TW202241413A - Pyrazoloquinazoline compound, and preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a pyrazoloquinazoline compound, and a preparation method therefor and the use thereof. The present invention particularly relates to a pyrazoloquinazoline compound as shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compound has an obvious inhibitory effect on PLK1.

Description

Pyrazoloquinazoline compounds, their preparation method and use

The invention relates to a pyrazoloquinazoline compound, its preparation method and application.

PLKs (Polo-like kinases) are serine/threonine kinases. So far, five subtypes have been found in the family, namely PLK1-5. PLKs are mainly expressed in dividing cells and play a crucial role in cell cycle control and mitosis. PLK1 is the most studied and detailed in the PLK family, and its biological activity is also the most clearly described. The scientific community generally agrees that PLK1 is a key kinase that guides mitotic entry, centrosome maturation and segregation, bipolar spindle formation, metaphase-to-anaphase transition, and initiation of cytoplasmic division. Studies have found that PLK1 is not only highly expressed in various tumor tissues, but also activated in DNA damage and replication stress, which is also consistent with the abnormally active tumor cell proliferation. Knocking out the PLK1 gene by chemical small molecule inhibitors or biological means can find that a large number of tumor cells stay in the G2/M phase, and further lead to tumor cell apoptosis. Therefore, PLK1 is considered to be a promising anti-tumor target, especially its high expression in a variety of tumor tissues may have broad-spectrum anti-tumor potential. In addition, the expression level of PLK1 is low in normal cells, so the development of PLK1 inhibitors as anti-tumor drugs may have a good safety margin.

Compared with the high expression of PLK1 in tumor cells, PLK2 and PLK3 are more expressed in post-mitotic cells such as nerve cells, so the development of PLK1-specific inhibitors may avoid the toxic side effects caused by simultaneous inhibition of PLK2/3. The PLK1 inhibitor Volasertib (BI-6727) developed by BI (Boehringer Ingelheim) has severe toxic side effects in clinical practice due to its lack of selectivity for PLK2/3, which limits its efficacy, which led to its Phase III clinical failure. As a PLK1-specific inhibitor, Onvansertib, a small molecule inhibitor developed by Cardiff Oncology, has shown good anti-tumor activity and controllable side effects in multiple phase II clinical trials of proof-of-concept. However, Onvansertib still has a lot of room for improvement, for example, its poor membrane-permeability results in low bioavailability. Moreover, due to its long half-life (t1/2 greater than 24 hours), it can only be administered intermittently during the treatment cycle, which further limits its therapeutic effect in addition to causing obvious toxic and side effects.

The technical problem to be solved by the present invention is that the PLK1 inhibitors in the prior art have defects such as single structure and poor inhibitory effect, and provide a pyrazoloquinazoline compound, its preparation method and application, and the compound has an obvious inhibitory effect on PLK1.

The present invention solves the above-mentioned technical problems through the following technical solutions.

其中，R ¹為C ₁~C ₄烷氧基、被一個或多個R ^1-1取代的C ₁~C ₄烷氧基或3~6元環烷基氧基；R ^1-1獨立地為鹵素或3~6元環烷烴； R ²為H、鹵素或C ₁~C ₄烷基； R ³為5~10元雜環烷基或被一個或多個R ^3-1取代的5~10元雜環烷基；該5~10元雜環烷基中，雜原子選自N、O和S中的一種或多種，雜原子的個數為1~2個；R ^3-1獨立地為C ₁~C ₄烷基； R ⁴為氰基、3~6元環烷烴、被一個或多個R ^4-1取代的3~6元環烷烴、3~6元雜環烷烴或被一個或多個R ^4-2取代的3~6元雜環烷烴；被一個或多個R ^4-3取代的C ₁~C ₄烷基；該3~6元雜環烷基中，雜原子選自N、O和S中的一種或多種，雜原子的個數為1~2個；R ^4-1獨立地為鹵素、羥基或C ₁~C ₄烷基；R ^4-2獨立地為鹵素或C ₁~C ₄烷基；R ^4-3獨立地為鹵素、氰基或羥基； R ⁵為H、羥基、C ₁~C ₄烷基或C ₁~C ₄烷氧基。 The present invention provides a pyrazoloquinazoline compound as shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate;

Wherein, R ¹ is C ₁ ~C ₄ alkoxy, C ₁ ~C ₄ alkoxy or 3~6 membered cycloalkyloxy substituted by one or more R ^1-1 ; R ^1-1 is independently is halogen or 3~6 membered cycloalkane; R ² is H, halogen or C ₁ ~C ₄ alkyl; R ³ is 5~10 membered heterocycloalkyl or 5~ substituted by one or more R ^3-1 10-membered heterocycloalkyl; in the 5-10-membered heterocycloalkyl, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-2; R ^3-1 is independently is C ₁ ~C ₄ alkyl; R ⁴ is cyano, 3~6 membered cycloalkane, 3~6 membered cycloalkane substituted by one or more R ^4-1 , 3~6 membered heterocycloalkane or substituted by one 3~6 membered heterocycloalkane substituted by one or more R ^4-2 ; C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 ; in the 3~6 membered heterocycloalkyl, the heteroatom is selected from From one or more of N, O and S, the number of heteroatoms is 1~2; R ^4-1 is independently halogen, hydroxyl or C ₁ ~C ₄ alkyl; R ^4-2 is independently halogen Or C ₁ ~C ₄ alkyl; R ^4-3 is independently halogen, cyano or hydroxyl; R ⁵ is H, hydroxyl, C ₁ ~C ₄ alkyl or C ₁ ~C ₄ alkoxy.

In a certain scheme, in the pyrazoloquinazoline compound, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, the definition of certain groups As described below, the definitions of the remaining groups are as described in any of the above schemes (hereinafter referred to as "in a certain scheme"):

In a certain aspect, R ^1-1 is independently F, Cl, Br or I, such as F.

In a certain aspect, R ^1-1 is independently a 3-6 membered cycloalkane, such as cyclopropane, cyclobutane or cyclopentane.

In a certain scheme, when R ¹ is C ₁ ~C ₄ alkoxy, the C ₁ ~C ₄ alkoxy is methoxy, ethoxy, isopropoxy or tert-butoxy, such as methyl Oxygen.

In a certain scheme, when R ¹ is a C ₁ ~C ₄ alkoxy group substituted by one or more R ^1-1 , the C ₁ ~C ₄ alkoxy group can be methoxy, ethoxy, Isopropoxy or tert-butoxy, eg methoxy.

In ^a certain scheme, when R is 3-6 membered cycloalkyloxy, the 3-6 membered cycloalkoxy is cyclopropyloxy, cyclobutyloxy or cyclopentyloxy, for example Cyclopropyloxy or cyclobutyloxy.

、

、

、

、

，、

或

，例如

、

、

或

。 In ^a certain scheme, R1 can be

,

,

,

,

,,

or

,E.g

,

,

or

.

^In a certain aspect, when R2 is halogen, the halogen can be F, Cl, Br or I.

In a certain scheme, when R ² is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Or tert-butyl, eg methyl.

In a certain scheme, when R ^3-1 is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or tert-butyl, eg methyl.

In a certain scheme, when R ³ is a 5-10 membered heterocycloalkyl group substituted by one or more R ^3-1 , the 5-10 membered heterocycloalkyl group can be a 6-9 membered heterocycloalkyl group , such as a 6-9 membered heterocycloalkyl group containing two Ns, and other examples include piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl, 3,8-diazabicyclo[3.2.1]octyl, Octahydropyrrole[1,2-a]pyrazinyl, 2,6-diazaspiro[3.4]octanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 1,6- Diazaspiro[3.4]octyl or octahydropyrrole[3,4-c]pyrrolyl.

、

、

、

、

、

、

、

、

或

(b為與

的連接位點)。 In a certain scheme, R ³ is preferably

,

,

,

,

,

,

,

,

or

(b is with

connection point).

、

、

、

、

、

、

、

、

或

。 In a certain scheme, when ^R3 can be

,

,

,

,

,

,

,

,

or

.

、

、

、

、

、

、

、

、

或

。 In a certain scheme, ^R3 can be

,

,

,

,

,

,

,

,

or

.

In a certain scheme, R4 is a cyano group, a ³ ~6 membered cycloalkane, a 3~6 membered heterocycloalkane, or a 3~6 membered ^{heterocycloalkane substituted by one or more R4-2 .} ~6-membered heterocycloalkanes.

In a certain embodiment, R ^4-1 is halogen or hydroxy.

In a certain scheme, R ^4-2 is C ₁ -C ₄ alkyl.

In a certain embodiment, R ⁵ is H.

In a certain embodiment, when R ^4-1 is halogen, the halogen is F, Cl, Br or I, such as F.

In a certain scheme, when R ^4-1 is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or tert-butyl, eg methyl or ethyl.

In a certain scheme, when R ^4-2 is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or tert-butyl, eg methyl or ethyl.

In a certain embodiment, when R ^4-2 is halogen, the halogen is F, Cl, Br or I, such as F.

In a certain scheme, when R ⁴ is a 3-6-membered cycloalkane, the 3-6-membered cycloalkane can be cyclopropane, cyclobutane or cyclopentane, such as cyclopropane or cyclobutane.

In a certain scheme, when R ⁴ is a 3-6 membered cycloalkane substituted by one or more R ^4-1 , the 3-6 membered cycloalkane can be cyclopropane, cyclobutane or cyclopentane, for example cyclopropane or cyclobutane.

、

或

。 In a certain scheme, when R ⁴ is a 3-6 membered cycloalkane substituted by one or more R ^4-1 , the 3-6 membered cycloalkane substituted by one R ^4-1 can be

,

or

.

、

或

。 In a certain scheme, when R ⁴ is a 3-6 membered heterocycloalkane, the 3-6 membered heterocycloalkane can be

,

or

.

In a certain scheme, when R ⁴ is a 3-6 membered heterocycloalkane substituted by one R ^4-2 , the 3-6 membered heterocycloalkane can be a 4-membered heterocycloalkane containing one N or O or containing One N or O 5-membered heterocycloalkane.

、

或

。 In a certain scheme, when R ⁴ is a 3-6 membered heterocycloalkane substituted by one or more R ^4-2 , the 3-6 membered heterocycloalkane substituted by one or more R ^4-2 is

,

or

.

或

。 In a certain scheme, when R ⁴ is a 3-6 membered heterocycloalkane substituted by one or more R ^4-2 , the 3-6 membered heterocycloalkane substituted by one or more R ^4-2 is

or

.

。 In a certain scheme, when R ⁴ is a C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 , the C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 is

.

In a certain scheme, R4 is a cyano group, a ³ ~6 membered cycloalkane, a 3~6 membered heterocycloalkane, or a 3~6 membered ^{heterocycloalkane substituted by one or more R4-2 .} ~6-membered heterocycloalkane, or C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 .

In a certain scheme, R ⁴ is a 3-6 membered cycloalkane substituted by one or more R ^4-1 , wherein R ^4-1 is halogen or hydroxyl.

In a certain scheme, R ⁴ is a 3-6 membered heterocycloalkane substituted by one or more R ^4-2 , wherein R ^4-2 is C ₁ -C ₄ alkyl.

In a certain embodiment, R ⁴ is C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 , wherein R ^4-3 is hydroxyl.

