TW202126639A - Pyrrolidinyl-based compounds - Google Patents
Pyrrolidinyl-based compounds Download PDFInfo
- Publication number
- TW202126639A TW202126639A TW109134237A TW109134237A TW202126639A TW 202126639 A TW202126639 A TW 202126639A TW 109134237 A TW109134237 A TW 109134237A TW 109134237 A TW109134237 A TW 109134237A TW 202126639 A TW202126639 A TW 202126639A
- Authority
- TW
- Taiwan
- Prior art keywords
- cancer
- compound
- pharmaceutically acceptable
- acceptable salt
- group
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
Description
本申請案係關於化學、生物化學、及醫學之領域。更具體的是，本文中揭示吡咯啶基系化合物(連同醫藥組成物)，以及其合成方法。本文中亦揭示以一或多種本文所述之化合物來改善及/或治療本文所述之癌症之方法。This application is related to the fields of chemistry, biochemistry, and medicine. More specifically, this article discloses pyrrolidinyl-based compounds (along with pharmaceutical compositions) and methods for their synthesis. Also disclosed herein are methods for improving and/or treating the cancers described herein with one or more of the compounds described herein.
在各種細胞類型中，RAS/MAPK路徑係回應於生長因子結合而活化，並調控細胞生長、分化、及存活。此路徑之活化經由蛋白質磷酸化事件之級聯(cascade)而發生，該級聯結束於ERK(ERK1及/或ERK2)的磷酸化及活化。在RAS/MAPK路徑中，ERK處於小GTP酶RAS以及蛋白質激酶RAF及MEK的下游。其藉由RAS活化之後，RAF將MEK磷酸化，繼而將ERK磷酸化。活化的ERK將其他受質磷酸化，該等受質決定細胞的轉錄輸出。In various cell types, the RAS/MAPK pathway is activated in response to the binding of growth factors and regulates cell growth, differentiation, and survival. The activation of this pathway occurs through a cascade of protein phosphorylation events, which ends with the phosphorylation and activation of ERK (ERK1 and/or ERK2). In the RAS/MAPK pathway, ERK is downstream of the small GTPases RAS and protein kinases RAF and MEK. After it is activated by RAS, RAF phosphorylates MEK, which in turn phosphorylates ERK. Activated ERK phosphorylates other substrates, which determine the transcriptional output of cells.
本文中所揭示之一些實施例係關於一種式(I)化合物、或其醫藥上可接受之鹽。Some embodiments disclosed herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof.
本文所述之一些實施例係關於一種醫藥組成物，其可包括有效量之式(I)化合物、或其醫藥上可接受之鹽。Some embodiments described herein relate to a pharmaceutical composition, which may include an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
本文所述之一些實施例係關於一種用於改善及/或治療本文所述之癌症之方法，其可包括投予有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物至患有本文所述之癌症的對象。Some embodiments described herein relate to a method for improving and/or treating the cancer described herein, which may include administering an effective amount of a compound described herein (for example, a compound of formula (I), or a medicine thereof). Above acceptable salt) or a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) to a subject suffering from the cancer described herein.
本文所述之一些實施例係關於一種有效量之本文所述之化合物化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物在製造用於改善或治療本文所述之癌症之藥劑中之用途。Some embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or includes a compound described herein (e.g., formula (I) ) The use of the pharmaceutical composition of the compound or its pharmaceutically acceptable salt) in the manufacture of a medicament for improving or treating the cancer described herein.
本文所述之一些實施例係關於一種用於抑制惡性生長或腫瘤之複製之方法，其可包括使該生長或該腫瘤與有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物接觸，其中該惡性生長或該腫瘤係由本文所述之癌症引起。Some embodiments described herein relate to a method for inhibiting the replication of malignant growth or tumors, which may include combining the growth or tumor with an effective amount of a compound described herein (e.g., a compound of formula (I), or Contact with a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or the tumor is derived from the compound described herein The mentioned cancer is caused.
本文所述之一些實施例係關於一種本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物在製造用於抑制惡性生長或腫瘤之複製之藥劑中之用途，其中該惡性生長或腫瘤係由本文所述之癌症引起。Some embodiments described herein relate to a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or include a compound described herein (e.g., a compound of formula (I), or The use of the pharmaceutical composition of its pharmaceutically acceptable salt) in the manufacture of a medicament for inhibiting malignant growth or tumor replication, wherein the malignant growth or tumor is caused by the cancer described herein.
本文所述之一些實施例係關於一種用於改善或治療本文所述之癌症之方法，其可包括使惡性生長或腫瘤與有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物接觸。Some embodiments described herein relate to a method for ameliorating or treating the cancer described herein, which may include causing malignant growth or tumor and effective amount of a compound described herein (e.g., a compound of formula (I), or Or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof).
本文所述之一些實施例係關於一種本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物在製造用於藉由使惡性生長或腫瘤與有效量之化合物接觸來改善或治療本文所述之癌症之藥劑中之用途。Some embodiments described herein relate to a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or include a compound described herein (e.g., a compound of formula (I), or The use of the pharmaceutical composition of its pharmaceutically acceptable salt) in the manufacture of a medicament for improving or treating the cancer described herein by contacting malignant growth or tumor with an effective amount of the compound.
本文所述之一些實施例係關於一種用於抑制ERK1及/或ERK2之活性的方法，其可包括向樣本提供有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物，該樣本包括來自本文所述之癌症的癌細胞。Some embodiments described herein relate to a method for inhibiting the activity of ERK1 and/or ERK2, which may include providing a sample with an effective amount of a compound described herein (for example, a compound of formula (I), or a pharmaceutical Acceptable salt) or a pharmaceutical composition including a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), and the sample includes cancer cells derived from the cancer described herein.
本文所述之一些實施例係關於製造用於抑制ERK1及/或ERK2之活性之藥劑，其係藉由向樣本提供有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物，該樣本包含本文所述之癌症的癌細胞。Some embodiments described herein are related to the manufacture of agents for inhibiting the activity of ERK1 and/or ERK2 by providing a sample with an effective amount of a compound described herein (for example, a compound of formula (I), or a pharmaceutical product thereof). Above acceptable salt) or a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), the sample contains cancer cells of the cancer described herein.
以下更詳細地描述這些及其他實施例。These and other embodiments are described in more detail below.
[相關申請案之交互參照][Cross-reference of related applications]
任何及所有聲明主張國際或國內優先權的申請案，例如在隨本申請案提交的申請書資料表或請求書中聲明者，特此根據37 CFR 1.57及法則4.18及20.6以引用方式併入本文中，包括2019年10月1日提出的美國臨時專利申請案第62/908,736號，其全文係以引用之方式併入本文中。Any and all applications claiming international or domestic priority, such as those declared in the application data sheet or request submitted with this application, are hereby incorporated by reference in accordance with 37 CFR 1.57 and the rules 4.18 and 20.6 , Including U.S. Provisional Patent Application No. 62/908,736 filed on October 1, 2019, the full text of which is incorporated herein by reference.
在某些癌症類型的治療中，ERK抑制可具有治療效應。RAS/MAPK/ERK路徑已顯示可於某些腫瘤中異常活化，其係經由活化RAS及BRAF中的突變，而且此活化已牽涉到某些癌細胞的生長及病理表現。此路徑之組成性活化已在人類癌症中觀察到，而且已與癌細胞增生的高速率相關聯。具有BRAF或RAS突變的腫瘤細胞通常取決於關於生長及存活的改變蛋白質的活性，即經描述為「致癌基因依賴(oncogene addiction)」的現象。經報導，RAS的活化突變在所有癌症中佔了~30%，其中一些諸如胰臟癌及結腸癌分別具有~90%及~50%的突變率。RAS突變已經識別於~15%的黑色素瘤及~30%的NSCLC(非小細胞肺癌)。BRAF體細胞突變已經識別於50至70%的惡性黑色素瘤，其中所有突變係位於激酶域內，且單一取代(V600E)佔80%的突變。在各種人類癌症中亦有活化BRAF突變的記錄，包括結腸直腸癌(~10%)、NSCLC(2至3%)、及甲狀腺癌(~36%)。高突變頻率使得靶向此路徑成為用於癌症療法的策略。因此，在這些疾病中，特別是在晚期難治性疾病中，極需改善的療法來滿足醫療需求。In the treatment of certain cancer types, ERK inhibition can have a therapeutic effect. The RAS/MAPK/ERK pathway has been shown to be abnormally activated in certain tumors through the activation of mutations in RAS and BRAF, and this activation has been involved in the growth and pathological manifestations of certain cancer cells. Constitutive activation of this pathway has been observed in human cancers and has been associated with a high rate of cancer cell proliferation. Tumor cells with BRAF or RAS mutations usually depend on the activity of altered proteins for growth and survival, a phenomenon described as "oncogene addiction." It has been reported that RAS activating mutations account for ~30% of all cancers, some of which, such as pancreatic cancer and colon cancer, have mutation rates of ~90% and ~50%, respectively. RAS mutations have been identified in ~15% of melanomas and ~30% of NSCLC (non-small cell lung cancer). BRAF somatic mutations have been identified in 50 to 70% of malignant melanomas, all of which are located in the kinase domain, and a single substitution (V600E) accounts for 80% of the mutations. There are also records of activated BRAF mutations in various human cancers, including colorectal cancer (~10%), NSCLC (2 to 3%), and thyroid cancer (~36%). The high mutation frequency makes targeting this pathway a strategy for cancer therapy. Therefore, in these diseases, especially in late-stage refractory diseases, there is a great need for improved therapies to meet medical needs.
本文提供可抑制ERKl之激酶活性及/或ERK2之激酶活性的化合物。本文所述之化合物亦可抑制ERKl及ERK2之磷酸化，而因此可係ERK抑制劑(例如，ERK1抑制劑及/或ERK2抑制劑)。除了抑制RSK使ERK磷酸化以外，本文所述之化合物亦可透過雙重機制(經由抑制MEK使ERK磷酸化及活化)有效抑制MAPK傳訊。作為ERK抑制劑，本文所述之化合物可用於改善及/或治療各種癌症，諸如黑色素瘤、胰臟癌、甲狀腺癌、結腸/結腸直腸癌、及肺癌。 定義Provided herein are compounds that can inhibit the kinase activity of ERK1 and/or the kinase activity of ERK2. The compounds described herein can also inhibit the phosphorylation of ERK1 and ERK2, and therefore can be ERK inhibitors (for example, ERK1 inhibitors and/or ERK2 inhibitors). In addition to inhibiting RSK to phosphorylate ERK, the compounds described herein can also effectively inhibit MAPK signaling through a dual mechanism (by inhibiting MEK to phosphorylate and activate ERK). As ERK inhibitors, the compounds described herein can be used to improve and/or treat various cancers, such as melanoma, pancreatic cancer, thyroid cancer, colon/colorectal cancer, and lung cancer. definition
除非另有定義，否則本文中所使用之所有技術及科學用語具有與所屬技術領域中具有通常知識者所共同理解的相同含義。除非另有說明，本文所引用之所有專利、申請案、公開申請案、及其他出版物之全文均以引用之方式併入本文中。若在本文中之用語具有複數個定義，除非另有說明，否則以此節之定義為主。Unless otherwise defined, all technical and scientific terms used in this article have the same meaning as commonly understood by those with ordinary knowledge in the technical field. Unless otherwise stated, the full texts of all patents, applications, published applications, and other publications cited herein are incorporated herein by reference. If the terms in this article have multiple definitions, unless otherwise specified, the definitions in this section shall prevail.
如本文中所使用，任何(多個)「R」基團(諸如但不限於R1
、R2a
、R2b
、R3
、R4a
、R5
、X1
、X2
、X3
、X4
、A1
、及Ar)表示可附接至所指示之原子的取代基。R基可係經取代的或未經取代的。如果將兩個「R」基團描述為「一起(taken together)」，則該等R基團及其等所附接之原子可形成環烷基、環烯基、芳基、雜芳基、或雜環。例如但不限於，如果將NRa
Rb
基團之Ra
及Rb
指示為「一起」，則表示其等係彼此共價鍵結以形成環：
每當基團經描述為「可選地經取代的(optionally substituted)」時，即該基團可以係未經取代的或係經一或多個指示的取代基取代的。同樣，當基團經描述為「未經取代或經取代的(unsubstituted or substituted)」時，若經取代，則(多個)取代基可選自一或多個指示的取代基。若沒有指示取代基，則表示所指示的「可選地經取代的(optionally substituted)」或「經取代的(substituted)」基團可經一或多個個別地且獨立地選自下列的基團取代：烷基、烯基、炔基、環烷基、環烯基、醯基烷基、羥基、烷氧基、烷氧基烷基、胺基烷基、胺基酸、芳基、雜芳基、雜環基、芳基(烷基)、雜芳基(烷基)、雜環基(烷基)、羥烷基、醯基、氰基、鹵素、硫羰基、O-胺甲醯基、N‑胺甲醯基、O‑胺硫甲醯基、N‑胺硫甲醯基、C‑醯胺基、N‑醯胺基、S-磺醯胺基、N‑磺醯胺基、C‑羧基、O‑羧基、異氰酸基、硫氰基、異硫氰基、疊氮基、硝基、矽基、次磺醯基、亞磺醯基、磺醯基、鹵烷基、鹵烷氧基、三鹵甲烷磺醯基、三鹵甲烷磺醯胺基、胺基、經單取代的胺基、及經二取代的胺基。Whenever a group is described as "optionally substituted," that is, the group can be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "unsubstituted or substituted", if substituted, the substituent(s) can be selected from one or more of the indicated substituents. If no substituent is indicated, it means that the indicated "optionally substituted" or "substituted" group can be individually and independently selected from the following groups by one or more Group substitution: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acylalkyl, hydroxy, alkoxy, alkoxyalkyl, aminoalkyl, amino acid, aryl, hetero Aryl, heterocyclic, aryl (alkyl), heteroaryl (alkyl), heterocyclic (alkyl), hydroxyalkyl, cyano, cyano, halogen, thiocarbonyl, O-aminomethyl Group, N-carboxamide, O‑carboxamide, N‑carboxamide, C‑carboxamide, N‑carboxamide, S-carboxamide, N‑carboxamide , C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, azide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl , Haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonyl, amine, monosubstituted amine, and disubstituted amine.
如本文中所使用，「Ca 至Cb 」(其中「a」及「b」係整數)係指烷基、烯基、或炔基中的碳原子數目，或是環烷基、環烯基、芳基、雜芳基、或雜脂環基之環中的碳原子數目。亦即，烷基、烯基、炔基、環烷基之(多個)環、環烯基之(多個)環、芳基之(多個)環、雜芳基之(多個)環、或雜脂環基之(多個)環可含有「a」至「b」個(含)碳原子。因此，「C1 至C4 烷基」係指所有具有1至4個碳之烷基，亦即CH3 -、CH3 CH2 -、CH3 CH2 CH2 -、(CH3 )2 CH-、CH3 CH2 CH2 CH2 -、CH3 CH2 CH(CH3 )-、及(CH3 )3 C-。如果未針對烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、或雜脂環基指定「a」及「b」，則假定此等定義中所述之最寬廣範圍。As used herein, "C a to C b "(wherein "a" and "b" are integers) refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or cycloalkyl, cycloalkene The number of carbon atoms in the ring of a group, an aryl group, a heteroaryl group, or a heteroalicyclic group. That is, ring(s) of alkyl, alkenyl, alkynyl, cycloalkyl, ring(s) of cycloalkenyl, ring(s) of aryl, ring(s) of heteroaryl , Or the ring(s) of the heteroalicyclic group may contain "a" to "b" (inclusive) carbon atoms. Therefore, "C 1 to C 4 alkyl group" refers to all alkyl groups having 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH -, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )-, and (CH 3 ) 3 C-. If "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heteroalicyclic group, then it is assumed that those mentioned in these definitions The widest range.
如本文中所使用，「烷基(alkyl)」係指包含完全飽和(無雙鍵或三鍵)烴基之直鏈或支鏈烴鏈。烷基可具有1至20個碳原子(每當出現於本文中時，諸如「1至20」之數值範圍係指該給定範圍內之各個整數；例如，「1至20個碳原子」意謂烷基可由1個碳原子、2個碳原子、3個碳原子等，至多且包括20個碳原子組成，但當前定義亦涵蓋未指定數值範圍情况下出現之用語「烷基」)。烷基亦可係具有1至10個碳原子之中等大小烷基。烷基亦可係具有1至6個碳原子之低級烷基。化合物之烷基可指定為「C1 -C4 烷基」或類似名稱。僅舉實例而言，「C1 -C4 烷基」指示，在烷基鏈中有一至四個碳原子，亦即，烷基鏈係選自甲基、乙基、丙基、異丙基、正丁基、異丁基、二級丁基、及三級丁基。一般烷基包括但絕對不限於甲基、乙基、丙基、異丙基、丁基、異丁基、三級丁基、戊基、及己基。烷基可係經取代的或未經取代的。As used herein, "alkyl" refers to a straight or branched hydrocarbon chain containing a fully saturated (no double or triple bond) hydrocarbon group. Alkyl groups may have 1 to 20 carbon atoms (whenever appearing herein, a numerical range such as "1 to 20" refers to each integer within the given range; for example, "1 to 20 carbon atoms" means It is said that an alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but the current definition also covers the term "alkyl" when the numerical range is not specified). The alkyl group may also be an alkyl group having an equal size among 1 to 10 carbon atoms. The alkyl group may also be a lower alkyl group having 1 to 6 carbon atoms. The alkyl group of the compound can be designated as "C 1 -C 4 alkyl" or similar names. For example only, "C 1 -C 4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, that is, the alkyl chain is selected from methyl, ethyl, propyl, isopropyl , N-butyl, isobutyl, secondary butyl, and tertiary butyl. General alkyl groups include, but are definitely not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.
如本文中所使用，「烯基(alkenyl)」係指在直鏈或支鏈烴鏈中含有一或多個雙鍵之烷基。烯基之實例包括丙二烯基、乙烯甲基、及乙烯基。烯基可係未經取代的或經取代的。As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. Examples of alkenyl groups include allenyl, vinylmethyl, and vinyl. Alkenyl groups can be unsubstituted or substituted.
如本文中所使用，「炔基(alkynyl)」係指在直鏈或支鏈烴鏈中含有一或多個三鍵之烷基。炔基之實例包括乙炔基及丙炔基。炔基可係未經取代的或經取代的。As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. Examples of alkynyl groups include ethynyl and propynyl. Alkynyl groups can be unsubstituted or substituted.
如本文中所使用，「環烷基(cycloalkyl)」係指完全飽和的(無雙鍵或三鍵)單環或多環烴環系統。當由二或更多個環構成時，環可以稠合方式連接在一起。環烷基可在(多個)環中含有3至10個原子，或在(多個)環中含有3至8個原子。環烷基可係未經取代的或經取代的。一般環烷基包括但不限於環丙基、環丁基、環戊基、環己基、環庚基、環辛基、雙環[1.1.1]戊烷、雙環[2.1.1]庚烷、金剛烷基、及降莰基。As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bond) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be connected together in a fused manner. Cycloalkyl groups may contain 3 to 10 atoms in the ring(s), or 3 to 8 atoms in the ring(s). Cycloalkyl groups can be unsubstituted or substituted. General cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentane, bicyclo[2.1.1]heptane, diamond Alkyl, and norbornyl.
