WO2014075387A1

WO2014075387A1 - Diaryl hydantoin derivative, and preparation method, pharmaceutical composition and use thereof

Info

Publication number: WO2014075387A1
Application number: PCT/CN2013/001386
Authority: WO
Inventors: 段文虎; 万惠新; 夏广新; 梅德盛; 林逸鹏; 刘学军; 沈竞康
Original assignee: 上海医药集团股份有限公司; 中国科学院上海药物研究所
Priority date: 2012-11-14
Filing date: 2013-11-14
Publication date: 2014-05-22
Also published as: CN103804358A; CN103804358B

Abstract

Provided are a compound as represented by formula I, or pharmaceutically acceptable salt, solvate, precursor drug, stereoisomer, tautomer, polymorph or metabolite thereof, pharmaceutical composition containing same, and uses thereof in the preparation of drugs for treating androgen receptor related diseases.

Description

一类二芳基乙内酰脲衍生物、其制备方法、药物组合物和应用技术领域 A class of diarylhydantoin derivatives, preparation methods thereof, pharmaceutical compositions and applications

本发明属于医药化学领域，具体地涉及一类二芳基乙内酰脲衍生物、其制备方法、药物组合物以及在医药方面的用途。 The present invention is in the field of medical chemistry, and in particular relates to a class of diarylhydantoin derivatives, a process for their preparation, a pharmaceutical composition, and use in medicine.

背景技术 Background technique

雄激素受体（ androgen recepror，A )是一种 11万道尔顿（llOKDa) 的蛋白质，是类固醇受体（steroid receptor) 的一个成员。和其它类固醇受体相似， AR含有三个结构域： N-端结构域，位于中央的 DNA结合位点和包含核转移信号的结构域，以及含有配体结合位点的 C-端结构域。 N-端结构域含一个被称为激活活性 1 (activation flmction 1 ) 的转录功能位点，不需要其它结构区，这一转录位点本身就能激活目标基因的转录。 C-端含有被称为激活活性 2 (activation function 2) 的转录位点，在其配体的激活下能激活其目标基因的转录。无配体结合的 AR主要分布于细胞质中，和热休克蛋白形成复合物。当与雄激素（如睾酮和二氢睾酮等）结合后， AR从热休克蛋白形成的复合体中被释放出来，进行磷酸化反应，形成二聚体，并转移到细胞核内，结合到与它相关的 DNA片段上，从而刺激其目标基因的转录。配体结合所激活的雄激素受体的转录活性被认为是由一群被称为共活化子（coactivators) 如 SRC-1、 TIF-2和 AIB-1的蛋白质协调而完成。共活化子能修饰核染色体结构，有助于吸引和稳定转录子到目标基因上进行转录。而当与抑制剂结合时，共抑制子（corepressors) 如 NCoR或 SMRT会被吸引来，导致转录受到抑制。 The androgen receptor (orrogen recepror, A) is a 110,000 Dalton (llOKDa) protein that is a member of the steroid receptor. Similar to other steroid receptors, AR contains three domains: an N-terminal domain, a central DNA binding site and a domain containing a nuclear transfer signal, and a C-terminal domain containing a ligand binding site. The N-terminal domain contains a transcriptional functional site called activation flmction 1 that does not require additional structural regions, which itself activates transcription of the target gene. The C-terminus contains a transcriptional site called activation function 2, which activates the transcription of its target gene upon activation of its ligand. The ligand-free AR is mainly distributed in the cytoplasm and forms a complex with heat shock proteins. When combined with androgens (such as testosterone and dihydrotestosterone), AR is released from the complex formed by heat shock proteins, undergoes phosphorylation, forms dimers, and transfers to the nucleus, binding to it. Related DNA fragments, thereby stimulating transcription of its target gene. The transcriptional activity of the ligand-activated androgen receptor is thought to be coordinated by a group of proteins called coactivators such as SRC-1, TIF-2 and AIB-1. Co-activators modify the nuclear chromosome structure and help attract and stabilize transcripts to the target gene for transcription. When combined with inhibitors, corepressors such as NCoR or SMRT are attracted, resulting in inhibition of transcription.

具有选择性的 A 拮抗剂的主要作用是直接阻止睾酮或二氢睾酮与雄激素受体结合，阻断雄激素对细胞的作用，使得细胞产生 "饥饿"现象，最终促使细胞凋亡。其可用于： 1 ) 预防和治疗***癌（prostate cancer, PC)、乳腺癌、卵巢癌、 ***、膀胱癌等； 2) 治疗包括良性***肿大、青春痘、秃顶和毛发增生等疾病； 3 )男性避孕； 4)治疗一系列与男性荷尔蒙相关的失调如***过强和***失调； 5 ) 防止与雄激素减少相关的症状如去势后的发热； 6) 专门用于预防或抑制妇女在转性治疗过程中的肌肉增长。 The main role of the selective A antagonist is to directly prevent testosterone or dihydrotestosterone from binding to the androgen receptor, blocking the action of androgen on the cells, causing the cells to "starvation" and ultimately promoting apoptosis. It can be used for: 1) prevention and treatment of prostate cancer (PC), breast cancer, ovarian cancer, cervical cancer, bladder cancer, etc.; 2) treatment including benign prostatic enlargement, acne, baldness and hair hyperplasia; 3) male contraception; 4) treatment of a series of male hormone-related disorders such as excessive sexual desire and libido; 5) prevention of symptoms associated with androgen reduction such as post-castration fever; 6) specifically for preventing or inhibiting women Muscle growth during transfusion therapy.

治疗 PC是 AR拮抗剂在临床上的一个最重要的应用。 PC在男性恶性肿瘤中高居发病率第一死亡率第二，仅 2008年美国就有 186320个 PC新增病例，另有 26660病人死亡。中国的发病率虽低于西方，但随着生活节奏、生活水平和诊断水平的不断提高， PC正呈不断上升的趋势。此癌是一种进展比较迅速的恶性肿瘤，若得不到早期诊治，从发现症状开始，平均存活期只有 3-5年。早期 PC能通过手术或化疗得到有效的控制。但对于晚期 PC, 其一般治疗策略是基于雄激素及其受体（AR) 的抗雄激素疗法，即手术去势治疗（如双侧睾丸切除术等）和抗雄激素药物治疗。但绝大多数患者经此治疗后，在 18-24周会出现病情恶化，出现去势耐受型***癌（Castration-Resistant Prostate Cancer, CRPC)。此时，现有临床上所使用的抗雄激素药物不再对 CRPC具有抑制作用，反而有些药物如氟他胺和比卡鲁胺对 CRPC具有激动作用，有 80%的患者最终因 CRPC而死亡。进一步的研究表明，雄激素和它的结合的配体对 CRPC的生长是必需的，表明雄激素受体仍是此疾病的重要靶点。但由于 A 表达增加及 AR突变等原因，导致现有的抗***癌药物仅有弱的拮抗活性。因此，需要发展具有更高拮抗活性 A 拮抗剂来治疗 CRPC。 Therapeutic PC is one of the most important clinical applications of AR antagonists. PC is the second most common cause of morbidity in male malignancies. In 2008 alone, there were 186,320 new PC cases in the United States, and another 26,660 patients died. Although the incidence rate in China is lower than that in the West, with the continuous improvement of life rhythm, living standard and diagnostic level, PC is on the rise. This cancer is a malignant tumor that progresses rapidly. If it is not diagnosed early, the average survival time is only 3-5 years from the discovery of symptoms. Early PC can be effectively controlled by surgery or chemotherapy. But for the late PC, one of them The general treatment strategy is anti-androgen therapy based on androgen and its receptor (AR), namely surgical castration (such as bilateral orchiectomy) and anti-androgen therapy. However, in most patients, after treatment, the disease will worsen at 18-24 weeks, and there is a Castration-Resistant Prostate Cancer (CRPC). At this time, the anti-androgen drugs currently used in clinical practice no longer have an inhibitory effect on CRPC. On the contrary, some drugs such as flutamide and bicalutamide have an agonistic effect on CRPC, and 80% of patients eventually die due to CRPC. . Further studies have shown that androgen and its binding ligands are essential for the growth of CRPC, suggesting that androgen receptors remain an important target for this disease. However, due to increased A expression and AR mutation, the existing anti-prostate cancer drugs have only weak antagonistic activity. Therefore, there is a need to develop antagonists with higher antagonistic activity A to treat CRPC.

近几年来，对二芳基乙内酰脲类 A 拮抗剂的研究取得了里程碑样的进展，如 MDV3100 (IC₅₀ = 40 M, LNCaP cell) AR -509等。其中， MDV3100由 Medivation公司和阿斯特拉制药公司共同开发，已于 2012年 8月被美国 FDA批准用于治疗 CRPC。在一项随机、双盲、安慰剂对照研究将 1199名曾接受以多西紫杉醇为主的化学治疗方案的 CRPC 随机分为 MDV3100治疗组和安慰剂组。结果显示：与安慰剂组相比， MDV3100 治疗组患者总生存期中位数显著增加（18.4 vs 13.6 个月， P<0.0001)，死亡风险则较安慰剂组降低 37 %。另 MDV3100用于治疗乳腺癌目前处于 I 期临床。 ARN-509由安进公司开发，用于治疗 CRPC现处于 Ι/Π 期临床。 MDV3100和 ARN-509的研究进展表明二芳基乙内酰脲类 A 拮抗剂具有非常良好的发展前景。 In recent years, milestones have been made in the study of diarylhydantoin A antagonists, such as MDV3100 (IC ₅₀ = 40 M, LNCaP cell) AR-509. Among them, MDV3100 was jointly developed by Medivation and Astra Pharmaceuticals and was approved by the US FDA for the treatment of CRPC in August 2012. In a randomized, double-blind, placebo-controlled study, 1199 CRPCs who received a docetaxel-based chemotherapy regimen were randomized into a MDV3100 treatment group and a placebo group. The results showed a significant increase in the median overall survival (18.4 vs 13.6 months, P < 0.0001) in the MDV3100-treated group compared with the placebo group, and a 37% reduction in the risk of death compared with the placebo group. Another MDV3100 for the treatment of breast cancer is currently in Phase I clinical. ARN-509 was developed by Amgen for the treatment of CRPC and is currently in clinical practice. Advances in MDV3100 and ARN-509 indicate that diaryl hydantoin A antagonists have very good development prospects.

MDV3100 ARN-509 发明内容 MDV3100 ARN-509 Summary

本发明提供了一种与现有技术完全不同的二芳基乙内酰脲类衍生物、其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，及其制备方法、中间体，包含它们的药物组合物，以及它们在制备用于治疗雄激素受体相关疾病、特别是***癌的药物中的应用。本发明所制备的二芳基乙内酰脲类衍生物对雄激素受体具有较佳的抑制活性。 The present invention provides a diarylhydantoin derivative, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer thereof, which is completely different from the prior art, Polymorphs or metabolites, methods for their preparation, intermediates, pharmaceutical compositions comprising the same, and their use in the manufacture of a medicament for the treatment of androgen receptor-associated diseases, particularly prostate cancer. The diarylhydantoin derivative prepared by the present invention has a preferred inhibitory activity against androgen receptor.

一方面，本发明提供了一种如式 I所示的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物， In one aspect, the invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, of formula I ,

A环为 6〜10元芳环；优选为 6〜10元芳环；进一步优选为苯环或萘环；更优选为苯环； The A ring is a 6 to 10 membered aromatic ring; preferably a 6 to 10 membered aromatic ring; further preferably a benzene ring or a naphthalene ring; more preferably a benzene ring;

B环为苯环或 6元杂芳环；优选为苯环或吡啶环；进一步优选为苯环或 2，3，5-三取代吡啶环；更优选为苯环； The B ring is a benzene ring or a 6-membered heteroaryl ring; preferably a benzene ring or a pyridine ring; further preferably a benzene ring or a 2,3,5-trisubstituted pyridine ring; more preferably a benzene ring;

R¹为 H、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自 C3〜C6 环烷基、 C1〜C6烷氧基、 -NH₂、单 (； C1〜C6烷基)氨基、二 (； C1〜C6烷基)氨基、氘原子、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自 -NH₂、单 (C1〜C6烷基)氨基、二 (C1〜C6烷基) 氨基或至少含有 1个氮原子的 5〜7元杂环基，所述至少含有 1个氮原子的 5〜7元杂环基非必须地被 C1〜C4烷基所取代；优选为 H、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被 1个或多个选自 C3〜C6环烷基、 C1〜C4烷氧基、二 (； C1〜C4烷基)氨基、氘原子、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自 -NH₂或至少含有 1个氮原子的 5〜7元杂环基，所述至少含有 1个氮原子的 5〜7元杂环基非必须地被 C1〜C4烷基所取代；再优选为 H、 R ¹ is H, C1 to C4 alkyl or phenyl, and the C1 to C4 alkyl group is optionally one or more selected from the group consisting of C3 to C6 cycloalkyl, C1 to C6 alkoxy, -NH ₂ , single (; C1~C6 alkyl) amino, di (; C1~C6 alkyl) amino, deuterium atom, phenyl, and -C (0) is substituted by a group R ^8, wherein R ⁸ is selected from -NH _2, a mono(C1-C6 alkyl)amino group, a di(C1-C6 alkyl)amino group or a 5- to 7-membered heterocyclic group containing at least one nitrogen atom, and a 5- to 7-membered heterocyclic ring containing at least one nitrogen atom The group is optionally substituted by a C1 to C4 alkyl group; preferably H, a C1 to C4 alkyl group or a phenyl group, and the C1 to C4 alkyl group is optionally one or more selected from a C3 to C6 cycloalkyl group. , C1~C4 alkoxy, di (; C1~C4 alkyl) amino, deuterium atom, phenyl, and -C (0) R ⁸ substituted groups, wherein R ⁸ is selected from -NH _2, or at least containing a 5- to 7-membered heterocyclic group of one nitrogen atom, and the 5- to 7-membered heterocyclic group having at least one nitrogen atom is optionally substituted with a C1 to C4 alkyl group; more preferably H,

C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被 1个或多个选自 C3〜C6环烷基、 C1〜C4 烷氧基、二 (C1〜C4烷基)氨基、氘原子、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自 -NH₂ 或至少含有 1个氮原子的 6元杂环基，所述至少含有 1个氮原子的 6元杂环基非必须地被a C1 to C4 alkyl group or a phenyl group, and the C1 to C4 alkyl group is optionally one or more selected from the group consisting of C3 to C6 cycloalkyl groups, C1 to C4 alkoxy groups, and di(C1 to C4 alkyl)amino groups. Substituted by a group of a halogen atom, a phenyl group and a -C(0)R ⁸ wherein R ^{8 is} selected from -NH ₂ or a 6-membered heterocyclic group containing at least 1 nitrogen atom, said at least one nitrogen A 6-membered heterocyclic group of an atom is not necessarily

C1〜C4烷基所取代；进一步优选为 H、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自环丙基、环丁基、甲氧基、氘原子、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自氨基或 N-甲基哌嗪基；更优选为11、甲基、乙基、环丙基甲基、环丁基甲基、 Substituted by C1 to C4 alkyl; further preferably H, C1 to C4 alkyl or phenyl, the C1 to C4 alkyl optionally being one or more selected from the group consisting of cyclopropyl, cyclobutyl, methoxy Substituted by a halogen atom, a phenyl group and a group in -C(0)R ⁸ wherein R ^{8 is} selected from amino or N-methylpiperazinyl; more preferably 11, methyl, ethyl, cyclopropyl Methyl, cyclobutylmethyl,

苯基、苄基、 2- (甲氧基)乙基、 -CH₂C(0)NH₂或

Phenyl, benzyl, 2-(methoxy)ethyl, -CH ₂ C(0)NH ₂ or

^为卤素或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代; 优选为 H、 F、 Cl、 Br或 C1〜C3烷基；再优选为 H或卤素；更优选为 H或 F; ^ is a halogen or a C1 to C4 alkyl group, which is optionally substituted by one or more halogen atoms; Preferably it is H, F, Cl, Br or C1~C3 alkyl; more preferably H or halogen; more preferably H or F;

R³和 R⁴各自独立地为 -CH₂-R⁶，其中 11⁶为11、 OH、羧基、苄氧基、 C1〜C4烷氧基或卤代 C1〜C2烷基；优选 R³和 R⁴各自独立地为 -CH₂-R⁶，其中 ^为 C1〜C4烷氧基或卤代 C1〜C2烷基；更优选 R³和 R⁴各自独立地为 -CH₂-R⁶，其中 R⁶为 H、 -OCH₃或 -CH₂C1; 或者 R³、 R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或 4〜6元杂环基；优选 R³、R ³ and R ⁴ are each independently -CH ₂ -R ⁶ , wherein 11 ⁶ is 11, OH, carboxyl, benzyloxy, C1 to C4 alkoxy or halogenated C1 to C2 alkyl; preferably R ³ and R ⁴ each independently is -CH ₂ -R ⁶ , wherein ^ is a C1 to C4 alkoxy group or a halogenated C1 to C2 alkyl group; more preferably, R ³ and R ⁴ are each independently -CH ₂ -R ⁶ , wherein R ⁶ is H, -OCH ₃ or -CH ₂ C1; or R ³ , R ⁴ and the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclic group; preferably R ³ ,

R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或含有 1个氧原子的 4〜6元杂环基；其中所述的 3〜6 元环烷基优选为环丙基、环丁基或环戊基，进一步优选为环丙基、环丁基或环戊基，更优选为环丁基或环戊基；所述的 4〜6 元杂环基优选为氧杂环丁基、氮杂环丁基、四氢呋喃基、氧杂环己基、吡咯烷基、二氧六环基、哌啶基或 N-甲基哌啶基，进一步优选为氧杂环丁基、氮杂环丁基或氧杂环己基，更优选为氧杂环丁基或氧杂环己基；更优选 R³、 R⁴和与它们相连的碳原子共同形成环丁基、环戊基或氧杂环己基； R ⁴ and a carbon atom to which they are bonded together form a 3 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclic group having 1 oxygen atom; wherein the 3 to 6 membered cycloalkyl group is preferably a cyclopropyl group; The cyclobutyl or cyclopentyl group is further preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group, more preferably a cyclobutyl group or a cyclopentyl group; and the 4- to 6-membered heterocyclic group is preferably an oxetane group. Further, azacyclobutyl, tetrahydrofuranyl, oxetanyl, pyrrolidinyl, dioxolane, piperidinyl or N-methylpiperidinyl, further preferably oxetanyl, nitrogen heterocycle Butyl or oxeyl, more preferably oxetanyl or oxethanyl; more preferably R ³ , R ⁴ and the carbon atom to which they are attached form a cyclobutyl, cyclopentyl or oxetanyl group ;

R⁵为氰基、卤素、 C1〜C4烷基或 C1〜C4烷氧基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代；优选 R⁵为卤素、甲基、卤代甲基或 -OCH_{3 ;} 更优选 R⁵为卤素、 -CH₃、 -CF₃或 -OCH₃; R ⁵ is cyano, halogen, C1 to C4 alkyl or C1 to C4 alkoxy, said C1 to C4 alkyl being optionally substituted by one or more halogen atoms; preferably R ⁵ is halogen, methyl, halogen Methyl or -OCH _{3 ;} more preferably R ⁵ is halogen, -CH ₃ , -CF ₃ or -OCH ₃ ;

R⁷为 H或卤素，优选为 H或 F，更优选为 H; R ⁷ is H or halogen, preferably H or F, more preferably H;

X为 S或 0，优选为 S; X is S or 0, preferably S;

Y为 -(CH₂)_n -、 0或直接键，其中 -(CH₂)_n -非必须地被一个或多个氘原子或甲基取代， n 为 1或 2; 优选 Y为 -(CH₂)_n -或直接键，其中 -(CH2)_n-非必须地被一个或多个甲基取代， n 为 1或 2; 更优选 Y为 -(CH₂)2-或 -CH(CH₃)-。 Y is -(CH ₂ ) _n -, 0 or a direct bond, wherein -(CH ₂ ) _n - is optionally substituted by one or more deuterium atoms or methyl groups, n is 1 or 2; preferably Y is -(CH ₂ ) _n - or a direct bond, wherein -(CH2) _n - is optionally substituted by one or more methyl groups, n is 1 or 2; more preferably Y is -(CH ₂ )2- or -CH(CH ₃ )-.

在一个实施方式中，在通式 I中， In one embodiment, in Formula I,

A环为 6〜10元芳环；优选为苯环； Ring A is a 6 to 10 membered aromatic ring; preferably a benzene ring;

B环为苯环或 6元杂芳环；优选为苯环； The B ring is a benzene ring or a 6-membered heteroaryl ring; preferably a benzene ring;

R¹为 H或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个选自 C3〜C6环烷基、 C1〜C6烷氧基、 -NH₂、单 (C1〜C6烷基)氨基、二 (C1〜C6烷基)氨基、 -CONH₂、单 (C1〜C6 烷基)氨基甲酰基、二 (C1〜C6 烷基)氨基甲酰基和氘原子中的基团所取代；优选为 H 或R ¹ is H or a C1 to C4 alkyl group, and the C1 to C4 alkyl group is optionally one or more selected from the group consisting of C3 to C6 cycloalkyl groups, C1 to C6 alkoxy groups, -NH ₂ , and mono (C1~). a group of a C6 alkyl)amino group, a di(C1~C6 alkyl)amino group, a -CONH ₂ , a mono(C1 to C6 alkyl)carbamoyl group, a di(C1 to C6 alkyl)carbamoyl group, and a fluorene atom Substituted; preferably H or

C1〜C3烷基，所述 C1〜C3烷基非必须地被一个或多个选自 C3〜C6环烷基、 C1〜C4烷氧基、二 (C1〜C4烷基)氨基、 -CONH₂和氘原子中的基团所取代；进一步优选为 H或 C1〜C2烷基，所述 C1〜C2烷基非必须地被一个或多个选自环丙基、甲氧基、二乙基氨基、 -CONH₂ 和氘原子中的基团所取代；再优选 H、甲基、乙基、环丙基甲基、 2- (甲氧基)乙基、 2- (二乙基氨基)乙基、 -CH₂CONH₂或 -CD_{3 ;} 更优选为 H、甲基或乙基； a C1 to C3 alkyl group, the C1 to C3 alkyl group optionally being one or more selected from the group consisting of C3 to C6 cycloalkyl groups, C1 to C4 alkoxy groups, di(C1 to C4 alkyl)amino groups, -CONH ₂ And substituted with a group in a halogen atom; further preferably H or a C1 to C2 alkyl group, the C1 to C2 alkyl group optionally being one or more selected from the group consisting of a cyclopropyl group, a methoxy group, and a diethylamino group , -CONH ₂ and a group in a halogen atom; further preferably H, methyl, ethyl, cyclopropylmethyl, 2-(methoxy)ethyl, 2-(diethylamino)ethyl , -CH ₂ CONH ₂ or -CD _{3 ;} more preferably H, methyl or ethyl;

R²为 H、卤素或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代；优选为 H、 F、 Cl、 Br或 C1〜C3烷基；再优选为 H或卤素；更优选为 H或 F; R ² is H, halogen or C1 to C4 alkyl, and the C1 to C4 alkyl group is optionally substituted by one or more halogen atoms; Preferably it is H, F, Cl, Br or C1~C3 alkyl; more preferably H or halogen; more preferably H or F;

R³和 R⁴各自独立地为 -CH₂-R⁶，其中 11⁶为11、 OH、羧基、苄氧基或 C1〜C4烷氧基；优选为 H、 OH或 C1〜C4烷氧基；较佳地， R³和 R⁴中至少 1个为甲基；更佳地， R³和 R⁴均为甲基； R ³ and R ⁴ are each independently -CH ₂ -R ⁶ , wherein 11 ⁶ is 11, OH, carboxyl, benzyloxy or C1 to C4 alkoxy; preferably H, OH or C1 to C4 alkoxy; Preferably, at least one of R ³ and R ⁴ is a methyl group; more preferably, both R ³ and R ⁴ are a methyl group;

或者 R³、 R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或 4〜6元杂环基，其中所述的 3〜6 元环烷基优选为环丙基、环丁基或环戊基，进一步优选为环丙基或环丁基，更优选为环丁基；所述的 4〜6 元杂环基优选为氧杂环丁基、氮杂环丁基、四氢呋喃基、吡咯烷基、二氧六环基、哌啶基或 N-甲基哌啶基，进一步优选为氧杂环丁基或氮杂环丁基，更优选为氧杂环丁基； Or R ³ , R ⁴ and a carbon atom to which they are bonded together form a 3 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclic group, wherein the 3 to 6 membered cycloalkyl group is preferably a cyclopropyl group or a cyclobutyl group. Further, a cyclopropyl group or a cyclopentyl group is further preferably a cyclopropyl group or a cyclobutyl group, more preferably a cyclobutyl group; and the 4- to 6-membered heterocyclic group is preferably an oxetanyl group, an azetidinyl group or a tetrahydrofuranyl group. a pyrrolidinyl group, a dioxane group, a piperidinyl group or an N-methylpiperidinyl group, more preferably an oxetanyl group or an azetidinyl group, more preferably an oxetanyl group;

R⁵为氰基、卤素或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代；优选为氰基、 F、 Cl、 Br或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个选自 F、 C1和 Br中的原子取代；进一步优选为氰基、 F、 C1或 C1〜C2烷基，所述 C1〜C2 烷基非必须地被一个或多个 F原子取代；再优选为氰基、 F、 C1或 -CF_{3 ;} 更优选为 -CF_{3 ;} R ⁵ is cyano, halogen or C1 to C4 alkyl, and the C1 to C4 alkyl group is optionally substituted by one or more halogen atoms; preferably a cyano group, F, Cl, Br or a C1 to C4 alkyl group, The C1 to C4 alkyl group is optionally substituted by one or more atoms selected from the group consisting of F, C1 and Br; further preferably a cyano group, F, C1 or C1 to C2 alkyl group, the C1 to C2 alkyl group Optionally substituted by one or more F atoms; more preferably cyano, F, C1 or -CF _{3 ;} more preferably -CF _{3 ;}

X为 S或 0， X is S or 0,

Y为 CH₂)_n -、 0或直接键，其中 -(CH₂)_n -非必须地被一个或多个氘原子取代， n为 1 或 2; 优选 Y为 -CH₂-; 在本发明的又一实施方式中，所述通式 I的化合物优选为如式 Π所示的化合物， Y is CH ₂ ) _n -, 0 or a direct bond, wherein -(CH ₂ ) _n - is optionally substituted by one or more deuterium atoms, n is 1 or 2; preferably Y is -CH ₂ -; In still another embodiment, the compound of the formula I is preferably a compound of the formula ,,

II II

其中， among them,

R¹为 H、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自 C3〜C6环烷基、 C1〜C6烷氧基、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自氨基、单 (C1〜C6烷基)氨基、二 (C1〜C6烷基)氨基或至少含有 1个氮原子的 5〜7元杂环基，所述至少含有 1 个氮原子的 5〜7元杂环基非必须地被 C1〜C4烷基所取代；优选 R¹为 H、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自 C3〜C6环烷基、 C1〜C6烷氧基、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自氨基或至少含有 1个氮原子的 5〜7元杂环基，所述至少含有 1个氮原子的 5〜7元杂环基非必须地被 C1〜C4烷基所取代；再优选 R¹为 H、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自 C3〜C6环烷基、 C1〜C6 烷氧基、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自氨基或至少含有 1个氮原子的 6 元杂环基，所述至少含有 1个氮原子的 6元杂环基非必须地被 C1〜C4烷基所取代；进一步优选 R¹为 H、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自环丙基、环丁基、甲氧基、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自氨基或 N-甲基哌嗪基；更优选 ^为15、甲基、乙基、苯基、环丙基甲基、环丁基甲基、 2- (甲氧基)乙基、苄基、 y— Ν N— R ¹ is H, C1 to C4 alkyl or phenyl, and the C1 to C4 alkyl group is optionally one or more selected from the group consisting of C3 to C6 cycloalkyl, C1 to C6 alkoxy, phenyl and -C (0) is substituted by a group R ^8, wherein R ⁸ is selected from amino, mono (C1~C6 alkyl) amino, (C1~C6 alkyl) amino, or at least one nitrogen atom of 5 ~ 7 membered a heterocyclic group, wherein the 5- to 7-membered heterocyclic group having at least one nitrogen atom is optionally substituted with a C1 to C4 alkyl group; preferably, R ¹ is H, a C1 to C4 alkyl group or a benzene group. Group, a C1~C4 alkyl group be optionally substituted with one or more substituents C3~C6 cycloalkyl, substituted C1~C6 alkoxy, phenyl, and -C (0) R ⁸ group, Wherein R ^{8 is} selected from an amino group or a 5- to 7-membered heterocyclic group containing at least one nitrogen atom, and the 5- to 7-membered heterocyclic group having at least one nitrogen atom is optionally substituted with a C1 to C4 alkyl group; Still more preferably, R ¹ is H, C1 to C4 alkyl or phenyl, and the C1 to C4 alkyl group is optionally one or more selected from the group consisting of C3 to C6 cycloalkyl, C1 to C6 alkoxy, phenyl and Substituted by a group of -C(0)R ⁸ wherein R ^{8 is} selected from an amino group or a 6-membered heterocyclic group containing at least 1 nitrogen atom, and the 6-membered heterocyclic group having at least 1 nitrogen atom is not required The ground is replaced by a C1 to C4 alkyl group; further preferably R ¹ is H, a C1 to C4 alkyl group or a phenyl group, and the C1 to C4 alkyl group is optionally one or more selected from the group consisting of a cyclopropyl group and a cyclobutyl group. Substituted by a group in a methoxy group, a phenyl group, and a -C(0)R ⁸ wherein R ^{8 is} selected from amino or N-methylpiperazinyl; more preferably, it is 15, methyl, ethyl, benzene Base, cyclopropylmethyl, cyclobutylmethyl, 2-(methoxy)ethyl, benzyl , Y- Ν N-

-CH₂C(0)NH₂或^ 。 -CH ₂ C(0)NH ₂ or ^.

^为卤素或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代；优选 R²为 H或卤素；更优选 R²为 H或 F; ^ is halogen or C1~C4 alkyl, the C1~C4 alkyl group is optionally substituted by one or more halogen atoms; preferably R ² is H or halogen; more preferably R ² is H or F;

R³和 R⁴各自独立地为 -CH₂-R⁶，其中 11⁶为11、 C1〜C4烷氧基或卤代 C1〜C2烷基；优选 R³和 R⁴各自独立地为 -CH₂-R⁶，其中 R⁶为 H、 -OCH₃或 -CH₂C1; R ³ and R ⁴ are each independently -CH ₂ -R ⁶ , wherein 11 ⁶ is 11, C 1 -C 4 alkoxy or halogenated C 1 -C 2 alkyl; preferably R ³ and R ⁴ are each independently -CH ₂ -R ⁶ , wherein R ⁶ is H, -OCH ₃ or -CH ₂ C1;

或者 R³、 R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或 4〜6元杂环基；优选 R³、 R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或含有 1个氧原子的 4〜6元杂环基；更优选 R³、 R⁴和与它们相连的碳原子共同形成环丁基、环戊基或氧杂环己基； Or R ³ , R ⁴ and the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclic group; preferably, R ³ , R ⁴ and the carbon atom to which they are bonded form a 3 to 6 member. a cycloalkyl group or a 4 to 6 membered heterocyclic group having 1 oxygen atom; more preferably R ³ , R ⁴ and a carbon atom to which they are bonded form a cyclobutyl group, a cyclopentyl group or an oxetanyl group;

R⁵为卤素、 C1〜C4烷基或 C1〜C4烷氧基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代；优选 R⁵为卤素、甲基、卤代甲基或 -OCH_{3 ;} 更优选 R⁵为卤素、 -CH₃、 -CF₃ 或 -OCH₃; R ⁵ is halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, the C 1 -C 4 alkyl group is optionally substituted by one or more halogen atoms; preferably R ⁵ is halogen, methyl, halomethyl Or -OCH _{3 ;} more preferably R ⁵ is halogen, -CH ₃ , -CF ₃ or -OCH ₃ ;

R⁷为 H或卤素；优选为 H; R ⁷ is H or halogen; preferably H;

Y为 -(CH₂)_n-，其中 -(CH₂)_n -非必须地被一个或多个 C1〜C4烷基取代， n为 1或 2; 优选 Y为 CH₂)_n-，其中 -(CH₂)_n-非必须地被一个或多个甲基取代， n为 1或 2; 更优选 Y为 -(CH₂)₂-或 -CH(CH₃)-。 Y is -(CH ₂ ) _n -, wherein -(CH ₂ ) _n - is optionally substituted by one or more C1 to C4 alkyl groups, n is 1 or 2; preferably Y is CH ₂ ) _n -, wherein - (CH ₂ ) _n - optionally substituted by one or more methyl groups, n is 1 or 2; more preferably Y is -(CH ₂ ) ₂ - or -CH(CH ₃ )-.

在本发明的再一优选实施方式中，当 Y为 -CCH₂)₂-时，为11。 In still another preferred embodiment of the present invention, when Y is -CCH ₂ ) ₂ -, it is 11.

在本发明的一个优选实施方式中，提供了一种如上式 I或 Π所示的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， A环为苯环或喹啉环， B环为苯环，式 I或 II中其它取代基如上所定义和优选。在本发明的一个进一步优选的实施方式中，提供了一种如上式 I或 Π所示的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢 In a preferred embodiment of the present invention, there is provided a compound of the above formula I or hydrazine or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer thereof, a polymorph or metabolite, wherein the A ring is a benzene ring or a quinoline ring, the B ring is a benzene ring, and the other substituents of formula I or II are as defined above and preferred. In a further preferred embodiment of the present invention, there is provided a compound of the above formula I or hydrazine or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer thereof Body, polymorph or metabolism

X 产物，其中， A环为苯环或喹啉环，与 A环相连的氰基、 R⁵、 R⁷及 o ^³均位于 A环中 The X product, wherein the ring A is a benzene ring or a quinoline ring, and the cyano group, R ⁵ , R ⁷ and o ^ ³ attached to the ring A are all located in the ring A.

