TW202241413A

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

Info

Publication number: TW202241413A
Application number: TW110149601A
Authority: TW
Inventors: 魏釗; 王文義; 崔洪; 元念李; 周紅; 石峰
Original assignee: 大陸商恒元生物醫藥科技（蘇州）有限公司
Priority date: 2020-12-31
Filing date: 2021-12-30
Publication date: 2022-11-01
Also published as: WO2022143576A1; CN116528871A

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

吡唑並喹唑啉類化合物、其製備方法及用途Pyrazoloquinazoline compounds, their preparation method and use

發明係關於一種吡唑並喹唑啉類化合物、其製備方法及用途。The invention relates to a pyrazoloquinazoline compound, its preparation method and application.

PLKs（Polo-like kinases）屬於絲氨酸/蘇氨酸激酶。到目前為止，其家族共發現有5個亞型，分別為PLK1-5。PLKs主要在處於***中的細胞中表達並且對細胞週期的控制和有絲***起至關重要的作用。在PLK家族中PLK1是研究最多和最詳盡的，對它的生物學活性也描述的最清楚。科學界普遍認為PLK1是引導有絲***進入、中心體成熟和分離、雙極紡錘體形成、***中期到後期過渡以及細胞質***啟動的關鍵激酶。研究發現PLK1不僅在各種腫瘤組織中高度表達，而且也在DNA損傷和複製應激中被啟動，這也和腫瘤細胞增殖異常活躍相一致。透過化學小分子抑制劑或者生物學手段敲除PLK1基因均可發現腫瘤細胞大量停留在G2/M期，並進一步導致腫瘤細胞凋亡。因此，PLK1被認為是一個很有前景的抗腫瘤靶標，尤其是其在多種腫瘤組織中均有高表達的特性使其可能具有廣譜抗腫瘤的潛力。另外，在正常細胞中PLK1的表達水準較低，因此開發PLK1抑制劑作為抗腫瘤藥物可能具有很好的安全範圍。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.

相比較PLK1在腫瘤細胞中高表達，PLK2和PLK3在有絲***後的細胞如神經細胞中表達較多，因此開發PLK1特異性抑制劑可能會避免由於同時抑制PLK2/3而帶來的毒副反應。BI（Boehringer Ingelheim）開發的PLK1抑制劑Volasertib（BI-6727）由於沒有對PLK2/3的選擇性而在臨床上產生了較嚴重的毒副作用，限制了其療效，故而導致其三期臨床失敗。作為PLK1特異性抑制劑，Cardiff Oncology公司開發的小分子抑制劑Onvansertib在多個概念驗證的二期臨床中表現出了較好的抗腫瘤活性和可控的毒副作用。但是，Onvansertib仍然有較多可以改進的地方，例如較差的透膜性質而造成其生物利用度較低。而且，由於其較長的半衰期（t1/2大於24小時）導致在治療週期內只能間歇性給藥，除了致使其有較明顯的毒副作用外還進一步限制了其能帶來的治療效果。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.

本發明所要解決的技術問題是現有技術中PLK1抑制劑結構單一、抑制效果較差等缺陷，而提供了一種吡唑並喹唑啉類化合物、其製備方法及用途，該化合物對PLK1抑制效果明顯。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.

本發明是透過下述技術方案來解決上述技術問題的。The present invention solves the above-mentioned technical problems through the following technical solutions.

本發明提供了一種如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物；

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.

在某一方案中，該吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物合物或其藥學上可接受的鹽的溶劑合物裡，某些基團的定義如下所述，其餘基團的定義如上任一方案所述（以下簡稱「在某一方案中」）：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"):

在某一方案中，R ^1-1獨立地為F、Cl、Br或I，例如F。 In a certain aspect, R ^1-1 is independently F, Cl, Br or I, such as F.

在某一方案中，R ^1-1獨立地為3~6元環烷烴，例如環丙烷、環丁烷或環戊烷。 In a certain aspect, R ^1-1 is independently a 3-6 membered cycloalkane, such as cyclopropane, cyclobutane or cyclopentane.

在某一方案中，當R ¹為C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基。 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.

在某一方案中，當R ¹為被一個或多個R ^1-1取代的C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基可為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基。 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.

在某一方案中，當R ¹為3~6元環烷基氧基時，該3~6元環烷氧基為環丙基氧基、環丁基氧基或環戊基氧基，例如環丙基氧基或環丁基氧基。 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.

在某一方案中，R ¹可為

、

、

、

、

，、

或

，例如

、

或

。 In ^a certain scheme, R1 can be

,

,,

or

,E.g

,

or

.

在某一方案中，當R ²為鹵素時，該鹵素可為F、Cl、Br或I。 ^In a certain aspect, when R2 is halogen, the halogen can be F, Cl, Br or I.

在某一方案中，當R ²為C ₁~C ₄烷基時，該C ₁~C ₄烷基可為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基。 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.

在某一方案中，當R ^3-1為C ₁~C ₄烷基時，該C ₁~C ₄烷基可為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基。 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.

在某一方案中，當R ³為被一個或多個R ^3-1取代的5~10元雜環烷基時，該5~10元雜環烷基可為6~9元雜環烷基，例如含兩個N的6 ~9元雜環烷基，又例如呱嗪基、六氫噠嗪基、六氫嘧啶基、3,8-二氮雜雙環[3.2.1]辛烷基、八氫吡咯[1,2-a ]吡嗪基、2,6-二氮雜螺[3.4]辛烷基、3,6-二氮雜雙環[3.2.0]庚烷基、1,6-二氮雜螺[3.4]辛烷基或八氫吡咯[3,4-c ]吡咯基。 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.

在某一方案中，R ³較佳為

、

、

、

、

、

、

、

、

或

(b為與

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

,

or

(b is with

connection point).

在某一方案中，當R ³可為

、

、

、

、

、

、

、

、

或

。 In a certain scheme, when ^R3 can be

,

or

.

在某一方案中，R ³可為

、

、

、

、

、

、

、

或

。 In a certain scheme, ^R3 can be

,

or

.

在某一方案中，R ⁴為氰基、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。 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.

在某一方案中，R ^4-1為鹵素或羥基。 In a certain embodiment, R ^4-1 is halogen or hydroxy.

在某一方案中，R ^4-2為C ₁~C ₄烷基。 In a certain scheme, R ^4-2 is C ₁ -C ₄ alkyl.

在某一方案中，R ⁵為H。 In a certain embodiment, R ⁵ is H.

在某一方案中，當R ^4-1為鹵素時，該鹵素為F、Cl、Br或I，例如F。 In a certain embodiment, when R ^4-1 is halogen, the halogen is F, Cl, Br or I, such as F.

在某一方案中，當R ^4-1為C ₁~C ₄烷基時，該C ₁~C ₄烷基可為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基或乙基。 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.

在某一方案中，當R ^4-2為C ₁~C ₄烷基時，該C ₁~C ₄烷基可為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基或乙基。 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.

在某一方案中，當R ^4-2為鹵素時，該鹵素為F、Cl、Br或I，例如F。 In a certain embodiment, when R ^4-2 is halogen, the halogen is F, Cl, Br or I, such as F.

在某一方案中，當R ⁴為3~6元環烷烴時，該3~6元環烷烴可為環丙烷、環丁烷或環戊烷，例如環丙烷或環丁烷。 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.

在某一方案中，當R ⁴為被一個或多個R ^4-1取代的3~6元環烷烴時，該3~6元環烷烴可為環丙烷、環丁烷或環戊烷，例如環丙烷或環丁烷。 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.

在某一方案中，當R ⁴為被一個或多個R ^4-1取代的3~6元環烷烴時，該被一個R ^4-1取代的3~6元環烷烴可為

、

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

.

在某一方案中，當R ⁴為3~6元雜環烷烴時，該3~6元雜環烷烴可為

、

或

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

,

or

.

在某一方案中，當R ⁴為被一個R ^4-2取代的3~6元雜環烷烴時，該3~6元雜環烷烴可為包含一個N或O的4元雜環烷烴或包含一個N或O的5元雜環烷烴。 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.

在某一方案中，當R ⁴為被一個或多個R ^4-2取代的3~6元雜環烷烴時，該被一個或多個R ^4-2取代的3~6元雜環烷烴為

、

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

or

.

在某一方案中，當R ⁴為被一個或多個R ^4-3取代的C ₁~C ₄烷基時，該被一個或多個R ^4-3取代的C ₁~C ₄烷基為

。 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

.

在某一方案中，R ⁴為氰基、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，或被一個或多個R ^4-3取代的C ₁~C ₄烷基。 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 .

在某一方案中，R ⁴為被一個或多個R ^4-1取代的3~6元環烷烴，其中R ^4-1為鹵素或羥基。 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.

在某一方案中，R ⁴為被一個或多個R ^4-2取代的3~6元雜環烷烴，其中R ^4-2為C ₁~C ₄烷基。 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.

