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TWI690533B - Compounds as cdk small-molecule inhibitors and uses thereof - Google Patents

Compounds as cdk small-molecule inhibitors and uses thereof Download PDF

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TWI690533B
TWI690533B TW104141541A TW104141541A TWI690533B TW I690533 B TWI690533 B TW I690533B TW 104141541 A TW104141541 A TW 104141541A TW 104141541 A TW104141541 A TW 104141541A TW I690533 B TWI690533 B TW I690533B
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present
compound
inhibitor
independently
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TW201643171A (en
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劉兵
張英俊
聶凜凜
柏舜
常春 鄭
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南北兄弟藥業投資有限公司
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Abstract

本發明涉及新的作為CDK類小分子抑制劑的化合物(如式(I)所示)及其用途，還涉及含有上述化合物的藥物組合物，以及這些化合物和組合物在治療過度增殖性紊亂的疾病的用途。本發明的新化合物是有力的細胞週期蛋白依賴性激酶4(cdk4)或細胞週期蛋白依賴性激酶6(cdk6)抑制劑。 The present invention relates to new compounds as small molecule inhibitors of CDK (as shown in formula (I)) and uses thereof, and also to pharmaceutical compositions containing the above compounds, as well as the use of these compounds and compositions in the treatment of hyperproliferative disorders The use of disease. The novel compounds of the present invention are potent inhibitors of cyclin-dependent kinase 4 (cdk4) or cyclin-dependent kinase 6 (cdk6).

Figure 104141541-A0101-11-0001-1
Figure 104141541-A0101-11-0001-1

Description

CDK類小分子抑制劑的化合物及其用途 CDK-type small molecule inhibitor compounds and their use

本發明涉及新的作為CDK類小分子抑制劑的化合物及其藥物組合物，還涉及這些化合物和組合物在治療過度增殖性紊亂疾病的用途。 The present invention relates to new compounds as small molecule inhibitors of CDKs and their pharmaceutical compositions, and to the use of these compounds and compositions in the treatment of hyperproliferative disorders.

近年來，腫瘤已超越心血管疾病，成為全球第一大死亡疾病，抗腫瘤藥物研究具有重要的學術和現實意義。研究發現，幾乎所有的腫瘤都與細胞週期調控機制紊亂所導致的細胞生長失控，分化受阻以及凋亡異常有關。 In recent years, tumors have surpassed cardiovascular diseases and become the world's largest death disease. The study of anti-tumor drugs has important academic and practical significance. The study found that almost all tumors are related to uncontrolled cell growth, blocked differentiation, and abnormal apoptosis caused by disordered cell cycle regulatory mechanisms.

哺乳動物細胞週期的開始、進行和結束受各種對細胞生長很關鍵的細胞週期蛋白依賴性激酶(CDK)複合物調控。這些複合物至少包含催化(CDK本身)和調控(細胞週期蛋白)亞基。對於細胞週期調控而言一些更重要的複合物包括細胞週期蛋白A(CDK1-也稱為CDC2，和CDK2)，細胞週期蛋白B1-B3(CDK1)和細胞週期蛋白D1-D3(CDK2，CDK4，CDK5，CDK6)，細胞週期蛋白E(CDK2)。這些複合物各自參與細胞週期的特定階段。CDK的活性通過與其它蛋白的短暫締合和通過其細胞內定位的改變而在翻譯後被調控。腫瘤發生與CDK及其調控物的基因改變和失控緊密相關，這表明CDK的抑制劑可用於抗癌治療。 The beginning, progression, and end of the mammalian cell cycle are regulated by various cyclin-dependent kinase (CDK) complexes that are critical to cell growth. These complexes contain at least catalytic (CDK itself) and regulatory (cyclin) subunits. Some of the more important complexes for cell cycle regulation include cyclin A (CDK1-also known as CDC2, and CDK2), cyclin B1-B3 (CDK1) and cyclin D1-D3 (CDK2, CDK4, CDK5, CDK6), cyclin E (CDK2). These complexes are each involved in specific stages of the cell cycle. The activity of CDK is regulated after translation through transient association with other proteins and through changes in its intracellular localization. Oncogenesis is closely related to genetic changes and runaway of CDK and its regulators, which indicates that CDK inhibitors can be used for anti-cancer therapy.

CDK及其相關蛋白在增殖細胞統籌與驅動細胞週期的過程中起到了一些生化途徑的關鍵作用。在一般的CDK或特異性CDK上使用靶向療法，可用於增殖性障礙例如：癌症的治療。可以想像，CDK抑制劑也可以用於治療其他病症，例如病毒性感染、自身免疫性疾病和神經變性疾病等。CDK靶向治療與現有藥物進行組合治療，可獲得更好的臨床效果。相比許多現有的抗腫瘤藥物，CDK靶向抗癌治療具有更多的潛在性優點， 因為它們不直接與DNA相互作用，所以應當能夠降低繼發的腫瘤發展的風險。 CDK and its related proteins play a key role in some biochemical pathways in the process of proliferating cell coordination and driving the cell cycle. Targeted therapy on general CDK or specific CDK can be used for the treatment of proliferative disorders such as cancer. It is conceivable that CDK inhibitors can also be used to treat other conditions, such as viral infections, autoimmune diseases, and neurodegenerative diseases. CDK targeted therapy combined with existing drugs can achieve better clinical results. Compared with many existing anti-tumor drugs, CDK targeted anti-cancer therapy has more potential advantages, Because they do not directly interact with DNA, they should be able to reduce the risk of secondary tumor development.

雖然有許多CDK抑制劑類化合物已經被公開，但是，由於受CDK介導的病理的原因，仍然需要大量用於治療與CDK有關的障礙的大量藥物，特別是CDK4/6抑制劑類藥物。 Although many CDK inhibitor compounds have been published, due to the pathology mediated by CDK, a large number of drugs for treating CDK-related disorders are still needed, especially CDK4/6 inhibitor drugs.

大量用於與蛋白激酶有關的障礙，特別是可用於治療或預防或改善癌症，自身免疫性疾病和感染類疾病的一種或多種症狀的化合物仍然處於需要中。本發明提供的化合物可用於調節蛋白激酶如CDK系列的活性，主要是調節或抑制CDK1、CDK2、CDK4、CDK6或CDK9的活性，特別是調節或抑制CDK4或CDK6的活性，具有較好的臨床應用前景。與已有的同類化合物相比，本發明的化合物具有更好的體內藥效、藥代性質和/或毒理特性。 A large number of compounds that are used for disorders related to protein kinases, especially for treating or preventing or ameliorating cancer, autoimmune diseases, and one or more symptoms of infectious diseases are still in need. The compound provided by the present invention can be used to regulate the activity of protein kinases such as CDK series, mainly regulating or inhibiting the activity of CDK1, CDK2, CDK4, CDK6 or CDK9, especially regulating or inhibiting the activity of CDK4 or CDK6, and has good clinical application prospect. Compared with existing similar compounds, the compounds of the present invention have better in vivo pharmacodynamics, pharmacokinetic properties and/or toxicological properties.

一方面，本發明提供一種化合物，其為如式(I)所示的化合物，或式(I)所示的化合物的立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，代謝產物，酯，藥學上可接受的鹽或前藥，

Figure 104141541-A0101-12-0002-3
In one aspect, the invention provides a compound that is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the compound represented by formula (I), Hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
Figure 104141541-A0101-12-0002-3

其中：L為鍵，-(C(R3b)2)n-，-N(R1)-(C(R3b)2)n-，-O-(C(R3b)2)n-，-S(=O)m-或-C(=O)-(C(R3b)2)n-； A環為

Figure 104141541-A0101-12-0002-5
Figure 104141541-A0101-12-0003-23
 其中，當
Figure 104141541-A0101-12-0003-215
為=時，T為X，
Figure 104141541-A0101-12-0003-254
為
Figure 104141541-A0101-12-0003-256
當
Figure 104141541-A0101-12-0003-216
為-時，T為X6，
Figure 104141541-A0101-12-0003-255
為
Figure 104141541-A0101-12-0003-252
R為氫，R13，-(C(R3b)2)n-N(R1a)-C(=O)-(C(R3b)2)n-R13或-(CH2)n-C(=O)-N(R1a)-(C(R3b)2)n-R13；R13為氫，C3-9環烷基，C1-9雜芳基，C2-9雜環基，C5-11螺雜雙環基，C5-11橋雜雙環基或C5-11稠合雜雙環基；其中，X7，X5和X6各自獨立地為-C(R3a)2-，-N(R2)-，-O-，-S(=O)m-或-C(=O)-；X，X1，X2，X3和X4各自獨立地為CR3a或N；各n獨立地為0，1，2，3或4；各n1獨立地為1，2或3；各m獨立地為0，1或2；各R1a，R1和R2獨立地為氫，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，C2-9雜環基，C1-9雜芳基，C3-9環烷基或C1-4烷基；各R3a，R3b和R3獨立地為氫，氟，氯，溴，C1-4烷基，羥基，羧基， 氨基，C2-9雜環基，C1-9雜芳基，C3-9環烷基，C1-4鹵代烷基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-，H-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；各R4獨立地為氫，C1-4烷基，羥基，羧基，氨基，C1-4烷氧基，氨基C1-4烷基，NH2-C(=O)-，C2-9雜環基，C1-9雜芳基，C3-9環烷基，C1-4鹵代烷基或C1-4烷氨基；所述的A代表的各子結構式可獨立任選地被1，2，3或4個相同或不同之選自氫，C1-4烷基，氟，氯，溴，氨基，羥基，羧基，C1-4烷氧基，C1-4鹵代烷基，C1-4烷基氨基，氨基C1-4烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，氰基或硝基的取代基所取代；其中，R，R1a，R2，R1和R13中所述的烷基，鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，N(R4)2-C(=O)-，H-(C(R3)2)n-SO2-(C(R3)2)n-，-(C(R3)2)n-N(R4)2，HO-(C(R3)2)n-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，螺雜雙環基，橋雜雙環基，稠合雜雙環基，雜環基，環烷基，雜芳基，和H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，可獨立任選地被1，2，3或4個相同或不同的R5取代；各R5獨立地為氫，氧代(=O)，C1-6烷基，氟，氯，溴，氨基，羥基，羧基，C1-4烷氧基，C1-4烷氨基，氨基C1-4烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，C1-6鹵代烷基，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，氰基，C2-9雜環基，C3-9環烷基，C1-9雜芳基或硝基；各R5中所述的烷基，烷氧基，烷氨基，氨基烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-， H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，雜環基，環烷基和雜芳基獨立任選地進一步被1，2，3或4個相同或不同的R6取代；各R6獨立地為氫，氧代(=O)，C1-4烷基，氟，氯，溴，氨基，羥基，羧基，C1-4烷氧基，C1-4烷氨基，氨基C1-4烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，氰基，C2-9雜環基，C3-9環烷基，C1-9雜芳基或硝基。 Where: L is a bond, -(C(R 3b ) 2 ) n -, -N(R 1 )-(C(R 3b ) 2 ) n -, -O-(C(R 3b ) 2 ) n -, -S(=O) m -or -C(=O)-(C(R 3b ) 2 ) n -; ring A is
Figure 104141541-A0101-12-0002-5
Figure 104141541-A0101-12-0003-23
 Among them, when
Figure 104141541-A0101-12-0003-215
When =, T is X,
Figure 104141541-A0101-12-0003-254
for
Figure 104141541-A0101-12-0003-256
when
Figure 104141541-A0101-12-0003-216
Is-when T is X 6 ,
Figure 104141541-A0101-12-0003-255
for
Figure 104141541-A0101-12-0003-252
R is hydrogen, R 13 , -(C(R 3b ) 2 ) n -N(R 1a )-C(=O)-(C(R 3b ) 2 ) n -R 13 or -(CH 2 ) n- C(=O)-N(R 1a )-(C(R 3b ) 2 ) n -R 13 ; R 13 is hydrogen, C 3-9 cycloalkyl, C 1-9 heteroaryl, C 2-9 Heterocyclic group, C 5-11 spiro heterobicyclic group, C 5-11 bridge heterobicyclic group or C 5-11 fused heterobicyclic group; wherein, X 7 , X 5 and X 6 are each independently -C(R 3a ) 2 -, -N(R 2 )-, -O-, -S(=O) m -or -C(=O)-; X, X 1 , X 2 , X 3 and X 4 are each independently CR 3a or N; each n is independently 0, 1, 2, 3 or 4; each n1 is independently 1, 2 or 3; each m is independently 0, 1 or 2; each R 1a , R 1 and R 2 is independently hydrogen, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N- (C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C( R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C (=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, C 2-9 heterocyclyl, C 1-9 heteroaryl, C 3-9 cycloalkyl or C 1-4 alkyl; each R 3a , R 3b and R 3 are independently hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, hydroxy , Carboxyl, amino, C 2-9 heterocyclyl, C 1-9 heteroaryl, C 3-9 cycloalkyl, C 1-4 haloalkyl, H-(CH 2 ) n -O-(CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C(=O)-( CH 2 ) n -, H-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; each R 4 is independently hydrogen, C 1-4 alkyl, hydroxy, carboxy, amino, C 1-4 alkoxy, Amino C 1-4 alkyl, NH 2 -C(=O)-, C 2-9 heterocyclyl, C 1-9 heteroaryl, C 3-9 cycloalkyl, C 1-4 haloalkyl or C 1-4 alkylamino; each substructure represented by A can be optionally selected from 1, 2, 3 or 4 the same or different from hydrogen, C 1-4 alkyl, fluorine, chlorine, bromine , Amino, hydroxy, carboxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkylamino, amino C 1-4 alkyl, H-(C(R 3 ) 2 ) n- OC(=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(= O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)- (C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C( =O)-(C(R 3 ) 2 ) n -, substituted by a substituent of cyano or nitro; wherein, the alkyl, halogenated alkyl described in R, R 1a , R 2 , R 1 and R 13 , H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -,-(C(R 3 ) 2 ) n -N(R 4 ) 2 , HO-(C(R 3 ) 2 ) n- C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C( R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, spiro heterobicyclic group, bridge hetero Bicyclic group, fused heterobicyclic group, heterocyclic group, cycloalkyl group, heteroaryl group, and H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3) 2) n -, optionally substituted independently 2, 3 or 4 identical or different R 5; each R 5 is independently hydrogen, oxo (= O), C 1-6 alkyl , Fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C 1-4 alkoxy, C 1-4 alkylamino, amino C 1-4 alkyl, N( R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -C(=O)-, C 1-6 haloalkyl, H-(C(R 3 ) 2 ) n- OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, H- (C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, cyano, C 2-9 heterocyclyl, C 3-9 cycloalkyl, C 1-9 heteroaryl or Nitro; alkyl, alkoxy, alkylamino, aminoalkyl, N(R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -described in each R 5 C(=O)-, haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, heterocyclyl, ring Alkyl and heteroaryl are independently optionally further substituted with 1, 2, 3 or 4 identical or different R 6 ; each R 6 is independently hydrogen, oxo (=O), C 1-4 alkyl, Fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C 1-4 alkoxy, C 1-4 alkylamino, amino C 1-4 alkyl, N(R 4 ) 2 -C(=O)-, CN -(C(R 3 ) 2 ) n -C(=O)-, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(=O)-(C (R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, cyano, C 2-9 heterocyclyl, C 3-9 ring Alkyl, C 1-9 heteroaryl or nitro.

一些實施例中，本發明所述的化合物，其為如式(II)或式(III)所示的化合物，或式(II)或式(III)所示的化合物的立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，代謝產物，酯，藥學上可接受的鹽或前藥，

Figure 104141541-A0101-12-0005-16
In some embodiments, the compound of the present invention is a compound represented by formula (II) or formula (III), or a stereoisomer of a compound represented by formula (II) or formula (III), geometric Isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
Figure 104141541-A0101-12-0005-16

其中：L為鍵，-(CH2)n-，-N(R1)-，-O-，-S-或-C(=O)-；當

Figure 104141541-A0101-12-0005-217
為=時，T為X；當
Figure 104141541-A0101-12-0005-218
為-時，T為X6；n，R1，X，X1，X2，X3，X4，X5，X6，X7和R13具有如本發明所述的含義。 Where: L is a bond, -(CH 2 ) n -, -N(R 1 )-, -O-, -S- or -C(=O)-; when
Figure 104141541-A0101-12-0005-217
When =, T is X; when
Figure 104141541-A0101-12-0005-218
When is -, T is X 6 ; n, R 1 , X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and R 13 have the meanings as described in the present invention.

一些實施例中， R13為氫，

Figure 104141541-A0101-12-0006-18
Figure 104141541-A0101-12-0006-21
 其中，Y，Y1，Y7和Y2各自獨立地為-C(R3c)2-，-N(R2b)-，-O-，-S(=O)m-或-C(=O)-；Y3，Y4和Y5各自獨立地為CR3c或N；各e，r，g和f獨立地為0，1，2或3；各R2b獨立地為氫，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-或C1-4烷基；各R3c獨立地為氫，氟，氯，溴，C1-4烷基，羥基，羧基，氨基，C1-4鹵代烷基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-，H-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-。 In some embodiments, R 13 is hydrogen,
Figure 104141541-A0101-12-0006-18
Figure 104141541-A0101-12-0006-21
 Where Y, Y 1 , Y 7 and Y 2 are each independently -C(R 3c ) 2 -, -N(R 2b )-, -O-, -S(=O) m -or -C(= O)-; Y 3 , Y 4 and Y 5 are each independently CR 3c or N; each e, r, g and f are independently 0, 1, 2 or 3; each R 2b is independently hydrogen, C 1 -4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H- (C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H -(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-( C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -or C 1-4 alkyl; each R 3c is independently hydrogen, fluorine, chlorine , Bromine, C 1-4 alkyl, hydroxy, carboxy, amino, C 1-4 haloalkyl, H-(CH 2 ) n -O-(CH 2 ) n -, N(R 4 ) 2 -C(= O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C(=O)-(CH 2 ) n -, H-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -.

其中，R3、n、R4和m具有如本發明所述的含義。 Among them, R 3 , n, R 4 and m have the meanings as described in the present invention.

一些實施例中， R13為環丙基，環己基，環戊基，環丁基，氫，

Figure 104141541-A0101-12-0007-24
Figure 104141541-A0101-12-0007-25
 其中，所述的R13代表的各子結構式可獨立任選地進一步被R5單取代或相同或不同的多取代；其中，R5具有如本發明所述的含義。 In some embodiments, R 13 is cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl, hydrogen,
Figure 104141541-A0101-12-0007-24
Figure 104141541-A0101-12-0007-25
 Wherein, each sub-structural formula represented by R 13 may be independently further optionally substituted by R 5 or substituted by the same or different multiples; wherein, R 5 has the meaning as described in the present invention.

一些實施例中， A環為

Figure 104141541-A0101-12-0008-27
Figure 104141541-A0101-12-0008-28
 其中，所述的A代表的各子結構式可獨立任選地進一步被1，2，3或4個相同或不同之選自氫，C1-4烷基，氟，氯，溴，氨基，羥基，羧基，C1-4 烷氧基，C1-4鹵代烷基，C1-4烷基氨基，氨基C1-4烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，氰基或硝基的取代基所取代；R3a、R2、R3、R4和n具有如本發明所述的含義。 In some embodiments, ring A is
Figure 104141541-A0101-12-0008-27
Figure 104141541-A0101-12-0008-28
 Wherein, each sub-structural formula represented by A can be optionally further independently selected from 1, 2, 3 or 4 which are the same or different from hydrogen, C 1-4 alkyl, fluorine, chlorine, bromine, amino, Hydroxy, carboxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkylamino, amino C 1-4 alkyl, H-(C(R 3 ) 2 ) n -OC(= O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)- , N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C( R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O) -(C(R 3 ) 2 ) n -, substituted by a substituent of cyano or nitro; R 3a , R 2 , R 3 , R 4 and n have the meanings as described in the present invention.

一些實施例中，各R3a，R3b和R3獨立地為氫，氟，氯，溴，羥基，羧基，氨基，三氟甲基，甲基，乙基，丙基，丁基，環丙基，環己基，環戊基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；各R4獨立地為氫，羥基，羧基，氨基，甲氧基，氨基甲基，氨基乙基，NH2-C(=O)-，三氟甲基，2,2-二氟乙基，甲基，乙基，丙基或丁基；其中，n具有如本發明所述的含義。 In some embodiments, each R 3a , R 3b and R 3 are independently hydrogen, fluorine, chlorine, bromine, hydroxyl, carboxyl, amino, trifluoromethyl, methyl, ethyl, propyl, butyl, cyclopropyl Group, cyclohexyl, cyclopentyl, H-(CH 2 ) n -O-(CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; each R 4 is independently hydrogen , Hydroxyl, carboxyl, amino, methoxy, aminomethyl, aminoethyl, NH 2 -C(=O)-, trifluoromethyl, 2,2-difluoroethyl, methyl, ethyl, propylene Radical or butyl; wherein, n has the meaning as described in the present invention.

一些實施例中，本發明所述的化合物，各R1a，R1和R2獨立地為氫，3,3,3-三氟丙基，三氟甲基，1,1-二氟乙基，環丙基，環己基，環戊基，環丁基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，

Figure 104141541-A0101-12-0009-32
Figure 104141541-A0101-12-0009-31
，甲基，乙基，丙基或丁基；各R5獨立地為氫，氧代(=O)，甲基，乙基，丙基，丁基，氟，氯，溴，氨基，羥基，羧基，甲氧基，C1-4烷氨基，氨基C1-4烷基，N(R4)2-C(=O)-， CN-(C(R3)2)n-C(=O)-，三氟甲基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，
Figure 104141541-A0101-12-0010-36
Figure 104141541-A0101-12-0010-34
，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，氰基，環丙基，環己基，環戊基或硝基；各R6獨立地為氫，氧代(=O)，甲基，乙基，丙基，丁基，氟，氯，溴，氨基，羥基，羧基，甲氧基，C1-4烷氨基，氨基C1-4烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，氰基，C3-6雜環基，C3-6環烷基或硝基；其中，n1、R4、R3和n具有如本發明所述的含義。 In some embodiments, in the compound of the present invention, each R 1a , R 1 and R 2 are independently hydrogen, 3,3,3-trifluoropropyl, trifluoromethyl, 1,1-difluoroethyl , Cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)-, N(R 4 ) 2 -C(=O)-, HO-(C (R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -( C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -,
Figure 104141541-A0101-12-0009-32
Figure 104141541-A0101-12-0009-31
, Methyl, ethyl, propyl or butyl; each R 5 is independently hydrogen, oxo (=O), methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, amino, hydroxyl, Carboxy, methoxy, C 1-4 alkylamino, amino C 1-4 alkyl, N(R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -C(= O)-, trifluoromethyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -,
Figure 104141541-A0101-12-0010-36
Figure 104141541-A0101-12-0010-34
, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-( C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(= O)-(C(R 3 ) 2 ) n -, cyano, cyclopropyl, cyclohexyl, cyclopentyl or nitro; each R 6 is independently hydrogen, oxo (=O), methyl, ethyl Group, propyl, butyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, methoxy, C 1-4 alkylamino, amino C 1-4 alkyl, N(R 4 ) 2 -C(=O )-, CN-(C(R 3 ) 2 ) n -C(=O)-, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C( R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H- (C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, cyano, C 3-6 heterocyclyl, C 3-6 cycloalkyl or nitro; wherein, n1, R 4 , R 3 and n have The meaning of the invention.

一方面，本發明提供一種藥物組合物，包含一種如本發明所述化合物。 In one aspect, the invention provides a pharmaceutical composition comprising a compound according to the invention.

一些實施例中，本發明所述的藥物組合物，進一步包含藥學上可接受的載體，賦形劑，稀釋劑，輔劑，媒介物中的至少一種。 In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.

一些實施例中，本發明所述的藥物組合物，更進一步包含附加治療劑，這些附加治療劑為化學治療藥物，抗增殖劑，免疫抑制劑，免疫刺激劑，抗炎性試劑，用於治療動脈粥樣硬化的藥物，用於治療肺纖維化的藥物，CDK4/6激酶抑制劑，ABL抑制劑，ABL/Scr抑制劑，極光激酶抑制劑，Bcr-ABL的非-ATP競爭性抑制劑，c-KIT突變抑制劑，RET抑制劑，PDGFR抑制劑，VEGFR抑制劑，CSF1R抑制劑，FLT3抑制劑，FLT3-ITD抑制劑或它們的組合。 In some embodiments, the pharmaceutical composition of the present invention further includes additional therapeutic agents. These additional therapeutic agents are chemotherapeutic drugs, antiproliferative agents, immunosuppressive agents, immunostimulants, and anti-inflammatory agents. Atherosclerosis drugs, drugs used to treat pulmonary fibrosis, CDK4/6 kinase inhibitors, ABL inhibitors, ABL/Scr inhibitors, Aurora kinase inhibitors, non-ATP competitive inhibitors of Bcr-ABL, c-KIT mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFR inhibitor, CSF1R inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or a combination thereof.

一些實施例中，本發明所述的藥物組合物，其中所述的附加 治療劑是苯丁酸氮芥，美法侖，環磷醯胺，異環磷醯胺，白消安，卡莫司汀，洛莫司汀，鏈脲佐菌素，順鉑，卡鉑，奧沙利鉑，達卡巴嗪，替莫唑胺，丙卡巴肼，甲氨蝶呤，氟尿嘧啶，阿糖胞苷，吉西他濱，巰基嘌呤，氟達拉濱，長春鹼，長春新鹼，長春瑞濱，紫杉醇，多西紫杉醇，拓撲替康，伊立替康，依託泊苷，曲貝替定，更生黴素，多柔比星，表柔比星，道諾黴素，米托蒽醌，博來黴素，絲裂黴素C，伊沙匹隆，他莫昔芬，氟他胺，戈那瑞林類似物，甲地孕酮，強的松，地塞米松，甲潑尼龍，沙利度胺，干擾素α，亞葉酸鈣，西羅莫司，西羅莫司脂化物，依維莫司，阿法替尼，阿帕替尼，阿西替尼，硼替佐米，波舒替尼，卡博替尼(cabozantinib)，西地尼布，克卓替尼，達拉非尼(dabrafenib)，達克替尼(dacomitinib)，達沙替尼，多韋替尼(dovitinib)，厄洛替尼，吉非替尼，伊布替尼(ibrutinib)，埃克替尼，伊馬替尼，拉帕替尼，樂伐替尼(lenvatinib)，馬賽替尼，莫替沙尼，來那替尼，尼祿替尼，尼拉帕尼(niraparib)，奥拉帕尼(olaparib)，帕唑帕尼，帕納替尼(ponatinib)，瑞格菲尼(regorafenib)，瑞卡帕布(rucaparib)，魯索替尼(ruxolitinib)，塞卡替尼，索拉非尼，舒尼替尼，特拉替尼(telatinib)，托法替尼(tofacitinib)，曲美替尼(trametinib)，凡德他尼，維利帕尼(veliparib)，威羅菲尼，維莫德吉(vismodegib)，阿侖單抗，貝伐單抗，本妥昔單抗(brentuximab vedotin)，卡妥索單抗，西妥昔單抗，地諾單抗，吉妥珠單抗，伊匹單抗，尼妥珠單抗，奧法木單抗，帕尼單抗，利妥昔單抗，托西莫單抗，曲妥珠單抗，卡博替尼，普納替尼，米哚妥林(Midostaurin)，吉特替尼(gilteritinib)，法米替尼(Famitinib)，哌柏西利(palbociclib)，夫拉平度(Alvocidib)或它們的組合。 In some embodiments, the pharmaceutical composition of the present invention, wherein the additional Therapeutic agents are chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, Oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, Docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, Mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interference Alpha alpha, calcium folinate, sirolimus, sirolimus lipid, everolimus, afatinib, apatinib, axitinib, bortezomib, bosutinib, kabo Cabozantinib, sildenib, crizotinib, dabrafenib, dacomitinib, dasatinib, dovitinib, erlotinib, gil Fetinib, ibrutinib, icotinib, imatinib, lapatinib, lenvatinib, mazatinib, motezinib, lenatinib, nero Tenib, niraparib, olaparib, pazopanib, ponatinib, regorafenib, rucaparib, ruso Tenix (ruxolitinib), Secatinib, Sorafenib, Sunitinib, Telatinib, Tofacitinib, Trametinib, Vandetanib, Veliparib, velovinib, vismodegib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab Mab, denolimumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab Zumuzumab, Carbotinib, Punitinib, Midosturin, gilteritinib, Famitinib, palbociclib, Alvocidib ) Or a combination of them.

另一方面，本發明所述化合物或本發明所述的藥物組合物在製備用於預防，處理，治療或減輕患者由異常細胞增殖，自身免疫，炎性或感染引起的障礙或病症的藥物中的用途。 On the other hand, the compound of the present invention or the pharmaceutical composition of the present invention is in the preparation of a medicament for preventing, treating, treating or alleviating a disorder or condition caused by abnormal cell proliferation, autoimmunity, inflammation or infection in a patient the use of.

另一方面，一種運用本發明所述化合物或本發明所述的藥物組合物來製備預防，處理，治療或減輕患者由異常細胞增殖，自身免疫， 炎性或感染引起的障礙或病症的藥物的方法。 On the other hand, a compound of the present invention or the pharmaceutical composition of the present invention is used to prepare for prevention, treatment, treatment or alleviation of abnormal cell proliferation and autoimmunity in patients, Inflammation or infection caused by a method of medicine for disorders or conditions.

另一方面，本發明所述化合物或本發明所述的藥物組合物用於預防，處理，治療或減輕患者由異常細胞增殖，自身免疫，炎性或感染引起的障礙或病症。 In another aspect, the compound of the present invention or the pharmaceutical composition of the present invention is used to prevent, treat, treat or alleviate a patient's disorder or condition caused by abnormal cell proliferation, autoimmunity, inflammation or infection.

一些實施例中，本發明所述的用途，其中所述的異常細胞增殖疾病是指卵巢癌，子宮頸癌，睾丸癌，食道癌，胃癌，皮膚癌，肺癌，骨癌，急性髓性白血病，慢性髓性白血病，胃腸基質腫瘤，急性髓細胞性白血病(AML)，突變的慢性髓性白血病(CML)，急性淋巴細胞白血病(ALL)，結直腸癌，胃癌，乳腺癌，肺癌，肝癌，前列腺癌，胰腺癌，甲狀腺癌，腎癌，腦瘤，頸癌，中樞神經系統的癌症，惡性膠質瘤，骨髓增生病，動脈粥樣硬化，肺纖維化，白血病，淋巴癌，風濕性疾病，冷球蛋白血症，非淋巴網狀系統腫瘤，丘疹性黏蛋白沉積症，家族性脾性貧血，多發性骨髓瘤，澱粉樣變，孤立性漿細胞瘤，重鏈病，輕鏈病，惡性淋巴瘤，慢性淋巴細胞白血病，原發性巨球蛋白血症，半分子病，單核細胞白血病，原發性巨球蛋白血症紫癜，繼發性良性單克隆丙種球蛋白病，溶骨性病變，淋巴母細胞瘤，非霍奇金淋巴瘤，Sezary綜合征，傳染性單核細胞增多症，急性組織細胞增多症，霍奇金淋巴瘤，毛細胞白血病，結腸癌，直腸癌，腸道息肉，小細胞肺癌，神經母細胞瘤，神經內分泌細胞腫瘤，胰島細胞瘤，甲狀腺髓樣癌，黑色素瘤，視網膜母細胞瘤，子宮癌，卵巢癌，頭頸部鱗癌，消化道惡性腫瘤，非小細胞肺癌，宮頸癌，睾丸腫瘤，膠質母細胞瘤，套細胞淋巴瘤，慢性粒細胞白血病，急性粒細胞白血病，膀胱癌或骨髓瘤。 In some embodiments, the use according to the present invention, wherein the abnormal cell proliferation disease refers to ovarian cancer, cervical cancer, testicular cancer, esophageal cancer, gastric cancer, skin cancer, lung cancer, bone cancer, acute myeloid leukemia, Chronic myeloid leukemia, gastrointestinal stromal tumors, acute myeloid leukemia (AML), mutated chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate Cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, central nervous system cancer, malignant glioma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic disease, cold Globulinemia, non-lymphoid reticulum tumors, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma , Chronic lymphocytic leukemia, primary macroglobulinemia, semimolecular disease, monocyte leukemia, primary macroglobulinemia purpura, secondary benign monoclonal gammopathy, osteolytic lesions, Lymphoblastoma, non-Hodgkin's lymphoma, Sezary syndrome, infectious mononucleosis, acute histiocytosis, Hodgkin's lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyps, Small cell lung cancer, neuroblastoma, neuroendocrine cell tumor, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterine cancer, ovarian cancer, head and neck squamous cell carcinoma, gastrointestinal malignant tumor, non-small cell Lung cancer, cervical cancer, testicular tumor, glioblastoma, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, bladder cancer or myeloma.

一些實施例中，本發明所述的用途，其中，所述自身免疫疾病是風濕性關節炎，狼瘡，多發性硬化，甲狀腺炎，I型糖尿病，結節病，炎性腸病，克羅恩氏疾病或全身性狼瘡。 In some embodiments, the use according to the present invention, wherein the autoimmune disease is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, inflammatory bowel disease, Crohn's Disease or systemic lupus.

一些實施例中，本發明所述的用途，其中，其中所述的炎性疾病是指憩室炎，結腸炎，胰腺炎，肝炎，慢性肝炎，肝硬化，膽囊炎或慢性炎症。 In some embodiments, the use according to the present invention, wherein the inflammatory disease refers to diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.

一些實施例中，本發明所述的用途，其中所述的感染疾病是 指病毒感染和真菌感染。 In some embodiments, the use according to the present invention, wherein the infectious disease is Refers to viral infections and fungal infections.

一些實施例中，本發明所述的用途，其中所述障礙或病症是細胞週期蛋白依賴性激酶改變引起的疾病。 In some embodiments, the use according to the present invention, wherein the disorder or condition is a disease caused by changes in cyclin-dependent kinases.

一些實施例中，本發明所述的用途，所述的細胞週期蛋白依賴性激酶是指CDK1、CDK2、CDK4、CDK6或CDK9。 In some embodiments, in the use of the present invention, the cyclin-dependent kinase refers to CDK1, CDK2, CDK4, CDK6 or CDK9.

一種聯合用藥，其包含本發明所述的化合物或本發明所述的藥物組合物和一種或多種用於治療增殖性疾病、自體免疫疾病或炎性疾病的其他活性藥劑。 A combined medicine comprising the compound of the present invention or the pharmaceutical composition of the present invention and one or more other active agents for the treatment of proliferative diseases, autoimmune diseases or inflammatory diseases.

一些實施例中，本發明所述的聯合用藥，其中所述的其他活性藥劑是指化學治療藥物，抗增殖劑，免疫抑制劑，免疫刺激劑，抗炎性試劑，CDK4/6激酶抑制劑，ABL抑制劑，ABL/Scr抑制劑，極光激酶抑制劑，Bcr-ABL的非-ATP競爭性抑制劑，c-KIT突變抑制劑，RET抑制劑，PDGFR抑制劑，VEGFR抑制劑，CSF1R抑制劑，FLT3抑制劑，FLT3-ITD抑制劑或它們的組合。 In some embodiments, the combination of the present invention, wherein the other active agents refer to chemotherapeutic drugs, antiproliferative agents, immunosuppressive agents, immunostimulants, anti-inflammatory agents, CDK4/6 kinase inhibitors, ABL inhibitor, ABL/Scr inhibitor, Aurora kinase inhibitor, non-ATP competitive inhibitor of Bcr-ABL, c-KIT mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFR inhibitor, CSF1R inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or a combination thereof.

本發明的化合物適宜作為藥物組合物中的活性劑，所述藥物組合物可有效治療與蛋白激酶有關的病症，例如癌症、移植物排斥和自身免疫性疾病。各種實施方案中的藥物組合物具有藥學有效量的本發明的活性劑以及其它藥學可接受的賦形劑、載體、填充劑、稀釋劑等。本發明所用的措辭“藥學有效量”表示為實現治療結果、尤其是調控、調節或抑制蛋白激酶活性，例如抑制蛋白激酶活性或治療癌症、移植物排斥或自身免疫性疾病而必須施用於宿主或施用於宿主的細胞、組織或器官的量。 The compounds of the present invention are suitable as active agents in pharmaceutical compositions that can effectively treat protein kinase-related disorders, such as cancer, graft rejection, and autoimmune diseases. The pharmaceutical composition in various embodiments has a pharmaceutically effective amount of the active agent of the present invention and other pharmaceutically acceptable excipients, carriers, fillers, diluents, and the like. The expression "pharmaceutically effective amount" as used in the present invention means that it must be administered to the host or to achieve therapeutic results, especially to regulate, regulate or inhibit protein kinase activity, such as inhibiting protein kinase activity or treating cancer, graft rejection or autoimmune diseases. The amount of cells, tissues or organs applied to the host.

另外，本發明提供了一種抑制蛋白激酶活性的方法。該方法包括使細胞與任何一種本發明的化合物接觸。在一個相關的實施方案中，該方法進一步提供了以有效地選擇性抑制蛋白激酶活性的量存在的所述化合物。 In addition, the present invention provides a method for inhibiting protein kinase activity. The method includes contacting the cells with any of the compounds of the invention. In a related embodiment, the method further provides the compound present in an amount effective to selectively inhibit protein kinase activity.

前面所述內容只概述了本發明的某些方面，但並不限於這些方面。其他的方面的內容將在下面作更加具體完整的描述。 The foregoing describes only certain aspects of the invention, but is not limited to these aspects. The content of other aspects will be described more specifically and completely below.

定義和一般術語Definitions and general terms

現在詳細描述本發明的某些實施方案，其實例由隨附的結構式和化學式說明。本發明意圖涵蓋所有的替代、修改和等同技術方案，它們均包括在如申請專利範圍所定義的本發明範圍內。本領域技術人員應認識到，許多與本發明所述類似或等同的方法和材料能夠用於實踐本發明。本發明絕不限於本發明所述的方法和材料。在所結合的文獻、專利和類似材料的一篇或多篇與本申請不同或相矛盾的情況下(包括但不限於所定義的術語、術語應用、所描述的技術，等等)，以本申請為準。 Some embodiments of the present invention will now be described in detail, examples of which are illustrated by the accompanying structural formula and chemical formula. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included in the scope of the present invention as defined by the scope of the patent application. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is by no means limited to the methods and materials described in the present invention. In the case where one or more of the incorporated documents, patents, and similar materials are different or contradictory to this application (including but not limited to defined terms, terminology, described technology, etc.), The application shall prevail.

應進一步認識到，本發明的某些特徵，為清楚可見，在多個獨立的實施方案中進行了描述，但也可以在單個實施例中以組合形式提供。反之，本發明的各種特徵，為簡潔起見，在單個實施方案中進行了描述，但也可以單獨或以任意適合的子組合提供。 It should be further recognized that certain features of the present invention have been described in multiple independent embodiments for clarity, but may also be provided in combination in a single embodiment. Conversely, various features of the invention have been described in a single embodiment for the sake of brevity, but can also be provided individually or in any suitable sub-combination.

除非另外說明，本發明所使用的所有科技術語具有與本發明所屬領域技術人員的通常理解相同的含義。本發明涉及的所有專利和公開出版物通過引用方式整體併入本發明。 Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated by reference in their entirety.

除非另外說明，應當應用本發明所使用的下列定義。出於本發明的目的，化學元素與元素週期表CAS版，和《化學和物理手冊》，第75版，1994一致。此外，有機化學一般原理可參考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito：1999，和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley & Sons,New York：2007中的描述，其全部內容通過引用併入本發明中。 Unless otherwise stated, the following definitions used in the present invention shall apply. For the purposes of the present invention, chemical elements are consistent with the CAS version of the periodic table of elements, and the Handbook of Chemistry and Physics, 75th edition, 1994. In addition, the general principles of organic chemistry can refer to "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 The entire content of the description is incorporated into the present invention by reference.

除非另有說明或者上下文中有明顯的衝突，本發明所使用的冠詞“一”、“一個(種)”和“所述”旨在包括“至少一個”或“一個或多個”。因此，本發明所使用的這些冠詞是指一個或多於一個(即至少一個)賓語的冠詞。例如，“一組分”指一個或多個組分，即可能有多於一個的組分被考慮 在所述實施方案的實施方式中採用或使用。 Unless otherwise stated or there is a clear conflict in the context, the articles "a", "an" and "said" used in the present invention are intended to include "at least one" or "one or more". Therefore, the articles used in the present invention refer to one or more than one (ie, at least one) object articles. For example, "a component" refers to one or more components, ie more than one component may be considered Used or used in the embodiments of the embodiments.

本發明所使用的術語“受試物件”是指動物。典型地所述動物是哺乳動物。受試物件，例如也指靈長類動物(例如人類，男性或女性)、牛、綿羊、山羊、馬、犬、貓、兔、大鼠、小鼠、魚、鳥等。在某些實施方案中，所述受試物件是靈長類動物。在其他實施方案中，所述受試物件是人。 The term "test object" as used in the present invention refers to an animal. Typically the animal is a mammal. The test object, for example, also refers to primates (eg, humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the test object is a primate. In other embodiments, the test object is a human.

本發明所使用的術語“患者”是指人(包括成人和兒童)或者其他動物。在一些實施方案中，“患者”是指人。 As used herein, the term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

術語“包含”為開放式表達，即包括本發明所指明的內容，但並不排除其他方面的內容。 The term "comprising" is an open-ended expression, that is, it includes the content specified by the present invention, but does not exclude other aspects.

“立體異構體”是指具有相同化學構造，但原子或基團在空間上排列方式不同的化合物。立體異構體包括對映異構體、非對映異構體、構象異構體(旋轉異構體)、幾何異構體(順/反)異構體、阻轉異構體，等等。 "Stereoisomer" refers to compounds that have the same chemical structure, but the atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

“手性”是具有與其鏡像不能重疊性質的分子；而“非手性”是指與其鏡像可以重疊的分子。 "Chiral" is a molecule that has the property of not overlapping with its mirror image; "Achiral" refers to a molecule that can overlap with its mirror image.

“對映異構體”是指一個化合物的兩個不能重疊但互成鏡像關係的異構體。 "Enantiomer" refers to two isomers of a compound that cannot overlap but are mirror images of each other.

“非對映異構體”是指有兩個或多個手性中心並且其分子不互為鏡像的立體異構體。非對映異構體具有不同的物理性質，如熔點、沸點、光譜性質和反應性。非對映異構體混合物可通過高分辨分析操作如電泳和色譜，例如HPLC來分離。 "Diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Diastereomer mixtures can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.

本發明所使用的立體化學定義和規則一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley & Sons，Inc.，New York，1994。 The stereochemical definitions and rules used in the present invention generally follow SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

許多有機化合物以光學活性形式存在，即它們具有使平面偏振光的平面發生旋轉的能力。在描述光學活性化合物時，使用首碼D和L或R和S來表示分子關於其一個或多個手性中心的絕對構型。首碼d和l或 (+)和(-)是用於指定化合物所致平面偏振光旋轉的符號，其中(-)或l表示化合物是左旋的。首碼為(+)或d的化合物是右旋的。一種具體的立體異構體是對映異構體，這種異構體的混合物稱作對映異構體混合物。對映異構體的50：50混合物稱為外消旋混合物或外消旋體，當在化學反應或過程中沒有立體選擇性或立體特異性時，可出現這種情況。 Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the first codes D and L or R and S are used to denote the absolute configuration of the molecule about one or more of its chiral centers. First code d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by a compound, where (-) or l indicates that the compound is left-handed. Compounds with an initial code (+) or d are right-handed. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

本發明公開化合物的任何不對稱原子(例如，碳等)都可以以外消旋或對映體富集的形式存在，例如(R)-、(S)-或(R,S)-構型形式存在。在某些實施方案中，各不對稱原子在(R)-或(S)-構型方面具有至少50%對映體過量，至少60%對映體過量，至少70%對映體過量，至少80%對映體過量，至少90%對映體過量，至少95%對映體過量，或至少99%對映體過量。 Any asymmetric atoms (for example, carbon, etc.) of the compounds disclosed in the present invention can exist in racemic or enantiomerically enriched forms, such as (R)-, (S)-, or (R,S)-configuration exist. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, at least in the (R)- or (S)-configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

依據起始物料和方法的選擇，本發明化合物可以以可能的異構體中的一個或它們的混合物，例如外消旋體和非對應異構體混合物(這取決於不對稱碳原子的數量)的形式存在。光學活性的(R)-或(S)-異構體可使用手性合成子或手性試劑製備，或使用常規技術拆分。如果化合物含有一個雙鍵，取代基可能為E或Z構型；如果化合物中含有二取代的環烷基，環烷基的取代基可能有順式或反式構型。 Depending on the choice of starting materials and methods, the compounds of the invention may be in one of the possible isomers or their mixtures, such as racemates and diastereomer mixtures (this depends on the number of asymmetric carbon atoms) Form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.