X 的苯环上，且氰基与 o ^³彼此呈对位取代， B环为苯环，式 I或 II中其它取代基如上所定义和优选。在本发明的一个再优选的实施方式中，提供了一种如上式 I或 Π所示的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，、入 On the phenyl ring of X, the cyano group and o^ ³ are para-substituted with each other, the B ring is a benzene ring, and the other substituents of formula I or II are as defined and preferred above. In a further preferred embodiment of the present invention, there is provided a compound of the above formula I or hydrazine or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer thereof Body, polymorph or metabolite,

其中， A环为苯环，与 A环相连的氰基与。在 A环上彼此呈对位取代， R⁵为三氟甲基或卤素， R⁷为 H或卤素， B环为苯环，式 I或 II中其它取代基如上所定义和优选。在本发明的一个再进一步优选的实施方式中，提供了一种如上式 I或 Π所示的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代、入 Among them, the A ring is a benzene ring and a cyano group attached to the A ring. Substituting each other on the A ring, R ⁵ is trifluoromethyl or halogen, R ⁷ is H or halogen, and B ring is a benzene ring, and other substituents of formula I or II are as defined above and preferred. In a still further preferred embodiment of the present invention, there is provided a compound of the above formula I or hydrazine or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer thereof Construct, polymorph or generation

谢产物，其中， A环为苯环，与 A环相连的氰基与。在 A环上彼此呈对位取代， R⁵ 为三氟甲基， R⁷为 H， B环为苯环，式 I或 II中其它取代基如上所定义和优选。在本发明的一个更加优选的实施方式中，提供了一种如上式 I或 Π所示的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产、入物，其中， A环为苯环， R⁵为三氟甲基， R⁷为 H，与 A环相连的氰基与。在 A环上彼此呈对位取代，与 A环相连的氰基与 R⁵在 A环上彼此呈邻位取代， B环为苯环，式 I 或 Π中其它取代基如上所定义和优选。、入 The product is a benzene ring and a cyano group attached to the ring A. Substituting each other on the A ring, R ⁵ is a trifluoromethyl group, R ⁷ is H, and the B ring is a benzene ring, and other substituents of formula I or II are as defined above and preferred. In a more preferred embodiment of the present invention, there is provided a compound of the above formula I or hydrazine or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer thereof a compound, a polymorph or a metabolite, wherein the ring A is a benzene ring, R ⁵ is a trifluoromethyl group, and R ⁷ is H, a cyano group attached to the ring A. Substituted on the A ring, the cyano group attached to the A ring and R ⁵ are ortho substituted with each other on the A ring, and the B ring is a benzene ring, and other substituents in the formula I or oxime are as defined above and preferred. In

在本发明的一个优选实施方式中，当 R²为卤素时， R²与。在 B环上彼此呈邻位取代。、入 In a preferred embodiment of the invention, when R ² is halogen, R ² is. Substituting one another on the B ring. In

在本发明的一个进一步优选的实施方式中，当 R²为 F时， R²与。在 B环上彼此呈邻位取代。 In a further preferred embodiment of the invention, when R ² is F, R ² is. Substituting one another on the B ring.

在本发明的进一步优选的实施方式中，本发明式 I或 Π所示的化合物优选选自如下化合物： In a further preferred embodiment of the invention, the compound of formula I or 本 of the invention is preferably selected from the following compounds:

98CT00/CI0rN3/X3d L8£SL0/ 10Z OAV

98CT00/CI0rN3/X3d L8£SL0/ 10Z OAV

36 36

另一方面，本发明提供了所述的式 I化合物的制备方法。本发明所述的式 I化合物可通过如下方法制备： In another aspect, the invention provides a process for the preparation of a compound of formula I as described. The compounds of formula I according to the invention can be prepared by the following methods:

方法 1 目标化 Method 1 Targeting

其中，各基团定义如前所述。 Among them, each group is defined as described above.

具体地，将 1-1和 1-2加入到第一种极性溶剂中，加热该混合物（加热方式采用微波或油浴加热，温度 30〜 150°C ) 至 TLC检测反应完全后，向反应混合液中加入酸 A的水溶液和第二种极性溶剂（其与第一种溶剂相同或不同），加热回流该混合物直至 TLC检测反应完全，从该混合物中分离纯化得到目标化合物 I。其中，第一种极性溶剂包括 DMF、 DMA, DMSO、 NMP等，优选 DMF; 第二种极性溶剂包括甲醇、乙醇、异丙醇、正丙醇、正丁醇、 DMF等，优选甲醇；酸 A包括盐酸、硫酸、磷酸等，优选盐酸和硫酸。 Specifically, 1-1 and 1-2 are added to the first polar solvent, and the mixture is heated (heating method is heated by microwave or oil bath, temperature is 30 to 150 ° C) until the reaction is completed by TLC, and the reaction is carried out. An aqueous solution of acid A and a second polar solvent (which is the same as or different from the first solvent) are added to the mixture, and the mixture is heated to reflux until the reaction is completed by TLC, and the target compound I is isolated and purified from the mixture. Wherein, the first polar solvent comprises DMF, DMA, DMSO, NMP, etc., preferably DMF; the second polar solvent comprises methanol, ethanol, isopropanol, n-propanol, n-butanol, DMF, etc., preferably methanol; The acid A includes hydrochloric acid, sulfuric acid, phosphoric acid, etc., preferably hydrochloric acid and sulfuric acid.

其中，中间体 1-2可由中间体 1-5和原料 1-6反应制得，或者由中间体 1-5、原料 1-7 和金属氰化物（NaCN， KCN等）或三烷基氰硅烷反应制得。 Wherein intermediate 1-2 can be prepared by reacting intermediate 1-5 with starting materials 1-6, or intermediate 1-5, starting materials 1-7 and metal cyanide (NaCN, KCN, etc.) or trialkyl cyanosilane. The reaction is prepared.

1-5 1-6 1-7 反应条件和操作步骤可按照国际专利申请 WO2006/124118和期刊文献 J. Med. Chem. 2010, 53, 2779-2796.中所公开的内容进行。 1-5 1-6 1-7 The reaction conditions and procedures can be carried out in accordance with the disclosure of the international patent application WO2006/124118 and the journal J. Med. Chem. 2010, 53, 2779-2796.

方法 2 目标化合物 I由中间体 1-3和 1-4反应制得

Method 2 The target compound I is prepared by reacting intermediates 1-3 and 1-4.

1-3 1-4 1-3 1-4

其中，在 1-3中 X为 O或 S; 在 1-4中 R¹与式 I中定义相同，只是不为 H; 在该反应生成的目标化合物 I中 X为 0，其他各基团定义如前所述。 Wherein X is O or S in 1-3; R ¹ is the same as defined in formula I in 1-4, except that it is not H; X is 0 in the target compound I produced by the reaction, and other groups are defined As mentioned earlier.

在温度 -80〜 0 °C下，将 1-3溶于极性非质子溶剂中（优选 DMF和 DMSO), 加入碱金属氢化物（优选氢化钠），继续于该温度下搅拌 10〜100分钟，然后升温到 20〜 30°C，加入卤代烷烃 1-4， TLC检测反应完成，从反应混合物中分离纯化得到目标化合物 I。 At a temperature of -80 to 0 ° C, 1-3 is dissolved in a polar aprotic solvent (preferably DMF and DMSO), an alkali metal hydride (preferably sodium hydride) is added, and stirring is continued at this temperature for 10 to 100 minutes. Then, the temperature is raised to 20 to 30 ° C, and the halogenated alkane 1-4 is added. The reaction is completed by TLC, and the target compound I is isolated and purified from the reaction mixture.

其中，中间体 1-3可由 1-1和 1-2 (其中 R¹为 H) 反应制得。反应条件和操作步骤同方法 1中 1-1和 1-2的反应。 Among them, the intermediate 1-3 can be obtained by reacting 1-1 and 1-2 (wherein R ¹ is H). The reaction conditions and procedures are the same as those of the 1-1 and 1-2 of the method 1.

其中，各基团定义如前所述。在温度 -80〜0 °C下，将 1-8溶于极性非质子溶剂中（优选 DMF和 DMSO), 加入碱金属氢化物（优选氢化钠），继续于该温度下搅拌， TLC检测反应完成，从反应混合物中分离纯化得到目标化合物 I。

Among them, each group is defined as described above. Dissolve 1-8 in a polar aprotic solvent (preferably DMF and DMSO) at a temperature of -80 to 0 ° C, add an alkali metal hydride (preferably sodium hydride), continue stirring at this temperature, and detect the reaction by TLC. Upon completion, separation and purification from the reaction mixture gave the target compound I.

应当理解的是，对于本发明所述的式 I或 Π化合物，本领域技术人员在上述方法的教导下，可以用有机合成或药物化学领域的技术人员熟知的多种方法的组合来制备，可以将上文中所描述的方法，与本领域已知的合成方法或本领域技术人员所理解的在其上的变化相结合，来合成本发明化合物，而并不限于上述方法。 It should be understood that, for the formula I or hydrazine compound of the present invention, those skilled in the art, under the teaching of the above methods, may be prepared by a combination of various methods well known to those skilled in the art of organic synthesis or medicinal chemistry. The compounds of the present invention are synthesized by combining the methods described above with synthetic methods known in the art or variations as understood by those skilled in the art, and are not limited to the above methods.

本发明所述式 I或 Π化合物可以从易于获得的起始原料使用以下的一般性方法和过程来制备。应当理解的是，本发明给出的是典型或优选的工艺操作条件（即，反应温度、时间、反应物的摩尔比、溶剂、压力、加料方法或顺序等等），还可以使用其他工艺操作条件，除非另有说明。最佳反应条件可以随所用的具体原料、中间体、试剂、催化剂或溶剂而变化，但这些条件可以由本领域技术人员通过常规最佳化过程加以确定。 The formula I or hydrazine compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that the present invention provides typical or preferred process operating conditions (i.e., reaction temperature, time, mole ratio of reactants, solvent, pressure, addition method or sequence, etc.), and may be operated using other processes. Conditions, unless otherwise stated. The optimum reaction conditions may vary depending on the particular starting materials, intermediates, reagents, catalysts or solvents employed, but these conditions can be determined by one skilled in the art by routine optimization procedures.

本发明所述式 I或 Π化合物可以用本领域已知的任何适宜的方法对制备过程进行监控或对化学结构进行鉴定。例如，薄层色谱、液相色谱、气相色谱、质谱、 LC-MS、核磁共振、红外光谱、紫外光谱等。 The Formula I or hydrazine compound of the present invention can be monitored by any suitable method known in the art. Or identify the chemical structure. For example, thin layer chromatography, liquid chromatography, gas chromatography, mass spectrometry, LC-MS, nuclear magnetic resonance, infrared spectroscopy, ultraviolet spectroscopy, and the like.

化合物的制备可以涉及多个化学基团的保护和脱保护。对于保护和脱保护的需要，以及对适当的保护基的选择可以由本领域技术人员容易的加以确定，保护基的化学过程在例如 Greene等人编著的 Protective Groups in Organic Synthesis (第二版， Wiley&Sons, 1991 ) 中找到，其在此以整体的形式引入作为参考。 The preparation of the compounds can involve the protection and deprotection of multiple chemical groups. The need for protection and deprotection, as well as the selection of suitable protecting groups, can be readily determined by those skilled in the art, and the chemical process of the protecting group is, for example, in Protective Groups in Organic Synthesis by Greene et al. (Second Edition, Wiley & Sons, Found in 1991), which is hereby incorporated by reference in its entirety.

另一方面，本发明还提供了一种药物组合物，其包含治疗有效量的式 I或 Π所示的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，以及至少一种药用辅料。所述药物组合物包括口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型。在一些实施方式中，所述药物组合物的口服剂型包括片剂、胶囊、丸剂、粉剂、缓控释制剂、溶液和悬浮液等，胃肠外给药剂型包括无菌溶液、悬浮液或乳液，外用剂型包括软膏、油剂、乳液、凝胶、悬浮液、溶液、洗剂或乳膏，直肠给药剂型包括栓剂、滴剂。药用辅料的选择因施用途径和作用特点而异，通常可为填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、乳化剂或助悬剂等。在其它实施方式中，所述药物组合物还包含至少一种其他治疗剂。较佳地，本发明提供的药物组合物为口服剂型。 In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or hydrazine, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer thereof, Tautomers, polymorphs or metabolites, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition includes an oral dosage form, a parenteral administration dosage form, a external dosage form, and a rectal administration dosage form. In some embodiments, the oral dosage form of the pharmaceutical composition includes tablets, capsules, pills, powders, controlled release preparations, solutions and suspensions, and the like, and parenteral dosage forms include sterile solutions, suspensions or emulsions. The external dosage form includes an ointment, an oil, an emulsion, a gel, a suspension, a solution, a lotion or a cream, and the rectal administration form includes a suppository and a drop. The choice of pharmaceutical excipients will vary depending on the route of administration and the nature of the action, and may generally be a filler, a diluent, a binder, a wetting agent, a disintegrating agent, a lubricant, an emulsifier or a suspending agent. In other embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent. Preferably, the pharmaceutical composition provided by the present invention is an oral dosage form.

另一方面，本发明提供了一种调节雄激素受体活性的方法，包括将所述式 I或 Π化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，或者包含上述物质的药物组合物与雄激素受体相接触。较佳地，本发明所述的调节雄激素受体活性为抑制雄激素受体活性。 In another aspect, the invention provides a method of modulating androgen receptor activity comprising administering a compound of formula I or hydrazine, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mutual An isomer, a polymorph or a metabolite, or a pharmaceutical composition comprising the above, is contacted with an androgen receptor. Preferably, the modulation of androgen receptor activity according to the invention inhibits androgen receptor activity.

又一方面，本发明还提供了所述式 I或 Π化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，或者包含上述物质的药物组合物在制备药物中的应用，所述药物用于治疗雄激素受体相关疾病。根据本发明的一个实施方式，所述雄激素受体相关疾病包括***癌、乳腺癌、 ***增生、多毛症、粉刺、秃头、肌肉衰竭、性腺功能衰弱、骨质疏松症、胆固醇过高、男性不育、男性性功能不良、贫血肥胖、***望低下和忧郁症。根据本发明一个优选的实施方式，所述的雄激素受体相关疾病为去势耐受型***癌。 In still another aspect, the present invention provides the Formula I or hydrazine compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof Or the use of a pharmaceutical composition comprising the above substance for the preparation of a medicament for the treatment of androgen receptor-associated diseases. According to one embodiment of the present invention, the androgen receptor-related diseases include prostate cancer, breast cancer, benign prostatic hyperplasia, hirsutism, acne, baldness, muscle failure, gonadal dysfunction, osteoporosis, hypercholesterolemia, male Infertility, male sexual dysfunction, anemia, obesity, low sexual desire and depression. According to a preferred embodiment of the present invention, the androgen receptor-associated disease is castration-tolerant prostate cancer.

再一方面，本发明还提供了将所述式 I或 Π化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，或者包含上述物质的药物组合物用于治疗雄激素受体相关疾病的方法，所述的治疗方法包括将上述活性物质与哺乳动物相接触。根据本发明的一个实施方式，所述雄激素受体相关疾病包括***癌、乳腺癌、 ***增生、多毛症、粉刺、秃头、肌肉衰竭、性腺功能衰弱、骨质疏松症、胆固醇过高、男性不育、男性性功能不良、贫血肥胖、 ***望低下和忧郁症。根据本发明一个优选的实施方式，所述的雄激素受体相关疾病为去势耐受型***癌。 In a further aspect, the invention provides a compound of formula I or hydrazine, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolism thereof A product, or a pharmaceutical composition comprising the above, for use in a method of treating an androgen receptor-related disease, the method comprising contacting the active substance with a mammal. According to one embodiment of the present invention, the androgen receptor-related diseases include prostate cancer, breast cancer, benign prostatic hyperplasia, hirsutism, acne, baldness, muscle failure, gonadal dysfunction, osteoporosis, hypercholesterolemia, Male infertility, male sexual dysfunction, anemia and obesity, low sexual desire and depression. According to a preferred embodiment of the present invention, the androgen receptor-associated disease is castration-tolerant prostate cancer.

某些化学或药学术语 Certain chemical or pharmaceutical terms

除非另外特别指明，本申请的权利要求书和说明书中的化学术语和药学术语具有如下所述的含义。 The chemical and pharmaceutical terms in the claims and the specification of the present application have the meanings as described below unless otherwise specifically indicated.

"卤素"是指氟、氯、溴或碘。 "Halogen" means fluorine, chlorine, bromine or iodine.

"氰基"是指 -CN。 "Cyano" means -CN.

"异氰基"是指 -N=C=0。 "Isocyano" means -N=C=0.

"异硫氰基"是指 -N=C=S。 "Isothiocyano" means -N=C=S.

"羟基"是指 -OH。 "Hydroxy" means -OH.

"羧基"是指 -COOH。 "Carboxyl" means -COOH.

"苄氧基"是指 -OCH₂C₆H₅。 "Benzyloxy" means -OCH ₂ C ₆ H ₅ .

縮写 "DMA"是指 N，N-二甲基乙酰胺。 The abbreviation "DMA" means N,N-dimethylacetamide.

縮写 "NMP"是指 N-甲基吡咯烷酮。 The abbreviation "NMP" refers to N-methylpyrrolidone.

"C1〜C4"是指其所定义的基团（如烷基、烷氧基、环烷基等）中碳原子数目为 1、 2、 3或 4。由此可推知其他以类似方式描述的术语的含义，如 "C1〜C6" 、 "C3〜C6"等。 "C1 to C4" means that the number of carbon atoms in the group (e.g., alkyl group, alkoxy group, cycloalkyl group, etc.) defined therein is 1, 2, 3 or 4. From this, it is possible to infer the meanings of other terms described in a similar manner, such as "C1 to C6", "C3 to C6", and the like.

"6-10元"是指其所定义的闭合环系基团（如芳基、杂芳基、杂环基等）中围成该闭合环骨架本身的原子数目为 6、 7、 8、 9或 10，可根据闭合环系基团的环数、饱和度以及构成该环的原子性质等而取不同的数目。由此可推知其他以类似方式描述的术语的含义，如 "3〜6元" 、 "4〜6元"等。 "6-10元" means that the number of atoms enclosing the closed ring skeleton itself in the closed ring group (e.g., aryl, heteroaryl, heterocyclic, etc.) defined therein is 6, 7, 8, 9 Or 10 may take a different number depending on the number of rings of the closed ring system group, the degree of saturation, and the nature of the atoms constituting the ring. From this, the meanings of other terms described in a similar manner, such as "3 to 6 yuan", "4 to 6 yuan", etc., can be inferred.

"烷基"是指仅由碳原子和氢原子组成、不含不饱和键、具有例如 1 至 12 个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。通常，烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、 2-甲基丁基、 2，2-二甲基丙基、正己基、庚基、 2-甲基己基、 3-甲基己基、辛基、壬基和癸基等。 "Alkyl" means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 12 carbon atoms, and attached to the remainder of the molecule by a single bond. . In general, examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.

"烷氧基"是指式 -OR基团，其中 R为如上文所定义的烷基。通常，烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基等。 "Alkoxy" refers to a radical of the formula -OR wherein R is alkyl as defined above. In general, examples of the alkoxy group include, but are not limited to, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group, a t-butoxy group and the like.

"单 (C1〜C6烷基)氨基"是指式 -NHR基团，其中 R为如上文所定义的具有 1〜6个碳原子的烷基。 "Single (C1-C6 alkyl)amino" means a radical of the formula -NHR wherein R is alkyl as defined above having from 1 to 6 carbon atoms.

"二 (C1〜C6烷基)氨基"是指式 -NRaRb基团，其中 Ra、 R_b各自独立地为如上文所定义的具有 1〜6个碳原子的烷基。 "单 (C1〜C6烷基)氨基甲酰基"是指式 -CONHR基团，其中 R为如上文所定义的具有 1〜6个碳原子的烷基。 "Di(C1-C6 alkyl)amino" refers to a radical of the formula -NRaRb, wherein each of Ra, _{Rb is} independently alkyl as defined above having from 1 to 6 carbon atoms. "Mono(C1-C6 alkyl)carbamoyl" refers to a radical of the formula -CONHR wherein R is alkyl as defined above having from 1 to 6 carbon atoms.

"二 (C1〜C6烷基)氨基甲酰基"是指式 -CONRaRb基团，其中 Ra、 R_b各自独立地为如上文所定义的具有 1〜6个碳原子的烷基。 "Bis(C1-C6 alkyl)carbamoyl" refers to a radical of the formula -CONRaRb wherein each of Ra, _{Rb is} independently alkyl as defined above having from 1 to 6 carbon atoms.

"环烷基"是指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，可包括稠合环体系、桥环体系或螺环体系，通常具有 3至 15个碳原子。其可经由环上任何适宜的碳原子通过单键与分子的其余部分连接。通常，环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。就本发明的目的而言，优选具有 3至 6个碳原子的单环体系的环烷基，更优选具有 3至 5个碳原子的单环体系的环烷基。 "Cycloalkyl" means a stable, non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and may include fused ring systems, bridged ring systems or spiro ring systems, usually having from 3 to 15 carbons atom. It can be attached to the remainder of the molecule via a single bond via any suitable carbon atom on the ring. In general, examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. For the purpose of the present invention, a cycloalkyl group having a monocyclic ring system of 3 to 6 carbon atoms is preferred, and a cycloalkyl group of a monocyclic ring system having 3 to 5 carbon atoms is more preferred.

"杂环基"是指由 2至 14个碳原子以及 1至 6个选自氮、氧和硫的杂原子共同组成的稳定的 3元至 20元非芳香族环状基团，其可以为单环、双环、三环或更多环的环体系，也可包括稠合环体系、桥环体系或螺环体系。其可经由环上任意适宜的碳原子或者杂原子通过单键与分子的其余部分连接。其中的氮原子可任选被其他基团进一步取代以形成叔胺或季铵结构。通常，杂环基的实例包括但不限于氮杂环丙基、氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑啉基、吡唑烷基、咪唑烷基、噻唑烷基、异噻唑烷基、异噁唑烷基、四氢呋喃基、二氧戊环基、氧杂环己基、吗啉基、哌嗪基、 N-取代哌嗪基、高哌嗪基、 N-取代高哌嗪基、哌啶基、 N-取代哌啶基、二氧六环基、二氢吲哚基、四氢异喹啉基、十氢异喹啉基等。就本发明的目的而言，优选 3元至 7元且至少含有 1个选自氮、氧或硫的杂原子的单环体系的杂环基，进一步优选 4元至 6元且至少含有 1个选自氮或氧的杂原子的单环体系的杂环基，更优选 4元至 6元且至少含有 1〜2个选自氮或氧的杂原子的单环体系的杂环基。 "Heterocyclyl" means a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which may be Ring systems of monocyclic, bicyclic, tricyclic or more rings may also include fused ring systems, bridged ring systems or spiro ring systems. It can be attached to the remainder of the molecule via a single bond via any suitable carbon or heteroatom on the ring. The nitrogen atom therein may be optionally further substituted with other groups to form a tertiary amine or quaternary ammonium structure. In general, examples of heterocyclic groups include, but are not limited to, azacyclopropyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, Isothiazolidinyl, isoxazolidinyl, tetrahydrofuranyl, dioxolanyl, oxetanyl, morpholinyl, piperazinyl, N-substituted piperazinyl, homopiperazinyl, N-substituted homoperazine Azinyl, piperidinyl, N-substituted piperidinyl, dioxolyl, indanyl, tetrahydroisoquinolinyl, decahydroisoquinolyl and the like. For the purpose of the present invention, a heterocyclic group of a monocyclic system of 3 to 7 members and containing at least one hetero atom selected from nitrogen, oxygen or sulfur is preferred, and further preferably 4 to 6 and at least 1 The heterocyclic group of the monocyclic ring system selected from hetero atoms of nitrogen or oxygen is more preferably a heterocyclic group of a monocyclic ring system of 4 to 6 members and containing at least 1 to 2 hetero atoms selected from nitrogen or oxygen.

"芳基"或 "芳环"是指具有 6至 18个碳原子的共轭芳香性烃环体系基团，可以为单环、双环、三环或更多环体系。其可经由芳香环上的原子通过单键与分子的其余部分连接。通常，芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基等。就本发明的目的而言，优选具有 6至 10个碳原子的单环或双环体系的芳基或芳环。 "Aryl" or "aryl ring" means a conjugated aromatic hydrocarbon ring system group having 6 to 18 carbon atoms and may be a monocyclic, bicyclic, tricyclic or more ring system. It can be attached to the remainder of the molecule via a single bond via an atom on the aromatic ring. In general, examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthryl and the like. For the purpose of the present invention, an aryl or aromatic ring of a monocyclic or bicyclic system having 6 to 10 carbon atoms is preferred.

"杂芳基"或 "杂芳环"是指由 1至 15个碳原子和 1至 6个选自氮、氧和硫的杂原子共同组成的 5元至 16元共轭芳香性环系基团，可以为单环、双环、三环或更多环体系，其可经由芳香环上的原子通过单键与分子的其余部分连接。通常，杂芳基的实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、三氮唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、苯并三氮唑基、喹啉基、异喹啉基、苯并噻唑基、苯并哒嗪基、喹唑啉基、喹喔啉基等。就本发明的目的而言，优选 6至 10元且至少含有 1个选自氮、氧或硫的杂原子的单环或双环体系的杂芳基或杂芳环，更优选由至少含 1个氮原子的 5至 6元杂芳环与苯环稠合而成的双环体系的杂芳基或杂芳环。 "Heteroaryl" or "heteroaromatic ring" means a 5- to 16-membered conjugated aromatic ring system consisting of 1 to 15 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The group may be a monocyclic, bicyclic, tricyclic or more ring system which may be attached to the remainder of the molecule via a single bond through an atom on the aromatic ring. In general, examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetra Azazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, fluorenyl, isodecyl, oxazolyl, benzimidazolyl, benzotriazolyl, quinolinyl, isoquinoline Benzothiazolyl, benzoxazinyl, quinazolinyl, Quinoxaline and the like. For the purpose of the present invention, a heteroaryl or heteroaryl ring of 6 to 10 members and containing at least one monocyclic or bicyclic ring system selected from nitrogen, oxygen or sulfur, more preferably at least one a heteroaryl or heteroaryl ring of a bicyclic system in which a 5- to 6-membered heteroaryl ring of a nitrogen atom is fused with a benzene ring.

"药学上可接受的酸加成盐 "是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、 2，2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、 4-氨基水杨酸盐、萘二磺酸盐等。 "药学上可接受的碱加成盐 "是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、乙二胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、 2-二甲氨基乙醇、 2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、葡萄糖胺等。这些盐可通过本专业已知的方法制备。 "Pharmaceutically acceptable acid addition salt" means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, besylate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, and the like. "Pharmaceutically acceptable base addition salt" means a salt formed with an inorganic base or an organic base capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins. For example, ammonia, isopropylamine, trimethylamine, diethylamine, ethylenediamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylamino Ethanol, dicyclohexylamine, lysine, arginine, histidine, glucosamine, and the like. These salts can be prepared by methods known in the art.

"溶剂化物"是指本发明的某些化合物分子在结晶过程中，与一个或多个溶剂分子缔合而形成的聚集体。溶剂分子可以为水或其他有机溶剂（如甲醇、乙醇、丙酮等）。 "Solvate" means an aggregate formed by the association of one or more solvent molecules during the crystallization of certain compound molecules of the present invention. The solvent molecule can be water or other organic solvent (such as methanol, ethanol, acetone, etc.).

"前体药物"是指本发明的某些化合物在药学上可接受的代谢前体，其通常不具有活性，但可在体内生理条件下转化成具有生物活性的本发明的母体化合物。通常可改善母体化合物在溶解度、组织相容性或药物代谢动力学等方面的性质。 "Prodrug" means a pharmaceutically acceptable metabolic precursor of certain compounds of the invention which are generally not active but which can be converted to the biologically active parent compound of the invention under physiological conditions in vivo. The properties of the parent compound in terms of solubility, histocompatibility or pharmacokinetics are generally improved.

"立体异构体 "是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明所述的式 I或 II化合物涵盖各种可能的旋光异构体、顺反异构体及其混合物。 "Stereoisomer" means a compound composed of the same atom, bonded by the same bond, but having a different three-dimensional structure. The compounds of formula I or II according to the invention encompass various possible optical isomers, cis and trans isomers and mixtures thereof.

"互变异构体"是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明所述的式 I或 II化合物涵盖各种可能的互变异构体及其混合物。 "Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. The compounds of formula I or II according to the invention encompass various possible tautomers and mixtures thereof.

"多晶型物"是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明所述的式 I或 Π化合物涵盖各种可能的晶型及其混合物。 "Polymorph" refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. The Formula I or hydrazine compounds described herein encompass a wide variety of possible crystalline forms and mixtures thereof.

"代谢产物"是指本发明的某些化合物被机体吸收后，在酶的作用下经过体内的官能团化反应（I 相生物转化反应，包括氧化、还原、水解等）和结合反应（Π相生物转化反应) 等生物转化而产生的化合物。 "metabolite" means that some of the compounds of the present invention are absorbed by the body and pass through the functional groups in the body under the action of the enzyme. A compound produced by biotransformation such as a reaction (I phase biotransformation reaction, including oxidation, reduction, hydrolysis, etc.) and a binding reaction (Π phase biotransformation reaction).

"药物组合物"是指由本发明的化合物与任选的本领域通常接受的用于将生物活性化合物输送至哺乳动物（例如人）的介质所构成的药物制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。其中，"药学上可接受的载体"包括但不限于任何被相关的政府管理部门许可为可供人类或家畜使用的、相对无毒且对人类或家畜不造成不良生理反应的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料 /着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂等。 "Pharmaceutical composition" refers to a pharmaceutical formulation consisting of a compound of the invention and optionally a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human. The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, and to facilitate the absorption of the active ingredient to exert biological activity. Wherein, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier that is relatively non-toxic and which does not cause adverse physiological reactions to humans or livestock, which is approved by the relevant government authorities for use by humans or domestic animals. Excipients, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents Or emulsifier, etc.

具体实式 Specific form

下面结合具体实施例对本发明作进一步阐述，但不限制本发明。 The invention is further illustrated by the following specific examples, without limiting the invention.

下述制备例中， 1H-NMR用 Varian Mercury AMX300型仪测定。 MS用 VG ZAB-HS 或 VG-7070型以及 Esquire 3000 plus-01005测定。 In the following preparation examples, 1H-NMR was measured using a Varian Mercury AMX300 type instrument. MS was measured with VG ZAB-HS or VG-7070 and Esquire 3000 plus-01005.

化合物制备实施例 Compound preparation example

实施例 1 4-异硫氰基 -2-三氟甲基苯甲腈（中间体 2) Example 1 4-Isothiocyanato-2-trifluoromethylbenzonitrile (Intermediate 2)

4-胺基 -2-三氟甲基苄腈（ 10.0 g， 53.8 mmoL)加入到正己烷（22.5 mL)和水（25.0 mL) 中，加料完毕此混合体系中室温下搅拌 8分钟。在冰浴下，将硫光气（4.5 mL, 58.5 mmoL) 滴加到上述混合体系中，加料完毕置于室温搅拌过夜。过滤，固体用正己烷（2x25.0 mL) 洗涤，弃去固体，滤液减压蒸至原体积之五分之一，放置于 4°C冰箱过夜。过滤，固体高真空干燥，得白色固体 11.0 g，产率为 81%。 1H NMR (CDC1₃， 300 MHz) 3 (ppm) 7.84 (d， J=8.4Hz， 1H), 7.59 (d，J=1.8Hz， 1H), 7.49 (dd， J尸 8.4Hz， J₂= 1.8Hz, 1H). 4-Amino-2-trifluoromethylbenzonitrile (10.0 g, 53.8 mmol) was added to n-hexane (22.5 mL) and water (25.0 mL), and the mixture was stirred at room temperature for 8 minutes. Sulfur phosgene (4.5 mL, 58.5 mmoL) was added dropwise to the above mixed system under an ice bath, and the mixture was stirred at room temperature overnight. After filtration, the solid was washed with n-hexane (2×25.0 mL), and the solid was discarded. The filtrate was evaporated under reduced pressure to one-half of the original volume and placed in a refrigerator at 4 ° C overnight. Filtration and drying under high vacuum gave a white solid (11.0 g). 1H NMR (CDC1 ₃ , 300 MHz) 3 (ppm) 7.84 (d, J=8.4Hz, 1H), 7.59 (d, J=1.8Hz, 1H), 7.49 (dd, J 8.4Hz, J ₂ = 1.8 Hz, 1H).

实施例 2 2-甲基 -4-硝基苯甲酸甲酯 Example 2 Methyl 2-methyl-4-nitrobenzoate

CH-,

CH-,

在冰浴下，将 S0C1₂ (4.8 mL, 66.2mmoL) 滴加到无水甲醇（100 mL) 中。后再滴加 2-甲基 -4-硝基苯甲酸（ 10.0 g， 55.2 mmoL) 的无水甲醇（70 mL) 溶液， 1小时滴加完毕。此混合体系置于油浴 70°C反应 7小时， TLC检测反应完全。冷却，减压蒸去溶剂。残留物溶于乙酸乙酯（lOO mL) 中，加入饱和碳酸氢钠（lOO mL), 分液，水相用乙酸乙酯（50 mL) 提取一次。合并有机相，无水硫酸镁干燥，过滤，减压蒸去溶剂，高真空干燥，得白色固体 10.5 g，产率为 98%。1H NMR (CDC1₃， 300 MHz) 3 (ppm) 8.10-8.01 (m， 3H) 3.95 (s, 3H), 2.69 (s, 3H). S0C1 ₂ (4.8 mL, 66.2 mmoL) was added dropwise to dry methanol (100 mL) under ice bath. Then, a solution of 2-methyl-4-nitrobenzoic acid (10.0 g, 55.2 mmoL) in anhydrous methanol (70 mL) was added dropwise, and the mixture was added dropwise over 1 hour. Complete. The mixed system was placed in an oil bath at 70 ° C for 7 hours, and the reaction was completed by TLC. After cooling, the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (EtOAc) (EtOAc)EtOAc. The organic layer was combined, dried over anhydrous magnesium sulfate, filtered, evaporated 1H NMR (CDC1 ₃ , 300 MHz) 3 (ppm) 8.10-8.01 (m, 3H) 3.95 (s, 3H), 2.69 (s, 3H).

