TW202017927A - Substituted [1, 2, 4] triazolo [1, 5-a] pyridine compounds as ret kinase inhibitors - Google Patents
Substituted [1, 2, 4] triazolo [1, 5-a] pyridine compounds as ret kinase inhibitors Download PDFInfo
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Abstract
Description
本申請要求美國臨時申請62/736,566的優先權，其全部內容透過引用整體併入本申請。This application claims the priority of US provisional application 62/736,566, the entire contents of which are incorporated by reference in their entirety.
本發明涉及一類可抑制RET激酶的新化合物或其藥學上可接受的鹽，其可用作藥物來治療過度增殖性疾病如癌症和發炎，或免疫和自體免疫疾病。The present invention relates to a new class of compounds that can inhibit RET kinase or pharmaceutically acceptable salts thereof, which can be used as drugs to treat hyperproliferative diseases such as cancer and inflammation, or immune and autoimmune diseases.
過度增殖性疾病如癌症和發炎吸引著學術界爲其提供有效治療手段。並在這方面已做出努力，鑑定並標靶了在增殖性疾病中發揮作用的特定機制。Hyperproliferative diseases such as cancer and inflammation attract academics to provide effective treatments. In this regard, efforts have been made to identify and target specific mechanisms that play a role in proliferative diseases.
轉染重排(RET)激酶是一種單次跨膜受體酪胺酸激酶，對於各種組織和細胞類型的正常發育、成熟和維持起重要作用。RET具有受體酪胺酸激酶的經典結構：富含半胱胺酸的類鈣黏蛋白細胞外結構域、跨膜區和催化酪胺酸激酶的細胞內區域。RET訊息可透過與一些可溶性蛋白質配體相結合而活化，所述配體爲神經膠質細胞系衍生的神經營養因子(GDNF)家族(GFL)。該家族還包括neurturin (NTRN)、青蒿琥酯(ARTN)和persephin (PSPN)。在RET被活化的過程中，GFL首先結合RET一個附加的輔受體，即GDNF家族受體α (GFRα)家族的四成員之一，形成配體-輔受體複合物。而後，配體-輔受體複合物與RET的細胞外結構域結合，誘導RET二聚化和磷酸化，進而透過PI3K/Akt/mTOR和RAS/MAPK/ERK活化下游訊息傳遞途徑，或者招募CBL家族泛素連接酶。Transfection rearrangement (RET) kinase is a single transmembrane receptor tyrosine kinase, which plays an important role in the normal development, maturation and maintenance of various tissues and cell types. RET has the classic structure of receptor tyrosine kinases: cysteine-rich cadherin-like extracellular domains, transmembrane regions, and intracellular regions that catalyze tyrosine kinases. The RET message can be activated by binding to some soluble protein ligands, which are glial cell line-derived neurotrophic factor (GDNF) family (GFL). The family also includes neurturin (NTRN), artesunate (ARTN) and persephin (PSPN). During the activation of RET, GFL first binds to RET, an additional co-receptor, one of the four members of the GDNF family receptor alpha (GFRα) family, forming a ligand-co-receptor complex. Then, the ligand-co-receptor complex binds to the extracellular domain of RET, induces RET dimerization and phosphorylation, and then activates downstream signaling pathways through PI3K/Akt/mTOR and RAS/MAPK/ERK, or recruits CBL Family ubiquitin ligase.
RET 基因的改變，包括基因融合和單核苷酸改變，以多種方式增強RET訊息途徑的功能，進而促進激酶的活化和原癌基因的轉化。因此，RET 基因改變加劇了許多對人類健康有負面影響的異常生理過程。現已發現異常的RET表現和/或活化與各種疾病的發生密切相關，如甲狀腺髓質癌、乳頭狀甲狀腺癌、2型多發性內分泌腫瘤、非小細胞肺癌、腸躁症候群等胃腸道疾病等。RET 基因的改變可以作爲標靶治療的預測性生物標記。當前已證明RET訊息途徑的抑制劑在多種臨床前癌症動物模型可作爲有效治療方法。正在進行的臨床試驗也已證明，選擇性RET抑制劑對RET 基因改變的腫瘤患者有益。Changes in the RET gene, including gene fusion and single nucleotide changes, enhance the function of the RET signaling pathway in multiple ways, thereby promoting the activation of kinases and the transformation of proto-oncogenes. Therefore, RET gene changes have exacerbated many abnormal physiological processes that have a negative impact on human health. It has been found that abnormal RET performance and/or activation is closely related to the occurrence of various diseases, such as medullary thyroid cancer, papillary thyroid cancer, type 2 multiple endocrine tumors, non-small cell lung cancer, gastrointestinal diseases such as intestinal manic syndrome . Changes in the RET gene can be used as predictive biomarkers for target therapy. Inhibitors of the RET signaling pathway have proven to be effective treatments in various preclinical animal models of cancer. Ongoing clinical trials have also shown that selective RET inhibitors are beneficial for cancer patients with RET gene changes.
雖然RET抑制劑在文獻中已有報道，如WO 2009099801和WO 2009003136，許多半衰期較短或者有毒性。因此，對新穎RET抑制劑的需求仍很迫切，其在治療異常增殖疾病中，其在療效、穩定性、選擇性、安全性和藥效學特徵至少有一方面具有優勢。本發明涉及一類新穎RET抑制劑。Although RET inhibitors have been reported in the literature, such as WO 2009099801 and WO 2009003136, many have short half-lives or are toxic. Therefore, the demand for novel RET inhibitors is still very urgent. In the treatment of abnormally proliferative diseases, it has advantages in at least one aspect of efficacy, stability, selectivity, safety and pharmacodynamics. The present invention relates to a novel class of RET inhibitors.
本發明涉及一類新穎化合物、其藥學可接受的鹽及其藥學組成物，以及作爲藥物的應用。The invention relates to a novel compound, its pharmaceutically acceptable salt and its pharmaceutical composition, and its application as a medicine.
在一個方面，本發明提供式(I)所示的化合物：
另一方面，本發明提供藥物組成物，其包含式(I)化合物或其藥學上可接受的鹽，和藥學上可接受的載體。In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
另一方面，本發明提供用於調節RET激酶的方法，包括對有需要的系統或個體給予治療有效量的式(I)化合物或藥學上可接受的鹽或藥學組成物，從而調節RET激酶。In another aspect, the present invention provides a method for modulating RET kinase, comprising administering to a system or individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition, thereby modulating RET kinase.
本發明還提供了一種治療、改善或預防對抑制RET激酶反應的病症的方法，包括給予有需要的系統或個體有效量的式(I)化合物或其藥學上可接受的鹽或藥學組成物，或與另一治療藥物聯合使用，治療上述病症。The present invention also provides a method of treating, ameliorating or preventing a condition responsive to the inhibition of RET kinase, comprising administering to a system or individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, Or used in combination with another therapeutic drug to treat the above-mentioned conditions.
或者，本發明提供了式(I)化合物或其藥學上可接受的鹽用於製造治療RET激酶媒介病症的藥物的用途。在特定實施例中，所述化合物可單獨或與另一治療藥物聯合使用治療RET激酶媒介病症。Alternatively, the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of RET kinase-mediated disorders. In certain embodiments, the compound may be used alone or in combination with another therapeutic agent to treat RET kinase-mediated disorders.
或者，本發明提供了式(I)化合物用於治療RET激酶媒介病症。Alternatively, the present invention provides compounds of formula (I) for use in the treatment of RET kinase-mediated disorders.
特定的，其中所述病症包括但不僅限於，自體免疫性疾病、移植疾病、感染性疾病或細胞增殖失調。Specifically, where the disorder includes, but is not limited to, autoimmune diseases, transplantation diseases, infectious diseases, or cell proliferation disorders.
此外，本發明提供了一種治療細胞增殖性病症的方法，該方法包括給予有需要的系統或個體有效量的式(I)化合物或其藥學上可接受的鹽或藥學組成物，或與另一治療藥物聯合使用，治療上述病症。In addition, the present invention provides a method for treating a cell proliferative disorder, the method comprising administering to a system or individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, or in combination with another Therapeutic drugs are used in combination to treat the aforementioned conditions.
或者，本發明提供了式(I)化合物和/或藥學上可接受的鹽用於製造治療細胞增殖性病症的藥物的用途。在特定實施例中，所述化合物可單獨或與另一治療藥物聯合使用治療細胞增殖性病症。Alternatively, the present invention provides the use of compounds of formula (I) and/or pharmaceutically acceptable salts for the manufacture of a medicament for the treatment of cell proliferative disorders. In certain embodiments, the compound may be used alone or in combination with another therapeutic agent to treat cell proliferative disorders.
特定的，其中所述病症包括但不限於，淋巴瘤、骨肉瘤、黑色素瘤，或乳腺、腎、前列腺、結腸直腸、甲狀腺、卵巢、胰腺、神經元、肺、子宮或胃腸道腫瘤。Specifically, where the condition includes, but is not limited to, lymphoma, osteosarcoma, melanoma, or breast, kidney, prostate, colorectal, thyroid, ovary, pancreas, neuron, lung, uterus, or gastrointestinal tract tumors.
在使用本發明所述化合物的上述方法中，式(I)化合物或藥學上可接受的鹽可給予由細胞或組織構成的系統，或包括哺乳動物個體，如人或動物在內的個體。In the above method using the compound of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt can be administered to a system composed of cells or tissues, or an individual including a mammalian individual, such as a human or animal.
術語the term
除非另有定義，本專利使用的所有技術和科學術語與該領域專業人員通常理解的含義相同。除非另有說明，本專利參考的所有專利、專利申請、公開披露的資料等全文納入參考文獻。如本專利中同一術語有多個定義，以本節中的定義爲準。Unless otherwise defined, all technical and scientific terms used in this patent have the same meaning as commonly understood by professionals in the field. Unless otherwise stated, all patents, patent applications, publicly disclosed materials, etc. referred to in this patent are incorporated by reference in their entirety. If there are multiple definitions for the same term in this patent, the definition in this section shall prevail.
需要理解的是，前文的一般描述和後文的詳細描述僅僅是解釋性的，對任何申請專利範圍都無限制性。在本專利申請中，使用的單數包含複數，除非另有說明。需要注意的是，說明書和所附申請專利範圍中，單數形式指代如“一”、“一個”、“這個”，包含複數指代，除非文中另有說明。還需注意的是，“或”代表“和/或”，除非另有說明。此外，“包含”、“包括”等類似術語不是限制性的。It should be understood that the foregoing general description and the following detailed description are merely explanatory, and are not limiting on the scope of any patent application. In this patent application, the singular used includes the plural unless otherwise stated. It should be noted that in the description and the scope of the attached patent applications, singular forms refer to “a”, “one”, “this”, including plural referents unless otherwise stated in the text. It should also be noted that "or" stands for "and/or" unless stated otherwise. In addition, "including", "including" and the like are not limiting.
除非另有說明，本專利使用的質譜、核磁共振、高效液相層析、紅外和紫外/可見光譜和藥理學常規技術是現有技術。除非有特別定義，本專利中的分析化學、有機合成化學、藥物和製藥化學中所涉及的命名、實驗方法和技術均是已知的。標準技術可用於化學合成、化學分析、藥物製備、製劑和給藥，以及治療患者。反應和純化技術可參考製造商說明書，或參考已知常用技術，或參照本專利中描述方法實施。上述的技術和操作可運用已知常規的和本說明書中所引用文獻的方法實施。在說明書中，基團和取代基可由該領域專業人員選擇，以形成穩定結構和化合物。Unless otherwise stated, the mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy and conventional pharmacological techniques used in this patent are prior art. Unless otherwise specified, the nomenclature, experimental methods and techniques involved in analytical chemistry, organic synthetic chemistry, pharmaceutical and pharmaceutical chemistry in this patent are known. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and administration, and treatment of patients. The reaction and purification techniques may refer to the manufacturer's instructions, or to the known common techniques, or to the methods described in this patent. The above techniques and operations can be implemented using known conventional methods and documents cited in this specification. In the description, groups and substituents can be selected by those skilled in the art to form stable structures and compounds.
當用化學式指代取代基時，化學式中的取代基從左至右書寫與從右至左書寫相同。例如，CH2 O與OCH2 相同。When a chemical formula is used to refer to a substituent, the substituent in the chemical formula is written from left to right as from right to left. For example, CH 2 O is the same as OCH 2 .
“取代”是指氫原子被取代基取代。需要注意的是，特定原子上的取代基是被其原子價限制的。"Substitute" means that the hydrogen atom is replaced by a substituent. It should be noted that the substituent on a particular atom is limited by its valence.
本文使用的術語“Ci-j ”或“i-j員”是指該部分具有i-j個碳原子或i-j個原子。例如，“C1-6 烷基”是指所述烷基具有1-6個碳原子。同樣，C3-10 環烷基是指所述環烷基具有3-10個碳原子。As used herein, the term "C ij "or "ij member" means that the moiety has ij carbon atoms or ij atoms. For example, "C 1-6 alkyl" means that the alkyl group has 1-6 carbon atoms. Similarly, C 3-10 cycloalkyl means that the cycloalkyl has 3-10 carbon atoms.
當任何變量(如R)出現在化合物的結構上超過一次時，其在每種情況下獨立定義。因此，例如，如果基團被0-2個R取代，則該基團可以任選地被至多兩個R取代，並且R在每種情況下具有獨立的選擇。另外，僅當這樣的組合將産生穩定的化合物時，才允許取代基和/或其變體的組合。When any variable (such as R) appears in the structure of a compound more than once, it is independently defined in each case. Thus, for example, if a group is substituted with 0-2 Rs, the group can be optionally substituted with up to two Rs, and R has an independent choice in each case. In addition, combinations of substituents and/or their variants are only allowed when such combinations will produce stable compounds.
“一個或多個”或“至少一個”是指一個，兩個，三個，四個，五個，六個，七個，八個，九個或更多個。"One or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine or more.
除非另有說明，否則術語“雜”是指雜原子或雜原子基團(即含有雜原子的基團)，即碳和氫原子以外的原子或含有這些原子的基團。優選地，雜原子獨立地選自O，N，S，P等。在涉及兩個或更多個雜原子的實施方案中，兩個或更多個雜原子可以是相同的，或者兩個或更多個雜原子可以部分不同或全部不同。Unless otherwise stated, the term "hetero" refers to heteroatoms or heteroatom groups (ie groups containing heteroatoms), ie atoms other than carbon and hydrogen atoms or groups containing these atoms. Preferably, the heteroatoms are independently selected from O, N, S, P and the like. In embodiments involving two or more heteroatoms, the two or more heteroatoms may be the same, or the two or more heteroatoms may be partially or completely different.
“烷基”不論單獨使用或與其他術語合用，是指具有特定碳原子數的分支或直鏈飽和脂肪族烴基團。除另有註明外，“烷基”是指C1 -10 烷基。例如，“C1 -6 烷基”中的“C1 -6 ”指的是有1、2、3、4、5或6個碳原子的直鏈或分支排列的基團。例如，“C1 -8 烷基”包括但不限於甲基、乙基、正丙基、異丙基、正丁基、叔丁基、異丁基、戊基、己基、庚基和辛基。"Alkyl" whether used alone or in combination with other terms, refers to a branched or linear saturated aliphatic hydrocarbon group having a specified number of carbon atoms. Unless otherwise specified, "alkyl" refers to C 1 - 10 alkyl. For example, "C 1 - 6 alkyl""C 1 - 6" means having 5 or 6 carbon atoms, or a linear group branched arrangement. For example, "C 1 - 8 alkyl" includes but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl .
