TW202110801A - Novel amide compounds and uses thereof - Google Patents

Novel amide compounds and uses thereof Download PDF

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Publication number
TW202110801A
TW202110801A TW109116218A TW109116218A TW202110801A TW 202110801 A TW202110801 A TW 202110801A TW 109116218 A TW109116218 A TW 109116218A TW 109116218 A TW109116218 A TW 109116218A TW 202110801 A TW202110801 A TW 202110801A
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Taiwan
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alkyl
compound
haloalkyl
group
pharmaceutically acceptable
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TW109116218A
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Chinese (zh)
Inventor
慰國 蘇
戴廣袖
張維漢
賈紅
楊海彬
蔡華慶
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大陸商和記黃埔醫藥（上海）有限公司
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Priority claimed from CN201910409909.5A external-priority patent/CN112047877A/en
Application filed by 大陸商和記黃埔醫藥（上海）有限公司 filed Critical 大陸商和記黃埔醫藥（上海）有限公司
Publication of TW202110801A publication Critical patent/TW202110801A/en

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    • A61P19/00—Drugs for skeletal disorders
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Abstract

The present invention relates to novel amide compounds of formula (I), pharmaceutical compositions thereof, methods for preparing thereof, and uses thereof, wherein the symbols are as defined in the specification.

Description

新型醯胺類化合物及其用途 Novel amide compounds and their uses

本發明涉及新的醯胺類化合物、包含它們的醫藥組成物以及它們的製備方法和用途。 The present invention relates to new amide compounds, pharmaceutical compositions containing them, and their preparation methods and uses.

在哺乳動物細胞中，L-色胺酸(L-Trp)主要經由“犬尿胺酸途徑”被降解為L-犬尿胺酸(L-Kynurenine)，其中的第一步L-色胺酸生成N-甲醯基-L-犬尿胺酸是犬尿胺酸代謝途徑中的限速步驟。目前的研究表明主要有三種酶，即IDO1(吲哚胺-2,3-雙加氧酶1)、IDO2(吲哚胺-2,3-雙加氧酶2)和TDO(色胺酸2,3-雙加氧醇)，參與了如下圖所示的L-色胺酸代謝反應。 In mammalian cells, L -tryptophan ( L- Trp) is mainly degraded into L -kynurenine ( L- Kynurenine) through the "kynurenine pathway", the first step of which is L -tryptophan The formation of N -formyl- L -kynurenine is the rate-limiting step in the metabolic pathway of kynurenine. Current research shows that there are three main enzymes, namely IDO1 (indoleamine-2,3-dioxygenase 1), IDO2 (indoleamine-2,3-dioxygenase 2) and TDO (tryptophan 2) ,3-Dioxyethanol), participates in the metabolic reaction of L-tryptophan as shown in the figure below.

Figure 109116218-A0101-12-0001-4
Figure 109116218-A0101-12-0001-4

IDO1是由位於人8p22染色體上INDO基因編碼生成的大小約為45Kd的細胞質鐵血紅素酶，普遍表達於體內多種組織和細胞中，包括免疫細胞、內皮細胞和成纖維細胞等。IDO1的表達主要受由炎性信號，如IFN γ、CpG-DNA以及LPS等的調控。IDO2是由INDOL1基因編碼，與IDO1相比約有42%的胺基酸序列相同，結構非常相似，但體外研究顯示人IDO2只具有極低的酶活 性，且存在高比例的遺傳多態性而導致其失去酶活性。目前對IDO2生物學功能的研究還不充分。TDO是由TDO2基因編碼，雖然功能上與IDO1和IDO2相關，但是僅有10%的胺基酸序列相同，在肝臟中組成性的高表達，其功能主要是維持人體內L-色胺酸穩定。近來的研究發現某些腫瘤藉由高表達TDO來介導腫瘤細胞對宿主的免疫系統的耐受，但目前為止，還沒有TDO在免疫細胞中表達的報導。 IDO1 is a 45Kd cytoplasmic heme enzyme encoded by the INDO gene located on the human 8p22 chromosome. It is commonly expressed in a variety of tissues and cells in the body, including immune cells, endothelial cells, and fibroblasts. The expression of IDO1 is mainly regulated by inflammatory signals such as IFN γ, CpG-DNA and LPS. IDO2 is encoded by the INDOL1 gene. Compared with IDO1, there are about 42% of the amino acid sequence identical and very similar in structure. However, in vitro studies have shown that human IDO2 has only extremely low enzymatic activity and a high proportion of genetic polymorphisms. Cause it to lose enzyme activity. The current research on the biological functions of IDO2 is still insufficient. TDO is encoded by the TDO2 gene. Although it is functionally related to IDO1 and IDO2, only 10% of the amino acid sequence is identical. It is constitutively highly expressed in the liver. Its function is mainly to maintain the stability of L -tryptophan in the human body. . Recent studies have found that some tumors mediate the tolerance of tumor cells to the host's immune system by high expression of TDO, but so far, there is no report of TDO expression in immune cells.

IDO1表達與腫瘤的發生、發展密切相關。研究發現在多種原發性和轉移性人類腫瘤中，如急性髓系白血病、肺癌、黑色素瘤等腫瘤中IDO1的高表達與腫瘤的惡性程度、轉移及預後相關，這暗示著IDO1可能是一個潛在的治療靶點。在腫瘤微環境中，一些促炎因子如IFN γ等可以誘導腫瘤細胞或者宿主免疫細胞(主要是抗原呈遞細胞，如樹突狀細胞、巨噬細胞等)表達IDO1。這些被誘導表達出來的IDO1催化L-色胺酸的代謝反應，在腫瘤微環境中藉由同時降低L-色胺酸的濃度和升高生成的L-犬尿胺酸及其進一步的代謝產物(如3-羥基犬尿胺酸和3-羥基-2-胺基苯甲酸等)的濃度來抑制效應淋巴細胞，如T細胞、NK細胞的增殖，誘導其進入週期阻滯、凋亡。並同時上調免疫抑制性的調節性T細胞，從而幫助腫瘤細胞逃脫宿主的免疫監視，獲得惡性生長的機會。 The expression of IDO1 is closely related to the occurrence and development of tumors. Studies have found that in a variety of primary and metastatic human tumors, such as acute myeloid leukemia, lung cancer, melanoma and other tumors, the high expression of IDO1 is related to the malignancy, metastasis and prognosis of the tumor, which implies that IDO1 may be a potential Therapeutic target. In the tumor microenvironment, some pro-inflammatory factors such as IFN γ can induce tumor cells or host immune cells (mainly antigen-presenting cells, such as dendritic cells, macrophages, etc.) to express IDO1. These induced IDO1 catalyze the metabolic reaction of L -tryptophan, by simultaneously reducing the concentration of L -tryptophan and increasing the production of L -kynurenine and its further metabolites in the tumor microenvironment (Such as 3-hydroxykynurenine and 3-hydroxy-2-aminobenzoic acid, etc.) concentration to inhibit the proliferation of effector lymphocytes, such as T cells and NK cells, and induce them to enter cycle arrest and apoptosis. At the same time, it up-regulates immunosuppressive regulatory T cells to help tumor cells escape the host's immune surveillance and obtain opportunities for malignant growth.

臨床前的動物實驗顯示了靶向IDO1的有效性。如，採用基因剔除IDO1蛋白，或者使用IDO1小分子抑制劑如INCB024360(Epacadostat)和NLG919抑制IDO1蛋白活性，都能夠有效的降低動物體內犬尿胺酸的水平，從而解除IDO1介導的腫瘤對機體免疫系統耐受，活化T細胞、NK細胞等效應細胞，進而起到抑制腫瘤生長的作用。目前已有IDO1抑制劑(如INCB024360、BMS-986205和Pf-06840003)或IDO1/TDO的小分子抑制劑(如NLG919)進入了早期的臨床試 驗。早期的臨床試驗結果表明，靶向IDO1是一種安全的治療手段，參與試驗的病人均表現出了良好的耐受性。此外在接受IDO1小分子抑制劑治療一段時間後，病人無論是在血漿還是腫瘤內均觀測到了不同程度的犬尿胺酸水平下降。而且早期的療效數據顯示，相比單藥，IDO1抑制劑與免疫檢查點CTLA4或PD1抗體聯用在一些腫瘤中表現出了更好的療效，例如，在黑色素瘤病人中開展的IDO1抑制劑INCB024360聯合PD-1抗體Pembrolizumab的1/2期臨床試驗結果顯示其客觀緩解率(ORR)達到58%，且明顯好於Pembrolizumab單用的臨床試驗數據(3期，ORR，32.9%)。這些結果顯示，IDO1是一個潛在的治療惡性腫瘤的靶點(ESMO,2016，摘要1110PD；ASCO,2017，摘要4503；JCO.2017.35(15_suppl)：摘要1103；JCO.2017.35(15_suppl)：摘要3003；Cancer Res.,2017,77(13 Suppl)：摘要CT116；Analyst and Investor Day Meeting,NewLink Genetics Corporation,2016年10月25日)。 Preclinical animal experiments have shown the effectiveness of targeting IDO1. For example, the use of gene knockout IDO1 protein, or the use of IDO1 small molecule inhibitors such as INCB024360 (Epacadostat) and NLG919 to inhibit the activity of IDO1 protein can effectively reduce the level of kynurenine in animals, thereby eliminating IDO1-mediated tumors from affecting the body The immune system is tolerant, activating effector cells such as T cells and NK cells, thereby inhibiting tumor growth. At present, IDO1 inhibitors (such as INCB024360, BMS-986205 and Pf-06840003) or IDO1/TDO small molecule inhibitors (such as NLG919) have entered early clinical trials. Test. Early clinical trial results show that targeting IDO1 is a safe treatment, and the patients participating in the trial have shown good tolerance. In addition, after receiving IDO1 small molecule inhibitor treatment for a period of time, patients have observed varying degrees of kynurenine levels in both plasma and tumors. Moreover, early efficacy data showed that, compared with single drugs, IDO1 inhibitors combined with immune checkpoint CTLA4 or PD1 antibodies showed better efficacy in some tumors. For example, the IDO1 inhibitor INCB024360 was developed in melanoma patients. The Phase 1/2 clinical trial results of the combined PD-1 antibody Pembrolizumab showed that its objective response rate (ORR) reached 58%, which was significantly better than the clinical trial data of Pembrolizumab alone (Phase 3, ORR, 32.9%). These results show that IDO1 is a potential target for the treatment of malignant tumors (ESMO, 2016, abstract 1110PD; ASCO, 2017, abstract 4503; JCO.2017.35(15_suppl): abstract 1103; JCO.2017.35(15_suppl): abstract 3003; Cancer Res., 2017, 77 (13 Suppl): Abstract CT116; Analyst and Investor Day Meeting, NewLink Genetics Corporation, October 25, 2016).

除了腫瘤外，其它一些疾病，例如慢性感染、HIV病毒、多發性硬化症、神經抑鬱等疾病也與IDO1活性相關。因此，IDO1抑制劑也可能用於開發治療這些疾病(Trends Immunol.,2013,34(3)：137-143)。目前還沒有靶向IDO1藥物獲批上市，當前進入臨床研究的IDO1抑制劑存在某些缺陷，仍然需要新的IDO1抑制劑用以治療這些疾病，特別是癌症。本發明解決了這些需求。 In addition to tumors, other diseases, such as chronic infection, HIV virus, multiple sclerosis, neurodepression and other diseases are also related to IDO1 activity. Therefore, IDO1 inhibitors may also be used to develop treatments for these diseases (Trends Immunol., 2013, 34(3):137-143). At present, no drugs targeting IDO1 have been approved for marketing. The IDO1 inhibitors currently entering clinical research have certain defects. New IDO1 inhibitors are still needed to treat these diseases, especially cancer. The present invention addresses these needs.

本發明提供了式(I)的化合物： The present invention provides compounds of formula (I):

Figure 109116218-A0101-12-0004-5
或其藥學上可接受的鹽，和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中：
Figure 109116218-A0101-12-0004-5
 Or its pharmaceutically acceptable salts, and/or its deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers, wherein:

X為N或CR3；Y為N或CR4； X is N or CR 3 ; Y is N or CR 4 ;

R1、R2、R3和R4分別獨立地選自：氫、鹵素、-OH、-CN、-NH2、C1-6烷基、C1-6鹵烷基、-O(C1-6烷基)、-NH(C1-6烷基)或-N(C1-6烷基)2； R 1 , R 2 , R 3 and R 4 are each independently selected from: hydrogen, halogen, -OH, -CN, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 ;

Z為O、NR5或CR6R7； Z is O, NR 5 or CR 6 R 7 ;

R5選自：氫、C1-6烷基或C3-6環烷基； R 5 is selected from: hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl;

R6和R7分別獨立地選自：氫、鹵素、-CN、C1-6鹵烷基、-O(C1-6鹵烷基)、-OH、C1-6烷基、C3-6環烷基或-O(C1-6烷基)； R 6 and R 7 are each independently selected from: hydrogen, halogen, -CN, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -OH, C 1-6 alkyl, C 3 -6 cycloalkyl or -O (C 1-6 alkyl);

Figure 109116218-A0101-12-0004-7
為苯基、5-6員雜芳基或吲唑基；它們各自視需要地被一個或多個選 自以下的基團所取代：鹵素、-CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-O(C1-6烷基)或-O(C1-6鹵烷基)；
Figure 109116218-A0101-12-0004-7
Is a phenyl group, a 5-6 membered heteroaryl group or an indazolyl group; each of them is optionally substituted by one or more groups selected from the group consisting of halogen, -CN, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -O(C 1-6 alkyl) or -O(C 1-6 haloalkyl);

Figure 109116218-A0101-12-0004-6
為吡啶基、嘧啶基、吡嗪基、噠嗪基或三嗪基，它們各自視需要地被 一個或多個選自以下的基團所取代：鹵素、-(C1-6烷基)n-CN、-NO2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-(C1-6烷基)n-C3-6環烷基、-(C1-6烷基)n-苯基、-(C1-6烷基)n-4-6員雜環基、-(C1-6烷基)n-5-6員雜芳基、-(C1-6烷基)n-NR1’R2’、-(C1-6烷基)n-CONR1’R2’、-(C1-6烷基)n-NR1’R2’C(O)R3’、-(C1-6烷基)n-C(O)R3’-、-(C1-6烷基)n-C(O)OR4’、-(C1-6烷基)n-OR5’、-(C1-6烷基)n-S(O)mNR1’R2’、-(C1-6烷 基)n-NR1’R2’S(O)mR6’、-(C1-6烷基)n-S(O)mR6’和-(C1-6烷基)n-SR7’；其中，該苯基、C3-6環烷基、4-6員雜環基和5-6員雜芳基視需要地被一個或多個選自以下的基團所取代：鹵素、-CN、-OH、-NH2、C1-6鹵烷基、-O(C1-6鹵烷基)、C1-6烷基、-O(C1-6烷基)、-NH(C1-6烷基)、-N(C1-6烷基)2、C2-6烯基、C2-6炔基和C3-6環烷基；
Figure 109116218-A0101-12-0004-6
Is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, each of which is optionally substituted by one or more groups selected from the group consisting of halogen, -(C 1-6 alkyl) n -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -(C 1-6 alkyl) n -C 3- 6 cycloalkyl, -(C 1-6 alkyl) n -phenyl, -(C 1-6 alkyl) n -4-6 membered heterocyclyl, -(C 1-6 alkyl) n -5 -6-membered heteroaryl, - (C 1-6 alkyl) n -NR 1 'R 2' , - (C 1-6 alkyl) n -CONR 1 'R 2' , - (C 1-6 alkyl yl) n -NR 1 'R 2' C (O) R 3 ', - (C 1-6 alkyl) n -C (O) R 3 ' -, - (C 1-6 alkyl) n -C (O) OR 4 ', - (C 1-6 alkyl) n -OR 5', - ( C 1-6 alkyl) n -S (O) m NR 1 'R 2', - (C 1- 6 alkyl) n -NR 1 'R 2' S (O) m R 6 ', - (C 1-6 alkyl) n -S (O) m R 6' and - (C 1-6 alkyl) n -SR 7 '; wherein the phenyl group, C 3-6 cycloalkyl group, 4-6 membered heterocyclic group and 5-6 membered heteroaryl group are optionally substituted by one or more groups selected from the following Substitution: halogen, -CN, -OH, -NH 2 , C 1-6 haloalkyl, -O (C 1-6 haloalkyl), C 1-6 alkyl, -O (C 1-6 alkyl ), -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl;

n為0或1； n is 0 or 1;

m為1或2； m is 1 or 2;

p為0或1； p is 0 or 1;

R1’、R2’、R3’、R4’、R5’、R6’和R7’分別獨立地選自氫、C1-6烷基、C1-6鹵烷基、-(C1-6烷基)-O-(C1-6烷基)、-(C1-6烷基)-OH、-(C1-6烷基)-CN、-(C1-6烷基)-NH2或C3-6環烷基；或者R1’、R2’與它們相連的N原子一起形成一個4-6員的雜環。 R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 6 'and R 7 ' are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl,- (C 1-6 alkyl)-O-(C 1-6 alkyl), -(C 1-6 alkyl)-OH, -(C 1-6 alkyl)-CN, -(C 1-6 Alkyl) -NH 2 or C 3-6 cycloalkyl; or R 1 ′ and R 2 ′ together with the N atom to which they are connected form a 4-6 membered heterocyclic ring.

上述化合物以及本發明在上下文中所公開的被該範圍涵蓋的活性化合物總稱為“本發明的化合物”。 The above-mentioned compounds and the active compounds covered by the scope disclosed in the context of the present invention are collectively referred to as "compounds of the present invention".

本發明還提供了一種醫藥組成物，其包含本發明的化合物，並且視需要地包含藥學上可接受的賦形劑。 The present invention also provides a pharmaceutical composition, which comprises the compound of the present invention, and optionally a pharmaceutically acceptable excipient.

本發明還提供了一種體內或體外抑制IDO活性的方法，其包括使有效量的本發明的化合物與IDO接觸。 The present invention also provides a method for inhibiting IDO activity in vivo or in vitro, which comprises contacting an effective amount of the compound of the present invention with IDO.

本發明還提供了一種治療由IDO介導或至少部分由IDO介導的疾病的方法，其包括給需要其的個體施用有效量的本發明的化合物。 The present invention also provides a method for treating diseases mediated or at least partially mediated by IDO, which comprises administering an effective amount of a compound of the present invention to an individual in need thereof.

本發明還提供了一種治療癌症的方法，其包括給需要其的個體施用有效量的本發明的化合物。 The present invention also provides a method of treating cancer, which comprises administering an effective amount of the compound of the present invention to an individual in need thereof.

本發明還提供了本發明的化合物在治療由IDO介導或至少部分由IDO介導的疾病中的用途。 The present invention also provides the use of the compounds of the present invention in the treatment of diseases mediated by IDO or at least partly by IDO.

本發明還提供了本發明的化合物在治療癌症或自身免疫性疾病中的用途。 The present invention also provides the use of the compounds of the present invention in the treatment of cancer or autoimmune diseases.

本發明還提供了本發明的化合物在製備藥物中的用途，所述藥物用於治療由IDO介導或至少部分由IDO介導的疾病。 The present invention also provides the use of the compounds of the present invention in the preparation of medicines for the treatment of diseases mediated by IDO or at least partly by IDO.

本發明還提供了本發明的化合物在製備藥物中的用途，所述藥物用於治療癌症或自身免疫性疾病。 The present invention also provides the use of the compound of the present invention in the preparation of medicines for the treatment of cancer or autoimmune diseases.

發明詳述 Detailed description of the invention

定義 definition

本申請中所用的下列單詞、短語和符號具有如下所述的含義，其所處的上下文中另有說明的除外。 The following words, phrases and symbols used in this application have the following meanings, unless otherwise specified in the context in which they are located.

不在兩個字母或符號之間的短橫(“-”)表示取代基的連接位點。例如，-OR3是指藉由氧原子與分子的其餘部分連接R3。 A dash ("-") that is not between two letters or symbols indicates the point of attachment of the substituent. For example, -OR 3 refers to connecting R 3 to the rest of the molecule through an oxygen atom.

本文所用的術語“烷基”是指含有1-18個碳原子、較佳1-10個碳原子、特別佳1-6個碳原子的直鏈或支鏈的飽和烴基。例如，“C1-6烷基”表示所述的具有1-6個碳原子的烷基。烷基的例子包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基和第三丁基。 The term "alkyl" as used herein refers to a linear or branched saturated hydrocarbon group containing 1-18 carbon atoms, preferably 1-10 carbon atoms, particularly preferably 1-6 carbon atoms. For example, "C 1-6 alkyl" means the aforementioned alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, and tertiary butyl.

位於兩個短橫(“-”)之間的烷基表示伸烷基連接基團，例如，“-(C1-6烷基)-”表示直鏈或支鏈的C1-6伸烷基連接基團。本文所用的術語“伸烷 基”是指含有1-18個碳原子、較佳1-10個碳原子、特別佳1-6個碳原子、進一步較佳1-4個碳原子的直鏈或支鏈的飽和二價烴基。例如，“-(C1-6烷基)n-”表示具有1-6個碳原子的直鏈或支鏈伸烷基，其中n是0或1，例如-CH2-CH(CH3)-CH2-、-CH(CH3)-CH2-、-CH(CH3)-CH2-CH2-等。較佳直鏈的C1-6亞烷基，更佳-CH2-和-CH2-CH2-。 The alkyl group located between two dashes ("-") represents an alkylene linking group, for example, "-(C 1-6 alkyl)-" represents a linear or branched C 1-6 alkylene Group linking group. As used herein, the term "alkylene" refers to a straight chain or chain containing 1-18 carbon atoms, preferably 1-10 carbon atoms, particularly preferably 1-6 carbon atoms, and more preferably 1-4 carbon atoms. A branched saturated divalent hydrocarbon group. For example, "-(C 1-6 alkyl) n -" represents a straight or branched chain alkylene having 1 to 6 carbon atoms, where n is 0 or 1, for example, -CH 2 -CH(CH 3 ) -CH 2 -, -CH(CH 3 )-CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, etc. A linear C 1-6 alkylene group is preferred, and -CH 2 -and -CH 2- CH 2 -are more preferred.

本文所用的術語“烯基”是指含有一個或多個、例如1、2或3個碳碳雙鍵(C=C)的、含有2-10個碳原子、較佳2-6個碳原子、更佳2-4個碳原子的直鏈或支鏈的不飽和烴基。例如，“C2-6烯基”表示所述的具有2-6個碳原子的烯基，較佳“C2-4烯基”，即所述的具有2-4個碳原子的烯基。烯基的例子包括但不限於乙烯基、2-丙烯基和2-丁烯基。烯基的連接點可以在雙鍵上，也可以不在雙鍵上。 The term "alkenyl" as used herein refers to those containing one or more, for example, 1, 2 or 3 carbon-carbon double bonds (C=C), containing 2-10 carbon atoms, preferably 2-6 carbon atoms , More preferably, a linear or branched unsaturated hydrocarbon group of 2 to 4 carbon atoms. For example, "C 2-6 alkenyl" means the alkenyl group having 2-6 carbon atoms, preferably "C 2-4 alkenyl", that is, the alkenyl group having 2-4 carbon atoms. . Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The point of attachment of the alkenyl group may or may not be on the double bond.

本文所用的術語“炔基”是指含有一個或多個、例如1、2或3個碳碳三鍵(C≡C)的、含有2-10個碳原子、較佳2-6個碳原子、更佳2-4個碳原子的直鏈或支鏈的不飽和烴基。例如，“C2-6炔基”表示所述的具有2-6個碳原子的炔基，較佳“C2-4炔基”，即所述的具有2-4個碳原子的炔基。炔基的例子包括但不限於乙炔基、2-丙炔基和2-丁炔基。炔基的連接點可以在三鍵上，也可以不在三鍵上。 The term "alkynyl" as used herein refers to those containing one or more, such as 1, 2 or 3 carbon-carbon triple bonds (C≡C), containing 2-10 carbon atoms, preferably 2-6 carbon atoms , More preferably, a linear or branched unsaturated hydrocarbon group of 2 to 4 carbon atoms. For example, "C 2-6 alkynyl" means the alkynyl group having 2-6 carbon atoms, preferably "C 2-4 alkynyl", that is, the alkynyl group having 2-4 carbon atoms . Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The point of attachment of the alkynyl group may or may not be on the triple bond.

本文所用的術語“鹵素”或“鹵”是指氟、氯、溴和碘，較佳氟、氯和溴，更佳氟和氯。 The term "halogen" or "halogen" as used herein refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

本文所用的術語“鹵烷基”是指其中一個或多個氫原子、例如1、2、3、4或5個氫原子被鹵素原子替代的本文所定義的烷基，並且當超過一個氫原子被鹵素原子替代時，該鹵素原子可以彼此相同或不同。在一個實施方案 中，本文所用的術語“鹵烷基”是指其中兩個或更多個氫原子、例如2、3、4或5個氫原子被鹵素原子替代的本文所定義的烷基，其中該鹵素原子彼此相同。在另一個實施方案中，本文所用的術語“鹵烷基”是指其中兩個或更多個氫原子、例如2、3、4或5個氫原子被鹵素原子替代的本文所定義的烷基，其中該鹵素原子彼此不同。鹵烷基的例子包括但不限於-CF3、-CHF2、-CH2CF3、-CH(CF3)2等。 The term "haloalkyl" as used herein refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, or 5 hydrogen atoms are replaced by halogen atoms, and when more than one hydrogen atom When substituted by halogen atoms, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein in which two or more hydrogen atoms, for example, 2, 3, 4, or 5 hydrogen atoms are replaced by halogen atoms, Wherein the halogen atoms are the same as each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein in which two or more hydrogen atoms, for example, 2, 3, 4, or 5 hydrogen atoms are replaced by halogen atoms , Where the halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CH(CF 3 ) 2 and the like.

本文所用的術語“環烷基”是指含有3-12個環碳原子(例如含有3-8個環碳原子、5-7個環碳原子、4-7個環碳原子或3-6個環碳原子)的飽和的或部分不飽和的環狀烴基；其可以具有一個或多個環，例如1、2或3個，較佳具有1個或2個環。例如，“C3-12環烷基”表示該具有3-12個環碳原子的環烷基，“C3-8環烷基”表示該具有3-8個環碳原子的環烷基。環烷基可包括稠合的或橋連的環以及螺環。環烷基的環可以是飽和的，其環上也可以含有一個或多個，例如一個或兩個雙鍵(即部分不飽和的)，但是其不是完全共軛的，也不是本發明中所定義的“芳基”。環烷基的例子包括但不限於環丙基、環丁基、環戊基、環己基、環庚基、環辛基、雙[4.1.0]庚烷基、雙環[3.1.1]庚烷基、螺[3.3]庚烷基、螺[2.2]戊烷基、環丙烯基、環丁烯基、環戊烯基、環戊二烯基、環己烯基、環庚烯基、環辛烯基和雙環[3.1.1]庚-2-烯。 The term "cycloalkyl" as used herein refers to 3-12 ring carbon atoms (e.g., 3-8 ring carbon atoms, 5-7 ring carbon atoms, 4-7 ring carbon atoms, or 3-6 ring carbon atoms). (Ring carbon atoms) saturated or partially unsaturated cyclic hydrocarbon group; it may have one or more rings, such as 1, 2 or 3, preferably 1 or 2 rings. For example, "C 3-12 cycloalkyl" means the cycloalkyl group having 3-12 ring carbon atoms, and "C 3-8 cycloalkyl" means the cycloalkyl group having 3-8 ring carbon atoms. Cycloalkyl groups can include fused or bridged rings as well as spiro rings. The ring of a cycloalkyl group can be saturated, and it can also contain one or more, such as one or two double bonds (that is, partially unsaturated), but it is not completely conjugated, nor is it used in the present invention. "Aryl" as defined. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bis[4.1.0]heptyl, bicyclo[3.1.1]heptane Group, spiro[3.3]heptyl, spiro[2.2]pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctyl Alkenyl and bicyclo[3.1.1]hept-2-ene.

本文所用的術語“雜環烷基”、“雜環基”或“雜環”是指：具有3-12個環原子(例如具有3-8個環原子、5-7個環原子、4-7個環原子、4-6個環原子或3-6個環原子)的飽和的或部分不飽和的環、環中包含一個或多個(例如1、2或3個、較佳1或2個)獨立地選自N、O和S的環雜原子，其餘環原子是碳原子；其可以具有一個或多個環，例如1、2或3個，較佳具有1個或2個環。其中，N和 S可視需要地被氧化成各種氧化狀態，雜環烷基的連接點可以在N雜原子上或碳原子上。例如“3-12員雜環烷基”表示該具有3-12個環原子的雜環烷基，其包含至少一個選自N、O和S的雜原子，“4-6員雜環烷基”或“4-6員雜環基”表示所述的具有4-6個環原子的雜環烷基，其包含至少一個選自N、O和S的雜原子。雜環烷基可包括稠合的或橋連的環以及螺環。雜環烷基的環可以是飽和的，其環上也可以含有一個或多個，例如一個或兩個雙鍵(即部分不飽和的)，但是其不是完全共軛的，也不是本發明中所定義的“雜芳基”。雜環烷基的例子包括但不限於：4-6員雜環基例如氧雜環丁烷基、氮雜環丁烷基、吡咯烷基、四氫呋喃基、二氧雜環戊基、嗎啉基、硫嗎啉基、哌啶基、哌嗪基、吡唑烷基，以及氧雜螺[3.3]庚烷基。 The term "heterocycloalkyl", "heterocyclyl" or "heterocycle" as used herein refers to: having 3-12 ring atoms (for example, having 3-8 ring atoms, 5-7 ring atoms, 4- 7 ring atoms, 4-6 ring atoms or 3-6 ring atoms) saturated or partially unsaturated ring, the ring contains one or more (for example, 1, 2 or 3, preferably 1 or 2 A) ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; it may have one or more rings, such as 1, 2 or 3, preferably 1 or 2 rings. Where N and S can optionally be oxidized to various oxidation states, and the point of attachment of the heterocycloalkyl group can be on the N heteroatom or on the carbon atom. For example, "3-12 membered heterocycloalkyl" means the heterocycloalkyl group having 3-12 ring atoms, which contains at least one heteroatom selected from N, O and S, "4-6 membered heterocycloalkyl" "Or "4-6 membered heterocyclic group" means the described heterocycloalkyl group having 4-6 ring atoms, which contains at least one heteroatom selected from N, O and S. Heterocycloalkyl groups can include fused or bridged rings as well as spiro rings. The heterocycloalkyl ring can be saturated, and it can also contain one or more, such as one or two double bonds (that is, partially unsaturated), but it is not fully conjugated, nor is it in the present invention. "Heteroaryl" as defined. Examples of heterocycloalkyl groups include, but are not limited to: 4-6 membered heterocyclic groups such as oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, morpholinyl , Thiomorpholinyl, piperidinyl, piperazinyl, pyrazolidinyl, and oxaspiro[3.3]heptanyl.

本文所用的術語“芳基”或“芳香環”是指由一個環或多個稠環組成的含有6-14個碳原子的碳環烴基，其中至少一個環是芳族環，例如苯基、萘基、1,2,3,4-四氫萘基、茚基、茚滿基、薁基，較佳苯基和萘基。 The term "aryl" or "aromatic ring" as used herein refers to a carbocyclic hydrocarbon group containing 6-14 carbon atoms composed of one ring or multiple condensed rings, at least one of which is an aromatic ring, such as phenyl, Naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl.