实施例 3 2- (溴甲基) -4-硝基苯甲酸甲酯 Example 3 Methyl 2-(bromomethyl)-4-nitrobenzoate

CH

CH

将 2-甲基 -4-硝基苯甲酸甲酯（200 mg， 1.0 mmoL) ，过氧化苯甲酰（48.5 mg， 0.2 mmoL), N-溴代丁二酰亚胺（213 mg， 1.2 mmoL) 加入到 CCI4 ( 15 mL) 中，于 Ar气保护下，加热回流反应 7小时，冷却，依次用饱和碳酸氢钠（3x20 mL)、饱和食盐水（20 mL) 洗涤，减压蒸去溶剂，残留物用快速柱层析分离，洗脱剂为 PE:EA=20: 1，得白色固体 124 mg，产率为 44% 1H NMR (CDC1₃, 300 MHz) δ (ppm) 8.34-8.01 (m, 3H), 4.97 (s, 2H), 4.00 (s， 3H). Methyl 2-methyl-4-nitrobenzoate (200 mg, 1.0 mmoL), benzoyl peroxide (48.5 mg, 0.2 mmoL), N-bromosuccinimide (213 mg, 1.2 mmoL) After adding to CCI4 (15 mL), the mixture was heated under reflux for 7 hours under argon atmosphere, cooled, washed successively with saturated sodium bicarbonate (3×20 mL), brine (20 mL), and evaporated. The residue was purified by flash column chromatography, eluent PE: EA = 20: 1, to give a white solid 124 mg, yield _{44% 1H NMR (CDC1 3,} 300 MHz) δ (ppm) 8.34-8.01 (m , 3H), 4.97 (s, 2H), 4.00 (s, 3H).

实施例 4 5-硝基 -1-异二氢吲哚酮 Example 4 5-Nitro-1-isoindanone

将 2- (溴甲基) -4-硝基苯甲酸甲酯（250 mg， 0.92 mmoL)加入到氨（NH₃ ) 的饱和甲醇溶液（5 mL) 中，于室温下搅拌 2小时， TLC检测反应完全。减压蒸去溶剂，残留物加入到乙酸乙酯（7 mL) 中，超声 3分钟，置于 -20°C冰箱 3 分钟，出现大量固体，过滤，高真空干燥，得淡黄色固体 150 mg，产率为 92%。 1H NMR (CDC1₃， 300 MHz) δ (ppm) 9.01 (s， 1H)， 8.47 (d，J=0.9Hz， 1H), 8.30 (dd， =8.1Hz， J₂ =0.9Hz， 1H), 7.89 (d, J=8.1, 1H). 2- (bromomethyl) -4-nitrobenzoate (250 mg, 0.92 mmoL) was added to the ammonia (NH ₃₎ a saturated methanol solution (5 mL) and stirred for 2 hours at room temperature, TLC detection The reaction is complete. The solvent was evaporated under reduced pressure. EtOAc was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The yield was 92%. 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 9.01 (s, 1H), 8.47 (d, J = 0.9 Hz, 1H), 8.30 (dd, = 8.1 Hz, J ₂ = 0.9 Hz, 1H), 7.89 (d, J=8.1, 1H).

实施例 5 5-氨基 -1-异二氢吲哚酮（ a) Example 5 5-Amino-1-isoindanone (a)

将 5-硝基 -1-异吲哚酮（100 mg， 0.56 mmoL) ，还原铁粉（314 mg， 5.6 mmoL) 加入到乙醇 (2.0 mL) 和浓盐酸（0.5 mL) 中，加热回流 2小时， TLC检测反应完全。冷却，用氨（NH₃) 的饱和甲醇溶液中和酸，硅藻土过滤，甲醇洗涤，减压蒸去溶剂，得白色固体 70.0 mg，产率为 84 %。 1H NMR (CD₃OD， 300 MHz) δ (ppm) 7.48-7.46 (d, J=6.6Hz, 1H), 6.73-6.71 (m， 2H), 4.30 (s， 2H). Add 5-nitro-1-isoindolone (100 mg, 0.56 mmoL), reduced iron powder (314 mg, 5.6 mmoL) The mixture was heated to reflux for 2 hours in ethanol (2.0 mL) and concentrated hydrochloric acid (0.5 mL). Cooling, methanol saturated with ammonia (NH ₃₎ and the acid, filtered through Celite, washed with methanol, the solvent was evaporated under reduced pressure to give a white solid 70.0 mg, 84% yield. 1H NMR (CD ₃ OD, 300 MHz) δ (ppm) 7.48-7.46 (d, J = 6.6 Hz, 1H), 6.73-6.71 (m, 2H), 4.30 (s, 2H).

实施例 6 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a) Example 6 2-Methyl-2-(1-oxoisoindoline-5-ylamino)propanenitrile (Intermediate 9a)

将 5-氨基 -1-异二氢吲哚酮 (中间体 8a，2.1 g， 14.2 mmoL) ，丙酮 ( 3.5 mL, 47.6 mmoL) 和*** （2.1 g, 46.8 mmoL) 加入到 90%的醋酸（45 mL) 中。加料完毕，室温搅拌 48 小时。向反应液中加入水（50mL)和乙酸乙酯（lOO mL), 分液，有机相依次用水（3x50 mL)、饱和碳酸氢钠（50 mL)、水（50 mL)洗，无水硫酸镁干燥，过滤，减压蒸去溶剂，残留物用快速柱层析分离，洗脱剂为 PE:EA=1 : 1，得白色固体 2.7 g，产率为 88%。1H NMR (CDC1₃, 300 MHz) δ (ppm) 8.10 (s, 1H), 7.48-7.44 (d, J=8.4Hz， 1H), 6.92-6.89 (m, 2H), 6.68 (s， 1H), 4.28 (s, 1H)， 1.68 (s, 6H).

Add 5-amino-1-isoindolinone (Intermediate 8a, 2.1 g, 14.2 mmoL), acetone (3.5 mL, 47.6 mmoL) and sodium cyanide (2.1 g, 46.8 mmoL) to 90% acetic acid (45 mL). After the addition was completed, stir at room temperature for 48 hours. Water (50 mL) and ethyl acetate (100 mL) were added to the mixture, and the organic layer was washed with water (3×50 mL), saturated sodium hydrogen carbonate (50 mL), water (50 mL) The mixture was dried, filtered, and evaporated, evaporated]]]]]]]]] 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.10 (s, 1H), 7.48-7.44 (d, J=8.4Hz, 1H), 6.92-6.89 (m, 2H), 6.68 (s, 1H), 4.28 (s, 1H), 1.68 (s, 6H).

实施例 7 4-[4，4-二甲基 -5-氧代 -3-(l-氧代异二氢吲哚 -5-基) -2-硫代咪唑烷 -1-基] -2- (三氟甲基）苯甲腈（化合物 1 ) Example 7 4-[4,4-Dimethyl-5-oxo-3-(l-oxoisoindoline-5-yl)-2-thioimidazolidine-1-yl]-2 - (trifluoromethyl)benzonitrile (Compound 1)

将 4-异硫氰基 -2-三氟甲基苯甲腈（中间体 9a， 209 mg， 0.92 mmoL) ， 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（ 100 mg， 0.46 mmoL) 加入到无水 DMF ( 5.0 mL) 中，微波 50°C反应 6小时， TLC检测反应完全。加入到 2N HC1 (4.0 mL) 和甲醇（4.0 mL) 中，加热回流 1小时。冷却，减压蒸去溶剂。残留物加入到乙酸乙酯中，用饱和碳酸氢钠将 pH值调至中性，分液。有机相减压蒸去溶剂，残留物用快速柱层析分离，洗脱剂为二氯甲烷：丙酮 =20: 1，得白色固体 55 mg，产率为 30%。 1H NMR {OMDO-d6, 300 MHz) δ (ppm) 8.05 (t， 1H), 8.01-7.97 (m， 2H), 7.86-7.84 (m， 1H), 7.44-7.42 (m， 1H), 6.45 (s， 1H), 4.56 (s， 2H), 1.63 (s, 6H).

4-Isothiocyanato-2-trifluoromethylbenzonitrile (Intermediate 9a, 209 mg, 0.92 mmoL), 2-methyl-2-(1-oxoisoindoline-5-yl) Acrylonitrile (100 mg, 0.46 mmoL) was added to anhydrous DMF (5.0 mL) and reacted in a microwave at 50 ° C for 6 hours. The reaction was complete by TLC. It was added to 2N HCl (4.0 mL) and methanol (4.0 mL) and heated to reflux for 1 hour. After cooling, the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate, and the pH was adjusted to neutral with saturated sodium hydrogen carbonate. The organic phase was evaporated under reduced pressure. the residue was purified mjjjjjjj 1H NMR {OMDO-d6, 300 MHz) δ (ppm) 8.05 (t, 1H), 8.01-7.97 (m, 2H), 7.86-7.84 (m, 1H), 7.44-7.42 (m, 1H), 6.45 ( s, 1H), 4.56 (s, 2H), 1.63 (s, 6H).

实施例 8 2-溴 -6-氟 -3-硝基苯甲酸（中间体 4b)

在冰浴下将发烟硝酸（ 1.0 mL, 11.4 mmoL)滴加到 2-溴 -6-氟苯甲酸（2.5 g, 11.4 mmoL) 和浓硫酸（7.5 mL) 的混合溶液中。滴加完毕后，此体系置于室温搅拌 2小时。倾倒入冰水（40.0 mL)中，出现大量固体，过滤，固体用水洗，高真空干燥，得白色固体 2.5 g，产率为 83%。直接用于下步反应。 Example 8 2-Bromo-6-fluoro-3-nitrobenzoic acid (Intermediate 4b)

Fuming nitric acid (1.0 mL, 11.4 mmoL) was added dropwise to a mixed solution of 2-bromo-6-fluorobenzoic acid (2.5 g, 11.4 mmoL) and concentrated sulfuric acid (7.5 mL) under ice bath. After the dropwise addition was completed, the system was stirred at room temperature for 2 hours. Pour into ice water (40.0 mL), a large amount of solid appeared, filtered, solid washed with water, and dried under high vacuum to give a white solid 2.5 g, yield 83%. Used directly in the next step of the reaction.

实施例 9 2-溴 -6-氟 -3-硝基苯甲酸甲酯（中间体 5b) Example 9 Methyl 2-bromo-6-fluoro-3-nitrobenzoate (intermediate 5b)

将 2-溴 -6-氟 -3-硝基苯甲酸（中间体 4b，2.5 g，9.5 mmoL) 加入到二氯亚砜 ( l l .O mL) 中，加热回流 1小时。减压蒸去可挥发物质，残留物加入到无水甲醇（30mL) 中，加热回流 1小时。减压蒸去溶剂，高真空干燥，得白色固体 2.5 g，产率为 96%。直接用于下步反应。

2-Bromo-6-fluoro-3-nitrobenzoic acid (Intermediate 4b, 2.5 g, 9.5 mmoL) was added to dichloromethane (ll.OmL) and heated to reflux for 1 hour. The volatile material was evaporated under reduced pressure. The solvent was evaporated under reduced pressure and dried under high vacuum to afford white crystals (yel. Used directly in the next step of the reaction.

实施例 10 2-溴 -6-氟 -3-胺基苯甲酸甲酯（中间体 6b) Example 10 Methyl 2-bromo-6-fluoro-3-aminobenzoate (Intermediate 6b)

将 2-溴 -6-氟 -3-硝基苯甲酸甲酯（中间体 5b， 2.5 g， 9.0 mmoL) , 还原铁粉（1.0 g， 17.8 mmoL) 加入到冰醋酸（13.0 mL) 中，加热回流 2小时， TLC检测反应完成。硅藻土过滤，乙酸乙酯洗涤，减压蒸去溶剂。残留物加入到乙酸乙酯 GO mL)和水（10 mL) 中，分液，减压蒸去溶剂，残留物用快速柱层析分离，洗脱剂为石油醚 /乙酸乙酯 =10/1，得无色液体 1.7 g，产率为 70% 1H NMR (ΌΜΌΟ-ά6, 300 MHz) δ (ppm) 8.05 (t， 1H)， 7.05 (t， 1H), 6.92-6.90 (m， 1H), 5.44 (s， 2H), 3.86. (s， 3H).

Methyl 2-bromo-6-fluoro-3-nitrobenzoate (intermediate 5b, 2.5 g, 9.0 mmoL), reduced iron powder (1.0 g, 17.8 mmoL) was added to glacial acetic acid (13.0 mL), heated After refluxing for 2 hours, the reaction was completed by TLC. The mixture was filtered over Celite, and ethyl acetate was evaporated. The residue was taken up in ethyl acetate (EtOAc) (EtOAc) (EtOAc) , 1.7 g of colorless liquid, yield 70% 1H NMR (ΌΜΌΟ-ά6, 300 MHz) δ (ppm) 8.05 (t, 1H), 7.05 (t, 1H), 6.92-6.90 (m, 1H), 5.44 (s, 2H), 3.86. (s, 3H).

实施例 11 3-胺 -2-腈基 -6-氟苯甲酸甲酯（中间体 7b) Example 11 Methyl 3-amine-2-carbonitrile-6-fluorobenzoate (Intermediate 7b)

将 2-溴 -6-氟 -3-胺基苯甲酸甲酯（中间体 6b， 1.7 g， 6.9 mmoL), 腈化亚铜（6.5 g， 73.1 mmoL) 加入到无水 DMF (50 mL) 中，于油浴 160°C反应 15分钟， TLC检测反应完成。冷却，硅藻土过滤，乙酸乙酯洗涤，减压蒸去溶剂。残留物加入到乙酸乙酯中，用水洗涤。减压蒸去溶剂，残留物快速柱层析分离，洗脱剂为石油醚 /乙酸乙酯 =3/1，得白色固体 530 mg，产率为 40%。1H NMR (CDC1₃， 300 MHz) δ (ppm) 7.16(t, 1H)， 6.90-6.85(dd, J; =9.0Hz, J₂ =3.9Hz, 1H)， 4.53(br, 2H), 3.99(s, 3H).

Methyl 2-bromo-6-fluoro-3-aminobenzoate (intermediate 6b, 1.7 g, 6.9 mmoL), cuprous nitrile (6.5 g, 73.1 mmoL) in anhydrous DMF (50 mL) The reaction was carried out in an oil bath at 160 ° C for 15 minutes, and the reaction was completed by TLC. The mixture was cooled, filtered over Celite, ethyl acetate. The residue was taken up in ethyl acetate and washed with water. The solvent was evaporated under reduced pressure, and the residue was evaporated, mjjjjjjj 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 7.16(t, 1H), 6.90-6.85 (dd, J; = 9.0 Hz, J ₂ = 3.9 Hz, 1H), 4.53 (br, 2H), 3.99 ( s, 3H).

实施例 12 4-胺基 -7-氟异二氢吲 -1-酮（中间体 8b) Example 12 4-Amino-7-fluoroisoindoline-1-one (Intermediate 8b)

将 3-胺 -2-腈基 -6-氟苯甲酸甲酯（中间体 7b， 275 mg， 1.4 mmoL) 和雷尼镍 (30 mg) 加入到甲醇（19 mL)和水（6 mL)的混合溶液中，于 50°C， 3公斤压力加压氢化 7小时，硅藻土过滤，减压蒸去溶剂，高真空干燥，得白色固体 210 mg, 产率为 89%。直接用于下步反应。 1H NMR (丙酮 -ί¾， 300 MHz) δ (ppm) 7.45(br, 1H)， 6.92-6.82(m, 2H), 4.78(br, 2H), 4.29(s, 2H). MS (ESI): m/z =189.0 (M+Na)+. Add methyl 3-amine-2-carbonitrile-6-fluorobenzoate (intermediate 7b, 275 mg, 1.4 mmoL) and Raney nickel (30 mg) to methanol (19 mL) and water (6 mL) The mixed solution was subjected to hydrogenation under reduced pressure of 3 kg at 5 ° C for 7 hours, filtered through Celite, and evaporated to dryness vacuo. Used directly in the next step. 1H NMR (acetone-ί3⁄4, 300 MHz) δ (ppm) 7.45 (br, 1H), 6.92-6.82 (m, 2H), 4.78 (br, 2H), 4.29 (s, 2H). MS (ESI): m /z =189.0 (M+Na)+.

实施例 13 2-(7-氟 -1-氧代异二氢吲哚 -4-基胺基 )-2-甲基丙腈（中间体 9b) Example 13 2-(7-Fluoro-1-oxoisoindoline-4-ylamino)-2-methylpropanenitrile (Intermediate 9b)

除了用中间体 8b代替中间体 8a之外，中间体 9b 的制备同中间体 9a，白色固体，产率为 51%。！H NMR (丙酮 -ί¾， 300 MHz) δ (ppm) 7.55 (br， 1H), 7.29 (dd， J; =6.6Hz， J₂=2.7Hz, 1H)， 7.13 (t， 1H), 5.03 (s， 1H), 4.37 (s， 2H), 1.78 (s， 6H).

Intermediate 9b was prepared as the intermediate 9a as a white solid, yield 51%, except that Intermediate 8b was used instead of Intermediate 8a. ! H NMR (acetone-ί3⁄4, 300 MHz) δ (ppm) 7.55 (br, 1H), 7.29 (dd, J; =6.6Hz, J ₂ =2.7Hz, 1H), 7.13 (t, 1H), 5.03 (s , 1H), 4.37 (s, 2H), 1.78 (s, 6H).

实施例 14 4-[3-(7-氟 -1-氧代异二氢吲哚 -4-基) -4，4-二甲基 -5-氧代 -2-硫代咪唑烷 -1- 基] -2- (三氟甲基）苯甲腈（化 2) Example 14 4-[3-(7-Fluoro-1-oxoisoindoline-4-yl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1- Benzyl-2-(trifluoromethyl)benzonitrile (Chemical 2)

除了用中间体 9b代替中间体 9a之外，化合物 2的制备同化合物 1，白色固体，产率为 35 NMR (CDCI3, 300 MHz) δ (ppm) 7.98(dd, J; =19.2Hz, J₂=2.4Hz， 1H)， 7.84 (dd， J; =8.4Hz， J₂=2.1Hz, 1H)， 7.46 (dd， =8.7Hz， J₂=3.9Hz, 1H)， 7.31 (t， 1H)， 7.10 (s， 1H)， 4.50 (q， 2H), 1.75 (s, 3H), 1.53 (s, 3H). Preparation of Compound 2 is the same as Compound 1, White solid, Yield, except Intermediate 9b is used instead of Intermediate 9a 35 NMR (CDCI3, 300 MHz) δ (ppm) 7.98 (dd, J; = 19.2 Hz, J ₂ = 2.4 Hz, 1H), 7.84 (dd, J; = 8.4 Hz, J ₂ = 2.1 Hz, 1H) , 7.46 (dd, =8.7Hz, J ₂ =3.9Hz, 1H), 7.31 (t, 1H), 7.10 (s, 1H), 4.50 (q, 2H), 1.75 (s, 3H), 1.53 (s, 3H).

实施例 15 2-溴 -3-氟 -6-硝基苯甲酸（中间体 4c) 和 2-溴 -3-氟 -5-硝基苯甲酸（中间体 Example 15 2-Bromo-3-fluoro-6-nitrobenzoic acid (intermediate 4c) and 2-bromo-3-fluoro-5-nitrobenzoic acid (intermediate)

4e) 4e)

4e 在冰浴下，将发烟硝酸（2 mL, 22.83 mmoL)滴加到 2-溴 -3-氟-苯甲酸（5 g， 22.8 mmoL) 和浓硫酸（15 mL) 的混合溶液中。滴加完毕后，置于室温搅拌 2小时。倾倒至冰水中，出现大量固体，过滤，固体用水洗涤，高真空干燥，白色固体 5.3 g，为中间体 4c和 4e 的混合物（4c/4e = 2/l )，产率为 88%。该混合物的大部分直接用于下一步反应，少量经柱层析分离，鉴定如下： 4e In a ice bath, fuming nitric acid (2 mL, 22.83 mmoL) was added dropwise to a mixed solution of 2-bromo-3-fluoro-benzoic acid (5 g, 22.8 mmoL) and concentrated sulfuric acid (15 mL). After the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours. Pour into ice water, a large amount of solid appeared, filtered, solid washed with water, dried under high vacuum, 5.3 g of white solid, a mixture of intermediates 4c and 4e (4c/4e = 2/l), yield 88%. Most of the mixture was directly used in the next reaction, and a small amount was separated by column chromatography and identified as follows:

中间体 4c, 1H NMR (CDCI3, 300 MHz) δ (ppm) 8.26 (dd， =6.9， J₂=3.3 Hz, 1 H)， 7.48 (dd， J; =6.9Hz， J₂=5.7Hz, 1 H)。 Intermediate 4c, 1H NMR (CDCI3, 300 MHz) δ (ppm) 8.26 (dd, = 6.9, J ₂ = 3.3 Hz, 1 H), 7.48 (dd, J; = 6.9 Hz, J ₂ = 5.7 Hz, 1 H).

中间体 4e， 1H NMR (CD3OD, 400 MHz) δ (ppm) 8.39 (dd， J! =1.8Hz, J₂=1.2Hz, 1 H)， 8.18 (dd, J;=6.0Hz, J₂=1.8Hz, 1 H). Intermediate 4e, 1H NMR (CD3OD, 400 MHz) δ (ppm) 8.39 (dd, J! = 1.8 Hz, J ₂ = 1.2 Hz, 1 H), 8.18 (dd, J; = 6.0 Hz, J ₂ = 1.8 Hz, 1 H).

实施例 16 2-溴 -3-氟 -6-硝基苯甲酸甲酯（中间体 5c) 和 2-溴 -3-氟 -5-硝基苯甲酸甲酯 (中间体 5e)。 Example 16 Methyl 2-bromo-3-fluoro-6-nitrobenzoate (intermediate 5c) and methyl 2-bromo-3-fluoro-5-nitrobenzoate (intermediate 5e).

5e 除了用中间体 4c和中间体 4e混合物代替中间体 4b之外，中间体 5c和中间体 5e混合物的制备同中间体 5b，得红棕色目标产物，产率为 100%，直接用于下一步。 5e In addition to the intermediate 4b and the intermediate 4e mixture being used in place of the intermediate 4b, the intermediate 5c and the intermediate 5e are prepared in the same manner as the intermediate 5b to give the reddish brown desired product in 100% yield. .

实施例 17 6-氨基 -2-溴 -3-氟苯甲酸甲酯（中间体 6c) 和 5-胺基 2-溴 -3-氟苯甲酸甲酯 (中间体 6e)

Example 17 Methyl 6-amino-2-bromo-3-fluorobenzoate (Intermediate 6c) and methyl 5-amino-2-bromo-3-fluorobenzoate (Intermediate 6e)

6e 除了用中间体 5c和中间体 5e混合物代替中间体 5b之外，中间体 6c和中间体 6e混合物的制备同中间体 6b。产物经柱层析分离，得中间体 6c和中间体 6e纯品。 6e The intermediate 6c and intermediate 6e mixtures were prepared in the same manner as the intermediate 6b except that the intermediate 5c and the intermediate 5e mixture were used in place of the intermediate 5b. The product was separated by column chromatography to give Intermediate 6c and Intermediate 6e.

中间体 6c，白色固体，产率为 53%。TLC: Rf= 0.66 (展开剂：石油醚 /乙酸乙酯 = 6 ： D o 1H NMR (CDC1₃， 300 MHz) δ (ppm) 6.99 (dd， J! =9.0 Hz, J₂=7.8 Hz, 1 H)， 6.60 (dd， J! =9.0 Hz, J₂=4.2 Hz, 1 H)， 4.58(br, 2H), 3.94(s, 3H). Intermediate 6c, white solid, yield 53%. TLC: Rf = 0.66 (developing solvent: petroleum ether / ethyl acetate = 6 : D o 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 6.99 (dd, J! = 9.0 Hz, J ₂ = 7.8 Hz, 1 H), 6.60 (dd, J! = 9.0 Hz, J ₂ = 4.2 Hz, 1 H), 4.58 (br, 2H), 3.94 (s, 3H).

中间体 6e，白色固体，产率为 27%。 TLC: Rf = 0.33 (展开剂：石油醚 /乙酸乙酯 = 6 ： D o 1H NMR (CDC1₃, 300 MHz) δ (ppm) 6.88 (dd, J; =2.7 Hz, J₂=1.2 Hz, 1 H), 6.56 (dd, J; =9.9 Hz, J₂=2.7 Hz, 1 H)， 3.97 (s， 5H). Intermediate 6e, white solid, yield 27%. TLC: Rf = 0.33 (developing solvent: petroleum ether / ethyl acetate = 6 : D o 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 6.88 (dd, J; =2.7 Hz, J ₂ = 1.2 Hz, 1 H), 6.56 (dd, J; = 9.9 Hz, J ₂ = 2.7 Hz, 1 H), 3.97 (s, 5H).

实施例 18 6-氨基 -2-腈基 -3-氟（中间体 7c) Example 18 6-Amino-2-cyano-3-fluoro (Intermediate 7c)

除了用中间体 6c代替中间体 6b之外，中间体 7c的制备同中间体 7b，白色固体，产率为 30%。直接用于下步反应。 The intermediate 7c was prepared in the same manner as the intermediate 7b as a white solid, yield 30%, except that the intermediate 6b was used instead of the intermediate 6b. Used directly in the next step of the reaction.

实施例 19 7-胺基 -4-氟异二氢吲 -1-酮（中间体 8c) Example 19 7-Amino-4-fluoroisoindoline-1-one (Intermediate 8c)

除了用中间体 7c代替中间体 7b之外，中间体 8c的制备同中间体 8b，白色固体，产率为 58%。 1H NMR (丙酮 - ， 300 MHz) δ (ppm) 7.41 (br, 1H)， 7.00 (t， 3H), 6.30 (dd, J! =9.0 Hz, J₂=3.6 Hz, 1 H)， 5.72 (br, 2H), 4.39 (s， 3H). Intermediate 8c was prepared as the intermediate 8b as a white solid with a yield of 58%, except for the intermediate 7b. 1H NMR (Acetone-, 300 MHz) δ (ppm) 7.41 (br, 1H), 7.00 (t, 3H), 6.30 (dd, J! = 9.0 Hz, J ₂ = 3.6 Hz, 1 H), 5.72 (br , 2H), 4.39 (s, 3H).

实施例 20 2-(7-氟 -3-氧代异二氢吲哚 -4-基胺基 )-2-甲基丙腈（中间体 9c) H

除了用中间体 8c代替中间体 8a之外，中间体 9c的制备同中间体 9a，白色固体，产率为 62% 1H NMR (丙酮 - ， 300 MHz) δ (ppm) 7.66 (br, 1H), 7.23 (dd， J! =17.7 Hz, J₂=8.7 Hz, 1 H)， 7.02 (br, 1H), 6.98(dd， J! =8.4 Hz, J₂=5.7 Hz, 1 H)， 4.46(s， 2H), 1.78(s, 6H). Example 20 2-(7-Fluoro-3-oxoisoindoline-4-ylamino)-2-methylpropanenitrile (Intermediate 9c) H

The intermediate 9c was prepared as the intermediate 9a as a white solid, yield 62% 1H NMR (acetone-, 300 MHz) δ (ppm) 7.66 (br, 1H), except for the intermediate 8c. 7.23 (dd, J! =17.7 Hz, J ₂ =8.7 Hz, 1 H), 7.02 (br, 1H), 6.98 (dd, J! =8.4 Hz, J ₂ =5.7 Hz, 1 H), 4.46(s , 2H), 1.78(s, 6H).

实施例 21 4-[3-(7-氟 -3-氧代异二氢吲哚 -4-基) -4，4-二甲基 -5-氧代 -2-硫代咪唑烷 -1- 基] -2- (三氟甲基）苯甲腈（化 Example 21 4-[3-(7-Fluoro-3-oxoisoindoline-4-yl)-4,4-dimethyl-5-oxo-2-thioimidazol-1- Benzyl-2-(trifluoromethyl)benzonitrile

除了用中间体 9c代替中间体 9a之外，化合物 3的制备同化合物 1，白色固体，产率为 36% 1H NMR (CDC1₃， 300 MHz) δ (ppm) 7.98-7.95 ( m， 1H), 7.90-7.87(m, 1H)， 7.45-7.36(m, 1H)， 7.35-7.26(m, 1H)， 6.42(br, 1H)， 4.52(s, 2H), 1.73(s, 3H), 1.51(s， 3H). The compound 3 was prepared in the same manner as the compound 1 as a white solid, yield 36% 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 7.98-7.95 (m, 1H), except for the intermediate 9c. 7.90-7.87(m, 1H), 7.45-7.36(m, 1H), 7.35-7.26(m, 1H), 6.42(br, 1H), 4.52(s, 2H), 1.73(s, 3H), 1.51( s, 3H).

实施例 22 2-溴 -4-氟 -5-苯甲酸（中间体 4d Example 22 2-Bromo-4-fluoro-5-benzoic acid (intermediate 4d)

除了用 2-溴 -4-氟苯甲酸代替 2-溴 -6-氟苯甲酸之外，中间体 4d的合成同中间体 4b，白色固体，产率为 91%。 1H NMR (CDC1₃, 300 MHz) δ (ppm) 8.59 (d, J=7.8 Hz, 1 H), 7.88 (d, J=5.7 Hz, 1 H). The intermediate 4d was synthesized in the same manner as the intermediate 4b as a white solid in a yield of 91%, except that 2-bromo-4-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid. 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.59 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 5.7 Hz, 1 H).

实施例 23 2-溴 -4-氟 -5-苯甲酸甲酯中间体 5d) Example 23 2-Bromo-4-fluoro-5-benzoic acid methyl ester Intermediate 5d)

在冰浴下，将氯化亚砜（4.1 mL， 56.0 mmoL) 滴加到无水甲醇（244mL) 中，滴加完毕后，在此条件下继续搅拌 30分钟。加入 2-溴 -4-氟 -5-苯甲酸（ 13.4 g， 50.8 mmoL) ，于 60°C加热反应 18小时。减压蒸去溶剂，加入乙酸乙酯，用饱和碳酸钠洗涤，减压蒸去溶剂，高真空干燥，得淡黄色固体 14 g，产率为 99%。直接用于下步反应。 1H NMR (CDC1₃， 300 MHz) δ (ppm) 8.62 (d， J=7.8 Hz, 1 H)， 7.69 (d， J=9.3 Hz, 1 H)， 3.99 (s， 3H). Thionyl chloride (4.1 mL, 56.0 mmoL) was added dropwise to anhydrous methanol (244 mL) under ice-cooling, and after the addition was completed, stirring was continued for 30 minutes under the conditions. Add 2-bromo-4-fluoro-5-benzoic acid ( 13.4 g, 50.8 mmoL) to The reaction was heated at 60 ° C for 18 hours. The solvent was evaporated under reduced pressure. EtOAc was evaporated, evaporated, evaporated. Used directly in the next step of the reaction. 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.62 (d, J = 7.8 Hz, 1 H), 7.69 (d, J = 9.3 Hz, 1 H), 3.99 (s, 3H).

实施例 24 5-氨基 -2-溴 -4-氟苯甲酸甲酯中间体 6d) Example 24 5-Amino-2-bromo-4-fluorobenzoic acid methyl ester Intermediate 6d)

将 2-溴 -4-氟 -5-苯甲酸甲酯 ( 14.0 g, 50.3 mmoL)和还原铁粉 ( 14.1 g, 252.0 mmoL)加入到乙醇（396.0 mL)，水（96.0 mL)和冰醋酸（19.3 mL) 的混合溶液中，于 110°C加热反应 1 小时， TLC检测反应完全。冷却，减压蒸去溶剂，残留物中加乙酸乙酯和饱和碳酸氢钠。分液，有机相用无水硫酸镁干燥，过滤，减压蒸去溶剂，高真空干燥，得黄色固体 10.0 g，产率为 80% 1H NMR (CDC1₃， 300 MHz) δ (ppm) 7.30-7.18 (m， 2H), 3.92 (s, 3H). 实施例 25 5-氨基 -2-腈基 -4-氟苯甲酸甲酯中间体 7d)

Methyl 2-bromo-4-fluoro-5-benzoate (14.0 g, 50.3 mmoL) and reduced iron powder (1.l g, 252.0 mmoL) were added to ethanol (396.0 mL), water (96.0 mL) and glacial acetic acid ( In a mixed solution of 19.3 mL), the reaction was heated at 110 ° C for 1 hour, and the reaction was completed by TLC. After cooling, the solvent was evaporated under reduced pressure and ethyl acetate and saturated sodium hydrogen sulfate were evaporated. Liquid separation, the organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, dried under high vacuum to give a yellow solid 10.0 g, yield _{80% 1H NMR (CDC1 3,} 300 MHz) δ (ppm) 7.30- 7.18 (m, 2H), 3.92 (s, 3H). Example 25 5-amino-2-carbonitrile-4-fluorobenzoic acid methyl ester intermediate 7d)

除了用中间体 6d代替中间体 6b之外，中间体 7d的制备同中间体 7b，白色固体，产率为 18%。 1H NMR (CDC1₃， 300 MHz) δ (ppm) 8.62 (d， J=8.7 Hz, 1 H)， 7.69 (d， J=10.5 Hz, 1 H)， 3.95 (s, 3H).

Intermediate 7d was prepared as the intermediate 7b as a white solid, yield 18%, except for the intermediate 6d. 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.62 (d, J = 8.7 Hz, 1 H), 7.69 (d, J = 10.5 Hz, 1 H), 3.95 (s, 3H).

