TW202229268A

TW202229268A - Cdk2 inhibitor and preparation method thereof

Info

Publication number: TW202229268A
Application number: TW110148178A
Authority: TW
Inventors: 鄒昊; 劉浩淼; 李雲飛; 龔紅龍; 張超; 龐夏明; 張芳
Original assignee: 大陸商上海拓界生物醫藥科技有限公司
Priority date: 2020-12-22
Filing date: 2021-12-22
Publication date: 2022-08-01
Also published as: WO2022135442A1

Abstract

The present disclosure provides CDK2 inhibitor and preparation method thereof. Specifically, the present disclosure provides a compound shown in formula I or a pharmaceutically acceptable salt or tautomer thereof, wherein each group is as defined in the present disclosure. The compound shown in formula I can be used as a cyclin dependent kinase inhibitor to prevent and / or treat diseases related to protein dependent kinase or cyclin, such as cell proliferative diseases, cancer or immune diseases.

Description

CDK2抑制劑及其製備方法 CDK2 inhibitor and preparation method thereof

本揭露屬於醫藥領域，且關於一種CDK2抑制劑。 The present disclosure belongs to the field of medicine, and relates to a CDK2 inhibitor.

細胞週期蛋白-依賴性激酶(CDK)是絲胺酸/蘇胺酸激酶亞家族的成員，每個CDK/細胞週期蛋白複合物負責細胞週期內特定期的轉換或進展，其在調節真核細胞***和增殖中發揮重要作用。細胞週期蛋白-依賴性激酶催化單元被稱為細胞週期蛋白的調節亞基啟動。已經鑑定出至少16種哺乳動物細胞週期蛋白(Annu.Rev.Pharmacol.Toxicol.(1999)39：295-312)。細胞週期蛋白B/CDK1、細胞週期蛋白A/CDK2、細胞週期蛋白E/CDK2、細胞週期蛋白D/CDK4、細胞週期蛋白D/CDK6和可能的其他heterodynes是細胞週期進展的重要調節因子。細胞週期蛋白/CDK heterodynes的其他功能包括轉錄調節、DNA修復、分化和凋亡(Annu.Rev.Cell.Dev.Biol.(1997)13：261-291)。 Cyclin-dependent kinases (CDKs) are members of the serine/threonine kinase subfamily, and each CDK/cyclin complex is responsible for the transition or progression of a specific phase within the cell cycle, which regulates eukaryotic cells. plays an important role in division and proliferation. Cyclin-dependent kinase catalytic units are activated by regulatory subunits called cyclins. At least 16 mammalian cyclins have been identified (Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and possibly other heterodynes are important regulators of cell cycle progression. Other functions of cyclin/CDK heterodynes include transcriptional regulation, DNA repair, differentiation and apoptosis (Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).

近年來，乳腺癌治療領域最大的進展無疑是CDK4/6單用或聯合內分泌治療在激素受體陽性晚期乳腺癌，如帕博西尼(palbociclib)、瑞博西尼(ribociclib)和玻瑪西尼(abemaciclib)已被批准與芳香酶抑制劑組合用於治療絕經後婦女的激素受體(HR)-陽性、人類表皮生長因子受體2 (HER2)-陰性晚期或轉移性乳腺癌，並且帕博西尼和玻瑪西尼(abemaciclib)已被批准與氟維司群組合用於在內分泌療法後疾病進展後治療絕經後婦女的激素受體(HR)-陽性、人類表皮生長因子受體2(HER2)-陰性晚期或轉移性乳腺癌(Nature Reviews(2016)13：417-430、J Clin Oncol 2017,35,2875-2884)。儘管CDK4/6抑制劑在***受體ER陽性轉移性乳腺癌中顯示出顯著的臨床功效，但與其他激酶一樣，它們的作用可能隨著時間的推移被原發性或獲得性抗性的發展限制。 In recent years, the biggest progress in the field of breast cancer treatment is undoubtedly CDK4/6 alone or in combination with endocrine therapy in hormone receptor-positive advanced breast cancer, such as palbociclib (palbociclib), ribociclib (ribociclib and pomaciclib) Abemaciclib has been approved in combination with an aromatase inhibitor for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 in postmenopausal women (HER2)-negative advanced or metastatic breast cancer, and palbociclib and abemaciclib have been approved in combination with fulvestrant for the treatment of hormone receptors in postmenopausal women following disease progression on endocrine therapy Human (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (Nature Reviews (2016) 13:417-430, J Clin Oncol 2017, 35, 2875-2884). Although CDK4/6 inhibitors have shown significant clinical efficacy in estrogen receptor ER-positive metastatic breast cancer, as with other kinases, their effects may be mediated over time by primary or acquired resistance Development restrictions.

CDK2的過表達與細胞週期的異常調節有關。細胞週期蛋白E/CDK2複合物在調節G1/S轉換、組蛋白生物合成和中心體複製中起重要作用。細胞週期蛋白D/Cdk4/6和細胞週期蛋白E/Cdk2對Rb的進行性磷酸化釋放G1轉錄因子E2F，並促進S期進入。在早期S期期間細胞週期蛋白A/CDK2的啟動促進內源性受質的磷酸化，其允許DNA複製和E2F的失活，以完成S期(Nat.Rev.Drug.Discov.2015；14(2)：130-146)。細胞週期蛋白E在多種癌症中過度表達，特別是乳腺癌、肺癌、白血病、淋巴瘤(郭翠萍等，細胞週期蛋白E的調控與惡性腫瘤.國際腫瘤學雜誌，2012,39(005)：337-340)，細胞週期蛋白E的擴增或過表達也與卵巢癌、胃癌、子宮內膜癌和其他癌症的不良預後有關。 Overexpression of CDK2 is associated with dysregulation of the cell cycle. The cyclin E/CDK2 complex plays an important role in regulating G1/S transition, histone biosynthesis, and centrosome duplication. Progressive phosphorylation of Rb by cyclin D/Cdk4/6 and cyclin E/Cdk2 releases the G1 transcription factor E2F and promotes S-phase entry. Initiation of cyclin A/CDK2 during early S phase promotes phosphorylation of endogenous substrates, which allows DNA replication and inactivation of E2F to complete S phase (Nat. Rev. Drug. Discov. 2015; 14( 2): 130-146). Cyclin E is overexpressed in a variety of cancers, especially breast cancer, lung cancer, leukemia, and lymphoma (Guo Cuiping et al. Regulation of Cyclin E and Malignancies. International Journal of Oncology, 2012, 39(005): 337- 340), amplification or overexpression of cyclin E has also been associated with poor prognosis in ovarian, gastric, endometrial and other cancers.

研究表明，抑制CDK2激酶會誘導腫瘤細胞調亡，但對於正常細胞只會造成較小的損傷。CDK激酶的單體形式是無活性的，而細胞週期蛋白A/E與CDK2結合並促發磷酸化的結合啟動CDK2。CDK2還可結合細胞週期蛋白A用於S期的整個進展並參與DNA修復。近幾年各大公司分別鑑定發現了一系列選擇性抑制CDK 2的抑制劑，用於治療癌症等疾病，如Seliciclib、Dinaciclib等，但是為了達到更好的癌症治療效果的目的，更好的滿足市場需求，仍需要開發出新一代的高效低毒的選擇性CDK2抑制劑。 Studies have shown that inhibition of CDK2 kinase induces tumor cell apoptosis, but causes only minor damage to normal cells. The monomeric form of CDK kinase is inactive, whereas cyclin A/E binds to CDK2 and initiates phosphorylation to initiate CDK2. CDK2 also binds cyclin A for the entire progression of S phase and is involved in DNA repair. In recent years, major companies have identified and discovered a series of inhibitors that selectively inhibit CDK 2 for the treatment of diseases such as cancer. However, in order to achieve better cancer treatment effect and better meet market demand, it is still necessary to develop a new generation of selective CDK2 inhibitors with high efficiency and low toxicity.

本揭露提供式I化合物或其可藥用鹽、互變異構體： The present disclosure provides compounds of formula I or pharmaceutically acceptable salts, tautomers thereof:

其中，-L₁-、-L₂-各自獨立選自鍵、C₁-C₆亞(伸)烷基、-O-和-NH-，該C_1-6亞烷基(伸)視需要地被一個或多個選自羥基、烷基、烷氧基、鹵烷基、鹵烷氧基、鹵素、羥基、氰基、胺基和硝基的取代基取代； Wherein, -L ₁ -, -L ₂ - are each independently selected from bond, C ₁ -C ₆ (extended) alkylene, -O- and -NH-, the C _1-6 alkylene (extended) is optional is substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, amino and nitro;

R₁選自環烷基、雜環基、芳基和雜芳基，其中該環烷基、雜環基、芳基或雜芳基視需要地被一個或多個Z取代； R is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with _one or more Z;

一些實施方案中，R₂、R₃各自獨立選自氫、氘、鹵素、烷基、氰基、羥基、硝基、側氧基、環烷基、雜環基、芳基和雜芳基，其中該烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自鹵素、烷基、烷氧基、氰基、胺基、硝基、羥基、羥烷基、羧基、環烷基、雜環基、芳基和雜芳基的取代基取代； In some embodiments, R ₂ , R ₃ are each independently selected from hydrogen, deuterium, halogen, alkyl, cyano, hydroxy, nitro, pendant oxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally selected from one or more groups selected from halogen, alkyl, alkoxy, cyano, amine, nitro, hydroxy, hydroxyalkane Substituent substitution of radicals, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

一些實施方案中，R₂、R₃共同構成3-8員環，該3-8員環視需要地被一個或多個Z取代； In some embodiments, R ₂ , R ₃ together form a 3-8 membered ring, which is optionally substituted with one or more Z;

一些實施方案中，R₄選自單環和多環，視需要地被一個或多個Z取代，且R₅選自氫、氘、烷基和鹵素，其中該烷基視需要被一個或多個選自鹵素、烷基、烷氧基、氰基、胺基、硝基、羥基、羥烷基、羧基、環烷基、雜環基、芳基和雜芳基的取代基取代， _In some embodiments, R is selected from monocyclic and polycyclic rings, optionally substituted with one or more Z, and R is selected from hydrogen, _deuterium , alkyl, and halogen, wherein the alkyl is optionally substituted by one or more substituted with a substituent selected from the group consisting of halogen, alkyl, alkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

條件是，當R₄選自單環時，R₄選自

，且R₁選自

或 _Provided that when R4 is selected from monocyclic ring, _R4 is selected from

, and R ₁ is selected from

or

R₆選自氫、氘、鹵素和烷基； R is selected from hydrogen, deuterium, halogen and alkyl _;

R₇相同或不同，且R₇各自獨立選自氫、氘、鹵素、羥基、硝基、氰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、SR'、SOR'、SO₂R'、SO₂NR'(R")、NR'(R")、COOR'、CONR'(R")和-(P=O)R'(R")，該烷基、烷氧基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自鹵素、羥基、側氧、硝基、氰基、SR'、SOR'、SO₂R'、SO₂NR'(R")、NR'(R")、COR'、COOR'、CONR'(R")或-(P=O)R'(R")的取代基取代；或任意兩個相鄰R₇共同構成3-8員環，該3-8員環視需要地被一個或多個Z取代； R ₇ are the same or different, and each R ₇ is independently selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR ', SOR', SO ₂ R', SO ₂ NR'(R"), NR'(R"), COOR', CONR'(R"), and -(P=O)R'(R"), the Alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, as desired, is optionally substituted by one or more groups selected from halogen, hydroxy, pendant oxygen, nitro, cyano, SR', SOR', SO ₂ R', SO ₂ NR'(R"), NR'(R"), COR', COOR', CONR'(R") or -(P=O)R'(R") substituent; Or any two adjacent R ₇ together form a 3-8 membered ring, the 3-8 membered ring is optionally substituted by one or more Z;

一些實施方案中，R₄、R₅與它們所連接的N原子共同構成多環，視需要地被一個或多個Z取代； In some embodiments, R ₄ , R ₅ and the N atom to which they are attached together form a polycyclic ring, optionally substituted with one or more Z;

Z選自鹵素、氰基、羥基、硝基、側氧基、烷基、鹵烷基、羥烷基、環烷基、雜環基、芳基、雜芳基、SR'、SOR'、SO₂R'、SO₂NR'(R")、NR'(R")、COR'、COOR'、CONR'(R")和-(P=O)R'(R")； Z is selected from halogen, cyano, hydroxy, nitro, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR', SOR', SO ₂ R', SO ₂ NR'(R"), NR'(R"), COR', COOR', CONR'(R") and -(P=O)R'(R");

每個R'或R"獨立地選自氫、氘、羥基、烷基、烷氧基、環烷基、雜環基、芳基和雜芳基，該烷基、烷氧基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自鹵素、羥基、側氧、硝基和氰基的取代基取代； Each R' or R" is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the alkyl, alkoxy, cycloalkyl , heterocyclyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, pendant oxygen, nitro and cyano;

本揭露中，式I所示的化合物不是

和 In the present disclosure, the compound represented by formula I is not

and

一些實施方案中，化合物I為： In some embodiments, Compound 1 is:

其中，R₇相同或不同，且R₇各自獨立選自氫、氘、鹵素、C_1-6烷基、C_3-7環烷基、3-7員雜環基、5-12員芳基、5-12員雜芳基和-(P=O)R'(R")，該C_3-7環烷基、3-7員雜環基、5-12員芳基、5-12員雜芳基視需要被一個或多個選自鹵素、羥基、側氧、硝基、烷基和烷氧基的取代基取代。 Wherein, R ₇ is the same or different, and R ₇ is each independently selected from hydrogen, deuterium, halogen, C _1-6 alkyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, 5-12 membered aryl , 5-12-membered heteroaryl and -(P=O)R'(R"), the C _3-7 cycloalkyl, 3-7-membered heterocyclyl, 5-12-membered aryl, 5-12-membered Heteroaryl groups are optionally substituted with one or more substituents selected from halogen, hydroxy, pendant oxygen, nitro, alkyl, and alkoxy.

一些實施方案中，化合物IIa包括： In some embodiments, Compound IIa includes:

和

；

and

;

化合物IIb包括： Compound IIb includes:

和

。

and

.

一些實施方案中，R₇相同或不同，且R₇各自獨立選自氫、氘、氟、氯、溴、甲基、乙基、丙基、異丙基、-(P=O)R'(R")、

和

；其中， In some embodiments, _R7 is the same or different, and each _R7 is independently selected from hydrogen, deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, -(P=O)R'( R"),

and

;in,

R'或R"獨立地選自氫、氘、甲基、乙基、丙基、異丙基和苯基； R' or R" is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl and phenyl;

X選自-CH和N； X is selected from -CH and N;

Y選自-CH₂-、-CH(CH₃)-、-NH-、-N(CH₃)-和-O-。 Y is selected from _-CH2- , -CH( _CH3 )-, -NH-, -N( _CH3 )- and -O-.

一些具體的實施方案中R₇相同或不同，且R₇各自獨立選自氫、氘、甲基、-(P=O)(CH₃)₂、

和

。 In some specific embodiments R ₇ is the same or different, and each R ₇ is independently selected from hydrogen, deuterium, methyl, -(P=O)(CH ₃ ) ₂ ,

and

.

一些實施方案中，化合物I為： In some embodiments, Compound 1 is:

其中，環A選自C_3-7環烷基、5-8員芳基和5-8員雜環基，該C_3-7環烷基、5-8員芳基、5-8員雜環基視需要地被一個或多個Z取代。 Wherein, ring A is selected from C _3-7 cycloalkyl, 5-8-membered aryl and 5-8-membered heterocyclic group, the C _3-7 cycloalkyl, 5-8-membered aryl, 5-8-membered heterocyclic Cyclyl is optionally substituted with one or more Z.

一些實施方案中，化合物IIc包括： In some embodiments, Compound IIc comprises:

和

；

and

;

該化合物IId包括： The compound IId includes:

和

。

and

.

一些實施方案中，環A選自5-8員雜環基，該5-8員雜環基視需要地被選自鹵素、羥基、側氧、硝基、烷基和烷氧基中的一個或多個取代基所取代。 In some embodiments, Ring A is selected from a 5-8 membered heterocyclyl optionally selected from one of halogen, hydroxy, pendant oxygen, nitro, alkyl, and alkoxy or more substituents.

一些實施方案中，環A選自

和

；其中，Y選自-CH₂-、-CH(CH₃)-、-NH-、-N(CH₃)-和-O-。 In some embodiments, Ring A is selected from

and

; wherein Y is selected from -CH ₂ -, -CH(CH ₃ )-, -NH-, -N(CH ₃ )- and -O-.

一些具體的實施方案中，環A選自

和

。 In some specific embodiments, Ring A is selected from

and

.

一些實施方案中，R₆選自氫、氘、鹵素和C_1-6烷基，例如氫、氘、氟、氯、溴、甲基、乙基、丙基和異丙基。 In some embodiments, R ₆ is selected from hydrogen, deuterium, halogen, and C _1-6 alkyl, such as hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, and isopropyl.

一些具體的實施方案中，R₆選自甲基。 In some specific embodiments, R ₆ is selected from methyl.

另一些實施方案中，當R₄選自多環時，R₁選自C₆-C₁₂芳基和5-10員雜芳基，其中該C₆-C₁₂芳基或5-10員雜芳基視需要地被一個或多個Z取代。 In other embodiments, when R ₄ is selected from polycyclic, R ₁ is selected from C ₆ -C ₁₂ aryl and 5-10 membered heteroaryl, wherein the C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl Aryl is optionally substituted with one or more Z.

一些具體的實施方案中，C₆-C₁₂芳基或5-10員雜芳基選自吡唑基、***基、異噁唑基(isoxazolyl)、噁唑基(oxazolyl)、噻唑基、噻二唑基(thiadiazolyl)、咪唑基、吡啶基、吡嗪基、吲唑基、苯并咪唑基和苯基，較佳異噁唑基，其中該C₆-C₁₂芳基或5-10員雜芳基視需要地被一個或多個Z取代。 In some specific embodiments, C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl is selected from pyrazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, Thiadiazolyl, imidazolyl, pyridyl, pyrazinyl, indazolyl, benzimidazolyl and phenyl, preferably isoxazolyl, wherein the _C6 - _C12aryl or 5-10 Member heteroaryl is optionally substituted with one or more Z.

一些實施方案中，化合物I為： In some embodiments, Compound 1 is:

一些實施方案中，化合物III包括 In some embodiments, Compound III includes

和

。

and

.

一些實施方案中Z選自氟、氯、溴、甲基、乙基、丙基、異丙基、氰基、羥基、鹵烷基、-(P=O)R'(R")、

和

的取代基取代；其中， In some embodiments Z is selected from fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, cyano, hydroxy, haloalkyl, -(P=O)R'(R"),

and

substituted by the substituents; wherein,

X選自-CH和N； X is selected from -CH and N;

一些具體的實施方案中，Z選自甲基、-(P=O)(CH₃)₂、

和

的取代基取代。 In some specific embodiments, Z is selected from methyl, -(P=O)(CH ₃ ) ₂ ,

and

Substituents are substituted.

一些具體的實施方案中，Z選自甲基。 In some specific embodiments, Z is selected from methyl.

一些實施方案中，化合物III為

。 In some embodiments, Compound III is

.

一些實施方案中，R₄選自螺環、稠環和橋環，並視需要地被一個或多個Z取代，該螺環、稠環或橋環由任一個的碳或氮原子連接到式I結構中。 _In some embodiments, R is selected from spiro, fused and bridged rings, optionally substituted with one or more Z, which spiro, fused or bridged rings are attached to the formula by any carbon or nitrogen atom. I structure.

一些實施方案中，螺環包括螺環烷基或螺雜環基，選自[3.3]、[3.4]、[3.5]、[3.6]、[4.4]、[4.5]、[4.6]、[5.5]、[5.6]和[6.7]螺環。 In some embodiments, the spiro ring includes spirocycloalkyl or spiroheterocyclyl selected from [3.3], [3.4], [3.5], [3.6], [4.4], [4.5], [4.6], [5.5 ], [5.6] and [6.7] Spiro.

一些具體的實施方案中，螺環選自

、

、

、

、

、

、

、

、

和

，螺環藉由任一*表示的連接位點連接到式I結構，並視需要地進一步被一個或多個Z取代。 In some specific embodiments, the spiro ring is selected from

,

and

, the spiro ring is attached to the structure of Formula I via any of the attachment sites represented by *, and is optionally further substituted with one or more Zs.

一些具體的實施方案中，螺環選自

和

，該螺環藉由*表示的連接位點連接到式I結構中。 In some specific embodiments, the spiro ring is selected from

and

, the spiro ring is connected to the structure of formula I through the attachment site indicated by *.

一些實施方案中，稠環包括稠環烷基或稠雜環基，選自二環和三環，視需要地進一步被一個或多個Z取代。 In some embodiments, fused rings include fused cycloalkyl or fused heterocyclyl, selected from bicyclic and tricyclic rings, optionally further substituted with one or more Z.

一些具體的實施方案中，稠環選自

、

、

、

、

和

，稠環藉由任一*表示的連接位點連接到式I結構中，視需要地進一步被一個或多個Z取代。 In some specific embodiments, the fused ring is selected from

,

and

, the fused ring is attached to the structure of Formula I through any of the attachment sites represented by *, optionally further substituted with one or more Zs.

一些具體的實施方案中，稠環選自

，藉由*表示的連接位點連接到式I結構中。 In some specific embodiments, the fused ring is selected from

, linked to the structure of formula I through the linking site indicated by *.

一些實施方案中，橋環包括橋環烷基或橋雜環基，選自二環和三環，每條橋上碳原子數為0-3個，視需要地被一個或多個Z取代。 In some embodiments, the bridged ring includes a bridged cycloalkyl or bridged heterocyclyl group selected from bicyclic and tricyclic rings, each bridge having 0-3 carbon atoms, optionally substituted with one or more Z.

一些具體的實施方案中，橋環選自

、

、

、

和

，藉由任一*表示的連接位點連接到式I結構中，視需要地進一步被一個或多個Z取代。 In some specific embodiments, the bridged ring is selected from

,

and

, is attached to the structure of Formula I via any of the attachment sites indicated by *, optionally further substituted with one or more Zs.

一些具體的實施方案中，橋環選自

和

，藉由*表示的連接位點連接到式I結構中。 In some specific embodiments, the bridged ring is selected from

and

, linked to the structure of formula I through the linking site indicated by *.

一些實施方案中，R₅選自氫、氘、鹵素和C_1-6烷基。 In some embodiments, R ₅ is selected from hydrogen, deuterium, halogen and C _1-6 alkyl.

一些實施方案中，R₅選自氫、氘、氟、氯、溴、甲基、乙基、丙基和異丙基。 _In some embodiments, R5 is selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, and isopropyl.

一些具體的實施方案中，R₅選自氫。 _In some specific embodiments, R5 is selected from hydrogen.

另一些實施方案中，當R₄、R₅與它們所連接的N原子共同構成的多環時，該化合物I為

， In other embodiments, when R ₄ , R ₅ and the N atom to which they are attached together form a polycyclic ring, the compound I is

,

其中環C選自

、

、

、

、

、

、

、 wherein ring C is selected from

,

、

、

、

、

、

和

；視需要地被一個或多個Z取代。

,

and

; optionally replaced by one or more Z.