本文所用的術語“雜芳基”或“雜芳環”是指：具有5-12個環原子(例如具有5-10個環原子、5-6個環原子或6個環原子)的芳香族環，環中包含一個或多個(例如1、2、3或4個、更佳1、2或3個)獨立地選自N、O和S的環雜原子，其餘環原子是碳原子；其可以具有一個或多個環，例如1、2或3個，較佳具有1個或2個環，例如，該雜芳基包括： The term "heteroaryl" or "heteroaromatic ring" as used herein refers to an aromatic having 5-12 ring atoms (for example, having 5-10 ring atoms, 5-6 ring atoms, or 6 ring atoms) Ring, the ring contains one or more (for example, 1, 2, 3 or 4, more preferably 1, 2 or 3) ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon atoms; It may have one or more rings, such as 1, 2, or 3, preferably 1 or 2 rings. For example, the heteroaryl group includes:

具有5、6或7個環原子(較佳具有5或6個環原子，即5-6員雜芳基)的單環芳族烴基，其在環中包含一個或多個、例如1、2、3或4個、更佳1、2或3個獨立地選自N、O和S(較佳N和O)的環雜原子，其餘環原子是碳原子；和 A monocyclic aromatic hydrocarbon group with 5, 6 or 7 ring atoms (preferably with 5 or 6 ring atoms, that is, 5-6 membered heteroaryl), which contains one or more, such as 1, 2 , 3 or 4, more preferably 1, 2 or 3 ring heteroatoms independently selected from N, O and S (preferably N and O), the remaining ring atoms are carbon atoms; and

具有8-12個環原子(較佳具有9或10個環原子)的雙環芳族烴基，其在環中包含一個或多個、例如1、2、3或4個、較佳1、2或3個獨立地選自N、O和S(較佳N)的環雜原子，其餘環原子是碳原子，其中至少一個環是芳族環。例如，雙環雜芳基包括與5-6員環烷基環稠合的5-6員雜芳基環。當雜芳基中的S和O原子的總數超過1時，這些S和O雜原子彼此不相鄰。 A bicyclic aromatic hydrocarbon group with 8-12 ring atoms (preferably with 9 or 10 ring atoms), which contains one or more, such as 1, 2, 3 or 4, preferably 1, 2 or 3 ring heteroatoms independently selected from N, O and S (preferably N), the remaining ring atoms are carbon atoms, and at least one ring is an aromatic ring. For example, bicyclic heteroaryl includes a 5-6 membered heteroaryl ring fused to a 5-6 membered cycloalkyl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other.

雜芳基的例子包括但不限於：5-6員雜芳基，例如吡啶基、N-氧化吡啶基、吡嗪基、嘧啶基、三嗪基、吡唑基、咪唑基、噁唑基、異噁唑基、噁二唑基(例如1,2,4-噁二唑基、1,2,5-噁二唑基和1,3,4-噁二唑基)、噻唑基、異噻唑基、噻二唑基、四唑基、***基、噻吩基、呋喃基、吡喃基、吡咯基、噠嗪基，以及雙環雜芳基例如苯並間二氧雜環戊烯基、苯並噁唑基、苯並異噁唑基、苯並噻吩基、苯並噻唑基、苯並異噻唑基、咪唑並吡啶基(例如咪唑並[1,2-a]吡啶基)、咪唑並噠嗪基(例如咪唑並[1,2-b]噠嗪基)、吡咯並吡啶基(例如1H-吡咯並[2,3-b]吡啶基)、吡咯並嘧啶基(例如吡咯並[3,4-d]嘧啶基)、吡唑並吡啶基(例如1H-吡唑並[3,4-b]吡啶基)、吡唑並嘧啶基(例如吡唑並[1,5-a]嘧啶基)、***並吡啶基(例如[1,2,4]***並[4,3-a]吡啶基和[1,2,4]***並[1,5-a]吡啶基)、四唑並吡啶基(例如四唑並[1,5-a]吡啶基)、苯並呋喃基、苯並咪唑啉基、吲哚基、吲唑基、嘌呤基、喹啉基、異喹啉基和喹唑啉基。 Examples of heteroaryl groups include, but are not limited to: 5-6 membered heteroaryl groups, such as pyridyl, N-oxide pyridyl, pyrazinyl, pyrimidinyl, triazinyl, pyrazolyl, imidazolyl, oxazolyl, Isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl), thiazolyl, isothiazole Group, thiadiazolyl, tetrazolyl, triazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl, and bicyclic heteroaryl groups such as benzodioxolyl, benzene Oxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, imidazopyridyl (e.g. imidazo[1,2-a]pyridyl), imidazopyridyl Azinyl (e.g. imidazo[1,2-b]pyridazinyl), pyrrolopyridyl (e.g. 1 H -pyrrolo[2,3-b]pyridyl), pyrrolopyrimidinyl (e.g. pyrrolo[3 ,4-d]pyrimidinyl), pyrazolopyridyl (e.g. 1H -pyrazolo[3,4-b]pyridyl), pyrazolopyrimidinyl (e.g. pyrazolo[1,5-a] Pyrimidyl), triazolopyridyl (e.g. [1,2,4]triazolo[4,3-a]pyridyl and [1,2,4]triazolo[1,5-a]pyridyl ), tetrazolopyridyl (e.g. tetrazolo[1,5-a]pyridyl), benzofuranyl, benzimidazolinyl, indolyl, indazolyl, purinyl, quinolinyl, iso Quinolinyl and quinazolinyl.

本文所述的術語“羥基”是指-OH基團。 The term "hydroxy" as used herein refers to the -OH group.

本文所用的術語“氧代”是指=O基團。 The term "oxo" as used herein refers to the =0 group.

如果本文的某個結構式包含星號“*”，則表示該化合物中“*”標記處的手性中心為(R)構型或(S)構型的單一構型；其中該標記“*”的單一構型的化合物的含量至少為90%(例如90%、91%、92%、93%、94%、95%、96%、 97%、98%、99%、99.5%、99.9%、100%，或任何在這些列舉的數值之間的數值)。 If a structural formula in this document contains an asterisk "*", it means that the chiral center at the "*" mark in the compound is a single configuration of (R) configuration or (S) configuration; where the mark "*" The content of the single-configuration compound is at least 90% (e.g. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between these listed values).

本文所用的術語“視需要”、“視需要的”或“視需要地”意指隨後描述的事件或情況可以發生或可以不發生，並且該描述包括該事件或情況發生的情形以及該事件或情況不發生的情形。例如，“視需要被取代的烷基”包括本文定義的“未被取代的烷基”和“被取代的烷基”。本領域技術人員應當理解的是，對於含有一個或多個取代基的任意基團而言，該基團不包括任何在空間上不切實際的、化學上不正確的、合成上不可行的和/或內在不穩定的取代模式。 The term "as needed", "as needed" or "as needed" as used herein means that the event or situation described later may or may not occur, and the description includes the circumstances under which the event or situation occurred and the event or situation Circumstances where the situation does not happen. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined herein. Those skilled in the art should understand that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically impractical and / Or an inherently unstable substitution pattern.

本文所用的術語“被取代的”或“被……取代”意指給定原子或基團上的一個或多個氫原子被一個或多個選自給定的取代基組的取代基替換，條件是不超過該給定原子的正常化合價。當取代基是側氧基(即=O)時，則單個原子上的兩個氫原子被替換。只有當取代基和/或變量的組合導致化學上正確的且穩定的化合物時，這類組合才是允許的。化學上正確的且穩定的化合物意味著化合物足夠穩定，以至於能從反應混合物中被分離出來，並且隨後能被配製成至少具有實際效用的製劑。 The term "substituted" or "substituted" as used herein means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from the given substituent group, provided that Is not exceeding the normal valence of the given atom. When the substituent is a pendant oxy group (ie =0), then two hydrogen atoms on a single atom are replaced. Combinations of substituents and/or variables are permissible only when they result in chemically correct and stable compounds. A chemically correct and stable compound means that the compound is sufficiently stable that it can be separated from the reaction mixture and can then be formulated into a preparation that has at least practical utility.

除非另有說明，取代基被命名入核心結構中。例如，應當理解的是，當(環烷基)烷基被列為一種可能的取代基時，其表示該取代基與核心結構的連接點在烷基部分。 Unless otherwise stated, substituents are named into the core structure. For example, it should be understood that when a (cycloalkyl)alkyl group is listed as a possible substituent, it means that the point of attachment of the substituent to the core structure is at the alkyl moiety.

本文所用的術語“被一個或多個取代基取代”意指給定的原子或基團上的一個或多個氫原子獨立地被一個或多個選自給定基團的取代基替換。 在一些實施方案中，“被一個或多個取代基取代”意指給定的原子或基團被1、2、3或4個獨立地選自給定基團的取代基取代。 The term "substituted by one or more substituents" as used herein means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more substituents selected from the given group. In some embodiments, "substituted by one or more substituents" means that a given atom or group is substituted with 1, 2, 3, or 4 substituents independently selected from the given group.

本領域技術人員應當理解的是，一些式(I)的化合物可以包含一個或多個手性中心，因此存在兩個或更多個立體異構體。這些異構體的外消旋混合物、單個異構體和一種對映異構體富集的混合物，以及當有兩個手性中心時的非對映異構體和特定的非對映異構體部分富集的混合物均在本發明的範圍內。本領域技術人員還應當理解的是，本發明包括式(I)的化合物的所有單個立體異構體(例如對映異構體)、外消旋混合物或部分拆分的混合物，以及在適當的情況下，包括其單個互變異構體。 Those skilled in the art should understand that some compounds of formula (I) may contain one or more chiral centers, so there are two or more stereoisomers. Racemic mixtures of these isomers, single isomers and one enantiomer-enriched mixture, as well as diastereomers and specific diastereomers when there are two chiral centers The mixtures enriched in the body part are all within the scope of the present invention. Those skilled in the art should also understand that the present invention includes all individual stereoisomers (such as enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (I), and where appropriate In the case, a single tautomer is included.

外消旋混合物可以以其本身的形式使用或者可以被拆分成它們的單個異構體。藉由拆分可以得到立體化學上的純的化合物或者富集一種或多種異構體的混合物。分離異構體的方法是眾所周知的(參見Allinger N.L.和Eliel E.L.,"Topics in Stereochemistry"，第6卷，Wiley Interscience，1971)，包括物理方法，例如使用手性吸附劑的色譜法。可以由手性前體製備得到手性形式的單個異構體。或者，可以藉由與手性酸(例如10-樟腦磺酸、樟腦酸、α-溴樟腦酸、酒石酸、二乙醯基酒石酸、蘋果酸、吡咯烷酮-5-羧酸等的單個對映異構體)形成非對映異構體鹽而由混合物化學分離得到單個異構體，將該鹽分級結晶，然後游離出拆分的鹼中的一個或兩個，視需要地重複這一過程，從而得到一個或兩個基本上不包含另一種異構體的異構體，即光學純度>95%的異構體。或者，可以將外消旋物共價連接到手性化合物(輔助物)上，得到非對映異構體，可藉由色譜法或分級結晶法將其分離，之後化學除去手性輔助物，得到純的對映異構體。 The racemic mixture can be used in its own form or can be resolved into their individual isomers. By resolution, a stereochemically pure compound or a mixture enriched in one or more isomers can be obtained. Methods for separating isomers are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry" , Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared from chiral precursors. Alternatively, it can be combined with a chiral acid (such as 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.). Form a diastereomeric salt and chemically separate the mixture to obtain a single isomer, the salt is fractionally crystallized, and then one or two of the resolved bases are freed, and this process is repeated as necessary, thereby Obtain one or two isomers that do not substantially contain another isomer, that is, isomers with an optical purity of >95%. Alternatively, the racemate can be covalently attached to a chiral compound (auxiliary) to obtain diastereomers, which can be separated by chromatography or fractional crystallization, and then the chiral auxiliary may be chemically removed to obtain Pure enantiomers.

術語“互變異構體”指的是因分子中某一原子在兩個位置迅速移動而產生的官能團異構體。互變異構體之間可以互相轉換，例如烯醇式和酮式是典型的互變異構體。 The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. Tautomers can be converted to each other, for example, the enol form and the keto form are typical tautomers.

“藥學上可接受的鹽”，指的是無毒的、生物學上可耐受的或其他生物學上適合於給予治療個體的式(I)的化合物的游離酸或鹼的鹽。例如，酸加成鹽包括例如衍生自無機酸和有機酸的加成鹽，該無機酸包括例如鹽酸、氫溴酸、氫碘酸、硫酸、磷酸和硝酸，該有機酸包括例如對甲苯磺酸、水楊酸、甲磺酸、草酸、琥珀酸、檸檬酸、蘋果酸、乳酸、富馬酸等。有關藥學上可接受的鹽的一般描述參見例如：S.M.Berge等人，“Pharmaceutical Salts”,J.Pharm.Sci.,1977,66：1-19，以及Handbook of Pharmaceutical Salts,Properties,Selection,and Use,Stahl和Wermuth編，Wiley-VCH and VHCA,Zurich,2002。 "Pharmaceutically acceptable salt" refers to the free acid or base salt of the compound of formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. For example, acid addition salts include, for example, addition salts derived from inorganic acids and organic acids, the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid, and the organic acids include, for example, p-toluenesulfonic acid. , Salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. For a general description of pharmaceutically acceptable salts, see, for example: SMBerge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use , Edited by Stahl and Wermuth, Wiley-VCH and VHCA, Zurich, 2002.

此外，如果本文所述的化合物是以酸加成鹽的形式得到的，其游離鹼形式可以藉由鹼化該酸加成鹽的溶液獲得。相反地，如果產物是游離鹼形式，則其酸加成鹽、特別是藥學上可接受的酸加成鹽可以按照由鹼性化合物製備酸加成鹽的常規操作藉由將游離鹼溶於合適的溶劑並且用酸處理該溶液來得到。本領域技術人員無需過多實驗即可確定各種可用來製備無毒的藥學上可接受的酸加成鹽或鹼加成鹽的合成方法。 In addition, if the compound described herein is obtained in the form of an acid addition salt, its free base form can be obtained by alkalizing a solution of the acid addition salt. On the contrary, if the product is in the form of a free base, its acid addition salt, especially a pharmaceutically acceptable acid addition salt, can be prepared by dissolving the free base in a suitable And the solution is treated with an acid. Those skilled in the art can determine various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts without undue experimentation.

術語“溶劑合物”意指包含化學計量的或非化學計量的溶劑的溶劑加成形式。一些化合物具有在固體狀態中網羅固定莫耳比的溶劑分子的傾向，從而形成溶劑合物。如果溶劑是水，則形成的溶劑合物是水合物，當溶劑是乙醇時，則形成的溶劑合物是乙醇合物。水合物是藉由一個或多個分子的水 與一分子該物質形成的，其中水保留其H2O的分子狀態，這樣的組合能形成一種或多種水合物，例如半水合物、一水合物和二水合物。 The term "solvate" means a solvent addition form that contains stoichiometric or non-stoichiometric solvent. Some compounds have a tendency to trap solvent molecules of a fixed molar ratio in the solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more molecules of water and one molecule of the substance. The water retains its H 2 O molecular state. Such a combination can form one or more hydrates, such as hemihydrate and monohydrate. And dihydrate.

本文所用的術語“基團”和“基”是同義詞，用於表示可與其它分子片段連接的官能團或分子片段。 The terms "group" and "base" as used herein are synonymous and are used to indicate functional groups or molecular fragments that can be linked to other molecular fragments.

術語“活性成分”用來表示具有生物活性的化學物質。在一些實施方案中，“活性成分”是具有製藥用途的化學物質。在美國，實際的藥物活性可藉由適當的無論是體外的或體內的臨床前試驗來確定。但是能夠足以被監管機構(例如美國的FDA)接受的藥物活性，要有比臨床前試驗更高的標準。這樣一種更高標準的藥物活性，其是否能成功獲得一般不能從臨床前的試驗結果合理地預期到，但可以藉由在人體中進行的適當並有效的隨機、雙盲、可控的臨床試驗來確立。 The term "active ingredient" is used to mean a chemical substance with biological activity. In some embodiments, the "active ingredient" is a chemical substance that has pharmaceutical uses. In the United States, the actual drug activity can be determined by appropriate preclinical tests, whether in vitro or in vivo. However, drug activity that can be accepted by regulatory agencies (such as the US FDA) must have a higher standard than preclinical trials. Whether such a higher standard of drug activity can be successfully obtained is generally not reasonably expected from the results of preclinical trials, but it can be achieved through appropriate and effective randomized, double-blind, and controllable clinical trials in humans. To establish.

術語“處置”或“治療”疾病或障礙是指給患有該疾病或障礙、或者具有該疾病或障礙的症狀、或者具有易患該疾病或障礙的體質的個體施用一種或多種藥物物質、特別是本文所述的式(I)化合物或其藥學上可接受的鹽，用以治癒、癒合、緩解、減輕、改變、醫治、改善、改進或影響該疾病或障礙、該疾病或障礙的症狀或者易患該疾病或障礙的體質。在一些實施方案中，該疾病或障礙是癌症。 The term "treatment" or "treatment" of a disease or disorder refers to administering one or more pharmaceutical substances, particularly to individuals who suffer from the disease or disorder, or have symptoms of the disease or disorder, or have a physique prone to the disease or disorder. It is the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for curing, healing, alleviating, alleviating, changing, treating, improving, improving or affecting the disease or disorder, the symptoms of the disease or disorder, or The physique susceptible to the disease or disorder. In some embodiments, the disease or disorder is cancer.

當涉及化學反應時，術語“處理”、“接觸”和“反應”意指在適當的條件下加入或混合兩種或更多種試劑，以產生所示的和/或所需的產物。應當理解的是，產生所示的和/或所需的產物的反應可能不一定直接來自最初加入的兩種試劑的組合，即，在混合物中可能存在生成的一個或多個中間體，這些中間體最終導致了所示的和/或所需的產物的形成。 When referring to chemical reactions, the terms "treating", "contacting" and "reacting" mean the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction to produce the indicated and/or desired product may not necessarily come directly from the combination of the two reagents initially added, that is, one or more intermediates may be present in the mixture. The body ultimately leads to the formation of the indicated and/or desired product.

本文所用的術語“有效量”是指通常足以對需要治療具有由IDO活性介導或至少部分由IDO介導的疾病或障礙的患者產生有益治療效果的IDO抑制劑的量或劑量。可以藉由常規方法(例如建模、劑量遞增研究或臨床試驗)結合常規影響因素(例如給藥或施藥的方式或途徑、藥物成分的藥代動力學、疾病或障礙的嚴重程度和病程、個體先前的或正在進行的治療、個體的健康狀況和對藥物的反應、以及主治醫生的判斷)來確定本發明中活性成分的有效量或劑量。在美國，有效劑量的確定一般難以從臨床前試驗中預知。事實上，劑量是完全不可預知的，劑量在原始用於隨機的、雙盲的、可控的臨床試驗後會發展出新的不可預知的劑量方案。 The term "effective amount" as used herein refers to an amount or dose of an IDO inhibitor that is generally sufficient to produce a beneficial therapeutic effect for patients in need of treatment of a disease or disorder mediated by IDO activity or at least partially mediated by IDO. Conventional methods (such as modeling, dose escalation studies, or clinical trials) can be combined with conventional influencing factors (such as the mode or route of administration or administration, the pharmacokinetics of the drug components, the severity and course of the disease or disorder, The individual’s previous or ongoing treatment, the individual’s health status and response to drugs, and the judgment of the attending physician) determine the effective amount or dosage of the active ingredient in the present invention. In the United States, the determination of effective doses is generally difficult to predict from preclinical trials. In fact, the dose is completely unpredictable. After the dose was originally used in a randomized, double-blind, and controllable clinical trial, a new unpredictable dose schedule will be developed.

典型的劑量範圍是從約0.0001至約200毫克活性成分每公斤個體體重每天，例如從約為0.001至100毫克/公斤/天，或者約為0.01至35毫克/公斤/天，或者約為0.1至10毫克/公斤，每日一次或分劑量單位服用(例如，每日兩次、每日三次、每日四次)。對於一個70公斤的人而言，合適劑量例證範圍是從約0.05至約7克/天，或者約為0.2至約5克/天。一旦患者的疾病或障礙出現改善，可以調整劑量以維持治療。例如，根據症狀的變化可以將給藥劑量或給藥次數，或者將給藥劑量和給藥次數減少至維持所期望的治療效果的水平。當然，如果症狀減輕到了適當的水平，可以停止治療。然而，對於症狀的復發，患者可能需要間歇性長期治療。 A typical dosage range is from about 0.0001 to about 200 mg of active ingredient per kilogram of individual body weight per day, for example from about 0.001 to 100 mg/kg/day, or about 0.01 to 35 mg/kg/day, or about 0.1 to 10 mg/kg, once a day or in divided dose units (for example, twice a day, three times a day, four times a day). For a 70 kg person, an exemplary range of suitable dosages is from about 0.05 to about 7 grams per day, or from about 0.2 to about 5 grams per day. Once the patient's disease or disorder improves, the dosage can be adjusted to maintain treatment. For example, according to changes in symptoms, the dosage or frequency of administration can be reduced, or the dosage and frequency of administration can be reduced to a level that maintains the desired therapeutic effect. Of course, if the symptoms are reduced to an appropriate level, treatment can be stopped. However, for recurrence of symptoms, patients may require intermittent long-term treatment.

術語“抑制”是指生物活動或過程的基線活性的降低。術語“抑制IDO活性”是用於本發明目的的實際藥物活性，是指相對於不存在式(I)化合物和/或其藥學上可接受的鹽時的IDO活性，對存在本文所述的式(I)化合物和/或其藥學上可接受的鹽的直接或間接響應導致的IDO活性的降低。活性的降低可 以是由本文所述的式(I)化合物和/或其藥學上可接受的鹽與IDO直接相互作用引起的，或者是由本文所述的式(I)化合物和/或其藥學上可接受的鹽與一種或多種其它因子相互作用進而影響IDO活性引起的。例如，本文所述的式(I)化合物和/或其藥學上可接受的鹽的存在可藉由直接與IDO結合而降低IDO的活性、可藉由直接或間接地影響另一種因子來降低IDO的活性，或者藉由直接或間接地減少存在於細胞或機體中的IDO的量來降低IDO的活性。 The term "inhibition" refers to a decrease in the baseline activity of a biological activity or process. The term "inhibition of IDO activity" refers to the actual pharmaceutical activity used for the purpose of the present invention, and refers to the IDO activity in the absence of the compound of formula (I) and/or its pharmaceutically acceptable salt. (I) The direct or indirect response of the compound and/or its pharmaceutically acceptable salt results in the reduction of IDO activity. The decrease in activity can be It is caused by the direct interaction of the compound of formula (I) and/or its pharmaceutically acceptable salt and IDO as described herein, or is caused by the compound of formula (I) described herein and/or its pharmaceutically acceptable The salt interacts with one or more other factors to affect IDO activity. For example, the presence of the compound of formula (I) and/or its pharmaceutically acceptable salt described herein can reduce the activity of IDO by directly binding to IDO, and can reduce IDO by directly or indirectly affecting another factor. The activity of IDO, or by directly or indirectly reducing the amount of IDO present in the cell or body to reduce the activity of IDO.

本文所用的術語“個體”是指哺乳動物和非哺乳動物。哺乳動物是指哺乳類的任何成員，其包括但不限於：人；非人靈長類動物，如黑猩猩及其它猿類和猴類物種；農場動物，如牛、馬、綿羊、山羊和豬；家畜，如兔、狗和貓；實驗室動物，包括齧齒類動物，如大鼠、小鼠和豚鼠；等。非哺乳動物的例子包括但不限於鳥等。術語“個體”並不限定特定的年齡或性別。在一些實施方案中，個體是人。 The term "individual" as used herein refers to mammals and non-mammals. Mammal refers to any member of the mammalian class, which includes but is not limited to: humans; non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cows, horses, sheep, goats, and pigs; domestic animals , Such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs; etc. Examples of non-mammals include but are not limited to birds and the like. The term "individual" does not limit a specific age or gender. In some embodiments, the individual is a human.

一般而言，術語“約”在本文中用於將所給出的數值調整至高於或低於該數值20%。 Generally speaking, the term "about" is used herein to adjust a given value to 20% above or below that value.

本文所用的未具體定義的技術和科學術語具有本發明所屬領域的技術人員通常理解的含義。 The technical and scientific terms used herein that are not specifically defined have meanings commonly understood by those skilled in the art to which the present invention belongs.

本發明提供了式(I)的化合物： The present invention provides compounds of formula (I):

Figure 109116218-A0101-12-0016-8
或其藥學上可接受的鹽，和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中：
Figure 109116218-A0101-12-0016-8
 Or its pharmaceutically acceptable salts, and/or its deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers, wherein:

X為N或CR3；Y為N或CR4； X is N or CR 3 ; Y is N or CR 4 ;

R1、R2、R3和R4分別獨立地選自：氫、鹵素、-OH、-CN、-NH2、C1-6烷基、C1-6鹵烷基、-O(C1-6烷基)、-NH(C1-6烷基)或-N(C1-6烷基)2； R 1 , R 2 , R 3 and R 4 are each independently selected from: hydrogen, halogen, -OH, -CN, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 ;

Z為O、NR5或CR6R7； Z is O, NR 5 or CR 6 R 7 ;

R5選自：氫、C1-6烷基或C3-6環烷基； R 5 is selected from: hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl;

R6和R7分別獨立地選自：氫、鹵素、-CN、C1-6鹵烷基、-O(C1-6鹵烷基)、-OH、C1-6烷基、C3-6環烷基或-O(C1-6烷基)； R 6 and R 7 are each independently selected from: hydrogen, halogen, -CN, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -OH, C 1-6 alkyl, C 3 -6 cycloalkyl or -O (C 1-6 alkyl);

Figure 109116218-A0101-12-0017-9
為苯基、5-6員雜芳基或吲唑基；它們各自視需要地被一個或多個選 自以下的基團所取代：鹵素、-CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-O(C1-6烷基)或-O(C1-6鹵烷基)；
Figure 109116218-A0101-12-0017-9
Is a phenyl group, a 5-6 membered heteroaryl group or an indazolyl group; each of them is optionally substituted by one or more groups selected from the group consisting of halogen, -CN, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -O(C 1-6 alkyl) or -O(C 1-6 haloalkyl);

Figure 109116218-A0101-12-0017-10
為吡啶基、嘧啶基、吡嗪基、噠嗪基或三嗪基，它們各自視需要地被 一個或多個選自以下的基團所取代：鹵素、-(C1-6烷基)n-CN、-NO2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-(C1-6烷基)n-C3-6環烷基、-(C1-6烷基)n-苯基、-(C1-6烷基)n-4-6員雜環基、-(C1-6烷基)n-5-6員雜芳基、-(C1-6烷基)n-NR1’R2’、-(C1-6烷基)n-CONR1’R2’、-(C1-6烷基)n-NR1’R2’C(O)R3’、-(C1-6烷基)n-C(O)R3’-、-(C1-6烷基)n-C(O)OR4’、-(C1-6烷基)n-OR5’、-(C1-6烷基)n-S(O)mNR1’R2’、-(C1-6烷基)n-NR1’R2’S(O)mR6’、-(C1-6烷基)n-S(O)mR6’和-(C1-6烷基)n-SR7’；其中，該的苯基、C3-6環烷基、4-6員雜環基和5-6員雜芳基視需要地被一個或多個選自以下的基團所取代：鹵素、-CN、-OH、-NH2、C1-6鹵烷基、-O(C1-6鹵烷基)、C1-6 烷基、-O(C1-6烷基)、-NH(C1-6烷基)、-N(C1-6烷基)2、C2-6烯基、C2-6炔基和C3-6環烷基；
Figure 109116218-A0101-12-0017-10
Is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, each of which is optionally substituted by one or more groups selected from the group consisting of halogen, -(C 1-6 alkyl) n -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -(C 1-6 alkyl) n -C 3- 6 cycloalkyl, -(C 1-6 alkyl) n -phenyl, -(C 1-6 alkyl) n -4-6 membered heterocyclyl, -(C 1-6 alkyl) n -5 -6-membered heteroaryl, - (C 1-6 alkyl) n -NR 1 'R 2' , - (C 1-6 alkyl) n -CONR 1 'R 2' , - (C 1-6 alkyl yl) n -NR 1 'R 2' C (O) R 3 ', - (C 1-6 alkyl) n -C (O) R 3 ' -, - (C 1-6 alkyl) n -C (O) OR 4 ', - (C 1-6 alkyl) n -OR 5', - ( C 1-6 alkyl) n -S (O) m NR 1 'R 2', - (C 1- 6 alkyl) n -NR 1 'R 2' S (O) m R 6 ', - (C 1-6 alkyl) n -S (O) m R 6' and - (C 1-6 alkyl) n -SR 7 '; wherein the phenyl group, C 3-6 cycloalkyl group, 4-6 membered heterocyclic group and 5-6 membered heteroaryl group are optionally selected by one or more groups selected from the following Substituted: halogen, -CN, -OH, -NH 2 , C 1-6 haloalkyl, -O (C 1-6 haloalkyl), C 1-6 alkyl, -O (C 1-6 alkane Group), -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl;

n為0或1； n is 0 or 1;

m為1或2； m is 1 or 2;

p為0或1； p is 0 or 1;

R1’、R2’、R3’、R4’、R5’、R6’和R7’分別獨立地選自氫、C1-6烷基、C1-6鹵烷基、-(C1-6烷基)-O-(C1-6烷基)、-(C1-6烷基)-OH、-(C1-6烷基)-CN、-(C1-6烷基)-NH2或C3-6環烷基；或者R1’、R2’與它們相連的N原子一起形成一個4-6員的雜環。 R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 6 'and R 7 ' are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl,- (C 1-6 alkyl)-O-(C 1-6 alkyl), -(C 1-6 alkyl)-OH, -(C 1-6 alkyl)-CN, -(C 1-6 Alkyl) -NH 2 or C 3-6 cycloalkyl; or R 1 ′ and R 2 ′ together with the N atom to which they are connected form a 4-6 membered heterocyclic ring.

在式(I)化合物的一些實施方案中，X為CR3；Y為CR4。 In some embodiments of the compound of Formula (I), X is CR 3 ; Y is CR 4 .

在式(I)化合物的一些實施方案中，X為CH；Y為CH。 In some embodiments of the compound of Formula (I), X is CH; Y is CH.

在式(I)化合物的一些實施方案中，R1、R2、R3、R4、R6和R7分別獨立地選自：氫和鹵素(例如F)。 In some embodiments of the compound of formula (I), R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are each independently selected from: hydrogen and halogen (eg, F).

在式(I)化合物的一些實施方案中，R1、R2、R3、R4、R5、R6和R7均為氫。 In some embodiments of the compound of Formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are all hydrogen.

在式(I)化合物的一些實施方案中，X為CH；Y為N。 In some embodiments of the compound of Formula (I), X is CH; Y is N.

在式(I)化合物的一些實施方案中，X為N；Y為N。 In some embodiments of the compound of Formula (I), X is N; Y is N.

