CN112142763A

CN112142763A - Pyrazolone pyrimidine compound, preparation method and application thereof

Info

Publication number: CN112142763A
Application number: CN202010600148.4A
Authority: CN
Inventors: 王倩; 张霖; 夏广新; 楼江松; 葛辉; 霍国永; 舒思杰; 石辰; 张弛; 张智慧; 毛煜; 张冰宾; 余建鑫; 柯樱; 刘彦君
Original assignee: Shanghai Phaarmaceuticals Holding Co ltd
Current assignee: Shanghai Phaarmaceuticals Holding Co ltd
Priority date: 2019-06-28
Filing date: 2020-06-28
Publication date: 2020-12-29
Anticipated expiration: 2040-06-28
Also published as: CN112142763B

Abstract

The invention discloses a pyrazolone pyrimidine compound, a preparation method and application thereof. The invention provides a pyrazolone pyrimidine compound shown as a formula A, which has better inhibition activity on WEE1 kinase.

Description

Pyrazolone pyrimidine compound, preparation method and application thereof

Technical Field

The invention relates to a pyrazolone pyrimidine compound, a preparation method and application thereof.

Background

The cell cycle is closely related to the DNA damage repair process. The cell cycle refers to the whole process of cell division, and is divided into two stages, inter phase (interphase) and mitotic phase (M). The cell cycle checkpoint (checkpoint) is a key point for regulating the cell cycle, and mainly has the functions of ensuring that each event in the cycle can be completed in time and order and regulating the cell state to be adaptive to the external environment.

The main test points of cells are: 1) G1/S checkpoint: in mammals, termed the r (restriction) point, the control cell passes from the resting G1 phase into the DNA synthesis phase; 2) checking points in the S phase: whether DNA replication is complete; 3) G2/M checkpoint: is a control point that regulates the entry of cells into the division phase; 4) mid-late checkpoint: also known as spindle assembly checkpoints, cause cell cycle disruption if the centromere is not properly attached to the spindle. If abnormalities in certain processes of the cell division cycle exist, such as DNA damage, the checkpoint senses and initiates repair in time. The P53 protein is an important protein for regulating a G1 checkpoint, prevents cells from entering S phase when DNA is damaged, activates a DNA repair mechanism, and is important for maintaining the integrity of cell genomes. However, since tumor cells often have a P53 mutation that makes the G1 checkpoint deficient, cell division cycle regulation in P53 mutated cells is dependent on the G2/M checkpoint.

WEE1 kinase is a cell cycle regulatory protein, can regulate and control the phosphorylation state of cyclin-dependent kinase 1 (CDK 1), thereby regulating the activity of CDK1 and cyclin B (cyclin B) complex to realize regulation and control of cell cycle, and has important regulation effect on DNA damage check points. WEE1 is a key gene of G2/M phase block, plays an important monitoring role, and can cause mitotic catastrophe by over-expression, inhibition or down-regulation of WEE1 kinase in some cancers, so WEE1 kinase inhibitor has a key role in anticancer therapy and is a research and development hotspot of anticancer agents at present.

International patent applications WO2019037678, WO2019028008, WO2018133829, WO2010098367, WO2010067886, WO2008115742, WO2008115738, WO2007126122, WO2007126128, WO2004007499 and the like disclose partial small molecule WEE1 kinase inhibitors, but no small molecule WEE1 kinase inhibitor is on the market at present, and a new WEE1 kinase inhibitor with good anticancer activity and high safety needs to be developed in the field.

Disclosure of Invention

The invention aims to solve the technical problem that the existing compound with the inhibition activity on WEE1 kinase has a single structure, so that the invention provides a pyrazolone pyrimidine compound, a preparation method and application thereof, and the compound has better inhibition activity on WEE1 kinase.

The invention provides a pyrazolone pyrimidine compound shown as a formula A or pharmaceutically acceptable salt thereof;

x is a single bond or CH₂；

Y is N or CH;

z is a single bond or CH₂；

R¹Is H, -CN, -C (═ O) R^1-1、-C(＝NR^1-2)R^1-3、-S(＝O)₂R^1-4、

Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

R^1-1is hydrogen, cyano, -NR^1-1-1R^1-1-2、-OR^1-1-3Or, optionally substituted with 1,2 or 3R^1-1-4Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

R^1-1-1and R^1-1-2Independently of one another is hydrogen, C₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

or, R^1-1-1、R^1-1-2And the nitrogen atom to which they are attached form C₃～C₁₄A heterocycloalkyl group; said C₃～C₁₄1 or 2 or more methylene groups in the heterocycloalkyl group are optionally and independently replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group or-N (R)^1-1-1-1) -substitution of the indicated group; r^1-1-1-1Independently halogen, -OH, C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-1-3is hydrogen, C₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

R^1-1-4independently halogen, -OH, -CN, amino, mercapto, C₁～C₇Alkyl radical, C₁～C₇Alkoxy radical, C₁～C₇Alkylthio radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl radical, C₁～C₇Heteroaryl, or substituted by 1 or 2R^1-1-4-1A substituted amino group; r^1-1-4-1Independently is C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-2is hydrogen, -CN, -OR^1-2-1Or C₁～C₇An alkyl group;

R^1-2-1is hydrogen, C₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

R^1-3is-NR^1-3-1R^1-3-2Or, optionally substituted with 1,2 or 3R^1-3-3Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

R^1-3-1and R^1-3-2Independently of one another is hydrogen, C₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

or, R^1-3-1、R^1-3-2And the nitrogen atom to which they are attached form C₃～C₁₄A heterocycloalkyl group; said C₃～C₁₄1 or 2 or more methylene groups in the heterocycloalkyl group are optionally and independently replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group or-N (R)^1-3-1-1) -substitution of the indicated group; r^1-3-1-1Independently halogen, -OH, C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-3-3independently halogen, -OH, -CN, amino, mercapto, C₁～C₇Alkyl radical, C₁～C₇Alkoxy radical, C₁～C₇Alkylthio radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl radical, C₁～C₇Heteroaryl, or substituted by 1 or 2R^1-3-3-1A substituted amino group; r^1-3-3-1Independently is C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-4is-OH, -NR^1-4-1R^1-4-2Or, optionally substituted with 1,2 or 3R^1-4-3Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl, or, C₁～C₇A heteroaryl group;

R^1-4-1and R^1-4-2Independently of one another is hydrogen, C₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

or, R^1-4-1、R^1-4-2And the nitrogen atom to which they are attached form C₃～C₁₄A heterocycloalkyl group; said C₃～C₁₄1 or 2 or more methylene groups in the heterocycloalkyl group are optionally and independently replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group or-N (R)^1-4-1-1) -substitution of the indicated group; r^1-4-1-1Independently halogen, -OH, C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-4-3independently halogen, -OH, -CN, amino, mercapto, C₁～C₇Alkyl radical, C₁～C₇Alkoxy radical, C₁～C₇Alkylthio radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl radical, C₁～C₇Heteroaryl, or substituted by 1 or 2R^1-4-3-1A substituted amino group; r^1-4-3-1Independently is C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-5independently halogen, -OH, -SH, -CN, -NR^1-5-1R^1-5-2、-(C＝O)R^1-5-3Or, optionally substituted with 1,2 or 3R^1-5-4Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₁～C₇Alkoxy radical, C₁～C₇Alkanemercapto group, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₁₀A heteroaryl group;

R^1-5-1and R^1-5-2Independently of one another is hydrogen, C₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

or, R^1-5-1、R^1-5-2And the nitrogen atom to which they are attached form C₃～C₁₄A heterocycloalkyl group; said C₃～C₁₄1 or 2 or more methylene groups in the heterocycloalkyl group are optionally and independently replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group or-N (R)^1-5-1-1) -substitution of the indicated group; r^1-5-1-1Independently halogen, -OH, C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-5-3independently hydrogen, -OR^1-5-3-1、-NR^1-5-3-2R^1-5-3-3、C₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

R^1-5-3-1、R^1-5-3-2and R^1-5-3-3Independently of one another is hydrogen, C₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

R^1-5-4independently halogen, -OH, -CN, amino, mercapto, C₁～C₇Alkyl radical, C₁～C₇Alkoxy radical, C₁～C₇Alkylthio radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl radical, C₁～C₇Heteroaryl, or substituted by 1 or 2R^1-5-4-1A substituted amino group; r^1-5-4-1Independently is C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-6and R^1-7Independently is hydrogen or C₁～C₇An alkyl group;

R²is optionally substituted by 1,2 or 3R^2-1Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl or C₃～C₁₄A heterocycloalkyl group;

R^2-1independently halogen, hydroxy, amino, C₁～C₇Alkyl radical, C₁～C₇Alkoxy radical, C₃～C₁₄Cycloalkyl or C₃～C₁₄A heterocycloalkyl group;

in any of the above cases, C is₃～C₁₄Heterocycloalkyl radical, C₁～C₇The heteroatoms in the heteroaryl group are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus; the number of heteroatoms is independently 1,2, 3 or 4.

In one embodiment, certain substituents of the pyrazolopyrimidine compound of formula a or a pharmaceutically acceptable salt thereof may further have the following definitions, where the definition of the substituents not referred to below is as described in any of the above (hereinafter referred to simply as "in one embodiment"):

the pyrazolone pyrimidine compound shown as the formula A is not

In one aspect:

said

Is composed of

In one aspect of the present invention,

for example

Also for example

Also for example

In a certain scheme, the pyrazolone pyrimidine compound shown in the formula A is a compound shown in the formula I

Said

Is composed of

In one aspect:

when R is¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl radicals such as C₁～C₃Alkyl, again for example methyl, ethyl, n-propyl or isopropyl.

In one aspect:

when R is^1-5Independently halogen, such as fluorine, chlorine, bromine or iodine, and further such as fluorine.

In one aspect:

when R is¹Is represented by 1,2 or 3R^1-5Substituted C₁～C₇Alkyl radical, R^1-5Independently halogen, said "is substituted by 1,2 or 3R^1-5Substituted C₁～C₇Alkyl "may be 2, 2-difluoroethyl or 3,3, 3-trifluoropropyl.

In one aspect:

when R is¹Is 1R^1-5Substituted C₁～C₇Alkyl radical, R^1-5Independently CN, said "is substituted by 1R^1-5Substituted C₁～C₇Alkyl "may be 2-cyanoethyl.

In one aspect:

when R is^1-5Independently is C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl radicals such as C₃～C₁₄Monocyclic cycloalkyl, C₃～C₁₄Spirocyclic cycloalkyl radical, C₃～C₁₄Cycloalkyl having condensed rings or C₃～C₁₄Bridged cycloalkyl.

Said C₃～C₁₄Monocyclic cycloalkyl such as C₃～C₆Monocyclic cycloalkyl, in turn, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and also for example cyclobutyl, cyclopentyl or cyclohexyl.

Said C₃～C₁₄Bridged cycloalkyl radicals such as C₅～C₈Bridged cycloalkyl radicals, e.g.

Or

In one aspect:

when R is^1-5Independently is C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl radicals such as C₃～C₁₄A saturated cycloalkyl group.

In one aspect:

when R is¹Is 1R^1-5Substituted C₁～C₇Alkyl radical, R^1-5Independently is C₃～C₁₄When cycloalkyl is present, said "is substituted by 1R^1-5Substituted C₁～C₇Alkyl "may be cyclopropylmethyl or cyclohexylmethyl.

In one aspect:

when R is^1-5-3-1Is C₁～C₇When alkyl, said C₁～C₇Alkyl radicals such as C₁～C₃Alkyl, such as methyl, ethyl, n-propyl or isopropyl, and also ethyl.

In one aspect:

when R is¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl radicals such as C₃～C₁₄Monocyclic cycloalkyl, C₃～C₁₄Spirocyclic cycloalkyl radical, C₃～C₁₄Cycloalkyl having condensed rings or C₃～C₁₄Bridged cycloalkyl.

Or

In one aspect:

when R is¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl radicals such as C₃～C₁₄A saturated cycloalkyl group.

In one aspect:

when R is¹Is 1R^1-5Substituted C₃～C₁₄Cycloalkyl radical, R^1-5Independently is-NR^1-5-1R^1-5-2When said is "by 1R^1-5Substituted C₃～C₁₄Cycloalkyl "is for example 3-aminocyclobutyl.

In one aspect:

when R is¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When it is heterocycloalkyl, said C₃～C₁₄Heterocycloalkyl radicals such as C₃～C₁₄Monocyclic heterocycloalkyl, C₃～C₁₄Spirocyclic heterocycloalkyl, C₃～C₁₄Condensed ring heterocycloalkyl or C₃～C₁₄Bridged heterocycloalkyl.

Said C₃～C₁₄Monocyclic heterocycloalkyl such as "C having 1 or 2 hetero atoms selected from N, O and S₃～C₉Monocyclic heterocycloalkyl ", for example, having" 1 or 2 heteroatom (S) selected from N, O and C of one or both of S₃～C₅Monocyclic heterocycloalkyl ", also for example" C having 1 or 2 heteroatoms selected from one or both of N, O and S₃～C₅Monocyclic heterocycloalkyl ", and which is linked to the benzene ring via a carbon atomAnd further for example oxetanyl or piperidinyl.

Said piperidinyl radical for example

Said oxetane group being, for example

In one aspect:

when R is¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When it is heterocycloalkyl, except R^1-5In addition, said C₃～C₁₄The heteroatoms in the heterocycloalkyl group may be unsubstituted.