一些實施方案中，化合物IV化合物包括 In some embodiments, Compound IV compounds include

和

。

and

.

一些實施方案中，R₁選自C₆-C₁₂芳基和5-10員雜芳基，其中該C₆-C₁₂芳基或5-10員雜芳基視需要地被一個或多個Z取代。 In some embodiments, R ₁ is selected from C ₆ -C ₁₂ aryl and 5-10 membered heteroaryl, wherein the C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl is optionally separated by one or more Z replaces.

一些具體的實施方案中，R₁選自吡唑基、***基、異噁唑基(isoxazolyl)、噁唑基(oxazolyl)、噻唑基、噻二唑基(thiadiazolyl)、咪唑基、吡啶基、吡嗪基、吲唑基、苯并咪唑基和苯基，視需要地被一個或多個Z取代。 In some specific embodiments, R ₁ is selected from pyrazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridyl , pyrazinyl, indazolyl, benzimidazolyl and phenyl, optionally substituted with one or more Z.

一些實施方案中，化合物IV為： In some embodiments, Compound IV is:

一些實施方案中，化合物IVa化合物包括： In some embodiments, Compound IVa compounds include:

和

。

and

.

和

and

substituted by the substituents; wherein,

X選自-CH和N； X is selected from -CH and N;

一些具體的實施方案中，Z選自甲基、-(P=O)(CH₃)₂、

和

and

Substituents are substituted.

一些實施方案中，-L₂-選自鍵、-CH₂-、-CH(CH₃)-、-CH₂-CH₂-、-O-和-NH-。 In some embodiments, _-L2- is selected from bond, _-CH2- , -CH( _CH3 )-, _-CH2 _- CH2-, -O-, and -NH-.

一些具體的實施方案中，-L₂-選自-CH₂-和-CH(CH₃)-。 In some specific embodiments, -L2- is selected from _-CH2- and -CH( _CH3 ₎ -.

一些實施方案中，R₂、R₃各自獨立選自氫、氘、氟、氯、溴、甲基、乙基、丙基、異丙基、苯基、氰基、羥基和側氧基。 In some embodiments, R2, _R3 are each independently selected from _hydrogen , deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, phenyl, cyano, hydroxy, and pendant oxy.

一些具體的實施方案中，R₂、R₃各自獨立選自氫、氘、氟、氯和甲基。 In some specific embodiments, R ₂ , R ₃ are each independently selected from hydrogen, deuterium, fluorine, chlorine, and methyl.

一些具體的實施方案中，R₂、R₃各自獨立選自氫。 In some specific embodiments, R ₂ , R ₃ are each independently selected from hydrogen.

另一些實施方案中，R₂、R₃共同構成3-8員環，該3-8員環選自C_3-7環烷基、3-8員雜環基、5-8員芳基和5-8員雜芳基，該3-8員環視需要地被一個或多個Z取代。 In other embodiments, R ₂ and R ₃ together form a 3-8 membered ring, and the 3-8 membered ring is selected from C _3-7 cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered aryl and 5-8 membered heteroaryl, the 3-8 membered ring is optionally substituted with one or more Z.

一些具體的實施方案中，R₂、R₃共同構成的3-8員環選自環丙基、環丁基、環戊基，該3-8員環視需要地被一個或多個Z取代，其中Z選自氟、氯、溴、甲基、乙基、丙基、異丙基、苯基、氰基、羥基和側氧基。 In some specific embodiments, the 3-8 membered ring formed by R ₂ and R ₃ is selected from cyclopropyl, cyclobutyl, and cyclopentyl, and the 3-8 membered ring is optionally substituted by one or more Z, wherein Z is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, phenyl, cyano, hydroxy, and pendant oxy.

一些具體的實施方案中，R₂、R₃共同構成的3-8員環選自被一個Z取代的環丙基、環丁基、環戊基，其中Z選自氟、氯和甲基。 In some specific embodiments, the 3-8 membered ring formed by R ₂ and R ₃ is selected from cyclopropyl, cyclobutyl, and cyclopentyl substituted with one Z, wherein Z is selected from fluorine, chlorine and methyl.

一些具體的實施方案中，R₂、R₃共同構成環丙基、環丁基或環戊基。 In some specific embodiments, R ₂ and R ₃ together constitute cyclopropyl, cyclobutyl or cyclopentyl.

一些具體的實施方案中，R₂、R₃共同構成環丙基。 In some specific embodiments, R ₂ and R ₃ together form a cyclopropyl group.

一些實施方案中，-L₁-選自鍵、-CH₂-、-CH(CH₃)-、-CH₂-CH₂-、-O-和-NH-。 In some embodiments, -L ₁ - is selected from bond, -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -, -O-, and -NH-.

一些具體的實施方案中，-L₁-選自-CH₂-和-O-。 In some specific embodiments, -L ₁ - is selected from -CH ₂ - and -O-.

第二方面，本揭露還提供一系列化合物，選自： In a second aspect, the present disclosure also provides a series of compounds selected from:

、

和

，或其可藥用鹽、互變異構體。

,

and

, or its pharmaceutically acceptable salts, tautomers.

一些具體的實施方案中，本揭露還提供一系列化合物，選自： In some specific embodiments, the present disclosure also provides a series of compounds selected from:

和

，

and

,

或其可藥用鹽、互變異構體。 or its pharmaceutically acceptable salts, tautomers.

協力廠商面，本揭露還提供第一或第二方面所述化合物或其可藥用鹽、互變異構體的製備方法。 In terms of third-party manufacturers, the present disclosure also provides methods for preparing the compounds described in the first or second aspects or their pharmaceutically acceptable salts and tautomers.

一些實施方案中，包括如下步驟： In some embodiments, the following steps are included:

；其中，

;in,

式I-5所示化合物與式I-6所示化合物在鹼性條件下，經取代反應，然後脫去保護基團LG₁，得到式I所示化合物； The compound represented by the formula I-5 and the compound represented by the formula I-6 undergo a substitution reaction under basic conditions, and then the protecting group LG ₁ is removed to obtain the compound represented by the formula I;

鹼性條件的試劑選自有機鹼或無機鹼，該有機鹼選自三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、雙三甲基矽基胺基鋰、醋酸鉀、第三丁醇鈉和第三丁醇鉀；該無機鹼選自氫化鈉、磷酸鉀、碳酸鈉、碳酸鉀、甲醇鈉、乙醇鈉、第三丁醇鈉、醋酸鉀、碳酸銫、氫氧化鈉和氫氧化鋰； The reagent of alkaline condition is selected from organic bases or inorganic bases, and the organic bases are selected from triethylamine, N , N -diisopropylethylamine, n-butyllithium, diisopropylamide lithium, bistrimethylamine Lithium silylamide, potassium acetate, sodium tertiary butoxide and potassium tertiary butoxide; the inorganic base is selected from sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium tertiary butoxide, Potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;

LG₁選自保護基^tBu、S(=O)^tBu、Cbz、Boc、Bn、PMB、SEM、THP； LG ₁ is selected from protecting groups ^t Bu, S(=O) ^t Bu, Cbz, Boc, Bn, PMB, SEM, THP;

LG₃選自苯氧基、4-硝基苯氧基。 LG ₃ is selected from phenoxy, 4-nitrophenoxy.

一些具體的實施方案中，當式I中-L₁-選自-O-時，包括如下步驟： In some specific embodiments, when -L ₁ - in formula I is selected from -O-, the following steps are included:

另一些實施方案中，當式I中-L₁-選自-O-時，包括如下步驟： In other embodiments, when -L ₁ - in formula I is selected from -O-, the following steps are included:

；其中，

;in,

式I-4所示化合物與式I-6所示化合物在醯化試劑存在條件下，經胺基甲酸酯化反應，然後脫去保護基團LG₁，得到式I所示化合物； The compound represented by the formula I-4 and the compound represented by the formula I-6 are subjected to urethane esterification reaction in the presence of an acylation reagent, and then the protecting group LG ₁ is removed to obtain the compound represented by the formula I;

該醯化試劑選自三光氣、1,1'-羰基二咪唑； The acylation reagent is selected from triphosgene, 1,1'-carbonyldiimidazole;

LG₁選自保護基^tBu、S(=O)^tBu、Cbz、Boc、Bn、PMB、SEM、THP。 LG ₁ is selected from protecting groups ^tBu , S(=O) ^tBu , Cbz, Boc, Bn, PMB, SEM, THP.

一些實施方案中，式I-4由式I-3所示化合物經還原反應得到： In some embodiments, formula I-4 is obtained by reducing the compound represented by formula I-3:

一些實施方案中，式I-3所示化合物由式I-1所示的化合物與式I-2所示化合物在縮合劑存在條件下，或者在鹼性條件下，經醯化反應得到： In some embodiments, the compound represented by the formula I-3 is obtained from the compound represented by the formula I-1 and the compound represented by the formula I-2 in the presence of a condensing agent, or under basic conditions, through an acylation reaction:

，其中，LG₂選自羥基、烷氧基、鹵素。

, wherein, LG ₂ is selected from hydroxyl, alkoxy, and halogen.

一些實施方案中，該縮合劑選自二環己基碳二亞胺、二異丙基碳二亞胺、1-(3-二甲胺基丙基)-3-乙基碳二亞胺、HATU、HBTU、TBTU、HCTU、TSTU、TNTU、PyBOP、1-丙基磷酸酐。 In some embodiments, the condensing agent is selected from the group consisting of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATU , HBTU, TBTU, HCTU, TSTU, TNTU, PyBOP, 1-propyl phosphoric anhydride.

一些實施方案中，鹼性條件試的試劑包括有機鹼和無機鹼類，該有機鹼選自三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、雙三甲基矽基胺基鋰、醋酸鉀、第三丁醇鈉和第三丁醇鉀，該無機鹼選自氫化鈉、磷酸鉀、碳酸鈉、碳酸鉀、甲醇鈉、乙醇鈉、第三丁醇鈉、醋酸鉀、碳酸銫、氫氧化鈉和氫氧化鋰。 In some embodiments, the reagent of the alkaline condition test includes organic bases and inorganic bases, and the organic bases are selected from triethylamine, N , N -diisopropylethylamine, n-butyllithium, diisopropylamine Lithium, lithium bistrimethylsilylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide, the inorganic base being selected from the group consisting of sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, Tertiary sodium butoxide, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.

第四方面，本揭露還提供一種醫藥組成物，其包含第一或第二方面所述的化合物或其可藥用鹽，和至少一種藥學上可接受的載體、稀釋劑或者賦形劑。 In a fourth aspect, the present disclosure further provides a pharmaceutical composition comprising the compound described in the first or second aspect or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

在一些實施方案中，該醫藥組成物的單位劑量為0.001mg-1000mg。 In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

在某些實施方案中，基於組成物的總重量，該醫藥組成物含有0.01-99.99%的前述化合物或其可藥用的鹽。在某些實施方案中，該醫藥組成物含有0.1-99.9%的前述化合物或其可藥用的鹽。在某些實施方案中，該醫藥組成物含有0.5%-99.5%的化合物或其可藥用的鹽。在某些實施方案中，該醫藥組成物含有1%-99%的化合物或其可藥用的鹽。在某些實施方案中，該醫藥組成物含有2%-98%的化合物或其可藥用的鹽。 In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the compound or a pharmaceutically acceptable salt thereof.

在某些實施方案中，基於組成物的總重量，該醫藥組成物含有0.01%-99.99%的藥學上可接受的賦形劑。在某些實施方案中，該醫藥組成物含有0.1%-99.9%的藥學上可接受的賦形劑。在某些實施方案中，該醫藥組成物含有0.5%-99.5%的藥學上可接受的賦形劑。在某些實施方案中，該醫藥組成物含有1%-99%的藥學上可接受的賦形劑。在某些實施方案中，該醫藥組成物含有2%-98%的藥學上可接受的賦形劑。 In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.

第五方面，本揭露還提供一種預防和/或治療患有與蛋白依賴性激酶相關疾病的患者的方法，其藉由向該患者施用治療有效量的本揭露所述的化合物或其可藥用的鹽或前述醫藥組成物。 In a fifth aspect, the present disclosure also provides a method of preventing and/or treating a patient suffering from a protein-dependent kinase-related disease by administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable compound thereof. The salt or the aforementioned pharmaceutical composition.

另一方面，本揭露還提供一種預防和/或治療患有與細胞週期蛋白相關疾病的患者的方法，其藉由向該患者施用治療有效量的本揭露所述的化合物或其可藥用的鹽或前述醫藥組成物。 In another aspect, the present disclosure also provides a method of preventing and/or treating a patient suffering from a cyclin-related disease by administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable form thereof. A salt or the aforementioned pharmaceutical composition.

在一些實施方案中，該與蛋白依賴性激酶相關疾病或與細胞週期蛋白相關疾病選細胞增殖性疾病，癌症或免疫性疾病。 In some embodiments, the protein-dependent kinase-related disease or cyclin-related disease is a cell proliferative disease, cancer, or an immune disease.

在一些實施方案中，該與蛋白依賴性激酶相關疾病或與細胞週期蛋白相關疾病選自乳腺癌、卵巢癌、***癌、黑色素瘤、腦瘤、食道癌、胃癌、肝癌(包括HCC)、胰腺癌、結直腸癌、肺癌(包括NSCLC、SCLC、鱗狀細胞癌或腺癌)、腎癌(包括RCC)、皮膚癌、成膠質細胞瘤、神經母細胞瘤、肉瘤、脂肪肉瘤、骨軟骨瘤、骨瘤、骨肉瘤、精原細胞瘤、睾丸腫瘤、子宮癌、頭頸癌、多發性骨髓瘤、惡性淋巴瘤、真性紅細胞增多症、白血病、甲狀腺癌、輸尿管腫瘤、膀胱腫瘤、膽囊癌、膽管癌、絨毛膜上皮癌或兒科腫瘤。 In some embodiments, the protein-dependent kinase-related disease or cyclin-related disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreas carcinoma, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma , osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallbladder cancer, bile duct carcinoma, choriocarcinoma, or pediatric tumor.

一些具體的實施方案中，該癌症選自細胞週期蛋白E1和/或細胞週期蛋白E2擴增的癌症。 In some specific embodiments, the cancer is selected from cyclin El and/or cyclin E2 amplified cancers.

本揭露還提供一種預防和/或治療患有癌症的患者的方法，其藉由向該患者施用治療有效量的本揭露所述的化合物或其可藥用的鹽或前述醫藥組成物，該癌症選自乳腺癌、卵巢癌、***癌、黑色素瘤、腦瘤、食道癌、胃癌、肝癌(包括HCC)、胰腺癌、結直腸癌、肺癌(包括NSCLC、 SCLC、鱗狀細胞癌或腺癌)、腎癌(包括RCC)、皮膚癌、成膠質細胞瘤、神經母細胞瘤、肉瘤、脂肪肉瘤、骨軟骨瘤、骨瘤、骨肉瘤、精原細胞瘤、睾丸腫瘤、子宮癌、頭頸癌、多發性骨髓瘤、惡性淋巴瘤、真性紅細胞增多症、白血病、甲狀腺癌、輸尿管腫瘤、膀胱腫瘤、膽囊癌、膽管癌、絨毛膜上皮癌或兒科腫瘤。 The present disclosure also provides a method of preventing and/or treating a patient suffering from cancer, by administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition, the cancer selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophagus cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma , testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, chorioepithelial cancer or pediatric tumor.

本揭露提供了治療有效量的本揭露所述的化合物或其可藥用的鹽或前述醫藥組成物在製備用於預防和/或治療與蛋白依賴性激酶相關疾病的藥物中的用途， The present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating a protein-dependent kinase-related disease,

一些具體的實施方案中，蛋白依賴性激酶選自CDK2，與蛋白依賴性激酶相關疾病選自細胞增殖性疾病，癌症或免疫性疾病。 In some specific embodiments, the protein-dependent kinase is selected from CDK2, and the disease associated with the protein-dependent kinase is selected from cell proliferative diseases, cancer or immune diseases.

另一方面，本揭露提供了治療有效量的本揭露所述的化合物或其可藥用的鹽或前述醫藥組成物在製備用於預防和/或治療與細胞週期蛋白相關疾病的藥物中的用途。 On the other hand, the present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating cyclin-related diseases .

一些具體的實施方案中，細胞週期蛋白選自細胞週期蛋白E，例如細胞週期蛋白E1、細胞週期蛋白E2。與細胞週期蛋白相關疾病選自細胞增殖性疾病，癌症或免疫性疾病。 In some specific embodiments, the cyclin is selected from cyclin E, eg, cyclin El, cyclin E2. The cyclin-related diseases are selected from cell proliferative diseases, cancer or immune diseases.

在一些實施方案中，本揭露提供了治療有效量的本揭露所述的化合物或其可藥用的鹽或前述醫藥組成物在製備治療癌症的藥物中的用途。 In some embodiments, the present disclosure provides the use of a therapeutically effective amount of a compound described in the present disclosure, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, in the manufacture of a medicament for the treatment of cancer.

一些具體的實施方案中，該癌症選自選自乳腺癌、卵巢癌、***癌、黑色素瘤、腦瘤、食道癌、胃癌、肝癌(包括HCC)、胰腺癌、結直腸癌、肺癌(包括NSCLC、SCLC、鱗狀細胞癌或腺癌)、腎癌(包括RCC)、皮膚癌、成膠質細胞瘤、神經母細胞瘤、肉瘤、脂肪肉瘤、骨軟骨瘤、骨瘤、骨肉瘤、精原細胞瘤、睾丸腫瘤、子宮癌、頭頸癌、多發性骨髓瘤、惡性淋巴瘤、真性紅細胞增多症、白血病、甲狀腺癌、輸尿管腫瘤、膀胱腫瘤、膽囊癌、膽管癌、絨毛膜上皮癌或兒科腫瘤。 In some specific embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma , testicular tumors, uterine cancer, head and neck cancer, multiple bone marrow tumor, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, chorioepithelial cancer, or pediatric tumor.

本揭露中所述化合物可藥用鹽選自無機鹽或有機鹽，本揭露所述化合物可與酸性或鹼性物質反應成相應鹽。 The pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts, and the compounds described in the present disclosure can react with acidic or basic substances to form corresponding salts.

另一方面，本揭露化合物可以存在特定的幾何或立體異構體形式。本揭露設想所有的這類化合物，包括順式和反式異構體、(-)-和(+)-對對映體、(R)-和(S)-對映體、非對映異構體、(D)-異構體、(L)-異構體，及其外消旋混合物和其他混合物，例如對映異構體或非對映體富集的混合物，所有這些混合物都屬於本揭露的範圍之內。烷基等取代基中可存在另外的不對稱碳原子。所有這些異構體以及它們的混合物，均包括在本揭露的範圍之內。 On the other hand, compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.

另外，本揭露的化合物和中間體還可以以不同的互變異構體形式存在，並且所有這樣的形式包含於本揭露的範圍內。術語“互變異構體”或“互變異構體形式”是指可經由低能壘互變的不同能量的結構異構體。例如，質子互變異構體(也稱為質子轉移互變異構體)包括經由質子遷移的互變，如酮-烯醇及亞胺-烯胺、內醯胺-內醯亞胺異構化、吡唑基異構化。 In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions via migration of protons, such as keto-enols and imine-enamines, lactam- lactimine isomerizations, Pyrazolyl isomerization.

吡唑基平衡實例是在如下所示的E和F之間： An example of a pyrazolyl balance is between E and F as shown below:

本發明中的所有化合物可以被畫成E型或F型，例如： All compounds in the present invention can be drawn as E or F, for example:

所有的互變異構形式在本發明的範圍內。化合物的命名不排除任何互變異構體。 All tautomeric forms are within the scope of the present invention. The naming of compounds does not exclude any tautomers.

本揭露化合物可以是不對稱的，例如，具有一個或多個立體異構體。除非另有說明，所有立體異構體都包括，如對映異構體和非對映異構體。本揭露的含有不對稱碳原子的化合物可以以光學活性純的形式或外消旋形式被分離出來。光學活性純的形式可以從外消旋混合物拆分，或藉由使用手性原料或手性試劑合成。 Compounds of the present disclosure may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

可以藉由的手性合成或手性試劑或者其他常規技術製備光學活性的(R)-和(S)-異構體以及D和L異構體。如果想得到本揭露某化合物的一種對映體，可以藉由不對稱合成或者具有手性助劑的衍生作用來製備，其中將所得非對映體混合物分離，並且輔助基團裂開以提供純的所需對映異構體。或者，當分子中含有鹼性官能團(如胺基)或酸性官能團(如羧基)時，與適當的光學活性的酸或鹼形成非對映異構體的鹽，然後藉由本領域所公知的常規方法進行非對映異構體拆分，然後回收得到純的對映體。此外，對映異構體和非對映異構體的分離通常是藉由使用色譜法完成的，該色譜法採用手性固定相，並視需要地與化學衍生法相結合(例如由胺生成胺基甲酸鹽)。 Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomeric salt is formed by conventional methods known in the art. The method performs the resolution of diastereomers, followed by recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (eg from amine to amine carboxylate).

本揭露還包括一些與本文中記載的那些相同的，但一個或多個原子被原子量或質量數不同於自然中通常發現的原子量或質量數的原子置換的同位素標記的本揭露化合物。可結合到本揭露化合物的同位素的實例包括氫、碳、氮、氧、磷、硫、氟、碘和氯的同位素，諸如分別為²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、¹²³I、¹²⁵I和³⁶Cl等。 The present disclosure also includes certain isotopically-labeled compounds of the present disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic weight or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, ^3H , ^11C , ^13C , ^14C , ¹³ , ^respectively N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl and the like.

除另有說明，當一個位置被特別地指定為氘(D)時，該位置應理解為具有大於氘的天然豐度(其為0.015%)至少1000倍的豐度的氘(即，至少10%的氘摻入)。示例中化合物的具有大於氘的天然豐度可以是至少1000倍的豐度的氘、至少2000倍的豐度的氘、至少3000倍的豐度的氘、至少4000倍的豐度的氘、至少5000倍的豐度的氘、至少6000倍的豐度的氘或更高豐度的氘。本揭露還包括各種氘化形式的式I化合物。與碳原子連接的各個可用的氫原子可獨立地被氘原子替換。所屬技術領域具有通常知識者能夠參考相關文獻合成氘化形式的式I化合物。在製備氘代形式的式I化合物時可使用市售的氘代起始物質，或它們可使用常規技術採用氘代試劑合成，氘代試劑包括但不限於氘代硼烷、三氘代硼烷四氫呋喃溶液、氘代氫化鋰鋁、氘代碘乙烷和氘代碘甲烷等。 Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (ie, at least 10 times greater than the natural abundance of deuterium, which is 0.015%), at least 1000 times greater % deuterium incorporation). Exemplary compounds having natural abundance greater than deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 4000 times more abundant 5000 times more abundant deuterium, at least 6000 times more abundant deuterium or more abundant deuterium. The present disclosure also includes compounds of Formula I in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. One of ordinary skill in the art can refer to the relevant literature to synthesize the compound of formula I in deuterated form. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds of formula I, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane Tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.

