TW202410899A

TW202410899A - Anti cancer combinations comprising chemotherapy

Info

Publication number: TW202410899A
Application number: TW112130324A
Authority: TW
Inventors: 長島建之
Original assignee: 日商安斯泰來製藥股份有限公司
Priority date: 2022-08-12
Filing date: 2023-08-11
Publication date: 2024-03-16

Abstract

There is provided herein a combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anti-cancer agent for use in the treatment of cancer, wherein the compound of formula (I) and the anti-cancer agent are as described in the description.

Description

抗癌組合之化學療法 Chemotherapy of anticancer combination

本發明係關於用於治療癌症，諸如胰臟癌、大腸直腸癌及肺癌之特定抗癌化合物之組合，及包含其之醫藥組合物以及套組。 The present invention relates to a combination of specific anticancer compounds for treating cancers, such as pancreatic cancer, colorectal cancer and lung cancer, and pharmaceutical compositions and kits containing the same.

KRAS(基爾斯滕大鼠肉瘤病毒(Kirsten rat sarcoma virus))係提供用於產生蛋白質之指令之基因，該蛋白質稱為K-Ras且係RAS/MAPK路徑之一部分。該蛋白質將來自細胞外部之信號轉送至細胞之核。此等信號指示細胞生長及***(增殖)或成熟且採用特定功能(分化)。 KRAS (Kirsten rat sarcoma virus) is a gene that provides instructions for producing a protein called K-Ras that is part of the RAS/MAPK pathway. The protein transmits signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferation) or to mature and adopt a specific function (differentiation).

KRAS突變已涉及各種惡性病，包括癌症，諸如肺腺癌、黏液腺瘤、胰臟之導管癌及大腸直腸癌。 KRAS mutations have been implicated in a variety of malignancies, including cancers such as lung adenocarcinoma, mucinous adenoma, pancreatic ductal carcinoma, and colorectal cancer.

大腸直腸癌為具有高發病率及死亡率之癌症，全世界每年報導約1.4百萬新病例(世界癌症報告(World Cancer Report)2014)。用於治療大腸直腸癌之最有效方式為手術，而化學療法、放射療法及類似者近年來已取得顯著進展。主要在歐洲及美國中進行之大規模臨床試驗已揭示，組合若干類型之抗癌劑的組合化學療法對於大腸直腸癌奏效且有助於腫瘤消退及延長預後(J.Clin.Oncol.,22，第229-237頁，2004)。除了化學療法，分子目標藥物，諸如抗VEGF(血管內皮生長因子)抗體或抗EGFR(表皮生長因子受體)抗體用作與化學療法組合之首選藥物。關於EGFR抗體藥物，顯而易見的是RAS基因中之突變為作用之陰性預測因子(Cancer Res.，66，第3992-3995頁，2006)，且在大腸直腸癌中，EGFR抗體藥物在當前情況下僅適用於具有野生型RAS基因之患者。 Colorectal cancer is a cancer with high morbidity and mortality, with approximately 1.4 million new cases reported worldwide each year (World Cancer Report 2014). The most effective way to treat colorectal cancer is surgery, while chemotherapy, radiotherapy and the like have made significant progress in recent years. Large-scale clinical trials conducted mainly in Europe and the United States have revealed that combination chemotherapy combining several types of anticancer agents is effective for colorectal cancer and helps tumor regression and prolongs prognosis (J. Clin. Oncol., 22, pp. 229-237, 2004). In addition to chemotherapy, molecular targeted drugs such as anti-VEGF (vascular endothelial growth factor) antibodies or anti-EGFR (epidermal growth factor receptor) antibodies are used as the first choice drugs in combination with chemotherapy. Regarding EGFR antibody drugs, it is clear that mutations in the RAS gene are negative predictors of action (Cancer Res., 66, pp. 3992-3995, 2006), and in colorectal cancer, EGFR antibody drugs are currently only applicable to patients with wild-type RAS genes.

另外，由於肺癌所致之死亡數目佔所有癌症所致死亡之19%，其為最高值，且全世界每年報導約1.8百萬新患者(世界癌症報告2014)。特定言之，據報導非小細胞肺癌(NSCLC)患者佔彼等肺癌患者之80%至85%(American Cancer Society,Cancer Facts and Figures,2016)。考慮手術療法直至某一階段，但在該階段之後很少採用手術，且化學療法或放射療法隨後變成主要療法。基於細胞形態學，腺癌及鱗狀細胞癌歸類為最典型類型之NSCLC。此等腫瘤遵循類似臨床病程，但腺癌之特徵在於定位在肺周邊。 In addition, the number of deaths due to lung cancer accounts for 19% of all cancer deaths, which is the highest value, and about 1.8 million new patients are reported worldwide each year (World Cancer Report 2014). Specifically, non-small cell lung cancer (NSCLC) patients are reported to account for 80% to 85% of those lung cancer patients (American Cancer Society, Cancer Facts and Figures, 2016). Surgical treatment is considered until a certain stage, but surgery is rarely used after this stage, and chemotherapy or radiation therapy then becomes the main treatment. Based on cell morphology, adenocarcinoma and squamous cell carcinoma are classified as the most typical types of NSCLC. These tumors follow a similar clinical course, but adenocarcinoma is characterized by being localized in the periphery of the lung.

主要包括胰管腺癌之胰臟癌為具有極差預後之五年存活率為10%或更少的癌症(CA Cancer J.Clin.,2016,66，第7-30頁)，且全世界每年報導約340,000新病例(GLOBOCAN 2012)。用於治療胰臟癌之最有效療法為手術。然而，因為早期偵測較困難，所以癌症通常已轉移，且癌症通常不可手術。若不可手術，則採用化學療法或放射療法，但存活率並非如此良好。現今，FOLFIRINOX療法(三種化學療法劑5-FU、伊立替康及奧沙利鉑加左亞葉酸鹽(levofolinate)之多藥物治療)用作胰臟癌之標準療法。然而，由於強毒性，個體患者必須謹慎選擇，例如療法僅施用於ECOG體能狀態為1或更小之患者(J.Clin.Oncol.,2018,36，第2545-2556頁)。作為分子目標藥物，表皮生長因子受體(EGFR)抑制劑埃羅替尼(Erlotinib)已批准用於與吉西他濱之組合療法。然而，相較於單獨的吉西他濱，總存活期之延長僅為約兩週且未實現令人滿意的治療效果。 Pancreatic cancer, which mainly includes pancreatic ductal adenocarcinoma, is a cancer with an extremely poor prognosis of a five-year survival rate of 10% or less (CA Cancer J. Clin., 2016, 66, pp. 7-30), and approximately 340,000 new cases are reported worldwide each year (GLOBOCAN 2012). The most effective treatment for pancreatic cancer is surgery. However, because early detection is difficult, the cancer has often metastasized, and the cancer is often inoperable. If surgery is not possible, chemotherapy or radiation therapy is used, but the survival rate is not so good. Today, FOLFIRINOX therapy (a multidrug therapy of three chemotherapy agents, 5-FU, irinotecan, and oxaliplatin plus levofolinate) is used as a standard treatment for pancreatic cancer. However, due to strong toxicity, individual patients must be carefully selected, for example, the treatment is only applied to patients with an ECOG performance status of 1 or less (J. Clin. Oncol., 2018, 36, pp. 2545-2556). As a molecular targeted drug, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been approved for combination therapy with gemcitabine. However, compared with gemcitabine alone, the extension of overall survival is only about two weeks and a satisfactory treatment effect has not been achieved.

RAS蛋白為由188至189個胺基酸構成的約21kDa之低分子量三磷酸鳥苷(GTP)結合蛋白，且包括由三種基因KRAS基因、NRAS基因及HRAS基因產生的四種主要類型之蛋白質(KRAS(KRAS 4A及KRAS 4B)、NRAS及HRAS)。RAS蛋白劃分為活性GTP結合型及非活性GDP結合型。由於例如針對膜受體(諸如EGFR)之配位體刺激，RAS蛋白藉由用GTP置換二磷酸鳥苷(GDP)而活化。活性RAS結合至多達二十種之效應蛋白(諸如RAF、PI3K及RALGDS)以活化下游信號級聯。在另一方面，由於固有GTP水解(GTP酶)活性，活性RAS藉由用GDP置換GTP而轉化成非活性類型。GTP酶活性藉由GTP酶活化蛋白(GAP)增強。如自以上陳述可見，RAS在EGFR或類似物之胞內信號轉導路徑中具有「分子開關」之重要功能，且在細胞生長、增殖、血管生成及類似過程中發揮關鍵作用(Nature Rev.Cancer,2011,11，第761-774頁，Nature Rev.Drug Discov.,2014,13，第828-851頁，Nature Rev.Drug Discov.,2016,15，第771-785頁)。 RAS proteins are low molecular weight guanosine triphosphate (GTP) binding proteins of approximately 21 kDa composed of 188 to 189 amino acids, and include four major types of proteins (KRAS (KRAS 4A and KRAS 4B), NRAS and HRAS) produced by three genes, the KRAS gene, the NRAS gene and the HRAS gene. RAS proteins are divided into active GTP-bound and inactive GDP-bound types. RAS proteins are activated by replacing guanosine diphosphate (GDP) with GTP due to, for example, ligand stimulation of membrane receptors (such as EGFR). Active RAS binds to up to twenty effector proteins (such as RAF, PI3K and RALGDS) to activate downstream signaling cascades. On the other hand, due to intrinsic GTP hydrolysis (GTPase) activity, active RAS is converted into an inactive type by replacing GTP with GDP. GTPase activity is enhanced by GTPase activating protein (GAP). As can be seen from the above statement, RAS has an important function as a "molecular switch" in the intracellular signal transduction pathway of EGFR or analogs, and plays a key role in cell growth, proliferation, angiogenesis and similar processes (Nature Rev. Cancer, 2011, 11, pp. 761-774, Nature Rev. Drug Discov., 2014, 13, pp. 828-851, Nature Rev. Drug Discov., 2016, 15, pp. 771-785).

由於RAS作為GTP酶之功能低下或對GAP之低反應性，藉由RAS基因之自發突變取代胺基酸產生恆定活化狀態，且隨後向下游連續傳送信號。過度信號傳導可引起癌發生或癌症生長加速。 Due to the low function of RAS as a GTPase or its low responsiveness to GAP, spontaneous mutations in the RAS gene replace amino acids to produce a constant activation state, and then continuously transmit signals downstream. Excessive signaling can cause cancer or accelerate cancer growth.

舉例而言，已發現胰管腺癌在胰臟上皮內瘤形成(PanIN)中出現較弱異形階段及後續的高度異形階段，且已在PanIN之初始階段中辨識到KRAS基因之突變。隨後，在腫瘤抑制基因INK4A、p53及SMAD4中出現異常，從而導致惡性腫瘤(Nature Rev.Cancer,2010,10，第683-695頁)。此外，在90%或更多之胰管腺癌病例中，在KRAS基因中見到突變，且其中大多數為位於KRAS外顯子2中之密碼子12中之自發性點突變(Cancer Cell 2017,32，第185-203頁)。如自以上陳述中可見，KRAS在癌發生過程及胰臟癌進展中發揮關鍵作用。 For example, pancreatic ductal adenocarcinoma has been found to have a weakly atypical stage and a subsequent highly atypical stage in pancreatic intraepithelial neoplasia (PanIN), and mutations in the KRAS gene have been identified in the initial stage of PanIN. Subsequently, abnormalities occur in the tumor suppressor genes INK4A, p53, and SMAD4, leading to malignant tumors (Nature Rev. Cancer, 2010, 10, pp. 683-695). In addition, mutations are seen in the KRAS gene in 90% or more of pancreatic ductal adenocarcinoma cases, and most of them are spontaneous point mutations located in codon 12 in exon 2 of KRAS (Cancer Cell 2017, 32, pp. 185-203). As can be seen from the above description, KRAS plays a key role in the carcinogenesis and progression of pancreatic cancer.

作為KRAS基因之突變，KRAS G12C突變、KRAS G12D突變及類似者為已知的。G12C突變型KRAS通常出現在非小細胞肺癌中，但在胰臟癌中存在極少百分比(Cancer Cell 2014,25，第272-281頁)，且需要針對另一KRAS突變之治療劑。在約34%之胰臟癌病例中見到G12D突變型KRAS，且據報導此比率在KRAS突變中為最高的(Nat.Rev.Cancer,2018,18，第767-777頁)。 As mutations of the KRAS gene, KRAS G12C mutation, KRAS G12D mutation, and the like are known. G12C mutant KRAS usually appears in non-small cell lung cancer, but exists in a very small percentage in pancreatic cancer (Cancer Cell 2014, 25, pp. 272-281), and requires a treatment targeting another KRAS mutation. G12D mutant KRAS is seen in about 34% of pancreatic cancer cases, and this rate is reported to be the highest among KRAS mutations (Nat. Rev. Cancer, 2018, 18, pp. 767-777).

WO 2016/049565、WO 2016/049568及WO 2017/172979揭示某些KRAS抑制劑且表明該等試劑適用於在KRAS之密碼子12中具有突變之癌症。G12D突變為此類突變中之一者，但未描述對G12D突變型KRAS癌症之任何作用。 WO 2016/049565, WO 2016/049568 and WO 2017/172979 disclose certain KRAS inhibitors and indicate that these agents are suitable for cancers with mutations in codon 12 of KRAS. The G12D mutation is one of these mutations, but no effect on G12D mutant KRAS cancers is described.

近年來，作為用於誘導目標蛋白之降解的技術，發現共同稱為PROTAC(蛋白質水解靶向嵌合體)或SNIPER(特異性及非遺傳性IAP依賴性蛋白質清除劑)之雙官能性化合物且預期為一種新穎的藥物研發模式技術(Drug.Discov.Today Technol.,2019,31，第15-27頁)。此類雙官能化合物促進在細胞中形成目標蛋白與E3連接酶之複合物，且目標蛋白之降解藉由使用泛素-蛋白酶體系統誘導。泛素-蛋白酶體系統為細胞間蛋白質降解機制之一。稱為E3連接酶之蛋白質鑑別待降解以將蛋白質轉化至泛蛋白中之蛋白質，藉此促進藉由蛋白酶體降解。 In recent years, bifunctional compounds collectively called PROTAC (Proteolysis Targeting Chimera) or SNIPER (Specific and Non-Genetic IAP-Dependent Protein Clearer) have been discovered as a technology for inducing the degradation of target proteins and are expected to be a novel drug development model technology (Drug. Discov. Today Technol., 2019, 31, pp. 15-27). Such bifunctional compounds promote the formation of a complex of target protein and E3 ligase in cells, and the degradation of target protein is induced by using the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the intracellular protein degradation mechanisms. Proteins called E3 ligases identify proteins to be degraded to convert proteins into ubiquitin, thereby promoting degradation by proteasomes.

六百(600)或更多個E3連接酶存在於生物體中，且大致劃分為四種類型之HECT-域E3、U-盒E3、單體環E3及多次單元E3。用作雙官能性降解誘導劑之E3連接酶(其稱為PROTAC、SNIPER或類似物)當前有限，且其典型實例包括Von Hippel-Lindau(VHL)、celebron(CRBN)、細胞凋亡蛋白之抑制劑(IAP)及小鼠雙微體2同源物(MDM2)。特定言之，VHL報導於WO 2013/106643中且CRBN報導於WO 2015/160845中。 Six hundred (600) or more E3 ligases exist in organisms and are roughly divided into four types of HECT-domain E3, U-box E3, monomeric ring E3, and multi-unit E3. E3 ligases used as bifunctional degradation inducers (which are called PROTACs, SNIPERs, or the like) are currently limited, and their typical examples include Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2). Specifically, VHL is reported in WO 2013/106643 and CRBN is reported in WO 2015/160845.

雙官能性化合物為其中目標蛋白之配位體及E3連接酶之配位體經由連接子結合的化合物，且已報導一些用於降解KRAS蛋白之雙官能性化合物(Cell.Chem.Biol.,2020,27，第19-31頁，ACS Cent.Sci.,2020,6，第1367-1375頁，US 2018/0015087,WO 2019/195609,WO 2020/018788)。 Bifunctional compounds are compounds in which the ligand of the target protein and the ligand of the E3 ligase are bound via a linker, and some bifunctional compounds for degrading KRAS protein have been reported (Cell. Chem. Biol., 2020, 27, pp. 19-31, ACS Cent. Sci., 2020, 6, pp. 1367-1375, US 2018/0015087, WO 2019/195609, WO 2020/018788).

目前出人意料地發現，如本文所定義之式(I)化合物與如本文所定義之某些額外抗癌劑之組合代表用於治療癌症之有前景的策略。 It has now surprisingly been found that the combination of compounds of formula (I) as defined herein with certain additional anticancer agents as defined herein represents a promising strategy for the treatment of cancer.

以不受理論約束為前提，咸信如本文所定義之式(I)化合物為雙官能化合物，且其對G12D突變型KRAS蛋白及G12D突變型KRAS抑制活性具有降解誘導作用，且可與抗癌劑一起用於治療癌症。特定言之，咸信式(I)化合物與抗癌劑之組合在治療癌症中引起強效協同作用，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 Without being bound by theory, it is believed that the compound of formula (I) as defined herein is a bifunctional compound, and it has a degradation-inducing effect on the G12D mutant KRAS protein and the inhibitory activity of the G12D mutant KRAS, and can be used together with an anticancer agent to treat cancer. Specifically, it is believed that the combination of the compound of formula (I) and an anticancer agent induces a potent synergistic effect in the treatment of cancer, and the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds and prodrugs thereof.

因此，在本發明之一第一範疇中，提供式(I)化合物或其醫藥學上可接受之鹽與抗癌劑或其醫藥學上可接受之鹽的組合，其用於治療癌症，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥，其中式(I)化合物係選自由以下組成之群： Therefore, in a first aspect of the present invention, a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof is provided for the treatment of cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof, wherein the compound of formula (I) is selected from the group consisting of:

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]- 7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]- 7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-[(1R)-2-羥基-1-{4-[4-(羥基甲基)-1,3-噻唑-5-基]苯基}乙基]-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(2-側氧基-1,3-

唑啶-3-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(1-甲基-1H-吡唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基- 1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺，及 (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-

唑-5-基)苯基]乙基}-L-脯胺醯胺。 (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

本發明之第二範疇為根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽，其用於治療癌症，其中該治療進一步包含投予抗癌劑或其醫藥學上可接受之鹽，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 The second category of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first category of the present invention, which is used for treating cancer, wherein the treatment further comprises administering an anticancer agent or a pharmaceutically acceptable salt thereof, the anticancer agent being selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof.

本發明之替代性第二範疇為用於治療癌症的抗癌劑或其醫藥學上可接受之鹽，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥，其中該治療進一步包含投予根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽。 The alternative second category of the present invention is an anticancer agent or a pharmaceutically acceptable salt thereof for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds and prodrugs thereof, wherein the treatment further comprises administering a compound of formula (I) according to the first category of the present invention or a pharmaceutically acceptable salt thereof.

本發明之第三範疇為醫藥組合物，其包含根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽以及視情況選用之一種或多種醫藥學上可接受之賦形劑，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 The third category of the present invention is a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first category of the present invention and an anticancer agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable formulations selected as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof.

本發明之第四範疇為用於治療癌症之醫藥組合物，其包含根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽以及視情況選用之一種或多種醫藥學上可接受之賦形劑，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 The fourth category of the present invention is a pharmaceutical composition for treating cancer, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first category of the present invention and an anticancer agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable formulations selected as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof.

本發明之第五範疇為一種治療癌症之方法，其包含向有需要之患者投予治療有效量的根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽，及治療有效量的抗癌劑或其醫藥學上可接受之鹽，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 The fifth category of the present invention is a method for treating cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the first category of the present invention or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

本發明之第六範疇為根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽的用途，其用於製造用於治療癌症之藥劑，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 The sixth category of the present invention is the use of the compound of formula (I) or its pharmaceutically acceptable salt and anticancer agent or its pharmaceutically acceptable salt according to the first category of the present invention for the manufacture of a drug for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

本發明之第七範疇為一種組分套組(kit-of-parts)，其包含： The seventh category of the present invention is a kit-of-parts, which includes:

(A)包含以下之醫藥組合物：根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽，及視情況選用之一種或多種醫藥學上可接受之賦形劑，及 (A) A pharmaceutical composition comprising: a compound of formula (I) according to the first category of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected as appropriate, and

(B)包含以下之醫藥組合物：抗癌劑或其醫藥學上可接受之鹽，及視情況選用之一種或多種醫藥學上可接受之賦形劑，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥， (B) A pharmaceutical composition comprising: an anticancer agent or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable formulations as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof,

該等組分(A)及(B)各自以適用於與另一組分結合投予之形式提供， Each of the components (A) and (B) is provided in a form suitable for administration in combination with the other component,

該組分套組用於治療癌症。 This kit is used to treat cancer.

本發明之第八範疇為根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽的用途，其用於治療癌症，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 The eighth category of the present invention is the use of the compound of formula (I) or its pharmaceutically acceptable salt and anticancer agent or its pharmaceutically acceptable salt according to the first category of the present invention for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

除非另外指示，否則本文所使用之所有技術及科學術語皆具有與本發明所涉及領域中一般熟習此項技術者通常所理解之含義相同之含義。 Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the field to which the present invention relates.

除非上下文另有指示，否則本發明之給定範疇、實施例、特徵或參數之偏好及選項應視為已與本發明之所有其他範疇、特徵及參數的任何及所有偏好及選項組合地加以揭示。 Unless the context indicates otherwise, preferences and options for a given aspect, embodiment, feature or parameter of the invention should be considered disclosed in combination with any and all preferences and options for all other aspects, features and parameters of the invention.

