups, C1~ C7 heteroaryl group or one or two R 1-8-1 is an amino group substituted by R 1-8-1 are independently a C1 to C7 alkyl group or a C3 to C 14 is a cycloalkyl group, R 2 optionally one, two or three R 2-2 C2-C7 alkyl groups, C3-C 14 Cycloalkyl group or C3-C 14 is a heterocycloalkyl group, R 2-2are independently a halogen or a hydroxy group; In any of the above cases, the above C3 to C 14 The heteroatoms in the heterocycloalkyl group and the C1-C7 heteroaryl group are independently selected from one or more of boron, silicon, oxygen, sulfur, serine, nitrogen, and phosphorus, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0183] In one embodiment, A is one or two R 1 C3 to C substituted by 20 is a cycloalkyl group, R 1 are independently a cyano group, a halogen, or -NR 1-3 R 1-4 , -C(=O)R 1-5 , -C(=NR 1-6 )R 1-7 , C1 to C7 heteroaryl group or C3 to C 14 is a heterocycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 or a C1 to C7 alkyl group, and R 1-3-1 are independently a C1 to C7 alkyl group, R 1-5 is independently -NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 are independently hydrogen or a C1 to C7 alkyl group, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a halogen or a hydroxy group.

[0184] In one embodiment, A is one R 1 C3 to C substituted by 20 is a cycloalkyl group, R 1 Ha-NR 1-3 R 1-4 , -C(=O)R 1-5 Or C3~C 14 is a heterocycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 or a C1 to C7 alkyl group, and R 1-3-1 are independently a C1 to C7 alkyl group, R 1-5 Ha-NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 is hydrogen or a C1-C7 alkyl group, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a hydroxy group.

[0185] In one embodiment, A is one R 1 C3 to C substituted by 20 is a cycloalkyl group, R 1 Ha-NR 1-3 R 1-4 , -C(=O)R 1-5 Or C3~C 14 is a heterocycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 or a C1 to C7 alkyl group, and R 1-3-1 are independently a C1 to C7 alkyl group, R 1-5 Ha-NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 is hydrogen, R 2 is one R 2-2 a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a hydroxy group.

[0186] In one embodiment, A is

[0187] [ka] and R 1 Ha-NR 1-3 R 1-4 , -C(=O)R 1-5 Or C3~C 14 is a heterocycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 or a C1 to C7 alkyl group, and R 1-3-1 are independently a C1 to C7 alkyl group, R 1-5 Ha-NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 is hydrogen or a C1-C7 alkyl group, R 2 is one R 2-2a C2 to C7 alkyl group or a C3 to C 14 is a heterocycloalkyl group, and R 2-2 is a hydroxy group.

[0188] In one embodiment, A is

[0189] [ka] and R 1 Ha-NR 1-3 R 1-4 , -C(=O)R 1-5 Or C3~C 14 is a heterocycloalkyl group, R 1-3 , R 1-4 are independently hydrogen, -S(=O)R 1-3-1 or a C1 to C7 alkyl group, and R 1-3-1 are independently a C1 to C7 alkyl group, R 1-5 Ha-NR 1-5-1 R 1-5-2 , -OR 1-5-3 Or C3~C 14 is a heterocycloalkyl group, and R 1-5-1 , R 1-5-2 are independently hydrogen, a C1 to C7 alkyl group, or a C3 to C 14 is a cycloalkyl group, and R 1-5-3 is hydrogen or a C1-C7 alkyl group, R 2 teeth

[0190] [ka] is.

[0191] In one embodiment, the pyrazolone-fused pyrimidine compound of formula II is The pyrazolone-fused pyrimidine compound of formula II, which is a salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof, is any of the following compounds:

[0192] [ka] TIFF0007789567000060.tif80170

[0193] In one aspect, the pyrazolone-fused pyrimidine compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof, is any of the following compounds:

[0194] [ka] 1 H NMR(400MHz,MeOD)δ 8.85(s,1H),8.00(t,J=7.9Hz,1H),7.80(d,J=8.1Hz,1H),7.68(d,J=7.7Hz,1H),7. 62(d,J=8.6Hz,2H),7.28(d,J=8.6Hz,2H),5.78-5.68(m,1H),5.06(d,J=10.3Hz,1H) ,4.95(s,1H),4.82(s,2H),3.82-3.76(m,1H),2.81(s,1H),2.71(s,3H),2.49(s,1H) ,2.08(d,J=10.9Hz,3H),1.94(d,J=15.0Hz,3H),1.72(s,4H),1.59(d,J=7.0Hz,6H).

[0195] [ka] 11H NMR (400 MHz, CDCl3) δ 8.87 (d, J = 2.1 Hz, 1H), 7.91 (td, J = 7.9, 1.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.9 Hz, 2H), 7.39 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 5.72 (ddt, J = 16.4, 10.2, 6.2 Hz, 1H), 5.07 (dd, J = 10.2, 1.1 Hz, 1H), 4.96 (dd, J = 17.1, 1.2 Hz, 1H), 4.77 (d, J = 6.2 Hz, 2H), 4.25 - 4.10 (m, 2H), 3.95 (s, 1H), 2.73 (s, 1H), 2.56 (dt, J = 15.5, 10.8 Hz, 1H), 2.28 (d, J = 7.9 Hz, 1H), 2.14 (d, J = 10.6 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.78 (dd, J = 19.0, 8.5 Hz, 1H), 1.67 (dt, J = 10.1, 6.1 Hz, 3H), 1.61 (s, 6H), 1.59 - 1.44 (m, 1H), and from 1.34 to 1.26 (m, 3H).

[0196]

Chem.

[0197]

Chem.

[0198]

Chem.

[0199]

Chem.

[0200]

Chem.

[0202]

Chem.

[0203]

Chem.

[0204]

Chem.

[0205]

Chem.

[0206]

Chem.

[0207]

Chem.

[0208]

Chem.

[0209]

Chem.

[0210]

Chem.

[0211]

Chem.

[0212]

Chem.

[0213] In one aspect, the pyrazolone-fused pyrimidine compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof, is any of the following compounds:

[0214] [ka] TIFF0007789567000081.tif75170

[0215] In one aspect, the pyrazolone-fused pyrimidine compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof, is any of the following compounds:

[0216] [ka] 1 H NMR(400MHz,MeOD)δ 8.85(s,1H),8.46(s,2H),7.99(t,J=7.9Hz,1H),7.79(d,J=8.0Hz,1H),7.65(dd,J=16.6 ,8.1Hz,3H),7.22(d,J=8.6Hz,2H),5.73(ddt,J=16.3,10.2,6.1Hz,1H),5.05(dd,J=10. 3,1.1Hz,1H),4.93(dd,J=17.1,1.3Hz,1H),4.82(d,J=6.1Hz,2H),2.90(s,6H),2.60(d, J=8.4Hz,1H),2.21(s,2H),2.10(d,J=10.6Hz,2H),1.70(d,J=11.4Hz,4H),1.59(s,6H).

[0217] [ka] 11H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.54 (s, 1H), 7.95 (t, J = 7.9 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 5.72 (ddt, J = 16.5, 10.3, 6.2 Hz, 1H), 5.06 (d, J = 10.2 Hz, 1H), 4.95 (dd, J = 17.1, 1.0 Hz, 1H), 4.75 (d, J = 6.1 Hz, 2H), 3.05 (m, 1H), 2.93 (m, 1H), 2.68 (s, 6H), 2.32 (m, 2H), 1.84 (m, 6H), 1.60 (s, 6H).

[0218]

Chem.

[0220]

Chem.

[0221]

Chem.

[0222]

Chem.

[0223]

Chem.

[0224]

Chem.

[0225]

Chem.

[0226]

Chem.

[0227]

Chem.

[0228] [ka] is an uncertain cis-trans configuration.

[0229] In one aspect, the pyrazolone-fused pyrimidine compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof, is any of the following compounds:

[0230] [ka] the 1 H NMR (400 MHz, CDCl3) shows peaks at 1.23-1.08. During the ceremony,

[0231] [ka] is an uncertain cis-trans configuration.

[0232] In one aspect, the pyrazolone-fused pyrimidine compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof, is any of the following compounds: Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 50% mobile phase B. Under these conditions, a retention time of 10.55 minutes was obtained.

[0233] [ka] is. Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 50% mobile phase B. Under these conditions, a retention time of 10.78 minutes was obtained.

[0234] [ka] is. Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 50% mobile phase B. Under these conditions, a retention time of 11.01 minutes was obtained.

[0235] [ka] is. Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 50% mobile phase B. Under these conditions, the retention time was 11.20 minutes.

[0236] [ka] is. Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 50% mobile phase B. Under these conditions, a retention time of 10.78 minutes was obtained.

[0237] [ka] is. Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 50% mobile phase B. Under these conditions, the retention time was 11.0 minutes.

[0238] [ka] is. Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 95% mobile phase B. Under these conditions, a retention time of 7.02 minutes was obtained.

[0239] [ka] is. Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 95% mobile phase B. Under these conditions, a retention time of 7.16 minutes was obtained.

[0240] [ka] is. Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 95% mobile phase B. Under these conditions, a retention time of 7.14 minutes was obtained.

[0241] [ka] is. Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 95% mobile phase B. Under these conditions, a retention time of 7.15 minutes was obtained.

[0242] [ka] is. Using an Agilent 1260 high performance liquid chromatograph, mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column transit time was 15 minutes, the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, and the gradient elution was 5% mobile phase B → 95% mobile phase B. Under these conditions, a retention time of 6.17 minutes was obtained.

[0243] [ka] is. The Agilent 1260 high-performance liquid chromatograph was used, with mobile phase A being water (0.1% formic acid), mobile phase B being acetonitrile, the column transit time being 15 minutes, and the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm, with 5% mobile phase B. → Gradient elution of 95% mobile phase B. Under the above conditions, the retention time was 6.28 minutes.

[0244] [ka] is. During the ceremony,

[0245] [ka] is an uncertain cis-trans configuration.

[0246] In one aspect, the pyrazolone-fused pyrimidine compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof, is any of the following compounds:

[0247] [ka]

[0248] The present invention further provides a method for producing the compound II, which is any one of the following methods: Method 1 includes step 1 in which compound II-1A is oxidized with an oxidizing agent in an organic solvent to obtain compound II-1B, and step 2 in which compound II-1B and compound II-1C are reacted in an organic solvent under basic conditions to obtain compound II.

[0249] [ka] Method 2, comprising: 1 is hydrolyzed to give compound II-2B (R 1 Step 1 is to obtain -(C=O)-OH), and step 2 is to obtain compound II (R 1 -(C=O)-NR 1-5-1 R 1-5-2 2. obtaining a

[0250] [ka]

[0251] The reaction conditions and steps described in Method 1 may be conventional in the art. In the present invention, the following reaction conditions are particularly preferred: In step 1, the organic solvent is preferably one or more of methanol, dichloromethane, acetonitrile, toluene, and DMF, more preferably dichloromethane or toluene, the oxidizing agent may be an oxidizing agent commonly used in the art for oxidizing thioethers to sulfoxides, preferably metachloroperbenzoic acid (mCPBA), the molar ratio of compound II-1A to mCPBA is preferably 1:(1-1.2), the reaction time is preferably 1-12 hours, and the reaction temperature is preferably 0-35°C.

[0252] In step 2, the organic solvent is preferably dichloromethane or toluene, the basic condition is preferably an organic base, for example, N,N-diisopropylethylamine (DIPEA) or triethylamine, more preferably N,N-diisopropylethylamine (DIPEA), the molar ratio of compound II-1B, compound II-1C, and DIPEA is preferably 1:1:2, the reaction time is preferably 0 to 12 hours, and the reaction temperature is preferably 0 to 35°C.

[0253] The reaction conditions and steps described in Method 2 may be conventional in the art. In the present invention, the following reaction conditions are particularly preferred: In Step 1, the reaction conditions for the hydrolysis may be any suitable reaction conditions commonly used in the art, such as base hydrolysis or acid hydrolysis, and the base hydrolysis may be, for example, hydrolysis with sodium hydroxide or hydrolysis with lithium hydroxide.

[0254] In step 2, the amine compound may be a primary amine or a secondary amine, the organic solvent is preferably dichloromethane or DMF, and the condensation reaction conditions may be any suitable reaction conditions commonly used in the art, such as EDCI / HOBT / DIPEA or HATU / DIPEA.

[0255] The present invention further provides a compound of formula II-1C:

[0256] [ka] In the formula, X is CH or N, and A is defined as above.

[0257] In one aspect, the compound of formula II-1C can be any of the following compounds:

[0258] [ka]

[0259] In one aspect, the compound of formula II-1C can be any of the following compounds:

[0260] [ka] 1H NMR(400MHz,CDCl3)δ 7.08-6.96(m,2H),6.70-6.60(m,2H),3.57(s,2H),3.22(t,J=7.0Hz,4H),2.38(tt,J=12. 1,3.2Hz,1H),2.15-1.95(m,5H),1.95-1.81(m,4H),1.51-1.30(m,2H),1.21-1.04(m,2H). Or,

[0261] [ka] 1 H NMR(400MHz,MeOD)δ 7.10-6.97(m,2H),6.74-6.63(m,2H),4.22-4.08(t,J=8.0Hz,4H),3.47 -3.38(m,1H),2.61-2.52(m,1H),2.52-2.28(m,2H),1.92-1.62(m,8H).

[0262] The present invention further provides a method for preparing the compound represented by formula II-1C, which is any of the following methods: In Method A, in Step 1, compound II-1C1 is subjected to N-protection of the amino group under basic conditions in an organic solvent to give compound II-1C2. In Step 2, compound II-1C4 is obtained by Suzuki-Miyaura coupling of compound II-1C2 and compound II-1C3. In Step 3, compound II-1C5 is obtained by removing the ketal from compound II-1C4. In Step 4, compound II-1C6 is obtained by reductive amination of compound II-1C5. In Step 5, compound II-1C6 is obtained by simultaneously removing the amino-protecting group PG and reducing the double bond using a reducing agent to give compound II-1C.

[0263] [ka] where PG is an amino protecting group and R 1 Ha-NR 1-3 R 1-4 and R 1-3 and R 1-4The definition is as described above. Method B includes step 1 of obtaining compound II-1C3' from compound II-1C' and compound II-1C2' by Suzuki-Miyaura coupling, and step 2 of obtaining compound II-1C by reduction of compound II-1C3'.

[0264] [ka] In the formula, R 1 is -C(=O)R 1-5 and R 1-5 The definition is as described above. Method C: Compound II-1C1″ (Ring A is an oxygen-substituted C4-C6 cycloalkyl group) is subjected to reductive amination to give Compound II-1C2″ (R 1 Ha-NR 1-3 R 1-4 ) and Buchwald-Hartwig amination of compound II-1C2'' with benzophenone imine to give compound II-1C3'' (R 1 Ha-NR 1-3 R 1-4 ), and step 3, which involves removing the diphenyl group from compound II-1C3″ to obtain compound II-1C.

[0265] [ka] In the formula, A and R 1-3 and R 1-4 The definition is as described above.

[0266] The reaction conditions and steps described in Method A may be conventional in the art. In the present invention, the following reaction conditions are particularly preferred: In step 1, the amino-protecting group PG may be any suitable amino-protecting group commonly used in the art, preferably Cbz, and its purpose is to protect compound II-1C1 so that some of its reactive groups (e.g., amino groups) do not participate in the reaction during the reaction. Compound II-1C1 is preferably bromide or iodide.

[0267] In step 2, the Suzuki-Miyaura coupling conditions may be any suitable reaction conditions commonly used in the art, preferably Pd(PhP) or Pd(dppf)Cl, potassium carbonate, 1,2-dimethoxyethane, or dioxane.

[0268] In step 3, the ketal removal conditions may be any suitable reaction conditions commonly used in this field, and the removal is preferably carried out using hydrochloric acid, and the reaction temperature is preferably 50 to 100°C.

[0269] In step 4, the reaction conditions for the reductive amination may be any suitable reaction conditions commonly used in the art, and the reducing agent is preferably sodium triacetoxyborohydride.

[0270] In step 5, the conditions for removing the amino-protecting group PG and simultaneously reducing the double bond using a reducing agent may be those commonly used in the art. The amino-protecting group PG is, for example, a benzyl group or Cbz, preferably Cbz. The reducing agent is preferably palladium carbon / hydrogen gas.

[0271] The reaction conditions and steps described in Method B may be conventional in the art. In the present invention, the following reaction conditions are particularly preferred: In Step 1, the Suzuki-Miyaura coupling conditions may be any suitable reaction conditions commonly used in the art, preferably Pd(PhP) or Pd(dppf)Cl, potassium carbonate, 1,2-dimethoxyethane, or dioxane.

[0272] In step 2, the reductive conditions may be any suitable reaction conditions commonly used in the art that can reduce a nitro group and a double bond, such as palladium on carbon / hydrogen gas, palladium on carbon / ammonium formate, or palladium on carbon / hydrazine hydrate.

[0273] The reaction conditions and steps described in Method C may be conventional in the art. In the present invention, the following reaction conditions are particularly preferred: In step 1, the reaction conditions for the reductive amination may be any suitable reaction conditions commonly used in the art. The reaction conditions are appropriate, and the reducing agent is preferably sodium triacetoxyborohydride.

[0274] In step 2, the Buchwald-Hartwig amination conditions may be any suitable reaction conditions commonly used in the art, and the Buchwald-Hartwig amination conditions are preferably Pd2(dba)3 / sodium tert-butoxide / Binap.

[0275] In step 3, the reaction conditions for removing the diphenyl group may be any suitable reaction conditions commonly used in the art, and the reaction conditions are preferably sodium acetate / hydroxylamine hydrochloride.

[0276] The present invention further provides a method for producing Compound I, which is any of the following methods: Method 1 includes step 1 of oxidizing compound 1A with an oxidizing agent in an organic solvent to obtain compound 1B, and step 2 of reacting compound 1B with compound 1C in an organic solvent under basic conditions to obtain compound I.