、

、

、

、

和

。 In a certain scheme, R ⁴ is selected from the group consisting of cyano,

,

,

,

,

with

.

In a certain embodiment, R ⁵ is H or hydroxyl.

In a certain scheme, R ⁵ is C ₁ ~C ₄ alkyl, and the C ₁ ~C ₄ alkyl can be methyl, ethyl, isopropyl or tert-butyl, such as methyl or ethyl.

In a certain scheme, R ⁵ is C ₁ ~C ₄ alkoxy, and the C ₁ ~C ₄ alkoxy is methoxy, ethoxy, isopropoxy or tert-butoxy, such as methoxy

。 The present invention also provides a pyrazoloquinazoline compound as shown in formula Ia, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate:

.

。 In a certain scheme, the present invention provides any one of the following pyrazoloquinazoline compounds, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate:

.

其中，R ¹為被一個或多個R ^1-1取代的C ₁~C ₄烷氧基；R ^1-1獨立地為鹵素； R ²為H、鹵素或C ₁~C ₄烷基； R ³’為7~9元雜環烷基或被一個R ^3-1取代的7~9元雜環烷基；該7~9元雜環烷基為7~9元雜螺環烷基或7~9元雜橋環烷基；該被一個R ^3-1取代的7~9元雜環烷基為被一個R ^3-1取代的7~9元雜螺環烷基或被一個R ^3-1取代的7~9元雜橋環烷基；雜原子選自N、O和S中的一種或多種，雜原子的個數為1~2個；R ^3-1為C ₁~C ₄烷基； R ⁴’獨立地為被一個R ^4-3取代的C ₁~C ₄烷基；R ^4-3為羥基或鹵素； R ⁵為H、羥基C ₁~C ₄烷基或C ₁~C ₄烷氧基。 The present invention also provides a pyrazoloquinazoline compound as shown in formula II, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate:

Wherein, R ¹ is C ₁ ~C ₄ alkoxy substituted by one or more R ^1-1 ; R ^1-1 is independently halogen; R ² is H, halogen or C ₁ ~C ₄ alkyl; R ³ ' is a 7~9 membered heterocycloalkyl group or a 7~9 membered heterocycloalkyl group substituted by one R ^3-1 ; the 7~9 membered heterocycloalkyl group is a 7~9 membered heterospirocycloalkyl group or 7 ~9-membered heterobridged cycloalkyl; the 7-9-membered heterocycloalkyl substituted by one R ^3-1 is a 7-9-membered heterospirocycloalkyl substituted by one R ^3-1 or one R ^{3- 1} Substituted 7-9 membered heterobridged cycloalkyl group; the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-2; R ^3-1 is C ₁ -C ₄ alkane R ⁴ ' is independently C ₁ ~C ₄ alkyl substituted by one R ^4-3 ; R ^4-3 is hydroxyl or halogen; R ⁵ is H, hydroxyl C ₁ ~C ₄ alkyl or C ₁ ~ C ₄ alkoxy.

In a certain aspect, R ^1-1 is F, Cl, Br or I, such as F.

In a certain scheme, when R ¹ is a C ₁ ~C ₄ alkoxy group substituted by one or more R ^1-1 , the C ₁ ~C ₄ alkoxy group can be methoxy, ethoxy, Isopropoxy or tert-butoxy, eg methoxy.

、

、

、

，例如

。 In ^a certain scheme, R1 is

,

,

,

,E.g

.

In a certain scheme, when R ² is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Or tert-butyl, eg methyl.

In a certain aspect, ^R3-1 can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, eg methyl.

或

。 In a certain scheme, when R ^3' is a 7~9 membered heterospirocycloalkyl group, the 7~9 membered heterospirocycloalkyl group can be a 7~9 membered heterospirocycloalkyl group containing two nitrogen atoms, E.g

or

.

或

。 In a certain scheme, when R ^3' is a 7-9 membered heterospirocycloalkyl substituted by one R ^3-1 , the 7-9 membered heterospirocycloalkyl substituted or unsubstituted by one R ^3-1 It can be a 7-9 membered heterospirocycloalkyl group substituted by one R ^3-1 containing two nitrogen atoms, for example

or

.

。 In a certain scheme, when R ^3' is a 7-9 membered heterobridged cycloalkyl group, the 7-9 membered heterobridged cycloalkyl group can be a 7-9 membered heterobridged cycloalkyl group containing two Ns, for example

.

、或

。 In a certain scheme, when R ^3' is a 7-9 membered heterobridged cycloalkyl group substituted by one R ^3-1 , the 7~9 membered heterobridged cycloalkyl group substituted by one R ^3-1 may contain A 7-9 membered heterobridged cycloalkyl group with two nitrogens substituted by one R ^3-1 , for example

,or

.

In a certain embodiment, when R ^4-3 is halogen, the halogen is F, Cl, Br or I.

In a certain scheme, when R ⁴ ' is independently a C ₁ ~C ₄ alkyl substituted by one R ^4-3 , the C ₁ ~C ₄ alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, eg methyl.

^In a certain aspect, R4 can be _-CH2OH .

In a certain scheme, when R ⁵ is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl can be methyl, ethyl, isopropyl or tert-butyl, such as methyl or ethyl.

In a certain scheme, when R ⁵ is C ₁ ~C ₄ alkoxy, the C ₁ ~C ₄ alkoxy is methoxy, ethoxy, isopropoxy or tert-butoxy, such as methyl Oxygen.

。 In a certain scheme, the pyrazoloquinazoline compound shown in formula II, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt can be any of the following Shown:

.

其中，R ¹為C ₁~C ₄烷氧基或被一個或多個R ^1-1取代的C ₁~C ₄烷氧基；R ^1-1獨立地為鹵素或3~6元環烷烴； R ²為H、鹵素或C ₁~C ₄烷基； R ³為5~10元雜環烷基或被一個或多個R ^3-1取代的5~10元雜環烷基；該5~10元雜環烷基中，雜原子選自N、O和S中的一種或多種，雜原子的個數為1~2個；R ^3-1獨立地為C ₁~C ₄烷基； R ⁴為氰基、3~6元環烷烴、被一個或多個R ^4-1取代的3~6元環烷烴、3~6元雜環烷烴或被一個或多個R ^4-2取代的3~6元雜環烷烴；被一個或多個R ^4-3取代的C ₁~C ₄烷基；該3~6元雜環烷基中，雜原子選自N、O和S中的一種或多種，雜原子的個數為1~2個；R ^4-1獨立地為鹵素、羥基或C ₁~C ₄烷基；R ^4-2獨立地為鹵素或C ₁~C ₄烷基；R ^4-3獨立地為鹵素、氰基或羥基； R ⁵為H、羥基、C ₁~C ₄烷基或C ₁~C ₄烷氧基。 The present invention also provides a pyrazoloquinazoline compound as shown in formula III, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate:

Wherein, R ¹ is a C ₁ ~C ₄ alkoxy group or a C ₁ ~C ₄ alkoxy group substituted by one or more R ^1-1 ; R ^1-1 is independently a halogen or a 3-6 membered cycloalkane; R ² is H, halogen or C ₁ ~C ₄ alkyl; R ³ is 5~10 membered heterocycloalkyl or 5~10 membered heterocycloalkyl substituted by one or more R ^3-1 ; the 5~10 membered heterocycloalkyl In a 10-membered heterocycloalkyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 2; R ^3-1 is independently C ₁ ~C ₄ alkyl; R ⁴ is cyano, 3~6 membered cycloalkane, 3~6 membered cycloalkane substituted by one or more R ^4-1 , 3~6 membered heterocycloalkane or 3 substituted by one or more R ^4-2 ~6-membered heterocycloalkane; C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 ; in the 3~6-membered heterocycloalkyl, the heteroatom is selected from one of N, O and S or Multiple, the number of heteroatoms is 1~2; R ^4-1 is independently halogen, hydroxyl or C ₁ ~C ₄ alkyl; R ^4-2 is independently halogen or C ₁ ~C ₄ alkyl; R ^4-3 is independently halogen, cyano or hydroxyl; R ⁵ is H, hydroxyl, C ₁ ~C ₄ alkyl or C ₁ ~C ₄ alkoxy.

In a certain scheme, R ¹ is C ₁ ~C ₄ alkoxy, such as methoxy, ethoxy, isopropoxy or tert-butoxy.

In a certain scheme, R ¹ is C ₁ ~C ₄ alkoxy substituted by one or more R ^1-1 , wherein the C ₁ ~C ₄ alkoxy can be methoxy, ethoxy, iso Propoxy or tert-butoxy, eg methoxy.

In a certain embodiment, R ¹ is C ₁ ~C ₄ alkoxy substituted by one or more R ^1-1 , wherein R ^1-1 is independently F, Cl, Br or I, such as F.

、

、

、

、

或

。 In a certain scheme, R ¹ can be selected from

,

,

,

,

or

.

、

或

。 In a certain scheme, R ¹ can be selected from

,

or

.

In a certain embodiment, R ² is H.

In a certain aspect, R ² is halo which is F, Cl, Br or I.

In a certain scheme, R ² is C ₁ ~C ₄ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In a certain scheme, ^R3 is a 5-10 membered heterocycloalkyl group, such as a 6-9 membered heterocycloalkyl group, such as a 6-9 membered heterocycloalkyl group containing two Ns, and another example is piperazinyl, hexa Hydropyridazinyl, hexahydropyrimidinyl, 3,8-diazabicyclo[3.2.1]octanyl, octahydropyrrole[1,2-a]pyrazinyl, 2,6-diazaspiro[ 3.4]octyl, 3,6-diazabicyclo[3.2.0]heptyl, 1,6-diazaspiro[3.4]octyl or octahydropyrrole[3,4-c]pyrrolyl .

In a certain scheme, R ³ is a 5-10 membered heterocycloalkyl group substituted by one or more R ^3-1 , wherein the 5-10 membered heterocycloalkyl group is, for example, a 6-9 membered heterocycloalkyl group, For example, a 6-9 membered heterocycloalkyl group containing two Ns, and other examples include piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl, 3,8-diazabicyclo[3.2.1]octyl, octane Hydropyrrole[1,2-a]pyrazinyl, 2,6-diazaspiro[3.4]octyl, 3,6-diazabicyclo[3.2.0]heptanyl, 1,6-di Azaspiro[3.4]octyl or octahydropyrrole[3,4-c]pyrrolyl, wherein R ^3-1 is C ₁ ~C ₄ alkyl, such as methyl, ethyl, n-propyl, isopropyl base, n-butyl, isobutyl or tert-butyl.

、

、

、

、

、

、

、

、

或

。 In a certain scheme, ^R3 is

,

,

,

,

,

,

,

,

or

.

、

、

、

、

、

、

、

、

或

。 In a certain scheme, ^R3 is

,

,

,

,

,

,

,

,

or

.

、

、

、

、

、

、

、

、

或

。 In a certain scheme, ^R3 is

,

,

,

,

,

,

,

,

or

.

In a certain embodiment, R ⁴ is cyano.

In a certain scheme, R ⁴ is a 3-6 membered cycloalkane, such as cyclopropane, cyclobutane or cyclopentane.

In a certain scheme, R ⁴ is a 3-6 membered cycloalkane substituted by one or more R ^4-1 , wherein the 3-6 membered cycloalkane is, for example, cyclopropane, cyclobutane or cyclopentane, and R ^{4 -1} is halogen, such as F, Cl, Br or I.