“環烷基”不論單獨使用或與其他術語合用，是指單環或橋聯飽和烴環體系。單環環烷基是包含3-10個碳原子的單環烴體系，無雜原子，無雙鍵。單環系統的實例包括但不僅限於環丙基、環丁基、環戊基、環己基、環庚基和環辛基。橋環烷基是含有3-10個碳原子的多環體系，其含有一個或兩個伸烷基橋，每個伸烷基橋由1、2或3個碳原子組成，它們連接環系上兩個不相鄰的碳原子。環烷基可以與芳基或雜芳基稠合。在一些實施方案中，環烷基是苯並稠合的。橋環烷體系的代表性例子包含，但不僅限於，雙環[3.1.1]庚烷，雙環[2.2.1]庚烷，雙環[2.2.2]辛烷，雙環[3.2.2]壬烷，雙環[3.3.1]壬烷，雙環[4.2.1]壬烷，三環[3.3.1.03,7]壬烷，和三環[3.3.1.13,7]癸烷(金剛烷)。單環和橋烴環可透過環系中任意可取代的原子與母體分子部分相連。"Cycloalkyl" whether used alone or in combination with other terms, refers to a monocyclic or bridged saturated hydrocarbon ring system. Monocyclic cycloalkyl is a monocyclic hydrocarbon system containing 3-10 carbon atoms, no heteroatoms, no double bonds. Examples of monocyclic systems include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A bridged cycloalkyl is a polycyclic ring system containing 3-10 carbon atoms, which contains one or two alkylene bridges, each alkylene bridge is composed of 1, 2 or 3 carbon atoms, they are connected to the ring system Two non-adjacent carbon atoms. The cycloalkyl group may be fused with an aryl group or a heteroaryl group. In some embodiments, the cycloalkyl group is benzo-fused. Representative examples of bridged cycloalkane systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, Bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane, and tricyclo[3.3.1.13,7]decane (adamantane). Monocyclic and bridged hydrocarbon rings can be connected to the parent molecular moiety through any substitutable atom in the ring system.
“烯基”不論單獨使用或與其他術語合用，是指含有2-10個碳原子且至少有一個碳碳雙鍵的非芳香直鏈、分支或環狀烴基。在一些實施例中，存在1個碳碳雙鍵，多達4個非芳香性的碳碳雙鍵可能存在。因此，“C2 － 6 烯基”是指含有2-6個碳原子的烯基。烯基基團包括但不限於乙烯基、丙烯基、丁烯基、2-甲基丁烯基和環己烯基。烯基中的直鏈、分支或環狀部分可能含有雙鍵，且若標明取代烯基表示其可能被取代。"Alkenyl" whether used alone or in combination with other terms, refers to a non-aromatic linear, branched, or cyclic hydrocarbon group containing 2 to 10 carbon atoms and having at least one carbon-carbon double bond. In some embodiments, there is 1 carbon-carbon double bond, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C 2 - 6 alkenyl" means an alkenyl group containing 2-6 carbon atoms. Alkenyl groups include but are not limited to vinyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The linear, branched, or cyclic portion of the alkenyl group may contain double bonds, and if a substituted alkenyl group is indicated, it may be substituted.
“炔基”不論單獨使用或與其他術語合用，是指含有2-10個碳原子且至少一個碳碳三鍵的直鏈、分支或環狀烴基。在一些實施例中，可存在多達3個碳碳三鍵。因此，“C2 -6 炔基”指含有2-6個碳原子的炔基。炔基基團包括但不限於乙炔基、丙炔基、丁炔基、3-甲基丁炔基等。炔基中的直鏈、分支或環狀部分可能含有三鍵，若標明取代炔基表示其可能被取代。"Alkynyl" whether used alone or in combination with other terms, refers to a straight-chain, branched or cyclic hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, there may be up to 3 carbon-carbon triple bonds. Thus, "C 2 - 6 alkynyl" means an alkynyl group containing 2-6 carbon atoms. Alkynyl groups include but are not limited to ethynyl, propynyl, butynyl, 3-methylbutynyl and the like. The straight-chain, branched or cyclic part of the alkynyl group may contain a triple bond. If a substituted alkynyl group is indicated, it may be substituted.
“鹵素”是指氟、氯、溴、碘。"Halogen" means fluorine, chlorine, bromine and iodine.
“烷氧基”，其單獨使用或與其他術語合用，是指與氧原子以單鍵相連的如上定義的烷基。烷氧基與分子透過氧原子相連。烷氧基可以表示爲-O-烷基。“C1-10 烷氧基”是指含有1-10個碳原子的烷氧基，可爲直鏈或分支結構。烷氧基包括但不僅限於，甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、戊氧基、己氧基等。"Alkoxy", used alone or in combination with other terms, refers to an alkyl group as defined above connected to a single bond with an oxygen atom. The alkoxy group is connected to the molecule through an oxygen atom. Alkoxy can be represented as -O-alkyl. "C 1-10 alkoxy" refers to an alkoxy group containing 1-10 carbon atoms, which may be linear or branched. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.
“環烷氧基”，其單獨使用或與其他術語合用，是指與氧原子以單鍵相連的如上定義的環烷基。環烷氧基與分子透過氧原子相連。環烷氧基可以表示爲-O-環烷基。“C3-10 環烷氧基”是指含有3-10個碳原子的環烷氧基。環烷氧基可以與芳基或雜芳基稠合。在一些實施方案中，環烷氧基是苯並稠合的。環烷氧基包括但不僅限於，環丙氧基、環丁氧基、環戊氧基、環己氧基等。"Cycloalkoxy", used alone or in combination with other terms, refers to a cycloalkyl group as defined above connected to a single bond with an oxygen atom. The cycloalkoxy group is connected to the molecule through an oxygen atom. Cycloalkoxy can be represented as -O-cycloalkyl. "C 3-10 cycloalkoxy" refers to a cycloalkoxy group containing 3-10 carbon atoms. The cycloalkoxy group may be fused with an aryl group or a heteroaryl group. In some embodiments, the cycloalkoxy group is benzo-fused. Cycloalkoxy includes, but is not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
“烷硫基”，其單獨使用或與其他術語合用，是指與硫原子以單鍵相連的如上定義的烷基。烷硫基與分子透過硫原子相連。烷硫基可以表示爲-S-烷基。“C1-10 烷硫基”是指含有1-10個碳原子的烷硫基，可爲直鏈或分支結構。烷硫基包括但不僅限於，甲硫基、乙硫基、丙硫基、異丙硫基、丁硫基和己硫基等。"Alkylthio", used alone or in combination with other terms, refers to an alkyl group as defined above connected to a sulfur atom with a single bond. The alkylthio group is connected to the molecule through a sulfur atom. The alkylthio group can be represented as -S-alkyl. "C 1-10 alkylthio" refers to an alkylthio group containing 1-10 carbon atoms, which may be linear or branched. The alkylthio group includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio and hexylthio.
“環烷硫基”，其單獨使用或與其他術語合用，是指與硫原子以單鍵相連的如上定義的環烷基。環烷硫基與分子透過硫原子相連。環烷硫基可以表示爲-S-環烷基。“C3-10 環烷硫基”是指含有3-10個碳原子的環烷硫基。環烷硫基可以與芳基或雜芳基稠合。在一些實施方案中，環烷硫基是苯並稠合的。環烷硫基包括但不僅限於，環丙硫基、環丁硫基和環己硫基等。"Cycloalkylthio", used alone or in combination with other terms, refers to a cycloalkyl group as defined above connected to a sulfur atom by a single bond. The cycloalkylthio group is connected to the molecule through a sulfur atom. The cycloalkylthio group may be represented as -S-cycloalkyl. "C 3-10 cycloalkylthio" refers to cycloalkylthio containing 3-10 carbon atoms. The cycloalkylthio group may be fused with an aryl group or a heteroaryl group. In some embodiments, the cycloalkylthio group is benzo-fused. The cycloalkylthio group includes, but is not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.
“烷胺基”，其單獨使用或與其他術語合用，是指與氮原子以單鍵相連的如上定義的烷基。烷胺基與另一分子透過氮原子相連。烷胺基可以表示爲-NH (烷基)。“C1-10 烷胺基”是指含有1-10個碳原子的烷胺基，可爲直鏈或分支結構。烷胺基包括但不僅限於，甲胺基、乙胺基、丙胺基、異丙胺基、丁胺基和己胺基等。"Alkylamino", used alone or in combination with other terms, refers to an alkyl group as defined above connected to a nitrogen atom by a single bond. The alkylamine group is connected to another molecule through a nitrogen atom. The alkylamine group may be represented as -NH (alkyl). "C 1-10 alkylamino group" refers to an alkylamino group containing 1 to 10 carbon atoms, and may have a linear or branched structure. Alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino and hexylamino.
“環烷胺基”，其單獨使用或與其他術語合用，是指與氮原子以單鍵相連的如上定義的環烷基。環烷胺基與另一分子透過氮原子相連。環烷胺基可以表示爲-NH (環烷基)。“C3-10 環烷胺基”是指含有3-10個碳原子的環烷胺基。環烷基胺基可以與芳基或雜芳基稠合。在一些實施方案中，環烷基胺基是苯並稠合的。環烷胺基包括但不僅限於，環丙胺基、環丁胺基和環己胺基等。"Cycloalkylamino", used alone or in combination with other terms, refers to a cycloalkyl group as defined above connected to a nitrogen atom by a single bond. The cycloalkylamine group is connected to another molecule through a nitrogen atom. The cycloalkylamino group can be represented as -NH (cycloalkyl). "C 3-10 cycloalkylamino group" means a cycloalkylamino group containing 3 to 10 carbon atoms. The cycloalkylamine group may be fused with an aryl group or a heteroaryl group. In some embodiments, the cycloalkylamine group is benzo-fused. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino, and the like.
“二(烷基)胺基”，其單獨使用或與其他術語合用，是指與氮原子以單鍵相連的兩個如上定義的烷基。二(烷基)胺基與分子透過氮原子相連。二(烷基)胺基可以表示爲-N (烷基)2 。“二(C1-10 烷基)胺基”是指兩個烷基部分分別含有1-10個碳原子的二(C1-10 烷基)胺基，可爲直鏈或分支結構。"Di(alkyl)amino", used alone or in combination with other terms, refers to two alkyl groups as defined above connected to a nitrogen atom by a single bond. The di(alkyl)amine group is connected to the molecule through a nitrogen atom. The di(alkyl)amine group can be represented as -N (alkyl) 2 . "Di(C 1-10 alkyl)amine group" refers to a di(C 1-10 alkyl)amine group containing two alkyl moieties each containing 1-10 carbon atoms, and may have a linear or branched structure.
“芳基”，其單獨使用或與其他術語合用，是指具有6、7、8、9、10、11、12、13或14個碳原子(“C6-14 芳基”基團)的單價、單環、雙環或三環的芳烴環系統，特別是具有6個碳原子的環(“C6 芳基”基團)，例如苯基；或具有10個碳原子的環(“C10 芳基”基團)，例如萘基；或具有14個碳原子的環(“C14 芳基”基團)，例如蒽基。芳基可以與環烷基或雜環基稠合。"Aryl", used alone or in combination with other terms, means having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14 aryl" group) Monovalent, monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring systems, especially rings with 6 carbon atoms (“C 6 aryl” group), such as phenyl; or rings with 10 carbon atoms (“C 10 "Aryl" group), for example naphthyl; or a ring with 14 carbon atoms ("C 14 aryl" group), for example anthracenyl. The aryl group may be fused with a cycloalkyl group or a heterocyclic group.
由取代的苯類衍生物形成的且在環原子上存在自由價電子的二價基團，被命名爲取代的亞苯基基團。衍生自名字以“-基”結尾的一價多環烴基團的二價基團，其是在含有自由價電子上的碳原子上再去掉一個氫原子而得到的，其名稱爲在單價基團名字加上“-亞(-idene)”，例如，有兩個連接位點的萘基就被稱爲亞萘基。The divalent group formed by substituted benzene derivatives and having free valence electrons on ring atoms is named as a substituted phenylene group. A divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends in "- group", which is obtained by removing one more hydrogen atom from a carbon atom containing a free valence electron, and is named as a monovalent group Add "-idene" to the name. For example, a naphthyl group with two attachment sites is called a naphthylene group.
“雜芳基”，其單獨使用或與其他術語合用，是指具有5、6、7、8、9、10、11、12、13或14個環原子(“5至14員雜芳基”基團)的單價，單環，雙環或三環的芳環系統，特別是5或6或9或10個原子，並且含有至少一個可以相同或不同的雜原子，所述雜原子選自N，O和S。雜芳基可以與環烷基或雜環基稠合。在一些實施例中，“雜芳基”是指 5員到8員的芳香單環，該環含有選自N，O和S的，數目爲1到4個，在某些實施例中爲1到3個的雜原子，其餘均爲碳原子；和 8員到-12員雙環，該環含有選自N，O和S的，數目爲1到6個，在某些實施例中爲1到4個的雜原子，或在某些實施例中爲1到3個的雜原子，其餘均爲碳原子，且其中至少有一個雜原子出現在芳環中；和 11員到14員三環，該環含有選自N，O和S的，數目爲1到8個，在某些實施例中爲數目爲1到6個，或在某些實施例中爲數目爲1到4個，或在某些實施例中爲1到3個的雜原子，其餘均爲碳原子。"Heteroaryl", used alone or in combination with other terms, means having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms ("5 to 14 member heteroaryl" Group) monovalent, monocyclic, bicyclic or tricyclic aromatic ring system, especially 5 or 6 or 9 or 10 atoms, and contains at least one heteroatom which may be the same or different, the heteroatom is selected from N, O and S. The heteroaryl group may be fused with a cycloalkyl group or a heterocyclic group. In some embodiments, "heteroaryl" refers to 5-membered to 8-membered aromatic monocyclic ring, the ring contains one selected from N, O and S, the number is 1 to 4, in some embodiments is 1 to 3 heteroatoms, the rest are carbon atoms; with 8-membered to -12 membered bicyclic ring, the ring contains one selected from N, O and S, the number is 1 to 6, in some embodiments 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, the rest are all carbon atoms, and at least one of the heteroatoms appears in the aromatic ring; and 11-member to 14-member tricyclic ring, the ring contains one selected from N, O and S, the number is 1 to 8, the number is 1 to 6 in some embodiments, or the number is in some embodiments It is 1 to 4, or in some embodiments, 1 to 3 heteroatoms, and the rest are carbon atoms.
當雜芳基中S和O的總數大於1時，這些雜原子彼此不相鄰。在一些實施例中，雜芳基中S和O的總數不大於2。在一些實施例中，雜芳基中S和O的總數不大於1。When the total number of S and O in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O in the heteroaryl group is not greater than 2. In some embodiments, the total number of S and O in the heteroaryl group is not greater than 1.
雜芳基的例子包括但不限於2-吡啶基，3-吡啶基，4-吡啶基，2-吡嗪基，3-吡嗪基，2-嘧啶基，4-嘧啶基，5-嘧啶基，6-嘧啶基，1-吡唑基，3-吡唑基，4-吡唑基，5-吡唑基，1-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基，噠嗪基，三嗪基，吡咯基，噁唑基，異噁唑基，噻唑基，異噻唑基，噻二唑基，三唑基，四唑基，噻吩基，呋喃基。Examples of heteroaryl groups include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 3-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl , 6-pyrimidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, Pyridazinyl, triazinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thienyl, furyl.
進一步地，雜芳基包括但不限於吲哚基，苯並噻吩基，苯並呋喃基，苯並咪唑基，苯並三唑基，喹喔啉基，喹啉基和異喹啉基。“雜芳基”包括任何含氮雜芳基的N氧化衍生物。Further, heteroaryl groups include but are not limited to indolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzotriazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl. "Heteroaryl" includes any N-oxidized derivative of a nitrogen-containing heteroaryl.