本文中採用字詞「約」的地方(例如，在活性成分之劑量的上下文中)，應瞭解此類變數為大致的且因此可與本文所指定的數目相差±10%，例如±5%且較佳±2%(例如，±1%)。 Where the word "about" is used herein (e.g., in the context of the dosage of an active ingredient), it is understood that such variables are approximate and may therefore vary from the numbers specified herein by ±10%, such as ±5% and preferably ±2% (e.g., ±1%).

熟習此項技術者應理解，對特定病狀之「治療(治療)」(及類似地「治療(treating)」)之提及在醫學領域中採用其標準含義。特定言之，該等術語可指實現降低與病狀相關之一種或多種臨床症狀之嚴重程度或延長將治療之患者之壽命。 Those skilled in the art will understand that references to "treatment" (and similarly "treating") of a particular condition adopt their standard meanings in the medical art. Specifically, such terms may refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition or prolonging the life of the patient being treated.

如本文所使用，對患者之提及將係指經治療之活個體，包括哺乳動物(例如人類)患者。在本發明之相關範疇(例如，本發明之第一、第二、第四、第五、第六及第八範疇)的特定實施例中，治療係在哺乳動物(例如，人類)中。 As used herein, reference to a patient will refer to a living individual being treated, including a mammalian (e.g., human) patient. In certain embodiments of the relevant categories of the invention (e.g., the first, second, fourth, fifth, sixth, and eighth categories of the invention), the treatment is in a mammal (e.g., a human).

如本文所使用，術語治療有效量將係指對所治療之患者賦予治療作用之化合物的量。效果可為客觀的(亦即，可藉由某種測試或標記量測)或主觀的(亦即，個體給出效果之指示及/或感覺到效果)。舉例而言，關於形成為一種或多種實體腫瘤之癌症，該治療作用可觀測為彼等腫瘤中之一或多者之體積減小。 As used herein, the term therapeutically effective amount will refer to the amount of a compound that confers a therapeutic effect on the patient being treated. The effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the individual gives an indication of the effect and/or feels the effect). For example, with respect to a cancer that forms as one or more solid tumors, the therapeutic effect may be observable as a reduction in the size of one or more of those tumors.

為避免疑問，如本文所描述之式(I)化合物及抗癌劑可以以之形式存在之形式存在，且因此本發明之範疇包括其所有非晶形、結晶及部分結晶形式，且亦可以油狀物之形式存在。當此類化合物以結晶及部分結晶形式存在時，此類形式可包括水合物及溶劑合物，其包括於本發明之範疇中。化合物亦可存在於溶液中。 For the avoidance of doubt, the compounds of formula (I) and anticancer agents described herein may exist in the form of, and therefore the scope of the present invention includes all amorphous, crystalline and partially crystalline forms thereof, and may also exist in the form of oils. When such compounds exist in crystalline and partially crystalline forms, such forms may include hydrates and solvates, which are included in the scope of the present invention. The compounds may also exist in a solution.

供使用之化合物 Compounds for use

如本文所描述，在本發明之一第一範疇中，提供式(I)化合物或其醫藥學上可接受之鹽與抗癌劑或其醫藥學上可接受之鹽的組合，其用於治療癌症，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥，其中式(I)化合物係選自由以下組成之群： As described herein, in a first aspect of the present invention, a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof is provided for the treatment of cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof, wherein the compound of formula (I) is selected from the group consisting of:

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基] 苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

在本發明之在第二範疇中，提供根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽，其用於治療癌症，其中該治療進一步包含投予抗癌劑或其醫藥學上可接受之鹽，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 In the second aspect of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention is provided for use in treating cancer, wherein the treatment further comprises administering an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

在本發明之一替代性第二範疇中，提供用於治療癌症的抗癌劑或其醫藥學上可接受之鹽，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥，其中該治療進一步包含投予根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽。 In an alternative second embodiment of the present invention, an anticancer agent or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, alkaloid analogs, fluoropyrimidine compounds and prodrugs thereof, wherein the treatment further comprises administering a compound of formula (I) according to the first embodiment of the present invention or a pharmaceutically acceptable salt thereof.

式(I)化合物 Compound of formula (I)

如本文中所提及之式(I)化合物為選自由以下組成之群的化合物： The compound of formula (I) mentioned herein is a compound selected from the group consisting of:

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基] 苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(2-側氧基-1,3-

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide,

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

為避免疑問，式(I)化合物之結構對應於實例1至8中提供之結構。 For the avoidance of doubt, the structures of the compounds of formula (I) correspond to the structures provided in Examples 1 to 8.

在一實施例中，式(I)化合物為(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺。 In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

在一實施例中，式(I)化合物為(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-[(1R)-2-羥基-1-{4-[4-(羥基甲基)-1,3-噻唑-5-基]苯基}乙基]-L-脯胺醯胺。 In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide.

在一實施例中，式(I)化合物為(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(2-側氧基-1,3-

唑啶-3-基)苯基]乙基}-L-脯胺醯胺。 In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

[0134] Oxydridine-3-yl)phenyl]ethyl}-L-prolinamide.

在一實施例中，式(I)化合物為(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(1-甲基-1H-吡唑-5-基)苯基]乙基}-L-脯胺醯胺。 In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide.

在一實施例中，式(I)化合物為(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺。 In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide.

在一實施例中，式(I)化合物為(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺。 In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

在一實施例中，式(I)化合物為(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺。 In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide.

在一實施例中，式(I)化合物為(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-

唑-5-基)苯基]乙基}-L-脯胺醯胺。 In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

在特定實施例中，式(I)化合物係選自由以下組成之群： In a specific embodiment, the compound of formula (I) is selected from the group consisting of:

(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-[(1R)-2-羥基-1-{4-[4-(羥基甲基)-1,3-噻唑-5-基]苯基}乙基]-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2- 基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(2-側氧基-1,3-

唑啶-3-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(1-甲基-1H-吡唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺，及 (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and

(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-

唑-5-基)苯基]乙基}-L-脯胺醯胺。 (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

在某些實施例中，式(I)化合物係選自由以下組成之群： In certain embodiments, the compound of formula (I) is selected from the group consisting of:

(4R)-1-[(2S)-2-(4-{4-[({(7P)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7P)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-[(1R)-2-羥基-1-{4-[4-(羥基甲基)-1,3-噻唑-5-基]苯基}乙基]-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7P)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(2-側氧基-1,3-

唑啶-3-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7P)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(1-甲基-1H-吡唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7P)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5- 基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5- yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7P)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({(7P)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺，及 (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and

(4R)-1-[(2S)-2-(4-{4-[({(7P)-6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-

唑-5-基)苯基]乙基}-L-脯胺醯胺。 (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

式(I)化合物及抗癌劑視取代基之類型而定可具有互變異構物或幾何異構物。在本說明書中，式(I)化合物及抗癌劑有時可僅描述為異構物中之一者，但本發明包括除所描述之一種以外對互變異構物或幾何異構物，且包括經分離之異構物或其混合物。 The compound of formula (I) and the anticancer agent may have tautomers or geometric isomers depending on the type of substituents. In the present specification, the compound of formula (I) and the anticancer agent may sometimes be described as only one of the isomers, but the present invention includes tautomers or geometric isomers other than the one described, and includes separated isomers or mixtures thereof.

式(I)化合物可具有一個或多個不對稱碳原子，且因此可以其特定鏡像異構物及非鏡像異構物之形式存在。本發明包括式(I)化合物之經分離鏡像異構物及非鏡像異構物或其混合物。 The compound of formula (I) may have one or more asymmetric carbon atoms and may therefore exist in the form of its specific mirror image isomers and non-mirror image isomers. The present invention includes separated mirror image isomers and non-mirror image isomers of the compound of formula (I) or mixtures thereof.

具有一個或多個不對稱碳原子之對掌性化合物之鏡像異構物可基於此項技術中已知之方法(例如，使用Cahn-Ingold-Prelog優先規則)相對於各對掌性點以「(R)」及「(S)」標記給出。 Mirror isomers of chiral compounds having one or more asymmetric carbon atoms can be given with "(R)" and "(S)" labels relative to each chiral point based on methods known in the art (e.g., using the Cahn-Ingold-Prelog priority rule).

在某些實施例中，對式(I)化合物之特定立體異構物的參考可指在基本上不存在其他立體異構物(亦即，立體異構物在一個或多個相關對掌性點處具有不同組態)的情況下所存在的特定立體異構物(例如，所指示之特定鏡像異構物或非鏡像異構物)。 In certain embodiments, reference to a particular stereoisomer of a compound of Formula (I) may refer to the presence of that particular stereoisomer (e.g., a particular mirror image isomer or non-mirror image isomer indicated) in the substantial absence of other stereoisomers (i.e., the stereoisomers have different configurations at one or more relevant chiral points).

在此類情況下，呈相關組態之化合物可視需要以至少60%(諸如至少70%、80%、90%、95%或98%，或特定言之至少99%，例如至少99.9%)之鏡像異構物過量(e.e.)或非鏡像異構物過量(d.e.)存在。 In such cases, the compound in the relevant configuration may be present in an excess of at least 60% (e.g. at least 70%, 80%, 90%, 95% or 98%, or in particular at least 99%, for example at least 99.9%) of the mirror image isomer or the non-mirror image isomer (d.e.) as desired.

式(I)化合物可具有軸向對掌性，其可指具有一個或多個軸之化合物，取代基集合圍繞該等軸保持在不與其鏡像重疊之空間排列中。為避免疑問，此類化合物之所有軸向排列均在本發明之範疇內。 Compounds of formula (I) may have axial chirality, which may refer to compounds having one or more axes around which the substituents are arranged in a spatial arrangement that does not overlap with their mirror images. For the avoidance of doubt, all axial arrangements of such compounds are within the scope of the present invention.

軸向對掌性化合物之鏡像異構物可基於此項技術中已知之方法(例如，使用Cahn-Ingold-Prelog優先規則，其中附加規則為兩個「接近的」取代基具有比遠取代基更高的優先級)以「M」及「P」標記給出。 Mirror isomers of axially chiral compounds can be given with "M" and "P" labels based on methods known in the art (e.g., using the Cahn-Ingold-Prelog priority rules with the additional rule that two "proximal" substituents have higher priority than distal substituents).

在某些實施例中，對式(I)化合物之特定軸向立體異構物的參考可指在基本上不存在對應相反立體異構物(例如，具有P-對掌性之異構物)的情況下所存在的特定立體異構物(例如，具有M-軸向對掌性之異構物)。 In certain embodiments, reference to a specific stereoisomer of a compound of formula (I) may refer to the presence of a specific stereoisomer (e.g., an isomer having M-chirality) in the substantial absence of the corresponding opposite stereoisomer (e.g., an isomer having P-chirality).

在此類情況下，相對於其他軸向立體異構物(例如，相對於P-軸向對掌性異構物)，式(I)化合物軸向立體異構物(例如，M-軸向異構物)之純度為至少70%(例如，至少80%、90%、95%或99%)。 In such cases, the purity of the axial stereoisomer (e.g., M-axial isomer) of the compound of formula (I) relative to the other axial stereoisomers (e.g., relative to the P-axial chiral isomer) is at least 70% (e.g., at least 80%, 90%, 95% or 99%).

為避免疑問，在限定位置處具有特定立體化學(例如，軸向對掌性)之化合物亦可在一個或多個其他位置處具有立體化學，且因此可以關於彼等位置處之立體化學的鏡像異構物或非鏡像異構物之混合物的形式存在。 For the avoidance of doubt, a compound having a particular stereochemistry at a defined position (e.g. axial chirality) may also have stereochemistry at one or more other positions and may therefore exist as a mixture of mirror image isomers or non-mirror image isomers with respect to the stereochemistry at those positions.

此外，本發明包括由式(I)表示之化合物及抗癌劑的醫藥學上可接受之前藥(其可稱為前驅物)。醫藥學上可接受之前藥將包括具有可藉由溶劑分解或在生理條件下轉化成胺基、羥基、羧基或類似基團之基團的化合物。可用於形成前藥之基團的實例包括以下中描述之基團：Prog.Med.,1985,5，第2157-2161頁或「Iyakuhin no Kaihatsu(development of pharmaceuticals)」，第7卷，Bunshi-sekkei(molecular design),Hirokawa Shoten,1990，第163-198頁。前藥包括酯及胺基甲酸酯衍生物或諸如結合物之衍生物(例如，白蛋白結合型紫杉醇之結合物)。 In addition, the present invention includes pharmaceutically acceptable prodrugs (which may be referred to as prodrivers) of compounds represented by formula (I) and anticancer agents. Pharmaceutically acceptable prodrugs will include compounds having groups that can be decomposed by solvents or converted into amine, hydroxyl, carboxyl or similar groups under physiological conditions. Examples of groups that can be used to form prodrugs include those described in: Prog. Med., 1985, 5, pp. 2157-2161 or "Iyakuhin no Kaihatsu (development of pharmaceuticals)", Vol. 7, Bunshi-sekkei (molecular design), Hirokawa Shoten, 1990, pp. 163-198. Prodrugs include ester and carbamate derivatives or derivatives such as conjugates (e.g., conjugates of albumin-bound paclitaxel).

前藥可稱為活性化合物(亦即，式(I)化合物及抗癌劑)之前驅物，其可指經代謝以在活體內形成活性化合物之化合物。 Prodrugs may be referred to as precursors of active compounds (i.e., compounds of formula (I) and anticancer agents), which may refer to compounds that are metabolized to form active compounds in vivo.

醫藥學上可接受之鹽包括酸加成鹽及鹼加成鹽。此類鹽可藉由習知方式形成，例如藉由使本發明調配物中所包含之化合物的游離酸或游離鹼形式與一種或多種適當酸或鹼之等效物視情況在溶劑中或在該鹽不可溶之介質中反應，隨後使用標準技術(例如藉由在減壓下旋轉蒸發、藉由冷凍乾燥或藉由過濾)移除該溶劑或該介質。鹽亦可藉由例如使用適合之離子交換樹脂交換本發明調配物中所包含之呈鹽形式之化合物的相對離子與另一相對離子來製備。 Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed in a known manner, for example by reacting a free acid or free base form of a compound contained in a formulation of the invention with one or more equivalents of an appropriate acid or base, as appropriate, in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques, for example by rotary evaporation under reduced pressure, by freeze drying or by filtration. Salts can also be prepared by exchanging the counter ion of a compound in salt form contained in a formulation of the invention with another counter ion, for example using a suitable ion exchange resin.

例示性鹽包括P.Heinrich Stahl,Handbook of Pharmaceutical Salts Properties,Selection,and Use,Wiley-VCH,2008中所示之鹽。特定實例包括與無機酸之酸加成鹽，諸如鹽酸、氫溴酸、氫碘酸、硫酸、硝酸或磷酸；或與有機酸之酸加成鹽，諸如甲酸、乙酸、丙酸、草酸、丙二酸、丁二酸、反丁烯二酸、順丁烯二酸、乳酸、蘋果酸、杏仁酸、酒石酸、二苯甲醯酒石酸、二甲苯醯基酒石酸、檸檬酸、甲磺酸、乙磺酸、苯磺酸、對甲苯磺酸、天冬胺酸或麩胺酸；與無機金屬之鹽，諸如鈉、鉀、鎂、鈣或鋁；與有機鹼之鹽，諸如甲胺、乙胺或乙醇胺；與各種胺基酸及胺基酸衍生物之鹽，諸如乙醯白胺酸、離胺酸及鳥胺酸；以及銨鹽。 Exemplary salts include those listed in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specific examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid; or acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, citric acid, lactic acid, apple acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluyltartaric acid, Tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamine; salts of inorganic metals, such as sodium, potassium, magnesium, calcium or aluminum; salts of organic bases, such as methylamine, ethylamine or ethanolamine; salts of various amino acids and amino acid derivatives, such as acetylleucine, lysine and ornithine; and ammonium salts.

在一實施例中，式(I)化合物及/或抗癌劑的醫藥學上可接受之鹽為鹽酸(HCl)鹽。 In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I) and/or the anticancer agent is a hydrochloric acid (HCl) salt.

此外，本發明亦包括式(I)化合物及抗癌劑之多種水合物、溶劑合物、晶體多晶型物質及非晶形固體形式，以及其鹽。另外，本發明亦包括用各種放射性或非放射性同位素標記之化合物。「非晶形固體形式」包括在粉末X射線繞射(XRD)圖案中未展示峰之形式及具有低結晶度之形式兩者。 In addition, the present invention also includes various hydrates, solvates, crystalline polymorphs and amorphous solid forms of the compound of formula (I) and anticancer agents, as well as salts thereof. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes. "Amorphous solid forms" include both forms that do not show peaks in the powder X-ray diffraction (XRD) pattern and forms with low crystallinity.

抗癌劑 Anticancer agent

如本文所描述，抗癌劑係選自包含以下之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物及氟嘧啶化合物，及其前藥。 As described herein, the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs and fluoropyrimidine compounds, and prodrugs thereof.

術語「紫杉烷」係指一類二萜化合物，其首先源自天然來源，諸如紅豆杉屬之植物，但一些係經人工合成。紫杉烷之特徵在於紫杉烯核心。如本文中所使用，紫杉烷包括紫杉醇、多西他賽、卡巴利他索(cabazitaxel)及巴卡丁III。 The term "taxane" refers to a class of diterpenoid compounds that are primarily derived from natural sources such as plants of the genus Taxus, but some are synthesized artificially. Taxanes are characterized by the taxene core. As used herein, taxanes include paclitaxel, docetaxel, cabazitaxel, and baccatin III.

在一個實施例中，抗癌劑為紫杉烷。在一特定實施例中，紫杉烷為紫杉醇。 In one embodiment, the anticancer agent is a taxane. In a specific embodiment, the taxane is paclitaxel.

紫杉醇係指具有名稱苯甲酸[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-二乙醯基氧基-15-[(2R,3S)-3-苯甲醯胺基-2-羥基-3-苯基丙醯基]氧基-1,9-二羥基-10,14,17,17-四甲基-11-側氧基-6-氧雜四環[11.3.1.03,10.04,7]十七-13-烯-2-基]酯及以下結構的化合物： Paclitaxel refers to a compound having the name benzoic acid [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diethyloxy-15-[(2R,3S)-3-benzylamino-2-hydroxy-3-phenylpropionyl]oxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxotetracyclo[11.3.1.03,10.04,7]heptadeca-13-en-2-yl] ester and the following structure:

在一特定實施例中，紫杉烷為多西他賽。 In a specific embodiment, the taxane is docetaxel.

多西他賽係指具有名稱苯甲酸[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-乙醯氧基-1,9,12-三羥基-15-[(2R,3S)-2-羥基-3-[(2-甲基丙-2-基)氧基羰基胺基]-3-苯基丙醯基]氧基-10,14,17,17-四甲基-11-側氧基-6-氧雜四環[11.3.1.03,10.04,7]十七-13-烯-2-基]酯及以下結構的化合物： Docetaxel refers to a compound with the name of benzoic acid [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-acetyloxy-1,9,12-trihydroxy-15-[(2R,3S)-2-hydroxy-3-[(2-methylprop-2-yl)oxycarbonylamino]-3-phenylpropionyl]oxy-10,14,17,17-tetramethyl-11-oxotetracyclo[11.3.1.03,10.04,7]heptadeca-13-en-2-yl] ester and the following structure:

核苷為諸如DNA及RNA之核酸之結構性次單元，且由核鹼基(亦稱為含氮鹼)及五碳糖(核糖或2'-去氧核糖)組成。 Nucleosides are structural subunits of nucleic acids such as DNA and RNA and are composed of a nucleobase (also called a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose).

「含氟核苷」係指一類化學治療劑。如本文中所使用，「含氟核苷」包括其中核苷上之氫取代基中之至少一者已經一個或多個氟取代基置換的核苷。「含氟核苷」包括吉西他濱及氟達拉濱(fludarabine)。 "Fluorinated nucleosides" refers to a class of chemotherapeutic agents. As used herein, "fluorinated nucleosides" include nucleosides in which at least one of the hydrogen substituents on the nucleoside has been replaced with one or more fluorine substituents. "Fluorinated nucleosides" include gemcitabine and fludarabine.

在一個實施例中，抗癌劑為含氟核苷。在特定實施例中，含氟核苷含有核苷之糖單元上之至少一個氟取代基。 In one embodiment, the anticancer agent is a fluorinated nucleoside. In a particular embodiment, the fluorinated nucleoside contains at least one fluorine substituent on the sugar unit of the nucleoside.

在特定實施例中，含氟核苷為吉西他濱。 In certain embodiments, the fluorinated nucleoside is gemcitabine.

吉西他濱係指具有名稱4-胺基-1-[(2R,4R,5R)-3,3-二氟-4-羥基-5-(羥甲基)氧雜環戊烷-2-基]嘧啶-2-酮及以下結構的化合物： Gemcitabine refers to a compound with the name 4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxacyclopentane-2-yl]pyrimidin-2-one and the following structure:

如本文中所使用，「鉑化合物」係指基於鉑之化學治療劑。「鉑化合物」為鉑之配位複合物，諸如順鉑、奧沙利鉑、卡鉑、奈達鉑(nedaplatin)、四硝酸三鉑、菲鉑(phenanthriplatin)、吡鉑(picoplatin)及賽特鉑(satraplatin)。 As used herein, "platinum compound" refers to a platinum-based chemotherapeutic agent. "Platum compound" is a coordination complex of platinum, such as cisplatin, oxaliplatin, carboplatin, nedaplatin, triplatinum tetranitrate, phenanthriplatin, picoplatin, and satraplatin.

在一個實施例中，抗癌劑為鉑化合物。在特定實施例中，鉑化合物為奧沙利鉑。 In one embodiment, the anticancer agent is a platinum compound. In a specific embodiment, the platinum compound is oxaliplatin.