在式(I)化合物的一些實施方案中，p為0，Z為CR6R7；R6和R7分別獨立地選自：氫、鹵素、-CN、C1-6鹵烷基、-O(C1-6鹵烷基)、-OH、C1-6烷基、C3-6環烷基或-O(C1-6烷基)。 In some embodiments of the compound of formula (I), p is 0 and Z is CR 6 R 7 ; R 6 and R 7 are each independently selected from: hydrogen, halogen, -CN, C 1-6 haloalkyl,- O (C 1-6 haloalkyl), -OH, C 1-6 alkyl, C 3-6 cycloalkyl, or -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，p為0，Z為CHR6；R6選自：氫、-OH、C1-6烷基或-O(C1-6烷基)。 In some embodiments of the compound of formula (I), p is 0 and Z is CHR 6 ; R 6 is selected from: hydrogen, -OH, C 1-6 alkyl, or -O(C 1-6 alkyl).

在式(I)化合物的一些實施方案中，p為0，Z為CH2。 In some embodiments of the compound of Formula (I), p is 0 and Z is CH 2 .

在式(I)化合物的一些實施方案中，p為1，Z為CR6R7；R6和R7分別獨立地選自：氫、鹵素、-CN、C1-6鹵烷基、-O(C1-6鹵烷基)、-OH、C1-6烷基、C3-6環烷基或-O(C1-6烷基)。 In some embodiments of the compound of formula (I), p is 1, Z is CR 6 R 7 ; R 6 and R 7 are each independently selected from: hydrogen, halogen, -CN, C 1-6 haloalkyl,- O (C 1-6 haloalkyl), -OH, C 1-6 alkyl, C 3-6 cycloalkyl, or -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，p為1，Z為CHR6；R6選自：氫、-OH、C1-6烷基或-O(C1-6烷基)。 In some embodiments of the compound of formula (I), p is 1, Z is CHR 6 ; R 6 is selected from: hydrogen, -OH, C 1-6 alkyl, or -O(C 1-6 alkyl).

在式(I)化合物的一些實施方案中，p為1，Z為NR5；R5選自：氫、C1-6烷基或C3-6環烷基。 In some embodiments of the compound of formula (I), p is 1, Z is NR 5 ; R 5 is selected from: hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl.

在式(I)化合物的一些實施方案中，p為1，Z為NR5；R5為氫或C1-6烷基。 In some embodiments of the compound of Formula (I), p is 1, Z is NR 5 ; R 5 is hydrogen or C 1-6 alkyl.

在式(I)化合物的一些實施方案中，p為1，Z為O。 In some embodiments of the compound of Formula (I), p is 1 and Z is O.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0019-11
為苯基或5-6員雜芳基， 它們視需要地被一個或多個選自以下的基團所取代：鹵素、-CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-O(C1-6烷基)或-O(C1-6鹵烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0019-11
Are phenyl or 5-6 membered heteroaryl groups, which are optionally substituted by one or more groups selected from the group consisting of halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -O (C 1-6 alkyl) ) Or -O(C 1-6 haloalkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0019-13
為苯基、吡啶基、嘧啶 基、吲唑基、吡咯基、吡唑基或噻吩基，它們視需要地被一個或多個選自以下的基團所取代：鹵素、-CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-O(C1-6烷基)或-O(C1-6鹵烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0019-13
Are phenyl, pyridyl, pyrimidinyl, indazolyl, pyrrolyl, pyrazolyl or thienyl, which are optionally substituted by one or more groups selected from the group consisting of halogen, -CN, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) ) 2 , -O (C 1-6 alkyl) or -O (C 1-6 haloalkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0020-14
為苯基，其視需要地被 一個或多個選自以下的基團所取代：鹵素、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-NH2、-O(C1-6鹵烷基)或-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0020-14
Is a phenyl group, which is optionally substituted by one or more groups selected from the group consisting of halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 Haloalkyl, -NH 2 , -O (C 1-6 haloalkyl) or -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0020-15
為苯基，其視需要地被 一個或多個選自以下的基團所取代：鹵素、CN、C1-6烷基、C2-6炔基、C1-6鹵烷基、-O(C1-6鹵烷基)或-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0020-15
Is a phenyl group, optionally substituted by one or more groups selected from the group consisting of halogen, CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) or -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0020-16
為苯基，其視需要地被 一個或多個選自以下的基團所取代：F、Cl、Br、CN、甲基、乙基、乙炔基、三氟甲基、-O(三氟甲基)、-OCHF2或甲氧基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0020-16
It is a phenyl group, which is optionally substituted by one or more groups selected from the group consisting of F, Cl, Br, CN, methyl, ethyl, ethynyl, trifluoromethyl, -O(trifluoromethyl Group), -OCHF 2 or methoxy.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0020-17
為苯基，其被一個或多 個選自以下的基團所取代：F、Cl、Br、CN、甲基、乙基、-CF3、-OCF3、-OCHF2或甲氧基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0020-17
It is a phenyl group, which is substituted by one or more groups selected from F, Cl, Br, CN, methyl, ethyl, -CF 3 , -OCF 3 , -OCHF 2 or methoxy.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0020-23
為被乙炔基取代的苯 基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0020-23
Is phenyl substituted by ethynyl.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0020-19
為被鹵素取代的苯基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0020-19
Is a phenyl substituted by halogen.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0020-20
為被-OCF3或-OCHF2取代 的苯基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0020-20
It is a phenyl group substituted by -OCF 3 or -OCHF 2.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0020-21
為被CN取代的苯基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0020-21
Is a phenyl substituted by CN.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0021-24
為吡啶基，其視需要地 被一個或多個選自以下的基團所取代：C2-6炔基或-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0021-24
It is a pyridyl group, which is optionally substituted with one or more groups selected from the group consisting of C 2-6 alkynyl or -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0021-25
為視需要被鹵素或CN取 代的吡咯基或噻吩基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0021-25
Pyrrolyl or thienyl substituted by halogen or CN as needed.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0021-26
為吡啶基、嘧啶基、吡 嗪基、噠嗪基、或三嗪基，它們視需要地被一個或多個選自以下的基團所取代： In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0021-26
Are pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, which are optionally substituted by one or more groups selected from the following:

1)鹵素； 1) Halogen;

2)-NO2； 2)-NO 2 ;

3)側氧基； 3) Pendant groups;

4)-(C1-6烷基)n-CN； 4)-(C 1-6 alkyl) n -CN;

5)C1-6烷基； 5) C 1-6 alkyl;

6)C1-6鹵烷基； 6) C 1-6 haloalkyl;

7)C3-6環烷基； 7) C 3-6 cycloalkyl;

8)(C1-6烷基)n-4-6員雜環基； 8) (C 1-6 alkyl) n -4-6 membered heterocyclyl;

9)5-6員雜芳基； 9) 5-6 membered heteroaryl groups;

10)(C1-6烷基)n-NR1’R2’； 10) (C 1-6 alkyl) n -NR 1 'R 2' ;

11)-CONR1’R2’； 11) -CONR 1 'R 2' ;

12)-NR1’R2’C(O)R3’； 12) -NR 1 'R 2' C (O) R 3 ';

13)-C(O)OR4’； 13)-C(O)OR 4 ';

14)-(C1-6烷基)n-OR5’； 14)-(C 1-6 alkyl) n -OR 5 ';

15)-S(O)2NR1’R2’；或 15) -S (O) 2 NR 1 'R 2'; or

16)-NR1’R2’S(O)2R6’； 16) -NR 1 'R 2' S (O) 2 R 6 ';

其中，該的4-6員雜環基和5-6員雜芳基視需要地被一個或多個選自以下的基團所取代：C1-6烷基、-O(C1-6烷基)或-NH(C1-6烷基)； Wherein, the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by one or more groups selected from: C 1-6 alkyl, -O(C 1-6 Alkyl) or -NH (C 1-6 alkyl);

n為0或1； n is 0 or 1;

R1’、R2’、R3’、R4’、R5’和R6’分別獨立地選自氫、C1-6烷基、C1-6鹵烷基、-(C1-6烷基)-O-(C1-6烷基)、-(C1-6烷基)-OH、-(C1-6烷基)-CN、-(C1-6烷基)-NH2或C3-6環烷基；或者R1’、R2’與它們相連的N原子一起形成一個4-6員的雜環。 R 1 ', R 2 ', R 3 ', R 4 ', R 5 'and R 6 ' are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1- 6 alkyl)-O-(C 1-6 alkyl), -(C 1-6 alkyl)-OH, -(C 1-6 alkyl)-CN, -(C 1-6 alkyl)- NH 2 or C 3-6 cycloalkyl; or R 1 ′, R 2 ′ and the N atom to which they are connected together form a 4-6 membered heterocyclic ring.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0022-27
為吡啶基、嘧啶基或噠 嗪基，它們被一個、兩個或三個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0022-27
They are pyridyl, pyrimidinyl or pyridazinyl, which are substituted by one, two or three groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkane base).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0022-28
為被胺基取代的吡啶 基、被胺基取代的嘧啶基或被胺基取代的噠嗪基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0022-28
It is a pyridyl group substituted by an amino group, a pyrimidinyl group substituted by an amino group or a pyridazinyl group substituted by an amino group, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1- 6 haloalkyl), -O(C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0022-29
為被-(C1-6烷基)-OH取代 的吡啶基、被-(C1-6烷基)-OH取代的嘧啶基或被-(C1-6烷基)-OH取代的噠嗪基，它 們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0022-29
As being - (C 1-6 alkyl) -OH substituted pyridinyl, by - (C 1-6 alkyl) -OH substituted pyrimidyl or - (C 1-6 alkyl) -OH-substituted pyridazin Azinyl groups, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -(C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0023-30
為吡啶基或嘧啶基，它 們視需要地被一個或多個選自以下的基團所取代： In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0023-30
They are pyridyl or pyrimidinyl, which are optionally substituted by one or more groups selected from:

1)鹵素； 1) Halogen;

2)-NO2； 2)-NO 2 ;

3)側氧基； 3) Pendant groups;

4)-(C1-6烷基)n-CN； 4)-(C 1-6 alkyl) n -CN;

5)C1-6烷基； 5) C 1-6 alkyl;

6)C1-6鹵烷基； 6) C 1-6 haloalkyl;

7)-C3-6環烷基； 7) -C 3-6 cycloalkyl;

8)-(C1-6烷基)n-4-6員雜環基； 8)-(C 1-6 alkyl) n -4-6 membered heterocyclyl;

9)-5-6員雜芳基； 9)-5-6-membered heteroaryl;

10)-(C1-6烷基)n-NR1’R2’； 10) - (C 1-6 alkyl) n -NR 1 'R 2' ;

11)-CONR1’R2’； 11) -CONR 1 'R 2' ;

12)-NR1’R2’C(O)R3’； 12) -NR 1 'R 2' C (O) R 3 ';

13)-C(O)OR4’； 13)-C(O)OR 4 ';

14)-(C1-6烷基)n-OR5’； 14)-(C 1-6 alkyl) n -OR 5 ';

15)-S(O)2NR1’R2’；或 15) -S (O) 2 NR 1 'R 2'; or

16)-NR1’R2’S(O)2R6’； 16) -NR 1 'R 2' S (O) 2 R 6 ';

其中，該的4-6員雜環基和5-6員雜芳基視需要地被一個或多個選自以下的基團所取代：C1-6烷基、-O(C1-6烷基)或-NH(C1-6烷基)； Wherein, the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by one or more groups selected from: C 1-6 alkyl, -O(C 1-6 Alkyl) or -NH (C 1-6 alkyl);

n為0或1； n is 0 or 1;

R1’、R2’、R3’、R4’、R5’和R6’分別獨立地選自氫、C1-6烷基、C1-6鹵烷基、-(C1-6烷基)-O-(C1-6烷基)、-(C1-6烷基)-CN或C3-6環烷基；或者R1’、R2’與它們相連的N原子一起形成一個4-6員的雜環。 R 1 ', R 2 ', R 3 ', R 4 ', R 5 'and R 6 ' are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1- 6 alkyl)-O-(C 1-6 alkyl), -(C 1-6 alkyl)-CN or C 3-6 cycloalkyl; or R 1 ', R 2 'and the N atom to which they are connected Together to form a 4-6 member heterocyclic ring.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0024-31
為吡啶基或嘧啶基，它 們被一個、兩個或三個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0024-31
Are pyridyl or pyrimidinyl, which are substituted by one, two or three groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1- 6 Alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0024-32
為被胺基取代的吡啶基 或被胺基取代的嘧啶基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0024-32
Is a pyridyl substituted by an amino group or a pyrimidinyl substituted by an amino group, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkane Group), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O( C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0024-33
為被-(C1-6烷基)-OH取代 的吡啶基或被-(C1-6烷基)-OH取代的嘧啶基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0024-33
As being - (C 1-6 alkyl) -OH substituted pyridyl or - (C 1-6 alkyl) -OH substituents pyrimidinyl, each of which simultaneously one or two groups selected from the Substitution: halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 halo Alkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0024-34
為吡啶基，其視需要地 被一個或多個選自以下的基團所取代： In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0024-34
Is pyridyl, optionally substituted with one or more groups selected from:

1)鹵素； 1) Halogen;

2)-NO2； 2)-NO 2 ;

3)側氧基； 3) Pendant groups;

4)-(C1-6烷基)n-CN； 4)-(C 1-6 alkyl) n -CN;

5)C1-6烷基； 5) C 1-6 alkyl;

6)C1-6鹵烷基； 6) C 1-6 haloalkyl;

7)-C3-6環烷基； 7) -C 3-6 cycloalkyl;

8)-(C1-6烷基)n-4-6員雜環基； 8)-(C 1-6 alkyl) n -4-6 membered heterocyclyl;

9)-5-6員雜芳基； 9)-5-6-membered heteroaryl;

10)-(C1-6烷基)n-NR1’R2’； 10) - (C 1-6 alkyl) n -NR 1 'R 2' ;

11)-CONR1’R2’； 11) -CONR 1 'R 2' ;

12)-NR1’R2’C(O)R3’； 12) -NR 1 'R 2' C (O) R 3 ';

13)-C(O)OR4’； 13)-C(O)OR 4 ';

14)-(C1-6烷基)n-OR5’； 14)-(C 1-6 alkyl) n -OR 5 ';

15)-S(O)2NR1’R2’；或 15) -S (O) 2 NR 1 'R 2'; or

16)-NR1’R2’S(O)2R6’； 16) -NR 1 'R 2' S (O) 2 R 6 ';

其中，該的4-6員雜環基和5-6員雜芳基視需要地被一個或多個選自以下的基團所取代：C1-6烷基、-O(C1-6烷基)或-NH(C1-6烷基)； Wherein, the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by one or more groups selected from: C 1-6 alkyl, -O(C 1-6 Alkyl) or -NH (C 1-6 alkyl);

n為0或1； n is 0 or 1;

R1’、R2’、R3’、R4’、R5’和R6’分別獨立地選自氫、C1-6烷基、C1-6鹵烷基、-(C1-6烷基)-O-(C1-6烷基)、-(C1-6烷基)-CN或C3-6環烷基；或者R1’、R2’與它們相連的N原子一起形成一個4-6員的雜環。 R 1 ', R 2 ', R 3 ', R 4 ', R 5 'and R 6 ' are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1- 6 alkyl)-O-(C 1-6 alkyl), -(C 1-6 alkyl)-CN or C 3-6 cycloalkyl; or R 1 ', R 2 'and the N atom to which they are connected Together to form a 4-6 member heterocyclic ring.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0025-36
為吡啶基，其被一個、 兩個或三個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0025-36
It is a pyridyl group, which is substituted by one, two or three groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) ) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0026-37
為被胺基取代的吡啶 基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0026-37
It is a pyridyl group substituted by an amino group, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1- 6 Alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0026-38
為被-(C1-6烷基)-OH取代 的吡啶基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0026-38
Is a pyridyl substituted by -(C 1-6 alkyl)-OH, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkane Group), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O( C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0026-39
為被-(C1-6烷基)-OH和C1-6 鹵烷基取代的吡啶基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0026-39
It is pyridyl substituted by -(C 1-6 alkyl)-OH and C 1-6 haloalkyl.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0026-40
為
Figure 109116218-A0101-12-0026-41
或
Figure 109116218-A0101-12-0026-43
，其 視需要地被一個或多個選自以下的基團所取代： In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0026-40
for
Figure 109116218-A0101-12-0026-41
or
Figure 109116218-A0101-12-0026-43
, Which is optionally substituted by one or more groups selected from:

1)鹵素； 1) Halogen;

2)-NO2； 2)-NO 2 ;

3)側氧基； 3) Pendant groups;

4)-(C1-6烷基)n-CN； 4)-(C 1-6 alkyl) n -CN;

5)C1-6烷基； 5) C 1-6 alkyl;

6)C1-6鹵烷基； 6) C 1-6 haloalkyl;

7)-C3-6環烷基； 7) -C 3-6 cycloalkyl;

8)-(C1-6烷基)n-4-6員雜環基； 8)-(C 1-6 alkyl) n -4-6 membered heterocyclyl;

9)-5-6員雜芳基； 9)-5-6-membered heteroaryl;

10)-(C1-6烷基)n-NR1’R2’； 10) - (C 1-6 alkyl) n -NR 1 'R 2' ;

11)-CONR1’R2’； 11) -CONR 1 'R 2' ;

12)-NR1’R2’C(O)R3’； 12) -NR 1 'R 2' C (O) R 3 ';

13)-C(O)OR4’； 13)-C(O)OR 4 ';

14)-(C1-6烷基)n-OR5’； 14)-(C 1-6 alkyl) n -OR 5 ';

15)-S(O)2NR1’R2’；或 15) -S (O) 2 NR 1 'R 2'; or

16)-NR1’R2’S(O)2R6’； 16) -NR 1 'R 2' S (O) 2 R 6 ';

其中，該的4-6員雜環基和5-6員雜芳基視需要地被一個或多個選自以下的基團所取代：C1-6烷基、-O(C1-6烷基)或-NH(C1-6烷基)； Wherein, the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by one or more groups selected from: C 1-6 alkyl, -O(C 1-6 Alkyl) or -NH (C 1-6 alkyl);

n為0或1； n is 0 or 1;

R1’、R2’、R3’、R4’、R5’和R6’分別獨立地選自氫、C1-6烷基、C1-6鹵烷基、-(C1-6烷基)-O-(C1-6烷基)、-(C1-6烷基)-CN或C3-6環烷基；或者R1’、R2’與它們相連的N原子一起形成一個4-6員的雜環。 R 1 ', R 2 ', R 3 ', R 4 ', R 5 'and R 6 ' are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1- 6 alkyl)-O-(C 1-6 alkyl), -(C 1-6 alkyl)-CN or C 3-6 cycloalkyl; or R 1 ', R 2 'and the N atom to which they are connected Together to form a 4-6 member heterocyclic ring.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0027-44
為
Figure 109116218-A0101-12-0027-45
或
Figure 109116218-A0101-12-0027-48
，其 視需要地被一個或多個選自以下的基團所取代：CN、鹵素、C1-6烷基、C1-6鹵烷基、-O-(C1-6烷基)、-O-(C1-6鹵烷基)、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2或-NH(C1-6鹵烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0027-44
for
Figure 109116218-A0101-12-0027-45
or
Figure 109116218-A0101-12-0027-48
, Which is optionally substituted by one or more groups selected from: CN, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -O-(C 1-6 alkyl), -O-(C 1-6 haloalkyl), -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 or -NH(C 1-6 haloalkyl) ).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0027-49
為
Figure 109116218-A0101-12-0027-50
或
Figure 109116218-A0101-12-0027-51
，其 被一個、兩個或三個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0027-49
for
Figure 109116218-A0101-12-0027-50
or
Figure 109116218-A0101-12-0027-51
, Which is substituted by one, two or three groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0028-52
為被胺基取代的
Figure 109116218-A0101-12-0028-53
或
Figure 109116218-A0101-12-0028-56
，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、- NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0028-52
Is substituted by an amine group
Figure 109116218-A0101-12-0028-53
or
Figure 109116218-A0101-12-0028-56
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0028-54
為被-(C1-6烷基)-OH取代 的
Figure 109116218-A0101-12-0028-57
或
Figure 109116218-A0101-12-0028-59
，其同時被一個或兩個選自以下的基團所取代：鹵素、 CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0028-54
Is substituted by -(C 1-6 alkyl)-OH
Figure 109116218-A0101-12-0028-57
or
Figure 109116218-A0101-12-0028-59
, Which is simultaneously substituted by one or two groups selected from: halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0028-60
為被-(C1-6烷基)-OH和C1-6 鹵烷基取代的
Figure 109116218-A0101-12-0028-63
或
Figure 109116218-A0101-12-0028-62
。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0028-60
Is substituted by -(C 1-6 alkyl)-OH and C 1-6 haloalkyl
Figure 109116218-A0101-12-0028-63
or
Figure 109116218-A0101-12-0028-62
.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0028-61
為嘧啶基，其視需要地 被一個或多個選自以下的基團所取代：鹵素、-CN、C1-6烷基、C1-6鹵烷基、4-6員雜環基、-NR1’R2’或-OR5’；R1’、R2’和R5’分別獨立地選自氫、C1-6烷基或C1-6鹵烷基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0028-61
Is a pyrimidinyl group, which is optionally substituted by one or more groups selected from the group consisting of halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, 4-6 membered heterocyclic group, -NR 1 'R 2' or -OR 5 '; R 1', R 2 ' and R 5' are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 haloalkyl.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0028-64
為嘧啶基，其被一個、 兩個或三個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0028-64
It is a pyrimidinyl group, which is substituted by one, two or three groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) ) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0029-66
為嘧啶基，其被一個、 兩個或三個選自以下的基團所取代：-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2和C1-6鹵烷基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0029-66
Is a pyrimidinyl group, which is substituted by one, two or three groups selected from: -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 and C 1-6 haloalkyl.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0029-65
為被胺基取代的嘧啶 基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0029-65
It is a pyrimidinyl group substituted by an amino group, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1- 6 Alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0029-69
為被胺基取代的嘧啶 基，其同時被一個或兩個選自以下的基團所取代：-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2和C1-6鹵烷基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0029-69
It is a pyrimidinyl group substituted by an amino group, which is simultaneously substituted by one or two groups selected from: -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 and C 1-6 haloalkyl.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0029-67
為被-(C1-6烷基)-OH取代 的嘧啶基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0029-67
It is a pyrimidinyl substituted by -(C 1-6 alkyl)-OH, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkane Group), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O( C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0029-68
為被-(C1-6烷基)-OH和C1-6 鹵烷基取代的嘧啶基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0029-68
It is a pyrimidinyl substituted by -(C 1-6 alkyl)-OH and C 1-6 haloalkyl.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0029-70
為
Figure 109116218-A0101-12-0029-71
，其視需要地 被一個或多個選自以下的基團所取代：鹵素、-CN、C1-6烷基、C1-6鹵烷基、4-6員雜環基、-NR1’R2’或-OR5’；R1’、R2’和R5’分別獨立地選自氫、C1-6烷基或C1-6鹵烷基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0029-70
for
Figure 109116218-A0101-12-0029-71
, Which is optionally substituted by one or more groups selected from the group consisting of halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, 4-6 membered heterocyclyl, -NR 1 'R 2 'or -OR 5 '; R 1 ', R 2 ' and R 5 'are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 haloalkyl.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0030-74
為
Figure 109116218-A0101-12-0030-280
，其視需要地 被一個或多個選自以下的基團所取代：CN、鹵素、C1-6烷基、C1-6鹵烷基、-O-(C1-6烷基)、-O-(C1-6鹵烷基)、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2或-NH(C1-6鹵烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0030-74
for
Figure 109116218-A0101-12-0030-280
, Which is optionally substituted by one or more groups selected from: CN, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -O-(C 1-6 alkyl), -O-(C 1-6 haloalkyl), -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 or -NH(C 1-6 haloalkyl) ).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0030-75
為
Figure 109116218-A0101-12-0030-82
，其被一個、 兩個或三個選自以下的基團所取代：鹵素、C1-6烷基、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0030-75
for
Figure 109116218-A0101-12-0030-82
, Which is substituted by one, two or three groups selected from the group consisting of halogen, C 1-6 alkyl, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1 -6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0030-76
為
Figure 109116218-A0101-12-0030-81
，其被一個、 兩個或三個選自以下的基團所取代：-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2和C1-6鹵烷基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0030-76
for
Figure 109116218-A0101-12-0030-81
, Which is substituted by one, two or three groups selected from: -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 and C 1-6 Haloalkyl.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0030-77
為被胺基取代的
Figure 109116218-A0101-12-0030-78
，其同時被一個或兩個選自以下的基團所取代：鹵素、C1-6烷基、CN、- NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0030-77
Is substituted by an amine group
Figure 109116218-A0101-12-0030-78
, Which is simultaneously substituted by one or two groups selected from: halogen, C 1-6 alkyl, CN , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 Alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0030-79
為被胺基取代的
Figure 109116218-A0101-12-0030-80
，其同時被一個或兩個選自以下的基團所取代：-NH2、-NH(C1-6烷基)、- N(C1-6烷基)2和C1-6鹵烷基。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0030-79
Is substituted by an amine group
Figure 109116218-A0101-12-0030-80
, Which is simultaneously substituted by one or two groups selected from: -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 and C 1-6 haloalkane base.

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0031-83
為被-(C1-6烷基)-OH取代 的
Figure 109116218-A0101-12-0031-86
，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、- NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0031-83
Is substituted by -(C 1-6 alkyl)-OH
Figure 109116218-A0101-12-0031-86
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I)化合物的一些實施方案中，

Figure 109116218-A0101-12-0031-84
為被-(C1-6烷基)-OH和C1-6 鹵烷基取代的
Figure 109116218-A0101-12-0031-85
。 In some embodiments of the compound of Formula (I),
Figure 109116218-A0101-12-0031-84
Is substituted by -(C 1-6 alkyl)-OH and C 1-6 haloalkyl
Figure 109116218-A0101-12-0031-85
.

在式(I)化合物的一些實施方案中，式(I)化合物具有式(I-1)結構： In some embodiments of the compound of formula (I), the compound of formula (I) has the structure of formula (I-1):

Figure 109116218-A0101-12-0031-87
Figure 109116218-A0101-12-0031-87

在式(I-1)化合物的一些實施方案中，X為N或CH；Y為N或CH。 In some embodiments of the compound of Formula (I-1), X is N or CH; Y is N or CH.

在式(I-1)化合物的一些實施方案中，X為CH；Y為CH。 In some embodiments of the compound of Formula (I-1), X is CH; Y is CH.

在式(I-1)化合物的一些實施方案中，X為CH；Y為N。 In some embodiments of the compound of Formula (I-1), X is CH; Y is N.

在式(I-1)化合物的一些實施方案中，X為N；Y為N。 In some embodiments of the compound of Formula (I-1), X is N; Y is N.

在式(I)化合物的一些實施方案中，Z為NR5、CR6R7或O；其中，R6和R7獨立地選自：氫、-OH、C1-6烷基或-O(C1-6烷基)；R5為氫或C1-6烷基。 In some embodiments of the compound of formula (I), Z is NR 5 , CR 6 R 7 or O; wherein R 6 and R 7 are independently selected from: hydrogen, -OH, C 1-6 alkyl, or -O (C 1-6 alkyl); R 5 is hydrogen or C 1-6 alkyl.

在式(I-1)化合物的一些實施方案中，Z為O。 In some embodiments of the compound of Formula (I-1), Z is O.

在式(I-1)化合物的一些實施方案中，Z為CH2。 In some embodiments of a compound of Formula (I-1), Z is CH 2 .

在式(I-1)化合物的一些實施方案中，Z為NH。 In some embodiments of the compound of Formula (I-1), Z is NH.

在式(I-1)化合物的一些實施方案中，Ra選自：鹵素、CN、C1-6烷基、C2-6炔基、C1-6鹵烷基、-O(C1-6鹵烷基)或-O(C1-6烷基)。 In the formula (I-1) of some embodiments of compounds, R a is selected from: halo, CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O (C 1 -6 haloalkyl) or -O(C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，Ra選自：F、Cl、Br、CN、甲基、乙基、乙炔基、三氟甲基、-O(三氟甲基)或甲氧基。 In the formula (I-1) of some embodiments of compounds, R a is selected from: F, Cl, Br, CN , methyl, ethyl, ethynyl, trifluoromethyl, -O (trifluoromethyl), or Methoxy.

在式(I-1)化合物的一些實施方案中，Ra選自：F、Cl、Br、CN、甲基、乙基、-CF3、-OCF3或甲氧基。 In the formula (I-1) of some embodiments of compounds, R a is selected from: F, Cl, Br, CN , methyl, ethyl, -CF 3, -OCF 3 or methoxy.

在式(I-1)化合物的一些實施方案中，Ra為乙炔基。 In some embodiments of compounds of formula (I-1), R a is ethynyl.

在式(I-1)化合物的一些實施方案中，Ra為鹵素。 In the formula (I-1) of some embodiments of compounds, R a is halo.

在式(I-1)化合物的一些實施方案中，Ra為-OCF3或-OCHF2。 In some embodiments of compounds of formula (I-1), R a is as -OCF 3 or -OCHF 2.

在式(I-1)化合物的一些實施方案中，Ra為CN。 In some embodiments of compounds of formula (I-1) in a, R a is CN.

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0032-73
為被胺基取代的吡啶 基、被胺基取代的嘧啶基或被胺基取代的噠嗪基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0032-73
It is a pyridyl group substituted by an amino group, a pyrimidinyl group substituted by an amino group or a pyridazinyl group substituted by an amino group, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1- 6 haloalkyl), -O(C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0032-72
為被胺基取代的吡啶基 或被胺基取代的嘧啶基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0032-72
Is a pyridyl substituted by an amino group or a pyrimidinyl substituted by an amino group, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkane Group), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O( C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0033-88
為被胺基取代的吡啶 基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0033-88
It is a pyridyl group substituted by an amino group, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1- 6 Alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0033-89
為被胺基取代的
Figure 109116218-A0101-12-0033-92
或
Figure 109116218-A0101-12-0033-91
，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、- NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0033-89
Is substituted by an amine group
Figure 109116218-A0101-12-0033-92
or
Figure 109116218-A0101-12-0033-91
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0033-93
為被胺基取代的嘧啶 基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0033-93
It is a pyrimidinyl group substituted by an amino group, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1- 6 Alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0033-96
為被胺基取代的嘧啶基，其同時 被一個或兩個選自以下的基團所取代：-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2和C1-6鹵烷基。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0033-96
It is a pyrimidinyl group substituted by an amino group, which is simultaneously substituted by one or two groups selected from: -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 and C 1-6 haloalkyl.

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0033-94
為被胺基取代的
Figure 109116218-A0101-12-0033-95
，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、- NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0033-94
Is substituted by an amine group
Figure 109116218-A0101-12-0033-95
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0034-97
為被胺基取代的
Figure 109116218-A0101-12-0034-99
，其同時被一個或兩個選自以下的基團所取代：-NH2、-NH(C1-6烷基)、- N(C1-6烷基)2和C1-6鹵烷基。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0034-97
Is substituted by an amine group
Figure 109116218-A0101-12-0034-99
, Which is simultaneously substituted by one or two groups selected from: -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 and C 1-6 haloalkane base.

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0034-98
為被-(C1-6烷基)-OH取代 的吡啶基、被-(C1-6烷基)-OH取代的嘧啶基或被-(C1-6烷基)-OH取代的噠嗪基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0034-98
As being - (C 1-6 alkyl) -OH substituted pyridinyl, by - (C 1-6 alkyl) -OH substituted pyrimidyl or - (C 1-6 alkyl) -OH-substituted pyridazin Azinyl groups, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -(C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0034-101
為被-(C1-6烷基)-OH取代 的吡啶基或被-(C1-6烷基)-OH取代的嘧啶基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0034-101
As being - (C 1-6 alkyl) -OH substituted pyridyl or - (C 1-6 alkyl) -OH substituents pyrimidinyl, each of which simultaneously one or two groups selected from the Substitution: halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 halo Alkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0034-103
為被-(C1-6烷基)-OH取代 的吡啶基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0034-103
Is a pyridyl substituted by -(C 1-6 alkyl)-OH, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkane Group), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O( C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0034-104
為被-(C1-6烷基)-OH和C1- 6鹵烷基取代的吡啶基。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0034-104
As being - (C 1-6 alkyl) -OH and C 1- 6 haloalkyl substituted pyridyl.