如本文中所使用，「環烯基(cycloalkenyl)」係指在至少一個環中含有一或多個雙鍵之單環或多環烴環系統；但是，若存在多於一個，則雙鍵不能在所有環中形成完全離域的π電子系統(否則該基團會如本文中所定義為「芳基」)。環烯基可在(多個)環中含有3至10個原子，或在(多個)環中含有3至8個原子。當由二或更多個環構成時，環可以稠合方式連接在一起。環烯基可係未經取代的或經取代的。As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one is present, the double bond cannot A completely delocalized π-electron system is formed in all rings (otherwise the group will be defined as "aryl" as defined herein). The cycloalkenyl group may contain 3 to 10 atoms in the ring(s), or 3 to 8 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused manner. Cycloalkenyl can be unsubstituted or substituted.
如本文中所使用，「芳基(aryl)」係指碳環(全碳)單環或多環芳環系統(包括兩個碳環共用化學鍵之稠合環系統)，其在所有環中具有完全離域的π電子系統。芳基中的碳原子數目可有所變化。例如，芳基可以係C6 -C14 芳基、C6 -C10 芳基、或C6 芳基。芳基的實例包括但不限於苯、萘、及薁。芳基可係經取代的或未經取代的。As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including a fused ring system in which two carbon rings share a chemical bond), which has A completely delocalized π-electron system. The number of carbon atoms in the aryl group can vary. For example, the aryl group may be a C 6 -C 14 aryl group, a C 6 -C 10 aryl group, or a C 6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups can be substituted or unsubstituted.
如本文中所使用，「雜芳基(heteroaryl)」係指單環或多環芳環系統(具有完全離域的π電子系統之環系統)，其含有一、二、三、或多個雜原子，亦即除碳之外的元素，包括但不限於氮、氧、及硫。雜芳基之(多個)環中的原子數目可有所變化。例如，雜芳基可在(多個)環中含有4至14個原子、在(多個)環中含有5至10個原子、或在(多個)環中含有5至6個原子。此外，用語「雜芳基(heteroaryl)」包括稠合環系統，其中兩個環(諸如至少一個芳基環及至少一個雜芳基環、或至少兩個雜芳基環)共用至少一個化學鍵。雜芳基環之實例包括但不限於本文中所述者以及下列者：呋喃、呋呫、噻吩、苯并噻吩、呔
如本文中所使用，「雜環基(heterocyclyl)」或「雜脂環基(heteroalicyclyl)」係指三、四、五、六、七、八、九、十、至多18員單環、雙環、及三環環系統，其中碳原子與1至5個雜原子一起構成該環系統。雜環可以可選地含有一或多個以這種方式定位之不飽和鍵，然而，完全離域的π電子系統不會發生在所有環中。(多個)雜原子係除碳以外的元素，包括但不限於氧、硫、及氮。雜環可進一步含有一或多個羰基或硫羰基官能性，以使定義包括側氧基系統及硫基系統，諸如內醯胺、內酯、環狀醯亞胺、環狀硫醯亞胺、及環狀胺甲酸酯。當由二或更多個環構成時，環可以稠合方式連接在一起。此外，雜環基中之任何氮可為四級銨化的。雜環基或雜脂環基團可係未經取代的或經取代的。此類「雜環基」或「雜脂環基」基團之實例包括但不限於本文中所述者以及下列者：1,3-戴奧辛、1,3-二
如本文中所使用，「芳烷基(aralkyl)」及「芳基(烷基) (aryl(alkyl))」係指經由低級伸烷基連接作為取代基之芳基。芳烷基之低級伸烷基及芳基可係經取代的或未經取代的。實例包括但不限於苄基、2-苯基烷基、3-苯基烷基、及萘基烷基。As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group connected as a substituent via a lower alkylene group. The lower alkylene and aryl groups of the aralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.
如本文中所使用，「雜芳烷基(heteroaralkyl)」及「雜芳基(烷基) (heteroaryl(alkyl))」係指經由低級伸烷基連接作為取代基之雜芳基。雜芳烷基之低級伸烷基及雜芳基可係經取代的或未經取代的。實例包括但不限於2-噻吩基烷基、3-噻吩基烷基、呋喃基烷基、噻吩基烷基、吡咯基烷基、吡啶基烷基、異㗁唑基烷基、咪唑基烷基、及其苯并稠合類似物。As used herein, "heteroaralkyl" and "heteroaryl (alkyl)" refer to a heteroaryl group connected as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of the heteroaralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl , And its benzo-fused analogs.
「雜脂環基(烷基) (heteroalicyclyl(alkyl))」及「雜環基(烷基) (heterocyclyl(alkyl))」係指經由低級伸烷基連接作為取代基之雜環基或雜脂環基。雜脂環基(烷基)之低級伸烷基及雜環基可係經取代的或未經取代的。實例包括但不限於四氫-2H-哌喃-4-基(甲基)、哌啶-4-基(乙基)、哌啶-4-基(丙基)、四氫-2H-噻喃-4-基(甲基)、及1,3-噻嗪-4-基(甲基) (1,3-thiazinan-4-yl(methyl))。"Heteroalicyclyl (alkyl)" and "heterocyclyl (alkyl)" refer to a heterocyclic group or heteroaliphatic group connected as a substituent via a lower alkylene group Ring base. The lower alkylene and heterocyclic groups of the heteroalicyclic group (alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-piperan-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiopyran -4-yl (methyl), and 1,3-thiazinan-4-yl (methyl) (1,3-thiazinan-4-yl(methyl)).
「低級伸烷基(lower alkylene group)」係形成鍵以經由其末端碳原子連接分子片段的直鏈-CH2 -繫鏈基團(tethering group)。實例包括但不限於亞甲基(-CH2 -)、伸乙基(-CH2 CH2 -)、伸丙基(-CH2 CH2 CH2 -)、及伸丁基(-CH2 CH2 CH2 CH2 -)。低級伸烷基可藉由以「經取代的(substituted)」的定義所列出的(多個)取代基，置換該低級伸烷基中之一或多個氫來取代。 The "lower alkylene group" is a linear -CH 2 -tethering group that forms a bond to connect molecular fragments via its terminal carbon atom. Examples include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), and ethylene (-CH 2 CH 2 CH 2 CH 2 -). The lower alkylene group can be substituted by replacing one or more hydrogens in the lower alkylene group with the substituent(s) listed in the definition of "substituted".
如本文中所使用，「烷氧基(alkoxy)」係指式–OR，其中R係本文中所定義之烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。烷氧基之非限制性列表係甲氧基、乙氧基、正丙氧基、1-甲基乙氧基(異丙氧基)、正丁氧基、異丁氧基、二級丁氧基、三級丁氧基、苯氧基、及苄醯氧基。烷氧基可係經取代的或未經取代的。As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl as defined herein Group, heterocyclic group, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). A non-limiting list of alkoxy groups is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, secondary butoxy Group, tertiary butoxy, phenoxy, and benzyloxy. The alkoxy group may be substituted or unsubstituted.
如本文中所使用，「醯基(acyl)」係指經由羰基連接作為取代基之氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。實例包括甲醯基、乙醯基、丙醯基、苄醯基、及丙烯醯基。醯基可係經取代的或未經取代的。As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic group attached as a substituent via a carbonyl group Group, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). Examples include formyl, acetyl, propyl, benzyl, and acryl. The acyl group can be substituted or unsubstituted.
如本文中所使用，「醯基烷基(acylalkyl)」係指經由低級伸烷基連接作為取代基之醯基。實例包括芳基-C(=O)-(CH2 )n -及雜芳基-C(=O)-(CH2 )n -，其中n係在1至6之範圍中之整數。As used herein, "acylalkyl" refers to an acylalkyl group connected as a substituent via a lower alkylene group. Examples include aryl-C(=O)-(CH 2 ) n -and heteroaryl-C(=O)-(CH 2 ) n -, where n is an integer in the range of 1 to 6.
如本文中所使用，「烷氧基烷基(alkoxyalkyl)」係指經由低級伸烷基連接作為取代基之烷氧基。實例包括C1-4 烷基-O-(CH2 )n -，其中n係在1至6之範圍中之整數。As used herein, "alkoxyalkyl" refers to an alkoxy group connected as a substituent via a lower alkylene group. Examples include C 1-4 alkyl-O-(CH 2 ) n -, where n is an integer in the range of 1 to 6.
如本文中所使用，「胺基烷基(aminoalkyl)」係指經由低級伸烷基連接作為取代基之可選地經取代的胺基。實例包括H2 N(CH2 )n -，其中n係在1至6之範圍中之整數。As used herein, "aminoalkyl" refers to an optionally substituted amino group linked as a substituent via a lower alkylene group. Examples include H 2 N(CH 2 ) n -, where n is an integer in the range of 1 to 6.
如本文中所使用，「羥烷基(hydroxyalkyl)」係指其中一或多個氫原子經羥基置換的烷基。例示性羥烷基包括但不限於2-羥乙基、3-羥丙基、2-羥丙基、及2,2-二羥乙基。羥烷基可係經取代的或未經取代的。As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl groups can be substituted or unsubstituted.
如本文中所使用，「鹵烷基(haloalky)」係指其中一或多個氫原子經鹵素置換的烷基(例如，單鹵烷基、二鹵烷基、及三鹵烷基)。此類基團包括但不限於氯甲基、氟甲基、二氟甲基、三氟甲基、氯基-氟烷基、氯基-二氟烷基、及2-氟異丁基。鹵烷基可係經取代的或未經取代的。As used herein, "haloalky" refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen (eg, monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl, and 2-fluoroisobutyl. The haloalkyl group can be substituted or unsubstituted.
如本文中所使用，「鹵烷氧基(haloalkoxy)」係指其中一或多個氫原子經鹵素置換的烷氧基(例如，單鹵烷氧基、二鹵烷氧基、及三鹵烷氧基)。此類基團包括但不限於氯甲氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、氯基-氟烷基、氯基-二氟烷氧基、及2-氟異丁氧基。鹵烷氧基可係經取代的或未經取代的。As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Oxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloro-fluoroalkyl, chloro-difluoroalkoxy, and 2-fluoro Isobutoxy. The haloalkoxy group may be substituted or unsubstituted.
「次磺醯基(sulfenyl)」基團係指「‑SR」基團，其中R可係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。次磺醯基可係經取代的或未經取代的。The "sulfenyl" group refers to the "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, Heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl). The sulfenyl group may be substituted or unsubstituted.
「亞磺醯基(sulfinyl)」基團係指「‑S(=O)‑R」基團，其中R可係與關於次磺醯基所定義者相同。亞磺醯基可係經取代的或未經取代的。The "sulfinyl" group refers to the "-S(=O)-R" group, where R may be the same as defined for the sulfinyl group. The sulfinyl group may be substituted or unsubstituted.
「磺醯基(sulfonyl)」係指「SO2 R」基團，其中R可與關於次磺醯基所定義者相同。磺醯基可係經取代的或未經取代的。"Sulfonyl" refers to the "SO 2 R" group, where R may be the same as defined for sulfonyl. The sulfonyl group may be substituted or unsubstituted.
「O-羧基(O‑carboxy)」基團係指「RC(=O)O-」基團，其中R可係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)，如本文中所定義。O-羧基可係經取代的或未經取代的。"O-carboxy" group refers to "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic Group, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl), as defined herein. The O-carboxy group may be substituted or unsubstituted.
用語「酯(ester)」及「C‑羧基(C-carboxy)」係指「‑C(=O)OR」基團，其中R可與關於O-羧基所定義者相同。酯及C-羧基可係經取代的或未經取代的。The terms "ester" and "C-carboxy" refer to the "-C(=O)OR" group, where R can be the same as defined for O-carboxy. The ester and C-carboxy group may be substituted or unsubstituted.
「硫羰基(thiocarbonyl)」係指「‑C(=S)R」基團，其中R可與關於O-羧基所定義者相同。硫羰基可係經取代的或未經取代的。"Thiocarbonyl" refers to the "-C(=S)R" group, where R can be the same as defined for O-carboxy. The thiocarbonyl group may be substituted or unsubstituted.
「三鹵甲烷磺醯基(trihalomethanesulfonyl)」係指「X3 CSO2 ‑」基團，其中各X係鹵素。"Trihalomethanesulfonyl" refers to the "X 3 CSO 2 ‑" group, where each X is a halogen.
「三鹵甲烷磺醯胺基(trihalomethanesulfonamido)」基團係指「X3 CS(O)2 N(RA )-」基團，其中各X係鹵素，且RA 係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。"Sulfonic group trihalomethanes (trihalomethanesulfonamido)" refers to the group "X 3 CS (O) 2 N (R A) - " group, wherein each X is a halogen-based, and R A-based hydrogen, alkyl, alkenyl, Group, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic Group (alkyl).
如本文中所使用，用語「胺基(amino)」係指–NH2 基團。As used herein, the term "amino" refers to the -NH 2 group.
如本文中所使用，用語「羥基(hydroxy)」係指–OH基團。As used herein, the term "hydroxy" refers to the -OH group.
「氰基(cyano)」係指「‑CN」基團。"Cyano" refers to the "-CN" group.
如本文中所使用，用語「疊氮基(azido)」係指–N3 基團。As used herein, the term "azido" refers to the -N 3 group.
「異氰酸基(isocyanato)」係指「‑NCO」基團。"Isocyanato" refers to the "‑NCO" group.
「氰硫基(thiocyanato)」係指「‑CNS」基團。"Thiocyanato" refers to the "-CNS" group.
「異硫氰基(isothiocyanato)」係指「-NCS」基團。"Isothiocyanato" refers to the "-NCS" group.
「羰基(carbonyl)」係指C=O基團。"Carbonyl (carbonyl)" refers to a C=O group.
「S-磺醯胺基(S‑sulfonamido)」係指「‑SO2 N(RA RB )」基團，其中RA 及RB 可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。S‑磺醯胺基可係經取代的或未經取代的。"Sulfonic group S- (S-sulfonamido)" means "-SO 2 N (R A R B ) " group, wherein R A and R B is independently hydrogen-based, alkyl, alkenyl, alkynyl , Cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl) ). The S-sulfonamide group can be substituted or unsubstituted.
「N-磺醯胺基(N‑sulfonamido)」係指「RSO2 N(RA )‑」基團，其中R及RA 可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。N‑磺醯胺基可係經取代的或未經取代的。"Sulfonic amine N- (N-sulfonamido)" means "RSO 2 N (R A) -" group, wherein R A and R may independently be based hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl Group, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). The N-sulfonamide group can be substituted or unsubstituted.
「O-胺甲醯基(O‑carbamyl)」係指「‑OC(=O)N(RA RB )」基團，其中RA 及RB 可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。O‑胺甲醯基可係經取代的或未經取代的。"Carbamoyl acyl O- (O-carbamyl)" means "-OC (= O) N (R A R B) " group, wherein R A and R B is independently hydrogen-based, alkyl, alkenyl, , Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl). The O-aminomethanyl group can be substituted or unsubstituted.
「N-胺甲醯基(N‑carbamyl)」係指「ROC(=O)N(RA )‑」基團，其中R及RA 可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。N‑胺甲醯基可係經取代的或未經取代的。"Acyl N- methyl amine (N-carbamyl)" means "ROC (= O) N (R A) - " group, wherein R and R A is independently hydrogen-based, an alkyl group, alkenyl group, alkynyl group , Cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl) ). The N-aminomethanyl group can be substituted or unsubstituted.
「O-胺硫甲醯基(O‑thiocarbamyl)」係指「‑OC(=S)‑N(RA RB )」基團，其中RA 及RB 可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。O‑胺硫甲醯基可係經取代的或未經取代的。"O- acyl amine thiomethyl (O-thiocarbamyl)" means "-OC (= S) -N (R A R B) " group, wherein R A and R B is independently hydrogen-based, an alkyl group, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or hetero Cyclic (alkyl). The O-aminothiomethionyl group can be substituted or unsubstituted.
「N-胺硫甲醯基(N‑thiocarbamyl)」係指「ROC(=S)N(RA )‑」基團，其中R及RA 可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。N‑胺硫甲醯基可係經取代的或未經取代的。"Thiomethyl acyl amine N- (N-thiocarbamyl)" means "ROC (= S) N (R A) - " group, wherein R A and R may independently be based hydrogen, alkyl, alkenyl, alkynyl, Group, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclyl (alkyl) base). The N-aminothiomethionyl group can be substituted or unsubstituted.
「C-醯胺基(C‑amido)」係指「‑C(=O)N(RA RB )」基團，其中RA 及RB 可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。C‑醯胺基可係經取代的或未經取代的。"Amino acyl C- (C-amido)" means "-C (= O) N (R A R B) " group, wherein R A and R B is independently hydrogen-based, alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclyl ( alkyl). The C-amino group can be substituted or unsubstituted.
「N-醯胺基(N‑amido)」係指「RC(=O)N(RA )‑」基團，其中R及RA 可獨立地係氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、環烷基(烷基)、芳基(烷基)、雜芳基(烷基)、或雜環基(烷基)。N‑醯胺基可係經取代的或未經取代的。"Acyl amine N- (N-amido)" means "RC (= O) N (R A) - " group, wherein R and R A is independently hydrogen-based, an alkyl group, alkenyl group, alkynyl group, Cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl) . The N-amino group can be substituted or unsubstituted.
如本文中所使用之用語「鹵素原子(halogen atom)」或「鹵素(halogen)」意指元素周期表第7欄之任一種放射穩定原子，諸如氟、氯、溴、及碘。The term "halogen atom" or "halogen" as used herein means any radio-stable atom in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.
如本文中所使用，除非另有說明，「------ 」指示單鍵或雙鍵。As used herein, unless otherwise specified, " ------ " indicates a single bond or a double bond.
當未指定取代基的數目(例如，鹵烷基)時，則可能有一或多個取代基存在。例如，「鹵烷基(haloalkyl)」可包括一或多個相同或不同的鹵素。作為另一個實例，「C1 -C3 烷氧基苯基(C1 -C3 alkoxyphenyl)」可包括一或多個相同或不同之含有一、二、或三個原子的烷氧基。When the number of substituents (e.g., haloalkyl) is not specified, one or more substituents may be present. For example, "haloalkyl" can include one or more halogens that are the same or different. As another example, "C 1 -C 3 alkoxy, phenyl (C 1 -C 3 alkoxyphenyl)" may include one or more of the same or different, containing one, two, three atoms, or alkoxy.
如本文中所使用，除非另有說明，用於任何保護基、胺基酸及其他化合物的縮寫係根據其常見使用、公認縮寫、或IUPAC-IUB生物化學命名委員會(IUPAC-IUB Commission on Biochemical Nomenclature)(參見Biochem. 11:942-944 (1972))。As used herein, unless otherwise specified, the abbreviations used for any protecting groups, amino acids, and other compounds are based on their common usage, recognized abbreviations, or IUPAC-IUB Commission on Biochemical Nomenclature (IUPAC-IUB Commission on Biochemical Nomenclature ) (See Biochem. 11:942-944 (1972)).