一價雜芳基基團的命名以“-基”結尾，其衍生的二價基團的就是在含有自由價電子上的碳原子上再去掉一個氫原子而得到的，該二價基團的命名系在一價基團的名稱加上“-亞(-idene)”，例如：有兩個連接位點的吡啶基被稱爲吡啶亞基。The name of the monovalent heteroaryl group ends with "- group", and the derived divalent group is obtained by removing one more hydrogen atom from the carbon atom containing the free valence electron. The nomenclature is the name of a monovalent group plus "-idene", for example, a pyridyl group having two connection sites is called a pyridyl group.
“雜環”(和由此衍變的如“雜環的”或“雜環基”)泛指飽和或不包含、單環或多環(如：雙環)的環狀脂肪烴系統，通常有3至12個環原子，至少含有1個(如：2，3或4個)獨立地選自氧、硫、氮和磷的雜原子(優選氧，硫，氮)。在多環系統中兩個或更多個環可以透過稠合、橋接或螺環鏈接，雜環可以與芳基或雜芳基稠合。在一些實施例中，雜環是苯並稠合的。雜環還包括被一個或多個氧代或亞胺基部分取代的環系。在一些實施例中，雜環中的C，N，S和P原子任選被氧代取代。在一些實施例中，雜環中的C，S和P原子任選地被亞胺基取代，且亞胺基可以是未取代的或取代的。雜環上的碳原子或雜原子均可是聯接位點，前提是形成一個穩定的結構。當雜環上有取代基時，該取代基可以和雜環上的任何雜原子或碳原子連接，前提是形成一個穩定的化學結構。"Heterocycle" (and derived from such as "heterocyclic" or "heterocyclic group") generally refers to a saturated or non-containing, monocyclic or polycyclic (eg bicyclic) cyclic aliphatic hydrocarbon system, usually 3 Up to 12 ring atoms, containing at least one (eg, 2, 3 or 4) heteroatoms (preferably oxygen, sulfur, nitrogen) independently selected from oxygen, sulfur, nitrogen and phosphorus. In a polycyclic ring system, two or more rings may be linked by fused, bridged, or spiro rings, and the heterocyclic ring may be fused with an aryl group or a heteroaryl group. In some embodiments, the heterocycle is benzo-fused. Heterocycles also include ring systems that are partially substituted with one or more oxo or imino groups. In some embodiments, the C, N, S and P atoms in the heterocycle are optionally substituted with oxo. In some embodiments, the C, S, and P atoms in the heterocycle are optionally substituted with an imino group, and the imino group may be unsubstituted or substituted. Either the carbon atom or the hetero atom on the heterocycle can be the linking site, provided that a stable structure is formed. When there is a substituent on the heterocycle, the substituent can be connected to any hetero atom or carbon atom on the heterocycle, provided that a stable chemical structure is formed.
適宜的雜環包括，例如1-吡咯烷基，2-吡咯烷基，3-吡咯烷基，1-咪唑烷基，2-咪唑烷基，3-咪唑烷基，4-咪唑烷基，5-咪唑烷基，1-吡唑烷基，2-吡唑烷基，3-吡唑烷基，4-吡唑烷基，5-吡唑烷基，1-呱啶基，2-呱啶基，3-呱啶基，4-呱啶基，1-呱嗪基，2-呱嗪基，3-呱嗪基，1-六氫噠嗪基，3-六氫噠嗪基和4-六氫噠嗪基。具有一個或多個氧代部分的雜環的實例包括但不限於呱啶基-N-氧化物，嗎啉基-N-氧化物，1-氧代-硫代嗎啉基和1,1-二氧代-硫代嗎啉基。雙環雜環包括但不僅限於：
此處所用的“芳基-烷基”是指如上定義的芳基取代的如上定義的烷基。示例的芳烷基包括但不僅限於苄基，苯乙基和萘甲基等。在一些實施中，芳烷基含7-20或7-11個碳原子。當使用“芳基C1-4 烷基”時，其中“C1-4 ”是指烷基部分而不是芳基部分的碳原子數。As used herein, "aryl-alkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above. Exemplary aralkyl groups include but are not limited to benzyl, phenethyl, naphthylmethyl, and the like. In some implementations, the aralkyl group contains 7-20 or 7-11 carbon atoms. When "aryl C 1-4 alkyl" is used, where "C 1-4 "refers to the number of carbon atoms in the alkyl portion rather than the aryl portion.
此處所用的“雜環基-烷基”是指如上定義的雜環基取代的如上定義的的烷基。當使用“雜環基C1-4 烷基”時，其中“C1-4 ”是指烷基部分而不是雜環基部分的碳原子數。As used herein, "heterocyclyl-alkyl" refers to an alkyl group as defined above substituted with a heterocyclic group as defined above. When "heterocyclyl C 1-4 alkyl" is used, "C 1-4 "refers to the number of carbon atoms in the alkyl portion instead of the heterocyclic portion.
此處所用的“環烷基-烷基”是指如上定義的環烷基取代的如上定義的烷基。當使用“C3-10 環烷基-C1-4 烷基”時，其中“C3-10 ”是指環烷基部分而不是烷基部分的碳原子數。其中“C1-4 ”是指烷基部分而不是環烷基部分的碳原子數。As used herein, "cycloalkyl-alkyl" refers to an alkyl group as defined above substituted with a cycloalkyl group as defined above. When "C 3-10 cycloalkyl-C 1-4 alkyl" is used, "C 3-10 "refers to the number of carbon atoms in the cycloalkyl portion instead of the alkyl portion. Where "C 1-4 "refers to the number of carbon atoms in the alkyl portion rather than the cycloalkyl portion.
此處所用的“雜芳基-烷基”是指如上定義的雜芳基取代的如上定義的烷基。當使用“雜芳基-C1-4 烷基”時，其中“C1-4 ”是指烷基部分而不是雜芳基部分的碳原子數。As used herein, "heteroaryl-alkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above. When "heteroaryl-C 1-4 alkyl" is used, "C 1-4 "refers to the number of carbon atoms in the alkyl portion instead of the heteroaryl portion.
爲避免歧義，例如：當提到烷基，環烷基，雜環基烷基，芳基，和/或其雜芳基取代時，其意是指每個這些基團單獨地取代，或是指這些基團混合取代。亦即：如果R是芳基-C1-4 烷基，並且可以是未取代的或被至少一個取代基取代，如1、2、3或4個獨立地選自RX 的取代基取代，應該理解，芳基部分可以是未取代的或被至少一個，如1、2、3或4個獨自選自RX 的取代基取代，烷基部分也可爲未被取代的或被至少一個，如1、2、3或4個獨自選自RX 的取代基取代。To avoid ambiguity, for example: when referring to alkyl, cycloalkyl, heterocyclylalkyl, aryl, and/or heteroaryl substitution, it means that each of these groups is substituted individually, or Refers to the mixed substitution of these groups. That is: if R is aryl-C 1-4 alkyl, and may be unsubstituted or substituted with at least one substituent, such as 1, 2, 3, or 4 substituents independently selected from R X , It should be understood that the aryl moieties may be unsubstituted or substituted with at least one, such as 2, 3 or 4 independently selected R X substituents, the alkyl portion may be at least one unsubstituted or substituted, For example, 1, 2, 3 or 4 substituents independently selected from R X are substituted.
“藥學上可接受的鹽”，是指與藥學上可接受的無毒的鹼或酸，包括無機或有機鹼和無機或有機酸製成的鹽。無機鹼的鹽可以選自，例如：鋁、銨、鈣、銅、鐵、亞鐵、鋰、鎂、錳、二價錳、鉀、鈉、鋅鹽。進一步，藥學上可接受的無機鹼的鹽可選自銨，鈣，鎂，鉀，鈉鹽。在固體鹽中可能存在一個或多個晶體形態，或多晶型物，也有可能存在溶劑合物，如水合物的形式。藥學上可接受的有機無毒鹼的鹽可選自，例如：伯胺，仲胺和叔胺鹽，取代胺包括自然存在的取代胺，環胺，鹼性離子交換樹脂，如精胺酸，甜菜鹼，咖啡鹼，膽鹼，N,N' -二苄基乙二胺，二乙胺，2-二乙胺基乙醇，2-二甲胺基乙醇，乙醇胺，乙二胺，N -乙基嗎啉，N -乙基呱啶，葡萄糖胺，胺基葡萄糖，組胺酸，海巴明胺，異丙胺，離胺酸，甲基葡糖胺，嗎啉，呱嗪，呱啶，多胺樹脂，普魯卡因，嘌呤，可可鹼，三乙胺，三甲胺，三丙胺，胺丁三醇。"Pharmaceutically acceptable salt" refers to a salt made with a pharmaceutically acceptable non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. The salt of the inorganic base may be selected from, for example, aluminum, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganese, divalent manganese, potassium, sodium, zinc salts. Further, the salts of pharmaceutically acceptable inorganic bases may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. There may be one or more crystal forms or polymorphs in the solid salt, and there may also be solvates, such as hydrates. The salts of pharmaceutically acceptable organic non-toxic bases can be selected from, for example: primary, secondary and tertiary amine salts. Substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins such as arginine, beet Alkali, caffeine, choline, N,N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N -ethyl? Porphyrin, N -ethylpyridine, glucosamine, glucosamine, histidine, hepamine, isopropylamine, lysine, methylglucamine, morpholine, pyrazine, pyridine, polyamine resin , Procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine.
當本專利所指化合物是鹼時，需要與至少一種藥學上可接受的無毒酸製備其鹽，這些酸選自無機酸和有機酸。例如，選自醋酸，苯磺酸，苯甲酸，樟腦磺酸，檸檬酸，乙烷磺酸，富馬酸，葡萄糖酸，麩胺酸，氫溴酸，鹽酸，羥乙磺酸，乳酸，馬來酸，蘋果酸，杏仁酸，甲烷磺酸，黏酸，硝酸，撲酸，泛酸，磷酸，琥珀酸，硫酸，酒石酸，對甲苯磺酸。在一些實施例中，可選擇這些酸，例如：檸檬酸，氫溴酸，鹽酸，馬來酸，磷酸，硫酸，富馬酸，酒石酸。When the compound referred to in this patent is a base, it is necessary to prepare its salt with at least one pharmaceutically acceptable non-toxic acid selected from inorganic acids and organic acids. For example, selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, equine Leucic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, palmic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid. In some embodiments, these acids can be selected, for example: citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, tartaric acid.
化合物或其藥學上可接受的鹽的“給予”或“給藥”是指爲需要治療的個體提供本發明中的化合物或其藥學可接受的鹽。"Administration" or "administration" of a compound or a pharmaceutically acceptable salt thereof refers to providing a compound of the present invention or a pharmaceutically acceptable salt thereof to an individual in need of treatment.
“有效量”是指化合物或其藥學上可接受的鹽能夠引起組織、系統、動物或人類出現可被研究人員、獸醫、臨床醫生或其他臨床人員觀察到的生物學或醫學反應的劑量。"Effective amount" refers to a dose of a compound or a pharmaceutically acceptable salt thereof that can cause a tissue, system, animal, or human to exhibit a biological or medical response that can be observed by a researcher, veterinarian, clinician, or other clinical personnel.
“組成物”，包括：包含特定量的特定成分的産品，以及任何直接或間接這些特定量的特定成分的組合而成的産品。藥物組成物，包含：包含有效成分和作爲載體的惰性成分的産品，以及任何兩個或兩個以上的成分直接或間接，透過組合、複合或聚集而製成的産品，或透過一個或更多的成分分解産生的産品，或透過一個或更多的成分發生其他類型反應或相互作用産生的産品。"Composition" includes: a product containing a specific amount of a specific ingredient, and any combination of these specific amounts of a specific ingredient directly or indirectly. Pharmaceutical composition, including: a product containing an active ingredient and an inert ingredient as a carrier, and any two or more ingredients directly or indirectly, a product made by combining, compounding, or aggregating, or through one or more Products resulting from the decomposition of the ingredients or other types of reactions or interactions through one or more ingredients.
“藥學可接受”是指與製劑中的其它組分相容，並且對使用者無不可接受的毒害。"Pharmaceutically acceptable" means that it is compatible with other components in the formulation and has no unacceptable toxicity to the user.
“個體”是指患有疾病、病症之類的個體，包括哺乳動物和非哺乳動物。哺乳動物包括，但不僅限於，哺乳類的任何成員：人類，非人類的靈長類動物如黑猩猩，和其他猿類和猴子；農場動物如牛、馬、綿羊、山羊、豬；家畜如兔、狗和貓；實驗動物包括嚙齒類如大鼠、小鼠和豚鼠等。非哺乳類動物包括，但不僅限於，鳥類、魚類等。本發明的一個實施例中，哺乳動物爲人類。"Individual" refers to individuals suffering from diseases and disorders, including mammals and non-mammals. Mammals include, but are not limited to, any member of the mammals: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits and dogs And cats; experimental animals include rodents such as rats, mice, and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, etc. In one embodiment of the invention, the mammal is a human.
“治療”包括緩解、減輕或改善疾病或症狀，預防其他症狀，改善或預防症狀的潛在代謝因素，抑制疾病或症狀，例如，阻止疾病或症狀發展，減輕疾病或症狀，促進疾病或症狀緩解，或使疾病或症狀的病徵停止，和延伸至包括預防。“治療”還包括實現治療性獲益和/或預防性獲益。治療性獲益是指根除或改善所治療的病症。此外，治療性獲益透過根除或改善一個或多個與潛在疾病相關的生理病徵達到，儘管患者可能仍患有潛在疾病，但可觀察到患者疾病的改善。預防性獲益是指，患者爲預防某種疾病風險而使用組成物，或患者出現一個或多個疾病生理病症時使用，儘管尚未診斷此疾病。"Treatment" includes alleviating, alleviating or ameliorating the disease or symptom, preventing other symptoms, improving or preventing the underlying metabolic factors of the symptom, inhibiting the disease or symptom, for example, preventing the development of the disease or symptom, reducing the disease or symptom, and promoting the relief of the disease or symptom, Or stop the symptoms of the disease or symptom, and extend to include prevention. "Treatment" also includes achieving therapeutic and/or preventive benefits. Therapeutic benefit refers to the eradication or improvement of the condition being treated. In addition, the therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms related to the underlying disease. Although the patient may still have the underlying disease, an improvement in the patient's disease can be observed. Prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or when the patient has one or more disease physiological conditions, although the disease has not been diagnosed.
“保護基”(Pg)是指一類用於與化合物上其它官能基反應而阻隔或保護特定官能基的取代基。例如，“胺基保護基”是指聯接在胺基上阻隔或保護化合物上胺基官能基的取代基。適合的胺基保護基團包括乙醯基、三氟乙醯基，叔丁氧羰基(BOC)，苄氧羰基(CBZ)和9-芴基甲氧基羰基保護基(Fmoc)。同樣，“羥基保護基”是指一類羥基取代基可有效阻擋或保護羥基功能。適當的保護基包括但不限於乙醯基和矽烷基。“羧基保護基”是指一類羧基取代基能有效阻擋或保護羧基的功能。常用羧基保護基包括-CH2 CH2 SO2 Ph，氰乙基，2-(三甲矽基)乙基，2-(三甲矽基)乙氧基甲基，2-(對甲苯磺醯基)乙基，2-(對硝基苯亞磺醯基)乙基，2-(二苯基膦)-乙基，硝基乙基等。對於保護基的一般描述和使用說明，見參考文獻：T. W. Greene, Protective Groups in Organic Synthesis,John Wiley & Sons, New York, 1991 。"Protective group" (Pg) refers to a type of substituent used to block or protect a specific functional group by reacting with other functional groups on the compound. For example, "amine protecting group" refers to a substituent that is attached to an amine group to block or protect the amine functional group on the compound. Suitable amine protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl protecting groups (Fmoc). Similarly, "hydroxyl protecting group" refers to a class of hydroxy substituents that can effectively block or protect hydroxy functions. Suitable protecting groups include but are not limited to acetyl and silane. "Carboxyl protecting group" refers to a class of carboxyl substituents that can effectively block or protect the function of carboxyl groups. Commonly used carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl) Ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, etc. For a general description and instructions for protecting groups, see references: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 .