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0035-105
為被-(C1-6烷基)-OH取代 的
Figure 109116218-A0101-12-0035-112
或
Figure 109116218-A0101-12-0035-110
，其同時被一個或兩個選自以下的基團所取代：鹵素、 CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0035-105
Is substituted by -(C 1-6 alkyl)-OH
Figure 109116218-A0101-12-0035-112
or
Figure 109116218-A0101-12-0035-110
, Which is simultaneously substituted by one or two groups selected from: halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0035-106
為被-(C1-6烷基)-OH和C1- 6鹵烷基取代的
Figure 109116218-A0101-12-0035-109
或
Figure 109116218-A0101-12-0035-108
。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0035-106
As being - (C 1-6 alkyl) -OH and C 1- 6 haloalkyl substituted
Figure 109116218-A0101-12-0035-109
or
Figure 109116218-A0101-12-0035-108
.

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0035-107
為被-(C1-6烷基)-OH取代 的嘧啶基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0035-107
It is a pyrimidinyl substituted by -(C 1-6 alkyl)-OH, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkane Group), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O( C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0035-113
為被-(C1-6烷基)-OH和C1- 6鹵烷基取代的嘧啶基。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0035-113
As being - (C 1-6 alkyl) -OH and C 1- 6 haloalkyl substituted pyrimidinyl.

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0035-116
為被-(C1-6烷基)-OH取代 的
Figure 109116218-A0101-12-0035-115
，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、- NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0035-116
Is substituted by -(C 1-6 alkyl)-OH
Figure 109116218-A0101-12-0035-115
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-1)化合物的一些實施方案中，

Figure 109116218-A0101-12-0036-119
為被-(C1-6烷基)-OH和C1- 6鹵烷基取代的
Figure 109116218-A0101-12-0036-118
。 In some embodiments of the compound of Formula (I-1),
Figure 109116218-A0101-12-0036-119
As being - (C 1-6 alkyl) -OH and C 1- 6 haloalkyl substituted
Figure 109116218-A0101-12-0036-118
.

在式(I)化合物的一些實施方案中，式(I)化合物具有式(I-2)結構： In some embodiments of the compound of formula (I), the compound of formula (I) has the structure of formula (I-2):

Figure 109116218-A0101-12-0036-117
Figure 109116218-A0101-12-0036-117

在式(I-2)化合物的一些實施方案中，X為N或CH；Y為N或CH。 In some embodiments of the compound of formula (I-2), X is N or CH; Y is N or CH.

在式(I-2)化合物的一些實施方案中，X為CH；Y為CH。 In some embodiments of the compound of Formula (I-2), X is CH; Y is CH.

在式(I-2)化合物的一些實施方案中，X為CH；Y為N。 In some embodiments of the compound of Formula (I-2), X is CH; Y is N.

在式(I-2)化合物的一些實施方案中，X為N；Y為N。 In some embodiments of the compound of Formula (I-2), X is N; Y is N.

在式(I-2)化合物的一些實施方案中，Ra選自：鹵素、CN、C1-6烷基、C2-6炔基、C1-6鹵烷基、-O(C1-6鹵烷基)或-O(C1-6烷基)。 In some embodiments of compounds of formula (I-2), R a is selected from: halo, CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O (C 1 -6 haloalkyl) or -O(C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，Ra選自：F、Cl、Br、CN、甲基、乙基、乙炔基、三氟甲基、-O(三氟甲基)或甲氧基。 In the formula (I-2) in some embodiments of compounds, R a is selected from: F, Cl, Br, CN , methyl, ethyl, ethynyl, trifluoromethyl, -O (trifluoromethyl), or Methoxy.

在式(I-2)化合物的一些實施方案中，Ra選自：F、Cl、Br、CN、甲基、乙基、-CF3、-OCF3或甲氧基。 In the formula (I-2) in some embodiments of compounds, R a is selected from: F, Cl, Br, CN , methyl, ethyl, -CF 3, -OCF 3 or methoxy.

在式(I-2)化合物的一些實施方案中，Ra為乙炔基。 Some embodiments of the compounds (I-2) in the formula, R a is ethynyl.

在式(I-2)化合物的一些實施方案中，Ra為鹵素。 In the formula (I-2) in some embodiments of compounds, R a is halo.

在式(I-2)化合物的一些實施方案中，Ra為-OCF3或-OCHF2。 In some embodiments of compounds of formula (I-2), R a is as -OCF 3 or -OCHF 2.

在式(I-2)化合物的一些實施方案中，Ra為CN。 In some embodiments of compounds of formula (I-2), R a is as CN.

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0037-120
為被胺基取代的吡啶 基、被胺基取代的嘧啶基或被胺基取代的噠嗪基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0037-120
It is a pyridyl group substituted by an amino group, a pyrimidinyl group substituted by an amino group or a pyridazinyl group substituted by an amino group, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1- 6 haloalkyl), -O(C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0037-124
為被胺基取代的吡啶基 或被胺基取代的嘧啶基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0037-124
Is a pyridyl substituted by an amino group or a pyrimidinyl substituted by an amino group, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkane Group), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O( C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0037-122
為被胺基取代的吡啶 基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0037-122
It is a pyridyl group substituted by an amino group, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1- 6 Alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0037-125
為被胺基取代的
Figure 109116218-A0101-12-0037-126
或
Figure 109116218-A0101-12-0037-127
，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、- NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0037-125
Is substituted by an amine group
Figure 109116218-A0101-12-0037-126
or
Figure 109116218-A0101-12-0037-127
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0037-129
為被胺基取代的嘧啶 基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0037-129
It is a pyrimidinyl group substituted by an amino group, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1- 6 Alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0038-131
為被胺基取代的嘧啶 基，其同時被一個或兩個選自以下的基團所取代：-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2和C1-6鹵烷基。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0038-131
It is a pyrimidinyl group substituted by an amino group, which is simultaneously substituted by one or two groups selected from: -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 and C 1-6 haloalkyl.

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0038-130
為被胺基取代的
Figure 109116218-A0101-12-0038-132
，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、- NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0038-130
Is substituted by an amine group
Figure 109116218-A0101-12-0038-132
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0038-135
為被胺基取代的
Figure 109116218-A0101-12-0038-133
，其同時被一個或兩個選自以下的基團所取代：-NH2、-NH(C1-6烷基)、- N(C1-6烷基)2和C1-6鹵烷基。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0038-135
Is substituted by an amine group
Figure 109116218-A0101-12-0038-133
, Which is simultaneously substituted by one or two groups selected from: -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 and C 1-6 haloalkane base.

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0038-134
為被-(C1-6烷基)-OH取代 的吡啶基、被-(C1-6烷基)-OH取代的嘧啶基或被-(C1-6烷基)-OH取代的噠嗪基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0038-134
As being - (C 1-6 alkyl) -OH substituted pyridinyl, by - (C 1-6 alkyl) -OH substituted pyrimidyl or - (C 1-6 alkyl) -OH-substituted pyridazin Azinyl groups, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -(C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0038-136
為被-(C1-6烷基)-OH取代 的吡啶基或被-(C1-6烷基)-OH取代的嘧啶基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0038-136
As being - (C 1-6 alkyl) -OH substituted pyridyl or - (C 1-6 alkyl) -OH substituents pyrimidinyl, each of which simultaneously one or two groups selected from the Substitution: halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 halo Alkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0039-137
為被-(C1-6烷基)-OH取代 的吡啶基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷某)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0039-137
Is a pyridyl substituted by -(C 1-6 alkyl)-OH, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkane Some), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O( C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0039-138
為被-(C1-6烷基)-OH和C1- 6鹵烷基取代的吡啶基。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0039-138
As being - (C 1-6 alkyl) -OH and C 1- 6 haloalkyl substituted pyridyl.

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0039-139
為被-(C1-6烷基)-OH取代 的
Figure 109116218-A0101-12-0039-140
或
Figure 109116218-A0101-12-0039-141
，其同時被一個或兩個選自以下的基團所取代：鹵素、 CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0039-139
Is substituted by -(C 1-6 alkyl)-OH
Figure 109116218-A0101-12-0039-140
or
Figure 109116218-A0101-12-0039-141
, Which is simultaneously substituted by one or two groups selected from: halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0039-142
為被-(C1-6烷基)-OH和C1- 6鹵烷基取代的
Figure 109116218-A0101-12-0039-143
或
Figure 109116218-A0101-12-0039-144
。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0039-142
As being - (C 1-6 alkyl) -OH and C 1- 6 haloalkyl substituted
Figure 109116218-A0101-12-0039-143
or
Figure 109116218-A0101-12-0039-144
.

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0039-145
為被-(C1-6烷基)-OH取代 的嘧啶基，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0039-145
It is a pyrimidinyl substituted by -(C 1-6 alkyl)-OH, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkane Group), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O( C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0039-146
為被-(C1-6烷基)-OH和C1- 6鹵烷基取代的嘧啶基。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0039-146
As being - (C 1-6 alkyl) -OH and C 1- 6 haloalkyl substituted pyrimidinyl.

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0040-147
為被-(C1-6烷基)-OH取代 的
Figure 109116218-A0101-12-0040-150
，其同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、- NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0040-147
Is substituted by -(C 1-6 alkyl)-OH
Figure 109116218-A0101-12-0040-150
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl).

在式(I-2)化合物的一些實施方案中，

Figure 109116218-A0101-12-0040-148
為被-(C1-6烷基)-OH和C1- 6鹵烷基取代的
Figure 109116218-A0101-12-0040-149
。 In some embodiments of the compound of Formula (I-2),
Figure 109116218-A0101-12-0040-148
As being - (C 1-6 alkyl) -OH and C 1- 6 haloalkyl substituted
Figure 109116218-A0101-12-0040-149
.

本發明還提供了選自在實驗部分編號為化合物1-331的化合物，和/或其藥學上可接受的鹽。 The present invention also provides a compound selected from the group numbered compound 1-331 in the experimental part, and/or a pharmaceutically acceptable salt thereof.

在一個實施方案中，本發明的化合物不包括如下化合物： In one embodiment, the compounds of the present invention do not include the following compounds:

Figure 109116218-A0101-12-0040-151
Figure 109116218-A0101-12-0040-151

Figure 109116218-A0101-12-0041-152
Figure 109116218-A0101-12-0041-152

Figure 109116218-A0101-12-0042-153
Figure 109116218-A0101-12-0042-153

另一方面，本發明還提供了一種醫藥組成物，其包含一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽，以及至少一種藥學上可接受的賦形劑(例如，一種藥學上可接受的載體)。 In another aspect, the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable salt. Accepted excipients (e.g., a pharmaceutically acceptable carrier).

另一方面，本發明還提供了一種體內或體外抑制IDO活性的方法，其包括使有效量的一種式(I)的化合物(例如，本文中的任何化合物)和/或其藥學上可接受的鹽與IDO接觸。 On the other hand, the present invention also provides a method for inhibiting IDO activity in vivo or in vitro, which comprises making an effective amount of a compound of formula (I) (for example, any compound herein) and/or its pharmaceutically acceptable Salt comes into contact with IDO.

另一方面，本發明還提供了一種體內或體外抑制IDO活性的方法，其包括使有效量的一種醫藥組成物與IDO接觸，該醫藥組成物包含一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽，以及至少一種藥學上可接受的賦形劑(例如，一種藥學上可接受的載體)。 On the other hand, the present invention also provides a method for inhibiting IDO activity in vivo or in vitro, which comprises contacting an effective amount of a medical composition with IDO, the medical composition comprising a compound of formula (I) (for example, herein Any compound of) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (for example, a pharmaceutically acceptable carrier).

另一方面，本發明還提供了一種治療個體中由IDO介導或至少部分由IDO介導的疾病的方法，其包括給需要其的個體施用有效量的一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽。 On the other hand, the present invention also provides a method for treating a disease mediated by IDO or at least partly by IDO in an individual, which comprises administering to an individual in need thereof an effective amount of a compound of formula (I) (e.g., Any compound herein) and/or a pharmaceutically acceptable salt thereof.

另一方面，本發明還提供了一種治療個體中癌症的方法，其包括給需要其的個體施用有效量的一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽。 On the other hand, the present invention also provides a method of treating cancer in an individual, which comprises administering to an individual in need thereof an effective amount of a compound of formula (I) (for example, any compound herein) and/or a pharmacological agent thereof. The acceptable salt.

另一方面，本發明還提供了一種治療個體中由IDO介導或至少部分由IDO介導的疾病的方法，其包括給需要其的個體施用有效量的一種醫藥組成物，該醫藥組成物包含一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽，以及至少一種藥學上可接受的賦形劑(例如，一種藥學上可接受的載體)。 On the other hand, the present invention also provides a method for treating an IDO-mediated or at least partially IDO-mediated disease in an individual, which comprises administering an effective amount of a pharmaceutical composition to an individual in need thereof, the pharmaceutical composition comprising A compound of formula (I) (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (for example, a pharmaceutically acceptable carrier) .

另一方面，本發明還提供了一種治療個體中癌症或自身免疫性疾病的方法，其包括給需要其的個體施用有效量的一種醫藥組成物，該醫藥組成物包含一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽，以及至少一種藥學上可接受的賦形劑(例如，一種藥學上可接受的載體)。 On the other hand, the present invention also provides a method for treating cancer or autoimmune disease in an individual, which comprises administering an effective amount of a pharmaceutical composition to an individual in need thereof, the pharmaceutical composition comprising a compound of formula (I) (E.g., any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

另一方面，本發明還提供了本文所述的一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽在治療由IDO介導或至少部分由IDO介導的疾病中的用途。 In another aspect, the present invention also provides a compound of formula (I) described herein (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof in the treatment of being mediated by IDO or at least in part by Use in IDO-mediated diseases.

另一方面，本發明還提供了本文所述的一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽在治療癌症或自身免疫性疾病中的用途。 In another aspect, the present invention also provides a compound of formula (I) described herein (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof in the treatment of cancer or autoimmune diseases. use.

另一方面，本發明還提供了本文所述的一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽在製備藥物中的用途，該藥物用於治療由IDO介導或至少部分由IDO介導的疾病。 On the other hand, the present invention also provides the use of a compound of formula (I) (for example, any compound in this document) and/or a pharmaceutically acceptable salt thereof as described herein in the preparation of a medicament. For the treatment of IDO-mediated or at least partially IDO-mediated diseases.

另一方面，本發明還提供了本文所述的一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽在製備藥物中的用途，該藥物用於治療癌症、自身免疫性疾病、肥胖或肥胖相關性疾病。 On the other hand, the present invention also provides the use of a compound of formula (I) (for example, any compound in this document) and/or a pharmaceutically acceptable salt thereof as described herein in the preparation of a medicament. For the treatment of cancer, autoimmune diseases, obesity or obesity-related diseases.

另一方面，本發明還提供了一種組合，其包含一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽，以及至少一種額外治療劑。 In another aspect, the present invention also provides a combination comprising a compound of formula (I) (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

在一些實施方案中，該額外治療劑是抗腫瘤藥劑。 In some embodiments, the additional therapeutic agent is an anti-tumor agent.

在一些實施方案中，該額外治療劑是化療劑。 In some embodiments, the additional therapeutic agent is a chemotherapeutic agent.

在一些實施方案中，該額外治療劑是免疫檢查點抑制劑。 In some embodiments, the additional therapeutic agent is an immune checkpoint inhibitor.

另一方面，本發明還提供了一種治療個體中由IDO介導或至少部分由IDO介導的疾病的方法，其包括給需要其的個體施用有效量的一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽，以及抗腫瘤藥劑。 On the other hand, the present invention also provides a method for treating a disease mediated by IDO or at least partly by IDO in an individual, which comprises administering to an individual in need thereof an effective amount of a compound of formula (I) (e.g., Any compound herein) and/or a pharmaceutically acceptable salt thereof, and an anti-tumor agent.

另一方面，本發明還提供了一種治療個體中癌症的方法，其包括給需要其的個體施用有效量的一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽，以及免疫檢查點抑制劑、靶向治療劑或化療劑。 On the other hand, the present invention also provides a method of treating cancer in an individual, which comprises administering to an individual in need thereof an effective amount of a compound of formula (I) (for example, any compound herein) and/or a pharmacological agent thereof. Acceptable salts, as well as immune checkpoint inhibitors, targeted therapeutics or chemotherapeutics.

另一方面，本發明還提供了本文所述的一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽與抗腫瘤藥劑在製備聯合用藥物中的用途，該聯合用藥物用於治療由IDO介導或至少部分由IDO介導的疾病。 On the other hand, the present invention also provides a compound of formula (I) described herein (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof and an anti-tumor agent in the preparation of a combination medicament The combined drug is used to treat diseases mediated by IDO or at least partly by IDO.

另一方面，本發明還提供了本文該的一種式(I)的化合物(例如，本文中的任何化合物)和/或一種其藥學上可接受的鹽與免疫檢查點抑制劑、靶向治療劑或化療劑在製備聯合用藥物中的用途，該聯合用藥物用於治療癌症或自身免疫性疾病。 On the other hand, the present invention also provides a compound of formula (I) (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof, an immune checkpoint inhibitor, and a targeted therapeutic agent. Or the use of a chemotherapeutic agent in the preparation of a combination drug for the treatment of cancer or autoimmune diseases.

在一些實施方案中，該免疫檢查點抑制劑選自抗PD-1抑制劑、CTLA-4抑制劑或OX-40抑制劑。 In some embodiments, the immune checkpoint inhibitor is selected from an anti-PD-1 inhibitor, a CTLA-4 inhibitor, or an OX-40 inhibitor.

在一些實施方案中，該免疫檢查點抑制劑選自潘利珠單抗(pembrolizumab)、尼伏單抗(nivolumab)和易普利姆瑪(ipilimumab)。 In some embodiments, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab and ipilimumab.

在一些實施方案中，該由IDO介導或至少部分由IDO介導的疾病是癌症或自身免疫性疾病。 In some embodiments, the IDO-mediated or at least partially IDO-mediated disease is cancer or an autoimmune disease.

在一些實施方案中，該癌症是實體瘤或血液系統惡性腫瘤，例如：白血病、淋巴瘤或骨髓瘤。 In some embodiments, the cancer is a solid tumor or hematological malignancy, such as leukemia, lymphoma, or myeloma.

在一些實施方案中，該癌症選自皮膚癌(例如黑色素瘤和基底癌)、肺癌、非小細胞肺癌、腎癌、頭頸癌、尿路上皮癌、胰腺癌、宮頸癌、膀胱癌、肝癌、子宮內膜癌、卵巢癌、乳腺癌、結腸癌、結腸直腸癌、***癌、胃癌、食道癌、腦瘤(包括神經膠質瘤和成膠質細胞瘤(GBM))、甲狀腺癌、間皮內膜癌、絨毛膜癌、腎上腺癌、肉瘤(例如卡波西氏肉瘤(Kaposi's sarcoma))、白血病、淋巴瘤或骨髓瘤。 In some embodiments, the cancer is selected from skin cancer (e.g., melanoma and basal cancer), lung cancer, non-small cell lung cancer, kidney cancer, head and neck cancer, urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer, liver cancer, Endometrial cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, brain tumors (including glioma and glioblastoma (GBM)), thyroid cancer, mesothelioma Carcinoma, choriocarcinoma, adrenal carcinoma, sarcoma (e.g. Kaposi's sarcoma), leukemia, lymphoma or myeloma.

在一些實施方案中，該癌症選自黑色素瘤、肺癌、腎細胞癌、頭頸癌、尿路上皮癌、胰腺癌、宮頸癌、膀胱癌、肝細胞癌、子宮內膜癌、卵巢癌、乳腺癌、結腸直腸癌、***癌、胃癌、食道癌、神經膠質瘤、成膠質細 In some embodiments, the cancer is selected from melanoma, lung cancer, renal cell carcinoma, head and neck cancer, urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatocellular carcinoma, endometrial cancer, ovarian cancer, breast cancer , Colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, glioma, glioma

胞瘤(GBM)、急性髓細胞性白血病(AML)、人急性單核細胞白血病(M(5))、急性淋巴細胞白血病(ALL)和瀰漫性大B細胞淋巴瘤(DLBCL)。 Cell tumor (GBM), acute myeloid leukemia (AML), human acute monocytic leukemia (M(5)), acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL).

在一些實施方案中，該身免疫性疾病選自關節炎，例如類風濕性關節炎、膠原誘導性關節炎等。 In some embodiments, the immune disease is selected from arthritis, such as rheumatoid arthritis, collagen-induced arthritis, and the like.

在一些實施方案中，該肥胖相關性疾病選自糖尿病、高血壓、胰島素耐受綜合症、血脂異常、心臟病、心血管疾病(包括動脈粥樣硬化、心律異常、心律不齊、心肌梗塞、充血性心力衰竭、冠心病、心絞痛)、腦梗塞、腦出血、骨關節炎、代謝綜合症、非酒精性脂肪肝、非酒精性脂肪性肝炎等。 In some embodiments, the obesity-related disease is selected from diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, arrhythmia, arrhythmia, myocardial infarction, Congestive heart failure, coronary heart disease, angina pectoris), cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver, non-alcoholic steatohepatitis, etc.

公開的實施方案的通用合成方法The general synthetic method of the disclosed embodiment

本文所述的式(I)的化合物和/或其藥學上可接受的鹽可以用商業上可獲得的原料、藉由本領域已知的方法或本專利申請所公開的方法合成。流程1-3中所示的合成路線舉例說明了本發明的化合物的通用合成方法。 The compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof can be synthesized using commercially available raw materials, by methods known in the art or methods disclosed in this patent application. The synthetic routes shown in Schemes 1-3 illustrate general synthetic methods of the compounds of the present invention.

方法1： method 1:

Figure 109116218-A0101-12-0046-155
Figure 109116218-A0101-12-0046-155

如流程1所示，分子式(1-1)表示的化合物，在鈀試劑(例如但不限於Pd(PPh3)4)催化下與(1-2)進行偶聯反應，得到分子式(1-3)表示的化合物；然後，在酸性條件下(例如但不限於TFA等)脫除保護基，得到分子式(1-4)表示的化合物；最後，在縮合劑(例如但不限於HATU等)存在下，與分子式(1-5)表示的化合物經過縮合反應，得到分子式(1-6)表示的化合物。其中，R1、R2、X、Y、 p、

Figure 109116218-A0101-12-0047-157
、
Figure 109116218-A0101-12-0047-158
如本文中所定義；Ra和Rb分別為一個或多個取代基；W為離去基 團。 As shown in Scheme 1, the compound represented by the molecular formula (1-1) undergoes a coupling reaction with (1-2) under the catalysis of a palladium reagent (such as but not limited to Pd(PPh 3 ) 4) to obtain the molecular formula (1-3 ); then, the protective group is removed under acidic conditions (such as but not limited to TFA, etc.) to obtain the compound represented by formula (1-4); finally, in the presence of a condensing agent (such as but not limited to HATU, etc.) , And the compound represented by the molecular formula (1-5) undergo condensation reaction to obtain the compound represented by the molecular formula (1-6). Among them, R 1 , R 2 , X, Y, p,
Figure 109116218-A0101-12-0047-157
,
Figure 109116218-A0101-12-0047-158
As defined herein; R a and R b are each one or more substituent groups; W is a leaving group.

方法2： Method 2:

Figure 109116218-A0101-12-0047-156
Figure 109116218-A0101-12-0047-156

如流程2所示，分子式(2-1)表示的化合物，在縮合劑(例如但不限於HATU等)存在下，與分子式(2-2)表示的化合物經過縮合反應，得到分子式(2-3)表示的化合物；然後，在鈀試劑(例如但不限於Pd(PPh3)4)催化下進行偶聯反應，得到分子式(2-4)表示的化合物；最後，在鈀試劑(例如但不限於Pd(PPh3)4)催化下，與分子式(2-5)表示的化合物進一步經過縮合反應，得到分子式(2-6)表示 的化合物。其中，R1、R2、X、Y、p、

Figure 109116218-A0101-12-0048-160
、
Figure 109116218-A0101-12-0048-161
如本文中所定義；Ra和Rb分 別為一個或多個取代基；W為離去基團。 As shown in Scheme 2, the compound represented by the formula (2-1) undergoes a condensation reaction with the compound represented by the formula (2-2) in the presence of a condensing agent (such as but not limited to HATU, etc.) to obtain the formula (2-3 ); then, the coupling reaction is carried out under the catalysis of a palladium reagent (such as but not limited to Pd(PPh 3 ) 4 ) to obtain the compound represented by the formula (2-4); finally, in the palladium reagent (such as but not limited to Pd(PPh 3) 4) Under the catalysis of Pd(PPh 3 ) 4 ), it undergoes further condensation reaction with the compound represented by the molecular formula (2-5) to obtain the compound represented by the molecular formula (2-6). Among them, R 1 , R 2 , X, Y, p,
Figure 109116218-A0101-12-0048-160
,
Figure 109116218-A0101-12-0048-161
As defined herein; R a and R b are each one or more substituent groups; W is a leaving group.

方法3： Method 3:

Figure 109116218-A0101-12-0048-159
Figure 109116218-A0101-12-0048-159

如流程3所示，分子式(3-1)表示的化合物，與分子式(3-2)表示的化合物進行偶聯反應，得到分子式(3-3)表示的化合物；然後，在酸性條件下(例如但不限於TFA等)脫除保護基，得到分子式(3-4)表示的化合物；最後，在縮合劑(例如但不限於HATU等)存在下，與分子式(3-5)表示的化合物經過縮合反應， 得到分子式(3-6)表示的化合物。其中，R1、R2、X、Y、p、

Figure 109116218-A0101-12-0048-162
、
Figure 109116218-A0101-12-0048-163
如本文 中所定義；Ra和Rb分別為一個或多個取代基；W為離去基團；M為C1-6烷基取代的錫、硼酸或硼酸酯。 As shown in the scheme 3, the compound represented by the formula (3-1) is coupled with the compound represented by the formula (3-2) to obtain the compound represented by the formula (3-3); then, under acidic conditions (for example, But not limited to TFA, etc.) Remove the protective group to obtain the compound represented by the molecular formula (3-4); finally, in the presence of a condensing agent (such as but not limited to HATU, etc.), it is condensed with the compound represented by the molecular formula (3-5) After the reaction, the compound represented by the molecular formula (3-6) is obtained. Among them, R 1 , R 2 , X, Y, p,
Figure 109116218-A0101-12-0048-162
,
Figure 109116218-A0101-12-0048-163
As defined herein; R a and R b are each one or more substituents; W is a leaving group; M is a C 1-6 alkyl substituted tin, boronic acid, or boronic acid ester.

可以進一步修飾藉由上述方法獲得的化合物的取代基，從而得到其它的所需化合物。合成化學轉化方法可參考例如：R.Larock,Comprehensive Organic Transformations,VCH Publishers(1989)；L.Fieser和M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,John Wiley and Sons(1994)；和L.Paquette 編，Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons(1995)及其後續版本。 The substituents of the compounds obtained by the above methods can be further modified to obtain other desired compounds. The synthetic chemical transformation method can refer to, for example: R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette Edited, Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) and subsequent editions.

在使用前，本文該的式(I)的化合物和/或其藥學上可接受的鹽可以藉由管柱色譜、高效液相色譜、結晶或其它適當的方法進行純化。 Before use, the compound of formula (I) and/or its pharmaceutically acceptable salt herein can be purified by column chromatography, high performance liquid chromatography, crystallization or other appropriate methods.

醫藥組成物和實際用途Pharmaceutical composition and practical use

本文所述的式(I)的化合物(例如，本文中的任何化合物)和/或其藥學上可接受的鹽可單獨或者與一種或多種另外的活性成分聯合配製成醫藥組成物。醫藥組成物包括：(a)有效量的本文所述的一種式(I)的化合物和/或一種其藥學上可接受的鹽；和(b)一種藥學上可接受的賦形劑(例如，一種藥學上可接受的載體)。 The compound of formula (I) described herein (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition alone or in combination with one or more additional active ingredients. The pharmaceutical composition includes: (a) an effective amount of a compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient (e.g., A pharmaceutically acceptable carrier).

藥學上可接受的載體是指能與組合物中的活性成分相容(在一些實施方案中，能穩定活性成分)並且對所治療的個體無害的載體。例如，增溶劑如環糊精(其能與本文所述的式(I)的化合物和/或其藥學上可接受的鹽形成特定的、溶解性更強的複合物)可用作藥物賦形劑來遞送活性成分。其它載體的例子包括膠態二氧化矽、硬脂酸鎂、纖維素、十二烷基硫酸鈉以及色素如D&C黃色10號(D&C Yellow # 10)。合適的藥學上可接受的載體在本領域一本標準的參考書(Remington's Pharmaceutical Sciences,A.Osol)中公開。 A pharmaceutically acceptable carrier refers to a carrier that is compatible with the active ingredient in the composition (in some embodiments, can stabilize the active ingredient) and is not harmful to the individual being treated. For example, a solubilizer such as cyclodextrin (which can form a specific and more soluble complex with the compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof) can be used as a pharmaceutical excipient Agent to deliver the active ingredient. Examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are disclosed in a standard reference book in the art (Remington's Pharmaceutical Sciences, A. Osol).

包含本文所述的式(I)化合物(例如，本文中的任何化合物)和/或其藥學上可接受的鹽的醫藥組成物可以以各種已知的方式、例如口服、局部、直腸、腸胃外、吸入或植入等方式施用。本文所用的術語“腸胃外”包括 皮下、皮內、靜脈、肌內、關節內、動脈內、滑膜內、胸骨內、脊椎內、患處內以及顱內注射或輸注。 The pharmaceutical composition comprising the compound of formula (I) described herein (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof can be used in various known ways, such as oral, topical, rectal, parenteral , Inhalation or implantation. The term "parenteral" as used herein includes Subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intra-affected and intracranial injection or infusion.

本文所述的醫藥組成物被製備成的形式可以是片劑、膠囊、袋裝沖劑、糖衣丸、散劑、顆粒劑、含片、粉針劑、液體製劑或栓劑。在一些實施方案中，包含式(I)化合物和/或其藥學上可接受的鹽的醫藥組成物可被配製成用於靜脈滴注、局部給藥或口服給藥的形式。 The pharmaceutical composition described herein can be prepared in the form of tablets, capsules, pouched granules, dragees, powders, granules, lozenges, powder injections, liquid preparations or suppositories. In some embodiments, the pharmaceutical composition comprising the compound of formula (I) and/or a pharmaceutically acceptable salt thereof may be formulated for intravenous drip, topical administration or oral administration.

口服施用的組合物可以是任何口服可接受的劑型，包括但不限於：片劑、膠囊、乳劑以及水性的混懸劑、分散劑和溶液。常用的片劑載體包括乳糖和玉米澱粉。潤滑劑如硬脂酸鎂也常加入到片劑中。以膠囊形式口服施用時，有用的稀釋劑包括乳糖和乾燥的玉米澱粉。當以水性混懸劑或乳劑形式口服施用時，可用乳化劑或助懸劑使活性成分混懸或溶解於油相中。若有需要，還可添加某些甜味劑、矯味劑或色素。 The composition for oral administration can be any orally acceptable dosage form, including but not limited to: tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. Commonly used tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also often added to tablets. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When administered orally in the form of an aqueous suspension or emulsion, an emulsifier or suspending agent may be used to suspend or dissolve the active ingredient in the oil phase. If necessary, some sweeteners, flavors or colors can also be added.