In one aspect:

when R is¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When it is heterocycloalkyl, said C₃～C₁₄The methylene group in the heterocycloalkyl group may be unsubstituted or substituted.

In one aspect:

when R is^1-5Is optionally substituted by 1,2 or 3R^1-5-4Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl radicals such as C₁～C₃Alkyl, again for example methyl, ethyl, n-propyl or isopropyl.

In one aspect:

when R is¹Is optionally substituted by 1R^1-5Substituted C₃～C₁₄Heterocycloalkyl, R^1-5Is C₁～C₇When alkyl, said "is optionally substituted by 1R^1-5Substituted C₃～C₁₄Heterocycloalkyl "e.g.

In one aspect:

when R is^1-1Is optionally substituted by 1,2 or 3R^1-1-4Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl radicals such as C₁～C₃Alkyl, in turn, for example methyl, ethyl, n-propyl or isopropyl, and also for example methyl or ethyl.

In one aspect:

when R is^1-1Is optionally substituted by 1R^1-1-4Substituted C₁～C₇Alkyl radical, R^1-1-4When it is-OH, said "is optionally substituted by 1R^1-1-4Substituted C₁～C₇Alkyl groups "such as hydroxymethyl.

In one aspect:

when R is^1-1Is optionally substituted by 1,2 or 3R^1-1-4Substituted C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl radicals such as C₃～C₁₄Monocyclic cycloalkyl, C₃～C₁₄Spirocyclic cycloalkyl radical, C₃～C₁₄Cycloalkyl having condensed rings or C₃～C₁₄Bridged cycloalkyl.

Or

In one aspect:

when R is^1-1Is optionally substituted by 1,2 or 3R^1-1-4Substituted C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl radicals such as C₃～C₁₄A saturated cycloalkyl group.

In one aspect:

when R is^1-6Is C₁～C₇When alkyl, said C₁～C₇Alkyl radicals are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also, for example, methyl or ethyl.

In one aspect:

when R is^1-7Is C₁～C₇When alkyl, said C₁～C₇Alkyl radicals are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also, for example, methyl or ethyl.

In one aspect:

when R is²Is optionally substituted by 1,2 or 3R^2-1Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl radicals such as C₁～C₄Alkyl radicals, such as, in turn, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also, for example, isopropyl.

In one aspect:

when R is²Is 1R^2-1Substituted C₁～C₇Alkyl radical, R^2-1When it is hydroxy, the group is substituted by 1R^2-1Substituted C₁～C₇Alkyl radicals such as

In one aspect:

when R is²Is optionally substituted by 1,2 or 3R^2-1Substituted C₃～C₁₄When it is heterocycloalkyl, said C₃～C₁₄Heterocycloalkyl radicals such as C₃～C₁₄Monocyclic heterocycloalkyl, C₃～C₁₄Spirocyclic heterocycloalkyl, C₃～C₁₄Condensed ring heterocycloalkyl or C₃～C₁₄Bridged heterocycloalkyl.

Said C₃～C₁₄Monocyclic heterocycloalkyl such as "C having 1 or 2 hetero atoms selected from N, O and S₃～C₉Monocyclic heterocycloalkyl ", for example, having" 1 or 2 heteroatom (S) selected from N, O and C of one or both of S₃～C₅Monocyclic heterocycloalkyl ", also for example" C having 1 or 2 heteroatoms selected from one or both of N, O and S₃～C₅Monocyclic heterocycloalkyl ", and which is linked to the benzene ring via a carbon atom, such as for example an oxetanyl group, more for example an oxetan-3-yl group.

In one aspect:

when R is²Is optionally substituted by 1,2 or 3R^2-1Substituted C₃～C₁₄When it is heterocycloalkyl, except R^2-1In addition, said C₃～C₁₄The heteroatoms in the heterocycloalkyl group may be unsubstituted.

In one aspect:

when R is²Is optionally substituted by 1,2 or 3R^2-1Substituted C₃～C₁₄When it is heterocycloalkyl, said C₃～C₁₄The methylene group in the heterocycloalkyl group may be unsubstituted or substituted.

In one aspect:

when R is²Is 1R^2-1Substituted C₃～C₁₄Heterocycloalkyl, R^2-1When it is halogen or hydroxy, the substituted aryl is substituted by 1R^2-1Substituted C₃～C₁₄Heterocycloalkyl radicals such as

In one aspect:

the atoms in the pyrazolone pyrimidine compound shown in the formula A or the pharmaceutically acceptable salt thereof can exist in the form of natural abundance.

In one aspect:

R¹is H, -C (═ O) R^1-1、-C(＝NR^1-2)R^1-3、-S(＝O)₂R^1-4Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl or C₁～C₁₀A heteroaryl group.

In one aspect:

R¹is H, -C (═ O) R^1-1、

Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl, or, C₃～C₁₄A heterocycloalkyl group.

In one aspect:

R¹is H, -C (═ O) R^1-1Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl, or, C₃～C₁₄A heterocycloalkyl group.

In one aspect:

R^1-1is-NR^1-1-1R^1-1-2、-OR^1-1-3Cyano, or, optionally, substituted by 1R^1-1-4Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl or C₃～C₁₄A heterocycloalkyl group; r^1-1-1And R^1-1-2Is hydrogen or C₁～C₇An alkyl group; r^1-1-3Is hydrogen, C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group; r^1-1-4Is halogen, OH or C₁～C₇An alkyl group.

In one aspect:

R^1-1is optionally substituted by 1R^1-1-4Substituted: c₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group; r^1-1-4is-OH.

In one aspect:

R^1-2is hydrogen, -CN or-OH.

In one aspect:

R^1-3is hydrogen, -NR^1-3-1R^1-3-2Or C₃～C₁₄A heterocycloalkyl group; r^1-3-1And R^1-3-2Independently is hydrogen or C₁～C₇An alkyl group.

In one aspect:

R^1-5independently halogen, -CN, -NR^1-5-1R^1-5-2、-(C＝O)R^1-5-3、C₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl or C₁～C₁₀A heteroaryl group;

R^1-5-1and R^1-5-2Independently is hydrogen or C₁～C₇An alkyl group;

R^1-5-3independently hydrogen, -OR^1-5-3-1Or C₁～C₇An alkyl group; r^1-5-3-1Is C₁～C₇An alkyl group.

In one aspect:

R^1-5independently halogen, -CN, -NR^1-5-1R^1-5-2、-(C＝O)R^1-5-3、C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-5-1and R^1-5-2Is hydrogen;

R^1-5-3independently is-OR^1-5-3-1；R^1-5-3-1Independently is C₁～C₇An alkyl group.

In one aspect:

R²is 1R^2-1Substituted: c₁～C₇Alkyl or C₃～C₁₄A heterocycloalkyl group; r^2-1Independently a hydroxyl group or a halogen.

In one aspect:

R²is 1R^2-1Substituted: c₁～C₇Alkyl or C₃～C₁₄A heterocycloalkyl group; r^2-1Is a hydroxyl group.

In one aspect:

x is a single bond or CH₂(ii) a Y is C; z is a single bond or CH₂。

In one aspect:

x is a single bond or CH₂(ii) a Y is C; z is a single bond or CH₂；

R¹Is composed of

R^1-6And R^1-7Independently is C₁～C₇An alkyl group;

R²is optionally substituted by 1,2 or 3R^2-1Substituted: c₁～C₇Alkyl or C₃～C₁₄A heterocycloalkyl group;

R^2-1is a hydroxyl group.

In one aspect:

R¹is H, -C (═ O) R^1-1、-C(＝NR^1-2)R^1-3、-S(＝O)₂R^1-4Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl or C₁～C₁₀A heteroaryl group;

R^1-1is-NR^1-1-1R^1-1-2、-OR^1-1-3Cyano, or, optionally, substituted by 1R^1-1-4Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl or C₃～C₁₄A heterocycloalkyl group; r^1-1-1And R^1-1-2Is hydrogen or C₁～C₇An alkyl group; r^1-1-3Is hydrogen, C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group; r^1-1-4Is halogen, OH or C₁～C₇An alkyl group;

R^1-2is hydrogen, -CN or-OH;

R^1-3is hydrogen, -NR^1-3-1R^1-3-2Or C₃～C₁₄A heterocycloalkyl group; r^1-3-1And R^1-3-2Independently is hydrogen or C₁～C₇An alkyl group;

R^1-5-1and R^1-5-2Independently is hydrogen or C₁～C₇An alkyl group;

R^1-5-3independently hydrogen, -OR^1-5-3-1Or C₁～C₇An alkyl group; r^1-5-3-1Is C₁～C₇An alkyl group;

In one aspect:

R¹is H, -C (═ O) R^1-1、

Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl, or, C₃～C₁₄A heterocycloalkyl group;

R^1-1is optionally substituted by 1R^1-1-4Substituted: c₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group; r^1-1-4is-OH;

R^1-5-1and R^1-5-2Is hydrogen;

R^1-5-3independently is-OR^1-5-3-1；R^1-5-3-1Independently is C₁～C₇An alkyl group;

R^1-6and R^1-7Independently is hydrogen or C₁～C₇An alkyl group;

In one aspect:

R¹is H, -C (═ O) R^1-1Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl, or, C₃～C₁₄A heterocycloalkyl group;

R^1-5-1and R^1-5-2Is hydrogen;

In one aspect:

R¹is H, -C (═ O) R^1-1、

R^1-5-1and R^1-5-2Is hydrogen;

R^1-6and R^1-7Independently is hydrogen or C₁～C₇An alkyl group;

In one aspect:

R^1-5independently halogen, -CN, -NR^1-5-1R^1-5-2、-(C＝O)R^1-5-3、C₁～C₇Alkyl orC₃～C₁₄A cycloalkyl group;

R^1-5-1and R^1-5-2Is hydrogen;

In a certain embodiment, in the pyrazolone pyrimidine compound shown in formula a or a pharmaceutically acceptable salt thereof, the pyrazolone pyrimidine compound shown in formula a has any one of the following structures:

the invention also provides a preparation method of the compound A, which is any one of the following methods:

the method comprises the following steps: which comprises the following steps: step one, oxidizing a compound 1A in an organic solvent by an oxidant to obtain a compound 1B; reacting the compound 1B with the compound 1C 'under the organic solvent and alkaline conditions to obtain a compound 1D'; removing the protecting group PG on N from the compound 1D 'to obtain a compound 1E'; step four, carrying out reductive amination reaction on the compound 1E' and aldehyde or ketone in an organic solvent to obtain a compound A;

the method 2 comprises the following steps: carrying out substitution reaction on the compound 2A' and the compound 1A to obtain a compound A;

the method 3 comprises the following steps: compound 1E' and Compound R^1-1Carrying out condensation reaction on-COOH to obtain a compound A;

the conditions and steps of the reaction described in method 1 may be those conventional in the art, and the following reaction conditions are particularly preferred in the present invention:

step one, the organic solvent is preferably one or more of methanol, dichloromethane, acetonitrile, toluene and DMF, and more preferably dichloromethane or toluene; the oxidizing agent may be an oxidizing agent conventionally used in the art for the oxidation of thioethers to sulfoxides, preferably m-chloroperoxybenzoic acid (m-CPBA).

Step two, the organic solvent is preferably dichloromethane or toluene; the basic conditions are preferably organic bases, such as N, N-Diisopropylethylamine (DIPEA), triethylamine; the molar ratio of the compound 1B, the compound 1C' and DEIPA is preferably 1: 1: 2, the reaction time is preferably 0-12 hours, and the reaction temperature is preferably 0-35 ℃.

Step three, the protecting group PG on N can be any suitable amino protecting group commonly used in the art, preferably Boc, which aims to protect the compound 1C' from reacting some reactive groups (such as amino) thereon; the conditions for removing the protecting group PG from N can be the conventional conditions for removing various protecting groups in the field, such as the conditions of hydrolysis reaction, aminolysis reaction, hydrogenation reaction and the like; if Boc is used as a protecting group, the deprotection reaction can be carried out under standard conditions, for example, a dichloromethane/trifluoroacetic acid system, saturated hydrogen chloride dioxane solution; after the reaction for removing the protecting group is finished, preferably, the method can further comprise the operation of post-treatment; the methods and conditions of the work-up may be those conventional in the art for such post-reaction work-up, and are preferably: washing, drying, filtering and evaporating a solvent of a reaction system, and then carrying out column chromatography; or evaporating the solvent of the reaction system, washing and filtering; or evaporating the reaction system to remove the solvent, and carrying out thin layer chromatography.

Step four, the solvent is preferably methanol and dichloromethane; the reaction conditions for the reductive amination may be those commonly used in the art, preferably sodium acetate borohydride or sodium cyanoborohydride; the reaction time is preferably 0-12 hours; the reaction temperature is preferably from 0 ℃ to 35 ℃.

The conditions and steps of the reaction described in method 2 may be those conventional in the art, and may be as described for the substitution reaction in method 1.

The conditions and steps of the reaction described in method 3 may be those conventional in the art.

The invention also provides a compound shown as the formula 1C 'or 2A':

wherein R is¹X, Y, Z and PG are as defined above.