[0277] [ka] Method 2, comprising: 1 is obtained by hydrolysis of -(C=O)-O-C2H5) to give compound 2B (R 1Step 1 is to obtain compound I (R 1 -(C=O)-NR 1-5-1 R 1-5-2 2. obtaining a

[0278] [ka]

[0279] The reaction conditions and steps described in Method 1 may be conventional in the art. In the present invention, the following reaction conditions are particularly preferred: In step 1, the organic solvent is preferably one or more of methanol, dichloromethane, acetonitrile, toluene, and DMF, more preferably dichloromethane or toluene, the oxidizing agent may be an oxidizing agent commonly used in the art for oxidizing thioethers to sulfoxides, preferably metachloroperbenzoic acid (mCPBA), the molar ratio of compound 1A to mCPBA is preferably 1:(1-1.2), the reaction time is preferably 1-12 hours, and the reaction temperature is preferably 0-35°C.

[0280] In step 2, the organic solvent is preferably dichloromethane or toluene, the basic condition is preferably an organic base, for example, N,N-diisopropylethylamine (DIPEA) or triethylamine, more preferably N,N-diisopropylethylamine (DIPEA), the molar ratio of compound 1B, compound 1C, and DIPEA is preferably 1:1:2, the reaction time is preferably 0 to 12 hours, and the reaction temperature is preferably 0 to 35°C.

[0281] The reaction conditions and steps described in Method 2 may be conventional in the art. In the present invention, the following reaction conditions are particularly preferred: In Step 1, the reaction conditions for the hydrolysis may be any suitable reaction conditions commonly used in the art, such as base hydrolysis or acid hydrolysis, and the base hydrolysis may be, for example, hydrolysis with sodium hydroxide or hydrolysis with lithium hydroxide.

[0282] In step 2, the amine compound may be a primary amine or a secondary amine, the organic solvent is preferably dichloromethane or DMF, and the condensation reaction conditions may be any suitable reaction conditions commonly used in the art, such as EDCI / HOBT / DIPEA or HATU / DIPEA.

[0283] The present invention further provides compounds of formula 1C:

[0284] [ka] In the formula, A is one R 1 C3 to C substituted by 20 is a cycloalkyl group, and R 1 Ha-NR 1-3 R 1-4 or -C(=O)R 1-5 and R 1-3 , R 1-4 and R 1-5 The definition is as described above.

[0285] In one aspect, the compound of formula 1C may be any of the following compounds:

[0286] [ka]

[0287] In one aspect, the compound of formula 1C may be any of the following compounds:

[0288] [ka] 1H NMR(400MHz,CDCl3)δ 7.08-6.96(m,2H),6.70-6.60(m,2H),3.57(s,2H),3.22(t,J=7.0Hz,4H),2.38(tt,J=12. 1,3.2Hz,1H),2.15-1.95(m,5H),1.95-1.81(m,4H),1.51-1.30(m,2H),1.21-1.04(m,2H). Or,

[0289] [ka] 1 H NMR(400MHz,MeOD)δ 7.10-6.97(m,2H),6.74-6.63(m,2H),4.22-4.08(t,J=8.0Hz,4H),3.47 -3.38(m,1H),2.61-2.52(m,1H),2.52-2.28(m,2H),1.92-1.62(m,8H).

[0290] The present invention further provides a method for preparing the compound represented by formula 1C, which is any of the following methods: In Method A, in Step 1, compound 1C1 is subjected to N-protection of the amino group under basic conditions in an organic solvent to obtain compound 1C2. In Step 2, compound 1C4 is obtained by Suzuki-Miyaura coupling of compound 1C2 and compound 1C3. In Step 3, compound 1C5 is obtained by removing the ketal from compound 1C4. In Step 4, compound 1C6 is obtained by reductive amination of compound 1C5. In Step 5, compound 1C6 is obtained by removing the amino-protecting group PG from compound 1C6 using a reducing agent, while simultaneously reducing the double bond to obtain compound 1C.

[0291] [ka] where PG is an amino protecting group and R 1 Ha-NR 1-3 R 1-4 and R 1-3 sum R 1-4 The definition is as described above. Method B: Compound 1C' and Compound 1C2' are reacted by Suzuki-Miyaura coupling to give The method includes step 1 of obtaining compound 1C3' and step 2 of obtaining compound 1C by reduction of compound 1C3'.

[0292] [ka] In the formula, R 1 is -C(=O)R 1-5 and R 1-5 The definition is as described above. Method C: Compound 1C2″ (R 1 Ha-NR 1-3 R 1-4 ) and Buchwald-Hartwig amination of compound 1C2'' with benzophenone imine to give compound 1C3'' (R 1 Ha-NR 1-3 R 1-4 ), and step 3, which removes the diphenyl group from compound 1C3″ to obtain compound 1C.

[0293] [ka] In the formula, A and R 1-3 and R 1-4 The definition is as described above.

[0294] The reaction conditions and steps described in Method A may be conventional in the art. In the present invention, the following reaction conditions are particularly preferred: In step 1, the amino-protecting group PG may be any suitable amino-protecting group commonly used in the art, preferably Cbz, and the purpose is to protect compound 1C1 so that some of its reactive groups (e.g., amino groups) do not participate in the reaction during the reaction. Compound 1C1 is preferably bromide or iodide.

[0295] In step 2, the Suzuki-Miyaura coupling conditions may be any suitable reaction conditions commonly used in the art, preferably Pd(PhP) or Pd(dppf)Cl, potassium carbonate, 1,2-dimethoxyethane, or dioxane.

[0296] In step 3, the ketal removal conditions may be any suitable reaction conditions commonly used in this field, and the removal is preferably performed using hydrochloric acid, and the reaction temperature is preferably 50 to 100°C. It's nice.

[0297] In step 4, the reaction conditions for the reductive amination may be any suitable reaction conditions commonly used in the art, and the reducing agent is preferably sodium triacetoxyborohydride.

[0298] In step 5, the conditions for removing the amino-protecting group PG and simultaneously reducing the double bond using a reducing agent may be those commonly used in the art. The amino-protecting group PG is, for example, a benzyl group or Cbz, preferably Cbz. The reducing agent is preferably palladium carbon / hydrogen gas.

[0299] The reaction conditions and steps described in Method B may be conventional in the art. In the present invention, the following reaction conditions are particularly preferred: In Step 1, the Suzuki-Miyaura coupling conditions may be any suitable reaction conditions commonly used in the art, preferably Pd(PhP) or Pd(dppf)Cl, potassium carbonate, 1,2-dimethoxyethane, or dioxane.

[0300] In step 2, the reductive conditions may be any suitable reaction conditions commonly used in the art that can reduce a nitro group and a double bond, such as palladium on carbon / hydrogen gas, palladium on carbon / ammonium formate, or palladium on carbon / hydrazine hydrate.

[0301] The reaction conditions and steps described in Method C may be conventional in the art. In the present invention, the following reaction conditions are particularly preferred: In step 1, the reaction conditions for the reductive amination may be any suitable reaction conditions commonly used in the art, and the reducing agent is preferably sodium triacetoxyborohydride.

[0302] In step 2, the Buchwald-Hartwig amination conditions may be any suitable reaction conditions commonly used in the art, and the Buchwald-Hartwig amination conditions are preferably Pd2(dba)3 / sodium tert-butoxide / Binap.

[0303] In step 3, the reaction conditions for removing the diphenyl group may be any suitable reaction conditions commonly used in the art, and the reaction conditions are preferably sodium acetate / hydroxylamine hydrochloride.

[0304] The present invention further provides the use of substance X for the manufacture of a kinase (eg, WEE1 kinase) inhibitor. The substance X is a pyrazolone-fused pyrimidine compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof.

[0305] The present invention further provides the use of substance X for the manufacture of a medicament. The substance X is a pyrazolone-fused pyrimidine compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof.

[0306] The present invention further provides the use of substance X for the manufacture of a medicament, said medicament being used for treating and / or preventing diseases associated with WEE1 kinase. The substance X is a pyrazolone-fused pyrimidine compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof.

[0307] The disease associated with WEE1 kinase is, for example, cancer, such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, gastric cancer, gallbladder bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis and ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, nephroblastoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, or Hodgkin's lymphoma, or such as breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, or Hodgkin's lymphoma, or such as colon cancer or ovarian cancer.

[0308] The present invention further provides the use of substance X for the manufacture of a medicament, said medicament being used for treating and / or preventing cancer. The substance X is a pyrazolone-fused pyrimidine compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof.

[0309] Examples of the cancer include brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, stomach cancer, gallbladder bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis and ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, nephroblastoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and Hodgkin's lymphoma. Examples of the cancer include breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and Hodgkin's lymphoma. Examples of the cancer include colon cancer and ovarian cancer.

[0310] The present invention further provides a method for treating and / or preventing a disease associated with WEE1 kinase, which comprises administering a therapeutically effective amount of substance X to a patient. The substance X is a pyrazolone-fused pyrimidine compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof.

[0311] The disease associated with WEE1 kinase is, for example, cancer, such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, gastric cancer, gallbladder bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis and ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, nephroblastoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, or Hodgkin's lymphoma, or such as breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, or Hodgkin's lymphoma, or such as colon cancer or ovarian cancer.

[0312] The present invention further provides a method for treating and / or preventing cancer, comprising administering to a patient a therapeutically effective amount of substance X. The substance X is a pyrazolone-fused pyrimidine compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof.

[0313] The cancers include, for example, brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, stomach cancer, gallbladder bile duct cancer, liver cancer, pancreatic cancer, colon cancer, and rectal cancer. cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis and ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, nephroblastoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, or Hodgkin's lymphoma, and also, for example, breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, and further, for example, colon cancer or ovarian cancer.

[0314] The present invention further provides a pharmaceutical composition comprising substance X and excipient(s). The substance X is a pyrazolone-fused pyrimidine compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof.

[0315] The present invention further provides a combination comprising substance X and an anti-cancer drug. The substance X is a pyrazolone-fused pyrimidine compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable solvate of a salt thereof, a metabolite thereof, or a prodrug thereof.

[0316] The anticancer drug may be a conventional anticancer drug in the art (but is not the substance X), such as one or more of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer drugs, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxyurea, pentostatin, retinoic acid, alefacept, darbepoetin alfa, anastrozole, exemestane, bicalutamide, leuprorelin, flutamide, fulvestrant, pegaptanib sodium, denileukin diftitox 2, aldesleukin, thyroid-stimulating hormone α, arsenic trioxide, bortezomib, capecitabine, and goserelin, or may be an anticancer antimetabolite.

[0317] The anti-cancer alkylating agent may be any anti-cancer alkylating agent conventional in the art, such as one or more of nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, dibromomannitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, and carmustine.

[0318] The anticancer antimetabolite may be a conventional anticancer antimetabolite in the art, such as one or more of methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine sodium octadecyl phosphate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium, and also, for example, 5-fluorouracil.

[0319] The anti-cancer antibiotic may be any anti-cancer antibiotic commonly used in the art, such as one or more of actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus, and valrubicin.

[0320] The plant-derived anticancer agent may be a plant-derived anticancer agent commonly used in the art, such as one or more of vincristine, vinblastine, vindesine, rastedt, sobuzoxane, docetaxel, paclitaxel, and vinorelbine.

[0321] The anti-cancer platinum coordination compound can be any anti-cancer platinum coordination compound conventional in the art, such as one or more of cisplatin, carboplatin, nedaplatin, and oxaliplatin.

[0322] The anti-cancer camptothecin derivative may be a conventional anti-cancer camptothecin derivative in the art, such as one or more of irinotecan, topotecan, and camptothecin.

[0323] The anti-cancer tyrosine kinase inhibitor may be a conventional anti-cancer tyrosine kinase inhibitor in the art, such as one or more of gefitinib, imatinib, and erlotinib.

[0324] The monoclonal antibody may be any monoclonal antibody conventional in the art, such as one or more of cetuximab, bevacizumab, rituximab, alemtuzumab, and trastuzumab.

[0325] The interferon may be any interferon conventional in the art, such as one or more of interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a and interferon gamma-n1.

[0326] The biological response modifier may be a biological response modifier commonly used in the art, such as one or more of Coriolus versicolor polysaccharide, lentinan, schizofiran, picibanil, and ubenimex.

[0327] The components of the combination may be used simultaneously or separately (e.g., sequentially). When the components of the combination are used simultaneously, the components of the combination may be homogeneously mixed (i.e., a mixture of the components).

[0328] The components of the combination may be used simultaneously in a single pharmaceutical composition, or each component may be used as a separate pharmaceutical composition (e.g., in the form of a kit), and these separate pharmaceutical compositions may be used simultaneously or separately (e.g., sequentially).

[0329] The present invention further provides use of said combination for the manufacture of a medicament for preventing and / or treating cancer.

[0330] Examples of the cancer include brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, stomach cancer, gallbladder bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis and ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, nephroblastoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and Hodgkin's lymphoma. Examples of the cancer include breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and Hodgkin's lymphoma. Examples of the cancer include colon cancer and ovarian cancer.

[0331] In the use according to the present invention, the substance X and the anticancer drug may be administered simultaneously or separately (for example, sequentially).

[0332] The present invention further provides a method for treating cancer comprising administering to a patient a therapeutically effective amount of the combination. and / or methods for preventing the same.

[0333] The anti-cancer drug may be as described above.

[0334] Examples of the cancer include brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, stomach cancer, gallbladder bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis and ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, nephroblastoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and Hodgkin's lymphoma. Examples of the cancer include breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and Hodgkin's lymphoma. Examples of the cancer include colon cancer and ovarian cancer.

[0335] The present invention further provides the use of said substance X for producing a medicament, wherein said medicament is used for preventing and / or treating cancer in combination with an anti-cancer drug.

[0336] The anti-cancer drug may be as described above.

[0337] Examples of the cancer include brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, stomach cancer, gallbladder bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis and ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, nephroblastoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and Hodgkin's lymphoma. Examples of the cancer include breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and Hodgkin's lymphoma. Examples of the cancer include colon cancer and ovarian cancer.

[0338] In the use according to the present invention, the substance X and the anticancer drug may be administered simultaneously or separately (for example, sequentially).

[0339] The present invention further provides the use of an anti-cancer drug for producing a drug, which is used in combination with substance X to prevent and / or treat cancer.

[0340] The anti-cancer drug may be as described above.

[0341] Examples of the cancer include brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer, stomach cancer, gallbladder bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis and ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, nephroblastoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and Hodgkin's lymphoma. Examples of the cancer include breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and Hodgkin's lymphoma. Examples of the cancer include colon cancer and ovarian cancer.

[0342] In the use according to the present invention, the substance X and the anticancer drug may be administered simultaneously or separately (for example, sequentially).

[0343] The present invention further provides a pharmaceutical composition comprising the combination and excipient(s).

[0344] The pharmaceutical composition may consist of the combination and the excipient.

[0345] The present invention further provides a combination kit comprising Pharmaceutical Composition A and Pharmaceutical Composition B. said pharmaceutical composition A comprising said substance X and (one or more) pharmaceutical excipients; The pharmaceutical composition B contains an anticancer drug and (one or more) pharmaceutical excipients.

[0346] The anti-cancer drug may be as described above.

[0347] The combination kit may comprise the pharmaceutical composition A and the pharmaceutical composition B.

[0348] The pharmaceutical composition A may comprise a substance X and a pharmaceutical excipient; The pharmaceutical composition B may consist of an anticancer drug and a pharmaceutical additive.

[0349] Each pharmaceutical composition in the combination kit may be used simultaneously or separately (eg, sequentially).

[0350] Unless otherwise stated, the following terms appearing in the specification and claims of this invention have the following meanings. The term "pharmaceutically acceptable" means that the salts, solvents, additives, etc. are generally non-toxic, safe, and suitable for use in a patient. The "patient" is preferably a mammal, more preferably a human.

[0351] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, and diethanolamine salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in pure solution or in a suitable inert solvent. Pharmaceutically acceptable acids include inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including, but not limited to, acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base or acid addition salts.For more information, see Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science 66:1-19 (1977), and Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0352] The term "solvate" refers to a compound formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric solvent. The solvent molecules in a solvate may be arranged in an ordered or disordered manner. Examples of solvents include, but are not limited to, water, methanol, ethanol, etc.

[0353] As described above, the terms "solvate of a pharmaceutically acceptable salt" and "solvate" refer to a substance formed by combining (1) a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base, and (2) a compound of the present invention with a stoichiometric or non-stoichiometric solvent. The term "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of the compound of the present invention.

[0354] The terms "compound," "pharmaceutically acceptable salt," "solvate," or "solvate of a pharmaceutically acceptable salt" refer to compounds that exist in crystalline or amorphous form. The term "crystalline" refers to the regularity of the ions or molecules of an object being arranged in a precise, periodic manner in three-dimensional space in a defined form, and appearing periodically at regular intervals. The differences in this periodic arrangement give rise to multiple crystalline forms, or polymorphs. The term "amorphous" refers to a state in which the ions or molecules of an object are irregularly distributed, i.e., the ions or molecules are arranged non-periodically.

[0355] The terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" refer to compounds, when stereoisomers exist, that exist in the form of a single stereoisomer or a mixture thereof (e.g., a racemate). The term "stereoisomer" refers to a cis-trans isomer or an optical isomer. Such stereoisomers can be separated, purified, or enriched by asymmetric synthesis or chiral separation techniques (including, but not limited to, thin layer chromatography, rotational thin layer chromatography, column chromatography, gas chromatography, high performance liquid chromatography, etc.), or obtained by chiral resolution, such as by bonding (e.g., chemical bonding) or salt formation (e.g., physical bonding) with another chiral compound. The term "single stereoisomer" refers to a compound of the present invention in which the mass content of a particular stereoisomer relative to all stereoisomers of the compound is 95% or greater.

[0356] The terms "compound," "pharmaceutically acceptable salt," "solvate," or "solvate of a pharmaceutically acceptable salt" refer to compounds that, when present in tautomer form, exist in the form of a single tautomer or a mixture thereof, preferably in a form in which a stable tautomer predominates.

[0357] In the term "compound," "pharmaceutically acceptable salt," "solvate," or "solvate of a pharmaceutically acceptable salt," atoms may exist in natural abundance or non-natural abundance. For example, in the case of a hydrogen atom, the natural abundance is about 99.985% protium and about 0.015% deuterium, and the non-natural abundance is, for example, about 95% deuterium. In other words, in the term "compound," "pharmaceutically acceptable salt," "solvate," or "solvate of a pharmaceutically acceptable salt," one or more atoms may exist in non-natural abundance.