实施例 26 6-胺基 -5-氟异二氢吲 -1-酮（中间体 8d) Example 26 6-Amino-5-fluoroisoindoline-1-one (Intermediate 8d)

除了用中间体 7d代替中间体 7b之外，中间体 8d的制备同中间体 8b，白色固体，产率为 85% 1H NMR (DMSO- ， 300 MHz) δ (ppm) 8.34 (s， 1H)， 7.19(d, J=10.8 Hz, 1 H)， 7.01 (d， J=8.1 Hz, 1 H)， 5.32 (s， 2H), 4.17 (s， 2H). The intermediate 8d was prepared as the intermediate 8b as a white solid, yield 85% 1H NMR (DMSO-, 300 MHz) δ (ppm) 8.34 (s, 1H), except for the intermediate 7b. 7.19 (d, J = 10.8 Hz, 1 H), 7.01 (d, J = 8.1 Hz, 1 H), 5.32 (s, 2H), 4.17 (s, 2H).

实施例 27 2-(6-氟 -3-氧代异二氢吲哚 -5-基胺基 )-2-甲基丙腈 (中间体 9d)

除了用中间体 8d代替中间体 8a之外，中间体 9d的制备同中间体 9a，白色固体，产率为 73% 1H NMR (OMSO-d6, 300 MHz) δ (ppm) 8.51(s， 1H), 7.39(d, J=l l . l Hz, 1 H)， 7.26 (d， J=7.8 Hz, 1 H)， 5.92 (s， 1H), 4.25 (s， 2H), 1.67(s, 6H). Example 27 2-(6-Fluoro-3-oxoisoindoline-5-ylamino)-2-methylpropanenitrile (Intermediate 9d)

Intermediate 9d was prepared as the intermediate 9a as a white solid, yield 73% 1H NMR (OMSO-d6, 300 MHz) δ (ppm) 8.51 (s, 1H). , 7.39(d, J=ll . l Hz, 1 H), 7.26 (d, J=7.8 Hz, 1 H), 5.92 (s, 1H), 4.25 (s, 2H), 1.67(s, 6H).

实施例 28 4-[3-(6-氟 -3-氧代异二氢吲哚 -5-基) -4，4-二甲基 -5-氧代 -2-硫代咪唑烷 -1- 基] -2- (三氟甲基）苯甲腈（化 Example 28 4-[3-(6-Fluoro-3-oxoisoindoline-5-yl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1- Benzyl-2-(trifluoromethyl)benzonitrile

除了用中间体 9d代替中间体 9a之外，化合物 4的制备同化合物 1，白色固体，产率为 18%。1H NMR (CDC1₃， 300 MHz) δ (ppm) 8.00-7.98(m, 2H), 7.89-7.82(m, 2H), 7.46-7.43(d, J =9.0 Hz, 1H)， 6.78(s, 1H)， 4.55(s， 2H), 1.70(s, 3H), 1.54(s， 3H). MS (ESI): m/z =461.0 (M-H)— . The compound 4 was prepared in the same manner as the compound 1 as a white solid in a yield of 18%, except that the intermediate 9d was used instead of the intermediate 9a. 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.00-7.98 (m, 2H), 7.89-7.82 (m, 2H), 7.46-7.43 (d, J = 9.0 Hz, 1H), 6.78 (s, 1H) ), 4.55(s, 2H), 1.70(s, 3H), 1.54(s, 3H). MS (ESI): m/z =461.0 (MH) - .

实施例 29 5-胺基 -2-腈基 -3-氟甲酸甲酯（中间体 7e) Example 29 5-Amino-2-cyano-3-fluorocarboxylic acid methyl ester (Intermediate 7e)

除了用中间体 6e代替中间体 6b之外，中间体 7e的制备同中间体 7b，白色固体，产率为 38 NMR (DMSO- ^, 300 MHz) δ (ppm) 7.09(d, J=2.4 Hz, 1H), 6.81 (s， 2H), 6.63 (dd， J; =12.6 Hz, J₂ =2.4 Hz, 1 H)， 3.84 (s,3H). Intermediate 7e was prepared as the intermediate 7b as a white solid, yield 38 NMR (DMSO-^, 300 MHz) δ (ppm) 7.09 (d, J = 2.4 Hz). , 1H), 6.81 (s, 2H), 6.63 (dd, J; = 12.6 Hz, J ₂ = 2.4 Hz, 1 H), 3.84 (s, 3H).

实施例 30 6-胺基 -4-氟异二氢吲 -1-酮（中间体 8e) Example 30 6-Amino-4-fluoroisoindoline-1-one (Intermediate 8e)

除了用中间体 7e代替中间体 7b之外，中间体 8e的制备同中间体 8b，白色固体，产率为 68%。1H NMR (OMSO-d6, 300 MHz) δ (ppm) 8.47 (s， 1H), 6.66 (d， J=1.5 Hz, 1H), 6.52 (dd， J; =11.4 Hz, J₂ =1.8 Hz, 1 H), 5.58 (s, 2H), 4.21 (s， 2H). The preparation of intermediate 8e is identical to intermediate 8b, white solid, yield, except for the intermediate 7b. It is 68%. 1H NMR (OMSO-d6, 300 MHz) δ (ppm) 8.47 (s, 1H), 6.66 (d, J=1.5 Hz, 1H), 6.52 (dd, J; =11.4 Hz, J ₂ =1.8 Hz, 1 H), 5.58 (s, 2H), 4.21 (s, 2H).

实施例 31 2-(7-氟 -3-氧代异二氢 )-2-甲基丙腈（中间体 9e) Example 31 2-(7-Fluoro-3-oxoisodihydro)-2-methylpropanenitrile (Intermediate 9e)

除了用中间体 8e代替中间体 8a之外，中间体 9e的制备同中间体 7a，白色固体，产率为 61%。 1H NMR (DMSO- ， 300 MHz) δ (ppm) 8.65(s， 1H), 6.92(s, 1H), 6.79(d, J=12.3 Hz, 1H), 6.62(s, 1H)， 4.30(s, 2H), 1.65(s， 6H). Intermediate 9e was prepared as the intermediate 7a as a white solid with a yield of 61%, except that Intermediate 8e was used instead of Intermediate 8a. 1H NMR (DMSO- , 300 MHz) δ (ppm) 8.65 (s, 1H), 6.92 (s, 1H), 6.79 (d, J = 12.3 Hz, 1H), 6.62 (s, 1H), 4.30 (s, 2H), 1.65(s, 6H).

实施例 32 4-[3-(7-氟 -3-氧代异二氢吲哚 -5-基) -4，4-二甲基 -5-氧代 -2-硫代咪唑烷 -1- 基] -2- (三氟甲基）苯甲腈（化 Example 32 4-[3-(7-Fluoro-3-oxoisoindoline-5-yl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1- Benzyl-2-(trifluoromethyl)benzonitrile

除了用中间体 9e代替中间体 9a之外，化合物 5的制备同化合物 1，白色固体，产率为 37% 1H NMR (CD₃OD， 300 MHz) δ (ppm) 8.20-8.15(m, 2H), 8.03-7.99(m, 2H), 7.67(d, J =1.2 Hz, 1H), 7.51 (dd, J; =9.0 Hz, J₂ =1.2 Hz, 1 H)， 4.61(s， 2H), 1.61(s, 6H). The compound 5 was prepared in the same manner as the compound 1 as a white solid, yield 37% 1H NMR (CD ₃ OD, 300 MHz) δ (ppm) 8.20-8.15 (m, 2H). , 8.03-7.99(m, 2H), 7.67(d, J =1.2 Hz, 1H), 7.51 (dd, J; =9.0 Hz, J ₂ =1.2 Hz, 1 H), 4.61(s, 2H), 1.61 (s, 6H).

实施例 33 2-溴 -6-氟 -4-硝基苯甲 (中间体 4f) Example 33 2-Bromo-6-fluoro-4-nitrobenzene (intermediate 4f)

将 2-氟 -1-甲基 -4-硝基苯 (20.0 g, 129 mmoL), 铁粉 ( 0.87 g, 15.5 mmoL)加入到液溴 (45.6 g， 284 mmoL)中，于封管中油浴 100°C 加热反应 100小时。冷却，倾倒至冰水中，用亚硫酸钠处理过量的溴。 ***提取，合并有机相，用饱和食盐水洗涤，分液。减压蒸去溶剂，残留物用快速柱层析分离，洗脱剂为石油醚，得 1-溴 -3-氟 -2-甲基 -5-硝基苯，白色固体 7.5 g，产率为 25% 1H NMR (CDC1₃， 300 MHz) δ (ppm) 2.41 (d， J=3.0 Hz, 1H), 8.26(s, 1H), 7.86(d, J=8.4 Hz, 1H ). MS (ESI): m/z =232.0 (M-H)— . 2-Fluoro-1-methyl-4-nitrobenzene (20.0 g, 129 mmoL), iron powder (0.87 g, 15.5 mmoL) was added to liquid bromine (45.6 g, 284 mmoL) to seal the oil bath The reaction was heated at 100 ° C for 100 hours. Cool, pour into ice water and treat excess bromine with sodium sulfite. The organic layer was combined, washed with brine and separated. The solvent was evaporated under reduced pressure. the residue was purified eluting eluting elut elut elut elut elut 25% 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 2.41 (d, J = 3.0 Hz, 1H), 8.26 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H ). MS (ESI) : m/z =232.0 (MH)— .

将 1-溴 -3-氟 -2-甲基 -5-硝基苯 ( 6.0 g， 25.8 mmoL), 高锰酸钾 ( 16.3 g， 103.0 mmoL), 氢氧化钾（11.5 g， 206 mmoL)加入到水（60.0 mL)中，油浴 70°C 加热反应 8小时， TLC 检测反应完全。硅藻土趁热过滤，热水洗涤。冷却，用浓盐酸将 pH值调至中性， ***提取，减压蒸去溶剂，残留物用快速柱层析分离，洗脱剂为乙酸乙酯 /甲醇 =9/1，得白色固体 1.7 g，产率为 25%。 1H NMR (OMSO-d6, 300 MHz) δ (ppm) 8.10 (dd, J; =2.4 Hz, J₂ =1.2 Hz, 1 H)， 7.96 (dd, J! =8.1 Hz, J₂ =2.4 Hz, 1 H). MS (ESI): m/z =262.0 (M-H)— . Add 1-bromo-3-fluoro-2-methyl-5-nitrobenzene (6.0 g, 25.8 mmoL), potassium permanganate (16.3 g, 103.0 mmoL), potassium hydroxide (11.5 g, 206 mmoL) In water (60.0 mL), the oil bath was heated at 70 ° C for 8 hours, TLC The reaction was detected to be complete. The diatomaceous earth is filtered hot and washed with hot water. After cooling, the pH was adjusted to neutral with concentrated hydrochloric acid, ethyl ether was evaporated, and the solvent was evaporated to dryness. The residue was purified by flash column chromatography eluting with ethyl acetate/methanol=9/1 to give white solid 1.7 g , the yield is 25%. 1H NMR (OMSO-d6, 300 MHz) δ (ppm) 8.10 (dd, J; =2.4 Hz, J ₂ =1.2 Hz, 1 H), 7.96 (dd, J! =8.1 Hz, J ₂ =2.4 Hz, 1 H). MS (ESI): m/z =262.0 (MH) - .

实施例 34 2-溴 -6-氟 -4-硝基苯甲（中间体 5f) Example 34 2-Bromo-6-fluoro-4-nitrobenzidine (Intermediate 5f)

除了用中间体 4f代替中间体 4b之外，中间体 5f的制备同中间体 5b，白色固体，产率为 93%。直接用于下步反应。 Intermediate 5f was prepared as the intermediate 5b as a white solid with a yield of 93%, except that intermediate 4f was used instead of intermediate 4b. Used directly in the next step of the reaction.

实施例 35 4-胺基 -2-腈基 -6-氟苯甲酸甲酯（中间体 6f) Example 35 4-Amino-2-carbonitrile-6-fluorobenzoic acid methyl ester (Intermediate 6f)

除了用中间体 5f代替中间体 5b之外，中间体 6f的制备同中间体 6b，白色固体，产率为 93%。直接用于下步反应。 The intermediate 6f was prepared in the same manner as the intermediate 6b as a white solid, with a yield of 93%, except that the intermediate 5f was used instead of the intermediate 5b. Used directly in the next step of the reaction.

实施例 36 2-腈基 -6-氟 -4-硝基苯（中间体 7f) Example 36 2-Nitrile-6-fluoro-4-nitrobenzene (Intermediate 7f)

除了用中间体 6f代替中间体 6b之外，中间体 7f的制备同中间体 7b，白色固体，产率为 43%。 1H NMR (DMSO- ， 300 MHz) δ (ppm) 6.84 (d， J=2.1 Hz, 1H), 6.69 (s， 2H), 6.57 (d， J=14.1 Hz, 1H)， 3.78 (s， 3H). MS (ESI): m/z =193.0 (M-H)". Intermediate 7f was prepared as the intermediate 7b as a white solid with a yield of 43%, except that intermediate 6f was used instead of intermediate 6b. 1H NMR (DMSO- , 300 MHz) δ (ppm) 6.84 (d, J = 2.1 Hz, 1H), 6.69 (s, 2H), 6.57 (d, J = 14.1 Hz, 1H), 3.78 (s, 3H) MS (ESI): m/z =193.0 (MH)".

实施例 37 5-胺基 -7-氟异二氢吲 -1-酮（中间体 8f) Example 37 5-Amino-7-fluoroisoindoline-1-one (Intermediate 8f)

除了用中间体 7f代替中间体 7b之外，中间体 8f的制备同中间体 8b，白色固体，产率为 58%。 1H NMR (OMSO-d6, 300 MHz) δ (ppm) 7.88 (s， 1H), 6.41 (d， J=1.2 Hz, 1H), 6.27 (dd， J; =12.3 Hz，J₂ =1.5 Hz, 1 H)， 6.02 (s， 2H), 4.18 (s， 2H). MS (ESI): m/z =189.0 (M+Na)+. 实施例 38 2-(7-氟 -1-氧代异二氢吲哚 -5-基胺基 )-2-甲基丙腈（中间体 9f) The preparation of intermediate 8f is the same as intermediate 8b, white solid, except for intermediate 7f instead of intermediate 7b. The rate is 58%. 1H NMR (OMSO-d6, 300 MHz) δ (ppm) 7.88 (s, 1H), 6.41 (d, J = 1.2 Hz, 1H), 6.27 (dd, J; = 12.3 Hz, J ₂ = 1.5 Hz, 1 H), 6.02 (s, 2H), 4.18 (s, 2H). MS (ESI): m/z = 189.0 (M+Na)+. Example 38 2-(7-fluoro-1-oxoiso Hydroquinone-5-ylamino)-2-methylpropionitrile (intermediate 9f)

除了用中间体 8f代替中间体 8a之外，中间体 9f的制备同中间体 9a，白色固体，产率为 56% 1H NMR (DMSO- ， 300 MHz) δ (ppm) 8.10 (s， 1H), 6.97 (s， 1H), 6.73 (s， 1H)， 6.53 (d， J=12.3 Hz, 1H), 4.29 (d， 2H), 1.68 (s， 6H). MS (ESI): m/z =256.0 (M+Na)+.

Intermediate 9f was prepared as the intermediate 9a as a white solid, yield 56% 1H NMR (DMSO-, 300 MHz) δ (ppm) 8.10 (s, 1H), 6.97 (s, 1H), 6.73 (s, 1H), 6.53 (d, J = 12.3 Hz, 1H), 4.29 (d, 2H), 1.68 (s, 6H). MS (ESI): m/z =256.0 (M+Na)+.

实施例 39 4-[3-(7-氟 -1-氧代异二氢吲哚 -5-基) -4，4-二甲基 -5-氧代 -2-硫代咪唑烷 -1- 基] -2- (三氟甲基）苯甲腈（化 6 ) Example 39 4-[3-(7-Fluoro-1-oxoisoindoline-5-yl)-4,4-dimethyl-5-oxo-2-thioimidazol-1- Benzyl-2-(trifluoromethyl)benzonitrile (6)

除了用中间体 9f代替中间体 9a之外，化合物 6的制备同化合物 1，白色固体，产率为 37% 1H NMR (CD₃OD， 300 MHz) δ (ppm) 8.18-8.16 (m， 2H), 8.01-7.99(m, 1H)， 7.48(s, 1H), 7.33(d, J=7.2 Hz, 1H)， 4.56 (s， 2H), 1.61 (s， 6H). MS (ESI): m/z =463.0 (M+H)+. Compound 6 was prepared in the same manner as Compound 1, white solid, yield 37% 1H NMR (CD ₃ OD, 300 MHz) δ (ppm) 8.18-8.16 (m, 2H) , 8.01-7.99(m, 1H), 7.48(s, 1H), 7.33(d, J=7.2 Hz, 1H), 4.56 (s, 2H), 1.61 (s, 6H). MS (ESI): m/ z = 463.0 (M+H)+.

实施例 40 4-[3-(6-氟 -2-甲基 -3-氧代异二氢吲哚 -5-基 4，4-二甲基 -2，，5-二氧代咪唑烷小基] -2- (三氟甲基）苯甲腈（化合物 7 ) Example 40 4-[3-(6-Fluoro-2-methyl-3-oxoisoindoline-5-yl 4,4-dimethyl-2,5-dioxoimidazolidine small Benzyl-2-(trifluoromethyl)benzonitrile (Compound 7)

在冰浴下，将 60%的氢化钠（3.5 mg， 0.087 mmoL) 加入到化合物 4 (30.0 mg， 0.067 mmoL) 的无水 DMF ( 3.0 mL) 中。加料完毕后，继续在冰浴下搅拌 30分钟。撤去冰浴，在室温下加入碘甲烷（21 L， 0.33 mmoL)。继续在室温下搅拌 3小时， TLC检测反应完成。加入乙酸乙酯，用水洗涤。减压蒸去溶剂，快速柱层析分离，洗脱剂为石油醚 /乙酸乙酯 =1/2，得白色固体 25.0 mg，产率为 81%。 1H NMR (CD₃OD， 300 MHz) δ (ppm) 8. 19(s, 1H), 8.05(d， J=8.4 Hz, 1H), 7.94(d, J=8.4 Hz, 1H), 7.80 (d， J=6.6 Hz, 1H), 7.38(d, J=8.7 Hz, 1H), 4.45(s,2H), 3.22(s,3H), 1.58(s， 6H). MS (ESI): m/z =461.0 (M+H)+.

60% sodium hydride (3.5 mg, 0.087 mmoL) was added to compound 4 (30.0 mg, 0.067 mmol) in anhydrous DMF (3.0 mL). After the addition was completed, stirring was continued for 30 minutes in an ice bath. The ice bath was removed and methyl iodide (21 L, 0.33 mmoL) was added at room temperature. Stirring was continued for 3 hours at room temperature, and the reaction was completed by TLC. Ethyl acetate was added and washed with water. The solvent was evaporated under reduced pressure and purified by flash chromatography. 1H NMR (CD ₃ OD, 300 MHz) δ (ppm) 8. 19(s, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.80 (d, J=6.6 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H) , 4.45(s,2H), 3.22(s,3H), 1.58(s, 6H). MS (ESI): m/z =461.0 (M+H)+.

实施例 41 4-[3-(6-氟 -3-氧代异二氢吲哚 -5-基) -4，4-二甲基 -2，，5-二氧代咪唑烷 -1- 基] -2- (三氟甲基）苯甲腈（化合物 8) Example 41 4-[3-(6-Fluoro-3-oxoisoindoline-5-yl)-4,4-dimethyl-2,5-dioxoimidazolidine-1-yl ] -2-(trifluoromethyl)benzonitrile (Compound 8)

在冰浴下，将 60%的氢化钠（3.5 mg， 0.087 mmoL) 加入到化合物 4 (30.0 mg， 0.067 mmoL) 的无水 DMF (3.0 mL) 中。加料完毕后，继续在冰浴下搅拌 30分钟。撤去冰浴，在室温下搅拌 3小时， TLC检测反应完成。加入乙酸乙酯，用水（3x)洗涤。减压蒸去溶剂，快速柱层析分离，洗脱剂为石油醚 /乙酸乙酯 =1/2，得白色固体 21.0 mg，产率为 70 %。 1H NMR (CD₃OD， 300 MHz) δ (ppm) 8. 19(s, 1H), 8.07(d, J=12.0 Hz, 1H), 7.96(d, J=8.4 Hz, 1H), 7.84 (d， J=6.6 Hz, 1H), 7.42(d, J=8.7 Hz, 1H), 6.50(s， 1H), 4.54(s,2H), 1.59(s, 6H). MS (ESI): m/z =447.0 (M+H)+.

60% sodium hydride (3.5 mg, 0.087 mmoL) was added to compound 4 (30.0 mg, 0.067 mmol) in anhydrous DMF (3.0 mL). After the addition was completed, stirring was continued for 30 minutes in an ice bath. The ice bath was removed, stirred at room temperature for 3 hours, and the reaction was completed by TLC. Ethyl acetate was added and washed with water (3x). The solvent was evaporated under reduced pressure and purified by flash chromatography. 1H NMR (CD ₃ OD, 300 MHz) δ (ppm) 8. 19(s, 1H), 8.07 (d, J = 12.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.84 (d , J=6.6 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.50(s, 1H), 4.54(s,2H), 1.59(s, 6H). MS (ESI): m/z =447.0 (M+H)+.

实施例 42 4-[3-(2-乙基 6-氟 -3-氧代异二氢吲哚 -5-基 4，4-二甲基 -2，，5-二氧代咪唑烷小基] -2- (三氟甲基）苯甲腈化合物 9) Example 42 4-[3-(2-Ethyl 6-fluoro-3-oxoisoindoline-5-yl 4,4-dimethyl-2,5-dioxoimidazolidine small base ] -2-(trifluoromethyl)benzonitrile compound 9)

除了用碘乙烷代替碘甲烷之外，化合物 9的制备同化合物 7，白色固体，产率为 62%。 1H NMR (CD₃OD， 300 MHz) δ (ppm) 8.22(s, 1H), 8.08(dd， J; =8.7 Hz, J₂=1.8 Hz, 1 H)， 8.00(d J=8.4 Hz, 1H)， 7.83 (d, J=6.6 Hz, 1H)， 7.43(d, J=8.7 Hz, 1H)， 4.49(s， 2H), 3.73(q, 2H), 1.61(s， 6H)， 1.33(t, J=7.2 Hz, 3H). MS (ESI): m/z =475.0 (M+H)+.

Compound 9 was prepared in the same manner as Compound 7, white solid, yield 62%, except that ethyl iodoethane was used instead of methyl iodide. 1H NMR (CD ₃ OD, 300 MHz) δ (ppm) 8.22(s, 1H), 8.08 (dd, J; =8.7 Hz, J ₂ =1.8 Hz, 1 H), 8.00 (d J=8.4 Hz, 1H ), 7.83 (d, J=6.6 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 4.49(s, 2H), 3.73(q, 2H), 1.61(s, 6H), 1.33(t , J=7.2 Hz, 3H). MS (ESI): m/z =475.0 (M+H)+.

实施例 43 l-(7-氟 -3-氧代异二氢吲哚 -5-基胺基)环丁基甲腈（中间体 9g)

将中间体 8e ( 180 mg， 0.92 mmoL)和三甲基腈硅烷（2.0 mL)加入到环丁酮（7.0 mL) 中，油浴 70 °C加热反应过夜小时， TLC检测反应完全。加入饱和碳酸钾（2.0 mL) ，乙酸乙酯提取，减压蒸去溶剂，残留物用快速柱层析分离，洗脱剂为甲醇 /二氯甲烷 =1/20，得淡黄色固体 220.0 mg，产率为 98 %。直接用于下步反应。 Example 43 l-(7-Fluoro-3-oxoisoindoline-5-ylamino)cyclobutylcarbonitrile (Intermediate 9g)

Intermediate 8e (180 mg, 0.92 mmoL) and trimethylsilyl silane (2.0 mL) were added to cyclobutanone (7.0 mL), and the reaction was heated at 70 ° C overnight in an oil bath, and the reaction was completed by TLC. After adding saturated potassium carbonate (2.0 mL), EtOAc (EtOAc)EtOAc. The yield was 98%. Used directly in the next step of the reaction.

实施例 44 4-[[5-(7-氟 -3-氧代异二氢吲哚 -5-基) -8-氧代 -6-硫氧代 -5,7- 二氮杂螺 [3.4] 辛烷 -7-基]] -2- (三氟甲基）苯甲腈（化合物 10) Example 44 4-[[5-(7-Fluoro-3-oxoisoindoline-5-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4 Octane-7-yl]]-2-(trifluoromethyl)benzonitrile (Compound 10)

除了用中间体 9g代替中间体 9a之外，化合物 10的制备同化合物 1，白色固体，产率为 41%。 1H NMR (丙酮 -ί¾， 300 MHz) δ (ppm) 8.27(d, J=7.2 Hz, 1H)， 8.17(s, 1H)， 8.07(d, J=6.3 Hz, 1H), 8.00-7.90(mlH), 7.65(d, J=1.5 Hz, 1H), 7.53(dd, J; =9.3 Hz, J₂ =1.5 Hz, 1 H)， 4.66(s, 2H), 2.76-2.62(m, 4H), 2.14-2.07(m, 1H), 1.68-1.64(m, 1H). MS (ESI): m/z =475.0 (M+H)+.

Compound 10 was prepared in the same manner as Compound 1, a white solid, yield 41%, except that Intermediate 9g was used instead of Intermediate 9a. 1H NMR (acetone-ί3⁄4, 300 MHz) δ (ppm) 8.27 (d, J = 7.2 Hz, 1H), 8.17 (s, 1H), 8.07 (d, J = 6.3 Hz, 1H), 8.00-7.90 (mlH ), 7.65 (d, J = 1.5 Hz, 1H), 7.53 (dd, J; = 9.3 Hz, J ₂ = 1.5 Hz, 1 H), 4.66 (s, 2H), 2.76-2.62 (m, 4H), 2. </ RTI> 2.

实施例 45 5- [双 (叔丁氧羰基)氨基 -2-腈基 -4-氟苯甲酸甲酯（中间体 10a) Example 45 5- [Bis(tert-Butoxycarbonyl)amino-2-carbonitrile-4-fluorobenzoic acid methyl ester (Intermediate 10a)

在冰浴下，将中间体 8d ( 1.9g, 9.9mmoL) ， Boc酸酐 ( 5.7 g, 21.7 mmoL), N，N-二甲基胺基吡啶（122 mg， 1.0 mmoL) 加入到无水 THF中，自然升温，搅拌过夜。减压蒸去溶剂，残留物用快速柱层析分离，洗脱剂为石油醚，得白色固体 2.2 g，产率为 56%。1H NMR (CDC1₃, 300 MHz) δ (ppm) 8.01(d， J=7.5 Hz, 1H), 7.54(d, J=9.0 Hz, 1H), 3.99(s, 3H), 1.44(s， 18H). MS (ESI): m/z =417.0 (M+Na)+.

Intermediate 8d (1.9 g, 9.9 mmoL), Boc anhydride (5.7 g, 21.7 mmoL), N,N-dimethylaminopyridine (122 mg, 1.0 mmoL) was added to dry THF under ice bath. , naturally warmed up, stirred overnight. The solvent was evaporated under reduced pressure and the~~~~~~~~~~~~~~~~ 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.01 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 3.99 (s, 3H), 1.44 (s, 18H) MS (ESI): m/z =417.0 (M+Na)+.

实施例 46 6- [双 (叔丁氧羰基)氨基] -5-氟异二氢吲哚 -1-酮（中间体 11a)

Example 46 6- [Bis(tert-Butoxycarbonyl)amino]-5-fluoroisoindoline-1-one (Intermediate 11a)

除了用中间体 10a代替中间体 7b之外，中间体 11a的制备同中间体 8b，白色固体，产率为 63%。 1H NMR (丙酮 -ί¾， 300 MHz) δ (ppm) 7.65(d, J=6.9 Hz, 1H), 7.49(d, J=9.6 Hz_: 1H), 4.51(s， 2H), 1.44(s， 18H). MS (ESI): m/z =389.0 (M+Na)+. Intermediate 11a was prepared as the intermediate 8b as a white solid with a yield of &lt 1H NMR (acetone-ί3⁄4, 300 MHz) δ (ppm) 7.65 (d, J = 6.9 Hz, 1H), 7.49 (d, J = 9.6 Hz _: 1H), 4.51 (s, 2H), 1.44 (s, 18H) MS (ESI): m/z =389.0 (M+Na)+.

实施例 47 6- [双 (叔丁氧羰基)氨基] -5-氟异二氢吲哚 -1-酮（中间体 12a) Example 47 6- [Bis(tert-Butoxycarbonyl)amino]-5-fluoroisoindoline-1-one (Intermediate 12a)

将中间体 lla ( 1.2 g, 3.28 mmoL) , 碳酸铯（3.24 g， 10.0 mmoL)和碘甲烷（ 1.1 mL, 16.0 mmoL) 加入到无水 DMF ( lO.O mL) 中，室温搅拌过夜。混合体系加入到乙酸乙酯中，用水洗涤，减压蒸去溶剂，残留物用快速柱层析分离，洗脱剂为石油醚 /乙酸乙酯 =5/1，得白色固体 720.0 mg，产率为 58 %。 'H NMR (丙酮 -^¾， 300 MHz) δ (ppm) 7.6 l(d, J=6.9 Hz, 1H), 7.48(d, J=9.6 Hz, 1H), 4.50(s, 2H), 3.11(s, 3H), 1.43(s, 18H). MS (ESI): m/z =403.0 (M+Na)+. Intermediate lla (1.2 g, 3.28 mmoL), cesium carbonate (3.24 g, 10.0 mmoL) and methyl iodide (1.1 mL, 16.0 mmoL) were added to dry DMF (10 mL) and stirred at room temperature overnight. The mixed system was added to ethyl acetate, and the mixture was washed with H2HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH It is 58%. 'H NMR (acetone-^3⁄4, 300 MHz) δ (ppm) 7.6 l (d, J = 6.9 Hz, 1H), 7.48 (d, J = 9.6 Hz, 1H), 4.50 (s, 2H), 3.11 ( s, 3H), 1.43(s, 18H). MS (ESI): m/z =403.0 (M+Na)+.

实施例 48 6-氨基 -5-氟 -2-甲基异（中间体 13a) Example 48 6-Amino-5-fluoro-2-methyliso (Intermediate 13a)

在冰浴下，将三氟乙酸（14.4 mL) 滴加到中间体 12a (720 mg, 1.9 mmoL) 的二氯甲烷（28.8 mL) 中。自然升至室温，搅拌过夜。减压蒸去溶剂，残留物加入到乙酸乙酯中，依次用饱和碳酸氢钠和水洗涤，减压蒸去溶剂，高真空干燥，得白色固体 310 mg，产率为 91%。 1H NMR (CDC1₃， 300 MHz) δ (ppm) 7.2 l(d, J=6.3 Hz, 1H)， 7.03(d, J=7.8 Hz, 1H)， 4.24(s, 2H), 3.90(br, 2H), 3.15(s, 3H). MS (ESI): m/z =203.0 (M+Na)+. Trifluoroacetic acid (14.4 mL) was added dropwise to dichloromethane (28.8 mL) of Intermediate 12a (720 mg, 1.9 mmoL). Raise to room temperature naturally and stir overnight. The solvent was evaporated under reduced pressure. EtOAc EtOAc m. 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 7.2 l (d, J = 6.3 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 4.24 (s, 2H), 3.90 (br, 2H) ), 3.15(s, 3H). MS (ESI): m/z =203.0 (M+Na)+.

实施例 49 2-(6-氟 -2-甲基 -3-氧代异二氢吲哚 -5-基氨基 )-2-甲基丙腈（中间体 14a)

除了用中间体 13a代替中间体 8a之外，中间体 14a的制备同中间体 9a，白色固体，产率为 62%。 1H NMR (；丙酮， 300 MHz) δ (ppm) 7.45(d, J=6.0Hz, 1H), 7.30(d, J=8.6 Hz, 1H), 5.25(s, 1H), 4.34(s, 2H), 3.08(s, 3H), 1.79(s, 6H). MS (ESI): m/z =270.0 (M+Na)+. Example 49 2-(6-Fluoro-2-methyl-3-oxoisoindoline-5-ylamino)-2-methylpropanenitrile (Intermediate 14a)

Intermediate 14a was prepared as the intermediate 9a as a white solid in a yield of 62%, except that Intermediate 13a was used instead of Intermediate 8a. 1H NMR (Acetone, 300 MHz) δ (ppm) 7.45 (d, J = 6.0 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 5.25 (s, 1H), 4.34 (s, 2H) , MS (ESI): m/z =270.0 (M+Na)+.

实施例 50 4-[3-(6-氟 -2-甲基 -3-氧代异二氢吲哚 -5-基) -4，4-二甲基 -5-氧代 -2-硫代咪唑烷小基 ]-2— (三氟甲基）苯甲腈 11 ) Example 50 4-[3-(6-Fluoro-2-methyl-3-oxoisoindoline-5-yl)-4,4-dimethyl-5-oxo-2-thio Imidazolidine small group]-2-(trifluoromethyl)benzonitrile 11 )

除了用中间体 14a代替中间体 9a之外，化合物 11的制备同化合物 1，得白色固体，产率为 32% 1H NMR (CDC1₃， 300 MHz) δ (ppm) 8.00-7.96(m, 2H), 7.86(dd, J; =8.4 Hz, J₂ =2.4 Hz, 1 H), 7.79(d, J=6.6 Hz, 1H), 7.40(d, J=8.4 Hz, 1H), 4.47(s, 2H), 3.22(s, 3H), 1.69(s, 3H), 1.53(s, 3H). MS-EI: m/z =476.0 (M)+. The compound 11 was prepared in the same manner as the compound 1 to give a white solid, yield 32% 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.00-7.96 (m, 2H). , 7.86(dd, J; =8.4 Hz, J ₂ =2.4 Hz, 1 H), 7.79(d, J=6.6 Hz, 1H), 7.40(d, J=8.4 Hz, 1H), 4.47(s, 2H ), 3.22(s, 3H), 1.69(s, 3H), 1.53(s, 3H). MS-EI: m/z =476.0 (M)+.