In one embodiment, the compound represented by formula 1C 'or 2A' may be any one of the following compounds:

the invention also provides a preparation method of the compound shown in the formula 1C', which comprises the following steps: firstly, in a solvent, under the action of alkali, carrying out substitution reaction on a compound 1C1 'and halogenated nitrobenzene to obtain a compound 1C 2'; step two, in a solvent, reducing the catalyst of the compound 1C2 'to obtain a compound 1C';

the conditions and steps of the reaction described in equation 1 may be those conventional in the art, and the following reaction conditions are particularly preferred in the present invention:

in step one, the solvent is preferably dimethyl sulfoxide.

In step one, the base is preferably an inorganic base, such as potassium carbonate, sodium carbonate, cesium carbonate, more preferably potassium carbonate.

In the first step, the halogenated nitrobenzene is preferably fluoronitrobenzene or chloronitrobenzene, and more preferably fluoronitrobenzene.

In the second step, the solvent is preferably methanol or ethanol.

In the second step, the reduction catalyst can be reduced iron powder, reduced zinc powder, selenious dichloride, platinum dioxide and palladium carbon, preferably palladium carbon; if palladium on carbon is used as the reduction catalyst, the hydrogen supply used may be any of those commonly used in the art, such as hydrogen, hydrazine hydrate, ammonium formate, preferably ammonium formate.

In the second step, the reaction temperature is preferably the solvent reflux temperature, and the reaction time is preferably 2-12 hours.

The invention also provides a preparation method of the compound shown in the formula 2A', which is any one of the following methods:

in the method 1: step one, carrying out reductive amination reaction on a compound 1C 1' and aldehyde or ketone to obtain a compound 2A 1; removing a protecting group PG on N in the compound 2A1 'to obtain a compound 2A 2'; performing substitution reaction on the compound 2A2 'and fluoronitrobenzene to obtain a compound 2A 3'; fourthly, reducing the compound 2A3 'by a catalyst to obtain a compound 2A';

in the method 2: removing a protecting group PG on N in a compound 1C2 'to obtain a compound 2A 4'; secondly, carrying out substitution reaction on the compound 2A4 and a halogen substituted compound under alkaline conditions to obtain a compound 2A 5', wherein the alkaline conditions are preferably potassium carbonate or silver oxide; the halogen substituted compound is preferably bromide and iodide; reducing the compound 2A5 'by a catalyst to obtain a compound 2A';

the conditions and steps of the reaction described in equation 2 may be those conventional in the art. The conditions and steps of the reaction described in equation 3 may be those conventional in the art.

The invention also provides the application of the substance X in preparing a kinase (such as WEE1 kinase) inhibitor;

the substance X is the pyrazolone pyrimidine compound shown in the formula A or pharmaceutically acceptable salt thereof.

The invention also provides the application of the substance X in preparing the medicament;

The invention also provides the application of the substance X in preparing the medicament; the medicament is used for treating and/or preventing diseases related to WEE1 kinase;

The WEE1 kinase related diseases such as cancer. Such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gall bladder-bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, carcinoma of the uterus, cervical cancer, renal pelvis-ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, wilms ' tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or Hodgkin's lymphoma, and for example breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's lymphoma, and also for example colon cancer or ovarian cancer.

The invention also provides the application of the substance X in preparing the medicament; the medicament is used for treating and/or preventing cancer;

Such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gall bladder-bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, carcinoma of the uterus, cervical cancer, renal pelvis-ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, wilms ' tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or Hodgkin's lymphoma, and for example breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's lymphoma, and also for example colon cancer or ovarian cancer.

The invention also provides a pharmaceutical composition comprising substance X and (one or more) pharmaceutical excipient(s);

The present invention provides a combination comprising a substance X and an anti-cancer drug,

The anticancer drug may be an anticancer drug conventional in the art (but not the above-mentioned substance X), such as an anticancer alkylating agent, an anticancer metabolic antagonist, an anticancer antibiotic, an anticancer agent derived from plants, an anticancer platinum coordination compound, an anticancer camptothecin derivative, an anticancer tyrosine kinase inhibitor, a monoclonal antibody, an interferon, a biological response modifier, mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxyurea, pentostatin, one or more of tretinoin, alfacalcitabine, alfadaptidine, anastrozole, exemestane, bicalutamide, leuprolide, flutamide, fulvestrant, pegaptanib sodium, dinil interleukin 2, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine and goserelin, again for example an anti-cancer metabolic antagonist.

The anticancer alkylating agent may be one or more of the anticancer alkylating agents conventional in the art, such as nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, milfoil, busulfan, dibromomannitol, carboquinone, thiotepa, ramustine, nimustine, temozolomide, and carmustine.

The anti-cancer metabolic antagonist may be an anti-cancer metabolic antagonist conventional in the art, such as one or more of methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine sodium octadecyl phosphate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium, and further such as 5-fluorouracil.

The anticancer antibiotic may be one or more of anticancer antibiotics conventional in the art, such as actinomycin D, doxorubicin, daunorubicin, neocarzinostain, bleomycin, pelomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, netstastin, idarubicin, sirolimus, and valrubicin.

The plant-derived anticancer agent may be one or more of vincristine, vinblastine, vindesine, etoposide, sobuzolff, docetaxel, paclitaxel and vinorelbine, which are conventional in the art.

The anticancer platinum coordination compound may be an anticancer platinum coordination compound conventional in the art, such as one or more of cisplatin, carboplatin, nedaplatin, and oxaliplatin.

The anticancer camptothecin derivative can be an anticancer camptothecin derivative conventional in the art, such as one or more of irinotecan, topotecan and camptothecin.

The anticancer tyrosine kinase inhibitor may be an anticancer tyrosine kinase inhibitor conventional in the art, such as one or more of gefitinib, imatinib, and erlotinib.

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

The interferon may be one or more of interferon alpha, interferon alpha-2 a, interferon alpha-2 b, interferon beta, interferon gamma-1 a and interferon gamma-n 1, which are conventional in the art.

The biological response modifier may be one or more of those conventional in the art, such as coriolus versicolor polysaccharide, lentinan, cezopyran, saperin and ubenimex.

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 can be mixed homogeneously (i.e., a mixture of the components).

The components of the combination may be formulated together in a single pharmaceutical composition or separately in separate pharmaceutical compositions (e.g. in kit form) for simultaneous or separate use (e.g. sequential use).

The invention also provides the application of the combination in preparing a medicament for preventing and/or treating cancer.

In the use of the present invention, the substance X as described above, and the anticancer drug as described above may be administered simultaneously or separately (e.g., sequentially).

The invention also provides the application of the substance X in preparing a medicament, and the medicament and the anti-cancer medicament are combined for preventing and/or treating cancer.

The invention also provides the application of the anti-cancer drug in preparing a drug, and the drug is combined with the substance X for preventing and/or treating cancer.

The invention also provides a pharmaceutical composition comprising the combination described above and (one or more) pharmaceutical excipients.

The pharmaceutical composition may consist of the combination and the pharmaceutical excipient.

The invention also provides a combination kit comprising a pharmaceutical composition a and a pharmaceutical composition B;

the medicine composition A comprises the substance X and (one or more) pharmaceutical excipients;

the medicine composition B comprises the anti-cancer medicine and (one or more) pharmaceutic adjuvants.

The combination kit can consist of the pharmaceutical composition A and the pharmaceutical composition B.

The pharmaceutical composition A can consist of a substance X and a pharmaceutical excipient;

the medicine composition B can be composed of the anti-cancer medicine and pharmaceutic adjuvants.

The individual pharmaceutical compositions of the combination kit can be used simultaneously or separately (e.g., sequentially).

In a certain scheme, the pyrazolone pyrimidine compound shown in the formula A or the pharmaceutically acceptable salt thereof can be a pyrazolone pyrimidine compound shown in the formula I or a pharmaceutically acceptable salt thereof;

R¹is H, -CN, -C (═ O) R^1-1、-C(＝NR^1-2)R^1-3、-S(＝O)₂R^1-4Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

or, R^1-1-1、R^1-1-2And the nitrogen atom to which they are attached form C₃～C₁₄A heterocycloalkyl group; said C₃～C₁₄1 or more than 2 methylene groups in the heterocyclic alkyl are optionally independentlyBy an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group or-N (R)^1-1-1-1) -substitution of the indicated group; r^1-1-1-1Independently halogen, -OH, C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-2is hydrogen, -CN, -OR^1-2-1Or C₁～C₇An alkyl group;

R^1-5independently halogen, -OH, -SH, -CN, -NR^1-5-1R^1-5-2、-(C＝O)R^1-5-3Or, optionally substituted with 1,2 or 3R^1-5-4Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₁～C₇Alkoxy radical, C₁～C₇Alkanemercapto group, C₃～C₁₄HeterocycloalkanesBase, C₆～C₁₀Aryl or C₁～C₁₀A heteroaryl group;

in any of the above cases, C is₃～C₁₄Heterocycloalkyl radical, C₁～C₇The heteroatoms in the heteroaryl group are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus; the number of heteroatoms is independently 1,2, 3 or 4;

the pyrazolone pyrimidine compound shown in the formula I is not

R¹is H, -CN, -C (═ O) R^1-1、-C(＝NR^1-2)R^1-3、-S(＝O)₂R^1-4Or, orIs selected from 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

R^1-2is hydrogen, -CN, -OR^1-2-1Or C₁～C₇An alkyl group;

or, R^1-4-1、R^1-4-2And the nitrogen atom to which they are attached form C₃～C₁₄A heterocycloalkyl group; said C₃～C₁₄Heterocycloalkanes1 or 2 or more methylene groups in the group are optionally and independently substituted by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group or-N (R)^1-4-1-1) -substitution of the indicated group; r^1-4-1-1Independently halogen, -OH, C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R²is optionally substituted by 1,2 or 3R^2-1Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl or C₃～C₁₄Heterocyclic ringsAn alkyl group;

In one embodiment, certain substituents of the pyrazolopyrimidine compound of formula I or a pharmaceutically acceptable salt thereof may further have the following definitions, where substituents not mentioned below are as defined in any of the above (hereinafter referred to simply as "in one embodiment"):

said

Is composed of

In one aspect:

when R is¹Is represented by 1,2 or 3R^1-5Substituted C₁～C₇Alkyl radical, R^1-5Independently halogen, said "is substituted by 1,2 or 3R^1-5Substituted C₁～C₇Alkyl "may be2, 2-difluoroethyl or 3,3, 3-trifluoropropyl.

In one aspect:

Or

In one aspect:

when R is¹Is 1R^1-5Substituted C₁～C₇Alkyl radical, R^1-5Independently is C₃～C₁₄When cycloalkyl is present, said "is substituted by 1R^1-5Substituted C₁～C₇Alkyl "may beCyclopropylmethyl or cyclohexylmethyl.

In one aspect:

Or

In one aspect:

when R is¹Is 1R^1-5Substituted C₃～C₁₄Cycloalkyl radical, R^1-5Independently is-NR^1-5-1R^1-5-2When it is, the "quilt1R^1-5Substituted C₃～C₁₄Cycloalkyl "is for example 3-aminocyclobutyl.

In one aspect:

Said C₃～C₁₄Monocyclic heterocycloalkyl such as "C having 1 or 2 hetero atoms selected from N, O and S₃～C₉Monocyclic heterocycloalkyl ", for example, having" 1 or 2 heteroatom (S) selected from N, O and C of one or both of S₃～C₅Monocyclic heterocycloalkyl ", also for example" C having 1 or 2 heteroatoms selected from one or both of N, O and S₃～C₅Monocyclic heterocycloalkyl "and which is linked to the benzene ring via a carbon atom, such as, for example, oxetanyl or piperidinyl.

Said piperidinyl radical for example

Said oxetane group being, for example

In one aspect:

when R is¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When it is heterocycloalkyl, theC is₃～C₁₄The methylene group in the heterocycloalkyl group may be unsubstituted or substituted.

In one aspect:

In one aspect:

Or

In one aspect:

In one aspect:

when R is²Is optionally substituted by 1,2 or 3R^2-1Substituted C₃～C₁₄HeterocycloalkanesWhen it is basic, said C₃～C₁₄Heterocycloalkyl radicals such as C₃～C₁₄Monocyclic heterocycloalkyl, C₃～C₁₄Spirocyclic heterocycloalkyl, C₃～C₁₄Condensed ring heterocycloalkyl or C₃～C₁₄Bridged heterocycloalkyl.

In one aspect:

In one aspect:

the atoms in the pyrazolone pyrimidine compound shown in the formula I or the pharmaceutically acceptable salt thereof can exist in the form of natural abundance.

In one aspect:

R^1-2is hydrogen, -CN or-OH.

In one aspect:

R^1-5-1and R^1-5-2Independently is hydrogen or C₁～C₇An alkyl group;

In one aspect:

R^1-5-1and R^1-5-2Is hydrogen;

In one aspect:

R^1-2is hydrogen, -CN or-OH;

R^1-5-1and R^1-5-2Independently is hydrogen or C₁～C₇An alkyl group;

R²is 1R^2-1Substituted: c₁～C₇Alkyl or C₃～C₁₄Heterocycloalkyl radicals；R^2-1Independently a hydroxyl group or a halogen.

