TW202404600A - Combination therapy using a ptpn11 inhibitor and a pd-1/pd-l1 inhibitor - Google Patents

Combination therapy using a ptpn11 inhibitor and a pd-1/pd-l1 inhibitor Download PDF

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TW202404600A
TW202404600A TW112115152A TW112115152A TW202404600A TW 202404600 A TW202404600 A TW 202404600A TW 112115152 A TW112115152 A TW 112115152A TW 112115152 A TW112115152 A TW 112115152A TW 202404600 A TW202404600 A TW 202404600A
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黎賢 金
保羅 哈魯斯加
約瑟夫 費奧雷
拉塔 賈雅萊曼
馬修 梅爾
宇 劉
布萊恩 Ａ 波爾森
妮可 潘
佩卓 貝川
卡爾 丹柯斯基
天霧 林
安娜 韋德
艾利 瓦勒斯
玉婷 孫
南西 寇爾
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美商必治妥美雅史谷比公司
美商納維爾製藥有限公司
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Abstract

The present disclosure provides a method of treating a disease or disorder (e.g., cancer) in a subject. The method including administering to the subject: (a) a therapeutically effective amount of a PTPN11 inhibitor; and (b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PTPN11 inhibitor is represent by formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or a combination thereof, wherein the subscripts a and b, Y1, Y2, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R13 are as provided herein. In particular, the present disclosure provides a method of treating a solid tumor (e.g., an advanced non-small cell lung cancer) with a therapeutically effective amount of a compound of formula (10b) (i.e., 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(Ra)-(2,3-dichlorophenyl)-2,5-dimethyl-4(3H)-pyrimidinone) in combination with a PD-1/PD-L1 inhibitor (except for nivolumab) in a subject, wherein the subject has one or more mutations in KRAS.

Description

使用PTPN11抑制劑及PD-1/PD-L1抑制劑之組合療法Combination therapy using PTPN11 inhibitors and PD-1/PD-L1 inhibitors

計畫性死亡-1 (PD-1)係由活化T及B細胞表現之關鍵免疫查核點受體並介導免疫抑制。PD-1具有兩種配體，PD-L1及PD-L2，其等係B7家族之成員。PD-L1係表現於抗原呈遞細胞及許多人類癌症上且已顯示在結合至PD-1時下調T細胞活化及細胞介素分泌。PD-1/PD-L1相互作用之抑制於臨床前模型中介導強效抗腫瘤活性及用於治療癌症之PD-1/PD-L1相互作用之多種抗體抑制劑已批准用於臨床用途。其中，已提出靶向PD-1受體之帕博利珠單抗(pembrolizumab)用於治療多種適應症，包括黑色素瘤、肺癌、頭頸癌、何傑金氏(Hodgkin)淋巴瘤及胃癌。特定言之，帕博利珠單抗係用以治療不能手術的或轉移性黑色素瘤及轉移性非小細胞肺癌(NSCLC)；作為無法接受基於順鉑之化學療法且具有高含量PD-L1之病患中用於轉移性膀胱癌之第一線治療；作為在基於鉑之化學療法後，用於頭頸部鱗狀細胞癌(HNSCC)之第二線治療；用於治療患有難治性經典何傑金氏淋巴瘤(cHL)之成人及兒童病患；及用於復發性局部晚期或轉移性食管鱗狀細胞癌。帕博利珠單抗亦經批准用以治療具有某些遺傳異常(錯配修復缺陷或高微衛星不穩定性及高腫瘤突變負荷)之任何不可切除或轉移性實體腫瘤。Programmed death-1 (PD-1) is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family. PD-L1 is expressed on antigen-presenting cells and many human cancers and has been shown to downregulate T cell activation and interleukin secretion when bound to PD-1. Inhibition of the PD-1/PD-L1 interaction mediates potent antitumor activity in preclinical models and multiple antibody inhibitors of the PD-1/PD-L1 interaction for the treatment of cancer have been approved for clinical use. Among them, pembrolizumab targeting the PD-1 receptor has been proposed for the treatment of multiple indications, including melanoma, lung cancer, head and neck cancer, Hodgkin's lymphoma and gastric cancer. Specifically, pembrolizumab is indicated for the treatment of inoperable or metastatic melanoma and metastatic non-small cell lung cancer (NSCLC) that are refractory to cisplatin-based chemotherapy and have high levels of PD-L1 For first-line treatment of metastatic bladder cancer in patients; as second-line treatment for head and neck squamous cell carcinoma (HNSCC) after platinum-based chemotherapy; for the treatment of patients with refractory classic He Jie Adult and pediatric patients with King's lymphoma (cHL); and for recurrent locally advanced or metastatic esophageal squamous cell carcinoma. Pembrolizumab is also approved for the treatment of any unresectable or metastatic solid tumor with certain genetic abnormalities (mismatch repair deficiency or high microsatellite instability and high tumor mutation burden).

蛋白質-酪胺酸磷酸酶非受體11型(PTPN11，亦稱為Src同源-2磷酸酶(SHP2))係由PTPN11基因編碼之非受體蛋白酪胺酸磷酸酶。SHP2於RTK介導之MAPK訊息傳導路徑中發揮關鍵作用。此PTP含有兩個串聯Src同源-2 (SH2)域，其等用作磷酸-酪胺酸結合域、催化域及C末端尾。在基礎狀態下，該蛋白質通常以無活性、自我抑制之構象存在及N末端SH2域阻斷活性位點。當藉由細胞介素介導之訊息傳導及磷酸化蛋白與SH2域之生長因子結合刺激時，自我抑制經緩解，此使得該活性位點可用於PTPN11受質之去磷酸化(MG Mohl, BG Neel, Curr. Opin. Genetics Dev. 2007, 17, 23-30. KS Grossmann, Adv. Cancer Res. 2010, 106, 53-89。W.Q. Huang等人，Curr. Cancer Drug Targets 2014, 14, 567-588。C. Gordon等人，Cancer Metastasis Rev. 2008, 27, 179-192.)。Protein-tyrosine phosphatase non-receptor type 11 (PTPN11, also known as Src homology-2 phosphatase (SHP2)) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 plays a key role in the RTK-mediated MAPK signaling pathway. This PTP contains two tandem Src homology-2 (SH2) domains, which serve as the phospho-tyrosine binding domain, catalytic domain, and C-terminal tail. In the basal state, the protein usually exists in an inactive, self-inhibitory conformation with the N-terminal SH2 domain blocking the active site. Autoinhibition is relieved when stimulated by cytokine-mediated signaling and growth factor binding of phosphorylated proteins to the SH2 domain, making this active site available for dephosphorylation of the PTPN11 receptor (MG Mohl, BG Neel, Curr. Opin. Genetics Dev. 2007, 17, 23-30. KS Grossmann, Adv. Cancer Res. 2010, 106, 53-89. W.Q. Huang et al., Curr. Cancer Drug Targets 2014, 14, 567-588 . C. Gordon et al., Cancer Metastasis Rev. 2008, 27, 179-192.).

已報導PTPN11中之生殖系列及體細胞突變於數種人類疾病中導致催化活性之功能獲得，該等疾病包括努南症候群(Noonan Syndrome)及豹皮症候群(Leopard Syndrome)；及多種癌症，諸如少年性骨髓單核球白血病、神經母細胞瘤、骨髓化生不良症候群、B細胞急性淋巴母細胞白血病/淋巴瘤、黑色素瘤、急性骨髓性白血病及乳癌、肺癌及結腸癌(MG Mohl, BG Neel, Curr. Opin. Genetics Dev. 2007, 17, 23-30)。近期研究已證實單個PTPN11突變能夠於小鼠中誘導努南症候群、JMML樣骨髓增生性疾病及急性白血病。此等突變破壞N-SH2域與催化位點之間的自身抑制作用，容許受質組成性進入酵素之催化位點(E. Darian等人，Proteins, 2011, 79, 1573-1588。Z-H Yu等人，JBC, 2013, 288, 10472, W Qiu等人，BMC Struct. Biol. 2014, 14, 10)。Germline and somatic mutations in PTPN11 have been reported to cause a gain of function in catalytic activity in several human diseases, including Noonan Syndrome and Leopard Syndrome; and in various cancers, such as juvenile Myelomonocytic leukemia, neuroblastoma, myelodysplasia syndrome, B-cell acute lymphoblastic leukemia/lymphoma, melanoma, acute myelogenous leukemia and breast, lung and colon cancer (MG Mohl, BG Neel, Curr. Opin. Genetics Dev. 2007, 17, 23-30). Recent studies have demonstrated that a single PTPN11 mutation can induce Noonan syndrome, JMML-like myeloproliferative disorders, and acute leukemia in mice. These mutations disrupt the autoinhibitory interaction between the N-SH2 domain and the catalytic site, allowing constitutive access of the substrate to the catalytic site of the enzyme (E. Darian et al., Proteins, 2011, 79, 1573-1588. Z-H Yu et al. Human, JBC, 2013, 288, 10472, W Qiu et al., BMC Struct. Biol. 2014, 14, 10).

PTPN11係廣泛表現於大多數組織中並在對細胞功能多樣性而言重要的各種細胞傳訊事件中透過包括Ras-MAPK、JAK-STAT或PI3K-AKT路徑之多種傳訊路徑而發揮調節作用，該細胞功能包括增生、分化、細胞週期維持、上皮-間充質轉化(EMT)、有絲***活化、代謝控制、轉錄調節及細胞遷移(Tajan, M.等人，Eur. J. Medical Genetics, 2015, 58, 509-525。Prahallad, A.等人，Cell Reports, 2015, 12, 1978-1985)。PTPN11 is widely expressed in most tissues and plays a regulatory role in various cellular signaling events that are important for cell functional diversity through multiple signaling pathways including Ras-MAPK, JAK-STAT or PI3K-AKT pathways. This cell Functions include proliferation, differentiation, cell cycle maintenance, epithelial-mesenchymal transition (EMT), mitotic activation, metabolic control, transcriptional regulation and cell migration (Tajan, M. et al., Eur. J. Medical Genetics, 2015, 58, 509-525. Prahallad, A. et al., Cell Reports, 2015, 12, 1978-1985).

另外，越來越多之證據表明PTPN11/SHP2係與腫瘤發生過程中之免疫逃逸相關，且因此SHP2抑制劑可刺激癌症病患中之免疫反應(Cancer Res. 2015 Feb 1;75(3):508-18. T Yokosuka T, J Exp Med. 2012, 209(6), 1201. S Amarnath Sci Transl Med. 2011, 3, 111ra120. T Okazaki, PNAS 2001, 98:24, 13866-71)。In addition, increasing evidence indicates that PTPN11/SHP2 is related to immune evasion during tumorigenesis, and therefore SHP2 inhibitors can stimulate immune responses in cancer patients (Cancer Res. 2015 Feb 1;75(3): 508-18. T Yokosuka T, J Exp Med. 2012, 209(6), 1201. S Amarnath Sci Transl Med. 2011, 3, 111ra120. T Okazaki, PNAS 2001, 98:24, 13866-71).

然而，儘管有PD-1/PD-L1抑制劑之治療選項，仍出現耐藥性。因此，仍需有效且安全之治療劑來治療此等耐藥性病例。However, despite the availability of PD-1/PD-L1 inhibitor treatment options, resistance still emerges. Therefore, effective and safe therapeutic agents are still needed to treat these drug-resistant cases.

本發明提供治療藉由投與PTPN11抑制劑(例如，式(10b)化合物，如本文描述)及PD-1/PD-L1抑制劑兩者治療疾病及疾患(例如，癌症)之方法。The present invention provides methods of treating diseases and disorders (eg, cancer) by administering both a PTPN11 inhibitor (eg, a compound of Formula (10b), as described herein) and a PD-1/PD-L1 inhibitor.

在一項態樣中，本發明提供一種於個體中治療癌症之方法，該方法包括對該個體投與： a)治療有效量之PTPN11抑制劑；及 b)治療有效量之PD-1/PD-L1抑制劑， 其中該PTPN11抑制劑係由式(I)表示： (I) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中下標a及b、Y 1、Y 2及R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11及R 13係如本文提供；及該PD-1/PD-L1抑制劑係如本文定義及描述。 In one aspect, the invention provides a method of treating cancer in an individual, the method comprising administering to the individual: a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of PD-1/PD -L1 inhibitor, wherein the PTPN11 inhibitor is represented by formula (I): (I) Or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof, wherein the subscripts a and b, Y 1 , Y 2 and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 13 are as provided herein; and the PD-1/PD-L1 inhibition Agents are as defined and described herein.

在另一態樣中，本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物： (10b)， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之PD-1/PD-L1抑制劑， 其中該PD-1/PD-L1抑制劑係如本文定義及描述。在一些實施例中，該PD-1/PD-L1抑制劑不為納武單抗(nivolumab)。 In another aspect, the invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b): (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) a therapeutically effective amount of PD-1/PD - an L1 inhibitor, wherein the PD-1/PD-L1 inhibitor is as defined and described herein. In some embodiments, the PD-1/PD-L1 inhibitor is other than nivolumab.

在另一態樣中，本發明提供一種於個體中治療實體腫瘤(例如，晚期非小細胞肺癌)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物： (10b)， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之PD-1/PD-L1抑制劑， 其中該個體具有KRAS突變(例如，如本文描述)。在一些實施例中，該PD-1/PD-L1抑制劑不為納武單抗。 In another aspect, the invention provides a method of treating a solid tumor (e.g., advanced non-small cell lung cancer) in an individual, the method comprising administering to an individual in need thereof: a) a therapeutically effective amount of the formula ( Compounds represented by 10b): (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) a therapeutically effective amount of PD-1/PD - an L1 inhibitor, wherein the individual has a KRAS mutation (eg, as described herein). In some embodiments, the PD-1/PD-L1 inhibitor is not nivolumab.

相關申請案之交叉參考Cross-references to related applications

本申請案主張2022年4月22日申請之美國臨時申請案第63/333,958號之優先權，其係出於所有目的以全文引用之方式併入本文中。 I. 概述 This application claims priority to U.S. Provisional Application No. 63/333,958, filed on April 22, 2022, which is incorporated by reference in its entirety for all purposes. I. Overview

本發明提供一種於個體中治療疾病或疾患(例如，癌症，諸如實體腫瘤)之組合療法。該方法包括對該個體投與a)治療有效量之PTPN11抑制劑；及b)治療有效量之PD-1/PD-L1抑制劑，其中該PTPN11抑制劑係由如本文定義及描述之式(I)表示(例如，由式(10b)表示之化合物)。該PD-1/PD-L1抑制劑可至少部分抑制PD-1/PD-L1蛋白。該PD-1/PD-L1抑制劑可為PD-1抑制劑。該PD-1/PD-L1抑制劑可為PD-L1抑制劑。該PD-1/PD-L1抑制劑可為選擇性PD-1/PD-L1抑制劑，選擇性抑制PD-1及/或PD-L1。該PD-1/PD-L1抑制劑可抑制PD-1及PD-L1兩者。該PD-1/PD-L1抑制劑可另外抑制PD-L2。本發明亦提供用於治療個體之疾病或疾患(例如，癌症)之其醫藥組合物及其套組。The present invention provides a combination therapy for the treatment of a disease or disorder (eg, cancer, such as solid tumors) in an individual. The method includes administering to the subject a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PTPN11 inhibitor is represented by the formula as defined and described herein ( I) represents (for example, a compound represented by formula (10b)). The PD-1/PD-L1 inhibitor can at least partially inhibit PD-1/PD-L1 protein. The PD-1/PD-L1 inhibitor can be a PD-1 inhibitor. The PD-1/PD-L1 inhibitor can be a PD-L1 inhibitor. The PD-1/PD-L1 inhibitor can be a selective PD-1/PD-L1 inhibitor that selectively inhibits PD-1 and/or PD-L1. The PD-1/PD-L1 inhibitor can inhibit both PD-1 and PD-L1. The PD-1/PD-L1 inhibitor may additionally inhibit PD-L2. The present invention also provides pharmaceutical compositions and kits thereof for treating a disease or disorder (eg, cancer) in an individual.

本發明亦提供一種於個體中使用治療有效量之式(10b)化合物與PD-1/PD-L1抑制劑之組合治療實體腫瘤(例如，晚期非小細胞肺癌)之方法，其中該個體之KRAS中具有一或多個突變。特定言之，該實體腫瘤係由KRAS中之突變引起之晚期非小細胞肺癌(NSCLC)。在一些實施例中，該PD-1/PD-L1抑制劑不為納武單抗。在一些實施例中，該癌症之特徵在於除Q61X突變外之KRAS突變。 II.     定義 The invention also provides a method of treating solid tumors (e.g., advanced non-small cell lung cancer) using a therapeutically effective amount of a compound of formula (10b) in combination with a PD-1/PD-L1 inhibitor in an individual, wherein the individual has KRAS has one or more mutations. Specifically, the solid tumor is advanced non-small cell lung cancer (NSCLC) caused by mutations in KRAS. In some embodiments, the PD-1/PD-L1 inhibitor is not nivolumab. In some embodiments, the cancer is characterized by a KRAS mutation in addition to the Q61X mutation. II. Definition

如本文使用，下文術語具有本發明指示之含義。As used herein, the following terms have the meanings indicated herein.

除非另有明確指示，否則如本文於式(例如，(2b)、(10b))中之任一者中所使用之基團「 」，係指甲基。 As used herein in any of the formulas (e.g., (2b), (10b)), a group " ”, which is the nail base.

「包含」、「包括」及「具有」及其派生詞可於本文中作為全面開放式術語互換使用。例如，「包含」、「包括」或「具有」的使用意謂無論包含、具有或包括何種元素，均不為含有該動詞之從句之主語包含之唯一元素。The terms "comprises," "includes," and "having" and their derivatives may be used interchangeably herein as blanket open-ended terms. For example, the use of "includes," "includes," or "has" means that whatever element contains, has, or includes is not the only element included in the subject of the clause containing that verb.

當本發明揭示值之範圍，及使用記法「n 1…至n 2」或「介於n 1…與n 2之間」時，其中n 1及n 2係數字，則除非另有規定，否則此記法意欲包括該等數字本身及介於其等之間的範圍。此範圍可為介於端值之間整數或連續且包括該等端值。僅以實例說明之，範圍「2至6個碳」意欲包括二、三、四、五及六個碳，因為碳以整數單元存在。僅以實例說明之，比較範圍「1至3 µM (微莫耳)」，其意欲包括1 µM、3 µM，及介於至任何數量之有效數字之間的一切(例如，1.255 µM、2.1 µM、2.9999 µM等)。 When this disclosure discloses a range of values and uses the notation "n 1 ... to n 2 " or "between n 1 ... and n 2 ", where n 1 and n 2 are numbers, then unless otherwise specified, This notation is intended to include the numbers themselves and the ranges between them. The range may be an integer between the endpoints or continuous, inclusive of the endpoints. By way of example only, the range "2 to 6 carbons" is intended to include two, three, four, five and six carbons, since the carbons are present in integer units. By way of example only, the comparative range "1 to 3 µM (micromolar)" is intended to include 1 µM, 3 µM, and everything in between to any number of significant figures (e.g., 1.255 µM, 2.1 µM , 2.9999 µM, etc.).

如本文使用，「約」意欲限定其修飾之數值，表示此值為誤差範圍內之變量。當未列舉特定之誤差範圍，諸如圖表或資料表中給定之平均值之標準偏差時，應瞭解術語「約」意謂將包含列舉值之範圍及考慮到有效數字，將藉由向上或向下捨入至該數字包括之範圍。As used herein, "about" is intended to limit the value it modifies, indicating that the value is a variable within a margin of error. When a specific error range is not recited, such as the standard deviation of a mean given in a chart or data table, it should be understood that the term "about" will include the range of the recited value and will be calculated by upward or downward accounting for significant digits. Round to the inclusive range of the number.

如本文使用，單獨或組合的「烯基」係指具有一或多個雙鍵且含有2至20個碳原子之直鏈或分支鏈烴基。在某些實施例中，該烯基將包含2至6個碳原子。術語「伸烯基」係指於兩個或更多個位置處附接之碳碳雙鍵系統，諸如伸乙烯基[(-CH=CH-),(-C::C-)]。合適之烯基之實例包括乙烯基、丙烯基、2-甲基丙烯基、1,4-丁二烯基及類似物。除非另有規定，否則術語「烯基」可包括「伸烯基」。As used herein, "alkenyl" alone or in combination refers to a straight or branched chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkenyl group will contain 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, such as vinylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl groups include vinyl, propenyl, 2-methacenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term "alkenyl" may include "alkenyl".

「炔基」係指具有至少2個碳原子及至少一個三鍵且具有本發明指示之碳原子數量之直鏈或分支鏈烴(即，C 2-6意謂二至六個碳)。炔基可包括任何數量之碳，諸如C 2、C 2-3、C 2-4、C 2-5、C 2-6、C 2-7、C 2-8、C 2-9、C 2-10、C 3、C 3-4、C 3-5、C 3-6、C 4、C 4-5、C 4-6、C 5、C 5-6及C 6。炔基之實例包括(但不限於)乙炔基、丙炔基、1-丁炔基、2-丁炔基、丁二炔基、1-戊炔基、2-戊炔基、異戊炔基、1,3-戊二炔基、1,4-戊二炔基、1-己炔基、2-己炔基、3-己炔基、1,3-己二炔基、1,4-己二炔基、1,5-己二炔基、2,4-己二炔基及1,3,5-己三炔基。 "Alkynyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one triple bond and having the number of carbon atoms indicated herein (ie, C 2-6 means two to six carbons). Alkynyl groups may include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2 -10 , C3 , C3-4 , C3-5 , C3-6 , C4 , C4-5 , C4-6 , C5 , C5-6 and C6 . Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl , 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4- Hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl and 1,3,5-hexanetriynyl.

如本文使用，單獨或組合的「烷氧基」係指烷基醚基，其中術語烷基係如下文定義。合適之烷基醚基之實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基、第三丁氧基，及類似物。As used herein, "alkoxy" alone or in combination refers to an alkyl ether group, where the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 2nd butoxy, 3rd butoxy, and Analogues.

如本文使用，單獨或組合的「烷基」係指含有1至20個碳原子之直鏈或分支鏈烷基。在某些實施例中，該烷基將包含1至10個碳原子。在其他實施例中，該烷基將包含1至8個碳原子。烷基係未經取代或如本文定義經取代。烷基之實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、己基、辛基、壬基(noyl)及類似物。如本文使用，單獨或組合的術語「伸烷基」係指來源於在兩個或更多個位置處附接之直鏈或分支鏈飽和烴之飽和脂族基團，諸如亞甲基(-CH 2-)。除非另有規定，否則術語「烷基」可包括「伸烷基」。 As used herein, "alkyl" alone or in combination refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms. In certain embodiments, the alkyl group will contain 1 to 10 carbon atoms. In other embodiments, the alkyl group will contain 1 to 8 carbon atoms. Alkyl is unsubstituted or substituted as defined herein. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, nonyl base (noyl) and the like. As used herein, the term "alkylene", alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (- CH 2 -). Unless otherwise specified, the term "alkyl" may include "alkylene".

如本文使用，單獨或組合的「烷基胺基」係指透過胺基附接至母體分子部分之烷基。合適之烷基胺基可為單烷基化或二烷基化形成之基團，諸如，舉例而言，N-甲基胺基、N-乙基胺基、N,N-二甲基胺基、N,N-乙基甲基胺基及類似物。As used herein, "alkylamino" alone or in combination refers to an alkyl group attached to the parent molecular moiety through an amine group. Suitable alkylamino groups may be monoalkylated or dialkylated groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamine base, N,N-ethylmethylamino group and the like.

如本文使用，單獨或組合的「醯胺基」及「胺甲醯基」係指如下文描述透過羰基附接至母體分子部分之胺基，或反之亦然。如本文使用之「醯胺基」包括「C-醯胺基」及「N-醯胺基」。如本文使用之單獨或組合的術語「C-醯胺基」係指具有如本文定義或如由本發明指定之明確枚舉之「R」基團定義之R及R’的-C(O)N(RR’)基團。在一些實施例中，該「醯胺基」包括-C(O)NH 2、C 1-4烷基醯胺基及二(C 1-4烷基)醯胺基。如本文使用，術語「C 1-4烷基醯胺基」係指-C(O)NH(C 1-4烷基)，其中C 1-4烷基係如本文定義。如本文使用，單獨或組合的術語「N-醯胺基」係指具有如本文定義或如由本發明指定之明確枚舉之「R」基團定義之R及R’的RC(O)N(R’)-基團。如本文使用之單獨或組合的術語「醯基胺基」包括透過胺基附接至母體部分之醯基。「醯基胺基」之實例係乙醯基胺基(CH 3C(O)NH-)。 As used herein, "amide" and "carbamide" alone or in combination refer to an amine group attached to the parent molecular moiety through a carbonyl group as described below, or vice versa. "Camide group" as used herein includes "C-amide group" and "N-amide group." The term "C-amide" as used herein, alone or in combination, refers to -C(O)N having R and R' as defined herein or as specifically enumerated "R" groups specified by this invention. (RR') group. In some embodiments, the "amide group" includes -C(O)NH 2 , C 1-4 alkyl amide group, and di(C 1-4 alkyl) amide group. As used herein, the term "C 1-4 alkylamide" refers to -C(O)NH(C 1-4 alkyl), where C 1-4 alkyl is as defined herein. As used herein, the term "N-amide group" alone or in combination refers to an RC(O)N( R')-group. The term "acylamine group" as used herein, alone or in combination, includes a acyl group attached to the parent moiety through an amine group. An example of "acylamino" is acetylamino (CH 3 C(O)NH-).

如本文使用，單獨或組合的「胺基」係指-NRR ’，其中R及R ’係獨立地選自氫、烷基、醯基、雜烷基、芳基、環烷基、雜芳基及雜環烷基，其等中之任一者本身可未經取代或經取代。另外，R及R’可組合以形成雜環烷基，其等中之任一者係未經取代或經取代。 As used herein, "amine" alone or in combination refers to -NRR ' , where R and R ' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, any of which may itself be unsubstituted or substituted. Additionally, R and R' may be combined to form heterocycloalkyl, either of which may be unsubstituted or substituted.

如本文使用，單獨或組合的「芳基」意謂含有一、二或三個環之碳環芳族系統，其中此等多環系統係稠合在一起。術語「芳基」包括芳族基團，諸如苯基、萘基、蒽基及菲基。As used herein, "aryl" alone or in combination means a carbocyclic aromatic system containing one, two or three rings in which these multiple ring systems are fused together. The term "aryl" includes aromatic groups such as phenyl, naphthyl, anthracenyl and phenanthrenyl.

如本文使用，單獨或組合的「氰基」係指-CN。As used herein, "cyano" alone or in combination refers to -CN.

如本文使用，單獨或組合的「環烷基」或者「碳環」係指飽和或部分飽和單環、雙環或三環烷基，其中各環形部分含有3至12個碳原子環成員且其可視需要為未經取代或如本文定義經取代之苯并稠環系統。術語「環烯基」係指具有一或兩個雙鍵之環烷基。在某些實施例中，該環烷基(或環烯基)將包含5至7個碳原子。此等基團之實例包括環丙基、環丁基、環戊基、環己基、環庚基、環丁烯基、環戊烯基、環己烯基、四氫萘基、二氫茚基、八氫萘基、2,3-二氫-1H-茚基、金剛烷基及類似物。如本文使用之「雙環」及「三環」意欲包括稠環系統，諸如十氫萘、八氫萘及多環(多中心)飽和或部分不飽和類型。後一類型之異構體一般係由二環[1,1,1]戊烷、樟腦、金剛烷及二環[3,2,1]辛烷例示。As used herein, "cycloalkyl" or "carbocycle" alone or in combination refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group in which each cyclic moiety contains from 3 to 12 carbon atom ring members and is visible Required benzofused ring systems that are unsubstituted or substituted as defined herein. The term "cycloalkenyl" refers to a cycloalkyl group having one or two double bonds. In certain embodiments, the cycloalkyl (or cycloalkenyl) group will contain 5 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydronaphthyl, indenyl , octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like. "Bicyclic" and "tricyclic" as used herein are intended to include fused ring systems such as decalin, octahydronaphthalene, and polycyclic (multi-center) saturated or partially unsaturated types. Isomers of the latter type are generally exemplified by bicyclo[1,1,1]pentane, camphor, adamantane and bicyclo[3,2,1]octane.

如本文使用，單獨或組合的「鹵基」或「鹵素」係指氟、氯、溴或碘。As used herein, "halo" or "halogen" alone or in combination refers to fluorine, chlorine, bromine or iodine.

如本文使用，單獨或組合的「鹵基烷氧基」係指透過氧原子附接至母體分子部分之鹵烷基。As used herein, "haloalkoxy" alone or in combination refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

如本文使用，單獨或組合的「鹵烷基」係指具有如上文定義之含義之烷基，其中一或多個氫係經鹵素置換。明確包括單鹵烷基、二鹵烷基及多鹵烷基。針對一項實例，單鹵烷基於該基團內可具有碘、溴、氯或氟原子。二鹵基及多鹵烷基可具有相同鹵原子中之兩者或更多者或不同鹵基之組合。鹵烷基之實例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基及二氯丙基。「鹵伸烷基」係指於兩個或更多個位置處附接之鹵烷基。實例包括氟亞甲基(-CFH-)、二氟亞甲基(-CF 2-)、氯亞甲基(-CHCl-)及類似物。 As used herein, "haloalkyl" alone or in combination refers to an alkyl group having the meaning as defined above, in which one or more hydrogens are replaced by halogen. Monohaloalkyl, dihaloalkyl and polyhaloalkyl are expressly included. For one example, a monohaloalkyl group can have iodine, bromine, chlorine or fluorine atoms within the group. Dihalo and polyhaloalkyl groups may have two or more of the same halogen atoms or a combination of different halogen groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, Dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF 2 -), chloromethylene (-CHCl-), and the like.

如本文使用，單獨或組合的「雜芳基」係指3至15員不飽和雜單環，或稠合單環、雙環或三環系統，其中該等稠環中之至少一者係芳族的，其含有至少一個選自N、O及S之原子。在某些實施例中，該雜芳基將包含1至4個雜原子作為環成員。在其他實施例中，該雜芳基將包含1至2個雜原子作為環成員。在某些實施例中，該雜芳基將包含5至7個原子。該術語亦包括稠合多環基團，其中雜環係與芳基環稠合，其中雜芳基環係與其他雜芳基環稠合，其中雜芳基環係與雜環烷基環稠合，或其中雜芳基環係與環烷基環稠合。雜芳基之實例包括吡咯基、吡咯啶基、咪唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、噠嗪基、***基、哌喃基、呋喃基、噻吩基、噁唑基、異噁唑基、噁二唑基、噻唑基、噻二唑基、異噻唑基、吲哚基、異吲哚基、吲哚嗪基、苯并咪唑基、喹啉基、異喹啉基、喹喔啉基、喹唑啉基、吲唑基、苯并***基、苯并二氧雜環戊烯基、苯并哌喃基、苯并噁唑基、苯并噁二唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、苯并噻吩基、色酮基、香豆素基、苯并哌喃基、四氫喹啉基、四唑并噠嗪基、四氫異喹啉基、噻吩吡啶基、氟吡啶基、吡咯并吡啶基及類似物。例示性三環雜環基團包括哢唑基、苯并吲哚基(benzidolyl)、菲咯啉基、二苯并呋喃基、吖啶基、菲啶基、呫噸基及類似物。As used herein, "heteroaryl" alone or in combination refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic or tricyclic ring system, wherein at least one of the fused rings is aromatic , which contains at least one atom selected from N, O and S. In certain embodiments, the heteroaryl group will contain 1 to 4 heteroatoms as ring members. In other embodiments, the heteroaryl group will contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl group will contain 5 to 7 atoms. The term also includes fused polycyclic groups in which a heterocyclic ring system is fused to an aryl ring, in which a heteroaryl ring system is fused to another heteroaryl ring, and in which a heteroaryl ring system is fused to a heterocycloalkyl ring. fused, or wherein the heteroaryl ring system is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, piperanyl, furyl, thienyl, oxazole base, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolazinyl, benzimidazolyl, quinolyl, isoquinoline base, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl , benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromone, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl , tetrahydroisoquinolyl, thienopyridyl, fluoropyridyl, pyrrolopyridyl and the like. Exemplary tricyclic heterocyclic groups include benzidolyl, benzidolyl, phenanthrolinyl, dibenzofuryl, acridinyl, phenanthridinyl, xanthyl, and the like.

如本文使用，單獨或組合的「雜環烷基」及(可互換地)「雜環」各係指含有至少一個雜原子作為環成員之飽和、部分不飽和或完全不飽和(但非芳族)單環、雙環或三環雜環基團，其中各該雜原子可獨立地選自氮、氧及硫。在某些實施例中，該雜環烷基將包含1至4個雜原子作為環成員。在其他實施例中，該雜環烷基將包含1至2個雜原子作為環成員。在某些實施例中，該雜環烷基將於各環中包含3至8個環成員。在其他實施例中，該雜環烷基將於各環中包含3至7個環成員。在又其他實施例中，該雜環烷基將於各環中包含5至6個環成員。「雜環烷基」及「雜環」意欲包括碸、亞碸、第三氮環成員之N-氧化物，及碳環稠環及苯并稠環系統；另外，兩種術語亦包括其中雜環係稠合至如本文定義的芳基，或另外雜環基團之系統。雜環基團之實例包括氮丙啶基、氮雜環丁烷基、1,3-苯并二氧雜環戊烯基、二氫異吲哚基、二氫異喹啉基、二氫噌嗪基、二氫苯并二氧雜環己二烯基、二氫[1,3]噁唑并[4,5-b]吡啶基、苯并噻唑基、二氫吲哚基、二氫吡啶基、1,3-二噁烷基、1,4-二噁烷基、1,3-二氧雜環戊基、異吲哚啉基、嗎啉基、哌嗪基、吡咯啶基、四氫吡啶基、哌啶基、硫嗎啉基，及類似物。除非明確禁止，否則該等雜環基團係未經取代或經取代的。As used herein, "heterocycloalkyl" and (interchangeably) "heterocycle", alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) ring member containing at least one heteroatom as a ring member. ) monocyclic, bicyclic or tricyclic heterocyclic group, wherein each heteroatom can be independently selected from nitrogen, oxygen and sulfur. In certain embodiments, the heterocycloalkyl group will contain 1 to 4 heteroatoms as ring members. In other embodiments, the heterocycloalkyl group will contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl group will contain 3 to 8 ring members in each ring. In other embodiments, the heterocycloalkyl group will contain 3 to 7 ring members in each ring. In yet other embodiments, the heterocycloalkyl group will contain 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include styrene, styrene, N-oxides of the third nitrogen ring member, and carbocyclic fused ring and benzo fused ring systems; in addition, both terms also include heterocyclic A system in which a ring system is fused to an aryl group, as defined herein, or to another heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolyl, dihydroisoquinolyl Azinyl, dihydrobenzodioxadienyl, dihydro[1,3]oxazolo[4,5-b]pyridyl, benzothiazolyl, indolyl, dihydropyridine base, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrakis Hydropyridyl, piperidyl, thiomorpholinyl, and the like. Unless expressly prohibited, such heterocyclic groups are unsubstituted or substituted.

如本文使用，單獨或組合的「羥基」係指-OH。As used herein, "hydroxy" alone or in combination refers to -OH.

如本文使用，單獨或組合的「羥基烷基」係指透過烷基附接至母體分子部分之羥基。As used herein, "hydroxyalkyl" alone or in combination refers to a hydroxyl group attached to the parent molecular moiety through an alkyl group.

如本文使用，單獨或組合的「側氧基」係指=O。As used herein, "pendant oxy" alone or in combination refers to =O.

如本文使用，關於化學結構或其部分的「環(Ring)」或等同地「環(cycle)」意謂其中每個原子均為共同環狀結構中之成員之基團。除非另有規定，否則環可為飽和或不飽和的，包括芳族，且可具有介於3與9之間的成員。若該環為雜環，則其可含有介於1與4個之間的雜原子或含有雜原子之基團，其等選自B、N、O、S、C(O)、S(O)m。除非明確禁止，否則環係未經取代或經取代的。As used herein, "Ring" or equivalently "cycle" with respect to a chemical structure or part thereof means a group in which each atom is a member of a common cyclic structure. Unless otherwise specified, rings may be saturated or unsaturated, including aromatic, and may have between 3 and 9 members. If the ring is heterocyclic, it may contain between 1 and 4 heteroatoms or heteroatom-containing groups selected from the group consisting of B, N, O, S, C(O), S(O )m. Unless expressly prohibited, a ring system is unsubstituted or substituted.

如本文使用，單獨或組合的「磺酸鹽」、「磺酸」及「磺」係指-SO 3H基團及其陰離子，因為磺酸係用以形成鹽。 As used herein, "sulfonate,""sulfonicacid," and "sulfon" alone or in combination refer to the -SO3H group and its anion, since sulfonic acids are used to form salts.

本文之任何定義均可與任何其他定義組合使用以描述複雜結構基團。按照慣例，任何此定義之拖尾元素均附接至母體部分。例如，複雜基團烷基醯胺基將表示透過醯胺基附接至母體分子之烷基，及術語烷氧基烷基將表示透過烷基附接至該母體分子之烷氧基。Any definition herein may be used in combination with any other definition to describe complex structural groups. By convention, any trailing element defined this way is attached to the parent part. For example, the complex group alkylamido would mean an alkyl group attached to the parent molecule through a amide group, and the term alkoxyalkyl would mean an alkoxy group attached to the parent molecule through an alkyl group.

「鍵」係指兩個原子之間的共價鍵聯，或當認為由該鍵連接之原子係較大子結構之部分時兩個部分之間的共價鍵聯。除非另有規定，否則鍵可為單鍵、雙鍵或三鍵。於分子繪圖中兩個原子之間的虛線指示於該位置可存在或缺乏另外鍵。"Bond" means a covalent bond between two atoms, or between two parts when the atoms connected by the bond are considered to be part of a larger substructure. Unless otherwise specified, bonds may be single, double or triple bonds. A dashed line between two atoms in a molecular drawing indicates the presence or absence of another bond at that position.

本文揭示之化合物中存在非對稱中心。此等中心係由符號「R」或「S」指定，取決於對掌性碳原子周圍取代基之構型。應瞭解本發明包含所有立體化學異構體形式，包括非對映體、對映體及差向異構體形式，及d-異構體與1-異構體，及其混合物。化合物之個別立體異構體可由含有對掌性中心之市售起始材料合成製備或藉由製備對映體產物之混合物，接著分離，諸如轉化為非對映體之混合物，接著分離或重結晶，層析技術，於對掌性層析管柱上直接分離對映體，或任何其他適當之方法。具有特定立體化學之起始化合物可購買獲得或可藉由各種技術製備及解析。另外，本文揭示之化合物可呈幾何異構體存在。本發明包括所有順(cis)、反、順式(syn)、反式(anti)、異側(entgegen) (E)及同側(zusammen) (Z)異構體及其適當之混合物。另外，化合物可呈互變異構體存在；由本發明提供所有互變異構體異構體。另外，本文揭示之化合物可以與醫藥上可接受之溶劑(諸如水、乙醇，及類似物)之未溶劑化及溶劑化形式存在。一般而言，認為該等溶劑化形式等同於該等未溶劑化形式。Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbol "R" or "S", depending on the configuration of the substituents surrounding the chiral carbon atom. It is to be understood that the present invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of a compound may be prepared synthetically from commercially available starting materials containing chiral centers or by preparing mixtures of enantiomeric products followed by separation, such as conversion to mixtures of diastereomers followed by separation or recrystallization , chromatography technology, direct separation of enantiomers on a chiral chromatography column, or any other appropriate method. Starting compounds with specific stereochemistry are commercially available or can be prepared and resolved by various techniques. Additionally, the compounds disclosed herein may exist as geometric isomers. The invention includes all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by the present invention. Additionally, the compounds disclosed herein can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered to be equivalent to the unsolvated forms.

如本文使用，單獨或組合之「互變異構體」係指兩種或更多種快速相互轉化之異構體中之一者。一般而言，此相互轉化係足夠快使得在缺乏另一互變異構體之情況下未分離個別互變異構體。互變異構體之量之比率可取決於溶劑組合物、離子強度及pH，及其他溶液參數。互變異構體之量之比率於特定溶液中及於該溶液之生物分子結合位點之微環境中可為不同的。互變異構體之實例包括酮/烯醇、烯胺/亞胺及內醯胺/內醯亞胺互變異構體。互變異構體之另外實例包括2-羥基吡啶/2(1H)-吡啶酮及2-胺基吡啶/ 2(1H)-亞胺基吡啶酮互變異構體。As used herein, "tautomer" alone or in combination refers to one of two or more isomers that rapidly convert into each other. Generally, this interconversion is rapid enough that individual tautomers are not separated in the absence of the other tautomer. The ratio of the amounts of tautomers can depend on solvent composition, ionic strength and pH, among other solution parameters. The ratio of the amounts of tautomers can vary within a particular solution and within the microenvironment of the biomolecule binding site of that solution. Examples of tautomers include ketone/enol, enamine/imine, and lactam/lactamimine tautomers. Additional examples of tautomers include 2-hydroxypyridine/2(1H)-pyridone and 2-aminopyridine/2(1H)-iminopyridone tautomers.

本文揭示之化合物中存在構象異構體。當R 1在下式中為芳基或雜芳基時： ， 該芳基或雜芳基可相對於嘧啶酮部分以不同之構象定向，如由下式表示： (S a形式)及 (R a形式)。 此等形式係由符號「S a」或「R a」指定，取決於芳基或雜芳基相對於嘧啶酮部分之構象。「S a」及「R a」形式之實例可於國際專利申請案第PCT/US2019/045903號之實例1至20中找到，該案係出於所有目的係全文引用之方式併入本文中。式(10b)化合物係大體上呈「R a」形式。 Conformational isomers exist among the compounds disclosed herein. When R 1 is aryl or heteroaryl in the following formula: , the aryl or heteroaryl group can be oriented in different conformations relative to the pyrimidinone moiety, as represented by the following formula: (S a form) and (R a form). These forms are designated by the symbols "S a " or "R a ", depending on the conformation of the aryl or heteroaryl group relative to the pyrimidinone moiety. Examples of the forms “S a ” and “R a ” can be found in Examples 1 to 20 of International Patent Application No. PCT/US2019/045903, which is incorporated by reference in its entirety for all purposes. The compound of formula (10b) is generally in the form of "R a ".

「醫藥上可接受」係指彼等適用於與病患之組織接觸使用而無過度之毒性、刺激及過敏反應，與合理之利益/風險比相稱且針對其等預期用途有效之化合物(鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體等)。本文揭示之化合物可呈醫藥上可接受之鹽存在，如本文定義及描述。"Pharmaceutically acceptable" refers to compounds (salts, Hydrates, solvates, stereoisomers, conformational isomers, tautomers, etc.). The compounds disclosed herein may exist as pharmaceutically acceptable salts, as defined and described herein.

「鹽」係指本發明之化合物之酸或鹼鹽。醫藥上可接受之酸加成鹽之說明性實例係礦物酸(鹽酸、氫溴酸、磷酸，及類似物)鹽及有機酸(乙酸、丙酸、麩胺酸、檸檬酸及類似物)鹽。醫藥上可接受之鹼加成鹽之實例包括鈉鹽、鉀鹽、鈣鹽、銨鹽、有機胺基或鎂鹽，或類似鹽。應瞭解該等醫藥上可接受之鹽為無毒的。有關合適之醫藥上可接受之鹽之另外資訊可於Remington's Pharmaceutical Sciences，第17版，Mack Publishing Company, Easton, Pa., 1985中找到，其係以引用之方式併入本文中。"Salt" refers to an acid or base salt of a compound of the present invention. Illustrative examples of pharmaceutically acceptable acid addition salts are salts of mineral acids (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) and organic acids (acetic acid, propionic acid, glutamic acid, citric acid, and the like) . Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts, or similar salts. It should be understood that such pharmaceutically acceptable salts are non-toxic. Additional information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

「溶劑化物」係指本文提供之化合物或其鹽，其進一步包括化學計量或非化學計量的由非共價分子間作用力結合之溶劑。"Solvate" refers to a compound provided herein or a salt thereof, which further includes stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces.

「水合物」係指與水分子錯合之化合物。本發明之化合物可與½個水分子或1至10個水分子錯合。"Hydrate" refers to a compound complexed with water molecules. The compounds of the present invention can be complexed with ½ water molecule or with 1 to 10 water molecules.

「組合療法」意謂投與兩種或更多種治療劑以治療本發明中描述之治療病症或疾患。此投與包括以大體上同時之方式共投與此等治療劑，諸如以具有固定比率之活性成分之單個膠囊，或以多個各活性成分的各別膠囊。另外，此投與亦包括以依序方式使用各類型之治療劑。在任一情況下，治療方案將提供藥物組合於治療本文描述之病症或疾患中之有利效應。"Combination therapy" means the administration of two or more therapeutic agents to treat the condition or disorder described in this invention. Such administration includes co-administration with the therapeutic agents in a substantially simultaneous manner, such as in a single capsule with a fixed ratio of the active ingredients, or in a plurality of separate capsules of each active ingredient. Additionally, such administration also includes administration of various types of therapeutic agents in a sequential manner. In either case, the treatment regimen will provide for the beneficial effects of the drug combination in treating the condition or disorder described herein.

本文描述之「PTPN11抑制劑」係指如國際專利申請案第PCT/US2019/045903號一般描述之PTPN11分析(例如，實例21之重組人類PTPN11蛋白之酵素活性)中量測，針對PTPN11活性顯示不多於約100微莫耳(μM)及更通常不多於約50 μM之IC 50之化合物。「IC 50」係將酵素(例如，PTPN11)之活性降低至半最大水準之抑制劑濃度。在某些實施例中，如其中描述之PTPN11分析中量測，PCT/US2019/045903中揭示之化合物針對PTPN11抑制顯示不多於約10 μM之IC 50；在其他實施例中，化合物針對PTPN11抑制顯示不多於約1 μM之IC 50；在又其他實施例中，化合物針對PTPN11抑制顯示不多於約200 nM之IC 50；在又其他實施例中，化合物針對PTPN11抑制顯示不多於約100 nM之IC 50；及在又其他實施例中，化合物針對PTPN11抑制顯示不多於約50 nM之IC 50。在某些實施例中，式(2b)化合物針對PTPN11(例如，PTPN11-E76K突變體酵素)抑制顯示不多於150 nM之IC 50。在某些實施例中，式(10b)化合物針對PTPN11 (例如，PTPN11-E76K突變體酵素)抑制顯示不多於50 nM之IC 50。 The "PTPN11 inhibitor" described herein refers to the PTPN11 assay as generally described in International Patent Application No. PCT/US2019/045903 (for example, the enzymatic activity of the recombinant human PTPN11 protein in Example 21) as measured in the PTPN11 activity. Compounds with an IC50 of more than about 100 micromolar (μM) and more typically not more than about 50 μM. “IC 50 ” is the inhibitor concentration that reduces the activity of an enzyme (e.g., PTPN11) to half-maximal levels. In certain embodiments, the compounds disclosed in PCT/US2019/045903 exhibit an IC50 for PTPN11 inhibition of no more than about 10 μM as measured in the PTPN11 assay described therein; in other embodiments, the compounds inhibit PTPN11 Exhibit an IC50 of no more than about 1 μM; in yet other embodiments, the compound exhibits an IC50 against PTPN11 inhibition of no more than about 200 nM; in yet other embodiments, the compound exhibits an IC50 against PTPN11 inhibition of no more than about 100 An IC50 of nM; and in yet other embodiments, the compound exhibits an IC50 for PTPN11 inhibition of no more than about 50 nM. In certain embodiments, a compound of Formula (2b) exhibits an IC50 of no more than 150 nM against PTPN11 (eg, PTPN11-E76K mutant enzyme) inhibition. In certain embodiments, a compound of Formula (10b) exhibits an IC50 of no more than 50 nM against PTPN11 (eg, PTPN11-E76K mutant enzyme) inhibition.

「治療有效量」係指適用於治療或改善已鑑別之疾病或病症，或適用於顯示可偵測治療或抑制效應之化合物或醫藥組合物之量。精確量將取決於治療之目的，且將可由熟習此項技術者使用已知技術確定(例如，參見Lieberman, Pharmaceutical Dosage Forms (第1至3卷，1992)；Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999)；Pickar, Dosage Calculations (1999)；及Remington: The Science and Practice of Pharmacy，第20版，2003, Gennaro編，Lippincott, Williams & Wilkins)。A "therapeutically effective amount" means an amount of a compound or pharmaceutical composition suitable for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The precise amount will depend on the purpose of treatment and will be determined by one skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Volume 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, Gennaro, ed. Lippincott, Williams & Wilkins).

「治療(Treat、treating及treatment)」係指成功治療或改善損傷、病理或病症之任何指標，包括任何客觀或主觀參數，諸如減輕；緩解；減少症狀或使得病患對該損傷、病理或病症更耐受；減緩退化或衰退之速率；使得退化之終點較不虛弱；及/或改善病患之身體或精神健康。症狀之治療或改善可基於客觀或主觀參數；包括身體檢查、分析(例如，個體之體液(諸如血液、血漿或尿)之分析)、影像分析、神經精神檢查及/或精神評估之結果。"Treat, treating and treatment" means any indicator of successful treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter, such as alleviation; alleviation; reduction of symptoms or improvement of the injury, pathology or condition To be more tolerable; to slow down the rate of degeneration or decline; to make the end point of degeneration less debilitating; and/or to improve the patient's physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters; including results of physical examination, analysis (e.g., analysis of an individual's body fluids (such as blood, plasma, or urine)), imaging analysis, neuropsychiatric examination, and/or psychiatric evaluation.

「投與」係指諸如藉由口服投與或靜脈內投與，對個體治療性提供化合物或其形式。"Administration" means the therapeutic provision of a compound or a form thereof to an individual, such as by oral administration or intravenous administration.

「病患」或「個體」係指罹患或易患可藉由投與如本文提供之醫藥組合物治療之疾病或病症之活機體。非限制性實例包括人類、非人類靈長類動物(例如，猴)、山羊、豬、綿羊、奶牛、鹿、馬、牛科動物、大鼠、小鼠、兔、倉鼠、天竺鼠、貓、狗，及其他非哺乳類動物。在一些實施例中，該個體為人類。在一些實施例中，個體為成人(例如，至少18週歲)。"Patient" or "individual" refers to a living organism suffering from or susceptible to a disease or condition treatable by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, non-human primates (eg, monkeys), goats, pigs, sheep, cows, deer, horses, bovines, rats, mice, rabbits, hamsters, guinea pigs, cats, dogs , and other non-mammalian animals. In some embodiments, the individual is a human. In some embodiments, the individual is an adult (eg, at least 18 years old).

如本文使用之「組合物」意欲包含含有指定量的指定成分之產品，及直接或間接由指定量之指定成分之組合產生之任何產品。「醫藥上可接受之」意謂必須可與調配物之其他成分相容且對其接受者無害之載劑、稀釋劑或賦形劑。"Composition" as used herein is intended to include products containing specified amounts of specified ingredients, and any product resulting directly or indirectly from a combination of specified amounts of specified ingredients. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

「醫藥上可接受之賦形劑」係指有助於對個體投與活性劑並由該個體吸收之物質。適用於本發明中之醫藥賦形劑包括(但不限於)黏合劑、填充劑、崩解劑、潤滑劑、包衣、甜味劑、調味劑及染料。其他醫藥賦形劑可適用於本發明中。"Pharmaceutically acceptable excipient" means a substance that facilitates administration of an active agent to an individual and absorption by that individual. Pharmaceutical excipients suitable for use in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings and dyes. Other pharmaceutical excipients may be suitable for use in the present invention.

「錠劑」係指有及無包衣之固體醫藥調配物。術語「錠劑」亦係指具有一層、兩層、三層或甚至更多層之錠劑，其中先前提及類型之錠劑中之各者可沒有或有一或多個包衣。在一些實施例中，本發明之錠劑可藉由碾壓或此項技術中已知的其他合適方式製備。術語「錠劑」亦包含微錠、融化錠、咀嚼錠、發泡錠及口腔崩解錠。錠劑包括式(I)或式(10b)化合物及一或多種醫藥賦形劑(例如，填充劑、黏合劑、助流劑、崩解劑、表面活性劑、黏合劑、潤滑劑，及類似物)。視需要，亦可包括包衣劑。出於計算錠劑調配物之重量百分比之目的，該計算中不包括包衣劑之量。即，本文報告之重量百分比為未包衣錠劑之重量百分比。“Tablets” refer to solid pharmaceutical formulations with or without coatings. The term "tablet" also refers to a tablet having one, two, three or even more layers, wherein each of the previously mentioned types of tablets may be without or with one or more coatings. In some embodiments, tablets of the present invention may be prepared by rolling or other suitable means known in the art. The term "lozenge" also includes micro-tablets, melting tablets, chewable tablets, foaming tablets and orally disintegrating tablets. Tablets include a compound of formula (I) or formula (10b) and one or more pharmaceutical excipients (e.g., fillers, binders, glidants, disintegrants, surfactants, binders, lubricants, and the like) things). If necessary, a coating agent may also be included. For purposes of calculating the weight percent of the tablet formulation, the amount of coating is not included in the calculation. That is, the weight percent reported herein is the weight percent of the uncoated tablet.

除非另有明確指示，否則(例如)錠劑調配物中式(I)或式(10b)化合物之含量係在無鹽且無水之基礎上，基於該式(I)或式(10b)化合物之標準化重量計算。即，該計算中不包括該式(I)或式(10b)化合物中鹽及/或水含量。Unless otherwise expressly indicated, the content of a compound of formula (I) or formula (10b) in, for example, a tablet formulation is on a salt-free and anhydrous basis, based on the standardization of the compound of formula (I) or formula (10b). Weight calculation. That is, the salt and/or water content of the compound of formula (I) or formula (10b) is not included in the calculation.

如本文使用之「PD-1/PD-L1抑制劑」 (亦稱為免疫查核點抑制劑)係指靶向、減少或抑制計畫性細胞死亡蛋白1 (PD-1)及/或計畫性死亡配體1 (PD-L1)之合成或生物活性之化合物。PD-1具有兩種配體，PD-L1及PD-L2。該PD-1/PD-L1抑制劑阻斷PD-L1及/或PD-L2結合至PD-1。該PD-1/PD-L1抑制劑可至少部分抑制PD-1及/或PD-L1。該PD-1/PD-L1抑制劑可為PD-1抑制劑。該PD-1/PD-L1抑制劑可為PD-L1抑制劑。該PD-1/PD-L1抑制劑可為選擇性PD-1/PD-L1抑制劑。在彼等情況下，該選擇性PD-1/PD-L1抑制劑針對PD-1/PD-L1可具有高效力，連同對相關計畫性死亡配體2 (PD-L2)之低親和力。As used herein, "PD-1/PD-L1 inhibitors" (also known as immune checkpoint inhibitors) refer to targeting, reducing, or inhibiting programmed cell death protein 1 (PD-1) and/or programmed cell death protein 1 (PD-1). Synthetic or biologically active compounds of sex death ligand 1 (PD-L1). PD-1 has two ligands, PD-L1 and PD-L2. The PD-1/PD-L1 inhibitor blocks the binding of PD-L1 and/or PD-L2 to PD-1. The PD-1/PD-L1 inhibitor can at least partially inhibit PD-1 and/or PD-L1. The PD-1/PD-L1 inhibitor can be a PD-1 inhibitor. The PD-1/PD-L1 inhibitor can be a PD-L1 inhibitor. The PD-1/PD-L1 inhibitor can be a selective PD-1/PD-L1 inhibitor. In these cases, the selective PD-1/PD-L1 inhibitor can have high potency against PD-1/PD-L1, along with low affinity for the related programmed death ligand 2 (PD-L2).