如本文中所使用之用語「保護基(protecting group)」係指添加至分子以防止分子中的現存基團經歷非所要的化學反應之任何原子或原子基團。保護基部分之實例係描述於T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis
, 3.Ed. John Wiley & Sons, 1999及J.F.W. McOmie,Protective Groups in Organic Chemistry
Plenum Press, 1973，兩者皆特此以引用方式併入本文中，以達揭示合適保護基的限定目的。保護基部份可經選擇以使得彼等對某些反應條件穩定且易於在方便階段使用該領域已知之方法移除。保護基之非限制性列表包括苄基；經取代的苄基；烷基羰基及烷氧基羰基(例如，三級丁氧羰基(t‑butoxycarbonyl, BOC)、乙醯基、或異丁醯基)；芳基烷基羰基及芳基烷氧基羰基(例如，苄氧基羰基)；經取代的甲基醚(例如，甲氧基甲基醚)；經取代的乙基醚；經取代的苄基醚；四氫呋喃基醚；矽基(例如，三甲基矽基、三乙基矽基、三異丙基矽基、三級丁基二甲基矽基、三異丙基矽基氧基甲基、[2-(三甲基矽基)乙氧基]甲基、或三級丁基二苯基矽基)；酯(例如苯甲酸酯)；碳酸酯(例如甲氧基甲基碳酸酯)；磺酸酯(例如甲苯磺酸酯或甲磺酸酯)；非環狀縮酮(例如二甲基縮醛)；環狀縮酮(例如1,3-二
如本文中所使用，用語「脫離基(leaving group)」係指能夠在化學反應中經另一種原子或部分置換的任何原子或部分。更具體而言，在一些實施例中，「脫離基」係指在親核取代反應中經置換的原子或部分。在一些實施例中，「脫離基」係強酸的共軛鹼之任何原子或部分。合適的脫離基之實例包括但不限於甲苯磺酸酯、甲磺酸酯、三氟乙酸酯、及鹵素(例如，I、Br、及Cl)。脫離基的非限制性特徵與實例可見於例如Organic Chemistry , 2d ed., Francis Carey (1992), pages 328-331；Introduction to Organic Chemistry , 2d ed., Andrew Streitwieser and Clayton Heathcock (1981), pages 169-171；及Organic Chemistry , 5th ed., John McMurry (2000), pages 398 and 408；以上全部皆以引用方式併入本文中，以達揭示脫離基特徵與實例的限定目的。As used herein, the term "leaving group" refers to any atom or part that can be replaced by another atom or part in a chemical reaction. More specifically, in some embodiments, the "leaving group" refers to an atom or moiety that is replaced in a nucleophilic substitution reaction. In some embodiments, the "leaving group" is any atom or part of the conjugate base of a strong acid. Examples of suitable leaving groups include, but are not limited to, tosylate, mesylate, trifluoroacetate, and halogens (e.g., I, Br, and Cl). Non-limiting features and examples of free radicals can be found in, for example, Organic Chemistry , 2d ed., Francis Carey (1992), pages 328-331; Introduction to Organic Chemistry , 2d ed., Andrew Streitwieser and Clayton Heathcock (1981), pages 169 -171; and Organic Chemistry , 5 th ed., John McMurry (2000), pages 398 and 408; all of the above are incorporated into this article by reference for the purpose of revealing the limited purpose of deviating from the basic features and examples.
用語「醫藥上可接受之鹽(pharmaceutically acceptable salt)」係指不會對其所投予至之生物體造成顯著刺激且不會使化合物之生物活性及性質無效化的化合物之鹽。在一些實施例中，鹽係化合物之酸加成鹽。醫藥鹽可藉由使化合物與無機酸反應而獲得，無機酸諸如氫鹵酸(例如，氫氯酸或氫溴酸)、硫酸、硝酸、及磷酸。醫藥鹽亦可藉由使化合物與有機酸反應而獲得，該有機酸諸如脂族或芳族羧酸或磺酸，例如甲酸、乙酸、琥珀酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、菸鹼酸、甲磺酸、乙磺酸、對甲苯磺酸、水楊酸、或萘磺酸。醫藥鹽亦可藉由使化合物與鹼反應以形成鹽而獲得，該鹽諸如胺鹽、鹼金屬鹽(諸如鈉鹽或鉀鹽)、鹼土金屬鹽(諸如鈣或鎂鹽)、有機鹼(諸如二環己基胺、N-甲基-D-還原葡萄糖胺、參(羥甲基)甲基胺、C1 -C7 烷基胺、環己基胺、三乙醇胺、乙二胺)之鹽、及與胺基酸(諸如精胺酸及離胺酸)之鹽。The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not invalidate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting compounds with inorganic acids, such as hydrohalic acid (for example, hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting compounds with organic acids, such as aliphatic or aromatic carboxylic acids or sulfonic acids, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, Nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as amine salt, alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as calcium or magnesium salt), organic base (such as Dicyclohexylamine, N-methyl-D-reduced glucosamine, ginseng (hydroxymethyl) methylamine, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine) salt, and Salts with amino acids (such as arginine and lysine).
除非另有明確說明，否則本申請案中所使用之用語、及片語、及其變化(尤其在隨附申請專利範圍中)應解讀為開放式的而非限制性的。作為前述之實例，用語「包括(including)」應解讀為意指「包括但不限於(including, without limitation/including but not limited to)」或類似者；如本文中所使用之用語「包含(comprising)」與「包括(including)」、「含有(containing)」、或「其特徵為(characterized by)」係同義詞，且係包含式或開放式且不排除額外、未列舉之元件或方法步驟；用語「具有(having)」應解讀為「至少具有(having at least)」；用語「包括(include)」應解讀為「包括但不限於」；用語「實例(example)」係用於提供討論項目之例示性例子而非其詳盡或限制性列表；且用語如「較佳地(preferably)」、「較佳的(preferred)」、或「所欲(desired/desirable)」及類似意義文字的使用，不應理解為暗示某些特徵對於結構或功能而言係關鍵、必要、甚或重要的，反而只是意圖強調可在一具體實施例中利用或不利用之替代或額外特徵。此外，用語「包含(comprising)」應與片語「至少具有(having at least)」或「至少包括(including at least)」同義地解釋。當用於製程之上下文中時，用語「包含(comprising)」意指製程包括至少列舉之步驟，但可包括額外步驟。當用於化合物、組成物、或裝置之上下文中時，用語「包含」意指化合物、組成物、或裝置至少包括所列舉特徵或組分，但亦可包括額外特徵或組分。同樣地，除了申請專利範圍以外，不應將以連接詞「及(and)」連接之一群項目解讀為每一個該些項目皆必需存在於該群組中，反而應解讀為「及/或(and/or)」，除非另有明確說明。類似地，除了申請專利範圍以外，不應將以連接詞「或(or)」連接之一群項目解讀為該群組之中必需有互相排他性，反而應解讀為「及/或(and/or)」，除非另有明確說明。Unless explicitly stated otherwise, the terms and phrases used in this application, and their variations (especially in the scope of the attached application), should be interpreted as open-ended rather than restrictive. As an example of the foregoing, the term "including" should be interpreted as meaning "including, without limitation/including but not limited to" or the like; as used herein, the term "comprising" )" and "including", "containing", or "characterized by" are synonymous, and are inclusive or open-ended and do not exclude additional, unlisted elements or method steps; The term "having" should be read as "having at least"; the term "include" should be read as "including but not limited to"; the term "example" is used to provide discussion items Illustrative examples rather than an exhaustive or restrictive list; and the use of terms such as "preferably", "preferred", or "desired/desirable" and similar meanings It should not be understood as implying that certain features are critical, necessary, or even important to the structure or function, but only intended to emphasize alternative or additional features that can be used or not used in a specific embodiment. In addition, the term "comprising" should be interpreted synonymously with the phrase "having at least" or "including at least". When used in the context of a manufacturing process, the term "comprising" means that the manufacturing process includes at least the listed steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the listed features or components, but may also include additional features or components. Similarly, in addition to the scope of the patent application, a group of items connected with the conjunction "and (and)" should not be interpreted as each of these items must exist in the group, but should be interpreted as "and/or ( and/or)" unless expressly stated otherwise. Similarly, in addition to the scope of the patent application, a group of items connected by the conjunction "or (or)" should not be interpreted as that the group must be mutually exclusive. Instead, it should be interpreted as "and/or (and/or) ", unless expressly stated otherwise.
關於在本文中使用實質上任何複數及/或單數用語，所屬技術領域中具有通常知識者可視適合上下文及/或應用之情況，從複數轉換成單數及/或從單數轉換成複數。各種單數/複數排列組合可在本文中明確闡述以求清晰。不定冠詞「一(a或an)」並不排除複數。在互不相同的附屬項中列舉某些措施的單純事實，並不表示這些措施之組合無法有益地使用。Regarding the use of substantially any plural and/or singular terms in this article, those with ordinary knowledge in the relevant technical field may convert the plural to the singular and/or from the singular to the plural as appropriate to the context and/or application. Various singular/plural permutations and combinations can be clearly stated in this article for clarity. The indefinite article "一 (a or an)" does not exclude the plural. The mere fact that certain measures are listed in different subsidiary items does not mean that the combination of these measures cannot be used beneficially.
應理解，在本文所述之具有一或多個掌性中心之任何化合物中，若未明確指示絕對立體化學，則各中心可獨立地具有R-組態、或S-組態、或其混合物。因此，本文中所提供之化合物可係鏡像異構地純的、鏡像異構地富集的外消旋混合物、非鏡像異構地純的、非鏡像異構地富集的、或立體異構的混合物。此外，應當理解，在具有一或多個雙鍵產生幾何異構物(可定義為E或Z)之任何本文中所述化合物中，各雙鍵可獨立地係E或Z或其混合物。It should be understood that in any compound having one or more palm centers described herein, if the absolute stereochemistry is not clearly indicated, each center may independently have an R-configuration, or an S-configuration, or a mixture thereof . Therefore, the compounds provided herein can be a racemic mixture that is enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched, or stereoisomeric. mixture. In addition, it should be understood that in any of the compounds described herein that have one or more double bonds that give rise to geometric isomers (which can be defined as E or Z), each double bond can independently be E or Z or a mixture thereof.
同樣地，應理解，在任何所述化合物中，亦意欲將所有互變異構形式包括在內。Likewise, it should be understood that in any of the compounds described, it is also intended to include all tautomeric forms.
應理解，在本文中揭示之化合物具有未填滿價數時，則價數應以氫或其同位素填滿，例如氫-1(氕)及氫-2(氘)。It should be understood that when the compound disclosed herein has an unfilled valence, the valence should be filled with hydrogen or its isotopes, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).
應理解，本文所述之化合物可經同位素標示。以諸如氘之同位素取代可得到由較高代謝穩定性帶來的某些治療優點，例如體內半衰期增長或劑量需求降低。在化合物結構中表示之各化學元素可包括該元素之任何同位素。例如，在化合物結構中，氫原子可明確揭示或理解成存在於化合物中。在化合物之可能存在氫原子的任何位置處，氫原子可為氫之任何同位素，包括但不限於氫-1(氕)及氫-2(氘)。因此，在本文中參照之化合物涵蓋所有潛在同位素形式，除非上下文清楚另行表明。It should be understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium can obtain certain therapeutic advantages brought about by higher metabolic stability, such as increased in vivo half-life or decreased dosage requirements. Each chemical element represented in the structure of the compound may include any isotope of the element. For example, in the structure of a compound, a hydrogen atom can be clearly disclosed or understood as being present in the compound. At any position where a hydrogen atom may be present in the compound, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, the compounds referenced herein encompass all potential isotopic forms unless the context clearly indicates otherwise.
應理解，本文所述之方法及組合包括晶形(亦稱為多形體，其包括化合物之相同元素組成之不同晶體堆積排列)、非晶相、鹽、溶劑合物、及水合物。在一些實施例中，本文所述之化合物以與醫藥上可接受之溶劑(諸如水、乙醇、或類似溶劑)之溶劑合物形式存在。在其他實施例中，本文描述之化合物以非溶劑合物形式存在。溶劑合物含有化學計量或非化學計量之量的溶劑，且可與醫藥上可接受的溶劑(例如水、乙醇、或類似物)在結晶製程期間形成。當溶劑係水時即形成水合物，當溶劑係醇時即形成醇合物。此外，本文中所提供之化合物可以非溶劑合形式以及溶劑合形式存在。一般而言，針對本文中所提供之化合物及方法的目的，將溶劑合形式視為等同於非溶劑合形式。It should be understood that the methods and combinations described herein include crystalline forms (also called polymorphs, which include different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist as solvates with pharmaceutically acceptable solvents such as water, ethanol, or similar solvents. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain stoichiometric or non-stoichiometric amounts of solvents, and can be formed with pharmaceutically acceptable solvents (such as water, ethanol, or the like) during the crystallization process. When the solvent is water, it forms a hydrate, and when the solvent is an alcohol, it forms an alcoholate. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Generally speaking, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.
當提供數值之範圍時，應理解範圍之上限及下限以及在上限及下限之間的各介入數值皆涵蓋於實施例內。 化合物 式(I)When a range of values is provided, it should be understood that the upper limit and lower limit of the range and the intervening values between the upper limit and the lower limit are all included in the embodiment. Compound Formula (I)
本文所揭示之一些實施例係關於一種式(I)化合物、或其醫藥上可接受之鹽，其具有以下結構：
式(I)化合物、或其醫藥上可接受之鹽的實例包括具有下列通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)、及(Ig)者、或其醫藥上可接受之鹽：
式(I)化合物、或其醫藥上可接受之鹽的其他實例係描述於下文實例中。通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)、及(Ig)中之變項係以與式(I)之對應變項相同的方式定義。除非上下文另有明確指示，否則在本文中提及之式(I)化合物的特徵、或其醫藥上可接受之鹽的特徵，將由所屬技術領域中具有通常知識者理解為適用於通式(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)、及/或(Ig)之化合物的對應特徵、或其醫藥上可接受之鹽的對應特徵(反之亦然)。Other examples of compounds of formula (I), or pharmaceutically acceptable salts thereof, are described in the examples below. The variables in general formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig) are defined in the same way as the corresponding variables in formula (I). Unless the context clearly indicates otherwise, the characteristics of the compound of formula (I) mentioned herein, or the characteristics of a pharmaceutically acceptable salt thereof, will be understood by those with ordinary knowledge in the technical field to be applicable to the general formula (Ia ), (Ib), (Ic), (Id), (Ie), (If), and/or (Ig) the corresponding characteristics of the compound, or the corresponding characteristics of the pharmaceutically acceptable salt thereof (and vice versa) .
在式(I)或其醫藥上可接受之鹽的各種實施例中，環Ar可係苯基。在其他實施例中，環Ar可係吡啶基。在其他實施例中，環Ar可係嘧啶基。吡啶基環及嘧啶基環之(多個)環氮可位於不同位置處，例如式(Ib)及(Ic)、以及下文實例中所述之各種化合物所示。In various embodiments of formula (I) or a pharmaceutically acceptable salt thereof, ring Ar may be a phenyl group. In other embodiments, ring Ar may be pyridyl. In other embodiments, ring Ar may be pyrimidinyl. The ring nitrogen(s) of the pyridyl ring and the pyrimidinyl ring can be located at different positions, as shown in the formulas (Ib) and (Ic), as well as the various compounds described in the examples below.
在式(I)或其醫藥上可接受之鹽的各種實施例中，變項m可係1或2，而因此在一些實施例中，環Ar可經一個R1
基團取代，且在其他實施例中，環Ar可經兩個R1
基團取代。各R1
之位置可有所變化。以下表示其中(多個)R1
基團可存在的實例：
在一些實施例中，R1 可係–OR4A ，其中R4A 可係可選地經取代的烷基或可選地經取代的環烷基。例如，在一實施例中，R4A 可係可選地經取代的烷基，諸如未經取代的烷基或帶有可選取代基的烷基(如本文別處所述)(諸如「可選地經取代的(optionally substituted)」所描述之該等基團)。在一實施例中，R4A 可係未經取代的C1-6 烷基。在一些實施例中，R4A 可係甲基、乙基、正丙基、異丙基、正丁基、二級丁基、異丁基、三級丁基、戊基(支鏈及直鏈)、及己基(支鏈及直鏈改變)。在一些實施例中，R4A 可係甲基。In some embodiments, R 1 may be -OR 4A , where R 4A may be an optionally substituted alkyl group or an optionally substituted cycloalkyl group. For example, in one embodiment, R 4A may be an optionally substituted alkyl group, such as an unsubstituted alkyl group or an alkyl group with optional substituents (as described elsewhere herein) (such as "optionally "Optionally substituted" groups described in). In one embodiment, R 4A may be an unsubstituted C 1-6 alkyl group. In some embodiments, R 4A can be methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tertiary butyl, pentyl (branched and linear ), and hexyl (branched and straight chain changes). In some embodiments, R 4A may be a methyl group.
在其他實施例中，R4A 可係可選地經取代的環烷基，諸如未經取代的環烷基或帶有可選取代基的環烷基(如本文別處所述)。在各種實施例中，R4A 可係可選地經取代的C3-6 環烷基，諸如可選地經取代的C3-6 環烷基。例如，在各種實施例中，R4A 可係可選地經取代的環丙基、可選地經取代的環丁基、可選地經取代的環戊基、可選地經取代的雙環[1.1.1]戊基、或可選地經取代的環己基。在各種實施例中，R4A 可係經取代的環烷基，諸如經取代的C3-6 環烷基。例如，在各種實施例中，R4A 可係經取代的環丙基、經取代的環丁基、經取代的環戊基、經取代的雙環[1.1.1]戊基、或經取代的環己基。在其他實施例中，R4A 係未經取代的環烷基，諸如未經取代的C3-6 環烷基。例如，在各種實施例中，R4A 可係未經取代的環丙基、未經取代的環丁基、未經取代的環戊基、未經取代的雙環[1.1.1]戊基、或未經取代的環己基。In other embodiments, R 4A may be an optionally substituted cycloalkyl, such as an unsubstituted cycloalkyl or a cycloalkyl with optional substituents (as described elsewhere herein). In various embodiments, R 4A can be an optionally substituted C 3-6 cycloalkyl, such as an optionally substituted C 3-6 cycloalkyl. For example, in various embodiments, R 4A can be an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted bicyclic [ 1.1.1] Pentyl, or optionally substituted cyclohexyl. In various embodiments, R 4A can be a substituted cycloalkyl, such as a substituted C 3-6 cycloalkyl. For example, in various embodiments, R 4A can be substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl, substituted bicyclo[1.1.1]pentyl, or substituted ring Hexyl. In other embodiments, R 4A is an unsubstituted cycloalkyl, such as an unsubstituted C 3-6 cycloalkyl. For example, in various embodiments, R 4A can be unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted bicyclo[1.1.1]pentyl, or Unsubstituted cyclohexyl.
在一實施例中，R1 可係鹵素。合適的鹵素之實例包括氟、氯、溴、及碘。在其他實施例中，R1 可係可選地經取代的烷基，諸如未經取代的烷基或帶有可選取代基的烷基(如本文別處所述)。在一實施例中，R1 可係未經取代的C1-6 烷基。C1-6 烷基之實例包括甲基、乙基、正丙基、異丙基、正丁基、二級丁基、異丁基、三級丁基、戊基(支鏈及直鏈)、及己基(支鏈及直鏈改變)。In one embodiment, R 1 may be halogen. Examples of suitable halogens include fluorine, chlorine, bromine, and iodine. In other embodiments, R 1 may be an optionally substituted alkyl group, such as an unsubstituted alkyl group or an alkyl group with optional substituents (as described elsewhere herein). In one embodiment, R 1 may be an unsubstituted C 1-6 alkyl group. Examples of C 1-6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tertiary butyl, pentyl (branched and linear) , And hexyl (branched and straight chain changes).