在某一方案中，R ⁴為被一個或多個R ^4-3取代的C ₁~C ₄烷基，其中R ^4-3為羥基。 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.

在某一方案中，R ⁴選自下組：氰基、

、

和

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

,

with

.

在某一方案中，R ⁵為H或羥基。 In a certain embodiment, R ⁵ is H or hydroxyl.

在某一方案中，R ⁵為C ₁~C ₄烷基，該C ₁~C ₄烷基可為甲基、乙基、異丙基或叔丁基，例如甲基或乙基。 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.

在某一方案中，R ⁵為C ₁~C ₄烷氧基，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基 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

本發明還提供了一種如式Ia所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物：

。 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:

.

在某一方案中，本發明提供了如下任一所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物：

。 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:

.

本發明還提供了一種如式II所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物：

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.

在某一方案中，R ^1-1為F、Cl、Br或I，例如F。 In a certain aspect, R ^1-1 is F, Cl, Br or I, such as F.

在某一方案中，R ¹為

、

，例如

。 In ^a certain scheme, R1 is

,

,E.g

.

在某一方案中，R ^3-1可為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基。 In a certain aspect, ^R3-1 can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, eg methyl.

在某一方案中，當R ^3’為7~9元雜螺環烷基時，該7~9元雜螺環烷基可為含兩個氮原子的7~9元雜螺環烷基，例如

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

.

在某一方案中，當R ^3’為被一個R ^3-1取代的7~9元雜螺環烷基時，該被一個R ^3-1取代或未取代7~9元雜螺環烷基可為含兩個氮原子的被一個R ^3-1取代的7~9元雜螺環烷基，例如

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

.

在某一方案中，當R ^3’為7~9元雜橋環烷基時，該7~9元雜橋環烷基可為含兩個N的7~9元雜橋環烷基，例如

。 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

.

在某一方案，當R ^3’為被一個R ^3-1取代的7~9元雜橋環烷基時，該被一個R ^3-1取代的7~9元雜橋環烷基可為含兩個氮的被一個R ^3-1取代的7~9元雜橋環烷基，例如

、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

.

在某一方案中，當R ^4-3為鹵素時，該鹵素為F、Cl、Br或I。 In a certain embodiment, when R ^4-3 is halogen, the halogen is F, Cl, Br or I.

在某一方案中，當R ⁴’獨立地為被一個R ^4-3取代的C ₁~C ₄烷基時，該C ₁~C ₄烷基可為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基。 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.

在某一方案中，R ⁴可為-CH ₂OH。 ^In a certain aspect, R4 can be _-CH2OH .

在某一方案中，當R ⁵為C ₁~C ₄烷基時，該C ₁~C ₄烷基可為甲基、乙基、異丙基或叔丁基，例如甲基或乙基。 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.

在某一方案中，當R ⁵為C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基。 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.

在某一方案中，該如式II所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物可如下任一所示：

。 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:

.

本發明還提供了一種如式III所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物：

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.

在某一方案中，R ¹為C ₁~C ₄烷氧基，例如甲氧基、乙氧基、異丙氧基或叔丁氧基。 In a certain scheme, R ¹ is C ₁ ~C ₄ alkoxy, such as methoxy, ethoxy, isopropoxy or tert-butoxy.

在某一方案中，R ¹為被一個或多個R ^1-1取代的C ₁~C ₄烷氧基，其中該C ₁~C ₄烷氧基可為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基。 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.

在某一方案中，R ¹為被一個或多個R ^1-1取代的C ₁~C ₄烷氧基，其中R ^1-1獨立地為F、Cl、Br或I，例如F。 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.

在某一方案中，R ¹可選自

、

或

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

,

or

.

在某一方案中，R ¹可選自

、

或

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

,

or

.

在某一方案中，R ²為H。 In a certain embodiment, R ² is H.

在某一方案中，R ²為鹵素，該鹵素為F、Cl、Br或I。 In a certain aspect, R ² is halo which is F, Cl, Br or I.

在某一方案中，R ²為C ₁~C ₄烷基，例如甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基。 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.

在某一方案中，R ³為5~10元雜環烷基，例如6~9元雜環烷基，例如含兩個N的6~9元雜環烷基，又例如呱嗪基、六氫噠嗪基、六氫嘧啶基、3,8-二氮雜雙環[3.2.1]辛烷基、八氫吡咯[1,2-a]吡嗪基、2,6-二氮雜螺[3.4]辛烷基、3,6-二氮雜雙環[3.2.0]庚烷基、1,6-二氮雜螺[3.4]辛烷基或八氫吡咯[3,4-c]吡咯基。 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 .

在某一方案中，R ³為被一個或多個R ^3-1取代的5~10元雜環烷基，其中該5~10元雜環烷基例如為6~9元雜環烷基，例如含兩個N的6~9元雜環烷基，又例如呱嗪基、六氫噠嗪基、六氫嘧啶基、3,8-二氮雜雙環[3.2.1]辛烷基、八氫吡咯[1,2-a]吡嗪基、2,6-二氮雜螺[3.4]辛烷基、3,6-二氮雜雙環[3.2.0]庚烷基、1,6-二氮雜螺[3.4]辛烷基或八氫吡咯[3,4-c]吡咯基，其中R ^3-1為C ₁~C ₄烷基，例如甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基。 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.

在某一方案中，R ³為

、

、

、

或

。 In a certain scheme, ^R3 is

,

or

.

在某一方案中，R ³為

、

或

。 In a certain scheme, ^R3 is

,

or

.

在某一方案中，R ³為

、

或

。 In a certain scheme, ^R3 is

,

or

.

在某一方案中，R ⁴為氰基。 In a certain embodiment, R ⁴ is cyano.

在某一方案中，R ⁴為3~6元環烷烴，例如環丙烷、環丁烷或環戊烷。 In a certain scheme, R ⁴ is a 3-6 membered cycloalkane, such as cyclopropane, cyclobutane or cyclopentane.

在某一方案中，R ⁴為被一個或多個R ^4-1取代的3~6元環烷烴，其中該3~6元環烷烴例如為環丙烷、環丁烷或環戊烷，R ^4-1為鹵素，例如F、Cl、Br或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 halogen, such as F, Cl, Br or I.

在某一方案中，R ⁴為被一個或多個R ^4-1取代的3~6元環烷烴，其中該3~6元環烷烴例如為環丙烷、環丁烷或環戊烷，R ^4-1為C ₁~C ₄烷基，例如甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基。 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.

在某一方案中，R ⁴為

、

或

。 ^In a certain scheme, R4 is

,

or

.

在某一方案中，R ⁴為3~6元雜環烷烴，例如包含一個N或O的4元雜環烷烴或包含一個N或O的5元雜環烷烴。 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.

在某一方案中，R ⁴為被一個或多個R ^4-2取代的3~6元雜環烷烴，例如包含一個N或O的4元雜環烷烴或包含一個N或O的5元雜環烷烴，其中R ^4-2為鹵素，例如F、Cl、Br或I。 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.

在某一方案中，R ⁴為

或

。 ^In a certain scheme, R4 is

or

.

在某一方案中，R ⁴為被一個或多個R ^4-2取代的3~6元雜環烷烴，例如包含一個N或O的4元雜環烷烴或包含一個N或O的5元雜環烷烴，其中R ^4-2為C ₁~C ₄烷基，例如甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基。 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.

在某一方案中，R ⁴為被一個或多個R ^4-3取代的C ₁~C ₄烷基，其中該C ₁~C ₄烷基為甲基、乙基、異丙基或叔丁基，R ^4-3為鹵素，例如F、Cl、Br或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 group, R ^4-3 is halogen, such as F, Cl, Br or I.

在某一方案中，R ⁴為被一個或多個R ^4-3取代的C ₁~C ₄烷基，其中該C ₁~C ₄烷基為甲基、乙基、異丙基或叔丁基，R ^4-3為氰基。 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.

在某一方案中，R ⁴為被一個或多個R ^4-3取代的C ₁~C ₄烷基，其中該C ₁~C ₄烷基為甲基、乙基、異丙基或叔丁基，R ^4-3為羥基。 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.

在某一方案中，R ⁴為

。 ^In a certain scheme, R4 is

.

在某一方案中，R ⁵為C ₁~C ₄烷基，例如甲基、乙基、異丙基或叔丁基。 In a certain scheme, R ⁵ is C ₁ ~C ₄ alkyl, such as methyl, ethyl, isopropyl or tert-butyl.

在某一方案中，R ⁵為C ₁~C ₄烷氧基，例如甲氧基、乙氧基、異丙氧基或叔丁氧基。 In a certain scheme, R ⁵ is C ₁ ~C ₄ alkoxy, such as methoxy, ethoxy, isopropoxy or tert-butoxy.

在某一方案中，該如式III所示的吡唑並喹唑啉類化合物為：

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

.

