TWI687420B - Fused-ring or tricyclic aryl pyridine compuond used as kinase inhibitor - Google Patents

Fused-ring or tricyclic aryl pyridine compuond used as kinase inhibitor Download PDF

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TWI687420B
TWI687420B TW106144294A TW106144294A TWI687420B TW I687420 B TWI687420 B TW I687420B TW 106144294 A TW106144294 A TW 106144294A TW 106144294 A TW106144294 A TW 106144294A TW I687420 B TWI687420 B TW I687420B
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dihydro
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indol
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TW201808953A (en
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丁照中
陳曙輝
趙保平
劉希樂
肖琳霞
丁超
王非
黎健
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大陸商南京聖和藥業股份有限公司
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Abstract

The present invention discloses a fused-ring or tricyclic aryl pyridine compound used as a mutation selective EGFR inhibitor. And more specifically, the present invention discloses a compound used as an EGFR inhibitor or pharmaceutically acceptable salt thereof. The structure of the compound is shown in Formula (I).

Description

稠環或三環芳基嘧啶化合物用作激酶抑制劑Fused ring or tricyclic arylpyrimidine compounds used as kinase inhibitors

本發明涉及一種稠環或三環芳基嘧啶化合物作為突變選擇性的EGFR抑制劑。具體地，本發明涉及作為EGFR抑制劑的式（I）的化合物或其藥學上可接受的鹽。

Figure 02_image001
The invention relates to a fused ring or tricyclic arylpyrimidine compound as a mutation selective EGFR inhibitor. In particular, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof as EGFR inhibitors.
Figure 02_image001

蛋白酪氨酸激酶是一類催化位於蛋白質底物上的磷酸基團從ATP或GTP轉移到酪氨酸殘基的酶。受體酪氨酸激酶通過從細胞外到細胞內傳遞信號引起磷酸化來啟動次級信號通路。多種細胞過程都是由這些信號調控，包括增殖，碳水化合物利用，蛋白質合成，血管生成，細胞生長和細胞存活。此外，許多疾病或病症是與一種或多種激酶的活性失常，異常或失調相關。Protein tyrosine kinases are a class of enzymes that catalyze the transfer of phosphate groups on protein substrates from ATP or GTP to tyrosine residues. Receptor tyrosine kinase initiates secondary signaling pathways by transmitting signals from outside to inside to cause phosphorylation. A variety of cellular processes are regulated by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival. In addition, many diseases or conditions are associated with abnormal, abnormal or dysregulated activity of one or more kinases.

表皮生長因數受體屬於跨膜酪氨酸激酶受體ErbB家族，該家族包括EGFR（也稱為的ErbB或HER1），ErbB2的（HER2或neu基因），ErbB3的（HER3）和ErbB4（HER4）。除HER3以外，均具有酪氨酸激酶活性。所述EGFR/ ErbB家族酪氨酸激酶受體在細胞增殖，分化和凋亡中具有不可或缺的作用，並因此成為用於防止腫瘤生長和轉移的有效靶標。第一代的表皮生長因數受體酪氨酸激酶抑制劑（EGFR-TKI中），包括吉非替尼(J Med 2004;350:2129-39)和厄洛替尼( Lancet Oncol 2011;12:735-42)，它們已被證明在具有體細胞活化突變的晚期NSCLC患者中是有效的。這些突變在編碼表皮生長因數受體的激酶結構域，如多核苷酸19號外顯子的框內缺失和21號外顯子上的858位的亮氨酸置換為精氨酸的點突變（L858R）(Nat Rev Cancer 2007;7:169-81)。 然而，病人在接受第一代EGFR-TKIs後最終會由於耐藥而導致腫瘤產生繼發性生長。790號位的蘇氨酸置換為甲硫氨酸（T790M)的二次突變是最普遍認為的耐藥機制。這種突變在50%~60%疾病出現進展的病人的腫瘤細胞中被檢測出來( N Engl J Med 2005;353:207-8)。第二代EGFR-TKIs，如阿法替尼(Lancet Oncol 2014; 15:213-22)和dacomitinib (Cancer 2014;120:1145-54)的開發用以克服一代TKIs 產生的耐藥性。它們可以不可逆的共價結合EGFR上797位的半胱氨酸。共價機制被認為可以克服雙突變體所增加的ATP的親和力。然而半胱氨酸-797存在於所有形式的EGFR中。因此這些第二代的化合物，不僅對活性突變和二次突變的EGFR有活性，而且對野生型的EGFR也具有活性。對野生型EGFR的抑制不被認為有助於其臨床療效，而是會導致皮疹和腹瀉的副作用(Curr. Med. Chem. 2006, 13, 3483−3492)。Epidermal growth factor receptor belongs to the transmembrane tyrosine kinase receptor ErbB family, which includes EGFR (also known as ErbB or HER1), ErbB2 (HER2 or neu gene), ErbB3 (HER3) and ErbB4 (HER4) . Except for HER3, all have tyrosine kinase activity. The EGFR/ErbB family tyrosine kinase receptor has an indispensable role in cell proliferation, differentiation and apoptosis, and thus has become an effective target for preventing tumor growth and metastasis. The first generation of epidermal growth factor receptor tyrosine kinase inhibitors (in EGFR-TKI), including gefitinib (J Med 2004; 350: 2129-39) and erlotinib (Lancet Oncol 2011; 12: 735-42), they have been shown to be effective in advanced NSCLC patients with somatic activation mutations. These mutations are in the kinase domain encoding the epidermal growth factor receptor, such as the point deletion of the polynucleotide in exon 19 of the polynucleotide and the substitution of leucine at position 858 on exon 21 with arginine (L858R) (Nat Rev Cancer 2007; 7:169-81). However, after receiving the first generation of EGFR-TKIs, patients will eventually develop secondary tumor growth due to drug resistance. The second mutation of substitution of threonine at position 790 with methionine (T790M) is the most widely accepted mechanism of resistance. This mutation was detected in tumor cells of 50% to 60% of patients with disease progression (N Engl J Med 2005; 353:207-8). The second generation of EGFR-TKIs, such as afatinib (Lancet Oncol 2014; 15:213-22) and dacomitinib (Cancer 2014;120:1145-54), were developed to overcome the resistance generated by the first generation of TKIs. They can covalently bind cysteine at position 797 on EGFR irreversibly. The covalent mechanism is believed to overcome the increased ATP affinity of the double mutant. However, cysteine-797 is present in all forms of EGFR. Therefore, these second-generation compounds are not only active against EGFR and secondary mutant EGFR, but also active against wild-type EGFR. Inhibition of wild-type EGFR is not considered to contribute to its clinical efficacy, but it can cause side effects of rash and diarrhea (Curr. Med. Chem. 2006, 13, 3483−3492).

因此第三代EGFR-TKIs，包括AZD9291( Cancer Discov 2014;4:1046-61), CO-1686(Cancer Res. 2013;19:2240-2247) 和 HM61713(US 2013011213), 它們是口服的不可逆的具有突變選擇性的EGFR-TKIs，可以抑制T790M突變和傳統的EGFR突變，而對野生型EGFR沒有作用。它們在T790M陽性腫瘤中有高效，但他們仍然存在一定的毒性，像依然會產生腹瀉，皮疹，噁心甚至高血糖等臨床副作用（(J Clin Oncol 2014;32:abstr 8009；J Clin Oncol 2014;32:abstr 8010)。很顯然，一個具有更高活性和低毒性的化合物會帶來更大好處。Therefore, the third generation of EGFR-TKIs, including AZD9291 (Cancer Discov 2014; 4:1046-61), CO-1686 (Cancer Res. 2013; 19:2240-2247) and HM61713 (US 2013011213), are irreversible by mouth Mutation-selective EGFR-TKIs can inhibit T790M mutation and traditional EGFR mutation, but have no effect on wild-type EGFR. They are highly effective in T790M-positive tumors, but they still have some toxicity, like clinical side effects such as diarrhea, rash, nausea and even high blood sugar ((J Clin Oncol 2014; 32:abstr 8009; J Clin Oncol 2014; 32 :abstr 8010). Obviously, a compound with higher activity and low toxicity will bring greater benefits.

本發明涉及一系列新型的稠合或三環芳基嘧啶化合物，該系列化合物對敏感突變和雙突變的EGFR（敏感和T790M耐藥）顯示出優良的活性，並對野生型EGFR具有較高選擇性。它們對由表皮生長因數受體的酶的異常引起的疾病有可能提供更有效的治療。The present invention relates to a series of novel fused or tricyclic arylpyrimidine compounds. The series of compounds show excellent activity against sensitive mutant and double mutant EGFR (sensitive and T790M resistant) and have a higher selection for wild-type EGFR Sex. They may provide a more effective treatment for diseases caused by abnormalities of the epidermal growth factor receptor enzyme.

本發明的目的在於提供式（Ⅰ）所示化合物或其藥學上可接受的鹽，

Figure 02_image003
其中，W選自：
Figure 02_image005
、
Figure 02_image007
、
Figure 02_image009
；n = 0、1或2；m=1、2或3Y1 、Y2 、Y3 、和Y4 分別獨立地選自–O-、-S-、-C(R)2 -、-N(R)-、-S(=O)2 -、-S(=O)-、-C(=O)-、-C(=S)-；X1 選自CRX1 、N；X2 選自CRX2 、N；X3 選自CRX3 、N；RX1 、RX2 、RX3 分別獨立地選自 H、F、Cl、Br、I、CN、OH、SH、NH2 ，或RX1 、RX2 、RX3 分別獨立地選自任選被1、2、3或4個R取代的：C1-6 烷基、C1-6 雜烷基；R1 選自H、F、Cl、Me、CN、CF3 ；R2 選自R02 、OR02 、SR02 ；R02 獨立地選自任選被1、2、3或4個R取代的：C1-4 烷基、C1-4 雜烷基、C3-5 環烷基-(CH2 )0-3 -； R3 選自任選被1、2、3或4個R取代的：C1-6 烷基、C1-6 雜烷基、C2 -4 炔基、3~7元環烷基、3~7元環烷基-L-、3~7 元雜環烷基、3~7元雜環烷基-L-；L 選自–O-、-S-、-C(=O)-、-S(=O)2 -、-S(=O)-，或L選自任選被1、2、3或4個R取代的： NH, C1-4 烷基、C1-4 雜烷基； “雜”代表雜原子或雜原子團，其選自：-C(=O)NH-、-NH-、-O-、-S-、N、=O、=S、-C(=O)O-、-C(=O)- 、-C(=S)- 、-S(=O) -、-S(=O)2 -；雜原子或雜原子團的數目分別獨立地選自0、1、2、3；R選自H、F、Cl、Br、I、OH、CN，或R選自任選被1、2、3或4個R’取代的：NH2 、C1-4 烷基、C1-4 雜烷基、3~7 元環烷基、或 3~7元雜環烷基；R’ 選自F、Cl、Br、I、CN、OH、NH2 、CF3 、NHCH3 、CH2 OCH3 、N(CH3 )2 。The object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure 02_image003
Among them, W is selected from:
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
; N = 0, 1 or 2; m = 1, 2 or 3Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from -O-, -S-, -C(R) 2 -, -N (R)-, -S(=O) 2 -, -S(=O)-, -C(=O)-, -C(=S)-; X 1 is selected from CR X1 and N; X 2 is selected From CR X2 , N; X 3 is selected from CR X3 , N; R X1 , R X2 , R X3 are independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , or R X1 , R X2 and R X3 are independently selected from the group optionally substituted by 1, 2, 3 or 4 R: C 1-6 alkyl, C 1-6 heteroalkyl; R 1 is selected from H, F, Cl , Me, CN, CF 3 ; R 2 is selected from R 02 , OR 02 , and SR 02 ; R 02 is independently selected from those optionally substituted by 1, 2, 3, or 4 R: C 1-4 alkyl, C 1-4 heteroalkyl, C 3-5 cycloalkyl-(CH 2 ) 0-3 -; R 3 is selected from 1, 2, 3 or 4 R optionally substituted: C 1-6 alkyl, C 1-6 heteroalkyl, C 2 -4 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkyl-L-, 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkane Radical -L-; L is selected from -O-, -S-, -C(=O)-, -S(=O) 2 -, -S(=O)-, or L is selected from optionally 2, 3 or 4 R substituted: NH, C 1-4 alkyl, C 1-4 heteroalkyl; "hetero" represents a heteroatom or heteroatom group, which is selected from: -C(=O)NH-, -NH-, -O-, -S-, N, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O ) -, -S(=O) 2 -; the number of heteroatoms or heteroatom groups are independently selected from 0, 1, 2, and 3; R is selected from H, F, Cl, Br, I, OH, CN, or R is selected from optionally substituted with 1 , 2 , 3 or 4 R′: NH 2 , C 1-4 alkyl, C 1-4 heteroalkyl, 3~7 membered cycloalkyl, or 3~7 membered heterocycloalkyl; R 'is selected from F, Cl, Br, I, CN, OH, NH 2, CF 3, NHCH 3, CH 2 OCH 3, N (CH 3) 2.

本發明的一個方案中，上述R選自H、F、Cl、Br、I、OH、NH2 、CN、Me、Et、CF3 、N(CH3 )2 、N(CD3 )2 、NHCH3 、

Figure 02_image011
、
Figure 02_image013
。In one aspect of the present invention, the above R is selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, Et, CF 3 , N(CH 3 ) 2 , N(CD 3 ) 2 , NHCH 3 .
Figure 02_image011
,
Figure 02_image013
.

本發明的一個方案中，上述Y1 、Y2 、Y3 和Y4 分別獨立地選自：-O-、-S-、-CH2 -、-CF2 -、-CHF-、-C(Me)2 -、-CH(Me)- 、-CH(OH)- 、-C(=O)-、-S(=O)2 -、-S(=O)-。In one aspect of the present invention, the above Y 1 , Y 2 , Y 3 and Y 4 are independently selected from the group consisting of: -O-, -S-, -CH 2 -, -CF 2 -, -CHF-, and -C( Me) 2 -, -CH(Me)-, -CH(OH)-, -C(=O)-, -S(=O) 2 -, -S(=O)-.

本發明的一個方案中，上述Y1和Y3選自：-CH2-、-C(Me)2-、-CH(Me)-、-C(=O)-、-CF2-、-CHF-、-CH(OH)-。In one aspect of the present invention, the above Y1 and Y3 are selected from: -CH2-, -C(Me)2-, -CH(Me)-, -C(=O)-, -CF2-, -CHF-,- CH(OH)-.

本發明的一個方案中，上述Y2 和Y4 分別獨立選自：單鍵、–O-、-S-、-S(=O)2 -、–CH2 -、-C(Me)2 -、-C(=O)- 、-CF2 -、-CH(OH)-、-CH(Me)- 、-CHF-。In one aspect of the present invention, the above Y 2 and Y 4 are independently selected from: single bond, -O-, -S-, -S(=O) 2 -, -CH 2 -, -C(Me) 2- , -C(=O)-, -CF 2 -, -CH(OH)-, -CH(Me)-, -CHF-.

本發明的一個方案中，上述結構單元

Figure 02_image015
選自：
Figure 02_image017
、
Figure 02_image019
、
Figure 02_image021
、
Figure 02_image023
、
Figure 02_image025
、
Figure 02_image027
、
Figure 02_image029
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
Figure 02_image045
、
Figure 02_image047
、
Figure 02_image049
、
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
、
Figure 02_image057
。In one aspect of the present invention, the above structural unit
Figure 02_image015
From:
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
Figure 02_image031
,
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
Figure 02_image045
,
Figure 02_image047
,
Figure 02_image049
,
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image055
,
Figure 02_image057
.

本發明的一個方案中，上述結構單元

Figure 02_image059
選自：
Figure 02_image061
、
Figure 02_image063
、
Figure 02_image065
、
Figure 02_image067
。In one aspect of the present invention, the above structural unit
Figure 02_image059
From:
Figure 02_image061
,
Figure 02_image063
,
Figure 02_image065
,
Figure 02_image067
.

本發明的一個方案中，上述結構單元

Figure 02_image069
選自：
Figure 02_image071
、
Figure 02_image073
、
Figure 02_image075
、
Figure 02_image077
。In one aspect of the present invention, the above structural unit
Figure 02_image069
From:
Figure 02_image071
,
Figure 02_image073
,
Figure 02_image075
,
Figure 02_image077
.

本發明的一個方案中，上述L選自-O-、-S-、-C(=O)-、 -S(=O)2 -、-S(=O)-，或L選自任選被1、2或3個R取代的：NH、C1-3 烷基、-O-C1-3 烷基、-S-烷基、-NH-C1-3 烷基。In one aspect of the present invention, the above-mentioned L is selected from -O-, -S-, -C(=O)-, -S(=O) 2 -, -S(=O)-, or L is selected from optional Substituted by 1, 2 or 3 Rs: NH, C 1-3 alkyl, -OC 1-3 alkyl, -S-alkyl, -NH-C 1-3 alkyl.

本發明的一個方案中，上述L選自：-O-、-S-、-C(=O)-、-S(=O)2 -、-S(=O)-，或 L選自任選被1、2或3個R取代的：-NH-、-CH2 -、

Figure 02_image079
、
Figure 02_image081
、
Figure 02_image083
、
Figure 02_image085
、
Figure 02_image087
。In one aspect of the present invention, the above L is selected from: -O-, -S-, -C(=O)-, -S(=O) 2 -, -S(=O)-, or L is selected from any Choose one substituted by 1, 2 or 3 R: -NH-, -CH 2 -,
Figure 02_image079
,
Figure 02_image081
,
Figure 02_image083
,
Figure 02_image085
,
Figure 02_image087
.

本發明的一個方案中，上述L選自：-O-、-S-、-C(=O)-、-NH-、-N(CH3 )-、-CH2 -、

Figure 02_image079
、
Figure 02_image089
、
Figure 02_image091
、
Figure 02_image093
、
Figure 02_image095
。In one aspect of the present invention, the above L is selected from: -O-, -S-, -C(=O)-, -NH-, -N(CH 3 )-, -CH 2 -,
Figure 02_image079
,
Figure 02_image089
,
Figure 02_image091
,
Figure 02_image093
,
Figure 02_image095
.

本發明的一個方案中，上述R3 選自任選被1、2、3或4個R取代的：-C1-4 烷基、-NH-C1-4 烷基、-NH-C(=O)-C1-4 烷基、-O-C1-4 烷基、-S-烷基、-S(=O)-C1-4 烷基、-S(=O)2 -C1-4 烷基、C2 -3 炔基、3~6元環烷基、3~6元環烷基-L-、3~6元雜環烷基、3~6 元雜環烷基-L-，所述“雜”代表雜原子或雜原子團，其選自：-C(=O)NH-、-NH-、-O-、-S-、N、=O、=S、-C(=O)O-、-C(=O)- 、-C(=S)- 、-S(=O) -、-S(=O)2 -，雜原子或雜原子團的數目分別獨立地選自0、1、2、3。In one embodiment of the present invention, the above R 3 is selected from the group optionally substituted with 1, 2, 3, or 4 R: -C 1-4 alkyl, -NH-C 1-4 alkyl, -NH-C ( =O)-C 1-4 alkyl, -OC 1-4 alkyl, -S-alkyl, -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1- 4 alkyl, C 2 -3 alkynyl, 3-6 member cycloalkyl, 3-6 member cycloalkyl-L-, 3-6 member heterocycloalkyl, 3-6 member heterocycloalkyl-L- , The "hetero" represents a heteroatom or a heteroatom group selected from: -C(=O)NH-, -NH-, -O-, -S-, N, =O, =S, -C(= O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) 2- , the number of heteroatoms or heteroatom groups are independently selected from 0, 1, 2, 3.

本發明的一個方案中，上述R3 選自任選被1、2、3或4個R取代的：

Figure 02_image097
、
Figure 02_image099
、
Figure 02_image101
、
Figure 02_image103
、
Figure 02_image105
、
Figure 02_image107
、
Figure 02_image109
、
Figure 02_image111
、
Figure 02_image113
、
Figure 02_image115
、
Figure 02_image117
、
Figure 02_image119
、
Figure 02_image121
、
Figure 02_image123
、
Figure 02_image125
、
Figure 02_image127
、
Figure 02_image129
、
Figure 02_image131
、
Figure 02_image133
、
Figure 02_image135
、
Figure 02_image137
、
Figure 02_image139
、
Figure 02_image141
、
Figure 02_image143
、
Figure 02_image145
、
Figure 02_image147
、
Figure 02_image149
、
Figure 02_image151
、
Figure 02_image153
。In one embodiment of the present invention, the above R 3 is selected from 1, 2, 3, or 4 Rs that are optionally substituted:
Figure 02_image097
,
Figure 02_image099
,
Figure 02_image101
,
Figure 02_image103
,
Figure 02_image105
,
Figure 02_image107
,
Figure 02_image109
,
Figure 02_image111
,
Figure 02_image113
,
Figure 02_image115
,
Figure 02_image117
,
Figure 02_image119
,
Figure 02_image121
,
Figure 02_image123
,
Figure 02_image125
,
Figure 02_image127
,
Figure 02_image129
,
Figure 02_image131
,
Figure 02_image133
,
Figure 02_image135
,
Figure 02_image137
,
Figure 02_image139
,
Figure 02_image141
,
Figure 02_image143
,
Figure 02_image145
,
Figure 02_image147
,
Figure 02_image149
,
Figure 02_image151
,
Figure 02_image153
.

本發明的一個方案中，上述R3 選自：

Figure 02_image155
、
Figure 02_image157
、
Figure 02_image159
、
Figure 02_image161
、
Figure 02_image163
、
Figure 02_image165
、
Figure 02_image167
、
Figure 02_image169
、
Figure 02_image171
、
Figure 02_image173
、
Figure 02_image175
、
Figure 02_image177
、
Figure 02_image179
、
Figure 02_image181
、
Figure 02_image183
、
Figure 02_image185
、
Figure 02_image187
、
Figure 02_image189
、
Figure 02_image191
、
Figure 02_image193
、
Figure 02_image195
、
Figure 02_image197
、
Figure 02_image199
、
Figure 02_image201
、
Figure 02_image203
、
Figure 02_image205
、
Figure 02_image207
、
Figure 02_image209
、
Figure 02_image211
、
Figure 02_image213
、
Figure 02_image215
、
Figure 02_image217
、
Figure 02_image219
、
Figure 02_image221
、
Figure 02_image223
、
Figure 02_image225
、
Figure 02_image227
、
Figure 02_image229
、
Figure 02_image231
、
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、
Figure 02_image235
、
Figure 02_image237
、
Figure 02_image239
、
Figure 02_image241
、
Figure 02_image243
、
Figure 02_image245
、
Figure 02_image247
、
Figure 02_image249
。In one aspect of the present invention, the above R 3 is selected from:
Figure 02_image155
,
Figure 02_image157
,
Figure 02_image159
,
Figure 02_image161
,
Figure 02_image163
,
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,
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,
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,
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,
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,
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,
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,
Figure 02_image181
,
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,
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Figure 02_image187
,
Figure 02_image189
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Figure 02_image191
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,
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,
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,
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,
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,
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,
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,
Figure 02_image237
,
Figure 02_image239
,
Figure 02_image241
,
Figure 02_image243
,
Figure 02_image245
,
Figure 02_image247
,
Figure 02_image249
.

本發明的一個方案中，上述R02 選自Me、CHF2 、CH2 CH3 、CH(CH3 )2 。In one aspect of the present invention, the above R 02 is selected from Me, CHF 2 , CH 2 CH 3 , and CH(CH 3 ) 2 .

本發明的一個方案中，上述化合物選自：

Figure 02_image251
Figure 02_image253
Figure 02_image255
Figure 02_image257
Figure 02_image259
Figure 02_image261
Figure 02_image263
Figure 02_image265
Figure 02_image267
Figure 02_image269
Figure 02_image271
Figure 02_image273
Figure 02_image275
Figure 02_image277
Figure 02_image279
Figure 02_image281
Figure 02_image283
Figure 02_image285
Figure 02_image287
Figure 02_image289
Figure 02_image291
Figure 02_image293
Figure 02_image295
Figure 02_image297
Figure 02_image299
Figure 02_image301
Figure 02_image303
Figure 02_image305
Figure 02_image307
Figure 02_image309
Figure 02_image311
Figure 02_image313
Figure 02_image315
Figure 02_image317
Figure 02_image319
Figure 02_image321
Figure 02_image323
Figure 02_image325
Figure 02_image327
Figure 02_image329
Figure 02_image331
Figure 02_image333
Figure 02_image335
。In one embodiment of the present invention, the above compound is selected from:
Figure 02_image251
Figure 02_image253
Figure 02_image255
Figure 02_image257
Figure 02_image259
Figure 02_image261
Figure 02_image263
Figure 02_image265
Figure 02_image267
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Figure 02_image271
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Figure 02_image333
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.

定義和說明。Definition and description.

除非另有說明，本文所用的下列術語和短語旨在具有下列含義。一個特定的術語或短語在沒有特別定義的情況下不應該被認為是不確定的或不清楚的，而應該按照普通的含義去理解。當本文中出現商品名時，意在指代其對應的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding trade product or its active ingredient.

C1-6 選自C1 、C2 、C3 、C4 、C5 和C6 ；3~7元選自3元、4元、5元、6元和7元。C 1-6 is selected from C 1 , C 2 , C 3 , C 4 , C 5 and C 6 ; 3 to 7 yuan are selected from 3 yuan, 4 yuan, 5 yuan, 6 yuan and 7 yuan.

這裡所採用的術語“藥學上可接受的”，是針對那些化合物、材料、組合物和/或劑型而言，它們在可靠的醫學判斷的範圍之內，適用於與人類和動物的組織接觸使用，而沒有過多的毒性、刺激性、過敏性反應或其它問題或併發症，與合理的利益/風險比相稱。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

術語“藥學上可接受的鹽”是指本發明化合物的鹽，由本發明發現的具有特定取代基的化合物與相對無毒的酸或鹼製備。當本發明的化合物中含有相對酸性的功能團時，可以通過在純的溶液或合適的惰性溶劑中用足夠量的鹼與這類化合物的中性形式接觸的方式獲得鹼加成鹽。藥學上可接受的鹼加成鹽包括鈉、鉀、鈣、銨、有機氨或鎂鹽或類似的鹽。當本發明的化合物中含有相對鹼性的官能團時，可以通過在純的溶液或合適的惰性溶劑中用足夠量的酸與這類化合物的中性形式接觸的方式獲得酸加成鹽。藥學上可接受的酸加成鹽的實例包括無機酸鹽，所述無機酸包括例如鹽酸、氫溴酸、硝酸、碳酸，碳酸氫根，磷酸、磷酸一氫根、磷酸二氫根 、硫酸、硫酸氫根、氫碘酸、亞磷酸等；以及有機酸鹽，所述有機酸包括如乙酸、丙酸、異丁酸、馬來酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、酒石酸和甲磺酸等類似的酸；還包括氨基酸（如精氨酸等）的鹽，以及如葡糖醛酸等有機酸的鹽（參見Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977))。本發明的某些特定的化合物含有鹼性和酸性的官能團，從而可以被轉換成任一鹼或酸加成鹽。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also includes salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any base or acid addition salt.

優選地，以常規方式使鹽與鹼或酸接觸，再分離母體化合物，由此再生化合物的中性形式。化合物的母體形式與其各種鹽的形式的不同之處在於某些物理性質，例如在極性溶劑中的溶解度不同。Preferably, the salt is contacted with a base or an acid in a conventional manner, and then the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

本文所用的“藥學上可接受的鹽”屬於本發明化合物的衍生物，其中，通過與酸成鹽或與鹼成鹽的方式修飾所述母體化合物。藥學上可接受的鹽的實例包括但不限於：鹼基比如胺的無機酸或有機酸鹽、酸根比如羧酸的鹼金屬或有機鹽等等。藥學上可接受的鹽包括常規的無毒性的鹽或母體化合物的第四銨鹽，例如無毒的無機酸或有機酸所形成的鹽。常規的無毒性的鹽包括但不限於那些衍生自無機酸和有機酸的鹽，所述的無機酸或有機酸選自2-乙醯氧基苯甲酸、2-羥基乙磺酸、乙酸、抗壞血酸、苯磺酸、苯甲酸、碳酸氫根、碳酸、檸檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富馬酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氫溴酸、鹽酸、氫碘酸鹽、羥基、羥萘、羥乙磺酸、乳酸、乳糖、十二烷基磺酸、馬來酸、蘋果酸、扁桃酸、甲烷磺酸、硝酸、草酸、雙羥萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水楊酸、硬脂酸、亞乙酸、琥珀酸、氨基磺酸、對氨基苯磺酸、硫酸、單寧、酒石酸和對甲苯磺酸。As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by salt formation with acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic acids or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or the fourth ammonium salt of the parent compound, such as salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-ethoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid , Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid , Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid , Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin , Tartaric acid and p-toluenesulfonic acid.

本發明的藥學上可接受的鹽可由含有酸根或鹼基的母體化合物通過常規化學方法合成。一般情況下，這樣的鹽的製備方法是：在水或有機溶劑或兩者的混合物中，經由游離酸或鹼形式的這些化合物與化學計量的適當的鹼或酸反應來製備。一般地，優選醚、乙酸乙酯、乙醇、異丙醇或乙腈等非水介質。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

除了鹽的形式，本發明所提供的化合物還存在前藥形式。本文所​​描述的化合物的前藥容易地在生理條件下發生化學變化從而轉化成本發明的化合物。此外，前體藥物可以在體內環境中通過化學或生化方法被轉換到本發明的化合物。In addition to salt forms, the compounds provided by the invention also exist in prodrug forms. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform the compounds of the invention. In addition, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in the in vivo environment.

本發明的某些化合物可以以非溶劑化形式或者溶劑化形式存在，包括水合物形式。一般而言，溶劑化形式與非溶劑化的形式相當，都包含在本發明的範圍之內。本發明的某些化合物可以以多晶或無定形形式存在。Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and is included in the scope of the present invention. Certain compounds of the invention may exist in polycrystalline or amorphous forms.

本發明的某些化合物可以具有不對稱碳原子（光學中心）或雙鍵。外消旋體、非對映異構體、幾何異構體和單個的異構體都包括在本發明的範圍之內。Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.

本文中消旋體、ambiscalemic and scalemic或者對映體純的化合物的圖示法來自Maehr, J. Chem. Ed. 1985, 62: 114-120。 1985年，62：114-120。除非另有說明，用楔形鍵和虛線鍵表示一個立體中心的絕對構型。當本文所述化合物含有烯屬雙鍵或其它幾何不對稱中心，除非另有規定，它們包括E 、 Z 幾何異構體。同樣地，所有的互變異構形式均包括在本發明的範圍之內。The graphical representation of the racemic, ambiscalemic and scalemic or enantiomerically pure compounds in this article is from Maehr, J. Chem. Ed. 1985, 62: 114-120. In 1985, 62: 114-120. Unless otherwise stated, the absolute configuration of a three-dimensional center is indicated by a wedge-shaped key and a dotted key. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, they include E and Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the present invention.

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

可以通過的手性合成或手性試劑或者其他常規技術製備光學活性的(R )-和(S )-異構體以及D 和L 異構體。如果想得到本發明某化合物的一種對映體，可以通過不對稱合成或者具有手性助劑的衍生作用來製備，其中將所得非對映體混合物分離，並且輔助基團裂開以提供純的所需對映異構體。 或者，當分子中含有鹼性官能團（如氨基）或酸性官能團（如羧基）時，與適當的光學活性的酸或鹼形成非對映異構體的鹽，然後通過本領域所公知的分步結晶法或色譜法進行非對映異構體拆分，然後回收得到純的對映體。此外，對映異構體和非對映異構體的分離通常是通過使用色譜法完成的，所述色譜法採用手性固定相，並任選地與化學衍生法相結合（例如由胺生成氨基甲酸鹽）。The optically active ( R )- and ( S )-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure Enantiomers are required. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of a diastereomer is formed with an appropriate optically active acid or base, and then passed through stepwise known in the art The diastereomer is resolved by crystallization or chromatography, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography, which uses a chiral stationary phase, and is optionally combined with chemical derivatization methods (for example, the formation of amino groups from amines) Formate).

本發明的化合物可以在一個或多個構成該化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素標記化合物，比如氚（3 H），碘-125（125 I）或C-14（14 C）。本發明的化合物的所有同位素組成的變換，無論放射性與否，都包括在本發明的範圍之內。The compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). The conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included in the scope of the present invention.

術語“藥學上可接受的載體”是指能夠遞送本發明有效量活性物質、不干擾活性物質的生物活性並且對宿主或者患者無毒副作用的任何製劑或載體介質代表性的載體包括水、油、蔬菜和礦物質、膏基、洗劑基質、軟膏基質等。這些基質包括懸浮劑、增粘劑、透皮促進劑等。它們的製劑為化妝品領域或局部藥物領域的技術人員所周知。關於載體的其他資訊，可以參考Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005)，該文獻的內容通過引用的方式併入本文。The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and having no toxic side effects to the host or patient. Representative carriers include water, oil, vegetables And minerals, paste base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulation is well known to those skilled in the cosmetics field or topical pharmaceutical field. For other information about the carrier, please refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

術語“賦形劑”通常是指配製有效的藥物組合物所需要載體、稀釋劑和/或介質。The term "excipient" generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.

針對藥物或藥理學活性劑而言，術語“有效量”或“治療有效量”是指無毒的但能達到預期效果的藥物或藥劑的足夠用量。對於本發明中的口服劑型，組合物中一種活性物質的“有效量”是指與該組合物中另一種活性物質聯用時為了達到預期效果所需要的用量。有效量的確定因人而異，取決於受體的年齡和一般情況，也取決於具體的活性物質，個案中合適的有效量可以由本領域技術人員根據常規試驗確定。For drugs or pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or medicament that is non-toxic but achieves the desired effect. For the oral dosage form of the present invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art based on routine experiments.

術語“活性成分”、“治療劑”，“活性物質”或“活性劑”是指一種化學實體，它可以有效地治療目標紊亂、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat a target disorder, disease or disorder.

術語“被取代的”是指特定原子上的任意一個或多個氫原子被取代基取代，包括重氫和氫的變體，只要特定原子的價態是正常的並且取代後的化合物是穩定的。當取代基為酮基（即=O）時，意味著兩個氫原子被取代。酮取代不會發生在芳香基上。術語“任選被取代的”是指可以被取代，也可以不被取代，除非另有規定，取代基的種類和數目在化學上可以實現的基礎上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including heavy hydrogen and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution is stable . When the substituent is a keto group (ie = O), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis that they are chemically achievable.

當任何變數（例如R）在化合物的組成或結構中出現一次以上時，其在每一種情況下的定義都是獨立的。因此，例如，如果一個基團被0-2個R所取代，則所述基團可以任選地至多被兩個R所取代，並且每種情況下的R都有獨立的選項。此外，取代基和/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R in each case has independent options. In addition, combinations of substituents and/or variants thereof are only allowed if such combinations will produce stable compounds.

當其中一個變數選自單鍵時，表示其連接的兩個基團直接相連，比如A-L-Z中L代表單鍵時表示該結構實際上是A-Z。When one of the variables is selected from a single bond, it means that the two groups to which it is connected are directly connected. For example, when L represents a single bond in A-L-Z, it means that the structure is actually A-Z.

當一個取代基的鍵可以交叉連接到一個環上的兩個原子時，這種取代基可以與這個環上的任意原子相鍵合。當所列舉的取代基中沒有指明其通過哪一個原子連接到化學結構通式中包括但未具體提及的化合物時，這種取代基可以通過其任何原子相鍵合。取代基和/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。例如， 結構單元

Figure 02_image337
或
Figure 02_image339
表示其可在環己基或者環基二烯上的任意一個位置發生取代。When the bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the substituents listed do not indicate through which atom they are connected to a compound included in the chemical structure formula but not specifically mentioned, such substituents may be bonded through any of their atoms. Combinations of substituents and/or variants thereof are only allowed if such combinations will produce stable compounds. For example, structural unit
Figure 02_image337
or
Figure 02_image339
It means that it can be substituted at any position on the cyclohexyl group or the cyclodiene.

烷基和雜烷基原子團的取代基一般被稱為“烷基取代基”，它們可以選自但不限於下列基團中的一個或多個： -R’、-OR’、 =O、=NR’、=N-OR’、-NR’R”、-SR’、鹵素、-SiR’R”R”’、OC(O)R’、-C(O)R’、 -CO2 R’、 -CONR’R”、-OC(O)NR’R”、 -NR”C(O)R’、NR’ C(O)NR”R”’、-NR”C(O)2 R’、-NR””’-C(NR’R”R’”)=NR””、NR”” C(NR’R”)=NR’”、-S(O)R’、-S(O)2 R’、-S(O)2 NR’R”、NR”SO2 R’、-CN、–NO2 、 -N3 、-CH(Ph)2 和氟代(C1 -C4 )烷基, 取代基的數目為0～（2m’+1）,其中m’是這類原子團中碳原子的總數。R'、R”、R”'、R’’’’和R’’’’’各自獨立地優選氫、被取代或未被取代的雜烷基、被取代或未被取代的芳基（例如被1～3個鹵素取代芳基）、被取代或未被取代的烷基、烷氧基、硫代烷氧基基團或芳烷基。當本發明的化合物包括一個以上的R基團時，例如，每一個R基團是獨立地加以選擇的，如同當存在一個以上的R'、R”、R”'、R’’’’和R’’’’’基團時的每個這些基團。當R'和R”附著於同一個氮原子時，它們可與該氮原子結合形成5-，6-或7-元環。例如，-NR'R“意在包括但不僅限於1-吡咯烷基和4-嗎啉基。根據上述關於取代基的討論中，本領域技術人員可以理解，術語“烷基”意在包括碳原子鍵合於非氫基團所構成的基團，如鹵代烷基（例如-CF3 、-CH2 CF3 ）和醯基（例如-C(O)CH3 、-C(O)CF3 、-C(O)CH2 OCH3 等）。The substituents of the alkyl and heteroalkyl radicals are generally referred to as "alkyl substituents", which can be selected from but not limited to one or more of the following groups: -R', -OR', =O, = NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO 2 R' , -CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"',-NR"C(O) 2 R', -NR""'-C(NR'R"R'")=NR"", NR""C(NR'R")=NR'",-S(O)R', -S(O) 2 R', -S(O) 2 NR'R", NR"SO 2 R', -CN, -NO 2 , -N 3 , -CH(Ph) 2 and fluoro(C 1 -C 4 ) alkyl , The number of substituents is 0 ~ (2m'+1), where m'is the total number of carbon atoms in this type of atomic group. R', R", R"', R"" and R'"" Each independently preferably hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (for example, aryl substituted with 1 to 3 halogens), substituted or unsubstituted alkyl, alkyl Oxy, thioalkoxy or aralkyl groups. When the compound of the invention includes more than one R group, for example, each R group is independently selected as if more than one R is present ', R", R"', R"" and R"" groups each of these groups. When R'and R" are attached to the same nitrogen atom, they can The atoms combine to form a 5-, 6- or 7-membered ring. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to include carbon Groups composed of atoms bonded to non-hydrogen groups, such as haloalkyl (eg -CF 3 , -CH 2 CF 3 ) and acetyl groups (eg -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 etc.).

與烷基原子團所述取代基相似，芳基和雜芳基取代基一般統稱為“芳基取代基”，選自例如-R’、-OR’、-NR’R”、-SR’、-鹵素, -SiR’R”R”’、OC(O)R’、-C(O)R’、 -CO2R’、-CONR’R”、-OC(O)NR’R”、 -NR”C(O)R’、NR’ C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)=NR””、NR”” C(NR’R”)=NR’”、-S(O)R’、-S(O)2 R’、-S(O)2 NR’R”、NR”SO2 R’、-CN、–NO2 、-N3 、-CH(Ph)2 、氟(C1 -C4 )烷氧基和氟(C1 -C4 )烷基等，取代基的數量為0到芳香環上開放化合價的總數之間；其中R’、R”、R”’、R”” 和R””’獨立地優選自氫、被取代或未被取代的烷基、被取代或未被取代的雜烷基、被取代或未被取代的芳基和被取代或未被取代的雜芳基。當本發明的化合物包括一個以上的R基團時，例如，每個R基團是獨立地加以選擇的，如同當存在一個以上R’、R”、R”’、R”” 和R””’基團時的每個這些基團。Similar to the substituents described for alkyl radicals, aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" and are selected from, for example, -R', -OR', -NR'R", -SR',- Halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C (O)R', NR'C(O)NR"R"',-NR"C(O)2R',-NR""'-C(NR'R"R'")=NR"", NR ""C(NR'R")=NR'",-S(O)R', -S(O) 2 R', -S(O) 2 NR'R", NR"SO 2 R',- CN, -NO 2 , -N 3 , -CH(Ph) 2 , fluoro (C 1 -C 4 ) alkoxy and fluoro (C 1 -C 4 ) alkyl, etc., the number of substituents is 0 to aromatic ring Between the total number of open valences; where R', R", R"', R"" and R""' are independently preferably from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted Heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compound of the present invention includes more than one R group, for example, each R group is independently added It is selected like each of these groups when there is more than one R', R", R"', R"" and R""' groups.

除非另有規定，芳基或雜芳基環的相鄰原子上的兩個取代基可以任選地被通式為-T-C(O)-(CRR’)q-U-的取代基所取代，其中T和U獨立地選自-NR-、-O-、CRR'-或單鍵，q是0到3的整數。作為替代選擇，芳基或雜芳基環的相鄰原子上的兩個取代基可以任選地被通式為-A (CH2 )r B-的取代基所取代，其中A和B獨立的選自-CRR’-、-O-、-NR-、-S-、-S(O)-、S(O)2 -、-S(O)2 NR’-或單鍵，r是1～4的整數。任選地，由此形成的新環上的一個單鍵可以替換為雙鍵。作為替代選擇，芳基或雜芳基環的相鄰原子上的兩個取代基可以任選地被通式為-A (CH2 )r B-的取代基所取代，其中s和d分別獨立的選自0～3的整數，X是-O-、-NR’、-S-、-S(O)-、-S(O)2 -或 -S(O)2 NR’-。取代基R、R’、R”和R”’分別獨立地優選自氫和被取代或未被取代的(C1 -C6 )烷基。Unless otherwise specified, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, where T And U are independently selected from -NR-, -O-, CRR'- or a single bond, and q is an integer from 0 to 3. As an alternative, the two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the formula -A (CH 2 )r B-, where A and B are independently Selected from -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or single bond, r is 1～ An integer of 4. Optionally, a single bond on the new ring thus formed can be replaced with a double bond. As an alternative, the two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the formula -A (CH 2 )r B-, where s and d are independently Is an integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 -or -S(O) 2 NR'-. The substituents R, R', R" and R"' are independently preferably from hydrogen and substituted or unsubstituted (C 1 -C 6 ) alkyl.

除非另有規定，術語“鹵代素”或“鹵素”本身或作為另一取代基的一部分表示氟、氯、溴或碘原子。此外，術語“鹵代烷基”意在包括單鹵代烷基和多鹵代烷基。例如，術語“鹵代（C1 -C4 ）烷基”意在包括但不僅限於三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。Unless otherwise specified, the term "halogen" or "halogen" itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. In addition, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1 -C 4 )alkyl" is intended to include but is not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. Wait.

鹵代烷基的實例包括但不僅限於：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。“烷氧基”代表通過氧橋連接的具有特定數目碳原子的上述烷基。C1-6 烷氧基包括C1 、C2 、C3 、C4 、C5 和C6 的烷氧基。烷氧基的例子包括但不限於：甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、二級丁氧基、三級丁氧基、正戊氧基和S -戊氧基。“環烷基”包括飽和環基，如環丙基、環丁基或環戊基。3-7環烷基包括C3 、C4 、C5 、C6 和C7 環烷基。“鏈烯基”包括直鏈或支鏈構型的烴鏈，其中該鏈上任何的穩定位點上存在一個或多個碳-碳雙鍵，例如乙烯基和丙烯基。Examples of haloalkyl include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents the above alkyl group having a specific number of carbon atoms connected by an oxygen bridge. C 1-6 alkoxy groups include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secondary butoxy, tertiary butoxy, n-pentyloxy and S -pentyloxy. "Cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. The 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups. "Alkenyl" includes straight or branched hydrocarbon chains in which one or more carbon-carbon double bonds are present at any stable site on the chain, such as vinyl and propenyl.

術語“鹵”或“鹵素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

除非另有規定，術語“雜”表示雜原子或雜原子團(即含有雜原子的原子團)，包括碳（C）和氫（H）以外的原子以及含有這些雜原子的原子團，例如包括氧（O）、氮（N）、硫（S）、矽（Si）、鍺（Ge）、鋁（Al）、硼（B）、-O-、-S-、=O、=S、-C(=O)O-、-C(=O) -、-C(=S)-、-S(=O) 、-S(=O)2 -，以及任選被被取代的-C(=O)N(H)-、-N(H)-、-C(=NH)-、-S(=O)2 N(H)-或-S(=O)N(H)-。Unless otherwise specified, the term "hetero" means heteroatoms or heteroatom groups (ie, atomic groups containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and atomic groups containing these heteroatoms, including, for example, oxygen (O ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O)O-, -C(=O) -, -C(=S)-, -S(=O), -S(=O) 2 -, and optionally substituted -C(=O) N(H)-, -N(H)-, -C(=NH)-, -S(=O) 2 N(H)- or -S(=O)N(H)-.

除非另有規定，“環”表示被取代或未被取代的環烷基、雜環烷基、環烯基、雜環烯基、環炔基、雜環炔基、芳基或雜芳基。所謂的環包括單環、聯環、螺環、並環或橋環。環上原子的數目通常被定義為環的元數，例如，“5～7元環”是指環繞排列5～7個原子。除非另有規定，該環任選地包含1～3個雜原子。因此，“5～7元環”包括例如苯基、吡啶和呱啶基；另一方面，術語“5～7元雜環烷基環”包括吡啶基和呱啶基，但不包括苯基。術語“環”還包括含有至少一個環的環系，其中的每一個“環”均獨立地符合上述定義。Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl group. The so-called ring includes a single ring, a bicyclic ring, a spiro ring, a parallel ring or a bridge ring. The number of atoms on a ring is usually defined as the number of ring members. For example, "5-7 member ring" refers to 5-7 atoms arranged around. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Thus, "5-7 membered ring" includes, for example, phenyl, pyridine, and pyridyl; on the other hand, the term "5-7 membered heterocycloalkyl ring" includes pyridyl and pyridyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, where each "ring" independently conforms to the above definition.

除非另有規定，術語“雜環”或“雜環基”意指穩定的含雜原子或雜原子團的單環、雙環或三環，它們可以是飽和的、部分不飽和的或不飽和的（芳族的），它們包含碳原子和1、2、3或4個獨立地選自N、O和S的環雜原子，其中上述任意雜環可以稠合到一個苯環上形成雙環。氮和硫雜原子可任選被氧化（即NO和S (O) p）。氮原子可以是被取代的或未取代的（即N或NR，其中R是H或本文已經定義過的其他取代基）。該雜環可以附著到任何雜原子或碳原子的側基上從而形成穩定的結構。如果產生的化合物是穩定的，本文所述的雜環可以發生碳位或氮位上的取代。雜環中的氮原子任選地被四級銨化。一個優選方案是，當雜環中S及O原子的總數超過1時，這些雜原子彼此不相鄰。另一個優選方案是，雜環中S及O原子的總數不超過1。如本文所用，術語“芳族雜環基團”或“雜芳基”意指穩定的5、6、7元單環或雙環或7、8、9或10元雙環雜環基的芳香環，它包含碳原子和1、2、3或4個獨立地選自N、O和S的環雜原子。氮原子可以是被取代的或未取代的（即N或NR，其中R是H或本文已經定義過的其他取代基）。氮和硫雜原子可任選被氧化（即NO和S(O)p）。值得注意的是，芳香雜環上S和O原子的總數不超過1。橋環也包含在雜環的定義中。當一個或多個原子（即C、O、N或S）連接兩個不相鄰的碳原子或氮原子時形成橋環。優選的橋環包括但不限於：一個碳原子、兩個碳原子、一個氮原子、兩個氮原子和一個碳-氮基。值得注意的是，一個橋總是將單環轉換成三環。橋環中，環上的取代基也可以出現在橋上。Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable heteroatom or heteroatom-containing monocyclic, bicyclic or tricyclic ring, which may be saturated, partially unsaturated or unsaturated ( Aromatic), they contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring. Nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p). The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents that have been defined herein). The heterocyclic ring can be attached to any heteroatom or carbon atom side group to form a stable structure. If the resulting compound is stable, the heterocycle described herein may be substituted at the carbon or nitrogen position. The nitrogen atom in the heterocycle is optionally quaternized. A preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" means a stable 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9, or 10 membered bicyclic heterocyclic aromatic ring, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents that have been defined herein). Nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed 1. Bridged rings are also included in the definition of heterocycles. When one or more atoms (ie C, O, N or S) connect two non-adjacent carbon or nitrogen atoms to form a bridge ring. Preferred bridge rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In the bridge ring, the substituents on the ring may also appear on the bridge.

雜環化合物的實例包括但不限於：吖啶基、吖辛因基、苯並咪唑基、苯並呋喃基、苯並巰基呋喃基、苯並巰基苯基、苯並惡唑基、苯並惡唑啉基、苯並噻唑基、苯並***基、苯並四唑基、苯並異惡唑基、苯並異噻唑基、苯並咪唑啉基、哢唑基、4aH -哢唑基、哢啉基、苯並二氫吡喃基、色烯、噌啉基十氫喹啉基、2H , 6H -1, 5,2-二噻嗪基、二氫呋喃並[2,3-b ]四氫呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H -吲唑基、吲哚烯基、二氫吲哚基、中氮茚基、吲哚基、3H -吲哚基、isatino基、異苯並呋喃基、吡喃、異吲哚基、異二氫吲哚基、異吲哚基、吲哚基、異喹啉基、異噻唑基、異惡唑基、亞甲二氧基苯基、嗎啉基、萘啶基，八氫異喹啉基、惡二唑基、1,2,3-惡二唑基、1,2,4-惡二唑基、1,2,5-惡二唑基、1,3,4-惡二唑基、惡唑烷基、惡唑基、異惡唑基、羥吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯並黃嘌呤基、酚惡嗪基、酞嗪基、呱嗪基、呱啶基、呱啶酮基、4-呱啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、噠嗪基、吡啶並惡唑、吡啶並咪唑、吡啶並噻唑、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H -吡咯基、吡咯基、吡唑基、喹唑啉基、喹啉基、4H -喹嗪基、喹喔啉基、奎寧環基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、四唑基，6H -1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、異噻唑基噻吩基、噻吩基、噻吩並惡唑基、噻吩並噻唑基、噻吩並咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫噸基。還包括稠環和螺環化合物。Examples of heterocyclic compounds include, but are not limited to: acridinyl, azeinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxanyl Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, oxazolyl, 4a H -oxazolyl , Porphyrinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2 H , 6 H -1, 5,2-dithiazinyl, dihydrofuro[2,3 -b ] Tetrahydrofuranyl, furanyl, furazyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H -indazolyl, indolenyl, dihydroindolyl, indolizinyl, indolyl , 3 H -indolyl, isatinoyl, isobenzofuranyl, pyran, isoindolyl, isoindoline, isoindolyl, indolyl, isoquinolinyl, isothiazolyl, Isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- Oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindoleyl, pyrimidinyl, phenanthrene Pyridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthinyl, phenoxazinyl, phthalazinyl, pyrazinyl, pyridinyl, pyridinone, 4-pyridinone, Piperonyl, pteridyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridine , Pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2 H -pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolinyl, 4 H -quinazinyl, quinoxalinyl, quinine ring Group, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6 H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2 ,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthryl, thiazolyl, isothiazolylthienyl, thienyl, thienoxazole Group, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1 , 3,4-triazolyl and xanthene. Also includes fused ring and spiro compounds.

除非另有規定，術語“烴基”或者其下位概念（比如烷基、烯基、炔基、苯基等等）本身或者作為另一取代基的一部分表示直鏈的、支鏈的或環狀的烴原子團或其組合，可以是完全飽和的、單元或多元不飽和的，可以是單取代、二取代或多取代的，可以是一價（如甲基）、二價（如亞甲基）或者多價（如次甲基），可以包括二價或多價原子團，具有指定數量的碳原子（如C1 -C10 表示1至10個碳）。 “烴基”包括但不限於脂肪烴基和芳香烴基，所述脂肪烴基包括鏈狀和環狀，具體包括但不限於烷基、烯基、炔基，所述芳香烴基包括但不限於6-12元的芳香烴基，例如苯、萘等。在一些實施例中，術語“烴基”表示直鏈的或支鏈的原子團或它們的組合，可以是完全飽和的、單元或多元不飽和的，可以包括二價和多價原子團。飽和烴原子團的實例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、第三丁基、異丁基、第二丁基、異丁基、環己基、（環己基）甲基、環丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子團的同系物或異構體。不飽和烷基具有一個或多個雙鍵或三鍵，其實例包括但不限於乙烯基、2 -丙烯基、丁烯基、巴豆基、2-異戊烯基、2-（丁二烯基）、2，4-戊二烯基、3-（1，4 -戊二烯基）、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高級的同系物和異構體。Unless otherwise specified, the term "hydrocarbyl" or its subordinate concepts (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means linear, branched or cyclic Hydrocarbon radicals or combinations thereof may be fully saturated, unit or polyunsaturated, may be mono-substituted, di-substituted or multi-substituted, may be monovalent (such as methyl), divalent (such as methylene) or Multivalent (such as methine), which can include divalent or multivalent atomic groups, with a specified number of carbon atoms (such as C 1 -C 10 represents 1 to 10 carbons). "Hydrocarbyl" includes but is not limited to aliphatic hydrocarbon groups and aromatic hydrocarbon groups, the aliphatic hydrocarbon groups include chain and cyclic, specifically including but not limited to alkyl, alkenyl, alkynyl groups, the aromatic hydrocarbon groups include but are not limited to 6-12 members Aromatic hydrocarbon groups such as benzene, naphthalene, etc. In some embodiments, the term "hydrocarbyl" refers to linear or branched radicals or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and may include divalent and polyvalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, third butyl, isobutyl, second butyl, isobutyl, cyclohexyl, (cyclo (Hexyl) methyl, cyclopropylmethyl, and homologues or isomers of atomic groups such as n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. The unsaturated alkyl group has one or more double bonds or triple bonds, and examples thereof include, but are not limited to, vinyl, 2-propenyl, butenyl, crotonyl, 2-isopentenyl, 2-(butadienyl ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and iso Constructor.

除非另有規定，術語“雜烴基”或者其下位概念（比如雜烷基、雜烯基、雜炔基、雜芳基等等）本身或者與另一術語聯合表示穩定的直鏈的、支鏈的或環狀的烴原子團或其組合，有一定數目的碳原子和至少一個雜原子組成。在一些實施例中，術語“雜烷基”本身或者與另一術語聯合表示穩定的直鏈的、支鏈的烴原子團或其組合物，有一定數目的碳原子和至少一個雜原子組成。在一個典型實施例中，雜原子選自B、O、N和S，其中氮和硫原子任選地被氧化，氮雜原子任選地被四級銨化。雜原子或雜原子團可以位於雜烴基的任何內部位置（包括該烴基附著於分子其餘部分的位置）。實例包括但不限於-CH2 -CH2 -O-CH3 、-CH2 -CH2 -NH-CH3 、-CH2 -CH2 -N(CH3 )-CH3 、-CH2 -S-CH2 -CH3 、-CH2 -CH2 、-S(O)-CH3 、-CH2 -CH2 -S(O)2 -CH3 、-CH=CH-O-CH3 、 -CH2 -CH=N-OCH3 和-CH=CH-N(CH3 )-CH3 。至多兩個雜原子可以是連續的，例如-CH2 -NH-OCH3 。Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in conjunction with another term means a stable linear, branched chain The cyclic or cyclic hydrocarbon atom group or a combination thereof has a certain number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in combination with another term means a stable linear, branched hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The heteroatom or heteroatom group may be located at any internal position of the heterohydrocarbon group (including the position where the hydrocarbon group is attached to the rest of the molecule). Examples include but are not limited to -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S -CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 ,- CH 2 -CH=N-OCH 3 and -CH=CH-N(CH 3 )-CH 3 . Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.

除非另有規定，術語“烷氧基”、“烷氨基”和“烷硫基”（或硫代烷氧基）屬於慣用表達，是指分別通過一個氧原子、氨基或硫原子連接到分子的其餘部分的那些烷基基團。Unless otherwise specified, the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are conventional expressions and refer to those linked to the molecule through an oxygen atom, amino group or sulfur atom, respectively The rest of those alkyl groups.

除非另有規定，術語“環烴基”、“雜環烴基”或者其下位概念（比如芳基、雜芳基、環烷基、雜環烷基、環烯基、雜環烯基、環炔基、雜環炔基等等）本身或與其他術語聯合分別表示環化的“烴基”、“雜烴基”。此外，就雜烴基或雜環烴基（比如雜烷基、雜環烷基）而言，雜原子可以佔據該雜環附著於分子其餘部分的位置。環烷基的實例包括但不限於環戊基、環己基、1-環己烯基、3-環己烯基、環庚基等。雜環基的非限制性實例包括1-（1,2,5,6-四氫吡啶基）、1-呱啶基、2-呱啶基，3-呱啶基、4-嗎啉基、3-嗎啉基、四氫呋喃-2-基、四氫呋喃吲哚-3-基、四氫噻吩-2-基、四氫噻吩-3 -基，1-呱嗪基和2-呱嗪基。Unless otherwise specified, the term "cyclohydrocarbyl", "heterocyclic hydrocarbyl" or its subordinate concepts (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) , Heterocyclic alkynyl, etc.) by itself or in combination with other terms means cyclized "hydrocarbyl" and "heterohydrocarbyl", respectively. In addition, in the case of heterohydrocarbon groups or heterocyclic hydrocarbon groups (such as heteroalkyl, heterocycloalkyl), heteroatoms can occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-pyridyl, 2-pyridyl, 3-pyridyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran indol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-pentazinyl and 2-pentazinyl.

除非另有規定，術語“芳基”表示多不飽和的芳族烴取代基，可以是單取代、二取代或多取代的，可以是一價、二價或者多價，它可以是單環或多環（比如1至3個環；其中至少一個環是芳族的），它們稠合在一起或共價連接。術語“雜芳基”是指含有一至四個雜原子的芳基（或環）。在一個示範性實例中，雜原子選自B、N、O和S，其中氮和硫原子任選地被氧化，氮原子任選地被四級銨化。雜芳基可通過雜原子連接到分子的其餘部分。芳基或雜芳基的非限制性實施例包括苯基、1-萘基、2-萘基、4-聯苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-惡唑基、4-惡唑基、2-苯基-4- 惡唑基、5-惡唑基、3 -異惡唑基、4-異惡唑基、5-異惡唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯並噻唑基、嘌呤基、2-苯並咪唑基、5-吲哚基、1-異喹啉基、5-異喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。除非另有規定，芳基在與其他術語聯合使用時（例如芳氧基、芳硫基、芳烷基）包括如上定義的芳基和雜芳基環。因此，術語“芳烷基”意在包括芳基附著於烷基的那些原子團（例如苄基、苯乙基、吡啶基甲基等），包括其中碳原子（如亞甲基）已經被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-（1-萘氧基）丙基等。Unless otherwise specified, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which may be mono-substituted, di-substituted or poly-substituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic rings (such as 1 to 3 rings; at least one of which is aromatic) fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms. In an exemplary example, the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. Heteroaryl groups can be attached to the rest of the molecule through heteroatoms. Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyryl Oxazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxyl Oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thiophene Group, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. Unless otherwise specified, aryl when used in combination with other terms (eg, aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above. Therefore, the term "aralkyl" is intended to include those radicals where the aryl group is attached to the alkyl group (eg, benzyl, phenethyl, pyridylmethyl, etc.), including where carbon atoms (eg, methylene) have been replaced by, for example, oxygen Those alkyl groups substituted by atoms are, for example, phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl, and the like.

術語“離去基團”是指可以被另一種官能團或原子通過取代反應（例如親和取代反應）所取代的官能團或原子。例如，代表性的離去基團包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、對溴苯磺酸酯、對甲苯磺酸酯等；醯氧基，如乙醯氧基、三氟乙醯氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate Ester, etc.; Acyloxy, such as acetoxy, trifluoroethoxy, etc.

術語“保護基”包括但不限於“氨基保護基”、“羥基保護基”或“巰基保護基”。術語“氨基保護基”是指適合用於阻止氨基氮位上副反應的保護基團。代表性的氨基保護基包括但不限於：甲醯基；醯基，例如鏈烷醯基（如乙醯基、三氯乙醯基或三氟乙醯基）；烷氧基羰基，如第三丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基（Bn）、三苯甲基(Tr)、1,1-二-（4'-甲氧基苯基）甲基；甲矽烷基，如三甲基甲矽烷基（TMS）和第三丁基二甲基甲矽烷基（TBS）等等。術語“羥基保護基”是指適合用於阻止羥基副反應的保護基。代表性羥基保護基包括但不限於：烷基，如甲基、乙基和第三丁基；醯基，例如鏈烷醯基（如乙醯基）；芳基甲基，如苄基（Bn），對甲氧基苄基（PMB）、9-芴基甲基(Fm)和二苯基甲基（二苯甲基，DPM）；甲矽烷基，如三甲基甲矽烷基（TMS）和第三丁基二甲基甲矽烷基（TBS）等等。The term "protecting group" includes but is not limited to "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: methyl acetyl; acetyl, such as alkanoyl (such as acetyl, trichloroethyl acetyl, or trifluoroethyl acetyl); alkoxycarbonyl, such as the third Butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorene methoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr ), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tertiary butyldimethylsilyl (TBS), etc. Wait. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of hydroxyl groups. Representative hydroxy protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acetyl groups, such as alkanoyl groups (such as acetyl group); arylmethyl groups, such as benzyl group (Bn ), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) And tertiary butyldimethylsilyl (TBS) and so on.

本發明的化合物可以通過本領域技術人員所熟知的多種合成方法來製備，包括下面列舉的具體實施方式、其與其他化學合成方法的結合所形成的實施方式以及本領域技術上人員所熟知的等同替換方式，優選的實施方式包括但不限於本發明的實施例。The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthetic methods, and equivalents well known to those skilled in the art Alternatively, preferred embodiments include but are not limited to the embodiments of the present invention.

本發明所使用的溶劑可經市售獲得。本發明採用下述縮略詞：aq代表水；DCM代表二氯甲烷；PE代表石油醚；DMF代表N，N-二甲基甲醯胺；DMA代表N，N-二甲基乙醯胺；MeCN 代表乙腈；NMP 代表N-甲基-2-吡咯烷酮；DME代表1,2-二甲氧基乙烷；TsOH代表對甲苯磺酸；DMSO代表二甲亞碸；EtOH代表乙醇；MeOH代表甲醇；HOAc代表乙酸；NaCNBH3代表氰基硼氫化鈉；THF代表四氫呋喃；Boc2O代表二-第三丁基二碳酸酯；TFA代表三氟乙酸；DIEA代表二異丙基乙基胺；Pd(dppf)Cl2代表 [1,1' - 雙（二苯基膦基）二茂鐵]二氯化鈀（II）；NaH代表氫化鈉；LAH代表氫化鋁鋰；Pd(OAc)2 代表鈀（II）乙酸鹽；Pd2 (dba)3 代表三（二亞苄基丙酮）二鈀；Xantphos代表4,5 - 雙（二苯基膦基）-9,9 - 二甲基；MeSO3 H代表甲磺酸；t-BuOK代表第三丁醇鉀；MsCl代表甲烷磺醯氯；HATU代表O-(7-氮雜苯並***-1- 基）-N，N，N'，N'-四甲基脲六氟磷酸鹽；Cs2 CO3 代表碳酸銫；K2 CO3 代表碳酸鉀；NaHCO3 代表碳酸氫鈉；Na2 SO4 代表硫酸鈉；KOAc代表醋酸鉀；t-BuOH代表第三丁醇；TFAA代表三氟乙酸酐；FA代表甲酸；DBU代表1,8-二氮雜雙環[5.4.0]十一-7-烯；m-CPBA代表3-氯過氧苯甲酸；DAST代表二乙基氨基三氟化硫。The solvent used in the present invention is commercially available. This invention uses the following abbreviations: aq stands for water; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; DMA stands for N,N-dimethylacetamide; MeCN stands for acetonitrile; NMP stands for N-methyl-2-pyrrolidone; DME stands for 1,2-dimethoxyethane; TsOH stands for p-toluenesulfonic acid; DMSO stands for dimethyl sulfoxide; EtOH stands for ethanol; MeOH stands for methanol; HOAc stands for acetic acid; NaCNBH3 stands for sodium cyanoborohydride; THF stands for tetrahydrofuran; Boc2O stands for di-third butyl dicarbonate; TFA stands for trifluoroacetic acid; DIEA stands for diisopropylethylamine; Pd(dppf)Cl2 stands for [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloride; NaH stands for sodium hydride; LAH stands for lithium aluminum hydride; Pd(OAc) 2 stands for palladium(II) acetate; Pd 2 (dba) 3 represents tris(dibenzylideneacetone) dipalladium; Xantphos represents 4,5 -bis(diphenylphosphino)-9,9 -dimethyl; MeSO 3 H represents methanesulfonic acid; t -BuOK stands for potassium tributoxide; MsCl stands for methanesulfonyl chloride; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexa Fluorophosphate; Cs 2 CO 3 represents cesium carbonate; K 2 CO 3 represents potassium carbonate; NaHCO 3 represents sodium bicarbonate; Na 2 SO 4 represents sodium sulfate; KOAc represents potassium acetate; t-BuOH represents third butanol; TFAA Stands for trifluoroacetic anhydride; FA stands for formic acid; DBU stands for 1,8-diazabicyclo[5.4.0]undec-7-ene; m-CPBA stands for 3-chloroperoxybenzoic acid; DAST stands for diethylamino Sulfur trifluoride.

化合物經手工或者ChemDraw® 軟體命名，市售化合物採用供應商目錄名稱。Compounds are named by hand or ChemDraw ® software, and commercially available compounds use the supplier catalog name.