“NH保護基”包含，但不僅限於，三氯乙氧羰基、三溴乙氧羰基、苄氧羰基、對硝基苄甲醯基、鄰溴苄氧羰基、氯乙醯基、二氯乙醯基、三氯乙醯基、三氟乙醯基、苯乙醯基、甲醯基、乙醯基、苯甲醯基、叔戊氧羰基、叔丁氧羰基、對甲氧基苄氧羰基、3,4-二甲氧基苄氧羰基、4-(苯偶氮基)苄氧羰基、2-糠基氧羰基、二苯基甲氧羰基、1,1-二甲基丙氧基羰基、異丙氧羰基、鄰苯二甲醯基、琥珀醯基、丙胺醯基、亮胺醯基、1-金剛烷氧羰基、8-喹啉基氧羰基、苄基、二苯甲基、三苯甲基、2-硝基苯硫基、甲磺醯基、對甲苯磺醯基、N,N -二甲基胺基亞甲基、苯亞甲基、2-羥基苯亞甲基、2-羥基-5-氯苯亞甲基、2-羥基-l-萘基亞甲基、3-羥基-4-吡啶基亞甲基、亞環己基、2-乙氧基羰基亞環己基、2-乙氧基羰基亞環戊基、2-乙醯基亞環己基、3,3-二甲基-5-氧亞環己基、二苯基磷醯基、二苄基磷醯基、5-甲基-2-氧基-2H -l,3-二氧環戊烯-4-基-甲基、三甲基矽烷基、三乙基矽烷基和三苯基矽烷基。"NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylmethanyl, o-bromobenzyloxycarbonyl, chloroethyiyl, dichloroethyi Group, trichloroacetyl group, trifluoroacetyl group, phenylethyl group, methyl group, acetyl group, benzoyl group, tert-pentyloxycarbonyl group, tert-butoxycarbonyl group, p-methoxybenzyloxycarbonyl group, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, Isopropyloxycarbonyl, o-xylylene, succinyl, propylamine, leucine, 1-adamantyloxycarbonyl, 8-quinolinyloxycarbonyl, benzyl, benzhydryl, triphenyl Methyl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N,N -dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2- Hydroxy-5-chlorobenzylidene, 2-hydroxy-1-l-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonylcyclohexylene, 2- Ethoxycarbonylcyclopentylene, 2-ethoxycyclohexylene, 3,3-dimethyl-5-oxocyclohexylene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl Yl-2-oxy- 2H -1,3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.
“C(O)OH”保護基包含，但不僅限於，甲基、乙基、正丙基、異丙基、1,1-二甲基丙基、正丁基、叔丁基、苯基、萘基、苄基、二苯甲基、三苯甲基、對硝基苄基、對甲氧基苄基、雙(對甲氧苯基)甲基、乙醯甲基、苯甲醯甲基、對硝基苯甲醯甲基、對溴苯甲醯甲基、對甲磺醯苯甲醯甲基、2-四氫吡喃基、2-四氫呋喃基、2,2,2-三氯乙基、2-(三甲基矽烷基)乙基、乙醯氧基甲基、丙醯氧基甲基、新戊醯氧基甲基、鄰苯二甲醯亞胺甲基、琥珀醯亞胺甲基、環丙基、環丁基、環戊基、環己基、甲氧基甲基、甲氧基乙氧基甲基、2-(三甲基矽烷基)乙氧基甲基、苄基氧基甲基、甲基硫基甲基、2-甲基硫基乙基、苯基硫基甲基、1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基、三甲基矽烷基、三乙基矽烷基、三異丙基矽烷基、二乙基異丙基矽烷基、叔丁基二甲基矽烷基、叔丁基二苯基矽烷基、二苯基甲基矽烷基和叔丁基甲氧基苯基矽烷基。The "C(O)OH" protecting group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, Naphthyl, benzyl, benzhydryl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetomethyl, benzylmethyl , P-nitrobenzylmethyl, p-bromobenzylmethyl, p-toluenesulfonylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl Group, 2-(trimethylsilyl)ethyl, acetoxymethyl, propyloxymethyl, neopentyloxymethyl, phthalimide methyl, succinimide Methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl Oxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butene Group, allyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, diethylisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilane Group, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.
“OH或SH”保護基包含，但不僅限於，苄氧羰基、4-硝基苄氧羰基、4-溴苄氧羰基、4-甲氧基苄氧羰基、3,4-二甲氧基苄氧羰基、甲氧基羰基、乙氧基羰基、叔丁氧羰基、1,1-二甲基丙氧基羰基、異丙氧羰基、異丁氧羰基、二苯基甲氧基羰基、2,2,2-三氯乙氧基羰基、2,2,2-三溴乙氧基羰基、2-(三甲基矽烷)乙氧基羰基、2-(苯磺醯基)乙氧基羰基、2-(三苯基磷鎓基)乙氧基羰基、2-糠基氧基羰基、1-金剛烷氧基羰基、乙烯基氧基羰基、烯丙基氧基羰基、4-乙氧基-1-萘基氧基羰基、8-喹啉基氧基羰基、乙醯基、甲酸基、氯乙醯基、二氯乙醯基、三氯乙醯基、三氟乙醯基、甲氧基乙醯基、苯氧基乙醯基、特戊醯基、苯甲醯基、甲基、叔丁基、2,2,2-三氯乙基、2-三甲基矽烷基乙基、1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基、苄基(苯基甲基)、對甲氧基苄基、3,4-二甲氧基苄基、二苯基甲基、三苯基甲基、四氫呋喃基、四氫吡喃基、四氫噻喃基、甲氧基甲基、甲基硫基甲基、苄基氧基甲基、2-甲氧基乙氧基甲基、2,2,2-三氯-乙氧基甲基、2-(三甲基矽烷基)乙氧基甲基、1-乙氧基乙基、甲磺醯基、對甲苯磺醯基、三甲基矽烷基、三乙基矽烷基、三異丙基矽烷基、二乙基異丙基矽烷基、叔丁基二甲基矽烷基、叔丁基二苯基矽烷基、二苯基甲基矽烷基和叔丁基甲氧基苯基矽烷基。"OH or SH" protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl Oxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2, 2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilane)ethoxycarbonyl, 2-(benzenesulfonyl)ethoxycarbonyl, 2-(triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy- 1-naphthyloxycarbonyl, 8-quinolinyloxycarbonyl, acetyl, formate, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxy Acetyl, phenoxyacetyl, pentyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1 ,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3,4-dimethoxy Benzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl , 2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, Methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.
本發明化合物中可能存在幾何異構體。本發明化合物可能存在E或Z構型的碳-碳雙鍵或碳-氮雙鍵，其中“E”代表按Cahn-Ingold-Prelog優先規則，較優的取代基在碳-碳雙鍵或碳-氮雙鍵的異側，而“Z”代表較優的取代基在碳-碳雙鍵或碳-氮雙鍵的同側。本發明化合物也可能以“E”和“Z”異構體的混合物形式存在。環烷基或雜環基周圍的取代基可以定爲順式或反式構型。此外，本發明包括由金剛烷環系周圍取代基排列不同形成的不同異構體及其混合物。金剛烷環系中的一個單環周圍的兩個取代基被定爲Z或E相對構型。例如，見C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760。Geometric isomers may exist in the compounds of the present invention. The compounds of the present invention may have a carbon-carbon double bond or a carbon-nitrogen double bond in the E or Z configuration, where "E" represents the Cahn-Ingold-Prelog priority rule, and the preferred substituent is in the carbon-carbon double bond or carbon -The opposite side of the nitrogen double bond, and "Z" represents the preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond. The compounds of the present invention may also exist as a mixture of "E" and "Z" isomers. The substituents around the cycloalkyl or heterocyclic group can be set to cis or trans configuration. In addition, the present invention includes different isomers and mixtures thereof formed by different arrangement of substituents around the adamantane ring system. The two substituents around a single ring in the adamantane ring system are designated as Z or E relative configuration. For example, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760.
本發明化合物可能含有R或S構型的不對稱取代的碳原子，“R”和“S”的定義見IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10。含有不對稱取代碳原子的化合物，若R和S構型的量相同，則爲外消旋體。若其中一種構型比另一構型的量更多，則掌性碳原子的構型以量多的構型表示，優選對映體過量約85-90%，更優選約95-99%，進一步約99%以上。因此，本發明包含外消旋混合物、相對和絕對立體異構體、和相對和絕對立體異構體的混合物。同位素富集或標記化合物 The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration. For the definitions of "R" and "S", see IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13- 10. Compounds containing asymmetrically substituted carbon atoms are racemates if the amounts of R and S configurations are the same. If one of the configurations is more in amount than the other configuration, the configuration of palmitic carbon atoms is expressed as a configuration with a large amount, preferably an enantiomeric excess of about 85-90%, more preferably about 95-99%, Further about 99%. Therefore, the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers. Isotope enrichment or labeling of compounds
本發明化合物可以同位素標記或富集的形式存在，包含一個或多個與自然界最普遍原子質量和質量數不同的原子。同位素可以爲放射性或非放射性同位素。原子如氫、碳、氮、氧、磷、硫、氟、氯和碘的同位素包括，但不僅限於，2 H、3 H、13 C、14 C、15 N、18 O、32 P、35 S、18 F、36 Cl和125 I。含有這些原子的其他同位素和/或其他原子也在本發明範圍內。The compounds of the present invention may exist in isotopically labeled or enriched form, containing one or more atoms with different atomic mass and mass number from the most common in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S , 18 F, 36 Cl and 125 I. Other isotopes and/or other atoms containing these atoms are also within the scope of the present invention.
在另一實施例中，同位素標記化合物含有氘(2 H)、氚(3 H)或14 C同位素。本發明的同位素標記化合物可使用該領域專業人員熟知的方法獲得。這些同位素標記化合物可透過參照本發明實施例和反應圖示，將非標記試劑替換爲同位素標記試劑而得到。在某些例子中，可用同位素標記試劑處理化合物，將原子替換爲同位素原子，例如，將氫替換爲氘可透過氘代酸如D2 SO4 /D2 O的作用交換。In another embodiment, the isotopically labeled compound contains deuterium ( 2 H), tritium ( 3 H) or 14 C isotopes. The isotopically labeled compounds of the present invention can be obtained using methods well known to those skilled in the art. These isotope-labeled compounds can be obtained by referring to the embodiments and reaction diagrams of the present invention, by replacing non-labeled reagents with isotopically labeled reagents. In some examples, compounds can be treated with isotope labeling reagents, replacing atoms with isotopic atoms, for example, replacing hydrogen with deuterium can be exchanged through the action of deuterated acids such as D 2 SO 4 /D 2 O.
本發明同位素標記化合物可作爲RET抑制劑藥效結合試驗的標準。含同位素的化合物可用於藥學研究，評估非同位素標記母體化合物的作用機制和代謝途徑，研究化合物的體內代謝結果(Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975))。這類代謝研究對於設計安全有效的治療藥物十分重要，可判斷是患者使用的體內活性化合物或是母體化合物的代謝産物具有毒性或致癌性(Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al, J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol, 77, 79-88 (1999))。The isotope-labeled compound of the present invention can be used as a standard for RET inhibitor drug efficacy binding test. Compounds containing isotopes can be used in pharmaceutical research to evaluate the mechanism of action and metabolic pathways of non-isotopically labeled parent compounds, and to study the metabolic results of compounds in vivo (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)) . This type of metabolic research is very important for the design of safe and effective therapeutic drugs. It can be judged that the metabolites of the active compounds in the body or the parent compounds used by patients are toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp . 2-36, Academic press, London, 1985; Kato et al, J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol, 77 , 79-88 (1999)).
此外，含非反射性活性同位素的藥物，例如氘代藥物，稱爲“重藥(heavy drugs)”，可用於治療與RET活性相關的疾病和病症。化合物中某種同位素比例超過其自然豐度被稱爲富集。富集的量包括但不僅限於，例如，從約0.5、1、2、3、4、5、6、7、8、9、10、12、16、21、25、29、33、37、42、46、50、54、58、63、67、71、75、79、84、88、92、96至約100 mol %。In addition, drugs containing non-reflective active isotopes, such as deuterated drugs, called "heavy drugs", can be used to treat diseases and conditions associated with RET activity. A certain isotope ratio in a compound that exceeds its natural abundance is called enrichment. The amount of enrichment includes, but is not limited to, for example, from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42 , 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%.
藥物穩定的的同位素標記可以改變其物理化學性質，例如pKa和液體溶解性。如果同位素取代影響了配體-受體相互作用相關的區域，那麽這些作用和改變可能影響藥物分子的藥效反應。穩定同位素標記分子的某些物理性質與未標記分子不同，而化學和生物學性質相同，但有一個重要區別：由於重同位素的質量增加，任何包含重同位素和另一原子的化學鍵比輕同位素更強。相應的，代謝或酶轉化位點存在同位素會減緩該反應，從而與非同位素標記的化合物相比，可能改變其藥代動力學特徵或藥效。Drug stable isotope labels can change their physicochemical properties, such as pKa and liquid solubility. If isotope substitutions affect regions related to ligand-receptor interactions, these effects and changes may affect the pharmacodynamic response of drug molecules. Stable isotope-labeled molecules have different physical properties than unlabeled molecules, but have the same chemical and biological properties, but there is an important difference: due to the increase in the weight of heavy isotopes, any chemical bond that contains a heavy isotope and another atom is more than a light isotope. Strong. Correspondingly, the presence of isotopes in the metabolic or enzymatic conversion sites will slow down the reaction, and thus may change its pharmacokinetic characteristics or efficacy compared to non-isotopically labeled compounds.
在實施方案(1)中，本發明提供式(I)所示的化合物：
在另一個實施方案(2)中，本發明提供實施方案(1)的化合物或其藥學上可接受的鹽，其中Q1
是吡啶基，化合物如式(II)所示：
在另一個實施方案(3)中，本發明提供實施方案(1)-(2)中任一項的化合物，或其藥學上可接受的鹽，其中Q2 選自5-7員雜環基。In another embodiment (3), the present invention provides the compound of any one of embodiments (1)-(2), or a pharmaceutically acceptable salt thereof, wherein Q 2 is selected from 5-7 membered heterocyclyl .
在另一個實施方案(4)中，本發明提供實施方案(3)的化合物或其藥學上可接受的鹽，其中Q2
選自
在另一個實施方案(5)中，本發明提供實施方案(1)-(4)中任一項的化合物，或其藥學上可接受的鹽，其中R1 是氫。In another embodiment (5), the present invention provides the compound of any one of embodiments (1)-(4), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
在另一個實施方案(6)中，本發明提供實施方案(1)-(5)中任一項的化合物，或其藥學上可接受的鹽，其中R2 選自氫、C1-10 烷基、雜環基、-ORA2 、-C(O)RA2 、-C(O)ORA2 、-S(O)r RA2 ，其中烷基和雜環基分別是未被取代的或被至少一個獨立選自RX 的取代基取代。In another embodiment (6), the present invention provides the compound of any one of embodiments (1)-(5), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, C 1-10 alkane Group, heterocyclic group, -OR A2 , -C(O)R A2 , -C(O)OR A2 , -S(O) r R A2 , wherein the alkyl group and heterocyclic group are unsubstituted or At least one substituent independently selected from R X is substituted.
