TW202440574A - Heteroaryl compounds as pkmyt1 inhibitors - Google Patents

Abstract

The present invention relates to novel heteroaryl compounds of Formula (I) and their pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including other possible isotopes thereof as inhibitors of PKMYT1. The present invention also provides the process of preparation of compounds of Formula (I) for treating cancer.

Description

Translated fromChinese

作為PKMYT1抑制劑的雜芳基化合物Heteroaryl compounds as PKMYT1 inhibitors

本發明涉及如式(I)之新型雜芳基化合物作為PKMYT1抑制劑、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。The present invention relates to novel heteroaryl compounds of formula (I) as PKMYT1 inhibitors, or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).

本發明另涉及如式(I)的新型雜芳基化合物的製造方法、包含該新型雜芳基化合物的藥物組合物以及其在治療癌症中的用途。The present invention also relates to a method for preparing a novel heteroaryl compound of formula (I), a pharmaceutical composition comprising the novel heteroaryl compound, and its use in treating cancer.

細胞DNA不斷暴露於各種內源性和外源性損傷，因此需要修復才能完成細胞週期並進行細胞增殖。多種蛋白質協調並協同工作，透過各種複雜的信號傳導途徑(稱為DNA損傷反應(DDR))進行。DDR和檢查點路徑是相互交織的訊號網絡，可阻止細胞週期、識別和修復遺傳錯誤(Curr Cancer Drug Targets,2012 May；12(4)：356-71)。大多數癌症沒有正常功能的G1/S檢查點，因此更依賴有效的G2檢查點(Cell Prolif.2000,33,261-274)。PKMYT1(膜相關酪胺酸和蘇胺酸特異性cdc2抑制激酶)作為CDK1(細胞週期蛋白依賴性激酶1)的負調節因子，並導致G2/M檢查點細胞週期停滯(Nature,Vol.604,April 28,2022)。抑制此功能會導致CCNE1過表達細胞中CDK1選擇性地意外活化。這促進了正在進行DNA合成的細胞的早期有絲分裂，並最終透過細胞凋亡導致細胞死亡(Journal of Hematology & Oncology(2020)13：126)。CRISPR篩選證實CCNE1過表達細胞的確依賴PKMYT1的功能(Journal of Hematology & Oncology(2020)13：126)。Cellular DNA is constantly exposed to a variety of endogenous and exogenous damage, and therefore needs to be repaired to complete the cell cycle and undergo cell proliferation. Multiple proteins coordinate and work together through a variety of complex signaling pathways (called DNA damage response (DDR)). DDR and checkpoint pathways are intertwined signaling networks that can block cell cycles, recognize and repair genetic errors (Curr Cancer Drug Targets, 2012 May; 12(4): 356-71). Most cancers do not have a properly functioning G1/S checkpoint and therefore rely more on an effective G2 checkpoint (Cell Prolif. 2000, 33, 261-274). PKMYT1 (membrane-associated tyrosine and threonine-specific cdc2-inhibitory kinase) acts as a negative regulator of CDK1 (cell cycle protein-dependent kinase 1) and causes G2/M checkpoint cell cycle arrest (Nature, Vol. 604, April 28, 2022). Inhibition of this function leads to the selective and unexpected activation of CDK1 in CCNE1-overexpressing cells. This promotes early mitosis of cells undergoing DNA synthesis and ultimately leads to cell death through apoptosis (Journal of Hematology & Oncology (2020) 13: 126). CRISPR screening confirmed that CCNE1 overexpressing cells are indeed dependent on the function of PKMYT1 (Journal of Hematology & Oncology (2020) 13: 126).

在卵巢癌中，約有20%的腫瘤中檢測到CCNE1擴增(Nature,2015,521,489-494；Clin.Cancer Res.2009,15,1417-1427)。CCNE1擴增的腫瘤其預後較差，且僅有非常有限的治療選擇(Curr.Opin.Obstet.Gynecol.,2017,29,26-34,J.Med.Chem.2022,65,15,10251-10284)。細胞週期蛋白E本身由於其在細胞週期中的重要作用，被認為是不可作為製作藥物的標的，但其同源細胞週期蛋白-依賴性激酶CDK2，則是可作為製作藥物的標的。CDK2抑制在CCNE1擴增細胞系中顯示出有顯著的活性(Clin.Cancer Res.,2013,19,5960-5971)，選擇性CDK2抑制劑正開始進入臨床開發。In ovarian cancer, CCNE1 amplification is detected in approximately 20% of tumors (Nature, 2015, 521, 489-494; Clin. Cancer Res. 2009, 15, 1417-1427). Tumors with CCNE1 amplification have a poor prognosis and very limited treatment options (Curr. Opin. Obstet. Gynecol., 2017, 29, 26-34, J. Med. Chem. 2022, 65, 15, 10251-10284). Cyclic protein E itself is considered not to be a target for drug production due to its important role in the cell cycle, but its homologous cyclic protein-dependent kinase CDK2 can be used as a target for drug production. CDK2 inhibition has shown significant activity in CCNE1-expanded cell lines (Clin. Cancer Res., 2013, 19, 5960-5971), and selective CDK2 inhibitors are beginning to enter clinical development.

然而，CDK抑制劑抗藥性的出現需要評估其他新型治療標靶，例如PKMYT1。選擇性PKMYT1抑制劑專為治療CCNE1擴增的癌症患者而設計。However, the emergence of resistance to CDK inhibitors requires the evaluation of other novel therapeutic targets, such as PKMYT1. Selective PKMYT1 inhibitors are designed specifically for the treatment of cancer patients with CCNE1 amplification.

PCT國際申請公開號WO2021/195781公開了用於對抗PKMYT1的不同化合物。PCT International Application Publication No. WO2021/195781 discloses different compounds for combating PKMYT1.

作為具有PKMYT1抑制作用的化合物，例如，已知尚有以下發表文獻中所揭露的化合物：WO2023/155870、WO2023/155871、WO2023/155892、WO2023/174329、WO2023/174397、WO2023/174329、WO2023/174397、WO2023/174329、WO2023/174397、WO2023/174329、WO2023/174397、WO2023/1783/311971397.US2023/0122909和US2023/0142913。As compounds having PKMYT1 inhibitory effects, for example, compounds disclosed in the following publications are known: WO2023/155870, WO2023/155871, WO2023/155892, WO2023/174329, WO2023/174397, WO2023/174329, WO2023/174397, WO2023/174329, WO2023/174397, WO2023/174329, WO2023/174397, WO2023/1783/311971397. US2023/0122909 and US2023/0142913.

儘管有現有的已知化合物，但仍需要開發新型且更有效的PKMYT1抑制劑作為抗癌藥物，以有效提供針對癌症的標靶治療。Despite the existing known compounds, there is still a need to develop novel and more effective PKMYT1 inhibitors as anticancer drugs to effectively provide targeted therapy against cancer.

本發明的主要目的是提供如式(I)所示之新型雜芳基化合物作為PKMYT1抑制劑。The main purpose of the present invention is to provide a novel heteroaryl compound as shown in formula (I) as a PKMYT1 inhibitor.

本發明的另一個目的是提供如式(I)所示之新型雜芳基化合物的藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。Another object of the present invention is to provide pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof) of the novel heteroaryl compounds represented by formula (I).

本發明的另一個目的是提供一種製備如式(I)所示之新型雜芳基化合物的方法。Another object of the present invention is to provide a method for preparing a novel heteroaryl compound as shown in formula (I).

本發明的另一個目的是製備包含如式(I)所示之雜芳基化合物的藥物組合物。Another object of the present invention is to prepare a pharmaceutical composition comprising a heteroaryl compound as shown in formula (I).

本發明的另一個目的是提供一種使用包含如式(I)所示之新型雜芳基化合物的組合物治療癌症的方法。Another object of the present invention is to provide a method for treating cancer using a composition comprising a novel heteroaryl compound as shown in formula (I).

本發明提供如下所示之新型雜芳基化合物。The present invention provides novel heteroaryl compounds as shown below.

如式(I)所示之雜芳基化合物Heteroaryl compounds as shown in formula (I)

其中，in,

環A係選自取代的或未取代的芳基、取代的或未取代的5至6員雜芳基、取代或未取代的5至8員碳環和取代或未取代的5至8員雜環；Ring A is selected from substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-8 membered carbon ring and substituted or unsubstituted 5-8 membered hetero ring;

X和Y獨立地選自-N或-CR⁶；X and Y are independently selected from -N or -CR⁶ ;

R¹和R²係獨立地選自氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、取代或未取代的雜芳基、烯基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂以及-N(R^7b)₂，或R¹和R²一起形成之取代的或未取代的-5-8員雜環；R¹ and R² are independently selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, alkenyl, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ and -N(R^7b )₂ , or a substituted or unsubstituted 5-8 membered heterocyclic ring formed by R¹ and R² together;

R³和R⁴係獨立地選自氰基、取代的或未取代的雜芳基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂以及-N(R^7b)₂，或R³和R⁴一起形成之取代或未取代的5-8員雜環，或取代或未取代的5-6員雜芳基；^R3 and^R4 are independently selected from cyano, substituted or unsubstituted heteroaryl,^-NR7bC (=O)^R7a ,^-OR7b , -C(=O)^OR7b , -C(=O)N(^R7b )₂ and -N(^R7b )₂ , or^R3 and^R4 together form a substituted or unsubstituted 5-8 membered heterocyclic ring, or a substituted or unsubstituted 5-6 membered heteroaryl;

R⁵係選自氫、羥基、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂以及-N(R^7b)₂；R⁵ is selected from hydrogen, hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ and -N(R^7b )₂ ;

R⁶係選自氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環以及-N(R^7b)₂；R⁶ is selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic and -N(R^7b )₂ ;

R^7a係選自取代的或未取代的烷基、取代的或未取代的環烷基以及取代的或未取代的雜環；R^7a is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic;

R^7b係選自氫、取代或未取代的烷基、取代或未取代的環烷基和取代或未取代的雜環；R^7b is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic;

n為選自1-5的整數；以及n is an integer selected from 1-5; and

當R¹和R²一起不是取代的或未取代的5-8員雜環且R³和R⁴一起不是取代的或未取代的5-8員雜環或取代的或未取代的5-6員雜芳基時，則n為2或大於2，且當-OR^7b是R⁵的一部分時，R^7b為氫；When^R1 and^R2 together are not substituted or unsubstituted 5-8 membered heterocyclic and^R3 and^R4 together are not substituted or unsubstituted 5-8 membered heterocyclic or substituted or unsubstituted 5-6 membered heteroaryl, then n is 2 or greater, and when^-OR7b is part of^R5 ,^R7b is hydrogen;

或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or its pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).

如上述所定義的式(I)化合物、或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中，環A係選自取代的或未取代的芳基或取代的或未取代的5至6員雜芳基。As defined above, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including isotopes thereof), wherein ring A is selected from substituted or unsubstituted aryl or substituted or unsubstituted 5-6 membered heteroaryl.

式(IA)之化合物由下列結構表示：The compound of formula (IA) is represented by the following structure:

其中，in,

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹和R²係為甲基；^R1 and^R2 are methyl groups;

R³和R⁴一起可形成取代或未取代的5-8員雜環，或取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-8 membered heterocyclic ring, or a substituted or unsubstituted 5-6 membered heteroaryl group; and

R⁵和n各自與上述式(I)化合物中的定義相同；R⁵ and n are each the same as defined in the compound of formula (I) above;

或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or its pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).

式(IA)之化合物由下列結構表示：The compound of formula (IA) is represented by the following structure:

其中，in,

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹係為甲基；R²係為環烷基或雜環或雜芳基或OR^7b，其中R^7b是烷基或環烷基；R¹ is methyl; R² is cycloalkyl or heterocyclic or heteroaryl or OR^7b , wherein R^7b is alkyl or cycloalkyl;

R³和R⁴一起可形成取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group; and

R⁵和n各自與上述式(I)化合物中的定義相同；R⁵ and n are each the same as defined in the compound of formula (I) above;

或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).

式(IA)之化合物由下列結構表示：The compound of formula (IA) is represented by the following structure:

其中，in,

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹係為環烷基或雜環或OR^7b，其中，R^7b是烷基或環烷基；R²係為甲基；R¹ is a cycloalkyl group or a heterocyclic group or OR^7b , wherein R^7b is an alkyl group or a cycloalkyl group; R² is a methyl group;

R³和R⁴一起可形成取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group; and

R⁵和n各自與上述式(I)化合物中的定義相同；R⁵ and n are each the same as defined in the compound of formula (I) above;

或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).

式(IA)之化合物由下列結構表示：The compound of formula (IA) is represented by the following structure:

其中，in,

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹係為甲基；^R1 is methyl;

R²係為取代的烷基，其中取代基是-OR^8b；R² is a substituted alkyl group, wherein the substituent is -OR^8b ;

R^8b係選自氫、烷基、鹵代烷基、環烷基；R^8b is selected from hydrogen, alkyl, halogenated alkyl, and cycloalkyl;

R³和R⁴一起可形成取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group; and

R⁵和n各自與式(I)化合物中的定義相同；R⁵ and n are each the same as defined in the compound of formula (I);

或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).

式(IB)之化合物由下列結構表示：The compound of formula (IB) is represented by the following structure:

其中，in,

環A是苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹和R²係為甲基；^R1 and^R2 are methyl groups;

R³為-C(=O)N(R^7b)₂，且R⁴為-N(R^7b)₂，其中R^7b為氫；以及R³ is -C(=O)N(R^7b )₂ , and R⁴ is -N(R^7b )₂ , wherein R^7b is hydrogen; and

R⁵和n各自與式(I)化合物中的定義相同；R⁵ and n are each the same as defined in the compound of formula (I);

或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).

式(IC)和式(ID)的化合物由下列結構表示：The compounds of formula (IC) and formula (ID) are represented by the following structures:

其中in

Y係為N或CR⁶；Y is N or CR⁶ ;

R¹和R²獨立地為氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、取代或未取代的雜芳基、烯基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂或-N(R^7b)₂；R¹ and R² are independently hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, alkenyl, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ or -N(R^7b )₂ ;

R^5a為C_1-4烷基或鹵素；R^5a is C_1-4 alkyl or halogen;

R^5b為氫、C_1-4烷基或鹵素；R^5b is hydrogen, C_1-4 alkyl or halogen;

R^5c為羥基；R^5c is hydroxyl;

R^5d為氫或羥基；R^5d is hydrogen or hydroxy;

R⁶為氫、鹵素或C_1-4-烷基；^R6 is hydrogen, halogen or_C1-4 -alkyl;

R^7a為取代的或未取代的烷基、取代的或未取代的環烷基、或取代的或未取代的雜環；以及R^7a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclic; and

R^7b是氫、取代或未取代的烷基、取代或未取代的環烷基、或取代或未取代的雜環；R^7b is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclic;

或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).

如上述所定義的式(IC)和式(ID)的化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中As defined above, the compounds of formula (IC) and formula (ID), or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof), wherein

Y係為CR⁶；Y is CR⁶ ;

R¹和R²獨立地為氫；鹵素；硝基；氰基；C_1-4烷基選擇性地被一個或多個選自鹵素、-O-R^8b、-N(H)R⁸、-N(烷基)R⁸、C_3-6環烷基、以及雜環的基團取代，其中所述C_3-6環烷基和雜環可進一步被一個或多個選自鹵素、氰基、C_1-4烷基、-O-R^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；C_3-6環烷基選擇性地被一個或多個選自鹵素、氰基、C_1-4烷基、-O-R^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；雜環選擇性地被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、-CH₂-OR^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；雜芳基選擇性地被一個或多個選自鹵素、氰基、C_1-4烷基、-O-(C_1-4烷基)、C_1-4鹵代烷基、-O-(C_1-4鹵代烷基)、-N(烷基)烷基、-N(H)烷基、以及-NH₂的基團取代；C_2-4烯基；-OR^7b；或-N(R^7b)₂；^R1 and^R2 are independently hydrogen; halogen; nitro; cyano;_C1-4 alkyl is optionally substituted by one or more groups selected from halogen,^-OR8b , -N(H)^R8 , -N(alkyl)^R8 ,_C3-6 cycloalkyl, and heterocyclic ring, wherein the_C3-6 cycloalkyl and heterocyclic ring may be further substituted by one or more groups selected from halogen, cyano,_C1-4 alkyl,^-OR8b ,_C1-4 halogenated alkyl, -N(H)^R8 , and -N(alkyl)^R8 ;_C3-6 cycloalkyl is optionally substituted by one or more groups selected from halogen, cyano,_C1-4 alkyl,^-OR8b ,_C1-4 halogenated alkyl, -N(H)^R8 , and -N(alkyl)R⁸ ; the heterocyclic group is optionally substituted with one or more groups selected from halogen, cyano, -OR^8b , C_1-4 alkyl, -CH₂ -OR^8b , C_1-4 halogenated alkyl, -N(H)R⁸ , and -N(alkyl)R⁸ ; the heteroaryl group is optionally substituted with one or more groups selected from halogen, cyano, C_1-4 alkyl, -O-(C_1-4 alkyl), C_1-4 halogenated alkyl, -O-(C_1-4 halogenated alkyl), -N(alkyl)alkyl, -N(H)alkyl, and -NH₂ ; C_2-4 alkenyl; -OR^7b ; or -N(R^7b )₂ ;

R^7b係為氫；C_3-6環烷基；或C_1-4烷基選擇性地被一個或多個選自鹵素和C_3-6環烷基的基團取代；R^7b is hydrogen; C_3-6 cycloalkyl; or C_1-4 alkyl is optionally substituted with one or more groups selected from halogen and C_3-6 cycloalkyl;

R⁸係為氫、C_1-4烷基或C_3-6環烷基；以及^R8 is hydrogen,_C1-4 alkyl or_C3-6 cycloalkyl; and

R^8b係為氫、C_1-4烷基、C_1-4鹵代烷基或C_3-6環烷基。R^8b is hydrogen, C_1-4 alkyl, C_1-4 halogenated alkyl or C_3-6 cycloalkyl.

如上述所定義的式(IC)和式(ID)的化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘化化合物(包括其同位素)，其中：As defined above, the compounds of formula (IC) and formula (ID), or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof), wherein:

R¹和R²係獨立地為氫；鹵素；硝基；氰基；C_1-4烷基選擇性地被一個或多個選自鹵素、-O-R^8b、-N(H)R⁸、-N(烷基)R⁸、C_3-6環烷基、哌啶基(piperidinyl)、吡咯烷基(pyrrolidinyl)和嗎啉基(morpholinyl)，其中所述C_3-6環烷基、哌啶基、吡咯烷基和嗎啉基可以進一步被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、C_1-4的鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；C_3-6環烷基選擇性地被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；哌啶基、吡咯烷基、嗎啉基或6-氮雜螺[2.5]辛基(6-azaspiro[2.5]octyl)，各自可被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、-CH₂-OR^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸；吡唑基選擇性被一個或多個選自鹵素、氰基、C_1-4烷基、-O-(C_1-4烷基)、C_1-4鹵代烷基、-O-(C_1-4鹵代烷基)、-N(烷基)烷基、-N(H)烷基、以及-NH₂；C_2-4烯基；-OR^7b；或-N(R^7b)₂；^R1 and^R2 are independently hydrogen; halogen; nitro; cyano;_C1-4 alkyl is optionally substituted by one or more groups selected from halogen,^-OR8b , -N(H)^R8 , -N(alkyl)^R8 ,_C3-6 cycloalkyl, piperidinyl, pyrrolidinyl and morpholinyl, wherein the_C3-6 cycloalkyl, piperidinyl, pyrrolidinyl and morpholinyl may be further substituted by one or more groups selected from halogen, cyano,^-OR8b , C1-4 alkyl,_C1-4 halogenated alkyl, -N(H)R8, and -N(alkyl)^R8 ;_C3-6 cycloalkyl is optionally substituted by one or more groups selected from halogen, cyano,^-OR8b , C1-4 alkyl,_C1-4 halogenated alkyl, -N(H)^R8 , and -N(alkyl)R8; , C_1-4 alkyl, C_1-4 halogenated alkyl, -N(H)R⁸ , and -N(alkyl)R⁸ ; piperidinyl, pyrrolidinyl, morpholinyl or 6-azaspiro[2.5]octyl, each of which may be substituted with one or more selected from halogen, cyano, -OR^8b , C_1-4 alkyl, -CH₂ -OR^8b , C_1-4 halogenated alkyl, -N(H)R⁸ , and -N(alkyl)R⁸ ; pyrazolyl may be optionally substituted with one or more selected from halogen, cyano, C_1-4 alkyl, -O-(C_1-4 alkyl), C_1-4 halogenated alkyl, -O-(C_1-4 halogenated alkyl), -N(alkyl)alkyl, -N(H)alkyl, and -NH₂ ; C_2-4 alkenyl; -OR^7b ; or -N(R^7b )₂ ;

R^7b係為氫；C_3-6環烷基；或C_1-4烷基選擇性地被一個或多個選自鹵素和C_3-6環烷基的基團取代；R^7b is hydrogen; C_3-6 cycloalkyl; or C_1-4 alkyl is optionally substituted with one or more groups selected from halogen and C_3-6 cycloalkyl;

R⁸係為氫、C_1-4烷基、或C_3-6環烷基；以及^R8 is hydrogen,_C1-4 alkyl, or_C3-6 cycloalkyl; and

R^8b係為氫、C_1-4烷基、C_1-4鹵代烷基、或C_3-6環烷基。R^8b is hydrogen, C_1-4 alkyl, C_1-4 halogenated alkyl, or C_3-6 cycloalkyl.

式(I)化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中所述化合物選自由以下組成的群組：A compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including isotopes thereof) thereof, wherein the compound is selected from the group consisting of:

本發明提供了一種製備式(I)的雜芳基化合物的方法The present invention provides a method for preparing a heteroaryl compound of formula (I)

其中，in,

環A係選自取代的或未取代的芳基、取代的或未取代的5至6員雜芳基、取代或未取代的5至8員碳環和取代或未取代的5至8員雜環；Ring A is selected from substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-8 membered carbon ring and substituted or unsubstituted 5-8 membered hetero ring;

X和Y獨立地選自-N或-CR⁶；X and Y are independently selected from -N or -CR⁶ ;

R¹和R²係獨立地選自氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、取代或未取代的雜芳基、烯基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)2和-N(R^7b)₂，或R¹和R²一起形成之取代的或未取代的-5-8員雜環；^R1 and^R2 are independently selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, alkenyl,^-NR7bC (=O)^R7a ,^-OR7b , -C(=O)^OR7b , -C(=O)N(^R7b )2 and -N(^R7b )₂ , or a substituted or unsubstituted 5-8 membered heterocyclic ring formed by^R1 and^R2 together;

R³和R⁴係獨立地選自氰基、取代的或未取代的雜芳基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂和-N(R^7b)₂或R³和R⁴一起形成之取代或未取代的5-8員雜環，或取代或未取代的5-6員雜芳基；^R3 and^R4 are independently selected from cyano, substituted or unsubstituted heteroaryl,^-NR7bC (=O)^R7a ,^-OR7b , -C(=O)^OR7b , -C(=O)N(^R7b )₂ and -N(^R7b )₂ , or a substituted or unsubstituted 5-8 membered heterocyclic ring formed by^R3 and^R4 , or a substituted or unsubstituted 5-6 membered heteroaryl;

R⁵係選自氫、羥基、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂和-N(R^7b)₂；R⁵ is selected from hydrogen, hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ and -N(R^7b )₂ ;

R⁶係選自氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環和-N(R^7b)₂；R⁶ is selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic and -N(R^7b )₂ ;

R^7a係選自取代的或未取代的烷基、取代的或未取代的環烷基和取代的或未取代的雜環；R^7a is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic;

R^7b係選自氫、取代或未取代的烷基、取代或未取代的環烷基和取代或未取代的雜環；R^7b is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic;

R^8b係選自氫、烷基、鹵代烷基、以及環烷基；R^8b is selected from hydrogen, alkyl, halogenated alkyl, and cycloalkyl;

n為選自1-5的整數；以及n is an integer selected from 1-5; and

當R¹和R²一起不是取代的或未取代的5-8員雜環且R³和R⁴一起不是取代的或未取代的5-8員雜環或取代的或未取代的5-6員雜芳基時，則n為2或大於2，且當-OR^7b是R⁵的一部分時，R^7b為氫；When^R1 and^R2 together are not substituted or unsubstituted 5-8 membered heterocyclic and^R3 and^R4 together are not substituted or unsubstituted 5-8 membered heterocyclic or substituted or unsubstituted 5-6 membered heteroaryl, then n is 2 or greater, and when^-OR7b is part of^R5 ,^R7b is hydrogen;

或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，包括以下步驟：Or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including its isotope), comprising the following steps:

(i)在鹼、催化劑和溶劑存在下，以化合物(d)處理起始化合物(a)以獲得化合物(b)；(i) treating the starting compound (a) with the compound (d) in the presence of a base, a catalyst and a solvent to obtain the compound (b);

(ii)在鹼、催化劑和溶劑存在下，以腈(nitrile)處理步驟(i)的化合物(b)，以獲得化合物(c)；(ii) treating the compound (b) of step (i) with a nitrile in the presence of a base, a catalyst and a solvent to obtain a compound (c);

(iii)以試劑處理步驟(ii)的化合物(c)以獲得式(I)的雜芳基化合物或雜環；以及(iii) treating the compound (c) of step (ii) with a reagent to obtain a heteroaryl compound or a heterocyclic compound of formula (I); and

(iv)選擇性地，將步驟(ii)的化合物(c)去保護基，得到式(I)化合物；其中式(I)化合物係為式(IA)化合物、式(IB)化合物、式(IC)化合物或式(ID)化合物。(iv) selectively removing the protecting group of the compound (c) in step (ii) to obtain a compound of formula (I); wherein the compound of formula (I) is a compound of formula (IA), a compound of formula (IB), a compound of formula (IC) or a compound of formula (ID).

如以上所述之方法，其中步驟(i)中的鹼係選自由碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、氫氧化銨、碳酸鉀、碳酸氫鉀、以及碳酸鎂所組成的群組，其中優選的鹼係為碳酸銫。The method as described above, wherein the base in step (i) is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, ammonium hydroxide, potassium carbonate, potassium bicarbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate.

如以上所述之方法，其中步驟(i)中的溶劑係選自由乙醚、二甲基甲醯胺、四氫呋喃、二氯甲烷、甲醇、二甲基亞碸(DMSO)、二甲氧基乙烷、二甲氧基甲烷、二丁醚、乙醇、異丙醇、乙腈、以及二異丙醚所組成之群組，其中優選的溶劑係為1,2-二甲氧基乙烷。As described above, the solvent in step (i) is selected from the group consisting of diethyl ether, dimethylformamide, tetrahydrofuran, dichloromethane, methanol, dimethyl sulfoxide (DMSO), dimethoxyethane, dimethoxymethane, dibutyl ether, ethanol, isopropanol, acetonitrile, and diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane.

如以上所述之方法，其中步驟(ii)中所述的腈係選自由丙二腈、丙腈和乙腈、以及苯甲腈所組成的群組，其中優選的腈係為丙二腈。The method as described above, wherein the nitrile described in step (ii) is selected from the group consisting of malononitrile, propionitrile and acetonitrile, and benzonitrile, wherein the preferred nitrile is malononitrile.

如以上所述之方法，其中步驟(ii)中的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫氧化銨、氫化鉀、氫化銣、氫化銫或氫化鋁鋰所組成的群組，其中優選的鹼係為叔丁醇鈉、碳酸氫鈉或氫化鈉。The method as described above, wherein the base in step (ii) is selected from the group consisting of sodium tert-butoxide, sodium hydroxide, lithium hydroxide, ammonium hydroxide, potassium hydroxide, cadmium hydroxide, cesium hydroxide or aluminum lithium hydroxide, wherein the preferred base is sodium tert-butoxide, sodium bicarbonate or sodium hydroxide.

如以上所述之方法，其中步驟(ii)中的催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)、以及三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦基)二茂鐵]二氯化鈀(II價)。As described above, the catalyst in step (ii) is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent), and tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent).

如以上所述之方法，其中步驟(ii)中的溶劑係選自由DMSO、1,2-二甲氧基乙烷、甲醇、二氯甲烷、甲苯、二甲基甲醯胺、四氫呋喃、乙醚、以及氯化溶劑所組成的群組，其中優選的溶劑係為1,2-二甲氧基乙烷。As described above, the solvent in step (ii) is selected from the group consisting of DMSO, 1,2-dimethoxyethane, methanol, dichloromethane, toluene, dimethylformamide, tetrahydrofuran, diethyl ether, and chlorinated solvents, wherein the preferred solvent is 1,2-dimethoxyethane.

如以上所述之方法，其中步驟(iii)的試劑選自由甲醯胺、乙酸乙酯、碳酸二乙酯(ethyl carbonate)、以及鹽酸胍(guanidine hydrochloride)所組成的群組。The method as described above, wherein the reagent in step (iii) is selected from the group consisting of formamide, ethyl acetate, ethyl carbonate, and guanidine hydrochloride.

本發明提供了一種藥物組合物，其包含上述化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)、以及藥學上可接受的賦形劑或載體。The present invention provides a pharmaceutical composition comprising the above-mentioned compound, or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including its isotope), and a pharmaceutically acceptable excipient or carrier.

本發明提供了上述化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)在製備用於治療與PKMYT1蛋白相關的癌症的藥物中的用途。The present invention provides the use of the above-mentioned compound, or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including its isotope) in the preparation of drugs for treating cancers associated with PKMYT1 protein.

本發明提供上述化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)在用於治療與PKMYT1蛋白相關的癌症的用途。The present invention provides the use of the above-mentioned compound, or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including its isotope) for treating cancer associated with PKMYT1 protein.

本發明提供上述化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，以用於治療與PKMYT1蛋白相關的癌症。The present invention provides the above-mentioned compound, or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including its isotope) for the treatment of cancer associated with PKMYT1 protein.

本發明提供了抑制PKMYT1蛋白的方法，包括向癌症患者投予治療有效量的藥物組合物，所述藥物組合物包含至少一種如上述所定義之化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物包括其同位素，其中所述治療癌症的方法係與PKMYT1蛋白有關。The present invention provides a method for inhibiting PKMYT1 protein, comprising administering a therapeutically effective amount of a drug composition to a cancer patient, wherein the drug composition comprises at least one compound as defined above, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound including isotopes thereof, wherein the method for treating cancer is related to PKMYT1 protein.

如以上所述之方法，其中所述癌症與PKMYT1的活性相關，其中所述癌症會過度表現CCNE1。The method as described above, wherein the cancer is associated with the activity of PKMYT1, wherein the cancer overexpresses CCNE1.

如以上所述之方法，其中所述癌症在FBXW7和PPP2R1A基因中具有失活突變，其中所述癌症是實體固態腫瘤。The method as described above, wherein the cancer has inactivating mutations in the FBXW7 and PPP2R1A genes, wherein the cancer is a solid tumor.

如以上所述之方法，其中所述癌症是乳癌(breast cancer)、大腸直腸癌(colorectal cancer)、子宮內膜癌(endometrial cancer)、食道癌(esophageal cancer)、膠質母細胞瘤(glioblastoma)、肝細胞癌(hepatocellular carcinoma)、肺癌(lung cancer)、神經母細胞瘤(neuroblastoma)、卵巢癌(ovarian cancer)、前列腺癌(prostate cancer)、胃癌(stomach cancer)或子宮癌(uterine cancer)。The method as described above, wherein the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer or uterine cancer.

本申請案係主張2023年2月9日提出之印度專利申請案No.202341008447和2023年8月10日提出之印度專利申請案No.202341053729之優先權及權益，其公開內容經引用併入本文。This application claims priority and benefits over Indian Patent Application No. 202341008447 filed on February 9, 2023 and Indian Patent Application No. 202341053729 filed on August 10, 2023, the disclosures of which are incorporated herein by reference.

透過參考以下詳細描述、實施例和表格可以更容易理解本文所述的實施例。在不脫離本發明的精神和範圍的情況下，針對本發明所進行之各種修改和改良對於本領域技術人員來說是顯而易見的。The embodiments described herein can be more easily understood by referring to the following detailed description, examples and tables. Various modifications and improvements made to the present invention without departing from the spirit and scope of the present invention will be obvious to those skilled in the art.

本揭露公開了本發明關於式(I)的新型雜芳基化合物和其藥學上可接受的鹽、溶劑化物、多晶型、互變異構體、阻轉異構體、光學和幾何異構體、前驅藥物或氘代化合物(包括其同位素)的詳細描述。This disclosure discloses a detailed description of the novel heteroaryl compounds of formula (I) and their pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs or deuterated compounds (including their isotopes) of the present invention.

式(I)中所使用的通用術語如下述之定義；然而，下述的定義不應被解釋為限制該術語本身的範圍。The general terms used in formula (I) are as defined below; however, the following definitions should not be construed as limiting the scope of the terms themselves.

術語「鹵素」或「鹵代」是指氟(F)或氟代、氯(Cl)或氯代、溴(Br)或溴代、或碘(I)或碘代。The term "halogen" or "halogenated" refers to fluorine (F) or fluoro, chlorine (Cl) or chloro, bromine (Br) or bromo, or iodine (I) or iodo.

術語「烷基」是指衍生自烷烴的烴基，其在主鏈中僅包含碳和氫原子，不含不飽和鍵，具有1至6個碳原子，即C_1-6，優選1至4個碳原子，即C_1-4，並透過單鍵連接到分子的其餘部分，例如，甲基、乙基、正丙基、1-甲基乙基(異丙基)、正丁基、正戊基、1,1-二甲基乙基(叔丁基)等。本文所使用的「C_1-4-烷基」是指具有1至4個直鏈或支鏈排列的碳原子的基團，並且包括甲基、乙基、丙基、異丙基、正丁基、1-甲基丙基、2-甲基丙基和叔丁基。除非相反地闡述或敘述，本文描述或要求保護的所有烷基可以是直鏈或支鏈、取代或未取代的。The term "alkyl" refers to a hydrocarbon group derived from an alkane, which contains only carbon and hydrogen atoms in the main chain, contains no unsaturated bonds, has 1 to 6 carbon atoms, i.e.,_C1-6 , preferably 1 to 4 carbon atoms, i.e.,_C1-4 , and is connected to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), etc. "_C1-4 -alkyl" as used herein refers to a group having 1 to 4 carbon atoms in a straight or branched arrangement, and includes methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl and tert-butyl. Unless stated or described to the contrary, all alkyl groups described or claimed herein may be linear or branched, substituted or unsubstituted.

當「烷基」例如C_1-4-烷基被取代時，其被1至4個獨立地選自氧代(=O)、氰基、鹵素、鹵代烷基、環烷基、取代或未取代的芳基、取代或未取代的雜環、-OR^8b、-SO₂R^8a、-C(=O)OR^8b、-OC(=O)R^8a、-OC(=O)OR^8a、-C(=O)N(H)R⁸、-C(=O)N(烷基)R⁸、-N(H)C(=O)R^8a、-N(H)R⁸和-N(烷基)R⁸。When "alkyl" such as_C1-4 -alkyl is substituted, it is replaced by 1 to 4 groups independently selected from oxo (=O), cyano, halogen, halogenated alkyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle,^-OR8b ,_-SO2R8a , -C(=O)^OR8b , -OC(=O)^R8a , -OC(=O^)OR8a, -C(=O)N(H)^R8 , -C(=O)N(alkyl)^R8 , -N(H)C(=O)^R8a , -N(H)^R8 and -N(alkyl)^R8 .

術語「烯基」是指衍生自烯烴的烴基，其在主鏈中僅包含碳和氫原子，包含一個或多個雙鍵，具有2至6個碳原子，即C_2-6，優選2至4個碳原子，即C_2-4，並以單鍵連接至分子的其餘部分，例如乙烯基、烯丙基、丙-1-烯-2-基(prop-1-en-2-yl)、丁-3-烯-1-基(but-3-en-1-yl)、丁-2-烯-1-基(but-2-en-1-yl)、丁-1-烯-2-基(but-1-en-2-yl)、戊-4-烯-1-基(pent-4-en-1-yl)、己-5-烯-1-基(hex-5-en-1-yl)等。本文所使用的「C_2-4-烯基」基團是指具有2至4個直鏈或支鏈排列的碳原子的基團，並且包括但不限於乙烯基、烯丙基、丙-1-烯-2-基和丁-3-烯-1-基。The term "alkenyl" refers to a alkyl group derived from an alkene, which contains only carbon and hydrogen atoms in the main chain, contains one or more double bonds, has 2 to 6 carbon atoms, i.e.,_C2-6 , preferably 2 to 4 carbon atoms, i.e.,_C2-4 , and is connected to the rest of the molecule by a single bond, for example, vinyl, allyl, prop-1-en-2-yl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-2-yl, pent-4-en-1-yl, hex-5-en-1-yl, etc. As used herein, a "_C2-4 -alkenyl" group refers to a group having 2 to 4 carbon atoms in a linear or branched arrangement and includes, but is not limited to, vinyl, allyl, prop-1-en-2-yl and but-3-en-1-yl.

術語「鹵代烷基」是指被一個或多個鹵素原子取代的烷基，並且包括其中所述烷基的所有氫原子被鹵素取代的全鹵代烷基(perhaloalkyl)。例如，「C_1-4-鹵代烷基」包括但不限於氟甲基(fluoromethyl)、二氟甲基(difluoromethyl)、三氟甲基(trifluoromethyl)、氯甲基(chloromethyl)、二氯甲基(diehloromethyl)、溴甲基(bromomethyl)、氟乙基(fluoroethyl)、二氟乙基(difluoroethyl)、五氟乙基(pentafluoroethyl)、二氯乙基(dichloroethyl)和氯丙基(chloropropyl)。在一實施例，所述C_1-4-鹵代烷基包括二氟甲基或三氟甲基，而在另一實施例中，所述C_1-4-鹵代烷基包括三氟甲基。The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, and includes perhaloalkyl groups in which all hydrogen atoms of the alkyl group are substituted with halogens. For example, "C_1-4 -haloalkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, diehloromethyl, bromomethyl, fluoroethyl, difluoroethyl, pentafluoroethyl, dichloroethyl, and chloropropyl. In one embodiment, the C_1-4 -haloalkyl group includes difluoromethyl or trifluoromethyl, and in another embodiment, the C_1-4 -haloalkyl group includes trifluoromethyl.