「PD-L1陽性癌症」係指具有PD-L1之表現或過表現之癌症。"PD-L1 positive cancer" refers to a cancer that has expression or overexpression of PD-L1.

「對PD-1/PD-L1抑制劑耐藥性之癌症」、「呈對PD-1/PD-L1抑制劑耐藥性之PD-1/PD-L1陽性癌症之癌症」及/或「呈對PD-1/PD-L1抑制劑耐藥性之KRAS陽性癌症之癌症」係指對先前使用PD-1/PD-L1抑制劑之治療無法有利地產生反應，或者，在對PD-1/PD-L1抑制劑有利地產生反應後再現或復發之癌症或腫瘤。"Cancers that are resistant to PD-1/PD-L1 inhibitors", "cancers that are PD-1/PD-L1-positive cancers that are resistant to PD-1/PD-L1 inhibitors" and/or " "KRAS-positive cancers that are resistant to PD-1/PD-L1 inhibitors" refer to cancers that have failed to respond favorably to prior treatment with a PD-1/PD-L1 inhibitor or that have failed to respond favorably to PD-1 inhibitors. /PD-L1 inhibitors favorably produce cancers or tumors that reappear or relapse after response.

「KRAS陽性癌症」係指KRAS基因經重排、突變或擴增之癌症。「KRAS G12C陽性癌症」係指KRAS G12C基因經重排、突變或擴增之癌症。"KRAS-positive cancer" refers to cancer in which the KRAS gene is rearranged, mutated, or amplified. "KRAS G12C-positive cancer" refers to cancer in which the KRAS G12C gene is rearranged, mutated or amplified.

「對KRAS抑制劑耐藥性之癌症」及/或「呈對KRAS抑制劑耐藥性之KRAS陽性癌症之癌症」係指對使用先前KRAS抑制劑之治療無法有利地產生反應，或者，在對KRAS抑制劑有利地產生反應後再現或復發之癌症或腫瘤。「對KRAS G12C抑制劑耐藥性之癌症」及/或「呈對KRAS G12C抑制劑耐藥性之KRAS G12C陽性癌症之癌症」係指對使用先前KRAS G12C抑制劑之治療無法有利地產生反應，或者，對KRAS G12C抑制劑有利地產生反應後再現或復發之癌症或腫瘤。“KRAS inhibitor-resistant cancer” and/or “KRAS-positive cancer that is KRAS inhibitor-resistant” means a cancer that has failed to respond favorably to prior treatment with a KRAS inhibitor or, after treatment with a prior KRAS inhibitor, KRAS inhibitors favorably produce cancers or tumors that reappear or relapse after response. "Cancer that is resistant to KRAS G12C inhibitors" and/or "cancer that is a KRAS G12C positive cancer that is resistant to KRAS G12C inhibitors" means a cancer that has failed to respond favorably to treatment with a previous KRAS G12C inhibitor, Alternatively, the cancer or tumor reappears or recurs after responding favorably to a KRAS G12C inhibitor.

如本文使用之「聯合治療有效量」意謂當對溫血動物，尤其對待治療之人類單獨給藥時(以時間交錯之方式，尤其順序特定之方式)，治療劑顯示(加性，但較佳協同)相互作用(聯合治療效應)之量。此種情況是否存在可尤其藉由跟蹤血液濃度確定，顯示至少在特定時間間隔內，兩種化合物均存在於該待治療之人類之血液中。As used herein, "combination therapeutically effective amount" means that when administered alone (in a time-staggered manner, especially a sequence-specific manner) to warm-blooded animals, particularly humans to be treated, the therapeutic agent appears to be (additive, but less effective) The amount of optimal synergy) interaction (combination therapeutic effect). Whether this is the case can be determined, inter alia, by tracking blood concentrations, showing that both compounds are present in the blood of the human to be treated, at least for a specific time interval.

如本文使用之「協同效應」係指至少兩種治療劑：如本文定義之PTPN11抑制劑；及如本文定義之PD-1/PD-L1抑制劑之效應，其大於自身投與之各藥物之效應之簡單相加。該效應可(例如)為減緩增生性疾病，諸如癌症，特定言之肺癌(例如，非小細胞肺癌症)，或其症狀之症狀性進展。類似地，「協同有效量」係指獲得協同效應所需之量。"Synergistic effect" as used herein refers to the effect of at least two therapeutic agents: a PTPN11 inhibitor, as defined herein; and a PD-1/PD-L1 inhibitor, as defined herein, that is greater than the effect of each drug administered by itself. Simple summation of effects. The effect may, for example, be to slow the symptomatic progression of a proliferative disease, such as cancer, in particular lung cancer (eg, non-small cell lung cancer), or symptoms thereof. Similarly, a "synergistically effective amount" refers to the amount required to achieve a synergistic effect.

當本文涉及一組取代基或「取代基」使用「一」、「一個」或「一(個)」時，意謂至少一個。例如，在化合物經「一個」烷基或芳基取代之情況下，該化合物係經至少一個烷基及/或至少一個芳基取代，其中各烷基及/或芳基視需要係不同的。在另一實例中，在化合物經「一個」取代基取代時，該化合物係經至少一個取代基取代，其中各取代基視需要係不同的。 III.    組合療法 When "a", "an" or "an" is used herein in reference to a group of substituents or "substituents", it means at least one. For example, where a compound is substituted with "an" alkyl or aryl group, the compound is substituted with at least one alkyl group and/or at least one aryl group, wherein each alkyl group and/or aryl group is optionally different. In another example, when a compound is substituted with "a" substituent, the compound is substituted with at least one substituent, wherein each substituent is optionally different. III. Combination therapy

在一項態樣中，本發明提供一種於個體中治療癌症之方法。該方法包括對該個體投與： a)治療有效量之PTPN11抑制劑；及 b)治療有效量之PD-1/PD-L1抑制劑， 其中該PTPN11抑制劑係由式(I)表示： (I)， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合， 其中： 下標a係0或1； 下標b係0或1； Y 1係直接鍵或CR 17R 18； Y 2係選自由以下組成之群：C 1-4烷基、胺基、C 1-4烷基C(O)O-、C 1-4烷基胺基及C 1-4胺基烷基； R 1係選自由以下組成之群：C 6-10芳基、C 3-8環烷基、C 3-8環烯基及具有1至4個獨立地選自N、C(O)、O及S之雜原子或基團作為環頂點之5至10員雜芳基；R 1之該芳基或雜芳基係未經取代或經1至5個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4羥基烷基、C 1-4鹵烷基、C 1-4胺基烷基、C 3-8環烷基、C 3-8環烯基、NR 15C(O)R 14、NR 15C(O)OR 14、NR 14C(O)NR 15R 16、NR 15S(O)R 14、NR 15S(O) 2R 14、C(O)NR 15R 16、S(O)NR 15R 16、S(O) 2NR 15R 16、C(O)R 14、C(O)OR 14、OR 14、SR 14、S(O)R 14及S(O) 2R 14； R 2、R 3、R 10及R 11係各獨立地選自由以下組成之群：氫、C 1-4烷基及C 3-8環烷基； R 4、R 5、R 8及R 9係各獨立地選自由以下組成之群：氫、氰基、C 1-4烷基、C 1-4烷氧基、胺基、羥基、C 3-8環烷基、鹵基及C 1-4烷基胺基； R 6係選自由以下組成之群：胺基、C 1-4胺基烷基及C 1-4烷基胺基； R 7係選自由以下組成之群：氫、醯胺基、氰基、鹵基及羥基，或係選自由以下組成之群：C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基，及5或6員雜芳基，其等中之任一者係未經取代或經1至5個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基； 或R 6及R 7連同其等均附接之碳原子一起形成3至7員飽和或不飽和環，其具有0至3個獨立地選自N、C(O)、O及S(O) m之雜原子或基團作為環頂點；下標m係0、1或2；及由R 6及R 7形成之該飽和或不飽和環係未經取代或經1至3個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基； R 2、R 3、R 4、R 5、R 7、R 8、R 9、R 10及R 11中之任兩個基團可形成5至6員環，其具有0至2個選自N、O及S之雜原子作為環頂點； R 2、R 4、R 6、R 8及R 10中之任兩個基團可形成直接鍵，或1或2個原子碳橋； R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6 二羥基烷基、-NH-NHR 19、-NHR 19、-OR 19、-NHC(O)R 19、-NHC(O)NHR 19、-NHS(O) 2NHR 19、-NHS(O) 2R 19、-C(O)OR 19、-C(O)NR 19R 20、-C(O)NH(CH 2) qOH、-C(O)NH(CH 2) qR 21、-C(O)R 21、-NH 2、-OH、-S(O) 2NR 19R 20、C 3-8環烷基、芳基、具有1至5個選自N、O、S及P之雜原子作為環頂點之雜環基，及具有1至5個選自N、O、S及P之雜原子作為環頂點之雜芳基；下標q係0至6之整數；及R 13之芳基、雜芳基、雜環基及環烷基中之各者係未經取代或經1至3個獨立地選自由以下組成之群之基團取代：C 1-4烷基、-OH、-NH 2、-OR 21、鹵基、氰基及側氧基； R 14、R 15及R 16係各獨立地選自由以下組成之群：氫、C 1-4烷基、C 3-8環烷基、C 6-10芳基及5至10員雜芳基，其等中之任一者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基； R 17及R 18係各獨立地選自由以下組成之群：氫、C 1-4烷基及CF 3； R 19及R 20係各獨立地選自由以下組成之群：氫、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 2-6烯基、C 2-6炔基及C 3-6環烷基；及 各R 21係獨立地選自由以下組成之群：氫、-OH、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 2-6烯基、C 2-6炔基及C 3-6環烷基。 In one aspect, the invention provides a method of treating cancer in an individual. The method includes administering to the individual: a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PTPN11 inhibitor is represented by Formula (I): (I), or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof, wherein: subscript a is 0 or 1; subscript b is 0 or 1; Y 1 is a direct bond or CR 17 R 18 ; Y 2 is selected from the group consisting of: C 1-4 alkyl, amino, C 1-4 alkyl C(O)O-, C 1-4 alkylamino and C 1-4 aminoalkyl; R 1 is selected from the group consisting of: C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl And a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms or groups independently selected from N, C(O), O and S as ring vertices; the aryl or heteroaryl group of R 1 is not Substituted or substituted with 1 to 5 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amine, C 1-4 alkylamino, di(C 1-4 alkyl)amine group, cyano group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 hydroxyalkyl group, C 1-4 haloalkyl group, C 1-4 aminoalkyl group, C 3-8 ring Alkyl, C 3-8 cycloalkenyl, NR 15 C(O)R 14 , NR 15 C(O)OR 14 , NR 14 C(O)NR 15 R 16 , NR 15 S(O)R 14 , NR 15 S(O) 2 R 14 , C(O)NR 15 R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 14 , C(O)OR 14 , OR 14 , SR 14 , S(O)R 14 and S(O) 2 R 14 ; R 2 , R 3 , R 10 and R 11 are each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-8 cycloalkyl; R 4 , R 5 , R 8 and R 9 are each independently selected from the group consisting of: hydrogen, cyano group, C 1-4 alkyl, C 1-4 alkyl Oxygen group, amino group, hydroxyl group, C 3-8 cycloalkyl group, halo group and C 1-4 alkylamino group; R 6 is selected from the group consisting of: amino group, C 1-4 aminoalkyl group and C 1-4 alkylamino; R 7 is selected from the group consisting of hydrogen, amide, cyano, halo and hydroxyl, or is selected from the group consisting of C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which is unsubstituted or consists of 1 to 5 independently selected from the following Group substitution: amino group, halo group, hydroxyl group, cyano group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 haloalkyl group, C 1-4 haloalkoxy group , C 1-4 alkylamino and C 1-4 aminoalkyl; or R 6 and R 7 together with the carbon atoms to which they are attached form a 3 to 7 membered saturated or unsaturated ring, which has 0 to 3 heteroatoms or groups independently selected from N, C(O), O and S(O) m serve as ring vertices; the subscript m is 0, 1 or 2 ; and the The saturated or unsaturated ring system is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of: amino, halo, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; R 2 , R 3 , R 4 , R 5. Any two groups among R 7 , R 8 , R 9 , R 10 and R 11 can form a 5 to 6 membered ring, which has 0 to 2 heteroatoms selected from N, O and S as ring vertices. ; Any two groups among R 2 , R 4 , R 6 , R 8 and R 10 can form a direct bond, or a 1 or 2 atom carbon bridge; R 13 is selected from the group consisting of: hydrogen, halo group , cyano group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 hydroxyalkyl group, C 1-6 dihydroxyalkyl group, -NH-NHR 19 , -NHR 19 , -OR 19 , -NHC(O)R 19 , -NHC(O)NHR 19 , -NHS(O) 2 NHR 19 , -NHS(O) 2 R 19 , -C(O)OR 19 , -C(O)NR 19 R 20 , -C(O)NH(CH 2 ) q OH, -C(O)NH(CH 2 ) q R 21 , -C(O)R 21 , -NH 2 , -OH, -S(O) 2 NR 19 R 20 , C 3-8 cycloalkyl, aryl, heterocyclic group with 1 to 5 heteroatoms selected from N, O, S and P as ring vertices, and 1 to 5 heteroatoms selected from N , the heteroatoms of O, S and P serve as the heteroaryl group at the ring vertex; the subscript q is an integer from 0 to 6; and each of the aryl, heteroaryl, heterocyclyl and cycloalkyl groups of R 13 is Unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of: C 1-4 alkyl, -OH, -NH 2 , -OR 21 , halo, cyano and pendant oxygen; R 14 , R 15 and R 16 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5 to 10 membered heteroaryl , any of which is unsubstituted or substituted with one or more groups independently selected from the group consisting of: amide group, amine group, halo group, hydroxyl group, cyano group, C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; R 17 and R 18 is each independently selected from the group consisting of: hydrogen, C 1-4 alkyl and CF 3 ; R 19 and R 20 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl; and each R 21 is independently selected from the following Group: hydrogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl base.

在另一態樣中，本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物： (10b)， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之PD-1/PD-L1抑制劑， 其中該PD-1/PD-L1抑制劑係如本文定義及描述。 In another aspect, the invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need thereof: a) a therapeutically effective amount of a compound represented by formula (10b): (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) a therapeutically effective amount of PD-1/PD - an L1 inhibitor, wherein the PD-1/PD-L1 inhibitor is as defined and described herein.

在另一態樣中，本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物： (10b)， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之PD-1/PD-L1抑制劑， 其中該個體具有KRAS突變(例如，如本文描述)。 III-1：    PTPN11抑制劑及/或PD-1/PD-L1抑制劑 In another aspect, the invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) a therapeutically effective amount of formula (10b) Represented compound: (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) a therapeutically effective amount of PD-1/PD - an L1 inhibitor, wherein the individual has a KRAS mutation (eg, as described herein). III-1: PTPN11 inhibitor and/or PD-1/PD-L1 inhibitor

由式(I)表示之PTPN11抑制劑係進一步根據第IV.節化合物進一步描述。在一些實施例中，該式(I)之PTPN11抑制劑係如第IV.節化合物中描述之實施例中之任一者。PTPN11 inhibitors represented by formula (I) are further described in terms of the compounds of Section IV. In some embodiments, the PTPN11 inhibitor of Formula (I) is any of the embodiments described in Compounds of Section IV.

在一些實施例中，PTPN11抑制劑係由式(2b)表示： (2b)， 或其醫藥上可接受之鹽、立體異構體、構象異構體，或其組合。 In some embodiments, the PTPN11 inhibitor is represented by Formula (2b): (2b), or a pharmaceutically acceptable salt, stereoisomer, conformational isomer, or combination thereof.

在一些實施例中，PTPN11抑制劑係由式(2b)表示： (2b)， 具有6-((3S,4S)-4-胺基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-8-基)-3-(R a)-(2,3-二氯苯基)-2-甲基-4(3H)-嘧啶酮之名稱。 In some embodiments, the PTPN11 inhibitor is represented by formula (2b): (2b), having 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-3-(R a ) The name of -(2,3-dichlorophenyl)-2-methyl-4(3H)-pyrimidinone.

在一些實施例中，PTPN11抑制劑係由式(10b)表示： (10b)， 或其醫藥上可接受之鹽、立體異構體、構象異構體，或其組合。 In some embodiments, the PTPN11 inhibitor is represented by Formula (10b): (10b), or a pharmaceutically acceptable salt, stereoisomer, conformational isomer, or combination thereof.

式(I)、式(2b)及式(10b)中之任一者之化合物可呈醫藥上可接受之鹽形式或呈中性形式，其等中之各者係視需要呈溶劑化物或水合物形式。The compound of any one of Formula (I), Formula (2b) and Formula (10b) may be in the form of a pharmaceutically acceptable salt or in a neutral form, each of which may be in a solvate or hydrated form as appropriate. object form.

在一些實施例中，式(I)、式(2b)及式(10b)中之任一者之化合物係呈醫藥上可接受之鹽形式。在一些實施例中，式(10b)化合物之醫藥上可接受之酸加成鹽係由式(10b-HX)表示： (10b-HX)， 其中HX係醫藥上可接受之酸加成物。 In some embodiments, a compound of any of Formula (I), Formula (2b), and Formula (10b) is in a pharmaceutically acceptable salt form. In some embodiments, a pharmaceutically acceptable acid addition salt of the compound of formula (10b) is represented by formula (10b-HX): (10b-HX), where HX is a pharmaceutically acceptable acid adduct.

可接受之酸加成鹽之實例包括彼等來源於無機酸者，諸如鹽酸、氫溴酸、硝酸、碳酸、一氫碳酸、磷酸、一氫磷酸、二氫磷酸、硫酸、一氫硫酸、氫碘酸或亞磷酸及類似物，及來源於有機酸之鹽，諸如乙酸、丙酸、異丁酸、馬來酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富馬酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、酒石酸、甲磺酸，及類似物。Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydrogen sulfate Iodic acid or phosphorous acid and the like, and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid , mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.

在一些實施例中，式(I)、式(2b)及式(10b)中之任一者之化合物係呈中性形式。在一些實施例中，該式(10b)化合物係呈中性形式。In some embodiments, a compound of any of Formula (I), Formula (2b), and Formula (10b) is in a neutral form. In some embodiments, the compound of formula (10b) is in neutral form.

在一些實施例中，式(10b)化合物具有6-((3S,4S)-4-胺基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-8-基)之基本部分及如式(10b)中顯示之立體化學： (10b)。 In some embodiments, the compound of formula (10b) has 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl) The basic parts and the stereochemistry as shown in formula (10b): (10b).

在一些實施例中，式(10b)化合物係大體上呈如式(10b)中顯示之R a構型： (10b)。 In some embodiments, the compound of Formula (10b) is substantially in the R a configuration as shown in Formula (10b): (10b).

在一些實施例中，式(10b)化合物係由下式表示： (10b)， 具有6-((3S,4S)-4-胺基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-8-基)-3-(R a)-(2,3-二氯苯基)-2,5-二甲基-4(3H)-嘧啶酮之名稱。 In some embodiments, the compound of formula (10b) is represented by the following formula: (10b), having 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-3-(R a ) The name of -(2,3-dichlorophenyl)-2,5-dimethyl-4(3H)-pyrimidinone.

在一些實施例中，式(10b)化合物包括一或多種相應之對映體、非對映體及/或構象異構體，如分別由下式表示： 對映體(3R, 4R, S a) 非對映體(3R, 4S, R a) 非對映體(3S, 4R, S a) 非對映體(3R, 4R, R a) 非對映體(3S, 4S, S a) 非對映體(3S, 4R, R a) 非對映體(3R, 4S, S a)       In some embodiments, the compound of formula (10b) includes one or more corresponding enantiomers, diastereomers and/or conformational isomers, as respectively represented by the following formula: Enantiomers (3R, 4R, S a ) Diastereomers (3R, 4S, R a ) Diastereomers (3S, 4R, S a ) Diastereomers (3R, 4R, R a ) Diastereomers (3S, 4S, S a ) Diastereomers (3S, 4R, R a ) Diastereomers (3R, 4S, S a )

在一些實施例中，式(10b)化合物具有藉由對掌性高效液相層析術(HPLC)測定的至少約95面積%之純度。在一些實施例中，該式(10b)化合物具有藉由對掌性高效液相層析術(HPLC)測定的約95面積%至約99面積%、約96面積%至約99面積%、約97面積%至約99面積%或約98面積%至約99面積%之純度。在一些實施例中，該式(10b)化合物具有約98面積%至約99面積%之純度。In some embodiments, the compound of formula (10b) has a purity of at least about 95 area% as determined by chiral high performance liquid chromatography (HPLC). In some embodiments, the compound of formula (10b) has an area % of about 95 to about 99 area %, about 96 to about 99 area %, about Purity from 97 area% to about 99 area% or from about 98 area% to about 99 area%. In some embodiments, the compound of formula (10b) has a purity of about 98 area% to about 99 area%.

在一些實施例中，式(10b)化合物包括一或多種對應之對映體、非對映體及/或構象異構體，如由上式表示；及該一或多種異構體之總量藉由對掌性高效液相層析術(HPLC)係不多於約5面積%。In some embodiments, the compound of formula (10b) includes one or more corresponding enantiomers, diastereomers and/or conformational isomers, as represented by the above formula; and the total amount of the one or more isomers By chiral high performance liquid chromatography (HPLC) no more than about 5 area %.

在一些實施例中，式(10b)化合物中存在之該式(10b)化合物之相應之對映體、非對映體及/或構象異構體滿足如下可接受之標準：對映體(3R, 4R, S a) ＜0.5面積%；非對映體(3R, 4S, R a) ＜1.2面積%；非對映體(3S, 4R, S a) ＜0.5面積%；非對映體(3R, 4R, R a) ＜0.5面積%；非對映體(3S, 4S, S a) ＜0.5面積%；非對映體(3S, 4R, R a) ＜0.5面積%；及非對映體(3R, 4S, S a) ＜0.5面積%，其等中之各者係藉由對掌性高效液相層析術(HPLC)測定。在一些實施例中，該式(10b)化合物具有至少約95面積%之純度，其中對映體(3R, 4R, S a) ＜ 0.5面積%；非對映體(3R, 4S, R a) ＜ 1.2面積%；非對映體(3S, 4R, S a) ＜ 0.5面積%；非對映體(3R, 4R, R a) ＜ 0.5面積%；非對映體(3S, 4S, S a) ＜ 0.5面積%；非對映體(3S, 4R, R a) ＜ 0.5面積%；及非對映體(3R, 4S, S a) ＜ 0.5面積%，其等中之各者係藉由對掌性高效液相層析術(HPLC)測定。在一些實施例中，該式(10b)化合物具有約95面積%至約99面積%、約96面積%至約99面積%、約97面積%至約99面積%或約98面積%至約99面積%之純度，其中對映體(3R, 4R, S a) ＜ 0.5面積%；非對映體(3R, 4S, R a) ＜ 1.2面積%；非對映體(3S, 4R, S a) ＜ 0.5面積%；非對映體(3R, 4R, R a) ＜ 0.5面積%；非對映體(3S, 4S, S a) ＜ 0.5面積%；非對映體(3S, 4R, R a) ＜ 0.5面積%；及非對映體(3R, 4S, S a) ＜ 0.5面積%，其等中之各者係藉由對掌性高效液相層析術(HPLC)測定。在一些實施例中，該式(10b)化合物具有約98面積%至約99面積%之純度，其中未偵測到對映體(3R, 4R, S a)；非對映體(3R, 4S, R a)係約0.86面積%；未偵測到非對映體(3S, 4R, S a)；非對映體(3R, 4R, R a)係約0.07面積%；未偵測到非對映體(3S, 4S, S a)；未偵測到非對映體(3S, 4R, R a)；及未偵測到非對映體(3R, 4S, S a)，其等中之各者係藉由對掌性高效液相層析術(HPLC)測定。 In some embodiments, the corresponding enantiomers, diastereomers and/or conformational isomers of the compound of formula (10b) present in the compound of formula (10b) satisfy the following acceptance criteria: Enantiomer (3R , 4R, S a ) ＜ 0.5 area %; diastereomer (3R, 4S, R a ) ＜ 1.2 area %; diastereomer (3S, 4R, S a ) ＜ 0.5 area %; diastereomer ( 3R, 4R, R a ) < 0.5 area%; diastereomers (3S, 4S, S a ) < 0.5 area%; diastereomers (3S, 4R, R a ) < 0.5 area%; and diastereomers Body (3R, 4S, S a ) < 0.5 area%, each of which is determined by chiral high performance liquid chromatography (HPLC). In some embodiments, the compound of formula (10b) has a purity of at least about 95 area%, wherein enantiomers (3R, 4R, S a ) < 0.5 area %; diastereomers (3R, 4S, R a ) ＜ 1.2 area %; diastereomer (3S, 4R, S a ) ＜ 0.5 area %; diastereomer (3R, 4R, R a ) ＜ 0.5 area %; diastereomer (3S, 4S, S a ) < 0.5 area %; diastereomer (3S, 4R, R a ) < 0.5 area %; and diastereomer (3R, 4S, S a ) < 0.5 area %, each of which is determined by Determination of chiral high performance liquid chromatography (HPLC). In some embodiments, the compound of formula (10b) has an area ratio of about 95 to about 99 area%, about 96 to about 99 area%, about 97 to about 99 area%, or about 98 to about 99 area%. Purity of area %, where enantiomer (3R, 4R, S a ) < 0.5 area %; diastereomer (3R, 4S, R a ) < 1.2 area %; diastereomer (3S, 4R, S a ) ＜ 0.5 area %; diastereomers (3R, 4R, R a ) ＜ 0.5 area %; diastereomers (3S, 4S, S a ) ＜ 0.5 area %; diastereomers (3S, 4R, R a ) < 0.5 area %; and diastereomers (3R, 4S, S a ) < 0.5 area %, each of which is determined by chiral high-performance liquid chromatography (HPLC). In some embodiments, the compound of formula (10b) has a purity of about 98 area % to about 99 area %, in which no enantiomer (3R, 4R, Sa ) is detected; diastereomer (3R, 4S) , R a ) is about 0.86 area%; no diastereomers (3S, 4R, S a ) are detected; diastereomers (3R, 4R, R a ) are about 0.07 area%; no non-diastereomers are detected Enantiomers (3S, 4S, S a ); no diastereomers (3S, 4R, R a ) detected; and no diastereomers (3R, 4S, S a ) detected, among others Each was measured by chiral high performance liquid chromatography (HPLC).

在一些實施例中，式(I)、式(2b)、式(10b)及式(10b-HX)中之任一者之化合物係呈溶劑化物及/或水合物形式。In some embodiments, compounds of any one of Formula (I), Formula (2b), Formula (10b), and Formula (10b-HX) are in solvate and/or hydrate form.

PD-1/PD-L1抑制劑可為描述用以治療癌症之抑制劑。在一些實施例中，該PD-1/PD-L1抑制劑至少部分抑制PD-1及/或PD-L1蛋白。在一些實施例中，該PD-1/PD-L1抑制劑另外抑制PD-L2。在一些實施例中，該PD-1/PD-L1抑制劑係選擇性PD-1/PD-L1抑制劑，選擇性抑制PD-1及/或PD-L1。在一些實施例中，該PD-1/PD-L1抑制劑係PD-1抑制劑。在一些實施例中，該PD-1/PD-L1抑制劑係PD-L1抑制劑。在一些實施例中，該PD-1/PD-L1抑制劑抑制PD-1及PD-L1兩者。PD-1/PD-L1 inhibitors may be described as inhibitors used to treat cancer. In some embodiments, the PD-1/PD-L1 inhibitor at least partially inhibits PD-1 and/or PD-L1 protein. In some embodiments, the PD-1/PD-L1 inhibitor additionally inhibits PD-L2. In some embodiments, the PD-1/PD-L1 inhibitor is a selective PD-1/PD-L1 inhibitor that selectively inhibits PD-1 and/or PD-L1. In some embodiments, the PD-1/PD-L1 inhibitor is a PD-1 inhibitor. In some embodiments, the PD-1/PD-L1 inhibitor is a PD-L1 inhibitor. In some embodiments, the PD-1/PD-L1 inhibitor inhibits both PD-1 and PD-L1.

在一些實施例中，PD-1/PD-L1抑制劑係帕博利珠單抗、納武單抗、阿替利珠單抗(atezolizumab)、度伐利尤單抗(durvalumab)、阿維魯單抗(avelumab)、西米普利單抗-rwlc (cemiplimab-rwlc)、卡瑞利珠單抗(camrelizumab)、特瑞普利單抗(toripalimab)、帕洛利單抗(prolgolimab)、替雷利珠單抗(tislelizumab)、巴替利單抗(balstilimab)、多塔利單抗(dostarlimab)、M7824、斯巴達珠單抗(spartalizumab)、薩善利單抗(sasanlimab)、瑞弗利單抗(retifanlimab)、BMS-986213或特泊利單抗(tebotelimab)。在一些實施例中，該PD-1/PD-L1抑制劑係帕博利珠單抗。在一些實施例中，當該PTPN11抑制劑係式(10b)化合物時，該PD-1/PD-L1抑制劑不為納武單抗。In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avirut Avelumab, cemiplimab-rwlc (cemiplimab-rwlc), camrelizumab, toripalimab, prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab, sasanlimab, reveli monoclonal antibody (retifanlimab), BMS-986213 or tebolizumab (tebotelimab). In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab. In some embodiments, when the PTPN11 inhibitor is a compound of formula (10b), the PD-1/PD-L1 inhibitor is not nivolumab.

在一些實施例中，PTPN11抑制劑係由式(2b)表示；及該PD-1/PD-L1抑制劑係帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213或特泊利單抗。在一些實施例中，該PTPN11抑制劑係由式(2b)表示；及該PD-1/PD-L1抑制劑係帕博利珠單抗。在一些實施例中，該PTPN11抑制劑係由式(2b)表示；及該PD-1/PD-L1抑制劑係納武單抗。In some embodiments, the PTPN11 inhibitor is represented by formula (2b); and the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalizumab Avelumab, avelumab, cimepilimab-rwlc, camrelizumab, toripalimab, palolizumab, tislelizumab, batizumab anti, dotilizumab, M7824, spartalizumab, saxanilumab, reflimab, BMS-986213 or terpolizumab. In some embodiments, the PTPN11 inhibitor is represented by Formula (2b); and the PD-1/PD-L1 inhibitor is pembrolizumab. In some embodiments, the PTPN11 inhibitor is represented by formula (2b); and the PD-1/PD-L1 inhibitor is nivolumab.

在一些實施例中，PTPN11抑制劑係由式(10b)表示；及該PD-1/PD-L1抑制劑係帕博利珠單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213或特泊利單抗。在一些實施例中，該PTPN11抑制劑係由式(10b)表示；及該PD-1/PD-L1抑制劑係帕博利珠單抗。 III-2.癌症/實體腫瘤 In some embodiments, the PTPN11 inhibitor is represented by formula (10b); and the PD-1/PD-L1 inhibitor is pembrolizumab, atezolizumab, durvalumab, alfa Vilumab, cimepilimab-rwlc, camrelizumab, toripalimab, palolizumab, tislelizumab, batilizumab, dotalizumab monoclonal antibody, M7824, spartalizumab, saxanilumab, refulimab, BMS-986213 or terpolizumab. In some embodiments, the PTPN11 inhibitor is represented by formula (10b); and the PD-1/PD-L1 inhibitor is pembrolizumab. III-2. Cancer/Solid Tumor

癌症可為對PTPN11抑制劑及/或PD-1/PD-L1抑制劑之治療產生反應之任何癌症。在一些實施例中，該癌症表現PD-L1。在一些實施例中，該癌症之特徵在於高程度之微衛星不穩定性(MSI-H)、錯配修復缺陷(dMMR)、高程度之腫瘤突變負荷(TMB-H)，或其組合。在一些實施例中，該癌症之特徵在於高程度之微衛星不穩定性(MSI-H)。在一些實施例中，該癌症之特徵在於錯配修復缺陷(dMMR)。在一些實施例中，該癌症之特徵在於高程度之腫瘤突變負荷(TMB-H)。在一些實施例中，該癌症之起因及/或特徵在於KRAS突變，諸如KRAS G12C突變。在一些實施例中，該癌症之特徵在於除Q61X突變外之KRAS突變。在一些實施例中，該癌症係PD-L1陽性癌症。在一些實施例中，該癌症係KRAS陽性癌症。在一些實施例中，該癌症係KRAS G12C陽性癌症(例如，特徵在於KRAS中之G12C突變之癌症)。The cancer can be any cancer that responds to treatment with a PTPN11 inhibitor and/or a PD-1/PD-L1 inhibitor. In some embodiments, the cancer expresses PD-L1. In some embodiments, the cancer is characterized by a high degree of microsatellite instability (MSI-H), a high degree of mismatch repair deficiency (dMMR), a high degree of tumor mutation burden (TMB-H), or a combination thereof. In some embodiments, the cancer is characterized by a high degree of microsatellite instability (MSI-H). In some embodiments, the cancer is characterized by mismatch repair deficiency (dMMR). In some embodiments, the cancer is characterized by a high degree of tumor mutation burden (TMB-H). In some embodiments, the cancer is caused and/or characterized by a KRAS mutation, such as a KRAS G12C mutation. In some embodiments, the cancer is characterized by a KRAS mutation in addition to the Q61X mutation. In some embodiments, the cancer is PD-L1 positive cancer. In some embodiments, the cancer is a KRAS positive cancer. In some embodiments, the cancer is a KRAS G12C positive cancer (eg, a cancer characterized by a G12C mutation in KRAS).

在一些實施例中，癌症之特徵在於KRAS突變，諸如密碼子12、13或61中之突變(例如，G12C、G12D、G12S、G12V、G12R、G12A、G12F、G12I、G12L、G13D、G13A、G13C、G13R、G13S、G13V、Q61E、Q61K、Q61L、Q61P、Q61R及/或Q61H突變)。在一些實施例中，該癌症之特徵在於選自以下之KRAS突變：G12C、G12D、G12S、G12V、G12R、G12A、G13D、G13A、G13C、G13R、G13S、G13V，及其組合。在一些實施例中，該癌症之特徵在於KRAS G12C突變。在一些實施例中，KRAS蛋白不包含於Q61處之突變。In some embodiments, the cancer is characterized by a KRAS mutation, such as a mutation in codons 12, 13, or 61 (e.g., G12C, G12D, G12S, G12V, G12R, G12A, G12F, G12I, G12L, G13D, G13A, G13C , G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R and/or Q61H mutations). In some embodiments, the cancer is characterized by a KRAS mutation selected from: G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, and combinations thereof. In some embodiments, the cancer is characterized by a KRAS G12C mutation. In some embodiments, the KRAS protein does not comprise a mutation at Q61.

癌症之特徵可在於實體腫瘤及/或液體腫瘤。在一些實施例中，該癌症包括實體腫瘤。在一些實施例中，該癌症包括液體腫瘤。Cancer can be characterized as a solid tumor and/or a liquid tumor. In some embodiments, the cancer includes solid tumors. In some embodiments, the cancer includes liquid tumors.

在一些實施例中，癌症係肛門癌、膽管癌、膀胱癌、腦癌、子宮頸癌、結直腸癌(CRC)、子宮內膜癌、食管癌、胃癌、頭頸部鱗狀細胞癌(HNSCC)、肝細胞癌(HCC)、默克細胞癌(merkel cell carcinoma)、黑色素瘤、間皮瘤、非小細胞肺癌(NSCLC)、卵巢癌、***癌、腎細胞癌(RCC)、小細胞肺癌(SCLC)、鱗狀細胞癌(SCC)、三陰性乳癌(TNBC)、何傑金氏淋巴瘤(Hodgkin’s lymphoma)、原發性縱隔大B細胞淋巴瘤(PMBCL)、瀰漫性大B細胞淋巴瘤(DLBCL)，或其組合。在一些實施例中，該癌症係肛門癌、膽管癌、膀胱癌、腦癌、子宮頸癌、結直腸癌(CRC)、子宮內膜癌、食管癌、胃癌、頭頸部鱗狀細胞癌(HNSCC)、肝細胞癌(HCC)、默克細胞癌、黑色素瘤、間皮瘤、非小細胞肺癌(NSCLC)、卵巢癌、***癌、腎細胞癌(RCC)、小細胞肺癌(SCLC)、鱗狀細胞癌(SCC)、三陰性乳癌(TNBC)，或其組合。在一些實施例中，該癌症係何傑金氏淋巴瘤、原發性縱隔大B細胞淋巴瘤(PMBCL)、瀰漫性大B細胞淋巴瘤(DLBCL)，或其組合。在一些實施例中，該癌症係何傑金氏淋巴瘤。在一些實施例中，該癌症係瀰漫性大B細胞淋巴瘤(DLBCL)。In some embodiments, the cancer is anal cancer, cholangiocarcinoma, bladder cancer, brain cancer, cervical cancer, colorectal cancer (CRC), endometrial cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma (HNSCC) , hepatocellular carcinoma (HCC), Merkel cell carcinoma, melanoma, mesothelioma, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, renal cell carcinoma (RCC), small cell lung cancer ( SCLC), squamous cell carcinoma (SCC), triple negative breast cancer (TNBC), Hodgkin's lymphoma (Hodgkin's lymphoma), primary mediastinal large B-cell lymphoma (PMBCL), diffuse large B-cell lymphoma ( DLBCL), or a combination thereof. In some embodiments, the cancer is anal cancer, cholangiocarcinoma, bladder cancer, brain cancer, cervical cancer, colorectal cancer (CRC), endometrial cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma (HNSCC) ), hepatocellular carcinoma (HCC), Merck cell carcinoma, melanoma, mesothelioma, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, renal cell carcinoma (RCC), small cell lung cancer (SCLC), squamous cell carcinoma cystic cell carcinoma (SCC), triple negative breast cancer (TNBC), or a combination thereof. In some embodiments, the cancer is Hodgkin's lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), diffuse large B-cell lymphoma (DLBCL), or a combination thereof. In some embodiments, the cancer is Hodgkin's lymphoma. In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

在一些實施例中，癌症係結直腸癌(CRC)。在一些實施例中，該癌症係非小細胞肺癌(NSCLC)。In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

在一些實施例中，癌症係結直腸癌(CRC)，其特徵在於KRAS突變，諸如密碼子12中之突變(例如，KRAS G12C、G12D或G12R)。In some embodiments, the cancer is colorectal cancer (CRC), characterized by a KRAS mutation, such as a mutation in codon 12 (eg, KRAS G12C, G12D, or G12R).

在一些實施例中，癌症係NSCLC，其特徵在於KRAS突變，諸如KRAS G12C突變。在一些實施例中，KRAS蛋白包括G12C、G12D、G12S、G12V、G12R、G12A、G13D、G13A、G13C、G13R、G13S、G13V、Q61E、Q61K、Q61L、Q61P、Q61R及/或Q61H突變。在一些實施例中，KRAS蛋白包括G12C、G12D或G12V突變。在一些實施例中，該癌症係NSCLC，其特徵在於KRAS中之G12C、G12D或G12V突變。在一些實施例中，該癌症係NSCLC，其特徵在於表皮生長因子受體(EGFR)蛋白中之突變。在一些實施例中，該癌症係NSCLC，其特徵不在於EGFR、KRAS或間變性淋巴瘤激酶(ALK)中之突變。In some embodiments, the cancer is NSCLC, characterized by a KRAS mutation, such as a KRAS G12C mutation. In some embodiments, the KRAS protein includes G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and/or Q61H mutations. In some embodiments, the KRAS protein includes G12C, G12D, or G12V mutations. In some embodiments, the cancer is NSCLC characterized by G12C, G12D or G12V mutations in KRAS. In some embodiments, the cancer is NSCLC, characterized by mutations in the epidermal growth factor receptor (EGFR) protein. In some embodiments, the cancer is NSCLC, which is not characterized by mutations in EGFR, KRAS, or anaplastic lymphoma kinase (ALK).

癌症亦可為對PD-1/PD-L1抑制劑之治療耐藥性之任何癌症。在一些實施例中，該癌症係對如本文定義及描述之PD-1/PD-L1抑制劑耐藥性。在一些實施例中，該癌症之特徵在於對PD-1/PD-L1抑制劑之固有及/或獲得性耐藥性。在一些實施例中，該癌症係對PD-1/PD-L1抑制劑耐藥性之PD-1/PD-L1陽性癌症。在一些實施例中，該癌症係PD-1/PD-L1陽性癌症，其特徵在於對PD-1/PD-L1抑制劑之固有及/或獲得性耐藥性。在一些實施例中，該癌症係對PD-1/PD-L1抑制劑耐藥性之KRAS陽性癌症。在一些實施例中，該癌症係KRAS陽性癌症，其特徵在於對PD-1/PD-L1抑制劑之固有及/或獲得性耐藥性。The cancer may also be any cancer that is resistant to treatment with PD-1/PD-L1 inhibitors. In some embodiments, the cancer is resistant to a PD-1/PD-L1 inhibitor as defined and described herein. In some embodiments, the cancer is characterized by intrinsic and/or acquired resistance to PD-1/PD-L1 inhibitors. In some embodiments, the cancer is a PD-1/PD-L1 positive cancer that is resistant to a PD-1/PD-L1 inhibitor. In some embodiments, the cancer is a PD-1/PD-L1 positive cancer characterized by intrinsic and/or acquired resistance to PD-1/PD-L1 inhibitors. In some embodiments, the cancer is a KRAS-positive cancer that is resistant to a PD-1/PD-L1 inhibitor. In some embodiments, the cancer is a KRAS-positive cancer characterized by intrinsic and/or acquired resistance to PD-1/PD-L1 inhibitors.

在一些實施例中，癌症係對選自由以下組成之群之PD-1/PD-L1抑制劑耐藥性：帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213及特泊利單抗。在一些實施例中，該癌症係對帕博利珠單抗耐藥性。在一些實施例中，該癌症係對納武單抗耐藥性。In some embodiments, the cancer line is resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, durvalizumab Avelumab, avelumab, cimepilimab-rwlc, camrelizumab, toripalimab, palolizumab, tislelizumab, batizumab anti, dotalizumab, M7824, spartalizumab, saxanilumab, refulimab, BMS-986213 and terpolizumab. In some embodiments, the cancer line is resistant to pembrolizumab. In some embodiments, the cancer is resistant to nivolumab.

在一些實施例中，癌症係對選自由以下組成之群之PD-1/PD-L1抑制劑耐藥性之PD-L1陽性癌症：帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213及特泊利單抗。在一些實施例中，該癌症係對帕博利珠單抗耐藥性之PD-L1陽性癌症。在一些實施例中，該癌症係對納武單抗耐藥性之PD-L1陽性癌症。In some embodiments, the cancer is a PD-L1 positive cancer that is resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab monoclonal antibody, durvalumab, avelumab, cimepilimab-rwlc, camrelizumab, toripalimab, palolizumab, tislelizumab anti-, batizumab, dotalizumab, M7824, spartalizumab, saxalizumab, refulimab, BMS-986213 and terpolizumab. In some embodiments, the cancer is a PD-L1 positive cancer that is resistant to pembrolizumab. In some embodiments, the cancer is a PD-L1 positive cancer that is resistant to nivolumab.

在一些實施例中，癌症係對選自由以下組成之群之PD-1/PD-L1抑制劑耐藥性之KRAS陽性癌症：帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213及特泊利單抗。在一些實施例中，該癌症係對帕博利珠單抗耐藥性之KRAS陽性癌症。在一些實施例中，該癌症係對納武單抗耐藥性之KRAS陽性癌症。In some embodiments, the cancer is a KRAS-positive cancer that is resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab , durvalumab, avelumab, cimepilimab-rwlc, camrelizumab, toripalimab, palolizumab, tislelizumab, Battilizumab, dotalizumab, M7824, spartalizumab, saxanilumab, reflimab, BMS-986213 and terpolizumab. In some embodiments, the cancer is a KRAS-positive cancer that is resistant to pembrolizumab. In some embodiments, the cancer is a KRAS-positive cancer that is resistant to nivolumab.

在一些實施例中，癌症之特徵在於對另一療法，諸如KRAS調節劑、基於鉑之療法或紫杉烷療法之固有及/或獲得性耐藥性。In some embodiments, the cancer is characterized by intrinsic and/or acquired resistance to another therapy, such as a KRAS modulator, platinum-based therapy, or taxane therapy.

實體腫瘤可為對PTPN11抑制劑及抗PD-1/PD-L1藥劑(例如，納武單抗)之治療產生反應之任何實體腫瘤。在一些實施例中，該實體腫瘤係KRAS中之一或多個基因經重排、突變或擴增之腫瘤，限制條件為該腫瘤非由BRAF V600X、PTPN11 (SHP2)或KRAS Q61X中之一或多個另外活化突變引起。The solid tumor can be any solid tumor that responds to treatment with a PTPN11 inhibitor and an anti-PD-1/PD-L1 agent (eg, nivolumab). In some embodiments, the solid tumor is a tumor in which one or more genes in KRAS are rearranged, mutated or amplified, with the proviso that the tumor is not caused by one of BRAF V600X, PTPN11 (SHP2) or KRAS Q61X or Caused by multiple additional activating mutations.

在一些實施例中，實體腫瘤係由KRAS中之突變引起之晚期非小細胞肺癌(NSCLC)。在一些實施例中，該實體腫瘤係由KRAS中之突變引起之晚期非小細胞肺癌(NSCLC)，限制條件為該腫瘤非由BRAF V600X、PTPN11 (SHP2)或KRAS Q61X中之一或多個另外活化突變引起。在一些實施例中，該實體腫瘤係KRAS G12C陽性實體腫瘤。在一些實施例中，該實體腫瘤晚期或轉移性KRASG12C陽性非小細胞肺癌(NSCLC)。In some embodiments, the solid tumor is advanced non-small cell lung cancer (NSCLC) caused by mutations in KRAS. In some embodiments, the solid tumor is advanced non-small cell lung cancer (NSCLC) caused by mutations in KRAS, with the proviso that the tumor is not caused by one or more of BRAF V600X, PTPN11 (SHP2), or KRAS Q61X. Caused by activating mutations. In some embodiments, the solid tumor is a KRAS G12C positive solid tumor. In some embodiments, the solid tumor is advanced or metastatic KRASG12C-positive non-small cell lung cancer (NSCLC).

實體腫瘤亦可為對KRAS G12C抑制劑(例如，索托拉西布(sotorasib) (AMG-510)、阿達格拉西布(adagrasib) (MRTX-849)、MRTX1257、ARS-853、ARS-1620、JNJ-74699157(ARS-3248)、LY3537982及LY3499446)之治療耐藥性之任何腫瘤。在一些實施例中，該實體腫瘤係對KRAS G12C抑制劑耐藥性。在一些實施例中，該實體腫瘤之特徵在於對如本文定義及描述之KRAS G12C抑制劑之固有及/或獲得性耐藥性。在一些實施例中，該實體腫瘤係對KRAS G12C抑制劑耐藥性之KRAS G12C陽性實體腫瘤。在一些實施例中，該實體腫瘤係特徵在於對KRAS G12C抑制劑之固有及/或獲得性耐藥性之KRAS G12C陽性實體腫瘤。在一些實施例中，該實體腫瘤係對選自由以下組成之群之KRAS G12C抑制劑之治療耐藥性：索托拉西布(AMG-510)、阿達格拉西布(MRTX-849)、MRTX1257、ARS-853、ARS-1620、JNJ-74699157(ARS-3248)、LY3537982及LY3499446。在一些實施例中，該實體腫瘤係對索托拉西布(AMG-510)耐藥性。在一些實施例中，該實體腫瘤係對阿達格拉西布(MRTX-849)耐藥性。在一些實施例中，該實體腫瘤係對選自由以下組成之群之KRAS G12C抑制劑之治療耐藥性的KRAS陽性實體腫瘤：索托拉西布(AMG-510)、阿達格拉西布(MRTX-849)、MRTX1257、ARS-853、ARS-1620、JNJ-74699157(ARS-3248)、LY3537982及LY3499446。在一些實施例中，該實體腫瘤係對索托拉西布(AMG-510)耐藥性之KRAS陽性實體腫瘤。在一些實施例中，該實體腫瘤係對阿達格拉西布(MRTX-849)耐藥性之KRAS陽性實體腫瘤。在一些實施例中，該實體腫瘤係對選自由以下組成之群之KRAS G12C抑制劑之治療耐藥性的KRAS G12C陽性實體腫瘤：索托拉西布(AMG-510)、阿達格拉西布(MRTX-849)、MRTX1257、ARS-853、ARS-1620、JNJ-74699157(ARS-3248)、LY3537982及LY3499446。在一些實施例中，該實體腫瘤係對索托拉西布(AMG-510)耐藥性之KRAS G12C陽性實體腫瘤。在一些實施例中，該實體腫瘤係對阿達格拉西布(MRTX-849)耐藥性之KRAS G12C陽性實體腫瘤。Solid tumors may also be resistant to KRAS G12C inhibitors (e.g., sotorasib (AMG-510), adagrasib (MRTX-849), MRTX1257, ARS-853, ARS-1620, Any tumor that is resistant to treatment with JNJ-74699157 (ARS-3248), LY3537982 and LY3499446). In some embodiments, the solid tumor line is resistant to a KRAS G12C inhibitor. In some embodiments, the solid tumor is characterized by intrinsic and/or acquired resistance to a KRAS G12C inhibitor as defined and described herein. In some embodiments, the solid tumor is a KRAS G12C positive solid tumor that is resistant to a KRAS G12C inhibitor. In some embodiments, the solid tumor is a KRAS G12C positive solid tumor characterized by intrinsic and/or acquired resistance to a KRAS G12C inhibitor. In some embodiments, the solid tumor is resistant to treatment with a KRAS G12C inhibitor selected from the group consisting of sotoraxib (AMG-510), adagrasiib (MRTX-849), MRTX1257 , ARS-853, ARS-1620, JNJ-74699157 (ARS-3248), LY3537982 and LY3499446. In some embodiments, the solid tumor line is resistant to sotoraxib (AMG-510). In some embodiments, the solid tumor line is resistant to adagrasib (MRTX-849). In some embodiments, the solid tumor is a KRAS positive solid tumor that is resistant to treatment with a KRAS G12C inhibitor selected from the group consisting of: sotoraxib (AMG-510), adagrasiib (MRTX) -849), MRTX1257, ARS-853, ARS-1620, JNJ-74699157 (ARS-3248), LY3537982 and LY3499446. In some embodiments, the solid tumor is a KRAS-positive solid tumor that is resistant to sotoraxib (AMG-510). In some embodiments, the solid tumor is a KRAS-positive solid tumor that is resistant to adagrasib (MRTX-849). In some embodiments, the solid tumor is a KRAS G12C positive solid tumor that is resistant to treatment with a KRAS G12C inhibitor selected from the group consisting of: sotoraxib (AMG-510), adagrasiib ( MRTX-849), MRTX1257, ARS-853, ARS-1620, JNJ-74699157 (ARS-3248), LY3537982 and LY3499446. In some embodiments, the solid tumor is a KRAS G12C-positive solid tumor that is resistant to sotoraxib (AMG-510). In some embodiments, the solid tumor is a KRAS G12C-positive solid tumor that is resistant to adagrasib (MRTX-849).

實體腫瘤亦可為對PD-1/PD-L1抑制劑(例如，帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213及特泊利單抗)之治療耐藥性之任何腫瘤。在一些實施例中，該實體腫瘤係對如本文定義及描述之PD-1/PD-L1抑制劑耐藥性。在一些實施例中，該實體腫瘤之特徵在於對如本文定義及描述之PD-1/PD-L1抑制劑之固有及/或獲得性耐藥性。在一些實施例中，該實體腫瘤係對PD-1/PD-L1抑制劑耐藥性之PD-1/PD-L1陽性實體腫瘤。在一些實施例中，該實體腫瘤係特徵在於對PD-1/PD-L1抑制劑之固有及/或獲得性耐藥性之PD-1/PD-L1陽性實體腫瘤。在一些實施例中，該實體腫瘤係對PD-1/PD-L1抑制劑耐藥性之KRAS陽性實體腫瘤。在一些實施例中，該實體腫瘤係特徵在於對PD-1/PD-L1抑制劑之固有及/或獲得性耐藥性之KRAS陽性實體腫瘤。Solid tumors may also be resistant to PD-1/PD-L1 inhibitors (e.g., pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, Mippilimab-rwlc, camrelizumab, toripalimab, palolizumab, tislelizumab, batilizumab, dotalizumab, M7824, Any tumor that is resistant to treatment with badalizumab, saxanilumab, refulimab, BMS-986213 and terpolizumab). In some embodiments, the solid tumor is resistant to a PD-1/PD-L1 inhibitor as defined and described herein. In some embodiments, the solid tumor is characterized by intrinsic and/or acquired resistance to a PD-1/PD-L1 inhibitor as defined and described herein. In some embodiments, the solid tumor is a PD-1/PD-L1 positive solid tumor that is resistant to a PD-1/PD-L1 inhibitor. In some embodiments, the solid tumor is a PD-1/PD-L1 positive solid tumor characterized by intrinsic and/or acquired resistance to a PD-1/PD-L1 inhibitor. In some embodiments, the solid tumor is a KRAS-positive solid tumor that is resistant to a PD-1/PD-L1 inhibitor. In some embodiments, the solid tumor is a KRAS-positive solid tumor characterized by intrinsic and/or acquired resistance to a PD-1/PD-L1 inhibitor.

在一些實施例中，實體腫瘤係對選自由以下組成之群之PD-1/PD-L1抑制劑耐藥性：帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213及特泊利單抗。在一些實施例中，該實體腫瘤係對帕博利珠單抗耐藥性。在一些實施例中，該實體腫瘤係對納武單抗耐藥性。在一些實施例中，該實體腫瘤係對選自由以下組成之群之PD-1/PD-L1抑制劑耐藥性的PD-L1陽性實體腫瘤：帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213及特泊利單抗。在一些實施例中，該實體腫瘤係對帕博利珠單抗耐藥性之PD-L1陽性實體腫瘤。在一些實施例中，該實體腫瘤係對納武單抗耐藥性之PD-L1陽性實體腫瘤。In some embodiments, the solid tumor is resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab, duvalumab Rilumab, avelumab, cimepilimab-rwlc, camrelizumab, toripalimab, palolizumab, tislelizumab, batizumab monoclonal antibody, dotalizumab, M7824, spartalizumab, saxanilumab, refulimab, BMS-986213 and terpolizumab. In some embodiments, the solid tumor line is resistant to pembrolizumab. In some embodiments, the solid tumor is resistant to nivolumab. In some embodiments, the solid tumor is a PD-L1 positive solid tumor that is resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of: pembrolizumab, nivolumab, Tilizumab, durvalumab, avelumab, cimepilimab-rwlc, camrelizumab, toripalimab, palolizumab, tiramer Lizumab, batizumab, dotalizumab, M7824, spartalizumab, saxalizumab, refulimab, BMS-986213 and terpolizumab. In some embodiments, the solid tumor is a PD-L1 positive solid tumor that is resistant to pembrolizumab. In some embodiments, the solid tumor is a PD-L1 positive solid tumor that is resistant to nivolumab.

在一些實施例中，實體腫瘤係對選自由以下組成之群之PD-1/PD-L1抑制劑耐藥性之KRAS陽性實體腫瘤：帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213及特泊利單抗。在一些實施例中，該實體腫瘤係對帕博利珠單抗耐藥性之KRAS陽性實體腫瘤。在一些實施例中，該實體腫瘤係對納武單抗耐藥性之KRAS陽性實體腫瘤。In some embodiments, the solid tumor is a KRAS-positive solid tumor that is resistant to a PD-1/PD-L1 inhibitor selected from the group consisting of: pembrolizumab, nivolumab, atezolizumab monoclonal antibody, durvalumab, avelumab, cimepilimab-rwlc, camrelizumab, toripalimab, palolizumab, tislelizumab anti-, batizumab, dotalizumab, M7824, spartalizumab, saxalizumab, refulimab, BMS-986213 and terpolizumab. In some embodiments, the solid tumor is a KRAS-positive solid tumor that is resistant to pembrolizumab. In some embodiments, the solid tumor is a KRAS-positive solid tumor that is resistant to nivolumab.