本發明還提供了一種如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物的製備方法，其包括下述步驟，有機溶劑中，鹼試劑中，鈀類催化劑的作用下，將化合物1g、配體試劑與R ³-H進行偶聯反應，制得化合物I即可；

。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.

在該偶聯反應中，該鈀類催化劑可為三二亞苄基丙酮二鈀。In the coupling reaction, the palladium catalyst may be tridibenzylideneacetone dipalladium.

在該偶聯反應中，該有機溶劑可為本領域該類反應的常規溶劑，例如一四二氧六環。In the coupling reaction, the organic solvent can be a conventional solvent for this type of reaction in the art, such as tetradioxane.

在該偶聯反應中，該鹼試劑可為碳酸銫。In the coupling reaction, the base reagent can be cesium carbonate.

在該偶聯反應中，該配體試劑可為4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽。In the coupling reaction, the ligand reagent can be 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

本發明還提供了一種如式II所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其包括下述步驟，有機溶劑中，鈀類催化劑的作用下，將化合物1g、配體試劑與R ³-L進行偶聯反應，制得化合物II即可；

。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.

在該偶聯反應中，該鹼可為碳酸銫。In the coupling reaction, the base can be cesium carbonate.

本發明提供了一種如上所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物在製備PLK1抑制劑中的用途；該抑制劑較佳為在體外使用的抑制劑。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.

本發明還提供了一種藥物組合物，該藥物組合物還包括如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物和藥用輔料。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.

本發明還提供了一種如上所述如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物在製備藥物中的用途；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;

該藥物為治療下述至少一種疾病的藥物：乳腺癌、***癌、肺癌、結直腸癌、肝癌、胰腺癌、胃癌、食管癌、黑色素瘤、多發性骨髓瘤、白血病和淋巴癌。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.

本發明提供了一種如上所述如式II所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物在製備PLK1抑制劑中的用途；該抑制劑較佳為在體外使用的抑制劑。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.

本發明還提供了一種藥物組合物，該藥物組合物包含如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物和藥用輔料。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.

本發明還提供了一種如上所述的如式II所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物在製備藥物中的用途；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;

該藥物為治療下述至少一種疾病的藥物：乳腺癌、***癌、肺癌、結直腸癌、肝癌、胰腺癌、胃癌、食管癌、卵巢癌、黑色素瘤、骨肉瘤、多發性骨髓瘤、白血病和淋巴癌。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.

本發明還提供了一種藥物組合物，其包含本發明的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，以及一種或多種化療劑。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.

在某一方案中，該一種或多種化療劑與本發明的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物同時、分別或連續使用。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.

術語解釋Terminology Explanation

在本說明書的各部分，本發明揭露化合物的取代基按照基團種類或範圍揭露。特別指出，本發明包括這些基團種類和範圍的各個成員的每一個獨立的次級組合。例如，術語「C ₁~C ₄烷基」特指獨立揭露的甲基、乙基、C ₃烷基（即丙基，包括正丙基和異丙基）、C ₄烷基（即丁基，包括正丁基、異丁基、仲丁基和叔丁基）。 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).

當所列舉的取代基中沒有指明其透過哪一個原子連接到化學結構通式中包括但未具體提及的化合物時，這種取代基可以透過其任何原子相鍵合。取代基及/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。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.

當所列舉的基團中沒有明確指明其具有取代基時，這種基團僅指未被取代。例如當「C ₁~C ₄烷基」前沒有「取代或未取代的」的限定時，僅指「C ₁~C ₄烷基」本身或「未取代的C ₁~C ₄烷基」。 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".

術語「C _i-C _j」表示碳原子數的範圍，其中i和j為整數且j大於i，並且碳原子數的範圍包括端點（即i和j）以及端點之間的每個整數點。例如，C ₁~C ₆表示1至6個碳原子的範圍，包括1個碳原子、2個碳原子、3個碳原子、4個碳原子、5個碳原子和6個碳原子。在一些實施方案中，術語「C ₁-C ₁₂」表示1至12、特別地1至10、特別地1至8、特別地1至6、特別地1至5、特別地1至4、特別1至3、或特別地1至2個碳原子。 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.

術語「烷基」是指飽和的直鏈或支鏈烴基。術語「C _i-C _j烷基」指具有i至j個碳原子的烷基。在一些實施方案中，烷基包含1至12個碳原子。在一些實施方案中，烷基包含1至11個碳原子、1至10個碳原子、1至9個碳原子、1至8個碳原子、1至7個碳原子、1至6個碳原子、1至5個碳原子、1至4個碳原子、1至3個碳原子、或1至2個碳原子。烷基的例子包括但不限於甲基、乙基、1-丙基（正丙基）、2-丙基（異丙基）、1-丁基（正丁基）、2-甲基-1-丙基（異丁基）、2-丁基（新丁基）、2-甲基-2-丙基（叔丁基）、1-戊基（正戊基）、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基、1-辛基等。 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.

術語「烷氧基」是指透過氧原子連接至母體分子的如上定義的烷基。術語「C _i-C _j烷氧基」是指烷氧基的烷基部分具有i至j個碳原子。在一些實施方案中，烷氧基含有1至12個碳原子。在一些實施方案中，烷氧基含有1至11個碳原子。在一些實施方案中，烷氧基含有1至10個碳原子、1至9個碳原子、1至8個碳原子、1至7個碳原子、1至6個碳原子、1至5個碳原子、1至4個碳原子、1至3個碳原子、或1至2個碳原子。 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.

術語「環烷烴」或「環烷基」是指具有指定的碳原子數（例如C ₃~C ₆）的、僅由碳原子組成的、飽和的單環環狀基團。環烷基包括但不限於環丙基、環丁基、環戊基、環己基等。 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.

術語「雜環烷基」是指具有指定環原子數（例如5~10元）的、指定雜原子數（例如1個、2個或3個）的、指定雜原子種類（N、O和S中的一種或多種）的環狀基團，其為單環、橋環或螺環，且每一個環均為飽和的。橋環是指單環之間共用兩個或兩個以上原子的多環。螺環是指單環之間共用一個原子的多環。雜環烷基包括但不限於氮雜環丁烷基、四氫吡咯基、四氫呋喃基、嗎啉基、呱啶基等。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.

術語「藥學上可接受的鹽」是指化合物與藥學上可接受的（相對無毒、安全、適合於患者使用）酸或鹼反應得到的鹽。當化合物中含有相對酸性的官能團時，可以透過在合適的惰性溶劑中用足量的藥學上可接受的鹼與化合物的游離形式接觸的方式獲得鹼加成鹽。藥學上可接受的鹼加成鹽包括但不限於鈉鹽、鉀鹽、鈣鹽、鋁鹽、鎂鹽、鉍鹽、銨鹽等。當化合物中含有相對鹼性的官能團時，可以透過在合適的惰性溶劑中用足量的藥學上可接受的酸與化合物的游離形式接觸的方式獲得酸加成鹽。藥學上可接受的酸加成鹽包括但不限於鹽酸鹽、硫酸鹽、甲磺酸鹽等。具體參見Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002)。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).

術語「溶劑合物」是指化合物與溶劑（包括但不限於：水、甲醇、乙醇等）結晶後形成的物質。溶劑合物分為化學計量類溶劑合物和非化學計量類溶劑合物。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.

術語「藥學上可接受的鹽的溶劑合物」是指化合物與藥學上可接受的（相對無毒、安全、適合於患者使用）酸或鹼、溶劑（包括但不限於：水、甲醇、乙醇等）結合形成的物質，其中，藥學上可接受的鹽與上文術語「藥學上可接受的鹽」的含義相同，溶劑為化學計量的或非化學計量的。藥學上可接受的鹽的溶劑合物包括但不限於鹽酸鹽一水合物。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.

術語「藥用輔料」是指生產藥品和調配處方時使用的賦形劑和附加劑，是除活性成分以外，包含在藥物製劑中的所有物質。具體參見中華人民共和國藥典（2020年版）或Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009)。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).

除非另有規定，本文使用的所有技術術語和科學術語具有要求保護主題所屬領域的標準含義。倘若對於某術語存在多個定義，則以本文定義為准。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.

應該理解，在本發明中使用的單數形式，如「一種」或「一個」，包括複數指代，除非另有規定。此外，術語「包括」是開放性限定並非封閉式，即包括本發明所指明的內容，但並不排除其他方面的內容。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.

除非另有說明，本發明採用質譜、元素分析的傳統方法，各步驟和條件可參照本領域常規的操作步驟和條件。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.

除非另有指明，本發明採用分析化學、有機合成化學和光學的標準命名及標準實驗室步驟和技術。在某些情況下，標準技術被用於化學合成、化學分析、發光器件性能檢測。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.

另外，需要說明的是，除非以其他方式明確指出，在本發明中所採用的描述方式「…獨立地為」應做廣義理解，是指所描述的各個個體之間是相互獨立的，可以獨立地為相同或不同的具體基團。更詳細地，描述方式「…獨立地為」既可以是指在不同基團中，相同符號之間所表達的具體選項之間互相不影響；也可以表示在相同的基團中，相同符號之間所表達的具體選項之間互相不影響。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.