In one aspect:

R^1-5-1and R^1-5-2Is hydrogen;

In one aspect:

R^1-5independently of the other is halogen、-CN、-NR^1-5-1R^1-5-2、-(C＝O)R^1-5-3、C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-5-1and R^1-5-2Is hydrogen;

In a certain embodiment, in the pyrazolone pyrimidine compound shown in formula I or a pharmaceutically acceptable salt thereof, the pyrazolone pyrimidine compound shown in formula I has any one of the following structures:

the invention also provides a preparation method of the compound I, which is any one of the following methods:

the method comprises the following steps: which comprises the following steps: step one, oxidizing a compound 1A in an organic solvent by an oxidant to obtain a compound 1B; reacting the compound 1B with the compound 1C under the organic solvent and alkaline conditions to obtain a compound 1D; removing the protecting group PG on the N from the compound 1D to obtain a compound 1E; step four, carrying out reductive amination reaction on the compound 1E and aldehyde or ketone in an organic solvent to obtain a compound I;

the method 2 comprises the following steps: carrying out substitution reaction on the compound 2A and the compound 1A to obtain a compound I;

the method 3 comprises the following steps: compound 1E and Compound R^1-1Carrying out condensation reaction on-COOH to obtain a compound I;

Step two, the organic solvent is preferably dichloromethane or toluene; the basic conditions are preferably organic bases, such as N, N-Diisopropylethylamine (DIPEA), triethylamine; the molar ratio of the compound 1B to the compound 1C, DEIPA is preferably 1: 1: 2, the reaction time is preferably 0-12 hours, and the reaction temperature is preferably 0-35 ℃.

Step three, the protecting group PG on N can be any suitable amino protecting group commonly used in the art, preferably Boc, which aims to protect the compound 1C from some reactive groups (such as amino) when participating in the reaction; the conditions for removing the protecting group PG from N can be the conventional conditions for removing various protecting groups in the field, such as the conditions of hydrolysis reaction, aminolysis reaction, hydrogenation reaction and the like; if Boc is used as a protecting group, the deprotection reaction can be carried out under standard conditions, for example, a dichloromethane/trifluoroacetic acid system, saturated hydrogen chloride dioxane solution; after the reaction for removing the protecting group is finished, preferably, the method can further comprise the operation of post-treatment; the methods and conditions of the work-up may be those conventional in the art for such post-reaction work-up, and are preferably: washing, drying, filtering and evaporating a solvent of a reaction system, and then carrying out column chromatography; or evaporating the solvent of the reaction system, washing and filtering; or evaporating the reaction system to remove the solvent, and carrying out thin layer chromatography.

The invention also provides a compound shown as the formula 1C or 2A:

wherein R is¹And PG is as defined above.

In a certain embodiment, the compound shown in formula 1C or 2A may be any one of the following compounds:

the invention also provides a preparation method of the compound shown in the formula 1C, which comprises the following steps: firstly, in a solvent, under the action of alkali, carrying out substitution reaction on a compound 1C1 and halogenated nitrobenzene to obtain a compound 1C 2; step two, in a solvent, reducing the catalyst of the compound 1C2 to obtain a compound 1C;

in step one, the solvent is preferably dimethyl sulfoxide.

In the second step, the solvent is preferably methanol or ethanol.

The invention also provides a preparation method of the compound shown in the formula 2A, which is any one of the following methods:

in the method 1: step one, carrying out reductive amination reaction on a compound 1C1 and aldehyde or ketone to obtain a compound 2A 1; removing a protecting group PG on N in the compound 2A1 to obtain a compound 2A 2; performing substitution reaction on the compound 2A2 and fluoronitrobenzene to obtain a compound 2A 3; step four, reducing the compound 2A3 by a catalyst to obtain a compound 2A;

in the method 2: removing a protecting group PG on N in a compound 1C2 to obtain a compound 2A 4; performing substitution reaction on the compound 2A4 and a halogen substituted compound under an alkaline condition to obtain a compound 2A5, wherein the alkaline condition is preferably potassium carbonate or silver oxide; the halogen substituted compound is preferably bromide and iodide; step three, reducing the compound 2A5 by a catalyst to obtain a compound 2A;

the substance X is the pyrazolone pyrimidine compound shown in the formula I or pharmaceutically acceptable salt thereof.

Unless otherwise indicated, the following terms appearing in the specification and claims of the invention have the following meanings:

the term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for use by the patient. The "patient" is preferably a mammal, more preferably a human.

The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The 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 acids include 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, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, 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), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).

The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or unordered arrangement. Such solvents include, but are not limited to: water, methanol, ethanol, and the like.

The terms "pharmaceutically acceptable salt" and "solvate" in the term "solvate of a pharmaceutically acceptable salt" as defined above refer to a substance formed by combining compound 1 of the present invention, prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, and 2, with a stoichiometric or non-stoichiometric amount of a solvent. The "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of the compound of the present invention.

The terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" can exist in crystalline or amorphous form. The term "crystal form" refers to a form in which ions or molecules are arranged strictly periodically in a three-dimensional space in a defined manner and have a periodic recurring pattern at a distance; due to the above described periodic arrangement, various crystal forms, i.e. polymorphism, may exist. The term "amorphous" refers to a state in which ions or molecules are distributed in a disordered manner, i.e., the ions and molecules do not have a periodic arrangement.

The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" if stereoisomers are present, may be present as a single stereoisomer or as a mixture thereof (e.g. as a racemate). The term "stereoisomer" refers to either a cis-trans isomer or an optical isomer. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound according to the invention is not less than 95% relative to all stereoisomers of the compound.

The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" if present as a tautomer, may exist as a single tautomer or as a mixture thereof, preferably as a predominantly more stable tautomer.

The atoms in the terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" may be present in their natural or unnatural abundance. In the case of hydrogen atoms, in its natural abundance, it is understood that about 99.985% is protium and about 0.015% is deuterium; in a non-naturally abundant form such as wherein about 95% is deuterium. That is, one or more atoms in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" can be an atom that is present in a non-natural abundance.

When any variable (e.g. R)^1-1-1) In the definition of a compound, the occurrence at each position of the variable is defined multiple times independently of the occurrence at the remaining positions, and their meanings are independent of each other and independent of each other. Thus, if a group is substituted by 1,2 or 3R^1-1-1Substituted by radicals, i.e. the radical may be substituted by up to 3R^1-1-1Substituted in the position R^1-1-1Is defined by the definition of (1) and the remaining positions R^1-1-1Are defined independently of each other. In addition, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

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

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

The term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical having from one to twelve carbon atoms (e.g., C)₁-C₆Alkyl radicals, also e.g. C₁-C₄Alkyl groups). Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-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-2-pentyl, 2-methyl-1-butyl, 2-pentyl, 2-methyl-2-pentyl, 2-, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, 1-heptyl and 1-octyl.

The term "alkenyl" refers to a group having at least one site of unsaturation, i.e., a carbon-carbon sp²A monovalent hydrocarbon radical of a double bond, linear or branched, of two to twelve carbon atoms (e.g. C)₂-C₆Alkenyl radicals, further e.g. C₂-C₄Alkenyl) and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples include, but are not limited to, vinyl, allyl.

The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond (e.g., C)₂-C₆Alkynyl, further such as C₂-C₄Alkynyl). Examples include, but are not limited to, ethynyl and propynyl.

The term "cycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) non-aromatic cyclic hydrocarbon radical having three to twenty carbon atoms (e.g., C)₃-C₆Cycloalkyl) including monocyclic cycloalkyl and polycyclic cycloalkyl. Cycloalkyl groups contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms.

Examples of monocyclic cycloalkyls 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-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

Polycyclic cycloalkyl groups are polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, including spiro, fusedCyclic and bridged cycloalkyl groups. Wherein spirocyclic cycloalkyl "refers to a polycyclic group having a5 to 20 membered monocyclic ring sharing one carbon atom (called the spiro atom) between them, which may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Examples of spirocycloalkyl groups include, but are not limited to:

"fused-ring cycloalkyl" refers to a5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Examples of fused ring alkyl groups include, but are not limited to:

"bridged cycloalkyl" refers to a5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Examples of bridged cycloalkyl groups include, but are not limited to:

the term "heterocycloalkyl" refers to a saturated carbocyclic group having from 3 to 20 ring atoms in which at least one ring atom is a heteroatom independently selected from boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, the remaining ring atoms being C. The group may be a carbon group or a heteroatom group (i.e. it may be C-linked or N-linked, as long as it is possible). Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thioxanyl, and piperazinyl. Fused ring moieties, spiro moieties and bridged ring moieties are also included within this definition. For example, the group derived from tetrahydropyrrole may be tetrahydropyrrole-1-yl (N-linked) or tetrahydropyrrole-3-yl (C-linked). For example, a 3-7 membered ring monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, B, Si, S and Se, where N, B, P or Se are optionally substituted by one or more oxygen atoms to give a ring system like NO, BOH, PO₂A group of SeO; n may be optionally quaternized; s atoms optionally substituted by one or more oxygen or nitrogen atoms to give compounds like SO, SO₂、S(＝O)(＝NR^a),S(＝NR^b) Or S (═ NR)^c)₂A group of (A) and, at the same time, R^a、R^bAnd R^cIndependently of the other is cyano, C₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl, one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus as heteroatoms, and 1-4C as heteroatoms₃～C₁₄The heterocyclic alkyl group, the heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the heteroatom number is 1-4C₁～C₇Heteroaryl ", C₆～C₁₀Aryl or C₁～C₇An alkoxy group; at the same time, -CH₂The-group may optionally be substituted by-C (═ O) -, -C (═ S) -or-C (═ NR)^d) -substitution, R^dIndependently of the other is cyano, C₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl, one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus as heteroatoms, and 1-4C as heteroatoms₃～C₁₄The heterocyclic alkyl group, the heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the heteroatom number is 1-4C₁～C₇Heteroaryl ", C₆～C₁₀Aryl or C₁～C₇An alkoxy group; when the ring is a three-membered ring, in which there is only one heteroatom), or, a bicyclic ring of 7-10 atoms (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, B, Si, S, where N, S, B or P is optionally substituted with one or more oxygen atoms to give a ring like NO, BOH, SO₂，PO，PO₂The group of SeO, simultaneously with-CH₂The group may optionally be replaced by-C (═ O) -. Depending on the structure, the heterocyclic group may be a monovalent group or a divalent group, i.e., a heterocyclylene group.

The term "aryl" refers to any stable monocyclic or bicyclic carbocyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic. Examples of the above aryl unit include phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl). It will be understood that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through an aromatic ring.

The term "heteroaryl" refers to a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline. "heteroaryl" is also to be understood as including any N-oxide derivative of a nitrogen-containing heteroaryl group. In which the heteroaryl substituent is a bicyclic substituent and one ring is non-aromatic or non-aromaticWhere heteroatoms are included, it is understood that the linkages are each through an aromatic ring. The heteroaromatic ring, bicyclic heteroaromatic ring system may form a ring in a fused form. Wherein N, S, B, P or Se are optionally substituted by one or more oxygen atoms to give compounds like NO, SO₂、BOH、PO、PO₂The group of SeO, the N atom may be quaternized. The heteroaryl radical may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. Depending on the structure, heteroaryl groups can be monovalent or divalent, i.e., heteroarylene.

The term "alkoxy" refers to an alkyl group attached through an oxygen bridge; the alkyl group is as defined above.

The term "alkylmercapto" refers to an alkyl group attached through a sulfur bridge; the alkyl group is as defined above.

The term "component" refers to each component of the combination of the present invention, i.e. compound I, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or a prodrug thereof, or an anti-cancer drug.

The term "pharmaceutical excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is intended to include all substances in a pharmaceutical formulation, except for the active ingredient. See the pharmacopoeia of the people's republic of China (2015 Edition), or, Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition).

The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or leads to a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of a disorder or disorder.

The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.

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

The term "patient" refers to any animal, preferably a mammal, most preferably a human, who is about to, or has received administration of the compound or composition according to the embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.

The term "active ingredient" refers to the active ingredients in the pharmaceutical composition or combination kit of the present invention, i.e., compound I, its pharmaceutically acceptable salt, its solvate of pharmaceutically acceptable salt, its metabolite or its prodrug, an anticancer drug, or a combination thereof.

Using wedge and dotted bonds

Indicating the absolute configuration of a stereocenter.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the compound of the invention has better inhibition activity on WEE1 kinase and better bioavailability.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The structures of all compounds of the invention can be determined by nuclear magnetic resonance(¹H NMR) and/or mass spectrometric detection (MS).¹H NMR chemical shifts () recorded in PPM (10)^-6). NMR was performed on a Bruker AVANCE-400 spectrometer.

LC-MS was determined by Agilent 1200HPLC/6120 mass spectrometer.

The thin-layer silica gel plate is a silicon source HSGF254 or Qingdao GF254 silica gel plate. The column chromatography generally uses 200-mesh and 300-mesh silica gel of the yellow sea of the tobacco Taiwan as a carrier.