在一些實施例中，具有式（I）的化合物可以按照方案A中所述的合成方法製備。其中W選自以下結構：

Figure 02_image341
In some embodiments, compounds of formula (I) can be prepared according to the synthetic methods described in Scheme A. Where W is selected from the following structures:
Figure 02_image341

方案A：

Figure 02_image343
Option A:
Figure 02_image343

在上述方案A中，二氯嘧啶衍生物（A）在路易士酸如FeCl3 或AlCl3 的存在下與富電的三環或二環化合物(B)發生類富克反應，或者與硼酸酯(C)經由Suzuki偶合反應生成化合物(D)。化合物(D)與芳胺（E）在如TsOH 或 TfOH酸存在下經由SNAr取代，或在鈀催化下，在鹼如無水磷酸鉀，在配體如XPhos存在下發生偶合反應得到（F），收率中等到優良。（F）與不同的親核試劑如N1，N1二甲基乙烷-1,2-二胺，在鹼如DIEA存在下得到化合物(G)，它可以在還原劑如Pd/C, NH4Cl/Fe條件下還原得到胺(H)。胺(H)可以與丙烯醯氯(I)在鹼如DIEA存在下，在低溫如（(-40~0℃)）直接醯化得式一化合物(K)，也可以由胺(H)與3-氯代丙醯氯(J)先經一步醯化，再在鹼如NaOH存下發生消除反應得到式一的化合物(K)。In the above scheme A, the dichloropyrimidine derivative (A) in the presence of Lewis acid such as FeCl 3 or AlCl 3 undergoes a rich-like reaction with an electrically rich tricyclic or bicyclic compound (B), or with boric acid The ester (C) generates the compound (D) via the Suzuki coupling reaction. Compound (D) and aromatic amine (E) are substituted by SNAr in the presence of acid such as TsOH or TfOH, or under palladium catalysis, coupling reaction occurs in the presence of a base such as anhydrous potassium phosphate and a ligand such as XPhos to obtain (F), The yield is medium to excellent. (F) With different nucleophiles such as N1, N1 dimethylethane-1,2-diamine, compound (G) is obtained in the presence of a base such as DIEA, which can be used in reducing agents such as Pd/C, NH4Cl/ Reduction under Fe gives amine (H). The amine (H) can be directly compounded with propylene acetyl chloride (I) in the presence of a base such as DIEA at a low temperature such as ((-40~0°C)) to obtain the compound of formula one (K). 3-Chloropropionyl chloride (J) undergoes one-step acylation, and then undergoes elimination reaction in the presence of a base such as NaOH to obtain the compound of formula one (K).

方案B為合成

Figure 02_image345
的一般方法，其中n 等於0，Y1 、Y2 和Y3 是 CH2 。Scheme B is synthesis
Figure 02_image345
The general method, where n is equal to 0, Y 1 , Y 2 and Y 3 are CH 2 .

方案B：

Figure 02_image347
Option B:
Figure 02_image347

醛(L)與磷酸酯經由wittig反應得到(M)，用還原劑如LAH還原(M)，接著用MsCl酯化得到(N)， (N)可在鹼如NaH存在下環化得到(O)，它可以與二氯嘧啶衍生物（A）按照方案A反應得到(D)。Aldehyde (L) and phosphate are obtained by wittig reaction (M), reduced with a reducing agent such as LAH (M), followed by esterification with MsCl to obtain (N), (N) can be obtained by cyclization in the presence of a base such as NaH (O ), which can be reacted with dichloropyrimidine derivative (A) according to scheme A to obtain (D).

方案C為合成

Figure 02_image345
的一般方法，其中n 等於1，Y1 和Y3 是 CH2 ，Y2 是O。
Figure 02_image349
Scheme C is synthesis
Figure 02_image345
The general method, where n is equal to 1, Y 1 and Y 3 are CH 2 , Y 2 is O.
Figure 02_image349

取代2-羥甲基吲哚(P)與二苯基乙烯基鋶鹽（Q）在鹼如氫氧化鉀，溶劑如二氯甲烷的存在下經由加成和分子內關環反應得到(R)，它可以與二氯嘧啶衍生物（A）按照方案A反應得到(D)。Substituted 2-hydroxymethylindole (P) and diphenylvinyl alkoxide salt (Q) are obtained by addition and intramolecular ring closure reaction in the presence of a base such as potassium hydroxide and a solvent such as dichloromethane (R) It can be reacted with dichloropyrimidine derivative (A) according to scheme A to obtain (D).

方案D為合成

Figure 02_image059
的一般方法，其中Y1 、Y2 和Y3 是CH2 。Scheme D is synthesis
Figure 02_image059
The general method, wherein Y 1 , Y 2 and Y 3 are CH 2 .

流程 C：

Figure 02_image352
Process C:
Figure 02_image352

取代的7-羥基吲哚與鹵代醇（T）經由Mitsunobu反應得吲哚衍生物（U）， 化合物（U）在鹼如鈉氫的存在下關環得到化合物（V），它可以與二氯嘧啶衍生物（A）按照方案A反應得到(D)。The substituted 7-hydroxyindole and halohydrin (T) are reacted via Mitsunobu to obtain the indole derivative (U). The compound (U) is ring-closed in the presence of a base such as sodium hydrogen to obtain the compound (V). The chloropyrimidine derivative (A) is reacted according to Scheme A to obtain (D).

下面的說明性實施例已使用本文公開的方法的方法進行製備，分離和表徵。為了更詳細地說明本發明，給出下列實例，但本發明的範圍並非限定於此。The following illustrative examples have been prepared, isolated, and characterized using the methods disclosed herein. In order to explain the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

流程1Process 1

中間體A和B的一般製備方法：

Figure 02_image354
General preparation methods of intermediates A and B:
Figure 02_image354

實施例A1 。Example A1.

4-氟-2-甲氧基苯胺。

Figure 02_image356
4-fluoro-2-methoxyaniline.
Figure 02_image356

將2 - 甲氧基 - 4- 氟硝基苯（100.00克，584.35毫莫耳）溶於甲醇（400mL）中，氮氣置換後加入Pd/C（10%，10克）。混合物在H2 中（壓力為50 Psi）加熱至40°C，攪拌12小時。TLC顯示反應完成，將反應混合物過濾，濾液濃縮至乾，得到標題化合物（紅色油狀，83.00克，產率93.28%)。LCMS (ESI) (10-80CD): m/z: 142.1 [M+1]。Dissolve 2-methoxy-4-fluoronitrobenzene (100.00 g, 584.35 mmol) in methanol (400 mL), add Pd/C (10%, 10 g) after nitrogen replacement. The mixture was heated to 40°C in H 2 (pressure 50 Psi) and stirred for 12 hours. TLC showed that the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to dryness to obtain the title compound (red oil, 83.00 g, yield 93.28%). LCMS (ESI) (10-80CD): m/z: 142.1 [M+1].

實施例A2 。Example A2.

4-氟-2-甲氧基–5–硝基苯胺。

Figure 02_image358
4-fluoro-2-methoxy-5–nitroaniline.
Figure 02_image358

在0°C下，將實施例A1（83.00克，558.67毫莫耳）慢慢滴加至濃H2 SO4 （415mL）中，然後分批加入KNO3 （56.48克，558.67毫莫耳）。混合物在0-10°C下攪拌3小時。TLC顯示反應完成，向反應混合物中加入NH3 ·H2 O至pH為8，溫度控制在10°C下。將得到的混合物過濾，濾餅用水（500mL）洗滌後，溶於DCM（1L），並用無水硫酸鈉乾燥，濃縮後，用柱色譜（PE：DCM = 5:1，1:10）分離純化，得到標題化合物（黃色固體，60.00克，產率54.81%)。1 H NMR (400 MHz, CDCl3): δ 7.40 (d, J=7.2 Hz, 1 H), 6.64 (d, J=12.4 Hz, 1 H), 3.86 - 3.97 (m, 5 H)。At 0°C, Example A1 (83.00 g, 558.67 mmol) was slowly added dropwise to concentrated H 2 SO 4 (415 mL), and then KNO 3 (56.48 g, 558.67 mmol) was added in portions. The mixture was stirred at 0-10°C for 3 hours. TLC showed that the reaction was completed, and NH 3 .H 2 O was added to the reaction mixture until the pH was 8, and the temperature was controlled at 10°C. The obtained mixture was filtered, and the filter cake was washed with water (500 mL), dissolved in DCM (1 L), and dried over anhydrous sodium sulfate. After concentration, it was separated and purified by column chromatography (PE: DCM = 5:1, 1:10). The title compound was obtained (yellow solid, 60.00 g, yield 54.81%). 1 H NMR (400 MHz, CDCl3): δ 7.40 (d, J=7.2 Hz, 1 H), 6.64 (d, J=12.4 Hz, 1 H), 3.86-3.97 (m, 5 H).

實施例A3 。Example A3.

（E）- 乙基3-（1H-吲哚-2-基）丙烯酸乙酯。

Figure 02_image360
(E)-ethyl 3-(1H-indol-2-yl)acrylate.
Figure 02_image360

在0°C下，將2 - 膦酸二乙酯-乙酸乙酯（18.53克，82.67毫莫耳）溶於THF（100mL），向該混合物中加入NaH（4.13克，60%w，103.33毫莫耳），攪拌1小時。再滴加入1 – 氫 - 2 – 甲醛吲哚（10克，69.89毫莫耳）的THF（80mL）溶液，升溫至20°C，攪拌10小時。TLC顯示反應完成，向反應混合物中加入飽和NH4 Cl（100mL）溶液，濃縮除去THF後，用EA（100mL x 3）萃取，並用飽和食鹽水（100mL x 2）洗滌後，無水硫酸鈉乾燥，濃縮得到標題化合物（黃色固體，12.20克，產率74.05%)。1 H NMR (400MHz, CDCl3): δ, 8.60(br. s., 1H), 7.71(d, J = 16.0Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.39 (d, J = 8.4Hz, 1H), 7.30-7.26 (m, 1H), 7.15-7.14 (m, 1H), 6.84 (s, 1H), 6.28 (d, J = 16.0Hz, 1H), 4.33-4.28 (m, 2H), 1.39-1.35 (m, 3H)。At 0°C, diethylphosphonate-ethyl acetate (18.53 g, 82.67 mmol) was dissolved in THF (100 mL), and NaH (4.13 g, 60%w, 103.33 mmol) was added to the mixture. Mohr), stirring for 1 hour. A solution of 1-hydro-2-formaldehyde indole (10 g, 69.89 mmol) in THF (80 mL) was added dropwise, the temperature was raised to 20°C, and the mixture was stirred for 10 hours. TLC showed that the reaction was completed. To the reaction mixture was added a saturated NH 4 Cl (100 mL) solution. After concentration to remove THF, it was extracted with EA (100 mL x 3), washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. Concentration gave the title compound (yellow solid, 12.20 g, yield 74.05%). 1 H NMR (400MHz, CDCl3): δ, 8.60(br. s., 1H), 7.71(d, J = 16.0Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.39 (d, J = 8.4Hz, 1H), 7.30-7.26 (m, 1H), 7.15-7.14 (m, 1H), 6.84 (s, 1H), 6.28 (d, J = 16.0Hz, 1H), 4.33-4.28 (m, 2H), 1.39-1.35 (m, 3H).

實施例A4 。Example A4.

3-（1H-吲哚-2-基）丙-1-醇。

Figure 02_image362
3-(1H-Indol-2-yl)propan-1-ol.
Figure 02_image362

在0°C下，將LiAlH4 （4.58克，120.79毫莫耳）懸浮於THF（100mL），向該混合物中加入實施例A3（13.00克，60.69毫莫耳）的THF（50mL）溶液，攪拌8小時。TLC顯示反應完成，向反應混合物中依次加入水（4.5mL）、15%的NaOH（4.5mL）溶液和水（13.5mL），攪拌30分鐘，無水硫酸鎂乾燥。混合物過濾，濾液濃縮後，用柱色譜（PE：EA = 6:1，1:1）分離純化，得到標題化合物（黃色油狀，9.00克，產率76.54%)。1 H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.56 (d, J = 7.6Hz, 1H), 7.34-7.27 (m, 1H), 7.18-7.08 (m, 2H), 6.27 (s, 1H), 3.83-3.71 (m, 2H), 2.94-2.81 (m, 2H), 2.04-1.91 (m, 2H)。At 0°C, LiAlH 4 (4.58 g, 120.79 mmol) was suspended in THF (100 mL), to this mixture was added a solution of Example A3 (13.00 g, 60.69 mmol) in THF (50 mL), and stirred 8 hours. TLC showed that the reaction was completed, and water (4.5 mL), 15% NaOH (4.5 mL) solution and water (13.5 mL) were added to the reaction mixture in this order, stirred for 30 minutes, and dried over anhydrous magnesium sulfate. The mixture was filtered, and after the filtrate was concentrated, it was separated and purified by column chromatography (PE:EA = 6:1, 1:1) to obtain the title compound (yellow oil, 9.00 g, yield 76.54%). 1 H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.56 (d, J = 7.6Hz, 1H), 7.34-7.27 (m, 1H), 7.18-7.08 (m, 2H), 6.27 ( s, 1H), 3.83-3.71 (m, 2H), 2.94-2.81 (m, 2H), 2.04-1.91 (m, 2H).

實施例A5。Example A5.

3-（1H-吲哚-2-基）丙基甲磺酸酯。

Figure 02_image364
3-(1H-Indol-2-yl)propyl methanesulfonate.
Figure 02_image364

在0°C下，將實施例A4（9.23克，42.12毫莫耳）和TEA（8.52克，84.24毫莫耳）溶於DCM（100mL），向該混合物中加入甲磺醯氯（7.24克，63.18毫莫耳），攪拌10小時。TLC顯示反應完成，向混合物中加入水（30mL），用DCM（30mL x3）萃取，有機層經無水硫酸鈉乾燥，濃縮後，用柱色譜（PE：EA = 20:1，3:1）分離純化，得到標題化合物（棕色固體，4.50克，產率37.96%)。1 H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.56 (d, J = 7.6Hz, 1H), 7.34-7.27 (m, 1H), 7.18-7.08 (m, 2H), 6.28 (s, 1H), 4.32-4.29 (m, 2H), 3.02 (s, 3H), 2.94-2.90 (m, 2H), 2.20-2.13 (m, 2H)。At 0°C, Example A4 (9.23 g, 42.12 mmol) and TEA (8.52 g, 84.24 mmol) were dissolved in DCM (100 mL), to this mixture was added mesyl chloride (7.24 g, 63.18 millimoles), stirring for 10 hours. TLC showed that the reaction was completed. Water (30 mL) was added to the mixture, extracted with DCM (30 mL x 3), the organic layer was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE: EA = 20:1, 3:1) Purification gave the title compound (brown solid, 4.50 g, yield 37.96%). 1 H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.56 (d, J = 7.6Hz, 1H), 7.34-7.27 (m, 1H), 7.18-7.08 (m, 2H), 6.28 ( s, 1H), 4.32-4.29 (m, 2H), 3.02 (s, 3H), 2.94-2.90 (m, 2H), 2.20-2.13 (m, 2H).

實施例A6 。Example A6.

2,3-二氫-1H-吡咯並[1,2-α]吲哚。

Figure 02_image366
2,3-dihydro-1H-pyrrolo[1,2-α]indole.
Figure 02_image366

在25°C下，將實施例A5（4.50克，17.76毫莫耳）溶於THF（150mL），向該混合物中加入NaH（852.48毫克，60%w，35.52毫莫耳），攪拌12小時。TLC顯示反應完成，向混合物中加入飽和NH4 Cl溶液至呈中性，濃縮除去THF後，用EA（30mL x3）萃取，有機層經無水硫酸鈉乾燥，濃縮後，用柱色譜（PE：EA = 200:1，100:1）分離純化，得到標題化合物（黃色固體，2.80克，產率95.27%)。1 H NMR (400MHz, CDCl3): δ 7.57(d, J =8.8Hz, 1H), 7.28-7.24 (m, 1H), 7.14-7.11 (m, 1H), 7.10-7.04 (m, 1H), 6.19 (br. s., 1H), 4.12-4.06 (m, 2H), 3.09-3.00 (m, 2H), 2.69-2.59 (m, 2H)。At 25°C, Example A5 (4.50 g, 17.76 mmol) was dissolved in THF (150 mL), and NaH (852.48 mg, 60%w, 35.52 mmol) was added to the mixture, and stirred for 12 hours. TLC showed that the reaction was completed, and a saturated NH 4 Cl solution was added to the mixture until it was neutral. After concentration and removal of THF, it was extracted with EA (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate. After concentration, it was subjected to column chromatography (PE: EA) = 200:1, 100:1) isolated and purified to obtain the title compound (yellow solid, 2.80 g, yield 95.27%). 1 H NMR (400MHz, CDCl3): δ 7.57(d, J =8.8Hz, 1H), 7.28-7.24 (m, 1H), 7.14-7.11 (m, 1H), 7.10-7.04 (m, 1H), 6.19 (br. s., 1H), 4.12-4.06 (m, 2H), 3.09-3.00 (m, 2H), 2.69-2.59 (m, 2H).

實施例A。Example A.

9 - （2 -氯嘧啶-4-基） -2,3- 二氫 - 1H - 吡咯並[1,2-α]吲哚。

Figure 02_image368
9-(2-chloropyrimidin-4-yl) -2,3-dihydro-1H-pyrrolo[1,2-α]indole.
Figure 02_image368

將實施例A6（3.50克，22.26毫莫耳）與2，4 – 二氯嘧啶（6.63克，44.53毫莫耳）溶於DME（40mL），向該混合物中加入FeCl3 （3.61克，22.26毫莫耳），並升溫至70°C攪拌12小時。TLC顯示反應液中有60%的標題化合物和40%的實施例1F，將混合物過濾，濃縮，向其中加入水（20mL），用EA（20mL x3）萃取，有機層經無水硫酸鈉乾燥，濃縮後，用柱色譜（PE：EA = 200:1，100:1）分離純化，得到標題化合物（白色固體，3.00克，產率47.47%)。1 H NMR (400MHz, CDCl3): δ 8.41 (d, J = 5.2Hz, 1H), 8.36-8.31 (m, 1H), 7.38 (d, J = 5.6Hz, 1H), 7.33-7.27 (m, 3H), 4.20-4.15 (m, 2H), 3.44-3.37 (m, 2H), 2.79-2.73 (m, 2H)。LCMS (ESI) (5-95AB):m/z: 269.9 [M+1]。Example A6 (3.50 g, 22.26 mmol) and 2,4-dichloropyrimidine (6.63 g, 44.53 mmol) were dissolved in DME (40 mL), and FeCl 3 (3.61 g, 22.26 mmol) was added to the mixture Mohr), and heated to 70 °C and stirred for 12 hours. TLC showed 60% of the title compound and 40% of Example 1F in the reaction solution. The mixture was filtered and concentrated. Water (20 mL) was added to it and extracted with EA (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated. After that, it was separated and purified by column chromatography (PE:EA=200:1, 100:1) to obtain the title compound (white solid, 3.00 g, yield 47.47%). 1 H NMR (400MHz, CDCl3): δ 8.41 (d, J = 5.2Hz, 1H), 8.36-8.31 (m, 1H), 7.38 (d, J = 5.6Hz, 1H), 7.33-7.27 (m, 3H ), 4.20-4.15 (m, 2H), 3.44-3.37 (m, 2H), 2.79-2.73 (m, 2H). LCMS (ESI) (5-95AB): m/z: 269.9 [M+1].

實施例B 。Example B.

4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）-N-（4-氟-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image370
4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidine -2-amine.
Figure 02_image370

將實施例A（2.40克，8.90毫莫耳）與2 – 甲氧基 – 4 – 氟 - 5 – 硝基苯胺（1.66克，8.90毫莫耳）溶於1，4 - 二氧六環（40mL），向該混合物中加入TsOH（1.53克，8.90毫莫耳），並升溫至120°C攪拌10小時。LCMS顯示反應完成，向混合物中加入飽和NaHCO3 溶液（30mL），濃縮除去1，4 - 二氧六環，再加入水（50mL），用DCM（50mL x3）萃取，有機層經無水硫酸鈉乾燥，濃縮後，得到粗產品。該產品經PE/EA（5: 1, 20mL x 2）洗滌後，得到標題化合物（黃色固體，3.30克，產率83.99%)。1 H NMR (400MHz, CDCl3): δ 9.46 (d, J = 8.0Hz, 1H), 8.41 (d, J = 5.2Hz, 1H), 8.33-8.23 (m, 1H), 7.58 (s, 1H), 7.35-7.30 (m, 1H), 7.28-7.24 (m, 2H), 7.15 (d, J = 5.2Hz, 1H), 6.78 (d, J = 12.4Hz, 1H), 4.22-4.16 (m, 2H), 4.06 (s, 3H), 3.47 (t, J = 7.2 Hz, 2H), 2.78-2.73 (m, 2H)。LCMS (ESI) (5-95AB):m/z: 420.0 [M+1]。Example A (2.40 g, 8.90 mmol) and 2-methoxy-4-fluoro-5-nitroaniline (1.66 g, 8.90 mmol) were dissolved in 1,4-dioxane (40 mL) ), TsOH (1.53 g, 8.90 mmol) was added to the mixture, and the temperature was raised to 120°C and stirred for 10 hours. LCMS showed that the reaction was complete. To the mixture was added saturated NaHCO 3 solution (30 mL), concentrated to remove 1,4-dioxane, water (50 mL) was added, extracted with DCM (50 mL x 3), and the organic layer was dried over anhydrous sodium sulfate After concentration, a crude product is obtained. After washing the product with PE/EA (5: 1, 20 mL x 2), the title compound (yellow solid, 3.30 g, yield 83.99%) was obtained. 1 H NMR (400MHz, CDCl3): δ 9.46 (d, J = 8.0Hz, 1H), 8.41 (d, J = 5.2Hz, 1H), 8.33-8.23 (m, 1H), 7.58 (s, 1H), 7.35-7.30 (m, 1H), 7.28-7.24 (m, 2H), 7.15 (d, J = 5.2Hz, 1H), 6.78 (d, J = 12.4Hz, 1H), 4.22-4.16 (m, 2H) , 4.06 (s, 3H), 3.47 (t, J = 7.2 Hz, 2H), 2.78-2.73 (m, 2H). LCMS (ESI) (5-95AB): m/z: 420.0 [M+1].

流程2。Process 2.

實施例1的一般製備方法：

Figure 02_image372
General preparation method of Example 1:
Figure 02_image372

實施例1。Example 1.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2（（2-（二甲基氨基）乙基）氨基）-4-甲氧苯基）丙烯醯胺。

Figure 02_image374
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2((2-( Dimethylamino)ethyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image374

實施例1A。Example 1A.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-N4-（2-（二甲基氨基）乙基）-2-甲氧基 - N 4 - 甲基-5-硝基苯-1,4-二胺。

Figure 02_image376
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N4-(2-(dimethylamino)ethyl Group)-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image376

將實施例B（2.80克，6.68毫莫耳）與N,N’,N’ – 三甲基 – 1,2 - 乙二胺（1.02克，10.01毫莫耳）溶於DMA（50mL），向該混合物中加入DIEA（1.29克，10.01毫莫耳），並升溫至90°C攪拌2小時。LCMS顯示反應完成，混合物濃縮除去DMA，加入水（30mL），用DCM（50mL x3）萃取，有機層經無水硫酸鈉乾燥，濃縮後，得到粗產品。該產品經PE/EA（5: 1, 20mL x 2）洗滌後，得到標題化合物（紅色固體，3.20克，產率90.73%)。1 H NMR (400MHz, CDCl3): δ 9.03 (s, 1H), 8.35-8.24 (m, 2H), 7.36 (d, J = 7.2Hz, 1H), 7.24-7.12 (m, 3H), 7.09 (s, 1H), 4.21-4.14 (m, 2H), 4.10 (s, 3H), 3.53-3.48 (m, 2H), 3.43-3.37 (m, 4H), 2.99 (s, 6H), 2.88 (s, 3H), 2.76-2.69 (m, 2H)。LCMS (ESI) (0-60AB):m/z: 502.2 [M+1]。Example B (2.80 g, 6.68 mmol) and N,N',N'-trimethyl-1,2-ethylenediamine (1.02 g, 10.01 mmol) were dissolved in DMA (50 mL), DIEA (1.29 g, 10.01 mmol) was added to the mixture, and the temperature was raised to 90°C and stirred for 2 hours. LCMS showed that the reaction was completed, the mixture was concentrated to remove DMA, water (30 mL) was added, extracted with DCM (50 mL x 3), the organic layer was dried over anhydrous sodium sulfate, and after concentration, a crude product was obtained. After washing the product with PE/EA (5: 1, 20 mL x 2), the title compound (red solid, 3.20 g, yield 90.73%) was obtained. 1 H NMR (400MHz, CDCl3): δ 9.03 (s, 1H), 8.35-8.24 (m, 2H), 7.36 (d, J = 7.2Hz, 1H), 7.24-7.12 (m, 3H), 7.09 (s , 1H), 4.21-4.14 (m, 2H), 4.10 (s, 3H), 3.53-3.48 (m, 2H), 3.43-3.37 (m, 4H), 2.99 (s, 6H), 2.88 (s, 3H ), 2.76-2.69 (m, 2H). LCMS (ESI) (0-60AB): m/z: 502.2 [M+1].

實施例1B。Example 1B.

N4-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image378
N4-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N 1 -(2-(dimethylamino) Ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image378

在25°C下，將實施例1A（3.20克，6.38毫莫耳）溶於MeOH（100mL），氮氣置換後加入Pd/C（10%，500毫克）。混合物在H2 中（壓力為15 Psi），攪拌2小時。LCMS顯示反應完成，將反應混合物過濾，濾液濃縮至乾，得到標題化合物（灰色固體，2.42克，產率76.41%)。1 H NMR (400MHz, CDCl3): δ 8.53-8.48 (m, 1H), 8.33 (d, J = 5.2Hz, 1H), 8.16 (s, 1H), 7.56 (s, 1H), 7.33-7.29 (m, 1H), 7.28-7.23 (m, 2H), 6.95 (d, J = 5.2Hz, 1H), 6.70 (s, 1H), 4.17 (t, J = 7.2Hz, 2H), 3.87 (s, 3H), 3.39 (t, J = 7.6Hz, 2H), 3.22 (t, J = 6.4Hz, 2H), 2.83 (t, J = 6.0Hz, 2H), 2.78-2.71(m, 5H), 2.63 (s, 6H)。LCMS (ESI) (0-60AB):m/z: 472.2 [M+1]。At 25°C, Example 1A (3.20 g, 6.38 mmol) was dissolved in MeOH (100 mL), and after nitrogen substitution, Pd/C (10%, 500 mg) was added. The mixture was stirred in H 2 (pressure 15 Psi) for 2 hours. LCMS showed the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to dryness to obtain the title compound (gray solid, 2.42 g, yield 76.41%). 1 H NMR (400MHz, CDCl3): δ 8.53-8.48 (m, 1H), 8.33 (d, J = 5.2Hz, 1H), 8.16 (s, 1H), 7.56 (s, 1H), 7.33-7.29 (m , 1H), 7.28-7.23 (m, 2H), 6.95 (d, J = 5.2Hz, 1H), 6.70 (s, 1H), 4.17 (t, J = 7.2Hz, 2H), 3.87 (s, 3H) , 3.39 (t, J = 7.6Hz, 2H), 3.22 (t, J = 6.4Hz, 2H), 2.83 (t, J = 6.0Hz, 2H), 2.78-2.71(m, 5H), 2.63 (s, 6H). LCMS (ESI) (0-60AB): m/z: 472.2 [M+1].

實施例1C。Example 1C.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2（（2-（二甲基氨基）乙基）氨基）-4-甲氧苯基）丙烯醯胺。

Figure 02_image374
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2((2-( Dimethylamino)ethyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image374

在-40°C下，將實施例1B（2.40克，5.09毫莫耳）與DIEA（789.40毫克，6.11毫莫耳）溶於DCM（150mL），向該混合物中加入乙醯氯（460.00毫克，5.09毫莫耳），攪拌1小時。LCMS顯示有產物，向反應混合物中加入水（100mL），用DCM（50mL x3）萃取，有機相分離，無水硫酸鈉乾燥並濃縮，得到粗產物，粗產品通過製備HPLC分離純化，得到標題化合物（鹽酸鹽，859.00毫克，產率29.87%)。1 H NMR (400MHz, CD3OD): δ 8.30 (br. s., 1H), 8.01 (d, J = 7.2Hz, 1H), 7.88 (br. s., 1H), 7.43-7.39 (m, 1H), 7.31-7.17 (m, 3H), 7.10 (s, 1H), 6.75-6.70 (m, 1H), 6.47 (dd, J1 = 1.6Hz, J2 = 16.8Hz, 1H), 5.89-5.84 (m, 1H), 4.22 (t, J = 7.2Hz, 2H), 3.98 (s, 3H), 3.65-3.54 (m, 2H), 3.41-3.39 (m, 4H), 2.93 (s, 6H), 2.83 (s, 3H), 2.75 (t, J = 7.2Hz, 2H)。LCMS (ESI) (0-60AB):m/z: 526.2 [M+1]。At -40°C, Example 1B (2.40 g, 5.09 mmol) and DIEA (789.40 mg, 6.11 mmol) were dissolved in DCM (150 mL), and to this mixture was added acetyl chloride (460.00 mg, 5.09 millimoles), stirring for 1 hour. LCMS showed product, water (100 mL) was added to the reaction mixture, extracted with DCM (50 mL x 3), the organic phase was separated, dried over anhydrous sodium sulfate and concentrated to obtain crude product, which was separated and purified by preparative HPLC to obtain the title compound ( Hydrochloride, 859.00 mg, yield 29.87%). 1 H NMR (400MHz, CD3OD): δ 8.30 (br. s., 1H), 8.01 (d, J = 7.2Hz, 1H), 7.88 (br. s., 1H), 7.43-7.39 (m, 1H) , 7.31-7.17 (m, 3H), 7.10 (s, 1H), 6.75-6.70 (m, 1H), 6.47 (dd, J1 = 1.6Hz, J2 = 16.8Hz, 1H), 5.89-5.84 (m, 1H ), 4.22 (t, J = 7.2Hz, 2H), 3.98 (s, 3H), 3.65-3.54 (m, 2H), 3.41-3.39 (m, 4H), 2.93 (s, 6H), 2.83 (s, 3H), 2.75 (t, J = 7.2Hz, 2H). LCMS (ESI) (0-60AB): m/z: 526.2 [M+1].

實施例2。Example 2.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（3-（二甲基氨基）氮雜環丁烷-1-基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image381
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino) azetidine-1-yl)-4-methoxyphenyl) acrylamide.
Figure 02_image381

實施例2A。Example 2A.

4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）-N-（4-（3-（二甲基氨基）氮雜環丁烷-1-基）-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image383
4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-(3-(dimethylamino)azetidine-1 -Yl)-2-methoxy-5-nitrophenyl)pyrimidine-2-amine.
Figure 02_image383

本實施例根據實施例1A的方法製備，將N,N’,N’ – 三甲基 – 1,2 - 乙二胺替換為3 - N,N – 二甲基胺環丁胺鹽酸鹽。得到標題化合物（紅色固體，180.00毫克，產率90.67%)。1 H NMR (400MHz, CDCl3): δ 9.01 (br. s., 1H), 8.30-8.12 (m, 2H), 7.28-7.24 (m, 1H), 7.19 (d, J = 2.4Hz, 2H), 7.04 (d, J = 5.6Hz, 1H), 6.09 (s, 1H), 4.19-4.09 (m, 4H), 3.98-3.96 (m, 5H), 3.60 (br. s., 1H), 3.19-3.12 (m, 2H), 2.69-2.67 (m, 2H), 2.51 (br. s., 6H)。LCMS (ESI) (0-60AB):m/z: 500.2 [M+1]。This example was prepared according to the method of Example 1A, and N,N',N'-trimethyl-1,2-ethylenediamine was replaced with 3-N,N-dimethylamine cyclobutylamine hydrochloride. The title compound was obtained (red solid, 180.00 mg, yield 90.67%). 1 H NMR (400MHz, CDCl3): δ 9.01 (br. s., 1H), 8.30-8.12 (m, 2H), 7.28-7.24 (m, 1H), 7.19 (d, J = 2.4Hz, 2H), 7.04 (d, J = 5.6Hz, 1H), 6.09 (s, 1H), 4.19-4.09 (m, 4H), 3.98-3.96 (m, 5H), 3.60 (br. s., 1H), 3.19-3.12 (m, 2H), 2.69-2.67 (m, 2H), 2.51 (br. s., 6H). LCMS (ESI) (0-60AB): m/z: 500.2 [M+1].

實施例2B。Example 2B.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-4-（3-（二甲基氨基）氮雜環丁烷-1-基）-6-甲基苯-1,3-二胺。

Figure 02_image385
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)nitrogen Heterocyclobutan-1-yl)-6-methylbenzene-1,3-diamine.
Figure 02_image385

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例2A。得到標題化合物（棕色固體，170.00毫克，產率94.50%)。LCMS (ESI) (5-95AB):m/z: 470.2 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 2A. The title compound was obtained (brown solid, 170.00 mg, yield 94.50%). LCMS (ESI) (5-95AB): m/z: 470.2 [M+1].

實施例2C。Example 2C.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（3-（二甲基氨基）氮雜環丁烷-1-基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image381
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino) azetidine-1-yl)-4-methoxyphenyl) acrylamide.
Figure 02_image381

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例2B。得到標題化合物（TFA鹽，40.00毫克，產率26.11%)。1 H NMR (400MHz, DMSO-d6): δ 8.97 (br. s., 1H), 8.29-8.23 (m, 2H), 7.90 (s, 1H), 7.53 (s, 1H), 7.39-7.34 (m, 1H), 7.18-7.12 (m, 2H), 6.97 (d, J = 5.6Hz, 1H), 6.53-6.39 (m, 1H), 6.26 (s, 1H), 6.19 (dd, J1 = 2.0Hz, J2 = 17.2Hz, 1H), 5.65 (d, J = 10.4Hz, 1H), 4.15 (t, J = 7.2Hz, 2H), 3.97-3.94 (m, 2H), 3.87 (s, 3H), 3.64-3.62 (m, 2H), 3.31 (t, J = 7.6Hz, 2H), 2.66-2.62 (m, 3H), 2.14 (s, 6H)。LCMS (ESI) (5-95AB):m/z: 524.2 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 2B. The title compound (TFA salt, 40.00 mg, yield 26.11%) was obtained. 1 H NMR (400MHz, DMSO-d6): δ 8.97 (br. s., 1H), 8.29-8.23 (m, 2H), 7.90 (s, 1H), 7.53 (s, 1H), 7.39-7.34 (m , 1H), 7.18-7.12 (m, 2H), 6.97 (d, J = 5.6Hz, 1H), 6.53-6.39 (m, 1H), 6.26 (s, 1H), 6.19 (dd, J1 = 2.0Hz, J2 = 17.2Hz, 1H), 5.65 (d, J = 10.4Hz, 1H), 4.15 (t, J = 7.2Hz, 2H), 3.97-3.94 (m, 2H), 3.87 (s, 3H), 3.64- 3.62 (m, 2H), 3.31 (t, J = 7.6Hz, 2H), 2.66-2.62 (m, 3H), 2.14 (s, 6H). LCMS (ESI) (5-95AB): m/z: 524.2 [M+1].

實施例3。Example 3.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（2-（二甲基氨基）乙氧基）-4-甲氧苯基）丙烯醯胺。

Figure 02_image388
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(2-( Dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide.
Figure 02_image388

實施例3A。Example 3A.

4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）-N-（4-（2-（二甲基氨基）乙氧基）-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image390
4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-(2-(dimethylamino)ethoxy)-2- Methoxy-5-nitrophenyl)pyrimidine-2-amine.
Figure 02_image390

在0-10°C下，將2 - N,N - 二甲基胺乙醇（47.82毫克，536.47微莫耳）溶於DMA（3mL），向此混合物中加入實施例B（2.80克，6.68毫莫耳）與N,N’,N’ – 三甲基 – 1,2 - 乙二胺，向該混合物中加入NaH（28.61毫克，715.29微莫耳），並升溫至20-30°C攪拌30分鐘。降溫至0-10°C，再加入實施例B（150.00毫克，357.65微莫耳）的DMA（8mL）溶液，並升溫至40°C攪拌12小時。TLC顯示反應完成，混合物降溫至0-10°C，加入NH4 Cl飽和溶液（8mL），用DCM（8mL x 3）萃取，有機層經無水硫酸鈉乾燥，濃縮後，用製備板分離純化，得到標題化合物（黃色固體，140.00毫克，產率72.11%)。LCMS (ESI) (10-80AB): m/z: 489.3 [M+1]。At 0-10°C, 2-N,N-dimethylamine ethanol (47.82 mg, 536.47 μmol) was dissolved in DMA (3 mL), and Example B (2.80 g, 6.68 mmol) was added to this mixture Molar) and N,N',N'-trimethyl-1,2-ethylenediamine, to this mixture was added NaH (28.61 mg, 715.29 micromolar), and the temperature was raised to 20-30 °C and stirred for 30 minute. The temperature was lowered to 0-10°C, and then the DMA (8 mL) solution of Example B (150.00 mg, 357.65 micromolar) was added, and the temperature was raised to 40°C and stirred for 12 hours. TLC showed that the reaction was completed, the mixture was cooled to 0-10°C, a saturated solution of NH 4 Cl (8 mL) was added, extracted with DCM (8 mL x 3), the organic layer was dried over anhydrous sodium sulfate, after concentration, it was separated and purified using a preparation plate, The title compound (yellow solid, 140.00 mg, yield 72.11%) was obtained. LCMS (ESI) (10-80AB): m/z: 489.3 [M+1].

實施例3B。Example 3B.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-4-（2-（二甲基氨基）甲氧基）-6-甲基苯-1,3-二胺。

Figure 02_image392
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)methyl Oxy)-6-methylbenzene-1,3-diamine.
Figure 02_image392

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例3A。得到標題化合物（黃色固體，70.00毫克，產率34.80%)。LCMS (ESI) (10-80AB): m/z: 459.2 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 3A. The title compound was obtained (yellow solid, 70.00 mg, 34.80% yield). LCMS (ESI) (10-80AB): m/z: 459.2 [M+1].

實施例3C。Example 3C.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2 - （2-（二甲基氨基）乙氧基）-4-甲氧苯基）丙烯醯胺。

Figure 02_image388
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2 -(2-( Dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide.
Figure 02_image388

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例3B。得到標題化合物（FA鹽，20.00毫克，產率24.79%)。1 H NMR (400 MHz, MeOH-d4): δ 8.59-8.63 (m, 1H), 8.45-8.52 (m, 1H), 8.25-8.31 (m, 1H), 8.18-8.25 (m, 1H), 7.27-7.34 (m, 1H), 7.07-7.18 (m, 2H), 7.00-7.05 (m, 1H), 6.87-6.92 (m, 1H), 6.50-6.60 (m, 1H), 6.35-6.44 (m, 1H), 5.79-5.86 (m, 1H), 4.42-4.50 (m, 2H), 4.11 (s, 2H), 3.99 (s, 3H), 3.38-3.42 (m, 2H), 3.37 (s, 2H), 2.87 (s, 6H), 2.60-2.70 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 513.2 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 3B. The title compound (FA salt, 20.00 mg, yield 24.79%) was obtained. 1 H NMR (400 MHz, MeOH-d4): δ 8.59-8.63 (m, 1H), 8.45-8.52 (m, 1H), 8.25-8.31 (m, 1H), 8.18-8.25 (m, 1H), 7.27 -7.34 (m, 1H), 7.07-7.18 (m, 2H), 7.00-7.05 (m, 1H), 6.87-6.92 (m, 1H), 6.50-6.60 (m, 1H), 6.35-6.44 (m, 1H), 5.79-5.86 (m, 1H), 4.42-4.50 (m, 2H), 4.11 (s, 2H), 3.99 (s, 3H), 3.38-3.42 (m, 2H), 3.37 (s, 2H) , 2.87 (s, 6H), 2.60-2.70 (m, 2H). LCMS (ESI) (5-95AB): m/z: 513.2 [M+1].

實施例4。Example 4.

2 – （2 – 甲氧基 – 4 –（N – 甲基)呱嗪 - 5 – 丙烯醯胺基苯胺基） – 4 -（3 - （1，2，3 – 二氫吡咯並[1，2-a]吲哚））嘧啶。

Figure 02_image395
2-(2-methoxy-4-(N-methyl)pyrazine-5-acrylaminoanilinyl)-4-(3-(1,2,3-dihydropyrrolo[1,2 -a] indole)) pyrimidine.
Figure 02_image395

實施例4A。Example 4A.

4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）-N-（2-甲氧基-4-（4-甲基呱嗪-1-基）-5-硝基苯基）嘧啶-2-胺。

Figure 02_image397
4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(2-methoxy-4-(4-methylpyrazine-1- Radical)-5-nitrophenyl)pyrimidine-2-amine.
Figure 02_image397

本實施例根據實施例1A的方法製備，將N,N’,N’ – 三甲基 – 1,2 - 乙二胺替換為N – 甲基呱嗪。得到標題化合物（黃色固體，80.00毫克，產率43.88%)。LCMS (ESI) (5-95AB): m/z: 500.1 [M+1] 。This example was prepared according to the method of Example 1A, and N,N',N'-trimethyl-1,2-ethylenediamine was replaced with N-methylpyrazine. The title compound was obtained (yellow solid, 80.00 mg, yield 43.88%). LCMS (ESI) (5-95AB): m/z: 500.1 [M+1].

實施例4B。Example 4B.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-6-甲氧基-4-（4-甲基呱嗪-1-基）苯-1,3-二胺。

Figure 02_image399
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-6-methoxy-4-(4-methyl Base pyrazin-1-yl)benzene-1,3-diamine.
Figure 02_image399

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例4A。得到標題化合物（黃色固體，80.00毫克，產率43.88%)。LCMS (ESI) (5-95AB): m/z: 470.1 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 4A. The title compound was obtained (yellow solid, 80.00 mg, yield 43.88%). LCMS (ESI) (5-95AB): m/z: 470.1 [M+1].

實施例4C。Example 4C.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-4-甲氧基-2-（4-甲基呱嗪-1-基）苯基）丙烯醯胺。

Figure 02_image401
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-4-methoxy- 2-(4-methylpyrazin-1-yl)phenyl)acrylamide.
Figure 02_image401

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例4B。得到標題化合物（FA鹽，17.60毫克，產率19.33%）。1 H NMR (400 MHz, METHANOL-d6): δ 8.85 (s, 1 H), 8.34 (br. s., 2H), 8.18 - 8.28 (m, 2H), 7.25 - 7.30 (m, 1H), 7.09 - 7.18 (m, 2H), 7.03 (d, J = 4 Hz, 1H), 6.92 (s, 1H), 6.57 (dd, J = 16, 12 Hz, 1H), 6.31 (d, J = 20 Hz, 1H), 5.79 (d, J = 8 Hz, 1H), 4.07 (t, J = 8 Hz, 2H), 3.95 (s, 3H), 3.32 - 3.35 (m, 2H), 3.24 - 3.30 (m, 4H), 3.17 (m, 4H), 2.87 (s, 3H), 2.56 - 2.66 (m, 2H)。LCMS (ESI) (0-60AB): m/z: 524.2 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 4B. The title compound (FA salt, 17.60 mg, yield 19.33%) was obtained. 1 H NMR (400 MHz, METHANOL-d6): δ 8.85 (s, 1 H), 8.34 (br. s., 2H), 8.18-8.28 (m, 2H), 7.25-7.30 (m, 1H), 7.09 -7.18 (m, 2H), 7.03 (d, J = 4 Hz, 1H), 6.92 (s, 1H), 6.57 (dd, J = 16, 12 Hz, 1H), 6.31 (d, J = 20 Hz, 1H), 5.79 (d, J = 8 Hz, 1H), 4.07 (t, J = 8 Hz, 2H), 3.95 (s, 3H), 3.32-3.35 (m, 2H), 3.24-3.30 (m, 4H ), 3.17 (m, 4H), 2.87 (s, 3H), 2.56-2.66 (m, 2H). LCMS (ESI) (0-60AB): m/z: 524.2 [M+1].

實施例5。Example 5.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-4-甲氧基-2-（甲基（2-（吡咯烷-1-基）乙基）氨基）苯基）丙烯醯胺。

Figure 02_image403
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-4-methoxy- 2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide.
Figure 02_image403

實施例5A。Example 5A.

第三丁基（2-（吡咯烷-1-基）乙基）氨基甲酸酯。

Figure 02_image405
Tertiary butyl (2-(pyrrolidin-1-yl)ethyl) carbamate.
Figure 02_image405

在0°C下，將2 - 吡咯乙胺（2.50克，21.89毫莫耳）溶於THF（50mL），向該混合物中滴加入(Boc)2 O（4.78克，21.89毫莫耳），並升溫至15°C攪拌12小時。LCMS顯示反應完成，將混合物濃縮，得到標題化合物（黃色油狀，4.50克，產率95.26%)。1 H NMR (400 MHz, CDCl3): δ 5.09 (br. s., 1H), 3.22 (m, 2H), 2.54 (t, J = 6.0 Hz, 2H), 2.48 (br. s., 4H), 1.74 (m, 4H), 1.43 (s, 9H)。LCMS (0-60CD):m/z: 215.2 [M+1]。At 0°C, 2-pyrrolidine (2.50 g, 21.89 mmol) was dissolved in THF (50 mL), (Boc) 2 O (4.78 g, 21.89 mmol) was added dropwise to the mixture, and Warm to 15°C and stir for 12 hours. LCMS showed the reaction was completed, and the mixture was concentrated to give the title compound (yellow oil, 4.50 g, yield 95.26%). 1 H NMR (400 MHz, CDCl3): δ 5.09 (br. s., 1H), 3.22 (m, 2H), 2.54 (t, J = 6.0 Hz, 2H), 2.48 (br. s., 4H), 1.74 (m, 4H), 1.43 (s, 9H). LCMS (0-60CD): m/z: 215.2 [M+1].

實施例5B。Example 5B.

N-甲基-2-（吡咯烷-1-基）乙胺。

Figure 02_image407
N-methyl-2-(pyrrolidin-1-yl)ethylamine.
Figure 02_image407

在0°C下，將實施例5A（2.00克，9.33毫莫耳）溶於THF（100mL），向該混合物中分批加入LAH（1.06克，27.99毫莫耳），並升溫至70°C攪拌12小時。TLC顯示反應完成，升溫至0°C，向反應混合物中依次加入NaOH（1N，2mL）溶液和水（2mL），將混合物過濾，濾液用DCM（50mL）稀釋，經無水硫酸鈉乾燥後，濃縮，得到標題化合物（黃色油狀，1.00克，產率79.42%)。1 H NMR (400 MHz, CDCl3): δ 2.67 - 2.72 (m, 2H), 2.57 - 2.61 (m, 2H), 2.48 - 2.53 (m, 4H), 2.44 (s, 3H), 1.74 - 1.80 (m, 4H)。At 0°C, Example 5A (2.00 g, 9.33 mmol) was dissolved in THF (100 mL), and LAH (1.06 g, 27.99 mmol) was added to the mixture in portions, and the temperature was raised to 70°C Stir for 12 hours. TLC showed that the reaction was completed. The temperature was raised to 0°C. To the reaction mixture, NaOH (1N, 2mL) solution and water (2mL) were added in sequence. The mixture was filtered. The filtrate was diluted with DCM (50mL), dried over anhydrous sodium sulfate, and concentrated To give the title compound (yellow oil, 1.00 g, yield 79.42%). 1 H NMR (400 MHz, CDCl3): δ 2.67-2.72 (m, 2H), 2.57-2.61 (m, 2H), 2.48-2.53 (m, 4H), 2.44 (s, 3H), 1.74-1.80 (m , 4H).

實施例5C。Example 5C.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-2-甲氧基 - N 4 - 甲基-5硝基-N-4-（2-（吡咯烷-1-基）乙基）苯-1,4-二胺。

Figure 02_image409
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-2-methoxy-N 4 -methyl- 5 Nitro-N-4-(2-(pyrrolidin-1-yl)ethyl)benzene-1,4-diamine.
Figure 02_image409

本實施例根據實施例1A的方法製備，將N,N’,N’ – 三甲基 – 1,2 - 乙二胺替換為實施例5B。得到標題化合物（黃色固體，200.00毫克，產率79.49%)。LCMS (5-95AB):m/z: 528.2 [M+1]。This example was prepared according to the method of Example 1A, and N,N',N'-trimethyl-1,2-ethylenediamine was replaced with Example 5B. The title compound was obtained (yellow solid, 200.00 mg, yield 79.49%). LCMS (5-95AB): m/z: 528.2 [M+1].

實施例5D。Example 5D.

N4-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-5-甲氧基-N 1 - 甲基-N1 - （2-（吡咯烷-1-基）乙基）苯-1,2,4-三胺。

Figure 02_image411
N4-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl- N1-(2-(pyrrolidin-1-yl)ethyl)benzene-1,2,4-triamine.
Figure 02_image411

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例5C。得到標題化合物（白色固體，160.00毫克，產率81.43%)。LCMS (5-95AB):m/z: 498.2 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 5C. The title compound was obtained (white solid, 160.00 mg, yield 81.43%). LCMS (5-95AB): m/z: 498.2 [M+1].

實施例5E。Example 5E.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-4-甲氧基-2-（甲基（2-（吡咯烷-1-基）乙基）氨基）苯基）丙烯醯胺。

Figure 02_image403
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-4-methoxy- 2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide.
Figure 02_image403

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例5D。得到標題化合物（FA鹽，16.20毫克，產率7.34%)。1 H NMR (400MHz, CD3OD): δ 8.47 (s, 1H), 8.43 (br. s., 1H), 8.25 - 8.29 (m, 1H), 8.23 (d, J = 4 Hz, 1H), 7.27 - 7.32 (m, 1H), 7.07 - 7.15 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.3 6 - 6.57 (m, 2H), 5.87 (dd, J = 10, 2.0 Hz, 1H), 4.06 - 4.12 (m, 2H), 4.00 (s, 3H), 3.44 - 3.53 (m, 2H), 3.32 - 3.38 (m, 4H), 3.23 - 3.31 (m, 4H), 2.73 (s, 3H), 2.60 - 2.68 (m, 2H), 2.09 - 2.22 (m, 4H)。LCMS (0-60AB):m/z: 552.3 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 5D. The title compound (FA salt, 16.20 mg, yield 7.34%) was obtained. 1 H NMR (400MHz, CD3OD): δ 8.47 (s, 1H), 8.43 (br. s., 1H), 8.25-8.29 (m, 1H), 8.23 (d, J = 4 Hz, 1H), 7.27- 7.32 (m, 1H), 7.07-7.15 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.3 6-6.57 (m, 2H), 5.87 (dd, J = 10, 2.0 Hz, 1H), 4.06-4.12 (m, 2H), 4.00 (s, 3H), 3.44-3.53 (m, 2H), 3.32-3.38 (m, 4H), 3.23-3.31 (m, 4H ), 2.73 (s, 3H), 2.60-2.68 (m, 2H), 2.09-2.22 (m, 4H). LCMS (0-60AB): m/z: 552.3 [M+1].

實施例6。Example 6.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（3-（二甲基氨基）吡咯烷-1-基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image414
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide.
Figure 02_image414

實施例6A。Example 6A.

N，N-二甲基吡咯烷-3-胺。

Figure 02_image416
N,N-dimethylpyrrolidine-3-amine.
Figure 02_image416

在25°C下，將3 - （N,N – 二甲胺基）吡咯甲酸第三丁酯（300.00毫克，1.40毫莫耳）溶於DCM（20mL），向該混合物中加入TFA（1.60克，14.00毫莫耳），並攪拌30分鐘。TLC顯示反應完成，將反應混合物濃縮，得到標題化合物（1.50克，粗品）。At 25°C, 3-butyl(3-N,N-dimethylamino)pyrrolecarboxylic acid (300.00 mg, 1.40 mmol) was dissolved in DCM (20 mL), and TFA (1.60 g) was added to the mixture , 14.00 millimoles), and stir for 30 minutes. TLC showed the reaction was completed, and the reaction mixture was concentrated to give the title compound (1.50 g, crude product).

實施例6B。Example 6B.

4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）-N-（4-（3-（二甲基氨基）吡咯烷-1-基）-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image418
4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-(3-(dimethylamino)pyrrolidin-1-yl) -2-methoxy-5-nitrophenyl)pyrimidine-2-amine.
Figure 02_image418

本實施例根據實施例1A的方法製備，將N,N’,N’ – 三甲基 – 1,2 - 乙二胺替換為實施例6A。得到標題化合物（黃色固體，250.00毫克，產率75.95%）。LCMS (0-60AB): m/z: 514.2 [M+1]。This example was prepared according to the method of Example 1A, and N,N',N' -trimethyl-1,2-ethylenediamine was replaced with Example 6A. The title compound was obtained (yellow solid, 250.00 mg, yield 75.95%). LCMS (0-60AB): m/z: 514.2 [M+1].

實施例6C。Example 6C.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-4-（3-（二甲基氨基）吡咯烷-1-基）-6-甲基苯-1,3-二胺。

Figure 02_image420
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)pyrrole Alkan-1-yl)-6-methylbenzene-1,3-diamine.
Figure 02_image420

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例6B。得到標題化合物（白色固體，200.00毫克，產率80.54%）。LCMS (5-95AB):m/z: 484.2 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 6B. The title compound was obtained (white solid, 200.00 mg, yield 80.54%). LCMS (5-95AB): m/z: 484.2 [M+1].

實施例6D。Example 6D.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（3-（二甲基氨基）吡咯烷-1-基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image414
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide.
Figure 02_image414

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例6C。得到標題化合物（FA鹽，17.75毫克，產率6.17%)。1 H NMR (400MHz, CD3OD): δ 8.46 (s, 1H), 8.26-8.15 (m, 2H), 7.28 (dd, J = 2.0, 8.0Hz, 1H), 7.17-7.10 (m, 2H), 7.00 (d, J = 6.0Hz, 1H), 6.71 (s, 1H), 6.59-6.49 (m, 1H), 6.31 (dd, J = 2.0, 16.0Hz, 1H), 5.76 (dd, J = 2.0, 12.0Hz, 1H), 4.08 (t, J = 8.0Hz, 2H), 3.93 (s, 3H), 3.37-3.32 (m, 2H), 3.29-3.23 (m, 4H), 3.16-3.06 (m, 1H), 2.67-2.56 (m, 2H), 2.45 (s, 6H), 2.31-2.20 (m, 1H), 2.00-1.90 (m, 1H)。LCMS (0-60AB):m/z: 538.3 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 6C. The title compound (FA salt, 17.75 mg, yield 6.17%) was obtained. 1 H NMR (400MHz, CD3OD): δ 8.46 (s, 1H), 8.26-8.15 (m, 2H), 7.28 (dd, J = 2.0, 8.0Hz, 1H), 7.17-7.10 (m, 2H), 7.00 (d, J = 6.0Hz, 1H), 6.71 (s, 1H), 6.59-6.49 (m, 1H), 6.31 (dd, J = 2.0, 16.0Hz, 1H), 5.76 (dd, J = 2.0, 12.0 Hz, 1H), 4.08 (t, J = 8.0Hz, 2H), 3.93 (s, 3H), 3.37-3.32 (m, 2H), 3.29-3.23 (m, 4H), 3.16-3.06 (m, 1H) , 2.67-2.56 (m, 2H), 2.45 (s, 6H), 2.31-2.20 (m, 1H), 2.00-1.90 (m, 1H). LCMS (0-60AB): m/z: 538.3 [M+1].

實施例7。Example 7.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（（3-（二甲基氨基）丙基）（甲基）氨基）-4-甲氧苯基）丙烯醯胺。

Figure 02_image423
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-((3- (Dimethylamino)propyl) (methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image423

實施例7A。Example 7A.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-N4-（3-（二甲基氨基）丙基）-2-甲氧基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image425
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N4-(3-(dimethylamino)propane Group)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image425

本實施例根據實施例1A的方法製備，將N,N’,N’ – 三甲基 – 1,2 - 乙二胺替換為N,N’,N’ – 三甲基 – 1,2 – 丙二胺。得到標題化合物（200.00毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 516.2 [M+1]。This example was prepared according to the method of Example 1A, replacing N,N',N'-trimethyl-1,2- ethylenediamine with N,N',N'-trimethyl-1,2-propane Diamine. The title compound (200.00 mg, crude) was obtained. LCMS (ESI) (0-60AB): m/z: 516.2 [M+1].

實施例7B。Example 7B.

N4-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-N 1 - （3-（二甲基氨基）丙基）-5-甲氧基-N1-甲基苯-1,2,4-三胺。

Figure 02_image427
N4-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N 1 -(3-(dimethylamino) Propyl)-5-methoxy-N1-methylbenzene-1,2,4-triamine.
Figure 02_image427

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例7A。得到標題化合物（白色固體，200.00毫克，粗品)。LCMS (ESI) (0-60AB): m/z: 486.2 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 7A. The title compound (white solid, 200.00 mg, crude) was obtained. LCMS (ESI) (0-60AB): m/z: 486.2 [M+1].

實施例7C。Example 7C.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（（3-（二甲基氨基）丙基）（甲基）氨基）-4-甲氧苯基）丙烯醯胺。

Figure 02_image423
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-((3- (Dimethylamino)propyl) (methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image423

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例7B。得到標題化合物（FA鹽，40.00毫克，產率17.58%)。1 H NMR (400MHz, CD3OD): δ 8.78 (s, 1H), 8.45 (br. s., 1H), 8.19-8.33 (m, 2H), 7.30 (d, J=5.09 Hz, 1H), 6.99-7.19 (m, 3H), 6.96 (s, 1H), 6.49-6.71 (m, 1H), 6.33 (d, J=16.95 Hz, 1H), 5.80 (d, J=10.55 Hz, 1H), 4.12 (t, J=6.88 Hz, 2H), 3.96 (s, 3H), 2.99-3.20 (m, 4H), 2.54-2.93 (m, 11H), 1.76-2.00 (m, 2H)。LCMS (ESI) (0-60AB): m/z: 540.2 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 7B. The title compound (FA salt, 40.00 mg, yield 17.58%) was obtained. 1 H NMR (400MHz, CD3OD): δ 8.78 (s, 1H), 8.45 (br. s., 1H), 8.19-8.33 (m, 2H), 7.30 (d, J=5.09 Hz, 1H), 6.99- 7.19 (m, 3H), 6.96 (s, 1H), 6.49-6.71 (m, 1H), 6.33 (d, J=16.95 Hz, 1H), 5.80 (d, J=10.55 Hz, 1H), 4.12 (t , J=6.88 Hz, 2H), 3.96 (s, 3H), 2.99-3.20 (m, 4H), 2.54-2.93 (m, 11H), 1.76-2.00 (m, 2H). LCMS (ESI) (0-60AB): m/z: 540.2 [M+1].

流程3。

Figure 02_image430
Process 3.
Figure 02_image430

實施例8。Example 8.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（3-（二甲氨基）丙-1-炔-1-基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image432
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino) prop-1-yn-1-yl)-4-methoxyphenyl) acrylamide.
Figure 02_image432

實施例8A。Example 8A.

4-溴-2-甲氧基-5-硝基苯胺。

Figure 02_image434
4-Bromo-2-methoxy-5-nitroaniline.
Figure 02_image434

在0~5°C下，將2 – 甲氧基 – 4 – 溴苯胺（5.00克，24.75毫莫耳）加至濃H2 SO4 （50毫升）中，然後分批加入硝酸胍（3.02克，24.75毫莫耳）。混合物在0~5°C下攪拌30分鐘。TLC顯示反應完成，將反應混合物慢慢滴加入NaHCO3 （100克）的水（1L）溶液中，溫度控制在15°C下。將得到的混合物過濾，得到標題化合物（黃色固體，5.40克，產率83.90%)。1 H NMR (400MHz, CDCl3): δ, 7.39 (s, 1H), 7.01 (s, 1H), 4.09 (br. s., 2H), 3.96 (s, 3H)。At 0~5°C, add 2-methoxy-4-bromoaniline (5.00 g, 24.75 mmol) to concentrated H 2 SO 4 (50 mL), then add guanidine nitrate (3.02 g) in portions , 24.75 millimoles). The mixture was stirred at 0~5°C for 30 minutes. TLC showed that the reaction was completed, and the reaction mixture was slowly added dropwise to a solution of NaHCO 3 (100 g) in water (1 L), and the temperature was controlled at 15°C. The resulting mixture was filtered to obtain the title compound (yellow solid, 5.40 g, yield 83.90%). 1 H NMR (400MHz, CDCl3): δ, 7.39 (s, 1H), 7.01 (s, 1H), 4.09 (br. s., 2H), 3.96 (s, 3H).

實施例8B。Example 8B.

N-（4-溴-2-甲氧基-5-硝基苯基）-4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-胺。

Figure 02_image436
N-(4-Bromo-2-methoxy-5-nitrophenyl)-4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidine -2-amine.
Figure 02_image436

將實施例8A（1.51克，5.56毫莫耳）和實施例A（1.50克，5.56毫莫耳）加入到1，4-二氧六環（20mL）中，向此混合物中加入TsOH·H2 O（1.27克，6.67毫莫耳），並升溫至75~85°C攪拌12小時。TLC顯示反應完成，將反應混合物濃縮，加入DCM（20mL）溶解，用飽和NaHCO3 （20mL）洗滌，有機相濃縮後，用柱色譜（DCM/MeOH = 100:0 to 100:1）分離純化，得到標題化合物（黃色固體，2.40克，產率85.38%)。1 H NMR (400 MHz, DMSO-d6): δ, 9.08 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.35 (d, J = 8 Hz, 1H), 8.30 (s, 1H), 7.53 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.12-7.21 (m, 3H), 4.18 (t, J = 7.2 Hz, 2H), 4.05 (s, 3H), 3.23-3.33 (m, 2H), 2.64-2.67 (m, 2H)。Example 8A (1.51 g, 5.56 mmol) and Example A (1.50 g, 5.56 mmol) were added to 1,4-dioxane (20 mL), and TsOH·H 2 was added to this mixture O (1.27 g, 6.67 mmol), and warmed to 75~85°C and stirred for 12 hours. TLC showed that the reaction was completed, the reaction mixture was concentrated, dissolved in DCM (20 mL), washed with saturated NaHCO 3 (20 mL), and after the organic phase was concentrated, it was separated and purified by column chromatography (DCM/MeOH = 100:0 to 100:1), The title compound was obtained (yellow solid, 2.40 g, yield 85.38%). 1 H NMR (400 MHz, DMSO-d6): δ, 9.08 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.35 (d, J = 8 Hz, 1H), 8.30 (s, 1H ), 7.53 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.12-7.21 (m, 3H), 4.18 (t, J = 7.2 Hz, 2H), 4.05 (s, 3H), 3.23 -3.33 (m, 2H), 2.64-2.67 (m, 2H).

實施例8C。Example 8C.

4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）-N-（4-（3-（二甲基氨基）丙-1-炔-1-基）-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image438
4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-(3-(dimethylamino)prop-1-yne-1 -Yl)-2-methoxy-5-nitrophenyl)pyrimidine-2-amine.
Figure 02_image438

在10~20°C下，將實施例8B（1.00克，2.08毫莫耳），CuI（39.65毫克，208.00微莫耳）和Pd(PPh3 )2 Cl2 （73.07毫克，104.00微莫耳）加入到DMF（20mL）中，並攪拌1小時，然後向此混合物中加入1 – 二甲基胺基 – 2 – 丙炔（345.82毫克，4.16毫莫耳）和DIEA（537.64毫克，4.16毫莫耳），並升溫至65~75°C攪拌23小時。TLC顯示反應完成，將反應混合物過濾，濃縮，用柱色譜（DCM/MeOH = 100:0 to 100:5）分離純化，得到標題化合物（黃色固體，500.00克，產率45.33%)。LCMS (ESI) (0-60AB): m/z: 483.1 [M+1]。At 10-20°C, Example 8B (1.00 g, 2.08 mmol), CuI (39.65 mg, 208.00 μmol) and Pd(PPh 3 ) 2 Cl 2 (73.07 mg, 104.00 μmol) Add to DMF (20mL) and stir for 1 hour, then add 1-dimethylamino-2-propyne (345.82 mg, 4.16 mmol) and DIEA (537.64 mg, 4.16 mmol) to this mixture ), and heated to 65 ~ 75 °C and stirred for 23 hours. TLC showed that the reaction was completed. The reaction mixture was filtered, concentrated, and purified by column chromatography (DCM/MeOH = 100:0 to 100:5) to obtain the title compound (yellow solid, 500.00 g, yield 45.33%). LCMS (ESI) (0-60AB): m/z: 483.1 [M+1].

實施例8D。Example 8D.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-4-（3-（二甲基氨基）丙-1-炔-1-基）-6-甲基苯-1,3-二胺。

Figure 02_image440
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)propane -1-yn-1-yl)-6-methylbenzene-1,3-diamine.
Figure 02_image440

將實施例8C（200.00毫克，414.48微莫耳）和NH4 Cl（110.85毫克，2.07毫莫耳）加入到丙酮（9mL）和水（1mL）中，向此混合物中加入鋅粉（110.85毫克，2.07毫莫耳），並升溫至60~70°C攪拌16小時。TLC顯示反應完成，將反應混合物過濾，加入飽和Na2 CO3 至pH為9。用DCM（10mL×2）萃取，濃縮後，用製備析（DCM/MeOH = 20:1）分離純化，得到標題化合物（黃色固體，20.00毫克，產率10.12%)。LCMS (ESI) (0-60AB): m/z: 453.1 [M+1]。Example 8C (200.00 mg, 414.48 μmol) and NH 4 Cl (110.85 mg, 2.07 mmol) were added to acetone (9 mL) and water (1 mL), and zinc powder (110.85 mg, 2.07 millimoles), and heated to 60 ~ 70 °C and stirred for 16 hours. TLC showed the reaction was completed, the reaction mixture was filtered, and saturated Na 2 CO 3 was added to pH 9. It was extracted with DCM (10 mL×2), after concentration, it was separated and purified by preparative analysis (DCM/MeOH = 20:1) to obtain the title compound (yellow solid, 20.00 mg, yield 10.12%). LCMS (ESI) (0-60AB): m/z: 453.1 [M+1].