在一些實施方案中，式(I)的化合物和/或其藥學上可接受的鹽在片劑中的量可以是1、5、10、15、20、25、50、75、80、85、90、95、100、125、150、200、250、300、400和500毫克。在一些實施方案中，式(I)的化合物和/或其藥學上可接受的鹽在膠囊中的量可以是1、5、10、15、20、25、50、75、80、85、90、95、100、125、150、200、250、300、400和500毫克。 In some embodiments, the amount of the compound of formula (I) and/or its pharmaceutically acceptable salt in the tablet can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg. In some embodiments, the amount of the compound of formula (I) and/or its pharmaceutically acceptable salt in the capsule can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90 , 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg.

無菌可注射組合物(如水性或油性混懸劑)可按照本領域已知的技術，使用適合的分散劑或潤濕劑(例如，吐溫80)以及助懸劑來配製。無菌可注射中間介質也可以是在無毒的腸胃外可接受的稀釋劑或溶劑中的無菌可注射溶液或混懸液，例如在1,3-丁二醇中的溶液。藥學上可接受的載體和溶劑尤其可使用的是甘露醇、水、林格氏液和生理鹽水。此外，無菌的不易揮發的油例如 合成的單或二甘油酯通常用作溶劑或混懸介質。脂肪酸例如油酸及其甘油酯衍生物以及天然的藥學上可接受的油例如橄欖油或蓖麻油(尤其是其聚氧乙基化形式)常用作可注射中間介質。這些油溶液或混懸液也可含有長鏈的醇類稀釋劑或分散劑、或羧甲基纖維素或類似的分散劑。 Sterile injectable compositions (such as aqueous or oily suspensions) can be formulated according to techniques known in the art using suitable dispersing or wetting agents (for example, Tween 80) and suspending agents. The sterile injectable intermediate medium may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the pharmaceutically acceptable carriers and solvents that can be used are mannitol, water, Ringer's solution, and physiological saline. In addition, sterile non-volatile oils such as Synthetic mono- or diglycerides are usually used as solvents or suspension media. Fatty acids such as oleic acid and its glyceride derivatives and natural pharmaceutically acceptable oils such as olive oil or castor oil (especially in its polyoxyethylated form) are commonly used as injectable intermediates. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants.

使用苯甲醇或其它適宜的防腐劑、使用提高生物利用度的吸收促進劑、使用碳氟化合物和/或其它本領域已知的增溶劑或分散劑，可以根據藥物製劑領域眾所周知的技術製備吸入組合物，也可將其製成在鹽水中的溶液。 Using benzyl alcohol or other suitable preservatives, using absorption enhancers that improve bioavailability, using fluorocarbons and/or other solubilizers or dispersants known in the art, the inhalation combination can be prepared according to techniques well-known in the pharmaceutical preparation field It can also be made into a solution in salt water.

局部組合物可配製為油、乳膏劑、洗劑、軟膏劑等形式。用於組合物的適合載體包括植物油或礦物油、白凡士林(白軟石蠟)、支鏈脂肪或油、動物脂肪和高分子量的醇(即，碳原子數大於12的醇)。在一些實施方案中，藥學上可接受的載體是活性成分能溶解於其中的載體。如有需要，組合物還可以包含乳化劑、穩定劑、濕潤劑和抗氧化劑，以及賦予其顏色或香味的物質。此外，局部製劑中還可加入透皮滲透促進劑。這類促進劑的例子可見於美國專利No.3,989,816和4,444,762。 The topical composition can be formulated in the form of oils, creams, lotions, ointments, and the like. Suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (ie, alcohols with more than 12 carbon atoms). In some embodiments, the pharmaceutically acceptable carrier is a carrier in which the active ingredient can be dissolved. If necessary, the composition may also contain emulsifiers, stabilizers, wetting agents, and antioxidants, as well as substances that impart color or fragrance. In addition, a transdermal penetration enhancer can also be added to the topical formulation. Examples of such accelerators can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

乳膏劑可以由礦物油、自乳化蜂蠟和水的混合物配製，將溶解於少量油脂例如杏仁油中的活性成分混合在其中。乳膏劑的一個例子包含以重量計約40份水、約20份蜂蠟、約40份礦物油以及約1份杏仁油。軟膏劑可藉由將活性成分在植物油例如杏仁油中的溶液與溫熱的軟石蠟混合並將混合物冷卻來配製。軟膏劑的一個例子包含以重量計約30%杏仁油和約70%白軟石蠟。 Creams can be formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, in which active ingredients dissolved in a small amount of fat such as almond oil are mixed. An example of a cream includes by weight about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil, and about 1 part almond oil. Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and cooling the mixture. An example of an ointment contains about 30% almond oil and about 70% white soft paraffin by weight.

合適的體外實驗可用於評價本文所述的式(I)的化合物和/或其藥學上可接受的鹽在抑制IDO活性中的實際用途。可進一步藉由體內試驗檢測本文所述的式(I)的化合物和/或其藥學上可接受的鹽在治療癌症中的另外的實際用 途。例如，可將本文所述的式(I)的化合物和/或其藥學上可接受的鹽施用給患有癌症的動物(如小鼠模型)，然後評估其治療效果。如果臨床前試驗的結果是成功的，還可以預測其對動物例如人的劑量範圍和施用途徑。 Appropriate in vitro experiments can be used to evaluate the actual use of the compound of formula (I) and/or its pharmaceutically acceptable salt in inhibiting IDO activity as described herein. The compound of formula (I) described herein and/or its pharmaceutically acceptable salt can be further tested by in vivo experiments for additional practical use in the treatment of cancer. way. For example, the compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof can be administered to an animal (such as a mouse model) suffering from cancer, and then the therapeutic effect thereof can be evaluated. If the results of preclinical trials are successful, the dose range and route of administration for animals such as humans can also be predicted.

本文所述的式(I)的化合物和/或其藥學上可接受的鹽可顯示有足夠的臨床前的實際用途以值得進行臨床試驗，並期望顯示有益的治療或預防效果，例如，在患有癌症的個體中顯示有益的治療或預防效果。 The compound of formula (I) described herein and/or its pharmaceutically acceptable salt may show sufficient pre-clinical practical use to be worthy of clinical trials, and is expected to show beneficial therapeutic or preventive effects, for example, It shows beneficial therapeutic or preventive effects in individuals with cancer.

本文所用的術語“癌症”是指以失控或失調的細胞增殖、減少的細胞分化、不恰當的侵入周圍組織的能力和/或在其它部位建立新生長灶的能力為特徵的細胞障礙。術語“癌症”包括但不限於：實體瘤和血液系統惡性腫瘤。術語“癌症”包括皮膚、組織、器官、骨骼、軟骨、血液和血管的癌症。術語“癌症”既包括原發性癌症，也包括轉移性癌症。 The term "cancer" as used herein refers to a cellular disorder characterized by uncontrolled or unregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new growth foci in other locations. The term "cancer" includes but is not limited to: solid tumors and hematological malignancies. The term "cancer" includes cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" includes both primary cancer and metastatic cancer.

實體瘤的非限制性例子包括胰腺癌；膀胱癌；結腸直腸癌；乳腺癌，包括轉移性乳腺癌；***癌，包括雄性激素依賴性和非雄性激素依賴性***癌；睾丸癌；腎癌，包括例如轉移性腎細胞癌；尿路上皮癌；肝癌；肝細胞癌；肺癌，包括例如非小細胞肺癌(NSCLC)、細支氣管肺泡癌(BAC)和肺腺癌；卵巢癌，包括例如進行性上皮癌或原發性腹膜癌；宮頸癌；子宮內膜癌；胃癌；食道癌；頭頸癌，包括例如頭頸部鱗狀細胞癌；皮膚癌，包括例如惡性黑色素瘤和基底癌；神經內分泌癌，包括轉移性神經內分泌瘤；腦瘤，包括例如神經膠質瘤、間變性少突神經膠質瘤、成人多形性成膠質細胞瘤和成人間變型星形細胞瘤；骨癌；肉瘤，包括例如卡波西氏肉瘤(Kaposi's sarcoma)；腎上腺癌；間皮內膜癌；絨毛膜癌；肌肉癌；結締組織癌；和甲狀腺癌。 Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; testicular cancer; kidney cancer, Including, for example, metastatic renal cell carcinoma; urothelial carcinoma; liver cancer; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive Epithelial or primary peritoneal cancer; cervical cancer; endometrial cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, head and neck squamous cell carcinoma; skin cancer, including, for example, malignant melanoma and basal carcinoma; neuroendocrine cancer, Including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; sarcoma, including, for example, Kaposi Kaposi's sarcoma (Kaposi's sarcoma); adrenal gland cancer; mesothelial endometrial cancer; choriocarcinoma; muscle cancer; connective tissue cancer; and thyroid cancer.

血液系統惡性腫瘤的非限制性例子包括急性髓細胞性白血病(AML)；慢性髓細胞性白血病(CML)，包括加速期CML和CML急變期(CML-BP)；急性淋巴細胞白血病(ALL)；慢性淋巴細胞白血病(CLL)；霍奇金淋巴瘤；非霍奇金淋巴瘤(NHL)；濾泡型淋巴瘤；套細胞淋巴瘤(MCL)；B細胞淋巴瘤；T細胞淋巴瘤；瀰散性大B細胞淋巴瘤(DLBCL)；多發性骨髓瘤(MM)；瓦爾登斯特倫巨球蛋白血症；骨髓增生異常綜合症(MDS)，包括頑固性貧血(RA)、環狀鐵粒幼細胞頑固性貧血(RARS)、過量芽細胞頑固性貧血(RAEB)和過量芽細胞頑固性貧血合併急性轉化(RAEB-T)；以及骨髓增生綜合症(myeloproliferative syndrome)。 Non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast phase (CML-BP); acute lymphocytic leukemia (ALL); Chronic Lymphocytic Leukemia (CLL); Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma (NHL); Follicular Lymphoma; Mantle Cell Lymphoma (MCL); B-cell Lymphoma; T-cell Lymphoma; Diffuse Large B-cell lymphoma (DLBCL); Multiple myeloma (MM); Waldenstrom macroglobulinemia; Myelodysplastic syndrome (MDS), including refractory anemia (RA), ring sideroblasts Cellular refractory anemia (RARS), excessive bud cell refractory anemia (RAEB) and excessive bud cell refractory anemia with acute transformation (RAEB-T); and myeloproliferative syndrome (myeloproliferative syndrome).

在一些實施方案中，實體瘤包括黑色素瘤、肺癌(例如非小細胞肺癌)、腎細胞癌、頭頸癌(例如頭頸部鱗狀細胞癌)、尿路上皮癌、胰腺癌、宮頸癌、膀胱癌、肝細胞癌、子宮內膜癌、卵巢癌、乳腺癌、結腸直腸癌、***癌、胃癌、食道癌、神經膠質瘤和成膠質細胞瘤(GBM)。 In some embodiments, solid tumors include melanoma, lung cancer (e.g., non-small cell lung cancer), renal cell carcinoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), urothelial cancer, pancreatic cancer, cervical cancer, bladder cancer , Hepatocellular carcinoma, endometrial cancer, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, glioma and glioblastoma (GBM).

在一些實施方案中，典型的血液系統惡性腫瘤包括白血病，例如急性淋巴細胞白血病(ALL)、急性髓細胞性白血病(AML)、慢性淋巴細胞白血病(CLL)和慢性髓細胞性白血病(CML)；多發性骨髓瘤(MM)；以及淋巴瘤，例如霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、套細胞淋巴瘤(MCL)、濾泡型淋巴瘤、B細胞淋巴瘤、T細胞淋巴瘤和瀰散性大B細胞淋巴瘤(DLBCL)。 In some embodiments, typical hematological malignancies include leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML); Multiple myeloma (MM); and lymphomas, such as Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T cell Lymphoma and diffuse large B-cell lymphoma (DLBCL).

本文所述的式(I)的化合物和/或其藥學上可接受的鹽可用來達到有益的治療或預防效果，例如，在患有癌症的個體中達到有益的治療或預防效果。 The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein can be used to achieve beneficial therapeutic or preventive effects, for example, to achieve beneficial therapeutic or preventive effects in individuals suffering from cancer.

本文所述的式(I)的化合物和/或其藥學上可接受的鹽可用來達到有益的治療或預防效果，例如，在患有自身免疫性疾病的個體中達到有益的治療或預防效果。 The compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein can be used to achieve beneficial therapeutic or preventive effects, for example, to achieve beneficial therapeutic or preventive effects in individuals suffering from autoimmune diseases.

術語“自身免疫性疾病”是指機體對自身抗原發生免疫反應而導致自身組織或器官損害所引起的疾病或病症。自身免疫性疾病的例子包括但不限於：慢性阻塞性肺病(COPD)、變應性鼻炎、紅斑狼瘡、重症肌無力、多發性硬化(MS)、類風濕性關節炎(RA)、膠原誘導性關節炎、銀屑病、炎性腸病(inflammatory bowel disease)、哮喘和特發性血小板減少性紫癜(idiopathic thrombocytopenic purpura)以及骨髓增生性疾病(myeloproliferative disease)，例如骨髓纖維化(myelofibrosis)、真性紅細胞增多症/原發性血小板增多症性骨髓纖維化(post-polycythemia vera/essential thrombocytosis myelofibrosis,post-PV/ET myelofibrosis)。 The term "autoimmune disease" refers to a disease or disorder caused by the body's immune response to self-antigens, resulting in damage to its own tissues or organs. Examples of autoimmune diseases include but are not limited to: chronic obstructive pulmonary disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis (RA), collagen-induced Arthritis, psoriasis, inflammatory bowel disease, asthma, idiopathic thrombocytopenic purpura, and myeloproliferative diseases, such as myelofibrosis, authenticity Polycythemia/essential thrombocytosis myelofibrosis (post-polycythemia vera/essential thrombocytosis myelofibrosis, post-PV/ET myelofibrosis).

術語“肥胖相關性疾病”是指與肥胖相關、由肥胖引發或由肥胖導致的疾病或病症。肥胖相關性疾病的例子包括但不限於：糖尿病、高血壓、胰島素耐受綜合症、血脂異常、心臟病、心血管疾病(包括動脈粥樣硬化、心律異常、心律不齊、心肌梗塞、充血性心力衰竭、冠心病、心絞痛)、腦梗塞、腦出血、骨關節炎、代謝綜合症、非酒精性脂肪肝、非酒精性脂肪性肝炎等。 The term "obesity-related disease" refers to a disease or condition related to, caused by, or caused by obesity. Examples of obesity-related diseases include, but are not limited to: diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, abnormal heart rhythm, arrhythmia, myocardial infarction, congestive Heart failure, coronary heart disease, angina pectoris), cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver, non-alcoholic steatohepatitis, etc.

此外，本文所述的式(I)的化合物(例如，本文中的任何化合物)和/或其藥學上可接受的鹽可與額外的治療劑聯合用藥，用於治療癌症。額外的治療劑可以與本文所述的式(I)的化合物和/或其藥學上可接受的鹽分開給藥，或者可以根據本公開將其包含在醫藥組成物中，例如固定劑量的複方藥品。在一 些實施方案中，額外的治療劑是那些已知的或已被發現對治療由IDO介導或至少部分由IDO介導的疾病有效的成分，例如另一種IDO抑制劑或一種能有效拮抗與該特定的疾病相關的另一個靶點的化合物。聯合用藥可用於提高療效(例如，藉由將一種能增強本文所述的式(I)的化合物和/或其藥學上可接受的鹽的效力或有效性的化合物包含入聯合用藥中)，降低一種或多種副作用，或者減少所需的本文所述的式(I)的化合物和/或其藥學上可接受的鹽的劑量。 In addition, the compound of formula (I) described herein (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof can be used in combination with additional therapeutic agents for the treatment of cancer. The additional therapeutic agent may be administered separately from the compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof, or may be included in a pharmaceutical composition according to the present disclosure, such as a fixed-dose compound drug . In a In some embodiments, additional therapeutic agents are those that are known or have been found to be effective in the treatment of diseases mediated or at least partially mediated by IDO, such as another IDO inhibitor or an effective antagonist against the disease. A compound that is another target related to a specific disease. Combination drugs can be used to improve the therapeutic effect (for example, by including a compound that can enhance the potency or effectiveness of the compound of formula (I) and/or its pharmaceutically acceptable salt as described herein in the combination drug), reduce One or more side effects, or reduce the required dosage of the compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof.

在一些實施方案中，本文所述的式(I)的化合物(例如，本文中的任何化合物)和/或其藥學上可接受的鹽可與抗腫瘤藥劑聯合用藥。本文使用的術語“抗腫瘤藥劑”指給予患有癌症的對象的、用於治療癌症目的的任何藥劑，包括但不限於放療劑、化療劑、免疫療法製劑、靶向治療劑等。 In some embodiments, the compound of formula (I) described herein (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof can be used in combination with an anti-tumor agent. The term "anti-tumor agent" as used herein refers to any agent administered to a subject suffering from cancer for the purpose of treating cancer, including but not limited to radiotherapy agents, chemotherapeutics, immunotherapy agents, targeted therapeutic agents, and the like.

在一些實施方案中，本文所述的式(I)的化合物(例如，本文中的任何化合物)和/或其藥學上可接受的鹽可與免疫檢查點抑制劑、靶向治療劑或化療劑聯合用藥。 In some embodiments, the compound of formula (I) described herein (for example, any compound herein) and/or a pharmaceutically acceptable salt thereof can be combined with an immune checkpoint inhibitor, a targeted therapeutic agent, or a chemotherapeutic agent. Combination medication.

免疫檢查點抑制劑的非限定性例子包括抗PD-1抗體，例如潘利珠單抗(pembrolizumab)和尼伏單抗(nivolumab)；抗PD-L1抗體，例如阿替珠單抗(atezolizumab)、度伐單抗(durvalumab)和阿維單抗(avelumab)；抗CTLA-4抗體，例如易普利姆瑪(ipilimumab)；以及BTLA抗體、LAG-3抗體、TIM3抗體、TIGIT抗體、VISTA抗體等。 Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 antibodies, such as pembrolizumab and nivolumab; anti-PD-L1 antibodies, such as atezolizumab, Durvalumab and avelumab; anti-CTLA-4 antibodies, such as ipilimumab; and BTLA antibodies, LAG-3 antibodies, TIM3 antibodies, TIGIT antibodies, VISTA antibodies, etc.

化療劑的非限定性例子包括拓撲異構酶I抑制劑(例如依立替康、托泊替康、喜樹鹼及其類似物或代謝物以及阿黴素)；拓撲異構酶II抑制劑(例如依託泊苷、替尼泊苷、米托蒽醌、去甲氧基柔紅黴素和道諾黴素)；烷化劑(例如美法侖、苯丁酸氮芥、白消安、噻替派、異環磷醯胺、亞硝基脲氮芥、環己 亞硝脲、甲基環己亞硝脲、鏈脲黴素、胺烯咪胺、甲胺喋呤、絲裂黴素C和環磷醯胺)；DNA嵌入劑(例如順鉑、奧沙利鉑和卡波鉑)；DNA嵌入劑和自由基產生劑如博來黴素；以及核苷類似物(例如5-氟尿嘧啶、卡培他濱、吉西他濱、氟達拉濱、阿糖胞苷、阿紮胞苷、巰基嘌呤、硫鳥嘌呤、噴司他丁和羥基脲)；紫杉醇、紫杉萜及有關的類似物；長春新鹼、長春鹼及有關的類似物；鎮靜劑及有關的類似物(例如CC-5013和CC-4047)。 Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (such as irinotecan, topotecan, camptothecin and its analogs or metabolites, and doxorubicin); topoisomerase II inhibitors ( Such as etoposide, teniposide, mitoxantrone, desmethoxydaunorubicin and daunorubicin); alkylating agents (such as melphalan, chlorambucil, busulfan, Tepa, ifosfamide, nitrosourea, cyclohexyl Nitrosourea, methylcyclohexylnitrosourea, streptozotocin, dimethamine, methotrexate, mitomycin C and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxali Platinum and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside analogs (e.g. 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, ara Zacitidine, mercaptopurine, thioguanine, pentostatin and hydroxyurea); paclitaxel, docetaxel and related analogs; vincristine, vinblastine and related analogs; tranquilizers and related analogs ( For example, CC-5013 and CC-4047).

靶向治療劑的非限定性例子包括：蛋白酪胺酸激酶抑制劑(例如甲磺酸伊馬替尼和吉非替尼)；蛋白酶體抑制劑(例如硼替佐米)；NF-κ B抑制劑，包括I κ B激酶抑制劑；與癌症中過度表達的蛋白結合從而下調細胞複製的抗體(例如曲妥單抗、利妥昔單抗、西妥昔單抗和貝伐單抗)；以及其他的蛋白或酶抑制劑，已知這些蛋白或酶在癌症中會被上調、過度表達或激活，並且對它們的抑制能夠下調細胞複製。 Non-limiting examples of targeted therapeutic agents include: protein tyrosine kinase inhibitors (such as imatinib mesylate and gefitinib); proteasome inhibitors (such as bortezomib); NF-κB inhibitors , Including IκB kinase inhibitors; antibodies that bind to proteins overexpressed in cancer to down-regulate cell replication (such as trastuzumab, rituximab, cetuximab, and bevacizumab); and others It is known that these proteins or enzymes are up-regulated, over-expressed or activated in cancer, and their inhibition can down-regulate cell replication.

實施例 Example

下述實施例是對本發明的舉例說明，不以任何方式限制本發明。所給出的數據(如，量、溫度等)力爭保證其準確性，但是本領域技術人員應當理解其會有一些實驗誤差和偏移。除非另外說明，否則所有份數均是重量份數，溫度為攝氏溫度，壓力為大氣壓或接近大氣壓。所有質譜數據均由安捷倫(Agilent)6120和1100測得。所有核磁共振數據均由瓦裡安(Varian)400MR測得。除了合成的中間體外，本發明所用的所有試劑均為商業渠道獲得。除試劑外所有化合物的名稱均由Chemdraw 16.0生成。 The following examples are illustrative of the present invention and do not limit the present invention in any way. The given data (such as quantity, temperature, etc.) strives to ensure its accuracy, but those skilled in the art should understand that there will be some experimental errors and deviations. Unless otherwise specified, all parts are parts by weight, temperature is in Celsius, and pressure is at or near atmospheric. All mass spectra data are measured by Agilent 6120 and 1100. All NMR data are measured by Varian 400MR. Except for synthetic intermediates, all reagents used in the present invention are obtained from commercial sources. The names of all compounds except reagents are generated by Chemdraw 16.0.

在本申請的任何結構式中，如果任何原子上存在空餘化合價，該空餘化合價實際上是為了簡便沒有具體描繪的氫原子。 In any structural formula of this application, if there is a spare valence on any atom, the spare valence is actually a hydrogen atom that is not specifically depicted for simplicity.

在本申請中，如果針對一個化合物同時給出了該化合物的名稱和結構式，在二者不一致的情況下，以化合物的結構為准，除非上下文表明化合物的結構不正確、而名稱正確。 In this application, if the name and structural formula of the compound are given for a compound at the same time, if the two are inconsistent, the structure of the compound shall prevail, unless the context indicates that the structure of the compound is incorrect but the name is correct.

以下實施例中使用的縮寫列表： List of abbreviations used in the following examples:

Figure 109116218-A0101-12-0057-164
Figure 109116218-A0101-12-0057-164

TFA 三氟乙酸 TFA trifluoroacetic acid

Ti(OiPr)4 四異丙氧基鈦 Ti(OiPr) 4 Titanium tetraisopropoxide

實施例1Example 1

化合物1 Compound 1

N-(1-(4-(3-胺基-5-(三氟甲基)吡啶-2-基)苯基)環丙基)-4-氯苯甲醯胺 N -(1-(4-(3-Amino-5-(trifluoromethyl)pyridin-2-yl)phenyl)cyclopropyl)-4-chlorobenzamide

Figure 109116218-A0101-12-0058-165
Figure 109116218-A0101-12-0058-165

a)(1-(4-(3-胺基-5-(三氟甲基)吡啶-2-基)苯基)環丙基)胺基甲酸第三丁酯 a) (1-(4-(3-Amino-5-(trifluoromethyl)pyridin-2-yl)phenyl)cyclopropyl)aminocarbamate

將(1-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)環丙基)胺基甲酸第三丁酯(359mg，1.0mmol)、2-溴-5-(三氟甲基)吡啶-3-胺(241mg，1.0mmol)、K2CO3(276mg，2.0mmol)和Pd(dppf)Cl2．CH2Cl2(82mg，0.1mmol)溶解在10mL二噁烷和3mL水中，該溶液經氮氣置換後，回流反應過夜。反應液蒸乾後，藉由管柱層析分離(流動相：乙酸乙酯/石油醚=0~100%)，得到白色固體狀目標化合物(230mg)，收率：58.5%。MS(m/z)：394.2(M+1)+。1H NMR(399MHz,DMSO-d6)δ 8.14(d,J=0.8Hz,1H),7.74(s,1H),7.59-7.56(m,2H),7.37(d,J=1.6Hz,1H),7.21-7.18(m,2H),5.54(s,2H),1.37(s,9H),1.15(brs,4H)。 Add (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate to Tributyl ester (359mg, 1.0mmol), 2-bromo-5-(trifluoromethyl)pyridin-3-amine (241mg, 1.0mmol), K 2 CO 3 (276mg, 2.0mmol) and Pd(dppf)Cl 2 . CH 2 Cl 2 (82 mg, 0.1 mmol) was dissolved in 10 mL of dioxane and 3 mL of water. After the solution was replaced with nitrogen, the reaction was refluxed overnight. After the reaction solution was evaporated to dryness, it was separated by column chromatography (mobile phase: ethyl acetate/petroleum ether=0~100%) to obtain the target compound (230 mg) as a white solid, yield: 58.5%. MS (m/z): 394.2 (M+1) + . 1 H NMR(399MHz, DMSO- d6 )δ 8.14(d, J = 0.8Hz, 1H), 7.74(s, 1H), 7.59-7.56(m, 2H), 7.37(d, J = 1.6Hz, 1H) , 7.21-7.18 (m, 2H), 5.54 (s, 2H), 1.37 (s, 9H), 1.15 (brs, 4H).

b)N-(1-(4-(3-胺基-5-(三氟甲基)吡啶-2-基)苯基)環丙基)-4-氯苯甲醯胺 b) N -(1-(4-(3-Amino-5-(trifluoromethyl)pyridin-2-yl)phenyl)cyclopropyl)-4-chlorobenzamide

將(1-(4-(3-胺基-5-(三氟甲基)吡啶-2-基)苯基)環丙基)胺基甲酸第三丁酯(230mg，0.58mmol)溶解在5mL TFA中，濃縮蒸乾，所得殘餘物溶解在3mL DMF中，向該溶液中依次加入4-氯苯甲酸(92mg，0.58mmol)、HATU (222mg，0.58mmol)和DIEA(151mg，1.16mmol)，然後，室溫攪拌30分鐘。反應結束後，藉由管柱層析分離(流動相：甲醇/水=0~100%)，得到白色固體狀目標化合物(170mg)，收率：67.5%。MS(m/z)：432.1(M+1)+。1H NMR(399MHz,DMSO-d6)δ 9.31(s,1H),8.14-8.13(m,1H),7.92-7.88(m,2H),7.59-7.50(m,4H),7.36(d,J=2.0Hz,1H),7.28-7.24(m,2H),5.55(s,2H),1.29(brs,4H)。 (1-(4-(3-Amino-5-(trifluoromethyl)pyridin-2-yl)phenyl)cyclopropyl) tertiary butyl carbamate (230mg, 0.58mmol) was dissolved in 5mL In TFA, concentrate and evaporate to dryness, and the resulting residue was dissolved in 3mL DMF. To this solution was added 4-chlorobenzoic acid (92mg, 0.58mmol), HATU (222mg, 0.58mmol) and DIEA (151mg, 1.16mmol) in sequence, Then, it was stirred at room temperature for 30 minutes. After the reaction, it was separated by column chromatography (mobile phase: methanol/water=0~100%) to obtain the target compound (170 mg) as a white solid, with a yield of 67.5%. MS (m/z): 432.1 (M+1) + . 1 H NMR (399MHz, DMSO- d 6) δ 9.31 (s, 1H), 8.14-8.13 (m, 1H), 7.92-7.88 (m, 2H), 7.59-7.50 (m, 4H), 7.36 (d, J=2.0Hz, 1H), 7.28-7.24 (m, 2H), 5.55 (s, 2H), 1.29 (brs, 4H).

以下化合物是按照化合物1的操作使用相應的中間體和試劑在本領域技術人員認為適宜的條件下製備的。 The following compounds are prepared according to the operation of compound 1 using corresponding intermediates and reagents under conditions deemed suitable by those skilled in the art.