Example 1 and example 39

The first step is as follows:

the compound (I-1-a) (3aR,6aS) -2,3,3a, 4,6,6 a-hexahydro-1H-pyrrolo [3, 4-c)]Tert-butyl pyrrole-5-carboxylate (2000mg, 9.4211mmol) was dissolved in DMSO (30mL), potassium carbonate (3eq, 28.263mmol) and 1-fluoro-4-nitro-benzene (I-1-b) (1eq, 9.4211mmol) were added and the reaction was heated to 120 ℃ and stirred for 2 hours. The reaction was poured into 5ml of water to form a yellow solid. The solid was filtered, washed with water (2X 5ml), the solid was collected and dried in vacuo to give compound (I-1-c) tert-butyl (3aR,6aS) -2- (4-nitrophenyl) -1,3,3a, 4,6,6 a-hexahydropyrrolo [3, 4-c)]Tert-butyl pyrrole-5-carboxylate (3g, 8.998mmol), yield 95.51% as a yellow solid. LC-MS M/z (M + H-tBu)⁺＝278.2。

The second step is that:

the compound (I-1-c) (3aR,6aS) -2- (4-nitrophenyl) -1,3,3a, 4,6,6 a-hexahydropyrrolo [3, 4-c)]Tert-butyl pyrrole-5-carboxylate (0.4g, 1mmol) was dissolved in a solution of ethanol (70mL) and THF (10mL) and Pd/C (0.1eq, 0.1mmol) and ammonium formate (10eq, 10mmol) were added. The reaction was heated to reflux and stirred for 1 hour. The reaction was filtered and concentrated to give compound (I-1-d) (3aR,6aS) -2- (4-aminophenyl) -1,3,3a, 4,6,6 a-hexahydropyrrolo [3, 4-c)]Tert-butyl pyrrole-5-carboxylate (0.36g, 1.2mmol), yield 100%, black solid. LC-MS M/z (M + H)⁺＝304.2。

The third step:

reacting the compound (I-1-e) 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-6-methylsulfanyl-pyrazolo [3,4-d]Pyrimidin-3-one (357mg, 0.9989mmol) was dissolved in toluene (15mL) solution, then mCPBA (1.2eq, 1.199mmol, 77%) was added and the reaction was stirred at room temperature for 2 hours. Then, the compound (I-1-d) (3aR,6aS) -2- (4-aminophenyl) -1,3,3a, 4,6,6 a-hexahydropyrrolo [3,4-c ] is added to the reaction solution]A solution of tert-butyl pyrrole-5-carboxylate (1.2eq, 0.18mmol) in toluene (2mL) and DIPEA (2eq, 1.998mmol) was stirred at room temperature for 12 hours. The reaction was quenched with water and extracted with ethyl acetate (2 × 20ml), the organic phase was washed with brine (1 × 20ml), Na₂SO₄Dried, filtered and concentrated to give the crude product. The crude product was washed once with methanol 2ML, filtered and yielded compound (I-39) (3aR,6aS) -2- [4- [ [ 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-]Tert-butyl ester pyridyl]-3-oxo-pyrazolo [3,4-d]Pyrimidin-6-yl]Amino group]Phenyl radical]-1,3,3a, 4,6,6 a-hexahydropyrrolo [3,4-c ]]Pyrrole-5-carboxylate (320mg, 0.5223mmol), yield 52.29% as a yellow solid.¹H NMR(400MHz,MeOD)8.77(s,1H),7.97(t,J＝7.9Hz,1H),7.80(s,1H),7.64(d,J＝7.7Hz,1H),7.47(d,J＝7.8Hz,1H),6.60(d,J＝9.0Hz,2H),5.80–5.66(m,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.93(dd,J＝17.1,1.3Hz,1H),4.82(d,J＝6.1Hz,2H),3.67(s,2H),3.56–3.47(m,2H),3.38(d,J＝8.6Hz,1H),3.30(s,1H),3.23(dd,J＝9.8,3.5Hz,2H),3.07(s,2H),1.59(s,6H),1.52–1.43(m,9H).LC-MS:m/z:(M+H)⁺＝613.3。

The fourth step:

the compound (I-39) (3aR,6aS) -2- [4- [ [ 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridyl]-3-oxo-tert-butylpyrazolo [3,4-d]Pyrimidin-6-yl]Amino group]Phenyl radical]-1,3,3a, 4,6,6 a-hexahydropyrrolo [3,4-c ]]Pyrrole-5-carboxylate (320mg, 0.52mmol) was dissolved in dichloromethane (5mL) and trifluoroacetic acid (1mL) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction was concentrated and saturated NaHCO was added₃The solution was dissolved and then extracted with ethyl acetate (2 × 40 ml). The organic layer was washed with Na₂SO₄Drying, filtering and concentrating to obtain the compound (I-1)6- [4- [ (3aR,6As) -2,3,3a, 4,6,6 a-hexahydro-1H-pyrrolo [3, 4-c)]Pyrrol-5-yl]Anilino radical]-2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]Pyrazolo [3,4-d]Pyrimidin-3-one (110mg, 0.2146mmol), 41.09% yield as a yellow solid. LC-MS M/z (M + H)⁺＝513.3。

Example 2

The compound (I-1)6- [4- [ (3aR,6aS) -2,3,3a, 4,6,6 a-hexahydro-1H-pyrrolo [3, 4-c)]Pyrrol-5-yl]Anilino radical]-2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]Pyrazolo [3,4-d]Pyrimidin-3-one (110mg, 0.2146mmol) was dissolved in methanol solution (6mL), then formaldehyde (10eq, 2.146mmol, 37%) and glacial acetic acid (0.2mL) were added and the reaction was stirred at room temperature for 5 min. Then, sodium borohydride acetate (2eq, 0.4292mmol) was added thereto, and the reaction solution was further stirred at room temperature for 12 hours. NaHCO for reaction₃The aqueous solution was quenched and extracted with ethyl acetate (2X20ML), the organic layer was washed with brine (1X 20mL) and Na₂SO₄Drying, filtering and concentrating to obtain a crude product. The crude product was further purified by Pre-HPLC using CH₃CN/water (0.1% HCOOH) from 20% to 50% to give the compound (I-2)6- [4- [ (3aR,6aS) -2-methyl-1, 3,3a, 4,6,6 a-hexahydropyrrolo [3,4-c ] hexahydropyrrolo [2]Pyrrol-5-yl]Anilino radical]-2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]Pyrazolo [3,4-d]Pyrimidin-3-one (40mg, 0.07596mmol), yield 35.40% as a yellow solid.¹H NMR(400MHz,MeOD)8.80(s,1H),8.42(s,1H),7.97(t,J＝7.9Hz,1H),7.78(d,J＝8.0Hz,1H),7.65(d,J＝7.7Hz,1H),7.54(d,J＝8.7Hz,2H),6.82(d,J＝9.0Hz,2H),5.79–5.67(m,1H),5.05(dd,J＝10.2,1.2Hz,1H),4.93(dd,J＝17.1,1.3Hz,1H),4.81(s,2H),3.64(s,2H),3.55(d,J＝10.0Hz,2H),3.29(s,4H),3.15(dd,J＝9.9,5.7Hz,2H),2.92(s,3H),1.58(d,J＝8.3Hz,6H).LC-MS:m/z:(M+H)⁺＝527.3。

Example 15

The first step is as follows:

1g of tert-butyl (3aR,6aS) -5- (4-nitrophenyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylate (I-1-c) was dissolved in 40ml of dichloromethane, 10ml of trifluoroacetic acid was added, and after 1 hour of reaction at room temperature, the reaction liquid was spin-dried to obtain 0.7g of yellow solid (I-15-a) in 91% yield. LC-MS M/z (M + H)⁺＝234.1。

The second step is that:

reacting (3aR,6aS) -2- (4-nitrophenyl) octahydropyrrole [3,4-c]Pyrrole (I-15-a) (200mg,0.26mmol) was dissolved in 15ml acetonitrile, and potassium carbonate (170mg,1.72mmol) and bromoacetonitrile (I-15-b) (124mg, 1mmol) were added. After 18h at room temperature, the mixture was concentrated and extracted with 30ml of dichloromethane and 10ml of water. By thin layer chromatography (DCM/CH)₃OH-10/1) to yield 40mg of a yellow solid (I-15-c) in 56% yield. LC-MS M/z (M + H)⁺＝273.1。

The third step:

2- ((3AR, 6AS) -5- (4-nitrophenyl) -3a, 6 a-dimethylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) acetonitrile (I-15-c) (50mg, 0.18mmol) was dissolved in 5ml of tetrahydrofuran and reacted at room temperature for half an hour under an atmosphere of hydrogen gas. The reaction mixture was filtered and concentrated to give 42mg of a pale brown solid (I-15-d) in 94% yield. LC-MS M/z (M + H)⁺＝243.2。

The fourth step:

2-allyl-1- (6- (2-hydroxypropane-2-yl) pyridin-2-yl) -6- (methylthio) -1, 2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (I-1-e) (850mg, 0.14mmol) was dissolved in 10ml of toluene, 3-chloroperoxybenzoic acid (38mg, 0.17mol) was added thereto, and the mixture was stirred at room temperature for 20 minutes and then spin-dried. Adding 2- ((3AR, 6AS) -5- (4-phenylamine) -3a, 6 a-dimethylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) acetonitrile (I-15-d) (742mg) was dissolved in 5ml dimethyl sulfoxide, triethylamine (28mg, 0.28mmol) was added, the temperature was raised to 60 ℃ and stirred for about 18 hours. The reaction mixture was cooled and extracted with water and ethyl acetate, concentrated and subjected to thin layer chromatography (DCM/CH)₃OH/NH₃.CH₃OH 100/10/1.5) three times to give 24mg of a yellow solid (I-15) in 32% yield.¹H NMR(400MHz,Methanol-d₄)8.78(s,1H),8.06–7.88(m,1H),7.78(d,J＝8.1Hz,1H),7.64(dd,J＝7.7,0.9Hz,1H),7.48(d,J＝8.4Hz,2H),6.82–6.63(m,2H),5.73(ddt,J＝17.1,10.2,6.1Hz,1H),5.05(dq,J＝10.2,1.2Hz,1H),4.97–4.89(m,2H),4.82(dt,J＝6.2,1.3Hz,2H),3.40(dd,J＝9.5,7.5Hz,2H),3.19(dd,J＝9.5,3.0Hz,2H),3.09–2.98(m,2H),2.94(dd,J＝9.0,7.1Hz,2H),2.65(dd,J＝9.3,3.4Hz,2H),1.59(s,6H).LC-MS:m/z:(M+H)⁺＝552.3。

Example 32

2-allyl-6- (((4- ((3aR, 6aS) -5- (azetidin-3-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (I-33) (41mg,0.072mmol) was dissolved in methanol (10mL) and then a solution of formaldehyde (0.1mL) and sodium triacetoxyborohydride (46mg, 0.216mmol) were added, stirred at room temperature for 16 hours the reaction was concentrated, dissolved with a mixture of dichloromethane and methanol (10/1,20mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the resulting crude product was concentrated and purified by thin layer chromatography (7M ammonia methanol: dichloromethane ═ 0 to 10%) to give the target compound (I-32)24mg in 57% yield. 1H NMR (400MHz, CDCl3)8.84(s,1H),7.87(t, J ═ 7.9Hz,1H),7.78(d, J ═ 8.1Hz,1H),7.43(d, J ═ 7.1Hz,2H),7.35(d, J ═ 7.6Hz,1H),6.67(d, J ═ 8.9Hz,2H),5.72(ddt, J ═ 16.4,10.2,6.2Hz,1H), 5.16-5.03 (M,1H),4.96(dd, J ═ 17.1,1.2Hz,1H),4.76(d, J ═ 6.1Hz,2H),3.76(s,2H), 3.48-3.32 (M,2H),3.22(dd, 5.5H), 15.6 (d, J ═ 6.1H), 3.5 (M,2H), 3.5 (M ═ 2H, 3.5H, 2H, 3.5 (d, 2H), 3.3.5H, 2H, 3.5 (d, 2H), 2H, 3.3.5H, 2H, 3.5H, 2H, 3.3.3.5H, 2H) + (LC, 2.

Example 33

2-allyl-6- ((4- (((3aR, 6aS) -hexahydro-pyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1, 2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (I-1) (80mg,0.156mmol) was dissolved in methanol (10ml), followed by addition of tert-butyl 3-oxaazetidine-1-carboxylate (267mg,1.56mmol) and sodium triacetoxyborohydride (66mg, 0.312mmol), and stirring at room temperature for 18 hours. The reaction mixture was concentrated, dissolved in a mixture of dichloromethane and methanol (10/1,20mL), washed twice with saturated sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, filtered, and the resulting crude product was concentrated and purified by thin layer chromatography (7M ammonia methanol: dichloromethane ═ 0 to 10%) to give the Boc-protected target compound, which was dissolved in 20mL of dichloromethane, added to 0.5mL of 4N hydrogen chloride dioxane solution and stirred at room temperature for 16 hours. Concentrating under reduced pressure, dissolving the obtained crude product with water, and extracting with dichloromethane. The aqueous layer was taken out and adjusted to pH 10 with 2N NaOH solution, and filtered to obtain 47mg of the objective compound (I-33) as a yellow solid in 53% yield.¹H NMR(400MHz,MeOD)8.85–8.72(m,1H),7.97(t,J＝7.9Hz,1H),7.78(d,J＝7.8Hz,1H),7.64(dd,J＝7.7,0.7Hz,1H),7.48(d,J＝8.3Hz,2H),6.70(d,J＝9.0Hz,2H),5.72(ddt,J＝16.4,10.3,6.1Hz,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.94(d,J＝1.3Hz,1H),4.82(d,J＝6.1Hz,1H),3.80–3.44(m,2H),3.44–3.36(m,0H),3.31–3.15(m,2H),2.97(s,1H),2.89–2.71(m,1H),2.37(dd,J＝9.1,4.1Hz,1H),1.59(s,3H).LC-MS:m/z:(M+H)⁺＝568.3。