在另一個實施方案(7)中，本發明提供實施方案(6)的化合物或其藥學上可接受的鹽，其中R2 選自氫、甲基、乙基、-S(O)r RA2 、-C(O)RA2 和-C(O)ORA2 ，其中甲基和乙基分別是未被取代的或被至少一個獨立選自RX 的取代基取代，RX 獨立選自芳基和雜芳基，其中芳基和雜芳基分別是未被取代的或被至少一個獨立選自RY 的取代基取代。In another embodiment (7), the invention provides a compound of embodiment (6) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, methyl, ethyl, -S(O) r R A2 , -C(O)R A2 and -C(O)OR A2 , wherein methyl and ethyl are unsubstituted or substituted by at least one substituent independently selected from R X , R X is independently selected from aryl And heteroaryl, wherein aryl and heteroaryl are respectively unsubstituted or substituted with at least one substituent independently selected from R Y.
在另一個實施方案(8)中，本發明提供實施方案(7)的化合物或其藥學上可接受的鹽，其中RX 獨立選自苯基、吡啶基、吡嗪基和噠嗪基，其中苯基、吡啶基、吡嗪基和噠嗪基分別是未被取代的或被至少一個獨立選自鹵素，C1-10 烷基和-ORb2 的取代基取代。In another embodiment (8), the invention provides a compound of embodiment (7) or a pharmaceutically acceptable salt thereof, wherein R X is independently selected from phenyl, pyridyl, pyrazinyl, and pyridazinyl, wherein Phenyl, pyridyl, pyrazinyl, and pyridazinyl are unsubstituted or substituted with at least one substituent independently selected from halogen, C 1-10 alkyl, and -OR b2 .
在另一個實施方案(9)中，本發明提供實施方案(6)的化合物或其藥學上可接受的鹽，其中RA2 選自氫、C1-10 烷基、芳基、芳基-C1-4 烷基、雜芳基和雜芳基-C1-4 烷基，其中烷基、芳基和雜芳基分別是未被取代的或被至少一個獨立選自RX 的取代基取代。In another embodiment (9), the invention provides a compound of embodiment (6) or a pharmaceutically acceptable salt thereof, wherein R A2 is selected from hydrogen, C 1-10 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, aryl and heteroaryl are unsubstituted or substituted by at least one substituent independently selected from R X .
在另一個實施方案(10)中，本發明提供實施方案(9)的化合物或其藥學上可接受的鹽，其中RA2 選自氫、鹵素、甲基、乙基、叔丁基、苄基、吡啶基、吡嗪基和噠嗪基，RX 獨立選自C1-10 烷基、鹵素和-OH，其中烷基是未被取代的或被至少一個獨立選自RY 的取代基取代。In another embodiment (10), the invention provides a compound of embodiment (9) or a pharmaceutically acceptable salt thereof, wherein R A2 is selected from hydrogen, halogen, methyl, ethyl, tert-butyl, benzyl , Pyridyl, pyrazinyl and pyridazinyl, R X is independently selected from C 1-10 alkyl, halogen and -OH, wherein the alkyl group is unsubstituted or substituted with at least one substituent independently selected from R Y .
在另一個實施方案(11)中，本發明提供實施方案(7)的化合物或其藥學上可接受的鹽，其中R2
選自氫、甲基、乙基、BOC、
在另一個實施方案(12)中，本發明提供實施方案(1)-(11)中任一項的化合物或其藥學上可接受的鹽，其中R3 是C1-10 烷基，其中烷基是未被取代的或被至少一個獨立選自RX 的取代基取代。In another embodiment (12), the present invention provides the compound of any one of embodiments (1) to (11) or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-10 alkyl, wherein alkane group is unsubstituted or substituted with at least one R X is independently selected from the group.
在另一個實施方案(13)中，本發明提供實施方案(12)的化合物或其藥學上可接受的鹽，其中R3 是甲基。In another embodiment (13), the invention provides a compound of embodiment (12) or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.
在另一個實施方案(14)中，本發明提供的化合物選自
在另一個實施方案(15)中，本發明提供藥物組成物，其包含實施方案(1)-(14)中任一項的化合物或其藥學上可接受的鹽和至少一種藥學上可接受的載體。In another embodiment (15), the present invention provides a pharmaceutical composition comprising the compound of any one of embodiments (1) to (14) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable Carrier.
在另一個實施方案(16)中，本發明提供了治療、改善或預防對抑制RET反應的病況的方法，包括給予有此需要的個體有效量的實施方案(1)-(14)中任一項的化合物或其藥學上可接受的鹽，或至少一種其藥物組成物，任選地與第二治療劑聯合使用。In another embodiment (16), the present invention provides a method of treating, ameliorating, or preventing a condition that responds to RET inhibition, including administering to an individual in need thereof an effective amount of any of embodiments (1)-(14) The compound of item or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally used in combination with a second therapeutic agent.
在另一個實施方案(17)中，本發明提供了實施方案(1)-(14)中任一項的化合物或其藥學上可接受的鹽在製備用於治療由RET媒介疾病的藥物中的用途。In another embodiment (17), the present invention provides the compound of any one of embodiments (1)-(14) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of RET-mediated diseases use.
在另一方面，本發明提供了包含本文公開的化合物或其藥學上可接受的鹽的試劑盒；以及包括以下一項或多項資訊的說明書：成分應用於何種疾病狀態、成分的儲存資訊、劑量資訊以及如何使用成分的說明。在一個特殊變體中，試劑盒包含多劑量形式的化合物。In another aspect, the present invention provides a kit comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and instructions including one or more of the following: the disease state to which the ingredient is applied, storage information of the ingredient, Dosage information and instructions on how to use the ingredients. In a particular variant, the kit contains the compound in multiple dose forms.
在另一方面，本發明提供了包含本文公開的化合物或其藥學上可接受的鹽的製品；以及包裝材料。在一種變化中，包裝材料包括容器。在一個特殊變化中，所述容器包括標籤，其標明一項或多項以下內容：化合物應用於何種疾病狀態、儲存資訊、劑量資訊和/或如何使用化合物的說明。在另一種變體中，製品包括多劑量形式的化合物。In another aspect, the present invention provides a product comprising the compound disclosed herein or a pharmaceutically acceptable salt thereof; and packaging materials. In a variation, the packaging material includes a container. In a particular variation, the container includes a label indicating one or more of the following: what disease state the compound is applied to, storage information, dosage information, and/or instructions on how to use the compound. In another variant, the preparation includes the compound in multiple dose forms.
在另一方面，本發明提供了一種治療方法，包含向個體給予本文公開的化合物或其藥學上可接受的鹽。In another aspect, the invention provides a method of treatment comprising administering to a subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.
在另一方面，本發明提供了一種透過本文公開的化合物或其藥學上可接受的鹽與RET激酶作用從而抑制RET激酶的方法。In another aspect, the present invention provides a method of inhibiting RET kinase through the action of a compound disclosed herein or a pharmaceutically acceptable salt thereof with RET kinase.
在另一方面，本發明提供了一種抑制RET激酶的方法，包括使本文公開的化合物或其藥學上可接受的鹽，出現在個體體內，以抑制體內RET激酶活性。In another aspect, the present invention provides a method of inhibiting RET kinase, comprising causing a compound disclosed herein or a pharmaceutically acceptable salt thereof to appear in an individual to inhibit RET kinase activity in vivo.
在另一方面，本發明提供了一種抑制RET激酶的方法，包括對個體給藥第一化合物，此化合物在體內轉化爲第二化合物，其中第二化合物抑制體內RET激酶活性，且第二化合物是以上實施方案中任一項的化合物和變體。In another aspect, the present invention provides a method of inhibiting RET kinase, comprising administering to a subject a first compound, which is converted into a second compound in vivo, wherein the second compound inhibits RET kinase activity in vivo, and the second compound is The compounds and variants of any of the above embodiments.
在另一方面，本發明提供了一種治療疾病狀態的方法，RET激酶活性造成了該疾病狀態的病理和/或症狀，該方法包括使對該疾病狀態治療有效量的本文公開的化合物或其藥學上可接受的鹽出現在個體體內。In another aspect, the present invention provides a method of treating a disease state in which RET kinase activity causes the pathology and/or symptoms of the disease state, the method comprising administering a therapeutically effective amount of the compound disclosed herein or a pharmaceutical thereof to the disease state The acceptable salt appears in the individual.
在另一方面，本發明提供了一種治療疾病狀態的方法，RET激酶活性造成了該疾病狀態的病理和/或症狀，該方法包含對個體給藥第一化合物，此化合物在體內轉化爲第二化合物，其中第二化合物抑制體內RET激酶活性。值得注意的是，本發明所述化合物可以是轉化前或轉化後的化合物。In another aspect, the present invention provides a method of treating a disease state in which RET kinase activity causes the pathology and/or symptoms of the disease state, the method comprising administering to the individual a first compound, which is converted to a second in vivo Compounds, wherein the second compound inhibits RET kinase activity in vivo. It is worth noting that the compound of the present invention may be a compound before or after conversion.
上述每個方法的變化中，疾病狀態選自：癌性增殖性疾病(例如腦、肺、鱗狀細胞、膀胱、胃、胰腺、乳腺、頭、頸、腎臟區(renal)、腎、卵巢、前列腺、結直腸、表皮、食道、睾丸、婦科或甲狀腺癌)；非癌性增殖性疾病(例如良性皮膚增生(如銀屑病)、再狹窄和良性前列腺肥大(BPH))；胰腺炎；腎臟疾病；疼痛；防止胚泡著床；治療與血管發生或血管生成相關疾病(例如腫瘤血管生成、急性和慢性發炎性疾病如類風濕性關節炎、動脈粥狀硬化、發炎性腸病、皮膚病如銀屑病、濕疹和硬皮病、糖尿病、糖尿病性視網膜病變、早産兒視網膜病變、老年性黃斑部病變、血管瘤、神經膠質瘤、黑色素瘤、卡波西氏肉瘤和卵巢癌、乳腺癌、肺癌、胰腺癌、前列腺癌、結腸癌和表皮樣癌)；哮喘；嗜中性顆粒細胞趨化性(例如，心肌梗塞和中風的再灌注損傷和發炎性關節炎)；敗血性休克；T細胞媒介的疾病，其中免疫抑制很有價值(如預防器官移植排斥、移植物抗宿主病、紅斑性狼瘡、多發性硬化和類風濕關節炎)；動脈粥狀硬化；抑制對生長因子混合物反應的角質細胞；慢性阻塞性肺臟疾病(COPD)和其他疾病。In the variation of each of the above methods, the disease state is selected from the group consisting of cancerous proliferative diseases (such as brain, lung, squamous cells, bladder, stomach, pancreas, breast, head, neck, renal area, kidney, ovary, Prostate, colorectal, epidermis, esophagus, testis, gynecological, or thyroid cancer); non-cancerous proliferative diseases (eg, benign skin hyperplasia (eg, psoriasis), restenosis, and benign prostatic hypertrophy (BPH)); pancreatitis; kidneys Diseases; pain; prevention of blastocyst implantation; treatment of diseases associated with angiogenesis or angiogenesis (eg, tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases Such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast Cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid cancer); asthma; neutrophil granulocyte chemotaxis (eg, myocardial infarction and stroke reperfusion injury and inflammatory arthritis); septic shock; T-cell-mediated diseases, of which immunosuppression is valuable (such as prevention of organ transplant rejection, graft-versus-host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibition of responses to growth factor mixtures Keratinocytes; chronic obstructive pulmonary disease (COPD) and other diseases.
在另一方面，本發明提供了一種治療疾病狀態的方法，RET激酶基因突變造成了該疾病的病理和/或症狀，例如黑色素瘤、肺癌、結腸癌和其他類型腫瘤。In another aspect, the present invention provides a method of treating a disease state in which mutations in the RET kinase gene cause pathology and/or symptoms of the disease, such as melanoma, lung cancer, colon cancer, and other types of tumors.
在另一方面，本發明涉及以上實施方案中任一項的化合物和變體作爲藥物的用途。在另一方面，本發明涉及以上實施方案中任一項的化合物和變體用於製備抑制RET激酶藥物的用途。In another aspect, the invention relates to the use of the compounds and variants of any of the above embodiments as medicaments. In another aspect, the invention relates to the use of compounds and variants of any of the above embodiments for the preparation of RET kinase inhibiting drugs.
在另一方面，本發明涉及以上實施方案中任一項的化合物和變體用於製備治療RET激酶活性造成的病理和/或症狀的疾病狀態的藥物的用途。給藥和藥物組成物 In another aspect, the present invention relates to the use of the compounds and variants of any of the above embodiments for the preparation of a medicament for treating a disease state of pathology and/or symptoms caused by RET kinase activity. Administration and drug composition
一般地，本發明所述化合物將以治療有效量經由任何本領域已知的普通及可接受的方式，單獨或與一種或多種治療劑合用給藥。治療有效量可以廣泛變化，取決於受試者的疾病嚴重性、年齡和相對健康狀況，所用化合物的藥效以及其他本領域已知的因素。例如，對於腫瘤性疾病和免疫系統疾病的治療，所需劑量將根據給藥模式，待治療的具體病症和所需效果而異。Generally, the compounds of the present invention will be administered in a therapeutically effective amount via any ordinary and acceptable means known in the art, alone or in combination with one or more therapeutic agents. The therapeutically effective amount can vary widely, depending on the severity of the subject's disease, age and relative health, the efficacy of the compound used, and other factors known in the art. For example, for the treatment of neoplastic diseases and immune system diseases, the required dose will vary depending on the mode of administration, the specific condition to be treated and the desired effect.
一般地，每日劑量爲0.001至100 mg/kg體重時可達到滿意的結果，具體來說，從約0.03至2.5 mg/kg體重。較大型哺乳動物的日劑量，如人類，可從約0.5 mg至約2000 mg，或更具體來說，從0.5 mg至1000 mg，以方便的形式給藥，例如，以分劑量最多每日四次或以緩釋形式。合適的口服給藥的單位劑量形式包含約1至50 mg活性成分。In general, satisfactory results can be achieved with a daily dose of 0.001 to 100 mg/kg body weight, specifically from about 0.03 to 2.5 mg/kg body weight. The daily dose of larger mammals, such as humans, can be administered from about 0.5 mg to about 2000 mg, or more specifically from 0.5 mg to 1000 mg, in a convenient form, for example, in divided doses of up to four daily Or in the form of sustained release. Suitable unit dosage forms for oral administration contain about 1 to 50 mg of active ingredient.
本發明所述化合物可以以藥物組成物形式給藥，透過任何常規途徑給藥；例如經腸，例如口服，例如以片劑或膠囊形式，腸胃外，例如以可注射溶液或懸浮液形式；或局部給藥，例如以洗劑，凝膠劑，軟膏劑或乳膏劑，或者以鼻或栓劑形式。The compounds of the present invention can be administered in the form of a pharmaceutical composition and administered by any conventional route; for example, enterally, for example, orally, for example, in the form of tablets or capsules, and parenterally, for example, in the form of injectable solutions or suspensions; or Topical administration, for example in the form of lotions, gels, ointments or creams, or in the form of nose or suppositories.
含有本發明所述的以游離鹼或藥學可接受鹽型的化合物與至少一種藥學可接受的載體或稀釋劑的藥物組成物，可以常規方式透過混合、製粒、包衣、溶解或冷凍乾燥流程來製造。例如，藥物組成物包含一個本發明所述化合物與至少一個藥學可接受載體或稀釋劑組合，可以以常規方式透過與藥學可接受載體或稀釋劑混合製成。用於口服的單位劑量形式包含，例如，從約0.1 mg至約500 mg活性物質。The pharmaceutical composition containing the compound of the present invention in the form of a free base or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent can be mixed, granulated, coated, dissolved or freeze-dried in a conventional manner To manufacture. For example, a pharmaceutical composition comprising a compound of the present invention in combination with at least one pharmaceutically acceptable carrier or diluent can be prepared in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. The unit dosage form for oral administration contains, for example, from about 0.1 mg to about 500 mg of active substance.