實施例8E。Example 8E.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（3-（二甲氨基）丙-1-炔-1-基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image442
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino) prop-1-yn-1-yl)-4-methoxyphenyl) acrylamide.
Figure 02_image442

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例8D。得到標題化合物（FA鹽，7.00毫克，產率20.84%)。1 H NMR (400MHz, CD3OD): δ 8.88 (s, 1H), 8.43 (br. s., 1H), 8.27-8.29 (m, 2H), 7.30-7.32 (m, 1H), 7.08-7.18 (m, 4H), 6.50-6.54 (m, 1H), 6.34-6.39 (m, 1H), 5.81 (dd, J = 1.13, 10 Hz, 1H), 4.07-4.09 (m, 2H), 3.99 (s, 3H), 3.90 (s, 2H), 3.29-3.30 (m, 2H), 2.55-2.72 (m, 8H)。LCMS (ESI) (0-60AB): m/z: 507.2 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 8D. The title compound (FA salt, 7.00 mg, yield 20.84%) was obtained. 1 H NMR (400MHz, CD3OD): δ 8.88 (s, 1H), 8.43 (br. s., 1H), 8.27-8.29 (m, 2H), 7.30-7.32 (m, 1H), 7.08-7.18 (m , 4H), 6.50-6.54 (m, 1H), 6.34-6.39 (m, 1H), 5.81 (dd, J = 1.13, 10 Hz, 1H), 4.07-4.09 (m, 2H), 3.99 (s, 3H ), 3.90 (s, 2H), 3.29-3.30 (m, 2H), 2.55-2.72 (m, 8H). LCMS (ESI) (0-60AB): m/z: 507.2 [M+1].

實施例9。Example 9.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-4-甲氧基-2-（嗎啉代甲基）苯基）丙烯醯胺。

Figure 02_image444
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-4-methoxy- 2-(morpholinomethyl)phenyl) acrylamide.
Figure 02_image444

實施例9A。Example 9A.

3-甲氧基-4-（2,2,2-三氟乙基）苯甲酸。

Figure 02_image446
3-methoxy-4-(2,2,2-trifluoroethyl)benzoic acid.
Figure 02_image446

在0~5°C下，將4-胺基-3-甲氧基苯甲酸（10.00克，59.82毫莫耳）加入到TFA（60mL）中，向此混合物中滴加TFAA（31.41克，59.82毫莫耳），並攪拌30分鐘。TLC顯示反應完成，將反應混合物倒入冰水（1 L）中，攪拌30分鐘後過濾，濾餅經乾燥，得到標題化合物（14.50克，產率87.50%）。1 H NMR (400MHz, CDCl3): δ 8.74 (br. s., 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 1.2, 7.2 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 4.05 (s, 3H)。At 0~5°C, 4-amino-3-methoxybenzoic acid (10.00 g, 59.82 mmol) was added to TFA (60 mL), and TFAA (31.41 g, 59.82) was added dropwise to this mixture Millimoles) and stir for 30 minutes. TLC showed that the reaction was completed. The reaction mixture was poured into ice water (1 L), stirred for 30 minutes and filtered. The filter cake was dried to obtain the title compound (14.50 g, yield 87.50%). 1 H NMR (400MHz, CDCl3): δ 8.74 (br. s., 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 1.2, 7.2 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 4.05 (s, 3H).

實施例9B。Example 9B.

5-甲氧基-2-硝基-4-（2,2,2-三氟乙基）苯甲酸。

Figure 02_image448
5-Methoxy-2-nitro-4-(2,2,2-trifluoroethyl)benzoic acid.
Figure 02_image448

在0°C下，將實施例9A（13.50克，51.30毫莫耳）分批加入到發煙硝酸（100mL）中，向此混合物中滴加TFAA（31.41克，59.82毫莫耳），並攪拌30分鐘。TLC顯示反應完成，將反應混合物倒入冰水（1 L）中，攪拌30分鐘後過濾，濾餅經乾燥，得到標題化合物（灰白色固體，13.50克，產率76.85%）。1 H NMR (400 MHz, CDCl3): δ 9.01 (s, 1H), 8.65 (br. s., 1H), 7.36 (s, 1H), 4.13 (s, 3H)。At 0°C, Example 9A (13.50 g, 51.30 mmol) was added portionwise to fuming nitric acid (100 mL), and TFAA (31.41 g, 59.82 mmol) was added dropwise to this mixture with stirring 30 minutes. TLC showed that the reaction was completed. The reaction mixture was poured into ice water (1 L), stirred for 30 minutes and filtered. The filter cake was dried to obtain the title compound (off-white solid, 13.50 g, yield 76.85%). 1 H NMR (400 MHz, CDCl3): δ 9.01 (s, 1H), 8.65 (br. s., 1H), 7.36 (s, 1H), 4.13 (s, 3H).

實施例9C。Example 9C.

2,2,2-三氟-N-（2-甲氧基-4-（嗎啉-4-羰基）-5-硝基苯基）乙醯胺。

Figure 02_image450
2,2,2-trifluoro-N-(2-methoxy-4-(morpholine-4-carbonyl)-5-nitrophenyl)acetamide.
Figure 02_image450

在10~20°C下，將實施例9B（5.00克，16.22毫莫耳）和嗎啡啉（1.70克，19.46毫莫耳）加入到DMF（50mL）中，向此混合物中加入HATU（7.40克，19.46毫莫耳）和DIEA（3.14克，24.33毫莫耳），並攪拌3小時。TLC顯示反應完成，將反應混合物慢慢加入至水（200mL）中，過濾，濾餅經乾燥，得到標題化合物（黃色固體，13.50克，產率76.85%）。1 H NMR (400 MHz, CDCl3): δ 9.22 (s, 1H), 8.60 (br. s., 1H), 6.90 (s, 1H), 4.09 (s, 3H), 3.60-3.94 (m, 6H), 3.22 (t, J=4.8 Hz, 2H)。At 10-20°C, Example 9B (5.00 g, 16.22 mmol) and morpholine (1.70 g, 19.46 mmol) were added to DMF (50 mL), and HATU (7.40 g) was added to this mixture , 19.46 millimoles) and DIEA (3.14 grams, 24.33 millimoles), and stirred for 3 hours. TLC showed that the reaction was completed, and the reaction mixture was slowly added to water (200 mL), filtered, and the filter cake was dried to obtain the title compound (yellow solid, 13.50 g, yield 76.85%). 1 H NMR (400 MHz, CDCl3): δ 9.22 (s, 1H), 8.60 (br. s., 1H), 6.90 (s, 1H), 4.09 (s, 3H), 3.60-3.94 (m, 6H) , 3.22 (t, J=4.8 Hz, 2H).

實施例9D。Example 9D.

（4-氨基-5-甲氧基-2-硝基苯基）（嗎啉代）甲酮。

Figure 02_image452
(4-Amino-5-methoxy-2-nitrophenyl) (morpholino) ketone.
Figure 02_image452

將實施例9C（4.00克，10.60毫莫耳）加入到MeOH/H2 O（1:1，40mL）中，向此混合物中加入K2 CO3 （7.33克，53.00毫莫耳），並升溫至65°C攪拌5小時。TLC顯示反應完成，將反應混合物濃縮除去MeOH，用EA（15mL×2）萃取，有機相經無水硫酸鈉乾燥，濃縮後，得到標題化合物（黃色固體，2.50克，粗品）。Example 9C (4.00 g, 10.60 mmol) was added to MeOH/H 2 O (1:1, 40 mL), and K 2 CO 3 (7.33 g, 53.00 mmol) was added to this mixture, and the temperature was raised Stir at 65°C for 5 hours. TLC showed that the reaction was completed. The reaction mixture was concentrated to remove MeOH, extracted with EA (15 mL×2), and the organic phase was dried over anhydrous sodium sulfate. After concentration, the title compound was obtained (yellow solid, 2.50 g, crude product).

實施例9E。Example 9E.

2-甲氧基-4-（嗎啉代）-5-硝基苯胺。

Figure 02_image454
2-methoxy-4-(morpholino)-5-nitroaniline.
Figure 02_image454

在5~15°C下，將實施例9D（1.00克，3.56毫莫耳）加入到THF（10mL）中，向此混合物中加入BH3 -Me2 S（10M，1.78mL），並升溫至66°C攪拌2小時。TLC顯示反應完成，向反應混合物中慢慢滴加MeOH（5mL），並在66°C下攪拌1小時。將反應混合物濃縮，得到標題化合物（黃色固體，700.00毫克，產率72.83%）。LCMS (ESI) (0-60AB): m/z: 268.0 [M+1]。At 5~15°C, Example 9D (1.00 g, 3.56 mmol) was added to THF (10 mL), to this mixture was added BH 3 -Me 2 S (10M, 1.78 mL), and the temperature was raised to Stir at 66°C for 2 hours. TLC showed that the reaction was completed, and MeOH (5 mL) was slowly added dropwise to the reaction mixture, and stirred at 66°C for 1 hour. The reaction mixture was concentrated to obtain the title compound (yellow solid, 700.00 mg, yield 72.83%). LCMS (ESI) (0-60AB): m/z: 268.0 [M+1].

實施例9F。Example 9F.

4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）-N-（2-甲氧基-4-（嗎啉代甲基）-5-硝基苯基）嘧啶-2-胺。

Figure 02_image456
4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(2-methoxy-4-(morpholinomethyl)-5- Nitrophenyl)pyrimidine-2-amine.
Figure 02_image456

將實施例9E（435.13毫克，1.63毫莫耳）和實施例A（400.00毫克，1.48毫莫耳）加入到t -BuOH（10mL）中，向此混合物中加入甲磺酸（170.69毫克，1.78毫莫耳），並升溫至75~85°C攪拌48小時。TLC顯示反應完成，將反應混合物濃縮，用DCM（10mL）溶解，分別用NaHCO3 （5mL）和食鹽水（5mL）洗滌，濃縮，用柱色譜（DCM/MeOH = 100:0 to 100:1）分離純化，得到標題化合物（黃色油狀，400.00毫克，產率43.74%）。LCMS (ESI) (0-60AB): m/z: 501.2 [M+1]。Example 9E (435.13 mg, 1.63 mmol) and Example A (400.00 mg, 1.48 mmol) were added to t- BuOH (10 mL), and methanesulfonic acid (170.69 mg, 1.78 mmol) was added to this mixture Mohr), and heated to 75 ~ 85 °C and stirred for 48 hours. TLC showed that the reaction was completed. The reaction mixture was concentrated, dissolved in DCM (10 mL), washed with NaHCO 3 (5 mL) and brine (5 mL), concentrated, and separated by column chromatography (DCM/MeOH = 100:0 to 100:1) Purification afforded the title compound (yellow oil, 400.00 mg, 43.74% yield). LCMS (ESI) (0-60AB): m/z: 501.2 [M+1].

實施例9G。Example 9G.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-6-甲氧基-4-（嗎啉代甲基）苯-1,3-二胺。

Figure 02_image458
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-6-methoxy-4-(morpholino Methyl)benzene-1,3-diamine.
Figure 02_image458

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例9F。得到標題化合物（紅色油狀，300.00毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 471.2 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 9F. The title compound was obtained (red oil, 300.00 mg, crude). LCMS (ESI) (0-60AB): m/z: 471.2 [M+1].

實施例9H。Example 9H.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-4-甲氧基-2-（嗎啉代甲基）苯基）丙烯醯胺。

Figure 02_image444
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-4-methoxy- 2-(morpholinomethyl)phenyl) acrylamide.
Figure 02_image444

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例9G。得到標題化合物（FA鹽，37.00毫克，產率11.02%)。1 H NMR (400MHz, CD3OD) : δ 8.84 (s, 1H), 8.18-8.37 (m, 4H), 7.34 (d, J = 7.6 Hz, 1H), 7.05-7.23 (m, 3H), 6.34-6.52 (m, 2H), 5.86 (dd, J = 2.38, 9.16 Hz, 1H), 4.13 (t, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.85 (d, J = 12.8 Hz, 6H), 2.84 (br. s., 4H), 2.53-2.73 (m, 3H)。LCMS (ESI) (0-60AB): m/z: 525.2 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 9G. The title compound (FA salt, 37.00 mg, yield 11.02%) was obtained. 1 H NMR (400MHz, CD3OD): δ 8.84 (s, 1H), 8.18-8.37 (m, 4H), 7.34 (d, J = 7.6 Hz, 1H), 7.05-7.23 (m, 3H), 6.34-6.52 (m, 2H), 5.86 (dd, J = 2.38, 9.16 Hz, 1H), 4.13 (t, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.85 (d, J = 12.8 Hz, 6H) , 2.84 (br. s., 4H), 2.53-2.73 (m, 3H). LCMS (ESI) (0-60AB): m/z: 525.2 [M+1].

實施例10。Example 10.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（3-（二甲基氨基）丙基）-4-甲基苯基）丙烯醯胺。

Figure 02_image461
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)propyl)-4-methylphenyl)acrylamide.
Figure 02_image461

實施例10A。Example 10A.

3-甲氧基-4-硝基苯甲醛。

Figure 02_image463
3-methoxy-4-nitrobenzaldehyde.
Figure 02_image463

將3-甲氧基-4-硝基苯甲醇（4.70克，25.66毫莫耳）加入到DCM（50mL）中，向此混合物中加入MnO2 （13.39克，153.96毫莫耳），並升溫至40°C攪拌12小時。TLC顯示反應完成，將反應混合物過濾，濾液濃縮，得到標題化合物（黃色固體，3.90克，產率79.71%）1 H NMR (300 MHz, CDCl3): δ 10.0 -10.20 (m, 1 H), 7.87 - 8.05 (m, 1 H), 7.47 - 7.72 (m, 2 H), 3.96 - 4.14 (m, 3 H)。3-Methoxy-4-nitrobenzyl alcohol (4.70 g, 25.66 mmol) was added to DCM (50 mL), to this mixture was added MnO 2 (13.39 g, 153.96 mmol), and the temperature was raised to Stir at 40°C for 12 hours. TLC showed the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to give the title compound (yellow solid, 3.90 g, yield 79.71%) 1 H NMR (300 MHz, CDCl3): δ 10.0 -10.20 (m, 1 H), 7.87 -8.05 (m, 1 H), 7.47-7.72 (m, 2 H), 3.96-4.14 (m, 3 H).

實施例10B。Example 10B.

（Z） - 乙基-3-（3-甲氧基-4-硝基苯基）丙烯酸酯。

Figure 02_image465
(Z)-Ethyl-3-(3-methoxy-4-nitrophenyl) acrylate.
Figure 02_image465

在5°C下，將實施例10A（3.90克，21.53毫莫耳）加入到THF（20mL）中，向此混合物中分批加入NaH（60%，1.29克，32.30毫莫耳），並攪拌30分鐘。再向此混合物中滴加入二乙氧基膦醯乙酸乙酯（7.24克，32.30毫莫耳），並升溫至20°C攪拌2.5小時。TLC顯示反應完成，向反應混合物中加入飽和NH4 Cl水溶液（5mL），濃縮除去THF。將得到的混合物加入DCM（20mL）溶解，用H2 O（30mL×3）洗滌，有機相無水硫酸鈉乾燥後，濃縮，用柱色譜（PE/EA = 10:1-5:1）分離純化，得到標題化合物（黃色固體，2.95克，產率53.89%）。LCMS (ESI) (5-95AB): m/z: 252.1 [M+1]。At 5°C, Example 10A (3.90 g, 21.53 mmol) was added to THF (20 mL), and NaH (60%, 1.29 g, 32.30 mmol) was added portionwise to this mixture with stirring 30 minutes. Ethyl diethoxyphosphonoacetate (7.24 g, 32.30 mmol) was added dropwise to this mixture, and the temperature was raised to 20°C and stirred for 2.5 hours. TLC showed that the reaction was completed. To the reaction mixture was added saturated aqueous NH 4 Cl (5 mL), and the THF was concentrated to remove. The obtained mixture was dissolved in DCM (20 mL), washed with H 2 O (30 mL×3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE/EA = 10:1-5:1) To give the title compound (yellow solid, 2.95 g, 53.89% yield). LCMS (ESI) (5-95AB): m/z: 252.1 [M+1].

實施例10C。（3-（4-氨基-3-甲氧基苯基）丙酸酯。

Figure 02_image467
Example 10C. (3-(4-Amino-3-methoxyphenyl) propionate.
Figure 02_image467

在16°C下，將實施例10B（2.75克，10.95毫莫耳）溶於MeOH（25mL），氮氣置換後加入Pd/C（10%，300毫克）。混合物在H2 （壓力為15 Psi）中，攪拌5小時。LCMS顯示反應完成，將反應混合物過濾，濾液濃縮至乾，得到標題化合物（淡紅色固體，2.30克，產率96.40%)。LCMS (ESI) (5-95AB): m/z: 224.2 [M+1]。At 16°C, Example 10B (2.75 g, 10.95 mmol) was dissolved in MeOH (25 mL), and after nitrogen replacement, Pd/C (10%, 300 mg) was added. The mixture was stirred in H 2 (pressure 15 Psi) for 5 hours. LCMS showed the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to dryness to obtain the title compound (light red solid, 2.30 g, yield 96.40%). LCMS (ESI) (5-95AB): m/z: 224.2 [M+1].

實施例10D。Example 10D.

3-（4-氨基-3-甲氧基苯基）丙-1-醇。

Figure 02_image469
3-(4-amino-3-methoxyphenyl)propan-1-ol.
Figure 02_image469

在20°C下，將實施例10C（1.90克，8.51毫莫耳）加入到THF（10mL）中，向此混合物中加入LAH（322.95克，8.51毫莫耳），並攪拌5小時。LCMS顯示反應完成，向反應混合物中依次加入水（0.3mL）和NaOH（1M，1mL）。將得到的混合物過濾，用DCM（20mL）洗滌濾餅，濾液濃縮，得到標題化合物（黃色油狀，1.4克，粗品）。LCMS (ESI) (5-95AB): m/z: 182.0 [M+1]。At 20°C, Example 10C (1.90 g, 8.51 mmol) was added to THF (10 mL), and LAH (322.95 g, 8.51 mmol) was added to this mixture, and stirred for 5 hours. LCMS showed the reaction was completed, and water (0.3 mL) and NaOH (1 M, 1 mL) were added to the reaction mixture in sequence. The resulting mixture was filtered, the filter cake was washed with DCM (20 mL), and the filtrate was concentrated to obtain the title compound (yellow oil, 1.4 g, crude). LCMS (ESI) (5-95AB): m/z: 182.0 [M+1].

實施例10E。Example 10E.

第三丁基（4-（3-羥丙基）-2-甲基苯基）氨基甲酸酯。

Figure 02_image471
Third butyl (4-(3-hydroxypropyl)-2-methylphenyl) carbamate.
Figure 02_image471

將實施例10D（1.50克，8.28毫莫耳）加入到THF（10mL）中，向此混合物中分批加入Boc2 O（1.81克，8.28毫莫耳），並升溫至60~70°C攪拌5小時。TLC顯示反應完成，將反應混合物濃縮除，用柱色譜（PE/EA = 10:1-5:1）分離純化，得到標題化合物（黃色油狀，1.20克，粗品）。LCMS (ESI) (5-95AB): m/z: 282.0 [M+1]。Example 10D (1.50 g, 8.28 mmol) was added to THF (10 mL), and Boc 2 O (1.81 g, 8.28 mmol) was added to this mixture in portions, and the temperature was raised to 60-70°C and stirred 5 hours. TLC showed that the reaction was completed, and the reaction mixture was concentrated and separated by column chromatography (PE/EA = 10:1-5:1) to obtain the title compound (yellow oil, 1.20 g, crude product). LCMS (ESI) (5-95AB): m/z: 282.0 [M+1].

實施例10F。Example 10F.

第三丁基（2-甲氧基-4-（3-氧代丙基）苯基）氨基甲酸酯。

Figure 02_image473
Third butyl (2-methoxy-4-(3-oxopropyl)phenyl) carbamate.
Figure 02_image473

在20°C下，將實施例10E（1.20克，粗品）加入到DCM（10mL）中，向此混合物中分批加入DMP（1.81克，4.27毫莫耳），並攪拌3小時。TLC顯示反應完成，向反應混合物中加入飽和Na2 CO3 水溶液（5mL），用DCM（10mL×6）萃取，有機相水（20mL）洗，用無水硫酸鈉乾燥後，濃縮，得到標題化合物（紅色油狀，1.23克，粗品）。LCMS (ESI) (5-95AB): m/z: 180.1 [M+1-100]。At 20°C, Example 10E (1.20 g, crude) was added to DCM (10 mL), and DMP (1.81 g, 4.27 mmol) was added to this mixture in portions, and stirred for 3 hours. TLC showed that the reaction was completed. To the reaction mixture was added saturated Na 2 CO 3 aqueous solution (5 mL), extracted with DCM (10 mL×6), the organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound ( Red oily, 1.23g, crude). LCMS (ESI) (5-95AB): m/z: 180.1 [M+1-100].

實施例10G。Example 10G.

第三丁基（4-（3-（二甲基氨基）丙基）-2-甲氧基苯基）氨基甲酸酯。

Figure 02_image475
Third butyl (4-(3-(dimethylamino)propyl)-2-methoxyphenyl) carbamate.
Figure 02_image475

在20°C下，將實施例10F（1.2克，粗品）加入到MeOH（20mL）中，向此混合物中加入二甲胺鹽酸鹽（701.24毫克，8.60毫莫耳）和NaBH3 CN（810.64毫克，12.90毫莫耳），並攪拌5小時。LCMS顯示反應完成，向反應混合物中加入飽和Na2 CO3 水溶液（5mL）。用DCM（20mL）萃取，有機層用無水硫酸鈉乾燥後，濃縮，得到標題化合物（黃色油狀，750.00毫克，粗品）。LCMS (ESI) (5-95AB): m/z: 309.2 [M+1]。At 20°C, Example 10F (1.2 g, crude) was added to MeOH (20 mL), to this mixture was added dimethylamine hydrochloride (701.24 mg, 8.60 mmol) and NaBH 3 CN (810.64 Mg, 12.90 mmol), and stirred for 5 hours. LCMS showed that the reaction was complete, and saturated aqueous Na 2 CO 3 solution (5 mL) was added to the reaction mixture. After extraction with DCM (20 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (yellow oil, 750.00 mg, crude). LCMS (ESI) (5-95AB): m/z: 309.2 [M+1].

實施例10H。Example 10H.

4-（3-（二甲基氨基）丙基）-2-甲氧基-5-硝基苯胺。

Figure 02_image477
4-(3-(dimethylamino)propyl)-2-methoxy-5-nitroaniline.
Figure 02_image477

在0°C下，將實施例10G（720.00毫克，2.33毫莫耳）加入到H2 SO4 （3mL）中，向此混合物中加入硝酸胍（284.45毫克，2.33毫莫耳），並攪拌2小時，再升溫至20°C攪拌1小時。TLC顯示反應完成，向反應混合物中加入飽和Na2 CO3 水溶液至pH為7~8，用DCM（10mL×2）萃取，有機層用無水硫酸鈉乾燥後，濃縮，用柱色譜（DCM/MeOH = 10:1）分離純化，得到標題化合物（黃色固體，270.00毫克，產率40.08%）。LCMS (ESI) (5-95AB): m/z: 254.2 [M+1]。At 0°C, Example 10G (720.00 mg, 2.33 mmol) was added to H 2 SO 4 (3 mL), to this mixture was added guanidine nitrate (284.45 mg, 2.33 mmol), and stirred for 2 Hour, and then heated to 20 °C and stirred for 1 hour. TLC showed that the reaction was completed. To the reaction mixture was added saturated Na 2 CO 3 aqueous solution to pH 7-8, extracted with DCM (10 mL×2), the organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (DCM/MeOH) = 10:1) isolated and purified to obtain the title compound (yellow solid, 270.00 mg, yield 40.08%). LCMS (ESI) (5-95AB): m/z: 254.2 [M+1].

實施例10I。Example 10I.

4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）-N-（4-（3-（二甲基氨基）丙基）-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image479
4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-(3-(dimethylamino)propyl)-2-methyl Oxy-5-nitrophenyl)pyrimidine-2-amine.
Figure 02_image479

本實施例根據實施例1A的方法製備，將N,N’,N’ – 三甲基 – 1,2 - 乙二胺替換為實施例10H。得到標題化合物（紅色固體，300.00毫克，粗品)。LCMS (ESI) (5-95AB): m/z: 487.3 [M+1]。This example was prepared according to the method of Example 1A, and N,N',N'-trimethyl-1,2-ethylenediamine was replaced with Example 10H. The title compound (red solid, 300.00 mg, crude) was obtained. LCMS (ESI) (5-95AB): m/z: 487.3 [M+1].

實施例10J。Example 10J.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-4-（3-（二甲基氨基）丙基）-6-甲基苯-1,3-二胺。

Figure 02_image481
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)propane Radical)-6-methylbenzene-1,3-diamine.
Figure 02_image481

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例10I。得到標題化合物（黃色固體，200.00毫克，產率66.21%）。LCMS (ESI) (5-95AB): m/z: 457.2 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 10I. The title compound was obtained (yellow solid, 200.00 mg, yield 66.21%). LCMS (ESI) (5-95AB): m/z: 457.2 [M+1].

實施例10K。Example 10K.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（3-（二甲基氨基）丙基）-4-甲基苯基）丙烯醯胺。

Figure 02_image483
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)propyl)-4-methylphenyl)acrylamide.
Figure 02_image483

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例10J。得到標題化合物（FA鹽，30.00毫克，產率11.80%)。1 H NMR (400 MHz, CDCl3) ppm δ 9.22 (br. s., 1 H), 8.58 - 8.78 (m, 1 H), 8.50 (s, 1 H), 8.19 - 8.37 (m, 2 H), 7.65 - 7.79 (m, 1 H), 7.16 - 7.26 (m, 2 H), 7.00 (d, J = 5.40 Hz, 1 H), 6.63 - 6.72 (m, 1 H), 6.35 - 6.52 (m, 2 H), 5.63 - 5.78 (m, 1 H), 4.10 (t, J = 7.15 Hz, 2 H), 3.82 - 3.92 (m, 3 H), 3.28 - 3.43 (m, 2 H), 2.53 - 2.78 (m, 12 H), 1.88 - 2.18 (m, 2 H)。LCMS (ESI) (5-95AB): m/z: 511.3 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 10J. The title compound (FA salt, 30.00 mg, yield 11.80%) was obtained. 1 H NMR (400 MHz, CDCl3) ppm δ 9.22 (br. s., 1 H), 8.58-8.78 (m, 1 H), 8.50 (s, 1 H), 8.19-8.37 (m, 2 H), 7.65-7.79 (m, 1 H), 7.16-7.26 (m, 2 H), 7.00 (d, J = 5.40 Hz, 1 H), 6.63-6.72 (m, 1 H), 6.35-6.52 (m, 2 H), 5.63-5.78 (m, 1 H), 4.10 (t, J = 7.15 Hz, 2 H), 3.82-3.92 (m, 3 H), 3.28-3.43 (m, 2 H), 2.53-2.78 ( m, 12 H), 1.88-2.18 (m, 2 H). LCMS (ESI) (5-95AB): m/z: 511.3 [M+1].

實施例11。Example 11.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（（1-（二甲基氨基）丙-2-基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image485
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-((1- (Dimethylamino)propan-2-yl) (methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image485

實施例11A。Example 11A.

2 - （（4-氨基-5-甲氧基-2-硝基苯基）（甲基）氨基）-N，N-二甲基丙醯胺。

Figure 02_image487
2-((4-Amino-5-methoxy-2-nitrophenyl) (methyl)amino)-N,N-dimethylpropylamide.
Figure 02_image487

將N，N-二甲基-2-（甲基氨基）丙醯胺（4.80克，36.87毫莫耳）和4-氟-2-甲氧基-5-硝基苯胺（6.86克，36.87毫莫耳）加入到MeCN（10mL）中，向此混合物中加入Cs2 CO3 （48.05克，147.48毫莫耳），並升溫至100°C攪拌12小時。TLC顯示反應完成，向反應混合物中加入水（25mL），用DCM（60mL×3）萃取。有機相用飽和食鹽水（15mL）洗滌，經無水硫酸鈉乾燥後，濃縮，用柱色譜（PE/EA = 5:1-1:2）分離純化，得到標題化合物（紅色油狀，1.00克，產率6.49%）。1 H NMR (400MHz, CDCl3): δ 7.25 (s, 1H), 6.71 (s, 1H), 4.11-4.17 (m, 1H), 3.92 (s, 3H), 2.93 (d, J = 8.0 Hz, 6H), 2.82 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H)。LCMS (ESI) (10-80_CD):m/z: 297.2 [M+1]。Combine N,N-dimethyl-2-(methylamino)propionamide (4.80 g, 36.87 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (6.86 g, 36.87 mmol) Mole) was added to MeCN (10 mL), Cs 2 CO 3 (48.05 g, 147.48 mmol) was added to this mixture, and the temperature was raised to 100°C and stirred for 12 hours. TLC showed that the reaction was completed, and water (25 mL) was added to the reaction mixture, which was extracted with DCM (60 mL×3). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (PE/EA = 5:1-1:2) to obtain the title compound (red oil, 1.00 g, Yield 6.49%). 1 H NMR (400MHz, CDCl3): δ 7.25 (s, 1H), 6.71 (s, 1H), 4.11-4.17 (m, 1H), 3.92 (s, 3H), 2.93 (d, J = 8.0 Hz, 6H ), 2.82 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). LCMS (ESI) (10-80_CD): m/z: 297.2 [M+1].

實施例11B。Example 11B.

N1-（1-（二甲基氨基）丙-2-基）-5-甲氧基N1甲基-2-硝基苯-1,4-二胺。

Figure 02_image489
N1-(1-(dimethylamino)propan-2-yl)-5-methoxy N1methyl-2-nitrobenzene-1,4-diamine.
Figure 02_image489

將實施例11A（1.00克，3.37毫莫耳）加入到THF（40mL）中，向此混合物中加入BH3 /Me2 S（10 M，1.69mL），並升溫至80°C攪拌3小時。冷卻至室溫，向反應混合物中加入MeOH（40mL），並攪拌30分鐘，再升溫至80°C攪拌1小時。TLC顯示反應完成，將反應混合物濃縮，用製備板（DCM/MeOH = 10:1）分離純化，得到標題化合物（紅色油狀，480.00毫克，產率37.09%）。1 H NMR (400MHz, CDCl3): δ 7.20 (s, 1H), 6.59 (s, 1H), 3.84 (s, 3H), 3.55-3.72 (m, 2H), 3.38-3.42 (m, 1H), 2.61 (s, 3H), 2.45-2.48 (m, 1H), 2.23-2.32 (m, 1H), 2.15 (s, 6H), 1.14 (d, J = 6.4 Hz, 3H)。LCMS (ESI) (10-80_CD):m/z: 283.2 [M+1]。Example 11A (1.00 g, 3.37 mmol) was added to THF (40 mL), to this mixture was added BH 3 /Me 2 S (10 M, 1.69 mL), and the temperature was raised to 80°C and stirred for 3 hours. After cooling to room temperature, MeOH (40 mL) was added to the reaction mixture and stirred for 30 minutes, and then heated to 80°C and stirred for 1 hour. TLC showed that the reaction was completed, the reaction mixture was concentrated, and purified using a preparation plate (DCM/MeOH = 10:1) to obtain the title compound (red oil, 480.00 mg, yield 37.09%). 1 H NMR (400MHz, CDCl3): δ 7.20 (s, 1H), 6.59 (s, 1H), 3.84 (s, 3H), 3.55-3.72 (m, 2H), 3.38-3.42 (m, 1H), 2.61 (s, 3H), 2.45-2.48 (m, 1H), 2.23-2.32 (m, 1H), 2.15 (s, 6H), 1.14 (d, J = 6.4 Hz, 3H). LCMS (ESI) (10-80_CD): m/z: 283.2 [M+1].

實施例11C。Example 11C.

N1-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-N4-（1-（二甲基氨基）丙-2-基）-2-甲氧基-N-4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image491
N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N4-(1-(dimethylamino)propane -2-yl)-2-methoxy-N-4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image491

將實施例11B（165.00毫克，584.40微莫耳）和實施例A（173.39毫克，642.84微莫耳）加入到二氧六環（10mL）中，向此混合物中加入Pd(OAc)2 （13.12毫克，58.44微莫耳），Xantphos（33.81毫克，58.44微莫耳）和K3 PO4 （248.10毫克，1.17毫莫耳），氮氣置換後，升溫至100°C攪拌12小時。LCMS顯示反應完成，將反應混合物濃縮，加入飽和Na2 CO3 水溶液（10mL），用DCM（30mL×3）萃取。有機相用飽和食鹽水（10mL）洗滌，經無水硫酸鈉乾燥後，濃縮，用製備板（DCM/MeOH = 10:1）分離純化，得到標題化合物（紅色油狀，220.00毫克，產率66.25%）。LCMS (ESI) (0-60_AB):m/z: 516.2 [M+1]。Example 11B (165.00 mg, 584.40 μmol) and Example A (173.39 mg, 642.84 μmol) were added to dioxane (10 mL), and Pd(OAc) 2 (13.12 mg) was added to this mixture , 58.44 micromolar), Xantphos (33.81 mg, 58.44 micromolar) and K 3 PO 4 (248.10 mg, 1.17 mmol), after nitrogen replacement, the temperature was raised to 100°C and stirred for 12 hours. LCMS showed the reaction was completed, the reaction mixture was concentrated, saturated aqueous Na 2 CO 3 solution (10 mL) was added, and extracted with DCM (30 mL×3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified using a preparation plate (DCM/MeOH = 10:1) to obtain the title compound (red oil, 220.00 mg, yield 66.25%) ). LCMS (ESI) (0-60_AB): m/z: 516.2 [M+1].

實施例11D。Example 11D.

N4-（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）-N 1 - （1-（二甲基氨基）丙-2-基）-5-甲氧基-N 1 - 甲基苯-1,2,4-三胺。

Figure 02_image493
N4-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N 1 -(1-(dimethylamino) Prop-2-yl)-5-methoxy-N 1 -methylbenzene-1,2,4-triamine.
Figure 02_image493

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例11C。得到標題化合物（棕色油狀，200.00毫克，產率92.81%）。LCMS (ESI) (0-60_AB):m/z: 486.3 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 11C. The title compound was obtained (brown oil, 200.00 mg, yield 92.81%). LCMS (ESI) (0-60_AB): m/z: 486.3 [M+1].

實施例11E。Example 11E.

N-（5 - （（4-（2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）-2-（（1-（二甲基氨基）丙-2-基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image495
N-(5-((4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-((1- (Dimethylamino)propan-2-yl) (methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image495

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例11D。得到標題化合物（FA鹽，75.92毫克，產率30.52%)。1 H NMR (400MHz, CD3OD) δ 8.51 (s, 1H), 8.26-8.31(m, 2H), 7.32-7.35 (m, 1H), 6.87-7.17 (m, 3H), 6.88 (s, 1H), 6.47-6.51 (m, 2H), 5.85-5.88 (m, 1H), 4.16 (t, J = 7.2 Hz, 2H), 3.91-4.07 (m, 4H), 3.35-3.42 (m, 2H), 3.12-3.15 (m, 1H), 2.83-2.97 (m, 7H), 2.67-2.74 (m, 5H), 1.40 (d, J = 6.4 Hz, 3H)。LCMS (ESI) (0-60_AB):m/z: 540.3 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 11D. The title compound (FA salt, 75.92 mg, 30.52% yield) was obtained. 1 H NMR (400MHz, CD3OD) δ 8.51 (s, 1H), 8.26-8.31(m, 2H), 7.32-7.35 (m, 1H), 6.87-7.17 (m, 3H), 6.88 (s, 1H), 6.47-6.51 (m, 2H), 5.85-5.88 (m, 1H), 4.16 (t, J = 7.2 Hz, 2H), 3.91-4.07 (m, 4H), 3.35-3.42 (m, 2H), 3.12- 3.15 (m, 1H), 2.83-2.97 (m, 7H), 2.67-2.74 (m, 5H), 1.40 (d, J = 6.4 Hz, 3H). LCMS (ESI) (0-60_AB): m/z: 540.3 [M+1].

流程4。

Figure 02_image497
Process 4.
Figure 02_image497

實施例12。Example 12.

N-（2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基-5 - （（4-（1-氧代-2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）苯基）丙烯醯胺。

Figure 02_image499
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-oxo-2,3-dihydro- 1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)phenyl)acrylamide.
Figure 02_image499

實施例12A。Example 12A.

甲基-1-氧代-2,3-二氫-1H-吡咯並[1,2-a]吲哚-2-甲酸酯。

Figure 02_image501
Methyl-1-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylic acid ester.
Figure 02_image501

將2-羧酸乙酯吲哚（4.00克，21.14毫莫耳）和丙烯酸甲酯（3.28克，38.05毫莫耳）加入到甲苯（200mL）中，向此混合物中加入NaH（60%，974.13毫克，40.59毫莫耳），並升溫至100°C攪拌16小時。LCMS顯示反應完成，向反應混合物中加入飽和NH4 Cl（100mL）水溶液。用EA（300mL×3）萃取，有機相經無水硫酸鈉乾燥後，濃縮，得到標題化合物（黃色油狀，3.73克，產率76.97%）。LCMS (ESI) (5-95AB):m/z: 229.9 [M+1]。Ethyl 2-carboxylate indole (4.00 g, 21.14 mmol) and methyl acrylate (3.28 g, 38.05 mmol) were added to toluene (200 mL), and NaH (60%, 974.13) was added to this mixture Milligrams, 40.59 millimoles), and heated to 100 ° C and stirred for 16 hours. LCMS showed the reaction was complete, and saturated aqueous NH 4 Cl (100 mL) was added to the reaction mixture. It was extracted with EA (300 mL×3), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (yellow oil, 3.73 g, yield 76.97%). LCMS (ESI) (5-95AB): m/z: 229.9 [M+1].

實施例12B。Example 12B.

2,3-二氫-1H-吡咯並[1,2-a]吲哚-1-酮。

Figure 02_image503
2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one.
Figure 02_image503

將實施例12A（3.73克，16.27毫莫耳）加入到二氧六環（150mL）中，向此混合物中加入鹽酸（2 M，40mL），並升溫至80°C攪拌16小時。LCMS顯示反應完成，向反應混合物中加入氫氧化鈉溶液（2 M，100mL）。將得到的混合物用EA（100mL×3）萃取，有機相經濃縮，用柱色譜（PE/EA = 100:1-5:1）分離純化，得到標題化合物（黃色固體，1.52克，產率51.84%）。1 H NMR (400 MHz, CDCl3): d, 7.80-7.78 (m, 1H), 7.47-7.39 (m, 2H), 7.39-7.22 (m, 1H), 7.04 (d, J = 0.8 Hz, 1 H), 4.49-4.46 (m, 2 H), 3.27-3.24 (m, 2 H)。LCMS (ESI) (5-95AB):m/z: 171.9 [M+1]。Example 12A (3.73 g, 16.27 mmol) was added to dioxane (150 mL), hydrochloric acid (2 M, 40 mL) was added to this mixture, and the temperature was raised to 80°C and stirred for 16 hours. LCMS showed the reaction was completed, and sodium hydroxide solution (2 M, 100 mL) was added to the reaction mixture. The obtained mixture was extracted with EA (100 mL×3), the organic phase was concentrated, and purified by column chromatography (PE/EA = 100:1-5:1) to obtain the title compound (yellow solid, 1.52 g, yield 51.84 %). 1 H NMR (400 MHz, CDCl3): d, 7.80-7.78 (m, 1H), 7.47-7.39 (m, 2H), 7.39-7.22 (m, 1H), 7.04 (d, J = 0.8 Hz, 1 H ), 4.49-4.46 (m, 2 H), 3.27-3.24 (m, 2 H). LCMS (ESI) (5-95AB): m/z: 171.9 [M+1].

實施例12C。Example 12C.

9-溴-2,3-二氫-1H-吡咯並[1,2-a]吲哚-1-酮。

Figure 02_image505
9-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one.
Figure 02_image505

在20°C下，將實施例12B（6.00克，35.05毫莫耳）加入到DMF（100mL）中，向此混合物中加入NBS（6.24克，35.05毫莫耳），並攪拌2小時。將反應混合物過濾，濾液濃縮後，用柱色譜（PE/EA = 20:1-3:1）分離純化，得到標題化合物（黃色固體，7.98克，產率591.04%）。1 H NMR (400 MHz, CDCl3): d, 7.74 (d, J = 8.4 Hz, 1 H), 7.47-7.42 (m, 2 H), 7.31-7.27 (m, 1), 4.46-4.43 (m, 2 H), 3.26-3.29 (m, 2 H)。LCMS (ESI) (5-95AB):m/z: 251.9 [M+3]。At 20°C, Example 12B (6.00 g, 35.05 mmol) was added to DMF (100 mL), and NBS (6.24 g, 35.05 mmol) was added to this mixture, and stirred for 2 hours. The reaction mixture was filtered, and after the filtrate was concentrated, it was separated and purified by column chromatography (PE/EA = 20:1-3:1) to obtain the title compound (yellow solid, 7.98 g, yield 591.04%). 1 H NMR (400 MHz, CDCl3): d, 7.74 (d, J = 8.4 Hz, 1 H), 7.47-7.42 (m, 2 H), 7.31-7.27 (m, 1), 4.46-4.43 (m, 2 H), 3.26-3.29 (m, 2 H). LCMS (ESI) (5-95AB): m/z: 251.9 [M+3].

實施例12D。Example 12D.

9-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）-2,3-二氫-1H-吡咯並[1,2-a]吲哚-1-酮。

Figure 02_image507
9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a] Indol-1-one.
Figure 02_image507

將實施例12C（7.80克，31.19毫莫耳）和B2 Pin2 （11.98克，93.57毫莫耳）加入到甲苯（150mL）中，向此混合物中加入Pd2 (dba)3 （571.23毫克，623.80微莫耳），X-phos（1.19克，2.50毫莫耳）和TEA（9.47克，93.57毫莫耳），氮氣置換後，升溫至80°C攪拌3小時。LCMS顯示反應完成，將反應混合物過濾，濾液濃縮，得到標題化合物（棕色油狀，10.00克，粗品）。LCMS (ESI) (5-95AB):m/z: 298.0 [M+1]。Example 12C (7.80 g, 31.19 mmol) and B 2 Pin 2 (11.98 g, 93.57 mmol) were added to toluene (150 mL), and Pd 2 (dba) 3 (571.23 mg, 623.80 micromolar), X-phos (1.19 grams, 2.50 millimoles) and TEA (9.47 grams, 93.57 millimoles). After nitrogen substitution, the temperature was raised to 80°C and stirred for 3 hours. LCMS showed the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to give the title compound (brown oil, 10.00 g, crude product). LCMS (ESI) (5-95AB): m/z: 298.0 [M+1].

實施例12E。Example 12E.

9-（2-氯嘧啶-4-基）-2,3-二氫-1H-吡咯並[1,2-a]吲哚-1-酮。

Figure 02_image509
9-(2-chloropyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one.
Figure 02_image509

將實施例12D（11.00克，37.02毫莫耳）和2，4 - 二氯嘧啶（11.03克，74.03毫莫耳）加入到二氧六環/水（15：1，160mL）中，向此混合物中加入Pd(dppf)Cl2 （812.56毫克，1.11毫莫耳），K2 CO3 （10.23克，74.03毫莫耳），氮氣置換後，升溫至70°C攪拌10小時。LCMS顯示反應完成，將反應混合物過濾，濾液濃縮後，用柱色譜（PE/DCM/EA = 10: 1:0 - 0:1:3）分離純化，得到標題化合物（黃色固體，1.80克，產率12.00%）。1 H NMR (400MHz, CDCl3): δ 9.00 (d, J = 8.8Hz, 1H), 8.73-8.80 (m, 1H), 8.61 (d, J = 5.2Hz, 1H), 7.53-7.40 (m, 3H), 4.55 (t, J = 6.4Hz, 2H), 3.43-3.36 (m, 2H)。LCMS (ESI) (5-95AB):m/z: 283.9 [M+1]。Example 12D (11.00 g, 37.02 mmol) and 2,4-dichloropyrimidine (11.03 g, 74.03 mmol) were added to dioxane/water (15:1, 160 mL) to this mixture Pd(dppf)Cl 2 (812.56 mg, 1.11 mmol), K 2 CO 3 (10.23 g, 74.03 mmol) were added, and after nitrogen substitution, the temperature was raised to 70°C and stirred for 10 hours. LCMS showed that the reaction was completed. The reaction mixture was filtered. After the filtrate was concentrated, it was separated and purified by column chromatography (PE/DCM/EA = 10: 1:0-0: 1:3) to obtain the title compound (yellow solid, 1.80 g, yield) Rate 12.00%). 1 H NMR (400MHz, CDCl3): δ 9.00 (d, J = 8.8Hz, 1H), 8.73-8.80 (m, 1H), 8.61 (d, J = 5.2Hz, 1H), 7.53-7.40 (m, 3H ), 4.55 (t, J = 6.4Hz, 2H), 3.43-3.36 (m, 2H). LCMS (ESI) (5-95AB): m/z: 283.9 [M+1].

實施例12F。Example 12F.

9-（2 - （（4-氟-2-甲氧基-5-硝基苯基）氨基）嘧啶-4-基）-2,3-二氫-1H-吡咯並[1,2-a]吲哚-1-酮。

Figure 02_image511
9-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[1,2-a ] Indol-1-one.
Figure 02_image511

本實施例根據實施例B的方法製備，將實施例A替換為實施例12E。得到標題化合物（黃色固體，280.00毫克，產率8.31%)。LCMS (ESI) (5-95AB):m/z: 434.0 [M+1]。This example was prepared according to the method of Example B, and Example A was replaced with Example 12E. The title compound (yellow solid, 280.00 mg, yield 8.31%) was obtained. LCMS (ESI) (5-95AB): m/z: 434.0 [M+1].

實施例12G。Example 12G.

9-（2 - （（4 - （（2-（二甲基氨基）乙基）（甲基）氨基）-2-甲氧基-5-硝基苯基）氨基）嘧啶-4-基）-2,3-二氫-1H-吡咯並[1,2-a]吲哚-1-酮。

Figure 02_image513
9-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl) -2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one.
Figure 02_image513

本實施例根據實施例1A的方法製備，將實施例B替換為實施例12F。得到標題化合物（棕色固體，140.00毫克，產率54.04%)。1 H NMR (400MHz, CDCl3): δ, 9.03 (s, 1H), 8.35-8.24 (m, 2H), 7.36 (d, J = 7.2Hz, 1H), 7.24-7.12 (m, 3H), 7.09 (s, 1H), 4.21-4.14 (m, 2H), 4.10 (s, 3H), 3.53-3.48 (m, 2H), 3.43-3.37 (m, 4H), 2.99 (s, 6H), 2.88 (s, 3H), 2.76-2.69 (m, 2H)。LCMS (ESI) (0-60AB):m/z: 516.2 [M+1]。This example was prepared according to the method of Example 1A, and Example B was replaced with Example 12F. The title compound was obtained (brown solid, 140.00 mg, yield 54.04%). 1 H NMR (400MHz, CDCl3): δ, 9.03 (s, 1H), 8.35-8.24 (m, 2H), 7.36 (d, J = 7.2Hz, 1H), 7.24-7.12 (m, 3H), 7.09 ( s, 1H), 4.21-4.14 (m, 2H), 4.10 (s, 3H), 3.53-3.48 (m, 2H), 3.43-3.37 (m, 4H), 2.99 (s, 6H), 2.88 (s, 3H), 2.76-2.69 (m, 2H). LCMS (ESI) (0-60AB): m/z: 516.2 [M+1].

實施例12H。Example 12H.

9-（2 - （（5-氨基-4 - （（2-（二甲基氨基）乙基）（甲基）氨基）-2-甲基苯基）氨基）嘧啶-4-基）-2,3-二氫-1H-吡咯並[1,2-a]吲哚-1-酮。

Figure 02_image515
9-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methylphenyl)amino)pyrimidin-4-yl)-2 ,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one.
Figure 02_image515

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例12G。得到標題化合物（棕色固體，140.00毫克，粗品）。1H NMR (400MHz, CDCl3): δ 8.98 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 8.06-8.01 (m, 1H), 7.68 (s, 1H), 7.50-7.48 (m., 2H), 7.02-6.99 (m, 1H), 6.74-6.69 (m, 1H), 4.55 (t, J = 6.0Hz, 2H), 3.89 (s, 3H), 3.38-3.37 (m, 2H), 3.28-3.26 (m, 2H), 3.11 (s, 3H), 2.95-2.94 (m., 2H), 2.75 (s, 6H)。LCMS (ESI) (0-60AB):m/z: 486.1 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 12G. The title compound (brown solid, 140.00 mg, crude) was obtained. 1H NMR (400MHz, CDCl3): δ 8.98 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 8.06-8.01 (m, 1H), 7.68 (s, 1H), 7.50-7.48 (m., 2H), 7.02-6.99 (m, 1H), 6.74-6.69 (m, 1H), 4.55 (t, J = 6.0Hz, 2H), 3.89 (s, 3H), 3.38-3.37 (m, 2H), 3.28-3.26 (m, 2H), 3.11 (s, 3H), 2.95-2.94 (m., 2H), 2.75 (s, 6H). LCMS (ESI) (0-60AB): m/z: 486.1 [M+1].

實施例12I。Example 12I.

N-（2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基-5 - （（4-（1-氧代-2,3-二氫-1H-吡咯並[1,2-a]吲哚-9-基）嘧啶-2-基）氨基）苯基）丙烯醯胺。

Figure 02_image517
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-oxo-2,3-dihydro- 1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)phenyl)acrylamide.
Figure 02_image517

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例12H。得到標題化合物（FA鹽，50.00毫克，產率28.78%)。1 H NMR (400MHz, CD3OD): δ 8.75-8.64 (m, 2H), 8.21 (d, J = 6.4Hz, 1H), 7.82-7.68 (m, 2H), 7.52 (t, J = 8.0Hz, 1H), 7.38-7.35 (m, 1H), 7.11 (s, 1H), 6.71-6.60 (m, 1H), 6.53-6.43 (m, 1H), 5.87 (dd, J1 = 1.6, J2 =10.4Hz, 1H), 4.6-4.63 (m, 2H), 3.97 (s, 3H), 3.64-3.56 (m, 2H), 3.46-3.36 (m, 4H), 2.94 (s, 6H), 2.84 (s, 3H)。LCMS (ESI) (5-95AB): m/z: 540.2 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 12H. The title compound (FA salt, 50.00 mg, 28.78% yield) was obtained. 1 H NMR (400MHz, CD3OD): δ 8.75-8.64 (m, 2H), 8.21 (d, J = 6.4Hz, 1H), 7.82-7.68 (m, 2H), 7.52 (t, J = 8.0Hz, 1H ), 7.38-7.35 (m, 1H), 7.11 (s, 1H), 6.71-6.60 (m, 1H), 6.53-6.43 (m, 1H), 5.87 (dd, J1 = 1.6, J2 =10.4Hz, 1H ), 4.6-4.63 (m, 2H), 3.97 (s, 3H), 3.64-3.56 (m, 2H), 3.46-3.36 (m, 4H), 2.94 (s, 6H), 2.84 (s, 3H). LCMS (ESI) (5-95AB): m/z: 540.2 [M+1].

流程5。

Figure 02_image519
Process 5.
Figure 02_image519

實施例13。Example 13.

N-〔2-〔2-（二甲基氨基）乙基 - 甲基 - 氨基] -5 - [[4-（6-氟-2,3-二氫-1H-吡咯並[1,2-a]吲哚-4-基）嘧啶-2-基]氨基] -4-甲氧基苯基]丙-2-烯醯胺。

Figure 02_image521
N-[2-[2-(dimethylamino)ethyl-methyl-amino] -5-[[4-(6-fluoro-2,3-dihydro-1H-pyrrolo[1,2- a] Indol-4-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide.
Figure 02_image521

實施例13A。Example 13A.

乙基-5-氟-1H-吲哚-2-羧酸酯。

Figure 02_image523
Ethyl-5-fluoro-1H-indole-2-carboxylate.
Figure 02_image523

在0°C下，將5 – 氟 – 2 - 羧酸吲哚（5.00克，27.91毫莫耳）加入到乙醇（50mL）中，向此混合物中加入SOCl2 （9.84克，82.71毫莫耳），並升溫回流攪拌5小時。TLC顯示反應完成，將反應混合物濃縮，向其中加入飽和NaHCO3 （15mL）水溶液。用DCM（100mL×2）萃取，有機相經無水硫酸鈉乾燥後，濃縮，得到標題化合物（淡黃色固體，5.50克，產率85.60%）。1 H-NMR (400 MHz, CDCl3) δ 9.00 (br. s., 1 H), 7.31 - 7.39 (m, 2 H), 7.19 (d, J=1.2Hz, 1 H), 7.10 (td, J=9.0, 2.4 Hz, 1 H), 4.43 (q, J=7.1 Hz, 2 H), 1.43 (t, J=7.1 Hz, 3 H)。At 0°C, add 5-fluoro-2 -carboxylic acid indole (5.00 g, 27.91 mmol) to ethanol (50 mL), and add SOCl 2 (9.84 g, 82.71 mmol) to this mixture , And stirred at reflux for 5 hours. TLC showed that the reaction was completed, the reaction mixture was concentrated, and saturated aqueous NaHCO 3 (15 mL) was added thereto. It was extracted with DCM (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (light yellow solid, 5.50 g, yield 85.60%). 1 H-NMR (400 MHz, CDCl3) δ 9.00 (br. s., 1 H), 7.31-7.39 (m, 2 H), 7.19 (d, J=1.2Hz, 1 H), 7.10 (td, J =9.0, 2.4 Hz, 1 H), 4.43 (q, J=7.1 Hz, 2 H), 1.43 (t, J=7.1 Hz, 3 H).

實施例13B。Example 13B.

甲基6-氟-3-氧代-1,2-二氫吡咯並[1,2-a]吲哚-2-甲酸酯。

Figure 02_image525
Methyl 6-fluoro-3-oxo-1,2-dihydropyrrolo[1,2-a]indole-2-carboxylate.
Figure 02_image525

本實施例根據實施例12A的方法製備，將2-羧酸乙酯吲哚替換為實施例13A。得到標題化合物（黃色油狀，8.20克，粗品)。LCMS (ESI) (5-95 AB):m/z: 270.0 [M+23] RT: 0.658min/ 2 min。This example was prepared according to the method of Example 12A, and ethyl 2-carboxylate indole was replaced with Example 13A. The title compound was obtained (yellow oil, 8.20 g, crude). LCMS (ESI) (5-95 AB): m/z: 270.0 [M+23] RT: 0.658 min/2 min.

實施例13C。Example 13C.

6-氟-1,2-二氫吡咯並[1,2-a]吲哚-3-酮。

Figure 02_image527
6-fluoro-1,2-dihydropyrrolo[1,2-a]indole-3-one.
Figure 02_image527

本實施例根據實施例12B的方法製備，將實施例12A替換為實施例13B。得到標題化合物（黃色固體，3.08克，產率48.43%)。1 H-NMR (400 MHz, CDCl3 ) δ 7.35 - 7.45 (m, 1 H), 7.10 - 7.20 (m, 1 H), 6.96 (s, 1 H), 4.44 (t, J=6.1 Hz, 2 H), 3.23 (t, J=6.0 Hz, 2 H)。This example was prepared according to the method of Example 12B, and Example 12A was replaced with Example 13B. The title compound was obtained (yellow solid, 3.08 g, yield 48.43%). 1 H-NMR (400 MHz, CDCl 3 ) δ 7.35-7.45 (m, 1 H), 7.10-7.20 (m, 1 H), 6.96 (s, 1 H), 4.44 (t, J=6.1 Hz, 2 H), 3.23 (t, J=6.0 Hz, 2 H).

實施例13D。Example 13D.

6-氟-2,3-二氫-1H-吡咯並[1,2-α]吲哚。

Figure 02_image529
6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-α]indole.
Figure 02_image529

將實施例13C（3.04克，16.07毫莫耳）加入到一縮二乙二醇（50mL）中，向此混合物中加入K2 CO3 （15.00克，108.53毫莫耳）和N2 H4. H2 O（5.96克，119.07毫莫耳），氮氣置換後，升溫至160°C攪拌2.5小時，再升溫至180°C攪拌2.5小時。TLC顯示反應完成，向反應混合物中加入EA（100mL）。用水（30mL×2）洗滌，有機相經濃縮後，用製備板（PE/EA = 3:1）分離純化，得到標題化合物（白色固體，1.02克，產率32.81%）。1 H-NMR (400 MHz, CDCl3) δ 7.21 (dd, J=10.0, 2.5 Hz, 1 H), 7.14 (dd, J=8.7, 4.5 Hz, 1 H), 6.87 (td, J=9.1, 2.5 Hz, 1 H), 6.15 (s, 1 H), 4.07 (t, J=7.0 Hz, 2 H), 3.04 (t, J=7.4 Hz, 2 H), 2.56 - 2.70 (m, 2 H)。Example 13C (3.04 g, 16.07 mmol) was added to diethylene glycol (50 mL), and to this mixture was added K 2 CO 3 (15.00 g, 108.53 mmol) and N 2 H 4. H 2 O (5.96 grams, 119.07 millimoles). After nitrogen substitution, the temperature was raised to 160°C and stirred for 2.5 hours, and then heated to 180°C and stirred for 2.5 hours. TLC showed the reaction was completed, and EA (100 mL) was added to the reaction mixture. After washing with water (30 mL×2), the organic phase was concentrated, and separated and purified using a preparation plate (PE/EA = 3:1) to obtain the title compound (white solid, 1.02 g, yield 32.81%). 1 H-NMR (400 MHz, CDCl3) δ 7.21 (dd, J=10.0, 2.5 Hz, 1 H), 7.14 (dd, J=8.7, 4.5 Hz, 1 H), 6.87 (td, J=9.1, 2.5 Hz, 1 H), 6.15 (s, 1 H), 4.07 (t, J=7.0 Hz, 2 H), 3.04 (t, J=7.4 Hz, 2 H), 2.56-2.70 (m, 2 H).

實施例13E。Example 13E.

4-（2-氯嘧啶-4-基）-6-氟-2,3-二氫-1H-吡咯並[1,2-α]吲哚。

Figure 02_image531
4-(2-chloropyrimidin-4-yl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-α]indole.
Figure 02_image531

本實施例根據實施例A的方法製備，將實施例A6替換為實施例13D。得到標題化合物（黃色固體，716.00毫克，產率38.35%)。1 H-NMR (400 MHz, CDCl3) δ 8.41 (d, J=5.5 Hz, 1 H), 8.08 (dd, J=10.3, 2.4 Hz, 1 H), 7.28 (s, 1 H), 7.27 (s, 1 H), 7.20 (dd, J=8.7, 4.5 Hz, 1 H), 7.00 (td, J=8.9, 2.5 Hz, 1 H), 4.17 (t, J=7.2 Hz, 2 H), 3.40 (t, J=7.5 Hz, 2 H), 2.77 (quin, J=7.3 Hz, 2 H)。This example was prepared according to the method of Example A, and Example A6 was replaced with Example 13D. The title compound was obtained (yellow solid, 716.00 mg, yield 38.35%). 1 H-NMR (400 MHz, CDCl3) δ 8.41 (d, J=5.5 Hz, 1 H), 8.08 (dd, J=10.3, 2.4 Hz, 1 H), 7.28 (s, 1 H), 7.27 (s , 1 H), 7.20 (dd, J=8.7, 4.5 Hz, 1 H), 7.00 (td, J=8.9, 2.5 Hz, 1 H), 4.17 (t, J=7.2 Hz, 2 H), 3.40 ( t, J=7.5 Hz, 2 H), 2.77 (quin, J=7.3 Hz, 2 H).

實施例13F。Example 13F.

4-（6-氟-2,3-二氫-1H-吡咯並[1,2-a]吲哚基-4-基）-N- （4-氟-2-甲氧基-5-硝基 - 苯基）嘧啶-2-胺。

Figure 02_image533
4-(6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indolyl-4-yl)-N- (4-fluoro-2-methoxy-5-nitro Group-phenyl) pyrimidine-2-amine.
Figure 02_image533

本實施例根據實施例B的方法製備，將實施例A替換為實施例13E。得到標題化合物（黃色固體，378.00毫克，粗品)。LCMS (ESI) (5-95 AB):m/z: 438.1 [M+1] RT: 0.672min/ 2min。This example was prepared according to the method of Example B, and Example A was replaced with Example 13E. The title compound was obtained (yellow solid, 378.00 mg, crude). LCMS (ESI) (5-95 AB): m/z: 438.1 [M+1] RT: 0.672 min/2 min.

實施例13G。Example 13G.

N4-〔2-（二甲基氨基）乙基]-N 1 - [4-（6-氟-2,3-二氫-1H-吡咯並[1,2-a]吲哚-4-基）嘧啶-2-基]-2-甲氧基-N-4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image535
N4-[2-(dimethylamino)ethyl]-N 1-[4-(6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-4-yl ) Pyrimidin-2-yl]-2-methoxy-N-4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image535

本實施例根據實施例1A的方法製備，將實施例B替換為實施例13F。得到標題化合物（棕色固體，373.00毫克，產率69.78%)。1 H-NMR (400 MHz, CDCl3 ) δ 9.09 (s, 1 H), 8.36 (d, J=4.0 Hz, 1 H), 7.99 (d, J=8.91 Hz, 1 H), 7.44 (s, 1 H), 7.20 (dd, J=8.72, 4.58 Hz, 1 H), 6.92 - 7.01 (m, 2 H), 6.72 (s, 1 H), 4.15 (t, J=7.15 Hz, 2 H), 4.01 (s, 3 H), 3.42 (t, J=7.47 Hz, 2 H), 3.32 (t, J=7.03 Hz, 2 H), 2.90 (s, 3 H), 2.74 (quin, J=7.31 Hz, 2 H), 2.66 (d, J=6.65 Hz, 2 H), 2.34 (s, 6 H)。This example was prepared according to the method of Example 1A, and Example B was replaced with Example 13F. The title compound was obtained (brown solid, 373.00 mg, yield 69.78%). 1 H-NMR (400 MHz, CDCl 3 ) δ 9.09 (s, 1 H), 8.36 (d, J=4.0 Hz, 1 H), 7.99 (d, J=8.91 Hz, 1 H), 7.44 (s, 1 H), 7.20 (dd, J=8.72, 4.58 Hz, 1 H), 6.92-7.01 (m, 2 H), 6.72 (s, 1 H), 4.15 (t, J=7.15 Hz, 2 H), 4.01 (s, 3 H), 3.42 (t, J=7.47 Hz, 2 H), 3.32 (t, J=7.03 Hz, 2 H), 2.90 (s, 3 H), 2.74 (quin, J=7.31 Hz , 2 H), 2.66 (d, J=6.65 Hz, 2 H), 2.34 (s, 6 H).

實施例13H。Example 13H.

N1-[2-（二甲氨基）乙基]-N4-[4-（6-氟-2,3-二氫-1H-吡咯並[1,2-a]吲哚-4-基）嘧啶-2-基]-5-甲氧基-N 1 - 甲基苯-1,2,4-三胺。

Figure 02_image537
N1-[2-(dimethylamino)ethyl]-N4-[4-(6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-4-yl)pyrimidine -2-yl]-5-methoxy-N 1 -methylbenzene-1,2,4-triamine.
Figure 02_image537

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例12G。得到標題化合物（粉色固體，306.00毫克，產率64.46%）。1 H-NMR (400 MHz, CDCl3 ) δ 8.21 - 8.29 (m, 2 H), 8.05 (s, 1 H), 7.52 (s, 1 H), 7.15 (dd, J=8.6, 4.5 Hz, 1 H), 6.89 - 6.99 (m, 1 H), 6.78 (d, J=5.4 Hz, 1 H), 6.73 (s, 1 H), 4.09 (t, J=7.2 Hz, 2 H), 3.83 - 3.90 (m, 3 H), 3.30 (t, J=7.4 Hz, 2 H), 2.98 (t, J=6.9 Hz, 2 H) 2.65 - 2.73 (m, 4 H), 2.38 - 2.48 (m, 2 H), 2.23 - 2.30 (m, 6 H)。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 12G. The title compound was obtained (pink solid, 306.00 mg, yield 64.46%). 1 H-NMR (400 MHz, CDCl 3 ) δ 8.21-8.29 (m, 2 H), 8.05 (s, 1 H), 7.52 (s, 1 H), 7.15 (dd, J=8.6, 4.5 Hz, 1 H), 6.89-6.99 (m, 1 H), 6.78 (d, J=5.4 Hz, 1 H), 6.73 (s, 1 H), 4.09 (t, J=7.2 Hz, 2 H), 3.83-3.90 (m, 3 H), 3.30 (t, J=7.4 Hz, 2 H), 2.98 (t, J=6.9 Hz, 2 H) 2.65-2.73 (m, 4 H), 2.38-2.48 (m, 2 H ), 2.23-2.30 (m, 6 H).

實施例13I。Example 13I.

N-〔2-〔2-（二甲基氨基）乙基 - 甲基 - 氨基] -5 - [[4-（6-氟-2,3-二氫-1H-吡咯並[1,2-a]吲哚-4-基）嘧啶-2-基]氨基] -4-甲氧基苯基]丙-2-烯醯胺。

Figure 02_image539
N-[2-[2-(dimethylamino)ethyl-methyl-amino] -5-[[4-(6-fluoro-2,3-dihydro-1H-pyrrolo[1,2- a] Indol-4-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide.
Figure 02_image539

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例13H。得到標題化合物（FA鹽，13.60毫克，產率7.53%)。LCMS (ESI) (0-60 AB):m/z: 544.2 [M+1] RT: 2.075min/ 4 min;1 H-NMR (400 MHz, DMSO) δ 10.08 (s, 1 H), 8.61 (s, 1 H), 8.27 (br. s., 1 H), 8.24 (d, J=5.4 Hz, 1 H), 8.17 (s, 1 H), 8.01 (d, J=10.9 Hz, 1 H), 7.34 (dd, J=8.7, 4.7 Hz, 1 H), 7.00 (s, 1 H), 6.93 (td, J=9.1, 2.64 Hz, 1 H), 6.89 (d, J=5.5 Hz, 1 H), 6.43 (dd, J=17.0, 10.1 Hz, 1 H), 6.15 (dd, J=17.0, 1.88 Hz, 1 H), 5.66 - 5.72 (m, 1 H), 4.12 (t, J=7.1 Hz, 2 H), 3.78 (s, 3 H), 3.27 (t, J=7.4 Hz, 3 H), 2.93 (t, J=5.5 Hz, 2 H), 2.69 (s, 3 H), 2.59 (quin, J=7.2 Hz, 2 H), 2.44 (t, J=5.6 Hz, 2 H)。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 13H. The title compound (FA salt, 13.60 mg, yield 7.53%) was obtained. LCMS (ESI) (0-60 AB): m/z: 544.2 [M+1] RT: 2.075min/ 4 min; 1 H-NMR (400 MHz, DMSO) δ 10.08 (s, 1 H), 8.61 ( s, 1 H), 8.27 (br. s., 1 H), 8.24 (d, J=5.4 Hz, 1 H), 8.17 (s, 1 H), 8.01 (d, J=10.9 Hz, 1 H) , 7.34 (dd, J=8.7, 4.7 Hz, 1 H), 7.00 (s, 1 H), 6.93 (td, J=9.1, 2.64 Hz, 1 H), 6.89 (d, J=5.5 Hz, 1 H ), 6.43 (dd, J=17.0, 10.1 Hz, 1 H), 6.15 (dd, J=17.0, 1.88 Hz, 1 H), 5.66-5.72 (m, 1 H), 4.12 (t, J=7.1 Hz , 2 H), 3.78 (s, 3 H), 3.27 (t, J=7.4 Hz, 3 H), 2.93 (t, J=5.5 Hz, 2 H), 2.69 (s, 3 H), 2.59 (quin , J=7.2 Hz, 2 H), 2.44 (t, J=5.6 Hz, 2 H).