術語「碳環」或「環烷基」是指具有3至12個碳原子，即C_3-12，優選3至6個碳原子，即C_3-6的非芳香族單環或多環系統，例如環丙基(cyclopropyl)、環丁基(cyclobutyl)、環戊基(cyclopentyl)、環己基(cyclohexyl)、環庚基(cycloheptyl)、環辛基(cyclooctyl)等。例如，「C_3-6-環烷基」包括但不限於環丙基、環丁基、環戊基和環己基。除非相反地闡述或敘述，本文描述或要求保護的所有環烷基可以是取代的或未取代的。本文所使用的「5至8員碳環」基團包括但不限於環戊基、環己基、環庚基和環辛基。The term "carbocycle" or "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic system having 3 to 12 carbon atoms, i.e.,_C3-12 , preferably 3 to 6 carbon atoms, i.e.,_C3-6 , such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. For example, "_C3-6 -cycloalkyl" includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified or described, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted. As used herein, the "5- to 8-membered carbon ring" group includes, but is not limited to, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

當「碳環」或「環烷基」例如C_3-6-環烷基被取代時，其被1至4個獨立地選自氧代(=O)、氰基、鹵素、烷基、鹵代烷基、-OR^8b、-SO₂R^8a、-OC(=O)R^8a、-OC(=O)OR^8a、-C(=O)N(H)R⁸、-C(=O)N(烷基)R⁸、-N(H)C(=O)R^8a、-N(H)R⁸和-N(烷基)R⁸的取代基所取代。When “carbocycle” or “cycloalkyl” such as C_3-6 -cycloalkyl is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (═O), cyano, halogen, alkyl, halogenated alkyl, -OR^8b , -SO₂ R^8a , -OC(═O)R^8a , -OC(═O)OR^8a , -C(═O)N(H)R⁸ , -C(═O)N(alkyl)R⁸ , -N(H)C(═O)R^8a , -N(H)R⁸ and -N(alkyl)R⁸ .

本文所使用的術語「芳基」是指單價單環、雙環或三環芳香烴環系統。芳基的例子包括苯基、萘基、蒽基(anthracenyl)、芴基(fluorenyl)、茚基(indenyl)、薁基(azulenyl)等。在一實施例中，芳基包括苯基或萘基，並且在另一實施例中，芳基包括苯基。As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. In one embodiment, the aryl group includes phenyl or naphthyl, and in another embodiment, the aryl group includes phenyl.

當「芳基」被取代時，其被1至4個選自鹵素、烷基、氰基、鹵代烷基、環烷基、-O-烷基、-O-鹵代烷基、-O-C(=O)-芳基、-N(烷基)烷基、-N(H)烷基、-NH₂、-N(烷基)C(=O)烷基、-N(H)C(=O)烷基、-C(=O)N(烷基)烷基、-C(=O)N(H)烷基、-C(=O)NH₂、-SO₂N(烷基)烷基、-SO₂N(H)烷基、-SO₂NH₂、-C(=O)OH、-C(=O)-烷基、以及-C(=O)O-烷基的取代基所取代。When “aryl” is substituted, it is substituted with 1 to 4 substituents selected from halogen, alkyl, cyano, haloalkyl, cycloalkyl, -O-alkyl, -O-haloalkyl, -OC(=O)-aryl, -N(alkyl)alkyl, -N(H)alkyl,_-NH2 , -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)_NH2 ,_-SO2N (alkyl)alkyl,_-SO2N (H)_{alkyl, -SO2NH2,} -C(=O)OH, -C(=O)-alkyl and -C(=O)O-alkyl.

本文所用的術語「雜芳基」是指具有1-4個選自O、N或S的環雜原子的5-14員單環、雙環或三環環系統，且其餘環原子為碳(搭配適當的氫原子，除非另有說明)，其中環系統中的至少一個環是芳香族的。此類雜芳基的實施例包括吡咯基(pyrrolyl)、吡唑基(pyrazolyl)、咪唑基(imidazolyl)、三唑基(triazolyl)、四唑基(tetrazolyl)、呋喃基(furyl)、噁唑基(1,3-噁唑基)(oxazolyl；1,3-oxazolyl)、異噁唑基(1,2-噁唑基)(isoxazolyl；1,2-oxazolyl)、惡二唑基(oxadiazolyl)、噻吩基(thienyl)、噻唑基(1,3-噻唑基)(thiazolyl；1,3-thiazolyl)、異噻唑基(1,2-噻唑基)(isothiazolyl；1,2-thiazolyl)、噻二唑基(thiadiazolyl)、吡啶基(pyridyl)、噠嗪基(pyridazinyl)、嘧啶基(pyrimidinyl)、吡嗪基(pyrazyl)、吲哚基(indolyl)、異吲哚基(isoindolyl)、苯并呋喃基(benzofuryl)、苯并噻吩基(benzothienyl)、吲唑基(indazolyl)、苯并咪唑基(benzimidazolyl)、苯并噁唑基(benzoxazolyl)、苯并噻唑基(benzothiazolyl)、喹啉基(quinolyl)、異喹啉基(isoquinolyl)、噌啉基(cirnolinyl)、喹唑啉基(quinazolinyl)、喹喔啉基(quinoxalyl)、吡咯并吡啶基(pyrolopyridyl)和咪唑并吡啶基(imidazolopyridyl)。本文所使用的「5至6員雜芳基」基團包括但不限於吡咯基、吡唑基、咪唑基、三唑基、四唑基、呋喃基、噁唑基、異噁唑基、惡二唑基、噻吩基、噻唑基、異噻唑基、噻二唑基、吡啶基、噠嗪基。The term "heteroaryl" as used herein refers to a 5-14 membered monocyclic, bicyclic or tricyclic ring system having 1-4 heteroatoms selected from O, N or S, and the remaining ring atoms are carbon (with appropriate hydrogen atoms unless otherwise stated), wherein at least one ring in the ring system is aromatic. Examples of such heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, oxazolyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl ... pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cirnolinyl, quinazolinyl, quinoxalyl, pyrolopyridyl and imidazolopyridyl. The "5- to 6-membered heteroaryl" group used herein includes but is not limited to pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, and oxazinyl.

當「雜芳基」被取代時，其被1至4個選自鹵素、烷基、氰基、鹵代烷基、環烷基、-O-烷基、-O-鹵代烷基、-N(烷基)烷基、-N(H)烷基、-NH₂、-N(烷基)C(=O)烷基、-N(H)C(=O)烷基、-C(=O)N(烷基)烷基、-C(=O)N(H)烷基、-C(=O)NH₂、-SO₂N(烷基)烷基、-SO₂N(H)烷基、-SO₂NH₂、-C(=O)OH、-C(=O)-烷基、以及-C(=O)O-烷基的取代基所取代。When the “heteroaryl” is substituted, it is substituted with 1 to 4 substituents selected from halogen, alkyl, cyano, haloalkyl, cycloalkyl, -O-alkyl, -O-haloalkyl, -N(alkyl)alkyl, -N(H)alkyl,_-NH2 , -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)_N (H)alkyl,_-C (=O)NH2,_-SO2N (alkyl)alkyl, -SO2N(_H )alkyl,_-SO2NH2 , -C(=O)OH, -C(=O)-alkyl, and -C(=O)O-alkyl.

除非另有說明，術語「雜環」是指取代或未取代的非芳香族3-至15-員環，其由碳原子組成並具有一個或多個(例如，2或3個)獨立地選自N、O或S的雜原子。此雜環的一價基的例如包括氮丙啶基(aziridinyl)、氮雜環丁烷基(azetidinyl)、吡咯烷基(pyrrolidinyl)、哌啶基(piperidinyl)、二氫吡啶基(dihydropyridyl)、四氫吡啶基(tetrahydropyridyl)、二氫噠嗪基(dihydropyridazinyl)、四氫噠嗪基(tetrahydropyridazinyl)、二氫嘧啶基(dihydropyrimidinyl)、四氫嘧啶基(tetrahydropyrimidinyl)、二氫吡嗪基(dihydropyrazinyl)、四氫吡嗪基(tetrahydropyrazinyl)、氧雜環丁基(oxetanyl)、四氫呋喃基(tetrahydrofuryl)、二氫呋喃基(dihydrofuryl)、四氫吡喃基(tetrahydropyranyl)、二氫吡喃基(dihydropyranyl)、四氫噻吩基(tetrahydrothienyl)、四氫噻喃基(tetrahydrothiopyranyl)、二氫噻喃基(dihydrothiopyranyl)、哌嗪基(piperazinyl)、嗎啉基(morpholinyl)、硫代嗎啉基(thiomorpholinyl)、二氫吲哚基(dihydroindolyl)、二氫異吲哚基(dihydroisoindolyl)、二氫苯并呋喃基(dihydrobenzofuryl)、二氫異苯并呋喃基(dihydroisobenzofuryl)、四氫苯并噁唑基(tetrahydrobenzoxazolyl)、二氫呋喃吡啶基(dihydrofuropyridyl)、二氫吡唑并嗎啉基(dihydropyrazolomorpholinyl)、吡啶二噁烷基(pyridinodioxanyl)、二氫氮雜苯并呋喃基(dihydroazabenzofuryl)、二氫氮雜異苯并呋喃基(dihydroazaisobenzofuryl)、二氫氮雜吲哚基(dihydroazaindolyl)及6-氮雜螺[2.5]辛基(6-azaspiro[2.5]octyl)。本文所使用「5至8員雜環」基的一價基團包括但不限於吡咯烷基、哌啶基、二氫吡啶基、四氫吡啶基、二氫噠嗪基、四氫噠嗪基、二氫嘧啶基、四氫嘧啶基、二氫吡嗪基、四氫吡嗪基、四氫呋喃基、二氫呋喃基、四氫吡喃基、二氫吡喃基、四氫噻吩基、四氫噻喃基、二氫噻喃基、哌嗪基、嗎啉基、硫代嗎啉基和6-氮雜螺[2.5]辛基。Unless otherwise indicated, the term "heterocyclic" refers to a substituted or unsubstituted non-aromatic 3- to 15-membered ring consisting of carbon atoms and having one or more (e.g., 2 or 3) heteroatoms independently selected from N, O, or S. Examples of monovalent groups of such heterocyclic groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, dihydropyridyl, tetrahydropyridyl, dihydropyridazinyl, tetrahydropyridazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hydropyrimidinyl), dihydropyrazinyl, tetrahydropyrazinyl, oxetanyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl anyl), dihydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuryl, dihydroisobenzofuryl, tetrahydrobenzoxazolyl yl), dihydrofuropyridyl, dihydropyrazolomorpholinyl, pyridinodioxanyl, dihydroazabenzofuryl, dihydroazaisobenzofuryl, dihydroazaindolyl and 6-azaspiro[2.5]octyl. The monovalent group of the "5- to 8-membered heterocyclic ring" used herein includes, but is not limited to, pyrrolidinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, dihydrooxazinyl, tetrahydrooxazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, dihydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, and 6-azaspiro[2.5]octyl.

當「雜環」被取代時，其被1至4個獨立地選自氧代(=O)、氰基、鹵素、烷基、鹵代烷基、-OR^8b、CH₂-OR^8b、-C(=O)OR^8b、-OC(=O)R^8a,-OC(=O)OR^8a,-C(=O)N(H)R⁸,-C(=O)N(烷基)R⁸,-N(H)C(=O)R^8a,-N(H)R⁸和-N(烷基)R⁸，的取代基所取代，相同或相鄰碳上的兩個取代基將形成環烷基環。When the “heterocyclic” is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), cyano, halogen, alkyl, halogenated alkyl, -OR^8b , CH₂ -OR^8b , -C(=O)OR^8b , -OC(=O)R^8a , -OC(=O)OR^8a , -C(=O)N(H)R⁸ , -C(=O)N(alkyl)R⁸ , -N(H)C(=O)R^8a , -N(H)R⁸ and -N(alkyl)R⁸ , and two substituents on the same or adjacent carbons will form a cycloalkyl ring.

在本說明書及權利要求中，每個R⁸係獨立地選自氫、烷基和環烷基；In the present specification and claims, each R⁸ is independently selected from hydrogen, alkyl and cycloalkyl;

每個R^8a係獨立選自烷基、鹵代烷基和環烷基；以及Each R^8a is independently selected from alkyl, haloalkyl and cycloalkyl; and

每個R^8b係選自氫、烷基、鹵代烷基和環烷基。Each R^8b is selected from hydrogen, alkyl, haloalkyl and cycloalkyl.

術語「氧代」是指連接至母基團的二價氧(=O)。例如，與碳連接的氧代形成羰基，在環己烷上取代的氧代形成環己酮等。The term "oxo" refers to a divalent oxygen (=O) attached to a parent group. For example, an oxo attached to carbon forms a carbonyl, an oxo substituted on cyclohexane forms cyclohexanone, etc.

應注意，式(IA)、(IB)、(IC)和(ID)的化合物係包括在式(I)的化合物的範圍內，因此，式(IA)、(IB)、(IC)和(ID)化合物的合適的範例或實施例是指對於式(I)化合物所例舉的該些範例。It should be noted that the compounds of formula (IA), (IB), (IC) and (ID) are included in the scope of the compounds of formula (I), and therefore, suitable examples or embodiments of the compounds of formula (IA), (IB), (IC) and (ID) refer to those examples cited for the compounds of formula (I).

根據以上所述，在一實施例，本發明提供了如式(I)之化合物：According to the above, in one embodiment, the present invention provides a compound of formula (I):

或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物、氘代化合物(包括其同位素)，其中：Or its pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs, deuterated compounds (including isotopes thereof), wherein:

環A係選自取代的或未取代的芳基、取代的或未取代的5至6員雜芳基、取代或未取代的5至8員碳環和取代或未取代的5至8員雜環；Ring A is selected from substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-8 membered carbon ring and substituted or unsubstituted 5-8 membered hetero ring;

X和Y獨立地選自-N或-CR⁶；X and Y are independently selected from -N or -CR⁶ ;

R¹和R²係獨立地選自氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、取代或未取代的雜芳基、烯基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂以及-N(R^7b)₂，或R¹和R²一起形成之取代的或未取代的-5-8員雜環；R¹ and R² are independently selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, alkenyl, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ and -N(R^7b )₂ , or a substituted or unsubstituted 5-8 membered heterocyclic ring formed by R¹ and R² together;

R³和R⁴係獨立地選自氰基、取代的或未取代的雜芳基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂以及-N(R^7b)₂，或R³和R⁴一起形成之取代或未取代的5-8員雜環，或取代或未取代的5-6員雜芳基；^R3 and^R4 are independently selected from cyano, substituted or unsubstituted heteroaryl,^-NR7bC (=O)^R7a ,^-OR7b , -C(=O)^OR7b , -C(=O)N(^R7b )₂ and -N(^R7b )₂ , or^R3 and^R4 together form a substituted or unsubstituted 5-8 membered heterocyclic ring, or a substituted or unsubstituted 5-6 membered heteroaryl;

R⁵係選自氫、羥基、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂以及-N(R^7b)₂；R⁵ is selected from hydrogen, hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ and -N(R^7b )₂ ;

R⁶係選自氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環以及-N(R^7b)₂；R⁶ is selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic and -N(R^7b )₂ ;

R^7a係選自取代的或未取代的烷基、取代的或未取代的環烷基以及取代的或未取代的雜環；R^7a is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic;

R^7b係選自氫、取代或未取代的烷基、取代或未取代的環烷基和取代或未取代的雜環；R^7b is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic;

n為選自1-5的整數；以及n is an integer selected from 1-5; and

當R¹和R²一起不是取代的或未取代的5-8員雜環且R³和R⁴一起不是取代的或未取代的5-8員雜環或取代的或未取代的5-6員雜芳基時，則n為2或大於2，且當-OR^7b是R⁵的一部分時，R^7b為氫。When^R1 and^R2 together are not substituted or unsubstituted 5-8 membered heterocyclic and^R3 and^R4 together are not substituted or unsubstituted 5-8 membered heterocyclic or substituted or unsubstituted 5-6 membered heteroaryl, then n is 2 or greater, and when^-OR7b is part of^R5 ,^R7b is hydrogen.

在另一實施例中，本發明提供如式(IA)的化合物，In another embodiment, the present invention provides a compound of formula (IA),

或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中：or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including isotopes thereof), wherein:

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹和R²係為甲基；^R1 and^R2 are methyl groups;

R³和R⁴一起可形成取代或未取代的5-8員雜環，或取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-8 membered heterocyclic ring, or a substituted or unsubstituted 5-6 membered heteroaryl group; and

R⁵和n各自與上述式(I)化合物中的定義相同。R⁵ and n are each the same as defined above in the compound of formula (I).

在另一實施例中，本發明提供如式(IA)的化合物，其中：In another embodiment, the present invention provides a compound of formula (IA), wherein:

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹係為甲基；R²係為環烷基或雜環或雜芳基或OR^7b，其中R^7b是烷基或環烷基；R¹ is methyl; R² is cycloalkyl or heterocyclic or heteroaryl or OR^7b , wherein R^7b is alkyl or cycloalkyl;

R³和R⁴一起可形成取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group; and

R⁵和n各自與上述式(I)化合物中的定義相同。R⁵ and n are each the same as defined above in the compound of formula (I).

在另一實施例中，本發明提供如式(IA)的化合物，其中：In another embodiment, the present invention provides a compound of formula (IA), wherein:

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹係為環烷基或雜環或OR^7b，其中，R^7b是烷基或環烷基；R²係為甲基；R¹ is a cycloalkyl group or a heterocyclic group or OR^7b , wherein R^7b is an alkyl group or a cycloalkyl group; R² is a methyl group;

R³和R⁴一起可形成取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group; and

R⁵和n各自與上述式(I)化合物中的定義相同。R⁵ and n are each the same as defined above in the compound of formula (I).

在另一實施例中，本發明提供如式(IA)的化合物，其中：In another embodiment, the present invention provides a compound of formula (IA), wherein:

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹係為甲基；^R1 is methyl;

R²係為取代的烷基，其中取代基是-OR^8b；R² is a substituted alkyl group, wherein the substituent is -OR^8b ;

R^8b係選自氫、烷基、鹵代烷基、環烷基；R^8b is selected from hydrogen, alkyl, halogenated alkyl, and cycloalkyl;

R³和R⁴一起可形成取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group; and

R⁵和n各自與式(I)化合物中的定義相同。R⁵ and n are each the same as defined in the compound of formula (I).

在另一實施例中，本發明提供如式(IB)的化合物，In another embodiment, the present invention provides a compound of formula (IB),

或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中：or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including isotopes thereof), wherein:

環A是苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹和R²係為甲基；^R1 and^R2 are methyl groups;

R³為-C(=O)N(R^b)₂，且R⁴為-N(R^7b)₂，其中R^7b為氫；以及R³ is -C(=O)N(R^b )₂ , and R⁴ is -N(R^7b )₂ , wherein R^7b is hydrogen; and

R⁵和n各自與式(I)化合物中的定義相同。R⁵ and n are each the same as defined in the compound of formula (I).

在式(I)化合物的另一個實施例中，本發明提供如下列結構所表示的式(IC)化合物和式(ID)化合物：In another embodiment of the compound of formula (I), the present invention provides compounds of formula (IC) and formula (ID) represented by the following structures:

其中in

Y係為N或CR⁶；Y is N or CR⁶ ;

R¹和R²獨立地為氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、取代或未取代的雜芳基、烯基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂或-N(R^7b)₂；R¹ and R² are independently hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, alkenyl, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ or -N(R^7b )₂ ;

R^5a為C_1-4烷基或鹵素；R^5a is C_1-4 alkyl or halogen;

R^5b為氫、C_1-4烷基或鹵素；R^5b is hydrogen, C_1-4 alkyl or halogen;

R^5c為羥基；R^5c is hydroxyl;

R^5d為氫或羥基；R^5d is hydrogen or hydroxy;

R⁶為氫、鹵素或C_1-4-烷基；^R6 is hydrogen, halogen or_C1-4 -alkyl;

R^7a為取代的或未取代的烷基、取代的或未取代的環烷基、或取代的或未取代的雜環；以及R^7a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclic; and

R^7b是氫、取代或未取代的烷基、取代或未取代的環烷基、或取代或未取代的雜環；R^7b is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclic;

或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).

在式(IC)化合物或式(ID)化合物的另一個實施例中，本發明提供式(IC)和式(ID)化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中：In another embodiment of the compound of formula (IC) or the compound of formula (ID), the present invention provides compounds of formula (IC) and formula (ID), or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof), wherein:

Y係為CR⁶；Y is CR⁶ ;

R¹和R²獨立地為氫；鹵素；硝基；氰基；C_1-4烷基選擇性地被一個或多個選自鹵素、-O-R^8b、-N(H)R⁸、-N(烷基)R⁸、C_3-6環烷基、以及雜環的基團取代，其中所述C_3-6環烷基和雜環可進一步被一個或多個選自鹵素、氰基、C_1-4烷基、-O-R^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；C_3-6環烷基選擇性地被一個或多個選自鹵素、氰基、C_1-4烷基、-O-R^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；雜環選擇性地被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、-CH₂-OR^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；雜芳基選擇性地被一個或多個選自鹵素、氰基、C_1-4烷基、-O-(C_1-4烷基)、C_1-4鹵代烷基、-O-(C_1-4鹵代烷基)、-N(烷基)烷基、-N(H)烷基、以及-NH₂的基團取代；C_2-4烯基；-OR^7b；或-N(R^7b)₂；^R1 and^R2 are independently hydrogen; halogen; nitro; cyano;_C1-4 alkyl is optionally substituted by one or more groups selected from halogen,^-OR8b , -N(H)^R8 , -N(alkyl)^R8 ,_C3-6 cycloalkyl, and heterocyclic ring, wherein the_C3-6 cycloalkyl and heterocyclic ring may be further substituted by one or more groups selected from halogen, cyano,_C1-4 alkyl,^-OR8b ,_C1-4 halogenated alkyl, -N(H)^R8 , and -N(alkyl)^R8 ;_C3-6 cycloalkyl is optionally substituted by one or more groups selected from halogen, cyano,_C1-4 alkyl,^-OR8b ,_C1-4 halogenated alkyl, -N(H)^R8 , and -N(alkyl)R⁸ ; the heterocyclic group is optionally substituted with one or more groups selected from halogen, cyano, -OR^8b , C_1-4 alkyl, -CH₂ -OR^8b , C_1-4 halogenated alkyl, -N(H)R⁸ , and -N(alkyl)R⁸ ; the heteroaryl group is optionally substituted with one or more groups selected from halogen, cyano, C_1-4 alkyl, -O-(C_1-4 alkyl), C_1-4 halogenated alkyl, -O-(C_1-4 halogenated alkyl), -N(alkyl)alkyl, -N(H)alkyl, and -NH₂ ; C_2-4 alkenyl; -OR^7b ; or -N(R^7b )₂ ;

R^7b係為氫；C_3-6環烷基；或C_1-4烷基選擇性地被一個或多個選自鹵素和C_3-6環烷基的基團取代；R^7b is hydrogen; C_3-6 cycloalkyl; or C_1-4 alkyl is optionally substituted with one or more groups selected from halogen and C_3-6 cycloalkyl;

R⁸係為氫、C_1-4烷基或C_3-6環烷基；以及^R8 is hydrogen,_C1-4 alkyl or_C3-6 cycloalkyl; and

R^8b係為氫、C_1-4烷基、C_1-4鹵代烷基或C_3-6環烷基。R^8b is hydrogen, C_1-4 alkyl, C_1-4 halogenated alkyl or C_3-6 cycloalkyl.

在式(IC)化合物或式(ID)化合物的另一個實施例中，本發明提供式(IC)和式(ID)化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中：In another embodiment of the compound of formula (IC) or the compound of formula (ID), the present invention provides compounds of formula (IC) and formula (ID), or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof), wherein:

R¹和R²係獨立地為氫；鹵素；硝基；氰基；C_1-4烷基選擇性地被一個或多個選自鹵素、-O-R^8b、-N(H)R⁸、-N(烷基)R⁸、C_3-6環烷基、哌啶基(piperidinyl)、吡咯烷基(pyrrolidinyl)和嗎啉基(morpholinyl)，其中所述C_3-6環烷基、哌啶基、吡咯烷基和嗎啉基可以進一步被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、C_1-4的鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；C_3-6環烷基選擇性地被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；哌啶基、吡咯烷基、嗎啉基或6-氮雜螺[2.5]辛基(6-azaspiro[2.5]octyl)，各自可被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、-CH₂-OR^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸；吡唑基選擇性被一個或多個選自鹵素、氰基、C_1-4烷基、-O-(C_1-4烷基)、C_1-4鹵代烷基、-O-(C_1-4鹵代烷基)、-N(烷基)烷基、-N(H)烷基、以及-NH₂；C_2-4烯基；-OR^7b；或-N(R^7b)₂；^R1 and^R2 are independently hydrogen; halogen; nitro; cyano;_C1-4 alkyl is optionally substituted by one or more groups selected from halogen,^-OR8b , -N(H)^R8 , -N(alkyl)^R8 ,_C3-6 cycloalkyl, piperidinyl, pyrrolidinyl and morpholinyl, wherein the_C3-6 cycloalkyl, piperidinyl, pyrrolidinyl and morpholinyl may be further substituted by one or more groups selected from halogen, cyano,^-OR8b , C1-4 alkyl,_C1-4 halogenated alkyl, -N(H)R8, and -N(alkyl)^R8 ;_C3-6 cycloalkyl is optionally substituted by one or more groups selected from halogen, cyano,^-OR8b , C1-4 alkyl,_C1-4 halogenated alkyl, -N(H)^R8 , and -N(alkyl)R8; , C_1-4 alkyl, C_1-4 halogenated alkyl, -N(H)R⁸ , and -N(alkyl)R⁸ ; piperidinyl, pyrrolidinyl, morpholinyl or 6-azaspiro[2.5]octyl, each of which may be substituted with one or more selected from halogen, cyano, -OR^8b , C_1-4 alkyl, -CH₂ -OR^8b , C_1-4 halogenated alkyl, -N(H)R⁸ , and -N(alkyl)R⁸ ; pyrazolyl may be optionally substituted with one or more selected from halogen, cyano, C_1-4 alkyl, -O-(C_1-4 alkyl), C_1-4 halogenated alkyl, -O-(C_1-4 halogenated alkyl), -N(alkyl)alkyl, -N(H)alkyl, and -NH₂ ; C_2-4 alkenyl; -OR^7b ; or -N(R^7b )₂ ;

R^7b係為氫；C_3-6環烷基；或C_1-4烷基選擇性地被一個或多個選自鹵素和C_3-6環烷基的基團取代；R^7b is hydrogen; C_3-6 cycloalkyl; or C_1-4 alkyl is optionally substituted with one or more groups selected from halogen and C_3-6 cycloalkyl;

R⁸係為氫、C_1-4烷基、或C_3-6環烷基；以及^R8 is hydrogen,_C1-4 alkyl, or_C3-6 cycloalkyl; and

R^8b係為氫、C_1-4烷基、C_1-4鹵代烷基、或C_3-6環烷基。R^8b is hydrogen, C_1-4 alkyl, C_1-4 halogenated alkyl, or C_3-6 cycloalkyl.

在式(IC)化合物或式(ID)化合物的另一個實施例中，本發明提供式(IC)和式(ID)化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中：In another embodiment of the compound of formula (IC) or the compound of formula (ID), the present invention provides compounds of formula (IC) and formula (ID), or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof), wherein:

Y係為CH；Y is CH;

R¹係為C_1-4-烷基；R¹ is C_1-4 -alkyl;

R²係為C_3-6-環烷；雜環；雜芳基；-OR^7b；或任選被一個或多個-O-R^8b取代的C_1-4-烷基；R² is C_3-6 -cycloalkane; heterocyclic; heteroaryl; -OR^7b ; or C_1-4 -alkyl optionally substituted by one or more -OR^8b ;

R7^b是C_3-6-環烷基或C_1-4-烷基；^R7b is_C3-6 -cycloalkyl or_C1-4 -alkyl;

R^8b是氫、C_1-4-烷基、C_1-4-鹵代烷基或C_3-6-環烷基。R^8b is hydrogen, C_1-4 -alkyl, C_1-4 -haloalkyl or C_3-6 -cycloalkyl.

在式(IC)化合物或式(ID)化合物的另一個實施例中，本發明提供式(IC)和式(ID)化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中：In another embodiment of the compound of formula (IC) or the compound of formula (ID), the present invention provides compounds of formula (IC) and formula (ID), or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof), wherein:

Y係為CH；Y is CH;

R¹係為C_1-4-烷基；R¹ is C_1-4 -alkyl;

R²係為C_3-6-環烷；哌啶基；吡咯烷基；嗎啉基；6-氮雜螺[2.5]辛基；吡唑基；-OR^7b；或任選被一個或多個-O-R^8b取代的C_1-4-烷基；^R2 is_C3-6 -cycloalkane; piperidinyl; pyrrolidinyl; oxolinyl; 6-azaspiro[2.5]octyl; pyrazolyl;^-OR7b ; or_C1-4 -alkyl optionally substituted by one or more^-OR8b ;

R^7b是C_3-6-環烷基或C_1-4-烷基；R^7b is C_3-6 -cycloalkyl or C_1-4 -alkyl;

R^8b是氫、C_1-4-烷基、C_1-4-鹵代烷基或C_3-6-環烷基。R^8b is hydrogen, C_1-4 -alkyl, C_1-4 -haloalkyl or C_3-6 -cycloalkyl.

在式(IC)化合物或式(ID)化合物的另一個實施例中，本發明提供式(IC)和式(ID)化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中：In another embodiment of the compound of formula (IC) or the compound of formula (ID), the present invention provides compounds of formula (IC) and formula (ID), or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof), wherein:

Y係為CH；Y is CH;

R¹係為C_3-6-環烷；雜環；雜芳基；-OR^7b；或任選被一個或多個-O-R^8b取代的C_1-4-烷基；R¹ is C_3-6 -cycloalkane; heterocyclic; heteroaryl; -OR^7b ; or C_1-4 -alkyl optionally substituted by one or more -OR^8b ;

R²係為C_1-4-烷基；R² is C_1-4 -alkyl;

R^7b是C_3-6-環烷基或C_1-4-烷基；R^7b is C_3-6 -cycloalkyl or C_1-4 -alkyl;

R^8b是氫、C_1-4-烷基、C_1-4-鹵代烷基或C_3-6-環烷基。R^8b is hydrogen, C_1-4 -alkyl, C_1-4 -haloalkyl or C_3-6 -cycloalkyl.

在式(IC)化合物或式(ID)化合物的另一個實施例中，本發明提供式(IC)和式(ID)化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中：In another embodiment of the compound of formula (IC) or the compound of formula (ID), the present invention provides compounds of formula (IC) and formula (ID), or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof), wherein:

Y係為CH；Y is CH;

R¹係為C_3-6-環烷；哌啶基；吡咯烷基；嗎啉基；6-氮雜螺[2.5]辛基；吡唑基；-OR^7b；或任選被一個或多個-O-R^8b取代的C_1-4-烷基；R¹ is C_3-6 -cycloalkane; piperidinyl; pyrrolidinyl; oxolinyl; 6-azaspiro[2.5]octyl; pyrazolyl; -OR^7b ; or C_1-4 -alkyl optionally substituted by one or more -OR^8b ;

R²係為C_1-4-烷基；R² is C_1-4 -alkyl;

R^7b是C_3-6-環烷基或C_1-4-烷基；R^7b is C_3-6 -cycloalkyl or C_1-4 -alkyl;

R^8b是氫、C_1-4-烷基、C_1-4-鹵代烷基或C_3-6-環烷基。R^8b is hydrogen, C_1-4 -alkyl, C_1-4 -haloalkyl or C_3-6 -cycloalkyl.

在不脫離式(I)化合物和源自式(I)、(IA)、(IB)、(IC)和(IC)的具體化合物下給出的定義範圍的情況下，由式(I)化合物所得的特定化合物ID)總結於下表1中，涵蓋式(I)化合物內的化合物的全部範圍。Without departing from the definition given under the compounds of formula (I) and specific compounds derived from formula (I), (IA), (IB), (IC) and (IC), specific compounds (ID) obtained from the compounds of formula (I) are summarized in the following Table 1, covering the entire range of compounds within the compounds of formula (I).

表1：式(I)化合物的結構列表Table 1: Structures of compounds of formula (I)

化學結構中的”or1”表示在給定的立體中心，兩種楔形鍵中的一種是有效的(純的但未知)。"or1" in a chemical structure means that at a given stereocenter, one of two wedge-shaped bonds is active (pure but unknown).

在另一實施例中，本發明提供如式(I)之化合物、或其藥學上可接受的鹽類、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)的用途。In another embodiment, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including isotopes thereof).

除非特別指出，通式(I)應涵蓋互變異構體和所有立體異構體、光學異構體和幾何異構體(例如：對映異構體、非對映異構體、E/Z異構體等)和其外消旋體以及不同比例的單獨對映異構體的混合物、非對映異構體的混合物、或其中存在此類異構體和對映異構體的任何前述形式的混合物，以及鹽，包括其藥學上可接受的鹽和其溶劑化物，例如水合物，包括該化合物原始藥物分子的溶劑化物和水合物，或該化合物的鹽的溶劑化物和水合物。Unless otherwise specified, the general formula (I) shall include tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and their racemates, as well as mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or mixtures in which any of the aforementioned forms of such isomers and enantiomers exist, and salts thereof, including pharmaceutically acceptable salts thereof and solvates thereof, such as hydrates, including solvates and hydrates of the original drug molecule of the compound, or solvates and hydrates of salts of the compound.

一般而言，基本上純的立體異構體可以根據本領域技術人員已知的合成原理獲得，例如，透過分離相應的混合物、透過使用純的立體化學的起始材料和/或透過立體選擇性合成。本領域已知如何製備光學活性形式，例如透過對外消旋形式的拆分或透過合成，例如透過合成時，從光學活性起始材料開始和/或透過使用掌性試劑。In general, substantially pure stereoisomers can be obtained according to synthesis principles known to the person skilled in the art, for example by separation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis. It is known in the art how to prepare optically active forms, for example by resolution of racemic forms or by synthesis, for example by starting from optically active starting materials and/or by using chiral reagents.

術語「藥學上可接受的鹽」被認為是指活性成分，其包含以一種鹽的形式存在的式(I)化合物，特別是如果這種鹽形式能夠賦予活性成分比活性成分的自由形式或者比早期使用的活性成分的任何其他鹽形式更好的藥代動力學性質。活性成分的藥學上可接受的鹽形式還可以首次為該活性成分提供其先前不具有的期望的藥物動力學性質，甚至可以對該活性成分在身體裡的治療功效的藥效學產生積極影響。具有鹼性胺基的化合物可以與藥學上可接受的酸形成藥學上可接受的鹽。本文所述化合物的適當的藥學上可接受的酸加成鹽包括無機酸(例如鹽酸、氫溴酸、磷酸、硝酸和硫酸)和有機酸(例如乙酸、三氟乙酸、苯磺酸、苯甲酸、甲磺酸和對甲苯磺酸)的鹽。具有酸性基團的化合物例如羧酸可以與藥學上可接受的鹼形成藥學上可接受的鹽。適當的藥學上可接受的鹼性鹽包括銨鹽、鹼金屬鹽(例如鈉鹽和鉀鹽)和鹼土金屬鹽(例如鎂鹽和鈣鹽)。The term "pharmaceutically acceptable salt" is understood to mean an active ingredient comprising a compound of formula (I) in the form of a salt, in particular if this salt form is capable of conferring on the active ingredient better pharmacokinetic properties than the free form of the active ingredient or than any other salt form of the active ingredient previously used. A pharmaceutically acceptable salt form of an active ingredient may also provide the active ingredient for the first time with desirable pharmacokinetic properties that it did not previously possess, or may even have a positive effect on the pharmacodynamics of the therapeutic efficacy of the active ingredient in the body. Compounds having a basic amine group may form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (e.g., acetic acid, trifluoroacetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds having acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable alkaline salts include ammonium salts, alkaline metal salts (e.g., sodium salts and potassium salts), and alkaline earth metal salts (e.g., magnesium salts and calcium salts).

術語「位置異構體」是指位置上的異構體，其是結構異構體的一類，其中位置或取代基在母體結構上改變位置。在本文中，在不脫離式(I)化合物的範圍的情況下，術語「位置異構體」本質上包括純的位置異構體、或兩種或更多種位置異構體的混合物的所有位置異構體。由於本發明化合物的位置異構體的藥物活性可能不同，因此可能需要使用位置異構體。在這些情況下，位置異構體可在任何可能的階段透過本領域技術人員熟知的方法以中間體或以最終產物之形式分離，或甚至以原樣使用於合成中。The term "positional isomer" refers to positional isomers, which are a type of structural isomers in which the position or substituent changes position on the parent structure. In this article, without departing from the scope of the compound of formula (I), the term "positional isomer" essentially includes all positional isomers of pure positional isomers or mixtures of two or more positional isomers. Since the pharmaceutical activity of the positional isomers of the compounds of the present invention may be different, it may be necessary to use positional isomers. In these cases, the positional isomers can be separated at any possible stage as intermediates or as final products by methods well known to those skilled in the art, or even used as such in the synthesis.

術語「互變異構體」是指本發明所述的式(I)化合物，其中任何氫原子被雙鍵碳上的羥基所取代。本發明包括所有可能的互變異構形式。The term "tautomer" refers to a compound of formula (I) described in the present invention, wherein any hydrogen atom is replaced by a hydroxyl group on a dibonded carbon. The present invention includes all possible tautomeric forms.

術語「前驅藥物」是指具有可透過溶劑分解或在生理條件下轉化為氨基、羥基、羧基等的基團的化合物。用於形成前驅藥物的基團的範例如文獻Prog.Med.,2010,5,2157-2161(1985)中所描述。The term "prodrug" refers to a compound having a group that can be decomposed by a solvent or converted to an amino group, a hydroxyl group, a carboxyl group, etc. under physiological conditions. Examples of groups used to form prodrugs are described in the literature Prog. Med., 2010, 5, 2157-2161 (1985).

本發明進一步提供了藥物組合物，其包含至少一種根據式(I)的化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘化化合物(包括其同位素)、以及藥學上可接受的賦形劑或載體。The present invention further provides a pharmaceutical composition comprising at least one compound according to formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer thereof, a prodrug or a deuterated compound (including isotopes thereof), and a pharmaceutically acceptable excipient or carrier.

所述「藥學上可接受的賦形劑」和「藥學上可接受的載體」是指有助於活性劑配製和/或向受試者施用和/或被受試者吸收的物質，並且可以包含在本揭露的組合物中而不會對受試著造成顯著的不良毒理作用。藥學上可接受的載體和/或稀釋劑的非限制性實施例包括水、氯化鈉、生理食鹽水溶液、乳酸林格氏液、標準蔗糖、標準葡萄糖、黏合劑、填充劑、崩解劑、潤滑劑、包衣劑、甜味劑、調味料、鹽溶液(如林格氏液溶液)、醇、油、明膠、碳水化合物如乳糖、直鏈澱粉或澱粉、脂肪酸酯、羥甲基纖維素、聚乙烯吡咯烷和色素等。如果需要的話，此類製劑可經滅菌，可與助劑混合，所述助劑例如潤滑劑、防腐劑、穩定劑、潤濕劑、乳化劑、影響滲透壓的鹽、緩衝劑、著色劑和/或芳香族物質等，不會發生有害反應影響或干擾本揭露所提出的化合物的活性。本領域普通技術人員將可認知到其他藥物賦形劑適合與所揭露的化合物一起使用。The "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that facilitate the formulation of the active agent and/or administration to the subject and/or absorption by the subject, and can be included in the composition of the present disclosure without causing significant adverse toxicological effects on the subject. Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, sodium chloride, physiological saline solution, lactated Ringer's solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, saline solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, linear starch or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine and pigments, etc. If necessary, such preparations can be sterilized and mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants and/or aromatic substances, etc., which will not react adversely to affect or interfere with the activity of the compounds proposed in this disclosure. Ordinary technicians in this field will recognize that other drug excipients are suitable for use with the disclosed compounds.