“視需要地”或“視需要”是指意味著隨後所描述的事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生的場合。例如“視需要的被鹵素或者氰基取代的C_1-6烷基”是指鹵素或者氰基可以但不必須存在，該說明包括烷基被鹵素或者氰基取代的情形和烷基不被鹵素和氰基取代的情形。 "Optionally" or "optionally" is meant to mean that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "optionally substituted C _1-6 alkyl substituted by halogen or cyano" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.

本發明所述化合物的化學結構中，鍵“／”表示未指定構型，即如果化學結構中存在手性異構體，鍵“／”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。雖然為簡便起見將全部上述結構式畫成某些異構體形式，但是本發明可以包括所有的異構體，如互變異構體、旋轉異構體、幾何異構體、非對映異構體、外消旋體和對映異構體。本揭露所述化合物的化學結構中，鍵“

”並未指定構型，即鍵“

”的構型可以為E型或Z型，或者同時包含E和Z兩種構型。 In the chemical structure of the compounds described in the present invention, the bond "/" represents an unspecified configuration, that is, if there is a chiral isomer in the chemical structure, the bond "/" can be "/"

"or"

", or both "

"and"

"Two configurations. Although all of the above structural formulae are drawn as certain isomeric forms for simplicity, the present invention encompasses all isomers such as tautomers, rotamers, geometric isomers isomers, diastereomers, racemates and enantiomers. In the chemical structures of the compounds described in this disclosure, the bond "

"No configuration specified, i.e. bond"

The configuration of " can be E or Z, or both E and Z configurations.

術語解釋：Terminology Explanation:

術語“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 The term "pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically acceptable salt or prodrug thereof, with other chemical components, together with other components such as a physiologically acceptable carrier and excipient. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

術語“可藥用賦形劑”或“藥學上可接受的賦形劑”包括但不限於任何已經被美國食品和藥物管理局批准對於人類或家畜動物使用可接受的任何助劑、載體、賦形劑、助流劑、甜味劑、稀釋劑、防腐劑、染料/著色劑、增香劑、表面活性劑、潤濕劑、分散劑、助懸劑、穩定劑、等滲劑、溶劑或乳化劑。 The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by the U.S. Food and Drug Administration and is acceptable for use in humans or livestock animals. Excipients, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifier.

術語“有效量”或“有效治療量”包含足以改善或預防醫學病症的症狀或病症的量。有效量還意指足以允許或促進診斷的量。用於特定患者或獸醫學受試者的有效量可依據以下因素而變化：如待治療的病症、患者的總體健康情況、給藥的方法途徑和劑量以及副作用嚴重性。有效量可以是避免顯著副作用或毒性作用的最大劑量或給藥方案。 The term "effective amount" or "therapeutically effective amount" includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

術語“烷基”指飽和脂肪族烴基團，其為包含1至20個碳原子的直鏈或支鏈基團，較佳含有1至12個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各種支鏈異構體等。更佳的是含有1至6個碳原子的烷基，非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，該取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基。 The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyhexyl Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. More preferred are alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second Butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl , 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl Methylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl pentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto group, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxygen group, carboxyl group or carboxylate group.

術語“亞(伸)烷基”表示烷烴分子中去除2個氫原子後餘下的部分，包括1至20個碳原子的直鏈和支鏈亞(伸)基團。含有1至6個碳原子的亞(伸)烷基，非限制性實施例包括亞甲基(-CH₂-)、亞(伸)乙基(如-CH₂CH₂-或-CH(CH₃)-)、亞(伸)丙基(如-CH₂CH₂CH₂-或-CH(CH₂CH₃)-)、亞(伸)丁基(如-CH₂CH₂CH₂CH₂-)。如無特殊說明，亞(伸)烷基可以是取代的或未取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，較佳一個或多個以下基團，獨立地選自氘、芳基、雜芳基、鹵素所取代。 The term "(extended)alkylene" refers to the portion of an alkane molecule remaining after removal of two hydrogen atoms, including straight and branched chain (extended) groups of 1 to 20 carbon atoms. (Ethylene) alkylene groups containing 1 to 6 carbon atoms, non-limiting examples include methylene ( _-CH2- ), (endylene) ethylidene (such as _-CH2CH2- or -CH(CH2- ₎ ₃ )-), (extended) propylidene (such as -CH ₂ CH ₂ CH ₂ -or -CH(CH ₂ CH ₃ )-), (extended) butylidene (such as -CH ₂ CH ₂ CH ₂ CH ₂ -). Unless otherwise specified, (extended) alkylene may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently is substituted from deuterium, aryl, heteroaryl, halogen.

術語“環烷基”或“碳環”指飽和或部分不飽和單環或多環環狀烴取代基，環烷基環包含3至20個碳原子，較佳包含3至7個碳原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基等；多環環烷基包括螺環、稠環和橋環的環烷基。環烷基可以是取代的或未取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，較佳一個或多個以下基團，獨立地選自鹵素、氘、羥基、側氧、硝基、氰基、C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基，該C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基視需要被一個或多個選自鹵素、氘、羥基、側氧、硝基、氰基所取代。 The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro Ring, fused and bridged cycloalkyl groups. Cycloalkyl may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy , pendant oxygen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 Alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl Optionally substituted with one or more selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano.

該環烷基環可以稠合於芳基或雜芳基環上，其中與母體結構連接在一起的環為環烷基，非限制性實例包括茚滿基、四氫萘基、苯并環庚烷基等。環烷基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、氘、羥基、側氧、硝基、氰基、C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基，該C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基視需要被一個或多個選自鹵素、氘、羥基、側氧、硝基、氰基所取代。 The cycloalkyl ring can be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl Alkyl etc. Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano base, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy base, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynoxy, C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano.

術語“雜環烷基”或“雜環”指飽和或部分不飽和單環或多環環狀烴取代基，其包含3至20個環原子，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包含3至12個環原子，其中1~4個是雜原子；更佳包含3至7個環原子。單環雜環烷基的非限制性實例包括吡咯烷基、咪唑烷基、四氫呋喃基、四氫噻吩基、二氫咪唑基、二氫呋喃基、二氫吡唑基、二氫吡咯基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基等。多環雜環烷基包括螺環、稠環和橋環的雜環烷基。“雜環烷基”非限制性實例包括： The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which are selected from nitrogen, Oxygen or heteroatoms of S(O) _m (where m is an integer from 0 to 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piper pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyl groups include spiro, fused and bridged ring heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:

，

和

，等等。

,

and

,and many more.

該雜環烷基環可以稠合於芳基或雜芳基環上，其中與母體結構連接在一起的環為雜環烷基，其非限制性實例包括： The heterocycloalkyl ring can be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

和

等。

and

Wait.

雜環烷基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、氘、羥基、側氧、硝基、氰基、C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基，該C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基視需要被一個或多個選自鹵素、氘、羥基、側氧、硝基、氰基所取代。 Heterocycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkane oxy, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _{2- 6} -alkynyloxy, C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl optionally replaced by one or more Substituted from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano.

術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團，較佳為6至12員，例如苯基和萘基。該芳基環可以稠合於雜芳基、雜環烷基或環烷基環上，其中與母體結構連接在一起的環為芳基環，其非限制性實例包括： The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, e.g. Phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:

和

；

and

;

芳基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、氘、羥基、側氧、硝基、氰基、C_1-6烷基、 C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基，該C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基視需要被一個或多個選自鹵素、氘、羥基、側氧、硝基、氰基所取代。 Aryl can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy , C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl as required by one or more selected from halogen, Deuterium, hydroxyl, side oxygen, nitro, cyano substituted.

術語“雜芳基”指包含1至4個雜原子、5至14個環原子的雜芳族體系，其中雜原子選自氧、硫和氮。雜芳基較佳為6至12員，更佳為5員或6員。例如。其非限制性實例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基(oxazolyl)、異噁唑基(isoxazolyl)、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基、***基、吲唑基、苯并咪唑基、

，

、

等。 The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12 members, more preferably 5 or 6 members. E.g. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl , thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl,

,

Wait.

該雜芳基環可以稠合於芳基、雜環烷基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，其非限制性實例包括： The heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:

和

。

and

.

雜芳基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、氘、羥基、側氧、硝基、氰基、C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基，該C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基視需要被一個或多個選自鹵素、氘、羥基、側氧、硝基、氰基所取代。 Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano base, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy base, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynoxy, C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano.

術語“螺環”指兩環共用一個原子的化合物。 The term "spirocycle" refers to a compound in which two rings share one atom.

術語“螺環烷基”指5至20員的單環之間共用一個碳原子(稱螺原子)的多環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據環與環之間共用螺原子的數目將螺環烷基分為單螺環烷基、雙螺環烷基或多螺環烷基，較佳為單螺環烷基和雙螺環烷基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺環烷基。“螺碳環”指的是螺環烷基中的環系。螺環烷基的非限制性實例包括： The term "spirocycloalkyl" refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated π electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl, double-spirocycloalkyl or poly-spirocycloalkyl, preferably mono-spirocycloalkyl and double-spirocycloalkyl . More preferably 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-/5-member or 5-/6-membered monospirocycloalkyl. "Spirocarbocycle" refers to the ring system in a spirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

和

。

and

.

術語“螺雜環基”指5至20員的單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基、雙螺雜環基或多螺雜環基，較佳為單螺雜環基和雙螺雜環基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺雜環基。“螺雜環”指的是螺雜環基中的環系。螺雜環基的非限制性實例包括： The term "spiroheterocyclyl" refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, spiroheterocyclyl groups are classified into mono-spiroheterocyclyl, bis-spiro-heterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiroheterocyclyl and bis-spiro-heterocyclyl . More preferably a 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-/5-member or 5-/6-membered monospiroheterocyclyl. "Spiroheterocycle" refers to the ring system in a spiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl include:

和

。

and

.

術語“稠環”指兩個或兩個以上環藉由共用兩個相鄰的原子稠合而成的化合物。 The term "fused ring" refers to a compound in which two or more rings are fused by sharing two adjacent atoms.

術語“稠環烷基”指5至20員，系統中的每個環與體系中的其他環共用毗鄰的一對碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環稠環烷基，較佳為雙環或三環，更佳為5員/5員或5員/6員雙環烷基。“稠碳環”指的是稠環烷基中的環系。稠環烷基的非限制性實例包括： The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. "Fused carbocycle" refers to the ring system in a fused cycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

和

。

and

.

術語“稠雜環基”指5至20員，系統中的每個環與體系中的其他環共用毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環稠雜環基，較佳為雙環或三環，更佳為5員/5員或5員/6員雙環稠雜環基。“稠雜環”指的是稠雜環基中的環系。稠雜環基的非限制性實例包括： The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), the remaining rings Atom is carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group . "Fused heterocycle" refers to a ring system in a fused heterocyclyl. Non-limiting examples of fused heterocyclyl groups include:

和

。

and

.

術語“稠雜芳基”可以是含有5-14個環原子(其中至少含有一個雜原子)由兩個或兩個以上環狀結構彼此共用兩個相鄰的原子連接起來形成的不飽和的具有芳香性的稠環結構，同時包括碳原子、氮原子和硫原子可以被側氧，較佳"5-12員稠雜芳基"、"7-12員稠雜芳基"、"9-12員稠雜芳基"等，例如苯并呋喃基、苯并異呋喃基、苯并噻吩基、吲哚基、異吲哚、苯并噁唑基、苯并咪唑基、吲唑基、苯并***基、喹啉基、2-喹啉酮、4-喹啉酮、1-異喹啉酮、異喹啉基、吖啶基、菲啶基、苯并噠嗪基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、萘啶基、吩嗪、吩噻嗪等。“稠雜芳環”指的是稠雜芳基中的環系。 The term "fused heteroaryl" may be an unsaturated heteroaryl group containing 5-14 ring atoms (including at least one heteroatom) formed by two or more cyclic structures that share two adjacent atoms connected to each other. Aromatic condensed ring structure, including carbon atom, nitrogen atom and sulfur atom can be oxygen side, preferably "5-12 condensed heteroaryl", "7-12 condensed heteroaryl", "9-12 condensed heteroaryl" Heteroaryl" etc Triazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridine, phenanthridine, benzopyridazinyl, phthalazinyl, Quinazolinyl, quinoxalinyl, phenazine, pteridyl, purinyl, naphthyridinyl, phenazine, phenothiazine and the like. "Fused heteroaromatic ring" refers to the ring system in a fused heteroaryl group.

稠雜芳基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 The fused heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, carboxyl or carboxylate.

術語“橋環”指兩個或兩個以上環狀結構彼此共用兩個非相鄰的環原子所形成的結構。 The term "bridged ring" refers to a structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other.

術語“橋環烷基”指5至20員，任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，較佳為雙環、三環或四環，更佳為雙環或三環。橋環烷基的非限制性實例包括： The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings has complete Conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

和

。

and

.

術語“橋雜環基”指5至14員，任意兩個環共用兩個不直接連接的原子的多環雜環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環橋雜環基，較佳為雙環、三環或四環，更佳為雙環或三環。橋雜環基的非限制性實例包括： The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group of any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a complete common A pi-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

和

。

and

.

術語“烷氧基”指-O-(烷基)和-O-(非取代的環烷基)，其中烷基的定義如上所述。烷氧基的非限制性實例包括：甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基。烷氧基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、氘、羥基、側氧、硝基、氰基、C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基，該C_1-6烷基、C_1-6烷氧基、C_2-6烯氧基、C_2-6炔氧基、C_3-6環烷氧基、3至6員雜環烷氧基、C_3-8環烯氧基、5至6員芳基或雜芳基視需要被一個或多個選自鹵素、氘、羥基、側氧、硝基、氰基所取代。同理，“炔氧基”、“烯氧基”、“環烷氧基”、“雜環烷氧基”、“環烯氧基”的定義如上述“烷氧基”定義。 The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano base, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy base, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, the C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyloxy, C _2-6 Alkynoxy, C _3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C _3-8 cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl are optionally selected by one or more Substituted from halogen, deuterium, hydroxyl, pendant oxygen, nitro, cyano. Similarly, the definitions of "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy" and "cycloalkenyloxy" are as defined above for "alkoxy".

術語“羥基”指-OH基團。 The term "hydroxy" refers to the -OH group.

術語“鹵素”指氟、氯、溴或碘。 The term "halogen" refers to fluorine, chlorine, bromine or iodine.

術語“鹵烷基”指被鹵素取代的烷基，其中烷基如上所定義。 The term "haloalkyl" refers to an alkyl group substituted with halogen, wherein alkyl is as defined above.

術語“氰基”指-CN。 The term "cyano" refers to -CN.

術語“硝基”指-NO₂。 The term "nitro" refers to _-NO2 .

術語“側氧”指=O基團。例如，碳原子與氧原子藉由雙鍵連接，其中形成酮或醛基。 The term "pendant oxygen" refers to the =O group. For example, a carbon atom is linked to an oxygen atom by a double bond, in which a ketone or aldehyde group is formed.

術語“胺基”指-NH₂。 The term "amino" refers to _-NH2 .

術語“氰基”指-CN。 The term "cyano" refers to -CN.

術語“硝基”指-NO₂。 The term "nitro" refers to _-NO2 .

術語“羧基”指-C(O)OH。 The term "carboxy" refers to -C(O)OH.

術語“醛基”指-CHO。 The term "aldehyde group" refers to -CHO.

術語“取代的”指基團中的一個或多個氫原子，較佳為最多5個，更佳為1~3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻，取代基僅處在它們的可能的化學位置，所屬技術領域具有通常知識者能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。 The term "substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those of ordinary skill in the art can Enough to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.

“被一個或多個……取代”是指可以被單個或多個取代基取代。當被多個取代基取代時，可以是複數個相同取代基，也可以是一個或複數個不同取代基的組合。 "Substituted with one or more" means that it may be substituted with single or multiple substituents. When substituted by a plurality of substituents, it may be a plurality of the same substituents, or a combination of one or a plurality of different substituents.

以下結合實施例進一步描述本揭露，但這些實施例並非限制著本揭露的範圍。 The present disclosure is further described below with reference to the embodiments, but these embodiments do not limit the scope of the present disclosure.

本揭露實施例中未註明具體條件的實驗方法，通常按照常規條件，或按照原料或商品製造廠商所建議的條件。未註明具體來源的試劑，為市場購買的常規試劑。 In the examples of the present disclosure, experimental methods without specific conditions are generally based on conventional conditions or conditions suggested by raw material or commodity manufacturers. Reagents with no specific source indicated are conventional reagents purchased in the market.

化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(δ)以10^-6(ppm)的單位給出。NMR的測定是用Bruker AVANCE-400核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d₆)，氘代氯仿(CDCl₃)，氘代甲醇(CD₃OD)，內標為四甲基矽烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

MS的測定用Shimadzu 2010 Mass Spectrometer或Agilent 6110A MSD質譜儀。 MS was measured with a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer.

HPLC的測定使用Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷倫Agilent 1200 LC高壓液相色譜儀(Ultimate XB-C18 3.0*150mm色譜管柱或Xtimate C18 2.1*30mm色譜管柱)。 The determination of HPLC was performed using Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatograph (Ultimate XB-C18 3.0*150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column).

手性HPLC分析測定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色譜管柱； Chiral HPLC analysis was determined using Chiralpak IC-3 100×4.6mm I.D., 3um, Chiralpak AD-3 150×4.6mm I.D., 3um, Chiralpak AD-3 50×4.6mm I.D., 3um, Chiralpak AS-3 150×4.6mm I.D., 3um, Chiralpak AS-3 100×4.6mm I.D., 3μm, ChiralCel OD-3 150×4.6mm I.D., 3um, Chiralcel OD-3 100×4.6mm I.D., 3μm, Chiralcel OJ-H 150×4.6mm I.D., 5um, Chiralcel OJ-3 150×4.6mm I.D., 3um column;

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.15mm~0.2mm，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。 The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for TLC separation and purification products is 0.4mm ~0.5mm.

管柱層析一般使用煙臺黃海矽膠100~200目、200~300目或300~400目矽膠為載體。 Column chromatography generally uses Yantai Huanghai silica gel 100~200 mesh, 200~300 mesh or 300~400 mesh silica gel as the carrier.

手性製備管柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。 The chiral preparative column used DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).

CombiFlash快速製備儀使用Combiflash Rf150(TELEDYNE ISCO)。 The CombiFlash rapid preparation instrument used Combiflash Rf150 (TELEDYNE ISCO).

激酶平均抑制率及IC₅₀值的測定用NovoStar酶標儀(德國BMG公司)。 The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

本揭露的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自ABCR GmbH & Co.KG，Acros Organics，Aldrich Chemical Company，韶遠化學科技(Accela ChemBio Inc)、達瑞化學品等公司。 The known starting materials of the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Accela ChemBio Inc. Darui Chemicals and other companies.

實施例中無特殊說明，反應能夠均在氬氣氛或氮氣氛下進行。 There is no special description in the examples, and the reactions can all be carried out in an argon atmosphere or a nitrogen atmosphere.

氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。 Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

加壓氫化反應使用Parr 3916EKX型氫化儀和清藍QL-500型氫氣發生器或HC2-SS型氫化儀。 The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

氫化反應通常抽真空，充入氫氣，重複操作3次。 The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

微波反應使用CEM Discover-S 908860型微波反應器。 The microwave reaction used a CEM Discover-S 908860 microwave reactor.

實施例中無特殊說明，溶液是指水溶液。 There is no special description in the examples, and the solution refers to an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫，為20℃~30℃。 There is no special description in the examples, and the temperature of the reaction is room temperature, which is 20°C to 30°C.

實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑，純化化合物採用的管柱層析的沖提劑的體系和薄層色譜法的展開劑體系包括：A：二氯甲烷/甲醇體系，B：正己烷/乙酸乙酯體系，C：石油醚/乙酸乙酯體系，D：石油醚/乙酸乙酯/甲醇，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和醋酸等鹼性或酸性試劑進行調節。 The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing agent system of the thin layer chromatography include: A : dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: petroleum ether/ethyl acetate/methanol, the volume ratio of the solvent depends on the polarity of the compound For adjustment, a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

實施例1Example 1

順式-3-(5-(2-(3-甲基異噻唑-5-基)乙醯胺基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯異構體 cis-3-(5-(2-(3-methylisothiazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentylbicyclo[1.1.1]pentane -1-ylcarbamate isomer

第一步 first step

甲基3,3-二甲氧基環戊烷-1-羧酸酯1b Methyl 3,3-dimethoxycyclopentane-1-carboxylate 1b

將化合物1a(15g,0.12mol)溶於200mL甲醇中，在室溫下加入原甲酸三甲酯(76.8mL,0.70mol)和對甲苯磺酸(0.4g,2.3mmol)，並在室溫下攪拌20小時。反應完畢後，加入飽和碳酸氫鈉水溶液(20mL)，用乙酸乙酯萃取(80mL×3)，合併有機相，用水洗滌(150mL)，飽和氯化鈉溶液洗滌(150mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮得到標題化合物1b(23g，產率：84%)。 Compound 1a (15 g, 0.12 mol) was dissolved in 200 mL of methanol, trimethyl orthoformate (76.8 mL, 0.70 mol) and p-toluenesulfonic acid (0.4 g, 2.3 mmol) were added at room temperature, and at room temperature Stir for 20 hours. After the reaction, saturated aqueous sodium bicarbonate solution (20 mL) was added, extracted with ethyl acetate (80 mL×3), the organic phases were combined, washed with water (150 mL), washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, The filtrate was collected by filtration, and the filtrate was concentrated under reduced pressure to give the title compound 1b (23 g, yield: 84%).

第二步 second step

3-羰基-3-(3-羰基環戊基)丙腈1c 3-Carbonyl-3-(3-carbonylcyclopentyl)propionitrile 1c

在-65℃和氮氣氛下，依次將n-BuLi(98mL,0.24mmol)和乙腈(13mL,0.24mol)滴入100mL THF中，反應1h後，將化合物1b(23g,0.12mol)的THF溶液(100mL)緩慢滴入反應液中，待反應完畢後，加入飽和氯化銨溶液淬滅反應，隨後加入3M HCl至pH為2，充分攪拌後，用乙酸乙酯萃取(80mL×3)，合併有機相，用水洗滌(150mL)，飽和氯化鈉溶液洗滌(150mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮得到標題化合物1c(30g，產率：87%)。 Under a nitrogen atmosphere at -65°C, n -BuLi (98 mL, 0.24 mmol) and acetonitrile (13 mL, 0.24 mol) were dropped into 100 mL of THF in turn. After reacting for 1 h, the THF solution of compound 1b (23 g, 0.12 mol) was added. (100mL) was slowly dropped into the reaction solution, after the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, then 3M HCl was added to pH 2, after thorough stirring, extracted with ethyl acetate (80mL×3), combined The organic phase was washed with water (150 mL), saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to give the title compound 1c (30 g, yield: 87%).