所得的任何立體異構體的混合物可以依據組分物理化學性質上的差異被分離成純的或基本純的幾何異構體，對映異構體，非對映異構體，例如，通過色譜法和/或分步結晶法。 The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography Method and/or step crystallization method.

可以用已知的方法將任何所得終產物或中間體的外消旋體通過本領域技術人員熟悉的方法拆分成光學對映體，如，通過對獲得的其非對映異構的鹽進行分離。外消旋的產物也可以通過手性色譜來分離，如，使用手性吸附劑的高效液相色譜(HPLC)。特別地，對映異構體可以通過不對稱合成製備，例如，可參考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques：A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH & Co.KGaA,Weinheim,Germany,2007)。 The racemates of any resulting end products or intermediates can be resolved into optical enantiomers by methods known to those skilled in the art using known methods, for example, by obtaining the diastereomeric salts obtained Separate. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis ( 2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

術語“互變異構體”或“互變異構形式”是指具有不同能量的可通過低能壘(low energy barrier)互相轉化的結構異構體。若互變異構是可能的(如在溶液中)，則可以達到互變異構體的化學平衡。例如，質子互變異構體(protontautomer)(也稱為質子轉移互變異構體(prototropic tautomer))包括通過質子遷移來進行的互相轉化，如酮-烯醇異構化和亞胺-烯胺異構化。價鍵互變異構體(valence tautomer)包括通過一些成鍵電子的重組來進行的互相轉化。酮-烯醇互變異構的具體實例是戊烷-2,4-二酮和4-羥基戊-3-烯-2-酮互變異構體的互變。互變異構的另一個實例是酚-酮互變異構。酚-酮互變異構的一個具體實例是吡啶-4-醇和吡啶-4(1H)-酮互變異構體的互變。除非另外指出，本發明化合物的所有互變異構體形式都在本發明的範圍之內。 The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversion through proton migration, such as keto-enol isomerization and imine-enamine isomerization Texturing. Valence tautomers include interconversion through the recombination of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

在本說明書的各部分，本發明公開化合物的取代基按照基團種類或範圍公開。特別指出，本發明包括這些基團種類和範圍的各個成員的每一個獨立的次級組合。例如，術語“C1-C6烷基”特別指獨立公開的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。 In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of groups. In particular, the present invention includes each independent sub-combination of each member of these group types and ranges. For example, the term “C 1 -C 6 alkyl” particularly refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.

在本發明的各部分，描述了連接取代基。當該結構清楚地需要連接基團時，針對該基團所列舉的馬庫什變數應理解為連接基團。例如，如果該結構需要連接基團並且針對該變數的馬庫什基團定義列舉了“烷基”或“芳基”，則應該理解，該“烷基”或“芳基”分別代表連接的亞烷基基團或亞芳基基團。 In various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents the linked group, respectively An alkylene group or an arylene group.

像本發明所描述的，本發明的化合物可以獨立任選地被一個或多個取代基所取代，如上面的通式化合物，或者像實施例裡面特殊的例子，子類，和本發明所包含的一類化合物。應瞭解“任選取代的”這個術語與“取代或非取代的”這個術語可以交換使用。一般而言，術語“獨立任選地”不論是否位於術語“取代的”之前，表示所給結構中的一個或多個氫原子可以被具體取代基1所取代或未取代。除非其他方面表明，一個任選的取代基團可以有一個取代基1在基團的各個可取代的位置進行取代或未取代。當 所給出的結構式中不只一個位置能被選自具體基團的一個或多個取代基1所取代，那麼取代基可以相同或不同地在各個位置取代。其中所述的取代基1可以是，但並不限於：氧代(=O)，氟，氯，溴，碘，羥基，氨基，羧基，烷基，烷基-S(=O)t-，鹵代烷基，羥基烷基，氨基烷基，醛基，氨基醯基，烷氧基，烷氨基，烷硫基，鹵代烷氧基，氰基，芳基，雜芳基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基烷氧基，烷基-(C=O)-，苄基，環丙基，苯基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，或烷氧基烷基等。在合理的情況下，取代基1能進一步被取代基2單取代或相同或不同的多取代。其中所述的取代基2可以是，但不限於：氧代(=O)，氟，氯，溴，碘，羥基，氨基，羧基，烷基，烷基-S(=O)t-，鹵代烷基，羥基烷基，氨基烷基，醛基，氨基醯基，烷氧基，烷氨基，烷硫基，鹵代烷氧基，氰基，芳基，雜芳基，烯基，炔基，雜環基，巰基，硝基，芳氧基，羥基烷氧基，烷基-(C=O)-，苄基，環丙基，苯基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，或烷氧基烷基等。其中，t為0，1或2；n，R3和R4具有如本發明所述的含義。 As described in the present invention, the compounds of the present invention may be independently and optionally substituted with one or more substituents, such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples A class of compounds. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". In general, the term "independently optional" whether or not preceding the term "substituted" means that one or more hydrogen atoms in a given structure may be substituted or unsubstituted by a specific substituent 1. Unless otherwise indicated, an optional substituent may have a substituent 1 substituted or unsubstituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents 1 selected from specific groups, then the substituents can be substituted at the same positions or differently. The substituent 1 can be, but not limited to: oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S(=O) t -, Haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde, aminoacyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, hetero Cyclic, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, N(R 4 ) 2 -C(=O)- , CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, or Alkoxyalkyl and so on. Under reasonable circumstances, the substituent 1 can be further mono-substituted by the substituent 2 or multi-substituted by the same or different. The substituent 2 may be, but not limited to: oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S(=O) t -, haloalkane Group, hydroxyalkyl, aminoalkyl, aldehyde, aminoacyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic Group, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, N(R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, or alkane Oxyalkyl and so on. Where t is 0, 1 or 2; n, R 3 and R 4 have the meanings as described in the present invention.

本發明使用的術語“烷基”包括1-20個碳原子飽和直鏈或支鏈的單價烴基，其中烷基可以獨立獨立任選地被一個或多個本發明所描述的取代基所取代。其中一些實施例是，烷基基團含有1-10個碳原子；另外一些實施例是，烷基基團含有1-8個碳原子；另外一些實施例是，烷基基團含有1-6個碳原子，另外一些實施例是，烷基基團含有1-4個碳原子；另外一些實施例是，烷基基團含有1-3個碳原子。烷基基團更進一步的實例包括，但並不限於，甲基(Me，-CH3)，乙基(Et，-CH2CH3)，正丙基(n-Pr，-CH2CH2CH3)，異丙基(i-Pr，-CH(CH3)2)，正丁基(n-Bu，-CH2CH2CH2CH3)，2-甲基丙基或異丁基(i-Bu，-CH2CH(CH3)2)，1-甲基丙基或仲丁基(s-Bu，-CH(CH3)CH2CH3)，叔丁基(t-Bu，-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基 (-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。術語“烷基”和其首碼“烷”在此處使用，都包含直鏈和支鏈的飽和碳鏈。烷基可以被本發明所述的取代基所取代。 The term "alkyl" used in the present invention includes a monovalent hydrocarbon group saturated with a linear or branched chain of 1 to 20 carbon atoms, wherein the alkyl group may be independently substituted with one or more substituents described in the present invention. Some of these embodiments are that the alkyl group contains 1-10 carbon atoms; other embodiments are that the alkyl group contains 1-8 carbon atoms; other embodiments are that the alkyl group contains 1-6 In other embodiments, the alkyl group contains 1-4 carbon atoms; in other embodiments, the alkyl group contains 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu , -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 ) CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH (CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3 -Pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-di Methyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3), N-heptyl, n-octyl, etc. The term "alkyl" and its initial "alkane" are used herein to include both linear and branched saturated carbon chains. The alkyl group may be substituted with the substituents described in the present invention.

術語“鹵代烷基”表示烷基可以被一個或多個相同或不同鹵素原子所取代的情況。其中烷基基團具有如本發明所述的含義，這樣的實例包括，但並不限於三氟甲基，2,2-二氟乙基，3,3,3-三氟丙基等。鹵代烷基可以被本發明所述的取代基所取代。 The term "haloalkyl" means that the alkyl group may be substituted with one or more same or different halogen atoms. Where the alkyl group has the meaning as described in the present invention, such examples include, but are not limited to trifluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, and the like. The haloalkyl group may be substituted with the substituents described in the present invention.

術語“氨基”是指具有式-NH2的基團。 The term "amino" refers to a group having the formula -NH 2.

術語“氨基烷基”是指具有式R’R”N-烷基的基團，其中R’和R”分別獨立地是氫，烷基或鹵代烷基。是指烷基可以被一個或多個相同或不同的氨基取代的情況。其中，烷基具有如本發明所述的含義。氨基烷基可以被本發明所述的取代基所取代。 The term "aminoalkyl" refers to a group having the formula R'R"N-alkyl, where R'and R" are each independently hydrogen, alkyl or haloalkyl. Refers to the case where the alkyl group may be substituted with one or more same or different amino groups. Among them, the alkyl group has the meaning as described in the present invention. The aminoalkyl group may be substituted with the substituents described in the present invention.

術語“氨基醯基”是指具有式R’R”N-C(=O)-的基團，其中R’和R”分別獨立地是氫，烷基或鹵代烷基。 The term "aminoacyl" refers to a group having the formula R'R"N-C(=O)-, wherein R'and R" are each independently hydrogen, alkyl or haloalkyl.

術語“烷氨基”或者“烷基氨基”包括“N-烷基氨基”和“N，N-二烷基氨基”，其中氨基基團分別獨立地被一個或兩個烷基基團所取代，其中烷基基團具有如本發明所述的含義。其中一些實施例是，烷基氨基是一個或兩個C1-6烷基連接到氮原子上的較低級的烷基氨基基團。另外一些實施例是，烷基氨基是C1-3的較低級的烷基氨基基團。合適的烷基氨基基團可以是單烷基氨基或二烷基氨基，這樣的實例包括，但並不限於，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基等等。烷氨基或者烷基氨基可以被本發明所述的取代基所取代。 The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted by one or two alkyl groups, Wherein the alkyl group has the meaning as described in the present invention. In some of these embodiments, the alkylamino group is a lower alkylamino group having one or two C 1-6 alkyl groups attached to a nitrogen atom. In other embodiments, the alkylamino group is a lower alkylamino group of C 1-3 . Suitable alkylamino groups may be monoalkylamino or dialkylamino, such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N -Diethylamino and so on. The alkylamino group or alkylamino group may be substituted with the substituents described in the present invention.

本發明中所使用的術語“烷氧基”，涉及到烷基，像本發明所定義的，通過氧原子連接到主要的碳鏈上。這樣的實施例包括，但並不限 於，甲氧基，乙氧基，丙氧基等等。烷氧基可以被本發明所述的取代基所取代。 The term "alkoxy" used in the present invention refers to an alkyl group, as defined in the present invention, is connected to the main carbon chain through an oxygen atom. Such embodiments include, but are not limited to Yu, methoxy, ethoxy, propoxy and so on. The alkoxy group may be substituted by the substituent described in the present invention.

術語“環烷基”或“碳環”是指一價或多價，非芳香族，飽和或部分不飽和環，且不包含雜原子，其中包括3-12個碳原子的單環或7-12個碳原子的二環或三環。具有7-12個原子的雙碳環可以是二環[4,5]，[5,5]，[5,6]或[6,6]體系，同時具有9或10個原子的雙碳環可以是二環[5,6]或[6,6]體系。合適的環烷基基團包括，但並不限於，環烷基，環烯基和環炔基。環烷基基團的實例進一步包括，但絕不限於，環丙基，環丁基，環戊基，1-環戊基-1-烯基，1-環戊基-2-烯基，1-環戊基-3-烯基，環己基，1-環己基-1-烯基，1-環己基-2-烯基，1-環己基-3-烯基，環己二烯基，環庚基，環辛基，環壬基，環癸基，環十一烷基，環十二烷基，金剛烷基等等。視結構而定，環烷基可為單價基團或二價基團，即亞環烷基。C4環烷基是指環丁基，C5環烷基是指環戊基，C7環烷基是指環庚基。環烷基可以被本發明所述的取代基所取代。 The term "cycloalkyl" or "carbocyclic ring" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring, and does not contain heteroatoms, including a monocyclic ring of 3-12 carbon atoms or 7- 12 carbon atoms bicyclic or tricyclic. Bicarbon rings with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, and bicarbon rings with 9 or 10 atoms It can be a bicyclic [5,6] or [6,6] system. Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of cycloalkyl groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1 -Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cyclo Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl and so on. Depending on the structure, the cycloalkyl group may be a monovalent group or a divalent group, that is, a cycloalkylene group. C 4 cycloalkyl refers to cyclobutyl, C 5 cycloalkyl refers to cyclopentyl, and C 7 cycloalkyl refers to cycloheptyl. The cycloalkyl group may be substituted with the substituents described in the present invention.

術語“芳基”可以是單環，雙環，和三環的碳環體系，其中，至少一個環體系是芳香族的，其中每一個環體系包含3-7個原子，且只有一個附著點與分子的其餘部分相連。術語“芳基”可以和術語“芳香環”交換使用，如芳香環可以包括苯基，萘基和蒽。視結構而定，芳基可為單價基團或二價基團，即亞芳基。芳基可以被本發明所述的取代基所取代。 The term "aryl" can be monocyclic, bicyclic, and tricyclic carbocyclic systems, where at least one ring system is aromatic, where each ring system contains 3-7 atoms, and there is only one attachment point with the molecule The rest of the connection. The term "aryl" may be used interchangeably with the term "aromatic ring". For example, the aromatic ring may include phenyl, naphthyl, and anthracene. Depending on the structure, the aryl group may be a monovalent group or a divalent group, that is, an arylene group. The aryl group may be substituted with the substituents described in the present invention.

術語“雜芳基”，“雜芳環”在此處可交換使用，都是指單環，雙環，三環或者四環體系，其中，雙環雜芳環，三環雜芳環或者四環雜芳環體系以稠合的形式成環。其中，雜芳環體系至少一個環體系是芳香族的，，環上一個或多個原子獨立任選地被雜原子所取代(雜原子選自N，O，P，S，在此S或P獨立任選地被一個或多個氧原子所取代得到像SO，SO2，PO，PO2的基團)。雜芳體系可以在任何雜原子或者碳原子上連接到主結構上從而形成穩定的化合物。雜芳體系基團可以是3-7個原子組成的單環，或7-10個原子組成的雙環，或10-15個原子組成的三環。具有7-10個原子的雙環可以是二環[4,5]，[5,5]，[5,6]或[6,6]體系，具有10-15個原子的三環可以是三環[5,5,6]，[5,7,6]或[6,5,6]體系。 The terms "heteroaryl" and "heteroaryl ring" are used interchangeably herein, and all refer to monocyclic, bicyclic, tricyclic or tetracyclic ring systems, where bicyclic heteroaryl ring, tricyclic heteroaryl ring or tetracyclic hetero ring Aromatic ring systems form rings in fused form. Among them, at least one ring system of the heteroaromatic ring system is aromatic, and one or more atoms on the ring are optionally substituted by heteroatoms (the heteroatoms are selected from N, O, P, S, where S or P Independently optionally substituted with one or more oxygen atoms to give groups like SO, SO 2 , PO, PO 2 ). The heteroaromatic system can be connected to the main structure at any heteroatom or carbon atom to form a stable compound. The heteroaromatic system group may be a monocyclic ring composed of 3-7 atoms, or a bicyclic ring composed of 7-10 atoms, or a tricyclic ring composed of 10-15 atoms. Bicyclic rings with 7-10 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, tricyclic rings with 10-15 atoms can be tricyclic [5,5,6], [5,7,6] or [6,5,6] system.

另外一些實施例是，雜芳體系(包含雜芳基，雜芳環)包括以下例子，但並不限於這些例子：呋喃-2-基，呋喃-3-基，N-咪唑基，咪唑-2-基，咪唑-4-基，咪唑-5-基，異噁唑-3-基，異噁唑-4-基，異噁唑-5-基，噁唑-2-基，噁唑-4-基，噁唑-5-基，4-甲基異噁唑-5-基，N-吡咯基，吡咯-2-基，吡咯-3-基，吡啶-2-基，吡啶-3-基，吡啶-4-基，嘧啶-2-基，嘧啶-4-基，嘧啶-5-基，噠嗪基(如噠嗪-3-基)，噻唑-2-基，噻唑-4-基，噻唑-5-基，四唑基(如四唑-5-基)，三唑基(如三唑-2-基和三唑-5-基)，噻吩-2-基，噻吩-3-基，吡唑基(如吡唑-2-基)，異噻唑基，噁唑並吡啶基，環氧乙烷基，茶嵌二氮苯基，菲啶基，菲繞啉基，吩砒嗪基，吩嗪基，吩噻嗪基，吩噁嗪基，酞嗪基，蝶啶基，吡啶並吡啶基，喹唑啉基，喹噁啉基，硫代苯基，三嗪基，咪唑並[2',1'：2,3]噻唑並[5,4-b]吡啶基，咪唑並[2',1'：2,3]噻唑並[4,5-c]吡啶基，1H-苯並[f]咪唑並[4,5-b][1,4]硫氮雜卓基等。雜芳基可以被本發明所述的取代基所取代。 In other embodiments, the heteroaromatic system (including heteroaryl, heteroaromatic ring) includes the following examples, but is not limited to these examples: furan-2-yl, furan-3-yl, N-imidazolyl, imidazol-2 -Yl, imidazol-4-yl, imidazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazole-4 -Yl, oxazol-5-yl, 4-methylisoxazol-5-yl, N-pyrrolyl, pyrrol-2-yl, pyrrol-3-yl, pyridin-2-yl, pyridin-3-yl , Pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazinyl (such as pyridazin-3-yl), thiazol-2-yl, thiazol-4-yl, Thiazol-5-yl, tetrazolyl (such as tetrazole-5-yl), triazolyl (such as triazol-2-yl and triazol-5-yl), thiophen-2-yl, thiophen-3-yl , Pyrazolyl (such as pyrazol-2-yl), isothiazolyl, oxazolopyridyl, oxirane, diazaphenyl, phenanthridinyl, phenanthridinyl, phenanthridinyl , Phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridinyl, quinazolinyl, quinoxalinyl, thiophenyl, triazinyl, imidazo[ 2',1': 2,3]thiazolo[5,4-b]pyridyl, imidazo[2',1': 2,3]thiazolo[4,5-c]pyridyl, 1H-benzene And [f] imidazo[4,5-b][1,4] thiazolidine and so on. The heteroaryl group may be substituted with the substituents described in the present invention.

術語“雜環基”，“雜環”，“雜脂環族”或“雜環的”在此處可交換使用，都是指單環，雙環，三環或者四環體系，其中環上一個或多個原子獨立任選地被雜原子所取代，環可以是完全飽和的或包含一個或多個不飽和度，但絕不是芳香族類。雜環體系可以在任何雜原子或者碳原子上連接到主結構上從而形成穩定的化合物。一個或多個環上的氫原子獨立任選地被一個或多個本發明所描述的取代基所取代。其中一些實施例是，“雜環基”，“雜環”，“雜脂環族”或“雜環的”基團是3-7元環的單環(1-6個碳原子和選自N，O，P，S的1-3個雜原子，在此S或P獨立任選地被一個或多個氧原子所取代得到像SO，SO2，PO，PO2的基團，同時，-CH2-基團可以獨立任選地被-C(=O)-替代；當所述的環為三元環時，其中只有一個雜原子)，或7-10個原子組成的雙環(4-9個碳原子和選自N，O，P，S的1-3個雜原子，在此N，S或P獨立任選地被一個或多個氧原子所取代得到像NO，NO2，SO，SO2，PO，PO2的基團，同時，-CH2-基團可以獨立任選地被-C(=O)-替代；)。 The terms "heterocyclic", "heterocyclic", "heteroalicyclic" or "heterocyclic" are used interchangeably herein, and refer to monocyclic, bicyclic, tricyclic or tetracyclic systems, where one of the rings Or multiple atoms are independently optionally substituted with heteroatoms, the ring may be fully saturated or contain one or more unsaturations, but by no means are aromatic. Heterocyclic systems can be attached to the main structure at any heteroatom or carbon atom to form a stable compound. The hydrogen atoms on one or more rings are independently optionally substituted with one or more substituents described in the present invention. Some of these embodiments are that the "heterocyclyl", "heterocyclic", "heteroalicyclic" or "heterocyclic" groups are 3-7 membered monocyclic rings (1-6 carbon atoms and 1-3 heteroatoms of N, O, P, S, where S or P are independently optionally substituted with one or more oxygen atoms to obtain groups like SO, SO 2 , PO, PO 2 and, at the same time, The -CH 2 -group can be optionally replaced by -C(=O)-; when the ring is a three-membered ring, in which there is only one heteroatom), or a bicyclic ring consisting of 7-10 atoms (4 -9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where N, S or P are independently optionally substituted by one or more oxygen atoms to obtain NO, NO 2 , SO, SO 2 , PO, PO 2 groups, and at the same time, -CH 2 -group can be independently and optionally replaced by -C(=O)-;).

“雜環基”可以是碳基或雜原子基。“雜環基”同樣也包括雜環基團與飽和或部分不飽和碳環或雜環併合所形成的基團。雜環的實例包 括，但並不限於，吡咯烷基，四氫呋喃基，二氫呋喃基，四氫噻吩基，四氫吡喃基，二氫吡喃基，四氫噻喃基，呱啶基，噻噁烷基，氮雜環丁基，氧雜環丁基，硫雜環丁基，呱啶基，高呱啶基，環氧丙基，氮雜環庚基，氧雜環庚基，硫雜環庚基，N-嗎啉基，2-嗎啉基，3-嗎啉基，硫代嗎啉基，N-呱嗪基，2-呱嗪基，3-呱嗪基，高呱嗪基，1,2,3,6-四氫吡啶-1-基，氧氮雜卓基，二氮雜卓基，硫氮雜卓基，吡咯啉-1-基，2-吡咯啉基，3-吡咯啉基，二氫吲哚基，2-吲哚啉基，2H-吡喃基，4H-吡喃基，二氧雜環己基，1,3-二氧戊基，二噻烷基，二噻茂烷基，二氫噻吩基，咪唑烷基，1,2,3,4-四氫異喹啉基，1,2,6-噻二嗪烷1,1-二氧-2-基，六氫-2H-[1,4]二氧芑[2,3-c]吡咯基，喹嗪基，1,1-二氧化硫代嗎啉基，2,3,3a,7a-四氫-1H-異吲哚基，異吲哚啉基，1,2,3,4-四氫喹啉基，二氫苯並異噻嗪基，二氫苯並異噁嗪基，二氧戊環基，二氫吡嗪基，二氫吡啶基，二氫吡唑基，二氫嘧啶基，二氫吡咯基，1,4-二噻烷基，呋喃酮基，呋喃基，咪唑烷基，咪唑啉基，咪唑基，咪唑並吡啶基，咪唑並噻唑基，吲唑基，二氫吲哚基，吲哚嗪基，吲哚基，異苯並四氫呋喃基，異苯並四氫噻嗯基，異苯並二氫吡喃基，異香豆素基，異二氫吲哚基，異噻唑烷基，異噁唑烷基，嗎啉基，十氫吲哚基，十氫異吲哚基，噁唑烷二酮基，噁唑烷基，環氧乙烷基，呱嗪基，呱啶基，4-呱啶酮基，吡唑烷基，喹寧環基，四氫異喹啉基，四氫噻嗯基，硫嗎啉基，噻唑烷基，1,3,5-三噻烷基，2-氧代吡咯烷基，氧代-1,3-噻唑烷基，2-呱啶酮基，3,5-二氧代呱啶基，吲哚啉基，1,2,3,4-四氫異喹啉基，1,3-苯並二噁茂基，2-氧雜-5-氮雜雙環[2.2.1]庚-5-基，4-氧代嗎啉基和嘧啶二酮基。 The "heterocyclic group" may be a carbon group or a heteroatom group. "Heterocyclyl" also includes groups formed by the combination of a heterocyclic group with a saturated or partially unsaturated carbocyclic or heterocyclic ring. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, pyridinyl, Thioxanyl, azetidinyl, oxetanyl, thietanyl, pyridinyl, homopyridinyl, epoxypropyl, azacycloheptyl, oxetanyl, sulfur Heterocyclic heptyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-pentazinyl, 2-pentazinyl, 3-pentazinyl, homopyrazine Group, 1,2,3,6-tetrahydropyridin-1-yl, oxazepinyl, diazepinyl, thiazolyl, pyrrolin-1-yl, 2-pyrrolinyl, 3 -Pyrrolidinyl, dihydroindolyl, 2-indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, dithienyl, Dithioalkyl, dihydrothienyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxo-2-yl , Hexahydro-2 H -[1,4]dioxin[2,3-c]pyrrolyl, quinazinyl, 1,1-dithiothiomorpholinyl, 2,3,3a,7a-tetrahydro- 1H-isoindolyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dioxolyl , Dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, 1,4-dithioalkyl, furanone, furanyl, imidazolidinyl, imidazoline Group, imidazolyl, imidazopyridyl, imidazothiazolyl, indazolyl, dihydroindolyl, indolizinyl, indolyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, iso Benzodihydropyranyl, isocoumarinyl, isodihydroindolyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, decahydroindolyl, decahydroisoindolyl, oxazole Alkanedione, oxazolidinyl, ethylene oxide, pyrazinyl, pyridinyl, 4-pyridinone, pyrazolidinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydro Thienyl, thiomorpholinyl, thiazolidinyl, 1,3,5-trithianyl, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-pyridinone, 3,5-dioxopyridinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxoloyl, 2-oxa-5-aza Bicyclo[2.2.1]hept-5-yl, 4-oxomorpholinyl and pyrimidinedione.

在一些實施例中，雜環基為4-7個原子組成的雜環基，是指包含4-7個環原子的飽和或部分不飽和的單環，其中至少一個環原子選自氮、硫和氧原子。4-7個原子組成的雜環基的實例包括，但不限於，氮雜環丁基，氧雜環丁基，硫雜環丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氫呋喃基，二氫呋喃基，四氫噻吩基，二氫噻吩基，1,3-二氧環戊基，二硫環戊基，四氫吡喃基，二氫吡喃基，2H-吡喃基，4H-吡喃基，四氫噻喃基，呱啶基，嗎啉基，硫代嗎啉基，呱嗪基，二噁烷基，二噻烷基，噻噁烷基，高呱嗪基，高呱啶基， 氧雜環庚烷基，硫雜環庚烷基，氧氮雜□基，二氮雜□基，硫氮雜□基，等等。雜環基中-CH2-基團被-C(=O)-替代的實例包括，但不限於，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-呱啶酮基、3,5-二氧代呱啶基、嘧啶二酮基，等等。雜環基中硫原子被氧化的實例包括，但不限於，環丁碸基、硫代嗎啉基1,1-二氧化物，等等。所述的4-7個原子組成的雜環基基團任選地被一個或多個本發明所描述的取代基所取代。 In some embodiments, the heterocyclic group is a heterocyclic group composed of 4-7 atoms, which means a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms, wherein at least one ring atom is selected from nitrogen and sulfur And oxygen atoms. Examples of heterocyclic groups consisting of 4-7 atoms include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl, 4 H -pyranyl, tetrahydrothiopyranyl, pyridinyl, morpholinyl, thiomorpholinyl, Pyrazinyl, dioxanyl, dithianyl, thioxanyl, homopyrazinyl, homopyridinyl, oxepanyl, thiazepanyl, oxazepinyl, di Azazepine, thiazazepine, etc. Examples of the -CH 2 -group replaced by -C(=O)- in the heterocyclic group include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-pyridinium Ketone, 3,5-dioxopyridinyl, pyrimidinedione, etc. Examples of oxidized sulfur atoms in the heterocyclic group include, but are not limited to, cyclobutane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclic group consisting of 4-7 atoms is optionally substituted with one or more substituents described in the present invention.

術語“螺環基”，“螺環”，“螺雙環基”，“螺雙環”表示一個環起源於另一個環上特殊的環狀碳。例如，像下面所描述的，一個飽和的橋環體系(環D和B')被稱為“稠合雙環”，反之環A’和環D在兩個飽和的環體系中共用一個碳原子，則被稱為“螺環”。螺環裡面的每一個環要麼是碳環要麼是雜脂環族。這樣的實例包括，但並不限於，螺[2.4]庚烷-5-基，螺[4.4]壬烷基，等。 The terms "spiro ring group", "spiro ring", "spiro bicyclic group", "spiro bicyclic group" mean that one ring originates from a special cyclic carbon on another ring. For example, as described below, a saturated bridge ring system (rings D and B') is called a "fused bicyclic ring", whereas ring A'and ring D share a carbon atom in two saturated ring systems, It is called "spiral ring". Each ring in the spiro ring is either carbocyclic or heteroalicyclic. Such examples include, but are not limited to, spiro[2.4]heptan-5-yl, spiro[4.4]nonanyl, and the like.

Figure 104141541-A0101-12-0023-37
Figure 104141541-A0101-12-0023-37

術語“螺雜雙環基”表示一個環起源於另一個環上特殊的環狀碳。例如，像上面所描述的，一個飽和的橋環體系(環D和B')被稱為“稠合雙環”，反之環A’和環D在兩個飽和的環體系中共用一個碳原子，則被稱為“螺環”。且至少一個環體系包含一個或多個雜原子，其中每一個環體系包含3-7個原子，即包含1-6個碳原子和選自N，O，P，S的1-3個雜原子，在此N，S或P獨立任選地被一個或多個氧原子所取代得到像NO，NO2，SO，SO2，PO，PO2的基團，-CH2-基團可以獨立任選地被-C(=O)-替代；這樣的實例包括，但並不限於4-氮雜螺[2.4]庚烷基，4-氧雜螺[2.4]庚烷基，5-氮雜螺[2.4]庚烷基，2-氮雜螺[4.5]癸烷基，2-氮雜螺[3.3]庚烷基，2-氮雜螺[4.4]壬烷基，3-氮雜螺[5.4]癸烷基，2-氧-6-氮雜螺[3.3]庚烷基，2,6-二氮雜螺[3.3]庚烷基，2-硫-6-氮雜螺[3.3]庚烷基2-一氧化物，2-硫-6-氮雜螺[3.3]庚烷基2,2-二氧化物，2,8-二氮雜螺[4.5]癸烷基，2,7-二氮雜螺[4.4]辛烷基，2,7-二氮雜螺[4.5]癸烷基，2,6-二氮雜螺[4.5]癸烷基，2,8-二氮雜螺[4.5]癸烷-3-酮- 基，1,8-二氮雜螺[4.5]癸烷基，1,7-二氮雜螺[4.4]壬烷基，1,7-二氮雜螺[4.4]壬烷-6-酮-基，2,9-二氮雜螺[5.5]十一烷-1-酮-基，1-氧-3,8-二氮雜螺[4.5]癸烷-2-酮-基，1-氧-3,7-二氮雜螺[4.5]癸烷-2-酮-基，2,6-二氮雜螺[3.4]辛烷基，2,5-二氮雜螺[3.5]壬烷基，2,6-二氮雜螺[3.3]庚烷基，2-氧-7-氮雜螺[3.5]壬烷基，2-氧-6-氮雜螺[3.4]辛烷基等。視結構而定，螺雜雙環基可為單價基團或二價基團，即亞螺雜雙環基。螺雜環基可以被本發明所述的取代基所取代。 The term "spiroheterobicyclyl" means that one ring originates from a special cyclic carbon on the other ring. For example, as described above, a saturated bridge ring system (rings D and B') is called a "fused bicyclic ring", whereas ring A'and ring D share a carbon atom in two saturated ring systems, It is called a "spiral ring". And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 atoms, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , Where N, S or P are independently optionally substituted with one or more oxygen atoms to obtain groups like NO, NO 2 , SO, SO 2 , PO, PO 2 , -CH 2 -groups can be independently Is optionally replaced by -C(=O)-; such examples include, but are not limited to, 4-azaspiro[2.4]heptane, 4-oxaspiro[2.4]heptane, 5-azaspiro [2.4]Heptyl, 2-azaspiro[4.5]decyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[4.4]nonyl, 3-azaspiro[5.4 ]Decyl, 2-oxo-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-thio-6-azaspiro[3.3]heptane 2-monooxide, 2-thio-6-azaspiro[3.3]heptane 2,2-dioxide, 2,8-diazaspiro[4.5]decyl, 2,7-di Azaspiro[4.4]octyl, 2,7-diazaspiro[4.5]decyl, 2,6-diazaspiro[4.5]decylspiro, 2,8-diazaspiro[4.5 ]Decane-3-one-yl, 1,8-diazaspiro[4.5]decyl, 1,7-diazaspiro[4.4]nonyl, 1,7-diazaspiro[4.4 ] Nonane-6-keto-yl, 2,9-diazaspiro[5.5]undecane-1-one-yl, 1-oxo-3,8-diazaspiro[4.5]decane-2 -Keto-yl, 1-oxo-3,7-diazaspiro[4.5]decane-2-one-yl, 2,6-diazaspiro[3.4]octane, 2,5-diaza Heterospiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptane, 2-oxo-7-azaspiro[3.5]nonyl, 2-oxo-6-azaspiro[ 3.4] Octyl and so on. Depending on the structure, the spiro heterobicyclic group may be a monovalent group or a divalent group, that is, a spiro heterobicyclic group. The spiro heterocyclic group may be substituted with the substituents described in the present invention.

術語“稠合雙環”，“稠環”，“稠合雙環基”或“稠環基”表示飽和或不飽和的稠環體系，涉及到非芳香族的雙環體系，至少有一個環是非芳香性的。這樣的體系可以包含獨立的或共軛的不飽和狀態，但其核心結構不包含芳香環或芳雜環(但是芳香族可以作為其上的取代基)。稠合雙環中的每一個環要麼是碳環要麼是雜脂環族，這樣的實例包括，但並不限於，六氫-呋喃[3,2-b]呋喃基，2,3,3a,4,7,7a-六氫-1H-茚基，7-氮雜雙環[2.2.1]庚烷基，稠合雙環[3.3.0]辛烷基，稠合雙環[3.1.0]己烷基，1,2,3,4,4a,5,8,8a-八氫萘基，這些都包含在稠合雙環的體系之內。 The term "fused bicyclic", "fused ring", "fused bicyclic group" or "fused ring group" means a saturated or unsaturated fused ring system, which refers to a non-aromatic bicyclic system, at least one ring is non-aromatic of. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain aromatic rings or aromatic heterocycles (but aromatic groups can be used as substituents thereon). Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic. Examples include, but are not limited to, hexahydro-furan[3,2-b]furanyl, 2,3,3a,4 ,7,7a-Hexahydro-1H-indenyl, 7-azabicyclo[2.2.1]heptanyl, fused bicyclic[3.3.0]octyl, fused bicyclic[3.1.0]hexane , 1,2,3,4,4a,5,8,8a-octahydronaphthyl, these are included in the fused bicyclic system.

術語“稠合雜雙環基”表示飽和或不飽和的稠環體系，涉及到非芳香族的雙環體系，至少有一個環是非芳香性的。這樣的體系可以包含獨立的或共軛的不飽和狀態，但其核心結構不包含芳香環或芳雜環(但是芳香族可以作為其上的取代基)。且至少一個環體系包含一個或多個雜原子，其中每一個環體系包含3-7個原子組成的環，即包含1-6個碳原子和選自N，O，P，S的1-3個雜原子，在此N，S或P獨立任選地被一個或多個氧原子所取代得到像NO，NO2，SO，SO2，PO，PO2的基團，-CH2-基團可以獨立任選地被-C(=O)-替代，這樣的實例包括，但並不限於，六氫-2H-[1,4]二氧芑[2,3-c])吡咯基，3-氮雜雙環[3.3.0]辛烷基，8-氮雜雙環[4.3.0]壬烷基，8-氮雜雙環[4.3.0]壬烷3-基，3-氮雜雙環[4.3.0]壬烷-3-基，1,5-二氧-8-氮雜雙環[4.3.0]壬烷基，(1R,6S)-2,5-二氧-8-氮雜雙環[4.3.0]壬烷基，(1R,6R)-2,5-二氧-8-氮雜雙環[4.3.0]壬烷基，異吲哚啉基，1,2,3,4-四氫喹啉基，(1S,5S)-1-羥基-3-氮雜雙環[3.1.0]己烷基，(1R,5S)-1-羥基-3-氮雜雙環[3.1.0]己烷基，3-氮-7-氧雜雙環[3.3.0]辛烷基，3,7-二氮雜雙環[3.3.0]辛烷基，2,6-二氮雜雙 環[3.3.0]辛烷基，2,7-二氮雜雙環[3.3.0]辛烷基，2,7-二氮雜雙環[3.3.0]辛烷基，2,8-二氮雜雙環[4.3.0]壬烷基，3,8-二氮雜雙環[4.3.0]壬烷基，3-氧-8-氮雜雙環[4.3.0]壬烷基，2-氧-8-氮雜雙環[4.3.0]壬烷基，2,8-二氮-5-氧雜雙環[4.3.0]壬烷基，4,9-二氮雜雙環[4.3.0]壬烷基，2,9-二氮雜雙環[4.3.0]壬烷基，2-氧代-3-氧-8-氮雜雙環[4.3.0]壬烷基，3-氧代-2,4,8-三氮雜雙環[4.3.0]壬烷基，3-氧代-4-氧-2,8-二氮雜雙環[4.3.0]壬烷基，3-氧代-2,8-二氮雜雙環[4.3.0]壬烷基，3,8-二氮雜雙環[4.3.0]壬烷基，3,7-二氮雜雙環[4.3.0]壬烷基，3,9-二氮雜雙環[4.3.0]壬烷基，3-氧-8-氮雜雙環[4.3.0]壬烷基，3-硫-8-氮雜雙環[4.3.0]壬烷基，5,6-二氫-4H-吡咯並[3,4-c]異惡唑基，[1,2,4]三氮唑[4,3-a]並呱啶基，異惡唑並[4,3-c]呱啶基，4,5,6,7-四氫異惡唑並[3,4-c]吡啶基，[1,2,4]三氮唑並[4,3-a]呱嗪基，2-氧代-3-氧-8-氮雜雙環[4.3.0]壬烷基，2-氧-7-氮雜雙環[4.4.0]癸烷基，1,5-二氧-9-氮雜雙環[4.4.0]癸烷基，3-氮雜雙環[4.4.0]癸烷基，2,7-二氮雜十氫萘基，2-氧-8-氮雜雙環[4.4.0]癸烷基，六氫吡咯並[1,2-a]吡嗪-1(2H)-酮-基，十氫-1H-吡啶並[1,2-a]吡嗪-1-酮-基，3-氮雜雙環[3,1,0]己烷-1-氨基-基等。稠合雜雙環基可以被本發明所述的取代基所取代。 The term "fused heterobicyclic group" means a saturated or unsaturated fused ring system, which refers to a non-aromatic bicyclic system, at least one ring is non-aromatic. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain aromatic rings or aromatic heterocycles (but aromatic groups can be used as substituents thereon). And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 3-7 atoms, that is, contains 1-6 carbon atoms and is selected from N, O, P, S 1-3 Heteroatoms, where N, S or P are independently optionally substituted by one or more oxygen atoms to give groups like NO, NO 2 , SO, SO 2 , PO, PO 2 , -CH 2 -groups may be independently optionally substituted with -C (= O) - Alternatively, examples include, but are not limited to, hexahydro -2 H - [1,4] dioxyno [2,3-c]) pyrrolyl, 3-azabicyclo[3.3.0]octyl, 8-azabicyclo[4.3.0]nonanyl, 8-azabicyclo[4.3.0]nonane 3-yl, 3-azabicyclo[ 4.3.0] Nonane-3-yl, 1,5-dioxa-8-azabicyclo[4.3.0]nonanyl, (1R,6S)-2,5-dioxa-8-azabicyclo [4.3.0] Nonanyl, (1R,6R)-2,5-dioxa-8-azabicyclo[4.3.0]nonyl, isoindolinyl, 1,2,3,4- Tetrahydroquinolinyl, (1S,5S)-1-hydroxy-3-azabicyclo[3.1.0]hexane, (1R,5S)-1-hydroxy-3-azabicyclo[3.1.0] Hexyl, 3-aza-7-oxabicyclo[3.3.0]octane, 3,7-diazabicyclo[3.3.0]octane, 2,6-diazabicyclo[3.3. 0] octyl, 2,7-diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl, 2,8-diazabicyclo[4.3 .0] Nonanyl, 3,8-diazabicyclo[4.3.0]nonyl, 3-oxo-8-azabicyclo[4.3.0]nonyl, 2-oxa-8-aza Bicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl, 4,9-diazabicyclo[4.3.0]nonyl, 2, 9-diazabicyclo[4.3.0]nonyl, 2-oxo-3-oxo-8-azabicyclo[4.3.0]nonyl, 3-oxo-2,4,8-tri Azabicyclo[4.3.0]nonanyl, 3-oxo-4-oxo-2,8-diazabicyclo[4.3.0]nonanyl, 3-oxo-2,8-diaza Bicyclo[4.3.0]nonyl, 3,8-diazabicyclo[4.3.0]nonyl, 3,7-diazabicyclo[4.3.0]nonyl, 3,9-diaza Heterobicyclo[4.3.0]nonyl, 3-oxo-8-azabicyclo[4.3.0]nonyl, 3-thio-8-azabicyclo[4.3.0]nonyl, 5,6 -Dihydro-4H-pyrrolo[3,4-c]isoxazolyl, [1,2,4]triazole[4,3-a]pyridoxyl, isoxazolo[4,3 -c]pyridinyl, 4,5,6,7-tetrahydroisoxazolo[3,4-c]pyridyl, [1,2,4]triazolo[4,3-a]Xia Azinyl, 2-oxo-3-oxo-8-azabicyclo[4.3.0]nonanyl, 2-oxo-7-azabicyclo[4.4.0]decyl, 1,5-dioxo-9- Azabicyclo[4.4.0]decyl, 3-azabicyclo[4.4.0]decyl, 2,7-diazadecahydronaphthyl, 2-oxo-8-azabicyclo[4.4. 0]decyl, hexahydropyrrolo[1,2-a]pyrazine-1(2H)-one-yl, decahydro-1H-pyrido[1,2-a]pyrazine-1-one- Group, 3-azabicyclo[3,1,0]hexane-1-amino-yl and so on. The fused heterobicyclic group may be substituted with the substituents described in the present invention.

術語“橋雙環基”表示飽和或不飽和的橋環體系，涉及到非芳香族的雙環體系。這樣的體系可以包含獨立的或共軛的不飽和狀態，但其核心結構不包含芳香環或芳環(但是芳香族可以作為其上的取代基)。其中每一個環體系包含3-7個原子，這樣的實例包括，但並不限於，雙環[2.2.1]庚烷基，2-甲基-雜二環[2.2.1]庚烷基，等。 The term "bridged bicyclic group" means a saturated or unsaturated bridged ring system, and refers to a non-aromatic bicyclic system. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain aromatic rings or aromatic rings (but aromatic groups can be used as substituents thereon). Each ring system contains 3-7 atoms, such examples include, but are not limited to, bicyclo[2.2.1]heptane, 2-methyl-heterobicyclo[2.2.1]heptane, etc. .