在一個實施例中，藥物組成物爲活性成分的溶液，包括懸浮液或分散體，如等張水溶液。在僅包含活性成分或與如甘露醇的載體混合的凍乾組成物的情況下，分散體或懸浮液可在使用前製備。藥物組成物可以被滅菌和/或含有佐劑，如防腐劑、穩定劑、濕潤劑或乳化劑、溶解促進劑、調節滲透壓的鹽和/或緩衝劑。合適的防腐劑包括但不僅限於抗氧化劑如抗壞血酸，殺微生物劑，如山梨酸或苯甲酸。溶液或懸浮液還可以包含增稠劑，包括但不僅限於羧甲基纖維素鈉、羧甲基纖維素、葡聚糖、聚乙烯吡咯烷酮、明膠，或增溶劑，例如吐溫80 (聚氧乙烯(20)山梨醇酐單油酸酯)。In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an isotonic aqueous solution. In the case of a lyophilized composition containing only the active ingredient or mixed with a carrier such as mannitol, the dispersion or suspension may be prepared before use. The pharmaceutical composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution promoters, salts for adjusting osmotic pressure and/or buffers. Suitable preservatives include but are not limited to antioxidants such as ascorbic acid, microbicides such as sorbic acid or benzoic acid. Solutions or suspensions may also contain thickeners, including but not limited to sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizers, such as Tween 80 (polyoxyethylene (20) Sorbitan monooleate).
在油中的懸浮液可能包含作爲油性成分的植物油，合成或半合成的油，常用於注射目的。實施例包括含有作爲酸組分的具有8至22個碳原子，或在一些實施方案中，從12至22個碳原子的長鏈脂肪酸的液態脂肪酸酯。合適的液態脂肪酸酯包括但不限於月桂酸，十三烷酸，肉豆蔻酸，十五烷酸，棕櫚酸，十七烷酸，硬脂酸，花生酸，山萮酸或相應的不飽和酸，例如油酸，反油酸，芥酸，巴西烯酸和亞油酸，如果需要，可以含有抗氧化劑，例如維生素E，3-胡蘿蔔素或3,5-二-叔丁基-羥基甲苯。這些脂肪酸酯的醇組分可以具有六個碳原子，並且可以是單價或多價的，例如單-，二-或三價的醇。合適的醇組分包括但不限於甲醇，乙醇，丙醇，丁醇或戊醇或者其異構體，乙二醇和甘油。Suspensions in oil may contain vegetable oils, synthetic or semi-synthetic oils, as oily ingredients, and are often used for injection purposes. Examples include liquid fatty acid esters containing, as acid components, long chain fatty acids having 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acid or the corresponding unsaturated Acids, such as oleic acid, elaidic acid, erucic acid, pelenoic acid and linoleic acid, if necessary, may contain antioxidants, such as vitamin E, 3-carotene or 3,5-di-tert-butyl-hydroxytoluene . The alcohol component of these fatty acid esters may have six carbon atoms, and may be monovalent or polyvalent, such as mono-, di-, or trivalent alcohols. Suitable alcohol components include but are not limited to methanol, ethanol, propanol, butanol or amyl alcohol or isomers thereof, ethylene glycol and glycerin.
其它合適的脂肪酸酯包括但不限於油酸乙酯，肉豆蔻酸異丙酯，棕櫚酸異丙酯，LABRAFIL® M2375，(聚氧乙烯甘油)，LABRAFIL® M1944 CS (透過醇解杏仁油製備的不飽和聚乙二醇化甘油酯，含有甘油酯和聚乙二醇酯)，LABRASOLTM (透過醇解TCM製備的飽和聚乙二醇化甘油酯，包含甘油酯和聚乙二醇酯；均可從法國GaKefosse公司獲得)，和/或MIGLYOL® 812 (德國Hüls AG公司的鏈長爲C8至C12的飽和脂肪酸甘油三酯)，以及植物油如棉子油，杏仁油，橄欖油，蓖麻油，芝麻油，豆油或花生油。Other suitable fatty acid esters include but are not limited to ethyl oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL ® M2375, (polyoxyethylene glycerin), LABRAFIL ® M1944 CS (prepared by alcoholylated almond oil Unsaturated PEGylated glycerides, containing glycerides and polyethylene glycol esters), LABRASOL TM (saturated pegylated glycerides prepared by alcoholysis TCM, including glycerides and polyethylene glycol esters; both (Available from GaKefosse, France), and/or MIGLYOL ® 812 (saturated fatty acid triglycerides with a chain length of C8 to C12 from Hüls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil , Soybean oil or peanut oil.
用於口服給藥的藥物組成物可以透過，例如，透過將活性成分與一種或多種固體載體混合，如果需要，顆粒化所得的混合物，並透過加入另外的賦形劑加工所述混合物或顆粒，以形式片劑或片芯。Pharmaceutical compositions for oral administration can be permeated, for example, by mixing the active ingredient with one or more solid carriers, granulating the resulting mixture if necessary, and processing the mixture or granules by adding additional excipients, In the form of tablets or tablet cores.
合適的載體包括但不限於填充劑，例如糖，例如乳糖，蔗糖，甘露醇或山梨醇，纖維素製劑和/或磷酸鈣，例如磷酸三鈣或磷酸氫鈣，和黏合劑，例如澱粉，例如玉米，小麥，大米或馬鈴薯澱粉，甲基纖維素，羥丙基甲基纖維素，羧甲基纖維素鈉和/或聚乙烯吡咯烷酮，和/或，如果需要的話，崩解劑，如上述澱粉，羧甲基澱粉，交聯聚乙烯吡咯烷酮，藻酸或其鹽，如藻酸鈉。另外的賦形劑包括流動調節劑和潤滑劑，例如矽酸，滑石粉，硬脂酸或其鹽，如硬脂酸鎂或硬脂酸鈣，和/或聚乙二醇，或其衍生物。Suitable carriers include, but are not limited to, fillers, such as sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate, and binders, such as starch, for example Corn, wheat, rice or potato starch, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrating agents, such as the starches described above , Carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or its salts, such as sodium alginate. Additional excipients include flow modifiers and lubricants, such as silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof .
可以爲片劑芯提供合適的，可選腸溶的包衣，透過使用特別是，濃縮的糖溶液，其可包括阿拉伯樹膠，滑石，聚乙烯吡咯烷酮，聚乙二醇和/或二氧化鈦，或者溶於合適有機溶劑或溶劑混合物的塗層溶液，或者，對於腸溶衣，合適的纖維素製劑的溶液，如乙醯纖維素鄰苯二甲酸酯或羥丙基甲基纖維素鄰苯二甲酸酯溶液。染料或顔料可以加入片劑或片劑包衣中，例如用於標識目的或指示不同劑量的活性成分。Tablet cores can be provided with suitable, optionally enteric coatings, through the use of, in particular, concentrated sugar solutions, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or soluble Coating solutions of suitable organic solvents or solvent mixtures, or, for enteric coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate Ester solution. Dyestuffs or pigments can be added to the tablets or tablet coatings, for example, for identification purposes or to indicate different doses of the active ingredient.
用於口服給藥的藥物組成物還可以包括硬膠囊，包括明膠或含有明膠和增塑劑，如甘油或山梨醇的軟密封膠囊。硬膠囊劑可含有活性成分的顆粒的形式，例如與填充劑如玉米澱粉，黏合劑和/或助流劑如滑石粉或硬脂酸鎂，和任選的穩定劑混合。在軟膠囊中，活性成分可以溶解或懸浮於合適的液體賦形劑如脂肪油，石蠟油或液體聚乙二醇或者乙二醇或丙二醇的脂肪酸酯中，也可向其中加入穩定劑和洗滌劑，例如聚氧乙烯山梨糖醇的脂肪酸酯型，也可加入。Pharmaceutical compositions for oral administration may also include hard capsules, including gelatin or soft sealed capsules containing gelatin and plasticizers such as glycerin or sorbitol. Hard capsules may contain the active ingredient in the form of granules, for example, mixed with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate, and optional stabilizers. In soft capsules, the active ingredient can be dissolved or suspended in suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, and stabilizers and Detergents, such as the fatty acid ester type of polyoxyethylene sorbitol, can also be added.
適用於直腸給藥的藥物組成物，例如栓劑，其包含活性成分和栓劑基質的組合。合適的栓劑基質是，例如，天然或合成的甘油三酯，石蠟烴，聚乙二醇或高級烷醇。Pharmaceutical compositions suitable for rectal administration, such as suppositories, contain a combination of active ingredients and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
適於胃腸外給藥的藥物組成物可包含水溶性形式的活性成分，例如水溶性鹽或包含增加黏度的物質的含水注射懸浮液，例如羧甲基纖維素鈉，山梨糖醇的水溶液和/或葡聚糖，和，如果需要，穩定劑。將活性成分，任選地與賦形劑，也可以是在一個冷凍乾燥的形式，並且可在非腸道給藥前透過加入合適的溶劑製成的溶液。使用的解決方案，例如，用於胃腸外給藥，也可以用作輸注溶液。注射製劑的製備通常在無菌條件下，填充進，例如，安瓿或小瓶，和密封的容器中。Pharmaceutical compositions suitable for parenteral administration may contain active ingredients in water-soluble form, for example water-soluble salts or aqueous injection suspensions containing viscosity-increasing substances, for example aqueous sodium carboxymethyl cellulose, aqueous solutions of sorbitol and/or Or dextran, and, if necessary, stabilizers. The active ingredient, optionally with excipients, can also be in a freeze-dried form and can be prepared by adding a suitable solvent to the solution before parenteral administration. The solution used, for example, for parenteral administration, can also be used as an infusion solution. Injectable preparations are usually prepared under sterile conditions and filled into, for example, ampoules or vials, and sealed containers.
本發明還提供了藥物組合，例如一種藥盒，其包含a)本發明所公開的化合物，可以爲游離形式或藥學可接受的鹽形式，和b)至少一種助劑。該藥盒可以包含其使用說明書。聯合療法 The present invention also provides a pharmaceutical combination, for example, a kit comprising a) the compound disclosed in the present invention, which may be in a free form or a pharmaceutically acceptable salt form, and b) at least one adjuvant. The kit may contain instructions for its use. Combination therapy
本專利所述化合物或藥學可接受的鹽可單獨使用，或與其他治療劑聯合使用。The compounds or pharmaceutically acceptable salts described in this patent can be used alone or in combination with other therapeutic agents.
例如，使用佐劑(adjuvant)可增強本發明中的化合物的治療效果(例如，單獨使用輔佐藥物的治療性獲益極小，但與另一種藥物合用時，可增強個體的治療性獲益)，或者，例如，本發明的化合物與另一個同樣具有療效的治療劑合用可增強個體的治療獲益。例如，治療痛風時，使用本發明的化合物時，合併使用另一種治療痛風的藥物，有可能會增強臨床獲益。或者，例如，如果使用本發明化合物的不良反應是噁心，那麽可合用抗噁心的藥物。或者，還可以聯合的療法包括，但不僅限於物理療法、心理療法、放射療法、疾病區域的壓迫療法、休息、膳食改善等。無論何種疾病、病症或病況，兩種療法使個體的治療受益應具有加成效應或協同效應。For example, the use of adjuvants can enhance the therapeutic effect of the compounds of the present invention (for example, the adjuvant drug alone has little therapeutic benefit, but when combined with another drug, it can enhance the therapeutic benefit of the individual), Or, for example, the compound of the present invention may be combined with another therapeutic agent that is also therapeutically effective to enhance the therapeutic benefit of the individual. For example, in the treatment of gout, when the compound of the present invention is used, the combined use of another drug for the treatment of gout may enhance the clinical benefit. Or, for example, if the adverse reaction of using the compound of the present invention is nausea, anti-nausea drugs may be combined. Alternatively, therapies that can be combined include, but are not limited to physical therapy, psychological therapy, radiotherapy, compression therapy in the diseased area, rest, diet improvement, etc. Regardless of the disease, disorder or condition, the two therapies benefiting the individual's treatment should have an additive or synergistic effect.
在本專利化合物與其他治療劑合用情況下，本專利化合物的藥物組成物給藥途徑可與其他藥物相同，或由於物理和化學性質不同，給藥途徑可以不相同。例如，本專利化合物口服給藥可産生並維持良好血藥位準，而另一種治療劑可能需要靜脈給藥。因此本專利化合物與另一治療劑可同時、先後或分別給藥。實施例 In the case where the compound of the present patent is used in combination with other therapeutic agents, the route of administration of the pharmaceutical composition of the compound of the present patent may be the same as other drugs, or the route of administration may be different due to different physical and chemical properties. For example, oral administration of the compound of this patent may produce and maintain good blood levels, while another therapeutic agent may require intravenous administration. Therefore, the compound of this patent and another therapeutic agent can be administered simultaneously, sequentially or separately. Examples
式(I)化合物或其藥學可接受的鹽的合成方法有多種，在本實例中列舉出的是具有代表性的方法。然而，需要指出的是，式(I)的化合物或其藥學可接受的鹽也可能透過其它合成方案的合成得到。There are various methods for synthesizing the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the representative methods are listed in this example. However, it should be pointed out that the compound of formula (I) or a pharmaceutically acceptable salt thereof may also be obtained through other synthetic schemes.
式(I)的某個化合物中，原子與其它原子之間的連接可能導致存在特殊的立體異構體(如掌性中心)。合成式(I)的化合物或其藥學可接受的鹽可能産生不同異構體(對映異構體，非對映異構體)的混合物。除非特別說明是某個特定的立體構型，所列舉的化合物均包括了其可能存在的不同立體異構體。In a compound of formula (I), the connection between atoms and other atoms may lead to the presence of special stereoisomers (such as palm centers). The synthesis of the compound of formula (I) or a pharmaceutically acceptable salt thereof may produce a mixture of different isomers (enantiomers, diastereomers). Unless specifically stated to be a specific stereo configuration, the listed compounds include the different stereo isomers that may exist.
式(I)的化合物也可以製成藥學可接受的酸加成鹽，例如，透過將本發明化合物的游離鹼的形式與藥學可接受的無機或有機酸反應。或者將一個式(I)的化合物以游離酸的形式與藥學可接受的無機或有機鹼反應，將其製成藥學可接受的鹼加成鹽。適宜於製備式(I)化合物的藥學可接受鹽的無機和有機的酸和鹼已在本申請書的定義部分做了說明。此外，式(I)化合物鹽的形式也可以透過使用起始原料或中間物的鹽進行製備。The compounds of formula (I) can also be prepared as pharmaceutically acceptable acid addition salts, for example, by reacting the free base form of the compounds of the invention with pharmaceutically acceptable inorganic or organic acids. Alternatively, a compound of formula (I) may be reacted with a pharmaceutically acceptable inorganic or organic base in the form of a free acid to prepare a pharmaceutically acceptable base addition salt. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of compounds of formula (I) have been described in the definition section of this application. In addition, the salt form of the compound of formula (I) can also be prepared by using the salts of the starting materials or intermediates.
式(I)化合物的游離酸或游離鹼可以透過其相應的鹼加成鹽或者酸加成鹽製備得到。式(I)化合物的酸加成鹽形式可轉化成相應的游離鹼，例如透過用合適的鹼(如氫氧化銨溶液、氫氧化鈉等)處理。式(I)化合物的鹼加成鹽形式可轉化爲相應的游離酸，例如透過用合適的酸(如鹽酸等)處理。The free acid or free base of the compound of formula (I) can be prepared by its corresponding base addition salt or acid addition salt. The acid addition salt form of the compound of formula (I) can be converted into the corresponding free base, for example by treatment with a suitable base (eg ammonium hydroxide solution, sodium hydroxide, etc.). The base addition salt form of the compound of formula (I) can be converted into the corresponding free acid, for example by treatment with a suitable acid (such as hydrochloric acid, etc.).