第三步 third step

3-(5-胺基-1-(第三-丁基)-1H-吡唑-3-基)環戊烷-1-酮1d 3-(5-Amino-1-(3-butyl)-1H-pyrazol-3-yl)cyclopentan-1-one 1d

室溫下，將氫氧化鈉(0.5g,13mmol)加入到第三丁基肼(1.6g,13mmol)的乙醇(10mL)溶液中，攪拌1h後，將化合物1c(3.0g,20mmol)的乙醇溶液(10mL)加入到上述反應液中，在75℃下，攪拌15h至反應完全，反應液減壓濃縮，殘餘物用矽膠色譜法層析石油醚和乙酸乙酯沖提純化，減壓濃縮得到標題化合物1d(3.0g，產率：68%)。 At room temperature, sodium hydroxide (0.5 g, 13 mmol) was added to a solution of tert-butylhydrazine (1.6 g, 13 mmol) in ethanol (10 mL), and after stirring for 1 h, compound 1c (3.0 g, 20 mmol) in ethanol was added The solution (10 mL) was added to the above reaction solution, stirred at 75°C for 15 h until the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel chromatography with petroleum ether and ethyl acetate, and concentrated under reduced pressure to obtain The title compound 1d (3.0 g, yield: 68%).

MS(ESI)m/z 222.3[M+H]⁺ MS(ESI)m/z 222.3[M+H] ⁺

第四步 the fourth step

N-(1-(第三-丁基)-3-(3-羰基環戊基)-1H-吡唑-5-基)-2-(3-甲基異噻唑-5-基)乙醯胺1f N-(1-(3-butyl)-3-(3-carbonylcyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisothiazol-5-yl)acetone Amine 1f

氮氣氛下，依次將化合物1d(0.90g，4.1mmol)、2-(3-甲基異噻唑-5-基)乙酸(0.69g，4.9mmol)、N,N-二異丙基乙胺(1.5g,11mmol)溶於16mL二氯甲烷中。在室溫下加入1-丙基磷酸酐溶液(50%wt，6.5g,10mmol)並在室溫下攪拌2小時。加入100mL飽和碳酸氫鈉溶液淬滅反應。用100mL二氯甲烷萃取，有機相用飽和氯化鈉溶液洗滌(100mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘餘物用C-18反相色譜法水和乙腈沖提純化得到標題化合物1f(760mg，產率：54%)。 Under nitrogen atmosphere, compound 1d (0.90 g, 4.1 mmol), 2-(3-methylisothiazol-5-yl)acetic acid (0.69 g, 4.9 mmol), N,N-diisopropylethylamine ( 1.5 g, 11 mmol) was dissolved in 16 mL of dichloromethane. A solution of 1-propylphosphoric anhydride (50% wt, 6.5 g, 10 mmol) was added at room temperature and stirred at room temperature for 2 hours. The reaction was quenched by the addition of 100 mL of saturated sodium bicarbonate solution. Extracted with 100 mL of dichloromethane, the organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure, and the residue was washed with C-18 reverse phase chromatography with water and acetonitrile Purification gave the title compound 1f (760 mg, yield: 54%).

MS(ESI)m/z 345.4[M+H]⁺ MS(ESI)m/z 345.4[M+H] ⁺

第五步 the fifth step

N-(1-(第三-丁基)-3-(3-羥基環戊基)-1H-吡唑-5-基)-2-(3-甲基異噻唑-5-基)乙醯胺1g N-(1-(3-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisothiazol-5-yl)acetone Amine 1g

氮氣氛下，將化合物1f(760mg，2.2mmol)溶於16mL四氫呋喃中。降溫至-60℃，將三乙基硼氫化鋰(1mol/L，4.4mL，4.4mmol)滴加到反應中，並在-60℃條件下反應2小時。加入80mL飽和碳酸氫鈉溶液淬滅反應。用乙酸乙酯萃取(80mL×3)，合併有機相，用飽和氯化銨溶液洗滌(150mL)，用飽和氯化鈉溶液洗滌(150mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮得到標題化合物1g(836mg，產率：100%)。 Under nitrogen atmosphere, compound 1f (760 mg, 2.2 mmol) was dissolved in 16 mL of tetrahydrofuran. The temperature was lowered to -60°C, lithium triethylborohydride (1 mol/L, 4.4 mL, 4.4 mmol) was added dropwise to the reaction, and the reaction was carried out at -60°C for 2 hours. The reaction was quenched by the addition of 80 mL of saturated sodium bicarbonate solution. Extracted with ethyl acetate (80 mL×3), combined the organic phases, washed with saturated ammonium chloride solution (150 mL), washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, collected the filtrate, and the filtrate was decompressed Concentration gave the title compound 1 g (836 mg, yield: 100%).

MS(ESI)m/z 347.5[M+H]⁺ MS(ESI)m/z 347.5[M+H] ⁺

第六步 Step 6

3-(1-(第三-丁基)-5-(2-(3-甲基異噻唑-5-基)乙醯胺基)-1H-吡唑-3-基)環戊基(4-硝基苯基)碳酸酯1h 3-(1-(T-butyl)-5-(2-(3-methylisothiazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentyl (4 -Nitrophenyl) carbonate 1h

氮氣氛下，依次將化合物1g(836mg，2.4mmol)、吡啶(570mg，7.2mmol)、4-二甲胺基吡啶(29mg,0.24mmol)、氯化酯4-硝基苯基(677mg,3.4mmol)溶於16mL二氯甲烷中。在室溫下攪拌3小時。將溶劑旋乾，加入100mL乙酸乙酯，用飽和氯化銨溶液洗滌(100mL)，用飽和氯化鈉溶液洗滌(100mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘餘物用C-18反相色譜法水和乙腈沖提純化得到標題化合物1h(900mg，產率：72%)。 Under nitrogen atmosphere, compound 1 g (836 mg, 2.4 mmol), pyridine (570 mg, 7.2 mmol), 4-dimethylaminopyridine (29 mg, 0.24 mmol), chloride ester 4-nitrophenyl (677 mg, 3.4 mmol) in 16 mL of dichloromethane. Stir at room temperature for 3 hours. The solvent was spin-dried, 100 mL of ethyl acetate was added, washed with saturated ammonium chloride solution (100 mL), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure, and the residue was Purification by C-18 reverse phase chromatography eluting with water and acetonitrile gave the title compound 1h (900 mg, yield: 72%).

MS(ESI)m/z 512.5[M+H]⁺ MS(ESI)m/z 512.5[M+H] ⁺

第七步 Step 7

3-(1-(第三-丁基)-5-(2-(3-甲基異噻唑-5-基)乙醯胺基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯1i 3-(1-(T-butyl)-5-(2-(3-methylisothiazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentylbicyclo [1.1.1]Pentan-1-ylcarbamate 1i

氮氣氛下，依次將化合物1h(45mg，0.09mmol)、N,N-二異丙基乙胺(46mg,0.35mmol)、二環[1.1.1]戊烷-1-胺鹽酸鹽(9.5mg,0.11mmol)溶於5mL四氫呋喃中。在60℃條件下反應3小時。將溶劑旋乾，加入20mL飽和碳酸氫鈉溶液，用乙酸乙酯萃取(20mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(50mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮得到標題化合物1i(42mg，產率：100%)。 Under nitrogen atmosphere, compound 1h (45 mg, 0.09 mmol), N,N-diisopropylethylamine (46 mg, 0.35 mmol), and bicyclo[1.1.1]pentan-1-amine hydrochloride (9.5 mg, 0.11 mmol) was dissolved in 5 mL of tetrahydrofuran. The reaction was carried out at 60°C for 3 hours. The solvent was spin-dried, 20 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. Concentration under reduced pressure gave the title compound 1i (42 mg, yield: 100%).

MS(ESI)m/z 456.5[M+H]⁺ MS(ESI)m/z 456.5[M+H] ⁺

第八步 Step 8

3-(5-(2-(3-甲基異噻唑-5-基)乙醯胺基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯1 3-(5-(2-(3-Methylisothiazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentylbicyclo[1.1.1]pentane-1- urethane 1

氮氣氛下，依次將化合物1i(42mg，0.09mmol)溶於1mL甲酸中。在75℃條件下反應4小時。將溶劑旋乾，加入20mL飽和碳酸氫鈉溶液，用乙酸乙酯萃取(20mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(50mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘餘物用Waters Xbridge C-18(OBD®；19*150mm,Eluent of 50~70%乙腈/水(0.05%FA)gradient @ 15mL/min)反相色譜法純化得到，第一個流出物(t_R=6.91min)凍乾得到11.8mg，產率：32%)；第二個流出物(t_R=7.35min)凍乾得到3.5mg，產率：9.5%) Compound 1i (42 mg, 0.09 mmol) was sequentially dissolved in 1 mL of formic acid under nitrogen atmosphere. The reaction was carried out at 75°C for 4 hours. The solvent was spin-dried, 20 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. Concentrated under reduced pressure, the residue was purified by reverse phase chromatography with Waters Xbridge C-18 (OBD®; 19*150mm, Eluent of 50~70% acetonitrile/water (0.05%FA) gradient @ 15mL/min), the first The effluent (t _R =6.91 min) was lyophilized to give 11.8 mg, yield: 32%); the second effluent (t _R =7.35 min) was lyophilized to give 3.5 mg, yield: 9.5%)

保留時間為6.91min的異構體： Isomer with retention time of 6.91 min:

MS(ESI)m/z 400.4[M+H]⁺ MS(ESI)m/z 400.4[M+H] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ=12.09(br s,1H),10.67(br s,1H),7.77(br s,1H),6.28(s,1H),6.22(s,1H),4.98(br s,1H),3.83(s,2H),3.04(br t,J=8.0Hz,1H),2.49-2.41(m,1H),2.34(br s,1H),2.20(s,3H),2.05-1.96(m,1H),1.89(br s,7H),1.76-1.51(m,3H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ = 12.09(br s, 1H), 10.67(br s, 1H), 7.77(br s, 1H), 6.28(s, 1H), 6.22(s, 1H) ,4.98(br s,1H),3.83(s,2H),3.04(br t, J =8.0Hz,1H),2.49-2.41(m,1H),2.34(br s,1H),2.20(s, 3H), 2.05-1.96(m, 1H), 1.89(br s, 7H), 1.76-1.51(m, 3H)

保留時間為7.35min的異構體： Isomer with retention time of 7.35 min:

MS(ESI)m/z 400.4[M+H]⁺ MS(ESI)m/z 400.4[M+H] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ=10.68(br s,1H),7.79(br s,1H),6.28(s,1H),6.22(s,1H),5.05(br s,1H),3.83(s,2H),2.36(s,1H),2.20(s,3H),2.16-1.97(m,3H),1.91(s,7H),1.82(ddd,J=6.0,10.5,13.6Hz,1H),1.59(br d,J=8.8Hz,3H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ = 10.68(br s, 1H), 7.79(br s, 1H), 6.28(s, 1H), 6.22(s, 1H), 5.05(br s, 1H) ,3.83(s,2H),2.36(s,1H),2.20(s,3H),2.16-1.97(m,3H),1.91(s,7H),1.82(ddd, J =6.0,10.5,13.6Hz ,1H),1.59(br d, J =8.8Hz,3H)

實施例2Example 2

順式-3-(5-(2-(3-甲基異噻唑-5-基)乙醯胺基)-1H-吡唑-3-基)環戊基螺[3.3]庚烷-2-基胺基甲酸酯異構體 cis-3-(5-(2-(3-methylisothiazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentylspiro[3.3]heptane-2- carbamate isomer

實施例2的合成步驟參見實施例1，其中以化合物螺[3.3]庚烷-2-胺鹽酸鹽替換二環[1.1.1]戊烷-1-胺鹽酸鹽製備獲得實施例2。 For the synthesis steps of Example 2, refer to Example 1, wherein the compound spiro[3.3]heptane-2-amine hydrochloride was replaced with bicyclo[1.1.1]pentane-1-amine hydrochloride to obtain Example 2.

分離方法：Waters Xbridge C-18(OBD®；30*150mm,Eluent of 40~55%乙腈/水(0.1%NH₄OH)gradient @ 30mL/min)反相色譜法純化，第一個流出物(t_R=7.48min)2a(10.2mg，產率：24%)；第二個流出物(t_R=8.15min)2b(2.2mg，產率：5.2%)。 Separation method: Waters Xbridge C-18 (OBD®; 30*150mm, Eluent of 40~55% acetonitrile/water (0.1% NH ₄ OH) gradient @ 30 mL/min) purified by reverse phase chromatography, the first effluent ( t _R = 7.48 min) 2a (10.2 mg, yield: 24%); second effluent (t _R = 8.15 min) 2b (2.2 mg, yield: 5.2%).

保留時間為7.48min的異構體： Isomer with retention time of 7.48 min :

MS(ESI)m/z 428.5[M+H]⁺ MS(ESI)m/z 428.5[M+H] ⁺

¹H NMR(400MHz,DMSO-d6)δ=12.11(s,1H),10.63(s,1H),7.28(br d,J=7.8Hz,1H),6.28(s,1H),6.22(s,1H),4.96(br s,1H),3.82(s,2H),3.80-3.73(m,1H),3.11-2.94(m,1H),2.46-2.37(m,1H),2.20(s,3H),2.17(br s,1H),2.05-1.92(m,3H),1.91-1.61(m,10H),1.61-1.49(m,1H) ¹ H NMR(400MHz,DMSO-d6)δ=12.11(s,1H),10.63(s,1H),7.28(br d,J=7.8Hz,1H),6.28(s,1H),6.22(s, 1H), 4.96(br s, 1H), 3.82(s, 2H), 3.80-3.73(m, 1H), 3.11-2.94(m, 1H), 2.46-2.37(m, 1H), 2.20(s, 3H ),2.17(br s,1H),2.05-1.92(m,3H),1.91-1.61(m,10H),1.61-1.49(m,1H)

保留時間為8.15min的異構體： Isomer with retention time of 8.15 min :

MS(ESI)m/z 428.5[M+H]⁺ MS(ESI)m/z 428.5[M+H] ⁺

¹H NMR(400MHz,DMSO-d6)δ=12.14(s,1H),10.63(s,1H),7.27-7.27(m,1H),7.30(br d,J=8.0Hz,1H),6.28(s,1H),6.21(s,1H),5.02(br s,1H),3.82(s,2H),3.80-3.75(m,1H),3.23-3.14(m,1H),2.19(s,3H),2.14-2.04(m,2H),2.03-1.93(m,1H),1.97(br t,J=7.2Hz,3H),1.88-1.73(m,8H),1.66-1.52(m,2H) ¹ H NMR(400MHz,DMSO-d6)δ=12.14(s,1H),10.63(s,1H),7.27-7.27(m,1H),7.30(br d,J=8.0Hz,1H),6.28( s, 1H), 6.21(s, 1H), 5.02(br s, 1H), 3.82(s, 2H), 3.80-3.75(m, 1H), 3.23-3.14(m, 1H), 2.19(s, 3H) ),2.14-2.04(m,2H),2.03-1.93(m,1H),1.97(br t,J=7.2Hz,3H),1.88-1.73(m,8H),1.66-1.52(m,2H)

實施例3Example 3

順式-3-(5-(2-(3-甲基異噻唑-5-基)乙醯胺基)-1H-吡唑-3-基)環戊基螺[2.3]己烷-4-基胺基甲酸酯異構體 cis-3-(5-(2-(3-methylisothiazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentylspiro[2.3]hexane-4- carbamate isomer

實施例3的合成步驟參見實施例1，其中以化合物螺[2.3]己烷-4-胺鹽酸鹽替換二環[1.1.1]戊烷-1-胺鹽酸鹽製備獲得實施例3。 For the synthesis steps of Example 3, refer to Example 1, wherein the compound spiro[2.3]hexane-4-amine hydrochloride was used to replace bicyclo[1.1.1]pentane-1-amine hydrochloride to obtain Example 3.

分離方法：Waters Xbridge C-18(OBD®；30*150mm,Eluent of 30~95%乙腈/水(0.1%FA)gradient @ 30mL/min)反相色譜法純化，第一個流出物(t_R=7.50min)(5.8mg，產率：16%)；第二個流出物(t_R=7.89min)2b(2.0mg，產率：5.5%)。 Separation method: Waters Xbridge C-18 (OBD®; 30*150mm, Eluent of 30~95% acetonitrile/water (0.1%FA) gradient @ 30mL/min) purified by reverse phase chromatography, the first effluent (t _R = 7.50 min) (5.8 mg, yield: 16%); second effluent (t _R = 7.89 min) 2b (2.0 mg, yield: 5.5%).

保留時間為7.50min的異構體： Isomer with retention time of 7.50 min :

MS(ESI)m/z 414.4[M+H]⁺ MS(ESI)m/z 414.4[M+H] ⁺

¹H NMR(400MHz,DMSO-d6)δ=12.11(s,1H),10.64(s,1H),7.23(d,J=8.3Hz,1H),6.28(s,1H),6.22(s,1H),4.93(d,J=6.9Hz,1H),4.20-4.06(m,1H),3.83(s,2H),3.11-2.96(m,1H),2.46-2.37(m,1H),2.20(s,4H),2.06-1.80(m,4H),1.68(q,J=7.6,7.1Hz,3H),0.53(dt,J=10.2,5.0Hz,1H),0.36(tq,J=10.0,4.8Hz,2H),0.29-0.18(m,1H). ¹ H NMR(400MHz, DMSO-d6) δ =12.11(s,1H),10.64(s,1H),7.23(d,J=8.3Hz,1H),6.28(s,1H),6.22(s,1H) ),4.93(d,J=6.9Hz,1H),4.20-4.06(m,1H),3.83(s,2H),3.11-2.96(m,1H),2.46-2.37(m,1H),2.20( s,4H),2.06-1.80(m,4H),1.68(q,J=7.6,7.1Hz,3H),0.53(dt,J=10.2,5.0Hz,1H),0.36(tq,J=10.0, 4.8Hz,2H),0.29-0.18(m,1H).

實施例4Example 4

順式-3-(3-(2-(3-(二甲基磷基)苯基)乙醯胺基)-1H-吡唑-5-基)環戊基(1-甲基環丙基)胺基甲酸酯異構體 cis-3-(3-(2-(3-(dimethylphosphoryl)phenyl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl) ) urethane isomer

第一步 first step

2-(3-(二甲基磷基)苯基)乙酸4b 2-(3-(Dimethylphosphoryl)phenyl)acetic acid 4b

氮氣氛圍下，將化合物4a(500mg,2.0mmol)，二甲基氧化膦(240.8mg,3.1mmol)，Xantphos(238.0mg,0.41mmol)，K₃PO₄(654.89mg,3.1mmol)和Pd(OAc)₂(46.2mg,0.2mmol)溶於5mL DMF中，在135℃下微波反應1.5h。反應完畢後，加入水洗滌(10mL×3)，用乙酸乙酯萃取(15mL×3)，合併有機相，用水洗滌(20mL)，飽和氯化鈉溶液洗滌(20mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮得到粗品(520mg)。將該粗品溶解於THF(3mL)和水(1mL)中，將3M NaOH(2mL)加入到上述溶液中，室溫攪拌6h。反應完畢後，加入2N HCl調pH至酸性，用C-18反相色譜法純化得到標題化合物4b(200mg，產率：45%)。 Under nitrogen atmosphere, compound 4a (500 mg, 2.0 mmol), dimethylphosphine oxide (240.8 mg, 3.1 mmol), Xantphos (238.0 mg, 0.41 mmol), K ₃ PO ₄ (654.89 mg, 3.1 mmol) and Pd ( OAc) ₂ (46.2 mg, 0.2 mmol) was dissolved in 5 mL of DMF, and the reaction was microwaved at 135° C. for 1.5 h. After the reaction was completed, washed with water (10 mL×3), extracted with ethyl acetate (15 mL×3), combined the organic phases, washed with water (20 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered , the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the crude product (520 mg). The crude product was dissolved in THF (3 mL) and water (1 mL), 3M NaOH (2 mL) was added to the above solution, and the solution was stirred at room temperature for 6 h. After the completion of the reaction, 2N HCl was added to adjust the pH to acidity, and purification was performed by C-18 reverse phase chromatography to obtain the title compound 4b (200 mg, yield: 45%).

MS(ESI)m/z 213.2[M+H]⁺ MS(ESI)m/z 213.2[M+H] ⁺

第二步 second step

順式-3-(1-(第三-丁基)-3-(2-(3-(二甲基磷基)苯基)乙醯胺基)-1H-吡唑-5-基)環戊基(1-methylcyclopropyl)胺基甲酸酯4d cis-3-(1-(3-butyl)-3-(2-(3-(dimethylphosphoryl)phenyl)acetamido)-1H-pyrazol-5-yl)cycle Amyl (1-methylcyclopropyl) carbamate 4d

氮氣氛下，依次將化合物4b(200mg,0.94mmol)、順式-3-(3-胺基-1-(第三-丁基)-1H-吡唑-5-基)環戊基(1-甲基環丙基)胺基甲酸酯4c(302mg,0.94mmol，採用專利申請“WO 2020/157652 A2”公開的方法製備而得)、N,N-二異丙基乙胺(0.31mL,1.89mmol)溶於5mL二氯甲烷中。在室溫下加入1-丙基磷酸酐溶液(50%wt，600mg,1.89mmol)，在室溫下攪拌2小時。加入100mL飽和碳酸氫鈉溶液淬滅反應。用100mL二氯甲烷萃取，有機相用飽和氯化鈉溶液洗滌(100mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘餘物用C-18反相色譜法純化得到標題化合物1f(102mg，產率：21%)。 Under nitrogen atmosphere, compound 4b (200 mg, 0.94 mmol), cis-3-(3-amino-1-(3-butyl)-1H-pyrazol-5-yl)cyclopentyl (1 -methylcyclopropyl)carbamate 4c (302mg, 0.94mmol, prepared by the method disclosed in patent application "WO 2020/157652 A2"), N,N-diisopropylethylamine (0.31mL , 1.89 mmol) was dissolved in 5 mL of dichloromethane. A solution of 1-propylphosphoric anhydride (50% wt, 600 mg, 1.89 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of 100 mL of saturated sodium bicarbonate solution. Extracted with 100 mL of dichloromethane, the organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, the filtrate was concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to obtain the title compound 1f (102 mg, yield: 21%).

MS(ESI)m/z 515.3[M+H]⁺ MS(ESI)m/z 515.3[M+H] ⁺

第三步 third step

順式-3-(3-(2-(3-(二甲基磷基)苯基)乙醯胺基)-1H-吡唑-5-基)環戊基(1-甲基環丙基)胺基甲酸酯4e cis-3-(3-(2-(3-(dimethylphosphoryl)phenyl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl) ) urethane 4e

氮氣氛下，依次將化合物4d(50mg，0.1mmol)溶於1mL甲酸中。在75℃條件下反應4小時。將溶劑旋乾，加入20mL飽和碳酸氫鈉溶液，用乙酸乙酯萃取(20mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(50mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，用C-18反相色譜法純化得到標題化合物4e(20mg，產率：42%)。 Under nitrogen atmosphere, compound 4d (50 mg, 0.1 mmol) was sequentially dissolved in 1 mL of formic acid. The reaction was carried out at 75°C for 4 hours. The solvent was spin-dried, 20 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. Concentration under reduced pressure and purification by C-18 reverse phase chromatography gave the title compound 4e (20 mg, yield: 42%).