本領域之具備通常知識者可以理解，根據本領域中使用的慣例，本申請描述基團的結構式中所使用的「

」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.

在不違背本領域常識的基礎上，上述各較佳條件，可任意組合，即得本發明各較佳實例。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.

本發明所用試劑和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.

本發明的積極進步效果在於，本發明提供了一種吡唑並喹唑啉類化合物、其製備方法及用途，該化合物至少具有如下任一優點對PLK1抑制效果明顯、能進一步地調節藥物半衰期。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.

具體實施方式detailed description

下面透過實施例的方式進一步說明本發明，但並不因此將本發明限制在所述的實施例範圍之中。下列實施例中未注明具體條件的實驗方法，按照常規方法和條件，或按照商品說明書選擇。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.

實施例1

Example 1

第一步室溫下，將化合物1a（480 mg，2.0 mmol）和2-肼基乙醇（152 mg，2.0 mmol）溶於5 mL冰醋酸中並攪拌5小時。反應結束，除去大部分冰醋酸後將粗品分散在乙酸乙酯（20 mL）和水（30 mL）中，水相再用乙酸乙酯萃取（20 mL x 1），有機相依次經飽和碳酸氫鈉水溶（20 mL x 1）和飽和食鹽水（20 mL x 1）洗滌，無水硫酸鈉乾燥，過濾，濃縮得到化合物1b（430 mg，收率：85%）。 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%).

第二步在氮氣保護下，將化合物1b（800 mg，3.2 mmol）和二甲基甲醯胺二叔丁基縮醛（709 mg，3.5 mmol）的二甲基甲醯胺（20 mL）溶液加熱至60℃並反應2小時。反應結束。冷卻，向反應液中加入水（50 mL），乙酸乙酯萃取（20 mL x 2），有機相依次經水（20 mL x 1）和飽和食鹽水（20 mL x 1）洗滌，無水硫酸鈉乾燥，過濾，濃縮，得到化合物1c（750 mg，收率：76%）。 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%).

第三步氮氣保護下，將化合物1c（750 mg，2.4 mmol）和化合物1d（728 mg，2.4 mmol）的二甲基甲醯胺（10 mL）溶液加熱至120℃並攪拌2小時。反應結束。冷卻，加入水30（mL），乙酸乙酯（20 mL x 2）萃取，有機相依次經過水（20 mL x 1）和飽和食鹽水（20 mL x 1）洗滌，無水硫酸鈉乾燥，過濾，濃縮，得到的粗品經矽膠柱層析（甲醇/二氯甲烷 = 0/100%）得到化合物1e（780 mg，收率：59%）。 LCMS（M+H）+ m/z：542/544。 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.

第四步室溫下，向化合物1e（780 mg，1.4 mmol）的乙醇（10 mL）溶液中加入氫氧化鉀的乙醇溶液（1.5 M，3 mL）。所得反應液繼續攪拌4小時。反應結束。過濾，得到化合物1f（650 mg，收率：82%）。 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%).

第五步室溫和氮氣保護下，向化合物1f（650 mg，1.2 mmol），氯化銨（80 mg，1.5 mmol）和三乙胺（310 mg，3.6 mmol）的二甲基甲醯胺（5 mL）溶液中加入2-(7-氮雜苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯（684 mg，1.8 mmol），並反應2小時。反應結束。用水（20 mL）稀釋反應液，乙酸乙酯（20 mL x 3）萃取，有機相依次經水（10 mL x 1）和飽和食鹽水（10 mL x 1）洗滌，無水硫酸鈉乾燥，過濾，濃縮，得到化合物1g（510 mg，收率：83%）。 LCMS（M+H）+ m/z：513/515。 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.

第六步在氮氣保護下，將化合物1g（51 mg，0.1 mmol），8-甲基-3,8-二氮雜二環[3.2.1]辛烷二鹽酸鹽（24 mg，0.12 mmol），碳酸銫（130 mg，0.4 mmol），4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽（24 mg，0.04 mmol）和三二亞苄基丙酮二鈀（18 mg，0.02 mmol）的1，4-二氧六環（2 mL）溶液加熱回流4小時。反應結束。冷卻，向反應液中加入水（10 mL），乙酸乙酯（15 mL x 3）萃取，有機相依次經過水（10 mL x 1）和飽和食鹽水（10 mL x 1）洗滌，無水硫酸鈉乾燥，過濾，濃縮，得到的粗品經製備HPLC純化得到化合物1（1.5 mg，收率：27%）。 LCMS（M+H）+ m/z：559。 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.

實施例2

Example 2

第一步按照實施例1的方法由化合物1g得到化合物2（3.0 mg）。 LCMS（M+H）+ m/z：559。 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.

實施例3

Example 3

第一步按照實施例1的方法由化合物1g得到化合物3（1.6 mg）。 LCMS（M+H）+ m/z：545。 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.

實施例4

Example 4

第一步按照實施例1的方法由化合物1g得到化合物4（1.3 mg）。 LCMS（M+H）+ m/z：545。 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.

實施例5

Example 5

第一步按照實施例1的方法由化合物1g得到化合物5（2.0 mg）。 LCMS（M+H）+ m/z：545。 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.

實施例6

Example 6

第一步將1,2-環己二酮6F_1（100 g, 0.892 mol）溶解在甲苯（700 mL）和MeOH（500 mL）的混合溶劑中。加入對甲苯磺酸（15.4 g，89.2 mmol）並將溶液在100℃下攪拌48小時。蒸發溶劑並將殘餘物用DCM（500 mL）溶解並用NaHCO ₃的飽和溶液（500 mL）洗滌。有機相用Na ₂SO ₄乾燥並濃縮。透過矽膠柱色譜法（PE中的0%~30% EA）純化，得到油狀的2-甲氧基環己基-2-烯-1-酮6F_2（42g，37.3%）。ESI-MS (M+H)+=127。 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.

第二步在N ₂氛圍下，在-50℃下將LiHMDS（51 mL，51.0 mmol，1M在THF中）逐滴加入2-甲氧基環己基-2-烯-1-酮（6.40 g，45.7 mmol）在THF（60 mL）中的溶液中。在-50℃攪拌30分鐘後，加入草酸二乙酯（7.47 g，51.0 mmol）。將溶液在25℃下攪拌16小時。反應結束後，加入水（100 mL），加入1N HCl調節pH至4-5，所得溶液用EA（50 mL*3）萃取。有機層用Na ₂SO ₄乾燥並蒸發至幹。粗品透過柱（0%~15% EA在PE中）純化，得到淺黃色油狀2-(3-甲氧基-2-氧代環己-3-烯-1-基)-2-氧代乙酸乙酯6F_3（8.2g，71.4%）。 ¹HNMR (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)。 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).

第三步在25℃下向2-(3-乙氧基-2-氧代環己-3-烯-1-基)-2-氧代乙酸乙酯6F_3（3.0 g，0.012 mmol）的乙醇（30 mL）溶液中加入羥乙基肼（0.6 mL，0.012 mmol）。將反應在80℃下攪拌5小時。然後蒸發溶劑並將殘餘物用DCM（30 mL）重新溶解。有機層用水洗滌，用Na ₂SO ₄乾燥並濃縮。將殘餘物溶解在THF（12 mL）和HCl（12 mL，1 mol/L）中，並在25℃下攪拌2小時，反應用飽和NaHCO ₃溶液（50 mL）淬滅，用EA（50 mL*3），合併的有機層用鹽水洗滌，經無水硫酸鈉乾燥，過濾，減壓蒸發，得到呈棕色油狀的1-(2-羥乙基)-7-氧代-4,5,6,7-四氫-1H-吲唑-3-甲酸乙酯6F_3（2.4 g，粗品）。ESI-MS(M+H)+=253。 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.

第四步在25℃下把6F_3（4 g, 15.9 mmol）溶解在DMF（24 mL），然後加入8 mL的DMFDMA。將所得混合物在80℃下攪拌20 h，然後冷卻至25℃，濃縮除溶劑，粗產物經柱純化（PE中20%~50% EA）得到6F（3.25 g, 66.7%）為黃色固體。 ¹HNMR (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 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).

第五步 5-溴-4-氟-2-甲氧基苯胺6A（7.5 g, 34.3 mmol）溶於EtOH（90 mL），加入Ac ₂O（8.7 g, 85.6 mmol）。將混合物在25℃下攪拌2.5 h，蒸發溶劑得到N-(5-溴-4-氟-2-甲氧基苯基)乙醯胺6A_1（8 g粗品）為棕色固體。ESI-MS(M+H)+=262。 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.