在實施例之任一者中，沒有護理標準或治療性療法可用於治療癌症或實體腫瘤，如本文描述。 III-3：    個體 In any of the embodiments, no standard of care or therapeutic therapy may be used to treat cancer or solid tumors, as described herein. III-3: Individual

在一些實施例中，個體係人類。在一些實施例中，該個體係處於執業醫生(諸如醫師)之護理下。在一些實施例中，該個體已診斷患有癌症。在一些實施例中，該個體已復發。在一些實施例中，該個體先前已進入改善期。在一些實施例中，該個體先前已經受、正經受或將經受單一療法療程之治療。在一些實施例中，該個體先前已經受、正經受或將經受放射療法。在一些實施例中，該個體先前已經受、正經受或將經受免疫療法。在一些實施例中，該個體先前已經受、正經受或將經受化學療法。在一些實施例中，該個體先前已經受、正經受或將經受基於鉑之化學療法。在一些實施例中，該個體先前已經受、正經受或將經受包括投與KRAS調節劑(例如，KRAS抑制劑)之治療方案。在一些實施例中，該個體先前已經受、正經受或將經受包括投與抗PD-1/PD-L1抑制劑(例如，查核點抑制劑)之治療方案。In some embodiments, the individual system is human. In some embodiments, the system is under the care of a medical practitioner, such as a physician. In some embodiments, the individual has been diagnosed with cancer. In some embodiments, the individual has relapsed. In some embodiments, the individual has previously entered a period of improvement. In some embodiments, the subject has previously been, is undergoing, or will undergo a course of monotherapy. In some embodiments, the individual has previously undergone, is undergoing, or will undergo radiation therapy. In some embodiments, the subject has previously undergone, is undergoing, or will undergo immunotherapy. In some embodiments, the individual has previously undergone, is undergoing, or will undergo chemotherapy. In some embodiments, the subject has previously undergone, is undergoing, or will undergo platinum-based chemotherapy. In some embodiments, the subject has previously undergone, is undergoing, or will undergo a treatment regimen that includes administration of a KRAS modulator (eg, a KRAS inhibitor). In some embodiments, the subject has previously undergone, is undergoing, or will undergo a treatment regimen that includes administration of an anti-PD-1/PD-L1 inhibitor (eg, a checkpoint inhibitor).

個體可患有藉由分子診斷使用適當之經臨床驗證及/或FDA批准之測試評估具有KRAS突變(例如，排除KRAS Q61X)且無可用之護理標準或治療性療法之晚期(例如，原發性或復發性)實體腫瘤。在一些實施例中，在進行如本文描述之治療前至少一(1)年內藉由分子診斷使用適當之經臨床驗證及/或FDA批准之測試評估，該個體具有KRAS中之突變(排除KRAS Q61X)。Individuals may have advanced disease (e.g., primary disease) with KRAS mutations (e.g., excluding KRAS Q61X) as assessed by molecular diagnostics using appropriate clinically validated and/or FDA-approved tests for which standard of care or therapeutic therapies are not available. or recurrent) solid tumors. In some embodiments, the individual has a mutation in KRAS (excluding KRAS) as assessed by molecular diagnostics using an appropriate clinically validated and/or FDA-approved test at least one (1) year prior to treatment as described herein. Q61X).

在一些實施例中，個體具有KRAS中之突變，限制條件為該突變不為KRAS Q61X (例如，該個體患有特徵在於除KRAS Q61X外之KRAS中之突變之癌症)。在一些實施例中，KRAS蛋白包括G12C、G12D、G12S、G12V、G12R、G12A、G13D、G13A、G13C、G13R、G13S及/或G13V突變(例如，該個體患有特徵在於KRAS中之G12C、G12D、G12S、G12V、G12R、G12A、G13D、G13A、G13C、G13R、G13S及/或G13V突變之癌症)。在一些實施例中，個體具有KRAS突變，包括KRAS G12C突變。在一些實施例中，個體具有KRAS突變，包括KRAS G12A突變、KRAS G12D突變、KRAS G12F突變、KRAS G12I突變、KRAS G12L突變、KRAS G12R突變、KRAS G12S突變、KRAS G12V突變、KRAS G12Y突變、KRAS G13D突變，或其組合(例如，該個體患有特徵在於KRAS突變，包括KRAS G12C突變、KRAS G12A突變、KRAS G12D突變、KRAS G12F突變、KRAS G12I突變、KRAS G12L突變、KRAS G12R突變、KRAS G12S突變、KRAS G12V突變、KRAS G12Y突變、KRAS G13D突變，或其組合之癌症)。In some embodiments, the individual has a mutation in KRAS, with the proviso that the mutation is not KRAS Q61X (e.g., the individual has a cancer characterized by a mutation in KRAS other than KRAS Q61X). In some embodiments, the KRAS protein includes G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, and/or G13V mutations (e.g., the individual has the G12C, G12D characteristic of KRAS , G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S and/or G13V mutations). In some embodiments, the individual has a KRAS mutation, including the KRAS G12C mutation. In some embodiments, the individual has a KRAS mutation, including KRAS G12A mutation, KRAS G12D mutation, KRAS G12F mutation, KRAS G12I mutation, KRAS G12L mutation, KRAS G12R mutation, KRAS G12S mutation, KRAS G12V mutation, KRAS G12Y mutation, KRAS G13D mutation, or a combination thereof (e.g., the individual has a disease characterized by a KRAS mutation, including the KRAS G12C mutation, the KRAS G12A mutation, the KRAS G12D mutation, the KRAS G12F mutation, the KRAS G12I mutation, the KRAS G12L mutation, the KRAS G12R mutation, the KRAS G12S mutation, Cancers with KRAS G12V mutations, KRAS G12Y mutations, KRAS G13D mutations, or combinations thereof).

在一些實施例中，個體患有在先前至少一線全身性療法(包括基於鉑之雙藥化學療法及/或抗PD-1/PD-L1療法)進行中或之後進展或復發之實體腫瘤，該等療法中之各者係以單一療法給與或其等中之兩者係以組合療法給與。In some embodiments, the individual has a solid tumor that has progressed or relapsed during or after at least one prior line of systemic therapy, including platinum-based doublet chemotherapy and/or anti-PD-1/PD-L1 therapy, the Each of the therapies is administered as a single therapy or two of the therapies are administered as a combination therapy.

在一些實施例中，個體患有在抗PD-1/PD-L1療法之治療期間或在終止抗PD-1/PD-L1療法後約90天內進展或復發之實體腫瘤。In some embodiments, the individual has a solid tumor that progresses or relapses during treatment with anti-PD-1/PD-L1 therapy or within about 90 days of discontinuation of anti-PD-1/PD-L1 therapy.

在一些實施例中，個體患有根據實體腫瘤之反應評估標準(RECIST)之可量測疾病。In some embodiments, the subject has measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST).

在一些實施例中，在開始使用式(I)或式(10b)化合物與PD-1/PD-L1抑制劑之組合之治療前，在至少約四(4)週或介入臨床研究中所使用之藥劑之五(5)個半衰期內，以較短者為準，個體先前未參與該介入臨床研究。In some embodiments, at least about four (4) weeks before initiating treatment with a compound of Formula (I) or Formula (10b) in combination with a PD-1/PD-L1 inhibitor or during an interventional clinical study Within five (5) half-lives of the agent, whichever is shorter, the individual has not previously participated in the interventional clinical study.

在一些實施例中，個體先前未接受放射療法或質子療法，包括在開始使用式(I)或式(10b)化合物與PD-1/PD-L1抑制劑之組合之治療前，i)在約一(1)週之週期內，用於緩和之有限放射場，或ii)在約四(4)週之週期內，對超過約30%之骨髓放射或廣泛之放射場。In some embodiments, the subject has not previously received radiation therapy or proton therapy, including before initiating treatment with a combination of a compound of Formula (I) or Formula (10b) and a PD-1/PD-L1 inhibitor, i) within about A limited radiation field for palliation over a period of one (1) week, or ii) radiation to more than approximately 30% of the bone marrow or an extensive radiation field over a period of approximately four (4) weeks.

在一些實施例中，在開始使用式(I)或式(10b)化合物與PD-1/PD-L1抑制劑之組合之治療前，在約14天或五(5)個半衰期內，以較長者為準，個體尚未服用或未正在服用a) CYP3A4之強效或中度誘導劑或抑制劑及/或P-gp誘導劑或抑制劑中之一或多者(包括草藥補充劑或含有葡萄柚汁、楊桃或塞維利亞橙之食品)；及/或在開始使用該式(I)或式(10b)化合物與該PD-1/PD-L1抑制劑之組合之治療前約7天之週期內，個體尚未服用或未正在服用b)為P-gp、乳癌耐藥蛋白(BCRP)、多藥及毒素外排轉運蛋白(MATE)1及/或MATE2-K運輸蛋白之已知受質的藥物。In some embodiments, prior to initiating treatment with a combination of a compound of Formula (I) or Formula (10b) and a PD-1/PD-L1 inhibitor, the drug is administered for about 14 days or five (5) half-lives. The older person shall prevail, the individual has not taken or is not taking a) one or more of the strong or moderate inducers or inhibitors of CYP3A4 and/or P-gp inducers or inhibitors (including herbal supplements or drugs containing grape grapefruit juice, star fruit or Seville orange food); and/or about 7 days before starting treatment with the combination of the compound of formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor During the cycle, the individual has not taken or is not taking b) is a known receptor of P-gp, breast cancer resistance protein (BCRP), multidrug and toxin efflux transporter (MATE) 1 and/or MATE2-K transporter quality medicine.

在一些實施例中，個體沒有器官功能不足，包括充足之血液學、腎、肝及凝血功能，如下文定義： 血液學a. 白細胞計數＜2,000/µL； b. 絕對中性粒細胞計數＜1,500/µL； c. 血小板＜100,000/µL；及 d. 血紅蛋白＜9 g/dL及不輸血≤2週或促紅細胞生成刺激劑(例如，Epo，普羅克裡特(Procrit)) ≤6週。 腎d. 血清肌酐＞ 1.5 × ULN，除非肌酐清除率≥ 40 mL/min (使用科克羅夫特-高爾特(Cockcroft-Gault)公式量測或計算) 肝e. 若由研究者證實，已診斷病患患有吉伯特(Gilbert)症候群或溶血性貧血，則血清總膽紅素≥1.5×體制正常值上限(ULN)或≥3.0×體制ULN；及 f. 天冬胺酸胺基轉移酶/血清麩胺酸草乙酸轉胺酶(AST/SGOT)及/或丙胺酸胺基轉移酶/血清麩胺酸丙酮酸轉胺酶(ALT/SGPT) ＞2.5×ULN。 凝血g. 除非病患正接受抗凝療法，否則國際標準化比值(INR)或凝血酶原時間(PT) ＞1.5×ULN且只要PT或活化部分凝血活酶時間(aPTT)係於抗凝劑之預期使用之治療範圍內；及 h. 除非病患正接受抗凝療法，否則活化部分凝血活酶時間＞1.5×ULN且只要PT或aPTT係於抗凝劑之預期使用之治療範圍內。 In some embodiments, the subject does not have organ insufficiency, including adequate hematologic, renal, hepatic, and coagulation function, as defined below: Hematology a. White blood cell count <2,000/µL; b. Absolute neutrophil count <1,500 /µL; c. Platelets <100,000/µL; and d. Hemoglobin <9 g/dL and no blood transfusion for ≤2 weeks or erythropoiesis-stimulating agents (e.g., Epo, Procrit) ≤6 weeks. Kidney d. Serum creatinine > 1.5 × ULN unless creatinine clearance ≥ 40 mL/min (measured or calculated using the Cockcroft-Gault formula) Liver e. If confirmed by the investigator, If the patient has been diagnosed with Gilbert syndrome or hemolytic anemia, the serum total bilirubin is ≥1.5×systemic upper limit of normal (ULN) or ≥3.0×systemic ULN; and f. Aspartate aminotransfer Enzyme/serum glutamic acid oxalacetic acid transaminase (AST/SGOT) and/or alanine aminotransferase/serum glutamic acid pyruvate aminotransferase (ALT/SGPT) >2.5×ULN. Coagulationg . Unless the patient is receiving anticoagulant therapy, the international normalized ratio (INR) or prothrombin time (PT) is >1.5×ULN and as long as the PT or activated partial thromboplastin time (aPTT) is associated with the anticoagulant Within the therapeutic range of intended use; and h. Unless the patient is receiving anticoagulant therapy, the activated partial thromboplastin time is >1.5×ULN and as long as the PT or aPTT is within the therapeutic range of intended use of the anticoagulant.

在一些實施例中，個體未患有具有可量測病毒載量之活動性B型肝炎感染、C型肝炎感染或人類免疫缺乏病毒(HIV)感染。In some embodiments, the subject does not have an active hepatitis B infection, hepatitis C infection, or human immunodeficiency virus (HIV) infection with a measurable viral load.

在一些實施例中，個體尚未患有危及生命之疾病、醫療狀況、活動性不受控制之感染或器官系統功能障礙(例如，腹水、凝血障礙或腦病)。In some embodiments, the subject does not yet suffer from a life-threatening disease, medical condition, active uncontrolled infection, or organ system dysfunction (eg, ascites, coagulopathy, or encephalopathy).

在一些實施例中，個體尚未患有一或多種心臟相關之疾病或結果： a)於開始治療前最近6個月內，有重大心血管疾病史(例如，腦血管意外、心肌梗死或不穩定型心絞痛)； b)臨床顯著之心臟病，包括紐約心臟協會II級或更高級別之心力衰竭； c)於開始治療前的前12個月內，有左心室射出分率(LVEF) ＜50%之病史； d)靜息校正QT間期(QTc) ＞470毫秒，使用提供之ECG機器，從三個心電圖(ECG)中作為平均值導出；及/或 e)靜息ECG之節律、傳導或形態之任何臨床顯著異常(例如，三度心傳導阻滯、莫式II型心傳導阻滯、室性心律失常、不受控制之心房纖顫)。 In some embodiments, the subject does not yet suffer from one or more heart-related diseases or outcomes: a) Have a history of major cardiovascular disease (for example, cerebrovascular accident, myocardial infarction or unstable angina) within the last 6 months before starting treatment; b) Clinically significant heart disease, including New York Heart Association class II or higher heart failure; c) Have a history of left ventricular ejection fraction (LVEF) <50% within the first 12 months before starting treatment; d) Resting corrected QT interval (QTc) >470 msec, derived as the average of three electrocardiograms (ECG) using the provided ECG machine; and/or e) Any clinically significant abnormality in the rhythm, conduction, or morphology of the resting ECG (e.g., third-degree heart block, Mohs type II heart block, ventricular arrhythmias, uncontrolled atrial fibrillation).

在一些實施例中，個體在過去3年內尚未診斷患有另外侵入性惡性腫瘤，限制條件為該另外侵入性惡性腫瘤不為經治癒性治療之非黑色素瘤皮膚癌、淺表性尿路上皮癌、原位子宮頸癌，或在使用式(I)或式(10b)化合物與PD-1/PD-L1抑制劑之組合之治療過程中預期無需治療復發之任何其他經治癒性治療之惡性腫瘤。In some embodiments, the individual has not been diagnosed with another invasive malignancy within the past 3 years, with the proviso that the additional invasive malignancy is not curatively treated non-melanoma skin cancer, superficial urothelial carcinoma carcinoma, cervical cancer in situ, or any other curatively treated malignancy in which recurrence without treatment is expected during treatment with a compound of formula (I) or a compound of formula (10b) in combination with a PD-1/PD-L1 inhibitor. Tumor.

在一些實施例中，個體不患有一或多個來自非腦腫瘤之未經治療之腦轉移。In some embodiments, the subject does not have one or more untreated brain metastases from non-brain tumors.

在一些實施例中，在開始使用式(I)或式(10b)化合物與PD-1/PD-L1抑制劑之組合之治療(例如，第1週期，第1天)前至少4週內已切除腦轉移或已接受放射療法之個體係合格的，限制條件為該個體在開始該治療前滿足所有下列標準：a)與CNS治療相關之殘餘神經系統症狀等級≤2；b)若適用，則在第1週期第1天前至少2週，以≤ 10 mg每日強體松(或當量)之穩定或減少劑量；及c)於第1週期第1天前4週內之隨訪磁振造影(MRI)顯示未出現新病變。In some embodiments, at least 4 weeks prior to initiating treatment (e.g., Cycle 1, Day 1) with a compound of Formula (I) or Formula (10b) in combination with a PD-1/PD-L1 inhibitor Individuals who have had brain metastases resected or who have received radiation therapy are eligible if they meet all of the following criteria before initiating such treatment: a) Residual neurological symptoms grade ≤ 2 related to CNS treatment; b) If applicable, then Stable or reduced dose of ≤ 10 mg daily prednisone (or equivalent) for at least 2 weeks before Day 1 of Cycle 1; and c) Follow-up MRI within 4 weeks before Day 1 of Cycle 1 (MRI) showed no new lesions.

在一些實施例中，個體在加入使用式(I)或式(10b)化合物與PD-1/PD-L1抑制劑之組合之治療前4週內尚未經受大手術，限制條件為該手術或程序不為周邊***之中心導管線放置、胸腔穿刺術、腔液穿刺術、生檢或膿腫引流術。In some embodiments, the subject has not undergone major surgery within 4 weeks prior to joining treatment with a compound of Formula (I) or Formula (10b) in combination with a PD-1/PD-L1 inhibitor, provided that such surgery or procedure Not for peripherally inserted central line placement, thoracentesis, hydrocentesis, biopsies, or abscess drainage.

在一些實施例中，個體沒有對PD-1/PD-L1抑制劑或式(I)或式(10b)化合物、該PD-1/PD-L1抑制劑或該式(I)或式(10b)化合物之活性或非活性賦形劑或具有與該PD-1/PD-L1抑制劑或該式(I)或式(10b)化合物類似之化學結構或類別之藥物(取決於該個體可接受之組合類型)之超敏反應史。In some embodiments, the subject has no response to a PD-1/PD-L1 inhibitor or a compound of Formula (I) or Formula (10b), the PD-1/PD-L1 inhibitor, or the Formula (I) or Formula (10b) ) active or inactive excipients of the compound or drugs having a similar chemical structure or class to the PD-1/PD-L1 inhibitor or the compound of formula (I) or formula (10b) (depending on the individual's acceptable A history of hypersensitivity reactions (combined types).

在一些實施例中，個體不具有BRAF V600X、PTPN11 (SHP2)及/或KRAS Q61X中之一或多個另外活化突變。在一些實施例中，該個體未患有攜載BRAF V600X、PTPN11 (SHP2)及/或KRAS Q61X中之一或多個另外活化突變之腫瘤。In some embodiments, the individual does not have one or more additional activating mutations in BRAF V600X, PTPN11 (SHP2), and/or KRAS Q61X. In some embodiments, the individual does not have a tumor harboring one or more additional activating mutations in BRAF V600X, PTPN11 (SHP2), and/or KRAS Q61X.

在一些實施例中，個體先前未經PTPN11抑制劑(例如，SHP2抑制劑)治療，限制條件為該PTPN11抑制劑不為式(I)或式(10b)化合物。在一些實施例中，該個體先前未經使用選自由以下組成之群之PTPN11抑制劑治療：TNO-155、RMC-4630、RLY-1971、JAB-3068、JAB-3312、PF-07284892及ERAS601。在一些實施例中，該個體先前未經該式(I)或式(10b)化合物治療。在一些實施例中，該個體先前已經SHP2抑制劑治療，包括以下中之任一者：TNO-155、RMC-4630、RLY-1971、JAB-3068、JAB-3312、PF-07284892、ERAS601及該式(I)或式(10b)化合物。In some embodiments, the subject has not been previously treated with a PTPN11 inhibitor (eg, a SHP2 inhibitor), with the proviso that the PTPN11 inhibitor is not a compound of Formula (I) or Formula (10b). In some embodiments, the subject has not been previously treated with a PTPN11 inhibitor selected from the group consisting of: TNO-155, RMC-4630, RLY-1971, JAB-3068, JAB-3312, PF-07284892, and ERAS601. In some embodiments, the subject has not been previously treated with the compound of Formula (I) or Formula (10b). In some embodiments, the subject has been previously treated with a SHP2 inhibitor, including any of the following: TNO-155, RMC-4630, RLY-1971, JAB-3068, JAB-3312, PF-07284892, ERAS601, and the Compounds of formula (I) or formula (10b).

在一些實施例中，個體尚未患有胃腸道疾病(例如，胃切除術後、短腸症候群、不受控制之克羅恩氏(Crohn’s)病、乳糜瀉伴絨毛萎縮或慢性胃炎)，其可妨礙式(I)或式(10b)化合物之吸收。In some embodiments, the individual does not already have gastrointestinal disease (eg, post-gastrectomy, short bowel syndrome, uncontrolled Crohn's disease, celiac disease with villous atrophy, or chronic gastritis), which may Prevent the absorption of compounds of formula (I) or formula (10b).

在一些實施例中，個體未進行透析。In some embodiments, the subject is not on dialysis.

在一些實施例中，個體沒有同種異體骨髓移植史。In some embodiments, the subject has no history of allogeneic bone marrow transplantation.

在一些實施例中，個體在開始使用抗PD-1/PD-L1藥劑之治療前120天內尚未經歷疾病進展(PD) (例如，原發性難治性)。In some embodiments, the subject has not experienced disease progression (PD) (eg, primary refractory) within 120 days prior to initiating treatment with an anti-PD-1/PD-L1 agent.

在一些實施例中，個體尚未經歷認為與先前抗PD-1/PD-L1治療相關之≥ 3級毒性，其需終止療法。In some embodiments, the subject has not experienced grade ≥ 3 toxicities considered to be related to prior anti-PD-1/PD-L1 therapy, requiring discontinuation of therapy.

在一些實施例中，個體未患有已知或疑似自體免疫疾病，限制條件為該自體免疫疾病不為1型糖尿病、僅需激素替代之低甲狀腺功能症、無需全身性治療之皮膚病(例如，白癜風、牛皮廯或脫髮)，或預期在缺乏外部誘發因素之情況下不再現之病症。In some embodiments, the individual does not have a known or suspected autoimmune disease, with the proviso that the autoimmune disease is not type 1 diabetes, hypothyroidism requiring hormone replacement, or a skin disease that does not require systemic treatment. (e.g., vitiligo, psoriasis, or alopecia), or a condition that is not expected to reappear in the absence of external triggers.

在一些實施例中，個體在開始治療(例如，第1週期，第1天)前14天內未患有需使用皮質類固醇(＞10 mg強體松當量)或其他免疫抑制藥物之全身性治療之病症。在一些實施例中，當個體不為主動自體免疫疾病時，容許該個體服用吸入或局部類固醇，及＞10 mg強體松當量的腎上腺替代類固醇。In some embodiments, the individual has not had systemic therapy requiring the use of corticosteroids (>10 mg prednisone equivalent) or other immunosuppressive drugs within 14 days prior to initiating treatment (e.g., Cycle 1, Day 1) disease. In some embodiments, when an individual does not have an active autoimmune disease, the individual is allowed to take inhaled or topical steroids, and >10 mg prednisone equivalent of adrenal replacement steroids.

在一些實施例中，個體在開始治療前30天內尚未接受活/減毒疫苗。In some embodiments, the individual has not received a live/attenuated vaccine within 30 days prior to initiating treatment.

實例2中描述用於可從使用式(I)或式(10b)化合物與納武單抗之組合之治療中獲益之個體，諸如參與SHP2抑制劑化合物(10b)與PD-1/PD-L1抑制劑之組合之臨床研究之個體之其他納入及排除標準。Example 2 is described for use in individuals who may benefit from treatment with a compound of formula (I) or formula (10b) in combination with nivolumab, such as those involving a SHP2 inhibitor compound (10b) with PD-1/PD- Other inclusion and exclusion criteria for individuals in clinical studies of combinations of L1 inhibitors.

在一些實施例中，個體滿足如實例2中描述之1)至10)之所有納入標準。在一些實施例中，該個體滿足如實例2中描述之1)至10)之所有納入標準，限制條件為該個體不滿足如實例2中描述之1)至22)之排除標準中之任一者。 III-4：    治療週期及劑量調整 In some embodiments, the individual meets all inclusion criteria 1) through 10) as described in Example 2. In some embodiments, the individual meets all inclusion criteria 1) to 10) as described in Example 2, with the proviso that the individual does not meet any of the exclusion criteria 1) to 22) as described in Example 2 By. III-4: Treatment cycle and dose adjustment

使用式(I)或式(10b)化合物與KRAS G12C抑制劑之組合之治療可包括一或多個治療週期(例如，至少1、2、3或更多個治療週期)。在一些實施例中，該治療包括一或多個治療週期(例如，至少1、2、3或更多個治療週期)。在一些實施例中，該治療包括至少2、3或更多個治療週期。在一些實施例中，該治療包括2至3個治療週期。在一些實施例中，該治療包括3個治療週期。在一些實施例中，該治療包括多於3個治療週期。Treatment with a combination of a compound of Formula (I) or Formula (10b) and a KRAS G12C inhibitor can comprise one or more treatment cycles (eg, at least 1, 2, 3 or more treatment cycles). In some embodiments, the treatment includes one or more treatment cycles (eg, at least 1, 2, 3, or more treatment cycles). In some embodiments, the treatment includes at least 2, 3 or more treatment cycles. In some embodiments, the treatment includes 2 to 3 treatment cycles. In some embodiments, the treatment includes 3 treatment cycles. In some embodiments, the treatment includes more than 3 treatment cycles.

在一些實施例中，一或多個治療週期中之各者具有約28天之持續時間；及式(I)或式(10b)化合物係每天投與。在一些實施例中，一或多個治療週期中之各者具有約28天之持續時間；及PD-1/PD-L1抑制劑係每1、2、3、4、5或6週，諸如每3週或每6週投與。在一些實施例中，一或多個治療週期中之各者具有約28天之持續時間；該式(I)或式(10b)化合物係每天投與；及該PD-1/PD-L1抑制劑每1、2、3、4、5或6週，諸如每3週或每6週投與。In some embodiments, each of the one or more treatment cycles has a duration of about 28 days; and the compound of Formula (I) or Formula (10b) is administered daily. In some embodiments, each of the one or more treatment cycles has a duration of about 28 days; and the PD-1/PD-L1 inhibitor is every 1, 2, 3, 4, 5, or 6 weeks, such as Give every 3 weeks or every 6 weeks. In some embodiments, each of the one or more treatment cycles has a duration of about 28 days; the compound of Formula (I) or Formula (10b) is administered daily; and the PD-1/PD-L1 inhibition The doses are administered every 1, 2, 3, 4, 5 or 6 weeks, such as every 3 weeks or every 6 weeks.

治療包括劑量遞增期，在此期間，在先前治療週期後，可調整(例如，劑量遞增或遞減)或保留式(I)或式(10b)化合物之劑量。劑量調整可至少部分基於安全性評估(例如，劑量限制毒性(DLT)評估)。在一些實施例中，該式(I)或式(10b)化合物之投與包括一或多個劑量遞增、劑量保留或劑量遞減，其等中之各者係藉由劑量限制毒性(DLT)評估確定。在一些實施例中，該式(I)或式(10b)化合物之投與包括一或多個劑量遞增、劑量保留或劑量遞減，其等中之各者係藉由劑量限制毒性(DLT)評估確定，如實例2及圖3中描述。Treatment includes a dose escalation period during which the dose of a compound of Formula (I) or Formula (10b) may be adjusted (eg, dose escalated or tapered) or maintained after a previous treatment cycle. Dose adjustments may be based at least in part on safety assessments (eg, dose-limiting toxicity (DLT) assessments). In some embodiments, administration of the compound of Formula (I) or Formula (10b) includes one or more dose escalations, dose sparing, or dose reductions, each of which is assessed by dose-limiting toxicity (DLT) determine. In some embodiments, administration of the compound of Formula (I) or Formula (10b) includes one or more dose escalations, dose sparing, or dose reductions, each of which is assessed by dose-limiting toxicity (DLT) Determine as described in Example 2 and Figure 3.

在一些實施例中，當藉由DLT評估確定劑量限制毒性(DLT)率係小於(例如)約19.7%時，式(I)或式(10b)化合物之投與包括先前治療週期後之劑量遞增。在一些實施例中，當藉由DLT評估確定劑量限制毒性(DLT)率係小於(例如)約19.7%時，該式(I)或式(10b)化合物之投與包括第一治療週期後第二治療週期中之劑量遞增。在一些實施例中，當藉由DLT評估確定劑量限制毒性(DLT)率係小於(例如)約19.7%時，該式(I)或式(10b)化合物之投與包括第二治療週期後第三治療週期中之劑量遞增。In some embodiments, when the dose-limiting toxicity (DLT) rate is less than, for example, about 19.7%, as determined by DLT assessment, administration of a compound of Formula (I) or Formula (10b) includes dose escalation following a previous treatment cycle . In some embodiments, when the dose-limiting toxicity (DLT) rate is less than, for example, about 19.7% as determined by DLT assessment, administration of the compound of Formula (I) or Formula (10b) includes a second treatment cycle after the first treatment cycle. Dose escalation in two treatment cycles. In some embodiments, when the dose-limiting toxicity (DLT) rate is less than, for example, about 19.7% as determined by DLT assessment, administration of the compound of Formula (I) or Formula (10b) includes the second treatment cycle after the second treatment cycle. Dose escalation over three treatment cycles.

在一些實施例中，當藉由DLT評估確定劑量限制毒性係大於(例如)約29.8%時，式(I)或式(10b)化合物之投與包括先前治療週期後之劑量遞減。在一些實施例中，當藉由DLT評估確定劑量限制毒性率係大於(例如)約29.8%時，該式(I)或式(10b)化合物之投與包括第一治療週期後第二治療週期中之劑量保留。在一些實施例中，當藉由DLT評估確定劑量限制毒性率係大於(例如)約29.8%時，該式(I)或式(10b)化合物之投與包括第二治療週期後第三治療週期中之劑量保留。In some embodiments, administration of a compound of Formula (I) or Formula (10b) includes dose tapering after a previous treatment cycle when it is determined by DLT assessment that the dose-limiting toxicity is greater than, for example, about 29.8%. In some embodiments, when the dose-limiting toxicity rate is greater than, for example, about 29.8% as determined by DLT assessment, administration of the compound of Formula (I) or Formula (10b) includes a first treatment cycle followed by a second treatment cycle The dose is reserved. In some embodiments, when the dose-limiting toxicity rate is greater than, for example, about 29.8% as determined by DLT assessment, administration of the compound of Formula (I) or Formula (10b) includes a third treatment cycle after the second treatment cycle The dose is reserved.

在一些實施例中，當藉由DLT評估確定劑量限制毒性率係於約21.9%至約29.8%之範圍內時，式(I)或式(10b)化合物之投與包括先前治療週期後之劑量保留。在一些實施例中，當藉由DLT評估確定劑量限制毒性率係於約21.9%至約29.8%之範圍內時，該式(I)或式(10b)化合物之投與包括第一治療週期後第二治療週期中之劑量保留。在一些實施例中，當藉由DLT評估確定劑量限制毒性率係於約21.9%至約29.8%之範圍內時，該式(I)或式(10b)化合物之投與包括第二治療週期後第三治療週期中之劑量保留。In some embodiments, when the dose-limiting toxicity rate is determined to be in the range of about 21.9% to about 29.8% by DLT assessment, administration of the compound of Formula (I) or Formula (10b) includes the dose after the previous treatment cycle reserve. In some embodiments, when the dose-limiting toxicity rate is determined by DLT assessment to be in the range of about 21.9% to about 29.8%, the administration of the compound of Formula (I) or Formula (10b) includes after the first treatment cycle Dose retention during the second treatment cycle. In some embodiments, when the dose-limiting toxicity rate is determined by DLT assessment to be in the range of about 21.9% to about 29.8%, the administration of the compound of Formula (I) or Formula (10b) includes after the second treatment cycle Dose retention in the third treatment cycle.

在劑量遞增期後，治療進一步包括劑量擴大/優化期。在該劑量擴大/優化期之一些實施例中，式(I)或式(10b)化合物係以在該劑量遞增期內確定之劑量方案(例如，劑量方案1或劑量方案2)投與。After the dose escalation period, treatment further includes a dose expansion/optimization period. In some embodiments of the dose expansion/optimization period, the compound of Formula (I) or Formula (10b) is administered in a dosage regimen determined during the dose escalation period (eg, Dose Schedule 1 or Dose Schedule 2).

在一些實施例中，在劑量擴大/優化期內，式(I)或式(10b)化合物之投與視需要包括一或多次劑量調整。在一些實施例中，在該劑量擴大/優化期內，該式(I)或式(10b)化合物之投與視需要包括一或多次劑量調整；及該一或多次劑量調整係根據安全審查委員會(SRC)之安全性評估確定。In some embodiments, administration of a compound of Formula (I) or Formula (10b) optionally includes one or more dose adjustments during a dose expansion/optimization period. In some embodiments, during the dose expansion/optimization period, administration of the compound of Formula (I) or Formula (10b) optionally includes one or more dose adjustments; and the one or more dose adjustments are based on safety Safety assessment by the Review Committee (SRC).

在如本文描述之實施例之任一者中，未調整以總每日劑量之PD-1/PD-L1抑制劑(例如，在治療期間不容許任何劑量遞增及/或遞減)。In any of the embodiments as described herein, the total daily dose of the PD-1/PD-L1 inhibitor is not adjusted (eg, no dose escalation and/or deletion is allowed during treatment).

在一些實施例中，式(I)或式(10b)化合物及/或PD-1/PD-L1抑制劑之給藥調整、延遲及停用係進一步基於實例2之標準。 III-5：    治療有效量/投與 In some embodiments, dosing adjustments, delays, and discontinuation of compounds of Formula (I) or Formula (10b) and/or PD-1/PD-L1 inhibitors are further based on the criteria of Example 2. III-5: Therapeutically effective dose/administration

式(I)或式(10b)化合物及PD-1/PD-L1抑制劑可以聯合治療有效量或以協同有效量提供，或其等中之各者可以比當各單獨使用時低之劑量使用。在一些實施例中，該式(I)或式(10b)化合物及該PD-1/PD-L1抑制劑係以聯合治療有效量提供。在一些實施例中，該式(I)或式(10b)化合物及該PD-1/PD-L1抑制劑係以協同有效量提供。在一些實施例中，該式(I)或式(10b)化合物及該PD-1/PD-L1抑制劑所使用之各劑量低於分別單獨使用時之劑量。The compound of Formula (I) or Formula (10b) and the PD-1/PD-L1 inhibitor can be combined in a therapeutically effective amount or provided in a synergistically effective amount, or each of them can be used at a lower dose than when each is used alone. . In some embodiments, the compound of Formula (I) or Formula (10b) and the PD-1/PD-L1 inhibitor are provided in a combined therapeutically effective amount. In some embodiments, the compound of Formula (I) or Formula (10b) and the PD-1/PD-L1 inhibitor are provided in a synergistically effective amount. In some embodiments, the compound of Formula (I) or Formula (10b) and the PD-1/PD-L1 inhibitor are each used at a dose that is lower than when used individually.

式(I)或式(10b)化合物及PD-1/PD-L1抑制劑可同時或依序投與。在一些實施例中，該式(I)或式(10b)化合物及該PD-1/PD-L1抑制劑係同時投與。在一些實施例中，該式(I)或式(10b)化合物及該PD-1/PD-L1抑制劑係以包括該式(I)或式(10b)化合物及該PD-1/PD-L1抑制劑之醫藥組合物投與。在一些實施例中，該式(I)或式(10b)化合物及該KRAS G12C抑制劑係依序投與。在一些實施例中，該式(I)或式(10b)化合物係在投與該PD-1/PD-L1抑制劑之前投與。在一些實施例中，該式(I)或式(10b)化合物係在投與該PD-1/PD-L1抑制劑之後投與。The compound of Formula (I) or Formula (10b) and the PD-1/PD-L1 inhibitor can be administered simultaneously or sequentially. In some embodiments, the compound of Formula (I) or Formula (10b) and the PD-1/PD-L1 inhibitor are administered simultaneously. In some embodiments, the compound of formula (I) or formula (10b) and the PD-1/PD-L1 inhibitor include the compound of formula (I) or formula (10b) and the PD-1/PD- Administration of pharmaceutical compositions of L1 inhibitors. In some embodiments, the compound of Formula (I) or Formula (10b) and the KRAS G12C inhibitor are administered sequentially. In some embodiments, the compound of Formula (I) or Formula (10b) is administered prior to administration of the PD-1/PD-L1 inhibitor. In some embodiments, the compound of Formula (I) or Formula (10b) is administered after administration of the PD-1/PD-L1 inhibitor.

在無鹽且無水之基礎上，式(I)或式(10b)化合物之治療有效量可為不多於約2000 mg之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該式(I)或式(10b)化合物之治療有效量係不多於約2000 mg之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約10 mg至約2000 mg、約50 mg至約2000 mg、約80 mg至約2000 mg、約80 mg至約1000 mg、約80 mg至約700 mg、約80 mg至約550 mg、約80 mg至約400 mg、約80 mg至約250 mg或約80 mg至約150 mg該式(I)或式(10b)化合物之總每日劑量，或於其中之任何有用範圍。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約80 mg至約700 mg、約80 mg至約550 mg、約80 mg至約400 mg、約80 mg至約250 mg或約80 mg至約150 mg該式(I)或式(10b)化合物之總每日劑量，或於其中之任何有用範圍。The therapeutically effective amount of a compound of Formula (I) or Formula (10b) may be a total daily dose of no more than about 2000 mg on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount of the compound of Formula (I) or Formula (10b) is a total daily dose of no more than about 2000 mg on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is about 10 mg to about 2000 mg, about 50 mg to about 2000 mg, about 80 mg to about 2000 mg, about 80 mg to about 1000 mg on a salt-free and anhydrous basis. mg, about 80 mg to about 700 mg, about 80 mg to about 550 mg, about 80 mg to about 400 mg, about 80 mg to about 250 mg or about 80 mg to about 150 mg of formula (I) or formula (10b ) the total daily dose of a compound, or any useful range therein. In some embodiments, the therapeutically effective amount is about 80 mg to about 700 mg, about 80 mg to about 550 mg, about 80 mg to about 400 mg, about 80 mg to about 250 mg on a salt-free and anhydrous basis. mg or a total daily dose of about 80 mg to about 150 mg of the compound of formula (I) or formula (10b), or any useful range therein.

在一些實施例中，在無鹽且無水之基礎上，式(I)或式(10b)化合物之治療有效量係約100 mg至約2000 mg、約150 mg至約1000 mg、約250 mg至約1000 mg、約400 mg至約1000 mg、約250 mg至約700 mg、約250 mg至約550 mg、約250 mg至約400 mg、約400 mg至約550 mg或約550 mg至約700 mg之總每日劑量，或於其中之任何有用範圍。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約250 mg至約400 mg、約400 mg至約550 mg或約550 mg至約700 mg該式(I)或式(10b)化合物之總每日劑量，或於其中之任何有用範圍。In some embodiments, the therapeutically effective amount of a compound of Formula (I) or Formula (10b) is about 100 mg to about 2000 mg, about 150 mg to about 1000 mg, about 250 mg to about 1000 mg, on a salt-free and anhydrous basis. About 1000 mg, about 400 mg to about 1000 mg, about 250 mg to about 700 mg, about 250 mg to about 550 mg, about 250 mg to about 400 mg, about 400 mg to about 550 mg, or about 550 mg to about 700 mg total daily dose, or any useful range therein. In some embodiments, the therapeutically effective amount is about 250 mg to about 400 mg, about 400 mg to about 550 mg, or about 550 mg to about 700 mg of Formula (I) or Formula (I) on a salt-free and anhydrous basis. (10b) The total daily dose of the compound, or any useful range therein.

在無鹽且無水之基礎上，式(10b)化合物之治療有效量可為不多於約2000 mg之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係不多於約2000 mg之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約10 mg至約2000 mg、約50 mg至約2000 mg、約80 mg至約2000 mg、約80 mg至約1000 mg、約80 mg至約700 mg、約80 mg至約550 mg、約80 mg至約400 mg、約80 mg至約250 mg或約80 mg至約150 mg該式(10b)化合物之總每日劑量，或於其中之任何有用範圍。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約80 mg至約700 mg、約80 mg至約550 mg、約80 mg至約400 mg、約80 mg至約250 mg或約80 mg至約150 mg該式(10b)化合物之總每日劑量，或於其中之任何有用範圍。The therapeutically effective amount of the compound of formula (10b) may be a total daily dose of no more than about 2000 mg on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of no more than about 2000 mg on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is about 10 mg to about 2000 mg, about 50 mg to about 2000 mg, about 80 mg to about 2000 mg, about 80 mg to about 1000 mg on a salt-free and anhydrous basis. mg, about 80 mg to about 700 mg, about 80 mg to about 550 mg, about 80 mg to about 400 mg, about 80 mg to about 250 mg or about 80 mg to about 150 mg of the compound of formula (10b) per daily dose, or any useful range therein. In some embodiments, the therapeutically effective amount is about 80 mg to about 700 mg, about 80 mg to about 550 mg, about 80 mg to about 400 mg, about 80 mg to about 250 mg on a salt-free and anhydrous basis. mg or a total daily dose of about 80 mg to about 150 mg of the compound of formula (10b), or any useful range therein.

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約100 mg至約2000 mg、約150 mg至約1000 mg、約250 mg至約1000 mg、約400 mg至約1000 mg、約250 mg至約700 mg、約250 mg至約550 mg、約250 mg至約400 mg、約400 mg至約550 mg或約550 mg至約700 mg該式(10b)化合物之總每日劑量，或於其中之任何有用範圍。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約250 mg至約400 mg、約400 mg至約550 mg或約550 mg至約700 mg之總每日劑量，或於其中之任何有用範圍。In some embodiments, the therapeutically effective amount of the compound of formula (10b) is about 100 mg to about 2000 mg, about 150 mg to about 1000 mg, about 250 mg to about 1000 mg, about 400 mg to about 1000 mg, about 250 mg to about 700 mg, about 250 mg to about 550 mg, about 250 mg to about 400 mg, about 400 mg to about 550 mg or about 550 mg to about 700 mg of the formula (10b ) the total daily dose of a compound, or any useful range therein. In some embodiments, the therapeutically effective amount is a total daily dose of about 250 mg to about 400 mg, about 400 mg to about 550 mg, or about 550 mg to about 700 mg on a salt-free and anhydrous basis, or within any useful scope.

在一些實施例中，在無鹽且無水之基礎上，治療有效量係約80 mg、約150 mg、約250 mg、約400 mg、約550 mg或約700 mg式(10b)化合物之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約80 mg該式(10b)化合物之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約150 mg該式(10b)化合物之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約250 mg該式(10b)化合物之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約400 mg該式(10b)化合物之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約550 mg該式(10b)化合物之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量係約700 mg該式(10b)化合物之總每日劑量。In some embodiments, the therapeutically effective amount is about 80 mg, about 150 mg, about 250 mg, about 400 mg, about 550 mg, or about 700 mg of the total compound of formula (10b) per day on a salt-free and anhydrous basis. Daily dose. In some embodiments, the therapeutically effective amount is a total daily dose of about 80 mg of the compound of formula (10b) on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dose of about 150 mg of the compound of formula (10b) on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dose of about 250 mg of the compound of formula (10b) on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dose of about 400 mg of the compound of formula (10b) on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dose of about 550 mg of the compound of formula (10b) on a salt-free and anhydrous basis. In some embodiments, the therapeutically effective amount is a total daily dose of about 700 mg of the compound of formula (10b) on a salt-free and anhydrous basis.

PD-1/PD-L1抑制劑之治療有效量可為根據產品之給藥資訊推薦之劑量。在一些實施例中，該PD-1/PD-L1抑制劑之總劑量為每1、2、3、4、5或6週約介於約10至2000 mg之間，諸如每4週480 mg、每6週400 mg或每3週200 mg (例如，針對帕博利珠單抗)、每3週350 mg (例如，針對西米普利單抗)、每3週1200 mg (例如，針對阿替利珠單抗)、每2週800 mg (例如，針對阿維魯單抗)或每3至4週1500 mg (例如，針對度伐利尤單抗)。在一些實施例中，該PD-1/PD-L1抑制劑未經調整(例如，在治療期間不允許任何劑量遞增及/或遞減)。The therapeutically effective dose of the PD-1/PD-L1 inhibitor may be the dose recommended based on the product's dosing information. In some embodiments, the total dose of the PD-1/PD-L1 inhibitor is between about 10 and 2000 mg every 1, 2, 3, 4, 5, or 6 weeks, such as 480 mg every 4 weeks , 400 mg every 6 weeks or 200 mg every 3 weeks (e.g., for pembrolizumab), 350 mg every 3 weeks (e.g., for cimeplimab), 1200 mg every 3 weeks (e.g., for acetaminophen tilizumab), 800 mg every 2 weeks (eg, for avelumab), or 1500 mg every 3 to 4 weeks (eg, for durvalumab). In some embodiments, the PD-1/PD-L1 inhibitor is unadjusted (eg, does not allow any dose escalation and/or reduction during treatment).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係不多於約2000 mg之總每日劑量；及PD-1/PD-L1抑制劑之治療有效量係介於每1、2、3、4、5或6週約10至2000 mg之間的總劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約100 mg至約2000 mg、約150 mg至約1000 mg、約250 mg至約1000 mg、約400 mg至約1000 mg、約250 mg至約700 mg、約250 mg至約550 mg、約250 mg至約400 mg、約400 mg至約550 mg或約550 mg至約700 mg之總每日劑量，或於其中之任何有用範圍；及該PD-1/PD-L1抑制劑之治療有效量係介於每1、2、3、4、5或6週約10至2000 mg之間的總劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg至約400 mg、約400 mg至約550 mg或約550 mg至約700 mg之總每日劑量，或於其中之任何有用範圍；及該PD-1/PD-L1抑制劑之治療有效量係介於每1、2、3、4、5或6週約10至2000 mg之間的總劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of no more than about 2000 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor is The amount is a total dose of between approximately 10 and 2000 mg every 1, 2, 3, 4, 5 or 6 weeks. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is about 100 mg to about 2000 mg, about 150 mg to about 1000 mg, about 250 mg to about 1000 mg, on a salt-free and anhydrous basis. About 400 mg to about 1000 mg, about 250 mg to about 700 mg, about 250 mg to about 550 mg, about 250 mg to about 400 mg, about 400 mg to about 550 mg or about 550 mg to about 700 mg in total per day daily dose, or any useful range therein; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor is between about 10 and 2000 mg every 1, 2, 3, 4, 5 or 6 weeks total dose. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is about 250 mg to about 400 mg, about 400 mg to about 550 mg, or about 550 mg to about 700 mg on a salt-free and anhydrous basis. The total daily dose, or any useful range therein; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor is between approximately 10 and 2000 mg every 1, 2, 3, 4, 5 or 6 weeks total dose.

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg該式(10b)化合物之總每日劑量；及PD-1/PD-L1抑制劑之治療有效量係介於每1、2、3、4、5或6週約10至2000 mg之間的總劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量可為約250 mg該式(10b)化合物之總每日劑量；及該PD-1/PD-L1抑制劑之治療有效量係介於每1、2、3、4、5或6週約10至2000 mg之間的總劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量可為約400 mg該式(10b)化合物之總每日劑量；及該PD-1/PD-L1抑制劑之治療有效量係介於每1、2、3、4、5或6週約10至2000 mg之間的總劑量。在一些實施例中，在無鹽且無水之基礎上，該治療有效量可為約550 mg該式(10b)化合物之總每日劑量；及該PD-1/PD-L1抑制劑之治療有效量係介於每1、2、3、4、5或6週約10至2000 mg之間的總劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is about 250 mg, about 400 mg, or about 550 mg of the total daily dose of the compound of Formula (10b) on a salt-free and anhydrous basis; and PD The therapeutically effective amount of a -1/PD-L1 inhibitor is a total dose of between approximately 10 and 2000 mg every 1, 2, 3, 4, 5 or 6 weeks. In some embodiments, the therapeutically effective amount can be a total daily dose of about 250 mg of the compound of formula (10b) on a salt-free and anhydrous basis; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor The amount is a total dose of between approximately 10 and 2000 mg every 1, 2, 3, 4, 5 or 6 weeks. In some embodiments, the therapeutically effective amount may be a total daily dose of about 400 mg of the compound of formula (10b) on a salt-free and anhydrous basis; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor The amount is a total dose of between approximately 10 and 2000 mg every 1, 2, 3, 4, 5 or 6 weeks. In some embodiments, the therapeutically effective amount may be a total daily dose of about 550 mg of the compound of formula (10b) on a salt-free and anhydrous basis; and the therapeutically effective amount of the PD-1/PD-L1 inhibitor The amount is a total dose of between approximately 10 and 2000 mg every 1, 2, 3, 4, 5 or 6 weeks.

如本文描述之PTPN11抑制劑及如本文描述之PD-1/PD-L1抑制劑可口服投與或如本文描述之PTPN11抑制劑可口服投與及如本文描述之PD-1/PD-L1抑制劑可靜脈內投與。在一些實施例中，該PTPN11抑制劑及/或該PD-1/PD-L1抑制劑係口服投與。在一些實施例中，該PTPN11抑制劑係口服投與及該PD-1/PD-L1抑制劑係靜脈內投與。A PTPN11 inhibitor as described herein and a PD-1/PD-L1 inhibitor as described herein may be administered orally or a PTPN11 inhibitor as described herein may be administered orally and PD-1/PD-L1 inhibition as described herein The agent may be administered intravenously. In some embodiments, the PTPN11 inhibitor and/or the PD-1/PD-L1 inhibitor is administered orally. In some embodiments, the PTPN11 inhibitor is administered orally and the PD-1/PD-L1 inhibitor is administered intravenously.

一般而言，式(I)或式(10b)化合物可口服投與。在一些實施例中，該式(I)或式(10b)化合物係口服投與。在一些實施例中，該式(10b)化合物係口服投與。在一些實施例中，呈錠劑調配物之該式(10b)化合物係口服投與。Generally, compounds of formula (I) or formula (10b) may be administered orally. In some embodiments, the compound of Formula (I) or Formula (10b) is administered orally. In some embodiments, the compound of formula (10b) is administered orally. In some embodiments, the compound of formula (10b) in a lozenge formulation is administered orally.

一般而言，PD-1/PD-L1抑制劑可靜脈內投與。在一些實施例中，該PD-1/PD-L1抑制劑係靜脈內投與。Generally, PD-1/PD-L1 inhibitors can be administered intravenously. In some embodiments, the PD-1/PD-L1 inhibitor is administered intravenously.

一般而言，式(I)或式(10b)化合物可每天一次或多次(例如，2、3、4或更多次)投與。在一些實施例中，該式(I)或式(10b)化合物係每天一次、兩次、三次或四次投與。在一些實施例中，該式(10b)化合物係每天一次、兩次、三次或四次投與。在一些實施例中，該式(10b)化合物係每天投與一次。在一些實施例中，該式(10b)化合物係每天兩次投與。Generally speaking, a compound of Formula (I) or Formula (10b) may be administered one or more times (eg, 2, 3, 4 or more times) per day. In some embodiments, the compound of Formula (I) or Formula (10b) is administered once, twice, three times, or four times per day. In some embodiments, the compound of formula (10b) is administered once, twice, three times, or four times per day. In some embodiments, the compound of formula (10b) is administered once daily. In some embodiments, the compound of formula (10b) is administered twice daily.

一般而言，PD-1/PD-L1抑制劑可每1、2、3、4、5或6週投與一次或兩次。在一些實施例中，該PD-1/PD-L1抑制劑係每1、2、3、4、5或6週投與一次。Generally, PD-1/PD-L1 inhibitors may be administered once or twice every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments, the PD-1/PD-L1 inhibitor is administered every 1, 2, 3, 4, 5, or 6 weeks.

在一些實施例中，式(I)或式(10b)化合物係口服投與；及PD-1/PD-L1抑制劑係靜脈內投與。在一些實施例中，該式(10b)化合物係每天投與一次；及該PD-1/PD-L1抑制劑係每1、2、3、4、5或6週投與一次。In some embodiments, the compound of Formula (I) or Formula (10b) is administered orally; and the PD-1/PD-L1 inhibitor is administered intravenously. In some embodiments, the compound of Formula (10b) is administered once daily; and the PD-1/PD-L1 inhibitor is administered every 1, 2, 3, 4, 5, or 6 weeks.

式(I)或式(10b)化合物可以一或多種劑量強度之口服劑型，其中在無鹽且無水之基礎上，該式(I)或式(10b)化合物係以至少約1 mg、5 mg、10 mg、20 mg、30 mg、50 mg、90 mg、100 mg、120 mg、180 mg、200 mg、300 mg、400 mg或500 mg之量存在。在一些實施例中，該口服劑型係以一或多種劑量強度之錠劑調配物。在該錠劑調配物之一些實施例中，在無鹽且無水之基礎上，該式(I)或式(10b)化合物係以1至1000 mg、1至750 mg、1至500 mg、1至250 mg、30至1000 mg、30至750 mg、30至500 mg、30至200 mg、30至180 mg、30至120 mg、30至90 mg、50至1000 mg、50至750 mg、50至500 mg、50至250 mg、100至1000 mg、100至750 mg、100至500 mg、100至250 mg、200至1000 mg、200至750 mg、200至500 mg、300至1000 mg、300至750 mg、300至500 mg、400至1000 mg、400至750 mg、500至1000 mg、500至750 mg、600至1000 mg、5至250 mg或5至100 mg之量存在於各錠劑中。在該錠劑調配物之一些實施例中，在無鹽且無水之基礎上，該式(I)或式(10b)化合物係以約5 mg、10 mg、30 mg、50 mg、100 mg、150 mg、200 mg、250 mg、300 mg、400 mg、500 mg、600 mg、700 mg、800 mg、900 mg或1000 mg之量存在於各錠劑中。在該錠劑調配物之一些實施例中，在無鹽且無水之基礎上，該式(I)或式(10b)化合物係以約30 mg、50 mg或100 mg之量存在於各錠劑中。The compound of formula (I) or formula (10b) can be in one or more oral dosage forms of dosage strengths, wherein the compound of formula (I) or formula (10b) is at least about 1 mg, 5 mg on a salt-free and anhydrous basis. , 10 mg, 20 mg, 30 mg, 50 mg, 90 mg, 100 mg, 120 mg, 180 mg, 200 mg, 300 mg, 400 mg or 500 mg. In some embodiments, the oral dosage form is formulated as a lozenge in one or more dosage strengths. In some embodiments of the tablet formulation, the compound of Formula (I) or Formula (10b) is 1 to 1000 mg, 1 to 750 mg, 1 to 500 mg, 1 to 250 mg, 30 to 1000 mg, 30 to 750 mg, 30 to 500 mg, 30 to 200 mg, 30 to 180 mg, 30 to 120 mg, 30 to 90 mg, 50 to 1000 mg, 50 to 750 mg, 50 to 500 mg, 50 to 250 mg, 100 to 1000 mg, 100 to 750 mg, 100 to 500 mg, 100 to 250 mg, 200 to 1000 mg, 200 to 750 mg, 200 to 500 mg, 300 to 1000 mg, 300 to an amount of 750 mg, 300 to 500 mg, 400 to 1000 mg, 400 to 750 mg, 500 to 1000 mg, 500 to 750 mg, 600 to 1000 mg, 5 to 250 mg or 5 to 100 mg present in each tablet middle. In some embodiments of the tablet formulation, the compound of Formula (I) or Formula (10b) is present at about 5 mg, 10 mg, 30 mg, 50 mg, 100 mg, on a salt-free and anhydrous basis. Each tablet is present in a quantity of 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg. In some embodiments of the tablet formulations, the compound of Formula (I) or Formula (10b) is present in each tablet in an amount of about 30 mg, 50 mg, or 100 mg on a salt-free and anhydrous basis. middle.