本揭露在此公開了在有需要的受試者中治療至少部分地受PKMYT1調節的疾病的方法，包括向受試者施用治療有效量的本揭露所公開的化合物或其藥學上可接受的鹽。The present disclosure discloses a method for treating a disease at least partially regulated by PKMYT1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed in the present disclosure or a pharmaceutically acceptable salt thereof.

所述「受試者」係指哺乳動物，優選為人類，但也可以是需要獸醫治療的動物，例如伴侶動物(例如狗、貓等)、農場動物(例如牛、羊、豬)、馬等)和實驗動物(例如大鼠、小鼠、豚鼠等)。The "subject" mentioned above refers to mammals, preferably humans, but can also be animals that require veterinary treatment, such as companion animals (such as dogs, cats, etc.), farm animals (such as cattle, sheep, pigs, horses, etc.) and experimental animals (such as rats, mice, guinea pigs, etc.).

本揭露在此公開了一種治療有需要的受試者的方法，該方法包括向受試者施用治療有效量的本揭露所公開的化合物或其藥學上可接受的鹽。The present disclosure discloses a method for treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed in the present disclosure or a pharmaceutically acceptable salt thereof.

在一些實施例中，所述癌症與PKMYT1的活性相關。In some embodiments, the cancer is associated with the activity of PKMYT1.

在一些實施例中，所述癌症會過度表現CCNE1。In some embodiments, the cancer overexpresses CCNE1.

在一些實施例中，所述癌症包括但不限於具有高CCNE1過度表現發生率的癌症，包括例如乳癌、子宮內膜癌、食道癌、肺癌、卵巢癌、胃癌和子宮癌。In some embodiments, the cancer includes but is not limited to cancers with a high incidence of CCNE1 overexpression, including, for example, breast cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, gastric cancer, and uterine cancer.

在一些實施例中，所述癌症具有失活突變，包括但不限於FBXW7和PPP2R1A基因。在一些實施例中，所述具有FBXW7和PPP2R1A缺陷的癌症包括例如乳癌、大腸直腸癌、食道癌、肺癌和子宮癌。在一些實施例中，所述癌症是實體固態腫瘤。In some embodiments, the cancer has inactivating mutations, including but not limited to FBXW7 and PPP2R1A genes. In some embodiments, the cancers with FBXW7 and PPP2R1A defects include, for example, breast cancer, colorectal cancer, esophageal cancer, lung cancer, and uterine cancer. In some embodiments, the cancer is a solid tumor.

在一些實施例中，癌症包括但不限於乳癌、大腸直腸癌、子宮內膜癌、食道癌、膠質細胞瘤、肝細胞癌、肺癌、神經母細胞瘤、卵巢癌、攝護腺癌、胃癌或子宮癌。In some embodiments, the cancer includes but is not limited to breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, gastric cancer, or uterine cancer.

所述藥物製劑(Pharmaceutical formulations)可以適用於透過治療所需的任何適當的方法，例如透過口服(包括口服或舌下)、直腸、鼻、局部給藥(包括口服、舌下或經皮)、陰道或腸胃外方法(包括皮下注射、肌肉注射、靜脈注射或皮內注射)。此類製劑可以使用製藥領域已知的所有方法透過例如將活性成分與賦形劑或佐劑組合來製備。The pharmaceutical formulations may be suitable for any appropriate method of treatment, such as oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal injection). Such formulations may be prepared using all methods known in the pharmaceutical art, for example by combining the active ingredient with an excipient or adjuvant.

適合口服施用的藥物製劑可以作為單獨的單位施用，例如膠囊或片劑；粉末或顆粒；水性或非水性液體中的溶液或懸浮液；可食用泡沫或泡沫食品；或水包油液體乳液或油包水液體乳液。Pharmaceutical formulations suitable for oral administration may be administered as individual units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

例如，在作為片劑或膠囊口服施用的情況下，活性成分組分可以與口服、無毒且藥學上可接受的惰性賦形劑組合，例如乙醇、甘油、水等。粉狀藥物的製備係透過將化合物粉碎至適當的細小尺寸並將其與以類似方式粉碎的藥物賦形劑(例如可食用碳水化合物、澱粉或甘露醇)混合以製備成粉狀藥物。同樣可以存在風味劑、防腐劑、分散劑和染料。For example, in the case of oral administration as a tablet or capsule, the active ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as ethanol, glycerol, water, etc. Powdered drugs are prepared by pulverizing the compound to a suitable fine size and mixing it with a similarly pulverized drug excipient (such as edible carbohydrates, starch or mannitol) to prepare a powdered drug. Flavoring agents, preservatives, dispersants and dyes may also be present.

膠囊係透過製備如上所述的粉末混合物並用其填充成形明膠殼來製備。助滑劑和潤滑劑，例如固體形式的高度分散的矽酸、滑石粉、硬脂酸鎂、硬脂酸鈣或聚乙二醇可以在填充操作之前添加到粉末混合物中。崩解劑或增溶劑，例如瓊脂、碳酸鈣或碳酸鈉，同樣可以添加以提高服用膠囊後藥物的利用度。Capsules are prepared by preparing a powder mixture as described above and filling shaped gelatin shells therewith. Glidants and lubricants, for example, highly dispersed silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, may be added to the powder mixture before the filling operation. Disintegrants or solubilizers, for example agar, calcium carbonate or sodium carbonate, may also be added to improve the availability of the drug after administration of the capsule.

此外，如果需要或必要，同樣可以將適當的黏合劑、潤滑劑和崩解劑以及染色劑摻入混合物中。適當的黏合劑包括澱粉、明膠、天然糖例如葡萄糖或β-乳糖、由玉米製成的甜味劑、天然和合成橡膠例如阿拉伯樹膠、黃蓍膠或海藻酸鈉、羧甲基纖維素、聚乙二醇、蠟等。這些劑型所使用的潤滑劑包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、醋酸鈉、氯化鈉等。崩解劑包括但不限於澱粉、甲基纖維素、瓊脂、膨潤土、黃原膠等。片劑的配製方法，例如製備粉末混合物，將混合物造粒或乾壓，添加潤滑劑和崩解劑，然後將整個混合物壓制以獲得片劑。粉末混合物的製備係透過將以適當方式粉碎的化合物與如上述之稀釋劑或基質以及選擇性地與黏合劑(例如羧甲基纖維素、藻酸鹽、明膠或聚乙烯吡咯烷酮)、溶解阻滯劑(例如石蠟)、吸收促進劑(例如四級銨鹽)和/或吸收劑(例如膨潤土、高嶺土或磷酸二鈣)混合來製備粉末混合物。粉末混合物可以用黏合劑例如糖漿、澱粉糊、阿卡迪亞黏液或纖維素或聚合物材料的溶液潤濕後，並將其壓過篩子來製作成顆粒。作為製作顆粒的替代方案，粉末混合物可以通過壓片機，來產生形狀不均勻的塊狀物，接著將這些塊狀物破碎以形成顆粒。顆粒可以透過添加硬脂酸、硬脂酸鹽、滑石粉或礦物油來潤滑，以防止黏附在片劑鑄模上。接著將潤滑的混合物壓製成片劑。活性成分還可以與自由流動的惰性賦形劑混合，然後直接壓製成片劑，無需進行製粒或乾壓步驟。由蟲膠密封層、糖或聚合物材料層以及有光澤的蠟層所組成的透明或不透明保護層亦可以存在。染料亦可以被添加到這些塗層中，以便能夠區分不同的劑量單位。In addition, if desired or necessary, suitable binders, lubricants and disintegrants and coloring agents may also be added to the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, sweeteners made from corn, natural and synthetic rubbers such as gum arabic, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, wax, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include but are not limited to starch, methylcellulose, agar, bentonite, xanthan gum, etc. Tablets can be prepared by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant, and then compressing the entire mixture to obtain tablets. The powder mixture is prepared by mixing the compound pulverized in a suitable manner with a diluent or base as described above and optionally with a binder (e.g., carboxymethylcellulose, alginate, gelatin or polyvinyl pyrrolidone), a dissolution retardant (e.g., paraffin), an absorption promoter (e.g., quaternary ammonium salt) and/or an absorbent (e.g., bentonite, kaolin or dicalcium phosphate). The powder mixture can be moistened with a binder such as syrup, starch paste, acadian mucus or a solution of cellulose or a polymer material and pressed through a sieve to form granules. As an alternative to making granules, the powder mixture can be passed through a tablet press to produce lumps of uneven shape, which are then broken up to form granules. The granules can be lubricated by adding stearic acid, stearate salts, talc or mineral oil to prevent sticking to the tablet molds. The lubricated mixture is then compressed into tablets. The active ingredient can also be mixed with a free-flowing inert excipient and compressed directly into tablets without a granulation or dry-pressing step. A transparent or opaque protective layer consisting of a sealant layer of wormwood glue, a layer of sugar or polymer material and a glossy wax layer may also be present. Dyes may also be added to these coatings to be able to distinguish between different dosage units.

口服液體，例如溶液、糖漿和酏劑，可以以劑量單位的形式製備，使得給定量包含預先指定量的化合物。糖漿劑可以將化合物溶解在具有適當風味的水溶液中來製備，而酏劑則使用無毒的酒精載體來製備。懸浮液可以透過將化合物分散在無毒載體中來製備。增溶劑和乳化劑(例如乙氧基化異硬脂醇和聚氧乙烯山梨醇醚)、防腐劑、風味添加劑(例如薄荷油或天然甜味劑或糖精)，或其他人造甜味劑等也同樣可以添加。Oral liquids, such as solutions, syrups, and elixirs, can be prepared in dosage units so that a given amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with an appropriate flavor, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be prepared by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers (such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitan ethers), preservatives, flavoring agents (such as peppermint oil or natural sweeteners or saccharin), or other artificial sweeteners may also be added.

如果需要，用於口服給藥的劑量單位製劑可以封裝在微膠囊中。製劑也可以以延長或延遲釋放的方式製備，例如將顆粒材料塗覆或嵌入聚合物、蠟等。If desired, dosage unit preparations for oral administration can be encapsulated in microcapsules. Preparations can also be prepared in a manner that prolongs or delays release, such as by coating or embedding particulate materials with polymers, waxes, etc.

製劑可以是以脂質體遞送系統的形式存在，例如小單層囊泡、大單層囊泡和多層囊泡。脂質體可以由適當的脂質或磷脂質或兩者形成，例如膽固醇、硬脂胺或磷脂醯膽鹼(卵磷脂)等。適合經皮施用的藥物製劑可以作為獨立的膏藥施用，以與接受者的表皮進行長時間、緊密的接觸。因此，舉例來說，活性成分可以透過離子電滲透療法從膏藥中遞送，例如文獻Pharmaceutical Research,3(6),318(1986)中所描述。The formulation may be in the form of a liposomal delivery system, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes may be formed from suitable lipids or phospholipids or both, such as cholesterol, stearylamine or phosphatidylcholine (lecithin). Pharmaceutical formulations suitable for transdermal administration may be applied as a stand-alone patch for prolonged, intimate contact with the epidermis of the recipient. Thus, for example, the active ingredient may be delivered from the patch by ion electroporation, such as described in Pharmaceutical Research, 3(6), 318(1986).

適合局部施用的藥物化合物可以配製為軟膏劑、乳膏劑、懸浮液劑、乳液劑、粉末劑、溶液劑、貼劑、凝膠劑、噴霧劑、氣霧劑或油性劑。Pharmaceutical compounds suitable for topical administration may be formulated as ointments, creams, suspensions, emulsions, powders, solutions, patches, gels, sprays, aerosols or oils.

適合局部施用於眼睛的藥物製劑包括滴眼劑，其中活性成分溶解或懸浮在合適的載體中，特別是水性溶劑中。Pharmaceutical formulations suitable for topical administration to the eye include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

適合在口腔中局部施用的藥物製劑包括喉片、錠劑和漱口劑。Pharmaceutical preparations suitable for topical administration in the mouth include lozenges, tablets and mouthwashes.

適合鼻腔給藥的藥物製劑，其中載體物質是固體，包含顆粒尺寸例如在20-500微米範圍內的粗粉，其以鼻子吸入方式給藥，即從裝有粉末的容器靠近鼻子經由鼻道快速吸入。以液體作為載體物質的合適製劑以作為鼻噴劑或滴鼻劑施用包括含有活性成分的水或油中的溶液。Pharmaceutical formulations suitable for nasal administration, wherein the carrier substance is a solid, including a coarse powder with a particle size, for example, in the range of 20-500 microns, which is administered by nasal inhalation, i.e., rapid inhalation through the nasal passages from a container containing the powder close to the nose. Suitable formulations with liquids as carrier substances for administration as nasal sprays or nasal drops include solutions in water or oil containing the active ingredient.

適合透過吸入給藥的藥物製劑包括細顆粒粉塵或霧氣，可透過各種類型的帶有氣霧劑(aerosols)、霧化器或吸入器的加壓分配器產生。適合陰道施用的藥物製劑可作為子宮托、衛生棉條、乳膏、凝膠、糊劑、泡沫或噴霧製劑施用。適合於腸胃外施用的藥物製劑包括含有抗氧化劑、緩衝劑、抑菌劑和溶質的水性和非水性無菌注射溶液，透過所述溶液使製劑與待治療的接受者的血液等滲透壓；以及水性和非水性無菌懸浮液，可包含懸浮介質和增稠劑。製劑可以在單劑量或多劑量容器中施用，例如密封的安瓿和小瓶，並以冷凍乾燥(凍乾)狀態儲存，以便在使用前僅需添加必要的無菌載體液體，例如注射用水。Pharmaceutical formulations suitable for administration by inhalation include fine particle dusts or mists, which can be produced by various types of pressurized dispensers with aerosols, nebulizers or inhalers. Pharmaceutical formulations suitable for vaginal administration can be administered as pessaries, sanitary tampons, creams, gels, pastes, foams or spray formulations. Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostatics and solutes, through which the formulation is isosmotic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may contain suspending media and thickening agents. The formulations can be administered in unit-dose or multi-dose containers, such as sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state so that only the necessary sterile carrier liquid, such as water for injection, needs to be added prior to use.

依照配方製備的注射液和混懸液可以由無菌粉劑、顆粒劑和片劑製備。Injections and suspensions prepared according to the formula can be prepared from sterile powders, granules and tablets.

除了上述特別提及的成分之外，製劑還可以包含本領域中針對製劑的特定類型常用的其他試劑；因此，例如適合口服施用的製劑可以包含調味劑。In addition to the ingredients specifically mentioned above, the formulations may contain other agents customary in the art for the particular type of formulation; thus, for example, a formulation suitable for oral administration may contain a flavoring agent.

式(I)化合物和其他活性成分的治療有效量取決於許多因素，包括例如動物的年齡和體重、需要治療的確切疾病狀況及其嚴重程度、製劑的性質和給藥方法，最終由主治醫生或獸醫決定。然而，化合物的有效量通常在每天0.1至100mg/kg接受者(哺乳動物)體重的範圍內，特別典型地在每天1至10mg/kg體重的範圍內。因此，對於體重為70kg的成年哺乳動物來說，每天的實際用量通常在70至700mg之間，其中該用量可以作為每天單獨的劑量或通常以一系列部分劑量的形式施用(例如，每天兩次、三次、四次、五次或六次)，以使每日總劑量相同。式(I)化合物和其他活性成分的鹽、溶劑或其生理功能衍生物的有效量可以被視為原化合物本身有效量的一部分來確定。另一方面，本發明涉及製備式(I)的新化合物的方法。The therapeutically effective amount of the compound of formula (I) and other active ingredients depends on many factors, including, for example, the age and weight of the animal, the exact disease state to be treated and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the attending physician or veterinarian. However, the effective amount of the compound is usually in the range of 0.1 to 100 mg/kg of the recipient (mammal) body weight per day, and is particularly typically in the range of 1 to 10 mg/kg of body weight per day. Therefore, for an adult mammal weighing 70 kg, the actual daily dosage is usually between 70 and 700 mg, wherein the dosage can be administered as a single dose per day or usually in the form of a series of partial doses (e.g., twice, three times, four times, five times or six times a day) to keep the total daily dose the same. The effective amount of the compound of formula (I) and the salt, solvent or physiologically functional derivative thereof of other active ingredients can be determined as a part of the effective amount of the original compound itself. On the other hand, the present invention relates to a method for preparing a new compound of formula (I).

在另一方面，本發明提供了製備式(I)的新化合物的方法。In another aspect, the present invention provides a method for preparing the novel compound of formula (I).

式(I)的新型雜芳基化合物可以透過以下通用方法和步驟來製備。應理解，在給定的典型或優選的實驗條件(即反應溫度、時間、試劑摩爾數、溶劑等)的情況下，也可以使用其他實驗條件，除非另有說明。最佳反應條件可隨所使用的特定反應物或溶劑而變化，但此類情況可由本領域技術人員使用常規最佳化程序來決定。此外，透過利用詳細描述的步驟，本領域普通技術人員可以製備本揭露在此所請求保護的本發明的其他化合物。除非另有說明，所有溫度均以攝氏度(℃)為單位。The novel heteroaryl compounds of formula (I) can be prepared by the following general methods and steps. It should be understood that given typical or preferred experimental conditions (i.e., reaction temperature, time, molar number of reagents, solvents, etc.), other experimental conditions may also be used unless otherwise stated. The optimal reaction conditions may vary depending on the specific reactants or solvents used, but such situations can be determined by a person skilled in the art using conventional optimization procedures. In addition, by utilizing the steps described in detail, a person of ordinary skill in the art can prepare other compounds of the present invention claimed herein. Unless otherwise stated, all temperatures are in degrees Celsius (°C).

在此所描述的方法可實現合成本發明的化合物。然而，這些可能並非合成本發明中所描述的化合物的唯一方法。除此之外，本揭露所述的各種合成步驟可以交替順序進行以提供所需的化合物。The methods described herein can achieve the synthesis of the compounds of the present invention. However, these may not be the only methods for synthesizing the compounds described in the present invention. In addition, the various synthetic steps described in this disclosure can be performed in an alternate order to provide the desired compounds.

在一實施例中，本發明提供了一種製備式(I)化合物的方法，特別是在以下提出的流程方案中所描述的製備式(IA)和(IB)的化合物的方法。本領域技術人員將可意識到任何流程方案均可適用於製備根據本發明的式(I)化合物和式(I)化合物的藥學上可接受的鹽。除非另有說明，否則所有符號/變數均如以下定義。In one embodiment, the present invention provides a method for preparing a compound of formula (I), in particular a method for preparing compounds of formula (IA) and (IB) as described in the process schemes set forth below. A person skilled in the art will appreciate that any process scheme may be applicable to the preparation of compounds of formula (I) and pharmaceutically acceptable salts of compounds of formula (I) according to the present invention. Unless otherwise stated, all symbols/variables are as defined below.

在另一實施例中，本發明提供一種製備式(IA)和(IB)化合物的通用方法，其係透過使用化合物(a)作為起始材料而獲得，如流程I所示。In another embodiment, the present invention provides a general method for preparing compounds of formula (IA) and (IB), which are obtained by using compound (a) as a starting material, as shown in Scheme I.

在另一實施例中，本發明提供了一種製備式(IA)化合物的方法，包括以下步驟：In another embodiment, the present invention provides a method for preparing a compound of formula (IA), comprising the following steps:

步驟(i)：起始化合物(a)透過現有技術所公開的方法製備，並透過使用本領域已知的布赫瓦爾德-哈特維希胺化反應(Buchwald-Hartwig amination reaction)的方法以化合物(d)來處理。化合物(d)中的環A優選為苯基。此製備方法中使用的鹼選自由碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、碳酸鉀、碳酸鎂所組成的群組，其中優選的鹼是碳酸銫。本方法所使用的催化劑選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)(PdCl2dppf．CH2Cl2)、乙酸鈀(II價)([Pd(OAc)2]n)、四(三苯基膦)鈀(0價)(Pd(PPh3)4)或三(二亞芐基丙酮)二鈀(0價)(Pd2(dba)3)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)。反應中所使用的溶劑選自由乙醚、四氫呋喃、二甲氧基乙烷、二甲氧基甲烷、二丁醚、二異丙醚所組成之群組，其中優選的溶劑是1,2-二甲氧基乙烷。將適當的鹼和溶劑與起始化合物(a)和(d)混合。此反應在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)，在100至150℃的溫度下獲得化合物(b)。Step (i): The starting compound (a) is prepared by a method disclosed in the prior art, and treated with the compound (d) by a Buchwald-Hartwig amination reaction known in the art. The ring A in the compound (d) is preferably a phenyl group. The base used in this preparation method is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate. The catalyst used in the present method is selected from the group consisting of [bis(diphenylphosphino)ferrocene] dichloropalladium (II valent) (PdCl2dppf.CH2Cl2), palladium acetate (II valent) ([Pd(OAc)2]n), tetrakis(triphenylphosphine)palladium (0 valent) (Pd(PPh3)4) or tris(dibenzylideneacetone)dipalladium (0 valent) (Pd2(dba)3), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent). The solvent used in the reaction is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, dibutyl ether, diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane. A suitable base and solvent are mixed with the starting compounds (a) and (d). The reaction is carried out in the presence of a suitable catalyst, wherein the catalyst is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent), and compound (b) is obtained at a temperature of 100 to 150°C.

步驟(ii)：將步驟(i)中所獲得的化合物(b)進一步以腈處理，所述腈係選自由丙二腈、丙腈、乙腈、苯甲腈等所組成的群組，其中丙二腈是優選的。所述反應係在合適的鹼存在下進行，所述的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫化鉀、氫化銣、氫化銫、氫化鋁鋰所組成的群組，其中優選的鹼是叔丁醇鈉或氫化鈉。此反應係在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦)二茂鐵]二氯化鈀(II價)。此反應係在合適的溶劑存在下進行，所述溶劑係選自由1,2-二甲氧基乙烷、甲苯、四氫呋喃、乙醚或其氯化溶劑所組成的群組，在100至150℃的溫度範圍內進行，得到化合物(c)，其中環A係為苯基。Step (ii) : Compound (b) obtained in step (i) is further treated with a nitrile, wherein the nitrile is selected from the group consisting of malononitrile, propionitrile, acetonitrile, benzonitrile, etc., wherein malononitrile is preferred. The reaction is carried out in the presence of a suitable base, wherein the base is selected from the group consisting of sodium tert-butoxide, sodium hydride, lithium hydride, potassium hydride, cadmium hydride, aluminum lithium hydride, wherein the preferred base is sodium tert-butoxide or sodium hydride. The reaction is carried out in the presence of a suitable catalyst, the catalyst being selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent). The reaction is carried out in the presence of a suitable solvent, the solvent being selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, diethyl ether or a chlorinated solvent thereof, at a temperature range of 100 to 150° C. to obtain compound (c), wherein ring A is phenyl.

步驟(iii)：將步驟(ii)中所獲得的化合物(c)進一步以合適的試劑處理，所述試劑係選自由甲醯胺、碳酸二乙酯或鹽酸胍所組成的群組，以形成雜芳基或雜環化合物。Step (iii) : Compound (c) obtained in step (ii) is further treated with a suitable reagent selected from the group consisting of formamide, diethyl carbonate or guanidine hydrochloride to form a heteroaryl or heterocyclic compound.

步驟(iv)：步驟(iii)的化合物進一步透過本領域已知的方法進行保護基的去保護以獲得式(IA)的化合物。Step (iv) : The compound of step (iii) is further deprotected by a method known in the art to obtain a compound of formula (IA).

在本實施例中，流程I提供了式(IA)的化合物，其中：In this embodiment, process I provides a compound of formula (IA), wherein:

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹和R²係為甲基；^R1 and^R2 are methyl groups;

R³和R⁴一起可形成取代或未取代的5-8員雜環，或取代或未取代的5-6員雜芳基。^R3 and^R4 together may form a substituted or unsubstituted 5-8 membered heterocyclic ring, or a substituted or unsubstituted 5-6 membered heteroaryl group.

在另一實施例中，本發明提供了一種製備式(IB)化合物的方法，包括以下步驟：In another embodiment, the present invention provides a method for preparing a compound of formula (IB), comprising the following steps:

步驟(i)：起始化合物(a)透過現有技術所公開的方法製備，並透過使用本領域已知的布赫瓦爾德-哈特維希胺化反應(Buchwald-Hartwig amination reaction)的方法以化合物(d)來處理。化合物(d)中的環A優選為苯基。此製備方法中使用的鹼選自由碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、碳酸鉀、碳酸鎂所組成的群組，其中優選的鹼是碳酸銫。所述反應在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)。反應中所使用的溶劑選自由乙醚、四氫呋喃、二甲氧基乙烷、二甲氧基甲烷、二丁醚、二異丙醚所組成之群組，其中優選的溶劑是1,2-二甲氧基乙烷。在催化劑三(二亞芐基丙酮)二鈀(0價)存在下，將適當的鹼和溶劑與起始化合物(a)和(d)混合，在100至150℃的溫度下獲得化合物(b)。Step (i) : The starting compound (a) is prepared by a method disclosed in the prior art, and treated with the compound (d) by a Buchwald-Hartwig amination reaction known in the art. The ring A in the compound (d) is preferably a phenyl group. The base used in this preparation method is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate. The reaction is carried out in the presence of a suitable catalyst, which is selected from the group consisting of [bis(diphenylphosphino)ferrocene]dichloropalladium (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent). The solvent used in the reaction is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, dibutyl ether, and diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane. In the presence of tris(dibenzylideneacetone)dipalladium (0) as a catalyst, a suitable base and a solvent are mixed with the starting compounds (a) and (d) to obtain the compound (b) at a temperature of 100 to 150°C.

步驟(ii)：將步驟(i)中所獲得的化合物(b)進一步以腈處理，所述腈係選自由丙二腈、丙腈、乙腈、苯甲腈等所組成的群組，其中丙二腈是優選的。所述步驟係在合適的鹼存在下進行，所述的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫化鉀、氫化銣、氫化銫、氫化鋁鋰所組成的群組，其中優選的鹼是叔丁醇鈉或氫化鈉。此反應係在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦)二茂鐵]二氯化鈀(II價)。此反應係在合適的溶劑存在下進行，所述溶劑係選自由1,2-二甲氧基乙烷、甲苯、四氫呋喃、乙醚或其氯化溶劑所組成的群組，在100至150℃的溫度範圍內進行，得到化合物(c)。Step (ii) : Compound (b) obtained in step (i) is further treated with a nitrile, wherein the nitrile is selected from the group consisting of malononitrile, propionitrile, acetonitrile, benzonitrile, etc., wherein malononitrile is preferred. The step is carried out in the presence of a suitable base, wherein the base is selected from the group consisting of sodium tert-butoxide, sodium hydride, lithium hydride, potassium hydride, cadmium hydride, aluminum lithium hydride, wherein the preferred base is sodium tert-butoxide or sodium hydride. The reaction is carried out in the presence of a suitable catalyst, the catalyst being selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent). The reaction is carried out in the presence of a suitable solvent, the solvent being selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, diethyl ether or a chlorinated solvent thereof, at a temperature range of 100 to 150° C. to obtain compound (c).

步驟(iii)：將步驟(ii)所得的化合物(c)以選自由硫酸、過氧化氫、鹽酸、乙酸、碳酸氫鈉、碳酸氫鉀、碳酸氫鈣所組成的群組中的試劑處理，其中優選的試劑是硫酸或過氧化氫。所述試劑係在合適的鹼的存在下被提供，所述合適的鹼係選自由氫氧化鋰、氫氧化鉀、氫氧化鈉、氫氧化鎂所組成的群組，其中優選的鹼是氫氧化鋰。Step (iii) : Compound (c) obtained in step (ii) is treated with a reagent selected from the group consisting of sulfuric acid, hydrogen peroxide, hydrochloric acid, acetic acid, sodium bicarbonate, potassium bicarbonate, and calcium bicarbonate, wherein the preferred reagent is sulfuric acid or hydrogen peroxide. The reagent is provided in the presence of a suitable base, wherein the suitable base is selected from the group consisting of lithium hydroxide, potassium hydroxide, sodium hydroxide, and magnesium hydroxide, wherein the preferred base is lithium hydroxide.

步驟(iv)：使用本領域已知的方法將化合物(c)進一步進行保護基的去保護，以得到式(IB)的化合物。Step (iv): Compound (c) is further deprotected from protecting groups using methods known in the art to obtain a compound of formula (IB).

在本實施例中，流程I提供了式(IB)的化合物，其中：In this embodiment, process I provides a compound of formula (IB), wherein:

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹和R²係為甲基；^R1 and^R2 are methyl groups;

R³係為-C(=O)N(R^7b)₂，且R⁴係為-N(R^7b)₂；其中R^7b係為氫。R³ is -C(=O)N(R^7b )₂ , and R⁴ is -N(R^7b )₂ ; wherein R^7b is hydrogen.

在另一實施例中，本發明提供了一種由化合物(e)、(h)和(j)來製備式(IA)化合物的方法，如流程2所示。In another embodiment, the present invention provides a method for preparing a compound of formula (IA) from compounds (e), (h) and (j), as shown in Scheme 2.

在另一實施例中，本發明提供了製備式(IA)化合物的方法，包括以下步驟：In another embodiment, the present invention provides a method for preparing a compound of formula (IA), comprising the following steps:

步驟(i)：起始化合物(e)，其製備係透過現有技術中公開的方法，透過以選自由苯基硼酸、4-甲基苯基硼酸、4-氟苯基硼酸、3-甲基苯基硼酸、4-羧基苯基硼酸、3-羧基苯基硼酸、4-乙醯氨基苯基硼酸等所組成的群組中的硼酸來處理，其中R¹基團係為甲基，以本領域已知的方法進行Suzuki偶聯，然後還原硝基以獲得化合物(f)。Step (i) : The starting compound (e) is prepared by a method disclosed in the prior art, by treating with a boronic acid selected from the group consisting of phenylboronic acid, 4-methylphenylboronic acid, 4-fluorophenylboronic acid, 3-methylphenylboronic acid, 4-carboxyphenylboronic acid, 3-carboxyphenylboronic acid, 4-acetylaminophenylboronic acid, etc., wherein the^R1 group is methyl, and performing Suzuki coupling by a method known in the art, and then reducing the nitro group to obtain compound (f).

步驟(ii)：將步驟(i)所得的化合物(f)以溴或N-溴代琥珀醯亞胺(N-bromosuccinimide)處理，得到化合物(g)，其中R¹為甲基，R²為烷基或環烷基。將化合物(g)進一步以亞硝酸鈉重氮化(diazotization)，再用三溴氧磷(POBr₃)處理，以得到化合物(a)，其中R¹為甲基，R²為烷基、環烷基、雜環、雜芳基或-OR^7b，其中R^7b為烷基或環烷基。Step (ii) : Compound (f) obtained in step (i) is treated with bromine or N-bromosuccinimide to obtain compound (g), wherein R¹ is methyl and R² is alkyl or cycloalkyl. Compound (g) is further diazotized with sodium nitrite and then treated with phosphorus oxybromide (POBr₃ ) to obtain compound (a), wherein R¹ is methyl and R² is alkyl, cycloalkyl, heterocyclic, heteroaryl or -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(iii)：如一般流程中所提供的，以透過步驟(ii)獲得的化合物(a)作為起始材料，並透過使用本領域已知的Buchwald-Hartwig胺化反應的方法，以化合物(d)處理該起始材料。化合物(d)中的環A優選為苯基。在本方法中使用的鹼係選自碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、碳酸鉀、碳酸鎂所組成的群組，其中優選的鹼是碳酸銫。此製備方法所使用的催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)。反應中所使用的溶劑選自由乙醚、四氫呋喃、二甲氧基乙烷、二甲氧基甲烷、二丁醚、二異丙醚所組成之群組，其中優選的溶劑是1,2-二甲氧基乙烷。將適當的鹼和溶劑與起始化合物(a)和(d)混合。此反應在合適的催化劑存在下，在100至150℃的所需溫度下獲得化合物(b)，其中環A係為苯基。Step (iii) : As provided in the general process, the compound (a) obtained in step (ii) is used as a starting material, and the starting material is treated with compound (d) by using a Buchwald-Hartwig amination method known in the art. Ring A in compound (d) is preferably a phenyl group. The base used in this method is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate. The catalyst used in this preparation method is selected from the group consisting of [bis(diphenylphosphino)ferrocene]dichloropalladium (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent). The solvent used in the reaction is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, dibutyl ether, diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane. A suitable base and solvent are mixed with the starting compounds (a) and (d). This reaction is carried out in the presence of a suitable catalyst at a desired temperature of 100 to 150°C to obtain compound (b), wherein ring A is phenyl.

步驟(iv)：在步驟(iii)中所獲得的化合物(b)進一步在合適的鹼存在下，以丙二腈處理，所述合適的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫化鉀、氫化銣、氫化銫、氫化鋁鋰所組成的群組中，其中優選的鹼是叔丁醇鈉或氫化鈉。此反應係在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦)二茂鐵]二氯化鈀(II價)。此反應係在合適的溶劑存在下進行，所述溶劑係選自由1,2-二甲氧基乙烷、甲苯、四氫呋喃、乙醚或其氯化溶劑所組成的群組，在100至150℃的溫度範圍內進行，得到化合物(c)；其中環A是苯基，R¹係為甲基，R²係為環烷基或雜環或雜芳基或-OR^7b，其中R^7b是烷基或環烷基。Step (iv) : Compound (b) obtained in step (iii) is further treated with malononitrile in the presence of a suitable base, wherein the suitable base is selected from the group consisting of sodium tert-butoxide, sodium hydride, lithium hydride, potassium hydride, cadmium hydride, and aluminum lithium hydride, wherein the preferred base is sodium tert-butoxide or sodium hydride. The reaction is carried out in the presence of a suitable catalyst, wherein the catalyst is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent). The reaction is carried out in the presence of a suitable solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, diethyl ether or a chlorinated solvent thereof, at a temperature ranging from 100 to 150° C. to obtain compound (c); wherein ring A is phenyl, R¹ is methyl, R² is cycloalkyl or heterocyclic or heteroaryl or -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(v)：將步驟(iv)中所獲得的化合物(c)進一步以合適試劑處理，所述試劑係選自由甲醯胺、碳酸二乙酯或鹽酸胍所組成的群組，以形成雜芳基，即化合物(m)。Step (v) : Compound (c) obtained in step (iv) is further treated with a suitable reagent selected from the group consisting of formamide, diethyl carbonate or guanidine hydrochloride to form a heteroaryl group, namely compound (m).

步驟(vi)：所獲得的化合物(m)透過以本領域已知的方法進行保護基的去保護以獲得式(IA)的化合物。Step (vi) : The obtained compound (m) is deprotected by a method known in the art to obtain a compound of formula (IA).

在另一實施例中，本發明提供了一種製備式(IA)化合物的方法，包括以下步驟：In another embodiment, the present invention provides a method for preparing a compound of formula (IA), comprising the following steps:

步驟(i)：起始化合物(h)，其中R¹為甲基，其係透過現有技術中公開的方法製備，並以選自由1,2-二氯乙烷、1,2-二氯丁烷、1,2-二溴乙烷、1,2-二溴丁烷等組成的群組中的二鹵化物來進行處理，以在選自由氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂、碳酸鈣、碳酸鈉、碳酸鉀所組成的群組中的合適的鹼存在下，得到化合物(i)，其中R¹係為甲基且R²係為雜環。Step (i) : The starting compound (h), wherein^R1 is methyl, is prepared by a method disclosed in the prior art and treated with a dihalide selected from the group consisting of 1,2-dichloroethane, 1,2-dichlorobutane, 1,2-dibromoethane, 1,2-dibromobutane, etc., in the presence of a suitable base selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate, to obtain compound (i), wherein^R1 is methyl and^R2 is a heterocyclic ring.

步驟(ii)：將步驟(i)所得的化合物(i)進一步以N-溴代琥珀醯亞胺或溴等處理，以獲得化合物(a)，其中R¹係為甲基，R²係為烷基、環烷基、雜環、雜芳基或-OR^7b，其中R^7b是烷基或環烷基。Step (ii): Compound (i) obtained in step (i) is further treated with N-bromosuccinimide or bromine to obtain compound (a), wherein R¹ is methyl, R² is alkyl, cycloalkyl, heterocyclic, heteroaryl or -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(iii)：如一般流程中所提供的，化合物(a)被用以作為起始材料，並透過使用本領域已知的Buchwald-Hartwig胺化反應的方法，以化合物(d)處理該起始材料。化合物(d)中的環A優選為苯基。在本方法中使用的鹼係選自碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、碳酸鉀、碳酸鎂所組成的群組，其中優選的鹼是碳酸銫。此製備方法所使用的催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)。反應中所使用的溶劑選自由乙醚、四氫呋喃、二甲氧基乙烷、二甲氧基甲烷、二丁醚、二異丙醚所組成之群組，其中優選的溶劑是1,2-二甲氧基乙烷。將適當的鹼和溶劑與起始化合物(a)和(d)混合。此反應在合適的催化劑存在下，在100至150℃的所需溫度下獲得化合物(b)，其中環A係為苯基。Step (iii) : As provided in the general scheme, compound (a) is used as a starting material, and the starting material is treated with compound (d) by using a Buchwald-Hartwig amination method known in the art. Ring A in compound (d) is preferably a phenyl group. The base used in this method is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate. The catalyst used in this preparation method is selected from the group consisting of [bis(diphenylphosphino)ferrocene]dichloropalladium (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent). The solvent used in the reaction is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, dibutyl ether, diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane. A suitable base and solvent are mixed with the starting compounds (a) and (d). This reaction is carried out in the presence of a suitable catalyst at a desired temperature of 100 to 150°C to obtain compound (b), wherein ring A is phenyl.

步驟(iv)：在步驟(iii)中所獲得的化合物(b)進一步在合適的鹼存在下，以丙二腈處理，所述合適的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫化鉀、氫化銣、氫化銫、氫化鋁鋰所組成的群組中，其中優選的鹼是叔丁醇鈉或氫化鈉。此反應係在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦)二茂鐵]二氯化鈀(II價)。此反應係在合適的溶劑存在下進行，所述溶劑係選自由1,2-二甲氧基乙烷、甲苯、四氫呋喃、乙醚或其氯化溶劑所組成的群組，在100至150℃的溫度範圍內進行，得到化合物(c)；其中其中環A是苯基，R¹係為甲基，R²係為環烷基或雜環或雜芳基或-OR^7b，其中R^7b是烷基或環烷基。Step (iv): Compound (b) obtained in step (iii) is further treated with malononitrile in the presence of a suitable base, wherein the suitable base is selected from the group consisting of sodium tert-butoxide, sodium hydride, lithium hydride, potassium hydride, cadmium hydride, and aluminum lithium hydride, wherein the preferred base is sodium tert-butoxide or sodium hydride. The reaction is carried out in the presence of a suitable catalyst, wherein the catalyst is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent). The reaction is carried out in the presence of a suitable solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, diethyl ether or a chlorinated solvent thereof, at a temperature ranging from 100 to 150° C. to obtain compound (c); wherein ring A is phenyl, R¹ is methyl, R² is cycloalkyl or heterocyclic or heteroaryl or -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(v)：將步驟(iv)中所獲得的化合物(c)進一步以合適的試劑處理，所述試劑係選自由甲醯胺、碳酸二乙酯或鹽酸胍所組成的群組，以形成雜芳基，即化合物(m)。Step (v) : Compound (c) obtained in step (iv) is further treated with a suitable reagent selected from the group consisting of formamide, diethyl carbonate or guanidine hydrochloride to form a heteroaryl group, namely compound (m).