奧沙利鉑係指具有名稱[(1R,2R)-環己烷-1,2-二胺](乙二酸-O,O')鉑(II)及以下結構的化合物： Oxaliplatin refers to a compound with the name [(1R,2R)-cyclohexane-1,2-diamine](oxalate-O,O')platinum(II) and the following structure:

喜樹鹼類似物係指在結構上與喜樹鹼相關之化合物，諸如伊立替康、胺基喜樹鹼、9-硝基喜樹鹼(盧比替康(rubitecan))、吉馬替康(gimatecan)、拓樸替康(topotecan)、司拉替康(silatecan)、可司替康(cositecan)、依沙替康(exatecan)、勒托替康(lurtotecan)及貝洛替康(belotecan)。術語「喜樹鹼類似物」可包括包含以下子結構之化合物： Camptosine analogs are compounds that are structurally related to camptosine, such as irinotecan, aminocamptosine, 9-nitrocamptosine (rubitecan), gimatecan, topotecan, silatecan, cositecan, exatecan, lurtotecan, and belotecan. The term "camptosine analog" may include compounds that contain the following substructures:

在一個實施例中，抗癌劑為喜樹鹼類似物。在一特定實施例中，喜樹鹼類似物為伊立替康。 In one embodiment, the anticancer agent is a camptothecin analog. In a specific embodiment, the camptothecin analog is irinotecan.

伊立替康係指具有名稱[(19S)-10,19-二乙基-19-羥基-14,18-二側氧基-17-氧雜-3,13-二氮雜環戊并[11.8.0.02,11.04,9.015,20]二十一碳-1(21),2,4(9),5,7,10,15(20)-庚烯-7-基]4-哌啶-1-基哌啶-1-甲酸酯及以下結構之化合物： Irinotecan refers to a compound with the name [(19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazacyclopenta[11.8.0.02,11.04,9.015,20]heneicosane-1(21),2,4(9),5,7,10,15(20)-heptene-7-yl]4-piperidin-1-ylpiperidin-1-carboxylate and the following structure:

「氟嘧啶」化合物係指經至少一個氟取代基取代之嘧啶，且包括卡培他濱、氟尿苷及氟尿嘧啶(5-FU)。熟習此項技術者將理解卡培他濱為5-FU之前藥。 "Fluoropyrimidine" compounds refer to pyrimidines substituted with at least one fluorine substituent and include capecitabine, floxuridine and fluorouracil (5-FU). Those skilled in the art will understand that capecitabine is a prodrug of 5-FU.

在一個實施例中，抗癌劑為氟嘧啶化合物。在一特定實施例中，氟嘧啶化合物為5-氟尿嘧啶，亦稱為5-FU。 In one embodiment, the anticancer agent is a fluoropyrimidine compound. In a specific embodiment, the fluoropyrimidine compound is 5-fluorouracil, also known as 5-FU.

術語「5-氟尿嘧啶」及「5-FU」係指具有名稱5-氟-1H-嘧啶-2,4-二酮及以下結構的化合物： The terms "5-fluorouracil" and "5-FU" refer to a compound having the name 5-fluoro-1H-pyrimidine-2,4-dione and the following structure:

癌症 cancer

如本文中所使用，以下術語可理解為具有如所指示之含義。 As used herein, the following terms shall be understood to have the meanings as indicated.

「G12D突變」表示其中對應於野生型蛋白質中之密碼子12之胺基酸殘基自甘胺酸轉變成天冬胺酸的突變。 "G12D mutation" refers to a mutation in which the amino acid residue corresponding to codon 12 in the wild-type protein is changed from glycine to aspartic acid.

「G12D突變型KRAS」表示具有「G12D突變」之KRAS。 "G12D mutant KRAS" means KRAS with "G12D mutation".

「G12D突變型KRAS陽性癌症」為G12D突變型KRAS-陽性癌症，且例如為其中發生KRAS G12D突變之癌症及具有G12D突變型KRAS之高陽性率的癌症。 "G12D mutant KRAS-positive cancer" is a G12D mutant KRAS-positive cancer, and is, for example, a cancer in which the KRAS G12D mutation occurs and a cancer with a high positive rate for the G12D mutant KRAS.

「胰臟癌」為胰臟中產生之惡性腫瘤。其實例包括胰管癌瘤及胰管腺癌。在一實施例中，「胰臟癌」為胰管癌瘤，且在一實施例中，「胰臟癌」為胰管腺癌。 "Pancreatic cancer" is a malignant tumor that develops in the pancreas. Examples include pancreatic duct carcinoma and pancreatic duct adenocarcinoma. In one embodiment, "pancreatic cancer" is pancreatic duct carcinoma, and in one embodiment, "pancreatic cancer" is pancreatic duct adenocarcinoma.

「大腸直腸癌」為大腸中產生之惡性腫瘤。 "Colonectal cancer" is a malignant tumor that develops in the large intestine.

「肺癌」為肺中產生之惡性腫瘤。 "Lung cancer" is a malignant tumor that develops in the lungs.

在一個實施例中，癌症為轉移性、局部晚期、復發性及/或難治性癌症。 In one embodiment, the cancer is metastatic, locally advanced, recurrent and/or refractory cancer.

在某一實施例中，癌症為關於相關病狀先前未治療之患者(亦即，針對病狀無先前治療醫療史)之癌症，該患者(或特定言之，相關癌症)可稱為未治療。 In one embodiment, the cancer is in a patient who has not been previously treated for the relevant condition (i.e., has no history of prior treatment for the condition), and the patient (or specifically, the relevant cancer) may be referred to as treatment-naive.

在又一實施例中，癌症為針對相關病狀已接受治療(亦即，不同治療，除本發明之第一範疇中所定義以外的治療)且未對該治療作出反應或未恰當反應之患者的癌症。 In another embodiment, the cancer is in a patient who has been treated for a related condition (i.e., a different treatment, other than the treatment defined in the first category of the invention) and has not responded or has not responded adequately to that treatment.

在一個實施例中，癌症定義為難以治療(亦即，耐治療性癌症，為對其他醫學治療不反應或不恰當回應的癌症，該等其他醫學治療將指除本發明之第一範疇中所定義之彼等以外的醫學治療)。難治性癌症可自醫學治療開始呈現對治療之抗性，或癌細胞可在先前醫學治療之療程期間獲得抗性。 In one embodiment, cancer is defined as difficult to treat (i.e., a treatment-resistant cancer is a cancer that does not respond or responds inadequately to other medical treatments, which other medical treatments would refer to medical treatments other than those defined in the first category of the present invention). Refractory cancers may exhibit resistance to treatment from the start of medical treatment, or cancer cells may acquire resistance during a course of previous medical treatment.

在一特定實施例中，癌症相對於用不存在如本發明之第一範疇中所定義之組合的式(I)化合物之療法為難治性癌症(亦即，其中先前療法包括式(I)化合物，但其中該治療不包含用選自紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物及氟嘧啶化合物之抗癌劑治療)。 In a particular embodiment, the cancer is refractory to treatment with a compound of formula (I) in the absence of a combination as defined in the first category of the invention (i.e., wherein the prior treatment included a compound of formula (I), but wherein the treatment did not include treatment with an anticancer agent selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, campestrol analogs, and fluoropyrimidine compounds).

在一實施例中，癌症為胰臟癌。在特定實施例中，胰臟癌為胰管癌瘤或胰管腺癌。 In one embodiment, the cancer is pancreatic cancer. In a specific embodiment, the pancreatic cancer is pancreatic duct carcinoma or pancreatic duct adenocarcinoma.

在一實施例中，癌症為大腸直腸癌。在特定實施例中，大腸直腸癌症為大腸癌或直腸癌。 In one embodiment, the cancer is colorectal cancer. In a specific embodiment, the colorectal cancer is colorectal cancer or rectal cancer.

在一實施例中，癌症為肺癌。在一特定實施例中，肺癌為小細胞肺癌或非小細胞肺癌。 In one embodiment, the cancer is lung cancer. In a specific embodiment, the lung cancer is small cell lung cancer or non-small cell lung cancer.

在一個實施例中，癌症為G12D突變型KRAS陽性癌症。 In one embodiment, the cancer is a G12D mutant KRAS-positive cancer.

在一特定實施例中，G12D突變型KRAS陽性癌症為G12D突變型KRAS陽性胰臟癌。在一替代實施例中，G12D突變型KRAS陽性癌症為G12D突變型KRAS陽性大腸直腸癌。在一替代實施例中，G12D突變型KRAS陽性癌症為G12D突變型KRAS陽性肺癌。 In a specific embodiment, the G12D mutant KRAS-positive cancer is G12D mutant KRAS-positive pancreatic cancer. In an alternative embodiment, the G12D mutant KRAS-positive cancer is G12D mutant KRAS-positive colorectal cancer. In an alternative embodiment, the G12D mutant KRAS-positive cancer is G12D mutant KRAS-positive lung cancer.

根據本發明之第二範疇為用於治療癌症的抗癌劑或其醫藥學上可接受之鹽，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥，其中該治療進一步包含投予根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽。 The second category of the present invention is an anticancer agent or a pharmaceutically acceptable salt thereof for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds and prodrugs thereof, wherein the treatment further comprises administering a compound of formula (I) according to the first category of the present invention or a pharmaceutically acceptable salt thereof.

為避免疑問，本發明之第二範疇可具有本文關於本發明之第一範疇所描述之特定特徵及實施例中之任一者，包括其所有組合。 For the avoidance of doubt, the second aspect of the present invention may have any of the specific features and embodiments described herein with respect to the first aspect of the present invention, including all combinations thereof.

醫藥組合物 Pharmaceutical composition

根據本發明之第三範疇，提供一種醫藥組合物，其包含根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽以及視情況選用之一種或多種醫藥學上可接受之賦形劑，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物其及前藥。 According to the third aspect of the present invention, a pharmaceutical composition is provided, which comprises a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable formulations selected as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

為避免疑問，本發明之第三範疇之醫藥組合物可具有本文關於本發明之其他(例如，第一及第二)範疇所描述之特定特徵及實施例中之任一者，包括其所有組合。 For the avoidance of doubt, the pharmaceutical composition of the third category of the present invention may have any of the specific features and embodiments described herein with respect to other (e.g., first and second) categories of the present invention, including all combinations thereof.

適合之醫藥組合物可為可商購的或以其他方式描述於文獻(參見例如Remington，The Science and Practice of Pharmacy，第19版，Mack Printing Company，Easton，Pennsylvania(1995)及Martindale-The Complete Drug Reference(第35版)及本文中提及之文獻)中，該等文獻之全部相關揭示內容以引用的方式併入本文中。否則，適合組合物之製備，且特定言之包括式(I)化合物及抗癌劑或其醫藥學上可接受之鹽的組合製劑可藉由熟習此項技術者使用常規技術來達成。 Suitable pharmaceutical compositions may be commercially available or otherwise described in the literature (see, for example, Remington, The Science and Practice of Pharmacy, 19th edition, Mack Printing Company, Easton, Pennsylvania (1995) and Martindale-The Complete Drug Reference (35th edition) and the literature mentioned herein), all relevant disclosures of which are incorporated herein by reference. Otherwise, the preparation of suitable compositions, and in particular combination preparations comprising a compound of formula (I) and an anticancer agent or a pharmaceutically acceptable salt thereof, may be achieved by those skilled in the art using conventional techniques.

提及醫藥學上可接受之賦形劑可理解為包括如熟習此項技術者已知的醫藥學上可接受之稀釋劑、載劑及/或佐劑。 References to pharmaceutically acceptable formulations are understood to include pharmaceutically acceptable diluents, carriers and/or adjuvants as known to those skilled in the art.

在特定實施例中，醫藥組合物可根據如本文所描述之投予模式中之一或多者投予。 In certain embodiments, the pharmaceutical composition may be administered according to one or more of the modes of administration as described herein.

為避免疑問，如本文所描述之醫藥組合物可包含如本文所描述之式(I)化合物及/或抗癌劑的一個或多個劑量，或可包含此等組分之部分劑量(在此情況下，可在如本文所描述之治療過程中投予多個此類組合物)。 For the avoidance of doubt, a pharmaceutical composition as described herein may comprise one or more doses of a compound of formula (I) and/or an anticancer agent as described herein, or may comprise a partial dose of such components (in which case a plurality of such compositions may be administered during the course of treatment as described herein).

為避免疑問，如本文所描述之醫藥組合物亦可稱為醫藥調配物。 For the avoidance of doubt, a pharmaceutical composition as described herein may also be referred to as a pharmaceutical formulation.

根據本發明之第四範疇，提供一種用於治療癌症之醫藥組合物，其包含根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽以及視情況選用之一種或多種醫藥學上可接受之賦形劑，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 According to the fourth aspect of the present invention, a pharmaceutical composition for treating cancer is provided, which comprises a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable formulations selected as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof.

為避免疑問，本發明之第四範疇之醫藥組合物可具有本文關於本發明之其他(例如，第一至第三)範疇所描述之特定特徵及實施例中之任一者，包括其所有組合。 For the avoidance of doubt, the pharmaceutical composition of the fourth category of the present invention may have any of the specific features and embodiments described herein with respect to other (e.g., first to third) categories of the present invention, including all combinations thereof.

投予 Invest

如本文中所使用，提及涉及式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽(均如本發明之第一範疇中所定義)的方法及治療，吾等包括依序、分開或同時投予式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽(包括包含各對應組分之醫藥組合物)，作為針對相關疾病或病症之治療的醫學干預之部分。 As used herein, references to methods and treatments involving compounds of formula (I) or their pharmaceutically acceptable salts and anticancer agents or their pharmaceutically acceptable salts (both as defined in the first category of the invention) include sequential, separate or simultaneous administration of compounds of formula (I) or their pharmaceutically acceptable salts and anticancer agents or their pharmaceutically acceptable salts (including pharmaceutical compositions comprising the respective components) as part of a medical intervention for the treatment of the relevant disease or condition.

因此，在某些實施例中，相比於在相同治療過程中在不存在其他組分的情況下單獨(視情況重複)投予包含式(I)化合物或醫藥學上可接受之鹽的調配物或包含抗癌劑(如本發明之第一範疇中所定義)或醫藥學上可接受之鹽的調配物時，一起或在時間上充分接近地(視情況重複)投予兩種活性成分(亦即，式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽)以在治療相關病狀之療程中實現對於患者而言更高的有益作用。判定組合是否提供關於治療特定癌症及在該療程中之較大有益作用可由熟習此項技術者常規地達成。 Thus, in certain embodiments, the two active ingredients (i.e., the compound of formula (I) or its pharmaceutically acceptable salt and the anticancer agent or its pharmaceutically acceptable salt) are administered together or sufficiently close in time (as appropriate) to achieve a greater beneficial effect for the patient in the course of treatment of the relevant condition, compared to when a formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or a formulation comprising an anticancer agent (as defined in the first category of the present invention) or a pharmaceutically acceptable salt is administered alone (as appropriate) in the absence of other components in the same course of treatment. Determining whether a combination provides a greater beneficial effect for the patient in the treatment of a particular cancer and in the course of treatment can be routinely achieved by those skilled in the art.

在其他實施例中，兩種化合物或組合物係在投予另一組分之前、之後及/或同時(視情況重複)投予。當用於此上下文中時，術語「同時投予(administered simultaneously)」及「同時投予(administered at the same time as)」包括式(I)化合物或其醫藥學上可接受之鹽及抗癌劑(如本發明之第一範疇中所定義)或其醫藥學上可接受之鹽之個別劑量係在彼此2小時內(例如，在60分鐘、45分鐘、30分鐘、20分鐘或10分鐘內)投予。 In other embodiments, the two compounds or compositions are administered before, after and/or simultaneously (or repeatedly as appropriate) with the other component. When used in this context, the terms "administered simultaneously" and "administered at the same time as" include individual doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the anticancer agent (as defined in the first category of the present invention) or a pharmaceutically acceptable salt thereof being administered within 2 hours (e.g., within 60 minutes, 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other.

在某些實施例中，兩種化合物或組合物係依序(視情況重複)投予。當用於此上下文中時，術語「依序投予」包括式(I)化合物或其醫藥學上可接受之鹽及抗癌劑(如本發明之第一範疇中所定義)或其醫藥學上可接受之鹽的個別劑量係以彼此之2小時及7天(例如，3小時、4小時、6小時、8小時、12小時、24小時、2天、3天、4天、5天或6天)之間的時間間隔投予。 In certain embodiments, the two compounds or compositions are administered sequentially (or repeatedly, if appropriate). When used in this context, the term "sequential administration" includes that the individual doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the anticancer agent (as defined in the first category of the present invention) or a pharmaceutically acceptable salt thereof are administered at intervals of between 2 hours and 7 days (e.g., 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days or 6 days) from each other.

為避免疑問，式(I)化合物或其醫藥學上可接受之鹽(或包含其之醫藥組合物)可在投予抗癌劑或其醫藥學上可接受之鹽(或包含其之醫藥組合物)之前投予。替代地，抗癌劑或其醫藥學上可接受之鹽(或包含其之醫藥組合物)可在包含式(I)化合物或其醫藥學上可接受之鹽(或包含其之醫藥組合物)之前投予。 For the avoidance of doubt, the compound of formula (I) or its pharmaceutically acceptable salt (or pharmaceutical composition comprising the same) may be administered before the anticancer agent or its pharmaceutically acceptable salt (or pharmaceutical composition comprising the same). Alternatively, the anticancer agent or its pharmaceutically acceptable salt (or pharmaceutical composition comprising the same) may be administered before the compound of formula (I) or its pharmaceutically acceptable salt (or pharmaceutical composition comprising the same).

在一個實施例中，式(I)化合物或其醫藥學上可接受之鹽(或包含其之醫藥組合物)及包含抗癌劑或其醫藥學上可接受之鹽(或包含其之醫藥組合物)之調配物係依序投予，諸如其中在確定用第一藥物治療有效之後投予第二藥物。用於判定第一藥物之有效性的方法為熟習此項技術者已知的。 In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salt (or pharmaceutical composition comprising the same) and the formulation comprising the anticancer agent or its pharmaceutically acceptable salt (or pharmaceutical composition comprising the same) are administered sequentially, such as wherein the second drug is administered after determining that the treatment with the first drug is effective. Methods for determining the effectiveness of the first drug are known to those skilled in the art.

熟習此項技術者將理解如本文所定義之化合物及醫藥調配物可藉由與錠劑、丸劑、膠囊、粒劑、散劑、液體或其他藥劑一起經口投予或藉由與關節內、靜脈內、肌內或其他注射、經黏膜藥劑或吸入劑一起非經腸投予來進行投予。 Those skilled in the art will appreciate that the compounds and pharmaceutical formulations as defined herein may be administered orally with tablets, pills, capsules, granules, powders, liquids or other dosage forms or parenterally with intraarticular, intravenous, intramuscular or other injections, transmucosal dosage forms or inhalants.

作為用於經口投予之固體組合物，使用錠劑、散劑、粒劑或其他藥劑。在此類固體組合物中，將一種或兩種或更多種活性成分與至少一種非活性賦形劑混合。組合物可含有非活性添加劑，例如潤滑劑、崩解劑、穩定劑、根據普通方法之溶解助劑。錠劑或丸劑可視需要包覆有糖包衣或可溶於胃或腸道中之膜。 As solid compositions for oral administration, tablets, powders, granules or other medicaments are used. In such solid compositions, one or two or more active ingredients are mixed with at least one inactive excipient. The composition may contain inactive additives such as lubricants, disintegrants, stabilizers, dissolution aids according to common methods. Tablets or pills may be coated with a sugar coating or a film soluble in the stomach or intestines as required.

用於經口投予之液體組合物包括醫藥學上可接受之乳液、溶液、懸浮液、糖漿或酏劑，且含有通常使用之非活性稀釋劑，例如純化水或EtOH(乙醇)。液體組合物可含有除非活性稀釋劑以外的佐劑，諸如增溶劑、濕潤劑或懸浮劑、甜味劑、調味劑、芳香劑或防腐劑。 Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, and contain commonly used inactive diluents, such as purified water or EtOH (ethanol). Liquid compositions may contain adjuvants other than inactive diluents, such as solubilizers, wetting agents or suspending agents, sweeteners, flavoring agents, aromas or preservatives.

用於非經腸投予之注射劑包括無菌水性或非水性溶液、懸浮液或乳液藥劑。水性溶劑之實例包括注射用蒸餾水或生理食鹽水。非水性溶劑之實例為醇，諸如EtOH。此類組合物可進一步含有等滲劑、防腐劑、濕潤劑、乳化劑、分散劑、穩定劑或溶解助劑。此等組合物例如藉由經由細菌保持過濾器過濾、併入殺微生物劑或照射來滅菌。另外，此類組合物可以無菌固體組合物形式產生，在使用之前將其溶解或懸浮於無菌水或注射用無菌溶劑中。 Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of aqueous solvents include distilled water for injection or physiological saline. Examples of non-aqueous solvents are alcohols, such as EtOH. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or dissolution aids. Such compositions are sterilized, for example, by filtering through a bacteria-retaining filter, incorporating a microbicide or irradiating. In addition, such compositions can be produced in the form of sterile solid compositions, which are dissolved or suspended in sterile water or a sterile solvent for injection before use.

經黏膜藥劑，諸如吸入劑或經鼻藥劑係以固體、液體或半固體形式使用，且可根據常規地已知方法產生。舉例而言，可適當地添加已知賦形劑及另外的pH調節劑、防腐劑、界面活性劑、潤滑劑、穩定劑、增稠劑及其類似者。投予可藉由使用用於吸入或吹入之適當裝置來進行。舉例而言，藥劑可以單獨化合物形式或調配之混合物之散劑形式、或以與醫藥學上可接受之載劑組合之溶液或懸浮液形式使用已知裝置投予，諸如計量及投予吸入裝置、或霧化器。乾粉吸入器或類似物可用於單次投予或多次投予，且可使用乾燥散劑或含散劑之膠囊。替代地，試劑可使用適當的噴射劑，例如適合氣體，諸如氯氟烷烴或二氧化碳以加壓氣溶膠噴霧或類似物之形式使用。 Transmucosal dosage forms, such as inhalants or nasal dosage forms, are used in solid, liquid or semisolid form and can be produced according to conventional known methods. For example, known excipients and additional pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. Administration may be performed by using a suitable device for inhalation or insufflation. For example, the dosage form may be administered in the form of a powder of a single compound or a formulated mixture, or in the form of a solution or suspension in combination with a pharmaceutically acceptable carrier using known devices, such as a metered and administered inhalation device, or a nebulizer. A dry powder inhaler or the like can be used for single or multiple administrations, and a dry powder or a capsule containing the powder can be used. Alternatively, the reagent can be used in the form of a pressurized aerosol spray or the like using a suitable propellant, for example, a suitable gas such as chlorofluorocarbon or carbon dioxide.