在一實施例中，R1 可係可選地經取代的環烷基，諸如未經取代的環烷基或帶有可選取代基的環烷基(如本文別處所述)。在各種實施例中，R1 可係可選地經取代的C3-6 環烷基，諸如可選地經取代的C3-6 環烷基。例如，在各種實施例中，R1 可係可選地經取代的環丙基、可選地經取代的環丁基、可選地經取代的環戊基、可選地經取代的雙環[1.1.1]戊基、或可選地經取代的環己基。在一些實施例中，R1 可係經取代的環烷基，諸如經取代的C3-6 環烷基。例如，在各種實施例中，R1 可係經取代的環丙基、經取代的環丁基、經取代的環戊基、經取代的雙環[1.1.1]戊基、或經取代的環己基。在其他實施例中，R1 可係未經取代的環烷基，諸如未經取代的C3-6 環烷基。例如，在各種實施例中，R1 可係未經取代的環丙基、未經取代的環丁基、未經取代的環戊基、未經取代的雙環[1.1.1]戊基、或未經取代的環己基。In one embodiment, R 1 may be an optionally substituted cycloalkyl, such as an unsubstituted cycloalkyl or a cycloalkyl with optional substituents (as described elsewhere herein). In various embodiments, R 1 can be an optionally substituted C 3-6 cycloalkyl, such as an optionally substituted C 3-6 cycloalkyl. For example, in various embodiments, R 1 can be an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted bicyclic [ 1.1.1] Pentyl, or optionally substituted cyclohexyl. In some embodiments, R 1 may be a substituted cycloalkyl, such as a substituted C 3-6 cycloalkyl. For example, in various embodiments, R 1 can be substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl, substituted bicyclo[1.1.1]pentyl, or substituted ring Hexyl. In other embodiments, R 1 may be an unsubstituted cycloalkyl, such as an unsubstituted C 3-6 cycloalkyl. For example, in various embodiments, R 1 can be unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted bicyclo[1.1.1]pentyl, or Unsubstituted cyclohexyl.
在一實施例中，R1 可係可選地經取代的單取代胺基，諸如未經取代的單取代胺基或帶有額外可選取代基的單取代胺基(如本文別處所述)。在一實施例中，單取代胺基可係–NH(C1-6 烷基)，其在C1-6 烷基取代基上係未經取代的或可選地經取代的。在其他實施例中，R1 可係可選地經取代的二取代胺基，諸如未經取代的二取代胺基或帶有額外可選取代基的二取代胺基(如本文別處所述)。在一實施例中，二取代胺基可係–N(C1-6 烷基)2 基團，其在C1-6 烷基取代基之任一者或兩者上係未經取代的或可選地經取代的。In one embodiment, R 1 may be an optionally substituted monosubstituted amine group, such as an unsubstituted monosubstituted amine group or a monosubstituted amine group with additional optional substituents (as described elsewhere herein) . In one embodiment, the monosubstituted amino group may be —NH(C 1-6 alkyl), which is unsubstituted or optionally substituted on the C 1-6 alkyl substituent. In other embodiments, R 1 may be an optionally substituted disubstituted amine group, such as an unsubstituted disubstituted amine group or a disubstituted amine group with additional optional substituents (as described elsewhere herein) . In one embodiment, the disubstituted amino group may be a -N(C 1-6 alkyl) 2 group, which is unsubstituted or unsubstituted on either or both of the C 1-6 alkyl substituents Optionally substituted.
在一些實施例中，當m係2時，至少一個R1 可係–OR4A 。在一些實施例中，當m係2時，各R1 可係–OR4A 。在其他實施例中，至少一個R1 可係鹵素或可選地經取代的環烷基。在又其他實施例中，至少一個R1 可係可選地經取代的單取代胺基或可選地經取代的二取代胺基。In some embodiments, when m is 2, at least one R 1 may be -OR 4A . In some embodiments, when m is 2, each R 1 may be -OR 4A . In other embodiments, at least one R 1 may be halogen or optionally substituted cycloalkyl. In still other embodiments, at least one R 1 may be an optionally substituted mono-substituted amine group or an optionally substituted di-substituted amine group.
例示性環Ar部分包括但不限於下列：
環Ar可附接至另一個環結構，其中某些原子係由如式(I)所示之變項X1 、X2 、及X3 表示。在各種實施例中，X1 、X2 、及X3 可各自獨立地係N或CR5 ，其中各R5 可獨立地係氫、鹵素、或可選地經取代的烷基。在一實施例中，X1 、X2 、及X3 中之至少一者可係CR5 ，且各R5 可係氫。在各種實施例中，X1 、X2 、及X3 中任一、二、或三者可係N。在其他實施例中，X1 、X2 、及X3 中任一、二、或三者可係CR5 。例如，在一些實施例中，X1 、X2 、及X3 中任一者可係CR5 。在其他實施例中，X1 、X2 、及X3 中任二者可係CR5 。在又進一步實施例中，X1 、X2 、及X3 中之所有三者可係CR5 。在一些實施例中，X1 、X2 、及X3 之各者可係CR5 ，且各R5 可係氫。在其他實施例中，X1 、X2 、及X3 中之至少一者可係CR5 ，且各R5 可係氟、氯、嗅、或碘。在其他實施例中，X1 、X2 、及X3 中之至少一者可係CR5 ，且R5 可係未經取代的C1-6 烷基。在一些實施例中，X1 可係CR5 ，其中R5 可係鹵素(諸如氟基、氯基、或碘基)，且X2 及X3 之各者可係CR5 ，其中各R5 可係氫。The ring Ar may be attached to another ring structure in which certain atoms are represented by the variables X 1 , X 2 , and X 3 as shown in formula (I). In various embodiments, X 1 , X 2 , and X 3 may each independently be N or CR 5 , wherein each R 5 may independently be hydrogen, halogen, or optionally substituted alkyl. In an embodiment, at least one of X 1 , X 2 , and X 3 may be CR 5 , and each R 5 may be hydrogen. In various embodiments, any one, two, or three of X 1 , X 2 , and X 3 may be N. In other embodiments, any one, two, or three of X 1 , X 2 , and X 3 may be CR 5 . For example, in some embodiments, any of X 1 , X 2 , and X 3 may be CR 5 . In other embodiments, any two of X 1 , X 2 , and X 3 may be CR 5 . In still further embodiments, all three of X 1 , X 2 , and X 3 may be CR 5 . In some embodiments, each of X 1 , X 2 , and X 3 may be CR 5 , and each R 5 may be hydrogen. In other embodiments, at least one of X 1 , X 2 , and X 3 may be CR 5 , and each R 5 may be fluorine, chlorine, odor, or iodine. In other embodiments, at least one of X 1 , X 2 , and X 3 may be CR 5 , and R 5 may be an unsubstituted C 1-6 alkyl group. In some embodiments, X 1 may be CR 5 , wherein R 5 may be halogen (such as fluoro, chloro, or iodo), and each of X 2 and X 3 may be CR 5 , wherein each R 5 Can be hydrogen.
式(I)包括另一個環結構，該環結構包括變項X4 。在各種實施例中，X4 可係C、CH、或N。所屬技術領域中具有通常知識者將理解，當X4 係C時，則「 - - - - 」所描繪之鍵係雙鍵，而當X4 係CH或N時，則 「 - - - - 」所描繪之鍵係單鍵。式(Id)繪示化學結構，其中X4 係C，且「 - - - - 」所描繪之鍵係雙鍵。在一些實施例中，X4 可係C，且「 - - - - 」所描繪之鍵係雙鍵。在其他實施例中，X4 可係CH，且「 - - - - 」所描繪之鍵係單鍵。在又其他實施例中，X4 可係N，且「 - - - - 」所描繪之鍵係單鍵。Formula (I) includes another ring structure including the variable X 4 . In various embodiments, X 4 can be C, CH, or N. Those with ordinary knowledge in the technical field will understand that when X 4 is C, the bond described by "---- " is a double bond, and when X 4 is CH or N, then " ---- " The depicted bond is a single bond. The formula (Id) shows the chemical structure, where X 4 is C, and the bond depicted by "---- " is a double bond. In some embodiments, X 4 can be C, and the bond depicted by "---- " is a double bond. In other embodiments, X 4 can be CH, and the bond depicted by "---- " is a single bond. In still other embodiments, X 4 may be N, and the bond depicted by "---- " is a single bond.
式(I)中之X4
變項係附接至變項A1
(其表示可選地經取代的苯基或可選地經取代的雜芳基)。在一實施例中，A1
可係可選地經取代的苯基，諸如未經取代的苯基或帶有可選取代基的經取代的苯基(如本文別處所述)(諸如「可選地經取代的(optionally substituted)」所描述之該等基團)。在一實施例中，A1
可係未經取代的苯基。例如，式(Ie)繪示化學結構，其中A1
係未經取代的苯基。在其他實施例中，A1
可係經取代的苯基，諸如下文實例中所述之氟苯基。在一些實施例中，A1
可係可選地經取代的雜芳基，諸如未經取代的雜芳基或帶有可選取代基的經取代的雜芳基(如本文別處所述)。在一些實施例中，A1
可係可選地經取代的雜芳基，諸如可選地經取代的5員雜芳基。在其他實施例中，A1
可係可選地經取代的雜芳基，諸如可選地經取代的6員雜芳基。例如，在各種實施例中，A1
可係可選地經取代的噻吩基、可選地經取代的噻唑、可選地經取代的1,3,4-噻二唑、或可選地經取代的吡啶基。在一些實施例中，A1
可係經取代的雜芳基，諸如經取代的5員雜芳基或經取代的6員雜芳基。例如，在各種實施例中，A1
可係經取代的噻吩基、經取代的噻唑、經取代的1,3,4-噻二唑、或經取代的雜芳基。在一些實施例中，A1
可係未經取代的雜芳基。例如，式(If)及(Ig)繪示化學結構，其中A1
係未經取代的5員雜芳基或未經取代的6員雜芳基。在各種實施例中，A1
可係未經取代的噻吩基、未經取代的噻唑、未經取代的1,3,4-噻二唑、或經取代的吡啶基。A1
部分之實例包括下列：
如本文別處所述，式(I)之任何氫原子可係氫之任何同位素，包括氘。在一些實施例中，R2A 及R2B 可係各自獨立地係氫或氘。在一些實施例中，R2A 及R2B 中之至少一者可係氘。在其他實施例中，各R2A 及R2B 可係氫。As described elsewhere herein, any hydrogen atom of formula (I) can be any isotope of hydrogen, including deuterium. In some embodiments, R 2A and R 2B can each independently be hydrogen or deuterium. In some embodiments, at least one of R 2A and R 2B may be deuterium. In other embodiments, each of R 2A and R 2B may be hydrogen.
式(I)含有變項R3 所附接之***環結構。在各種實施例中，R3 可係鹵烷基、可選地經取代的烷基、或可選地經取代的環烷基。在一實施例中，R3 可係鹵烷基。例如，在各種實施例中，R3 可係C1-6 鹵烷基。合適的鹵烷基之實例包括氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、及氟丙基。The formula (I) contains the triazole ring structure to which the variable R 3 is attached. In various embodiments, R 3 can be haloalkyl, optionally substituted alkyl, or optionally substituted cycloalkyl. In one embodiment, R 3 may be a haloalkyl group. For example, in various embodiments, R 3 can be a C 1-6 haloalkyl group. Examples of suitable haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and fluoropropyl.
在各種實施例中，R3 可係可選地經取代的烷基。例如，在一實施例中，R3 可係可選地經取代的烷基，諸如未經取代的烷基或帶有可選取代基的烷基(如本文別處所述)。在一實施例中，R3 可係未經取代的C1-6 烷基，諸如甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、三級丁基、戊基(直鏈或支鏈)、或己基(直鏈或支鏈)。在一些實施例中，R3 可係甲基。在另一實施例中，R3 可係經取代的C1-6 烷基。例如，在一實施例中，R3 可係羥乙基。In various embodiments, R 3 can be an optionally substituted alkyl group. For example, in one embodiment, R 3 may be optionally substituted lines alkyl such as unsubstituted alkyl or alkyl optionally substituted with group (as described elsewhere herein). In one embodiment, R 3 can be an unsubstituted C 1-6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dibutyl, tri G-butyl, pentyl (straight or branched), or hexyl (straight or branched). In some embodiments, R 3 may be a methyl group. In another embodiment, R 3 may be a substituted C 1-6 alkyl group. For example, in one embodiment, R 3 may be hydroxyethyl.
在其他實施例中，R3 可係可選地經取代的環烷基，諸如未經取代的環烷基或帶有可選取代基的環烷基(如本文別處所述)(針對「可選地經取代的(optionally substituted)」所描述之該等基團)。在各種實施例中，R3 可係可選地經取代的C3-6 環烷基，諸如可選地經取代的C3-6 環烷基。例如，在各種實施例中，R3 可係可選地經取代的環丙基、可選地經取代的環丁基、可選地經取代的環戊基、可選地經取代的雙環[1.1.1]戊基、或可選地經取代的環己基。在一些實施例中，R3 可係經取代的環烷基，諸如經取代的C3-6 環烷基。例如，在各種實施例中，R3 可係經取代的環丙基、經取代的環丁基、經取代的環戊基、經取代的雙環[1.1.1]戊基、或經取代的環己基。在其他實施例中，R3 可係未經取代的環烷基，諸如未經取代的C3-6 環烷基。例如，在各種實施例中，R3 可係未經取代的環丙基、未經取代的環丁基、未經取代的環戊基、未經取代的雙環[1.1.1]戊基、或未經取代的環己基。In other embodiments, R 3 may be an optionally substituted cycloalkyl, such as an unsubstituted cycloalkyl or a cycloalkyl with optional substituents (as described elsewhere herein) (for "may The groups described in "optionally substituted"). In various embodiments, R 3 can be an optionally substituted C 3-6 cycloalkyl, such as an optionally substituted C 3-6 cycloalkyl. For example, in various embodiments, R 3 can be an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted bicyclic [ 1.1.1] Pentyl, or optionally substituted cyclohexyl. In some embodiments, R 3 may be a substituted cycloalkyl, such as a substituted C 3-6 cycloalkyl. For example, in various embodiments, R 3 can be substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl, substituted bicyclo[1.1.1]pentyl, or substituted ring Hexyl. In other embodiments, R 3 may be an unsubstituted cycloalkyl, such as an unsubstituted C 3-6 cycloalkyl. For example, in various embodiments, R 3 can be unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted bicyclo[1.1.1]pentyl, or Unsubstituted cyclohexyl.
在一實施例中，式(I)化合物之化合物包括至少一個可選地經取代的環烷基。例如，在一實施例中，R1 係-OR4A ，且R4A 係可選地經取代的環烷基。在另一實施例中，R3 係可選地經取代的環烷基。在一實施例中，R3 及R4A 中之至少一者係可選地經取代的環烷基。In one embodiment, the compound of the compound of formula (I) includes at least one optionally substituted cycloalkyl. For example, in one embodiment, R 1 is -OR 4A , and R 4A is an optionally substituted cycloalkyl. In another embodiment, R 3 is an optionally substituted cycloalkyl. In one embodiment, at least one of R 3 and R 4A is an optionally substituted cycloalkyl.
式(I)化合物之實例包括下列：
式(I)化合物之額外實例包括：
在某些實施例中，Ar不可係未經取代的吡啶基。在其他實施例中，Ar不可係經取代的吡啶基，例如經氟基取代的吡啶基、經氯基取代的吡啶基、經甲氧基取代的吡啶基、經乙氧基取代的吡啶基、經正丙氧基取代的吡啶基、經異丙氧基取代的吡啶基。在又其他實施例中，Ar不可係未經取代的苯基。在又再其他實施例中，Ar不可係經取代的苯基(諸如經氟基取代的苯基、經氯基取代的苯基、經甲氧基取代的苯基、經乙氧基取代的苯基、經正丙氧基取代的苯基、經異丙氧基取代的苯基)。在一些實施例中，X4 不可係C(碳)，且「 - - - - 」不可係雙鍵。在其他實施例中，X4 不可係CH，且「 - - - - 」不可係單鍵。在一些實施例中，R3 不可係未經取代的烷基，包括未經取代的C1-6 烷基(諸如甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、三級丁基、戊基(支鏈或直鏈)、及/或己基(支鏈或直鏈)。在其他實施例中，R3 不可係經取代的烷基，諸如經取代的C1-6 烷基。經取代的C1-6 烷基之實例包括經羥基取代的C1-6 烷基。在又其他實施例中，R3 不可係未經取代的環烷基，諸如未經取代的單環C3-6 環烷基。在又再其他實施例中，R3 不可係經取代的環烷基，例如經取代的單環C3-6 環烷基。在一些實施例中，R3 不可係鹵烷基(諸如經氟基取代的鹵烷基)。在一些實施例中，A1 不可係未經取代的苯基。在一些實施例中，A1 不可係經取代的苯基，例如經鹵基取代的苯基。在一些實施例中，式(I)化合物、或其醫藥上可接受之鹽不可係下列中之一或多者所述之化合物或鹽：Boga et al., ACS Medicinal Chemistry Letters (2018), 9(7), 761-767；U.S. 2014/0309234、WO 2009/105500、WO 2010/021978、WO 2016/100152、WO 2016/100147、及WO 2017/040362。 合成In certain embodiments, Ar cannot be unsubstituted pyridyl. In other embodiments, Ar cannot be substituted pyridyl, such as pyridyl substituted with fluoro, pyridyl substituted with chloro, pyridyl substituted with methoxy, pyridyl substituted with ethoxy, Pyridyl substituted with n-propoxy, pyridyl substituted with isopropoxy. In still other embodiments, Ar cannot be an unsubstituted phenyl group. In still other embodiments, Ar cannot be substituted phenyl (such as phenyl substituted with fluoro, phenyl substituted with chloro, phenyl substituted with methoxy, phenyl substituted with ethoxy Group, phenyl substituted with n-propoxy, phenyl substituted with isopropoxy). In some embodiments, X 4 cannot be C (carbon), and " ---- " cannot be a double bond. In other embodiments, X 4 cannot be CH, and " ---- " cannot be a single bond. In some embodiments, R 3 cannot be an unsubstituted alkyl group, including unsubstituted C 1-6 alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl). Group, secondary butyl, tertiary butyl, pentyl (branched or linear), and/or hexyl (branched or linear). In other embodiments, R 3 cannot be a substituted alkyl group, Such as substituted C 1-6 alkyl. Examples of substituted C 1-6 alkyl include C 1-6 alkyl substituted with hydroxy. In still other embodiments, R 3 may not be an unsubstituted ring Alkyl groups, such as unsubstituted monocyclic C 3-6 cycloalkyl groups. In still other embodiments, R 3 cannot be substituted cycloalkyl groups, such as substituted monocyclic C 3-6 cycloalkyl groups In some embodiments, R 3 cannot be a haloalkyl group (such as a haloalkyl group substituted with a fluoro group). In some embodiments, A 1 cannot be an unsubstituted phenyl group. In some embodiments, A 1 Cannot be substituted phenyl, such as phenyl substituted by halo. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, cannot be one or more of the following Compound or salt: Boga et al., ACS Medicinal Chemistry Letters (2018), 9(7), 761-767; US 2014/0309234, WO 2009/105500, WO 2010/021978, WO 2016/100152, WO 2016/100147 , And WO 2017/040362. Synthesis
式(I)化合物、以及本文所述者可以各種方式製備。式(I)化合物可利用本文中所提供之詳細指引說明的已知合成程序來製備。式(I)化合物之通常合成途徑、以及用於合成式(I)化合物的起始材料之一些實例係顯示並描述於本文中。本文所示及所述之途徑僅為示範，且並非意圖或經解讀為以任何方式限制申請專利範圍之範疇。所屬技術領域中具有通常知識者將可辨識對揭示合成之改良並基於在本文中之揭露來設計替代途徑；所有該等改良及替代途徑係屬申請專利範圍之範圍內。
方案1
如方案1所示，化合物(A)與化合物(B)可例如經由親核取代反應，偶合以形成式(I)化合物。化合物(A)與化合物(B)可使用所屬技術領域中具有通常知識者已知之方法來形成，並表示於本文中。在方案1中，LG1 可係合適的脫離基，諸如鹵素(例如，氯基或碘基)。在一些實施例中，在化合物(A)與化合物(B)之反應中可使用胺鹼。合適的胺鹼之實例包括但不限於：烷基胺(包括單烷基胺、二烷基胺、及三烷基胺(例如三乙胺))、可選地經取代的吡啶(例如柯林鹼(collidine))、及可選地經取代的咪唑(例如N-甲基咪唑)。在一些實施例中，***環可在化合物(A)與化合物(B)之間的反應之後附接至A1 。例如，當A1 係苯基時，帶有R3 基團之***可經由鈴木偶合反應加成至帶有-A1 -LG2 基團之經偶合之化合物，其中LG2 係第二脫離基。 醫藥組成物As shown in Scheme 1, compound (A) and compound (B) can be coupled to form a compound of formula (I), for example, via a nucleophilic substitution reaction. Compound (A) and compound (B) can be formed using methods known to those with ordinary knowledge in the relevant technical field, and are indicated herein. In Scheme 1, LG 1 may be a suitable leaving group, such as a halogen (for example, a chloro group or an iodo group). In some embodiments, an amine base may be used in the reaction of compound (A) and compound (B). Examples of suitable amine bases include, but are not limited to: alkylamines (including monoalkylamines, dialkylamines, and trialkylamines (e.g., triethylamine)), optionally substituted pyridines (e.g., Colin Base (collidine)), and optionally substituted imidazole (e.g. N-methylimidazole). In some embodiments, the triazole ring may be attached to A 1 after the reaction between compound (A) and compound (B). For example, when A 1 is a phenyl group, a triazole with R 3 group can be added to a coupled compound with a -A 1 -LG 2 group via Suzuki coupling reaction, where LG 2 is the second off base. Pharmaceutical composition
本文所述之一些實施例係關於一種醫藥組成物，其可包括有效量之一或多種本文所述之化合物(例如式(I)化合物、或其醫藥上可接受之鹽)及醫藥上可接受之載劑、稀釋劑、賦形劑、或其組合。Some embodiments described herein are related to a pharmaceutical composition, which may include an effective amount of one or more of the compounds described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable The carrier, diluent, excipient, or combination thereof.