步驟(vi)：所獲得的化合物(m)透過以本領域已知的方法進行保護基的去保護以獲得式(IA)的化合物。Step (vi): The obtained compound (m) is deprotected by a method known in the art to obtain a compound of formula (IA).

在另一實施例中，本發明提供了一種製備式(IA)化合物的方法，包括以下步驟：In another embodiment, the present invention provides a method for preparing a compound of formula (IA), comprising the following steps:

步驟(i)：起始化合物(j)係依照現有技術公開的方法來製備，其中R¹為甲基。將化合物(j)用N-溴琥珀醯亞胺或溴處理，以得到化合物(k)。將化合物(k)進一步用亞硝酸鈉進行重氮化，再用三溴氧磷(POBr₃)處理，以得到化合物(l)，其中R¹係為甲基。Step (i) : The starting compound (j) is prepared according to the method disclosed in the prior art, wherein R¹ is methyl. Compound (j) is treated with N-bromosuccinimide or bromine to obtain compound (k). Compound (k) is further diazotized with sodium nitrite and then treated with phosphorus oxybromide (POBr₃ ) to obtain compound (l), wherein R¹ is methyl.

步驟(ii)：將上一步驟(i)所獲得的化合物(1)以雜環處理以得到化合物(a)，其中R¹為甲基，R²為烷基、環烷基、雜環、雜芳基或-OR^7b，其中R^7b為烷基或環烷基。Step (ii) : Compound (1) obtained in the previous step (i) is treated with a heterocyclic ring to obtain compound (a), wherein R¹ is methyl, R² is alkyl, cycloalkyl, heterocyclic, heteroaryl or -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(iii)：如一般流程中所提供的，以透過步驟(ii)獲得的化合物(a)作為起始材料，並透過使用本領域已知的Buchwald-Hartwig胺化反應的方法，以化合物(d)處理該起始材料。化合物(d)中的環A優選為苯基。在本方法中使用的鹼係選自碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、碳酸鉀、碳酸鎂所組成的群組，其中優選的鹼是碳酸銫。反應係在適當的催化劑存在的情況下進行，所述適當的催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)。反應中所使用的溶劑選自由乙醚、四氫呋喃、二甲氧基乙烷、二甲氧基甲烷、二丁醚、二異丙醚所組成之群組，其中優選的溶劑是1,2-二甲氧基乙烷。在催化劑三(二亞芐基丙酮)二鈀(0價)存在下，將適當的鹼和溶劑與起始化合物(a)和(d)混合，在100至150℃的所需溫度下獲得化合物(b)，其中環A係為苯基。Step (iii) : As provided in the general process, the compound (a) obtained in step (ii) is used as a starting material, and the starting material is treated with compound (d) by using a Buchwald-Hartwig amination method known in the art. Ring A in compound (d) is preferably a phenyl group. The base used in this method is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate. The reaction is carried out in the presence of a suitable catalyst, which is selected from the group consisting of [bis(diphenylphosphino)ferrocene]dichloropalladium (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent). The solvent used in the reaction is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, dibutyl ether, and diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane. In the presence of a catalyst, tris(dibenzylideneacetone)dipalladium (0), a suitable base and a solvent are mixed with the starting compounds (a) and (d) to obtain compound (b) at a desired temperature of 100 to 150° C., wherein ring A is phenyl.

步驟(iv)：在步驟(iii)中所獲得的化合物(b)進一步在合適的鹼存在下，以丙二腈處理，所述合適的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫化鉀、氫化銣、氫化銫、氫化鋁鋰所組成的群組中，其中優選的鹼是叔丁醇鈉或氫化鈉。此反應係在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦)二茂鐵]二氯化鈀(II價)。此反應係在合適的溶劑存在下進行，所述溶劑係選自由1,2-二甲氧基乙烷、甲苯、四氫呋喃、乙醚或其氯化溶劑所組成的群組，在100至150℃的溫度範圍內進行，得到化合物(c)；其中其中環A是苯基，R¹係為甲基，R²係為環烷基或雜環或雜芳基或-OR^7b，其中R^7b是烷基或環烷基。Step (iv) : Compound (b) obtained in step (iii) is further treated with malononitrile in the presence of a suitable base, wherein the suitable base is selected from the group consisting of sodium tert-butoxide, sodium hydride, lithium hydride, potassium hydride, cadmium hydride, and aluminum lithium hydride, wherein the preferred base is sodium tert-butoxide or sodium hydride. The reaction is carried out in the presence of a suitable catalyst, wherein the catalyst is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent). The reaction is carried out in the presence of a suitable solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, diethyl ether or a chlorinated solvent thereof, at a temperature ranging from 100 to 150° C. to obtain compound (c); wherein ring A is phenyl, R¹ is methyl, R² is cycloalkyl or heterocyclic or heteroaryl or -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(v)：將步驟(iv)中所獲得的化合物(c)進一步以合適試劑處理，所述試劑係選自由甲醯胺、碳酸二乙酯或鹽酸胍所組成的群組，以形成雜芳基，即化合物(m)。Step (v) : Compound (c) obtained in step (iv) is further treated with a suitable reagent selected from the group consisting of formamide, diethyl carbonate or guanidine hydrochloride to form a heteroaryl group, namely compound (m).

步驟(vi)：所獲得的化合物(m)透過以本領域已知的方法進行保護基的去保護以獲得式(IA)的化合物。Step (vi) : The obtained compound (m) is deprotected by a method known in the art to obtain a compound of formula (IA).

在本實施例中，流程2提供了式(IA)的化合物，其中：In this embodiment, Scheme 2 provides a compound of formula (IA), wherein:

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹係為甲基；R²係為環烷基或雜環或雜芳基或OR^7b，其中R^7b是烷基或環烷基；R¹ is methyl; R² is cycloalkyl or heterocyclic or heteroaryl or OR^7b , wherein R^7b is alkyl or cycloalkyl;

R³和R⁴一起可形成取代或未取代的5-6員雜芳基。^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group.

在另一實施例中，本發明提供了一種製備式(IA)化合物的方法，如流程3所示。In another embodiment, the present invention provides a method for preparing a compound of formula (IA), as shown in Scheme 3.

流程3揭示一種從化合物(q)或(t)製備式(IA)化合物的方法。Scheme 3 discloses a method for preparing a compound of formula (IA) from compound (q) or (t).

在另一實施例中，本發明提供了一種製備式(IA)化合物的方法，包括以下步驟：In another embodiment, the present invention provides a method for preparing a compound of formula (IA), comprising the following steps:

步驟(i)：起始化合物(q)的製備係透過現有技術中公開的方法，以選自由苯基硼酸、4-甲基苯基硼酸、4-氟苯基硼酸、3-甲基苯基硼酸、4-羧基苯基硼酸、3-羧基苯基硼酸、4-乙醯氨基苯基硼酸等所組成的群組中的硼酸來處理，以本領域已知的方法進行Suzuki偶聯，然後還原硝基以獲得化合物(r)。Step (i) : The starting compound (q) is prepared by a method disclosed in the prior art, treated with a boronic acid selected from the group consisting of phenylboronic acid, 4-methylphenylboronic acid, 4-fluorophenylboronic acid, 3-methylphenylboronic acid, 4-carboxyphenylboronic acid, 3-carboxyphenylboronic acid, 4-acetylaminophenylboronic acid, etc., and subjected to Suzuki coupling by a method known in the art, followed by reduction of the nitro group to obtain compound (r).

步驟(ii)：將步驟(i)所得的化合物(r)以溴或N-溴代琥珀醯亞胺等處理，以得到化合物(s)，其中R²係為甲基，R¹係為烷基、環烷基、雜環、雜芳基或-OR^7b，其中R^7b為烷基或環烷基。Step (ii) : Compound (r) obtained in step (i) is treated with bromine or N-bromosuccinimide to obtain compound (s), wherein R² is methyl, R¹ is alkyl, cycloalkyl, heterocyclic, heteroaryl or -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(iii)：將步驟(ii)所獲得的化合物(s)進一步以亞硝酸鈉在選自由硝酸、磷酸、硼酸、鹽酸、硫酸、氫氟酸所組成的群組中的無機酸存在下進行重氮化，其中優選酸為硝酸。此反應接著以選自由三溴氧磷、1-溴丙烷、2-溴丙烷、溴甲烷、三溴化硼所組成的群組中的反應物進行處理，其中優選三溴氧磷以獲得化合物(a)，其中R²是甲基，R¹是烷基、環烷基、雜環、-OR^7b，其中R^7b是烷基或環烷基。Step (iii) : Compound (s) obtained in step (ii) is further diazotized with sodium nitrite in the presence of an inorganic acid selected from the group consisting of nitric acid, phosphoric acid, boric acid, hydrochloric acid, sulfuric acid, and hydrofluoric acid, wherein the preferred acid is nitric acid. This reaction is then treated with a reactant selected from the group consisting of phosphorus oxybromide, 1-bromopropane, 2-bromopropane, methyl bromide, and boron tribromide, wherein phosphorus oxybromide is preferred to obtain compound (a), wherein R² is methyl, R¹ is alkyl, cycloalkyl, heterocyclic, -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(iv)：如一般流程中所提供的，以透過步驟(iii)獲得的化合物(a)作為起始材料，並透過使用本領域已知的Buchwald-Hartwig胺化反應的方法，以化合物(d)處理該起始材料。在本方法中使用的鹼係選自碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、碳酸鉀、碳酸鎂所組成的群組，其中優選的鹼是碳酸銫。此反應係在合適的催化劑存在下進行，所述合適的催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)。反應中所使用的溶劑選自由乙醚、四氫呋喃、二甲氧基乙烷、二甲氧基甲烷、二丁醚、二異丙醚所組成之群組，其中優選的溶劑是1,2-二甲氧基乙烷。將適當的鹼和溶劑與化合物(v)和化合物(d)在合適的催化劑存在下混合，在100至150℃的溫度下獲得化合物(b)，其中環A係為苯基。Step (iv) : As provided in the general scheme, the compound (a) obtained in step (iii) is used as a starting material, and the starting material is treated with compound (d) by using a Buchwald-Hartwig amination method known in the art. The base used in this method is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate. The reaction is carried out in the presence of a suitable catalyst, which is selected from the group consisting of [bis(diphenylphosphino)ferrocene]dichloropalladium (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent). The solvent used in the reaction is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, dibutyl ether, and diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane. A suitable base and a solvent are mixed with compound (v) and compound (d) in the presence of a suitable catalyst at a temperature of 100 to 150° C. to obtain compound (b), wherein ring A is phenyl.

步驟(v)：在步驟(iv)中所獲得的化合物(b)進一步在合適的鹼存在下，以丙二腈處理，所述合適的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫化鉀、氫化銣、氫化銫、氫化鋁鋰所組成的群組中，其中優選的鹼是叔丁醇鈉或氫化鈉。此反應係在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦)二茂鐵]二氯化鈀(II價)。此反應係在合適的溶劑存在下進行，所述溶劑係選自由1,2-二甲氧基乙烷、甲苯、四氫呋喃、乙醚或其氯化溶劑所組成的群組，在100至150℃的溫度範圍內進行，得到化合物(c)；其中環A是苯基，R²係為甲基，R¹係為環烷基或雜環或-OR^7b，其中R^7b是烷基或環烷基。Step (v) : Compound (b) obtained in step (iv) is further treated with malononitrile in the presence of a suitable base, wherein the suitable base is selected from the group consisting of sodium tert-butoxide, sodium hydride, lithium hydride, potassium hydride, cadmium hydride, and aluminum lithium hydride, wherein the preferred base is sodium tert-butoxide or sodium hydride. The reaction is carried out in the presence of a suitable catalyst, wherein the catalyst is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent). The reaction is carried out in the presence of a suitable solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, diethyl ether or a chlorinated solvent thereof, at a temperature ranging from 100 to 150° C. to obtain compound (c); wherein ring A is phenyl, R² is methyl, R¹ is cycloalkyl or heterocyclic or -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(vi)：將步驟(v)中所獲得的化合物(c)進一步以合適試劑處理，所述試劑係選自由甲醯胺、碳酸二乙酯或鹽酸胍所組成的群組，以形成雜芳基，即化合物(m)。Step (vi) : Compound (c) obtained in step (v) is further treated with a suitable reagent selected from the group consisting of formamide, diethyl carbonate or guanidine hydrochloride to form a heteroaryl group, namely compound (m).

步驟(vii)：所獲得的化合物(m)透過以本領域已知的方法進行保護基的去保護以獲得式(IA)的化合物。Step (vii) : The obtained compound (m) is deprotected by a method known in the art to obtain a compound of formula (IA).

在另一實施例中，本發明提供了一種製備式(IA)化合物的方法，包括以下步驟：In another embodiment, the present invention provides a method for preparing a compound of formula (IA), comprising the following steps:

步驟(i)：起始化合物(t)係透過現有技術中公開的方法製備，並以選自由1,2-二氯乙烷、1,2-二氯丁烷、1,2-二溴乙烷、1,2-二溴丁烷等組成的群組中的二鹵化物來進行處理，以在選自由氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂、碳酸鈣、碳酸鈉、碳酸鉀所組成的群組中的合適的鹼存在下，得到化合物(u)，其中R²係為甲基，R¹係為雜環。Step (i) : The starting compound (t) is prepared by a method disclosed in the prior art and treated with a dihalide selected from the group consisting of 1,2-dichloroethane, 1,2-dichlorobutane, 1,2-dibromoethane, 1,2-dibromobutane, etc., in the presence of a suitable base selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium carbonate, sodium carbonate, potassium carbonate, to obtain compound (u), wherein^R2 is methyl and^R1 is a heterocyclic ring.

步驟(ii)：將化合物(u)進一步以N-溴代琥珀醯亞胺或溴等處理，以獲得化合物(a)，其中R²係為甲基，R¹係為烷基、環烷基、雜環或-OR^7b，其中R^7b是烷基或環烷基。Step (ii) : Compound (u) is further treated with N-bromosuccinimide or bromine to obtain compound (a), wherein R² is methyl, R¹ is alkyl, cycloalkyl, heterocyclic or -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(iii)：如一般流程中所提供的，化合物(a)被用以作為起始材料，並透過使用本領域已知的Buchwald-Hartwig胺化反應的方法，以化合物(d)處理該起始材料。在本方法中使用的鹼係選自碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、碳酸鉀、碳酸鎂所組成的群組，其中優選的鹼是碳酸銫。所述反應在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)。反應中所使用的溶劑選自由乙醚、四氫呋喃、二甲氧基乙烷、二甲氧基甲烷、二丁醚、二異丙醚所組成之群組，其中優選的溶劑是1,2-二甲氧基乙烷。將適當的鹼和溶劑與起始化合物(a)和(d)混合，在合適的催化劑存在下，在100至150℃的溫度下獲得化合物(b)，其中環A係為苯基。Step (iii) : As provided in the general scheme, compound (a) is used as a starting material, and the starting material is treated with compound (d) by using a Buchwald-Hartwig amination method known in the art. The base used in this method is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate. The reaction is carried out in the presence of a suitable catalyst, which is selected from the group consisting of [bis(diphenylphosphino)ferrocene]dichloropalladium (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent). The solvent used in the reaction is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, dibutyl ether, and diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane. A suitable base and a solvent are mixed with the starting compounds (a) and (d) in the presence of a suitable catalyst at a temperature of 100 to 150° C. to obtain compound (b), wherein ring A is phenyl.

步驟(iv)：在步驟(iii)中所獲得的化合物(b)進一步在合適的鹼存在下，以丙二腈處理，所述合適的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫化鉀、氫化銣、氫化銫、氫化鋁鋰所組成的群組中，其中優選的鹼是叔丁醇鈉或氫化鈉。此反應係在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦)二茂鐵]二氯化鈀(II價)。此反應係在合適的溶劑存在下進行，所述溶劑係選自由1,2-二甲氧基乙烷、甲苯、四氫呋喃、乙醚或氯化溶劑所組成的群組，在100至150℃的溫度範圍內進行，得到化合物(c)；其中其中環A是苯基，R²係為甲基，R¹係為環烷基或雜環或-OR^7b，其中R^7b是烷基或環烷基。Step (iv) : Compound (b) obtained in step (iii) is further treated with malononitrile in the presence of a suitable base, wherein the suitable base is selected from the group consisting of sodium tert-butoxide, sodium hydride, lithium hydride, potassium hydride, cadmium hydride, and aluminum lithium hydride, wherein the preferred base is sodium tert-butoxide or sodium hydride. The reaction is carried out in the presence of a suitable catalyst, wherein the catalyst is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent). The reaction is carried out in the presence of a suitable solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, diethyl ether or a chlorinated solvent at a temperature ranging from 100 to 150° C. to obtain compound (c); wherein ring A is phenyl, R² is methyl, R¹ is cycloalkyl or heterocyclic or -OR^7b , wherein R^7b is alkyl or cycloalkyl.

步驟(v)：將步驟(iv)中所獲得的化合物(c)以合適的試劑處理，所述試劑係選自由甲醯胺、碳酸二乙酯或鹽酸胍所組成的群組，以形成雜芳基，即化合物(m)。Step (v) : The compound (c) obtained in step (iv) is treated with a suitable reagent selected from the group consisting of formamide, diethyl carbonate or guanidine hydrochloride to form a heteroaryl group, namely, compound (m).

步驟(vi)：化合物(m)透過以本領域已知的方法進行保護基的去保護以獲得式(IA)的化合物。Step (vi) : Compound (m) is deprotected by a method known in the art to obtain a compound of formula (IA).

在本實施例中，流程3提供了式(IA)的化合物，其中：In this embodiment, Scheme 3 provides a compound of formula (IA), wherein:

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹係為環烷基或雜環或OR^7b，其中R^7b是烷基或環烷基；R²係為甲基；R¹ is a cycloalkyl group or a heterocyclic group or OR^7b , wherein R^7b is an alkyl group or a cycloalkyl group; R² is a methyl group;

R³和R⁴一起可形成取代或未取代的5-6員雜芳基。^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group.

在另一實施例中，本發明提供了一種製備式(IA)化合物的方法，如流程4所示。In another embodiment, the present invention provides a method for preparing a compound of formula (IA), as shown in Scheme 4.

流程4揭示一種從化合物(v)或(w)製備式(IA)化合物的方法。Scheme 4 discloses a method for preparing a compound of formula (IA) from compound (v) or (w).

在另一實施例中，本發明提供了一種製備式(IA)化合物的方法，包括以下步驟：In another embodiment, the present invention provides a method for preparing a compound of formula (IA), comprising the following steps:

步驟(i)：依照先前技術(WO2008085119)中所揭露的方法製備化合物(v)，並以三溴氧磷處理以獲得化合物(w)。透過本領域已知的方法將化合物(w)的乙酯轉化為Weinreb醯胺或化合物(x)。Step (i) : Compound (v) is prepared according to the method disclosed in the prior art (WO2008085119), and treated with phosphorus oxybromide to obtain compound (w). The ethyl ester of compound (w) is converted into Weinreb amide or compound (x) by methods known in the art.

步驟(ii)：將前述步驟(i)所得的化合物(x)以選自由甲基溴化鎂、乙基溴化鎂、異丙基溴化鎂、烯丙基溴化鎂等組成的群組中的試劑處理，其中優選的試劑為甲基溴化鎂，得到化合物(y)。Step (ii) : Compound (x) obtained in the above step (i) is treated with a reagent selected from the group consisting of methyl magnesium bromide, ethyl magnesium bromide, isopropyl magnesium bromide, allyl magnesium bromide, etc., wherein the preferred reagent is methyl magnesium bromide, to obtain compound (y).

步驟(iii)：透過本領域已知的方法將步驟(ii)中獲得的所得化合物(y)進一步還原以獲得相應的化合物(z)(一種醇類)。Step (iii) : The compound (y) obtained in step (ii) is further reduced to obtain the corresponding compound (z) (an alcohol) by a method known in the art.

步驟(iv)：將步驟(iii)中所獲得的化合物(z)，以選自由溴乙烷、溴甲烷、1-氯丙烷、2-氯丙烷、異丙基溴、叔丁基溴等所組成的群組中的烷基鹵化物進行烷基化，並使用選自由碳酸鉀、碳酸銫、碳酸鈉、碳酸鎂、氫化鈉、叔丁醇鈉等所組成的群組中的鹼，以得到化合物(a)，其中R¹為甲基，R²為取代的烷基，其中取代基為-OR^8b。Step (iv) : Alkylation of the compound (z) obtained in step (iii) with an alkyl halide selected from the group consisting of ethyl bromide, methyl bromide, 1-chloropropane, 2-chloropropane, isopropyl bromide, tert-butyl bromide, etc., and with a base selected from the group consisting of potassium carbonate, cesium carbonate, sodium carbonate, magnesium carbonate, sodium hydroxide, sodium tert-butoxide, etc., to obtain compound (a), wherein R¹ is methyl, R² is substituted alkyl, wherein the substituent is -OR^8b .

步驟(v)：如一般流程中所提供的，以透過步驟(iv)獲得的化合物(a)作為起始材料，並透過使用本領域已知的Buchwald-Hartwig胺化反應的方法，以化合物(d)處理該起始材料。化合物(d)中的環A優選為苯基。在本方法中使用的鹼係選自碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、碳酸鉀、碳酸鎂所組成的群組，其中優選的鹼是碳酸銫。此方法所使用的催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)。反應中所使用的溶劑選自由乙醚、四氫呋喃、二甲氧基乙烷、二甲氧基甲烷、二丁醚、二異丙醚所組成之群組，其中優選的溶劑是1,2-二甲氧基乙烷。將適當的鹼和溶劑與化合物(a)和化合物(d)在合適的催化劑存在下混合，在100至150℃的所需溫度下獲得化合物(b)，其中環A係為苯基。Step (v) : As provided in the general process, the compound (a) obtained in step (iv) is used as a starting material, and the starting material is treated with compound (d) by using a Buchwald-Hartwig amination method known in the art. Ring A in compound (d) is preferably a phenyl group. The base used in this method is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate. The catalyst used in this method is selected from the group consisting of [bis(diphenylphosphino)ferrocene]dichloropalladium (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent). The solvent used in the reaction is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, dibutyl ether, and diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane. An appropriate base and solvent are mixed with compound (a) and compound (d) in the presence of a suitable catalyst to obtain compound (b) at a desired temperature of 100 to 150°C, wherein ring A is phenyl.

步驟(vi)：在步驟(v)中所獲得的化合物(b)進一步在合適的鹼存在下，以丙二腈處理，所述合適的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫化鉀、氫化銣、氫化銫、氫化鋁鋰所組成的群組中，其中優選的鹼是叔丁醇鈉或氫化鈉。此反應係在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦)二茂鐵]二氯化鈀(II價)。此反應係在合適的溶劑存在下進行，所述溶劑係選自由1,2-二甲氧基乙烷、甲苯、四氫呋喃、乙醚或其氯化溶劑所組成的群組，在100至150℃的溫度範圍內進行，得到化合物(c)；其中環A是苯基，R¹係為甲基，R²係為取代的烷基，其中取代基為-OR^8b。Step (vi) : Compound (b) obtained in step (v) is further treated with malononitrile in the presence of a suitable base, wherein the suitable base is selected from the group consisting of sodium tert-butoxide, sodium hydride, lithium hydride, potassium hydride, cadmium hydride, and aluminum lithium hydride, wherein the preferred base is sodium tert-butoxide or sodium hydride. The reaction is carried out in the presence of a suitable catalyst, wherein the catalyst is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent). The reaction is carried out in the presence of a suitable solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, diethyl ether or a chlorinated solvent thereof, at a temperature range of 100 to 150°C to obtain compound (c); wherein ring A is phenyl, R¹ is methyl, and R² is a substituted alkyl, wherein the substituent is -OR^8b .

步驟(vii)：將步驟(vi)中所獲得的化合物(c)進一步以合適試劑處理，所述試劑係選自由甲醯胺、碳酸二乙酯或鹽酸胍所組成的群組，以形成雜芳基，即化合物(m)。Step (vii) : Compound (c) obtained in step (vi) is further treated with a suitable reagent selected from the group consisting of formamide, diethyl carbonate or guanidine hydrochloride to form a heteroaryl group, namely compound (m).

步驟(viii)：所獲得的化合物(m)透過以本領域已知的方法進行保護基的去保護以獲得式(IA)的化合物。Step (viii) : The obtained compound (m) is deprotected by a method known in the art to obtain a compound of formula (IA).

在另一實施例中，本發明提供了一種製備式(IA)化合物的方法，包括以下步驟：In another embodiment, the present invention provides a method for preparing a compound of formula (IA), comprising the following steps:

步驟(i)：將化合物(w)還原以獲得化合物(α)。化合物(α)進一步以選自由溴乙烷、溴甲烷、1-氯丙烷、2-氯丙烷、異丙基溴、叔丁基溴等所組成的群組中的烷基鹵化物進行烷基化，並使用選自由碳酸鉀、碳酸銫、碳酸鈉、碳酸鎂、氫化鈉、叔丁醇鈉等所組成的群組中的鹼，以得到化合物(a)，其中R¹為甲基，R²為取代的烷基，其中取代基為-OR^8b。Step (i) : Compound (w) is reduced to obtain compound (α). Compound (α) is further alkylated with an alkyl halide selected from the group consisting of ethyl bromide, methyl bromide, 1-chloropropane, 2-chloropropane, isopropyl bromide, tert-butyl bromide, etc., and a base selected from the group consisting of potassium carbonate, cesium carbonate, sodium carbonate, magnesium carbonate, sodium hydroxide, sodium tert-butoxide, etc., to obtain compound (a), wherein R¹ is methyl, R² is substituted alkyl, wherein the substituent is -OR^8b .

步驟(ii)：如一般流程中所提供的，以透過步驟(i)獲得的化合物(a)作為起始材料，並透過使用本領域已知的Buchwald-Hartwig胺化反應的方法，以化合物(d)處理該起始材料。化合物(d)中的環A優選為苯基。在本方法中使用的鹼係選自碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、碳酸鉀、碳酸鎂所組成的群組，其中優選的鹼是碳酸銫。此方法所使用的催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)。反應中所使用的溶劑選自由乙醚、四氫呋喃、二甲氧基乙烷、二甲氧基甲烷、二丁醚、二異丙醚所組成之群組，其中優選的溶劑是1,2-二甲氧基乙烷。將適當的鹼和溶劑與化合物(a)和化合物(d)在合適的催化劑存在下混合，在100至150℃的所需溫度下獲得化合物(b)，其中環A係為苯基。Step (ii) : As provided in the general process, the compound (a) obtained in step (i) is used as a starting material, and the starting material is treated with compound (d) by using a Buchwald-Hartwig amination method known in the art. Ring A in compound (d) is preferably a phenyl group. The base used in this method is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate. The catalyst used in this method is selected from the group consisting of [bis(diphenylphosphino)ferrocene]dichloropalladium (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent). The solvent used in the reaction is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, dibutyl ether, diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane. An appropriate base and solvent are mixed with compound (a) and compound (d) in the presence of a suitable catalyst to obtain compound (b) at a desired temperature of 100 to 150°C, wherein ring A is phenyl.

步驟(iii)：在步驟(ii)中所獲得的化合物(b)進一步在合適的鹼存在下，以丙二腈處理，所述合適的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫化鉀、氫化銣、氫化銫、氫化鋁鋰所組成的群組中，其中優選的鹼是叔丁醇鈉或氫化鈉。此反應係在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦)二茂鐵]二氯化鈀(II價)。此反應係在合適的溶劑存在下進行，所述溶劑係選自由1,2-二甲氧基乙烷、甲苯、四氫呋喃、乙醚或其氯化溶劑所組成的群組，在100至150℃的溫度範圍內進行，得到化合物(c)；其中環A是苯基，R¹係為甲基，R²係為取代的烷基，其中取代基為-OR^8b。Step (iii) : Compound (b) obtained in step (ii) is further treated with malononitrile in the presence of a suitable base, wherein the suitable base is selected from the group consisting of sodium tert-butoxide, sodium hydride, lithium hydride, potassium hydride, cadmium hydride, and aluminum lithium hydride, wherein the preferred base is sodium tert-butoxide or sodium hydride. The reaction is carried out in the presence of a suitable catalyst, wherein the catalyst is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent). The reaction is carried out in the presence of a suitable solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, diethyl ether or a chlorinated solvent thereof, at a temperature range of 100 to 150°C to obtain compound (c); wherein ring A is phenyl, R¹ is methyl, and R² is a substituted alkyl, wherein the substituent is -OR^8b .

步驟(iv)：將步驟(iii)中所獲得的化合物(c)進一步以合適試劑處理，所述試劑係選自由甲醯胺、碳酸二乙酯或鹽酸胍所組成的群組，以形成雜芳基，即化合物(m)。Step (iv) : Compound (c) obtained in step (iii) is further treated with a suitable reagent selected from the group consisting of formamide, diethyl carbonate or guanidine hydrochloride to form a heteroaryl group, namely compound (m).

步驟(v)：所獲得的化合物(m)透過以本領域已知的方法進行保護基的去保護以獲得式(IA)的化合物。Step (v) : The obtained compound (m) is deprotected by a method known in the art to obtain a compound of formula (IA).

在本實施例中，流程4提供了式(IA)的化合物，其中：In this embodiment, Scheme 4 provides a compound of formula (IA), wherein:

環A係為苯基；Ring A is a phenyl group;

X係為N，Y係為-CH-；X is N, Y is -CH-;

R¹係為甲基；^R1 is methyl;

R²係為取代的烷基，其中取代基為-OR^8b；R² is a substituted alkyl group, wherein the substituent is -OR^8b ;

R^8b係選自氫、鹵化烷基、以及環烷基；R^8b is selected from hydrogen, halogenated alkyl, and cycloalkyl;

R³和R⁴一起可形成取代或未取代的5-6員雜芳基。^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group.

在另一實施例中，本發明提供了一種製備式(IC)的化合物和式(ID)的化合物的方法。一般而言，式(IC)的化合物或式(ID)的化合物或其藥學上可接受的鹽可透過分別移除式(A1)的化合物或式(A2)的化合物的保護基來製備：In another embodiment, the present invention provides a method for preparing a compound of formula (IC) and a compound of formula (ID). Generally speaking, a compound of formula (IC) or a compound of formula (ID) or a pharmaceutically acceptable salt thereof can be prepared by removing the protecting group of a compound of formula (A1) or a compound of formula (A2), respectively:

其中in

Pr¹係為受保護的羥基，Pr¹ is a protected hydroxyl group,

Pr²係為氫或受保護的羥基，以及^Pr2 is hydrogen or a protected hydroxyl group, and

R¹、R²、R^5a、R^5b和Y與式(IC)的化合物和式(ID)的化合物中的定義相同，R¹ , R² , R^5a , R^5b and Y are the same as defined in the compound of formula (IC) and the compound of formula (ID),

或其鹽。Or its salt.

式(A1)的化合物和(A2)的化合物的合適的鹽可以視為式(I)的化合物所示例的鹽。Suitable salts of the compound of formula (A1) and the compound of formula (A2) can be regarded as the salts exemplified for the compound of formula (I).

Pr¹和Pr²的受保護羥基的適當保護基係為甲基或4-甲氧基芐基(4-methoxybenzyl)，其可以透過本領域已知的常規方法和條件被移除，例如透過與下面實施例1或16類似的條件。A suitable protecting group for the protected hydroxyl groups of Pr¹ and Pr² is methyl or 4-methoxybenzyl, which can be removed by conventional methods and conditions known in the art, for example by conditions similar to those in Example 1 or 16 below.

式(A1)的化合物和(A2)的化合物可以依流程A所示製備，如以下所示：The compound of formula (A1) and the compound of formula (A2) can be prepared according to process A, as shown below:

其中R¹、R²、R^5a、R^5b、Y、Pr¹和Pr²與式(IC)、(ID)、(A1)以及(A2)的化合物中所定義的相同。wherein R¹ , R² , R^5a , R^5b , Y, Pr¹ and Pr² are the same as defined in the compounds of formula (IC), (ID), (A1) and (A2).

步驟(i)：式(D)化合物透過使用式(B)化合物與式(C)化合物反應來製備。Step (i): The compound of formula (D) is prepared by reacting the compound of formula (B) with the compound of formula (C).

此反應在與例如上述流程I的步驟(i)中提到的相同條件下進行，即：This reaction is carried out under the same conditions as those mentioned in step (i) of the above-mentioned process I, namely:

此製備方法中使用的鹼選自由碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、碳酸鉀、碳酸鎂所組成的群組，其中優選的鹼是碳酸銫。本方法所使用的催化劑選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)(PdCl2dppf．CH2Cl2)、乙酸鈀(II價)([Pd(OAc)2]n)、四(三苯基膦)鈀(0價)(Pd(PPh3)4)或三(二亞芐基丙酮)二鈀(0價)(Pd2(dba)3)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)。反應中所使用的溶劑選自由乙醚、四氫呋喃、二甲氧基乙烷、二甲氧基甲烷、二丁醚、二異丙醚所組成之群組，其中優選的溶劑是1,2-二甲氧基乙烷。將適當的鹼和溶劑與起始化合物(B)和(C)混合。此反應在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為三(二亞芐基丙酮)二鈀(0價)，在100至150℃的溫度下獲得化合物(D)。The base used in the preparation method is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, and magnesium carbonate, wherein the preferred base is cesium carbonate. The catalyst used in the method is selected from the group consisting of [bis(diphenylphosphino)ferrocene]dichloropalladium (II valent) (PdCl2dppf.CH2Cl2), palladium acetate (II valent) ([Pd(OAc)2]n), tetrakis(triphenylphosphine)palladium (0 valent) (Pd(PPh3)4) or tris(dibenzylideneacetone)dipalladium (0 valent) (Pd2(dba)3), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent). The solvent used in the reaction is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethoxyethane, dimethoxymethane, dibutyl ether, and diisopropyl ether, wherein the preferred solvent is 1,2-dimethoxyethane. A suitable base and solvent are mixed with the starting compounds (B) and (C). The reaction is carried out in the presence of a suitable catalyst, wherein the catalyst is selected from the group consisting of [bis(diphenylphosphino)ferrocene]dichloropalladium (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent) or tris(dibenzylideneacetone)dipalladium (0 valent), wherein the preferred catalyst is tris(dibenzylideneacetone)dipalladium (0 valent), and compound (D) is obtained at a temperature of 100 to 150°C.

步驟(ii)：式(E)化合物透過使式(D)化合物與丙二腈反應來製備。Step (ii): The compound of formula (E) is prepared by reacting the compound of formula (D) with malononitrile.

此反應在與例如上述流程I的步驟(ii)中提到的相同條件下進行，即：This reaction is carried out under the same conditions as mentioned in step (ii) of the above process I, namely:

所述反應係在合適的鹼存在下進行，所述的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫化鉀、氫化銣、氫化銫、氫化鋁鋰所組成的群組，其中優選的鹼是叔丁醇鈉或氫化鈉。此反應係在合適的催化劑存在下進行，所述催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)或三(二亞芐基丙酮)二鈀(0價)所組成的群組，其中優選的催化劑係為[雙(二苯基膦)二茂鐵]二氯化鈀(II價)。此反應係在合適的溶劑存在下進行，所述溶劑係選自由1,2-二甲氧基乙烷、甲苯、四氫呋喃、乙醚或其氯化溶劑所組成的群組，在100至150℃的溫度範圍內進行，得到化合物(E)。The reaction is carried out in the presence of a suitable base, which is selected from the group consisting of sodium tert-butoxide, sodium hydride, lithium hydride, potassium hydride, cadmium hydride, and lithium aluminum hydride, wherein the preferred base is sodium tert-butoxide or sodium hydride. The reaction is carried out in the presence of a suitable catalyst, which is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valence), palladium acetate (II valence), tetrakis(triphenylphosphine)palladium (0 valence) or tris(dibenzylideneacetone)dipalladium (0 valence), wherein the preferred catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valence). This reaction is carried out in the presence of a suitable solvent, which is selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, diethyl ether or its chlorinated solvents, at a temperature range of 100 to 150°C to obtain compound (E).

步驟(iii)：式(A1)或(A2)化合物的製備係透過使式(E)化合物與適當試劑反應而獲得，所述適當試劑係選自甲醯胺(以形成式(A1)的化合物)或胍(以形成式(A2)的化合物)，例如鹽酸胍或碳酸胍。所述反應在常規溶劑如二甲基乙醯胺中在加熱下進行。當甲醯胺為反應物時，其也可被當作溶劑使用。Step (iii): The compound of formula (A1) or (A2) is prepared by reacting a compound of formula (E) with a suitable reagent selected from formamide (to form a compound of formula (A1)) or guanidine (to form a compound of formula (A2)), such as guanidine hydrochloride or guanidine carbonate. The reaction is carried out in a conventional solvent such as dimethylacetamide under heating. When formamide is a reactant, it can also be used as a solvent.

透過上述方法獲得的化合物可以透過常規方法來分離和純化，例如粉碎、再結晶、層析法和再沉澱等方法。The compounds obtained by the above method can be separated and purified by conventional methods, such as pulverization, recrystallization, chromatography and reprecipitation.

製備示例性式(I)化合物及其中間體化合物的詳細合成方案可以參考下面的實施例和製備或與其類似的方式或常規方式。The detailed synthesis scheme for preparing the exemplary compound of formula (I) and its intermediate compound can refer to the following examples and preparation or similar methods or conventional methods.

實施例Embodiment

儘管本發明已透過某些前述實施例進行說明，但不應將其解釋為受此限制。相反地，本發明涵蓋如上文所揭露的一般領域。在不脫離其精神和範圍的情況下可以做出各種修改和實施例。Although the present invention has been described by certain aforementioned embodiments, it should not be construed as being limited thereto. Rather, the present invention covers the general area as disclosed above. Various modifications and embodiments may be made without departing from its spirit and scope.

製備1：2,3-二溴-5,6-二甲基吡啶：Preparation 1: 2,3-Dibromo-5,6-dimethylpyridine:

標題所述之化合物係依照與Zeitschrift fuer Chemie(1988),28(2),59-60所述相同的反應方案來製備。The title compound was prepared according to the same reaction scheme as described in Zeitschrift fuer Chemie (1988), 28(2), 59-60.

製備2：5-環丙基-6-甲基吡啶-2-胺Preparation 2: 5-cyclopropyl-6-methylpyridin-2-amine

標題所述之化合物係依照與WO2019213295 A1中所述相同的反應方案來製備。The compound described in the title was prepared according to the same reaction scheme as described in WO2019213295 A1.

製備3：5-環丁基-6-甲基吡啶-2-胺Preparation 3: 5-cyclobutyl-6-methylpyridin-2-amine

標題所述之化合物係依照與WO2022152821 A1中所述相同的反應方案來製備。The compound described in the title was prepared according to the same reaction scheme as described in WO2022152821 A1.