術語“橋雜雙環基”表示飽和或不飽和的橋環體系，涉及到非芳香族的雙環體系。這樣的體系可以包含獨立的或共軛的不飽和狀態，但其核心結構不包含芳香環或芳雜環(但是芳香族可以作為其上的取代基)。且至少一個環體系包含一個或多個雜原子，其中每一個環體系包含3-7個原子，即包含1-6個碳原子和選自N，O，P，S的1-3個雜原子，在此N，S或P獨立任選地被一個或多個氧原子所取代得到像NO，NO2，SO，SO2，PO，PO2的基團，-CH2-基團可以獨立任選地被-C(=O)-替代，這樣的實例包括，但並不限於2-氧-5-氮雜雙環[2.2.1]庚烷基，2-硫代-5-氮雜雙環[2.2.1]庚烷基，2-氧代-5-氮雜雙環[2.2.1]庚烷基，2,5-二氮雜二環[2.2.1]庚烷基， (1S,4S)-2,5-二氮雜雙環[2.2.1]庚烷基，3,8-二氮雜雙環[3.2.1]辛烷基，(1S,5S)-3,8-二氮雜雙環[3.2.1]辛烷基，1,4-二氮雜雙環[3.2.2]壬烷-3-酮-基，8-氧-3-氮-雜雙環[3.2.1]辛烷基，等。橋雜雙環基可以被本發明所述的取代基所取代。 The term "bridged heterobicyclic group" means a saturated or unsaturated bridged ring system, and refers to a non-aromatic bicyclic system. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain aromatic rings or aromatic heterocycles (but aromatic groups can be used as substituents thereon). And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 atoms, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , Where N, S or P are independently optionally substituted with one or more oxygen atoms to obtain groups like NO, NO 2 , SO, SO 2 , PO, PO 2 , -CH 2 -groups can be independently Optionally replaced by -C(=O)-, such examples include, but are not limited to, 2-oxo-5-azabicyclo[2.2.1]heptane, 2-thio-5-azabicyclo[ 2.2.1]Heptyl, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S) -2,5-diazabicyclo[2.2.1]heptane, 3,8-diazabicyclo[3.2.1]octyl, (1S,5S)-3,8-diazabicyclo[ 3.2.1] Octane, 1,4-diazabicyclo[3.2.2]nonane-3-one-yl, 8-oxo-3-aza-heterocyclo[3.2.1]octanyl, etc. . The bridged heterobicyclic group may be substituted with the substituents described in the present invention.

術語“螺雜雙環基-NH-”，“橋雜雙環基-NH-”，“稠合雜雙基-NH-”，涉及到螺雜雙環基，橋雜雙環基和稠合雜雙基，其中螺雜雙環基，橋雜雙環基和稠合雜雙基團具有如本發明所述的含義。這樣的實例包括，但並不限於，N-3-氮雜雙環[3.1.0]己烷氨基，N-3-氮雜雙環[4.4.0]癸烷氨基，等。 The terms "spiroheterobicyclyl-NH-", "bridge heterobicyclyl-NH-", "fused heterobicyclyl-NH-" refer to spiroheterobicyclic, bridged heterobicyclyl and fused heterobiyl, Among them, spiroheterobicyclic group, bridged heterobicyclic group and fused heterobicyclic group have the meaning as described in the present invention. Such examples include, but are not limited to, N-3-azabicyclo[3.1.0]hexaneamino, N-3-azabicyclo[4.4.0]decaneamino, and the like.

“抗增殖劑”是指抗代謝物(例如，5-氟代-尿嘧啶、氨甲喋呤、fludarabine)、抗微管劑(例如，長春生物鹼如長春新鹼、長春花鹼，紫杉烷例如紫杉醇、多烯紫衫醇)、烷基化試劑(例如環磷醯胺、美法侖、卡氮芥、亞硝基脲如雙氯乙基亞硝基脲和羥基脲)、鉑試劑(例如順鉑、卡波鉑、奧克賽鉑、JM-216、Cl-973)，anthracyclines(例如doxrubicin、正定黴素)、抗腫瘤抗生素(例如絲裂黴素、黃膽素、阿黴素、正定黴素)、局部異構酶抑制劑(例如足葉乙甙、喜樹鹼)、抗血管生成劑(例如和Bevacizumab)或任何細胞毒試劑(雌氮芥磷酸鹽、潑尼氮芥)、荷爾蒙或荷爾蒙激動劑、拮抗劑、局部激動劑或局部拮抗劑、激酶抑制劑和輻射治療。 "Antiproliferative agent" refers to antimetabolites (eg, 5-fluoro-uracil, methotrexate, fludarabine), anti-microtubule agents (eg, vinca alkaloids such as vincristine, vinblastine, taxanes such as paclitaxel , Polyene taxol), alkylating agents (such as cyclophosphamide, melphalan, carmustine, nitrosourea such as dichloroethylnitrosourea and hydroxyurea), platinum reagents (such as cis Platinum, Carboplatin, Oxyplatin, JM-216, Cl-973), anthracyclines (e.g. doxrubicin, dioxomycin), anti-tumor antibiotics (e.g. mitomycin, flavin, doxorubicin, oxytetracycline Hormone), topoisomerase inhibitors (e.g. etoposide, camptothecin), anti-angiogenic agents (e.g. and Bevacizumab) or any cytotoxic agent (estrogen phosphate, prednisolone), hormones or Hormonal agonists, antagonists, local agonists or local antagonists, kinase inhibitors and radiation therapy.

如本發明所描述，取代基R’由一個鍵連接到中心的環上形成的環體系代表取代基R’可以在環上任何可取代或任何合理的位置進行取代。例如，式a代表A’環或B’環上任何可能被取代的位置均可被R’取代，如式b，式c，式d，式e，式f，式g，和式h所示。 As described in the present invention, the ring system formed by the substituent R'connected to the central ring by a bond means that the substituent R'can be substituted at any substitutable or any reasonable position on the ring. For example, formula a represents that any position on the A'ring or B'ring that may be substituted can be substituted by R', as shown in formula b, formula c, formula d, formula e, formula f, formula g, and formula h .

Figure 104141541-A0101-12-0026-38
Figure 104141541-A0101-12-0026-38

如本發明所描述，附著點可以在環上任何可連接的位置與分子其餘部分連接。例如，式i代表A’環或B’環上任何可能被連接的位置均可作為連接的點。 As described in the present invention, the attachment point can be connected to the rest of the molecule at any connectable position on the ring. For example, formula i means that any position on the A'ring or B'ring that may be connected can be used as a connection point.

Figure 104141541-A0101-12-0027-39
Figure 104141541-A0101-12-0027-39

像本發明所描述，環C上有兩個連接點可與分子其餘部分相連，例如，如式j所示，表示既可以是E端也可以是E’端與分子的其餘部分相連，即兩端的連接方式可以互換。 As described in the present invention, there are two connection points on ring C that can be connected to the rest of the molecule. For example, as shown in formula j, it can be connected to the rest of the molecule either at the E end or E′ end, that is, two The connection mode of the terminal can be interchanged.

Figure 104141541-A0101-12-0027-40
Figure 104141541-A0101-12-0027-40

如本發明所描述，附著點可以在環上任何可連接的位置與分子其餘部分連接，同時連接的兩端可以互換。例如，式y代表環上任何可能被連接的位置均可作為連接的點，同時連接點的兩端可以互換。 As described in the present invention, the attachment point can be connected to the rest of the molecule at any connectable position on the ring, and the two ends of the connection can be interchanged. For example, formula y means that any position on the ring that may be connected can be used as a connection point, and the two ends of the connection point can be interchanged.

另外，需要說明的是，除非以其他方式明確指出，在本發明中通篇採用的描述方式“各...和...獨立地為”、“...和...各自獨立地為”和“...和...分別獨立地為”可以互換，應做廣義理解，其既可以是指在不同基團中，相同符號之間所表達的具體選項之間互相不影響，也可以表示在相同的基團中，相同符號之間所表達的具體選項之間互相不影響。例如，“H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-”中“R3”表示相同或不同的基團，且相互之間不影響；“n”表示相同或不同的取值，且相互之間不影響。 In addition, it should be noted that, unless explicitly stated otherwise, the descriptions used throughout the present invention "each... and... are independently", "... and... are independently "And"...and...respectively independently" are interchangeable and should be understood in a broad sense, which can mean that in different groups, the specific options expressed between the same symbols do not affect each other, and It can be expressed that in the same group, the specific options expressed between the same symbols do not affect each other. For example, "H- (C (R 3 ) 2) n -O- (C (R 3) 2) n1 -C (= O) - (C (R 3) 2) n -" in "R 3" represents The same or different groups do not affect each other; "n" means the same or different values, and does not affect each other.

符號“

Figure 104141541-A0101-12-0027-241
”表示如本發明所描述的單鍵“-”或雙鍵“=”。 symbol"
Figure 104141541-A0101-12-0027-241
"" means a single key "-" or a double key "=" as described in the present invention.

術語“藥學上可接受的”是指當給人施用時生理上可耐受的並且一般不產生過敏或相似不適當的反應，例如腸胃不適、眩暈等的分子實體和組合物。較佳地，本發明所用的術語“藥學上可接受的”是指聯邦監管機構或國家政府批准的或美國藥典或其他一般認可的藥典上列舉的在動物中、更特別在人體中使用的。 The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similarly inappropriate reactions, such as gastrointestinal discomfort, dizziness, and the like. Preferably, the term "pharmaceutically acceptable" as used in the present invention refers to use in animals, more particularly in humans, approved by the federal regulatory agency or national government or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia.

術語“載體”指與所述化合物一同施用的稀釋劑、輔劑、賦形劑或基質。這些藥物載體可以是無菌液體，例如水和油類，包括石油、動物、植物或合成來源的，例如花生油、大豆油、礦物油、芝麻油等。水和水性溶液鹽水溶液和水性葡萄糖與甘油溶液較佳用作載體、特別是可注射溶液。適宜的藥物載體描述於E.W.Martin的“Remington' s Pharmaceutical Sciences”中。 The term "carrier" refers to a diluent, adjuvant, excipient or base for administration with the compound. These pharmaceutical carriers can be sterile liquids, such as water and oils, including petroleum, animal, vegetable, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water and aqueous solutions Saline solutions and aqueous glucose and glycerol solutions are preferably used as carriers, especially injectable solutions. Suitable pharmaceutical carriers are described in EWMartin in "Remington 's Pharmaceutical Sciences" in.

本發明中立體化學的定義和慣例的使用通常參考以下文獻：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994．本發明的化合物可以包含不對稱中心或手性中心，因此存在不同的立體異構體。本發明的化合物所有的立體異構形式，包括但絕不限於，非對映體，對映異構體，阻轉異構體，和它們的混合物，如外消旋混合物，組成了本發明的一部分。很多有機化合物都以光學活性形式存在，即它們有能力旋轉平面偏振光的平面。在描述光學活性化合物時，首碼D、L或R、S用來表示分子手性中心的絕對構型。首碼d、l或(+)、(-)用來命名化合物平面偏振光旋轉的符號，(-)或l是指化合物是左旋的，首碼(+)或d是指化合物是右旋的。這些立體異構體的化學結構是相同的，但是它們的立體結構不一樣。特定的立體異構體可以是對映體，異構體的混合物通常稱為對映異構體混合物。50：50的對映體混合物被稱為外消旋混合物或外消旋體，這可能導致化學反應過程中沒有立體選擇性或立體定向性。術語“外消旋混合物”和“外消旋體”是指等摩爾的兩個對映異構體的混合物，缺乏光學活性。 The definition and usage of stereochemistry in the present invention generally refer to the following documents: SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. , "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994 . The compound of the present invention may contain an asymmetric center or a chiral center, and thus different stereoisomers exist. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention Part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the initial code D, L or R, S is used to indicate the absolute configuration of the molecular chiral center. The first code d, l or (+), (-) is used to name the symbol of compound plane polarized light rotation, (-) or l means the compound is left-handed, the first code (+) or d means the compound is right-handed . The chemical structures of these stereoisomers are the same, but their stereostructures are different. The specific stereoisomer may be an enantiomer, and a mixture of isomers is generally called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, lacking optical activity.

“異構體”為具有相同分子式的不同化合物。“立體異構體”為僅僅原子的空間排列方式不同的異構體。如本發明使用的術語“異構體”包括任何和所有的幾何異構體和立體異構體。例如，“異構體”包括順式和反式異構體、E-和Z-異構體、R-和S-對映異構體、非對映異構體、(d)異構體、(l)-異構體、其外消旋混合物、及落入本說明書範圍的其它其混合物。 "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of atoms. The term "isomer" as used in the present invention includes any and all geometric isomers and stereoisomers. For example, "isomer" includes cis and trans isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (d) isomers , (L)-isomers, their racemic mixtures, and other mixtures falling within the scope of this specification.

本發明的“水合物”是指本發明所提供的化合物或其鹽，其還 包括化學量或非化學當量通過非共價分子間力結合的水，也可說是溶劑分子是水所形成的締合物。 The "hydrate" of the present invention refers to the compound or salt thereof provided by the present invention, which also It includes water that is chemically or non-stoichiometrically bound by non-covalent intermolecular forces. It can also be said that the solvent molecule is an association formed by water.

本發明的“溶劑化物”是指一個或多個溶劑分子與本發明的化合物所形成的締合物。形成溶劑化物的溶劑包括，但並不限於，水，異丙醇，乙醇，甲醇，二甲亞碸，乙酸乙酯，乙酸，氨基乙醇。 The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.

本發明的“酯”是指含有羥基的式(I)-式(III)所示化合物可形成體內可水解的酯。這樣的酯是例如在人或動物體內水解產生母體醇的藥學上可接受的酯。含有羥基的式(I)-式(III)所示化合物體內可水解的酯的基團包括，但不限於，磷酸基，乙醯氧基甲氧基，2,2-二甲基丙醯氧基甲氧基，烷醯基，苯甲醯基，苯甲乙醯基，烷氧基羰基，二烷基氨基甲醯基和N-(二烷基氨基乙基)-N-烷基氨基甲醯基等。 The "ester" in the present invention means that the compound represented by formula (I)-formula (III) containing a hydroxyl group can form an in vivo hydrolyzable ester. Such esters are, for example, pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent alcohol. The hydrolyzable ester groups of the compounds represented by formula (I)-formula (III) containing hydroxyl groups in the body include, but are not limited to, phosphate groups, acetoxymethoxy, 2,2-dimethylpropaneoxy Methoxy, alkoxy, benzoyl, benzoyl acetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl Base etc.

本發明的“氮氧化物”是指當化合物含幾個胺官能團時，可將1個或大於1個的氮原子氧化形成N-氧化物。N-氧化物的特殊實例是叔胺的N-氧化物或含氮雜環氮原子的N-氧化物。可用氧化劑例如過氧化氫或過酸(例如過氧羧酸)處理相應的胺形成N-氧化物(參見Advanced Organic Chemistry,Wiley Interscience，第4版，Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法製備(Syn.Comm.1977,7,509-514)，其中例如在惰性溶劑例如二氯甲烷中，使胺化合物與間-氯過氧苯甲酸(MCPBA)反應。 "Nitrogen oxide" in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen heterocyclic nitrogen atoms. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (eg peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxide can be prepared by the method of LWDeady (Syn. Comm. 1977, 7,509-514), in which, for example, in an inert solvent such as methylene chloride, the amine compound and m-chloroperoxybenzoic acid (MCPBA) reaction.

化合物可存在多種不同幾何異構體和互變異構體，所述式(I)-式(III)化合物包括所有此類形式。為避免疑惑，當化合物以幾種幾何異構體或互變異構體之一存在並且只具體描述或顯示一種時，顯然所有其它形式包括在式(I)-式(III)中。 Compounds can exist in many different geometric isomers and tautomers, and the compounds of formula (I)-formula (III) include all such forms. For the avoidance of doubt, when a compound exists as one of several geometric isomers or tautomers and only one is specifically described or shown, it is clear that all other forms are included in formula (I)-formula (III).

本發明所使用的術語“前藥”，代表一個化合物在體內轉化為式(I)-式(III)所示的化合物。這樣的轉化受前體藥物在血液中水解或在血液或組織中經酶轉化為母體結構的影響。本發明前體藥物類化合物可以是酯，在現有的發明中酯可以作為前體藥物的有苯酯類，脂肪族(C1-24)酯類，醯氧基甲基酯類，碳酸酯，氨基甲酸酯類和氨基酸酯類。例如本發明裡的一個化合物包含羥基，即可以將其醯化得到前體藥物形式的化合物。其他 的前體藥物形式包括磷酸酯，如這些磷酸酯類化合物是經母體上的羥基磷酸化得到的。關於前體藥物完整的討論可以參考以下文獻：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs：Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。 The term "prodrug" used in the present invention means that a compound is converted into a compound represented by formula (I)-formula (III) in vivo. Such conversion is affected by prodrug hydrolysis in the blood or enzymatic conversion into the parent structure in the blood or tissue. The prodrug compounds of the present invention may be esters. In the present invention, esters may be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, oxymethyl esters, carbonates, Carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be compounded to obtain a prodrug compound. Other prodrug forms include phosphate esters, as these phosphate compounds are obtained by phosphorylation of hydroxyl groups on the parent. For a complete discussion of prodrugs, please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery , 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008 , 51, 2328-2345.

除非其他方面表明，本發明的化合物的所有互變異構形式都包含在本發明的範圍之內。 Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention.

另外，除非其他方面表明，本發明所描述的化合物的結構式包括一個或多個不同的原子的富集同位素。本發明包括同位素標記的化合物，它們等同於式(I)-式(III)所述的化合物，但一個或多個原子被原子品質或質量數不同於自然界常見的原子品質或質量數的原子所代替。可以引入本發明化合物中的同位素的實例包括氫、碳、氮、氧、磷、硫、氟和氯的同位素，分別例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本發明化合物、其前體藥物和所述化合物或所述前體藥物的藥學上可接受的鹽都屬於本發明的範圍。某些同位素標記的本發明化合物、例如引入放射性同位素(例如3H和14C)的那些可用於藥物和/或底物組織分佈測定。同位素標記的本發明式(I)-式(II)所示化合物及其前體藥物一般可以這樣製備，在進行下述流程和/或實施例與製備例所公開的工藝時，用容易得到的同位素標記的試劑代替非同位素標記的試劑。 In addition, unless otherwise indicated, the structural formula of the compounds described in this invention includes one or more different atom-enriched isotopes. The present invention includes isotopically-labeled compounds, which are equivalent to the compounds described in formula (I)-formula (III), but one or more atoms are affected by atoms whose atomic mass or mass number is different from the atomic mass or mass number common in nature instead. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18, respectively O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically-labeled compounds of the invention, such as those incorporating radioisotopes (eg, 3 H and 14 C), can be used for drug and/or substrate tissue distribution determination. Isotope-labeled compounds of formula (I)-formula (II) of the present invention and their prodrugs can generally be prepared in this way. When performing the processes disclosed in the following schemes and/or examples and preparation examples, the readily available Isotopically labeled reagents replace non-isotopically labeled reagents.

“代謝產物”是指具體的化合物或其鹽在體內通過代謝作用所得到的產物。一個化合物的代謝產物可以通過所屬領域公知的技術來進行鑒定，其活性可以通過如本發明所描述的那樣採用試驗的方法進行表徵。這樣的產物可以是通過給藥化合物經過氧化，還原，水解，醯氨化，脫醯氨作用，酯化，脫脂作用，酶裂解等等方法得到。相應地，本發明包括化合物的代謝產物，包括將本發明的化合物與哺乳動物充分接觸一段時 間所產生的代謝產物。 "Metabolite" refers to a product obtained by metabolizing a specific compound or its salt in the body. The metabolite of a compound can be identified by techniques well known in the art, and its activity can be characterized by an experimental method as described in the present invention. Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the present invention includes metabolites of the compound, including a period of sufficient contact between the compound of the present invention and the mammal Metabolites produced during the process.

本發明化合物的各種藥學上可接受的鹽形式都是有用的。術語“藥學上可接受的鹽”是指那些鹽形式對於製藥化學家而言是顯而易見的，即它們基本上無毒並能提供所需的藥代動力學性質、適口性、吸收、分佈、代謝或排泄。其他因素，在性質上更加實用，對於選擇也很重要，這些是：原材料的成本、結晶的容易、產率、穩定性、吸濕性和結果原料藥的流動性。簡單地講，藥物組合物可以通過有效成分與藥學上可接受的載體製備得到。 Various pharmaceutically acceptable salt forms of the compounds of the present invention are useful. The term "pharmaceutically acceptable salts" refers to those salt forms that are obvious to pharmaceutical chemists, that is, they are substantially non-toxic and can provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, are also important for selection. These are: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity, and fluidity of the resulting drug substance. Briefly, the pharmaceutical composition can be prepared by using active ingredients and a pharmaceutically acceptable carrier.

本發明所使用的“藥學上可接受的鹽”是指本發明的化合物的有機鹽和無機鹽。藥學上可接受的鹽在所屬領域是為我們所熟知的，如文獻：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66：1-19,1977.所記載的。藥學上可接受的無毒的酸形成的鹽包括，但並不限於，與氨基基團反應形成的無機酸鹽有鹽酸鹽，氫溴酸鹽，磷酸鹽，硫酸鹽，高氯酸鹽，硝酸鹽等，和有機酸鹽如乙酸鹽，丙酸鹽，乙醇酸鹽，草酸鹽，馬來酸鹽，丙二酸鹽，琥珀酸鹽，富馬酸鹽，酒石酸鹽，枸櫞酸鹽，苯甲酸鹽，扁桃酸鹽，甲磺酸鹽，乙磺酸鹽，甲苯磺酸鹽，磺基水楊酸鹽等，或通過書籍文獻上所記載的其他方法如離子交換法來得到這些鹽。 As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and nitric acid Salts, etc., and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citrate, Benzoate, mandelate, methanesulfonate, ethanesulfonate, tosylate, sulfosalicylic acid, etc., or other methods described in books and literature such as ion exchange to obtain these salts .

其他藥學上可接受的鹽包括己二酸鹽、蘋果酸鹽、2-羥基丙酸、藻酸鹽、抗壞血酸鹽、天冬氨酸鹽、苯磺酸鹽、苯甲酸鹽、重硫酸鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、環戊基丙酸鹽、二葡萄糖酸鹽、十二烷基硫酸鹽、乙磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、甘油磷酸鹽、葡萄糖酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、氫碘酸鹽、2-羥基-乙磺酸鹽、乳糖醛酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、丙二酸鹽、甲磺酸鹽、2-萘磺酸鹽、煙酸鹽、硝酸鹽、油酸鹽、棕櫚酸鹽、撲酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、苦味酸鹽、特戊酸鹽、丙酸鹽、硬脂酸鹽、硫氰酸鹽、對甲苯磺酸鹽、十一酸鹽、戊酸鹽、等等。通過適當的鹼得到的鹽包括鹼金屬，鹼土金屬，銨和N+(C1-4烷基)4的鹽。 Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate , Glucoheptonic salt, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurel Acid salt, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, paraben, pectin Salt, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, pentanoate Acid salt, etc. Salts obtained by suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.

本發明也擬構思了任何包含N的基團的化合物所形成的季 銨鹽。水溶性或油溶性或分散產物可以通過季銨化作用得到。鹼金屬或鹼土金屬鹽包括鈉鹽、鋰鹽、鉀鹽、鈣鹽、鎂鹽、鐵鹽、鋅鹽、銅鹽、錳鹽、鋁鹽等等。藥學上可接受的鹽進一步包括適當的、無毒的銨，季銨鹽和抗平衡離子形成的胺陽離子，如鹵化物，氫氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。胺鹽，例如但不限於N,N’-二苄基乙二胺，氯普魯卡因，膽鹼，氨，二乙醇胺和其它羥烷基胺，乙二胺，N-甲基還原葡糖胺，普魯卡因，N-苄基苯乙胺，1-對-氯苄基-2-吡咯烷-1’-基甲基-苯並咪唑，二乙胺和其它烷基胺，呱嗪和三(羥甲基)氨基甲烷；鹼土金屬鹽，例如但不限於鋇，鈣和鎂；過渡金屬鹽，例如但不限於鋅。 The present invention also contemplates the formation of quaternary ammonium salts of any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. The alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, aluminum salt and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1- 8 sulfonate and aromatic sulfonate. Amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl reduced glucose Amine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, pyrazine And tris(hydroxymethyl)aminomethane; alkaline earth metal salts such as but not limited to barium, calcium and magnesium; transition metal salts such as but not limited to zinc.

術語“保護基團”或“Pg”是指一個取代基與別的官能團起反應的時候，通常用來阻斷或保護特殊的功能性。例如，“氨基的保護基團”是指一個取代基與氨基基團相連來阻斷或保護化合物中氨基的功能性，合適的氨基保護基團包括乙醯基，三氟乙醯基，叔丁氧羰基(BOC)，苄氧羰基(CBZ)和9-芴亞甲氧羰基(Fmoc)。相似地，“羥基保護基團”是指羥基的取代基用來阻斷或保護羥基的功能性，合適的保護基團包括乙醯基和甲矽烷基。“羧基保護基團”是指羧基的取代基用來阻斷或保護羧基的功能性，一般的羧基保護基包括-CH2CH2SO2Ph，氰基乙基，2-(三甲基矽烷基)乙基，2-(三甲基矽烷基)乙氧基甲基，2-(對甲苯磺醯基)乙基，2-(對硝基苯磺醯基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。對於保護基團一般的描述可參考文獻：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.。 The term "protecting group" or "Pg" means that when a substituent reacts with another functional group, it is usually used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyl Oxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorene methyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of the hydroxyl group substituent to block or protect the hydroxyl group. Suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl group used to block or protect the functionality of carboxyl group, general carboxyl protecting group includes -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Group) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(di Phenylphosphino) ethyl, nitroethyl, etc. For a general description of protecting groups, reference can be made to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 ; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005 .

在本說明書中，如果在化學名稱和化學結構間存在任何差異，結構是較優勢的。 In this specification, if there is any difference between the chemical name and the chemical structure, the structure is more advantageous.

本發明所使用的任何保護基團、氨基酸和其它化合物的縮寫，除非另有說明，都以它們通常使用的、公認的縮寫為準，或參照IUPAC-IUB Commission on Biochemical Nomenclature(參見Biochem.1972，11：942-944)。 Unless otherwise stated, any abbreviations of protecting groups, amino acids and other compounds used in the present invention are based on their commonly used and recognized abbreviations, or refer to IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11:942-944).

本發明化合物的描述Description of the compounds of the invention

大量用於治療或預防或改善與蛋白激酶有關的障礙，還可用於治療或預防或改善癌症、自身免疫性疾病和感染類疾病的一種或多種症狀的化合物仍然處於需要中。本發明提供的化合物可用於調節蛋白激酶如CDK系列的活性，特別是調節或抑制CDK4或CDK6的活性。 A large number of compounds that are used to treat or prevent or ameliorate protein kinase-related disorders, and can also be used to treat or prevent or ameliorate one or more symptoms of cancer, autoimmune diseases, and infectious diseases are still needed. The compounds provided by the present invention can be used to modulate the activity of protein kinases such as CDK series, in particular, modulate or inhibit the activity of CDK4 or CDK6.

一方面，本發明提供一種化合物，其為如式(I)所示的化合物，或式(I)所示的化合物的立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，代謝產物，酯，藥學上可接受的鹽或前藥，

Figure 104141541-A0101-12-0033-41
In one aspect, the invention provides a compound that is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the compound represented by formula (I), Hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
Figure 104141541-A0101-12-0033-41

其中：L為鍵，-(C(R3b)2)n-，-N(R1)-(C(R3b)2)n-，-O-(C(R3b)2)n-，-C(=O)-(C(R3b)2)n-，-(CH2)n-，-N(R1)-(CH2)n-，-C(=O)-N(R1)-(CH2)n-，-O-(CH2)n-，-S(=O)m-或-C(=O)-(CH2)n-；1)A環為

Figure 104141541-A0101-12-0033-200
Figure 104141541-A0101-12-0033-44
Figure 104141541-A0101-12-0034-45
 其中，當
Figure 104141541-A0101-12-0034-225
為=時，T為X，
Figure 104141541-A0101-12-0034-257
為
Figure 104141541-A0101-12-0034-222
當
Figure 104141541-A0101-12-0034-226
為-時，T為X6，
Figure 104141541-A0101-12-0034-258
為
Figure 104141541-A0101-12-0034-224
R為C5-11螺雜雙環基，C5-11橋雜雙環基，C5-11稠合雜雙環基，C3-9環烷基，C2-9雜環基或C1-9雜芳基；2)或者
Figure 104141541-A0101-12-0034-55
為如下各子結構式：
Figure 104141541-A0101-12-0034-56
 其中，X7，X5和X6各自獨立地為-C(R3a)2-，-N(R2)-，-O-，-S(=O)m-或-C(=O)-；X，X1，X2，X3和X4各自獨立地為CR3a或N；各n獨立地為0，1，2，3或4；各n1獨立地為1，2或3；各m獨立地為0，1或2；各R1a，R1和R2獨立地為氫，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-， CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，C3-9環烷基，C2-9雜環基，C1-9雜芳基或C1-4烷基；各R3a，R3b和R3獨立地為氫，氟，氯，溴，C1-4烷基，羥基，羧基，氨基，C3-9環烷基，C2-9雜環基，C1-9雜芳基，C1-4鹵代烷基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-，H-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；各R4獨立地為氫，C1-4烷基，羥基，羧基，氨基，C1-4烷氧基，氨基C1-4烷基，NH2-C(=O)-，C3-9環烷基，C2-9雜環基，C1-9雜芳基，C1-4鹵代烷基或C1-4烷氨基；所述的A代表的各子結構式可獨立任選地被1，2，3或4個相同或不同的選自氫，C1-4烷基，氟，氯，溴，氨基，羥基，羧基，C1-4烷氧基，C1-4鹵代烷基，C1-4烷基氨基，氨基C1-4烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，氰基或硝基的取代基所取代；其中，R，R1a，R1和R2中所述的烷基，鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，N(R4)2-C(=O)-，H-(C(R3)2)n-SO2-(C(R3)2)n-，-(C(R3)2)n-N(R4)2，HO-(C(R3)2)n-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，螺雜雙環基，橋雜雙環基，稠合雜雙環基，雜環基，環烷基，雜芳基，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，芳基，四元雜環基，五元雜環基，六元雜環基和七元雜環基可獨立任選地被1，2，3或4個相同或不同的R5取代；各R5獨立地為氫，氧代(=O)，C1-6烷基，氟，氯，溴，氨基，羥基，羧基，C1-4烷氧基，C1-4烷氨基，氨基C1-4烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，C1-6鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，-(C(R3)2)n-N(R4)2，HO-(C(R3)2)n-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，N(R4)2-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，螺 雜雙環基，橋雜雙環基，稠合雜雙環基，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，氰基，C2-9雜環基，C3-9環烷基，C1-9雜芳基或硝基；R5中所述的烷基，鹵代烷基，烷氧基，烷氨基，氨基烷基，螺雜雙環基，橋雜雙環基，稠合雜雙環基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，-(C(R3)2)n-N(R4)2，HO-(C(R3)2)n-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，N(R4)2-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，雜環基，環烷基和雜芳基獨立任選地進一步被1，2，3或4個相同或不同的R6取代；各R6獨立地為氫，氧代(=O)，C1-4烷基，氟，氯，溴，氨基，羥基，羧基，C1-4烷氧基，C1-4烷氨基，氨基C1-4烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，-(C(R3)2)n-N(R4)2，HO-(C(R3)2)n-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，N(R4)2-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，螺雜雙環基，橋雜雙環基，稠合雜雙環基，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，氰基，C2-9雜環基，C3-9環烷基，C1-9雜芳基或硝基。 Where: L is a bond, -(C(R 3b ) 2 ) n -, -N(R 1 )-(C(R 3b ) 2 ) n -, -O-(C(R 3b ) 2 ) n -, -C(=O)-(C(R 3b ) 2 ) n -, -(CH 2 ) n -, -N(R 1 )-(CH 2 ) n -, -C(=O)-N(R 1 )-(CH 2 ) n -, -O-(CH 2 ) n -, -S(=O) m -or -C(=O)-(CH 2 ) n -; 1) A ring is
Figure 104141541-A0101-12-0033-200
Figure 104141541-A0101-12-0033-44
Figure 104141541-A0101-12-0034-45
 Among them, when
Figure 104141541-A0101-12-0034-225
When =, T is X,
Figure 104141541-A0101-12-0034-257
for
Figure 104141541-A0101-12-0034-222
when
Figure 104141541-A0101-12-0034-226
Is-when T is X 6 ,
Figure 104141541-A0101-12-0034-258
for
Figure 104141541-A0101-12-0034-224
R is C 5-11 spiro heterobicyclic group, C 5-11 bridge heterobicyclic group, C 5-11 fused heterobicyclic group, C 3-9 cycloalkyl group, C 2-9 heterocyclic group or C 1-9 Heteroaryl; 2) or
Figure 104141541-A0101-12-0034-55
The following sub-structure formulas:
Figure 104141541-A0101-12-0034-56
 Wherein, X 7 , X 5 and X 6 are each independently -C(R 3a ) 2 -, -N(R 2 )-, -O-, -S(=O) m -or -C(=O) -; X, X 1 , X 2 , X 3 and X 4 are each independently CR 3a or N; each n is independently 0, 1 , 2 , 3 or 4; each n 1 is independently 1, 2 or 3; Each m is independently 0, 1 or 2; each R 1a , R 1 and R 2 are independently hydrogen, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)- (C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)-, N( R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C (R 3 ) 2 ) n -, C 3-9 cycloalkyl, C 2-9 heterocyclyl, C 1-9 heteroaryl or C 1-4 alkyl; each R 3a , R 3b and R 3 are independent Ground is hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, hydroxy, carboxy, amino, C 3-9 cycloalkyl, C 2-9 heterocyclyl, C 1-9 heteroaryl, C 1- 4 Haloalkyl, H-(CH 2 ) n -O-(CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C(=O)-(CH 2 ) n -, H-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; each R 4 is independently hydrogen, C 1-4 alkyl, hydroxy, carboxy, amino, C 1-4 alkoxy, amino C 1-4 alkyl, NH 2 -C (=O)-, C 3-9 cycloalkyl, C 2-9 heterocyclyl, C 1-9 heteroaryl, C 1-4 haloalkyl or C 1-4 alkylamino; said A represents Each sub-structure can be independently selected by 1, 2, 3 or 4 identical or different from hydrogen, C 1-4 alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxy, C 1-4 alkyl Oxygen, C 1-4 haloalkyl, C 1-4 alkylamino, amino C 1-4 alkyl, H-(C(R 3 ) 2 ) n- OC(=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(= O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)- (C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C( =O)-(C(R 3 ) 2 ) n -, substituted by a substituent of cyano or nitro; wherein, the alkyl, haloalkyl, R- described in R, R 1a , R 1 and R 2 (C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -,-(C(R 3 ) 2 ) n -N(R 4 ) 2 , HO-(C(R 3 ) 2 ) n -C(= O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, spiro-heterobicyclic, bridging heterobicyclic, Fused heterobicyclic, heterocyclic, cycloalkyl, heteroaryl, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, aryl, four-membered heterocyclic group, five-membered heterocyclic group, six-membered heterocyclic group and seven-membered heterocyclic group may be independently optionally substituted with 1, 2, 3 or 4 identical or different R 5 ; Each R 5 is independently hydrogen, oxo (=O), C 1-6 alkyl, fluorine, chlorine, bromine, amino, hydroxy, carboxy, C 1-4 alkoxy, C 1-4 alkylamino, Amino C 1-4 alkyl, N(R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -C(=O)-, C 1-6 haloalkyl, H- (C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -,-(C(R 3 ) 2 ) n -N(R 4 ) 2 , HO-( C(R 3 ) 2 ) n -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, N(R 4 ) 2 -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, spiro Bicyclic group, bridged heterobicyclic group, fused heterobicyclic group, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, cyanide Group, C 2-9 heterocyclic group, C 3-9 cycloalkyl group, C 1-9 heteroaryl group or nitro group; alkyl group described in R 5 , haloalkyl group, alkoxy group, alkylamino group, aminoalkyl group Group, spiroheterobicyclic group, bridged heterobicyclic group, fused heterobicyclic group, N(R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -C(=O)- , H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, -(C(R 3 ) 2 ) n -N(R 4 ) 2 , HO-(C(R 3 ) 2 ) n -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, N(R 4 ) 2 -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(=O)-(C(R 3 ) 2 ) n -, H-(C (R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-( C(R 3 ) 2 ) n -, heterocyclic group, cycloalkyl group and heteroaryl group are independently further optionally substituted with 1, 2, 3 or 4 same or different R 6 ; each R 6 is independently hydrogen , Oxo (=O), C 1-4 alkyl, fluorine, chlorine, bromine, amino, hydroxy, carboxy, C 1-4 alkoxy, C 1-4 alkylamino, amino C 1-4 alkyl, N(R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -C(=O)-, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -,-(C(R 3 ) 2 ) n -N(R 4 ) 2 , HO-(C(R 3 ) 2 ) n -C(=O )-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, N(R 4 ) 2 -C( =O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, spiroheterobicyclic, bridged heterobicyclic, fused heterobicyclic , H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, cyano, C 2-9 heterocyclyl, C 3- 9 cycloalkyl, C 1-9 heteroaryl or nitro.

一方面，本發明提供一種化合物，其為如式(I)所示的化合物，或式(I)所示的化合物的立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，代謝產物，酯，藥學上可接受的鹽或前藥，

Figure 104141541-A0101-12-0036-57
In one aspect, the invention provides a compound that is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the compound represented by formula (I), Hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
Figure 104141541-A0101-12-0036-57

其中：A環、L和R具有如本發明所述的含義。 Among them: ring A, L and R have the meaning as described in the present invention.

一些實施例中， L為鍵，-(C(R3b)2)n-，-N(R1)-(C(R3b)2)n-，-O-(C(R3b)2)n-，-S(=O)m-或-C(=O)-(C(R3b)2)n-；其中，n，m，R1和R3b具有如本發明所述的含義。 In some embodiments, L is a bond, -(C(R 3b ) 2 ) n -, -N(R 1 )-(C(R 3b ) 2 ) n -, -O-(C(R 3b ) 2 ) n -, -S(=O) m -or -C(=O)-(C(R 3b ) 2 ) n -; wherein, n, m, R 1 and R 3b have the meanings as described in the present invention.

一些實施例中， A環

Figure 104141541-A0101-12-0037-60
Figure 104141541-A0101-12-0037-61
 其中，當
Figure 104141541-A0101-12-0037-231
為=時，T為X，
Figure 104141541-A0101-12-0037-246
為
Figure 104141541-A0101-12-0037-228
當
Figure 104141541-A0101-12-0037-232
為-時，T為X6，
Figure 104141541-A0101-12-0037-244
為
Figure 104141541-A0101-12-0037-243
其中，X7，X5，和X6各自獨立地為-C(R3a)2-，-N(R2)-，-O-，-S(=O)m-或-C(=O)-；X，X1，X2，X3和X4各自獨立地為CR3a或N；其中，m，R2和R3a具有如本發明所述的含義。 In some embodiments, ring A
Figure 104141541-A0101-12-0037-60
Figure 104141541-A0101-12-0037-61
 Among them, when
Figure 104141541-A0101-12-0037-231
When =, T is X,
Figure 104141541-A0101-12-0037-246
for
Figure 104141541-A0101-12-0037-228
when
Figure 104141541-A0101-12-0037-232
Is-when T is X 6 ,
Figure 104141541-A0101-12-0037-244
for
Figure 104141541-A0101-12-0037-243
Wherein, X 7 , X 5 , and X 6 are each independently -C(R 3a ) 2 -, -N(R 2 )-, -O-, -S(=O) m -or -C(=O )-; X, X 1 , X 2 , X 3 and X 4 are each independently CR 3a or N; wherein, m, R 2 and R 3a have the meanings as described in the present invention.

一些實施例中，R為氫，R13，-(C(R3b)2)n-N(R1a)-C(=O)-(C(R3b)2)n-R13或 -(CH2)n-C(=O)-N(R1a)-(C(R3b)2)n-R13；R13為氫，C3-9環烷基，C1-9雜芳基，C2-9雜環基或R0；R0，R和R13可獨立任選地被1，2，3或4個相同或不同的R5取代；其中，各R5，n，R0，R1a和各R3b具有如本發明所述的含義。 In some embodiments, R is hydrogen, R 13 , -(C(R 3b ) 2 ) n -N(R 1a )-C(=O)-(C(R 3b ) 2 ) n -R 13 or -( CH 2 ) n -C(=O)-N(R 1a )-(C(R 3b ) 2 ) n -R 13 ; R 13 is hydrogen, C 3-9 cycloalkyl, C 1-9 heteroaryl , C 2-9 heterocyclyl or R 0 ; R 0 , R and R 13 may be independently and optionally substituted with 1, 2, 3 or 4 identical or different R 5 ; wherein, each R 5 , n, R 0 , R 1a and each R 3b have the meaning as described in the present invention.

一些實施例中，各n獨立地為0，1，2，3或4。 In some embodiments, each n is independently 0, 1, 2, 3, or 4.

一些實施例中，各n1獨立地為1，2或3。 In some embodiments, each n1 is independently 1, 2, or 3.

一些實施例中，各m獨立地為0，1或2。 In some embodiments, each m is independently 0, 1, or 2.

一些實施例中，R0為C5-11螺雜雙環基，C5-11橋雜雙環基或C5-11稠合雜雙環基；可獨立任選地被1，2，3或4個相同或不同的R5取代；各R5具有如本發明所述的含義。 In some embodiments, R 0 is a C 5-11 spiroheterobicyclic group, a C 5-11 bridge heterobicyclic group or a C 5-11 fused heterobicyclic group; it can be independently optionally substituted by 1, 2, 3 or 4 The same or different R 5 substitutions; each R 5 has the meaning as described in the present invention.

一些實施例中，各R01獨立地為C2-9雜環基，C1-9雜芳基或C3-9環烷基；各R01可獨立任選地被1，2，3或4個相同或不同的R5取代；各R5具有如本發明所述的含義。 In some embodiments, each R 01 is independently C 2-9 heterocyclyl, C 1-9 heteroaryl or C 3-9 cycloalkyl; each R 01 may be independently optionally 1, 2, 3 or 4 identical or different R 5 substitutions; each R 5 has the meaning as described in the present invention.

一些實施例中，各R00獨立地為C2-9雜環基，C1-9雜芳基或C3-9環烷基；各R00可獨立任選地被1，2，3或4個相同或不同的R5取代；各R5具有如本發明所述的含義。 In some embodiments, each R 00 is independently C 2-9 heterocyclyl, C 1-9 heteroaryl, or C 3-9 cycloalkyl; each R 00 may be optionally substituted by 1, 2, 3, or 4 identical or different R 5 substitutions; each R 5 has the meaning as described in the present invention.

一些實施例中，各R1獨立地為氫，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，R00或C1-4烷基；各R1可獨立任選地 被1，2，3或4個相同或不同的R5取代；其中，各R5，各n，R00，各R4和各R3具有如本發明所述的含義。 In some embodiments, each R 1 is independently hydrogen, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, ( R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n- SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -,CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, R 00 or C 1-4 alkyl; each R 1 may be independently substituted with 1, 2, 3 or 4 identical or different R 5 ; wherein, each R 5 , each n, R 00 , each R 4 and each R 3 has the meaning as described in the present invention.