Example 35

The first step is as follows:

reacting 6- [4- [ (3aR,6aS) -2,3,3a, 4,6,6 a-hexahydro-1H-pyrrolo [3,4-c ]]Pyrrol-5-yl]Anilino radical]-2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]Pyrazolo [3,4-d]Pyrimidin-3-one (I-1) (80mg, 0.1561mmol) was dissolved in methanol solution (6mL), then tert-butyl N- (3-oxocyclobutyl) carbamate (I-35-a) (10eq, 1.561mmol) and sodium borohydride acetate (2eq, 0.3121mmol) were added and the reaction was stirred at room temperature for 12 hours. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (2X20ML), the organic layer washed with brine (1X 20mL), andwith Na₂SO₄Drying, filtering and concentrating to obtain N- [3- [ (3aS, 6aR) -tert-butyl-2- [4- [ [ 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridyl]-3-oxo-pyrazolo [3,4-d]Pyrimidin-6-yl]Amino group]Phenyl radical]-1,3,3a, 4,6,6 a-hexahydropyrrolo [3,4-c ]]Pyrrol-5-yl]Cyclobutyl radical]Carbamate (I-35-b)50mg, yellow solid, yield 46.99%. LC-MS M/z (M + H)⁺＝682.5。

The second step is that:

reacting N- [3- [ (3aS, 6aR) -2- [4- [ [ 2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridyl]Of tert-butyl]-3-oxo-pyrazolo [3,4-d]Pyrimidin-6-yl]Amino group]Phenyl radical]-1,3,3a, 4,6,6 a-hexahydropyrrolo [3,4-c ]]Pyrrol-5-yl to a solution of cyclohexylcarbamate (I-35-b) (50mg, 0.07334mmol) in dichloromethane (2mL) was added TFA (1 mL). The reaction was stirred at room temperature for 12 hours. The product was quenched with saturated aqueous sodium bicarbonate and concentrated to give the crude product. The crude product was purified by preparative HPLC eluting with acetonitrile/water (0.1% formic acid) from 20% to 50% to give 6- [4- [ (3aS, 6aR) -5- (3-aminocyclobutyl) -1,3]3A, 4,6,6a hexahydropyrrolo [3,4-c ]]Pyrrol-2-yl]Anilino radical]-2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]Pyrazolo [3,4-d]Pyrimidin-3-one (I-35)15mg as a yellow solid, yield 35.16%.¹HNMR(400MHz,MeOD)8.79(s,1H),7.97(t,J＝7.9Hz,1H),7.79(d,J＝7.0Hz,1H),7.65(d,J＝7.7Hz,1H),7.50(d,J＝9.2Hz,2H),6.74(d,J＝9.0Hz,2H),5.77–5.67(m,1H),5.05(d,J＝9.0Hz,1H),4.95(d,J＝1.3Hz,1H),4.83(d,J＝6.1Hz,2H),3.30(s,0H),3.03(s,2H),2.90(dd,J＝25.5,8.3Hz,3H),2.56(s,2H),2.45(dd,J＝10.5,6.8Hz,3H),2.28(s,2H),2.13–2.00(m,2H),1.59(s,6H).LC-MS:m/z:(M+H)⁺＝582.3。

EXAMPLE 41

The compound (I-1)6- [4- [ (3AR,6AS) -2,3,3a, 4,6,6 a-hexahydro-1H-pyrrolo [3, 4-c)]Pyrrol-5-yl]Anilino radical]-2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]Pyrazolo [3,4-d]Pyrimidin-3-one (100mg,0.1596mmol) was dissolved in dichloromethane (5mL), DIPEA (2equiv.,0.3192mmol) was added, and the reaction was stirred at room temperature for 5 minutes. 2-Hydroxyacetic acid (1.3equiv.,0.2075mmol) and HATU (1equiv.,0.1596mmol) were added to the reaction solution in this order, and stirring was continued at room temperature for 12 hours. NaHCO for reaction₃The aqueous solution was quenched and extracted with dichloromethane (2X20ML), the organic layer was washed with brine (1X 20mL) and Na₂SO₄Drying, filtering and concentrating to obtain a crude product. The crude product was further purified by normal phase silica gel column, and eluted from 0% to 8% with methanol/methylene chloride to give the compound (I-41)6- [4- [ (3AR,6AS) -5- (2-hydroxyacetyl) -1,3,3a, 4,6,6 a-hexahydropyrrolo [3, 4-c)]Pyrrol-2-yl]Anilino radical]-2-allyl-1- [6- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]Pyrazolo [3,4-d]Pyrimidin-3-one (50mg,0.08763mmol), yield 54.9% as a yellow solid.¹H NMR(400MHz,MeOD)8.78(s,0H),7.97(t,J＝7.9Hz,1H),7.80(s,1H),7.64(dd,J＝7.7,0.8Hz,1H),7.47(s,2H),6.61(d,J＝9.0Hz,2H),5.78–5.67(m,1H),5.09–5.01(m,1H),4.94(d,J＝1.3Hz,1H),4.82(d,J＝6.1Hz,2H),4.19(s,2H),3.85–3.74(m,2H),3.53(ddd,J＝14.2,10.7,4.0Hz,3H),3.42(dd,J＝10.8,4.9Hz,1H),3.30–3.23(m,2H),3.16(dd,J＝25.6,13.0Hz,3H),1.59(s,6H).LC-MS:m/z:(M+H)⁺＝571.3。

Example 47

The first step is as follows:

reacting hexahydropyrrolidinyl tert [3,4-c ]]Pyrrole-2 (1H) -carboxylate (2.36mmol) (I-47-a) was dissolved in dichloromethane (20mL), formaldehyde (11.8mmol) and sodium triacetoxyborohydride (7.07mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. Adding potassium carbonate aqueous solution into the reaction liquid to adjust the pH value to 9, extracting by dichloromethane, washing an organic phase saturated saline solution, drying by anhydrous sodium sulfate, filtering, evaporating filtrate to dryness to obtain a crude target compound 5-methyl hexahydro-pyrrolo [3,4-c ] of the target compound]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (I-47-b) (480mg, 90.0%) as a colorless oil. LC-MS M/z (M + H)⁺＝227.2。

The second step is that:

reacting 5-methyl hexahydropyrrolo [3,4-c ]]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (I-47-b) (2.12mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (10mL) was added, and the reaction was stirred at room temperature for 0.5H. Evaporating the reaction solution to dryness to obtain a crude product of the target compound 2-methyl octahydropyrrolo [3,4-c]Pyrrole 2,2, 2-trifluoroacetate (I-47-c) (250mg, 93.4%) as a yellow solid. LC-MS M/z (M + H)⁺＝127.2。

The third step:

2-methyl octahydro pyrrolo [3, 4-c)]Pyrrole 2,2, 2-trifluoroacetate salt (1.98mmol) (I-47-c) was dissolved in acetonitrile (20mL), and potassium carbonate (5.94mmol) and 1-fluoro-4-nitrobenzene (I-1-b) (2.97mmol) were added to the reaction solution, which was heated to reflux and stirred for 16 hours. Filtering the reaction solution, evaporating the filtrate to dryness to obtain a crude product, and purifying the crude product by column chromatography (dichloromethane/methanol is 100/0-95/5) to obtain the target compound 2-methyl-5- (4-nitrophenyl) octahydropyrrolo [3,4-c]Pyrrole (I-47-d) (250mgg, 51.0%) as a yellow solid. LC-MS M/z (M + H)⁺＝248.3。

The fourth step:

120mg (0.48mmol) of 2-methyl-5- (4-nitrophenyl) -1,3,3a, 4,6,6 a-hexahydropyrrolo [3, 4-c)]Pyrrole was dissolved in 5ml methanol, then 10mg (10%) Pd/C was added and stirred under hydrogen atmosphere at room temperature for 0.5 hours. Filtering and concentrating the reaction solution to obtain 4- (5-methyl hexahydro-pyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) aniline (I-47-e)100mg, 94% yield, light brown solid. LC-MS M/z (M + H)⁺＝218.3。

The fifth step:

206mg (0.55mmol) of 2-allyl-1- [6- (3-hydroxyoxetan-3-yl) -2-pyridyl]-6-methylthiopyrazolo [3,4-d]Dissolving pyrimidin-3-one (I-47-f) in 10ml of toluene, adding 103mg (0.60mol) of 3-chloroperoxybenzoic acid, stirring at room temperature for about 1 hour, and adding 100mg (0.46mmol) of 4- (5-methylhexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) -phenylamine (shown as formula I-47-e) and 120mg (0.92mmol) DIPEA, heating to 30 deg.C, stirring for 16 hr, concentrating the reaction solution, and performing column chromatography (DCM/CH)₃OH-10/1) and then by thin layer chromatography (DCM/CH)₃OH/NH₃.CH₃OH 100/10/1.5) three times to give 2-allyl-1- (6- (3-hydroxyoxetan-3-yl) pyridin-2-yl) -6- ((4- (5-methylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (I-47)800mg, 32% yield, yellow solid.¹H NMR(400MHz,CDCl3)8.82(s,0H),8.03(t,J＝7.9Hz,1H),7.88(d,J＝8.0Hz,1H),7.39(d,J＝8.2Hz,2H),6.67(dd,J＝9.0,2.1Hz,1H),5.73(ddt,J＝16.3,10.2,6.1Hz,1H),5.14–5.06(m,2H),4.98(dd,J＝17.1,1.2Hz,1H),4.80(d,J＝7.2Hz,1H),4.67(d,J＝6.0Hz,1H),3.41(s,1H),3.25(dd,J＝9.4,2.7Hz,1H),3.03(d,J＝2.5Hz,1H),2.86–2.76(m,1H),2.51(s,1H),2.38(s,2H).LC-MS:m/z:(M+H)⁺＝541.3。

Example 57

The first step is as follows:

to a solution of tert-butyl (3ar,6as) -5-oxohexahydrocyclopenta [ c ] pyrrole-2 (1h) -carboxylate (I-57-a) in methanol (5ml) was added dimethylamine tetrahydrofuran solution (2M,1.07mmol,0.54ml), followed by addition of sodium borohydride acetate (566mg, 1.07mmol), and the mixture was stirred at room temperature for 16 hours. The reaction was spun dry in vacuo and extracted with saturated potassium carbonate solution (10ml) and dichloromethane (3 × 10 ml). The organic layer was dried over sodium sulfate solid and filtered. The organic layer solution was concentrated to give I-57-b (158mg, 70%) as a yellow solid.

The second step is that:

trifluoroacetic acid (5ml) was added to a solution of (3ar,6as) -n, n-dimethyldihydrocyclopenta [ c ] pyrrol-5-amine (I-57-b) in methanol (5ml), and the mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give crude I-57-c (94mg, 99%) as a pale brown product.

The third step:

to an acetonitrile (5ml) solution of (3ar,6as) -n, n-dimethyldihydrocyclopenta [ c ] pyrrol-5-amine (I-57-c) (94mg,0.625mmol) was added potassium carbonate (862mg,0.625mmol), and after stirring at room temperature for 10 minutes, p-fluoronitrobenzene (88mg,0.625mmol) was added. The reaction was stirred under reflux for 16 hours. After cooling, the reaction was concentrated and extracted with water (20ml) and dichloromethane (3 × 10 ml). The organic layer was dried over sodium sulfate solid and filtered. The organic layer solution was concentrated to give I-57-d (66mg, 42%) as a yellow solid.

The fourth step:

to a solution of (3ar,6as) -n, n-dimethyl-2- (4-nitrophenyl) octahydrocyclopenta [ c ] pyrrol-5-amine (I-57-d) (66mg,0.27mmol) in methanol (5ml) was added palladium on carbon (20mg, 10%) and the reaction was stirred under hydrogen at room temperature for 16 hours. The reaction was filtered and concentrated to give I-57-e (30mg, 56%) as a pale brown solid.

The fifth step:

to a solution of 2-allyl-1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- (methylthio) -1, 2-dihydro-3 h-pyrazolo [3,4-d ] pyrimidin-3-one (I-1-h) in toluene (3ml) was added m-chloroperoxybenzoic acid (34mg,0.166mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to a solid, which was then dissolved in dimethyl sulfoxide, and then compound I-57-e (30mg,0.138mmol) and trifluoroacetic acid (0.02ml) were added thereto, followed by stirring at 60 ℃ for 16 hours. After the reaction was cooled to room temperature, it was extracted with water (5ml) and dichloromethane (3 × 10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was separated on a thin layer chromatography plate (dichloromethane: ethyl acetate: methanolic ammonia (7M): 10:4:1) to give I-57 as a pale yellow solid (8mg, 10%).

With reference to the above examples, the compounds shown in table 1 were prepared and their structural characterization is as follows:

TABLE 1 list of compounds

Effect example 1

First, compound inhibition to WEE1 kinase in vitro

The test method comprises the following steps:

test compounds were screened on WEE1 kinase using ELISA at an ATP concentration of Km. A screen of 3 compounds was performed on WEE1 kinase to evaluate the kinase inhibitory activity of the test compounds. In the detection process, the initial concentration of the tested compound is selected to be 100nM, each compound is selected to be at 6 gradient dilution concentrations, the gradient dilution multiple is 4 times, each concentration is detected in 2 duplicate wells, and MK1775 is used as a standard control.