一個式(I)的化合物或其一個藥學可接受的鹽的N-氧化物可透過本領域已知的方法制得。例如，N-氧化物可以透過將式(I)化合物的非氧化形式在0~80°C的條件下與氧化劑(如三氟過氧乙酸、過氧馬來酸(permaleic acid)、過氧苯甲酸、過氧乙酸和間氯過氧苯甲酸等)在惰性有機溶劑(如二氯甲烷等鹵化烴)中反應得到。另擇地，式(I)化合物的N-氧化物也可透過起始原料的N-氧化物製備得到。The N-oxide of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known in the art. For example, N-oxide can be prepared by combining the non-oxidized form of the compound of formula (I) at 0~80°C with an oxidizing agent (such as trifluoroperoxyacetic acid, permaleic acid, peroxybenzene Formic acid, peroxyacetic acid, m-chloroperoxybenzoic acid, etc.) are obtained by reacting in an inert organic solvent (such as halogenated hydrocarbons such as methylene chloride). Alternatively, the N-oxide of the compound of formula (I) can also be prepared from the N-oxide of the starting material.
非氧化形式的式(I)化合物可透過將其N-氧化物與還原劑(如硫、二氧化硫、三苯基膦、硼氫化鋰、硼氫化鈉、三氯化磷和三溴化磷等)在0~80°C的條件下在相應的惰性有機溶劑(如乙腈、乙醇和二氧六環水溶液等)中反應製得。The non-oxidized form of the compound of formula (I) can be obtained by combining its N-oxide with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide, etc.) It is prepared by reacting in the corresponding inert organic solvents (such as acetonitrile, ethanol and dioxane aqueous solution) under the condition of 0~80°C.
式(I)化合物的保護衍生物可以透過本領域人員熟知的方法製備得到。關於保護基團的加入和去除的詳細技術描述參見：T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999。The protected derivatives of compounds of formula (I) can be prepared by methods well known to those skilled in the art. For a detailed technical description of the addition and removal of protecting groups, see: T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
這些方法、路線與實施例中所使用的標誌和常識，均與現行的科學文獻相一致，例如，美國化學協會雜誌或生物化學雜誌。除非另有說明，標準的單字母或三字母的縮寫通常指L型胺基酸殘基。除非另有說明，所有使用的起始原料均從市場供應商購買得到，使用時並未進一步純化。例如，在實例及整個說明書中會用到以下縮寫：g (克)、mg (毫克)、L (升)、mL (毫升)、μL (微升)、psi (磅每平方英寸)、M (莫耳)、mM (毫莫耳)、i.v. (靜脈注射)、Hz (赫茲)、MHz (兆赫)、mol (莫耳)、mmol (毫莫耳)、RT (環境溫度)、min (分鐘)、h (小時)、mp (熔點)、TLC (薄層層析法)、Rt (保留時間)、RP (反相)、MeOH (甲醇)、i-PrOH (異丙醇)、TEA (三乙胺)、TFA (三氟乙酸)、TFAA (三氟乙酸酐)、THF (四氫呋喃)、DMSO (二甲基亞碸)、EtOAc (乙酸乙酯)、DME (1,2-二甲基乙烷)、DCM (二氯甲烷)、DCE (二氯乙烷)、DMF (N ,N -二甲基甲醯胺)、DMPU (N ,N' -二甲基丙烯基脲)、CDI (1,1-羰基二咪唑)、IBCF (氯甲酸異丁酯)、HOAc (乙酸)、HOSu (N-羥基琥珀醯亞胺)、HOBT (1-羥基苯並三氮唑)、Et2 O (乙醚)、EDCI (1-(3-二甲基胺基丙基)3-乙基碳二亞胺鹽酸鹽)、BOC (叔丁氧羰基)、FMOC (9-芴基甲氧羰基)、DCC (二環己基碳二亞胺)、CBZ (苄氧羰基)、Ac (乙醯基)、atm (大氣壓)、TMSE (2-(三甲矽基)乙基)、TMS (三甲矽基)、TIPS (三異丙基矽基)、TBS (叔丁基二甲矽基)、DMAP (4-二甲基胺基吡啶)、Me (甲基)、Ome (甲氧基)、Et (乙基)、tBu (叔丁基)、HPLC (高效液相層析法)、BOP (雙(2-氧代-3-噁唑烷基)次磷醯氯)、TBAF (四正丁基氟化銨)、mCPBA (間氯過氧苯甲酸)。These methods, routes, and the signs and common sense used in the examples are consistent with the current scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biochemistry. Unless otherwise stated, standard one-letter or three-letter abbreviations usually refer to L-amino acid residues. Unless otherwise stated, all starting materials used were purchased from market suppliers and were not further purified when used. For example, the following abbreviations are used throughout the examples and throughout the specification: g (grams), mg (mg), L (liters), mL (milliliters), μL (microliters), psi (pounds per square inch), M ( Mol), mM (millimol), iv (intravenous), Hz (hertz), MHz (megahertz), mol (mol), mmol (millimol), RT (ambient temperature), min (minutes) , H (hour), mp (melting point), TLC (thin layer chromatography), Rt (retention time), RP (reverse phase), MeOH (methanol), i-PrOH (isopropanol), TEA (triethyl ether) Amine), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), DME (1,2-dimethylethane ), DCM (dichloromethane), DCE (dichloroethane), DMF ( N , N -dimethylformamide), DMPU ( N , N' -dimethylpropenyl urea), CDI (1, 1-carbonyldiimidazole), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et 2 O (ether) , EDCI (1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride), BOC (tert-butoxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC ( Dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetylcarbonyl), atm (atmospheric pressure), TMSE (2-(trimethylsilyl)ethyl), TMS (trimethylsilyl), TIPS ( Triisopropylsilyl), TBS (tert-butyldimethylsilyl), DMAP (4-dimethylaminopyridine), Me (methyl), Ome (methoxy), Et (ethyl), tBu (tert-butyl), HPLC (high performance liquid chromatography), BOP (bis(2-oxo-3-oxazolidinyl) phosphinyl chloride), TBAF (tetra-n-butylammonium fluoride), mCPBA (m-chloroperoxybenzoic acid).
醚或Et2 O均是指乙醚；鹽水則是指飽和NaCl水溶液。除非另有說明，所有的溫度均是指℃溫度(攝氏度)，所有的反應都是在室溫下的惰性氛圍中反應。Ether or Et 2 O refers to ether; brine refers to saturated aqueous NaCl solution. Unless otherwise stated, all temperatures refer to °C (degrees Celsius), and all reactions are conducted in an inert atmosphere at room temperature.
1 H NMR譜採用Varian Mercury Plus 400核磁共振光譜儀記錄。化學位移爲以ppm表示。耦合常數均以赫茲爲單位(Hz)。以分割模式描述表觀多樣性，並定爲s (單峰)、d (雙峰)、t (三重峰)、q (四重峰)、m (多重峰)和br (寬峰)。 The 1 H NMR spectrum was recorded using a Varian Mercury Plus 400 nuclear magnetic resonance spectrometer. Chemical shifts are expressed in ppm. The coupling constants are in hertz (Hz). Describe the apparent diversity in a split mode and define it as s (single peak), d (double peak), t (triplet), q (quartet), m (multiplet), and br (broad).
低分辨質譜(MS)和化合物純度數據來自Shimadzu LC/MS單個四極桿系統，該系統配備有電噴霧離子檢測器(ESI)，紫外探測器(220和254 nm)及蒸發光散射檢測器(ELSD)。薄層層析法使用的是0.25 mm旭泊化成矽膠板(60F-254)，5%的磷鉬酸乙醇溶液，茚三酮或p-甲氧基苯甲醛溶液並在紫外燈下觀察。快速柱層析使用的是矽膠(200-300目，青島海洋化工有限公司)。合成方案 Low-resolution mass spectrometry (MS) and compound purity data are from a Shimadzu LC/MS single quadrupole system equipped with electrospray ionization detectors (ESI), ultraviolet detectors (220 and 254 nm) and evaporative light scattering detectors (ELSD ). The TLC method uses a 0.25 mm Asahi chemical silicon plate (60F-254), 5% phosphomolybdic acid ethanol solution, ninhydrin or p-methoxybenzaldehyde solution and observes it under an ultraviolet lamp. The silica gel (200-300 mesh, Qingdao Ocean Chemical Co., Ltd.) is used for flash column chromatography. Synthesis scheme
在如下所述諸反應中可能有必要對活性基團進行保護，以免這些活性基團參與其它不期望的反應：這些基團如羥基、胺基、亞胺基、含巰基或羧基，最終産物中含有這些基團。常用的保護基團可參考T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991。In the reactions described below, it may be necessary to protect the active groups to prevent these active groups from participating in other undesirable reactions: these groups such as hydroxyl, amine, imine, mercapto or carboxyl groups, in the final product Contains these groups. Commonly used protecting groups can refer to T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.
本發明的所有化合物的合成方案由以下方案和實施例加以說明。所用起始原料源於市售商品或可根據已有工藝方法或者此處示例的方法製備。The synthetic schemes of all compounds of the present invention are illustrated by the following schemes and examples. The starting materials used are derived from commercially available products or can be prepared according to existing processes or the methods exemplified here.
以下合成方案所列的中間物或根據文獻得到，或根據已有的類似的合成方法合成。The intermediates listed in the following synthesis schemes are either obtained from the literature, or synthesized according to existing similar synthesis methods.
方案1披露了本發明公開的式I化合物的一種合成方法。以由商業提供的或者文獻報導的中間物II爲起始物，中間物式IV可以透過有文獻報導合成方法的II與中間物III在過渡金屬催化下發生交叉偶聯反應來製備。鹵化物IV與式V中間物的進一步交叉偶聯製得式I化合物。
作爲說明，式Ia化合物的一條合成路線如合成方案2所示。以商業提供的IIa-A開始，可根據WO 2018/005586中所述的方法製備化合物IIa。在適當的Suzuki偶聯條件下，透過鹵化物IIa與硼酸IIIa和硼酸酯Va相繼的交叉偶聯得到化合物Ia-A，Ia-A吡啶部分的進一步的官能基化可以透過與INT-A的S N
Ar取代反應和其它必要的衍生反應實現，得到如合成方案2中的式Ia化合物。
在某些情況下，爲了促進反應或避免不必要的反應産物産生，上述合成方案可根據情況調整順序。爲了使本發明被更充分地理解，提供了以下實施例。這些實施例只是示例，不應將其理解成是對本發明的限制。實施例 1 In some cases, in order to promote the reaction or avoid unnecessary reaction products, the above synthesis scheme can adjust the order according to the situation. In order for the present invention to be more fully understood, the following examples are provided. These embodiments are only examples and should not be construed as limiting the present invention. Example 1
6-(1- 甲基 -1H- 吡唑 -4- 基 )-8-(6-( 呱嗪 -1- 基 ) 吡啶 -3- 基 )-[1,2,4] 三唑並 [1,5-a] 吡啶 (1) 
6- 溴 -8- 碘 -[1,2,4] 三唑並 [1,5-a] 吡啶 (1a ) 6- Bromo -8- iodo- [1,2,4] triazolo [1,5-a] pyridine ( 1a )
6-溴-8-碘-[1,2,4]三唑並[1,5-a ]吡啶(1a )是參照文獻WO 2018/005586描述的方法製備得到。6-Bromo-8-iodo-[1,2,4]triazolo[1,5- a ]pyridine ( 1a ) was prepared by referring to the method described in document WO 2018/005586.
6- 溴 -8-(6- 氟吡啶 -3- 基 )-[1,2,4] 三唑並 [1,5-a] 吡啶 (1b ) 6- Bromo -8-(6- fluoropyridin- 3 -yl )-[1,2,4] triazolo [1,5-a] pyridine ( 1b )
6-溴-8-碘-[1,2,4]三唑並[1,5-a ]吡啶(1a )(800 mg, 2.47 mmol)，2-氟吡啶-5-硼酸(700 mg, 4.96 mmol)，Pd(OAc)2 (111 mg, 0.493 mmol)和PCy3 (276 mg, 0.986 mmol)在甲苯(20 mL)中的混合物和Na2 CO3 水溶液(2 M, 3.7 ml)在氮氣保護下，80°C攪拌過夜。將混合物冷卻至室溫並用水稀釋，用EtOAc (2 × 100 mL)萃取。有機相用Na2 SO4 乾燥並濃縮。殘留物用矽膠柱層析純化，PE/EtOAc (20:1~5:1)洗提得到標題化合物6-溴-8-(6-氟吡啶-3-基)-[1,2,4]三唑並[1,5-a ]吡啶(1b )。 MS-ESI (m/z): 293 [M+1]+ 。6-Bromo-8-iodo-[1,2,4]triazolo[1,5- a ]pyridine ( 1a ) (800 mg, 2.47 mmol), 2-fluoropyridine-5-boronic acid (700 mg, 4.96 mmol), a mixture of Pd(OAc) 2 (111 mg, 0.493 mmol) and PCy 3 (276 mg, 0.986 mmol) in toluene (20 mL) and aqueous Na 2 CO 3 solution (2 M, 3.7 ml) under nitrogen protection Under stirring at 80 °C overnight. The mixture was cooled to room temperature and diluted with water, and extracted with EtOAc (2×100 mL). The organic phase was dried with Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (20:1~5:1) to give the title compound 6-bromo-8-(6-fluoropyridin-3-yl)-[1,2,4] Triazolo[1,5- a ]pyridine ( 1b ). MS-ESI (m/z): 293 [M+1] + .
8-(6- 氟吡啶 -3- 基 )-6-(1- 甲基 -1H- 吡唑 -4- 基 )-[1,2,4] 三唑並 [1,5-a] 吡啶 (1c ) 8-(6- fluoropyridin- 3 -yl )-6-(1 -methyl -1H- pyrazol- 4 -yl )-[1,2,4] triazolo [1,5-a] pyridine ( 1c )
6-溴-8-(6-氟吡啶-3-基)-[1,2,4]三唑並[1,5-a ]吡啶(1b )(330 mg, 1.13 mmol)，1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-1H -吡唑(280 mg, 1.35 mmol)與Pd(PPh3 )4 (130 mg, 0.113 mmol)在二氧六環(7 mL)中的混合物和Na2 CO3 水溶液(2 M, 1.7 ml)在氮氣保護下，80°C攪拌6 h。將混合物冷卻至室溫並用水稀釋。過濾收集濾餅並乾燥得到標題化合物8-(6-氟吡啶-3-基)-6-(1-甲基-1H -吡唑-4-基)-[1,2,4]三唑並[1,5-a ]-吡啶(1c )。 MS-ESI (m/z): 295 [M+1]+ 。6-Bromo-8-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5- a ]pyridine ( 1b ) (330 mg, 1.13 mmol), 1-methyl -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -pyrazole (280 mg, 1.35 mmol) and Pd( PPh 3 ) 4 (130 mg, 0.113 mmol) in dioxane (7 mL) and Na 2 CO 3 aqueous solution (2 M, 1.7 ml) were stirred at 80°C for 6 h under nitrogen protection. The mixture was cooled to room temperature and diluted with water. The filter cake was collected by filtration and dried to give the title compound 8-(6-fluoropyridin-3-yl)-6-(1-methyl- 1H -pyrazol-4-yl)-[1,2,4]triazole And [1,5- a ]-pyridine ( 1c ). MS-ESI (m/z): 295 [M+1] + .