第六步在圓底燒瓶中加入N-(5-溴-4-氟-2-甲氧基苯基)乙醯胺6A_1（1.5 g, 5.74 mmol）、Davephos（90 mg, 0.223 mmol）、Pd ₂(dba) ₃（105 mg, 0.115 mmol）和THF（7.5 mL）。將燒瓶抽真空並回填氮氣。滴加LiHMDS（1 mol/L在四氫呋喃中，12.63 mL）和N-甲基呱嗪（690 mg，6.89 mmol），反應在70℃回流1 h。反應混合物加飽和NH4Cl水溶液（10 mL），用EA（10 mL*3）萃取，有機層用鹽水洗淨，無水硫酸鈉乾燥，過濾，在減壓下蒸發。殘渣經柱層析（2.5%~5%甲醇，二氯甲烷）純化得到N-(4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯基)乙醯胺6A_2（400 mg, 24.8%）為淡黃色固體。LCMS(M+H)+=282。 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.

第七步把N-(4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯基)乙醯胺6A_2（400 mg, 1.67 mmol）溶解在EtOH（4 mL），室溫攪拌，向溶液中加入HCl（1.2 mL, 12 mol/L）。在80℃下攪拌6 h，反應結束後，加入2mol /L NaOH，將反應混合物的pH調至8~9。水相用EA（10 mL×3）萃取，有機層用鹽水洗滌，Na ₂SO ₄乾燥並濃縮。殘渣經柱純化（PE中1%~50% EA）得到4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯胺6B（300 mg, 88.2%）為黃色固體。 ¹HNMR (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). 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).

第八步把4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯胺6B（150 mg, 0.514 mmol）溶解在鹽酸（6 mol/L，1 mL）中，加入氰胺（345 mg，4.11 mmol，50%在H ₂O中），並將反應在80℃下攪拌48 H。將混合物冷卻至25℃，用水（3 mL）稀釋，並用二氯甲烷萃取。水相透過加入2 mol/L NaOH將pH值調節至＞11。水相用EA（10mL*3）萃取，經Na ₂SO ₄乾燥並濃縮以得到呈棕色固體狀的1-(4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯基)胍6C（150 mg，粗品）。 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).

第九步在25℃下1-(4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯基)胍6C（300 mg，0.98 mmol）和6-((二甲氨基)亞甲基)-1-(2-羥乙基)-7-氧代-4,5,6,7-四氫-1H-吲唑-3-甲酸乙酯6F在DMF溶液（3.5 mL）中的攪拌。在80℃攪拌12小時後，減壓蒸發反應混合物。殘餘物透過柱（2%~5% MeOH的DCM溶液）純化，得到乙基8-((4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯基)氨基)-1-(2-羥乙基)-4,5-二氫-1H-吡唑並[4,3 -h]喹喔啉-3-甲酸乙酯6D（150 mg，26.7%），為淺黃色固體。LCMS(M+H)+=526。 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.

第十步將乙基8-((4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯基)氨基)-1-(2-羥乙基)-4,5-二氫-1H-吡唑並[4,3 -h]喹喔啉-3-甲酸乙酯6D（110 mg，0.222 mmol）在NH ₃的MeOH溶液（1.5 mL，7 M）中的溶液在80℃下在10 mL封管中攪拌36小時。反應結束後，減壓蒸發反應混合物，並且透過柱層析（DCM:MeOH=10:1）純化殘餘物以得到呈淺黃色固體狀的8-((4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯基)氨基)-1-(2-羥乙基)-4,5-二氫-1H-吡唑並[4,3-h]喹唑啉-3-甲醯胺6（12.0 mg，11.5%）。 ¹HNMR (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。 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.

實施例7

Example 7

第一步在N ₂氛圍下，把(Z)-6-((二甲氨基)亞甲基)-1-(2-羥乙基)-7-氧代-4,5,6,7-四氫-1H-吲唑-3-甲酸乙酯6F（570 mg，1.88 mmol）在DMF（50ml)中的溶液中加入碳酸胍（849.4 mg，4.64 mmol）。在110°C攪拌16小時後，將反應混合物加入水（50 mL），過濾並真空乾燥。殘餘物透過柱層析（20%~50% EA/PE）純化以得到淺黃色固體狀的8-氨基-1-(2-羥乙基)-4,5-二氫-1H-吡唑並[4,3-h]喹唑啉-3-甲酸乙酯7F_1（307 mg，53.8%）。ESI-MS(M+H)+=304。 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.

第二步在N ₂下，向8-氨基-1-(2-羥乙基)-4,5-二氫-1H-吡唑並[4,3-h]喹唑啉-3-甲酸乙酯7F_1（303 mg，1.00 mmol）的THF（30 ml）溶液中加入碘化亞銅（57.1 mg，0.300 mmol）、碘（126.5 mg，0.500 mmol）、碘化銫（259 mg，1.00）和亞硝酸異戊酯（176 mg，1.50 mmol）。將反應在80℃下攪拌12小時。反應混合物用DCM（50 mL）稀釋，用20% NH ₃．H ₂O（80mL）、飽和N _a2S ₂O ₃水溶液（80 mL）、鹽水（80 mL）洗滌，經無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物透過柱層析（2.5%~10% MeOH的DCM溶液）純化，得到呈黃色固體狀的1-(2-羥乙基)-8-碘-4,5-二氫-1H-吡唑並[4,3-h]喹唑啉-3-甲酸乙酯7F_2（300 mg，52%）。ESI-MS(M+H)+=415。 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.

第三步在圓底燒瓶中裝入1-溴-2-氟-4-(三氟甲氧基)苯7A（27 g, 104 mmol），並在N ₂下加入硝酸鉀（14 g，138 mmol）、濃硫酸（60 ml）。將反應在25℃下攪拌2小時。反應混合物用水（200 mL）淬滅，用DCM（50 mL*3）萃取，合併的有機層用飽和NaHCO ₃水溶液（100 mL）、鹽水（100 mL）洗滌，經無水硫酸鈉乾燥，過濾，減壓蒸發。殘餘物透過柱（0%~5% EA在PE中）純化以得到呈淺黃色油狀的1-溴-2-氟-5-硝基-4-(三氟甲氧基)苯7B（30 g，95%）。ESI-MS(M+H)+=303。 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.

第四步在N ₂下，向1-溴-2-氟-5-硝基-4-(三氟甲氧基)苯7B（25.0 g，12.1 mmol）在AcOH（50 mL）和EtOH（50 ml）中的溶液中加入鐵粉（22.0 g，0.393 mol）。將反應在25℃下攪拌3小時。將反應混合物濃縮並用水（100 ml）稀釋，用EA（30 mL*3)萃取，合併的有機層用鹽水洗滌，經無水硫酸鈉乾燥，過濾，減壓蒸發。殘餘物透過柱（5%~20% EA在PE中）純化，得到呈黃色固體狀的5-溴-4-氟-2-(三氟甲氧基)苯胺7C（21.2 g，93.8%）。 ¹HNMR (400 MHz, CDCl3) δ H 7.00-6.95 (m, 2H), 3.79 (brs, 2H)。ESI-MS(M+H)+=274.1。 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.

第五步按照實施例6的合成方法，由化合物7C出發經兩步反應得到化合物7D。 the fifth step According to the synthesis method of Example 6, starting from compound 7C, compound 7D was obtained through two-step reaction.

第六步在N ₂下，向1-(2-羥乙基)-8-碘-4,5-二氫-1H-吡唑並[4,3-h]喹唑啉-3-甲酸乙酯7F_2（126.6 mg，0.432 mmol）在DMF（6 ml）中的溶液中加入4-氟-5-(4-甲基呱嗪-1-基)-2-(三氟甲氧基)苯胺7D（60 mg，0.144 mmol）、Pd(OAc)2（3.2 mg，0.0144 mmol）、BINAP（18.0 mg，0.0289 mmol），K ₂CO ₃（59.6 mg，0.432 mmol）。將反應在80℃下攪拌4小時。將反應混合物濃縮並用水（20 mL）稀釋，用EA（10 mL*3）萃取，合併的有機層用鹽水洗滌，經無水硫酸鈉乾燥，過濾，減壓蒸發。殘餘物透過柱層析（DCM中的10% MeOH）純化以得到呈淺黃色固體狀的8-((4-氟-5-(4-甲基呱嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-1-(2-羥乙基)-4,5-二氫-1H-吡唑並[4 ,3-h]喹唑啉-3-甲酸乙酯7F（75 mg，16%）。ESI-MS(M+H)+=580。 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.

第七步按照實施例6的合成方法，由化合物7F（75 mg，0.129 mmol）出發經一步反應得到化合物7（5.2 mg，7.3%）。 ¹HNMR (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。 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.

實施例8

Example 8

第一步按照實施例6的合成方法，由化合物8-1出發經過3步得到化合物8A。 ¹HNMR (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)。 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).