式(10b)化合物可以一或多種劑量強度之口服劑型，其中在無鹽且無水之基礎上，該式(10b)化合物係以至少約1 mg、5 mg、10 mg、20 mg、30 mg、50 mg、90 mg、100 mg、120 mg、180 mg、200 mg、300 mg、400 mg或500 mg之量存在。在一些實施例中，該口服劑型係以一或多種劑量強度之錠劑調配物。在該錠劑調配物之一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係以1至1000 mg、1至750 mg、1至500 mg、1至250 mg、30至1000 mg、30至750 mg、30至500 mg、30至200 mg、30至180 mg、30至120 mg、30至90 mg、50至1000 mg、50至750 mg、50至500 mg、50至250 mg、100至1000 mg、100至750 mg、100至500 mg、100至250 mg、200至1000 mg、200至750 mg、200至500 mg、300至1000 mg、300至750 mg、300至500 mg、400至1000 mg、400至750 mg、500至1000 mg、500至750 mg、600至1000 mg、5至250 mg或5至100 mg之量存在於各錠劑中。在該錠劑調配物之一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係以約5 mg、10 mg、30 mg、50 mg、100 mg、150 mg、200 mg、250 mg、300 mg、400 mg、500 mg、600 mg、700 mg、800 mg、900 mg或1000 mg之量存在於各錠劑中。在該錠劑調配物之一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係以約30 mg、50 mg或100 mg之量存在於各錠劑中。在該錠劑調配物之一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係以約30 mg之量存在於各錠劑中。在該錠劑調配物之一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係以約50 mg之量存在於各錠劑中。在該錠劑調配物之一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係以約100 mg之量存在於各錠劑中。The compound of formula (10b) can be in one or more oral dosage forms of dosage strengths, wherein the compound of formula (10b) is in the form of at least about 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, on a salt-free and anhydrous basis. Present in quantities of 50 mg, 90 mg, 100 mg, 120 mg, 180 mg, 200 mg, 300 mg, 400 mg or 500 mg. In some embodiments, the oral dosage form is formulated as a lozenge in one or more dosage strengths. In some embodiments of the tablet formulation, the compound of formula (10b) is 1 to 1000 mg, 1 to 750 mg, 1 to 500 mg, 1 to 250 mg, 30 mg on a salt-free and anhydrous basis. to 1000 mg, 30 to 750 mg, 30 to 500 mg, 30 to 200 mg, 30 to 180 mg, 30 to 120 mg, 30 to 90 mg, 50 to 1000 mg, 50 to 750 mg, 50 to 500 mg, 50 to 250 mg, 100 to 1000 mg, 100 to 750 mg, 100 to 500 mg, 100 to 250 mg, 200 to 1000 mg, 200 to 750 mg, 200 to 500 mg, 300 to 1000 mg, 300 to 750 mg, 300 is present in each tablet in an amount of up to 500 mg, 400 to 1000 mg, 400 to 750 mg, 500 to 1000 mg, 500 to 750 mg, 600 to 1000 mg, 5 to 250 mg or 5 to 100 mg. In some embodiments of the tablet formulation, the compound of formula (10b) is present at about 5 mg, 10 mg, 30 mg, 50 mg, 100 mg, 150 mg, 200 mg on a salt-free and anhydrous basis. , 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg present in each tablet. In some embodiments of the tablet formulations, the compound of formula (10b) is present in each tablet in an amount of about 30 mg, 50 mg, or 100 mg on a salt-free and anhydrous basis. In some embodiments of the tablet formulations, the compound of formula (10b) is present in each tablet in an amount of about 30 mg on a salt-free and anhydrous basis. In some embodiments of the tablet formulations, the compound of formula (10b) is present in each tablet in an amount of about 50 mg on a salt-free and anhydrous basis. In some embodiments of the tablet formulations, the compound of formula (10b) is present in each tablet in an amount of about 100 mg on a salt-free and anhydrous basis.

在一些實施例中，式(10b)化合物係每天投與一次以提供不多於約2000 mg該式(10b)化合物之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係每天投與一次以提供約100 mg至約2000 mg、約150 mg至約1000 mg、約250 mg至約1000 mg、約400 mg至約1000 mg、約250 mg至約700 mg、約250 mg至約550 mg、約250 mg至約400 mg、約400 mg至約550 mg或約550 mg至約700 mg該式(10b)化合物之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係每天投與一次以提供約250 mg至約400 mg、約400 mg至約550 mg或約550 mg至約700 mg該式(10b)化合物之總每日劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係每天投與一次以提供約250 mg、約400 mg、約550 mg該式(10b)化合物之總每日劑量。In some embodiments, the compound of Formula (10b) is administered once daily to provide a total daily dose of no more than about 2000 mg of the compound of Formula (10b). In some embodiments, the compound of formula (10b) is administered once daily to provide about 100 mg to about 2000 mg, about 150 mg to about 1000 mg, about 250 mg to about 1000 mg, on a salt-free and anhydrous basis. mg, about 400 mg to about 1000 mg, about 250 mg to about 700 mg, about 250 mg to about 550 mg, about 250 mg to about 400 mg, about 400 mg to about 550 mg, or about 550 mg to about 700 mg the Total daily dose of compound of formula (10b). In some embodiments, the compound of formula (10b) is administered once daily to provide about 250 mg to about 400 mg, about 400 mg to about 550 mg, or about 550 mg to about 700 mg on a salt-free and anhydrous basis. mg total daily dose of the compound of formula (10b). In some embodiments, the compound of formula (10b) is administered once daily to provide a total daily dose of about 250 mg, about 400 mg, about 550 mg of the compound of formula (10b) on a salt-free and anhydrous basis. .

在一些實施例中，式(10b)化合物係每天投與一次以提供不多於約2000 mg該式(10b)化合物之總每日劑量；及PD-1/PD-L1抑制劑係每1、2、3、4、5或6週投與一次以提供介於約10至2000 mg之間的總劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係每天投與一次以提供約100 mg至約2000 mg、約150 mg至約1000 mg、約250 mg至約1000 mg、約400 mg至約1000 mg、約250 mg至約700 mg、約250 mg至約550 mg、約250 mg至約400 mg、約400 mg至約550 mg或約550 mg至約700 mg該式(10b)化合物之總每日劑量；及該PD-1/PD-L1抑制劑係每1、2、3、4、5或6週投與一次以提供介於約10至2000 mg之間的總劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係每天投與一次以提供約250 mg至約400 mg、約400 mg至約550 mg或約550 mg至約700 mg該式(10b)化合物之總每日劑量；及該PD-1/PD-L1抑制劑係每四(4)週投與一次以提供介於約10至2000 mg之間的總劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物係每天投與一次以提供約250 mg、約400 mg、約550 mg該式(10b)化合物之總每日劑量；及該PD-1/PD-L1抑制劑係每1、2、3、4、5或6週投與一次以提供介於約10至2000 mg之間的總劑量。In some embodiments, the compound of Formula (10b) is administered once daily to provide a total daily dose of no more than about 2000 mg of the compound of Formula (10b); and the PD-1/PD-L1 inhibitor is administered once daily, Administer once every 2, 3, 4, 5 or 6 weeks to provide a total dose of between about 10 and 2000 mg. In some embodiments, the compound of formula (10b) is administered once daily to provide about 100 mg to about 2000 mg, about 150 mg to about 1000 mg, about 250 mg to about 1000 mg, on a salt-free and anhydrous basis. mg, about 400 mg to about 1000 mg, about 250 mg to about 700 mg, about 250 mg to about 550 mg, about 250 mg to about 400 mg, about 400 mg to about 550 mg, or about 550 mg to about 700 mg the The total daily dose of the compound of formula (10b); and the PD-1/PD-L1 inhibitor is administered every 1, 2, 3, 4, 5 or 6 weeks to provide between about 10 and 2000 mg total dose. In some embodiments, the compound of formula (10b) is administered once daily to provide about 250 mg to about 400 mg, about 400 mg to about 550 mg, or about 550 mg to about 700 mg on a salt-free and anhydrous basis. mg of the total daily dose of the compound of Formula (10b); and the PD-1/PD-L1 inhibitor is administered every four (4) weeks to provide a total daily dose of between about 10 and 2000 mg. In some embodiments, the compound of formula (10b) is administered once daily to provide a total daily dose of about 250 mg, about 400 mg, about 550 mg of the compound of formula (10b) on a salt-free and anhydrous basis. ; and the PD-1/PD-L1 inhibitor is administered every 1, 2, 3, 4, 5 or 6 weeks to provide a total dose of between about 10 and 2000 mg.

在一些實施例中，式(10b)化合物係在一或多個治療週期之各者期間每天投與一次，如本文描述。在一些實施例中，PD-1/PD-L1抑制劑係在一或多個治療週期之各者期間每1、2、3、4、5或6週投與一次，如本文描述。在一些實施例中，在一或多個治療週期之各者期間，該式(10b)化合物係每天投與一次及該PD-1/PD-L1抑制劑係每1、2、3、4、5或6週投與一次，如本文描述。In some embodiments, a compound of Formula (10b) is administered once daily during each of one or more treatment cycles, as described herein. In some embodiments, the PD-1/PD-L1 inhibitor is administered every 1, 2, 3, 4, 5, or 6 weeks during each of one or more treatment cycles, as described herein. In some embodiments, the compound of formula (10b) is administered once daily and the PD-1/PD-L1 inhibitor is administered every 1, 2, 3, 4, Administer once every 5 or 6 weeks as described herein.

一般而言，推薦在無食物之情況下(例如，禁食整夜後(最短8小時)，接著在服用劑量後禁食2小時)對個體投與式(10b)化合物。除該投與之前及之後一(1)小時外，容許該個體喝水及在該投與時給予該個體水(例如，240 mL)。在一些實施例中，在該投與之前至少約8小時及該投與之後至少約2小時，在無食物之情況下，對個體投與該式(10b)化合物。In general, it is recommended to administer a compound of formula (10b) to an individual without food (eg, after an overnight fast (minimum 8 hours), followed by a 2-hour fast following the dose). The individual is allowed to drink water and is given water (e.g., 240 mL) at the time of administration except one (1) hour before and after the administration. In some embodiments, the compound of Formula (10b) is administered to the subject without food at least about 8 hours before and at least about 2 hours after the administration.

在一些實施例中，PD-1/PD-L1抑制劑係在投與式(10b)化合物後約30分鐘內，每1、2、3、4、5或6週靜脈內投與一次。 III-6：    效用 In some embodiments, the PD-1/PD-L1 inhibitor is administered intravenously every 1, 2, 3, 4, 5, or 6 weeks within about 30 minutes of administration of the compound of Formula (10b). III-6: Utility

可進行PTPN抑制劑(例如，由式(10b)表示之化合物)與PD-1/PD-L1抑制劑之組合之臨床研究以評估該組合之安全性、耐受性及效用以減少或穩定個體之癌症(例如，包含實體腫瘤之癌症)。在一些實施例中，該等個體患有包括非小細胞肺癌(NSCLC)之實體腫瘤。在一些實施例中，該等個體患有非小細胞肺癌(NSCLC)。在一些實施例中，該等個體患有特徵在於KRAS突變之NSCLC。Clinical studies of a combination of a PTPN inhibitor (e.g., a compound represented by Formula (10b)) and a PD-1/PD-L1 inhibitor can be conducted to evaluate the safety, tolerability, and efficacy of the combination to reduce or stabilize an individual's of cancers (e.g., cancers including solid tumors). In some embodiments, the individuals have solid tumors including non-small cell lung cancer (NSCLC). In some embodiments, the individuals have non-small cell lung cancer (NSCLC). In some embodiments, the individuals have NSCLC characterized by KRAS mutations.

投與治療有效量之式(I)或式(10b)化合物與治療有效量之PD-1/PD-L1抑制劑之組合可減少或大體上消除個體之癌症或實體腫瘤。在一些實施例中，該治療有效量之式(I)或式(10b)與PD-1/PD-L1抑制劑之組合大體上消除該實體腫瘤。在一些實施例中，該治療有效量之式(I)或式(10b)與PD-1/PD-L1抑制劑之組合減小該實體腫瘤之體積至少約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%、約90%或更大。在一些實施例中，該治療有效量之式(I)或式(10b)與PD-1/PD-L1抑制劑之組合減小該實體腫瘤之體積約10%至約90%、約10%至約80%、約10%至約70%、約10%至約60%、約10%至約50%、約10%至約40%、約10%至約30%、約10%至約20%、約20%至約90%、約20%至約80%、約20%至約70%、約20%至約60%、約20%至約50%、約20%至約40%、約20%至約30%、約30%至約90%、約30%至約80%、約30%至約70%、約30%至約60%、約30%至約50%、約30%至約40%、約40%至約90%、約40%至約80%、約40%至約70%、約40%至約60%、約40%至約50%、約50%至約90%、約50%至約80%、約50%至約70%、約50%至約60%、約60%至約90%、約60%至約80%、約60%至約70%、約70%至約90%、約70%至約80%、約80%至約90%之尺寸，或於其中之任何範圍。在一些實施例中，該治療有效量之式(I)或式(10b)與PD-1/PD-L1抑制劑之組合減小該實體腫瘤之體積約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%或約90%。Administration of a therapeutically effective amount of a compound of Formula (I) or Formula (10b) in combination with a therapeutically effective amount of a PD-1/PD-L1 inhibitor can reduce or substantially eliminate cancer or solid tumors in an individual. In some embodiments, the therapeutically effective amount of Formula (I) or Formula (10b) in combination with a PD-1/PD-L1 inhibitor substantially eliminates the solid tumor. In some embodiments, the therapeutically effective amount of Formula (I) or Formula (10b) in combination with a PD-1/PD-L1 inhibitor reduces the volume of the solid tumor by at least about 10%, about 20%, about 30 %, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or greater. In some embodiments, the combination of the therapeutically effective amount of Formula (I) or Formula (10b) and a PD-1/PD-L1 inhibitor reduces the volume of the solid tumor by about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40% , about 20% to about 30%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 90%, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 90%, about 70% to about 80%, about 80% to about 90% of the size, or any range therein. In some embodiments, the therapeutically effective amount of Formula (I) or Formula (10b) in combination with a PD-1/PD-L1 inhibitor reduces the volume of the solid tumor by about 10%, about 20%, or about 30% , about 40%, about 50%, about 60%, about 70%, about 80% or about 90%.

投與治療有效量之式(I)或式(10b)化合物與治療有效量之PD-1/PD-L1抑制劑之組合可穩定個體之癌症或實體腫瘤。在一些實施例中，該治療有效量之式(I)或式(10b)與PD-1/PD-L1抑制劑之組合穩定該實體腫瘤。Administration of a therapeutically effective amount of a compound of Formula (I) or Formula (10b) in combination with a therapeutically effective amount of a PD-1/PD-L1 inhibitor can stabilize a cancer or solid tumor in an individual. In some embodiments, the therapeutically effective amount of a combination of Formula (I) or Formula (10b) and a PD-1/PD-L1 inhibitor stabilizes the solid tumor.

投與治療有效量之式(I)或式(10b)化合物與治療有效量之PD-1/PD-L1抑制劑之組合可於一定時間週期(例如，1至12個月)內維持個體之癌症或實體腫瘤之減小或穩定。在一些實施例中，用治療有效量之式(I)或式(10b)化合物與PD-1/PD-L1抑制劑之組合使該實體腫瘤減小或穩定至少約一個月之週期。在一些實施例中，用該治療有效量之式(I)或式(10b)化合物與PD-1/PD-L1抑制劑之組合使該實體腫瘤減小或穩定至少約2、3、4、5、6、7、8、9、10、11或12個月之週期。在一些實施例中，使該實體腫瘤減小或穩定約1至約12個月、約1至約6個月、約1至約3個月或約1至約2個月之週期。Administration of a therapeutically effective amount of a compound of Formula (I) or Formula (10b) in combination with a therapeutically effective amount of a PD-1/PD-L1 inhibitor can maintain an individual's immune function over a period of time (e.g., 1 to 12 months). Reduction or stabilization of cancer or solid tumors. In some embodiments, the solid tumor is reduced or stabilized with a therapeutically effective amount of a compound of Formula (I) or Formula (10b) in combination with a PD-1/PD-L1 inhibitor for at least about one month. In some embodiments, the combination of a therapeutically effective amount of a compound of Formula (I) or Formula (10b) and a PD-1/PD-L1 inhibitor reduces or stabilizes the solid tumor by at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 month cycles. In some embodiments, the solid tumor is reduced or stabilized for a period of about 1 to about 12 months, about 1 to about 6 months, about 1 to about 3 months, or about 1 to about 2 months.

在一些實施例中，藉由一或多種測試進一步評估個體以提供總體評估，包括血漿藥物動力學及/或藥效學概況。In some embodiments, individuals are further evaluated by one or more tests to provide an overall assessment, including plasma pharmacokinetic and/or pharmacodynamic profiles.

在一些實施例中，進一步評估個體的一或多種生物標誌物以確定該一或多種生物標誌物與抗腫瘤反應之相關性。 III-7：    實施例 In some embodiments, the subject is further evaluated for one or more biomarkers to determine the correlation of the one or more biomarkers with the anti-tumor response. III-7: Example

實施例1A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之帕博利珠單抗。 Example 1A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of pembrolizumab.

實施例1B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之帕博利珠單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 1B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of pembrolizumab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例2A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之阿替利珠單抗。 Example 2A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of atezolizumab.

實施例2B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之阿替利珠單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 2B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of atezolizumab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例3A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之度伐利尤單抗。 Example 3A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of durvalumab.

實施例3B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之度伐利尤單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 3B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of durvalumab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例4A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之阿維魯單抗。 Example 4A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of avelumab.

實施例4B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之阿維魯單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 4B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of avelumab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例5A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之西米普利單抗-rwlc。 Example 5A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of cimipilimab-rwlc.

實施例5B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之西米普利單抗-rwlc， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 5B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of cimipilimab-rwlc, wherein the individual has a KRAS mutation (eg, as described herein).

實施例6A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之卡瑞利珠單抗。 Example 6A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of camrelizumab.

實施例6B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之卡瑞利珠單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 6B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of camrelizumab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例7A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之特瑞普利單抗。 Example 7A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of toripalimab.

實施例7B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之特瑞普利單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 7B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of toripalimab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例8A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之帕洛利單抗。 Example 8A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of palolizumab.

實施例8B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之帕洛利單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 8B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of palolizumab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例9A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之替雷利珠單抗。 Example 9A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of tislelizumab.

實施例9B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之替雷利珠單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 9B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of tislelizumab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例10A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之巴替利單抗。 Example 10A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of batilimab.

實施例10B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之巴替利單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 10B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of batilimab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例11A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之多塔利單抗。 Example 11A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of dotalizumab.

實施例11B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之多塔利單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 11B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of dotalizumab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例12A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之M7824。 Example 12A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of M7824.

實施例12B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之M7824， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 12B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of M7824, wherein the individual has a KRAS mutation (eg, as described herein).

實施例13A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之斯巴達珠單抗。 Example 13A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of spartalizumab.

實施例13B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之斯巴達珠單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 13B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of spartalizumab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例14A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之薩善利單抗。 Example 14A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of saxanlimab.

實施例14B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之薩善利單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 14B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of saxanlimab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例15A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之瑞弗利單抗。 Example 15A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of reflimab.

實施例15B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之瑞弗利單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 15B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of reflimab, wherein the individual has a KRAS mutation (eg, as described herein).

實施例16A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之BMS-986213。 Example 16A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of BMS-986213.

實施例16B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之BMS-986213， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 16B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of BMS-986213, wherein the individual has a KRAS mutation (eg, as described herein).

實施例17A：本發明提供一種於個體中治療癌症之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物，或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之特泊利單抗。 Example 17A: The present invention provides a method of treating cancer in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof; and b) A therapeutically effective amount of terpolizumab.

實施例17B：本發明提供一種於個體中治療實體腫瘤(例如，如本文描述)之方法，該方法包括對有此需要之個體投與： a)治療有效量之由式(10b)表示之化合物， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合；及 b)治療有效量之特泊利單抗， 其中該個體具有KRAS突變(例如，如本文描述)。 Example 17B: The present invention provides a method of treating a solid tumor (e.g., as described herein) in an individual, the method comprising administering to an individual in need thereof: a) A therapeutically effective amount of a compound represented by formula (10b), or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof; and b) A therapeutically effective amount of terpolizumab, wherein the individual has a KRAS mutation (eg, as described herein).

參考實施例1A至17A及1B至17B中之任一者，式(10b)化合物係根據第III-1節：PTPN11抑制劑及/或PD-1/PD-L1抑制劑描述。在一些實施例中，該式(10b)化合物係如第III-1節：PTPN11抑制劑及/或PD-1/PD-L1抑制劑中描述之實施例之任一者。在一些實施例中，該式(10b)化合物係由下式表示： (10b)， 或其醫藥上可接受之鹽、立體異構體、構象異構體，或其組合。在一些實施例中，該式(10b)化合物具有6-((3S,4S)-4-胺基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-8-基)-3-(R a)-(2,3-二氯苯基)-2,5-二甲基-4(3H)-嘧啶酮之名稱。 With reference to any one of Examples 1A to 17A and 1B to 17B, the compound of formula (10b) is described according to Section III-1: PTPN11 inhibitors and/or PD-1/PD-L1 inhibitors. In some embodiments, the compound of formula (10b) is any of the embodiments described in Section III-1: PTPN11 inhibitors and/or PD-1/PD-L1 inhibitors. In some embodiments, the compound of formula (10b) is represented by the following formula: (10b), or a pharmaceutically acceptable salt, stereoisomer, conformational isomer, or combination thereof. In some embodiments, the compound of formula (10b) has 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl )-3-(R a )-(2,3-dichlorophenyl)-2,5-dimethyl-4(3H)-pyrimidinone.

參考實施例1A至17A及1B至17B中之任一者，癌症或實體腫瘤係根據第III-2節：癌症/實體腫瘤描述。在一些實施例中，該癌症或實體腫瘤係如第III-2節：癌症/實體腫瘤中描述之實施例之任一者。在一些實施例中，該癌症或實體腫瘤係結直腸癌(CRC)。在一些實施例中，該癌症或實體腫瘤係非小細胞肺癌(NSCLC)。With reference to any of Examples 1A to 17A and 1B to 17B, cancer or solid tumors are described in accordance with Section III-2: Cancer/Solid Tumors. In some embodiments, the cancer or solid tumor is any of the embodiments described in Section III-2: Cancer/Solid Tumor. In some embodiments, the cancer or solid tumor is colorectal cancer (CRC). In some embodiments, the cancer or solid tumor is non-small cell lung cancer (NSCLC).

參考實施例1A至17A及1B至17B中之任一者，個體係根據第III-3節：個體描述。在一些實施例中，該個體係如第III-3節：個體中描述之實施例之任一者。在一些實施例中，該個體具有KRAS中之突變，限制條件為該突變不為KRAS Q61X (例如，該個體患有特徵在於除KRAS Q61X外之KRAS中之突變的癌症或實體腫瘤)。With reference to any of Examples 1A to 17A and 1B to 17B, individual systems are described in accordance with Section III-3: Individuals. In some embodiments, the system is any of the embodiments described in Section III-3: Individuals. In some embodiments, the individual has a mutation in KRAS, with the proviso that the mutation is not KRAS Q61X (e.g., the individual has a cancer or solid tumor characterized by a mutation in KRAS other than KRAS Q61X).

參考實施例1A至17A及1B至17B中之任一者，治療週期及劑量調整係根據第III-4節：治療週期及劑量調整描述。在一些實施例中，治療有效量及/或投與係如第III-4節：治療週期及劑量調整中描述之實施例之任一者。Referring to any of Examples 1A to 17A and 1B to 17B, treatment cycles and dose adjustments are as described in Section III-4: Treatment Cycles and Dose Adjustments. In some embodiments, the therapeutically effective amount and/or administration is any of the embodiments described in Section III-4: Treatment Periods and Dose Adjustments.

參考實施例1A至17A及1B至17B中之任一者，治療有效量及/或投與係根據第III-5節：治療有效量/投與描述。在一些實施例中，該治療有效量及/或投與係如第III-5節：治療有效量/投與中描述之實施例之任一者。 帕博利珠單抗 Referring to any of Examples 1A to 17A and 1B to 17B, the therapeutically effective dose and/or administration is as described in Section III-5: Therapeutically Effective Dose/Administration. In some embodiments, the therapeutically effective dose and/or administration is any of the embodiments described in Section III-5: Therapeutically Effective Dose/Administration. pembrolizumab

參考實施例1A或1B，帕博利珠單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，帕博利珠單抗之治療有效量係以每三週(q3週) 200 mg或每六週(q6週) 400 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，帕博利珠單抗之治療有效量係以每三週200 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，帕博利珠單抗之治療有效量係以每六週400 mg藉由靜脈內(IV)投與之劑量。Referring to Example 1A or 1B, the therapeutically effective dose of pembrolizumab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of pembrolizumab is administered intravenously (IV) at a dose of 200 mg every three weeks (q3 weeks) or 400 mg every six weeks (q6 weeks). In some embodiments, the therapeutically effective amount of pembrolizumab is administered intravenously (IV) at a dose of 200 mg every three weeks. In some embodiments, the therapeutically effective amount of pembrolizumab is administered intravenously (IV) at a dose of 400 mg every six weeks.

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及帕博利珠單抗之治療有效量係以每三週(q3週) 200 mg或每六週(q6週) 400 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及帕博利珠單抗之治療有效量係以每三週(q3週) 200 mg或每六週(q6週) 400 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及帕博利珠單抗之治療有效量係以每三週(q3週) 200 mg或每六週(q6週) 400 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及帕博利珠單抗之治療有效量係以每三週(q3週) 200 mg或每六週(q6週) 400 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and treatment with pembrolizumab The effective dose is administered intravenously (IV) at 200 mg every three weeks (q3 weeks) or 400 mg every six weeks (q6 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of pembrolizumab is every three weeks. The dose is administered intravenously (IV) at 200 mg every q3 weeks or 400 mg every 6 weeks (q6 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of pembrolizumab is every three weeks. The dose is administered intravenously (IV) at 200 mg every q3 weeks or 400 mg every 6 weeks (q6 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of pembrolizumab is every three weeks. The dose is administered intravenously (IV) at 200 mg every q3 weeks or 400 mg every 6 weeks (q6 weeks).

以總每日劑量之式(10b)化合物之治療有效量；及以q3週劑量或q6週劑量之帕博利珠單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of pembrolizumab as a q3 weekly dose or a q6 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及帕博利珠單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and pembrolizumab is administered intravenously.

在一些實施例中，式(10b)化合物及帕博利珠單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及帕博利珠單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及帕博利珠單抗所使用之各劑量低於分別單獨使用時之劑量。 阿替利珠單抗 In some embodiments, the compound of formula (10b) and pembrolizumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and pembrolizumab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and pembrolizumab are each used at a dose that is lower than when used alone. atezolizumab

參考實施例2A或2B，阿替利珠單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，阿替利珠單抗之治療有效量係以每兩週(q2週) 840 mg、每三週(q3週) 1200 mg或每四週(q4週) 1680 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，阿替利珠單抗之治療有效量係以每兩週(q2週) 840 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，阿替利珠單抗之治療有效量係以每三週(q3週) 1200 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，阿替利珠單抗之治療有效量係以每四週(q4週) 1680 mg藉由靜脈內(IV)投與之劑量。Referring to Example 2A or 2B, the therapeutically effective dose of atezolizumab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of atezolizumab is administered intravenously at 840 mg every two weeks (q2 weeks), 1200 mg every three weeks (q3 weeks), or 1680 mg every four weeks (q4 weeks). (IV) Administer the dose. In some embodiments, the therapeutically effective amount of atezolizumab is administered intravenously (IV) at a dose of 840 mg every two weeks (q2 weeks). In some embodiments, the therapeutically effective amount of atezolizumab is administered intravenously (IV) at a dose of 1200 mg every three weeks (q3 weeks). In some embodiments, the therapeutically effective amount of atezolizumab is administered intravenously (IV) at a dose of 1680 mg every four weeks (q4 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及阿替利珠單抗之治療有效量係以每兩週(q2週) 840 mg、每三週(q3週) 1200 mg或每四週(q4週) 1680 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及阿替利珠單抗之治療有效量係以每兩週(q2週) 840 mg、每三週(q3週) 1200 mg或每四週(q4週) 1680 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及阿替利珠單抗之治療有效量係以每兩週(q2週) 840 mg、每三週(q3週) 1200 mg或每四週(q4週) 1680 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及阿替利珠單抗之治療有效量係以每兩週(q2週) 840 mg、每三週(q3週) 1200 mg或每四週(q4週) 1680 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and atezolizumab The therapeutically effective dose is administered intravenously (IV) at 840 mg every two weeks (q2 weeks), 1200 mg every three weeks (q3 weeks), or 1680 mg every four weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of atezolizumab is every two days. Doses are administered intravenously (IV) at 840 mg every q2 weeks, 1200 mg every 3 weeks (q3 weeks), or 1680 mg every 4 weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of atezolizumab is every two days. Doses are administered intravenously (IV) at 840 mg every q2 weeks, 1200 mg every 3 weeks (q3 weeks), or 1680 mg every 4 weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of atezolizumab is every two days. Doses are administered intravenously (IV) at 840 mg every q2 weeks, 1200 mg every 3 weeks (q3 weeks), or 1680 mg every 4 weeks (q4 weeks).

以總每日劑量之式(10b)化合物之治療有效量；及以q2週劑量、q3週劑量或q4週劑量之阿替利珠單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of atezolizumab as a q2 weekly dose, a q3 weekly dose, or a q4 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及阿替利珠單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and atezolizumab is administered intravenously.

在一些實施例中，式(10b)化合物及阿替利珠單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及阿替利珠單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及阿替利珠單抗所使用之各劑量低於分別單獨使用時之劑量。 度伐利尤單抗 In some embodiments, the compound of formula (10b) and atezolizumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and atezolizumab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and atezolizumab are each used at a dose that is lower than when used alone. durvalumab

參考實施例3A或3B，度伐利尤單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，度伐利尤單抗之治療有效量係以針對個體(體重＞ 30 kg)每三週(q3週)或每四週(q4週) 1500 mg藉由靜脈內(IV)投與之劑量。Referring to Example 3A or 3B, the therapeutically effective dose of durvalumab may be the recommended dose according to the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of durvalumab is administered intravenously (IV) at 1500 mg every three weeks (q3 weeks) or every four weeks (q4 weeks) to an individual (body weight >30 kg). with dose.

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及度伐利尤單抗之治療有效量係以針對個體(體重＞ 30 kg)每三週(q3週)或每四週(q4週) 1500 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及度伐利尤單抗之治療有效量係以針對個體(體重＞ 30 kg)每三週(q3週)或每四週(q4週) 1500 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及度伐利尤單抗之治療有效量係以針對個體(體重＞ 30 kg)每三週(q3週)或每四週(q4週) 1500 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及度伐利尤單抗之治療有效量係以針對個體(體重＞ 30 kg)每三週(q3週)或每四週(q4週) 1500 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and durvalumab The therapeutically effective dose is 1500 mg administered intravenously (IV) every three weeks (q3 weeks) or every four weeks (q4 weeks) to individuals (body weight > 30 kg). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of durvalumab is in an individual (Body weight > 30 kg) 1500 mg administered intravenously (IV) every three weeks (q3 weeks) or every four weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of durvalumab is in an individual (Body weight > 30 kg) 1500 mg administered intravenously (IV) every three weeks (q3 weeks) or every four weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of durvalumab is in an individual (Body weight > 30 kg) 1500 mg administered intravenously (IV) every three weeks (q3 weeks) or every four weeks (q4 weeks).

以總每日劑量之式(10b)化合物之治療有效量；及以q3週劑量或q4週劑量之度伐利尤單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of durvalumab as a q3 weekly dose or a q4 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及度伐利尤單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and durvalumab is administered intravenously.

在一些實施例中，式(10b)化合物及度伐利尤單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及度伐利尤單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及度伐利尤單抗所使用之各劑量低於分別單獨使用時之劑量。 阿維魯單抗 In some embodiments, the compound of formula (10b) and durvalumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and imrvalumab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and durvalumab are each used at a lower dosage than when used alone. avelumab

參考實施例4A或4B，阿維魯單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，阿維魯單抗之治療有效量係以每兩週(q2週) 800 mg藉由靜脈內(IV)投與之劑量。Referring to Example 4A or 4B, the therapeutically effective dose of avelumab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of avelumab is administered intravenously (IV) at a dose of 800 mg every two weeks (q2 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及阿維魯單抗之治療有效量係以每兩週(q2週) 800 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及阿維魯單抗之治療有效量係以每兩週(q2週) 800 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及阿維魯單抗之治療有效量係以每兩週(q2週) 800 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及阿維魯單抗之治療有效量係以每兩週(q2週) 800 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and treatment with avelumab The effective dose is administered intravenously (IV) at 800 mg every two weeks (q2 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of avelumab is every two weeks. (q2 weeks) 800 mg dose administered by intravenous (IV). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of avelumab is every two weeks. (q2 weeks) 800 mg dose administered by intravenous (IV). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of avelumab is every two weeks. (q2 weeks) 800 mg dose administered by intravenous (IV).

以總每日劑量之式(10b)化合物之治療有效量；及以每兩週一次劑量之阿維魯單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of avelumab as a biweekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及阿維魯單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and avelumab is administered intravenously.

在一些實施例中，式(10b)化合物及阿維魯單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及阿維魯單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及阿維魯單抗所使用之各劑量低於分別單獨使用時之劑量。 西米普利單抗-rwlc In some embodiments, the compound of formula (10b) and avelumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and avelumab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and avelumab are each used at a dose that is lower than when used alone. cimepilimab-rwlc

參考實施例5A或5B，阿維魯單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，西米普利單抗-rwlc之治療有效量係以每三週(q3週) 350 mg藉由靜脈內(IV)投與之劑量。Referring to Example 5A or 5B, the therapeutically effective dose of avelumab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of cimepilimab-rwlc is administered intravenously (IV) at a dose of 350 mg every three weeks (q3 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及西米普利單抗-rwlc之治療有效量係以每三週(q3週) 350 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及西米普利單抗-rwlc之治療有效量係以每三週(q3週) 350 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及西米普利單抗-rwlc之治療有效量係以每三週(q3週) 350 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及西米普利單抗-rwlc之治療有效量係以每三週(q3週) 350 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and cimepilimab- The therapeutically effective dose of rwlc is administered intravenously (IV) at a dose of 350 mg every three weeks (q3 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of cimepilimab-rwlc is A dose of 350 mg is administered intravenously (IV) every three weeks (q3 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of cimepilimab-rwlc is A dose of 350 mg is administered intravenously (IV) every three weeks (q3 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of cimepilimab-rwlc is A dose of 350 mg is administered intravenously (IV) every three weeks (q3 weeks).

以總每日劑量之式(10b)化合物之治療有效量；及以q3週劑量之西米普利單抗-rwlc之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of cimipilimab-rwlc as a q3 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及西米普利單抗-rwlc係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and cimepilimab-rwlc is administered intravenously.

在一些實施例中，式(10b)化合物及西米普利單抗-rwlc係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及西米普利單抗-rwlc係以協同有效量提供。在一些實施例中，該式(10b)化合物及西米普利單抗-rwlc所使用之各劑量低於分別單獨使用時之劑量。 卡瑞利珠單抗 In some embodiments, the compound of formula (10b) and cimepilimab-rwlc are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and cimepilimab-rwlc are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and cimepilimab-rwlc are each used at a lower dosage than when used alone. Camrelizumab

參考實施例6A或6B，卡瑞利珠單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，卡瑞利珠單抗之治療有效量係以每兩或三週(q2週或q3週)約60 mg至約400 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，卡瑞利珠單抗之治療有效量係以每兩週(q2週)約200 mg藉由靜脈內(IV)投與之劑量。Referring to Example 6A or 6B, the therapeutically effective dose of camrelizumab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of camrelizumab is administered intravenously (IV) at a dose of about 60 mg to about 400 mg every two or three weeks (q2 or q3 weeks). In some embodiments, the therapeutically effective amount of camrelizumab is administered intravenously (IV) at a dose of about 200 mg every two weeks (q2 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及卡瑞利珠單抗之治療有效量係以每兩或三週(q2週或q3週)約60 mg至約400 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及卡瑞利珠單抗之治療有效量係以每兩週(q2週)約200 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及卡瑞利珠單抗之治療有效量係以每兩週(q2週)約200 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及卡瑞利珠單抗之治療有效量係以每兩週(q2週)約200 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and camrelizumab is The therapeutically effective amount is administered intravenously (IV) at a dose of about 60 mg to about 400 mg every two or three weeks (q2 or q3 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of camrelizumab is every two days. The dose is administered intravenously (IV) at a dose of approximately 200 mg every q2 weeks. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of camrelizumab is every two days. The dose is administered intravenously (IV) at a dose of approximately 200 mg every q2 weeks. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of camrelizumab is every two days. The dose is administered intravenously (IV) at a dose of approximately 200 mg every q2 weeks.

以總每日劑量之式(10b)化合物之治療有效量；及以q2週或q3週劑量之卡瑞利珠單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of camrelizumab as a q2 or q3 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及卡瑞利珠單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and camrelizumab is administered intravenously.

在一些實施例中，式(10b)化合物及卡瑞利珠單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及卡瑞利珠單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及卡瑞利珠單抗所使用之各劑量低於分別單獨使用時之劑量。 特瑞普利單抗 In some embodiments, the compound of formula (10b) and camrelizumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and camrelizumab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and camrelizumab are each used at a dose that is lower than when used alone. Toripalimab

參考實施例7A或7B，特瑞普利單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，特瑞普利單抗之治療有效量係以每三週(q3週) 240 mg藉由靜脈內(IV)投與之劑量。Referring to Example 7A or 7B, the therapeutically effective dose of toripalimab may be the recommended dose according to the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of toripalimab is administered intravenously (IV) at a dose of 240 mg every three weeks (q3 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及特瑞普利單抗之治療有效量係以每三週(q3週) 240 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及特瑞普利單抗之治療有效量係以每三週(q3週) 240 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及特瑞普利單抗之治療有效量係以每三週(q3週) 240 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及特瑞普利單抗之治療有效量係以每三週(q3週) 240 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and toripalimab is The therapeutically effective dose is administered intravenously (IV) at a dose of 240 mg every three weeks (q3 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of toripalimab is every three days. The dose is 240 mg administered weekly (q3 weeks) by intravenous (IV). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of toripalimab is every three days. The dose is 240 mg administered weekly (q3 weeks) by intravenous (IV). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of toripalimab is every three days. The dose is 240 mg administered weekly (q3 weeks) by intravenous (IV).

以總每日劑量之式(10b)化合物之治療有效量；及以q3週劑量之特瑞普利單抗之治療有效量之可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of toripalimab as a q3 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及特瑞普利單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and toripalimab is administered intravenously.

在一些實施例中，式(10b)化合物及特瑞普利單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及特瑞普利單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及特瑞普利單抗所使用之各劑量低於分別單獨使用時之劑量。 帕洛利單抗 In some embodiments, the compound of formula (10b) and toripalimab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and toripalimab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and toripalimab are each used at a dose that is lower than when used alone. palolizumab

參考實施例8A或8B，帕洛利單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，帕洛利單抗之治療有效量係以每三週(q3週) 250 mg或每兩週(q2週) 1 mg/kg藉由靜脈內(IV)投與之劑量。Referring to Example 8A or 8B, the therapeutically effective dose of palolizumab may be the recommended dose according to the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of palolizumab is administered intravenously (IV) at a dose of 250 mg every three weeks (q3 weeks) or 1 mg/kg every two weeks (q2 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及帕洛利單抗之治療有效量係以每三週(q3週) 250 mg或每兩週(q2週) 1 mg/kg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及帕洛利單抗之治療有效量係以每三週(q3週) 250 mg或每兩週(q2週) 1 mg/kg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及帕洛利單抗之治療有效量係以每三週(q3週) 250 mg或每兩週(q2週) 1 mg/kg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及帕洛利單抗之治療有效量係以每三週(q3週) 250 mg或每兩週(q2週) 1 mg/kg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and treatment with palolizumab The effective dose is administered intravenously (IV) at 250 mg every three weeks (q3 weeks) or 1 mg/kg every two weeks (q2 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of palolizumab is every three weeks. Dosage administered by intravenous (IV) 250 mg every q3 weeks or 1 mg/kg every 2 weeks (q2 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of palolizumab is every three weeks. Dosage administered by intravenous (IV) 250 mg every q3 weeks or 1 mg/kg every 2 weeks (q2 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of palolizumab is every three weeks. Dosage administered by intravenous (IV) 250 mg every q3 weeks or 1 mg/kg every 2 weeks (q2 weeks).

以總每日劑量之式(10b)化合物之治療有效量；及以q2週或q3週劑量之帕洛利單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of palolizumab as a q2 or q3 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及帕洛利單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and palolizumab is administered intravenously.

在一些實施例中，式(10b)化合物及帕洛利單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及帕洛利單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及帕洛利單抗所使用之各劑量低於分別單獨使用時之劑量。 替雷利珠單抗 In some embodiments, the compound of formula (10b) and palolizumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and palolizumab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and palolizumab are each used at a dose that is lower than when used alone. Tislelizumab

參考實施例9A或9B，替雷利珠單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，替雷利珠單抗之治療有效量係以每三週(q3週) 200 mg藉由靜脈內(IV)投與之劑量。Referring to Example 9A or 9B, the therapeutically effective dose of tislelizumab may be the recommended dose according to the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of tislelizumab is administered intravenously (IV) at a dose of 200 mg every three weeks (q3 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及替雷利珠單抗之治療有效量係以每三週(q3週) 200 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及替雷利珠單抗之治療有效量係以每三週(q3週) 200 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及替雷利珠單抗之治療有效量係以每三週(q3週) 200 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及替雷利珠單抗之治療有效量係以每三週(q3週) 200 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and tislelizumab The therapeutically effective dose is administered intravenously (IV) at a dose of 200 mg every three weeks (q3 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of tislelizumab is every three days. Dosage of 200 mg administered weekly (q3 weeks) by intravenous (IV). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of tislelizumab is every three days. Dosage of 200 mg administered weekly (q3 weeks) by intravenous (IV). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of tislelizumab is every three days. Dosage of 200 mg administered weekly (q3 weeks) by intravenous (IV).

以總每日劑量之式(10b)化合物之治療有效量；及以q3週劑量之替雷利珠單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of tislelizumab as a q3 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及替雷利珠單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and tislelizumab is administered intravenously.

在一些實施例中，式(10b)化合物及替雷利珠單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及替雷利珠單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及替雷利珠單抗所使用之各劑量低於分別單獨使用時之劑量。 巴替利單抗 In some embodiments, the compound of formula (10b) and tislelizumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and tislelizumab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and tislelizumab are each used at a dose that is lower than when used alone. Battilizumab

參考實施例10A或10B，巴替利單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，巴替利單抗之治療有效量係以每三週(q3週) 300 mg或每兩週(q2週) 3 mg/kg藉由靜脈內(IV)投與之劑量。Referring to Example 10A or 10B, the therapeutically effective dose of batizumab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of batizumab is administered intravenously (IV) at a dose of 300 mg every three weeks (q3 weeks) or 3 mg/kg every two weeks (q2 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及巴替利單抗之治療有效量係以每三週(q3週) 300 mg或每兩週(q2週) 3 mg/kg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及巴替利單抗之治療有效量係以每三週(q3週) 300 mg或每兩週(q2週) 3 mg/kg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及巴替利單抗之治療有效量係以每三週(q3週) 300 mg或每兩週(q2週) 3 mg/kg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及巴替利單抗之治療有效量係以每三週(q3週) 300 mg或每兩週(q2週) 3 mg/kg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and treatment with batizumab The effective dose is administered intravenously (IV) at 300 mg every three weeks (q3 weeks) or 3 mg/kg every two weeks (q2 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of batilimab is every three weeks. The dose is administered intravenously (IV) at 300 mg (q3 weeks) or 3 mg/kg every 2 weeks (q2 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of batilimab is every three weeks. The dose is administered intravenously (IV) at 300 mg (q3 weeks) or 3 mg/kg every 2 weeks (q2 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of batilimab is every three weeks. The dose is administered intravenously (IV) at 300 mg (q3 weeks) or 3 mg/kg every 2 weeks (q2 weeks).

以總每日劑量之式(10b)化合物之治療有效量；及以q2週或q3週劑量之巴替利單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of batilizumab as a q2 or q3 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及巴替利單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and batizumab is administered intravenously.

在一些實施例中，式(10b)化合物及巴替利單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及巴替利單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及巴替利單抗所使用之各劑量低於分別單獨使用時之劑量。 多塔利單抗 In some embodiments, the compound of formula (10b) and batizumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and batilimab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and batilimab are each used at a dose that is lower than when used alone. dotalizumab

參考實施例11A或11B，多塔利單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，多塔利單抗之治療有效量係以每三週(q3週) 500 mg或每六週(q6週) 1000 mg藉由靜脈內(IV)投與之劑量。Referring to Example 11A or 11B, the therapeutically effective dose of dotilizumab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of dotilizumab is administered intravenously (IV) at a dose of 500 mg every three weeks (q3 weeks) or 1000 mg every six weeks (q6 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及多塔利單抗之治療有效量係以每三週(q3週) 500 mg或每六週(q6週) 1000 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及多塔利單抗之治療有效量係以每三週(q3週) 500 mg或每六週(q6週) 1000 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及多塔利單抗之治療有效量係以每三週(q3週) 500 mg或每六週(q6週) 1000 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及多塔利單抗之治療有效量係以每三週(q3週) 500 mg或每六週(q6週) 1000 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and treatment with dotaliumab The effective dose is administered intravenously (IV) as 500 mg every three weeks (q3 weeks) or 1000 mg every six weeks (q6 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of dotilizumab is every three weeks. The dose is administered intravenously (IV) at 500 mg every q3 weeks or 1000 mg every 6 weeks (q6 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of dotilizumab is every three weeks. The dose is administered intravenously (IV) at 500 mg every q3 weeks or 1000 mg every 6 weeks (q6 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of dotilizumab is every three weeks. The dose is administered intravenously (IV) at 500 mg every q3 weeks or 1000 mg every 6 weeks (q6 weeks).

以總每日劑量之式(10b)化合物之治療有效量；及以q3週或q6週劑量之多塔利單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of dotilizumab as a q3 or q6 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及多塔利單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and dotilizumab is administered intravenously.

在一些實施例中，式(10b)化合物及多塔利單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及多塔利單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及多塔利單抗所使用之各劑量低於分別單獨使用時之劑量。 斯巴達珠單抗 In some embodiments, the compound of formula (10b) and dotilizumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and dotalizumab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and dotilizumab are each used at a dose that is lower than when used alone. Spartalizumab

參考實施例13A或13B，斯巴達珠單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，斯巴達珠單抗之治療有效量係以每三週(q3週) 300 mg或每四週(q4週) 400 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，斯巴達珠單抗之治療有效量係以每四週(q4週) 400 mg藉由靜脈內(IV)投與之劑量。Referring to Example 13A or 13B, the therapeutically effective dose of spartalizumab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of spartalizumab is administered intravenously (IV) at a dose of 300 mg every three weeks (q3 weeks) or 400 mg every four weeks (q4 weeks). In some embodiments, the therapeutically effective amount of spartalizumab is administered intravenously (IV) at a dose of 400 mg every four weeks (q4 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及斯巴達珠單抗之治療有效量係以每三週(q3週) 300 mg或每四週(q4週) 400 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及斯巴達珠單抗之治療有效量係以每三週(q3週) 300 mg或每四週(q4週) 400 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及斯巴達珠單抗之治療有效量係以每三週(q3週) 300 mg或每四週(q4週) 400 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及斯巴達珠單抗之治療有效量係以每三週(q3週) 300 mg或每四週(q4週) 400 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and spartalizumab is The therapeutically effective dose is administered intravenously (IV) at 300 mg every three weeks (q3 weeks) or 400 mg every four weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of spartalizumab is every three days. The dose is administered intravenously (IV) at 300 mg every q3 weeks or 400 mg every 4 weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of spartalizumab is every three days. The dose is administered intravenously (IV) at 300 mg every q3 weeks or 400 mg every 4 weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of spartalizumab is every three days. The dose is administered intravenously (IV) at 300 mg every q3 weeks or 400 mg every 4 weeks (q4 weeks).

以總每日劑量之式(10b)化合物之治療有效量；及以q3週或q4週劑量之斯巴達珠單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of spartalizumab as a q3 or q4 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及斯巴達珠單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and spartalizumab is administered intravenously.

在一些實施例中，式(10b)化合物及斯巴達珠單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及斯巴達珠單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及斯巴達珠單抗所使用之各劑量低於分別單獨使用時之劑量。 薩善利單抗 In some embodiments, the compound of formula (10b) and spartalizumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and spartalizumab are provided in synergistically effective amounts. In some embodiments, the compound of formula (10b) and spartalizumab are each used at a dose that is lower than when used alone. saxanlimab

參考實施例14A或14B，薩善利單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，薩善利單抗之治療有效量係以每三週(q3週) 0.5 mg至10 mg/kg藉由靜脈內(IV)投與，或每四週(q4週) 300 mg藉由皮下(SC)投與之劑量。在一些實施例中，薩善利單抗之治療有效量係以每四週(q4週) 300 mg藉由皮下(SC)投與之劑量。Referring to Example 14A or 14B, the therapeutically effective dose of saxanilimab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of saxalimab is administered intravenously (IV) at 0.5 mg to 10 mg/kg every three weeks (q3 weeks), or 300 mg every four weeks (q4 weeks). Doses are administered subcutaneously (SC). In some embodiments, the therapeutically effective amount of saxalizumab is administered subcutaneously (SC) at a dose of 300 mg every four weeks (q4 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及薩善利單抗之治療有效量係以每三週(q3週) 0.5 mg至10 mg/kg藉由靜脈內(IV)投與，或每四週(q4週) 300 mg藉由皮下(SC)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及薩善利單抗之治療有效量係以每三週(q3週) 0.5 mg至10 mg/kg藉由靜脈內(IV)投與，或每四週(q4週) 300 mg藉由皮下(SC)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及薩善利單抗之治療有效量係以每三週(q3週) 0.5 mg至10 mg/kg藉由靜脈內(IV)投與，或每四週(q4週) 300 mg藉由皮下(SC)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及薩善利單抗之治療有效量係以每三週(q3週) 0.5 mg至10 mg/kg藉由靜脈內(IV)投與，或每四週(q4週) 300 mg藉由皮下(SC)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of saxanlimab is Doses are 0.5 mg to 10 mg/kg administered intravenously (IV) every three weeks (q3 weeks), or 300 mg administered subcutaneously (SC) every four weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of saxanlimab is administered every three weeks ( Doses of 0.5 mg to 10 mg/kg administered intravenously (IV) every four weeks (q4 weeks) or 300 mg administered subcutaneously (SC) every four weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of saxanlimab is administered every three weeks ( Doses of 0.5 mg to 10 mg/kg administered intravenously (IV) every four weeks (q4 weeks) or 300 mg administered subcutaneously (SC) every four weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of saxanlimab is administered every three weeks ( Doses of 0.5 mg to 10 mg/kg administered intravenously (IV) every four weeks (q4 weeks) or 300 mg administered subcutaneously (SC) every four weeks (q4 weeks).

以總每日劑量之式(10b)化合物之治療有效量；及以q3週或q4週劑量之薩善利單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of saxalimab as a q3 or q4 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及薩善利單抗係靜脈內投與。在一些實施例中，式(10b)化合物係口服投與；及薩善利單抗係皮下投與。In some embodiments, the compound of formula (10b) is administered orally; and saxanlimab is administered intravenously. In some embodiments, the compound of formula (10b) is administered orally; and saxanlimab is administered subcutaneously.

在一些實施例中，式(10b)化合物及薩善利單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及薩善利單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及薩善利單抗所使用之各劑量低於分別單獨使用時之劑量。 瑞弗利單抗 In some embodiments, the compound of formula (10b) and saxanlimab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and saxanilimab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and saxanilimab are each used at a dose that is lower than when used alone. Riflimab

參考實施例15A或15B，瑞弗利單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，瑞弗利單抗之治療有效量係以每四週(q4週) 500 mg藉由靜脈內(IV)投與之劑量。Referring to Example 15A or 15B, the therapeutically effective dose of reflimab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of reflimab is administered intravenously (IV) at a dose of 500 mg every four weeks (q4 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及瑞弗利單抗之治療有效量係以每四週(q4週) 500 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及瑞弗利單抗之治療有效量係以每四週(q4週) 500 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及瑞弗利單抗之治療有效量係以每四週(q4週) 500 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及瑞弗利單抗之治療有效量係以每四週(q4週) 500 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and treatment with reflimab The effective dose is administered intravenously (IV) at 500 mg every four weeks (q4 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of reflimab is every four weeks ( q4 weeks) 500 mg dose administered by intravenous (IV). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of reflimab is every four weeks ( q4 weeks) 500 mg dose administered by intravenous (IV). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of reflimab is every four weeks ( q4 weeks) 500 mg dose administered by intravenous (IV).

以總每日劑量之式(10b)化合物之治療有效量；及以q4週劑量之瑞弗利單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of reflimab as a q4 weekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及瑞弗利單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and reflimab is administered intravenously.

在一些實施例中，式(10b)化合物及瑞弗利單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及瑞弗利單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及瑞弗利單抗所使用之各劑量低於分別單獨使用時之劑量。 BMS-986213 In some embodiments, the compound of formula (10b) and reflimab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and reflimab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and reflimab are each used at a dose that is lower than when used alone. BMS-986213

參考實施例16A或16B，BMS-986213之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。Referring to Example 16A or 16B, the therapeutically effective dose of BMS-986213 may be the recommended dose based on the dosing information of the product when used alone.

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及BMS-986213之治療有效量係當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及BMS-986213之治療有效量係當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及BMS-986213之治療有效量係當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及BMS-986213之治療有效量係當單獨使用時根據產品之給藥資訊之推薦劑量。In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and a therapeutically effective amount of BMS-986213 Recommended dosage based on product dosing information when used alone. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of BMS-986213 is based on the product when used alone Dosage information for recommended dosages. In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of BMS-986213 is based on the product when used alone Dosage information for recommended dosages. In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of BMS-986213 is based on the product when used alone Dosage information for recommended dosages.

以總每日劑量之式(10b)化合物之治療有效量；及以推薦劑量之BMS-986213之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of BMS-986213 as a recommended dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及BMS-986213係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and BMS-986213 is administered intravenously.

在一些實施例中，式(10b)化合物及BMS-986213係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及BMS-986213係以協同有效量提供。在一些實施例中，該式(10b)化合物及BMS-986213所使用之各劑量低於分別單獨使用時之劑量。 特泊利單抗 In some embodiments, the compound of formula (10b) and BMS-986213 are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and BMS-986213 are provided in synergistically effective amounts. In some embodiments, the dosage of each compound of formula (10b) and BMS-986213 is lower than when used alone. Tepolizumab

參考實施例17A或17B，特泊利單抗之治療有效量可為當單獨使用時根據產品之給藥資訊之推薦劑量。在一些實施例中，特泊利單抗之治療有效量係以每兩週(q2週) 120 mg、240 mg、400或600 mg藉由靜脈內(IV)投與之劑量。Referring to Example 17A or 17B, the therapeutically effective dose of terpolizumab may be the recommended dose based on the dosing information of the product when used alone. In some embodiments, the therapeutically effective amount of terpolizumab is administered intravenously (IV) at a dose of 120 mg, 240 mg, 400 or 600 mg every two weeks (q2 weeks).