一些實施例中，各R1a獨立地為氫，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，R00或C1-4烷基；各R1a可獨立任選地被1，2，3或4個相同或不同的R5取代；其中，各R5，各n，R00，各R4和各R3具有如本發明所述的含義。 In some embodiments, each R 1a is independently hydrogen, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, ( R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n- SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -,CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, R 00 or C 1-4 alkyl; each R 1a may be independently substituted with 1, 2, 3 or 4 identical or different R 5 ; wherein, each R 5 , each n, R 00 , each R 4 and each R 3 has the meaning as described in the present invention.

一些實施例中，各R2獨立地為氫，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，R00或C1-4烷基；各R2可獨立任選地被1，2，3或4個相同或不同的R5取代；其中，各R5，各n，R00，各R4和各R3具有如本發明所述的含義。 In some embodiments, each R 2 is independently hydrogen, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, ( R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n- SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -,CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, R 00 or C 1-4 alkyl; each R 2 may be independently optionally substituted with 1, 2, 3 or 4 identical or different R 5 ; wherein each R 5 , each n, R 00 , each R 4 and each R 3 has the meaning as described in the present invention.

一些實施例中，各R3獨立地為氫，氟，氯，溴，C1-4烷基，羥基，羧基，氨基，R01，C1-4鹵代烷基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-，H-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；其中，各n，各R01和各R4具有如本發明所述的含義。 In some embodiments, each R 3 is independently hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, hydroxy, carboxy, amino, R 01 , C 1-4 haloalkyl, H-(CH 2 ) n- O-(CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C (=O)-(CH 2 ) n -, H-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; where, each n, each R 01 and each R 4 have the meaning as described in the present invention.

一些實施例中，各R3a獨立地為氫，氟，氯，溴，C1-4烷基，羥基，羧基，氨基，R01，C1-4鹵代烷基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-，H-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；其中，各n，各R01和各R4具有如本發明所述的含義。 In some embodiments, each R 3a is independently hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, hydroxy, carboxy, amino, R 01 , C 1-4 haloalkyl, H-(CH 2 ) n- O-(CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C (=O)-(CH 2 ) n -, H-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; where, each n, each R 01 and each R 4 have the meaning as described in the present invention.

一些實施例中，各R3b獨立地為氫，氟，氯，溴，C1-4烷基，羥基，羧基，氨基，R01， C1-4鹵代烷基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-，H-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；其中，各n，各R01和各R4具有如本發明所述的含義。 In some embodiments, each R 3b is independently hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, hydroxy, carboxy, amino, R 01 , C 1-4 haloalkyl, H-(CH 2 ) n- O-(CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C (=O)-(CH 2 ) n -, H-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; where, each n, each R 01 and each R 4 have the meaning as described in the present invention.

一些實施例中，各R4獨立地為氫，C1-4烷基，羥基，羧基，氨基，C1-4烷氧基，氨基C1-4烷基，NH2-C(=O)-，R01，C1-4鹵代烷基或C1-4烷氨基；其中，各R01具有如本發明所述的含義。 In some embodiments, each R 4 is independently hydrogen, C 1-4 alkyl, hydroxy, carboxy, amino, C 1-4 alkoxy, amino C 1-4 alkyl, NH 2 -C(=O) -, R 01 , C 1-4 haloalkyl or C 1-4 alkylamino; wherein each R 01 has the meaning as described in the present invention.

一些實施例中，所述的A代表的各子結構式可獨立任選地被1，2，3或4個相同或不同的選自氫，C1-4烷基，氟，氯，溴，氨基，羥基，羧基，C1-4烷氧基，C1-4鹵代烷基，C1-4烷基氨基，氨基C1-4烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，氰基或硝基的取代基所取代；其中，n，各R4和各R3具有如本發明所述的含義。 In some embodiments, each sub-structure represented by A can be optionally selected from 1, 2, 3, or 4 identical or different from hydrogen, C 1-4 alkyl, fluorine, chlorine, bromine, Amino, hydroxy, carboxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkylamino, amino C 1-4 alkyl, H-(C(R 3 ) 2 ) n -OC (=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O )-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-( C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C(= O)-(C(R 3 ) 2 ) n -, substituted by a substituent of cyano or nitro; wherein, n, each R 4 and each R 3 have the meanings as described in the present invention.

一些實施例中，各R5獨立地為氫，氧代(=O)，C1-6烷基，氟，氯，溴，氨基，羥基，羧基，C1-4烷氧基，C1-4烷氨基，氨基C1-4烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，C1-6鹵代烷基，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，氰基，C2-9雜環基，C3-9環烷基，C1-9雜芳基或硝基；各R5中所述的烷基，烷氧基，烷氨基，氨基烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，雜環基，環烷基和雜芳基獨立任選地進一步被1， 2，3或4個相同或不同的R6取代；其中，各R6，n1，各n，各R4和各R3具有如本發明所述的含義。 In some embodiments, each R 5 is independently hydrogen, oxo (=O), C 1-6 alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxy, C 1-4 alkoxy, C 1- 4 alkylamino, amino C 1-4 alkyl, N(R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -C(=O)-, C 1-6 haloalkane Radical, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C (=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O) -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, cyano, C 2-9 heterocyclyl, C 3 -9 cycloalkyl, C 1-9 heteroaryl or nitro; the alkyl, alkoxy, alkylamino, aminoalkyl, N(R 4 ) 2 -C(=O) described in each R 5 -, CN-(C(R 3 ) 2 ) n -C(=O)-, haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n- C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C (R 3 ) 2 ) n -, heterocyclic group, cycloalkyl group and heteroaryl group are independently and optionally further substituted with 1, 2, 3 or 4 same or different R 6 ; wherein, each R 6 , n1, Each n, each R 4 and each R 3 have the meanings as described in the present invention.

一些實施例中，各R6獨立地為氫，氧代(=O)，C1-4烷基，氟，氯，溴，氨基，羥基，羧基，C1-4烷氧基，C1-4烷氨基，氨基C1-4烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，氰基，C2-9雜環基，C3-9環烷基，C1-9雜芳基或硝基；n1，各n，各R4和各R3具有如本發明所述的含義。 In some embodiments, each R 6 is independently hydrogen, oxo (=O), C 1-4 alkyl, fluorine, chlorine, bromine, amino, hydroxy, carboxy, C 1-4 alkoxy, C 1- 4 alkylamino, amino C 1-4 alkyl, N(R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -C(=O)-, C 1-4 haloalkane Radical, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O)-C (=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-(C( R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(=O) -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, cyano, C 2-9 heterocyclyl, C 3 -9 cycloalkyl, C 1-9 heteroaryl or nitro; n1, each n, each R 4 and each R 3 have the meaning as described in the present invention.

一些實施例中，本發明所述的化合物，其為如式(II)所示的化合物，或式(II)所示的化合物的立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，代謝產物，酯，藥學上可接受的鹽或前藥，

Figure 104141541-A0101-12-0041-67
In some embodiments, the compound of the present invention is a compound represented by formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen of the compound represented by formula (II) Oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
Figure 104141541-A0101-12-0041-67

其中：L為鍵，-(CH2)n-，-N(R1)-，-O-，-S-或-C(=O)-；當

Figure 104141541-A0101-12-0041-233
為=時，T為X；當
Figure 104141541-A0101-12-0041-234
為-時，T為X6；n，R1，X，X2，X3，X4，X5，X6和R13具有如本發明所述的含義。 Where: L is a bond, -(CH 2 ) n -, -N(R 1 )-, -O-, -S- or -C(=O)-; when
Figure 104141541-A0101-12-0041-233
When =, T is X; when
Figure 104141541-A0101-12-0041-234
When is -, T is X 6 ; n, R 1 , X, X 2 , X 3 , X 4 , X 5 , X 6 and R 13 have the meanings as described in the present invention.

一些實施例中，本發明所述的化合物，其為如式(III)所示的化合物，或式(III)所示的化合物的立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，代謝產物，酯，藥學上可接受的鹽或前藥，

Figure 104141541-A0101-12-0042-70
In some embodiments, the compound of the present invention is a compound represented by formula (III), or a stereoisomer, geometric isomer, tautomer, nitrogen of the compound represented by formula (III) Oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
Figure 104141541-A0101-12-0042-70

L，X，X1，X2，X3，X5，X6，X7和R13具有如本發明所述的含義。 L, X, X 1 , X 2 , X 3 , X 5 , X 6 , X 7 and R 13 have the meanings as described in the present invention.

一些實施例中， R0為

Figure 104141541-A0101-12-0042-72
Figure 104141541-A0101-12-0042-73
 其中，Y，Y1，Y7和Y2各自獨立地為-C(R3c)2-，-N(R2b)-，-O-，-S(=O)m-或-C(=O)-；各Y9獨立地為-CR3c-或-N-，各e，r，g和f獨立地為0，1，2或3；R0可獨立任選地被1，2，3或4個相同或不同的R5取代；其中，各R5、各R3c、各R2b和m具有如本發明所述的含義。 In some embodiments, R 0 is
Figure 104141541-A0101-12-0042-72
Figure 104141541-A0101-12-0042-73
 Where Y, Y 1 , Y 7 and Y 2 are each independently -C(R 3c ) 2 -, -N(R 2b )-, -O-, -S(=O) m -or -C(= O)-; each Y 9 is independently -CR 3c -or -N-, each e, r, g and f is independently 0, 1, 2 or 3; R 0 may be independently optionally 1, 2, 3 or 4 identical or different R 5 substitutions; wherein each R 5 , each R 3c , each R 2b and m have the meanings as described in the present invention.

一些實施例中，各R2b獨立地為氫，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-， (R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-或C1-4烷基；各R2b可獨立任選地被1，2，3或4個相同或不同的R5取代；其中，各R5，各n，各R4和各R3具有如本發明所述的含義。 In some embodiments, each R 2b is independently hydrogen, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, ( R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n- SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -,CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -or C 1- 4 alkyl; each R 2b may be independently optionally substituted with 1, 2, 3 or 4 identical or different R 5 ; wherein each R 5 , each n, each R 4 and each R 3 have The meaning mentioned.

一些實施例中，各R3c獨立地為氫，氟，氯，溴，C1-4烷基，羥基，羧基，氨基，C1-4鹵代烷基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-，H-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；其中，各n和各R4具有如本發明所述的含義。 In some embodiments, each R 3c is independently hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, hydroxy, carboxy, amino, C 1-4 haloalkyl, H-(CH 2 ) n -O-( CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C(=O )-(CH 2 ) n -, H-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; where each n and each R 4 has the meaning as described in the present invention.

一些實施例中，各R01獨立地為

Figure 104141541-A0101-12-0043-75
Figure 104141541-A0101-12-0043-77
 其中，Y和Y1各自獨立地為-C(R3c)2-，-N(R2b)-，-O-，-S(=O)m-或-C(=O)-；Y3，Y4和Y5各自獨立地為CR3c或N；各e，r和f獨立地為0，1，2或3；各R01可獨立任選地被1，2，3或4個相同或不同的R5取代；其中，各R5、各R3c、各R2b和m具有如本發明所述的含義。 In some embodiments, each R 01 is independently
Figure 104141541-A0101-12-0043-75
Figure 104141541-A0101-12-0043-77
 Wherein Y and Y 1 are independently -C(R 3c ) 2 -, -N(R 2b )-, -O-, -S(=O) m -or -C(=O)-; Y 3 , Y 4 and Y 5 are each independently CR 3c or N; each e, r, and f are independently 0, 1, 2, or 3; each R 01 may be independently selected by 1, 2, 3, or 4 Or different R 5 substitutions; wherein each R 5 , each R 3c , each R 2b and m have the meanings as described in the present invention.

一些實施例中，各R00獨立地為

Figure 104141541-A0101-12-0043-79
Figure 104141541-A0101-12-0043-80
 其中，Y和Y1各自獨立地為-C(R3c)2-，-N(R2b)-，-O-，-S(=O)m-或-C(=O)-；Y3，Y4和Y5各自獨立地為CR3c或N；各e，r和f獨立地為0，1，2或3；各R00可獨立任選地被1，2，3或4個相同或不同的R5取代；其中，各R5、各R3c、各R2b和m具有如本發明所述的含義。 In some embodiments, each R 00 is independently
Figure 104141541-A0101-12-0043-79
Figure 104141541-A0101-12-0043-80
 Wherein Y and Y 1 are independently -C(R 3c ) 2 -, -N(R 2b )-, -O-, -S(=O) m -or -C(=O)-; Y 3 , Y 4 and Y 5 are each independently CR 3c or N; each e, r, and f are independently 0, 1, 2, or 3; each R 00 may be independently selected by 1, 2, 3, or 4 Or different R 5 substitutions; wherein each R 5 , each R 3c , each R 2b and m have the meanings as described in the present invention.

一些實施例中，R0為

Figure 104141541-A0101-12-0044-82
Figure 104141541-A0101-12-0044-83
Figure 104141541-A0101-12-0045-84
Figure 104141541-A0101-12-0046-85
 其中，所述的R0代表的各子結構式可獨立任選地進一步被1，2，3或4個相同或不同的R5取代；其中，各R5具有如本發明所述的含義。 In some embodiments, R 0 is
Figure 104141541-A0101-12-0044-82
Figure 104141541-A0101-12-0044-83
Figure 104141541-A0101-12-0045-84
Figure 104141541-A0101-12-0046-85
 Wherein, each sub-structural formula represented by R 0 may be independently further optionally substituted with 1, 2, 3 or 4 R 5 which are the same or different; wherein each R 5 has the meaning as described in the present invention.

一些實施例中， 各R00獨立地為環丙基，環己基，環戊基，環丁基，

Figure 104141541-A0101-12-0046-202
Figure 104141541-A0101-12-0046-201
 其中，所述的R00代表的各子結構式可獨立任選地進一步被1，2，3或4個相同或不同的R5取代；其中，各R5具有如本發明所述的含義。 In some embodiments, each R 00 is independently cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl,
Figure 104141541-A0101-12-0046-202
Figure 104141541-A0101-12-0046-201
 Wherein, each sub-structural formula represented by R 00 may be independently and optionally further substituted with 1, 2, 3 or 4 same or different R 5 ; wherein each R 5 has the meaning as described in the present invention.

一些實施例中， 各R01獨立地為環丙基，環己基，環戊基，環丁基，

Figure 104141541-A0101-12-0046-88
Figure 104141541-A0101-12-0046-89
Figure 104141541-A0101-12-0047-90
 其中，所述的R01代表的各子結構式可獨立任選地進一步被1，2，3或4個相同或不同的R5取代；其中，各R5具有如本發明所述的含義。 In some embodiments, each R 01 is independently cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl,
Figure 104141541-A0101-12-0046-88
Figure 104141541-A0101-12-0046-89
Figure 104141541-A0101-12-0047-90
 Wherein, each sub-structural formula represented by R 01 may be independently and optionally further substituted with 1, 2, 3 or 4 R 5 which are the same or different; wherein each R 5 has the meaning as described in the present invention.

一些實施例中，A環為

Figure 104141541-A0101-12-0047-248
Figure 104141541-A0101-12-0047-93
Figure 104141541-A0101-12-0048-95
 其中，所述的A代表的各子結構式可獨立任選地進一步被1，2，3或4個相同或不同的選自氫，C1-4烷基，氟，氯，溴，氨基，羥基，羧基，C1-4烷氧基，C1-4鹵代烷基，C1-4烷基氨基，氨基C1-4烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，氰基或硝基的取代基所取代；各R3、各R3a、各R4、R2和n具有如本發明所述的含義。 In some embodiments, ring A is
Figure 104141541-A0101-12-0047-248
Figure 104141541-A0101-12-0047-93
Figure 104141541-A0101-12-0048-95
 Wherein, each sub-structure represented by A can be optionally further independently selected from 1, 2, 3 or 4 identical or different ones selected from hydrogen, C 1-4 alkyl, fluorine, chlorine, bromine, amino, Hydroxy, carboxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkylamino, amino C 1-4 alkyl, H-(C(R 3 ) 2 ) n -OC(= O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)- , N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C( R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O) -(C(R 3 ) 2 ) n -, substituted by a cyano or nitro substituent; each R 3 , each R 3a , each R 4 , R 2 and n have the meanings as described in the present invention.

一些實施例中，R13為如下各子結構式：氫，R0，

Figure 104141541-A0101-12-0048-96
Figure 104141541-A0101-12-0048-97
 其中，Y，Y1，Y7和Y2各自獨立地為-C(R3c)2-，-N(R2b)-，-O-，-S(=O)m-或-C(=O)-；Y3，Y4和Y5各自獨立地為CR3c或N；各e，r和f獨立地為0，1，2或3；其中，各R3c、R0、各R2b和m具有如本發明所述的含義。 In some embodiments, R 13 is the following sub-structure formulas: hydrogen, R 0 ,
Figure 104141541-A0101-12-0048-96
Figure 104141541-A0101-12-0048-97
 Where Y, Y 1 , Y 7 and Y 2 are each independently -C(R 3c ) 2 -, -N(R 2b )-, -O-, -S(=O) m -or -C(= O)-; Y 3 , Y 4 and Y 5 are each independently CR 3c or N; each e, r and f are independently 0, 1, 2 or 3; wherein, each R 3c , R 0 , each R 2b And m have the meaning as described in the present invention.

一些實施例中，R13為氫，R0，

Figure 104141541-A0101-12-0048-203
Figure 104141541-A0101-12-0049-99
 其中，所述的R13代表的各子結構式可獨立任選地進一步被1，2，3或4個相同或不同的R5取代；其中，各R5、R0和n具有如本發明所述的含義。 In some embodiments, R 13 is hydrogen, R 0 ,
Figure 104141541-A0101-12-0048-203
Figure 104141541-A0101-12-0049-99
 Wherein, each sub-structural formula represented by R 13 can be independently and optionally further substituted with 1, 2, 3 or 4 R 5 which are the same or different; wherein each R 5 , R 0 and n have The meaning.

一些實施例中，各R3獨立地為氫，氟，氯，溴，羥基，羧基，氨基，三氟甲基，甲基，乙基，丙基，丁基，環丙基，環己基，環戊基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；其中，各n和各R4具有如本發明所述的含義。 In some embodiments, each R 3 is independently hydrogen, fluorine, chlorine, bromine, hydroxy, carboxy, amino, trifluoromethyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclohexyl, cyclic Amyl, H-(CH 2 ) n -O-(CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; wherein each n and each R 4 have The meaning mentioned.

一些實施例中， 各R3a獨立地為氫，氟，氯，溴，羥基，羧基，氨基，三氟甲基，甲基，乙基，丙基，丁基，環丙基，環己基，環戊基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；其中，各n和各R4具有如本發明所述的含義。 In some embodiments, each R 3a is independently hydrogen, fluorine, chlorine, bromine, hydroxy, carboxy, amino, trifluoromethyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclohexyl, cyclic Amyl, H-(CH 2 ) n -O-(CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; wherein each n and each R 4 have The meaning mentioned.

一些實施例中，各R3b獨立地為氫，氟，氯，溴，羥基，羧基，氨基，三氟甲基，甲基，乙基，丙基，丁基，環丙基，環己基，環戊基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；其中，各n和各R4具有如本發明所述的含義。 In some embodiments, each R 3b is independently hydrogen, fluorine, chlorine, bromine, hydroxy, carboxy, amino, trifluoromethyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclohexyl, cyclic Amyl, H-(CH 2 ) n -O-(CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; wherein each n and each R 4 have The meaning mentioned.

一些實施例中，各R3c獨立地為氫，氟，氯，溴，羥基，羧基，氨基，三氟甲基，甲基，乙基，丙基，丁基，H-(CH2)n-O-(CH2)n-，N(R4)2-C(=O)-，H-(CH2)n-SO2-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；其中，各n和各R4具有如本發明所述的含義。 In some embodiments, each R 3c is independently hydrogen, fluorine, chlorine, bromine, hydroxyl, carboxyl, amino, trifluoromethyl, methyl, ethyl, propyl, butyl, H-(CH 2 ) n- O-(CH 2 ) n -, N(R 4 ) 2 -C(=O)-, H-(CH 2 ) n -SO 2 -(CH 2 ) n -, HO-(CH 2 ) n -C (=O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; wherein each n and each R 4 have the meaning as described in the present invention.

一些實施例中，各R4獨立地為氫，羥基，羧基，氨基，甲氧基，氨基甲基，氨基乙基，NH2-C(=O)-，三氟甲基，2,2-二氟乙基，甲基，乙基，丙基或丁基。 In some embodiments, each R 4 is independently hydrogen, hydroxy, carboxy, amino, methoxy, aminomethyl, aminoethyl, NH 2 -C(=O)-, trifluoromethyl, 2,2- Difluoroethyl, methyl, ethyl, propyl or butyl.

一些實施例中，各R1獨立地為氫，3,3,3-三氟丙基，三氟甲基，1,1-二氟乙基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，R00，甲基，乙基，丙基或丁基；其中，各R00、各R4、各R3、和各n具有如本發明所述的含義。 In some embodiments, each R 1 is independently hydrogen, 3,3,3-trifluoropropyl, trifluoromethyl, 1,1-difluoroethyl, H-(C(R 3 ) 2 ) n- OC(=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(= O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)- (C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C( =O)-(C(R 3 ) 2 ) n -, R 00 , methyl, ethyl, propyl or butyl; wherein each R 00 , each R 4 , each R 3 , and each n have the same The meaning of the invention.

一些實施例中，各R1a獨立地為氫，3,3,3-三氟丙基，三氟甲基，1,1-二氟乙基， H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，R00，甲基，乙基，丙基或丁基；其中，各R00、各R4、各R3、和各n具有如本發明所述的含義。 In some embodiments, each R 1a is independently hydrogen, 3,3,3-trifluoropropyl, trifluoromethyl, 1,1-difluoroethyl, H-(C(R 3 ) 2 ) n- OC(=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(= O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)- (C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C( =O)-(C(R 3 ) 2 ) n -, R 00 , methyl, ethyl, propyl or butyl; wherein each R 00 , each R 4 , each R 3 , and each n have the same The meaning of the invention.

一些實施例中，各R1b獨立地為氫，3,3,3-三氟丙基，三氟甲基，1,1-二氟乙基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，R00，甲基，乙基，丙基或丁基；其中，各R00、各R4、各R3、和各n具有如本發明所述的含義。 In some embodiments, each R 1b is independently hydrogen, 3,3,3-trifluoropropyl, trifluoromethyl, 1,1-difluoroethyl, H-(C(R 3 ) 2 ) n- OC(=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(= O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)- (C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C( =O)-(C(R 3 ) 2 ) n -, R 00 , methyl, ethyl, propyl or butyl; wherein each R 00 , each R 4 , each R 3 , and each n have the same The meaning of the invention.

一些實施例中，各R2獨立地為氫，3,3,3-三氟丙基，三氟甲基，1,1-二氟乙基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，R00，甲基，乙基，丙基或丁基；其中，各R00、各R4、各R3、和各n具有如本發明所述的含義。 In some embodiments, each R 2 is independently hydrogen, 3,3,3-trifluoropropyl, trifluoromethyl, 1,1-difluoroethyl, H-(C(R 3 ) 2 ) n- OC(=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(= O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)- (C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C( =O)-(C(R 3 ) 2 ) n -, R 00 , methyl, ethyl, propyl or butyl; wherein each R 00 , each R 4 , each R 3 , and each n have the same The meaning of the invention.

一些實施例中，各R2b獨立地為氫，3,3,3-三氟丙基，三氟甲基，1,1-二氟乙基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，N(R4)2-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，CN-(C(R3)2)n-C(=O)-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，甲基，乙基，丙基或丁基； 其中，各R4、各R3、和各n具有如本發明所述的含義。 In some embodiments, each R 2b is independently hydrogen, 3,3,3-trifluoropropyl, trifluoromethyl, 1,1-difluoroethyl, H-(C(R 3 ) 2 ) n- OC(=O)-(C(R 3 ) 2 ) n -, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(= O)-, N(R 4 ) 2 -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)- (C(R 3 ) 2 ) n -, CN-(C(R 3 ) 2 ) n -C(=O)-, H-(C(R 3 ) 2 ) n -OC(=O)-C( =O)-(C(R 3 ) 2 ) n -, methyl, ethyl, propyl or butyl; wherein each R 4 , each R 3 , and each n have the meanings as described in the present invention.

在一些實施例中，各R5獨立地為氫，氧代(=O)，甲基，乙基，丙基，丁基，氟，氯，溴，氨基，羥基，羧基，甲氧基，C1-4烷氨基，氨基C1-4烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，三氟甲基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，

Figure 104141541-A0101-12-0052-100
，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，氰基，環丙基，環己基，環戊基或硝基；其中，n1、各R4、各R3、和各n具有如本發明所述的含義。 In some embodiments, each R 5 is independently hydrogen, oxo (=O), methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxy, methoxy, C 1-4 alkylamino, amino C 1-4 alkyl, N(R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -C(=O)-, trifluoromethyl Radical, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -,
Figure 104141541-A0101-12-0052-100
, C 1-4 haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-( C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(= O)-(C(R 3 ) 2 ) n -, cyano, cyclopropyl, cyclohexyl, cyclopentyl or nitro; wherein, n1, each R 4 , each R 3 , and each n have the present invention The meaning.

在一些實施例中，各R6獨立地為氫，氧代(=O)，甲基，乙基，丙基，丁基，氟，氯，溴，氨基，羥基，羧基，甲氧基，C1-4烷氨基，氨基C1-4烷基，N(R4)2-C(=O)-，CN-(C(R3)2)n-C(=O)-，C1-4鹵代烷基，H-(C(R3)2)n-O-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n1-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，氰基，C3-6雜環基，C3-6環烷基或硝基；其中，n1、各R4、各R3、和各n具有如本發明所述的含義。 In some embodiments, each R 6 is independently hydrogen, oxo (=O), methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxy, methoxy, C 1-4 alkylamino, amino C 1-4 alkyl, N(R 4 ) 2 -C(=O)-, CN-(C(R 3 ) 2 ) n -C(=O)-, C 1- 4 Haloalkyl, H-(C(R 3 ) 2 ) n -OC(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O) -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-( C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n1 -C(= O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, cyano, C 3-6 heterocyclyl, C 3-6 cycloalkyl or nitro; wherein n1, each R 4 , each R 3 , and each n have the meanings as described in the present invention.

在一些實施例中，

Figure 104141541-A0101-12-0052-101
為如下各子結構式：
Figure 104141541-A0101-12-0053-102
 R2和R3a具有如本發明所述的含義。 In some embodiments,
Figure 104141541-A0101-12-0052-101
The following sub-structure formulas:
Figure 104141541-A0101-12-0053-102
 R 2 and R 3a have the meaning as described in the present invention.

在一些實施例中，

Figure 104141541-A0101-12-0053-105
為如下各子結構式：
Figure 104141541-A0101-12-0053-107
 其中，所述的各子結構式可獨立任選地進一步被1，2，3或4個相同或不同的R5取代；各R5具有如本發明所述的含義。 In some embodiments,
Figure 104141541-A0101-12-0053-105
The following sub-structure formulas:
Figure 104141541-A0101-12-0053-107
 Wherein, each of the sub-structural formulas described above may be independently and optionally further substituted with 1, 2, 3 or 4 identical or different R 5 ; each R 5 has the meaning as described in the present invention.

一方面，本發明所述的化合物，其為如下之一的結構所示的化合物，或所示的化合物的立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，代謝產物，酯，藥學上可接受的鹽或前藥，

Figure 104141541-A0101-12-0054-108
Figure 104141541-A0101-12-0055-109
Figure 104141541-A0101-12-0056-110
Figure 104141541-A0101-12-0057-111
Figure 104141541-A0101-12-0058-112
Figure 104141541-A0101-12-0059-113
Figure 104141541-A0101-12-0060-114
 In one aspect, the compound of the present invention is a compound represented by one of the following structures, or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates Solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,
Figure 104141541-A0101-12-0054-108
Figure 104141541-A0101-12-0055-109
Figure 104141541-A0101-12-0056-110
Figure 104141541-A0101-12-0057-111
Figure 104141541-A0101-12-0058-112
Figure 104141541-A0101-12-0059-113
Figure 104141541-A0101-12-0060-114

一方面，本發明提供一種藥物組合物，包含一種如本發明所述的化合物。 In one aspect, the invention provides a pharmaceutical composition comprising a compound according to the invention.

一些實施例中，本發明所述的藥物組合物，進一步包含藥學上可接受的載體，賦形劑，稀釋劑，輔劑，媒介物中的至少一種。 In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.

另一方面，本發明所述的化合物或本發明所述的藥物組合物 在製備用於預防，處理，治療或減輕患者由異常細胞增殖，自身免疫，炎性或感染引起的障礙或病症的藥物中的用途。 In another aspect, the compound of the present invention or the pharmaceutical composition of the present invention Use in the preparation of a medicament for preventing, treating, treating or alleviating a patient's disorder or condition caused by abnormal cell proliferation, autoimmunity, inflammation or infection.

另一方面，一種運用本發明所述化合物或本發明所述的藥物組合物來製備預防，處理，治療或減輕患者由異常細胞增殖，自身免疫，炎性或感染引起的障礙或病症的藥物的方法。 On the other hand, a drug using the compound of the present invention or the pharmaceutical composition of the present invention for the preparation, prevention, treatment, treatment or alleviation of a disorder or condition caused by abnormal cell proliferation, autoimmunity, inflammation or infection in a patient method.

另一方面，本發明所述化合物或本發明所述的藥物組合物用於預防，處理，治療或減輕患者由異常細胞增殖，自身免疫，炎性或感染引起的障礙或病症。 In another aspect, the compound of the present invention or the pharmaceutical composition of the present invention is used to prevent, treat, treat or alleviate a patient's disorder or condition caused by abnormal cell proliferation, autoimmunity, inflammation or infection.

另一方面，用於預防，處理，治療或減輕患者由異常細胞增殖，自身免疫，炎性或感染引起的障礙或病症的如本發明所述化合物或藥物組合物。 On the other hand, the compound or pharmaceutical composition according to the present invention is used for preventing, treating, treating or alleviating a patient's disorder or condition caused by abnormal cell proliferation, autoimmunity, inflammation or infection.

一些實施例中，本發明所述的用途，其中所述的異常細胞增殖疾病是指卵巢癌，子宮頸癌，睾丸癌，食道癌，胃癌，皮膚癌，肺癌，骨癌，急性髓性白血病，慢性髓性白血病，胃腸基質腫瘤，急性髓細胞性白血病(AML)，突變的慢性髓性白血病(CML)，急性淋巴細胞白血病(ALL)，結直腸癌，胃癌，乳腺癌，肺癌，肝癌，前列腺癌，胰腺癌，甲狀腺癌，腎癌，腦瘤，頸癌，中樞神經系統的癌症，惡性膠質瘤，骨髓增生病，動脈粥樣硬化，肺纖維化，白血病，淋巴癌，風濕性疾病，冷球蛋白血症，非淋巴網狀系統腫瘤，丘疹性黏蛋白沉積症，家族性脾性貧血，多發性骨髓瘤，澱粉樣變，孤立性漿細胞瘤，重鏈病，輕鏈病，惡性淋巴瘤，慢性淋巴細胞白血病，原發性巨球蛋白血症，半分子病，單核細胞白血病，原發性巨球蛋白血症紫癜，繼發性良性單克隆丙種球蛋白病，溶骨性病變，淋巴母細胞瘤，部分非霍奇金淋巴瘤，Sezary綜合征，傳染性單核細胞增多症，急性組織細胞增多症，霍奇金淋巴瘤，毛細胞白血病，結腸癌，直腸癌，腸道息肉，小細胞肺癌，神經母細胞瘤，神經內分泌細胞腫瘤，胰島細胞瘤，甲狀腺髓樣癌，黑色素瘤，視網膜母細胞瘤，子宮癌，卵巢癌，頭頸部鱗癌，消化道惡性腫瘤，非小細胞肺癌，宮頸癌，睾丸腫瘤，膠質母細胞瘤，套細胞淋巴瘤，慢性粒細胞白血病，急性粒細胞白血病，膀胱癌或骨髓瘤。 In some embodiments, the use according to the present invention, wherein the abnormal cell proliferation disease refers to ovarian cancer, cervical cancer, testicular cancer, esophageal cancer, gastric cancer, skin cancer, lung cancer, bone cancer, acute myeloid leukemia, Chronic myeloid leukemia, gastrointestinal stromal tumors, acute myeloid leukemia (AML), mutated chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate Cancer, pancreatic cancer, thyroid cancer, kidney cancer, brain tumor, neck cancer, central nervous system cancer, malignant glioma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic disease, cold Globulinemia, non-lymphoid reticulum tumors, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma , Chronic lymphocytic leukemia, primary macroglobulinemia, semimolecular disease, monocyte leukemia, primary macroglobulinemia purpura, secondary benign monoclonal gammopathy, osteolytic lesions, Lymphoblastoma, some non-Hodgkin's lymphoma, Sezary syndrome, infectious mononucleosis, acute histiocytosis, Hodgkin's lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyps , Small cell lung cancer, neuroblastoma, neuroendocrine cell tumor, islet cell tumor, medullary thyroid carcinoma, melanoma, retinoblastoma, uterine cancer, ovarian cancer, head and neck squamous cell carcinoma, gastrointestinal malignant tumor, non-small Cell lung cancer, cervical cancer, testicular tumor, glioblastoma, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, bladder cancer or myeloma.

一些實施例中，本發明所述的用途，其中，所述自身免疫疾病是風濕性關節炎，狼瘡，多發性硬化，甲狀腺炎，I型糖尿病，結節病，炎性腸病，克羅恩氏疾病或全身性狼瘡。 In some embodiments, the use according to the present invention, wherein the autoimmune disease is rheumatoid arthritis, lupus, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, inflammatory bowel disease, Crohn's Disease or systemic lupus.

一些實施例中，本發明所述的用途，其中，其中所述的炎性疾病是指憩室炎，結腸炎，胰腺炎，肝炎，慢性肝炎，肝硬化，膽囊炎或慢性炎症。 In some embodiments, the use according to the present invention, wherein the inflammatory disease refers to diverticulitis, colitis, pancreatitis, hepatitis, chronic hepatitis, cirrhosis, cholecystitis or chronic inflammation.

一些實施例中，本發明所述的用途，其中所述的感染疾病是指病毒感染和真菌感染。 In some embodiments, the use according to the present invention, wherein the infectious diseases refer to viral infections and fungal infections.

一些實施例中，本發明所述的用途，其中所述疾病是由細胞週期蛋白依賴性激酶改變引起的疾病。 In some embodiments, the use according to the present invention, wherein the disease is caused by changes in cyclin-dependent kinases.

另一些實施例中，本發明所述的用途，所述的細胞週期蛋白依賴性激酶是指CDK1、CDK2、CDK4、CDK6或CDK9。 In other embodiments, for the use of the present invention, the cyclin-dependent kinase refers to CDK1, CDK2, CDK4, CDK6 or CDK9.

又一些實施例中，本發明所述的用途，其中所述疾病是CDK4或CDK6蛋白激酶改變引起的疾病。 In still other embodiments, the use according to the present invention, wherein the disease is a disease caused by changes in CDK4 or CDK6 protein kinase.

一方面，本發明提供一種聯合用藥，其包含本發明所述的化合物或藥物組合物和一種或多種用於治療增殖性疾病、自身免疫疾病或炎性疾病的其他活性藥劑。 In one aspect, the present invention provides a combination medicine comprising the compound or pharmaceutical composition described in the present invention and one or more other active agents for treating proliferative diseases, autoimmune diseases or inflammatory diseases.

一些實施例中，本發明所述的藥物聯合，其中所述的其他活性藥劑是指化學治療藥物，抗增殖劑，免疫抑制劑，免疫刺激劑，抗炎性試劑，CDK4/6激酶抑制劑，ABL抑制劑，ABL/Scr抑制劑，極光激酶抑制劑，Bcr-ABL的非-ATP競爭性抑制劑，c-KIT突變抑制劑，RET抑制劑，PDGFR抑制劑，VEGFR抑制劑，CSF1R抑制劑，FLT3抑制劑，FLT3-ITD抑制劑或它們的組合；所述的化合物或藥物組合物為CDK4/6激酶抑制劑；較佳地，所述的其他活性製劑為FLT3抑制劑或FLT3-ITD抑制劑。 In some embodiments, the drug combination of the present invention, wherein the other active agents refer to chemotherapeutic drugs, antiproliferative agents, immunosuppressive agents, immunostimulants, anti-inflammatory agents, CDK4/6 kinase inhibitors, ABL inhibitor, ABL/Scr inhibitor, Aurora kinase inhibitor, non-ATP competitive inhibitor of Bcr-ABL, c-KIT mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFR inhibitor, CSF1R inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or a combination thereof; the compound or pharmaceutical composition is a CDK4/6 kinase inhibitor; preferably, the other active agent is a FLT3 inhibitor or FLT3-ITD inhibitor .

除非其他方面表明，本發明的化合物所有的立體異構體，幾何異構體，互變異構體，氮氧化物，水合物，溶劑化物，代謝產物，鹽和藥學上可接受的前藥都屬於本發明的範圍。具體地說，鹽是藥學上可接受的鹽。術語“藥學上可接受的”包括物質或組合物必須是適合化學或毒理學， 與組成製劑的其他組分和用於治療的哺乳動物有關。本發明的化合物的鹽還包括用於製備或純化式(I)-(III)所示化合物的中間體或式(I)-(III)所示化合物分離的對映異構體的鹽，但不一定是藥學上可接受的鹽。 Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention belong to The scope of the invention. Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes substances or compositions that must be suitable for chemistry or toxicology, It is related to the other components that make up the preparation and the mammal used for treatment. The salts of the compounds of the present invention also include intermediates used to prepare or purify intermediates of compounds represented by formulae (I)-(III) or isolated enantiomers of compounds represented by formulae (I)-(III), but It is not necessarily a pharmaceutically acceptable salt.

如果本發明的化合物是鹼性的，則想得到的鹽可以通過文獻上提供的任何合適的方法製備得到，例如，使用無機酸，如鹽酸，氫溴酸，硫酸，硝酸和磷酸等等。或者使用有機酸，如乙酸，馬來酸，琥珀酸，扁桃酸，富馬酸，丙二酸，丙酮酸，蘋果酸，2-羥基丙酸，枸櫞酸，草酸，羥乙酸和水楊酸；吡喃糖酸，如葡萄糖醛酸和半乳糖醛酸；α-羥酸，如檸檬酸和酒石酸；氨基酸，如天門冬氨酸和谷氨酸；芳香族酸，如苯甲酸和肉桂酸；磺酸，如對甲苯磺酸，苯磺酸，甲磺酸，乙磺酸，三氟甲磺酸等等或它們的組合。 If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Or use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid and salicylic acid ; Pyranonic acid, such as glucuronic acid and galacturonic acid; α-hydroxy acid, such as citric acid and tartaric acid; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic acid and cinnamic acid; Sulfonic acid, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, etc. or a combination thereof.

如果本發明的化合物是酸性的，則想得到的鹽可以通過合適的方法製備得到，如，使用無機鹼或有機鹼，如氨(伯氨，仲氨，叔氨)，鹼金屬氫氧化物，銨，N+(Rx)4的鹽和鹼土金屬氫氧化物，等等。合適的鹽包括，但並不限於，從氨基酸得到的有機鹽，如甘氨酸和精氨酸，氨，如伯氨、仲氨和叔氨，N+(Rx)4的鹽，如Rx是H、C1-4烷基、C6-10芳基、C6-10芳基C1-4烷基等，和環狀氨，如呱啶，嗎啉和呱嗪等，和從鈉，鈣，鉀，鎂，錳，鐵，銅，鋅，鋁和鋰得到無機鹽。也包括適當的、無毒的銨，季銨鹽和抗平衡離子形成的胺陽離子，如鹵化物，氫氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。 If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic base or an organic base, such as ammonia (primary, secondary, tertiary), alkali metal hydroxide, ammonium , N + (R x ) 4 salts and alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary ammonia, N + (R x ) 4 salts, such as R x is H, C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, etc., and cyclic ammonia, such as pyridine, morpholine, and pyrazine, etc., and from sodium, Calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium get inorganic salts. Also includes suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and aromatics Sulfonate.

本發明化合物是CDK4和CDK6的抑制劑，並且因此可用於治療以異常細胞增殖為特徵的疾病或障礙。特別的是，本發明化合物可用於治療癌症。 The compounds of the present invention are inhibitors of CDK4 and CDK6, and thus can be used to treat diseases or disorders characterized by abnormal cell proliferation. In particular, the compounds of the present invention can be used to treat cancer.

CDK4和CDK6通過pRb的磷酸化調節它們對細胞週期的作用。期望本發明化合物(其是CDK4/6活性的有效抑制劑從而抑制pRb磷酸化)抑制任何癌症類型中的細胞增殖(並且因此抑制腫瘤生長)，在所述的癌症類型中細胞是增殖的並且包含功能性的完整Rb1基因(其編碼pRb)。因此，本發明化合物可用於治療哺乳動物中pRb+癌症，例如結腸直腸癌、乳腺癌、肺癌、前列腺癌、慢性粒細胞白血病、急性粒細胞白血病(Fry，D.W. 等人.Mol.Cancer Ther.(2004)，3(11)，1427)、套細胞淋巴瘤(Marzec，M.等人，Blood(2006)，108(5)，1744)、卵巢癌(Kim，T.M.等人，Cancer Research(1994)，54，605)、胰腺癌(Schutte，M.等人，Cancer Research(1997)，57，3126)、惡性黑素瘤和轉移性惡性黑素瘤(Maelandsmo，G.M.等人，British Journal of Cancer(1996)，73，909)。還期望本發明化合物可用於治療哺乳動物中的橫紋肌肉瘤(Saab，R.等人，Mol.Cancer Ther.(2006)，5(5)，1299)和多發性骨髓瘤(Baughn，L.B.等人，Cancer Res.(2006)，66(15)，7661)。一些實施例，所治療的哺乳動物是人。 CDK4 and CDK6 regulate their effects on the cell cycle through pRb phosphorylation. It is expected that the compounds of the present invention, which are effective inhibitors of CDK4/6 activity and thus inhibit pRb phosphorylation, inhibit cell proliferation (and therefore tumor growth) in any cancer type in which the cells are proliferating and contain Functional complete Rb1 gene (which encodes pRb). Therefore, the compounds of the present invention can be used to treat pRb+ cancer in mammals, such as colorectal cancer, breast cancer, lung cancer, prostate cancer, chronic myeloid leukemia, acute myeloid leukemia (Fry, D.W. Et al. Mol. Cancer Ther. (2004), 3(11), 1427), mantle cell lymphoma (Marzec, M. et al., Blood (2006), 108(5), 1744), ovarian cancer (Kim, TM et al., Cancer Research (1994), 54,605), pancreatic cancer (Schutte, M. et al., Cancer Research (1997), 57, 3126), malignant melanoma, and metastatic malignant melanoma (Maelandsmo, GM et al., British Journal of Cancer (1996), 73, 909). It is also expected that the compounds of the present invention can be used to treat rhabdomyosarcoma in mammals (Saab, R. et al., Mol. Cancer Ther. (2006), 5(5), 1299) and multiple myeloma (Baughn, LB et al., Cancer Res. (2006), 66(15), 7661). In some embodiments, the mammal being treated is a human.

本發明化合物可以用於治療哺乳動物中癌症、特別是上述癌症的方法，該方法包括給需要該治療的哺乳動物施用有效量的本發明化合物。 The compound of the present invention can be used in a method of treating cancer in a mammal, particularly the above-mentioned cancer, which method comprises administering an effective amount of the compound of the present invention to a mammal in need of such treatment.