用語「醫藥組成物(pharmaceutical composition)」係指本文中所揭示之一或多種化合物與其他化學組分(諸如稀釋劑或載劑)之混合物。醫藥組成物有利於該化合物向生物體之投予。醫藥組成物亦可藉由使化合物與無機或有機酸(諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸、甲烷磺酸、乙烷磺酸、對甲苯磺酸、及水楊酸)反應來獲得。醫藥組成物通常將針對特定意圖投予途徑設計。The term "pharmaceutical composition" refers to a mixture of one or more of the compounds disclosed herein and other chemical components (such as diluents or carriers). The pharmaceutical composition facilitates the administration of the compound to the organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid) . The pharmaceutical composition will generally be designed for a specific intended route of administration.
用語「生理上可接受(physiologically acceptable)」定義載劑、稀釋劑、或賦形劑，其不會消除化合物之生物活性及性質，亦不會對預期遞送組成物之動物引起明顯損傷或損害。The term "physiologically acceptable" defines a carrier, diluent, or excipient that will not eliminate the biological activity and properties of the compound, nor will it cause significant damage or damage to the animal intended to deliver the composition.
如本文中所使用，「載劑(carrier)」係指促進化合物併入細胞或組織中之化合物。例如(但不限於)，二甲基亞碸(DMSO)係經常利用的載劑，其促進許多有機化合物被攝入對象的細胞或組織中。As used herein, "carrier" refers to a compound that promotes the incorporation of the compound into cells or tissues. For example (but not limited to), dimethyl sulfoxide (DMSO) is a frequently used carrier, which promotes the uptake of many organic compounds into the cells or tissues of the subject.
如本文中所使用，「稀釋劑(diluent)」係指醫藥組成物中缺乏明顯藥理學活性但可能為醫藥上必需或所欲之成分。例如，稀釋劑可用於增加質量過小而無法用於製造及/或投予之有效藥物的體積。其亦可為用於溶解將藉由注射、攝取或吸入投予之藥物的液體。所屬技術領域中常見形式的稀釋劑為緩衝水溶液，諸如但不限於模擬人類血液之pH及等滲性之磷酸鹽緩衝鹽水。As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that lacks obvious pharmacological activity but may be medically necessary or desired. For example, diluents can be used to increase the volume of effective drugs that are too small to be used for manufacturing and/or administration. It can also be a liquid used to dissolve the drug to be administered by injection, ingestion or inhalation. A common form of diluent in the technical field is a buffered aqueous solution, such as but not limited to phosphate buffered saline that mimics the pH and isotonicity of human blood.
如本文中所使用，「賦形劑(excipient)」係指基本上惰性的物質，其經添加至醫藥組成物中以向該組成物提供(但不限於)體積、稠度、穩定性、結合能力、潤滑、崩解能力等。「稀釋劑(diluent)」係一種類型的賦形劑。As used herein, "excipient" refers to a substantially inert substance that is added to a pharmaceutical composition to provide (but not limited to) volume, consistency, stability, and binding capacity to the composition , Lubrication, disintegration ability, etc. "Diluent" is a type of excipient.
本文所述之醫藥組成物本身可向人類患者投予，或可以其中彼等與其他活性成分(如在組合療法中)、或載劑、稀釋劑、賦形劑或其組合混合之醫藥組成物向人類患者投予。適當配方取決於選擇的投予途徑。用於本文所述之化合物的配方及投予之技術係所屬技術領域中具有通常知識者已知的。The pharmaceutical compositions described herein can be administered to human patients by themselves, or can be pharmaceutical compositions in which they are mixed with other active ingredients (such as in combination therapy), or carriers, diluents, excipients, or combinations thereof Administer to human patients. The appropriate formulation depends on the route of administration chosen. The formulation and administration techniques used for the compounds described herein are known to those with ordinary knowledge in the art.
本文所揭示之醫藥組成物可以本身已知之方式製造，例如藉由習知之混合、溶解、造粒、糖衣錠製造、研調、乳化、囊封、包封、或製錠製程。此外，所含有的活性成分之量可有效達成其意圖目的。在本文中揭示之醫藥組合中使用的許多化合物可提供為含有醫藥上相容的相對離子之鹽。The pharmaceutical composition disclosed herein can be manufactured in a manner known per se, for example, by the conventional mixing, dissolving, granulating, dragee manufacturing, researching, emulsifying, encapsulating, encapsulating, or tableting process. In addition, the amount of active ingredients contained can effectively achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein can be provided as salts containing pharmaceutically compatible opposing ions.
所屬技術領域存在多種投予化合物之技術，包括但不限於口服、直腸、肺、局部、氣溶膠、注射、及腸胃外遞送，包括肌肉內、皮下、靜脈內、髓內注射、鞘內、直接室內(direct intraventricular)、腹膜內、鼻內、及眼內注射。There are many techniques for administering compounds in the technical field, including but not limited to oral, rectal, pulmonary, topical, aerosol, injection, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct Indoor (direct intraventricular), intraperitoneal, intranasal, and intraocular injections.
亦可以局部而非全身方式投予化合物，例如經由將通常呈貯劑(depot)或持續釋放配方之化合物直接注射至或植入受侵襲區域中。另外，可以標靶藥物遞送系統(例如塗佈組織‑特異性抗體之脂質體)投予化合物。脂質體將靶向器官且由器官選擇性吸收。例如，可能需要鼻內或肺遞送以靶向呼吸感染。The compound may also be administered locally rather than systemically, for example, by direct injection or implantation of the compound, which is usually in a depot or sustained release formulation, into the affected area. In addition, the compound can be administered in a targeted drug delivery system (for example, liposomes coated with tissue-specific antibodies). Liposomes will target the organ and be taken up selectively by the organ. For example, intranasal or pulmonary delivery may be required to target respiratory infections.
如本文中所述，式(I)化合物、或其醫藥上可接受之鹽可藉由各種方法投予。在本文所述之一些方法中，投予可藉由在1分鐘、5分鐘、10分鐘、30分鐘、1小時、2小時、6小時、12小時、24小時或更長、或任何居中時間的過程中進行注射、輸注、及/或靜脈內投予。本文所述之其他方法可包括口服、靜脈內、及/或腹膜內投予至有需要之對象，例如投予至對ERK抑製劑有反應的對象治療本文所述之癌症。As described herein, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered by various methods. In some of the methods described herein, administration can be performed at 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours or longer, or any intermediate time. During the process, injection, infusion, and/or intravenous administration are performed. Other methods described herein may include oral, intravenous, and/or intraperitoneal administration to a subject in need, such as administration to a subject responding to an ERK inhibitor to treat the cancer described herein.
所欲時，組成物可呈現於可含有一或多個(含有活性成分之)單位劑型之包裝或分配裝置中。包裝可例如包含金屬或塑膠箔，例如泡殼包裝。包裝或分配器裝置可隨附投予說明。包裝或分配裝置亦可伴隨有與該容器關聯之通知來管理藥品的製造、使用或銷售，形式係由政府機構所規範，該通知反映該機構批准該藥物形式用於人類或獸醫投予。舉例來說，該通知可為美國食品與藥品管理局批准用於處方藥的標籤或產品仿單。亦可製備可包括在相容醫藥載劑中配製的本文所述之化合物的組成物，將其等置於適當容器中並標示用來治療所指示之病況。 使用方法When desired, the composition can be presented in a packaging or dispensing device that can contain one or more unit dosage forms (containing the active ingredient). The packaging may for example comprise metal or plastic foil, such as a blister pack. The packaging or dispenser device may be accompanied by instructions for casting. The packaging or dispensing device may also be accompanied by a notice associated with the container to manage the manufacture, use, or sale of the drug. The form is regulated by a government agency, and the notice reflects that the agency approves the form of the drug for human or veterinary administration. For example, the notification may be a label or product copy approved by the US Food and Drug Administration for prescription drugs. It is also possible to prepare a composition that may include the compounds described herein formulated in a compatible pharmaceutical carrier, place them in a suitable container and label them for the treatment of the indicated condition. Instructions
本文所述之一些實施例係關於一種用於改善及/或治療本文所述之癌症之方法，其可包括向有需要之對象投予有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物至患有本文所述之癌症的對象。本文所述之其他實施例係關於一種有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)的醫藥組成物在製造用於改善及/或治療本文所述之癌症之藥劑中的用途。Some embodiments described herein relate to a method for improving and/or treating the cancer described herein, which may include administering to a subject in need an effective amount of a compound described herein (e.g., formula (I) A compound, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof) to a subject suffering from the cancer described herein . Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or includes a compound described herein (e.g., formula (I) The use of the pharmaceutical composition of the compound or its pharmaceutically acceptable salt) in the manufacture of a medicament for improving and/or treating the cancer described herein.
本文所述之一些實施例係關於一種用於抑制惡性生長或腫瘤之複製之方法，其可包括使該生長或該腫瘤與有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物接觸，其中該惡性生長或該腫瘤係由本文所述之癌症引起。本文所述之其他實施例係關於一種有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物在製造用於抑制惡性生長或腫瘤之複製之藥劑中的用途，其中該惡性生長或該腫瘤係由本文所述之癌症引起。Some embodiments described herein relate to a method for inhibiting the replication of malignant growth or tumors, which may include combining the growth or tumor with an effective amount of a compound described herein (e.g., a compound of formula (I), or Contact with a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or the tumor is derived from the compound described herein The mentioned cancer is caused. Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or includes a compound described herein (e.g., formula (I) The use of the pharmaceutical composition of the compound or its pharmaceutically acceptable salt) in the manufacture of a medicament for inhibiting malignant growth or tumor replication, wherein the malignant growth or the tumor is caused by the cancer described herein.
本文所述之一些實施例係關於一種用於改善或治療本文所述之癌症之方法，其可包括使惡性生長或腫瘤與有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物接觸，其中該惡性生長或腫瘤係由本文所述之癌症引起。本文所述之其他實施例係關於一種有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物在製造用於改善或治療癌症之藥劑中的用途，其可包括使惡性生長或腫瘤與該化合物接觸，其中該惡性生長或腫瘤係由本文所述之癌症引起。Some embodiments described herein relate to a method for ameliorating or treating the cancer described herein, which may include causing malignant growth or tumor and effective amount of a compound described herein (e.g., a compound of formula (I), or Contact with a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is contacted by the compound described herein Caused by cancer. Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or includes a compound described herein (e.g., formula (I) The use of the pharmaceutical composition of the compound or its pharmaceutically acceptable salt) in the manufacture of a medicament for improving or treating cancer, which may include contacting a malignant growth or tumor with the compound, wherein the malignant growth or tumor is caused by Caused by the cancer described herein.
本文所述之一些實施例係關於一種用於抑制ERK1及/或ERK2之活性的方法，其可包括向樣本提供有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物，該樣本包括來自本文所述之癌症的癌細胞。本文所述之其他實施例係關於一種有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)的醫藥組成物在製造用於抑制ERK1及/或ERK2之活性之藥劑中的用途。Some embodiments described herein relate to a method for inhibiting the activity of ERK1 and/or ERK2, which may include providing a sample with an effective amount of a compound described herein (for example, a compound of formula (I), or a pharmaceutical Acceptable salt) or a pharmaceutical composition including a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof), and the sample includes cancer cells derived from the cancer described herein. Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or includes a compound described herein (e.g., formula (I) The use of the pharmaceutical composition of the compound or its pharmaceutically acceptable salt) in the manufacture of a medicament for inhibiting the activity of ERK1 and/or ERK2.
本文所述之一些實施例係關於一種用於改善或治療本文所述之癌症之方法，其可包括使用下列來抑制ERK1及/或ERK2之活性：有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)之醫藥組成物。本文所述之其他實施例係關於一種有效量之本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)或包括本文所述之化合物(例如，式(I)化合物、或其醫藥上可接受之鹽)的醫藥組成物在製造用於藉由抑制ERK1及/或ERK2之活性來改善或治療本文所述之癌症之藥劑中的用途。Some embodiments described herein relate to a method for ameliorating or treating the cancers described herein, which may include using the following to inhibit the activity of ERK1 and/or ERK2: an effective amount of a compound described herein (e.g., formula (I) a compound, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or includes a compound described herein (e.g., formula (I) The use of the pharmaceutical composition of the compound or its pharmaceutically acceptable salt) in the manufacture of a medicament for improving or treating the cancer described herein by inhibiting the activity of ERK1 and/or ERK2.
合適癌症之實例包括但不限於：肺癌、胰臟癌、結腸癌、骨髓性白血病、甲狀腺癌、骨髓發育不良症候群(myelodysplastic syndrome, MDS)、膀胱癌、表皮癌、黑色素瘤、乳癌、***癌、頭頸癌、卵巢癌、腦癌、間葉來源之癌症、肉瘤、畸形癌(tetracarcinoma)、神經母細胞瘤、腎癌、肝腫瘤、非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)、多發性骨髓瘤、未分化甲狀腺癌、及神經纖維瘤。Examples of suitable cancers include, but are not limited to: lung cancer, pancreatic cancer, colon cancer, myelogenous leukemia, thyroid cancer, myelodysplastic syndrome (myelodysplastic syndrome, MDS), bladder cancer, epidermal cancer, melanoma, breast cancer, prostate cancer, Head and neck cancer, ovarian cancer, brain cancer, mesenchymal cancer, sarcoma, tetracarcinoma, neuroblastoma, kidney cancer, liver tumor, non-Hodgkin's lymphoma, multiple Myeloma, undifferentiated thyroid cancer, and neurofibroma.
如本文中所使用，「對象(subject)」係指作為治療、觀察、或實驗之目標的動物。「動物(Animal)」包括冷血及溫血脊椎動物及無脊椎動物，例如魚、甲殼類動物、爬蟲類及特別是哺乳動物。「哺乳動物(Mammal)」包括但不限於小鼠、大鼠、兔、天竺鼠、犬、貓、綿羊、山羊、牛、馬、靈長類動物，諸如猴、黑猩猩、及猿，且特別是人類。在一些實施例中，對象可以是人。在一些實施例中，對象可以是兒童及/或嬰兒，例如患有發燒的兒童或嬰兒。在其他實施例中，對象可為成人。As used herein, "subject" refers to an animal that is the target of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles and especially mammals. "Mammal" includes but is not limited to mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and especially humans . In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and/or infant, such as a child or infant suffering from fever. In other embodiments, the subject may be an adult.
如本文中所使用，用語「治療(treat, treating, treatment, therapeutic)」及「療法(therapy)」不必然意指完全治癒或消除疾病或病況。可將疾病或病況之任何非所欲的徵象或症狀有任何程度的任何減輕視為治療及/或療法。另外，治療可包括可使對象對福祉或外觀的整體感覺惡化之行為，且該等行為可正面地影響疾病之一或多個症狀或態樣，同時對疾病之其他態樣或不相關系統(可視為非所欲的)具有影響。As used herein, the terms "treat, treating, treatment, therapeutic" and "therapy" do not necessarily mean the complete cure or elimination of a disease or condition. Any reduction in any degree of any undesirable signs or symptoms of the disease or condition may be considered as treatment and/or therapy. In addition, treatment may include behaviors that can worsen the subject's overall perception of well-being or appearance, and these behaviors can positively affect one or more symptoms or aspects of the disease, and at the same time affect other aspects of the disease or unrelated systems ( Can be regarded as undesirable) has an impact.
用語「治療有效量(therapeutically effective amount)」及「有效量(effective amount)」用於指示引發指示生物或藥物反應之活性化合物或醫藥製劑的量。例如，化合物之治療有效量可係治療、減輕、或改善疾病之一或多種症狀或病況、或延長受治療對象之存活所需的量。此反應可發生在組織、系統、動物、或人類中，且包括減輕受治療疾病之徵象或症狀。鑒於在本文中提供之揭露，有效量之判定完全在所屬技術領域中具有通常知識者之能力範圍以內。The terms "therapeutically effective amount" and "effective amount" are used to indicate the amount of the active compound or pharmaceutical preparation that elicits an indicator biological or drug response. For example, the therapeutically effective amount of the compound can be the amount required to treat, alleviate, or ameliorate one or more symptoms or conditions of the disease, or prolong the survival of the subject. This reaction can occur in tissues, systems, animals, or humans, and includes alleviating signs or symptoms of the disease being treated. In view of the disclosure provided in this article, the determination of the effective amount is completely within the ability of a person with ordinary knowledge in the relevant technical field.