[0358] A specific variable (e.g., R 1-1-1) occurs more than once in a definition of a compound, the definition of that variable at each occurrence is independent of the definition at any other occurrence, and their meanings are independent of each other and do not influence each other. Thus, a particular group may be one, two or three groups R 1-1-1 By "substituted by" it is meant that the group is substituted by up to three R 1-1-1 By replacing by R at that position 1-1-1 The definition of R in other positions 1-1-1 The definitions of each are independent of each other. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0359] The term "optionally substituted" means that it may or may not be substituted.

[0360] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0361] The term "alkyl group" refers to a saturated, linear or branched, monovalent hydrocarbon group having from 1 to 12 carbon atoms (eg, a C1-C6 alkyl group, a C1-C4 alkyl group). Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, and 1-octyl.

[0362] The term "alkenyl group" refers to an alkenyl group having at least one site of unsaturation, i.e., carbon-carbon sp 2A linear or branched monovalent hydrocarbon group having a double bond and consisting of 2 to 12 carbon atoms (e.g., C2-C6 alkenyl, C2-C4 alkenyl), including groups having a "cis" or "trans" orientation or an "E" or "Z" orientation. Examples include, but are not limited to, ethenyl and allyl.

[0363] The term "alkynyl group" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms (e.g., a C2-C6 alkynyl group, a C2-C4 alkynyl group) containing at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Examples include, but are not limited to, ethynyl and propynyl groups.

[0364] The term "cycloalkyl group" refers to a saturated or partially unsaturated (containing one or two double bonds) non-aromatic cyclic hydrocarbon group having 3 to 20 carbon atoms (e.g., a C3-C6 cycloalkyl group), including monocyclic and polycyclic cycloalkyl groups. Cycloalkyl groups contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms.

[0365] Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 5-hexenyl, 1-cyclohexen-1-enyl, 1-cyclohexen-2-enyl, and 1-cyclohexen-3-enyl groups.

[0366] Polycyclic cycloalkyl groups are polycyclic (e.g., bicyclic, tricyclic) cycloalkyl structures, including spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. A "spirocyclic cycloalkyl group" is a polycyclic group in which 5- to 20-membered monocyclic rings share one carbon atom (referred to as a spiro atom), and may contain one or more double bonds, with no ring having a completely conjugated π-electron system. It preferably has 6 to 14 members, and more preferably 7 to 10 members. Based on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, and multispirocycloalkyl groups, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Examples of spirocycloalkyl groups include:

[0367] [ka] "Fused-ring cycloalkyl groups" include, but are not limited to, 5 to 20-membered all-carbon polycyclic groups in which each ring in the ring system shares an adjacent pair of carbon atoms with another ring in the ring system, and may contain one or more double bonds, with no ring having a completely conjugated π-electron system. Preferably, they are 6 to 14-membered, more preferably 7 to 10-membered. Based on the number of component rings, fused cycloalkyl groups are classified as bicyclic, tricyclic, tetracyclic, and polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, and more preferably 5-membered / 5-membered or 5-membered / 6-membered biscycloalkyl groups. Examples of fused cycloalkyl groups are:

[0368] [ka] The term "bridged ring cycloalkyl group" includes, but is not limited to, the following. A "bridged ring cycloalkyl group" is a 5-20 membered all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Based on the number of component rings, bridged cycloalkyl groups are classified as bicyclic, tricyclic, tetracyclic, and polycyclic, and are preferably bicyclic, tricyclic, and tetracyclic, and more preferably bicyclic and tricyclic. Examples of bridged cycloalkyl groups are:

[0369] [ka] Including, but not limited to:

[0370] The term "heterocycloalkyl" refers to a saturated carbocyclic group having 3 to 20 ring atoms, at least one of which is a heteroatom independently selected from boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and the remaining ring atoms are C. The group may be a carbon or heteroatom group (i.e., C- or N-attached, if present). Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thioxanyl, and piperazinyl. Fused ring moieties, spiro ring moieties, and bridged ring moieties are also included within the definition. For example, a group derived from tetrahydropyrrole may be tetrahydropyrrol-1-yl (N-attached) or tetrahydropyrrol-3-yl (C-attached). For example, a 3- to 7-membered monocyclic ring (consisting of 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, B, Si, S, and Se, in which N, B, P, or Se is optionally substituted with one or more oxygen atoms to form a group such as NO, BOH, PO, PO2, or SeO, in which N may be optionally quaternized). S atoms are optionally replaced by one or more oxygen or nitrogen atoms to form SO, SO2, S(=O)(=NR a ), S(=NR b ), S(=NR c )2 and R a , R b , R c are independently a cyano group, a C1-C7 alkyl group, a C3-C 14 Cycloalkyl groups, "C3-C alkyl groups in which the heteroatom is one or more of boron, silicon, oxygen, sulfur, serine, nitrogen, and phosphorus, and the number of heteroatoms is 1 to 4" 14 "Heterocycloalkyl group", "C1-C7 heteroaryl group in which the heteroatom is one or more of boron, silicon, oxygen, sulfur, serine, nitrogen and phosphorus and the number of heteroatoms is 1 to 4", C6-C 10 an aryl group or a C1-C7 alkoxy group, and the -CH2- group is optionally -C(=O)-, -C(=S)-, or -C(=NR d )-, and R d are independently a cyano group, a C1-C7 alkyl group, a C3-C 14 Cycloalkyl groups, "C3-C alkyl groups in which the heteroatom is one or more of boron, silicon, oxygen, sulfur, serine, nitrogen, and phosphorus, and the number of heteroatoms is 1 to 4" 14 "heterocycloalkyl group," "C1-C7 heteroaryl group having 1 to 4 heteroatoms, the heteroatom being one or more of boron, silicon, oxygen, sulfur, serine, nitrogen and phosphorus," "C6-C 10 The heterocyclic group is an aryl group or a C1-C7 alkoxy group. When the ring is three-membered, there is only one heteroatom), or a bicyclic ring consisting of 7 to 10 atoms (consisting of 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, B, Si, and S, where N, S, B, or P is optionally substituted with one or more oxygen atoms to form groups such as NO, BOH, SO, SO2, PO, PO2, and SeO, and the -CH2- group is optionally substituted with -C(=O)-). Depending on the structure, the heterocyclic group may be a monovalent group or a divalent group (i.e., a heterocyclylene group).

[0371] The term "aryl group" refers to any stable monocyclic or bicyclic carbon ring having up to 10 atoms in each ring, at least one of which is aromatic. Examples of such aryl units include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, and acenaphthyl. It is understood that when an aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, it is connected via an aromatic ring.

[0372] The term "heteroaryl group" refers to a stable monocyclic or bicyclic ring containing up to seven atoms in each ring, at least one of which is aromatic and contains from one to four heteroatoms selected from boron, silicon, oxygen, sulfur, serine, nitrogen, and phosphorus. Heteroaryl groups falling within this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and tetrahydroquinoline. A "heteroaryl group" may also be any N-oxide derivative of a nitrogen-containing heteroaryl group. When the heteroaryl substituent is a bicyclic substituent and one ring is non-aromatic or does not contain heteroatoms, it is understood that the respective connections are made via the aromatic ring. Aromatic and aromatic rings, and bicyclic heteroaromatic ring systems may be formed by fusion. N, S, B, P, or Se may optionally be replaced by one or more oxygen atoms to form groups such as NO, SO, SO2, BOH, PO, PO2, and SeO, and N atoms may be quaternized. Heteroaryl groups may be attached to the parent structure from any heteroatom or carbon atom to form a stable compound. Depending on the structure, heteroaryl groups may be monovalent or divalent (i.e., heteroarylene).

[0373] The term "alkoxy group" refers to an alkyl group connected through an oxygen bridge, said alkyl group being as defined above.

[0374] The term "alkylmercapto group" refers to an alkyl group connected via a sulfur bridge, said alkyl group being as defined above.

[0375] The term "uncertain cis-trans configuration" refers to either the cis or trans configuration.

[0376] The term "component" refers to each component of the combination of the present invention, i.e., Compound I (or Compound II), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or a prodrug thereof, or an anticancer drug.

[0377] The term "pharmaceutical excipients" refers to the excipients and additives used in the manufacture and formulation of pharmaceuticals, including all substances other than the active ingredients contained in drug formulations. Refer to the Chinese Pharmacopoeia (2015 Edition), Part 4, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0378] The term "treatment" refers to a therapeutic approach. When a specific condition is the subject of treatment, treatment can mean (1) alleviating one or more biological behaviors of a disease or condition, (2) interfering with (a) one or more points in the biological cascade that causes or contributes to the condition, or (b) one or more biological behaviors of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the disease or one or more biological behaviors of the condition.

[0379] The term "prevention" refers to reducing the risk of developing or contracting a disease or disorder.

[0380] The term "therapeutically effective amount" refers to the amount of compound administered to a patient sufficient to treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition, its severity, and the age of the patient being treated, and can be adjusted according to the needs of one skilled in the art.

[0381] The term "patient" refers to any animal, preferably a mammal, with humans being most preferred, that will receive or has received the compounds or compositions according to embodiments of the present invention. The term "mammal" includes any mammal, including, but not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being most preferred.

[0382] The term "active ingredient" refers to the active ingredient in the pharmaceutical composition or combination kit of the present invention, i.e., Compound I (or Compound II), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite or a prodrug thereof, an anticancer drug, or the above combinations formed by them.

[0383] Unless contrary to common knowledge in the art, any combination of the above-mentioned preferred conditions can be used to obtain preferred examples of the present invention.

[0384] All of the reagents and raw materials used in the present invention may be commercially available products.

[0385] The present invention has the following beneficial effects: The compounds according to the present invention have excellent inhibitory activity against WEE1 kinase and excellent bioavailability. DETAILED DESCRIPTION OF THE INVENTION

[0386] The present invention will be further explained below with reference to examples, but the present invention is not limited to the scope of these examples. In the following examples, the experimental methods for which conditions are not specified are carried out according to conventional methods and conditions, or are selected according to the product instructions.

[0387] The structures of all compounds in the present invention are determined by nuclear magnetic resonance ( 1 The identity can be determined by 1 H NMR and / or mass spectrometry (MS).

[0388] 1 In H NMR, the chemical shift (δ) is in ppm (10 -6 NMR is measured on a Bruker AVANCE-400 nuclear magnetic resonance spectrometer.

[0389] LC-MS is measured by a mass spectrometer Agilent 1200HPLC / 6120.

[0390] HPLC data were measured using an Agilent 1260 high-performance liquid chromatograph. The HPLC conditions were as follows: mobile phase A was water (0.1% formic acid), mobile phase B was acetonitrile, the column run time was 15 minutes, and the column format was a Waters Xselect, 5 μm, 4.6 × 250 mm.

[0391] The silica gel TLC plate is HSGF254 manufactured by Anhui Liangchen Silicon Material Co., Ltd. or GF254 silica gel plate manufactured by Qingdao Ocean Chemical Co., Ltd. In column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai is generally used as the carrier.

[0392] Example 1:

[0393] [ka]

[0394] Step 1: 4-Bromoaniline (I-1-a, 58.1 mmol) was dissolved in toluene (250 mL), and potassium carbonate (87.2 mmol) and benzyl chloride (87.2 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was washed with ethyl acetate to obtain the target compound, benzyl (4-bromophenyl)carbamate (I-1-b, 15.2 g, 85.4%). It was a gray solid. LC-MS: m / z: (M+H) + =307.0.

[0395] Step 2: Benzyl (4-bromophenyl)carbamate (16.0 mmol, I-1-b) in 1 The reaction mixture was dissolved in 1,2-dimethoxyethane (50 mL), and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane (I-1-c, 16.0 mmol), sodium carbonate (42.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.6 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100:0 to 95:5) to obtain the target compound, benzyl (4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)carbamate (I-1-d, 5.6 g, 94%). It was a white solid. LC-MS: m / z: (M+H) + =366.2.

[0396] Step 3: Benzyl (4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)carbamate (I-1-d, 15 mmol) was dissolved in tetrahydrofuran (15 mL). Hydrochloric acid (30.0 mL, 4N) was added to the reaction mixture, and the mixture was stirred at 50°C for 16 hours. The reaction mixture was adjusted to pH 9 using potassium carbonate, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude target compound, benzyl (4'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)carbamate (I-1-e, 4.0 g, 81%). The product was a yellow solid. LC-MS: m / z: (M+H) + =322.1.

[0397] Step 4: Benzyl (4'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)carbamate (I-1-e, 12.0 mmol) was dissolved in dichloromethane (25 mL), and dimethylamine hydrochloride (25.0 mmol) and diisopropylethylamine (25.0 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (37.0 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 9 with saturated potassium carbonate solution and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100:0 to 95:5) to obtain the target compound, benzyl (4'-(dimethylamino)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)carbamate (I-1-f, 3.5 g, 80%), as a yellow solid. LC-MS: m / z: (M+H) + =351.2.

[0398] Step 5: Benzyl (4'-(dimethylamino)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)carbamate (I-1-f, 10.0 mmol) was dissolved in methanol (20 mL), palladium on carbon (0.35 g) was added, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness to give the crude product. The crude product was washed with ethyl acetate and filtered. The filter cake was the target compound, 4-(4-(dimethylamino)cyclohexyl)aniline (I-1-g, 1.20 g, 55%). It was a white solid. LC-MS: m / z: (M+H) + =219.2.

[0399] Step 6: 2-(1,1-difluoroallyl)-1-(6-(2-hydroxypropan-2-yl) )pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Formula I-1-h, 150 mg, 0.42 mmol) was dissolved in toluene (20 mL), 3-chlorophenoxyformic acid (105 mg, 0.47 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated to dryness to give a sulfoxide intermediate, which was dissolved in dimethyl sulfoxide (10 mL), and 4-(4-methylpiperazin-1-yl)aniline (120 mg, 0.55 mmol) and trifluoroacetic acid (0.2 mL) were added. The reaction mixture was heated to 60° C. and stirred for 24 hours. The reaction mixture was adjusted to pH 9 using saturated sodium carbonate solution, and water (50 mL) and dichloromethane (50 mL) were added. The layers were separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by preparative liquid chromatography to give Compounds I-1-1 and I-1-2. Compound I-1-1: HPLC retention time (RT) = 10.55 minutes (HPLC conditions: gradient elution from 5% mobile phase B to 50% mobile phase B) The yield of the compound was 56% (110 mg). It was a white solid. 1H NMR(400MHz,MeOD)δ 8.85(s,1H),8.46(s,2H),7.99(t,J=7.9Hz,1H),7.79(d,J=8.0Hz,1H),7.65(dd,J=16.6 ,8.1Hz,3H),7.22(d,J=8.6Hz,2H),5.73(ddt,J=16.3,10.2,6.1Hz,1H),5.05(dd,J=10. 3,1.1Hz,1H),4.93(dd,J=17.1,1.3Hz,1H),4.82(d,J=6.1Hz,2H),2.90(s,6H),2.60(d, J=8.4Hz,1H),2.21(s,2H),2.10(d,J=10.6Hz,2H),1.70(d,J=11.4Hz,4H),1.59(s,6H). LC-MS:m / z:(M+H) + =528.3. Compound I-1-2: HPLC retention time (RT) = 10.78 minutes (HPLC conditions: 5% mobile phase B → 50% mobile phase B mixed elution), the compound yield is 72% (160 mg). White solid color. 1 H NMR(400MHz, CDCl3)δ 8.86(s,1H),8.54(s,1H),7.95(t,J=7.9Hz,1H),7.75(d,J=8.0Hz,1H),7.59(d,J= 8.5Hz,2H),7.43(d,J=7.6Hz,1H),7.32(d,J=8.5Hz,2H),5.72(ddt,J=16.5,10.3,6 .2Hz,1H),5.06(d,J=10.2Hz,1H),4.95(dd,J=17.1,1.0Hz,1H),4.75(d,J=6.1Hz, 2H),3.05(m,1H),2.93(m,1H),2.68(s,6H),2.32(m,2H),1.84(m,6H),1.60(s,6H). LC-MS:m / z:(M+H) + =528.3.

[0400] Example 3:

[0401]

change

[0402] [ka]

[0403] Step 1: To a solution of tert-butyl carbamate (4'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)carbamate (0.46 g, 1.6 mmol, I-8-c) and tetrahydropyrrole (0.28 g, 3.9 mmol) in 20 mL of dichloromethane, sodium triacetoxyborohydride (0.85 g, 4 mmol) was added and stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous sodium carbonate (20 mL), water (2 × 10 mL), and saturated brine. The organic phase was dried over anhydrous sodium sulfate, mixed with silica gel, and purified by column chromatography (7 M ammonia / methanol:(dichloromethane:ethyl acetate=12:2) = 0-15%) to give compound I-3-a as a white solid (200 mg). The yield was 40%. LC-MS: m / z: (M+H) + =343.

[0404] Step 2: (4'-(Pyrrolidin-1-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl) tert-butylcarbamate (300 mg, 0.87 mmol, I-3-a) and 10% palladium on carbon (100 mg) were added to 30 mL of methanol. The reaction flask was vented three times with a hydrogen balloon, and the reaction mixture was stirred overnight under a hydrogen atmosphere at room temperature. The reaction mixture was filtered and evaporated to dryness to give the crude product. Separation on a silica gel TLC plate (7 M ammonia-methanol:(dichloromethane:ethyl acetate)=9:3=1:12) afforded compound I-3-2-b, 70 mg (Rf=0.7), as a white solid. Compound I-3-1-b, 90 mg (Rf=0.5), as a white solid. The overall yield was 52%. LC-MS: m / z: (M+H) + =345.

[0405] Step 3: (4-(4-(pyrrolidinyl-1-yl)cyclohexyl)phenyl)tert-butyl The carboxylate (I-3-2-b, Rf = 0.7, 70 mg, 0.2 mmol) was added to 2 mL of dichloromethane, followed by 2 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a brown oil (I-3-2-c), which was used directly in the next step. LC-MS: m / z: (M+H) + =245.