在一些實施例中，本發明化合物可以用於治療癌症的方法，所述的癌症選自結腸直腸癌、套細胞淋巴瘤、乳腺癌、膠質母細胞瘤、急性粒細胞白血病和肺癌，特別是非小細胞肺癌。 In some embodiments, the compounds of the present invention can be used in a method of treating cancer selected from colorectal cancer, mantle cell lymphoma, breast cancer, glioblastoma, acute myeloid leukemia, and lung cancer, especially non-small Cell lung cancer.

在另一些實施例中，本發明化合物可以用於治療癌症的方法，所述的癌症選自結腸直腸癌、膠質母細胞瘤、急性粒細胞白血病和肺癌。 In other embodiments, the compounds of the present invention can be used in a method of treating cancer selected from colorectal cancer, glioblastoma, acute myeloid leukemia, and lung cancer.

在另一些實施例中，本發明化合物可以用於治療哺乳動物中膠質母細胞瘤或星形細胞瘤的方法，所述的方法包括給需要的哺乳動物施用治療有效的本發明化合物和替莫唑胺的組合。 In other embodiments, the compounds of the present invention can be used in a method of treating glioblastoma or astrocytoma in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective combination of a compound of the present invention and temozolomide .

在另一些實施例中，本發明化合物可以用於治療哺乳動物中非小細胞肺癌、胰腺癌、卵巢癌或轉移性乳腺癌的方法，該方法包括給需要的哺乳動物施用治療有效的本發明化合物和鹽酸吉西他濱的組合。 In other embodiments, the compounds of the present invention can be used in a method of treating non-small cell lung cancer, pancreatic cancer, ovarian cancer, or metastatic breast cancer in mammals, the method comprising administering to a mammal in need thereof a therapeutically effective compound of the present invention Combination with gemcitabine hydrochloride.

另外，本發明化合物可以用於製備用於治療癌症、特別是上述癌症的藥物。 In addition, the compounds of the present invention can be used in the preparation of medicaments for the treatment of cancer, especially the aforementioned cancers.

在一些實施例中，本發明化合物可以用於製備用於治療癌症的藥物，所述的癌症選自結腸直腸癌、套細胞淋巴瘤、乳腺癌、膠質母細胞瘤、急性粒細胞白血病和肺癌，特別是非小細胞肺癌。 In some embodiments, the compounds of the present invention can be used to prepare a medicament for treating cancer selected from colorectal cancer, mantle cell lymphoma, breast cancer, glioblastoma, acute myeloid leukemia, and lung cancer, Especially non-small cell lung cancer.

在另一些實施例中，本發明化合物可以用於製備用於治療癌 症藥物，所述的癌症選自結腸直腸癌、膠質母細胞瘤、急性粒細胞白血病和肺癌。 In other embodiments, the compounds of the present invention can be used to prepare for the treatment of cancer The cancer is selected from colorectal cancer, glioblastoma, acute myeloid leukemia and lung cancer.

在另一些實施例中，本發明提供了本發明化合物在製備用於治療膠質母細胞瘤或星形細胞瘤的藥物中的用途，其中藥物還包括替莫唑胺或者是與替莫唑胺同時、分開或依次施用的。 In other embodiments, the present invention provides the use of the compound of the present invention in the preparation of a medicament for treating glioblastoma or astrocytoma, wherein the medicament also includes temozolomide or is administered simultaneously, separately, or sequentially with temozolomide .

在另一些實施例中，本發明提供了本發明化合物在製備用於治療非小細胞肺癌、胰腺癌、卵巢癌或轉移性乳腺癌的藥物中的用途，其中藥物還包括鹽酸吉西他濱或者是與鹽酸吉西他濱同時、分開或依次施用的。還提供了治療癌症、特別是上述癌症的藥物製劑，所述的藥物製劑包含本發明化合物或其可藥用鹽以及可藥用載體。 In other embodiments, the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment of non-small cell lung cancer, pancreatic cancer, ovarian cancer or metastatic breast cancer, wherein the medicament also includes gemcitabine hydrochloride or hydrochloride Gemcitabine is administered simultaneously, separately or sequentially. There is also provided a pharmaceutical preparation for treating cancer, especially the above-mentioned cancer, the pharmaceutical preparation comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

在一些實施例中，還提供了治療癌症的藥物製劑，所述的癌症選自結腸直腸癌、套細胞淋巴瘤、乳腺癌、膠質母細胞瘤、急性粒細胞白血病和肺癌，特別是非小細胞肺癌，所述的藥物製劑包含本發明化合物或其可藥用鹽以及可藥用載體。 In some embodiments, there is also provided a pharmaceutical preparation for treating cancer selected from colorectal cancer, mantle cell lymphoma, breast cancer, glioblastoma, acute myeloid leukemia, and lung cancer, especially non-small cell lung cancer The pharmaceutical preparation contains the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

在一些實施例中，還提供了治療癌症的藥物製劑，所述的癌症選自結腸直腸癌、膠質母細胞瘤、急性粒細胞白血病和肺癌，所述的藥物製劑包含本發明化合物或其可藥用鹽以及可藥用載體。 In some embodiments, a pharmaceutical preparation for treating cancer is further provided. The cancer is selected from colorectal cancer, glioblastoma, acute myeloid leukemia, and lung cancer. The pharmaceutical preparation comprises a compound of the present invention or a pharmaceutically acceptable Use salts and pharmaceutically acceptable carriers.

在另一些實施例中，本發明提供了治療膠質母細胞瘤或星形細胞瘤的藥物製劑，所述的藥物製劑包含本發明化合物和替莫唑胺以及可藥用載體。 In other embodiments, the present invention provides a pharmaceutical preparation for treating glioblastoma or astrocytoma, the pharmaceutical preparation comprising the compound of the present invention and temozolomide and a pharmaceutically acceptable carrier.

在另一些實施例中，本發明提供了治療非小細胞肺癌、胰腺癌、卵巢癌或轉移性乳腺癌的藥物製劑，所述的藥物製劑包含本發明化合物和鹽酸吉西他濱以及可藥用載體。 In other embodiments, the present invention provides a pharmaceutical preparation for treating non-small cell lung cancer, pancreatic cancer, ovarian cancer, or metastatic breast cancer. The pharmaceutical preparation comprises the compound of the present invention and gemcitabine hydrochloride and a pharmaceutically acceptable carrier.

本發明還提供了藥物製劑，其包含本發明化合物或其可藥用鹽和替莫唑胺，以及可藥用載體、稀釋劑或賦形劑。 The present invention also provides a pharmaceutical preparation comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and temozolomide, as well as a pharmaceutically acceptable carrier, diluent or excipient.

本發明還提供了藥物製劑，其包含本發明化合物或其可藥用鹽和鹽酸吉西他濱，以及可藥用載體、稀釋劑或賦形劑。 The present invention also provides a pharmaceutical preparation comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and gemcitabine hydrochloride, and a pharmaceutically acceptable carrier, diluent or excipient.

本發明進一步提供了藥物製劑，其包含本發明化合物或其可藥用鹽以及可藥用載體和任選其它治療成分。 The present invention further provides a pharmaceutical formulation comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.

在癌症、移植物排斥和自身免疫性疾病中的用途Use in cancer, graft rejection and autoimmune diseases

本發明的化合物具有有價值的藥理學性質，可用於治療疾病。在某些實施例中，本發明的化合物可用於治療增殖性疾病或癌症。 The compounds of the present invention have valuable pharmacological properties and can be used to treat diseases. In certain embodiments, the compounds of the present invention can be used to treat proliferative diseases or cancer.

增殖性疾病主要是腫瘤疾病(或癌症)(和/或任何轉移灶)。本發明的化合物特別是可用於治療下列腫瘤：乳腺癌、泌尿生殖器癌、肺癌、胃腸癌、表皮樣癌、黑素瘤、卵巢癌、胰腺癌、神經母細胞瘤、頭和/或頸癌或膀胱癌，或者從更廣義上說，可用於治療腎癌、腦癌或胃癌；特別是(i)乳房腫瘤；表皮樣腫瘤，如表皮樣頭和/或頸腫瘤或口腔腫瘤；肺腫瘤，例如小細胞或非小細胞肺腫瘤；胃腸腫瘤，例如，結腸直腸腫瘤；或泌尿生殖系統腫瘤，例如，前列腺腫瘤(尤其是激素難以治療的前列腺腫瘤)；或(ii)用其它化療劑難以治療的增殖性疾病；或(iii)由於多重耐藥性而用其它化療劑難以治療的腫瘤。 Proliferative diseases are mainly neoplastic diseases (or cancer) (and/or any metastases). The compounds of the present invention are particularly useful for treating the following tumors: breast cancer, urogenital cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, head and/or neck cancer or Bladder cancer, or more broadly, can be used to treat kidney cancer, brain cancer, or stomach cancer; in particular (i) breast tumors; epidermoid tumors, such as epidermoid head and/or neck tumors, or oral tumors; lung tumors, for example Small cell or non-small cell lung tumors; gastrointestinal tumors, for example, colorectal tumors; or genitourinary tumors, for example, prostate tumors (especially prostate tumors that are difficult to treat with hormones); or (ii) difficult to treat with other chemotherapeutic agents Proliferative diseases; or (iii) tumors that are difficult to treat with other chemotherapeutic agents due to multiple drug resistance.

在本發明的更廣義上，增殖性疾病還可以是過度增殖性(hyperproliferative)情況，如白血病、增生、纖維化(尤其是肺纖維化，還有其它類型的纖維化，如腎纖維化)、血管生成、銀屑病、動脈粥樣硬化和血管平滑肌增生，如血管成形術後的狹窄和再狹窄。 In the broader sense of the present invention, proliferative diseases can also be hyperproliferative conditions, such as leukemia, hyperplasia, fibrosis (especially pulmonary fibrosis, and other types of fibrosis, such as renal fibrosis), Angiogenesis, psoriasis, atherosclerosis, and vascular smooth muscle hyperplasia, such as stenosis and restenosis after angioplasty.

不管腫瘤和/或轉移灶的位置如何，在提及腫瘤、腫瘤疾病、癌或癌症的情況下，作為替代選擇或另外地，也包括位於初始器官或組織和/或任何其它位置中的轉移灶。 Regardless of the location of the tumor and/or metastasis, where a tumor, tumor disease, cancer, or cancer is mentioned, as an alternative or in addition, metastases located in the original organ or tissue and/or any other location are also included .

與正常細胞相比，本發明的化合物對迅速增殖的細胞有選擇毒性或者更大毒性，所述迅速增殖的細胞特別是人癌症細胞，例如癌性腫瘤，所述化合物具有顯著的抗增殖作用並促進分化，例如細胞週期停滯和細胞凋亡。 Compared with normal cells, the compounds of the present invention are selective or more toxic to rapidly proliferating cells. The rapidly proliferating cells, especially human cancer cells, such as cancerous tumors, have significant antiproliferative effects and Promote differentiation, such as cell cycle arrest and apoptosis.

在另外的某些實施例中，本發明的化合物可用於治療移植物排斥。可以用本發明的化合物治療的移植物排斥的實例包括但不限於移植物抗宿主病、與異種移植有關的排斥、與器官移植有關的排斥、與急性移植物有關的排斥、異種移植物或同種移植物排斥和器官移植期間發生的缺血或再灌注損傷。 In certain other embodiments, the compounds of the present invention can be used to treat graft rejection. Examples of graft rejection that can be treated with the compounds of the invention include, but are not limited to, graft-versus-host disease, xenotransplantation-related rejection, organ transplantation-related rejection, acute graft-related rejection, xenograft or allograft Graft rejection and ischemia or reperfusion injury during organ transplantation.

在又另外的某些實施例中，本發明的化合物可用於治療自身免疫性疾病。可以用本發明的化合物治療的自身免疫性疾病的實例包括但不限於自身免疫性溶血性貧血、自身免疫性新生兒血小板減少、特發性血小板減少性紫癜、自身免疫性血細胞減少、溶血性貧血、抗磷脂綜合征、皮炎、變應性腦脊髓炎、心肌炎、復發性多軟骨炎、風濕性心臟病、腎小球腎炎、多發性硬化、神經炎、葡萄膜炎眼炎、多內分泌腺病、紫癜、賴特爾病、僵人綜合征、自身免疫性肺炎、孤獨症、吉-巴綜合征、胰島素依賴性糖尿病、自身免疫性炎性眼病、自身免疫性甲狀腺炎、甲狀腺功能減退症、系統性紅斑狼瘡、古德曼綜合征、天皰瘡、受體自身免疫性、自身免疫性溶血性貧血、自身免疫性血小板減少性紫癜、類風濕性關節炎、混合性結締組織病、多肌炎/皮肌炎、惡性貧血、特發性艾迪生病、不孕、腎小球腎炎、大皰性類天皰瘡、舍葛籣綜合征、糖尿病、腎上腺素能藥耐藥性、慢性活動性肝炎、原發性膽汁性肝硬化、白斑、脈管炎、MI後、心切開術綜合征、蕁麻疹、特應性皮炎、哮喘、炎性肌病、慢性活動性肝炎、原發性膽汁性肝硬化和T-細胞介導的超敏反應疾病。 In still other certain embodiments, the compounds of the present invention can be used to treat autoimmune diseases. Examples of autoimmune diseases that can be treated with the compounds of the present invention include, but are not limited to, autoimmune hemolytic anemia, autoimmune neonatal thrombocytopenia, idiopathic thrombocytopenic purpura, autoimmune hematocytopenia, hemolytic anemia , Antiphospholipid syndrome, dermatitis, allergic encephalomyelitis, myocarditis, relapsing polychondritis, rheumatic heart disease, glomerulonephritis, multiple sclerosis, neuritis, uveitis ophthalmia, polyendocrine gland disease , Purpura, Wright's disease, stiff person syndrome, autoimmune pneumonia, autism, Ji-ba syndrome, insulin-dependent diabetes, autoimmune inflammatory eye disease, autoimmune thyroiditis, hypothyroidism, Systemic lupus erythematosus, Goodman syndrome, pemphigus, recipient autoimmunity, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, rheumatoid arthritis, mixed connective tissue disease, polymyositis Inflammation/dermatomyositis, pernicious anemia, idiopathic Addison's disease, infertility, glomerulonephritis, bullous pemphigoid, Sergeant's syndrome, diabetes, adrenergic drug resistance, chronic activity Hepatitis, primary biliary cirrhosis, leukoplakia, vasculitis, post-MI, cardiotomy syndrome, urticaria, atopic dermatitis, asthma, inflammatory myopathy, chronic active hepatitis, primary bile Liver cirrhosis and T-cell-mediated hypersensitivity disease.

如果沒有另外說明，在適宜和有利時，術語“用途”分別包括本發明下列實施例中的任何一種或多種：在治療與蛋白激酶有關的病症中的用途；在製備用於治療這些疾病的藥物組合物中的用途，例如，在製備藥物中的用途；在這些疾病的治療中使用本發明的化合物的方法；用於治療這些疾病的含有本發明的化合物的藥物製劑；和用於治療這些疾病的本發明的化合物。所治療的疾病並且因此本發明的化合物較佳的用途特別是選自癌症、移植物排斥或自身免疫性疾病以及依賴於蛋白激酶活性的那些疾病。術語“用途”進一步包括足以用作示蹤劑或標籤之與蛋白激酶結合的本發明的組合物的實施例，從而使得當與螢光(fluor)或標記物偶聯或被製備為放射活性的時，可用作研究試劑或用作診斷劑或顯像劑。 If not stated otherwise, where appropriate and advantageous, the term "use" includes any one or more of the following examples of the present invention: use in the treatment of conditions associated with protein kinases; in the preparation of medicaments for the treatment of these diseases Uses in the composition, for example, in the preparation of medicines; methods of using the compounds of the present invention in the treatment of these diseases; pharmaceutical preparations containing the compounds of the present invention for the treatment of these diseases; and for the treatment of these diseases Of the compounds of the invention. The diseases to be treated and therefore the preferred use of the compounds of the invention are in particular selected from cancer, graft rejection or autoimmune diseases and those diseases which depend on the activity of protein kinases. The term "use" further includes an embodiment of the composition of the present invention that is sufficient for use as a tracer or tag in combination with a protein kinase, such that when conjugated with fluor or a label or prepared as radioactive Can be used as a research reagent or as a diagnostic or imaging agent.

本發明的化合物的組合物Composition of the compound of the present invention

本發明提供藥物組合物，包含治療有效量的式(I)-式(III)所示化合物或其藥學上可接受的鹽和藥學上可接受的載體、稀釋劑或賦形劑。當本發明的化合物以藥物的形式施用於哺乳動物例如人時，其可以以化合 物本身的形式被給予或者可以以含有例如0.1至99.5%(更佳0.5至90%)活性成分以及藥學可接受的載體的藥物組合物的形式被給予。 The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I)-formula (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient. When the compound of the present invention is administered to a mammal such as a human in the form of a drug, it can be combined The substance itself is administered or may be administered in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient and a pharmaceutically acceptable carrier.

“有效量”是治療或預防與蛋白激酶有關的病症例如預防與蛋白激酶有關的病症的各種形態和軀體症狀和/或本發明所述的疾病或情況所需的或者足夠的量。在一個實例中，本發明的化合物的有效量是足以治療個體的與蛋白激酶有關的病症的量。有效量可以根據諸如個體的大小和體重、疾患的類型或本發明的具體化合物等因素而變化。例如，本發明的化合物的選擇可影響“有效量”的構成。本領域普通技術人員將能研究本發明所包含的因素和在不進行過度實驗的情況下確定本發明的化合物的有效量。 An "effective amount" is an amount necessary or sufficient to treat or prevent a protein kinase-related disorder, such as various morphological and somatic symptoms of a protein kinase-related disorder and/or the disease or condition described herein. In one example, an effective amount of a compound of the invention is an amount sufficient to treat a protein kinase-related disorder in an individual. The effective amount can vary depending on factors such as the size and weight of the individual, the type of disorder, or the specific compound of the invention. For example, the choice of a compound of the invention can affect the composition of an "effective amount." Those of ordinary skill in the art will be able to study the factors involved in the present invention and determine the effective amount of the compounds of the present invention without undue experimentation.

施用方案可影響有效量的構成。本發明的化合物可在與蛋白激酶有關的病症發作之前或之後被施用於個體。此外，可以每天或相繼施用多個分劑量以及錯開的劑量，或者可以連續輸注給藥，或者可以推注給藥。此外，本發明的化合物的劑量可以根據治療或預防的情形的緊迫性按比例酌情增加或減少。 The application regime can affect the composition of the effective amount. The compounds of the present invention can be administered to an individual before or after the onset of a protein kinase-related disorder. In addition, multiple divided doses and staggered doses can be administered daily or sequentially, or can be administered by continuous infusion, or can be administered by bolus injection. In addition, the dosage of the compound of the present invention can be increased or decreased as appropriate according to the urgency of the treatment or prevention.

“聯合”表示在單個劑量單位形式中的固定組合或用於組合施用的部分的藥盒，其中本發明公開化合物和組合伴侶可以在同一時間獨立施用或者可以在一定的時間間隔內分別施用，特別是使聯合合伴侶表現出合作、例如協同作用。如本發明所用的術語“共同給藥”或“聯合給藥”等意欲囊括將所選的組合夥伴施用於需要其的單個個體(例如患者)，並且意欲包括其中物質不必通過相同施用途徑或同時施用的治療方案。如本發明所用的術語“藥物組合產品”表示將一種以上活性成分混合或組合所得到的產品，並且既包括活性成分的固定組合也包括非固定組合。術語“固定聯合”表示活性成分如本發明公開化合物和組合夥伴以單一實體或劑量的形式同時施用於患者。術語“非固定聯合”表示活性成分如本發明公開化合物化合物和組合夥伴均作為單獨實體同時、共同或無特定時間限制地先後施用於患者，其中該施用在患者體內提供了兩種化合物的治療有效水準。後者還適用於雞尾酒療法，例如施用3種或更多種活性成分。 "Combination" means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein the compounds disclosed herein and the combination partner can be administered independently at the same time or can be administered separately within a certain time interval, in particular It is to make the joint partner show cooperation, such as synergy. The terms "co-administered" or "co-administered" as used in the present invention are intended to encompass the administration of the selected combination partner to a single individual in need thereof (eg, a patient), and are intended to include where the substances do not have to go through the same route of administration or simultaneously Treatment regimen administered. The term "pharmaceutical combination product" as used in the present invention means a product obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients such as the disclosed compounds and combination partners of the present invention are administered to a patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that the active ingredients as disclosed in the present invention are compound compounds and combination partners are both administered as separate entities to a patient simultaneously, jointly or without a specific time limit, wherein the administration provides the therapeutic effectiveness of the two compounds in the patient level. The latter also applies to cocktail therapy, such as the administration of 3 or more active ingredients.

本發明的化合物可用於治療本發明所述的狀態、病症或疾 病，或用於製備治療這些疾病的藥物組合物。本發明的化合物在這些疾病治療中的使用方法或用於治療這些疾病的含有本發明的化合物的藥物製劑。 The compounds of the present invention can be used to treat the conditions, disorders or diseases described in the present invention Diseases, or for the preparation of pharmaceutical compositions for the treatment of these diseases. Methods of using the compounds of the present invention in the treatment of these diseases or pharmaceutical preparations containing the compounds of the present invention for the treatment of these diseases.

措辭“藥物組合物”包括適於施用於哺乳動物例如人的製劑。當本發明的化合物以藥物的形式施用於哺乳動物例如人時，其可以以化合物本身的形式被給予或者可以以含有例如0.1至99.5%(更佳0.5至90%)活性成分以及藥學可接受的載體的藥物組合物的形式被給予。 The expression "pharmaceutical composition" includes formulations suitable for administration to mammals such as humans. When the compound of the present invention is administered to a mammal such as a human in the form of a drug, it may be administered in the form of the compound itself or may contain, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient and pharmaceutically acceptable The carrier is administered in the form of a pharmaceutical composition.

措辭“藥學可接受的載體”在本領域中是公認的，包括適於將本發明的化合物施用於哺乳動物的藥學可接受的材料、組合物或載體。所述載體包括參與攜帶主題物質或將其從一個器官或機體的一部分轉移到另一個器官或機體的另一部分的液體或固體填充劑、稀釋劑、賦形劑、溶劑或包封材料。各載體在與製劑中的其它成分相容和對患者無害的意義上必須是“可接受的”。可用作藥學可接受的載體的材料的一些實例包括：糖類，如乳糖、葡萄糖和蔗糖；澱粉類，如玉米澱粉和馬鈴薯澱粉；纖維素及其衍生物，如羧甲基纖維素鈉、乙基纖維素和醋酸纖維素；粉狀西黃蓍膠；麥芽；明膠；滑石粉；賦形劑，如可哥脂和栓劑蠟類；油類，如花生油、棉子油、紅花油、芝麻油、橄欖油、玉米油和豆油；二醇類，如丙二醇；多元醇類，如甘油、山梨醇、甘露醇和聚乙二醇；酯類，如油酸乙酯和月桂酸乙酯；瓊脂；緩衝劑，如氫氧化鎂和氫氧化鋁；海藻酸；無熱原的水；等張鹽水；林格氏溶液；乙醇；磷酸鹽緩衝液；和藥物製劑中所用的其它無毒的可相容的物質。 The expression "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions or carriers suitable for administering the compounds of the present invention to mammals. The carrier includes liquid or solid fillers, diluents, excipients, solvents or encapsulating materials that are involved in carrying the subject substance or transferring it from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl acetate Cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil , Olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffer Agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical preparations .

在組合物中也可以存在潤濕劑、乳化劑和潤滑劑如十二烷基硫酸鈉和硬脂酸鎂，以及著色劑、釋放劑、包衣劑、甜味劑、矯味劑和芳香劑、防腐劑和抗氧化劑。 Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring agents and flavoring agents, Preservatives and antioxidants.

藥學可接受的抗氧化劑的實例包括：水溶性抗氧化劑，如抗壞血酸、鹽酸半胱氨酸、硫酸氫鈉、焦亞硫酸鈉、亞硫酸鈉等；油溶性抗氧化劑，如棕櫚酸抗壞血酸酯、丁基化羥基苯甲醚(BHA)、丁化羥基甲苯(BHT)、卵磷脂、棓酸丙酯、α-生育酚等；和金屬螯合劑，如檸檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。 Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxybenzene Methyl ether (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid , Phosphoric acid, etc.

本發明的製劑包括適於口服、鼻、局部、口含、舌下、直腸、陰道和/或胃腸外施用的那些。製劑可以方便地以單位劑型形式存在並且可以通過藥學領域公知的任何方法來製備。可以與載體物質組合來製備單劑量形式的活性成分的量一般是產生治療作用的化合物的量。一般而言，以百分之一為單位，該量為約1%至約99%活性成分，較佳約5%至約70%，最佳約10至約30%。 The formulations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any method known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to prepare a single dosage form is generally that amount of the compound that produces a therapeutic effect. Generally speaking, the amount is about 1% to about 99% active ingredient, preferably about 5% to about 70%, most preferably about 10 to about 30%, in units of one percent.

製備這些製劑或組合物的方法包括使本發明的化合物與載體、獨立任選地和一種或多種輔助成分結合的步驟。一般而言，製劑是通過將本發明的化合物與液體載體或很細的固體載體或這二者均勻且緊密地結合在一起、然後如果需要的話，將該產物成型來製備的。 The method of preparing these formulations or compositions includes the step of bringing the compound of the invention into association with a carrier, independently and optionally one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately combining the compound of the present invention with a liquid carrier or a very fine solid carrier or both, and then shaping the product if necessary.

適於口服施用之本發明的製劑可以是膠囊劑、扁囊劑、丸劑、片劑、錠劑(使用矯味的基質，通常為蔗糖和阿拉伯膠或西黃蓍膠)、散劑、顆粒劑、或者在水性或非水性液體中的溶液劑或混懸劑、或者水包油或油包水型液體乳劑、或者酏劑或糖漿劑、或者軟錠劑(使用惰性基質，如明膠和甘油、或蔗糖和阿拉伯膠)和/或漱口劑等的形式，其各自含有既定量的本發明的化合物作為活性成分。本發明的化合物還可以以大丸劑、藥糖劑或糊劑的形式施用。 The preparation of the present invention suitable for oral administration may be capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), powders, granules, or Solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, or elixirs or syrups, or pastilles (using an inert base such as gelatin and glycerin, or sucrose And gum arabic) and/or mouthwash, etc., each containing a certain amount of the compound of the present invention as an active ingredient. The compounds of the present invention can also be administered in the form of bolus, sugar or paste.

在用於口服施用之本發明的固體劑型(膠囊劑、片劑、丸劑、糖衣丸、散劑、顆粒劑等)中，將活性成分與一種或多種藥學可接受的載體如檸檬酸鈉或磷酸二鈣和/或任何下列物質混合：填充劑或增量劑，如澱粉類、乳糖、蔗糖、葡萄糖、甘露醇和/或矽酸；黏合劑，例如，羧甲基纖維素、藻酸鹽類、明膠、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯膠；保濕劑，如甘油；崩解劑，如瓊脂、碳酸鈣、馬鈴薯澱粉或木薯澱粉、海藻酸、某些矽酸和碳酸鈉；溶液阻滯劑(solution retarding agent)，如石蠟；吸收促進劑，如季銨化合物；潤濕劑，例如，鯨蠟醇和甘油單硬脂酸酯；吸附劑，如高嶺土和皂土；潤滑劑，如滑石粉、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、十二烷基硫酸鈉，以及其混合物；和著色劑。在膠囊劑、片劑和丸劑的情況下，藥物組合物還可包含緩衝劑。類似類型的固體組合物還可在使用賦形劑如乳糖或奶糖以及高分子量聚乙二醇等的軟和硬填充明膠膠囊中用作 填充物。 In the solid dosage form of the invention (capsules, tablets, pills, dragees, powders, granules, etc.) for oral administration, the active ingredient is combined with one or more pharmaceutically acceptable carriers such as sodium citrate or diphosphate Mixture of calcium and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, for example, carboxymethyl cellulose, alginates, gelatin , Polyvinylpyrrolidone, sucrose and/or gum arabic; humectants, such as glycerin; disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicic acid, and sodium carbonate; solution blockers ( solution retarding agent), such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate; adsorbents, such as kaolin and bentonite; lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain buffering agents. Similar types of solid compositions can also be used in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol Filler.

片劑可以通過壓製或模製來製備，可任選地使用一種或多種輔助成分。壓製片可以用黏合劑(例如，明膠或羥丙基甲基纖維素)、潤滑劑、惰性稀釋劑、防腐劑、崩解劑(例如，羥乙酸澱粉鈉或交聯羧甲基纖維素鈉)、表面活性劑或分散劑來製備。模製片可以通過將用惰性液體稀釋劑潤濕的粉狀化合物的混合物在合適的機器中進行模製來製備。 Tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may use binders (eg, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (eg, sodium starch glycolate or croscarmellose sodium) , Surfactant or dispersant to prepare. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

片劑和本發明的藥物組合物的其它固體劑型如糖衣丸、膠囊劑、丸劑和顆粒劑可任選地被刻痕或用包衣和殼如腸溶衣和製藥領域公知的其它包衣來製備。也可以將它們用例如提供所需釋放性質的各種比例的羥丙基甲基纖維素、其它聚合物基質、脂質體和/或微球進行配製以便提供其中的活性成分的緩慢釋放或控制釋放。可將它們例如通過用截留細菌的濾器過濾或通過在使用前即刻摻入可溶解於無菌水或一些其它可注射無菌溶媒中的無菌固體組合物形式的滅菌劑來進行滅菌。這些組合物還可任選地含有遮光劑並且可以是僅在或優先在胃腸道的某個部分中釋放活性成分、任選以延遲方式釋放活性成分的組合物。可使用的包埋組合物的實例包括聚合物物質和蠟類。活性成分也可以是微囊化的形式，如果適宜的話，使用一種或多種上述賦形劑。 Tablets and other solid dosage forms of the pharmaceutical composition of the present invention such as sugar-coated pills, capsules, pills, and granules can optionally be scored or come with coatings and shells such as enteric coatings and other coatings known in the pharmaceutical art preparation. They can also be formulated with, for example, hydroxypropyl methylcellulose, other polymer matrices, liposomes, and/or microspheres in various ratios to provide the desired release properties in order to provide slow or controlled release of the active ingredients therein. They can be sterilized, for example, by filtration through bacteria-retaining filters or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other injectable sterile vehicle immediately before use. These compositions may also optionally contain opacifiers and may be compositions that release the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, using one or more of the above-mentioned excipients.

用於口服施用的本發明的化合物的液體劑型包括藥學可接受的乳劑、微乳、溶液、混懸液、糖漿劑和酏劑。除活性成分以外，液體劑型還可含有本領域中常用的惰性稀釋劑例如水或其它溶劑、增溶劑和乳化劑如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油類(特別是棉子油、花生油、玉米油、胚芽油、橄欖油、蓖麻油和芝麻油)、甘油、四氫糠醇醇、聚乙二醇和失水山梨醇的脂肪酸酯以及其混合物。 Liquid dosage forms of the compounds of the present invention for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid dosage form may also contain inert diluents commonly used in the art such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate Esters, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and Fatty acid esters of sorbitol and their mixtures.

除惰性稀釋劑以外，口服組合物還可包含輔劑(adjuvant)如潤濕劑、乳化劑和助懸劑、甜味劑、矯味劑、著色劑、芳香劑和防腐劑。 In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances and preservatives.

除活性化合物以外，混懸劑還可包含助混劑，例如乙氧基化異硬脂醇、聚氧乙烯山梨醇和失水山梨醇酯、微晶纖維素、偏氫氧化鋁(aluminummetahydroxide)、皂土、瓊脂和西黃蓍膠以及其混合物。 In addition to the active compound, the suspension may also contain adjuvants such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, soap Earth, agar and tragacanth and mixtures thereof.

用於直腸或陰道施用之本發明的藥物組合物的製劑可以以栓劑的形式存在，其可以通過將一種或多種本發明的化合物與一種或多種合適的無刺激的賦形劑或載體(包括例如可哥脂、聚乙二醇、栓劑蠟或水楊酸酯)混合來製備，並且其在室溫下是固體，但是在體溫下是液體，因此將在直腸或陰道腔中熔化並釋放出活性化合物。 The formulation of the pharmaceutical composition of the present invention for rectal or vaginal administration may exist in the form of suppositories, which may be obtained by combining one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers (including, for example, Cocoa butter, polyethylene glycol, suppository wax, or salicylate) are mixed and prepared, and it is solid at room temperature, but liquid at body temperature, so it will melt in the rectum or vaginal cavity and release activity Compound.

適於陰道施用之本發明的製劑還包括含有本領域中已知適宜的載體的陰道栓、衛生栓、乳膏劑、凝膠劑、糊劑、泡沫劑或噴霧製劑。 The formulations of the present invention suitable for vaginal administration also include vaginal suppositories, sanitary suppositories, creams, gels, pastes, foams or spray formulations containing suitable carriers known in the art.

本發明的化合物之用於局部或透皮施用的劑型包括散劑、噴霧劑、軟膏劑、糊劑、乳膏劑、洗劑、凝膠劑、溶液劑、貼劑和吸入劑。可以將活性成分在無菌條件下與藥學可接受的載體和可能需要的任何防腐劑、緩衝劑或拋射劑混合。 Dosage forms of the compounds of the present invention for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required.

除本發明的活性化合物以外，軟膏劑、糊劑、乳膏劑和凝膠劑還可包含賦形劑，如動物和植物脂肪、油類、蠟類、石蠟類、澱粉、西黃蓍膠、纖維素衍生物、聚乙二醇類、矽氧烷類、皂土類、矽酸、滑石粉和氧化鋅、或其混合物。 In addition to the active compounds of the present invention, ointments, pastes, creams and gels can also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, fiber Element derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

除本發明的化合物以外，散劑和噴霧劑還可包含賦形劑如乳糖、滑石粉、矽酸、氫氧化鋁、矽酸鈣和聚醯胺粉末或這些物質的混合物。噴霧劑還可包含常規拋射劑如氯氟烴類和揮發性的未被取代的烴類，如丁烷和丙烷。 In addition to the compounds of the present invention, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Sprays can also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

透皮貼劑具有為機體提供本發明的化合物的控制傳遞的另外的優點。該類劑型可以通過將化合物溶解或分散於合適的溶媒中來製備。還可以使用吸收促進劑來增加通過皮膚的化合物通量。可以通過提供控速膜或將活性化合物分散於聚合物基質或凝膠中來控制該類流動的速度。 Transdermal patches have the additional advantage of providing the body with controlled delivery of the compounds of the present invention. Such dosage forms can be prepared by dissolving or dispersing the compound in the proper solvent. Absorption enhancers can also be used to increase the flux of compounds through the skin. The rate of such flow can be controlled by providing a rate-controlling membrane or dispersing the active compound in a polymer matrix or gel.

在本發明的範圍內還包括眼用製劑、眼用軟膏劑、散劑、溶液劑等。 Within the scope of the present invention, ophthalmic preparations, ophthalmic ointments, powders, solutions, etc. are also included.

適於胃腸外施用之本發明的藥物組合物包含一種或多種本發明的化合物以及一種或多種藥學可接受之無菌的等張的水性或非水性溶液、分散物、混懸劑或乳劑、或者可在使用前即刻被重組到無菌之可注射 溶液或分散物中的無菌粉末，其可包含抗氧化劑、緩衝劑、抑菌劑、使得製劑與接受者的血液等張的溶質或助懸劑或增稠劑。 The pharmaceutical composition of the present invention suitable for parenteral administration comprises one or more compounds of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or may Reconstituted into sterile injectables immediately before use Sterile powders in solutions or dispersions may contain antioxidants, buffers, bacteriostatic agents, solutes or suspending agents or thickening agents that make the formulation isotonic with the blood of the recipient.

可用於本發明的藥物組合物中之合適的水性和非水性載體的實例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)以及其合適的混合物、植物油類如橄欖油和可注射的有機酯類如油酸乙酯。可以例如通過使用包衣材料如卵磷脂、在分散物的情況下通過維持所需的細微性、和通過使用表面活性劑來維持合適的流動性。 Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical composition of the present invention include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil and Injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required fineness in the case of dispersions, and by using surfactants.

這些組合物還可包含輔劑如防腐劑、潤濕劑、乳化劑和分散劑。可以通過包含各種抗細菌劑和抗真菌劑例如尼泊金酯、三氯叔丁醇、苯酚、山梨酸等來確保預防微生物的作用。還可能需要在組合物中包含等張劑如糖類、氯化鈉等。此外，可以通過包含延遲吸收的物質如單硬脂酸鋁和明膠來造成可注射藥物形式的延長吸收。 These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The effect of preventing microorganisms can be ensured by including various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be necessary to include isotonic agents such as sugars, sodium chloride and the like in the composition. In addition, prolonged absorption of injectable pharmaceutical forms can be caused by the inclusion of substances that delay absorption, such as aluminum monostearate and gelatin.

在一些情況中，為了延長藥物的作用，需要減慢得自皮下或肌內注射的藥物吸收。這可以通過使用水溶性差的結晶性或無定形物質的液體混懸液來實現。這樣，藥物的吸收速率將取決於其溶出速率，溶出速率又可能取決於晶體大小和晶形。或者，通過將藥物溶解或混懸於油性基質中來實現胃腸外施用的藥物形式的延長吸收。 In some cases, in order to prolong the action of drugs, it is necessary to slow down the absorption of drugs obtained by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous substances with poor water solubility. In this way, the absorption rate of the drug will depend on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, prolonged absorption of parenterally administered drug forms is achieved by dissolving or suspending the drug in an oily matrix.

可注射的儲庫形式是通過在可生物降解的聚合物如聚丙交酯-聚乙交酯中形成主題化合物的微囊基質來製備的。根據藥物與聚合物的比例以及所用的具體化合物的性質，可以控制藥物釋放速率。其它可生物降解的聚合物的實例包括聚(原酸酯)和聚(酸酐)。可注射的儲庫製劑也可以通過將藥物包在與機體組織相容的脂質體或微乳中來製備。 The injectable depot form is prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the specific compound used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot preparations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

本發明的製劑可以被口服、胃腸外、局部或直腸施用。它們當然是以適合於各施用途徑的形式被給予。例如，它們以片劑或膠囊劑的形式被施用，通過注射劑、吸入劑、眼用洗劑、軟膏劑、栓劑等被施用，通過注射、輸注或吸入被施用；通過洗劑或軟膏劑被局部施用；通過栓劑被直腸施用。較佳的是口服和/或靜脈內施用。 The formulation of the present invention can be administered orally, parenterally, topically or rectally. They are of course administered in a form suitable for each route of administration. For example, they are administered in the form of tablets or capsules, by injection, inhalation, ophthalmic lotion, ointment, suppository, etc., by injection, infusion or inhalation; by lotion or ointment topical Administration; rectal administration via suppository. It is preferably administered orally and/or intravenously.

本發明所用的措辭“胃腸外施用”意指除腸內和局部施用以外的施用方式，通常是通過注射施用，非限制性地包括靜脈內、肌內、動 脈內、鞘內、囊內、眶內、心內、真皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛網膜下、脊柱內和胸骨內注射和輸注。 The expression "parenteral administration" as used in the present invention means an administration mode other than enteral and local administration, usually by injection, and includes, without limitation, intravenous, intramuscular, and dynamic Intravenous, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspine, and intrasternal injection and infusion.

本發明所用的措辭“全身施用”和“外周施用”意指化合物、藥物或其它材料的除直接施用於中樞神經系統以外的施用，從而使得其進入患者的系統中並因此進行代謝和其它相似過程，例如皮下施用。 The terms "systemic administration" and "peripheral administration" as used in the present invention mean administration of compounds, drugs or other materials other than direct administration to the central nervous system, so that it enters the patient's system and thus undergoes metabolism and other similar processes , For example subcutaneously.

這些化合物可通過任何合適的施用途徑被施用於人和其它動物來進行治療，包括口服、鼻(例如以噴霧劑形式)、直腸、陰道內、胃腸外、腦池內和局部(以散劑、軟膏劑或滴劑形式)施用，所述局部施用包括口含和舌下施用。 These compounds can be administered to humans and other animals for treatment by any suitable route of administration, including oral, nasal (e.g. in the form of a spray), rectum, intravaginal, parenteral, intracisternal and topical (in powder, ointment) In the form of an agent or drops), the topical application includes buccal and sublingual administration.

不管所選擇的施用途徑如何，用本領域技術人員已知的常規方法將可以以合適的水合形式使用的本發明的化合物和/或本發明的藥物組合物配製成藥學可接受的劑型。 Regardless of the route of administration chosen, the compounds of the invention and/or the pharmaceutical compositions of the invention, which can be used in suitable hydrated forms, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

可以改變本發明的藥物組合物中活性成分的實際劑量水準以獲得對特定患者、組合物和施用方式而言可有效實現所需治療回應、對患者無毒的活性成分的量。 The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of the active ingredient that is effective for a particular patient, composition, and mode of administration to achieve the desired therapeutic response and is non-toxic to the patient.

所選擇的劑量水準將取決於多種因素，包括所用之具體的本發明的化合物或其酯、鹽或醯胺的活性、施用途徑、施用時間、所用的具體化合物的排泄速率、治療的持續時間、與所用的具體化合物組合使用的其它藥物、化合物和/或材料、所治療的患者的年齡、性別、體重、情況、一般健康狀況和既往醫學史以及醫學領域中公知的類似因素。 The dosage level chosen will depend on a variety of factors, including the activity of the specific compound of the invention or its ester, salt or amide used, the route of administration, the time of administration, the rate of excretion of the specific compound used, the duration of treatment, Other drugs, compounds and/or materials used in combination with the specific compound used, the age, sex, weight, condition, general health status and previous medical history of the patient being treated, and similar factors known in the medical field.

具有本領域普通技能的醫師或獸醫可容易地確定和開具出所需的藥物組合物的有效量。例如，醫師或獸醫可以以低於獲得所需治療作用所需要的劑量的水準開始藥物組合物中所用的本發明的化合物的劑量並逐漸增加其劑量直至實現所需的作用。 A physician or veterinarian with ordinary skill in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start the dosage of the compound of the present invention used in the pharmaceutical composition at a level lower than that required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

一般而言，本發明的化合物之合適的日劑量將是有效產生治療作用的最低劑量的化合物量。該類有效劑量一般將取決於上述因素。一般而言，當用於所示的鎮痛作用時，本發明的化合物用於患者的靜脈內和皮下劑量為約0.0001至約100mg/kg體重/天，更佳約0.01至約50mg/kg/天，還更佳為約1.0至約100mg/kg/天。有效量是治療與蛋白激酶有關的病症的量。 In general, a suitable daily dose of a compound of the invention will be the lowest dose of the compound effective to produce a therapeutic effect. Such effective dose will generally depend on the above factors. In general, when used for the analgesic effect shown, the compound of the present invention is used in patients with an intravenous and subcutaneous dose of about 0.0001 to about 100 mg/kg body weight/day, more preferably about 0.01 to about 50 mg/kg/day , Even more preferably from about 1.0 to about 100 mg/kg/day. An effective amount is an amount that treats protein kinase-related disorders.

如果需要的話，活性化合物的有效日劑量可以在一天中以分開施用的二、三、四、五、六或更多個亞劑量以適宜的時間間隔施用，任選地，所述亞劑量是單位劑型。 If desired, the effective daily dose of the active compound can be administered at appropriate intervals in two, three, four, five, six or more sub-doses administered separately during the day, optionally, the sub-dose is a unit Dosage form.

對於約50-70kg的個體，本發明的藥物組合物或組合可以為約1-1000mg活性成分的單位劑量，或者約1-500mg或者約1-250mg或者約1-150mg或者約0.5-100mg或者約1-50mg的活性成分。化合物、其藥物組合物或組合的治療有效劑量取決於個體的種類、體重、年齡和個體條件、治療的障礙或疾病或其嚴重程度。具有普通技術的醫師、臨床醫師或獸醫能夠容易地確定預防、治療或抑制障礙或疾病的進程所需的每種活性成分的有效量。 For an individual of about 50-70 kg, the pharmaceutical composition or combination of the invention may be a unit dose of about 1-1000 mg of active ingredient, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg or about 1-50mg of active ingredient. The therapeutically effective dose of a compound, its pharmaceutical composition, or combination depends on the type, weight, age, and condition of the individual, the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of a disorder or disease.