第二步在25℃向8-((4-氟-5-(4-甲基呱嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-1-(2-羥乙基)-4,5-二氫-1H-吡唑並[4,3-h]喹唑啉-3-甲酸乙酯8A（100 mg，0.138 mmol）在DCM（5 mL)溶液中加入TFA（0.5 mL），在25℃下攪拌4小時。加入飽和NaHCO ₃水溶液（30 mL）淬滅反應，用DCM（15 mL*2）萃取，有機層用鹽水洗滌，經無水硫酸鈉乾燥，過濾，減壓蒸發，殘餘物透過柱層析（2%~8% MeOH的DCM溶液）純化，得到8-((4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯基)氨基)-4,5-二氫-1H-吡唑並[4,3-h]喹唑啉-3-甲酸乙酯8B（40 mg，60.2%）。ESI-MS(M+H)+=482。 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.

第三步按照實施例6的合成方法，由化合物8B出發經一步反應得到化合物8C。 third step According to the synthesis method of Example 6, starting from compound 8B, compound 8C was obtained through one-step reaction.

第三步在0℃下，向8-((4-氟-5-(4-甲基呱嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-1-(2-羥乙基)-4,5-二氫-1H-吡唑並[4,3-h]喹唑林-3-甲醯胺8C（30 mg，0.066 mmol）的DMF（3 mL）溶液中加入Cs ₂CO ₃（32.6 mg，0.1 mmol）和2-氯乙腈（6.0 mg，在1 mL DMF中，0.08 mmol）。在25℃攪拌4小時後，用水（10 mL）淬滅反應混合物。混合物用EA（15 mL*2）萃取，合併的有機層用鹽水洗滌，經無水硫酸鈉乾燥，過濾，減壓蒸發。透過柱層析（DCM:MeOH=15:1）純化殘餘物以得到呈淺黃色固體狀的1-(氰甲基)-8-((4-氟-2-甲氧基-5-(4-甲基呱嗪-1-基)苯基)氨基)-4,5-二氫-1H-吡唑並[4,3-h] 喹唑啉-3-甲醯胺8（16.7mg，51.2%）。 ¹HNMR (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。 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.

實施例9

Example 9

按照實施例8的合成方法，由化合物8-3和化合物7D出發經4步反應得到化合物9。 ¹HNMR (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。 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.

實施例10

Example 10

按照實施例7和8的合成方法，由化合物8-3和化合物10-1出發經4步反應得到化合物10。 ¹HNMR (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。 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.

實施例11

Example 11

按照實施例9的合成方法，由化合物10C出發經1步反應得到化合物11. ¹HNMR (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。 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.

實施例12

Example 12

第一步將1-羥基環丙烷-1-甲酸甲酯12A（3.0 g，25.8 mmol）溶解在MeOH（15 mL）中，並加入水合肼（6.37 g，258 mmol）。將混合物在60℃攪拌16小時，蒸發溶劑。將殘餘物與EA（30 mL）一起研磨0.5小時並過濾得到白色固體1-羥基環丙烷-1-甲醯肼12E_1 (2.8g，93.3%)。LCMS (M+H)+=117。 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.

第二步在-5-0℃、N ₂氛圍下，將1-羥基環丙烷-1-甲醯肼12E_1（3.0 g，258 mmol）在THF（15 mL）中的懸浮液逐滴加入BH3．THF（258 mL，258 mmol，1 M）。反應混合物在60℃攪拌21小時。在-5-0℃在N ₂保護下將MeOH（50 mL）滴加到反應混合物中，然後在20-25℃攪拌0.5小時，濃縮反應混合物得到殘餘物。將殘餘物溶解在50 mL MeOH中並在80℃下攪拌3小時。將混合物冷卻至25℃並蒸發得到殘餘物。將殘餘物與DCM（30 mL）一起研磨0.5小時並過濾。蒸發濾液，得到淺黃色油狀的粗產物1-(肼基甲基)環丙烷-1-醇12E_2（2.2 g，75%）。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 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).

第三步按照實施例9的合成方法，由化合物12E_2和化合物6F_3出發經4步反應得到化合物12。 ¹HNMR (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。 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.

實施例13

Example 13

按照實施例9的合成方法，由化合物10C出發經1步反應得到化合物13。 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)。 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).

實施例14

Example 14

按照實施例9的合成方法，由化合物10C出發經1步反應得到化合物14。 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。 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.

實施例15

Example 15

按照實施例9的合成方法，由化合物10C出發經1步反應得到化合物15。 ¹HNMR (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。 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.

實施例16

Example 16

第一步在0℃下，向16A（193 mg，1 mmol）的DMF（5 mL）溶液中加入Cs ₂CO ₃（650 mg，2 mmol）和(2-溴乙氧基)叔丁基二甲基矽烷（480 mg，2 mmol）。在25℃攪拌過夜，用水（10 mL）淬滅反應混合物。混合物用EA（15 mL*2）萃取，合併的有機層用鹽水洗滌，經無水硫酸鈉乾燥，過濾，減壓蒸發。透過柱層析（PE:EA=5:1）純化殘餘物以得到白色固體狀的16B（220 mg，64%）。 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.

第二步將16B 510 mg用三(二甲基氨基)甲烷（2 mL）處理，並將反應在90℃下攪拌過夜，在減壓下除去揮發物，並將殘餘物未經進一步純化地使用。 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.

第三步按照實施例10的合成方法，由化合物16B和化合物15-1出發經1步反應得到化合物16D。 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.

第四步將甲基9-(2-((叔丁基二甲基甲矽烷基)氧基)乙基)-2-((5-(4-甲基呱嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-6,9-二氫-5H -吡咯並[3,2-h]喹唑啉-7-甲酸甲酯16D（330 mg，0.5 mmol）混懸於二氧六環（5 mL）中，並在回流溫度用2N NaOH溶液（5 mL，10 mmol）處理過夜，加入H ₂O（50 mL）並將溶液用2N HCl酸化pH=4。減壓濃縮，殘餘物透過柱層析（DCM:MeOH 10:1）得到黃色固體產物9-(2-羥乙基)-2-((5-(4-甲基呱嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-6,9-二氫-5H-吡咯並[3,2-h] 喹唑啉-7-甲酸（240 mg，產率90%）。LC-MS (M+H)+: 533。 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.

第五步將9-(2-羥乙基)-2-((5-(4-甲基呱嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-6,9-二氫-5H-吡咯並[3,2-h]喹唑啉-7-甲酸（240 mg, 0.45 mmol）溶解於DMF中，向反應混合物中加入HOBt（121 mg，0.9 mmol）和EDCI（172 mg，0.9 mmol），攪拌0.5h。隨後，加入NH4OH（4 eq）。將反應混合物在室溫攪拌14小時，將反應混合物在減壓下濃縮，透過製備HPLC得到9-(2-羥乙基)-2-((5-(4-甲基呱嗪-1-基)-2-(三氟甲氧基)苯基)氨基)-6,9-二氫-5H-吡咯並[3,2-h]喹唑啉-7-甲醯胺，白色固體（106 mg，產率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)。 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).

實施例17

Example 17

第一步在5℃下，向環丙基甲醇17A（721.00 μL，9.09 mmol）的THF（24 mL）溶液中滴加LiHMDS（1M THF溶液，6.06 mL，9.09 mmol）。30分鐘後，快速加入4-氟-3-硝基溴苯（1.11 mL，9.09 mmol）並使反應混合物自然升溫至室溫並攪拌過夜。用水淬滅反應混合物並用EA萃取，收集有機層用鹽水洗滌，經無水硫酸鈉乾燥，過濾並濃縮，透過矽膠柱色譜法（PE/EA，100:0至20:1）純化殘餘物，得到3.02 g 4-溴-1-(環丙基甲氧基)-2-硝基苯17B。LCMS(M+H)+=272。 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.

第二步 N ₂氛圍下，向乾燥的1,4-二氧六環（20 mL）中加入4-溴-1-(環丙基甲氧基)-2-硝基苯（587 mg，2.16 mmol）、XANTPHOS（0.37 g，0.65 mmol）、Pd ₂(dba) ₃（0.39g，0.43mmol，Aldrich）、Cs ₂CO ₃（1.4 g，4.3 mmol）和1-甲基呱嗪（0.43 g，4.3 mmol）。在90℃加熱過夜後，將反應加水淬滅，用乙酸乙酯（50 mL×3）萃取，將有機相用硫酸鈉乾燥，濃縮，透過柱色譜法（二氯甲烷/甲醇 20:1）純化，得到1-(4-(環丙基甲氧基)-3-硝基苯基)-4-甲基呱嗪17C（383 mg，1.32 mmol，61%），為棕褐色固體。ESI-MS (M+H)+=292。 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.

第三步將1-(4-(環丙基甲氧基)-3-硝基苯基)-4-甲基呱嗪17C（291 mg，1 mmol）溶於乙酸（10 mL）和乙醇（10 mL）的混合溶劑中，加入鋅粉（650 mg，10 mmol），在80℃攪拌3h，用矽藻土過濾，濃縮，透過柱色譜法（二氯甲烷/甲醇 20:1）純化，得到2-(環丙基甲氧基)-5-(4-甲基呱嗪-1-基)苯胺17D（185 mg，0.71 mmol，71%）。ESI-MS(M+H)+=262。 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.