製備4：6-甲基-5-(丙-1-烯-2-基)吡啶-2-胺Preparation 4: 6-methyl-5-(prop-1-en-2-yl)pyridin-2-amine

於25℃下，在含有5-溴-6-甲基吡啶-2-胺(5g，26.7mmol)的二噁烷(40ml)的攪拌溶液加入頻那醇硼烷(4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧硼戊烷；4,4,5,5-Tetramethyl-1,3,2-dioxaborolane)(6.7g，40.098mmol)、K₂CO₃(7.3g，53.4mmol)和四(三苯基膦)鈀(0價)(0.169g，0.1335mmol)。接著在其中加入水(8ml)，並將所得混合物以氮氣吹掃15分鐘。然後將反應混合物在100℃攪拌16小時。將反應混合物冷卻至25℃並以乙酸乙酯(EtOAc)(50ml)稀釋。過濾反應混合物，並用水(50ml)洗滌濾液。分離各層並以鹽水(50ml)洗滌有機層。將有機層經無水硫酸鈉(anhydrous Na₂SO₄)乾燥、過濾及真空濃縮，以得到4.5g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至40%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(4.1g)，為淡黃色固體。LCMS m/z=149([M+H]⁺,100%)。Pinacolane (4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane) (6.7 g, 40.098 mmol), K₂ CO₃ (7.3 g, 53.4 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.169 g, 0.1335 mmol) were added to a stirred solution of 5-bromo-6-methylpyridin-2-amine (5 g, 26.7 mmol) in dioxane (40 ml) at 25° C. Then, water (8 ml) was added thereto, and the resulting mixture was purged with nitrogen for 15 minutes. The reaction mixture was then stirred at 100° C. for 16 hours. The reaction mixture was cooled to 25°C and diluted with ethyl acetate (EtOAc) (50 ml). The reaction mixture was filtered and the filtrate was washed with water (50 ml). The layers were separated and the organic layer was washed with brine (50 ml). The organic layer was dried over anhydrous Na₂ SO₄ , filtered and concentrated in vacuo to give 4.5 g of crude compound. The crude residue was purified on a combiflash instrument on a redisep® column with a gradient of 0 to 40% EtOAc in hexane to give the title compound (4.1 g) as a light yellow solid. LCMS m/z=149 ([M+H]⁺ , 100%).

製備5：5-異丙基-6-甲基吡啶-2-胺Preparation 5: 5-isopropyl-6-methylpyridin-2-amine

於25℃下，在含有6-甲基-5-(丙-1-烯-2-基)吡啶-2-胺(4.3g)的甲醇(50ml)的攪拌溶液加入鈀/碳(Pd/C,5% wet,0.8g)。在25℃下將所得混合物用氣球在氫氣氛下攪拌16小時。將反應混合物在真空下以矽藻土過濾，以甲醇(50ml)洗滌並將濾液蒸發，以得到4.1g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至30%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(3.8g)，為白色固體。LCMS m/z=151([M+H]⁺,100%)。Palladium/carbon (Pd/C, 5% wet, 0.8 g) was added to a stirred solution of 6-methyl-5-(prop-1-en-2-yl)pyridin-2-amine (4.3 g) in methanol (50 ml) at 25°C. The resulting mixture was stirred under hydrogen atmosphere with a balloon for 16 hours at 25°C. The reaction mixture was filtered through celite under vacuum, washed with methanol (50 ml) and the filtrate was evaporated to give 4.1 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument, eluting with a gradient of 0 to 30% ethyl acetate/hexane (EtOAc in hexane) to give the title compound (3.8 g) as a white solid. LCMS m/z=151([M+H]⁺ ,100%).

製備6：3-溴-5-氟-6-甲基吡啶-2-胺Preparation 6: 3-Bromo-5-fluoro-6-methylpyridin-2-amine

在25℃下，將5-氟-6-甲基吡啶-2-胺(10g，79.28mmol)在AcOH(50ml)中的攪拌溶液中，逐滴加入溴(4.1ml，79.28mmol)。在25℃下將所得混合物攪拌1小時。將反應混合物以飽和碳酸氫鈉水溶液鹼化並以乙酸乙酯(100ml×2)萃取。分離各層並以鹽水(100ml)洗滌合併的有機層。將有機層經無水硫酸鈉乾燥、過濾及真空濃縮，以得到15.2g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至30%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(13.6g)，為灰白色固體。LCMS m/z=205,207(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。To a stirred solution of 5-fluoro-6-methylpyridin-2-amine (10 g, 79.28 mmol) in AcOH (50 ml) at 25°C, bromine (4.1 ml, 79.28 mmol) was added dropwise. The resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was alkalized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (100 ml x 2). The layers were separated and the combined organic layer was washed with brine (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 15.2 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and a gradient of 0-30% EtOAc in hexane to afford the title compound (13.6 g) as an off-white solid. LCMS m/z = 205, 207 (1:1; [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備7：3-溴-5-氯-6-甲基吡啶-2-胺Preparation 7: 3-Bromo-5-chloro-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-5-氟-6-甲基吡啶-2-胺中所述相同的反應方案(製備6)，並使用適當的起始原料來製備。LCMS m/z=221,223,225(0.8：1：0.2；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-5-fluoro-6-methylpyridin-2-amine (Preparation 6) using appropriate starting materials. LCMS m/z=221,223,225 (0.8:1:0.2; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備8：3-溴-5-環丙基-6-甲基吡啶-2-胺Preparation 8: 3-Bromo-5-cyclopropyl-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-5-氟-6-甲基吡啶-2-胺中所述相同的反應方案(製備6)，並使用適當的起始原料來製備。LCMS m/z=227,229(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-5-fluoro-6-methylpyridin-2-amine (Preparation 6) using appropriate starting materials. LCMS m/z=227,229 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備9：3-溴-5-環丁基-6-甲基吡啶-2-胺Preparation 9: 3-Bromo-5-cyclobutyl-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-5-氟-6-甲基吡啶-2-胺中所述相同的反應方案(製備6)，並使用適當的起始原料來製備。LCMS m/z=241,243(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-5-fluoro-6-methylpyridin-2-amine (Preparation 6) using appropriate starting materials. LCMS m/z=241,243 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備10：3-溴-5-異丙基-6-甲基吡啶-2-胺Preparation 10: 3-Bromo-5-isopropyl-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-5-氟-6-甲基吡啶-2-胺中所述相同的反應方案(製備6)，並使用適當的起始原料來製備。LCMS m/z=229,231(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-5-fluoro-6-methylpyridin-2-amine (Preparation 6) using appropriate starting materials. LCMS m/z=229,231 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備11：6-氨基-5-溴-2,4-二甲基煙腈Preparation 11: 6-amino-5-bromo-2,4-dimethyl nicotinoonitrile

標題所述之化合物係依照與合成3-溴-5-氟-6-甲基吡啶-2-胺中所述相同的反應方案(製備6)，並使用適當的起始原料來製備。LCMS m/z=226,228(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-5-fluoro-6-methylpyridin-2-amine (Preparation 6) using appropriate starting materials. LCMS m/z=226,228 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備12：3-溴-4,5,6-三甲基吡啶-2-胺Preparation 12: 3-Bromo-4,5,6-trimethylpyridin-2-amine

在0℃下，在含有4,5,6-三甲基吡啶-2-胺(4,5,6-trimethylpyridin-2-amine)(如CN107082759 A中報導的方式合成，2g，14.70mmol)的乙腈(15ml)的攪拌溶液分批添加NBS(8.4g，19.11mmol)。在25℃下將所得混合物攪拌2小時。將反應混合物用水(50ml)稀釋並以乙酸乙酯(50ml×2)萃取。分離各層並以鹽水(50ml)洗滌合併的有機層。將有機層經無水硫酸鈉乾燥、過濾及真空濃縮，以得到1.8g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至10%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(1.4g)，為灰白色固體。LCMS m/z=214,216(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。At 0°C, NBS (8.4 g, 19.11 mmol) was added in batches to a stirred solution of acetonitrile (15 ml) containing 4,5,6-trimethylpyridin-2-amine (synthesized as reported in CN107082759 A, 2 g, 14.70 mmol). The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml x 2). The layers were separated and the combined organic layer was washed with brine (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 1.8 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and a gradient of 0-10% EtOAc in hexane to afford the title compound (1.4 g) as an off-white solid. LCMS m/z = 214, 216 (1:1; [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備13：3-溴-5-氟-6-甲基吡啶-2-醇Preparation 13: 3-Bromo-5-fluoro-6-methylpyridin-2-ol

在25℃下將硫酸(9.8ml，189mmol)緩慢加入水(100ml)中。將3-溴-5-氟-6-甲基吡啶-2-胺(10.5g，42mmol)一次性加入其中，以得到澄清溶液。用冰水浴將此溶液冷卻至0℃至5℃。將含有NaNO₂(3.62g，52.5mmol)的水(10ml)溶液逐滴加入至所得懸浮液中。移除冰浴，將懸浮液在25℃攪拌1小時。在低於20℃的溫度下逐滴添加2N NaOH溶液以調節至pH 8並以乙酸乙酯(100ml x 2)萃取。分離各層並以鹽水(100ml)洗滌合併的有機層。將有機層經無水硫酸鈉乾燥、過濾及真空濃縮，以得到7.4g粗化合物，其將原樣用於下一步驟。LCMS m/z=206,208(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。Sulfuric acid (9.8 ml, 189 mmol) was slowly added to water (100 ml) at 25°C. 3-Bromo-5-fluoro-6-methylpyridin-2-amine (10.5 g, 42 mmol) was added in one portion to obtain a clear solution. The solution was cooled to 0°C to 5°C using an ice-water bath. A solution of water (10 ml) containing NaNO₂ (3.62 g, 52.5 mmol) was added dropwise to the resulting suspension. The ice bath was removed and the suspension was stirred at 25°C for 1 hour. 2N NaOH solution was added dropwise at a temperature below 20°C to adjust to pH 8 and extracted with ethyl acetate (100 ml x 2). The layers were separated and the combined organic layers were washed with brine (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 7.4 g of crude compound, which was used as such in the next step. LCMS m/z = 206, 208 (1:1; [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備14：3-溴-5-氯-6-甲基吡啶-2-醇Preparation 14: 3-Bromo-5-chloro-6-methylpyridin-2-ol

標題所述之化合物係依照與合成3-溴-5-氟-6-甲基吡啶-2-醇中所述相同的反應方案(製備13)，並使用適當的起始原料來製備。LCMS m/z=222,224(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-5-fluoro-6-methylpyridin-2-ol (Preparation 13) using appropriate starting materials. LCMS m/z=222,224 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備15：3-溴-5-環丙基-6-甲基吡啶-2-醇Preparation 15: 3-Bromo-5-cyclopropyl-6-methylpyridin-2-ol

標題所述之化合物係依照與合成3-溴-5-氟-6-甲基吡啶-2-醇中所述相同的反應方案(製備13)，並使用適當的起始原料來製備。LCMS m/z=228,230(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-5-fluoro-6-methylpyridin-2-ol (Preparation 13) using appropriate starting materials. LCMS m/z=228,230 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備16：3-溴-5-環丁基-6-甲基吡啶-2-醇Preparation 16: 3-Bromo-5-cyclobutyl-6-methylpyridin-2-ol

標題所述之化合物係依照與合成3-溴-5-氟-6-甲基吡啶-2-醇中所述相同的反應方案(製備13)，並使用適當的起始原料來製備。LCMS m/z=241,243(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-5-fluoro-6-methylpyridin-2-ol (Preparation 13) using appropriate starting materials. LCMS m/z=241,243 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備17：3-溴-5-異丙基-6-甲基吡啶-2-醇Preparation 17: 3-Bromo-5-isopropyl-6-methylpyridin-2-ol

標題所述之化合物係依照與合成3-溴-5-氟-6-甲基吡啶-2-醇中所述相同的反應方案(製備13)，並使用適當的起始原料來製備。LCMS m/z=229,231(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-5-fluoro-6-methylpyridin-2-ol (Preparation 13) using appropriate starting materials. LCMS m/z=229,231 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備18：3-溴-4,5,6-三甲基吡啶-2-醇Preparation 18: 3-Bromo-4,5,6-trimethylpyridin-2-ol

標題所述之化合物係依照與合成3-溴-5-氟-6-甲基吡啶-2-醇中所述相同的反應方案(製備13)，並使用適當的起始原料來製備。LCMS m/z=215,217(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-5-fluoro-6-methylpyridin-2-ol (Preparation 13) using appropriate starting materials. LCMS m/z=215,217 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備19：5,6-二溴-2-甲基菸鹼酸乙酯Preparation 19: 5,6-dibromo-2-methylnicotinic acid ethyl ester

在90℃下，在含有5-溴-6-氯-2-甲基菸鹼酸乙酯(如WO2008085119 A1中所述之方式合成，2.1g，7.5mmol)的甲苯(10ml)的攪拌溶液加入在甲苯(10ml)的POBr₃(4.76g,16mmol)懸浮液，並攪拌3小時。將反應混合物以乙酸乙酯(50ml)稀釋並以水(50ml)洗滌。將有機層以飽和碳酸氫鈉水溶液鹼化。分離各層並以鹽水(50ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到2.3g固體狀之標題所述之化合物。LCMS m/z=321,323,325(1：2：1；[M+H]⁺,[(M+H)+2]⁺；[(M+H)+4]⁺；100%)。A stirred solution of 5-bromo-6-chloro-2-methylnicotinic acid ethyl ester (synthesized as described in WO2008085119 A1, 2.1 g, 7.5 mmol) in toluene (10 ml) was added to a suspension of POBr₃ (4.76 g, 16 mmol) in toluene (10 ml) at 90°C and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml). The organic layer was alkalized with saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.3 g of the title compound as a solid. LCMS m/z=321,323,325 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ ; [(M+H)+4]⁺ ; 100%).

製備20：5,6-二溴-2-甲基菸鹼酸Preparation 20: 5,6-dibromo-2-methylnicotinic acid

在0℃下，在含有5,6-二溴-2-甲基菸鹼酸乙酯(0.5g，1.55mmol)的THF(10ml)的攪拌溶液加入LiOH.H₂O(391mg，9.31mmol)的水(4ml)溶液，並在25℃下攪拌16小時。將反應混合物以1N鹽酸(50ml)淬熄(quenched)並以乙酸乙酯(25ml×2)萃取。分離各層並以鹽水(50ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到459mg灰白色固體狀之標題化合物。LCMS m/z=293,295,297(1：2：1；[M+H]⁺,[(M+H)+2]⁺；[(M+H)+4]⁺；100%)。To a stirred solution of ethyl 5,6-dibromo-2-methylnicotinate (0.5 g, 1.55 mmol) in THF (10 ml) was added a solution of LiOH.H₂ O (391 mg, 9.31 mmol) in water (4 ml) at 0°C and stirred at 25°C for 16 hours. The reaction mixture was quenched with 1N hydrochloric acid (50 ml) and extracted with ethyl acetate (25 ml x 2). The layers were separated and the combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 459 mg of the title compound as an off-white solid. LCMS m/z=293,295,297 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ ; [(M+H)+4]⁺ ; 100%).

製備21：5,6-二溴-N-甲氧基-N,2-二甲基菸鹼醯胺Preparation 21: 5,6-dibromo-N-methoxy-N,2-dimethylnicotinamide

在0℃下，在含有5,6-二溴-2-甲基菸鹼酸(0.45g,1.53mmol)的二氯甲烷(10ml)的攪拌溶液加入N,O-二甲基羥胺鹽酸鹽(179mg，1.83mmol)和三乙胺(0.25ml，1.83mmol)。將其加入1-乙基-3-(3-二甲基氨基丙基)碳二亞胺鹽酸鹽(351mg，1.83mmol)，並在25℃下攪拌4小時。將反應混合物以水(50ml)淬熄並以乙酸乙酯(25ml×2)萃取。分離各層並以鹽水(50ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.1g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至30%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到。LCMS m/z=336,338,340(1：2：1；[M+H]⁺,[(M+H)+2]⁺；[(M+H)+4]⁺；100%)。At 0°C, N,O-dimethylhydroxylamine hydrochloride (179 mg, 1.83 mmol) and triethylamine (0.25 ml, 1.83 mmol) were added to a stirred solution of 5,6-dibromo-2-methylnicotinic acid (0.45 g, 1.53 mmol) in dichloromethane (10 ml). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (351 mg, 1.83 mmol) was added and stirred at 25°C for 4 hours. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (25 ml×2). The layers were separated and the combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.1 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and eluted with a gradient of 0 to 30% EtOAc in hexane to give. LCMS m/z=336,338,340 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ;[(M+H)+4]⁺ ;100%).

製備22：1-(5,6-二溴-2-甲基吡啶-3-基)乙烷-1-酮Preparation 22: 1-(5,6-dibromo-2-methylpyridin-3-yl)ethan-1-one

在0℃下，在含有5,6-二溴-N-甲氧基-N,2-二甲基菸鹼醯胺(0.33g，0.9766mmol)的無水THF(10ml)的攪拌溶液加入1M甲基溴化鎂於THF(2.4ml)的溶液，並攪拌2小時。將所得混合物在25℃下攪拌1小時。將反應混合物以飽和氯化銨水溶液(sat.aq.NH₄Cl)(50ml)淬熄並以乙酸乙酯(25ml×2)萃取。分離各層並以鹽水(50ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.25g黃色液體狀之標題化合物。LCMS m/z=291,293,295(1：2：1；[M+H]⁺,[(M+H)+2]⁺；[(M+H)+4]⁺；100%)。To a stirred solution of 5,6-dibromo-N-methoxy-N,2-dimethylnicotinamide (0.33 g, 0.9766 mmol) in anhydrous THF (10 ml) was added a 1 M solution of methylmagnesium bromide in THF (2.4 ml) at 0°C and stirred for 2 hours. The resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (sat.aq. NH₄ Cl) (50 ml) and extracted with ethyl acetate (25 ml×2). The layers were separated and the combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 0.25 g of the title compound as a yellow liquid. LCMS m/z=291,293,295 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ ; [(M+H)+4]⁺ ; 100%).

製備23：1-(5,6-二溴-2-甲基吡啶-3-基)乙-1-醇Preparation 23: 1-(5,6-dibromo-2-methylpyridin-3-yl)ethan-1-ol

在0℃下，在含有1-(5,6-二溴-2-甲基吡啶-3-基)乙-1-酮(2.5g，8.538mmol)的甲醇(25ml)的攪拌溶液加入NaBH₄(0.419g,11.099mmol)。將所得混合物在25℃下攪拌3小時。將反應混合物以飽和氯化銨水溶液(sat.aq.NH₄Cl)(100ml)淬熄並以乙酸乙酯(50ml×2)萃取。分離各層並以鹽水(100ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到2.5g黃色液體狀之標題所述之化合物。LCMS m/z=293,295,297(1：2：1；[M+H]⁺,[(M+H)+2]⁺；[(M+H)+4]⁺；100%)。NaBH₄ (0.419 g, 11.099 mmol) was added to a stirred solution of 1-(5,6-dibromo-2-methylpyridin-_{3-yl)ethan-1-one (2.5 g, 8.538 mmol) in methanol (25 ml) at 0°C. The resulting mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (sat.aq. NH 4} Cl) (100 ml) and extracted with ethyl acetate (50 ml×2). The layers were separated and the combined organic layer was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 2.5 g of the title compound as a yellow liquid. LCMS m/z=293,295,297 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ ; [(M+H)+4]⁺ ; 100%).

製備24：2,3-二溴-5-(1-甲氧基乙基)-6-甲基吡啶Preparation 24: 2,3-Dibromo-5-(1-methoxyethyl)-6-methylpyridine

在0℃下，在含有1-(5,6-二溴-2-甲基吡啶-3-基)乙-1-醇(2.5g，8.475mmol)的無水THF(30ml)的攪拌溶液加入氫化鈉(NaH，679mg，16.95mmol)。待10分鐘後，將其逐滴加入碘甲烷(0.8ml，12.71mmol)並於25℃的氮氣氣氛下攪拌2小時。將反應混合物以飽和氯化銨水溶液(sat.aq.NH₄Cl)(100ml)稀釋並以乙酸乙酯(50ml×2)萃取。分離各層並以鹽水(50ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到2.2g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至20%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(2g)，為淡黃色液體。LCMS m/z=307,309,311(1：2：1；[M+H]⁺,[(M+H)+2]⁺；[(M+H)+4]⁺；100%)。At 0°C, sodium hydride (NaH, 679 mg, 16.95 mmol) was added to a stirred solution of 1-(5,6-dibromo-2-methylpyridin-3-yl)ethan-1-ol (2.5 g, 8.475 mmol) in anhydrous THF (30 ml). After 10 minutes, iodomethane (0.8 ml, 12.71 mmol) was added dropwise and stirred for 2 hours at 25°C under a nitrogen atmosphere. The reaction mixture was diluted with a saturated aqueous ammonium chloride solution (sat. aq. NH₄ Cl) (100 ml) and extracted with ethyl acetate (50 ml×2). The layers were separated and the combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.2 g of crude compound. The crude residue was purified on a combiflash instrument on a redisep® column with a gradient of 0 to 20% EtOAc in hexane to give the title compound (2 g) as a light yellow liquid. LCMS m/z=307,309,311 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ;[(M+H)+4]⁺ ;100%).

製備25：2,3-二溴-5-(1-乙氧基乙基)-6-甲基吡啶Preparation 25: 2,3-Dibromo-5-(1-ethoxyethyl)-6-methylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-(1-甲氧基乙基)-6-甲基吡啶中所述相同的反應方案(製備24)，並使用適當的起始原料來製備。LCMS m/z=321,323,325(1：2：1；[M+H]⁺,[(M+H)+2]⁺；[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2,3-dibromo-5-(1-methoxyethyl)-6-methylpyridine (Preparation 24) using appropriate starting materials. LCMS m/z=321,323,325 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ; [(M+H)+4]⁺ ; 100%).

製備26：2,3-二溴-6-甲基-5-(1-丙氧基乙基)吡啶Preparation 26: 2,3-Dibromo-6-methyl-5-(1-propoxyethyl)pyridine

標題所述之化合物係依照與合成2,3-二溴-5-(1-甲氧基乙基)-6-甲基吡啶中所述相同的反應方案(製備24)，並使用適當的起始原料來製備。LCMS m/z=335,337,339(1：2：1；[M+H]⁺,[(M+H)+2]⁺；[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2,3-dibromo-5-(1-methoxyethyl)-6-methylpyridine (Preparation 24) using appropriate starting materials. LCMS m/z=335,337,339 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ; [(M+H)+4]⁺ ; 100%).

製備27：2-(5,6-二溴-2-甲基吡啶-3-基)丙-2-醇Preparation 27: 2-(5,6-dibromo-2-methylpyridin-3-yl)propan-2-ol

在0℃下，在含有5,6-二溴-2-甲基菸酸乙酯(2g，6.213mmol)的無水THF(30ml)的攪拌溶液加入2M甲基溴化鎂於THF(24.8ml)的溶液。將所得混合物在25℃下攪拌16小時。將反應混合物以飽和氯化銨水溶液(sat.aq.NH₄Cl)(100ml)淬熄並以乙酸乙酯(50ml×2)萃取。分離各層並以鹽水(100ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到2.2g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至50%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.68g)，為灰白色固體。LCMS m/z=308,310,312(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。At 0°C, a solution of 2M methylmagnesium bromide in THF (24.8ml) was added to a stirred solution of ethyl 5,6-dibromo-2-methylnicotinate (2g, 6.213mmol) in anhydrous THF (30ml). The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (sat.aq. NH₄ Cl) (100ml) and extracted with ethyl acetate (50ml×2). The layers were separated and the combined organic layer was washed with brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 2.2g of a crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient elution from 0 to 50% EtOAc in hexane to afford the title compound (0.68 g) as an off-white solid. LCMS m/z = 308, 310, 312 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備28：2,3-二溴-5-(2-甲氧基丙-2-基)-6-甲基吡啶Preparation 28: 2,3-Dibromo-5-(2-methoxyprop-2-yl)-6-methylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-(1-甲氧基乙基)-6-甲基吡啶中所述相同的反應方案(製備24)，並使用適當的起始原料來製備。LCMS m/z=322,324,326(1：2：1,[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2,3-dibromo-5-(1-methoxyethyl)-6-methylpyridine (Preparation 24) using appropriate starting materials. LCMS m/z=322,324,326 (1:2:1, [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備29：(5,6-二溴-2-甲基吡啶-3-基)甲醇Preparation 29: (5,6-dibromo-2-methylpyridin-3-yl)methanol

在-20℃下，在含有5,6-二溴-2-甲基菸鹼酸乙酯(1.6g，4.96mol)的THF(10ml)的攪拌溶液加入氫化二異丁基鋁(diisobutylaluminium hydride)(14.9ml，14.9mol)，並攪拌1小時。將反應混合物以1N鹽酸(50ml)淬熄並以乙酸乙酯(50ml)萃取。分離各層並以鹽水(50ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到1.3g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至20%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.68g)，為灰白色固體。LCMS m/z=279,281,283(1：2：1；[M+H]⁺,[(M+H)+2]⁺；[(M+H)+4]⁺；100%)。Diisobutylaluminium hydride (14.9 ml, 14.9 mol) was added to a stirred solution of ethyl 5,6-dibromo-2-methylnicotinate (1.6 g, 4.96 mol) in THF (10 ml) at -20°C and stirred for 1 hour. The reaction mixture was quenched with 1N hydrochloric acid (50 ml) and extracted with ethyl acetate (50 ml). The layers were separated and the organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.3 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient chromatography from 0 to 20% ethyl acetate/hexane to afford the title compound (0.68 g) as an off-white solid. LCMS m/z = 279, 281, 283 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ ; [(M+H)+4]⁺ ; 100%).

製備30：(5,6-二溴-2-甲基吡啶-3-基)甲磺酸甲酯Preparation 30: Methyl (5,6-dibromo-2-methylpyridin-3-yl)methanesulfonate

在0℃下，在含有5,6-二溴-2-甲基吡啶-3-基)甲醇(0.2g，0.711mmol)的二氯甲烷(5ml)的攪拌溶液加入三乙胺(0.198ml，1.422mol)，然後加入甲磺醯氯(122.33mg，1.067mmol)，並在25℃下攪拌1小時。分離各層並以鹽水(50ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.2g粗化合物。將此粗殘留物與戊烷(2ml)一起研磨，以得到標題所述之化合物(0.19g)，為灰白色固體。LCMS m/z=357,359,361(1：2：1；[M+H]⁺,[(M+H)+2]⁺；[(M+H)+4]⁺；100%)。To a stirred solution of 5,6-dibromo-2-methylpyridin-3-yl)methanol (0.2 g, 0.711 mmol) in dichloromethane (5 ml) at 0°C was added triethylamine (0.198 ml, 1.422 mol) followed by methanesulfonyl chloride (122.33 mg, 1.067 mmol) and stirred at 25°C for 1 hour. The layers were separated and the organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.2 g of the crude compound. The crude residue was triturated with pentane (2 ml) to give the title compound (0.19 g) as an off-white solid. LCMS m/z=357,359,361 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ ; [(M+H)+4]⁺ ; 100%).

製備31：2,3-二溴-5-(溴甲基)-6-甲基吡啶Preparation 31: 2,3-Dibromo-5-(bromomethyl)-6-methylpyridine

在0℃下，在含有5,6-二溴-2-甲基吡啶-3-基)甲醇(3g，10.6799mmol)的二氯甲烷(25ml)的攪拌溶液加入PBr₃(3.48ml，12.8158mmol)，並於25℃攪拌2小時。將反應混合物以飽和碳酸氫鈉(100ml)水溶液淬熄，並以二氯甲烷(50ml x 2)萃取。分離各層並以鹽水(50ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到3.8g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至10%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(3.5g)，為橘色固體。LCMS m/z=342,344,346,348(1：3：3：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺,[(M+H)+6]⁺；100%)。PBr₃ (3.48 ml, 12.8158 mmol) was added to a stirred solution of 5,6-dibromo-2-methylpyridin-3-yl)methanol (3 g, 10.6799 mmol) in dichloromethane (25 ml) at 0°C and stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (100 ml) and extracted with dichloromethane (50 ml x 2). The layers were separated and the organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3.8 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient elution from 0 to 10% EtOAc in hexane to afford the title compound (3.5 g) as an orange solid. LCMS m/z = 342, 344, 346, 348 (1:3:3:1; [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ , [(M+H)+6]⁺ ; 100%).

製備32：2,3-二溴-5-氟-6-甲基吡啶Preparation 32: 2,3-Dibromo-5-fluoro-6-methylpyridine

在90℃下，在含有3-溴-5-氟-6-甲基吡啶-2-醇(7.4g，36.09mmol)的DMF(22ml)和甲苯(22ml)的攪拌溶液，於10分鐘內逐滴加入溶解在甲苯(15ml)中的POBr₃(20.64g，72.19mmol)。將所得混合物在110℃下攪拌16小時。將反應混合物冷卻至室溫，倒入至0℃的飽和碳酸氫鈉水溶液中，並以MTBE(100ml x 2)萃取。分離各層並以鹽水(100ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到8.2g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至5%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(6.1g)，為灰白色固體。LCMS m/z=268,270,272(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。To a stirred solution of 3-bromo-5-fluoro-6-methylpyridin-2-ol (7.4 g, 36.09 mmol) in DMF (22 ml) and toluene (22 ml) was added POBr₃ (20.64 g, 72.19 mmol) dissolved in toluene (15 ml) dropwise over 10 min at 90°C. The resulting mixture was stirred at 110°C for 16 h. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium bicarbonate solution at 0°C, and extracted with MTBE (100 ml x 2). The layers were separated and the combined organic layer was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 8.2 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient elution from 0 to 5% EtOAc in hexane to afford the title compound (6.1 g) as an off-white solid. LCMS m/z = 268, 270, 272 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備33：2,3-二溴-5-氯-6-甲基吡啶Preparation 33: 2,3-Dibromo-5-chloro-6-methylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-氟-6-甲基吡啶中所述相同的反應方案(製備32)，並使用適當的起始原料來製備。LCMS m/z=283,285,287(100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of 2,3-dibromo-5-fluoro-6-methylpyridine (Preparation 32) using appropriate starting materials. LCMS m/z=283,285,287 (100%).

製備34：2,3-二溴-5-環丙基-6-甲基吡啶Preparation 34: 2,3-Dibromo-5-cyclopropyl-6-methylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-氟-6-甲基吡啶中所述相同的反應方案(製備32)，並使用適當的起始原料來製備。LCMS m/z=290,292,294(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2,3-dibromo-5-fluoro-6-methylpyridine (Preparation 32) using appropriate starting materials. LCMS m/z=290,292,294 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ).

製備35：2,3-二溴-5-環丁基-6-甲基吡啶Preparation 35: 2,3-Dibromo-5-cyclobutyl-6-methylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-氟-6-甲基吡啶中所述相同的反應方案(製備32)，並使用適當的起始原料來製備。LCMS m/z=303,305,307(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺,100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2,3-dibromo-5-fluoro-6-methylpyridine (Preparation 32) using appropriate starting materials. LCMS m/z=303,305,307 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ,100%).

製備36：2,3-二溴-5-異丙基-6-甲基吡啶Preparation 36: 2,3-Dibromo-5-isopropyl-6-methylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-氟-6-甲基吡啶中所述相同的反應方案(製備32)，並使用適當的起始原料來製備。LCMS m/z=291,293,295(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺,100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2,3-dibromo-5-fluoro-6-methylpyridine (Preparation 32) using appropriate starting materials. LCMS m/z=291,293,295 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ,100%).

製備37：2,3-二溴-4,5,6-三甲基吡啶Preparation 37: 2,3-Dibromo-4,5,6-trimethylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-氟-6-甲基吡啶中所述相同的反應方案(製備32)，並使用適當的起始原料來製備。LCMS m/z=278,280,282(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2,3-dibromo-5-fluoro-6-methylpyridine (Preparation 32) using appropriate starting materials. LCMS m/z=278,280,282 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備38：5,6-二溴-2,4-二甲基煙腈Preparation 38: 5,6-Dibromo-2,4-dimethylnicotinonitrile

在0℃下，在含有6-氨基-5-溴-2,4-二甲基煙腈(0.55g，2.43mmol)的乙腈(10ml)溶液加入叔丁醇鈉(0.497g，4.13mmol)和CuBr₂(814.8mg，3.6mmol)，並攪拌2小時。將反應混合物以1N鹽酸酸化至pH 6，並以乙酸乙酯(20ml×2)萃取。分離各層並以鹽水(50ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.7g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至20%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.25g)，為灰白色固體。LCMS m/z=289,291,293(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。At 0°C, sodium tert-butoxide (0.497 g, 4.13 mmol) and CuBr₂ (814.8 mg, 3.6 mmol) were added to a solution of 6-amino-5-bromo-2,4-dimethylnicotinonitrile (0.55 g, 2.43 mmol) in acetonitrile (10 ml), and stirred for 2 hours. The reaction mixture was acidified to pH 6 with 1N hydrochloric acid and extracted with ethyl acetate (20 ml x 2). The layers were separated and the combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 0.7 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient chromatography from 0 to 20% EtOAc in hexane to afford the title compound (0.25 g) as an off-white solid. LCMS m/z = 289, 291, 293 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備39：5-溴-N,N,2-三甲基吡啶-3-胺Preparation 39: 5-Bromo-N,N,2-trimethylpyridin-3-amine

將含有5-溴-2-甲基吡啶-3-胺(2g)的96%甲酸(7.5ml)和37%甲醛(7.5ml)水溶液1：1混合物加熱回流16小時。減壓去除揮發物並以飽和碳酸氫鈉溶液中和殘留物。水溶液層以乙酸乙酯(100ml×2)萃取。分離各層並以鹽水(100ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到1.4g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至30%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(1g)，為灰白色固體。LCMS m/z=215,217(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。A 1:1 mixture of 96% formic acid (7.5 ml) and 37% formaldehyde (7.5 ml) aqueous solution containing 5-bromo-2-methylpyridin-3-amine (2 g) was heated to reflux for 16 hours. The volatiles were removed under reduced pressure and the residue was neutralized with saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (100 ml x 2). The layers were separated and the combined organic layer was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 1.4 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and a gradient of 0-30% EtOAc in hexane to afford the title compound (1 g) as an off-white solid. LCMS m/z = 215, 217 (1:1; [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備40：4-(5-溴-2-甲基吡啶-3-基)嗎啉Preparation 40: 4-(5-bromo-2-methylpyridin-3-yl)morpholine

標題所述之化合物係依照與WO2014151616 A1中所述相同的反應方案來製備。LCMS m/z=257,259(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in WO2014151616 A1. LCMS m/z=257,259 (1:1; [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備41：5-溴-2-甲基-3-(哌啶-1-基)吡啶Preparation 41: 5-Bromo-2-methyl-3-(piperidin-1-yl)pyridine

標題所述之化合物係依照與合成5-溴-2-甲基-3-(哌啶-1-基)吡啶中所述相同的反應方案(製備40)，並使用適當的起始原料來製備。LCMS m/z=255,257(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of 5-bromo-2-methyl-3-(piperidin-1-yl)pyridine (Preparation 40) using appropriate starting materials. LCMS m/z=255,257 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備42：5-溴-2-甲基-3-(吡咯烷-1-基)吡啶Preparation 42: 5-Bromo-2-methyl-3-(pyrrolidin-1-yl)pyridine

標題所述之化合物係依照與合成5-溴-2-甲基-3-(哌啶-1-基)吡啶中所述相同的反應方案(製備40)，並使用適當的起始原料來製備。LCMS m/z=241,243(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5-bromo-2-methyl-3-(piperidin-1-yl)pyridine (Preparation 40) using appropriate starting materials. LCMS m/z=241,243 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備43：6-溴-3-甲基-2-(吡咯烷-1-基)吡啶Preparation 43: 6-Bromo-3-methyl-2-(pyrrolidin-1-yl)pyridine

標題所述之化合物係依照與合成5-溴-2-甲基-3-(哌啶-1-基)吡啶中所述相同的反應方案(製備40)，並使用適當的起始原料來製備。LCMS m/z=241,243(1：1；[M+H]⁺,[(M+H)+2]⁺,100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5-bromo-2-methyl-3-(piperidin-1-yl)pyridine (Preparation 40) using appropriate starting materials. LCMS m/z=241,243 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ,100%).

製備44：6-溴-3-甲基-2-(哌啶-1-基)吡啶Preparation 44: 6-Bromo-3-methyl-2-(piperidin-1-yl)pyridine

標題所述之化合物係依照與合成5-溴-2-甲基-3-(哌啶-1-基)吡啶中所述相同的反應方案(製備40)，並使用適當的起始原料來製備。LCMS m/z=255,257(1：1；[M+H]⁺,[(M+H)+2]⁺,100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5-bromo-2-methyl-3-(piperidin-1-yl)pyridine (Preparation 40) using appropriate starting materials. LCMS m/z=255,257 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ,100%).

製備45：6-溴-N,N,3-三甲基吡啶-2-胺Preparation 45: 6-Bromo-N,N,3-trimethylpyridin-2-amine

標題所述之化合物係依照與合成5-溴-2-甲基-3-(哌啶-1-基)吡啶中所述相同的反應方案(製備40)，並使用適當的起始原料來製備。LCMS m/z=215,217(1：1；[M+H]⁺,[(M+H)+2]⁺,100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5-bromo-2-methyl-3-(piperidin-1-yl)pyridine (Preparation 40) using appropriate starting materials. LCMS m/z=215,217 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ,100%).