上述劑量性質在體外和體內試驗中應用有利的哺乳動物，例如小鼠、大鼠、狗、猴或其相關器官、組織或製備物可進行說明。本發明化合物可以在體外以溶液劑例如水溶液劑的形式應用，並且可以在體內以腸內、非腸道、有利地以靜脈內例如作為混懸劑或水溶液劑應用。體外劑量範圍可以是約10-3摩爾至10-9摩爾濃度之間。體內治療有效量範圍可以取決於施用途徑，為約0.1-500mg/kg或約1-100mg/kg之間。 The above-mentioned dosage properties can be explained by the use of advantageous mammals in in vitro and in vivo tests, such as mice, rats, dogs, monkeys or related organs, tissues or preparations thereof. The compound of the present invention can be applied in the form of a solution such as an aqueous solution in vitro, and can be applied in the body in the intestinal, parenteral, and advantageously intravenously, for example, as a suspension or aqueous solution. The in vitro dose range may be between about 10-3 molar and 10-9 molar concentrations. The therapeutically effective amount in vivo can range from about 0.1-500 mg/kg or about 1-100 mg/kg depending on the route of administration.

本發明所用的術語“個體”意指動物。通常，動物是哺乳動物。個體還意指例如靈長類(例如人，男性或女性)、牛、綿羊、山羊、馬、狗、貓、兔、大鼠、小鼠、魚、鳥等。在某些實施例中，個體是靈長類。在其它實施例中，個體是人。 As used herein, the term "individual" means an animal. Usually, the animal is a mammal. Individuals also mean, for example, primates (eg, human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In some embodiments, the individual is a primate. In other embodiments, the individual is a human.

雖然本發明的化合物可以單獨施用，但是較佳以藥物組合物的形式施用所述化合物。 Although the compound of the present invention can be administered alone, it is preferable to administer the compound in the form of a pharmaceutical composition.

藥物聯合Drug combination

使用本發明所提供的一種或多種化合物或組合物，或其藥學上可接受的衍生物與其它的藥物活化劑聯合來組合治療，用於治療本發明所述的疾病和病症。 Use one or more compounds or compositions provided by the present invention, or a pharmaceutically acceptable derivative thereof in combination with other drug activators for combination therapy for the treatment of the diseases and disorders described in the present invention.

將配製用於口服、全身性傳遞包括腸道外或靜脈內傳遞或用於局部或表面施用的有效量的化合物或包含治療有效濃度的化合物的組合物給予表現出疾病或病症症狀而需要治療的個體。所述量有效地治療、控 制或緩解了該疾病或病症的一種或多種症狀。 Administration of an effective amount of a compound formulated for oral, systemic delivery, including parenteral or intravenous delivery, or for topical or topical administration, or a composition containing a therapeutically effective concentration of the compound, to an individual in need of treatment showing symptoms of a disease or disorder . The amount is effectively treated, controlled One or more symptoms of the disease or condition have been suppressed or alleviated.

本領域普通技術人員能夠理解本發明所提供的化合物、異構體、前體藥物和藥學上可接受的衍生物，包括藥物組合物和包含這些化合物的製劑，可廣泛應用於聯合治療以治療本發明所述的不適和疾病。因此，本發明預期將本發明所提供的化合物、異構體、前體藥物和藥學上可接受的衍生物與其它活性藥物聯合使用，以用於治療本發明所述的疾病/不適。 Those of ordinary skill in the art can understand that the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided by the present invention, including pharmaceutical compositions and formulations containing these compounds, can be widely used in combination therapy to treat the present The discomfort and disease described in the invention. Therefore, the present invention contemplates the use of the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided by the present invention in combination with other active drugs for the treatment of the diseases/discomforts described in the present invention.

本發明所提供的化合物或組合物或其藥學上可接受的衍生物可以在一種或多種附加治療劑給藥的同時、之前或之後給藥。附加治療劑特別是有用於治療困擾受試者的增生性病症或癌症的治療劑。 The compound or composition provided by the present invention or a pharmaceutically acceptable derivative thereof can be administered at the same time, before or after the administration of one or more additional therapeutic agents. The additional therapeutic agent is particularly useful for the treatment of proliferative disorders or cancer that bothers the subject.

在一些實施方案中，一種或多種附加治療劑選自抗癌劑(如細胞信號傳導抑制劑，有絲分裂抑制劑，烷化劑，抗代謝藥，嵌合(intercalating)抗癌劑，拓撲異構酶抑制劑，免疫治療劑，或抗激素劑)，類固醇藥物，甲氨蝶呤，來氟米特，抗TNF-α劑，鈣調神經磷酸酶(calcineurin)抑制劑，抗組胺藥物，化學治療藥物，抗增殖劑，免疫抑制劑，免疫刺激劑，抗炎性試劑，CDK4/6激酶抑制劑，ABL抑制劑，ABL/Scr抑制劑，極光激酶抑制劑，Bcr-ABL的非-ATP競爭性抑制劑，c-KIT突變抑制劑，RET抑制劑，PDGFR抑制劑，VEGFR抑制劑，CSF1R抑制劑，FLT3抑制劑，FLT3-ITD抑制劑或它們的組合。 In some embodiments, the one or more additional therapeutic agents are selected from anticancer agents (eg, cell signaling inhibitors, mitotic inhibitors, alkylating agents, antimetabolites, intercalating anticancer agents, topoisomerase Inhibitors, immunotherapeutics, or antihormones), steroids, methotrexate, leflunomide, anti-TNF-α agents, calcineurin inhibitors, antihistamines, chemotherapy Drugs, anti-proliferative agents, immunosuppressive agents, immunostimulants, anti-inflammatory agents, CDK4/6 kinase inhibitors, ABL inhibitors, ABL/Scr inhibitors, aurora kinase inhibitors, non-ATP competitive Bcr-ABL Inhibitors, c-KIT mutation inhibitors, RET inhibitors, PDGFR inhibitors, VEGFR inhibitors, CSF1R inhibitors, FLT3 inhibitors, FLT3-ITD inhibitors or combinations thereof.

在一些實施方案中，抗癌劑選自烷化劑(如環磷醯胺、一環磷醯胺、美法侖、白消安、尼莫司丁、雷莫司汀、達卡巴嗪、替莫唑胺、鹽酸氮芥、二溴甘露醇等)、鉑絡合劑(例如順鉑、卡鉑、奧沙利鉑等)、代謝拮抗劑(如甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他濱、卡倍他濱、氟維司群、培美曲塞等)、植物生物鹼(例如長春新鹼、長春鹼、長春地辛、依託泊苷、多西他賽、紫杉醇、伊立替康、長春瑞濱、米托蒽醌、長春氟寧、拓撲替康等)、抗體藥物(例如曲妥單抗、帕妥珠單抗、利妥昔單抗、西妥昔單抗、帕尼單抗、貝伐單抗等)、激素抗癌劑(例如亮丙瑞林、戈舍瑞林、度他雄胺、地塞米松、他莫西芬等)、蛋白酶體抑制劑(例如硼替佐米、來那度胺等)、芳香化沒抑制劑(例如依西美坦、來曲唑、阿那曲唑等)、VEGFR抑制劑(例如舒尼替尼、索拉菲尼、伊馬替尼、吉非替 尼、埃羅替尼、凡德他尼、帕唑替尼、拉帕替尼等)、mTOR抑制劑(例如依維莫司、西羅莫司、佐他莫司等)。 In some embodiments, the anticancer agent is selected from alkylating agents (e.g., cyclophosphamide, monocyclophosphamide, melphalan, busulfan, nimustine, ramustine, dacarbazine, temozolomide, Nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (e.g., cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (e.g., methotrexate, 5-fluorouracil, tegafur, gemcitabine, carboplatin) Betaine, fulvestrant, pemetrexed, etc.), plant alkaloids (e.g. vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine , Mitoxantrone, vinflunine, topotecan, etc.), antibody drugs (such as trastuzumab, pertuzumab, rituximab, cetuximab, panitumumab, bevac Monoclonal antibodies, etc.), hormonal anticancer agents (e.g. leuprolide, goserelin, dutasteride, dexamethasone, tamoxifen, etc.), proteasome inhibitors (e.g. bortezomib, lenalidomide) Amines, etc.), aromatization inhibitors (e.g. exemestane, letrozole, anastrozole, etc.), VEGFR inhibitors (e.g. sunitinib, sorafenib, imatinib, gefitinib) Nigrosine, erlotinib, vandetanib, pazotinib, lapatinib, etc.), mTOR inhibitors (eg everolimus, sirolimus, zotarolimus, etc.).

在一些實施方案中，附加治療劑可以是：鏈脲佐菌素，奧沙利鉑，替莫唑胺，甲氨蝶呤，氟尿嘧啶，吉西他濱，巰基嘌呤，長春瑞濱，多西紫杉醇，拓撲替康，伊立替康，曲貝替定，更生黴素，絲裂黴素C，伊沙匹隆，戈那瑞林類似物，甲地孕酮，強的松，甲潑尼龍，沙利度胺，干擾素α，亞葉酸鈣，西羅莫司，西羅莫司脂化物，依維莫司，阿法替尼，阿帕替尼，阿西替尼，硼替佐米，波舒替尼，卡博替尼(cabozantinib)，西地尼布，克卓替尼，達拉非尼(dabrafenib)，達克替尼(dacomitinib)，達沙替尼，多韋替尼(dovitinib)，厄洛替尼，吉非替尼，伊布替尼(ibrutinib)，埃克替尼，伊馬替尼，拉帕替尼，樂伐替尼(lenvatinib)，馬賽替尼，莫替沙尼，來那替尼，尼祿替尼，尼拉帕尼(niraparib)，奧拉帕尼(olaparib)，帕唑帕尼，帕納替尼(ponatinib)，瑞格菲尼(regorafenib)，瑞卡帕布(rucaparib)，魯索替尼(ruxolitinib)，塞卡替尼，索拉非尼，舒尼替尼，特拉替尼(telatinib)，托法替尼(tofacitinib)，曲美替尼(trametinib)，凡德他尼，維利帕尼(veliparib)，威羅菲尼，維莫德吉(vismodegib)，阿侖單抗，貝伐單抗，本妥昔單抗(brentuximab vedotin)，卡妥索單抗，西妥昔單抗，地諾單抗，吉妥珠單抗，伊匹單抗，尼妥珠單抗，奧法木單抗，帕尼單抗，利妥昔單抗，托西莫單抗，曲妥珠單抗，白消安，二丙胺磺酯，呱泊舒凡，苄替呱，卡波醌，四甲脲烷亞胺，烏瑞替呱，六甲密胺，曲他胺，三亞乙基磷醯胺(triethylenephosphoramide)，三亞乙基硫代磷醯胺(triethylenethiophosphoramide)，三羥甲密胺，苯丁酸氮芥，萘氮芥，環磷醯胺，雌莫司汀，異環磷醯胺，氮芥，鹽酸氧化氮芥，美法侖，新氮芥，苯芥膽甾醇，松龍苯芥，三芥環磷醯胺，尿嘧啶氮芥，卡莫司汀，氯脲菌素，福莫司汀(fotemustine)，洛莫司汀(lomustine)，尼莫司汀(nimustine)，雷莫司汀(ranimustine)，達卡巴嗪，甘露氮芥，二溴甘露醇，二溴衛矛醇，呱泊溴烷，阿克拉黴素，放線菌素F(1)，氨茴黴素，偶氮絲氨酸，博來黴素，放線菌素C，卡柔比星(carubicin)，嗜癌黴素(carzinophilin)，色黴素(chromomycin)，放線菌素D，柔紅黴素(daunorubicin)， 道諾黴素(daunomycin)，6-重氮基-5-氧代-1-正亮氨酸，多柔比星，表柔比星，絲裂黴素C，麥考酚酸，諾加黴素(nogalamycin)，橄欖黴素(olivomycin)，培洛黴素(peplomycin)，普卡黴素(plicamycin)，泊非黴素(porfiromycin)，嘌呤黴素(puromycin)，鏈黑黴素(streptonigrin)，鏈脲黴素(streptozocin)，殺結核菌素(tubercidin)，烏苯美司(ubenimex)，淨司他丁(zinostatin)，佐柔比星，二甲葉酸(denopterin)，甲氨喋呤，蝶羅呤(pteropterin)，三甲曲沙(trimetrexate)，氟達拉濱，硫咪嘌呤(thiamiprine)，硫鳥嘌呤(thioguanine)，安西他濱(ancitabine)，阿紮胞苷(azacitidine)，6-氮尿苷(6-azauridine)，卡莫氟(carmofur)，阿糖胞苷(cytarabine)，二去氧尿苷(dideoxyuridine)，去氧氟尿苷(doxifluridine)，依諾他濱(enocitabine)，氟尿苷(floxuridine)，氟脲嘧啶(fluorouracil)，替加氟，L-天門冬醯胺酶，阿法去氧核糖核酸酶，醋葡醛內酯，醛磷醯胺苷(aldophosphamide glycoside)，氨基乙醯丙酸，安吖啶，苯丁酸氮芥與β-雌二醇苯甲酸酯的結合物(bestrabucil)，比生群，卡鉑，順鉑，地磷醯胺(defofamide)，秋水仙胺，地吖醌，依氟鳥氨酸(elfornithine)，醋酸羥嗶哢唑，依託格魯，依託泊苷，氟他胺，硝酸鎵，羥基脲，干擾素α，干擾素β，干擾素γ，白細胞介素-2，香菇多糖，氯尼達明，潑尼松，地塞米松，甲醯四氫葉酸，丙米腙，米托蒽醌，蒙匹胺醇(mopidamol)，二胺硝吖啶，噴司他丁，蛋氨氮芥，吡柔比星(pirarubicin)，鬼臼酸，2-乙基醯肼，丙卡巴肼，雷佐生，西佐喃(sizofiran)，鍺螺胺(spirogermanium)，紫杉醇，他莫昔芬，替尼泊苷，細交鏈孢菌酮酸，三亞胺醌，2,2’,2”-三氯三乙基胺，烏拉坦，長春鹼，長春新鹼，長春地辛，地拉羅斯，卡博替尼，普納替尼，米哚妥林(Midostaurin)，吉特替尼(gilteritinib)，法米替尼(Famitinib)，哌柏西利(palbociclib)，夫拉平度(Alvocidib)或它們的組合。 In some embodiments, the additional therapeutic agent may be: streptozotocin, oxaliplatin, temozolomide, methotrexate, fluorouracil, gemcitabine, mercaptopurine, vinorelbine, docetaxel, topotecan, it Rinotecan, trabectedin, probiotic, mitomycin C, ixabepilone, gonadorelin analogs, megestrol, prednisone, methylprednisolone, thalidomide, interferon Alpha, folinic acid calcium, sirolimus, sirolimus lipid, everolimus, afatinib, apatinib, axitinib, bortezomib, bosutinib, carboteib (Cabozantinib), sildenibu, crizotinib, dabrafenib, dacomitinib, dasatinib, dovitinib, erlotinib, gefitinib Tinib, ibrutinib, icotinib, imatinib, lapatinib, lenvatinib, mazatinib, motizanib, lenatinib, nilotinib Ni, niraparib, olaparib, pazopanib, ponatinib, regorafenib, rucaparib, rusoty (Ruxolitinib), Secatinib, Sorafenib, Sunitinib, Telatinib, tofacitinib, trametinib, vandetanib, vinde Veliparib, velovinib, vismodegib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab Anti-, Denolimumab, Gituzumab, Ipilimumab, Nimotuzumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab Monoclonal antibody, busulfan, dipropylamine sulfonate, gipoxyfam, benzetidine, carboquinone, tetramethylurethaneimine, uritriptyl, hexamethylmelamine, tromethamine, triethylenephosphamide Amine (triethylenephosphoramide), triethylenethiophosphoramide (triethylenethiophosphoramide), trimetholamine, chlorambucil, naphthalene mustard, cyclophosphamide, estramustine, ifosfamide, nitrogen Mustard, nitric oxide hydrochloride mustard, melphalan, neonitrogen mustard, benzene mustard cholesterol, pine long mustard, triparochloride, uracil nitrogen mustard, carmustine, chlorurosporin, formalin Fotemustine, lomustine, nimustine, ranimustine, dacarbazine, mannose mustard, dibromomannitol, dibromomantelol, carbamide Bromine, clarithromycin, actinomycin F(1), anthranilin, azoserine, bleomycin, actinomycin C, carubicin ), carzinophilin, chromomycin, actinomycin D, daunorubicin, Daunomycin, 6-diazo-5-oxo-1-norleucine, doxorubicin, epirubicin, mitomycin C, mycophenolic acid, nogamycin Nogalamycin, olivomycin, peplomycin, plicamycin, porfiromycin, puromycin, streptonigrin , Streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, methotrexate, Pteropterin, trimetrexate, fludarabine, thiamiprine, thioguanine, thioguanine, ancitabine, azacitidine, 6- 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, Fluoxuridine, fluorouracil, tegafur, L-asparaginase, alfa deoxyribonuclease, acetglucuronide, aldophosphamide glycoside, Conjugates of amino acetopropionic acid, an acridine, chlorambucil and β-estradiol benzoate (bestrabucil), bisantrene, carboplatin, cisplatin, defofamide, Colchicine, diacridone, elfornithine, oxypyrazole acetate, etoglu, etoposide, flutamide, gallium nitrate, hydroxyurea, interferon alpha, interferon beta, interference Γ, interleukin-2, lentinan, lonidamine, prednisone, dexamethasone, methyltetrahydrofolate, imipramine, mitoxantrone, mopidamol, diamine nitrate Acridine, pentostatin, methamine mustard, pirarubicin, podophyllic acid, 2-ethyl hydrazide, procarbazine, rezosen, sizofiran, spirogermanium ), paclitaxel, tamoxifen, teniposide, streptozotocin, triiminoquinone, 2,2',2"-trichlorotriethylamine, uratan, vinblastine, vincristine , Vindesine, delaros, carbotinib, punatinib, midosturin, gilteritinib ), Famitinib (Famitinib), pabociclib (palbociclib), flavin (Alvocidib) or a combination thereof.

在一些實施方案中，還提供了藥物組合物，其包含本發明所提供的化合物或其藥學上可接受的衍生物，和一種或多種其它活性藥物，可作為單個劑量形式或者與化合物和組合物分開作為多劑量形式的一部分。其它活性藥物可以與本發明公開的化合物同時給予或者不同時給予。在後一種情況下，給藥可以錯開，例如：6小時、12小時、1天、2天、 3天、1周、2周、3周、1個月或2個月。 In some embodiments, there is also provided a pharmaceutical composition comprising the compound provided by the present invention or a pharmaceutically acceptable derivative thereof, and one or more other active drugs, either as a single dosage form or with the compound and composition Separate as part of a multi-dose form. Other active drugs may be administered at the same time as the compounds disclosed in the present invention or at different times. In the latter case, the administration can be staggered, for example: 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.

在一些實施方案中，還提供聯合療法，其治療或預防症狀、或與癌症和相關疾病和病症相關的併發症的發生，該療法包括向有此種需要的個體給予一種本發明所公開的化合物或組合物、或其藥學上可接受的衍生物，和一或多種其它活性藥物。 In some embodiments, there is also provided a combination therapy, which treats or prevents symptoms, or the occurrence of complications associated with cancer and related diseases and disorders, the therapy comprising administering to a subject in need thereof a compound disclosed in the present invention Or a composition, or a pharmaceutically acceptable derivative thereof, and one or more other active drugs.

在一些實施方案中，聯合用藥給藥時，有兩種方式：1)將本發明所述的化合物或藥物組合物與可聯用的其他活性藥物分別製成單獨的製劑，兩種劑型可以相同或不同，使用時可以先後使用，也可以同時使用；先後使用時，給予第二種藥物是第一種藥物還未喪失其在體內的有效作用；2)將本發明化合物或藥物組合物和可聯用的其他活性藥物製成單一製劑，同時給藥。 In some embodiments, there are two ways to administer the drug in combination: 1) Separate preparation of the compound or pharmaceutical composition of the present invention and other active drugs that can be used in combination, the two dosage forms may be the same Or different, it can be used sequentially or simultaneously; when used sequentially, the second drug is given because the first drug has not lost its effective effect in the body; 2) the compound or pharmaceutical composition of the present invention and the The other active drugs used in combination are made into a single preparation and administered simultaneously.

在一些實施方案中，特別提供FLT3抑制劑或FLT3-ITD抑制劑和CDK4/6激酶抑制劑的聯合用藥。本發明作為CDK4/6激酶抑制劑的化合物或組合物或其藥學上可接受的衍生物可以在一種或多種附加治療劑給藥的同時、之前或之後給藥。附加治療劑特別是FLT3抑制劑或FLT3-ITD抑制劑。 In some embodiments, FLT3 inhibitors or combinations of FLT3-ITD inhibitors and CDK4/6 kinase inhibitors are specifically provided. The compound or composition of the present invention as a CDK4/6 kinase inhibitor or a pharmaceutically acceptable derivative thereof can be administered at the same time, before or after the administration of one or more additional therapeutic agents. Additional therapeutic agents are in particular FLT3 inhibitors or FLT3-ITD inhibitors.

在一些實施方案中，FLT3抑制劑或FLT3-ITD抑制劑是卡博替尼，普納替尼，Midostaurin，Pacritinib，quizartinib，gilteritinib，AKN-028，AT-9283，Crenolanib，ENMD-2076，Famitinib，Dovitinib，PLX-3397，等。 In some embodiments, the FLT3 inhibitor or FLT3-ITD inhibitor is carbotinib, punatinib, Midostaurin, Pacritinib, quizartinib, gilteritinib, AKN-028, AT-9283, Crenolanib, ENMD-2076, Famitinib, Dovitinib, PLX-3397, etc.

一般合成方法General synthesis method

一般地，本發明的化合物可以通過本發明所描述的方法製備得到，除非有進一步的說明，其中取代基的定義如式(I)-(III)所示化合物。下面的反應方案和實施例用於進一步舉例說明本發明的內容。 Generally, the compound of the present invention can be prepared by the method described in the present invention, unless otherwise specified, wherein the definition of the substituent is as shown in formula (I)-(III). The following reaction schemes and examples are used to further illustrate the content of the present invention.

所屬領域的技術人員將認識到：本發明所描述的化學反應可以用來合適地製備許多本發明的其他化合物，且用於製備本發明的化合物的其它方法都被認為是在本發明的範圍之內。例如，根據本發明那些非例證的化合物的合成可以成功地被所屬領域的技術人員通過修飾方法完成，如適當的保護干擾基團，通過利用其他已知的試劑除了本發明所描述的，或將反應條件做一些常規的修改。另外，本發明所公開的反應或已知的反 應條件也公認地適用於本發明其他化合物的製備。 Those skilled in the art will recognize that the chemical reactions described in the present invention can be used to properly prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to the description of the present invention, or will The reaction conditions should be modified regularly. In addition, the reactions disclosed in the present invention or known reactions The conditions are also generally applicable to the preparation of other compounds of the invention.

下面所描述的實施例，除非其他方面表明所有的溫度定為攝氏度。試劑購買於商品供應商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用時都沒有經過進一步純化，除非其他方面表明。一般的試劑從汕頭西隴化工廠，廣東光華化學試劑廠，廣州化學試劑廠，天津好寓宇化學品有限公司，青島騰龍化學試劑有限公司，和青島海洋化工廠購買得到。 The embodiments described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents are purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

無水四氫呋喃，二氧六環，甲苯，乙醚是經過金屬鈉回流乾燥得到。無水二氯甲烷和氯仿是經過氫化鈣回流乾燥得到。乙酸乙酯，石油醚，正己烷，N，N-二甲基乙醯胺和N，N-二甲基甲醯胺是經無水硫酸鈉事先乾燥使用。 Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by refluxing and drying sodium metal. Anhydrous dichloromethane and chloroform are obtained by refluxing calcium hydride and drying. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried in advance using anhydrous sodium sulfate.

以下反應一般是在氮氣或氬氣正壓下或在無水溶劑上套一乾燥管(除非其他方面表明)，反應瓶都塞上合適的橡皮塞，底物通過注射器打入。玻璃器皿都是乾燥過的。 The following reaction is generally carried out under a positive pressure of nitrogen or argon or a dry tube on an anhydrous solvent (unless otherwise indicated), the reaction bottles are plugged with a suitable rubber stopper, and the substrate is injected through a syringe. Glassware is dried.

色譜柱是使用矽膠柱。矽膠(300-400目)購於青島海洋化工廠。核磁共振光譜以CDCl3,d6-DMSO,CD3OD或d6-丙酮為溶劑(報導以ppm為單位)，用TMS(0ppm)或氯仿(7.25ppm)作為參照標準。當出現多重峰的時候，將使用下面的縮寫：s(singlet，單峰)，d(doublet，雙峰)，t(triplet，三重峰)，m(multiplet，多重峰)，br(broadened，寬峰)，dd(doublet of doublets，四重峰)，dt(doublet of triplets，雙三重峰)。偶合常數，用赫茲(Hz)表示。 Chromatography column is a silica gel column. Silicone (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy uses CDCl 3 , d 6 -DMSO, CD 3 OD or d 6 -acetone as the solvent (reported in ppm), and uses TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide Peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplet). Coupling constant, expressed in Hertz (Hz).

低解析度質譜(MS)資料通過配備G1312A二元泵和a G1316A TCC(柱溫保持在30℃)的Agilent 6320系列LC-MS的光譜儀來測定的，G1329A自動採樣器和G1315B DAD檢測器應用於分析，ESI源應用於LC-MS光譜儀。 Low-resolution mass spectrometry (MS) data was measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C). The G1329A automatic sampler and G1315B DAD detector were applied Analysis, ESI source applied to LC-MS spectrometer.

低解析度質譜(MS)資料通過配備G1311A四元泵和G1316ATCC(柱溫保持在30℃)的Agilent 6120系列LC-MS的光譜儀來測定的，G1329A自動採樣器和G1315D DAD檢測器應用於分析，ESI源應用於LC-MS光譜儀。 Low-resolution mass spectrometry (MS) data was measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316ATCC (column temperature maintained at 30°C). The G1329A automatic sampler and G1315D DAD detector were used for analysis. ESI sources are used in LC-MS spectrometers.

以上兩種光譜儀都配備了Agilent Zorbax SB-C18柱，規格為2.1×30mm，5μm。注射體積是通過樣品濃度來確定；流速為0.6mL/min；HPLC的峰值是通過在210nm和254nm處的UV-Vis波長來記錄讀取的。流動相為0.1%的甲酸乙腈溶液(相A)和0.1%的甲酸超純水溶液(相B)。梯度洗脫條件如表1所示：

Figure 104141541-A0101-12-0081-115
Both of the above spectrometers are equipped with an Agilent Zorbax SB-C18 column with specifications of 2.1×30mm and 5μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; the peak of HPLC is recorded by the UV-Vis wavelength at 210 nm and 254 nm. The mobile phase was 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient elution conditions are shown in Table 1:
Figure 104141541-A0101-12-0081-115

化合物純化是通過Agilent 1100系列高效液相色譜(HPLC)來評價的，其中UV檢測在210nm和254nm處，Zorbax SB-C18柱，規格為2.1×30mm，4μm，10分鐘，流速為0.6mL/min，5-95%的(0.1%甲酸乙腈溶液)的(0.1%甲酸水溶液)，柱溫保持在40℃。 Compound purification was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), where UV detection was at 210nm and 254nm, Zorbax SB-C18 column, specification was 2.1×30mm, 4μm, 10 minutes, flow rate was 0.6mL/min , 5-95% (0.1% formic acid in acetonitrile) (0.1% formic acid in water), the column temperature is maintained at 40 ℃.

下面簡寫詞的使用貫穿本發明：

Figure 104141541-A0101-12-0081-119
Figure 104141541-A0101-12-0082-120
 The following abbreviations are used throughout the present invention:
Figure 104141541-A0101-12-0081-119
Figure 104141541-A0101-12-0082-120

合成方案Synthesis scheme 合成中間體方案1Synthetic Intermediate Scheme 1

Figure 104141541-A0101-12-0082-121
Figure 104141541-A0101-12-0082-121

本發明化合物中間體(4a)可以通過合成中間體方案1的合成方法得到：化合物(1a)與化合物(2)在鹼性條件下，加熱反應生成化合物(3a)；化合物(3a)經過催化氫化得到中間體化合物(4a)。其中A、R和L具有如本發明所述的含義。 The compound intermediate (4a) of the present invention can be obtained by the synthesis method of the synthetic intermediate scheme 1 : Compound (1a) and compound (2) are reacted under heating under basic conditions to produce compound (3a) ; compound (3a) undergoes catalytic hydrogenation The intermediate compound (4a) is obtained . Where A, R and L have the meaning as described in the present invention.

合成中間體方案2Synthetic Intermediate Scheme 2

Figure 104141541-A0101-12-0082-122
Figure 104141541-A0101-12-0082-122

本發明化合物中間體(14)可以通過合成中間體方案2的合成方法得到：化合物(11)與化合物(12)在鹼性條件下，加熱反應生成化合物(13)；化合物(13)經過催化氫化得到中間體化合物(14)。其中A具有如本發明所述的含義。 The compound intermediate (14) of the present invention can be obtained by the synthesis method of the synthetic intermediate scheme 2 : Compound (11) and compound (12) are reacted under heating under basic conditions to form compound (13) ; compound (13) undergoes catalytic hydrogenation The intermediate compound (14) is obtained . Where A has the meaning as described in the present invention.

合成中間體方案5Synthetic Intermediate Scheme 5

Figure 104141541-A0101-12-0083-124
Figure 104141541-A0101-12-0083-124

本發明化合物中間體(4d)可以通過合成中間體方案5的合成方法得到：化合物(1ad)在錫試劑作用下發生still反應得到化合物(1ae)，然後化合物(1ae)在鹼(鹼可以是，但不限於RNH2)作用下加熱關環得到化合物(1af)，化合物(1af)還原醯胺得到化合物(1ag)，化合物(1ag)在HBr和AcOH作用下，脫甲基得到化合物(1ah)，化合物(1ah)在POCl3作用下得到化合物(1ai)，進一步在氨水作用下得到化合物(4d)。其中R具有如本發明所述的含義。 The compound intermediate (4d) of the present invention can be obtained by the synthesis method of the synthetic intermediate scheme 5 : the compound (1ad) undergoes a still reaction under the action of a tin reagent to obtain the compound (1ae) , and then the compound (1ae) is in the base (the base may be, However, it is not limited to RNH 2 ) heating and ring closure to obtain compound (1af) , compound (1af) reduces amide to obtain compound (1ag) , compound (1ag) is demethylated under the action of HBr and AcOH to obtain compound (1ah) , Compound (1ah) obtains compound (1ai) under the action of POCl 3 , and further obtains compound (4d) under the action of ammonia water. Where R has the meaning as described in the present invention.

合成方案1Synthesis Scheme 1

Figure 104141541-A0101-12-0083-126
Figure 104141541-A0101-12-0083-126

本發明化合物可以通過合成方案1的合成方法得到：化合物(4a)與化合物(7)在合適的溶劑中發生偶聯反應，得到化合物(5)；化合物(5)在鈀催化劑作用下，發生偶聯反應得到化合物(6)，再進一步在酸性條件下重排得到目標產物(8)。其中A、R和L具有如本發明所述的含義。 The compound of the present invention can be obtained by the synthesis method of Synthesis Scheme 1 : Compound (4a) and Compound (7) undergo a coupling reaction in a suitable solvent to obtain Compound (5) ; Compound (5) is coupled under the action of a palladium catalyst The combined reaction yields compound (6) , which is further rearranged under acidic conditions to obtain the target product (8) . Where A, R and L have the meaning as described in the present invention.

合成方案2Synthesis Scheme 2

Figure 104141541-A0101-12-0083-128
Figure 104141541-A0101-12-0083-128

本發明化合物可以通過合成方案2的合成方法得到：化合物 (7)在合適的溶劑中在鈀催化劑作用下，發生偶聯反應，到化合物(9)；化合物(9)與化合物(4a)在鹼的作用下，發生偶聯反應得到化合物(8)。其中A、R和L具有如本發明所述的含義。 The compound of the present invention can be obtained by the synthesis method of Synthesis Scheme 2 : Compound (7) in a suitable solvent under the action of a palladium catalyst, a coupling reaction occurs to compound (9) ; compound (9) and compound (4a) in the base Under the action of, coupling reaction occurs to obtain compound (8) . Where A, R and L have the meaning as described in the present invention.

合成方案3Synthesis Scheme 3

Figure 104141541-A0101-12-0084-129
Figure 104141541-A0101-12-0084-129

本發明化合物可以通過合成方案3的合成方法得到：化合物(5)在錫催化劑作用下，發生偶聯反應得到化合物(8)。其中A、R和L具有如本發明所述的含義。 The compound of the present invention can be obtained by the synthesis method of Synthesis Scheme 3 : Compound (5) undergoes a coupling reaction under the action of a tin catalyst to obtain compound (8) . Where A, R and L have the meaning as described in the present invention.

合成方案4Synthesis Scheme 4

Figure 104141541-A0101-12-0084-130
Figure 104141541-A0101-12-0084-130

本發明化合物可以通過合成方案4的合成方法得到：中間體化合物(14)與化合物(7)在合適的溶劑中發生偶聯反應，得到化合物(15)；化合物(15)在鈀催化劑作用下，發生偶聯反應得到化合物(16)，再進一步在酸性條件下重排得到目標產物(17)。其中A具有如本發明所述的含義。 The compound of the present invention can be obtained by the synthesis method of Synthesis Scheme 4 : the intermediate compound (14) and the compound (7) undergo a coupling reaction in a suitable solvent to obtain the compound (15) ; the compound (15) is under the action of a palladium catalyst, A coupling reaction occurs to obtain compound (16) , which is further rearranged under acidic conditions to obtain the target product (17) . Where A has the meaning as described in the present invention.

合成方案5Synthesis Scheme 5

Figure 104141541-A0101-12-0085-131
Figure 104141541-A0101-12-0085-131

本發明化合物可以通過合成方案5的合成方法得到：化合物(7)在合適的溶劑中在錫催化劑作用下，發生偶聯反應得到化合物(10)；化合物(10)在酸性條件下重排得到化合物(9)，化合物(9)在氨水作用得到化合物(18)，化合物(18)與化合物(1ai)在鈀試劑的作用下偶聯得到最終化合物(19)。其中R具有如本發明所述的含義。 The compound of the present invention can be obtained by the synthesis method of Scheme 5 : Compound (7) in a suitable solvent under the action of a tin catalyst, a coupling reaction occurs to obtain compound (10) ; compound (10) is rearranged under acidic conditions to obtain compound (9) Compound (9) is reacted with ammonia water to obtain compound (18) , and compound (18) and compound (1ai) are coupled under the action of palladium reagent to obtain final compound (19) . Where R has the meaning as described in the present invention.

合成方案6Synthesis Scheme 6

Figure 104141541-A0101-12-0085-132
Figure 104141541-A0101-12-0085-132

本發明化合物可以通過合成方案6的合成方法得到：化合物(7)在氨水作用下，得到化合物(20)，化合物(20)在鈀催化劑作用下，發生偶聯反應得到化合物(21)，化合物(21)在酸性條件下重排得到化合物(18)，化合物(18)在鹼性條件下與化合物(4b)在鈀催化劑作用下，發生偶聯反應得到化合物(23)。其中，X為鹵素等易離去基團；A，R和L具有如本發明所述的含義。 The compound of the present invention can be obtained by the synthesis method of Synthesis Scheme 6 : Compound (7) under the action of ammonia water to obtain compound (20) , compound (20) under the action of palladium catalyst, coupling reaction to obtain compound (21) , compound ( 21) Rearrangement under acidic conditions yields compound (18) . Compound (18) undergoes a coupling reaction with compound (4b) under a palladium catalyst under basic conditions to yield compound (23) . Among them, X is an easily leaving group such as halogen; A, R and L have the meanings as described in the present invention.

下面的實施例可以對本發明做進一步的描述，然而，這些實施例不應作為對本發明的範圍的限制。 The following examples may further describe the present invention, however, these examples should not be taken as limiting the scope of the present invention.

實施例Examples 實施例1 Example 1 6-乙醯基-8-環戊基-5-甲基-2-[(1--(呱啶-4-基)-1H-吲哚-5-基)氨基]-吡啶並[2,3-d]嘧啶-7(8H)-酮6-Acetyl-8-cyclopentyl-5-methyl-2-[(1--(pyridin-4-yl)-1 H -indol-5-yl)amino]-pyrido[2 ,3-d]pyrimidin-7(8 H )-one

Figure 104141541-A0101-12-0086-133
Figure 104141541-A0101-12-0086-133

步驟1)4-(5-硝基-1H-吲哚-1-基)呱嗪-1-甲酸叔丁酯 Step 1) 4-(5-Nitro- 1H -indol-1-yl)pyrazine-1-carboxylic acid tert-butyl ester

冰浴下，在5-硝基吲哚(3.0g,18.3mmol)的DMF(45mL)溶液中加入NaH(1.5g,38mmol)，室溫下攪拌30min後，滴加1-Boc-4-甲烷磺醯氧基呱啶(5.2g,19mmol)的DMF(50mL)溶液，然後加熱到100℃反應12h。反應液冷卻後倒入飽和碳酸氫鈉水溶液中(150mL)，乙酸乙酯萃取(300mL×3)，有機相用飽和食鹽水洗，無水硫酸鈉乾燥後過濾，減壓除去溶劑後的粗產物經矽膠柱層析分離純化(石油醚/乙酸乙酯(V/V)=10/1)，得到黃色油狀物(1.1g,15.8%)。 Under ice bath, NaH (1.5g, 38mmol) was added to a solution of 5-nitroindole (3.0g, 18.3mmol) in DMF (45mL). After stirring at room temperature for 30min, 1-Boc-4-methane was added dropwise Sulfonyl pyridine (5.2g, 19mmol) in DMF (50mL) was then heated to 100°C for 12h. After cooling, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (150 mL), extracted with ethyl acetate (300 mL×3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the crude product after removing the solvent under reduced pressure was passed through a silica gel Column chromatography separated and purified (petroleum ether/ethyl acetate (V/V)=10/1) to obtain a yellow oil (1.1 g, 15.8%).

LC-MS：(pos.ion)m/z：346.4[M+1]+。 LC-MS: (pos.ion) m/z: 346.4 [M+1] + .

步驟2)4-(5-氨基-1H-吲哚-1-基)呱嗪-1-甲酸叔丁酯 Step 2) 4-(5-Amino- 1H -indol-1-yl)pyrazine-1-carboxylic acid tert-butyl ester

4-(5-硝基-1H-吲哚-1-基)呱嗪-1-甲酸叔丁酯(0.80g,2mmol)溶解在甲醇(50mL)中，加入10% Pd/C(0.10g)，然後置換氫氣，室溫下反應10h。反應液用矽藻土過濾後濃縮，矽膠柱層析分離純化(二氯甲烷/甲醇(V/V)=50/1)，得到棕色固體(0.30g,40.1%)。 4-(5-Nitro- 1H -indol-1-yl)pyrazine-1-carboxylic acid tert-butyl ester (0.80g, 2mmol) was dissolved in methanol (50mL) and 10% Pd/C (0.10g) was added ), then replace the hydrogen and react at room temperature for 10h. The reaction solution was filtered through diatomaceous earth, concentrated, and purified by silica gel column chromatography (dichloromethane/methanol (V/V)=50/1) to obtain a brown solid (0.30 g, 40.1%).

LC-MS：(pos.ion)m/z：316.3[M+1]+。 LC-MS: (pos.ion) m/z: 316.3 [M+1] + .

步驟3)4-(5-((6-溴-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)-1H-吲哚-1-基)呱嗪-1-甲酸叔丁酯 Step 3) 4-(5-((6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )Amino)-1 H -indol-1-yl)terazine-carboxylic acid tert-butyl ester

將6-溴-2-氯-8-環戊基-5-甲基-吡啶並[2,3-d]嘧啶-7(8H)-酮(170mg,0.5mmol)(參考文獻WO2003062236A1)和4-(5-氨基-1H-吲哚-1-基)呱嗪-1-甲酸叔丁酯(230mg,0.73mmol)溶解在無水DMSO(20mL)中，加入粉末狀分子篩(200mg)，然後置換氮氣，120℃下反應12h。反應 液冷卻後加入水中，二氯甲烷萃取(100mL×3)，有機相用水洗(30mL)，飽和食鹽水洗(30mL)，無水硫酸鈉乾燥，過濾，濃縮後的粗產物經矽膠柱層析分離純化(二氯甲烷/甲醇(V/V)=20/1)，得到黃色固體(0.20g,60.2%)。 6-Bromo-2-chloro-8-cyclopentyl-5-methyl-pyrido[2,3-d]pyrimidin-7(8 H )-one (170 mg, 0.5 mmol) (reference WO2003062236A1) and 4-(5-Amino- 1H -indol-1-yl)pyrazine-1-carboxylic acid tert-butyl ester (230mg, 0.73mmol) was dissolved in anhydrous DMSO (20mL), powdered molecular sieve (200mg) was added, and then Displace nitrogen and react at 120°C for 12h. After cooling, the reaction solution was added to water, extracted with dichloromethane (100 mL×3), the organic phase was washed with water (30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was separated by silica gel column chromatography Purification (dichloromethane/methanol (V/V)=20/1) gave a yellow solid (0.20 g, 60.2%).

LC-MS：(pos.ion)m/z：621.3[M+1]+。 LC-MS: (pos.ion) m/z: 621.3 [M+1] + .

步驟4)4-(5-((6-乙醯基-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)-1H-吲哚-1-基)呱嗪-1-甲酸叔丁酯 Step 4) 4-(5-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2 -Yl)amino)-1 H -indol-1-yl)pyrazine-1-carboxylic acid tert-butyl ester

將4-(5-((6-溴-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)-1H-吲哚-1-基)呱嗪-1-甲酸叔丁酯(130mg,0.21mmol)和[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(15mg,0.02mmol)溶解在正丁醇(20mL)中，加入DIPEA(0.05mL,0.30mmol)和乙烯基正丁醚(0.1mL,0.80mmol)，然後置換氮氣，95℃下反應10h。反應液減壓濃縮除去溶劑後倒入飽和碳酸氫鈉水溶液中(50mL)，二氯甲烷萃取(100mL×3)，有機相用飽和食鹽水洗(30mL)，無水硫酸鈉乾燥，過濾，濃縮過，得到黃色固體粗產物(100mg,74.6%)。 4-(5-((6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amine Yl)-1 H -indol-1-yl)pyrazine-1-carboxylic acid tert-butyl ester (130 mg, 0.21 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloride Palladium (15 mg, 0.02 mmol) was dissolved in n-butanol (20 mL), DIPEA (0.05 mL, 0.30 mmol) and vinyl n-butyl ether (0.1 mL, 0.80 mmol) were added, then nitrogen was replaced, and the reaction was performed at 95° C. for 10 h. The reaction solution was concentrated under reduced pressure to remove the solvent, then poured into saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (100 mL×3), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was obtained as a yellow solid (100 mg, 74.6%).

LC-MS：(pos.ion)m/z：641.5[M+1]+。 LC-MS: (pos.ion) m/z: 641.5 [M+1] + .