流程6。

Figure 02_image541
Process 6.
Figure 02_image541

實施例14。Example 14.

N-〔5 - 〔〔4-（7,7-二氟-8,9-二氫-6H-吡啶並[1,2-a]吲哚-10-基）嘧啶-2-基]氨基] -2-[2-（二甲基氨基）乙基 - 甲基 - 氨基] -4-甲氧基苯基]丙-2-烯醯胺。

Figure 02_image543
N-[5-[[4-(7,7-difluoro-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]amino] -2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxyphenyl]prop-2-enamide.
Figure 02_image543

實施例14A。Example 14A.

乙基（E）-3-（1H-吲哚-2-基）丙-2-烯酸酯。

Figure 02_image545
Ethyl (E)-3-(1H-indol-2-yl)prop-2-enoate.
Figure 02_image545

在25°C下，將2 – 甲醛吲哚（5.00克，51.66毫莫耳）加入到THF（30mL）中，向此混合物中慢慢加入2 – 二乙氧基膦醯乙酸乙酯（11.58克，51.66毫莫耳）和NaH（2.76克，68.88毫莫耳），氮氣置換後，攪拌3小時。TLC顯示反應完成，將反應混合物慢慢加入飽和NH4 Cl（15mL）水溶液，用DCM（20mL×3）萃取，有機相經飽和食鹽水（10mL）洗滌，用無水硫酸鈉乾燥後，濃縮，用柱色譜（PE/EA = 20:1 - 10:1）分離純化，得到標題化合物（淡黃色固體，5.20克，產率70.15%）。1 H NMR (400 MHz, CDCl3) δ 8.33 (br. s., 1H), 7.69 (d, J=16.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.34 - 7.39 (m, 1H), 7.26 - 7.30 (m, 1H), 7.09 - 7.15 (m, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.22 (d, J=16.0 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H), 1.35 (t, J=7.15 Hz, 3H)。At 25°C, 2-formaldehyde indole (5.00 g, 51.66 mmol) was added to THF (30 mL), and to this mixture was slowly added ethyl 2-diethoxyphosphonoacetate (11.58 g , 51.66 millimoles) and NaH (2.76 grams, 68.88 millimoles), after nitrogen replacement, stirring for 3 hours. TLC showed that the reaction was completed. The reaction mixture was slowly added to a saturated aqueous solution of NH 4 Cl (15 mL) and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. Column chromatography (PE/EA = 20:1-10:1) was separated and purified to obtain the title compound (light yellow solid, 5.20 g, yield 70.5%). 1 H NMR (400 MHz, CDCl3) δ 8.33 (br. s., 1H), 7.69 (d, J=16.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.34-7.39 (m, 1H), 7.26-7.30 (m, 1H), 7.09-7.15 (m, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.22 (d, J=16.0 Hz, 1H), 4.28 (q, J =7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H), 1.35 (t, J=7.15 Hz, 3H).

實施例14B。Example 14B.

乙基（E）-3-〔1-（2-第三丁氧基-2-氧代乙基）吲哚-2-基]丙-2-烯酸酯。

Figure 02_image547
Ethyl (E)-3-[1-(2-third butoxy-2-oxoethyl)indol-2-yl]prop-2-enoate.
Figure 02_image547

將實施例14A（7.00克，32.52毫莫耳）加入到DMF（100mL）中，向此混合物中加入2 – 溴乙酸第三丁酯（12.69克，65.04毫莫耳）和Cs2 CO3 （21.19克，65.04毫莫耳），並升溫至50°C攪拌12小時。TLC顯示反應完成，將反應混合物過濾，濾餅用EA（150mL）洗滌，濾液濃縮後，用柱色譜（PE/EA = 10:1）分離純化，得到標題化合物（淡黃色固體，8.50克，產率73.80%）。1 H-NMR (400 MHz, CDCl3): δ 7.61 - 7.73 (m, 2 H),7.29 - 7.31 (m, 1 H), 7.24 - 7.28 (m, 1 H), 7.16 (ddd,J =7.9, 6.0, 1.8 Hz, 1 H), 7.03 (s, 1 H), 6.49 (d,J =15.8 Hz, 1 H), 4.25 - 4.34 (m, 2 H), 1.46 (s, 9 H), 1.36 (t,J =7.1 Hz, 3 H)。Example 14A (7.00 g, 32.52 mmol) was added to DMF (100 mL), to this mixture was added 3-butyl bromoacetate (12.69 g, 65.04 mmol) and Cs 2 CO 3 (21.19 Grams, 65.04 millimoles), and heated to 50 ° C and stirred for 12 hours. TLC showed that the reaction was completed. The reaction mixture was filtered. The filter cake was washed with EA (150 mL). After the filtrate was concentrated, it was separated and purified by column chromatography (PE/EA = 10:1) to obtain the title compound (light yellow solid, 8.50 g, yield). Rate 73.80%). 1 H-NMR (400 MHz, CDCl3): δ 7.61-7.73 (m, 2 H), 7.29-7.31 (m, 1 H), 7.24-7.28 (m, 1 H), 7.16 (ddd, J =7.9, 6.0, 1.8 Hz, 1 H), 7.03 (s, 1 H), 6.49 (d, J =15.8 Hz, 1 H), 4.25-4.34 (m, 2 H), 1.46 (s, 9 H), 1.36 ( t, J =7.1 Hz, 3 H).

實施例14C。Example 14C.

3- [1-（2-第三丁氧基-2-氧代乙基）吲哚-2-基]丙酸酯。

Figure 02_image549
3- [1-(2-Third-butoxy-2-oxoethyl) indol-2-yl] propionate.
Figure 02_image549

在20°C下，將實施例14B（8.50克，25.81毫莫耳）溶於MeOH（100mL），氮氣置換後加入Pd/C（10%，800毫克）。混合物在H2 中（壓力為15 Psi），攪拌12小時。LCMS顯示反應完成，將反應混合物過濾，濾液濃縮至乾，得到標題化合物（黃色油狀，8.00克，粗品)。At 20°C, Example 14B (8.50 g, 25.81 mmol) was dissolved in MeOH (100 mL), and after nitrogen substitution, Pd/C (10%, 800 mg) was added. The mixture was stirred in H 2 (pressure 15 Psi) for 12 hours. LCMS showed the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (yellow oil, 8.00 g, crude).

實施例14D。Example 14D.

7-氧代-8,9-二氫-6H-吡啶並[1,2-a]吲哚-6-羧酸酯。

Figure 02_image551
7-oxo-8,9-dihydro-6H-pyrido[1,2-a]indole-6-carboxylate.
Figure 02_image551

在0°C下，將實施例14C（8.00克，24.14毫莫耳）加入到THF（60mL）中，向此混合物中加入t -BuOK（5.42克，48.28毫莫耳），並攪拌2小時。TLC顯示反應完成，向反應混合物加入稀鹽酸（0.5 M）至pH為6~7。再加入EA（150mL）和水（30mL），分液後，有機相濃縮，用柱色譜（PE/EA = 60:1 - 20:1）分離純化，得到標題化合物（棕色固體，7.00克，產率98.59%）。1 H-NMR (400 MHz, CDCl3 ): δ 7.59 (d,J =7.1 Hz, 1 H), 7.13 - 7.26 (m, 3 H), 6.39 (s, 1 H), 5.42 (s, 1 H), 3.25 - 3.41 (m, 2 H), 2.95 (dt,J =16.3, 4.1 Hz, 1 H), 2.62 - 2.75 (m, 1 H), 1.41 (s, 9 H)。At 0°C, Example 14C (8.00 g, 24.14 mmol) was added to THF (60 mL), and t- BuOK (5.42 g, 48.28 mmol) was added to this mixture, and stirred for 2 hours. TLC showed that the reaction was completed, and dilute hydrochloric acid (0.5 M) was added to the reaction mixture to pH 6-7. Then, EA (150 mL) and water (30 mL) were added. After separation, the organic phase was concentrated and separated and purified by column chromatography (PE/EA = 60:1-20:1) to obtain the title compound (brown solid, 7.00 g, produced) Rate 98.59%). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.59 (d, J =7.1 Hz, 1 H), 7.13-7.26 (m, 3 H), 6.39 (s, 1 H), 5.42 (s, 1 H ), 3.25-3.41 (m, 2 H), 2.95 (dt, J =16.3, 4.1 Hz, 1 H), 2.62-2.75 (m, 1 H), 1.41 (s, 9 H).

實施例14E。Example 14E.

8,9-二氫-6H-吡啶並[1,2-a]吲哚-7-酮。

Figure 02_image553
8,9-dihydro-6H-pyrido[1,2-a]indole-7-one.
Figure 02_image553

將實施例14D（7.00克，24.53毫莫耳）加入到甲苯（100mL）中，向此混合物中加入SiO2 （7.00克，116.52毫莫耳），並氮氣置換，升溫至110 °C攪拌12小時。TLC顯示反應完成，將反應混合物過濾，濾液濃縮後，用柱色譜（PE/EA = 50:1）分離純化，得到標題化合物（黃色固體，1.75克，產率35.82%）。1 H-NMR (400 MHz, CDCl3 ): δ 7.60 (d,J =7.6 Hz, 1 H), 7.19 - 7.26 (m, 2 H), 7.13 - 7.19 (m, 1 H), 6.38 (s, 1 H), 4.69 (s, 2 H), 3.28 (t,J =6.5 Hz, 2 H), 2.74 - 2.86 (m, 2 H)。Example 14D (7.00 g, 24.53 mmol) was added to toluene (100 mL), SiO 2 (7.00 g, 116.52 mmol) was added to this mixture, and replaced with nitrogen, and the temperature was raised to 110 °C and stirred for 12 hours . TLC showed that the reaction was completed. The reaction mixture was filtered. After the filtrate was concentrated, it was separated and purified by column chromatography (PE/EA = 50:1) to obtain the title compound (yellow solid, 1.75 g, yield 35.82%). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.60 (d, J =7.6 Hz, 1 H), 7.19-7.26 (m, 2 H), 7.13-7.19 (m, 1 H), 6.38 (s, 1 H), 4.69 (s, 2 H), 3.28 (t, J =6.5 Hz, 2 H), 2.74-2.86 (m, 2 H).

實施例14F。Example 14F.

7,7-二氯-8,9-二氫-6H-吡啶並[1,2-α]吲哚。

Figure 02_image555
7,7-dichloro-8,9-dihydro-6H-pyrido[1,2-α]indole.
Figure 02_image555

在-40°C下，將實施例14E（1.70克，9.18毫莫耳）加入到DCM（20mL）中，向此混合物中加入DAST（5.92克，36.72毫莫耳），並攪拌2小時。TLC顯示反應完成，向反應混合物加入飽和NaHCO3 水溶液（10mL），再加入DCM（50mL）萃取，有機相用水（15mL）洗滌後，濃縮，用柱色譜（PE/EA = 30:1 - 10:1）分離純化，得到標題化合物（黃色固體，1.17克，產率59.66%）。1 H-NMR (400 MHz, CDCl3): δ 7.56 (d,J =7.6 Hz, 1 H), 7.12 - 7.26 (m, 3 H), 6.31 (s, 1 H), 4.35 (t,J =12.7 Hz, 2 H), 3.20 (t,J =6.8 Hz, 2 H), 2.38 (tt,J =13.4, 6.7 Hz, 2 H)。At -40°C, Example 14E (1.70 g, 9.18 mmol) was added to DCM (20 mL), and DAST (5.92 g, 36.72 mmol) was added to this mixture, and stirred for 2 hours. TLC showed that the reaction was completed. To the reaction mixture was added saturated aqueous NaHCO 3 (10 mL), and then DCM (50 mL) was added for extraction. After the organic phase was washed with water (15 mL), it was concentrated and column chromatography (PE/EA = 30:1-10: 1) Separation and purification to obtain the title compound (yellow solid, 1.17 g, yield 59.66%). 1 H-NMR (400 MHz, CDCl3): δ 7.56 (d, J =7.6 Hz, 1 H), 7.12-7.26 (m, 3 H), 6.31 (s, 1 H), 4.35 (t, J =12.7 Hz, 2 H), 3.20 (t, J =6.8 Hz, 2 H), 2.38 (tt, J =13.4, 6.7 Hz, 2 H).

實施例14G。Example 14G.

10-（2-氯嘧啶-4-基）-7,7-二氟-8,9-二氫-6H-吡啶並[1,2-α]吲哚。

Figure 02_image557
10-(2-chloropyrimidin-4-yl)-7,7-difluoro-8,9-dihydro-6H-pyrido[1,2-α]indole.
Figure 02_image557

本實施例根據實施例A的方法製備，將實施例A6替換為實施例14F。得到標題化合物（黃色固體，600.00毫克，產率49.25%)。1 H-NMR (400 MHz, CDCl3): δ 8.52 - 8.56 (m, 1 H), 8.03 - 8.10 (m, 1 H), 7.58 (d,J =5.4 Hz, 1 H), 7.30 - 7.37 (m, 3 H), 4.43 (t,J =12.3 Hz, 2 H), 3.69 (t,J =6.8 Hz, 2 H), 2.47 (tt,J =13.4, 6.7 Hz, 2 H)。This example was prepared according to the method of Example A, and Example A6 was replaced with Example 14F. The title compound was obtained (yellow solid, 600.00 mg, yield 49.25%). 1 H-NMR (400 MHz, CDCl3): δ 8.52-8.56 (m, 1 H), 8.03-8.10 (m, 1 H), 7.58 (d, J =5.4 Hz, 1 H), 7.30-7.37 (m , 3 H), 4.43 (t, J =12.3 Hz, 2 H), 3.69 (t, J = 6.8 Hz, 2 H), 2.47 (tt, J =13.4, 6.7 Hz, 2 H).

實施例14H。Example 14H.

4-（7,7-二氯-8,9-二氫-6H-吡啶並[1,2-a]吲哚-10-基）-N-（4-氟-2-甲氧基-5-硝基 - 苯基）嘧啶-2-胺。

Figure 02_image559
4-(7,7-dichloro-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl)-N-(4-fluoro-2-methoxy-5 -Nitro-phenyl)pyrimidine-2-amine.
Figure 02_image559

本實施例根據實施例B的方法製備，將實施例A替換為實施例14G。得到標題化合物（黃色固體，1.06克，產率78.01%)。1 H-NMR (400 MHz, DMSO-d6 ): δ 8.96 (m, 1 H), 8.26 - 8.60 (m, 2 H), 8.08 (m, 1 H) ,7.54 (m, 1 H), 7.12 - 7.44 (m, 4 H), 4.65 (m, 2 H), 4.02 (m., 3 H) 3.49 (m, 2 H) 2.52 (m, 2 H)。This example was prepared according to the method of Example B, and Example A was replaced with Example 14G. The title compound was obtained (yellow solid, 1.06 g, yield 78.01%). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 8.96 (m, 1 H), 8.26-8.60 (m, 2 H), 8.08 (m, 1 H), 7.54 (m, 1 H), 7.12 -7.44 (m, 4 H), 4.65 (m, 2 H), 4.02 (m., 3 H) 3.49 (m, 2 H) 2.52 (m, 2 H).

實施例14I。Example 14I.

N1-[4-（7,7-二氟-8,9-二氫-6H-吡啶並[1,2-a]吲哚-10-基）嘧啶-2-基]-N4-[2-（二甲基氨基）乙基]-2-甲氧基 - N 4 - 甲基-5-硝基苯-1,4-二胺。

Figure 02_image561
N1-[4-(7,7-difluoro-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]-N4-[2- (Dimethylamino)ethyl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image561

本實施例根據實施例1A的方法製備，將實施例B替換為實施例14I。得到標題化合物（棕色固體，1.05克，產率75.98%)。LCMS (ESI) (5-95 AB):m/z: 552.2 [M+1]。This example was prepared according to the method of Example 1A, and Example B was replaced with Example 14I. The title compound was obtained (brown solid, 1.05 g, yield 75.98%). LCMS (ESI) (5-95 AB): m/z: 552.2 [M+1].

實施例14J。Example 14J.

N4-〔4-（7,7-二氟-8,9-二氫-6H-吡啶並[1,2-a]吲哚-10-基）嘧啶-2-基]-N 1 - [2-（二甲基氨基）乙基]-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image563
N4-[4-(7,7-difluoro-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]-N 1 -[2 -(Dimethylamino) ethyl]-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image563

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例14I。得到標題化合物（粉色固體，491.00毫克，粗品）。LCMS (ESI) (5-95 AB):m/z: 522.3 [M+1]。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 14I. The title compound (pink solid, 491.00 mg, crude) was obtained. LCMS (ESI) (5-95 AB): m/z: 522.3 [M+1].

實施例14K。Example 14K.

N-〔5 - 〔〔4-（7,7-二氟-8,9-二氫-6H-吡啶並[1,2-a]吲哚-10-基）嘧啶-2-基]氨基] -2-[2-（二甲基氨基）乙基 - 甲基 - 氨基] -4-甲氧基苯基]丙-2-烯醯胺。

Figure 02_image565
N-[5-[[4-(7,7-difluoro-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]amino] -2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxyphenyl]prop-2-enamide.
Figure 02_image565

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例14J。得到標題化合物（FA鹽，141.90毫克，產率23.81%)。1 H-NMR (400 MHz, MeOD): δ 8.56 (s, 2 H), 8.39 (d,J =5.4 Hz, 1 H), 8.07 (d,J =7.15Hz, 1 H), 7.43 (d,J =7.1 Hz, 1 H), 7.15 - 7.28 (m, 3 H), 6.96 (s, 1 H), 6.38 - 6.54 (m, 2 H), 5.85 (dd,J =9.0, 2.7 Hz, 1 H), 4.50 (t,J =12.6 Hz, 2 H), 4.00 (s, 3 H), 3.54 (t,J =6.8 Hz, 2 H), 3.43 (t,J =5.5 Hz, 2 H), 3.17 (d,J =5.2 Hz, 2 H), 2.79 (s, 6 H) 2.71 (s, 3 H), 2.42 (tt,J =13.5, 6.9 Hz, 2 H)。LCMS (ESI) (0-60 AB):m/z: 576.3 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 14J. The title compound (FA salt, 141.90 mg, yield 23.81%) was obtained. 1 H-NMR (400 MHz, MeOD): δ 8.56 (s, 2 H), 8.39 (d, J =5.4 Hz, 1 H), 8.07 (d, J =7.15Hz, 1 H), 7.43 (d, J =7.1 Hz, 1 H), 7.15-7.28 (m, 3 H), 6.96 (s, 1 H), 6.38-6.54 (m, 2 H), 5.85 (dd, J =9.0, 2.7 Hz, 1 H ), 4.50 (t, J =12.6 Hz, 2 H), 4.00 (s, 3 H), 3.54 (t, J =6.8 Hz, 2 H), 3.43 (t, J =5.5 Hz, 2 H), 3.17 (d, J =5.2 Hz, 2 H), 2.79 (s, 6 H) 2.71 (s, 3 H), 2.42 (tt, J =13.5, 6.9 Hz, 2 H). LCMS (ESI) (0-60 AB): m/z: 576.3 [M+1].

實施例15。Example 15.

N-（2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基-5-（（4-（6,7,8,9-四氫吡啶並[1,2-a]吲哚-10-基）嘧啶-2-基）氨基）苯基）丙烯醯胺。

Figure 02_image567
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyrido [1,2-a]Indol-10-yl)pyrimidin-2-yl)amino)phenyl)acrylamide.
Figure 02_image567

實施例15A。Example 15A.

6,7,8,9-四氫吡啶並[1,2-α]吲哚。

Figure 02_image569
6,7,8,9-tetrahydropyrido[1,2-α]indole.
Figure 02_image569

本實施例根據實施例13D的方法製備，將實施例13C替換為8,9-二氫吡啶並[1,2-a]吲哚-7（6H）酮。得到標題化合物（棕色固體，182.00毫克，產率26.24%）。1 H NMR (400MHz, CD3 OD): δ 7.57-7.60 (m, 1H), 7.31-7.33 (m, 1H), 7.13-7.19 (m, 2H), 6.25 (s, 1H), 4.06-4.11 (m, 2H), 3.01-3.04 (m, 2H), 2.11-2.15 (m, 2H), 1.92-1.97 (m, 2H)。This example was prepared according to the method of Example 13D, and Example 13C was replaced with 8,9-dihydropyrido[1,2-a]indole-7(6H)one. The title compound was obtained (brown solid, 182.00 mg, yield 26.24%). 1 H NMR (400MHz, CD 3 OD): δ 7.57-7.60 (m, 1H), 7.31-7.33 (m, 1H), 7.13-7.19 (m, 2H), 6.25 (s, 1H), 4.06-4.11 ( m, 2H), 3.01-3.04 (m, 2H), 2.11-2.15 (m, 2H), 1.92-1.97 (m, 2H).

實施例15B。Example 15B.

10-（2-氯嘧啶-4-基）-6,7,8,9-四氫吡啶並[1,2-α]吲哚。

Figure 02_image571
10-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-α]indole.
Figure 02_image571

本實施例根據實施例A的方法製備，將實施例A6替換為實施例15A。得到標題化合物（棕色油狀，100.00毫克，產率18.44%)。LCMS (ESI) (5-95_AB):m/z: 284.1 [M+1]。This example was prepared according to the method of Example A, and Example A6 was replaced with Example 15A. The title compound was obtained (brown oil, 100.00 mg, yield 18.44%). LCMS (ESI) (5-95_AB): m/z: 284.1 [M+1].

實施例15C。Example 15C.

N-（4-氟-2-甲氧基-5-硝基苯基）-4-（6,7,8,9-四氫吡啶並[1,2-a]吲哚-10-基）嘧啶-2-胺。

Figure 02_image573
N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl) Pyrimidine-2-amine.
Figure 02_image573

本實施例根據實施例B的方法製備，將實施例A替換為實施例15B。得到標題化合物（黃色固體，(150.00毫克，產率37.43%)。LCMS (ESI) (5-95_AB):m/z: 434.0 [M+1]。This example was prepared according to the method of Example B, and Example A was replaced with Example 15B. The title compound (yellow solid, (150.00 mg, yield 37.43%) was obtained. LCMS (ESI) (5-95_AB): m/z: 434.0 [M+1].

實施例15D。Example 15D.

N1-（2-（二甲基氨基）乙基）-5-甲氧基-N1-甲基-2-硝基N4-（4-（6,7,8,9-四氫吡啶並[1,2-a]吲哚-10-基）嘧啶-2-基）苯-1,4-二胺。

Figure 02_image575
N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-2-nitro N4-(4-(6,7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)pyrimidin-2-yl)benzene-1,4-diamine.
Figure 02_image575

本實施例根據實施例1A的方法製備，將實施例B替換為實施例15C。得到標題化合物（棕色固體，300.00毫克，產率79.26%)。LCMS (ESI) (5-95_AB):m/z: 516.2 [M+1]。This example was prepared according to the method of Example 1A, and Example B was replaced with Example 15C. The title compound was obtained (brown solid, 300.00 mg, yield 79.26%). LCMS (ESI) (5-95_AB): m/z: 516.2 [M+1].

實施例15E。Example 15E.

N1-（2-（二甲基氨基）乙基）-5-甲氧基N1甲基N4-（4-（6,7,8,9-四氫吡啶並[1,2-a]吲哚-10-基）嘧啶吡啶-2-基）苯-1,2,4-三胺。

Figure 02_image577
N1-(2-(dimethylamino)ethyl)-5-methoxy N1 methyl N4-(4-(6,7,8,9-tetrahydropyrido[1,2-a]indole -10-yl)pyrimidinepyridin-2-yl)benzene-1,2,4-triamine.
Figure 02_image577

本實施例根據實施例1B的方法製備，將實施例1A替換為實施例15D。得到標題化合物（粉色固體，250.00毫克，粗品）。This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 15D. The title compound (pink solid, 250.00 mg, crude) was obtained.

實施例15F。Example 15F.

N-（2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基-5-（（4-（6,7,8,9-四氫吡啶並[1,2-a]吲哚-10-基）嘧啶-2-基）氨基）苯基）丙烯醯胺。

Figure 02_image579
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyrido [1,2-a]Indol-10-yl)pyrimidin-2-yl)amino)phenyl)acrylamide.
Figure 02_image579

本實施例根據實施例1C的方法製備，將實施例1B替換為實施例15E。得到標題化合物（FA鹽，46.00毫克，產率11.64%)。1 H NMR (400MHz, CD3 OD): δ 8.60 (s, 1H), 8.48 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.12-7.20 (m, 3H), 6.97 (s, 1H), 6.48-6.50 (m, 2H), 5.88 (t, J = 5.8 Hz, 1H), 4.16 (t, J = 5.8 Hz, 2H), 4.03 (s, 3H), 3.49 (t, J = 5.4 Hz, 2H), 3.24-3.30 (m, 4H), 2.86 (s, 6H), 2.72 (s, 3H), 2.08-2.19 (m, 2H) , 1.98-1.88 (m, 2H)。LCMS (ESI) (5-95_AB):m/z: 540.3 [M+1]。This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 15E. The title compound (FA salt, 46.00 mg, yield 11.64%) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.60 (s, 1H), 8.48 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.12-7.20 (m, 3H), 6.97 (s, 1H), 6.48-6.50 (m, 2H), 5.88 (t, J = 5.8 Hz, 1H), 4.16 (t, J = 5.8 Hz, 2H), 4.03 (s, 3H), 3.49 (t, J = 5.4 Hz, 2H), 3.24-3.30 (m, 4H), 2.86 (s, 6H), 2.72 (s, 3H), 2.08-2.19 (m, 2H), 1.98-1.88 (m, 2H). LCMS (ESI) (5-95_AB): m/z: 540.3 [M+1].

流程7。Process 7.

中間體C和D的一般製備方法：

Figure 02_image581
General preparation methods of intermediates C and D:
Figure 02_image581

實施例C1。Example C1.

2-溴乙基三氟甲磺酸酯。

Figure 02_image583
2-Bromoethyl trifluoromethanesulfonate.
Figure 02_image583

在-20°C下，將三氟甲磺酸酐（20.06克，63.86毫莫耳）滴加入吡啶（20mL）與DCM（70mL）中，攪拌10分鐘後，向該混合物中滴加2-溴乙醇（7.60克，60.82毫莫耳），攪拌10分鐘，並使溫度至10°C。將反應混合物過濾，濾液濃縮（20°C以下），得到的粗產品溶於石油醚（60mL）中，劇烈攪拌後過濾，濾液濃縮，得到標題化合物（17.90克，粗品)。1 H NMR (300 MHz, CDCl3 ): δ 3.61 (t, J = 6.0 Hz, 2 H) 4.75 (t, J = 6.0 Hz, 2 H)。At -20°C, trifluoromethanesulfonic anhydride (20.06 g, 63.86 mmol) was added dropwise to pyridine (20 mL) and DCM (70 mL), and after stirring for 10 minutes, 2-bromoethanol was added dropwise to the mixture (7.60 grams, 60.82 millimoles), stir for 10 minutes, and bring the temperature to 10°C. The reaction mixture was filtered, and the filtrate was concentrated (below 20°C). The obtained crude product was dissolved in petroleum ether (60 mL). After vigorously stirring and filtered, the filtrate was concentrated to obtain the title compound (17.90 g, crude product). 1 H NMR (300 MHz, CDCl 3 ): δ 3.61 (t, J = 6.0 Hz, 2 H) 4.75 (t, J = 6.0 Hz, 2 H).

實施例C2。Example C2.

（2-溴乙基）二苯基鋶。

Figure 02_image585
(2-Bromoethyl) diphenyl alkane.
Figure 02_image585

在25°C下，將實施例C1（17.90克，69.64毫莫耳）加入甲苯（40mL）中，向該混合物中加入二苯硫醚（13.81克，69.64毫莫耳），並升溫至100°C，氮氣中攪拌5小時。將反應混合物冷卻至25°C，加入***（80mL）後過濾，濾餅乾燥後，得到標題化合物（11.90克，產率34.69%）。1 H NMR (400 MHz, CDCl3 ): δ 3.64-3.74 (t, J = 6.0 Hz 2 H) 4.87 (t, J = 6.0 Hz, 2 H) 7.69-7.82 (m, 6 H) 8.09 (d, J = 8.0 Hz, 4 H)。At 25°C, Example C1 (17.90 g, 69.64 mmol) was added to toluene (40 mL), diphenyl sulfide (13.81 g, 69.64 mmol) was added to the mixture, and the temperature was raised to 100° C. Stir for 5 hours under nitrogen. The reaction mixture was cooled to 25°C, diethyl ether (80 mL) was added and filtered, and after the filter cake was dried, the title compound (11.90 g, yield 34.69%) was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 3.64-3.74 (t, J = 6.0 Hz 2 H) 4.87 (t, J = 6.0 Hz, 2 H) 7.69-7.82 (m, 6 H) 8.09 (d, J = 8.0 Hz, 4 H).

實施例C3。Example C3.

二苯基（乙烯基）鋶。

Figure 02_image587
Diphenyl (vinyl) carbamide.
Figure 02_image587

在25°C下，將實施例C2（11.20克，25.27毫莫耳）加入THF/H2 O（2:1，36mL）中，向該混合物中加入KHCO3 （3.04克，30.32毫莫耳），並攪拌20分鐘。立即將反應混合物濃縮（溫度不高於20°C），加入DCM（40mL），用無水硫酸鎂乾燥，濃縮後，用柱色譜（DCM：MeOH = 20:1，10:1）分離純化，得到標題化合物（棕色油狀，6.20克，產率54.16%)。1 H NMR (400 MHz, CDCl3 ): δ 6.50 (dd, J = 16.0, 4 Hz, 1 H) 6.71 (dd, J = 8.0, 4 Hz, 1 H) 7.53 (dd, J = 16.0, 8.0 Hz, 1 H) 7.65-7.78 (m, 2 H) 7.83-7.93 (m, 1 H)。At 25°C, Example C2 (11.20 g, 25.27 mmol) was added to THF/H 2 O (2:1, 36 mL), and KHCO 3 (3.04 g, 30.32 mmol) was added to the mixture. And stir for 20 minutes. The reaction mixture was immediately concentrated (temperature not higher than 20°C), DCM (40 mL) was added, dried over anhydrous magnesium sulfate, after concentration, it was separated and purified by column chromatography (DCM: MeOH = 20:1, 10:1) to obtain The title compound (brown oil, 6.20 g, 54.16% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 6.50 (dd, J = 16.0, 4 Hz, 1 H) 6.71 (dd, J = 8.0, 4 Hz, 1 H) 7.53 (dd, J = 16.0, 8.0 Hz , 1 H) 7.65-7.78 (m, 2 H) 7.83-7.93 (m, 1 H).

實施例C4。Example C4.

3,4-二氫-1H- [1,4]惡嗪[4,3-a]吲哚。

Figure 02_image589
3,4-dihydro-1H-[1,4]oxazine[4,3-a]indole.
Figure 02_image589

在0°C下，將2 – 羥甲基 – 吲哚（2.50克，16.99毫莫耳）加入DCM（250mL）中，向該混合物中加入KOH（1.14克，20.39毫莫耳），並攪拌30分鐘。再將實施例C3（6.16克，16.99毫莫耳）的DCM（50mL）溶液滴加入到該混合物中，並升溫至20°C攪拌11.5小時。反應混合物濃縮後，用柱色譜（PE/EA = 20:1）分離純化，得到標題化合物（黃色固體，1.50克，產率48.42%)。1 H NMR (400 MHz, CDCl3 ): δ 7.59 (d, J = 8.0Hz, 1H), 7.34-7.29 (m, 1H), 7.21 (dt, J = 1.2, 7.6Hz, 1H), 7.17-7.12 (m, 1H), 6.24 (d, J = 0.8Hz, 1H), 5.01 (d, J = 0.8Hz, 2H), 4.22-4.17 (m, 2H), 4.13-4.08 (m, 2H)。At 0°C, 2-hydroxymethyl-indole (2.50 g, 16.99 mmol) was added to DCM (250 mL), KOH (1.14 g, 20.39 mmol) was added to the mixture, and stirred for 30 minute. A solution of Example C3 (6.16 g, 16.99 mmol) in DCM (50 mL) was added dropwise to the mixture, and the temperature was raised to 20°C and stirred for 11.5 hours. After the reaction mixture was concentrated, it was separated and purified by column chromatography (PE/EA = 20:1) to obtain the title compound (yellow solid, 1.50 g, yield 48.42%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.59 (d, J = 8.0Hz, 1H), 7.34-7.29 (m, 1H), 7.21 (dt, J = 1.2, 7.6Hz, 1H), 7.17-7.12 (m, 1H), 6.24 (d, J = 0.8Hz, 1H), 5.01 (d, J = 0.8Hz, 2H), 4.22-4.17 (m, 2H), 4.13-4.08 (m, 2H).

實施例C。Example C.

10-（2-氯嘧啶-4-基）-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image591
10-(2-chloropyrimidin-4-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image591

本實施例根據實施例A的方法製備，將實施例A6替換為實施例C4。得到標題化合物（棕色固體，1.30克，粗品)。LCMS (ESI) (10-80 AB):m/z: 286.1 [M+1]。This example was prepared according to the method of Example A, and Example A6 was replaced with Example C4. The title compound (brown solid, 1.30 g, crude) was obtained. LCMS (ESI) (10-80 AB): m/z: 286.1 [M+1].

實施例D。Example D.

4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-N-（4-氟-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image593
4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-N-(4-fluoro-2-methoxy-5- Nitrophenyl)pyrimidine-2-amine.
Figure 02_image593

本實施例根據實施例B的方法製備，將實施例A替換為實施例C。得到標題化合物（黃色固體，311.00毫克，粗品)。LCMS (ESI) (5-95 AB):m/z: 436.0 [M+1]。This example was prepared according to the method of Example B, and Example A was replaced with Example C. The title compound was obtained (yellow solid, 311.00 mg, crude). LCMS (ESI) (5-95 AB): m/z: 436.0 [M+1].

流程8。

Figure 02_image595
Process 8.
Figure 02_image595

實施例16。Example 16.

N-（2 - （（2-（二乙氨基）乙基）（甲基）氨基）-5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image597
N-(2-((2-(diethylamino)ethyl)(methyl)amino)-5 -((4-(3,4-dihydro-1H- [1,4]oxazino[4 ,3-a]indol-10-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image597

實施例16A。Example 16A.

N1-（2-（二乙基氨基）乙基）-N4-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-甲氧基-N 1 - 甲基-2-硝基苯-1,4-二胺。

Figure 02_image599
N1-(2-(diethylamino)ethyl)-N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10- Group)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine.
Figure 02_image599

在氮氣保護下，將中間體D（150.00毫克，344.50微莫耳）與N，N-二乙基-N-甲基乙烷-1,2-二胺（134.59毫克，1.03毫莫耳）溶於DMA（5mL），向該混合物中加入DIEA（133.57毫克，1.03毫莫耳），並升溫至90°C攪拌12小時。LCMS顯示反應完成，將反應液用水（5mL）稀釋，並用DCM（10mL*2）萃取，有機相合併後用無水硫酸鈉乾燥，過濾，濾液濃縮乾得到標題化合物（黃色固體，300.00毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 546.3 [M+1]。Under nitrogen protection, dissolve intermediate D (150.00 mg, 344.50 μmol) and N,N-diethyl-N-methylethane-1,2-diamine (134.59 mg, 1.03 mmol) To DMA (5 mL), DIEA (133.57 mg, 1.03 mmol) was added to the mixture, and the temperature was raised to 90°C and stirred for 12 hours. LCMS showed that the reaction was completed. The reaction solution was diluted with water (5 mL) and extracted with DCM (10 mL*2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the title compound (yellow solid, 300.00 mg, crude product) . LCMS (ESI) (0-60AB): m/z: 546.3 [M+1].

實施例16B。Example 16B.

N1-（2-（二乙基氨基）乙基）-N4-（4-（3,4-二氫-1H-[1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image601
N1-(2-(diethylamino)ethyl)-N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10- Group) pyrimidin-2-yl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image601

在25°C下，將實施例16A（300.00毫克，549.82微莫耳）溶於MeOH（5mL）中，氮氣置換後加入Pd/C（10%，0.20克）。混合物用H2 置換3次後在15 Psi的壓力下攪拌2小時。TLC（DCM:MeOH=20:1）顯示反應完成，將反應混合物過濾，濾液濃縮至乾，得到標題化合物（黃色固體，200.00毫克，產率70.54%）。LCMS (ESI)(0-60AB): m/z: 516.3 [M+1]。At 25°C, Example 16A (300.00 mg, 549.82 μmol) was dissolved in MeOH (5 mL), and after nitrogen substitution, Pd/C (10%, 0.20 g) was added. After the mixture was replaced with H 2 three times, it was stirred at a pressure of 15 Psi for 2 hours. TLC (DCM:MeOH=20:1) showed that the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (yellow solid, 200.00 mg, yield 70.54%). LCMS (ESI) (0-60AB): m/z: 516.3 [M+1].

實施例16C。Example 16C.

N-（2 - （（2-（二乙氨基）乙基）（甲基）氨基）-5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image285
N-(2-((2-(diethylamino)ethyl)(methyl)amino)-5 -((4-(3,4-dihydro-1H- [1,4]oxazino[4 ,3-a]indol-10-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image285

在0°C下，將實施例16B（200.00毫克，387.86微莫耳）溶於四氫呋喃（3mL）和水（1mL）的混合溶劑中，向該混合物中加入3 – 氯丙醯氯（73.87毫克，581.79微莫耳），攪拌0.5小時，然後向該混合物中加入氫氧化鈉（62.06毫克，1.55毫莫耳）並升溫至70°C攪拌12小時。LCMS顯示反應完成，向混合物中加入水（2mL），用DCM（10*2）萃取，有機相濃縮後，粗產品經製備HPLC分離純化得標題化合物（FA鹽，45.80毫克，產率19.14%）。1 H NMR (400MHz, CD3 OD): δ 8.53 (br. s., 1 H), 8.28- 8.30(m, 2 H), 8.01 - 8.03 (m, 1 H), 7.39 - 7.40 (m, 1 H), 7.21-7.23(m, 2 H), 7.09 (d, J=5.20 Hz, 1 H), 6.95 (s, 1 H), 6.53 - 6.55 (m, 1 H), 6.40 - 6.44 (m, 1 H), 5.84 - 5.87 (m, 1 H), 5.14 (s, 2 H), 4.09 (s, 4 H), 4.00 (s, 3 H), 3.29 - 3.51 (m, 2 H), 3.27 (t, J=5.60 Hz, 2 H), 3.20 （q, J=7.20 Hz, 4 H), 2.74 (s, 3 H), 1.25 (t, J=7.20 Hz, 6 H)。LCMS (ESI) (0-60AB): m/z: 570.3 [M+1]。At 0°C, Example 16B (200.00 mg, 387.86 μmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and water (1 mL), and to this mixture was added 3-chloropropyl acetyl chloride (73.87 mg, 581.79 micromolar), stirring for 0.5 hours, then sodium hydroxide (62.06 mg, 1.55 mmol) was added to the mixture and the temperature was raised to 70°C and stirred for 12 hours. LCMS showed that the reaction was completed. Water (2 mL) was added to the mixture and extracted with DCM (10*2). After the organic phase was concentrated, the crude product was separated and purified by preparative HPLC to obtain the title compound (FA salt, 45.80 mg, yield 19.14%) . 1 H NMR (400MHz, CD 3 OD): δ 8.53 (br. s., 1 H), 8.28- 8.30(m, 2 H), 8.01-8.03 (m, 1 H), 7.39-7.40 (m, 1 H), 7.21-7.23(m, 2 H), 7.09 (d, J=5.20 Hz, 1 H), 6.95 (s, 1 H), 6.53-6.55 (m, 1 H), 6.40-6.44 (m, 1 H), 5.84-5.87 (m, 1 H), 5.14 (s, 2 H), 4.09 (s, 4 H), 4.00 (s, 3 H), 3.29-3.51 (m, 2 H), 3.27 ( t, J=5.60 Hz, 2 H), 3.20 (q, J=7.20 Hz, 4 H), 2.74 (s, 3 H), 1.25 (t, J=7.20 Hz, 6 H). LCMS (ESI) (0-60AB): m/z: 570.3 [M+1].

實施例17。Example 17.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image604
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image604

實施例17A。Example 17A.

4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-N-（4-氟-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image606
4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-N-(4-fluoro-2-methoxy-5- Nitrophenyl)pyrimidine-2-amine.
Figure 02_image606

本實施例根據實施例16A的方法製備，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（黃色固體，230.00毫克，產率87.95%）。LCMS (0-60AB):m/z: 518.2 [M+1]。This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N',N' -trimethyl -1,2 -Ethylenediamine. The title compound was obtained (yellow solid, 230.00 mg, yield 87.95%). LCMS (0-60AB): m/z: 518.2 [M+1].

實施例17B。Example 17B.

N4-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image608
N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N 1 -(2- (Dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image608

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例17A。得到標題化合物（黃色固體，170.00毫克，產率72.96%)。LCMS (0-60AB):m/z: 488.2 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 17A. The title compound was obtained (yellow solid, 170.00 mg, yield 72.96%). LCMS (0-60AB): m/z: 488.2 [M+1].

實施例17C。Example 17C.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image604
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image604

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例17B。得到標題化合物（FA鹽，20.00毫克，產率10.29%)。1 H NMR (400MHz, CD3 OD): δ 8.49 (br. s., 1H), 8.33 (d, J = 4.0Hz, 1H), 8.29 (s, 1H), 8.08-8.01 (m, 1H), 7.46-7.40 (m, 1H), 7.26-7.20 (m, 2H), 7.17 (d, J = 4.0Hz, 1H), 6.95 (s, 1H), 6.59-6.38 (m, 2H), 5.84 (dd, J = 2.0, 8.0Hz, 1H), 5.18 (s, 2H), 4.17-4.11 (m, 4H), 3.97 (s, 3H), 3.45 (t, J = 6.0Hz, 2H), 3.20 (t, J = 6.0Hz, 2H), 2.81 (s, 6H), 2.72 (s, 3H)。 LCMS (0-60AB): m/z: 542.2 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 17B. The title compound (FA salt, 20.00 mg, yield 10.29%) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.49 (br. s., 1H), 8.33 (d, J = 4.0Hz, 1H), 8.29 (s, 1H), 8.08-8.01 (m, 1H), 7.46-7.40 (m, 1H), 7.26-7.20 (m, 2H), 7.17 (d, J = 4.0Hz, 1H), 6.95 (s, 1H), 6.59-6.38 (m, 2H), 5.84 (dd, J = 2.0, 8.0Hz, 1H), 5.18 (s, 2H), 4.17-4.11 (m, 4H), 3.97 (s, 3H), 3.45 (t, J = 6.0Hz, 2H), 3.20 (t, J = 6.0Hz, 2H), 2.81 (s, 6H), 2.72 (s, 3H). LCMS (0-60AB): m/z: 542.2 [M+1].

實施例18。Example 18.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（乙基（甲基）氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image287
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image287

實施例18A。Example 18A.

N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-2-甲氧基-N 4 - 甲基-N 4 - （2-（甲基氨基）乙基）-5-硝基苯-1,4-二胺。

Figure 02_image612
N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-2-methoxy- N 4 -methyl-N 4 -(2-(methylamino)ethyl)-5-nitrobenzene-1,4-diamine.
Figure 02_image612

本實施例根據實施例16A的方法製備，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N1，N2-二甲基乙烷-1,2-二胺。得到標題化合物（黃色固體，160.00毫克，收率85.24%）。LCMS (ESI)(0-60AB): m/z: 504.3 [M+1]。This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N1,N2-dimethylethane-1,2-di amine. The title compound was obtained (yellow solid, 160.00 mg, yield 85.24%). LCMS (ESI) (0-60AB): m/z: 504.3 [M+1].

實施例18B。Example 18B.

N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N4-（2-（乙基（甲基）氨基）乙基）-2-甲氧基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image614
N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N4-(2-( Ethyl(methyl)amino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image614

將實施例18A（100.00 毫克，198.59微莫耳）、MeCHO（26.24 毫克，595.77微莫耳）與醋酸（5.96 毫克，99.30微莫耳）溶於DCE（5mL）中，得到的混合物升溫至40°C攪拌2小時。然後向該反應液中加入NaBH(OAc)3 （126.27 毫克，595.77微莫耳），加完後得到的混合液再在40°C攪拌2小時。LCMS顯示反應完成，反應混合物用水（5mL）稀釋，用DCM（10mL x3）萃取，有機層經無水硫酸鈉乾燥，濃縮後，得到標題化合物（黃色固體，140.00毫克，粗品）。LCMS (ESI)(0-60AB): m/z: 532.3 [M+1]。Example 18A (100.00 mg, 198.59 micromolar), MeCHO (26.24 mg, 595.77 micromolar) and acetic acid (5.96 mg, 99.30 micromolar) were dissolved in DCE (5 mL), and the resulting mixture was warmed to 40° C was stirred for 2 hours. Then, NaBH(OAc) 3 (126.27 mg, 595.77 micromolar) was added to the reaction solution, and the mixture obtained after the addition was stirred at 40°C for 2 hours. LCMS showed that the reaction was completed. The reaction mixture was diluted with water (5 mL), extracted with DCM (10 mL x 3), and the organic layer was dried over anhydrous sodium sulfate. After concentration, the title compound was obtained (yellow solid, 140.00 mg, crude). LCMS (ESI) (0-60AB): m/z: 532.3 [M+1].

實施例18C。Example 18C.

N4-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N 1 - （2-（乙基（甲基）氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image616
N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N 1 -(2- (Ethyl(methyl)amino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image616

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例18B。得到標題化合物（黃色固體，100.00毫克，粗品）。LCMS (ESI)(0-60AB): m/z: 502 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 18B. The title compound was obtained (yellow solid, 100.00 mg, crude). LCMS (ESI) (0-60AB): m/z: 502 [M+1].

實施例18D。Example 18D.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（乙基（甲基）氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image618
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image618

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例18C。得到標題化合物（FA鹽，38.3毫克，產率31.89%）。1 H NMR (400MHz, CD3 OD): δ 8.46 (br. s., 1 H), 8.34 (s, 1 H), 8.23 (br. s., 1 H), 7.96 (d, J=4.80 Hz, 1 H), 7.33 - 7.34 (m, 1 H), 7.17 - 7.19 (m, 2 H), 7.01 (d, J=5.20 Hz, 1 H), 6.94 (s, 1 H), 6.56 - 6.63 (m, 1 H), 6.41 - 6.45 (m, 1 H), 5.85 (d, J=10.40 Hz, 1 H), 5.06 (br. s., 2 H), 4.01 (br. S., 4 H), 3.98(s, 3 H), 3.48 (br. s., 2 H), 3.26 (br. s., 2 H), 3.12 - 3.21 (m, 2 H), 2.82 (s, 3 H), 2.72 (s, 3 H), 1.25 (t, J=7.20 Hz, 3 H)。LCMS (ESI) (0-60AB): m/z: 556.4 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 18C. The title compound (FA salt, 38.3 mg, 31.89% yield) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.46 (br. s., 1 H), 8.34 (s, 1 H), 8.23 (br. s., 1 H), 7.96 (d, J=4.80 Hz , 1 H), 7.33-7.34 (m, 1 H), 7.17-7.19 (m, 2 H), 7.01 (d, J=5.20 Hz, 1 H), 6.94 (s, 1 H), 6.56-6.63 ( m, 1 H), 6.41-6.45 (m, 1 H), 5.85 (d, J=10.40 Hz, 1 H), 5.06 (br. s., 2 H), 4.01 (br. S., 4 H) , 3.98(s, 3 H), 3.48 (br. s., 2 H), 3.26 (br. s., 2 H), 3.12-3.21 (m, 2 H), 2.82 (s, 3 H), 2.72 (s, 3 H), 1.25 (t, J=7.20 Hz, 3 H). LCMS (ESI) (0-60AB): m/z: 556.4 [M+1].

實施例19。Example 19.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image289
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image289

實施例19A。Example 19A.

N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N4-（2-（二甲基氨基）乙基）-N 4 - 乙基-2-甲氧基-5-硝基苯-1,4-二胺。

Figure 02_image621
N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N4-(2-( Dimethylamino)ethyl)-N 4 -ethyl-2-methoxy-5-nitrobenzene-1,4-diamine.
Figure 02_image621

本實施例根據實施例16A的方法製備，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N1乙基-N2，N2-二甲基乙烷-1,2-二胺。得到標題化合物（黃色固體，80毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 532.3 [M+1]。This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N1 ethyl-N2,N2-dimethylethane-1 ,2-diamine. The title compound (yellow solid, 80 mg, crude) was obtained. LCMS (ESI) (0-60AB): m/z: 532.3 [M+1].

實施例19B。Example 19B.

N4-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-N1乙基-5-甲氧基苯-1,2,4-三胺。

Figure 02_image623
N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N 1 -(2- (Dimethylamino)ethyl)-N1 ethyl-5-methoxybenzene-1,2,4-triamine.
Figure 02_image623

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例19A。得到標題化合物（黃色固體，80毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 502.3 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 19A. The title compound (yellow solid, 80 mg, crude) was obtained. LCMS (ESI) (0-60AB): m/z: 502.3 [M+1].

實施例19C。Example 19C.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image625
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image625

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例19B。得到標題化合物（FA鹽，13.40毫克，產率13.79%）。1 H NMR (400MHz, CD3 OD): δ 8.49 (br. s., 1 H), 8.32 (d, J=5.60 Hz, 1 H), 8.28 (s, 1H), 8.04 (d, J=8.80 Hz, 1 H), 7.41 - 7.44 (m, 1 H), 7.23 - 7.25 (m, 2 H), 7.14 (d, J=5.60 Hz, 1 H), 6.96 (s, 1 H), 6.48 - 6.54 (m, 2 H), 5.83 - 5.92 (m, 1 H), 5.16 (s, 2 H), 4.12 (s, 3 H), 3.99 (s, 2 H), 3.52 (t, J=5.80 Hz, 1 H), 3.25 (t, J=5.60 Hz, 1 H), 3.08 (d, J=6.80 Hz, 1 H), 2.85 (s, 2 H), 1.06 (t, J=7.20 Hz, 1 H)。LCMS (ESI)(0-60AB): m/z: 556.3 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 19B. The title compound (FA salt, 13.40 mg, yield 13.79%) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.49 (br. s., 1 H), 8.32 (d, J=5.60 Hz, 1 H), 8.28 (s, 1H), 8.04 (d, J=8.80 Hz, 1 H), 7.41-7.44 (m, 1 H), 7.23-7.25 (m, 2 H), 7.14 (d, J=5.60 Hz, 1 H), 6.96 (s, 1 H), 6.48-6.54 (m, 2 H), 5.83-5.92 (m, 1 H), 5.16 (s, 2 H), 4.12 (s, 3 H), 3.99 (s, 2 H), 3.52 (t, J=5.80 Hz, 1 H), 3.25 (t, J=5.60 Hz, 1 H), 3.08 (d, J=6.80 Hz, 1 H), 2.85 (s, 2 H), 1.06 (t, J=7.20 Hz, 1 H) . LCMS (ESI) (0-60AB): m/z: 556.3 [M+1].

實施例20。Example 20.

N-（5 - （（4-（3,4-二氫-1H-[1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（1-（二甲基氨基）丙-2-基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image627
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((1-(dimethylamino)propan-2-yl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image627

實施例20A。Example 20A.

N1-（4-（3,4-二氫-1H-[1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N4-（1-（二甲基氨基）丙-2-基）-2-甲氧基 - N 4 - 甲基-5-硝基苯-1,4-二胺。

Figure 02_image629
N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N4-(1-( Dimethylamino)prop-2-yl)-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image629

本實施例根據實施例16A的方法製備，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’-三甲基 1-甲基-1,2-乙二胺。得到標題化合物（紅色油狀，270.00毫克，產率48.90%）。LCMS (ESI) (0-60AB):m/z: 532.3 [M+1]。This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N',N'-trimethyl 1-methyl -1,2-ethylenediamine. The title compound was obtained (red oil, 270.00 mg, yield 48.90%). LCMS (ESI) (0-60AB): m/z: 532.3 [M+1].

實施例20B。Example 20B.

N4-（4-（3,4-二氫-1H-[1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N 1 - （1-（二甲基氨基）丙-2-基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image631
N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N 1 -(1- (Dimethylamino)prop-2-yl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image631

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例20A。得到標題化合物（棕色油狀，227.00毫克，產率75.03%)。LCMS (ESI) (0-60AB):m/z: 502.3 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 20A. The title compound was obtained (brown oil, 227.00 mg, yield 75.03%). LCMS (ESI) (0-60AB): m/z: 502.3 [M+1].

實施例20C。Example 20C.

N-（5 - （（4-（3,4-二氫-1H-[1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（1-（二甲基氨基）丙-2-基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image633
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((1-(dimethylamino)propan-2-yl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image633

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例20B。得到標題化合物（FA鹽，7.71毫克，產率2.83%)。1 H NMR (400MHz, CD3 OD): δ 8.29 (s, 2H), 8.22 (d, J = 5.2 Hz, 1H), 8.08 (s, 1H), 7.94-7.97 (m, 1H), 7.32-7.34 (m, 1H), 7.12-7.16 (m, 2H), 7.06 (d, J = 5.2 Hz, 1H), 6.71-6.74 (m, 1H), 6.36-6.43 (m, 2H), 5.73-5.76 (m, 1H), 5.06-5.08 (m, 2H), 3.97-4.07 (m, 5H), 3.85-3.87 (m, 3H), 3.10-3.16 (m, 1H), 2.91-2.95 (m, 1H), 2.77 (s, 6H), 2.55-2.58 (m, 3H), 1.29-1.33 (m, 3H), 1.12-1.16 (m, 1H)。LCMS (ESI) (0-60AB):m/z: 556.4 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 20B. The title compound (FA salt, 7.71 mg, yield 2.83%) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.29 (s, 2H), 8.22 (d, J = 5.2 Hz, 1H), 8.08 (s, 1H), 7.94-7.97 (m, 1H), 7.32-7.34 (m, 1H), 7.12-7.16 (m, 2H), 7.06 (d, J = 5.2 Hz, 1H), 6.71-6.74 (m, 1H), 6.36-6.43 (m, 2H), 5.73-5.76 (m , 1H), 5.06-5.08 (m, 2H), 3.97-4.07 (m, 5H), 3.85-3.87 (m, 3H), 3.10-3.16 (m, 1H), 2.91-2.95 (m, 1H), 2.77 (s, 6H), 2.55-2.58 (m, 3H), 1.29-1.33 (m, 3H), 1.12-1.16 (m, 1H). LCMS (ESI) (0-60AB): m/z: 556.4 [M+1].

流程9。

Figure 02_image635
Process 9.
Figure 02_image635

實施例21。Example 21.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2-（乙基（2-（甲基氨基）乙基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image291
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-(ethyl(2-(methylamino)ethyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image291

實施例21A。Example 21A.

N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N 4 - 乙基-N 4 - （2-（甲基氨基）乙基）-2-甲氧基-5-硝基苯-1,4-二胺。

Figure 02_image638
N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N 4 -ethyl- N 4 -(2-(methylamino)ethyl)-2-methoxy-5-nitrobenzene-1,4-diamine.
Figure 02_image638

本實施例根據實施例16A的方法製備，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N1，N2-二乙基乙烷-1,2-二胺。得到標題化合物（紅色油狀物，520毫克，粗品）。 LCMS (ESI) (0-60AB): m/z: 532.2 [M+1]。This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N1,N2-diethylethane-1,2-di amine. The title compound (red oil, 520 mg, crude) was obtained. LCMS (ESI) (0-60AB): m/z: 532.2 [M+1].

實施例21B。Example 21B.

第三丁基（2 - （（4 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-5-甲氧基-2-硝基苯基）（乙基）氨基）甲基）（乙基）氨基甲酸第三丁酯。

Figure 02_image640
Tertiary butyl (2-((4-((4-(3,4-dihydro-1H-[1,4]oxazido[4,3-a]indol-10-yl)pyrimidine-2 -Yl)amino)-5-methoxy-2-nitrophenyl)(ethyl)amino)methyl)(ethyl)carbamic acid tert-butyl ester.
Figure 02_image640

將實施例21A（260.00 毫克，489.09微莫耳），(Boc)2 O（260.00 毫克，489.09微莫耳）和碳酸鉀（101.40 毫克，733.63微莫耳）溶於THF（5mL）和水（1mL）。該混合液在25°C攪拌12小時。LCMS顯示反應完成，反應混合物用水（10mL）稀釋，用EtOAc（30mL x2）萃取，有機層濃縮後得到的粗品用製備板（DCM/MeOH = 20:1）分離純化，得到標題化合物（紅色有狀物，230毫克，產率71.98%）。LCMS (ESI) (0-60AB): m/z: 632.3 [M+1]。Example 21A (260.00 mg, 489.09 micromolar), (Boc) 2 O (260.00 mg, 489.09 micromolar) and potassium carbonate (101.40 mg, 733.63 micromolar) were dissolved in THF (5 mL) and water (1 mL ). The mixture was stirred at 25°C for 12 hours. LCMS showed that the reaction was completed. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (30 mL x 2), and the crude product obtained after concentration of the organic layer was separated and purified using a preparation plate (DCM/MeOH = 20:1) to obtain the title compound (red colored) Substance, 230 mg, yield 71.98%). LCMS (ESI) (0-60AB): m/z: 632.3 [M+1].

實施例21C。Example 21C.

第三丁基（2 - （（2-氨基-4 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-5-甲基苯基）（乙基）氨基）甲基）（乙基）氨基甲酸第三丁酯。

Figure 02_image642
Tertiary butyl (2-((2-amino-4-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl ) Pyrimidin-2-yl)amino)-5-methylphenyl)(ethyl)amino)methyl)(ethyl)carbamic acid tert-butyl ester.
Figure 02_image642

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例21B。得到標題化合物（棕色油狀物，180毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 602.3[M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 21B. The title compound (brown oil, 180 mg, crude) was obtained. LCMS (ESI) (0-60AB): m/z: 602.3 [M+1].

實施例21D。Example 21D.

第三丁基（2 - （（2-丙烯醯氨基-4 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-5-甲基苯基）（乙基）氨基）甲基）（乙基）氨基甲酸第三丁酯。

Figure 02_image644
Tertiary butyl (2-((2-propenylamino-4-((4-(3,4-dihydro-1H- [1,4]oxazino[4,3-a]indole-10 -Yl)pyrimidin-2-yl)amino)-5-methylphenyl)(ethyl)amino)methyl)(ethyl)carbamic acid tert-butyl ester.
Figure 02_image644

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例21C。得到標題化合物（棕色油狀物，180毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 656.3[M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 21C. The title compound (brown oil, 180 mg, crude) was obtained. LCMS (ESI) (0-60AB): m/z: 656.3 [M+1].

實施例21E。Example 21E.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2-（乙基（2-（甲基氨基）乙基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image646
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-(ethyl(2-(methylamino)ethyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image646

在 0°C下，將實施例21D（180毫克，273.64微莫耳）溶於DCM（5mL）中，向該混合物中緩慢加入TFA（1.54克，13.51毫莫耳）。加料完成後，反應液在25°C下攪拌12小時。LCMS顯示反應完成。反應液濃縮，粗品溶於DCM（20mL）並用飽和的NaHCO3 調pH到9~10。 有機相分離出後進行濃縮得到粗產品，粗產品通過製備HPLC（FA）分離純化，得到標題化合物（黃色固體FA鹽，32.23毫克，產率19.51%）。1 H NMR (400MHz, CD3OD): δ 8.23 (d, J=5.5Hz, 1H), 8.09 (s, 1H), 7.95 (d, J=8.2Hz, 1H), 7.31 - 7.37 (m, 1H), 7.10 - 7.18 (m, 2H), 7.07 (d, J=5.5Hz, 1H), 6.82 (s, 1H), 6.38 - 6.48 (m, 1H), 6.26 - 6.34 (m, 1H), 5.74 (d, J=10.1Hz, 1H), 5.07 (s, 2 H), 4.04 (br. s., 4H), 3.87 (s, 3H), 3.38 (br. s., 2H), 3.04 (d, J=5.0Hz, 2H), 2.87 - 3.01 (m, 4H), 1.22 - 1.33 (m, 3H), 0.94 (t, J=7.0Hz, 3H)。LCMS (ESI) (0-60AB): m/z: 556.3[M+1]。At 21°C, Example 21D (180 mg, 273.64 micromolar) was dissolved in DCM (5 mL), and TFA (1.54 g, 13.51 mmol) was slowly added to the mixture. After the addition was completed, the reaction solution was stirred at 25°C for 12 hours. LCMS showed the reaction was complete. The reaction solution was concentrated, and the crude product was dissolved in DCM (20 mL) and adjusted to pH 9-10 with saturated NaHCO 3 . The organic phase was separated and concentrated to obtain the crude product. The crude product was separated and purified by preparative HPLC (FA) to obtain the title compound (yellow solid FA salt, 32.23 mg, yield 19.51%). 1 H NMR (400MHz, CD3OD): δ 8.23 (d, J=5.5Hz, 1H), 8.09 (s, 1H), 7.95 (d, J=8.2Hz, 1H), 7.31-7.37 (m, 1H), 7.10-7.18 (m, 2H), 7.07 (d, J=5.5Hz, 1H), 6.82 (s, 1H), 6.38-6.48 (m, 1H), 6.26-6.34 (m, 1H), 5.74 (d, J=10.1Hz, 1H), 5.07 (s, 2 H), 4.04 (br. s., 4H), 3.87 (s, 3H), 3.38 (br. s., 2H), 3.04 (d, J=5.0 Hz, 2H), 2.87-3.01 (m, 4H), 1.22-1.33 (m, 3H), 0.94 (t, J=7.0Hz, 3H). LCMS (ESI) (0-60AB): m/z: 556.3 [M+1].

實施例22。Example 22.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2-（乙基（2-（乙基（甲基）氨基）。

Figure 02_image293
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-(ethyl (2-(ethyl(methyl)amino).
Figure 02_image293

實施例22A。Example 22A.

N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N 4 - 乙基-N4-（2-（乙基（甲基）氨基）乙基）-2-甲氧基-5-硝基苯-1,4-二胺。

Figure 02_image649
N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N 4 -ethyl- N4-(2-(ethyl(methyl)amino)ethyl)-2-methoxy-5-nitrobenzene-1,4-diamine.
Figure 02_image649

在 25°C下，將N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N 4 - 乙基-N 4 - （2-（甲基氨基）乙基）-2-甲氧基-5-硝基苯-1,4-二胺（260.00 毫克，489.09微莫耳）, HCHO（44.06 毫克，1.47毫莫耳，40.42 uL）和HOAc（2.94 毫克，2.80uL）溶於（5mL）MeOH中並攪拌0.5 小時。向反應液中加入NaBH(OAc)3 （310.97 毫克，1.47毫莫耳），得到的反應液在25°C繼續攪拌12小時。LCMS顯示反應完成。向反應液中加入NaHCO3 水溶液（10mL），用DCM（30mL*2）萃取，有機相分離並濃縮。粗產品用柱色譜（DCM, DCM: MeOH=60:1; DCM: MeOH=30:1）分離純化，得到標題化合物（黃色油狀物，184.00毫克，產率61.71%）。LCMS (ESI) (0-60AB):m/z: 546.3 [M+1]。At 25°C, place N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl) -N 4 -ethyl-N 4 -(2-(methylamino)ethyl)-2-methoxy-5-nitrobenzene-1,4-diamine (260.00 mg, 489.09 micromolar), HCHO (44.06 mg, 1.47 mmol, 40.42 uL) and HOAc (2.94 mg, 2.80 uL) were dissolved in (5 mL) MeOH and stirred for 0.5 hour. NaBH(OAc) 3 (310.97 mg, 1.47 mmol) was added to the reaction solution, and the resulting reaction solution was further stirred at 25°C for 12 hours. LCMS showed the reaction was complete. An aqueous NaHCO 3 solution (10 mL) was added to the reaction solution, extracted with DCM (30 mL*2), and the organic phase was separated and concentrated. The crude product was separated and purified by column chromatography (DCM, DCM: MeOH=60:1; DCM:MeOH=30:1) to obtain the title compound (yellow oil, 184.00 mg, 61.71% yield). LCMS (ESI) (0-60AB): m/z: 546.3 [M+1].

實施例22B。Example 22B.

N4-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N1乙基N1-（2-（乙基（甲基）氨基）乙基）-5-甲氧基苯-1,2,4-三胺。

Figure 02_image651
N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N1ethyl N1-( 2-(ethyl(methyl)amino)ethyl)-5-methoxybenzene-1,2,4-triamine.
Figure 02_image651

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例22A。得到標題化合物（棕色油狀物，155毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 516.3 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 22A. The title compound (brown oil, 155 mg, crude) was obtained. LCMS (ESI) (0-60AB): m/z: 516.3 [M+1].