WEE1, available from carna biosciences, inc., cat #: 05-177; dimethyl sulfoxide, purchased from Sigma-Aldrich, cat #: d8418; ATP, purchased from Sigma-Aldrich, cat #: a7699; DTT solution, purchased from Sigma-Aldrich, cat #: 43816; protein Tyrosine Kinase (PTK) substrate (poly-Glu-Tyr), purchased from Sigma-Aldrich, cat #: p4476; P-Tyr (PY99), available from Santa Cruz, cat #: sc-7020; anti-mouse IgG HRP-linked Antibody, purchased from Santa Cruz, cat #: 7076S; TMB liquid Substrate System, available from Sigma-Aldrich, cat #: t0440; costar Strepwell Microplate No Lid 1X 8Flat Bottom, Certified High Binding, available from Sigma-Aldrich, Cat #: 42592; 96-well compound plates, purchased from Thermo Scientific, cat #: 267245.

the testing steps are as follows:

1. coating a substrate: 1) a suitable volume of the substrate stock Protein Tyrosine Kinase (PTK) substrate (poly-Glu-Tyr) was diluted 10-fold with PBS to a concentration of 25mg/mL from 250 mg/mL. Add to high adsorption 96-well plates, 125 μ L per well. Incubate overnight at 37 ℃ for coating. 2) After 24h, the 96-well plate was removed, the liquid in the 96-well plate was decanted, washed 3 times with washing buffer, and dried in an inverted incubator at 37 ℃ for 2 h.

2. Preparation and transfer of compounds: 1) compound dilution: taking 10mM stock solution of test compound, diluting the compound with DMSO in 96-well compound plates in multiple steps to obtain the compound with the initial concentration of 100 x, and then taking the compound with the concentration as the first concentration, and performing 4-fold gradient dilution with DMSO to dilute for 6 concentrations; then, 2 mu L of gradient diluent is respectively added into 48 mu L of 1 multiplied by reaction buffer solution to prepare 4 multiplied by compound for standby; 2)4 × transfer of compound: transferring 10 μ L of 4 × compound from the 96-well compound plate prepared in the above step into a dried high adsorption 96-well plate; to the no compound control well and ATP-control well was added 10 μ L of the following liquids: mu.L of DMSO was added to 48. mu.L of 1 × reaction buffer.

3. And (3) an enzyme reaction stage: 1) WEE1 kinase and ATP were prepared as a2 Xenzyme solution and a4 XATP solution, respectively, using 1 Xreaction buffer. Wherein in the screening, the final concentration of WEE1 kinase is as follows: 0.15 ng/. mu.L, ATP final concentration: 12 mu M; 2) add 20. mu.L of 2 enzyme solution to the high adsorption 96 well plate; 3) add 10. mu.L of 4 × ATP solution to the high adsorption 96 well plate, 10. mu.L of 1 × reaction buffer to the ATP-control air; 4) the plate was centrifuged at 2000rpm in a HERAEUS Multifuge X1R centrifuge for 20s, and then the plate was left to react at room temperature for 60 min.

4. And (3) reaction termination stage: 1) pouring out the reaction solution in the plate, adding 200 mu L washing buffer into each hole, and washing for 5 times; anti-P-Tyr (PY99) (dilution ratio 1: 2000) was added at 100. mu.L/well for 30min at room temperature. 2) Pouring out the primary antibody in the plate, adding 200 mu L washing buffer into each hole, and washing for 5 times; a secondary Antibody Anti-mouse IgG HRP-linked Antibody (dilution ratio 1: 2000) was added at 100. mu.L per well for 30min at room temperature. 3) And (3) pouring the secondary antibody in the plate, washing for 5 times by using washing buffer, adding TMB (Tetramethylbenzidine) with the volume of 100 mu L per hole, and developing for 10-30 min according to the color depth. The reaction was stopped with 1N sulfuric acid before reading.

5. Detection and data processing: 1) light absorption at a wavelength of 450nM was read on a ThermoScientific MultiScan GO while background was read at 650 nM. 2) Log (inhibition) vs. stress-Variable slope (four parameters) curve fitting was performed on the data using Graphpad Prism 5.0 to calculate the corresponding IC₅₀(half maximal inhibitory concentration)。

Second, test result data

The structure of the control sample used in the test is shown in table 2.

TABLE 2 control sample Structure

The test results are detailed in table 3.

TABLE 3 WEE1 enzyme inhibitory Activity test results

Compound numbering	WEE1IC₅₀,nM	Compound numbering	WEE1IC₅₀,nM
				Control 1	2.57	I-1	2.63
I-2	1.83	I-3	1.84
				I-5	1.86	I-11	9.75
I-15	7.74	I-16	6.09
				I-19	3.12	I-25	3.38
I-32	3.68	I-33	6.29
				I-34	4.58	I-35	1.68
I-37	1.59	I-38	2.33
				I-40	7.99	I-41	3.71
I-42	5.27	I-46	3.06
				I-47	2.73	I-53	4.95
I-54	1.90	I-55	1.52
				I-56	4.38	I-57	1.02
I-58	2.57

Effect example 2

Bioavailability test in mice

First, experimental animal and test article

1. Laboratory animal

The above are provided by Shanghai Seipaibikai laboratory animals Co.

2. Preparation of test article

2.1 preparation of mother liquor

The compound powder of the invention is added with 404.6 mul DMSO, and is completely dissolved to prepare a mother solution with 50mg/ml, and the state is clear.

2.2 preparation of dosing solution

The compounds of the present invention: precisely measuring 24 μ l of the mother solution, and adding 0.9% physiological saline: PEG400 ═ 8: 2 to 4mL, the solution was clarified and used as an intravenous solution at a concentration of 0.3 mg/mL. Another 80. mu.l of mother liquor is precisely measured, 0.5% CMC-Na is added to 8mL, and the mixture is ground into a uniform suspension state, wherein the concentration is as follows: 0.5mg/mL as a gavage solution.

Second, animal experiment

Vein group: ICR mice 24, 20 ± 2g, administered intravenously with an intravenous administration solution of a compound of the invention, administration volume: 10ml/kg, administration dose: 3mg/kg, 0.08ml of blood was taken from the fundus vein of the mouse before and 2, 5, 15, 30, 60, 90, 120, 240, 360, 480, 600, 1440 minutes after the administration.

And (3) gastric lavage group: ICR mice 24, 20 ± 2g, gavage a gavage solution of a compound of the invention, dosing volume: 20ml/kg, administration dose: 10mg/kg, 0.08ml of blood was taken from the fundus vein of the mouse before and 5, 15, 30, 60, 90, 120, 240, 360, 480, 600, 1440 minutes after the administration.

The blood sample is centrifuged at 8000rpm for 5min, and the plasma is stored in a centrifuge tube at-20 ℃ for later use.

Third, plasma sample processing

1. Preparation of standard curve

Concentration range of standard curve working fluid: 60, 20, 6, 2, 0.6, 0.2, 0.1, 0.04, 0.02 μ g/mL.

Taking 47.5 mu L of blank mouse plasma, adding 2.5 mu L of standard curve working solution to prepare 3, 1, 0.3, 0.1, 0.0.3, 0.01, 0.005, 0.002 and 0.001 mu g/mL series concentration samples, mixing uniformly by vortex, adding 300 mu L of acetonitrile (Propranol, 25ng/mL) containing an internal standard to precipitate protein, oscillating by vortex for 10min, 6000g and centrifuging for 10min at 4 ℃, and taking supernatant to inject in a 96-well plate.

QC sample processing

Concentration range of QC working solution: low: 0.06 mug/mL; middle part: 1.6 mu g/mL; high: 48. mu.g/mL.

Taking 47.5 mu L of blank mouse plasma, adding 2.5 mu L of QC working solution to prepare samples with series concentration of 2.4, 0.08 and 0.003 mu g/mL, uniformly mixing by vortex, adding 300 mu L of acetonitrile (Propranol, 25ng/mL) containing an internal standard to precipitate protein, oscillating by vortex for 10min, 6000g and centrifuging for 10min at 4 ℃, and taking supernatant to inject in a 96-well plate.

3. Plasma sample processing

Plasma sample 50 u L, adding 300 u L containing internal standard acetonitrile (Propranol, 25ng/mL) precipitation protein, vortex 10min, 6000g, 4 degrees C, centrifugation 10min, the supernatant until 1 hours of intravenous injection is diluted 10 times with containing internal standard acetonitrile, the rest supernatant is not diluted, again 6000g, 4 degrees C, centrifugation 10min, the supernatant is injected into 96 pore plate.

Fourth, the experimental result of the bioavailability in the body of the mouse

1. Test parameters

The Dose; peak concentration of C_max(ii) a Time to peak T_max；AUC_lastArea under the time curve of drug administration from 0 to time t; half life T_1/2(ii) a Average residence time MRT; the clearance rate Cl; apparent volume of distribution V_z(ii) a Volume V of steady state distribution_ss(ii) a Absolute bioavailability F.

2. Mouse pharmacokinetic data

The pharmacokinetic parameters of the compounds in mice after intravenous or gavage administration are given in table 4 below.

Table 4 in vivo drug parameters of the compounds in mice

And (4) conclusion: the compound can obviously improve the pharmacokinetics of the mouse.

Claims

1. A pyrazolone pyrimidine compound shown as a formula A or pharmaceutically acceptable salt thereof;

x is a single bond or CH₂；

Y is N or CH;

z is a single bond or CH₂；

R¹Is H, -CN, -C (═ O) R^1-1、-C(＝NR^1-2)R^1-3、-S(＝O)₂R^1-4、

R^1-2is hydrogen, -CN, -OR^1-2-1Or C₁～C₇An alkyl group;

R^1-3is-NR^1-3-1R^1-3-2Or, optionally substituted with 1,2 or 3R^1-3-3Substituted by：C₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇A heteroaryl group;

R^1-5-4independently is halogen, -OH, -CN,Amino, mercapto, C₁～C₇Alkyl radical, C₁～C₇Alkoxy radical, C₁～C₇Alkylthio radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl radical, C₁～C₇Heteroaryl, or substituted by 1 or 2R^1-5-4-1A substituted amino group; r^1-5-4-1Independently is C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group;

R^1-6and R^1-7Independently is hydrogen or C₁～C₇An alkyl group;

2. The pyrazolone pyrimidine compound of formula a or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pyrazolone pyrimidine compound of formula a or a pharmaceutically acceptable salt thereof is a pyrazolone pyrimidine compound of formula I or a pharmaceutically acceptable salt thereof;

R^1-2is hydrogen, -CN, -OR^1-2-1Or C₁～C₇An alkyl group;

R^1-3-1and R^1-3-2Independently of one another is hydrogen, C₁～C₇Alkyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl radical, C₆～C₁₀Aryl or C₁～C₇Heteroaryl radical；

R²is optionally substituted by 1,2 or 3R^2-1Substituted:C₁～C₇alkyl radical, C₃～C₁₄Cycloalkyl or C₃～C₁₄A heterocycloalkyl group;

3. The pyrazolopyrimidine compound of formula a or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that

Is composed of

And/or the pyrazolone pyrimidine compound shown as the formula A is not

And/or the presence of a gas in the gas,

is composed of

And/or when R¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl is C₁～C₃An alkyl group;

and/or when R^1-5When independently halogen, said halogen is fluorine, chlorine, bromine or iodine;

and/or when R¹Is 1R^1-5Substituted C₁～C₇Alkyl radical, R^1-5Independently CN, said "is substituted by 1R^1-5Substituted C₁～C₇Alkyl "is 2-cyanoethyl;

and/or when R^1-5Independently is C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl being C₃～C₁₄Monocyclic cycloalkyl, C₃～C₁₄Spirocyclic cycloalkyl radical, C₃～C₁₄Cycloalkyl having condensed rings or C₃～C₁₄A bridged cycloalkyl group;

and/or when R^1-5Independently is C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl being C₃～C₁₄A saturated cycloalkyl group;

and/or when R^1-5-3-1Is C₁～C₇When alkyl, said C₁～C₇Alkyl is C₁～C₃An alkyl group;

and/or when R¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl being C₃～C₁₄Monocyclic cycloalkyl, C₃～C₁₄Spirocyclic cycloalkyl radical, C₃～C₁₄Cycloalkyl having condensed rings or C₃～C₁₄A bridged cycloalkyl group;

and/or when R¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl being C₃～C₁₄A saturated cycloalkyl group;

and/or when R¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When it is heterocycloalkyl, said C₃～C₁₄Heterocycloalkyl being C₃～C₁₄Monocyclic heterocycloalkyl, C₃～C₁₄Spirocyclic heterocycloalkyl, C₃～C₁₄Condensed ring heterocycloalkyl or C₃～C₁₄Bridged heterocycloalkyl;

and/or when R¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When it is heterocycloalkyl, except R^1-5In addition, said C₃～C₁₄The heteroatoms in the heterocycloalkyl group are unsubstituted;

and/or when R¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄When it is heterocycloalkyl, said C₃～C₁₄Methylene groups in the heterocycloalkyl group are not replaced or substituted;

and/or when R^1-5Is optionally substituted by 1,2 or 3R^1-5-4Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl is C₁～C₃An alkyl group;

and/or when R^1-1Is optionally substituted by 1,2 or 3R^1-1-4Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl is C₁～C₃An alkyl group;

and/or when R^1-1Is optionally substituted by 1,2 or 3R^1-1-4Substituted C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl being C₃～C₁₄Monocyclic cycloalkyl, C₃～C₁₄Spirocyclic cycloalkyl radical, C₃～C₁₄Cycloalkyl having condensed rings or C₃～C₁₄A bridged cycloalkyl group;

and/or when R^1-1Is optionally substituted by 1,2 or 3R^1-1-4Substituted C₃～C₁₄When there is a cycloalkyl group, said C₃～C₁₄Cycloalkyl being C₃～C₁₄A saturated cycloalkyl group;

and/or when R^1-6Is C₁～C₇When alkyl, said C₁～C₇The alkyl is methyl, ethyl, n-propyl, isopropyl,N-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R^1-7Is C₁～C₇When alkyl, said C₁～C₇Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R²Is optionally substituted by 1,2 or 3R^2-1Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl is C₁～C₄An alkyl group;

and/or when R²Is optionally substituted by 1,2 or 3R^2-1Substituted C₃～C₁₄When it is heterocycloalkyl, said C₃～C₁₄Heterocycloalkyl being C₃～C₁₄Monocyclic heterocycloalkyl, C₃～C₁₄Spirocyclic heterocycloalkyl, C₃～C₁₄Condensed ring heterocycloalkyl or C₃～C₁₄Bridged heterocycloalkyl;

and/or when R²Is optionally substituted by 1,2 or 3R^2-1Substituted C₃～C₁₄When it is heterocycloalkyl, except R^2-1In addition, said C₃～C₁₄The heteroatoms in the heterocycloalkyl group are unsubstituted;

and/or when R²Is optionally substituted by 1,2 or 3R^2-1Substituted C₃～C₁₄When it is heterocycloalkyl, said C₃～C₁₄Methylene groups in the heterocycloalkyl group are not replaced or substituted;

and/or the atoms in the pyrazolone pyrimidine compound shown in the formula I or the pharmaceutically acceptable salt thereof exist in the form of natural abundance.