步驟5)6-乙醯基-8-環戊基-5-甲基-2-[(1-(呱啶-4-基)-1H-吲哚-5-基)氨基]-吡啶並[2,3-d]嘧啶-7(8H)-酮 Step 5) 6-Acetyl-8-cyclopentyl-5-methyl-2-[(1-(pyridin-4-yl)-1 H -indol-5-yl)amino]-pyrido [2,3-d]pyrimidin-7(8 H )-one

在4-(5-((6-乙醯基-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)-1H-吲哚-1-基)呱嗪-1-甲酸叔丁酯(100mg,0.16mmol)的二氯甲烷(20mL)溶液中加入三氟乙酸(0.06mL,0.8mmol)，加熱回流反應12h。反應液冷卻後加入飽和碳酸氫鈉水溶液(40mL)，二氯甲烷萃取(100mL×3)，有機相用飽和食鹽水洗(40mL)，無水硫酸鈉乾燥，過濾後濃縮得到的粗產物經製備型高效液相色譜分離，得到黃色固體產物(30mg,40.1%)。 In 4-(5-((6-acetoxy-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl ) Amino)-1 H -indol-1-yl)terazine-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (0.06 mL, 0.8 mmol) , Heated to reflux for 12h. After the reaction solution was cooled, saturated aqueous sodium bicarbonate solution (40 mL) was added, extracted with dichloromethane (100 mL×3), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and the crude product obtained after filtration and concentration was highly efficient Liquid chromatography separated the product as a yellow solid (30 mg, 40.1%).

LC-MS：(pos.ion)m/z：485.4[M+1]+；1H NMR(400MHz,DMSO-d 6)：δ 10.04-9.88(m,1H),8.91(s,1H),7.93(s,1H),7.52(d,J=8.8Hz,1H),7.44(d,J=3.2Hz,1H),7.32(d,J=8.4Hz,1H),6.39(d,J=2.8Hz,1H),5.85(s,1H),4.44-4.33(m,1H),3.08(d,J= 12.4Hz,2H),2.71(t,J=11.2Hz,2H),2.42(s,3H),2.30(s,3H),2.27-2.20(m,2H),2.01-1.94(m,1H),1.89(d,J=12.4Hz,2H),1.83(dd,J=11.8Hz,3.6Hz,2H),1.77-1.70(m,2H),1.56-1.47(m,2H),1.37-1.28(m,2H)。 LC-MS: (pos.ion) m/z: 485.4 [M+1] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ 10.04-9.88 (m, 1H), 8.91 (s, 1H), 7.93(s,1H),7.52(d, J =8.8Hz,1H),7.44(d, J =3.2Hz,1H),7.32(d, J =8.4Hz,1H),6.39(d, J =2.8 Hz, 1H), 5.85(s, 1H), 4.44-4.33(m, 1H), 3.08(d, J = 12.4Hz, 2H), 2.71(t, J =11.2Hz, 2H), 2.42(s, 3H ), 2.30 (s, 3H), 2.27-2.20 (m, 2H), 2.01-1.94 (m, 1H), 1.89 (d, J =12.4Hz, 2H), 1.83 (dd, J =11.8Hz, 3.6Hz , 2H), 1.77-1.70 (m, 2H), 1.56-1.47 (m, 2H), 1.37-1.28 (m, 2H).

實施例2 Example 2 6-乙醯基-8-環戊基-5-甲基-2-[[7-(1,2,3,6-四氫吡啶-4-基)噻吩並[3,2-d]嘧啶-4-基]胺基]吡啶並[2,3-d]嘧啶-7(8H)-酮6-Acetyl-8-cyclopentyl-5-methyl-2-[[7-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-d]pyrimidine -4-yl]amino]pyrido[2,3-d]pyrimidin-7(8 H )-one

Figure 104141541-A0101-12-0088-134
Figure 104141541-A0101-12-0088-134

步驟1)4-(4-氨基噻吩並[3,2-d]嘧啶-7-基)-5,6-二氫-1(2H)-吡啶叔丁基碳酸酯 Step 1) 4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-5,6-dihydro-1(2 H )-pyridine tert-butyl carbonate

在4-胺基-7-溴噻吩並[3,2-d]嘧啶(50mg,0.21mmol)和N-Boc-3,4-二氫-2H-吡啶-4-硼酸頻哪醇酯(100mg,0.32mmol)的1,4-二氧六環(10mL)溶液中加入碳酸鈉(72mg,0.68mmol)和雙(三苯基膦)二氯化鈀(16mg,0.023mmol)。置換N2，攪拌加熱至110℃反應。加入二氯甲烷(100mL)稀釋，再加入飽和食鹽水(20mL)洗滌，分液，無水硫酸鈉乾燥有機相，過濾，減壓濃縮溶劑，柱層析分離(石油醚/乙酸乙酯(v/v)=1/1)，得到黃色固體(68mg,94%)。 4-amino-7-bromothieno[3,2-d]pyrimidine (50mg, 0.21mmol) and N-Boc-3,4-dihydro- 2H -pyridine-4-boronic acid pinacol ester ( To a solution of 100 mg, 0.32 mmol) in 1,4-dioxane (10 mL) was added sodium carbonate (72 mg, 0.68 mmol) and bis(triphenylphosphine) palladium dichloride (16 mg, 0.023 mmol). Displace N 2 , stir and heat to 110° C. to react. Dichloromethane (100 mL) was added for dilution, and then saturated brine (20 mL) was added for washing, liquid separation, and the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was concentrated under reduced pressure, and separated by column chromatography (petroleum ether/ethyl acetate (v/ v)=1/1) to obtain a yellow solid (68 mg, 94%).

LC-MS：(pos.ion)m/z：333.0[M+1]+。 LC-MS: (pos.ion) m/z: 333.0 [M+1] + .

步驟2)6-(1-乙氧基乙烯)-8-環戊基-5-甲基-2-氯-8H-吡啶並[2,3-d]嘧啶-7-酮 Step 2) 6- (1-ethoxy-vinyl) -8-cyclopentyl-5-methyl-2-chloro -8 H - pyrido [2,3-d] pyrimidin-7-one

將化合物6-溴-8-環戊基-5-甲基-2-氯-8H-吡啶並[2,3-d]嘧啶-7-酮(1.00g,2.9mmol)溶解在40mL甲苯中，依次加入三丁基(1-乙氧基乙烯)錫(1.05g,2.9mmol)和四(三苯基膦)鈀(0.30g,0.26mmol)，混合物加熱到115℃反應4h，過濾，減壓除去溶劑。濃縮液經柱層析(石油醚/乙酸乙酯(V/V)=5/1)分離，得到白色固體(614mg,62.8%)。 The compound 6-bromo-8-cyclopentyl-5-methyl-2-chloro -8 H - pyrido [2,3-d] pyrimidin-7-one (1.00g, 2.9mmol) was dissolved in 40mL of toluene , Add tributyl (1-ethoxyethylene) tin (1.05g, 2.9mmol) and tetrakis (triphenylphosphine) palladium (0.30g, 0.26mmol) in succession, the mixture was heated to 115 ℃ for 4h, filtered, reduced Remove the solvent by pressing. The concentrated solution was separated by column chromatography (petroleum ether/ethyl acetate (V/V)=5/1) to obtain a white solid (614 mg, 62.8%).

LC-MS：(pos.ion)m/z：334.2[M+1]+。 LC-MS: (pos.ion) m/z: 334.2 [M+1] + .

步驟3)6-(1-乙醯基)-2-氯-8-環戊基-5-甲基-吡啶並[2,3-d]嘧啶-7(8H)-酮 Step 3) 6-(1-Acetyl)-2-chloro-8-cyclopentyl-5-methyl-pyrido[2,3-d]pyrimidin-7(8 H )-one

將6-(1-乙氧基乙烯)-8-環戊基-5-甲基-2-氯-8H-吡啶並[2,3-d]嘧啶-7-酮(614mg,1.84mmol)溶解在二氯甲烷中，加入TFA(1.4mL,18.4mmol)，加熱至50℃攪拌3h，反應完全，減壓除去溶劑。濃縮液經柱層析(石油醚/乙酸乙酯(V/V)=5/1)分離，得到白色固體(334mg,61.2%)。 6- (1-ethoxy-vinyl) -8-cyclopentyl-5-methyl-2-chloro -8 H - pyrido [2,3-d] pyrimidin-7-one (614mg, 1.84mmol) Dissolved in dichloromethane, added TFA (1.4mL, 18.4mmol), heated to 50 °C and stirred for 3h, the reaction was complete, the solvent was removed under reduced pressure. The concentrated solution was separated by column chromatography (petroleum ether/ethyl acetate (V/V)=5/1) to obtain a white solid (334 mg, 61.2%).

LC-MS：(pos.ion)m/z：306.2[M+1]+。 LC-MS: (pos.ion) m/z: 306.2 [M+1] + .

步驟4)4-[4-[(6-乙醯基-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺]噻吩[3,2-d]嘧啶-7-基]-5,6-二氫-2H-吡啶-1-叔丁基甲酸酯 Step 4) 4-[4-[(6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2 -Yl)amine]thiophene[3,2-d]pyrimidin-7-yl]-5,6-dihydro- 2H -pyridine-1-tert-butylformate

氮氣保護下將6-(1-乙醯基)-2-氯-8-環戊基-5-甲基-吡啶並[2,3-d]嘧啶-7(8H)-酮(65mg,0.21mmol)、4-(4-氨基噻吩並[3,2-d]嘧啶-7-基)-5,6-二氫-1(2H)-吡啶叔丁基碳酸酯(68mg,0.20mmol)、1,1'-雙(二苯基膦)二茂鐵二氯化鈀(16mg,0.022mmol)和叔丁醇鉀(50mg,0.42mmol)溶於甲苯(10mL)，加熱至110℃反應6h。停止反應，加入二氯甲烷(100mL)稀釋，矽藻土過濾。濾液減壓除去溶劑，柱層析分離(石油醚/乙酸乙酯(v/v)=1/1)，得到黃色固體(16mg,13%)。 Under nitrogen protection, 6-(1-acetyl)-2-chloro-8-cyclopentyl-5-methyl-pyrido[2,3-d]pyrimidin-7(8 H )-one (65 mg, 0.21mmol), 4-(4-aminothieno[3,2-d]pyrimidin-7-yl)-5,6-dihydro-1( 2H )-pyridine tert-butyl carbonate (68mg, 0.20mmol ), 1,1'-bis (diphenylphosphine) ferrocene palladium dichloride (16mg, 0.022mmol) and potassium tert-butoxide (50mg, 0.42mmol) dissolved in toluene (10mL), heated to 110 ℃ reaction 6h. The reaction was stopped, diluted with dichloromethane (100 mL), and filtered through celite. The filtrate was freed from the solvent under reduced pressure and separated by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain a yellow solid (16 mg, 13%).

LC-MS：(pos.ion)m/z：602.3[M+1]+。 LC-MS: (pos.ion) m/z: 602.3 [M+1] + .

步驟5)6-乙醯基-8-環戊基-5-甲基-2-[[7-(1,2,3,6-四氫吡啶-4-基)噻吩並[3,2-d]嘧啶-4-基]胺基]吡啶並[2,3-d]嘧啶-7(8H)-酮 Step 5) 6-Acetyl-8-cyclopentyl-5-methyl-2-[[7-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2- d]pyrimidin-4-yl]amino]pyrido[2,3-d]pyrimidin-7(8 H )-one

將4-[4-[(6-乙醯基-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺]噻吩[3,2-d]嘧啶-7-基]-5,6-二氫-2H-吡啶-1-叔丁基甲酸酯(309mg,0.51mmol)溶於二氯甲烷(20mL)，加入三氟乙酸(0.8mL,10mmol)，加熱至回流反應3h。停止反應，冷卻至室溫，加入飽和碳酸氫鈉水溶液(10mL)中和，分液，無水硫酸鈉乾燥有機相，過濾，減壓除去溶劑，得到粗產品，再經過柱層析分離(二氯甲烷/甲醇(v/v)=10/1)，得到黃色固體(126mg,48.9%)。 4-[4-[(6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )Amine]thiophene[3,2-d]pyrimidin-7-yl]-5,6-dihydro- 2H -pyridine-1-tert-butylformate (309mg, 0.51mmol) dissolved in dichloromethane (20mL) , Add trifluoroacetic acid (0.8mL, 10mmol), heated to reflux for 3h. Stop the reaction, cool to room temperature, add saturated aqueous sodium bicarbonate solution (10 mL) to neutralize, separate the layers, dry the organic phase over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to obtain the crude product, which is then separated by column chromatography (dichloromethane Methane/methanol (v/v)=10/1) to obtain a yellow solid (126 mg, 48.9%).

LC-MS：(pos.ion)m/z：502.3[M+1]+；1H NMR(600MHz,DMSO-d 6 )δ 11.32(s,1H),9.13(d,J=9.8Hz,1H),8.97(s,1H),8.92(s,1H),8.38-8.31(m,1H),7.41(s,1H),5.69(dt,J=17.1,8.6 Hz,1H),3.88(s,2H),3.17(m,2H),2.83(s,2H),2.46-2.40(m,3H),2.35(d,J=17.4Hz,3H),2.24-2.15(m,2H),1.77-1.63(m,4H),1.40(d,J=4.4Hz,2H)。 LC-MS: (pos.ion) m/z: 502.3 [M+1] + ; 1 H NMR (600 MHz, DMSO- d 6 ) δ 11.32 (s, 1H), 9.13 (d, J = 9.8 Hz, 1H ), 8.97 (s, 1H), 8.92 (s, 1H), 8.38-8.31 (m, 1H), 7.41 (s, 1H), 5.69 (dt, J =17.1, 8.6 Hz, 1H), 3.88 (s, 2H), 3.17(m, 2H), 2.83(s, 2H), 2.46-2.40(m, 3H), 2.35(d, J =17.4Hz, 3H), 2.24-2.15(m, 2H), 1.77-1.63 (m, 4H), 1.40 (d, J = 4.4Hz, 2H).

實施例3 Example 3 6-乙醯基-8-環戊基-5-甲基-2-((5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮6-acetoyl-8-cyclopentyl-5-methyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)pyrido[2, 3-d]pyrimidin-7(8 H )-one

Figure 104141541-A0101-12-0090-135
Figure 104141541-A0101-12-0090-135

步驟1)2-((6-乙醯基-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)氨基)-7,8-二氫-1,6-萘啶-6(5H)-甲酸叔丁酯 Step 1) 2-((6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) Amino)-7,8-dihydro-1,6-naphthyridine-6(5 H )-carboxylic acid tert-butyl ester

氮氣保護下將6-(1-乙醯基)-2-氯-8-環戊基-5-甲基-吡啶並[2,3-d]嘧啶-7(8H)-酮(502mg,1.64mmol)、2-氨基-7,8-二氫-1,6-萘啶-6(5H)-甲酸叔丁酯(329mg,1.32mmol)、1,1'-雙(二苯基膦)二茂鐵二氯化鈀(97mg,0.13mmol)和叔丁醇鉀(308mg,2.61mmol)溶於甲苯(30mL)，加熱至110℃反應4h。停止反應，加入二氯甲烷(100mL)稀釋，矽藻土過濾。濾液減壓除去溶劑，柱層析分離(石油醚/乙酸乙酯(v/v)=1/1)，得到黃色固體(189mg,27.6%)。 Under nitrogen protection, 6-(1-acetyl)-2-chloro-8-cyclopentyl-5-methyl-pyrido[2,3-d]pyrimidin-7(8 H )-one (502 mg, 1.64mmol), 2-amino-7,8-dihydro-1,6-naphthyridine-6( 5H )-carboxylic acid tert-butyl ester (329mg, 1.32mmol), 1,1'-bis(diphenylphosphine ) Ferrocene palladium dichloride (97mg, 0.13mmol) and potassium tert-butoxide (308mg, 2.61mmol) were dissolved in toluene (30mL), heated to 110 ℃ for 4h. The reaction was stopped, diluted with dichloromethane (100 mL), and filtered through celite. The filtrate was freed from the solvent under reduced pressure and separated by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain a yellow solid (189 mg, 27.6%).

LC-MS：(pos.ion)m/z：519.5[M+1]+。 LC-MS: (pos.ion) m/z: 519.5 [M+1] + .

步驟2)6-乙醯基-8-環戊基-5-甲基-2-((5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮 Step 2) 6-Acetyl-8-cyclopentyl-5-methyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)pyrido [2,3-d]pyrimidin-7(8 H )-one

在100mL單口燒瓶中，將2-((6-乙醯基-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)氨基)-7,8-二氫-1,6-萘啶-6(5H)-甲酸叔丁酯(52mg,0.1mmol)溶於甲醇(10mL)中，在冰浴條件下加入氯化氫/甲醇溶液(30%,15mL)，攪拌30min，然後緩慢升至室溫攪拌3h。減壓蒸除溶劑，冰浴下加入三乙胺(10mL)攪拌1h，減壓蒸除有機溶劑，粗產品經柱層析分離(二氯甲烷/甲醇(V/V)=10/1)，得到淡黃色固體(33mg,79.7%)。 In a 100 mL single-necked flask, place 2-((6-acetoxy-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine- 2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5 H )-carboxylic acid tert-butyl ester (52 mg, 0.1 mmol) was dissolved in methanol (10 mL) under ice bath conditions Hydrogen chloride/methanol solution (30%, 15mL) was added, stirred for 30min, then slowly raised to room temperature and stirred for 3h. The solvent was distilled off under reduced pressure, triethylamine (10 mL) was added under ice bath and stirred for 1 h, the organic solvent was distilled off under reduced pressure, and the crude product was separated by column chromatography (dichloromethane/methanol (V/V)=10/1), A light yellow solid was obtained (33 mg, 79.7%).

LC-MS：(pos.ion)m/z：419.6[M+1]+； 1H NMR(400MHz,DMSO-d 6)δ 10.42(s,1H),9.01(s,1H),7.97(d,J=8.5Hz,1H),7.70(d,J=8.6Hz,1H),5.95-5.79(m,1H),4.30(s,2H),3.51(m,2H),3.02(t,J=6.1Hz,2H),2.43(s,3H),2.33(s,3H),2.30-2.21(m,2H),1.96(s,3H),1.86-1.74(m,2H),1.66-1.56(m,2H)。 LC-MS: (pos.ion) m/z: 419.6 [M+1] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.42 (s, 1H), 9.01 (s, 1H), 7.97 (d , J = 8.5Hz, 1H), 7.70 (d, J = 8.6Hz, 1H), 5.95-5.79 (m, 1H), 4.30 (s, 2H), 3.51 (m, 2H), 3.02 (t, J = 6.1Hz, 2H), 2.43(s, 3H), 2.33(s, 3H), 2.30-2.21(m, 2H), 1.96(s, 3H), 1.86-1.74(m, 2H), 1.66-1.56(m , 2H).

實施例4 Example 4 6-乙醯基-8-環戊基-2-((6-(2-羥基乙醯基)-5,6,7,8-四氫-1,6-萘啶-2-基)氨基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮6-Acetyl-8-cyclopentyl-2-((6-(2-hydroxyacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino )-5-methylpyrido[2,3-d]pyrimidin-7(8 H )-one

Figure 104141541-A0101-12-0091-139
Figure 104141541-A0101-12-0091-139

往羥基乙酸(119mg,1.56mmol)的N,N-二甲基甲醯胺(20mL,258mmol,99.9mass%)溶液中加入HATU(612mg,1.56mmol)和DIPEA(0.30mL,1.8mmol)，攪拌10min後，加入6-乙醯基-8-環戊基-5-甲基-2-((5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮(669mg,1.60mmol)，室溫攪拌反應10h。停止反應，減壓濃縮，濃縮液進行柱層析分離(二氯甲烷/甲醇(v/v)=20/1)，得到黃色固體(207mg,27.9%)。 To a solution of glycolic acid (119 mg, 1.56 mmol) in N,N-dimethylformamide (20 mL, 258 mmol, 99.9 mass%) was added HATU (612 mg, 1.56 mmol) and DIPEA (0.30 mL, 1.8 mmol) and stirred After 10 min, add 6-acetoxy-8-cyclopentyl-5-methyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)pyridine and [2,3-d] pyrimidin -7 (8 H) - one (669mg, 1.60mmol), the reaction was stirred at room temperature 10h. The reaction was stopped, concentrated under reduced pressure, and the concentrated liquid was subjected to column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain a yellow solid (207 mg, 27.9%).

LC-MS：(pos.ion)m/z：477.5[M+1]+；1H NMR(600MHz,DMSO-d 6)δ 10.32(d,J=12.1Hz,1H),9.00(s,1H),7.95-7.89(m,1H),7.66(dd,J=34.7,8.3Hz,1H),5.86(dt,J=17.8,8.8Hz,1H),4.74-4.54(m,4H),4.21(dd,J=20.6,5.1Hz,2H),3.82(s,1H),3.69(d,J=5.4Hz,2H),2.43(s,3H),2.32(s,3H),2.26(s,2H),1.94(s,2H),1.78(dd,J=18.1,14.5Hz,2H),1.65-1.56(m,2H)。 LC-MS: (pos.ion) m/z: 477.5 [M+1] + ; 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.32 (d, J =12.1 Hz, 1H), 9.00 (s, 1H ), 7.95-7.89 (m, 1H), 7.66 (dd, J = 34.7, 8.3 Hz, 1H), 5.86 (dt, J = 17.8, 8.8 Hz, 1H), 4.74-4.54 (m, 4H), 4.21 ( dd, J = 20.6, 5.1Hz, 2H), 3.82(s, 1H), 3.69(d, J = 5.4Hz, 2H), 2.43(s, 3H), 2.32(s, 3H), 2.26(s, 2H ), 1.94 (s, 2H), 1.78 (dd, J =18.1, 14.5 Hz, 2H), 1.65-1.56 (m, 2H).

實施例5 Example 5 6-乙醯基-8-環戊基-5-甲基-2-((6-(3,3,3-三氟丙基)-5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮6-acetoyl-8-cyclopentyl-5-methyl-2-((6-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro-1,6 -Naphthyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8 H )-one

Figure 104141541-A0101-12-0092-204
Figure 104141541-A0101-12-0092-204

在100mL單口燒瓶中，將6-乙醯基-8-環戊基-5-甲基-2-((5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮(419mg,1.0mmol)溶於二氯甲烷(40mL)中，在冰浴條件下加入3,3,3-三氟丙醛(56mg,1.2mmol)和氰基硼氫化鈉(91mg,1.2mmol)，攪拌30min，然後緩慢升至室溫攪拌6h。減壓蒸除有機溶劑，向殘餘物中加入二氯甲烷(100mL)和水(100mL)，有機層用飽和碳酸氫鈉溶液(80mL×3)、飽和食鹽水洗滌(80mL×1)，有機層用無水硫酸鈉乾燥並濃縮。殘物進行柱層析分離(二氯甲烷/甲醇(V/V)=10/1)，得到淡黃色固體(243mg,47.44%)。 In a 100mL single-necked flask, place 6-acetyl-8-cyclopentyl-5-methyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl) Amino)pyrido[2,3-d]pyrimidin-7(8 H )-one (419 mg, 1.0 mmol) was dissolved in dichloromethane (40 mL), and 3,3,3-trifluoro was added under ice bath conditions Propionaldehyde (56 mg, 1.2 mmol) and sodium cyanoborohydride (91 mg, 1.2 mmol) were stirred for 30 min, then slowly raised to room temperature and stirred for 6 h. The organic solvent was distilled off under reduced pressure, dichloromethane (100 mL) and water (100 mL) were added to the residue, the organic layer was washed with saturated sodium bicarbonate solution (80 mL×3), saturated brine (80 mL×1), organic layer Dry over anhydrous sodium sulfate and concentrate. The residue was subjected to column chromatography (dichloromethane/methanol (V/V)=10/1) to obtain a pale yellow solid (243 mg, 47.44%).

MS-ESI：(ESI,pos.ion)m/z：515.3[M+1]+；1H NMR(600MHz,CDCl3)δ 8.87(s,1H),8.34(s,1H),8.13(d,J=8.4Hz,1H),7.42(d,J=8.5Hz,1H),5.93-5.84(m,1H),3.70-3.64(m,2H),3.00(t,J=5.7Hz,2H),2.90(t,J=5.9Hz,2H),2.88-2.82(m,2H),2.57(s,3H),2.46(dt,J=10.5,9.2Hz,2H),2.40(s,3H),2.37(dd,J=13.3,5.5Hz,2H),2.09(dt,J=13.5,6.9Hz,2H),1.94-1.85(m,2H),1.74-1.68(m,2H)。 MS-ESI: (ESI, pos.ion) m/z: 515.3 [M+1] + ; 1 H NMR (600 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.34 (s, 1H), 8.13 (d , J = 8.4Hz, 1H), 7.42 (d, J = 8.5Hz, 1H), 5.93-5.84 (m, 1H), 3.70-3.64 (m, 2H), 3.00 (t, J = 5.7Hz, 2H) , 2.90 (t, J = 5.9 Hz, 2H), 2.88-2.82 (m, 2H), 2.57 (s, 3H), 2.46 (dt, J =10.5, 9.2 Hz, 2H), 2.40 (s, 3H), 2.37 (dd, J =13.3, 5.5Hz, 2H), 2.09 (dt, J =13.5, 6.9Hz, 2H), 1.94-1.85 (m, 2H), 1.74-1.68 (m, 2H).

實施例6 Example 6 6-乙醯基-8-環戊基-5-甲基-2-((6-乙醯基-5,6,7,8-四氫-1,6-萘啶-2-基)氨基)-吡啶並[2,3-d]嘧啶-7(8H)-酮6-Acetyl-8-cyclopentyl-5-methyl-2-((6-acetoyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino )-Pyrido[2,3-d]pyrimidin-7(8 H )-one

Figure 104141541-A0101-12-0092-141
Figure 104141541-A0101-12-0092-141

在乙酸(30.8mg,0.51mmol)的N,N-二甲基甲醯胺(15mL)溶液中加入HATU(172mg,0.44mmol)和N,N-二異丙基乙胺(0.10mL,0.59mmol)，攪拌10min後，加入6-乙醯基-8-環戊基-5-甲基-2-((5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮(171mg,0.41mmol)，室溫攪 拌反應6h。停止反應，減壓除去溶劑，加入矽膠拌樣，柱層析分離(二氯甲烷/甲醇(v/v)=10/1)，得到黃色固體(143mg,76.3%)。 To a solution of acetic acid (30.8 mg, 0.51 mmol) in N,N-dimethylformamide (15 mL) was added HATU (172 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.59 mmol) ), after stirring for 10 min, add 6-acetoyl-8-cyclopentyl-5-methyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl) Amino)pyrido[2,3-d]pyrimidin-7(8 H )-one (171 mg, 0.41 mmol), and the reaction was stirred at room temperature for 6 h. The reaction was stopped, the solvent was removed under reduced pressure, silica gel was added for sample preparation, and column chromatography (dichloromethane/methanol (v/v)=10/1) was obtained to obtain a yellow solid (143 mg, 76.3%).

LC-MS：(pos.ion)m/z：461.5[M+1]+；1H NMR(600MHz,CDCl3)δ 8.84(d,J=4.3Hz,1H),8.20(dd,J=13.4,8.6Hz,1H),8.12(s,1H),7.49(dd,J=15.7,8.5Hz,1H),5.94-5.79(m,1H),4.75(s,1H),3.94(t,J=5.9Hz,1H),3.80(t,J=5.9Hz,1H),3.71(s,1H),2.99(t,J=5.7Hz,1H),2.93(t,J=5.7Hz,1H),2.54(d,J=8.6Hz,3H),2.38(d,J=8.7Hz,3H),2.36(s,2H),2.22(d,J=7.9Hz,3H),2.08(s,2H),1.91-1.85(m,2H),1.70(m,2H)。 LC-MS: (pos.ion) m/z: 461.5 [M+1] + ; 1 H NMR (600 MHz, CDCl 3 ) δ 8.84 (d, J =4.3 Hz, 1H), 8.20 (dd, J =13.4 , 8.6Hz, 1H), 8.12(s, 1H), 7.49(dd, J =15.7, 8.5Hz, 1H), 5.94-5.79(m, 1H), 4.75(s, 1H), 3.94(t, J = 5.9Hz, 1H), 3.80(t, J =5.9Hz, 1H), 3.71(s, 1H), 2.99(t, J =5.7Hz, 1H), 2.93(t, J =5.7Hz, 1H), 2.54 (d, J =8.6 Hz, 3H), 2.38 (d, J = 8.7 Hz, 3H), 2.36 (s, 2H), 2.22 (d, J = 7.9 Hz, 3H), 2.08 (s, 2H), 1.91 -1.85(m,2H), 1.70(m,2H).

實施例7 Example 7 6-乙醯基-8-環戊基-5-甲基-2-((6-乙基-5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮6-acetoyl-8-cyclopentyl-5-methyl-2-((6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino) Pyrido[2,3-d]pyrimidin-7(8 H )-one

Figure 104141541-A0101-12-0093-142
Figure 104141541-A0101-12-0093-142

將6-乙醯基-8-環戊基-5-甲基-2-((5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮(213mg,0.51mmol)溶解在N,N-二甲基甲醯胺(15mL)溶液中，加入碘乙烷(119mg,0.76mmol)和碳酸鉀(141mg,1.02mmol)，室溫攪拌，停止反應，減壓除去溶劑，加入矽膠拌樣，柱層析分離(二氯甲烷/甲醇(v/v)=10/1)，得到黃色固體(199mg,87.4%)。 6-Acetyl-8-cyclopentyl-5-methyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)pyrido[2 ,3-d]pyrimidin-7(8 H )-one (213 mg, 0.51 mmol) was dissolved in a solution of N,N-dimethylformamide (15 mL), and ethyl iodide (119 mg, 0.76 mmol) and carbonic acid were added Potassium (141mg, 1.02mmol), stirred at room temperature, the reaction was stopped, the solvent was removed under reduced pressure, silica gel was added for sample preparation, and column chromatography was separated (dichloromethane/methanol (v/v)=10/1) to obtain a yellow solid ( 199mg, 87.4%).

LC-MS：(pos.ion)m/z：447.5[M+1]+；1H NMR(600MHz,CDCl3)δ 8.85(s,1H),8.20--8.10(m,2H),7.42(d,J=8.5Hz,1H),5.86(dt,J=17.9,8.9Hz,1H),3.76(s,2H),3.05(d,J=18.7Hz,2H),3.04(s,2H),2.78(d,J=5.4Hz,3H),2.58(d,J=11.5Hz,3H),2.42--2.38(m,2H),2.38--2.32(m,2H),2.08(dd,J=12.7,8.9Hz,2H),1.89(dd,J=12.1,8.4Hz,2H),1.82--1.74(m,2H),1.30(d,J=5.5Hz,3H)。 LC-MS: (pos.ion) m/z: 447.5 [M+1] + ; 1 H NMR (600 MHz, CDCl 3 ) δ 8.85 (s, 1H), 8.20--8.10 (m, 2H), 7.42 ( d, J =8.5Hz,1H),5.86(dt, J =17.9,8.9Hz,1H),3.76(s,2H),3.05(d, J =18.7Hz,2H),3.04(s,2H), 2.78(d, J =5.4Hz,3H), 2.58(d, J =11.5Hz,3H),2.42--2.38(m,2H),2.38--2.32(m,2H),2.08(dd, J = 12.7, 8.9Hz, 2H), 1.89 (dd, J = 12.1, 8.4Hz, 2H), 1.82--1.74 (m, 2H), 1.30 (d, J = 5.5Hz, 3H).

實施例8-38Examples 8-38

通過用相應的起始原料重複實施例1或2所述的操作方法獲 得下列化合物：

Figure 104141541-A0101-12-0094-206
Figure 104141541-A0101-12-0095-143
Figure 104141541-A0101-12-0096-208
Figure 104141541-A0101-12-0097-207
Figure 104141541-A0101-12-0098-146
 By repeating the procedure described in Example 1 or 2 with the corresponding starting materials, the following compounds were obtained:
Figure 104141541-A0101-12-0094-206
Figure 104141541-A0101-12-0095-143
Figure 104141541-A0101-12-0096-208
Figure 104141541-A0101-12-0097-207
Figure 104141541-A0101-12-0098-146

實施例39 6-乙醯基-8-環戊基-5-甲基-2-[[6-(呱啶-4-基)-5,6,,7,8-四氫-1,6-萘啶-2-基]胺基]吡啶並[2,3-d]嘧啶-7(8H)-酮Example 39 6-Acetyl-8-cyclopentyl-5-methyl-2-[[6-(pyridin-4-yl)-5,6,,7,8-tetrahydro-1,6 -Naphthyridin-2-yl]amino]pyrido[2,3-d]pyrimidin-7(8 H )-one

Figure 104141541-A0101-12-0098-147
Figure 104141541-A0101-12-0098-147

步驟1)4-[2-[(6-乙醯基-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基]-7,8-二氫-1,6-萘啶-6(5H)-基]呱啶-1-甲酸叔丁酯 Step 1) 4-[2-[(6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2 -Yl)amino]-7,8-dihydro-1,6-naphthyridine-6(5H)-yl]pyridine-1-carboxylic acid tert-butyl ester

將6-乙醯基-8-環戊基-5-甲基-2-((5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮(294mg,0.70mmol)和N-叔丁氧羰基-4-呱啶酮(158mg,0.79mmol)溶於DMF(20mL)，攪拌10min後，再加入氰基硼氫化鈉(62.6mg,0.86mmol)，室溫下攪拌反應。LC-MS顯示有產物生成，停止反應，加入矽膠拌樣，減壓除去溶劑，柱層析分離(二氯甲烷/甲醇(v/v)=10/1)，得到黃色化合物(222mg,52.5%)。 6-Acetyl-8-cyclopentyl-5-methyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)pyrido[2 ,3-d]pyrimidin-7(8H)-one (294mg, 0.70mmol) and N-tert-butoxycarbonyl-4-pyridone (158mg, 0.79mmol) were dissolved in DMF (20mL), stirred for 10min, then Sodium cyanoborohydride (62.6 mg, 0.86 mmol) was added, and the reaction was stirred at room temperature. LC-MS showed product formation, stop the reaction, add silica gel to mix the sample, remove the solvent under reduced pressure, and separate by column chromatography (dichloromethane/methanol (v/v)=10/1) to obtain a yellow compound (222mg, 52.5% ).

LC-MS：(pos.ion)m/z：602.6[M+1]+。 LC-MS: (pos.ion) m/z: 602.6 [M+1] + .

步驟2)6-乙醯基-8-環戊基-5-甲基-2-[[6-(呱啶-4-基)-5,6,,7,8-四氫-1,6-萘啶-2-基]胺基]吡啶並[2,3-d]嘧啶-7(8H)-酮 Step 2) 6-Acetyl-8-cyclopentyl-5-methyl-2-[(6-(pyridin-4-yl)-5,6,,7,8-tetrahydro-1,6 -Naphthyridin-2-yl]amino]pyrido[2,3-d]pyrimidin-7(8 H )-one

將4-[2-[(6-乙醯基-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基]-7,8-二氫-1,6-萘啶-6(5H)-基]呱啶-1-甲酸叔丁酯(222mg,0.37mmol)溶於DCM(10mL)，加入TFA(2mL,25.8mmol)，室溫攪拌反應。反應完全後，減壓除去溶劑，柱層析分離(二氯甲烷/甲醇(v/v)=20/1)，得到黃色固體(160mg,86.5%)。 4-[2-[(6-acetoxy-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )Amino]-7,8-dihydro-1,6-naphthyridine-6(5H)-yl]pyridine-1-carboxylic acid tert-butyl ester (222mg, 0.37mmol) was dissolved in DCM (10mL), TFA was added (2mL, 25.8mmol), stir the reaction at room temperature. After the reaction was completed, the solvent was removed under reduced pressure and separated by column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain a yellow solid (160 mg, 86.5%).

LC-MS：(pos.ion)m/z：502.7[M+1]+；1H NMR(400MHz,CDCl3)δ：10.16(s,1H),8.86(s,1H),8.27(s,1H), 8.14(d,J=8.4Hz,1H),7.38(d,J=8.4Hz,1H),5.86-5.84(m,1H),3.78(s,2H),3.11(d,J=11.2Hz,2H),2.96(s,4H),2.64-2.58(m,1H),2.56(s,3H),2.43(s,3H),2.39(s,3H),2.08(s,3H),1.97(d,J=11.6Hz,2H),1.92-1.82(m,4H),1.76-1.67(m,2H)。 LC-MS: (pos.ion) m/z: 502.7 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ) δ: 10.16 (s, 1H), 8.86 (s, 1H), 8.27 (s, 1H), 8.14(d,J=8.4Hz,1H),7.38(d,J=8.4Hz,1H),5.86-5.84(m,1H),3.78(s,2H),3.11(d,J=11.2 Hz, 2H), 2.96 (s, 4H), 2.64-2.58 (m, 1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 2.08 (s, 3H), 1.97 (d, J=11.6Hz, 2H), 1.92-1.82(m, 4H), 1.76-1.67(m, 2H).

實施例40 6-乙醯基-8-環戊基-5-甲基-2-[[6-(1-甲基-4-呱啶基)-5,6,7,8-四氫-1,6-萘啶-2-基]胺基]吡啶並[2,3-d]嘧啶-7(8H)-酮Example 40 6-Acetyl-8-cyclopentyl-5-methyl-2-[[6-(1-methyl-4-pyridyl)-5,6,7,8-tetrahydro- 1,6-naphthyridin-2-yl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one

Figure 104141541-A0101-12-0099-148
Figure 104141541-A0101-12-0099-148

將6-乙醯基-8-環戊基-5-甲基-2-[[6-(呱啶-4-基)-5,6,,7,8-四氫-1,6-萘啶-2-基]胺基]吡啶並[2,3-d]嘧啶-7(8H)-酮(98mg,0.20mmol)和甲醛溶液(25mg,0.31mmol)溶於DMF(20mL)，攪拌10min後，再加入三乙醯氧基硼氫化鈉(53mg,0.24mmol)，室溫下攪拌反應。反應完全後，減壓除去溶劑，柱層析分離(二氯甲烷/甲醇(v/v)=10/1)，得到黃色固體(52.6g,52%)。 The 6-acetoyl-8-cyclopentyl-5-methyl-2-[[6-(pyridin-4-yl)-5,6,,7,8-tetrahydro-1,6-naphthalene Pyridin-2-yl]amino]pyrido[2,3-d]pyrimidin-7(8 H )-one (98 mg, 0.20 mmol) and formaldehyde solution (25 mg, 0.31 mmol) were dissolved in DMF (20 mL) and stirred After 10 min, sodium triethoxyborohydride (53 mg, 0.24 mmol) was added, and the reaction was stirred at room temperature. After the reaction was completed, the solvent was removed under reduced pressure, and column chromatography (dichloromethane/methanol (v/v)=10/1) was obtained to obtain a yellow solid (52.6 g, 52%).

LC-MS：(pos.ion)m/z：516.7[M+1]+；1H NMR(400MHz,CDCl3)δ 8.87(s,1H),8.29(s,1H),8.10(d,J=8.4Hz,1H),7.41(d,J=8.4Hz,1H),5.97-5.78(m,1H),3.78(s,2H),3.12(d,J=11.2Hz,2H),2.96(s,4H),2.64-2.58(m,1H),2.56(s,3H),2.43(s,3H),2.39(s,3H),2.25(s,3H),2.08(s,3H),1.97(d,J=11.6Hz,2H),1.92-1.82(m,4H),1.76-1.67(m,2H)。 LC-MS: (pos.ion) m/z: 516.7 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.29 (s, 1H), 8.10 (d, J =8.4Hz, 1H), 7.41(d, J=8.4Hz, 1H), 5.97-5.78(m, 1H), 3.78(s, 2H), 3.12(d, J=11.2Hz, 2H), 2.96(s , 4H), 2.64-2.58 (m, 1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H), 1.97 ( d, J=11.6Hz, 2H), 1.92-1.82 (m, 4H), 1.76-1.67 (m, 2H).

實施例41 6-乙醯基-8-環戊基-5-甲基-2-[[6-(氧雜環丁烷-3-基)-7,8-二氫-5H5,6,7,8-四氫-1,6-萘啶-2-基]氨基]吡啶並[2,3-d]嘧啶-7(8H)-酮Example 41 6-Acetyl-8-cyclopentyl-5-methyl-2-[[6-(oxetan-3-yl)-7,8-dihydro-5H5,6,7 ,8-tetrahydro-1,6-naphthyridin-2-yl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one

Figure 104141541-A0101-12-0099-149
Figure 104141541-A0101-12-0099-149

將6-乙醯基-8-環戊基-5-甲基-2-((5,6,7,8-四氫-1,6-萘啶-2- 基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮(109mg,0.26mmol)和3-氧雜環丁酮(25.6g,0.36mmol)溶於DMF(20mL)，攪拌10min後，再加入氰基硼氫化鈉(24.1mg,0.29mmol).室溫下攪拌反應。反應完全後，減壓除去溶劑，柱層析(二氯甲烷/甲醇(v/v)=10/1)分離，得到黃色固體(56.5mg,45.7%)。 The 6-acetoyl-8-cyclopentyl-5-methyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridine-2- Group) amino) pyrido[2,3-d]pyrimidin-7(8H)-one (109mg, 0.26mmol) and 3-oxetanone (25.6g, 0.36mmol) dissolved in DMF (20mL), stirred After 10 min, sodium cyanoborohydride (24.1 mg, 0.29 mmol) was added. The reaction was stirred at room temperature. After the reaction was completed, the solvent was removed under reduced pressure, and column chromatography (dichloromethane/methanol (v/v)=10/1) was separated to obtain a yellow solid (56.5 mg, 45.7%).

LC-MS：(pos.ion)m/z：475.5[M+1]+；1H NMR(400MHz,DMSO-d 6)δ 10.17(s,1H),8.97(s,1H),7.83(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),5.83(dd,J=17.7,8.9Hz,1H),4,63(t,J=6.5Hz,2H),4.54(t,J=6.1Hz,2H),3.68-3.58(m,2H),3.33(d,J=13.2Hz,1H),2.85(t,J=5.6Hz,2H),2.63(t,J=5.8Hz,2H),2.42(s,3H),2.31(s,3H),2.25(s,2H),1.91(s,2H),1.78(d,J=8.8Hz,2H),1.59(d,J=5.0Hz,2H)。 LC-MS: (pos.ion) m/z: 475.5 [M+1] + ; 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.17 (s, 1H), 8.97 (s, 1H), 7.83 (d , J =8.4Hz,1H),7.51(d, J =8.4Hz,1H),5.83(dd,J=17.7,8.9Hz,1H),4,63(t, J =6.5Hz,2H),4.54 (t, J =6.1Hz,2H),3.68-3.58(m,2H),3.33(d, J =13.2Hz,1H),2.85(t, J =5.6Hz,2H),2.63(t, J = 5.8Hz, 2H), 2.42(s, 3H), 2.31(s, 3H), 2.25(s, 2H), 1.91(s, 2H), 1.78(d, J =8.8Hz, 2H), 1.59(d, J =5.0Hz, 2H).

實施例42 6-乙醯基-8-環戊基-5-甲基-2-[(5-氧代-5,6,7,8-四氫-1,6-萘啶-2-基)胺基]吡啶並[2,3-d]嘧啶-7(8H)-酮Example 42 6-Acetyl-8-cyclopentyl-5-methyl-2-[(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl )Amino]pyrido[2,3-d]pyrimidin-7(8H)-one

Figure 104141541-A0101-12-0100-150
Figure 104141541-A0101-12-0100-150

步驟1).2-氯-5-氧代-7,8-二氫-1,6-萘啶-6(5H)-甲酸叔丁酯 Step 1). 2-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester

在100mL乾燥的單口燒瓶中依次加入2-氯-7,8-二氫-5H-1,6-萘啶-6-甲酸叔丁酯(500mg,1.86mmol)，三氯化釕(100mg,0.48mmol)溶於四氯化碳(16mL)，並加入高碘酸鈉(1.2g,5.6mmol)，反應液在室溫條件下攪拌。TLC和LC-MS檢測結果顯示反應已經基本完成，減壓蒸出有機溶劑，將殘餘物倒入100mL水中，並用二氯甲烷萃取(2x100mL)，飽和食鹽水洗(1x100mL)，合併有機層並減壓旋乾，經柱層析(二氯甲烷/甲醇(v/v)=10/1)純化後，得到黃色固體(451mg,85.73%)。 In a 100mL dry single-necked flask, add 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylic acid tert-butyl ester (500mg, 1.86mmol), ruthenium trichloride (100mg, 0.48) mmol) was dissolved in carbon tetrachloride (16 mL), and sodium periodate (1.2 g, 5.6 mmol) was added, and the reaction solution was stirred at room temperature. The results of TLC and LC-MS showed that the reaction had been basically completed. The organic solvent was distilled off under reduced pressure. The residue was poured into 100 mL of water and extracted with dichloromethane (2x100 mL), washed with saturated brine (1x100 mL), and the organic layers were combined and decompressed Spin dry and purify by column chromatography (dichloromethane/methanol (v/v)=10/1) to obtain a yellow solid (451 mg, 85.73%).