第四步按照實施例7的合成方法，由化合物17D和7F_2出發經2步反應得到化合物17，2-((2-(環丙基甲氧基)-5-(4-甲基呱嗪-1-基)苯基)氨基)-9-(2-羥乙基)-6,9-二氫-5H-吡咯並[3,2-h] 喹唑啉-7-甲醯胺。 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。 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.

實施例18

Example 18

透過專利CN101563351B中記載的方法制得18A。在-78℃下將18A（100mg，0.178mmol）在THF（2mL）中的攪拌溶液加入50mL密封管中的LiAlH ₄（28mg，0.712mmol）。在-78℃攪拌24小時後，將反應混合物冷卻至0℃，然後加入水（20mL）。混合物用EA（20mL*3）萃取，合併的有機層用鹽水洗滌，無水硫酸鈉乾燥，過濾，減壓蒸發。殘餘物透過柱層析（2.5%~10% MeOH的DCM溶液）純化，得到化合物18（15mg，16.2%），為淺黃色固體。 ¹HNMR (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。 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.

實施例19

Example 19

18A（0.15 g, 0.267 mmol）在 DCM（6 mL）中的攪拌溶液在 25℃下在 50 mL密封管中，EDCI（70.5 mg, 0.347 mmol）, DMAP（16.3 mg, 0.134 mmol），O-甲基-羥胺氯化物鹽（35.3mg，0.4mmol）。在30℃攪拌2小時，濃縮除去溶劑後，粗產物透過柱層析（DCM:MeOH=10:1）純化得到19（30mg）。 ¹HNMR (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。 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.

實施例20

Example 20

在圓底燒瓶中裝入17A（5 g, 0.023 mol）、環丙醇（1.32 g, 0.023 mol）、K ₂CO ₃（9.42 g, 0.068 mol）和DMF（10 mL）。反應在25℃攪拌過夜。透過加入H ₂O（100mL）淬滅反應混合物，用EA（100mL×3）萃取，用鹽水洗滌合併的有機層，用無水硫酸鈉乾燥，過濾，減壓蒸發。殘餘物透過柱（PE中的5%〜10% EA）純化以得到呈黃色固體狀的20A（5.3g，90.4%）。 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.

按照實施例17的合成方法，由化合物20A出發經4步反應得到化合物14。 ¹HNMR (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. 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.

實施例21Example 21

PLK1激酶活性測試PLK1 Kinase Activity Test

實驗材料： PLK1 Active購自CARNA； Casein Protein購自SignalChem； ADP-Glo Kinase Assay購自Promega； Kinase assay buffer III購自SignalChem； Nivo多標記分析儀(PerkinElmer)。 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).

實驗方法：experimental method:

使用試劑盒裡的kinase buffer稀釋酶，底物，ATP和抑制劑。將待測化合物用100%DMSO稀釋到1 mM作為第一個濃度，然後再用排槍進行5倍稀釋至第8個濃度，即從1 mM稀釋至0.013 μM。用1X kinase buffer 將化合物各濃度點進行20倍稀釋，配製成含有5% DMSO的化合物工作液，向微孔板中加入1 μL化合物各濃度梯度工作液，設置雙複孔。向微孔板中加入2 μl PLK1酶（15 ng），2 μl底物和ATP的混合物（20 μM ATP，0.2 μg/μl Casein protein），此時化合物終濃度梯度為10 μM稀釋至0.13 nM，反應體系置於25度反應60分鐘。反應結束後，每孔加入5 μl ADP-Glo試劑，25度繼續反應40分鐘，結束反應後每孔加入10 μL的kinase detection試劑，25度反應30分鐘後採用PerkinElmer Nivo多標記分析儀讀數化學發光，積分時間0.5秒。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.

資料分析：ANALYSE information:

利用方程式(Sample-Min)/(Max-Min)*100%將原始資料換算成抑制率，IC ₅₀的值即可透過四參數進行曲線擬合得出（GraphPad Prism中log(inhibitor) vs. response -- Variable slope模式得出）。 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).

下表示出了本申請化合物的PLK1激酶活性測試結果。化合物編號 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 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

體外細胞增殖分析In vitro cell proliferation assays

使用MTT法測定化合物對腫瘤細胞增殖的抑制活性。將處於細胞對數生長期的HT-29腫瘤細胞按一定的細胞量接種於培養板內，培育24h，加入不同濃度抑制劑，細胞在37℃、5% CO ₂條件下繼續培養48h，每孔加入20 μL MTT溶液繼續培養4h，用DMSO溶解結晶，用酶聯免疫檢測儀在570 nm波長處測定其OD值計算IC ₅₀。 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 .

下表示出了本申請化合物的HT-29腫瘤細胞增殖抑制活性測試結果。化合物編號 HT-29 IC ₅₀(nM) 6 269 10 111 11 232.2 12 75 15 71 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

無none

Claims

一種如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物：

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

如請求項1所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，R ^1-1獨立地為F、Cl、Br或I，例如F；及/或，R ^1-1獨立地為3~6元環烷烴，該3~6元環烷烴為環丙烷、環丁烷或環戊烷，例如環丙烷或環丁烷；及/或，當R ¹為C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基；及/或，當R ¹為被一個或多個R ^1-1取代的C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基；及/或，當R ¹為3~6元環烷基氧基時，該3~6元環烷氧基為環丙基氧基、環丁基氧基或環戊基氧基，例如環丙基氧基或環丁基氧基；及/或，當R ²為鹵素時，該鹵素為F、Cl、Br或I；及/或，當R ²為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基；及/或，當R ^3-1為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基；及/或，當R ³為被一個或多個R ^3-1取代的5~10元雜環烷基時，該5~10元雜環烷基為6~9元雜環烷基，例如含兩個N的6 ~9元雜環烷基，又例如呱嗪基、六氫噠嗪基、六氫嘧啶基、3,8-二氮雜雙環[3.2.1]辛烷基、八氫吡咯[1,2-a ]吡嗪基、2,6-二氮雜螺[3.4]辛烷基、3,6-二氮雜雙環[3.2.0]庚烷基、1,6-二氮雜螺[3.4]辛烷基或八氫吡咯[3,4-c ]吡咯基；及/或，當R ^4-1為鹵素時，該鹵素為F、Cl、Br或I，例如F；及/或，當R ^4-1為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基或乙基；及/或，當R ^4-2為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基或乙基；及/或，當R ^4-2為鹵素時，該鹵素為F、Cl、Br或I，例如F；及/或，當R ^4-3為鹵素時，該鹵素為F、Cl、Br或I，例如F；及/或，當R ⁴為3~6元環烷烴時，該3~6元環烷烴為環丙烷、環丁烷或環戊烷，例如環丙烷或環丁烷；及/或，當R ⁴為被一個或多個R ^4-1取代的3~6元環烷烴時，該3~6元環烷烴為環丙烷、環丁烷或環戊烷，例如環丙烷或環丁烷；及/或，當R ⁴為被一個或多個R ^4-2取代的3~6元雜環烷烴時，該3~6元雜環烷烴為包含一個N或O的4元雜環烷烴或包含一個N或O的5元雜環烷烴；及/或，當R ⁵為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、異丙基或叔丁基，例如甲基或乙基；及/或，當R ⁵為C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基。 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.

如請求項1所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，該R ¹為

、

、

、

、

、

或

，例如

、

或

；及/或，R ³為

、

、

、

、

、

、

、

、

或

；及/或，R ³為

、

、

、

、

、

、

、

、

或

；及/或，R ³為

、

、

、

、

、

、

、

或

；及/或，當R ⁴為被一個或多個R ^4-1取代的3~6元環烷烴時，該被一個或多個R ^4-1取代的3~6元環烷烴為

、

、

或

；及/或，當R ⁴為3~6元雜環烷烴時，該3~6元雜環烷烴為

、

或

；及/或，當R ⁴為被一個或多個R ^4-2取代的3~6元雜環烷烴時，該被一個或多個R ^4-2取代的3~6元雜環烷烴為

、

或

；及/或，當R ⁴為被一個或多個R ^4-3取代的C ₁~C ₄烷基時，該被一個或多個R ^4-3取代的C ₁~C ₄烷基為

。 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

.

如請求項1所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，R ⁴為氰基、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、被一個或多個R ^4-2取代的3~6元雜環烷烴，或被一個或多個R ^4-3取代的C ₁~C ₄烷基；及/或，R ^4-1為鹵素或羥基；及/或，R ^4-2為C ₁~C ₄烷基；及/或，R ^4-3為羥基；及/或，R ⁵為H、羥基或C ₁~C ₄烷氧基。 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.