實施例22C。Example 22C.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2-（乙基（2-（乙基（甲基）氨基）乙基）氨基）-4-甲氧苯基）丙烯醯胺。

Figure 02_image653
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-(ethyl(2-(ethyl(methyl)amino)ethyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image653

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例22B。得到標題化合物（FA鹽，38.72毫克，產率19.93%）。1 H NMR (400MHz, CD3 OD): δ 8.50 (br. s., 1H), 8.21 - 8.29 (m, 2H), 7.93 - 7.99 (m, 1H), 7.31 - 7.36 (m, 1H), 7.14 - 7.22 (m, 2H), 7.02 (d, J=5.4Hz, 1 H), 6.92 (s, 1H), 6.48 - 6.59 (m, 1H), 6.37 - 6.45 (m, 1H), 5.84 (dd, J=10.0, 1.6Hz, 1H), 5.07 (s, 2H), 4.02 (s, 4H), 3.92 - 3.99 (m, 3H), 3.51 (t, J=5.33 Hz, 2H), 3.23 (br. s., 2H), 2.99 - 3.18 (m, 4H), 2.79 (s, 3H), 1.21 (t, J=7.2Hz, 3H), 1.03 (t, J=7.0Hz, 3H)。LCMS(ESI)(0-60AB): m/z: 570.4 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 22B. The title compound (FA salt, 38.72 mg, yield 19.93%) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.50 (br. s., 1H), 8.21-8.29 (m, 2H), 7.93-7.99 (m, 1H), 7.31-7.36 (m, 1H), 7.14 -7.22 (m, 2H), 7.02 (d, J=5.4Hz, 1 H), 6.92 (s, 1H), 6.48-6.59 (m, 1H), 6.37-6.45 (m, 1H), 5.84 (dd, J=10.0, 1.6Hz, 1H), 5.07 (s, 2H), 4.02 (s, 4H), 3.92-3.99 (m, 3H), 3.51 (t, J=5.33 Hz, 2H), 3.23 (br. s ., 2H), 2.99-3.18 (m, 4H), 2.79 (s, 3H), 1.21 (t, J=7.2Hz, 3H), 1.03 (t, J=7.0Hz, 3H). LCMS (ESI) (0-60AB): m/z: 570.4 [M+1].

實施例23。Example 23.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（異丙基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image295
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(isopropylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image295

實施例23A。Example 23A.

第三丁基（2-羥乙基）（異丙基）氨基甲酸第三丁酯。

Figure 02_image656
Tertiary butyl (2-hydroxyethyl) (isopropyl) carbamate tertiary butyl.
Figure 02_image656

在25°C下，將2-（異丙基氨基）乙醇（18.30克，177.39毫莫耳）和K2 CO3 （49.04克，354.78毫莫耳）溶於THF （100mL） 和 H2 O （20mL）中，向該混合液中加入（Boc）2 O （58.07克，266.09毫莫耳）並攪拌3小時。TLC（PE: EtOAc = 2: 1）顯示反應完成。向反應液中加入水（50mL），用EtOAc（50mL*2）萃取。有機相合併後用無水Na2 SO4 乾燥，抽濾並濃縮。粗品用柱色譜（SiO2 , PE: EtOAc = 50:1 to 2:1）分離純化，得到標題化合物（黃色油狀物，24.00克，產率59.90%）。1 H NMR (400MHz, CDCl3 ): δ 4.28-4.06 (m, 1H), 3.78-3.65 (m, 2H), 3.31 (br. s., 2H), 1.50-1.48 (s, 9H), 1.14 (d, J = 6.8Hz, 6H)。At 25°C, dissolve 2-(isopropylamino)ethanol (18.30 g, 177.39 mmol) and K 2 CO 3 (49.04 g, 354.78 mmol) in THF (100 mL) and H 2 O ( 20 mL), (Boc) 2 O (58.07 g, 266.09 mmol) was added to the mixture and stirred for 3 hours. TLC (PE: EtOAc = 2: 1) showed the reaction was complete. Water (50 mL) was added to the reaction liquid, and extracted with EtOAc (50 mL*2). The combined organic phases are dried over anhydrous Na 2 SO 4 , filtered with suction and concentrated. The crude product was separated and purified by column chromatography (SiO 2 , PE: EtOAc = 50:1 to 2:1) to obtain the title compound (yellow oil, 24.00 g, yield 59.90%). 1 H NMR (400MHz, CDCl 3 ): δ 4.28-4.06 (m, 1H), 3.78-3.65 (m, 2H), 3.31 (br. s., 2H), 1.50-1.48 (s, 9H), 1.14 ( d, J = 6.8Hz, 6H).

實施例23B。Example 23B.

第三丁基-N-異丙基-N-（2-氧代乙基）氨基甲酸。

Figure 02_image658
Third butyl-N-isopropyl-N-(2-oxoethyl)carbamic acid.
Figure 02_image658

在 20°C下，將實施例23A（10.00克，49.19毫莫耳）溶於DCM（100mL）中。 向該反應液中加入dess-martin試劑（31.30克，73.79毫莫耳）並攪拌2小時。TLC（PE: EtOAc = 3: 1）顯示反應完成。反應液過濾，濾液濃縮得到的殘留物溶於EtOAc（50mL）中，用飽和NaHCO3 水溶液（50mL x 2）洗滌，並用無水Na2 SO4 乾燥，抽濾並濃縮。粗品粗品用柱色譜（SiO2 : PE: EtOAc = 100: 1 to 10:1）分離純化，得到標題化合物（黃色油狀物，7.90克，產率71.82%）。1 H NMR (400MHz, CDCl3 ): δ 9.53 (br. s., 1H), 4.63-4.21 (m, 1H), 3.86-3.61 (m, 2H), 1.50-1.39 (m, 9H), 1.12 (d, J = 6.8Hz, 6H)。At 20°C, Example 23A (10.00 g, 49.19 mmol) was dissolved in DCM (100 mL). To the reaction solution, dess-martin reagent (31.30 g, 73.79 mmol) was added and stirred for 2 hours. TLC (PE: EtOAc = 3: 1) showed that the reaction was complete. The reaction solution was filtered, and the residue obtained by concentration of the filtrate was dissolved in EtOAc (50 mL), washed with saturated aqueous NaHCO 3 (50 mL x 2), dried over anhydrous Na 2 SO 4 , filtered with suction, and concentrated. The crude product was separated and purified by column chromatography (SiO 2 : PE: EtOAc = 100: 1 to 10: 1) to obtain the title compound (yellow oil, 7.90 g, yield 71.82%). 1 H NMR (400MHz, CDCl 3 ): δ 9.53 (br. s., 1H), 4.63-4.21 (m, 1H), 3.86-3.61 (m, 2H), 1.50-1.39 (m, 9H), 1.12 ( d, J = 6.8Hz, 6H).

實施例23C。Example 23C.

第三丁基-N-異丙基-N- [2-（二甲氨基）乙基]氨基甲酸。

Figure 02_image660
Third butyl-N-isopropyl-N-[2-(dimethylamino)ethyl]carbamate.
Figure 02_image660

將實施例23B （1.80克，8.94毫莫耳）和甲胺鹽酸鹽（1.21克，17.89毫莫耳）溶於MeOH（200mL），氬氣置換後加入Pd/C（10%，100.00毫克）並用H2置換3次。反應液在50Psi壓力下加熱到50 °C，攪拌24小時。TLC（DCM: MeOH= 20:1）顯示反應完成後，將反應混合物過濾，濾液濃縮至乾，得到粗品溶於DCM（20mL）中，再用6N的NaOH（10mL x 2）洗滌，有機相用無水Na2 SO4 乾燥，抽濾並濃縮得標題化合物（黃色油狀，600.00毫克，產率26.37%）。1 H NMR (300MHz, CDCl3 ): δ 4.24-4.07 (m, 1H), 3.20-3.15 (m, 2H), 2.77-2.66 (m, 2H), 2.52-2.42 (m, 3H), 1.48 (s, 9H), 1.13 (d, J = 6.8Hz, 6H)。Example 23B (1.80 g, 8.94 mmol) and methylamine hydrochloride (1.21 g, 17.89 mmol) were dissolved in MeOH (200 mL), and Pd/C (10%, 100.00 mg) was added after argon replacement. Replace with H2 3 times. The reaction solution was heated to 50 °C under 50 Psi pressure and stirred for 24 hours. After TLC (DCM: MeOH=20:1) showed that the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to dryness. The crude product was dissolved in DCM (20mL), washed with 6N NaOH (10mL x 2), and the organic phase was used Anhydrous Na 2 SO 4 was dried, filtered with suction and concentrated to give the title compound (yellow oil, 600.00 mg, yield 26.37%). 1 H NMR (300MHz, CDCl 3 ): δ 4.24-4.07 (m, 1H), 3.20-3.15 (m, 2H), 2.77-2.66 (m, 2H), 2.52-2.42 (m, 3H), 1.48 (s , 9H), 1.13 (d, J = 6.8Hz, 6H).

實施例23D。Example 23D.

第三丁基（2 - （（4 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-5-甲氧基-2-硝基苯基）（甲基）氨基）乙基）（異丙基）氨基甲酸第三丁酯。

Figure 02_image662
Tertiary butyl (2-((4-((4-(3,4-dihydro-1H-[1,4]oxazido[4,3-a]indol-10-yl)pyrimidine-2 -Yl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)ethyl)(isopropyl)carbamic acid tert-butyl ester.
Figure 02_image662

本實施例根據實施例16A的方法製備，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為實施例23C。得到標題化合物（黃色固體，200毫克，產率88.4%）。LCMS (ESI) (5-95AB): m/z: 632.2 [M+1]。This example was prepared according to the method of Example 16A, and N,N-diethyl-N-methylethane-1,2-diamine was replaced with Example 23C. The title compound was obtained (yellow solid, 200 mg, yield 88.4%). LCMS (ESI) (5-95AB): m/z: 632.2 [M+1].

實施例23E。Example 23E.

第三丁基（2 - （（2-氨基-4 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-5-甲氧基苯基）（甲基）氨基）乙基）（異丙基）氨基甲酸第三丁酯。

Figure 02_image664
Tertiary butyl (2-((2-amino-4-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl )Pyrimidin-2-yl)amino)-5-methoxyphenyl)(methyl)amino)ethyl)(isopropyl)carbamic acid tert-butyl ester.
Figure 02_image664

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例23D。得到標題化合物（棕色固體，180毫克，粗品）。LCMS (ESI) (5-95AB): m/z: 602.4 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 23D. The title compound (brown solid, 180 mg, crude) was obtained. LCMS (ESI) (5-95AB): m/z: 602.4 [M+1].

實施例23F。Example 23F.

（2 - （（2-丙烯醯氨基-4 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-5-甲氧基苯基）（甲基）氨基）乙基）（異丙基）氨基甲酸第三丁酯。

Figure 02_image666
(2-((2-propenylamino-4-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidine -2-yl)amino)-5-methoxyphenyl)(methyl)amino)ethyl)(isopropyl)carbamic acid tert-butyl ester.
Figure 02_image666

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例23E。得到標題化合物（180 毫克，粗品），直接用於下一步。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 23E. The title compound (180 mg, crude) was obtained and used directly in the next step.

實施例23G。Example 23G.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2-（乙基（2-（異丙基氨基）乙基）氨基）-4-甲氧苯基）丙烯醯胺。

Figure 02_image295
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-(ethyl(2-(isopropylamino)ethyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image295

本實施例根據實施例21E的方法製備，將實施例21D替換為實施例23F。得到標題化合物（黃色固體FA鹽，24.30毫克，產率14.34%）。1 H NMR (400MHz, CD3 OD): δ 8.33 (d, J = 4.0 Hz, 1H), 8.27 (s, 1H), 8.08-8.03 (m, 1H), 7.46-7.42 (m, 1H), 7.28-7.20 (m, 2H), 7.15 (d, J = 4.0 Hz, 1H), 6.92 (s, 1H), 6.58-6.49 (m, 1H), 6.44-6.37 (m, 1H), 5.84 (dd, J = 2.0, 8.0 Hz, 1H), 5.19 (s, 2H), 4.14 (s, 4H), 3.98 (s, 3H), 3.44 (t, J = 6.0 Hz, 2H), 3.39-3.33 (m, 1H), 3.15 (t, J = 6.0 Hz, 2H), 2.72 (s, 3H), 1.35 (d, J = 8.0 Hz, 6H)。LCMS (ESI) (0-60AB): m/z: 556.4 [M+1]。This example was prepared according to the method of Example 21E, and Example 21D was replaced with Example 23F. The title compound (yellow solid FA salt, 24.30 mg, yield 14.34%) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.33 (d, J = 4.0 Hz, 1H), 8.27 (s, 1H), 8.08-8.03 (m, 1H), 7.46-7.42 (m, 1H), 7.28 -7.20 (m, 2H), 7.15 (d, J = 4.0 Hz, 1H), 6.92 (s, 1H), 6.58-6.49 (m, 1H), 6.44-6.37 (m, 1H), 5.84 (dd, J = 2.0, 8.0 Hz, 1H), 5.19 (s, 2H), 4.14 (s, 4H), 3.98 (s, 3H), 3.44 (t, J = 6.0 Hz, 2H), 3.39-3.33 (m, 1H) , 3.15 (t, J = 6.0 Hz, 2H), 2.72 (s, 3H), 1.35 (d, J = 8.0 Hz, 6H). LCMS (ESI) (0-60AB): m/z: 556.4 [M+1].

實施例24。Example 24.

N-（2 - （（2-（第三丁基氨基）乙基）（甲基）氨基）-5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image297
N-(2-((2-(tertiarybutylamino)ethyl)(methyl)amino)-5 -((4-(3,4-dihydro-1H- [1,4]oxazinon [4,3-a]Indol-10-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image297

實施例24A。Example 24A.

第三丁基（2-（第三丁基氨基）乙基）（甲基）氨基甲酸。

Figure 02_image670
Third butyl (2-(third butylamino) ethyl) (methyl) carbamic acid.
Figure 02_image670

在20 °C下，將2-甲基丙-2-胺（844.04 毫克，11.54毫莫耳）和第三丁基-N-甲基-N-（2-氧代乙基）氨基甲酸（1.00克，5.77毫莫耳）溶於MeOH（30mL），氬氣置換後加入Pd/C（10%，200.00毫克）並用H2 置換。反應液在H2 中50Psi壓力下攪拌16小時。LCMS顯示反應物完全消耗，並檢測到要的MS。反應混合物過濾，濾液濃縮至乾，得到粗品溶於DCM（30mL）中，再用水（30mL x 2）洗滌，有機相濃縮得標題化合物（橙色油狀，1.00克，產率71.48%）。1 H NMR (400MHz, CDCl3 ): δ 3.28 (t, J = 6.7 Hz, 2H), 2.92 - 2.82 (m, 3H), 2.75 - 2.65 (m, 2H), 1.53 - 1.39 (m, 10H), 1.08 (s, 9H)。At 20 °C, 2-methylpropan-2-amine (844.04 mg, 11.54 mmol) and tert-butyl-N-methyl-N-(2-oxoethyl)carbamic acid (1.00 Grams, 5.77 millimoles) was dissolved in MeOH (30 mL), Pd/C (10%, 200.00 mg) was added after replacement with argon and replaced with H 2 . The reaction was stirred under a pressure 50Psi H 2 16 hours. LCMS showed that the reactants were completely consumed and the desired MS was detected. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The crude product was dissolved in DCM (30 mL), washed with water (30 mL x 2), and the organic phase was concentrated to give the title compound (orange oil, 1.00 g, yield 71.48%). 1 H NMR (400MHz, CDCl 3 ): δ 3.28 (t, J = 6.7 Hz, 2H), 2.92-2.82 (m, 3H), 2.75-2.65 (m, 2H), 1.53-1.39 (m, 10H), 1.08 (s, 9H).

實施例24B。Example 24B.

N1-（第三丁基）-N2 - 二甲基乙烷-1,2-二胺。

Figure 02_image672
N1-(third butyl)-N2-dimethylethane-1,2-diamine.
Figure 02_image672

在20 °C下，將實施例24A（200.00 毫克，868.24微莫耳） 溶於EA（30mL）,向該混合液中加入HCl/EtOAc（4 莫耳/升，2.17mL），得到的反應液攪拌4小時。TLC（DCM/MeOH = 10/1）顯示起始原料消耗。反應液濃縮得到得標題化合物（白色粉末鹽酸鹽，160毫克，產率86.18%）。1 H NMR (400MHz, D2 O): δ 3.60 - 3.39 (m, 4H), 3.00 - 2.79 (m, 3H), 1.60 - 1.37 (m, 9H)。At 20 °C, Example 24A (200.00 mg, 868.24 μmol) was dissolved in EA (30 mL), and HCl/EtOAc (4 mol/L, 2.17 mL) was added to the mixture to obtain the reaction solution Stir for 4 hours. TLC (DCM/MeOH = 10/1) shows the consumption of starting materials. The reaction solution was concentrated to obtain the title compound (white powder hydrochloride, 160 mg, yield 86.18%). 1 H NMR (400MHz, D 2 O): δ 3.60-3.39 (m, 4H), 3.00-2.79 (m, 3H), 1.60-1.37 (m, 9H).

實施例24C。Example 24C.

N4-[2-（第三丁基氨基）乙基]-N 1 - [4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基] -2-甲氧基-N-4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image674
N4-[2-(Third-butylamino)ethyl]-N 1-[4-(3,4-dihydro-1H- [1,4]oxazino[4,3-a]indole- 10-yl)pyrimidin-2-yl]-2-methoxy-N-4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image674

本實施例根據實施例16A的方法製備，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為實施例24B。得到標題化合物（120.00毫克，粗品）。LCMS (ESI) (5-95AB):m/z: 546.3 [M+1]。This example was prepared according to the method of Example 16A, and N,N-diethyl-N-methylethane-1,2-diamine was replaced with Example 24B. The title compound (120.00 mg, crude) was obtained. LCMS (ESI) (5-95AB): m/z: 546.3 [M+1].

實施例24D。Example 24D.

N1-[2-（第三丁基氨基）乙基]-N4-[4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image676
N1-[2-(third butylamino)ethyl]-N4-[4-(3,4-dihydro-1H-[1,4]oxazido[4,3-a]indole-10 -Yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image676

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例24C。得到標題化合物（橙色粉末，100毫克，粗品）。LCMS (ESI) (5-95AB): m/z: 516.3 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 24C. The title compound (orange powder, 100 mg, crude) was obtained. LCMS (ESI) (5-95AB): m/z: 516.3 [M+1].

實施例24E。Example 24E.

N-（2 - （（2-（第三丁基氨基）乙基）（甲基）氨基）-5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image297
N-(2-((2-(tertiarybutylamino)ethyl)(methyl)amino)-5 -((4-(3,4-dihydro-1H- [1,4]oxazinon [4,3-a]Indol-10-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image297

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例24D。得到標題化合物（FA鹽，46.82毫克，產率39.41%）。1 H NMR (400MHz, DMSO-d6 ): δ 9.73 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.13 - 8.00 (m, 2H), 7.50 (d, J = 7.0 Hz, 1H), 7.29 - 7.16 (m, 2H), 7.10 (d, J = 5.5 Hz, 1H), 6.94 (s, 1H), 6.80 (dd, J = 10.3, 16.8 Hz, 1H), 6.22 (d, J = 16.8 Hz, 1H), 5.72 (d, J = 11.0 Hz, 1H), 5.13 (s, 2H), 4.15 (d, J = 4.8 Hz, 2H), 4.08 (d, J = 4.8 Hz, 2H), 3.85 (s, 3H), 3.22 (br. s., 2H), 2.93 (br. s., 2H), 2.60 (s, 3H), 1.35 - 1.03 (m, 9H)。 LCMS (ESI) (5-95AB): m/z: 570.4 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 24D. The title compound (FA salt, 46.82 mg, 39.41% yield) was obtained. 1 H NMR (400MHz, DMSO-d 6 ): δ 9.73 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.13-8.00 ( m, 2H), 7.50 (d, J = 7.0 Hz, 1H), 7.29-7.16 (m, 2H), 7.10 (d, J = 5.5 Hz, 1H), 6.94 (s, 1H), 6.80 (dd, J = 10.3, 16.8 Hz, 1H), 6.22 (d, J = 16.8 Hz, 1H), 5.72 (d, J = 11.0 Hz, 1H), 5.13 (s, 2H), 4.15 (d, J = 4.8 Hz, 2H ), 4.08 (d, J = 4.8 Hz, 2H), 3.85 (s, 3H), 3.22 (br. s., 2H), 2.93 (br. s., 2H), 2.60 (s, 3H), 1.35- 1.03 (m, 9H). LCMS (ESI) (5-95AB): m/z: 570.4 [M+1].

實施例25。Example 25.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）-2-甲基丙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image299
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image299

實施例25A。Example 25A.

1-氯-N，N，2-三甲基丙-2-胺。

Figure 02_image680
1-chloro-N,N,2-trimethylpropan-2-amine.
Figure 02_image680

將2-（二甲基氨基）-2-甲基丙-1-醇（10.00克，85.33毫莫耳）溶於甲苯（100mL）中，向該混合物中加入SOCl2 （20.30克，170.66毫莫耳）。加完後反應液升溫至100 °C並攪拌3小時。TLC（DCM/MeOH=10/1）監測顯示起始原料消耗完全。反應液濃縮得到標題化合物（橙色粉末，鹽酸鹽，12.00 g, 粗品）。1 H NMR (400MHz, CD3 OD): δ 3.65 - 3.56 (m, 2H), 3.05 (s, 6H), 1.77 - 1.68 (m, 6H)。2-(Dimethylamino)-2-methylpropan-1-ol (10.00 g, 85.33 mmol) was dissolved in toluene (100 mL), and SOCl 2 (20.30 g, 170.66 mmol) was added to the mixture ear). After the addition, the reaction solution was heated to 100 °C and stirred for 3 hours. TLC (DCM/MeOH=10/1) monitoring showed that the starting material was completely consumed. The reaction solution was concentrated to obtain the title compound (orange powder, hydrochloride salt, 12.00 g, crude product). 1 H NMR (400MHz, CD 3 OD): δ 3.65-3.56 (m, 2H), 3.05 (s, 6H), 1.77-1.68 (m, 6H).

實施例25B。Example 25B.

N1，N2，N2,2-四甲基丙烷-1,2-二胺。

Figure 02_image682
N1, N2, N2, 2-tetramethylpropane-1,2-diamine.
Figure 02_image682

在20 °C下，將1-氯-N，N，2-三甲基丙-2-胺（1.00克，5.81毫莫耳，鹽酸鹽）溶入H2 O（10mL）中，向該混合物中緩慢加入甲胺（1.80克，17.43毫莫耳），並攪拌2小時。LCMS顯示反應完成，向反應混合物中緩慢加入NaOH固體（2克），待反應液冷卻後用MTBE（20mL x2）萃取，分離的有機相濃縮至5mL後加入HCl/EA（5mL）並濃縮得到標題化合物（橙色粉末，1.00克，粗品，鹽酸鹽）。1 H NMR (400MHz, D2 O): δ 3.57 - 3.48 (m, 2H), 3.01 (s, 6H), 2.81 - 2.75 (m, 3H), 1.53 (s, 6H)。At 20 °C, 1-chloro-N,N,2-trimethylpropan-2-amine (1.00 g, 5.81 mmol, hydrochloride) was dissolved in H 2 O (10 mL). Methylamine (1.80 g, 17.43 mmol) was slowly added to the mixture and stirred for 2 hours. LCMS showed that the reaction was completed, and NaOH solid (2 g) was slowly added to the reaction mixture. After the reaction solution was cooled, it was extracted with MTBE (20 mL x 2). The separated organic phase was concentrated to 5 mL, then HCl/EA (5 mL) was added and concentrated to give the title Compound (orange powder, 1.00 g, crude, hydrochloride). 1 H NMR (400MHz, D 2 O): δ 3.57-3.48 (m, 2H), 3.01 (s, 6H), 2.81-2.75 (m, 3H), 1.53 (s, 6H).

實施例25C。Example 25C.

N1-〔4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-N4-[2-（二甲基氨基）-2-甲基丙基] -2-甲基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image684
N1-[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl]-N4-[2-( Dimethylamino)-2-methylpropyl]-2-methyl-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image684

本實施例根據實施例16A的方法製備，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為實施例25B。得到標題化合物（紅色粉末，100.00毫克，粗品）。LCMS (ESI) (5-95AB):m/z: 546.4 [M+1]。This example was prepared according to the method of Example 16A, and N,N-diethyl-N-methylethane-1,2-diamine was replaced with Example 25B. The title compound (red powder, 100.00 mg, crude) was obtained. LCMS (ESI) (5-95AB): m/z: 546.4 [M+1].

實施例25D。Example 25D.

N4-〔4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-N 1 - [2-（二甲基氨基）-2-甲基丙基]-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image686
N4-[4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl]-N 1 -[2- (Dimethylamino)-2-methylpropyl]-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image686

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例25C。得到標題化合物（橙色膠狀，70毫克，粗品）。LCMS (ESI) (5-95AB):m/z: 516.4 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 25C. The title compound was obtained (orange gum, 70 mg, crude). LCMS (ESI) (5-95AB): m/z: 516.4 [M+1].

實施例25E。Example 25E.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）-2-甲基丙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image688
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image688

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例25D。得到標題化合物（甲酸鹽，50.92 毫克，產率58.97%）。1 H NMR (400MHz, DMSO-d6 ): δ 10.59 (br. s., 1H), 8.53 (s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.28 (s, 2H), 8.12 - 8.03 (m, 2H), 7.54 - 7.45 (m, 1H), 7.26 - 7.19 (m, 2H), 7.15 - 7.06 (m, 2H), 6.48 (dd, J = 10.0, 16.8 Hz, 1H), 6.23 (dd, J = 1.4, 16.9 Hz, 1H), 5.75 (d, J = 11.5 Hz, 1H), 5.06 (s, 2H), 4.24 - 4.14 (m, 2H), 4.05 (d, J = 4.8 Hz, 2H), 3.87 - 3.83 (m, 3H), 3.12 (br. s., 2H), 2.69 (s, 3H), 2.35 (s, 6H), 1.07 - 0.89 (m, 6H)。 LCMS (ESI) (5-95AB): m/z: 570.4 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 25D. The title compound (formate, 50.92 mg, yield 58.97%) was obtained. 1 H NMR (400MHz, DMSO-d 6 ): δ 10.59 (br. s., 1H), 8.53 (s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.28 (s, 2H), 8.12 -8.03 (m, 2H), 7.54-7.45 (m, 1H), 7.26-7.19 (m, 2H), 7.15-7.06 (m, 2H), 6.48 (dd, J = 10.0, 16.8 Hz, 1H), 6.23 (dd, J = 1.4, 16.9 Hz, 1H), 5.75 (d, J = 11.5 Hz, 1H), 5.06 (s, 2H), 4.24-4.14 (m, 2H), 4.05 (d, J = 4.8 Hz, 2H), 3.87-3.83 (m, 3H), 3.12 (br. s., 2H), 2.69 (s, 3H), 2.35 (s, 6H), 1.07-0.89 (m, 6H). LCMS (ESI) (5-95AB): m/z: 570.4 [M+1].

實施例26。Example 26.

N-（2 - （（2-（氮丙啶-1-基）乙基）（甲基）氨基）-5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image690
N-(2-((2-(aziridin-1-yl)ethyl)(methyl)amino)-5-((4-(3,4-dihydro-1H-[1,4]ox Azino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image690

實施例26A。Example 26A.

N4-〔2-（氮丙啶-1-基）乙基]-N 1 - [4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-2-甲氧基 - N 4 - 甲基-5-硝基苯-1,4-二胺。

Figure 02_image692
N4-[2-(aziridin-1-yl)ethyl]-N 1-[4-(3,4-dihydro-1H-[1,4]oxazido[4,3-a]ind Indol-10-yl)pyrimidin-2-yl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image692

本實施例根據實施例16A的方法製備，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為2-（氮丙啶-1-基）-N-甲基甲胺。得到標題化合物（紅色粉末，150.00毫克，粗品）。LCMS (ESI) (5-95AB):m/z: 530.2 [M+1]。This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with 2-(aziridine-1-yl)-N-methyl Methyl methylamine. The title compound (red powder, 150.00 mg, crude) was obtained. LCMS (ESI) (5-95AB): m/z: 530.2 [M+1].

實施例26B。Example 26B.

N1-[2-（氮丙啶-1-基）乙基]-N4-[4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image694
N1-[2-(aziridin-1-yl)ethyl]-N4-[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole -10-yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image694

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例26A。得到標題化合物（棕色粉末，130.00毫克，粗品）。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 26A. The title compound was obtained (brown powder, 130.00 mg, crude).

實施例26C。Example 26C.

N-（2- （（2-（氮丙啶-1-基）乙基）（甲基）氨基）-5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image301
N-(2-((2-(aziridin-1-yl)ethyl)(methyl)amino)-5 -((4-(3,4-dihydro-1H-[1,4]ox Azino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image301

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例26B。得到標題化合物（FA鹽，57.26毫克，產率39.64%）。1 H NMR (400MHz, DMSO-d6 ): δ 9.28 (s, 1H), 8.36 - 8.31 (m, 2H), 8.30 (s, 1H), 8.11 - 7.98 (m, 2H), 7.55 - 7.44 (m, 1H), 7.27 - 7.16 (m, 2H), 7.11 - 7.05 (m, 1H), 6.88 (s, 1H), 6.68 (dd, J=10.2, 16.9 Hz, 1H), 6.20 (dd, J = 1.3, 17.1 Hz, 1H), 5.72 (d, J = 10.8 Hz, 1H), 5.11 (s, 2H), 4.15 (d, J = 5.0 Hz, 2H), 4.08 (d, J = 4.8 Hz, 2H), 3.82 (s, 3H), 3.23 (br. s., 2H), 3.10 (t, J=5.3 Hz, 2H), 3.00 (br. s., 4H), 2.55 (s, 3H), 1.97 (br. s., 2H)。LCMS (ESI) (5-95AB):m/z: 554.2 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 26B. The title compound (FA salt, 57.26 mg, 39.64% yield) was obtained. 1 H NMR (400MHz, DMSO-d 6 ): δ 9.28 (s, 1H), 8.36-8.31 (m, 2H), 8.30 (s, 1H), 8.11-7.98 (m, 2H), 7.55-7.44 (m , 1H), 7.27-7.16 (m, 2H), 7.11-7.05 (m, 1H), 6.88 (s, 1H), 6.68 (dd, J=10.2, 16.9 Hz, 1H), 6.20 (dd, J = 1.3 , 17.1 Hz, 1H), 5.72 (d, J = 10.8 Hz, 1H), 5.11 (s, 2H), 4.15 (d, J = 5.0 Hz, 2H), 4.08 (d, J = 4.8 Hz, 2H), 3.82 (s, 3H), 3.23 (br. s., 2H), 3.10 (t, J=5.3 Hz, 2H), 3.00 (br. s., 4H), 2.55 (s, 3H), 1.97 (br. s., 2H). LCMS (ESI) (5-95AB): m/z: 554.2 [M+1].

實施例27。Example 27.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-4-甲氧基-2-（甲基（2-（甲基氨基）乙基氨基）苯基）丙烯醯胺。

Figure 02_image303
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 4-Methoxy-2-(methyl(2-(methylamino)ethylamino)phenyl)acrylamide.
Figure 02_image303

本實施例合成流程同流程9。The synthesis process of this embodiment is the same as process 9.

實施例27A。Example 27A.

第三丁基（2 - （（4 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-5-甲氧基-2-硝基苯基）（甲基）氨基）乙基）（甲基）氨基甲酸。

Figure 02_image698
Tertiary butyl (2-((4-((4-(3,4-dihydro-1H-[1,4]oxazido[4,3-a]indol-10-yl)pyrimidine-2 -Yl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)ethyl)(methyl)carbamic acid.
Figure 02_image698

本實施例根據實施例21B的方法製備，將實施例21A替換為N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-2-甲氧基 - N 4 - 甲基-N 4 - （2-（甲基氨基）乙基）-5-硝基苯-1,4-二胺。得到標題化合物（黃色固體，150.00毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 604.3 [M+1]。This example was prepared according to the method of Example 21B, and Example 21A was replaced with N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole- 10-yl)pyrimidin-2-yl)-2-methoxy-N 4 -methyl-N 4 -(2-(methylamino)ethyl)-5-nitrobenzene-1,4-diamine . The title compound (yellow solid, 150.00 mg, crude) was obtained. LCMS (ESI) (0-60AB): m/z: 604.3 [M+1].

實施例27B。Example 27B.

第三丁基（2 - （（2-氨基-4 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-5-甲氧基苯基）（甲基）氨基）乙基）（甲基）氨基甲酸。

Figure 02_image700
Tertiary butyl (2-((2-amino-4-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl )Pyrimidin-2-yl)amino)-5-methoxyphenyl)(methyl)amino)ethyl)(methyl)carbamic acid.
Figure 02_image700

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例27A。得到標題化合物（黃色固體，100.00毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 574.3 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 27A. The title compound was obtained (yellow solid, 100.00 mg, crude). LCMS (ESI) (0-60AB): m/z: 574.3 [M+1].

實施例27C。Example 27C.

第三丁基（2 - （（2-丙烯醯氨基-4 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-5-甲氧基苯基）（甲基）氨基）乙基）（甲基）氨基甲酸。

Figure 02_image702
Tertiary butyl (2-((2-propenylamino-4-((4-(3,4-dihydro-1H- [1,4]oxazino[4,3-a]indole-10 -Yl)pyrimidin-2-yl)amino)-5-methoxyphenyl)(methyl)amino)ethyl)(methyl)carbamic acid.
Figure 02_image702

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例27B。得到標題化合物（黃色固體，150.00毫克，粗品）。LCMS (ESI) (0-60AB): m/z: 628.4 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 27B. The title compound (yellow solid, 150.00 mg, crude) was obtained. LCMS (ESI) (0-60AB): m/z: 628.4 [M+1].

實施例27D。Example 27D.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-4-甲氧基-2-（甲基（2-（甲基氨基）乙基氨基）苯基）丙烯醯胺。

Figure 02_image303
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 4-Methoxy-2-(methyl(2-(methylamino)ethylamino)phenyl)acrylamide.
Figure 02_image303

本實施例根據實施例21E的方法製備，將實施例21D替換為實施例27C。得到標題化合物（甲酸鹽，9.26毫克，產率6.65%）。1 H NMR (400MHz, CD3 OD): δ 8.44 (br. s., 1 H), 8.31 - 8.35 (m, 2 H), 8.03 - 8.06 (m, 1 H), 7.42 (s, 1 H), 7.21 - 7.28 (m, 2 H), 7.16 (d, J=5.60 Hz, 1 H), 6.94 (s, 1 H), 6.54 - 6.60 (m, 1 H), 6.40 - 6.45 (m, 1 H), 5.84 - 5.87 (m, 1 H), 5.17 (s, 2 H), 4.13 (s, 4 H), 3.98 (s, 3 H), 3.43 (t, J=5.20 Hz, 2 H), 3.17 (t, J=5.20 Hz, 2 H), 2.72 (d, J=1.20 Hz, 6 H)。LCMS (ESI) (0-60AB): m/z: 528.4 [M+1]。This example was prepared according to the method of Example 21E, and Example 21D was replaced with Example 27C. The title compound (formate, 9.26 mg, yield 6.65%) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.44 (br. s., 1 H), 8.31-8.35 (m, 2 H), 8.03-8.06 (m, 1 H), 7.42 (s, 1 H) , 7.21-7.28 (m, 2 H), 7.16 (d, J=5.60 Hz, 1 H), 6.94 (s, 1 H), 6.54-6.60 (m, 1 H), 6.40-6.45 (m, 1 H ), 5.84-5.87 (m, 1 H), 5.17 (s, 2 H), 4.13 (s, 4 H), 3.98 (s, 3 H), 3.43 (t, J=5.20 Hz, 2 H), 3.17 (t, J=5.20 Hz, 2 H), 2.72 (d, J=1.20 Hz, 6 H). LCMS (ESI) (0-60AB): m/z: 528.4 [M+1].

實施例28。Example 28.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲氨基）-4-乙氧基苯基）丙烯醯胺。

Figure 02_image305
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(dimethylamino)ethyl)(methylamino)-4-ethoxyphenyl) acrylamide.
Figure 02_image305

實施例28A。Example 28A.

4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-N-（2-甲氧基-4-氟-5-硝基苯基）嘧啶-2-胺。

Figure 02_image706
4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-N-(2-methoxy-4-fluoro-5- Nitrophenyl)pyrimidine-2-amine.
Figure 02_image706

本實施例根據實施例D的方法製備，將4-氟-2-甲氧基-5-硝基苯胺替換為2-乙基-4-氟-5-硝基苯胺。得到標題化合物（黃色固體，300.00毫克，粗品）。This example was prepared according to the method of Example D, replacing 4-fluoro-2-methoxy-5-nitroaniline with 2-ethyl-4-fluoro-5-nitroaniline. The title compound (yellow solid, 300.00 mg, crude) was obtained.

實施例28B。Example 28B.

N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N4-（2-（二甲基氨基）乙基）-2-甲氧基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image708
N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N4-(2-( Dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image708

本實施例根據實施例16A的方法製備，將實施例D替換為實施例28A，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（黃色固體，230.00毫克，粗品）。LCMS (ESI) (5-95AB): m/z: 532.2 [M+1]。This example was prepared according to the method of Example 16A, replacing Example D with Example 28A, and replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethylenediamine. The title compound (yellow solid, 230.00 mg, crude) was obtained. LCMS (ESI) (5-95AB): m/z: 532.2 [M+1].

實施例28C。Example 28C.

N4-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image710
N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N 1 -(2- (Dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image710

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例28B。得到標題化合物（棕色粉末，200.00毫克，粗品）。LCMS (ESI) (5-95AB): m/z: 502.3 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 28B. The title compound (brown powder, 200.00 mg, crude) was obtained. LCMS (ESI) (5-95AB): m/z: 502.3 [M+1].

實施例28D。Example 28D.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲氨基）-4-乙氧基苯基）丙烯醯胺。

Figure 02_image712
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(dimethylamino)ethyl)(methylamino)-4-ethoxyphenyl) acrylamide.
Figure 02_image712

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例28C。得到標題化合物（FA鹽，125.00毫克，產率50.65%）。1 H NMR (400MHz, CD3 OD): δ 8.46 (br. s., 1H), 8.35 (d, J = 4.0 Hz, 1H), 8.32 (s, 1H), 8.09-8.05 (m, 1H), 7.49-7.42 (m, 1H), 7.28-7.21 (m, 2H), 7.19 (d, J = 4.0 Hz, 1H), 6.95 (s, 1H), 6.57-6.42 (m, 2H), 5.86 (dd, J = 2.0, 8.0 Hz, 1H), 5.20 (s, 2H), 4.22 （q, J = 8.0 Hz, 2H), 4.16 (br. s., 4H), 3.46 (t, J=6.0 Hz, 1H), 3.25 - 3.20 (m, 1H), 2.84 (s, 2H), 2.73 (s, 1H), 1.49 (t, J = 8.0 Hz, 1H)。 LCMS (ESI) (0-60AB): m/z: 556.4 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 28C. The title compound (FA salt, 125.00 mg, yield 50.65%) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.46 (br. s., 1H), 8.35 (d, J = 4.0 Hz, 1H), 8.32 (s, 1H), 8.09-8.05 (m, 1H), 7.49-7.42 (m, 1H), 7.28-7.21 (m, 2H), 7.19 (d, J = 4.0 Hz, 1H), 6.95 (s, 1H), 6.57-6.42 (m, 2H), 5.86 (dd, J = 2.0, 8.0 Hz, 1H), 5.20 (s, 2H), 4.22 (q, J = 8.0 Hz, 2H), 4.16 (br. s., 4H), 3.46 (t, J=6.0 Hz, 1H) , 3.25-3.20 (m, 1H), 2.84 (s, 2H), 2.73 (s, 1H), 1.49 (t, J = 8.0 Hz, 1H). LCMS (ESI) (0-60AB): m/z: 556.4 [M+1].

實施例29。Example 29.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲氨基）-4-異丙基苯基）丙烯醯胺。

Figure 02_image714
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(dimethylamino)ethyl)(methylamino)-4-isopropylphenyl)acrylamide.
Figure 02_image714

實施例29A。Example 29A.

N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N4-（2-（二甲基氨基）乙基）-2-異丙氧基 - N 4 - 甲基-5-硝基苯-1,4-二胺。

Figure 02_image716
N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N4-(2-( Dimethylamino)ethyl)-2-isopropoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image716

在氮氣保護下向中間體C（200 毫克，699.96微莫耳）與N4-〔2-（二甲基氨基）乙基] -2-異丙氧基 - N 4 - 甲基-5-硝基 - 苯-1,4-二胺（207.44 毫克，699.96微莫耳）的10mL1,4-二氧六環溶液中加入Pd(OAc)2 （15.71 毫克，70.00微莫耳）, K3 PO4 （297.16 毫克，1.40毫莫耳）和 XPhos （33.37 毫克，70.00微莫耳），並升溫至90°C攪拌10小時。LCMS顯示反應完成，將混合物過濾，濃縮，粗品用製備板（SiO2 , DCM: MeOH = 10:1）分離純化，得到標題化合物（黃色色固體，130.00 毫克，產率26.45%）。LCMS (ESI) (5-95AB): m/z: 546.4 [M+1]。Under nitrogen protection, intermediate C (200 mg, 699.96 micromolar) and N4-[2-(dimethylamino)ethyl]-2-isopropoxy-N 4 -methyl-5-nitro -Pd(OAc) 2 (15.71 mg, 70.00 micromole), K 3 PO 4 (10.71 mg, 70.00 micromolar) in 10 mL of 1,4-dioxane solution of benzene-1,4-diamine (207.44 mg, 699.96 micromolar) 297.16 mg, 1.40 mmol) and XPhos (33.37 mg, 70.00 μmol), and heated to 90°C and stirred for 10 hours. LCMS showed that the reaction was completed, the mixture was filtered, concentrated, and the crude product was separated and purified using a preparation plate (SiO 2 , DCM: MeOH = 10:1) to obtain the title compound (yellow colored solid, 130.00 mg, yield 26.45%). LCMS (ESI) (5-95AB): m/z: 546.4 [M+1].

實施例29B。Example 29B.

N4-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-異丙基N1甲基苯-1,2,4-三胺。

Figure 02_image718
N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)-N 1 -(2- (Dimethylamino)ethyl)-5-isopropyl N1 methylbenzene-1,2,4-triamine.
Figure 02_image718

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例29A。得到標題化合物（淺黃色固體，120.00毫克，粗品）。LCMS (ESI) (5-95AB): m/z: 516.2 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 29A. The title compound was obtained (light yellow solid, 120.00 mg, crude). LCMS (ESI) (5-95AB): m/z: 516.2 [M+1].

實施例29C。Example 29C.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲氨基）-4-異丙基苯基）丙烯醯胺。

Figure 02_image714
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl)amino)- 2-((2-(dimethylamino)ethyl)(methylamino)-4-isopropylphenyl)acrylamide.
Figure 02_image714

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例29B。得到標題化合物（FA鹽，20.00毫克，產率13.96%）。1 H NMR (400MHz, CDCl3 ): δ 9.44 (br. s., 1H), 9.37 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 8.07-7.99 (m, 1H), 7.60 (s, 1H), 7.38-7.33 (m, 1H), 7.31-7.27 (m, 2H), 7.19 (d, J = 4.0 Hz, 1H), 6.80 (dd, J = 4.0, 16.0 Hz, 1H), 6.72 (s, 1H), 6.41 (dd, J = 4.0, 16.0 Hz, 1H), 5.74-5.65 (m, 1H), 5.39 (s, 2H), 4.50 （spt, J = 6.0 Hz, 1H), 4.16 (s, 4H), 3.18 (t, J = 6.0 Hz, 2H), 2.95 (t, J = 6.0 Hz, 2H), 2.67-2.64 (m, 9H), 1.39 (d, J = 6.0 Hz, 6H)。 LCMS (ESI) (0-60AB): m/z: 570.3 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 29B. The title compound (FA salt, 20.00 mg, yield 13.96%) was obtained. 1 H NMR (400MHz, CDCl 3 ): δ 9.44 (br. s., 1H), 9.37 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 8.07-7.99 (m, 1H), 7.60 (s, 1H), 7.38-7.33 (m, 1H), 7.31-7.27 (m, 2H), 7.19 (d, J = 4.0 Hz, 1H), 6.80 (dd, J = 4.0, 16.0 Hz, 1H), 6.72 (s, 1H), 6.41 (dd, J = 4.0, 16.0 Hz, 1H), 5.74-5.65 (m, 1H), 5.39 (s, 2H), 4.50 (spt, J = 6.0 Hz, 1H), 4.16 (s, 4H), 3.18 (t, J = 6.0 Hz, 2H), 2.95 (t, J = 6.0 Hz, 2H), 2.67-2.64 (m, 9H), 1.39 (d, J = 6.0 Hz, 6H) . LCMS (ESI) (0-60AB): m/z: 570.3 [M+1].

流程10。

Figure 02_image721
Process 10.
Figure 02_image721

實施例30。Example 30.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image723
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl )Amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image723

實施例30A。Example 30A.

10-（2-氯-5-氟 - 吡啶-4-基）-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image725
10-(2-chloro-5-fluoro-pyridin-4-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image725

在25°C下，將2,4-二氯-5-氟嘧啶（23.14克，138.56毫莫耳）溶於DME（400mL），向該混合物中分批加入AlCl3 （30.79克，230.94毫莫耳），接著分批加入3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚（20.00克，115.47毫莫耳），並攪拌12小時。TLC顯示反應完成。將反應液倒入攪拌下的水（1200mL）中析出固體，固體過濾並用甲醇（100mL）打漿。得到的固體真空乾燥後得標題化合物（黃色固體，31.10克，產率84.61%）。1 H NMR (400MHz, CDCl3 ): δ 8.41 (d, J = 2.80 Hz, 1 H), 7.94 - 7.98 (m, 1 H), 7.30 - 7.41 (m, 3 H), 5.26 (s, 2 H), 4.17 - 4.29 (m, 4 H)。At 25°C, 2,4-dichloro-5-fluoropyrimidine (23.14 g, 138.56 mmol) was dissolved in DME (400 mL), and to this mixture was added AlCl 3 (30.79 g, 230.94 mmol) in portions. Ear), then add 3,4-dihydro-1H-[1,4]oxazido[4,3-a]indole (20.00 g, 115.47 mmol) in portions and stir for 12 hours. TLC showed the reaction was complete. The reaction liquid was poured into stirred water (1200 mL) to precipitate a solid, and the solid was filtered and slurried with methanol (100 mL). The obtained solid was dried under vacuum to obtain the title compound (yellow solid, 31.10 g, yield 84.61%). 1 H NMR (400MHz, CDCl 3 ): δ 8.41 (d, J = 2.80 Hz, 1 H), 7.94-7.98 (m, 1 H), 7.30-7.41 (m, 3 H), 5.26 (s, 2 H ), 4.17-4.29 (m, 4 H).

實施例30B。Example 30B.

4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟-N-（4-氟-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image727
4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoro-N-(4-fluoro-2-methoxy Yl-5-nitrophenyl)pyrimidine-2-amine.
Figure 02_image727

在氮氣保護下將實施例30A（28.00克，92.19毫莫耳）與4-氟-2-甲氧基-5-硝基苯胺（18.02克，96.80毫莫耳）溶入1,4-二氧六環（300mL）中，向該混合液中加入K3 PO4 （39.14克，184.38毫莫耳），XPhos （4.39克，9.22毫莫耳）和Pd2 (dba)3 （8.44克，9.22毫莫耳），並升溫至120°C攪拌10小時。LCMS顯示反應完成，將混合物過濾，濾餅用水（300mL）洗滌並真空乾燥得到標題化合物（黃色色固體，32.06克，產率75.73%）。1 H NMR (400MHz, DMSO-d6 ): δ 8.89 (d, J = 8.40 Hz, 1 H), 8.59 (d, J = 3.20 Hz, 1 H), 8.50 (s, 1 H), 7.78 (dd, J = 7.60, 3.51 Hz, 1 H), 7.55 (d, J = 8.00 Hz, 1 H), 7.37 (d, J = 13.20 Hz, 1 H), 7.25 (d, J = 7.20 Hz, 1 H), 7.20 (d, J = 7.20 Hz, 1 H), 5.11 (s, 2 H), 4.20 (d, J = 8.00 Hz, 4 H), 4.02 (s, 3 H)。 LCMS (ESI) (5-95AB): m/z: 454.3 [M+1]。Example 30A (28.00 g, 92.19 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (18.02 g, 96.80 mmol) were dissolved in 1,4-diox under nitrogen protection To the six rings (300 mL), K 3 PO 4 (39.14 g, 184.38 mmol), XPhos (4.39 g, 9.22 mmol) and Pd 2 (dba) 3 (8.44 g, 9.22 mmol) were added to the mixture. Mohr), and heated to 120 °C and stirred for 10 hours. LCMS showed the reaction was completed, the mixture was filtered, the filter cake was washed with water (300 mL) and dried in vacuo to give the title compound (yellow colored solid, 32.06 g, yield 75.73%). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.89 (d, J = 8.40 Hz, 1 H), 8.59 (d, J = 3.20 Hz, 1 H), 8.50 (s, 1 H), 7.78 (dd , J = 7.60, 3.51 Hz, 1 H), 7.55 (d, J = 8.00 Hz, 1 H), 7.37 (d, J = 13.20 Hz, 1 H), 7.25 (d, J = 7.20 Hz, 1 H) , 7.20 (d, J = 7.20 Hz, 1 H), 5.11 (s, 2 H), 4.20 (d, J = 8.00 Hz, 4 H), 4.02 (s, 3 H). LCMS (ESI) (5-95AB): m/z: 454.3 [M+1].

實施例30C。Example 30C.

N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）-N4-（2-（二甲基氨基）乙基）-2-甲氧基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image729
N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl)-N4- (2-(dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image729

本實施例根據實施例16A的方法製備，將實施例D替換為實施例30B，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（紅色固體，35.50克，產率87.43%）。1 H NMR (400MHz, CDCl3 ): δ 9.06 (s, 1 H), 8.35 (d, J = 2.80 Hz, 1 H), 7.88 - 7.93 (m, 1 H), 7.54 (s, 1 H), 7.38 (s, 1 H), 7.32 (s, 2 H), 6.69 (s, 1 H), 5.29 (s, 2 H), 4.30 (d, J = 5.60 Hz, 2 H), 4.23 (d, J = 5.60 Hz, 2 H), 4.00 (s, 3 H), 3.25 - 3.31 (m, 2 H), 2.89 (s, 3 H), 2.53 - 2.61 (m, 2 H), 2.28 (s, 6 H)。LCMS (ESI) (0-60AB): m/z: 536.4 [M+1]。This example was prepared according to the method of Example 16A, replacing Example D with Example 30B, and replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethylenediamine. The title compound was obtained (red solid, 35.50 g, yield 87.43%). 1 H NMR (400MHz, CDCl 3 ): δ 9.06 (s, 1 H), 8.35 (d, J = 2.80 Hz, 1 H), 7.88-7.93 (m, 1 H), 7.54 (s, 1 H), 7.38 (s, 1 H), 7.32 (s, 2 H), 6.69 (s, 1 H), 5.29 (s, 2 H), 4.30 (d, J = 5.60 Hz, 2 H), 4.23 (d, J = 5.60 Hz, 2 H), 4.00 (s, 3 H), 3.25-3.31 (m, 2 H), 2.89 (s, 3 H), 2.53-2.61 (m, 2 H), 2.28 (s, 6 H ). LCMS (ESI) (0-60AB): m/z: 536.4 [M+1].

實施例30D。Example 30D.

N4-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image731
N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image731

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例30C。得到標題化合物（紅色固體，26.50克，產率79.32%）。1 H NMR (400MHz, CDCl3 ): δ 8.31 (d, J = 2.80 Hz, 1 H), 8.06 - 8.10 (m, 1 H), 8.03 (s, 1 H), 7.62 (s, 1 H), 7.39 (d, J = 4.80 Hz, 1 H), 7.29 - 7.34 (m, 2 H), 6.72 (s, 1 H), 5.20 (s, 2 H), 4.24 (dd, J = 16.40, 5.20 Hz, 4 H), 3.86 (s, 3 H), 2.98 (s, 2 H), 2.69 (s, 3 H), 2.39 - 2.46 (m, 2 H), 2.29 (s, 6 H)。LCMS (ESI) (0-60AB): m/z: 506.1 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 30C. The title compound was obtained (red solid, 26.50 g, yield 79.32%). 1 H NMR (400MHz, CDCl 3 ): δ 8.31 (d, J = 2.80 Hz, 1 H), 8.06-8.10 (m, 1 H), 8.03 (s, 1 H), 7.62 (s, 1 H), 7.39 (d, J = 4.80 Hz, 1 H), 7.29-7.34 (m, 2 H), 6.72 (s, 1 H), 5.20 (s, 2 H), 4.24 (dd, J = 16.40, 5.20 Hz, 4 H), 3.86 (s, 3 H), 2.98 (s, 2 H), 2.69 (s, 3 H), 2.39-2.46 (m, 2 H), 2.29 (s, 6 H). LCMS (ESI) (0-60AB): m/z: 506.1 [M+1].

實施例30E。Example 30E.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image733
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl )Amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image733

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例30D。得到標題化合物（23.20克，產率79.02%）。1 H NMR (400MHz, CDCl3 ): δ 10.09 - 10.17 (m, 1 H), 9.46 (s, 1 H), 8.39 (d, J = 3.20 Hz, 1 H), 7.89 - 7.94 (m, 1 H), 7.55 (s, 1 H), 7.34 - 7.38 (m, 1 H), 7.29 (s, 1 H), 7.24 - 7.28 (m, 1 H), 6.81 (s, 1 H), 6.26 - 6.43 (m, 2 H), 5.65 - 5.71 (m, 1 H), 5.31 (s, 2 H), 4.22 - 4.27 (m, 2 H), 4.20 (d, J = 5.60 Hz, 2 H), 3.90 (s, 3 H), 2.86 - 2.94 (m, 2 H), 2.73 (s, 3 H), 2.23 - 2.33 (m, 8 H)。LCMS (ESI) (0-60AB): m/z: 560.2 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 30D. The title compound (23.20 g, yield 79.02%) was obtained. 1 H NMR (400MHz, CDCl 3 ): δ 10.09-10.17 (m, 1 H), 9.46 (s, 1 H), 8.39 (d, J = 3.20 Hz, 1 H), 7.89-7.94 (m, 1 H ), 7.55 (s, 1 H), 7.34-7.38 (m, 1 H), 7.29 (s, 1 H), 7.24-7.28 (m, 1 H), 6.81 (s, 1 H), 6.26-6.43 ( m, 2 H), 5.65-5.71 (m, 1 H), 5.31 (s, 2 H), 4.22-4.27 (m, 2 H), 4.20 (d, J = 5.60 Hz, 2 H), 3.90 (s , 3 H), 2.86-2.94 (m, 2 H), 2.73 (s, 3 H), 2.23-2.33 (m, 8 H). LCMS (ESI) (0-60AB): m/z: 560.2 [M+1].

實施例31。Example 31.

N-[5 - [[4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基]氨基] -4-甲氧基-2-[甲基[2-（二甲基氨基）乙基]胺基]苯基]丙-2-烯醯胺。

Figure 02_image735
N-[5-[[4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl ]Amino]-4-methoxy-2-[methyl[2-(dimethylamino)ethyl]amino]phenyl]prop-2-enamide
Figure 02_image735

本實施例合成流程同流程9。The synthesis process of this embodiment is the same as process 9.

實施例31A。Example 31A.

N1-[4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基] -2-甲氧基 - N 4 - 甲基-N 4 - [2-（甲基氨基）乙基] -5-硝基苯-1,4-二胺。

Figure 02_image737
N1-[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl] -2- Methoxy-N 4 -methyl-N 4 -[2-(methylamino)ethyl]-5-nitrobenzene-1,4-diamine.
Figure 02_image737

本實施例根據實施例16A的方法製備，將實施例D替換為將4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟-N-（4-氟-2-甲氧基-5-硝基 - 苯基）嘧啶-2-胺，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N1，N2-二甲基乙烷-1,2-二胺。得到標題化合物（黃色固體，1.50克，產率93.08%）。1 H NMR (400MHz, CDCl3 ): δ 9.07 (s, 1 H), 8.35 (d, J = 2.80 Hz, 1 H), 7.90 (m, 1 H), 7.56 (s, 1 H), 7.36 - 7.42 (m, 1 H), 7.29 - 7.35 (m, 2 H), 6.67 (s, 1 H), 5.29 (s, 2 H), 4.18 - 4.35 (m, 5 H), 4.00 (s, 2 H), 3.37 (t, J = 6.00 Hz, 2 H), 2.78 - 2.87 (m, 4 H), 2.46 (s, 3 H)。 LCMS (ESI) (5-95AB): m/z: 522.3 [M+1]。This example was prepared according to the method of Example 16A, and Example D was replaced with 4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10- Group)-5-fluoro-N-(4-fluoro-2-methoxy-5-nitro-phenyl)pyrimidine-2-amine, the N,N-diethyl-N-methylethane- 1,2-diamine was replaced with N1,N2-dimethylethane-1,2-diamine. The title compound was obtained (yellow solid, 1.50 g, yield 93.08%). 1 H NMR (400MHz, CDCl 3 ): δ 9.07 (s, 1 H), 8.35 (d, J = 2.80 Hz, 1 H), 7.90 (m, 1 H), 7.56 (s, 1 H), 7.36- 7.42 (m, 1 H), 7.29-7.35 (m, 2 H), 6.67 (s, 1 H), 5.29 (s, 2 H), 4.18-4.35 (m, 5 H), 4.00 (s, 2 H ), 3.37 (t, J = 6.00 Hz, 2 H), 2.78-2.87 (m, 4 H), 2.46 (s, 3 H). LCMS (ESI) (5-95AB): m/z: 522.3 [M+1].

實施例31B。Example 31B.

第三丁基-N- [2-[4 - [[4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基]氨基] -5-甲氧基-N-甲基-2-硝基苯胺]乙基]-N-甲基氨基甲酸第三丁酯。

Figure 02_image739
Tert-Butyl-N- [2-[4-[[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)- 5-fluoropyridin-2-yl]amino]-5-methoxy-N-methyl-2-nitroaniline]ethyl]-N-methylcarbamic acid tert-butyl ester.
Figure 02_image739

本實施例根據實施例21B的方法製備，將實施例21A替換為實施例31A。得到標題化合物（黃色固體，1.45克，產率80.99%）。1 H NMR (400MHz, CDCl3 ): δ 9.07 (s, 1 H), 8.35 (d, J = 2.80 Hz, 1 H), 7.90 (m, 1 H), 7.56 (s, 1 H), 7.36 - 7.42 (m, 1 H), 7.29 - 7.35 (m, 2 H), 6.67 (s, 1 H), 5.29 (s, 2 H), 4.18 - 4.35 (m, 5 H), 4.00 (s, 2 H), 3.37 (t, J = 6.00 Hz, 2 H), 2.78 - 2.87 (m, 4 H), 2.46 (s, 3 H)。LCMS (ESI) (5-95AB): m/z: 522.3 [M+1]。This example was prepared according to the method of Example 21B, and Example 21A was replaced with Example 31A. The title compound was obtained (yellow solid, 1.45 g, yield 80.99%). 1 H NMR (400MHz, CDCl 3 ): δ 9.07 (s, 1 H), 8.35 (d, J = 2.80 Hz, 1 H), 7.90 (m, 1 H), 7.56 (s, 1 H), 7.36- 7.42 (m, 1 H), 7.29-7.35 (m, 2 H), 6.67 (s, 1 H), 5.29 (s, 2 H), 4.18-4.35 (m, 5 H), 4.00 (s, 2 H ), 3.37 (t, J = 6.00 Hz, 2 H), 2.78-2.87 (m, 4 H), 2.46 (s, 3 H). LCMS (ESI) (5-95AB): m/z: 522.3 [M+1].

實施例31C。Example 31C.

第三丁基-N- [2-[2-氨基-4 - [[4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟- 吡啶-2-基]氨基]-5-甲氧基-N-甲基苯胺基]乙基]-N-甲基氨基甲酸第三丁酯。

Figure 02_image741
Tert-Butyl-N- [2-[2-amino-4-[[4-(3,4-dihydro-1H-[1,4]oxazido[4,3-a]indole-10 -Yl)-5-fluoro-pyridin-2-yl]amino]-5-methoxy-N-methylanilino]ethyl]-N-methylcarbamic acid tert-butyl ester.
Figure 02_image741

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例31B。得到標題化合物（黃色固體，1.30克，產率94.30%）。LCMS (ESI) (5-95AB): m/z: 516.2 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 31B. The title compound was obtained (yellow solid, 1.30 g, yield 94.30%). LCMS (ESI) (5-95AB): m/z: 516.2 [M+1].

實施例31D。Example 31D.

第三丁基-N- [2-[4 - [[4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基]氨基] -5-甲氧基-N-甲基-2-（丙-2-烯醯基氨基） - 苯胺基]乙基]-N-甲基氨基甲酸第三丁酯。

Figure 02_image743
Tert-Butyl-N- [2-[4-[[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)- 5-fluoropyridin-2-yl]amino]-5-methoxy-N-methyl-2-(prop-2-enylamino)-anilino]ethyl]-N-methylcarbamic acid Tributyl ester.
Figure 02_image743

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例31C。得到標題化合物（黃色固體，1.2克，產率84.47%）。1 H NMR (400MHz, CDCl3 ): δ 9.28 - 9.47 (m, 1 H), 8.29 (d, J = 2.80 Hz, 1 H), 7.82 (d, J = 5.20 Hz, 1 H), 7.47 (s, 1 H), 7.27 - 7.30 (m, 1 H), 7.15 - 7.22 (m, 3 H), 6.69 (s, 1 H), 6.30 (d, J = 4.40 Hz, 2 H), 5.60 - 5.67 (m, 1 H), 5.22 (d, J = 2.80 Hz, 2 H), 4.07 - 4.21 (m, 4 H), 3.82 (s, 3 H), 3.24 - 3.34 (m, 2 H), 2.90 (br. s., 2 H), 2.77 (s, 3 H), 2.61 (s, 3 H), 1.39 (s, 8 H)。LCMS (ESI) (5-95AB): m/z: 645.5 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 31C. The title compound (yellow solid, 1.2 g, yield 84.47%) was obtained. 1 H NMR (400MHz, CDCl 3 ): δ 9.28-9.47 (m, 1 H), 8.29 (d, J = 2.80 Hz, 1 H), 7.82 (d, J = 5.20 Hz, 1 H), 7.47 (s , 1 H), 7.27-7.30 (m, 1 H), 7.15-7.22 (m, 3 H), 6.69 (s, 1 H), 6.30 (d, J = 4.40 Hz, 2 H), 5.60-5.67 ( m, 1 H), 5.22 (d, J = 2.80 Hz, 2 H), 4.07-4.21 (m, 4 H), 3.82 (s, 3 H), 3.24-3.34 (m, 2 H), 2.90 (br . s., 2 H), 2.77 (s, 3 H), 2.61 (s, 3 H), 1.39 (s, 8 H). LCMS (ESI) (5-95AB): m/z: 645.5 [M+1].

實施例31E。Example 31E.

N-[5 - [[4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基]氨基] -4-甲氧基-2-[甲基[2-（二甲基氨基）乙基]胺基]苯基]丙-2-烯醯胺。

Figure 02_image745
N-[5-[[4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl ]Amino]-4-methoxy-2-[methyl[2-(dimethylamino)ethyl]amino]phenyl]prop-2-enamide
Figure 02_image745

本實施例根據實施例21E的方法製備，將實施例21D替換為實施例31D。得到標題化合物（體甲酸鹽，235.20毫克，產率20.76%）。1 H NMR (400MHz, CD3 OD): δ 8.51 - 8.55 (m, 1 H), 8.42 (s, 1 H), 8.36 - 8.40 (m, 1 H), 7.84 - 7.92 (m, 1 H), 7.47 (d, J = 7.60 Hz, 1 H), 7.13 - 7.30 (m, 2 H), 6.93 (s, 1 H), 6.37 - 6.53 (m, 2 H), 5.80 - 5.88 (m, 1 H), 5.10 (s, 2 H), 4.21 (s, 4 H), 4.00 (s, 3 H), 3.39 - 3.45 (m, 3 H), 3.15 (br. s., 2 H), 2.71 (s, 3 H), 2.70 (s, 3 H)。LCMS (ESI) (0-60AB): m/z: 546.2 [M+1]。This example was prepared according to the method of Example 21E, and Example 21D was replaced with Example 31D. The title compound (body formate, 235.20 mg, yield 20.76%) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.51-8.55 (m, 1 H), 8.42 (s, 1 H), 8.36-8.40 (m, 1 H), 7.84-7.92 (m, 1 H), 7.47 (d, J = 7.60 Hz, 1 H), 7.13-7.30 (m, 2 H), 6.93 (s, 1 H), 6.37-6.53 (m, 2 H), 5.80-5.88 (m, 1 H) , 5.10 (s, 2 H), 4.21 (s, 4 H), 4.00 (s, 3 H), 3.39-3.45 (m, 3 H), 3.15 (br. s., 2 H), 2.71 (s, 3 H), 2.70 (s, 3 H). LCMS (ESI) (0-60AB): m/z: 546.2 [M+1].

實施例32。Example 32.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）氨基）-2 - （（2-（二甲基氨基）-2-甲基丙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image747
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl )Amino)-2 -((2-(dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image747

實施例32A。Example 32A.

N1-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）-N4-（2-（二甲基氨基）-2-甲基丙基）-2-甲基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image749
N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl)-N4- (2-(dimethylamino)-2-methylpropyl)-2-methyl-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image749

本實施例根據實施例16A的方法製備，將實施例D替換為4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟-N-（4-氟-2-甲氧基-5-硝基苯基）嘧啶-2-胺，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N1,N2,N2,2-四甲基丙烷-1,2-二胺。得到標題化合物（紅色固體，200.00毫克，產率80.44%）。1 H NMR (400MHz, CDCl3 ) : δ 9.02 (s, 1H), 8.28 (d, J=4.0 Hz, 1H), 7.85-7.79 (m, 1H), 7.61 (s, 1H), 7.33 - 7.29 (m, 1H), 7.29 - 7.26 (m, 1H), 7.25 - 7.20 (m, 2H), 5.23 (s, 2H), 5.19 (s, 2H), 4.24 - 4.18 (m, 2H), 4.16 - 4.11 (m, 2H), 4.09 (s, 3H), 2.93 (s, 3H), 2.68 (s, 6H), 1.34 (s, 6H)。This example was prepared according to the method of Example 16A, replacing Example D with 4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl )-5-fluoro-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidine-2-amine, the N,N-diethyl-N-methylethane-1, The 2-diamine was replaced with N1,N2,N2,2-tetramethylpropane-1,2-diamine. The title compound was obtained (red solid, 200.00 mg, yield 80.44%). 1 H NMR (400MHz, CDCl 3 ): δ 9.02 (s, 1H), 8.28 (d, J=4.0 Hz, 1H), 7.85-7.79 (m, 1H), 7.61 (s, 1H), 7.33-7.29 ( m, 1H), 7.29-7.26 (m, 1H), 7.25-7.20 (m, 2H), 5.23 (s, 2H), 5.19 (s, 2H), 4.24-4.18 (m, 2H), 4.16-4.11 ( m, 2H), 4.09 (s, 3H), 2.93 (s, 3H), 2.68 (s, 6H), 1.34 (s, 6H).