[0406] (4-(4-(pyrrolidinyl-1-yl)cyclohexyl)phenyl) tert-butylcarbamate (I-3-1-b, Rf=0.5, 70 mg, 0.2 mmol) was added to 2 mL of dichloromethane, followed by 2 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a brown oil, which was used directly in the next step (I-3-1-c). LC-MS: m / z: (M+H) + =245.

[0407] Step 4: To a solution of 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (I-1-h, 90 mg, 0.25 mmol) in 10 mL of toluene was added metachloroperbenzoic acid (66 mg, 0.326 mmol), resulting in a solution that was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and 4-(4-(azetidin-1-yl)cyclohexyl)aniline trifluoroacetate (I-3-1-c, 0.26 mmol), 0.15 mL of trifluoroacetic acid, and 3 mL of dimethyl sulfoxide were added, followed by stirring at 60 °C overnight. The reaction mixture was added with 2 mL of saturated aqueous sodium carbonate and 10 mL of water, and extracted three times with dichloromethane (3 × 10 mL). The combined organic phases were washed with 5 mL of water and 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was separated by thin-layer chromatography (7 M ammonia-methanol:(dichloromethane:ethyl acetate=5:1)=1:12) to give compound I-3-1. Compound I-3-1: 40 mg (Rf=0.4) of white solid in 28% yield. HPLC retention time (RT) = 11.01 min (HPLC conditions: mobile phase A = water (containing 0.1% HCOOH), mobile phase B = acetonitrile, gradient elution from 5% mobile phase B to 50% mobile phase B). 1 H NMR(400MHz,CDCl3)δ 8.87(s,1H),7.90(t,J=7.9Hz,1H),7.78(d,J=8.0Hz,1H),7.53(d,J=8.5Hz,2H),7.39(dd,J= 7.6,0.5Hz,1H),7.20(d,J=8.5Hz,2H),5.72(ddt,J=16.4,10.2,6.2Hz,1H),5.06(dd,J=10.2, 1.0Hz,1H),4.95(dd,J=17.1,1.2Hz,1H),4.76(d,J=6.2Hz,2H),4.04(s,1H),2.66(m,4H),2. 58-2.47(m,1H),2.16(m,4H),1.96(m,2H),1.87-1.78(m,4H),1.60(s,6H),1.58-1.39(m,4H). LC-MS: m / z: (M+H)+ =554.

[0408] To a solution of 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (I-1-h, 80 mg, 0.22 mmol) in 10 mL of toluene, metachloroperbenzoic acid (60 mg, 0.296 mmol) was added to obtain a solution, which was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and 4-(4-(azetidin-1-yl)cyclohexyl)aniline trifluoroacetate (I-3-2-c, 0.2 mmol), 0.15 mL of trifluoroacetic acid, and 3 mL of dimethyl sulfoxide were added, followed by stirring at 60°C overnight. 2 mL of saturated aqueous sodium carbonate and 10 mL of water were added to the reaction mixture, which was then extracted three times with dichloromethane (3 x 10 mL). The organic phases were combined, and the combined solution was diluted with 5 mL of water and 5 mL of saturated The crude product was separated by thin-layer chromatography (7M ammonia-methanol:(dichloromethane:ethyl acetate=5:1)=1:12) to give compound I-3-2. The product was a white solid (50 mg, Rf=0.6) in 40% yield. Compound I-3-2: HPLC retention time (RT) = 11.20 min (HPLC conditions: mobile phase A = water (containing 0.1% HCOOH), mobile phase B = acetonitrile, gradient elution from 5% mobile phase B to 50% mobile phase B). 1 H NMR (400 MHz, CDCl3) δ 8.87(s,1H),7.92(t,J=7.9Hz,1H),7.80(d,J=8.0Hz,1H),7.52(d,J=8.5Hz,2H) ,7.38(d,J=7.6Hz,1H),7.29(t,J=4.2Hz,2H),5.79-5.66(m,1H),5.06(dd,J=10 .2,1.0Hz,1H),4.96(dd,J=17.1,1.2Hz,1H),4.77(d,J=6.2Hz,2H),4.02(s,1H) ,2.70-2.50(m,5H),2.26(s,1H),1.98(m,4H),1.82(s,4H),1.69-1.56(m,10H). LC-MS: m / z: (M+H) + =554.

[0409] Example 4:

[0410] [ka]

[0411] Step 1: 1-Bromo-4-nitrobenzene (I-4-a, 692 mg, 3.43 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronecyclopentan-2-yl)cyclohex-3-ene-1-carboxylate (I-4-b, 800 mg, 2.85 mmol), tetrakis(triphenylphosphine)palladium(0) (330 mg, 0.286 mmol), triphenylphosphine (75 mg, 0.286 mmol), and potassium carbonate (789 mg, 5.71 mmol) were dissolved in 1,4-dioxane (20 mL). The mixture was protected with argon and heated to 90 °C for approximately 16 h. The reaction mixture was then concentrated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 100% to 90%) to afford 450 mg of the compound represented by formula I-4-c as a white solid. The yield was 47%. 1 H NMR(400MHz,CDCl3)δ 8.23-8.16(m,2H),7.57-7.49(m,2H),6.33(dd,J=5.1,2.8Hz,1H),4.26-4.15(m,2H),2.72-2.61(m,1H),2.59-2.5 1(m,4H),2.24(ddd,J=9.3,8.0,3.9Hz,1H),1.90(dddd,J=13.1,11.0,8.8,6.7Hz,1H),1.31(dd,J=9.2,5.1Hz,3H).

[0412] Step 2: Ethyl 4-(4-nitrophenyl)cyclohex-3-ene-1-carboxylate (I-4-c, 450 mg, 1.63 mmol) was dissolved in methanol (10 mL), palladium / carbon catalyst (45 mg, 10%) was added, and the mixture was stirred under hydrogen atmosphere at room temperature for about 2 days. After filtration, the filtrate was concentrated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 100% to 90%) to give 280 mg of the compound represented by formula I-4-d as a white solid in 69% yield. LC-MS: m / z: (M+H) + =248.4.

[0413] Step 3: 2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridinyl]-6-methylthiopyrazolo[3,4-d]pyrimidin-3-one (I-1-h, 428 mg, 1.20 mmol) was dissolved in toluene (20 mL), metachloroperbenzoic acid (259 mg, 1.5 mmol) was added, and the mixture was stirred at room temperature for approximately 1 hour. Subsequently, ethyl 4-(4-aminophenyl)cyclohexanecarboxylate (247 mg, 1.0 mmol) and DIPEA (258 mg, 2.0 mmol) were added, and the mixture was heated to 90 °C and stirred for approximately 16 hours. The reaction mixture was concentrated and purified by column chromatography (silica gel, dichloromethane:methanol = 100%-90%), preparative high-performance liquid chromatography (HPLC), and thin-layer chromatography (DCM:CHOH:NHCHOH = 10:1:0.15) to obtain 440 mg of compound shown in formula I-4 as a white solid. The yield was 79%. 1H NMR(400MHz,CDCl3)δ 8.87(d,J=2.1Hz,1H),7.91(td,J=7.9,1.5Hz,1H),7.78(d,J=8.0Hz,1H),7.54(t,J=7.9Hz,2H),7.39(d,J=7.7Hz,1H),7.21(d, J=8.5Hz,2H),5.72(ddt,J=16.4,10.2,6.2Hz,1H),5.07(dd,J=10.2,1.1Hz,1H),4.96(dd,J=17.1,1.2Hz,1H),4.77(d,J=6.2Hz, 2H),4.25-4.10(m,2H),3.95(s,1H),2.73(s,1H),2.56(dt,J=15.5,10.8Hz,1H),2.28(d,J=7.9Hz,1H),2.14(d,J=10.6Hz,1H),2 .05-1.97(m,1H),1.78(dd,J=19.0,8.5Hz,1H),1.67(dt,J=10.1,6.1Hz,3H),1.61(s,6H),1.59-1.44(m,1H),1.34-1.26(m,3H). LC-MS: m / z: (M+H) + =557.4.

[0414] Example 5:

[0415] [ka] 4-[4-[[2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridinyl]-3-oxo-pyrazolo[3,4-d]pyrimidine-6-ethyl[amino [Phenyl]cyclohexanecarboxylate (I-4, 420 mg, 0.75 mmol) was dissolved in methanol (20 mL), 2N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for approximately 3 days. The mixture was concentrated to remove the methanol, extracted with dichloromethane, and the organic layer was discarded. 1N aqueous hydrochloric acid was added to the aqueous layer to adjust the pH to 4, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica gel, dichloromethane:methanol = 100% to 95%) to obtain 256 mg of the compound shown in formula I-5. The yield was 64%. 1 H NMR(400MHz,MeOD)δ 8.84(d,J=1.4Hz,1H),8.00(td,J=7.9,4.0Hz,1H),7.83-7.76(m,1H),7.67(dd,J=7.7,0.7Hz,1H ),7.60(dd,J=8.4,5.7Hz,2H),7.19(dd,J=13.2,8.6Hz,2H),5.73(ddd,J=17.0,6.1,4.1Hz,1H),5 .08-5.03(m,1H),4.95(d,J=1.3Hz,1H),4.86-4.79(m,2H),2.72(s,1H),2.58(s,1H),2.27(d,J= 6.7Hz,1H), 2.13(d,J=10.0Hz,1H),1.96(d,J=10.2Hz,1H),1.80-1.66(m,4H),1.64-1.52(m,7H). LC-MS: m / z: (M+H) + =529.3.

[0416] Example 6:

[0417] [ka] 40 mg (0.076 mmol) of 4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)cyclohexane-1-carboxylic acid (I-5) was dissolved in 5 mL of dichloromethane, and 9 mg (0.11 mol) of dimethylamine hydrochloride, 17 mg of EDCI (0.11 mmol), 15 mg of HOBt (0.11 mmol), and 19 mg of DIPEA (0.15 mmol) were added. The mixture was stirred at room temperature for about 16 hours, and then purified by thin layer chromatography (DCM:CH3OH=100:10) to give 15 mg of a pale yellow solid (I-6) in a 35% yield. 1 H NMR(400MHz,CDCl3)δ 8.86(d,J=4.2Hz,1H),7.97-7.88(m,1H),7.79(d,J=8.0Hz,1H),7.53(dd,J=12.3,8.5Hz,2H),7.39(d,J =7.6Hz,1H),7.28-7.15(m,2H),5.80-5.65(m,1H),5.06(d,J=10.0Hz,1H),4.95(d,J=17.1Hz,1H),4.77( d,J=6.0Hz,2H),3.10(d,J=12.1Hz,3H),2.98(s,3H),2.67-2.57(m,1H),2.14(dd,J=20.9,10.3Hz,1H),2 .06-1.97(m,2H),1.92(d,J=14.0Hz,1H),1.78-1.66(m,4H),1.61(s,6H),1.49(dd,J=22.8,12.2Hz,1H). LC-MS: m / z: (M+H) + =556.3.

[0418] Example 7:

[0419] [ka] 40 mg (0.076 mmol) of 4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)cyclohexane-1-carboxylic acid (I-5) was dissolved in 5 mL of dichloromethane, and 9 mg (0.11 mol) of azetidine hydrochloride (I-7-a), 17 mg of EDCI (0.11 mmol), 15 mg of HOBt (0.11 mmol), and 19 mg of DIPEA (0.15 mmol) were added. The mixture was stirred at room temperature for approximately 16 hours, and then purified by thin layer chromatography (DCM:CH3OH=100:10) to give 15 mg of a pale yellow solid (I-7) in a 35% yield. 1 H NMR(400MHz,CDCl3)δ 8.85(d,J=4.7Hz,1H),7.91(dt,J=10.7,7.9Hz,1H),7.78(d,J=7.8Hz,1H),7.53(dd,J=12.0,8.5Hz,2H),7.39(dd,J=7.6,2 .4Hz,1H),7.22(dd,J=19.5,8.5Hz,2H),5.71(ddt,J=16.4,10.2,6.2Hz,1H),5.06(d,J=10.2Hz,1H),4.95(d,J=17.1Hz,1H) ,4.77(d,J=6.1Hz,2H),4.21(dd,J=16.4,8.6Hz,2H),4.10-4.02(m,2H),2.63-2.52(m,2H),2.35-2.20(m,2H),2.15-2.07(m ,1H),2.00(dd,J=13.4,3.0Hz,2H),1.92-1.83(m,1H),1.79-1.63(m,4H),1.60(s,6H),1.48(ddd,J=24.7,12.5,2.5Hz,1H). LC-MS: m / z: (M+H) + =568.4.

[0420] Example 8:

[0421] [ka]

[0422] Step 1: 4,4,5,5-Tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane (I-1-c, 19 g, 71.4 mmol), (4-bromophenyl) tert-butylcarbamate (I-8-a, 18.4 g, 67.6 mmol), 2 mol / L aqueous sodium carbonate (75 mL), and Pd(dppf)Cl (3.3 g, 4.5 mmol) were added to 250 mL of 1,4-dioxane, and the reaction flask was vented three times with a nitrogen balloon and stirred at 98 °C overnight. The reaction mixture was filtered and concentrated, and the aqueous phase was extracted with ethyl acetate (2 × 100 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 0-40%) to give 19 g of a brown solid (I-8-b) in 84.8% yield. LC-MS: m / z: (M-56+H) + =276.

[0423] Step 2: A solution of (4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl) tert-butylcarbamate (I-8-b, 16 g, 48 mmol) in 100 mL of tetrahydrofuran was added to 160 mL of 1.38 mol / L hydrochloric acid and stirred overnight at room temperature. After extraction with ethyl acetate (2 × 150 mL), the combined organic phase was washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 13.5 g of a tan solid (I-8-c), which was used directly in the next step. The yield was 97%. LC-MS: m / z: (M-56+H) + =232.

[0424] Step 3: To a solution of tert-butyl carbamate (4'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)carbamate (I-8-c, 10 g, 34.8 mmol) and azetidine hydrochloride (3 g, 32 mmol) in 100 mL of dichloromethane, N,N'-diisopropylethylamine (12 mL, 69 mmol) and sodium triacetoxyborohydride (14 g, 71 mmol) were added and stirred at room temperature overnight. The solvent was evaporated, and 100 mL of dichloromethane was added. The residue was washed with saturated aqueous sodium carbonate (20 mL), water (2 × 30 mL), and saturated brine, successively. The organic phase was dried over anhydrous sodium sulfate, mixed with silica gel, and purified by column chromatography (7 M ammonia·methanol:(dichloromethane:ethyl acetate=15:1)=0-15%) to obtain 7.3 g of a white solid (I-8-d) in 64% yield. LC-MS: m / z: (M+H) + =329.

[0425] Step 4: tert-Butyl (4'-(azetidin-1-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)carbamate (I-8-d, 7.3 g, 22 mmol) and 10% palladium on carbon (200 mg) were added to 150 mL of methanol. The reaction flask was vented three times with a hydrogen balloon, and the reaction mixture was stirred overnight under a hydrogen atmosphere at room temperature. The reaction mixture was filtered and evaporated to dryness to give the crude product, which was washed with ethyl acetate and filtered. The filter cake yielded 4.1 g of a white solid, compound I-8-e (Rf = 0.4). The overall yield was 85%. LC-MS: m / z: (M+H) + =331.

[0426] Step 5: tert-Butyl (4-(4-(azetidin-1-yl)cyclohexyl)phenyl)carbamate (3 g, 9 mmol, Formula I-8-e) was added to 20 mL of dichloromethane, followed by the addition of 20 mL of trifluoroacetic acid and stirring at room temperature for 2 hours. The reaction mixture was concentrated, and 10 mL of water and 20 mL of saturated sodium carbonate solution were added to obtain a solid, which was filtered, washed with water, and drained to give 1.8 g of a brown solid, compound I-8-f. This was used directly in the next step. The yield was 86%. 1 H NMR(400MHz,CDCl3)δ 7.08-6.96(m,2H),6.70-6.60(m,2H),3.57(s,2H),3.22(t,J=7.0Hz,4H),2.38(tt,J=12. 1,3.2Hz,1H),2.15-1.95(m,5H),1.95-1.81(m,4H),1.51-1.30(m,2H),1.21-1.04(m,2H). LC-MS: m / z: (M+H) + =231.

[0427] Step 6: To a solution of 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (1.86 g, 5.2 mmol, Formula I-1-h) in 60 mL of toluene was added metachloroperbenzoic acid (1.33 g, 6.57 mmol), resulting in a solution that was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and 4-(4-(azetidin-1-yl)cyclohexyl)aniline (1.2 g, 5.2 mmol, Formula I-8-f), 0.8 mL of trifluoroacetic acid, and 20 mL of dimethyl sulfoxide were added, followed by stirring at 60 °C overnight. The reaction mixture was added with 20 mL of saturated aqueous sodium carbonate and 50 mL of water, and extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with 50 mL of water and 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was separated by thin-layer chromatography (7 M ammonia-methanol:(dichloromethane:ethyl acetate=5:1)=1:12) to give compound I-8, 1.88 g, in 67% yield, as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.86(s,1H),7.93-7.85(m,1H),7.78(d,J=7.8Hz,1H),7.52(d,J=8.5Hz,2H),7.39(dd,J=7.6,0.7Hz,1H ),7.19(d,J=8.5Hz,2H),5.71(ddt,J=16.4,10.2,6.2Hz,1H),5.05(dd,J=10.2,1.1Hz,1H),4.94(dd,J=1 7.1,1.3Hz,1H),4.77(d,J=6.2Hz,2H),4.11(d,J=8.9Hz,1H),3.24(t,J=7.0Hz,4H),2.52-2.43(m,1H), 2.14-2.00(m,3H),1.92(d,J=11.2Hz,4H),1.60(s,6H),1.45(dt,J=14.9,7.5Hz,2H),1.23-1.08(m,2H). LC-MS: m / z: (M+H) + =540.4.

[0428] Example 8-1: The product of Example 8 (compound I-8) was analyzed by HPLC (conditions: mobile phase A was water (containing 0.1% HCOOH), mobile phase B was acetonitrile, and the gradient elution was from 5% mobile phase B to 50% mobile phase B). The HPLC retention time (RT) was 10.78 minutes. Therefore, the cyclohexyl group moiety was either in a cis or trans configuration, i.e.,

[0429] [ka] It was.