例如，有效量之化合物或輻射係導致以下結果之量：(a)由癌症引起之一或多種症狀减少、减輕、或消除，(b)腫瘤大小减小，(c)腫瘤消除，及/或(d)腫瘤之長期疾病穩定(生長停滯)。在肺癌(諸如非小細胞肺癌)的治療中，治療有效量係減輕或消除咳嗽、呼吸急促、及/或疼痛的量。作為另一個實例，有效量或治療有效量之ERK抑制劑係導致ERK(ERKI及/或ERK2)活性及/或磷酸化降低之量。ERK活性降低係所屬技術領域中具有通常知識者已知的，而且可藉由藥效動力學標記(諸如磷酸化RSKI,2、及磷酸化ERKI,2、及/或基因表現概況(mRNA))分析來判定。For example, an effective amount of the compound or radiation is an amount that results in: (a) one or more symptoms caused by cancer are reduced, alleviated, or eliminated, (b) tumor size is reduced, (c) tumor is eliminated, and/ Or (d) Long-term disease stability of the tumor (growth arrest). In the treatment of lung cancer (such as non-small cell lung cancer), a therapeutically effective amount is an amount that reduces or eliminates cough, shortness of breath, and/or pain. As another example, an effective amount or a therapeutically effective amount of an ERK inhibitor is an amount that causes a decrease in ERK (ERKI and/or ERK2) activity and/or phosphorylation. The reduction of ERK activity is known to those skilled in the art, and can be marked by pharmacodynamics (such as phosphorylated RSKI, 2, and phosphorylated ERKI, 2, and/or gene expression profile (mRNA)) Analysis to determine.
作為劑量所需之本文所揭示之化合物的治療有效量將取決於投予途徑、受治療的動物類型(包括人類)、及所考慮的特定動物之身體特徵。可調整劑量以達到所預的效果，但是取決於諸如體重、飲食、併用藥物、及所屬醫學領域中具有通常知識者將認識到的其他因素之因素。The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the particular animal under consideration. The dosage can be adjusted to achieve the desired effect, but it depends on factors such as weight, diet, concomitant drugs, and other factors that will be recognized by those with ordinary knowledge in the medical field.
各種用於判定用於治療癌症之方法的有效性之指標係所屬技術領域中具有通常知識者已知的。合適的指標之實例包括但不限於：由癌症引起之一或多種症狀减少、减輕、或消除，腫瘤大小减小，腫瘤消除，及/或腫瘤之長期疾病穩定(生長停滯)。Various indicators for judging the effectiveness of methods for treating cancer are known to those with ordinary knowledge in the relevant technical field. Examples of suitable indicators include, but are not limited to: reduction, alleviation, or elimination of one or more symptoms caused by cancer, reduction in tumor size, tumor elimination, and/or long-term disease stability (growth arrest) of the tumor.
如所屬技術領域中具有通常知識者將顯而易知的，欲投予之有用體內劑量及具體投予模式將取決於年齡、體重、病痛嚴重性、及所治療之哺乳動物物種、所採用之具體化合物、及採用此等化合物之具體用途而有所變化。有效劑量水準(即達到所欲效果所需之劑量水準)的判定可由所屬技術領域中具有通常知識者使用常規方法來達成，例如，人體臨床試驗及體內研究。As will be apparent to those with ordinary knowledge in the technical field, the useful internal dose to be administered and the specific mode of administration will depend on the age, weight, severity of the disease, and the mammalian species to be treated, and the The specific compounds and the specific uses of these compounds vary. The determination of the effective dose level (that is, the dose level required to achieve the desired effect) can be achieved by a person with ordinary knowledge in the relevant technical field using conventional methods, such as human clinical trials and in vivo studies.
劑量可為寬廣範圍，其取決於所欲效應及治療適應症。替代地，如所屬技術領域中具有通常知識者所理解，劑量可基於患者之表面積並進行計算。雖然確切劑量將基於各藥物來判定，但在大多數情況下，可進行關於劑量的一些歸納。用於成年人類患者的每日劑量方案可係例如介於0.01 mg與3000 mg(較佳的是介於1 mg與700 mg之間，例如5至200 mg)之間的各活性成分之口服劑量。視對象需要，劑量可係單一者或在一或多天的過程中給予的二或多者之系列。在一些實施例中，在一段連續療法期間(例如一週或更長時間、或幾個月或幾年)投予化合物。The dosage can be in a wide range, depending on the desired effect and therapeutic indication. Alternatively, as understood by those skilled in the art, the dose can be calculated based on the surface area of the patient. Although the exact dose will be determined on the basis of each drug, in most cases, some generalizations about the dose can be made. The daily dosage regimen for adult patients may be, for example, an oral dose of each active ingredient between 0.01 mg and 3000 mg (preferably between 1 mg and 700 mg, such as 5 to 200 mg) . Depending on the needs of the subject, the dose can be a single one or a series of two or more given over the course of one or more days. In some embodiments, the compound is administered during a period of continuous therapy (e.g., one week or more, or months or years).
在已針對至少一些病況建立人類化合物劑量的情況下，可使用該等相同劑量或以下劑量：介於約0.1%與500%之間，更佳的是介於約25%與250%之間的所建立人類劑量。當未建立人類劑量時，如在最新發現醫藥組成物的情況下，可自體外或體內研究導出的ED50 或ID50 值、或其他適當值(如藉由動物之毒性研究及療效研究所定性)，推測合適的人類劑量。Where human compound doses have been established for at least some conditions, the same doses or the following doses can be used: between about 0.1% and 500%, more preferably between about 25% and 250% Established human dose. When the human dose has not been established, such as the latest discovery of pharmaceutical compositions, the ED 50 or ID 50 values derived from in vitro or in vivo studies, or other appropriate values (such as qualitative studies by animal toxicity studies and efficacy studies) ), infer the appropriate human dose.
在投予醫藥上可接受之鹽的情況下，劑量可以游離鹼來計算。所屬技術領域中具有通常知識者將理解，在某些情况下，可能需要以超過或甚至遠超過上文所說明之較佳劑量範圍的量投予本文所揭示之化合物，以有效及積極地治療特別是侵襲性疾病或感染。In the case of administering a pharmaceutically acceptable salt, the dose can be calculated as the free base. Those skilled in the art will understand that, in some cases, it may be necessary to administer the compounds disclosed herein in an amount exceeding or even far exceeding the preferred dosage range described above in order to effectively and actively treat Especially aggressive diseases or infections.
劑量及時間間隔可經個別地調節，以提供足以維持調節效應之活性部分之血漿水準或最小有效濃度(minimal effective concentration, MEC)。各化合物之MEC將有所不同，但可自體外資料估計。達成MEC所需之劑量將視個體特徵及投藥途徑而定。然而，可使用HPLC檢定或生物檢定來判定血漿濃度。劑量時間間隔亦可使用MEC值來判定。組成物應使用維持血漿水準高於MEC達10至90%的時間、較佳地介於30至90%之間的時間且最佳的是介於50至90%之間的時間的方案投予。在局部投予或選擇性吸收之情況下，藥物之局部有效濃度可能與血漿濃度無關。The dosage and time interval can be adjusted individually to provide a plasma level or minimal effective concentration (MEC) sufficient to maintain the active part of the modulating effect. The MEC of each compound will be different, but it can be estimated from in vitro data. The dosage required to achieve MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentration. The interval between doses can also be determined using the MEC value. The composition should be administered using a regimen that maintains plasma levels higher than MEC for 10 to 90% of the time, preferably 30 to 90% of the time, and most preferably 50 to 90% of the time . In the case of local administration or selective absorption, the local effective concentration of the drug may not be related to plasma concentration.
應注意的是，主治醫師會知道如何及何時因毒性或器官功能異常而終止、中斷、或調整投予。相反地，主治醫師亦會知道若臨床反應不充足(排除毒性)，則將治療調整至較高水平。管理所關注病症時投予劑量之量值將隨待治療病況之嚴重性及投予途徑而異。病況之嚴重程度可例如部分地依據標準預後評估方法來評估。此外，劑量且可能給藥頻率亦將根據個別患者之年齡、體重、及反應而有所變化。與以上討論之計畫類似的計畫可用於獸醫學。It should be noted that the attending physician will know how and when to terminate, interrupt, or adjust the administration due to toxicity or abnormal organ function. Conversely, the attending physician will also know that if the clinical response is insufficient (to rule out toxicity), the treatment will be adjusted to a higher level. The amount of dose administered in the management of the condition of concern will vary with the severity of the condition to be treated and the route of administration. The severity of the condition can be assessed, for example, in part based on standard prognostic assessment methods. In addition, the dosage and possible frequency of administration will also vary according to the age, weight, and response of individual patients. Projects similar to those discussed above can be used in veterinary medicine.
可使用已知方法評估本文所揭示之化合物之療效及毒性。例如，特定化合物或共用某些化學部份之化合物亞組之毒物學可藉由判定對細胞系(例如哺乳動物且較佳人類細胞系)之體外毒性來建立。此類研究之結果通常可預測在動物(例如哺乳動物)或更具體而言在人類中之毒性。替代地，可使用已知方法判定動物模型(諸如小鼠、大鼠、兔、或猴)中特定化合物之毒性。特定化合物之療效可使用數種公認方法(例如體外方法、動物模型或人體臨床試驗)來建立。當選擇模型來判定療效時，熟習此項技術者可由目前最佳技術的引導以選擇適當模型、劑量、投予途徑及/或方案。實例 Known methods can be used to evaluate the efficacy and toxicity of the compounds disclosed herein. For example, the toxicology of a specific compound or a subgroup of compounds sharing certain chemical parts can be established by determining the in vitro toxicity to cell lines (e.g., mammalian and preferably human cell lines). The results of such studies can generally predict toxicity in animals (such as mammals) or more specifically in humans. Alternatively, known methods can be used to determine the toxicity of a particular compound in an animal model such as a mouse, rat, rabbit, or monkey. The efficacy of a particular compound can be established using several recognized methods (for example, in vitro methods, animal models, or human clinical trials). When choosing a model to determine the therapeutic effect, those familiar with the technology can choose the appropriate model, dose, route of administration and/or regimen under the guidance of the current best technology. Instance
提供此等實例的目的僅為示範而非限制本文所提供之申請專利範圍。中間物1 三級丁基(S
)-3-((3- 碘-1- 三苯甲基-1H
- 吲唑-5- 基) 胺甲醯基)-3-( 甲基硫基) 吡咯啶-1- 羧酸酯 
步驟1 ：1H - 吲唑-5- 胺： 向5-硝基-1H-吲唑(500 g, 4.05 mmol)於甲醇(20 mL)中之攪拌溶液添加10% Pd/C (200 mg)，並在室溫(rt)下於氫氣氛中攪拌2 h。將反應混合物通過矽藻土墊過濾並將有機流份濃縮以得到呈棕色固體之標題化合物(350 mg，65%產率)。1 H NMR (300 MHz, DMSO-d6 ) δ 12.56 (br s, 1H), 7.72 (s, 1H), 7.24 (d,J =8.4 Hz, 1H), 6.83-6.67 (m, 2H), 4.88 (br s, 2H)；MS (ESI)m/z 134.06 [M+1]+ 。 Step 1 : 1 H - Indazole-5- amine: Add 10% Pd/C (200 mg) to a stirred solution of 5-nitro-1H-indazole (500 g, 4.05 mmol) in methanol (20 mL) , And stirred for 2 h at room temperature (rt) in a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite and the organic fraction was concentrated to give the title compound (350 mg, 65% yield) as a brown solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.56 (br s, 1H), 7.72 (s, 1H), 7.24 (d, J =8.4 Hz, 1H), 6.83-6.67 (m, 2H), 4.88 (br s, 2H); MS (ESI) m/z 134.06 [M+1] + .
步驟 2 ： (S )- 三級丁基 3-(1H - 吲唑 -5- 基胺甲醯基 )-3-( 甲基硫基 ) 吡咯啶 -1- 羧酸酯 ： 向(S )-1-(三級丁氧羰基)-3-(甲基硫基)吡咯啶-3-羧酸(5 g, 19.15 mmol)(參見ACS Med Chem Lett 2018, 761之合成部分)於DMF (50 mL)中之攪拌溶液，添加1H -吲唑-5-胺(2.55 g , 19.1 mmol)、HATU (10.9 g, 28.72 mmol)、及N -乙基二異丙基胺(10.29 mL, 57.45 mmol)，將其在rt下攪拌16 h。將水(100 mL)添加至反應混合物，用乙酸乙酯(3 × 150 mL)萃取。將合併的有機層用水(3 × 100 mL)、鹽水(100 mL)洗滌，用硫酸鈉乾燥，然後濃縮。使用50%乙酸乙酯(於己烷中)作為洗提液，將所得殘餘物藉由管柱層析術(100至200二氧化矽)純化，以得到呈棕色固體之標題化合物(5 g，69%產率)。1 H NMR (400 MHz, DMSO-d6 ) δ 12.98 (br s, 1H), 9.70 (br d,J =5.9 Hz, 1H), 8.09-7.98 (m, 2H), 7.54-7.45 (m, 2H), 3.83-3.71 (m, 1H), 3.70-3.56 (m, 1H), 3.50-3.35 (m, 2H), 2.55-2.40 (m, 1H), 2.26 (br s, 1H), 2.08 (s, 3H), 1.22 (s, 9H)；MS (ESI)m/z 377.17 [M+1]+ 。 Step 2 : ( S ) -Tributyl 3-(1 H - indazol- 5 -ylaminomethanyl )-3-( methylthio ) pyrrolidine- 1- carboxylate : To ( S ) -1-(tertiary butoxycarbonyl)-3-(methylthio)pyrrolidine-3-carboxylic acid (5 g, 19.15 mmol) (see the synthesis section of ACS Med Chem Lett 2018, 761) in DMF (50 mL), add 1 H -indazol-5-amine (2.55 g, 19.1 mmol), HATU (10.9 g, 28.72 mmol), and N -ethyldiisopropylamine (10.29 mL, 57.45 mmol) ), which was stirred at rt for 16 h. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (3×150 mL). The combined organic layer was washed with water (3×100 mL), brine (100 mL), dried over sodium sulfate, and then concentrated. Using 50% ethyl acetate (in hexane) as the eluent, the resulting residue was purified by column chromatography (100 to 200 silica) to obtain the title compound as a brown solid (5 g, 69% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.98 (br s, 1H), 9.70 (br d, J =5.9 Hz, 1H), 8.09-7.98 (m, 2H), 7.54-7.45 (m, 2H) ), 3.83-3.71 (m, 1H), 3.70-3.56 (m, 1H), 3.50-3.35 (m, 2H), 2.55-2.40 (m, 1H), 2.26 (br s, 1H), 2.08 (s, 3H), 1.22 (s, 9H); MS (ESI) m/z 377.17 [M+1] + .
步驟 3 ： (S )- 三級丁基 3-(3- 碘 -1H - 吲唑 -5- 基胺甲醯基 )-3-( 甲基硫基 ) 吡咯啶 -1- 羧酸酯 ： 在0至5℃下，向(S )-三級丁基3-(1H-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯(5 g, 13.26 mmol)於DMF (50 mL)中之攪拌溶液，添加氫氧化鉀(7.31, 53.04 mmol)，接著添加碘(3.69 g, 14.58 mmol)。將混合物在0至5℃下攪拌3 h。將10% NaHSO4 (於水中，150 mL)添加至反應混合物，將其用乙酸乙酯(3 × 150 mL)萃取。將合併的有機層用水(150 mL)、鹽水(100 mL)洗滌，用硫酸鈉乾燥，然後濃縮。使用20%乙酸乙酯(於己烷中)作為洗提液，將所得殘餘物藉由管柱層析術純化，以得到呈固體之標題化合物(4.7 g，70%產率)。1 H NMR (300 MHz, DMSO-d6 ) δ = 13.45 (br s, 1H), 9.82 (br d,J =4.0 Hz, 1H), 7.85 (br s, 1H), 7.65 (br d,J =8.8 Hz, 1H), 7.51 (d,J =9.2 Hz, 1H), 3.84-3.58 (m, 3H), 3.52-3.27 (m, 3H), 2.90 (s, 1H), 2.73 (s, 1H), 2.38 - 2.19 (br d,J =8.8 Hz, 2H), 2.08 (s, 3H), 1.47-1.37 (m, 9H)。MS (ESI)m/z 503.09 [M+1]+ 。 Step 3 : ( S ) -Tributyl 3-(3- iodo -1 H - indazol- 5 -ylaminomethanyl )-3-( methylthio ) pyrrolidine- 1- carboxylate : At 0 to 5 ℃, to ( S )-tertiary butyl 3-(1H-indazol-5-ylaminomethanyl)-3-(methylthio)pyrrolidine-1-carboxylate ( A stirred solution of 5 g, 13.26 mmol) in DMF (50 mL), potassium hydroxide (7.31, 53.04 mmol), followed by iodine (3.69 g, 14.58 mmol). The mixture was stirred at 0 to 5°C for 3 h. 10% NaHSO 4 (in water, 150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (3×150 mL). The combined organic layer was washed with water (150 mL), brine (100 mL), dried over sodium sulfate, and then concentrated. Using 20% ethyl acetate (in hexane) as the eluent, the resulting residue was purified by column chromatography to obtain the title compound (4.7 g, 70% yield) as a solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ = 13.45 (br s, 1H), 9.82 (br d, J =4.0 Hz, 1H), 7.85 (br s, 1H), 7.65 (br d, J = 8.8 Hz, 1H), 7.51 (d, J =9.2 Hz, 1H), 3.84-3.58 (m, 3H), 3.52-3.27 (m, 3H), 2.90 (s, 1H), 2.73 (s, 1H), 2.38-2.19 (br d, J =8.8 Hz, 2H), 2.08 (s, 3H), 1.47-1.37 (m, 9H). MS (ESI) m/z 503.09 [M+1] + .