In a certain scheme, R ⁴ is a 3-6 membered cycloalkane substituted by one or more R ^4-1 , wherein the 3-6 membered cycloalkane is, for example, cyclopropane, cyclobutane or cyclopentane, and R ^{4 -1} is C ₁ ~C ₄ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

、

、

或

。 ^In a certain scheme, R4 is

,

,

or

.

In a certain scheme, R ⁴ is a 3-6 membered heterocycloalkane, such as a 4-membered heterocycloalkane containing one N or O or a 5-membered heterocycloalkane containing one N or O.

In a certain scheme, R ⁴ is a 3-6 membered heterocycloalkane substituted by one or more R ^4-2 , such as a 4-membered heterocycloalkane containing one N or O or a 5-membered heterocycloalkane containing one N or O Cycloalkanes, wherein R ^4-2 is halogen, such as F, Cl, Br or I.

或

。 ^In a certain scheme, R4 is

or

.

In a certain scheme, R ⁴ is a 3-6 membered heterocycloalkane substituted by one or more R ^4-2 , such as a 4-membered heterocycloalkane containing one N or O or a 5-membered heterocycloalkane containing one N or O Cycloalkane, wherein R ^4-2 is C ₁ ~C ₄ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In a certain scheme, R ⁴ is C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 , wherein the C ₁ ~C ₄ alkyl is methyl, ethyl, isopropyl or tert-butyl group, R ^4-3 is halogen, such as F, Cl, Br or I.

In a certain scheme, R ⁴ is C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 , wherein the C ₁ ~C ₄ alkyl is methyl, ethyl, isopropyl or tert-butyl Base, R ^4-3 is cyano.

In a certain scheme, R ⁴ is C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 , wherein the C ₁ ~C ₄ alkyl is methyl, ethyl, isopropyl or tert-butyl group, R ^4-3 is hydroxyl.

。 ^In a certain scheme, R4 is

.

In a certain embodiment, R ⁵ is H or hydroxyl.

In a certain scheme, R ⁵ is C ₁ ~C ₄ alkyl, such as methyl, ethyl, isopropyl or tert-butyl.

In a certain scheme, R ⁵ is C ₁ ~C ₄ alkoxy, such as methoxy, ethoxy, isopropoxy or tert-butoxy.

。 In a certain scheme, the pyrazoloquinazoline compound shown in formula III is:

.

。 其中，R ¹、R ²、R ³、R ⁴或R ⁵的定義如上所述；X為鹵素；L為鹽酸鹽。 The present invention also provides a preparation method of the pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, which The method includes the following steps: in an organic solvent, in an alkali reagent, and under the action of a palladium catalyst, carry out a coupling reaction of compound 1g, a ligand reagent and R ³ -H to obtain compound I;

. Wherein, R ¹ , R ² , R ³ , R ⁴ or R ⁵ are as defined above; X is halogen; L is hydrochloride.

In the coupling reaction, the palladium catalyst may be tridibenzylideneacetone dipalladium.

In the coupling reaction, the organic solvent can be a conventional solvent for this type of reaction in the art, such as tetradioxane.

In the coupling reaction, the base reagent can be cesium carbonate.

In the coupling reaction, the ligand reagent can be 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

。 其中，R ¹、R ²、R ³’、R ⁴’或R ⁵的定義如上所述；X為鹵素；L為鹽酸鹽。 The present invention also provides a pyrazoloquinazoline compound as shown in formula II, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, which includes the following step, in an organic solvent, under the action of a palladium catalyst, carry out a coupling reaction of compound 1g, a ligand reagent and R ³ -L to obtain compound II;

. Wherein, R ¹ , R ² , R ³ ′, R ⁴ ′ or R ⁵ are as defined above; X is halogen; L is hydrochloride.

In the coupling reaction, the palladium catalyst may be tridibenzylideneacetone dipalladium.

In the coupling reaction, the organic solvent can be a conventional solvent for this type of reaction in the art, such as tetradioxane.

In the coupling reaction, the base can be cesium carbonate.

In the coupling reaction, the ligand reagent can be 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

The present invention provides a kind of above-mentioned pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate. Use in a PLK1 inhibitor; the inhibitor is preferably an inhibitor used in vitro.

The present invention also provides a pharmaceutical composition, which also includes the pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable Salt solvates and pharmaceutical excipients.

The present invention also provides a pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate. use in medicine;

The medicine is a medicine for treating at least one of the following diseases: breast cancer, prostate cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, leukemia and lymphoma.

The present invention provides a pyrazoloquinazoline compound shown in formula II, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate in the preparation of PLK1 Use in an inhibitor; the inhibitor is preferably an inhibitor used in vitro.

The present invention also provides a pharmaceutical composition, which comprises the pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvates and pharmaceutical excipients.

The present invention also provides a kind of above-mentioned pyrazoloquinazoline compound represented by formula II, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt's solvate in use in the manufacture of medicines;

The drug is a drug for treating at least one of the following diseases: breast cancer, prostate cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, gastric cancer, esophageal cancer, ovarian cancer, melanoma, osteosarcoma, multiple myeloma, leukemia and lymphoma.

The present invention also provides a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and one or more chemotherapeutic agents.

In a certain regimen, the one or more chemotherapeutic agents are used simultaneously, separately or sequentially with a compound of the invention, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

Terminology Explanation

In each part of the specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C ₁ ~C ₄ alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl (ie propyl, including n-propyl and isopropyl), C ₄ alkyl (ie butyl , including n-butyl, isobutyl, sec-butyl and tert-butyl).

When a substituent is listed without specifying the atom through which it is bonded to a compound included in a general chemical formula but not specifically mentioned, such a substituent may be bonded through any atom thereof. Combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

When a substituent is not clearly indicated in the enumerated group, this group only means unsubstituted. For example, when there is no limitation of "substituted or unsubstituted" before "C ₁ ~C ₄ alkyl", it only refers to "C ₁ ~C ₄ alkyl" itself or "unsubstituted C ₁ ~C ₄ alkyl".

The term "C _i -C _j " denotes a range of carbon atoms, where i and j are integers and j is greater than i, and the range of carbon atoms includes the endpoints (i.e., i and j) and every integer between the endpoints point. For example, C ₁ ~C ₆ represent the range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms and 6 carbon atoms. In some embodiments, the term "C ₁ -C ₁₂ " means 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3, or especially 1 to 2 carbon atoms.

The term "alkyl" refers to a saturated straight or branched chain hydrocarbon group. The term "C _i -C _j alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms. In some embodiments, the alkyl group comprises 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms , 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1 -Propyl (isobutyl), 2-butyl (neobutyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3 -Pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2- Hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl -3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc.

The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecule through an oxygen atom. The term "C _i -C _j alkoxy" means that the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, alkoxy groups contain 1 to 12 carbon atoms. In some embodiments, alkoxy groups contain 1 to 11 carbon atoms. In some embodiments, the alkoxy group contains 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms atom, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

The term "cycloalkane" or "cycloalkyl" refers to a saturated monocyclic cyclic group consisting only of carbon atoms with a specified number of carbon atoms (eg, C ₃ -C ₆ ). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "heterocycloalkyl" refers to a specified number of ring atoms (such as 5 to 10 members), a specified number of heteroatoms (such as 1, 2 or 3), and a specified type of heteroatom (N, O and S one or more of ), which is a monocyclic ring, bridged ring or spiro ring, and each ring is saturated. Bridged rings refer to polycyclic rings that share two or more atoms between monocyclic rings. A spiro ring refers to multiple rings that share one atom between the single rings. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base. When the compound contains relatively acidic functional groups, base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like. When the compound contains relatively basic functional groups, acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, methanesulfonates, and the like. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

The term "solvate" refers to a substance formed after crystallization of a compound with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

The term "solvate of a pharmaceutically acceptable salt" refers to a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base, solvent (including but not limited to: water, methanol, ethanol, etc. ) combination, wherein the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent is stoichiometric or non-stoichiometric. Solvates of pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrate.

The term "pharmaceutical excipients" refers to the excipients and additives used in the production of drugs and the preparation of prescriptions, and refers to all substances contained in pharmaceutical preparations except active ingredients. For details, see Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

Unless defined otherwise, all technical and scientific terms used herein have meanings standard to the art to which the claimed subject matter belongs. In the event that more than one definition exists for a term, the definition herein controls.

It should be understood that use of the singular forms herein, such as "a" or "an", includes plural referents unless otherwise specified. In addition, the term "comprising" is an open definition rather than a closed one, that is, it includes the content specified in the present invention, but does not exclude other content.

Unless otherwise stated, the present invention adopts traditional methods of mass spectrometry and elemental analysis, and each step and condition can refer to the conventional operation steps and conditions in the art.

Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.

In addition, it should be noted that, unless otherwise clearly stated, the description method "...independently" used in the present invention should be understood in a broad sense, which means that the described individuals are independent of each other and can be independent are the same or different specific groups. In more detail, the description "...independently" can mean that in different groups, the specific options expressed by the same symbols do not affect each other; it can also mean that in the same group, the same symbols The specific options expressed between them do not affect each other.

」是指，相應的基團透過該位點與化合物中的其它片段、基團進行連接。 Those with ordinary knowledge in the art can understand that, according to the practice used in the art, the present application describes the structural formula of the group used "

" means that the corresponding group is connected to other fragments and groups in the compound through this site.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

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

The positive progress effect of the present invention is that the present invention provides a pyrazoloquinazoline compound, its preparation method and application. The compound has at least any of the following advantages: it has obvious inhibitory effect on PLK1 and can further regulate the half-life of the drug.

detailed description

The present invention will be further described below through examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

Example 1

first step Compound 1a (480 mg, 2.0 mmol) and 2-hydrazinoethanol (152 mg, 2.0 mmol) were dissolved in 5 mL of glacial acetic acid and stirred for 5 hours at room temperature. After the reaction was completed, the crude product was dispersed in ethyl acetate (20 mL) and water (30 mL) after removing most of the glacial acetic acid, and the aqueous phase was extracted with ethyl acetate (20 mL x 1), and the organic phase was successively washed with saturated bicarbonate Sodium aqueous solution (20 mL x 1) and saturated brine (20 mL x 1) were washed, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1b (430 mg, yield: 85%).

second step Under nitrogen protection, a solution of compound 1b (800 mg, 3.2 mmol) and dimethylformamide di-tert-butyl acetal (709 mg, 3.5 mmol) in dimethylformamide (20 mL) was heated to 60 °C and reacted for 2 hours. The reaction is over. Cool, add water (50 mL) to the reaction solution, extract with ethyl acetate (20 mL x 2), wash the organic phase with water (20 mL x 1) and saturated brine (20 mL x 1) successively, anhydrous sodium sulfate Drying, filtration, and concentration gave compound 1c (750 mg, yield: 76%).

third step Under nitrogen protection, a solution of compound 1c (750 mg, 2.4 mmol) and compound 1d (728 mg, 2.4 mmol) in dimethylformamide (10 mL) was heated to 120 °C and stirred for 2 hours. The reaction is over. Cool, add 30 mL of water, extract with ethyl acetate (20 mL x 2), wash the organic phase successively with water (20 mL x 1) and saturated brine (20 mL x 1), dry over anhydrous sodium sulfate, filter, After concentration, the obtained crude product was subjected to silica gel column chromatography (methanol/dichloromethane=0/100%) to obtain compound 1e (780 mg, yield: 59%). LCMS (M+H)+ m/z: 542/544.