Figure 109116218-A0101-12-0059-166
Figure 109116218-A0101-12-0059-166

Figure 109116218-A0101-12-0060-167
Figure 109116218-A0101-12-0060-167

Figure 109116218-A0101-12-0061-168
Figure 109116218-A0101-12-0061-168

Figure 109116218-A0101-12-0062-169
Figure 109116218-A0101-12-0062-169

Figure 109116218-A0101-12-0063-170
Figure 109116218-A0101-12-0063-170

Figure 109116218-A0101-12-0064-171
Figure 109116218-A0101-12-0064-171

Figure 109116218-A0101-12-0065-172
Figure 109116218-A0101-12-0065-172

Figure 109116218-A0101-12-0066-173
Figure 109116218-A0101-12-0066-173

Figure 109116218-A0101-12-0067-174
Figure 109116218-A0101-12-0067-174

Figure 109116218-A0101-12-0068-175
Figure 109116218-A0101-12-0068-175

Figure 109116218-A0101-12-0069-176
Figure 109116218-A0101-12-0069-176

Figure 109116218-A0101-12-0070-177
Figure 109116218-A0101-12-0070-177

Figure 109116218-A0101-12-0071-178
Figure 109116218-A0101-12-0071-178

Figure 109116218-A0101-12-0072-179
Figure 109116218-A0101-12-0072-179

Figure 109116218-A0101-12-0073-180
Figure 109116218-A0101-12-0073-180

Figure 109116218-A0101-12-0074-181
Figure 109116218-A0101-12-0074-181

Figure 109116218-A0101-12-0075-182
Figure 109116218-A0101-12-0075-182

Figure 109116218-A0101-12-0076-183
Figure 109116218-A0101-12-0076-183

Figure 109116218-A0101-12-0077-184
Figure 109116218-A0101-12-0077-184

Figure 109116218-A0101-12-0078-185
Figure 109116218-A0101-12-0078-185

Figure 109116218-A0101-12-0079-186
Figure 109116218-A0101-12-0079-186

Figure 109116218-A0101-12-0080-187
Figure 109116218-A0101-12-0080-187

Figure 109116218-A0101-12-0081-188
Figure 109116218-A0101-12-0081-188

Figure 109116218-A0101-12-0082-189
Figure 109116218-A0101-12-0082-189

Figure 109116218-A0101-12-0083-190
Figure 109116218-A0101-12-0083-190

Figure 109116218-A0101-12-0084-191
Figure 109116218-A0101-12-0084-191

Figure 109116218-A0101-12-0085-192
Figure 109116218-A0101-12-0085-192

Figure 109116218-A0101-12-0086-193
Figure 109116218-A0101-12-0086-193

Figure 109116218-A0101-12-0087-194
Figure 109116218-A0101-12-0087-194

Figure 109116218-A0101-12-0088-195
Figure 109116218-A0101-12-0088-195

Figure 109116218-A0101-12-0089-196
Figure 109116218-A0101-12-0089-196

Figure 109116218-A0101-12-0090-197
Figure 109116218-A0101-12-0090-197

Figure 109116218-A0101-12-0091-198
Figure 109116218-A0101-12-0091-198

Figure 109116218-A0101-12-0092-199
Figure 109116218-A0101-12-0092-199

Figure 109116218-A0101-12-0093-200
Figure 109116218-A0101-12-0093-200

Figure 109116218-A0101-12-0094-201
Figure 109116218-A0101-12-0094-201

Figure 109116218-A0101-12-0095-202
Figure 109116218-A0101-12-0095-202

Figure 109116218-A0101-12-0096-203
Figure 109116218-A0101-12-0096-203

Figure 109116218-A0101-12-0097-204
Figure 109116218-A0101-12-0097-204

Figure 109116218-A0101-12-0098-205
Figure 109116218-A0101-12-0098-205

Figure 109116218-A0101-12-0099-206
Figure 109116218-A0101-12-0099-206

Figure 109116218-A0101-12-0100-207
Figure 109116218-A0101-12-0100-207

Figure 109116218-A0101-12-0101-208
Figure 109116218-A0101-12-0101-208

Figure 109116218-A0101-12-0102-209
Figure 109116218-A0101-12-0102-209

Figure 109116218-A0101-12-0103-210
Figure 109116218-A0101-12-0103-210

Figure 109116218-A0101-12-0104-211
Figure 109116218-A0101-12-0104-211

Figure 109116218-A0101-12-0105-212
Figure 109116218-A0101-12-0105-212

Figure 109116218-A0101-12-0106-213
Figure 109116218-A0101-12-0106-213

Figure 109116218-A0101-12-0107-214
Figure 109116218-A0101-12-0107-214

Figure 109116218-A0101-12-0108-215
Figure 109116218-A0101-12-0108-215

Figure 109116218-A0101-12-0109-216
Figure 109116218-A0101-12-0109-216

Figure 109116218-A0101-12-0110-217
Figure 109116218-A0101-12-0110-217

Figure 109116218-A0101-12-0111-218
Figure 109116218-A0101-12-0111-218

Figure 109116218-A0101-12-0112-219
Figure 109116218-A0101-12-0112-219

其中，化合物219和220是從相應的消旋體化合物藉由手性製備色譜分離得到的兩個單一構型的對映異構體。手性拆分條件為：管柱為CHIRALPAK IG 20*250mm；流動相為20%乙醇和80%正庚烷；檢測波長為254nm；流速15mL/min。在該方法下，得到的第一個流動相蒸乾溶劑後所得的化合物為化合物219，得到的第二個流動相蒸乾溶劑後所得的化合物為化合物220。 Among them, compounds 219 and 220 are two single-configuration enantiomers separated from the corresponding racemate compounds by chiral preparative chromatography. The chiral resolution conditions are: the column is CHIRALPAK IG 20*250mm; the mobile phase is 20% ethanol and 80% n-heptane; the detection wavelength is 254nm; the flow rate is 15mL/min. In this method, the compound obtained by evaporating the solvent of the first mobile phase obtained is compound 219, and the compound obtained by evaporating the solvent of the second mobile phase obtained is compound 220.

化合物230和231是從相應的消旋體化合物藉由手性製備色譜分離得到的兩個單一構型的對映異構體。手性拆分條件為：管柱為CHIRALPAK IG 20*250mm；流動相為20%乙醇和80%正庚烷；檢測波長為254nm；流速15mL/min。在該方法下，得到的第一個流動相蒸乾溶劑後所得的化合物為化合物230，得到的第二個流動相蒸乾溶劑後所得的化合物為化合物231。 Compounds 230 and 231 are two single-configuration enantiomers separated from the corresponding racemate compounds by chiral preparative chromatography. The chiral resolution conditions are: the column is CHIRALPAK IG 20*250mm; the mobile phase is 20% ethanol and 80% n-heptane; the detection wavelength is 254nm; the flow rate is 15mL/min. Under this method, the compound obtained by evaporating the solvent of the first mobile phase is compound 230, and the compound obtained by evaporating the solvent of the second mobile phase is compound 231.

化合物233和234是從相應的消旋體化合物藉由手性製備色譜分離得到的兩個單一構型的對映異構體。在色譜分析條件下(管柱為CHIRALPAK IG 4.6*250mm；流動相為(正庚烷+0.1%二乙胺)：(乙醇+0.1%二乙胺)=8：2；檢測波長為254nm；流速為1mL/min；溫度為30℃)，化合物234的保留時間是5.244min，化合物233的保留時間是5.744min。 Compounds 233 and 234 are two single-configuration enantiomers separated from the corresponding racemate compounds by chiral preparative chromatography. Under chromatographic analysis conditions (column is CHIRALPAK IG 4.6*250mm; mobile phase is (n-heptane+0.1% diethylamine): (ethanol+0.1% diethylamine)=8:2; detection wavelength is 254nm; flow rate Is 1 mL/min; temperature is 30°C), the retention time of compound 234 is 5.244 min, and the retention time of compound 233 is 5.744 min.

實施例2Example 2

化合物300 Compound 300

N-(1-(4-(3-胺基-5-氯吡啶-2-基)-2-氟苯基)環丙基)-4-氟苯甲醯胺 N -(1-(4-(3-Amino-5-chloropyridin-2-yl)-2-fluorophenyl)cyclopropyl)-4-fluorobenzamide

Figure 109116218-A0101-12-0114-220
Figure 109116218-A0101-12-0114-220

a)1-(4-溴-2-氟苯基)環丙烷-1-胺 a) 1-(4-Bromo-2-fluorophenyl)cyclopropane-1-amine

將4-溴-2-氟苯甲腈(2.00克，10.0mmol)和Ti(OiPr)4(2.84克，10.0mmol)溶於100mL四氫呋喃，冷卻到-78℃，向其中緩慢滴加EtMgBr(6.67克，20.0mmol)，混合物升至室溫，攪拌反應2小時。然後，將反應液冷卻到0度，向其中滴加三氟化硼***溶液(2.84克，20.0mmol)。加畢，升到室溫，繼續反應5小時。反應結束後，加入2mol/L氫氧化鈉水溶液淬滅，然後藉由矽藻土過濾，濾餅用100mL甲醇沖洗，合併濾液，蒸乾，所得殘餘物經管柱層析分離(流動相：甲醇/二氯甲烷=0~10%)，得到黃色油狀物1-(4-溴-2-氟苯基)環丙烷-1-胺(300mg)。收率13.0%。MS(m/z)：230.0(M+1)+。 4-Bromo-2-fluorobenzonitrile (2.00 g, 10.0 mmol) and Ti(OiPr) 4 (2.84 g, 10.0 mmol) were dissolved in 100 mL of tetrahydrofuran, cooled to -78°C, and EtMgBr (6.67 G, 20.0 mmol), the mixture was warmed to room temperature, and the reaction was stirred for 2 hours. Then, the reaction solution was cooled to 0 degrees, and boron trifluoride ether solution (2.84 g, 20.0 mmol) was added dropwise thereto. After the addition, the temperature was raised to room temperature, and the reaction was continued for 5 hours. After the reaction is over, add 2mol/L sodium hydroxide aqueous solution to quench, then filter through celite, wash the filter cake with 100mL methanol, combine the filtrate and evaporate to dryness, the residue obtained is separated by column chromatography (mobile phase: methanol/ Dichloromethane=0~10%) to obtain 1-(4-bromo-2-fluorophenyl)cyclopropane-1-amine (300mg) as a yellow oil. The yield was 13.0%. MS (m/z): 230.0 (M+1) + .

b)N-(1-(4-溴-2-氟苯基)環丙基)-4-氟苯甲醯胺 b) N-(1-(4-Bromo-2-fluorophenyl)cyclopropyl)-4-fluorobenzamide

將1-((4-溴-2-氟苯基)環丙烷-1-胺((300mg，1.304mmol)、4-氟苯甲酸(182.7mg，1.304mmol)、HATU(743.7mg，1.956mmol)和DIEA(505.6mg，3.912mmol)溶於DMF中，混合物於室溫下反應過夜。反應完成後，濃縮，所得殘餘物經管柱層析分離(流動相：甲醇/水=0~100%)，得到黃色固體狀目標化合物。收率65.2%。MS(m/z)：352.0(M+1)+。 Combine 1-((4-bromo-2-fluorophenyl)cyclopropane-1-amine ((300mg, 1.304mmol), 4-fluorobenzoic acid (182.7mg, 1.304mmol), HATU (743.7mg, 1.956mmol) And DIEA (505.6mg, 3.912mmol) were dissolved in DMF, and the mixture was reacted overnight at room temperature. After the reaction was completed, concentrated, and the resulting residue was separated by column chromatography (mobile phase: methanol/water=0~100%), The target compound is obtained as a yellow solid. The yield is 65.2%. MS (m/z): 352.0 (M+1) + .

c)4-氟-N-(1-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基)環丙基)苯甲醯胺 c) 4-Fluoro- N -(1-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (Yl)cyclopropyl)benzamide

將N-(1-(4-溴-2-氟苯基)環丙基)-4-氟苯甲醯胺(300mg，0.852mmol)、聯硼酸頻那醇酯(216.4mg，0.852mmol)、KOAc(162.7mg，1.704mmol)和Pd(dppf)Cl2．CH2Cl2(69.4mg，0.085mmol)溶於40mL二噁烷中，氮氣保護下，混合物於80℃反應4小時。反應完成後，冷卻，濃縮，所得殘餘物經管柱層析分離(流動相：甲醇/水=0~100%)，得到黃色固體狀目標化合物，(300mg)。收率73.9%。MS(m/z)：400.2(M+1)+。 The N-(1-(4-bromo-2-fluorophenyl)cyclopropyl)-4-fluorobenzamide (300mg, 0.852mmol), pinacol diborate (216.4mg, 0.852mmol), KOAc (162.7mg, 1.704mmol) and Pd(dppf)Cl 2 . CH 2 Cl 2 (69.4 mg, 0.085 mmol) was dissolved in 40 mL of dioxane, and the mixture was reacted at 80° C. for 4 hours under the protection of nitrogen. After the reaction is completed, it is cooled and concentrated, and the resulting residue is separated by column chromatography (mobile phase: methanol/water = 0-100%) to obtain the target compound (300 mg) as a yellow solid. The yield was 73.9%. MS (m/z): 400.2 (M+1) + .

d)N-(1-(4-(3-胺基-5-氯吡啶-2-基)-2-氟苯基)環丙基)-4-氟苯甲醯胺 d) N -(1-(4-(3-Amino-5-chloropyridin-2-yl)-2-fluorophenyl)cyclopropyl)-4-fluorobenzamide

將4-氟-N-(1-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)苯基)環丙基)苯甲醯胺(120mg，0.301mmol)、2-溴-5-氯吡啶-3-胺(62.4mg，0.301mmol)、K2CO3(83.2mg，0.602mmol)和Pd(dppf)Cl2．CH2Cl2(24.5mg，0.03mmol)溶於10mL二噁烷和2mL水中，氮氣保護下，回流反應過夜。反應完成後，冷卻，濃縮，所得殘餘物經管柱層析分離(流動相：甲醇/水=0~100%)，得到黃色固體狀目標化合物，(66mg)。收率56.5%。MS(m/z)：400.1(M+1)+。1H NMR(399MHz,DMSO-d6)δ 9.23(s,1H),7.92-7.85(m,2H),7.83(d,J=2.2Hz,1H),7.62(t,J=8.2Hz,1H),7.39(dd,J=8.0,1.7Hz,1H),7.32(dd,J=12.2,1.7Hz,1H),7.27-7.21(m,2H),7.17(d,J=2.2Hz,1H),5.51(s,2H),1.27-1.15(m,4H)。 The 4-fluoro- N -(1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ) Cyclopropyl) benzamide (120mg, 0.301mmol), 2-bromo-5-chloropyridin-3-amine (62.4mg, 0.301mmol), K 2 CO 3 (83.2mg, 0.602mmol) and Pd( dppf)Cl 2 . CH 2 Cl 2 (24.5 mg, 0.03 mmol) was dissolved in 10 mL of dioxane and 2 mL of water, and under the protection of nitrogen, the reaction was refluxed overnight. After the reaction is completed, it is cooled and concentrated, and the resulting residue is separated by column chromatography (mobile phase: methanol/water = 0-100%) to obtain the target compound (66 mg) as a yellow solid. The yield was 56.5%. MS (m/z): 400.1 (M+1) + . 1 H NMR(399MHz,DMSO- d 6)δ 9.23(s,1H),7.92-7.85(m,2H),7.83(d, J =2.2Hz,1H), 7.62(t,J=8.2Hz,1H ),7.39(dd, J =8.0,1.7Hz,1H),7.32(dd, J =12.2,1.7Hz,1H),7.27-7.21(m,2H),7.17(d, J =2.2Hz,1H) , 5.51 (s, 2H), 1.27-1.15 (m, 4H).

以下化合物是按照化合物300的操作使用相應的中間體和試劑在本領域技術人員認為適宜的條件下製備的。 The following compounds were prepared according to the operation of compound 300 using corresponding intermediates and reagents under conditions deemed suitable by those skilled in the art.

Figure 109116218-A0101-12-0116-221
Figure 109116218-A0101-12-0116-221

實施例3Example 3

化合物318 Compound 318

N-(1-(5'-氯-[2,2'-聯吡啶]-5-基)環丙基)-4-乙炔基苯甲醯胺 N -(1-(5'-chloro-[2,2'-bipyridyl]-5-yl)cyclopropyl)-4-ethynylbenzamide

Figure 109116218-A0101-12-0117-222
Figure 109116218-A0101-12-0117-222

a)1-(6-溴吡啶-3-基)環丙烷-1-胺的合成 a) Synthesis of 1-(6-bromopyridin-3-yl)cyclopropane-1-amine

將6-溴煙腈(2.34克，12.8mmol)溶解於***(60mL)中，冷卻至-78℃，向其中緩慢滴加Ti(OiPr)4(4.16mL，14.1mmol)，繼續攪拌5分鐘，接著加入1mol/L的EtMgBr溶液(28.1mL，28.1mmol)，在-78℃下繼續攪拌30分鐘，緩慢升溫至室溫，攪拌反應1小時。然後，再加入三氟化硼***(3.22mL，25.6mmol)，混合物於室溫下反應2小時。反應結束後，向反應液中加入1M鹽酸溶液淬滅，用***萃取，分離出來的水相，用飽和碳酸鈉溶液調至pH值為10左右，再用乙酸乙酯萃取，合併有機相，經無水硫酸鈉乾燥，濃縮，得到得到黃色液體狀目標化合物(1.6g，58.7%)。MS(m/z)：212.9[M+1]+。 6-Bromonicotinonitrile (2.34 g, 12.8 mmol) was dissolved in ether (60 mL), cooled to -78°C, Ti (OiPr) 4 (4.16 mL, 14.1 mmol) was slowly added dropwise to it, and stirring was continued for 5 minutes. Then add 1 mol/L EtMgBr solution (28.1 mL, 28.1 mmol), continue stirring at -78°C for 30 minutes, slowly warm to room temperature, and stir to react for 1 hour. Then, diethyl ether of boron trifluoride (3.22 mL, 25.6 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction, the reaction solution was quenched by adding 1M hydrochloric acid solution, extracted with ether, and the separated aqueous phase was adjusted to a pH of about 10 with saturated sodium carbonate solution, and then extracted with ethyl acetate. The organic phases were combined. It was dried over anhydrous sodium sulfate and concentrated to obtain the target compound (1.6 g, 58.7%) as a yellow liquid. MS (m/z): 212.9 [M+1] + .

b)(1-(6-溴吡啶-3-基)環丙基)胺基甲酸第三丁酯 b) (1-(6-Bromopyridin-3-yl) cyclopropyl) tertiary butyl carbamate

將1-(6-溴吡啶-3-基)環丙烷-1-胺(1.6g，7.51mmol)溶於二氯甲烷(30mL)中，依次加入TEA(1.6mL，11.3mmol)和二碳酸二第三丁酯(1.97g，9.01mmol)，於室溫下攪拌過夜。反應濃縮後，經管柱層析分離(乙酸乙酯/石油醚=0~60%)得到黃色液體狀目標化合物(950mg)。收率：40%。MS(m/z)：313.0[M+1]+ Dissolve 1-(6-bromopyridin-3-yl)cyclopropane-1-amine (1.6g, 7.51mmol) in dichloromethane (30mL), add TEA (1.6mL, 11.3mmol) and dicarbonate in turn Tertiary butyl ester (1.97 g, 9.01 mmol), stirred overnight at room temperature. After the reaction was concentrated, it was separated by column chromatography (ethyl acetate/petroleum ether=0~60%) to obtain the target compound (950mg) as a yellow liquid. Yield: 40%. MS(m/z): 313.0[M+1] +

c)(1-(5'-氯-[2,2'-聯吡啶]-5-基)環丙基)胺基甲酸第三丁酯 c) (1-(5'-Chloro-[2,2'-bipyridyl]-5-yl)cyclopropyl) tertiary butyl carbamate

將(1-(6-溴吡啶-3-基)環丙基)胺基甲酸第三丁酯(313mg，1mmol)溶於甲苯(6mL)中，依次加入5-氯-2-(三丁基錫烷基)吡啶(563mg，1.4mmol)和Pd(PPh3)4(87mg，0.075mmol)，氮氣置換，混合物於100℃下反應過夜。反應結束後，將反應液過濾，濾液濃縮，經管柱層析分離(乙酸乙酯/石油醚=0~70%)，得到黃色固體狀目標化合物(240mg)。收率：69%。MS(m/z)：346.0[M+1]+。 (1-(6-Bromopyridin-3-yl)cyclopropyl)carbamate (313mg, 1mmol) was dissolved in toluene (6mL), and 5-chloro-2-(tributylstannane Pyridine (563 mg, 1.4 mmol) and Pd(PPh 3 ) 4 (87 mg, 0.075 mmol) were replaced with nitrogen, and the mixture was reacted at 100° C. overnight. After the reaction, the reaction solution was filtered, the filtrate was concentrated, and separated by column chromatography (ethyl acetate/petroleum ether=0~70%) to obtain the target compound (240 mg) as a yellow solid. Yield: 69%. MS (m/z): 346.0 [M+1] + .

d)N-(1-(5'-氯-[2,2'-聯吡啶]-5-基)環丙基)-4-乙炔基苯甲醯胺 d) N -(1-(5'-Chloro-[2,2'-bipyridyl]-5-yl)cyclopropyl)-4-ethynylbenzamide

向(1-(5'-氯-[2,2'-聯吡啶]-5-基)環丙基)胺基甲酸第三丁酯(240mg，0.69mmol)的二氯甲烷(12mL)溶液中，滴加TFA(3mlmL)，混合物於室溫下攪拌過夜。反應結束後，將反應液濃縮，用飽和碳酸鈉溶液調至pH值為10左右，乙酸乙酯萃取，合併有機相，經無水硫酸鈉乾燥，濃縮，得到黃色固體。然後，將上述該黃色固體溶於DMF(8mg)中，隨後依次加入對乙炔基苯甲酸(123mg，0.84mmol)、DIEA(0.24mL，1.38mmol)和HATU(340mg，0.9mmol)，於室溫下反應5小時。反應結束後，往反應液中加入水，用乙酸乙酯萃取，合併有機相，經無水硫酸鈉乾燥，濃縮後經管柱層析分離(乙酸乙酯/石油醚=0~70%)，得到黃色固體狀目標化合物(175mg)。收率：68%。MS(m/z)：374.0[M+1]+。1HNMR(399MHz,DMSO-d6)δ 9.38(s,1H),8.68(dd,J=2.5,0.6Hz,1H),8.50(dd,J=2.4,0.6Hz,1H),8.32(dd,J=8.6,0.6Hz,1H),8.23(dd,J=8.4,0.6Hz,1H),8.02(dd,J=8.6,2.5Hz,1H),7.93-7.86(m,2H),7.71(dd,J=8.4,2.5Hz,1H), 7.61-7.53(m,2H),4.37(s,1H),1.40(t,J=6.4Hz,2H),1.42-1.39(m,2H),1.35-1.32(m,2H)。 To a solution of (1-(5'-chloro-[2,2'-bipyridyl]-5-yl)cyclopropyl)carbamate (240mg, 0.69mmol) in dichloromethane (12mL) , TFA (3mlmL) was added dropwise, and the mixture was stirred overnight at room temperature. After the completion of the reaction, the reaction solution was concentrated, adjusted to a pH of about 10 with saturated sodium carbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid. Then, the above-mentioned yellow solid was dissolved in DMF (8mg), and then p-ethynylbenzoic acid (123mg, 0.84mmol), DIEA (0.24mL, 1.38mmol) and HATU (340mg, 0.9mmol) were added in sequence at room temperature. React for 5 hours. After the reaction, add water to the reaction solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate and separate by column chromatography (ethyl acetate/petroleum ether=0~70%) to obtain yellow The target compound (175 mg) as a solid. Yield: 68%. MS (m/z): 374.0 [M+1] + . 1 HNMR(399MHz,DMSO- d 6)δ 9.38(s,1H), 8.68(dd, J =2.5,0.6Hz,1H), 8.50(dd, J =2.4,0.6Hz,1H), 8.32(dd, J =8.6,0.6Hz,1H),8.23(dd, J =8.4,0.6Hz,1H),8.02(dd, J =8.6,2.5Hz,1H),7.93-7.86(m,2H),7.71(dd , J =8.4,2.5Hz,1H), 7.61-7.53(m,2H),4.37(s,1H),1.40(t, J =6.4Hz,2H),1.42-1.39(m,2H),1.35- 1.32(m,2H).

以下化合物是按照化合物318的操作使用相應的中間體和試劑在本領域技術人員認為適宜的條件下製備的。 The following compounds were prepared according to the operation of compound 318 using corresponding intermediates and reagents under conditions deemed suitable by those skilled in the art.

Figure 109116218-A0101-12-0119-224
Figure 109116218-A0101-12-0119-224

實施例4Example 4

化合物325 Compound 325

N-(3-(4-(5-氯吡啶-2-基)苯基)氮雜環丁烷-3-基)-4-乙炔基苯甲醯胺 N -(3-(4-(5-chloropyridin-2-yl)phenyl)azetidin-3-yl)-4-ethynylbenzamide

Figure 109116218-A0101-12-0120-225
Figure 109116218-A0101-12-0120-225

a)3-(4-溴苯基)-3-羥基氮雜環丁烷-1-羧酸第三丁酯 a) 3-(4-Bromophenyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester

1,4-二溴苯(2.36克，10.0mmol)溶於四氫呋喃(50mL)，冷卻到-78℃，然後向其中滴加正丁基鋰的正己烷溶液(6.25mL，1.6mol/L)，混合物在此溫度下攪拌1小時。然後，在該溫度下，向其中滴加3-側氧基氮雜環丁烷-1-甲酸第三丁酯(1.71克，10.0mmol)溶於5mL四氫呋喃的溶液，滴畢，升到室溫，反應過夜。反應結束後，向反應液中加入50mL氯化銨溶液淬滅，用100mL乙酸乙酯萃取兩次，合併有機相，經無水硫酸鈉乾燥，濃縮，濃縮所得殘餘物經管柱層析分離(流動相：乙酸乙酯/石油醚=1/3)，得到黃色固體狀目標化合物(2.1克)。收率：64.0%。MS(m/z)：272.0/274(M-56+1)+。 1,4-Dibromobenzene (2.36 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to -78°C, and then a n-butyl lithium solution in n-hexane (6.25 mL, 1.6 mol/L) was added dropwise to it, The mixture was stirred at this temperature for 1 hour. Then, at this temperature, a solution of tert-butyl 3-oxazetidine-1-carboxylate (1.71 g, 10.0 mmol) dissolved in 5 mL of tetrahydrofuran was added dropwise to it, and the mixture was dropped to room temperature. , React overnight. After the reaction, the reaction solution was quenched by adding 50 mL of ammonium chloride solution, and extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the concentrated residue was separated by column chromatography (mobile phase : Ethyl acetate/petroleum ether=1/3) to obtain the target compound (2.1 g) as a yellow solid. Yield: 64.0%. MS (m/z): 272.0/274 (M-56+1) + .

b)3-(4-溴苯基)-3-((甲基磺醯基)氧基)氮雜環丁烷-1-羧酸第三丁酯 b) 3-(4-Bromophenyl)-3-((methylsulfonyl)oxy)azetidine-1-carboxylic acid tert-butyl ester

將3-(4-溴苯基)-3-羥基氮雜環丁烷-1-羧酸第三丁酯(1.0克，3.04mmol)和DIEA(784mg，6.08mmol)溶於二氯甲烷(30mL)中，冷卻到0℃，向其中滴加MsCl(521mg，4.57mmol)，加畢，混合物升至室溫，反應過夜。反應結束後，向反應液中加入30mL飽和碳酸氫鈉溶液，用100mL二氯甲烷萃取兩次，合併有機相，經無水硫酸鈉乾燥，濃縮，得到黃色油狀的目標化合物(1.23克，3.04mmol)，直接投入到下一步。MS(m/z)：210.0/212.0(M-195)+。 3-(4-Bromophenyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.04 mmol) and DIEA (784 mg, 6.08 mmol) were dissolved in dichloromethane (30 mL ), cooled to 0°C, and MsCl (521 mg, 4.57 mmol) was added dropwise to it. After the addition, the mixture was warmed to room temperature and reacted overnight. After the reaction, 30 mL saturated sodium bicarbonate solution was added to the reaction solution, extracted twice with 100 mL dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the yellow oily target compound (1.23 g, 3.04 mmol ), directly into the next step. MS (m/z): 210.0/212.0 (M-195) + .

c)3-疊氮基-3-(4-溴苯基)氮雜環丁烷-1-羧酸第三丁酯 c) tert-butyl 3-azido-3-(4-bromophenyl)azetidine-1-carboxylate

將3-(4-溴苯基)-3-((甲基磺醯基)氧基)氮雜環丁烷-1-羧酸第三丁酯(1.23克，3.04mmol)和疊氮化鈉(392mg，6.04mmol)依次溶於15mL DMF中，混合物於60℃下攪拌反應過夜。反應結束後，冷卻至室溫，向其中加入50mL水，用二氯甲烷萃取兩次，合併有機相，濃縮，濃縮所得殘餘物經管柱層析分離(流動相：乙酸乙酯/石油醚=1/20~1/1)，得到黃色油狀的目標化合物(700mg)，收率65.0%。MS(m/z)：210.0/212.0(M-142)+。 Combine 3-(4-bromophenyl)-3-((methylsulfonyl)oxy)azetidine-1-carboxylic acid tert-butyl ester (1.23 g, 3.04 mmol) and sodium azide (392mg, 6.04mmol) was dissolved in 15mL DMF successively, and the mixture was stirred and reacted overnight at 60°C. After the reaction, cool to room temperature, add 50 mL of water to it, extract twice with dichloromethane, combine the organic phases, concentrate, and concentrate the residue to be separated by column chromatography (mobile phase: ethyl acetate/petroleum ether = 1 /20~1/1), the target compound (700mg) was obtained as a yellow oil with a yield of 65.0%. MS (m/z): 210.0/212.0 (M-142) + .

d)3-(4-溴苯基)-3-((三苯基-λ5-磷葉立德胺基)氮雜環丁烷-1-羧酸第三丁酯 d) 3-(4-Bromophenyl)-3-((triphenyl-λ 5 -phosphoroylidamino) azetidine-1-carboxylic acid tert-butyl ester

將3-疊氮基-3-(4-溴苯基)氮雜環丁烷-1-羧酸第三丁酯(700mg，1.97mmol)和PPh3(774mg，2.96mmol)溶於30mL四氫呋喃中，然後加入1mL胺水，混合物於室溫下攪拌反應過夜。反應結束後，濃縮，濃縮所得殘餘物經管柱層析分離(流動相：乙酸乙酯/石油醚=1/10~1/1)，得到白色固體狀目標化合物(500mg)。收率43.1%。MS(m/z)：587.2/589.2(M+1)+。 Dissolve 3-azido-3-(4-bromophenyl)azetidine-1-carboxylic acid tert-butyl ester (700mg, 1.97mmol) and PPh 3 (774mg, 2.96mmol) in 30mL of tetrahydrofuran Then, 1 mL of amine water was added, and the mixture was stirred at room temperature to react overnight. After the reaction is completed, it is concentrated, and the residue obtained from the concentration is separated by column chromatography (mobile phase: ethyl acetate/petroleum ether = 1/10~1/1) to obtain the target compound (500 mg) as a white solid. The yield was 43.1%. MS (m/z): 587.2/589.2 (M+1) + .

e)3-(4-(5-氯吡啶-2-基)苯基)-3-((三苯基-λ5-磷葉立德)胺基)氮雜環丁烷-1-羧酸第三丁酯 e) 3-(4-(5-chloropyridin-2-yl)phenyl)-3-((triphenyl-λ 5 -phosphorus ylide)amino)azetidine-1-carboxylic acid Butyl

將3-(4-溴苯基)-3-((三苯基-λ5-磷葉立德)胺基)氮雜環丁烷-1-羧酸第三丁酯(386mg，0.66mmol)、5-氯-2-(三丁基錫烷基)吡啶(317mg，0.79mmol)和Pd(PPh3)4(76mg，0.066mmol)溶於30mL二噁烷中，在氮氣保護下，於110度反應過夜。反應結束後，冷卻，向反應液中加入5mL氟化鉀水溶液淬滅，濃縮，濃縮所得殘餘物經管柱層析分離(流動相：甲醇/水=1~100%)，得到黃色固體狀目標化合物(270mg)。收率66.0%。MS(m/z)：620.3(M+1)+。 The 3-(4-bromophenyl)-3-((triphenyl-λ 5 -phosphorus ylide) amino) azetidine-1-carboxylic acid tert-butyl ester (386 mg, 0.66 mmol), 5 -Chloro-2-(tributylstannyl)pyridine ( 317 mg, 0.79 mmol) and Pd(PPh 3 ) 4 (76 mg, 0.066 mmol) were dissolved in 30 mL of dioxane, and reacted at 110°C overnight under the protection of nitrogen. After the reaction is completed, cool, add 5 mL of potassium fluoride aqueous solution to the reaction solution to quench, concentrate, and concentrate the residue obtained by column chromatography (mobile phase: methanol/water = 1~100%) to obtain the target compound as a yellow solid (270mg). The yield was 66.0%. MS (m/z): 620.3 (M+1) + .

f)3-胺基-3-(4-(5-氯吡啶-2-基)苯基)氮雜環丁烷-1-羧酸第三丁酯 f) 3-Amino-3-(4-(5-chloropyridin-2-yl)phenyl)azetidine-1-carboxylic acid tert-butyl ester

將3-(4-(5-氯吡啶-2-基)苯基)-3-((三苯基-λ5-磷葉立德)胺基)氮雜環丁烷-1-羧酸第三丁酯(270mg，0.44mmol)溶於5mL甲醇中，向其中加入2mL 2mol/L氫氧化鈉水溶液，混合物於室溫下攪拌反應過夜。反應結束後，將反應液濃縮，所得殘餘物經管柱層析分離(流動相：甲醇/水=1~100%)，得到黃色固體狀目標化合物(140mg)。收率88.4%。MS(m/z)：360.1(M+1)+。 Add 3-(4-(5-chloropyridin-2-yl)phenyl)-3-((triphenyl-λ 5 -phosphorylide)amino)azetidine-1-carboxylic acid tert-butyl The ester (270 mg, 0.44 mmol) was dissolved in 5 mL of methanol, 2 mL of 2 mol/L sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at room temperature for overnight reaction. After the reaction, the reaction solution was concentrated, and the resulting residue was separated by column chromatography (mobile phase: methanol/water = 1-100%) to obtain the target compound (140 mg) as a yellow solid. The yield was 88.4%. MS (m/z): 360.1 (M+1) + .

g)3-(4-(5-氯吡啶-2-基)苯基)-3-(4-乙炔基苯甲醯胺基)氮雜環丁烷-1-羧酸第三丁酯 g) 3-(4-(5-chloropyridin-2-yl)phenyl)-3-(4-ethynylbenzamide)azetidine-1-carboxylic acid tert-butyl ester

將3-胺基-3-(4-(5-氯吡啶-2-基)苯基)氮雜環丁烷-1-羧酸第三丁酯(140mg，0.39mmol)溶於DMF(5mL)中，向其中依次加入4-乙炔基苯甲酸(57mg，0.39mmol)、HATU(222mg，0.59mmol)和DIEA(100mg，0.78mmol)，混合物於室溫下攪拌反應過夜。反應結束後，將反應液濃縮，所得殘餘物經管柱層析分離 (流動相：甲醇/水=1~100%)，得到黃色固體狀目標化合物(100mg)。收率53.8%。MS(m/z)：488.0(M+1)+。 Dissolve 3-amino-3-(4-(5-chloropyridin-2-yl)phenyl)azetidine-1-carboxylic acid tert-butyl ester (140mg, 0.39mmol) in DMF (5mL) To it, 4-ethynyl benzoic acid (57 mg, 0.39 mmol), HATU (222 mg, 0.59 mmol) and DIEA (100 mg, 0.78 mmol) were sequentially added thereto, and the mixture was stirred at room temperature for overnight reaction. After the completion of the reaction, the reaction solution was concentrated, and the resulting residue was separated by column chromatography (mobile phase: methanol/water = 1-100%) to obtain the target compound (100 mg) as a yellow solid. The yield was 53.8%. MS (m/z): 488.0 (M+1) + .

h)N-(3-(4-(5-氯吡啶-2-基)苯基)氮雜環丁烷-3-基)-4-乙炔基苯甲醯胺 h) N -(3-(4-(5-chloropyridin-2-yl)phenyl)azetidin-3-yl)-4-ethynylbenzamide

將3-(4-(5-氯吡啶-2-基)苯基)-3-(4-乙炔基苯甲醯胺基)氮雜環丁烷-1-羧酸第三丁酯(100mg，0.21mmol)溶於1mL TFA中，混合物在室溫下攪拌5分鐘。反應結束後，將反應液濃縮，所得殘餘物經管柱層析分離(流動相：甲醇/水=1~100%)，得到黃色固體狀目標化合物(48mg)。收率：59.1%。MS(m/z)：388.1(M+1)+。1H NMR(399MHz,CD3OD)δ 8.57(m,1H),8.00(m,2H),7.89-7.83(m,4H),7.68(m,2H),7.56(m,2H),4.17(dd,J=34.1,9.4Hz,4H),3.69(s,1H)。 3-(4-(5-chloropyridin-2-yl)phenyl)-3-(4-ethynylbenzamide)azetidine-1-carboxylic acid tert-butyl ester (100mg, 0.21 mmol) was dissolved in 1 mL of TFA, and the mixture was stirred at room temperature for 5 minutes. After the completion of the reaction, the reaction solution was concentrated, and the resulting residue was separated by column chromatography (mobile phase: methanol/water = 1-100%) to obtain the target compound (48 mg) as a yellow solid. Yield: 59.1%. MS (m/z): 388.1 (M+1) + . 1 H NMR (399MHz, CD 3 OD) δ 8.57 (m, 1H), 8.00 (m, 2H), 7.89-7.83 (m, 4H), 7.68 (m, 2H), 7.56 (m, 2H), 4.17 ( dd, J = 34.1, 9.4 Hz, 4H), 3.69 (s, 1H).