實施例32B。Example 32B.

N4-（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）-N 1 - （2-（二甲基氨基）-2-甲基丙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image751
N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl)-N 1 -(2-(dimethylamino)-2-methylpropyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image751

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例32A。得到標題化合物（220.00毫克，產率92.94%）。1 H NMR (400MHz, CDCl3 ): δ 8.23 (d, J=4.0 Hz, 1H), 8.02 - 7.94 (m, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 7.32 - 7.27 (m, 1H), 7.26 - 7.20 (m, 2H), 6.57 - 6.54 (m, 1H), 5.08 (s, 2H), 4.22 - 4.15 (m, 2H), 4.14 - 4.09 (m, 2H), 3.77 (s, 3H), 3.21 (s, 2H), 2.72 (s, 3H), 2.67 (s, 6H), 1.33 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 534.3 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 32A. The title compound was obtained (220.00 mg, yield 92.94%). 1 H NMR (400MHz, CDCl 3 ): δ 8.23 (d, J=4.0 Hz, 1H), 8.02-7.94 (m, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 7.32-7.27 ( m, 1H), 7.26-7.20 (m, 2H), 6.57-6.54 (m, 1H), 5.08 (s, 2H), 4.22-4.15 (m, 2H), 4.14-4.09 (m, 2H), 3.77 ( s, 3H), 3.21 (s, 2H), 2.72 (s, 3H), 2.67 (s, 6H), 1.33 (s, 6H). LCMS (ESI) (5-95AB): m/z: 534.3 [M+1].

實施例32C。Example 32C.

N-（5 - （（4-（3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）氨基）-2 - （（2-（二甲基氨基）-2-甲基丙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image753
N-(5-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl )Amino)-2 -((2-(dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image753

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例32B。得到標題化合物（棕色固體，50.00毫克，產率20.38%）。1 H NMR (400MHz, CD3 OD): δ 8.39 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.15 - 7.09 (m, 1H), 7.09 - 7.03 (m, 1H), 7.01 (s, 1H), 6.43 - 6.33 (m, 2H), 5.82 - 5.72 (m, 1H), 4.92 (s, 2H), 4.06 (s, 4H), 3.89 (s, 3H), 3.66 - 3.27 (m, 2H), 2.67 (s, 3H), 2.63 (s, 6H), 1.22 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 588.3 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 32B. The title compound was obtained (brown solid, 50.00 mg, 20.38% yield). 1 H NMR (400MHz, CD 3 OD): δ 8.39 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.32 (d, J =8.0 Hz, 1H), 7.15-7.09 (m, 1H), 7.09-7.03 (m, 1H), 7.01 (s, 1H), 6.43-6.33 (m, 2H), 5.82-5.72 (m, 1H), 4.92 (s, 2H), 4.06 (s, 4H), 3.89 (s, 3H), 3.66-3.27 (m, 2H), 2.67 (s, 3H), 2.63 (s, 6H), 1.22 (s, 6H) . LCMS (ESI) (5-95AB): m/z: 588.3 [M+1].

實施例33。Example 33.

N- [2- [2-（二甲基氨基）乙基 - 甲基 - 氨基] -5 - [[5-氟-4-（7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]氨基] -4-甲氧基- 苯基] - 丙-2-烯醯胺。

Figure 02_image755
N- [2- [2-(dimethylamino)ethyl-methyl-amino] -5-[[5-fluoro-4-(7-fluoro-3,4-dihydro-1H- [1, 4] Oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl]-prop-2-enamide.
Figure 02_image755

本實施例合成流程同流程10。The synthesis process of this embodiment is the same as the process 10.

實施例33A。Example 33A.

6-氟-1-（對甲苯磺醯基）吲哚。

Figure 02_image757
6-fluoro-1-(p-toluenesulfonyl) indole.
Figure 02_image757

在0°C下，將6-氟-1H-吲哚（18.00克，133.20毫莫耳）溶於N,N – 二甲基甲醯胺（400mL），向該混合物中分批加入NaH（6.39克，60%w，159.84毫莫耳），攪拌1小時。然後向該混合物中緩慢加入4 – 甲基苯磺醯氯（30.47克， 159.84毫莫耳），升溫至15°C攪拌11小時。LCMS顯示反應完成，向混合物中加入飽和NH4 Cl溶液（500mL），將析出的固體過濾，濃縮，得到標題化合物（黃色固體，39.80克，粗品）。1 H NMR (400MHz, CDCl3 ): δ 7.71 - 7.81 (m, 3 H), 7.56 (d, J = 3.60 Hz, 1 H), 7.46 (dd, J = 8.40, 5.20 Hz, 1 H), 7.26 (d, J = 8.00 Hz, 2 H), 7.00 (m, 1 H), 6.64 (d, J = 3.60 Hz, 1 H), 2.37 (s, 3 H) 。At 0°C, 6-fluoro-1H-indole (18.00 g, 133.20 mmol) was dissolved in N,N-dimethylformamide (400 mL), and NaH (6.39) was added to the mixture in portions. Grams, 60%w, 159.84 millimoles), and stirred for 1 hour. Then, 4-methylbenzenesulfonyl chloride (30.47 g, 159.84 mmol) was slowly added to the mixture, and the temperature was raised to 15°C and stirred for 11 hours. LCMS showed that the reaction was completed, and a saturated NH 4 Cl solution (500 mL) was added to the mixture. The precipitated solid was filtered and concentrated to obtain the title compound (yellow solid, 39.80 g, crude product). 1 H NMR (400MHz, CDCl 3 ): δ 7.71-7.81 (m, 3 H), 7.56 (d, J = 3.60 Hz, 1 H), 7.46 (dd, J = 8.40, 5.20 Hz, 1 H), 7.26 (d, J = 8.00 Hz, 2 H), 7.00 (m, 1 H), 6.64 (d, J = 3.60 Hz, 1 H), 2.37 (s, 3 H).

實施例33B。Example 33B.

6-氟-1-（對甲苯磺醯基）吲哚-2-羧酸。

Figure 02_image759
6-fluoro-1-(p-toluenesulfonyl) indole-2-carboxylic acid.
Figure 02_image759

在-70°C下，將6-氟-1-（對甲苯磺醯基）吲哚（39.80克，132.06毫莫耳）溶於四氫呋喃（400mL），向該混合物中滴加正丁基鋰（2.5莫耳，52.82mL），攪拌1小時。然後向該混合物中緩慢加入乾冰（58.11克， 1.32毫莫耳），攪拌1.5小時。TLC顯示反應完成，向混合物中加入飽和NH4 Cl溶液（200mL），用EA（200mL x2）萃取，水相用濃鹽酸調節至pH=1，再用DCM（200mL x3）萃取，濃縮，得到標題化合物（黃色固體，32.75克，產率74.40%）。1 H NMR (400MHz, DMSO-d6 ): δ 7.96 (d, J=8.40 Hz, 1 H), 7.80 (d, J = 10.40 Hz, 1 H), 7.72 (dd, J = 8.80, 6.00 Hz, 1 H), 7.44 (d, J = 8.00 Hz, 2 H), 7.34 (s, 1 H), 7.23 (br. s., 1 H), 2.37 (s, 3 H)。At -70°C, 6-fluoro-1-(p-toluenesulfonyl)indole (39.80 g, 132.06 mmol) was dissolved in tetrahydrofuran (400 mL), and n-butyllithium was added dropwise to the mixture ( 2.5 mol, 52.82mL), stirred for 1 hour. Then dry ice (58.11 g, 1.32 mmol) was slowly added to the mixture, and stirred for 1.5 hours. TLC showed that the reaction was completed. To the mixture was added saturated NH 4 Cl solution (200 mL), extracted with EA (200 mL x 2), the aqueous phase was adjusted to pH=1 with concentrated hydrochloric acid, and then extracted with DCM (200 mL x 3) and concentrated to obtain the title Compound (yellow solid, 32.75 g, yield 74.40%). 1 H NMR (400MHz, DMSO-d 6 ): δ 7.96 (d, J=8.40 Hz, 1 H), 7.80 (d, J = 10.40 Hz, 1 H), 7.72 (dd, J = 8.80, 6.00 Hz, 1 H), 7.44 (d, J = 8.00 Hz, 2 H), 7.34 (s, 1 H), 7.23 (br. s., 1 H), 2.37 (s, 3 H).

實施例33C。Example 33C.

（6-氟-1H-吲哚-2-基）甲醇。

Figure 02_image761
(6-fluoro-1H-indol-2-yl) methanol.
Figure 02_image761

在0°C下，將6-氟-1-（對甲苯磺醯基）吲哚-2-羧酸（32.75克，98.25毫莫耳）溶於四氫呋喃（400mL），向該混合物中分批加入四氫鋁鋰（9.32克，245.63毫莫耳），25°C攪拌16小時。TLC顯示反應完成，向反應混合物中依次加入水（9.5mL）、15%的NaOH（9.5mL）溶液和水（28mL），混合物過濾，濾液濃縮後，得到粗產品，該產品經柱色譜（DCM：MeOH = 20:1，3:1）得到標題化合物（白色固體，5.11克，產率31.49%）。1 H NMR (400MHz, CDCl3 ): δ 8.37 (br. s., 1 H), 7.50 (dd, J = 8.40, 5.20 Hz, 1 H), 7.06 (dd, J = 9.60, 1.60 Hz, 1 H), 6.90 （td, J = 9.20, 2.00 Hz, 1 H), 6.41 (s, 1 H), 4.84 (s, 2 H)。At 0°C, 6-fluoro-1-(p-toluenesulfonyl)indole-2-carboxylic acid (32.75 g, 98.25 mmol) was dissolved in tetrahydrofuran (400 mL) and added to the mixture in portions. Lithium aluminum hydride (9.32g, 245.63 millimoles), stirred at 25°C for 16 hours. TLC showed that the reaction was completed. To the reaction mixture, water (9.5 mL), 15% NaOH (9.5 mL) solution and water (28 mL) were added in sequence. The mixture was filtered. After the filtrate was concentrated, a crude product was obtained, which was subjected to column chromatography (DCM : MeOH = 20:1, 3:1) to obtain the title compound (white solid, 5.11 g, yield 31.49%). 1 H NMR (400MHz, CDCl 3 ): δ 8.37 (br. s., 1 H), 7.50 (dd, J = 8.40, 5.20 Hz, 1 H), 7.06 (dd, J = 9.60, 1.60 Hz, 1 H ), 6.90 (td, J = 9.20, 2.00 Hz, 1 H), 6.41 (s, 1 H), 4.84 (s, 2 H).

實施例33D。Example 33D.

7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image763
7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image763

在0°C下，將（6-氟-1H-吲哚-2-基）甲醇（5.11克，30.94毫莫耳）與氫氧化鉀（4.34克，77.35毫莫耳）溶於二氯甲烷（300mL），向該混合物中滴加苯基乙烯基碸（14.02克，37.13毫莫耳），20°C攪拌12小時。TLC顯示反應完成，用水洗（200mL x2），有機相濃縮，得到粗產品，該產品經柱色譜（PE：EA = 500:1，200:1）分離純化得到標題化合物（白色固體，3.65克，產率61.70%）。1 H NMR (400MHz, CDCl3 ): δ 7.49 (dd, J = 8.40, 5.20 Hz, 1 H), 6.99 (dd, J = 9.20, 2.00 Hz, 1 H), 6.91 （ddd, J = 9.60, 8.40, 2.00 Hz, 1 H), 6.22 (s, 1 H), 4.98 (s, 2 H), 4.16 - 4.24 (m, 2 H), 4.01 - 4.09 (m, 2 H)。At 0°C, (6-fluoro-1H-indol-2-yl)methanol (5.11 g, 30.94 mmol) and potassium hydroxide (4.34 g, 77.35 mmol) were dissolved in dichloromethane ( 300mL), to this mixture was added dropwise phenylvinyl ash (14.02g, 37.13mmol), and stirred at 20°C for 12 hours. TLC showed that the reaction was completed, washed with water (200 mL x 2), and the organic phase was concentrated to obtain a crude product. The product was separated and purified by column chromatography (PE: EA = 500:1, 200:1) to obtain the title compound (white solid, 3.65 g, Yield 61.70%). 1 H NMR (400MHz, CDCl 3 ): δ 7.49 (dd, J = 8.40, 5.20 Hz, 1 H), 6.99 (dd, J = 9.20, 2.00 Hz, 1 H), 6.91 (ddd, J = 9.60, 8.40 , 2.00 Hz, 1 H), 6.22 (s, 1 H), 4.98 (s, 2 H), 4.16-4.24 (m, 2 H), 4.01-4.09 (m, 2 H).

實施例33E。Example 33E.

10-（2-氯-5-氟 - 吡啶-4-基）-7-氟 - 3,4,5a，9a中四氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image765
10-(2-chloro-5-fluoro-pyridin-4-yl)-7-fluoro-3,4,5a,9a tetrahydro-1H-[1,4]oxazino[4,3-a] Indole.
Figure 02_image765

本實施例根據實施例30A的方法製備，將3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚替換為實施例33D。得到標題化合物（黃色固體，3.40克，產率64.79%）。1 H NMR (400MHz, CDCl3 ): δ 8.44 (d, J = 2.80 Hz, 1 H), 7.85 - 7.96 (m, 1 H), 6.98 - 7.13 (m, 2 H), 5.24 (s, 2 H), 4.22 - 4.30 (m, 2 H), 4.10 - 4.20 (m, 2 H)。This example was prepared according to the method of Example 30A, replacing 3,4-dihydro-1H-[1,4]oxazido[4,3-a]indole with Example 33D. The title compound was obtained (yellow solid, 3.40 g, yield 64.79%). 1 H NMR (400MHz, CDCl 3 ): δ 8.44 (d, J = 2.80 Hz, 1 H), 7.85-7.96 (m, 1 H), 6.98-7.13 (m, 2 H), 5.24 (s, 2 H ), 4.22-4.30 (m, 2 H), 4.10-4.20 (m, 2 H).

實施例33F。Example 33F.

5-氟-4-（7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-N-（4-氟-2-甲氧基-5-硝基 - 苯基）嘧啶-2-胺。

Figure 02_image767
5-fluoro-4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-N-(4-fluoro- 2-methoxy-5-nitro-phenyl)pyrimidine-2-amine.
Figure 02_image767

本實施例根據實施例30B的方法製備，將實施例30A替換為實施例33E。得到標題化合物（黃色固體，5.10克，粗品）。1 H NMR (400MHz, CDCl3 ): δ 9.37 (d, J = 8.00 Hz, 1 H), 8.40 (d, J = 2.40 Hz, 1 H), 7.81 - 7.88 (m, 1 H), 7.67 (s, 1 H), 7.44 (m, 1 H), 7.05 - 7.11 (m, 2 H), 6.79 (d, J = 12.00 Hz, 1 H), 5.25 (s, 2 H), 4.27 - 4.33 (m, 2 H), 4.15 - 4.20 (m, 3 H), 4.06 (s, 3 H)。This example was prepared according to the method of Example 30B, and Example 30A was replaced with Example 33E. The title compound (yellow solid, 5.10 g, crude) was obtained. 1 H NMR (400MHz, CDCl 3 ): δ 9.37 (d, J = 8.00 Hz, 1 H), 8.40 (d, J = 2.40 Hz, 1 H), 7.81-7.88 (m, 1 H), 7.67 (s , 1 H), 7.44 (m, 1 H), 7.05-7.11 (m, 2 H), 6.79 (d, J = 12.00 Hz, 1 H), 5.25 (s, 2 H), 4.27-4.33 (m, 2 H), 4.15-4.20 (m, 3 H), 4.06 (s, 3 H).

實施例33G。Example 33G.

N4-[2-（二甲基氨基）乙基]-N 1 - [5-氟-4-（7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-2-甲氧基 - N 4 - 甲基-5-硝基苯-1,4-二胺。

Figure 02_image769
N4-[2-(dimethylamino)ethyl]-N 1 -[5-fluoro-4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4, 3-a] Indol-10-yl)pyrimidin-2-yl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image769

本實施例根據實施例16A的方法製備，將實施例D替換為實施例33F，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（黃色固體，4.20克，粗品）。1 H NMR (400MHz, CDCl3 ): δ 9.01 (s, 1 H), 8.33 (d, J = 2.80 Hz, 1 H), 7.76 - 7.86 (m, 1 H), 7.53 (s, 1 H), 6.97 - 7.08 (m, 2 H), 6.68 (s, 1 H), 5.23 (s, 2 H), 4.24 - 4.30 (m, 2 H), 4.10 - 4.17 (m, 2 H), 3.99 (s, 3 H), 3.26 (t, J = 7.20 Hz, 2 H), 2.88 (s, 3 H), 2.55 (t, J = 7.20 Hz, 2 H), 2.26 (s, 6 H)。LCMS (ESI) (5-95AB): m/z: 554.2 [M+1]。This example was prepared according to the method of Example 16A, replacing Example D with Example 33F, and replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethylenediamine. The title compound (yellow solid, 4.20 g, crude) was obtained. 1 H NMR (400MHz, CDCl 3 ): δ 9.01 (s, 1 H), 8.33 (d, J = 2.80 Hz, 1 H), 7.76-7.86 (m, 1 H), 7.53 (s, 1 H), 6.97-7.08 (m, 2 H), 6.68 (s, 1 H), 5.23 (s, 2 H), 4.24-4.30 (m, 2 H), 4.10-4.17 (m, 2 H), 3.99 (s, 3 H), 3.26 (t, J = 7.20 Hz, 2 H), 2.88 (s, 3 H), 2.55 (t, J = 7.20 Hz, 2 H), 2.26 (s, 6 H). LCMS (ESI) (5-95AB): m/z: 554.2 [M+1].

實施例33H。Example 33H.

N1-[2-（二甲氨基）乙基]-N4-[5-氟-4-（7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image771
N1-[2-(dimethylamino)ethyl]-N4-[5-fluoro-4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3- a] Indol-10-yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image771

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例33G。得到標題化合物（黃色固體，1.23克，產率30.95%）。1 H NMR (400MHz, CDCl3 ): δ. 8.32 (d, J = 2.40 Hz, 1 H), 8.00 (s, 1 H), 7.64 (s, 1 H), 6.99 - 7.13 (m, 2 H), 6.68 (s, 1 H), 5.15 (s, 2 H), 4.26 (d, J = 5.20 Hz, 2 H), 4.15 (d, J = 5.20 Hz, 2 H), 3.87 (s, 3 H), 3.35 (br. s., 2 H), 3.08 (br. s., 2 H), 2.84 (s, 6 H), 2.73 (s, 3 H)。LCMS (ESI) (0-60AB): m/z: 524.1 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 33G. The title compound was obtained (yellow solid, 1.23 g, yield 30.95%). 1 H NMR (400MHz, CDCl 3 ): δ. 8.32 (d, J = 2.40 Hz, 1 H), 8.00 (s, 1 H), 7.64 (s, 1 H), 6.99-7.13 (m, 2 H) , 6.68 (s, 1 H), 5.15 (s, 2 H), 4.26 (d, J = 5.20 Hz, 2 H), 4.15 (d, J = 5.20 Hz, 2 H), 3.87 (s, 3 H) , 3.35 (br. s., 2 H), 3.08 (br. s., 2 H), 2.84 (s, 6 H), 2.73 (s, 3 H). LCMS (ESI) (0-60AB): m/z: 524.1 [M+1].

實施例33I。Example 33I.

N- [2- [2-（二甲基氨基）乙基 - 甲基 - 氨基] -5 - [[5-氟-4-（7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]氨基] -4-甲氧基- 苯基] - 丙-2-烯醯胺。

Figure 02_image755
N- [2- [2-(dimethylamino)ethyl-methyl-amino] -5-[[5-fluoro-4-(7-fluoro-3,4-dihydro-1H- [1, 4] Oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl]-prop-2-enamide.
Figure 02_image755

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例33H。得到標題化合物（281.50克，產率24.41%）。1 H NMR (400MHz, CD3 OD): δ 8.54 (br. s., 1 H), 8.48 (br. s., 1 H), 8.38 (br. s., 1 H), 7.81 - 7.90 (m, 1 H), 7.17 - 7.25 (m, 1 H), 6.97 (s, 2 H), 6.41 - 6.52 (m, 2 H), 5.86 (m, 1 H), 5.07 (br. s., 3 H), 4.17 (d, J = 14.00 Hz, 4 H), 4.00 (s, 3 H), 3.41 (br. s., 3 H), 3.12 (br. s., 2 H), 2.76 (br. s., 6 H), 2.72 (s, 3 H)。LCMS (ESI) (0-60AB): m/z: 578.3 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 33H. The title compound (281.50 g, yield 24.41%) was obtained. 1 H NMR (400MHz, CD 3 OD): δ 8.54 (br. s., 1 H), 8.48 (br. s., 1 H), 8.38 (br. s., 1 H), 7.81-7.90 (m , 1 H), 7.17-7.25 (m, 1 H), 6.97 (s, 2 H), 6.41-6.52 (m, 2 H), 5.86 (m, 1 H), 5.07 (br. s., 3 H ), 4.17 (d, J = 14.00 Hz, 4 H), 4.00 (s, 3 H), 3.41 (br. s., 3 H), 3.12 (br. s., 2 H), 2.76 (br. s ., 6 H), 2.72 (s, 3 H). LCMS (ESI) (0-60AB): m/z: 578.3 [M+1].

實施例34。Example 34.

N-（5 - （（4-（7-氯-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image774
N-(5-((4-(7-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridine -2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image774

本實施例合成流程同流程10。The synthesis process of this embodiment is the same as the process 10.

實施例34A。Example 34A.

（6-氯-1H-吲哚-2-基）甲醇。

Figure 02_image776
(6-chloro-1H-indol-2-yl) methanol.
Figure 02_image776

本實施例根據實施例33C的方法製備，將6-氟-1-（對甲苯磺醯基）吲哚-2-羧酸替換為6-氯-1-甲苯磺醯基-1H-吲哚-2-羧酸。得到標題化合物（棕色固體，3.50克，產率79.30%）。1 H NMR (400MHz, CDCl3 ): δ 7.50 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.09 (dd, J=4.0, 8.0 Hz, 1H), 6.40 (s, 1H), 4.85 (s, 2H)。This example was prepared according to the method of Example 33C, replacing 6-fluoro-1-(p-toluenesulfonyl)indole-2-carboxylic acid with 6-chloro-1-tosyl-1H-indole- 2-carboxylic acid. The title compound was obtained (brown solid, 3.50 g, yield 79.30%). 1 H NMR (400MHz, CDCl 3 ): δ 7.50 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.09 (dd, J=4.0, 8.0 Hz, 1H), 6.40 (s, 1H) , 4.85 (s, 2H).

實施例34B。Example 34B.

7-氯-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image778
7-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image778

本實施例根據實施例33D的方法製備，將33C替換為34A。得到標題化合物（棕色固體，1.30克，產率29.17%）。1H NMR (400MHz, CDCl3): δ 7.49 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.11 (dd, J=0.8, 8.0 Hz, 1H), 6.22 (d, J=4.0 Hz, 1H), 4.99 (s, 2H), 4.26 - 4.14 (m, 2H), 4.10 - 4.04 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 210.0 [M+2]。This example was prepared according to the method of Example 33D, replacing 33C with 34A. The title compound was obtained (brown solid, 1.30 g, yield 29.17%). 1H NMR (400MHz, CDCl3): δ 7.49 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.11 (dd, J=0.8, 8.0 Hz, 1H), 6.22 (d, J=4.0 Hz , 1H), 4.99 (s, 2H), 4.26-4.14 (m, 2H), 4.10-4.04 (m, 2H). LCMS (ESI) (5-95AB): m/z: 210.0 [M+2].

實施例34C。Example 34C.

7-氯-10-（2-氯-5-氟吡啶-4-基）-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image780
7-chloro-10-(2-chloro-5-fluoropyridin-4-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image780

本實施例根據實施例30A的方法製備，將3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚替換為34B。得到標題化合物（黃色固體，480.00毫克，產率26.01%）。1 H NMR (400MHz, CDCl3 ): δ 8.44 (d, J=4.0 Hz, 1H), 7.88 (dd, J=4.0, 8.0 Hz, 1H), 7.39 (s, 1H), 7.31 - 7.29 (m, 1H), 5.25 (s, 2H), 4.31 - 4.14 (m, 4H)。LCMS (ESI) (5-95AB): m/z: 338.1 [M+1]。This example was prepared according to the method of Example 30A, replacing 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole with 34B. The title compound was obtained (yellow solid, 480.00 mg, yield 26.01%). 1 H NMR (400MHz, CDCl 3 ): δ 8.44 (d, J=4.0 Hz, 1H), 7.88 (dd, J=4.0, 8.0 Hz, 1H), 7.39 (s, 1H), 7.31-7.29 (m, 1H), 5.25 (s, 2H), 4.31-4.14 (m, 4H). LCMS (ESI) (5-95AB): m/z: 338.1 [M+1].

實施例34D。Example 34D.

4-（7-氯-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟-N-（4-氟-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image782
4-(7-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoro-N-(4-fluoro- 2-methoxy-5-nitrophenyl)pyrimidine-2-amine.
Figure 02_image782

本實施例根據實施例30B的方法製備，將30A替換為34C。得到標題化合物（黃色固體，450.00毫克，產率66.11%）。1 H NMR (400MHz, CDCl3 ): δ 9.25 (d, J=8.0 Hz, 1H), 8.30 (d, J=4.0 Hz, 1H), 7.71 (dd, J=4.0, 8.0 Hz, 1H), 7.57 (s, 1H), 7.30 (d, J=4.0 Hz, 1H), 7.17 (dd, J=4.0, 8.0 Hz, 1H), 6.69 (d, J=12.0 Hz, 1H), 5.16 (s, 2H), 4.23 - 4.17 (m, 2H), 4.11 - 4.07 (m, 2H), 3.96 (s, 3H)。LCMS (ESI) (5-95AB): m/z: 488.0 [M+1]。This example was prepared according to the method of Example 30B, replacing 30A with 34C. The title compound was obtained (yellow solid, 450.00 mg, yield 66.11%). 1 H NMR (400MHz, CDCl 3 ): δ 9.25 (d, J=8.0 Hz, 1H), 8.30 (d, J=4.0 Hz, 1H), 7.71 (dd, J=4.0, 8.0 Hz, 1H), 7.57 (s, 1H), 7.30 (d, J=4.0 Hz, 1H), 7.17 (dd, J=4.0, 8.0 Hz, 1H), 6.69 (d, J=12.0 Hz, 1H), 5.16 (s, 2H) , 4.23-4.17 (m, 2H), 4.11-4.07 (m, 2H), 3.96 (s, 3H). LCMS (ESI) (5-95AB): m/z: 488.0 [M+1].

實施例34E。Example 34E.

N1-（4-（7-氯-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）-N4-（2-（二甲基氨基）乙基）-2-甲氧基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image784
N1-(4-(7-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl )-N4-(2-(dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image784

本實施例根據實施例16A的方法製備，將實施例D替換為實施例34D，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（紅色固體，300.00毫克，產率85.58%）。1 H NMR (400MHz, CDCl3 ): δ 9.02 (s, 1H), 8.35 (d, J=4.0 Hz, 1H), 7.84 - 7.75 (m, 1H), 7.53 (s, 1H), 7.38 (d, J=4.0 Hz, 1H), 7.25 (dd, J=4.0, 8.0 Hz, 1H), 6.69 (s, 1H), 5.26 (s, 2H), 4.33 - 4.24 (m, 2H), 4.20-4.14 (m, 2H), 4.00 (s, 3H), 3.28 (t, J=8.0 Hz, 2H), 2.90 (s, 3H), 2.57 (t, J=8.0 Hz, 2H), 2.28 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 570.1 [M+1]。This example was prepared according to the method of Example 16A, replacing Example D with Example 34D, and replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethylenediamine. The title compound was obtained (red solid, 300.00 mg, yield 85.58%). 1 H NMR (400MHz, CDCl 3 ): δ 9.02 (s, 1H), 8.35 (d, J=4.0 Hz, 1H), 7.84-7.75 (m, 1H), 7.53 (s, 1H), 7.38 (d, J=4.0 Hz, 1H), 7.25 (dd, J=4.0, 8.0 Hz, 1H), 6.69 (s, 1H), 5.26 (s, 2H), 4.33-4.24 (m, 2H), 4.20-4.14 (m , 2H), 4.00 (s, 3H), 3.28 (t, J=8.0 Hz, 2H), 2.90 (s, 3H), 2.57 (t, J=8.0 Hz, 2H), 2.28 (s, 6H). LCMS (ESI) (5-95AB): m/z: 570.1 [M+1].

實施例34F。Example 34F.

N4-（4-（7-氯-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image786
N4-(4-(7-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridin-2-yl )-N 1 -(2-(dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image786

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例34E。得到標題化合物（棕色固體，200.00毫克，產率70.37%）。1 H NMR (400MHz, CDCl3 ): δ 8.22 (d, J=2.8 Hz, 1H), 7.91 - 7.86 (m, 2H), 7.52 (s, 1H), 7.29 (d, J=4.0 Hz, 1H), 7.16 (dd, J=4.0, 8.0 Hz, 1H), 6.63 (s, 1H), 5.08 (s, 2H), 4.19 - 4.15 (m, 2H), 4.10 - 4.06 (m, 2H), 3.77 (s, 3H), 2.88 (t, J=8.0 Hz, 2H), 2.60 (s, 3H), 2.33 (t, J=8.0 Hz, 2H), 2.19 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 540.2 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 34E. The title compound was obtained (brown solid, 200.00 mg, yield 70.37%). 1 H NMR (400MHz, CDCl 3 ): δ 8.22 (d, J=2.8 Hz, 1H), 7.91-7.86 (m, 2H), 7.52 (s, 1H), 7.29 (d, J=4.0 Hz, 1H) , 7.16 (dd, J=4.0, 8.0 Hz, 1H), 6.63 (s, 1H), 5.08 (s, 2H), 4.19-4.15 (m, 2H), 4.10-4.06 (m, 2H), 3.77 (s , 3H), 2.88 (t, J=8.0 Hz, 2H), 2.60 (s, 3H), 2.33 (t, J=8.0 Hz, 2H), 2.19 (s, 6H). LCMS (ESI) (5-95AB): m/z: 540.2 [M+1].

實施例34G。Example 34G.

N-（5 - （（4-（7-氯-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image788
N-(5-((4-(7-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridine -2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image788

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例34F。得到標題化合物（65.50毫克，產率29.27%）。1 H NMR (400MHz, CD3 OD): δ 8.98 (s, 1H), 8.36 (d, J=4.0 Hz, 1H), 7.82 (dd, J=4.0, 8.0 Hz, 1H), 7.50 (d, J=0.8 Hz, 1H), 7.16 (dd, J=0.8, 8.0 Hz, 1H), 6.98 (s, 1H), 6.52 (dd, J=12.0, 20.0 Hz, 1H), 6.28 (dd, J=0.8, 20.0 Hz, 1H), 5.77 (dd, J=0.8, 8.0 Hz, 1H), 5.10 (s, 2H), 4.17 (s, 4H), 3.94 (s, 3H), 3.06 (t, J=4.0 Hz, 2H), 2.71 (s, 3H), 2.44 (t, J=4.0 Hz, 2H), 2.30 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 594.2 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 34F. The title compound was obtained (65.50 mg, yield 29.27%). 1 H NMR (400MHz, CD 3 OD): δ 8.98 (s, 1H), 8.36 (d, J=4.0 Hz, 1H), 7.82 (dd, J=4.0, 8.0 Hz, 1H), 7.50 (d, J =0.8 Hz, 1H), 7.16 (dd, J=0.8, 8.0 Hz, 1H), 6.98 (s, 1H), 6.52 (dd, J=12.0, 20.0 Hz, 1H), 6.28 (dd, J=0.8, 20.0 Hz, 1H), 5.77 (dd, J=0.8, 8.0 Hz, 1H), 5.10 (s, 2H), 4.17 (s, 4H), 3.94 (s, 3H), 3.06 (t, J=4.0 Hz, 2H), 2.71 (s, 3H), 2.44 (t, J=4.0 Hz, 2H), 2.30 (s, 6H). LCMS (ESI) (5-95AB): m/z: 594.2 [M+1].

實施例35。Example 35.

N- [2- [2-（二甲基氨基）乙基 - 甲基氨基]-5 - [[5-氟-4-（6-甲氧基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]氨基] -4-甲氧基苯基]丙-2-烯醯胺。

Figure 02_image325
N- [2- [2-(dimethylamino)ethyl-methylamino]-5-[[5-fluoro-4-(6-methoxy-3,4-dihydro-1H- [1 ,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide.
Figure 02_image325

本實施例合成流程同流程10。The synthesis process of this embodiment is the same as the process 10.

實施例35A 。Example 35A.

（7-甲氧基-1H-吲哚-2-基）甲醇。

Figure 02_image791
(7-methoxy-1H-indol-2-yl) methanol.
Figure 02_image791

在0°C下，將乙基-7-甲氧基-1H-吲哚-2-羧酸乙酯（11.00克，50.17毫莫耳）溶於THF（100mL），向該混合物中分批加入四氫鋁鋰（2.86克，75.26毫莫耳），升溫到25°C攪拌3小時。LCMS顯示反應完成，向反應混合物中加入H2 O（1mL）和NaOH（1mL），然後加入H2O（3mL）,過濾，濃縮濾液得到標題化合物（棕色油狀，10.00克）。1 H NMR (400MHz, CDCl3 ): δ 8.57 (br. s., 1 H), 7.20 (d, J=8.0 Hz, 1 H), 7.03 (t, J=8.0 Hz, 1 H), 6.65 (d, J=8.0 Hz, 1 H), 6.40 (d, J=4.0 Hz, 1 H), 4.84 (d, J=4.0 Hz, 2 H), 3.97 (s, 3 H)。LCMS (ESI) (5-95AB): m/z: 178.1 [M+1]。At 0°C, ethyl-7-methoxy-1H-indole-2-carboxylic acid ethyl ester (11.00 g, 50.17 mmol) was dissolved in THF (100 mL), and the mixture was added in portions. Lithium aluminum hydride (2.86 grams, 75.26 millimoles), warmed to 25°C and stirred for 3 hours. LCMS showed that the reaction was completed. To the reaction mixture were added H 2 O (1 mL) and NaOH (1 mL), then H 2 O (3 mL), filtered, and the filtrate was concentrated to give the title compound (brown oil, 10.00 g). 1 H NMR (400MHz, CDCl 3 ): δ 8.57 (br. s., 1 H), 7.20 (d, J=8.0 Hz, 1 H), 7.03 (t, J=8.0 Hz, 1 H), 6.65 ( d, J=8.0 Hz, 1 H), 6.40 (d, J=4.0 Hz, 1 H), 4.84 (d, J=4.0 Hz, 2 H), 3.97 (s, 3 H). LCMS (ESI) (5-95AB): m/z: 178.1 [M+1].

實施例35B 。Example 35B.

6-甲氧基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image793
6-methoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image793

在0°C下，將（7-甲氧基-1H-吲哚-2-基）甲醇（10.00克， 56.43毫莫耳）和氫氧化鈉（7.92克，141.08毫莫耳）溶於二氯甲烷（300mL），在N2 保護下，向該混合物中緩慢滴加苯基乙烯基碸（24.54克，67.72毫莫耳）的二氯甲烷（200mL）溶液，升溫到25°C攪拌3小時。TLC顯示反應完成，向反應混合物中加入H2 O（700mL）用二氯甲烷（500mLx2）萃取，有機層用飽和食鹽水（1000mL）沖洗，經無水硫酸鈉（10克）乾燥，濃縮後，用柱色譜（PE：EA = 50:1，20:1）分離純化得到標題化合物（棕色固體，5.80克，50.58% yield）。1 H NMR （400 MHz, CDCl3 ): δ 7.18 (d, J=8.0 Hz, 1 H), 7.02 (t, J=8.0 Hz, 1 H), 6.63 (d, J=8.0 Hz, 1 H), 6.20 (s, 1 H), 4.99 (s, 2 H), 4.50-4.57 (m, 2 H), 4.10-4.17 (m, 2 H), 3.94 (s, 3 H)。Dissolve (7-methoxy-1H-indol-2-yl)methanol (10.00 g, 56.43 mmol) and sodium hydroxide (7.92 g, 141.08 mmol) in dichloromethane at 0°C Methane (300 mL), under the protection of N 2 , was slowly added dropwise a solution of phenyl vinyl sulfone (24.54 g, 67.72 mmol) in methylene chloride (200 mL) to the mixture, and the temperature was raised to 25°C and stirred for 3 hours. TLC showed that the reaction was completed. H 2 O (700 mL) was added to the reaction mixture and extracted with dichloromethane (500 mL×2). The organic layer was washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate (10 g), and concentrated. Column chromatography (PE: EA = 50:1, 20:1) separated and purified to obtain the title compound (brown solid, 5.80 g, 50.58% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 7.18 (d, J=8.0 Hz, 1 H), 7.02 (t, J=8.0 Hz, 1 H), 6.63 (d, J=8.0 Hz, 1 H) , 6.20 (s, 1 H), 4.99 (s, 2 H), 4.50-4.57 (m, 2 H), 4.10-4.17 (m, 2 H), 3.94 (s, 3 H).

實施例35C 。Example 35C.

10-（2-氯-5-氟-吡啶-4-基）-6-甲氧基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image795
10-(2-chloro-5-fluoro-pyridin-4-yl)-6-methoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole .
Figure 02_image795

本實施例根據實施例30A的方法製備，將3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚替換為35B。得到標題化合物（棕色固體，5.80克，50.58% yield）。1 H NMR （400 MHz, CDCl3 ): δ 8.41 (d, J=4.0 Hz, 1 H), 7.48 (dd, J=8.0, 4.00 Hz, 1 H) 7.17 (t, J=8.00 Hz, 1 H) 6.73 (d, J=8.00 Hz, 1 H), 5.22 (s, 2 H), 4.65 (t, J=4.00 Hz, 2 H), 4.17 (t, J=4.00 Hz, 2 H), 3.96 (s, 3 H)。LCMS (ESI) (5-95AB): m/z: 334.0 [M+1]。This example was prepared according to the method of Example 30A, replacing 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole with 35B. The title compound was obtained (brown solid, 5.80 g, 50.58% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 8.41 (d, J=4.0 Hz, 1 H), 7.48 (dd, J=8.0, 4.00 Hz, 1 H) 7.17 (t, J=8.00 Hz, 1 H ) 6.73 (d, J=8.00 Hz, 1 H), 5.22 (s, 2 H), 4.65 (t, J=4.00 Hz, 2 H), 4.17 (t, J=4.00 Hz, 2 H), 3.96 ( s, 3 H). LCMS (ESI) (5-95AB): m/z: 334.0 [M+1].

實施例35D。Example 35D.

5-氟-N-（4-氟-2-甲氧基-5-硝基苯基）-4-（6-甲氧基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-胺。

Figure 02_image797
5-fluoro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(6-methoxy-3,4-dihydro-1H-[1,4]oxazine And [4,3-a] indol-10-yl) pyrimidin-2-amine.
Figure 02_image797

本實施例根據實施例30B的方法製備，將30A替換為35C。得到標題化合物（黃色固體，3.2克）。1 H NMR （400 MHz, CDCl3 ): δ 9.37 (d, J=8.00 Hz, 1 H), 8.36 (d, J=2.00 Hz, 1 H), 7.64 (br. s., 1 H), 7.40 - 7.46 (m, 1 H), 7.14 (t, J=8.00 Hz, 1 H), 6.67-6.78 (m, 2 H), 5.21 (s, 2 H), 4.63 (t, J=4.00 Hz, 2 H), 4.20 (t, J=4.00 Hz, 2 H), 4.03 (s, 3 H), 3.96 (s, 3 H)。LCMS (ESI) (5-95AB): m/z: 484.0 [M+1]。This example was prepared according to the method of Example 30B, replacing 30A with 35C. The title compound (yellow solid, 3.2 g) was obtained. 1 H NMR (400 MHz, CDCl 3 ): δ 9.37 (d, J=8.00 Hz, 1 H), 8.36 (d, J=2.00 Hz, 1 H), 7.64 (br. s., 1 H), 7.40 -7.46 (m, 1 H), 7.14 (t, J=8.00 Hz, 1 H), 6.67-6.78 (m, 2 H), 5.21 (s, 2 H), 4.63 (t, J=4.00 Hz, 2 H), 4.20 (t, J=4.00 Hz, 2 H), 4.03 (s, 3 H), 3.96 (s, 3 H). LCMS (ESI) (5-95AB): m/z: 484.0 [M+1].

實施例35E 。Example 35E.

N4-〔2-（二甲基氨基）乙基]-N 1 - [5-氟-4-（6-甲氧基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]- 2-甲氧基-N--4-甲基-5-硝基苯-1,4-二胺基] 。

Figure 02_image799
N4-[2-(dimethylamino)ethyl]-N 1 -[5-fluoro-4-(6-methoxy-3,4-dihydro-1H-[1,4]oxazino[ 4,3-a]indol-10-yl)pyrimidin-2-yl]-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamino].
Figure 02_image799

本實施例根據實施例16A的方法製備，將實施例D替換為實施例35D，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（黃色固體，3.2克）。LCMS (ESI) (5-95AB): m/z: 566.1 [M+1]。This example was prepared according to the method of Example 16A, replacing Example D with Example 35D, and replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethylenediamine. The title compound (yellow solid, 3.2 g) was obtained. LCMS (ESI) (5-95AB): m/z: 566.1 [M+1].

實施例35F 。Example 35F.

N1-[2-（二甲氨基）乙基]-N4-[5-氟-4-（6-甲氧基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image801
N1-[2-(dimethylamino)ethyl]-N4-[5-fluoro-4-(6-methoxy-3,4-dihydro-1H-[1,4]oxazino[4, 3-a] Indol-10-yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image801

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例35E。得到標題化合物（棕色油狀，500毫克）。1 H NMR （400 MHz, CDCl3 ): δ 8.28 (d, J=4.00 Hz, 1 H), 8.03 (s, 1 H), 7.58 - 7.63 (m, 2 H), 7.14 (t, J=8.00 Hz, 1 H), 6.67 – 6.72 (m, 2 H), 5.13 (s, 2 H), 4.62 (t, J=4.00 Hz, 2 H), 4.16 (t, J=8.00 Hz, 2 H), 3.95 (s, 3 H), 3.84 (s, 3 H), 2.95 (t, J=8.00 Hz, 2 H), 2.67 (s, 3 H), 2.39 (t, J=4.00 Hz, 2 H), 2.26 (s, 6 H)。 LCMS (ESI) (5-95AB): m/z: 536.1 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 35E. The title compound was obtained (brown oil, 500 mg). 1 H NMR (400 MHz, CDCl 3 ): δ 8.28 (d, J=4.00 Hz, 1 H), 8.03 (s, 1 H), 7.58-7.63 (m, 2 H), 7.14 (t, J=8.00 Hz, 1 H), 6.67 – 6.72 (m, 2 H), 5.13 (s, 2 H), 4.62 (t, J=4.00 Hz, 2 H), 4.16 (t, J=8.00 Hz, 2 H), 3.95 (s, 3 H), 3.84 (s, 3 H), 2.95 (t, J=8.00 Hz, 2 H), 2.67 (s, 3 H), 2.39 (t, J=4.00 Hz, 2 H), 2.26 (s, 6 H). LCMS (ESI) (5-95AB): m/z: 536.1 [M+1].

實施例35G 。Example 35G.

N- [2- [2-（二甲基氨基）乙基 - 甲基氨基]-5 - [[5-氟-4-（6-甲氧基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]氨基] -4-甲氧基苯基]丙-2-烯醯胺。

Figure 02_image325
N- [2- [2-(dimethylamino)ethyl-methylamino]-5-[[5-fluoro-4-(6-methoxy-3,4-dihydro-1H- [1 ,4]oxazino[4,3-a]indol-10-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide.
Figure 02_image325

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例35F。得到標題化合物（210.00毫克，330.35微莫耳，58.98% yield）。1 H NMR （400 MHz, CD3 OD) : δ 8.46 - 8.57 (m, 2 H), 8.37 (d, J=3.00 Hz, 1 H),7.40 (dd, J=8.00, 3.45 Hz, 1 H) 7.06 (t, J=8.00 Hz, 1 H) 6.96 (s, 1 H) 6.75 (d, J=8.00b Hz, 1 H) 6.39 - 6.54 (m, 2 H) 5.82 - 5.90 (m, 1 H) 5.05 (s, 2 H) 4.58 (t, J=5.00 Hz, 2 H) 4.13 (t, J=5.00 Hz, 2 H) 4.00 (s, 3 H) 3.96 (s, 3 H) 3.39 (d, J=8.00 Hz, 2 H) 3.06 - 3.18 (m, 2 H) 2.70 - 2.77 (m, 9 H)。LCMS (ESI) (5-95AB): m/z: 590.3 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 35F. The title compound (210.00 mg, 330.35 micromolar, 58.98% yield) was obtained. 1 H NMR (400 MHz, CD 3 OD): δ 8.46-8.57 (m, 2 H), 8.37 (d, J=3.00 Hz, 1 H), 7.40 (dd, J=8.00, 3.45 Hz, 1 H) 7.06 (t, J=8.00 Hz, 1 H) 6.96 (s, 1 H) 6.75 (d, J=8.00b Hz, 1 H) 6.39-6.54 (m, 2 H) 5.82-5.90 (m, 1 H) 5.05 (s, 2 H) 4.58 (t, J=5.00 Hz, 2 H) 4.13 (t, J=5.00 Hz, 2 H) 4.00 (s, 3 H) 3.96 (s, 3 H) 3.39 (d, J =8.00 Hz, 2 H) 3.06-3.18 (m, 2 H) 2.70-2.77 (m, 9 H). LCMS (ESI) (5-95AB): m/z: 590.3 [M+1].

實施例36。Example 36.

N-（5 - （（4-（4,4-二甲基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺甲磺酸鹽。

Figure 02_image804
N-(5-((4-(4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazido[4,3-a]indol-10-yl)- 5-fluoropyridin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide mesylate.
Figure 02_image804

本實施例合成流程同流程10。The synthesis process of this embodiment is the same as the process 10.

實施例36A 。Example 36A.

1-（2-乙氧基-2-氧代乙基）-1H-吲哚-2-羧酸乙酯。

Figure 02_image806
1-(2-ethoxy-2-oxoethyl)-1H-indole-2-carboxylic acid ethyl ester.
Figure 02_image806

將吲哚-2-甲酸乙酯（32.00克，169.12毫莫耳），溴乙酸乙酯（70.61克，422.80毫莫耳）和碳酸鉀（70.12克，507.36毫莫耳）混合於乙腈（400mL）中，80°C下攪拌20小時。LCMS顯示反應完成。將反應混合物用乙酸乙酯（500mL）和水（500mL）稀釋後分液。將有機相濃縮後用柱色譜（PE：EA = 20:1）分離純化，得到標題化合物（無色油狀，46.00克，產率98.80%）。1 H NMR (400MHz, CDCl3 ): δ 7.72 (d, J=8.1 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.34 - 7.29 (m, 1H), 7.20 (t, J=7.5 Hz, 1H), 5.34 (s, 2H), 4.38 （q, J=7.2 Hz, 2H), 4.24 （q, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H)。LCMS (ESI) (5-95AB):m/z: 276.2 [M+1]。Mix ethyl indole-2-carboxylate (32.00 g, 169.12 mmol), ethyl bromoacetate (70.61 g, 422.80 mmol) and potassium carbonate (70.12 g, 507.36 mmol) in acetonitrile (400 mL) Medium, stirring at 80°C for 20 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with ethyl acetate (500 mL) and water (500 mL) and separated. The organic phase was concentrated and then separated and purified by column chromatography (PE:EA = 20:1) to obtain the title compound (colorless oil, 46.00 g, yield 98.80%). 1 H NMR (400MHz, CDCl 3 ): δ 7.72 (d, J=8.1 Hz, 1H), 7.43-7.35 (m, 2H), 7.34-7.29 (m, 1H), 7.20 (t, J=7.5 Hz, 1H), 5.34 (s, 2H), 4.38 (q, J=7.2 Hz, 2H), 4.24 (q, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H). LCMS (ESI) (5-95AB): m/z: 276.2 [M+1].

實施例36B。Example 36B.

乙基-1-（1-甲氧基-2-甲基-1-氧代丙-2-基）-1H-吲哚-2-羧酸乙酯。

Figure 02_image808
Ethyl-1-(1-methoxy-2-methyl-1-oxopropan-2-yl)-1H-indole-2-carboxylic acid ethyl ester.
Figure 02_image808

在-70°C下，將二（三甲基矽）氨基鉀（1M，334.18mL）滴入溶有實施例36A（46.00克，167.09毫莫耳）的四氫呋喃（300mL）中。混合液在-70°C下攪拌0.5小時後滴入碘甲烷（47.43克， 334.18毫莫耳）。混合物在5-15 °C繼續攪拌12小時。TLC顯示未反應完。將混合物用水（500mL）和乙酸乙酯（500mL）稀釋後分液。將有機相濃縮後用色譜柱（PE：EA=40:1，20:1）分離純化。得到的產物（48克）用四氫呋喃（200mL）溶解後在-70°C下滴加二（三甲基矽）氨基鉀（1M，497.70mL）。混合物在-70°C下攪拌0.5小時後滴入碘甲烷（70.64克， 497.70毫莫耳）。得到的混合物在0°C下攪拌3小時。LCMS顯示反應完全。將混合物用水（300mL）和乙酸乙酯（300mL）稀釋後分液。有機相濃縮後用色譜柱（PE：EA=30:1）分離純化，得到標題化合物（無色油狀，43.00克，產率85.44%）。1 H NMR (400MHz, CDCl3 ): δ 7.67 (dd, J=7.6, 13.6 Hz, 2H), 7.36 (s, 1H), 7.26 (s, 1H), 7.15 (t, J=7.2 Hz, 1H), 4.34 （q, J=7.2 Hz, 2H), 4.16 （q, J=7.2 Hz, 2H), 2.10 (s, 6H), 1.41 (t, J=7.2 Hz, 3H), 1.18 (t, J=7.2 Hz, 3H)。LCMS (ESI) (5-95AB):m/z: 304.1 [M+1]。At -70°C, potassium bis(trimethylsilyl)amide (1M, 334.18 mL) was dropped into tetrahydrofuran (300 mL) in which Example 36A (46.00 g, 167.09 mmol) was dissolved. The mixture was stirred at -70°C for 0.5 hour and then iodomethane (47.43 g, 334.18 mmol) was added dropwise. The mixture was stirred at 5-15 °C for 12 hours. TLC showed that the reaction was not completed. The mixture was diluted with water (500 mL) and ethyl acetate (500 mL) and separated. After concentrating the organic phase, it was separated and purified using a chromatographic column (PE:EA=40:1, 20:1). The obtained product (48 g) was dissolved in tetrahydrofuran (200 mL) and potassium bis(trimethylsilyl)amide (1M, 497.70 mL) was added dropwise at -70°C. After the mixture was stirred at -70°C for 0.5 hour, methyl iodide (70.64 g, 497.70 mmol) was added dropwise. The resulting mixture was stirred at 0°C for 3 hours. LCMS showed the reaction was complete. The mixture was diluted with water (300 mL) and ethyl acetate (300 mL) and separated. After concentration, the organic phase was separated and purified by chromatography column (PE:EA=30:1) to obtain the title compound (colorless oil, 43.00 g, yield 85.44%). 1 H NMR (400MHz, CDCl 3 ): δ 7.67 (dd, J=7.6, 13.6 Hz, 2H), 7.36 (s, 1H), 7.26 (s, 1H), 7.15 (t, J=7.2 Hz, 1H) , 4.34 (q, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 2.10 (s, 6H), 1.41 (t, J=7.2 Hz, 3H), 1.18 (t, J= 7.2 Hz, 3H). LCMS (ESI) (5-95AB): m/z: 304.1 [M+1].

實施例36C 。Example 36C.

2-（2-（羥基甲基）-1H-吲哚-1-基）-2-甲基丙-1-醇。

Figure 02_image810
2-(2-(hydroxymethyl)-1H-indol-1-yl)-2-methylpropan-1-ol.
Figure 02_image810

在0°C下，將四氫鋁鋰（3.75克，98.91毫莫耳）分批加入溶有實施例36B（10.00克，32.97毫莫耳）的四氫呋喃（100mL）中。混合物在40°C下攪拌1小時。TLC顯示反應完成。在0°C下，往混合物中滴加水（3.75mL）和15%氫氧化鈉水溶液（3.75mL），然後過濾。濾液濃縮得到標題化合物（白色固體，7.40克）。1 H NMR (400MHz, CDCl3 ): δ 7.52 (d, J=7.2 Hz, 2H), 7.13 (t, J = 6.8 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.22 (s, 1H), 4.51 (s, 2H), 3.55 (s, 2H), 3.39 (s, 2H), 1.64 (s, 6H)。At 0°C, lithium aluminum hydride (3.75 g, 98.91 mmol) was added portionwise to tetrahydrofuran (100 mL) in which Example 36B (10.00 g, 32.97 mmol) was dissolved. The mixture was stirred at 40°C for 1 hour. TLC showed the reaction was complete. At 0°C, water (3.75 mL) and 15% aqueous sodium hydroxide solution (3.75 mL) were added dropwise to the mixture, and then filtered. The filtrate was concentrated to give the title compound (white solid, 7.40 g). 1 H NMR (400MHz, CDCl 3 ): δ 7.52 (d, J=7.2 Hz, 2H), 7.13 (t, J = 6.8 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.22 (s , 1H), 4.51 (s, 2H), 3.55 (s, 2H), 3.39 (s, 2H), 1.64 (s, 6H).

實施例36D 。Example 36D.

4,4-二甲基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image812
4,4-Dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image812

在0°C下，將甲烷磺醯氯（3.16克，27.59毫莫耳）滴入溶有實施例36C（5.50克，25.08毫莫耳），,三乙胺（3.81克，37.62毫莫耳）和4-二甲氨基吡啶（（306.40毫克，2.51毫莫耳）的DMF（100mL）中。混合物在15-25°C下攪拌2小時。TLC顯示反應完全。將混合物用DMF（200mL）稀釋後加入鈉氫（2.01克，50.16毫莫耳）。混合物在70°C下攪拌4小時。LCMS監測到標題化合物的MS。向混合物中加入水（2mL）然後濃縮乾。將濃縮殘留物溶於二氯甲烷（100mL）中然後用水（50mL x 2）洗滌。有機相濃縮後用柱色譜（PE：EA = 40:1）分離純化，得到標題化合物（黃色固體，1.20克，產率23.77%）。1 H NMR (400MHz, CDCl3 ): δ 7.56 (t, J=8.6 Hz, 2H), 7.20 - 7.05 (m, 2H), 6.20 (s, 1H), 4.97 (s, 2H), 3.80 (s, 2H), 1.68 (s, 6H)。LCMS (ESI) (5-95AB):m/z: 202.0 [M+1]。At 0°C, methanesulfonyl chloride (3.16 g, 27.59 mmol) was dropped into Example 36C (5.50 g, 25.08 mmol), triethylamine (3.81 g, 37.62 mmol) And 4-dimethylaminopyridine ((306.40 mg, 2.51 mmol) in DMF (100 mL). The mixture was stirred at 15-25°C for 2 hours. TLC showed the reaction was complete. The mixture was diluted with DMF (200 mL) Sodium hydrogen (2.01 g, 50.16 mmol) was added. The mixture was stirred for 4 hours at 70°C. The MS of the title compound was monitored by LCMS. Water (2 mL) was added to the mixture and then concentrated to dryness. The concentrated residue was dissolved in dichloromethane. Chloromethane (100 mL) was then washed with water (50 mL x 2). The organic phase was concentrated and separated and purified by column chromatography (PE: EA = 40:1) to obtain the title compound (yellow solid, 1.20 g, yield 23.77%). 1 H NMR (400MHz, CDCl 3 ): δ 7.56 (t, J=8.6 Hz, 2H), 7.20-7.05 (m, 2H), 6.20 (s, 1H), 4.97 (s, 2H), 3.80 (s, 2H), 1.68 (s, 6H). LCMS (ESI) (5-95AB): m/z: 202.0 [M+1].

實施例36E。Example 36E.

10-（2-氯-5-氟 - 吡啶-4-基）-4,4-二甲基-1,3-二氫 - [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image814
10-(2-chloro-5-fluoro-pyridin-4-yl)-4,4-dimethyl-1,3-dihydro-[1,4]oxazino[4,3-a]indole .
Figure 02_image814

本實施例根據實施例30A的方法製備，將3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚替換為36D。得到標題化合物（黃色固體，1.30克，產率87.66%）。1 H NMR (400MHz, CDCl3 ): δ 8.35 (d, J=2.8 Hz, 1H), 7.87 - 7.77 (m, 1H), 7.61 - 7.51 (m, 1H), 7.25 - 7.13 (m, 2H), 5.10 (s, 2H), 3.78 (s, 2H), 1.67 (s, 6H)。This example was prepared according to the method of Example 30A, replacing 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole with 36D. The title compound was obtained (yellow solid, 1.30 g, yield 87.66%). 1 H NMR (400MHz, CDCl 3 ): δ 8.35 (d, J=2.8 Hz, 1H), 7.87-7.77 (m, 1H), 7.61-7.51 (m, 1H), 7.25-7.13 (m, 2H), 5.10 (s, 2H), 3.78 (s, 2H), 1.67 (s, 6H).

實施例36F。Example 36F.

4-（4,4-二甲基-1,3-二氫 - [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟-N-（4-氟-2-甲氧基-5-硝基 - 苯基）嘧啶-2-胺。

Figure 02_image816
4-(4,4-dimethyl-1,3-dihydro-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoro-N-(4- Fluoro-2-methoxy-5-nitro-phenyl)pyrimidine-2-amine.
Figure 02_image816

本實施例根據實施例30B的方法製備，將實施例30A替換為實施例36E。得到標題化合物（深黃色固體，1.30克，產率68.88%）。1 H NMR (400MHz, CDCl3 ): δ 9.38 (d, J=8.4 Hz, 1H), 8.38 (d, J=2.8 Hz, 1H), 7.89 - 7.81 (m, 1H), 7.70 - 7.59 (m, 2H), 7.32 - 7.19 (m, 1H), 6.76 (d, J=12.0 Hz, 1H), 5.21 (s, 2H), 4.03 (s, 3H), 3.90 (s, 2H), 1.76 (s, 6H)。LCMS (ESI) (5-95AB):m/z: 482.0 [M+1]。This example was prepared according to the method of Example 30B, and Example 30A was replaced with Example 36E. The title compound was obtained (dark yellow solid, 1.30 g, yield 68.88%). 1 H NMR (400MHz, CDCl 3 ): δ 9.38 (d, J=8.4 Hz, 1H), 8.38 (d, J=2.8 Hz, 1H), 7.89-7.81 (m, 1H), 7.70-7.59 (m, 2H), 7.32-7.19 (m, 1H), 6.76 (d, J=12.0 Hz, 1H), 5.21 (s, 2H), 4.03 (s, 3H), 3.90 (s, 2H), 1.76 (s, 6H ). LCMS (ESI) (5-95AB): m/z: 482.0 [M+1].

實施例36G。Example 36G.

N1-（4-（4,4-二甲基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）-N4-（2-（二甲基氨基）乙基）-2-甲氧基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image818
N1-(4-(4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridine -2-yl)-N4-(2-(dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image818

本實施例根據實施例16A的方法製備，將實施例D替換為實施例36F，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（紅色固體，750.00毫克，80.16% yield）。1 H NMR (400MHz, CDCl3 ): δ 9.07 (s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.91 - 7.79 (m, 1H), 7.70 - 7.60 (m, 1H), 7.56 (s, 1H), 7.25 (dd, J=3.2, 5.6 Hz, 1H), 6.68 (s, 1H), 5.21 (s, 2H), 3.98 (s, 3H), 3.90 (s, 2H), 3.27 (t, J=6.8 Hz, 2H), 2.88 (s, 3H), 2.57 (t, J=6.8 Hz, 2H), 2.27 (s, 6H), 1.75 (s, 6H)。This example was prepared according to the method of Example 16A, replacing Example D with Example 36F, and replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethylenediamine. The title compound was obtained (red solid, 750.00 mg, 80.16% yield). 1 H NMR (400MHz, CDCl 3 ): δ 9.07 (s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.91-7.79 (m, 1H), 7.70-7.60 (m, 1H), 7.56 ( s, 1H), 7.25 (dd, J=3.2, 5.6 Hz, 1H), 6.68 (s, 1H), 5.21 (s, 2H), 3.98 (s, 3H), 3.90 (s, 2H), 3.27 (t , J=6.8 Hz, 2H), 2.88 (s, 3H), 2.57 (t, J=6.8 Hz, 2H), 2.27 (s, 6H), 1.75 (s, 6H).

實施例36H。Example 36H.

N4-（4-（4,4-二甲基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image820
N4-(4-(4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridine -2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image820

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例36G。得到標題化合物（深黃色固體，600.00毫克，粗品）。1 H NMR (400MHz, CDCl3 ): δ 8.30 (d, J=2.5 Hz, 1H), 8.04 (s, 2H), 7.67 - 7.58 (m, 2H), 7.25 (dd, J=3.2, 6.4 Hz, 2H), 6.71 (s, 1H), 5.10 (s, 2H), 3.93 - 3.76 (m, 5H), 2.96 (t, J=6.8 Hz, 2H), 2.67 (s, 3H), 2.40 (t, J=6.8 Hz, 2H), 2.26 (s, 6H), 1.75 (s, 6H)。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 36G. The title compound (dark yellow solid, 600.00 mg, crude) was obtained. 1 H NMR (400MHz, CDCl 3 ): δ 8.30 (d, J=2.5 Hz, 1H), 8.04 (s, 2H), 7.67-7.58 (m, 2H), 7.25 (dd, J=3.2, 6.4 Hz, 2H), 6.71 (s, 1H), 5.10 (s, 2H), 3.93-3.76 (m, 5H), 2.96 (t, J=6.8 Hz, 2H), 2.67 (s, 3H), 2.40 (t, J =6.8 Hz, 2H), 2.26 (s, 6H), 1.75 (s, 6H).

實施例36I。Example 36I.

N4-（4-（4,4-二甲基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image822
N4-(4-(4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-5-fluoropyridine -2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image822

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例36H。得到標題化合物（深黃固體，330.00毫克，59.93% yield）。1 H NMR (400MHz, CDCl3 ): δ 9.40 (br. s., 1H), 8.36 (d, J=2.4 Hz, 1H), 7.91 - 7.77 (m, 1H), 7.65 - 7.52 (m, 2H), 7.21 (dd, J=2.8, 6.0 Hz, 2H), 6.69 (s, 1H), 6.36 (d, J=16.4 Hz, 1H), 5.68 (d, J=11.2 Hz, 1H), 5.20 (s, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.17 (br. s., 2H), 2.76 - 2.43 (m, 9H), 1.73 (s, 6H)。LCMS (ESI) (5-95AB):m/z: 588.2 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 36H. The title compound was obtained (dark yellow solid, 330.00 mg, 59.93% yield). 1 H NMR (400MHz, CDCl 3 ): δ 9.40 (br. s., 1H), 8.36 (d, J=2.4 Hz, 1H), 7.91-7.77 (m, 1H), 7.65-7.52 (m, 2H) , 7.21 (dd, J=2.8, 6.0 Hz, 2H), 6.69 (s, 1H), 6.36 (d, J=16.4 Hz, 1H), 5.68 (d, J=11.2 Hz, 1H), 5.20 (s, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.17 (br. s., 2H), 2.76-2.43 (m, 9H), 1.73 (s, 6H). LCMS (ESI) (5-95AB): m/z: 588.2 [M+1].

實施例36J。Example 36J.

N-（5 - （（4-（4,4-二甲基-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-5-氟吡啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺甲磺酸鹽。

Figure 02_image804
N-(5-((4-(4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazido[4,3-a]indol-10-yl)- 5-fluoropyridin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide mesylate.
Figure 02_image804

在70°C下，將實施例36I（330.00毫克，561.52微莫耳）加入到EA（0.66mL）中，向該溶液中滴加溶於EA（0.66mL）的甲烷磺酸（53.97毫克，561.52微莫耳）溶液。加完後維持在該溫度下攪拌1小時。有紅色沉澱析出。混合物過濾，濾餅用EA（3mL*2）洗滌並真空乾燥得到標題化合物（283.00毫克，產率73.22%）。1 H NMR (400MHz, CD3 OD): δ 8.39 (d, J=5.2 Hz, 1H), 7.94 - 7.85 (m, 2H), 7.82 (d, J=8.0 Hz, 1H), 7.38 - 7.21 (m, 2H), 7.10 (s, 1H), 6.70 - 6.58 (m, 1H), 6.51 - 6.38 (m, 1H), 5.87 (d, J=10.8 Hz, 1H), 5.00 (s, 2H), 3.99 (s, 3H), 3.85 (s, 2H), 3.59 (t, J=5.2 Hz, 2H), 3.37 (t, J=5.2 Hz, 2H), 2.93 (s, 6H), 2.83 (s, 3H), 2.73 (s, 4H), 1.74 (s, 6H)。LCMS (ESI) (5-95AB):m/z: 588.3 [M+1]。At 70°C, Example 36I (330.00 mg, 561.52 μmol) was added to EA (0.66 mL), and methanesulfonic acid (53.97 mg, 561.52) dissolved in EA (0.66 mL) was added dropwise to this solution. Micromolar) solution. After the addition was completed, the temperature was maintained and the mixture was stirred for 1 hour. There is red precipitation. The mixture was filtered, and the filter cake was washed with EA (3 mL*2) and dried in vacuo to obtain the title compound (283.00 mg, yield 73.22%). 1 H NMR (400MHz, CD 3 OD): δ 8.39 (d, J=5.2 Hz, 1H), 7.94-7.85 (m, 2H), 7.82 (d, J=8.0 Hz, 1H), 7.38-7.21 (m , 2H), 7.10 (s, 1H), 6.70-6.58 (m, 1H), 6.51-6.38 (m, 1H), 5.87 (d, J=10.8 Hz, 1H), 5.00 (s, 2H), 3.99 ( s, 3H), 3.85 (s, 2H), 3.59 (t, J=5.2 Hz, 2H), 3.37 (t, J=5.2 Hz, 2H), 2.93 (s, 6H), 2.83 (s, 3H), 2.73 (s, 4H), 1.74 (s, 6H). LCMS (ESI) (5-95AB): m/z: 588.3 [M+1].