the fourth step To a solution of compound 1e (780 mg, 1.4 mmol) in ethanol (10 mL) was added potassium hydroxide in ethanol (1.5 M, 3 mL) at room temperature. The resulting reaction solution was stirred for an additional 4 hours. The reaction is over. Filtration gave compound 1f (650 mg, yield: 82%).

the fifth step To a solution of compound 1f (650 mg, 1.2 mmol), ammonium chloride (80 mg, 1.5 mmol) and triethylamine (310 mg, 3.6 mmol) in dimethylformamide (5 mL) at room temperature under nitrogen protection 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (684 mg, 1.8 mmol) was added and reacted for 2 hours. The reaction is over. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was washed successively with water (10 mL x 1) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and filtered. Concentration gave compound 1g (510 mg, yield: 83%). LCMS (M+H)+ m/z: 513/515.

step six Under nitrogen protection, compound 1g (51 mg, 0.1 mmol), 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (24 mg, 0.12 mmol), carbonic acid Cesium (130 mg, 0.4 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (24 mg, 0.04 mmol) and tridibenzylideneacetone dipalladium (18 mg , 0.02 mmol) in 1,4-dioxane (2 mL) was heated to reflux for 4 hours. The reaction is over. Cool, add water (10 mL) to the reaction solution, extract with ethyl acetate (15 mL x 3), wash the organic phase with water (10 mL x 1) and saturated brine (10 mL x 1) successively, anhydrous sodium sulfate After drying, filtering and concentrating, the obtained crude product was purified by preparative HPLC to obtain compound 1 (1.5 mg, yield: 27%). LCMS (M+H)+ m/z: 559.

Example 2

first step According to the method of Example 1, compound 2 (3.0 mg) was obtained from compound 1g. LCMS (M+H)+ m/z: 559.

Example 3

first step According to the method of Example 1, compound 3 (1.6 mg) was obtained from compound 1g. LCMS (M+H)+ m/z: 545.

Example 4

first step According to the method of Example 1, compound 4 (1.3 mg) was obtained from compound 1g. LCMS (M+H)+ m/z: 545.

Example 5

first step According to the method of Example 1, compound 5 (2.0 mg) was obtained from compound 1g. LCMS (M+H)+ m/z: 545.

Example 6

In the first step, 1,2-cyclohexanedione 6F_1 (100 g, 0.892 mol) was dissolved in a mixed solvent of toluene (700 mL) and MeOH (500 mL). p-Toluenesulfonic acid (15.4 g, 89.2 mmol) was added and the solution was stirred at 100°C for 48 hours. The solvent was evaporated and the residue was dissolved with DCM (500 mL) and washed with a saturated solution of NaHCO ₃ (500 mL). The organic phase was dried _{over Na2SO4} and concentrated. Purification by silica gel column chromatography (0%~30% EA in PE) afforded 2-methoxycyclohexyl-2-en-1-one 6F_2 (42 g, 37.3%) as an oil. ESI-MS (M+H)+=127.

In the second step, LiHMDS (51 mL, 51.0 mmol, 1M in THF) was added dropwise to 2-methoxycyclohexyl- ₂ -en-1-one (6.40 g, 45.7 mmol) in THF (60 mL). After stirring at -50°C for 30 minutes, diethyl oxalate (7.47 g, 51.0 mmol) was added. The solution was stirred at 25°C for 16 hours. After the reaction, water (100 mL) was added, and 1N HCl was added to adjust the pH to 4-5, and the resulting solution was extracted with EA (50 mL*3). The organic layer was dried _{over Na2SO4} and evaporated to dryness. The crude product was purified by column (0%~15% EA in PE) to give 2-(3-methoxy-2-oxocyclohex-3-en-1-yl)-2-oxo Ethyl acetate 6F_3 (8.2 g, 71.4%). ¹ HNMR (400 MHz, CDCl3) δ H 14.86 (s, 1H), 5.89 (t, 1H), 4.35 (q, 2H), 3.66 (s, 3H), 2.90 (t, 2H), 2.45-2.38 (m , 2H) ), 1.38 (t, 3H).

The third step is to add 2-(3-ethoxy-2-oxocyclohex-3-en-1-yl)-2-oxoacetate ethyl 6F_3 (3.0 g, 0.012 mmol) in ethanol at 25 °C (30 mL) solution was added hydroxyethylhydrazine (0.6 mL, 0.012 mmol). The reaction was stirred at 80 °C for 5 hours. The solvent was then evaporated and the residue was redissolved with DCM (30 mL). The organic layer was washed with water, dried _{over Na2SO4} and concentrated. The residue was dissolved in THF (12 mL) and HCl (12 mL, 1 mol/L), and stirred at 25 °C for ₂ hours, the reaction was quenched with saturated NaHCO solution (50 mL), and EA (50 mL *3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 1-(2-hydroxyethyl)-7-oxo-4,5,6 as a brown oil , ethyl 7-tetrahydro-1H-indazole-3-carboxylate 6F_3 (2.4 g, crude). ESI-MS (M+H)+=253.

Step 4 Dissolve 6F_3 (4 g, 15.9 mmol) in DMF (24 mL) at 25 °C, and then add 8 mL of DMFDMA. The resulting mixture was stirred at 80°C for 20 h, then cooled to 25°C, concentrated to remove the solvent, and the crude product was purified by column (20%-50% EA in PE) to obtain 6F (3.25 g, 66.7%) as a yellow solid. ¹ HNMR (600 MHz, DMSOd6) δH 7.49 (s, 1H), 4.83 (t, 1H), 4.60 (t, 2H), 4.26 (q, 2H), 3.72 (q, 2H), 3.12 (s, 6H) , 2.95-2.80 (m, 4H), 1.29 (t, 3H).

Step 5 5-Bromo-4-fluoro-2-methoxyaniline 6A (7.5 g, 34.3 mmol) was dissolved in EtOH (90 mL), and Ac ₂ O (8.7 g, 85.6 mmol) was added. The mixture was stirred at 25°C for 2.5 h, and the solvent was evaporated to give N-(5-bromo-4-fluoro-2-methoxyphenyl)acetamide 6A_1 (8 g crude) as a brown solid. ESI-MS (M+H)+=262.

Step 6 Add N-(5-bromo-4-fluoro-2-methoxyphenyl)acetamide 6A_1 (1.5 g, 5.74 mmol), Davephos (90 mg, 0.223 mmol), Pd ₂ (dba) ₃ (105 mg, 0.115 mmol) and THF (7.5 mL). The flask was evacuated and backfilled with nitrogen. LiHMDS (1 mol/L in tetrahydrofuran, 12.63 mL) and N-methylpiperazine (690 mg, 6.89 mmol) were added dropwise, and the reaction was refluxed at 70°C for 1 h. The reaction mixture was added with saturated NH4Cl aqueous solution (10 mL), extracted with EA (10 mL*3), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (2.5%~5% methanol, dichloromethane) to obtain N-(4-fluoro-2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)ethyl Amide 6A_2 (400 mg, 24.8%) was a pale yellow solid. LCMS (M+H)+=282.

In the seventh step, N-(4-fluoro-2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)acetamide 6A_2 (400 mg, 1.67 mmol) was dissolved in EtOH (4 mL), stirred at room temperature, and added HCl (1.2 mL, 12 mol/L) to the solution. Stir at 80°C for 6 h. After the reaction, add 2 mol/L NaOH to adjust the pH of the reaction mixture to 8-9. The aqueous phase was extracted with EA (10 mL × 3), the organic layer was washed with brine, dried _{over Na2SO4} and concentrated. The residue was purified by column (1%~50% EA in PE) to give 4-fluoro-2-methoxy-5-(4-methylpiperazin-1-yl)aniline 6B (300 mg, 88.2%) as yellow solid. ¹ HNMR (400 MHz, DMSO-d6) δ H 6.68 (d, 1H), 6.37 (d, 1H), 4.47 (s, 2H), 3.69 (s, 3H), 2.85 (brs, 4H), 2.43 (brs , 4H), 2.20 (s, 3H).

Step 8 Dissolve 4-fluoro-2-methoxy-5-(4-methylpiperazin-1-yl)aniline 6B (150 mg, 0.514 mmol) in hydrochloric acid (6 mol/L, 1 mL) , cyanamide (345 mg, 4.11 mmol, 50% in _H2O ) was added, and the reaction was stirred at 80 °C for 48 H. The mixture was cooled to 25 °C, diluted with water (3 mL), and extracted with dichloromethane. The pH of the aqueous phase was adjusted to >11 by adding 2 mol/L NaOH. The aqueous phase was extracted with EA (10 mL*3), dried over _Na2SO4 and concentrated to give 1-( ₄ -fluoro-2-methoxy-5-(4-methylpiperazine-1) as a brown solid -yl)phenyl)guanidine 6C (150 mg, crude).

Ninth step 1-(4-fluoro-2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)guanidine 6C (300 mg, 0.98 mmol) and 6-((dimethyl Amino)methylene)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester 6F in DMF solution (3.5 mL ) in the stirring. After stirring at 80°C for 12 hours, the reaction mixture was evaporated under reduced pressure. The residue was purified by column (2%~5% MeOH in DCM) to give ethyl 8-((4-fluoro-2-methoxy-5-(4-methylpiperazin-1-yl)phenyl )amino)-1-(2-hydroxyethyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoxaline-3-carboxylic acid ethyl ester 6D (150 mg, 26.7%) , as light yellow solid. LCMS (M+H)+=526.

In the tenth step, ethyl 8-((4-fluoro-2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-1-(2-hydroxyethyl)- 4,5-Dihydro-1H-pyrazolo[4,3-h]quinoxaline-3-carboxylate ethyl ester 6D (110 mg, 0.222 mmol) in _NH3 in MeOH (1.5 mL, 7 M) The solution was stirred at 80 °C for 36 h in a 10 mL sealed tube. After the reaction was completed, the reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH=10:1) to obtain 8-((4-fluoro-2-methoxy-5 -(4-Methylpiperazin-1-yl)phenyl)amino)-1-(2-hydroxyethyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazole Phenyl-3-carboxamide 6 (12.0 mg, 11.5%). ¹ HNMR (400 MHz, CD3OD) δ H 8.27 (s, 1H), 7.70 (d, 1H), 6.88 (d, 1H), 4.74 (s, 2H), 3.87 (t, 2H), 3.84 (s, 3H ), 3.13-3.03 (m, 6H), 2.91-2.86 (m, 2H), 2.65 (brs, 4H), 2.36 (s, 3H). LCMS (M+H)+=497.2.

Example 7

In the first step, under N ₂ atmosphere, (Z)-6-((dimethylamino)methylene)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7- To a solution of ethyl tetrahydro-1H-indazole-3-carboxylate 6F (570 mg, 1.88 mmol) in DMF (50 ml) was added guanidine carbonate (849.4 mg, 4.64 mmol). After stirring at 110 °C for 16 h, the reaction mixture was added to water (50 mL), filtered and dried in vacuo. The residue was purified by column chromatography (20%~50% EA/PE) to give 8-amino-1-(2-hydroxyethyl)-4,5-dihydro-1H-pyrazolo as light yellow solid [4,3-h]quinazoline-3-carboxylic acid ethyl ester 7F_1 (307 mg, 53.8%). ESI-MS (M+H)+=304.