在一個實施例中，如本文所描述之化合物及組合物係經口、關節內、靜脈內、肌內、經黏膜或藉由吸入投予。在一特定實施例中，如本文所描述之化合物及組合物係經靜脈內投予。 In one embodiment, the compounds and compositions described herein are administered orally, intraarticularly, intravenously, intramuscularly, transmucosally, or by inhalation. In a specific embodiment, the compounds and compositions described herein are administered intravenously.

在一個實施例中，式(I)化合物或其醫藥學上可接受之鹽(或包含其之醫藥組合物)係經口、關節內、靜脈內、肌內、經黏膜或藉由吸入，諸如靜脈內投予。 In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same) is administered orally, intraarticularly, intravenously, intramuscularly, transmucosally or by inhalation, such as intravenously.

在一個實施例中，抗癌劑或其醫藥學上可接受之鹽(或包含其之醫藥組合物)係經口、關節內、靜脈內、肌內、經黏膜或藉由吸入，諸如經口或靜脈內投予(藉由所使用之抗癌劑測定)。 In one embodiment, the anticancer agent or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same) is administered orally, intraarticularly, intravenously, intramuscularly, transmucosally or by inhalation, such as orally or intravenously (as determined by the anticancer agent used).

在一個實施例中，式(I)化合物或其醫藥學上可接受之鹽與抗癌劑或其醫藥學上可接受之鹽經由相同投予途徑(例如，靜脈內)同時或依序投予。 In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the anticancer agent or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially via the same administration route (e.g., intravenously).

在替代實施例中，式(I)化合物或其醫藥學上可接受之鹽與抗癌劑或其醫藥學上可接受之鹽經由不同投予途徑依序投予。舉例而言，式(I)化合物或其醫藥學上可接受之鹽可靜脈內投予且抗癌劑或其醫藥學上可接受之鹽係經口投予。 In alternative embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the anticancer agent or a pharmaceutically acceptable salt thereof are administered sequentially via different routes of administration. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered intravenously and the anticancer agent or a pharmaceutically acceptable salt thereof may be administered orally.

劑量 Dosage

熟習此項技術者將能夠使用常規技術及參考關於其之相關文獻(諸如相關市場授權及/或及/或藥物處方集)測定如本文所描述之式(I)化合物及抗癌劑之適合(亦即，治療有效)劑量。 Those skilled in the art will be able to determine suitable (i.e., therapeutically effective) dosages of compounds of formula (I) and anticancer agents as described herein using conventional techniques and reference to the relevant literature thereon (such as relevant marketing authorizations and/or drug formularies).

為避免疑問，本文中提及用途、供使用之化合物、方法、組合、組合物及組分套組應包括本文中以其治療有效量使用之藥劑。 For the avoidance of doubt, references herein to uses, compounds for use, methods, combinations, compositions and kits of parts shall include references herein to agents used in therapeutically effective amounts thereof.

如本文所描述之式(I)化合物及抗癌劑之例示性劑量如下。 Exemplary dosages of the compounds of formula (I) and anticancer agents as described herein are as follows.

在經口投予的情況下，式(I)化合物及/或抗癌劑之日劑量可恰當地為約0.001至100mg/kg體重、較佳0.1至30mg/kg體重、更佳0.1至10mg/kg體重，且劑量一次性給予或分成一天兩次至四次(例如，一天兩次、三次或四次)。 In the case of oral administration, the daily dose of the compound of formula (I) and/or the anticancer agent may be appropriately about 0.001 to 100 mg/kg body weight, preferably 0.1 to 30 mg/kg body weight, more preferably 0.1 to 10 mg/kg body weight, and the dose may be given once or divided into two to four times a day (e.g., twice, three times or four times a day).

在靜脈內投予的情況下，式(I)化合物及/或抗癌劑之日劑量可恰當地為約0.0001至10mg/kg體重，且一次性給予或分成一天多次(例如，一天兩次、三次或四次)。 In the case of intravenous administration, the daily dose of the compound of formula (I) and/or the anticancer agent may be appropriately about 0.0001 to 10 mg/kg body weight, and may be given once or divided into multiple doses a day (e.g., twice, three times or four times a day).

另外，經黏膜藥劑之日劑量為約0.001至100mg/kg體重，且一次性給予或分成一天多次(例如，一天兩次、三次或四次)。 In addition, the daily dose of transmucosal drugs is about 0.001 to 100 mg/kg body weight, and is given once or divided into multiple times a day (for example, twice, three times or four times a day).

熟習此項技術者將理解，使用劑量視個人情況，考慮患者之症狀、年齡、性別及類似者來恰當地決定。 Those skilled in the art will understand that dosage is determined on an individual basis, taking into account the patient's symptoms, age, sex, and the like.

治療方法 Treatment methods

根據本發明之第五範疇為一種治療癌症之方法，其包含向有需要之患者投予治療有效量的本發明之第一範疇的化合物或根據本發明之第一範疇的其醫藥學上可接受之鹽，及治療有效量的抗癌劑或其醫藥學上可接受之鹽，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 According to the fifth category of the present invention, there is a method for treating cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the first category of the present invention or a pharmaceutically acceptable salt thereof according to the first category of the present invention, and a therapeutically effective amount of an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

為避免疑問，本發明之第五範疇之方法可具有上文針對本發明之其他(例如，第一至第四)範疇所描述之特定特徵及實施例中之任一者，包括其所有組合。 For the avoidance of doubt, the method of the fifth aspect of the present invention may have any of the specific features and embodiments described above for other aspects of the present invention (e.g., the first to fourth aspects), including all combinations thereof.

在製備藥劑中之用途 Use in the preparation of pharmaceutical preparations

為避免疑問，本發明之第六範疇的用途可具有上文針對本發明之其他(例如，第一至第五)範疇所描述的特定特徵及實施例中之任一者，包括其所有組合。 For the avoidance of doubt, the use of the sixth scope of the present invention may have any of the specific features and embodiments described above for other (e.g., the first to fifth) scopes of the present invention, including all combinations thereof.

組分套組 Component Kit

根據本發明之第七範疇，提供一種組分套組，其包含： According to the seventh aspect of the present invention, a component kit is provided, which comprises:

該組分套組用於治療癌症。 This kit is used to treat cancer.

如本文中所使用，提及彼此結合投予之組分，吾等包括此類組分作為針對治療如本文所描述之相關疾病或病症的醫學干預之部分經依序、分開或同時投予。 As used herein, referring to components administered in conjunction with one another, we include such components being administered sequentially, separately or simultaneously as part of a medical intervention directed to treating the relevant disease or condition as described herein.

在本發明之一替代性第七範疇中，提供一種組分套組，其包含： In an alternative seventh aspect of the present invention, a component kit is provided, which comprises:

(I)如本發明之第七範疇中所描述之組分(A)或(B)中之一者，及 (I) one of the components (A) or (B) described in the seventh aspect of the present invention, and

(II)使用與該兩種組分中之另一者結合使用該組分的說明書， (II) instructions for use of the component in combination with the other of the two components,

該組分套組用於治療癌症。 This kit is used to treat cancer.

為避免疑問，本發明之第七範疇之組分套組可具有上文針對本發明之其他(例如，第一至第六)範疇所描述的特定特徵及實施例中之任一者，包括其所有組合。 For the avoidance of doubt, the component kit of the seventh aspect of the present invention may have any of the specific features and embodiments described above for other aspects of the present invention (e.g., the first to sixth aspects), including all combinations thereof.

用於治療之用途 For therapeutic use

在本發明之一第八範疇，提供根據本發明之第一範疇的式(I)化合物或其醫藥學上可接受之鹽與抗癌劑或其醫藥學上可接受之鹽的用途，其用於治療癌症，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 In the eighth aspect of the present invention, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention and an anticancer agent or a pharmaceutically acceptable salt thereof for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

為避免疑問，本發明之第八範疇的用途可具有上文針對本發明之其他(例如，第一至第七)範疇所描述的特定特徵及實施例中之任一者，包括其所有組合。 For the avoidance of doubt, the use of the eighth aspect of the present invention may have any of the specific features and embodiments described above for other aspects of the present invention (e.g., the first to seventh aspects), including all combinations thereof.

化合物/組合物之製備 Preparation of compounds/compositions

如本文所描述之醫藥組合物、組合產物及套組可根據標準及/或公認醫藥實踐來製備。 The pharmaceutical compositions, combination products and kits described herein may be prepared in accordance with standard and/or generally accepted medical practice.

因此，在本發明之另一範疇中，提供一種用於製備如本文所描述之醫藥組合物的製程，該製程包含使均如本文所描述之式(I)化合物或其醫藥學上可接受之鹽及抗癌劑與一種或多種醫藥學上可接受之賦形劑結合。 Therefore, in another aspect of the present invention, a process for preparing a pharmaceutical composition as described herein is provided, which comprises combining a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent as described herein with one or more pharmaceutically acceptable excipients.

在本發明之其他範疇中，提供一種用於製備如上文中所定義之組合產品或組分套組的製程。該製程包含使均如本文所描述之式(I)化合物或其醫藥學上可接受之鹽及抗癌劑結合。 In other aspects of the present invention, a process for preparing a combination product or a kit of parts as defined above is provided. The process comprises combining a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein and an anticancer agent.

如本文所使用，對結合之提及將意謂使兩種組分適合於彼此一起投予。 As used herein, reference to combining will mean making the two components suitable for administration together with each other.

因此，關於製備如上文所定義之組分套組之方法，藉由使兩種組分彼此「結合」，吾等包括組分套組之兩種組分可： Therefore, with respect to the method of preparing a kit of parts as defined above, by "combining" the two components with each other, we include that the two components of the kit of parts may:

(i)提供為單獨調配物(亦即，彼此獨立)，其隨後結合在一起以在組合療法中彼此結合使用；或 (i) provided as separate formulations (i.e., separate from each other) which are subsequently combined together for use in combination with each other in combination therapy; or

(ii)包裝且一起呈現為用於在組合療法中彼此結合使用之「組合包裝」的各別組分。 (ii) The individual components are packaged and presented together as a "combination pack" for use in conjunction with each other in combination therapy.

如本文所描述之化合物，包括式(I)化合物及其醫藥學上可接受之鹽及如本文所描述之抗癌劑，可根據熟習此項技術者已熟知之技術，諸如下文中提供之實例中描述及/或公開文獻中關於各此類化合物所提供之彼等技術來製備。 The compounds described herein, including compounds of formula (I) and pharmaceutically acceptable salts thereof, and anticancer agents described herein, can be prepared according to techniques well known to those skilled in the art, such as those described in the examples provided below and/or those provided in the literature for each such compound.

如本文所描述之某些化合物，諸如如本文所描述之抗癌劑及包含其之醫藥組合物可購自熟習此項技術者已知之來源。 Certain compounds as described herein, such as anticancer agents as described herein, and pharmaceutical compositions containing the same can be purchased from sources known to those skilled in the art.

式(I)化合物及其鹽可藉由應用各種已知合成方法使用基於其基本結構或取代基類型之特徵來產生。此處，視官能基之類型而定，作為生產技術，有時有效的是在原材料至中間物之過程中用適當保護基(可容易轉化成官能基之基團)取代官能基。保護基之實例包括P.G.M.Wuts及T.W.Greene,「Greene's Protective Groups in Organic Synthesis」，第5版，John Wiley & Sons Inc.,2014中描述之保護基且適當選自該等保護基之基團視反應條件而使用。在此類方法中，在引入保護基的情況下進行反應，且隨後視需要移除保護基，藉此可獲得所需化合物。 The compound of formula (I) and its salt can be produced by applying various known synthesis methods using characteristics based on its basic structure or substituent type. Here, depending on the type of functional group, as a production technology, it is sometimes effective to replace the functional group with an appropriate protective group (a group that can be easily converted into a functional group) during the process from the raw material to the intermediate. Examples of protective groups include the protective groups described in P.G.M.Wuts and T.W.Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014, and the group appropriately selected from these protective groups is used depending on the reaction conditions. In this type of method, the reaction is carried out with the introduction of the protective group, and the protective group is then removed as necessary, thereby obtaining the desired compound.

另外，式(I)化合物之前藥可藉由在原材料至中間物之過程中引入就以上保護基而言之特定基團或藉由使用獲得之式(I)化合物進一步進行反應來產生。此反應可藉由應用熟習此項技術者已知之方法，諸如常用酯化、醯胺化或脫水來進行。 In addition, the prodrug of the compound of formula (I) can be produced by introducing a specific group in the process of converting the raw material into an intermediate with respect to the above protective group or by further reacting the obtained compound of formula (I). This reaction can be carried out by applying methods known to those skilled in the art, such as conventional esterification, amidation or dehydration.

分離及純化藉由應用常用化學操作，諸如萃取、分步結晶或各種類型之溶離層析法來進行。 Separation and purification are carried out by applying common chemical procedures such as extraction, fractional crystallization or various types of elution chromatography.

各種類型之異構物可藉由選擇適當的原材料化合物產生或可使用異構物之間的生理化學特性差異來分離。舉例而言，光學異構物可藉由外消旋物之通用光學離析方法(例如，用於將外消旋物誘導成具有光活性鹼或酸之非鏡像異構物鹽的分步結晶、使用對掌性管柱或類似物之層析，或類似法)獲得且亦可由適當的光活性原材料化合物產生。 Various types of isomers can be produced by selecting appropriate raw material compounds or can be separated using differences in the physiochemical properties between isomers. For example, optical isomers can be obtained by general optical separation methods for racemates (e.g., fractional crystallization for inducing racemates into non-image-bearing isomer salts with optically active bases or acids, chromatography using a chiral column or the like, or the like) and can also be produced from appropriate optically active raw material compounds.

另外，式(I)化合物或其中間物有時具有軸向對掌性且以軸向立體異構物之混合物形式獲得，且各軸向立體異構物可藉由使用常用分離操作，例如十八烷基矽基(ODS)管柱層析或矽膠管柱層析進行分離來分離。 In addition, the compound of formula (I) or its intermediate sometimes has axial chirality and is obtained as a mixture of axial stereoisomers, and each axial stereoisomer can be separated by using a common separation operation, such as octadecylsilyl (ODS) column chromatography or silica gel column chromatography.

本發明之優勢 Advantages of the present invention

如本文所描述之治療可具有以下優勢：其可比如先前技術中已知之針對系統病狀之治療更有效、毒性更小、作用愈久、更有效力、產生的副作用更小及/或治療概況更佳。 Treatments as described herein may have the following advantages: they may be more effective, less toxic, longer acting, more potent, produce fewer side effects and/or provide a better treatment profile than treatments for systemic conditions known in the prior art.

以不受理論約束為前提，咸信式(I)化合物對G12D突變型KRAS蛋白具有誘導降解作用及G12D突變型KRAS抑制活性，且可與抗癌劑一起使用以在治療癌症，且特定言之G12D突變型KRAS陽性癌症中協同地作用，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 Without theoretical constraints, it is believed that the compound of formula (I) has an inducing degradation effect on G12D mutant KRAS protein and G12D mutant KRAS inhibitory activity, and can be used together with anticancer agents to act synergistically in the treatment of cancer, and specifically G12D mutant KRAS positive cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, alkaloid analogs, fluoropyrimidine compounds and their prodrugs.

實例Examples

式(I)化合物之製造方法將在下文基於實例進一步詳細地描述。應注意，本發明不限於以下實例中所描述之化合物。原材料化合物之製造方法亦展示於該等製備實例中。式(I)化合物之製造方法不僅限於下文所描述之特定實例之製造方法，且式(I)化合物亦可藉由該等製造方法之組合或熟習此項技術者顯而易見的方法來產生。 The preparation method of the compound of formula (I) will be described in further detail below based on examples. It should be noted that the present invention is not limited to the compounds described in the following examples. The preparation method of the raw material compound is also shown in the preparation examples. The preparation method of the compound of formula (I) is not limited to the preparation method of the specific example described below, and the compound of formula (I) can also be produced by a combination of these preparation methods or a method that is obvious to those skilled in the art.

在命名法與如以圖形方式所描繪之化合物結構之間存在不一致的情況下，後者係主要的(除非與可給出之任何實驗細節相矛盾及/或除非自上下文中清楚可見)。 In case of inconsistency between nomenclature and the structure of the compound as depicted graphically, the latter is dominant (unless contradicted by any experimental details that can be given and/or unless clear from the context).

出於便利性之目的，濃度mol/L以M展示。舉例而言，1M氫氧化鈉水溶液意謂1mol/L之氫氧化鈉水溶液。 For the purpose of convenience, the concentration mol/L is shown as M. For example, 1M sodium hydroxide aqueous solution means 1 mol/L sodium hydroxide aqueous solution.

縮寫 Abbreviation

本文中可使用以下縮寫。 The following abbreviations may be used in this article.

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

DMAc：N,N-二甲基乙醯胺 DMAc: N,N-dimethylacetamide

THF：四氫呋喃 THF: Tetrahydrofuran

MeCN：乙腈 MeCN: acetonitrile

MeOH：甲醇 MeOH: methanol

EtOH：乙醇 EtOH: ethanol

DOX：1,4-二

烷 DOX: 1,4-dimethoxy

alkyl

DMSO：二甲亞碸 DMSO: dimethyl sulfoxide

TEA：三乙胺 TEA: triethylamine

DIPEA：N,N-二異丙基乙胺 DIPEA: N,N-diisopropylethylamine

tBuOK：三級丁醇鉀 tBuOK: Potassium tertiary butoxide

HATU：3-氧化物六氟磷酸1-[雙(二甲胺基)亞甲基]-1H-1,2,3-***并[4,5-b]吡錠 HATU: 3-oxide hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine

DABCO：1,4-二氮雜二環[2.2.2]辛烷 DABCO: 1,4-diazabicyclo[2.2.2]octane

PdCl₂(dppf)．CH₂Cl₂：[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(II)-二氯甲烷加合物 PdCl ₂ (dppf)．CH ₂ Cl ₂ ：[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct

Pd/C：鈀/碳 Pd/C: Palladium/Carbon

製備實例 Preparation Example

製備實例1 Preparation Example 1

將7-溴-2,4-二氯-8-氟-6-碘喹唑啉(100g)、DOX(1000mL)及THF(500mL)之混合物用冰浴冷卻，隨後添加DIPEA(240mL)及(1S,4S)-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(48g)，且將混合物在室溫下攪拌隔夜。向反應混合物中添加水且用乙酸乙酯萃取混合物。有機層用氯化鈉水溶液洗滌，經無水硫酸鎂乾燥，且隨後在減壓下濃縮直至溶液之總體積變成約400mL。將混合溶劑(己烷/乙酸乙酯=4/1，1000mL)添加至所得溶液中，且將混合物在室溫下攪拌。過濾沈澱之固體，得到呈固體狀之(1S,4S)-5-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(123g)。 A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL) and THF (500 mL) was cooled with an ice bath, followed by the addition of DIPEA (240 mL) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (48 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure until the total volume of the solution became about 400 mL. A mixed solvent (hexane/ethyl acetate = 4/1, 1000 mL) was added to the resulting solution, and the mixture was stirred at room temperature. The precipitated solid was filtered to obtain (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (123 g) as a solid.

製備實例2 Preparation Example 2

在室溫下在氬氣氛圍下在攪拌下向(1S,4S)-5-(7-溴-2-氯-8-氟-6-碘喹唑啉-4- 基)-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(30g)、四氫-2H-哌喃-4-醇(15.0mL)、DMF(150mL)、THF(100mL)及DABCO(1.15g)之混合物中添加碳酸銫(50.3g)，將混合物在室溫下攪拌隔夜。將約1kg冰水添加至反應混合物中，且將混合物在室溫下攪拌6小時。將沈澱之固體過濾，用水洗滌且在減壓下乾燥隔夜，得到呈固體狀之(1S,4S)-5-{7-溴-8-氟-6-碘-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(32.8g)。 To a mixture of (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (30 g), tetrahydro-2H-pyran-4-ol (15.0 mL), DMF (150 mL), THF (100 mL) and DABCO (1.15 g) was added cesium carbonate (50.3 g) with stirring at room temperature under an argon atmosphere, and the mixture was stirred at room temperature overnight. About 1 kg of ice water was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. The precipitated solid was filtered, washed with water and dried under reduced pressure overnight to obtain (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (32.8 g) as a solid.

製備實例3 Preparation Example 3

在氬氣流下，在冰浴冷卻下向(1S,4S)-5-{7-溴-8-氟-6-碘-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(11.9g)、苯甲醇(2.37g)及THF(40mL)之混合物中添加tBuOK(2.54g)，且將混合物在相同溫度下攪拌1.5小時。將冰水及飽和氯化銨水溶液添加至反應混合物中，混合物用乙酸乙酯萃取，且有機層經無水硫酸鎂乾燥。將溶液在減壓下濃縮，且將己烷/乙酸乙酯(6/1)之混合溶劑添加至所得殘餘物中。將混合物攪拌片刻，且將沈澱之固體過濾，且乾燥，得到呈固體狀之(1S,4S)-5-{8-(苯甲氧基)-7-溴-6-碘-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(11.8g)。 To a mixture of (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (11.9 g), benzyl alcohol (2.37 g) and THF (40 mL) was added tBuOK (2.54 g) under an argon stream with ice-bath cooling, and the mixture was stirred at the same temperature for 1.5 hours. Ice water and a saturated aqueous ammonium chloride solution were added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and a mixed solvent of hexane/ethyl acetate (6/1) was added to the resulting residue. The mixture was stirred for a while, and the precipitated solid was filtered and dried to obtain (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (11.8 g) as a solid.