[0430] [ka] is a cis or trans configuration.

[0431] The reaction pathway is as follows:

[0432] [ka]

[0433] Example 8-2:

[0434] [ka] 2-Allyl-1-(6-(2-hydroxypropyl)pyridin-2-yl)-6-((4-(4-oxocyclohexyl)phenyl)amino)-1,2-dihydro-3H-pyrazoline[3,4-d]pyrimidin-3-one (I-19-d, 19.0 mmol) was dissolved in dichloromethane (500 mL), and azetidine hydrochloride (21.0 mmol), N-ethyl-N-isopropyl-2-amine (38.0 mmol), and sodium triacetoxyborohydride (57 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was adjusted to pH 9 with water (300 mL) and potassium carbonate, extracted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to give the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 0:100 to 5:95) to give the target compound I-8-1 (1.8 g, 24.7%) and the target compound I-8-2 (4.7 g, 65.3%). Both were white solids.

[0435] Compound I-8-1: HPLC retention time (RT) = 10.78 min (HPLC conditions: mobile phase A was water (containing 0.1% HCOOH), mobile phase B was acetonitrile, gradient elution from 5% mobile phase B to 50% mobile phase B). 1 H NMR(400MHz,CDCl3)δ 8.86(s,1H),7.93-7.85(m,1H),7.78(d,J=7.8Hz,1H),7.52(d,J=8.5Hz,2H),7.39(dd,J=7.6,0.7Hz,1H),7.19(d,J =8.5Hz,2H),5.71(ddt,J=16.4,10.2,6.2Hz,1H),5.05(dd,J=10.2,1.1Hz, 1H),4.94(dd,J=17.1,1.3Hz,1H),4.77(d,J=6.2Hz,2H),4.11(d,J=8.9Hz, 1H),3.24(t,J=7.0Hz,4H),2.52-2.43(m,1H),2.14-2.00(m,3H),1.92(d,J =11.2Hz,4H),1.60(s,6H),1.45(dt,J=14.9,7.5Hz,2H),1.23-1.08(m,2H). LC-MS: m / z: (M+H) + =540.4.

[0436] Compound I-8-2: HPLC retention time (RT) = 11.00 min (HPLC conditions: mobile phase A was water (containing 0.1% HCOOH), mobile phase B was acetonitrile, gradient elution from 5% mobile phase B to 50% mobile phase B). 1 H NMR(400MHz,CDCl3)δ 8.87(s,1H),7.92(d,J=7.8Hz,1H),7.80(d,J=8.0Hz,1H),7.52(d,J=8.4Hz,2H),7.39(d ,J=7.6Hz,1H),7.29-7.25(m,2H),5.82-5.63(m,1H),5.12-4.91(m,2H),4.78(d,J=6.2H z,2H),4.01(s,1H),3.17(s,4H),2.53(s,1H),2.33(s,1H),2.06(d,J=4.4Hz,2H),1.89( d,J=11.6Hz,2H),1.75(d,J=14.1Hz,2H),1.59(d,J=17.2Hz,8H),1.46(t,J=13.1Hz,2H). LC-MS: 540.0 [M+1] + .

[0437] As is clear from the above, the cis and trans configurations 1 The two can be distinguished due to the large differences in their 1 H NMR data.

[0438] Example 8-3:

[0439] [ka]

[0440] Step 1: tert-Butyl (4'-(azetidin-1-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)carbamate (I-8-d, 7.3 g, 22 mmol) and 10% palladium on carbon (200 mg) were added to 150 mL of methanol. The reaction flask was vented three times with a hydrogen balloon, and the reaction mixture was stirred overnight under a hydrogen atmosphere at room temperature. The reaction mixture was filtered and evaporated to dryness to give the crude product. The crude product was mixed with silica gel and purified by column chromatography (7 M ammonia / methanol:(dichloromethane:ethyl acetate) = 12:3 = 0-15%) to give compound I-8-e'' (Rf = 0.6) as a white solid (2.1 g) and compound I-8-e' (Rf = 0.4) as a white solid (4.1 g). The overall yield was 85%. LC-MS: m / z: (M+H) + =331.

[0441] Step 2: tert-Butyl (4-(4-(azetidin-1-yl)cyclohexyl)phenyl)carbamate (2 g, 9 mmol, Formula I-8-e″) was added to 20 mL of dichloromethane, followed by the addition of 20 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and 10 mL of water and 20 mL of saturated sodium carbonate solution were added to obtain a solid, which was filtered, washed with water, and drained to give 1.2 g of a brown solid, compound I-8-f″. This was used directly in the next step. The yield was 86%. 1 H NMR(400MHz,MeOD)δ 7.10-6.97(m,2H),6.74-6.63(m,2H),4.22-4.08(t,J=8.0Hz,4H),3.47 -3.38(m,1H),2.61-2.52(m,1H),2.52-2.28(m,2H),1.92-1.62(m,8H). LC-MS: m / z: (M+H) + =231.

[0442] Step 3: To a solution of 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (1.86 g, 5.2 mmol, Formula I-1-h) in 60 mL of toluene was added metachloroperbenzoic acid (1.33 g, 6.57 mmol), resulting in a solution that was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and 4-(4-(azetidin-1-yl)cyclohexyl)aniline (1.2 g, 5.2 mmol, Formula I-8-f″), 0.8 mL of trifluoroacetic acid, and 20 mL of dimethyl sulfoxide were added, followed by stirring at 60 °C overnight. The reaction mixture was added with 20 mL of saturated aqueous sodium carbonate and 50 mL of water, and extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with 50 mL of water and 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was separated by thin-layer chromatography (7 M ammonia-methanol:(dichloromethane:ethyl acetate=5:1)=1:12) to give compound I-8-2, 1.88 g, in 67% yield, as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.87(s,1H),7.92(d,J=7.8Hz,1H),7.80(d,J=8.0Hz,1H),7.52(d,J=8.4Hz,2H),7.39(d ,J=7.6Hz,1H),7.29-7.25(m,2H),5.82-5.63(m,1H),5.12-4.91(m,2H),4.78(d,J=6.2H z,2H),4.01(s,1H),3.17(s,4H),2.53(s,1H),2.33(s,1H),2.06(d,J=4.4Hz,2H),1.89( d,J=11.6Hz,2H),1.75(d,J=14.1Hz,2H),1.59(d,J=17.2Hz,8H),1.46(t,J=13.1Hz,2H). LC-MS: m / z: (M+H) + =540.

[0443] Example 15:

[0444] [ka]

[0445] Step 1: 1 g (4.22 mmol) of 2,6-dibromopyridine (I-15-a) was dissolved in 30 mL of dichloromethane and cooled to -78 °C. 1.86 mL (4.64 mmol, 2 M dioxane solution) of n-butyllithium solution was slowly added dropwise. After stirring for about 15 minutes, 0.3 g (4.22 mmol) of oxetan-3-one (I-15-b) was added. The mixture was stirred for about 1 hour and quenched with saturated aqueous ammonium chloride solution. The mixture was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 100% to 50%) to obtain 660 mg of 3-(6-bromo-2-pyridinyl)oxetan-3-ol (I-15-c) as a white solid. The yield was 68%. LC-MS: m / z: (M+H) + =230.1.

[0446] Step 2: 106 mg (0.48 mmol) of 2-allyl-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-3-one (I-15-d) and 100 mg (0.43 mmol) of 3-(6-bromo-2-pyridinyl)oxetan-3-ol (I-15-c) were dissolved in 10 mL of 1,4-dioxane, followed by addition of 90 mg (0.65 mmol) of potassium carbonate, 83 mg (0.43 mmol) of cuprous iodide, and 77 mg (0.87 mmol) of N 1 ,N 2 The reaction mixture was added with 1,2-dimethylethyl-1,2-diamine, and the temperature was raised to 100°C under argon gas and stirred overnight. The mixture was concentrated and purified by silica gel column chromatography (UV, dichloromethane:methanol = 100% to 10%) to give 2-allyl-1-[6-(3-hydroxyoxetanyl-3-yl)-2-pyridinyl]-6-methylthiopyrazolo[3,4-d]pyrimidin-3-one (I-15-e), 140 mg of brown oil in 86% yield. LC-MS: m / z: (M+H) + =372.1.

[0447] Step 3: 549 mg (1.478 mmol) of 2-allyl-1-[6-(3-hydroxyoxetanyl-3-yl)-2-pyridinyl]-6-methylthiopyrazolo[3,4-d]pyrimidin-3-one (Formula I-15-e) was dissolved in 30 mL of toluene, and 397 mg (1.7 714 mmol) of 3-chloroperbenzoic acid was added and stirred at room temperature for about 1 hour. Then, 354 mg (1.622 mmol) of 4-(4-(dimethylamino)cyclohexyl)aniline (I-1-f) and 381 mg (2.9480 mmol) of DIPEA were added, the temperature was raised to 30°C and stirred for about 3 hours. The reaction solution was concentrated and purified by thin layer chromatography (dichloromethane:methanol:methanol solution of ammonia = 25:1:0.15) to obtain Compounds I-15-1 and I-15-2. Compound I-15-1: HPLC retention time (RT) = 7.02 minutes (HPLC conditions: gradient elution from 5% mobile phase B to 95% mobile phase B), yield of the compound was 10% (80 mg), and it was a white solid. 1 H NMR(400MHz,MeOD)δ 8.84(s,1H),8.04(t,J=7.9Hz,1H),7.92(d,J=8.1Hz,1H),7.67(d,J=7.6Hz,1H),7.60(d,J=8. 6Hz,2H),7.21(d,J=8.6Hz,2H),5.78(ddt,J=16.3,10.3,6.1Hz,1H),5.12-5.05(m,3H),4.98( dd,J=17.1,1.3Hz,1H),4.89(d,J=6.1Hz,2H),4.84(s,2H),3.68(s,2H),2.97-2.86(m,1H),2. 66(s,6H),2.60-2.50(m,1H),2.15(d,J=8.6Hz,2H),2.04(d,J=9.0Hz,2H),1.66-1.54(m,4H). LC-MS: m / z: (M+H) + =542.4. Compound I-15-2: HPLC retention time (RT) = 7.16 minutes (HPLC conditions: 5% mobile phase B → 95% mobile phase B mixed elution), the compound yield is 20% (160mg), and the white solid is obtained. 1 H NMR(400MHz,MeOD)δ 8.83(s,1H),8.04(t,J=7.9Hz,1H),7.92(d,J=8.0Hz,1H),7.67-7.62(m,1H),7.59(d,J =8.6Hz,2H),7.29(d,J=8.5Hz,2H),5.76(ddt,J=16.3,10.2,6.1Hz,1H),5.10-5.02(m, 3H),4.96(dd,J=17.1,1.3Hz,1H),4.87(d,J=6.8Hz,2H),4.82(d,J=6.8Hz,2H),2.73(d ,J=4.2Hz,1H),2.29(d,J=21.9Hz,7H),2.04-1.90(m,4H),1.66(dd,J=15.6,6.1Hz,4H). LC-MS:m / z:(M+H) + =542.3.

[0448] Example 19:

[0449]

change

[0450] ステップ1: 4,4,5,5-Tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane (0.8 g, 3 mmol, Formula I-1-c), 1-bromo-4-nitrobenzene (0.606 g, 3 mmol, I-4-a), 1 mol / L aqueous sodium carbonate (6 mL), and Pd(PPh)Cl (106 mg, 0.15 mmol) were added to 30 mL of 1,4-dioxane, and the reaction flask was vented three times with a nitrogen balloon and stirred at 95 °C overnight. The reaction mixture was filtered and concentrated, and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 0-30%) to give 0.73 g of 8-(4-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (I-19-a) as a brown solid in 90% yield. 1 H NMR(400MHz,CDCl3)δ 8.24-8.14(m,2H),7.60-7.50(m,2H),6.21(td,J=4.0,2.0Hz,1H),4.06(s,4H ),2.71(ddd,J=6.5,4.2,1.7Hz,2H),2.59-2.49(m,2H),1.97(t,J=6.5Hz,2H). LC-MS: m / z: (M+H) + =262.3.

[0451] Step 2: 8-(4-Nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (650 mg, 0.25 mmol, I-19-1) and 10% palladium on carbon (100 mg) were added to 50 mL of dichloromethane. The reaction flask was vented three times with a hydrogen balloon, and the reaction was stirred under a hydrogen atmosphere at room temperature for 4 h. The reaction was filtered and evaporated to dryness to give 560 mg of 4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline (I-19-b). The brown solid was used directly in the next step. The yield was 96%. LC-MS: m / z: (M+H) + =234.3.

[0452] Step 3: 2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine- To a solution of 3-one (72 mg, 0.2 mmol, I-1-h) in 15 mL of toluene was added metachloroperbenzoic acid (55 mg, 0.246 mmol), resulting in a solution that was stirred at room temperature for 1 h. The reaction mixture was concentrated, and 4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline (48 mg, 0.2 mmol, I-19-b), 0.15 mL of trifluoroacetic acid, and 3 mL of dimethyl sulfoxide were added, followed by stirring at 60 °C overnight. The reaction mixture was added with 10 mL of saturated aqueous sodium carbonate and 25 mL of water, and extracted three times with dichloromethane (3 × 20 mL). The combined organic phases were washed with 10 mL of water and 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was separated by thin-layer chromatography (7 M ammonia-methanol:(dichloromethane:ethyl acetate=5:1)=1:12) to give 60 mg of 6-((4-(1,4-dioxaspiro[4.5]dec-8-yl)phenyl)amino)-2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Formula I-19-c). The yield was 54%. LC-MS: m / z: (M+H) + =543.3.

[0453] Step 4: 6-((4-(1,4-Dioxaspiro[4.5]dec-8-yl)phenyl)amino)-2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (60 mg, 0.11 mmol, I-19-c) was added to a mixture of 3 mL of tetrahydrofuran and 3 mL of 2 mol / L hydrochloric acid and stirred overnight at room temperature. The pH of the reaction mixture was adjusted to approximately 10 with sodium bicarbonate, and the mixture was extracted with dichloromethane (2 × 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was separated by thin layer chromatography (methanol:(dichloromethane:ethyl acetate=9:3)=1:12) to give 50 mg of 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-oxocyclohexyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (I-19-d) as a white solid in 90% yield. LC-MS: m / z: (M+H) + =499.3.

[0454] Step 5: 2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-oxocyclohexyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (50 mg, 0.1 mmol, I-19-d) and ammonium acetate (77 mg, 1 mmol) were added to 10 mL of methanol and stirred at room temperature for 10 minutes. Sodium cyanoborohydride (30 mg, 0.5 mmol) was then added and stirred at room temperature overnight. The reaction mixture was concentrated, and 20 mL of dichloromethane was added. The mixture was washed sequentially with 10 mL of 1 mol / L sodium carbonate solution and 5 mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product, which was used directly in the next step. 40 mg of a white solid (I-19-e) was obtained in 80% yield. LC-MS: m / z: (M+H) + =500.3.

[0455] Step 6: 2-Allyl-6-((4-(4-aminocyclohexyl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (35 mg, 0.07 mmol, I-19-e), N,N-diisopropylethylamine (0.02 mL) were added to 10 mL of dichloromethane, followed by methanesulfonyl chloride (9 mg, 0.078 mmol). The mixture was added and stirred at room temperature overnight. The reaction mixture was concentrated and purified by high performance liquid chromatography to give 9 mg of N-(4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)cyclohexyl)methanesulfonamide (I-19). The yield was 22% as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.88(s,1H),7.91(t,J=7.9Hz,1H),7.77(d,J=7.9Hz,1H),7.56(d,J=8.5Hz,2H),7.40(d,J=7. 4Hz,1H),7.19(d,J=8.5Hz,2H),5.78-5.66(m,1H),5.07(dd,J=10.2,1.0Hz,1H),4.96(dd,J=1 7.1,1.2Hz,1H),4.77(d,J=6.2Hz,2H),4.42(d,J=7.6Hz,1H),3.49-3.35(m,1H),3.04(s,3H), 2.57-2.46(m,1H),2.29-2.17(m,2H),2.05-1.96(m,8H),1.56-1.65(m,2H),1.41-1.50(m,2H). LC-MS: m / z: (M+H) + =578.3.

[0456] Example 20:

[0457] [ka] 2-Allyl-6-((4-(4-aminocyclohexyl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (120 mg, 0.24 mmol, compound I-19-c), 1H-pyrazole-1-carboxylimine amide hydrochloride (45 mg, 0.31 mmol), and N,N-diisopropylethylamine (0.2 mL) were added to 5 mL of N,N-dimethylformamide and stirred overnight at 65 °C. The reaction mixture was concentrated and separated by thin-layer chromatography (7 M ammonia in methanol:dichloromethane = 1:8) to afford 30 mg of a white solid (compound I-20) in 23% yield. LC-MS: m / z: (M+H) + =542. 1 H NMR(400MHz,MeOD)δ 8.84(s,1H),8.02(m,1H),7.80(m,1H),7.72-7.58(m,3H),7.25(m,2H),5.73(ddt,J=16.5,10.3,6.1Hz,1H),5.05(dd,J=10.2,1.0Hz,1H),4.9 5(d,1H),4.83(d,J=6.1Hz,2H),3.54-3.42(m,1H),2.59(m,1H),2.14(m ,1H),1.98(m,2H),1.83(m,1H),1.68(m,2H),1.60(s,6H),1.50(m,2H).