The second step is under _N2 , to 8-amino-1-(2-hydroxyethyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid ethyl To a solution of ester 7F_1 (303 mg, 1.00 mmol) in THF (30 ml) was added cuprous iodide (57.1 mg, 0.300 mmol), iodine (126.5 mg, 0.500 mmol), cesium iodide (259 mg, 1.00) and Isoamyl nitrate (176 mg, 1.50 mmol). The reaction was stirred at 80 °C for 12 hours. The reaction mixture was diluted with DCM (50 mL), washed with 20% NH ₃ . H ₂ O (80 mL), saturated _Na2S2O3 aqueous solution (80 mL), brine (80 mL), dried _over anhydrous _sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (2.5%~10% MeOH in DCM) to give 1-(2-hydroxyethyl)-8-iodo-4,5-dihydro-1H-pyrazole as a yellow solid And[4,3-h]quinazoline-3-carboxylic acid ethyl ester 7F_2 (300 mg, 52%). ESI-MS (M+H)+=415.

Step 3 Charge 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene 7A (27 g, 104 mmol) in a round bottom flask and add potassium nitrate (14 _g , 138 mmol) under N mmol), concentrated sulfuric acid (60 ml). The reaction was stirred at 25 °C for 2 hours. The reaction mixture was quenched with water (200 mL), extracted with DCM (50 mL*3), the combined organic layers were washed with saturated aqueous NaHCO ₃ (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and reduced Pressure evaporated. The residue was purified by column (0%~5% EA in PE) to give 1-bromo-2-fluoro-5-nitro-4-(trifluoromethoxy)benzene 7B (30 g, 95%). ESI-MS (M+H)+=303.

Step 4 Add 1-bromo- ₂ -fluoro-5-nitro-4-(trifluoromethoxy)benzene 7B (25.0 g, 12.1 mmol) in AcOH (50 mL) and EtOH (50 ml) was added iron powder (22.0 g, 0.393 mol). The reaction was stirred at 25 °C for 3 hours. The reaction mixture was concentrated and diluted with water (100 ml), extracted with EA (30 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column (5%~20% EA in PE) to give 5-bromo-4-fluoro-2-(trifluoromethoxy)aniline 7C (21.2 g, 93.8%) as a yellow solid. ¹ HNMR (400 MHz, CDCl3) δ H 7.00-6.95 (m, 2H), 3.79 (brs, 2H). ESI-MS (M+H)+=274.1.

the fifth step According to the synthesis method of Example 6, starting from compound 7C, compound 7D was obtained through two-step reaction.

The sixth step is under N ₂ , to 1-(2-hydroxyethyl)-8-iodo-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid ethyl To a solution of ester 7F_2 (126.6 mg, 0.432 mmol) in DMF (6 ml) was added 4-fluoro-5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)aniline 7D (60 mg, 0.144 mmol), Pd(OAc)2 (3.2 mg, 0.0144 mmol), BINAP (18.0 mg, 0.0289 mmol), K ₂ CO ₃ (59.6 mg, 0.432 mmol). The reaction was stirred at 80 °C for 4 hours. The reaction mixture was concentrated and diluted with water (20 mL), extracted with EA (10 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (10% MeOH in DCM) to give 8-((4-fluoro-5-(4-methylpiperazin-1-yl)-2-(tri Fluoromethoxy)phenyl)amino)-1-(2-hydroxyethyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid ethyl ester 7F (75 mg, 16%). ESI-MS (M+H)+=580.

Step 7 According to the synthesis method of Example 6, compound 7 (5.2 mg, 7.3%) was obtained through one-step reaction starting from compound 7F (75 mg, 0.129 mmol). ¹ HNMR (400 MHz, CD3OD) δ H 8.27 (s, 1H), 7.45 (d, 1H), 7.17 (d, 1H), 4.78-4.74 (m, 2H), 3.81 (t, 2H), 3.26-3.21 (m, 4H), 3.10-3.05 (m, 2H), 2.90-2.83 (m, 2H), 2.67-2.62 (m, 4H), 2.36 (s, 3H). LCMS (M+H)+ m/z = 551.2.

Example 8

In the first step, according to the synthesis method of Example 6, starting from compound 8-1, compound 8A was obtained through 3 steps. ¹ HNMR (400 MHz, DMSO d6) δ H 8.15 (s, 1H), 7.95 (d, 1H), 7.26-7.15 (m, 9H), 7.05 (d, 6H), 6.87 (d, 1H), 4.23 ( q, 2H), 3.80 (s, 3H), 3.00 (t, 2H), 2.88-2.81 (m, 4H), 2.67-2.58 (m, 2H), 2.53-2.35 (m, 7H), 1.24 (t, 3H).

The second step is to 8-((4-fluoro-5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-1-(2- Ethyl hydroxyethyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate 8A (100 mg, 0.138 mmol) in DCM (5 mL) was added TFA (0.5 mL), stirred at 25 °C for 4 h. The reaction was quenched by adding saturated NaHCO ₃ aqueous solution (30 mL), extracted with DCM (15 mL*2), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure, and the residue was subjected to column chromatography (2% ~8% MeOH in DCM) to give 8-((4-fluoro-2-methoxy-5-(4-methylpiperazin-1-yl)phenyl)amino)-4,5-di Hydrogen-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid ethyl ester 8B (40 mg, 60.2%). ESI-MS (M+H)+=482.

third step According to the synthesis method of Example 6, starting from compound 8B, compound 8C was obtained through one-step reaction.

The third step is at 0°C, to 8-((4-fluoro-5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-1-( 2-Hydroxyethyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-carboxamide 8C (30 mg, 0.066 mmol) in DMF (3 mL) Cs ₂ CO ₃ (32.6 mg, 0.1 mmol) and 2-chloroacetonitrile (6.0 mg in 1 mL DMF, 0.08 mmol) were added to . After stirring at 25 °C for 4 hours, the reaction mixture was quenched with water (10 mL). The mixture was extracted with EA (15 mL*2), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=15:1) to give 1-(cyanomethyl)-8-((4-fluoro-2-methoxy-5-(4 -Methylpiperazin-1-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 8 (16.7mg, 51.2 %). ¹ HNMR (400 MHz, CD3OD) δ H 8.31 (s, 1H), 7.68 (d, 1H), 6.88 (d, 1H), 5.88 (s, 2H), 3.84 (s, 3H), 3.15-3.05 (m , 6H) ), 2.90 (t, 2H), 2.63-2.58 (m, 4H), 2.33 (s, 3H). LCMS [M+H]+: 492.3.

Example 9

According to the synthesis method of Example 8, starting from compound 8-3 and compound 7D, compound 9 was obtained through 4 steps of reaction. ¹ HNMR (400 MHz, CD3OD) δ H 8.30 (s, 1H), 7.45 (d, 1H), 7.14 (d, 1H), 5.80 (s, 2H), 3.18-3.05 (m, 6H), 2.90 (t , 2H), 2.68-2.60 (m, 4H), 2.36 (s, 3H). LCMS [M+H]+: 446.3.

Example 10

According to the synthesis methods of Examples 7 and 8, starting from compound 8-3 and compound 10-1, compound 10 was obtained through 4 steps of reaction. ¹ HNMR (400 MHz, CD3OD) δ H 8.37 (s, 1H), 7.54 (s, 1H), 7.26 (d, 1H), 6.85 (d, 1H), 5.87 (s, 2H), 3.31-3.25 (m , 4H), 3.14 (t, 2H), 2.96 (t, 2H), 2.71-2.63 (m, 4H), 2.38 (s, 3H). LCMS [M+H]+: 528.2.

Example 11

According to the synthetic method of Example ⁹ , compound 11.1 HNMR (400 MHz, CD3OD) δ H 8.31 (s, 1H), 7.45 (s, 1H), 7.25-7.20 (m, 1H), 6.85-6.77 (m, 1H), 5.10-5.02 (m, 2H), 4.62-4.51 (m, 2H), 4.34-4.28 (m, 1H), 3.26 (brs, 4H), 3.15-3.08 ( m, 2H), 2.94-2.86 (m, 2H), 2.61 (brs, 4H), 2.55-2.49 (m, 1H), 2.36 (s, 3H), 2.35-2.29 (m, 1H). LCMS [M+H]+: 559.2.

Example 12

first step Methyl 1-hydroxycyclopropane-1-carboxylate 12A (3.0 g, 25.8 mmol) was dissolved in MeOH (15 mL), and hydrazine hydrate (6.37 g, 258 mmol) was added. The mixture was stirred at 60°C for 16 hours and the solvent was evaporated. The residue was triturated with EA (30 mL) for 0.5 h and filtered to give 1-hydroxycyclopropane-1-carbohydrazine 12E_1 (2.8 g, 93.3%) as a white solid. LCMS (M+H)+=117.

In the second step, a suspension of 1-hydroxycyclopropane-1-carbohydrazine 12E_1 (3.0 g, 258 mmol) in THF (15 mL) was added dropwise to BH3 at -5-0 °C under N ₂ atmosphere. THF (258 mL, 258 mmol, 1 M). The reaction mixture was stirred at 60°C for 21 hours. MeOH (50 mL) was added dropwise to the reaction mixture at -5-0 °C under N protection, then stirred at 20-25 °C for _0.5 h, and the reaction mixture was concentrated to obtain a residue. The residue was dissolved in 50 mL MeOH and stirred at 80 °C for 3 hours. The mixture was cooled to 25°C and evaporated to a residue. The residue was triturated with DCM (30 mL) for 0.5 h and filtered. The filtrate was evaporated to give the crude product 1-(hydrazinomethyl)cyclopropan-1-ol 12E_2 (2.2 g, 75%) as light yellow oil. 1H NMR (400 MHz, CDCl3) d2.91(s, 2H), 0.83 (t, J = 6.0 Hz, 2H), 0.55-0.50 (m, 2H).

In the third step, according to the synthesis method of Example 9, starting from compound 12E_2 and compound 6F_3, compound 12 was obtained through 4 steps of reaction. ¹ HNMR (400 MHz, CD3OD) δ H 8.28 (s, 1H), 7.44 (s, 1H), 7.20 (d, 1H), 6.79 (d, 1H), 4.74 (s, 2H), 3.30-3.24 (m , 4H), 3.12-3.05 (m, 2H), 2.90-2.84 (m, 2H), 2.63-2.58 (m, 4H), 2.33 (s, 3H), 0.59-0.54 (m, 2H), 0.49-0.46 (m, 2H). LCMS [M+H]+: 559.2.

Example 13

According to the synthesis method of Example 9, starting from compound 10C, compound 13 was obtained through a one-step reaction. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.38 (s, 1H), 7.49 – 7.21 (m, 5H), 6.92 (dd, J = 9.1, 3.0 Hz, 1H), 4.79 ( d, J = 7.0 Hz, 2H), 4.40 (t, J = 7.0 Hz, 2H), 4.31 (t, J = 6.2 Hz, 2H), 3.56 (d, J = 12.3 Hz, 3H), 3.20 (ddt, J = 26.3, 15.4, 7.4 Hz, 4H), 3.00 (t, J = 7.5 Hz, 4H), 2.90 (s, 4H), 2.83 (t, J = 7.7 Hz, 3H).