製備46：4-(6-溴-3-甲基吡啶-2-基)嗎啉Preparation 46: 4-(6-bromo-3-methylpyridin-2-yl)morpholine

標題所述之化合物係依照與合成5-溴-2-甲基-3-(哌啶-1-基)吡啶中所述相同的反應方案(製備40)，並使用適當的起始原料來製備。LCMS m/z=257,259(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of 5-bromo-2-methyl-3-(piperidin-1-yl)pyridine (Preparation 40) using appropriate starting materials. LCMS m/z=257,259 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備47：6-溴-2-異丙氧基-3-甲基吡啶Preparation 47: 6-Bromo-2-isopropoxy-3-methylpyridine

在室溫下，在含有6-溴-2-氟-3-甲基吡啶(0.5g，2.6mmol)的IPA(4ml)攪拌溶液中加入叔丁醇鉀(224mg，5.2mmol)。並在80℃下攪拌16小時。將反應混合物真空濃縮，以得到0.38g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以100%的己烷進行流析，以得到標題所述之化合物(0.3g)，為無色液體。LCMS m/z=230,232(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。Potassium tert-butoxide (224 mg, 5.2 mmol) was added to a stirred solution of 6-bromo-2-fluoro-3-methylpyridine (0.5 g, 2.6 mmol) in IPA (4 ml) at room temperature. The mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated in vacuo to obtain 0.38 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and eluted with 100% hexane to obtain the title compound (0.3 g) as a colorless liquid. LCMS m/z=230,232 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備48：6-溴-2-(4,4-二氟哌啶-1-基)-3-甲基吡啶Preparation 48: 6-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-methylpyridine

在室溫下，在含有6-溴-2-氟-3-甲基吡啶(0.5g，2.63mmol)的DMSO(5ml)攪拌溶液中加入K₂CO₃(1.27g，9.21mmol)，並在120℃攪拌16小時。將反應混合物以乙酸乙酯(50ml)稀釋並以水(50ml)洗滌。將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.75g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至5%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.5g)，為灰白色固體。LCMS m/z=291,293(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。K₂ CO₃ (1.27 g, 9.21 mmol) was added to a stirred solution of 6-bromo-2-fluoro-3-methylpyridine (0.5 g, 2.63 mmol) in DMSO (5 ml) at room temperature and stirred at 120° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.75 g of crude compound. The crude residue was purified on a combiflash instrument on a redisep® column with a gradient of 0 to 5% ethyl acetate/hexane (EtOAc in hexane) to give the title compound (0.5 g) as an off-white solid. LCMS m/z=291,293 (1:1; [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備49：6-溴-2-(4-甲氧基哌啶-1-基)-3-甲基吡啶Preparation 49: 6-Bromo-2-(4-methoxypiperidin-1-yl)-3-methylpyridine

標題所述之化合物係依照與合成6-溴-2-(4,4-二氟哌啶-1-基)-3-甲基吡啶中所述相同的反應方案(製備48)，並使用適當的起始原料來製備。LCMS m/z=285,287(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 6-bromo-2-(4,4-difluoropiperidin-1-yl)-3-methylpyridine (Preparation 48) using appropriate starting materials. LCMS m/z=285,287 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備例50：6-(6-溴-3-甲基吡啶-2-基)-6-氮雜螺[2.5]辛烷Preparation Example 50: 6-(6-Bromo-3-methylpyridin-2-yl)-6-azaspiro[2.5]octane

標題所述之化合物係依照與合成6-溴-2-(4,4-二氟哌啶-1-基)-3-甲基吡啶中所述相同的反應方案(製備48)，並使用適當的起始原料來製備。LCMS m/z=281,283(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 6-bromo-2-(4,4-difluoropiperidin-1-yl)-3-methylpyridine (Preparation 48) using appropriate starting materials. LCMS m/z=281,283 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備例51：(R)-1-(5-溴-2-甲基吡啶-3-基)吡咯烷-3-醇Preparation Example 51: (R)-1-(5-bromo-2-methylpyridin-3-yl)pyrrolidin-3-ol

在25℃下，在含有5-溴-3-氟-2-甲基吡啶(1g，5.2628mmol)的NMP(6ml)攪拌溶液中加入(R)-吡咯烷-3-醇(2.2g，26.314mmol)，並在150℃攪拌16小時。將反應混合物以乙酸乙酯(50ml)稀釋並以水(50ml)洗滌。分離各層並以鹽水(50ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到1.3g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至100%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.9g)，為灰白色固體。LCMS m/z=257,259(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。(R)-pyrrolidin-3-ol (2.2 g, 26.314 mmol) was added to a stirred solution of 5-bromo-3-fluoro-2-methylpyridine (1 g, 5.2628 mmol) in NMP (6 ml) at 25°C and stirred at 150°C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml). The layers were separated and the organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.3 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient chromatography from 0 to 100% EtOAc in hexane to afford the title compound (0.9 g) as an off-white solid. LCMS m/z = 257, 259 (1:1; [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備例52：(S)-1-(5-溴-2-甲基吡啶-3-基)吡咯烷-3-醇Preparation Example 52: (S)-1-(5-bromo-2-methylpyridin-3-yl)pyrrolidin-3-ol

標題所述之化合物係依照與合成(R)-1-(5-溴-2-甲基吡啶-3-基)吡咯烷-3-醇中所述相同的反應方案(製備51)，並使用適當的起始原料來製備。LCMS m/z=257,259(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of (R)-1-(5-bromo-2-methylpyridin-3-yl)pyrrolidin-3-ol (Preparation 51) using appropriate starting materials. LCMS m/z=257,259 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備例53：(S)-(1-(5-溴-2-甲基吡啶-3-基)吡咯烷-2-基)甲醇Preparation Example 53: (S)-(1-(5-bromo-2-methylpyridin-3-yl)pyrrolidin-2-yl)methanol

標題所述之化合物係依照與合成(R)-1-(5-溴-2-甲基吡啶-3-基)吡咯烷-3-醇中所述相同的反應方案(製備51)，並使用適當的起始原料來製備。LCMS m/z=271,273(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of (R)-1-(5-bromo-2-methylpyridin-3-yl)pyrrolidin-3-ol (Preparation 51) using appropriate starting materials. LCMS m/z=271,273 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備54：5,6-二溴-N,N,2-三甲基吡啶-3-胺Preparation 54: 5,6-dibromo-N,N,2-trimethylpyridin-3-amine

在0℃下，在含有5-溴-N,N,2-三甲基吡啶-3-胺(1g，4.651mmol)的乙腈(10ml)攪拌溶液中加入NBS(1.07，6.046mmol)，並在25℃下攪拌2小時。將反應混合物以乙酸乙酯(20ml)稀釋並以水(20ml)洗滌。分離各層並以鹽水(20ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到1.3g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至20%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(1g)，為白色固體。LCMS m/z=293,295,297(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。NBS (1.07, 6.046 mmol) was added to a stirred solution of 5-bromo-N,N,2-trimethylpyridin-3-amine (1 g, 4.651 mmol) in acetonitrile (10 ml) at 0°C and stirred at 25°C for 2 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml). The layers were separated and the organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.3 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient chromatography from 0 to 20% ethyl acetate/hexane to afford the title compound (1 g) as a white solid. LCMS m/z = 293, 295, 297 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備例55：4-(5,6-二溴-2-甲基吡啶-3-基)嗎啉Preparation Example 55: 4-(5,6-Dibromo-2-methylpyridin-3-yl)morpholine

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=335,337,339(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=335,337,339 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備例56：2,3-二溴-6-甲基-5-(哌啶-1-基)吡啶Preparation Example 56: 2,3-Dibromo-6-methyl-5-(piperidin-1-yl)pyridine

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=333,335,337(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=333,335,337 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備例57：2,3-二溴-6-甲基-5-(吡咯烷-1-基)吡啶Preparation Example 57: 2,3-Dibromo-6-methyl-5-(pyrrolidin-1-yl)pyridine

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=319,321,323(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=319,321,323 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備例58：2,3-二溴-5-甲基-6-(吡咯烷-1-基)吡啶Preparation Example 58: 2,3-Dibromo-5-methyl-6-(pyrrolidin-1-yl)pyridine

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=319,321,323(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=319,321,323 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備例59：2,3-二溴-5-甲基-6-(哌啶-1-基)吡啶Preparation Example 59: 2,3-Dibromo-5-methyl-6-(piperidin-1-yl)pyridine

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=333,335,337(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=333,335,337 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備60：5,6-二溴-N,N,3-三甲基吡啶-2-胺Preparation 60: 5,6-dibromo-N,N,3-trimethylpyridin-2-amine

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=293,295,297(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=293,295,297 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備61：4-(5,6-二溴-3-甲基吡啶-2-基)嗎啉Preparation 61: 4-(5,6-dibromo-3-methylpyridin-2-yl)morpholine

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=335,337,339(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=335,337,339 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備62：2,3-二溴-6-異丙氧基-5-甲基吡啶Preparation 62: 2,3-Dibromo-6-isopropoxy-5-methylpyridine

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=308,310,312(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=308,310,312 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備63：2,3-二溴-6-(4,4-二氟哌啶-1-基)-5-甲基吡啶Preparation 63: 2,3-Dibromo-6-(4,4-difluoropiperidin-1-yl)-5-methylpyridine

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=369,371,373(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=369,371,373 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備64：2,3-二溴-6-(4-甲氧基哌啶-1-基)-5-甲基吡啶Preparation 64: 2,3-Dibromo-6-(4-methoxypiperidin-1-yl)-5-methylpyridine

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=363,365,367(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=363,365,367 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備65：6-(5,6-二溴-3-甲基吡啶-2-基)-6-氮雜螺[2.5]辛烷Preparation 65: 6-(5,6-dibromo-3-methylpyridin-2-yl)-6-azaspiro[2.5]octane

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=359,361,363(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=359,361,363 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備66：(R)-1-(5,6-二溴-2-甲基吡啶-3-基)吡咯烷-3-醇Preparation 66: (R)-1-(5,6-dibromo-2-methylpyridin-3-yl)pyrrolidin-3-ol

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=335,337,339(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=335,337,339 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備67：(S)-1-(5,6-二溴-2-甲基吡啶-3-基)吡咯烷-3-醇Preparation 67: (S)-1-(5,6-dibromo-2-methylpyridin-3-yl)pyrrolidin-3-ol

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=335,337,339(1：2：1；[M+H]⁺,[(M+H)+2]⁺，[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=335,337,339 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備68：(S)-(1-(5,6-二溴-2-甲基吡啶-3-基)吡咯烷-2-基)甲醇Preparation 68: (S)-(1-(5,6-dibromo-2-methylpyridin-3-yl)pyrrolidin-2-yl)methanol

標題所述之化合物係依照與合成5,6-二溴-N,N,2-三甲基吡啶-3-胺中所述相同的反應方案(製備54)，並使用適當的起始原料來製備。LCMS m/z=349,351,353(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 5,6-dibromo-N,N,2-trimethylpyridin-3-amine (Preparation 54) using appropriate starting materials. LCMS m/z=349,351,353 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備69：(R)-2,3-二溴-5-(3-甲氧基吡咯烷-1-基)-6-甲基吡啶Preparation 69: (R)-2,3-Dibromo-5-(3-methoxypyrrolidin-1-yl)-6-methylpyridine

在0℃下，在含有(R)-1-(5,6-二溴-2-甲基吡啶-3-基)吡咯烷-3-醇(0.6g)的THF(9ml)攪拌溶液中加入氫化鈉(NaH，85mg)。待10分鐘後，向其逐滴加入碘甲烷(380mg)並於25℃氮氣氣氛下攪拌2小時。將反應混合物以水(50ml)稀釋並以乙酸乙酯(50ml)萃取。分離各層並以鹽水(20ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.550g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至20%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.31g)，為灰白色固體。LCMS m/z=349,351,353(1:2:1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。Sodium hydride (NaH, 85 mg) was added to a stirred solution of (R)-1-(5,6-dibromo-2-methylpyridin-3-yl)pyrrolidin-3-ol (0.6 g) in THF (9 ml) at 0°C. After 10 minutes, iodomethane (380 mg) was added dropwise and stirred at 25°C under nitrogen atmosphere for 2 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The layers were separated and the organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 0.550 g of a crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient chromatography from 0 to 20% EtOAc in hexane to afford the title compound (0.31 g) as an off-white solid. LCMS m/z = 349, 351, 353 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備70:(S)-2,3-二溴-5-(3-甲氧基吡咯烷-1-基)-6-甲基吡啶Preparation 70: (S)-2,3-Dibromo-5-(3-methoxypyrrolidin-1-yl)-6-methylpyridine

標題所述之化合物係依照與合成(R)-2,3-二溴-5-(3-甲氧基吡咯烷-1-基)-6-甲基吡啶中所述相同的反應方案(製備69)，並使用適當的起始原料來製備。LCMS m/z=349,351,353(1:2:1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of (R)-2,3-dibromo-5-(3-methoxypyrrolidin-1-yl)-6-methylpyridine (Preparation 69) using appropriate starting materials. LCMS m/z=349,351,353 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備71:(S)-2,3-二溴-5-(2-(甲氧基甲基)吡咯烷-1-基)-6-甲基吡啶Preparation 71: (S)-2,3-Dibromo-5-(2-(methoxymethyl)pyrrolidin-1-yl)-6-methylpyridine

標題所述之化合物係依照與合成(R)-2,3-二溴-5-(3-甲氧基吡咯烷-1-基)-6-甲基吡啶中所述相同的反應方案(製備69)，並使用適當的起始原料來製備。LCMS m/z=363,365,367(1:2:1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of (R)-2,3-dibromo-5-(3-methoxypyrrolidin-1-yl)-6-methylpyridine (Preparation 69) using appropriate starting materials. LCMS m/z=363,365,367 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備72:1-(5,6-二溴-2-甲基吡啶-3-基)吡咯烷-3-酮Preparation 72: 1-(5,6-dibromo-2-methylpyridin-3-yl)pyrrolidin-3-one

在0℃下，在含有(R)-1-(5,6-二溴-2-甲基吡啶-3-基)吡咯烷-3-醇(0.2g，0.5952mmol)的二氯甲烷(5ml)攪拌溶液中加入1,1,1-三乙醯氧基-1,1-二氫-1,2-苯並氧酚-3(1H)-酮(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one)(380mg，0.8928mmol)，並在氮氣氣氛下攪拌2小時。將反應混合物以二氯甲烷(20ml)稀釋並以飽和Na₂SO₃水溶液(20ml)和飽和碳酸氫鈉水溶液(20ml)洗滌。分離各層並以鹽水(20ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.21g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至20%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(80mg)，為灰白色固體。LCMS m/z=333,335,337(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (380 mg, 0.8928 mmol) was added to a solution of (R)-1-(5,6-dibromo-2-methylpyridin-3-yl)pyrrolidin-3-ol (0.2 g, 0.5952 mmol) in dichloromethane (5 ml) at 0°C and stirred for 2 hours under nitrogen atmosphere. The reaction mixture was diluted with dichloromethane (20 ml) and washed with saturated_{aqueousNa2SO3} solution (20 ml) and saturated aqueous sodium bicarbonate solution (20 ml). The layers were separated and the organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.21 g of crude compound. The crude residue was purified on a combiflash instrument on a redisep® column with a gradient of 0 to 20% EtOAc in hexane to give the title compound (80 mg) as an off-white solid. LCMS m/z=333,335,337 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備73：2,3-二溴-5-異丙氧基-6-甲基吡啶Preparation 73: 2,3-Dibromo-5-isopropoxy-6-methylpyridine

在室溫下，將含有異丙醇(0.1g，1.66mmol)和叔丁醇鉀(0.205g，1.83mmol)的無水二甲基亞碸(3ml)溶液攪拌1小時。將其加入2,3-二溴-5-氟-6-甲基吡啶(0.981g，3.66mmol)，並將此反應混合物在室溫下攪拌過夜。將反應混合物以乙酸乙酯(50ml)稀釋並以水(20ml)洗滌。將反應混合物以水(50ml)稀釋並以乙酸乙酯(50ml)萃取。分離各層並以鹽水(20ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到1.3g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.1g)，為白色固體。LCMS m/z=308,310,312(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺)。A solution of isopropanol (0.1 g, 1.66 mmol) and potassium tert-butoxide (0.205 g, 1.83 mmol) in anhydrous dimethylsulfoxide (3 ml) was stirred at room temperature for 1 hour. 2,3-Dibromo-5-fluoro-6-methylpyridine (0.981 g, 3.66 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (20 ml). The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The layers were separated and the organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.3 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient chromatography from 0 to % EtOAc in hexane to afford the title compound (0.1 g) as a white solid. LCMS m/z = 308, 310, 312 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ).

製備74：2,3-二溴-5-(環丙基甲氧基)-6-甲基吡啶Preparation 74: 2,3-Dibromo-5-(cyclopropylmethoxy)-6-methylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-異丙氧基-6-甲基吡啶中所述相同的反應方案(製備73)，並使用適當的起始原料來製備。LCMS m/z=320,322,324(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺,100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2,3-dibromo-5-isopropoxy-6-methylpyridine (Preparation 73) using appropriate starting materials. LCMS m/z=320,322,324 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ,100%).

製備75：2,3-二溴-5-環丁氧基-6-甲基吡啶Preparation 75: 2,3-Dibromo-5-cyclobutoxy-6-methylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-異丙氧基-6-甲基吡啶中所述相同的反應方案(製備73)，並使用適當的起始原料來製備。LCMS m/z=320,322,324(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2,3-dibromo-5-isopropoxy-6-methylpyridine (Preparation 73) using appropriate starting materials. LCMS m/z=320,322,324 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備76：2,3-二溴-6-甲基-5-(2,2,2-三氟乙氧基)吡啶Preparation 76: 2,3-Dibromo-6-methyl-5-(2,2,2-trifluoroethoxy)pyridine

標題所述之化合物係依照與合成2,3-二溴-5-異丙氧基-6-甲基吡啶中所述相同的反應方案(製備73)，並使用適當的起始原料來製備。LCMS m/z=348,350,352(1：2：1；[M+H]⁺，[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2,3-dibromo-5-isopropoxy-6-methylpyridine (Preparation 73) using appropriate starting materials. LCMS m/z=348,350,352 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備77：2,3-二溴-6-甲基-5-(1H-吡唑-1-基)吡啶Preparation 77: 2,3-Dibromo-6-methyl-5-(1H-pyrazol-1-yl)pyridine

將含有2,3-二溴-5-氟-6-甲基吡啶(0.6g，2.231mmol)、1H-吡唑(182mg，2.677mmol)和碳酸鉀(461.8mg，3.346mmol)的2mL二甲基亞碸的攪拌溶液置於氮氣氣氛下於120℃加熱2小時。將反應混合物以水(50ml)稀釋並以乙酸乙酯(50ml)萃取。分離各層並以鹽水(20ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至20%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.19g)，為白色固體。LCMS m/z=316,318,320(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。A stirred solution of 2,3-dibromo-5-fluoro-6-methylpyridine (0.6 g, 2.231 mmol), 1H-pyrazole (182 mg, 2.677 mmol) and potassium carbonate (461.8 mg, 3.346 mmol) in 2 mL of dimethylsulfoxide was heated at 120° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The layers were separated and the organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient elution from 0 to 20% EtOAc in hexane to afford the title compound (0.19 g) as a white solid. LCMS m/z = 316, 318, 320 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備78：2,3-二溴-5-(甲氧基甲基)-6-甲基吡啶Preparation 78: 2,3-Dibromo-5-(methoxymethyl)-6-methylpyridine

在0℃下，在含有(5,6-二溴-2-甲基吡啶-3-基)甲醇(270mg，0.96mol)的THF(5ml)攪拌溶液中加入氫化鈉(46.08mg，1.93mol)並攪拌1小時。將其加入甲基碘(0.08ml，1.44mol)並在25℃攪拌16小時。將反應混合物以乙酸乙酯(50ml)稀釋並以水(20ml)洗滌。將反應混合物以乙酸乙酯(20ml)稀釋並以水(20ml)洗滌。分離各層並以鹽水(20ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.3g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至20%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.24g)，為灰白色固體。LCMS m/z=294,296,298(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。To a stirred solution of (5,6-dibromo-2-methylpyridin-3-yl)methanol (270 mg, 0.96 mol) in THF (5 ml) at 0°C was added sodium hydride (46.08 mg, 1.93 mol) and stirred for 1 hour. Methyl iodide (0.08 ml, 1.44 mol) was added and stirred at 25°C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (20 ml). The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml). The layers were separated and the organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.3 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient chromatography from 0 to 20% EtOAc in hexane to afford the title compound (0.24 g) as an off-white solid. LCMS m/z = 294, 296, 298 (1:2:1; [M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備79：2,3-二溴-5-(乙氧基甲基)-6-甲基吡啶Preparation 79: 2,3-Dibromo-5-(ethoxymethyl)-6-methylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-(甲氧基甲基)-6-甲基吡啶中所述相同的反應方案(製備78)，並使用適當的起始原料來製備。LCMS m/z=308,310,312(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described for the synthesis of 2,3-dibromo-5-(methoxymethyl)-6-methylpyridine (Preparation 78) using appropriate starting materials. LCMS m/z=308,310,312 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備80：2,3-二溴-5-(甲氧基甲基)-4,6-二甲基吡啶Preparation 80: 2,3-Dibromo-5-(methoxymethyl)-4,6-dimethylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-(甲氧基甲基)-6-甲基吡啶中所述相同的反應方案(製備78)，並使用適當的起始原料來製備。LCMS m/z=308,310,312(1：2：1；([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described for the synthesis of 2,3-dibromo-5-(methoxymethyl)-6-methylpyridine (Preparation 78) using appropriate starting materials. LCMS m/z=308,310,312 (1:2:1; ([M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備81：2,3-二溴-5-(異丙氧基甲基)-6-甲基吡啶Preparation 81: 2,3-Dibromo-5-(isopropoxymethyl)-6-methylpyridine

在0℃下，在IPA(2ml)中加入氫化鈉(10mg，0.2757mmol)並攪拌10分鐘。將其加入(5,6-二溴-2-甲基吡啶-3-基)甲磺酸甲酯(90mg，0.2506mmol)並在25℃攪拌1小時，然後在50℃攪拌1小時。將反應混合物以乙酸乙酯(20ml)稀釋並以水(20ml)洗滌。分離各層並以鹽水(20ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到70mg粗化合物，為白色固體。Sodium hydride (10 mg, 0.2757 mmol) was added to IPA (2 ml) at 0°C and stirred for 10 minutes. Methyl (5,6-dibromo-2-methylpyridin-3-yl)methanesulfonate (90 mg, 0.2506 mmol) was added and stirred at 25°C for 1 hour and then at 50°C for 1 hour. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml). The layers were separated and the organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 70 mg of crude compound as a white solid.

製備82：2,3-二溴-6-甲基-5-((2,2,2三氟乙氧基)甲基)吡啶Preparation 82: 2,3-Dibromo-6-methyl-5-((2,2,2-trifluoroethoxy)methyl)pyridine

標題所述之化合物係依照與合成2,3-二溴-5-(異丙氧基甲基)-6-甲基吡啶中所述相同的反應方案(製備81)，並使用適當的起始原料以及THF當作溶劑來製備。LCMS m/z=361,363,365(1：2：1；([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of 2,3-dibromo-5-(isopropoxymethyl)-6-methylpyridine (Preparation 81) using appropriate starting materials and THF as solvent. LCMS m/z=361,363,365 (1:2:1; ([M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備83：2,3-二溴-5-(環丁氧基甲基)-6-甲基吡啶Preparation 83: 2,3-Dibromo-5-(cyclobutoxymethyl)-6-methylpyridine

標題所述之化合物係依照與合成2,3-二溴-5-(異丙氧基甲基)-6-甲基吡啶中所述相同的反應方案(製備81)，並使用適當的起始原料以及THF當作溶劑來製備。LCMS m/z=333,335,337(1：2：1；([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of 2,3-dibromo-5-(isopropoxymethyl)-6-methylpyridine (Preparation 81) using appropriate starting materials and THF as solvent. LCMS m/z=333,335,337 (1:2:1; ([M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備84：(S)-2,3-二溴-5-(3-氟吡咯烷-1-基)-6-甲基吡啶Preparation 84: (S)-2,3-Dibromo-5-(3-fluoropyrrolidin-1-yl)-6-methylpyridine

在0℃下，在含有(R)-1-(5,6-二溴-2-甲基吡啶-3-基)吡咯烷-3-醇(200mg，0.5952mmol)的二氯甲烷(3ml)攪拌溶液中添加(二乙氨基)三氟化硫(191.8mg，1.1904mmol)並攪拌2小時。將反應混合物以飽和碳酸氫鈉水溶液(25ml)淬熄並以二氯甲烷(25ml)萃取。分離各層並以鹽水(20ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.12g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至10%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(80mg)，為灰白色固體。LCMS m/z=336,338,340(1：2：1；([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。To a stirred solution of (R)-1-(5,6-dibromo-2-methylpyridin-3-yl)pyrrolidin-3-ol (200 mg, 0.5952 mmol) in dichloromethane (3 ml) at 0°C was added (diethylamino)sulfur trifluoride (191.8 mg, 1.1904 mmol) and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (25 ml) and extracted with dichloromethane (25 ml). The layers were separated and the combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.12 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient chromatography from 0 to 10% ethyl acetate/hexane to afford the title compound (80 mg) as an off-white solid. LCMS m/z = 336, 338, 340 (1:2:1; ([M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備85：(R)-2,3-二溴-5-(3-氟吡咯烷-1-基)-6-甲基吡啶Preparation 85: (R)-2,3-Dibromo-5-(3-fluoropyrrolidin-1-yl)-6-methylpyridine

標題所述之化合物係依照與合成(S)-2,3-二溴-5-(3-氟吡咯烷-1-基)-6-甲基吡啶中所述相同的反應方案(製備84)，並使用適當的起始原料來製備。LCMS m/z=336,338,340(1：2：1；([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of (S)-2,3-dibromo-5-(3-fluoropyrrolidin-1-yl)-6-methylpyridine (Preparation 84) using appropriate starting materials. LCMS m/z=336,338,340 (1:2:1; ([M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備86：2,3-二溴-5-(3,3-二氟吡咯烷-1-基)-6-甲基吡啶Preparation 86: 2,3-Dibromo-5-(3,3-difluoropyrrolidin-1-yl)-6-methylpyridine

標題所述之化合物係依照與合成(S)-2,3-二溴-5-(3-氟吡咯烷-1-基)-6-甲基吡啶中所述相同的反應方案(製備84)，並使用1-(5,6-二溴-2-甲基吡啶-3-基)吡咯烷-3-酮(製備72)作為起始原料來製備。The title compound was prepared according to the same reaction scheme as described in the synthesis of (S)-2,3-dibromo-5-(3-fluoropyrrolidin-1-yl)-6-methylpyridine (Preparation 84) using 1-(5,6-dibromo-2-methylpyridin-3-yl)pyrrolidin-3-one (Preparation 72) as the starting material.

製備87：2,3-二溴-5-((3,3-二氟吡咯烷-1-基)甲基)-6-甲基吡啶Preparation 87: 2,3-Dibromo-5-((3,3-difluoropyrrolidin-1-yl)methyl)-6-methylpyridine

在0℃下，在3,3-二氟吡咯烷鹽酸鹽(367.41mg，2.559mmol)的攪拌溶液中加入碳酸鉀(707.44mg，5.1186mmol)。待10分鐘後，在0℃下加入2,3-二溴-5-(溴甲基)-6-甲基吡啶(800mg，2.3266mmol)並攪拌2小時。將反應混合物以水(50ml)淬熄並以乙酸乙酯(50ml)萃取。分離各層並以鹽水(50ml)洗滌合併的有機層。將有機層經無水硫酸鈉乾燥、過濾及真空濃縮，以得到1.1g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至10%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(600mg)，為灰白色固體。LCMS m/z=368,370,372(1：2：1；([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。Potassium carbonate (707.44 mg, 5.1186 mmol) was added to a stirred solution of 3,3-difluoropyrrolidine hydrochloride (367.41 mg, 2.559 mmol) at 0°C. After 10 minutes, 2,3-dibromo-5-(bromomethyl)-6-methylpyridine (800 mg, 2.3266 mmol) was added at 0°C and stirred for 2 hours. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (50 ml). The layers were separated and the combined organic layer was washed with brine (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 1.1 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient chromatography from 0 to 10% ethyl acetate/hexane to afford the title compound (600 mg) as an off-white solid. LCMS m/z = 368, 370, 372 (1:2:1; ([M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備88：1-(5,6-二溴-2-甲基吡啶-3-基)-N,N-二甲基甲胺Preparation 88: 1-(5,6-dibromo-2-methylpyridin-3-yl)-N,N-dimethylmethanamine

在0℃下，在含有2,3-二溴-5-(溴甲基)-6-甲基吡啶(750mg，2.1812mmol)的THF(10ml)攪拌溶液中加入二甲胺(295mg，6.5437mmol)水溶液，並在25℃下攪拌16小時。將反應混合物以水(50ml)淬熄並以乙酸乙酯(50ml)萃取。分離各層並以鹽水(50ml)洗滌合併的有機層。將有機層經無水硫酸鈉乾燥、過濾及真空濃縮，以得到1.05g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至10%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(640mg)，為灰白色固體。LCMS m/z=306,308,310(1：2：1；([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。To a stirred solution of 2,3-dibromo-5-(bromomethyl)-6-methylpyridine (750 mg, 2.1812 mmol) in THF (10 ml) at 0°C was added an aqueous solution of dimethylamine (295 mg, 6.5437 mmol) and stirred at 25°C for 16 hours. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (50 ml). The layers were separated and the combined organic layer was washed with brine (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.05 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient elution from 0 to 10% EtOAc in hexane to afford the title compound (640 mg) as an off-white solid. LCMS m/z = 306, 308, 310 (1:2:1; ([M+H]⁺ , [(M+H)+2]⁺ , [(M+H)+4]⁺ ; 100%).

製備89：2,3-二溴-6-甲基-5-(吡咯烷-1-基甲基)吡啶Preparation 89: 2,3-Dibromo-6-methyl-5-(pyrrolidin-1-ylmethyl)pyridine

標題所述之化合物係依照與合成1-(5,6-二溴-2-甲基吡啶-3-基)-N,N-二甲基甲胺中所述相同的反應方案(製備88)，並使用適當的起始原料來製備。LCMS m/z=332,334,336(1：2：1；([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 1-(5,6-dibromo-2-methylpyridin-3-yl)-N,N-dimethylmethanamine (Preparation 88) using appropriate starting materials. LCMS m/z=332,334,336 (1:2:1; ([M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備90：2,6-二氯-3,5-二甲氧基苯胺Preparation 90: 2,6-Dichloro-3,5-dimethoxyaniline

標題所述之化合物係依照與Journal of Medicinal Chemistry(2011),54(20),7066-7083所述相同的反應方案來製備。The compound described in the title was prepared according to the same reaction scheme as described in Journal of Medicinal Chemistry (2011), 54(20), 7066-7083.

製備91：2,6-二溴-3,5-二甲氧基苯胺Preparation 91: 2,6-Dibromo-3,5-dimethoxyaniline

標題所述之化合物係依照與Chemosphere(2013),92(3),286-292所述相似的反應方案來製備。The title compound was prepared by a reaction scheme similar to that described in Chemosphere (2013), 92(3), 286-292.

製備92：3,5-二甲氧基-2,6-二甲基苯胺Preparation 92: 3,5-Dimethoxy-2,6-dimethylaniline

在25℃下，在含有2,6-二溴-3,5-二甲氧基苯胺(0.75g，2.412mmol)的二噁烷(10ml)攪拌溶液中加入三甲基硼氧環烷(trimethylboroxine，908mg，7.237mmol)、PdCl₂dppf.CH₂Cl₂(133mg，0.2412mmol)和碳酸銫(2.3g，7.237mmol)。將反應混合物用氮氣脫氣15分鐘。將所得混合物置於微波反應器中於100℃下攪拌1小時。將反應混合物以乙酸乙酯(20ml)稀釋並以水(20ml)洗滌。分離各層並以鹽水(20ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.8g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至30%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.25g)，為灰白色固體。LCMS m/z=182([M+H]⁺,100%)。Trimethylboroxine (908 mg, 7.237 mmol), PdCl₂ dppf.CH₂ Cl₂ (133 mg, 0.2412 mmol) and cesium carbonate (2.3 g, 7.237 mmol) were added to a stirred solution of 2,6-dibromo-3,5-dimethoxyaniline (0.75 g, 2.412 mmol) in dioxane (10 ml) at 25°C. The reaction mixture was degassed with nitrogen for 15 minutes. The resulting mixture was placed in a microwave reactor and stirred at 100°C for 1 hour. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml). The layers were separated and the organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.8 g of crude compound. The crude residue was purified on a combiflash instrument on a redisep® column with a gradient of 0 to 30% EtOAc in hexane to give the title compound (0.25 g) as an off-white solid. LCMS m/z=182 ([M+H]⁺ , 100%).

製備93：3-甲氧基-2,6-二甲基苯胺Preparation 93: 3-Methoxy-2,6-dimethylaniline

標題所述之化合物係依照與US4564640A所述相同的反應方案來製備。The compound described in the title was prepared according to the same reaction scheme as described in US4564640A.

製備94：2,4-二甲基-3-硝基苯酚Preparation 94: 2,4-Dimethyl-3-nitrophenol

標題所述之化合物係依照與EP0887346A2所述相同的反應方案來製備。The compound described in the title is prepared according to the same reaction scheme as described in EP0887346A2.

製備95：1-((4-甲氧基芐基)氧基)-2,4-二甲基-3-硝基苯Preparation 95: 1-((4-methoxybenzyl)oxy)-2,4-dimethyl-3-nitrobenzene

在0℃下，在含有2,4-二甲基-3-硝基苯酚(2.2g，31.173mmol)的DMF(20ml)攪拌溶液中加入碳酸銫(5.8g，19.75mmol)和對-甲氧基氯化芐(2.6g，17.125mmol)，在25℃下。將所得混合物在70℃攪拌16小時。將反應混合物以乙酸乙酯(50ml)稀釋並以水(50ml)洗滌。分離各層並以鹽水(50ml)洗滌合併的有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到2.5g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至20%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(2.1g)，為灰白色固體。LCMS m/z=288[M+H]⁺。To a stirred solution of 2,4-dimethyl-3-nitrophenol (2.2 g, 31.173 mmol) in DMF (20 ml) at 0°C, cesium carbonate (5.8 g, 19.75 mmol) and p-methoxybenzyl chloride (2.6 g, 17.125 mmol) were added at 25°C. The resulting mixture was stirred at 70°C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml). The layers were separated and the combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.5 g of crude compound. The crude residue was purified on a combiflash instrument on a redisep® column with a gradient of 0-20% EtOAc in hexane to afford the title compound (2.1 g) as an off-white solid. LCMS m/z = 288 [M+H]⁺ .

製備96：3-((4-甲氧基芐基)氧基)-2,6-二甲基苯胺Preparation 96: 3-((4-methoxybenzyl)oxy)-2,6-dimethylaniline

在0℃下，在含有1-((4-甲氧基芐基)氧基)-2,4-二甲基-3-硝基苯(1.5g，5.22mmol)的甲醇(20ml)攪拌溶液中加入硼氫化鈉(NaBH₄，794mg，20.9mmol)，然後在10分鐘內分批加入氯化鎳(NiCl₂，123mg,0.523mmol)。將所得混合物在25℃攪拌2小時。將反應混合物以乙酸乙酯(50ml)稀釋並以水(50ml)洗滌。分離各層並以鹽水(50ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到1g標題所述之化合物，為灰白色固體。LCMS m/z=258([M+H]⁺,100%)。Sodium borohydride (NaBH₄ , 794 mg, 20.9 mmol) was added to a stirred solution of 1-((4-methoxybenzyl)oxy)-2,4-dimethyl-3-nitrobenzene (1.5 g, 5.22 mmol) in methanol (20 ml) at 0°C, followed by the addition of nickel chloride (NiCl₂ , 123 mg, 0.523 mmol) in portions over 10 minutes. The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml). The layers were separated and the organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1 g of the title compound as an off-white solid. LCMS m/z=258([M+H]⁺ ,100%).

製備97：3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺Preparation 97: 3-Bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine

在含有2,3-二溴-5,6-二甲基吡啶(400mg，1當量(eqv.))和2,6-二氯-3,5-二甲氧基苯胺(302mg，0.9eqv.)的二甲氧基乙烷(10ml)混合物在密封管中攪拌。在其中加入碳酸銫(1.47g，3eqv.)，並以氮氣脫氣10分鐘。在其中加入Xantphos(131mg，0.15eqv.)和Pd₂dba₃(111mg，0.08eqv.)，並再次以氮氣脫氣10分鐘。將所得混合物在90℃攪拌16小時。將反應混合物以乙酸乙酯(20ml)稀釋並以水(20ml)洗滌。分離各層並以鹽水(20ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.72g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至40%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.4g，65%)，為白色固體。LCMS m/z=405,407,409([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺)。A mixture of 2,3-dibromo-5,6-dimethylpyridine (400 mg, 1 equivalent (eqv.)) and 2,6-dichloro-3,5-dimethoxyaniline (302 mg, 0.9 eqv.) in dimethoxyethane (10 ml) was stirred in a sealed tube. Csium carbonate (1.47 g, 3 eqv.) was added thereto, and the mixture was degassed with nitrogen for 10 minutes. Xantphos (131 mg, 0.15 eqv.) and Pd₂ dba₃ (111 mg, 0.08 eqv.) were added thereto, and the mixture was degassed with nitrogen again for 10 minutes. The resulting mixture was stirred at 90° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml). The layers were separated and the organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.72 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and eluted with a gradient of 0 to 40% EtOAc in hexane to give the title compound (0.4 g, 65%) as a white solid. LCMS m/z=405,407,409 ([M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ).

製備98：3-溴-N-(2,6-二溴-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺Preparation 98: 3-Bromo-N-(2,6-dibromo-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=493,495,497,499([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺,[(M+H)+6]⁺)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=493,495,497,499 ([M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ,[(M+H)+6]⁺ ).

製備99：3-溴-N-(3,5-二甲氧基-2,6-二甲基苯基)-5,6-二甲基吡啶-2-胺Preparation 99: 3-Bromo-N-(3,5-dimethoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=365,367(1：1,[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=365,367 (1:1, [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備例100：3-溴-N-(3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺Preparation Example 100: 3-Bromo-N-(3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=337,339(1：1,[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=337,339 (1:1, [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備101：3-溴-N-(3-甲氧基-2,6-二甲基苯基)-5,6-二甲基吡啶-2-胺Preparation 101: 3-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=335,337(1：1,[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=335,337 (1:1, [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備102：3-溴-5-氟-N-(3-甲氧基-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 102: 3-Bromo-5-fluoro-N-(3-methoxy-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=339,341(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=339,341 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備103：3-溴-5-氯-N-(3-甲氧基-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 103: 3-Bromo-5-chloro-N-(3-methoxy-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=355,357,359([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=355,357,359 ([M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ).