4. The pyrazolopyrimidine compound of formula A or a pharmaceutically acceptable salt thereof as set forth in claim 3, characterized in that

Is composed of

Said

Is composed of

And/or the presence of a gas in the gas,

is composed of

And/or when R¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl is methyl, ethyl, n-propyl or isopropyl;

and/or when R^1-5When independently halogen, said halogen is fluorine;

and/or when R^1-5Independently is C₃～C₁₄Cycloalkyl radical, said C₃～C₁₄Cycloalkyl being C₃～C₁₄When monocyclic cycloalkyl is present, said C₃～C₁₄Monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R^1-5Independently is C₃～C₁₄Cycloalkyl radical, said C₃～C₁₄Cycloalkyl being C₃～C₁₄When the bridged cycloalkyl is present, said C₃～C₁₄Bridged cycloalkyl radicals are

And/or when R^1-5-3-1Is C₁～C₇When alkyl, said C₁～C₇Alkyl is methyl, ethyl, n-propyl or isopropyl;

and/or when R¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄Cycloalkyl radical, said C₃～C₁₄Cycloalkyl being C₃～C₁₄When monocyclic cycloalkyl is present, said C₃～C₁₄Monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄Cycloalkyl radical, said C₃～C₁₄Cycloalkyl being C₃～C₁₄When the bridged cycloalkyl is present, said C₃～C₁₄Bridged cycloalkyl radicals are

And/or when R¹Is optionally substituted by 1,2 or 3R^1-5Substituted C₃～C₁₄Heterocycloalkyl of said formula C₃～C₁₄Heterocycloalkyl being C₃～C₁₄When monocyclic heterocycloalkyl is present, said C₃～C₁₄Monocyclic heterocycloalkyl is

And/or when R^1-5Is optionally substituted by 1,2 or 3R^1-5-4Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl is methyl, ethyl, n-propyl or isopropyl;

and/or when R^1-1Is optionally substituted by 1,2 or 3R^1-1-4Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl is methyl, ethyl, n-propyl or isopropyl;

and/or when R^1-1Is optionally substituted by 1,2 or 3R^1-1-4Substituted C₃～C₁₄Cycloalkyl radical, said C₃～C₁₄Cycloalkyl being C₃～C₁₄Monocyclic cycloalkyl ringSaid C is₃～C₁₄Monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R^1-1Is optionally substituted by 1,2 or 3R^1-1-4Substituted C₃～C₁₄Cycloalkyl radical, said C₃～C₁₄Cycloalkyl being C₃～C₁₄When the bridged cycloalkyl is present, said C₃～C₁₄Bridged cycloalkyl radicals are

And/or when R^1-6Is C₁～C₇When alkyl, said C₁～C₇Alkyl is methyl or ethyl;

and/or when R^1-7Is C₁～C₇When alkyl, said C₁～C₇Alkyl is methyl or ethyl;

and/or when R²Is optionally substituted by 1,2 or 3R^2-1Substituted C₁～C₇When alkyl, said C₁～C₇Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R²Is optionally substituted by 1,2 or 3R^2-1Substituted C₃～C₁₄Heterocycloalkyl radical, C₃～C₁₄Heterocycloalkyl being C₃～C₁₄When monocyclic heterocycloalkyl is present, said C₃～C₁₄Monocyclic heterocycloalkyl is oxetan-3-yl.

5. The pyrazolone pyrimidine compound of formula A or a pharmaceutically acceptable salt thereof according to claim 4, wherein,

is composed of

And/or when R¹Is represented by 1,2 or 3R^1-5Substituted C₁～C₇Alkyl radical, R^1-5Independently halogen, said "is substituted by 1,2 or 3R^1-5Substituted C₁～C₇Alkyl "is 2, 2-difluoroethyl or 3,3, 3-trifluoropropyl;

and/or when R¹Is 1R^1-5Substituted C₃～C₁₄Cycloalkyl radical, R^1-5Independently is-NR^1-5-1R^1-5-2When said is "by 1R^1-5Substituted C₃～C₁₄Cycloalkyl "is 3-aminocyclobutyl;

and/or when R¹Is optionally substituted by 1R^1-5Substituted C₃～C₁₄Heterocycloalkyl, R^1-5Is C₁～C₇When alkyl, said "is optionally substituted by 1R^1-5Substituted C₃～C₁₄Heterocycloalkyl "is

And/or when R^1-1Is optionally substituted by 1R^1-1-4Substituted C₁～C₇Alkyl radical, R^1-1-4When it is-OH, said "is optionally substituted by 1R¹ ^-1-4Substituted C₁～C₇Alkyl "is hydroxymethyl;

and/or when R²Is 1R^2-1Substituted C₁～C₇Alkyl radical, R^2-1When it is hydroxy, the group is substituted by 1R^2-1Substituted C₁～C₇Alkyl is

And/or when R²Is 1R^2-1Substituted C₃～C₁₄Heterocycloalkyl, R^2-1When it is halogen or hydroxy, the substituted aryl is substituted by 1R^2-1Substituted C₃～C₁₄Heterocycloalkyl is

6. The pyrazolopyrimidine compound of formula a or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is¹Is H, -C (═ O) R^1-1、-C(＝NR^1-2)R^1-3、-S(＝O)₂R^1-4Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl or C₁～C₁₀A heteroaryl group;

and/or, R^1-1is-NR^1-1-1R^1-1-2、-OR^1-1-3Cyano, or, optionally, substituted by 1R^1-1-4Substituted: c₁～C₇Alkyl radical, C₂～C₇Alkynyl, C₃～C₁₄Cycloalkyl or C₃～C₁₄A heterocycloalkyl group; r^1-1-1And R^1-1-2Is hydrogen or C₁～C₇An alkyl group; r^1-1-3Is hydrogen, C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group; r^1-1-4Is halogen, OH or C₁～C₇An alkyl group;

and/or, R^1-2Is hydrogen, -CN or-OH;

and/or, R^1-3Is hydrogen, -NR^1-3-1R^1-3-2Or C₃～C₁₄A heterocycloalkyl group; r^1-3-1And R^1-3-2Independently is hydrogen or C₁～C₇An alkyl group;

and/or, R^1-5Independently halogen, -CN, -NR^1-5-1R^1-5-2、-(C＝O)R^1-5-3、C₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl radical, C₃～C₁₄Heterocycloalkyl or C₁～C₁₀A heteroaryl group; r^1-5-1And R^1-5-2Independently is hydrogen or C₁～C₇An alkyl group; r^1-5-3Independently of each otherIs hydrogen, -OR^1-5-3-1Or C₁～C₇An alkyl group; r^1-5-3-1Is C₁～C₇An alkyl group;

and/or, R²Is 1R^2-1Substituted: c₁～C₇Alkyl or C₃～C₁₄A heterocycloalkyl group; r^2-1Independently a hydroxyl group or a halogen.

7. The pyrazolopyrimidine compound of formula A or a pharmaceutically acceptable salt thereof according to claim 6, wherein R is¹Is H, -C (═ O) R^1-1、

Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl, or, C₃～C₁₄A heterocycloalkyl group; preferably, R¹Is H, -C (═ O) R^1-1Or, optionally substituted with 1,2 or 3R^1-5Substituted: c₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl, or, C₃～C₁₄A heterocycloalkyl group;

and/or, R^1-1Is optionally substituted by 1R^1-1-4Substituted: c₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group; r^1-1-4is-OH;

and/or, R^1-5Independently halogen, -CN, -NR^1-5-1R^1-5-2、-(C＝O)R^1-5-3、C₁～C₇Alkyl or C₃～C₁₄A cycloalkyl group; r^1-5-1And R^1-5-2Is hydrogen; r^1-5-3Independently is-OR^1-5-3-1；R^1-5-3-1Independently is C₁～C₇An alkyl group;

and/or, R²Is 1R^2-1Substituted: c₁～C₇Alkyl or C₃～C₁₄A heterocycloalkyl group; r^2-1Is a hydroxyl group;

and/orX is a single bond or CH₂(ii) a Y is C; z is a single bond or CH₂。

8. The pyrazolone pyrimidine compound of formula a or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the pyrazolone pyrimidine compound of formula a is defined as in any one of the following schemes:

scheme (1):

R^1-2is hydrogen, -CN or-OH;

R^1-5-1and R^1-5-2Independently is hydrogen or C₁～C₇An alkyl group;

R²is 1R^2-1Substituted: c₁～C₇Alkyl or C₃～C₁₄A heterocycloalkyl group; r^2-1Independently is hydroxy or halogen;

scheme (2):

the pyrazolone pyrimidine compound shown in the formula A is a pyrazolone pyrimidine compound shown in the formula I;

R^1-2is hydrogen, -CN or-OH;

R^1-5-1and R^1-5-2Independently is hydrogen or C₁～C₇An alkyl group;

scheme (3):

R¹is H, -C (═ O) R^1-1、

R^1-5-1and R^1-5-2Is hydrogen;

R^1-6and R^1-7Independently is hydrogen or C₁～C₇An alkyl group;

scheme (4):

R^1-5-1and R^1-5-2Is hydrogen;

scheme (5):

the pyrazolone pyrimidine compound shown in the formula A is a pyrazolone pyrimidine compound shown in a formula A-1;

R¹is H, -C (═ O) R^1-1、

R^1-5-1and R^1-5-2Is hydrogen;

R^1-6and R^1-7Independently is hydrogen or C₁～C₇An alkyl group;

R²is 1R^2-1Substituted: c₁～C₇Alkyl or C₃～C₁₄A heterocycloalkyl group; r^2-1Is a hydroxyl group;

scheme (6):

the pyrazolone pyrimidine compound shown in the formula A is a pyrazolone pyrimidine compound shown in a formula I-1;

R^1-5-1and R^1-5-2Is hydrogen;

scheme (7):

x is a single bond or CH₂(ii) a Y is C; z is a single bond or CH₂；

R¹Is composed of

R^1-6And R^1-7Independently is C₁～C₇An alkyl group;

R^2-1is a hydroxyl group.

9. The pyrazolone pyrimidine compound of formula a or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the pyrazolone pyrimidine compound of formula a has any one of the following structures:

10. a method for preparing the pyrazolone pyrimidine compound shown in the formula a according to any one of claims 1 to 9, which is any one of the following methods:

11. the process for preparing a pyrazolone pyrimidine compound of formula a according to claim 10, wherein the pyrazolone pyrimidine compound of formula a is a pyrazolone pyrimidine compound of formula I, according to any one of the following methods:

12. a compound of formula 1C ', 2A', 1C or 2A:

wherein R is¹X, Y and Z are as defined in any one of claims 1 to 9, PG is an amino protecting group.

13. A compound according to claim 12 of formula 1C ', 2A', 1C or 2A, which is any one of the following:

14. use of a substance X for the preparation of a kinase inhibitor;

the substance X is the pyrazolone pyrimidine compound shown in the formula A or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9.

15. Use of a substance X for the manufacture of a medicament; the medicament is used for treating and/or preventing diseases related to WEE1 kinase or treating and/or preventing cancer;

16. A pharmaceutical composition comprising substance X and a pharmaceutical excipient;

17. A combination comprising substance X and an anti-cancer drug,

18. Use of a combination according to claim 17 for the preparation of a medicament for the prevention and/or treatment of cancer.

19. Use of substance X for the preparation of a medicament for the prevention and/or treatment of cancer in combination with an "anti-cancer agent as defined in claim 17";

20. Use of an anticancer agent according to claim 17 for the preparation of a medicament for the prevention and/or treatment of cancer in combination with substance X;

21. A pharmaceutical composition comprising a combination according to claim 17 and a pharmaceutically acceptable excipient.

22. A combination kit comprising pharmaceutical composition a and pharmaceutical composition B;

the pharmaceutical composition A comprises a substance X and a pharmaceutical excipient;

the pharmaceutical composition B comprises the anticancer drug of claim 17 and a pharmaceutical excipient;