Example 14

According to the synthesis method of Example 9, starting from compound 10C, compound 14 was obtained through a one-step reaction. 1H NMR (400 MHz, CD3OD-d4) δ ppm 8.51 (s, 1H), 7.53 (d, J = 2.9 Hz, 1H), 7.36 – 7.21 (m, 1H), 6.87 (dd, J = 9.1, 3.0 Hz , 1H), 4.76 (d, J = 12.7 Hz, 2H), 4.50 (d, J = 13.2 Hz, 1H), 4.42 (d, J = 12.7 Hz, 1H), 3.65 (d, J = 2.0 Hz, 2H ), 3.26 (dt, J = 18.0, 6.2 Hz, 6H), 3.06 (t, J = 7.7 Hz, 2H), 2.67 (t, J = 5.0 Hz, 4H), 2.40 (s, 3H), 1.42 (s , 3H). LCMS [M+H]+: 573.2.

Example 15

According to the synthesis method of Example 9, starting from compound 10C, compound 15 was obtained through one-step reaction. ¹ HNMR (400 MHz, CD3OD) δ H 8.35 (s, 1H), 7.53 (s, 1H), 7.26 (d, 1H), 6.85 (d, 1H), 5.00-4.88 (m, 1H), 4.65-4.58 (m, 1H), 3.29 (s, 4H), 3.15-3.08 (m, 2H), 2.93 (t, 2H), 2.80 (s, 4H), 2.49 (s, 3H), 2.21-2.12 (m, 1H ), 1.39-1.32 (m, 2H). LCMS [M+H]+: 579.2.

Example 16

In the first step, to a solution of 16A (193 mg, 1 mmol) in DMF (5 mL) at 0 °C was added _Cs2CO3 (650 mg, ₂ mmol) and (2-bromoethoxy)tert-butyldi Methylsilane (480 mg, 2 mmol). After stirring overnight at 25 °C, the reaction mixture was quenched with water (10 mL). The mixture was extracted with EA (15 mL*2), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (PE:EA=5:1) to afford 16B (220 mg, 64%) as a white solid.

second step 16B 510 mg was treated with tris(dimethylamino)methane (2 mL) and the reaction was stirred at 90 °C overnight, the volatiles were removed under reduced pressure and the residue was used without further purification.

third step According to the synthesis method of Example 10, starting from compound 16B and compound 15-1, compound 16D was obtained through one-step reaction.

In the fourth step, methyl 9-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-((5-(4-methylpiperazin-1-yl)-2 -(trifluoromethoxy)phenyl)amino)-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-7-carboxylic acid methyl ester 16D (330 mg, 0.5 mmol) Suspended in dioxane (5 mL) and treated with 2N NaOH solution (5 mL, 10 mmol) at reflux temperature overnight, H ₂ O (50 mL) was added and the solution was acidified to pH=4 with 2N HCl. Concentrated under reduced pressure, the residue was subjected to column chromatography (DCM:MeOH 10:1) to obtain a yellow solid product 9-(2-hydroxyethyl)-2-((5-(4-methylpiperazin-1-yl) -2-(trifluoromethoxy)phenyl)amino)-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-7-carboxylic acid (240 mg, 90% yield) . LC-MS (M+H)+: 533.

the fifth step 9-(2-hydroxyethyl)-2-((5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-6,9-di Hydrogen-5H-pyrrolo[3,2-h]quinazoline-7-carboxylic acid (240 mg, 0.45 mmol) was dissolved in DMF, and HOBt (121 mg, 0.9 mmol) and EDCI (172 mg , 0.9 mmol), stirred for 0.5h. Subsequently, NH4OH (4 eq) was added. The reaction mixture was stirred at room temperature for 14 hours, the reaction mixture was concentrated under reduced pressure, and 9-(2-hydroxyethyl)-2-((5-(4-methylpiperazin-1-yl) was obtained by preparative HPLC )-2-(trifluoromethoxy)phenyl)amino)-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-7-carboxamide, white solid (106 mg , yield 47%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.14 (s, 1H), 7.55 (s, 1H), 7.24 (d, J = 3.0 Hz, 1H), 7.21 (dq, J = 9.1, 1.4 Hz, 1H), 6.79 (d, J = 3.0 Hz, 1H), 6.77 (d, J = 3.0 Hz, 1H), 4.71 (t, J = 5.3 Hz, 1H), 4.35 (t, J = 5.0 Hz, 2H), 3.46 – 3.40 (m, 3H), 3.15 (dd, J = 6.4, 3.7 Hz, 4H), 2.98 (t, J = 7.7 Hz, 2H), 2.72 (t, J = 7.7 Hz, 2H), 2.46 (t, J = 5.0 Hz, 4H), 2.24 (s, 3H).

Example 17

first step To a solution of cyclopropylmethanol 17A (721.00 μL, 9.09 mmol) in THF (24 mL) was added LiHMDS (1M in THF, 6.06 mL, 9.09 mmol) dropwise at 5 °C. After 30 minutes, 4-fluoro-3-nitrobromobenzene (1.11 mL, 9.09 mmol) was added quickly and the reaction mixture was allowed to warm naturally to room temperature and stirred overnight. The reaction mixture was quenched with water and extracted with EA, the collected organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE/EA, 100:0 to 20:1) to give 3.02 g 4-Bromo-1-(cyclopropylmethoxy)-2-nitrobenzene 17B. LCMS (M+H)+=272.

In the second step, under _N2 atmosphere, add 4-bromo-1-(cyclopropylmethoxy)-2-nitrobenzene (587 mg, 2.16 mmol), XANTPHOS (0.37 g, 0.65 mmol), Pd ₂ (dba) ₃ (0.39 g, 0.43 mmol, Aldrich), Cs ₂ CO ₃ (1.4 g, 4.3 mmol) and 1-methylpiperazine (0.43 g, 4.3 mmol). After heating at 90 °C overnight, the reaction was quenched with water, extracted with ethyl acetate (50 mL×3), the organic phase was dried over sodium sulfate, concentrated, and purified by column chromatography (dichloromethane/methanol 20:1) , to give 1-(4-(cyclopropylmethoxy)-3-nitrophenyl)-4-methylpiperazine 17C (383 mg, 1.32 mmol, 61%) as a tan solid. ESI-MS (M+H)+=292.

third step Dissolve 1-(4-(cyclopropylmethoxy)-3-nitrophenyl)-4-methylpiperazine 17C (291 mg, 1 mmol) in acetic acid (10 mL) and ethanol (10 mL) Add zinc powder (650 mg, 10 mmol) to the mixed solvent, stir at 80°C for 3h, filter with diatomaceous earth, concentrate, and purify by column chromatography (dichloromethane/methanol 20:1) to obtain 2-( Cyclopropylmethoxy)-5-(4-methylpiperazin-1-yl)aniline 17D (185 mg, 0.71 mmol, 71%). ESI-MS (M+H)+=262.

the fourth step According to the synthetic method of Example 7, compound 17, 2-((2-(cyclopropylmethoxy)-5-(4-methylpiperazin-1-yl) is obtained through 2 steps of reaction from compound 17D and 7F_2 )phenyl)amino)-9-(2-hydroxyethyl)-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-7-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.05 (s, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.50 (s, 1H), 7.29 (s, 1H) , 6.94 (d, J = 8.9 Hz, 1H), 6.60 (dd, J = 8.8, 2.9 Hz, 1H), 4.78 (t, J = 5.6 Hz, 2H), 3.85 (d, J = 6.9 Hz, 2H) , 3.80 (t, J = 5.6 Hz, 2H), 3.05 (t, J = 5.0 Hz, 4H), 3.00 (d, J = 7.7 Hz, 2H), 2.83 (t, J = 7.6 Hz, 2H), 2.49 (t, J = 4.9 Hz, 4H), 2.25 (s, 3H), 1.29 – 1.18 (m, 1H), 0.60 – 0.51 (m, 2H), 0.36 – 0.28 (m, 2H). LCMS [M+H]+: 519.3.

Example 18

18A was prepared by the method described in the patent CN101563351B. A stirred solution of 18A (100 mg, 0.178 mmol) in THF ( ₂ mL) was added to LiAlH4 (28 mg, 0.712 mmol) in a 50 mL sealed tube at -78 °C. After stirring at -78°C for 24 hours, the reaction mixture was cooled to 0°C, then water (20 mL) was added. The mixture was extracted with EA (20 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (2.5%~10% MeOH in DCM) to give compound 18 (15 mg, 16.2%) as a pale yellow solid. ¹ HNMR (400 MHz, CD3OD) δH 8.27 (s, 1H), 7.54 (d, 1H), 7.20 (d, 1H), 6.79 (d, 1H), 4.71 (t, 2H), 4.60 (s, 2H) ,3.79 (t, 2H), 3.28-3.21 (m,4H), 2.90-2.80 (m, 4H), 2.66 (m, 4H), 2.38 (s, 3H). LC-MS[M+H]+: 520.20.

Example 19

A stirred solution of 18A (0.15 g, 0.267 mmol) in DCM (6 mL) at 25 °C in a 50 mL sealed tube, EDCI (70.5 mg, 0.347 mmol), DMAP (16.3 mg, 0.134 mmol), O-formazol Hydroxylamine chloride salt (35.3mg, 0.4mmol). Stirred at 30°C for 2 hours, concentrated to remove the solvent, the crude product was purified by column chromatography (DCM:MeOH=10:1) to give 19 (30 mg). ¹ HNMR (400 MHz, CD3OD) δH 8.30 (s, 1H), 7.51 (d, 1H), 7.21 (d, 1H), 6.79 (d, 1H), 4.76 (t, 2H), 3.82 (t, 2H) , 3.79 (s, 3H), 3.30-3.22 (m, 4H), 3.07 (t, 2H), 2.88 (t, 2H), 2.64-2.61 (m, 4H), 2.35 (s, 3H). LC-MS [M+H]+: 563.30.

Example 20

Charge a round bottom flask with 17A (5 g, 0.023 mol), cyclopropanol (1.32 g, 0.023 mol), K ₂ CO ₃ (9.42 g, 0.068 mol), and DMF (10 mL). The reaction was stirred overnight at 25°C. The reaction mixture was quenched by adding H ₂ O (100 mL), extracted with EA (100 mL×3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column (5%-10% EA in PE) to give 20A (5.3 g, 90.4%) as a yellow solid.

According to the synthesis method of Example 17, starting from compound 20A, compound 14 was obtained through 4 steps of reaction. ¹ HNMR (400 MHz, CD3OD) δH 8.30 (s, 1H), 7.82 (d, 1H), 7.24 (d, 1H), 6.72 (dd, 1H), 4.90-4.88 (m, 2H), 3.94 (t, 2H), 3.85-3.82 (m, 1H), 3.15-3.12 (m, 4H), 3.07 (t, 2H), 2.87 (t, 2H), 2.71-2.66 (m, 4H), 2.39 (s, 3H) , 0.79-0.77 (m, 2H), 0.74-0.72 (m, 2H). LC-MS[M+H]+: 505.30.