在一些實施例中，在無鹽且無水之基礎上，式(10b)化合物之治療有效量係約250 mg、約400 mg或約550 mg之總每日劑量；及特泊利單抗之治療有效量係以每兩週(q2週) 120 mg、240 mg、400或600 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約250 mg之總每日劑量；及特泊利單抗之治療有效量係以每兩週(q2週) 120 mg、240 mg、400或600 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約400 mg之總每日劑量；及特泊利單抗之治療有效量係以每兩週(q2週) 120 mg、240 mg、400或600 mg藉由靜脈內(IV)投與之劑量。在一些實施例中，在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約550 mg之總每日劑量；及特泊利單抗之治療有效量係以每兩週(q2週) 120 mg、240 mg、400或600 mg藉由靜脈內(IV)投與之劑量。In some embodiments, the therapeutically effective amount of the compound of Formula (10b) is a total daily dose of about 250 mg, about 400 mg, or about 550 mg on a salt-free and anhydrous basis; and treatment with terpolizumab An effective dose is administered intravenously (IV) at 120 mg, 240 mg, 400 or 600 mg every two weeks (q2 weeks). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 250 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of terpolizumab is every two weeks. (q2 weeks) 120 mg, 240 mg, 400, or 600 mg dose administered by intravenous (IV). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 400 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of terpolizumab is every two weeks. (q2 weeks) 120 mg, 240 mg, 400, or 600 mg dose administered by intravenous (IV). In some embodiments, the therapeutically effective amount of the compound of formula (10b) is a total daily dose of about 550 mg on a salt-free and anhydrous basis; and the therapeutically effective amount of terpolizumab is every two weeks. (q2 weeks) 120 mg, 240 mg, 400, or 600 mg dose administered by intravenous (IV).

以總每日劑量之式(10b)化合物之治療有效量；及以每兩週一次劑量之特泊利單抗之治療有效量可根據癌症進展及/或毒性調整。The therapeutically effective amount of the compound of formula (10b) as a total daily dose; and the therapeutically effective amount of terpolizumab as a biweekly dose may be adjusted based on cancer progression and/or toxicity.

在一些實施例中，式(10b)化合物係口服投與；及特泊利單抗係靜脈內投與。In some embodiments, the compound of Formula (10b) is administered orally; and terpolizumab is administered intravenously.

在一些實施例中，式(10b)化合物及特泊利單抗係以聯合治療有效量提供。在一些實施例中，該式(10b)化合物及特泊利單抗係以協同有效量提供。在一些實施例中，該式(10b)化合物及特泊利單抗所使用之各劑量低於分別單獨使用時之劑量。In some embodiments, the compound of formula (10b) and terpolizumab are provided in a combined therapeutically effective amount. In some embodiments, the compound of formula (10b) and terpolizumab are provided in a synergistically effective amount. In some embodiments, the compound of formula (10b) and terpolizumab are each used at a dose that is lower than when used alone.

參考實施例1A至17A及1B至17B中之任一者，治療之效用係根據第III-6節：效用描述。在一些實施例中，該治療之效用係如第III-6節：效用中描述之實施例之任一者。 IV.    化合物 With reference to any of Examples 1A to 17A and 1B to 17B, the effectiveness of the treatment is described in accordance with Section III-6: Utility. In some embodiments, the utility of the treatment is any of the embodiments described in Section III-6: Utility. IV. Compounds

本發明提供一種如第III節：組合療法中描述用於治療個體之疾病或疾患(例如，癌症)之方法中之由式(I)表示之PTPN11抑制劑，一種如第V節：組合物中描述用於治療個體之疾病或疾患(例如，癌症)之醫藥組合物；及一種如第VI節：套組中描述用於治療個體之疾病或疾患(例如，癌症)之套組。該PTPN11抑制劑係如WO 2020/033828中定義及描述，其全部內容係出於所有目的以引用之方式併入本文中。The present invention provides a PTPN11 inhibitor represented by Formula (I) in a method for treating a disease or disorder (eg, cancer) in an individual as described in Section III: Combination Therapies, a PTPN11 inhibitor represented by Formula (I) as described in Section V: Compositions A pharmaceutical composition is described for treating a disease or disorder (e.g., cancer) in an individual; and a kit for treating a disease or disorder (e.g., cancer) in an individual as described in Section VI: Kits. The PTPN11 inhibitor is as defined and described in WO 2020/033828, the entire content of which is incorporated herein by reference for all purposes.

PTPN11抑制劑係由式(I)表示： (I)， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合， 其中： 下標a係0或1； 下標b係0或1； Y 1係直接鍵或CR 17R 18； Y 2係選自由以下組成之群：C 1-4烷基、胺基、C 1-4烷基C(O)O-、C 1-4烷基胺基及C 1-4胺基烷基； R 1係選自由以下組成之群：C 6-10芳基、C 3-8環烷基、C 3-8環烯基、及具有1至4個獨立地選自N、C(O)、O及S之雜原子或基團作為環頂點之5至10員雜芳基；R 1之該芳基或雜芳基係未經取代或經1至5個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4羥基烷基、C 1-4鹵烷基、C 1-4胺基烷基、C 3-8環烷基、C 3-8環烯基、NR 15C(O)R 14、NR 15C(O)OR 14、NR 14C(O)NR 15R 16、NR 15S(O)R 14、NR 15S(O) 2R 14、C(O)NR 15R 16、S(O)NR 15R 16、S(O) 2NR 15R 16、C(O)R 14、C(O)OR 14、OR 14、SR 14、S(O)R 14及S(O) 2R 14； R 2、R 3、R 10及R 11係各獨立地選自由以下組成之群：氫、C 1-4烷基及C 3-8環烷基； R 4、R 5、R 8及R 9係各獨立地選自由以下組成之群：氫、氰基、C 1-4烷基、C 1-4烷氧基、胺基、羥基、C 3-8環烷基、鹵基及C 1-4烷基胺基； R 6係選自由以下組成之群：胺基、C 1-4胺基烷基及C 1-4烷基胺基； R 7係選自由以下組成之群：氫、醯胺基、氰基、鹵基及羥基，或係選自由以下組成之群：C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基，及5或6員雜芳基，其等中之任一者係未經取代或經1至5個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基； 或R 6及R 7連同其等均附接之碳原子一起形成3至7員飽和或不飽和環，其具有0至3個獨立地選自N、C(O)、O及S(O) m之雜原子或基團作為環頂點；下標m係0、1或2；且由R 6及R 7形成之該飽和或不飽和環係未經取代或經1至3個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基； R 2、R 3、R 4、R 5、R 7、R 8、R 9、R 10及R 11中之任兩個基團可形成具有0至2個選自N、O及S之雜原子作為環頂點之5至6員環； R 2、R 4、R 6、R 8及R 10中之任兩個基團可形成直接鍵，或1或2個原子之碳橋； R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基、-NH-NHR 19、-NHR 19、-OR 19、-NHC(O)R 19、-NHC(O)NHR 19、-NHS(O) 2NHR 19、-NHS(O) 2R 19、-C(O)OR 19、-C(O)NR 19R 20、-C(O)NH(CH 2) qOH、-C(O)NH(CH 2) qR 21、-C(O)R 21、-NH 2、-OH、-S(O) 2NR 19R 20、C 3-8環烷基、芳基、具有1至5個選自N、O、S及P之雜原子作為環頂點之雜環基，及具有1至5個選自N、O、S及P之雜原子作為環頂點之雜芳基；下標q係0至6之整數；及R 13之芳基、雜芳基、雜環基及環烷基中之各者係未經取代或經1至3個獨立地選自由以下組成之群之基團取代：C 1-4烷基、-OH、-NH 2、-OR 21、鹵基、氰基及側氧基； R 14、R 15及R 16係各獨立地選自由以下組成之群：氫、C 1-4烷基、C 3-8環烷基、C 6-10芳基及5至10員雜芳基，其等中之任一者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基； R 17及R 18係各獨立地選自由以下組成之群：氫、C 1-4烷基及CF 3； R 19及R 20係各獨立地選自由以下組成之群：氫、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 2-6烯基、C 2-6炔基及C 3-6環烷基；及 各R 21係獨立地選自由以下組成之群：氫、-OH、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 2-6烯基、C 2-6炔基及C 3-6環烷基。 The PTPN11 inhibitor is represented by formula (I): (I), or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof, wherein: subscript a is 0 or 1; subscript b is 0 or 1; Y 1 is a direct bond or CR 17 R 18 ; Y 2 is selected from the group consisting of: C 1-4 alkyl, amino, C 1-4 alkyl C(O)O-, C 1-4 alkylamino and C 1-4 aminoalkyl; R 1 is selected from the group consisting of: C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl , and a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms or groups independently selected from N, C(O), O and S as ring vertices; the aryl or heteroaryl group of R 1 is Unsubstituted or substituted with 1 to 5 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amine, C 1-4 alkylamino, di(C 1-4 alkyl) Amino group, cyano group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 hydroxyalkyl group, C 1-4 haloalkyl group, C 1-4 aminoalkyl group, C 3-8 Cycloalkyl, C 3-8 cycloalkenyl, NR 15 C(O)R 14 , NR 15 C(O)OR 14 , NR 14 C(O)NR 15 R 16 , NR 15 S(O)R 14 , NR 15 S(O) 2 R 14 , C(O)NR 15 R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 14 , C(O)OR 14 , OR 14 , SR 14 , S(O)R 14 and S(O) 2 R 14 ; R 2 , R 3 , R 10 and R 11 are each independently selected from the group consisting of: hydrogen, C 1- 4 alkyl and C 3-8 cycloalkyl; R 4 , R 5 , R 8 and R 9 are each independently selected from the group consisting of: hydrogen, cyano group, C 1-4 alkyl, C 1-4 Alkoxy group, amino group, hydroxyl group, C 3-8 cycloalkyl group, halo group and C 1-4 alkylamino group; R 6 is selected from the group consisting of: amino group, C 1-4 aminoalkyl group and C 1-4 alkylamino; R 7 is selected from the group consisting of: hydrogen, amide, cyano, halo and hydroxyl, or is selected from the group consisting of: C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which is unsubstituted or 1 to 5 independently selected from the following Group substitution consisting of: amino group, halo group, hydroxyl group, cyano group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 haloalkyl group, C 1-4 haloalkoxy group group, C 1-4 alkylamino group and C 1-4 aminoalkyl group; or R 6 and R 7 together with the carbon atoms to which they are attached form a 3 to 7-membered saturated or unsaturated ring, which has 0 To 3 heteroatoms or groups independently selected from N, C(O), O and S(O) m as ring vertices; the subscript m is 0, 1 or 2; and is formed by R 6 and R 7 The saturated or unsaturated ring system is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of: amino group, halo group, hydroxyl group, cyano group, C 1-4 alkyl group, C 1- 4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; R 2 , R 3 , R 4 , Any two groups among R 5 , R 7 , R 8 , R 9 , R 10 and R 11 may form a 5 to 6 membered ring having 0 to 2 heteroatoms selected from N, O and S as ring vertices. ; Any two groups among R 2 , R 4 , R 6 , R 8 and R 10 can form a direct bond, or a carbon bridge of 1 or 2 atoms; R 13 is selected from the group consisting of: hydrogen, halogen group, cyano group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 hydroxyalkyl group, C 1-6 dihydroxyalkyl group, -NH-NHR 19 , -NHR 19 , -OR 19 , -NHC(O)R 19 , -NHC(O)NHR 19 , -NHS(O) 2 NHR 19 , -NHS(O) 2 R 19 , -C(O)OR 19 , -C(O)NR 19 R 20 , -C(O)NH(CH 2 ) q OH, -C(O)NH(CH 2 ) q R 21 , -C(O)R 21 , -NH 2 , -OH, -S(O) 2 NR 19 R 20 , C 3-8 cycloalkyl, aryl, heterocyclic group with 1 to 5 heteroatoms selected from N, O, S and P as ring vertices, and 1 to 5 heteroatoms selected from The heteroatoms of N, O, S and P serve as the heteroaryl group at the ring vertex; the subscript q is an integer from 0 to 6; and each of R 13 is an aryl group, a heteroaryl group, a heterocyclyl group and a cycloalkyl group. It is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of: C 1-4 alkyl, -OH, -NH 2 , -OR 21 , halo, cyano and pendant oxygen. ; R 14 , R 15 and R 16 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5 to 10 membered heteroaryl group, any of which is unsubstituted or substituted by one or more groups independently selected from the group consisting of: amide group, amine group, halo group, hydroxyl group, cyano group, C 1- 4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; R 17 and R 18 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl and CF 3 ; R 19 and R 20 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl; and each R 21 is independently selected from the following Group: hydrogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 ring alkyl.

在式(I)之一些實施例中，Y 1係直接鍵。在一些實施例中，Y 1係CR 17R 18。在一些實施例中，R 17及R 18係各獨立地選自由以下組成之群：氫、C 1-4烷基及CF 3。在一些實施例中，R 17及R 18各獨立地係氫或C 1-4烷基。在一些實施例中，Y 1係-CH 2。 In some embodiments of formula (I), Y 1 is a direct bond. In some embodiments, Y 1 is CR 17 R 18 . In some embodiments, R 17 and R 18 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, and CF 3 . In some embodiments, R 17 and R 18 are each independently hydrogen or C 1-4 alkyl. In some embodiments, Y 1 is -CH 2 .

在式(I)之一些實施例中，Y 2係C 1-4烷基。在一些實施例中，Y 2係甲基。 In some embodiments of formula (I), Y 2 is C 1-4 alkyl. In some embodiments, Y2 is methyl.

在一些實施例中，化合物係由式(Ia)表示： (Ia)， 其中下標a及b、Y 1、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11及R 13係如本文定義及描述。 In some embodiments, the compound is represented by Formula (Ia): (Ia), where the subscripts a and b, Y 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 13 are As defined and described herein.

在一些實施例中，化合物係由式(Ib)表示： (Ib)， 其中下標a及b、Y 2、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11及R 13係如本文定義及描述。 In some embodiments, the compound is represented by Formula (Ib): (Ib), where the subscripts a and b, Y 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 13 are As defined and described herein.

在一些實施例中，化合物係由式(Ic)表示： (Ic)， 其中下標a及b、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11及R 13係如本文定義及描述。 In some embodiments, the compound is represented by Formula (Ic): (Ic), wherein subscripts a and b, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 13 are as defined herein and description.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，下標a及b各為1。In some embodiments of any of formulas (I), (Ia), (Ib), and (Ic), subscripts a and b are each 1.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 13係選自由以下組成之群：氫、鹵基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基、C 3-8環烷基、具有1至3個選自N、O及S之雜原子作為環頂點之3或6員雜環基；其中雜環基及環烷基係經0至3個獨立地選自由以下組成之群之基團取代：C 1-4烷基、-OH、-NH 2、-OR 21、鹵基、氰基及側氧基。在一些實施例中，R 13係選自由以下組成之群：氫、鹵基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基。在一些實施例中，R 13係選自由以下組成之群：氫、鹵基、C 1-6烷基及C 1-6鹵烷基。在一些實施例中，R 13係選自由以下組成之群：氫、鹵基、C 1-4烷基及C 1-4鹵烷基。在一些實施例中，R 13係選自由以下組成之群：-CH 2OH、CF 2OH及-CHFOH。在一些實施例中，R 13係選自由以下組成之群：氫、Cl、Br、甲基及CF 3。在一些實施例中，R 13係氫。在一些實施例中，R 13係Cl。在一些實施例中，R 13係Br。在一些實施例中，R 13係甲基。在一些實施例中，R 13係CF 3。 In some embodiments of any of formulas (I), (Ia), (Ib), and (Ic), R 13 is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl, C 3-8 cycloalkyl, with 1 to 3 heteroatoms selected from N, O and S as ring vertices 3- or 6-membered heterocyclyl; wherein the heterocyclyl and cycloalkyl are substituted by 0 to 3 groups independently selected from the group consisting of: C 1-4 alkyl, -OH, -NH 2 , -OR 21 , halo group, cyano group and side oxygen group. In some embodiments, R 13 is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxy Alkyl and C 3-8 cycloalkyl. In some embodiments, R 13 is selected from the group consisting of hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 13 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, and C 1-4 haloalkyl. In some embodiments, R 13 is selected from the group consisting of -CH 2 OH, CF 2 OH, and -CHFOH. In some embodiments, R 13 is selected from the group consisting of: hydrogen, Cl, Br, methyl, and CF 3 . In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is Cl. In some embodiments, R 13 is Br. In some embodiments, R 13 is methyl. In some embodiments, R 13 is CF 3 .

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係選自由以下組成之群：C 6-10芳基及具有1至4個獨立地選自N、C(O)、O及S之雜原子基團作為環頂點之5至9員雜芳基；及係未經取代或經1至5個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4羥基烷基、C 1-4鹵烷基、C 1-4胺基烷基、C 3-8環烷基、C 3-8環烯基、NR 15C(O)R 14、NR 15C(O)OR 14、NR 14C(O)NR 15R 16、NR 15S(O)R 14、NR 15S(O) 2R 14、C(O)NR 15R 16、S(O)NR 15R 16、S(O) 2NR 15R 16、C(O)R 14、C(O)OR 14、OR 14、SR 14、S(O)R 14及S(O) 2R 14。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R 1 is selected from the group consisting of: C 6-10 aryl and having 1 to 4 independent A 5- to 9-membered heteroaryl group independently selected from the group consisting of N, C(O), O, and S as the ring vertex; and is unsubstituted or 1 to 5 independently selected from the group consisting of: R 12 group substitution: halo, hydroxyl, amino, C 1-4 alkylamine, di(C 1-4 alkyl)amine, cyano, C 1-4 alkyl, C 1-4 alkyl Oxygen group, C 1-4 hydroxyalkyl group, C 1-4 haloalkyl group, C 1-4 aminoalkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkenyl group, NR 15 C(O) R 14 , NR 15 C(O)OR 14 , NR 14 C(O)NR 15 R 16 , NR 15 S(O)R 14 , NR 15 S(O) 2 R 14 , C(O)NR 15 R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 14 , C(O)OR 14 , OR 14 , SR 14 , S(O)R 14 and S(O ) 2R14 .

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係選自由以下組成之群：C 6-10芳基及具有1至4個獨立地選自N、C(O)、O及S之雜原子基團作為環頂點之5至9員雜芳基；及係未經取代或經1至5個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4羥基烷基、C 1-4鹵烷基、C 1-4胺基烷基、C 3-8環烷基、C 3-8環烯基、NR 15C(O)R 14、NR 15C(O)OR 14、NR 14C(O)NR 15R 16、NR 15S(O)R 14、NR 15S(O) 2R 14、C(O)NR 15R 16、S(O)NR 15R 16、S(O) 2NR 15R 16、C(O)R 14、C(O)OR 14、OR 14、SR 14、S(O)R 14及S(O) 2R 14；及R 14、R 15及R 16係各獨立地選自由以下組成之群：氫、C 1-4烷基、C 3-8環烷基、C 6-10芳基及5至10員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R 1 is selected from the group consisting of: C 6-10 aryl and having 1 to 4 independent A 5- to 9-membered heteroaryl group independently selected from the group consisting of N, C(O), O, and S as the ring vertex; and is unsubstituted or 1 to 5 independently selected from the group consisting of: R 12 group substitution: halo, hydroxyl, amino, C 1-4 alkylamine, di(C 1-4 alkyl)amine, cyano, C 1-4 alkyl, C 1-4 alkyl Oxygen group, C 1-4 hydroxyalkyl group, C 1-4 haloalkyl group, C 1-4 aminoalkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkenyl group, NR 15 C(O) R 14 , NR 15 C(O)OR 14 , NR 14 C(O)NR 15 R 16 , NR 15 S(O)R 14 , NR 15 S(O) 2 R 14 , C(O)NR 15 R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 14 , C(O)OR 14 , OR 14 , SR 14 , S(O)R 14 and S(O ) 2 R 14 ; and R 14 , R 15 and R 16 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5 to 10-membered heteroaryl, each of which is unsubstituted or substituted with one or more groups independently selected from the group consisting of: amide, amine, halo, hydroxy, cyano , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl base.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係選自由以下組成之群：C 6-10芳基及具有1至4個獨立地選自N、C(O)、O及S之雜原子基團作為環頂點之5至9員雜芳基；及係未經取代或經1至5個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4羥基烷基、C 1-4鹵烷基、C 1-4胺基烷基、C 3-8環烷基、C 3-8環烯基、NR 15C(O)R 14、NR 15C(O)OR 14、NR 14C(O)NR 15R 16、NR 15S(O)R 14、NR 15S(O) 2R 14、C(O)NR 15R 16、S(O)NR 15R 16、S(O) 2NR 15R 16、C(O)R 14、C(O)OR 14、OR 14、SR 14、S(O)R 14及S(O) 2R 14；及R 14、R 15及R 16係各獨立地選自由以下組成之群：氫、C 1-4烷基、C 3-8環烷基、C 6-10芳基及5至10員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：鹵基、羥基、氰基及C 1-4烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R 1 is selected from the group consisting of: C 6-10 aryl and having 1 to 4 independent A 5- to 9-membered heteroaryl group independently selected from the group consisting of N, C(O), O, and S as the ring vertex; and is unsubstituted or 1 to 5 independently selected from the group consisting of: R 12 group substitution: halo, hydroxyl, amino, C 1-4 alkylamine, di(C 1-4 alkyl)amine, cyano, C 1-4 alkyl, C 1-4 alkyl Oxygen group, C 1-4 hydroxyalkyl group, C 1-4 haloalkyl group, C 1-4 aminoalkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkenyl group, NR 15 C(O) R 14 , NR 15 C(O)OR 14 , NR 14 C(O)NR 15 R 16 , NR 15 S(O)R 14 , NR 15 S(O) 2 R 14 , C(O)NR 15 R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 14 , C(O)OR 14 , OR 14 , SR 14 , S(O)R 14 and S(O ) 2 R 14 ; and R 14 , R 15 and R 16 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5 to 10-membered heteroaryl, each of which is unsubstituted or substituted with one or more groups independently selected from the group consisting of: halo, hydroxyl, cyano, and C 1-4 alkyl .

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 .

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；及R 14係選自由以下組成之群：氫、C 1-4烷基、C 3-8環烷基、C 6-10芳基及5至10員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; and R 14 is selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5 to 10 membered heteroaryl, among which Each of them is unsubstituted or substituted with one or more groups independently selected from the group consisting of: amide group, amine group, halo group, hydroxyl group, cyano group, C 1-4 alkyl group, C 1 -4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；及R 14係選自由以下組成之群：氫、C 1-4烷基、C 3-8環烷基、C 6-10芳基及5至10員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：鹵基、羥基、氰基及C 1-4烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; and R 14 is selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5 to 10 membered heteroaryl, among which Each of them is unsubstituted or substituted with one or more groups independently selected from the group consisting of halo, hydroxyl, cyano and C 1-4 alkyl.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；及R 14係選自由以下組成之群：C 6-10芳基及5至10員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; and R 14 is selected from the group consisting of: C 6-10 aryl and 5 to 10 membered heteroaryl, each of which is unsubstituted or independently selected from one or more Substitution of the following groups: C 1-4 alkylamide, amine, halo, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 halo Alkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；及R 14係選自由以下組成之群：C 6-10芳基及5至10員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：鹵基、羥基、氰基及C 1-4烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; and R 14 is selected from the group consisting of: C 6-10 aryl and 5 to 10 membered heteroaryl, each of which is unsubstituted or independently selected from one or more Substitution with groups consisting of: halo, hydroxyl, cyano and C 1-4 alkyl.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；及R 14係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring apex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; and R 14 is phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is unsubstituted Or substituted by one or two groups independently selected from the group consisting of: C 1-4 alkylamide, amine, halo, hydroxyl, cyano, C 1-4 alkyl, C 1- 4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；及R 14係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：鹵基、羥基、氰基及C 1-4烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring apex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; and R 14 is phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is unsubstituted Or substituted with one or more groups independently selected from the group consisting of halo, hydroxyl, cyano and C 1-4 alkyl.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；及R 14係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; and R 14 is phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is unsubstituted Or substituted with one or more groups independently selected from the group consisting of C 1-4 alkylamide, halo, hydroxyl, cyano and C 1-4 alkyl.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；及R 14係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基及C 1-4烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; and R 14 is phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is unsubstituted Or substituted with one or more groups independently selected from the group consisting of: C 1-4 alkylamide group and C 1-4 alkyl group.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、C(O)、O及S之雜原子或基團作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 independently selected from N, C(O), O and a heteroatom or group of S as a 5- to 6-membered heteroaryl group at the ring apex; and is unsubstituted or substituted with 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo group , hydroxyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 aminoalkyl.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 2、R 3、R 10及R 11獨立地係氫或C 1-4烷基。在某些實施例中，R 2、R 3、R 10及R 11各為氫。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R 2 , R 3 , R 10 , and R 11 are independently hydrogen or C 1-4 alkyl. In certain embodiments, each of R 2 , R 3 , R 10 and R 11 is hydrogen.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 4、R 5、R 8及R 9係獨立地選自由以下組成之群：氫、C 1-4烷基、C 1-4烷氧基、胺基、羥基、C 3-8環烷基及C 1-4烷基胺基。在某些實施例中，R 4、R 5、R 8及R 9獨立地係氫或C 1-4烷基。在某些實施例中，R 4、R 5、R 8及R 9各為氫。 In some embodiments of any of formulas (I), (Ia), (Ib), and (Ic), R 4 , R 5 , R 8 , and R 9 are independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 1-4 alkoxy, amine, hydroxyl, C 3-8 cycloalkyl and C 1-4 alkylamine. In certain embodiments, R 4 , R 5 , R 8 and R 9 are independently hydrogen or C 1-4 alkyl. In certain embodiments, each of R 4 , R 5 , R 8 and R 9 is hydrogen.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、C(O)、O及S之雜原子或基團作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基；及R 4、R 5、R 8及R 9係獨立地選自由以下組成之群：氫、C 1-4烷基、C 1-4烷氧基、胺基、羥基、C 3-6環烷基及C 1-4烷基胺基。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R1 is phenyl or has 1 to 4 independently selected from N, C(O), O and a heteroatom or group of S as a 5- to 6-membered heteroaryl group at the ring apex; and is unsubstituted or substituted with 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo group , hydroxyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 aminoalkyl; and R 4 , R 5 , R 8 and R 9 are independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 1-4 alkoxy, amino , hydroxyl group, C 3-6 cycloalkyl group and C 1-4 alkylamino group.

在式(I)、(Ia)、(Ib)及(Ic)之任一者之一些實施例中，R 2、R 3、R 4、R 5、R 8、R 9、R 10及R 11各為氫。 In some embodiments of any of Formulas (I), (Ia), (Ib), and (Ic), R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 and R 11 Each is hydrogen.

在一些實施例中，化合物係由式(II)表示： (II)， 其中R 1、R 6、R 7及R 13係如本文定義及描述。 In some embodiments, the compound is represented by Formula (II): (II), wherein R 1 , R 6 , R 7 and R 13 are as defined and described herein.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6係選自由以下組成之群：胺基、C 1-4胺基烷基及C 1-4烷基胺基；及R 7係選自由以下組成之群：氫、醯胺基、氰基、鹵基及羥基，或係選自由以下組成之群：C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基，其等中之任一者係未經取代或經一至三個選自由以下組成之群之取代基取代：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。在一些實施例中，R 6係選自由以下組成之群：胺基、C 1-4胺基烷基及C 1-4烷基胺基；及R 7係選自由以下組成之群：氫、醯胺基、鹵基及羥基，或係選自由以下組成之群：C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基，其等中之任一者係未經取代或經一或兩個選自由以下組成之群之取代基取代：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R is selected from the group consisting of: amine, C 1-4 aminoalkyl, and C 1-4 alkylamino; and R 7 is selected from the group consisting of hydrogen, amide, cyano, halo and hydroxyl, or is selected from the group consisting of: C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is unsubstituted or substituted by one to three selected from the group consisting of Group substitution: amino group, halo group, hydroxyl group, cyano group, trifluoromethyl group, trifluoromethoxy group, C 1-4 alkyl group and C 1-4 alkoxy group. In some embodiments, R 6 is selected from the group consisting of: amine, C 1-4 aminoalkyl, and C 1-4 alkylamino; and R 7 is selected from the group consisting of: hydrogen, amide group, halo group and hydroxyl group, or are selected from the group consisting of: C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5 or 6-membered heteroaryl group, any one of which is unsubstituted or substituted with one or two substituents selected from the group consisting of: amino, halo, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy group, C 1-4 alkyl group and C 1-4 alkoxy group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6係選自由以下組成之群：胺基、C 1-4胺基烷基及甲基胺基。在一些實施例中，R 6係胺基或C 1-4胺基烷基。在某些實施例中，R 6係胺基、胺基甲基或甲基胺基。在某些實施例中，R 6係胺基或胺基甲基。在某些實施例中，R 6係胺基。在某些實施例中，R 6係胺基甲基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R is selected from the group consisting of: amino, C 1-4 aminoalkyl, and methyl. amine group. In some embodiments, R 6 is amino or C 1-4 aminoalkyl. In certain embodiments, R 6 is amine, aminomethyl or methylamino. In certain embodiments, R 6 is amino or aminomethyl. In certain embodiments, R 6 is amine. In certain embodiments, R 6 is aminomethyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 7係選自由以下組成之群：羥基、C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基，其等中之任一者係未經取代或經一或兩個選自由以下組成之群之基團取代：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。在一些實施例中，R 7係選自由以下組成之群：羥基、C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基。在一些實施例中，R 7係羥基、C 1-4烷基或C 1-4羥基烷基。在某些實施例中，R 7係C 1-4烷基。在某些實施例中，R 7係甲基。在某些實施例中，R 7係乙基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R 7 is selected from the group consisting of: hydroxyl, C 1-4 alkyl, C 1-4 Hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5- or 6-membered heteroaryl, any of which is unsubstituted or substituted with one or two groups selected from the group consisting of : Amino group, halo group, hydroxyl group, cyano group, trifluoromethyl group, trifluoromethoxy group, C 1-4 alkyl group and C 1-4 alkoxy group. In some embodiments, R 7 is selected from the group consisting of: hydroxyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, and 5- or 6-membered heteroaryl base. In some embodiments, R 7 is hydroxyl, C 1-4 alkyl, or C 1-4 hydroxyalkyl. In certain embodiments, R 7 is C 1-4 alkyl. In certain embodiments, R 7 is methyl. In certain embodiments, R 7 is ethyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6係C 1-4胺基烷基；及R 7係選自由以下組成之群：羥基、C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基，其等中之任一者係未經取代或經一至三個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R 6 is C 1-4 aminoalkyl; and R 7 is selected from the group consisting of: Hydroxy, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5- or 6-membered heteroaryl, any of which is unsubstituted or with one to Three groups independently selected from the group consisting of: amino, halo, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl and C 1-4 alkoxy base.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6係胺基甲基；及R 7係選自由以下組成之群：羥基、C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R 6 is aminomethyl; and R 7 is selected from the group consisting of: hydroxyl, C 1 -4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5- or 6-membered heteroaryl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6係胺基；及R 7係選自由以下組成之群：羥基、C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基，其等中之任一者係未經取代或經一至三個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。 In some embodiments of any one of formulas (I), (Ia) to (Ic), and (II), R 6 is an amine group; and R 7 is selected from the group consisting of: hydroxyl, C 1-4 Alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5- or 6-membered heteroaryl, any of which is unsubstituted or has one to three independently selected from Substitution with groups of the following group: amino, halo, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl and C 1-4 alkoxy.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6係胺基；及R 7係選自由以下組成之群：羥基、C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基。 In some embodiments of any one of formulas (I), (Ia) to (Ic), and (II), R 6 is an amine group; and R 7 is selected from the group consisting of: hydroxyl, C 1-4 Alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5- or 6-membered heteroaryl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6係胺基；及R 7係C 1-4羥基烷基。在一些實施例中，R 6係胺基；及R 7係羥基甲基。在一些實施例中，R 6係胺基；及R 7係C 1-4烷基。在某些實施例中，R 6係胺基；及R 7係甲基。在一些實施例中，R 6係胺基；及R 7係乙基。在一些實施例中，R 6係胺基甲基；及R 7係C 1-4烷基。在某些實施例中，R 6係胺基甲基；及R 7係甲基。在一些實施例中，R 6係胺基甲基；及R 7係乙基。 In some embodiments of any one of Formulas (I), (Ia) to (Ic), and (II), R 6 is amine; and R 7 is C 1-4 hydroxyalkyl. In some embodiments, R 6 is amine; and R 7 is hydroxymethyl. In some embodiments, R 6 is amine; and R 7 is C 1-4 alkyl. In certain embodiments, R 6 is amine; and R 7 is methyl. In some embodiments, R 6 is amine; and R 7 is ethyl. In some embodiments, R 6 is aminomethyl; and R 7 is C 1-4 alkyl. In certain embodiments, R 6 is aminomethyl; and R 7 is methyl. In some embodiments, R 6 is aminomethyl; and R 7 is ethyl.

在上文實施例之任一者中，R 7之醯胺基可明確為-C(O)NH 2。 In any of the above embodiments, the amide group of R 7 may be specifically -C(O)NH 2 .

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6及R 7連同其等均附接之碳原子一起形成3至7員飽和或不飽和環，其具有1至3個獨立地選自N、C(O)、O及S(O) m之雜原子或基團作為環頂點，且其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) through (Ic), and (II), R 6 and R 7 , together with the carbon atoms to which they are each attached, form a 3- to 7-membered saturated or unsaturated Saturated rings, which have 1 to 3 heteroatoms or groups independently selected from N, C(O), O and S(O) m as ring vertices, and which are unsubstituted or modified by one or two independently Substituted with a group selected from the group consisting of: amino, halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamine and C 1-4 amino alkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6及R 7連同其等均附接之碳原子一起形成4至6員飽和或不飽和環，其具有1至3個獨立地選自N、C(O)及O之雜原子或基團作為環頂點，且其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) through (Ic), and (II), R 6 and R 7 , together with the carbon atoms to which they are each attached, form a 4- to 6-membered saturated or unsaturated Saturated rings, which have 1 to 3 heteroatoms or groups independently selected from N, C(O) and O as ring vertices, and which are unsubstituted or have one or two independently selected from the following: Group substitution of groups: amino group, halo group, hydroxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino group and C 1-4 aminoalkyl group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6及R 7連同其等均附接之碳原子一起形成3至7員飽和環，其具有1至3個獨立地選自N、C(O)、O及S(O) m之雜原子或基團作為環頂點，且其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of formulas (I), (Ia) through (Ic), and (II), R 6 and R 7 , together with the carbon atoms to which they are each attached, form a 3- to 7-membered saturated ring, It has 1 to 3 heteroatoms or groups independently selected from N, C(O), O and S(O) m as ring vertices, and it is unsubstituted or has one or two independently selected from Substitution with groups consisting of: amino, halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6及R 7連同其等均附接之碳原子一起形成4至6員飽和環，其具有1至3個獨立地選自N、C(O)及O之雜原子或基團作為環頂點，且其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) through (Ic), and (II), R 6 and R 7 , together with the carbon atoms to which they are each attached, form a 4- to 6-membered saturated ring, It has 1 to 3 heteroatoms or groups independently selected from N, C(O) and O as ring vertices, and it is unsubstituted or has one or two groups independently selected from the group consisting of Group substitution: amino group, halo group, hydroxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino group and C 1-4 aminoalkyl group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6及R 7連同其等均附接之碳原子一起形成4至6員飽和環，其具有1至3個雜原子或基團作為獨立地選自N及O之環頂點，且其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) through (Ic), and (II), R and R , together with the carbon atoms to which they are each attached, form a 4- to 6-membered saturated ring, It has 1 to 3 heteroatoms or groups as ring vertices independently selected from N and O, and it is unsubstituted or substituted with one or two groups independently selected from the group consisting of: amine group , halo group, hydroxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino group and C 1-4 aminoalkyl group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6及R 7連同其等均附接之碳原子一起形成3至7員環烷基環，其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) through (Ic), and (II), R 6 and R 7 , together with the carbon atom to which they are each attached, form a 3- to 7-membered cycloalkyl group Ring, which is unsubstituted or substituted by one or two groups independently selected from the group consisting of: amino group, halo group, hydroxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino and C 1-4 aminoalkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 6及R 7連同其等均附接之碳原子一起形成4至6員環烷基環，其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) through (Ic), and (II), R 6 and R 7 , together with the carbon atoms to which they are each attached, form a 4- to 6-membered cycloalkyl group Ring, which is unsubstituted or substituted by one or two groups independently selected from the group consisting of: amino group, halo group, hydroxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino and C 1-4 aminoalkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；R 14係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基；R 6係選自由以下組成之群：胺基、C 1-4胺基烷基及C 1-4烷基胺基；及R 7係選自由以下組成之群：氫、鹵基及羥基，或係選自由以下組成之群：醯胺基、C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基，其等中之任一者係未經取代或經一或兩個選自由以下組成之群之取代基取代：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring apex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; R 14 is phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is unsubstituted or Substituted with one or two groups independently selected from the group consisting of C 1-4 alkylamide, amine, halo, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; R 6 is selected from the group consisting of: Amino, C 1-4 aminoalkyl and C 1-4 alkylamino; and R 7 is selected from the group consisting of hydrogen, halo and hydroxyl, or is selected from the group consisting of amide base, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5- or 6-membered heteroaryl, any of which is unsubstituted or Or substituted by two substituents selected from the following group: amino group, halo group, hydroxyl group, cyano group, trifluoromethyl group, trifluoromethoxy group, C 1-4 alkyl group and C 1-4 alkoxy group .

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；R 14係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基；R 6係胺基或胺基甲基；及R 7係選自由以下組成之群：羥基、C 1-4烷基及C 1-4羥基烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; R 14 is phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is unsubstituted or Substituted with one or two groups independently selected from the group consisting of C 1-4 alkylamide, amine, halo, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; R 6 is amino or aminomethyl ; and R 7 is selected from the group consisting of: hydroxyl, C 1-4 alkyl and C 1-4 hydroxyalkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；R 14係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基；及R 6及R 7連同其等均附接之碳原子一起形成3至7員飽和或不飽和環，其具有1至3個獨立地選自N、C(O)、O及S(O) m之雜原子或基團作為環頂點，且其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring apex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; R 14 is phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is unsubstituted or Substituted with one or two groups independently selected from the group consisting of C 1-4 alkylamide, amine, halo, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; and R 6 and R 7 together with the others The attached carbon atoms together form a 3- to 7-membered saturated or unsaturated ring having as ring vertices 1 to 3 heteroatoms or groups independently selected from N, C(O), O, and S(O) m , and it is unsubstituted or substituted by one or two groups independently selected from the group consisting of: amino group, halo group, hydroxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino and C 1-4 aminoalkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；R 14係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基；及R 6及R 7連同其等均附接之碳原子一起形成4至6員飽和或不飽和環，其具有1至3個獨立地選自N、C(O)及O之雜原子或基團作為環頂點，且其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; R 14 is phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is unsubstituted or Substituted with one or two groups independently selected from the group consisting of C 1-4 alkylamide, amine, halo, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; and R 6 and R 7 together with the others The attached carbon atoms together form a 4 to 6 membered saturated or unsaturated ring having 1 to 3 heteroatoms or groups independently selected from N, C(O) and O as ring vertices, and which are unsaturated Substituted or substituted by one or two groups independently selected from the group consisting of: amino, halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamine group and C 1-4 aminoalkyl group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14；R 14係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基；及R 6及R 7連同其等均附接之碳原子一起形成3至7員環烷基環，其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring apex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 ; R 14 is phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is unsubstituted or Substituted with one or two groups independently selected from the group consisting of C 1-4 alkylamide, amine, halo, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; and R 6 and R 7 together with the others The attached carbon atoms together form a 3 to 7 membered cycloalkyl ring which is unsubstituted or substituted with one or two groups independently selected from the group consisting of: amine, halo, hydroxyl, C1 -4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基；R 6係選自由以下組成之群：胺基、C 1-4胺基烷基及C 1-4烷基胺基；及R 7係選自由以下組成之群：氫、鹵基及羥基，或係選自由以下組成之群：醯胺基、C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基，其等中之任一者係未經取代或經一或兩個選自由以下組成之群之取代基取代：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring apex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 aminoalkyl ; R 6 is selected from the group consisting of: amine group, C 1-4 aminoalkyl group and C 1-4 alkylamino group; and R 7 is selected from the group consisting of: hydrogen, halo group and hydroxyl group, Or be selected from the group consisting of: amide group, C 1-4 alkyl group, C 1-4 hydroxyalkyl group, C 3-6 cycloalkyl group, phenyl group and 5- or 6-membered heteroaryl group, among which Any of them is unsubstituted or substituted with one or two substituents selected from the group consisting of: amino, halo, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, C 1- 4 alkyl and C 1-4 alkoxy.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基；R 6係胺基或胺基甲基；及R 7係選自由以下組成之群：羥基、C 1-4烷基及C 1-4羥基烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 aminoalkyl ; R 6 is amino or aminomethyl; and R 7 is selected from the group consisting of: hydroxyl, C 1-4 alkyl and C 1-4 hydroxyalkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基；及R 6及R 7連同其等均附接之碳原子一起形成3至7員飽和或不飽和環，其具有1至3個獨立地選自N、C(O)、O及S(O) m之雜原子或基團作為環頂點，且其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 aminoalkyl ; and R 6 and R 7 together with the carbon atoms to which they are each attached form a 3 to 7 membered saturated or unsaturated ring having 1 to 3 independently selected from N, C(O), O and S(O ) The heteroatom or group of m serves as the ring vertex, and it is unsubstituted or substituted by one or two groups independently selected from the group consisting of: amino group, halo group, hydroxyl group, C 1-4 alkane group, C 1-4 alkoxy group, C 1-4 alkylamino group and C 1-4 aminoalkyl group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基；及R 6及R 7連同其等均附接之碳原子一起形成4至6員飽和或不飽和環，其具有1至3個獨立地選自N、C(O)及O之雜原子或基團作為環頂點，且其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring vertex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 aminoalkyl ; and R 6 and R 7 together with the carbon atoms to which they are each attached form a 4 to 6 membered saturated or unsaturated ring having 1 to 3 heteroatoms independently selected from N, C(O) and O, or The group serves as the ring apex, and it is unsubstituted or substituted by one or two groups independently selected from the group consisting of: amino group, halo group, hydroxyl group, C 1-4 alkyl group, C 1-4 Alkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基；及R 6及R 7連同其等均附接之碳原子一起形成3至7員環烷基環，其係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or has 1 to 4 heteroatoms independently selected from N, O, and S A 5- to 6-membered heteroaryl group as the ring apex; and is unsubstituted or substituted by 1, 2 or 3 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amino, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 aminoalkyl ; and R 6 and R 7 together with the carbon atoms to which they are both attached form a 3 to 7 membered cycloalkyl ring, which is unsubstituted or substituted with one or two groups independently selected from the group consisting of : Amino group, halo group, hydroxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino group and C 1-4 aminoalkyl group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係選自由以下組成之群：苯基、吡啶基、嘧啶基、吡唑基、吡嗪基、噠嗪基及1,2,4-三嗪基；及係未經取代或經1、2或3個R 12取代，其中各R 12係如本文定義及描述，在一些實施例中，R 1係選自由以下組成之群：苯基、吡啶基、嘧啶基、吡嗪基、噠嗪基及1,2,4-三嗪基；及係未經取代或經1、2或3個R 12取代，其中各R 12係如本文定義及描述。在一些實施例中，R 1係苯基或吡啶基；及係未經取代或經1、2或3個R 12取代，其中各R 12係如本文定義及描述。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazinyl, pyridazinyl and 1,2,4-triazinyl; and are unsubstituted or substituted with 1, 2 or 3 R 12 , wherein each R 12 is as defined and described herein, in some embodiments In, R 1 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and 1,2,4-triazinyl; and is unsubstituted or substituted by 1, 2 or 3 R 12 substitutions, where each R 12 is as defined and described herein. In some embodiments, R 1 is phenyl or pyridyl; and is unsubstituted or substituted with 1, 2, or 3 R 12 , wherein each R 12 is as defined and described herein.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係選自由以下組成之群：苯基、吡啶基、嘧啶基、吡嗪基、噠嗪基及1,2,4-三嗪基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl and 1,2,4-triazinyl; and are unsubstituted or substituted with 1, 2 or 3 R 12 independently selected from the group consisting of: halo, hydroxyl, amine, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 .

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係選自由以下組成之群：苯基、吡啶基、嘧啶基、吡嗪基、噠嗪基及1,2,4-三嗪基；及係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is selected from the group consisting of: phenyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl and 1,2,4-triazinyl; and are unsubstituted or substituted with 1, 2 or 3 R 12 independently selected from the group consisting of: halo, hydroxyl, amine, C 1 -4- alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 aminoalkyl .

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或吡啶基，其等中之各者係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14。 In some embodiments of any of Formulas (I), (Ia) to (Ic) and (II), R1 is phenyl or pyridyl, each of which is unsubstituted or substituted with 1, 2 or 3 R 12 substitutes independently selected from the group consisting of: halo, hydroxyl, amine, C 1-4 alkylamino, di(C 1-4 alkyl)amine, C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 aminoalkyl and OR 14 .

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基或吡啶基，其等中之各者係未經取代或經1、2或3個獨立地選自由以下組成之群之R 12取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R1 is phenyl or pyridyl, each of which is unsubstituted or substituted with 1, 2 or 3 R 12 substitutes independently selected from the group consisting of halo, hydroxyl, amine, C 1-4 alkylamino, di(C 1-4 alkyl)amine, C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 aminoalkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係苯基及係未經取代或經1至3個R 12取代，R 12各係獨立地選自由以下組成之群：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14。在一些實施例中，R 1係苯基及係未經取代或經1至3個R 12取代，R 12各係獨立地選自由以下組成之群：鹵基、羥基、胺基、甲基胺基、二甲基胺基、氰基、C 1-4烷基、C 1-4鹵烷基及C 1-4烷氧基。在一些實施例中，R 1係苯基及係未經取代或經1至3個R 12取代，R 12各係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基及C 1-4烷氧基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R 1 is phenyl and is unsubstituted or substituted with 1 to 3 R 12 , each of R 12 is independently selected from the group consisting of: halo group, hydroxyl group, amino group, C 1-4 alkylamino group, di(C 1-4 alkyl)amine group, C 1-4 alkyl group, C 1-4 Alkoxy, C 1-4 haloalkyl, C 1-4 aminoalkyl and OR 14 . In some embodiments, R 1 is phenyl and is unsubstituted or substituted with 1 to 3 R 12 , each of R 12 is independently selected from the group consisting of: halo, hydroxyl, amino, methylamine group, dimethylamino group, cyano group, C 1-4 alkyl group, C 1-4 haloalkyl group and C 1-4 alkoxy group. In some embodiments, R 1 is phenyl and is unsubstituted or substituted with 1 to 3 R 12 , each of R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl and C 1-4 alkoxy.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係吡啶基及係未經取代或經1至3個R 12取代，R 12各係獨立地選自由以下組成之群：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14。在一些實施例中，R 1係吡啶基及係未經取代或經1至3個R 12取代，R 12各係獨立地選自由以下組成之群：鹵基、羥基、胺基、甲基胺基、二甲基胺基、氰基、C 1-4烷基、C 1-4鹵烷基及C 1-4烷氧基。在一些實施例中，R 1係吡啶基及係未經取代或經1至3個R 12取代，R 12各係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基及C 1-4烷氧基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R 1 is pyridyl and is unsubstituted or substituted with 1 to 3 R 12 , each of R 12 is independently selected from the group consisting of: halo group, hydroxyl group, amino group, C 1-4 alkylamino group, di(C 1-4 alkyl)amine group, C 1-4 alkyl group, C 1-4 Alkoxy, C 1-4 haloalkyl, C 1-4 aminoalkyl and OR 14 . In some embodiments, R 1 is pyridyl and is unsubstituted or substituted with 1 to 3 R 12 , each of R 12 is independently selected from the group consisting of: halo, hydroxyl, amino, methylamine group, dimethylamino group, cyano group, C 1-4 alkyl group, C 1-4 haloalkyl group and C 1-4 alkoxy group. In some embodiments, R 1 is pyridyl and is unsubstituted or substituted with 1 to 3 R 12 , each of R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl and C 1-4 alkoxy.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係選自由以下組成之群： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 及 ， 其中各R 12係如本文定義及描述。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R 1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , wherein each R 12 is as defined and described herein.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係選自由以下組成之群： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 及 ；及 各R 12係獨立地選自由以下組成之群：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14，其中R 14係如本文定義及描述。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R 1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; and each R 12 is independently selected from the group consisting of: halo, hydroxyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amine, C 1-4 alkyl , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 aminoalkyl and OR 14 , wherein R 14 is as defined and described herein.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係選自由以下組成之群： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 及 ；及 各R 12係獨立地選自由以下組成之群：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R 1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , and ; and each R 12 is independently selected from the group consisting of: halo, hydroxyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amine, C 1-4 alkyl , C 1-4 alkoxy group, C 1-4 haloalkyl group and C 1-4 aminoalkyl group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係選自由以下組成之群： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 及 ；及 各R 12係獨立地選自由以下組成之群：鹵基、羥基、胺基、甲基胺基、二甲基胺基、氰基、C 1-4烷基、C 1-4鹵烷基及C 1-4烷氧基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R 1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , and ; and each R 12 is independently selected from the group consisting of: halo, hydroxyl, amine, methylamino, dimethylamino, cyano, C 1-4 alkyl, C 1-4 haloalkyl group and C 1-4 alkoxy group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係選自由以下組成之群： 、 、 、 、 、 、 、 、 及 ；及 各R 12係獨立地選自由以下組成之群：鹵基、羥基、胺基、甲基胺基、二甲基胺基、氰基、C 1-4烷基、C 1-4鹵烷基及C 1-4烷氧基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is selected from the group consisting of: , , , , , , , , and ; and each R 12 is independently selected from the group consisting of: halo, hydroxyl, amine, methylamino, dimethylamino, cyano, C 1-4 alkyl, C 1-4 haloalkyl group and C 1-4 alkoxy group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係選自由以下組成之群： 、 、 、 、 、 、 、 及 ；及 各R 12係獨立地選自由以下組成之群：鹵基、羥基、胺基、甲基胺基、二甲基胺基、氰基、C 1-4烷基、C 1-4鹵烷基及C 1-4烷氧基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R 1 is selected from the group consisting of: , , , , , , , and ; and each R 12 is independently selected from the group consisting of: halo, hydroxyl, amino, methylamino, dimethylamino, cyano, C 1-4 alkyl, C 1-4 haloalkyl group and C 1-4 alkoxy group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，各R 12係獨立地選自由以下組成之群：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14。在一些實施例中，各R 12係獨立地選自由以下組成之群：鹵基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14。在一些實施例中，各R 12係獨立地選自由以下組成之群：鹵基、羥基、胺基、甲基胺基、二甲基胺基、氰基、C 1-4烷基、C 1-4鹵烷基及C 1-4烷氧基。在一些實施例中，各R 12係獨立地選自由以下組成之群：鹵基、C 1-4烷基、C 1-4烷氧基及C 1-4鹵烷基。在一些實施例中，各R 12係獨立地選自由以下組成之群：F、Cl、Br、CH 3、OCH 3及CF 3。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), each R 12 is independently selected from the group consisting of: halo, hydroxyl, amine, C 1 -4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 aminoalkyl and OR 14 . In some embodiments, each R 12 is independently selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and OR 14 . In some embodiments, each R 12 is independently selected from the group consisting of halo, hydroxyl, amine, methylamino, dimethylamino, cyano, C 1-4 alkyl, C 1 -4 haloalkyl and C 1-4 alkoxy. In some embodiments, each R 12 is independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl. In some embodiments, each R12 is independently selected from the group consisting of: F, Cl, Br, CH3 , OCH3 , and CF3 .

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，各R 12係獨立地選自由以下組成之群：F、Cl、Br、CH 3、OCH 3、CF 3、 、 、 及 。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), each R12 is independently selected from the group consisting of: F, Cl, Br, CH3 , OCH 3 , CF 3 , , , and .

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係選自由以下組成之群： 、 及 ；及 各R 12係獨立地選自由以下組成之群：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4胺基烷基及OR 14，其中R 14係如本文定義及描述。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R 1 is selected from the group consisting of: , and ; and each R 12 is independently selected from the group consisting of: halo, hydroxyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amine, C 1-4 alkyl , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 aminoalkyl and OR 14 , wherein R 14 is as defined and described herein.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，各R 12係獨立地選自由以下組成之群：F、Cl、Br、CH 3、OCH 3、CF 3及OR 14；及R 14係選自由以下組成之群： 、 、 及 。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), each R12 is independently selected from the group consisting of: F, Cl, Br, CH3 , OCH 3 , CF 3 and OR 14 ; and R 14 are selected from the group consisting of: , , and .