製備104：3-溴-5-環丙基-N-(3-甲氧基-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 104: 3-Bromo-5-cyclopropyl-N-(3-methoxy-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=361,363(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=361,363 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備105：3-溴-NPreparation 105: 3-Bromo-N²²-(3-甲氧基-2,6-二甲基苯基)-N-(3-methoxy-2,6-dimethylphenyl)-N⁵⁵,N,N⁵⁵,6-三甲基吡啶-2,5-二胺,6-Trimethylpyridine-2,5-diamine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=364,366(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=364,366 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備106：3-溴-N-(3-甲氧基-2,6-二甲基苯基)-6-甲基-5-(哌啶-1-基)吡啶-2-胺Preparation 106: 3-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(piperidin-1-yl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=404,406(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=404,406 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備107：3-溴-N-(3-甲氧基-2,6-二甲基苯基)-6-甲基-5-(嗎啉-4-基)吡啶-2-胺Preparation 107: 3-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(morpholin-4-yl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=406,408(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=406,408 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備108：3-溴-N-(3-甲氧基-2,6-二甲基苯基)-6-甲基-5-(吡咯烷-1-基)吡啶-2-胺Preparation 108: 3-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(pyrrolidin-1-yl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=390,392(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=390,392 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備109：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-6-(吡咯烷-1-基)吡啶-2-胺Preparation 109: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-6-(pyrrolidin-1-yl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=496,498(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=496,498 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備110：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-6-(哌啶-1-基)吡啶-2-胺Preparation 110: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-6-(piperidin-1-yl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=509,511(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=509,511 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備111：3-溴-NPreparation 111: 3-Bromo-N²²-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-N⁶⁶,N,N⁶⁶,5-三甲基吡啶-2,6-二胺,5-Trimethylpyridine-2,6-diamine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=470,472(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=470,472 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備112：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-6-(嗎啉-4-基)吡啶-2-胺Preparation 112: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-6-(oxolin-4-yl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=511,513(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=511,513 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備113：3-溴-5-異丙氧基-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 113: 3-Bromo-5-isopropoxy-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=485,487(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=485,487 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備114：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(1H-吡唑-1-基)吡啶-2-胺Preparation 114: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(1H-pyrazol-1-yl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=493,495(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=493,495 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備115：3-溴-5-環丁基-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 115: 3-Bromo-5-cyclobutyl-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=481,483(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=481,483 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備116：3-溴-5-異丙基-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 116: 3-Bromo-5-isopropyl-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=469,471(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=469,471 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備117：3-溴-5-(環丙基甲氧基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 117: 3-Bromo-5-(cyclopropylmethoxy)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=497,499(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=497,499 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備118：3-溴-5-環丁氧基-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 118: 3-Bromo-5-cyclobutoxy-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=497,499(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=497,499 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

備119：3-溴-6-異丙氧基-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基吡啶-2-胺Preparation 119: 3-Bromo-6-isopropoxy-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=485,487(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=485,487 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備120：3-溴-6-(4,4-二氟哌啶-1-基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基吡啶-2-胺Preparation 120: 3-Bromo-6-(4,4-difluoropiperidin-1-yl)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=546,548(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=546,548 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備121：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(4-甲氧基哌啶-1-基)-5-甲基吡啶-2-胺Preparation 121: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(4-methoxypiperidin-1-yl)-5-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=540,542(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=540,542 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備122：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-6-(6-氮雜螺[2.5]辛-6-基)吡啶-2-胺Preparation 122: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-6-(6-azaspiro[2.5]octan-6-yl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=536,538(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=536,538 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備123：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(甲氧基甲基)-6-甲基吡啶-2-胺Preparation 123: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(methoxymethyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=471,473(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=471,473 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備124：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(1-甲氧基乙基)-6-甲基吡啶-2-胺Preparation 124: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(1-methoxyethyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=485,487(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。此外消旋化合物經由掌性製備型HPLC純化，以得到如以下所示的兩種對映異構體。The title compound was prepared according to the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) and using appropriate starting materials. LCMS m/z = 485,487 (1:1; [M+H]⁺ , [(M+H)+2]⁺ ; 100%). The racemic compound was purified by chiral preparative HPLC to give two enantiomers as shown below.

製備125：3-溴-5-(1-乙氧基乙基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 125: 3-Bromo-5-(1-ethoxyethyl)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=499,501(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。此外消旋化合物經由掌性製備型HPLC純化，以得到如以下所示的兩種對映異構體。The title compound was prepared according to the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) and using appropriate starting materials. LCMS m/z = 499,501 (1:1; [M+H]⁺ , [(M+H)+2]⁺ ; 100%). The racemic compound was purified by chiral preparative HPLC to give two enantiomers as shown below.

製備126：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(1-丙氧基乙基)吡啶-2-胺Preparation 126: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(1-propoxyethyl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=512,514(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。此外消旋化合物經由掌性製備型HPLC純化，以得到如以下所示的兩種對映異構體。The title compound was prepared according to the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) and using appropriate starting materials. LCMS m/z = 512,514 (1:1; [M+H]⁺ , [(M+H)+2]⁺ ; 100%). The racemic compound was purified by chiral preparative HPLC to give two enantiomers as shown below.

製備127：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(2-甲氧基丙-2-基)-6-甲基吡啶-2-胺Preparation 127: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(2-methoxypropan-2-yl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=499,501(1：1；[M+H]⁺,[(M+H)+2]⁺；50%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=499,501 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 50%).

製備128：(S)-3-溴-5-(3-氟吡咯烷-1-基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 128: (S)-3-Bromo-5-(3-fluoropyrrolidin-1-yl)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=514,516(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=514,516 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備129：(R)-3-溴-5-(3-氟吡咯烷-1-基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 129: (R)-3-Bromo-5-(3-fluoropyrrolidin-1-yl)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=514,516(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=514,516 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備130：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(2,2,2-三氟乙氧基)吡啶-2-胺Preparation 130: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=525,527(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=525,527 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備131：5-溴-6-((3-甲氧基-2,6-二甲基苯基)氨基)-2,4-二甲基煙腈Preparation 131: 5-Bromo-6-((3-methoxy-2,6-dimethylphenyl)amino)-2,4-dimethylnitrilonitrile

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=360,362(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=360,362 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備132：3-溴-N-(3-甲氧基-2,6-二甲基苯基)-4,5,6-三甲基吡啶-2-胺Preparation 132: 3-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-4,5,6-trimethylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=349,351(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=349,351 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備133：(R)-1-(5-溴-6-((3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)氨基)-2-甲基吡啶-3-基)吡咯烷-3-醇Preparation 133: (R)-1-(5-bromo-6-((3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)amino)-2-methylpyridin-3-yl)pyrrolidin-3-ol

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=512,514(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=512,514 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備134：(R)-3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(3-甲氧基吡咯烷-1-基)-6-甲基吡啶-2-胺Preparation 134: (R)-3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(3-methoxypyrrolidin-1-yl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=526,528(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=526,528 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備135：(S)-3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(3-甲氧基吡咯烷-1-基)-6-甲基吡啶-2-胺Preparation 135: (S)-3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(3-methoxypyrrolidin-1-yl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=526,528(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=526,528 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備136：(S)-3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(2-(甲氧基甲基)吡咯烷-1-基)-6-甲基吡啶-2-胺Preparation 136: (S)-3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(2-(methoxymethyl)pyrrolidin-1-yl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=540,542(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=540,542 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備137：3-溴-5-(3,3-二氟吡咯烷-1-基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 137: 3-Bromo-5-(3,3-difluoropyrrolidin-1-yl)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=532,534(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=532,534 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備138：3-溴-5-((3,3-二氟吡咯烷-1-基)甲基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 138: 3-Bromo-5-((3,3-difluoropyrrolidin-1-yl)methyl)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=546,548(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=546,548 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備139：3-溴-5-((二甲氨基)甲基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 139: 3-Bromo-5-((dimethylamino)methyl)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=484,486(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=484,486 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備140：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(吡咯烷-1-基甲基)吡啶-2-胺Preparation 140: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(pyrrolidin-1-ylmethyl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=510,512(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=510,512 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備141：3-溴-5-(乙氧基甲基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 141: 3-Bromo-5-(ethoxymethyl)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=485,487(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=485,487 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備142：3-溴-5-(異丙氧基甲基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 142: 3-Bromo-5-(isopropoxymethyl)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=499,501(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=499,501 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備143：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(甲氧基甲基)-4,6-二甲基吡啶-2-胺Preparation 143: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(methoxymethyl)-4,6-dimethylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=485,487(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=485,487 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備144：3-溴-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-((2,2,2-三氟乙氧基)甲基)吡啶-2-胺Preparation 144: 3-Bromo-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-((2,2,2-trifluoroethoxy)methyl)pyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=539,541(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=539,541 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備145：3-溴-5-(環丁氧基甲基)-N-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基吡啶-2-胺Preparation 145: 3-Bromo-5-(cyclobutoxymethyl)-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methylpyridin-2-amine

標題所述之化合物係依照與合成3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺中所述相同的反應方案(製備97)，並使用適當的起始原料來製備。LCMS m/z=511,513(1：1；[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (Preparation 97) using appropriate starting materials. LCMS m/z=511,513 (1:1; [M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備146：2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 146: 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

在密封管中，將含有丙二腈(0.13g，1.9696mmol)和叔丁醇鈉(0.189g，1.9687mmol)的二甲氧基乙烷混合物以氮氣吹掃脫氣30分鐘。將其中加入3-溴-N-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基吡啶-2-胺(0.2g，0.4925mmol)，並將所得混合物以氮氣吹掃脫氣10分鐘。加入PdCl₂dppf.CH₂Cl₂(40mg，0.049mmol)並再次以氮氣將混合物脫氣10分鐘。將所得混合物在100℃下攪拌16小時。將所得混合物冷卻至25℃並真空濃縮，得到0.75g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至50%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(0.25g)，為灰白色固體。LCMS m/z=391,393([M+H]⁺,[(M+H)+2]⁺；100%)。In a sealed tube, a mixture of malononitrile (0.13 g, 1.9696 mmol) and sodium tert-butoxide (0.189 g, 1.9687 mmol) in dimethoxyethane was degassed with nitrogen for 30 minutes. 3-Bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine (0.2 g, 0.4925 mmol) was added thereto and the resulting mixture was degassed with nitrogen for 10 minutes. PdCl₂ dppf.CH₂ Cl₂ (40 mg, 0.049 mmol) was added and the mixture was degassed with nitrogen again for 10 minutes. The resulting mixture was stirred at 100° C. for 16 hours. The resulting mixture was cooled to 25° C. and concentrated in vacuo to give 0.75 g of the crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and a gradient of 0-50% EtOAc in hexane to afford the title compound (0.25 g) as an off-white solid. LCMS m/z=391,393 ([M+H]⁺ ,[(M+H)+2]⁺ ; 100%).

製備147：2-氨基-1-(2,6-二溴-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 147: 2-amino-1-(2,6-dibromo-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=478,480,482(1：2：1；[M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=478,480,482 (1:2:1; [M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備148：2-氨基-1-(3,5-二甲氧基-2,6-二甲基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 148: 2-amino-1-(3,5-dimethoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=351([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=351 ([M+H]⁺ ; 100%).

製備149：2-氨基-1-(3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 149: 2-amino-1-(3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=323([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=323 ([M+H]⁺ ; 100%).

製備150：2-氨基-1-(3-甲氧基-2,6-二甲基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 150: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=321([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=321 ([M+H]⁺ ; 100%).

製備151：2-氨基-5-氟-1-(3-甲氧基-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 151: 2-amino-5-fluoro-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=325([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=325 ([M+H]⁺ ; 100%).

製備152：2-氨基-5-氯-1-(3-甲氧基-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 152: 2-Amino-5-chloro-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=341,343(1：3,[M+H]⁺,[(M+H)+2]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=341,343 (1:3, [M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備153：2-氨基-5-環丙基-1-(3-甲氧基-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 153: 2-amino-5-cyclopropyl-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=347([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=347 ([M+H]⁺ ; 100%).

製備154：2-氨基-5-(二甲氨基)-1-(3-甲氧基-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 154: 2-amino-5-(dimethylamino)-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=350([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=350 ([M+H]⁺ ; 100%).

製備155：2-氨基-1-(3-甲氧基-2,6-二甲基苯基)-6-甲基-5-(哌啶-1-基)-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 155: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=390([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=390 ([M+H]⁺ ; 100%).

製備156：2-氨基-1-(3-甲氧基-2,6-二甲基苯基)-6-甲基-5-(嗎啉-4-基)-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 156: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(oxolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=392([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=392 ([M+H]⁺ ; 100%).

製備157：2-氨基-1-(3-甲氧基-2,6-二甲基苯基)-6-甲基-5-(吡咯烷-1-基)-1H-吡咯並[2,3-b]吡啶-3-腈Preparation 157: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=376([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=376 ([M+H]⁺ ; 100%).

製備158：2-氨基-1-(3-甲氧基-2,6-二甲基苯基)-4,6-二甲基-1H-吡咯并[2,3-b]吡啶-3,5-二甲腈Preparation 158: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3,5-dicarbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=346([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=346 ([M+H]⁺ ; 100%).

製備159：2-氨基-1-(3-甲氧基-2,6-二甲基苯基)-4,5,6-三甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 159: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-4,5,6-trimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=335([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=335 ([M+H]⁺ ; 100%).

製備160：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-6-(吡咯烷-1-基)-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 160: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-6-(pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=482([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=482 ([M+H]⁺ ; 100%).

製備161：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-6-(哌啶-1-基)-1H-吡咯並[2,3-b]吡啶-3-腈Preparation 161: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-6-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=496([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 496 ([M+H]⁺ ; 100%).

製備162：2-氨基-6-(二甲氨基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 162: 2-amino-6-(dimethylamino)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=456([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=456 ([M+H]⁺ ; 100%).

製備163：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-6-(嗎啉-4-基)-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 163: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-6-(oxolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=498([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=498 ([M+H]⁺ ; 100%).

製備164：2-氨基-5-異丙氧基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 164: 2-amino-5-isopropoxy-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=471([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 471 ([M+H]⁺ ; 100%).

製備165：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(1H-吡唑-1-基)-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 165: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=479([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=479 ([M+H]⁺ ; 100%).

製備166：2-氨基-5-環丁基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 166: 2-amino-5-cyclobutyl-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=467([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=467 ([M+H]⁺ ; 100%).

製備167：2-氨基-5-異丙基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 167: 2-amino-5-isopropyl-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=455([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=455 ([M+H]⁺ ; 100%).

製備168：2-氨基-5-(環丙基甲氧基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 168: 2-amino-5-(cyclopropylmethoxy)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=483([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=483 ([M+H]⁺ ; 100%).

製備169：2-氨基-5-環丁氧基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 169: 2-amino-5-cyclobutoxy-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=483([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=483 ([M+H]⁺ ; 100%).

製備170：2-氨基-6-異丙氧基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 170: 2-amino-6-isopropoxy-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=471([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 471 ([M+H]⁺ ; 100%).

製備171：2-氨基-6-(4,4-二氟哌啶-1-基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 171: 2-amino-6-(4,4-difluoropiperidin-1-yl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=532([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=532 ([M+H]⁺ ; 100%).

製備172：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(4-甲氧基哌啶-1-基)-5-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 172: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(4-methoxypiperidin-1-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=526[M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=526[M+H]⁺ ; 100%).

製備173：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-6-(6-氮雜螺[2.5]辛-6-基)-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 173: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-6-(6-azaspiro[2.5]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=522([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=522 ([M+H]⁺ ; 100%).

製備174：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(甲氧基甲基)-6-甲基-1H-吡咯並[2,3-b]吡啶-3-腈Preparation 174: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(methoxymethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=457([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=457 ([M+H]⁺ ; 100%).

製備175：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(1-甲氧基乙基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-I)Preparation 175: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(1-methoxyethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-I)

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=471([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 471 ([M+H]⁺ ; 100%).

製備176：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(1-甲氧基乙基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-II)Preparation 176: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(1-methoxyethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-II)

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=471([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 471 ([M+H]⁺ ; 100%).

製備177：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(2-甲氧基丙-2-基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 177: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(2-methoxypropan-2-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=485([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 485 ([M+H]⁺ ; 100%).

製備178：2-氨基-5-(1-乙氧基乙基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-I)Preparation 178: 2-amino-5-(1-ethoxyethyl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-I)

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=485([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 485 ([M+H]⁺ ; 100%).

製備179：2-氨基-5-(1-乙氧基乙基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-II)Preparation 179: 2-amino-5-(1-ethoxyethyl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-II)

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=485([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 485 ([M+H]⁺ ; 100%).

製備180：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(1-丙氧基乙基)-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-I)Preparation 180: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(1-propoxyethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-I)

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=499([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=499 ([M+H]⁺ ; 100%).

製備181：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(1-丙氧基乙基)-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-II)Preparation 181: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(1-propoxyethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (isomer-II)

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=499([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=499 ([M+H]⁺ ; 100%).

製備182：(S)-2-氨基-5-(3-氟吡咯烷-1-基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 182: (S)-2-amino-5-(3-fluoropyrrolidin-1-yl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=500([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 500 ([M+H]⁺ ; 100%).

製備183：(R)-2-氨基-5-(3-氟吡咯烷-1-基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 183: (R)-2-amino-5-(3-fluoropyrrolidin-1-yl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=500([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 500 ([M+H]⁺ ; 100%).

製備184：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(2,2,2-三氟乙氧基)-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 184: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(2,2,2-trifluoroethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=511([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 511 ([M+H]⁺ ; 100%).

製備185：(R)-2-氨基-5-(3-羥基吡咯烷-1-基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 185: (R)-2-amino-5-(3-hydroxypyrrolidin-1-yl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=498([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=498 ([M+H]⁺ ; 100%).

製備186：(R)-2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(3-甲氧基吡咯烷-1-基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 186: (R)-2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(3-methoxypyrrolidin-1-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=512([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=512 ([M+H]⁺ ; 100%).

製備187：(S)-2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(3-甲氧基吡咯烷-1-基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 187: (S)-2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(3-methoxypyrrolidin-1-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=LCMS m/z=512([M+H]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=LCMS m/z=512 ([M+H]⁺ ; 100%).

製備188：(S)-2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(2-(甲氧基甲基)吡咯烷-1-基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 188: (S)-2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(2-(methoxymethyl)pyrrolidin-1-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=526([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=526 ([M+H]⁺ ; 100%).

製備189：2-氨基-5-(3,3-二氟吡咯烷-1-基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯並[2,3-b]吡啶-3-腈Preparation 189: 2-amino-5-(3,3-difluoropyrrolidin-1-yl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=518([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=518 ([M+H]⁺ ; 100%).

製備190：2-氨基-5-((3,3-二氟吡咯烷-1-基)甲基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 190: 2-amino-5-((3,3-difluoropyrrolidin-1-yl)methyl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=532([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=532 ([M+H]⁺ ; 100%).

製備191：2-氨基-5-((二甲氨基)甲基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 191: 2-amino-5-((dimethylamino)methyl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=470([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=470 ([M+H]⁺ ; 100%).

製備192：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(吡咯烷-1-基甲基)-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 192: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=496([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 496 ([M+H]⁺ ; 100%).

製備193：2-氨基-5-(乙氧基甲基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯並[2,3-b]吡啶-3-腈Preparation 193: 2-amino-5-(ethoxymethyl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=471([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 471 ([M+H]⁺ ; 100%).

製備194：2-氨基-5-(異丙氧基甲基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 194: 2-amino-5-(isopropoxymethyl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=485([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 485 ([M+H]⁺ ; 100%).

製備195：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(甲氧基甲基)-4,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 195: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(methoxymethyl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=471([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z = 471 ([M+H]⁺ ; 100%).

製備196：2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-((2,2,2-三氟乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-腈Preparation 196: 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-((2,2,2-trifluoroethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=525([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=525 ([M+H]⁺ ; 100%).

製備197：2-氨基-5-(環丁氧基甲基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯並[2,3-b]吡啶-3-腈Preparation 197: 2-amino-5-(cyclobutoxymethyl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈中所述相同的反應方案(製備146)，並使用適當的起始原料來製備。LCMS m/z=497([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Preparation 146) using appropriate starting materials. LCMS m/z=497 ([M+H]⁺ ; 100%).

製備198：2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-甲醯胺Preparation 198: 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

在室溫下，將含有2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈(200mg)的硫酸溶液(1mL)攪拌1小時。然後將混合物緩慢倒入冷水(10ml)中，同時劇烈攪拌，接著透過添加濃氫氧化銨水溶液使其呈現弱鹼性。將反應混合物乙酸乙酯(20ml)萃取並用水(10ml×2)洗滌。分離各層並以鹽水(20ml)洗滌合併的有機層。將有機層經無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.21g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至5%的甲醇/二氯甲烷(MeOH in dichloromethane)的梯度流析，以得到標題所述之化合物(0.11g)，為灰白色固體。LCMS m/z=409,411([M+H]⁺,[(M+H)+2]⁺；100%)。A sulfuric acid solution (1 mL) containing 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (200 mg) was stirred at room temperature for 1 hour. The mixture was then slowly poured into cold water (10 ml) while stirring vigorously, and then made weakly alkaline by adding concentrated aqueous ammonium hydroxide solution. The reaction mixture was extracted with ethyl acetate (20 ml) and washed with water (10 ml×2). The layers were separated and the combined organic layer was washed with brine (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 0.21 g of crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and a gradient of 0 to 5% MeOH in dichloromethane to afford the title compound (0.11 g) as an off-white solid. LCMS m/z = 409, 411 ([M+H]⁺ , [(M+H)+2]⁺ ; 100%).

製備199：2-氨基-1-(2,6-二溴-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-甲醯胺Preparation 199: 2-amino-1-(2,6-dibromo-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-甲醯胺中所述相同的反應方案(製備198)，並使用適當的起始原料來製備。LCMS m/z=497,499,501([M+H]⁺,[(M+H)+2]⁺,[(M+H)+4]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (Preparation 198) using appropriate starting materials. LCMS m/z=497,499,501 ([M+H]⁺ ,[(M+H)+2]⁺ ,[(M+H)+4]⁺ ; 100%).

製備200：2-氨基-1-(3，5-二甲氧基-2，6-二甲基苯基)-5，6-二甲基-1H-吡咯並[2，3-b]吡啶-3-甲醯胺Preparation 200: 2-amino-1-(3,5-dimethoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-甲醯胺中所述相同的反應方案(製備198)，並使用適當的起始原料來製備。LCMS m/z=369([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (Preparation 198) using appropriate starting materials. LCMS m/z=369 ([M+H]⁺ ; 100%).

製備201：2-氨基-1-(3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-甲醯胺Preparation 201: 2-amino-1-(3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

標題所述之化合物係依照與合成2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-甲醯胺中所述相同的反應方案(製備198)，並使用適當的起始原料來製備。LCMS m/z=341([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (Preparation 198) using appropriate starting materials. LCMS m/z=341 ([M+H]⁺ ; 100%).

製備202：9-(3-甲氧基-2,6-二甲基苯基)-6,7-二甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺Preparation 202: 9-(3-methoxy-2,6-dimethylphenyl)-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

在200℃下，將含有2-氨基-1-(3-甲氧基-2,6-二甲基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈(100mg)的甲醯胺(1mL)攪拌3小時。將混合物冷卻至室溫，接著將其緩慢倒入冷水(10ml)中並劇烈攪拌。將沈澱的固體在布氏漏斗上過濾，然後與甲苯共沸乾燥，以得到固體狀標題所述之化合物(0.15g)，並將其原樣用於下一步驟。LCMS m/z=348([M+H]⁺；100%)。2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (100 mg) in formamide (1 mL) was stirred at 200°C for 3 hours. The mixture was cooled to room temperature and then slowly poured into cold water (10 ml) and stirred vigorously. The precipitated solid was filtered on a Buchner funnel and then azeotropically dried with toluene to give the title compound (0.15 g) as a solid, which was used as is in the next step. LCMS m/z=348 ([M+H]⁺ ; 100%).

表2中，製備的化合物係依照上述用於製備9-(3-甲氧基-2,6-二甲基苯基)-6,7-二甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺的類似反應方案(製備202)，並使用適當的起始原料來合成。In Table 2, the prepared compounds were synthesized according to a similar reaction scheme as described above for the preparation of 9-(3-methoxy-2,6-dimethylphenyl)-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 202) using appropriate starting materials.

表2：使用類似製備202的反應方案進行製備Table 2: Preparation using a similar reaction scheme to that used for Preparation 202

製備212：9-(3-甲氧基-2,6-二甲基苯基)-6,7-二甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-2,4-二胺Preparation 212: 9-(3-methoxy-2,6-dimethylphenyl)-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidine-2,4-diamine

在室溫下，在含有2-氨基-1-(3-甲氧基-2,6-二甲基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-腈(50mg，0.1562mmol)的二甲基乙醯胺(1.5mL)的攪拌溶液中加入碳酸胍(84.37，0.4687mmol)，並在150℃攪拌16小時。將反應混合物以乙酸乙酯(10ml)稀釋並以水(10ml×2)洗滌。分離各層並以鹽水(20ml)洗滌有機層，將有機層以無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.12g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至5%的甲醇/二氯甲烷(MeOH in dichloromethane)的梯度流析，以得到標題所述之化合物(40mg)，為灰白色固體。LCMS m/z=363([M+H]⁺；100%)。Guanidine carbonate (84.37, 0.4687 mmol) was added to a stirred solution of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (50 mg, 0.1562 mmol) in dimethylacetamide (1.5 mL) at room temperature and stirred at 150° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml×2). The layers were separated and the organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain 0.12 g of a crude compound. The crude residue was purified on a redisep® column using a combiflash instrument with a gradient of 0 to 5% MeOH in dichloromethane to afford the title compound (40 mg) as an off-white solid. LCMS m/z = 363 ([M+H]⁺ ; 100%).

製備213：9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II)Preparation 213: 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II)

將含有2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(1-甲氧基乙基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-II)(850mg)的原甲酸三乙酯(15mL)的攪拌溶液加熱至150℃持續24小時。將反應混合物真空濃縮並將殘留物溶解在甲醇(10ml)中。在0℃下，加入含有7N NH₃的甲醇溶液(4ml)，並將所得混合物在25℃下攪拌1小時。將反應混合物真空濃縮，將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至50%的乙酸乙酯/己烷(EtOAc in hexane)的梯度洗脫，以得到標題化合物(500mg)，為灰白色固體。LCMS：m/z=498([M+H]⁺；100%)。A stirred solution of 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(1-methoxyethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-II) (850 mg) in triethyl orthoformate (15 mL) was heated to 150 °C for 24 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in methanol (10 ml). A methanol solution (4 ml) containing 7N NH₃ was added at 0 °C and the resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo and the crude residue was purified on a redisep® column using a combiflash instrument eluting with a gradient of 0 to 50% EtOAc in hexane to afford the title compound (500 mg) as an off-white solid. LCMS: m/z = 498 ([M+H]⁺ ; 100%).

製備214：9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-I)Preparation 214: 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-I)

標題所述之化合物係依照與合成9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II)中所述相同的反應方案(製備213)，並使用2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-(1-甲氧基乙基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-I)作為起始原料來製備。LCMS m/z=498([M+H]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II) (Preparation 213) and using 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-(1-methoxyethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-I) as the starting material. LCMS m/z=498 ([M+H]⁺ ; 100%).

製備215：9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(2-甲氧基丙-2-基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺Preparation 215: 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(2-methoxyprop-2-yl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

標題所述之化合物係依照與合成9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II)中所述相同的反應方案(製備213)，並使用適當的起始原料來製備。LCMS m/z=512([M+H]⁺；100%)。The title compound was prepared by the same reaction scheme as described in the synthesis of 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II) (Preparation 213) using appropriate starting materials. LCMS m/z=512 ([M+H]⁺ ; 100%).

製備216：6-(1-乙氧基乙基)-9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-I)Preparation 216: 6-(1-ethoxyethyl)-9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-I)

標題所述之化合物係依照與合成9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II)中所述相同的反應方案(製備213)，並使用2-氨基-5-(1-乙氧基乙基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-I)作為起始原料來製備。The title compound was prepared according to the same reaction scheme as described in the synthesis of 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II) (Preparation 213) and using 2-amino-5-(1-ethoxyethyl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-I) as the starting material.

製備217：6-(1-乙氧基乙基)-9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II)Preparation 217: 6-(1-ethoxyethyl)-9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II)

標題所述之化合物係依照與合成9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II)中所述相同的反應方案(製備213)，並使用2-氨基-5-(1-乙氧基乙基)-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-II)作為起始原料來製備。The title compound was prepared according to the same reaction scheme as described in the synthesis of 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II) (Preparation 213) and using 2-amino-5-(1-ethoxyethyl)-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-II) as the starting material.

製備218：9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-7-甲基-6-(1-丙氧基乙基)-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-I)Preparation 218: 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-7-methyl-6-(1-propoxyethyl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-I)

標題所述之化合物係依照與合成9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II)中所述相同的反應方案(製備213)，並使用2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(1-丙氧基乙基)-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-I)作為起始原料來製備。LCMS m/z=526([M+H]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II) (Preparation 213) and using 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(1-propoxyethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-I) as the starting material. LCMS m/z=526 ([M+H]⁺ ; 100%).

製備219：9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-7-甲基-6-(1-丙氧基乙基)-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II)Preparation 219: 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-7-methyl-6-(1-propoxyethyl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II)

標題所述之化合物係依照與合成9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II)中所述相同的反應方案(製備213)，並使用2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-甲基-5-(1-丙氧基乙基)-1H-吡咯并[2,3-b]吡啶-3-腈(異構體-II)作為起始原料來製備。LCMS m/z=526([M+H]⁺；100%)。The title compound was prepared according to the same reaction scheme as described in the synthesis of 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II) (Preparation 213) and using 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-methyl-5-(1-propoxyethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (Isomer-II) as the starting material. LCMS m/z=526([M+H]⁺ ; 100%).

以下實施例提供了合成如前述表1所提供的式(I)化合物的方法。The following examples provide methods for synthesizing the compounds of formula (I) provided in Table 1 above.

實施例1：2-氨基-1-(2,6-二氯-3,5-二羥基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-甲醯胺Example 1: 2-amino-1-(2,6-dichloro-3,5-dihydroxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

在0℃下，在含有製備198(Preparation 198)所製備的2-氨基-1-(2,6-二氯-3,5-二甲氧基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-甲醯胺(160mg 0.39mmol)的二氯甲烷(3mL)的攪拌溶液中加入含有1M BBr₃的二氯甲烷(3.9ml,3.90mmol)，並於室溫下攪拌16小時。接著在劇烈攪拌下，以甲醇(5ml)緩慢淬熄混合物，然後真空濃縮，以得到0.156g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至7%的甲醇/二氯甲烷(MeOH in dichloromethane)的梯度流析，以得到標題所述之化合物(0.023g)，為灰白色固體。¹H NMR(400MHz,DMSO-d₆)10.57(s,2H),7.79(s,1H),6.99(s,2H),6.87(s,1H),6.63(s,2H),2.25(s,3H),2.24(s,3H)；LCMS m/z=381,383([M+H]⁺,[(M+H)+2]⁺；100%)。To a stirred solution of 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (160 mg 0.39 mmol) prepared in dichloromethane (3 mL) was added 1M BBr₃ in dichloromethane (3.9 ml, 3.90 mmol) at 0°C and stirred at room temperature for 16 hours. The mixture was then slowly quenched with methanol (5 ml) under vigorous stirring and then concentrated in vacuo to give 0.156 g of the crude compound. The crude residue was purified on a redisep® column using a combiflash instrument and gradient chromatography with 0 to 7% methanol/dichloromethane to afford the title compound (0.023 g) as an off-white solid.¹ H NMR (400 MHz, DMSO-d₆ ) 10.57 (s, 2H), 7.79 (s, 1H), 6.99 (s, 2H), 6.87 (s, 1H), 6.63 (s, 2H), 2.25 (s, 3H), 2.24 (s, 3H); LCMS m/z=381, 383 ([M+H]⁺ , [(M+H)+2]⁺ ; 100%).

表3中實施例的化合物依照與製備2-氨基-1-(2,6-二氯-3,5-二羥基苯基)-5,6-二甲基-1H-吡咯并[2,3-b]吡啶-3-甲醯胺(實施例1)中所述類似的反應方案，並使用適當的起始材料來合成。The compounds of the examples in Table 3 were synthesized according to a reaction scheme similar to that described in the preparation of 2-amino-1-(2,6-dichloro-3,5-dihydroxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (Example 1) using appropriate starting materials.

表3：使用類似實施例1的反應方案的實施例Table 3: Examples using a reaction scheme similar to Example 1

實施例16：3-(4-氨基-6-甲基-7-(吡咯烷-1-基)-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚Example 16: 3-(4-amino-6-methyl-7-(pyrrolidin-1-yl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

將含有2-氨基-1-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-5-甲基-6-(吡咯烷-1-基)-1H-吡咯并[2,3-b]吡啶-3-腈(160mg，1.811mmol)的甲醯胺(2mL)溶液混合物在200℃下加熱3小時。將反應混合物冷卻至室溫，並在劇烈攪拌下向其中緩慢加入冰水。透過在真空下在布氏漏斗上過濾來收集沉澱的固體。將殘留物溶解於含有10%甲醇的二氯甲烷中，並透過combiflash儀器在redisep®管柱上純化，並以含有5%甲醇的二氯甲烷溶液等梯度流析，以得到0.45g固體，並進一步以製備型HPLC純化，以得到標題所述化合物(0.010g)，為灰白色固體。¹H NMR(DMSO-d₆)9.35(s,1H),8.38(s,1H),8.08(s,1H),7.06(bs,2H),7.00(d,J=8.4Hz,1H),6.86(d,J=8.4Hz,1H),3.35(m,4H),2.43(s,3H),1.80(m,4H),1.69(s,3H),1.59(s,3H)；LCMS m/z=389[M+H]⁺。A mixture of a solution of 2-amino-1-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-5-methyl-6-(pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (160 mg, 1.811 mmol) in formamide (2 mL) was heated at 200° C. for 3 hours. The reaction mixture was cooled to room temperature, and ice water was slowly added thereto with vigorous stirring. The precipitated solid was collected by filtration on a Buchner funnel under vacuum. The residue was dissolved in dichloromethane containing 10% methanol and purified on a redisep® column using a combiflash instrument and isocratic chromatography with 5% methanol in dichloromethane to give 0.45 g of a solid, which was further purified by preparative HPLC to give the title compound (0.010 g) as an off-white solid.¹ H NMR (DMSO-d₆ )9.35(s,1H),8.38(s,1H),8.08(s,1H),7.06(bs,2H),7.00(d,J=8.4Hz,1H),6.86(d ,J=8.4Hz,1H),3.35(m,4H),2.43(s,3H),1.80(m,4H),1.69(s,3H),1.59(s,3H); LCMS m/z=389[M+H]⁺ .

表4中實施例的化合物依與製備3-(4-氨基-6-甲基-7-(吡咯烷-1-基)-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚所述的類似反應方案，並使用適當的起始原料和反應時間(3小時至12小時)來合成。The compounds of the examples in Table 4 were synthesized according to a similar reaction scheme as described for the preparation of 3-(4-amino-6-methyl-7-(pyrrolidin-1-yl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol using appropriate starting materials and reaction times (3 to 12 hours).

表4：使用類似實施例16的反應方案的實施例Table 4: Examples using a reaction scheme similar to Example 16

實施例49：3-(4-氨基-6-乙基-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚Example 49: 3-(4-amino-6-ethyl-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

在25℃下，在含有3-(4-氨基-7-甲基-6-乙烯基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚(30mg)的甲醇(2ml)的攪拌溶液中加入5%鈀/碳(Pd/C，20mg)，並用氣球在氫氣氛下攪拌16小時。將反應混合物在真空下以矽藻土床過濾。將濾液真空濃縮，以得到32mg粗化合物。將此粗殘留物以反相製備型HPLC純化，以得到標題所述之化合物(3mg)，為灰白色固體。¹H NMR(DMSO-d₆)9.51(s,1H),8.58(s,1H),8.19(s,1H),7.39(bs,2H),7.04(d,J=8.0Hz,1H),6.91(d,J=8.0Hz,1H),2.75(q,J=7.6Hz,2H),2.49(s,3H),1.65(s,3H),1.55(s,3H),1.29(t,J=7.6Hz,3H)；LCMS m/z=348[M+H]⁺。To a stirred solution of 3-(4-amino-7-methyl-6-vinyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (30 mg) in methanol (2 ml) was added 5% palladium/carbon (Pd/C, 20 mg) at 25°C and stirred for 16 hours under hydrogen atmosphere with a balloon. The reaction mixture was filtered through a diatomaceous earth bed under vacuum. The filtrate was concentrated under vacuum to give 32 mg of crude compound. The crude residue was purified by reverse phase preparative HPLC to give the title compound (3 mg) as an off-white solid.¹ H NMR (DMSO-d₆ )9.51(s,1H),8.58(s,1H),8.19(s,1H),7.39(bs,2H),7.04(d,J=8.0Hz,1H),6.91(d,J=8.0Hz ,1H),2.75(q,J=7.6Hz,2H),2.49(s,3H),1.65(s,3H),1.55(s,3H),1.29(t,J=7.6Hz,3H); LCMS m/z=348[M+H]⁺ .

實施例50：3-(4-氨基-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚(異構體-II)Example 50: 3-(4-amino-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Isomer-II)

在0℃下，在含有9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II，500mg)的甲醇(10mL)的攪拌溶液中加入含有4M鹽酸的二噁烷(2ml)。將所得混合物在25℃下攪拌16小時。在0℃下，將反應混合物以飽和碳酸氫鈉水溶液(50ml)鹼化，並以乙酸乙酯(25ml x 2)萃取。分離各層並以鹽水(50ml)洗滌合併的有機層。將有機層經無水硫酸鈉乾燥、過濾及真空濃縮，以得到0.62g粗化合物。將此粗殘留物透過combiflash儀器在redisep®管柱上純化，以0至50%的乙酸乙酯/己烷(EtOAc in hexane)的梯度流析，以得到標題所述之化合物(215mg)，為灰白色固體。¹H NMR(DMSO-d₆)9.44(s,1H),8.72(s,1H),8.20(s,1H),7.47(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),4.70(q,J=5.6Hz,1H),3.19(s,3H),2.49(s,3H),1.66(s,3H),1.55(s,3H),1.49(d,J=5.6Hz,3H)；LCMS m/z=378[M+H]⁺。To a stirred solution of 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II, 500 mg) in methanol (10 mL) was added 4M hydrochloric acid in dioxane (2 ml) at 0°C. The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was alkalized with saturated aqueous sodium bicarbonate solution (50 ml) at 0°C and extracted with ethyl acetate (25 ml x 2). The layers were separated and the combined organic layer was washed with brine (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.62 g of crude compound. The crude residue was purified on a combiflash instrument on a redisep® column with a gradient of 0 to 50% EtOAc in hexane to give the title compound (215 mg) as an off-white solid.¹ H NMR(DMSO-d₆ )9.44(s,1H),8.72(s,1H),8.20(s,1H),7.47(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),4.70(q,J=5.6 Hz,1H),3.19(s,3H),2.49(s,3H),1.66(s,3H),1.55(s,3H),1.49(d,J=5.6Hz,3H); LCMS m/z=378[M+H]⁺ .

實施例51：3-(4-氨基-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚(異構體-I)Example 51: 3-(4-amino-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Isomer-I)

標題所述之化合物係依照與合成3-(4-氨基-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚(異構體-II)中所述相同的反應方案(實施例50)，並使用9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-I)作為起始原料來製備。¹H NMR(DMSO-d₆)9.45(s,1H),8.72(s,1H),8.20(s,1H),7.47(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),4.70(q,J=5.6Hz,1H),3.19(s,3H),2.49(s,3H),1.66(s,3H),1.55(s,3H),1.49(d,J=5.6Hz,3H)；LCMS m/z=378[M+H]⁺。The title compound was prepared according to the same reaction scheme as described in the synthesis of 3-(4-amino-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Isomer-II) (Example 50) and using 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-I) as the starting material.¹ H NMR (DMSO-d₆ )9.45(s,1H),8.72(s,1H),8.20(s,1H),7.47(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),4 .70(q,J=5.6Hz,1H),3.19(s,3H),2.49(s,3H),1.66(s,3H),1.55(s,3H),1.49(d,J=5.6Hz,3H); LCMS m/z=378[M+H]⁺ .