Example 21

PLK1 Kinase Activity Test

Experimental Materials: PLK1 Active was purchased from CARNA; Casein Protein was purchased from SignalChem; ADP-Glo Kinase Assay was purchased from Promega; Kinase assay buffer III was purchased from SignalChem; Nivo Multilabel Analyzer (PerkinElmer).

experimental method:

Use the kinase buffer included in the kit to dilute the enzyme, substrate, ATP and inhibitor. The compound to be tested was diluted to 1 mM with 100% DMSO as the first concentration, and then diluted 5 times to the eighth concentration with a row gun, that is, diluted from 1 mM to 0.013 μM. Each concentration point of the compound was diluted 20 times with 1X kinase buffer to prepare a compound working solution containing 5% DMSO, and 1 μL of the compound concentration gradient working solution was added to the microplate to set up duplicate wells. Add 2 μl PLK1 enzyme (15 ng), 2 μl substrate and ATP mixture (20 μM ATP, 0.2 μg/μl Casein protein) to the microwell plate, at this time the compound concentration gradient is 10 μM and diluted to 0.13 nM, The reaction system was placed at 25°C for 60 minutes. After the reaction, 5 μl of ADP-Glo reagent was added to each well, and the reaction was continued at 25 degrees for 40 minutes. After the reaction was completed, 10 μL of kinase detection reagent was added to each well, and after 30 minutes of reaction at 25 degrees, the chemiluminescence was read with a PerkinElmer Nivo multi-label analyzer. , the integration time is 0.5 seconds.

ANALYSE information:

Using the equation (Sample-Min)/(Max-Min)*100% to convert the raw data into inhibition rate, the value of IC ₅₀ can be obtained by curve fitting with four parameters (log(inhibitor) vs. response in GraphPad Prism -- Variable slope mode derived).

The table below shows the test results of PLK1 kinase activity of the compounds of the present application. Compound number PLK1 IC ₅₀ (nM) 6 47.17 7 101.8 8 824.9 9 526 10 9.55 11 8.57 12 9.67 13 18.94 14 50.12 15 14.62 16 6.39 17 9.71

In vitro cell proliferation assays

The inhibitory activity of compounds on tumor cell proliferation was determined by MTT method. The HT-29 tumor cells in the logarithmic growth phase were inoculated into the culture plate according to a certain amount of cells, incubated for ₂₄ hours, and different concentrations of inhibitors were added. 20 μL of MTT solution was cultured for 4 hours, the crystals were dissolved with DMSO, and the OD value was measured with an enzyme-linked immunosorbent detector at a wavelength of 570 nm to calculate the IC ₅₀ .

The following table shows the test results of the anti-proliferation activity of the compounds of the present application on HT-29 tumor cells. Compound number HT-29 _IC50 (nM) 6 269 10 111 11 232.2 12 75 15 71

none

Claims (32)

A pyrazoloquinazoline compound as shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate:

Wherein, R ¹ is C ₁ ~C ₄ alkoxy, C ₁ ~C ₄ alkoxy or 3~6 membered cycloalkyloxy substituted by one or more R ^1-1 ; R ^1-1 is independently is halogen or 3~6 membered cycloalkane; R ² is H, halogen or C ₁ ~C ₄ alkyl; R ³ is 5~10 membered heterocycloalkyl or 5~ substituted by one or more R ^3-1 10-membered heterocycloalkyl; in the 5-10-membered heterocycloalkyl, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-2; R ^3-1 is independently is C ₁ ~C ₄ alkyl; R ⁴ is cyano, 3~6 membered cycloalkane, 3~6 membered cycloalkane substituted by one or more R ^4-1 , 3~6 membered heterocycloalkane or substituted by one 3~6 membered heterocycloalkane substituted by one or more R ^4-2 ; C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 ; in the 3~6 membered heterocycloalkyl, the heteroatom is selected from From one or more of N, O and S, the number of heteroatoms is 1~2; R ^4-1 is independently halogen, hydroxyl or C ₁ ~C ₄ alkyl; R ^4-2 is independently halogen Or C ₁ ~C ₄ alkyl; R ^4-3 is independently halogen, cyano or hydroxyl; R ⁵ is H, hydroxyl, C ₁ ~C ₄ alkyl or C ₁ ~C ₄ alkoxy. The pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate as described in Claim 1, wherein, R ^1-1 is independently F, Cl, Br or I, such as F; and/or, R ^1-1 is independently 3~6 membered cycloalkane, and the 3~6 membered cycloalkane is cyclopropane, cyclobutane or Cyclopentane, such as cyclopropane or cyclobutane; and/or, when R ¹ is C ₁ ~C ₄ alkoxy, the C ₁ ~C ₄ alkoxy is methoxy, ethoxy, isopropyl Oxygen or tert-butoxy, such as methoxy; and/or, when R ¹ is C ₁ ~C ₄ alkoxy substituted by one or more R ^1-1 , the C ₁ ~C ₄ alkoxy The base is methoxy, ethoxy, isopropoxy or tert-butoxy, such as methoxy; and/or, when R ¹ is a 3-6-membered cycloalkyloxy group, the 3-6-membered ring Alkoxy is cyclopropyloxy, cyclobutyloxy or cyclopentyloxy, for example cyclopropyloxy or cyclobutyloxy ^; and/or, when R is halogen, the halogen is F , Cl, Br or I; and/or, when R ² is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl or tert-butyl, such as methyl; and/or, when R ^3-1 is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl; and/or, when R ³ is a 5-10 membered heterocycloalkyl group substituted by one or more R ^3-1 , The 5-10 membered heterocycloalkyl group is a 6-9 membered heterocycloalkyl group, such as a 6-9 membered heterocycloalkyl group containing two Ns, and another example is piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl , 3,8-diazabicyclo[3.2.1]octyl, octahydropyrrole[1,2-a]pyrazinyl, 2,6-diazaspiro[3.4]octyl, 3,6 -diazabicyclo[3.2.0]heptyl, 1,6-diazaspiro[3.4]octyl or octahydropyrrole[3,4-c]pyrrolyl; and/or, when R ^4- When ¹ is halogen, the halogen is F, Cl, Br or I, such as F; and/or, when R ^4-1 is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl or ethyl; and/or, when R ^4-2 is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl or ethyl; and/or, when R ^4-2 When is a halogen, the halogen is F, Cl, Br or I, such as F; and/or, when R ^4-3 is a halogen, the halogen is F, Cl, Br or I, such as F; and/or, when When R ⁴ is a 3-6 membered cycloalkane, the 3-6 membered cycloalkane is cyclopropane, cyclobutane or cyclopentane, such as cyclopropane or cyclobutane; and/or, when R ⁴ is represented by one or more R ^{4 -1} substituted 3~6 membered cycloalkane, the 3~6 membered cycloalkane is cyclopropane, cyclobutane or cyclopentane, such as cyclopropane or cyclobutane; and/or, when R ⁴ is replaced by one or When multiple ^R4-2 substituted 3-6 membered heterocycloalkanes, the 3-6 membered heterocycloalkanes are 4-membered heterocycloalkanes containing one N or O or 5-membered heterocycloalkanes containing one N or O; And/or, when R ⁵ is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, ethyl, isopropyl or tert-butyl, such as methyl or ethyl; and/or , when R ⁵ is C ₁ ~C ₄ alkoxy, the C ₁ ~C ₄ alkoxy is methoxy, ethoxy, isopropoxy or tert-butoxy, such as methoxy. The pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate as described in Claim 1, wherein, the ^R1 is

,

,

,

,

,

or

,E.g

,

,

or

and/or, R ³ is

,

,

,

,

,

,

,

,

or

and/or, R ³ is

,

,

,

,

,

,

,

,

or

and/or, R ³ is

,

,

,

,

,

,

,

,

or

and/or, when R ⁴ is a 3-6-membered cycloalkane substituted by one or more R ^4-1 , the 3-6-membered cycloalkane substituted by one or more R ^4-1 is

,

,

or

and/or, when R ⁴ is 3~6 membered heterocycloalkane, the 3~6 membered heterocycloalkane is

,

or

and/or, when R ⁴ is a 3-6 membered heterocycloalkane substituted by one or more R ^4-2 , the 3-6 membered heterocycloalkane substituted by one or more R ^4-2 is

,

or

and/or, when R ⁴ is C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 , the C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 is

. The pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate as described in Claim 1, wherein, R ⁴ is cyano, 3~6 membered cycloalkane, 3~6 membered heterocycloalkane, 3~6 membered heterocycloalkane substituted by one or more R ^4-2 , substituted by one or more R ^4-1 , or C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 ; and/or, R ^4-1 is halogen or hydroxyl; and/or, R ^4-2 is C ₁ ~C ₄ alkyl; And/or, R ^4-3 is hydroxyl; and/or, R ⁵ is H, hydroxyl or C ₁ ~C ₄ alkoxy. The pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate as described in Claim 1, wherein, R ⁴ is cyano, 3~6 membered cycloalkane, 3~6 membered heterocycloalkane, 3~6 membered heterocycloalkane substituted by one or more R ^4-2 , substituted by one or more R ^4-1 , Or C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 ; R ^4-1 is halogen or hydroxyl; R ^4-2 is C ₁ ~C ₄ alkyl; R ^4-3 is hydroxyl; R ⁵ is H, hydroxyl or C ₁ ~C ₄ alkoxy. The pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate as described in Claim 5, wherein R ⁴ selected from the group consisting of: cyano,

,

,

,

,

with

. The pyrazoloquinazoline compound shown in formula I as described in Claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, which has the following Mode:

. The pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt as described in Claim 7, wherein R ¹ is a C ₁ ~C ₄ alkoxy group substituted by one or more R ^1-1 . The pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate as described in Claim 7, wherein R ² is H or halogen. The pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate as described in Claim 7, wherein R ⁴ selected from the group consisting of: cyano,

,

,

,

,

with

. A pyrazoloquinazoline compound, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, wherein the pyrazoloquinazoline compound is selected from any of the following One shown:

. A preparation method of a pyrazoloquinazoline compound as shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, comprising the following steps, In an organic solvent, under the action of a palladium catalyst, in an alkaline reagent, carry out a coupling reaction of compound 1g, a ligand reagent and R ³ -H to obtain compound I;

Wherein, the definition of R ¹ , R ² , R ³ , R ⁴ or R ⁵ is as described in claims 1-6; X is halogen. The preparation method as claimed in item 12, wherein the palladium catalyst is tridibenzylideneacetone dipalladium; And/or, the organic solvent is 1,4dioxane; And/or, the alkaline reagent is cesium carbonate; And/or, the ligand reagent is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene. A pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt as described in any one of the above claim items 1 to 11 Use of a solvate in the preparation of a PLK1 inhibitor; the inhibitor is preferably an inhibitor used in vitro. A pharmaceutical composition, wherein, it comprises the pyrazoloquinazoline compound shown in formula I as described in claims 1 to 11, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable Solvates of salts and pharmaceutical excipients are accepted. A pyrazoloquinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt as described in any one of claims 1 to 11 Use of solvates in the preparation of medicaments; The medicine is a medicine for treating at least one of the following diseases: breast cancer, prostate cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, leukemia and lymphoma. A pyrazoloquinazoline compound as shown in formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