流程11。

Figure 02_image825
Process 11.
Figure 02_image825

實施例37A。Example 37A.

（5-氟-1H-吲哚-2-基）甲醇。

Figure 02_image827
(5-fluoro-1H-indol-2-yl) methanol.
Figure 02_image827

在0°C下，將5-氟-1H-吲哚-2-羧酸（10.00克，55.82毫莫耳）溶於THF（100mL）中，向此混合物中加入LAH（3.18克，83.79毫莫耳），並在0~25°C攪拌4小時。TLC（PE: EtOAc = 1:1）顯示反應完成，向反應混合物中依次加入水（3mL）,15%NaOH溶液（3mL）和水（9mL），將得到的混合物過濾，濾液濃縮，得到標題化合物（黃色固體，9.00克，產率85.91%）。1 H NMR（300 MHz, CDCl3 ): δ 8.44 (br. S,, 1H), 7.20-7.27 (m, 2H), 6.97-6.92 (m, 1H), 6.38 (s, 1H), 4.83 (s, 3H), 2.09 (br. s., 1H)。At 0°C, 5-fluoro-1H-indole-2-carboxylic acid (10.00 g, 55.82 mmol) was dissolved in THF (100 mL), and to this mixture was added LAH (3.18 g, 83.79 mmol) Ear) and stir for 4 hours at 0~25°C. TLC (PE: EtOAc = 1:1) showed that the reaction was completed. To the reaction mixture were added water (3 mL), 15% NaOH solution (3 mL) and water (9 mL) in sequence. The resulting mixture was filtered and the filtrate was concentrated to obtain the title compound (Yellow solid, 9.00 g, yield 85.91%). 1 H NMR (300 MHz, CDCl 3 ): δ 8.44 (br. S,, 1H), 7.20-7.27 (m, 2H), 6.97-6.92 (m, 1H), 6.38 (s, 1H), 4.83 (s , 3H), 2.09 (br. s., 1H).

實施例37B。Example 37B.

8-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image829
8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image829

本實施例根據實施例C4的方法製備，將2 – 羥甲基 – 吲哚替換為（5-氟-1H-吲哚-2-基）甲醇。得到標題化合物（淺黃色固體，1.30克，產率50.54%）。1 H NMR （400 MHz, CDCl3 ): δ 7.18-7.27 (m, 2H), 6.95-6.93 (m, 1H), 6.21 (s, 1H), 5.00 (s, 2H), 4.17-4.22 (m, 2H), 4.06-4.11 (m, 2H)。This example was prepared according to the method of Example C4, replacing 2-hydroxymethyl-indole with (5-fluoro-1H-indol-2-yl)methanol. The title compound was obtained (light yellow solid, 1.30 g, yield 50.54%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.18-7.27 (m, 2H), 6.95-6.93 (m, 1H), 6.21 (s, 1H), 5.00 (s, 2H), 4.17-4.22 (m, 2H), 4.06-4.11 (m, 2H).

實施例37C。Example 37C.

10-溴-8-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image831
10-Bromo-8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image831

在-70°C下，將實施例37B（5.00克，26.15毫莫耳）溶於THF（100mL）中，向該混合液中加入NBS（5.12克，28.77毫莫耳），並在-70°C攪拌1小時。TLC（PE: EtOAc = 10:1）顯示反應完成，反應液用飽和NaHCO3 溶液（20mL）淬滅，並用EtOAc（30mL*2）萃取，合併有機相用無水硫酸鈉乾燥，抽濾並濃縮，得到的殘留物用柱色譜（SiO2: PE: EtOAc = 200: 1 to 25:1）純化得到標題化合物（白色固體，5.50克，產率77.87%）。1 H NMR （400 MHz, CDCl3 ): δ 7.27-7.17 (m, 1H), 7.02-6.99 (m, 1H), 4.93 (s, 2H), 4.22-4.14 (m, 2H), 4.12-4.03 (m, 2H)。At -70°C, Example 37B (5.00 g, 26.15 mmol) was dissolved in THF (100 mL), NBS (5.12 g, 28.77 mmol) was added to the mixture, and at -70° C was stirred for 1 hour. TLC (PE: EtOAc = 10: 1) showed that the reaction was completed. The reaction solution was quenched with saturated NaHCO 3 solution (20 mL) and extracted with EtOAc (30 mL*2). The combined organic phases were dried over anhydrous sodium sulfate, filtered with suction and concentrated. The obtained residue was purified by column chromatography (SiO2: PE: EtOAc = 200: 1 to 25: 1) to obtain the title compound (white solid, 5.50 g, yield 77.87%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.27-7.17 (m, 1H), 7.02-6.99 (m, 1H), 4.93 (s, 2H), 4.22-4.14 (m, 2H), 4.12-4.03 ( m, 2H).

實施例37D。Example 37D.

8-氟-10-（4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基）-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image833
8-fluoro-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-1H- [1,4] Oxazino[4,3-a]indole.
Figure 02_image833

將實施例37C（5.50克，20.36毫莫耳）和4,4,5,5-四甲基-1,3,2-二氧硼戊烷（5.21克，40.72毫莫耳，5.92mL）溶於甲苯（100mL）中，向該混合物中加入Pd2 （dba）3 （372.93毫克，407.20微莫耳），Et3 N（6.18克，61.08毫莫耳，8.47mL） 和X-PHOS（388.29毫克，814.40微莫耳），並置換N2 後，升溫至110°C攪拌3小時。TLC（PE: DCM = 10 : 1）顯示反應結束，將反應過濾並濃縮，殘留物用柱色譜（SiO2: PE: EtOAc = 200 : 1 to 20 :1）純化得到標題化合物（淺黃色固體，6.50克，產率90.59%）。1 H NMR （400 MHz, CDCl3 ): δ 7.67 (dd, J1 = 2.4Hz, J2 = 10 Hz, 1H), 7.19 (dd, J1 = 4.4Hz, J2 = 8.8 Hz, 1H), 6.97-6.94 (m, 1H), 5.17 (s, 2H), 4.21-4.15 (m, 2H), 4.11-4.05 (m, 2H), 1.36 (s, 12H)。Example 37C (5.50 g, 20.36 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.21 g, 40.72 mmol, 5.92 mL) were dissolved In toluene (100 mL), Pd 2 (dba) 3 (372.93 mg, 407.20 μmol), Et 3 N (6.18 g, 61.08 mmol, 8.47 mL) and X-PHOS (388.29 mg) were added to the mixture , 814.40 micromolar), and after replacing N 2 , the temperature was raised to 110°C and stirred for 3 hours. TLC (PE: DCM = 10: 1) showed the end of the reaction, the reaction was filtered and concentrated, and the residue was purified by column chromatography (SiO2: PE: EtOAc = 200: 1 to 20: 1) to give the title compound (light yellow solid, 6.50 Grams, yield 90.59%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.67 (dd, J1 = 2.4Hz, J2 = 10 Hz, 1H), 7.19 (dd, J1 = 4.4Hz, J2 = 8.8 Hz, 1H), 6.97-6.94 ( m, 1H), 5.17 (s, 2H), 4.21-4.15 (m, 2H), 4.11-4.05 (m, 2H), 1.36 (s, 12H).

實施例37E。Example 37E.

10-（2-氯嘧啶-4-基）-8-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image835
10-(2-chloropyrimidin-4-yl)-8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image835

將實施例37D（1.50克，4.73毫莫耳）和2,4 – 二氯嘧啶（1.41克，9.46毫莫耳）溶於THF（20mL）和水（3mL）中，向該混合物中加入Na2 CO3 （1.00毫克，9.46毫莫耳）和Pd（dppf）Cl2.CH2Cl2（200.00毫克，244.91微莫耳），在氮氣保護下升溫至50°C攪拌8小時。TLC（PE: EtOAc = 5:1）顯示反應結束，向反應液中加入水（10mL）並濃縮除去THF, 得到的固體抽濾並用PE: EtOAc（10:1）打漿，固體抽濾並濃縮得到標題化合物（白色固體，700.00克，38.98%）。1 H NMR （300 MHz, CDCl3 ): δ 8.53 (d, J = 5.4Hz, 1H), 7.71 (dd, J1 = 2.4Hz, J2 = 9.9Hz, 1H), 7.49 (d, J = 5.4Hz, 1H), 7.34-7.31 (m, 1H), 7.10-7.08 (m, 1H), 5.41 (s, 2H), 4.30-4.14 (m, 4H)。LCMS (ESI) (5-95AB): m/z: 304.0 [M+1]。Example 37D (1.50 g, 4.73 mmol) and 2,4-dichloropyrimidine (1.41 g, 9.46 mmol) were dissolved in THF (20 mL) and water (3 mL), and Na 2 was added to the mixture CO 3 (1.00 mg, 9.46 mmol) and Pd(dppf)Cl2.CH2Cl2 (200.00 mg, 244.91 µmol) were heated to 50°C under nitrogen and stirred for 8 hours. TLC (PE: EtOAc = 5:1) showed the end of the reaction. Water (10 mL) was added to the reaction solution and concentrated to remove THF. The resulting solid was filtered with suction and slurried with PE: EtOAc (10:1). The solid was filtered with suction and concentrated to obtain The title compound (white solid, 700.00 g, 38.98%). 1 H NMR (300 MHz, CDCl 3 ): δ 8.53 (d, J = 5.4Hz, 1H), 7.71 (dd, J1 = 2.4Hz, J2 = 9.9Hz, 1H), 7.49 (d, J = 5.4Hz, 1H), 7.34-7.31 (m, 1H), 7.10-7.08 (m, 1H), 5.41 (s, 2H), 4.30-4.14 (m, 4H). LCMS (ESI) (5-95AB): m/z: 304.0 [M+1].

實施例37F。Example 37F.

4-（8-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-N-（4-氟-2-甲氧基-5-硝基 - 苯基）嘧啶-2-胺。

Figure 02_image837
4-(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-N-(4-fluoro-2-methoxy Yl-5-nitro-phenyl)pyrimidine-2-amine.
Figure 02_image837

本實施例根據實施例D的方法製備，將實施例C替換為實施例37E。得到標題化合物（灰色固體，700.00 毫克，粗品）。1 H NMR (300MHz, CDCl3 ): δ 9.40 (d, J = 8.1Hz, 1H), 8.49 (d, J = 5.7Hz, 1H), 7.72 (d, J = 9.9Hz, 1H), 7.57 (s, 1H), 7.15 (d, J = 5.4Hz, 1H), 7.08-7.06 (m, 1H), 6.79 (d, J = 12.3Hz, 1H), 6.65 (d, J = 12.0Hz, 1H), 5.42 (s, 2H), 4.27-4.25 (m, 2H), 4.21-4.19 (m, 2H), 4.06 (s, 3H)。LCMS (ESI) (5-95AB): m/z: 454.2 [M+1]。This example was prepared according to the method of Example D, and Example C was replaced with Example 37E. The title compound was obtained (gray solid, 700.00 mg, crude). 1 H NMR (300MHz, CDCl 3 ): δ 9.40 (d, J = 8.1Hz, 1H), 8.49 (d, J = 5.7Hz, 1H), 7.72 (d, J = 9.9Hz, 1H), 7.57 (s , 1H), 7.15 (d, J = 5.4Hz, 1H), 7.08-7.06 (m, 1H), 6.79 (d, J = 12.3Hz, 1H), 6.65 (d, J = 12.0Hz, 1H), 5.42 (s, 2H), 4.27-4.25 (m, 2H), 4.21-4.19 (m, 2H), 4.06 (s, 3H). LCMS (ESI) (5-95AB): m/z: 454.2 [M+1].

實施例37G。Example 37G.

N4-〔2-（二甲基氨基）乙基]-N 1 - [4-（8-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-2-甲氧基 - N 4 - 甲基-5-硝基苯-1,4-二胺。

Figure 02_image839
N4-[2-(Dimethylamino)ethyl]-N 1-[4-(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a] Indol-10-yl)pyrimidin-2-yl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image839

本實施例根據實施例16A的方法製備，將實施例D替換為實施例37F，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（棕色固體，140.00毫克，產率88.89%）。1 H NMR (400MHz, CDCl3 ): δ 8.96 (s, 1H), 8.35 (d, J = 5.2Hz, 1H), 7.62 (dd, J1 = 2.4Hz, J2 = 10.0Hz, 1H), 7.36 (s, 1H), 7.22 (dd, J1 = 4.4Hz, J2 = 9.0Hz, 1H), 7.00-6.91 (m, 2H), 6.63 (s, 1H), 6.64-6.60 (m, 1H), 5.33 (s, 2H), 4.21-4.15 (m, 2H), 4.12-4.06 (m, 2H), 3.92 (s, 3H), 3.25-3.18 (m, 2H), 2.82 (s, 3H), 2.54 (t, J = 7.2Hz, 2H), 2.25(s, 6H)。LCMS (ESI) (5-95AB): m/z: 536.4 [M+1]。This example was prepared according to the method of Example 16A, replacing Example D with Example 37F, and replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethylenediamine. The title compound was obtained (brown solid, 140.00 mg, yield 88.89%). 1 H NMR (400MHz, CDCl 3 ): δ 8.96 (s, 1H), 8.35 (d, J = 5.2Hz, 1H), 7.62 (dd, J1 = 2.4Hz, J2 = 10.0Hz, 1H), 7.36 (s , 1H), 7.22 (dd, J1 = 4.4Hz, J2 = 9.0Hz, 1H), 7.00-6.91 (m, 2H), 6.63 (s, 1H), 6.64-6.60 (m, 1H), 5.33 (s, 2H), 4.21-4.15 (m, 2H), 4.12-4.06 (m, 2H), 3.92 (s, 3H), 3.25-3.18 (m, 2H), 2.82 (s, 3H), 2.54 (t, J = 7.2Hz, 2H), 2.25(s, 6H). LCMS (ESI) (5-95AB): m/z: 536.4 [M+1].

實施例37H。Example 37H.

N1-[2-（二甲氨基）乙基]-N4-[4-（8-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image841
N1-[2-(dimethylamino)ethyl]-N4-[4-(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole -10-yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image841

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例37G。得到標題化合物（棕色固體，160.00毫克，粗品）。1 H NMR (400MHz, CDCl3 ): δ 8.41 (d, J = 5.6 Hz, 1H), 7.95 (s, 1H), 7.85-7.82 (m, 1H), 7.80-7.71 (m, 1H), 7.48 (s, 1H), 7.07-7.02 (m, 1H), 6.93 (d, J = 5.6Hz, 1H), 6.73 (s, 1H), 5.38 (s, 2H), 4.27-4.22 (m, 2H), 4.21-4.16 (m, 2H), 3.86 (s, 3H), 3.04-3.00 (m, 2H), 2.70 (s, 3H), 2.49-2.46 (m, 2H), 2.32 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 506.1 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 37G. The title compound (brown solid, 160.00 mg, crude) was obtained. 1 H NMR (400MHz, CDCl 3 ): δ 8.41 (d, J = 5.6 Hz, 1H), 7.95 (s, 1H), 7.85-7.82 (m, 1H), 7.80-7.71 (m, 1H), 7.48 ( s, 1H), 7.07-7.02 (m, 1H), 6.93 (d, J = 5.6Hz, 1H), 6.73 (s, 1H), 5.38 (s, 2H), 4.27-4.22 (m, 2H), 4.21 -4.16 (m, 2H), 3.86 (s, 3H), 3.04-3.00 (m, 2H), 2.70 (s, 3H), 2.49-2.46 (m, 2H), 2.32 (s, 6H). LCMS (ESI) (5-95AB): m/z: 506.1 [M+1].

實施例37I。Example 37I.

N- [2- [2-（二甲基氨基）乙基 - 甲基 - 氨基] -5 - [4-（8-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]氨基] -4-甲氧基 - 苯基] - 丙-2-烯醯胺。

Figure 02_image311
N- [2- [2-(dimethylamino)ethyl-methyl-amino] -5-[4-(8-fluoro-3,4-dihydro-1H-[1,4]oxazinon [4,3-a]Indol-10-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl]-prop-2-enamide.
Figure 02_image311

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例37H。得到標題化合物（甲酸鹽，73.00毫克，產率37.33%）。1 H NMR (400MHz, DMSO-d6 ): δ 10.13 (s, 1H), 8.60 (s, 1H), 8.33 (d, J = 5.2Hz, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 7.85 (dd, J1 = 2.0Hz, J2 = 10.4Hz, 1H), 7.51 (dd, J1 = 4.6Hz, J2 = 8.8Hz, 1H), 7.13-6.97 (m, 3H), 6.44 (dd, J1 = 10.0Hz, J2 = 16.8Hz, 1H), 6.19 (dd, J1 = 2.0Hz, J2 =16.8z, 1H), 5.78-5.67 (m, 1H), 5.07 (s, 2H), 4.18-4.11 (m, 2H), 4.10-4.00 (m, 2H), 3.80 (s, 3H), 2.94 (t, J = 5.2Hz, 2H), 2.70(s, 3H), 2.44 (t, J = 5.6Hz, 2H), 2.29 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 560.1 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 37H. The title compound (formate, 73.00 mg, 37.33% yield) was obtained. 1 H NMR (400MHz, DMSO-d 6 ): δ 10.13 (s, 1H), 8.60 (s, 1H), 8.33 (d, J = 5.2Hz, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 7.85 (dd, J1 = 2.0Hz, J2 = 10.4Hz, 1H), 7.51 (dd, J1 = 4.6Hz, J2 = 8.8Hz, 1H), 7.13-6.97 (m, 3H), 6.44 (dd, J1 = 10.0Hz, J2 = 16.8Hz, 1H), 6.19 (dd, J1 = 2.0Hz, J2 =16.8z, 1H), 5.78-5.67 (m, 1H), 5.07 (s, 2H), 4.18-4.11 ( m, 2H), 4.10-4.00 (m, 2H), 3.80 (s, 3H), 2.94 (t, J = 5.2Hz, 2H), 2.70(s, 3H), 2.44 (t, J = 5.6Hz, 2H ), 2.29 (s, 6H). LCMS (ESI) (5-95AB): m/z: 560.1 [M+1].

實施例38。Example 38.

N- [2- [2-（二甲基氨基）乙基 - 甲基 - 氨基] -5 - [[4-（7-氟-3,4-二氫-1H-[1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]氨基] -4-甲氧基 - 苯基] - 丙-2-烯醯胺。

Figure 02_image313
N- [2- [2-(dimethylamino)ethyl-methyl-amino] -5-[[4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazine [4,3-a]indol-10-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl]-prop-2-enamide.
Figure 02_image313

本實施例合成流程同流程11。The synthesis process of this embodiment is the same as process 11.

實施例38A。Example 38A.

甲基-6-氟-1H-吲哚-2-羧酸乙酯。

Figure 02_image845
Ethyl methyl-6-fluoro-1H-indole-2-carboxylate.
Figure 02_image845

將2-溴-4-氟 - 苯甲醛（20.00克，98.52毫莫耳）和甲基-2-氨基乙酸（18.55克，147.78毫莫耳，鹽酸鹽）溶於NMP（500mL）中，向該混合物中加入Cs2 CO3 （64.20克，197.04毫莫耳）和Cu2 O（1.41克，9.85毫莫耳），在氮氣保護下將反應液升溫至100°C攪拌16小時。TLC（PE: DCM = 10 : 1）顯示反應結束，將反應過濾並濃縮，向殘留物中加入水（1000mL），並用EtOAc（200mL*2）萃取，合併有機相用無水硫酸鈉乾燥，抽濾並濃縮，得到的殘留物用柱色譜（SiO2 , PE: EtOAc = 500: 1 to 20: 1）純化得到標題化合物（黃色固體，5.00克，產率26.27%）。1 H NMR (400MHz, CDCl3 ): δ 9.20 (br. s., 1H), 7.62 (dd, J1 = 5.2Hz, J2 = 8.8Hz, 1H), 7.21 (d, J = 1.2Hz, 1H), 7.10 (dd, J1 = 2.0Hz, J2 = 9.6Hz, 1H), 6.94 （dt, J1 = 2.4Hz, J2 = 9.2Hz, 1H), 3.95 (s, 3H)。Dissolve 2-bromo-4-fluoro-benzaldehyde (20.00 g, 98.52 mmol) and methyl-2-aminoacetic acid (18.55 g, 147.78 mmol, hydrochloride) in NMP (500 mL). Cs 2 CO 3 (64.20 g, 197.04 mmol) and Cu 2 O (1.41 g, 9.85 mmol) were added to the mixture, and the reaction solution was heated to 100°C and stirred for 16 hours under nitrogen protection. TLC (PE: DCM = 10: 1) showed that the reaction was over. The reaction was filtered and concentrated. Water (1000 mL) was added to the residue and extracted with EtOAc (200 mL*2). The combined organic phases were dried over anhydrous sodium sulfate and filtered with suction. After concentration, the obtained residue was purified by column chromatography (SiO 2 , PE: EtOAc = 500: 1 to 20: 1) to obtain the title compound (yellow solid, 5.00 g, yield 26.27%). 1 H NMR (400MHz, CDCl 3 ): δ 9.20 (br. s., 1H), 7.62 (dd, J1 = 5.2Hz, J2 = 8.8Hz, 1H), 7.21 (d, J = 1.2Hz, 1H), 7.10 (dd, J1 = 2.0Hz, J2 = 9.6Hz, 1H), 6.94 (dt, J1 = 2.4Hz, J2 = 9.2Hz, 1H), 3.95 (s, 3H).

實施例38B。Example 38B.

（6-氟-1H-吲哚-2-基）甲醇。

Figure 02_image847
(6-fluoro-1H-indol-2-yl) methanol.
Figure 02_image847

本實施例根據實施例37A的方法製備，將5-氟-1H-吲哚-2-羧酸替換為甲基-6-氟-1H-吲哚-2-羧酸乙酯。得到標題化合物（黃色油狀，4.50克，89.49%）。1 H NMR (400MHz, CDCl3 ): δ 8.54 (br. s., 1H), 7.56-7.44 (m, 1H), 7.07-7.00 (m, 1H), 6.91-6.88 (m, 1H), 6.39 (s, 1H), 4.81 (s, 2H)。This example was prepared according to the method of Example 37A, and 5-fluoro-1H-indole-2-carboxylic acid was replaced with methyl-6-fluoro-1H-indole-2-carboxylic acid ethyl ester. The title compound was obtained (yellow oil, 4.50 g, 89.49%). 1 H NMR (400MHz, CDCl 3 ): δ 8.54 (br. s., 1H), 7.56-7.44 (m, 1H), 7.07-7.00 (m, 1H), 6.91-6.88 (m, 1H), 6.39 ( s, 1H), 4.81 (s, 2H).

實施例38C。Example 38C.

7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image849
7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image849

本實施例根據實施例37B的方法製備，將（5-氟-1H-吲哚-2-基）甲醇替換為（6-氟-1H-吲哚-2-基）甲醇。得到標題化合物（棕色固體，1.20克，31.10%）。1 H NMR （400 MHz, CDCl3 ): δ 7.49 (dd, J1 = 8.8Hz, J2 =5.2Hz, 1H), 6.84-7.03 (m, 2 H), 6.22 (s, 1H), 4.98 (s, 2 H), 4.17-4.22 (m, 2 H), 4.02-4.07 (m, 2 H)。This example was prepared according to the method of Example 37B, replacing (5-fluoro-1H-indol-2-yl)methanol with (6-fluoro-1H-indol-2-yl)methanol. The title compound was obtained (brown solid, 1.20 g, 31.10%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.49 (dd, J1 = 8.8Hz, J2 =5.2Hz, 1H), 6.84-7.03 (m, 2 H), 6.22 (s, 1H), 4.98 (s, 2 H), 4.17-4.22 (m, 2 H), 4.02-4.07 (m, 2 H).

實施例38D。Example 38D.

10-溴-7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image851
10-Bromo-7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image851

本實施例根據實施例37C的方法製備，將37B替換為38C。得到標題化合物（白色固體，2.20克，53.69%）。1 H NMR (400MHz, CDCl3 ): δ 7.42-7.31 (m, 1H), 6.95-6.81 (m, 2H), 4.84-4.73 (m, 2H), 4.11-4.03 (m, 2H), 3.97-3.85 (m, 2H)。This example was prepared according to the method of Example 37C, replacing 37B with 38C. The title compound was obtained (white solid, 2.20 g, 53.69%). 1 H NMR (400MHz, CDCl 3 ): δ 7.42-7.31 (m, 1H), 6.95-6.81 (m, 2H), 4.84-4.73 (m, 2H), 4.11-4.03 (m, 2H), 3.97-3.85 (m, 2H).

實施例38E。Example 38E.

7-氟-10-（4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基）-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image853
7-fluoro-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H- [1,4] Oxazino[4,3-a]indole.
Figure 02_image853

本實施例根據實施例37D的方法製備，將37C替換為38D。得到標題化合物（淺黃色固體，2.50克，96.72%）。1 H NMR (300MHz, CDCl3 ): δ 7.93-7.83 (m, 1H), 6.99-6.89 (m, 2H), 5.15 (s, 2H), 4.20-4.13 (m, 2H), 4.07-4.00 (m, 2H), 1.34 (s, 12H)。This example was prepared according to the method of Example 37D, replacing 37C with 38D. The title compound was obtained (light yellow solid, 2.50 g, 96.72%). 1 H NMR (300MHz, CDCl 3 ): δ 7.93-7.83 (m, 1H), 6.99-6.89 (m, 2H), 5.15 (s, 2H), 4.20-4.13 (m, 2H), 4.07-4.00 (m , 2H), 1.34 (s, 12H).

實施例38F。Example 38F.

10-（2-氯嘧啶-4-基）-7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚。

Figure 02_image855
10-(2-chloropyrimidin-4-yl)-7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.
Figure 02_image855

本實施例根據實施例37E的方法製備，將37D替換為38E。得到標題化合物（淺黃色固體，1.10克，47.45%）。1 H NMR (400MHz, CDCl3 ): δ 8.53 (d, J = 5.4Hz, 1H), 7.98 (dd, J = 5.2Hz, J2 = 9.2Hz, 1H), 7.53 (d, J = 5.2Hz, 1H), 7.14-7.05 (m, 2H), 5.43-5.35 (m, 2H), 4.26-4.21 (m, 2H), 4.18-4.13 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 304.0 [M+1]。This example was prepared according to the method of Example 37E, replacing 37D with 38E. The title compound was obtained (light yellow solid, 1.10 g, 47.45%). 1 H NMR (400MHz, CDCl 3 ): δ 8.53 (d, J = 5.4Hz, 1H), 7.98 (dd, J = 5.2Hz, J2 = 9.2Hz, 1H), 7.53 (d, J = 5.2Hz, 1H ), 7.14-7.05 (m, 2H), 5.43-5.35 (m, 2H), 4.26-4.21 (m, 2H), 4.18-4.13 (m, 2H). LCMS (ESI) (5-95AB): m/z: 304.0 [M+1].

實施例38G。Example 38G.

4-（7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）-N-（4-氟-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image857
4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl)-N-(4-fluoro-2-methoxy Yl-5-nitrophenyl)pyrimidine-2-amine.
Figure 02_image857

本實施例根據實施例D的方法製備，將實施例C替換為實施例38F。得到標題化合物（棕色固體，2.00克，粗品）。1 H NMR (400MHz, CDCl3 ): δ 9.39 (d, J = 8.4Hz, 1H), 8.48 (d, J = 5.2Hz, 1H), 7.97 (dd, J1 = 5.2Hz, J2 = 8.8Hz, 1H), 7.57 (s, 1H), 7.19 (d, J = 5.2Hz, 1H), 7.11-7.03 (m, 2H), 6.79 (d, J = 12.0Hz, 1H), 5.40 (s, 2H), 4.30-4.24 (m, 2H), 4.20-4.11 (m, 2H), 4.06 (s, 3H)。LCMS (ESI) (5-95AB): m/z: 454.0 [M+1]。This example was prepared according to the method of Example D, and Example C was replaced with Example 38F. The title compound was obtained (brown solid, 2.00 g, crude product). 1 H NMR (400MHz, CDCl 3 ): δ 9.39 (d, J = 8.4Hz, 1H), 8.48 (d, J = 5.2Hz, 1H), 7.97 (dd, J1 = 5.2Hz, J2 = 8.8Hz, 1H ), 7.57 (s, 1H), 7.19 (d, J = 5.2Hz, 1H), 7.11-7.03 (m, 2H), 6.79 (d, J = 12.0Hz, 1H), 5.40 (s, 2H), 4.30 -4.24 (m, 2H), 4.20-4.11 (m, 2H), 4.06 (s, 3H). LCMS (ESI) (5-95AB): m/z: 454.0 [M+1].

實施例38H。Example 38H.

N4-〔2-（二甲基氨基）乙基]-N 1 - [4-（7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]-2-甲氧基 - N 4 - 甲基-5-硝基苯-1,4-二胺。

Figure 02_image859
N4-[2-(Dimethylamino)ethyl]-N 1 -[4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a] Indol-10-yl)pyrimidin-2-yl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image859

本實施例根據實施例16A的方法製備，將實施例D替換為實施例38G，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（棕色固體，1.60克，產率71.70%）。1 H NMR (400MHz, CDCl3 ): δ 9.06 (s, 1H), 8.44 (d, J = 5.2Hz, 1H), 8.02-7.92 (m, 1H), 7.66-7.37 (m, 2H), 7.15-7.01 (m, 3H), 6.76 (s, 1H), 5.43 (s, 2H), 4.31-4.23 (m, 2H), 4.19-4.10 (m, 2H), 3.99 (s, 3H), 3.36-3.28 (m, 2H), 2.91 (s, 3H), 2.64-2.61 (m, 2H), 2.32 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 536.2 [M+1]。This example was prepared according to the method of Example 16A, replacing Example D with Example 38G, and replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethylenediamine. The title compound was obtained (brown solid, 1.60 g, yield 71.70%). 1 H NMR (400MHz, CDCl 3 ): δ 9.06 (s, 1H), 8.44 (d, J = 5.2Hz, 1H), 8.02-7.92 (m, 1H), 7.66-7.37 (m, 2H), 7.15- 7.01 (m, 3H), 6.76 (s, 1H), 5.43 (s, 2H), 4.31-4.23 (m, 2H), 4.19-4.10 (m, 2H), 3.99 (s, 3H), 3.36-3.28 ( m, 2H), 2.91 (s, 3H), 2.64-2.61 (m, 2H), 2.32 (s, 6H). LCMS (ESI) (5-95AB): m/z: 536.2 [M+1].

實施例38I。Example 38I.

N1-[2-（二甲氨基）乙基]-N4-[4-（7-氟-3,4-二氫-1H- [1,4]惡嗪並[4,3-[1吲哚-10-基）嘧啶-2-基]-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image861
N1-[2-(dimethylamino)ethyl]-N4-[4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-[1indole -10-yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image861

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例38H。得到標題化合物（棕色固體，1.50克，產率89.30%）。1 H NMR (400MHz, CDCl3 ): δ 8.41 (d, J = 5.2Hz, 1H), 8.09 (dd, J1 = 5.2Hz, J2 = 9.6 Hz, 1H), 7.97 (s, 1H), 7.64-7.57 (m, 1H), 7.49 (s, 1H), 7.09-7.06 (m, 1H), 6.97 (d, J = 5.2Hz, 1H), 6.73 (s, 1H), 5.37 (s, 2H), 4.27-4.20 (m, 2H), 4.17-4.10 (m, 2H), 3.86 (s, 3H), 3.04-2.97 (m, 2H), 2.70 (s, 3H), 2.52-2.43 (m, 3H), 2.32 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 506.2 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 38H. The title compound was obtained (brown solid, 1.50 g, yield 89.30%). 1 H NMR (400MHz, CDCl 3 ): δ 8.41 (d, J = 5.2Hz, 1H), 8.09 (dd, J1 = 5.2Hz, J2 = 9.6 Hz, 1H), 7.97 (s, 1H), 7.64-7.57 (m, 1H), 7.49 (s, 1H), 7.09-7.06 (m, 1H), 6.97 (d, J = 5.2Hz, 1H), 6.73 (s, 1H), 5.37 (s, 2H), 4.27- 4.20 (m, 2H), 4.17-4.10 (m, 2H), 3.86 (s, 3H), 3.04-2.97 (m, 2H), 2.70 (s, 3H), 2.52-2.43 (m, 3H), 2.32 ( s, 6H). LCMS (ESI) (5-95AB): m/z: 506.2 [M+1].

實施例38J。Example 38J.

N- [2- [2-（二甲基氨基）乙基 - 甲基 - 氨基] -5 - [[4-（7-氟-3,4-二氫-1H-[1,4]惡嗪並[4,3-a]吲哚-10-基）嘧啶-2-基]氨基] -4-甲氧基 - 苯基] - 丙-2-烯醯胺。

Figure 02_image313
N- [2- [2-(dimethylamino)ethyl-methyl-amino] -5-[[4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazine [4,3-a]indol-10-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl]-prop-2-enamide.
Figure 02_image313

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例38I。得到標題化合物（甲酸鹽，90.00毫克，產率39.84%）。1 H NMR (400MHz, DMSO-d6 ): δ 10.14 (s, 1H), 8.61 (s, 1H), 8.34 (d, J = 5.2Hz, 1H), 8.26 (s, 1H), 8.16-8.03 (m, 2H), 7.38 (dd, J1 = 2.4Hz, J2 = 9.6Hz, 1H), 7.08-6.94 (m, 3H), 6.44 (dd, J1 = 10.0Hz, J2 =16.8Hz, 1H), 6.19 (dd, J1 = 2.0Hz , J2 = 16.8Hz, 1H), 5.76-5.65 (m, 1H), 5.04 (s, 2H), 4.14-4.00 (m, 4H), 3.80 (s, 3H), 2.94 (t, J = 5.6Hz, 2H), 2.70 (s, 3H), 2.42 (t, J = 5.6Hz, 2H), 2.28 (s, 6H)。 LCMS (ESI) (5-95AB): m/z: 560.3 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 38I. The title compound (formate, 90.00 mg, 39.84% yield) was obtained. 1 H NMR (400MHz, DMSO-d 6 ): δ 10.14 (s, 1H), 8.61 (s, 1H), 8.34 (d, J = 5.2Hz, 1H), 8.26 (s, 1H), 8.16-8.03 ( m, 2H), 7.38 (dd, J1 = 2.4Hz, J2 = 9.6Hz, 1H), 7.08-6.94 (m, 3H), 6.44 (dd, J1 = 10.0Hz, J2 =16.8Hz, 1H), 6.19 ( dd, J1 = 2.0Hz, J2 = 16.8Hz, 1H), 5.76-5.65 (m, 1H), 5.04 (s, 2H), 4.14-4.00 (m, 4H), 3.80 (s, 3H), 2.94 (t , J = 5.6Hz, 2H), 2.70 (s, 3H), 2.42 (t, J = 5.6Hz, 2H), 2.28 (s, 6H). LCMS (ESI) (5-95AB): m/z: 560.3 [M+1].

實施例39。Example 39.

N-[5 - [[4-（8,9-二氫-6H-吡啶並[2,3]吡咯並[4,5-α][1,4]惡嗪-5-基）-5-氟吡啶-2-基]氨基] -2- [2-（二甲基氨基）乙基 - 甲基- 氨基]-4-甲氧苯基]丙-2-烯醯胺。

Figure 02_image327
N-[5-[[4-(8,9-dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazin-5-yl)-5- Fluoropyridin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxyphenyl]prop-2-enamide.
Figure 02_image327

本實施例合成流程同流程11。The synthesis process of this embodiment is the same as process 11.

實施例39A。Example 39A.

1H-吡咯並[2,3-b]吡啶-2-基甲醇。

Figure 02_image865
1H-pyrrolo[2,3-b]pyridin-2-ylmethanol.
Figure 02_image865

在0°C下，將1-（對甲苯磺醯基）吡咯並[2,3-b]吡啶-2-羧酸（26.00克，82.19毫莫耳）溶於四氫呋喃（300mL），向該混合物中分批加入四氫鋁鋰（12.48克，328.76毫莫耳），20°C攪拌32小時。TLC顯示反應完成，向反應混合物中依次加入水（13mL）、15%的NaOH（13mL）溶液和水（39mL），混合物過濾，濾液濃縮後，得到粗產品，該產品經柱色譜分離純化（DCM：MeOH = 1:0，10:1）得到標題化合物（黃色固體，2.90克，產率23.81%)。1 H NMR (400MHz,CD3 OD): δ 8.14 (dd, J = 4.80, 1.20 Hz, 1 H), 7.94 (d, J = 7.60 Hz, 1 H), 7.08 (dd, J = 8.00, 4.80 Hz, 1 H), 6.42 (s, 1 H), 4.77 (s, 3 H)。At 0°C, 1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (26.00 g, 82.19 mmol) was dissolved in tetrahydrofuran (300 mL) to the mixture Lithium aluminum hydride (12.48g, 328.76 millimoles) was added in portions, and stirred at 20°C for 32 hours. TLC showed that the reaction was completed. To the reaction mixture, water (13 mL), 15% NaOH (13 mL) solution and water (39 mL) were added in sequence. The mixture was filtered. After the filtrate was concentrated, a crude product was obtained, which was purified by column chromatography (DCM : MeOH = 1:0, 10:1) to give the title compound (yellow solid, 2.90 g, yield 23.81%). 1 H NMR (400MHz, CD 3 OD): δ 8.14 (dd, J = 4.80, 1.20 Hz, 1 H), 7.94 (d, J = 7.60 Hz, 1 H), 7.08 (dd, J = 8.00, 4.80 Hz , 1 H), 6.42 (s, 1 H), 4.77 (s, 3 H).

實施例39B。Example 39B.

8,9-二氫-6H-吡啶並[3,4]吡咯並[3,5-α][1,4]惡嗪。

Figure 02_image867
8,9-dihydro-6H-pyrido[3,4]pyrrolo[3,5-α][1,4]oxazine.
Figure 02_image867

在0°C下，將1H-吡咯並[2,3-b]吡啶-2-基甲醇（2.50克，16.87毫莫耳）與氫氧化鉀（2.37克，42.18毫莫耳）溶於二氯甲烷（900mL），向該混合物中滴加溶有苯基乙烯基碸（7.34克，20.24毫莫耳）的DCM(100mL)的溶液，20°C攪拌12小時。TLC顯示反應完成，用水洗（100mL x2），有機相濃縮，得到粗產品，該產品經柱色譜（DCM：MeOH = 1:0，10:1）得到標題化合物（白色固體，820.00毫克，產率27.90%)。Dissolve 1H-pyrrolo[2,3-b]pyridin-2-ylmethanol (2.50 g, 16.87 mmol) and potassium hydroxide (2.37 g, 42.18 mmol) in dichloromethane at 0°C Methane (900 mL), to this mixture was added dropwise a solution of phenyl vinyl sulfone (7.34 g, 20.24 mmol) in DCM (100 mL), and stirred at 20°C for 12 hours. TLC showed that the reaction was completed, washed with water (100 mL x 2), and the organic phase was concentrated to obtain a crude product, which was subjected to column chromatography (DCM: MeOH = 1:0, 10:1) to obtain the title compound (white solid, 820.00 mg, yield 27.90%).

實施例39C。Example 39C.

5-溴-8,9-二氫-6H-吡啶並[2,3]吡咯並[4,5-α][1,4]惡嗪。

Figure 02_image869
5-bromo-8,9-dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazine.
Figure 02_image869

本實施例根據實施例37C的方法製備，將實施例37B替換為實施例39B。得到標題化合物（黃色固體，180.00毫克，產率45.99%)。LCMS (ESI) (5-95AB): m/z: 253.00 [M+1]。This example was prepared according to the method of Example 37C, and Example 37B was replaced with Example 39B. The title compound was obtained (yellow solid, 180.00 mg, yield 45.99%). LCMS (ESI) (5-95AB): m/z: 253.00 [M+1].

實施例39D。Example 39D.

5-（4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基）-8,9-二氫-6H-吡啶並[3,4]吡咯並[3,5-α][1,4]惡嗪。

Figure 02_image871
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-8,9-dihydro-6H-pyrido[3,4]pyrrolo [3,5-α][1,4]oxazine.
Figure 02_image871

本實施例根據實施例37D的方法製備，將實施例37C替換為實施例39C。得到標題化合物（黃色固體，170.00毫克，產率73.97%)。LCMS (ESI) (5-95AB): m/z: 300.7 [M+1]。This example was prepared according to the method of Example 37D, and Example 37C was replaced with Example 39C. The title compound was obtained (yellow solid, 170.00 mg, yield 73.97%). LCMS (ESI) (5-95AB): m/z: 300.7 [M+1].

實施例39E。Example 39E.

5-（2-氯-5-氟 - 吡啶-4-基）-8,9-二氫-6H-吡啶並[2,3]吡咯並[4,5-α][1,4]惡嗪。

Figure 02_image873
5-(2-chloro-5-fluoro-pyridin-4-yl)-8,9-dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazine .
Figure 02_image873

本實施例根據實施例37E的方法製備，將實施例37D替換為實施例39D。得到標題化合物（黃色固體，90.00毫克，產率60.29%)。1 H NMR (400MHz, CDCl3 ): δ 8.12 - 8.58 (m, 4 H), 5.35 (br. s., 2 H), 4.09 - 4.59 (m, 4 H)。 LCMS (ESI) (5-95AB): m/z: 305.0 [M+1]。This example was prepared according to the method of Example 37E, and Example 37D was replaced with Example 39D. The title compound was obtained (yellow solid, 90.00 mg, yield 60.29%). 1 H NMR (400MHz, CDCl 3 ): δ 8.12-8.58 (m, 4 H), 5.35 (br. s., 2 H), 4.09-4.59 (m, 4 H). LCMS (ESI) (5-95AB): m/z: 305.0 [M+1].

實施例39F。Example 39F.

4-（8,9-二氫-6H-吡啶並[2,3]吡咯並[4,5-α][1,4]惡嗪-5-基）-5-氟-N-（4-氟-2-甲氧基-5-硝基 - 苯基）嘧啶-2-胺。

Figure 02_image875
4-(8,9-dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazin-5-yl)-5-fluoro-N-(4- Fluoro-2-methoxy-5-nitro-phenyl)pyrimidine-2-amine.
Figure 02_image875

本實施例根據實施例30B的方法製備，將實施例30A替換為實施例39E。得到標題化合物（黃色固體，88.00毫克，產率65.71%)。1 H NMR (400MHz, CDCl3 ): δ. 9.36 (br. s., 1 H), 8.08 - 8.58 (m, 2 H), 7.66 (br. s., 1 H), 7.35 - 7.52 (m, 1 H), 6.68 - 6.88 (m, 1 H), 5.34 (br. s., 2 H), 4.21 - 4.55 (m, 4 H), 4.08 (br. s., 3 H)。 LCMS (ESI) (5-95AB): m/z: 455.0 [M+1]。This example was prepared according to the method of Example 30B, and Example 30A was replaced with Example 39E. The title compound was obtained (yellow solid, 88.00 mg, yield 65.71%). 1 H NMR (400MHz, CDCl 3 ): δ. 9.36 (br. s., 1 H), 8.08-8.58 (m, 2 H), 7.66 (br. s., 1 H), 7.35-7.52 (m, 1 H), 6.68-6.88 (m, 1 H), 5.34 (br. s., 2 H), 4.21-4.55 (m, 4 H), 4.08 (br. s., 3 H). LCMS (ESI) (5-95AB): m/z: 455.0 [M+1].

實施例39G。Example 39G.

N1-[4-（8,9-二氫-6H-吡啶並[2,3]吡咯並[4,5-α][1,4]惡嗪-5-基）-5-氟吡啶-2-基]-N4- [2-（二甲基氨基）乙基]-2-甲氧基 - N 4 - 甲基-5-硝基苯-1,4-二胺。

Figure 02_image877
N1-[4-(8,9-dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazin-5-yl)-5-fluoropyridine-2 -Yl]-N4-[2-(dimethylamino)ethyl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image877

本實施例根據實施例16A的方法製備，將實施例D替換為實施例39F，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（黃色固體，55.00毫克，產率43.19%)。LCMS (ESI) (5-95AB): m/z: 537.2 [M+1]。This example was prepared according to the method of Example 16A, replacing Example D with Example 39F, and replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethylenediamine. The title compound was obtained (yellow solid, 55.00 mg, yield 43.19%). LCMS (ESI) (5-95AB): m/z: 537.2 [M+1].

實施例39H。Example 39H.

N4-[4-（8,9-二氫-6H-吡啶並[2,3]吡咯並[4,5-α][1,4]惡嗪-5-基）-5-氟吡啶-2-基]-N1- [2-（二甲基氨基）乙基]-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image879
N4-[4-(8,9-dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazin-5-yl)-5-fluoropyridine-2 -Yl]-N1-[2-(dimethylamino)ethyl]-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image879

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例39G。得到標題化合物（黃色固體，420.00毫克，產率99.13%)。LCMS (ESI) (5-95AB): m/z: 507.2 [M+1]。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 39G. The title compound (yellow solid, 420.00 mg, yield 99.13%) was obtained. LCMS (ESI) (5-95AB): m/z: 507.2 [M+1].

實施例39I。Example 39I.

N-[5 - [[4-（8,9-二氫-6H-吡啶並[2,3]吡咯並[4,5-α][1,4]惡嗪-5-基）-5-氟吡啶-2-基]氨基] -2- [2-（二甲基氨基）乙基 - 甲基- 氨基]-4-甲氧苯基]丙-2-烯醯胺。

Figure 02_image327
N-[5-[[4-(8,9-dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazin-5-yl)-5- Fluoropyridin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxyphenyl]prop-2-enamide.
Figure 02_image327

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例39H。得到標題化合物（8.60毫克，產率17.44%)。1 H NMR (400MHz, CD3 OD): δ 8.54 (br. s., 1 H), 8.48 (br. s., 1 H), 8.38 (br. s., 1 H), 7.81 - 7.90 (m, 1 H), 7.17 - 7.25 (m, 1 H), 6.97 (s, 2 H), 6.41 - 6.52 (m, 2 H), 5.86 (m, 1 H), 5.07 (br. s., 3 H), 4.17 (d, J = 14.00 Hz, 4 H), 4.00 (s, 3 H), 3.41 (br. s., 3 H), 3.12 (br. s., 2 H), 2.76 (br. s., 6 H), 2.72 (s, 3 H)。LCMS (ESI) (0-60AB): m/z: 578.3 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 39H. The title compound was obtained (8.60 mg, yield 17.44%). 1 H NMR (400MHz, CD 3 OD): δ 8.54 (br. s., 1 H), 8.48 (br. s., 1 H), 8.38 (br. s., 1 H), 7.81-7.90 (m , 1 H), 7.17-7.25 (m, 1 H), 6.97 (s, 2 H), 6.41-6.52 (m, 2 H), 5.86 (m, 1 H), 5.07 (br. s., 3 H ), 4.17 (d, J = 14.00 Hz, 4 H), 4.00 (s, 3 H), 3.41 (br. s., 3 H), 3.12 (br. s., 2 H), 2.76 (br. s ., 6 H), 2.72 (s, 3 H). LCMS (ESI) (0-60AB): m/z: 578.3 [M+1].

流程12。

Figure 02_image882
Process 12.
Figure 02_image882

實施例E1。Example E1.

7-(3-溴丙基)-1氫-吲哚。

Figure 02_image884
7-(3-bromopropyl)-1hydro-indole.
Figure 02_image884

將7-羥基吲哚(2.60克，19.49毫莫耳)溶於THF (10.00mL)中，10°C下加入三苯基膦 (10.22 g, 38.98 毫莫耳)和3-溴丙醇（5.42 g，38.98 毫莫耳），然後緩慢滴加DIAD(7.88 g, 38.98 毫莫耳)，混合物在30°C下攪拌12小時，TLC顯示反應完成。濃縮後，用柱色譜（PE：EA = 20:1，6: 1）分離純化，得到標題化合物（無色油狀物，3.27克，產率66.02%)。1 H NMR (400 MHz, CDCl3 ): δ 8.29 (br. s., 1 H) , 7.18 (d, J=2.13 Hz, 1 H), 7.11 (t, J=2.70 Hz, 1 H) , 6.91 - 6.98 (m, 1 H) , 6.59 (d, J=7.65 Hz, 1 H), 6.47 (dd, J=3.01, 2.26 Hz, 1 H), 4.16 - 4.28 (m, 2 H), 3.52 - 3.63 (m, 2 H) , 2.27 - 2.41 (m, 2 H)。Dissolve 7-hydroxyindole (2.60 g, 19.49 mmol) in THF (10.00 mL), add triphenylphosphine (10.22 g, 38.98 mmol) and 3-bromopropanol (5.42) at 10°C g, 38.98 mmol), then DIAD (7.88 g, 38.98 mmol) was slowly added dropwise, the mixture was stirred at 30°C for 12 hours, and TLC showed the reaction was completed. After concentration, it was separated and purified by column chromatography (PE:EA = 20:1, 6:1) to obtain the title compound (colorless oil, 3.27 g, yield 66.02%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.29 (br. s., 1 H), 7.18 (d, J=2.13 Hz, 1 H), 7.11 (t, J=2.70 Hz, 1 H), 6.91 -6.98 (m, 1 H), 6.59 (d, J=7.65 Hz, 1 H), 6.47 (dd, J=3.01, 2.26 Hz, 1 H), 4.16-4.28 (m, 2 H), 3.52-3.63 (m, 2 H), 2.27-2.41 (m, 2 H).

實施例E2 。Example E2.

4 - 氟 - 2 - 甲氧基 – 5 – 硝基苯胺。

Figure 02_image886
4-Fluoro-2-methoxy-5-nitroaniline.
Figure 02_image886

在0°C下，將實施例E1（2.07克，8.15毫莫耳）溶於DMF（10mL）中，然後分批加入NaH（0.652克，16.30毫莫耳, 60%純度）。混合物在30°C下攪拌2小時。TLC顯示反應完成，向反應混合物中加入H2 O （10mL），混合物加入EA（200mL）萃取，有機相濃縮後，用柱色譜（PE：EA = 30:1，20: 1）分離純化，得到標題化合物（白色固體，1.13克，產率80.05%)。1 H NMR (400 MHz, CDCl3 ): δ 7.27 - 7.33 (m, 1 H) ,7.09 (d, J=3.14 Hz, 1 H), 7.00 - 7.06 (m, 1 H) ,6.81 - 6.87 (m, 1 H), 6.58 (d, J=3.01 Hz, 1 H), 4.31 - 4.38 (m, 2 H) ,4.18 - 4.25 (m, 2 H) ,2.36 - 2.44 (m, 2 H)。At 0°C, Example E1 (2.07 g, 8.15 mmol) was dissolved in DMF (10 mL), and then NaH (0.652 g, 16.30 mmol, 60% purity) was added in portions. The mixture was stirred at 30°C for 2 hours. TLC showed that the reaction was complete. H 2 O (10 mL) was added to the reaction mixture. The mixture was extracted with EA (200 mL). After the organic phase was concentrated, it was separated and purified by column chromatography (PE: EA = 30:1, 20:1) The title compound (white solid, 1.13 g, yield 80.05%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.27-7.33 (m, 1 H), 7.09 (d, J=3.14 Hz, 1 H), 7.00-7.06 (m, 1 H), 6.81-6.87 (m , 1 H), 6.58 (d, J=3.01 Hz, 1 H), 4.31-4.38 (m, 2 H), 4.18-4.25 (m, 2 H), 2.36-2.44 (m, 2 H).

實施例E 。Example E.

7-（2-氯嘧啶-4-基）-3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚。

Figure 02_image888
7-(2-chloropyrimidin-4-yl)-3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indole.
Figure 02_image888

在10°C下，將AlCl3 （3.7 克，27.72毫莫耳）溶於DME（20mL），向該混合物中加入2,4-二氯嘧啶（2.75克，18.48毫莫耳），攪拌0.5小時。再分批緩慢加入實施例E2（1.6克，9.24毫莫耳），升溫至80°C，攪拌2小時。TLC顯示反應完成，向反應混合物中加入DCM（500mL）溶液，有機層用飽和食鹽水（200mL x 2）洗滌後，濃縮，粗品經過柱色譜（PE：EA = 3 :1，DCM）分離純化得到標題化合物（黃色固體，1.3克，產率49.24%)。1 H NMR (400 MHz, CDCl3 ): δ 8.45 - 8.52 (m, 1 H), 7.90 - 8.01 (m, 2 H), 7.52 (d, J=5.40 Hz, 1 H), 7.17 - 7.27 (m, 1 H), 6.94 (d, J=7.78 Hz, 1 H), 4.26 - 4.46 (m, 4 H) ,2.35 - 2.50 (m, 2 H)。At 10°C, AlCl 3 (3.7 g, 27.72 mmol) was dissolved in DME (20 mL), and 2,4-dichloropyrimidine (2.75 g, 18.48 mmol) was added to the mixture, and stirred for 0.5 hour . Then slowly add Example E2 (1.6 g, 9.24 mmol) in portions, warm to 80°C, and stir for 2 hours. TLC showed that the reaction was completed. A DCM (500 mL) solution was added to the reaction mixture. The organic layer was washed with saturated brine (200 mL x 2) and concentrated. The crude product was separated and purified by column chromatography (PE: EA = 3:1, DCM). The title compound (yellow solid, 1.3 g, yield 49.24%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.45-8.52 (m, 1 H), 7.90-8.01 (m, 2 H), 7.52 (d, J=5.40 Hz, 1 H), 7.17-7.27 (m , 1 H), 6.94 (d, J=7.78 Hz, 1 H), 4.26-4.46 (m, 4 H), 2.35-2.50 (m, 2 H).

實施例F。Example F.

4-（3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚-7-基）-N-（4-氟-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image890
4-(3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl)-N-(4-fluoro-2-methoxy-5 -Nitrophenyl)pyrimidine-2-amine.
Figure 02_image890

在室溫下，將實施例E（2.4克，8.40毫莫耳）和4-氟-2-甲氧基-5-硝基-苯胺（1.64克，8.82毫莫耳），對甲苯磺酸 （1.76克，1.1毫莫耳）加入1,4-二氧六環 （90mL）溶液中，升溫至110度，攪拌12小時。LCMS顯示反應完成，向反應混合物中加入氨水（50mL）調節溶液pH =8.混合物冷卻至20度，過濾。固體用甲醇 （50mL）洗滌，乾燥得到標題化合物（黃色固體，3.00克，產率82.02%)。1 H NMR (400 MHz, CDCl3 ): δ 9.10 (d, J=8.41 Hz, 1 H), 8.28 - 8.48 (m, 3 H), 8.07 (d, J=7.78 Hz, 1 H), 7.26 - 7.42 (m, 2 H), 7.01 (t, J=7.84 Hz, 1 H), 6.78 (d, J=7.53 Hz, 1 H) ,4.34 (d, J=4.64 Hz, 4 H) ,4.02 (s, 3 H), 2.34 (br. s., 2 H)。At room temperature, Example E (2.4 g, 8.40 mmol) and 4-fluoro-2-methoxy-5-nitro-aniline (1.64 g, 8.82 mmol), p-toluenesulfonic acid ( 1.76 g, 1.1 mmol) was added to a solution of 1,4-dioxane (90 mL), the temperature was raised to 110 degrees, and the mixture was stirred for 12 hours. LCMS showed that the reaction was completed, and ammonia water (50 mL) was added to the reaction mixture to adjust the solution pH = 8. The mixture was cooled to 20 degrees and filtered. The solid was washed with methanol (50 mL) and dried to give the title compound (yellow solid, 3.00 g, yield 82.02%). 1 H NMR (400 MHz, CDCl 3 ): δ 9.10 (d, J=8.41 Hz, 1 H), 8.28-8.48 (m, 3 H), 8.07 (d, J=7.78 Hz, 1 H), 7.26- 7.42 (m, 2 H), 7.01 (t, J=7.84 Hz, 1 H), 6.78 (d, J=7.53 Hz, 1 H), 4.34 (d, J=4.64 Hz, 4 H), 4.02 (s , 3 H), 2.34 (br. s., 2 H).

實施例40。Example 40.

N-（5 - （（4-（3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚-7-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image892
N-(5-((4-(3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl)pyrimidin-2-yl)amino) -2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image892

實施例40A。Example 40A.

N1-（4-（3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚-7-基）嘧啶-2-基）-N4-（2-（二甲基氨基）乙基）-2-甲氧基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image894
N1-(4-(3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl)pyrimidin-2-yl)-N4-(2- (Dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image894

本實施例根據實施例16A的方法製備，將實施例D替換為實施例F，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（黃色固體，1.00克，產率82.15%)。1 H NMR (400MHz, CDCl3 ): δ 9.62 (s, 1 H) , 8.42 (d, J=5.27 Hz, 1 H) ,8.32 (s, 1 H), 7.80 (d, J=7.91 Hz, 1 H), 7.52 - 7.61 (m, 1 H) ,7.14 - 7.25 (m, 2 H) ,6.91 (d, J=7.65 Hz, 1 H), 6.70 (s, 1 H) ,4.35 - 4.51 (m, 4 H) ,4.01 (s, 3 H) ,3.33 (t, J=7.09 Hz, 2 H), 2.93 (s, 3 H), 2.63 (t, J=7.09 Hz, 2 H) ,2.45 (dt, J =10.29, 5.40 Hz, 2 H) ,2.32 (s, 6 H)。This example was prepared according to the method of Example 16A, replacing Example D with Example F, and replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethylenediamine. The title compound was obtained (yellow solid, 1.00 g, yield 82.15%). 1 H NMR (400MHz, CDCl 3 ): δ 9.62 (s, 1 H), 8.42 (d, J=5.27 Hz, 1 H), 8.32 (s, 1 H), 7.80 (d, J=7.91 Hz, 1 H), 7.52-7.61 (m, 1 H), 7.14-7.25 (m, 2 H), 6.91 (d, J=7.65 Hz, 1 H), 6.70 (s, 1 H), 4.35-4.51 (m, 4 H), 4.01 (s, 3 H) ,3.33 (t, J=7.09 Hz, 2 H), 2.93 (s, 3 H), 2.63 (t, J=7.09 Hz, 2 H) ,2.45 (dt, J = 10.29, 5.40 Hz, 2 H), 2.32 (s, 6 H).

實施例40B。Example 40B.

N4-（4-（3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚-7-基）嘧啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image896
N4-(4-(3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl)pyrimidin-2-yl)-N 1 -(2 -(Dimethylamino) ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image896

本實施例根據實施例16B的方法製備，將實施例16A替換為實施例40A。得到標題化合物（黃色固體，0.8克，產率85.01%)。1 H NMR (400 MHz, CDCl3 ): δ 8.27 (d, J=5.27 Hz, 1 H) ,8.08 (t, J=3.95 Hz, 2 H) ,7.70 (s, 1 H) ,7.53 (s, 1 H), 7.10 (t, J=7.91 Hz, 1 H), 6.94 (d, J=5.27 Hz, 1 H) ,6.83 (d, J=7.65 Hz, 1 H) ,6.61 - 6.66 (m, 1 H) ,4.20 - 4.34 (m, 4 H), 3.75 - 3.80 (m, 3 H) ,2.94 (t, J=6.78 Hz, 2 H), 2.62 (s, 3 H) ,2.42 (t, J=6.59 Hz, 2 H), 2.30 - 2.38 (m, 2 H), 2.26 (s, 6 H)。This example was prepared according to the method of Example 16B, and Example 16A was replaced with Example 40A. The title compound was obtained (yellow solid, 0.8 g, yield 85.01%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.27 (d, J=5.27 Hz, 1 H), 8.08 (t, J=3.95 Hz, 2 H), 7.70 (s, 1 H), 7.53 (s, 1 H), 7.10 (t, J=7.91 Hz, 1 H), 6.94 (d, J=5.27 Hz, 1 H), 6.83 (d, J=7.65 Hz, 1 H), 6.61-6.66 (m, 1 H), 4.20-4.34 (m, 4 H), 3.75-3.80 (m, 3 H), 2.94 (t, J=6.78 Hz, 2 H), 2.62 (s, 3 H), 2.42 (t, J = 6.59 Hz, 2 H), 2.30-2.38 (m, 2 H), 2.26 (s, 6 H).

實施例40C。Example 40C.

N-（5 - （（4-（3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚-7-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image892
N-(5-((4-(3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl)pyrimidin-2-yl)amino) -2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image892

本實施例根據實施例16C的方法製備，將實施例16B替換為實施例40B。得標題化合物（120.00毫克，產率71.15%）。1 H NMR (400MHz, CDCl3 ): δ 10.21 (br. s., 1H), 9.84 (s, 1H), 9.07 (br. s., 1H), 8.40 (d, J=2.0 Hz, 1H), 7.81 - 7.68 (m, 2H), 7.22 (d, J=4.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.81 (s, 1H), 6.48 - 6.31 (m, 2H), 5.78 - 5.64 (m, 1H), 4.64 - 4.52 (m, 2H), 4.45 - 4.36 (m, 2H), 3.90 (s, 3H), 2.90 (t, J=4.0 Hz, 2H), 2.72 (s, 3H), 2.48 - 2.36 (m, 2H), 2.33 - 2.21 (m, 8H)。 LCMS (ESI) (5-95AB): m/z: 542.2 [M+1]。This example was prepared according to the method of Example 16C, and Example 16B was replaced with Example 40B. The title compound was obtained (120.00 mg, yield 71.15%). 1 H NMR (400MHz, CDCl 3 ): δ 10.21 (br. s., 1H), 9.84 (s, 1H), 9.07 (br. s., 1H), 8.40 (d, J=2.0 Hz, 1H), 7.81-7.68 (m, 2H), 7.22 (d, J=4.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.81 (s, 1H ), 6.48-6.31 (m, 2H), 5.78-5.64 (m, 1H), 4.64-4.52 (m, 2H), 4.45-4.36 (m, 2H), 3.90 (s, 3H), 2.90 (t, J =4.0 Hz, 2H), 2.72 (s, 3H), 2.48-2.36 (m, 2H), 2.33-2.21 (m, 8H). LCMS (ESI) (5-95AB): m/z: 542.2 [M+1].

實施例41。Example 41.

N-（5 - （（4-（3,3-二甲基-3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚-7-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image899
N-(5-((4-(3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image899

實施例41A。Example 41A.

7-（3-氯-2,2-二甲基丙基）-1H-吲哚。

Figure 02_image901
7-(3-chloro-2,2-dimethylpropyl)-1H-indole.
Figure 02_image901

在20°C下,將7-羥基吲哚（5.00克，37.55毫莫耳），3-氯-2,2-二甲基 - 丙-1-醇（6.91克，56.33毫莫耳），三苯基磷(1.57克，6.00毫莫耳)l溶於THF（150mL）中，氮氣置換後向混合液中滴加DIAD（15.19克，75.10毫莫耳）。混合物70°C下攪拌12小時。TLC顯示反應完成，將反應液濃縮乾，粗品用柱色譜（PE：EA = 50:1，20:1）分離純化，得到標題化合物（白色固體，3.5克，產率39.21%)。1 H NMR (400MHz, CDCl3 ): δ 7.29 (s, 1H), 7.21 (t, J=4.0 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 6.58 - 6.53 (m, 1H), 3.96 (s, 2H), 3.65 (s, 2H), 1.20 (s, 6H)。 LCMS (ESI) (5-95AB): m/z: 238.1 [M+1]。At 20°C, place 7-hydroxyindole (5.00 g, 37.55 mmol), 3-chloro-2,2-dimethyl-propan-1-ol (6.91 g, 56.33 mmol), three Phenylphosphine (1.57 g, 6.00 mmol) was dissolved in THF (150 mL). After nitrogen substitution, DIAD (15.19 g, 75.10 mmol) was added dropwise to the mixture. The mixture was stirred at 70°C for 12 hours. TLC showed that the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was separated and purified by column chromatography (PE:EA=50:1, 20:1) to obtain the title compound (white solid, 3.5 g, yield 39.21%). 1 H NMR (400MHz, CDCl 3 ): δ 7.29 (s, 1H), 7.21 (t, J=4.0 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz , 1H), 6.58-6.53 (m, 1H), 3.96 (s, 2H), 3.65 (s, 2H), 1.20 (s, 6H). LCMS (ESI) (5-95AB): m/z: 238.1 [M+1].

實施例41B。Example 41B.

3,3-二甲基-3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚。

Figure 02_image903
3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indole.
Figure 02_image903

在0°C下，將實施例41A（3.50克，14.72毫莫耳）溶於DMF（50mL），向該混合物中加入NaH(1.18克，29.44毫莫耳)，70 °C下攪拌2小時。TLC顯示反應完成，向混合物中加入水（50mL），用EA（50mL x2）萃取，有機層經無水硫酸鈉乾燥，濃縮後，用柱色譜（PE：EA = 20:1，10:1）分離純化，得到標題化合物（白色固體，2.80克，產率94.51%)。1 H NMR (400MHz, CDCl3 ): δ 7.28 (d, J=1.0 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.03 - 6.97 (m, 2H), 6.79 (dd, J=0.8, 7.7 Hz, 1H), 6.52 (d, J=3.1 Hz, 1H), 4.05 - 3.98 (m, 2H), 3.87 (s, 2H), 1.17 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 202.2[M+1]。At 41C, Example 41A (3.50 g, 14.72 mmol) was dissolved in DMF (50 mL), and NaH (1.18 g, 29.44 mmol) was added to the mixture, which was stirred at 70°C for 2 hours. TLC showed that the reaction was completed. Water (50 mL) was added to the mixture, extracted with EA (50 mL x 2), the organic layer was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE: EA = 20:1, 10:1) Purification gave the title compound (white solid, 2.80 g, yield 94.51%). 1 H NMR (400MHz, CDCl 3 ): δ 7.28 (d, J=1.0 Hz, 1H), 7.29-7.26 (m, 1H), 7.03-6.97 (m, 2H), 6.79 (dd, J=0.8, 7.7 Hz, 1H), 6.52 (d, J=3.1 Hz, 1H), 4.05-3.98 (m, 2H), 3.87 (s, 2H), 1.17 (s, 6H). LCMS (ESI) (5-95AB): m/z: 202.2 [M+1].