[0458] Example 23:

[0459] [ka] Potassium tert-butoxide (2 equiv., 0.2006 mmol) was dissolved in dry dimethyl sulfoxide (1 mL, 100% by weight) and then added to a solution of p-toluenesulfonylmethyl isocyanide (1.5 equiv., 0.1504 mmol) in dry dimethyl sulfoxide (1 mL) at room temperature. Compound I-19-d (50 mg, 0.1003 mmol) was dissolved in dry methanol (0.5 mL) and added to the reaction mixture, which was then stirred at room temperature for 12 hours. The reaction was quenched with water and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by normal phase silica gel column chromatography (elution conditions: dichloromethane:methanol system, methanol concentration 0%-10%, volume 12 columns) to obtain compound I-23 (15 mg, 0.02943 mmol) in 29.35% yield as a yellow solid. 1 H NMR(400MHz,DMSO)δ 10.28(s,1H),8.88(d,J=1.8Hz,1H),8.09-7.97(m,1H),7.75(d,J=8.4Hz,1H),7.66(dd,J=20.6,8 .5Hz,3H),7.19(dd,J=11.1,8.7Hz,2H),5.74-5.61(m,1H),5.00(d,J=10.2Hz,1H),4.82(d,J=17. 1Hz,1H),4.69(d,J=5.5Hz,2H),3.23(s,1H),2.74(t,J=12.1Hz,1H),2.53(s,1H),2.12(d,J=10.1 Hz,1H),1.98(d,J=13.2Hz,1H),1.82(d,J=13.2Hz,2H),1.77-1.57(m,3H),1.49(d,J=18.2Hz,6H). LC-MS: m / z: (M+H) + =510.2.

[0460] Example 31:

[0461] [ka]

[0462] Step 1: 3-(4-Bromophenyl)cyclobutanone (I-31-a, 4.40 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (8.9 mmol), dimethylamine hydrochloride (8.9 mmol), and sodium triacetoxyborohydride (8.9 mmol) were added to the reaction mixture and stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 9 with aqueous potassium carbonate and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to afford 1.1 g of crude 3-(4-bromophenyl)-N,N-dimethylcyclobutylamine (I-31-b) as a colorless oil in 97% yield. LC-MS: m / z: (M+H) + =255.4.

[0463] Step 2: 3-(4-Bromophenyl)-N,N-dimethylcyclobutylamine (I-31-b, 4.30 mmol) was dissolved in toluene (20 mL). Diphenylmethylamine (I-31-c, 4.8 mmol), sodium tert-butoxide (6.9 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.43 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.13 mmol) were added to the reaction mixture. The mixture was protected with nitrogen and heated to 90 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and concentrated to give the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100:0 to 95:5) to give 1.5 g of the target compound, 3-(4-((diphenylmethylene)amino)phenyl)-N,N-dimethylcyclobutylamine (I-31-d). A colorless oil was obtained in 98% yield. LC-MS: m / z: (M+H) + =355.3.

[0464] Step 3: 4-(3-Dimethylamino)cyclobutyl)aniline (I-31-d, 4.2 mmol) was dissolved in methanol (20 mL), and sodium acetate (13.0 mmol) and hydroxylamine hydrochloride (8.5 mmol) were added to the reaction mixture, which was then stirred at 50°C for 16 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was then purified by column chromatography (dicylic acid). The mixture was purified using a mixture of chloromethane and methanol (100:0 to 95:5) to obtain 0.75 g of the target compound, 4-(3-dimethylamino)cyclobutylaniline (I-31-e), with a yield of 93%. LC-MS: m / z: (M+H) + =191.3.

[0465] Step 4: 2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (I-1-h, 0.65 mmol) was dissolved in toluene (20 mL), 3-chlorophenoxyformic acid (0.62 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. 4-(3-dimethylamino)cyclobutyl)aniline (I-31-e, 0.67 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was then purified with ethyl acetate and dichloromethane to obtain 92 mg of the target compound, 2-allyl-6-((4-(3-(dimethylamino)cyclobutyl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (I-31). The yield was 32.9%. 1H NMR(400MHz,DMSO)δ 10.27(s,1H),8.89(s,1H),8.12(s,1H),7.74(dd,J=22.6,8.3Hz,3H),7.64(d,J= 7.3Hz,1H),7.37(d,J=8.5Hz,2H),5.76-5.61(m,1H),5.34(s,1H),5.01(dd,J=10 .3,1.2Hz,1H),4.84(d,J=17.1Hz,1H),4.70(d,J=5.7Hz,2H),3.62(s,1H),3.12( s, 1H), 2.71-2.58 (m, 8H), 2.38 (d, J=9.2Hz, 2H), 1.47 (s, 6H), 1.32-1.24 (m, 1H). LC-MS: m / z: (M+H) + =500.3.

[0466] Example 32:

[0467] [ka] Compound I-19-d (80 mg, 0.1604 mmol, 100% by weight) was dissolved in ethanol (4 mL, 100% by weight). Water (2 mL, 100% by weight) and hydroxylamine hydrochloride (3 equivalents, 0.4813 mmol, 100% by weight) were then added at room temperature, and the reaction mixture was stirred at 70°C for 12 hours. The reaction mixture was quenched with aqueous NaHCO3 and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was washed with 2 mL of methanol and filtered to give compound I-32 (60 mg, 0.1137 mmol) as a white solid in 70.88% yield. 1 H NMR(400MHz,DMSO)δ 10.26(s,1H),8.88(s,1H),8.07(t,J=7.8Hz,1H),7.76(d,J=8.0Hz,1 H),7.65(dd,J=14.5,7.9Hz,2H),7.22(d,J=8.5Hz,2H),5.74-5.60(m,1H),5.35(s ,1H),5.00(d,J=10.3Hz,1H),4.83(d,J=17.1Hz,1H),4.69(d,J=5.6Hz,2H),3.74( s,3H),3.24-3.15(m,1H),2.77(t,J=12.0Hz,1H),2.37(d,J=14.0Hz,1H),2.25(td ,J=13.4,4.6Hz,1H),1.99-1.84(m,3H),1.67-1.50(m,2H),1.49(d,J=14.0Hz,6H). LC-MS: m / z: (M+H) + =528.

[0468] Example 33:

[0469] [ka]

[0470] Step 1: Compound I-15-c (400 mg, 1.077 mmol) was dissolved in toluene (20 mL). mCPBA (1.2 equivalents, 1.292 mmol, 77% by weight) was then added at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. Compound I-33-a (1.2 equivalents, 1.292 mmol) and DIPEA (2 equivalents, 2.154 mmol) were added, in that order, to the reaction mixture, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by normal phase silica gel column chromatography (elution conditions: ethyl acetate:dichloromethane system, ethyl acetate concentration 0% to 10%, volume 24 columns) to obtain compound I-33-b (120 mg, 0.2341 mmol) in 21.74% yield as a yellow solid. 1H NMR(400MHz,DMSO)δ 8.91(d,J=2.4Hz,1H),8.11(t,J=7.9Hz,1H),7.89(d,J=8.3Hz,1H),7.68(d,J=8.2Hz,2H),7.57(d, J=7.7Hz,1H),7.28(d,J=8.6Hz,2H),5.72(ddd,J=23.0,10.3,5.9Hz,1H),5.02(dd,J=10.3,1.3Hz,1 H),4.95-4.89(m,2H),4.87(d,J=1.4Hz,1H),4.75(d,J=5.8Hz,1H),4.70(t,J=6.2Hz,2H),3.04(t,J =11.9Hz,1H),2.67-2.53(m,2H),2.30(t,J=15.0Hz,2H),2.08(d,J=10.0Hz,2H),1.96-1.81(m,2H).

[0471] Step 2: Compound I-33-b (100 mg, 0.1951 mmol) was dissolved in methanol (3 mL), followed by the addition of DIPEA (5 equiv., 0.9754 mmol), and the reaction was stirred at room temperature for 5 minutes. Na(OAc)3BH (3 equiv., 0.5853 mmol) was then added, and the reaction was stirred at room temperature for 12 hours. The reaction was quenched with aqueous NaHCO3 and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by normal phase silica gel column elution with dichloromethane:methanol (1% ammonia in methanol) system. The resulting mixture was purified by a 12-column column chromatography (0% to 10% methanol concentration) to give compound I-33 (80 mg, 0.15 mmol) as a white solid in 77.3% yield. 1H NMR(400MHz,MeOD)δ 8.86(s,0H),8.11-8.01(m,1H),7.94(d,J=7.9Hz,2H),7.67(d,J=7.6Hz,2H),7.62(d,J=8.6Hz,2H),7.28(d,J=8.5Hz,2H),5.83-5.74(m,1H) ,5.09(dd,J=7.9,4.4Hz,3H),4.98(dd,J=17.1,1.3Hz,2H),4.85(d,J=6.7Hz,2H),2.87(s,1H),2.64(s,1H),2.47(s,3H),1.97-1.67(m,8H). LC-MS: m / z: (M+H) + =529.2.

[0472] Example 34:

[0473] [ka] Compound I-33 (40 mg, 0.07582 mmol) and cyclopropylacetic acid (1.1 equiv., 73 mg) were dissolved in dichloromethane (2 mL). DIPEA (2 equiv., 0.1516 mmol) and HATU (1 equiv., 0.07582 mmol) were then added, in that order, and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with water and extracted with dichloromethane (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by normal-phase silica gel column elution (dichloromethane:methanol system, 0% to 10% methanol, 12 column volumes) to give compound I-34 (10 mg, 0.01679 mmol) in 22.14% yield as a yellow solid. 1H NMR(400MHz,MeOD)δ 8.87(d,J=6.6Hz,1H),8.06(t,J=7.9Hz,1H),7.95(d,J=7.9Hz,1H),7.68(dd,J=7.8,5.4Hz,2H),7.61(d,J=8.6Hz ,1H),7.41(d,J=8.4Hz,1H),7.24(t,J=8.7Hz,1H),5.84-5.72(m,1H),5.09(d,J=6.2Hz,2H),5.07(d,J=1.3Hz,1H) ,5.02-4.94(m,2H),4.90(s,2H),4.84(d,J=6.7Hz,2H),3.15(d,J=2.6Hz,1H),3.08(s,1H),2.95(s,1H),2.71(s,1 H),2.43(s,1H),1.93-2.03(m,3H),1.76(s,2H),1.51(s,1H),1.31(d,J=4.3Hz,3H),0.89(dd,J=20.1,9.0Hz,4H). LC-MS: m / z: (M+H) + =596.2.

[0474] Example 35:

[0475] [ka]

[0476] Step 1: Compound I-35-a (100 mg, 0.3444 mmol) was dissolved in tetrahydrofuran (5 mL). TEA (5 equiv., 1.722 mmol) and compound I-35-b (2 equiv., 0.6887 mmol) were added, and the reaction mixture was stirred at room temperature for 8 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by normal-phase silica gel column elution (petroleum ether:ethyl acetate system, 10% to 60% ethyl acetate, 12 column volumes) to give compound I-35-c (100 mg, 0.2532 mmol) in 73.54% yield as a white solid. LC-MS: m / z: (M+H-tBu)+ =339.1.

[0477] Step 2: Compound I-35-c (200 mg, 0.5065 mmol) was dissolved in tetrahydrofuran (5 mL). Sodium hydride (2 equivalents, 1.013 mmol, 60% by weight) was then added and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2×20 mL). The organic phase was washed with brine (1×20 mL), dried over NaSO, filtered, and concentrated to give compound I-35-d (180 mg, 0.502 mmol) in 99.14% yield as a white solid. 1 H NMR(400MHz,MeOD)δ 7.31(dt,J=11.6,8.5Hz,3H),7.15(d,J=8.5Hz,1H),4.07-3.92(m,1H),3.47(dt,J=29.5,7.2Hz,2H),2.3 9(dt,J=16.3,8.1Hz,2H),2.22(d,J=10.1Hz,1H),2.03(s,4H),1.84-1.57(m,6H),1.53(d,J=2.8Hz,9H). LC-MS: m / z: (M+H) + =359.1.

[0478] Step 3: Compound I-35-d (180 mg, 0.669 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred at room temperature for 12 hours. After concentrating the reaction mixture, aqueous NaHCO was added and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over NaSO, filtered, and concentrated. Condensation gave compound I-35-e (120 mg, 0.464 mmol) in 100% yield as a yellow solid. LC-MS: m / z: (M+H) + =259.1.

[0479] Step 4: Compound I-15-c (100 mg, 0.2693 mmol) was dissolved in toluene (2 mL). mCPBA (1.2 equiv., 0.3231 mmol, 77% wt.) was added at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. Compound I-35-e (1.2 equiv., 0.3231 mmol) and DIPEA (2 equiv., 0.5385 mmol) were added, in that order, at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by normal phase silica gel column chromatography (elution conditions: dichloromethane:tetrahydrofuran system, tetrahydrofuran concentration 0% to 30%, volume 12 columns) to give compound I-35 (40 mg, 0.06876 mmol) in 25.54% yield as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.87-8.79(m,1H),8.14-8.07(m,1H),8.04-7.96(m,1H),7.89-7.80(m,1H),7.61-7.50(m,2H),7.38-7.32(m, 1H),7.25-7.19(m,1H),7.01(t,J=3.4Hz,1H),5.72(ddd,J=16.6,11.1,8.6Hz,1H),5.17-5.09(m,2H),5.04-4. 98(m,1H),4.98-4.92(m,1H),4.87-4.77(m,2H),4.73-4.64(m,2H),4.20-4.06(m,1H),3.47-3.38(m,1H),3.3 8-3.29(m,1H),3.05-2.98(m,1H),2.49-2.35(m,2H),2.27-2.17(m,1H),2.07-1.86(m,4H),1.75-1.60(m,3H). LC-MS: m / z: (M+H) + =582.2.

[0480] Example 36:

[0481] [ka] 2-Allyl-1-(6-(3-(hydroxyoxetan-3-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Formula 1-15-c, 200 mg, 0.538 mmol) was dissolved in 5 mL of toluene, and 3-chloroperbenzoic acid (140 mg, 0.69 mmol) was added. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure. The obtained solid was dissolved in 5 mL of DMSO and trifluoroacetic acid (20 mg, 0.2 mmol), 4-(4-(azetidin-1-yl)cyclohexyl)aniline (formula I-36-a, 140 mg, 0.64 mmol) were added, and the reaction mixture was stirred at 65°C for 16 hours. The reaction mixture was quenched with water, extracted with dichloromethane (30 mL x 3), and the organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (methanol:dichloromethane:ethyl acetate = 0.5:10:4 to 1:10:4) to give a yellow solid (I-36-2, 22 mg, 7 0.4%), a yellow solid (I-36-1, 64 mg, 21.4%) was obtained. Compound I-36-1: HPLC retention time (RT) = 7.14 min (HPLC conditions: mobile phase A was water (containing 0.1% HCOOH), mobile phase B was acetonitrile, gradient elution from 5% mobile phase B to 95% mobile phase B). 1 H NMR(400MHz,CDCl3)δ 8.88(d,J=2.6Hz,1H),8.09(dd,J=15.0,7.8Hz,1H),7.99-7.83(m,2H),7.54(t,J=9.5Hz,2H),7.3 9(d,J=8.7Hz,1H),7.21(d,J=8.5Hz,1H),5.74(dq,J=10.5,5.9Hz,1H),5.12(t,J=8.8Hz,3H),4.9 9(d,J=17.1Hz,1H),4.80(d,J=6.3Hz,2H),4.67(d,J=6.0Hz,2H),3.39-3.24(m,4H),2.60-2.34(m ,3H),2.14(dt,J=14.0,6.8Hz,3H),1.96(d,J=10.8Hz,4H),1.55-1.37(m,2H),1.27-1.12(m,2H). LC-MS: m / z: (M+H)+ =554.1. Compound I-36-2: HPLC retention time (RT) = 7.15 minutes (HPLC conditions: mobile phase A water (containing 0.1% HCOOH), mobile phase B water, 5% mobile phase B → 95% mobile phase B blended elution). 1 H NMR(400MHz,MeOD)δ 8.86(s,1H),8.02(dt,J=24.0,7.9Hz,3H),7.64(dd,J=27.1,8.1Hz,3H),7.27(t,J=8.6Hz,2H) ,7.01-6.91(m,3H),6.72-6.64(m,3H),5.79(ddd,J=16.3,11.2,6.1Hz,1H),5.10-5.05(m,2H), 4.85(d,J=6.8Hz,2H),2.57(d,J=10.7Hz,1H),2.48-2.28(m,3H),2.23-2.06(m,3H),1.98-1.71 (m,6H),1.58(dd,J=23.2,12.9Hz,3H),1.44(ddd,J=16.1,13.2,3.5Hz,2H),1.19-1.00(m,2H). LC-MS:m / z:(M+H) + =554.1.

[0482] Example 37:

[0483]

change

[0484] ステップ1: Compound I-35-a (150mg, 0.5165mmol) をテトラヒドロフラン (6 The reaction mixture was dissolved in 1 mL of ethyl acetate (5 equiv., 2.583 mmol) and added with DIPEA (5 equiv., 2.583 mmol), and compound I-37-a (3 equiv., 1.550 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by normal-phase silica gel column chromatography (elution conditions: petroleum ether:ethyl acetate, 0% to 40% ethyl acetate, 12 column volumes) to give compound I-37-b (120 mg, 0.3023 mmol) in 58.53% yield as a white solid. 1 H NMR(400MHz,MeOD)δ 7.38-7.27(m,2H),7.24-7.18(m,1H),7.18-7.09(m,1H),4.38-4.23(m,2H),3.83-3.67(m,2H),2.63(td,J=14.1, 6.0Hz, 1H), 2.52-2.37 (m, 1H), 2.31 (s, 1H), 2.25-2.13 (m, 1H), 2.00-1.84 (m, 3H), 1.82-1.63 (m, 3H), 1.53 (s, 9H).

[0485] Step 2: Compound I-37-b (120 mg, 0.30 mmol) was dissolved in tetrahydrofuran (5 mL). Sodium hydride (2 equivalents, 0.607 mmol, 60% by weight) was then added and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2×20 mL). The organic phase was washed with brine (1×20 mL), dried over NaSO, filtered, and concentrated to give compound I-37-c (80 mg, 0.22 mmol) in 73.4% yield as a white solid. 1H NMR(400MHz,MeOD)δ 7.31(dt,J=18.7,8.6Hz,3H),7.15(d,J=8.5Hz,1H),4.42-4.26(m,2H),3.66(ddd,J=16.1,12.2,5.9Hz,2H ),2.50(s,1H),2.15(dd,J=17.3,6.4Hz,2H),1.99-1.79(m,4H),1.77-1.61(m,3H),1.53(d,J=1.7Hz,9H). LC-MS: m / z: (M+H) + =305.1.