MS(ESI)m/z 459.3[M+H]⁺ MS(ESI)m/z 459.3[M+H] ⁺

¹H NMR(400MHz,DMSO-d6)δ=12.07(s,1H),10.59(s,1H),7.74(dd,J=11.9,1.7Hz,1H),7.61(ddt,J=11.3,7.0,1.6Hz,1H),7.53-7.40(m,2H),7.34(s,1H),6.26(s,1H),4.96(s,1H),4.13(d,J=5.6Hz,1H),3.65(s,2H),3.01(d,J=9.4Hz,1H),2.42(dd,J=14.2,7.1Hz,1H),1.96(d,J=9.4Hz,1H),1.68(s,1H),1.65(s,3H),1.62(s,3H),1.21(s,3H),0.57(s,2H),0.49-0.41(m,2H) ¹ H NMR(400MHz, DMSO-d6) δ =12.07(s,1H),10.59(s,1H),7.74(dd,J=11.9,1.7Hz,1H),7.61(ddt,J=11.3,7.0, 1.6Hz, 1H), 7.53-7.40(m, 2H), 7.34(s, 1H), 6.26(s, 1H), 4.96(s, 1H), 4.13(d, J=5.6Hz, 1H), 3.65( s,2H),3.01(d,J=9.4Hz,1H),2.42(dd,J=14.2,7.1Hz,1H),1.96(d,J=9.4Hz,1H),1.68(s,1H), 1.65(s,3H),1.62(s,3H),1.21(s,3H),0.57(s,2H),0.49-0.41(m,2H)

第四步 the fourth step

化合物4e(12mg，0.027mmol)藉由手性拆分(Column：DAICEL CHIRALPAK IG(250mm * 30mm,10μm)Condition：60% EtOH(0.1% NH₃．H₂O)in CO2；FlowRate：80ml/min.)得到實施例4異構體。 Compound 4e (12 mg, 0.027 mmol) was resolved by chirality (Column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm) Condition: 60% _EtOH (0.1% NH3.H2O) in _CO2 ; FlowRate: 80 ml/min .) to give the Example 4 isomer.

保留時間為2.653min(分析方法：Column：Chiralpak IG-3(50mm * 4.6mm,3μm)Gradient：40% EtOH(0.05% DEA)in CO₂；FlowRate：4ml/min；ABPR：1500psi；Temperature：35℃)的異構體(2.1mg，產率：17%)。 The retention time was 2.653 min (Analytical method: Column: Chiralpak IG-3 (50mm*4.6mm, 3μm) Gradient: 40% EtOH (0.05% DEA) in CO ₂ ; FlowRate: 4ml/min; ABPR: 1500psi; Temperature: 35 °C) isomer (2.1 mg, yield: 17%).

MS(ESI)m/z 459.2[M+H]⁺ MS(ESI)m/z 459.2[M+H] ⁺

保留時間為4.489min(分析方法：Column：Chiralpak IG-3(50mm * 4.6mm,3μm)Gradient：40% EtOH(0.05% DEA)in CO₂；FlowRate：4ml/min；ABPR：1500psi；Temperature：35℃)的異構體(2.0mg，產率：16%)。 Retention time was 4.489 min (Analytical method: Column: Chiralpak IG-3 (50mm*4.6mm, 3μm) Gradient: 40% EtOH (0.05% DEA) in CO ₂ ; FlowRate: 4ml/min; ABPR: 1500psi; Temperature: 35 °C) isomer (2.0 mg, yield: 16%).

MS(ESI)m/z 459.3[M+H]⁺ MS(ESI)m/z 459.3[M+H] ⁺

實施例5Example 5

順式-3-(3-(2-(4-(二甲基磷基)苯基)乙醯胺基)-1H-吡唑-5-基)環戊基(1-甲基環丙基)胺基甲酸酯異構體 cis-3-(3-(2-(4-(dimethylphosphoryl)phenyl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl) ) urethane isomer

實施例5的合成步驟參見實施例4，其中以化合物乙基2-(4-碘苯基)乙酸酯替換化合物4a製備獲得實施例5。手性拆分條件：Column： Phenomenex-Cellulose-2(250mm * 30mm,10μm)Condition：45% EtOH in CO2；FlowRate：80ml/min. For the synthesis procedure of Example 5 , see Example 4, wherein compound 4a was replaced by compound ethyl 2-(4-iodophenyl)acetate to obtain Example 5 . Chiral separation conditions: Column: Phenomenex-Cellulose-2 (250mm * 30mm, 10μm) Condition: 45% EtOH in CO2; FlowRate: 80ml/min.

保留時間為6.249min(分析方法：Column：Cellulose 2(150mm * 4.6mm,5μm)Gradient：40% EtOH(0.05% DEA)in CO₂；FlowRate：2.5ml/min；ABPR：1500psi；Temperature：35℃)的異構體： The retention time is 6.249min (Analysis method: Column: Cellulose 2 (150mm*4.6mm, 5μm) Gradient: 40% EtOH (0.05% DEA) in CO ₂ ; FlowRate: 2.5ml/min; ABPR: 1500psi; Temperature: 35°C ) isomers:

MS(ESI)m/z 459.2[M+H]⁺ MS(ESI)m/z 459.2[M+H] ⁺

保留時間為8.351min(分析方法：Column：Cellulose 2(150mm * 4.6mm,5μm)Gradient：40% EtOH(0.05% DEA)in CO₂；FlowRate：2.5ml/min；ABPR：1500psi；Temperature：35℃)的異構體： The retention time was 8.351 min (Analysis method: Column: Cellulose 2 (150mm*4.6mm, 5μm) Gradient: 40% EtOH (0.05% DEA) in CO ₂ ; FlowRate: 2.5ml/min; ABPR: 1500psi; Temperature: 35°C ) isomers:

MS(ESI)m/z 459.2[M+H]⁺ MS(ESI)m/z 459.2[M+H] ⁺

實施例6Example 6

順式-3-(3-(2-(4-(2-羰基噁唑烷-3-基)苯基)乙醯胺基)-1H-吡唑-5-基)環戊基(1-甲基環丙基)胺基甲酸酯 cis-3-(3-(2-(4-(2-carbonyloxazolidin-3-yl)phenyl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1- Methylcyclopropyl)carbamate

第一步 first step

順式-3-(1-(第三-丁基)-5-(2-(4-(2-羰基噁唑烷-3-基)苯基)乙醯胺基)-1H-吡唑-3-基)環戊基(1-甲基環丙基)胺基甲酸酯6b cis-3-(1-(3-butyl)-5-(2-(4-(2-carbonyloxazolidin-3-yl)phenyl)acetamido)-1H-pyrazole- 3-yl)cyclopentyl(1-methylcyclopropyl)carbamate 6b

氮氣氛下，將2-(4-(2-羰基噁唑烷-3-基)苯基)乙酸(參照專利WO20110037780合成，50mg，0.2mmol)、(順式-3-(5-胺基-1-(第三-丁基)-1H-吡唑-3-基)環戊基(1-甲基環丙基)胺基甲酸酯(參照專利US2020247784合成，80mg，0.2mmol)、2-(7-偶氮苯并***)-N,N,N',N'- 四甲基脲六氟磷酸鹽(129mg，0.3mmol)、三乙胺(69mg，0.7mmol)溶於2mL N,N-二甲基甲醯胺中。在20℃條件下反應1小時，加入10mL水，用乙酸乙酯萃取，合併有機相，將有機相洗滌，乾燥，反應液減壓濃縮後殘餘物用矽膠正相色譜法純化得到標題化合物6b(80mg，產率：68%)。 Under nitrogen atmosphere, 2-(4-(2-carbonyloxazolidin-3-yl)phenyl)acetic acid (synthesized with reference to patent WO20110037780, 50 mg, 0.2 mmol), (cis-3-(5-amino- 1-(Third-butyl)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate (synthesized with reference to patent US2020247784, 80mg, 0.2mmol), 2- (7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (129 mg, 0.3 mmol), triethylamine (69 mg, 0.7 mmol) were dissolved in 2 mL of N, N-dimethylformamide, reacted at 20°C for 1 hour, added 10 mL of water, extracted with ethyl acetate, combined the organic phases, washed the organic phases, dried, the reaction solution was concentrated under reduced pressure, and the residue was washed with silica gel Purification by normal phase chromatography gave the title compound 6b (80 mg, yield: 68%).

MS(ESI)m/z 524.4[M+H]⁺ MS(ESI)m/z 524.4[M+H] ⁺

第二步 second step

順式-3-(3-(2-(4-(2-羰基噁唑烷-3-基)苯基)乙醯胺基)-1H-吡唑-5-基)環戊基(1-甲基環丙基)胺基甲酸酯6 cis-3-(3-(2-(4-(2-carbonyloxazolidin-3-yl)phenyl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1- Methylcyclopropyl)carbamate 6

氮氣氛下，將化合物順式-3-(1-(第三-丁基)-5-(2-(4-(2-羰基噁唑烷-3-基)苯基)乙醯胺基)-1H-吡唑-3-基)環戊基(1-甲基環丙基)胺基甲酸酯(30mg，0.06mmol)溶於1.5mL甲酸中。在80℃條件下微波反應1.5小時。將溶劑旋乾，加入20mL飽和碳酸氫鈉溶液，用乙酸乙酯萃取(20mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(50mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘餘物用C-18反相色譜法純化得到標題化合物6(14mg，產率：52%)，其為一對對映異構體。 Under nitrogen atmosphere, compound cis-3-(1-(3-butyl)-5-(2-(4-(2-carbonyloxazolidin-3-yl)phenyl)acetamido) -1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate (30 mg, 0.06 mmol) was dissolved in 1.5 mL of formic acid. The reaction was microwaved at 80°C for 1.5 hours. The solvent was spin-dried, 20 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. It was concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to give the title compound 6 (14 mg, yield: 52%) as a pair of enantiomers.

MS(ESI)m/z 468.3[M+H]⁺ MS(ESI)m/z 468.3[M+H] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ=12.05(br s,1H),10.48(br s,1H),7.49(d,J=8.5Hz,2H),7.39-7.26(m,3H),6.26(br s,1H),4.96(br s,1H),4.42(t,J=8.0Hz,2H),4.03(t,J=7.9Hz,2H),3.55(s,2H),3.01(br d,J=8.3Hz,1H),2.43(br d,J=6.8Hz,1H),1.96(br d,J=8.6Hz,1H),1.90-1.81(m,1H),1.73-1.60(m,2H),1.52(br s,1H),1.22(br s,3H),0.57(br s,2H),0.51-0.38(m,2H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ =12.05(br s,1H),10.48(br s,1H),7.49(d,J=8.5Hz,2H),7.39-7.26(m,3H), 6.26(br s,1H),4.96(br s,1H),4.42(t,J=8.0Hz,2H),4.03(t,J=7.9Hz,2H),3.55(s,2H),3.01(br d,J=8.3Hz,1H),2.43(br d,J=6.8Hz,1H),1.96(br d,J=8.6Hz,1H),1.90-1.81(m,1H),1.73-1.60(m ,2H),1.52(br s,1H),1.22(br s,3H),0.57(br s,2H),0.51-0.38(m,2H)

實施例7Example 7

順式-3-(3-(2-(4-(2-羰基吡咯烷-1-基)苯基)乙醯胺基)-1H-吡唑-5-基)環戊基(1-甲基環丙基)胺基甲酸酯 cis-3-(3-(2-(4-(2-carbonylpyrrolidin-1-yl)phenyl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methyl) cyclopropyl)carbamate

參照實施例6合成，其中化合物2-(4-(2-羰基吡咯烷-1-基)苯基)乙酸7a參照專利WO2015145371合成，得到的7是一對對映異構體。 Refer to Example 6 for synthesis, wherein compound 2-(4-(2-carbonylpyrrolidin-1-yl)phenyl)acetic acid 7a is synthesized with reference to patent WO2015145371, and the obtained 7 is a pair of enantiomers.

MS(ESI)m/z 466.2[M+H]⁺ MS(ESI)m/z 466.2[M+H] ⁺

¹H NMR(400MHz,DMSO-d6)δ=12.04(br s,1H),10.47(s,1H),7.57(d,J=8.6Hz,2H),7.34(br s,1H),7.29(d,J=8.8Hz,2H),6.26(br s,1H),4.96(br s,1H),3.80(t,J=7.1Hz,2H),3.54(s,2H),2.12-1.98(m,4H),1.96-1.79(m,2H),1.77-1.41(m,4H),1.27-1.17(m,4H),0.57(br s,2H),0.49-0.42(m,2H) ¹ H NMR(400MHz,DMSO-d6) δ =12.04(br s,1H),10.47(s,1H),7.57(d,J=8.6Hz,2H),7.34(br s,1H),7.29(d ,J=8.8Hz,2H),6.26(br s,1H),4.96(br s,1H),3.80(t,J=7.1Hz,2H),3.54(s,2H),2.12-1.98(m, 4H), 1.96-1.79(m, 2H), 1.77-1.41(m, 4H), 1.27-1.17(m, 4H), 0.57(br s, 2H), 0.49-0.42(m, 2H)

實施例8Example 8

(1R,3S)-3-(3-(2-(3-甲基-2-羰基-2,3-二氫苯并[d]噁唑-5-基)乙醯胺基)-1H-吡唑-5-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯 (1R,3S)-3-(3-(2-(3-Methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazol-5-yl)acetamido)-1H- Pyrazol-5-yl)cyclopentylbicyclo[1.1.1]pentan-1-ylcarbamate

第一步 first step

2-(2-側氧-2,3-二氫苯并[d]噁唑-5-基)乙酸甲酯INT-2 Methyl 2-(2-oxo-2,3-dihydrobenzo[ d ]oxazol-5-yl)acetate INT-2

氮氣氛下，常溫將化合物INT-1(2.5g,13.81mmol)溶於25mL無水四氫呋喃中，加入羰基二咪唑(3.3g,20.72mmol)，60℃條件下加熱反應10小時，反應液冷卻至室溫，減壓濃縮後殘餘物用矽膠管柱層析(石油醚/乙酸乙酯體系)得到題化合物INT-2(2.5g，產率：87.7%)。 Under a nitrogen atmosphere, compound INT-1 (2.5 g, 13.81 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran at room temperature, carbonyldiimidazole (3.3 g, 20.72 mmol) was added, and the reaction was heated at 60 ° C for 10 hours, and the reaction solution was cooled to room temperature After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate system) to obtain the title compound INT-2 (2.5 g, yield: 87.7%).

MS(ESI)m/z 208.1[M+H]⁺ MS(ESI)m/z 208.1[M+H] ⁺

第二步 second step

2-(3-甲基-2-側氧-2,3-二氫苯并[d]噁唑-5-基)乙酸甲酯INT-3 Methyl 2-(3-methyl-2-oxo-2,3-dihydrobenzo[ d ]oxazol-5-yl)acetate INT-3

氮氣氛下，常溫將化合物INT-2(2.5g,12.07mmol)溶於20mL無水N,N-二甲基甲醯胺中，加入碳酸鉀(2.5g,18.11mmol)，繼續攪拌20分鐘，接著降溫到0℃並滴加碘甲烷(2.1g,14.48mmol)，滴畢後升溫至室溫並繼續攪拌5小時。反應液用飽和氯化鈉溶液淬滅，用乙酸乙酯萃取(15mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(20mL)，無水硫酸鈉乾燥，過濾，收集濾液，減壓濃縮後殘餘物用矽膠管柱層析(正庚烷/乙酸乙酯體系)得到標題化合物INT-3(2.3g，產率：86.5%)。 Under a nitrogen atmosphere, compound INT-2 (2.5 g, 12.07 mmol) was dissolved in 20 mL of anhydrous N,N -dimethylformamide at room temperature, potassium carbonate (2.5 g, 18.11 mmol) was added, and stirring was continued for 20 minutes, followed by The temperature was lowered to 0° C. and iodomethane (2.1 g, 14.48 mmol) was added dropwise. After the dropping was completed, the temperature was raised to room temperature and stirring was continued for 5 hours. The reaction solution was quenched with saturated sodium chloride solution, extracted with ethyl acetate (15 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected and concentrated under reduced pressure The residue was subjected to silica gel column chromatography (n-heptane/ethyl acetate system) to obtain the title compound INT-3 (2.3 g, yield: 86.5%).

MS(ESI)m/z 222.1[M+H]⁺ MS(ESI)m/z 222.1[M+H] ⁺

第三步 third step

2-(3-甲基-2-側氧-2,3-二氫苯并[d]噁唑-5-基)乙酸INT-4 2-(3-Methyl-2-oxo-2,3-dihydrobenzo[ d ]oxazol-5-yl)acetic acid INT-4

氮氣氛下，常溫將化合物INT-3(300mg,1.36mmol)懸浮於20mL 6N鹽酸水溶液中，100℃條件下加熱反應3小時，反應液冷卻至室溫，過濾得到化合物INT-4(200mg，產率：71.4%)。 Under a nitrogen atmosphere, compound INT-3 (300 mg, 1.36 mmol) was suspended in 20 mL of 6N aqueous hydrochloric acid at room temperature, heated for 3 hours at 100 °C, the reaction solution was cooled to room temperature, and filtered to obtain compound INT-4 (200 mg, yielded rate: 71.4%).

MS(ESI)m/z 206.1[M-H]^- MS(ESI)m/z 206.1[MH] ^-

第四步 the fourth step

(1R,3S)-3-(5-(((苄氧基)羰基)胺基)-1-(第三-丁基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯 (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(3-butyl)-1H-pyrazol-3-yl)cyclopentylbicyclo[1.1 .1]Pentan-1-ylcarbamate

在室溫下，將苯甲基(1-(第三-丁基)-3-((1S,3R)-3-(((4-硝基苯氧基)羰基)氧基)環戊基)-1氫-吡唑-5-基)胺基甲酸酯8a(3.00g,5.74mmol)溶於30mL N,N-二甲基甲醯胺中，加入二環[1.1.1]戊烷-1-胺鹽酸8b(686mg，5.74mmol)和N,N-二異丙基乙胺(2226mg,17.22mmol)，將反應液升溫至60℃氬氣下攪拌反應16小時。反應結束後將反應液倒入200mL水中，用乙酸乙酯萃取(80mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(100mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，殘留物用矽膠色譜法以石油醚、乙酸乙酯沖提純化，得到標題化合物8c(2.50g，產率：93.3%)。 At room temperature, the benzyl (1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl )-1hydro-pyrazol-5-yl)carbamate 8a (3.00 g, 5.74 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and bicyclo[1.1.1]pentane was added -1-amine hydrochloride 8b (686 mg, 5.74 mmol) and N,N-diisopropylethylamine (2226 mg, 17.22 mmol), the reaction solution was heated to 60° C. and stirred under argon for 16 hours. After the reaction, the reaction solution was poured into 200 mL of water, extracted with ethyl acetate (80 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was decompressed. After concentration, the residue was purified by silica gel chromatography eluting with petroleum ether, ethyl acetate to give the title compound 8c (2.50 g, yield: 93.3%).

MS(ESI)m/z 467.5[M+H]⁺ MS(ESI)m/z 467.5[M+H] ⁺

第五步 the fifth step

(1R,3S)-3-(5-胺基-1-(第三-丁基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯 (1R,3S)-3-(5-Amino-1-(3-butyl)-1H-pyrazol-3-yl)cyclopentylbicyclo[1.1.1]pentan-1-ylamine carbamate

在室溫下，將(1R,3S)-3-(5-(((苄氧基)羰基)胺基)-1-(第三-丁基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯8c(2.50g,5.36mmol)溶於20mL二氯甲烷和16mL甲醇中，加入濕鈀/碳(500mg)，將反應液氫氣球下攪拌反應16小時。反應結束後將反應液過濾，收集濾液，濾液減壓濃縮，得到標題化合物8d(1.50g，產率：74.4%)。 At room temperature, the (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl) ring was Amylbicyclo[1.1.1]pentan-1-ylcarbamate 8c (2.50 g, 5.36 mmol) was dissolved in 20 mL of dichloromethane and 16 mL of methanol, wet palladium/carbon (500 mg) was added, and the reaction was quenched The reaction was stirred under a liquid hydrogen balloon for 16 hours. After the reaction, the reaction solution was filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the title compound 8d (1.50 g, yield: 74.4%).

MS(ESI)m/z 377.5[M+H]⁺ MS(ESI)m/z 377.5[M+H] ⁺

第六步 Step 6

(1R,3S)-3-(1-(第三-丁基)-5-(2-(3-甲基-2-羰基-2,3-二氫苯并[d]噁唑-5-基)乙醯胺基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯 (1R,3S)-3-(1-(3-butyl)-5-(2-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazole-5- yl)acetamido)-1H-pyrazol-3-yl)cyclopentylbicyclo[1.1.1]pentan-1-ylcarbamate

在室溫下，將(1R,3S)-3-(5-胺基-1-(第三-丁基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯8d(100mg,0.301mmol)和2-(3-甲基-2-羰基-2,3-二氫苯并[d]噁唑-5-基)乙酸INT-4(62.4mg，0.301mmol)溶於2mL二氯甲烷中，加入N,N-二異丙基乙胺(116.6mg，0.902mmol)和丙基磷酸三環酸酐溶液(574mg,0.902mmol，50%品質含量)，將反應液在氬氣球保護下攪拌反應2小時。反應結束後將反應液使用二氯甲烷(40mL)稀釋，用飽和氯化鈉溶液洗滌(20mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，得到標題化合物8e(130mg，產率：82.8%)。 At room temperature, (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylbicyclo[1.1.1]pentyl Alk-1-ylcarbamate 8d (100 mg, 0.301 mmol) and 2-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazol-5-yl)acetic acid INT -4 (62.4 mg, 0.301 mmol) was dissolved in 2 mL of dichloromethane, N,N-diisopropylethylamine (116.6 mg, 0.902 mmol) and propylphosphoric tricyclic anhydride solution (574 mg, 0.902 mmol, 50 % quality content), the reaction solution was stirred for 2 hours under the protection of an argon balloon. After the reaction, the reaction solution was diluted with dichloromethane (40 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the title compound 8e (130 mg, yield : 82.8%).

MS(ESI)m/z 521.6[M+H]⁺ MS(ESI)m/z 521.6[M+H] ⁺

第七步 Step 7

在室溫下，將(1R,3S)-3-(1-(第三-丁基)-5-(2-(3-甲基-2-羰基-2,3-二氫苯并[d]噁唑-5-基)乙醯胺基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯8e(130mg,0.249mmol)溶於2mL甲酸中，將反應液在85℃下氬氣球保護下攪拌反應16小時。反應8h結束後將反應液減壓濃縮，使用C18反相管柱得到標題化合物8(85mg，產率：73.3%)。 At room temperature, (1R,3S)-3-(1-(tert-butyl)-5-(2-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d ]oxazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentylbicyclo[1.1.1]pentan-1-ylcarbamate 8e (130 mg, 0.249 mmol ) was dissolved in 2 mL of formic acid, and the reaction solution was stirred for 16 hours at 85° C. under the protection of an argon balloon. After the reaction for 8 h, the reaction solution was concentrated under reduced pressure, and the title compound 8 (85 mg, yield: 73.3%) was obtained by using a C18 reversed-phase column.