製備實例4 Preparation Example 4

在氬氣氛圍下，將(1S,4S)-5-{8-(苯甲氧基)-7-溴-6-碘-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(5.47g)、MeCN(88mL)、DOX(10mL)、水(22mL)、環丙基硼酸(1.27g)、磷酸三鉀(5.67g)及PdCl₂(dppf)．CH₂Cl₂(600mg)之混合物在100℃下攪拌3小時。在使反應混合物冷卻至室溫之後，將溶液在減壓下濃縮。將飽和氯化鈉水溶液添加至所得殘餘物中，且混合物用CHCl₃萃取。有機層經無水硫酸鎂乾燥，且將溶液在減壓下濃縮。所得殘餘物藉由矽膠管柱層析(己烷/乙酸乙酯)來純化，得到呈泡沫樣固體狀之(1S,4S)-5-{8-(苯甲氧基)-7-溴-6-環丙基-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(3.8g)。 Under an argon atmosphere, a mixture of (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (5.47 g), MeCN (88 mL), DOX (10 mL), water (22 mL), cyclopropylboronic acid (1.27 g), tripotassium phosphate (5.67 g) and PdCl ₂ (dppf) ． CH ₂ Cl ₂ (600 mg) was stirred at 100° C. for 3 hours. After the reaction mixture was cooled to room temperature, the solution was concentrated under reduced pressure. A saturated aqueous sodium chloride solution was added to the obtained residue, and the mixture was extracted with CHCl _3. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (3.8 g) as a foamy solid.

製備實例5 Preparation Example 5

將(1S,4S)-5-{8-(苯甲氧基)-7-溴-6-環丙基-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(3.15g)、6-氟-5-甲基-1-(四氫-2H-哌喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1H-吲唑(1.92g)、磷酸三鉀(4.1g)、二環己基(2',6'-二異丙氧基-[1,1'-聯苯]-2-基)膦(0.12g)、(2-二環己基膦-2',6'-二異丙氧基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]甲磺酸鈀(II)(0.2g)、DOX(40mL)及水(8mL)之混合物脫氣且在室溫下在攪拌下用氬取代，且隨後，將混合物在100℃在氬氣氛圍下攪拌2.5小時。將水(約150mL)添加至經冷卻至室溫之反應混合物中，且用乙酸乙酯萃取混合物。在有機層經無水硫酸鎂乾燥之後，藉由過濾移除不可溶物質，且在減壓下濃縮濾液。所得殘餘物藉由矽膠管柱層析(鹼性矽膠，己烷/乙酸乙酯)來純化，且獲得分別含有以下之溶離份：(1)低極性非鏡像異構混合物(峰-1及峰-2；峰-1及峰-2具有相同的軸向對掌性)及(2)高極性非鏡像異構混合物(峰-3及峰-4；峰-3及峰-4具有相同的軸向對掌性)。在此等溶離份中，收集含有低極性非鏡像異構混合物(峰-1及峰-2，相同軸向對掌性)之溶離份，得到呈泡沫樣固體狀之(1S,4S)-5-{8-(苯甲氧基)-6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(1.42g)。另外，收集含有高極性非鏡像異構混合物(峰-3及峰-4，相同軸向對掌性)之溶離份，得到呈泡沫樣固體狀之(1S,4S)-5-{8-(苯甲氧基)-6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(1.37g)。將低極性非鏡像異構混合物用於後續反應。 (1S,4S)-5-{8-(Benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (3.15 g), 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentyl)-1H-indazole (1.92 g), tripotassium phosphate (4. A mixture of 2-(4-(2-(2-(2-amino-1,1'-biphenyl)-4-yl)-2-nitropropoxy)-1,2-dicyclohexylphosphine (0.1 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (0.12 g), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate (II) (0.2 g), DOX (40 mL) and water (8 mL) was degassed and replaced with hydrogen at room temperature with stirring, and then the mixture was stirred at 100° C. under an atmosphere of hydrogen for 2.5 hours. Water (about 150 mL) was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate), and fractions containing (1) a low-polarity non-mirror isomeric mixture (peak-1 and peak-2; peak-1 and peak-2 have the same axial chirality) and (2) a high-polarity non-mirror isomeric mixture (peak-3 and peak-4; peak-3 and peak-4 have the same axial chirality) were obtained. Among these fractions, the fraction containing a low-polarity non-mirror image-forming isomeric mixture (peak-1 and peak-2, same axial chirality) was collected to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (1.42 g) as a foamy solid. In addition, the fraction containing the highly polar non-mirror isomer mixture (peak-3 and peak-4, same axial chirality) was collected to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexyl-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (1.37 g) as a foamy solid. The low polar non-mirror isomer mixture was used for the subsequent reaction.

製備實例6 Preparation Example 6

向在製備實例11中獲得之低極性非鏡像異構混合物(1S,4S)-5-{8-(苯甲氧基)-6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(10g)之MeOH(200mL)溶液中添加10% Pd/C(50%潤濕，2g)，且將反應混合物在氫氣氛圍下在室溫下攪拌2小時。所得反應混合物經由矽藻土墊過濾且用MeOH洗滌。在減壓下濃縮濾液，且所得殘餘物藉由矽膠管柱層析(己烷/乙酸乙酯)來純化，得到呈泡沫樣固體狀之(1S,4S)-5-{6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-8-羥基-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(8.11g)。 To a MeOH (200 mL) solution of the low-polarity non-mirror isomeric mixture (1S, 4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (10 g) obtained in Preparation Example 11 was added 10% Pd/C (50% wet, 2 g), and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The obtained reaction mixture was filtered through a diatomaceous earth pad and washed with MeOH. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (8.11 g) as a foamy solid.

製備實例7 Preparation Example 7

在室溫下在攪拌下向(1S,4S)-5-{6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-8-羥基-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(7.48g)、DMF(70mL)及1-(氯甲基)-4-乙炔苯(1.9g)之混合物中添加碳酸銫(6.2g)，且將混合物在60℃在氬氣氛圍下攪拌2小時。向冷卻至室溫之反應混合物中添加冰水及飽和氯化銨水溶液，且用乙酸乙酯萃取混合物。有機層用飽和氯化鈉水溶液洗滌且經無水硫酸鎂乾燥。隨後，藉由過濾移除不可溶物質，且在減壓下濃縮濾液。所得殘餘物藉由矽膠管柱層析(鹼性矽膠，己烷/乙酸乙酯)來純化，且過濾所得固體，得到呈泡沫樣固體狀之(1S,4S)-5-{6-環丙基-8-[(4-乙炔基苯基)甲氧基]-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑- 4-基]-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(8.12g)。 To a mixture of (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (7.48 g), DMF (70 mL) and 1-(chloromethyl)-4-ethynylbenzene (1.9 g) was added cesium carbonate (6.2 g) with stirring at room temperature, and the mixture was stirred at 60° C. under an nitrogen atmosphere for 2 hours. To the reaction mixture cooled to room temperature were added ice water and a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Subsequently, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate), and the obtained solid was filtered to obtain (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol- 4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (8.12 g) as a foamy solid.

製備實例8 Preparation Example 8

在室溫下向(1S,4S)-5-{6-環丙基-8-[(4-乙炔基苯基)甲氧基]-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(4.24g)、(4R)-1-[(2S)-2-疊氮基-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺(2.30g)、抗壞血酸鈉(1.45g)、三級丁醇(35mL)、THF(35mL)及水(35mL)之混合物中添加無水硫酸銅(II)(389mg)，且將混合物在室溫下攪拌2.5小時。添加乙酸乙酯及水，且分離水層。水層用乙酸乙酯萃取，且合併之有機層用飽和氯化鈉水溶液洗滌且經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)純化，得到呈固體狀之(1S,4S)-5-{6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-羥基-2-({(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}胺甲醯基)吡咯啶-1-基]-3-甲基-1-側氧基丁-2-基}-1H-1,2,3-***-4-基)苯基]甲氧基}-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(5.62g)。 At room temperature, (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (4.24 g), (4R)-1-[(2S)-2-azido To a mixture of 1-[(4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (2.30 g), sodium ascorbate (1.45 g), tert-butyl alcohol (35 mL), THF (35 mL) and water (35 mL) was added anhydrous copper (II) sulfate (389 mg), and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate and water were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3 -thiazol-5-yl)phenyl]ethyl}aminoformyl)pyrrolidin-1-yl]-3-methyl-1-oxobutyl-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (5.62 g).

製備實例12 Preparation Example 12

在室溫下向(1S,4S)-5-{6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-羥基-2-(甲氧基羰基)吡咯啶-1-基]-3-甲基-1-側氧基丁-2-基}-1H-1,2,3-***-4-基)苯基]甲氧基}-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(3.97g)之1,2-二氯乙烷(60mL) 溶液中添加氫氧化三甲基錫(IV)(3.35g)，且將混合物在80℃攪拌18小時。在使混合物冷卻至室溫之後，添加鹽酸(1M，60mL)，且用CHCl₃/MeOH(9/1)萃取混合物。有機層用1M鹽酸洗滌且經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)純化，得到呈固體狀之(4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(三級丁氧基羰基)-2,5-二氮雜二環[2.2.1]庚-2-基]-6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-L-脯胺酸(3.26g)。 To a solution of (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidin-1-yl]-3-methyl-1-oxobutyl-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (3.97 g) in 1,2-dichloroethane (60 mL) was added at room temperature. To the solution was added trimethyltin(IV) hydroxide (3.35 g), and the mixture was stirred at 80° C. for 18 hours. After the mixture was cooled to room temperature, hydrochloric acid (1 M, 60 mL) was added, and the mixture was extracted with CHCl ₃ /MeOH (9/1). The organic layer was washed with 1 M hydrochloric acid and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tributyloxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-L-proline (3.26 g) as a solid.

製備實例13 Preparation Example 13

在冰浴冷卻下向(4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(三級丁氧基羰基)-2,5-二氮雜二環[2.2.1]庚-2-基]-6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-L-脯胺酸(150mg)、3-{4-[(1R)-1-胺基-2-羥乙基]苯基}-1,3-

唑啶-2-酮單鹽酸鹽(60mg)、DIPEA(70μL)及DMF(3mL)之混合物中添加HATU(70mg)，且將混合物在冰浴冷卻下攪拌1小時。將水、飽和氯化鈉水溶液及乙酸乙酯添加至混合物中，且分離水層。水層用乙酸乙酯萃取，且合併之有機層用水及飽和氯化鈉水溶液洗滌，且經無水硫酸鎂乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)純化，得到呈固體狀之(1S,4S)-5-{6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-羥基-2-({(1R)-2-羥基-1-[4-(2-側氧基-1,3-

唑啶-3-基)苯基]乙基}胺甲醯基)吡咯啶-1-基]-3-甲基-1-側氧基丁-2-基}-1H-1,2,3-***-4-基)苯基]甲氧基}-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1] 庚烷-2-甲酸三級丁酯(173mg)。 Under ice cooling, (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tributyloxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexyl-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-L-proline (150 mg), 3-{4-[(1R)-1-amino-2-hydroxyethyl]phenyl}-1,3-

To a mixture of oxazolidin-2-one monohydrochloride (60 mg), DIPEA (70 μL) and DMF (3 mL) was added HATU (70 mg), and the mixture was stirred for 1 hour under ice-bath cooling. Water, a saturated aqueous sodium chloride solution and ethyl acetate were added to the mixture, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

[0147] The mixture was mixed with 1,2-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (173 mg).

製備實例14 Preparation Example 14

在室溫下向N-[(1R)-1-(4-溴苯基)-2-羥乙基]胺基甲酸三級丁酯(5.01g)於DMAc(80mL)中之溶液中添加4-甲基-1,3-噻唑(2.88mL)及乙酸鉀(3.11g)，且將混合物脫氣且用氬氣填充三次。在室溫下添加乙酸鈀(356mg)且將混合物在100℃攪拌16小時。在將混合物冷卻至室溫之後，添加乙酸乙酯及水，且藉由用矽藻土墊過濾移除不可溶物質。將水添加至濾液中，且用乙酸乙酯萃取混合物三次。合併之有機層用飽和氯化鈉水溶液洗滌，且經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(鹼性矽膠，己烷/乙酸乙酯)純化，得到呈固體狀之{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}胺基甲酸三級丁酯(4.66g)。 To a solution of tributyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (5.01 g) in DMAc (80 mL) were added 4-methyl-1,3-thiazole (2.88 mL) and potassium acetate (3.11 g) at room temperature, and the mixture was degassed and filled with hydrogen three times. Potassium acetate (356 mg) was added at room temperature and the mixture was stirred at 100° C. for 16 hours. After the mixture was cooled to room temperature, ethyl acetate and water were added, and insoluble materials were removed by filtering through a diatomaceous earth pad. Water was added to the filtrate, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to obtain tert-butyl {(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamate (4.66 g) as a solid.

製備實例15 Preparation Example 15

在氬氣氛圍下，向N-[(1R)-1-(4-溴苯基)-2-羥乙基]胺基甲酸三級丁酯(4.43g)、1-乙基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1H-吡唑(4.67g)、碳酸鉀(3.87g)、DOX(80mL)及水(8mL)之混合物中添加PdCl₂(dppf)．CH₂Cl₂(1.14g)，且將混合物在100℃攪拌16小時。在使混合物冷卻至室溫之後，添加乙酸乙酯，且經由矽藻土墊過濾混合物且在減壓下濃縮。殘餘物藉由矽膠管柱層析(鹼性矽膠，己烷/乙酸乙酯)純化，得到呈固體狀之{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}胺基甲酸三級丁酯(3.74g)。 To a mixture of tributyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (4.43 g), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.67 g), potassium carbonate (3.87 g), DOX (80 mL) and water (8 mL) was added PdCl ₂ (dppf) ． CH ₂ Cl ₂ (1.14 g) under an argon atmosphere, and the mixture was stirred at 100° C. for 16 hours. After the mixture was cooled to room temperature, ethyl acetate was added, and the mixture was filtered through a diatomaceous earth pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica, hexane/ethyl acetate) to give tert-butyl {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamate (3.74 g) as a solid.

製備實例17 Preparation Example 17

在冰浴冷卻下向{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}胺基甲酸三級丁酯(4.41g)於CH₂Cl₂(50mL)及MeOH(50mL)中之溶液中逐滴添加鹽酸 (4M DOX溶液，20mL)，且將混合物在室溫下攪拌6小時。將二***添加至反應混合物中，且將所得固體過濾，用二***洗滌且在減壓下乾燥，得到呈固體狀之(2R)-2-胺基-2-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙-1-醇n．鹽酸鹽(2.12g)。在減壓下乾燥濃縮濾液，得到呈固體狀之(2R)-2-胺基-2-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙-1-醇n．鹽酸鹽(2.01g)。 To a solution of tributyl {(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamate (4.41 g) in CH ₂ Cl ₂ (50 mL) and MeOH (50 mL) was added hydrochloric acid (4M DOX solution, 20 mL) dropwise under ice-cooling, and the mixture was stirred at room temperature for 6 hours. Diethyl ether was added to the reaction mixture, and the resulting solid was filtered, washed with diethyl ether and dried under reduced pressure to give (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol hydrochloride (2.12 g) as a solid. The concentrated filtrate was dried under reduced pressure to obtain (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol hydrochloride (2.01 g) as a solid.

製備實例18 Preparation Example 18

在-20至-10℃向{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}胺基甲酸三級丁酯(3.34g)於CH₂Cl₂(25mL)及MeOH(25mL)中之溶液中添加鹽酸(4M DOX溶液，25.6mL)，且將混合物在室溫下攪拌5小時。將反應混合物在減壓下濃縮，得到呈固體狀之(2R)-2-胺基-2-[4-(1-乙基-1H-吡唑-5-基)苯基]乙-1-醇n．鹽酸鹽(3.06g)。 To a solution of tributyl {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamate (3.34 g) in CH ₂ Cl ₂ (25 mL) and MeOH (25 mL) was added hydrochloric acid (4M DOX solution, 25.6 mL) at -20 to -10°C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]ethan-1-ol hydrochloride (3.06 g) as a solid.

製備實例20 Preparation Example 20

在冰浴冷卻下向(2R)-2-胺基-2-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙-1-醇n．鹽酸鹽(2.12g)、(4R)-1-(三級丁氧基羰基)-4-羥基-L-脯胺酸(1.76g)及DMF(22mL)之混合物中添加添加DIPEA(4.7mL)，且隨後在冰浴冷卻下逐滴添加HATU(3.02g)以維持內部溫度低於5℃。將混合物在冰浴冷卻下攪拌1小時且在室溫下攪拌1小時。在冰浴冷卻下，添加水(120mL)、飽和氯化鈉水溶液(50ml)及乙酸乙酯，且用乙酸乙酯萃取水層三次，且隨後用乙酸乙酯/異丙醇(9/1)萃取三次。合併之有機層用飽和氯化鈉水溶液洗滌，且經無水硫酸鎂乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)純化，得到呈油狀物之(2S,4R)-4-羥基-2-({(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}胺甲醯基)吡咯啶-1-甲酸三級丁酯(3.09g)。 To a mixture of (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol hydrochloride (2.12 g), (4R)-1-(tert-butyloxycarbonyl)-4-hydroxy-L-proline (1.76 g) and DMF (22 mL) was added DIPEA (4.7 mL) under ice-bath cooling, and then HATU (3.02 g) was added dropwise under ice-bath cooling to maintain the internal temperature below 5° C. The mixture was stirred under ice-bath cooling for 1 hour and at room temperature for 1 hour. Under ice-cooling, water (120 mL), a saturated aqueous sodium chloride solution (50 ml) and ethyl acetate were added, and the aqueous layer was extracted three times with ethyl acetate and then three times with ethyl acetate/isopropanol (9/1). The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give tributyl (2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}aminocarbonyl)pyrrolidine-1-carboxylate (3.09 g) as an oily substance.

製備實例21 Preparation Example 21

在冰浴冷卻下向(2R)-2-胺基-2-[4-(1-乙基-1H-吡唑-5-基)苯基]乙-1-醇n．鹽酸鹽(3.43g)、(4R)-1-(三級丁氧基羰基)-4-羥基-L-脯胺酸(2.81g)及DMF(40mL)之混合物中添加DIPEA(7.8mL)，且隨後在冰浴冷卻下逐滴添加HATU(4.5g)。將混合物在冰浴冷卻下攪拌1小時且在室溫下攪拌1小時。在冰浴冷卻下，添加水、飽和氯化鈉水溶液及乙酸乙酯，且用乙酸乙酯萃取水層，且隨後用乙酸乙酯/異丙醇(9/1)萃取。合併之有機層用飽和氯化鈉水溶液洗滌，且經無水硫酸鎂乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)純化，得到呈油狀物之(2S,4R)-2-({(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}胺甲醯基)-4-羥基吡咯啶-1-甲酸三級丁酯(5.01g)。 To a mixture of (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]ethan-1-ol hydrochloride (3.43 g), (4R)-1-(tert-butyloxycarbonyl)-4-hydroxy-L-proline (2.81 g) and DMF (40 mL) was added DIPEA (7.8 mL) under ice-bath cooling, and then HATU (4.5 g) was added dropwise under ice-bath cooling. The mixture was stirred for 1 hour under ice-bath cooling and at room temperature for 1 hour. Under ice-bath cooling, water, a saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer was extracted with ethyl acetate, and then extracted with ethyl acetate/isopropanol (9/1). The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}aminocarbonyl)-4-hydroxypyrrolidine-1-carboxylic acid tributyl ester (5.01 g) as an oily substance.

製備實例23 Preparation Example 23

在冰浴冷卻下向(2S,4R)-4-羥基-2-({(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}胺甲醯基)吡咯啶-1-甲酸三級丁酯(3.09g)於CH₂Cl₂(18mL)及MeOH(18mL)中之溶液中添加鹽酸(4M DOX溶液，17mL)，且將混合物在冰浴冷卻下攪拌1小時、在室溫下攪拌5小時。將反應混合物濃縮且在減壓下乾燥，得到呈固體狀之(4R)-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺n．鹽酸鹽(2.92g)。 To a solution of tributyl (2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}aminocarbonyl)pyrrolidine-1-carboxylate (3.09 g) in _CH2Cl2 ( ₁₈ mL) and MeOH (18 mL) was added hydrochloric acid (4 M DOX solution, 17 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 5 hours. The reaction mixture was concentrated and dried under reduced pressure to give (4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide hydrochloride (2.92 g) as a solid.

製備實例24 Preparation Example 24

在-20至-10℃向(2S,4R)-2-({(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}胺甲醯基)-4-羥基吡咯啶-1-甲酸三級丁酯(5.01g)於CH₂Cl₂(35mL)及MeOH(30mL)中之溶液中添加鹽酸(4M DOX溶液，28mL)，且將混合物在室溫下攪拌5小時。將反應混合物在減壓下濃縮，得到呈固體狀之(4R)-N-{(1R)-1-[4-(1-乙基 -1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺n．鹽酸鹽(4.71g)。 To a solution of (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}aminocarbonyl)-4-hydroxypyrrolidine-1-carboxylic acid tributyl ester (5.01 g) in CH ₂ Cl ₂ (35 mL) and MeOH (30 mL) was added hydrochloric acid (4M DOX solution, 28 mL) at -20 to -10°C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (4R)-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide hydrochloride (4.71 g) as a solid.