如請求項1所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，R ⁴為氰基、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、被一個或多個R ^4-2取代的3~6元雜環烷烴，或被一個或多個R ^4-3取代的C ₁~C ₄烷基； R ^4-1為鹵素或羥基； R ^4-2為C ₁~C ₄烷基； R ^4-3為羥基； R ⁵為H、羥基或C ₁~C ₄烷氧基。 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.

如請求項5所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中R ⁴選自下組：氰基、

、

和

。 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

.

如請求項1所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其具有下式：

。 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:

.

如請求項7所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中R ¹為被一個或多個R ^1-1取代的C ₁~C ₄烷氧基。 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 .

如請求項7所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中R ²為H或鹵素。 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.

如請求項7所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中R ⁴選自下組：氰基、

、

和

。 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

.

一種吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，該吡唑並喹唑啉類化合物選自如下任一所示：

。 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:

.

一種如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物的製備方法，其包括下述步驟，有機溶劑中，鈀類催化劑的作用下，鹼試劑中，將化合物1g、配體試劑與R ³-H進行偶聯反應，製得化合物I即可；

其中，R ¹、R ²、R ³、R ⁴或R ⁵的定義如請求項1~6所述；X為鹵素。 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.

如請求項12所述的製備方法，其中，該鈀類催化劑為三二亞苄基丙酮二鈀；及/或，該有機溶劑為一四二氧六環；及/或，該鹼試劑為碳酸銫；及/或，該配體試劑為4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽。 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.

一種如上請求項1~11中任一項所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物在製備PLK1抑制劑中的用途；該抑制劑較佳為在體外使用的抑制劑。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.

一種藥物組合物，其中，其包含如請求項1~11所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物和藥用輔料。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.

一種如請求項1~11中任一項所述的如式I所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物在製備藥物中的用途；該藥物為治療下述至少一種疾病的藥物：乳腺癌、***癌、肺癌、結直腸癌、肝癌、胰腺癌、胃癌、食管癌、黑色素瘤、多發性骨髓瘤、白血病和淋巴癌。 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.

一種如式II所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物；

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’為被一個R ^3-1取代或未取代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；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。 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.

如請求項17所述的如式II所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物的製備方法，其中，R ^1-1為F、Cl、Br或I，例如F；及/或，當R ¹為被一個或多個R ^1-1取代的C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基；及/或，當R ²為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基；及/或，R ^3-1為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基；及/或，當R ^4-3為鹵素時，該鹵素為F、Cl、Br或I；及/或，當R ^4’獨立地為被一個R ^4-3取代的C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基；及/或，當R ⁵為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、異丙基或叔丁基，例如甲基或乙基；及/或，當R ⁵為C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基。 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.

如請求項17所述的如式II所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，R ¹為

、

，例如

；及/或，當R ^3’為7~9元雜螺環烷基時，該7~9元雜螺環烷基為含兩個氮原子的7~9元雜螺環烷基，例如

或

；及/或，當R ^3’為被一個R ^3-1取代的7~9元雜螺環烷基時，該被一個R ^3-1取代或未取代7~9元雜螺環烷基為含兩個氮原子的被一個R ^3-1取代的7~9元雜螺環烷基，例如

或

；及/或，當R ^3’為7~9元雜橋環烷基時，該7~9元雜橋環烷基為含兩個N的7~9元雜橋環烷基，例如

；及/或，當R ^3’為被一個R ^3-1取代的7~9元雜橋環烷基時，該被一個R ^3-1取代的7~9元雜橋環烷基為含兩個氮的被一個R ^3-1取代的7~9元雜橋環烷基，例如

、或

；及/或，R ⁴為-CH ₂OH。 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.

如請求項17所述的如式II所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，該如式II所示吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物可如下任一所示：

。 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:

.

一種如式II所示的吡唑並喹唑啉類化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物的製備方法，其包括下述步驟，有機溶劑中，鹼試劑中，鈀類催化劑的作用下，將化合物1g、配體試劑與R ³-H進行偶聯反應，製得化合物II即可；

其中，R ¹、R ²、R ^3’、R ^4’或R ⁵的定義如請求項12~15所述；X為鹵素。 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.

如請求項21所述的製備方法，其中，該鈀類催化劑為三二亞苄基丙酮二鈀；及/或，該有機溶劑為一四二氧六環；及/或，該鹼試劑為碳酸銫；及/或，該配體試劑為4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽。 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.

一種如式III所示的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物：

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、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。 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.

如請求項23所述的如式III所示的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，R ^1-1獨立地為F、Cl、Br或I，例如F；及/或，R ^1-1獨立地為3~6元環烷烴為環丙烷、環丁烷或環戊烷，例如環丙烷或環丁烷；及/或，當R ¹為C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基；及/或，當R ¹為被一個或多個R ^1-1取代的C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基；及/或，當R ²為鹵素時，該鹵素為F、Cl、Br或I；及/或，當R ²為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基；及/或，當R ^3-1為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基；及/或，當R ³為被一個或多個R ^3-1取代的5~10元雜環烷基時，該5~10元雜環烷基為6~9元雜環烷基，例如含兩個N的6~9元雜環烷基，又例如呱嗪基、六氫噠嗪基、六氫嘧啶基、3,8-二氮雜雙環[3.2.1]辛烷基、八氫吡咯[1,2-a ]吡嗪基、2,6-二氮雜螺[3.4]辛烷基、3,6-二氮雜雙環[3.2.0]庚烷基、1,6-二氮雜螺[3.4]辛烷基或八氫吡咯[3,4-c]吡咯基；及/或，當R ^4-1為鹵素時，該鹵素為F、Cl、Br或I，例如F；及/或，當R ^4-1為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基或乙基；及/或，當R ^4-2為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基，例如甲基或乙基；及/或，當R ^4-2為鹵素時，該鹵素為F、Cl、Br或I，例如F；及/或，當R ^4-3為鹵素時，該鹵素為F、Cl、Br或I，例如F；及/或，當R ⁴為3~6元環烷烴時，該3~6元環烷烴為環丙烷、環丁烷或環戊烷，例如環丙烷或環丁烷；及/或，當R ⁴為被一個或多個R ^4-1取代的3~6元環烷烴時，該3~6元環烷烴為環丙烷、環丁烷或環戊烷，例如環丙烷或環丁烷；及/或，當R ⁴為被一個或多個R ^4-2取代的3~6元雜環烷烴時，該3~6元雜環烷烴為包含一個N或O的4元雜環烷烴或包含一個N或O的5元雜環烷烴；及/或，當R ⁵為C ₁~C ₄烷基時，該C ₁~C ₄烷基為甲基、乙基、異丙基或叔丁基，例如甲基或乙基；及/或，當R ⁵為C ₁~C ₄烷氧基時，該C ₁~C ₄烷氧基為甲氧基、乙氧基、異丙氧基或叔丁氧基，例如甲氧基。 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.

如請求項23所述的如式III所示的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，該R ¹為

、

或

，例如

、

或

；及/或，R ³為

、

或

；及/或，R ³為

、

或

；及/或，R ³為

、

或

、

或

；及/或，當R ⁴為3~6元雜環烷烴時，該3~6元雜環烷烴為

、

或

。 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

,

or

,

or

.

如請求項23所述的如式III所示的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，R ⁴為氰基、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，或被一個或多個R ^4-3取代的C ₁~C ₄烷基；及/或，R ^4-1為鹵素或羥基；及/或，R ^4-2為C ₁~C ₄烷基；及/或，R ^4-3為羥基；及/或，R ⁵為H、羥基或C ₁~C ₄烷氧基。 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.

如請求項23所述的如式III所示的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中，R ⁴為氰基、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、被一個或多個R ^4-2取代的3~6元雜環烷烴，或被一個或多個R ^4-3取代的C ₁~C ₄烷基； R ^4-1為鹵素或羥基； R ^4-2為C ₁~C ₄烷基； R ^4-3為羥基； R ⁵為H、羥基或C ₁~C ₄烷氧基。 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.

如請求項23所述的如式III所示的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，其中該化合物為：

。 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:

.

一種如請求項1~28中任一項所述的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物在製備PLK1抑制劑中的用途；該抑制劑較佳為在體外使用的抑制劑。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.

一種藥物組合物，其包含如請求項1~28任一項所述的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物和藥用輔料。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.

一種如請求項1~28任一項所述的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物在製備藥物中的用途；該藥物為治療下述至少一種疾病的藥物：乳腺癌、***癌、肺癌、結直腸癌、肝癌、胰腺癌、胃癌、食管癌、卵巢癌、黑色素瘤、骨肉瘤、多發性骨髓瘤、白血病和淋巴癌。 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.

一種藥物組合，其包含如請求項1~28任一項所述的化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物，以及一種或多種化療劑，該一種或多種化療劑與該化合物、其藥學上可接受的鹽、其溶劑合物或其藥學上可接受的鹽的溶劑合物同時、分別或連續使用。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.