[0486] Step 3: Compound I-37-c (80 mg, 0.22 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred at room temperature for 12 hours. After concentrating the reaction mixture, aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified using a normal-phase silica gel column (elution conditions: petroleum ether:ethyl acetate system, ethyl acetate concentration 0% to 50%, volume 12 columns) to give compound I-37-d (60 mg, 0.2305 mmol) in 100% yield as a yellow solid. 1 H NMR(400MHz,MeOD)δ 7.11(d,J=8.1Hz,1H),7.00(d,J=8.3Hz,1H),6.78-6.66(m,2H),4.40-4.29(m,2H) ,3.70-3.57(m,4H),2.10(d,J=17.5Hz,1H),1.97-1.81(m,4H),1.72-1.57(m,3H). LC-MS: m / z: (M+H) + =261.1.

[0487] Step 4: Compound I-15-c (60 mg, 0.1616 mmol) was dissolved in toluene (2 mL). mCPBA (1.2 equivalents, 0.1939 mmol, 77% by weight) was then added at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. Compound I-37-d (1.4 equivalents, 0.2262 mmol) and DIPEA (2 equivalents, 0.3231 mmol) were then added, in that order, at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), and the NaSO was added. The crude product was dried over O4, filtered, and concentrated to give the crude product, which was purified using a normal-phase silica gel column (elution conditions: dichloromethane:tetrahydrofuran system, tetrahydrofuran concentration 0% to 50%, volume 12 columns) to give compound I-37 (15 mg, 0.02570 mmol) in 15.91% yield as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.77(s,1H),8.16-8.07(m,1H),8.03(d,J=7.6Hz,1H),7.83-7.75(m,1H),7.56(dd,J=12.6,6.1Hz,2H),7.33(d,J =8.5Hz,1H),7.21(d,J=8.5Hz,1H),5.72(dd,J=17.0,10.3Hz,1H),5.13(dd,J=9.1,6.1Hz,2H),4.96(d,J=17.0Hz ,2H),4.81(d,J=7.2Hz,2H),4.69(d,J=6.2Hz,2H),4.41-4.28(m,2H),3.86(s,1H),3.77(t,J=6.6Hz,1H),3.63-3 .50(m,2H),2.98(m,1H),2.15(m,1H),1.97(dd,J=18.9,9.6Hz,2H),1.78(d,J=5.0Hz,2H),1.65(d,J=8.7Hz,2H). LC-MS: m / z: (M+H) + =584.1.

[0488] Example 38:

[0489] [ka]

[0490] Step 1: Compound I-33-a (150 mg, 0.79260 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of (Boc)O (1.2 equivalents, 0.95112 mmol) and DIPEA (2 equivalents, 1.5852 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water and extracted with dichloromethane (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over NaSO, filtered, and concentrated to give compound I-38-a (250 mg, 0.8639 mmol) in 100.0% yield as a yellow solid. 1 H NMR(400MHz,DMSO)δ 9.25(s,1H),7.37(d,J=8.4Hz,2H),7.17(d,J=8.6Hz,2H),2.98(ddd,J=12.0,8.7,3.3Hz,1H),2.65-2.52(m,2H),2.2 5(dd,J=12.5,2.0Hz,2H),2.11-1.97(m,2H),1.83(ddd,J=25.9,13.2,4.0Hz,2H),1.47(s,9H).

[0491] Step 2: Potassium tert-butoxide (3 equiv., 1.866 mmol) was dissolved in dry tetrahydrofuran (1 mL), followed by the addition of a solution of p-toluenesulfonylmethyl isocyanide (1.5 equiv., 0.933 mmol) in dry tetrahydrofuran (1 mL) at room temperature. Compound I-38-a (180 mg, 0.6220 mmol) was dissolved in dry methanol (0.5 mL), and the solution was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by normal phase silica gel column chromatography (elution conditions: dichloromethane:methanol system, methanol concentration 0%-10%, volume 12 columns) to give compound I-38-b (60 mg, 0.1997 mmol) in 32.11% yield as a yellow solid. LC-MS: m / z: (M+H) + =244.7.

[0492] Step 3: Compound I-38-b (50 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred at room temperature for 12 hours. After concentrating the reaction mixture, aqueous NaHCO was added and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over NaSO, filtered, and concentrated to give compound I-38-c (50 mg, 0.159 mmol) in 96% yield as a yellow solid. LC-MS: m / z: (M+H) + =201.1.

[0493] Step 4: Compound I-15-c (50 mg, 0.1346 mmol) was dissolved in toluene (2 mL). mCPBA (1.2 equiv., 0.1616 mmol, 77% wt.) was added at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. Compound I-38-c (50 mg, 0.1346 mmol) and DIPEA (2 equiv., 0.2693 mmol) were added, in that order, at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with brine (1 × 20 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by normal phase silica gel column chromatography (elution conditions: dichloromethane:tetrahydrofuran system, tetrahydrofuran concentration 0% to 30%, volume 12 columns) to obtain compound I-38 (10 mg, 0.01910 mmol) in 14.19% yield as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.69(s,1H),8.18(d,J=8.0Hz,1H),8.10(dd,J=17.9,7.6Hz,1H),7.81-7.72(m,1H),7.63-7.49(m,2H),7.25(d, J=8.4Hz,1H),7.19(d,J=8.3Hz,1H),5.70(d,J=6.8Hz,1H),5.15(d,J=10.1Hz,1H),5.14-5.07(m,1H),4.95(d,J= 16.6Hz,1H),4.83(t,J=6.7Hz,2H),4.71(s,2H),2.54(dd,J=24.9,12.6Hz,2H),2.30(d,J=11.2Hz,1H),2.18(d, J=13.5Hz,1H), 2.02(d,J=12.9Hz,1H),1.96-1.80(m,2H),1.78(d,J=16.1Hz,1H),1.49(dd,J=26.4,11.2Hz,2H). LC-MS: m / z: (M+H) + =524.1.

[0494] Example 40:

[0495] [ka] Compound I-39 (70 mg, 0.12 mmol) was dissolved in a mixture of ethanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). Lithium hydroxide monohydrate (15 mg, 0.36 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by thin-layer chromatography (dichloromethane: ammonia·methanol (7 M): ethyl acetate = 7:1:1) to give a white solid (I-40, 40 mg, 60%). 1 H NMR(400MHz,CH3OH-d4)δ 8.84(s,1H),8.05(t,J=7.9Hz,1H),7.92(d,J=8.1Hz,1H),7.66(dd,J=7.6,0.9Hz,1H),7.6 3-7.53(m,2H),7.22-7.14(m,2H),5.84-5.74(m,1H),5.10-5.07(m,2H),5.06(q,J=1.3Hz, 1H),4.98(dq,J=17.0,1.4Hz,1H),4.89(dt,J=6.1,1.4Hz,2H),2.71(d,J=6.9Hz,1H),2.59 (s,1H),2.24(dd,J=16.4,7.8Hz,2H),2.04(d,J=8.5Hz,1H),1.73(td,J=10.9,6.8Hz,6H). LC-MS: m / z: [M+1] + =543.0.

[0496] Example 41:

[0497] [ka] Compound I-41-1 and Compound I-41-2 can be synthesized in the same manner as in Example 1 using 5-bromo-2-nitropyridine as a starting material. Compound 1-41-1: HPLC retention time (RT) = 6.17 minutes (HPLC conditions: mobile phase A was water (containing 0.1% HCOOH), mobile phase B was acetonitrile, gradient elution from 5% mobile phase B to 95% mobile phase B). 1H NMR(400MHz,CHCl3-d)δ 9.00(s,1H),8.30(d,J=8.6Hz,1H),8.22(d,J=2.4Hz,1H),7.96(t,J=7.9Hz,1H) ,7.73(dd,J=8.1,0.8Hz,1H),7.55(dd,J=8.7,2.4Hz,1H),7.44(dd,J=7.7,0.8Hz ,1H),5.77-5.66(m,1H),5.12-5.05(m,1H),4.97(dq,J=17.0,1.4Hz,1H),4.76(dt,J=6.3,1.3Hz ,2H),2.70(s,1H),2.56(s,6H),2.23(q,J=9.5Hz,4H),2.11-2.01(m,4H),1.58(t,J=10.3Hz,6H). LC-MS: m / z: [M+1] + =529.1. Compound 1-41-2: HPLC retention time (RT) = 6.28 min (HPLC conditions: mobile phase A was water (containing 0.1% HCOOH), mobile phase B was acetonitrile, gradient elution from 5% mobile phase B to 95% mobile phase B). 1 H NMR(400MHz,CHCl3-d)δ 8.99(s,1H),8.54(s,1H),8.32(d,J=8.7Hz,1H),8.26(d,J=2.4Hz,1H),8.10(t,J=7.7Hz,1H), 7.92(s,1H),7.78(dd,J=8.1,0.8Hz,1H),7.47-7.41(m,1H),5.79-5.71(m,1H),5.08(dq,J=10. 1,1.2Hz,1H),4.97(dq,J=17.0,1.3Hz,1H),4.77(dt,J=6.2,1.4Hz,2H),3.99(s,1H),2.75(d, J=11.0Hz,1H),2.52(s,6H),2.32-2.18(m,1H),2.09(d,J=14.4Hz,4H),1.31(d,J=22.8Hz,4H). LC-MS: m / z: [M+1] + =529.1.

[0498] With reference to the above examples, the compounds shown in Table 1 are prepared, whose structural characteristics are as follows:

[0499] [Table 1] TIFF0007789567000160.tif248170TIFF0007789567000161.tif245170

[0500] Effect Example 1: I. In vitro inhibitory effects of compounds on WEE1 kinase Test Method: Using ELISA, ATP concentration was measured using K m Test compounds were screened for WEE1 kinase. The kinase inhibitory activity of the test compounds was evaluated by screening the compounds for WEE1 kinase. During the measurement, the initial concentration of each test compound was 100 nM, and each compound was diluted to six concentrations with a 4-fold gradient dilution. Each concentration was measured in duplicate in the same wells, and MK1775 was used as the reference control.

[0501] WEE1 was purchased from CarnaBiosciences, Inc., catalog number 05-177; dimethyl sulfoxide was purchased from Sigma-Aldrich, catalog number D8418; ATP was purchased from Sigma-Aldrich, catalog number A7699; DTT solution was purchased from Sigma-Aldrich, catalog number 43816; protein tyrosine kinase (PTK) substrate (poly-Glu-Tyr) was purchased from Sigma-Aldrich, catalog number P4476; P-Tyr (PY99) was purchased from Santa Cruz, catalog number sc-7020; anti-mouse IgG HRP-linked antibody was purchased from Santa Cruz, catalog number 7076S; and TMB liquid substrate system (TMB liquid substrate system). The Costar Stripwell Microplate No Lid 1x8 Flat Bottom Certified High Binding was purchased from Sigma-Aldrich with a catalog number of 42592, and the 96-well compound storage plate was purchased from Thermo Scientific with a catalog number of 267245.

[0502] Test procedure: 1. Coating with substrate. 1) An appropriate volume of substrate stock solution, protein tyrosine kinase (PTK) substrate (poly-Glu-Tyr), was diluted 10-fold with PBS to a concentration of 250 mg / mL to 25 mg / mL. It was added to a high-adsorption 96-well plate, 125 μL per well. It was placed in a 37°C incubator for overnight coating. 2) After 24 hours, the 96-well plate was removed, the liquid was discarded, the plate was washed three times with washing buffer, and the plate was dried upside down in a 37°C incubator for 2 hours.

[0503] 2. Compound Preparation and Transfer. 1) Compound Dilution. Using a 10 mM test compound stock solution, the compound was serially diluted with DMSO in a 96-well compound storage plate to obtain an initial concentration of 100x. This concentration of compound was then used as the starting concentration, and a 4-fold gradient dilution with DMSO was performed to obtain six concentrations. 2 μL of each gradient dilution was then added to 48 μL of 1x reaction buffer to prepare 4x compound for use. 2) 4x Compound Transfer. 10 μL of 4x compound was transferred from the 96-well compound storage plate prepared in the previous step to a dry high-adsorption 96-well plate, and 10 μL of a solution prepared by adding 2 μL of DMSO to 48 μL of 1x reaction buffer was added to the no-compound control wells and ATP control wells.

[0504] 3. Enzyme reaction step. 1) Using 1x reaction buffer, a 2x enzyme solution was prepared from WEE1 kinase and a 4x ATP solution was prepared from ATP. In this screening, the final concentration of WEE1 kinase was 0.15 ng / μL, and the final concentration of ATP was 12 μM. 2) 20 μL of 2x enzyme solution was added to the high-binding 96-well plate. 3) 10 μL of 4x ATP solution was added to the high-binding 96-well plate, and 10 μL of 1x reaction buffer was added to the ATP control wells. 4) The plate was placed in a HERAEUS Multifuge X1R centrifuge and centrifuged at 2000 rpm for 20 seconds, then left to react at room temperature for 60 minutes.

[0505] 4. This is the end of the reaction. 1) The reaction mixture was discarded from the plate, and 200 μL of washing buffer was added to each well, followed by washing five times. 100 μL of primary antibody P-Tyr (PY99) (dilution ratio 1:2000) was added to each well and incubated at room temperature for 30 minutes. 2) The primary antibody was discarded from the plate, and 200 μL of washing buffer was added to each well and washed five times. 100 μL of secondary antibody anti-mouse IgG HRP-linked antibody (dilution ratio 1:2000) was added to each well and incubated at room temperature for 30 minutes. 3) The secondary antibody was discarded from the plate, and the plate was washed five times with washing buffer. 100 μL of TMB was added to each well and incubated for 10–30 minutes, depending on the desired color intensity. The reaction was terminated with 1N sulfuric acid before reading the results.

[0506] 5. Measurement and data processing. 1) The absorbance was measured at a wavelength of 450 nm using a ThermoScientific MultiScan GO, while the background was measured at 650 nm. 2) Using Graphpad Prism 5.0, the data were fitted with a Log (inhibitor) vs. response-variable slope (four parameters) curve to obtain the corresponding IC. 50 (half inhibitory concentration The maximum inhibitory concentration was calculated.

[0507] 2. Test result data See Table 2 for the structure of the control sample used in the test.

[0508] [Table 2]

[0509] See Table 3 for details of the test results.

[0510] [Table 3] Conclusion: As is clear from Table 3, the compounds according to the present invention have excellent inhibitory effects on WEE1 kinase.

[0511] Efficacy Example 2: In vivo bioavailability experiment using mice 1. Experimental animals and samples 1. Experimental Animals

[0512] [Table 4] The above animals were provided by Shanghai Xipulpikai Experimental Animal Co., Ltd.

[0513] 2. Sample Preparation 2.1 Preparation of mother liquor 404.6 μL of DMSO was added to the powder of the compound according to the present invention, and it was completely dissolved to obtain a 50 mg / mL mother liquid in a clarified state.

[0514] 2.2 Preparation of Dosing Solutions 24 μL of the mother solution of the compound of the present invention was accurately measured and diluted to 4 mL with 0.9% saline:PEG400 = 8:2 ratio to prepare a concentration of 0.3 mg / mL. The solution was clarified and used as an intravenous solution. 80 μL of the mother solution was also accurately measured and diluted with 0.5% CMC-Na to make 8 mL, followed by grinding to prepare a uniform solution of 0.5 mg / mL. A suitable suspension is obtained, which is used as the solution for intragastric administration.

[0515] 2. Animal Experiments The intravenous group consisted of 24 ICR mice weighing 20±2 g. An intravenous solution of the compound of the present invention was intravenously administered at a volume of 10 mL / kg and a dose of 3 mg / kg. 0.08 mL of blood was collected from the orbital venous plexus of the mice before administration and 2, 5, 15, 30, 60, 90, 120, 240, 360, 480, 600, and 1440 minutes after administration.

[0516] The intragastric administration group consisted of 24 ICR mice weighing 20±2 g. An intragastric administration solution of the compound according to the present invention was intragastrically administered at a volume of 20 mL / kg and a dose of 10 mg / kg. 0.08 mL of blood was collected from the orbital venous plexus of the mice before administration and 5, 15, 30, 60, 90, 120, 240, 360, 480, 600, and 1440 minutes after administration.

[0517] Blood samples were centrifuged at 8000 rpm for 5 minutes and plasma was collected in a centrifuge tube and stored at -20°C for further use.

[0518] 3. Plasma sample processing 1. Creating a standard curve The concentration ranges of the standard curve working solutions were 60, 20, 6, 2, 0.6, 0.2, 0.1, 0.04, and 0.02 μg / mL.

[0519] 2.5 μL of the standard curve working solution was added to 47.5 μL of blank mouse plasma to prepare samples with a series of concentrations of 3, 1, 0.3, 0.1, 0.0.3, 0.01, 0.005, 0.002, and 0.001 μg / mL. The samples were vortexed to mix uniformly, and 300 μL of acetonitrile containing an internal standard (propranolol, 25 ng / mL) was added to precipitate the proteins. The samples were vortexed and shaken for 10 minutes, then centrifuged at 6000 g and 4°C for 10 minutes, and the supernatants were injected into a 96-well plate.

[0520] 2. QC sample processing The concentration ranges of the QC working solutions were: low 0.06 μg / mL, middle 1.6 μg / mL, and high 48 μg / mL.

[0521] 2.5 μL of QC working solution was added to 47.5 μL of blank mouse plasma to prepare samples with a series of concentrations of 2.4, 0.08, and 0.003 μg / mL. The samples were vortexed to mix uniformly, and 300 μL of acetonitrile containing an internal standard (propranolol, 25 ng / mL) was added to precipitate the proteins. The samples were vortexed and shaken for 10 minutes, then centrifuged at 6000 g and 4°C for 10 minutes, and the supernatant was injected into a 96-well plate.

[0522] 3. Plasma Sample Processing 300 μL of acetonitrile containing an internal standard (propranolol, 25 ng / mL) was added to 50 μL of plasma sample to precipitate proteins, vortexed for 10 minutes, and centrifuged at 6000 g and 4°C for 10 minutes. The supernatant 1 hour before intravenous administration was diluted 10-fold with acetonitrile containing the internal standard, and the remaining supernatant was not diluted and centrifuged again at 6000 g and 4°C for 10 minutes. The supernatant was then injected into a 96-well plate.