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係由以下表示： 或 ；及 各R 12係獨立地選自由以下組成之群：鹵基、C 1-4烷基、C 1-4烷氧基及C 1-4鹵烷基。在一些實施例中，各R 12係獨立地選自由以下組成之群：F、Cl、Br、CH 3、OCH 3及CF 3。在一些實施例中，各R 12係Cl。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is represented by: or ; and each R 12 is independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 haloalkyl. In some embodiments, each R12 is independently selected from the group consisting of: F, Cl, Br, CH3 , OCH3 , and CF3 . In some embodiments, each R12 is Cl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係由以下表示： ；及 各R 12係獨立地選自由以下組成之群：鹵基、C 1-4烷基、C 1-4烷氧基及C 1-4鹵烷基。在一些實施例中，各R 12係獨立地選自由以下組成之群：F、Cl、Br、CH 3、OCH 3及CF 3。在一些實施例中，各R 12獨立地係Cl或Br。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R1 is represented by: ; and each R 12 is independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 haloalkyl. In some embodiments, each R12 is independently selected from the group consisting of: F, Cl, Br, CH3 , OCH3 , and CF3 . In some embodiments, each R12 is independently Cl or Br.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 14係獨立地選自由以下組成之群：C 6-10芳基及5至10員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。在一些實施例中，R 14係獨立地選自由以下組成之群：C 6-10芳基及5至10員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。在一些實施例中，R 14係獨立地選自由以下組成之群：C 6-10芳基及5至10員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：鹵基、羥基、氰基及C 1-4烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R 14 is independently selected from the group consisting of: C 6-10 aryl and 5 to 10 members Heteroaryl, each of which is unsubstituted or substituted with one or more groups independently selected from the group consisting of: C 1-4 alkylamide, amine, halo, hydroxyl , cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 Aminoalkyl. In some embodiments, R 14 is independently selected from the group consisting of: C 6-10 aryl and 5 to 10 membered heteroaryl, each of which is unsubstituted or substituted by one or two independently It is substituted by a group selected from the group consisting of: C 1-4 alkylamide group, halo group, hydroxyl group, cyano group and C 1-4 alkyl group. In some embodiments, R 14 is independently selected from the group consisting of: C 6-10 aryl and 5 to 10 membered heteroaryl, each of which is unsubstituted or substituted by one or two independently Ground is selected from the group consisting of substituted groups: halo, hydroxyl, cyano and C 1-4 alkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 14獨立地係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。在一些實施例中，R 14獨立地係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。在一些實施例中，R 14獨立地係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：鹵基、羥基、氰基及C 1-4烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R 14 is independently phenyl or has 1 to 4 independently selected from N, O, and S The heteroatom is a 5- to 6-membered heteroaryl group at the ring vertex, each of which is unsubstituted or substituted with one or more groups independently selected from the group consisting of: C 1-4 alkyl chelate Amino group, amine group, halo group, hydroxyl group, cyano group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 haloalkyl group, C 1-4 haloalkoxy group, C 1- 4- alkylamino and C 1-4 aminoalkyl. In some embodiments, R 14 is independently phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, each of which is Unsubstituted or substituted with one or two groups independently selected from the group consisting of C 1-4 alkylamide, halo, hydroxyl, cyano and C 1-4 alkyl. In some embodiments, R 14 is independently phenyl or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S as ring vertices, each of which is Unsubstituted or substituted with one or two groups independently selected from the group consisting of halo, hydroxyl, cyano and C 1-4 alkyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。在一些實施例中，R 14係苯基，未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。在一些實施例中，R 14係苯基，經C 1-4烷基醯胺基取代。在一些實施例中，R 14係經-C(O)NHMe取代之苯基。在一些實施例中，R 14係苯基。在一些實施例中，R 14係吡唑基，未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。在一些實施例中，R 14係經C 1-4烷基取代之吡唑基。在一些實施例中，R 14係經甲基取代之吡唑基。在一些實施例中，R 14係N-甲基吡唑基。在一些實施例中，R 14係吡唑基。 In some embodiments of any of Formulas (I), (Ia) to (Ic) and (II), R 14 is phenyl or pyrazolyl, each of which is unsubstituted or Or substituted by two groups independently selected from the group consisting of C 1-4 alkylamide group, halo group, hydroxyl group, cyano group and C 1-4 alkyl group. In some embodiments, R 14 is phenyl, unsubstituted or substituted with one or two groups independently selected from the group consisting of: C 1-4 alkylamide, halo, hydroxyl, cyano group and C 1-4 alkyl group. In some embodiments, R 14 is phenyl, substituted with C 1-4 alkylamide. In some embodiments, R 14 is phenyl substituted with -C(O)NHMe. In some embodiments, R 14 is phenyl. In some embodiments, R 14 is pyrazolyl, unsubstituted or substituted with one or two groups independently selected from the group consisting of: C 1-4 alkylamide group, halo group, hydroxyl group, Cyano group and C 1-4 alkyl group. In some embodiments, R 14 is pyrazolyl substituted with C 1-4 alkyl. In some embodiments, R 14 is pyrazolyl substituted with methyl. In some embodiments, R 14 is N-methylpyrazolyl. In some embodiments, R 14 is pyrazolyl.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係由以下表示： ； 各R 12係獨立地選自由以下組成之群：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及C 1-4胺基烷基；及R 14係苯基或具有1至4個獨立地選自N、O及S之雜原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。 In some embodiments of any of Formulas (I), (Ia) to (Ic), and (II), R1 is represented by: ; Each R 12 is independently selected from the group consisting of: halo group, hydroxyl group, amino group, C 1-4 alkylamino group, di(C 1-4 alkyl)amine group, C 1-4 alkyl group, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 aminoalkyl; and R 14 is phenyl or has 1 to 4 heteroatoms independently selected from N, O and S as 5- to 6-membered heteroaryl groups at the ring apex, each of which is unsubstituted or substituted by one or two groups independently selected from the group consisting of: C 1-4 alkyl amide group, Halogen group, hydroxyl group, cyano group and C 1-4 alkyl group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係由以下表示： ； 各R 12係獨立地選自由以下組成之群：鹵基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14；及R 14係苯基或具有1至4個雜獨立地選自N、O及S之原子作為環頂點之5至6員雜芳基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R1 is represented by: ; Each R 12 is independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and OR 14 ; and R 14 is phenyl or A 5- to 6-membered heteroaryl group having 1 to 4 atoms independently selected from N, O and S as ring vertices, each of which is unsubstituted or has one or two atoms independently selected from the following The group consisting of the group substitution: C 1-4 alkylamide group, halo group, hydroxyl group, cyano group and C 1-4 alkyl group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係由以下表示： ； 各R 12係獨立地選自由以下組成之群：鹵基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14；及R 14係選自由以下組成之群：苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R1 is represented by: ; Each R 12 is independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and OR 14 ; and R 14 is selected from the following The group consisting of: phenyl or pyrazolyl, each of which is unsubstituted or substituted with one or two groups independently selected from the group consisting of: C 1-4 alkyl amide group, Halogen group, hydroxyl group, cyano group and C 1-4 alkyl group.

在式(I)、(Ia)至(Ic)及(II)之任一者之一些實施例中，R 1係由以下表示： ； 各R 12係獨立地選自由以下組成之群：鹵基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14；及R 14係選自由以下組成之群：苯基、經C 1-4烷基醯胺基取代之苯基、吡唑基及經C 1-4烷基取代之吡唑基。在一些實施例中，各R 12係獨立地選自由以下組成之群：F、Cl、Br、CH 3、OCH 3及CF 3；及R 14係選自由以下組成之群：苯基、MeNHC(O)-苯基、吡唑基及N-甲基吡唑基。在一些實施例中，各R 12係Cl；及R 14係選自由以下組成之群：苯基、MeNHC(O)-苯基、吡唑基及N-甲基吡唑基。 In some embodiments of any of formulas (I), (Ia) to (Ic), and (II), R1 is represented by: ; Each R 12 is independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and OR 14 ; and R 14 is selected from the following The group consisting of: phenyl, phenyl substituted by C 1-4 alkylamide group, pyrazolyl and pyrazolyl substituted by C 1-4 alkyl. In some embodiments, each R 12 is independently selected from the group consisting of: F, Cl, Br, CH 3 , OCH 3 and CF 3 ; and R 14 is selected from the group consisting of: phenyl, MeNHC ( O)-phenyl, pyrazolyl and N-methylpyrazolyl. In some embodiments, each R 12 is Cl; and R 14 is selected from the group consisting of phenyl, MeNHC(O)-phenyl, pyrazolyl, and N-methylpyrazolyl.

在某些實施例中，化合物係由式(II)表示： (II) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中： R 1係苯基或吡啶基，其等中之各者係經0至3個R 12取代； 各R 12係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14； R 6係選自由以下組成之群：胺基、C 1-4胺基烷基及C 1-4烷基胺基； R 7係選自由以下組成之群：氫、氰基、醯胺基、鹵基及羥基，或係選自由以下組成之群：C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基，其等中之任一者係未經取代或經一至三個獨立地選自由以下組成之群之取代基取代：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基； R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基；及 R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。 In certain embodiments, the compound is represented by Formula (II): (II) Or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof, wherein: R 1 is phenyl or pyridyl, etc. Each of them is substituted by 0 to 3 R 12 ; each R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 haloalkyl and OR 14 ; R 6 is selected from the group consisting of amine, C 1-4 aminoalkyl and C 1-4 alkylamino; R 7 is selected from the group consisting of hydrogen , cyano, amide, halo and hydroxyl, or selected from the group consisting of: C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5 or 6-membered heteroaryl, any of which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: amino, halo, hydroxyl, cyano, trifluoromethyl , trifluoromethoxy, C 1-4 alkyl and C 1-4 alkoxy; R 13 is selected from the group consisting of: hydrogen, halo, cyano, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl; and R 14 is phenyl or pyrazolyl, each of which is without Substituted or substituted by one or two groups independently selected from the group consisting of C 1-4 alkylamide, halo, hydroxyl, cyano and C 1-4 alkyl.

在某些實施例中，化合物係由式(III)表示： (III) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中： R 1係苯基或吡啶基，其等中之各者係經0至3個R 12取代； 各R 12係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14； R 6係選自由以下組成之群：胺基、C 1-4胺基烷基及C 1-4烷基胺基； R 7係選自由以下組成之群：氫、氰基、醯胺基、鹵基及羥基，或係選自由以下組成之群：C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基，其等中之任一者係未經取代或經一至三個獨立地選自由以下組成之群之取代基取代：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基； R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基；及 R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。 In certain embodiments, the compound is represented by Formula (III): (III) Or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof, wherein: R 1 is phenyl or pyridyl, etc. Each of them is substituted by 0 to 3 R 12 ; each R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 haloalkyl and OR 14 ; R 6 is selected from the group consisting of amine, C 1-4 aminoalkyl and C 1-4 alkylamino; R 7 is selected from the group consisting of hydrogen , cyano, amide, halo and hydroxyl, or selected from the group consisting of: C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5 or 6-membered heteroaryl, any of which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: amino, halo, hydroxyl, cyano, trifluoromethyl , trifluoromethoxy, C 1-4 alkyl and C 1-4 alkoxy; R 13 is selected from the group consisting of: hydrogen, halo, cyano, C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl; and R 14 is phenyl or pyrazolyl, each of which is without Substituted or substituted by one or two groups independently selected from the group consisting of C 1-4 alkylamide, halo, hydroxyl, cyano and C 1-4 alkyl.

在某些實施例中，化合物係由式(IV)表示： (IV) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中： R 1係苯基或吡啶基，其等中之各者係經0至3個R 12取代； 各R 12係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14； R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基； R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基；及 各R a係獨立地選自由以下組成之群：胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及 C 1-4胺基烷基。 In certain embodiments, the compound is represented by Formula (IV): (IV) Or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof, wherein: R 1 is phenyl or pyridyl, etc. Each of them is substituted by 0 to 3 R 12 ; each R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 haloalkyl and OR 14 ; R 13 is selected from the group consisting of: hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl; R 14 is phenyl or pyrazolyl, each of which is unsubstituted or one or two independently selected from the group consisting of The group substitution: C 1-4 alkylamide group, halo group, hydroxyl, cyano group and C 1-4 alkyl group; and each R a is independently selected from the group consisting of: amine group, halo group, Hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1- 4 aminoalkyl.

在某些實施例中，化合物係由式(V)表示： (V) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中： R 1係苯基或吡啶基，其等中之各者係經0至3個R 12取代； 各R 12係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14；及 R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基； R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基；及 R a係選自由以下組成之群：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。 In certain embodiments, the compound is represented by Formula (V): (V) Or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof, wherein: R 1 is phenyl or pyridyl, etc. Each of them is substituted by 0 to 3 R 12 ; each R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 haloalkyl and OR 14 ; and R 13 is selected from the group consisting of: hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl; R 14 is phenyl or pyrazolyl, each of which is unsubstituted or has one or two independently selected from the following: Group substitution of the group: C 1-4 alkylamide group, halo group, hydroxyl, cyano group and C 1-4 alkyl group; and R a is selected from the group consisting of: amine group, halo group, hydroxyl group, Cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl and C 1-4 alkoxy.

在某些實施例中，化合物係由式(VI)表示： (VI) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中： R 1係苯基或吡啶基，其等中之各者係經0至3個R 12取代； 各R 12係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14；及 R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基； R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基；及 各R a係獨立地選自由以下組成之群：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。 In certain embodiments, the compound is represented by Formula (VI): (VI) Or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof, wherein: R 1 is phenyl or pyridyl, etc. Each of them is substituted by 0 to 3 R 12 ; each R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 haloalkyl and OR 14 ; and R 13 is selected from the group consisting of: hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl; R 14 is phenyl or pyrazolyl, each of which is unsubstituted or has one or two independently selected from the following: Group substitutions of the group: C 1-4 alkylamide group, halo group, hydroxyl, cyano group and C 1-4 alkyl group; and each R a is independently selected from the group consisting of: amine group, halo group , hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl and C 1-4 alkoxy.

在某些實施例中，化合物係由式(VII)表示： (VII) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中： R 1係苯基或吡啶基，其等中之各者係經0至3個R 12取代； 各R 12係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14；及 R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基； R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基；及 各R a係獨立地選自由以下組成之群：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。 In certain embodiments, the compound is represented by Formula (VII): (VII) or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof, wherein: R 1 is phenyl or pyridyl, etc. Each of them is substituted by 0 to 3 R 12 ; each R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 haloalkyl and OR 14 ; and R 13 is selected from the group consisting of: hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl; R 14 is phenyl or pyrazolyl, each of which is unsubstituted or has one or two independently selected from the following: Group substitutions of the group: C 1-4 alkylamide group, halo group, hydroxyl, cyano group and C 1-4 alkyl group; and each R a is independently selected from the group consisting of: amine group, halo group , hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl and C 1-4 alkoxy.

在某些實施例中，化合物係由式(VIII)表示： (VIII) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中： R 1係苯基或吡啶基，其等中之各者係經0至3個R 12取代； 各R 1係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14；及 R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基； R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基；及 各R a係獨立地選自由以下組成之群：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。 In certain embodiments, the compound is represented by Formula (VIII): (VIII) or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof, wherein: R 1 is phenyl or pyridyl, etc. Each of them is substituted by 0 to 3 R 12 ; each R 1 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 haloalkyl and OR 14 ; and R 13 is selected from the group consisting of: hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl; R 14 is phenyl or pyrazolyl, each of which is unsubstituted or has one or two independently selected from the following: Group substitutions of the group: C 1-4 alkylamide group, halo group, hydroxyl, cyano group and C 1-4 alkyl group; and each R a is independently selected from the group consisting of: amine group, halo group , hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl and C 1-4 alkoxy.

在某些實施例中，化合物係由式(IX)表示： (IX) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中： R 1係苯基或吡啶基，其等中之各者係經0至3個R 12取代； 各R 12係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14；及 R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基； R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基；及 R a係選自由以下組成之群：胺基、鹵基、羥基、氰基、三氟甲基、三氟甲氧基、C 1-4烷基及C 1-4烷氧基。 In certain embodiments, the compound is represented by Formula (IX): (IX) or its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, conformational isomers, tautomers, or combinations thereof, wherein: R 1 is phenyl or pyridyl, etc. Each of them is substituted by 0 to 3 R 12 ; each R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 haloalkyl and OR 14 ; and R 13 is selected from the group consisting of: hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl; R 14 is phenyl or pyrazolyl, each of which is unsubstituted or has one or two independently selected from the following: Group substitution of the group: C 1-4 alkylamide group, halo group, hydroxyl, cyano group and C 1-4 alkyl group; and R a is selected from the group consisting of: amine group, halo group, hydroxyl group, Cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl and C 1-4 alkoxy.

在某些實施例中，化合物係由式(X)表示： (X) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中： R 1係苯基或吡啶基，其等中之各者係經0至3個R 12取代； 各R 12係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14；及 R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基； R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基；及 各R a係獨立地選自由以下組成之群：胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In certain embodiments, the compound is represented by Formula (X): (X) Or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof, wherein: R 1 is phenyl or pyridyl, etc. Each of them is substituted by 0 to 3 R 12 ; each R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 haloalkyl and OR 14 ; and R 13 is selected from the group consisting of: hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl; R 14 is phenyl or pyrazolyl, each of which is unsubstituted or has one or two independently selected from the following: Group substitutions of the group: C 1-4 alkylamide group, halo group, hydroxyl, cyano group and C 1-4 alkyl group; and each R a is independently selected from the group consisting of: amine group, halo group , hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1 -4 aminoalkyl.

在某些實施例中，化合物係由式(XI)表示： (XI) 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合，其中： R 1係苯基或吡啶基，其等中之各者係經0至3個R 12取代； 各R 12係獨立地選自由以下組成之群：鹵基、羥基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14；及 R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基； R 14係苯基或吡唑基，其等中之各者係未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基；及 各R a係獨立地選自由以下組成之群：胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基。 In certain embodiments, the compound is represented by Formula (XI): (XI) or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof, wherein: R 1 is phenyl or pyridyl, etc. Each of them is substituted by 0 to 3 R 12 ; each R 12 is independently selected from the group consisting of: halo, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 haloalkyl and OR 14 ; and R 13 is selected from the group consisting of: hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl; R 14 is phenyl or pyrazolyl, each of which is unsubstituted or has one or two independently selected from the following: Group substitutions of the group: C 1-4 alkylamide group, halo group, hydroxyl, cyano group and C 1-4 alkyl group; and each R a is independently selected from the group consisting of: amine group, halo group , hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1 -4 aminoalkyl.

在式(II)至(XI)之任一者之一些實施例中，R 1、R 6、R 7、R 12、R 13及R 14可具有上述選定實施例之任一者或多者中列舉之含義。 In some embodiments of any one of formulas (II) to (XI), R 1 , R 6 , R 7 , R 12 , R 13 and R 14 can have any one or more of the selected embodiments described above. The meaning of enumeration.

在式(II)至(XI)之任一者之一些實施例中，R 13係選自由以下組成之群：氫、鹵基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基及C 3-8環烷基。在一些實施例中，R 13係選自由以下組成之群：氫、鹵基、C 1-6烷基及C 1-6鹵烷基。在一些實施例中，R 13係選自由以下組成之群：氫、鹵基、C 1-4烷基及C 1-4鹵烷基。在一些實施例中，R 13係選自由以下組成之群：氫、Cl、Br、甲基及CF 3。在一些實施例中，R 13係氫。在一些實施例中，R 13係Cl。在一些實施例中，R 13係Br。在一些實施例中，R 13係甲基。在一些實施例中，R 13係CF 3。 In some embodiments of any one of formulas (II) to (XI), R 13 is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl and C 3-8 cycloalkyl. In some embodiments, R 13 is selected from the group consisting of hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, R 13 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, and C 1-4 haloalkyl. In some embodiments, R 13 is selected from the group consisting of: hydrogen, Cl, Br, methyl, and CF 3 . In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is Cl. In some embodiments, R 13 is Br. In some embodiments, R 13 is methyl. In some embodiments, R 13 is CF 3 .

在式(II)至(XI)之任一者之一些實施例中，R 1係苯基或吡啶基，其等中之各者係經1至3個R 12取代。在一些實施例中，R 1係苯基或吡啶基，其等中之各者係經2或3個R 12取代。在一些實施例中，R 1係經2或3個R 12取代之苯基。在一些實施例中，R 1係經2個R 12取代之苯基。在一些實施例中，R 1係經3個R 12取代之苯基。在一些實施例中，R 1係經2個R 12取代之吡啶基。 In some embodiments of any of formulas (II) to (XI), R 1 is phenyl or pyridyl, each of which is substituted with 1 to 3 R 12 . In some embodiments, R 1 is phenyl or pyridyl, each of which is substituted with 2 or 3 R 12 . In some embodiments, R 1 is phenyl substituted with 2 or 3 R 12 . In some embodiments, R 1 is phenyl substituted with 2 R 12 . In some embodiments, R 1 is phenyl substituted with 3 R 12 . In some embodiments, R 1 is pyridyl substituted with 2 R 12 .

在式(II)至(XI)之任一者之一些實施例中，各R 12係獨立地選自由以下組成之群：鹵基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基及OR 14。在一些實施例中，各R 12係獨立地選自由以下組成之群：鹵基、羥基、胺基、甲基胺基、二甲基胺基、氰基、C 1-4烷基、C 1-4鹵烷基及C 1-4烷氧基。在一些實施例中，各R 12係獨立地選自由以下組成之群：鹵基、C 1-4烷基、C 1-4烷氧基及C 1-4鹵烷基。在一些實施例中，各R 12係獨立地選自由以下組成之群：F、Cl、Br、CH 3、OCH 3及CF 3。 In some embodiments of any one of formulas (II) to (XI), each R 12 is independently selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and OR 14 . In some embodiments, each R 12 is independently selected from the group consisting of halo, hydroxyl, amine, methylamino, dimethylamino, cyano, C 1-4 alkyl, C 1 -4 haloalkyl and C 1-4 alkoxy. In some embodiments, each R 12 is independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl. In some embodiments, each R12 is independently selected from the group consisting of: F, Cl, Br, CH3 , OCH3 , and CF3 .

在式(II)至(XI)之任一者之一些實施例中，各R 12係獨立地選自由以下組成之群：F、Cl、Br、CH 3、OCH 3、CF 3、 、 、 及 。 In some embodiments of any of formulas (II) to (XI), each R 12 is independently selected from the group consisting of: F, Cl, Br, CH 3 , OCH 3 , CF 3 , , , and .

在式(II)至(XI)之任一者之一些實施例中，R 1係經2個R 12取代之苯基；及各R 12係獨立地選自由以下組成之群：F、Cl、Br、CH 3、OCH 3及CF 3。在一些實施例中，R 1係經2個R 12取代之苯基；及各R 12係Cl。 In some embodiments of any one of formulas (II) to (XI), R 1 is phenyl substituted with 2 R 12 ; and each R 12 is independently selected from the group consisting of: F, Cl, Br, CH 3 , OCH 3 and CF 3 . In some embodiments, R 1 is phenyl substituted with 2 R 12 ; and each R 12 is Cl.

在式(II)至(XI)之任一者之一些實施例中，R 1係經3個R 12取代之苯基；及各R 12係獨立地選自由以下組成之群：F、Cl、Br、CH 3、OCH 3、CF 3、 、 、 及 。 In some embodiments of any one of formulas (II) to (XI), R 1 is phenyl substituted with 3 R 12 ; and each R 12 is independently selected from the group consisting of: F, Cl, Br, CH 3 , OCH 3 , CF 3 , , , and .

在式(II)至(XI)之任一者之一些實施例中，R 1係經3個R 12取代之苯基；第一及第二R 12各為Cl；及第三R 12為Br。在一些實施例中，R 1係經3個R 12取代之苯基；第一及第二R 12各為Cl；及第三R 12係選自由以下組成之群： 、 、 及 。 In some embodiments of any of formulas (II) to (XI), R 1 is phenyl substituted with 3 R 12 ; the first and second R 12 are each Cl; and the third R 12 is Br . In some embodiments, R 1 is phenyl substituted with 3 R 12 ; the first and second R 12 are each Cl; and the third R 12 is selected from the group consisting of: , , and .

在式(II)至(XI)之任一者之一些實施例中，在一些實施例中，R 14係苯基，未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。在一些實施例中，R 14係苯基，經C 1-4烷基醯胺基取代。在一些實施例中，R 14係經-C(O)NHMe取代之苯基。在一些實施例中，R 14係苯基。在一些實施例中，R 14係吡唑基，未經取代或經一或兩個獨立地選自由以下組成之群之基團取代：C 1-4烷基醯胺基、鹵基、羥基、氰基及C 1-4烷基。在一些實施例中，R 14係經C 1-4烷基取代之吡唑基。在一些實施例中，R 14係經甲基取代之吡唑基。在一些實施例中，R 14係N-甲基吡唑基。在一些實施例中，R 14係吡唑基。 In some embodiments of any one of formulas (II) to (XI), in some embodiments, R 14 is phenyl, unsubstituted or with one or two groups independently selected from the group consisting of Group substitution: C 1-4 alkyl amide group, halo group, hydroxyl group, cyano group and C 1-4 alkyl group. In some embodiments, R 14 is phenyl, substituted with C 1-4 alkylamide. In some embodiments, R 14 is phenyl substituted with -C(O)NHMe. In some embodiments, R 14 is phenyl. In some embodiments, R 14 is pyrazolyl, unsubstituted or substituted with one or two groups independently selected from the group consisting of: C 1-4 alkylamide group, halo group, hydroxyl group, Cyano group and C 1-4 alkyl group. In some embodiments, R 14 is pyrazolyl substituted with C 1-4 alkyl. In some embodiments, R 14 is pyrazolyl substituted with methyl. In some embodiments, R 14 is N-methylpyrazolyl. In some embodiments, R 14 is pyrazolyl.

在式(II)或(III)之一些實施例中，R 6係胺基或C 1-4胺基烷基。在某些實施例中，R 6係胺基或胺基甲基。在某些實施例中，R 6係胺基。在某些實施例中，R 6係胺基甲基。 In some embodiments of formula (II) or (III), R 6 is amino or C 1-4 aminoalkyl. In certain embodiments, R 6 is amino or aminomethyl. In certain embodiments, R 6 is amine. In certain embodiments, R 6 is aminomethyl.

在式(II)或(III)之一些實施例中，R 7係羥基、C 1-4烷基或C 1-4羥基烷基。在某些實施例中，R 7係C 1-4烷基。在某些實施例中，R 7係甲基。在某些實施例中，R 7係乙基。 In some embodiments of formula (II) or (III), R 7 is hydroxyl, C 1-4 alkyl or C 1-4 hydroxyalkyl. In certain embodiments, R 7 is C 1-4 alkyl. In certain embodiments, R 7 is methyl. In certain embodiments, R 7 is ethyl.

在式(II)或(III)之一些實施例中，R 6係胺基；及R 7係C 1-4烷基。在某些實施例中，R 6係胺基；及R 7係甲基。在一些實施例中，R 6係胺基；及R 7係乙基。在一些實施例中，R 6係胺基甲基；及R 7係C 1-4烷基。在某些實施例中，R 6係胺基甲基；及R 7係甲基。 In some embodiments of formula (II) or (III), R 6 is amine; and R 7 is C 1-4 alkyl. In certain embodiments, R 6 is amine; and R 7 is methyl. In some embodiments, R 6 is amine; and R 7 is ethyl. In some embodiments, R 6 is aminomethyl; and R 7 is C 1-4 alkyl. In certain embodiments, R 6 is aminomethyl; and R 7 is methyl.

在式(IV)至(XI)之任一者之一些實施例中，各R a係獨立地選自由以下組成之群：胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基及C 1-4鹵烷基。在一些實施例中，各R a獨立地係胺基或C 1-4烷基。在一些實施例中，各R a獨立地係胺基或甲基。 In some embodiments of any one of formulas (IV) to (XI), each R a is independently selected from the group consisting of: amine, halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 haloalkyl. In some embodiments, each R a is independently amine or C 1-4 alkyl. In some embodiments, each R a is independently amine or methyl.

在一些實施例中，化合物係由選自由以下組成之群的式表示： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 及 。 In some embodiments, the compound is represented by a formula selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

本發明亦提供其中上文任何實施例可與此等實施例中之任一者或多者組合之實施例，限制條件為該組合不為相互排斥的。The invention also provides embodiments in which any of the above embodiments can be combined with any one or more of these embodiments, with the proviso that the combinations are not mutually exclusive.

如本文使用，當將一個實施例定義為與另一個實施例不同之事物時，兩個實施例係「相互排斥」的。例如，其中兩個基團組合以形成環烷基之實施例係與其中一個基團為乙基另一個基團為氫之實施例相互排斥的。類似地，其中一個基團係CH 2之實施例係與其中相同基團為NH之實施例相互排斥的。 As used herein, when one embodiment is defined as something different than another embodiment, the two embodiments are "mutually exclusive." For example, embodiments in which two groups combine to form a cycloalkyl group are mutually exclusive from embodiments in which one group is ethyl and the other is hydrogen. Similarly, embodiments in which one group is CH2 are mutually exclusive from embodiments in which the same group is NH.

本文揭示之化合物可呈醫藥上可接受之鹽存在。本發明包括呈鹽(包括酸加成鹽)形式之上文列舉之化合物。合適之鹽包括彼等以有機酸及無機酸兩者形成者。此等酸加成鹽通常將為醫藥上可接受的。然而，非醫藥上可接受之鹽的鹽在所述化合物之製備及純化中可係有用的。亦可形成鹼性加成鹽且為醫藥上可接受的。The compounds disclosed herein may exist as pharmaceutically acceptable salts. The present invention includes the compounds enumerated above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will generally be pharmaceutically acceptable. However, salts other than pharmaceutically acceptable salts may be useful in the preparation and purification of the compounds. Basic addition salts may also be formed and are pharmaceutically acceptable.

術語「醫藥上可接受」係指彼等適用於與病患之組織接觸使用而無過度之毒性、刺激及過敏反應之化合物(或鹽、互變異構體、兩性離子形式等)，係與合理之利益/風險比相稱，且針對其等預期用途有效。The term "pharmaceutically acceptable" refers to compounds (or salts, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with patient tissues without undue toxicity, irritation, or allergic reactions, and are reasonably The benefit/risk ratio is proportionate and effective for its intended use.

如本文使用之術語「醫藥上可接受之鹽」表示本文揭示之化合物之鹽或兩性離子形式，其等如本文定義係水溶性或油溶性或可分散且醫藥上可接受的。該等鹽可在該等化合物之最終分離及純化期間或藉由使以游離鹼形式之適當之化合物與合適之酸反應單獨製備。代表性酸加成鹽包括乙酸鹽、己二酸鹽、海藻酸鹽、L-抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽(苯磺酸酯)、硫酸氫鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、雙葡萄糖酸鹽、甲酸鹽、富馬酸鹽、龍膽酸鹽、戊二酸鹽、甘油磷酸鹽、乙醇酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、馬尿酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、2-羥基乙磺酸鹽(羥乙基磺酸鹽)、乳酸鹽、馬來酸鹽、丙二酸鹽、DL-扁桃酸鹽、均三甲苯磺酸鹽、甲磺酸鹽、萘磺酸鹽、菸鹼酸鹽、2-萘磺酸鹽、草酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、膦酸鹽、苦味酸鹽、新戊酸鹽、丙酸鹽、焦麩胺酸鹽、琥珀酸鹽、磺酸鹽、酒石酸鹽、L-酒石酸鹽、三氯乙酸鹽、三氟乙酸鹽、磷酸鹽、麩胺酸鹽、碳酸氫鹽、對甲苯磺酸鹽(對甲苯磺酸酯)及十一酸鹽。此外，本文揭示之化合物中之鹼性基團可用以下四級銨化：甲基、乙基、丙基及丁基氯化物、溴化物及碘化物；二甲基、二乙基、二丁基及二戊基硫酸鹽；癸基、十二基、十四基及硬脂基氯化物、溴化物及碘化物；及苯甲基及苯乙基溴化物。可用以形成醫藥上可接受之加成鹽之酸之實例包括無機酸，諸如鹽酸、氫溴酸、硫酸及磷酸，及有機酸，諸如草酸、馬來酸、琥珀酸及檸檬酸。鹽亦可藉由該等化合物與鹼金屬或鹼土離子配位形成。因此，本發明審慎考慮本文揭示之化合物之鈉鹽、鉀鹽、鎂鹽及鈣鹽，及類似物。The term "pharmaceutically acceptable salts" as used herein means salts or zwitterionic forms of the compounds disclosed herein that are water- or oil-soluble or dispersible and pharmaceutically acceptable as defined herein. Such salts may be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (benzenesulfonate), bisulfate, Butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemi Sulfate, enanthate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate acid salt, malonate, DL-mandelate, mesitylate, methanesulfonate, naphthalene sulfonate, nicotinic acid salt, 2-naphthalene sulfonate, oxalate, dihydroxynaphthalene acid salt, pectate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate , tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate (p-toluenesulfonate) and undecanoate. In addition, the basic groups in the compounds disclosed herein can be ammonized in the following quaternary stages: methyl, ethyl, propyl and butyl chloride, bromide and iodide; dimethyl, diethyl, dibutyl and dipentyl sulfate; decyl, dodecyl, tetradecyl and stearyl chlorides, bromides and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination of these compounds with alkali metal or alkaline earth ions. Accordingly, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

鹼性加成鹽可在化合物之最終分離及純化期間藉由使羧基與合適之鹼(諸如金屬陽離子之氫氧化物、碳酸鹽或碳酸氫鹽)，或與氨或有機一級、二級或三級胺反應製備。醫藥上可接受之鹽之陽離子包括鋰、鈉、鉀、鈣、鎂及鋁，及無毒四級胺陽離子，諸如銨、四甲基銨、四乙基銨、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基嗎啉、二環己胺、普魯卡因、二苯甲基胺、N,N-二苯甲基苯乙胺、1-二苯羥甲胺及N,N'-二苯甲基乙二胺。適用於形成鹼加成鹽之其他代表性有機胺包括乙二胺、乙醇胺、二乙醇胺、哌啶及哌嗪。Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting the carboxyl group with a suitable base such as a hydroxide, carbonate or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary or tertiary salt. Grade amines are prepared by reaction. Pharmaceutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum, and non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine , triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine , diphenylmethylamine, N,N-diphenylmethylphenylethylamine, 1-diphenylhydroxymethylamine and N,N'-diphenylmethylethylenediamine. Other representative organic amines suitable for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

化合物之鹽可藉由使以游離鹼形式之適當之化合物與適當之酸反應製備。 V.     組合物 Salts of the compounds may be prepared by reacting the free base form of the appropriate compound with an appropriate acid. V. Composition

包括式(I)或式(10b)化合物之口服劑型可呈包括一或多種醫藥上可接受之載劑及/或賦形劑之任何口服劑型。口服製劑包括適用於由病患攝取之錠劑、藥丸、粉末、糖衣丸、膠囊、液體、***錠、扁囊劑、凝膠、糖漿、漿液、懸浮液等。Oral dosage forms including compounds of Formula (I) or Formula (10b) may be in any oral dosage form including one or more pharmaceutically acceptable carriers and/or excipients. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, buccal lozenges, cachets, gels, syrups, slurries, suspensions, etc. suitable for ingestion by patients.

為製備包括式(I)或式(10b)化合物之口服劑型，醫藥上可接受之載劑可為固體或液體。固體形式製劑包括粉末、錠劑、藥丸、膠囊、扁囊劑、栓劑及可分散顆粒。固體載劑可為一或多種物質，其等亦可充當稀釋劑、調味劑、黏合劑、防腐劑、錠劑崩解劑或囊封材料。有關用於調配及投與之技術之細節係詳細描述於科學及專利文獻中，例如，參見最新版Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA (「Remington’s」)。For the preparation of oral dosage forms comprising a compound of formula (I) or formula (10b), the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details regarding techniques for formulation and administration are described in detail in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

於粉末中，載劑係一種細碎之固體，其係與細碎之活性組分之混合。於錠劑中，該活性組分係與具有必需之結合性質之載劑以合適之比例混合並壓縮成所需之形狀及尺寸。In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compressed into the desired shape and size.

粉末、膠囊及錠劑較佳含有5%至70%之式(I)或式(10b)化合物，或約10%至約70%之式(I)或式(10b)化合物。合適之載劑係碳酸鎂、硬脂酸鎂、滑石、糖、乳糖、果膠、糊精、澱粉、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉、低熔點蠟、可可脂，及類似物。術語「製劑」旨在包括活性化合物與作為載劑之囊封材料之調配物，其提供一種有或無其他賦形劑之活性組分由載劑包圍(因此係與其結合)之膠囊。類似地，包括扁囊劑及***錠。錠劑、粉末、膠囊、藥丸、扁囊劑及***錠可用作適用於口服投與之固體劑型。Powders, capsules and tablets preferably contain 5% to 70% of a compound of formula (I) or formula (10b), or about 10% to about 70% of a compound of formula (I) or formula (10b). Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa Fats, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier, which provides a capsule in which the active ingredient, with or without other excipients, is surrounded by (and is therefore associated with) the carrier. Similarly, cachets and oral lozenges are included. Tablets, powders, capsules, pills, cachets and buccal lozenges may be used as solid dosage forms suitable for oral administration.

合適之固體賦形劑包括(但不限於)碳酸鎂；硬脂酸鎂；滑石；果膠；糊精；澱粉；黃蓍膠；低熔點蠟；可可脂；碳水化合物；糖類，包括(但不限於)乳糖、蔗糖、甘露醇或山梨醇、來自玉米、小麥、稻米、馬鈴薯或其他植物之澱粉；纖維素，諸如甲基纖維素、羥丙基甲基纖維素或羧甲基纖維素鈉；及樹膠，包括***樹膠及黃蓍膠；及蛋白質，包括(但不限於)明膠及膠原。視需要，可添加崩解劑或增溶劑，諸如交聯聚乙烯吡咯啶酮、瓊脂、海藻酸，或其鹽(諸如海藻酸鈉)。Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; low melting point wax; cocoa butter; carbohydrates; sugars, including but not Limited to) lactose, sucrose, mannitol or sorbitol, starch from corn, wheat, rice, potato or other plants; cellulose, such as methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose; and gums, including acacia and tragacanth; and proteins, including (but not limited to) gelatin and collagen. If desired, a disintegrant or solubilizing agent such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof (such as sodium alginate) may be added.

糖衣丸核心具有合適之包衣，諸如濃縮糖溶液，其等亦可含有***樹膠、滑石、聚乙烯吡咯啶酮、卡波姆(carbopol)凝膠、聚乙二醇及/或二氧化鈦、漆溶液、及合適之有機溶劑或溶劑混合物。可將染料或顏料添加至該等錠劑或糖衣丸包衣，用於產品鑑別或用以表徵活性化合物之量(即，劑量)。劑型之醫藥製劑亦可口服使用，例如，使用由明膠製成之推合式膠囊，及由明膠製成之軟質密封膠囊及包衣(諸如甘油或山梨醇)。推合式膠囊可含有與填充劑或黏合劑(諸如乳糖或澱粉)、潤滑劑(諸如滑石或硬脂酸鎂)及視需要選用之穩定劑混合之式(I)或式(10b)化合物。若軟質膠囊，則可將該式(I)或式(10b)化合物溶解或懸浮於合適之液體(諸如脂肪油、液體石蠟、或有或無穩定劑之液體聚乙二醇)中。The dragee core has a suitable coating, such as a concentrated sugar solution, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions , and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the amount of active compound (i.e., dosage). Pharmaceutical preparations in dosage forms can also be used orally, for example, using push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and coatings (such as glycerin or sorbitol). Push-fit capsules may contain a compound of formula (I) or formula (10b) mixed with a filler or binder such as lactose or starch, a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the case of soft capsules, the compound of formula (I) or formula (10b) can be dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin, or liquid polyethylene glycol with or without stabilizer).

為製備栓劑，使低熔點蠟(諸如脂肪酸甘油酯或可可脂之混合物)首先熔化及(諸如)藉由攪拌將式(I)或式(10b)化合物均勻分散於其中。然後將該熔化之均質混合物倒入尺寸合適之模具內，讓其等冷卻，並藉此固化。To prepare suppositories, a low-melting wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted and the compound of formula (I) or formula (10b) is uniformly dispersed therein, such as by stirring. The molten homogeneous mixture is then poured into a suitably sized mold and allowed to cool and solidify.

液體形式製劑包括溶液、懸浮液及乳液，例如，水或水/丙二醇溶液。Liquid form preparations include solutions, suspensions and emulsions, for example, water or water/propylene glycol solutions.

適用於口服使用之水溶液可藉由將式(I)或式(10b)化合物溶解於水中並視需要添加合適之著色劑、調味劑、穩定劑及增稠劑製備。適用於口服使用之水性懸浮液可藉由將細碎之活性組分分散於具有以下之水中製得：黏性材料，諸如天然或合成膠質、樹脂、甲基纖維素、羧甲基纖維素鈉、羥丙基甲基纖維素、海藻酸鈉、聚乙烯吡咯啶酮、黃蓍膠及***樹膠，及分散劑或潤濕劑，諸如天然生成之磷脂(例如，卵磷脂)、環氧烷與脂肪酸之縮合產物(例如，聚氧乙烯硬脂酸酯)、環氧乙烷與長鏈脂肪醇之縮合產物(例如，十七乙烯氧基鯨蠟醇)、環氧乙烷與來源於脂肪酸及己糖醇之偏酯之縮合產物(例如，聚氧乙烯山梨醇酐單油酸酯)或環氧乙烷與來源於脂肪酸及己醇酐之偏酯之縮合產物(例如，聚氧乙烯脫水山梨醇酐單油酸酯)。該水性懸浮液亦可含有一或多種防腐劑(諸如對羥基苯甲酸乙酯或正丙酯)、一或多種著色劑、一或多種調味劑及一或多種甜味劑(諸如蔗糖、阿斯巴甜或糖精)。可調整調配物之滲透性。Aqueous solutions suitable for oral use can be prepared by dissolving the compound of formula (I) or formula (10b) in water and adding suitable coloring agents, flavoring agents, stabilizers and thickeners if necessary. Aqueous suspensions suitable for oral use may be prepared by dispersing finely divided active ingredients in water containing: viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, Hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia, and dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), alkylene oxides and fatty acids Condensation products of ethylene oxide (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecyethyleneoxycetyl alcohol), ethylene oxide and fatty acids derived from fatty acids and hexane Condensation products of partial esters of sugar alcohols (e.g., polyoxyethylene sorbitan monooleate) or condensation products of ethylene oxide and partial esters derived from fatty acids and hexanol anhydride (e.g., polyoxyethylene sorbitan anhydride monooleate). The aqueous suspension may also contain one or more preservatives (such as ethyl or n-propyl parahydroxybenzoate), one or more coloring agents, one or more flavoring agents and one or more sweeteners (such as sucrose, aspen Batame or saccharin). The permeability of the formulation can be adjusted.

亦包括固體形式製劑，其等旨在使用前不久轉化為用於口服投與之液體形式製劑。此等液體形式包括溶液、懸浮液及乳液。除活性組分外，此等製劑可含有著色劑、調味劑、穩定劑、緩衝液、人工及天然甜味劑、分散劑、增稠劑、增溶劑，及類似物。Also included are solid form preparations which are intended to be converted shortly before use to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, such preparations may contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizers, and the like.

油懸浮液可藉由使式(I)或式(10b)化合物懸浮於植物油(諸如花生油、橄欖油、芝麻油或椰子油)中，或於礦物油(諸如液體石蠟)中；或此等之混合物調配。該等油懸浮液可含有增稠劑，諸如蜂蠟、硬質石蠟或鯨蠟醇。可添加甜味劑以提供適口之口服製劑，諸如甘油、山梨醇或蔗糖。此等調配物可藉由添加抗氧化劑(諸如抗壞血酸)保存。作為可注射油媒劑之一實例，參見Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997。包括式(I)或式(10b)化合物之醫藥調配物亦可呈水包油乳液之形式。油相可為植物油或礦物油，上文描述，或此等之混合物。合適之乳化劑包括天然生成之樹膠(諸如***樹膠及黃蓍膠)、天然生成之磷脂(諸如大豆卵磷脂)、來源於脂肪酸及己醇酐之酯或偏酯(諸如脫水山梨醇單油酸酯)及此等偏酯與環氧乙烷之縮合產物(諸如聚氧乙烯脫水山梨醇酐單油酸酯)。該乳液亦可含有甜味劑及調味劑，如於糖漿及酏劑之調配物中。此等調配物亦可含有緩和劑、防腐劑或著色劑。Oil suspensions can be obtained by suspending a compound of formula (I) or formula (10b) in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil), or in a mineral oil (such as liquid paraffin); or mixtures thereof Blending. These oil suspensions may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents may be added to provide a palatable oral preparation, such as glycerol, sorbitol, or sucrose. These formulations can be preserved by adding antioxidants such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Pharmaceutical formulations comprising compounds of formula (I) or formula (10b) may also be in the form of oil-in-water emulsions. The oil phase may be vegetable or mineral oil, as described above, or a mixture of these. Suitable emulsifiers include naturally occurring gums (such as acacia and tragacanth), naturally occurring phospholipids (such as soy lecithin), esters or partial esters derived from fatty acids and hexanol anhydrides (such as sorbitan monooleic acid). Esters) and the condensation products of these partial esters and ethylene oxide (such as polyoxyethylene sorbitan monooleate). The emulsions may also contain sweetening and flavoring agents, such as in the formulations of syrups and elixirs. These formulations may also contain demulcents, preservatives or coloring agents.

在一項態樣中，本發明提供一種於個體中治療癌症之醫藥組合物，該組合物包括： a)治療有效量之PTPN11抑制劑；及 b)治療有效量之PD-1/PD-L1抑制劑， 連同醫藥上可接受之載劑或賦形劑一起， 其中該PTPN11抑制劑係由如本文定義及描述之式(I)表示。 In one aspect, the invention provides a pharmaceutical composition for treating cancer in an individual, the composition comprising: a) A therapeutically effective amount of a PTPN11 inhibitor; and b) A therapeutically effective amount of a PD-1/PD-L1 inhibitor, Together with a pharmaceutically acceptable carrier or excipient, Wherein the PTPN11 inhibitor is represented by Formula (I) as defined and described herein.

癌症及/或實體腫瘤係根據第III-2節：癌症/實體腫瘤描述。在一些實施例中，該癌症及/或實體腫瘤係如第III-2節：癌症/實體腫瘤中描述之實施例之任一者。Cancer and/or solid tumors are described in accordance with Section III-2: Cancer/Solid Tumors. In some embodiments, the cancer and/or solid tumor is any of the embodiments described in Section III-2: Cancer/Solid Tumor.

個體係根據第III-3節：個體描述。在一些實施例中，該個體係如第III-3節：個體中描述之實施例之任一者。Individual systems are based on Section III-3: Individual Description. In some embodiments, the system is any of the embodiments described in Section III-3: Individuals.

由式(I)表示之PTPN11抑制劑係根據第III-1節：PTPN11抑制劑及/或PD-1/PD-L1抑制劑描述。在一些實施例中，式(I)之PTPN11抑制劑係如第III-1節：PTPN11抑制劑及/或PD-1/PD-L1抑制劑中描述之實施例之任一者。在一些實施例中，該式(I)之PTPN11抑制劑係式(10b)化合物。The PTPN11 inhibitor represented by formula (I) is described according to Section III-1: PTPN11 inhibitor and/or PD-1/PD-L1 inhibitor. In some embodiments, the PTPN11 inhibitor of formula (I) is any of the embodiments described in Section III-1: PTPN11 inhibitor and/or PD-1/PD-L1 inhibitor. In some embodiments, the PTPN11 inhibitor of Formula (I) is a compound of Formula (10b).

式(I)之PTPN11抑制劑係根據第IV.節化合物進一步描述。在一些實施例中，該式(I)之PTPN11抑制劑係如第IV.節化合物中描述之實施例之任一者。PTPN11 inhibitors of formula (I) are further described in terms of the compounds of Section IV. In some embodiments, the PTPN11 inhibitor of Formula (I) is any of the embodiments described in Section IV. Compounds.

PD-1/PD-L1抑制劑係根據第III-1節：PTPN11抑制劑及/或PD-1/PD-L1抑制劑描述。在一些實施例中，該PD-1/PD-L1抑制劑係如第III-1節：PTPN11抑制劑及/或PD-1/PD-L1抑制劑中描述之實施例之任一者。PD-1/PD-L1 inhibitors are described in Section III-1: PTPN11 inhibitors and/or PD-1/PD-L1 inhibitors. In some embodiments, the PD-1/PD-L1 inhibitor is any of the embodiments described in Section III-1: PTPN11 inhibitor and/or PD-1/PD-L1 inhibitor.

在一些實施例中，PD-1/PD-L1抑制劑係帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213或特泊利單抗。在一些實施例中，該PD-1/PD-L1抑制劑係帕博利珠單抗。在一些實施例中，當PTPN11抑制劑係由式(10b)表示時，該PD-1/PD-L1抑制劑不為納武單抗。In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cimepro RWLC, camrelizumab, toripalimab, palolizumab, tislelizumab, batilizumab, dotalizumab, M7824, Spartan cizumab, saxanilumab, refulimab, BMS-986213, or terpolizumab. In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab. In some embodiments, when the PTPN11 inhibitor is represented by Formula (10b), the PD-1/PD-L1 inhibitor is not nivolumab.

本發明之組合物(包括式(I)化合物及PD-1/PD-L1抑制劑)可以範圍廣泛之口服、非經腸及局部劑型製備。口服製劑包括適用於由病患攝取之錠劑、藥丸、粉末、糖衣丸、膠囊、液體、***錠、扁囊劑、凝膠、糖漿、漿液、懸浮液等。本發明之組合物亦可藉由注射投與，即，靜脈內、肌內、皮內、皮下、十二指腸內或腹腔內。此外，本文描述之組合物可藉由吸入(例如，鼻內)投與。另外，本發明之組合物可經皮投與。本發明之組合物亦可藉由眼內、***內及直腸內途徑(包括栓劑、吹入、粉末及噴霧劑調配物(針對類固醇吸入劑之實例，參見Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995；Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995))投與。The compositions of the invention (including compounds of formula (I) and PD-1/PD-L1 inhibitors) can be prepared in a wide range of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, buccal lozenges, cachets, gels, syrups, slurries, suspensions, etc. suitable for ingestion by patients. The compositions of the present invention may also be administered by injection, ie intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally or intraperitoneally. Additionally, the compositions described herein can be administered by inhalation (eg, intranasally). Additionally, the compositions of the present invention may be administered transdermally. Compositions of the present invention may also be administered by the intraocular, intravaginal, and intrarectal routes including suppository, insufflation, powder, and spray formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35: 1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995)).

為製備本發明之醫藥組合物(包括式(I)化合物及PD-1/PD-L1抑制劑)，醫藥上可接受之載劑可為固體或液體。固體形式製劑包括粉末、錠劑、藥丸、膠囊、扁囊劑、栓劑及可分散顆粒。固體載劑可為一或多種物質，其亦可充當稀釋劑、調味劑、黏合劑、防腐劑、錠劑崩解劑或囊封材料。有關用於調配及投與之技術之細節係詳細描述於科學及專利文獻中，例如，參見最新版Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA (「Remington’s」)。To prepare the pharmaceutical composition of the present invention (including the compound of formula (I) and the PD-1/PD-L1 inhibitor), the pharmaceutically acceptable carrier can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details regarding techniques for formulation and administration are described in detail in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

於粉末中，載劑係細碎之固體，其係與該細碎之活性組分混合。於錠劑中，該等活性組分係與具有必需之結合性質之載劑以合適之比例混合並壓縮成特定之形狀及尺寸。In powders, the carrier is a finely divided solid, which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compressed into specific shapes and sizes.

粉末、膠囊及錠劑較佳含有約5%至約70%之活性化合物，諸如約10%至約70%之活性化合物(例如，式(I)化合物及PD-1/PD-L1抑制劑)。合適之載劑係碳酸鎂、硬脂酸鎂、滑石、糖、乳糖、果膠、糊精、澱粉、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉、低熔點蠟、可可脂，及類似物。術語「製劑」旨在包括該活性化合物與作為載劑之囊封材料之調配物，提供一種有或無其他賦形劑之該活性組分係由載劑包圍(因此與其結合)之膠囊。類似地，包括扁囊劑及***錠。錠劑、粉末、膠囊、藥丸、扁囊劑及***錠可用作適用於口服投與之固體劑型。Powders, capsules and tablets preferably contain about 5% to about 70% active compound, such as about 10% to about 70% active compound (e.g., compounds of formula (I) and PD-1/PD-L1 inhibitors) . Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa Fats, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without other excipients, is surrounded by (and thus bound to) the carrier. Similarly, cachets and oral lozenges are included. Tablets, powders, capsules, pills, cachets and buccal lozenges are available as solid dosage forms suitable for oral administration.

合適之固體賦形劑包括(但不限於)碳酸鎂；硬脂酸鎂；滑石；果膠；糊精；澱粉；黃蓍膠；低熔點蠟；可可脂；碳水化合物；糖類，包括(但不限於)乳糖、蔗糖、甘露醇或山梨醇、來自玉米、小麥、稻米、馬鈴薯或其他植物之澱粉；纖維素，諸如甲基纖維素、羥丙基甲基纖維素或羧甲基纖維素鈉；及樹膠，包括***樹膠及黃蓍膠；及蛋白質，包括(但不限於)明膠及膠原。可添加崩解劑或增溶劑，諸如交聯聚乙烯吡咯啶酮、瓊脂、海藻酸，或其鹽(諸如海藻酸鈉)。Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; low melting point wax; cocoa butter; carbohydrates; sugars, including but not Limited to) lactose, sucrose, mannitol or sorbitol, starch from corn, wheat, rice, potato or other plants; cellulose, such as methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose; and gums, including acacia and tragacanth; and proteins, including (but not limited to) gelatin and collagen. Disintegrants or solubilizers such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or salts thereof (such as sodium alginate) may be added.

糖衣丸核心具有合適之包衣，諸如濃縮糖溶液，其等亦可含有***樹膠、滑石、聚乙烯吡咯啶酮、卡波姆凝膠、聚乙二醇及/或二氧化鈦、漆溶液及合適之有機溶劑或溶劑混合物。可將染料或顏料添加至錠劑或糖衣丸包衣用於產品鑑別或用以表徵活性化合物之量(即，劑量)。本發明之醫藥製劑亦可口服使用，例如，使用由明膠製成之推合式膠囊，及由明膠製成之軟質密封膠囊及包衣(諸如甘油或山梨醇)。推合式膠囊可含有與填充劑或黏合劑(諸如乳糖或澱粉)、潤滑劑(諸如滑石或硬脂酸鎂)及視需要選用之穩定劑混合之活性化合物(例如，式(I)化合物及PD-1/PD-L1抑制劑)。於軟質膠囊中，可將該等活性化合物(例如，該式(I)化合物及該PD-1/PD-L1抑制劑)溶解或懸浮於合適之液體(諸如脂肪油、液體石蠟或有或無穩定劑之液體聚乙二醇)中。The dragee core has a suitable coating, such as a concentrated sugar solution, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable Organic solvent or solvent mixture. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the amount of active compound (i.e., dosage). The pharmaceutical preparations of the present invention can also be used orally, for example, using push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and coatings (such as glycerin or sorbitol). Push-fit capsules may contain the active compounds (e.g., compounds of formula (I) and PD) mixed with fillers or binders such as lactose or starch, lubricants such as talc or magnesium stearate, and optionally stabilizers. -1/PD-L1 inhibitor). In soft capsules, the active compounds (eg, the compound of formula (I) and the PD-1/PD-L1 inhibitor) can be dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin, with or without stabilizer (liquid polyethylene glycol).

為製備栓劑，使低熔點蠟(諸如脂肪酸甘油酯或可可脂之混合物)首先熔化及(諸如)藉由攪拌將活性化合物(例如，式(I)化合物及PD-1/PD-L1抑制劑)均質分散於其中。然後將該熔化之均質混合物倒入尺寸合適之模具內，容許冷卻，並藉此固化。To prepare suppositories, a low-melting wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted and the active compound (e.g., a compound of formula (I) and a PD-1/PD-L1 inhibitor) is first melted, such as by stirring. homogeneously dispersed in it. The molten homogeneous mixture is then poured into appropriately sized molds and allowed to cool and thereby solidify.

液體形式製劑包括溶液、懸浮液及乳液，例如，水或水/丙二醇溶液。針對非經腸注射，液體製劑可調配於溶液於聚乙二醇水溶液中。Liquid form preparations include solutions, suspensions and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in aqueous polyethylene glycol solution.

適用於口服使用之水溶液可藉由將如本文定義及描述的活性化合物(例如，式(I)化合物及PD-1/PD-L1抑制劑)溶解於水中並添加任選之合適著色劑、調味劑、穩定劑及增稠劑製備。適用於口服使用之水性懸浮液可藉由將細碎之活性組分分散於具有以下之水中製得：黏性材料，諸如天然或合成樹膠、樹脂、甲基纖維素、羧甲基纖維素鈉、羥丙基甲基纖維素、海藻酸鈉、聚乙烯吡咯啶酮、黃蓍膠及***樹膠，及分散劑或潤濕劑，諸如天然生成之磷脂(例如，卵磷脂)、環氧烷與脂肪酸之縮合產物(例如，聚氧乙烯硬脂酸酯)、環氧乙烷與長鏈脂肪醇之縮合產物(例如，十七乙烯氧基鯨蠟醇)、環氧乙烷與來源於脂肪酸及己糖醇之偏酯之縮合產物(例如，聚氧乙烯山梨醇酐單油酸酯)或環氧乙烷與來源於脂肪酸及己醇酐之偏酯之縮合產物(例如，聚氧乙烯脫水山梨醇酐單油酸酯)。該水性懸浮液亦可含有一或多種防腐劑(諸如對羥基苯甲酸乙酯或正丙酯)、一或多種著色劑、一或多種調味劑及一或多種甜味劑(諸如蔗糖、阿斯巴甜或糖精)。可調整調配物之滲透性。Aqueous solutions suitable for oral use can be prepared by dissolving an active compound as defined and described herein (e.g., a compound of formula (I) and a PD-1/PD-L1 inhibitor) in water and optionally adding a suitable coloring agent, flavoring agent, etc. Preparation of agents, stabilizers and thickeners. Aqueous suspensions suitable for oral use may be prepared by dispersing finely divided active ingredients in water having: viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, Hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia, and dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), alkylene oxides and fatty acids Condensation products of ethylene oxide (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecyethyleneoxycetyl alcohol), ethylene oxide and fatty acids derived from fatty acids and hexane Condensation products of partial esters of sugar alcohols (e.g., polyoxyethylene sorbitan monooleate) or condensation products of ethylene oxide and partial esters derived from fatty acids and hexanol anhydride (e.g., polyoxyethylene sorbitan anhydride monooleate). The aqueous suspension may also contain one or more preservatives (such as ethyl or n-propyl parahydroxybenzoate), one or more coloring agents, one or more flavoring agents and one or more sweeteners (such as sucrose, aspen Batame or saccharin). The permeability of the formulation can be adjusted.