MS-ESI：(ESI,pos.ion)m/z：283.6[M+1]+；1H NMR(400MHz,CDCl3)δ 8.38(d,J=8.2Hz,1H),7.37(d,J=8.3Hz,1H),4.09(t,J=6.4Hz,2H),3.20(t,J=6.4Hz,2H),1.60(s,9H)。 MS-ESI: (ESI, pos.ion) m/z: 283.6 [M+1] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 8.3Hz, 1H), 4.09 (t, J = 6.4Hz, 2H), 3.20 (t, J = 6.4Hz, 2H), 1.60 (s, 9H).

步驟2)2-[(6-乙醯基-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2- 基)氨基]-5-氧代-7,8-二氫-1,6-萘啶-6(5H)-甲酸叔丁酯 Step 2) 2-[(6-Acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2- Group)amino]-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester

在100mL乾燥的單口瓶中加入2-氯-5-氧代-7,8-二氫-1,6-萘啶-6(5H)-甲酸叔丁酯(446mg,1.58mmol)、6-乙醯基-2-氨基-8-環戊基-5-甲基-吡啶並[2,3-d]嘧啶-7-酮(455mg,1.59mmol)和1,4-二氧六環(50mL)，繼續加入碳酸銫(1.76g,5.40mmol)、4,5-雙二苯基膦-9,9-二甲基氧雜蒽(90mg,0.15mmol)和三(二亞苄基丙酮)二鈀(150mg,0.16mmol)。在氮氣保護下加熱至110℃，反應過夜。反應完全，停止加熱，反應液過濾，濾液濃縮，殘留物經柱層析純化(二氯甲烷/甲醇(v/v)=10/1)，得到淡黃色固體(170mg,20.23%)。 Add 2-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (446mg, 1.58mmol), 6-ethyl to a 100mL dry single-necked bottle Acetyl-2-amino-8-cyclopentyl-5-methyl-pyrido[2,3-d]pyrimidin-7-one (455 mg, 1.59 mmol) and 1,4-dioxane (50 mL) , Continue to add cesium carbonate (1.76g, 5.40mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (90mg, 0.15mmol) and tris(dibenzylideneacetone) dipalladium (150 mg, 0.16 mmol). It was heated to 110°C under the protection of nitrogen and reacted overnight. The reaction was completed, the heating was stopped, the reaction solution was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (dichloromethane/methanol (v/v)=10/1) to obtain a pale yellow solid (170 mg, 20.23%).

MS-ESI：(ESI,pos.ion)m/z：533.4[M+1]+。 MS-ESI: (ESI, pos.ion) m/z: 533.4 [M+1] + .

步驟3)6-乙醯基-8-環戊基-5-甲基-2-[(5-氧代-5,6,7,8-四氫-1,6-萘啶-2-基)胺基]吡啶並[2,3-d]嘧啶-7(8H)-酮 Step 3) 6-acetoyl-8-cyclopentyl-5-methyl-2-[(5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl )Amino]pyrido[2,3-d]pyrimidin-7(8H)-one

在100mL乾燥的單口瓶中加入2-[(6-乙醯基-8-環戊基-5-甲基-7-氧代-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)氨基]-5-氧代-7,8-二氫-1,6-萘啶-6(5H)-甲酸叔丁酯(350mg,0.66mmol)，用二氯甲烷(19mL)溶解，繼續加入三氟乙酸(4mL)。反應液在室溫下攪拌反應過夜。反應完全後，反應液過濾，濾液濃縮，殘留物經柱層析純化(二氯甲烷/甲醇(v/v)=10/1)，得到淡黃色固體(270mg,95.0%)。 Add 2-[(6-acetoxy-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine to a 100mL dry single-necked bottle -2-yl)amino]-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (350 mg, 0.66 mmol) with dichloromethane (19 mL) Dissolve and continue to add trifluoroacetic acid (4 mL). The reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v)=10/1) to obtain a pale yellow solid (270 mg, 95.0%).

MS-ESI：(ESI,pos.ion)m/z：433.5[M+1]+；1H NMR(600MHz,DMSO-d 6)δ 10.69(s,1H),9.06(s,1H),8.13(dd,J=34.9,8.5Hz,2H),7.94(d,J=17.8Hz,1H),5.91-5.84(m,1H),3.46(d,J=14.0Hz,2H),2.98(t,J=6.0Hz,2H),2.89(s,2H),2.44(s,3H),2.34(s,3H),2.26(s,2H),1.96(s,2H),1.82(s,2H)。 MS-ESI: (ESI, pos.ion) m/z: 433.5 [M+1] + ; 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.69 (s, 1H), 9.06 (s, 1H), 8.13 (dd, J =34.9,8.5Hz,2H),7.94(d, J =17.8Hz,1H),5.91-5.84(m,1H),3.46(d, J =14.0Hz,2H),2.98(t, J = 6.0 Hz, 2H), 2.89 (s, 2H), 2.44 (s, 3H), 2.34 (s, 3H), 2.26 (s, 2H), 1.96 (s, 2H), 1.82 (s, 2H).

實施例43 6-乙醯基-8-環戊基-2-((6-(2-羥乙基)-5,6,7,8-四氫-1,6-萘啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮Example 43 6-acetoyl-8-cyclopentyl-2-((6-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl )Amino)-5-methylpyrido[2,3-d]pyrimidin-7(8 H )-one

Figure 104141541-A0101-12-0101-151
Figure 104141541-A0101-12-0101-151

將6-乙醯基-8-環戊基-5-甲基-2-((5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮(213mg,0.51mmol)溶解在N,N-二甲基甲醯胺(15mL)溶液中，加入溴乙醇(128mg,1.02mmol)和碳酸鉀(141mg,1.02mmol)，室溫攪拌，停止反應，減壓除去溶劑，加入矽膠拌樣，柱層析分離(二氯甲烷/甲醇(v/v)=10/1)，得到黃色固體(159mg,67.4%)。 6-Acetyl-8-cyclopentyl-5-methyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)pyrido[2 ,3-d]pyrimidin-7(8 H )-one (213 mg, 0.51 mmol) was dissolved in a solution of N,N-dimethylformamide (15 mL), and bromoethanol (128 mg, 1.02 mmol) and potassium carbonate were added (141mg, 1.02mmol), stirred at room temperature, the reaction was stopped, the solvent was removed under reduced pressure, silica gel was added for sample preparation, and column chromatography (dichloromethane/methanol (v/v)=10/1) was obtained to obtain a yellow solid (159mg , 67.4%).

LC-MS：(pos.ion)m/z：463.5[M+1]+；1H NMR(600MHz,CDCl3)δ 8.85(s,1H),8.13(d,J=8.2Hz,1H),8.09(s,1H),7.42(d,J=8.2Hz,1H),5.91-5.84(m,1H),3.77(s,2H),3.72(s,2H),3.00(d,J=4.6Hz,2H),2.95(d,J=5.1Hz,2H),2.79(s,2H),2.57(s,3H),2.40(s,3H),2.38-2.34(m,2H),2.09(s,2H),1.90(s,2H),1.71(s,2H)。 LC-MS: (pos.ion) m/z: 463.5 [M+1] + ; 1 H NMR (600 MHz, CDCl 3 ) δ 8.85 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.09(s,1H),7.42(d, J =8.2Hz,1H),5.91-5.84(m,1H),3.77(s,2H),3.72(s,2H),3.00(d, J =4.6Hz , 2H), 2.95 (d, J = 5.1Hz, 2H), 2.79 (s, 2H), 2.57 (s, 3H), 2.40 (s, 3H), 2.38-2.34 (m, 2H), 2.09 (s, 2H), 1.90 (s, 2H), 1.71 (s, 2H).

實施例44 6-乙醯基-8-環戊基-2-((6-(2-甲氧基乙基)-5,6,7,8-四氫-1,6-萘啶-2-基)胺基)-5-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮Example 44 6-acetoyl-8-cyclopentyl-2-((6-(2-methoxyethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2 -Yl)amino)-5-5-methylpyrido[2,3-d]pyrimidin-7(8 H )-one

Figure 104141541-A0101-12-0102-152
Figure 104141541-A0101-12-0102-152

將6-乙醯基-8-環戊基-5-甲基-2-((5,6,7,8-四氫-1,6-萘啶-2-基)氨基)吡啶並[2,3-d]嘧啶-7(8H)-酮(271mg,0.65mmol)溶解在N,N-二甲基甲醯胺(15mL)溶液中，加入1-溴-2-甲氧基乙烷(106mg,0.76mmol)和碳酸鉀(209mg,1.51mmol)，室溫攪拌，停止反應，減壓除去溶劑，加入矽膠拌樣，柱層析分離(二氯甲烷/甲醇(v/v)=10/1)，得到黃色固體(234mg,75.6%)。 6-Acetyl-8-cyclopentyl-5-methyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino)pyrido[2 ,3-d]pyrimidin-7(8 H )-one (271 mg, 0.65 mmol) was dissolved in a solution of N,N-dimethylformamide (15 mL), and 1-bromo-2-methoxyethane was added (106mg, 0.76mmol) and potassium carbonate (209mg, 1.51mmol), stirred at room temperature, the reaction was stopped, the solvent was removed under reduced pressure, silica gel was added to mix sample, column chromatography separation (dichloromethane/methanol (v/v) = 10 /1) to give a yellow solid (234 mg, 75.6%).

LC-MS：(pos.ion)m/z：477.5[M+1]+；1H NMR(600MHz,CDCl3)δ 8.88(s,1H),8.35(s,1H),8.10(d,J=8.4Hz,1H),7.41(d,J=8.4Hz,1H),5.92-5.85(m,1H),3.71(d,J=8.0Hz,2H),3.64(t,J=5.4Hz,2H),3.42(s,3H),3.01(t,J=5.7Hz,2H),2.93(t,J=5.9Hz,2H),2.82(t,J=5.4Hz,2H),2.57(s,3H),2.40(s,3H),2.37(dd,J=13.5,5.7Hz,2H),2.08(dt,J=12.7,5.6Hz,2H),1.90(dd,J=12.7,7.4Hz,2H),1.71(dd,J=10.7,5.5Hz,2H)。 LC-MS: (pos.ion) m/z: 477.5 [M+1] + ; 1 H NMR (600 MHz, CDCl 3 ) δ 8.88 (s, 1H), 8.35 (s, 1H), 8.10 (d, J =8.4Hz,1H),7.41(d, J =8.4Hz,1H),5.92-5.85(m,1H),3.71(d, J =8.0Hz,2H),3.64(t, J =5.4Hz,2H ), 3.42 (s, 3H), 3.01 (t, J = 5.7Hz, 2H), 2.93 (t, J = 5.9Hz, 2H), 2.82 (t, J = 5.4Hz, 2H), 2.57 (s, 3H ), 2.40 (s, 3H), 2.37 (dd, J =13.5, 5.7Hz, 2H), 2.08 (dt, J =12.7, 5.6Hz, 2H), 1.90 (dd, J =12.7, 7.4Hz, 2H) , 1.71 (dd, J =10.7, 5.5Hz, 2H).

本發明化合物的體外抗腫瘤活性測定Determination of the anti-tumor activity of the compound of the present invention in vitro 生物實施例1 本發明化合物的體外酶學抑制活性Biological Example 1 In vitro enzymatic inhibitory activity of compounds of the present invention

實驗方法：下述實驗中縮寫所代表的含義如下：HEPES：羥乙基呱嗪乙硫磺酸；Brij-35：十二烷基聚乙二醇醚；DTT：二硫蘇糖醇；EDTA：乙二胺四乙酸；CDK4/CycD3：週期蛋白依賴性蛋白激酶4；CDK6/CycD3：週期蛋白依賴性蛋白激酶6；Peptide FAM-P22：螢光素標記肽22；ATP：三磷酸酸腺苷；DMSO：二甲基亞碸；Staurosporine：星孢菌素；Coating Reagent #3：#3被膜劑 Experimental method: The meanings of the abbreviations in the following experiments are as follows: HEPES: hydroxyethylpyrazine ethanesulfonic acid; Brij-35: dodecyl polyethylene glycol ether; DTT: dithiothreitol; EDTA: ethyl Diaminetetraacetic acid; CDK4/CycD3: cyclin-dependent protein kinase 4; CDK6/CycD3: cyclin-dependent protein kinase 6; Peptide FAM-P22: luciferin-labeled peptide 22; ATP: adenosine triphosphate; DMSO : Dimethyl sulfoxide; Staurosporine: staurosporine; Coating Reagent #3: #3 coating agent

1. 1×激酶緩衝液及終止實驗緩衝液配製：(1)1×不含MnCl2激酶緩衝液(50mM HEPES,pH 7.5,0.0015% Brij-35,10mM MgCl2,2mM DTT)；(2)終止實驗緩衝液(100mM HEPES,pH 7.5,0.015% Brij-35,0.2% Coating Reagent #3,50mM EDTA)。 1. 1× kinase buffer and termination experiment buffer preparation: (1) 1× MnCl 2 free kinase buffer (50 mM HEPES, pH 7.5, 0.0015% Brij-35, 10 mM MgCl 2 , 2 mM DTT); (2) Stop the experiment buffer (100mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50mM EDTA).

2. 測試激酶的化合物連續稀釋準備：(1)採用100% DMSO將化合物稀釋到最高終濃度的50倍。將100μL該濃度的化合物溶液轉移至96孔板的一孔。(2)按20μL原溶液用60μL DMSO稀釋的比例依次稀釋化合物10個濃度。(3)將100μL 100% DMSO溶液加入到兩個空孔中，作為無化合物對照和無酶對照。(4)準備一張中間板，分別將10μL各濃度化合物從原板中轉移到中間板，並加入90μL 1×激酶緩衝液，振盪混勻10分鐘。(5)準備實驗板：從96孔板的中間板中對應孔轉移5μL化合物溶液到對應的384孔板中。 2. Preparation of serial dilutions of test kinase compounds: (1) Use 100% DMSO to dilute the compounds to 50 times the maximum final concentration. Transfer 100 μL of this concentration of compound solution to one well of a 96-well plate. (2) Dilute the compound 10 concentrations in order by diluting 20 μL of the original solution with 60 μL of DMSO. (3) Add 100 μL of 100% DMSO solution to the two empty wells to serve as no compound control and no enzyme control. (4) Prepare an intermediate plate, transfer 10 μL of each concentration of compound from the original plate to the intermediate plate, add 90 μL of 1×kinase buffer, and mix by shaking for 10 minutes. (5) Prepare the experimental plate: transfer 5 μL of the compound solution from the corresponding well in the middle plate of the 96-well plate to the corresponding 384-well plate.

3. 激酶反應 3. Kinase reaction

(1)準備2.5×酶溶液：將酶加入1×激酶緩衝液中。(2)準備2.5×肽溶液：將螢光素標記肽和ATP加入1×激酶緩衝液中。(3)將10μL 2.5×酶溶液加入到含有5μL DMSO含量為10%的化合物溶液的384孔實驗板中，室溫孵育10分鐘。(4)將10μL 2.5×肽溶液加入384孔實驗板中。(5)激酶反應及終止：28℃孵育相應的時間，加入25μL終止緩衝液終止反應。 (1) Prepare 2.5× enzyme solution: add enzyme to 1× kinase buffer. (2) Prepare 2.5× peptide solution: add luciferin-labeled peptide and ATP to 1× kinase buffer. (3) Add 10 μL of 2.5× enzyme solution to a 384-well experimental plate containing 5 μL of a DMSO content of 10% compound solution, and incubate at room temperature for 10 minutes. (4) Add 10 μL of 2.5× peptide solution to the 384-well experiment plate. (5) Kinase reaction and termination: Incubate at 28°C for the corresponding time, add 25 μL of termination buffer to terminate the reaction.

4. 資料測量：讀取資料並收集。 4. Data measurement: read and collect data.

5. 曲線擬合 5. Curve fitting

(1)拷貝並轉換測量的資料；(2)轉換為抑制率：抑制率=(最大值-樣本值)/(最大值-最小值)*100；“最大值”為無化合物對照值；“最小值”為無激酶對照孔數值。(3)將資料登錄相應分析軟體Xlfit得出IC50值。 (1) Copy and convert the measured data; (2) Convert to the inhibition rate: inhibition rate = (maximum value-sample value) / (maximum value-minimum value) * 100; "maximum value" is the control value of no compound; The "minimum value" is the value of the control well without kinase. (3) Register the data to the corresponding analysis software Xlfit to obtain the IC 50 value.

實驗結果如下：

Figure 104141541-A0101-12-0104-154
The experimental results are as follows:
Figure 104141541-A0101-12-0104-154

實驗結論：從表2可見，本發明大部分化合物對CDK4、CDK6激酶均有較強的抑制作用，體外酶學抑制活性均小於10μm。 Experimental conclusion: It can be seen from Table 2 that most of the compounds of the present invention have strong inhibitory effects on CDK4 and CDK6 kinases, and the enzymatic inhibitory activity in vitro is less than 10 μm.

生物實施例2 本發明化合物在大鼠體內的藥代動力學活性Biological Example 2 Pharmacokinetic activity of the compound of the present invention in rats

實驗方法：所用實驗試劑及供試品如下：Propranolol：普萘洛爾(內標)；MTBE：甲基叔丁基醚；Cremophor EL：聚氧乙烯蓖麻油；KolliphorHS 15：聚乙二醇12羥基硬脂酸酯；DMSO：二甲亞碸；PEG400：聚乙二醇400；SD大鼠：雄性，18隻。 Experimental method: The experimental reagents and test products used are as follows: Propranolol: propranolol (internal standard); MTBE: methyl tert-butyl ether; Cremophor EL: polyoxyethylene castor oil; KolliphorHS 15: polyethylene glycol 12 hydroxyl Stearate; DMSO: dimethyl sulfoxide; PEG400: polyethylene glycol 400; SD rats: male, 18.

1. 待測化合物溶液的配製：按5% DMSO+10% KolliphorHS 15+35% Saline或5% DMSO+60% PEG400+35% Saline配置溶液，具體根據每個化合物的溶解情況進行調整，使化合物能完全溶解。 1. Preparation of test compound solution: according to 5% DMSO+10% KolliphorHS 15+35% Saline or 5% DMSO+60% PEG400+35% Saline configuration solution, adjust according to the dissolution of each compound to make the compound Can be completely dissolved.

2. 動物實驗 2. Animal experiment

取190-250g雄性SD大鼠，隨機分為兩組，一組靜脈注射待測化合物，劑量為1.0mg/kg，另一組口服給予待測化合物，劑量為5mg/kg；給藥後靜脈注射按時間點0.0833、0.25、0.5、1、2、5、7和24小時尾靜脈採血；口服灌胃按時間點0.25、0.5、1、2、5、7和24小時尾靜脈採血。根據樣 品濃度建立合適範圍的標準曲線，使用LC-MS/MS法測定血漿樣品中待測化合物的濃度。根據藥物濃度-時間曲線，採用WinNonLin 6.3軟體非房室模型法計算藥動學參數。 190-250g male SD rats were randomly divided into two groups, one group was intravenously injected with the test compound at a dose of 1.0 mg/kg, and the other group was orally administered the test compound with a dose of 5 mg/kg; intravenously after administration According to time points 0.0833, 0.25, 0.5, 1, 2, 5, 7 and 24 hours tail vein blood sampling; oral gavage according to time points 0.25, 0.5, 1, 2, 5, 7 and 24 hours tail vein blood sampling. According to The concentration of the product was used to establish a standard curve in a suitable range, and the concentration of the test compound in the plasma sample was determined using the LC-MS/MS method. According to the drug concentration-time curve, WinNonLin 6.3 software non-compartment model method was used to calculate the pharmacokinetic parameters.

3. 實驗結果如下：

Figure 104141541-A0101-12-0105-155
3. The experimental results are as follows:
Figure 104141541-A0101-12-0105-155

本發明大部分化合物的體內代謝均較好，有較好的吸收和暴露量，生物利用度較高，且明顯優於Palbociclib的暴露量。 Most of the compounds of the present invention have better metabolism in vivo, have better absorption and exposure, have higher bioavailability, and are significantly better than the exposure of Palbociclib.

生物實施例3 本發明化合物在小鼠體內的藥代動力學活性Biological Example 3 Pharmacokinetic activity of the compound of the present invention in mice

實驗方法：將18隻體重在18~25g範圍的ICR小鼠隨機分為3組，每組6隻，每組中3隻小鼠靜脈注射和3隻小鼠灌胃給予待測化合物，給藥後按設計的時間點採集血液，血液離心後取血漿，處理後用LC-MS/MS測試血藥濃度，用Winnonlin以非房室模型計算藥代參數。實驗結果如下：實驗結論：本發明化合物在小鼠體內的代謝均較好，有較好的吸收和暴露量，生物利用度較高，且明顯優於Palbociclib的生物利用度，尤其是實施例1-44。 Experimental method: 18 ICR mice weighing 18~25g were randomly divided into 3 groups, 6 in each group, 3 mice in each group were injected intravenously and 3 mice were given the compound to be tested by intragastric administration Blood was collected at the designed time point, plasma was collected after centrifugation of blood, plasma concentration was measured by LC-MS/MS after treatment, and pharmacokinetic parameters were calculated with non-compartmental model using Winnonlin. The experimental results are as follows: Experimental conclusions: The compounds of the present invention have better metabolism in mice, have better absorption and exposure, and have higher bioavailability, and are significantly better than the bioavailability of Palbociclib, especially Example 1 -44.

在本說明書的描述中，參考術語“一個實施例”、“一些實施例”、“示例”、“具體示例”、或“一些示例”等的描述意指結合該實施例或示例描述的具體特徵、結構、材料或者特點包含於本發明的至少一個實施例或示例中。在本說明書中，對上述術語的示意性表述不必須針對的是相同的實施例或示例。而且，描述的具體特徵、結構、材料或者特點可以在任一個或多個實施例或示例中以合適的方式結合。此外，在不相互矛盾的情況下，本領域的技術人員可以將本說明書中描述的不同實施例或示例以及不同實 施例或示例的特徵進行結合和組合。 In the description of this specification, the description referring to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" means specific features described in conjunction with the embodiment or examples , Structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. In addition, without contradicting each other, those skilled in the art may combine different embodiments or examples and different implementations described in this specification. The features of the embodiments or examples are combined and combined.

儘管上面已經示出和描述了本發明的實施例，可以理解的是，上述實施例是示例性的，不能理解為對本發明的限制，本領域的普通技術人員在本發明的範圍內可以對上述實施例進行變化、修改、替換和變型。 Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and cannot be construed as limitations to the present invention, and those of ordinary skill in the art can understand the above within the scope of the present invention. The embodiments are changed, modified, replaced, and modified.

Figure 104141541-A0101-11-0002-2
Figure 104141541-A0101-11-0002-2

Claims (12)

一種化合物，其為如式(I)所示的化合物，或式(I)所示的化合物的立體異構體，幾何異構體，互變異構體，氮氧化物或藥學上可接受的鹽，
Figure 104141541-A0305-02-0109-1
 其中：L為鍵，-(C(R3b)2)n-，-O-(C(R3b)2)n-或-C(=O)-(C(R3b)2)n-； A環為
Figure 104141541-A0305-02-0109-2
或
Figure 104141541-A0305-02-0109-3
；R為氫或R13；R13為氫，
Figure 104141541-A0305-02-0109-4
，
Figure 104141541-A0305-02-0109-5
，
Figure 104141541-A0305-02-0109-6
，
Figure 104141541-A0305-02-0109-7
或
Figure 104141541-A0305-02-0109-8
；其中，Y和Y1各自獨立地為-C(R3c)2-，-N(R2b)-，-O-或-C(=O)-；各e，r和f獨立地為0，1，2或3；各R2b獨立地為氫或C1-4烷基；各R3c獨立地為氫，氟，氯，溴，C1-4烷基，羥基，羧基，氨基或C1-4鹵代烷基；其中，X7，X5和X6各自獨立地為-C(R3a)2-，-N(R2)-，-O-，-S(=O)m-或-C(=O)-；X，X1，X2，X3和X4各自獨立地為CR3a或N；各n獨立地為0，1，2，3或4；各m獨立地為0，1或2；各R2獨立地為氫，3,3,3-三氟丙基，三氟甲基，1,1-二氟乙基，環丙基，環己基，環戊基，環丁基，HO-(C(R3)2)n-C(=O)-，HO-(C(R3)2)n-， H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-SO2-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-，
Figure 104141541-A0305-02-0110-9
，
Figure 104141541-A0305-02-0110-10
，
Figure 104141541-A0305-02-0110-11
，
Figure 104141541-A0305-02-0110-12
，
Figure 104141541-A0305-02-0110-13
，
Figure 104141541-A0305-02-0110-14
，
Figure 104141541-A0305-02-0110-15
，
Figure 104141541-A0305-02-0110-16
，甲基，乙基，丙基或丁基；各R3a，R3b和R3獨立地為氫，氟，氯，溴，C1-4烷基，羥基，羧基，C1-4鹵代烷基，H-(CH2)n-O-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-，H-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；各R4獨立地為氫或C1-4烷基；所述的A代表的各子結構式可獨立任選地被1，2，3或4個相同或不同之選自氫，C1-4烷基，氟，氯，溴，氨基，羥基，C1-4烷氧基，C1-4鹵代烷基，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-和H-(C(R3)2)n-C(=O)-(C(R3)2)n-的取代基所取代；其中，R，R2和R13中所述的烷基，鹵代烷基，H-(C(R3)2)n-SO2-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-，H-(C(R3)2)n-C(=O)-(C(R3)2)n-，H-(C(R3)2)n-O-C(=O)-C(=O)-(C(R3)2)n-和各子結構式，可獨立任選地被1，2，3或4個相同或不同的R5取代；各R5獨立地為氫，氧代，甲基，乙基，丙基，丁基，氟，氯，溴，氨基，羥基，羧基，甲氧基，或C1-4鹵代烷基。 A compound which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt of a compound represented by formula (I) ,
Figure 104141541-A0305-02-0109-1
 Where: L is a bond, -(C(R 3b ) 2 ) n -, -O-(C(R 3b ) 2 ) n -or -C(=O)-(C(R 3b ) 2 ) n -; Ring A is
Figure 104141541-A0305-02-0109-2
or
Figure 104141541-A0305-02-0109-3
; R is hydrogen or R 13 ; R 13 is hydrogen,
Figure 104141541-A0305-02-0109-4
,
Figure 104141541-A0305-02-0109-5
,
Figure 104141541-A0305-02-0109-6
,
Figure 104141541-A0305-02-0109-7
or
Figure 104141541-A0305-02-0109-8
; Where Y and Y 1 are each independently -C(R 3c ) 2 -, -N(R 2b )-, -O- or -C(=O)-; each e, r, and f are independently 0 , 1, 2 or 3; each R 2b is independently hydrogen or C 1-4 alkyl; each R 3c is independently hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, hydroxy, carboxy, amino or C 1-4 haloalkyl; wherein, X 7 , X 5 and X 6 are each independently -C(R 3a ) 2 -, -N(R 2 )-, -O-, -S(=O) m -or -C(=O)-; X, X 1 , X 2 , X 3 and X 4 are each independently CR 3a or N; each n is independently 0, 1 , 2 , 3 or 4; each m is independently 0, 1 or 2; each R 2 is independently hydrogen, 3,3,3-trifluoropropyl, trifluoromethyl, 1,1-difluoroethyl, cyclopropyl, cyclohexyl, cyclopentyl, Cyclobutyl, HO-(C(R 3 ) 2 ) n -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O- (C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C (=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n- ,
Figure 104141541-A0305-02-0110-9
,
Figure 104141541-A0305-02-0110-10
,
Figure 104141541-A0305-02-0110-11
,
Figure 104141541-A0305-02-0110-12
,
Figure 104141541-A0305-02-0110-13
,
Figure 104141541-A0305-02-0110-14
,
Figure 104141541-A0305-02-0110-15
,
Figure 104141541-A0305-02-0110-16
, Methyl, ethyl, propyl or butyl; each R 3a , R 3b and R 3 is independently hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, hydroxy, carboxy, C 1-4 haloalkyl , H-(CH 2 ) n -O-(CH 2 ) n -, HO-(CH 2 ) n -C(=O)-(CH 2 ) n -, H-(CH 2 ) n -C(= O)-(CH 2 ) n -or N(R 4 ) 2 -(CH 2 ) n -; each R 4 is independently hydrogen or C 1-4 alkyl; each sub-structure represented by A can be Independently selected by 1, 2, 3 or 4 identical or different from hydrogen, C 1-4 alkyl, fluorine, chlorine, bromine, amino, hydroxyl, C 1-4 alkoxy, C 1-4 Haloalkyl, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -and H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) substituted by a substituent of n -; wherein, the alkyl, halogenated alkyl described in R, R 2 and R 13 , H-(C(R 3 ) 2 ) n -SO 2 -(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C(=O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -OC(=O)-C(=O)-(C(R 3 ) 2 ) n -and each sub-structure formula can be independently selected by 1, 2, 3 or 4 same or different R 5 substitution; each R 5 is independently hydrogen, oxo, methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, amino, hydroxy, carboxy, methoxy, or C 1-4 haloalkane base. 根據申請專利範圍第1項所述的化合物，其為如式(III)所示的化合物，或式(III)所示的化合物的立體異構體，幾何異構體，互變異構體，氮氧化物或藥學上可接受的鹽，
Figure 104141541-A0305-02-0111-17
 其中：L為鍵，-(CH2)n-，-O-或-C(=O)-。 The compound according to item 1 of the patent application scope, which is a compound represented by formula (III), or a stereoisomer, geometric isomer, tautomer, nitrogen of the compound represented by formula (III) Oxides or pharmaceutically acceptable salts,
Figure 104141541-A0305-02-0111-17
 Among them: L is a bond, -(CH 2 ) n -, -O- or -C(=O)-. 根據申請專利範圍第1項或第2項所述的化合物，其中， R13為環丙基，環己基，環戊基，環丁基，氫，
Figure 104141541-A0305-02-0111-19
，
Figure 104141541-A0305-02-0111-20
，
Figure 104141541-A0305-02-0111-21
，
Figure 104141541-A0305-02-0111-22
，
Figure 104141541-A0305-02-0111-18
Figure 104141541-A0305-02-0111-23
，
Figure 104141541-A0305-02-0111-24
，
Figure 104141541-A0305-02-0111-25
或
Figure 104141541-A0305-02-0111-26
；其中，所述的R13代表的各子結構式可獨立任選地進一步被1，2，3或4個相同或不同的R5取代。 The compound according to item 1 or 2 of the patent application scope, wherein R 13 is cyclopropyl, cyclohexyl, cyclopentyl, cyclobutyl, hydrogen,
Figure 104141541-A0305-02-0111-19
,
Figure 104141541-A0305-02-0111-20
,
Figure 104141541-A0305-02-0111-21
,
Figure 104141541-A0305-02-0111-22
,
Figure 104141541-A0305-02-0111-18
Figure 104141541-A0305-02-0111-23
,
Figure 104141541-A0305-02-0111-24
,
Figure 104141541-A0305-02-0111-25
or
Figure 104141541-A0305-02-0111-26
; Wherein, each sub-structural formula represented by R 13 may be independently and optionally further substituted with 1, 2, 3 or 4 identical or different R 5 . 根據申請專利範圍第1項所述的化合物，其中，A環為
Figure 104141541-A0305-02-0111-28
，
Figure 104141541-A0305-02-0111-29
，
Figure 104141541-A0305-02-0111-30
，
Figure 104141541-A0305-02-0111-31
，
Figure 104141541-A0305-02-0111-32
，
Figure 104141541-A0305-02-0111-33
，
Figure 104141541-A0305-02-0111-34
，
Figure 104141541-A0305-02-0111-27
Figure 104141541-A0305-02-0111-35
，
Figure 104141541-A0305-02-0111-36
，
Figure 104141541-A0305-02-0111-37
或
Figure 104141541-A0305-02-0111-38
； 其中，所述的A代表的各子結構式可獨立任選地進一步被1，2，3或4個相同或不同的選自氫，C1-4烷基，氟，氯，溴，氨基，羥基，C1-4烷氧基，C1-4鹵代烷基，(R4)2N-(C(R3)2)n-，HO-(C(R3)2)n-C(=O)-，HO-(C(R3)2)n-，H-(C(R3)2)n-O-(C(R3)2)n-和H-(C(R3)2)n-C(=O)-(C(R3)2)n-的取代基所取代。 The compound according to item 1 of the patent application scope, wherein ring A is
Figure 104141541-A0305-02-0111-28
,
Figure 104141541-A0305-02-0111-29
,
Figure 104141541-A0305-02-0111-30
,
Figure 104141541-A0305-02-0111-31
,
Figure 104141541-A0305-02-0111-32
,
Figure 104141541-A0305-02-0111-33
,
Figure 104141541-A0305-02-0111-34
,
Figure 104141541-A0305-02-0111-27
Figure 104141541-A0305-02-0111-35
,
Figure 104141541-A0305-02-0111-36
,
Figure 104141541-A0305-02-0111-37
or
Figure 104141541-A0305-02-0111-38
; Wherein, each sub-structural formula represented by A can be optionally further independently selected from 1, 2, 3 or 4 identical or different from hydrogen, C 1-4 alkyl, fluorine, chlorine, bromine, amino , Hydroxy, C 1-4 alkoxy, C 1-4 haloalkyl, (R 4 ) 2 N-(C(R 3 ) 2 ) n -, HO-(C(R 3 ) 2 ) n -C( =O)-, HO-(C(R 3 ) 2 ) n -, H-(C(R 3 ) 2 ) n -O-(C(R 3 ) 2 ) n -and H-(C(R 3 ) 2 ) n -C(=O)-(C(R 3 ) 2 ) n -is substituted by a substituent. 根據申請專利範圍第1項所述的化合物，其中，各R3a，R3b和R3獨立地為氫，氟，氯，溴，羥基，羧基，三氟甲基，甲基，乙基，丙基，丁基，H-(CH2)n-O-(CH2)n-，H-O-(CH2)n-C(=O)-(CH2)n-或N(R4)2-(CH2)n-；各R4獨立地為氫，甲基，乙基，丙基或丁基。 The compound according to item 1 of the patent application scope, wherein each of R 3a , R 3b and R 3 is independently hydrogen, fluorine, chlorine, bromine, hydroxyl, carboxyl, trifluoromethyl, methyl, ethyl, propylene Group, butyl, H-(CH 2 ) n -O-(CH 2 ) n -, HO-(CH 2 ) n -C(=O)-(CH 2 ) n -or N(R 4 ) 2- (CH 2 ) n -; Each R 4 is independently hydrogen, methyl, ethyl, propyl or butyl. 根據申請專利範圍第1項所述的化合物，其為如下之一的結構：
Figure 104141541-A0305-02-0112-39
Figure 104141541-A0305-02-0113-40
Figure 104141541-A0305-02-0114-41
Figure 104141541-A0305-02-0114-42
，
Figure 104141541-A0305-02-0114-44
或其立體異構體，幾何異構體，互變異構體，氮氧化物，藥學上可接受的鹽。 The compound according to item 1 of the patent application scope has one of the following structures:
Figure 104141541-A0305-02-0112-39
Figure 104141541-A0305-02-0113-40
Figure 104141541-A0305-02-0114-41
Figure 104141541-A0305-02-0114-42
,
Figure 104141541-A0305-02-0114-44
Or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, and pharmaceutically acceptable salts. 一種藥物組合物，包含申請專利範圍第1項至第6項中任一項所述的化合物，進一步包含藥學上可接受的載體，賦形劑，稀釋劑，輔劑，媒介物中的至少一種。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle . 根據申請專利範圍第7項所述的藥物組合物，更進一步包含附加治療 劑，所述附加治療劑為化學治療藥物，抗增殖劑，免疫抑制劑，免疫刺激劑，抗炎性試劑，用於治療動脈粥樣硬化的藥物，用於治療肺纖維化的藥物，CDK4/6激酶抑制劑，ABL抑制劑，ABL/Scr抑制劑，極光激酶抑制劑，Bcr-ABL的非-ATP競爭性抑制劑，c-KIT突變抑制劑，RET抑制劑，PDGFR抑制劑，VEGFR抑制劑，CSF1R抑制劑，FLT3抑制劑，FLT3-ITD抑制劑或它們的組合。 The pharmaceutical composition according to item 7 of the patent application scope further includes additional treatment Agents, the additional therapeutic agents are chemotherapeutic drugs, antiproliferative agents, immunosuppressive agents, immunostimulants, anti-inflammatory agents, drugs for treating atherosclerosis, drugs for treating pulmonary fibrosis, CDK4/ 6 Kinase inhibitor, ABL inhibitor, ABL/Scr inhibitor, Aurora kinase inhibitor, Bcr-ABL non-ATP competitive inhibitor, c-KIT mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFR inhibitor , CSF1R inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or a combination thereof. 根據申請專利範圍第8項所述的藥物組合物，其中所述的附加治療劑是苯丁酸氮芥，美法侖，環磷醯胺，異環磷醯胺，白消安，卡莫司汀，洛莫司汀，鏈脲佐菌素，順鉑，卡鉑，奧沙利鉑，達卡巴嗪，替莫唑胺，丙卡巴肼，甲氨蝶呤，氟尿嘧啶，阿糖胞苷，吉西他濱，巰基嘌呤，氟達拉濱，長春鹼，長春新鹼，長春瑞濱，紫杉醇，多西紫杉醇，拓撲替康，伊立替康，依託泊苷，曲貝替定，更生黴素，多柔比星，表柔比星，道諾黴素，米托蒽醌，博來黴素，絲裂黴素C，伊沙匹隆，他莫昔芬，氟他胺，戈那瑞林類似物，甲地孕酮，強的松，地塞米松，甲潑尼龍，沙利度胺，干擾素α，亞葉酸鈣，西羅莫司，西羅莫司脂化物，依維莫司，阿法替尼，阿帕替尼，阿西替尼，硼替佐米，波舒替尼，卡博替尼，西地尼布，克卓替尼，達拉非尼，達克替尼，達沙替尼，多韋替尼，厄洛替尼，吉非替尼，伊布替尼，埃克替尼，伊馬替尼，拉帕替尼，樂伐替尼，馬賽替尼，莫替沙尼，來那替尼，尼祿替尼，尼拉帕尼，奧拉帕尼，帕唑帕尼，帕納替尼，瑞格菲尼，瑞卡帕布，魯索替尼，塞卡替尼，索拉非尼，舒尼替尼，特拉替尼，托法替尼，曲美替尼，凡德他尼，維利帕尼，威羅菲尼，維莫德吉，阿侖單抗，貝伐單抗，本妥昔單抗，卡妥索單抗，西妥昔單抗，地諾單抗，吉妥珠單抗，伊匹單抗，尼妥珠單抗，奧法木單抗，帕尼單抗，利妥昔單抗，托西莫單抗，曲妥珠單抗，卡博替尼，普納替尼，米哚妥林，吉特替尼，法米替尼，哌柏西利，夫拉平度或它們的組合。 The pharmaceutical composition according to item 8 of the patent application scope, wherein the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, and carmus Ting, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine , Fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, anastamycin, doxorubicin, table Rexorubicin, Daunomycin, Mitoxantrone, Bleomycin, Mitomycin C, Ixabepilone, Tamoxifen, Flutamide, Gonarelin analogues, Megestrol , Prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, calcium folinate, sirolimus, sirolimus lipid, everolimus, afatinib, apa Tinib, acitinib, bortezomib, bosutinib, carbotinib, sildenib, crizotinib, dabrafenib, dacomitinib, dasatinib, dovetinib , Erlotinib, gefitinib, ibinib, icotinib, imatinib, lapatinib, lovastinib, mazatinib, motizani, lenatinib, ni Lutinib, Nilapani, Olapani, Pazopanib, Panatinib, Regafenib, Ricapabum, Rusotinib, Secatinib, Sorafenib, Shu Nitinib, Tratinib, Tofacitinib, Trametinib, Vandetanib, Veripani, Verofinib, Vimodijil, Alemtuzumab, Bevacizumab, Ben Tortuximab, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, Rituximab, tositumomab, trastuzumab, carbotinib, pratinib, middotulin, gefitinib, famitinib, peripexil, flavipine Or a combination of them. 一種根據申請專利範圍第1項至第6項中任一項所述的化合物或申請專利範圍第7項至第9項中任一項所述的藥物組合物在製備藥物中的用途，所述藥物用於預防，處理，治療或減輕患者由異常細胞增殖，自身免疫，炎性或感染引起的障礙或病症。 Use of a compound according to any one of patent application items 1 to 6 or a pharmaceutical composition according to any of patent application items 7 to 9 in the preparation of a medicament, said Medications are used to prevent, treat, treat, or alleviate a patient's disorder or condition caused by abnormal cell proliferation, autoimmunity, inflammation, or infection. 根據申請專利範圍第10項所述的用途，其中所述的障礙或病症是細胞週期蛋白依賴性激酶改變引起的障礙或病症；所述的細胞週期蛋白依賴性激酶是指CDK1、CDK2、CDK4、CDK6或CDK9。 The use according to item 10 of the patent application scope, wherein the disorder or disorder is a disorder or disorder caused by changes in cyclin-dependent kinase; the cyclin dependent kinase refers to CDK1, CDK2, CDK4, CDK6 or CDK9. 一種藥物聯合，包含申請專利範圍第1項至第6項中任一項所述的化合物或申請專利範圍第7項至第9項中任一項所述的藥物組合物，更進一步包含治療增殖性疾病、自體免疫疾病或炎性疾病的其他活性藥劑；所述的其他活性藥劑為化學治療藥物，抗增殖劑，免疫抑制劑，免疫刺激劑，抗炎性試劑，用於治療動脈粥樣硬化的藥物，用於治療肺纖維化的藥物，CDK4/6激酶抑制劑，ABL抑制劑，ABL/Scr抑制劑，極光激酶抑制劑，Bcr-ABL的非-ATP競爭性抑制劑，c-KIT突變抑制劑，RET抑制劑，PDGFR抑制劑，VEGFR抑制劑，CSF1R抑制劑，FLT3抑制劑，FLT3-ITD抑制劑或它們的組合。 A pharmaceutical combination comprising the compound described in any one of patent application items 1 to 6 or the pharmaceutical composition described in any one of patent application items 7 to 9 and further comprising therapeutic proliferation Other active agents for sexual diseases, autoimmune diseases or inflammatory diseases; the other active agents are chemotherapeutic drugs, anti-proliferative agents, immunosuppressive agents, immunostimulants, anti-inflammatory agents, used to treat atherosclerosis Sclerotic drugs, drugs used to treat pulmonary fibrosis, CDK4/6 kinase inhibitors, ABL inhibitors, ABL/Scr inhibitors, Aurora kinase inhibitors, non-ATP competitive inhibitors of Bcr-ABL, c-KIT Mutation inhibitor, RET inhibitor, PDGFR inhibitor, VEGFR inhibitor, CSF1R inhibitor, FLT3 inhibitor, FLT3-ITD inhibitor or a combination thereof.
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