实施例 51 l-(6-氟 -2-甲基 -3-氧代异二氢吲哚 -5-氨基）环丁腈（中间体 14b) Example 51 l-(6-Fluoro-2-methyl-3-oxoisoindoline-5-amino)cyclobutyronitrile (Intermediate 14b)

除了用环丁酮代替丙酮，及用 6-氨基 -5-氟 -2-甲基异二氢吲哚 -1-酮（中间体 13a)代替 5-氨基 -1-异二氢吲哚酮（中间体 8a)之外，中间体 14b的制备同 9a，得白色固体，产率为 55% 1H NMR (丙酮， 300 MHz) δ (ppm) 7.31(d, J=10.8Hz, 1H), 6.99(d， J=7.8 Hz, 1H)， 5.97(s, 1H), 4.34(s, 2H), 3.09(s, 3H), 2.83-2.81(m, 2H), 2.63-2.54(m, 2H), 2.23-2.18(m, 2H). MS (ESI): m/z =260.0 (M+H)+.

In addition to replacing acetone with cyclobutanone, and replacing 5-amino-1-isoindolinone with 6-amino-5-fluoro-2-methylisoindoline-1-one (intermediate 13a) In addition to the intermediate 8a), the intermediate 14b was obtained as a white solid, yield 55% 1H NMR (acetone, 300 MHz) δ (ppm) 7.31 (d, J = 10.8 Hz, 1H), 6.99 ( d, J=7.8 Hz, 1H), 5.97(s, 1H), 4.34(s, 2H), 3.09(s, 3H), 2.83-2.81(m, 2H), 2.63-2.54(m, 2H), 2.23 -2.18(m, 2H). MS (ESI): m/z =260.0 (M+H)+.

实施例 52 4-[[5-(6-氟 -2-甲基 -3-氧代异二氢吲哚 -5-基) -8-氧代 -6-硫氧代 -5，7- 二氮杂螺 [3.4]辛烷 -7-基]] -2- (三氟甲基）苯甲腈（化合物 12) Example 52 4-[[5-(6-Fluoro-2-methyl-3-oxoisoindoline-5-yl)-8-oxo-6-thioxo-5,7- Aza Spiro[3.4]octane-7-yl]]-2-(trifluoromethyl)benzonitrile (Compound 12)

除了用 1-(6-氟 -2-甲基 -3-氧代异二氢吲哚 -5-氨基）环丁腈（中间体 14b)代替 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈 (中间体 9a)之外，化合物 12的制备同化合物 1，得白色固体，产率为 26 %。 1H NMR (CDC1₃， 300 MHz) δ (ppm) 8.00-7.97(m, 2H), 7.89-7.83 (m， 2H), 7.44(d, J=8.1Hz， 1H), 4.49(s, 2H), 3.22(s, 3H), 2.75-2.57(m, 2H), 2.43-2.22(m, 2H), 1.69-1.59(m, 2H). MS (ESI): m/z =489.0 (M+H)+.

In addition to 1-(6-fluoro-2-methyl-3-oxoisoindoline-5-amino)cyclobutyronitrile (intermediate 14b) instead of 2-methyl-2-(1-oxo-iso-) In addition to the indoline-5-ylamino)propanenitrile (Intermediate 9a), Compound 12 was obtained in the same compound as Compound 1 to give a white solid. 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.00-7.97 (m, 2H), 7.89-7.83 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H), 4.49 (s, 2H), 3.22(s, 3H), 2.75-2.57(m, 2H), 2.43-2.22(m, 2H), 1.69-1.59(m, 2H). MS (ESI): m/z =489.0 (M+H)+ .

实施例 53 l-(7-氟 -1-氧代异二氢吲哚 -5-基胺基)环丁腈 Example 53 l-(7-Fluoro-1-oxoisoindoline-5-ylamino)cyclobutyronitrile

除了用环丁酮代替丙酮外，中间体 1-(7-氟 -1-氧代异二氢吲哚 -5-基胺基)环丁腈的制备同 2-甲基 -2- ( 1氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a)，白色固体，产率为 78%。 1H NMR (CDC1₃， 400 MHz) δ (ppm) 6.84 (s， 1H), 6.42 (s， 1H), 6.34 (dd， J= 10.9, 1.4 Hz, 1H)， 4.72 (s, 1H), 4.38 (s, 2H), 2.85 (ddd, J = 12.3, 8.8， 5.6 Hz, 2H), 2.42 (dd， J= 12.1, 8.3 Hz, 2H), 2.35 - 2.12 (m, 2H).

The preparation of the intermediate 1-(7-fluoro-1-oxoisoindoline-5-ylamino)cyclobutyronitrile is the same as 2-methyl-2-(1 oxygen) except that cyclobutanone is used instead of acetone. Diisoindoline-5-ylamino)propanenitrile (Intermediate 9a), white solid, yield 78%. 1H NMR (CDC1 ₃ , 400 MHz) δ (ppm) 6.84 (s, 1H), 6.42 (s, 1H), 6.34 (dd, J= 10.9, 1.4 Hz, 1H), 4.72 (s, 1H), 4.38 ( s, 2H), 2.85 (ddd, J = 12.3, 8.8, 5.6 Hz, 2H), 2.42 (dd, J= 12.1, 8.3 Hz, 2H), 2.35 - 2.12 (m, 2H).

实施例 54 4-[5-(7-氟 -1-氧代异二氢吲哚 -5-基) -8-氧代 -6-硫代 -5，7-二氮杂螺 [3，4]辛烷 -7-基] -²-(三氟甲基)苯甲腈（ Example 54 4-[5-(7-Fluoro-1-oxoisoindoline-5-yl)-8-oxo-6-thio-5,7-diazaspiro[3,4 ] octane-7-yl] - ² - (trifluoromethyl) benzonitrile (

除了用中间体 1-(7-氟 -1-氧代异二氢吲哚 -5-氨基)环丁腈替代 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a) 夕卜，化合物 13的制备同化合物 1，浅黄色固体，产率为 75% 1H NMR (CDC1₃， 300 MHz) δ (ppm) 7.99 (d, J = 8.4 Hz, 1H)， 7.97 (s， 1H)， 7.89 (s， 1H), 7.85 (dd，J= 8.2, 1.9 Hz, 1H), 7.28 (s， 1H), 7.14 (d, J= 8.9 Hz, 1H), 4.60 (s， 2H), 2.73 (m， 2H), 2.65 - 2.47 (m， 2H), 2.28 (m， 1H)， 1.72 (m， 1H). EI-MS 474.08[M]⁺. In place of the intermediate 1-(7-fluoro-1-oxoisoindoline-5-amino)cyclobutyronitrile instead of 2-methyl-2-(1-oxoisoindoline-5-yl) Amino)propanenitrile (Intermediate 9a), Compound 13 was prepared as Compound 1, a pale yellow solid, yield 75% 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 7.99 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.85 (dd, J= 8.2, 1.9 Hz, 1H), 7.28 (s, 1H), 7.14 (d, J= 8.9 Hz, 1H ), 4.60 (s, 2H), 2.73 (m, 2H), 2.65 - 2.47 (m, 2H), 2.28 (m, 1H), 1.72 (m, 1H). EI-MS 474.08[M] ⁺ .

实施例 55 6-溴 -5-氟异二氢吲哚 -1-酮 Example 55 6-Bromo-5-fluoroisoindoline-1-one

将 6-胺基 -5-氟异二氢吲哚 -1-酮（中间体 8d) (3.0 g， 18.1 mmoL)加入到水（110 mL) 和浓硫酸（40 mL) 的混合溶液中，冷却至 0°C，缓慢滴加 NaN0₂ ( 1.9 g)的水（30 mL) 溶液。滴加完毕后继续在此温度下搅拌 1小时。将 CuBr( 3.9 g)的 48%氢溴酸溶液（300 mL) 滴加到上述体系中，滴加完毕，在 60°C油浴加热反应， TLC检测反应的完成。加水稀释，用乙酸乙酯提取。有机相减压浓縮，残留物用快速柱层析分离，洗脱剂为二氯甲烷:甲醇 =50: 1，得灰色固体 3.6 g，产率为 88%。 1H NMR (DMSO- ， 300 MHz) δ (ppm) 8.73 (brs, 1H), 7.92 (d, J= 6.3 Hz, 1H),7.64 (d， J= 8.4 Hz, 1H), 4.35 (s, 2H). EI-MS 229.0[M]⁺.

6-Amino-5-fluoroisoindoline-1-one (intermediate 8d) (3.0 g, 18.1 mmoL) was added to a mixed solution of water (110 mL) and concentrated sulfuric acid (40 mL), cooled To 0 ° C, slowly add NaN0 ₂ (1.9 g) in water (30 mL). After the completion of the dropwise addition, stirring was continued at this temperature for 1 hour. A CuBr (3.9 g) 48% hydrobromic acid solution (300 mL) was added dropwise to the above system, and the addition was completed. The reaction was heated in an oil bath at 60 ° C, and the completion of the reaction was confirmed by TLC. Dilute with water and extract with ethyl acetate. The organic phase was concentrated under reduced pressure. EtOAc m. 1H NMR (DMSO- , 300 MHz) δ (ppm) 8.73 (brs, 1H), 7.92 (d, J = 6.3 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H) EI-MS 229.0[M] ⁺ .

实施例 56 6-溴 -2- (环丙基甲基 )-5-氟异二氢吲哚 -1-酮 Example 56 6-Bromo-2-(cyclopropylmethyl)-5-fluoroisoindoline-1-one

在冰浴下，将 NaH (60%, 5.1 mg， 0.127 mmoL) 加入到 6-溴 -5-氟异二氢吲哚 -1-酮 (20.0 mg， 0.087 mmoL)的无水 DMF(0.87 mL) 溶液中。加料完毕，搅拌 5分钟。加入溴甲基环丙烷（ 13.0 L，0.127 mmoL) 和四丁基碘化铵（9.5 mg， 0.024 mmoL)。继续在冰浴下搅拌 2小时， TLC检测反应的完成。用水萃灭反应，乙酸乙酯提取。有机相减压浓縮，残留物用制备薄层层析分离，展开剂为石油醚:乙酸乙酯 =2: 1，得白色固体 8.0 mg，产率为 32%。 1H NMR (丙酮 -ί¾， 300 MHz) δ (ppm) 7.91 (d， J= 4.8 Hz, 1H)， 7.56 (d， J= 6.6 Hz, 1H), 4.60 (s, 2H), 3.42 (d, J= 8.1 Hz, 2H), 1.07 (m， 1H), 0.56 (m， 2H), 0.33 (m， 1H).

Add NaH (60%, 5.1 mg, 0.127 mmoL) to 6-bromo-5-fluoroisoindoline-1-one (20.0 mg, 0.087 mmoL) in anhydrous DMF (0.87 mL). In solution. After the addition is completed, stir for 5 minutes. Bromomethylcyclopropane (13.0 L, 0.127 mmoL) and tetrabutylammonium iodide (9.5 mg, 0.024 mmoL) were added. Stirring was continued for 2 hours in an ice bath, and the completion of the reaction was detected by TLC. The reaction was extracted with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. EtOAc m. 1H NMR (acetone-ί3⁄4, 300 MHz) δ (ppm) 7.91 (d, J = 4.8 Hz, 1H), 7.56 (d, J = 6.6 Hz, 1H), 4.60 (s, 2H), 3.42 (d, J = 8.1 Hz, 2H), 1.07 (m, 1H), 0.56 (m, 2H), 0.33 (m, 1H).

实施例 57 2-[2- (环丙基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸 H〇〇C、 HN 将 6-溴 -2- (环丁基甲基 )-5-5-氟异二氢吲哚小酮（95.0 mg, 0.33 mmoL), 氨基异丁酸 (52.0 mg, 0.50 mmoL), K₂C0₃ (117.0 mg, 0.84 mmoL), CuCl (6.24 mg, 0.063 mmoL), 2-乙酰基环己酮 (9.0 L)和水 (14.0 加入到 DMF (0.45 mL)中，在氩气保护下于 105°C油浴反应过夜。减压蒸去溶剂，残留物加入水，用 1N 盐酸将 pH值调至中性。减压除去水，残留物用快速柱层析分离，洗脱剂为二氯甲烷:甲醇 =10:1，得淡红色油状物 40 mg，产率为 40%。 1H NMR (CD₃OD， 300 MHz) δ (ppm) 7.22 (brs, 1H)， 7.04 (br， 1H)， 4.47 (brs, 2H), 3.42 (d, J= 6.9 Hz, 1H), 1.98 (s, 1H), 1.59 (s, 6H)， 1.06 (m， 1H), 0.56 (m， 2H), 0.32 (m， 1H). 实施例 58 2-[2- (环丙基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸甲酯 Example 57 2-[2-(Cyclopropylmethyl)-6-fluoro-3-isoindoline-5-amino]-2-methylpropionic acid H〇〇C, HN 6-bromo-2-(cyclobutylmethyl)-5-5-fluoroisoindolizine (95.0 mg, 0.33 mmoL), aminoisobutyric acid (52.0 mg, 0.50 mmoL) , K ₂ C0 ₃ (117.0 mg, 0.84 mmoL), CuCl (6.24 mg, 0.063 mmoL), 2-acetylcyclohexanone (9.0 L) and water (14.0 added to DMF (0.45 mL), protected with argon The reaction was carried out in an oil bath at 105 ° C overnight. The solvent was evaporated under reduced pressure, and the residue was applied to water, and the pH was adjusted to neutral with 1 N hydrochloric acid. Water was removed under reduced pressure and the residue was purified by flash column chromatography. Dichloromethane: methanol = 10:1, 40 mg of pale red oil, yield 40%. 1H NMR (CD ₃ OD, 300 MHz) δ (ppm) 7.22 (brs, 1H), 7.04 (br, 1H) ), 4.47 (brs, 2H), 3.42 (d, J= 6.9 Hz, 1H), 1.98 (s, 1H), 1.59 (s, 6H), 1.06 (m, 1H), 0.56 (m, 2H), 0.32 (m, 1H). Example 58 2-[2-(Cyclopropylmethyl)-6-fluoro-3-isoindoline-5-amino]-2-methylpropanoate

将 2-[2- (；环丙基甲基) -6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸（40.0 mg, 0.13 mmoL), K₂C0₃ (22.0 mg), 碘甲烷（10 L)加入到无水 DMF (0.23 mL) 中，室温搅拌过夜。减压蒸去溶剂。残留物用制备薄层层析分离，展开剂为石油醚:乙酸乙酯 =1 :1，得黄色油状物 21 mg, 产率为 50%。 1H NMR (CDC1₃, 300 MHz) δ (ppm) 7.06 (d, J= 10.5 Hz, 1H), 6.97 (d, J= 7.8 Hz, 1H), 4.48 (brs, 1H), 4.34 (s， 2H), 3.74 (s， 3H), 3.41 (d， J= 7.2 Hz, 2H), 1.61 (s， 6H)， 1.00 (m， 1H), 0.56 (m， 2H), 0.29 (m， 1H).

2-[2-(;Cyclopropylmethyl)-6-fluoro-3-isoindoline-5-amino]-2-methylpropionic acid (40.0 mg, 0.13 mmoL), K ₂ C0 ₃ (22.0 mg), iodomethane (10 L) was added to dry DMF (0.23 mL). The solvent was evaporated under reduced pressure. The residue was separated by preparative EtOAc (EtOAc:EtOAc) 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 7.06 (d, J = 10.5 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 4.48 (brs, 1H), 4.34 (s, 2H) , 3.74 (s, 3H), 3.41 (d, J = 7.2 Hz, 2H), 1.61 (s, 6H), 1.00 (m, 1H), 0.56 (m, 2H), 0.29 (m, 1H).

实施例 59 4-[[3-[2- (环丙基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -4，4-二甲基 -5-氧代 -2 硫代咪唑烷 -1-基]] -2- (三 Example 59 4-[[3-[2-(Cyclopropylmethyl)-6-fluoro-3-isoindoline-5-amino]-4,4-dimethyl-5-oxo -2 thioimidazolidine-1-yl]] -2- (three

将 4-异硫氰基 -2-三氟甲基苯甲腈（中间体 2) (34 mg, 0.15 mmoL) 和 2-[2- (环丙基甲基) -6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸甲酯（21 mg, 0.066 mmoL)加入到无水 DMF (0.40 mL)中，于微波 50°C反应 6小时。减压蒸去溶剂，残留物用制备薄层层析分离，展开剂为二氯甲烷:丙酮 =20:1，得白色固体 17 mg，产率为 50%。 1H NMR (CDC1₃, 300 MHz) δ (ppm) 8.00 (m， 2H), 7.87 (dd， J=8.4, 1.5 Hz, 1H), 7.79 (d， J= 6.9 Hz, 1H), 7.42 (d， J= 8.7 Hz, 1H), 4.59 (s， 2H), 3.50 (m， 2H), 1.69 (s， 3H), 1.53 (s， 3H), 1.07 (m， 1H), 0.62 (m， 2H), 0.30(m, 1H). 4-Isothiocyanato-2-trifluoromethylbenzonitrile (Intermediate 2) (34 mg, 0.15 mmoL) and 2-[2-(cyclopropylmethyl)-6-fluoro-3-iso Dihydroindole-5-amino]methyl 2-methylpropionate (21 mg, 0.066 mmoL) was added to anhydrous DMF (0.40 mL), the reaction was carried out in a microwave at 50 ° C for 6 hours. The solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjj 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.00 (m, 2H), 7.87 (dd, J=8.4, 1.5 Hz, 1H), 7.79 (d, J = 6.9 Hz, 1H), 7.42 (d, J= 8.7 Hz, 1H), 4.59 (s, 2H), 3.50 (m, 2H), 1.69 (s, 3H), 1.53 (s, 3H), 1.07 (m, 1H), 0.62 (m, 2H), 0.30 (m, 1H).

实施例 60 4-[3-(6-氟 -2-乙酰氨基 -3-氧代异二氢吲哚 -5-基) -4，4-二甲基 -2-硫代 -5-氧代咪唑烷 -1基] -2- (三氟甲 Example 60 4-[3-(6-Fluoro-2-acetylamino-3-oxoisoindoline-5-yl)-4,4-dimethyl-2-thio-5-oxo Imidazolidin-1 -yl]-2-(trifluoromethyl)

将化合物 4 (46.0 mg, 0.10 mmoL), 2-溴乙酰胺（68.6 mg， 0.50 mmoL) 和无水碳酸钾（ 137.5 mg， 1.0 mmol) 加入到无水 DMF ( 1.0 mL) 中，于 50°C反应 24小时。减压蒸去溶剂，残留物用制备薄层层析分离，展开剂为 DCM_:MeOH = 20:l，得白色固体 6.0 mg，产率为 18%。 1H NMR (CD₃OD， 400 MHz) δ (ppm) 8.22-8.10 (m， 2H), 8.01 (dd， J = 8.3, 1.3 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.61 (d, J = 9.1 Hz, 1H), 4.66 (s， 2H), 4.40-4.24 (m， 2H), 1.66 (s, 3H), 1.52 (s, 3H). EI -MS 519.10[M]⁺. Add compound 4 (46.0 mg, 0.10 mmoL), 2-bromoacetamide (68.6 mg, 0.50 mmoL) and anhydrous potassium carbonate (137.5 mg, 1.0 mmol) to dry DMF (1.0 mL) at 50 °C Reaction for 24 hours. The solvent was distilled off under reduced pressure, the residue was separated by preparative thin layer chromatography, eluent _DCM: MeOH = _20: l, to give a white solid 6.0 mg, 18% yield. 1H NMR (CD ₃ OD, 400 MHz) δ (ppm) 8.22-8.10 (m, 2H), 8.01 (dd, J = 8.3, 1.3 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.61 (d, J = 9.1 Hz, 1H), 4.66 (s, 2H), 4.40-4.24 (m, 2H), 1.66 (s, 3H), 1.52 (s, 3H). EI -MS 519.10[M] ⁺ .

实施例 61 4-{3-[6-氟 -2-(2-(4-甲基哌嗪 -1-基) -2-氧代乙基) -3-氧代异二氢吲哚 -5- 基] -4,4-二甲基 -2-硫代 -5-氧代咪唑烷 -1基 -2- (三氟甲基)苯甲腈（化合物 16) Example 61 4-{3-[6-Fluoro-2-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-3-oxoisoindoline-5 -yl]-4,4-dimethyl-2-thio-5-oxoimidazolidin-1yl-2-(trifluoromethyl)benzonitrile (Compound 16)

将化合物 4 (30.0 mg, 0.06 mmoL), 碳酸铯（ 105.7 mg, 0.32 mmoL)加入到无水 DMF ( 1.0 mL) 中，然后加入 N-甲基氯乙酰哌嗪（27.7 mg，0.13 mmol), 50°C反应 24小时。减压蒸去溶剂，残留物用制备薄层层析分离，展开剂为 DCM_:MeOH = 10:l，得白色固体 2.33 mg, 收率为 12 NMR (CDC1₃， 300 MHz) δ (ppm) 8.01 (d, J= 8.1 Hz, 2H), 7.88 (d， J = 8.3 Hz, 1H)， 7.82 (d, J = 6.5 Hz, 1H)， 7.43 (d, J = 8.7 Hz, 1H)， 4.71 (dd, J = 28.1, 15.3 Hz, 2H), 4.41 (dd, J= 74.3, 22.4 Hz, 2H), 3.66 (d, J = 18.8 Hz, 4H)， 2.52 (d， J= 18.9 Hz, 4H)， 2.38 (s， 3H), 1.71 (s， 3H), 1.55 (s， 3H). EI-MS 602.17[M]⁺. Compound 4 (30.0 mg, 0.06 mmoL), cesium carbonate (105.7 mg, 0.32 mmoL) was added to dry DMF (1.0 mL) followed by N-methylchloroacetylpiperazine (27.7 mg, 0.13 mmol), 50 The reaction was carried out at ° C for 24 hours. The solvent was distilled off under reduced pressure, the residue was separated by preparative thin layer chromatography, eluent _DCM: MeOH = _10: l, to give a white solid 2.33 mg, yield _{12 NMR (CDC1 3, 300 MHz} ) δ (ppm) 8.01 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 6.5 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 4.71 (dd , J = 28.1, 15.3 Hz, 2H), 4.41 (dd, J= 74.3, 22.4 Hz, 2H), 3.66 (d, J = 18.8 Hz, 4H), 2.52 (d, J = 18.9 Hz, 4H), 2.38 (s, 3H), 1.71 (s, 3H), 1.55 (s, 3H). EI-MS 602.17[M] ⁺ .

实施例 62 4-[3-(6-氟 -2-叔丁氧羰基 -3-氧代异二氢吲哚 -5-基) -4，4-二甲基 -2-硫代 -5-氧代咪唑烷 -1基] -2- (三氟甲基)苯甲腈 Example 62 4-[3-(6-Fluoro-2-tert-butoxycarbonyl-3-oxoisoindoline-5-yl)-4,4-dimethyl-2-thio-5- Oxyimidazolidine-1yl]-2-(trifluoromethyl)benzonitrile

将化合物 4 ( 150.0 mg, 0.32 mmoL), DMAP (7.93 mg, 0.06 mmoL)和 (Boc)₂0 ( 106.2 mg,0.49 mmol)加入到无水 THF (5.0 mL) 中，室温反应 2小时。减压蒸去溶剂，残留物用制备薄层层析分离，展开剂为二氯甲烷:丙酮 = 20:1 , 得白色固体 146.0 mg, 产率为 80.0% 1H NMR (CDC1₃， 400 MHz ) δ (ppm) 7.98 (dd， J =10.0， 5.0 Hz, 2H), 7.91- 7.81 (m， 2H), 7.43 (d, J= 8.5 Hz, 1H), 4.84 (d, J= 2.6 Hz, 2H), 1.68 (s， 3H), 1.59 (s， 9H)， 1.52 (s,3H). 实施例 63 4-[3-(6-氟 -1，2-二甲基 -3-氧代异二氢吲哚 -5-基 4，4-二甲基 -2-硫代 -5-氧代咪唑烷 -1基] -2- (三氟甲基)苯甲腈（化合物 17) 和 4-[3-(6-氟小甲基 -3-氧代异二氢吲哚 -5- 基) -4,4-二甲基 - -硫代 -5-氧代咪唑烷 -1基] -2- (三氟甲基)苯甲腈（化合物 18) Compound 4 (150.0 mg, 0.32 mmol), DMAP (7.93 mg, 0.06 mmoL) and (Boc) ₂ 0 (106.2 mg, 0.49 mmol) were added to dry THF (5.0 mL) and allowed to react at room temperature for 2 hours. The solvent was distilled off under reduced pressure, the residue was separated by preparative thin layer chromatography, eluent, methylene chloride: acetone = 20: 1 to give a white solid 146.0 mg, yield _{80.0% 1H NMR (CDC1 3,} 400 MHz) δ (ppm) 7.98 (dd, J =10.0, 5.0 Hz, 2H), 7.91- 7.81 (m, 2H), 7.43 (d, J = 8.5 Hz, 1H), 4.84 (d, J = 2.6 Hz, 2H), 1.68 (s, 3H), 1.59 (s, 9H), 1.52 (s, 3H). Example 63 4-[3-(6-fluoro-1,2-dimethyl-3-oxoisoindoline哚-5-yl 4,4-dimethyl-2-thio-5-oxoimidazolidine-1yl]-2-(trifluoromethyl)benzonitrile (Compound 17) and 4-[3- (6-fluorosuccinic methyl-3-oxoisoindoline-5-yl)-4,4-dimethyl-thio-5-oxoimidazolidin-1yl]-2-(three Fluoromethyl)benzonitrile (Compound 18)

化合物 17 化合物 18 Compound 17 compound 18

将化合物 4 ( 146.0 mg, 0.26 mmoL), 碳酸铯（169.1 mg, 0.52 mmoL) 加入到无水 DMF (5.0 mL) 中，再加入碘甲烷（ 184.2 mg， 1.30 mmol), 室温反应过夜。加入饱和氯化铵稀释，用乙酸乙酯萃取 3次，合并有机相，加入 DCM (3.0 ml), 三氟醋酸（2.0 ml), 室温反应过夜。减压蒸去溶剂，残留物用制备薄层层析分离，展开剂为二氯甲烷:丙酮 = 化合物 17为白色固体， 4.0 mg, 产率为 3%。 'H NMR CDCl^ 400 MHz) δ (ppm) 7.98 (dd， J = 15.2, 5.0 Hz, 2H), 7.86 (dd， J = 8.3, 1.9 Hz, 1H)， 7.83-7.75 (m， 2H), 3.95 (d, J = 15.8 Hz, 1H), 3.23 (s, 3H), 1.71 (s, 3H), 1.56 (s,6H). EI-MS 490.11[M]+. Compound 4 (146.0 mg, 0.26 mmoL), cesium carbonate (169.1 mg, 0.52 mmoL) was added to dry DMF (5.0 mL), and then MeOH (184.2 mg, 1.30 mmol). The mixture was diluted with EtOAc (3 mL). The solvent was evaporated under reduced pressure and the residue was crystallijjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 'H NMR CDCl^ 400 MHz) δ (ppm) 7.98 (dd, J = 15.2, 5.0 Hz, 2H), 7.86 (dd, J = 8.3, 1.9 Hz, 1H), 7.83-7.75 (m, 2H), 3.95 (d, J = 15.8 Hz, 1H), 3.23 (s, 3H), 1.71 (s, 3H), 1.56 (s, 6H). EI-MS 490.11[M]+.

化合物 18为白色固体， 15.0 mg，产率为 13%。 'H NMR CDgOD, 400 MHz ) δ (ppm) 8.22 -8.11 (m， 2H), 8.02 (dd， J= 8.3, 1.7 Hz, 1H)， 7.82 (d, J= 6.6 Hz, 1H)， 7.62 (d, J= 9.0 1H), 4.80 (m， 1H), 1.67 (d， J= 3.8 Hz, 3H), 1.52 (t， J= 6.2 Hz, 6H). EI-MS 476.09[M]⁺. Compound 18 was a white solid, 15.0 mg, yield 13%. 'H NMR CDgOD, 400 MHz ) δ (ppm) 8.22 -8.11 (m, 2H), 8.02 (dd, J= 8.3, 1.7 Hz, 1H), 7.82 (d, J= 6.6 Hz, 1H), 7.62 (d, J= 9.0 1H), 4.80 (m, 1H) ), 1.67 (d, J = 3.8 Hz, 3H), 1.52 (t, J = 6.2 Hz, 6H). EI-MS 476.09 [M] ⁺ .

实施例 64 l-(6-氟 -3-氧代异二氢吲哚 -5-胺基）环戊基甲腈 Example 64 l-(6-Fluoro-3-oxoisoindoline-5-amino)cyclopentylcarbonitrile

除了用环戊酮代替丙酮外，化合物 1-(6-氟 -3-氧代异二氢吲哚 -5-氨基）环戊腈的制备同 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a)，得白色固体，产率为 26 %。 1H NMR (CDC1₃, 300 MHz) δ (_ppm) 8.00-7.97(m, 2H), 7.89-7.83 (m， 2H), 7.44(d, J=8.1Hz, 1H), 4.49(s， 2H), 3.22(s, 3H), 2.75-2.57(m, 2H), 2.43-2.22(m, 2H),1.69-1.59(m, 2H). MS-ESI: 489.0 [M+H] +.

The preparation of the compound 1-(6-fluoro-3-oxoisoindoline-5-amino)cyclopentanenitrile is the same as 2-methyl-2-(1-oxo-isolation) except that cyclopentanone is used instead of acetone. Indoline-5-ylamino)propanenitrile (Intermediate 9a) gave a white solid (yield: 26%). 1H NMR (CDC1 ₃ , 300 MHz) δ ( _ppm ) 8.00-7.97 (m, 2H), 7.89-7.83 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H), 4.49 (s, 2H), 3.22(s, 3H), 2.75-2.57 (m, 2H), 2.43-2.22 (m, 2H), 1.69-1.59 (m, 2H). MS-ESI: 489.0 [M+H] +.

实施例 65 4-[l-(6-氟 -3-氧代异二氢吲哚 -5-基) -4-氧代 -2-硫代 -1，3-二氮杂 [4.4]壬螺 -3- 基] -²-(三氟甲基)苯甲腈（化合物 19) Example 65 4-[l-(6-Fluoro-3-oxoisoindoline-5-yl)-4-oxo-2-thio-1,3-diazepine [4.4] -3-yl] - ² -(trifluoromethyl)benzonitrile (Compound 19)

除了用中间体 1-(6-氟 -3-氧代异二氢吲哚 -5-胺基）环戊基甲腈替代中间体 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a) 夕卜，化合物 19的制备同化合物 1，白色固体 41 mg，产率为 27%。 1H NMR (CDC1₃， 400 MHz) δ (ppm) 8.00-7.99 (m， 2H), 7.90-7.86 (m， 2H), 7.46 (d， J = 8.8 Hz, 1H), 7.09 (s， 1H), 4.57 (s， 2H), 2.42-2.29 (m， 4H)， 2.04-1.89 (m, 4H). MS-ESI 489 [M+H]+ . In addition to the intermediate 1-(6-fluoro-3-oxoisoindoline-5-amino)cyclopentylcarbonitrile instead of the intermediate 2-methyl-2-( 1-oxoisoindoline Indole-5-ylamino)propanenitrile (Intermediate 9a) Compound 19 was prepared as Compound 1 as a white solid 41 mg, yield 27%. 1H NMR (CDC1 ₃ , 400 MHz) δ (ppm) 8.00-7.99 (m, 2H), 7.90-7.86 (m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.09 (s, 1H), 4.57 (s, 2H), 2.42-2.29 (m, 4H), 2.04-1.89 (m, 4H). MS-ESI 489 [M+H]+ .

实施例 66 2-(6-氟 -3-氧代异二氢吲哚 -5-胺基) -3-甲氧基 -2-甲基丙腈 Example 66 2-(6-Fluoro-3-oxoisoindoline-5-amino)-3-methoxy-2-methylpropanenitrile

除了用 1-甲氧基丙酮代替丙酮外， 2-(6-氟 -3-氧代异二氢吲哚 -5-胺基) -3-甲氧基 -2-甲基丙腈的制备同 2-(6-氟 -3-氧代异二氢吲哚 -5-基胺基 )-2-甲基丙腈（中间体 9d)，白色固体 325 mg,产率为 51%。 1H NMR (CDC1₃, 400 MHz) δ (ppm) 7.57 (d, J= 8.0 Hz, 1H) ,7.51 (brs, 1H)， 7.19 (d， J= 10.0 Hz， 1H)， 4.77 (d， J= 3.6 Hz， 1H)， 4.39 (s，2H)， 3.73 (d, J= 9.2 Hz, 1H), 3.67 (d, J= 9.2 Hz, 1H), 3.53 (s， 3H), 1.73 (s， 3H).

The preparation of 2-(6-fluoro-3-oxoisoindoline-5-amino)-3-methoxy-2-methylpropionitrile is the same except that 1-methoxyacetone is used instead of acetone. 2-(6-Fluoro-3-oxoisoindoline-5-ylamino)-2-methylpropanenitrile (Intermediate 9d), white solid 325 mg, yield 51%. 1H NMR (CDC1 ₃ , 400 MHz) δ (ppm) 7.57 (d, J = 8.0 Hz, 1H), 7.51 (brs, 1H), 7.19 (d, J = 10.0 Hz, 1H), 4.77 (d, J = 3.6 Hz, 1H), 4.39 (s, 2H), 3.73 (d, J = 9.2 Hz, 1H), 3.67 (d, J = 9.2 Hz, 1H), 3.53 (s, 3H), 1.73 (s, 3H).