實施例41C。Example 41C.

7-（2-氯嘧啶-4-基）-3,3-二甲基-3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚。

Figure 02_image905
7-(2-chloropyrimidin-4-yl)-3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indole.
Figure 02_image905

本實施例依據實施例E的方法，將實施例E2替換為實施例41B。得到標題化合物（黃色固體，2.30克，產率64.13%)。1 H NMR (400MHz, CDCl3 ): δ 8.47 (d, J=4.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.49 (d, J=4.0 Hz, 1H), 7.19 (t, J=9.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.05 (s, 2H), 4.00 (s, 2H), 1.17 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 314.0 [M+1]。According to the method of Embodiment E, this embodiment replaces Embodiment E2 with Embodiment 41B. The title compound was obtained (yellow solid, 2.30 g, yield 64.13%). 1 H NMR (400MHz, CDCl 3 ): δ 8.47 (d, J=4.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.49 (d, J=4.0 Hz , 1H), 7.19 (t, J=9.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.05 (s, 2H), 4.00 (s, 2H), 1.17 (s, 6H). LCMS (ESI) (5-95AB): m/z: 314.0 [M+1].

實施例41D。Example 41D.

4-（3,3-二甲基-3,4-二氫-2H-[1,4]惡嗪[2,3,4- hi]吲哚-7-基）-N-（4-氟-2-甲氧基-5-硝基苯基）嘧啶-2-胺。

Figure 02_image907
4-(3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine[2,3,4- hi]indol-7-yl)-N-(4-fluoro -2-methoxy-5-nitrophenyl)pyrimidine-2-amine.
Figure 02_image907

本實施例依據實施例F的方法，將實施例E替換為實施例41C。得到標題化合物（黃色固體，3.00克，產率88.31%)。1 H NMR (400MHz, CDCl3 ): δ 9.85 (d, J=8.0 Hz, 1H), 8.45 (d, J=4.0 Hz, 1H), 8.20 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.26 (br. s., 1H), 7.18 (t, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.77 (d, J=12.0 Hz, 1H), 4.11 (s, 2H), 4.08 (s, 2H), 4.05 (s, 3H), 3.71 (s, 2H), 1.21 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 464.0 [M+1]。In this embodiment, according to the method of Embodiment F, Embodiment E is replaced with Embodiment 41C. The title compound was obtained (yellow solid, 3.00 g, yield 88.31%). 1 H NMR (400MHz, CDCl 3 ): δ 9.85 (d, J=8.0 Hz, 1H), 8.45 (d, J=4.0 Hz, 1H), 8.20 (s, 1H), 7.78 (d, J=8.0 Hz , 1H), 7.64 (s, 1H), 7.26 (br. s., 1H), 7.18 (t, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.77 (d, J =12.0 Hz, 1H), 4.11 (s, 2H), 4.08 (s, 2H), 4.05 (s, 3H), 3.71 (s, 2H), 1.21 (s, 6H). LCMS (ESI) (5-95AB): m/z: 464.0 [M+1].

實施例41E。Example 41E.

N1-（4-（3,3-二甲基-3,4-二氫-2H-[1,4]惡嗪[2,3,4- hi]吲哚-7-基）嘧啶-2-基）-N4-（2-（二甲基氨基）乙基）-2-甲氧基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image909
N1-(4-(3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine[2,3,4- hi]indol-7-yl)pyrimidine-2- Group)-N4-(2-(dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image909

本實施例依據實施例16A的方法，將實施例D替換為實施例41D，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得到標題化合物（黃色固體，1.70克，產率96.16%)。1 H NMR (400MHz, CDCl3 ): δ 9.55 (s, 1H), 8.41 (d, J=4.0 Hz, 1H), 8.20 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.60 - 7.50 (m, 1H), 7.23 - 7.13 (m, 2H), 6.87 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 4.11 (s, 2H), 4.07 (s, 2H), 4.00 (s, 3H), 3.36 - 3.26 (m, 2H), 2.92 (s, 3H), 2.61 (t, J=8.0 Hz, 2H), 2.35 - 2.24 (m, 6H), 1.21 (s, 6H)。 LCMS (ESI) (5-95AB): m/z: 546.2 [M+1]。In this example, according to the method of Example 16A, Example D was replaced with Example 41D, and N,N-diethyl-N-methylethane-1,2-diamine was replaced with N,N',N '-Trimethyl-1,2-ethylenediamine. The title compound was obtained (yellow solid, 1.70 g, yield 96.16%). 1 H NMR (400MHz, CDCl 3 ): δ 9.55 (s, 1H), 8.41 (d, J=4.0 Hz, 1H), 8.20 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.60 -7.50 (m, 1H), 7.23-7.13 (m, 2H), 6.87 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 4.11 (s, 2H), 4.07 (s, 2H), 4.00 (s, 3H), 3.36-3.26 (m, 2H), 2.92 (s, 3H), 2.61 (t, J=8.0 Hz, 2H), 2.35-2.24 (m, 6H), 1.21 (s, 6H) . LCMS (ESI) (5-95AB): m/z: 546.2 [M+1].

實施例41F。Example 41F.

N4-（4-（3,3-二甲基-3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚-7-基）嘧啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image911
N4-(4-(3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl)pyrimidine-2- Radical)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image911

本實施例依據實施例16B的方法，將實施例16A替換為實施例41E。得到標題化合物（黃色固體，1.50克，產率93.24%)。1 H NMR (400MHz, CDCl3 ): δ 8.35 (d, J=4.0 Hz, 1H), 8.18 - 8.08 (m, 2H), 7.76 - 7.69 (m, 1H), 7.60 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.02 (d, J=4.0 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 4.06 (s, 2H), 4.00 (s, 2H), 3.86 (s, 3H), 2.99 (t, J=6.0 Hz, 2H), 2.69 (s, 3H), 2.49 - 2.39 (m, 2H), 2.28 (s, 6H), 1.19 (s, 6H)。LCMS (ESI) (5-95AB): m/z: 516.2 [M+1]。In this embodiment, according to the method of Embodiment 16B, Embodiment 16A is replaced with Embodiment 41E. The title compound was obtained (yellow solid, 1.50 g, yield 93.24%). 1 H NMR (400MHz, CDCl 3 ): δ 8.35 (d, J=4.0 Hz, 1H), 8.18-8.08 (m, 2H), 7.76-7.69 (m, 1H), 7.60 (s, 1H), 7.17 ( t, J=8.0 Hz, 1H), 7.02 (d, J=4.0 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 4.06 (s, 2H), 4.00 ( s, 2H), 3.86 (s, 3H), 2.99 (t, J=6.0 Hz, 2H), 2.69 (s, 3H), 2.49-2.39 (m, 2H), 2.28 (s, 6H), 1.19 (s , 6H). LCMS (ESI) (5-95AB): m/z: 516.2 [M+1].

實施例41G。Example 41G.

N-（5 - （（4-（3,3-二甲基-3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚-7-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image899
N-(5-((4-(3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image899

本實施例依據實施例16C的方法，將實施例16B替換為實施例41F。得到標題化合物（棕色固體，1.30克，產率95.57%)。1 H NMR (400MHz, CDCl3 ): δ 10.24 (s, 1H), 9.85 (s, 1H), 9.08 (s, 1H), 8.40 (d, J=4.0 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.21 (d, J=4.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.87 - 6.79 (m, 2H), 6.50 - 6.32 (m, 2H), 5.72 (dd, J=2.0, 8.0 Hz, 1H), 4.26 (s, 2H), 4.07 (s, 2H), 3.89 (s, 3H), 2.92 - 2.85 (m, 2H), 2.71 (s, 3H), 2.29 (br. s., 2H), 2.27 (s, 6H), 1.18 (s, 6H)。 LCMS (ESI) (5-95AB): m/z: 570.2 [M+1]。In this embodiment, according to the method of Embodiment 16C, Embodiment 16B is replaced with Embodiment 41F. The title compound was obtained (brown solid, 1.30 g, yield 95.57%). 1 H NMR (400MHz, CDCl 3 ): δ 10.24 (s, 1H), 9.85 (s, 1H), 9.08 (s, 1H), 8.40 (d, J=4.0 Hz, 1H), 7.74 (s, 1H) , 7.68 (d, J=8.0 Hz, 1H), 7.21 (d, J=4.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.87-6.79 (m, 2H), 6.50-6.32 ( m, 2H), 5.72 (dd, J=2.0, 8.0 Hz, 1H), 4.26 (s, 2H), 4.07 (s, 2H), 3.89 (s, 3H), 2.92-2.85 (m, 2H), 2.71 (s, 3H), 2.29 (br. s., 2H), 2.27 (s, 6H), 1.18 (s, 6H). LCMS (ESI) (5-95AB): m/z: 570.2 [M+1].

實施例41H。Example 41H.

N-（5 - （（4-（3,3-二甲基-3,4-二氫-2H- [1,4]惡嗪[2,3,4- hi]吲哚-7-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺甲磺酸鹽。

Figure 02_image914
N-(5-((4-(3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide mesylate.
Figure 02_image914

本實施例依據實施例36J的方法，將實施例36I替換為實施例41G。得到標題化合物（1.36克，產率89.43%)。1 H NMR (400MHz, CD3 OD): δ 8.68 (s, 1H), 8.29 (d, J=4.0 Hz, 1H), 8.10 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.21 (d, J=4.0 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.97 (s, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.60 - 6.42 (m, 2H), 5.93 - 5.82 (m, 1H), 4.06 (s, 2H), 4.03 (s, 2H), 4.02 (s, 3H), 3.48 (t, J=6.0 Hz, 2H), 3.30 - 3.24 (m, 2H), 2.88 (s, 6H), 2.72 (s, 3H), 2.70 (s, 3H), 1.15 (s, 6H)。LCMS (ESI) (0-60AB): m/z: 570.2 [M+1]。In this embodiment, according to the method of Embodiment 36J, Embodiment 36I is replaced with Embodiment 41G. The title compound was obtained (1.36 g, yield 89.43%). 1 H NMR (400MHz, CD 3 OD): δ 8.68 (s, 1H), 8.29 (d, J=4.0 Hz, 1H), 8.10 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.21 (d, J=4.0 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.97 (s, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.60-6.42 (m, 2H ), 5.93-5.82 (m, 1H), 4.06 (s, 2H), 4.03 (s, 2H), 4.02 (s, 3H), 3.48 (t, J=6.0 Hz, 2H), 3.30-3.24 (m, 2H), 2.88 (s, 6H), 2.72 (s, 3H), 2.70 (s, 3H), 1.15 (s, 6H). LCMS (ESI) (0-60AB): m/z: 570.2 [M+1].

實施例42。Example 42.

N-（5 - （（4-（3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'-環丙基] -6-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image916
N-(5-((4-(3H-spiro[[1,4]oxazine[2,3,4- hi]indole-2,1'-cyclopropyl]-6-yl)pyrimidine-2 -Yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image916

實施例42A。Example 42A.

1-（2-硝基苯氧基）環丙烷羧酸。

Figure 02_image918
1-(2-nitrophenoxy) cyclopropanecarboxylic acid.
Figure 02_image918

在0°C下，將1-氟-2-硝基苯（10.37克，73.47毫莫耳）和1-羥基環丙烷羧酸（5.00克，48.98毫莫耳）溶於DMF（100mL）中，分批加入NaH（4.90克，122.45毫莫耳），混合物在80°C下攪拌12小時。TLC顯示反應基本完成。向其中加入水（20mL），用EA（100mL x2）萃取，水相用6 N HCl調節到PH=3，用EA（100mLx3）萃取，有機層合併後經無水硫酸鈉乾燥，濃縮至乾得標題化合物（黃色固體，6.00克，產率54.89%)。1 H NMR (400MHz, CDCl3 ): δ 7.84 (dd, J=2.0, 8.0 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 1.80 - 1.73 (m, 2H), 1.55 - 1.49 (m, 2H)。At 0°C, 1-fluoro-2-nitrobenzene (10.37 g, 73.47 mmol) and 1-hydroxycyclopropanecarboxylic acid (5.00 g, 48.98 mmol) were dissolved in DMF (100 mL), NaH (4.90 g, 122.45 mmol) was added in portions, and the mixture was stirred at 80°C for 12 hours. TLC showed that the reaction was almost complete. Water (20 mL) was added thereto, extracted with EA (100 mL x 2), the aqueous phase was adjusted to pH = 3 with 6 N HCl, and extracted with EA (100 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to dryness to give the title Compound (yellow solid, 6.00 g, yield 54.89%). 1 H NMR (400MHz, CDCl 3 ): δ 7.84 (dd, J=2.0, 8.0 Hz, 1H), 7.56-7.48 (m, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 1.80-1.73 (m, 2H), 1.55-1.49 (m, 2H).

實施例42B。Example 42B.

4-螺[苯並[b][1,4]惡嗪-2,1'-環丙基] -3（4H）-酮。

Figure 02_image920
4-spiro[benzo[b][1,4]oxazin-2,1'-cyclopropyl]-3(4H)-one.
Figure 02_image920

將實施例42A（11.00克，49.29毫莫耳），NH4Cl（10..55克，197.15毫莫耳），鐵粉（11.01克，197.15毫莫耳）溶於乙醇（15mL）和水（2mL）中。反應液用氮氣置換後升溫至90°C攪拌12小時。TLC顯示反應完全。反應液冷卻後過濾，濾餅用乙醇洗滌，濾液濃縮至乾得標題化合物（黃色固體，7.5克，產率98.89%)。1 H NMR (400MHz, CDCl3 ): δ 9.43 (br. s., 1H), 7.12 - 6.65 (m, 1H), 1.62 - 1.02 (m, 4H)。LCMS (ESI) (5-95AB): m/z: 176.0 [M+1]。Example 42A (11.00 g, 49.29 mmol), NH4Cl (10..55 g, 197.15 mmol), iron powder (11.01 g, 197.15 mmol) were dissolved in ethanol (15 mL) and water (2 mL) in. After the reaction liquid was replaced with nitrogen, the temperature was raised to 90°C and stirred for 12 hours. TLC showed the reaction was complete. The reaction solution was cooled and filtered, the filter cake was washed with ethanol, and the filtrate was concentrated to dryness to obtain the title compound (yellow solid, 7.5 g, yield 98.89%). 1 H NMR (400MHz, CDCl 3 ): δ 9.43 (br. s., 1H), 7.12-6.65 (m, 1H), 1.62-1.02 (m, 4H). LCMS (ESI) (5-95AB): m/z: 176.0 [M+1].

實施例42C。Example 42C.

6-3,4-二氫螺[苯並[b] [1,4]惡嗪-2,1'-環丙烷] 。

Figure 02_image922
6-3,4-Dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane].
Figure 02_image922

將實施例42B（8.50克，48.52毫莫耳）溶於THF（100mL）中，在70°C下加入LiAlH4（4.60克，121.30毫莫耳）後攪拌2小時。LCMS監測反應完全。向反應混合物中依次加入水（4.6mL）、15%的NaOH（4.6mL）溶液和水（13.8mL），攪拌30分鐘，混合物過濾，濾液濃縮至乾得標題化合物（黃色油狀物，7.5克，產率98.89%)。1 H NMR (400MHz, CDCl3 ): δ 6.85 - 6.77 (m, 1H), 6.77 - 6.72 (m, 1H), 6.71 - 6.65 (m, 2H), 3.86 (br. s., 1H), 3.33 (d, J=2.0 Hz, 2H), 1.11 - 1.03 (m, 2H), 0.74 - 0.67 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 162.1 [M+1]。Example 42B (8.50 g, 48.52 mmol) was dissolved in THF (100 mL), and LiAlH4 (4.60 g, 121.30 mmol) was added at 70°C and stirred for 2 hours. LCMS monitored the reaction to completion. To the reaction mixture were added water (4.6 mL), 15% NaOH (4.6 mL) solution and water (13.8 mL) in this order, stirred for 30 minutes, the mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (yellow oil, 7.5 g) , Yield 98.89%). 1 H NMR (400MHz, CDCl 3 ): δ 6.85-6.77 (m, 1H), 6.77-6.72 (m, 1H), 6.71-6.65 (m, 2H), 3.86 (br. s., 1H), 3.33 ( d, J=2.0 Hz, 2H), 1.11-1.03 (m, 2H), 0.74-0.67 (m, 2H). LCMS (ESI) (5-95AB): m/z: 162.1 [M+1].

實施例42D。Example 42D.

8-4-（2,2-二甲氧基乙基）-3,4-二氫螺[苯並[b] [1,4]惡嗪-2,1'-環丙烷] 。

Figure 02_image924
8-4-(2,2-dimethoxyethyl)-3,4-dihydrospiro[benzo[b] [1,4]oxazine-2,1'-cyclopropane].
Figure 02_image924

將實施例42C（7.50克，46.53毫莫耳），K2 CO3 （9.65克，69.8毫莫耳），KI（772.33毫克，4.65毫莫耳）和2-溴-1,1-二乙氧基乙烷（18.34克，93.06毫莫耳）溶於DMF（50mL）。氮氣置換後加熱到130°C並攪拌12小時。TLC顯示少量原料剩餘，向混合物中加入水（150mL），用DCM（100mL x2）萃取，有機層經無水硫酸鈉乾燥，濃縮後，粗品用柱色譜（PE：EA = 1000:1，100:1）分離純化，得到標題化合物（黃色油狀物，8.0克，產率61.99%)。1 H NMR (400MHz, CDCl3 ): δ 6.90 - 6.82 (m, 1H), 6.72 (d, J=8.0 Hz, 2H), 6.63 - 6.56 (m, 1H), 4.79 - 4.66 (m, 1H), 3.80 - 3.69 (m, 2H), 3.64 - 3.53 (m, 2H), 3.46 - 3.38 (m, 4H), 1.28 - 1.17 (m, 6H), 1.05 - 0.97 (m, 2H), 0.73 - 0.61 (m, 2H)。Example 42C (7.50 g, 46.53 mmol), K 2 CO 3 (9.65 g, 69.8 mmol), KI (772.33 mg, 4.65 mmol) and 2-bromo-1,1-diethoxy Ethyl ethane (18.34 g, 93.06 mmol) was dissolved in DMF (50 mL). After replacing with nitrogen, it was heated to 130°C and stirred for 12 hours. TLC showed a small amount of raw material remaining, water (150 mL) was added to the mixture, extracted with DCM (100 mL x 2), the organic layer was dried over anhydrous sodium sulfate, after concentration, the crude product was subjected to column chromatography (PE: EA = 1000:1, 100:1) ) Was isolated and purified to obtain the title compound (yellow oil, 8.0 g, yield 61.99%). 1 H NMR (400MHz, CDCl 3 ): δ 6.90-6.82 (m, 1H), 6.72 (d, J=8.0 Hz, 2H), 6.63-6.56 (m, 1H), 4.79-4.66 (m, 1H), 3.80-3.69 (m, 2H), 3.64-3.53 (m, 2H), 3.46-3.38 (m, 4H), 1.28-1.17 (m, 6H), 1.05-0.97 (m, 2H), 0.73-0.61 (m , 2H).

實施例42E。Example 42E.

10--3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'-環丙烷] 。

Figure 02_image926
10--3H-spiro[[1,4]oxazine[2,3,4- hi]indole-2,1'-cyclopropane].
Figure 02_image926

在0°C下，將AlCl3 （10.1克，75.72毫莫耳）加入到DCM（50mL）中，將實施例42D（7.00克，25.24毫莫耳）溶於DCM （130mL）後緩慢滴加到該混合物中。在0°C下攪拌10 分鐘，TLC顯示少量原料剩餘。將混合物緩慢倒入冰水（300mL ）中淬滅，用DCM（300mL x2）萃取，有機層經無水硫酸鈉乾燥，濃縮後，用柱色譜（PE：EA = 1000:1，100:1）分離純化，得到標題化合物（黃色油狀物，3.2克，產率68.45%)。1 H NMR (400MHz, CDCl3 ): δ 7.26 - 7.23 (m, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.51 (d, J=2.0 Hz, 1H), 4.19 (s, 2H), 1.27 - 1.19 (m, 2H), 0.88 - 0.81 (m, 2H)。At 0°C, AlCl 3 (10.1 g, 75.72 mmol) was added to DCM (50 mL). Example 42D (7.00 g, 25.24 mmol) was dissolved in DCM (130 mL) and slowly added dropwise to The mixture. After stirring at 0°C for 10 minutes, TLC showed a small amount of raw material remaining. The mixture was slowly poured into ice water (300 mL) to quench, extracted with DCM (300 mL x 2), the organic layer was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE: EA = 1000:1, 100:1) Purification gave the title compound (yellow oil, 3.2 g, yield 68.45%). 1 H NMR (400MHz, CDCl 3 ): δ 7.26-7.23 (m, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.62 (d, J= 8.0 Hz, 1H), 6.51 (d, J=2.0 Hz, 1H), 4.19 (s, 2H), 1.27-1.19 (m, 2H), 0.88-0.81 (m, 2H).

實施例42F。Example 42F.

6-（2-氯嘧啶-4-基）-3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'-環丙烷] 。

Figure 02_image928
6-(2-chloropyrimidin-4-yl)-3H-spiro[[1,4]oxazine[2,3,4-hi]indole-2,1'-cyclopropane].
Figure 02_image928

本實施例依據實施例E的方法，將實施例E2替換為實施例42E。得到標題化合物（黃色固體，1.30克，產率67.38%)。1 H NMR (400MHz, CDCl3 ): δ 8.49 (d, J=4.0 Hz, 1H), 8.02 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.54 (d, J=4.0 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H), 6.76 - 6.71 (m, 1H), 4.27 (s, 2H), 1.28 - 1.23 (m, 2H), 0.91 - 0.85 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 298.0 [M+1]。According to the method of Embodiment E, this embodiment replaces Embodiment E2 with Embodiment 42E. The title compound was obtained (yellow solid, 1.30 g, yield 67.38%). 1 H NMR (400MHz, CDCl 3 ): δ 8.49 (d, J=4.0 Hz, 1H), 8.02 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.54 (d, J=4.0 Hz , 1H), 7.19 (t, J=8.0 Hz, 1H), 6.76-6.71 (m, 1H), 4.27 (s, 2H), 1.28-1.23 (m, 2H), 0.91-0.85 (m, 2H). LCMS (ESI) (5-95AB): m/z: 298.0 [M+1].

實施例42G。Example 42G.

N-（4-氟-2-甲氧基-5-硝基苯基）-4-（3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'環丙基] -6-基）嘧啶-2-胺。

Figure 02_image930
N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(3H-spiro[[1,4]oxazine[2,3,4- hi]indole-2,1 'Cyclopropyl]-6-yl)pyrimidin-2-amine.
Figure 02_image930

本實施例依據實施例F的方法，將實施例E替換為實施例42F。得到標題化合物（黃色固體，1.80克，產率92.06%)。1 H NMR (400MHz, CDCl3 ): δ 9.90 (d, J=8.0 Hz, 1H), 8.48 - 8.42 (m, 1H), 8.33 (s, 1H), 7.71 - 7.58 (m, 2H), 7.28 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.82 - 6.67 (m, 2H), 4.40 - 4.26 (m, 2H), 4.08 - 3.99 (m, 3H), 1.31 - 1.17 (m, 2H), 1.02 - 0.82 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 448.1 [M+1]。In this embodiment, according to the method of Embodiment F, Embodiment E is replaced with Embodiment 42F. The title compound was obtained (yellow solid, 1.80 g, yield 92.06%). 1 H NMR (400MHz, CDCl 3 ): δ 9.90 (d, J=8.0 Hz, 1H), 8.48-8.42 (m, 1H), 8.33 (s, 1H), 7.71-7.58 (m, 2H), 7.28 ( s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.82-6.67 (m, 2H), 4.40-4.26 (m, 2H), 4.08-3.99 (m, 3H), 1.31-1.17 (m, 2H), 1.02-0.82 (m, 2H). LCMS (ESI) (5-95AB): m/z: 448.1 [M+1].

實施例42H。Example 42H.

N1-（4-（3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'-環丙基] -6-基）嘧啶-2-基）-N4-（2-（二甲基氨基）乙基）-2-甲氧基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image932
N1-(4-(3H-spiro[[1,4]oxazine[2,3,4-hi]indole-2,1'-cyclopropyl]-6-yl)pyrimidin-2-yl)- N4-(2-(dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image932

本實施例依據實施例16A的方法，將實施例D替換為實施例42G，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N,N’,N’ –三甲基–1,2-乙二胺。得標題化合物（黃色固體，1.80克，產率84.55%)。1 H NMR (400MHz, CDCl3 ): δ 9.63 (s, 1H), 8.42 (d, J=4.0 Hz, 1H), 8.35 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.22 (d, J=4.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.73 - 6.67 (m, 2H), 4.42 - 4.31 (m, 2H), 4.00 (s, 3H), 3.36 - 3.26 (m, 2H), 2.91 (s, 3H), 2.61 (t, J=8.0 Hz, 2H), 2.33 - 2.26 (m, 6H), 1.25 - 1.19 (m, 2H), 0.92 - 0.84 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 530.2 [M+1]。In this example, according to the method of Example 16A, Example D was replaced with Example 42G, and N,N-diethyl-N-methylethane-1,2-diamine was replaced with N,N',N '-Trimethyl-1,2-ethylenediamine. The title compound was obtained (yellow solid, 1.80 g, yield 84.55%). 1 H NMR (400MHz, CDCl 3 ): δ 9.63 (s, 1H), 8.42 (d, J=4.0 Hz, 1H), 8.35 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.58 -7.53 (m, 1H), 7.22 (d, J=4.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.73-6.67 (m, 2H), 4.42-4.31 (m, 2H), 4.00 (s, 3H), 3.36-3.26 (m, 2H), 2.91 (s, 3H), 2.61 (t, J=8.0 Hz, 2H), 2.33-2.26 (m, 6H), 1.25-1.19 (m, 2H), 0.92-0.84 (m, 2H). LCMS (ESI) (5-95AB): m/z: 530.2 [M+1].

實施例42I。Example 42I.

N4-（4-（3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'-環丙基] -6-基）嘧啶-2-基）-N 1 - （2-（二甲基氨基）乙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image934
N4-(4-(3H-spiro[[1,4]oxazine[2,3,4-hi]indole-2,1'-cyclopropyl]-6-yl)pyrimidin-2-yl)- N 1 -(2-(dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image934

本實施例依據實施例16B的方法，將實施例16A替換為實施例42H。得標題化合物（黃色固體，1.60克，產率94.12%)。1 H NMR (400MHz, CDCl3 ): δ 8.41 - 8.32 (m, 1H), 8.18 - 8.13 (m, 1H), 7.91 - 7.82 (m, 2H), 7.60 (s, 1H), 7.18 - 7.12 (m, 1H), 7.06 (d, J=4.0 Hz, 1H), 6.76 - 6.67 (m, 2H), 4.27 (s, 2H), 3.86 - 3.84 (m, 3H), 3.00 - 2.93 (m, 2H), 2.69 (s, 3H), 2.42 (t, J=8.0 Hz, 2H), 2.29 - 2.25 (m, 6H), 1.26 - 1.21 (m, 2H), 0.92 - 0.83 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 500.2 [M+1]。In this embodiment, according to the method of Embodiment 16B, Embodiment 16A is replaced with Embodiment 42H. The title compound was obtained (yellow solid, 1.60 g, yield 94.12%). 1 H NMR (400MHz, CDCl 3 ): δ 8.41-8.32 (m, 1H), 8.18-8.13 (m, 1H), 7.91-7.82 (m, 2H), 7.60 (s, 1H), 7.18-7.12 (m , 1H), 7.06 (d, J=4.0 Hz, 1H), 6.76-6.67 (m, 2H), 4.27 (s, 2H), 3.86-3.84 (m, 3H), 3.00-2.93 (m, 2H), 2.69 (s, 3H), 2.42 (t, J=8.0 Hz, 2H), 2.29-2.25 (m, 6H), 1.26-1.21 (m, 2H), 0.92-0.83 (m, 2H). LCMS (ESI) (5-95AB): m/z: 500.2 [M+1].

實施例42J。Example 42J.

N-（5 - （（4-（3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'-環丙基] -6-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）乙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image916
N-(5-((4-(3H-spiro[[1,4]oxazine[2,3,4- hi]indole-2,1'-cyclopropyl]-6-yl)pyrimidine-2 -Yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image916

本實施例依據實施例16C的方法，將實施例16B替換為實施例42I。得標題化合物（1.25克，產率85.09%)。1 H NMR (400MHz, CDCl3 ): δ 10.23 (br. s., 1H), 9.85 (s, 1H), 9.21 (br. s., 1H), 8.40 (d, J=4.0 Hz, 1H), 7.75 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.20 (d, J=4.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.81 (s, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.35 (d, J=4.0 Hz, 2H), 5.68 (t, J=6.0 Hz, 1H), 4.39 (s, 2H), 3.90 (s, 3H), 2.98 - 2.85 (m, 2H), 2.71 (s, 3H), 2.30 - 2.22 (m, 8H), 1.25 - 1.19 (m, 2H), 0.87 (s, 2H)。LCMS (ESI) (5-95AB): m/z: 554.2 [M+1]。In this embodiment, according to the method of Embodiment 16C, Embodiment 16B is replaced with Embodiment 42I. The title compound was obtained (1.25 g, yield 85.09%). 1 H NMR (400MHz, CDCl 3 ): δ 10.23 (br. s., 1H), 9.85 (s, 1H), 9.21 (br. s., 1H), 8.40 (d, J=4.0 Hz, 1H), 7.75 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.20 (d, J=4.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.81 (s, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.35 (d, J=4.0 Hz, 2H), 5.68 (t, J=6.0 Hz, 1H), 4.39 (s, 2H), 3.90 (s, 3H), 2.98-2.85 (m, 2H), 2.71 (s, 3H), 2.30-2.22 (m, 8H), 1.25-1.19 (m, 2H), 0.87 (s, 2H). LCMS (ESI) (5-95AB): m/z: 554.2 [M+1].

實施例43。Example 43.

N-（5 - （（4-（3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'-環丙基] -6-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）-2-甲基丙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image937
N-(5-((4-(3H-spiro[[1,4]oxazine[2,3,4- hi]indole-2,1'-cyclopropyl]-6-yl)pyrimidine-2 -Yl)amino)-2 -((2-(dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image937

實施例43A。Example 43A.

N1-（4-（3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'-環丙基] -6-基）嘧啶-2-基）-N4-（2-（二甲基氨基）-2-甲基丙基）-2-甲基-N--4-甲基-5-硝基苯-1,4-二胺。

Figure 02_image939
N1-(4-(3H-spiro[[1,4]oxazine[2,3,4-hi]indole-2,1'-cyclopropyl]-6-yl)pyrimidin-2-yl)- N4-(2-(dimethylamino)-2-methylpropyl)-2-methyl-N--4-methyl-5-nitrobenzene-1,4-diamine.
Figure 02_image939

本實施例依據實施例16A的方法，將實施例D替換為實施例42G，將N，N-二乙基-N-甲基乙烷-1,2-二胺替換為N1,N2,N2,2-四甲基丙烷-1,2-二胺。得標題化合物（黃色固體，500毫克，產率39.01%)。1 H NMR (400MHz, CDCl3 ): δ 9.61 (s, 1H), 8.43 (d,J =4.0 Hz, 1H), 8.27 (s, 1H), 7.74 - 7.58 (m, 2H), 7.31 (s, 1H), 7.23 (d,J =4.0 Hz, 1H), 7.16 (t,J =8.0 Hz, 1H), 6.71 (d,J =8.0 Hz, 1H), 4.34 (s, 2H), 4.22 - 4.11 (m, 3H), 3.86 (br. s., 2H), 3.03 (s, 3H), 2.73 (s, 6H), 1.43 (s, 6H), 1.28 - 1.22 (m, 2H), 0.91 - 0.86 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 558.2 [M+1]。In this example, according to the method of Example 16A, Example D was replaced with Example 42G, and N,N-diethyl-N-methylethane-1,2-diamine was replaced with N1,N2,N2, 2-tetramethylpropane-1,2-diamine. The title compound was obtained (yellow solid, 500 mg, yield 39.01%). 1 H NMR (400MHz, CDCl 3 ): δ 9.61 (s, 1H), 8.43 (d, J =4.0 Hz, 1H), 8.27 (s, 1H), 7.74-7.58 (m, 2H), 7.31 (s, 1H), 7.23 (d, J =4.0 Hz, 1H), 7.16 (t, J =8.0 Hz, 1H), 6.71 (d, J =8.0 Hz, 1H), 4.34 (s, 2H), 4.22-4.11 ( m, 3H), 3.86 (br. s., 2H), 3.03 (s, 3H), 2.73 (s, 6H), 1.43 (s, 6H), 1.28-1.22 (m, 2H), 0.91-0.86 (m , 2H). LCMS (ESI) (5-95AB): m/z: 558.2 [M+1].

實施例43B。Example 43B.

N4-（4-（3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'-環丙基] -6-基）嘧啶-2-基）-N 1 - （2-（二甲基氨基）-2-甲基丙基）-5-甲氧基N1甲基苯-1,2,4-三胺。

Figure 02_image941
N4-(4-(3H-spiro[[1,4]oxazine[2,3,4-hi]indole-2,1'-cyclopropyl]-6-yl)pyrimidin-2-yl)- N 1 -(2-(dimethylamino)-2-methylpropyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.
Figure 02_image941

本實施例依據實施例16B的方法，將實施例16A替換為實施例43A。得標題化合物（黃色固體，300.00毫克，產率63.41%)。1 H NMR (400MHz, CD3 OD): δ 8.31 (d,J =4.0 Hz, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.85 (d,J =8.0 Hz, 1H), 7.23 (d,J =4.0 Hz, 1H), 7.09 (t,J =8.0 Hz, 1H), 7.04 (s, 1H), 6.65 - 6.62 (m, 1H), 4.37 (s, 2H), 3.92 (s, 3H), 3.29 (s, 2H), 2.83 (s, 3H), 2.74 (s, 6H), 1.24 (s, 6H), 1.16 - 1.12 (m, 2H), 0.95 - 0.92 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 528.3 [M+1]。In this embodiment, according to the method of Embodiment 16B, Embodiment 16A is replaced with Embodiment 43A. The title compound was obtained (yellow solid, 300.00 mg, yield 63.41%). 1 H NMR (400MHz, CD 3 OD): δ 8.31 (d, J =4.0 Hz, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.85 (d, J =8.0 Hz, 1H), 7.23 (d, J =4.0 Hz, 1H), 7.09 (t, J =8.0 Hz, 1H), 7.04 (s, 1H), 6.65-6.62 (m, 1H), 4.37 (s, 2H), 3.92 (s , 3H), 3.29 (s, 2H), 2.83 (s, 3H), 2.74 (s, 6H), 1.24 (s, 6H), 1.16-1.12 (m, 2H), 0.95-0.92 (m, 2H). LCMS (ESI) (5-95AB): m/z: 528.3 [M+1].

實施例43C。Example 43C.

N-（5 - （（4-（3H-螺[[1,4]惡嗪[2,3,4- hi]吲哚-2,1'-環丙基] -6-基）嘧啶-2-基）氨基）-2 - （（2-（二甲基氨基）-2-甲基丙基）（甲基）氨基）-4-甲氧基苯基）丙烯醯胺。

Figure 02_image937
N-(5-((4-(3H-spiro[[1,4]oxazine[2,3,4- hi]indole-2,1'-cyclopropyl]-6-yl)pyrimidine-2 -Yl)amino)-2 -((2-(dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)acrylamide.
Figure 02_image937

本實施例依據實施例16C的方法，將實施例16B替換為實施例43B。得標題化合物（230.00毫克，產率69.54%)。1 H NMR (400MHz, CD3 OD): δ 8.56 (br. s., 1H), 8.29 (d, J=4.0 Hz, 1H), 8.09 (br. s., 1H), 7.82 (d, J=8.0 Hz, 1H), 7.22 (d, J=4.0 Hz, 1H), 7.14 (s, 1H), 7.02 (t, J=8.0 Hz, 1H), 6.60 - 6.49 (m, 3H), 5.90 (dd, J=4.0, 7.9 Hz, 1H), 4.34 (s, 2H), 4.03 (s, 3H), 3.69 - 3.41 (m, 2H), 2.80 (s, 3H), 2.75 (s, 6H), 1.34 (s, 6H), 1.16 - 1.11 (m, 2H), 0.95 - 0.90 (m, 2H)。LCMS (ESI) (5-95AB): m/z: 582.4 [M+1]。In this embodiment, according to the method of Embodiment 16C, Embodiment 16B is replaced with Embodiment 43B. The title compound was obtained (230.00 mg, yield 69.54%). 1 H NMR (400MHz, CD 3 OD): δ 8.56 (br. s., 1H), 8.29 (d, J=4.0 Hz, 1H), 8.09 (br. s., 1H), 7.82 (d, J= 8.0 Hz, 1H), 7.22 (d, J=4.0 Hz, 1H), 7.14 (s, 1H), 7.02 (t, J=8.0 Hz, 1H), 6.60-6.49 (m, 3H), 5.90 (dd, J=4.0, 7.9 Hz, 1H), 4.34 (s, 2H), 4.03 (s, 3H), 3.69-3.41 (m, 2H), 2.80 (s, 3H), 2.75 (s, 6H), 1.34 (s , 6H), 1.16-1.11 (m, 2H), 0.95-0.90 (m, 2H). LCMS (ESI) (5-95AB): m/z: 582.4 [M+1].

生化實驗 。Biochemical experiment.

實驗材料。Experimental Materials.

酶：EGFR野生型，EGFR T790M/L858R，EGFR T790M和INSR均購自Life technology (Madison, WI)， EGFR d746-750/T790M 購自Carna Biosciences (Japan)​。Enzymes: EGFR wild type, EGFR T790M/L858R, EGFR T790M and INSR were purchased from Life technology (Madison, WI), EGFR d746-750/T790M were purchased from Carna Biosciences (Japan)​​

HTRF試劑盒：購自Cis-Bio International，內含Eu標記TK1抗體，XL665和biotin標記的TK1多肽底物。HTRF kit: purchased from Cis-Bio International, containing Eu-labeled TK1 antibody, XL665 and biotin-labeled TK1 polypeptide substrate.

檢測儀器：Envision（PerkinElmer）。Testing equipment: Envision (PerkinElmer).

實驗方法：將測試化合物3倍梯度稀釋，獲得終濃度從300 nM 到0.015 nM 10個劑量。Experimental method: The test compound was diluted by a factor of 3 to obtain 10 doses with a final concentration from 300 nM to 0.015 nM.

野生型EGFR酶反應混合物體系：0.05 nM 野生型EGFR, 1 uM biotin-TK1 peptide, 25 uM ATP 的酶緩衝液共計 10 uL. 反應板為white Proxiplate 384-Plus plate (PerkinElmer)，23 °C反應60分鐘。Wild-type EGFR enzyme reaction mixture system: 0.05 nM wild-type EGFR, 1 uM biotin-TK1 peptide, 25 uM ATP enzyme buffer totaling 10 uL. The reaction plate is white Proxiplate 384-Plus plate (PerkinElmer), reaction at 23 °C 60 minute.

EGFR T790M/L858R酶反應混合物體系：0.04 nM EGFR T790M/L858R, 1 uM biotin-TK1 peptide, 20 uM ATP 的酶緩衝液共計 10 uL. 反應板為white Proxiplate 384-Plus plate (PerkinElmer)，23 °C反應60分鐘。EGFR T790M/L858R enzyme reaction mixture system: 0.04 nM EGFR T790M/L858R, 1 uM biotin-TK1 peptide, 20 uM ATP enzyme buffer total 10 uL. The reaction plate is white Proxiplate 384-Plus plate (PerkinElmer), 23 °C React for 60 minutes.

EGFR d746-750/T790M酶反應混合物體系：0.025 nM EGFR d746-750/T790M, 1 uM biotin-TK1 peptide, 40 uM ATP 的酶緩衝液共計 10 uL. 反應板為white Proxiplate 384-Plus plate (PerkinElmer)，23 °C反應60分鐘。EGFR d746-750/T790M enzyme reaction mixture system: 0.025 nM EGFR d746-750/T790M, 1 uM biotin-TK1 peptide, 40 uM ATP enzyme buffer total 10 uL. The reaction plate is white Proxiplate 384-Plus plate (PerkinElmer) At 23 °C for 60 minutes.

EGFR T790M酶反應混合物體系：0.03 nM EGFR T790M, 1 uM biotin-TK1 peptide, 10 uM ATP 的酶緩衝液共計 10 uL. 反應板為white Proxiplate 384-Plus plate (PerkinElmer)，23 °C反應60分鐘。EGFR T790M enzyme reaction mixture system: 0.03 nM EGFR T790M, 1 uM biotin-TK1 peptide, 10 uM ATP enzyme buffer total 10 uL. The reaction plate is white Proxiplate 384-Plus plate (PerkinElmer), and react at 23 °C for 60 minutes.

INSR酶反應混合物體系：0.5 nM INSR, 1 uM biotin-TK1 peptide, 35 uM ATP 的酶緩衝液共計 10 uL. 反應板為white Proxiplate 384-Plus plate (PerkinElmer)，23 °C反應60分鐘。INSR enzyme reaction mixture system: 0.5 nM INSR, 1 uM biotin-TK1 peptide, 35 uM ATP enzyme buffer total 10 uL. The reaction plate is white Proxiplate 384-Plus plate (PerkinElmer), and react at 23 °C for 60 minutes.

檢測反應：10ul檢測試劑 包含Antibody 2 nM 並加入 XL665 62.5 nM。23 °C孵育60分鐘。Envision讀板。Detection reaction: 10ul detection reagent contains Antibody 2 nM and add XL665 62.5 nM. Incubate at 23 °C for 60 minutes. Envision reading board.

資料分析：通過下列公式將讀數轉化成抑制率（％）(Min-Ratio)/(Max-Min)*100%。4參數曲線擬合（Model 205 in XLFIT5, iDBS）測得IC50數據。Data analysis: Convert the reading into the inhibition rate (%) (Min-Ratio)/(Max-Min)*100% by the following formula. 4 Parameter curve fitting (Model 205 in XLFIT5, iDBS) measured IC50 data.

細胞實驗。Cell experiment.

實驗材料：RPMI1640，胎牛血清，青黴素/鏈黴素溶液，均購自Life Technology (Madison, WI)。Cell Titer-Glo luminescent cell viability reagents購自Promega (Madison, WI)。A431 cell line 和 NCI-H1975 cell line均購自European Collection of Cell Cultures (ECACC)。讀板儀器：Envision（PerkinElmer）。Experimental materials: RPMI1640, fetal bovine serum, penicillin/streptomycin solution, all purchased from Life Technology (Madison, WI). Cell Titer-Glo luminescent cell viability reagents were purchased from Promega (Madison, WI). Both A431 cell line and NCI-H1975 cell line were purchased from European Collection of Cell Cultures (ECACC). Plate reader: Envision (PerkinElmer).

實驗方法 ：384孔板，每孔種300個A431 cells 和 NCI-H1975 cells 細胞，45ul體積。在CO 2培養箱中37℃過夜培養。 待測化合物做3倍梯度稀釋，獲得濃度從10 uM 到 0.508 nM 10個劑量濃度，兩複孔。中間板每孔加49ul培養基。從梯度稀釋化合物板轉移1ul化合物至中間板，混合充分。再從中間板取5ul液體轉至細胞板。細胞繼續在CO2培養箱中培養6天。6天后，加入25ul檢測試劑。室溫孵育10分鐘，Envision讀板。Experimental method: 384-well plate, 300 A431 cells and NCI-H1975 cells per well, 45ul volume. Incubate overnight at 37°C in a CO 2 incubator. The compound to be tested was subjected to a 3-fold gradient dilution to obtain 10 dose concentrations ranging from 10 uM to 0.508 nM, and two replicate wells. Add 49ul medium to each well of the middle plate. Transfer 1 ul of compound from the gradient dilution compound plate to the middle plate and mix well. Then take 5ul of liquid from the middle plate and transfer to the cell plate. The cells continue to be cultured in a CO2 incubator for 6 days. After 6 days, add 25ul of detection reagent. Incubate at room temperature for 10 minutes, and Envision reads the plate.

資料分析：通過下列公式將讀數轉化成抑制率（％）(Max-Sample)/(Max-Min)*100%。4參數曲線擬合（Model 205 in XLFIT5, iDBS）測得IC 50數據。Data analysis: Convert the reading into the inhibition rate (%) (Max-Sample)/(Max-Min)*100% by the following formula. 4 IC50 data was measured by parameter curve fitting (Model 205 in XLFIT5, iDBS).

本發明化合物的野生型EGFR酶抑制IC 50，EGFR L858R/T790M酶抑制IC 50，EGFR d746-750/T790M酶抑制IC 50，NCI-H1975細胞EGFR L858R/T790M的IC 50以及A431 細胞 EGFR WT 的IC50資料在以下表1中展示。 表 1

Figure 106144294-A0304-0001
Wild type EGFR enzyme inhibition IC 50, EGFR L858R/T790M enzyme inhibition IC 50, EGFR d746-750/T790M enzyme inhibition IC 50, NCI-H1975 cell EGFR L858R/T790M IC 50 and A431 cell EGFR WT IC 50 The information is shown in Table 1 below. Table 1
Figure 106144294-A0304-0001

本發明化合物的INSR酶抑制的IC50資料在以下表2中展示。 表 2

Figure 106144294-A0304-0002
The IC50 data of INSR enzyme inhibition of the compounds of the present invention are shown in Table 2 below. Table 2
Figure 106144294-A0304-0002

體內藥效研究 。In vivo drug efficacy research.

以下體內藥效資料表明，本發明的化合物在NCI-H1975非小細胞肺癌患者來源的異種移植（CDX）模型（BALB / c裸鼠）模型上展示了較強的抗腫瘤活性以及減小腫瘤體積。舉例來說，代表性化合物30，33，34，40,42和43在給藥21天后，腫瘤體積從最開始的約149 mm3 減小至3-39 mm3 。The following in vivo pharmacodynamic data indicate that the compounds of the present invention exhibit strong anti-tumor activity and reduce tumor volume in the NCI-H1975 non-small cell lung cancer-derived xenograft (CDX) model (BALB/c nude mice) model . For example, for representative compounds 30, 33, 34, 40, 42 and 43, after 21 days of administration, the tumor volume decreased from the initial about 149 mm 3 to 3-39 mm 3 .

在皮下植入NCI-H1975肺癌患者來源的異種移植（CDX）BALB / c裸小鼠上進行體內藥效實驗：BALB / c裸鼠，雌性，6-8周，體重約18-22克，將小鼠保持在一個特殊的無病原體的環境中，且在單個通風籠中（5只小鼠每籠）。所有的籠子，鋪墊和水在使用前進行消毒。所有的動物都可以自由獲取標準認證的商業實驗室飲食。共有100只購於北京維通利華的小鼠用於研究。每只小鼠在右脅腹皮下植入腫瘤組織（20-30立方毫米），用於腫瘤的生長。當平均腫瘤體積達到約150-200立方毫米時開始實驗。將試驗化合物每日口服給藥(化合物30按10毫克/公斤給藥，化合物33，34，40，42和43按20毫克/公斤給藥，化合物AZD9291按5毫克/公斤，連續給藥21天，資料列於表3）。腫瘤體積一周兩次用二維卡尺測量，體積以立方毫米計量，通過以下公式計算：V = V = 0.5 a x b2，其中a和b分別是腫瘤的長徑和短徑。抗腫瘤藥效是通過用化合物處理過的動物的平均腫瘤增加體積除以未處理過動物的平均腫瘤增加體積來確定。 表 3

Figure 106144294-A0304-0003
In vivo drug efficacy experiments were performed on BALB/c nude mice implanted subcutaneously with NCI-H1975 lung cancer patient-derived xenograft (CDX): BALB/c nude mice, female, 6-8 weeks old, weighing approximately 18-22 grams, will The mice were kept in a special pathogen-free environment and in a single ventilated cage (5 mice per cage). All cages, bedding and water are sterilized before use. All animals have free access to standard certified commercial laboratory diets. A total of 100 mice purchased from Beijing Viton Lihua were used for research. Each mouse was implanted with tumor tissue (20-30 mm3) subcutaneously in the right flank for tumor growth. The experiment started when the average tumor volume reached about 150-200 cubic millimeters. Test compounds were orally administered daily (compound 30 was administered at 10 mg/kg, compounds 33, 34, 40, 42 and 43 were administered at 20 mg/kg, and compound AZD9291 was administered at 5 mg/kg for 21 consecutive days , The information is listed in Table 3). The tumor volume was measured with a two-dimensional caliper twice a week, and the volume was measured in cubic millimeters, calculated by the following formula: V = V = 0.5 ax b2, where a and b are the long and short diameters of the tumor, respectively. The antitumor efficacy is determined by dividing the average tumor increase volume of animals treated with the compound by the average tumor increase volume of untreated animals. table 3
Figure 106144294-A0304-0003

體內選擇性研究。Selective studies in vivo.

以下體內選擇性實驗資料表明，本發明的化合物在A431人皮膚鱗狀細胞癌患者來源的異種移植（CDX）模型（BALB / c裸鼠）模型上展現了良好的體內選擇性。在此模型中，對腫瘤的抑制作用越弱，說明其體內選擇性越好。舉例來說，代表性化合物17，30，37及38(實驗一，結果見表4)在給藥（20毫克/公斤）21天后，腫瘤體積從最開始的約175 mm3 增長至1201~1434 mm3 ，而Afatinib（7.5毫克/公斤）只增長到479 mm3 。代表性化合物33，34及40 (實驗二，結果見表5)在給藥（20毫克/公斤）21天后，腫瘤體積從最開始的約144 mm3 增長至1135~1708 mm3 ，而AZD9291（5毫克/公斤）只增長到321 mm3 。The following in vivo selectivity experimental data indicate that the compound of the present invention exhibits good in vivo selectivity in the A431 human skin squamous cell carcinoma-derived xenograft (CDX) model (BALB/c nude mice) model. In this model, the weaker the inhibitory effect on the tumor, the better the selectivity in vivo. For example, for representative compounds 17, 30, 37, and 38 (Experiment 1, the results are shown in Table 4), after 21 days of administration (20 mg/kg), the tumor volume increased from the initial about 175 mm 3 to 1201~1434 mm 3 , while Afatinib (7.5 mg/kg) only grows to 479 mm 3 . Representative compounds 33, 34 and 40 (Experiment II, the results are shown in Table 5) 21 days after administration (20 mg/kg), the tumor volume increased from the initial about 144 mm 3 to 1135 ~ 1708 mm 3 , while AZD9291 ( 5 mg/kg) only increased to 321 mm 3 .

在皮下植入人皮膚鱗狀細胞A431異種移植（CDX）BALB / c裸小鼠上進行體內選擇性實驗：BALB / c裸鼠，雌性，6-8周，體重約18-20克，將小鼠保持在一個特殊的無病原體的環境中，且在單個通風籠中（5只小鼠每籠）。所有的籠子，鋪墊和水在使用前進行消毒。所有的動物都可以自由獲取標準認證的商業實驗室飲食。所有實驗用小鼠均購於上海BK Laboratory Animal Co., LTD的小鼠用於研究。每只小鼠在右脅腹皮下植入腫瘤組織（20-30立方毫米），用於腫瘤的生長。當平均腫瘤體積達到約150-200立方毫米時開始實驗。將試驗化合物口服給藥(化合物17，30，37和38按20毫克/公斤每日一次給藥，化合物AZD9291按5毫克/公斤每日一次給藥，化合物CO-1686按50毫克/公斤每日兩次給藥，化合物Erlotinib按75毫克/公斤每日一次給藥，化合物Afatinib按7.5毫克/公斤每日一次給藥，連續給藥21天，資料列於表4；化合物33，34，40，42和43按20毫克/公斤每日一次給藥，化合物AZD9291按5毫克/公斤每日一次給藥，連續給藥21天，資料列於表5）。腫瘤體積一周兩次用二維卡尺測量，體積以立方毫米計量，通過以下公式計算：V = V = 0.5 a x b2，其中a和b分別是腫瘤的長徑和短徑。抗腫瘤藥效是通過用化合物處理過的動物的平均腫瘤增加體積除以未處理過動物的平均腫瘤增加體積來確定。 表 4

Figure 106144294-A0304-0004
表5
Figure 106144294-A0304-0005
 In vivo selective experiments were performed on BALB/c nude mice implanted subcutaneously with human skin squamous cell A431 xenograft (CDX): BALB/c nude mice, female, 6-8 weeks old, weighing approximately 18-20 grams, will be small The rats were kept in a special pathogen-free environment and in a single ventilated cage (5 mice per cage). All cages, bedding and water are sterilized before use. All animals have free access to standard certified commercial laboratory diets. All experimental mice were purchased from Shanghai BK Laboratory Animal Co., LTD mice for research. Each mouse was implanted with tumor tissue (20-30 mm3) subcutaneously in the right flank for tumor growth. The experiment started when the average tumor volume reached about 150-200 cubic millimeters. Test compounds were administered orally (compounds 17, 30, 37 and 38 were administered at 20 mg/kg once daily, compound AZD9291 was administered at 5 mg/kg once daily, and compound CO-1686 was administered at 50 mg/kg daily For two administrations, compound Erlotinib was administered once daily at 75 mg/kg, and compound Afatinib was administered once daily at 7.5 mg/kg for 21 consecutive days. The data are listed in Table 4; compounds 33, 34, 40, 42 and 43 are administered once daily at 20 mg/kg, and compound AZD9291 is administered once daily at 5 mg/kg for 21 consecutive days. The data are listed in Table 5). The tumor volume was measured with a two-dimensional caliper twice a week, and the volume was measured in cubic millimeters, calculated by the following formula: V = V = 0.5 ax b2, where a and b are the long and short diameters of the tumor, respectively. The antitumor efficacy is determined by dividing the average tumor increase volume of animals treated with the compound by the average tumor increase volume of untreated animals. Table 4
Figure 106144294-A0304-0004
 table 5
Figure 106144294-A0304-0005

EGFR TKIs的臨床資料顯示，非選擇性抑制野生型EGFR有副作用，包括皮疹和腹瀉；抑制胰島素受體(INSR)會導致高血糖和高胰島素。表1~表5表明，我們的許多化合物不僅對L858R/EGFR T790M和EGFR790M具有優異的體外活性和選擇性，而且在體內具有較好的藥效和體內選擇性，選擇性由對野生型EGFR（A431）和對胰島素受體（INSR）的低抑制活性可以體現出來。這些體外、體內選擇性資料顯示我們的化合物將有更好的安全性。Clinical data of EGFR TKIs shows that non-selective inhibition of wild-type EGFR has side effects, including rash and diarrhea; inhibition of insulin receptor (INSR) can cause hyperglycemia and hyperinsulin. Tables 1 to 5 show that many of our compounds not only have excellent in vitro activity and selectivity for L858R/EGFR T790M and EGFR790M, but also have good efficacy and selectivity in vivo. A431) and low inhibitory activity on insulin receptor (INSR) can be reflected. These in vitro and in vivo selective data show that our compounds will have better safety.

無no

無no

Figure 106144294-A0101-11-0002-3
Figure 106144294-A0101-11-0002-3

Claims (11)

一種式(I)所示的化合物、其藥學上可接受的鹽或異構體，
Figure 106144294-A0305-02-0200-1
 其中，W為：
Figure 106144294-A0305-02-0200-2
 n=1；Y1、Y2和Y3均為-C(R)2-；X1選自CRX1、N；X2選自CRX2、N；X3選自CRX3、N；RX1、RX2、RX3分別獨立地選自H、F、Cl、Br、I、CN、OH、SH、NH2，或RX1、RX2、RX3分別獨立地選自任選被1、2、3或4個R取代的：C1-6烷基、C1-6雜烷基；R1選自H、F、Cl、Me、CN、CF3；R2選自R02、OR02、SR02；R02獨立地選自任選被1、2、3或4個R取代的：C1-4烷基、C1-4雜烷基、C3-5環烷基-(CH2)0-3-；R3選自任選被1、2、3或4個R取代的：C1-6烷基、C1-6雜烷基、C2-4炔基、3~7元環烷基、3~7元環烷基-L-、3~7元雜環烷基、3~7元雜環烷基-L-；L選自-O-、-S-、-C(=O)-、-S(=O)2-、-S(=O)-，或L選自任選被1、2、3或4個R取代的：NH,C1-4烷基、C1-4雜烷基； 「雜」代表雜原子或雜原子團，其選自：-C(=O)NH-、-NH-、-O-、-S-、N、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-；雜原子或雜原子團的數目分別獨立地選自0、1、2、3；R選自H、F、Cl、Br、I、OH、CN，或R選自任選被1、2、3或4個R’取代的：NH2、C1-4烷基、C1-4雜烷基、3~7元環烷基、或3~7元雜環烷基；R’選自F、Cl、Br、I、CN、OH、NH2、CF3、NHCH3、CH2OCH3、N(CH3)2。 A compound represented by formula (I), a pharmaceutically acceptable salt or isomer thereof,
Figure 106144294-A0305-02-0200-1
 Among them, W is:
Figure 106144294-A0305-02-0200-2
 n=1; Y 1 , Y 2 and Y 3 are all -C(R) 2 -; X 1 is selected from CR X1 and N; X 2 is selected from CR X2 and N; X 3 is selected from CR X3 and N; R X1 , R X2 and R X3 are independently selected from H, F, Cl, Br, I, CN, OH, SH, NH 2 , or R X1 , R X2 and R X3 are independently selected from the group consisting of 1, 2, 3 or 4 R substituted: C 1-6 alkyl, C 1-6 heteroalkyl; R 1 is selected from H, F, Cl, Me, CN, CF 3 ; R 2 is selected from R 02 , OR 02 , SR 02 ; R 02 is independently selected from the group optionally substituted by 1, 2, 3 or 4 R: C 1-4 alkyl, C 1-4 heteroalkyl, C 3-5 cycloalkyl-( CH 2 ) 0-3 -; R 3 is selected from optionally substituted with 1, 2, 3 or 4 R: C 1-6 alkyl, C 1-6 heteroalkyl, C 2 -4 alkynyl, 3 ~7 membered cycloalkyl, 3~7 membered cycloalkyl-L-, 3~7 membered heterocycloalkyl, 3~7 membered heterocycloalkyl-L-; L is selected from -O-, -S-, -C(=O)-, -S(=O) 2 -, -S(=O)-, or L is selected from optionally substituted with 1, 2, 3, or 4 R: NH, C 1-4 Alkyl, C 1-4 heteroalkyl; "hetero" represents a heteroatom or heteroatom group selected from: -C(=O)NH-, -NH-, -O-, -S-, N, =O , =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) 2 -; heteroatom or heteroatom The number of atomic groups is independently selected from 0, 1, 2, 3; R is selected from H, F, Cl, Br, I, OH, CN, or R is selected from optionally 1, 2, 3 or 4 R' Substituted: NH 2 , C 1-4 alkyl, C 1-4 heteroalkyl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl; R′ is selected from F, Cl, Br, I , CN, OH, NH 2 , CF 3 , NHCH 3 , CH 2 OCH 3 , N(CH 3 ) 2 . 如請求項1所述的化合物、其藥學上可接受的鹽或異構體，其中R選自H、F、Cl、Br、I、OH、NH2、CN、Me、Et、CF3、N(CH3)2、N(CD3)2、NHCH3、
Figure 106144294-A0305-02-0201-3
 The compound according to claim 1, a pharmaceutically acceptable salt or isomer thereof, wherein R is selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, Et, CF 3 , N (CH 3 ) 2 , N(CD 3 ) 2 , NHCH 3 ,
Figure 106144294-A0305-02-0201-3
 如請求項1或2所述的化合物、其藥學上可接受的鹽或異構體，其中， 結構單元
Figure 106144294-A0305-02-0201-4
選自：
Figure 106144294-A0305-02-0201-5
 The compound according to claim 1 or 2, a pharmaceutically acceptable salt or isomer thereof, wherein the structural unit
Figure 106144294-A0305-02-0201-4
From:
Figure 106144294-A0305-02-0201-5
 如請求項1或2所述的化合物、其藥學上可接受的鹽或異構體，其中R3選自任選被1、2、3或4個R取代的：-C1-4烷基、-NH-C1-4烷基、-NH-C(=O)-C1-4烷基、-O-C1-4烷基、-S-C1-4烷基、-S(=O)-C1-4烷基、-S(=O)2-C1-4烷基、C2-3炔基、3~6元環烷基、3~6元環烷基-L-、3~6元雜環烷基、3~6元雜環烷基-L-，所述「雜」代表雜原子或雜原子團，其選自：-C(=O)NH-、-NH-、-O-、-S-、N、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-，雜原子或雜原子團的數目分別獨立地選自0、1、2、3。 The compound according to claim 1 or 2, a pharmaceutically acceptable salt or isomer thereof, wherein R 3 is selected from optionally substituted with 1, 2, 3, or 4 R: -C 1-4 alkyl , -NH-C 1-4 alkyl, -NH-C(=O)-C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -S(=O)- C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl, C 2 -3 alkynyl, 3~6 membered cycloalkyl, 3~6 membered cycloalkyl-L-, 3~ 6-membered heterocycloalkyl, 3-6 membered heterocycloalkyl-L-, the "hetero" represents a heteroatom or a heteroatom group, selected from: -C(=O)NH-, -NH-, -O -, -S-, N, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S( =O) 2 -, the number of heteroatoms or heteroatom groups are independently selected from 0, 1, 2, and 3, respectively. 如請求項4所述的化合物、其藥學上可接受的鹽或異構體，其中，R3選自任選被1、2、3或4個R取代的：
Figure 106144294-A0305-02-0202-6
 The compound according to claim 4, or a pharmaceutically acceptable salt or isomer thereof, wherein R 3 is selected from optionally substituted with 1, 2, 3, or 4 R:
Figure 106144294-A0305-02-0202-6
 如請求項5所述的化合物、其藥學上可接受的鹽或異構體，其中，R3選自：
Figure 106144294-A0305-02-0202-7
 The compound according to claim 5, or a pharmaceutically acceptable salt or isomer thereof, wherein R 3 is selected from:
Figure 106144294-A0305-02-0202-7
 如請求項1或2所述的化合物、其藥學上可接受的鹽或異構體，其中R02選自Me、CHF2、CH2CH3、CH(CH3)2。 The compound according to claim 1 or 2, a pharmaceutically acceptable salt or isomer thereof, wherein R 02 is selected from Me, CHF 2 , CH 2 CH 3 , CH(CH 3 ) 2 . 如請求項1或2所述的化合物、其藥學上可接受的鹽或異構體，其選自：
Figure 106144294-A0305-02-0203-8
 The compound according to claim 1 or 2, a pharmaceutically acceptable salt or isomer thereof, which is selected from:
Figure 106144294-A0305-02-0203-8
 一種如請求項1-8之任一項所述的化合物、其藥學上可接受的鹽或異構體的製備方法，所述方法包括： 步驟1：式(A)化合物
Figure 106144294-A0305-02-0203-9
與式(B)化合物
Figure 106144294-A0305-02-0203-11
或式(C)化合物
Figure 106144294-A0305-02-0203-10
反應製得式(D)化合物
Figure 106144294-A0305-02-0203-12
； 步驟2：式(D)化合物
Figure 106144294-A0305-02-0203-13
與式(E)化合物
Figure 106144294-A0305-02-0203-14
反應製得式 (F)化合物
Figure 106144294-A0305-02-0203-15
； 步驟3：在鹼的存在下，式(F)化合物
Figure 106144294-A0305-02-0204-16
與R3H反應製得式(G) 化合物
Figure 106144294-A0305-02-0204-17
； 步驟4：式(G)化合物
Figure 106144294-A0305-02-0204-18
製備得到式(H)化合物
Figure 106144294-A0305-02-0204-19
；以及 步驟5：式(H)化合物
Figure 106144294-A0305-02-0205-20
與式(I)化合物
Figure 106144294-A0305-02-0205-21
或式(J)化 合物
Figure 106144294-A0305-02-0205-23
反應製得式(K)化合物
Figure 106144294-A0305-02-0205-22
；
Figure 106144294-A0305-02-0205-24
 其中R1、W、R2和R3如請求項1-8中所述。 A method for preparing a compound according to any one of claims 1-8, a pharmaceutically acceptable salt or isomer thereof, the method comprising: Step 1: a compound of formula (A)
Figure 106144294-A0305-02-0203-9
With compound of formula (B)
Figure 106144294-A0305-02-0203-11
Or compound of formula (C)
Figure 106144294-A0305-02-0203-10
Reaction to prepare compound of formula (D)
Figure 106144294-A0305-02-0203-12
; Step 2: Compound of formula (D)
Figure 106144294-A0305-02-0203-13
With compound of formula (E)
Figure 106144294-A0305-02-0203-14
Reaction to prepare compound of formula (F)
Figure 106144294-A0305-02-0203-15
; Step 3: In the presence of a base, the compound of formula (F)
Figure 106144294-A0305-02-0204-16
Reaction with R 3 H to prepare compound of formula (G)
Figure 106144294-A0305-02-0204-17
; Step 4: Compound of formula (G)
Figure 106144294-A0305-02-0204-18
Preparation of compound of formula (H)
Figure 106144294-A0305-02-0204-19
; And Step 5: Compound of formula (H)
Figure 106144294-A0305-02-0205-20
With the compound of formula (I)
Figure 106144294-A0305-02-0205-21
Or compound of formula (J)
Figure 106144294-A0305-02-0205-23
Reaction to prepare compound of formula (K)
Figure 106144294-A0305-02-0205-22
;
Figure 106144294-A0305-02-0205-24
 Wherein R 1 , W, R 2 and R 3 are as described in claim 1-8. 一種藥物組合物，其包含如請求項1-8之任一項所述的化合物、其藥學上可接受的鹽或異構體和藥學上可接受的載體。 A pharmaceutical composition comprising the compound according to any one of claims 1-8, a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier. 一種如請求項1-8之任一項所述的化合物、其藥學上可接受的鹽或異構體或如請求項10的藥物組合物在製備用於治療腫瘤的藥物中的應用。 Use of a compound according to any one of claims 1-8, a pharmaceutically acceptable salt or isomer thereof, or a pharmaceutical composition according to claim 10 in the preparation of a medicament for treating tumors.
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