MS(ESI)m/z 466.6[M+H] MS(ESI)m/z 466.6[M+H]

¹H NMR(400MHz,DMSO-d ₆)δ=10.70(s,1H),7.73(s,1H),7.25(dd,J=7.7,1.5Hz,1H),7.15-7.05(m,2H),6.26(s,1H),4.96(s,1H),3.94(s,2H),3.58(s,3H),3.04(d,J=10.0Hz,1H),2.48-2.39(m,1H),2.37-2.24(m,1H),1.98(d,J=9.8Hz,1H),1.92-1.80(m,7H),1.62(d,J=52.7Hz,3H). ¹ H NMR (400MHz, DMSO- d ₆ ) δ = 10.70(s, 1H), 7.73(s, 1H), 7.25(dd, J =7.7, 1.5Hz, 1H), 7.15-7.05(m, 2H), 6.26(s, 1H), 4.96(s, 1H), 3.94(s, 2H), 3.58(s, 3H), 3.04(d, J = 10.0Hz, 1H), 2.48-2.39(m, 1H), 2.37 -2.24(m,1H),1.98(d, J =9.8Hz,1H),1.92-1.80(m,7H),1.62(d, J =52.7Hz,3H).

實施例9Example 9

(1R,3S)-3-(3-(2-(3-甲基-2-羰基-2,3-二氫苯并[d]噁唑-7-基)乙醯胺基)-1H-吡唑-5-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯 (1R,3S)-3-(3-(2-(3-Methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazol-7-yl)acetamido)-1H- Pyrazol-5-yl)cyclopentylbicyclo[1.1.1]pentan-1-ylcarbamate

第一步 first step

2-(2-羥基-3-硝基苯基)乙酸甲酯INT-6 Methyl 2-(2-hydroxy-3-nitrophenyl)acetate INT-6

氮氣氛下，常溫將化合物INT-5(1.5g,9.03mmol)溶於12mL石油醚中，降溫到0℃左右滴加HNO₃(0.9mL)/AC₂O(9mL)溶液，繼續攪拌20分鐘。用冰水淬滅反應，用乙酸乙酯萃取(25mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(30mL)，無水硫酸鈉乾燥，過濾，收集濾液，減壓濃縮後殘餘物用矽膠管柱層析(正庚烷/乙酸乙酯體系)得到標題化合物INT-6(0.95g，產率：49.8%)。 Under nitrogen atmosphere, compound INT-5 (1.5 g, 9.03 mmol) was dissolved in 12 mL of petroleum ether at room temperature, cooled to about 0 °C, and HNO ₃ (0.9 mL)/AC ₂ O (9 mL) solution was added dropwise, and stirring was continued for 20 minutes. . The reaction was quenched with ice water, extracted with ethyl acetate (25 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was used Silica gel column chromatography (n-heptane/ethyl acetate system) gave the title compound INT-6 (0.95 g, yield: 49.8%).

第二步 second step

2-(3-胺基-2-羥基苯基)乙酸甲酯INT-7 Methyl 2-(3-amino-2-hydroxyphenyl)acetate INT-7

常溫將化合物INT-6(0.8g,3.79mmol)溶於20mL甲醇中，加入0.2g 10%Pd/C、氫氣置換三次，繼續攪拌12小時。過濾，濾餅用甲醇(20mL×3)洗滌，收集濾液，減壓濃縮後得到標題化合物INT-7(0.66g，產率：96%)。 Compound INT-6 (0.8 g, 3.79 mmol) was dissolved in 20 mL of methanol at room temperature, 0.2 g of 10% Pd/C was added, hydrogen was replaced three times, and stirring was continued for 12 hours. Filtration, the filter cake was washed with methanol (20 mL×3), the filtrate was collected and concentrated under reduced pressure to obtain the title compound INT-7 (0.66 g, yield: 96%).

MS(ESI)m/z 182.1[M+H]⁺ MS(ESI)m/z 182.1[M+H] ⁺

第三步 third step

2-(2-側氧-2,3-二氫苯并[d]噁唑-7-基)乙酸甲酯INT-8 Methyl 2-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)acetate INT-8

參照化合物INT-2的合成方法，以化合物INT-7(0.7g,3.86mmol)為原料得到化合物INT-8(0.65g，產率：81.2%)。 Referring to the synthesis method of compound INT-2 , compound INT-7 (0.7 g, 3.86 mmol) was used as raw material to obtain compound INT-8 (0.65 g, yield: 81.2%).

MS(ESI)m/z 208.1[M+H]⁺ MS(ESI)m/z 208.1[M+H] ⁺

第四步 the fourth step

2-(3-甲基-2-側氧-2,3-二氫苯并[d]噁唑-7-基)乙酸甲酯INT-9 Methyl 2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)acetate INT-9

參照化合物INT-3的合成方法，以化合物INT-8(0.5g,2.41mmol)為原料得到化合物INT-9(0.5g，產率：78.5%)。 Referring to the synthesis method of compound INT-3 , compound INT-8 (0.5 g, 2.41 mmol) was used as a raw material to obtain compound INT-9 (0.5 g, yield: 78.5%).

MS(ESI)m/z 222.1[M+H]⁺ MS(ESI)m/z 222.1[M+H] ⁺

第五步 the fifth step

2-(3-甲基-2-側氧-2,3-二氫苯并[d]噁唑-7-基)乙酸INT-10 2-(3-Methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)acetic acid INT-10

參照化合物INT-4的合成方法，以化合物INT-9(0.3g,1.36mmol)為原料得到化合物INT-10(0.2g，產率：72%)。 Referring to the synthesis method of compound INT-4 , compound INT-9 (0.3 g, 1.36 mmol) was used as raw material to obtain compound INT-10 (0.2 g, yield: 72%).

MS(ESI)m/z 206.1[M-H]^- MS(ESI)m/z 206.1[MH] ^-

第六步 Step 6

(1R,3S)-3-(1-(第三-丁基)-5-(2-(3-甲基-2-羰基-2,3-二氫苯并[d]噁唑-7-基)乙醯胺基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯 (1R,3S)-3-(1-(3-butyl)-5-(2-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazole-7- yl)acetamido)-1H-pyrazol-3-yl)cyclopentylbicyclo[1.1.1]pentan-1-ylcarbamate

在室溫下，將(1R,3S)-3-(5-胺基-1-(第三-丁基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯8d(80mg,0.241mmol)和2-(3-甲基-2-羰基-2,3-二氫苯并[d]噁唑-7-基)乙酸INT-10(50.0mg，0.241 mmol)溶於2mL二氯甲烷中，加入N,N-二異丙基乙胺(93.3mg，0.772mmol)和丙基磷酸三環酸酐溶液(459mg,0.722mmol，50%品質含量)，將反應在氬氣球下攪拌反應2小時。反應結束後將反應液使用二氯甲烷(40mL)稀釋，用飽和氯化鈉溶液洗滌(20mL)，無水硫酸鈉乾燥，過濾，收集濾液，濾液減壓濃縮，得到標題化合物9a(110mg，產率：87.6%)。 At room temperature, (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylbicyclo[1.1.1]pentyl Alk-1-ylcarbamate 8d (80 mg, 0.241 mmol) and 2-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d]oxazol-7-yl)acetic acid INT -10 (50.0 mg, 0.241 mmol) was dissolved in 2 mL of dichloromethane, N,N-diisopropylethylamine (93.3 mg, 0.772 mmol) and a solution of propylphosphoric tricyclic anhydride (459 mg, 0.722 mmol, 50 % quality content), the reaction was stirred under an argon balloon for 2 hours. After the reaction, the reaction solution was diluted with dichloromethane (40 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the title compound 9a (110 mg, yield : 87.6%).

MS(ESI)m/z 521.6[M+H]⁺ MS(ESI)m/z 521.6[M+H] ⁺

第七步 Step 7

在室溫下，將(1R,3S)-3-(1-(第三-丁基)-5-(2-(3-甲基-2-羰基-2,3-二氫苯并[d]噁唑-7-基)乙醯胺基)-1H-吡唑-3-基)環戊基二環[1.1.1]戊烷-1-基胺基甲酸酯9a(110mg,0.211mmol)溶於2mL甲酸中，將反應液在85℃氬氣球下攪拌反應16小時。反應結束後將反應液減壓濃縮，使用C18反相管柱得到標題化合物9(85mg，產率：86.6%)。 At room temperature, (1R,3S)-3-(1-(tert-butyl)-5-(2-(3-methyl-2-carbonyl-2,3-dihydrobenzo[d ]oxazol-7-yl)acetamido)-1H-pyrazol-3-yl)cyclopentylbicyclo[1.1.1]pentan-1-ylcarbamate 9a (110 mg, 0.211 mmol ) was dissolved in 2 mL of formic acid, and the reaction solution was stirred at 85° C. under an argon balloon for 16 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the title compound 9 (85 mg, yield: 86.6%) was obtained using a C18 reversed-phase column.

MS(ESI)m/z 466.6[M+H]⁺ MS(ESI)m/z 466.6[M+H] ⁺

實施例10Example 10

(1R,3S)-3-(5-(2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)環戊基(1-甲基環丙基)胺基甲酸酯 ( 1R,3S )-3-(5-(2-(2-chloro-4-(2-oxopyrrolidin-1-yl)phenyl)propylamino)-1H-pyrazol-3- yl )cyclopentane yl(1-methylcyclopropyl)carbamate

第一步 first step

2-(2-氯-4-硝基苯基)-2-甲基丙二酸二乙酯10C 2-(2-Chloro-4-nitrophenyl)-2-methylmalonate diethyl ester 10C

氮氣氛下，在0℃，60% NaH(3.1g,77.9mmol)加到DMF(100mL)，保持0℃逐滴加入化合物10B(11.8mL,68.4mmol)，滴畢0℃攪拌0.5小時。加入化合物10A(10g,56.9mmol)，將混合物加熱至70℃並攪拌3小時。將反應混合物倒入飽和NH₄Cl溶液中。用二氯甲烷萃取，用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物10C(17g，產率：99%)。 Under nitrogen atmosphere, 60% NaH (3.1 g, 77.9 mmol) was added to DMF (100 mL) at 0 °C, compound 10B (11.8 mL, 68.4 mmol) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Compound 10A (10 g, 56.9 mmol) was added and the mixture was heated to 70°C and stirred for 3 hours. The reaction mixture was poured into saturated _NH4Cl solution. It was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 10C (17 g, yield: 99%).

LCMS(ESI)m/z 330.2[M+H]⁺。 LCMS (ESI) m/z 330.2 [M+H] ⁺ .

第二步 second step

2-(2-氯-4-硝基苯基)丙酸10D 2-(2-Chloro-4-nitrophenyl)propionic acid 10D

將化合物10C(11g,33.3mmol)加入水(27mL)，乙酸(37mL)和硫酸(10mL)的混合溶液中回流反應24小時。反應液減壓濃縮，DCM萃取，有機層用飽和Na₂CO₃水溶液洗滌，用1N HCl酸化水層後用DCM萃取，乾燥濃縮得化合物10D(6.6g，產率：86%)。 Compound 10C (11 g, 33.3 mmol) was added to a mixed solution of water (27 mL), acetic acid (37 mL) and sulfuric acid (10 mL) to react under reflux for 24 hours. The reaction solution was concentrated under reduced pressure, extracted with DCM, the organic layer was washed with saturated aqueous Na ₂ CO ₃ solution, the aqueous layer was acidified with 1N HCl, extracted with DCM, dried and concentrated to obtain compound 10D (6.6 g, yield: 86%).

¹H NMR(400MHz,Chloroform-d)δ 8.33(d,J=2.4Hz,1H),8.18(dd,J=8.6,2.4Hz,1H),7.60(d,J=8.6Hz,1H),4.38(q,J=7.2Hz,1H),1.63(d,J=7.2Hz,3H)。 ¹ H NMR (400MHz, Chloroform- d ) δ 8.33(d, J =2.4Hz, 1H), 8.18(dd, J =8.6, 2.4Hz, 1H), 7.60(d, J =8.6Hz, 1H), 4.38 (q, J = 7.2Hz, 1H), 1.63 (d, J = 7.2Hz, 3H).

第三步 third step

2-(2-氯-4-硝基苯基)丙酸甲酯10E Methyl 2-(2-chloro-4-nitrophenyl)propanoate 10E

將化合物10D(6.6g,28.8mmol)溶於甲醇(100mL)，在濃硫酸(0.1g，1.1mmol)催化下回流3h。冷卻至室溫後，減壓濃縮反應液。MTBE(100×3mL)萃取，用飽和NaHCO₃水溶液和鹽水洗滌。用無水硫酸鈉乾燥，濃縮得化合物10E(7.0g，產率：100%)。 Compound 10D (6.6 g, 28.8 mmol) was dissolved in methanol (100 mL) and refluxed for 3 h under the catalysis of concentrated sulfuric acid (0.1 g, 1.1 mmol). After cooling to room temperature, the reaction solution was concentrated under reduced pressure. Extracted with MTBE (100 x 3 mL), washed with saturated aqueous _NaHCO3 and brine. It was dried over anhydrous sodium sulfate and concentrated to give compound 10E (7.0 g, yield: 100%).

第四步 the fourth step

2-(2-氯-4-胺基苯基)丙酸甲酯10F Methyl 2-(2-chloro-4-aminophenyl)propanoate 10F

氮氣氛下，將化合物10E(7g,28.6mmol)溶於甲醇(35mL)和水(28mL)的混合液中，加入NH₄Cl(1.2mL,34.3mmol)和鐵粉(4.8g,85.9mmol)。將混合物加熱至68℃，繼續攪拌2小時。將反應物冷卻至室溫並過濾，濾餅用甲醇(50mL×3)洗滌。濃縮濾液除MeOH，水相用乙酸乙酯(50mL×3)萃取，用鹽水(40mL×3)洗滌，無水硫酸鈉乾燥，過濾，濃縮得化合物10F(5.8g，產率：94%)。 Under nitrogen atmosphere, compound 10E (7 g, 28.6 mmol) was dissolved in a mixture of methanol (35 mL) and water (28 mL), NH ₄ Cl (1.2 mL, 34.3 mmol) and iron powder (4.8 g, 85.9 mmol) were added . The mixture was heated to 68°C and stirring was continued for 2 hours. The reaction was cooled to room temperature and filtered, and the filter cake was washed with methanol (50 mL x 3). The filtrate was concentrated to remove MeOH, the aqueous phase was extracted with ethyl acetate (50 mL×3), washed with brine (40 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 10F (5.8 g, yield: 94%).

LCMS(ESI)m/z 214.2[M+H]⁺。 LCMS (ESI) m/z 214.2 [M+H] ⁺ .

第五步 the fifth step

2-(2-氯-4-(4-氯丁胺基)苯基)丙酸甲酯10G Methyl 2-(2-chloro-4-(4-chlorobutylamino)phenyl)propanoate 10G

氮氣氛下，將化合物10F(3.2g,15.1mmol)溶於二氯甲烷(32mL)，加入三乙胺(3.1mL，22.5mmol)，在0℃下逐滴加入4-氯丁醯氯(3.7mL，32.9mmol)，在室溫反應3h。用水(30mL)淬滅，二氯甲烷萃取(100mL×3).鹽水(100mL)洗滌，無水硫酸鈉乾燥，濃縮得化合物10G(4.6g，產率：96%)。 Under nitrogen atmosphere, compound 10F (3.2 g, 15.1 mmol) was dissolved in dichloromethane (32 mL), triethylamine (3.1 mL, 22.5 mmol) was added, and 4-chlorobutane chloride (3.7 mmol) was added dropwise at 0°C mL, 32.9 mmol), reacted at room temperature for 3 h. Quenched with water (30 mL), extracted with dichloromethane (100 mL×3). Washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 10G (4.6 g, yield: 96%).

LCMS(ESI)m/z 318.2[M+H]⁺。 LCMS (ESI) m/z 318.2 [M+H] ⁺ .

第六步 Step 6

2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙酸甲酯10H Methyl 2-(2-chloro-4-(2-oxopyrrolidin-1-yl)phenyl)propanoate 10H

氮氣氛下，將化合物10G(4.6g,14.5mmol)溶於DMF(20mL)，在室溫下滴加DBU(1.5mL，10mmol)。反應在100℃下加熱攪拌過夜。用水(50mL)淬滅反應，並用二氯甲烷萃取(50mL×3)，用鹽水(50mL)洗滌，在無水硫酸鈉乾燥，濃縮得化合物10H(3.80g，產率：99%)。 Under nitrogen atmosphere, compound 10G (4.6 g, 14.5 mmol) was dissolved in DMF (20 mL), and DBU (1.5 mL, 10 mmol) was added dropwise at room temperature. The reaction was heated and stirred at 100°C overnight. The reaction was quenched with water (50 mL), extracted with dichloromethane (50 mL×3), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 10H (3.80 g, yield: 99%).

LCMS(ESI)m/z 282.3[M+H]⁺。 LCMS (ESI) m/z 282.3 [M+H] ⁺ .

第七步 Step 7

2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙酸10I 2-(2-Chloro-4-(2-oxopyrrolidin-1-yl)phenyl)propionic acid 10I

氮氣氛下，常溫將化合物10H(520mg,1.8mmol)懸浮於20mL 6N鹽酸水溶液中，100℃條件下加熱反應3小時，反應液冷卻至室溫，過濾得到化合物10I(460mg，產率：92%)。 Under a nitrogen atmosphere, compound 10H (520 mg, 1.8 mmol) was suspended in 20 mL of 6N aqueous hydrochloric acid at room temperature, heated for 3 hours at 100 °C, the reaction solution was cooled to room temperature, and filtered to obtain compound 10I (460 mg, yield: 92% ).

LCMS(ESI)m/z 268.4[M+H]⁺。 LCMS (ESI) m/z 268.4 [M+H] ⁺ .

第八步 Step 8

(1R,3S)-3-(1-(第三丁基)-5-(2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)環戊基(1-甲基環丙基)胺基甲酸酯10J ( 1R,3S )-3-(1-(tert-butyl)-5-(2-(2-chloro-4-(2-oxopyrrolidin-1- yl )phenyl)propylamino)-1H- Pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate 10J

氮氣氛下，將化合物10I(100mg,0.37mmol))和(1R,3S)-3-(3-胺基-1-(第三-丁基)-1H-吡唑-5-基)(46mg，採用專利申請“WO 2020/157652 A2”公開的方法製備而得)溶於DMF(20mL)，加入三乙胺(0.52mL，3.6mmol)，然後分批滴加T₃P(50% in EA，952mg)。在 80℃攪拌16小時。用Na₂CO₃水溶液(5ml)淬滅，EA萃取(15mL×3)，鹽水(10mL)洗滌，無水硫酸鈉乾燥，濃縮管柱層析得化合物10J(125mg，產率：71%)。 Under nitrogen atmosphere, compound 10I (100 mg, 0.37 mmol)) and (1R,3S)-3-(3-amino-1-(3-butyl)-1H-pyrazol-5-yl) (46 mg , prepared by the method disclosed in the patent application "WO 2020/157652 A2") was dissolved in DMF (20 mL), triethylamine (0.52 mL, 3.6 mmol) was added, and then T ₃ P (50% in EA) was added dropwise in batches , 952mg). Stir at 80°C for 16 hours. Quenched with Na ₂ CO ₃ aqueous solution (5 ml), extracted with EA (15 mL×3), washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain compound 10J (125 mg, yield: 71%).

LCMS(ESI)m/z 570.5[M+H]⁺。 LCMS (ESI) m/z 570.5 [M+H] ⁺ .

第九步 Step 9

(1R,3S)-3-(5-(2-(2-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)環戊基(1-甲基環丙基)胺基甲酸酯10 ( 1R,3S )-3-(5-(2-(2-chloro-4-(2-oxopyrrolidin-1-yl)phenyl)propylamino)-1H-pyrazol-3- yl )cyclopentane yl(1-methylcyclopropyl)carbamate 10

氮氣氛下，將化合物10J(125mg,0.21mmol)溶於4mL甲酸中，75℃條件下加熱反應20小時，反應液冷卻至室溫，減壓濃縮後殘餘物用飽和碳酸氫鈉溶液調至pH=7，用乙酸乙酯萃取(15mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(20mL)，無水硫酸鈉乾燥，過濾，收集濾液，減壓濃縮後殘餘物用矽膠管柱層析得到題化合物10(54mg，產率：47.9%)，為一對異構體。 Under nitrogen atmosphere, compound 10J (125 mg, 0.21 mmol) was dissolved in 4 mL of formic acid, heated at 75°C for 20 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was adjusted to pH with saturated sodium bicarbonate solution = 7, extracted with ethyl acetate (15 mL×3), combined the organic phases, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, collected the filtrate, concentrated under reduced pressure, and the residue was layered with a silica gel column The title compound 10 (54 mg, yield: 47.9%) was obtained by analysis as a pair of isomers.

LCMS(ESI)m/z 514.5[M+H]⁺。 LCMS (ESI) m/z 514.5 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ 10.51(s,1H),7.91(d,J=2.2Hz,1H),7.60-7.41(m,2H),7.36(s,1H),6.31(s,1H),5.00(s,1H),4.21(d,J=7.1Hz,1H),3.85(t,J=7.1Hz,2H),3.05(d,J=9.4Hz,1H),2.08(p,J=7.6Hz,3H),1.90(dt,J=9.0,4.8Hz,1H),1.71(s,2H),1.42(d,J=7.0Hz,3H),1.25(s,3H),0.61(s,2H),0.49(q,J=4.5Hz,2H). ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.51(s, 1H), 7.91(d, J =2.2Hz, 1H), 7.60-7.41(m, 2H), 7.36(s, 1H), 6.31(s ,1H),5.00(s,1H),4.21(d, J =7.1Hz,1H),3.85(t, J =7.1Hz,2H),3.05(d, J =9.4Hz,1H),2.08(p , J =7.6Hz,3H),1.90(dt, J =9.0,4.8Hz,1H),1.71(s,2H),1.42(d, J =7.0Hz,3H),1.25(s,3H),0.61 (s, 2H), 0.49(q, J =4.5Hz, 2H).

實施例11Example 11

(1R,3S)-3-(5-(2-(3-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)環戊基(1-甲基環丙基)胺基甲酸酯 ( 1R,3S )-3-(5-(2-(3-Chloro-4-(2-oxopyrrolidin-1-yl)phenyl)propylamino)-1H-pyrazol-3- yl )cyclopentane yl(1-methylcyclopropyl)carbamate

第一步 first step

2-(3-氯-4-硝基苯基)-2-甲基丙二酸二乙酯11C 2-(3-Chloro-4-nitrophenyl)-2-methylmalonate diethyl ester 11C

25℃，NaOH(2.4g，59.8mmol)，10B(10.3mL，59.8mmol)和11A(10g,96mmol)，加到N,N-二甲基甲醯胺(65mL)，混合物室溫攪拌14小時。將反應混合物用甲基第三丁基醚稀釋，用稀鹽酸調pH=7，萃取，用鹽水洗滌，用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物11C(17g，產率：90%)。 25°C, NaOH (2.4 g, 59.8 mmol), 10B (10.3 mL, 59.8 mmol) and 11A (10 g, 96 mmol) were added to N,N -dimethylformamide (65 mL), and the mixture was stirred at room temperature for 14 hours . The reaction mixture was diluted with methyl tert-butyl ether, adjusted to pH=7 with dilute hydrochloric acid, extracted, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 11C (17 g, yield: 90%).

LCMS(ESI)m/z 330.4[M+H]⁺。 LCMS (ESI) m/z 330.4 [M+H] ⁺ .