[0523] 4. Results of in vivo bioavailability experiments using mice 1. Test parameters Dose, peak concentration C max , peak time T max , the area under the drug-time curve from 0 to time t, AUC last , half-life T 1 / 2 , mean residence time MRT, clearance Rate Cl, apparent volume of distribution V z , steady-state volume of distribution V ss , absolute bioavailability F.

[0524] 2. Pharmacokinetic data in mice Pharmacokinetic parameters in mice after intravenous injection and intragastric administration of the compounds are shown in Tables 4 and 5 below.

[0525] [Table 5]

[0526] [Table 6] Conclusion: The compounds of the present invention can obviously improve the pharmacokinetics in mice.

[0527] Efficacy Example 3: In vivo bioavailability experiment using cynomolgus monkeys 1. Experimental animals and samples Twelve non-naive male cynomolgus monkeys were purchased from Guangxi Guidong Primate Development Experimental Co., Ltd.

[0528] [Table 7]

[0529] 2. Sample preparation Sample preparation is based on free base concentration, regardless of purity.

[0530] 3. Preparation of administration solution 1. Preparation of I-8-1: Accurately weigh 54.31 mg of I-8-1, add 1.08 mL of DMSO, vortex for 1 minute, sonicate for 15 minutes, then dilute to 36 mL with 10% HP-β-cyclodextrin (prepared in saline):PEG = 8:2, vortex for 1 minute, and prepare a colorless, clear, and clarified dosing solution (pH 7) at a concentration of 1.5 mg / mL for intravenous administration to Group 1.

[0531] Accurately weigh 300.9 mg of I-8-1 and add 75 mL of 0.5% CMC-Na. The mixture was thoroughly ground and stirred for 5 minutes to prepare a white suspension (pH about 7) with a concentration of 4 mg / mL, which was then used for oral administration to Group 2.

[0532] 2. Preparation of AZD1775: Accurately weigh out 54.05 mg of AZD1775, add 1.08 mL of DMSO, vortex for 1 minute, sonicate for 15 minutes, then dilute to 36 mL with 10% HP-β-cyclodextrin (prepared in saline):PEG = 8:2, vortex for 1 minute, and prepare a clear, yellow administration solution (pH 7) at a concentration of 1.5 mg / mL, which will be used for intravenous administration in Group 3.

[0533] Accurately weigh out 300.7 mg of AZD1775, add 75 mL of 0.5% CMC-Na, thoroughly grind, and stir for 5 minutes to prepare a yellow suspension (pH about 7) with a concentration of 4 mg / mL, which will be used for oral administration in Group 4.

[0534] 4. Animal Experiments 1. Dosage and administration method Prior to dosing, all animals are fasted overnight (approximately 12 hours), fed routinely, and dosed as follows:

[0535] [Table 8]

[0536] 2. Collection and processing of plasma samples Intravenous group: before administration (0 hours), 0.033 hours, 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration. Oral group: before administration (0 hours), 0.083 hours, 0.25 hours, 0.5 hours, 1.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours after administration.

[0537] Blood samples were collected by puncture from a leg vein or other suitable blood vessel at a rate of 1 mL per time point (a 3 mL blood sample was collected from each animal before administration), anticoagulated with sodium heparin, and placed on ice after collection. Plasma was obtained by separating at 2-8°C after 10 minutes at 2200 g / min. The plasma samples were then stored in a -80°C refrigerator before being handed over to the client. Plasma samples were stored on dry ice and handed over to the client. The final disposal of the samples was recorded in the experimental record.

[0538] 5. Plasma sample processing 1. Creating a standard curve The concentration ranges of the standard curve working solutions were 60, 20, 6, 2, 0.6, 0.2, 0.1, 0.04, and 0.02 μg / mL.

[0539] 2.5 μL of the standard curve working solution was added to 47.5 μL of blank cynomolgus monkey plasma to prepare a series of samples with concentrations of 3, 1, 0.3, 0.1, 0.03, 0.01, 0.005, 0.002, and 0.001 μg / mL. The samples were vortexed to homogenize, and 300 μL of acetonitrile containing the internal standard (propranolol, 25 ng / mL) was added to precipitate the proteins. The samples were vortexed and shaken for 10 minutes, then centrifuged at 6000×g for 10 minutes. 80 μL of the supernatant was injected into a 96-well plate.

[0540] 2. QC sample processing The concentration ranges of the QC working solutions were: low 0.06 μg / mL, middle 1.6 μg / mL, and high 48 μg / mL.

[0541] 2.5 μL of the standard curve working solution was added to 47.5 μL of blank cynomolgus monkey plasma to prepare a series of samples at concentrations of 2.4, 0.08, and 0.003 μg / mL. The mixture was vortexed to homogenize, and 300 μL of acetonitrile containing an internal standard (propranolol, 25 ng / mL) was added to precipitate the proteins. The mixture was vortexed and shaken for 10 minutes, then centrifuged at 6000 g for 10 minutes. 80 μL of the supernatant was injected into a 96-well plate.

[0542] 3. Plasma Sample Processing 300 μL of acetonitrile containing an internal standard (propranolol, 25 ng / mL) was added to 50 μL of plasma sample to precipitate proteins, followed by vortexing for 10 minutes and centrifugation at 6000 g for 10 minutes. The I-8-1 and AZD1775 intravenous administration groups were diluted 10-fold with acetonitrile containing an internal standard (propranolol, 25 ng / mL) one hour before administration. The remaining supernatant was not diluted and was again centrifuged at 6000 g and 4°C for 10 minutes, and the supernatant was injected into a 96-well plate.

[0543] 6. Results of bioavailability experiments using cynomolgus monkeys 1. Test parameters Dose, peak concentration C max , peak time T max , the area under the drug-time curve from 0 to time t, AUC last , half-life T 1 / 2 , mean residence time MRT, clearance rate Cl, apparent volume of distribution V z , steady-state volume of distribution V ss , absolute bioavailability F.

[0544] 2. Pharmacokinetic data See Table 6 for in vivo pharmacokinetic parameters in cynomolgus monkeys after intravenous injection and intragastric administration of the compounds.

[0545] [Table 9] Conclusion: The compounds of the present invention can obviously improve the pharmacokinetics in cynomolgus monkeys.

[0546] It should be noted that, for those skilled in the art, the specific embodiments of the present invention have been described above, but these are merely examples, and various changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Therefore, the scope of protection of the present invention is limited by the appended claims.

Claims

1. A pyrazolone-fused pyrimidine compound represented by Formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (Wherein A is one or two R １ C replaced by ３ ~C ２０ is a cycloalkyl group, X is CH or N; Each R １ are independently halogen, —CN, —NR １－３ R １－４ , -C(=O)R １－５ , C ３ ~C １４ Cycloalkyl group, C ３ ~C １４ heterocycloalkyl group, or C １ ~C ６ is a heteroaryl group, ３ ~C １４ Cycloalkyl group, C ３ ~C １４ heterocycloalkyl group, or C １ ~C ６ The heteroaryl group optionally comprises one, two, or three R １－８ is replaced by R １－３ and R １－４ are independently hydrogen, —C(═O)R １－３－２ , C １ ~C ６ Alkyl group, C ２ ~C ７ Alkenyl group, C ２ ~C ７ Alkynyl group, C ３ ~C １４ Cycloalkyl group, C ３ ~C １４ Heterocycloalkyl group, C ６ ~C １０ an aryl group, or C １ ~C ６ is a heteroaryl group, １ ~C ６ Alkyl group, C ２ ~C ７ Alkenyl group, C ２ ~C ７ Alkynyl group, C ３ ~C １４ Cycloalkyl group, C ３ ~C １４ Heterocycloalkyl group, C ６ ~C １０ an aryl group, or C １ ~C ６ The heteroaryl group optionally comprises one, two, or three R １－３－１１ is replaced by Or, R １－３ and R １－４ and the nitrogen atom connected thereto may optionally be one, two or three R １－３－１１ C replaced by ３ ~C １４ forming a heterocycloalkyl group, Each R １－３－２ is independently C １ ~C ７ Alkyl group or C ３ ~C １４ is a cycloalkyl group, R １－３－３ are independently hydrogen, -CN, C １ ~C ７ Alkyl group, C ２ ~C ７ Alkenyl group, C ２ ~C ７ Alkynyl group or C ３ ~C １４ is a cycloalkyl group, R １－３－５ , R １－３－６ , R １－３－７ , R １－３－８ , R １－３－９ , R １－３－１０ are independently hydrogen, C １ ~C ７ Alkyl group, C ２ ~C ７ Alkenyl group, C ２ ~C ７ Alkynyl group or C ３ ~C １４ is a cycloalkyl group, Each R １－３－１１ are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, C １ ~C ７ Alkyl group, C １ ~C ７ Alkoxy group, C １ ~C ７ Alkylthio group, C ２ ~C ７ Alkenyl group, C ２ ~C ７ Alkynyl group, C ３ ~C １４ Cycloalkyl group, C ３ ~C １４ Heterocycloalkyl group, C ６ ~C １０ Aryl group, C １ ~C ７ a heteroaryl group, or one or two R １－３－１１－１ and each R １－３－１１－１ is independently C １ ~C ７ Alkyl group or C ３ ~C １４ is a cycloalkyl group, Each R １－５ are independently hydrogen, —NR １－５－１ R １－５－２ , -OR １－５－３ , C ３ ~C １４ a cycloalkyl group, or C ３ ~C １４ is a heterocycloalkyl group, R １－５－１ , R １－５－２ are independently hydrogen, C １ ~C ７ an alkyl group or C ３ ~C １４ is a cycloalkyl group, R １－５－３ are independently hydrogen, C １ ~C ７ Alkyl group, or C ３ ~C １４ is a cycloalkyl group, Each R １－８ is independently C １ ~C ７ Alkyl group or C ３ ~C １４ is a cycloalkyl group, R ２ optionally one, two or three R ２－２ C, substituted by ２ ~C ７ Alkyl group, C ３ ~C １４ Cycloalkyl group or C ３ ~C １４ is a heterocycloalkyl group, R ２－２ are independently a halogen or a hydroxy group; In either case, the C ３ ~C １４ Heterocycloalkyl group and C １ ~C ７ The heteroatoms in the heteroaryl group are independently selected from one or more of oxygen, sulfur, and nitrogen, and the number of heteroatoms is independently 1, 2, 3, or 4.

2. A pyrazolone-fused pyrimidine compound represented by formula II according to claim 1, characterized in that it is a pyrazolone-pyrimidine compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 2】 (Wherein A is one or two R １ C replaced by ３ ~C ２０ is a cycloalkyl group, Each R １ are independently halogen, —CN, —NR １－３ R １－４ , -C(=O)R １－５ or optionally one, two or three R １－８ C, substituted by ３ ~C １４ Cycloalkyl group, C ３ ~C １４ Heterocycloalkyl group or C １ ~C ６ is a heteroaryl group, R １－３ and R １－４ are independently hydrogen, —C(═O)R １－３－２ or optionally one, two or three R １－３－１１ C, substituted by １ ~C ７ Alkyl group, C ２ ~C ７ Alkenyl group, C ２ ~C ７ Alkynyl group, C ３ ~C １４ Cycloalkyl group, C ３ ~C １４ Heterocycloalkyl group, C ６ ~C １０ an aryl group, or C １ ~C ６ is a heteroaryl group, Or, R １－３ , R １－４ and the nitrogen atom connected thereto may optionally be one or two R １－３－１２ C replaced by ３ ~C １４ forming a heterocycloalkyl group, Each R １－３－２ is independently C １ ~C ７ Alkyl group or C ３ ~C １４ is a cycloalkyl group, Each R １－３－１１ are independently a halogen, a hydroxy group, an amino group, a mercapto group, a cyano group, C １ ~C ７ Alkyl group, C １ ~C ７ Alkoxy group, C １ ~C ７ Alkylthio group, C ２ ~C ７ Alkenyl group, C ２ ~C ７ Alkynyl group, C ３ ~C １４ Cycloalkyl group, C ３ ~C １４ Heterocycloalkyl group, C ６ ~C １０ Aryl group, C １ ~C ６ a heteroaryl group, or one or two R １－３－１１－１ and each R １－３－１１－１ is independently C １ ~C ７ Alkyl group or C ３ ~C １４ is a cycloalkyl group, Each R １－５ are independently hydrogen, —NR １－５－１ R １－５－２ , -OR １－５－３ or optionally one, two or three R １－５－４ C, substituted by １ ~C ７ Alkyl group, C ２ ~C ７ Alkenyl group, C ２ ~C ７ Alkynyl group, C ３ ~C １４ Cycloalkyl group, C ３ ~C １４ Heterocycloalkyl group, C ６ ~C １０ an aryl group, or C １ ~C ６ is a heteroaryl group, R １－５－１ , R １－５－２ are independently hydrogen, C １ ~C ７ an alkyl group or C ３ ~C １４ is a cycloalkyl group, R １－５－３ are independently hydrogen, C １ ~C ７ Alkyl group, or C ３ ~C １４ is a cycloalkyl group, Each R １－８ is independently C １ ~C ７ Alkyl group or C ３ ~C １４ is a cycloalkyl group, R ２ optionally one, two or three R ２－２ C, substituted by ２ ~C ７ Alkyl group, C ３ ~C １４ Cycloalkyl group or C ３ ~C １４ is a heterocycloalkyl group, Each R ２－２ are independently a halogen or a hydroxy group; In either case, the C ３ ~C １４ Heterocycloalkyl group and C １ ~C ７ The heteroatoms in the heteroaryl group are independently selected from one or more of oxygen, sulfur, and nitrogen, and the number of heteroatoms is independently 1, 2, 3, or 4.

3. A is one or two R １ C replaced by ３ ~C ２０ When the C is a cycloalkyl group, ３ ~C ２０ The cycloalkyl group is C ３ ~C ２０ Monocyclic cycloalkyl group, C ３ ~C ２０ Spirocyclic cycloalkyl group, C ３ ~C ２０ fused ring cycloalkyl group or C ３ ~C ２０ A pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, characterized in that it is a bridged ring cycloalkyl group, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

4. A is one or two R １ C replaced by ３ ~C ２０ The cycloalkyl group is ３ ~C ２０ The cycloalkyl group is C ３ ~C ２０ When the C is a monocyclic cycloalkyl group, ３ ~C ２０ The monocyclic cycloalkyl group is C ３ ~C ６ A pyrazolone-fused pyrimidine compound of formula II according to claim 3, characterized in that it is a monocyclic cycloalkyl group, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

5. A is one or two R １ C replaced by ３ ~C ２０ When the C is a cycloalkyl group, ３ ~C ２０ The cycloalkyl group is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. ３ ~C ２０ A pyrazolone-fused pyrimidine compound of formula II according to claim 4, characterized in that it is a monocyclic cycloalkyl group, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

6. A is one R １ C replaced by ３ ~C ２０ A is a cycloalkyl group. 【Transformation 3】 and 【Chemistry 4】 teeth, 【Transformation 5】 and 【Transformation 6】 teeth, 【Transformation 7】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

7. A is one R １ C replaced by ３ ~C ２０ A pyrazolone-fused pyrimidine compound of formula II according to claim 1 or claim 2, characterized in that it is a cycloalkyl group, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

8. A is one R １ C replaced by ３ ~C ２０ is a cycloalkyl group, and R １ is C ３ ~C １４ A pyrazolone-fused pyrimidine compound of formula II according to claim 1 or claim 2, characterized in that it is a heterocycloalkyl group, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

9. R １ is C ４ ~C ６ 9. The pyrazolone-fused pyrimidine compound of formula II according to claim 8, wherein the heterocycloalkyl group is a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

10. The pyrazolone pyrimidine compound represented by formula II is a compound of formula I, 【Transformation 8】 A is one or two R １ replaced by 【Chemistry 9】 and Each R １ optionally one, two or three R １－８ C, substituted by ３ ~C １４ Cycloalkyl group or C ３ ~C １４ is a heterocycloalkyl group, Each R １－８ is independently C １ ~C ７ Alkyl group or C ３ ~C １４ is a cycloalkyl group, R ２ optionally one, two or three R ２－２ C, substituted by ２ ~C ７ Alkyl group, C ３ ~C １４ Cycloalkyl group or C ３ ~C １４ is a heterocycloalkyl group, Each R ２－２ are independently a halogen or a hydroxy group; In either case, the C ３ ~C １４ Heterocycloalkyl group and C １ ~C ７ A pyrazolone-fused pyrimidine compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, as described in claim 1 or claim 2, characterized in that the heteroatoms in the heteroaryl group are independently selected from one or more of oxygen, sulfur, and nitrogen, and the number of heteroatoms is independently 1, 2, 3, or 4.

11. The pyrazolone pyrimidine compound of formula II according to claim 1 or claim 2, characterized in that the pyrazolone pyrimidine compound is a compound selected from the following compounds: a pyrazolone-fused pyrimidine compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 10】

12. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 11】 1. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, which is compound I-1-1 or compound I-1-2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

13. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 12】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

14. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 13】 1. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, which is compound I-3-1 or compound I-3-2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

15. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 14】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

16. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 15】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

17. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 16】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

18. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 17】 or compound I-8-1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

19. The pyrazolone pyrimidine compound represented by formula II is [Chemistry 18] or compound I-8-2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

20. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 19】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, which is compound I-15-1 or compound I-15-2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

21. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 20】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

22. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 21】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

23. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 22】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

24. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 23】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

25. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 24】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

26. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 25】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

27. ​​The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 26】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

28. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 27】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

29. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 28】 or compound I-36-2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

30. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 29】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

31. The pyrazolone pyrimidine compound represented by formula II is 【Transformation 30】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

32. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 31】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

33. The pyrazolone pyrimidine compound represented by formula II is 【Chemistry 32】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

34. The pyrazolone pyrimidine compound represented by formula II is 【Transformation 33】 3. The pyrazolone-fused pyrimidine compound of formula II according to claim 1 or 2, which is compound I-41-1 or compound I-41-2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising a pharmaceutical additive and the pyrazolone-fused pyrimidine compound according to any one of claims 1 to 34, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

Images