实施例 67 4-[3-(6-氟 -3-氧代异二氢吲哚 -5-基) -4-甲氧基甲基 -4-甲基 -5-氧代 -2-硫代咪唑烷小基] -2- (三氟甲基）苯甲腈（化合物 20) Example 67 4-[3-(6-Fluoro-3-oxoisoindoline-5-yl)-4-methoxymethyl-4-methyl-5-oxo-2-thio Imidazolidine small group]-2-(trifluoromethyl)benzonitrile (compound 20)

除了用 2-(6-氟 -3-氧代异二氢吲哚 -5-胺基) -3-甲氧基 -2-甲基丙腈代替 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a)之外，化合物 20 的制备同化合物 1，白色固体，产率为 20%。 1H NMR (CDC1₃， 300ΜΗζ) δ (ppm) 8.00-7.82 (m, 4H), 7.45 (d, J= 8.7 Hz, 1H), 7.11 (brs, 1H), 4.55 (s, 2H), 3.76 (d, J= 9.9 Hz, 1H), 3.52 (d, J = 9.9 Hz, 1H), 3.50 (s, 3H), 1.45 (m， 3H). LRMS (ESI) m/z [M+H]⁺ 493.

In addition to 2-(6-fluoro-3-oxoisoindoline-5-amino)-3-methoxy-2-methylpropionitrile instead of 2-methyl-2-(1-oxo) In addition to isoindoline-5-ylamino)propanenitrile (intermediate 9a), compound 20 was prepared in the same manner as compound 1, as a white solid, yield 20%. 1H NMR (CDC1 ₃ , 300ΜΗζ) δ (ppm) 8.00-7.82 (m, 4H), 7.45 (d, J = 8.7 Hz, 1H), 7.11 (brs, 1H), 4.55 (s, 2H), 3.76 (d , J = 9.9 Hz, 1H), 3.52 (d, J = 9.9 Hz, 1H), 3.50 (s, 3H), 1.45 (m, 3H). LRMS (ESI) m/z [M+H] ⁺ 493.

实施例 68 2-氯 -4-[5 6-氟 -3-氧代异二氢吲哚 -5-基) -8-氧代 -6-硫氧代 -5，7- 二氮杂螺 [3.4]-2-辛烷 -7-基] -2- (三氟 Example 68 2-Chloro-4-[5 6-fluoro-3-oxoisoindoline-5-yl)-8-oxo-6-thioxo-5,7-diazaspiro[ 3.4]-2-octane-7-yl]-2-(trifluoro

除了用 4-异硫氰基 -2-氯苯甲腈代替 4-异硫氰基 -2-三氟甲基苯甲腈（中间体 2) 夕卜，化合物 21的制备同化合物 13，白色固体，产率为 29%。 1H NMR ( DMSO- ， 300 MHz,) δ (ppm) 8.83 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.02 (s, 1H), 7.78 (dd， J= 21.5, 9.7 Hz, 2H), 4.50 (s, 2H), 2.63 (m， 2H), 2.30 (m， 2H), 2.00 -1.59 (m， 2H). MS-EI 440.05[M]+. In addition to 4-isothiocyanato-2-chlorobenzonitrile instead of 4-isothiocyanato-2-trifluoromethylbenzonitrile (Intermediate 2), compound 21 was prepared as compound 13, white solid , the yield was 29%. 1H NMR ( DMSO- , 300 MHz,) δ (ppm) 8.83 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.02 (s, 1H), 7.78 (dd, J = 21.5, 9.7 Hz , 2H), 4.50 (s, 2H), 2.63 (m, 2H), 2.30 (m, 2H), 2.00 -1.59 (m, 2H). MS-EI 440.05[M]+.

实施例 69 4-[5-(6-氟 -3-氧代异二氢吲哚 -5-基 8-氧代 -6-硫代 -5，7-二氮杂螺 [3，4]辛烷—7—基 ]-2—溴苯甲腈（化合物 22) Example 69 4-[5-(6-Fluoro-3-oxoisoindoline-5-yl-8-oxo-6-thio-5,7-diazaspiro[3,4]octyl Alkan-7-yl]-2-bromobenzonitrile (Compound 22)

除了用 4-异硫氰基 -2-溴苯甲腈代替 4-异硫氰基 -2-三氟甲基苯甲腈（中间体 2) 夕卜，化合物 22的制备同化合物 13，白色固体，产率为 33%。 1H NMR (DMSO- ， 300 MHz) δ (ppm) 8.83 (s， 1H), 8.15 (d， J= 8.4 Hz, 2H), 7.84-7.74 (m， 2H), 4.49 (s， 2H), 2.63 (m， 2H)_: 2.33 (m， 2H), 1.97 -1.59 (m， 2H). MS-EI 485.0 [M+H]⁺.

In addition to 4-isothiocyanato-2-bromobenzonitrile instead of 4-isothiocyanato-2-trifluoromethylbenzonitrile (Intermediate 2), compound 22 was prepared as compound 13, white solid , the yield was 33%. 1H NMR (DMSO- , 300 MHz) δ (ppm) 8.83 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.84-7.74 (m, 2H), 4.49 (s, 2H), 2.63 ( m, 2H) _: 2.33 (m, 2H), 1.97 -1.59 (m, 2H). MS-EI 485.0 [M+H] ⁺ .

实施例 70 4-[5-(6-氟 -3-氧代异二氢吲哚 -5-基) -8-氧代 -6-硫代 -5，7-二氮杂螺 [3，4]辛烷 —7—基 ]-2—甲基苯甲腈（化合物 23 ) Example 70 4-[5-(6-Fluoro-3-oxoisoindoline-5-yl)-8-oxo-6-thio-5,7-diazaspiro[3,4 Octane-7-yl-2-methylbenzonitrile (Compound 23)

除了用 4-异硫氰基 -2-甲基苯甲腈代替 4-异硫氰基 -2-三氟甲基苯甲腈（中间体 2)夕卜，化合物 23的制备同化合物 13，黄色固体，产率为 38%。 1H NMR (CDC1₃， 300 MHz, ) δ (ppm) 7.89 (d， J= 6.7 Hz, 1H), 7.75 (d， J= 8.2 Hz, 1H), 7.43 (dd， J = 14.1， 8.2 Hz, 3H), 6.33 (s_: 1H), 4.57 (s， 2H), 2.67 (m， 2H), 2.43 - 2.16 (m， 2H), 1.67- 1.51 (m， 2H). MS-EI 420.11[M]⁺. 实施例 71 4-[5-(6-氟 -3-氧代异二氢吲哚 -5-基) -8-氧代 -6-硫代 -5，7-二氮杂螺 [3，4]辛烷 —7—基]—3-甲氧基苯甲腈（化合物 24)

In addition to 4-isothiocyanato-2-methylbenzonitrile instead of 4-isothiocyanato-2-trifluoromethylbenzonitrile (Intermediate 2), the preparation of compound 23 is the same as compound 13, yellow Solid, yield 38%. 1H NMR (CDC1 ₃ , 300 MHz, ) δ (ppm) 7.89 (d, J = 6.7 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.43 (dd, J = 14.1, 8.2 Hz, 3H ), 6.33 (s _: 1H), 4.57 (s, 2H), 2.67 (m, 2H), 2.43 - 2.16 (m, 2H), 1.67- 1.51 (m, 2H). MS-EI 420.11 [M] ⁺ . Example 71 4-[5-(6-Fluoro-3-oxoisoindoline-5-yl)-8-oxo-6-thio-5,7-diazaspiro[3,4 Octane-7-yl]-3-methoxybenzonitrile (Compound 24)

除了用 4-异硫氰基 -3-甲氧基苯甲腈代替 4-异硫氰基 -2-三氟甲基苯甲腈（中间体 2) 夕卜，化合物 24的制备同化合物 13，黄色固体，收率 42%。 1H NMR CCDC1₃， 300 MHz) δ (ppm) 7.89 (d, J= 6.7 Hz, 1H), 7.70 (d, J= 8.1 Hz, 1H), 7.46 (d, J= 8.5 Hz, 1H), 7.17- 7.07 (m， 2H), 6.34 (s， 1H), 4.57 (s， 2H), 3.98 (s， 3H), 2.80-2.57 (m， 2H), 2.44- 2.19 (m， 2H), 1.66 (m， 2H).MS-EI 436.10 [M]⁺. The preparation of compound 24 is the same as compound 13, except that 4-isothiocyanato-3-methoxybenzonitrile is substituted for 4-isothiocyanato-2-trifluoromethylbenzonitrile (Intermediate 2). Yellow solid, yield 42%. 1H NMR CCDC1 ₃ , 300 MHz) δ (ppm) 7.89 (d, J = 6.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.17- 7.07 (m, 2H), 6.34 (s, 1H), 4.57 (s, 2H), 3.98 (s, 3H), 2.80-2.57 (m, 2H), 2.44- 2.19 (m, 2H), 1.66 (m, 2H).MS-EI 436.10 [M] ⁺ .

实施例 72 6-溴 -2- (环丁基甲基-5-氟异二氢吲哚 -1-酮 Example 72 6-Bromo-2-(cyclobutylmethyl-5-fluoroisoindoline-1-one

除了用溴甲基环丁烷代替溴甲基环丙烷外， 6-溴 -2- (环丁基甲基 )-5-5-氟异二氢吲哚 -1- 酮的制备同 6-溴 -2- (环丙基甲基 )-5-5-氟异二氢吲哚 -1-酮，黄色固体，产率为 SOo/ H NMR (CDC1₃, 300 MHz) δ (ppm) 8.02 (d, J= 6.3 Hz, 1H), 7.19 (d， J= 7.8Hz, 1H),4.29 (s, 2H), 3.62 (d, J= 7.8 Hz, 2H), 2.70-2.60(m, 1H), 2.13-1.80(m, 6H).

In addition to bromomethylcyclobutane instead of bromomethylcyclopropane, 6-bromo-2-(cyclobutylmethyl)-5-5-fluoroisoindoline-1- The ketone was prepared as 6-bromo-2-(cyclopropylmethyl)-5-5-fluoroisoindol-1-one as a yellow solid in a yield of SOo / H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.02 (d, J = 6.3 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 4.29 (s, 2H), 3.62 (d, J = 7.8 Hz, 2H), 2.70-2.60 (m, 1H), 2.13-1.80 (m, 6H).

实施例 73 2-[2- (环丁基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸 Example 73 2-[2-(Cyclobutylmethyl)-6-fluoro-3-isoindoline-5-amino]-2-methylpropionic acid

除了用 6-溴 -2- (环丁基甲基 )-5-氟异二氢吲哚 -1-酮代替 6-溴 -2- (环丙基甲基 )-5-氟异二氢吲哚 -1-酮外， 2-[2- (环丁基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸的制备同 2-[2- (环丙基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸，黄色油状物，产率为 42%。直接用于下步反应。 In addition to 6-bromo-2-(cyclobutylmethyl)-5-fluoroisoindol-1-one instead of 6-bromo-2-(cyclopropylmethyl)-5-fluoroisoindoline- 1-[2-(cyclobutylmethyl)-6-fluoro-3-isoindoline-5-amino]-2-methylpropionic acid, 2-[2-(cyclo) Propylmethyl)-6-fluoro-3-isoindoline-5-amino]-2-methylpropionic acid, yellow oil, yield 42%. Used directly in the next step.

实施例 74 2-[2- (环丁基甲基-6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸甲酯 Example 74 2-[2-(Cyclobutylmethyl-6-fluoro-3-isoindoline-5-amino]-2-methylpropanoate

除了用 2-[2- (环丁基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸代替 2-[2- (环丙基甲基) -6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸外， 2-[2- (环丁基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸甲酯的制备同 2-[2- (环丙基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸甲酯，黄色油状物，产率为 38%o 1H NMR (CDCI3, 300 MHz) δ (ppm) 7.04 (d, J= 10.8 Hz, 1H)， 6.95 (d, J = 7.8 Hz, 1H), 4.48 (brs, 1H), 4.18 (s， 2H), 3.75 (s， 3H), 3.58 (d, J = 7.8 Hz, 2H), 2.66-2.61 (m, 1H), 2.66-1.67 (m, 6H), 1.62 (s, 6H).

In addition to 2-[2-(cyclobutylmethyl)-6-fluoro-3-isoindoline-5-amino]-2-methylpropionic acid instead of 2-[2-(cyclopropylmethyl) -6-Fluoro-3-isoindoline-5-amino]-2-methylpropionic acid, 2-[2-(cyclobutylmethyl)-6-fluoro-3-isoindoline- Preparation of methyl 5-amino]-2-methylpropanoate with 2-[2-(cyclopropylmethyl)-6-fluoro-3-isoindoline-5-amino]-2- Methyl methacrylate, yellow oil, yield 38% o 1H NMR (CDCI3, 300 MHz) δ (ppm) 7.04 (d, J = 10.8 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 4.48 (brs, 1H), 4.18 (s, 2H), 3.75 (s, 3H), 3.58 (d, J = 7.8 Hz, 2H), 2.66-2.61 (m, 1H), 2.66-1.67 (m , 6H), 1.62 (s, 6H).

实施例 75 4-[[3-[2- (环丁基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -4，4-二甲基 -5-氧代 -2 硫代咪唑烷 -1-基]] -2- (三氟甲基）苯甲腈（化合物 25 ) Example 75 4-[[3-[2-(Cyclobutylmethyl)-6-fluoro-3-isoindoline-5-amino]-4,4-dimethyl-5-oxo-2 Thiimidazolidine-1-yl]]-2-(trifluoromethyl)benzonitrile (Compound 25)

除了用 2-[2- (环丁基甲基 )-6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸甲酯代替 2-[2- (环丙基甲基) -6-氟 -3-异二氢吲哚 -5-胺基] -2-甲基丙酸甲酯外，化合物 25的制备同化合物 14，白色固体，产率为 54%。 NMR (丙酮 -^， 300 MHz) δ (ppm) 8.31-8.26 (m, 2H), 8.15-8.04 (m， 1H), 7.75 (d, J = 6.6 Hz, 1H), 7.62 (d, J = 9.3 Hz, 1H), 4.58 (s， 2H), 3.63 (d, J = 7.5 Hz, 2H), 2.82-2.75 (m， 1H), 2.12-2.04 (m， 6H)， 1.85 (s, 3H), 1.75 (s, 3H). MS-ESI 531.0 [M+H]+. 实施例 76 4-[3-(6-氟 -3-氧代 -2-苯基异二氢吲哚 -5-基) -4，4-二甲基 -5-氧代 -2-硫代咪唑烷小基 ]-2— (三氟甲基)苯甲腈（化合物 26)

In addition to 2-[2-(cyclobutylmethyl)-6-fluoro-3-isoindoline-5-amino]-2-methylpropanoic acid methyl ester instead of 2-[2-(cyclopropyl-methyl) Except for methyl-6-fluoro-3-isoindoline-5-amino]-2-methylpropanoate, compound 25 was prepared as the compound 14 as a white solid, yield 54%. NMR (Acetone-^, 300 MHz) δ (ppm) 8.31-8.26 (m, 2H), 8.15-8.04 (m, 1H), 7.75 (d, J = 6.6 Hz, 1H), 7.62 (d, J = 9.3 Hz, 1H), 4.58 (s, 2H), 3.63 (d, J = 7.5 Hz, 2H), 2.82-2.75 (m, 1H), 2.12-2.04 (m, 6H), 1.85 (s, 3H), 1.75 (s, 3H). MS-ESI 531.0 [M+H] +. Example 76 4-[3-(6-fluoro-3-oxo-2-phenylisoindoline-5-yl) 4,4-Dimethyl-5-oxo-2-thioimidazolidine small group]-2-(trifluoromethyl)benzonitrile (Compound 26)

将化合物 4 (50.0 mg， 0.108 mmoL), 碘苯（14 0.13 mmoL), Cul (2.1 mg， 0.0108 moL), K3PO4 (41.0 mg， 0.216 mmoL)和 Ν,Ν'-二甲基乙二胺（3.0 μΐ, 0.216 mmoL)加到无水甲苯（l.O mL)中，在氩气保护下于油浴 120°C反应过夜。加入水，用乙酸乙酯萃取。有机相减压浓縮，残留物用快速柱层析分离，洗脱剂为石油醚:乙酸乙酯 =2:1，得白色固体 24.0mg，产率为 42% 1H NMR (丙酮 - ， 300 MHz) δ (ppm) 8.32-8.28 (m， 2H), 8.14 (dd， J = 6.0， 1.5Hz， 1H)， 7.98 (dd， J= 6.6， 0.9Hz,2H), 7.88 (d, J= 5.1Hz, 1H)， 7.75 (d, J= 6.9Hz， 1H)， 7.48-7.44 (m， 2H), 7.23-7.19 (m， 1H)， 5.15 (d, J = 4.8Hz， 2H), 1.78 (s, 3H), 1.61 (s, 3H). MS-ESI 539.0 [M+H]⁺. Compound 4 (50.0 mg, 0.108 mmoL), iodobenzene (14 0.13 mmoL), Cul (2.1 mg, 0.0108 moL), K3PO4 (41.0 mg, 0.216 mmoL) and hydrazine, Ν'-dimethylethylenediamine (3.0 Μΐ, 0.216 mmoL) was added to anhydrous toluene (10 mL) and allowed to react overnight at 120 ° C in an oil bath under argon atmosphere. Water was added and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. EtOAc EtOAc (EtOAc) δ (ppm) 8.32-8.28 (m, 2H), 8.14 (dd, J = 6.0, 1.5Hz, 1H), 7.98 (dd, J= 6.6, 0.9Hz, 2H), 7.88 (d, J= 5.1Hz , 1H), 7.75 (d, J= 6.9Hz, 1H), 7.48-7.44 (m, 2H), 7.23-7.19 (m, 1H), 5.15 (d, J = 4.8Hz, 2H), 1.78 (s, 3H), 1.61 (s, 3H). MS-ESI 539.0 [M+H] ⁺ .

实施例 77 4-[3-(2-苄基 -6-氟 -3-氧代异二氢吲哚 -5-基) -4，4-二甲基 -2-硫代 -5-氧代咪唑烷 -1基] -2-三氟甲基苯（化合物 27) Example 77 4-[3-(2-Benzyl-6-fluoro-3-oxoisoindoline-5-yl)-4,4-dimethyl-2-thio-5-oxo Imidazolidine-1yl]-2-trifluoromethylbenzene (Compound 27)

将化合物 4 (46.2 mg， 0.1 mmoL), 溴化苄（17.1 mg,0.1 mmoL)和碳酸铯加入到无水二甲亚砜（5.0 mL) 中，在氩气保护下于油浴 50°C反应 6小时。加入乙酸乙酯，水洗除去二甲亚砜。有机相浓縮，残留物用快速柱层析分离，洗脱剂为为石油醚:乙酸乙酯 =2:1，得白色固体 3.0 mg, 产率为 5.5%。 1H NMR (丙酮- ，300 MHz) 3 (ppm) 8.31-8.26 (m，2H)， 8.11 (d, J= 9.1Hz, 1H), 7.80 (d, J= 6.5Hz 1H), 7.65 (d, J=3.2 Hz, 1H), 7.38 (m， 5H)， 4.78 (d， J= 14.2 Hz, 2H), 4.50 (d, J= 3.2 Hz ,2H), 1.75 (s， 3H), 1.58 (s, 1H). MS-ESI 551.0[M-H]". 实施例 78 4-(6-氟 -3-氧代异氢 -2H-吡喃 -4-甲腈 Compound 4 (46.2 mg, 0.1 mmoL), benzyl bromide (17.1 mg, 0.1 mmoL) and cesium carbonate were added to anhydrous dimethyl sulfoxide (5.0 mL) and reacted in an oil bath at 50 ° C under argon atmosphere. 6 hours. Ethyl acetate was added and washed with water to remove dimethyl sulfoxide. The organic phase was concentrated and the residue was purifiedjjjjjjjjjj 1H NMR (Acetone-, 300 MHz) 3 (ppm) 8.31-8.26 (m, 2H), 8.11 (d, J = 9.1 Hz, 1H), 7.80 (d, J = 6.5 Hz 1H), 7.65 (d, J =3.2 Hz, 1H), 7.38 (m, 5H), 4.78 (d, J= 14.2 Hz, 2H), 4.50 (d, J= 3.2 Hz , 2H), 1.75 (s, 3H), 1.58 (s, 1H) ). MS-ESI 551.0[MH]". Example 78 4-(6-Fluoro-3-oxoisohydro-2H-pyran-4-carbonitrile

除了用 4-氧代环己酮代替丙酮外， 4-(6-氟 -3-氧代异二氢吲哚 -5-基胺基)四氢 -2H-吡喃 -4-甲腈的制备同 2-(6-氟 -3-氧代异二氢吲哚 -5-基胺基 )-2-甲基丙腈（中间体 9d)，白色固体，产率为 91.0%。直接用于下步反应。 Preparation of 4-(6-fluoro-3-oxoisoindoline-5-ylamino)tetrahydro-2H-pyran-4-carbonitrile except 4-oxocyclohexanone instead of acetone With 2-(6-fluoro-3-oxoisoindoline-5-ylamino)-2-methylpropanenitrile (Intermediate 9d) as a white solid, yield 91.0%. Used directly in the next step of the reaction.

实施例 79 4-[1-(6-氟 -3-氧代异二氢吲哚 -5-基) -4-氧代 -2-硫代 -1,3-二氮螺 [4,5]葵烷 -3- 基] -2-三氟甲基苯甲腈（化合物 28) Example 79 4-[1-(6-Fluoro-3-oxoisoindoline-5-yl)-4-oxo-2-thio-1,3-diazaspiro[4,5] Alkyl-3-yl]-2-trifluoromethylbenzonitrile (Compound 28)

除了用中间体 4-(6-氟 -3-氧代异二氢吲哚 -5-基胺基)四氢 -2H-吡喃 -4-甲腈替代 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a) 夕卜，化合物 28的制备同化合物 1，黄色固体，产率为 60%。 1H NMR (CD₃OD， 300 MHz) δ (ppm) 8.18 (m， 2H), 8.04 (d, J= 6.2 Hz, 2H), 7.81 (d, J = 6.6 Hz, 1H)， 7.62 (d, J = 9.0 Hz, 1H)， 4.58 (s， 2H), 4.12 (q， 2H), 3.86 (m， 2H), 2.33 (m， 2H), 2.15 (m， 1H), 1.88 (m， 1H). MS-EI 504.0[M]⁺.

In place of the intermediate 4-(6-fluoro-3-oxoisoindoline-5-ylamino)tetrahydro-2H-pyran-4-carbonitrile instead of 2-methyl-2-( 1- Oxoisoindoline-5-ylamino)propanenitrile (Intermediate 9a) Compound 28 was prepared as Compound 1, a yellow solid, yield 60%. 1H NMR (CD ₃ OD, 300 MHz) δ (ppm) 8.18 (m, 2H), 8.04 (d, J = 6.2 Hz, 2H), 7.81 (d, J = 6.6 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 4.58 (s, 2H), 4.12 (q, 2H), 3.86 (m, 2H), 2.33 (m, 2H), 2.15 (m, 1H), 1.88 (m, 1H). MS -EI 504.0[M] ⁺ .

实施例 80 4-氯 -2-(6-氟 -3-氧代异二氢吲哚 -5-基胺基 )-2-甲基丁腈 Example 80 4-Chloro-2-(6-fluoro-3-oxoisoindoline-5-ylamino)-2-methylbutyronitrile

除了用 4-氯 -2-丁酮酮代替丙酮外， 4-氯 -2-(6-氟 -3-氧代异二氢吲哚 -5-基胺基 )-2-甲基丁腈的制备同 2-(6-氟 -3-氧代异二氢吲哚 -5-基胺基 )-2-甲基丙腈（中间体 9d)，产率为 76%。直接用于下步反应。

4-chloro-2-(6-fluoro-3-oxoisoindoline-5-ylamino)-2-methylbutyronitrile except 4-chloro-2-butanone The same as 2-(6-fluoro-3-oxoisoindoline-5-ylamino)-2-methylpropanenitrile (Intermediate 9d) was obtained in a yield of 76%. Used directly in the next step of the reaction.

实施例 81 4-[4-(2-氯甲基 H6-氟 -2-乙酰氨基 -3-氧代异二氢吲哚 -5-基) -4-甲基 -2- 硫代 -5-氧代咪唑烷 -1-基] -2-三氟甲基苯甲腈（化合物 29)

除了用中间体 4-氯 -2-(6-氟 -3-氧代异二氢吲哚 -5-基胺基 )-2-甲基丁腈代替中间体 2- 甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a)夕卜，化合物 29的制备同化合物 1，浅黄色固体，收率 19%。 1H NMR (丙酮 - ， 300 MHz) δ (ppm) 8.40-8.33 (m， 2H), 8.25-8.22 (d， J= 8.9Hz， 1H), 7.88 (s，lH)， 7.5 (brs, 1H), 7.38 (s， 1H), 4.67 (t， J= 7.8 Hz, 2H), 4.46 (s， 2H)_: 3.18 (t, J= 6.9 Hz, 2H),2.15 (s, 3H). MS-EI 510.0[M]+. Example 81 4-[4-(2-ChloromethylH6-fluoro-2-acetylamino-3-oxoisoindoline-5-yl)-4-methyl-2-thio-5- Oxyimidazolidine-1-yl]-2-trifluoromethylbenzonitrile (Compound 29)

In addition to the intermediate 4-chloro-2-(6-fluoro-3-oxoisoindoline-5-ylamino)-2-methylbutyronitrile instead of the intermediate 2-methyl-2- (1 -Oxoisoindoline-5-ylamino)propanenitrile (Intermediate 9a). Compound 29 was obtained as Compound 1 as a pale yellow solid, yield 19%. 1H NMR (Acetone-, 300 MHz) δ (ppm) 8.40-8.33 (m, 2H), 8.25-8.22 (d, J = 8.9 Hz, 1H), 7.88 (s, lH), 7.5 (brs, 1H), 7.38 (s, 1H), 4.67 (t, J = 7.8 Hz, 2H), 4.46 (s, 2H) _: 3.18 (t, J= 6.9 Hz, 2H), 2.15 (s, 3H). MS-EI 510.0[ M]+.

实施例 82 2-甲基 -2-(6-甲 -5-氧代 -6，7-二氢 -5H-吡咯 [3，4-b]并吡啶 -3-基胺基)丙腈

Example 82 2-Methyl-2-(6-methyl-5-oxo-6,7-dihydro-5H-pyrrole[3,4-b]pyridin-3-ylamino)propanenitrile

除了用 3-胺基 -6-甲基 -6,7-二氢 -5H-吡咯 [3，4-b]并吡啶 -5-酮替代中间体 5-氨基 -1-异二氢吲哚酮（；中间体 8a)外，中间体 2-甲基 -2-C6-甲基 -5-氧代 -6,7-二氢 -5H-吡咯 [3，4-b]并吡啶 -3-基胺基)丙腈的制备同 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a)。白色固体，产率为 60%。直接用于下步反应。 In addition to 3-amino-6-methyl-6,7-dihydro-5H-pyrrole[3,4-b]pyridin-5-one in place of the intermediate 5-amino-1-isoindolinone (; intermediate 8a), intermediate 2-methyl-2-C6-methyl-5-oxo-6,7-dihydro-5H-pyrrole[3,4-b]pyridin-3-yl The preparation of the amino)propionitrile is the same as 2-methyl-2-(1-oxoisoindoline-5-ylamino)propanenitrile (Intermediate 9a). White solid with a yield of 60%. Used directly in the next step of the reaction.

实施例 83 4-(3-(6-甲基 -5-氧代 -6,7-二氢 -5H-吡咯 [3，4-b]并吡啶 -3-基) -4,4-二甲基 -5- 氧代 -2-硫代咪唑烷 -1-基) - 2-三氟甲基苯甲腈（化合物 30) Example 83 4-(3-(6-Methyl-5-oxo-6,7-dihydro-5H-pyrrole[3,4-b]pyridin-3-yl)-4,4-dimethyl 5--5-oxo-2-thioimidazol-1-yl)-2-trifluoromethylbenzonitrile (Compound 30)

除了用中间体 2-甲基 -2-(6-甲基 -5-氧代 -6,7-二氢 -5H-吡咯 [3，4-b]并吡啶 3-基胺基)丙腈替代中间体 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a) 夕卜，化合物 30 的制备同化合物 1。浅黄色固体，产率为 7%。 1H NMR (CD₃OD, 300 MHz) δ (ppm) 8.77 (d, J = 5.4 Hz, 1H), 8.20 (m， 3H), 8.05 (d, J = 8.4 Hz, 1H), 4.65 (s， 2H), 3.25 (s， 3H), 1.61 (s， 6H). MS-EI 459.1[M]⁺.

In addition to the intermediate 2-methyl-2-(6-methyl-5-oxo-6,7-dihydro-5H-pyrrole[3,4-b]pyridin-3-ylamino)propionitrile Intermediate 2-Methyl-2-(1-oxoisoindoline-5-ylamino)propanenitrile (Intermediate 9a) Compound 30 was prepared as Compound 1. Light yellow solid, yield 7%. 1H NMR (CD ₃ OD, 300 MHz) δ (ppm) 8.77 (d, J = 5.4 Hz, 1H), 8.20 (m, 3H), 8.05 (d, J = 8.4 Hz, 1H), 4.65 (s, 2H ), 3.25 (s, 3H), 1.61 (s, 6H). MS-EI 459.1 [M] ⁺ .

实施例 84 2-甲基 -4-硝基苯甲酸甲酯 e

Example 84 Methyl 2-methyl-4-nitrobenzoate e

将 2-甲基 -4-硝基苯甲酸（5.0 g， 27.60 mmol)溶于甲醇 C60 mL)中，搅拌下滴加浓硫酸 (1.5 mL)。加料完毕，加热回流 22小时。冷却，浓縮，加入水，用二氯甲烷萃取，合并有机相，饱和食盐水洗涤。有机相用无水硫酸钠干燥，过滤，减压蒸去溶剂，得黄色固体 5.26 g，产率为 98%。直接用于下步反应。 1H NMR (CDC1₃, 300 MHz) ^ (ppm) 8.11-8.05 (m， 3H), 3.95 (s， 3H), 2.69 (s， 3H). 2-Methyl-4-nitrobenzoic acid (5.0 g, 27.60 mmol) was dissolved in methanol (60 mL), and concentrated sulfuric acid (1.5 mL) was added dropwise with stirring. After the addition was completed, the mixture was heated to reflux for 22 hours. After cooling, concentrating, water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated. Used directly in the next step of the reaction. 1H NMR (CDC1 ₃ , 300 MHz) ^ (ppm) 8.11-8.05 (m, 3H), 3.95 (s, 3H), 2.69 (s, 3H).

实施例 85 2- (溴甲基) -4-硝基苯甲酸甲酯 Example 85 Methyl 2-(bromomethyl)-4-nitrobenzoate

将 2-甲基 -4-硝基苯甲酸甲酯（5.0 g， 25.62 mmoL)加入到 CC^PO mL)中，在搅拌下加入 N-溴代丁二酰亚胺（6.84 g， 38.43 mmoL)和偶氮二异丁腈（421 mg， 2.56 mmoL)。在氩气保护下加热至 70°C，搅拌 2小时。冷却，减压蒸去溶剂，残留物用快速柱层析分离，得白色固体 3.49 g，产率为 50%。 1H NMR (CDC1₃, 300 MHz) δ (ppm) 8.34 (d, J= 2.1 Hz, 1H), 8.21 (d, J= 8.7, 2.1 Hz, 1H), 8.12 (d, J= 8.4 Hz, 1H), 4.98 (s， 2H), 4.01 (s， 3H). Methyl 2-methyl-4-nitrobenzoate (5.0 g, 25.62 mmoL) was added to CC^PO mL), and N-bromosuccinimide (6.84 g, 38.43 mmoL) was added with stirring. And azobisisobutyronitrile (421 mg, 2.56 mmoL). Heat to 70 ° C under argon and stir for 2 hours. After cooling, the solvent was evaporated under reduced pressure. 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.34 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 8.7, 2.1 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H) , 4.98 (s, 2H), 4.01 (s, 3H).

实施例 86 2- (腈甲基) -4-硝基苯甲酸甲酯 Example 86 Methyl 2-(nitrilemethyl)-4-nitrobenzoate

将 2- (溴甲基) -4-硝基苯甲酸甲酯（3.4 g， 12.41 mmoL),***（608 mg， 12.41 mmoL) 加到二氧六环 C15 mL) 和水 C20 mL) 混合体系中，加热至 80°C，搅拌 4小时。冷却，加入水，用乙酸乙酯萃取。减压蒸去溶剂，残留物用快速柱层析分离，得白色固体 1.11 g，产率为 41%。 1H NMR (CDC1₃， 300 MHz) δ (ppm) 8.44 (m， 1H)， 8.28-8.27 (m， 2H), 4.31 (s， 2H), 4.01 (s, 3H). Methyl 2-(bromomethyl)-4-nitrobenzoate (3.4 g, 12.41 mmoL), sodium cyanide (608 mg, 12.41 mmoL) to dioxane (15 mL) and water (20 mL) In the system, it was heated to 80 ° C and stirred for 4 hours. After cooling, water was added and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the~~~~~~~ 1H NMR (CDC1 ₃ , 300 MHz) δ (ppm) 8.44 (m, 1H), 8.28-8.27 (m, 2H), 4.31 (s, 2H), 4.01 (s, 3H).