Wherein, R ¹ is C ₁ ~C ₄ alkoxy substituted by one or more R ^1-1 ; R ^1-1 is independently halogen; R ² is H, halogen or C ₁ ~C ₄ alkyl; R ^3' is a 7-9 membered heterocycloalkyl group substituted or unsubstituted by one R ^3-1 ; the 7-9 membered heterocycloalkyl group is a 7-9 membered heterospirocycloalkyl group or a 7-9 membered heterobridged cycloalkane group; heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1~2; R ^3-1 is C ₁ ~C ₄ alkyl; R ^4' is independently represented by one R ^4-3 substituted C ₁ ~C ₄ alkyl; R ^4-3 is hydroxyl or halogen; R ⁵ is H, hydroxyl, C ₁ ~C ₄ alkyl or C ₁ ~C ₄ alkoxy. The preparation method of the pyrazoloquinazoline compound represented by formula II, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate as described in claim item 17, Wherein, R ^1-1 is F, Cl, Br or I, such as F; and/or, when R ¹ is a C ₁ ~C ₄ alkoxy group substituted by one or more R ^1-1 , the C ₁ ~C ₄ alkoxy is methoxy, ethoxy, isopropoxy or tert-butoxy, such as methoxy; and/or, when R ² is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl; and/or, R ^3-1 is methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl; and/or, when R ^4-3 is halogen, the halogen is F, Cl, Br or I; and /or, when R ^4' is independently a C ₁ ~C ₄ alkyl substituted by one R ^4-3 , the C ₁ ~C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl or tert-butyl, such as methyl; and/or, when R ⁵ is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, ethyl, isopropyl or tert-butyl, such as methyl or ethyl; and/or, when R ⁵ is C ₁ ~C ₄ alkoxy, the C ₁ ~C ₄ alkoxy is methoxy, ethoxy, iso Propoxy or tert-butoxy, eg methoxy. The pyrazoloquinazoline compound represented by formula II, its pharmaceutically acceptable salt, its solvate or its solvate of its pharmaceutically acceptable salt as described in Claim 17, wherein, R ¹ for

,

,

,

,E.g

and/or, when R ^3' is a 7~9 membered heterospirocycloalkyl group, the 7~9 membered heterospirocycloalkyl group is a 7~9 membered heterospirocycloalkyl group containing two nitrogen atoms, for example

or

and/or, when R ^3' is a 7-9 membered heterospirocycloalkyl substituted by one R ^3-1 , the substituted or unsubstituted 7-9 membered heterospirocycloalkyl group by one R ^3-1 is A 7-9 membered heterospirocycloalkyl group containing two nitrogen atoms substituted by one R ^3-1 , for example

or

and/or, when R ^3' is a 7~9 membered heterobridged cycloalkyl group, the 7~9 membered heterobridged cycloalkyl group is a 7~9 membered heterobridged cycloalkyl group containing two Ns, for example

and/or, when R ^3' is a 7~9 membered heterobridged cycloalkyl group substituted by one R ^3-1 , the 7~9 membered heterobridged cycloalkyl group substituted by one R ^3-1 contains two A 7-9 membered heterobridged cycloalkyl group substituted by one R ^3-1 of nitrogen, for example

,or

and/or, R ⁴ is -CH ₂ OH. The pyrazoloquinazoline compound shown in formula II, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate as described in Claim 17, wherein, the The pyrazoloquinazoline compound shown in formula II, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt can be shown as any of the following:

. A preparation method of a pyrazoloquinazoline compound as shown in formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, comprising the following steps, In an organic solvent, in an alkaline reagent, under the action of a palladium catalyst, carry out a coupling reaction of compound 1g, a ligand reagent and R ³ -H to obtain compound II;

Wherein, the definition of R ¹ , R ² , R ^3' , R ^4' or R ⁵ is as described in claims 12-15; X is halogen. The preparation method as claimed in item 21, wherein the palladium catalyst is tridibenzylideneacetone dipalladium; And/or, the organic solvent is 1,4dioxane; And/or, the alkaline reagent is cesium carbonate; And/or, the ligand reagent is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene. A compound as shown in formula III, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate:

Wherein, R ¹ is a C ₁ ~C ₄ alkoxy group, a C ₁ ~C ₄ alkoxy group substituted by one or more R ^1-1 , and R ^1-1 is independently a halogen or a 3-6 membered cycloalkane; R ² is H, halogen or C ₁ ~C ₄ alkyl; R ³ is 5~10 membered heterocycloalkyl or 5~10 membered heterocycloalkyl substituted by one or more R ^3-1 ; the 5~10 membered heterocycloalkyl In a 10-membered heterocycloalkyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 2; R ^3-1 is independently C ₁ ~C ₄ alkyl; R ⁴ is cyano, 3~6 membered cycloalkane, 3~6 membered cycloalkane substituted by one or more R ^4-1 , 3~6 membered heterocycloalkane or 3 substituted by one or more R ^4-2 ~6-membered heterocycloalkane; C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 ; in the 3~6-membered heterocycloalkyl, the heteroatom is selected from one of N, O and S or Multiple, the number of heteroatoms is 1~2; R ^4-1 is independently halogen, hydroxyl or C ₁ ~C ₄ alkyl; R ^4-2 is independently halogen or C ₁ ~C ₄ alkyl; R ^4-3 are independently halogen, cyano or hydroxyl; R ⁵ is H, hydroxyl C ₁ ~C ₄ alkyl or C ₁ ~C ₄ alkoxy. The compound represented by formula III, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt's solvate as described in claim 23, wherein, R ^1-1 is independently F , Cl, Br or I, such as F; and/or, R ^1-1 is independently 3~6 membered cycloalkane is cyclopropane, cyclobutane or cyclopentane, such as cyclopropane or cyclobutane; and/or , when R ¹ is C ₁ ~C ₄ alkoxy, the C ₁ ~C ₄ alkoxy is methoxy, ethoxy, isopropoxy or tert-butoxy, such as methoxy; and/ Or, when R ¹ is C ₁ ~C ₄ alkoxy substituted by one or more R ^1-1 , the C ₁ ~C ₄ alkoxy is methoxy, ethoxy, isopropoxy or tert-butoxy, such as methoxy; and/or, when R ² is halogen, the halogen is F, Cl, Br or I; and/or, when R ² is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl; and/or, when R ^3-1 is C ₁ When ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl; and/or, When R ³ is a 5-10 membered heterocycloalkyl group substituted by one or more R ^3-1 , the 5-10 membered heterocycloalkyl group is a 6-9 membered heterocycloalkyl group, for example containing two N 6-9 membered heterocycloalkyl groups, such as piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl, 3,8-diazabicyclo[3.2.1]octyl, octahydropyrrole[1,2 -a]pyrazinyl, 2,6-diazaspiro[3.4]octyl, 3,6-diazabicyclo[3.2.0]heptanyl, 1,6-diazaspiro[3.4] Octyl or octahydropyrrole [3,4-c] pyrrolyl; And/or, when R ^4-1 is halogen, the halogen is F, Cl, Br or I, such as F; And/or, when R When ^4-1 is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl and/or, when R ^4-2 is C ₁ ~C ₄ alkyl, the C ₁ ~C ₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl or tert-butyl, such as methyl or ethyl; and/or, when R ^4-2 is halogen, the halogen is F, Cl, Br or I, such as F; and/or, when R ⁴ When ^-3 is a halogen, the halogen is F, Cl, Br or I, such as F; and/or, when R ⁴ is a 3-6-membered cycloalkane, the 3-6-membered cycloalkane is cyclopropane, cyclobutane Or cyclopentane, such as cyclopropane or cyclobutane; And/or, when R ⁴ is 3~6 membered cycloalkane substituted by one or more R ^4-1 , the 3~6 membered cycloalkane is cyclopropane , cyclobutane or cyclopentane, such as cyclopropane or cyclobutane; and/or, when R ⁴ is a 3-6 membered heterocycloalkane substituted by one or more R ^4-2 , the 3-6 membered heterocycloalkane is a 4-membered heterocycloalkane containing one N or O or a 5-membered heterocycloalkane containing one N or O; and/or, when R ⁵ is C ₁ ~C ₄ alkyl , the C ₁ ~C ₄ alkyl is methyl, ethyl, isopropyl or tert-butyl, such as methyl or ethyl; and/or, when R ⁵ is C ₁ ~C ₄ alkoxy, the C ₁ -C ₄ alkoxy is methoxy, ethoxy, isopropoxy or tert-butoxy, such as methoxy. The compound shown in formula III, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt's solvate as described in Claim 23, wherein, the R ¹ is

,

,

,

,

or

,E.g

,

or

and/or, R ³ is

,

,

,

,

,

,

,

,

or

and/or, R ³ is

,

,

,

,

,

,

,

,

or

and/or, R ³ is

,

,

,

,

,

,

,

,

or

and/or, when R ⁴ is a 3-6-membered cycloalkane substituted by one or more R ^4-1 , the 3-6-membered cycloalkane substituted by one or more R ^4-1 is

,

,

or

and/or, when R ⁴ is 3~6 membered heterocycloalkane, the 3~6 membered heterocycloalkane is

,

or

and/or, when R ⁴ is a 3-6 membered heterocycloalkane substituted by one or more R ^4-2 , the 3-6 membered heterocycloalkane substituted by one or more R ^4-2 is

or

and/or, when R ⁴ is C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 , the C ₁ ~C ₄ alkyl substituted by one or more R ^4-3 is

. The compound shown in formula III, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt as described in Claim 23, wherein, R ⁴ is cyano, replaced by one Or multiple R ^4-1 substituted 3~6 membered cycloalkane, 3~6 membered heterocycloalkane or 3~6 membered heterocycloalkane substituted by one or more R ^4-2 , or substituted by one or more R ^4-3 substituted C ₁ ~C ₄ alkyl; and/or, R ^4-1 is halogen or hydroxyl; and/or, R ^4-2 is C ₁ ~C ₄ alkyl; and/or, R ^{4- 3} is hydroxyl; and/or, R ⁵ is H, hydroxyl or C ₁ ~C ₄ alkoxy. The compound shown in formula III, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt as described in Claim 23, wherein, R ⁴ is cyano, replaced by one Or multiple R ^4-1 substituted 3~6 membered cycloalkane, 3~6 membered heterocycloalkane, 3~6 membered heterocycloalkane substituted by one or more R ^4-2 , or substituted by one or more R ^4-3 substituted C ₁ ~C ₄ alkyl; R ^4-1 is halogen or hydroxyl; R ^4-2 is C ₁ ~C ₄ alkyl; R ^4-3 is hydroxyl; R ⁵ is H, hydroxyl or C ₁ ~C ₄ alkoxyl. The compound shown in formula III, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt's solvate as described in Claim 23, wherein the compound is:

. A use of a compound as described in any one of claims 1 to 28, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a PLK1 inhibitor; the The inhibitor is preferably an inhibitor used in vitro. A pharmaceutical composition, which comprises the compound as described in any one of Claims 1 to 28, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate and pharmaceutical excipients. A use of a compound as described in any one of Claims 1 to 28, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament; The drug is a drug for treating at least one of the following diseases: breast cancer, prostate cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, gastric cancer, esophageal cancer, ovarian cancer, melanoma, osteosarcoma, multiple myeloma, leukemia and lymphoma. A pharmaceutical combination comprising a compound as described in any one of claims 1 to 28, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and one or more chemotherapeutic agents agent, the one or more chemotherapeutic agents are used simultaneously, separately or sequentially with the compound, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt's solvate.