以下化合物是按照化合物325的操作使用相應的中間體和試劑在本領域技術人員認為適宜的條件下製備的。 The following compounds were prepared according to the operation of compound 325 using corresponding intermediates and reagents under conditions deemed suitable by those skilled in the art.

Figure 109116218-A0101-12-0123-226
Figure 109116218-A0101-12-0123-226

實施例5Example 5

化合物327 Compound 327

N-(1-(4-(6-乙醯胺基吡啶-3-基)苯基)環丙基)-4-乙炔基苯甲醯胺 N -(1-(4-(6-acetamidopyridin-3-yl)phenyl)cyclopropyl)-4-ethynylbenzamide

Figure 109116218-A0101-12-0124-227
Figure 109116218-A0101-12-0124-227

將化合物N-(1-(4-(6-胺基吡啶-3-基)苯基)環丙基)-4-乙炔基苯甲醯胺(100mg,0.283mmol)(按照實施例1中所描述的類似方法製備得到)溶於四氫呋喃(10mL)中，冷卻到0℃，向其中依次加入DIEA(0.140mL,0.849mmol)和乙醯氯(44.4mg,0.566mmol)，混合物於室溫下反應1小時。反應結束後，濃縮，所得殘餘物經管柱層析分離(流動相：甲醇/水=10~100%)，得到黃色固體狀目標化合物(60mg)。收率：53.7%。MS(m/z)：396.2(M+1)+。1H NMR(399MHz,DMSO-d6)δ 10.54(s,1H),9.30(s,1H),8.57(d,J=2.5Hz,1H),8.11(d,J=8.7Hz,1H),8.01(dd,J=8.7,2.5Hz,1H),7.95-7.82(m,2H),7.64-7.50(m,4H),7.26(d,J=8.5Hz,2H),4.37(s,1H),2.08(s,3H),1.28(s,4H)。 The compound N- (1-(4-(6-aminopyridin-3-yl)phenyl)cyclopropyl)-4-ethynylbenzamide (100mg, 0.283mmol) (according to Example 1 Prepared by the similar method described above) was dissolved in tetrahydrofuran (10mL), cooled to 0°C, DIEA (0.140mL, 0.849mmol) and acetyl chloride (44.4mg, 0.566mmol) were added to it, and the mixture was reacted at room temperature. 1 hour. After the reaction is completed, it is concentrated, and the obtained residue is separated by column chromatography (mobile phase: methanol/water=10-100%) to obtain the target compound (60 mg) as a yellow solid. Yield: 53.7%. MS (m/z): 396.2 (M+1) + . 1 H NMR(399MHz, DMSO- d 6)δ 10.54(s,1H), 9.30(s,1H), 8.57(d, J =2.5Hz,1H), 8.11(d, J =8.7Hz,1H), 8.01(dd, J =8.7,2.5Hz,1H),7.95-7.82(m,2H),7.64-7.50(m,4H),7.26(d, J =8.5Hz,2H),4.37(s,1H) ,2.08(s,3H),1.28(s,4H).

實施例6Example 6

SKOV-3細胞中IDO1活性的測定 Determination of IDO1 activity in SKOV-3 cells

1.試劑和材料 1. Reagents and materials

SKOV-3細胞：SKOV-3細胞購自美國標準生物品收藏中心ATCC細胞庫，採用含有3.7g/L碳酸氫鈉和4.5g/L葡萄糖的DMEM培養基，補加2mM穀胺醯胺和10%胎牛血清FBS，於5% CO2、37℃的細胞培養箱中正常培養； SKOV-3 cells: SKOV-3 cells were purchased from the ATCC cell bank of the American Standard Biology Collection Center, using DMEM medium containing 3.7g/L sodium bicarbonate and 4.5g/L glucose, supplemented with 2mM glutamine and 10% Fetal bovine serum FBS, cultured normally in a 5% CO 2 , 37°C cell incubator;

DMEM：GIBCO，貨號31053028； DMEM: GIBCO, article number 31053028;

穀胺醯胺(Glutamax)：GIBCO，貨號35050061； Glutamax: GIBCO, article number 35050061;

胎牛血清(FBS)：GIBCO，貨號10099-141； Fetal Bovine Serum (FBS): GIBCO, catalog number 10099-141;

人IFN γ：R&D Systems，貨號285-IF-100； Human IFN γ: R&D Systems, article number 285-IF-100;

色胺酸(L-Trp)：Sigma-Aldrich，貨號T0254； Tryptophan (L-Trp): Sigma-Aldrich, catalog number T0254;

三氯乙酸(6.1N)：Sigma-Aldrich，貨號T0699； Trichloroacetic acid (6.1N): Sigma-Aldrich, catalog number T0699;

對(N,N-二甲基)苯甲醛：Sigma-Aldrich，貨號156477； P-(N,N-dimethyl)benzaldehyde: Sigma-Aldrich, catalog number 156477;

犬尿胺酸(L-Kynurenine)：Sigma-Aldrich，貨號K8625； Kynurenine (L-Kynurenine): Sigma-Aldrich, catalog number K8625;

微孔讀板儀：SpectraMax M2，Molecular Devices； Microplate reader: SpectraMax M2, Molecular Devices;

96孔板：Beckman Dickinson，貨號353072。 96-well plate: Beckman Dickinson, catalog number 353072.

2.溶液製備 2. Solution preparation

標準曲線儲備溶液：以細胞培養基DMEM稀釋系列濃度的犬尿胺酸溶液製備標準曲線儲備溶液。最終梯度濃度為240、120、60、30、15、7.5、3.75和1.87μM。 Standard curve stock solution: Prepare a standard curve stock solution with a series of kynurenine solutions diluted in cell culture medium DMEM. The final concentration of 240,120,60,30,15,7.5,3.75 gradient and 1.87 μ M.

3.方法 3. Method

化合物活性測定時，將SKOV-3細胞按照1.0 x 104個細胞/孔，即180μL/孔種到96孔板中，於5% CO2、37℃的細胞培養箱中培養。待細胞貼壁後，於當日將待測化合物以無血清DMEM培養基3倍梯度稀釋至相應濃度，然後將10μL/孔稀釋後的不同濃度的待測化合物(待測化合物終濃度為1.0、0.33、0.11、0.037、0.012、0.0041、0.0014和0.00046μM，DMSO終濃度為0.25%)或10μL/孔對照液(0.25%DMSO)分別加入到180μL/孔細胞培養體系中，然後再加入10μL/孔以無血清DMEM培養基稀釋後的人IFN γ(終濃度為50ng/mL)和L-Trp(終濃度為150μmol/L)混合液，於5% CO2、37℃的細胞培養箱中培養，孵育48小時。 When the active compound was measured, according to the SKOV-3 cells 1.0 x 10 4 cells / well, i.e., 180 μ L / hole seeded into 96-well plates, cell incubator at 5% CO 2, 37 ℃ cultured. After the cells adhere to the wall, the test compound is diluted to the corresponding concentration by 3 times in serum-free DMEM medium on the same day, and then 10 μL/well of the test compound is diluted in different concentrations (the final concentration of the test compound is 1.0, 0.33, 0.11, 0.037, 0.012, 0.0041, 0.0014 and 0.00046μM, the final concentration of DMSO is 0.25%) or 10μL/well control solution (0.25% DMSO) were added to the 180μL/well cell culture system, and then 10μL/well was added to the cell culture system. diluted human serum free DMEM media IFN γ (final concentration of 50ng / mL) and L-Trp (final concentration 150 μ mol / L) mixed solution, CO 2, cells were cultured in 37 ℃ incubator at 5%, were incubated 48 hours.

於96孔板的各孔中吸取140μL/孔培養上清液加到新的96孔板中，然後加入10μL/孔三氯乙酸，混合後，於65℃水浴鍋中孵育20分鐘，再離心(1200g)10分鐘，然後吸取100μL/孔上清液加到新的96孔板中，最後加入100μL/孔以冰醋酸配製的20g/L對(N,N-二甲基)苯甲醛，混合均勻。 Pipette 140μL/well of culture supernatant from each well of a 96-well plate and add it to a new 96-well plate, then add 10μL/well of trichloroacetic acid, mix, incubate in a 65℃ water bath for 20 minutes, and then centrifuge ( 1200g) for 10 minutes, and then add 100μL/well of supernatant to a new 96-well plate, and finally add 100μL/well of 20g/L p-(N,N-dimethyl)benzaldehyde prepared with glacial acetic acid, and mix well.

4.檢測 4. Detection

混合1分鐘後，使用SpectraMax M2微孔讀板儀於波長480nm處檢測吸收光光密度信號。以細胞培養基稀釋系列濃度的犬尿胺酸標準品，並按上述的步驟處理後檢測每個濃度點的光密度值。然後在EXCEL軟件中以光密度信號為縱坐標，犬尿胺酸濃度為橫坐標做出犬尿胺酸標準品曲線圖，擬合出線性回歸方程，據此方程計算出各個濃度的待測化合物處理孔以及人IFN-γ對照處理孔中的犬尿胺酸濃度。根據每孔犬尿胺酸濃度分別計算出各個濃度待測化合物的抑制率(%)，然後用XL-Fit 5.3軟件(ID Business Solutions Limited)中205模型計算，獲得IC50值。 After mixing for 1 minute, use the SpectraMax M2 microplate reader to detect the absorption optical density signal at a wavelength of 480nm. Dilute serial concentrations of kynurenine standard with cell culture medium, and detect the optical density value of each concentration point after processing according to the above steps. Then use the optical density signal as the ordinate and the concentration of kynurenine as the abscissa in the EXCEL software to make a curve diagram of the kynurenine standard product, fit the linear regression equation, and calculate the test compound of each concentration according to this equation The concentration of kynurenine in the treated wells and the human IFN-γ control wells. According to the concentration of kynurenic acid in each hole, the inhibition rate (%) of each concentration of the compound to be tested was calculated, and then calculated with the 205 model in the XL-Fit 5.3 software (ID Business Solutions Limited) to obtain the IC 50 value.

抑制率計算如下： The inhibition rate is calculated as follows:

Figure 109116218-A0101-12-0126-228
其中，
Figure 109116218-A0101-12-0126-228
 among them,

[犬尿胺酸]化合物：表示含有人IFN-γ和待測化合物的細胞孔的犬尿胺酸濃度。 [Kynurenic acid] compound : indicates the concentration of kynurenine in cell wells containing human IFN-γ and the test compound.

[犬尿胺酸]IFN-γ：表示只含人IFN-γ的細胞孔的犬尿胺酸濃度。 [Kynurenic acid] IFN-γ : indicates the concentration of kynurenine in cell pores containing only human IFN-γ.

5.測試結果 5. Test results

Figure 109116218-A0101-12-0127-229
Figure 109116218-A0101-12-0127-229

Figure 109116218-A0101-12-0128-230
Figure 109116218-A0101-12-0128-230

Figure 109116218-A0101-12-0129-231
Figure 109116218-A0101-12-0129-231

實施例7 人全血中IDO1活性的測定Example 7 Determination of IDO1 activity in human whole blood

1.試劑和材料 1. Reagents and materials

人外周全血：於5% CO2、37℃的細胞培養箱中正常培養； Human peripheral whole blood: Normally cultured in a cell incubator at 5% CO 2 and 37°C;

RPMI-1640：GIBCO，貨號11875-093； RPMI-1640: GIBCO, article number 11875-093;

人IFN γ：R&D Systems，貨號285-IF-100； Human IFN γ: R&D Systems, article number 285-IF-100;

脂多糖(LPS,Salmonella typhimurium)：Calbiochem，貨號437650； Lipopolysaccharide (LPS, Salmonella typhimurium): Calbiochem, catalog number 437650;

色胺酸(L-Trp)：Sigma-Aldrich，貨號T0254； Tryptophan (L-Trp): Sigma-Aldrich, catalog number T0254;

犬尿胺酸(L-Kynurenine)：Sigma-Aldrich，貨號K8625； Kynurenine (L-Kynurenine): Sigma-Aldrich, catalog number K8625;

96孔板：Beckman Dickinson，貨號353072； 96-well plate: Beckman Dickinson, catalog number 353072;

二甲基亞碸(DMSO)：Sigma-Aldrich，貨號34869-4L。 Dimethyl sulfide (DMSO): Sigma-Aldrich, catalog number 34869-4L.

2.溶液製備 2. Solution preparation

標準曲線樣品的製備：將5μL的標準曲線工作液分別加入到45μL經過活性碳去除內源性犬尿胺酸的空白血漿中，充分渦旋後，得到標準曲線樣品。最終梯度濃度為50、20、5.0、2.0、1.0、0.50、0.20，0.10和0.050μM。 Standard curve samples were prepared: A mixture of 5 μ L of standard curve working solution were added to 45 μ L of activated carbon after the removal of endogenous leucine blank plasma kynurenic, thoroughly vortexed, standard curve samples. The final concentration gradient 50,20,5.0,2.0,1.0,0.50,0.20,0.10 and 0.050 μ M.

3.方法 3. Method

化合物活性測定時，將採取的人外周全血按照180μL/孔種到96孔板中，於5% CO2、37℃的細胞培養箱中培養。半小時後，將待測化合物以無血清RPMI-1640培養基3倍梯度稀釋至相應濃度，然後將10μL/孔稀釋後的不同濃度的待測化合物(待測化合物終濃度為0.30、0.10、0.033、0.011、0.0037和0.0012μM，DMSO終濃度為0.25%)或10μL/孔對照液(0.25% DMSO)分別加入到180μL/孔人全血培養體系中，然後再加入10μL/孔以無血清RPMI-1640培養基稀釋後的人IFN γ(終濃度為150ng/mL)，LPS(終濃度為150ng/mL)和L-Trp(終濃度為50μmol/L)混合液，於5% CO2、37℃的細胞培養箱中培養，孵育24小時。 When the active compound was measured, to be taken in accordance with the kinds of human peripheral whole blood of 180 μ L / pore 96-well plate, cell culture incubator at 5% CO 2, 37 ℃ cultured. After half an hour, the test compound was diluted 3-fold with serum-free RPMI-1640 medium to the corresponding concentration, and then 10 μL/well was diluted with different concentrations of the test compound (the final concentration of the test compound was 0.30, 0.10, 0.033, 0.011, 0.0037 and 0.0012μM, DMSO final concentration is 0.25%) or 10μL/well control solution (0.25% DMSO) were added to 180μL/well human whole blood culture system, and then 10μL/well was added to serum-free RPMI-1640 Human IFN γ (final concentration of 150ng/mL), LPS (final concentration of 150ng/mL) and L-Trp (final concentration of 50 μ mol/L) after the culture medium is diluted, at 5% CO 2 , 37°C Culture in the cell culture incubator and incubate for 24 hours.

將96孔板離心10分鐘後，各孔中吸取70μL血漿上清液加到新的1.5mL管中，然後進行檢測。 After centrifuging the 96-well plate for 10 minutes, aspirate 70 μL of the plasma supernatant from each well and add it to a new 1.5 mL tube for testing.

4.檢測 4. Detection

採用液相色譜-串聯質譜(LC-MS/MS)分析方法，測定樣品中犬尿胺酸的濃度。犬尿胺酸和內標化合物峰面積由軟體Analyst 1.6.2自動採集和積分，定量用標準曲線是將犬尿胺酸理論濃度與犬尿胺酸和內標化合物的峰面積 比值採用線性回歸方程擬合得到，然後，根據標準曲線計算出各個樣品中的犬尿胺酸的濃度。根據每孔犬尿胺酸濃度分別計算出各個濃度待測化合物的抑制率(%)，然後用XL-Fit 5.3軟件(ID Business Solutions Limited)中205模型計算，獲得IC50值。 Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis method, the concentration of kynurenine in the sample was determined. The peak areas of kynurenine and internal standard compounds are automatically collected and integrated by the software Analyst 1.6.2. The standard curve for quantification is to compare the theoretical concentration of kynurenine and the peak areas of kynurenine and internal standard compounds. The ratio is obtained by fitting a linear regression equation, and then the concentration of kynurenine in each sample is calculated according to the standard curve. According to the concentration of kynurenic acid in each hole, the inhibition rate (%) of each concentration of the compound to be tested was calculated, and then calculated with the 205 model in the XL-Fit 5.3 software (ID Business Solutions Limited) to obtain the IC50 value.

抑制率計算如下： The inhibition rate is calculated as follows:

抑制率(%)=100%-{(待測化合物處理孔-對照處理孔)/(人IFN-γ對照處理孔-對照處理孔)}×100%，其中， Inhibition rate (%)=100%-{(test compound treatment well-control treatment well)/(human IFN-γ control treatment well-control treatment well)}×100%, where,

待測化合物處理孔：表示含有人IFN-γ和待測化合物處理的人全血血漿中的犬尿胺酸濃度。 Test compound treatment hole: indicates the concentration of kynurenine in human whole blood plasma treated with human IFN-γ and test compound.

人IFN-γ對照處理孔：表示只含人IFN-γ處理的人全血血漿中的犬尿胺酸濃度。 Human IFN-γ control treatment well: indicates the kynurenine concentration in human whole blood plasma treated with only human IFN-γ.

對照處理孔：表示未經過培養的人全血血漿中的犬尿胺酸濃度。 Control treatment well: indicates the concentration of kynurenine in human whole blood plasma that has not been cultured.

5.測試結果 5. Test results

Figure 109116218-A0101-12-0131-232
Figure 109116218-A0101-12-0131-232

Figure 109116218-A0101-12-0132-233
Figure 109116218-A0101-12-0132-233

實施例8Example 8

化合物對CYP酶抑制活性測定： Determination of compound's inhibitory activity on CYP enzyme:

1.實驗材料及其方法 1. Experimental materials and methods

1.1.實驗材料 1.1. Experimental materials

待測化合物、雙氯芬酸鈉鹽(Diclofenac sodium)、4’-羥基雙氯芬酸(4’-Hydroxydiclofenac)、氫溴酸右美沙芬(Dextromethorphan)、酒石酸右啡烷(Dextrophan)、奎尼丁(Quinidine anhydrous)、磺胺苯吡唑(Sulfaphenazole)等均從美國Sigma-Aldrich公司購得。混合人肝微粒體組分(Pooled human liver microsomes，HLM)購自美國CellzDirect,Life Technologies公司。葡萄糖-6-磷酸鹽(G-6-P)，葡萄糖-6-磷酸脫氫酶(G-6-PDH)及煙醯胺腺嘌呤二核苷酸磷酸(NADP)購自美國Sigma-Aldrich公司。內標：7-羥基香豆素(7-hydroxycoumarin，用於CYP2C9)、非那西丁(phenacetin，用於CYP2D6)均為美國Sigma-Aldrich公司產品。乙腈、甲醇(色譜純)購自美國Fisher Scientific公司，甲酸(色譜純)購自美國Sigma-Aldrich公司。DMSO，EDTA和MgCl2購自國藥集團化學試劑有限公司。分析用純水由Millipore超純水系統製備。 Test compound, Diclofenac sodium, 4'-Hydroxydiclofenac, Dextromethorphan, Dextrophan, Quinidine anhydrous, Sulfaphenazole and others were purchased from Sigma-Aldrich, USA. The mixed human liver microsomes (Pooled human liver microsomes, HLM) were purchased from CellzDirect, Life Technologies, USA. Glucose-6-phosphate (G-6-P), glucose-6-phosphate dehydrogenase (G-6-PDH) and nicotinamide adenine dinucleotide phosphate (NADP) were purchased from Sigma-Aldrich, USA . Internal standard: 7-hydroxycoumarin (for CYP2C9) and phenacetin (for CYP2D6) are all products of Sigma-Aldrich, USA. Acetonitrile and methanol (chromatographically pure) were purchased from Fisher Scientific, USA, and formic acid (chromatographically pure) was purchased from Sigma-Aldrich, USA. DMSO, EDTA and MgCl 2 were purchased from Sinopharm Chemical Reagent Co., Ltd. Pure water for analysis was prepared by Millipore ultrapure water system.

1.2.孵育條件 1.2. Incubation conditions

不同亞型酶的孵育條件如受質種類及其濃度、蛋白含量、孵育時間、陽性抑制劑種類及其濃度、內標等信息見表1。孵育體系的詳細構成見表2。根據實驗需求按表中該試劑配製微粒體溶液、磷酸鹽緩衝液和受質工作液 等。NADPH再生系統包括G-6-P(終濃度為5mM，pH 7.4)、G-6-PD(終濃度為1U/mL，pH 7.4)、NADP(終濃度為1mM，pH 7.4)、MgCl2(終濃度為3mM)、EDTA(終濃度為1mM)和磷酸鹽緩衝液(終濃度為50mM，pH 7.4)，將上述溶液混合後在37℃水浴中孵育10min後置於冰上冷卻備用。待測化合物預先溶解在DMSO中分別配製成濃度為10mM的儲備液，然後用80%乙腈分別稀釋至1mM的工作液。在最終孵育體系中所含有機溶劑的比例不超過1%。待測化合物及各陽性抑制劑均設有溶劑對照組(空白溶劑不含待測化合物或者陽性抑制劑)。根據表2該加入各個組分，孵育體系的總體積為125μL。其中待測化合物及陽性抑制劑與微粒體溶液預先混合，然後加入NDAPH再生系統並放入37℃水浴中來啟動反應。反應體系在37℃孵育20分鐘後加入125μL冰乙腈溶液(含相應濃度的內標)中止反應(見表1)。終止反應溶液經4400rpm在4℃條件下離心10min，取上清液進行LC-MS/MS分析。 The incubation conditions for different subtypes of enzymes, such as the type of substrate and its concentration, protein content, incubation time, the type and concentration of positive inhibitors, and internal standards are shown in Table 1. The detailed composition of the incubation system is shown in Table 2. Prepare microsomal solution, phosphate buffer solution and substrate working solution according to the reagents in the table according to the experimental requirements. The NADPH regeneration system includes G-6-P (final concentration of 5mM, pH 7.4), G-6-PD (final concentration of 1U/mL, pH 7.4), NADP (final concentration of 1mM, pH 7.4), MgCl 2 ( The final concentration is 3 mM), EDTA (final concentration is 1 mM) and phosphate buffer (final concentration is 50 mM, pH 7.4). The above solutions are mixed and incubated in a 37°C water bath for 10 minutes and then placed on ice to cool for later use. The test compounds were pre-dissolved in DMSO to prepare a stock solution with a concentration of 10 mM, and then diluted with 80% acetonitrile to a working solution of 1 mM. The proportion of organic solvent contained in the final incubation system does not exceed 1%. The test compound and each positive inhibitor are provided with a solvent control group (the blank solvent does not contain the test compound or the positive inhibitor). According to Table 2, each component was added, and the total volume of the incubation system was 125 μL . The test compound and the positive inhibitor are pre-mixed with the microsome solution, then added to the NDAPH regeneration system and placed in a 37°C water bath to start the reaction. After the reaction system was incubated at 37°C for 20 minutes, 125 μL ice acetonitrile solution (containing the internal standard of the corresponding concentration) was added to stop the reaction (see Table 1). The terminated reaction solution was centrifuged at 4400 rpm for 10 min at 4°C, and the supernatant was taken for LC-MS/MS analysis.

1.3 數據分析 1.3 Data analysis

用Analyst 1.4.2(Applied Biosystem，USA)軟體對受質代謝產物以及內標進行積分。用受質代謝產物與內標的峰面積比值進行計算，酶剩餘活力百分比的計算公式如下： Analyst 1.4.2 (Applied Biosystem, USA) software was used to integrate the substrate metabolites and internal standards. Use the ratio of the peak area of the substrate metabolite to the internal standard to calculate, and the formula for calculating the percentage of enzyme remaining activity is as follows:

酶剩餘活率百分比=抑制劑組代謝產物生成量/溶劑對照組代謝產物生成量×100% Percentage of remaining enzyme activity = the amount of metabolites produced in the inhibitor group/the amount of metabolites produced in the solvent control group × 100%

表1.孵育條件

Figure 109116218-A0101-12-0134-234
Table 1. Incubation conditions
Figure 109116218-A0101-12-0134-234

表2.孵育體系中各組分構成

Figure 109116218-A0101-12-0134-235
Table 2. The composition of each component in the incubation system
Figure 109116218-A0101-12-0134-235

經測試，本發明的一些化合物對2D6、2C9的抑制作用如下表所示。 After testing, the inhibitory effects of some compounds of the present invention on 2D6 and 2C9 are shown in the following table.

表3

Figure 109116218-A0101-12-0135-236
table 3
Figure 109116218-A0101-12-0135-236

實施例9 Example 9

使用Caco-2細胞單層模型評價化合物的跨膜通透性 Use the Caco-2 cell monolayer model to evaluate the transmembrane permeability of compounds

1．實驗材料： 1. Experimental Materials:

Caco-2(人結腸腺癌)細胞購自上海生命科學研究院細胞資源中心。1X Hank’s平衡鹽溶液(HBSS)及羥乙基哌嗪乙磺酸(HEPES)均購自美國Life technologies公司。可的松、鹽酸普萘洛爾、螢光素鈉鹽及甲酸均購自美國Sigma-Aldrich公司。甲醇、乙腈、異丙醇及乙酸乙酯均為色譜純並購自美國Fisher Scientific公司。DMSO(二甲亞碸)購自國藥集團化學試劑有限公司。去離子水(電阻率

Figure 109116218-A0101-12-0135-286
18MΩ‧cm)由本公司Millipore®水純化系統製備。HTS Transwell® 24孔細胞培養系統購自美國Corning公司，此系統包含一塊含24個小室的嵌套板(下文均稱為A側小室)和一塊普通24孔細胞培養板(下文均稱為B側培養板)，其中，A側小室的底部是孔徑為0.4μm的聚碳酸酯通透性支持物，底面積為0.33cm2。 Caco-2 (human colon adenocarcinoma) cells were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences. 1X Hank's balanced salt solution (HBSS) and hydroxyethylpiperazine ethanesulfonic acid (HEPES) were both purchased from Life technologies, USA. Cortisone, propranolol hydrochloride, luciferin sodium salt and formic acid were all purchased from Sigma-Aldrich, USA. Methanol, acetonitrile, isopropanol and ethyl acetate are all chromatographically pure and purchased from Fisher Scientific in the United States. DMSO (Dimethyl Sulfate) was purchased from Sinopharm Chemical Reagent Co., Ltd. Deionized water (resistivity
Figure 109116218-A0101-12-0135-286
18MΩ‧cm) is prepared by our company's Millipore® water purification system. The HTS Transwell® 24-well cell culture system was purchased from Corning, USA. This system includes a nesting plate with 24 cells (hereinafter referred to as the A-side cell) and a common 24-well cell culture plate (hereinafter referred to as the B-side cell). Culture plate), wherein the bottom of the A-side chamber is a polycarbonate permeable support with a pore size of 0.4 μm, and the bottom area is 0.33 cm 2 .

2．溶液配製： 2. Solution preparation:

10mM待測化合物儲備液：稱取一定量的待測化合物，採用適量體積的DMSO溶解，配成濃度為10mM的儲備液備用。 10mM test compound stock solution: Weigh a certain amount of test compound, dissolve it with an appropriate volume of DMSO, and prepare a stock solution with a concentration of 10mM for later use.