製備實例26 Preparation Example 26

向(4R)-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺n．鹽酸鹽(3.81g)、N-(三級丁氧基羰基)-L-纈胺酸(2.16g)及DMF(45mL)之混合物中添加DIPEA(6.2mL)，隨後在冰浴冷卻下逐滴添加HATU(3.61g)。將混合物在冰浴冷卻下攪拌1小時且在室溫下攪拌1小時。在冰浴冷卻下，添加水、飽和氯化鈉水溶液及乙酸乙酯，且用乙酸乙酯萃取水層，隨後用乙酸乙酯/異丙醇(9/1)萃取。合併之有機層用飽和氯化鈉水溶液洗滌，且經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)純化，得到呈固體狀之N-(三級丁氧基羰基)-L-纈胺醯基-(4R)-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺(4.43g)。 To a mixture of (4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide hydrochloride (3.81 g), N-(tert-butyloxycarbonyl)-L-valeric acid (2.16 g) and DMF (45 mL) was added DIPEA (6.2 mL), followed by dropwise addition of HATU (3.61 g) under ice-bath cooling. The mixture was stirred for 1 hour under ice-bath cooling and at room temperature for 1 hour. Under ice-bath cooling, water, a saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer was extracted with ethyl acetate, followed by extraction with ethyl acetate/isopropanol (9/1). The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give N-(tert-butyloxycarbonyl)-L-prolinamide-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (4.43 g) as a solid.

製備實例29 Preparation Example 29

在-20至-15℃向N-(三級丁氧基羰基)-L-纈胺醯基-(4R)-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺(4.43g)於CH₂Cl₂(35mL)及MeOH(35mL)中之溶液中添加鹽酸(4M DOX溶液，20mL)，且將混合物在室溫下攪拌6小時。將反應混合物在減壓下濃縮，得到呈固體狀之L-纈胺醯基-(4R)-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺n．鹽酸鹽(4.21g)。 To a solution of N-(tert-butyloxycarbonyl)-L-prolinamide-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (4.43 g) in _CH2Cl2 ( ₃₅ mL) and MeOH (35 mL) was added hydrochloric acid (4M DOX solution, 20 mL) at -20 to -15°C, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give L-prolinamide-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide hydrochloride (4.21 g) as a solid.

製備實例33 Preparation Example 33

在冰浴冷卻下歷經10分鐘或更長時間向L-纈胺醯基-(4R)-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺n．鹽酸鹽(1.71g)、TEA(3.2mL)、THF(20mL)及MeCN(20mL)之混合物中逐滴添加2-疊氮基-1,3-二甲基咪唑鎓六氟磷酸鹽(1.06g)之MeCN(5mL)溶液，且將混合物在冰浴冷卻下攪拌5小時。添加水、飽和氯化鈉水溶液及乙酸乙酯，且分離水層。用乙酸乙酯萃取水層，且合併之有機層經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)純化，得到呈固體狀之(4R)-1-[(2S)-2-疊氮基-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺(1.07g)。 To a mixture of L-hydroxy-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide hydrochloride (1.71 g), TEA (3.2 mL), THF (20 mL) and MeCN (20 mL) was added dropwise a solution of 2-azido-1,3-dimethylimidazolium hexafluorophosphate (1.06 g) in MeCN (5 mL) over 10 minutes or longer under ice-cooling, and the mixture was stirred under ice-cooling for 5 hours. Water, a saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give (4R)-1-[(2S)-2-azido-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (1.07 g) as a solid.

製備實例37 Preparation Example 37

將N-[(1R)-1-(4-溴苯基)-2-羥乙基]胺基甲酸三級丁酯(2.04g)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二-1,3,2-二氧雜硼戊烷(2.05g)、乙酸鉀(1.91g)、DOX(40mL)及雙(三苯膦)二氯化鈀(II)(460mg)之混合物在氬氣氛圍下在100℃攪拌隔夜。經冷卻至室溫之反應溶液用乙酸乙酯稀釋，且經由矽藻土墊過濾混合物。濾液用水及飽和氯化鈉水溶液洗滌，且經無水硫酸鎂乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(己烷/乙酸乙酯)純化，得到呈油狀物之{(1R)-2-羥基-1-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯基]乙基}胺基甲酸三級丁酯(3.21g)。 A mixture of tributyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (2.04 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di-1,3,2-dioxaborolane (2.05 g), potassium acetate (1.91 g), DOX (40 mL) and bis(triphenylphosphine)palladium(II) dichloride (460 mg) was stirred at 100° C. overnight under an atmosphere of hydrogen. The reaction solution cooled to room temperature was diluted with ethyl acetate, and the mixture was filtered through a diatomaceous earth pad. The filtrate was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tributyl {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (3.21 g) as an oily substance.

製備實例38 Preparation Example 38

在氬氣氛圍下，在室溫下向{(1R)-2-羥基-1-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯基]乙基}胺基甲酸三級丁酯(3.21g)、5-溴-1,3-噻唑-4-甲酸甲酯(2.6g)、磷酸三鉀(3.8g)、二環己基(2',6'-二甲氧基二苯基-2-基)膦(730mg)、DOX(30mL)及水(6mL)之混合物中添加乙酸鈀(II)(200mg)，且將混合物在100℃攪拌3小時。在使混合物冷卻至室溫之後，添加乙酸乙酯，且用水及飽和氯化鈉水溶液洗滌混合物。在有機層經無水硫酸鎂乾燥之後，藉由過濾移除不可溶物質，且在減壓下濃縮濾液。所得殘餘物藉由矽膠管柱層析(己烷/乙酸乙酯)來純化，得到呈固體狀之5-(4-{(1R)-1-[(三級丁氧基羰基)胺基]-2-羥基乙基}苯基)-1,3-噻唑-4-甲酸甲酯(1.48g)。 To a mixture of tributyl {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (3.21 g), methyl 5-bromo-1,3-thiazole-4-carboxylate (2.6 g), tripotassium phosphate (3.8 g), dicyclohexyl(2',6'-dimethoxydiphenyl-2-yl)phosphine (730 mg), DOX (30 mL) and water (6 mL) was added potassium (II) acetate (200 mg) at room temperature under an argon atmosphere, and the mixture was stirred at 100° C. for 3 hours. After the mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and a saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous magnesium sulfate, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 5-(4-{(1R)-1-[(tributyloxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiazole-4-carboxylic acid methyl ester (1.48 g) as a solid.

製備實例39 Preparation Example 39

在氮氣氛下，在冰浴冷卻下向5-(4-{(1R)-1-[(三級丁氧基羰基)胺基]-2-羥基乙基}苯基)-1,3-噻唑-4-甲酸甲酯(1.01g)之CH₂Cl₂(20mL)溶液中逐滴添加二異丁基氫化鋁(1M甲苯溶液，11mL)，且將混合物在冰浴冷卻下攪拌1小時。在冰浴冷卻下，反應物用MeOH淬滅，且添加10%酒石酸鈉鉀水溶液(60mL)及CHCl₃，且將混合物攪拌隔夜。將混合物分成各層，水層用CHCl3萃取，且有機層經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。將殘餘物溶解於MeOH(10mL)中，且在冰浴冷卻下添加硼氫化鈉(350mg)。將混合物在冰浴冷卻下攪拌1小時。添加水且用CHCl₃萃取混合物。有機層經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)純化，得到呈固體狀之[(1R)-2-羥基-1-{4-[4-(羥基甲基)-1,3-噻唑-5-基]苯基}乙基]胺基甲酸三級丁酯(588mg)。 To a solution of methyl 5-(4-{(1R)-1-[(tert-butyloxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiazole-4-carboxylate (1.01 g) in CH ₂ Cl ₂ (20 mL) was added diisobutylaluminum hydroxide (1M toluene solution, 11 mL) dropwise under nitrogen atmosphere with ice-bath cooling, and the mixture was stirred with ice-bath cooling for 1 hour. The reaction was quenched with MeOH with ice-bath cooling, and 10% aqueous sodium potassium tartrate solution (60 mL) and CHCl ₃ were added, and the mixture was stirred overnight. The mixture was separated into layers, the aqueous layer was extracted with CHCl 3, and the organic layer was dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), and sodium borohydride (350 mg) was added under ice-bath cooling. The mixture was stirred for 1 hour under ice-bath cooling. Water was added and the mixture was extracted with CHCl _{3. The organic layer was dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), and sodium borohydride (350 mg) was added under ice-bath cooling. The mixture was stirred for 1 hour under ice-bath cooling. Water was added and the mixture was extracted with CHCl 3.} The organic layer was dried over anhydrous sodium sulfate. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to obtain tert-butyl [(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]carbamate (588 mg) as a solid.

製備實例41 Preparation Example 41

向N-[(1R)-1-(4-溴苯基)-2-羥乙基]胺基甲酸三級丁酯(1g)、2,2-二甲氧基丙烷(3.3mL)及丙酮(15mL)之混合物中添加三氟化硼-二***複合物(26μL)，且將混合物在室溫下攪拌1小時。將TEA(66μL)添加至混合物中，且將混合物在室溫下攪拌10分鐘。將混合物在減壓下濃縮，且殘餘物藉由矽膠管柱層析(己烷/乙酸乙酯)純化，得到呈固體狀之(4R)-4-(4-溴苯基)-2,2-二甲基-1,3-

唑啶-3-甲酸三級丁酯(1.09g)。 To a mixture of tributyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (1 g), 2,2-dimethoxypropane (3.3 mL) and acetone (15 mL) was added boron trifluoride-diethyl ether complex (26 μL), and the mixture was stirred at room temperature for 1 hour. TEA (66 μL) was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-

Tributyl oxazolidinone-3-carboxylate (1.09 g).

製備實例42 Preparation Example 42

在室溫下向(4R)-4-(4-溴苯基)-2,2-二甲基-1,3-

唑啶-3-甲酸三級丁酯(300mg)及1,3-

唑啶-2-酮(183mg)之DOX(1.69mL)溶液中添加碘化銅(I)(32mg)、外消旋-(1R,2R)-環己烷-1,2-二胺(20μL)及碳酸鉀(290mg)。在微波照射下，將混合物在140℃攪拌2小時且在150℃攪拌1小時。添加乙酸乙酯及水，且經由矽藻土墊過濾混合物。在減壓下濃縮濾液，且殘餘物藉由矽膠管柱層析(己烷/乙酸乙酯)純化，得到呈固體狀之(4R)-2,2-二甲基-4-[4-(2-側氧基-1,3-

唑啶-3-基)苯基]-1,3-

唑啶-3-甲酸三級丁酯(120mg)。 At room temperature, (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-

Azolidin-3-carboxylic acid tributyl ester (300 mg) and 1,3-

To a solution of oxazolidin-2-one (183 mg) in DOX (1.69 mL) were added copper (I) iodide (32 mg), racemic-(1R,2R)-cyclohexane-1,2-diamine (20 μL) and potassium carbonate (290 mg). Under microwave irradiation, the mixture was stirred at 140° C. for 2 hours and at 150° C. for 1 hour. Ethyl acetate and water were added, and the mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain (4R)-2,2-dimethyl-4-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]-1,3-

Tributyl oxazolidinone-3-carboxylate (120 mg).

製備實例48 Preparation Example 48

在冰浴冷卻下在攪拌下向(1S,4S)-5-{8-(苯甲氧基)-6-環丙基-2-(乙基硫基)-7-[6-氟-5-甲基-2-(三苯基甲基)-2H-吲唑-4-基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(350mg)及CH₂Cl₂(7mL)之混合物中添加間氯過苯甲酸(約30%含水量，100mg)。將反應混合物在冰浴冷卻下攪拌1.5小時，且用CH₂Cl₂稀釋，用飽和碳酸氫鈉水溶液及飽和硫代硫酸鈉水溶液洗滌。有機層經無水硫酸鎂乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液，得到亞碸。將所得亞碸與(S)-2-甲氧基丙醇(45mg)及THF(4mL)混合。在冰甲醇浴冷卻下向混合物中添加KOtBu(80mg)，且將混合物在室溫下在氬氣氛圍下攪拌1小時。將冰水及氯化銨水溶液添加至反應混合物中，且用乙酸乙酯萃取產物兩次。合併之有機層用飽和氯化鈉水溶液洗滌且經無水硫酸鎂乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。所得殘餘物藉由矽膠管柱層析(鹼性矽膠，己烷/乙酸乙酯)來純化，得到呈泡沫樣固體狀之(1S,4S)-5-{8-(苯甲氧基)-6-環丙基-7-[6-氟-5-甲基-2-(三苯基甲基)-2H-吲唑-4-基]-2-[(2S)-2-甲氧基丙氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(280mg)。 To a mixture of (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (350 mg) and CH ₂ Cl ₂ (7 mL) was added m-chloroperbenzoic acid (about 30% water content, 100 mg) with stirring under ice-cooling. The reaction mixture was stirred under ice-cooling for 1.5 hours, and diluted with CH ₂ Cl ₂ , washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain sulfoxide. The obtained sulfoxide was mixed with (S)-2-methoxypropanol (45 mg) and THF (4 mL). KOtBu (80 mg) was added to the mixture under ice-methanol bath cooling, and the mixture was stirred at room temperature under an argon atmosphere for 1 hour. Ice water and an aqueous solution of ammonium chloride were added to the reaction mixture, and the product was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica, hexane/ethyl acetate) to give (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (280 mg) as a foamy solid.

製備實例51 Preparation Example 51

將MeOH(3mL)添加至(1S,4S)-5-{6-環丙基-8-[(4-乙炔基苯基)甲氧基]-7-[6-氟-5-甲基-2-(三苯基甲基)-2H-吲唑-4-基]-2-[(2S)-2-甲氧基丙氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(211mg)中且在室溫下在攪拌下添加4-甲基苯-1-磺酸單水合物(48mg)。隨後，將混合物在室溫下在氬氣氛圍下攪拌1小時。將冰及飽和碳酸氫鈉水溶液添加至反應混合物中，且用乙酸乙酯萃取混合物兩次。合併之有機層用飽和氯化鈉水溶液洗滌且經無水硫酸鎂乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。所得殘餘物藉由矽膠管柱層析(鹼性矽膠，己烷/乙酸乙酯)來純化，得到呈固體狀之低極性非鏡像異構物(1S,4S)-5-{6-環丙基-8-[(4-乙炔基苯基)甲氧基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(單軸向立體異構物，87mg)及呈固體狀之高極性非鏡像異構物(1S,4S)-5-{6-環丙基-8-[(4-乙炔基苯基)甲氧基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(單軸向立體異構物，59mg)。將低極性非鏡像異構物用於後續反應。 MeOH (3 mL) was added to (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (211 mg) and 4-methylbenzene-1-sulfonic acid monohydrate (48 mg) was added at room temperature with stirring. Subsequently, the mixture was stirred at room temperature under an atmosphere of hydrogen for 1 hour. Ice and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to obtain the low-polarity non-mirror image isomer (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl butyl as a solid. Ester (single axial stereoisomer, 87 mg) and the highly polar non-mirror image isomer (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (single axial stereoisomer, 59 mg) in the form of a solid. The low polar non-mirror image isomer was used for the subsequent reaction.

製備實例52 Preparation Example 52

在室溫下向(1S,4S)-5-{6-環丙基-8-[(4-乙炔基苯基)甲氧基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(80mg)於t-BuOH(0.7mL)、THF(0.7mL)、水(0.7mL)中之溶液中添加(4R)-1-[(2S)-2-疊氮基-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺(53mg)、抗壞血酸鈉(33mg)及CuI(12 mg)，且將混合物在50℃攪拌3小時。冷卻至室溫後，添加EDTA二鈉鹽於水中之溶液。混合物用CH₂Cl₂萃取三次，且有機層經硫酸鎂乾燥，過濾且在減壓下濃縮。殘餘物藉由矽膠管柱層析(鹼性矽膠，CHCl₃/MeOH)純化，得到呈泡沫樣固體狀之(1S,4S)-5-{6-環丙基-7-(6-氟-5-甲基-1H-吲唑-4-基)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-羥基-2-({(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}胺甲醯基)吡咯啶-1-基]-3-甲基-1-側氧基丁-2-基}-1H-1,2,3-***-4-基)苯基]甲氧基}-2-[(2S)-2-甲氧基丙氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(102mg)。 (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (80 mg) was dissolved in t-BuOH (0.7 mL) at room temperature. To a solution of (4R)-1-[(2S)-2-azido-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (53 mg), sodium ascorbate (33 mg) and CuI (12 mg) in 4% paraformaldehyde (0.7 mL), THF (0.7 mL) and water (0.7 mL) was added, and the mixture was stirred at 50° C. for 3 hours. After cooling to room temperature, a solution of EDTA disodium salt in water was added. The mixture was extracted three times with CH ₂ Cl ₂ , and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (basic silica gel, CHCl ₃ /MeOH) to give (1S,4S)-5-{6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}aminocarbonyl)pyrrolidin-1-yl]-3-methyl-1-oxobutyl-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (102 mg) as a foamy solid.

製備實例57 Preparation Example 57

在室溫下向4-溴-6-氟-1H-吲唑(235g)、TEA(183mL)及CH₂Cl₂(1880mL)之混合物中添加1,1',1"-(氯甲烷三基)三苯(335g)。且將混合物在25℃攪拌16小時。將反應混合物傾入冰水(1.5L)中，且分離有機層及水層。用CH₂Cl₂(400mL)萃取水層三次。合併之有機層經無水硫酸鈉乾燥。隨後，藉由過濾移除不可溶物質，且在減壓下濃縮濾液。將石油醚(550mL)添加至所得殘餘物中以用於研磨(0℃，2小時)，且隨後藉由過濾收集及在減壓下乾燥獲得呈固體狀之4-溴-6-氟-2-(三苯基甲基)-2H-吲唑(508.98g)。 To a mixture of 4-bromo-6-fluoro-1H-indazole (235 g), TEA (183 mL) and CH ₂ Cl ₂ (1880 mL) was added 1,1',1"-(chloromethanetriyl)triphenyl (335 g) at room temperature. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into ice water (1.5 L), and the organic and aqueous layers were separated. CH ₂ Cl ₂ The aqueous layer was extracted three times with 400 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. Subsequently, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Petroleum ether (550 mL) was added to the resulting residue for trituration (0° C., 2 hours), and then collected by filtration and dried under reduced pressure to obtain 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) as a solid.

製備實例58 Preparation Example 58

在-78℃在氮氣氛下向4-溴-6-氟-2-(三苯基甲基)-2H-吲唑(100g)及2-甲基四氫呋喃(1000mL)之混合物中添加二異丙胺鋰(2M THF溶液，214.28mL)，且將混合物在-78℃攪拌2.5小時。在-78℃添加碘甲烷(26.68mL)，且將混合物在25℃攪拌2.5小時。添加水(2000mL)以淬滅反應物，且用乙酸乙酯(800mL)萃取混合物兩次。合併之有機層經無水硫酸鈉乾燥。隨後，藉由過濾移除不可溶物質，且在減壓下濃縮濾液。將乙酸乙酯(50mL)/石油醚(50mL)添加至所得殘餘物中以用於研磨，且隨後藉由過濾及在減壓下乾燥獲得呈固體狀之4-溴-6-氟-5-甲基-2-(三苯基甲基)-2H-吲唑(81g)。 To a mixture of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (100 g) and 2-methyltetrahydrofuran (1000 mL) was added lithium diisopropylamine (2M THF solution, 214.28 mL) at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 2.5 hours. Iodomethane (26.68 mL) was added at -78°C, and the mixture was stirred at 25°C for 2.5 hours. Water (2000 mL) was added to quench the reactant, and the mixture was extracted twice with ethyl acetate (800 mL). The combined organic layers were dried over anhydrous sodium sulfate. Subsequently, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (50 mL)/petroleum ether (50 mL) was added to the resulting residue for trituration, and then 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (81 g) was obtained as a solid by filtration and drying under reduced pressure.

製備實例59 Preparation Example 59

在室溫下在氮氣氛下向4-溴-6-氟-5-甲基-2-(三苯基甲基)-2H-吲唑(100g)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二-1,3,2-二氧雜硼戊烷(61.42g)、三苯膦(10.57g)、乙酸鉀(59.34g)及DOX(1000mL)之混合物中添加乙酸鈀(4.52g)。將反應混合物脫氣且每次用氮氣填充三次之後，將混合物在100℃下在氮氣氛下攪拌12小時在冷卻至環境溫度之後，添加水(1500mL)，且用乙酸乙酯(900mL)萃取混合物三次。合併之有機層經無水硫酸鈉乾燥，且隨後藉由過濾移除不可溶材料。將活化碳(50g)添加至所得溶液中，且將溶液在20℃攪拌1小時且過濾，同時用乙酸乙酯(50ml)洗滌三次。濃縮濾液。將甲醇(200mL)添加至所得殘餘物中以用於研磨，且將所得固體過濾且在減壓下乾燥，得到呈固體狀之6-氟-5-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-2-(三苯基甲基)-2H-吲唑(110g)。 To a mixture of 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (100 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di-1,3,2-dioxaborolane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g) and DOX (1000 mL) was added potassium acetate (4.52 g) at room temperature under nitrogen atmosphere. After the reaction mixture was degassed and filled with nitrogen three times each time, the mixture was stirred at 100° C. under nitrogen atmosphere for 12 hours. After cooling to ambient temperature, water (1500 mL) was added, and the mixture was extracted three times with ethyl acetate (900 mL). The combined organic layers were dried over anhydrous sodium sulfate, and then insoluble materials were removed by filtration. Activated carbon (50 g) was added to the resulting solution, and the solution was stirred at 20° C. for 1 hour and filtered, while washing three times with ethyl acetate (50 ml). The filtrate was concentrated. Methanol (200 mL) was added to the resulting residue for trituration, and the resulting solid was filtered and dried under reduced pressure to obtain 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (110 g) as a solid.