实施例 87 4-胺基 -2- (腈甲基)苯甲酸甲酯

Example 87 4-Amino-2-(nitrilemethyl)benzoic acid methyl ester

2- (腈甲基) -4-硝基苯甲酸甲酯（1.13 g， 5.06 mmoL), 甲醇 (10 mL)，四氢呋喃（10 mL) 和氯化铵 (2.7 g, 50.55 mmoL) 加入到水 (20 mL) 和铁粉 ( 1.42 g, 25.28 mmoL) 的混合体系中，加热至 80°C，搅拌 3小时。冷却，加入水，用乙酸乙酯萃取，合并有机相，饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸去溶剂，得黄色固体 962 mg，产率为 100%。直接用于下步反应。 1H NMR (OMSO-d6, 300 MHz) δ (ppm) 7.72 (d， J= 8.7 Hz, 1H)， 6.66 (d， J = 2.4 Hz, 1H), 6.53 (dd，J= 8.7, 2.1Hz, 1H), 6.19 (s, 2H), 4.16 (s, 2H), 3.74 (s, 3H). 2-(Nitrilemethyl)-4-nitrobenzoic acid methyl ester (1.13 g, 5.06 mmoL), methanol (10 mL), tetrahydrofuran (10 mL) and ammonium chloride (2.7 g, 50.55 mmoL) added to water ( In a mixed system of 20 mL) and iron powder (1.42 g, 25.28 mmoL), heat to 80 ° C and stir for 3 hours. After cooling, water was added, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, Used directly in the next step. 1H NMR (OMSO-d6, 300 MHz) δ (ppm) 7.72 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.53 (dd, J = 8.7, 2.1 Hz, 1H ), 6.19 (s, 2H), 4.16 (s, 2H), 3.74 (s, 3H).

实施例 88 6-胺基 -3，4-二氢异喹啉 -1(2H)-酮 Example 88 6-Amino-3,4-dihydroisoquinoline-1(2H)-one

除了用 4-胺基 -2- (腈甲基)苯甲酸甲酯代替将 3-胺 -2-腈基 -6-氟苯甲酸甲酯外， 6-胺基 -3,4-二氢异喹啉 -1(2H)-酮的制备同 4-胺基 -7-氟异二氢吲哚 -1-酮（中间体 8b)。白色固体，产率为 85% 1H NMR (DMSO- ， 300 MHz) δ (ppm) 7.50 (d， J= 8.4 Hz, 1H), 7.36 (s， 1H)， 6.44 (dd， J = 8.4， 1.6 Hz, 1H)， 6.33 (s, 1H)， 5.69 (s, 2H), 3.29-3.25 (m， 2H), 2.70 (t， J = 6.4 Hz, 2H).

In addition to methyl 4-amino-2-(nitrilemethyl)benzoate instead of methyl 3-amine-2-carbonitrile-6-fluorobenzoate, 6-amino-3,4-dihydroiso The quinoline-1 (2H)-one was prepared as 4-amino-7-fluoroisoindoline-1-one (Intermediate 8b). White solid, yield 85% 1H NMR (DMSO-, 300 MHz) δ (ppm) 7.50 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 6.44 (dd, J = 8.4, 1.6 Hz , 1H), 6.33 (s, 1H), 5.69 (s, 2H), 3.29-3.25 (m, 2H), 2.70 (t, J = 6.4 Hz, 2H).

实施例 89 2-甲基氧代 -1，2，啉 -6-基胺基)丙腈 Example 89 2-Methyloxo-1,2, porphyrin-6-ylamino)propanenitrile

除了用 6-胺基 -3,4-二氢异喹啉 - 2H)-酮代替 5-氨基 -1-异二氢吲哚酮（中间体 8a)外，中间体 2-甲基 -2-(1-氧代 -1，2，3，4-四氢异喹啉 -6-y基胺基)丙腈的制备同 2-甲基 -2- ( 1-氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a)。白色固体 191 mg，产率为 67%。 1H NM (DMSO- ， 300 MHz) δ (ppm) 7.66 (d， J= 8.4 Hz, 1H), 7.56 (s， 1H), 6.74 (dd， J= 8.4， 2.4 Hz, 1H), 6.69 (s， 1H), 6.63 (d, J = 2.0 Hz, 1H), 3.30-3.34 (m， 2H), 2.81 (t， J = 6.4 Hz, 2H), 1.67 (s， 6H). In addition to the 6-amino-3,4-dihydroisoquinoline-2H)-one instead of 5-amino-1-isoindolinone (Intermediate 8a), the intermediate 2-methyl-2- Preparation of (1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yylamino)propanenitrile with 2-methyl-2-(1-oxoisoindoline) 5-Aminoamino)propanenitrile (Intermediate 9a). The white solid was 191 mg in 67% yield. 1H NM (DMSO- , 300 MHz) δ (ppm) 7.66 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 6.74 (dd, J= 8.4, 2.4 Hz, 1H), 6.69 (s, 1H), 6.63 (d, J = 2.0 Hz, 1H), 3.30-3.34 (m, 2H), 2.81 (t, J = 6.4 Hz, 2H), 1.67 (s, 6H).

实施例 90 4-[4，4-二甲基 -5-氧代 -3-(l-氧代 -1，2，3，4-四氢喹啉 -6-基) -2-t硫代咪唑烷 -1- 基) - 2-三氟甲基苯甲腈（化合物 31 ) Example 90 4-[4,4-Dimethyl-5-oxo-3-(l-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-tthio Imidazolidin-1-yl)-2-trifluoromethylbenzonitrile (Compound 31)

除了用中间体 2-甲基 -2-(1-氧代 -1，2，3，4-四氢异喹啉 -6-基胺基)丙腈代替 2-甲基 -2- ( 1- 氧代异二氢吲哚 -5-基胺基）丙腈（中间体 9a)外，化合物 31的制备同化合物 1。白色固体，产率为 30% 1H NMR (丙酮 300 MHz) δ (ppm) 8.29 (d, J = 8.7 Hz, 1H)， 8.22 (m， 1H)， 8.12-8.09 (m, 2H), 7.42-7.40 (m, 2H), 7.18 (brs, 1H), 3.57-3.63 (m, 2H), 3.09 (t, J = 6.6 Hz, 2H), 1.64 (s, 6H). MS-EI m/z 458 M+. In addition to the intermediate 2-methyl-2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ylamino)propionitrile instead of 2-methyl-2-( 1- In addition to the oxoisoindoline-5-ylamino)propanenitrile (intermediate 9a), the compound 31 was prepared in the same manner as the compound 1. White solid, Yield 30% 1H NMR (Acetone 300 MHz) δ (ppm) 8.29 (d, J = 8.7 Hz, 1H), 8.22 (m, 1H), 8.12-8.09 (m, 2H), 7.42-7.40 (m, 2H), 7.18 (brs, 1H), 3.57-3.63 (m, 2H), 3.09 (t, J = 6.6 Hz, 2H), 1.64 (s, 6H). MS-EI m/z 458 M+.

实施例 91 7-硝基 -3，4-二氢 -2H-异喹啉 -1-酮制备（中间体 15 ) Example 91 Preparation of 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (Intermediate 15)

将原料 3，4-二氢 -2H-异喹啉 -1-酮（1.47 g， 9.99 mmoL) 用硫酸（20 ml) 溶解，冰浴冷却条件下滴加发烟硝酸（2 ml)。室温搅拌 45分钟，反应液倒入大量冰水中。水溶液用乙酸乙酯萃取，乙酸乙酯层用水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓縮至干得到黄色油状物，快速柱层析分离（石油醚：乙酸乙酯 =3: 1 )得到中间体 15 ( 800 mg)。LC-MS: C₉H₈N₂0₃ [M+H] ⁺计算值 1⁹³.0⁵，实测值 I⁹².⁹.

The raw material 3,4-dihydro-2H-isoquinolin-1-one (1.47 g, 9.99 mmoL) was dissolved in sulfuric acid (20 ml), and fuming nitric acid (2 ml) was added dropwise under ice-cooling. After stirring at room temperature for 45 minutes, the reaction solution was poured into a large amount of ice water. The aqueous solution was extracted with EtOAc. EtOAc (EtOAc)EtOAc. : 1) Intermediate 15 (800 mg) was obtained. _{_{LC-MS: C 9 H 8}} N 2 0 3 [M + H] + calcd ¹⁹³ ^0.05, Found I ⁹² ^9..

实施例 92 7-氨基 -3,4-二氢 -2H-异喹啉 -1-酮制备（中间体 16) Example 92 Preparation of 7-Amino-3,4-dihydro-2H-isoquinolin-1-one (Intermediate 16)

取中间体 15 (500 mg) 用 30 ml的甲醇溶解，加入 1 g的 Raney-Ni催化剂，氢气条件下搅拌过夜. 反应液过滤，滤饼用 200 ml的甲醇洗涤，合并滤液，浓縮至干得到白色固体。该固体快速柱层析分离（石油醚：乙酸乙酯 =1 : 1 ) 得到中间体 16 (400 mg)。 NMR (OMSO-d6, 400 MHz) δ (ppm) 8.55(d， 1H, J=2Hz), 8.32(dd, 1H, J=2, 8.4Hz)， 7.64(d, 1H, J=8.4Hz), 3.44(m, 2H), 3.07(m, 2H). LC-MS: C₉H₁₀N₂O [M+H] +计算值 163.08，实测值 164.0.

Intermediate 15 (500 mg) was dissolved in 30 ml of methanol, 1 g of Raney-Ni catalyst was added, and stirred under hydrogen overnight. The reaction mixture was filtered, and the filter cake was washed with 200 ml of methanol, and the filtrate was concentrated to dryness. A white solid was obtained. The Solid column chromatography (petroleum ether: ethyl acetate = 1 : 1) gave Intermediate 16 (400 mg). NMR (OMSO-d6, 400 MHz) δ (ppm) 8.55 (d, 1H, J = 2 Hz), 8.32 (dd, 1H, J = 2, 8.4 Hz), 7.64 (d, 1H, J = 8.4 Hz), 3.44 (m, 2H), 3.07 (m, 2H) LC-MS:. C 9 H 10 N 2 O [m + H] + calcd 163.08, found 164.0.

实施例 93 2-甲基 -2-[(l-氧 -3 -二氢 -2H-异喹啉 -7-基)胺基]丙腈制备（中间体 17 )

Example 93 Preparation of 2-methyl-2-[(l-oxo-3-dihydro-2H-isoquinolin-7-yl)amino]propanenitrile (Intermediate 17)

将中间体 16 ( 400 mg)用 10 ml丙酮溶解，加入三甲基硅氰（2 ml)和 2 ml醋酸，封管，加热到 60°C过夜。反应液冷却到室温，减压浓縮后加水，水溶液用乙酸乙酯（100 mlx3 ) 萃取，乙酸乙酯层用水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓縮至干得到黄色油状物，快速柱层析分离（石油醚：乙酸乙酯 =2 : 1 )得到中间体 17 (460 mg)。（DMSO- ， 400 MHz) δ (ppm) 7.40(d, 1H, J=3.2Hz), 7.13(d, 1H, J=8.0Hz)， 6.95(dd， 1H, J=2.8, 8.0Hz), 6.15(s, 1H), 3.33(t, 2H, J=)， 2.77(t, 2H), 1.63(s, 6H). LC-MS: C₁₃H₁₅N₃0 [M+H] +计算值 230.1 , 实测值 230.0. Intermediate 16 (400 mg) was dissolved in 10 ml of acetone, trimethylsilyl cyanide (2 ml) and 2 ml of acetic acid were added, the tube was sealed and heated to 60 ° C overnight. The reaction mixture was cooled to room temperature, EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated. Oil, flash column chromatography (petrole ether: ethyl acetate = 2:1) gave Intermediate 17 (460 mg). (DMSO- , 400 MHz) δ (ppm) 7.40 (d, 1H, J = 3.2 Hz), 7.13 (d, 1H, J = 8.0 Hz), 6.95 (dd, 1H, J = 2.8, 8.0 Hz), 6.15 (s, 1H), 3.33(t, 2H, J=), 2.77(t, 2H), 1.63(s, 6H). LC-MS: C ₁₃ H ₁₅ N ₃ 0 [M+H] + calc. , measured value 230.0.

实施例 94 4-(4，4-二甲基 -5-氧 -3-(l-氧 -1，2，3，4-四氢异喹啉 -7-基) -2-硫代咪唑烷 -1- 基) -2- (三氟甲基)苯甲腈制备（化合物 32 ) Example 94 4-(4,4-Dimethyl-5-oxo-3-(l-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-thioimidazolidine Preparation of -1-yl)-2-(trifluoromethyl)benzonitrile (Compound 32)

中间体 17 (460 mg, 2.006 mmoL)， 4-异硫氰酸基 -2- (三氟甲基）苯甲腈 (480 mg, 2.1 mmoL)和催化量三乙胺溶解于无水四氢呋喃中，封管，加热到 50°C，搅拌过夜。反应液冷却到室温，减压浓縮至干。所得粗品溶解于 10 ml的甲醇中，加入 3 ml的 2N的盐酸溶液，回流 1 小时后冷却至室温，浓縮蒸去甲醇，乙酸乙酯萃取. 有机层用无水硫酸镁干燥，过滤，浓縮至干，所得油状物快速柱层析 (二氯甲烷:丙酮 =10: 1)得到目标化合物。（CD₃OD， 400 MHz) δ (ppm) 8.11-8.21(m, 2H), 8.03(d, 1H, J=8.0Hz), 7.95(d, 1H, J=2.0Hz), 7.53-7.55(m,2 H)， 3.59(t, 2H, J=6.8Hz), 3.11(t, 2H, J=6.4Hz), 1.60(s, 6H). LC-MS: C₂₂H₁₇F₃N₄0₂S [M+H] +计算值 4 59.1 , 实测值 458.8.

Intermediate 17 (460 mg, 2.006 mmoL), 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (480 mg, 2.1 mmoL) and a catalytic amount of triethylamine dissolved in anhydrous tetrahydrofuran. The tube was sealed, heated to 50 ° C and stirred overnight. The reaction solution was cooled to room temperature and concentrated to dryness. The obtained crude product was dissolved in 10 ml of methanol, 3 ml of 2N hydrochloric acid solution was added, and the mixture was refluxed for 1 hour, and then cooled to room temperature. The mixture was reduced to dryness, and the obtained oil was subjected to flash column chromatography (dichloromethane: acetone = 10:1) to give the desired compound. (CD ₃ OD, 400 MHz) δ (ppm) 8.11-8.21(m, 2H), 8.03(d, 1H, J=8.0Hz), 7.95(d, 1H, J=2.0Hz), 7.53-7.55(m , 2 H), 3.59 (t, 2H, J = 6.8 Hz), 3.11 (t, 2H, J = 6.4 Hz), 1.60 (s, 6H). LC-MS: C ₂₂ H ₁₇ F ₃ N ₄ 0 ₂ S [M+H] + calculated value 4 59.1 , found 458.8.

实施例 95 5-氟异吲哚啉 -1-酮制备（中间体 18 )

Example 95 Preparation of 5-Fluoroisoindoline-1-one (Intermediate 18)

2-氰基 -4-氟苯甲酸甲酯（；1.5 _§，8.4 11^101^用30 1^的甲醇溶解，加入 lg的 Raney-Ni 催化剂，氢气条件下搅拌过夜。反应液过滤，滤饼用乙酸乙酯（200 ml) 洗涤，合并滤液，浓縮至干得到粗品。快速柱层析分离（石油醚：乙酸乙酯 =5: 1 )得到中间体 18 ( 1.2 g，白色固体). LC-MS: C₈H₆FNO [M+H] +计算值 152.0，实测值 152.0. Methyl 2-cyano-4-fluorobenzoate (; 1.5 _§ , 8.4 11 ^ 101 ^ was dissolved in 30 1 ^ methanol, added lg of Raney-Ni catalyst, stirred under hydrogen overnight. The reaction solution was filtered, filter cake Wash with ethyl acetate (200 ml), EtOAc (EtOAc)EtOAc. -MS: C ₈ H ₆ FNO [M+H] + calc. 152.0, found 152.0.

实施例 96 5-氟 -2-(2-甲氧 -1-酮制备（中间体 19)

Example 96 Preparation of 5-fluoro-2-(2-methoxy-1-one (Intermediate 19)

将原料中间体 18 (700 mg， 4.6315 mmoL) 用 10 ml DMF溶解，冰浴冷却下分批加入钠氢（65%， 342 mg 所得混合物搅拌 30分钟后加入 1-溴 -2-甲氧基乙烷（800 mg)，所得黑色溶液加热到 60°C，搅拌 5小时。反应液冷却至室温， LC-MS 检测显示反应完全，反应液倒入冰水中。水溶液用乙酸乙酯（100 mlx3 ) 萃取，乙酸乙酯层用水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓縮至干得到黄色油状物，快速柱层析分离（石油醚：乙酸乙酯 =1： 1 )得到中间体 19 (800 mg)。 1H NMR (CDC1₃， 400 MHz) δ (ppm) 7.83-7.80(m,lH), 7.16-7.12(m,lH), 4.52(s,2H), 3.79(t, 2H, J=4.8Hz), 3.64(t, 2H, J=4.8Hz), 3.33(s, 3H). LC-MS: CnH₁₂FN0₂ [M+H] ⁺计算值 210.1，实测值 210.0. The starting material intermediate 18 (700 mg, 4.6315 mmoL) was dissolved in 10 ml of DMF, and sodium hydrogen was added portionwise in an ice bath (65%, 342 mg of the mixture was stirred for 30 minutes, then 1-bromo-2-methoxyB was added. Alkane (800 mg), the obtained black solution was heated to 60 ° C, and stirred for 5 hours. The reaction solution was cooled to room temperature, and the reaction was completed by LC-MS. The reaction mixture was poured into ice water. The aqueous solution was extracted with ethyl acetate (100 ml x 3 ) The ethyl acetate layer was washed with water, washed with brine, dried over anhydrous sodium sulfatesssssssssssssssssssssssssss 19 (800 mg). 1H NMR (CDC1 ₃ , 400 MHz) δ (ppm) 7.83-7.80 (m, lH), 7.16-7.12 (m, lH), 4.52 (s, 2H), 3.79 (t, 2H, J=4.8Hz), 3.64(t, 2H, J=4.8Hz), 3.33(s, 3H). LC-MS: CnH ₁₂ FN0 ₂ [M+H] ⁺ calculated 210.1, found 210.0.

实施例 97 5-氟 -2-(2-甲氧 -6-硝基-异吲哚啉 -1-酮制备（中间体 20)

Example 97 Preparation of 5-fluoro-2-(2-methoxy-6-nitro-isoindolin-1-one (Intermediate 20)

取中间体 19 (800 mg), 用硫酸（20 ml) 溶解，冰浴冷却条件下滴加发烟硝酸（2 ml). 室温搅拌 3小时，反应液倒入大量冰水中。水溶液用乙酸乙酯萃取，乙酸乙酯层用水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓縮至干得到黄色油状物，快速柱层析分离（石油醚：乙酸乙酯 =10: 1 )得到中间体 20 (黄色固体， 800 mg)。 LC-MS: C„H„FN₂0₄ 计算值 [M+H] ⁺ 255.1，实测值 254.9. Intermediate 19 (800 mg) was dissolved in sulfuric acid (20 ml). Toluene nitric acid (2 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 3 hours and poured into a large amount of ice water. The aqueous solution was extracted with EtOAc. EtOAc (EtOAc)EtOAc. : 1) Intermediate 20 (yellow solid, 800 mg) was obtained. LC-MS: C „H „FN ₂ 0 ₄ calc. [M+H] ⁺ 255.1, found 254.9.

实施例 98 6-氨基 -5-氟 -2- -甲氧乙基)异吲哚啉 -1-酮制备（中间体 21 )

Example 98 Preparation of 6-Amino-5-fluoro-2-methoxyethyl)isoindoline-1-one (Intermediate 21)

中间体 20 (800 mg) 用 30 ml的甲醇溶解，加入 lg的 Raney-Ni催化剂，氢气条件下搅拌过夜。反应液过滤，滤饼用乙酸乙酯（200 ml) 洗涤，合并滤液，浓縮至干得到中间体 21 ( 700 mg) o 1H NMR (CD₃OD， 400 MHz) δ (ppm) 7.20-7.17(m, 2H), 4.44(s， 2H), 3.76(t, 2H, J=5.2Hz), 3.64(t, 2H, J=5.2Hz), 3.37(s, 3H). LC-MS: C11H13FN2O2 [M+H] +计算值 225.1，实测值 225.0. Intermediate 20 (800 mg) was dissolved in 30 ml of methanol, and lg of Raney-Ni catalyst was added under hydrogen. Stir overnight. The reaction was filtered, the filter cake with ethyl acetate (200 ml), dried combined filtrate was concentrated to dryness to give Intermediate 21 (700 mg) o 1H NMR (CD 3 OD, 400 MHz) δ (ppm) 7.20-7.17 ( m, 2H), 4.44(s, 2H), 3.76(t, 2H, J=5.2Hz), 3.64(t, 2H, J=5.2Hz), 3.37(s, 3H). LC-MS: C11H13FN2O2 [M +H] + calculated value 225.1, measured value 225.0.

实施例 99 2-[[6-氟 -2-(2-甲氧基 )-3-氧-异吲哚啉 -5-基]氨基] -2-甲基丙腈制备（中间体 Example 99 Preparation of 2-[[6-fluoro-2-(2-methoxy)-3-oxo-isoindoline-5-yl]amino]-2-methylpropanenitrile (Intermediate

22)

twenty two)

取中间体 21 (400 mg) 用 30 ml丙酮溶解，加入三甲基硅氰（1 ml) 和数滴醋酸，封管，加热到 50°C并恒温持续搅拌 48小时。反应液冷却到室温，减压浓縮后加水，水溶液用乙酸乙酯（100 mlx3 )萃取，乙酸乙酯层用水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓縮至干得到黄色油状物，快速柱层析分离（石油醚：乙酸乙酯 =1 : 2)得到中间体 22 (400 mg)。 1H NMR (CD3OD, 400 MHz) δ (ppm) 7.55(d, 1H, J=8.0Hz), 7.30(d,lH, J=6.8Hz), 4.88(s， 3H), 4.50(s, 2H), 3.79(t, 2H, J=4.8Hz)， 3.65(t, 2H, J=4.8Hz)， 1.78(s, 6H). LC-MS: Ci₅H₁₈FN₃0₂ [M+H] ⁺计算值 292.1，实测值 291.9. Intermediate 21 (400 mg) was dissolved in 30 ml of acetone, trimethylsilyl cyanide (1 ml) and a few drops of acetic acid were added, the tube was sealed, heated to 50 ° C and stirred at constant temperature for 48 hours. The reaction mixture was cooled to room temperature. EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The oil was isolated by flash column chromatography (EtOAc:EtOAc:EtOAc) 1H NMR (CD3OD, 400 MHz) δ (ppm) 7.55 (d, 1H, J = 8.0 Hz), 7.30 (d, lH, J = 6.8 Hz), 4.88 (s, 3H), 4.50 (s, 2H), 3.79(t, 2H, J=4.8Hz), 3.65(t, 2H, J=4.8Hz), 1.78(s, 6H). LC-MS: Ci ₅ H ₁₈ FN ₃ 0 ₂ [M+H] ⁺ Calculation The value is 292.1, the measured value is 291.9.

实施例 100 4-(3-(6-氟 -2-(2-甲氧乙基) -3-氧代吲哚啉 -5-基) -4，4-二甲基 -5-氧 -2-硫代咪唑烷小基) -2- (三氟甲基)苯 Example 100 4-(3-(6-Fluoro-2-(2-methoxyethyl)-3-oxoporphyrin-5-yl)-4,4-dimethyl-5-oxo-2 -thioimidazolidine small group)-2-(trifluoromethyl)benzene

4-异硫氰酸酯基 -2- (三氟甲基）苯甲腈（160 mg)和中间体 22 (200 mg)溶解于无水 DMF中，封管，加热到 80°C，搅拌过夜。反应液冷却到室温，所得粗品加入 10 ml的甲醇中，随后加入 3 ml的 2N的盐酸溶液，室温搅拌 3小时，浓縮蒸去甲醇，乙酸乙酯萃取。有机层用无水硫酸镁干燥，过滤，浓縮至干，所得油状物制备薄层层析 (二氯甲烷:丙酮 =10: 1)得到化合物 33 o 1H NMR (DMSO- ^, 400 MHz) δ (ppm) 8.42-8.40(m, 1H)， 8.34(s, 1H)， 8.14-8.11(m, 1H), 7.80-7.77(m, 1H), 4.62(s, 2H), 3.73-3.64(m, 4H)， 3.28(s, 3H), 1.60(s, 3H), 1.51(s,3H). LC-MS: C24H20F4N4O3S [M+H] +计算值 521.1，实测值 520.8. 4-Isothiocyanate-2-(trifluoromethyl)benzonitrile (160 mg) and intermediate 22 (200 mg) were dissolved in anhydrous DMF, sealed, heated to 80 ° C and stirred overnight. . The reaction solution was cooled to room temperature, and the obtained crude product was added to 10 ml of methanol, and then 3 ml of 2N hydrochloric acid solution was added, and the mixture was stirred at room temperature for 3 hr. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated tolulululujjjjjjjjjjjjjjj (ppm) 8.42-8.40 (m, 1H), 8.34 (s, 1H), 8.14-8.11 (m, 1H), 7.80-7.77 (m, 1H), 4.62 (s, 2H), 3.73-3.64 (m, 4H), 3.28(s, 3H), 1.60(s, 3H), 1.51 (s, 3H). LC-MS: C24H20F4N4O3S [M+H] + calc. 521.1, found 520.8.

实施例 101 2-甲基 -3，4-二氢异喹啉 -1(2H)酮制备（中间体 23 )

将原料 3,4-二氢异喹啉 -1(2H)酮（8 g， 54.36 mmoL) 用 DMF ( 100 ml) 溶解，冰浴冷却，分批加入钠氢（60%， 3.0 g)，所得混合物继续搅拌 30分钟后，加入碘甲烷（15 g， 105.68 mmoDo 反应液室温搅拌过夜，倒入冰水中，乙酸乙酯（500 mlx3 ) 萃取，乙酸乙酯层用水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓縮至干得到黄色油状物，快速柱层析分离（石油醚：乙酸乙酯 =1 : 1 )得到中间体 23 (7.5 g，黄色油状物）。1H NMR (CDC1₃， 400 MHz) δ (ppm) 8.10(dd， 1H, J=1.6， 7.6Hz),7.42(t, 1H, J=5.6Hz), 7.35(t,lH, J=7.6Hz), 7.17(dd, 1H, J=0.4， 7.6Hz), 3.58(t, 2H, J=6.8Hz), 3.17(s,3H), 3.02(t, 2H, J=6.8Hz). LC-MS: CioHnNO 计算值 [M+H] + 162.1，实测值 162.0. Example 101 Preparation of 2-methyl-3,4-dihydroisoquinolin-1(2H)one (Intermediate 23)

The raw material 3,4-dihydroisoquinolin-1(2H)one (8 g, 54.36 mmoL) was dissolved in DMF (100 ml), cooled in an ice bath, and sodium hydrogen (60%, 3.0 g) was added in portions. After the mixture was stirred for 30 minutes, iodomethane (15 g, 105.68 mmol) was stirred at room temperature overnight, poured into ice water, ethyl acetate (500 ml×3), ethyl acetate layer washed with water, brine over sodium sulfate, filtered and concentrated to dryness to give a yellow oil which was flash column chromatographed (petroleum ether: ethyl acetate = 1: 1) to give intermediate 23 (7.5 g, yellow oil) .1H NMR (CDC1 ₃ , 400 MHz) δ (ppm) 8.10 (dd, 1H, J=1.6, 7.6 Hz), 7.42 (t, 1H, J = 5.6 Hz), 7.35 (t, lH, J = 7.6 Hz), 7.17 (dd, 1H, J=0.4, 7.6Hz), 3.58(t, 2H, J=6.8Hz), 3.17(s,3H), 3.02(t, 2H, J=6.8Hz). LC-MS: CioHnNO Calculated value [M +H] + 162.1, measured 162.0.

实施例 102 2-甲基 -7-硝基 -3，4-二氢异喹啉 -1(2H)酮制备（中间体 24) Example 102 Preparation of 2-methyl-7-nitro-3,4-dihydroisoquinoline-1(2H)one (Intermediate 24)

将中间体 23 (7.5 g) 用硫酸（100 ml) 溶解，冰浴冷却条件下滴加发烟硝酸（20 ml). 室温搅拌过夜，反应液倒入大量冰水中.。水溶液用乙酸乙酯萃取，乙酸乙酯层用水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓縮至干得到黄色固体，石油醚：乙酸乙酯 =10: 1 洗涤，过滤得到中间体 24黄色固体， 8.5 g o 1H NMR (CDC1₃， 400 MHz) δ (ppm) 8.93(dd, 1H， J=2.4Hz), 8.28(dd, 1H， J=2.4, 8.0Hz), 7.39(d, 1H， J=8.4Hz), 3.66(t, 2H, J=6.8Hz), 3.22(s, 3H), 3.15(t, 2H, J=6.4Hz).

Intermediate 23 (7.5 g) was dissolved in sulfuric acid (100 ml). Toluene nitric acid (20 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature overnight and poured into a large amount of ice water. The aqueous solution was extracted with EtOAc. EtOAc (EtOAc)EtOAc. Bulk 24 yellow solid, 8.5 ° 1H NMR (CDC1 ₃ , 400 MHz) δ (ppm) 8.93 (dd, 1H, J = 2.4 Hz), 8.28 (dd, 1H, J = 2.4, 8.0 Hz), 7.39 (d, 1H, J=8.4Hz), 3.66(t, 2H, J=6.8Hz), 3.22(s, 3H), 3.15(t, 2H, J=6.4Hz).

实施例 103 7-氨基 -2-甲基 -3，4-二氢异喹啉 -1C2H)酮制备（中间体 25 ) Example 103 Preparation of 7-Amino-2-methyl-3,4-dihydroisoquinoline-1C2H)one (Intermediate 25)

将中间体 24 ( 8.5 g)用 250 ml的甲醇溶解，加入 1 g的 Raney-Ni催化剂，氢气条件下搅拌过夜. 反应液过滤，滤饼用甲醇（200 ml)洗涤，合并滤液，浓縮至干得到中间体 25。 1H NMR (CD₃OD， 400 MHz) δ (ppm) 7.30(dd, 1H, J=2.4Hz), 7.00(d, 1H, J=8.0Hz)， 6.84(dd， 1H, J=2.4, 8.0Hz), 3.57(t, 2H, J=6.8Hz),3.13(s, 3H), 2.89(t, 2H, J=6.8Hz). 实施例 104 2-甲基甲基 -1-氧代 -1，2，3，4-四氢异喹啉 -7-氨基)丙腈制备（中间体

The intermediate 24 (8.5 g) was dissolved in 250 ml of methanol, 1 g of Raney-Ni catalyst was added, and the mixture was stirred under hydrogen overnight. The reaction mixture was filtered, and the filter cake was washed with methanol (200 ml). Dry to give intermediate 25. 1H NMR (CD ₃ OD, 400 MHz) δ (ppm) 7.30 (dd, 1H, J = 2.4 Hz), 7.00 (d, 1H, J = 8.0 Hz), 6.84 (dd, 1H, J = 2.4, 8.0 Hz ), 3.57(t, 2H, J=6.8Hz), 3.13(s, 3H), 2.89(t, 2H, J=6.8Hz). Example 104 Preparation of 2-methylmethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-amino)propanenitrile (Intermediate

将中间体 25 ( 3.3 g)用 10 ml丙酮溶解，加入三甲基硅氰（5 ml)和数滴醋酸，封管，加热到 90°C并恒温持续搅拌 48小时。反应液冷却到室温，减压浓縮后加水，水溶液用乙酸乙酯（100 mlx3 )萃取，乙酸乙酯层用水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓縮至干得到黄色油状物，快速柱层析分离（二氯甲烷：甲醇 =5 : 1 ) 得到中间体 26 (3.0 g)。 1H NMR (CDC1₃, 400 MHz) δ (ppm) 7.58(s, 1H)， 7.13-7.09(m, 2H), 3.75(brs, 1H), 3.55(t, 2H, 9.6Hz)， 3.17(s, 1H), 2.93(t, 2H, J=9.6Hz),1.73(s, 6H). Intermediate 25 (3.3 g) was dissolved in 10 ml of acetone, trimethylsilyl cyanide (5 ml) and a few drops of acetic acid were added, the tube was sealed, heated to 90 ° C and stirred at constant temperature for 48 hours. The reaction mixture was cooled to room temperature. EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Oil, flash column chromatography (dichloromethane:methanol = 5:1) gave Intermediate 26 (3.0 g). 1H NMR (CDC1 ₃ , 400 MHz) δ (ppm) 7.58 (s, 1H), 7.13-7.09 (m, 2H), 3.75 (brs, 1H), 3.55 (t, 2H, 9.6 Hz), 3.17 (s, 1H), 2.93(t, 2H, J=9.6Hz), 1.73(s, 6H).