實施例52：3-(4-氨基-6-(2-甲氧基丙烷-2-基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚Example 52: 3-(4-amino-6-(2-methoxypropane-2-yl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

標題所述之化合物係依照與合成3-(4-氨基-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚中所述相同的反應方案(實施例50)，並使用9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-6-(2-甲氧基丙-2-基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺作為起始原料來製備。¹H NMR(DMSO-d₆)9.45(s,1H),8.52(s,1H),8.20(s,1H),7.47(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),2.95(s,3H),2.67(s,3H),1.66(s,9H),1.57(s,3H)；LCMS m/z=392[M+H]⁺。The compound described in the title was prepared according to the same reaction scheme as described in the synthesis of 3-(4-amino-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Example 50) and using 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-6-(2-methoxypropan-2-yl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine as the starting material.¹ H NMR (DMSO-d₆ )9.45(s,1H),8.52(s,1H),8.20(s,1H),7.47(bs,2H),7.04(d,J=8.4Hz,1H),6 .91(d,J=8.4Hz,1H),2.95(s,3H),2.67(s,3H),1.66(s,9H),1.57(s,3H); LCMS m/z=392[M+H]⁺ .

實施例53：3-(4-氨基-6-(1-乙氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚(異構體-I)Example 53: 3-(4-amino-6-(1-ethoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Isomer-I)

標題所述之化合物係依照與合成3-(4-氨基-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚中所述相同的反應方案(實施例50)，並使用6-(1-乙氧基乙基)-9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-I)作為起始原料來製備。¹H NMR(DMSO-d₆)9.44(s,1H),8.52(s,1H),8.20(s,1H),7.50(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),2.95(s,3H),2.67(s,3H),1.66(m,9H),1.57(s,3H)；LCMS m/z=392[M+H]⁺。The title compound was prepared according to the same reaction scheme as described in the synthesis of 3-(4-amino-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Example 50) and using 6-(1-ethoxyethyl)-9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-I) as the starting material.¹ H NMR (DMSO-d₆ )9.44(s,1H),8.52(s,1H),8.20(s,1H),7.50(bs,2H),7.04(d,J=8.4Hz,1H),6 .91(d,J=8.4Hz,1H),2.95(s,3H),2.67(s,3H),1.66(m,9H),1.57(s,3H); LCMS m/z=392[M+H]⁺ .

實施例54：3-(4-氨基-6-(1-乙氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚(異構體-II)Example 54: 3-(4-amino-6-(1-ethoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Isomer-II)

標題所述之化合物係依照與合成3-(4-氨基-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚中所述相同的反應方案(實施例50)，並使用6-(1-乙氧基乙基)-9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-7-甲基-9H-吡啶並[3',2'：4,5]吡咯並[2,3-d]嘧啶-4-胺(異構體-II)作為起始原料來製備。¹H NMR(DMSO-d₆)9.44(s,1H),8.73(s,1H),8.20(s,1H),7.47(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),4.79(m,1H),3.43(m,2H),2.49(s,3H),1.66(s,3H),1.55(s,3H),1.49(m,3H),1.14(m,3H)；LCMS m/z=392[M+H]⁺。The title compound was prepared according to the same reaction scheme as described in the synthesis of 3-(4-amino-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Example 50) using 6-(1-ethoxyethyl)-9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II) as the starting material.¹ H NMR (DMSO-d₆ )9.44(s,1H),8.73(s,1H),8.20(s,1H),7.47(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H LCMS m/z=392[M+H]⁺ .

實施例55：3-(4-氨基-7-甲基-6-(1-丙氧基乙基)-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚(異構體-I)Example 55: 3-(4-amino-7-methyl-6-(1-propoxyethyl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Isomer-I)

標題所述之化合物係依照與合成3-(4-氨基-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚中所述相同的反應方案(實施例50)，並使用9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-7-甲基-6-(1-丙氧基乙基)-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-I)作為起始原料來製備。¹H NMR(DMSO-d₆)9.44(s,1H),8.72(s,1H),8.20(s,1H),7.45(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),4.78(m,1H),3.28(m,2H),2.49(s,3H),1.65(s,3H),1.56(s,3H),1.49(m,6H),0.87(t,J=7.6Hz,3H)；LCMS m/z=406[M+H]⁺。The title compound was prepared according to the same reaction scheme as described in the synthesis of 3-(4-amino-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Example 50) and using 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-7-methyl-6-(1-propoxyethyl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-I) as the starting material.¹ H NMR (DMSO-d₆ )9.44(s,1H),8.72(s,1H),8.20(s,1H),7.45(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),4. 78(m,1H),3.28(m,2H),2.49(s,3H),1.65(s,3H),1.56(s,3H),1.49(m,6H),0.87(t,J=7.6Hz,3H); LCMS m/z=406[M+H]⁺ .

實施例56：3-(4-氨基-7-甲基-6-(1-丙氧基乙基)-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚(異構體-II)Example 56: 3-(4-amino-7-methyl-6-(1-propoxyethyl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Isomer-II)

標題所述之化合物係依照與合成3-(4-氨基-6-(1-甲氧基乙基)-7-甲基-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-9-基)-2,4-二甲基苯酚中所述相同的反應方案(實施例50)，並使用9-(3-((4-甲氧基芐基)氧基)-2,6-二甲基苯基)-7-甲基-6-(1-丙氧基乙基)-9H-吡啶并[3',2'：4,5]吡咯并[2,3-d]嘧啶-4-胺(異構體-II)作為起始原料來製備。¹H NMR(DMSO-d₆)9.44(s,1H),8.72(s,1H),8.20(s,1H),7.45(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),4.78(m,1H),3.28(m,2H),2.49(s,3H),1.65(s,3H),1.56(s,3H),1.49(m,6H),0.87(t,J=7.6Hz,3H)；LCMS m/z=406[M+H]⁺。The compound described in the title was prepared according to the same reaction scheme as described in the synthesis of 3-(4-amino-6-(1-methoxyethyl)-7-methyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol (Example 50) and using 9-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-7-methyl-6-(1-propoxyethyl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (Isomer-II) as the starting material.¹ H NMR (DMSO-d₆ )9.44(s,1H),8.72(s,1H),8.20(s,1H),7.45(bs,2H),7.04(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),4. 78(m,1H),3.28(m,2H),2.49(s,3H),1.65(s,3H),1.56(s,3H),1.49(m,6H),0.87(t,J=7.6Hz,3H); LCMS m/z=406[M+H]⁺ .

阻轉異構體的外消旋混合物係使用掌性超臨界流體層析(SFC)方法分離。將每個吸收峰適當的分部(fractions)合併、濃縮，並通常放入水和適當的可混溶的有機溶劑(例如乙醇、異丙醇、乙腈或其混合物)的混合物中並冷凍乾燥。分離的產物透過掌性超臨界流體層析重新分析以評估掌性純度。Racemic mixtures of atropisomers are separated using chiral supercritical fluid chromatography (SFC) techniques. Appropriate fractions of each absorbance peak are combined, concentrated, and usually placed in a mixture of water and a suitable miscible organic solvent (e.g., ethanol, isopropanol, acetonitrile, or mixtures thereof) and lyophilized. The separated products are reanalyzed by chiral supercritical fluid chromatography to assess chiral purity.

表5：式(I)化合物的阻轉異構體的外消旋混合物的分析數據Table 5: Analytical data of the racemic mixture of atropisomers of the compound of formula (I)

示例性分離的阻轉異構體及其光譜數據如下表6所示。Exemplary separated atropisomers and their spectral data are shown in Table 6 below.

表6：式(I)化合物的分離的阻轉異構體及光譜數據Table 6: Isolated atropisomers and spectral data of the compound of formula (I)

說明書中所使用之縮寫：Abbreviations used in this manual:

AcOH=乙酸或醋酸AcOH = acetic acid or acetic acid

℃=攝氏度℃=degrees Celsius

DEA=二乙胺DEA=Diethylamine

DMF=N,N-二甲基甲醯胺DMF=N,N-dimethylformamide

EtOAc=乙酸乙酯EtOAc = ethyl acetate

EtOH=乙醇EtOH = ethanol

h=小時h=hours

IPA=2-丙醇IPA=2-propanol

LCMS=液相層析質譜法LCMS=Liquid chromatography mass spectrometry

MeOH=甲醇MeOH=Methanol

mg=毫克mg=milligram

ml=毫升ml=milliliter

min=分鐘min=minutes

MTBE=甲基叔丁基醚MTBE=Methyl tert-butyl ether

m/z=質荷比m/z=mass-to-charge ratio

NBS=N-溴代琥珀醯亞胺NBS=N-bromosuccinimide

¹H NMR=質子核磁共振¹ H NMR = proton nuclear magnetic resonance

-OPMB=4-甲氧基芐氧基-OPMB=4-methoxybenzyloxy

PdCl₂dppf.CH₂Cl₂=[1,1'雙(二苯基膦)二茂鐵]二氯化鈀(II)，與二氯甲烷的錯合物PdCl₂ dppf.CH₂ Cl₂ =[1,1' Bis(diphenylphosphino)ferrocene]palladium(II) dichloride, complex with dichloromethane

Pd₂dba₃=三(二亞芐基丙酮)二鈀(0價)Pd₂ dba₃ = tris(dibenzylideneacetone)dipalladium (0 valent)

r.t.=室溫r.t.=room temperature

THF=四氫呋喃THF=Tetrahydrofuran

Xantphos=4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽Xantphos=4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene

藥理活性：Pharmacological activity:

PKMYT1生化分析PKMYT1 biochemical analysis

化合物對人類PKMYT1(Thermo Scientific # A30984)酵素活性的抑制，係使用ADP-Glo^TM檢測試劑盒(Promega(# V9101))來進行分析測量。將化合物、酵素和ATP以含有70mM HEPES、3mM MgCl2、3mM MnCl2、磷酸酶抑制劑和1.2mM DTT的反應緩衝液稀釋。將1.66μl重組人PKMYT-1蛋白(最終濃度100nM)與1.66μl測試化合物或在反應緩衝液中製備的DMSO對照一起醞釀。將此化合物和酵素的混合物在室溫下醞釀15分鐘。醞釀後，加入最終濃度為10μM的1.66μl ATP。將反應混合物在30℃下搖晃醞釀1小時。然後加入5μl ADP-Glo試劑並在黑暗中進一步醞釀30分鐘。將10μl KINASE Glo檢測試劑加入反應混合物中，並在室溫下醞釀30分鐘。發光計數係使用Victor Nivo Multimode多功能盤式分析儀(PerkinElmer)以1000ms積分時間測量。Inhibition of human PKMYT1 (Thermo Scientific # A30984) enzyme activity by compounds was measured using the ADP-Glo^™ assay kit (Promega (# V9101)). Compounds, enzyme, and ATP were diluted in reaction buffer containing 70 mM HEPES, 3 mM MgCl2, 3 mM MnCl2, phosphatase inhibitors, and 1.2 mM DTT. 1.66 μl of recombinant human PKMYT-1 protein (final concentration 100 nM) was incubated with 1.66 μl of test compound or DMSO control prepared in reaction buffer. This mixture of compound and enzyme was incubated at room temperature for 15 minutes. After incubation, 1.66 μl ATP was added to a final concentration of 10 μM. The reaction mixture was incubated at 30°C for 1 hour with shaking. Then 5 μl ADP-Glo reagent was added and incubated for a further 30 minutes in the dark. 10 μl KINASE Glo detection reagent was added to the reaction mixture and incubated for 30 minutes at room temperature. Luminescence counts were measured using a Victor Nivo Multimode multi-function plate analyzer (PerkinElmer) with an integration time of 1000 ms.

結果計算：Result calculation:

%抑制率=100-((RLU在以化合物處理的孔盤)/(RLU在DMSO的孔盤)*100)。% inhibition rate = 100-((RLU in the wells treated with the compound)/(RLU in the wells treated with DMSO)*100).

表7：式(I)化合物對人類PKMYT1酵素活性的抑制Table 7: Inhibition of human PKMYT1 enzyme activity by compounds of formula (I)

%抑制率@ 100nM：>70%=***；50-70%=**；<50%=*% inhibition rate @ 100nM: >70%=***; 50-70%=**; <50%=*

表8：式(I)化合物的阻轉異構體對人類PKMYT1酵素活性的抑制Table 8: Inhibition of human PKMYT1 enzyme activity by atropisomers of the compound of formula (I)

%抑制率@ 100nM：>70%=***；50-70%=**；<50%=*% inhibition rate @ 100nM: >70%=***; 50-70%=**; <50%=*

IC₅₀：<20nM=***；20-100nM=**；100-1000nM=*IC₅₀ : <20nM=***;20-100nM=**; 100-1000nM=*

Claims (39)

Translated fromChinese

一種如式(I)之化合物A compound of formula (I)

其中，in,環A係為選自取代的或未取代的芳基、取代的或未取代的5至6員雜芳基、取代或未取代的5至8員碳環、以及取代或未取代的5至8員雜環；Ring A is selected from substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-8 membered carbon ring, and substituted or unsubstituted 5-8 membered hetero ring;X和Y係獨立地選自-N或-CR⁶；X and Y are independently selected from -N or -CR⁶ ;R¹和R²係獨立地選自氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、取代或未取代的雜芳基、烯基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂以及-N(R^7b)₂，或R¹和R²一起形成之取代的或未取代的-5-8員雜環；R¹ and R² are independently selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, alkenyl, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ and -N(R^7b )₂ , or a substituted or unsubstituted 5-8 membered heterocyclic ring formed by R¹ and R² together;R³和R⁴係獨立地選自氰基、取代的或未取代的雜芳基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂以及-N(R^7b)₂，或R³和R⁴一起形成之取代或未取代的5-8員雜環，或取代或未取代的5-6員雜芳基；^R3 and^R4 are independently selected from cyano, substituted or unsubstituted heteroaryl,^-NR7bC (=O)^R7a ,^-OR7b , -C(=O)^OR7b , -C(=O)N(^R7b )₂ and -N(^R7b )₂ , or^R3 and^R4 together form a substituted or unsubstituted 5-8 membered heterocyclic ring, or a substituted or unsubstituted 5-6 membered heteroaryl;R⁵係選自氫、羥基、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂以及-N(R^7b)₂；R⁵ is selected from hydrogen, hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ and -N(R^7b )₂ ;R⁶係選自氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環以及-N(R^7b)₂；R⁶ is selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic and -N(R^7b )₂ ;R^7a係選自取代的或未取代的烷基、取代的或未取代的環烷基以及取代的或未取代的雜環；R^7a is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic;R^7b係選自氫、取代或未取代的烷基、取代或未取代的環烷基和取代或未取代的雜環；R^7b is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic;n為選自1-5的整數；以及n is an integer selected from 1-5; and當R¹和R²一起不是取代的或未取代的5-8員雜環且R³和R⁴一起不是取代的或未取代的5-8員雜環或取代的或未取代的5-6員雜芳基時，則n為2或大於2，且當-OR^7b是R⁵的一部分時，R^7b為氫；When^R1 and^R2 together are not substituted or unsubstituted 5-8 membered heterocyclic and^R3 and^R4 together are not substituted or unsubstituted 5-8 membered heterocyclic or substituted or unsubstituted 5-6 membered heteroaryl, then n is 2 or greater, and when^-OR7b is part of^R5 ,^R7b is hydrogen;或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or its pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).如請求項1所述之化合物、或或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中，環A係選自取代的或未取代的芳基或取代的或未取代的5至6員雜芳基。The compound as described in claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including isotopes thereof), wherein ring A is selected from substituted or unsubstituted aryl or substituted or unsubstituted 5-6 membered heteroaryl.如請求項1之化合物，其係為由下列結構表示的式(IA)化合物：The compound of claim 1 is a compound of formula (IA) represented by the following structure:

式(IA)

Formula (IA)其中，in,環A係為苯基；Ring A is a phenyl group;X係為N，Y係為-CH-；X is N, Y is -CH-;R¹和R²係為甲基；^R1 and^R2 are methyl groups;R³和R⁴一起可形成取代或未取代的5-8員雜環，或取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-8 membered heterocyclic ring, or a substituted or unsubstituted 5-6 membered heteroaryl group; andR⁵和n各自與請求項1中的定義相同；^R5 and n are each the same as defined in claim 1;或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or its pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).如請求項1之化合物，其係為由下列結構表示的式(IA)化合物：The compound of claim 1 is a compound of formula (IA) represented by the following structure:

其中，in,環A係為苯基；Ring A is a phenyl group;X係為N，Y係為-CH-；X is N, Y is -CH-;R¹係為甲基；R²係為環烷基或雜環或雜芳基或OR^7b，其中R^7b是烷基或環烷基；R¹ is methyl; R² is cycloalkyl or heterocyclic or heteroaryl or OR^7b , wherein R^7b is alkyl or cycloalkyl;R³和R⁴一起可形成取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group; andR⁵和n各自與請求項1中的定義相同；^R5 and n are each the same as defined in claim 1;或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).如請求項1之化合物，其係為由下列結構表示的式(IA)化合物：The compound of claim 1 is a compound of formula (IA) represented by the following structure:

其中，in,環A係為苯基；Ring A is a phenyl group;X係為N，Y係為-CH-；X is N, Y is -CH-;R¹係為環烷基或雜環或OR^7b，其中，R^7b是烷基或環烷基；R²係為甲基；R¹ is a cycloalkyl group or a heterocyclic group or OR^7b , wherein R^7b is an alkyl group or a cycloalkyl group; R² is a methyl group;R³和R⁴一起可形成取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group; andR⁵和n各自與請求項1中的定義相同；^R5 and n are each the same as defined in claim 1;或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).如請求項1之化合物，其係為由下列結構表示的式(IA)化合物：The compound of claim 1 is a compound of formula (IA) represented by the following structure:

其中，in,環A係為苯基；Ring A is a phenyl group;X係為N，Y係為-CH-；X is N, Y is -CH-;R¹係為甲基；^R1 is methyl;R²係為取代的烷基，其中取代基是-OR^8b；R² is a substituted alkyl group, wherein the substituent is -OR^8b ;R^8b係選自氫、烷基、鹵代烷基、環烷基；R^8b is selected from hydrogen, alkyl, halogenated alkyl, and cycloalkyl;R³和R⁴一起可形成取代或未取代的5-6員雜芳基；以及^R3 and^R4 together may form a substituted or unsubstituted 5-6 membered heteroaryl group; andR⁵和n各自與請求項1中的定義相同；^R5 and n are each the same as defined in claim 1;或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).如請求項1之化合物，其係為由下列結構表示的式(IB)化合物：The compound of claim 1 is a compound of formula (IB) represented by the following structure:

其中，in,環A是苯基；Ring A is a phenyl group;X係為N，Y係為-CH-；X is N, Y is -CH-;R¹和R²係為甲基；^R1 and^R2 are methyl groups;R³為-C(=O)N(R^7b)₂，且R⁴為-N(R^7b)₂，其中R^7b為氫；以及R³ is -C(=O)N(R^7b )₂ , and R⁴ is -N(R^7b )₂ , wherein R^7b is hydrogen; andR⁵和n各自與請求項1中的定義相同；^R5 and n are each the same as defined in claim 1;或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).如請求項1之化合物，其係為由下列結構表示的式(IC)化合物和式(ID)化合物：The compound of claim 1 is a compound of formula (IC) and a compound of formula (ID) represented by the following structures:

其中inY係為N或CR⁶；Y is N or CR⁶ ;R¹和R²獨立地為氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、取代或未取代的雜芳基、烯基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂或-N(R^7b)₂；R¹ and R² are independently hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, alkenyl, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ or -N(R^7b )₂ ;R^5a為C_1-4烷基或鹵素；R^5a is C_1-4 alkyl or halogen;R^5b為氫、C_1-4烷基或鹵素；R^5b is hydrogen, C_1-4 alkyl or halogen;R^5c為羥基；R^5c is hydroxyl;R^5d為氫或羥基；R^5d is hydrogen or hydroxy;R⁶為氫、鹵素或C_1-4-烷基；^R6 is hydrogen, halogen or_C1-4 -alkyl;R^7a為取代的或未取代的烷基、取代的或未取代的環烷基、或取代的或未取代的雜環；以及R^7a is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclic; andR^7b是氫、取代或未取代的烷基、取代或未取代的環烷基、或取代或未取代的雜環；R^7b is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclic;或藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical isomers and geometric isomers, prodrugs or deuterated compounds (including isotopes thereof).如請求項8之化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，The compound of claim 8, or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including its isotope),其中inY係為CR⁶；Y is CR⁶ ;R¹和R²獨立地為氫；鹵素；硝基；氰基；C_1-4烷基選擇性地被一個或多個選自鹵素、-O-R^8b、-N(H)R⁸、-N(烷基)R⁸、C_3-6環烷基、以及雜環的基團取代，其中所述C_3-6環烷基和雜環可進一步被一個或多個選自鹵素、氰基、C_1-4烷基、-O-R^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；C_3-6環烷基選擇性地被一個或多個選自鹵素、氰基、C_1-4烷基、-O-R^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；雜環選擇性地被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、-CH₂-OR^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；雜芳基選擇性地被一個或多個選自鹵素、氰基、C_1-4烷基、-O-(C_1-4烷基)、C_1-4鹵代烷基、-O-(C_1-4鹵代烷基)、-N(烷基)烷基、-N(H)烷基、以及-NH₂的基團取代；C_2-4烯基；-OR^7b；或-N(R^7b)₂；^R1 and^R2 are independently hydrogen; halogen; nitro; cyano;_C1-4 alkyl is optionally substituted by one or more groups selected from halogen,^-OR8b , -N(H)^R8 , -N(alkyl)^R8 ,_C3-6 cycloalkyl, and heterocyclic ring, wherein the_C3-6 cycloalkyl and heterocyclic ring may be further substituted by one or more groups selected from halogen, cyano,_C1-4 alkyl,^-OR8b ,_C1-4 halogenated alkyl, -N(H)^R8 , and -N(alkyl)^R8 ;_C3-6 cycloalkyl is optionally substituted by one or more groups selected from halogen, cyano,_C1-4 alkyl,^-OR8b ,_C1-4 halogenated alkyl, -N(H)^R8 , and -N(alkyl)R⁸ ; the heterocyclic group is optionally substituted by one or more groups selected from halogen, cyano, -OR^8b , C_1-4 alkyl, -CH₂ -OR^8b , C_1-4 halogenated alkyl, -N(H)R⁸ , and -N(alkyl)R⁸ ; the heteroaryl group is optionally substituted by one or more groups selected from halogen, cyano, C_1-4 alkyl, -O-(C_1-4 alkyl), C_1-4 halogenated alkyl, -O-(C_1-4 halogenated alkyl), -N(alkyl)alkyl, -N(H)alkyl, and -NH₂ ; C_2-4 alkenyl; -OR^7b ; or -N(R^7b )₂ ;R^7b係為氫；C_3-6環烷基；或C_1-4烷基選擇性地被一個或多個選自鹵素和C_3-6環烷基的基團取代；R^7b is hydrogen; C_3-6 cycloalkyl; or C_1-4 alkyl is optionally substituted with one or more groups selected from halogen and C_3-6 cycloalkyl;R⁸係為氫、C_1-4烷基或C_3-6環烷基；以及^R8 is hydrogen,_C1-4 alkyl or_C3-6 cycloalkyl; andR^8b係為氫、C_1-4烷基、C_1-4鹵代烷基或C_3-6環烷基。R^8b is hydrogen, C_1-4 alkyl, C_1-4 halogenated alkyl or C_3-6 cycloalkyl.如請求項9之化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘化化合物(包括其同位素)，其中The compound of claim 9, or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including its isotope), whereinR¹和R²係獨立地為氫；鹵素；硝基；氰基；C_1-4烷基選擇性地被一個或多個選自鹵素、-O-R^8b、-N(H)R⁸、-N(烷基)R⁸、C_3-6環烷基、哌啶基(piperidinyl)、吡咯烷基(pyrrolidinyl)和嗎啉基(morpholinyl)，其中所述C_3-6環烷基、哌啶基、吡咯烷基和嗎啉基可以進一步被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、C_1-4的鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；C_3-6環烷基選擇性地被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸的基團取代；哌啶基、吡咯烷基、嗎啉基或6-氮雜螺[2.5]辛基(6-azaspiro[2.5]octyl)，各自可被一個或多個選自鹵素、氰基、-O-R^8b、C_1-4烷基、-CH₂-OR^8b、C_1-4鹵代烷基、-N(H)R⁸、以及-N(烷基)R⁸；吡唑基選擇性被一個或多個選自鹵素、氰基、C_1-4烷基、-O-(C_1-4烷基)、C_1-4鹵代烷基、-O-(C_1-4鹵代烷基)、-N(烷基)烷基、-N(H)烷基、以及-NH₂；C_2-4烯基；-OR^7b；或-N(R^7b)₂；^R1 and^R2 are independently hydrogen; halogen; nitro; cyano;_C1-4 alkyl is optionally substituted by one or more groups selected from halogen,^-OR8b , -N(H)^R8 , -N(alkyl)^R8 ,_C3-6 cycloalkyl, piperidinyl, pyrrolidinyl and morpholinyl, wherein the_C3-6 cycloalkyl, piperidinyl, pyrrolidinyl and morpholinyl may be further substituted by one or more groups selected from halogen, cyano,^-OR8b , C1-4 alkyl,_C1-4 halogenated alkyl, -N(H)R8, and -N(alkyl)^R8 ;_C3-6 cycloalkyl is optionally substituted by one or more groups selected from halogen, cyano,^-OR8b , C1-4 alkyl,_C1-4 halogenated alkyl, -N(H)^R8 , and -N(alkyl)R8; , C_1-4 alkyl, C_1-4 halogenated alkyl, -N(H)R⁸ , and -N(alkyl)R⁸ ; piperidinyl, pyrrolidinyl, morpholinyl or 6-azaspiro[2.5]octyl, each of which may be substituted with one or more selected from halogen, cyano, -OR^8b , C_1-4 alkyl, -CH₂ -OR^8b , C_1-4 halogenated alkyl, -N(H)R⁸ , and -N(alkyl)R⁸ ; pyrazolyl may be optionally substituted with one or more selected from halogen, cyano, C_1-4 alkyl, -O-(C_1-4 alkyl), C_1-4 halogenated alkyl, -O-(C_1-4 halogenated alkyl), -N(alkyl)alkyl, -N(H)alkyl, and -NH₂ ; C_2-4 alkenyl; -OR^7b ; or -N(R^7b )₂ ;R^7b係為氫；C_3-6環烷基；或C_1-4烷基選擇性地被一個或多個選自鹵素和C_3-6環烷基的基團取代；R^7b is hydrogen; C_3-6 cycloalkyl; or C_1-4 alkyl is optionally substituted with one or more groups selected from halogen and C_3-6 cycloalkyl;R⁸係為氫、C_1-4烷基、或C_3-6環烷基；以及^R8 is hydrogen,_C1-4 alkyl, or_C3-6 cycloalkyl; andR^8b係為氫、C_1-4烷基、C_1-4鹵代烷基、或C_3-6環烷基。R^8b is hydrogen, C_1-4 alkyl, C_1-4 halogenated alkyl, or C_3-6 cycloalkyl.如請求項1之化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，其中所述化合物係選自由以下組成的群組：A compound as claimed in claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including isotopes thereof), wherein the compound is selected from the group consisting of:

一種製備式(I)的雜芳基化合物的方法，A method for preparing a heteroaryl compound of formula (I),

其中，in,環A係選自取代的或未取代的芳基、取代的或未取代的5至6員雜芳基、取代或未取代的5至8員碳環和取代或未取代的5至8員雜環；Ring A is selected from substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-8 membered carbon ring and substituted or unsubstituted 5-8 membered hetero ring;X和Y獨立地選自-N或-CR⁶；X and Y are independently selected from -N or -CR⁶ ;R¹和R²係獨立地選自氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、取代或未取代的雜芳基、烯基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)2和-N(R^7b)₂，或R¹和R²一起形成之取代的或未取代的-5-8員雜環；^R1 and^R2 are independently selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, alkenyl,^-NR7bC (=O)^R7a ,^-OR7b , -C(=O)^OR7b , -C(=O)N(^R7b )2 and -N(^R7b )₂ , or a substituted or unsubstituted 5-8 membered heterocyclic ring formed by^R1 and^R2 together;R³和R⁴係獨立地選自氰基、取代的或未取代的雜芳基、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂和-N(R^7b)₂或R³和R⁴一起形成之取代或未取代的5-8員雜環，或取代或未取代的5-6員雜芳基；^R3 and^R4 are independently selected from cyano, substituted or unsubstituted heteroaryl,^-NR7bC (=O)^R7a ,^-OR7b , -C(=O)^OR7b , -C(=O)N(^R7b )₂ and -N(^R7b )₂ , or a substituted or unsubstituted 5-8 membered heterocyclic ring formed by^R3 and^R4 , or a substituted or unsubstituted 5-6 membered heteroaryl;R⁵係選自氫、羥基、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環、-NR^7bC(=O)R^7a、-OR^7b、-C(=O)OR^7b、-C(=O)N(R^7b)₂和-N(R^7b)₂；R⁵ is selected from hydrogen, hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, -NR^7b C(=O)R^7a , -OR^7b , -C(=O)OR^7b , -C(=O)N(R^7b )₂ and -N(R^7b )₂ ;R⁶係選自氫、鹵素、硝基、氰基、取代或未取代的烷基、取代或未取代的環烷基、取代或未取代的雜環和-N(R^7b)₂；R⁶ is selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic and -N(R^7b )₂ ;R^7a係選自取代的或未取代的烷基、取代的或未取代的環烷基和取代的或未取代的雜環；R^7a is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic;R^7b係選自氫、取代或未取代的烷基、取代或未取代的環烷基和取代或未取代的雜環；R^7b is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclic;R^8b係選自氫、烷基、鹵代烷基、以及環烷基；R^8b is selected from hydrogen, alkyl, halogenated alkyl, and cycloalkyl;n為選自1-5的整數；以及n is an integer selected from 1-5; and當R¹和R²一起不是取代的或未取代的5-8員雜環且R³和R⁴一起不是取代的或未取代的5-8員雜環或取代的或未取代的5-6員雜芳基時，則n為2或大於2，且當-OR^7b是R⁵的一部分時，R^7b為氫；When^R1 and^R2 together are not substituted or unsubstituted 5-8 membered heterocyclic and^R3 and^R4 together are not substituted or unsubstituted 5-8 membered heterocyclic or substituted or unsubstituted 5-6 membered heteroaryl, then n is 2 or greater, and when^-OR7b is part of^R5 ,^R7b is hydrogen;或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，包括以下步驟：Or its pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including its isotope), comprising the following steps:(i)在鹼、催化劑和溶劑存在下，以化合物(d)處理起始化合物(a)以獲得化合物(b)；(i) treating the starting compound (a) with the compound (d) in the presence of a base, a catalyst and a solvent to obtain the compound (b);

(ii)在鹼、催化劑和溶劑存在下，以腈(nitrile)處理步驟(i)的化合物(b)，以獲得化合物(c)；(ii) treating the compound (b) of step (i) with a nitrile in the presence of a base, a catalyst and a solvent to obtain a compound (c);

(iii)以試劑處理步驟(ii)的化合物(c)以獲得式(I)的雜芳基化合物或雜環；以及(iii) treating the compound (c) of step (ii) with a reagent to obtain a heteroaryl compound or a heterocyclic compound of formula (I); and(iv)選擇性地，將步驟(ii)的化合物(c)去保護基，得到式(I)化合物；(iv) selectively removing the protecting group of the compound (c) in step (ii) to obtain a compound of formula (I);其中式(I)化合物係為式(IA)化合物、式(IB)化合物、式(IC)化合物或式(ID)化合物。Wherein the compound of formula (I) is a compound of formula (IA), a compound of formula (IB), a compound of formula (IC) or a compound of formula (ID).如請求項12所述之方法，其中步驟(i)中的鹼係選自由碳酸鈉、碳酸銫、碳酸鋰、碳酸鈣、碳酸氫鈉、氫氧化銨、碳酸鉀、碳酸氫鉀、以及碳酸鎂所組成的群組。The method as claimed in claim 12, wherein the base in step (i) is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, sodium bicarbonate, ammonium hydroxide, potassium carbonate, potassium bicarbonate, and magnesium carbonate.如請求項13所述之方法，其中所述的鹼係為碳酸銫。The method as described in claim 13, wherein the base is cesium carbonate.如請求項12所述之方法，其中步驟(i)中的催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)、以及三(二亞芐基丙酮)二鈀(0價)所組成的群組。The method as described in claim 12, wherein the catalyst in step (i) is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent), and tris(dibenzylideneacetone)dipalladium (0 valent).如請求項15所述之方法，其中所述的催化劑係為三(二亞芐基丙酮)二鈀(0價)。The method as described in claim 15, wherein the catalyst is tris(dibenzylideneacetone)dipalladium (0 valent).如請求項12所述之方法，其中步驟(i)中的溶劑係選自由乙醚、二甲基甲醯胺、四氫呋喃、二氯甲烷、甲醇、二甲基亞碸(DMSO)、二甲氧基乙烷、二甲氧基甲烷、二丁醚、乙醇、異丙醇、乙腈、以及二異丙醚所組成之群組。The method as claimed in claim 12, wherein the solvent in step (i) is selected from the group consisting of diethyl ether, dimethylformamide, tetrahydrofuran, dichloromethane, methanol, dimethyl sulfoxide (DMSO), dimethoxyethane, dimethoxymethane, dibutyl ether, ethanol, isopropanol, acetonitrile, and diisopropyl ether.如請求項17所述之方法，其中所述的溶劑係為1,2-二甲氧基乙烷。The method as described in claim 17, wherein the solvent is 1,2-dimethoxyethane.如請求項12所述之方法，其中步驟(ii)中所述的腈係選自由丙二腈、丙腈和乙腈、以及苯甲腈所組成的群組。The method as claimed in claim 12, wherein the nitrile described in step (ii) is selected from the group consisting of malononitrile, propionitrile and acetonitrile, and benzonitrile.如請求項19所述之方法，其中所述的腈係為丙二腈。The method as described in claim 19, wherein the nitrile is malononitrile.如請求項12所述之方法，其中步驟(ii)中的鹼係選自由叔丁醇鈉、氫化鈉、氫化鋰、氫氧化銨、氫化鉀、氫化銣、氫化銫或氫化鋁鋰所組成的群組。The method as claimed in claim 12, wherein the base in step (ii) is selected from the group consisting of sodium tert-butoxide, sodium hydroxide, lithium hydroxide, ammonium hydroxide, potassium hydroxide, cadmium hydroxide, cesium hydroxide or aluminum lithium hydroxide.如請求項21所述之方法，其中所述的鹼係為叔丁醇鈉、碳酸氫鈉或氫化鈉。The method as described in claim 21, wherein the base is sodium tert-butoxide, sodium bicarbonate or sodium hydroxide.如請求項12所述之方法，其中步驟(ii)中的催化劑係選自由[雙(二苯基膦)二茂鐵]二氯化鈀(II價)、乙酸鈀(II價)、四(三苯基膦)鈀(0價)、以及三(二亞芐基丙酮)二鈀(0價)所組成的群組。The method as described in claim 12, wherein the catalyst in step (ii) is selected from the group consisting of [bis(diphenylphosphino)ferrocene]palladium dichloride (II valent), palladium acetate (II valent), tetrakis(triphenylphosphine)palladium (0 valent), and tris(dibenzylideneacetone)dipalladium (0 valent).如請求項23所述之方法，其中所述之催化劑係為[雙(二苯基膦基)二茂鐵]二氯化鈀(II價)。The method as described in claim 23, wherein the catalyst is [bis(diphenylphosphino)ferrocene]palladium dichloride (II valence).如請求項12所述之方法，其中步驟(ii)中的溶劑係選自由DMSO、1,2-二甲氧基乙烷、甲醇、二氯甲烷、甲苯、二甲基甲醯胺、四氫呋喃、乙醚、以及氯化溶劑所組成的群組。The method as claimed in claim 12, wherein the solvent in step (ii) is selected from the group consisting of DMSO, 1,2-dimethoxyethane, methanol, dichloromethane, toluene, dimethylformamide, tetrahydrofuran, diethyl ether, and chlorinated solvents.如請求項25所述之方法，其中所述之溶劑係為1,2-二甲氧基乙烷。The method as described in claim 25, wherein the solvent is 1,2-dimethoxyethane.如請求項12所述之方法，其中步驟(iii)的試劑選自由甲醯胺、乙酸乙酯、碳酸二乙酯、以及鹽酸胍所組成的群組。The method as described in claim 12, wherein the reagent in step (iii) is selected from the group consisting of formamide, ethyl acetate, diethyl carbonate, and guanidine hydrochloride.一種醫藥組合物，其係包含請求項1至11中任一項所述之化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)、以及藥學上可接受的賦形劑或載體。A pharmaceutical composition comprising a compound described in any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer thereof, a prodrug or a deuterated compound (including its isotope), and a pharmaceutically acceptable excipient or carrier.一種如請求項1至11中任一項所述之化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)在製備用於治療與PKMYT1蛋白相關的癌症的藥物中的用途。Use of a compound as described in any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including its isotope) thereof in the preparation of a drug for treating cancer associated with PKMYT1 protein.一種如請求項1至11中任一項所述之化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)在用於治療與PKMYT1蛋白相關的癌症的用途。A compound as described in any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including its isotope) thereof for use in treating cancer associated with PKMYT1 protein.一種如請求項1至11中任一項所述之化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)，以用於治療與PKMYT1蛋白相關的癌症。A compound as described in any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including isotopes thereof) thereof, for use in treating cancer associated with PKMYT1 protein.一種抑制PKMYT1蛋白的方法，包括向患者投予治療有效量的藥物組合物，所述藥物組合物包含至少一種如請求項1至11中任一項所述之化合物、或其藥學上可接受的鹽、溶劑化物、多晶型物、互變異構體、阻轉異構體、光學異構體和幾何異構體、前驅藥物或氘代化合物(包括其同位素)。A method for inhibiting PKMYT1 protein, comprising administering to a patient a therapeutically effective amount of a drug composition, wherein the drug composition comprises at least one compound as described in any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, atropisomer, optical isomer and geometric isomer, prodrug or deuterated compound (including isotopes thereof).如請求項32所述之方法，其係用於治療與PKMYT1蛋白相關的癌症。The method as described in claim 32 is used to treat cancer associated with PKMYT1 protein.如請求項32或33所述之方法，其中所述患者患有癌症。The method of claim 32 or 33, wherein the patient suffers from cancer.如請求項32所述之方法，其中所述癌症依賴取決於PKMYT1的活性。The method of claim 32, wherein the cancer is dependent on the activity of PKMYT1.如請求項32或33中任一項所述之方法，其中所述癌症過表達CCNE1。A method as described in any of claim 32 or 33, wherein the cancer overexpresses CCNE1.如請求項32至34中任一項所述之方法，其中所述癌症在FBXW7和PPP2R1A基因中具有失活突變。A method as described in any one of claims 32 to 34, wherein the cancer has inactivating mutations in the FBXW7 and PPP2R1A genes.如請求項32至35中任一項所述之方法，其中所述癌症是實體固態腫瘤。A method as described in any one of claims 32 to 35, wherein the cancer is a solid tumor.如請求項32至35中任一項所述之方法，其中所述癌症是乳癌、大腸直腸癌、子宮內膜癌、食道癌、膠質母細胞瘤、肝細胞癌、肺癌、神經母細胞瘤、卵巢癌、前列腺癌、胃癌或子宮癌。A method as described in any one of claims 32 to 35, wherein the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, gastric cancer or uterine cancer.