亦包括固體形式製劑，其等旨在使用前不久轉化為用於口服投與之液體形式製劑。此等液體形式包括溶液、懸浮液及乳液。除活性組分外，此等製劑可含有著色劑、調味劑、穩定劑、緩衝液、人工及天然甜味劑、分散劑、增稠劑、增溶劑，及類似物。Also included are solid form preparations which are intended to be converted shortly before use to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, such preparations may contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizers, and the like.

油懸浮液可藉由使活性化合物(例如，式(I)化合物及PD-1/PD-L1抑制劑)懸浮於植物油(諸如花生油、橄欖油、芝麻油或椰子油)中，或於礦物油(諸如液體石蠟)中；或此等之混合物調配。該等油懸浮液可含有增稠劑，諸如蜂蠟、硬質石蠟或鯨蠟醇。可添加甜味劑以提供適口之口服製劑，諸如甘油、山梨醇或蔗糖。此等調配物藉由添加抗氧化劑諸如抗壞血酸保存。作為可注射油媒劑之一實例，參見Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997。本發明之醫藥調配物亦可呈水包油乳液之形式。油相可為植物油或礦物油，上文描述，或此等之混合物。合適之乳化劑包括天然生成之樹膠(諸如***樹膠及黃蓍膠)、天然生成之磷脂(諸如大豆卵磷脂)、來源於脂肪酸及己醇酐之酯或偏酯(諸如脫水山梨醇單油酸酯)及此等偏酯與環氧乙烷之縮合產物(諸如聚氧乙烯脫水山梨醇酐單油酸酯)。該乳液亦可含有甜味劑及調味劑，如於糖漿及酏劑之調配物中。此等調配物亦可含有緩和劑、防腐劑或著色劑。Oil suspensions can be prepared by suspending the active compounds (e.g., compounds of formula (I) and PD-1/PD-L1 inhibitors) in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil), or in mineral oil ( Such as liquid paraffin); or mixtures thereof. These oil suspensions may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents may be added to provide a palatable oral preparation, such as glycerol, sorbitol, or sucrose. These formulations are preserved by adding antioxidants such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be vegetable or mineral oil, as described above, or a mixture of these. Suitable emulsifiers include naturally occurring gums (such as acacia and tragacanth), naturally occurring phospholipids (such as soy lecithin), esters or partial esters derived from fatty acids and hexanol anhydrides (such as sorbitan monooleic acid). Esters) and the condensation products of these partial esters and ethylene oxide (such as polyoxyethylene sorbitan monooleate). The emulsions may also contain sweetening and flavoring agents, such as in the formulations of syrups and elixirs. These formulations may also contain demulcents, preservatives or coloring agents.

本發明之組合物(包括式(I)化合物及PD-1/PD-L1抑制劑)可藉由任何合適之方式遞送，包括口服、非經腸及局部方法。經皮投與方法，藉由局部途徑，可調配成敷藥棒、溶液、懸浮液、乳液、凝膠、藥膏、軟膏、糊劑、凍膠劑、塗劑、粉末及噴霧劑。The compositions of the present invention (including compounds of formula (I) and PD-1/PD-L1 inhibitors) can be delivered by any suitable means, including oral, parenteral and topical methods. Transdermal administration method, through topical route, can be formulated into application sticks, solutions, suspensions, emulsions, gels, ointments, ointments, pastes, jelly, paints, powders and sprays.

本發明之組合物(包括式(I)化合物及PD-1/PD-L1抑制劑)亦可呈於體內緩慢釋放之微球遞送。例如，微球可經調配用於經由皮內注射含有藥物之微球，該等微球於皮下緩慢釋放(參見Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995；呈可生物降解及可注射凝膠調配物(例如，參見Gao Pharm. Res. 12:857-863, 1995)；或呈用於口服投與之微球(例如，參見Eyles, J. Pharm. Pharmacol. 49:669-674, 1997)投與。經皮及皮內途徑均提供數週或數月之持續遞送。The composition of the present invention (including the compound of formula (I) and the PD-1/PD-L1 inhibitor) can also be delivered in the form of microspheres that are slowly released in the body. For example, microspheres can be formulated for intradermal injection of drug-containing microspheres that are slowly released subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; Biodegradable and injectable gel formulations (see, for example, Gao Pharm. Res. 12:857-863, 1995); or in the form of microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49 :669-674, 1997) administration. Both transdermal and intradermal routes provide sustained delivery over weeks or months.

在另一實施例中，本發明之組合物可經調配用於非經腸投與，諸如靜脈內(IV)投與或投與至器官之體腔或管腔內。用於投與之調配物將通常包含溶解於醫藥上可接受之載劑中之本發明之組合物之溶液。可採用之可接受之媒劑及溶劑係水及林格氏(Ringer’s)溶液，等滲氯化鈉。另外，無菌固定油可用作溶劑或懸浮介質。出於此目的，可採用任何溫和固定油，包括合成單甘油酯或雙甘油酯。另外，脂肪酸(諸如油酸)可同樣用以製備注射劑。此等溶液係無菌的且一般不含非所需之物質。此等調配物可藉由各種滅菌技術滅菌。該等調配物可視需要含有醫藥上可接受之輔助物質以接近生理條件，諸如pH調節劑及緩衝劑、毒性調節劑，例如，乙酸鈉、氯化鈉、氯化鉀、氯化鈣、乳酸鈉及類似物。此等調配物中本發明之組合物之濃度可廣泛變化，且將主要基於流體體積、黏度、體重，及類似物，根據選定之特定投與模式及病患之需求選擇。針對IV投與，該調配物可為無菌可注射製劑，諸如無菌可注射水性或油性懸浮液。此懸浮液可使用彼等合適之分散劑或潤濕劑及懸浮劑調配。該無菌可注射製劑亦可為於無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液，諸如1,3-丁二醇之溶液。In another embodiment, the compositions of the present invention may be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. Formulations for administration will generally comprise solutions of the compositions of the invention dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that may be used are water and Ringer's solution, isotonic sodium chloride. Alternatively, sterile fixed oils can be used as solvents or suspending media. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. These solutions are sterile and generally contain no undesirable materials. These formulations can be sterilized by various sterilization techniques. Such formulations may optionally contain pharmaceutically acceptable auxiliary substances to approximate physiological conditions, such as pH adjusters and buffers, toxicity adjusters, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and Analogues. The concentration of the compositions of the present invention in such formulations can vary widely and will be selected based primarily on fluid volume, viscosity, body weight, and the like, depending on the particular mode of administration selected and the needs of the patient. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension may be formulated using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol.

在另一實施例中，本發明之組合物之調配物可藉由使用與細胞膜融合或經內吞之脂質體遞送，即，藉由採用附接至該脂質體，或直接附接至寡核苷酸之配體，結合至細胞之表面膜蛋白受體導致內吞作用。藉由使用脂質體，特定言之在脂質體表面攜載對靶細胞特異之配體，或另外優先針對特定器官之情況下，吾人可關注於將本發明之組合物活體內遞送至該等靶細胞內。(例如，參見Al-Muhammed, J. Microencapsul. 13:293-306, 1996；Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995；Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989)。In another embodiment, formulations of the compositions of the present invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, i.e., by using a liposome attached to the liposome, or directly attached to the oligosome. It is a glycoside ligand that binds to cell surface membrane protein receptors resulting in endocytosis. By using liposomes, specifically carrying ligands specific for target cells on the surface of the liposomes, or otherwise preferentially targeting specific organs, one may focus on delivering the compositions of the invention to such targets in vivo. within the cell. (See, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576- 1587, 1989).

基於脂質之藥物遞送系統包括脂質溶液、脂質乳液、脂質分散體、自乳化藥物遞送系統(SEDDS)及自微乳化藥物遞送系統(SMEDDS)。特定言之，SEDDS及SMEDDS係脂質、表面活性劑及助表面活性劑之各向同性混合物，其等可自發分散於水性介質中並形成精細乳液(SEDDS)或微乳液(SMEDDS)。適用於本發明之調配物中之脂質包括任何天然或合成脂質，包括(但不限於)芝麻籽油、橄欖油、蓖麻油、花生油、脂肪酸酯、甘油酯、Labrafil®、Labrasol®、Cremophor®、Solutol®、Tween®、Capryol®、Capmul®、Captex®及Peceol®。Lipid-based drug delivery systems include lipid solutions, lipid emulsions, lipid dispersions, self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). Specifically, SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants and co-surfactants, which can spontaneously disperse in an aqueous medium and form fine emulsions (SEDDS) or microemulsions (SMEDDS). Lipids suitable for use in the formulations of the present invention include any natural or synthetic lipid including, but not limited to, sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerides, Labrafil®, Labrasol®, Cremophor® , Solutol®, Tween®, Capryol®, Capmul®, Captex® and Peceol®.

本發明之醫藥調配物可呈鹽提供且可用許多酸形成，包括(但不限於)鹽酸、硫酸、乙酸、乳酸、酒石酸、蘋果酸、琥珀酸等。鹽趨於更易溶於呈相應之游離鹼形式之水性或其他質子溶劑中。在其他情況下，製劑可為凍乾粉末，例如，以1 mM至50 mM組胺酸、0.1%至2%蔗糖、2%至7%甘露醇在4.5至5.5之pH範圍下，其係在使用前與緩衝液組合。Pharmaceutical formulations of the present invention may be provided as salts and may be formed with a number of acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents in the corresponding free base form. In other cases, the formulation may be a lyophilized powder, for example, 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol at a pH range of 4.5 to 5.5, in Combine with buffer before use.

本發明之醫藥調配物可呈鹽提供且可用鹼形成，即陽離子鹽，諸如鹼金屬及鹼土金屬鹽，諸如鈉、鋰、鉀、鈣、鎂及銨鹽，諸如銨鹽、三甲基銨鹽、二乙基銨鹽及參(羥基甲基)甲基銨鹽。 VI.    套組 The pharmaceutical formulations of the present invention may be provided as salts and may be formed with bases, ie cationic salts, such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium and ammonium salts, such as ammonium salts, trimethylammonium salts , diethyl ammonium salt and ginseng (hydroxymethyl) methyl ammonium salt. VI. Set

在另一態樣中，本發明提供一種於個體中治療癌症之套組，該套組包括： a)治療有效量之PTPN11抑制劑；及 b)治療有效量之PD-1/PD-L1抑制劑， 連同指示有效投藥之說明書， 其中該PTPN11抑制劑係由如本文定義及描述之式(I)表示。 In another aspect, the invention provides a kit for treating cancer in an individual, the kit comprising: a) A therapeutically effective amount of a PTPN11 inhibitor; and b) A therapeutically effective amount of a PD-1/PD-L1 inhibitor, together with instructions for effective administration, Wherein the PTPN11 inhibitor is represented by Formula (I) as defined and described herein.

癌症及/或實體腫瘤係根據第III-2節：癌症/實體腫瘤描述。在一些實施例中，該癌症及/或實體腫瘤係如第III-2節：癌症/實體腫瘤中描述之實施例之任一者。Cancer and/or solid tumors are described in accordance with Section III-2: Cancer/Solid Tumors. In some embodiments, the cancer and/or solid tumor is any of the embodiments described in Section III-2: Cancer/Solid Tumor.

個體係根據第III-3節：個體描述。在一些實施例中，該個體係如第III-3節：個體中描述之實施例之任一者。Individual systems are based on Section III-3: Individual Description. In some embodiments, the system is any of the embodiments described in Section III-3: Individuals.

由式(I)表示之PTPN11抑制劑係根據第III-1節：PTPN11抑制劑及/或PD-1/PD-L1抑制劑描述。在一些實施例中，該式(I)之PTPN11抑制劑係如第III-1節：PTPN11抑制劑及/或PD-1/PD-L1抑制劑中描述之實施例之任一者。在一些實施例中，該式(I)之PTPN11抑制劑係式(10b)化合物。The PTPN11 inhibitor represented by formula (I) is described according to Section III-1: PTPN11 inhibitor and/or PD-1/PD-L1 inhibitor. In some embodiments, the PTPN11 inhibitor of formula (I) is any of the embodiments described in Section III-1: PTPN11 inhibitor and/or PD-1/PD-L1 inhibitor. In some embodiments, the PTPN11 inhibitor of Formula (I) is a compound of Formula (10b).

式(I)之PTPN11抑制劑係根據第IV.節化合物進一步描述。在一些實施例中，該式(I)之PTPN11抑制劑係如第IV.節化合物中描述之實施例之任一者。PTPN11 inhibitors of formula (I) are further described in terms of the compounds of Section IV. In some embodiments, the PTPN11 inhibitor of Formula (I) is any of the embodiments described in Section IV. Compounds.

PD-1/PD-L1抑制劑係根據第III-1節：PTPN11抑制劑及/或PD-1/PD-L1抑制劑描述。在一些實施例中，該PD-1/PD-L1抑制劑係如第III-1節：PTPN11抑制劑及/或PD-1/PD-L1抑制劑中描述之實施例之任一者。PD-1/PD-L1 inhibitors are described in Section III-1: PTPN11 inhibitors and/or PD-1/PD-L1 inhibitors. In some embodiments, the PD-1/PD-L1 inhibitor is any of the embodiments described in Section III-1: PTPN11 inhibitor and/or PD-1/PD-L1 inhibitor.

在一些實施例中，PD-1/PD-L1抑制劑係帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213或特泊利單抗。在一些實施例中，該PD-1/PD-L1抑制劑係帕博利珠單抗。在一些實施例中，當該PTPN11抑制劑係由式(10b)表示時，該PD-1/PD-L1抑制劑不為納武單抗。In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cimepro RWLC, camrelizumab, toripalimab, palolizumab, tislelizumab, batilizumab, dotalizumab, M7824, Spartan cizumab, saxanilumab, refulimab, BMS-986213, or terpolizumab. In some embodiments, the PD-1/PD-L1 inhibitor is pembrolizumab. In some embodiments, when the PTPN11 inhibitor is represented by Formula (10b), the PD-1/PD-L1 inhibitor is not nivolumab.

在一些實施例中，套組包括用於投與式(I)或式(10b)化合物及PD-1/PD-L1抑制劑之說明書。在一些實施例中，該套組包括用於投與該式(10b)化合物及該PD-1/PD-L1抑制劑之說明書。在一些實施例中，此等說明書包括與安全規定及該式(I)或式(10b)化合物及該PD-1/PD-L1抑制劑之投與時間及投與量有關之指示。在一些實施例中，此等說明書包括與安全規定及該式(10b)化合物及該PD-1/PD-L1抑制劑之投與時間及投與量有關之指示。In some embodiments, the kit includes instructions for administering a compound of Formula (I) or Formula (10b) and a PD-1/PD-L1 inhibitor. In some embodiments, the kit includes instructions for administering the compound of formula (10b) and the PD-1/PD-L1 inhibitor. In some embodiments, the instructions include instructions regarding safety regulations and the timing and amount of administration of the compound of Formula (I) or Formula (10b) and the PD-1/PD-L1 inhibitor. In some embodiments, the instructions include instructions regarding safety regulations and the timing and amount of administration of the compound of formula (10b) and the PD-1/PD-L1 inhibitor.

如本文描述由式(I)或式(10b)表示之PTPN11抑制劑及如本文描述之PD-1/PD-L1抑制劑可經調配用於同時投與或依序投與。在一些實施例中，該式(I)或式(10b)之PTPN11抑制劑及該PD-1/PD-L1抑制劑係經調配用於同時投與。在一些實施例中，該式(I)或式(10b)之PTPN11抑制劑及該PD-1/PD-L1抑制劑係經調配用於依序投與。在一些實施例中，該式(I)或式(10b)之PTPN11抑制劑係在投與該PD-1/PD-L1抑制劑之前投與。在一些實施例中，該式(I)或式(10b)之PTPN11抑制劑係在投與該PD-1/PD-L1抑制劑之後投與。 VII.   縮寫之列表 縮寫 定義 (e)CRF (電子)病例報告表 (p)ERK (磷酸化)細胞外訊息調節激酶 ADA 抗藥物抗體 AE 不良事件 ALK 間變性淋巴瘤激酶 ALT 丙胺酸胺基轉移酶(或轉胺酶) ANC 絕對中性粒細胞計數 aPTT 活化部分凝血活酶時間 AST 天冬胺酸胺基轉移酶(或轉胺酶) AUC 濃度時間曲線下面積 BBP BridgeBio Pharma BCRP 乳癌耐藥蛋白 BICR 盲態獨立中心審查 BMS Bristol Myers Squibb BOIN 貝葉斯最優區間 CI 置信區間 C max 最大藥物濃度 CNS 中樞神經系統 CR 完全反應 CRO 合同研究組織 CT 電腦斷層攝影 CTCAE 不良事件之通用術語標準 CYP 細胞色素P450 DLT 劑量限制毒性 DNA 脫氧核糖核酸 DOR 反應持續時間 DUSP6 雙特異性磷酸酶6 ECG 心電圖 ECHO 心臟超音波檢查 ECOG 美國東部腫瘤協作組 EDC 電子資料摘取(系統) EGFR 上皮生長因子受體 EORTC 歐洲癌症研究與治療組織 EOS 研究結束 EOT 治療結束 FDA 美國食品藥品監督管理局 FSH 卵泡刺激激素 GCP 優良臨床試驗規範 GLP 優良實驗室操作準則 GMP 優良藥品製造規範 HBV B型肝炎病毒 HCV C型肝炎病毒 HIV 人類免疫缺乏病毒 IACS 應用癌症科學研究所 IB 研究者手冊 ICF 知情同意書 ICH 國際協調會議 IEC 獨立倫理委員會 INR 國際標準化比值 IRB 研究倫理委員會 IRR 輸注相關反應 IV 靜脈內 KRAS 柯爾斯頓(Kirsten)大鼠肉瘤病毒致癌基因同源物 LD (或LDi) 最長直徑 LVEF 左心室射出分率 MAPK 促***原活化蛋白激酶 MATE 多藥及毒素外排轉運蛋白 MRI 磁振造影 MTD 最大耐受劑量 MUGA 多門控採集掃描(放射性核素血管造影術) NCI 美國國家癌症研究所 NGS 次世代定序 NSCLC 非小細胞肺癌 OATP 有機陰離子轉運蛋白多肽 ORR 客觀反應率 OS 整體存活 PD 疾病進展 PD-1 計畫性細胞死亡-1 PD-L1 計畫性細胞死亡配體-1 PET 正電子發射斷層攝影術 PFS 無進展生存期 P-gp P-醣蛋白 PI 包裝插頁 PK 藥物動力學 PR 部分反應 PS 功能狀態評分 PT 凝血酶原時間 PTPN11 蛋白酪胺酸磷酸酶非受體11型，編碼SHP2之基因 QD 每天一次 RAF 快速加速纖維肉瘤 RAS 基因家族中之任一者，其經受突變為致癌基因且尤其突變為一些通常與人類癌症(如結腸癌、肺癌及胰臟癌)相關者 REB 研究倫理委員會 RECIST 實體腫瘤中之反應評估標準 RNA 核糖核酸 RP2D 推薦之第2階段劑量 RTK 受體酪胺酸激酶 SAE 嚴重不良事件 SAP 統計分析計劃 SD 疾病穩定 SGOT 血清麩胺酸草乙酸轉胺酶 SGPT 血清麩胺酸丙酮酸轉胺酶 SHP2 含Src同源2之蛋白酪胺酸磷酸酶2 SRC 安全審查委員會 STD10 10%動物嚴重毒性劑量 SUSAR 疑似突發性嚴重不良反應 TEAE 治療引發之不良事件 T max 藥物投與後達成最大藥物濃度之時間 ULN 正常值上限 US 美國 VIII. 實例 實例1：PD-1/PD-L1抑制劑及PTPN11抑制劑之組合之評估 周邊血單核球(PBMC)中之CD8+活化 A PTPN11 inhibitor represented by Formula (I) or Formula (10b) as described herein and a PD-1/PD-L1 inhibitor as described herein may be formulated for simultaneous administration or sequential administration. In some embodiments, the PTPN11 inhibitor of Formula (I) or Formula (10b) and the PD-1/PD-L1 inhibitor are formulated for simultaneous administration. In some embodiments, the PTPN11 inhibitor of Formula (I) or Formula (10b) and the PD-1/PD-L1 inhibitor are formulated for sequential administration. In some embodiments, the PTPN11 inhibitor of Formula (I) or Formula (10b) is administered prior to administration of the PD-1/PD-L1 inhibitor. In some embodiments, the PTPN11 inhibitor of Formula (I) or Formula (10b) is administered after administration of the PD-1/PD-L1 inhibitor. VII. List of abbreviations Abbreviation definition (e)CRF (Electronic) Case Report Form (p)ERK (phosphorylation) extracellular message-regulated kinase ADA anti-drug antibodies AE adverse events ALK anaplastic lymphoma kinase ALT Alanine aminotransferase (or transaminase) ANC absolute neutrophil count aPTT activated partial thromboplastin time AST Aspartate aminotransferase (or transaminase) AUC area under concentration time curve BBP BridgeBio Pharma BCRP Breast cancer drug resistance protein BICR Blind independent central review BMS Bristol Myers Squibb BOIN Bayesian optimal interval CI confidence interval C max maximum drug concentration CNS central nervous system CR full response CRO contract research organization CT computed tomography CTCAE Common Terminology Standards for Adverse Events CYP Cytochrome P450 DLT dose limiting toxicity DNA deoxyribonucleic acid DOR reaction duration DUSP6 dual-specificity phosphatase 6 ECG electrocardiogram ECHO Cardiac Ultrasound ECOG Eastern United States Cooperative Oncology Group EDC Electronic data extraction (system) EGFR epithelial growth factor receptor EORTC European Organization for Research and Treatment of Cancer EOS End of study EOT End of treatment FDA U.S. Food and Drug Administration FSH follicle stimulating hormone GCP Good clinical trial practice GLP Good Laboratory Practice Guidelines GMP Good Pharmaceutical Manufacturing Practice HBV Hepatitis B virus HCV Hepatitis C virus HIV human immunodeficiency virus IACS Applied Cancer Science Institute IB Researcher's Manual ICF informed consent ICH International Coordination Conference IEC independent ethics committee INR international normalized ratio IRB research ethics committee IRR infusion related reactions IV intravenously KRAS Kirsten rat sarcoma viral oncogene homolog LD (or LDi) longest diameter LVEF left ventricular ejection fraction MAPK mitogen-activated protein kinase MATE Multidrug and toxin efflux transporter MRI magnetic resonance imaging MTD maximum tolerated dose MUGA Multiple gated acquisition scans (radionuclide angiography) NCI National Cancer Institute NGS next generation sequencing NSCLC non-small cell lung cancer OATP Organic anion transporter polypeptide ORR objective response rate OS overall survival PD disease progression PD-1 Planned cell death-1 PD-L1 programmed cell death ligand-1 PET positron emission tomography PFS progression free survival P-gp P-glycoprotein PI Packaging insert PK Pharmacokinetics PR partial reaction P.S. functional status score PT prothrombin time PTPN11 Protein tyrosine phosphatase non-receptor type 11, the gene encoding SHP2 QD Once a day RAF rapidly accelerating fibrosarcoma RAS Any of a family of genes that undergoes mutations to become oncogenes and, in particular, those that are commonly associated with human cancers such as colon, lung, and pancreatic cancers REB research ethics committee RECIST Response assessment criteria in solid tumors RNA RNA RP2D Recommended Phase 2 Dosage RTK receptor tyrosine kinase SAE serious adverse events SAP statistical analysis plan SD disease stable SGOT serum glutamate oxalacetate transaminase SGPT Serum glutamate pyruvate transaminase SHP2 Src homolog 2-containing protein tyrosine phosphatase 2 SRC security review board STD10 10% severe toxicity dose for animals SUSAR Suspected sudden serious adverse reaction TEAE Adverse events arising from treatment Tmax The time to reach maximum drug concentration after drug administration ULN upper limit of normal value US America VIII. Examples Example 1: Assessment of CD8+ activation in peripheral blood mononuclear cells (PBMCs) with combinations of PD-1/PD-L1 inhibitors and PTPN11 inhibitors

進行研究以評估SHP2抑制劑化合物(10b)單獨及與αPD-L1之組合對T細胞細胞介素產生及回應於抗原刺激之殺傷潛力之影響。來自四個健康供體之PBMC用CEFT肽池刺激並用媒劑、同型對照、αPD-L1、化合物(10b)滴定，或化合物(10b)滴定及添加同型對照或αPD-L1處理。在初始CEFT刺激後，靜置培養物並添加細胞介素以擴大反應CD8+ T細胞之數量。然後用該CEFT肽池將細胞重新刺激24小時，並藉由流式細胞分析技術評估CD107a+細胞之頻率佔總CD8+ T細胞之百分比。另外，於刺激後5天，收穫上清液並藉由TR-FRET量測IFNγ之濃度。圖1A至圖1B包括來自此研究之結果。該等結果顯示供體2及4對CEFT刺激具有強召回反應，而供體1及3具有更溫和之反應。將該SHP2抑制劑化合物(10b)添加至分析導致供體之間的混合效應，其很可能係由供體之間抗原特異性前體頻率之可變性引起。Studies were conducted to evaluate the effect of SHP2 inhibitor compound (10b) alone and in combination with αPD-L1 on T cell interleukin production and killing potential in response to antigenic stimulation. PBMC from four healthy donors were stimulated with the CEFT peptide pool and treated with vehicle, isotype control, αPD-L1, titrated with compound (10b), or compound (10b) titrated with the addition of isotype control or αPD-L1. After initial CEFT stimulation, cultures were allowed to stand and interleukins were added to expand the number of responding CD8+ T cells. The cells were then restimulated with the CEFT peptide pool for 24 hours, and the frequency of CD107a+ cells as a percentage of total CD8+ T cells was assessed by flow cytometric analysis. In addition, 5 days after stimulation, the supernatant was harvested and the concentration of IFNγ was measured by TR-FRET. Figures 1A-1B include results from this study. These results showed that donors 2 and 4 had strong recall responses to CEFT stimulation, while donors 1 and 3 had more modest responses. Addition of the SHP2 inhibitor compound (10b) to the assay resulted in mixed effects between donors, most likely caused by variability in antigen-specific precursor frequencies between donors.

針對供體1，存在明顯之化合物(10b)劑量依賴性效應且化合物(10b)及αPD-L1之組合顯示協同作用，導致CD8+ T細胞經改善之活化，如由CD107a+CD8+ T細胞之較高含量指示。針對供體3，存在一些化合物(10b)效應且化合物(10b)及αPD-L1之組合顯示協同作用，導致CD8+ T細胞經改善之活化，如由CD107a+CD8+ T細胞之較高含量指示。針對供體2，添加化合物(10b)導致CD107a+CD8+ T細胞之百分比之劑量依賴性降低，且以化合物(10b)及αPD-L1之組合不存在協同作用。針對供體4，不存在化合物(10b)效應或以化合物(10b)及αPD-L1之組合不存在協同作用，如由CD107a+CD8+ T細胞含量中無變化指示。最後，CEFT刺激後5天之IFNγ含量在供體之間不一致(資料未顯示)。此等結果指示化合物(10b)及化合物(10b)及αPD-L1之組合於特異性增強弱或次優化CD8+ T細胞反應中可能發揮之作用。 實例2：SHP2抑制劑化合物(10b)與計畫性死亡受體-1阻斷抗體之組合於患有實體腫瘤之病患中之臨床研究 Against Donor 1, there was a clear dose-dependent effect of Compound (10b) and the combination of Compound (10b) and αPD-L1 showed a synergistic effect, leading to improved activation of CD8+ T cells, as demonstrated by higher CD107a+CD8+ T cells Content indication. For Donor 3, there were some compound (10b) effects and the combination of compound (10b) and αPD-L1 showed synergy, leading to improved activation of CD8+ T cells, as indicated by higher levels of CD107a+CD8+ T cells. For Donor 2, the addition of Compound (10b) resulted in a dose-dependent decrease in the percentage of CD107a+CD8+ T cells, and there was no synergy with the combination of Compound (10b) and αPD-L1. For Donor 4, there was no compound (10b) effect or synergy with the combination of compound (10b) and αPD-L1, as indicated by no change in CD107a+CD8+ T cell content. Finally, IFNγ levels 5 days after CEFT stimulation were inconsistent between donors (data not shown). These results indicate the possible role of Compound (10b) and the combination of Compound (10b) and αPD-L1 in specifically enhancing weak or suboptimal CD8+ T cell responses. Example 2: Clinical Study of Combination of SHP2 Inhibitor Compound (10b) and Programmed Death Receptor-1 Blocking Antibody in Patients with Solid Tumors

可進行SHP2抑制劑化合物(10b)與PD-1/PD-L1抑制劑(例如，除納武單抗外之PD-1/PD-L1抑制劑)之組合之臨床研究。該研究之個體患有實體腫瘤諸如非小細胞肺癌(NSCLC)，諸如特徵在於KRAS突變(例如，除Q61突變外之KRAS突變，諸如於密碼子12或13處之突變)之NSCLC。該個體可先前已完成標準之護理治療。Clinical studies of combinations of SHP2 inhibitor compound (10b) and PD-1/PD-L1 inhibitors (eg, PD-1/PD-L1 inhibitors other than nivolumab) can be performed. The subjects in the study had solid tumors such as non-small cell lung cancer (NSCLC), such as NSCLC characterized by a KRAS mutation (eg, a KRAS mutation other than the Q61 mutation, such as a mutation at codon 12 or 13). The individual may have previously completed standard of care treatment.

臨床研究可包括劑量遞增階段以評估當與PD-1/PD-L1抑制劑組合使用時，化合物(10b)之安全性、耐受性及推薦之第2階段劑量(RP2D)。該劑量遞增研究之另外目的可包括評估化合物(10b)與該PD-1/PD-L1抑制劑之組合之初步抗腫瘤活性(如由客觀反應率[ORR，完全反應(CR) +部分反應(PR)率]、反應持續時間[DOR]及無進展生存期[PFS]，根據實體腫瘤中之反應評估標準(RECIST) v1.1定義，及如由研究者評估，及整體存活[OS])；組合給與之化合物(10b)及該PD-1/PD-L1抑制劑之藥物動力學(PK)之表徵(例如，來自血漿或血清濃度時間資料之化合物(10b)及該PD-1/PD-L1抑制劑之曲線下面積[AUC]、最大藥物濃度[C max]、達成C max之時間[T max]、半衰期))；化合物(10b)與該PD-1/PD-L1抑制劑之組合之循環及腫瘤內靶向接合作用(藥效學活性)之表徵(例如，與該PD-1/PD-L1抑制劑組合之化合物(10b)活性之循環及腫瘤內靶向接合作用生物標誌物中之原始、標準化及/或基線調整之分析物訊息)；及當與化合物(10b)組合給與時，該PD-1/PD-L1抑制劑之免疫原性之表徵。亦可評估周邊及腫瘤內生物標誌物。該劑量遞增階段可包括(例如) 5至10個病患。 Clinical studies may include a dose escalation phase to evaluate the safety, tolerability and recommended phase 2 dose (RP2D) of Compound (10b) when combined with a PD-1/PD-L1 inhibitor. Additional objectives of the dose escalation study may include evaluating the preliminary anti-tumor activity of compound (10b) in combination with the PD-1/PD-L1 inhibitor (e.g., as determined by objective response rate [ORR, complete response (CR) + partial response ( PR) rate], duration of response [DOR], and progression-free survival [PFS], as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and if assessed by the investigator, and overall survival [OS]) ; Characterization of the pharmacokinetics (PK) of compound (10b) and the PD-1/PD-L1 inhibitor administered in combination (e.g., compound (10b) and the PD-1/PD-L1 inhibitor from plasma or serum concentration time data) Area under the curve [AUC], maximum drug concentration [C max ], time to reach C max [T max ], half-life) of the PD-L1 inhibitor; compound (10b) and the PD-1/PD-L1 inhibitor Characterization of the circulating and intratumoral targeted engagement (pharmacodynamic activity) of the combination (e.g., the circulating and intratumoral targeted engagement biological activity of compound (10b) in combination with the PD-1/PD-L1 inhibitor) Raw, normalized and/or baseline adjusted analyte information in the marker); and characterization of the immunogenicity of the PD-1/PD-L1 inhibitor when administered in combination with compound (10b). Peripheral and intratumoral biomarkers can also be assessed. The dose escalation phase may include, for example, 5 to 10 patients.

臨床研究亦可包括劑量擴大/優化期以評估當與PD-1/PD-L1抑制劑組合用於個體(例如，患有具有KRAS突變之晚期NSCLC且標準護理治療已失敗之個體)中時化合物(10b)之抗腫瘤活性，如由ORR (根據研究者)根據RECIST v1.1定義。劑量擴大/優化研究之另外目的可包括評估化合物(10b)與該PD-1/PD-L1抑制劑之組合之抗腫瘤活性之另外量測，包括ORR (根據盲態獨立中心審查[BICR])及DOR及PFS (根據研究者及BICR)，如由RECIST v1.1定義，及OS；評估化合物(10b)於RP2D，與該PD-1/PD-L1抑制劑之組合之安全性及耐受性；組合給與之化合物(10b)及該PD-1/PD-L1抑制劑之PK之表徵；化合物(10b)與該PD-1/PD-L1抑制劑之組合之循環及腫瘤內靶向接合作用(藥效學活性)之表徵；及當與化合物(10b)組合給與時，該PD-1/PD-L1抑制劑之免疫原性之表徵。亦可評估周邊及腫瘤內生物標誌物。該劑量擴大/優化期可包括(例如) 10至30個病患。Clinical studies may also include a dose expansion/optimization period to evaluate the compound when used in combination with a PD-1/PD-L1 inhibitor in individuals (e.g., individuals with advanced NSCLC with KRAS mutations who have failed standard of care treatments) Antitumor activity of (10b), as defined by ORR (per investigator) according to RECIST v1.1. Additional objectives of dose expansion/optimization studies may include assessment of additional measures of anti-tumor activity of compound (10b) in combination with the PD-1/PD-L1 inhibitor, including ORR (based on Blinded Independent Central Review [BICR]) and DOR and PFS (per investigator and BICR), as defined by RECIST v1.1, and OS; to assess the safety and tolerability of compound (10b) in RP2D, in combination with the PD-1/PD-L1 inhibitor properties; characterization of the PK of the combination of compound (10b) and the PD-1/PD-L1 inhibitor; circulatory and intratumoral targeting of the combination of compound (10b) and the PD-1/PD-L1 inhibitor Characterization of engagement (pharmacodynamic activity); and characterization of the immunogenicity of the PD-1/PD-L1 inhibitor when administered in combination with compound (10b). Peripheral and intratumoral biomarkers can also be assessed. The dose expansion/optimization period may include, for example, 10 to 30 patients.

臨床研究中所使用之PD-1/PD-L1抑制劑可(例如)為帕博利珠單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213或特泊利單抗。該PD-1/PD-L1抑制劑可藉由IV輸注投與。The PD-1/PD-L1 inhibitors used in clinical studies may be, for example, pembrolizumab, atezolizumab, durvalumab, avelumab, cilipril Monoclonal antibody-rwlc, camrelizumab, toripalimab, palolizumab, tislelizumab, batilizumab, dotalizumab, M7824, spartakizumab monoclonal antibody, saxanilumab, refulimab, BMS-986213 or terpolizumab. The PD-1/PD-L1 inhibitor can be administered by IV infusion.

化合物(10b)係如本文描述。化合物(10b)可呈(例如) 50及100 mg之口服膠囊投與。Compound (10b) is as described herein. Compound (10b) may be administered, for example, in oral capsules of 50 and 100 mg.

研究中之個體可已接受先前至少一線治療，其包括基於鉑之雙藥化學療法及抗PD-(L)1療法，作為一線或個別線之療法給與。該研究中之個體可患有實體腫瘤，諸如特徵在於KRAS突變(例如，密碼子12或13中之突變，如本文描述)之實體腫瘤。例如，該研究中之個體可患有具有KRAS突變之NSCLC。 納入標準 Individuals in the study may have received at least prior first-line therapy, including platinum-based doublet chemotherapy and anti-PD-(L)1 therapy, administered as first-line or separate lines of therapy. Individuals in the study may have solid tumors, such as those characterized by KRAS mutations (eg, mutations in codons 12 or 13, as described herein). For example, individuals in the study may have NSCLC with a KRAS mutation. inclusion criteria

參與臨床研究之病患將滿足下文列舉之納入標準(如適用)： 1. ≥18週歲且願意並能夠於篩選造訪時提供簽署之知情同意書及直到研究結束前遵守所有研究造訪及要求之個體。 2. 在篩選前1年內收集之腫瘤樣本中，具有來自當地或中央實驗室測試之KRAS突變之檔案。 3. 患有可藉由RECIST v1.1量測之疾病。 4. 具有＞12週之最短預期壽命。 5. 若女性具有生育潛力或先前已進行輸卵管結紮術(篩選前≥1年)、全子宮切除術或已絕經(定義為連續12個月閉經且藉由隨訪激素含量評估確認)，則必須進行陰性血清人類絨毛***測試。 6. 在研究期間具有生育潛力之病患必須使用2種避孕方法且女性病患在最後一個劑量之研究治療後至少5個月或男性病患在最後一個劑量之研究治療後105天，針對個別病患以較晚者為準。女性病患在此研究期間不應懷孕或哺乳。女性及男性病患亦必須同意分別在最後一個劑量之研究治療後至少5個月或105天不出於生殖目的捐贈卵子(卵、卵母細胞)或***。 7. 有組織學記錄，局部晚期且不可切除，或轉移性NSCLC。 8. 在先前至少一線全身性療法進行中或之後已進展或疾病復發，全身性療法必須包括基於鉑之雙藥化學療法及抗PD-(L)1療法，作為一線或個別線之療法給與。 9. 在治療期間或終止抗PD-(L)1療法後90天內發生經歷放射學記錄之疾病進展或復發。 10.    病患必須具有美國東部腫瘤協作組(ECOG)功能狀態評分(PS) 0至1及於前2週內無惡化。 排除標準 Patients participating in clinical studies will meet the inclusion criteria listed below (if applicable): 1. Individuals ≥18 years old who are willing and able to provide signed informed consent at the screening visit and comply with all study visits and requirements until the end of the study . 2. Have a profile of KRAS mutations from local or central laboratory testing in tumor samples collected within 1 year before screening. 3. Have a disease measurable by RECIST v1.1. 4. Have a minimum life expectancy of >12 weeks. 5. Mandatory if the woman is of childbearing potential or has previously undergone tubal ligation (≥1 year before screening), total hysterectomy, or is postmenopausal (defined as 12 consecutive months of amenorrhea and confirmed by follow-up hormone assessment) Negative serum human chorionic gonadotropin test. 6. Patients of childbearing potential must use 2 methods of contraception during the study period and at least 5 months after the last dose of study treatment for female patients or 105 days after the last dose of study treatment for male patients, on an individual basis. The patient will be admitted to the later stage. Female patients should not become pregnant or breast-feeding during this study. Female and male patients must also agree not to donate eggs (eggs, oocytes) or sperm for reproductive purposes for at least 5 months or 105 days, respectively, after the last dose of study treatment. 7. Histologically documented, locally advanced and unresectable, or metastatic NSCLC. 8. Progression or disease relapse during or after at least one previous first-line systemic therapy. Systemic therapy must include platinum-based doublet chemotherapy and anti-PD-(L)1 therapy, given as first-line or separate lines of therapy. . 9. Radiologically documented disease progression or recurrence occurs during treatment or within 90 days after discontinuation of anti-PD-(L)1 therapy. 10. Patients must have an Eastern Cooperative Oncology Group (ECOG) functional status (PS) score of 0 to 1 and no worsening within the previous 2 weeks. Exclusion criteria

滿足下文列舉之排除標準中之任一者之病患將無資格參與研究。 1. 於過去4週內或(若適用)在C1D1造訪前，於試驗研究藥物之半衰期之5倍內，以較短者為準，已參與介入臨床研究。病患應始終遵守適用於關於如下文指定之洗除期之指定伴隨用藥之其他資格標準。 2. 於開始研究治療之1週內已接受具有有限放射場之放射療法或質子療法用於緩和，或於開始研究治療之4週內已接受超過30%之骨髓或具有廣泛放射場之放射。 3. 已服用下列中之任一者： a. 於第1週期第1天之14天或5個半衰期(以較長者為準)內細胞色素P450 (CYP) 3A4之強效或中度誘導劑或抑制劑或P-醣蛋白(P-gp)誘導劑或抑制劑(包括草藥補充劑或含有葡萄柚汁、楊桃或塞維利亞橙之食品)，及/或 b. 除非在第1週期第1天前7天及研究持續時間內停止，否則作為P-gp、乳癌耐藥蛋白(BCRP)、多藥及毒素外排轉運蛋白(MATE) 1或MATE2-K之已知受質之藥物。 4. 患有如下文定義之器官功能不全： 血液學e. 白細胞計數＜2,000/µL f. 絕對中性粒細胞計數＜1,500/µL g. 血小板＜100,000/µL h. 血紅蛋白＜9 g/dL及不輸血≤2週或促紅細胞生成刺激劑(例如，Epo，普羅克裡特) ≤6週 腎e. 血清肌酐＞ 1.5 × ULN，除非肌酐清除率≥ 40 mL/min (使用科克羅夫特-高爾特公式量測或計算) 肝g. 若如由研究者證實，已診斷病患患有吉伯特症候群或溶血性貧血，則血清總膽紅素≥1.5×體制正常值上限(ULN)或≥3.0×體制ULN h. 天冬胺酸胺基轉移酶/血清麩胺酸草乙酸轉胺酶(AST/SGOT)及/或丙胺酸胺基轉移酶/血清麩胺酸丙酮酸轉胺酶(ALT/SGPT) ＞2.5×ULN 凝血i. 除非病患正接受抗凝療法，否則國際標準化比值(INR)或凝血酶原時間(PT) ＞1.5×ULN且只要PT或活化部分凝血活酶時間(aPTT)係於抗凝劑之預期使用之治療範圍內 j. 除非病患正接受抗凝療法，否則活化部分凝血活酶時間＞1.5×ULN且只要PT或aPTT係於抗凝劑之預期使用之治療範圍內 5.     患有活動性B型肝炎感染(由B型肝炎表面抗原[HBsAg]之存在或B型肝炎病毒[HBV] DNA之存在定義)、C型肝炎感染(由C型肝炎病毒[HCV]抗體及陽性HCV RNA之存在定義)或具有可量測病毒載量之人類免疫缺乏病毒(HIV)感染。 6.     患有危及生命之疾病、醫療狀況、活動性不受控制之感染或器官系統功能障礙(諸如腹水、凝血障礙或腦病)，或其他原因，在研究者看來，其等可危及參與病患之安全，或干擾或損害研究結果之完整性。 7.     患有下列心臟相關問題或結果中之任一者： a. 在開始研究治療前最近6個月內有重大心血管疾病，諸如腦血管意外、心肌梗死或不穩定型心絞痛之病史。 b. 臨床顯著之心臟病，包括紐約心臟協會II級或更高級別之心力衰竭。 c. 在開始研究治療前過去12個月內有左心室射出分率(LVEF) ＜50%之病史。 d. 靜息校正QT間期(QTc) ＞470毫秒，使用由贊助商出於研究目的提供之ECG機器，從三個心電圖(ECG)中作為平均值導出。 e. 靜息ECG之節律、傳導或形態之任何臨床顯著之異常(例如，三度心傳導阻滯、莫式II型心傳導阻滯、室性心律失常、不受控制之心房纖顫)。 8. 於過去3年內，除經治癒性治療之非黑色素瘤皮膚癌、淺表性尿路上皮癌、原位子宮頸癌，或在研究過程中預期無需針對復發進行治療之任何其他經治癒性治療之惡性腫瘤外，已診斷患有另一侵入性惡性腫瘤。 9. 患有來自非腦腫瘤之未經治療之腦轉移。在第1週期第1天前至少4週已切除腦轉移或已接受放射療法結束之病患若在首個劑量之研究藥物前滿足所有下列標準則其等係符合資格的：a)與CNS治療相關之殘餘神經系統症狀等級≤2；b)若適用，則在第1週期第1天前至少2週，以≤ 10 mg每日強體松(或當量)之穩定或減少劑量；及c)於C1D1前4週內隨訪磁振造影(MRI)顯示未出現新病變。 10. 在加入研究前4週內已經受大手術。 注意：此不包括已進行諸如周邊***中心導管線放置、胸腔穿刺術、腔液穿刺術、生檢或膿腫引流術之程序之病患。 11. 有對PD-1/PD-L1抑制劑或化合物(10b)、該PD-1/PD-L1抑制劑或化合物(10b)之活性或非活性賦形劑或具有與該PD-1/PD-L1抑制劑或化合物(10b)類似之化學結構或類別之藥物(取決於該病患可接受之組合類型)之超敏反應史。 12. 患有攜載BRAF V600X、PTPN11 (SHP2)或KRAS Q61X中之已知活化突變之腫瘤。 13. 先前已接受SHP2抑制劑(例如，TNO-155、RMC-4630、RLY-1971、JAB-3068、JAB-3312及PF-07284892)。 14. 患有在研究者看來將妨礙化合物(10b)之吸收的胃腸道疾病(例如，胃切除術後、短腸症候群、不受控制之克羅恩氏病、乳糜瀉伴絨毛萎縮或慢性胃炎)。 15. 正進行透析。 16. 有同種異體骨髓移植史。 17. 在不咀嚼、打碎、壓碎、打開或以其他方式改變產品劑型之情況下，無法吞嚥口服藥物(膠囊、錠劑)。 18. 於開始使用抗PD-(L)1藥劑之治療之前120天內經歷疾病進展(PD) (例如，原發性難治性)。 19. 經歷認為與先前抗PD-(L)1治療相關之≥ 3級毒性，其需終止療法。 20. 患有已知或疑似自體免疫疾病，除在1型糖尿病、僅需激素替代之低甲狀腺功能症、無需全身性治療之皮膚病(例如，白癜風、牛皮廯或脫髮)或預期在缺乏外部誘發因素之情況下不再現之病症之情況下允許病患加入外。 21. 於第1週期第1天之14天內患有需使用皮質類固醇(＞10 mg強體松當量)或其他免疫抑制藥物之全身性治療之病症。在缺乏主動自體免疫疾病之情況下允許吸入或局部類固醇，及＞10 mg強體松當量的腎上腺替代類固醇。 22. 於首次研究治療之30天內已接受任何活/減毒疫苗。 研究設計 Patients who meet any of the exclusion criteria listed below will not be eligible to participate in the study. 1. Participated in interventional clinical studies within the past 4 weeks or (if applicable) before the C1D1 visit, within 5 times the half-life of the experimental investigational drug, whichever is shorter. Patients should always adhere to other eligibility criteria applicable to designated concomitant medications with washout periods as specified below. 2. Have received radiotherapy or proton therapy with a limited radiation field for palliation within 1 week of starting study treatment, or have received more than 30% of bone marrow or radiation with a wide radiation field within 4 weeks of starting study treatment. 3. Have taken any of the following: a. A strong or moderate inducer of cytochrome P450 (CYP) 3A4 within 14 days or 5 half-lives (whichever is longer) from Day 1 of Cycle 1 or inhibitors or inducers or inhibitors of P-glycoprotein (P-gp) (including herbal supplements or foods containing grapefruit juice, star fruit or Seville orange), and/or b. Unless in Cycle 1 Drugs that are known substrates of P-gp, breast cancer resistance protein (BCRP), multidrug and toxin efflux transporter (MATE) 1 or MATE2-K are discontinued 7 days before day 1 and for the duration of the study . 4. Suffering from organ dysfunction as defined below: Hematology e. White blood cell count <2,000/µL f. Absolute neutrophil count <1,500/µL g. Platelets <100,000/µL h. Hemoglobin <9 g/dL and No transfusion for ≤2 weeks or erythropoiesis-stimulating agents (e.g., Epo, Procretin) for ≤6 weeks Renal e. Serum creatinine > 1.5 × ULN unless creatinine clearance ≥ 40 mL/min (with Cockcroft -Measurement or calculation by Galt's formula) Liver g. If the patient has been diagnosed with Gilbert's syndrome or hemolytic anemia, as confirmed by the investigator, the serum total bilirubin is ≥1.5 × the upper limit of institutional normal (ULN) Or ≥3.0×system ULN h. Aspartate aminotransferase/serum glutamic acid oxalacetic acid transaminase (AST/SGOT) and/or alanine aminotransferase/serum glutamic acid pyruvate aminotransferase (ALT/SGPT) >2.5×ULN coagulationi . Unless the patient is receiving anticoagulant therapy, the international normalized ratio (INR) or prothrombin time (PT) >1.5×ULN and as long as the PT or activated partial thromboplastin time (aPTT) is within the therapeutic range of the intended use of the anticoagulantj. Unless the patient is receiving anticoagulant therapy, the activated partial thromboplastin time is >1.5×ULN and as long as the PT or aPTT is within the intended therapeutic range of the anticoagulant Within the scope of treatment 5. Have active hepatitis B infection (defined by the presence of hepatitis B surface antigen [HBsAg] or the presence of hepatitis B virus [HBV] DNA), hepatitis C infection (defined by the presence of hepatitis C virus [HCV] defined by the presence of antibodies and positive HCV RNA) or human immunodeficiency virus (HIV) infection with a measurable viral load. 6. Suffer from a life-threatening disease, medical condition, active uncontrolled infection or organ system dysfunction (such as ascites, coagulopathy or encephalopathy), or other causes that, in the opinion of the investigator, may jeopardize participation in the disease endanger safety, or interfere with or impair the integrity of research results. 7. Suffer from any of the following heart-related problems or results: a. Have a history of major cardiovascular disease, such as cerebrovascular accident, myocardial infarction or unstable angina within the last 6 months before starting study treatment. b. Clinically significant heart disease, including New York Heart Association class II or higher heart failure. c. Have a history of left ventricular ejection fraction (LVEF) <50% in the past 12 months before starting study treatment. d. Resting corrected QT interval (QTc) >470 msec, derived as the average of three electrocardiograms (ECGs) using an ECG machine provided by the sponsor for research purposes. e. Any clinically significant abnormality in the rhythm, conduction, or morphology of the resting ECG (e.g., third-degree heart block, Mohs type II heart block, ventricular arrhythmias, uncontrolled atrial fibrillation). 8. In the past 3 years, any other cured non-melanoma skin cancer, superficial urothelial cancer, cervical cancer in situ, or any other cancer that is not expected to require treatment for recurrence during the course of the study, except curative treatment In addition to the malignant tumor being treated, another invasive malignant tumor has been diagnosed. 9. Suffering from untreated brain metastases from non-brain tumors. Patients who have had brain metastases removed or who have completed radiation therapy at least 4 weeks before Day 1 of Cycle 1 are eligible if they meet all of the following criteria before the first dose of study drug: a) Concurrent with CNS treatment Associated residual neurological symptoms grade ≤2; b) if applicable, on a stable or reduced dose of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks before Day 1 of Cycle 1; and c) Follow-up magnetic resonance imaging (MRI) within 4 weeks before C1D1 showed no new lesions. 10. Have undergone major surgery within 4 weeks before joining the study. Note: This does not include patients who have undergone procedures such as peripheral central line placement, thoracentesis, hydrocentesis, biopsies, or abscess drainage. 11. There are active or inactive excipients for the PD-1/PD-L1 inhibitor or compound (10b), the PD-1/PD-L1 inhibitor or the compound (10b), or compounds with the PD-1/ History of hypersensitivity reactions to PD-L1 inhibitors or drugs of a similar chemical structure or class of compounds (10b) (depending on the type of combination acceptable to the patient). 12. Tumors harboring known activating mutations in BRAF V600X, PTPN11 (SHP2), or KRAS Q61X. 13. Have previously received SHP2 inhibitors (eg, TNO-155, RMC-4630, RLY-1971, JAB-3068, JAB-3312, and PF-07284892). 14. Suffering from gastrointestinal diseases that in the opinion of the investigator will interfere with the absorption of compound (10b) (e.g., post-gastrectomy, short bowel syndrome, uncontrolled Crohn's disease, celiac disease with villous atrophy, or chronic gastritis). 15. Undergoing dialysis. 16. Have a history of allogeneic bone marrow transplantation. 17. Inability to swallow oral medications (capsules, tablets) without chewing, breaking, crushing, opening or otherwise changing the product dosage form. 18. Experienced disease progression (PD) within 120 days before starting treatment with an anti-PD-(L)1 agent (e.g., primary refractory). 19. Experience of ≥ grade 3 toxicity thought to be related to prior anti-PD-(L)1 therapy requiring discontinuation of therapy. 20. Suffering from known or suspected autoimmune diseases, except for type 1 diabetes, hypothyroidism requiring only hormone replacement, skin diseases that do not require systemic treatment (e.g., vitiligo, psoriasis or alopecia) or expected to be deficient in Patients are allowed to participate if the symptoms do not reappear due to external triggers. 21. Have a condition that requires systemic treatment with corticosteroids (>10 mg prednisone equivalent) or other immunosuppressive drugs within 14 days of Day 1 of Cycle 1. Inhaled or topical steroids, and >10 mg prednisone equivalent of adrenal replacement steroids are allowed in the absence of active autoimmune disease. 22. Have received any live/attenuated vaccine within 30 days of the first study treatment. research design

研究可包括初始篩選期(例如，30天篩選期)，接著包括多個連續治療週期之治療期及後續治療後隨訪期。除非病患自研究治療終止或退出該研究，否則給藥可持續1年或更多年。The study may include an initial screening period (eg, a 30-day screening period), followed by a treatment period including multiple consecutive treatment cycles and subsequent post-treatment follow-up periods. Dosing will continue for 1 year or more unless the patient discontinues study treatment or withdraws from the study.

臨床研究之劑量遞增階段可遵循貝葉斯最優區間(BOIN)設計。劑量遞增研究中可使用三種劑量之化合物(10b)，諸如250 mg、400 mg及550 mg。PD-1/PD-L1抑制劑將以適當之劑量，諸如由美國食品藥品監督管理局批准之劑量，與化合物(10b)組合投與。此劑量可(例如)介於每1、2、3、4、5或6週約10至2000 mg之間。該劑量遞增階段將用以確定該研究之劑量遞增階段中將使用之RP2D。The dose escalation phase of clinical studies can follow a Bayesian optimal interval (BOIN) design. Three doses of compound (10b) may be used in dose escalation studies, such as 250 mg, 400 mg and 550 mg. The PD-1/PD-L1 inhibitor will be administered in combination with Compound (10b) at an appropriate dose, such as a dose approved by the US Food and Drug Administration. This dosage may, for example, range from about 10 to 2000 mg every 1, 2, 3, 4, 5 or 6 weeks. This dose escalation phase will be used to determine the RP2D to be used in the dose escalation phase of the study.

在臨床研究之劑量遞增階段中，個體將以來自該劑量遞增階段之RP2D接受化合物(10b)與PD-1/PD-L1抑制劑之組合。取決於該劑量遞增階段之結果，可使用一或多個另外定群，包括以不同給藥水平給藥之化合物(10b)。In the dose escalation phase of the clinical study, subjects will receive Compound (10b) in combination with a PD-1/PD-L1 inhibitor at RP2D from the dose escalation phase. Depending on the outcome of this dose escalation phase, one or more additional cohorts may be used, including compound (10b) administered at different dosing levels.

例如，在藥物相關之不良事件之情況下，可調整化合物(10b)或PD-1/PD-L1抑制劑之給藥。For example, in the event of drug-related adverse events, dosing of compound (10b) or a PD-1/PD-L1 inhibitor may be adjusted.