製備實例60 Preparation Example 60

在氬氣氛圍下，將雙(三-三級丁基膦)鈀(0)(18mg)添加至4-甲基-1,3-

唑-5-甲酸(178mg)、氯化四正丁銨(195mg)、(4R)-4-(4-溴苯基)-2,2-二甲基-1,3-

唑啶-3-甲酸三級丁酯(250mg)、碳酸銫(344mg)及DMF(2.5mL)之混合物中，且將混合物在170℃在微波照射下攪拌30分鐘。將混合物冷卻至室溫且隨後用乙酸乙酯稀釋，且藉由經由矽藻土墊進行過濾移除不可溶物質。濾液用水及飽和氯化鈉水溶液洗滌且經無水硫酸鎂乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。所得殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)來純化，得到呈固體狀之(4R)- 2,2-二甲基-4-[4-(4-甲基-1,3-

唑-5-基)苯基]-1,3-

唑啶-3-甲酸三級丁酯(215mg)。 Under an argon atmosphere, bis(tri-butylphosphine)palladium(0) (18 mg) was added to 4-methyl-1,3-

Oxazole-5-carboxylic acid (178 mg), tetrabutylammonium chloride (195 mg), (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-

In a mixture of tributyl oxazolidine-3-carboxylate (250 mg), cesium carbonate (344 mg) and DMF (2.5 mL), the mixture was stirred at 170° C. under microwave irradiation for 30 minutes. The mixture was cooled to room temperature and then diluted with ethyl acetate, and the insoluble matter was removed by filtration through a diatomaceous earth pad. The filtrate was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give (4R)- 2,2-dimethyl-4-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]-1,3-

Tributyl oxazolidinone-3-carboxylate (215 mg).

在下表中，「PEx」表示「製備實例」且「PSyn」指示其他製備實例亦使用該表之相同列中與「PEx」相同之方法製備(亦即，「PEx」使用與用於製備「PSyn」欄中指示之製備實例數值的方法相同方法製備)。 In the following table, "PEx" indicates "Preparation Example" and "PSyn" indicates that other Preparation Examples were also prepared using the same method as "PEx" in the same column of the table (i.e., "PEx" was prepared using the same method as that used to prepare the Preparation Example value indicated in the "PSyn" column).

結構：化學結構式(化學結構式中具有「*」之化合物表示該化合物為單軸向立體異構物)。n HCl：n鹽酸鹽(「n HCl」展示該化合物為單鹽酸鹽至三鹽酸鹽)，資料：生理化學資料，ESI+：質譜分析中之m/z值(離子化方法ESI，除非另外指定，否則為[M+H]⁺)，ESI-：質譜分析中之m/z值(離子化方法ESI，除非另外指定，否則為[M-H]^-)，NMR：δDMSO-d₆中¹H-NMR(500MHz)中之峰值(ppm)，NMR(100℃)：δ在100℃下DMSO-d₆中¹H-NMR(500MHz)中之峰值(ppm)，s：單峰(光譜)，d：二重峰(光譜)，dd：雙重二重峰(光譜)，t：三重峰(光譜)，q：四重峰(光譜)，m：多重峰(光譜)，br：寬峰(光譜)(實例：br s)。 Structure: Chemical formula (the compound with "*" in the chemical formula indicates that the compound is a single axial stereoisomer). n HCl: n hydrochloride ("n HCl" indicates that the compound is a monohydrochloride to a trihydrochloride), Data: Physiological and chemical data, ESI+: m/z value in mass spectrometry (ionization method ESI, unless otherwise specified, [M+H] ⁺ ), ESI-: m/z value in mass spectrometry (ionization method ESI, unless otherwise specified, [MH] ^- ), NMR: ^{δ 1H} -NMR (500MHz) peak value (ppm) in DMSO-d ₆ , NMR (100℃): δ ^1H- NMR (500MHz) peak value (ppm) in DMSO-d ₆ at 100℃ Peak value (ppm) in H-NMR (500 MHz), s: singlet (spectrum), d: doublet (spectrum), dd: doublet of doublets (spectrum), t: triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad peak (spectrum) (Example: br s).

實例 Examples

以下為式(I)化合物及其特徵之實例。 The following are examples of compounds of formula (I) and their characteristics.

在以下實例中，星號指示化合物為單軸向立體異構物。 In the following examples, the asterisk indicates that the compound is a single axial stereoisomer.

實例1：(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺 Example 1: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide

在冰浴冷卻下向(1S,4S)-5-{6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H- 吲唑-4-基]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-羥基-2-({(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}胺甲醯基)吡咯啶-1-基]-3-甲基-1-側氧基丁-2-基}-1H-1,2,3-***-4-基)苯基]甲氧基}-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(5.61g)及CH₂Cl₂(60mL)之混合物中添加三氟乙酸(27mL)，且隨後將混合物在室溫下攪拌2小時。將所得反應混合物在減壓下濃縮，且將飽和碳酸氫鈉水溶液添加至殘餘物中。混合物用CHCl₃/MeOH(5/1)萃取三次，且隨後合併之有機層經無水硫酸鈉乾燥。將溶液在減壓下濃縮，且所得粗產物藉由ODS管柱層析(MeCN/0.1%甲酸水溶液)純化。將飽和碳酸氫鈉水溶液添加至含有目標化合物之溶離份中，且用CHCl₃/MeOH(5/1)萃取混合物三次。合併之有機層經無水硫酸鈉乾燥，且在減壓下濃縮溶液。殘餘物藉由矽膠管柱層析(鹼性矽膠，CHCl₃/MeOH)純化，得到產物。將乙酸異丙酯(70mL)添加至所得產物中，且將混合物在80℃攪拌10分鐘且在室溫下攪拌隔夜。添加己烷(70mL)且將混合物在室溫下攪拌1小時。隨後，將所得固體過濾，用乙酸異丙酯/己烷(1/1)洗滌，且在40℃在減壓下乾燥隔夜，得到呈固體狀之標題化合物(3.01g)。 Under ice-cooling, (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexyl-2-yl)-1H- To a mixture of indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}aminocarbonyl)pyrrolidin-1-yl]-3-methyl-1-oxobutyl-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (5.61 g) and CH ₂ Cl ₂ (60 mL) was added trifluoroacetic acid (27 mL), and then the mixture was stirred at room temperature for 2 hrs. The obtained reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted three times with CHCl ₃ /MeOH (5/1), and the combined organic layers were then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained crude product was purified by ODS column chromatography (MeCN/0.1% formic acid aqueous solution). A saturated aqueous sodium bicarbonate solution was added to the fraction containing the target compound, and the mixture was extracted three times with CHCl ₃ /MeOH (5/1). The combined organic layers were dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica, CHCl ₃ /MeOH) to give the product. Isopropyl acetate (70 mL) was added to the obtained product, and the mixture was stirred at 80° C. for 10 minutes and at room temperature overnight. Hexane (70 mL) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, the obtained solid was filtered, washed with isopropyl acetate/hexane (1/1), and dried at 40° C. under reduced pressure overnight to give the title compound (3.01 g) as a solid.

ESI+：1117.3； ESI+: 1117.3;

NMR(100℃)：0.48-0.68(4H,m),0.77(3H,br d),1.07(3H,br d),1.35-1.43(1H,m),1.66-1.77(3H,m),1.87(1H,br d),1.89-1.97(1H,m),1.98-2.10(3H,m),2.01(3H,d),2.10-2.21(1H,m),2.45(3H,s),2.50-2.59(1H,m),3.06(1H,dd),3.13(1H,d),3.35-3.45(2H,m),3.57-3.64(1H,m),3.65-3.75(3H,m),3.75-3.79(1H,m),3.80-3.90(3H,m),4.16(1H,dd),4.35(1H,br s),4.41-4.48(1H,m),4.48-4.56(1H,m),4.78-4.84(2H,m),4.84-4.95(1H,m),5.13(1H,br s),5.17-5.24(1H,m),5.24-5.31(2H,m),6.82(2H,d),7.30(1H,d),7.38-7.44(4H,m),7.44-7.48(2H,m),7.61(2H,br d),8.00(1H,br d),8.43(1H,br s),8.88(1H,s),12.75(1H,br s)。 NMR (100°C): 0.48-0.68 (4H, m), 0.77 (3H, br d), 1.07 (3H, br d), 1.35-1.43 (1H, m), 1.66-1.77 (3H, m), 1.87 (1H, br d), 1.89-1.97(1H,m), 1.98-2.10(3H,m), 2.01(3H,d), 2.10-2.21(1H,m), 2.45(3H,s), 2.50-2.59(1H,m), 3.06(1H,dd), 3.13(1H,d), 3.35-3.45(2H,m), 3.57-3.64(1H,m), 3.65-3.75(3H,m), 3.75-3.79(1H,m), 3.80-3.90(3H,m), 4.16(1H,dd), 4.35(1H,br s),4.41-4.48(1H,m),4.48-4.56(1H,m),4.78-4.84(2H,m),4.84-4.95(1H,m),5.13(1H,br s),5.17-5.24(1H,m),5.24-5.31(2H,m),6.82(2H,d),7.30(1H,d),7.38-7.44(4H,m),7.44-7.48(2H,m),7.61(2H,br d),8.00(1H,br d),8.43(1H,br s),8.88(1H,s),12.75(1H,br s).

實例2：(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-[(1R)-2-羥基-1-{4-[4-(羥基甲基)-1,3-噻唑-5-基]苯基}乙基]-L-脯胺醯胺三鹽酸鹽 Example 2: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide trihydrochloride

在氮氣氛下，在冰浴冷卻下向(4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(三級丁氧基羰基)-2,5-二氮雜二環[2.2.1]庚-2-基]-6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-L-脯胺酸(65mg)、(2R)-2-胺基-2-{4-[4-(羥基甲基)-1,3-噻唑-5-基]苯基}乙-1-醇二鹽酸鹽(25mg)及DMF(1mL)之混合物中依序添加DIPEA(50μL)及HATU(35mg)，且將混合物在室溫下攪拌1小時。添加水且用乙酸乙酯萃取混合物。有機層用水及飽和氯化鈉水溶液洗滌，且隨後經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。所得殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)來純化，得到醯胺產物(59mg)。隨後，將所得化合物溶解於CH₂Cl₂(0.5mL)及MeOH(0.5mL)中，且在冰浴冷卻下添加鹽酸(4M DOX溶液，0.5mL)。將混合物在室溫下攪拌2小時，且隨後在減壓下濃縮。將二***添加至所得殘餘物中，且將沈澱之固體過濾，用二***洗滌，且在減壓下乾燥，得到呈固體狀之標題化合物(43mg)。 Under a nitrogen atmosphere, (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tributyloxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzene was added to the mixture. To a mixture of (2R)-2-amino-2-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethan-1-ol dihydrochloride (25 mg) and DMF (1 mL) were added DIPEA (50 μL) and HATU (35 mg) in that order, and the mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give an amide product (59 mg). Subsequently, the obtained compound was dissolved in CH ₂ Cl ₂ (0.5 mL) and MeOH (0.5 mL), and hydrochloric acid (4 M DOX solution, 0.5 mL) was added under ice-bath cooling. The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Diethyl ether was added to the obtained residue, and the precipitated solid was filtered, washed with diethyl ether, and dried under reduced pressure to give the title compound (43 mg) as a solid.

ESI+：1133.3。 ESI+: 1133.3.

實例3：(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(2-側氧基-1,3-

唑啶-3-基)苯基]乙基}-L-脯胺醯胺 Example 3: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide

在冰浴冷卻下向(1S,4S)-5-{6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-羥基-2-({(1R)-2-羥基-1-[4-(2-側氧基-1,3-

唑啶-3-基)苯基]乙基}胺甲醯基)吡咯啶-1-基]-3-甲基-1-側氧基丁-2-基}-1H-1,2,3-***-4-基)苯基]甲氧基}-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(170mg)、CH₂Cl₂(2mL)及MeOH(2mL)之混合物中添加鹽酸(4M DOX溶液，0.988mL)，且將混合物在室溫下攪拌3小時。將混合物在減壓下濃縮，添加CHCl₃及飽和碳酸氫鈉水溶液，且將混合物攪拌片刻。隨後，用CHCl₃/MeOH(5/1)萃取水層，且合併之有機層經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(鹼性矽膠，CHCl₃/MeOH)純化，且隨後藉由ODS管柱層析(MeCN/0.1%甲酸水溶液溶液)純化。合併含有目標化合物之溶離份，用飽和碳酸氫鈉水溶液鹼化，且隨後用CHCl₃/MeOH(5/1)萃取兩次。合併之有機層經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。所得固體用二***洗滌，且在減壓下乾燥，得到呈固體狀之標題化合物(74mg)。 Under ice-cooling, (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexyl-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

To a mixture _of tributyl ₂ - _[ ( ... Subsequently, the aqueous layer was extracted with CHCl ₃ /MeOH (5/1), and the combined organic layers were dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃ /MeOH), and then purified by ODS column chromatography (MeCN/0.1% formic acid aqueous solution). The fractions containing the target compound were combined, alkalized with saturated sodium bicarbonate aqueous solution, and then extracted twice with CHCl ₃ /MeOH (5/1). The combined organic layers were dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether and dried under reduced pressure to give the title compound (74 mg) as a solid.

ESI+：1105.7。 ESI+: 1105.7.

實例4：(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(1-甲基-1H-吡唑-5-基)苯基]乙基}-L-脯胺醯胺 Example 4: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide

此化合物使用與以下實例5提供之方法類似的方法製備。 This compound was prepared using a method similar to that provided in Example 5 below.

ESI+：1100.4； ESI+: 1100.4;

NMR(100℃)：0.48-0.68(4H,m),0.77(3H,br d),1.03-1.10(3H,m),1.35-1.44(1H,m),1.66-1.77(3H,m),1.87(1H,br d),1.89-1.97(1H,m),1.98-2.10(3H,m),2.01(3H,d),2.11-2.24(1H,m),2.50-2.60(1H,m),3.06(1H,dd),3.14(1H,d),3.36-3.44(2H,m),3.56-3.64(1H,m),3.65-3.75(3H,m),3.77(1H,br s),3.80-3.92(6H,m),4.16(1H,dd),4.36(1H,br s),4.41-4.48(1H,m),4.49-4.57(1H,m),4.73-4.84(2H,m),4.87-4.96(1H,m),5.13(1H,br s),5.17-5.24(1H,m),5.24-5.32(2H,m),6.31(1H,d),6.82(2H,d),7.30(1H,d),7.38-7.45(5H,m),7.45(1H,d),7.47(1H,br s),7.61(2H,br d),8.01(1H,br d),8.43(1H,s),12.75(1H,br s)。 NMR (100 ° C): 0.48-0.68 (4H, m), 0.77 (3H, br d), 1.03-1.10 (3H, m), 1.35-1.44 (1H, m), 1.66-1.77 (3H, m), 1.87 (1H, br d), 1.89-1.97 (1H, m), 1.98-2.10 (3H, m), 2.01 (3H, d), 2.11-2.24 (1H, m), 2.50-2.60 (1H, m), 3.06 (1H, dd), 3.14 (1H, d), 3.36-3.44 (2H, m), 3.56-3.64 (1H, m), 3.65-3.75 (3H, m), 3.77 (1H, br s), 3.80-3.92(6H,m),4.16(1H,dd),4.36(1H,br s),4.41-4.48(1H,m),4.49-4.57(1H,m),4.73-4.84(2H,m),4.87-4.96(1H,m),5.13(1H,br s),5.17-5.24(1H,m),5.24-5.32(2H,m),6.31(1H,d),6.82(2H,d),7.30(1H,d),7.38-7.45(5H,m),7.45(1H,d),7.47(1H,br s),7.61(2H,br d),8.01(1H,br d),8.43(1H,s),12.75(1H,br s).

實例5：(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺 Example 5: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide

在冰浴冷卻下歷經20分鐘向(1S,4S)-5-(6-環丙基-8-{[4-(1-{(2S)-1-[(2S,4R)-2-({(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}胺甲醯基)-4-羥基吡咯啶-1-基]-3-甲基-1-側氧基丁-2-基}-1H-1,2,3-***-4-基)苯基]甲氧基}-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基)-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(5.72g)於CH₂Cl₂(55mL)中之溶液中逐滴添加三氟乙酸(27mL)，且將混合物在室溫下攪拌2小時。將所得反應混合物在減壓下濃縮，且將飽和碳酸氫鈉水溶液及CHCl₃/MeOH(9/1)添加至殘餘物中。混合物用CHCl₃/MeOH(9/1)萃取三次，且隨後合併之有機層經無水硫酸鈉乾燥。將溶液在減壓下濃縮，且所得粗產物藉由ODS管柱層析(MeCN/0.1%甲酸水溶液)純化。將飽和碳酸氫鈉水溶液添加至含有目標化合物之溶離份中，且用CHCl₃/MeOH(9/1)萃取混合物三次。合併之有機層經無水硫酸鈉乾燥，且在減壓下濃縮溶液。殘餘物藉由矽膠管柱層析(鹼性矽膠，CHCl₃/MeOH)純化，得到產物。將EtOH添加至所得產物中，且在減壓下濃縮混合物。將二***添加至殘餘物中且將所得沈澱物過濾，用二***洗滌，且在減壓下乾燥至呈固體狀之(2.98g)。 The mixture was added to (1S,4S)-5-(6-cyclopropyl-8-{[4-(1-{(2S)-1-[(2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamoyl)-4-hydroxypyrrolidin-1-yl]-3-methyl-1-oxobutyl To a solution _of _tributyl ₂ -[( ... The mixture was extracted three times with CHCl ₃ /MeOH (9/1), and the combined organic layers were then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting crude product was purified by ODS column chromatography (MeCN/0.1% formic acid aqueous solution). A saturated aqueous sodium bicarbonate solution was added to the fraction containing the target compound, and the mixture was extracted three times with CHCl ₃ /MeOH (9/1). The combined organic layers were dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃ /MeOH) to obtain the product. EtOH was added to the obtained product, and the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue and the obtained precipitate was filtered, washed with diethyl ether, and dried under reduced pressure to a solid state (2.98 g).

ESI+：1114.5； ESI+: 1114.5;

NMR(100℃)：0.48-0.68(4H,m),0.77(3H,br d),1.03-1.10(3H,m),1.30(3H,t),1.35-1.43(1H,m),1.66-1.77(3H,m),1.87(1H,br d),1.89-1.97(1H,m),1.98-2.10(3H,m),2.01(3H,d),2.11-2.20(1H,m),2.50-2.60(1H,m),3.06(1H,dd),3.13(1H,d),3.35-3.45(2H,m),3.57-3.64(1H,m),3.65-3.75(3H,m),3.75-3.79(1H,m),3.80-3.93(3H,m),4.11(2H,q),4.16(1H,dd),4.35(1H,br s),4.41-4.48(1H,m),4.49-4.57(1H,m),4.78-4.84(2H,m),4.87-4.96(1H,m),5.12(1H,br s),5.17-5.24(1H,m),5.24-5.32(2H,m),6.27(1H,d),6.82(2H,d),7.30(1H,d),7.35-7.40(2H,m),7.40-7.48(5H,m),7.61(2H,br d),8.01(1H,br d),8.43(1H,s),12.75(1H,br s)。 NMR (100°C): 0.48-0.68 (4H, m), 0.77 (3H, br d), 1.03-1.10 (3H, m), 1.30 (3H, t), 1.35-1.43 (1H, m), 1.66-1.77 (3H, m), 1.87 (1H, br d), 1.89-1.97 (1H, m), 1.98-2.10 (3H, m), 2.01 (3H, d), 2.11-2.20 (1H, m), 2.50-2.60 (1H, m), 3.06 (1H, dd), 3.13 (1H, d), 3.35-3.45 (2H, m), 3.57-3.64 (1H, m), 3.65-3.75 (3H, m), 3.75-3.79 (1H, m), 3.80-3.93 (3H, m), 4.11 (2H, q), 4.16 (1H, dd), 4.35 (1H, br s),4.41-4.48(1H,m),4.49-4.57(1H,m),4.78-4.84(2H,m),4.87-4.96(1H,m),5.12(1H,br s),5.17-5.24(1H,m),5.24-5.32(2H,m),6.27(1H,d),6.82(2H,d),7.30(1H,d),7.35-7.40(2H,m),7.40-7.48(5H,m),7.61(2H,br d),8.01(1H,br d),8.43(1H,s),12.75(1H,br s).