普萘洛爾(內標，正離子)儲備液：稱取一定量的鹽酸普萘洛爾，採用適量體積的DMSO溶解，配成濃度為10mM的儲備液備用。 Propranolol (internal standard, positive ion) stock solution: Weigh a certain amount of propranolol hydrochloride, dissolve it with an appropriate volume of DMSO, and prepare a stock solution with a concentration of 10 mM for later use.

螢光素鈉儲備液：稱取一定量的螢光素鈉，採用適量體積的DMSO溶解，配成濃度為10mM的儲備液備用。 Luciferin sodium stock solution: Weigh a certain amount of luciferin sodium, dissolve it with an appropriate volume of DMSO, and prepare a stock solution with a concentration of 10 mM for use.

可的松(內標，負離子)儲備液：稱取一定量的可的松，採用適量體積的DMSO溶解，配成濃度為50mM的儲備液備用。 Cortisone (internal standard, negative ion) stock solution: Weigh a certain amount of cortisone, dissolve it with an appropriate volume of DMSO, and prepare a stock solution with a concentration of 50 mM for use.

溶液1：495mL HBSS+5mL HEPES+5μL 10mM普萘洛爾。 Solution 1: 495mL HBSS+5mL HEPES+5μL 10mM propranolol.

稀釋液1：400mL去離子水+400mL乙腈+8μL 10mM普萘洛爾+16μL 50mM可的松。 Diluent 1: 400mL deionized water+400mL acetonitrile+8μL 10mM propranolol+16μL 50mM cortisone.

給藥試劑的配製：4.99mL溶液1+5μL 10mM待測化合物+5μL 10mM螢光素鈉。 Preparation of dosing reagent: 4.99mL solution 1+5μL 10mM test compound+5μL 10mM luciferin sodium.

3．實驗方法： 3. experimental method:

首先將在細胞培養箱培養了21天後的Transwell®培養系統A側小室、B側培養板內的培養基移除，A、B兩側分別先用37℃的溶液1清洗一次，然後分別加入0.3和1.0mL的溶液1。加好後放入搖床進行30分鐘的預孵育。預孵育結束後，測量跨膜電阻並計算TEER；只有TEER值大於150Ω‧cm2的單層細胞用於後續的轉運實驗。測試A→B方向的轉運時，吸出A側預孵育液，加入0.3mL給藥試劑；測試B→A方向的轉運時，吸出B側預孵育液，加入1.0mL給藥試劑。加藥後立即分別從加藥側取出10μL樣品作為0 h樣品。然後將培養系統放 入搖床上孵育60分鐘，孵育結束後收集兩側樣品，然後再次測量跨膜電阻並計算TEER值。 First, remove the culture medium in the A side chamber and the B side culture plate of the Transwell® culture system after 21 days of culture in the cell culture incubator. Wash the A and B sides with solution 1 at 37℃, and then add 0.3 respectively. And 1.0 mL of solution 1. After adding, put it in a shaker for 30 minutes of pre-incubation. After the pre-incubation, measure the transmembrane resistance and calculate the TEER; only the monolayer of cells with a TEER value greater than 150Ω‧cm 2 will be used in the subsequent transport experiments. When testing the transfer in the A→B direction, aspirate the pre-incubation solution on the A side and add 0.3mL dosing reagent; when testing the transfer in the B→A direction, aspirate the pre-incubation solution on the B side and add 1.0mL dosing reagent. Immediately after the addition of the drug, 10 μL samples were taken from the drug addition side as the 0 h sample. Then put the culture system on a shaker and incubate for 60 minutes. After the incubation, samples on both sides are collected, and then the transmembrane resistance is measured again and the TEER value is calculated.

0 h及給藥側樣品均先用溶液1稀釋20倍。將200μL稀釋後的樣品或150μL未被稀釋的接收側樣品分別再用稀釋液1稀釋2倍；混勻後分別取150μL溶液進行待測物濃度分析和螢光素的螢光強度的測定。 The samples at 0 h and the administration side were first diluted with solution 1 20 times. Dilute 200μL of the diluted sample or 150μL of the undiluted sample on the receiving side respectively with Diluent 1 to dilute 2 times; after mixing, take 150μL of the solution to analyze the concentration of the analyte and measure the fluorescence intensity of luciferin.

4．分析方法和數據處理： 4. Analysis methods and data processing:

採用液相色譜-串聯質譜(LC-MS/MS)分析方法，測定樣品中化合物的濃度。以化合物和內標的峰面積比作為相對濃度，計算各參數。 Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis method, the concentration of the compound in the sample was determined. Using the peak area ratio of the compound and the internal standard as the relative concentration, each parameter was calculated.

使用美國PerkinElmer VICTOR3TM 1420酶標儀測定螢光素的螢光強度。150μL上述經過預處理的樣品置於96孔板上，在激發波長為485nm、發射波長為535nm的條件下讀取螢光強度值。 The fluorescence intensity of luciferin was measured using PerkinElmer VICTOR3 TM 1420 microplate reader from the United States. 150μL of the above pretreated sample is placed on a 96-well plate, and the fluorescence intensity value is read under the conditions of excitation wavelength of 485nm and emission wavelength of 535nm.

各參數計算公式如下： The calculation formula of each parameter is as follows:

Figure 109116218-A0101-12-0137-237
Figure 109116218-A0101-12-0137-237

Papp：表觀通透係數； P app : apparent permeability coefficient;

Papp,B-A：基底側到頂側的表觀通透係數； P app,BA : the apparent permeability coefficient from the basal side to the top side;

Papp,A-B：頂側到基底側的表觀通透係數； P app, AB : Apparent permeability coefficient from the top side to the basal side;

Papp,LY：螢光素的表觀通透係數； P app,LY : the apparent permeability coefficient of luciferin;

Cr,t：t時間時接收側的藥物濃度； C r,t : drug concentration on the receiving side at time t;

Cd,t：t時間時加藥側的藥物濃度； C d,t : the concentration of the drug on the dosing side at time t;

Cd,0：孵育開始時(零點)加藥側的藥物濃度； C d,0 : the concentration of the drug on the dosing side at the beginning of the incubation (zero point);

Vr：接收側體積(A→B測試時為1mL；B→A測試時為0.3mL)； V r : volume of the receiving side (1mL for A→B test; 0.3mL for B→A test);

Vd：加藥側體積(A→B測試時為0.3mL；B→A測試時為1mL)； V d : Dosing side volume (0.3mL for A→B test; 1mL for B→A test);

S：單細胞層表面積，0.33cm2； S: surface area of single cell layer, 0.33cm 2 ;

t：孵育時間(秒)； t: Incubation time (seconds);

RFUr,t：t時間時接收側的相對螢光單位(RFU)； RFU r,t : Relative Fluorescence Unit (RFU) on the receiving side at time t;

RFUblank：空白溶液的相對螢光單位； RFU blank : the relative fluorescence unit of the blank solution;

RFUd,0：孵育開始時(零點)加藥側的相對螢光單位。 RFU d,0 : the relative fluorescence unit on the dosing side at the beginning of the incubation (zero point).

經上述測試，本發明的一些化合物的跨膜通透性如下表所示。 After the above tests, the transmembrane permeability of some compounds of the present invention is shown in the table below.

表4

Figure 109116218-A0101-12-0138-238
Table 4
Figure 109116218-A0101-12-0138-238

Figure 109116218-A0101-11-0002-3
Figure 109116218-A0101-11-0002-3

Claims (49)

一種式(I)的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體， A compound of formula (I) or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and tautomer ,
Figure 109116218-A0101-13-0001-240
Figure 109116218-A0101-13-0001-240
 其中： among them: X為N或CR3；Y為N或CR4； X is N or CR 3 ; Y is N or CR 4 ; R1、R2、R3和R4分別獨立地選自：氫、鹵素、-OH、-CN、-NH2、C1-6烷基、C1-6鹵烷基、-O(C1-6烷基)、-NH(C1-6烷基)或-N(C1-6烷基)2； R 1 , R 2 , R 3 and R 4 are each independently selected from: hydrogen, halogen, -OH, -CN, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 ; Z為O、NR5或CR6R7； Z is O, NR 5 or CR 6 R 7 ; R5選自：氫、C1-6烷基或C3-6環烷基； R 5 is selected from: hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; R6和R7分別獨立地選自：氫、鹵素、-CN、C1-6鹵烷基、-O(C1-6鹵烷基)、-OH、C1-6烷基、C3-6環烷基或-O(C1-6烷基)； R 6 and R 7 are each independently selected from: hydrogen, halogen, -CN, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -OH, C 1-6 alkyl, C 3 -6 cycloalkyl or -O (C 1-6 alkyl);
Figure 109116218-A0101-13-0001-242
為苯基、5-6員雜芳基或吲唑基；它們各自視需要地被一個或多個選 自以下的基團所取代：鹵素、-CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-O(C1-6烷基)或-O(C1-6鹵烷基)；
Figure 109116218-A0101-13-0001-242
Is a phenyl group, a 5-6 membered heteroaryl group or an indazolyl group; each of them is optionally substituted by one or more groups selected from the group consisting of halogen, -CN, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -O(C 1-6 alkyl) or -O(C 1-6 haloalkyl);
Figure 109116218-A0101-13-0001-241
為吡啶基、嘧啶基、吡嗪基、噠嗪基或三嗪基，它們各自視需要地 被一個或多個選自以下的基團所取代：鹵素、-(C1-6烷基)n-CN、-NO2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-(C1-6烷基)n-C3-6環烷基、-(C1-6烷基)n-苯基、-(C1-6烷基)n-4-6員雜環基、-(C1-6烷基)n-5-6員雜芳基、-(C1-6烷基)n-NR1’R2’、-(C1-6烷基)n-CONR1’R2’、-(C1-6烷基)n-NR1’R2’C(O)R3’、-(C1-6烷基)n- C(O)R3’-、-(C1-6烷基)n-C(O)OR4’、-(C1-6烷基)n-OR5’、-(C1-6烷基)n-S(O)mNR1’R2’、-(C1-6烷基)n-NR1’R2’S(O)mR6’、-(C1-6烷基)n-S(O)mR6’和-(C1-6烷基)n-SR7’；其中，該苯基、C3-6環烷基、4-6員雜環基和5-6員雜芳基視需要地被一個或多個選自以下的基團所取代：鹵素、-CN、-OH、-NH2、C1-6鹵烷基、-O(C1-6鹵烷基)、C1-6烷基、-O(C1-6烷基)、-NH(C1-6烷基)、-N(C1-6烷基)2、C2-6烯基、C2-6炔基和C3-6環烷基；
Figure 109116218-A0101-13-0001-241
Is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, each of which is optionally substituted by one or more groups selected from the group consisting of halogen, -(C 1-6 alkyl) n -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -(C 1-6 alkyl) n -C 3- 6 cycloalkyl, -(C 1-6 alkyl) n -phenyl, -(C 1-6 alkyl) n -4-6 membered heterocyclyl, -(C 1-6 alkyl) n -5 -6-membered heteroaryl, - (C 1-6 alkyl) n -NR 1 'R 2' , - (C 1-6 alkyl) n -CONR 1 'R 2' , - (C 1-6 alkyl yl) n -NR 1 'R 2' C (O) R 3 ', - (C 1-6 alkyl) n - C (O) R 3' -, - (C 1-6 alkyl) n -C (O) OR 4 ', - (C 1-6 alkyl) n -OR 5', - ( C 1-6 alkyl) n -S (O) m NR 1 'R 2', - (C 1- 6 alkyl) n -NR 1 'R 2' S (O) m R 6 ', - (C 1-6 alkyl) n -S (O) m R 6' and - (C 1-6 alkyl) n -SR 7 '; wherein the phenyl group, C 3-6 cycloalkyl group, 4-6 membered heterocyclic group and 5-6 membered heteroaryl group are optionally substituted by one or more groups selected from the following Substitution: halogen, -CN, -OH, -NH 2 , C 1-6 haloalkyl, -O (C 1-6 haloalkyl), C 1-6 alkyl, -O (C 1-6 alkyl ), -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl; n為0或1； n is 0 or 1; m為1或2； m is 1 or 2; p為0或1； p is 0 or 1; R1’、R2’、R3’、R4’、R5’、R6’和R7’分別獨立地選自氫、C1-6烷基、C1-6鹵烷基、-(C1-6烷基)-O-(C1-6烷基)、-(C1-6烷基)-OH、-(C1-6烷基)-CN、-(C1-6烷基)-NH2或C3-6環烷基；或者R1’、R2’與它們相連的N原子一起形成一個4-6員的雜環。 R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 6 'and R 7 ' are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl,- (C 1-6 alkyl)-O-(C 1-6 alkyl), -(C 1-6 alkyl)-OH, -(C 1-6 alkyl)-CN, -(C 1-6 Alkyl) -NH 2 or C 3-6 cycloalkyl; or R 1 ′ and R 2 ′ together with the N atom to which they are connected form a 4-6 membered heterocyclic ring. 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，X為CR3；Y為CR4。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, where X is CR 3 ; Y is CR 4 . 如申請專利範圍第2項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，R1、R2、R3和R4分別獨立地選自氫或鹵素。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, wherein R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen or halogen. 如申請專利範圍第3項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，R1、R2、R3和R4均為氫。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, in which R 1 , R 2 , R 3 and R 4 are all hydrogen. 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，X為CH；Y為N。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, where X is CH; Y is N. 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，X為N；Y為N。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, where X is N; Y is N. 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，p為0，Z為CR6R7。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, where p is 0 and Z is CR 6 R 7 . 如申請專利範圍第7項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，Z為CH2。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, where Z is CH 2 . 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，p為1，Z為CHR6。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, where p is 1, and Z is CHR 6 . 如申請專利範圍第9項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，R6為氫、-OH、C1-6烷基或-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, wherein R 6 is hydrogen, -OH, C 1-6 alkyl or -O (C 1-6 alkyl). 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，p為1，Z為NR5。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, where p is 1, and Z is NR 5 . 如申請專利範圍第11項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，R5為氫或C1-6烷基。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, wherein R 5 is hydrogen or C 1-6 alkyl. 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，p為1，Z為O。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, where p is 1 and Z is O. 如申請專利範圍第1至13項中任一項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非 對映異構體和互變異構體，其中，
Figure 109116218-A0101-13-0004-281
為苯基或5-6員雜芳基，它們視需要地 被一個或多個選自以下的基團所取代：鹵素、-CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-O(C1-6烷基)或-O(C1-6鹵烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, non- Enantiomers and tautomers, of which,
Figure 109116218-A0101-13-0004-281
Are phenyl or 5-6 membered heteroaryl groups, which are optionally substituted by one or more groups selected from the group consisting of halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -O (C 1-6 alkyl) ) Or -O(C 1-6 haloalkyl). 如申請專利範圍第14項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0004-282
為苯基、吡啶基、嘧啶基、吲唑基、吡咯基、吡唑基 或噻吩基，它們視需要地被一個或多個選自以下的基團所取代：鹵素、-CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-O(C1-6烷基)或-O(C1-6鹵烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0004-282
Are phenyl, pyridyl, pyrimidinyl, indazolyl, pyrrolyl, pyrazolyl or thienyl, which are optionally substituted by one or more groups selected from the group consisting of halogen, -CN, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) ) 2 , -O (C 1-6 alkyl) or -O (C 1-6 haloalkyl). 如申請專利範圍第15項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0004-283
為苯基，其視需要地被一個或多個選自以下的基團所 取代：鹵素、CN、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、-NH2、-O(C1-6鹵烷基)或-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0004-283
Is a phenyl group, which is optionally substituted by one or more groups selected from the group consisting of halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 Haloalkyl, -NH 2 , -O (C 1-6 haloalkyl) or -O (C 1-6 alkyl). 如申請專利範圍第16項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0004-284
為苯基，其視需要地被一個或多個選自以下的基團所 取代：F、Cl、Br、CN、甲基、乙基、乙炔基、三氟甲基、-O(三氟甲基)、-OCHF2或甲氧基。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0004-284
It is a phenyl group, which is optionally substituted by one or more groups selected from the group consisting of F, Cl, Br, CN, methyl, ethyl, ethynyl, trifluoromethyl, -O(trifluoromethyl Group), -OCHF 2 or methoxy. 如申請專利範圍第17項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0005-244
為苯基，其被一個或多個選自以下的基團所取代：F、 Cl、Br、CN、甲基、乙基、-CF3、-OCF3、-OCHF2或甲氧基。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0005-244
It is a phenyl group, which is substituted by one or more groups selected from F, Cl, Br, CN, methyl, ethyl, -CF 3 , -OCF 3 , -OCHF 2 or methoxy. 如申請專利範圍第17項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0005-245
為被乙炔基取代的苯基。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0005-245
Is phenyl substituted by ethynyl. 如申請專利範圍第16項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0005-247
為被鹵素取代的苯基。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0005-247
Is a phenyl substituted by halogen. 如申請專利範圍第18項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0005-249
為被-OCF3或-OCHF2取代的苯基。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0005-249
It is a phenyl group substituted by -OCF 3 or -OCHF 2. 如申請專利範圍第18項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0005-248
為被CN取代的苯基。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0005-248
Is a phenyl substituted by CN. 如申請專利範圍第1至6項中任一項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，該化合物具有式(I-1)結構： The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, non- Enantiomers and tautomers, wherein the compound has the structure of formula (I-1):
Figure 109116218-A0101-13-0006-250
Figure 109116218-A0101-13-0006-250
 其中Ra選自：鹵素、CN、C1-6烷基、C2-6炔基、C1-6鹵烷基、-O(C1-6鹵烷基) 或-O(C1-6烷基)，X、Y、Z和
Figure 109116218-A0101-13-0006-253
如申請專利範圍第1至6項中任一項所定 義。 Wherein R a is selected from: halo, CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), or -O (C 1- 6 alkyl), X, Y, Z and
Figure 109116218-A0101-13-0006-253
As defined in any one of items 1 to 6 of the scope of patent application. 如申請專利範圍第1至6項中任一項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中，該化合物具有式(I-2)結構： The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, non- Enantiomers and tautomers, wherein the compound has the structure of formula (I-2):
Figure 109116218-A0101-13-0006-252
Figure 109116218-A0101-13-0006-252
 其中Ra選自：鹵素、CN、C1-6烷基、C2-6炔基、C1-6鹵烷基、-O(C1-6鹵烷基) 或-O(C1-6烷基)，X、Y、Z和
Figure 109116218-A0101-13-0006-254
如申請專利範圍第1至6項中任一項所定 義。 Wherein R a is selected from: halo, CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), or -O (C 1- 6 alkyl), X, Y, Z and
Figure 109116218-A0101-13-0006-254
As defined in any one of items 1 to 6 of the scope of patent application. 如申請專利範圍第23或24項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中Ra選自：F、Cl、Br、CN、甲基、乙基、乙炔基、三氟甲基、-O(三氟甲基)、-OCHF2或-OCH3。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, or diastereomer as described in item 23 or 24 of the scope of patent application and tautomers thereof, wherein R a is selected from: F, Cl, Br, CN , methyl, ethyl, ethynyl, trifluoromethyl, -O (trifluoromethyl), - OCHF 2 or -OCH 3 . 如申請專利範圍第23或24項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中Ra為乙炔基。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, or diastereomer as described in item 23 or 24 of the scope of patent application and tautomers thereof, wherein R a is ethynyl. 如申請專利範圍第23或24項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中Ra為鹵素。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, or diastereomer as described in item 23 or 24 of the scope of patent application and tautomers thereof, wherein R a is halo. 如申請專利範圍第23或24項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其中Ra為CN。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer as described in item 23 or 24 of the scope of application and tautomers thereof, wherein R a is CN. 如申請專利範圍第1至28項中任一項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非 對映異構體和互變異構體，其中，
Figure 109116218-A0101-13-0007-255
為吡啶基、嘧啶基、吡嗪基、噠嗪基、 或三嗪基，它們視需要地被一個或多個選自以下的基團所取代： The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, non- Enantiomers and tautomers, of which,
Figure 109116218-A0101-13-0007-255
Is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, which are optionally substituted by one or more groups selected from the following: 1)鹵素； 1) Halogen; 2)-NO2； 2)-NO 2 ; 3)側氧基； 3) Pendant groups; 4)-(C1-6烷基)n-CN； 4)-(C 1-6 alkyl) n -CN; 5)C1-6烷基； 5) C 1-6 alkyl; 6)C1-6鹵烷基； 6) C 1-6 haloalkyl; 7)C3-6環烷基； 7) C 3-6 cycloalkyl; 8)(C1-6烷基)n-4-6員雜環基； 8) (C 1-6 alkyl) n -4-6 membered heterocyclyl; 9)5-6員雜芳基； 9) 5-6 membered heteroaryl groups; 10)(C1-6烷基)n-NR1’R2’； 10) (C 1-6 alkyl) n -NR 1 'R 2' ; 11)-CONR1’R2’； 11) -CONR 1 'R 2' ; 12)-NR1’R2’C(O)R3’； 12) -NR 1 'R 2' C (O) R 3 '; 13)-C(O)OR4’； 13)-C(O)OR 4 '; 14)-(C1-6烷基)n-OR5’； 14)-(C 1-6 alkyl) n -OR 5 '; 15)-S(O)2NR1’R2’；或 15) -S (O) 2 NR 1 'R 2'; or 16)-NR1’R2’S(O)2R6’； 16) -NR 1 'R 2' S (O) 2 R 6 '; 其中，該4-6員雜環基和5-6員雜芳基視需要地被一個或多個選自以下的基團所取代：C1-6烷基、-O(C1-6烷基)或-NH(C1-6烷基)； Wherein, the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by one or more groups selected from the following: C 1-6 alkyl, -O(C 1-6 alkane Group) or -NH(C 1-6 alkyl); n為0或1； n is 0 or 1; R1’、R2’、R3’、R4’、R5’和R6’分別獨立地選自氫、C1-6烷基、C1-6鹵烷基、-(C1-6烷基)-O-(C1-6烷基)、-(C1-6烷基)-OH、-(C1-6烷基)-CN、-(C1-6烷基)-NH2或C3-6環烷基；或者R1’、R2’與它們相連的N原子一起形成一個4-6員的雜環。 R 1 ', R 2 ', R 3 ', R 4 ', R 5 'and R 6 ' are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1- 6 alkyl)-O-(C 1-6 alkyl), -(C 1-6 alkyl)-OH, -(C 1-6 alkyl)-CN, -(C 1-6 alkyl)- NH 2 or C 3-6 cycloalkyl; or R 1 ′, R 2 ′ and the N atom to which they are connected together form a 4-6 membered heterocyclic ring. 如申請專利範圍第29項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0008-256
為吡啶基、嘧啶基或噠嗪基，它們被一個、兩個或三 個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0008-256
They are pyridyl, pyrimidinyl or pyridazinyl, which are substituted by one, two or three groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkane base). 如申請專利範圍第29項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0008-257
為被胺基取代的吡啶基、被胺基取代的嘧啶基或被胺 基取代的噠嗪基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、 -NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0008-257
It is a pyridyl group substituted by an amino group, a pyrimidinyl group substituted by an amino group or a pyridazinyl group substituted by an amino group, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1- 6 haloalkyl), -O(C 1-6 alkyl). 如申請專利範圍第29項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0009-258
為被-(C1-6烷基)-OH取代的吡啶基、被-(C1-6烷基)-OH取 代的嘧啶基或被-(C1-6烷基)-OH取代的噠嗪基，它們各自同時被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0009-258
As being - (C 1-6 alkyl) -OH substituted pyridinyl, by - (C 1-6 alkyl) -OH substituted pyrimidyl or - (C 1-6 alkyl) -OH-substituted pyridazin Azinyl groups, each of which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -(C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl). 如申請專利範圍第29項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0009-259
為
Figure 109116218-A0101-13-0009-260
或
Figure 109116218-A0101-13-0009-261
，其被一個、兩個或三個選自以 下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0009-259
for
Figure 109116218-A0101-13-0009-260
or
Figure 109116218-A0101-13-0009-261
, Which is substituted by one, two or three groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl). 如申請專利範圍第33項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0009-262
為被胺基取代的
Figure 109116218-A0101-13-0009-265
或
Figure 109116218-A0101-13-0009-264
，其同時被一個或 兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0009-262
Is substituted by an amine group
Figure 109116218-A0101-13-0009-265
or
Figure 109116218-A0101-13-0009-264
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl). 如申請專利範圍第33項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0009-266
為被-(C1-6烷基)-OH取代的
Figure 109116218-A0101-13-0009-269
或
Figure 109116218-A0101-13-0009-268
，其同時 被一個或兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0009-266
Is substituted by -(C 1-6 alkyl)-OH
Figure 109116218-A0101-13-0009-269
or
Figure 109116218-A0101-13-0009-268
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl). 如申請專利範圍第35項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0010-270
為被-(C1-6烷基)-OH和C1-6鹵烷基取代的
Figure 109116218-A0101-13-0010-273
或
Figure 109116218-A0101-13-0010-271
 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0010-270
Is substituted by -(C 1-6 alkyl)-OH and C 1-6 haloalkyl
Figure 109116218-A0101-13-0010-273
or
Figure 109116218-A0101-13-0010-271
 如申請專利範圍第29項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0010-272
為嘧啶基，其視需要地被一個或多個選自以下的基團 所取代：鹵素、-CN、C1-6烷基、C1-6鹵烷基、4-6員雜環基、-NR1’R2’或-OR5’； The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0010-272
Is a pyrimidinyl group, which is optionally substituted by one or more groups selected from the group consisting of halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, 4-6 membered heterocyclic group, -NR 1 'R 2' or -OR 5 '; R1’、R2’和R5’分別獨立地選自氫、C1-6烷基或C1-6鹵烷基。 R 1 ′, R 2 ′ and R 5 ′ are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 haloalkyl. 如申請專利範圍第29項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0010-275
為被-(C1-6烷基)-OH取代的嘧啶基，其同時被一個或兩 個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0010-275
It is a pyrimidinyl substituted by -(C 1-6 alkyl)-OH, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkane Group), -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O( C 1-6 alkyl). 如申請專利範圍第29項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0010-274
為被胺基取代的嘧啶基，其同時被一個或兩個選自以 下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0010-274
It is a pyrimidinyl group substituted by an amino group, which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH (C 1-6 alkyl), -N (C 1- 6 Alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O(C 1-6 haloalkyl), -O(C 1-6 alkyl). 如申請專利範圍第38項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0011-276
為被-(C1-6烷基)-OH取代的
Figure 109116218-A0101-13-0011-279
，其同時被一個或 兩個選自以下的基團所取代：鹵素、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0011-276
Is substituted by -(C 1-6 alkyl)-OH
Figure 109116218-A0101-13-0011-279
, Which is simultaneously substituted by one or two groups selected from the group consisting of halogen, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -( C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl). 如申請專利範圍第39項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和 互變異構體，其中，
Figure 109116218-A0101-13-0011-277
為被胺基取代的
Figure 109116218-A0101-13-0011-278
，其同時被一個或兩個選自以 下的基團所取代：鹵素、C1-6烷基、CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-(C1-6烷基)-OH、C1-6鹵烷基、-O(C1-6鹵烷基)、-O(C1-6烷基)。 The compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and Tautomers, of which,
Figure 109116218-A0101-13-0011-277
Is substituted by an amine group
Figure 109116218-A0101-13-0011-278
, Which is simultaneously substituted by one or two groups selected from: halogen, C 1-6 alkyl, CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 Alkyl) 2 , -(C 1-6 alkyl)-OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -O (C 1-6 alkyl). 如申請專利範圍第1項所述的式(I)的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，其選自化合物1-331或其藥學上可接受的鹽。 The compound of formula (I) or its pharmaceutically acceptable salt, and/or its deuterated compounds, solvates, racemic mixtures, enantiomers, and non-pairs as described in item 1 of the scope of the patent application Enantiomers and tautomers, which are selected from compounds 1-331 or pharmaceutically acceptable salts thereof. 一種醫藥組成物，其包含如申請專利範圍第1至42項中任一項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，並且視需要地包含藥學上可接受的賦形劑。 A pharmaceutical composition, which comprises a compound or a pharmaceutically acceptable salt thereof, and/or a deuterated compound, solvate, racemic mixture, Enantiomers, diastereomers and tautomers, and optionally contain pharmaceutically acceptable excipients. 一種如申請專利範圍第1至42項中任一項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體的用途，其用在製備用於治療個體中由IDO介導或至少部分由IDO介導的疾病的藥物。 A compound or a pharmaceutically acceptable salt thereof, and/or a deuterated compound, solvate, racemic mixture, enantiomer, The use of diastereomers and tautomers in the preparation of drugs for the treatment of IDO-mediated or at least partly IDO-mediated diseases in individuals. 如申請專利範圍第44項所述的用途，其中，該由IDO介導或至少部分由IDO介導的疾病是癌症、自身免疫性疾病、肥胖或肥胖相關性疾病。 The use according to item 44 of the scope of patent application, wherein the disease mediated or at least partially mediated by IDO is cancer, autoimmune disease, obesity or obesity-related disease. 如申請專利範圍第45項所述的用途，其中，該癌症選自實體瘤或血液系統惡性腫瘤；該自身免疫性疾病選自關節炎(例如類風濕性關節炎、膠原誘導性關節炎)。 The use according to item 45 of the scope of patent application, wherein the cancer is selected from solid tumors or hematological malignancies; the autoimmune disease is selected from arthritis (for example, rheumatoid arthritis, collagen-induced arthritis). 如申請專利範圍第46項所述的用途，其中，該癌症選自皮膚癌(包括黑色素瘤和基底癌)、肺癌(包括非小細胞肺癌)、腎癌、頭頸癌、尿路上皮癌、胰腺癌、宮頸癌、膀胱癌、肝癌、子宮內膜癌、卵巢癌、乳腺癌、結腸癌、結腸直腸癌、***癌、胃癌、食道癌、腦瘤(包括神經膠質瘤和成膠質細胞瘤(GBM))、甲狀腺癌、間皮內膜癌、絨毛膜癌、腎上腺癌、肉瘤(包括卡波西氏肉瘤(Kaposi's sarcoma))、白血病、淋巴瘤或骨髓瘤。 The use according to item 46 of the scope of patent application, wherein the cancer is selected from skin cancer (including melanoma and basal cancer), lung cancer (including non-small cell lung cancer), kidney cancer, head and neck cancer, urothelial cancer, pancreas Cancer, cervical cancer, bladder cancer, liver cancer, endometrial cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, brain tumors (including glioma and glioblastoma (GBM )), thyroid cancer, mesothelial endometrial cancer, choriocarcinoma, adrenal cancer, sarcoma (including Kaposi's sarcoma), leukemia, lymphoma or myeloma. 一種組合，其包含申請專利範圍第1至42項中任一項所述的化合物或其藥學上可接受的鹽、和/或其氘代化合物、溶劑合物、外消旋混合物、對映異構體、非對映異構體和互變異構體，以及至少一種額外治療劑。 A combination comprising the compound or its pharmaceutically acceptable salt, and/or its deuterated compound, solvate, racemic mixture, enantiomer according to any one of the scope of patent application 1 to 42 or its pharmaceutically acceptable salt Conformers, diastereomers and tautomers, and at least one additional therapeutic agent. 如申請專利範圍第48項所述的組合，其中，該額外治療劑是免疫檢查點抑制劑、靶向治療劑或化療劑。 The combination according to item 48 of the scope of patent application, wherein the additional therapeutic agent is an immune checkpoint inhibitor, a targeted therapeutic agent or a chemotherapeutic agent.
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