臨床研究可進一步擴大以併入「三重」療法，包括PTPN11抑制劑、PD-1/PD-L1抑制劑及KRAS G12C抑制劑，諸如索托拉西布(AMG-510)、阿達格拉西布(MRTX-849)、MRTX1257、ARS-853、ARS-1620、JNJ-74699157(ARS-3248)、LY3537982或LY3499446。Clinical studies can be further expanded to incorporate "triple" therapies, including PTPN11 inhibitors, PD-1/PD-L1 inhibitors, and KRAS G12C inhibitors, such as sotoraxib (AMG-510), adagrasiib ( MRTX-849), MRTX1257, ARS-853, ARS-1620, JNJ-74699157(ARS-3248), LY3537982 or LY3499446.

圖2顯示SHP2抑制劑化合物(10b)與PD-1/PD-L1抑制劑之組合於患有實體腫瘤(例如，非小細胞肺癌(NSCLC))之病患中之臨床研究。研究設計包括劑量遞增及劑量擴大/優化。Figure 2 shows a clinical study of a combination of SHP2 inhibitor compound (10b) and a PD-1/PD-L1 inhibitor in patients with solid tumors, such as non-small cell lung cancer (NSCLC). Study design included dose escalation and dose expansion/optimization.

圖3顯示使用BOIN設計進行之試驗之流程圖。縮寫：BOIN=貝葉斯最優區間設計；DLT=劑量限制毒性；MTD=最大耐受劑量。注意：λe = 19.7%及λd = 29.8%。在實務中，以6個病患/定群，若DLT率係≤1/6，則使劑量遞增，若該DLT率係≥2/6，則使該劑量遞減。 實例3：式(10b)及抗PD-1之組合於CT-26 CRISPR敲入KRAS D12C中之活體內效用 A.     材料 Figure 3 shows the flow chart of an experiment using the BOIN design. Abbreviations: BOIN = Bayesian optimal interval design; DLT = dose-limiting toxicity; MTD = maximum tolerated dose. Note: λe = 19.7% and λd = 29.8%. In practice, with 6 patients/group, if the DLT rate is ≤1/6, the dose is increased; if the DLT rate is ≥2/6, the dose is decreased. Example 3: In vivo efficacy of the combination of formula (10b) and anti-PD-1 in CT-26 CRISPR knock-in KRAS D12C A. Materials

測試品#1 -式(10b)Test item #1 - Formula (10b)

測試品#2 -抗體A；可變區抗原決定基：小鼠PD-1；恆定區：小鼠免疫球蛋白G1 (IgG1)；經單個胺基酸取代(於密碼子265處天冬胺酸轉化為丙胺酸(D265A))工程化，其防止Fcγ受體結合；及分子量：~150 kDa。 Test #2 - Antibody A; variable region epitope: mouse PD-1; constant region: mouse immunoglobulin G1 (IgG1); with a single amino acid substitution (aspartic acid at codon 265 Converted to alanine (D265A)) engineered, which prevents Fcγ receptor binding; and molecular weight: ~150 kDa.

同型對照品#1 - MOPC-21，活體內MAb小鼠IgG1同型對照；可變區抗原決定基：未知特異性；恆定區：小鼠免疫球蛋白G1 (IgG1)；及分子量：~150 kDa。 B.     實驗程序 Isotype Control #1 - MOPC-21, in vivo MAb mouse IgG1 isotype control; variable region epitope: unknown specificity; constant region: mouse immunoglobulin G1 (IgG1); and molecular weight: ~150 kDa. B. Experimental procedures

動物接收及安置。針對CT-26 CRISPR敲入KRAS D12C研究，由查爾斯河加速器及研發實驗室(the Charles River Accelerator and Development Lab，CRADL)機構動物照護及使用委員會(Institutional Animal Care and Use Committee，IACUC)在執行前審查並批准涉及動物之照護及使用的方案及程序。動物照護及使用程序已由國際實驗室動物照護評估及認證協會(the Association for Assessment and Accreditation of Laboratory Animal Care International，AAALAC)全面認證。訂購Balb/c雌性小鼠(Envigo；Inotiv Inc.)，收到時年齡為六至八週歲，並由耳號鑑別。在腫瘤接種前，使動物有十一天的適應期。在適應期之持續時間及整個研究過程中，小鼠係每個籠子至多五隻動物分組畜養於拋棄式聚碳酸酯IVC籠(Innovive; San Diego, CA)中，該籠由一層Alpha-Dri墊料(Sheppard Specialty Papers, Inc., Kalamazoo, MI)、經驗證之豐容塊(certified enrichment block)及菱形捻(diamond-twist)、及經驗證之聚碳酸酯外殼裝置構成。小鼠可隨意取用嚙齒動物顆粒飼料及經過照射之逆滲透Aquavive ®飲用水(Innovive; San Diego, CA)。動物飼養所溫度係維持在20℃至26℃之間及環境濕度介於30%至70%之間。室內照明係循環開啟十二小時及關閉十二小時。 Animal Reception and Placement. The CT-26 CRISPR knock-in KRAS D12C study was reviewed prior to execution by the Institutional Animal Care and Use Committee (IACUC) of the Charles River Accelerator and Development Lab (CRADL) and approves plans and procedures involving the care and use of animals. Animal care and use procedures have been fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). Balb/c female mice (Envigo; Inotiv Inc.) were ordered, aged six to eight years upon receipt, and identified by ear number. Animals were allowed an acclimation period of eleven days before tumor inoculation. For the duration of the acclimation period and throughout the study, mice were housed in groups of up to five animals per cage in disposable polycarbonate IVC cages (Innovive; San Diego, CA), which were protected by a layer of Alpha-Dri pads. Made from Sheppard Specialty Papers, Inc., Kalamazoo, MI, a certified enrichment block and diamond-twist, and a proven polycarbonate shell assembly. Mice had ad libitum access to rodent pellet chow and irradiated reverse osmosis Aquavive ® drinking water (Innovive; San Diego, CA). The temperature of the animal breeding house is maintained between 20°C and 26°C and the ambient humidity is between 30% and 70%. The indoor lighting system cycles on and off for twelve hours.

腫瘤細胞系培養及接種。鼠科結腸癌CT-26細胞系係藉由CRISPR技術基因工程化以編輯具有D12C之KRAS之三個內源性基因座，並於BMS內部註冊為BXA-229794-02-001。篩選細胞並證實對小鼠病原體(IDEXX)呈陰性及活體外維持在37℃，5% CO 2氣氛下之T150燒瓶上之10% (v/v)胎牛血清(FBS, Invitrogen)及90% (v/v)洛斯維派克紀念研究所(Roswell Park Memorial Institute，RPMI) 1640培養基(Gibco)中。針對植入，用0.25%胰蛋白酶-EDTA (Gibco)收穫細胞，於DPBS (Gibco)中清洗，計數並以台盼藍拒染法(trypan blue exclusion)使用Vi-Cell XR (Beckman Coulter)測定存活率，然後以1:1比率之DPBS:Matrigel培養至3x10 6個細胞/mL之最終濃度。單細胞懸浮液依每隻小鼠0.1 mL之體積植入各小鼠之皮下右後腹區內，3 x 10 5個細胞。 Tumor cell line culture and seeding. The murine colon cancer CT-26 cell line was genetically engineered through CRISPR technology to edit three endogenous loci of KRAS with D12C, and was registered within BMS as BXA-229794-02-001. Cells were screened and confirmed negative for mouse pathogens (IDEXX) and maintained in vitro in 10% (v/v) fetal bovine serum (FBS, Invitrogen) and 90% in T150 flasks at 37°C in a 5% CO2 atmosphere (v/v) in Roswell Park Memorial Institute (RPMI) 1640 medium (Gibco). For engraftment, cells were harvested with 0.25% trypsin-EDTA (Gibco), washed in DPBS (Gibco), counted, and viability determined with trypan blue exclusion using Vi-Cell XR (Beckman Coulter) rate, and then cultured with DPBS:Matrigel at a 1:1 ratio to a final concentration of 3x10 cells/mL. The single cell suspension was implanted into the subcutaneous right posterior abdominal area of each mouse in a volume of 0.1 mL per mouse, with 3 x 10 5 cells.

分組分配及給藥。接種後十六天，將Balb/c小鼠分配至治療組，及各組由n=10隻小鼠構成。選擇按腫瘤體積劃分之「分層」隨機化方法(StudyLog ®桌面軟體，版本4.5.5.523)，藉此各組平均腫瘤體積平均約為191 mm 3。 Group allocation and administration. Sixteen days after inoculation, Balb/c mice were assigned to treatment groups, and each group consisted of n=10 mice. A "stratified" randomization method by tumor volume was chosen ( StudyLog® desktop software, version 4.5.5.523), whereby the mean tumor volume in each group averaged approximately 191 mm 3 .

對攜載CT-26 KRAS D12C KI腫瘤之雌性Balb/c小鼠(10隻動物/組)投與下列治療方案中之一者直至達成實驗終點：1)媒劑對照(0.5% v/v甲基纖維素於無菌去離子水中) (PO，QDx35)及MOPC-21同型對照抗體(10 mg/kg PO，Q4Dx4)之組合，2)抗體A (10 mg/kg IP，Q4Dx4)，3)式(10b) (100 mg/kg PO，QDx35)，4)抗體A (10 mg/kg IP，Q4Dx4)及式(10b) (100 mg/kg PO，QDx35)之組合。Female Balb/c mice (10 animals/group) carrying CT-26 KRAS D12C KI tumors were administered one of the following treatment regimens until the experimental endpoint was reached: 1) vehicle control (0.5% v/v A Cellulose based in sterile deionized water) (PO, QDx35) and MOPC-21 isotype control antibody (10 mg/kg PO, Q4Dx4), 2) Antibody A (10 mg/kg IP, Q4Dx4), 3) Formula (10b) (100 mg/kg PO, QDx35), 4) Combination of Antibody A (10 mg/kg IP, Q4Dx4) and formula (10b) (100 mg/kg PO, QDx35).

式(10b)調配物。式(10b)調配物緩衝液(0.5% v/v甲基纖維素於無菌去離子水中)係藉由將所需量之甲基纖維素400 cp (例如，Sigma-Aldrich，目錄號M0262，黏度400 cP)稱重至玻璃瓶內每月一次製備。在用攪拌棒連續磁力攪拌下添加等同於預期最終體積之75% v/v之無菌去離子水並在室溫下攪拌直至完全溶解。然後用無菌去離子水使該緩衝液升至最終體積。Formula (10b) formulation. Formula (10b) formulation buffer (0.5% v/v methylcellulose in sterile deionized water) is prepared by adding the required amount of methylcellulose 400 cp (e.g., Sigma-Aldrich, catalog number M0262, viscosity 400 cP) weighed into glass bottles and prepared once a month. Add 75% v/v sterile deionized water equivalent to the desired final volume under continuous magnetic stirring with a stir bar and stir at room temperature until completely dissolved. The buffer was then brought to final volume with sterile deionized water.

於研究第1天開始，每週製備10 mg/mL活性醫藥成分(具有校正因子10.22 mg/mL)之式(10b)工作懸浮液並以10 mL/kg劑量體積藉由口服管飼法對小鼠每日投與100 mg/kg劑量長達35天。將1.022之校正因子應用於式(10b)調配物以適應純度(97.8%)。為製備式(10b)調配物，將化合物精確稱重至玻璃小瓶內。將相當於預期最終體積之70% v/v之式(10b)調配物緩衝液添加至含有原料藥之玻璃小瓶並使用1/4英吋探針充分混合4至9分鐘直至達成均質懸浮液及無大之可見團粒或顆粒。將懸浮媒劑之剩餘部分添加至含有原料藥之分散體以達成該預期最終體積。將該懸浮液充分混合30分鐘並儲存在2至8℃下。在每天給藥前及給藥期間將該懸浮液充分混合。Beginning on study day 1, a working suspension of formula (10b) of 10 mg/mL active pharmaceutical ingredient (with correction factor 10.22 mg/mL) was prepared weekly and administered to children by oral gavage at a dose volume of 10 mL/kg. Rats were administered 100 mg/kg daily for 35 days. A correction factor of 1.022 was applied to the formulation of formula (10b) to accommodate the purity (97.8%). To prepare formulations of formula (10b), the compounds are accurately weighed into glass vials. Add 70% v/v of Formula (10b) formulation buffer equivalent to the expected final volume to the glass vial containing the drug substance and mix thoroughly using a 1/4 inch probe for 4 to 9 minutes until a homogeneous suspension is achieved and No large visible clumps or particles. The remainder of the suspending vehicle is added to the dispersion containing the drug substance to achieve the desired final volume. The suspension was mixed thoroughly for 30 minutes and stored at 2 to 8°C. Mix the suspension thoroughly before and during daily dosing.

抗體A調配物。抗體A係鼠科抗PD-1鼠科免疫球蛋白G1-D265A (α-PD-1)，18.12 mg/mL之儲備濃度。mAb係經單個胺基酸取代(於密碼子處265天冬胺酸轉化為丙胺酸(D265A))工程化，其防止Fcγ受體結合。將儲備溶液儲存於受監測之2℃至8℃冷凍機中。每次研究製備一次給藥溶液，藉由稀釋至PBS，pH 7.2內至1 mg/mL濃度，等分並儲存於無菌容器中，及在給藥期間長度內保持在2℃至8℃下。於研究第1天開始，1 mg/mL抗體A調配物係以10 mL/kg劑量體積藉由對小鼠腹腔內投與10 mg/kg劑量，每四天投與四個劑量(Q4Dx4)。Antibody A formulation. Antibody A is murine anti-PD-1 murine immunoglobulin G1-D265A (α-PD-1), with a stock concentration of 18.12 mg/mL. The mAb is engineered with a single amino acid substitution (conversion of aspartate to alanine (D265A) at codon 265), which prevents Fcγ receptor binding. Stock solutions were stored in a monitored 2°C to 8°C freezer. Dosing solutions were prepared once per study by diluting into PBS, pH 7.2 to a concentration of 1 mg/mL, aliquoting and storing in sterile containers, and maintaining at 2°C to 8°C for the length of the dosing period. The 1 mg/mL Antibody A formulation was administered intraperitoneally to mice at a 10 mL/kg dose volume beginning on study day 1 for four doses every four days (Q4Dx4).

MOPC-21同型對照抗體調配物。MOPC-21係小鼠IgG1同型對照抗體，由BioXCell製造，批號78512101及儲備濃度10.22 mg/mL。片段抗原結合位點(Fab)尺寸對抗原具有未知特異性。將儲備材料儲存於受監測之2℃至8℃冷凍機中。藉由稀釋至PBS，pH 7.2內將給藥溶液製備至1 mg/mL濃度，等分並儲存於無菌容器內，及在給藥期間長度內保持在2℃至8℃下。於研究第1天開始，1 mg/mL MOPC-21調配物係以10 mL/kg劑量體積藉由對小鼠腹腔內投與10 mg/kg劑量，每四天投與四個劑量(Q4Dx4)。MOPC-21 isotype control antibody formulation. MOPC-21 mouse IgG1 isotype control antibody, manufactured by BioXCell, batch number 78512101 and stock concentration 10.22 mg/mL. Fragment antigen binding site (Fab) size has unknown specificity for antigen. Store reserve materials in monitored freezers at 2°C to 8°C. Prepare dosing solutions to a concentration of 1 mg/mL in PBS, pH 7.2, aliquot and store in sterile containers, and maintain at 2°C to 8°C for the length of the dosing period. The 1 mg/mL MOPC-21 formulation was administered intraperitoneally to mice at a 10 mL/kg dose volume beginning on study day 1, with four doses administered every four days (Q4Dx4) .

腫瘤及體重量測。使用卡尺每週兩次量測腫瘤長度[mm]及寬度[mm]，並使用公式計算腫瘤體積[mm 3]：腫瘤體積= (長度x寬度 2)/2，其中長度係定義為最長腫瘤直徑及寬度係定義為最短腫瘤直徑。 Tumor and weight measurement. Use calipers to measure tumor length [mm] and width [mm] twice a week, and use the formula to calculate tumor volume [mm 3 ]: Tumor volume = (length x width 2 )/2, where length is defined as the longest tumor diameter and width were defined as the shortest tumor diameter.

隨機分組後，每週一次記錄小鼠體重。After randomization, the body weight of the mice was recorded once a week.

計算及統計分析。由GraphPad Prism軟體(第9版)產生中數腫瘤體積及無進展至腫瘤負荷終點圖，及中數無進展、風險率及統計分析。Computational and statistical analysis. Median tumor volume and progression-free to tumor burden endpoint plots, as well as median progression-free, risk ratio and statistical analysis were generated by GraphPad Prism software (version 9).

自各組計算中數腫瘤體積以在小鼠達成腫瘤負荷前確定治療之效用。若小鼠於特定組中達成腫瘤負荷，則最後記錄之腫瘤體積係經擴展並包括於後續之中數計算中直至計算之中數係大於任何單個經擴展之值，或直至該組中50%或更多之小鼠達成腫瘤負荷。若在達成實驗終點(諸如給藥誤差)前發現死者，則來自該個體之個別腫瘤體積值不包括於任何時間點之中數內。Median tumor volumes were calculated from each group to determine the efficacy of treatment before mice reached tumor burden. If a mouse achieves tumor burden in a particular group, the last recorded tumor volume is expanded and included in subsequent median calculations until the calculated median is greater than any single expanded value, or until 50% of the group is or more mice to achieve tumor burden. If a deceased person is found before reaching an experimental endpoint (such as a dosing error), individual tumor volume values from that individual are not included in the figures at any time point.

產生卡普蘭-梅爾(Kaplan-Meier)圖以評估治療後小鼠腫瘤負荷終點之累積百分比。腫瘤負荷終點係定義為個體達成記錄體積為1,500 mm 3或更大之腫瘤負荷之實驗終點。使用曼特爾-亨塞爾(Mantel-Haenszel)方法計算風險率，鑑別腫瘤負荷發生率。 Kaplan-Meier plots were generated to assess the cumulative percentage of tumor burden endpoints in mice after treatment. The tumor burden endpoint was defined as the experimental endpoint in which an individual achieved a documented tumor burden of 1,500 mm3 or greater. The risk ratio was calculated using the Mantel-Haenszel method to identify the incidence of tumor burden.

在對數秩(Mantel-Cox)檢驗比較組合式(10b)加抗體A與單獨抗體A後，認為小於0.05之p值係統計學顯著的。After comparing combination (10b) plus antibody A with antibody A alone by log-rank (Mantel-Cox) test, a p value less than 0.05 was considered statistically significant.

實驗終點。在腫瘤細胞接種後，每天檢查動物之發病率及死亡率。在例行監測期間，檢查動物之腫瘤生長及治療對行為(諸如行動能力、食物及水之消耗、體重增加/減少、眼睛/頭髮纏結及任何其他異常)之任何影響。若小鼠體重相對於在治療之第一天之重量損失20%，則將小鼠安樂死。另外，若注意到動物之一般健康有顯著不利之變化，則將小鼠安樂死。若計算之腫瘤體係≥ 1,500 mm 3，則針對腫瘤負荷將小鼠安樂死。倘若所有小鼠達成腫瘤負荷(確定為研究第35天)，則開始進行研究。 C.     結果 Experimental endpoint. After tumor cell inoculation, animals were examined daily for morbidity and mortality. During routine monitoring, animals are examined for tumor growth and any effects of treatment on behavior (such as mobility, food and water consumption, weight gain/loss, eye/hair tangles, and any other abnormalities). Mice were euthanized if they lost 20% of their body weight relative to their weight on the first day of treatment. Additionally, mice were euthanized if significant adverse changes in the animal's general health were noted. If the calculated tumor system was ≥ 1,500 mm 3 , mice were euthanized for tumor burden. Once all mice reached tumor burden (determined as study day 35), the study was initiated. C. Result

進行此研究以確定SHP2抑制劑(式(10b))及鼠科抗PD-1 (抗體A)之組合相較於單獨任一種藥劑是否活體內增強抗腫瘤活性。該研究係於同基因CRC CT-26模型中進行，及於所有三個內源性基因座處均具有經CRISPR工程化之KRAS D12C敲入突變。This study was conducted to determine whether the combination of a SHP2 inhibitor (Formula (10b)) and murine anti-PD-1 (Antibody A) enhanced antitumor activity in vivo compared to either agent alone. The study was conducted in a syngeneic CRC CT-26 model with CRISPR-engineered KRAS D12C knock-in mutations at all three endogenous loci.

在攜載KRAS D12C KI突變之皮下CT-26同基因模型中使用SHP2i (式(10b))及抗PD-1 (抗體A)之組合治療導致腫瘤負荷之延遲進展。進行活體內研究以評估式(10b)與鼠科抗PD-1抗體(抗體A)之組合對攜載細胞系衍生之CT-26 CRC同基因模型，攜載於所有三個內源性基因座處之KRAS D12C突變之Balb/c小鼠中之腫瘤體積的影響。Combination treatment with SHP2i (formula (10b)) and anti-PD-1 (Antibody A) resulted in delayed progression of tumor burden in a subcutaneous CT-26 syngeneic model harboring the KRAS D12C KI mutation. In vivo studies were performed to evaluate the combination of formula (10b) with a murine anti-PD-1 antibody (Antibody A) on a cell line-derived CT-26 CRC isogenic model harboring all three endogenous loci. Effects of tumor volume in Balb/c mice harboring the KRAS D12C mutation.

在35天內每天一次口服投與式(10b) (100 mg/kg)，或腹腔內投與抗體A (10 mg/kg)每四天投與四個劑量，或與式(10b) (100 mg/kg)加抗體A (10 mg/kg)之組合後，在使用式(10b)及抗體A治療之組合臂中觀察到腫瘤負荷之進展延遲(圖4及圖6)。於圖4中：腫瘤負荷終點係定義為記錄個體之腫瘤體積＞1,500 mm 3時之腫瘤負荷終點。研究第1天係定義為給藥之第一天。 Antibody A (10 mg/kg) was administered orally once daily for 35 days for four doses every four days, or as Formula (10b) (100 mg/kg) intraperitoneally. mg/kg) plus Antibody A (10 mg/kg), a delay in the progression of tumor burden was observed in the combined arm treated with Formula (10b) and Antibody A (Figures 4 and 6). In Figure 4: The tumor burden endpoint is defined as the tumor burden endpoint when the individual tumor volume is >1,500 mm3 . Study Day 1 is defined as the first day of dosing.

如表1中顯示，相較於單獨任一種藥劑，在投與式(10b)加抗體A之組合後，中數增加九天或當相較於媒劑加同型對照時，中數增加十三天。 表1：在投與媒劑加同型對照，或單獨或組合投與式(10b)及抗體A後，具有KRAS D12C KI之攜載CT-26之Balb/c小鼠中達成中數無進展至腫瘤負荷終點之總結 組 (n=10) 治療 劑量 (mg/kg) 中數存活 (研究天數) 1 媒劑對照+ 0 15 MOPC-21同型 10 2 抗體A 10 19 3 式(10b) 100 19 4 抗體A + 10 28 式(10b) 100 縮寫：Balb/c =巴格白化小鼠(Bagg Albino)；KRAS =柯爾斯頓大鼠肉瘤病毒致癌基因同源物；D12C =於胺基酸密碼子編號十二處天冬胺酸轉化為半胱胺酸；KI =敲入；n=編號。 注意：腫瘤負荷終點係定義為記錄個體之腫瘤體積＞1,500 mm 3之情況。研究第1天係定義為給藥之第一天。 As shown in Table 1, median increases were nine days after administration of the combination of formula (10b) plus Antibody A compared to either agent alone or thirteen days when compared to vehicle plus isotype control . Table 1: Median No Progression to CT-26-Carrying Balb/c Mice with KRAS D12C KI Following Administration of Vehicle plus Isotype Control, or Formula (10b) and Antibody A, Alone or in Combination Summary of Tumor Burden Endpoints Group(n=10) treatment Dosage(mg/kg) Median survival (number of study days) 1 Vehicle Control+ 0 15 MOPC-21 same type 10 2 Antibody A 10 19 3 Formula (10b) 100 19 4 Antibody A+ 10 28 Formula (10b) 100 Abbreviations: Balb/c = Bagg Albino; KRAS = Kirsten rat sarcoma virus oncogene homolog; D12C = Conversion of aspartic acid at amino acid codon number twelve cysteine; KI = knock-in; n = no. Note: The tumor burden endpoint is defined as recording an individual's tumor volume >1,500 mm3 . Study Day 1 is defined as the first day of dosing.

如圖5中顯示，當使用對數秩(Mantel-Cox)檢驗自兩條無進展曲線評估對接受抗PD-1療法(抗體A)之小鼠替代品的小鼠添加SHP2抑制劑(式(10b))之益處時，觀察到進展至腫瘤負荷終點之統計學顯著延遲，p = 0.0309。於圖5中，縮寫：*，p ＜ 0.05。用對數秩(Mantel-Cox)檢驗進行無進展曲線抗體A與式(10b)組合之比較。腫瘤負荷終點係定義為記錄個體之腫瘤體積＞1,500 mm 3時之腫瘤負荷終點。研究第1天係定義為給藥之第一天。 As shown in Figure 5, when mice receiving a mouse surrogate for anti-PD-1 therapy (Antibody A) were evaluated using the log-rank (Mantel-Cox) test from two progression-free curves, the addition of a SHP2 inhibitor (Equation (10b) )), a statistically significant delay in progression to the tumor burden endpoint was observed, p = 0.0309. In Figure 5, abbreviation: *, p < 0.05. Comparison of progression-free curve combinations of antibody A and formula (10b) was performed using the log-rank (Mantel-Cox) test. The tumor burden endpoint was defined as the tumor burden endpoint when the individual tumor volume was >1,500 mm3 . Study Day 1 is defined as the first day of dosing.

另外，在無進展至腫瘤負荷終點曲線對之間的每個排列上確定曼特爾-亨塞爾風險率。在所有比較中，相較於彼等接受單獨治療者，或接受媒劑加同型對照之個體，於接受組合之式(10b)及抗體A之個體中發現降低之風險率發生率(表2)。 表2：在單獨或組合投與媒劑加同型對照、式(10b)及抗體A後，具有KRAS D12C KI之攜載CT-26之Balb/c小鼠中風險率之總結 組 (n=10) 治療 劑量 (mg/kg) 風險率 治療/對照 (第1組) 治療/抗體A (第2組) 治療/式(10b) (第3組) 1 媒劑對照+ 0 n/a - - MOPC-21同型 10 2 抗體A 100 0.244 n/a - 3 式(10b) 10 0.261 1.230 n/a 4 抗體A + 100 0.131 0.257 0.224 式(10b) 10 縮寫：Balb/c =巴格白化小鼠；KRAS =柯爾斯頓大鼠肉瘤病毒致癌基因同源物；D12C =於胺基酸密碼子編號十二處天冬胺酸轉化為半胱胺酸；KI =敲入；n=編號；n/a =不適用。 注意：使用基於無進展至腫瘤負荷終點曲線之曼特爾-亨塞爾測試確定風險率。腫瘤負荷終點係定義為記錄個體之腫瘤體積＞1,500 mm 3之情況。研究第1天係定義為給藥之第一天。 D.     結論 Additionally, Mantel-Hensel hazard ratios were determined on each permutation between pairs of progression-free to tumor burden endpoint curves. In all comparisons, a reduced risk rate incidence was found in individuals who received the combination of Formula (10b) and Antibody A compared to those who received treatment alone or vehicle plus isotype control (Table 2) . Table 2: Summary of hazard rates in CT-26-carrying Balb/c mice with KRAS D12C KI following administration of vehicle plus isotype control, Formula (10b), and Antibody A, alone or in combination. Group(n=10) treatment Dosage(mg/kg) risk rate Treatment/Control (Group 1) Treatment/Antibody A (Group 2) Treatment/Formula (10b) (Group 3) 1 Vehicle Control+ 0 n/a - - MOPC-21 same type 10 2 Antibody A 100 0.244 n/a - 3 Formula (10b) 10 0.261 1.230 n/a 4 Antibody A+ 100 0.131 0.257 0.224 Formula (10b) 10 Abbreviations: Balb/c = Balb albino mouse; KRAS = Kirsten rat sarcoma viral oncogene homolog; D12C = conversion of aspartate to cysteine at amino acid codon number twelve ; KI = knock-in; n = number; n/a = not applicable. NOTE: Hazard ratios were determined using the Mantel-Hensel test based on the progression-free to tumor burden endpoint curve. Tumor burden endpoint was defined as recording an individual's tumor volume >1,500 mm3 . Study Day 1 is defined as the first day of dosing. D. Conclusion

來自此活體內研究之結果證實在工程化KRAS D12C敲入結直腸癌CT-26同基因模型中，相較於單獨抗PD-1治療，添加SHP2抑制劑(式(10b))與納武單抗之小鼠替代品(即，鼠科抗PD-1抗體抗體A)組合顯示腫瘤負荷之顯著延遲。活體內研究支持組合SHP2抑制劑加抗PD-1療法(諸如納武單抗)之臨床評估，及顯示式(10b)之SHP2抑制可增強抗PD-1抗體之反應。Results from this in vivo study demonstrate that in the engineered KRAS D12C knock-in colorectal cancer CT-26 syngeneic model, the addition of a SHP2 inhibitor (formula (10b)) with nivolumab compared to anti-PD-1 treatment alone The mouse surrogate (i.e., murine anti-PD-1 antibody Antibody A) combination showed a significant delay in tumor burden. In vivo studies support the clinical evaluation of combining SHP2 inhibitors plus anti-PD-1 therapy (such as nivolumab) and show that SHP2 inhibition of formula (10b) enhances anti-PD-1 antibody responses.

儘管出於清楚瞭解之目的，已藉助於闡述及實例詳細描述前述揭示內容，但熟習此項技術者將認知可於隨附申請專利範圍之範疇內實踐某些改變及修飾。另外，本文提供之各參考文獻係以全文引用之方式併入本文中，該引用之程度就如同將各參考文獻以引用之方式個別地併入本文中一樣。當本申請案與本文提供之參考文獻之間存在衝突時，應以本申請案為準。Although the foregoing disclosure has been described in detail by illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. Additionally, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. In the event of a conflict between this application and a reference provided herein, this application shall control.

圖1A至圖1B顯示來自化合物(10b)對CD8+ T細胞之CD107a表現之影響之研究的結果。圖1A：供體1及3；及圖1B：供體2及4。Figures 1A-1B show results from studies of the effect of compound (10b) on CD107a expression of CD8+ T cells. Figure 1A: Donors 1 and 3; and Figure 1B: Donors 2 and 4.

圖2顯示化合物(10b)與PD-1/PD-L1抑制劑之組合於患有具有KRAS突變之晚期非小細胞肺癌之病患中之臨床研究之整體設計，如實例2中描述。Figure 2 shows the overall design of a clinical study of compound (10b) in combination with a PD-1/PD-L1 inhibitor in patients with advanced non-small cell lung cancer harboring KRAS mutations, as described in Example 2.

圖3顯示使用BOIN設計進行之試驗之流程圖。縮寫：BOIN=貝葉斯最優區間設計；DLT=劑量限制毒性；MTD=最大耐受劑量。注意：λe = 19.7%及λd = 29.8%。在實務中，以6個病患/定群，若DLT率係≤1/6，則使劑量遞增，若該DLT率係≥2/6，則使該劑量遞減。Figure 3 shows the flow chart of an experiment using the BOIN design. Abbreviations: BOIN = Bayesian optimal interval design; DLT = dose-limiting toxicity; MTD = maximum tolerated dose. Note: λe = 19.7% and λd = 29.8%. In practice, with 6 patients/group, if the DLT rate is ≤1/6, the dose is increased; if the DLT rate is ≥2/6, the dose is decreased.

圖4顯示在使用式(10b)及抗體A (作為抗PD-1療法)，單獨或組合治療攜載CT-26 KRAS D12C KI腫瘤之雌性Balb/c小鼠後，無進展至腫瘤負荷終點。Figure 4 shows that after treatment of female Balb/c mice bearing CT-26 KRAS D12C KI tumors with Formula (10b) and Antibody A (as anti-PD-1 therapy), alone or in combination, there was no progression to the tumor burden endpoint.

圖5顯示當使用式(10b)及抗體A之組合治療攜載CT-26 KRAS D12C KI腫瘤之雌性Balb/c小鼠時，腫瘤進展至負荷之統計學顯著延遲。Figure 5 shows a statistically significant delay in tumor progression to burden when female Balb/c mice bearing CT-26 KRAS D12C KI tumors were treated with the combination of Formula (10b) and Antibody A.

圖6顯示在使用式(10b)及抗體A (作為抗PD-1療法)，單獨或組合治療攜載CT-26 KRAS D12C KI腫瘤之雌性Balb/c小鼠後之腫瘤體積。Figure 6 shows tumor volume after treatment of CT-26 KRAS D12C KI tumor-bearing female Balb/c mice with Formula (10b) and Antibody A (as anti-PD-1 therapy), alone or in combination.

Claims (35)

一種於個體中治療癌症之方法，其包括對該個體投與： a)治療有效量之PTPN11抑制劑；及 b)治療有效量之PD-1/PD-L1抑制劑， 其中該PTPN11抑制劑係由式(I)表示： (I)， 或其醫藥上可接受之鹽、水合物、溶劑化物、立體異構體、構象異構體、互變異構體，或其組合， 其中： 下標a係0或1； 下標b係0或1； Y 1係直接鍵或CR 17R 18； Y 2係選自由以下組成之群：C 1-4烷基、胺基、C 1-4烷基C(O)O-、C 1-4烷基胺基及C 1-4胺基烷基； R 1係選自由以下組成之群：C 6-10芳基、C 3-8環烷基、C 3-8環烯基，及具有1至4個獨立地選自N、C(O)、O及S之雜原子或基團作為環頂點之5至10員雜芳基；R 1之該芳基或雜芳基係未經取代或經1至5個獨立地選自由以下組成之群之R 12基團取代：鹵基、羥基、胺基、C 1-4烷基胺基、二(C 1-4烷基)胺基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4羥基烷基、C 1-4鹵烷基、C 1-4胺基烷基、C 3-8環烷基、C 3-8環烯基、NR 15C(O)R 14、NR 15C(O)OR 14、NR 14C(O)NR 15R 16、NR 15S(O)R 14、NR 15S(O) 2R 14、C(O)NR 15R 16、S(O)NR 15R 16、S(O) 2NR 15R 16、C(O)R 14、C(O)OR 14、OR 14、SR 14、S(O)R 14及S(O) 2R 14； R 2、R 3、R 10及R 11係各獨立地選自由以下組成之群：氫、C 1-4烷基及C 3-8環烷基； R 4、R 5、R 8及R 9係各獨立地選自由以下組成之群：氫、氰基、C 1-4烷基、C 1-4烷氧基、胺基、羥基、C 3-8環烷基、鹵基及C 1-4烷基胺基； R 6係選自由以下組成之群：胺基、C 1-4胺基烷基及C 1-4烷基胺基； R 7係選自由以下組成之群：氫、醯胺基、氰基、鹵基及羥基，或係選自由以下組成之群：C 1-4烷基、C 1-4羥基烷基、C 3-6環烷基、苯基及5或6員雜芳基，其等中之任一者係未經取代或經1至5個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基； 或R 6及R 7連同其等均附接之碳原子一起形成3至7員飽和或不飽和環，其具有0至3個獨立地選自N、C(O)、O及S(O) m之雜原子或基團作為環頂點；下標m係0、1或2；及由R 6及R 7形成之該飽和或不飽和環係未經取代或經1至3個獨立地選自由以下組成之群之基團取代：胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基； R 2、R 3、R 4、R 5、R 7、R 8、R 9、R 10及R 11中之任兩個基團可形成5至6員環，其具有0至2個選自N、O及S之雜原子作為環頂點； R 2、R 4、R 6、R 8及R 10中之任兩個基團可形成直接鍵，或1或2個原子碳橋； R 13係選自由以下組成之群：氫、鹵基、氰基、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 1-6二羥基烷基、-NH-NHR 19、-NHR 19、-OR 19、-NHC(O)R 19、-NHC(O)NHR 19、-NHS(O) 2NHR 19、-NHS(O) 2R 19、-C(O)OR 19、-C(O)NR 19R 20、-C(O)NH(CH 2) qOH、-C(O)NH(CH 2) qR 21、-C(O)R 21、-NH 2、-OH、-S(O) 2NR 19R 20、C 3-8環烷基、芳基、具有1至5個選自N、O、S及P之雜原子作為環頂點之雜環基，及具有1至5個選自N、O、S及P之雜原子作為環頂點之雜芳基；下標q係0至6之整數；及R 13之芳基、雜芳基、雜環基及環烷基中之各者係未經取代或經1至3個獨立地選自由以下組成之群之基團取代：C 1-4烷基、-OH、-NH 2、-OR 21、鹵基、氰基及側氧基； R 14、R 15及R 16係各獨立地選自由以下組成之群：氫、C 1-4烷基、C 3-8環烷基、C 6-10芳基及5至10員雜芳基，其等中之任一者係未經取代或經一或多個獨立地選自由以下組成之群之基團取代：醯胺基、胺基、鹵基、羥基、氰基、C 1-4烷基、C 1-4烷氧基、C 1-4鹵烷基、C 1-4鹵基烷氧基、C 1-4烷基胺基及C 1-4胺基烷基； R 17及R 18係各獨立地選自由以下組成之群：氫、C 1-4烷基及CF 3； R 19及R 20係各獨立地選自由以下組成之群：氫、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 2-6烯基、C 2-6炔基及C 3-6環烷基；及 各R 21係獨立地選自由以下組成之群：氫、-OH、C 1-6烷基、C 1-6鹵烷基、C 1-6羥基烷基、C 2-6烯基、C 2-6炔基及C 3-6環烷基。 A method of treating cancer in an individual, comprising administering to the individual: a) a therapeutically effective amount of a PTPN11 inhibitor; and b) a therapeutically effective amount of a PD-1/PD-L1 inhibitor, wherein the PTPN11 inhibitor is Expressed by formula (I): (I), or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, conformational isomer, tautomer, or combination thereof, wherein: subscript a is 0 or 1; subscript b is 0 or 1; Y 1 is a direct bond or CR 17 R 18 ; Y 2 is selected from the group consisting of: C 1-4 alkyl, amino, C 1-4 alkyl C(O)O-, C 1-4 alkylamino and C 1-4 aminoalkyl; R 1 is selected from the group consisting of: C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl , and a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms or groups independently selected from N, C(O), O and S as ring vertices; the aryl or heteroaryl group of R 1 is Unsubstituted or substituted with 1 to 5 R 12 groups independently selected from the group consisting of: halo, hydroxyl, amine, C 1-4 alkylamino, di(C 1-4 alkyl) Amino group, cyano group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 hydroxyalkyl group, C 1-4 haloalkyl group, C 1-4 aminoalkyl group, C 3-8 Cycloalkyl, C 3-8 cycloalkenyl, NR 15 C(O)R 14 , NR 15 C(O)OR 14 , NR 14 C(O)NR 15 R 16 , NR 15 S(O)R 14 , NR 15 S(O) 2 R 14 , C(O)NR 15 R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 14 , C(O)OR 14 , OR 14 , SR 14 , S(O)R 14 and S(O) 2 R 14 ; R 2 , R 3 , R 10 and R 11 are each independently selected from the group consisting of: hydrogen, C 1- 4 alkyl and C 3-8 cycloalkyl; R 4 , R 5 , R 8 and R 9 are each independently selected from the group consisting of: hydrogen, cyano group, C 1-4 alkyl, C 1-4 Alkoxy group, amino group, hydroxyl group, C 3-8 cycloalkyl group, halo group and C 1-4 alkylamino group; R 6 is selected from the group consisting of: amino group, C 1-4 aminoalkyl group and C 1-4 alkylamino; R 7 is selected from the group consisting of: hydrogen, amide, cyano, halo and hydroxyl, or is selected from the group consisting of: C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and 5- or 6-membered heteroaryl, any of which is unsubstituted or 1 to 5 independently selected from the following Group substitution: amino group, halo group, hydroxyl group, cyano group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 haloalkyl group, C 1-4 haloalkoxy group , C 1-4 alkylamino and C 1-4 aminoalkyl; or R 6 and R 7 together with the carbon atoms to which they are attached form a 3 to 7 membered saturated or unsaturated ring, which has 0 to 3 heteroatoms or groups independently selected from N, C(O), O and S(O) m serve as ring vertices; the subscript m is 0, 1 or 2 ; and the The saturated or unsaturated ring system is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of: amino, halo, hydroxyl, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; R 2 , R 3 , R 4 , R 5. Any two groups among R 7 , R 8 , R 9 , R 10 and R 11 can form a 5 to 6 membered ring, which has 0 to 2 heteroatoms selected from N, O and S as ring vertices. ; Any two groups among R 2 , R 4 , R 6 , R 8 and R 10 can form a direct bond, or a 1 or 2 atom carbon bridge; R 13 is selected from the group consisting of: hydrogen, halo group , cyano group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 hydroxyalkyl group, C 1-6 dihydroxyalkyl group, -NH-NHR 19 , -NHR 19 , -OR 19 , -NHC(O)R 19 , -NHC(O)NHR 19 , -NHS(O) 2 NHR 19 , -NHS(O) 2 R 19 , -C(O)OR 19 , -C(O)NR 19 R 20 , -C(O)NH(CH 2 ) q OH, -C(O)NH(CH 2 ) q R 21 , -C(O)R 21 , -NH 2 , -OH, -S(O) 2 NR 19 R 20 , C 3-8 cycloalkyl, aryl, heterocyclic group with 1 to 5 heteroatoms selected from N, O, S and P as ring vertices, and 1 to 5 heteroatoms selected from N , the heteroatoms of O, S and P serve as the heteroaryl group at the ring vertex; the subscript q is an integer from 0 to 6; and each of the aryl, heteroaryl, heterocyclyl and cycloalkyl groups of R 13 is Unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of: C 1-4 alkyl, -OH, -NH 2 , -OR 21 , halo, cyano and pendant oxygen; R 14 , R 15 and R 16 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5 to 10 membered heteroaryl , any of which is unsubstituted or substituted with one or more groups independently selected from the group consisting of: amide group, amine group, halo group, hydroxyl group, cyano group, C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl; R 17 and R 18 is each independently selected from the group consisting of: hydrogen, C 1-4 alkyl and CF 3 ; R 19 and R 20 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl; and each R 21 is independently selected from the following Group: hydrogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl base. 如請求項1之方法，其中該PTPN11抑制劑係選自由以下組成之群： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 及 。 The method of claim 1, wherein the PTPN11 inhibitor is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . 如請求項1或2之方法，其中該PTPN11抑制劑係由式(2b)表示： (2b)， 具有6-((3S,4S)-4-胺基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-8-基)-3-(R a)-(2,3-二氯苯基)-2-甲基-4(3H)-嘧啶酮之名稱。 The method of claim 1 or 2, wherein the PTPN11 inhibitor is represented by formula (2b): (2b), having 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-3-(R a ) The name of -(2,3-dichlorophenyl)-2-methyl-4(3H)-pyrimidinone. 如請求項1或2之方法，其中該PTPN11抑制劑係由式(10b)表示： (10b)， 具有6-((3S,4S)-4-胺基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-8-基)-3-(R a)-(2,3-二氯苯基)-2,5-二甲基-4(3H)-嘧啶酮之名稱。 The method of claim 1 or 2, wherein the PTPN11 inhibitor is represented by formula (10b): (10b), having 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-3-(R a ) The name of -(2,3-dichlorophenyl)-2,5-dimethyl-4(3H)-pyrimidinone. 如請求項4之方法，其中該PD-1/PD-L1抑制劑不為納武單抗(nivolumab)。The method of claim 4, wherein the PD-1/PD-L1 inhibitor is not nivolumab. 如請求項1至4中任一項之方法，其中該PD-1/PD-L1抑制劑係帕博利珠單抗(pembrolizumab)、納武單抗、阿替利珠單抗(atezolizumab)、度伐利尤單抗(durvalumab)、阿維魯單抗(avelumab)、西米普利單抗-rwlc (cemiplimab-rwlc)、卡瑞利珠單抗(camrelizumab)、特瑞普利單抗(toripalimab)、帕洛利單抗(prolgolimab)、替雷利珠單抗(tislelizumab)、巴替利單抗(balstilimab)、多塔利單抗(dostarlimab)、M7824、斯巴達珠單抗(spartalizumab)、薩善利單抗(sasanlimab)、瑞弗利單抗(retifanlimab)、BMS-986213、或特泊利單抗(tebotelimab)，限制條件為，當該PTPN11抑制劑係由式(10b)表示時，該PD-1/PD-L1抑制劑不為納武單抗。As claimed in any one of the methods 1 to 4, wherein the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab-rwlc, camrelizumab, toripalimab ), prolgolimab, tislelizumab, balstilimab, dostarlimab, M7824, spartalizumab , sasanlimab, retifanlimab, BMS-986213, or tebotelimab, with the restriction that when the PTPN11 inhibitor is represented by formula (10b), This PD-1/PD-L1 inhibitor is not nivolumab. 如請求項1至6中任一項之方法，其中該癌症表現PD-L1，該癌症顯示高程度之微衛星不穩定性(MSI-H)、錯配修復缺陷(dMMR)或高程度之腫瘤突變負荷(TMB-H)，或該癌症係KRAS陽性癌症。Claim the method of any one of items 1 to 6, wherein the cancer expresses PD-L1, the cancer shows high-level microsatellite instability (MSI-H), mismatch repair deficiency (dMMR), or high-level tumors Mutation burden (TMB-H), or the cancer is KRAS-positive. 如請求項1至7中任一項之方法，其中該癌症包含實體腫瘤及/或液體腫瘤。The method of any one of claims 1 to 7, wherein the cancer includes solid tumors and/or liquid tumors. 如請求項1至8中任一項之方法，其中該癌症係肛門癌、膽管癌、膀胱癌、腦癌、子宮頸癌、結直腸癌(CRC)、子宮內膜癌、食管癌、胃癌、頭頸部鱗狀細胞癌(HNSCC)、肝細胞癌(HCC)、默克細胞癌(merkel cell carcinoma)、黑色素瘤、間皮瘤、非小細胞肺癌(NSCLC)、卵巢癌、***癌、腎細胞癌(RCC)、小細胞肺癌(SCLC)、鱗狀細胞癌(SCC)、三陰性乳癌(TNBC)，或其組合。The method of claim 1 to 8, wherein the cancer is anal cancer, bile duct cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer (CRC), endometrial cancer, esophageal cancer, gastric cancer, Head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), merkel cell carcinoma, melanoma, mesothelioma, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, renal cell carcinoma carcinoma (RCC), small cell lung cancer (SCLC), squamous cell carcinoma (SCC), triple negative breast cancer (TNBC), or combinations thereof. 如請求項9之方法，其中該癌症係結直腸癌(CRC)或非小細胞肺癌(NSCLC)。The method of claim 9, wherein the cancer is colorectal cancer (CRC) or non-small cell lung cancer (NSCLC). 如請求項1至10中任一項之方法，其中該癌症係對PD-1/PD-L1抑制劑耐藥性；及/或該癌症之特徵在於對PD-1/PD-L1抑制劑具有固有及/或獲得性耐藥性。The method of any one of claims 1 to 10, wherein the cancer is resistant to a PD-1/PD-L1 inhibitor; and/or the cancer is characterized by resistance to a PD-1/PD-L1 inhibitor Intrinsic and/or acquired resistance. 如請求項1至11中任一項之方法，其中該癌症係對帕博利珠單抗或納武單抗耐藥性之PD-L1陽性癌症；及/或該癌症係對帕博利珠單抗或納武單抗耐藥性之KRAS陽性癌症。The method of claim 1 to 11, wherein the cancer is a PD-L1-positive cancer that is resistant to pembrolizumab or nivolumab; and/or the cancer is resistant to pembrolizumab or nivolumab-resistant KRAS-positive cancer. 如請求項1至12中任一項之方法，其中該癌症之特徵在於KRAS G12C突變。The method of any one of claims 1 to 12, wherein the cancer is characterized by a KRAS G12C mutation. 如請求項1至13中任一項之方法，其中該癌症在先前至少一線包含基於鉑之雙藥化學療法及/或抗PD-1/PD-L1療法之全身性療法進行中或之後已進展或復發，其等中之各者係以單方療法給與或其等中之兩者係以組合療法給與。The method of any one of claims 1 to 13, wherein the cancer has progressed during or after at least one previous line of systemic therapy including platinum-based doublet chemotherapy and/or anti-PD-1/PD-L1 therapy. or relapse, each of which is given as a single therapy or two of them are given as a combination therapy. 如請求項1至14中任一項之方法，其中該癌症在抗PD-1/PD-L1療法之治療期間或於終止抗PD-1/PD-L1療法後約90天內已進展或復發。Claim the method of any one of items 1 to 14, wherein the cancer has progressed or relapsed during treatment with anti-PD-1/PD-L1 therapy or within about 90 days after discontinuation of anti-PD-1/PD-L1 therapy . 如請求項1至15中任一項之方法，其中該個體於BRAF V600X、PTPN11 (SHP2)或KRAS Q61X中不具有一或多個另外活化突變。The method of any one of claims 1 to 15, wherein the individual does not have one or more additional activating mutations in BRAF V600X, PTPN11 (SHP2), or KRAS Q61X. 如請求項1至16中任一項之方法，其中該個體先前未用PTPN抑制劑治療，限制條件為該PTPN抑制劑不為式(I)或式(10b)化合物。The method of any one of claims 1 to 16, wherein the subject has not been previously treated with a PTPN inhibitor, with the proviso that the PTPN inhibitor is not a compound of formula (I) or formula (10b). 如請求項1至17中任一項之方法，其中該個體係人類。The method of claim 1 to 17, wherein the system is human. 如請求項1至18中任一項之方法，其中該PTPN11抑制劑及該PD-1/PD-L1抑制劑係同時投與。The method of any one of claims 1 to 18, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are administered simultaneously. 如請求項1至18中任一項之方法，其中該PTPN11抑制劑及該PD-1/PD-L1抑制劑係依序投與。The method of any one of claims 1 to 18, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are administered sequentially. 如請求項20之方法，其中該PTPN11抑制劑係在投與該PD-1/PD-L1抑制劑之前投與；或該PTPN11抑制劑係在投與該PD-1/PD-L1抑制劑之後投與。The method of claim 20, wherein the PTPN11 inhibitor is administered before administering the PD-1/PD-L1 inhibitor; or the PTPN11 inhibitor is administered after the PD-1/PD-L1 inhibitor Invest. 如請求項1至21中任一項之方法，其中該PTPN11抑制劑係口服投與；及該PD-1/PD-L1抑制劑係靜脈內投與。The method of any one of claims 1 to 21, wherein the PTPN11 inhibitor is administered orally; and the PD-1/PD-L1 inhibitor is administered intravenously. 如請求項1至22中任一項之方法，其中該PTPN11抑制劑及該PD-1/PD-L1抑制劑係以聯合治療有效量提供。The method of any one of claims 1 to 22, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are provided in a combined therapeutically effective amount. 如請求項1至22中任一項之方法，其中該PTPN11抑制劑及該PD-1/PD-L1抑制劑係以協同有效量提供。The method of any one of claims 1 to 22, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are provided in a synergistically effective amount. 如請求項1至22中任一項之方法，其中該PTPN11抑制劑及該PD-1/PD-L1抑制劑所使用之各劑量低於分別單獨使用時之劑量。The method of any one of claims 1 to 22, wherein each dose of the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor is lower than the dose when used alone. 如請求項4至25中任一項之方法，其中在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約10 mg至約2000 mg、約50 mg至約2000 mg、約80 mg至約2000 mg、約80 mg至約1000 mg、約80 mg至約700 mg、約80 mg至約550 mg、約80 mg至約400 mg、約80 mg至約250 mg或約80 mg至約150 mg之總每日劑量。The method of any one of claims 4 to 25, wherein the therapeutically effective amount of the compound of formula (10b) is about 10 mg to about 2000 mg, about 50 mg to about 2000 mg, on a salt-free and anhydrous basis. About 80 mg to about 2000 mg, about 80 mg to about 1000 mg, about 80 mg to about 700 mg, about 80 mg to about 550 mg, about 80 mg to about 400 mg, about 80 mg to about 250 mg, or about 80 mg to a total daily dose of approximately 150 mg. 如請求項26之方法，其中在無鹽且無水之基礎上，該式(10b)化合物之治療有效量係約80 mg、約150 mg、約250 mg、約400 mg、約550 mg或約700 mg之總每日劑量。Such as the method of claim 26, wherein the therapeutically effective amount of the compound of formula (10b) is about 80 mg, about 150 mg, about 250 mg, about 400 mg, about 550 mg or about 700 mg on a salt-free and anhydrous basis. mg total daily dose. 如請求項1至27中任一項之方法，其中該PTPN11抑制劑係每天投與一次、兩次、三次或四次。The method of any one of claims 1 to 27, wherein the PTPN11 inhibitor is administered once, twice, three times, or four times per day. 如請求項28之方法，其中該PTPN11抑制劑係每天投與一次；及該PD-1/PD-L1抑制劑係每1、2、3、4、5或6週投與一次。The method of claim 28, wherein the PTPN11 inhibitor is administered once daily; and the PD-1/PD-L1 inhibitor is administered once every 1, 2, 3, 4, 5, or 6 weeks. 如請求項1至29中任一項之方法，其中使用該PTPN11抑制劑及該PD-1/PD-L1抑制劑之治療係減小癌症或實體腫瘤之體積至少約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%或約90%。The method of any one of claims 1 to 29, wherein the treatment using the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor reduces the volume of the cancer or solid tumor by at least about 10%, about 20%, About 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90%. 如請求項1至29中任一項之方法，其中使用該PTPN11抑制劑及該PD-1/PD-L1抑制劑之治療係穩定該癌症或實體腫瘤。The method of any one of claims 1 to 29, wherein treatment using the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor stabilizes the cancer or solid tumor. 一種於個體中治療癌症之套組，其包含： a)治療有效量之如請求項1至4中任一項之PTPN11抑制劑；及 b)治療有效量之PD-1/PD-L1抑制劑， 連同指示有效投藥之說明書。 A kit for treating cancer in an individual, comprising: a) A therapeutically effective amount of a PTPN11 inhibitor as claimed in any one of claims 1 to 4; and b) A therapeutically effective amount of a PD-1/PD-L1 inhibitor, Together with instructions for effective administration. 如請求項32之套組，其中該PD-1/PD-L1抑制劑係帕博利珠單抗、納武單抗、阿替利珠單抗、度伐利尤單抗、阿維魯單抗、西米普利單抗-rwlc、卡瑞利珠單抗、特瑞普利單抗、帕洛利單抗、替雷利珠單抗、巴替利單抗、多塔利單抗、M7824、斯巴達珠單抗、薩善利單抗、瑞弗利單抗、BMS-986213、或特泊利單抗，限制條件為，當該PTPN11抑制劑係由式(10b)表示時，該PD-1/PD-L1抑制劑不為納武單抗。Such as the set of request item 32, wherein the PD-1/PD-L1 inhibitor is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab , cimepilimab-rwlc, camrelizumab, toripalimab, palolizumab, tislelizumab, batilizumab, dotalizumab, M7824 , spartalizumab, saxanilumab, reflimab, BMS-986213, or terpolizumab, with the restriction that when the PTPN11 inhibitor is represented by formula (10b), the PD -1/PD-L1 inhibitor other than nivolumab. 如請求項32或33之套組，其中該PTPN11抑制劑及該PD-1/PD-L1抑制劑係經調配用於同時投與。Claim the set of claim 32 or 33, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are formulated for simultaneous administration. 如請求項32或33之套組，其中該PTPN11抑制劑及該PD-1/PD-L1抑制劑係經調配用於依序投與。Such as claim 32 or 33, wherein the PTPN11 inhibitor and the PD-1/PD-L1 inhibitor are formulated for sequential administration.
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