步驟4 ：(S
)- 三級丁基3-(3- 碘-1- 三苯甲基-1H- 吲唑-5- 基胺甲醯基)-3-( 甲基硫基) 吡咯啶-1- 羧酸酯：
在0至5℃下，向(S
)-三級丁基3-(3-碘-1H-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯(4.7 g, 9.36 mmol)於乙腈(50 mL)中之攪拌溶液，添加碳酸鉀(6.45 g, 46.8 mmol)，接著添加三苯甲基氯(trityl chloride) (2.87 g, 10.29 mmol)。將混合物在rt下攪拌3小時。將溶劑濃縮，接著添加水(150 mL)。將混合物用EtOAc (3 × 150 mL)萃取。將合併的有機層用鹽水(150 mL)洗滌，用硫酸鈉乾燥，然後濃縮。使用15%乙酸乙酯：己烷作為洗提液，將所得殘餘物藉由管柱層析術(100至200二氧化矽)純化，以得到呈棕色固體之標題化合物(4.5 g，65%產率)。1
H NMR (400 MHz, DMSO-d6
) δ = 9.79 (br d,J
=9.3 Hz, 1H), 7.86 (s, 1H), 7.41-7.10 (m, 16H), 6.33 (d,J
=9.3 Hz, 1H), 3.74 (br t,J
=13.0 Hz, 1H), 3.59 (br dd,J
=12.0, 17.4 Hz, 1H), 3.38 (br dd,J
=7.1, 13.9 Hz, 2H), 2.56-2.37 (m, 1H), 2.21 (br s, 1H), 2.04 (s, 3H), 1.40 (s, 9H)。中間物 2 三級丁基 (3S
)-3-((3- 碘 -1-( 四氫 -2H- 哌喃 -2- 基 )-1H- 吲唑 -5- 基 ) 胺甲醯基 )-3-( 甲基硫基 ) 吡咯啶 -1- 羧酸酯 
步驟1 ：(S
)- 三級丁基3-(3- 碘-1-( 四氫-2H- 哌喃-2- 基)-1H- 吲唑-5- 基胺甲醯基)-3-( 甲基硫基) 吡咯啶-1- 羧酸酯：
在0至5℃下，向(S
)-三級丁基3-(3-碘-1H-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯(18.5 g, 36.8 mmol)於二氯甲烷(200 mL)中之攪拌溶液，添加DHP (15.4 g, 183 mmole)，接著添加PTSA (0.699 g, 3.68 mmol)。將混合物在rt下攪拌3小時。將溶劑濃縮，接著添加水(300 mL)。將混合物用EtOAC (3 × 300 mL)萃取。將合併的有機層用鹽水(150 mL)洗滌，用硫酸鈉乾燥，然後濃縮。使用15%乙酸乙酯：己烷作為洗提液，將所得殘餘物藉由管柱層析術純化，以得到標題化合物(15.5 g，72%產率)。MS (ESI)m/z
587.35 [M+H]+
。中間物3 2- 氯-1-(4-(4-(1- 甲基-1H-1,2,4- ***-3- 基) 苯基)-3,6- 二氫吡啶-1(2
H)- 基) 乙-1- 酮-2,2-d2 
在0℃下向氯乙酸-d2
(250 mg, 2.57 mmol)於甲苯(5 mL)中之溶液，添加一滴DMF，接著添加草醯氯(0.4 mL, 3.86 mmol)，然後在rt下攪拌1 h。在0℃下，將所得澄清溶液逐滴添加至4-(4-(1-甲基-1H
-1,2,4-***-3-基)苯基)-1,2,3,6-四氫吡啶鹽酸鹽(500 mg, 1.80 mmol)及N,N
-二異丙基乙基胺(0.4 mL, 2.57 mmol)之二氯甲烷(15 mL)溶液，並將反應在rt下攪拌1 h。將反應混合物用碳酸氫鈉(10 mL)淬熄，然後用乙酸乙酯(2 × 20 mL)萃取。將合併的有機層用水(10 mL)、鹽水(10 mL)洗滌，用硫酸鈉乾燥，然後濃縮。使用5%的甲醇(於二氯甲烷中)作為洗提液，將所得粗製化合物藉由管柱層析術純化，以得到呈灰白色固體之標題化合物(200 mg，20%產率)。1
H NMR (300 MHz, DMSO-d6
) δ 8.51 (s, 1H), 7.96 (d,J
= 8.4 Hz, 2H), 7.56-7.52 (m, 2H), 6.28 (s, 1H), 4.20-4.14 (m, 2H), 3.91 (s, 3H), 3.72-3.66 (m, 2H), 2.73-2.61 (m, 2H)。MS (ESI)m/z
319.0 [M+1]+
。中間物 4 (S
)-N
-(3-(6- 環丙氧基吡啶 -3- 基 )-1H
- 吲唑 -5- 基 )-3-( 甲基硫基 ) 吡咯啶 -3- 羧醯胺 
步驟1 ：5- 溴-2- 環丙氧基吡啶： 在0℃下向5-溴-2-氟吡啶(12.0 g, 68.6 mmol)於NMP (120 mL)中之攪拌溶液，添加環丙醇(5.97 g, 102.9 mmol)、三級丁氧化鉀溶液於THF中(1M，103 mL，102.9 mmol)，然後在rt下攪拌2 h。將反應混合物用冷水(0至5℃)淬熄，並用50% EtOAc(於石油醚中，2 × 500 mL)萃取。將合併的有機層用水洗滌，並用硫酸鈉乾燥，然後在減壓下濃縮，以得到5-溴-2-環環氧吡啶(11.2 g，76%產率)，其直接用於下一個步驟。MS (ESI)m/z 213.8 [M+H]+ 。 Step 1 : 5- Bromo-2- cyclopropoxypyridine: To a stirred solution of 5-bromo-2-fluoropyridine (12.0 g, 68.6 mmol) in NMP (120 mL) at 0°C, add cyclopropanol (5.97 g, 102.9 mmol), tertiary potassium butoxide solution in THF (1M, 103 mL, 102.9 mmol), and then stirred at rt for 2 h. The reaction mixture was quenched with cold water (0 to 5°C) and extracted with 50% EtOAc (in petroleum ether, 2 x 500 mL). The combined organic layer was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure to obtain 5-bromo-2-cycloepoxypyridine (11.2 g, 76% yield), which was used directly in the next step. MS (ESI) m/z 213.8 [M+H] + .
步驟2 ：2- 環丙氧基-5-(4,4,5,5- 四甲基-1,3,2- 二 
步驟3：(3S
)-三級丁基3-(3-(6-環丙氧基吡啶-3-基)-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯：向(3S
)-三級丁基3-(3-碘-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯(14.0 g, 23.9 mmol)及2-環丙氧基-5-(4,4,5,5-四甲基-1,3,2-二
步驟4 ：(S
)-N
-(3-(6- 環丙氧基吡啶-3- 基)-1H
- 吲唑-5- 基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺：
向(3S
)-三級丁基3-(3-(6-環丙氧基吡啶-3-基)-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯(13.6 g, 22.9 mmol)之攪拌溶液，添加TFA (130 mL)，並將混合物在rt下攪拌16 h。將反應混合物在減壓下濃縮。使用10至20%二氯甲烷(於甲醇中)純化，將粗製化合物藉由管柱層析術純化，以得到(S
)-N
-(3-(6-環丙氧基吡啶-3-基)-1H
-吲唑-5-基)-3(甲基硫基)吡咯啶-3-羧醯胺(4.0 g，42%產率)，其不經任何進一步純化即用於下一個步驟。MS (ESI)m/z
410.11 [M+H]+
。中間物5 (S
)-N
-(3-(6- 環丁氧基吡啶-3- 基)-1H
- 吲唑-5- 基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用(S)
-三級丁基3-(3-碘-1-三苯甲基-1H
-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯及2-環丁氧基-5-(4,4,5,5-四甲基-1,3,2-二
使用三級丁基(3S
)-3-((3-碘-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-基)胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯及3-環丙氧基-2-甲氧基-6-(4,4,5,5-四甲基-1,3,2-二
步驟1 ：2- 氯-6- 碘-3-(4- 甲氧基苄氧基) 吡啶 ：向2-氯-6-碘吡啶-3-醇(6 g, 19.60 mmol)於DMF (30 mL)中之攪拌溶液，添加4-甲氧基苄基溴化物(3.6 mL, 25.5 mmol)、碳酸鉀(3.7 g, 29.40 mmol)，然後將反應混合物加熱至70℃達5 h。將反應混合物用水稀釋，並用乙酸乙酯(3 × 50 mL)萃取。將合併的有機層用水(2 × 50 mL)、鹽水(1 × 60 mL)洗滌，用硫酸鈉乾燥，然後濃縮。使用10%乙酸乙酯(於己烷中)作為洗提液，將所得殘餘物藉由管柱層析術純化，以得到呈固體之2-氯-6-碘-3-(4-甲氧基苄氧基)吡啶(7 g，80%產率)。MS (ESI)m/z 376.17 [M+H]+ 。 Step 1 : 2- Chloro-6- iodo-3-(4 -methoxybenzyloxy) pyridine : add 2-chloro-6-iodopyridin-3-ol (6 g, 19.60 mmol) in DMF (30 mL ), add 4-methoxybenzyl bromide (3.6 mL, 25.5 mmol), potassium carbonate (3.7 g, 29.40 mmol), and then heat the reaction mixture to 70°C for 5 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with water (2×50 mL), brine (1×60 mL), dried over sodium sulfate, and then concentrated. Using 10% ethyl acetate (in hexane) as the eluent, the resulting residue was purified by column chromatography to obtain 2-chloro-6-iodo-3-(4-methoxy Benzyloxy)pyridine (7 g, 80% yield). MS (ESI) m/z 376.17 [M+H] + .
步驟2 ：2- 乙氧基-6- 碘-3-(4- 甲氧基苄氧基) 吡啶 ：在rt下向2-氯-6-碘-3-(4-甲氧基苄氧基)吡啶(6.5 g, 17.3 mmol)於EtOH (65 mL)中之攪拌溶液，添加三級丁氧化鉀(1.94 g, 17.44 mmol)，然後在密封容器中將反應在80℃下攪拌24 h。於真空中移除溶劑，然後將殘餘物用水稀釋，並用乙酸乙酯(3 × 50 mL)萃取。將合併的有機層用水(2 × 40 mL)、鹽水(1 × 60 mL)洗滌，用硫酸鈉乾燥，然後濃縮。使用15%乙酸乙酯(於己烷中)，將所得殘餘物藉由管柱層析術純化，以得到呈液體之2-乙氧基-6-碘-3-(4-甲氧基苄氧基)吡啶(3.4 g，51%產率)。MS (ESI)m/z 385.92 [M+H]+ 。 Step 2 : 2- Ethoxy-6- iodo-3-(4 -methoxybenzyloxy) pyridine : to 2-chloro-6-iodo-3-(4-methoxybenzyloxy) at rt ) A stirred solution of pyridine (6.5 g, 17.3 mmol) in EtOH (65 mL), add tertiary potassium butoxide (1.94 g, 17.44 mmol), and then stir the reaction at 80°C for 24 h in a sealed container. The solvent was removed in vacuo, then the residue was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with water (2×40 mL), brine (1×60 mL), dried over sodium sulfate, and then concentrated. Using 15% ethyl acetate (in hexane), the resulting residue was purified by column chromatography to obtain 2-ethoxy-6-iodo-3-(4-methoxybenzyl) as a liquid (Oxy)pyridine (3.4 g, 51% yield). MS (ESI) m/z 385.92 [M+H] + .
步驟3 ：2- 乙氧基-6- 碘吡啶-3- 醇： 在0℃下，向化合物2-乙氧基-6-碘-3-(4-甲氧基苄氧基)吡啶(3 g, 7.79 mmol)於二氯甲烷(15 mL)中之攪拌溶液，添加TFA (5 mL)，然後將反應加熱至回流溫度達30 min。將反應混合物用NaHCO3 水溶液淬熄，並用乙酸乙酯(3 × 40 mL)萃取。將合併的有機層用水(2 × 30 mL)、鹽水(1 × 50 mL)洗滌，用硫酸鈉乾燥，然後濃縮。使用25%乙酸乙酯(於己烷中)作為洗提液，將所得殘餘物藉由管柱層析術純化，以得到呈液體之2-乙氧基-6-碘吡啶-3-醇(1.5 g，75%產率)。MS (ESI)m/z 266.04 [M+H]+ 。 Step 3 : 2- Ethoxy-6- iodopyridin-3- ol: At 0°C, the compound 2-ethoxy-6-iodo-3-(4-methoxybenzyloxy)pyridine (3 g, 7.79 mmol) in dichloromethane (15 mL), add TFA (5 mL), and then heat the reaction to reflux temperature for 30 min. The reaction mixture was quenched with aqueous NaHCO 3 and extracted with ethyl acetate (3×40 mL). The combined organic layer was washed with water (2×30 mL), brine (1×50 mL), dried over sodium sulfate, and then concentrated. Using 25% ethyl acetate (in hexane) as the eluent, the resulting residue was purified by column chromatography to obtain 2-ethoxy-6-iodopyridin-3-ol ( 1.5 g, 75% yield). MS (ESI) m/z 266.04 [M+H] + .
步驟4 ：3- 環丙氧基-2- 乙氧基-6- 碘吡啶： 在rt下，向2-乙氧基-6-碘吡啶-3-醇(1.5 g, 5.66 mmol)於DMF(30 mL)中之攪拌溶液，添加溴環丙烷(4.5 mL, 56.6 mmol)、碳酸銫(5.51 g, 17.0 mmol)、及碘化鈉(0.84 g, 5.66 mmol)。在密封容器中將混合物在150℃下攪拌12 h。將反應混合物用冰冷的水淬熄，然後用乙酸乙酯(2 × 40 mL)萃取。將合併的有機層用水(30 mL)及鹽水溶液(30 mL)洗滌，用硫酸鈉乾燥，在減壓下濃縮。使用5%乙酸乙酯(於石油醚中)，將所得粗產物藉由管柱層析術純化，以得到呈液體之3-環丙氧基-2-乙氧基-6-碘吡啶(550 mg，34%產率)。MS (ESI)m/z 306.18 [M+H]+ 。 Step 4 : 3- Cyclopropoxy-2- ethoxy-6- iodopyridine: At rt, add 2-ethoxy-6-iodopyridin-3-ol (1.5 g, 5.66 mmol) in DMF( 30 mL), add bromocyclopropane (4.5 mL, 56.6 mmol), cesium carbonate (5.51 g, 17.0 mmol), and sodium iodide (0.84 g, 5.66 mmol). The mixture was stirred at 150°C for 12 h in a sealed container. The reaction mixture was quenched with ice-cold water, and then extracted with ethyl acetate (2×40 mL). The combined organic layer was washed with water (30 mL) and brine solution (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. Using 5% ethyl acetate (in petroleum ether), the resulting crude product was purified by column chromatography to obtain 3-cyclopropoxy-2-ethoxy-6-iodopyridine (550 mg, 34% yield). MS (ESI) m/z 306.18 [M+H] + .
步驟5 ：3- 環丙氧基-2- 乙氧基-6-( 三甲基錫烷基) 吡啶：
在rt下，向3-環丙氧基-2-乙氧基-6-碘吡啶(350 mg, 1.14 mmol)於二
步驟6 ：(3S
)- 三級丁基3-(3-(5- 環丙氧基-6- 乙氧基吡啶-2- 基)-1-( 四氫-2H
- 哌喃-2- 基)-1H
- 吲唑-5- 基胺甲醯基)-3-( 甲基硫基) 吡咯啶-1- 羧酸酯：
在rt下，向上述反應混合物之攪拌及除氣溶液，添加3-環丙氧基-2-乙氧基-6-(三甲基錫烷基)吡啶(450 mg, 0.71 mmol)(於二
步驟7 ：(S
)-N
-(3-(5- 環丙氧基-6- 乙氧基吡啶-2- 基)-1H
- 吲唑-5- 基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺：
在0℃下向(3S
)-三級丁基3-(3-(5-環丙氧基-6-乙氧基吡啶-2-基)-1-(四氫-2H-哌喃-2-基)-1H-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯(190 mg, 0.29 mmol)添加TFA (5 mL)，並在rt下攪拌16 h。將反應物於真空中濃縮，並將粗製混合物用二乙基醚研製，以得到呈灰白色固體之(S
)-N
-(3-(5-環丙氧基-6-乙氧基吡啶-2-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺(80 mg，61%產率)。MS (ESI)m/z
454.10 [M+H]+
。中間物8 (S
)-N
-(3-(5- 環丙氧基-6-( 甲氧基-d3
) 吡啶-2- 基)-1H
- 吲唑-5- 基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用2-氯-6-碘-3-(4-甲氧基苄氧基)吡啶、鈉甲氧化物-d3
、及3-(3-碘-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯，依照針對中間物7所述程序來製備標題化合物。MS (ESI)m/z
443.20 [M+H]+
。中間物9 (S
)-N
-(3-(5- 環丙氧基-6- 甲基吡啶-2- 基)-1H
- 吲唑-5- 基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用6-溴-2-甲基吡啶-3-醇、溴環丙烷、及3-(3-碘-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯，依照針對中間物7所述程序來製備標題化合物。MS (ESI)m/z
423.17 [M+H]+
。中間物10 (S
)-N
-(3-(5- 環丙氧基-6-( 二甲基胺基) 吡啶-2- 基)-1H
- 吲唑-5- 基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用3-環丙氧基-N
,N
-二甲基-6-(三甲基錫烷基)吡啶-2-胺、及3-(3-碘-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯，依照針對中間物7所述程序來製備標題化合物。MS (ESI)m/z
453.15 [M+H]+
。中間物11 2- 氯-1-(4-(3- 氟-4-(1- 甲基-1H
-1,2,4- ***-3- 基) 苯基)-3,6- 二氫吡啶-1(2H
)- 基) 乙-1- 酮-2,2-d2 
使用4-(3-氟-4-(1-甲基-1H-1,2,4-***-3-基)苯基)-1,2,3,6-四氫吡啶鹽酸鹽、及氯乙酸-d3
，依照針對中間物3所述程序來製備標題化合物。MS (ESI)m/z
337.02 [M+H]+
。中間物12 (S
)-N
-(3-(6- 環丙氧基-5- 氟吡啶-2- 基)-1H
- 吲唑-5- 基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用3-(3-碘-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸酯、及(6-環丙氧基-5-氟吡啶-2-基)硼酸，依照針對中間物4所述程序來製備標題化合物。MS (ESI)m/z
428.10 [M+H]+
。中間物13 3-(6- 環丙氧基吡啶 -3- 基 )-7- 氟 -1-( 四氫 -2H
- 哌喃 -2- 基 )-1H
- 吲唑 -5- 胺 
步驟1 ：3- 溴-7- 氟-5- 硝基-1-( 四氫-2H - 哌喃-2- 基)-1H - 吲唑： 向3-溴-7-氟-5-硝基-1H -吲唑(3.5 g, 13.46 mmol)與對甲苯磺酸單水合物(0.256 g, 1.35 mmol)於二氯甲烷(67 mL)中之攪拌混合物，添加3,4-二氫-2H -哌喃(2.83 g, 33.7 mmol)。將混合物在rt下攪拌2 h，接著用水(100 mL)及碳酸氫鈉水溶液(100 mL)洗滌。將有機相於真空中濃縮以提供棕色固體，然後用二乙基醚/己烷混合物研製，接著進行過濾，以得到呈白色固體之3-溴-7-氟-5-硝基-1-(四氫-2H -哌喃-2-基)-1H -吲唑(3.1 g，67%產率)。MS (ESI)m/z 345.1 [M+H]+ 。 Step 1: 3-Bromo-7-fluoro-5-nitro-1- (tetrahydro -2 H - pyran-2-yl) -1 H - indazole: a solution of 3-bromo-7-fluoro-5- Stirring mixture of nitro-1 H -indazole (3.5 g, 13.46 mmol) and p-toluenesulfonic acid monohydrate (0.256 g, 1.35 mmol) in dichloromethane (67 mL), add 3,4-dihydro -2 H -piperan (2.83 g, 33.7 mmol). The mixture was stirred at rt for 2 h, then washed with water (100 mL) and aqueous sodium bicarbonate (100 mL). The organic phase was concentrated in vacuo to provide a brown solid, which was then triturated with a diethyl ether/hexane mixture, followed by filtration to obtain 3-bromo-7-fluoro-5-nitro-1-( tetrahydro -2 H - pyran-2-yl) -1 H - indazole (3.1 g, 67% yield). MS (ESI) m/z 345.1 [M+H] + .