實例6：(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}-L-脯胺醯胺 Example 6: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide

在冰甲醇浴冷卻下向(1S,4S)-5-{6-環丙基-7-(6-氟-5-甲基-1H-吲唑-4-基)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-羥基-2-({(1R)-2-羥基-1-[4-(4-甲基-1,3-噻唑-5-基)苯基]乙基}胺甲醯基)吡咯啶-1-基]-3-甲基-1-側氧基丁-2-基}-1H-1,2,3-***-4-基)苯基]甲氧基}-2-[(2S)-2-甲氧基丙氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(98mg)及CH₂Cl₂(3mL)之混合物中添加三氟乙酸(1mL)，且隨後將混合物在室溫下在氬氣氛圍下攪拌2小時。將所得反應混合物在減壓下濃縮，且將冰、飽和碳酸氫鈉水溶液及CHCl₃/MeOH(10/1)添加至殘餘物中。將混合物攪拌10分鐘，且隨後用CHCl₃/MeOH(10/1)萃取，且隨後合併之有機層經無水硫酸鎂乾燥。將溶液在減壓下濃縮，且將所得產物溶解於MeOH中且濃縮，在減壓下乾燥，得到呈固體狀之標題化合物(73mg)。 Under cooling in an ice-methanol bath, (1S,4S)-5-{6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}aminocarbonyl)pyrrolidin-1-yl]-3-methyl-1-oxobutyl-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (98 mg) and CH ₂ Cl ₂ were added. To a mixture of 4-(2-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ _[ [[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ _[ [[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[

ESI+：1105.7； ESI+: 1105.7;

NMR(100℃)：0.48-0.68(4H,m),0.77(3H,br d),1.04-1.10(3H,m),1.14(3H,d),1.35-1.43(1H,m),1.74(1H,br d),1.87(1H,br d),1.89-1.97(1H,m),2.00(3H,d),2.01-2.10(1H,m),2.10-2.32(1H,m),2.45(3H,s),2.45-2.60(1H,m),3.06(1H,dd),3.14(1H,d),3.30(3H,s),3.60(1H,br d),3.65-3.78(5H,m),3.84(1H,dd),4.16(1H,dd),4.28(1H,dd),4.32-4.38(2H,m),4.45(1H,br t),4.52(1H,br t),4.78-4.85(2H,m),4.86-4.94(1H,m),5.14(1H,br s),5.28(2H,d),6.83(2H,d),7.30(1H,d),7.37-7.43(4H,m),7.45(1H,d),7.47(1H,s),7.59(2H,br d),8.00(1H,br d),8.42(1H,s),8.88(1H,s),12.75(1H,br s)。 NMR (100 ° C): 0.48-0.68 (4H, m), 0.77 (3H, br d), 1.04-1.10 (3H, m), 1.14 (3H, d), 1.35-1.43 (1H, m), 1.74 (1H, br d), 1.87 (1H, br d), 1.89-1.97 (1H, m), 2.00 (3H, d), 2.01-2.10 (1H, m), 2.10-2.32 (1H, m), 2.45 (3H, s), 2.45-2.60 (1H, m), 3.06 (1H, dd), 3.14 (1H, d), 3.30 (3H, s), 3.60 (1H, br d), 3.65-3.78 (5H, m), 3.84 (1H, dd), 4.16 (1H, dd), 4.28 (1H, dd), 4.32-4.38 (2H, m), 4.45 (1H, br t), 4.52 (1H, br t), 4.78-4.85 (2H, m), 4.86-4.94 (1H, m), 5.14 (1H, br s), 5.28 (2H, d), 6.83 (2H, d), 7.30 (1H, d), 7.37-7.43 (4H, m), 7.45 (1H, d), 7.47 (1H, s), 7.59 (2H, br d), 8.00 (1H, br d), 8.42 (1H, s), 8.88 (1H, s), 12.75 (1H, br s).

實例7：(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺 Example 7: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide

此化合物使用與以上實例6提供之方法類似的方法製備。 This compound was prepared using a method similar to that provided in Example 6 above.

ESI+：1102.8； ESI+: 1102.8;

NMR(100℃)：0.48-0.68(4H,m),0.77(3H,br d),1.07(3H,d),1.14(3H,d),1.30(3H,t),1.35-1.43(1H,m),1.75(1H,br d),1.85-1.98(2H,m),2.00(3H,d),2.01-2.10(1H,m),2.42-2.51(1H,m),2.51-2.60(1H,m),3.07(1H,dd),3.16(1H,d),3.30(3H,s),3.60(1H,br d),3.65-3.78(4H,m),3.80(1H,br s),3.84(1H,br dd),4.07-4.15(2H,m),4.17(1H,dd),4.28(1H,dd),4.32-4.39(2H,m),4.42-4.48(1H,m),4.52(1H,br t),4.73-4.85(2H,m),4.87-4.96(1H,m),5.14(1H,br s),5.28(2H,br d),6.27(1H,d),6.83(2H,d),7.30(1H,d),7.35-7.40(2H,m),7.40-7.49(5H,m),7.59(2H,br d),8.01(1H,br d),8.42(1H,s),12.75(1H,br s)。 NMR (100 ° C): 0.48-0.68 (4H, m), 0.77 (3H, br d), 1.07 (3H, d), 1.14 (3H, d), 1.30 (3H, t), 1.35-1.43 (1H, m), 1.75 (1H, br d), 1.85-1.98 (2H, m), 2.00 (3H, d), 2.01-2.10 (1H, m), 2.42-2.51 (1H, m), 2.51-2.60 (1H, m), 3.07 (1H, dd), 3.16 (1H, d), 3.30 (3H, s), 3.60 (1H, br d), 3.65-3.78 (4H, m), 3.80 (1H, br s), 3.84 (1H, br dd), 4.07-4.15 (2H, m), 4.17 (1H, dd), 4.28 (1H, dd), 4.32-4.39 (2H, m), 4.42-4.48 (1H, m), 4.52 (1H, br t), 4.73-4.85 (2H, m), 4.87-4.96 (1H, m), 5.14 (1H, br s), 5.28 (2H, br d), 6.27 (1H, d), 6.83 (2H, d), 7.30 (1H, d), 7.35-7.40 (2H, m), 7.40-7.49 (5H, m), 7.59 (2H, br d), 8.01 (1H, br d), 8.42 (1H, s), 12.75 (1H, br s).

實例8：(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]-7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(2S)-2-甲氧基丙氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-4-羥基-N-{(1R)-2-羥基-1-[4-(4-甲基-1,3-

唑-5-基)苯基]乙基}-L-脯胺醯胺 Example 8: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide

ESI+：1089.9。 ESI+: 1089.9.

生物實例Biological examples

實例A：人類KRAS G12D突變陽性PK-59胰臟癌細胞株衍生之異種移植小鼠中與SOC之活體內組合療法 Example A: In vivo combination therapy with SOC in xenograft mice derived from human KRAS G12D mutation-positive PK-59 pancreatic cancer cell line

將PK-59細胞(RIKEN，目錄號RCB1901)在補充有10%胎牛血清之RPMI-1640培養基中在37℃下在空氣中5% CO₂之氣氛中培養。將6至8週齡雌性裸鼠(BALB/c裸鼠，來自Beijing Vital River Laboratory Animal Technology Co.,Ltd)皮下接種含PK-59細胞(3×10⁶)之0.2mL DPBS(含有50% BD基質膠(Corning Incorporated))以形成腫瘤。將動物隨機分組且在腫瘤接種之後的第7天開始處理，此時平均腫瘤大小達至大約120mm³。基於動物之腫瘤體積使用執行分層隨機化的基於Excel之隨機化軟體將動物分配至各組中。各組由5隻小鼠組成。如表2中所示投予測試物品。藉由將4體積%之乙醇、1體積%之50%(2-羥丙基)-β-環糊精、9體積%之聚氧乙烯氫化蓖麻油(HCO-40)混合於5%葡萄糖溶液中來製備溶劑A。將實例1之化合物溶解於其中。將吉西他濱及Abraxane^TM(奈米粒子白蛋白結合型(nab)紫杉醇)溶解於鹽水中。一週量測腫瘤大小及體重兩次至三次。使用下式計算腫瘤體積。 PK-59 cells (RIKEN, catalog number RCB1901) were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% CO ₂ in air. Female nude mice (BALB/c nude mice, from Beijing Vital River Laboratory Animal Technology Co., Ltd) aged 6 to 8 weeks were subcutaneously inoculated with PK-59 cells (3×10 ⁶ ) in 0.2 mL DPBS (containing 50% BD base gel (Corning Incorporated)) to form tumors. Animals were randomly divided into groups and treatment began on day 7 after tumor inoculation, when the average tumor size reached approximately 120 mm ³ . Animals were assigned to groups based on their tumor volume using Excel-based randomization software that performed hierarchical randomization. Each group consisted of 5 mice. Test articles were administered as shown in Table 2. Solvent A was prepared by mixing 4 volume % ethanol, 1 volume % 50% (2-hydroxypropyl)-β-cyclodextrin, and 9 volume % polyoxyethylene hydrogenated castor oil (HCO-40) in 5% glucose solution. The compound of Example 1 was dissolved therein. Gemcitabine and Abraxane ^TM (nanoparticle albumin-bound (nab) paclitaxel) were dissolved in saline. Tumor size and body weight were measured two to three times a week. Tumor volume was calculated using the following formula.

[腫瘤體積(mm³)]=[腫瘤之長直徑(mm)]×[腫瘤之短直徑(mm)]²×0.5 [Tumor volume (mm ³ )] = [Long diameter of tumor (mm)] × [Short diameter of tumor (mm)] ² × 0.5

使用下式計算各組之測試化合物的腫瘤生長抑制(TGI)率(%)：TGI(%)=[1-(Ti-T1)/(Vi-V1)]×100；Ti為治療組在給定日之平均腫瘤體積，T1為治療組在治療第一天之平均腫瘤體積，Vi為媒劑對照組在與Ti同一天之平均腫瘤體積，且V1為媒劑組在治療第一天之平均腫瘤體積。 The tumor growth inhibition (TGI) rate (%) of the test compound in each group was calculated using the following formula: TGI (%) = [1-(Ti-T1)/(Vi-V1)] × 100; Ti is the average tumor volume of the treatment group on a given day, T1 is the average tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the vehicle control group on the same day as Ti, and V1 is the average tumor volume of the vehicle group on the first day of treatment.

如表2中所描述之測試結果中所示，實例1之化合物與吉西他濱或Abraxane^TM組合在攜帶具有KRAS G12D突變之人類胰臟癌細胞之小鼠中顯示抗腫瘤活性，表明針對G12D突變型KRAS-陽性胰臟癌之治療，與實例1之化合物組合優於吉西他濱或Abraxane^TM單藥療法。 As shown in the test results described in Table 2, the compound of Example 1 in combination with gemcitabine or Abraxane ^TM showed anti-tumor activity in mice carrying human pancreatic cancer cells with KRAS G12D mutation, indicating that the combination with the compound of Example 1 is superior to gemcitabine or Abraxane ^TM monotherapy for the treatment of G12D mutant KRAS-positive pancreatic cancer.

實例B：人類KRAS G12D突變陽性GP2d大腸直腸癌細胞株衍生之異種移植小鼠中與SOC之活體內組合療法 Example B: In vivo combination therapy with SOC in xenograft mice derived from human KRAS G12D mutation-positive GP2d colorectal cancer cell lines

將GP2d細胞(European Collection of Authenticated Cell Cultures，目錄號95090714)在補充有10%胎牛血清(2mM麩醯胺酸)之DMEM培養基中在37℃在空氣中5% CO₂之氣氛中培養。將6至8週齡雌性裸鼠(BALB/c裸鼠，來自Beijing Vital River Laboratory Animal Technology Co.,Ltd)皮下接種含GP2d細胞(3×10⁶)之0.2mL DPBS(含有50% BD基質膠(Corning Incorporated))以形成腫瘤。將動物隨機分組且在腫瘤接種之後的第10天開始處理，此時平均腫瘤大小達至大約150mm³。基於動物之腫瘤體積使用執行分層隨機化的基於Excel之隨機化軟體將動物分配至各組中。各組由5隻小鼠組成。如表3中所示投予測試物品。藉由將4體積%之乙醇、1體積%之50%(2-羥丙基)-β-環糊精、9體積%之HCO-40混合於5%葡萄糖溶液中來製備溶劑A。將實例1之化合物溶解於其中。將5-FU、伊立替康溶解於鹽水中。將奧沙利鉑溶解於5%葡萄糖中。一週量測腫瘤大小及體重兩次至三次。使用下式計算腫瘤體積。 GP2d cells (European Collection of Authenticated Cell Cultures, catalog number 95090714) were cultured in DMEM supplemented with 10% fetal bovine serum (2 mM glutamine) at 37°C in an atmosphere of 5% CO ₂ in air. Female nude mice (BALB/c nude mice, from Beijing Vital River Laboratory Animal Technology Co., Ltd) aged 6 to 8 weeks were subcutaneously inoculated with GP2d cells (3×10 ⁶ ) in 0.2 mL DPBS (containing 50% BD base gel (Corning Incorporated)) to form tumors. Animals were randomly divided into groups and treatment began on day 10 after tumor inoculation, when the average tumor size reached approximately 150 mm ³ . Animals were assigned to groups based on their tumor volume using Excel-based randomization software that performed hierarchical randomization. Each group consisted of 5 mice. Test articles were administered as shown in Table 3. Solvent A was prepared by mixing 4 volume % ethanol, 1 volume % 50% (2-hydroxypropyl)-β-cyclodextrin, and 9 volume % HCO-40 in a 5% glucose solution. The compound of Example 1 was dissolved therein. 5-FU and irinotecan were dissolved in saline. Oxaliplatin was dissolved in 5% glucose. Tumor size and body weight were measured two to three times a week. Tumor volume was calculated using the following formula.

使用下式計算各組之測試化合物的TGI率(%)：TGI(%)=[1-(Ti-T1)/(Vi-V1)]×100；Ti為治療組在給定日之平均腫瘤體積，T1為治療組在治療第一天之平均腫瘤體積，Vi為媒劑對照組在與Ti同一天之平均腫瘤體積，且V1為媒劑組在治療第一天之平均腫瘤體積。 The TGI rate (%) of the test compound in each group was calculated using the following formula: TGI (%) = [1-(Ti-T1)/(Vi-V1)] × 100; Ti is the average tumor volume of the treatment group on a given day, T1 is the average tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the vehicle control group on the same day as Ti, and V1 is the average tumor volume of the vehicle group on the first day of treatment.

如表3中所描述之測試結果中所示，實例1之化合物與5-FU、伊立替康或奧沙利鉑組合在攜帶具有KRAS G12D突變之人類大腸直腸癌細胞之小鼠中顯示抗腫瘤活性，表明針對G12D突變型KRAS-陽性大腸直腸癌之治療，與實例1之化合物組合優於5-FU、伊立替康或奧沙利鉑單藥療法。 As shown in the test results described in Table 3, the compound of Example 1 combined with 5-FU, irinotecan or oxaliplatin showed anti-tumor activity in mice carrying human colorectal cancer cells with KRAS G12D mutation, indicating that the combination with the compound of Example 1 is superior to 5-FU, irinotecan or oxaliplatin monotherapy for the treatment of G12D mutant KRAS-positive colorectal cancer.

實例C：KRAS G12D突變陽性人類肺癌患者衍生之異種移植小鼠中與多西他賽之活體內組合療法 Example C: In vivo combination therapy with docetaxel in KRAS G12D mutation-positive human lung cancer patient-derived xenograft mice

將4至6週齡雌性裸鼠(對照：NMRI-Foxnlnu，來自Charles River)關進倉庫且皮下接種人類肺癌患者衍生之腫瘤(模型名稱：LXFA 2204(來自Charles River))。基於動物之腫瘤體積使用執行分層隨機化的基於Excel之隨機化軟體將動物分配至各組中。各組由8隻小鼠組成。如表4中所示投予測試物品。藉由將4體積%之乙醇、1體積%之50%(2-羥丙基)-β-環糊精、9體積%之HCO-40混合於5%葡萄糖溶液中來製備溶劑A。將實例1之化合物溶解於其中。將多西他賽溶解於0.9% NaCl溶液中。一週量測腫瘤直徑及重量體積兩次。使用下式計算腫瘤體積。 Female nude mice (control: NMRI-Foxnlnu, from Charles River) aged 4 to 6 weeks were housed and subcutaneously inoculated with human lung cancer patient-derived tumors (model name: LXFA 2204 (from Charles River)). Animals were assigned to groups based on their tumor volume using Excel-based randomization software that performed stratified randomization. Each group consisted of 8 mice. Test articles were administered as shown in Table 4. Solvent A was prepared by mixing 4 volume % ethanol, 1 volume % 50% (2-hydroxypropyl)-β-cyclodextrin, 9 volume % HCO-40 in 5% glucose solution. The compound of Example 1 was dissolved therein. Docetaxel was dissolved in 0.9% NaCl solution. Measure the tumor diameter and weight twice a week. Calculate the tumor volume using the following formula.

計算測試化合物之腫瘤生長抑制(TGI)率(%)，測試化合物-處理組在開始處理前一天對腫瘤體積為100%抑制及媒劑組在第一次處理後3週結束時對腫瘤體積為0%抑制。 The tumor growth inhibition (TGI) rate (%) of the test compound was calculated, with the test compound-treated group having 100% inhibition of tumor volume one day before the start of treatment and the vehicle group having 0% inhibition of tumor volume at the end of 3 weeks after the first treatment.

獲得以下結果(表4)。 The following results were obtained (Table 4).

如表4中所描述之測試結果所示，實例1之化合物與多西他賽組合在人類G12D突變型KRAS-陽性肺癌細胞株腫瘤攜帶小鼠中之抗腫瘤活性表明與實例1之化合物的組合可優於多西他賽單藥療法。 As shown in the test results described in Table 4, the anti-tumor activity of the compound of Example 1 in combination with docetaxel in human G12D mutant KRAS-positive lung cancer cell line tumor-bearing mice indicates that the combination with the compound of Example 1 may be superior to docetaxel monotherapy.

產業可利用性Industry Availability

本發明在抗腫瘤活性方面極佳，且可用於治療G12D突變型KRAS-陽性癌症，尤其G12D突變型KRAS-陽性胰臟癌、大腸直腸癌及/或肺癌及類似者。 The present invention is excellent in anti-tumor activity and can be used to treat G12D mutant KRAS-positive cancers, especially G12D mutant KRAS-positive pancreatic cancer, colorectal cancer and/or lung cancer and the like.

Claims

一種式(I)化合物或其醫藥學上可接受之鹽與抗癌劑或其醫藥學上可接受之鹽的組合，其用於治療癌症，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥，其中該式(I)化合物係選自由以下組成之群： A combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof, for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof, wherein the compound of formula (I) is selected from the group consisting of:

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-環丙基-4-[(1S,4S)-2,5-二氮雜雙環[2.2.1]庚-2-基]- 7-(6-氟-5-甲基-1H-吲唑-4-基)-2-[(氧雜環己-4-基)氧基]喹唑啉-8-基}氧基)甲基]苯基}-1H-1,2,3-***-1-基)-3-甲基丁醯基]-N-{(1R)-1-[4-(1-乙基-1H-吡唑-5-基)苯基]-2-羥基乙基}-4-羥基-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]- 7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide,

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

如請求項1所述之式(I)化合物或其醫藥學上可接受之鹽，其用於治療癌症，其中該治療進一步包含投予抗癌劑或其醫藥學上可接受之鹽，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 The compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 is used for treating cancer, wherein the treatment further comprises administering an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

一種醫藥組合物，其包含如請求項1所述之式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽以及視情況選用之一種或多種醫藥可接受之賦形劑，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 and an anticancer agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable formulations selected as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorine-containing nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds and prodrugs thereof.

如請求項3所述之醫藥組合物，其用於治療癌症。 The pharmaceutical composition as described in claim 3 is used for treating cancer.

一種治療癌症之方法，其包含向有需要之患者投予治療有效量的如請求項1所述之式(I)化合物或其醫藥學上可接受之鹽及治療有效量的抗癌劑或其醫藥學上可接受之鹽，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

一種如請求項1所述之式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽的用途，其用於治療癌症，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof as described in claim 1 for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, alkaloid analogs, fluoropyrimidine compounds and prodrugs thereof.

一種如請求項1所述之式(I)化合物或其醫藥學上可接受之鹽及抗癌劑或其醫藥學上可接受之鹽的用途，其用於製造用於治療癌症之藥劑，該抗癌劑選自由以下組成之群：紫杉烷化合物、含氟核苷、鉑化合物、喜樹鹼類似物、氟嘧啶化合物及其前藥。 A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof as described in claim 1, for the manufacture of a medicament for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, alkaloid analogs, fluoropyrimidine compounds and prodrugs thereof.

一種組分套組(kit-of-parts)，其包含： A kit-of-parts comprising:

(A)包含以下之醫藥組合物：如請求項1所述之式(I)化合物或其醫藥學上可接受之鹽，及視情況選用之一種或多種醫藥學上可接受之賦形劑，及 (A) A pharmaceutical composition comprising: a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected as appropriate, and

該組分套組用於治療癌症。 This kit is used to treat cancer.

如請求項1至8中任一項所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該抗癌劑為紫杉烷化合物。 A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 8, wherein the anticancer agent is a taxane compound.

如請求項9所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該紫杉烷化合物為紫杉醇。 A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in claim 9, wherein the taxane compound is paclitaxel.

如請求項9所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該紫杉烷化合物為多西他賽(docetaxel)。 A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in claim 9, wherein the taxane compound is docetaxel.

如請求項1至8中任一項所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該抗癌劑為含氟核苷。 A compound for use, a pharmaceutical composition for use, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 8, wherein the anticancer agent is a fluorinated nucleoside.

如請求項12所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該含氟核苷為吉西他濱(gemcitabine)。 The compound for use, pharmaceutical composition, pharmaceutical composition for use, method, use or kit of parts for use as described in claim 12, wherein the fluorinated nucleoside is gemcitabine.

如請求項1至8中任一項所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該抗癌劑為鉑化合物。 A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 8, wherein the anticancer agent is a platinum compound.

如請求項14所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該鉑化合物為奧沙利鉑(oxaliplatin)。 A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in claim 14, wherein the platinum compound is oxaliplatin.

如請求項1至8中任一項所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該抗癌劑為喜樹鹼類似物。 A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 8, wherein the anticancer agent is a catecholamine analog.

如請求項16所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該喜樹鹼類似物為伊立替康(irinotecan)。 A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in claim 16, wherein the campestrin analog is irinotecan.

如請求項1至8中任一項所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該抗癌劑為氟嘧啶化合物。 A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 8, wherein the anticancer agent is a fluoropyrimidine compound.

如請求項18所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該氟嘧啶化合物為5-FU。 A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in claim 18, wherein the fluoropyrimidine compound is 5-FU.

如請求項1至19中任一項所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該癌症為胰臟癌。 A compound for use, a pharmaceutical composition for use, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 19, wherein the cancer is pancreatic cancer.

如請求項1至19中任一項所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該癌症為大腸直腸癌。 A compound for use, a pharmaceutical composition for use, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 19, wherein the cancer is colorectal cancer.

如請求項1至19中任一項所述之供使用之化合物、醫藥組合物、供使用之醫藥組合物、方法、用途或供使用之組分套組，其中該癌症為肺癌。 A compound for use, a pharmaceutical composition for use, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 19, wherein the cancer is lung cancer.