第二步 second step

2-(3-氯-4-硝基苯基)丙酸11D 2-(3-Chloro-4-nitrophenyl)propionic acid 11D

參照化合物10D的合成方法，以化合物11C(17g,51.5mmol)為原料得到化合物11D(8.5g，產率：71%)。 Referring to the synthesis method of compound 10D , compound 11C (17 g, 51.5 mmol) was used as a raw material to obtain compound 11D (8.5 g, yield: 71%).

LCMS(ESI)m/z 228.0[M-H]⁺。 LCMS (ESI) m/z 228.0 [MH] ⁺ .

第三步 third step

2-(3-氯-4-硝基苯基)丙酸甲酯11E Methyl 2-(3-chloro-4-nitrophenyl)propanoate 11E

參照化合物10E的合成方法，以化合物11D(5g,21.8mmol)為原料得到化合物11E(4.8g，產率：90%)。 Referring to the synthesis method of compound 10E , compound 11E (4.8 g, yield: 90%) was obtained from compound 11D (5 g, 21.8 mmol) as raw material.

¹H NMR(400MHz,Chloroform-d)δ 7.90(d,J=8Hz,1H),7.53(s,1H),7.39(d,J=8Hz,1H),3.82(q,J=8Hz,16Hz,1H),3.74(s,3H),1.57(d,J=8Hz,3H)。 ¹ H NMR (400MHz, Chloroform- d ) δ 7.90(d, J =8Hz, 1H), 7.53(s, 1H), 7.39(d, J =8Hz, 1H), 3.82(q, J =8Hz, 16Hz, 1H), 3.74(s, 3H), 1.57(d, J = 8Hz, 3H).

第四步 the fourth step

2-(4-胺基-3-氯苯基)丙酸甲酯11F Methyl 2-(4-amino-3-chlorophenyl)propanoate 11F

參照化合物10F的合成方法，以化合物11E(4.8g,19.7mmol)為原料得到化合物11F(4.2g，產率：99%)。 Referring to the synthesis method of compound 10F , compound 11E (4.8 g, 19.7 mmol) was used as a raw material to obtain compound 11F (4.2 g, yield: 99%).

第五步 the fifth step

2-(3-氯-4-(4-氯丁胺基)苯基)丙酸甲酯11G Methyl 2-(3-chloro-4-(4-chlorobutylamino)phenyl)propanoate 11G

參照化合物10G的合成方法，以化合物11F(2g,9.4mmol)為原料得到化合物11G(2.9g，產率：97%)。 Referring to the synthesis method of compound 10G , compound 11G (2.9 g, yield: 97%) was obtained from compound 11F (2 g, 9.4 mmol) as raw material.

LCMS(ESI)m/z 318.2[M+H]⁺。 LCMS (ESI) m/z 318.2 [M+H] ⁺ .

第六步 Step 6

2-(3-氯-4-(2-側氧吡咯烷-1-基)苯基)丙酸甲酯11H Methyl 2-(3-chloro-4-(2-oxypyrrolidin-1-yl)phenyl)propanoate 11H

參照化合物10H的合成方法，以化合物11G(2.9g，9.1mmol)為原料得到化合物11H(1.6g，產率：62%)。 Referring to the synthesis method of compound 10H , compound 11G (2.9 g, 9.1 mmol) was used as a raw material to obtain compound 11H (1.6 g, yield: 62%).

LCMS(ESI)m/z 282.3[M+H]⁺。 LCMS (ESI) m/z 282.3 [M+H] ⁺ .

第七步 Step 7

2-(3-氯-4-(2-側氧吡咯烷-1-基)苯基)丙酸11I 2-(3-Chloro-4-(2-oxypyrrolidin-1-yl)phenyl)propionic acid 11I

參照化合物10I的合成方法，以化合物11H(760mg,2.6mmol)為原料得到化合物11I(650mg，產率：90%)。 Referring to the synthesis method of compound 10I , compound 11H (760 mg, 2.6 mmol) was used as a raw material to obtain compound 11I (650 mg, yield: 90%).

¹H NMR(400MHz,DMSO-d ₆)δ 12.51(s,1H),7.50(s,1H),7.39-7.33(m,2H),3.81-3.75(m,1H),3.70(t,J=8Hz,2H),2.44(t,J=4Hz,2H),2.20-2.12(m,2H),1.40(d,J=4Hz,3H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.51(s, 1H), 7.50(s, 1H), 7.39-7.33(m, 2H), 3.81-3.75(m, 1H), 3.70(t, J = 8Hz, 2H), 2.44(t, J = 4Hz, 2H), 2.20-2.12(m, 2H), 1.40(d, J = 4Hz, 3H).

第八步 Step 8

(1R,3S)-3-(1-(第三丁基)-5-(2-(3-氯-4-(2-氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)環戊基(1-甲基環丙基)胺基甲酸酯11J ( 1R,3S )-3-(1-(tert-butyl)-5-(2-(3-chloro-4-(2-oxopyrrolidin-1- yl )phenyl)propylamino)-1H- Pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate 11J

參照化合物10J的合成方法，以化合物11I(89mg，0.33mmol)為原料得到化合物11J(140mg，產率：88%)。 Referring to the synthesis method of compound 10J , compound 11I (89 mg, 0.33 mmol) was used as the starting material to obtain compound 11J (140 mg, yield: 88%).

LCMS(ESI)m/z 570.6[M+H]⁺。 LCMS (ESI) m/z 570.6 [M+H] ⁺ .

第九步 Step 9

(1R,3S)-3-(5-(2-(3-氯-4-(2-側氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)環戊基(1-甲基環丙基)胺基甲酸酯11 ( 1R,3S )-3-(5-(2-(3-chloro-4-(2-oxypyrrolidin-1-yl)phenyl)propylamino)-1H-pyrazol-3- yl )ring Amyl(1-methylcyclopropyl)carbamate 11

參照化合物10的合成方法，以化合物11J(140mg,0.25mmol)為原料得到化合物11(70mg，產率：55%)，為一對異構體。 Referring to the synthesis method of compound 10 , compound 11 (70 mg, yield: 55%) was obtained from compound 11J (140 mg, 0.25 mmol) as a pair of isomers.

MS(ESI)m/z 514.6[M+H]⁺。 MS (ESI) m/z 514.6 [M+H] ⁺ .

¹H NMR(400MHz,Chloroform-d)δ 8.36(s,1H),7.47(s,1H),7.29-7.26(m,2H),6.51(s,1H),5.23-5.20(m,1H),3.80(t,J=8Hz,2H),3.72-3.67(m,1H),3.17(s,1H),2.62(t,J=8Hz,2H),2.48(s,1H),2.32-2.25(m,2H),2.17-2.06(m,1H),1.99-1.79(m,4H),1.57(d,J=8Hz,3H),1.34-1.24(m,3H),0.78(s,2H),0.64(s,2H)。 ¹ H NMR (400MHz, Chloroform- d ) δ 8.36(s, 1H), 7.47(s, 1H), 7.29-7.26(m, 2H), 6.51(s, 1H), 5.23-5.20(m, 1H), 3.80(t, J =8Hz,2H),3.72-3.67(m,1H),3.17(s,1H),2.62(t, J =8Hz,2H),2.48(s,1H),2.32-2.25(m ,2H),2.17-2.06(m,1H),1.99-1.79(m,4H),1.57(d, J =8Hz,3H),1.34-1.24(m,3H),0.78(s,2H),0.64 (s, 2H).

實施例12Example 12

(1R,3S)-3-(3-((S)-2-(2-氯-4-(2-側氧吡咯烷-1-基)苯基)丙醯胺)-1H-吡唑-5-基)環戊(1-甲基環丙基)胺基甲酸酯異構體1 ( 1R,3S) -3-(3-(( S )-2-(2-chloro-4-(2-oxypyrrolidin-1-yl)phenyl)propionamide)-1H-pyrazole- 5-yl)cyclopenta(1-methylcyclopropyl)carbamate Isomer 1

(1R,3S)-3-(3-((R)-2-(2-氯-4-(2-側氧吡咯烷-1-基)苯基)丙醯胺)-1H-吡唑-5-基)環戊(1-甲基環丙基)胺基甲酸酯異構體2 ( 1R,3S) -3-(3-(( R )-2-(2-chloro-4-(2-oxypyrrolidin-1-yl)phenyl)propionamide)-1H-pyrazole- 5-yl)cyclopenta(1-methylcyclopropyl)carbamate Isomer 2

藉由實施例10的方法製備得到(1R,3S)-3-(5-(2-(2-氯-4-(2-側氧吡咯烷-1-基)苯基)丙胺基)-1H-吡唑-3-基)環戊基(1-甲基環丙基)胺基甲酸酯10 100mg，藉由手性拆分[Column：DAICEL CHIRALPAK AD(250mm*30mm,10um),Condition：0.1%胺水IPA,Begin B：45%；End B：45%；FlowRate(ml/min)：80)]得到標題化合物異構體1(40mg，產率：40%)和標題化合物異構體2(40mg，產率：40%)。 ( 1R,3S )-3-(5-(2-(2-chloro-4-(2-oxypyrrolidin-1- yl )phenyl)propylamino)-1H was prepared by the method of Example 10 -Pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate 10 100mg, resolved by chirality [Column: DAICEL CHIRALPAK AD (250mm*30mm, 10um), Condition: 0.1% amine water IPA, Begin B: 45%; End B: 45%; FlowRate (ml/min): 80)] to obtain the title compound isomer 1 (40 mg, yield: 40%) and the title compound isomer 2 (40 mg, yield: 40%).

分析方法： Analytical method:

Column：DAICEL CHIRALCEL AD-3(100mm * 4.6mm,3μm)； Column: DAICEL CHIRALCEL AD-3 (100mm * 4.6mm, 3μm);

Mobile phase：40% of iso-propanol(0.05% DEA)in CO₂； Mobile phase: 40% of iso-propanol (0.05% DEA) in CO ₂ ;

FlowRate：2.5mL/min； FlowRate: 2.5mL/min;

ABPR：1500psi； ABPR: 1500psi;

Temperature：35℃。 Temperature: 35℃.

將保留時間為3.829min的化合物定義為異構體1； The compound whose retention time is 3.829min is defined as isomer 1 ;

MS(ESI)m/z 514.2[M+H]⁺ MS(ESI)m/z 514.2[M+H] ⁺

¹H NMR(400MHz,Chloroform-d)δ 8.05(br s,1H),7.77(d,J=2.4Hz,1H),7.54-7.48(m,1H),7.46-7.40(m,1H),6.51(br s,1H),5.17(br s,2H),4.18(q,J=7.2Hz,1H),3.83(t,J=7.2Hz,2H),3.13(br s,1H),2.62(t,J=8.4Hz,2H),2.45(br s,1H),2.18(quin,J=7.6Hz,2H), 2.09(br s,1H),1.93-1.78(m,4H),1.65(br s,1H),1.55(d,J=7.2Hz,3H),1.34(br s,3H),0.74(br s,2H),0.60(br s,2H). ¹ H NMR (400MHz, Chloroform- d ) δ 8.05(br s, 1H), 7.77(d, J =2.4Hz, 1H), 7.54-7.48(m, 1H), 7.46-7.40(m, 1H), 6.51 (br s, 1H), 5.17(br s, 2H), 4.18(q, J =7.2Hz, 1H), 3.83(t, J =7.2Hz, 2H), 3.13(br s, 1H), 2.62(t , J =8.4Hz,2H),2.45(br s,1H),2.18(quin, J =7.6Hz,2H), 2.09(br s,1H),1.93-1.78(m,4H),1.65(br s ,1H),1.55(d, J =7.2Hz,3H),1.34(br s,3H),0.74(br s,2H),0.60(br s,2H).

將保留時間為5.777min的化合物定義為異構體2； The compound whose retention time is 5.777min is defined as isomer 2 ;

MS(ESI)m/z 514.2[M+H]⁺ MS(ESI)m/z 514.2[M+H] ⁺

¹H NMR(400MHz,Chloroform-d)δ 8.01(br s,1H),7.77(d,J=2.4Hz,1H),7.55-7.49(m,1H),7.45-7.40(m,1H),6.51(br s,1H),5.16(br s,2H),4.18(q,J=7.2Hz,1H),3.83(t,J=7.2Hz,2H),3.13(br s,1H),2.62(t,J=8.4Hz,2H),2.45(br s,1H),2.18(quin,J=7.6Hz,2H),2.09(br d,J=7.6Hz,1H),1.98-1.76(m,5H),1.55(d,J=7.2Hz,3H),1.34(br s,3H),0.74(br s,2H),0.60(br s,2H). ¹ H NMR (400MHz, Chloroform- d ) δ 8.01(br s, 1H), 7.77(d, J =2.4Hz, 1H), 7.55-7.49(m, 1H), 7.45-7.40(m, 1H), 6.51 (br s, 1H), 5.16(br s, 2H), 4.18(q, J =7.2Hz, 1H), 3.83(t, J =7.2Hz, 2H), 3.13(br s, 1H), 2.62(t , J =8.4Hz,2H),2.45(br s,1H),2.18(quin, J =7.6Hz,2H),2.09(br d, J =7.6Hz,1H),1.98-1.76(m,5H) ,1.55(d, J =7.2Hz,3H),1.34(br s,3H),0.74(br s,2H),0.60(br s,2H).

生物學評價Biological evaluation

以下結合測試例進一步描述解釋本揭露，但這些實施例並非意味著限制本揭露的範圍。 The present disclosure is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present disclosure.

本揭露化合物對細胞週期蛋白-依賴性激酶活性檢測。 Detection of cyclin-dependent kinase activity by compounds of the present disclosure.

1.實驗材料及儀器 1. Experimental materials and instruments

2.實驗步驟 2. Experimental steps

使用Echo 550將化合物稀釋液轉移到測定板的每個孔中(784075，Greiner)。密封測定板，以1000g離心測定板1分鐘；在1x激酶緩衝液(由1體積的5X激酶緩衝液和4體積的蒸餾水及50uM DTT製備得到)中準備2x酶，將2.5μl 2x酶加入384孔測定板，將板在1000g下離心30s，在室溫放置10分鐘。在1x激酶緩衝液中製備2x受質和ATP混合物，加入2.5μl 2x受質和ATP混合物開始反應。將板以1000g離心30秒，密封測定板，室溫反應1小時。加入4μl ADP-Glo試劑，在室溫下孵育40分鐘，再加入8μl激酶檢測試劑，在室溫下孵育40分鐘。 Compound dilutions were transferred to each well of an assay plate using an Echo 550 (784075, Greiner). Seal assay plate, centrifuge plate at 1000g for 1 min; prepare 2x enzyme in 1x kinase buffer (prepared from 1 volume 5X kinase buffer and 4 volumes distilled water and 50uM DTT), add 2.5 μl 2x enzyme to 384 wells Plates were assayed, centrifuged at 1000 g for 30 s and left at room temperature for 10 minutes. Prepare a 2x substrate and ATP mix in 1x kinase buffer and add 2.5 μl of the 2x substrate and ATP mix to start the reaction. The plate was centrifuged at 1000 g for 30 seconds, the assay plate was sealed, and the reaction was carried out at room temperature for 1 hour. Add 4 μl of ADP-Glo reagent and incubate at room temperature for 40 minutes, then add 8 μl of kinase detection reagent and incubate at room temperature for 40 minutes.

在Envision 2104讀板器上讀取每個孔發光信號。 The luminescence signal from each well was read on an Envision 2104 plate reader.

抑制百分率計算如下： The percent inhibition was calculated as follows:

抑制百分率=100-(cmpd信號-Ave_PC信號)/(Ave_VC信號-Ave_PC信號)×100。 Inhibition percentage=100-(cmpd signal-Ave_PC signal)/(Ave_VC signal-Ave_PC signal)×100.

使用GraphPad 8.0藉由將抑制百分率值和化合物濃度的對數擬合為非線性回歸(劑量回應-可變斜率)來計算IC50。 IC50s were calculated using GraphPad 8.0 by fitting the percent inhibition values and the logarithm of compound concentration to a nonlinear regression (dose response - variable slope).

Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

X：抑制劑濃度的對數；Y：%抑制。 X: log of inhibitor concentration; Y: % inhibition.

測得的IC₅₀值見表1。 The measured _IC50 values are shown in Table 1.

表1中NA表示未測。 NA in Table 1 means not tested.

Claims

一種式I所示的化合物或其可藥用鹽、互變異構體， A compound shown in formula I or its pharmaceutically acceptable salt, tautomer,

其中，-L₁-、-L₂-各自獨立選自鍵、C₁-C₆亞(伸)烷基、-O-和-NH-，該C_1-6亞(伸)烷基視需要被一個或多個選自羥基、烷基、烷氧基、鹵烷基、鹵烷氧基、鹵素、羥基、氰基、胺基和硝基的取代基取代； Wherein, -L ₁ -, -L ₂ - are each independently selected from the bond, C ₁ -C ₆ (extended) alkylene, -O- and -NH-, the C _1-6 (extended) alkylene is optional substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, hydroxy, cyano, amino and nitro;

R₁選自環烷基、雜環基、芳基和雜芳基，其中該環烷基、雜環基、芳基或雜芳基各自獨立視需要被一個或多個Z取代； R ₁ is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted with one or more Z;

R₂、R₃各自獨立選自氫、氘、鹵素、烷基、氰基、羥基、硝基、側氧基、環烷基、雜環基、芳基和雜芳基，其中該烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自鹵素、烷基、烷氧基、氰基、胺基、硝基、羥基、羥烷基、羧基、環烷基、雜環基、芳基和雜芳基的取代基取代；或R₂、R₃共同構成3-8員環，該3-8員環視需要地被一個或多個Z取代； R ₂ and R ₃ are each independently selected from hydrogen, deuterium, halogen, alkyl, cyano, hydroxyl, nitro, pendant oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, A cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more groups selected from halogen, alkyl, alkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, carboxyl, cyclic Substituent substitution of alkyl, heterocyclyl, aryl and heteroaryl; or R ₂ and R ₃ together form a 3-8 membered ring, and the 3-8 membered ring is optionally substituted by one or more Z;

R₄選自單環、多環，視需要地被一個或多個Z取代，且R₅選自氫、氘、烷基和鹵素，其中該烷基視需要被一個或多個選自鹵素、烷基、烷氧基、氰基、胺基、硝基、羥基、羥烷基、羧基、環烷基、雜環基、芳基和雜芳基的取代基取代，條件是，當R₄選自單環時，R₄選自

，且R₁ 選自

或

； R ₄ is selected from monocyclic, polycyclic, optionally substituted by one or more Z, and R ₅ is selected from hydrogen, deuterium, alkyl and halogen, wherein the alkyl is optionally substituted by one or more selected from halogen, Substituent substitution of alkyl, alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, provided that when R _is selected From a single ring, R ₄ is selected from

, and R ₁ is selected from

or

;

R₆選自氫、氘、鹵素、烷基； R ₆ is selected from hydrogen, deuterium, halogen, alkyl;

R₇各自獨立選自氫、氘、鹵素、羥基、硝基、氰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、SR'、SOR'、SO₂R'、SO₂NR'(R")、NR'(R")、COOR'、CONR'(R")和-(P=O)R'(R")，該烷基、烷氧基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自鹵素、羥基、側氧、硝基、氰基、SR'、SOR'、SO₂R'、SO₂NR'(R")、NR'(R")、COR'、COOR'、CONR'(R")和-(P=O)R'(R")的取代基取代；或任意兩個相鄰R₇共同構成3-8員環，該3-8員環視需要地被一個或多個Z取代； R ₇ is each independently selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR', SOR', SO ₂ R', SO ₂ NR'(R"), NR'(R"), COOR', CONR'(R") and -(P=O)R'(R"), the alkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally replaced by one or more selected from halogen, hydroxy, pendant oxygen, nitro, cyano, SR', SOR', _SO2R ', _SO2NR Substituent substitution of '(R"), NR'(R"), COR', COOR', CONR'(R") and -(P=O)R'(R"); or any two adjacent R's ₇ together form a 3-8 membered ring optionally substituted by one or more Z;

或R₄、R₅與它們所連接的N原子共同構成多環，並視需要地被一個或多個Z取代； Or R ₄ , R ₅ and the N atoms to which they are attached together form a polycyclic ring, and are optionally substituted by one or more Z;

每個R'或R"獨立地選自氫、氘、羥基、烷基、烷氧基、環烷基、雜環基、芳基和雜芳基，該烷基、烷氧基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自鹵素、羥基、側氧、硝基、氰基的取代基取代； Each R' or R" is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the alkyl, alkoxy, cycloalkyl , heterocyclyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, pendant oxygen, nitro, cyano;

條件是，式I所示的化合物不是

和 provided that the compound of formula I is not

and

如請求項1所述的化合物或其可藥用的鹽、互變異構體，當R₄選自單環時，其中該化合物I為， The compound according to claim 1 or a pharmaceutically acceptable salt or tautomer thereof, when R ₄ is selected from a monocyclic ring, wherein the compound I is,

或

，其中，

or

,in,

R₇各自獨立選自氫、氘、鹵素、C_1-6烷基、C_3-7環烷基、3-7員雜環基、5-12員芳基、5-12員雜芳基和-(P=O)R'(R")，該C_3-7環烷基、3-7員雜環基、5-12員芳基、5-12員雜芳基視需要被一個或多個選自鹵素、羥基、側氧、硝基、烷基和烷氧基的取代基取代； R ₇ is each independently selected from hydrogen, deuterium, halogen, C _1-6 alkyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl and -(P=O)R'(R"), the C _3-7 cycloalkyl, 3-7-membered heterocyclyl, 5-12-membered aryl, 5-12-membered heteroaryl group is optionally replaced by one or more substituted with a substituent selected from halogen, hydroxyl, pendant oxygen, nitro, alkyl and alkoxy;

-L₁-、-L₂-、R₂、R₃、R₅、R₆、R'或R"如請求項1中所定義。 -L ₁ -, -L ₂ -, R ₂ , R ₃ , R ₅ , R ₆ , R' or R" are as defined in claim 1.

如請求項2所述的化合物或其可藥用的鹽、互變異構體，其中該化合物IIa選自， The compound of claim 2 or a pharmaceutically acceptable salt, tautomer thereof, wherein the compound IIa is selected from,

和

；

and

;

該化合物IIb選自： The compound IIb is selected from:

和

and

-L₁-、-L₂-、R₂、R₃、R₅、R₆、R₇、R'或R"如請求項2中所定義。 -L ₁ -, -L ₂ -, R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R' or R" are as defined in claim 2.

如請求項2或3所述的化合物或其可藥用的鹽、互變異構體，其中該R₇選自氫、氘、氟、氯、溴、甲基、乙基、丙基、異丙基、-(P=O)R'(R")、

和

；其中， The compound as claimed in claim 2 or 3 or a pharmaceutically acceptable salt or tautomer thereof, wherein R ₇ is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl base, -(P=O)R'(R"),

and

;in,

X選自-CH和N； X is selected from -CH and N;

Y選自-CH₂-、-CH(CH₃)-、-NH-、-N(CH₃)-和-O-；較佳地，該R₇選自氫、氘、甲基、-(P=O)(CH₃)₂、

和

。 Y is selected from -CH ₂ -, -CH(CH ₃ )-, -NH-, -N(CH ₃ )- and -O-; preferably, the R ₇ is selected from hydrogen, deuterium, methyl, -( P=O)(CH ₃ ) ₂ ,

and

.