叔丁基 4-(5-(6-(1- 甲基 -1H- 吡唑 -4- 基 )-[1,2,4] 三唑並 [1,5-a] 吡啶 -8- 基 ) 吡啶 -2- 基 ) 呱嗪 -1- 羧酸酯 (1d ) Tert-Butyl 4-(5-(6-(1 -methyl -1H- pyrazol- 4 -yl )-[1,2,4] triazolo [1,5-a] pyridin -8- yl ) Pyridin -2- yl ) pyrazine- 1- carboxylate ( 1d )
8-(6-氟吡啶-3-基)-6-(1-甲基-1H -吡唑-4-基)-[1,2,4]三唑並[1,5-a ]吡啶(1c )( 150 mg, 0.508 mmol)，叔丁基呱嗪-1-羧酸酯(114 mg, 0.613 mmol)和K2 CO3 (350 mg, 2.54 mmol)加入DMSO (5 mL)中，氮氣保護下，120°C攪拌40 h。將混合物冷卻至室溫並用水稀釋，用DCM (3 × 50 mL)萃取。有機相用水洗滌，Na2 SO4 乾燥並濃縮。殘留物用矽膠柱層析純化，DCM/MeOH (100:1~40:1)洗提得到標題化合物叔丁基4-(5-(6-(1-甲基-1H -吡唑-4-基)-[1,2,4]三唑並[1,5-a ]吡啶-8-基)吡啶-2-基)呱嗪-1-羧酸酯(1d )。 MS-ESI (m/z): 461 [M+1]+ 。8-(6-fluoropyridin-3-yl)-6-(1-methyl-1 H -pyrazol-4-yl)-[1,2,4]triazolo[1,5- a ]pyridine ( 1c ) ( 150 mg, 0.508 mmol), tert-butylpyrazine-1-carboxylate (114 mg, 0.613 mmol) and K 2 CO 3 (350 mg, 2.54 mmol) were added to DMSO (5 mL), nitrogen Under protection, stir at 120°C for 40 h. The mixture was cooled to room temperature and diluted with water, and extracted with DCM (3×50 mL). The organic phase was washed with water, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography and eluted with DCM/MeOH (100:1~40:1) to obtain the title compound tert-butyl 4-(5-(6-(1-methyl- 1H -pyrazole-4 -Yl)-[1,2,4]triazolo[1,5- a ]pyridin-8-yl)pyridin-2-yl)pyrazine-1-carboxylic acid ester ( 1d ). MS-ESI (m/z): 461 [M+1] + .
6-(1- 甲基 -1H- 吡唑 -4- 基 )-8-(6-( 呱嗪 -1- 基 ) 吡啶 -3- 基 )-[1,2,4] 三唑並 [1,5-a] 吡啶 (1) 6-(1 -methyl -1H- pyrazol- 4 -yl )-8-(6-( pentazin- 1 -yl ) pyridin- 3 -yl )-[1,2,4] triazolo [1 ,5-a] pyridine ( 1)
向4-(5-(6-(1-甲基-1H -吡唑-4-基)-[1,2,4]三唑並[1,5-a ]吡啶-8-基)吡啶-2-基)呱嗪-1-羧酸酯(1d )(160 mg, 0.347 mmol)的DCM (4 mL)溶液中加入TFA (1 ml)。該混合物在室溫下攪拌1 h後濃縮。殘留物用飽和NaHCO3 水溶液(20 mL)稀釋並用DCM/MeOH (10:1)(4 × 20 ml)萃取。有機相用水洗滌，Na2 SO4 乾燥並濃縮。殘留物用矽膠柱層析純化，DCM/MeOH (50:1~10:1) 洗提得到標題化合物6-(1-甲基-1H -吡唑-4-基)-8-(6-(呱嗪-1-基)吡啶-3-基)-[1,2,4]三唑並[1,5-a ]吡啶(1) 。 MS-ESI (m/z): 361 [M+1]+ 。實施例 2 To 4-(5-(6-(1-methyl- 1H -pyrazol-4-yl)-[1,2,4]triazolo[1,5- a ]pyridin-8-yl)pyridine To a solution of 2-yl)pyrazine-1-carboxylate ( 1d ) (160 mg, 0.347 mmol) in DCM (4 mL) was added TFA (1 ml). The mixture was stirred at room temperature for 1 h and concentrated. The residue was diluted with saturated aqueous NaHCO 3 (20 mL) and extracted with DCM/MeOH (10:1) (4×20 ml). The organic phase was washed with water, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography and eluted with DCM/MeOH (50:1~10:1) to obtain the title compound 6-(1-methyl- 1H -pyrazol-4-yl)-8-(6- (Pyrazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5- a ]pyridine ( 1) . MS-ESI (m/z): 361 [M+1] + . Example 2
6-(1- 甲基 -1H- 吡唑 -4- 基 )-8-(6-(4- 甲基呱嗪 -1- 基 ) 吡啶 -3- 基 )-[1,2,4] 三唑並 [1,5-a] 吡啶
(2
)
向6-(1-甲基-1H -吡唑-4-基)-8-(6-(呱嗪-1-基)吡啶-3-基)-[1,2,4]三唑並[1,5-a ]吡啶(1) (7.4 mg, 0.0206 mmol)的DCM (1 mL)溶液加入HCHO (37%水溶液，2.5 mg，0.0309 mmol)，隨後加入NaBH(OAc)3 (13 mg, 0.0618 mmol)。該混合物在室溫下攪拌0.5 h。將混合物倒入飽和NaHCO3 水溶液並用DCM (4 × 20 ml)萃取。有機相用水洗滌，用Na2 SO4 乾燥並濃縮，殘留物用矽膠柱層析純化，DCM/MeOH (30:1~10:1)洗提得到標題化合物6-(1-甲基-1H -吡唑-4-基)-8-(6-(4-甲基呱嗪-1-基)吡啶-3-基)-[1,2,4]三唑並[1,5-a ]吡啶(2 )。 MS-ESI (m/z): 375 [M+1]+ 。實施例 3 To 6-(1-methyl- 1H -pyrazol-4-yl)-8-(6-(pentazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo [1,5- a ]pyridine ( 1) (7.4 mg, 0.0206 mmol) in DCM (1 mL) was added HCHO (37% aqueous solution, 2.5 mg, 0.0309 mmol), followed by NaBH(OAc) 3 (13 mg, 0.0618 mmol). The mixture was stirred at room temperature for 0.5 h. The mixture was poured into saturated aqueous NaHCO 3 and extracted with DCM (4×20 ml). The organic phase was washed with water, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column chromatography and eluted with DCM/MeOH (30:1~10:1) to give the title compound 6-(1-methyl-1 H -Pyrazol-4-yl)-8-(6-(4-methylpyrazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5- a ] Pyridine ( 2 ). MS-ESI (m/z): 375 [M+1] + . Example 3
8-(6-(4- 乙基呱嗪 -1- 基 ) 吡啶 -3- 基 )-6-(1- 甲基 -1H- 吡唑 -4- 基 )-[1,2,4] 三唑並 [1,5-a] 吡啶
(3
)
標題化合物8-(6-(4-乙基呱嗪-1-基)吡啶-3-基)-6-(1-甲基-1H -吡唑-4-基)-[1,2,4]三唑並[1,5-a ]吡啶(3 )根據2 的合成方法製備得到，將HCHO替換成CH3 CHO。 MS-ESI (m/z): 389 [M+1]+ 。實施例 4 The title compound 8-(6-(4-ethylpyrazine-1-yl)pyridin-3-yl)-6-(1-methyl- 1H -pyrazol-4-yl)-[1,2, 4] Triazolo[1,5- a ]pyridine ( 3 ) is prepared according to the synthesis method of 2 , replacing HCHO with CH 3 CHO. MS-ESI (m/z): 389 [M+1] + . Example 4
1- 苄基 -4-(5-(6-(1- 甲基 -1H- 吡唑 -4- 基 )-[1,2,4] 三唑並 [1,5-a] 吡啶 -8- 基 ) 吡啶 -2- 基 ) 呱嗪 -2- 酮 ( 4
)
標題化合物1-苄基-4-(5-(6-(1-甲基-1H -吡唑-4-基)-[1,2,4]三唑並-[1,5-a ]吡啶-8-基)吡啶-2-基)呱嗪-2-酮(4 )根據1d 的合成方法製備得到，將叔丁基呱嗪-1-羧酸酯替換成1-苄基呱嗪-2-酮。 MS-ESI (m/z): 465 [M+1]+ 。實施例 5 The title compound 1-benzyl-4-(5-(6-(1-methyl- 1H -pyrazol-4-yl)-[1,2,4]triazolo-[1,5- a ] Pyridin-8-yl)pyridin-2-yl)pyrazin-2-one ( 4 ) was prepared according to the synthesis method of 1d , replacing tert-butylpyrazine-1-carboxylate with 1-benzylpyrazine- 2-one. MS-ESI (m/z): 465 [M+1] + . Example 5
甲基 4-(5-(6-(1- 甲基 -1H- 吡唑 -4- 基 )-[1,2,4] 三唑並 [1,5-a] 吡啶 -8- 基 ) 吡啶 -2- 基 ) 呱嗪 -1- 羧酸酯
(5
)
向6-(1-甲基-1H -吡唑-4-基)-8-(6-(呱嗪-1-基)吡啶-3-基)-[1,2,4]三唑並[1,5-a ]吡啶(1 )(10 mg, 0.0277 mmol)的DCM (1 mL)溶液中加入TEA (8.4 mg, 0.0831 mmol)，接著加入氯甲酸甲酯(4 mg, 0.0416 mmol)。在室溫下攪拌2 h後，將該混合物濃縮，殘留物用矽膠柱層析純化，DCM/MeOH (30:1~10:1)洗提得到標題化合物甲基4-(5-(6-(1-甲基-1H -吡唑-4-基)-[1,2,4]三唑並[1,5-a ]吡啶- 8-基)吡啶-2-基)呱嗪-1-羧酸酯(5 )。 MS-ESI (m/z): 419 [M+1]+ 。實施例 6 To 6-(1-methyl- 1H -pyrazol-4-yl)-8-(6-(pentazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo To a solution of [1,5- a ]pyridine ( 1 ) (10 mg, 0.0277 mmol) in DCM (1 mL) was added TEA (8.4 mg, 0.0831 mmol), followed by methyl chloroformate (4 mg, 0.0416 mmol). After stirring at room temperature for 2 h, the mixture was concentrated, and the residue was purified by silica gel column chromatography, and eluted with DCM/MeOH (30:1~10:1) to give the title compound methyl 4-(5-(6- (1-methyl-1 H -pyrazol-4-yl)-[1,2,4]triazolo[1,5- a ]pyridin-8-yl)pyridin-2-yl)pyrazine-1 -Carboxylate ( 5 ). MS-ESI (m/z): 419 [M+1] + . Example 6
(R)-2- 羥基 -1-(4-(5-(6-(1- 甲基 -1H- 吡唑 -4- 基 )-[1,2,4] 三唑並 [1,5-a] 吡啶 -8- 基 ) 吡啶 -2- 基 ) 呱嗪 -1- 基 )-2- 苯基乙烷 -1- 酮
(6
)
向6-(1-甲基-1H -吡唑-4-基)-8-(6-(呱嗪-1-基)吡啶-3-基)-[1,2,4]三唑並[1,5-a ]吡啶 (1) (10 mg, 0.0277 mmol)的DCM (1 mL)溶液中加入(R )-2-羥基-2-苯基乙酸(5 mg, 0.0332 mmol)，EDCI (16 mg, 0.0831 mmol)，HOBT (11 mg, 0.0831 mmol)，接著加入TEA (9 mg, 0.0831 mmol)。在室溫下攪拌過夜後，將混合物濃縮，殘留物用矽膠柱層析純化，DCM/MeOH (30:1~10:1)洗提得到標題化合物(R )-2-羥基-1-(4-(5-(6-(1-甲基-1H -吡唑-4-基)-[1,2,4]三唑並[1,5-a ]吡啶-8-基)吡啶-2-基)呱嗪-1-基)-2-苯基乙烷-1-酮(6 )。 MS-ESI (m/z): 495 [M+1]+ 。To 6-(1-methyl- 1H -pyrazol-4-yl)-8-(6-(pentazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo [1,5- a ]pyridine ( 1) (10 mg, 0.0277 mmol) in DCM (1 mL) was added ( R )-2-hydroxy-2-phenylacetic acid (5 mg, 0.0332 mmol), EDCI ( 16 mg, 0.0831 mmol), HOBT (11 mg, 0.0831 mmol), followed by TEA (9 mg, 0.0831 mmol). After stirring at room temperature overnight, the mixture was concentrated, the residue was purified by silica gel column chromatography, and eluted with DCM/MeOH (30:1~10:1) to give the title compound ( R )-2-hydroxy-1-(4 -(5-(6-(1-methyl-1 H -pyrazol-4-yl)-[1,2,4]triazolo[1,5- a ]pyridin-8-yl)pyridine-2 -Yl)pyrazin-1-yl)-2-phenylethane-1-one ( 6 ). MS-ESI (m/z): 495 [M+1] + .
表1中列出實施例7-13是基本上按照與實施例1-6相同的方法，使用的起始物料是商購或者根據文獻方法製得。表1給出了實施例7-13的名稱及結構。
表1
MTS檢測試劑盒購自Promega。RPMI-1640培養基、F12培養基、F12K培養基、胎牛血清和青黴素-鏈黴素購自BI。Glutamine和二甲基亞碸(DMSO)購自Sigma。TT和LC-2/ad細胞分別培養於含10%胎牛血清的F12K和含10%胎牛血清、2 mM Glutamine的HamF12：RPMI1640 (1:1)的培養基中。The MTS detection kit was purchased from Promega. RPMI-1640 medium, F12 medium, F12K medium, fetal bovine serum, and penicillin-streptomycin were purchased from BI. Glutamine and dimethyl sulfoxide (DMSO) were purchased from Sigma. TT and LC-2/ad cells were cultured in F12K containing 10% fetal bovine serum and HamF12: RPMI1640 (1:1) containing 10% fetal bovine serum and 2 mM Glutamine, respectively.
透過測定化合物對TT (RET基因點突變C634W)和LC-2/ad (CCDC6-RET融合)細胞增殖的抑制作用，檢測化合物對RET基因融合和/或突變的抑制作用。消化酶處理細胞，將細胞均按5000個/井的細胞濃度接種於96井培養盤，37℃，5% CO2 培育24 h。96井細胞培養盤中加入平行3井不同濃度(終濃度10000、3333.3、1111.1、370.4、123.5、41.2、13.7、4.6和1.5 nM)的化合物，於37℃，5% CO2 培育(TT細胞168h；LC-2/ad 12h)。每井按照每100 µL培養基20 µL MTS的濃度加入MTS。培育2 h後，每井加入25 µL 10% SDS終止反應。用微量培養盤讀取儀測量490 nm和650 nm處的吸收。用GraphPad Prism 5.0計算IC50 。By measuring the compound's inhibitory effect on TT (RET gene point mutation C634W) and LC-2/ad (CCDC6-RET fusion) cell proliferation, the compound's inhibitory effect on RET gene fusion and/or mutation was detected. The cells were treated with digestive enzymes, and the cells were seeded in 96-well culture plates at a cell concentration of 5000 cells/well, and incubated at 37°C, 5% CO 2 for 24 h. Compounds with different concentrations (final concentrations 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6 and 1.5 nM) were added to the 96-well cell culture plate and incubated at 37°C, 5% CO 2 (TT cells 168h ; LC-2/ad 12h). MTS was added to each well at a concentration of 20 µL MTS per 100 µL medium. After incubation for 2 h, 25 µL of 10% SDS was added to each well to stop the reaction. Measure the absorption at 490 nm and 650 nm with a microplate reader. Calculated using GraphPad Prism 5.0 IC 50.
根據本文中所述的生物學方法對上述製備的所選化合物進行試驗。其結果如下表2所示：
表2
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