实施例 105 4-(4，4-二甲基 -3-(2-甲基- 1 -氧- 1 ,2,3，4-四氢异喹啉 -7-基) -5-氧 -2-硫代咪唑烷- i -基 )-2— (三氟甲基)苯甲腈制备（化合物 34) Example 105 4-(4,4-Dimethyl-3-(2-methyl- 1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-oxo-2 -thioimidazolidine-i-yl)-2-(trifluoromethyl)benzonitrile (Compound 34)

将中间体 26 ( 160 mg)和 4-异硫氰酸酯基 -2- (三氟甲基）苯甲腈（160 mg)溶解于无水 DMF中，封管，加热到 80°C，搅拌过夜。反应液冷却到室温，所得粗品加入 10 ml的甲醇中，随后加入 3 ml的 2N的盐酸溶液，室温搅拌过夜，浓縮蒸去甲醇，乙酸乙酯萃取。有机层用无水硫酸钠干燥，过滤，浓縮至干，所得油状物制备薄层层析 (石油醚:乙酸乙酯 =1 : 2)得到化合物 34 ( 180 mg, 黄色固体）。 1H NMR (CDC1₃， 400 MHz) δ (ppm) 8.05-7.99(m, 3H), 7.88-7.86(m, 1H), 7.9(s, 1H), 3.67(t, 2H, J=6.8Hz), 3.21(s,3H), 3.13(t, 2H, J=6.8Hz), 1.59(s， 6H). LC-MS: C₂₃H₁₉F₃N₄0₂S [M+H] +计算值 473.1，实测值 473丄

Dissolve intermediate 26 (160 mg) and 4-isothiocyanate-2-(trifluoromethyl)benzonitrile (160 mg) in dry DMF, seal, heat to 80 ° C, stir overnight. The reaction solution was cooled to room temperature, and the obtained crude product was added to 10 ml of methanol, and then 3 ml of 2N hydrochloric acid solution was added, and the mixture was stirred overnight at room temperature, and the mixture was evaporated to ethyl ether. The organic layer was dried with anhydrous sodium sulfate (MgSO4) 1H NMR (CDC1 ₃ , 400 MHz) δ (ppm) 8.05-7.99 (m, 3H), 7.88-7.86 (m, 1H), 7.9 (s, 1H), 3.67 (t, 2H, J = 6.8 Hz), 3.21(s,3H), 3.13(t, 2H, J=6.8Hz), 1.59(s, 6H). LC-MS: C ₂₃ H ₁₉ F ₃ N ₄ 0 ₂ S [M+H] + Calculated 473.1 , measured value 473丄

实施例 106 2-氯-4-(4，4-二甲基-3-(2-甲基-1-氧-1，2，3，4-四氢异喹啉-7-基)-5-氧-2-硫代咪唑烷 -1-基）苯甲腈制备（化合物 35 )

将中间体 26 ( 120 mg)和 2-氯 -4-异硫氰酸酯基苯甲腈（110 mg)溶解于无水 DMF中，封管，加热到 80°C，搅拌过夜。反应液冷却到室温，所得粗品加入 10 ml的甲醇中，随后加入 3 ml的 2N的盐酸溶液，室温搅拌过夜，浓縮蒸去甲醇，乙酸乙酯萃取。有机层用无水硫酸钠干燥，过滤，浓縮至干，所得油状物制备薄层层析 (石油醚:乙酸乙酯 =1 : 2)得到目标化合物（34 mg , 黄色固体）。 1H NMR (DMSO-d6 , 400 MHz) δ (ppm) 8.19(d， 1H， J=8.4Hz), 8.04(d，lH，J=1.6Hz)， 7.86(s, 1H), 7.75(m, 1H), 7.49-7.46(m,2H), 3.61(t, 2H, J=6.4Hz)， 3.09(t, 2H, J=6.4Hz), 3.05(s,3H), 1.50(s, 6H). LC-MS: C₂₂H₁₉C1 ₄0₂S [M+H] +计算值 439.1，实测值 439.1. Example 106 2-Chloro-4-(4,4-dimethyl-3-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5 -Oxo-2-thioimidazol-1-yl)benzonitrile preparation (Compound 35)

Intermediate 26 (120 mg) and 2-chloro-4-isothiocyanatebenzonitrile (110 mg) were dissolved in dry DMF, then filtered, warmed to <RTIgt; The reaction solution was cooled to room temperature, and the obtained crude product was added to 10 ml of methanol, and then 3 ml of a 2N hydrochloric acid solution was added, and the mixture was stirred overnight at room temperature, and the mixture was evaporated to ethyl ether. The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.19 (d, 1H, J = 8.4 Hz), 8.04 (d, lH, J = 1.6 Hz), 7.86 (s, 1H), 7.75 (m, 1H) ), 7.49-7.46(m,2H), 3.61(t, 2H, J=6.4Hz), 3.09(t, 2H, J=6.4Hz), 3.05(s,3H), 1.50(s, 6H). LC - MS: C ₂₂ H ₁₉ C1 ₄ 0 ₂ S [M+H] + calc. 439.1, found 439.1.

实施例 107 4-氨基 -2,6-二氟 -苯乙腈制备（中间体 27 ) Example 107 Preparation of 4-amino-2,6-difluoro-phenylacetonitrile (Intermediate 27)

将 4-溴 -3， 5-二氟苯胺（1.0 g)和氰化锌 (5.6 g), Pd(PPh₃)₄ (320 mg) 混合在 NMP(5 ml) 溶剂中，体系用氩气交换后加热至 100°C反应搅拌过夜。 TLC监测反应已经结束。用乙酸乙酯和水稀释并过滤后分层，有机相用水洗，饱和食盐水洗涤，干燥后过滤蒸干得到粗产品，经快速柱层析分离 (石油醚:乙酸乙酯 =15 : 1)得到中间体 27黄色固体（320 mg) o 1H NMR (CDC1₃ , 400 MHz) δ (ppm) 6.23(d, 2H), 4.62(brs, 2H). LC-MS: C₇H₄F₂N₂ [M+H] +计算值 155.0, 实测值 155.0.

4-Bromo-3, 5-difluoroaniline (1.0 g) and zinc cyanide (5.6 g), Pd(PPh ₃ ) ₄ (320 mg) were mixed in NMP (5 ml) solvent, and the system was exchanged with argon gas. After heating to 100 ° C, the reaction was stirred overnight. The TLC monitoring reaction has ended. Diluted with ethyl acetate and water, and filtered, and the layers were separated. The organic phase was washed with EtOAc. . to give intermediate 27 as a yellow solid (320 mg) o 1H NMR ( CDC1 3, 400 MHz) δ (ppm) 6.23 (d, 2H), 4.62 (brs, 2H) LC-MS: C 7 H 4 F 2 N 2 [M+H] + calculated 155.0, found 155.0.

实施例 108 2，6-二氟 -4-异硫中间体 28 )

Example 108 2,6-Difluoro-4-isosulfide intermediate 28)

将中间体 27 (300 mg)混悬于二氯甲烷和水（20 ml: 20 ml), 加入 1 g固体碳酸氢钠。所得反应液滴加硫光气 (400 mg) 的二氯甲烷溶液，室温搅拌过夜。 TLC显示反应完成，二氯甲烷层分离，无水硫酸钠干燥，过滤，浓縮得到中间体 28，直接用于下步反应。 Intermediate 27 (300 mg) was suspended in dichloromethane and water (20 ml: 20 ml) and 1 g solid sodium hydrogen carbonate was added. The resulting reaction solution was added with a solution of thiophosgene (400 mg) in dichloromethane and stirred at room temperature overnight. TLC showed the reaction was completed, the methylene chloride layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to afford intermediate 28, which was used directly in the next step.

实施例 109 4-(4，4-二甲基 -3-(2-甲基- 1 -氧- 1 ,2,3，4-四氢异喹啉 -7-基) -5-氧 -2-硫代咪唑烷小基 )-2，₆-二氟苯甲腈制备（化合物 36) Example 109 4-(4,4-Dimethyl-3-(2-methyl- 1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-oxo-2 -thioimidazole Small alkyl-yl) -2, ₆ - difluorobenzonitrile (Compound 36)

将中间体 26 ( 120 mg) 和中间体 28 (120 mg)溶解于无水 DMF中，封管，加热到 80°C，搅拌过夜。反应液冷却到室温，所得粗品加入 10 ml的甲醇中，随后加入 3 ml的 2N的盐酸溶液，室温搅拌过夜，浓縮蒸去甲醇，乙酸乙酯萃取。有机层用无水硫酸钠干燥，过滤，浓縮至干，所得油状物制备薄层层析 (石油醚:乙酸乙酯 =1 : 1)得到化合物 36 ( 18 mg，黄色固体）。 1H NMR (CDC1₃， 400 MHz) δ (ppm) 8.03(d, 1H, J=2.0Hz), 7.38-7.30(m, 4H),3.67(t, 2H, J=6.8Hz), 3.20(s,3H), 3.12(t, 2H, J=6.8Hz), 1.60(s, 6H). LC-MS: C22H18F2N4O2S [M+H] + 计算值 441.0，实测值 441.1.

Intermediate 26 (120 mg) and intermediate 28 (120 mg) were dissolved in dry DMF, then filtered, warmed to <RTIgt; The reaction solution was cooled to room temperature, and the obtained crude product was added to 10 ml of methanol, and then 3 ml of a 2N hydrochloric acid solution was added, and the mixture was stirred overnight at room temperature, and the mixture was evaporated to ethyl ether. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. 1H NMR (CDC1 ₃ , 400 MHz) δ (ppm) 8.03 (d, 1H, J = 2.0 Hz), 7.38-7.30 (m, 4H), 3.67 (t, 2H, J = 6.8 Hz), 3.20 (s, 3H), 3.12 (t, 2H, J = 6.8 Hz), 1.60 (s, 6H). LC-MS: C22H18F2N4O2S [M+H] + calc. 441.0, found 441.1.

生物活性测试例 1 化合物抑制雄激素 DHT对雄激素受体活化作用检测 Biological Activity Test Example 1 Compound inhibits androgen DHT detection of androgen receptor activation

目的：考察受试化合物细胞水平对由 DHT引起的雄激素受体活化的抑制作用。 Objective: To investigate the inhibitory effect of test compound cell levels on androgen receptor activation induced by DHT.

细胞：雄激素受体阳性细胞 LNCaP, 并过表达雄激素受体、同时稳转入受雄激素受体调控表达的荧光素酶（luciferase) 质粒；以下简称 LIAR细胞。 Cells: The androgen receptor-positive cell LNCaP, which overexpresses the androgen receptor, and stably transfers to the luciferase plasmid regulated by the androgen receptor; hereinafter referred to as LIAR cells.

实验使用 Luciferase assay system试剂盒（PROMEGA; E1501 ), 检测细胞内 The assay was performed using the Luciferase assay system kit (PROMEGA; E1501).

Luciferase酶活性。 Luciferase enzyme activity.

实验步骤： Experimental steps:

1、正常培养 LIAR细胞（含 10% FBS的 RPMI-1640培养基），消化后将培养液换成含 10% Charcoal Stripped FBS (活性炭处理胎牛血清）的 RPMI-1640培养液，按每孔 2000 个细胞密度种板于 96孔板； 1. Normally culture LIAR cells (RPMI-1640 medium containing 10% FBS). After digestion, replace the culture medium with RPMI-1640 medium containing 10% Charcoal Stripped FBS (activated activated fetal bovine serum) at 2000 per well. Cell density plate in 96-well plates;

2、种板 3天后，加药：设置细胞对照组， DHT对照组（加入终浓度 1 tiM DHT), 化合物测试组（含终浓度 InM DHT,化合物起始浓度为 1800 nM，依次 3倍稀释为 1800、 600、 200、 66.67、 22.22、 7.41、 2.47、 0.82 M) 2. After 3 days of seeding, dosing: set the cell control group, DHT control group (adding final concentration of 1 tiM DHT), compound test group (containing final concentration of InM DHT, the initial concentration of compound was 1800 nM, and the dilution was 3 times in order. 1800, 600, 200, 66.67, 22.22, 7.41, 2.47, 0.82 M)

3、化合物处理 3天后，弃上清，每孔加入室温平衡的细胞裂解液 20 μΐ, 摇床震荡使细胞充***解。 3. After compound treatment for 3 days, discard the supernatant, add 20 μΐ of cell lysate equilibrated at room temperature to each well, and shake the shaker to fully lyse the cells.

4、将细胞裂解后液体移入 96孔不透明白板内，每孔加入 100 μΐ Luciferase assay检测试剂，混匀后立即用 PerkinEmlerEnvision™仪器在全波长段测定荧光强度（Relative Light Unit, RLU)o 5、化合物对 A 活化抑制率计算： 4. After lysing the cells, transfer the liquid into a 96-well opaque whiteboard. Add 100 μΐ Luciferase assay detection reagent to each well. Immediately after mixing, measure the fluorescence intensity (Relative Light Unit, RLU) at the full wavelength range with a PerkinEmlerEnvisionTM instrument. 5. Calculation of compound inhibition rate of A activation:

抑制率（％) = (药物实验孔 -DHT对照组） I (细胞对照组 -DHT对照组） X 100 Inhibition rate (%) = (drug test well - DHT control group) I (cell control group - DHT control group) X 100

6、米用 Graphpad Prism 5.0对数据进亍 Log(inhibitor) vs.response- Variable slope (four parameters)曲线拟合，计算相应的 IC₅o。 6. The curve is fitted to the log (inhibitor) vs. response-variable slope (four parameters) using Graphpad Prism 5.0, and the corresponding IC ₅ o is calculated.

测试结果： Test Results:

生物活性测试例 2 化合物对 DHT诱导***癌 LNCaP细胞 PSA蛋白分泌的抑制作用实验方法：使用 ALPCO公司生产的 PSA (Total) EIA检测试剂盒，检测细胞上清 PSA 的含量。

Biological Activity Test Example 2 Inhibition of DHT-induced PSA protein secretion in prostate cancer LNCaP cells Experimental method: Cell supernatant PSA was detected using APSCO's PSA (Total) EIA assay kit The content.

实验步骤： Experimental steps:

1、正常培养 LNCaP细胞（含 10% FBS的 RPMI1640培养基），消化后将培养液换成含 10%CS-FBS (炭吸附处理血清）的 RPMI1640培养液，种板于 96孔板，细胞密度为 2χ 10⁴ /ml, 约 2000个 /孔； 1. Normally culture LNCaP cells (RPMI1640 medium containing 10% FBS), digest the culture medium into RPMI1640 medium containing 10% CS-FBS (carbon adsorption treatment serum), seed plate in 96-well plate, cell density 2 χ 10 ⁴ /ml, about 2000 / hole;

2、种板 3 天后，更新含 InM DHT的含 10%CS-FBS (炭吸附处理血清）的 RPMI1640 培养液。加药：设置 1 孔为阴性对照孔（加入 InM DHT, 不加化合物），阳性化合物 MDV3100和实施例化合物起始浓度为 10000 nM，依次 5倍稀释为 2000、 400、 80、 16、 3.2、 0.64、 0.128nM。 2. After 3 days of seeding, RPMI1640 medium containing 10% CS-FBS (carbon adsorption-treated serum) containing InM DHT was renewed. Dosing: Set 1 well as negative control well (add InM DHT, no compound), positive compound MDV3100 and the initial concentration of the compound of the example are 10000 nM, and then 5 times diluted to 2000, 400, 80, 16, 3.2, 0.64 , 0.128nM.

3、化合物处理 3 d后，取上清 50 μΐ使用 ALPCO公司生产的 PSA ( Total) EIA检测试剂盒，检测细胞上清 PSA的含量。 FlexStation 3在波长 450nm处测定光密度值（Optical Density, OD)。 3. After the compound was treated for 3 days, the supernatant was taken 50 μL and the PSA (Total) EIA test kit manufactured by ALPCO was used to detect the content of PSA in the supernatant of the cells. The FlexStation 3 measures the Optical Density (OD) at a wavelength of 450 nm.

处理和结果： Processing and results:

1、实验结束时间点，显微镜下观察，化合物对细胞生长无明显的抑制作用，初步肯定各化合物的细胞生长抑制率低于 30%，排除细胞毒作用。 1. At the end of the experiment, under the microscope, the compound has no obvious inhibitory effect on cell growth, and the cell growth inhibition rate of each compound is initially determined to be less than 30%, and the cytotoxic effect is excluded.

2、 PSA蛋白分泌的抑制率计算：抑制率（％) = [1- (药物受试孔-阴性对照孔） I 阴性对照孔] 100 2. Calculation of inhibition rate of PSA protein secretion: Inhibition rate (%) = [1- (drug test well - negative control well) I negative control well] 100

3、根据各浓度的抑制率，用 GraphPad Prism计算 IC_5Q，结果如下表所示： 3. Calculate IC _5Q using GraphPad Prism according to the inhibition rate of each concentration. The results are shown in the following table:

Claims

权利要求 Rights request

1、一种如式 I所示的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物， A compound of formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof,

A环为 6〜10元芳环； Ring A is a 6 to 10 membered aromatic ring;

B环为苯环或 6元杂芳环； The B ring is a benzene ring or a 6-membered heteroaryl ring;

R¹为 H、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自 C3〜C6 环烷基、 C1〜C6烷氧基、 -NH₂、单 (； C1〜C6烷基)氨基、二 (； C1〜C6烷基)氨基、氘原子、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自 -NH₂、单 (C1〜C6烷基)氨基、二 (C1〜C6烷基) 氨基或至少含有 1个氮原子的 5〜7元杂环基，所述至少含有 1个氮原子的 5〜7元杂环基非必须地被 C1〜C4烷基所取代； R ¹ is H, C1 to C4 alkyl or phenyl, and the C1 to C4 alkyl group is optionally one or more selected from the group consisting of C3 to C6 cycloalkyl, C1 to C6 alkoxy, -NH ₂ , single (; C1~C6 alkyl) amino, di (; C1~C6 alkyl) amino, deuterium atom, phenyl, and -C (0) is substituted by a group R ^8, wherein R ⁸ is selected from -NH _2, a mono(C1-C6 alkyl)amino group, a di(C1-C6 alkyl)amino group or a 5- to 7-membered heterocyclic group containing at least one nitrogen atom, and a 5- to 7-membered heterocyclic ring containing at least one nitrogen atom The base is optionally substituted by a C1~C4 alkyl group;

R²为 H、卤素或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代； R³和 R⁴各自独立地为 -CH₂-R⁶，其中 11⁶为11、 OH、羧基、苄氧基、 C1〜C4烷氧基或卤代 C1〜C2烷基； R ² is H, halogen or C1 to C4 alkyl, and the C1 to C4 alkyl group is optionally substituted by one or more halogen atoms; and R ³ and R ⁴ are each independently -CH ₂ -R ⁶ , wherein 11 ⁶ is 11, OH, a carboxyl group, a benzyloxy group, a C1 to C4 alkoxy group or a halogenated C1 to C2 alkyl group;

或者 R³、 R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或 4〜6元杂环基； R⁵为氰基、卤素、 C1〜C4烷基或 C1〜C4烷氧基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代； Or R ³ , R ⁴ and the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclic group; R ⁵ is a cyano group, a halogen, a C1 to C4 alkyl group or a C1 to C4 alkoxy group. a C1 to C4 alkyl group optionally substituted with one or more halogen atoms;

R⁷为 H或卤素； R ⁷ is H or halogen;

X为 S或 0; X is S or 0;

Y为 -(CH₂)_n -、 0或直接键，其中 -(CH₂)_n -非必须地被一个或多个氘原子或甲基取代， n 为 1或 2。 Y is -(CH ₂ ) _n -, 0 or a direct bond, wherein -(CH ₂ ) _n - is optionally substituted by one or more deuterium atoms or methyl groups, and n is 1 or 2.

2、根据权利要求 1所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中： 2. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein:

A环为 6〜10元芳环； Ring A is a 6 to 10 membered aromatic ring;

B环为苯环或 6元杂芳环； R¹为 H或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个选自 C3〜C6环烷基、 C1〜C6烷氧基、 -NH₂、单 (C1〜C6烷基)氨基、二 (C1〜C6烷基)氨基、 -CONH₂、单 (C1〜C6 烷基)氨基甲酰基、二 (C1〜C6烷基)氨基甲酰基和氘原子中的基团所取代； The B ring is a benzene ring or a 6-membered heteroaryl ring; R ¹ is H or a C1 to C4 alkyl group, and the C1 to C4 alkyl group is optionally one or more selected from the group consisting of C3 to C6 cycloalkyl groups, C1 to C6 alkoxy groups, -NH ₂ , and mono (C1~). a group of a C6 alkyl)amino group, a di(C1-C6 alkyl)amino group, a -CONH ₂ , a mono(C1 to C6 alkyl)carbamoyl group, a di(C1-C6 alkyl)carbamoyl group, and a fluorene atom Replaced

^为卤素或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代； R³和 R⁴各自独立地为 -CH₂-R⁶，其中 ^为 OH、羧基、苄氧基或 C1〜C4烷氧基；或者 R³、 R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或 4〜6元杂环基； ^ is halogen or C1 to C4 alkyl, the C1 to C4 alkyl group is optionally substituted by one or more halogen atoms; R ³ and R ⁴ are each independently -CH ₂ -R ⁶ , wherein ^ is OH, a carboxyl group, a benzyloxy group or a C1 to C4 alkoxy group; or R ³ , R ⁴ and a carbon atom to which they are bonded together form a 3 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclic group;

R⁵为氰基、卤素或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代； R ⁵ is cyano, halogen or C1 to C4 alkyl, and the C1 to C4 alkyl group is optionally substituted by one or more halogen atoms;

X为 S或 0; X is S or 0;

Y为 CH₂)_n -、 0或直接键，其中 -(CH₂)_n -非必须地被一个或多个氘原子取代， n为 1 或 2; Y is CH ₂ ) _n -, 0 or a direct bond, wherein -(CH ₂ ) _n - is optionally substituted by one or more deuterium atoms, n being 1 or 2;

3、如权利要求 2所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， A环为苯环， B环为苯环。 The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein the ring A is The benzene ring and the B ring are benzene rings.

4、如权利要求 3所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体、入 4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, prodrug thereof, stereo, or

异构体、互变异构体、多晶型物或代谢产物，其中， A环上的氰基与彼此呈对位取代。 Isomers, tautomers, polymorphs or metabolites in which the cyano groups on the A ring are aligned with each other.

5、如权利要求 2所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R¹为 H或 C1〜C3烷基，所述 C1〜C3 烷基非必须地被一个或多个选自 C3〜C6环烷基、 C1〜C4烷氧基、二 (C1〜C4烷基)氨基、 -CONH₂和氘原子中的基团所取代。 The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ¹ is H or a C1 to C3 alkyl group, the C1 to C3 alkyl group optionally being one or more selected from the group consisting of C3 to C6 cycloalkyl groups, C1 to C4 alkoxy groups, di(C1 to C4 alkyl)amino groups, Substitution of CONH ₂ and a halogen atom.

6、如权利要求 5所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R¹为 H或 C1〜C2烷基，所述 C1〜C2 烷基非必须地被一个或多个选自环丙基、甲氧基、二乙基氨基、 -CONH₂和氘原子中的基团所取代。 The compound of claim 5, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ¹ is H or a C1 to C2 alkyl group, the C1~C2 alkyl group being optionally substituted by one or more groups selected from the group consisting of a cyclopropyl group, a methoxy group, a diethylamino group, a -CONH ₂ and a ruthenium atom .

7、如权利要求 6所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， 1^为15、甲基、乙基、环丙基甲基、 2- (甲氧基)乙基、 2- (二乙基氨基)乙基、 -CH₂CONH₂或 -CD₃。 The compound of claim 6 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein 15, methyl, ethyl, cyclopropylmethyl, 2-(Methoxy)ethyl, 2-(diethylamino)ethyl, -CH ₂ CONH ₂ or -CD ₃ .

8、如权利要求 7所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， 1^为15、甲基或乙基。 The compound of claim 7 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein 15, methyl or ethyl.

9、如权利要求 2所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R²为 H或卤素。 The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ² is H or halogen.

10、如权利要求 9所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R²为！！或！^。 The compound according to claim 9 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ² is ! ! or! ^.

11、如权利要求 2所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中，当 R³和 R⁴各自独立地为 -CH₂-R⁶时， R H。 The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ³ And R ⁴ are each independently -CH ₂ -R ⁶ , RH.

12、如权利要求 2所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中，当 R³、 R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或 4〜6元杂环基时，所述的 3〜6元环烷基为环丙基、环丁基或环戊基， 4〜6元杂环基为氧杂环丁基或氮杂环丁基。 The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ³ When R ⁴ and the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclic group, the 3 to 6 membered cycloalkyl group is a cyclopropyl group, a cyclobutyl group or a cyclopentane group. The 4- to 6-membered heterocyclic group is oxetanyl or azacyclobutyl.

13、如权利要求 12所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， 3〜6元环烷基为环丁基， 4〜6元杂环基为氧杂环丁基。 The compound according to claim 12, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein 3 to 6 The cycloalkyl group is a cyclobutyl group, and the 4 to 6 membered heterocyclic group is an oxetanyl group.

14、如权利要求 2所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R⁵为氰基或 C1〜C4烷基，所述 C1〜C4 烷基非必须地被一个或多个选自 F、 C1和 Br中的原子取代。 The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ⁵ is A cyano group or a C1 to C4 alkyl group, which is optionally substituted with one or more atoms selected from the group consisting of F, C1 and Br.

15、如权利要求 14所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R⁵为 C1〜C2烷基，所述 C1〜C2 烷基非必须地被一个或多个 F原子取代。 The compound according to claim 14 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ⁵ is A C1 to C2 alkyl group, which is optionally substituted by one or more F atoms.

16、如权利要求 15所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R⁵为 -CF₃。 The compound of claim 15 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ⁵ is -CF ₃ .

17、如权利要求 2所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， Y为 -CH₂-。 17. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof Isomers, tautomers, polymorphs or metabolites, wherein, Y is -CH ₂ -.

18、如权利要求 1所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中，式 I的化合物为下面式 Π所示的化合物： The compound of claim 1 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein The compound is a compound of the formula:

R¹为 H、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自 C3〜C6 环烷基、 C1〜C6烷氧基、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自氨基、单 (C1〜C6 烷基)氨基、二 (C1〜C6烷基)氨基或至少含有 1个氮原子的 5〜7元杂环基，所述至少含有 1 个氮原子的 5〜7元杂环基非必须地被 C1〜C4烷基所取代； R ¹ is H, C1 to C4 alkyl or phenyl, and the C1 to C4 alkyl group is optionally one or more selected from the group consisting of C3 to C6 cycloalkyl, C1 to C6 alkoxy, phenyl and -C (0) is substituted by a group R ^8, wherein R ⁸ is selected from amino, mono (C1~C6 alkyl) amino, (C1~C6 alkyl) amino, or at least one nitrogen atom of 5 ~ 7 membered a heterocyclic group, wherein the 5- to 7-membered heterocyclic group having at least one nitrogen atom is optionally substituted with a C1 to C4 alkyl group;

R²为 H、卤素或 C1〜C4烷基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代； R³和 R⁴各自独立地为 -CH₂-R⁶，其中 ^为 C1〜C4烷氧基或卤代 C1〜C2烷基；或者 R³、 R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或 4〜6元杂环基； R⁵为卤素、 C1〜C4烷基或 C1〜C4烷氧基，所述 C1〜C4烷基非必须地被一个或多个卤素原子取代； R ² is H, halogen or a C1 to C4 alkyl group, and the C1 to C4 alkyl group is optionally substituted by one or more halogen atoms; and R ³ and R ⁴ are each independently -CH ₂ -R ⁶ , wherein Is a C1~C4 alkoxy group or a halogenated C1~C2 alkyl group; or R ³ , R ⁴ and a carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclic group; R ⁵ is a halogen, a C1 to C4 alkyl group or a C1 to C4 alkoxy group, the C1 to C4 alkyl group being optionally substituted by one or more halogen atoms;

R⁷为 H或卤素； R ⁷ is H or halogen;

Y为 -(CH₂)_n-，其中 -(CH₂)_n -非必须地被一个或多个 C1〜C4烷基取代， n为 1或 2。Y is -(CH ₂ ) _n -, wherein -(CH ₂ ) _n - is optionally substituted by one or more C1 to C4 alkyl groups, and n is 1 or 2.

19、如权利要求 18所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， 1^为 11、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自 C3〜C6环烷基、 C1〜C6烷氧基、苯基和 -C(0)R⁸ 中的基团所取代，其中 R⁸选自氨基或至少含有 1个氮原子的 5〜7元杂环基，所述至少含有 1个氮原子的 5〜7元杂环基非必须地被 C1〜C4烷基所取代； The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein 11. A C1 to C4 alkyl group or a phenyl group, the C1 to C4 alkyl group optionally being one or more selected from the group consisting of C3 to C6 cycloalkyl groups, C1 to C6 alkoxy groups, phenyl groups and -C(0) R groups substituted ^8, wherein R ⁸ is selected from an amino group or a 5 ~ 7 membered heterocyclic group containing at least one nitrogen atom, the 5 ~ 7 membered heterocyclic group containing at least one nitrogen atom is not necessarily Substituted by a C1~C4 alkyl group;

20、如权利要求 19所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， 1^为 11、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自 C3〜C6环烷基、 C1〜C4烷氧基、苯基和 -C(0)R⁸ 中的基团所取代，其中 R⁸选自氨基或至少含有 1个氮原子的 6元杂环基，所述至少含有 1个氮原子的 6元杂环基非必须地被 C1〜C4烷基所取代。 The compound of claim 19, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein 11. A C1 to C4 alkyl group or a phenyl group, the C1 to C4 alkyl group optionally being one or more selected from the group consisting of C3 to C6 cycloalkyl groups, C1 to C4 alkoxy groups, phenyl groups and -C(0) R ⁸ Substituted by a group in which R ^{8 is} selected from an amino group or a 6-membered heterocyclic group containing at least one nitrogen atom, and the 6-membered heterocyclic group having at least one nitrogen atom is optionally C1 to C4 alkyl Replaced.

21、如权利要求 20所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， 1^为 11、 C1〜C4烷基或苯基，所述 C1〜C4烷基非必须地被一个或多个选自环丙基、环丁基、甲氧基、苯基和 -C(0)R⁸中的基团所取代，其中 R⁸选自氨基或 N-甲基哌嗪基。 The compound of claim 20, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein 11. A C1 to C4 alkyl group or a phenyl group, the C1 to C4 alkyl group optionally being one or more selected from the group consisting of cyclopropyl, cyclobutyl, methoxy, phenyl and -C(0)R ⁸ Substituted in a group wherein R ^{8 is} selected from amino or N-methylpiperazinyl.

22、如权利要求 21所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R¹为 H、甲基、乙基、苯基、环 The compound of claim 21, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ¹ is H, methyl, ethyl, phenyl, ring

丙基甲基、环丁基甲基、 2- (甲氧基)乙基、苄基、 -CH₂C(0)NH₂或

23、如权利要求 18所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R²为 H或卤素。 Propylmethyl, cyclobutylmethyl, 2-(methoxy)ethyl, benzyl, -CH ₂ C(0)NH ₂ or

The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ² is H or halogen.

24、如权利要求 23所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R²为！！或！^。 The compound of claim 23, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ² is ! ! or! ^.

25、如权利要求 18所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中，当 R³和 R⁴各自独立地为 -CH₂-R⁶ 时， 1 ⁶为11、 -OCH₃或 -CH₂C1。 The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ³ When R ^{4 is} each independently -CH ₂ -R ⁶ , ¹⁶ is 11, -OCH ₃ or -CH ₂ C1.

26、如权利要求 18所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中，当 R³、 R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或 4〜6元杂环基时，所述的 4〜6元杂环基为含有 1个氧原子的 4〜6 元杂环基。 The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein, when R ³ When R ⁴ and the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclic group, the 4 to 6 membered heterocyclic group is 4 to 6 members containing 1 oxygen atom. Heterocyclic group.

27、如权利要求 26所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中，当 R³、 R⁴和与它们相连的碳原子共同形成 3〜6元环烷基或 4〜6元杂环基时， 3〜6元环烷基为环丁基或环戊基， 4〜6元杂环基为氧杂环己基。 The compound of claim 26, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ³ When R ⁴ and the carbon atom to which they are bonded form a 3 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclic group, the 3 to 6 membered cycloalkyl group is a cyclobutyl group or a cyclopentyl group, and 4 to 6 members are hetero The ring group is an oxetanyl group.

28、如权利要求 18所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R⁵为卤素、甲基、卤代甲基或 -OCH₃。 The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ⁵ is Halogen, methyl, halomethyl or -OCH ₃ .

29、如权利要求 28所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R⁵为卤素、甲基、 -CF₃或 -OCH₃。 The compound of claim 28, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ⁵ is Halogen, methyl, -CF ₃ or -OCH ₃ .

30、如权利要求 18的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R⁷为 H或氟。 The compound according to claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R ⁷ is H or fluorine.

31、如权利要求 18的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， Y为 -(CH₂)_n -，其中 -(CH₂)_n -非必须地被一个或多个甲基取代， n为 1或 2。 The compound according to claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein Y is -(CH) ₂ ) _n -, wherein -(CH ₂ ) _n - is optionally substituted by one or more methyl groups, and n is 1 or 2.

32、如权利要求 31 的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， Y为 -(CH₂)₂-或 -CH(CH₃)-。 The compound according to claim 31, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein Y is -(CH) ₂ ) ₂ - or -CH(CH ₃ )-.

33、如权利要求 32的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中，当 Y为 -(CH₂)₂-时， 11²为11。 The compound according to claim 32, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein, when Y is -( When CH ₂ ) ₂ -, 11 ² is 11.

34、如权利要求 1所述的化合物或其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中，所述化合物选自如下化合物： The compound of claim 1 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein the compound Selected from the following compounds:

36 36

35、一种药物组合物，其包含治疗有效量的选自根据权利要求 1〜34中任意一项所述的化合物、其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物和代谢产物中的一种或多种，以及任选的一种或多种药用辅料。 A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 34, a pharmaceutically acceptable salt, solvate, prodrug thereof, stereoisomer thereof One or more of a tautomer, a polymorph and a metabolite, and optionally one or more pharmaceutical excipients.

36、权利要求 1〜34任意一项所述的化合物、其药学上可接受的盐、溶剂化物、前体药物、立体异构体、互变异构体、多晶型物或代谢产物，或权利要求 35所述的药物组合物在制备用于治疗雄性激素受体相关疾病的药物中的应用。 36. The compound of any one of claims 1 to 34, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, or Use of the pharmaceutical composition of claim 35 for the manufacture of a medicament for the treatment of androgen receptor-associated diseases.

37、根据权利要求 36所述的应用，其中，所述雄激素受体相关疾病为***癌、乳腺癌、 ***增生、多毛症、粉束 I」、秃头、肌肉衰竭、性腺功能衰弱、骨质疏松症、胆固醇过高、男性不育、男性性功能不良、贫血肥胖、 ***望低下或忧郁症。 37. The use according to claim 36, wherein the androgen receptor-related diseases are prostate cancer, breast cancer, benign prostatic hyperplasia, hirsutism, powder bundle I", baldness, muscle failure, gonadal dysfunction, bone mass Osteoporosis, high cholesterol, male infertility, male sexual dysfunction, anemia, obesity, low sexual desire or depression.

38、根据权利要求 36所述的应用，其中，所述雄激素受体相关疾病为去势耐受型前列腺癌。 The use according to claim 36, wherein the androgen receptor-associated disease is castration-tolerant prostate cancer.