如請求項1所述的化合物或其可藥用的鹽、互變異構體，其中該化合物I為： The compound as claimed in claim 1 or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound I is:

或

，其中，環A選自C_3-7環烷基、5-8員芳基和5-8員雜環基，該C_3-7環烷基、5-8芳基、5-8雜芳基視需要地被一個或多個Z取代；

or

, wherein, ring A is selected from C _3-7 cycloalkyl, 5-8 membered aryl and 5-8 membered heterocyclyl, the C _3-7 cycloalkyl, 5-8 aryl, 5-8 heteroaryl base optionally substituted with one or more Z;

-L₁-、-L₂-、R₂、R₃、R₅、R₆、Z如請求項1中所定義。 -L ₁ -, -L ₂ -, R ₂ , R ₃ , R ₅ , R ₆ , Z are as defined in claim 1 .

如請求項5所述的化合物或其可藥用的鹽、互變異構體，其中 The compound of claim 5 or a pharmaceutically acceptable salt or tautomer thereof, wherein

該化合物IIc選自： The compound IIc is selected from:

和

；

and

;

該化合物IId選自： The compound IId is selected from:

和

；

and

;

其中，環A、-L₁-、-L₂-、R₂、R₃、R₅、R₆、Z如請求項5中所定義。 Wherein, ring A, -L ₁ -, -L ₂ -, R ₂ , R ₃ , R ₅ , R ₆ , Z are as defined in claim 5.

如請求項5或6所述的化合物或其可藥用的鹽、互變異構體，其中該環A選自5-8員雜環基，該5-8員雜環基視需要地被一個或多個選自鹵素、羥基、側氧、硝基、烷基和烷氧基的取代基取代。 The compound as claimed in claim 5 or 6, or a pharmaceutically acceptable salt or tautomer thereof, wherein the ring A is selected from a 5-8 membered heterocyclic group, the 5-8 membered heterocyclic group optionally being replaced by a Substituted with one or more substituents selected from halogen, hydroxy, pendant oxygen, nitro, alkyl and alkoxy.

如請求項7所述的化合物或其可藥用的鹽、互變異構體，其中該環A選自

和

； The compound as claimed in claim 7 or a pharmaceutically acceptable salt or tautomer thereof, wherein the ring A is selected from

and

;

其中， in,

Y選自-CH₂-、-CH(CH₃)-、-NH-、-N(CH₃)-和-O-；較佳地，該環A選自

和

。 Y is selected from -CH ₂ -, -CH(CH ₃ )-, -NH-, -N(CH ₃ )- and -O-; preferably, the ring A is selected from

and

.

如請求項1至8中任一項所述的化合物或其可藥用的鹽、互變異構體，R₆選自氫、氘、鹵素和C_1-6烷基；較佳選自氫、氘、氟、氯、溴、甲基、乙基、丙基和異丙基，更佳甲基。 The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or tautomer thereof, R ₆ is selected from hydrogen, deuterium, halogen and C _1-6 alkyl; preferably selected from hydrogen, Deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl, more preferably methyl.

如請求項1或2所述的化合物或其可藥用的鹽、互變異構體，當R₄選自多環時，R₁選自C₆-C₁₂芳基和5-10員雜芳基，其中該C₆-C₁₂芳基或5-10員雜芳基視需要地被一個或多個Z取代； The compound according to claim 1 or 2 or a pharmaceutically acceptable salt or tautomer thereof, when R ₄ is selected from polycyclic rings, R ₁ is selected from C ₆ -C ₁₂ aryl and 5-10 membered heteroaryl group, wherein the C ₆ -C ₁₂ aryl or 5-10 membered heteroaryl is optionally substituted with one or more Z;

Z如請求項1中所定義；較佳地，該C₆-C₁₂芳基或5-10員雜芳基選自吡唑基、***基、異噁唑基(isoxazolyl)、噁唑基(oxazolyl)、噻唑基、噻二唑基(thiadiazolyl)、咪唑基、吡啶基、吡嗪基、吲唑基、苯并咪唑基和苯基，最佳異噁唑基，其中該C₆-C₁₂芳基或5-10員雜芳基視需要地被一個或多個Z取代； Z is as defined in claim ₁ ; preferably, the _C6 -C12 aryl or 5-10 membered heteroaryl is selected from pyrazolyl, triazolyl, isoxazolyl, oxazolyl (oxazolyl), thiazolyl, thiadiazolyl, imidazolyl, pyridyl, pyrazinyl, indazolyl, benzimidazolyl and phenyl, most preferably isoxazolyl, wherein the _C6 -C ₁₂ aryl or 5-10 membered heteroaryl optionally substituted with one or more Z;

Z如請求項1中所定義。 Z is as defined in claim 1.

如請求項10所述的化合物或其可藥用的鹽、互變異構體，其中該化合物I為： The compound of claim 10 or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound I is:

，-L₁-、-L₂-、R₂、R₃、R₄、R₅、Z如請求項1中所定義。

, -L ₁ -, -L ₂ -, R ₂ , R ₃ , R ₄ , R ₅ , Z are as defined in claim 1.

如請求項11所述的化合物或其可藥用的鹽、互變異構體，其中該化合物III選自 The compound of claim 11 or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound III is selected from

和

；

and

;

-L₁-、-L₂-、R₂、R₃、R₄、R₅、Z如請求項11中所定義。 -L ₁ -, -L ₂ -, R ₂ , R ₃ , R ₄ , R ₅ , Z are as defined in claim 11.

如請求項10至12中任一項所述的化合物或其可藥用的鹽、互變異構體，其中該Z選自氟、氯、溴、甲基、乙基、丙基、異丙基、氰基、羥基、鹵烷基、-(P=O)R'(R")、

和

的取代基取代；其中， The compound of any one of claims 10 to 12, or a pharmaceutically acceptable salt, tautomer thereof, wherein Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl , cyano, hydroxyl, haloalkyl, -(P=O)R'(R"),

and

substituted by the substituents; wherein,

X選自-CH和N； X is selected from -CH and N;

Y選自-CH₂-、-CH(CH₃)-、-NH-、-N(CH₃)-和-O-；較佳地，該Z選自甲基、-(P=O)(CH₃)₂、

和

的取代基取代，最佳甲基。 Y is selected from -CH ₂ -, -CH(CH ₃ )-, -NH-, -N(CH ₃ )- and -O-; preferably, the Z is selected from methyl, -(P=O)( CH ₃ ) ₂ ,

and

Substituents are substituted, preferably methyl.

如請求項11至13中任一項所述的化合物或其可藥用的鹽、互變異構體，該化合物III為 The compound according to any one of claims 11 to 13 or a pharmaceutically acceptable salt or tautomer thereof, the compound III is

，-L₁-、-L₂-、R₂、R₃、R₄、R₅如請求項11中所定義。

, -L ₁ -, -L ₂ -, R ₂ , R ₃ , R ₄ , R ₅ are as defined in claim 11.

如請求項1、10至14中任一項所述的化合物或其可藥用的鹽、互變異構體，當R₄選自多環時，R₄選自螺環、稠環和橋環，並視需要地被一個或多個Z取代； The compound according to any one of claims 1, 10 to 14, or a pharmaceutically acceptable salt or tautomer thereof, when R ₄ is selected from polycyclic rings, R ₄ is selected from spiro rings, fused rings and bridged rings , and optionally replaced by one or more Z;

該螺環選自螺環烷基和螺雜環基，選自[3.3]、[3.4]、[3.5]、[3.6]、[4.4]、[4.5]、[4.6]、[5.5]、[5.6]和[6.7]螺環； The spiro ring is selected from spirocycloalkyl and spiroheterocyclyl, selected from [3.3], [3.4], [3.5], [3.6], [4.4], [4.5], [4.6], [5.5], [ 5.6] and [6.7] Spiro;

該稠環選自稠環烷基、稠雜環基和稠雜芳基，選自二環和三環； The fused ring is selected from fused cycloalkyl, fused heterocyclic and fused heteroaryl, and is selected from bicyclic and tricyclic;

該橋環選自橋環烷基和橋雜環基，選自二環和三環，每條橋上碳原子數為0-3個； The bridged ring is selected from bridged cycloalkyl and bridged heterocyclyl, selected from bicyclic and tricyclic, and the number of carbon atoms on each bridge is 0-3;

該螺環、稠環或橋環由任一個的碳或氮原子連接到式I結構中； The spiro, fused or bridged ring is attached to the structure of formula I by any carbon or nitrogen atom;

Z如請求項1中所定義。 Z is as defined in claim 1.

如請求項15所述的化合物或其可藥用的鹽、互變異構體，其中 The compound of claim 15 or a pharmaceutically acceptable salt, tautomer thereof, wherein

該螺環選自

、

、

、

、

、

、

、

、

和

，視需要地進一步被一個或多個Z取代； The spiro ring is selected from

,

and

, optionally further replaced by one or more Z;

該螺環藉由任一*表示的連接位點連接到式I結構中； The spiro ring is attached to the structure of formula I through any of the attachment sites represented by *;

Z如請求項1中所定義；較佳地，該螺環選自

和

，該螺環藉由*表示的連接位點連接到式I結構中。 Z is as defined in claim 1; preferably, the spiro ring is selected from

and

如請求項15所述的化合物或其可藥用的鹽、互變異構體，其中該稠環選自

、

、

、

、

和

，視需要地進一步被一個或多個Z取代； The compound as claimed in claim 15 or a pharmaceutically acceptable salt or tautomer thereof, wherein the fused ring is selected from

,

and

, optionally further replaced by one or more Z;

該稠環藉由任一*表示的連接位點連接到式I結構中； The fused ring is attached to the structure of formula I through any of the attachment sites represented by *;

Z如請求項1中所定義；較佳地，該稠環選自

，藉由*表示的連接位點連接到式I結構中。 Z is as defined in claim 1; preferably, the fused ring is selected from

, linked to the structure of formula I through the linking site indicated by *.

如請求項15所述的化合物或其可藥用的鹽、互變異構體，其中該橋環選自

、

、

、

和

，視需要地進一步被一個或多個Z取代； The compound as claimed in claim 15 or a pharmaceutically acceptable salt or tautomer thereof, wherein the bridged ring is selected from

,

and

, optionally further replaced by one or more Z;

該橋環藉由任一*表示的連接位點連接到式I結構中； The bridged loop is attached to the structure of formula I through any of the attachment sites indicated by *;

Z如請求項1中所定義；較佳地，該橋環選自

和

，藉由*表示的連接位點連接到式I結構中。 Z is as defined in claim 1; preferably, the bridge ring is selected from

and

, linked to the structure of formula I through the linking site indicated by *.

如請求項1至18中任一項所述的化合物或其可藥用的鹽、互變異構體，R₅選自氫、氘、鹵素和C_1-6烷基；較佳選自氫、氘、氟、氯、溴、甲基、乙基、丙基和異丙基，更佳氫。 The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt or tautomer thereof, R ₅ is selected from hydrogen, deuterium, halogen and C _1-6 alkyl; preferably selected from hydrogen, Deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl, more preferably hydrogen.

如請求項1所述的化合物或其可藥用的鹽、互變異構體，當R₄、R₅與它們所連接的N原子共同構成的多環時，該化合物I為 The compound according to claim 1 or a pharmaceutically acceptable salt or tautomer thereof, when R ₄ , R ₅ and the N atom to which they are attached together form a polycyclic ring, the compound I is

其中環C選自

、

、

、

、

、

、

、 wherein ring C is selected from

,

、

、

、

、

、

和

；視需要地被一個或多個Z取代；

,

and

; optionally replaced by one or more Z;

-L₁-、-L₂-、R₁、R₂、R₃如請求項1中所定義。 -L ₁ -, -L ₂ -, R ₁ , R ₂ , R ₃ are as defined in claim 1 .

如請求項20所述的化合物或其可藥用的鹽、互變異構體，其中該化合物IV化合物選自 The compound of claim 20 or a pharmaceutically acceptable salt, tautomer thereof, wherein the compound IV compound is selected from

和

；

and

;

-L₁-、-L₂-、R₁、R₂、R₃、環C如請求項20中所定義。 -L ₁ -, -L ₂ -, R ₁ , R ₂ , R ₃ , ring C are as defined in claim 20.

如請求項20或21所述的化合物或其可藥用的鹽、互變異構體，其中該R₁選自C₆-C₁₂芳基和5-10員雜芳基，其中該C₆-C₁₂芳基或5-10員雜芳基視需要地被一個或多個Z取代； The compound as claimed in claim 20 or 21 or a pharmaceutically acceptable salt or tautomer thereof, wherein the R ₁ is selected from C ₆ -C ₁₂ aryl and 5-10 membered heteroaryl, wherein the C ₆ - C ₁₂ aryl or 5-10 membered heteroaryl optionally substituted with one or more Z;

Z如請求項1中所定義；較佳地，該C₆-C₁₂芳基或5-10員雜芳基選自吡唑基、***基、異噁唑基(isoxazolyl)、噁唑基(oxazolyl)、噻唑基、噻二唑基(thiadiazolyl)、咪唑基、吡啶基、吡嗪基、吲唑基、苯并咪唑基和苯基，較佳異噁唑基，其中該C₆-C₁₂芳基或5-10員雜芳基視需要地被一個或多個Z取代； Z is as defined in claim ₁ ; preferably, the _C6 -C12 aryl or 5-10 membered heteroaryl is selected from pyrazolyl, triazolyl, isoxazolyl, oxazolyl (oxazolyl), thiazolyl, thiadiazolyl, imidazolyl, pyridyl, pyrazinyl, indazolyl, benzimidazolyl and phenyl, preferably isoxazolyl, wherein the _C6 -C ₁₂ aryl or 5-10 membered heteroaryl optionally substituted with one or more Z;

Z如請求項1中所定義。 Z is as defined in claim 1.

如請求項20至22中任一項所述的化合物或其可藥用的鹽、互變異構體，其中該化合物IV為： The compound of any one of claims 20 to 22 or a pharmaceutically acceptable salt, tautomer thereof, wherein the compound IV is:

，-L₁-、-L₂-、R₂、R₃、R₄、R₅、Z如請求項1中所定義，環C如請求項20中所定義。

, -L ₁ -, -L ₂ -, R ₂ , R ₃ , R ₄ , R ₅ , Z are as defined in claim 1, and ring C is as defined in claim 20.

如請求項23所述的化合物或其可藥用的鹽、互變異構體，其中該化合物IVa化合物選自： The compound as claimed in claim 23 or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound IVa compound is selected from:

和

；

and

;

-L₁-、-L₂-、R₂、R₃、R₄、R₅、Z、環C如請求項23中所定義。 -L ₁ -, -L ₂ -, R ₂ , R ₃ , R ₄ , R ₅ , Z, ring C are as defined in claim 23.

如請求項20至24中任一項所述的化合物或其可藥用的鹽、互變異構體，其中該Z選自氟、氯、溴、甲基、乙基、丙基、異丙基、氰基、羥基、鹵烷基、-(P=O)R'(R")、

和

的取代基取代；其中， The compound of any one of claims 20 to 24, or a pharmaceutically acceptable salt, tautomer thereof, wherein Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl , cyano, hydroxyl, haloalkyl, -(P=O)R'(R"),

and

Substituents are substituted; wherein,

X選自-CH和N； X is selected from -CH and N;

和

的取代基取代，較佳甲基。 Y is selected from -CH ₂ -, -CH(CH ₃ )-, -NH-, -N(CH ₃ )- and -O-; preferably, the Z is selected from methyl, -(P=O)( CH ₃ ) ₂ ,

and

Substituents are substituted, preferably methyl.

如請求項1至25中任一項所述的化合物或其可藥用的鹽、互變異構體，其中該-L₂-選自鍵、-CH₂-、-CH(CH₃)-、-CH₂-CH₂-、-O-和-NH-，較佳-CH₂-和-CH(CH₃)-。 The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, tautomer thereof, wherein the -L ₂ - is selected from a bond, -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -, -O- and -NH-, preferably -CH ₂ - and -CH(CH ₃ )-.

如請求項1至26中任一項所述的化合物或其可藥用的鹽、互變異構體，其中該R₂、R₃各自獨立選自氫、氘、氟、氯、溴、甲基、乙基、丙基、異丙基、苯基、氰基、羥基和側氧基，較佳選自氫、氘、氟、氯和甲基，更佳氫。 The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or tautomer thereof, wherein each of R ₂ and R ₃ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl , ethyl, propyl, isopropyl, phenyl, cyano, hydroxyl and pendant oxy, preferably selected from hydrogen, deuterium, fluorine, chlorine and methyl, more preferably hydrogen.

如請求項1至27中任一項所述的化合物或其可藥用的鹽、互變異構體，其中該R₂、R₃共同構成3-8員環，該3-8員環選自C_3-7環烷基、3-8員雜環基、5-8員芳基和5-8員雜芳基，該3-8員環視需要地被一個或多個Z取代； The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or tautomer thereof, wherein the R ₂ and R ₃ together form a 3-8 membered ring, and the 3-8 membered ring is selected from the group consisting of C _3-7 cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered aryl and 5-8 membered heteroaryl, the 3-8 membered ring is optionally substituted by one or more Z;

Z如請求項1中所定義；較佳地，該3-8員環選自環丙基、環丁基和環戊基，該3-8員環視需要地被一個或多個Z取代，該Z選自氟、氯、溴、甲基、乙基、丙基、異丙基、苯基、氰基、羥基和側氧基，較佳選自氟、氯和甲基。 Z is as defined in claim 1; preferably, the 3-8 membered ring is selected from cyclopropyl, cyclobutyl and cyclopentyl, the 3-8 membered ring is optionally substituted with one or more Z, the Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, phenyl, cyano, hydroxy and pendant oxy, preferably from fluorine, chlorine and methyl.

如請求項1至28中任一項所述的化合物或其可藥用的鹽、互變異構體，該-L₁-選自鍵、-CH₂-、-CH(CH₃)-、-CH₂-CH₂-、-O-和-NH-，較佳選自-CH₂-和-O-，更佳-O-。 The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or tautomer thereof, wherein -L ₁ - is selected from bond, -CH ₂ -, -CH(CH ₃ )-, - CH ₂ -CH ₂ -, -O- and -NH- are preferably selected from -CH ₂ - and -O-, more preferably -O-.

如請求項1所述的化合物或其可藥用的鹽、互變異構體，其中該化合物選自： The compound as claimed in claim 1 or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is selected from:

和

，或其可藥用鹽、互變異構體。

and

, or its pharmaceutically acceptable salts, tautomers.

一種如請求項1至30中任一項所述的化合物的同位素取代物，較佳地，該同位素取代物為氘原子取代。 An isotopic substitution of the compound according to any one of claims 1 to 30, preferably, the isotopic substitution is deuterium atom substitution.

一種醫藥組成物，包括至少一種治療有效量的如請求項1至30中任一項所述的化合物或其可藥用的鹽、互變異構體或如請求項31所述的同位素取代物以及藥學上可接受的賦形劑。 A pharmaceutical composition comprising at least one therapeutically effective amount of a compound as described in any one of claims 1 to 30 or a pharmaceutically acceptable salt, tautomer or isotopic substitution as described in claim 31 and Pharmaceutically acceptable excipients.

一種如請求項1至30中任一項所述的化合物或其可藥用的鹽、互變異構體或如請求項31所述的同位素取代物或如請求項32所述的醫藥組成物在製備用於預防和/或治療與蛋白依賴性激酶相關疾病的藥物中的用途，該蛋白依賴性激酶較佳CDK2，該與蛋白依賴性激酶相關疾病較佳細胞增殖性疾病，癌症或免疫性疾病。 A compound as described in any one of claims 1 to 30 or a pharmaceutically acceptable salt, tautomer or isotopic substitution as described in claim 31 or a pharmaceutical composition as described in claim 32 in Use in the preparation of a medicament for the prevention and/or treatment of diseases related to protein-dependent kinases, preferably CDK2, and the diseases related to protein-dependent kinases are preferably cell proliferative diseases, cancer or immune diseases .

一種如請求項1至30中任一項所述的化合物或其可藥用的鹽、互變異構體或如請求項31所述的同位素取代物或如請求項32所述的醫藥組成物在製備用於預防和/或治療與細胞週期蛋白相關疾病的藥物中的用途，該細胞週期蛋白較佳細胞週期蛋白E，更佳細胞週期蛋白E1、細胞週期蛋白E2，該與細胞週期蛋白相關疾病較佳細胞增殖性疾病，癌症或免疫性疾病。 A compound as described in any one of claims 1 to 30 or a pharmaceutically acceptable salt, tautomer or isotopic substitution as described in claim 31 or a pharmaceutical composition as described in claim 32 in Use in the preparation of a medicament for preventing and/or treating cyclin-related diseases, preferably cyclin E, more preferably cyclin E1, cyclin E2, and cyclin-related diseases Preferably cell proliferative diseases, cancer or immune diseases.

一種如請求項1至30中任一項所述的化合物或其可藥用的鹽、互變異構體或如請求項31所述的同位素取代物或如請求項32所述的醫藥組成物在製備用於預防和/或治療癌症的藥物中的用途，該癌症選自乳腺癌、卵巢癌、***癌、黑色素瘤、腦瘤、食道癌、胃癌、肝癌(包括HCC)、胰腺癌、結直腸癌、肺癌(包括NSCLC、SCLC、鱗狀細胞癌或腺癌)、腎癌(包括RCC)、皮膚癌、成膠質細胞瘤、神經母細胞瘤、肉瘤、脂肪肉瘤、骨軟骨瘤、骨瘤、骨肉瘤、精原細胞瘤、睾丸腫瘤、子宮癌、頭頸癌、多發性骨髓瘤、惡性淋巴瘤、真性紅細胞增多症、白血病、甲狀腺癌、輸尿管腫瘤、膀胱腫瘤、膽囊癌、膽管癌、絨毛膜上皮癌或兒科腫瘤。 A compound as described in any one of claims 1 to 30 or a pharmaceutically acceptable salt, tautomer or isotopic substitution as described in claim 31 or a pharmaceutical composition as described in claim 32 in Use in the preparation of a medicament for the prevention and/or treatment of cancer selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer carcinoma, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, lipid Liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder Tumor, gallbladder, bile duct, choriocarcinoma, or pediatric tumor.

一種製備如請求項1所述的化合物或其可藥用的鹽、互變異構體的方法，包括如下步驟： A method for preparing a compound as claimed in claim 1 or a pharmaceutically acceptable salt or tautomer thereof, comprising the steps of:

；其中，

;in,

LG₃選自苯氧基、4-硝基苯氧基； LG ₃ is selected from phenoxy, 4-nitrophenoxy;

R₁、R₂、R₃、R₄、R₅、L₁、L₂如請求項1中定義。 R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , L ₁ , L ₂ are as defined in claim 1 .

一種製備如請求項1所述的化合物或其可藥用的鹽、互變異構體的方法，當-L₁-選自-O-時，包括如下步驟： A method for preparing the compound as claimed in claim 1 or a pharmaceutically acceptable salt or tautomer thereof, when -L ₁ - is selected from -O-, the method comprises the following steps:

；其中，

;in,

R₁、R₂、R₃、R₄、R₅、L₂如請求項1中定義。 R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , L ₂ are as defined in claim 1 .