步驟2 ：3-(6- 環丙氧基吡啶-3- 基)-7- 氟-5- 硝基-1-( 四氫-2H
- 哌喃-2- 基)-1H
- 吲唑：
向3-溴-7-氟-5-硝基-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑(2.0 g, 5.8 mmol)於DME:H2
O (8:2, 20 mL)中之混合物，添加2-環丙氧基-5-(4,4,5,5-四甲基-1,3,2-二
步驟3 ：3-(6- 環丙氧基吡啶-3- 基)-7- 氟-1-( 四氫-2H
- 哌喃-2- 基)-1H
- 吲唑-5- 胺：
向3-(6-環丙氧基吡啶-3-基)-7-氟-5-硝基-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑(1.5 g, 3.7 mmol)於甲苯：MeOH(1:1 v/v，總計40 mL)中之溶液，添加10% Pd/C (500 mg)。將反應在H2
(60 psi)下攪拌6 h。將混合物通過矽藻土床過濾，並將濾液在減壓下濃縮以得到呈棕色固體之3-(6-環丙氧基吡啶-3-基)-7-氟-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-胺(1.3 g，3.33 mmol，94%產率)，其直接用於下一個步驟。MS (ESI) m/z 369.54 [M+H]+
。通用程序A ：醯胺偶合 
向對應胺(A
)(1當量，PG1
= Trt或THP)於DMF(0.1至0.5 M，胺於DMF中的初始濃度基於溶解度而有0.1 M至0.5 M的變化)中之攪拌溶液，添加對應的羧酸(B)
(1.0至1.1當量，PG2
= Cbz或Boc)、HATU(1.0至1.2當量)、及DIPEA(2至4當量)，並在rt下攪拌4至16 h。添加水，並將混合物用乙酸乙酯萃取。將合併的有機層用水、鹽水洗滌，用硫酸鈉乾燥，然後濃縮。使用乙酸乙酯(於己烷中)，將殘餘物藉由管柱層析術純化，以得到所欲對應化合物。通用程序B ：胺/ 吲唑之去保護 
將C (1當量，PG1 = Trt或THP，PG2 = Cbz或Boc)於DCM/TFA/水(0.05或0.5 M，3:1:0.5比，條件基於起始材料的溶解度而有所變化；混合的DCM/TFA溶劑係用於一些製劑中，亦參見註記#1)中之溶液在25℃下攪拌過夜。在完成(如LCMS所判定)之後，將反應用飽和碳酸氫鈉水溶液淬熄，並用二氯甲烷萃取(或用乙酸乙酯或乙酸乙酯/四氫呋喃混合物萃取)。將合併的有機層用硫酸鈉乾燥、過濾並濃縮以得到粗產物D 。然後，將粗產物D ，1)在矽膠管柱上純化，其以0至100%二氯甲烷/(於甲醇中為0至10%的7 M NH3 )/二氯甲烷洗提，或2)在rp-C18 HPLC管柱上純化，其在0.1%甲酸存在下純化以0至100%乙腈洗提，以得到純化合物D 。當粗製材料在rp-C18 HPLC管柱或C18卡匣上純化時，將化合物使用水性飽和碳酸氫鈉水溶液來游離鹼化，並用二氯甲烷、乙酸乙酯、乙酸乙酯/THF混合物萃取。Combine C (1 equivalent, PG 1 = Trt or THP, PG 2 = Cbz or Boc) in DCM/TFA/water (0.05 or 0.5 M, 3:1:0.5 ratio, the conditions vary based on the solubility of the starting material ; Mixed DCM/TFA solvent is used in some formulations, see also note #1) The solution in the solution was stirred overnight at 25°C. After completion (as judged by LCMS), the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (or with ethyl acetate or ethyl acetate/tetrahydrofuran mixture). The combined organic layer was dried with sodium sulfate, filtered, and concentrated to give the crude product D. Then, the crude product D , 1) is purified on a silica gel column, which is eluted with 0 to 100% dichloromethane/(0 to 10% 7 M NH 3 in methanol)/dichloromethane, or 2 ) Purified on an rp-C18 HPLC column, which was purified in the presence of 0.1% formic acid and eluted with 0 to 100% acetonitrile to obtain pure compound D. When the crude material was purified on an rp-C18 HPLC column or a C18 cartridge, the compound was free-basified with an aqueous saturated sodium bicarbonate aqueous solution and extracted with a mixture of dichloromethane, ethyl acetate, and ethyl acetate/THF.
註記#1：在一些情況下，使用HCl於醇溶劑中的溶液以將PG1
及PG2
兩者去保護。通用程序C ：二級胺的烷化( 代表性實例) 
在25℃下，向對應二級胺D (1當量)於N,N -二甲基甲醯胺(0.1至0.5 M，二級胺於DMF中的初始濃度基於溶解度而有0.1 M至0.5 M的變化)中之溶液，添加純N -乙基-N -異丙基丙-2-胺(3至6當量，使用過量N -乙基-N -異丙基丙-2-胺，或者以三甲胺置換N -乙基-N -異丙基丙-2-胺)及對應烷化劑E (1.0至1.1當量，較佳的是使用1.0當量的烷化劑，以將過度烷化降至最低)於一部分中。將混合物在rt下攪拌6至24 h；若需要，將混合物在50℃下加熱。在完成(如LCMS或TLC所判定)之後，將混合物1)直接濃縮於旋轉蒸發器上，以給出粗製混合物，將其在矽膠管柱上純化，以甲醇(於二氯甲烷中)洗提，或2)在rp-C18 HPLC管柱上純化，在0.1%甲酸存在下以乙腈(於水中)洗提，以得到所欲對應化合物F 。通用程序D ：鹽酸鹽的製備 At 25℃, to the corresponding secondary amine D (1 equivalent) in N,N -dimethylformamide (0.1 to 0.5 M, the initial concentration of the secondary amine in DMF is 0.1 M to 0.5 M based on solubility Change), add pure N -ethyl- N -isopropylpropan-2-amine (3 to 6 equivalents, use excess N -ethyl- N -isopropylpropan-2-amine, or Trimethylamine replaces N -ethyl- N -isopropylpropan-2-amine) and the corresponding alkylating agent E (1.0 to 1.1 equivalents, preferably 1.0 equivalent of alkylating agent is used to reduce over-alkylation to Lowest) in a part. The mixture was stirred at rt for 6 to 24 h; if necessary, the mixture was heated at 50°C. After completion (as judged by LCMS or TLC), the mixture 1) was directly concentrated on a rotary evaporator to give a crude mixture, which was purified on a silica gel column and eluted with methanol (in dichloromethane) , Or 2) Purify on rp-C18 HPLC column, eluting with acetonitrile (in water) in the presence of 0.1% formic acid to obtain the desired corresponding compound F. General Procedure D : Preparation of Hydrochloride
將化合物F
溶解於合適的溶劑(0.1至0.5 M，二氯甲烷、甲醇、或異丙醇)中。在0℃下，添加鹽酸(1至3當量，於二乙基醚中為2.0 M)。將沉澱物在0℃下攪拌5至10 min。在0℃下使用旋轉蒸發器來移除(多種)過量溶劑及鹽酸。將產物乾燥以得到為鹽酸鹽(鹽酸鹽的當量係藉由1
H NMR分析來判定)的對應化合物G
。實例1 (S)-1-(2-(4-(4-(1- 環丙基-1H-1,2,4- ***-3- 基) 苯基)-3,6- 二氫吡啶-1(2H)- 基)-2- 側氧乙基)-N-(3-(6- 異丙氧吡啶-3- 基)-1H- 吲唑-5- 基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用3-(6-異丙氧吡啶-3-基)-1-三苯甲基-1H
-吲唑-5-胺(參見WO 2016/161160)、(S
)-1-(三級丁氧羰基)-3-(甲基硫基)吡咯啶-3-羧酸(參見ACS Med Chem Lett 2018
, 761之合成部分)、及2-氯-1-(4-(4-(1-環丙基-1H-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H)-基)乙酮(參見WO 2016/161160)，依照通用程序A、B、及C來製備標題化合物。1
H NMR (400 MHz, DMSO-d6
) δ 13.19 (s, 1H), 9.98 (d,J
= 11.4 Hz, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 8.18 (d,J
= 8.80 Hz, 1H), 7.92 (d,J
= 8.80 Hz, 1H), 7.86 (d,J
= 12.0 Hz, 1H), 7.77 (d,J
= 8.80,1.60 Hz, 1H), 7.53-7.47 (m, 2H), 7.40 (d,J
= 8.80 Hz, 1H), 6.92-6.88 (m, 1H), 6.25-6.20 (m, 1H), 5.33-5.28 (m, 1H), 4.26-4.12 (m, 3H), 3.84-3.60 (m, 4H), 3.55-3.44 (m, 3H), 2.88-2.70 (m, 4H), 2.05 (s, 3H), 2.00-1.95 (m, 1H), 1.33 (s, 3H), 1.31 (s, 3H), 1.15-1.02 (m, 4H)。MS (ESI)m/z
718.42 [M+H]+
。實例2 (S)-N-(3-(6- 環丙氧基吡啶-3- 基)-1H- 吲唑-5- 基)-1-(2-(4-(4-(1- 甲基-1H-1,2,4- ***-3- 基) 苯基)-3,6- 二氫吡啶-1(2H)- 基)-2- 側氧乙基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用(3S
)-三級丁基3-(3-(6-環丙氧基吡啶-3-基)-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸、及2-氯-1-(4-(4-(1-甲基-1H
-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H
)-基)乙酮(參見WO 2016/161160)，依照通用程序B及C來製備標題化合物。mp：156至158℃：1
H NMR (400 MHz, DMSO-d 6
) δ 13.25 (s, 1H), 9.99 (s, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.21 (d,J
= 8.7 Hz, 1H), 7.95-7.84 (m, 2H), 7.76 (d,J
= 9.3 Hz, 1H), 7.55-7.84 (m, 2H), 7.41 (d,J
= 8.4 Hz, 1H), 7.06-6.99 (m, 1H), 6.27-6.19 (m, 1H), 4.27-4.20 (m, 2H), 4.16-4.14 (m, 1H), 3.91 (s, 3H), 3.72-3.66 (m, 3H), 3.50-3.46 (m, 3H), 2.79-2.64 (m, 5H), 2.05 (s, 3H), 1.99-1.97 (m, 1H), 0.83-0.71 (m, 4H)；MS (ESI)m/z
690.14 [M+H]+
。實例 3 (S
)-N
-(3-(6- 環丙氧基吡啶 -3- 基 )-1H
- 吲唑 -5- 基 )-1-(2-(4-(4-(1- 甲基 -1H
-1,2,4- *** -3- 基 ) 苯基 )-3,6- 二氫吡啶 -1(2H
)- 基 )-2- 側氧乙基 -1,1-d2
)-3-( 甲基硫基 ) 吡咯啶 -3- 羧醯胺 
使用(3S
)三級丁基3-(3-(6-環丙氧基吡啶-3-基)-1-(四氫-2H
-哌喃-2-基)-1H
-吲唑-5-基胺甲醯基)-3-(甲基硫基)吡咯啶-1-羧酸、及2-氯-1-(4-(4-(1-甲基-1H
-1,2,4-***-3-基)苯基)-3,6-二氫吡啶-1(2H
)-基)乙-1-酮-2,2-d2
，依照通用程序B及C來製備標題化合物。mp：156至158℃；1
H NMR (300 MHz, DMSO-d 6
) δ 13.25 (s, 1H), 9.99 (s, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.21 (d,J
= 8.7 Hz, 1H), 7.95-7.84 (m, 2H), 7.76 (d,J
= 9.3 Hz, 1H), 7.55-7.84 (m, 2H), 7.41 (d,J
= 8.4 Hz, 1H), 7.06-6.99 (m, 1H), 6.27– 6.19 (m, 1H), 4.27-4.14 (m, 3H), 3.91 (s, 3H), 3.72-3.66 (m, 2H), 3.50-3.46 (m, 1H), 2.80-2.64 (m, 6H), 2.05 (s, 3H), 1.99-1.97 (m, 1H), 0.83-0.71 (m, 4H)；MS (ESI)m/z
: 692.15 [M+H]+
。實例 4 (S
)-N
-(3-(6- 環丁氧基吡啶 -3- 基 )-1H
- 吲唑 -5- 基 )-1-(2-(4-(4-(1- 甲基 -1H
-1,2,4- *** -3- 基 ) 苯基 )-3,6- 二氫吡啶 -1(2H
)- 基 )-2- 側氧乙基 -1,1-d2
)-3-( 甲基硫基 ) 吡咯啶 -3- 羧醯胺 
使用(S)
-N
-(3-(6-環丁氧基吡啶-3-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(4-(1-甲基-1H-1,2,4-***-3-基)苯基)-3,6-二氫吡啶-1(2H
)-基)乙-1-酮-2,2-d2
，依照通用程序C來製備標題化合物。1
H NMR (DMSO–d6
, 400 MHz) δ 13.21 (s, 1H), 9.95-9.93 (m, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 8.39 (s, 1H), 8.18 (dd,J
= 8.8, 2.8 Hz, 1H), 7.96-7.85 (m, 2H), 7.76 (d,J
= 8.8 Hz, 1H), 7.55-7.47 (m, 2H), 7.41 (d,J
= 8.4 Hz, 1H), 6.97-6.91 (m, 1H), 6.27-6.18 (m, 1H), 5.19 (qt,J
= 7.6 Hz, 1H), 4.27-4.07 (m, 2H), 3.91 (s, 3H), 3.77-3.63 (m, 2H), 3.50-3.46 (m, 1H), 2.86-2.57 (m, 5H), 2.44-2.38 (m, 3H), 2.15-1.96 (m, 6H), 1.83-1.76 (m, 1H), 1.69-1.60 (m, 1H)。MS (ESI)m/z
706.60 [M+H]+
。實例5 (S
)-N
-(3-(5- 環丙氧基-6- 甲氧基吡啶-2- 基)-1H
- 吲唑-5- 基)-1-(2-(4-(4-(1- 甲基-1H
-1,2,4- ***-3- 基) 苯基)-3,6- 二氫吡啶-1(2H
)- 基)-2- 側氧乙基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用(S
)-N
-(3-(5-環丙氧基-6-甲氧基吡啶-2-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(4-(1-甲基-1H
-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H
)-基)乙酮，依照通用程序C來製備標題化合物。mp：144至146℃；1
H NMR (400 MHz, DMSO-d 6,
VT NMR, 90℃) δ 13.02 (s, 1H), 9.62 (s, 1H), 8.98 (s,
1H), 8.41 (s, 1H), 7.90 (d,J
= 8.0 Hz, 2H), 7.68 (d,J
= 8.0 Hz, 1H), 7.60 (d,J
= 8.4 Hz, 1H), 7.46-7.40 (m, 4H), 6.23-6.17 (m,
1H), 4.22-4.10 (m, 2H), 4.09 (s, 3H), 3.96-3.87 (m, 4H), 3.73-3.69 (m, 2H), 3.51-3.43 (m, 3H), 2.86-2.75 (m, 3H), 2.67-2.60 (m, 1H), 2.54-2.52 (m, 2H), 2.07 (s, 3H), 2.05-1.98 (m, 1H), 0.81-0.68 (m, 4H)。MS (ESI)m/z
720.58 [M+H]+
。實例 6 (S
)-N
-(3-(5- 環丙氧基 -6- 乙氧基吡啶 -2- 基 )-1H
- 吲唑 -5- 基 )-1-(2-(4-(4-(1- 甲基 -1H
-1,2,4- *** -3- 基 ) 苯基 )-3,6- 二氫吡啶 -1(2H
)- 基 )-2- 側氧乙基 )-3-( 甲基硫基 ) 吡咯啶 -3- 羧醯胺 
使用(S
)-N
-(3-(5-環丙氧基-6-乙氧基吡啶-2-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(4-(1-甲基-1H-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H
)-基)乙酮，依照通用程序C來製備標題化合物。1
H NMR (400 MHz, DMSO-d6
) δ 13.05 (s, 1H), 9.83-9.81 (m, 1H), 9.09-9.05 (m, 1H), 8.49 (s, 1H), 7.92 (d,J
= 8 Hz, 1H), 7.86 (d,J
= 8.4 Hz, 1H), 7.72-7.69 (m, 1H), 7.65-7.60 (m, 1H), 7.50-7.47 (m, 2H), 7.42-7.38 (m, 2H), 6.27-6.18 (m,
1H), 4.63-4.57 (m, 2H), 4.28-4.08 (m, 3H), 3.91 (s, 3H), 3.90-3.87 (m, 1H) 3.74-3.65 (m, 2H), 3.49–3.41 (m, 4H), 2.79-2.65 (m, 4H), 2.06 (s, 3H), 2.02-1.99 (m, 1H), 1.40 (t,J
= 6.8 Hz, 3H), 0.82-0.72 (m, 4H)。MS (ESI)m/z
734.59 [M+H]+
。實例7 (S
)-N
-(3-(6- 環丙氧基吡啶-3- 基)-1H
- 吲唑-5- 基)-1-(2-(4-(5-(1- 甲基-1H
-1,2,4- ***-3- 基) 噻唑-2- 基)-3,6- 二氫吡啶-1(2H
)- 基)-2- 側氧乙基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用(S
)-N
-(3-(6-環丙氧基吡啶-3-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(5-(1-甲基-1H
-1,2,4-***-3-基)噻唑-2-基)-5,6-二氫吡啶-1(2H
)-基)乙酮(參見WO 2018/067512)，依照通用程序C來製備標題化合物。mp：138至140℃；1
H NMR (400 MHz, DMSO-d 6
) δ 13.21 (s, 1H), 9.97-9.90 (m, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.25-8.17 (m, 1H), 8.15-8.09 (m, 1H), 7.74 (d,J
= 8.8 Hz, 1H), 7.50 (d,J
= 9.2 Hz, 1H), 7.02 (d,J
= 8.8 Hz, 1H), 6.70-6.60 (m, 1H), 4.40-4.20 (m, 2H), 4.22-4.15 (m, 1H), 3.90 (s, 3H), 3.72-3.66 (m, 2H), 3.53-3.29 (m, 3H), 2.83-2.70 (m, 3H), 2.70-2.60 (m, 3H), 2.03 (s, 3H), 2.02-1.93(m, 1H), 0.83-0.70 (m, 4H)；MS (ESI)m/z
697.52 [M+H]+
。實例 8 (S
)-N
-(3-(6- 環丙氧基吡啶 -3- 基 )-1H
- 吲唑 -5- 基 )-1-(2-(4-(5-(1- 甲基 -1H
-1,2,4- *** -3- 基 )-1,3,4- 噻二唑 -2- 基 )-3,6- 二氫吡啶 -1(2H
)- 基 )-2- 側氧乙基 )-3-( 甲基硫基 ) 吡咯啶 -3- 羧醯胺 
使用(S
)-N
-(3-(6-環丙氧基吡啶-3-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(5-(1-甲基-1H-1,2,4-***-3-基)-1,3,4-噻二唑-2-基)-5,6-二氫吡啶-1(2H
)-基)乙酮(參見WO 2018/067512)，依照通用程序C來製備標題化合物。mp：95至97℃；1
H NMR (400 MHz, DMSO-d6
) δ 13.17 (s, 1H), 9.91 (s, 1H), 8.72 (d,J
= 13.6 Hz, 2H), 8.38 (d,J
= 8.4 Hz, 1H), 8.21 (dd,J
= 8.4, 2 Hz, 1H), 7.75-7.72 (m, 1H), 7.50 (d,J
= 8.8 Hz, 1H), 7.02 (d,J
= 8.4 Hz, 1H), 6.78-6.71 (m, 1H), 4.36-4.23 (m, 3H), 3.98 (s, 3H), 3.75-3.71 (m, 2H), 3.54-3.34 (m, 3H), 2.82-2.61 (m, 6H), 2.04 (s, 3H), 2.01-1.98 (m, 1H), 0.82-0.70 (m, 4H)。MS (ESI)m/z
698.18 [M+H]+
。實例 9 (S
)-N
-(3-(5- 環丙氧基 -6- 甲氧基吡啶 -2- 基 )-1H
- 吲唑 -5- 基 )-1-(2-(4-(4-(1- 甲基 -1H
-1,2,4- *** -3- 基 ) 苯基 )-3,6- 二氫吡啶 -1(2H
)- 基 )-2- 側氧乙基 -1,1-d2
)-3-( 甲基硫基 ) 吡咯啶 -3- 羧醯胺 
使用(S
)-N
-(3-(5-環丙氧基-6-甲氧基吡啶-2-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(4-(1-甲基-1H
-1,2,4-***-3-基)苯基)-3,6-二氫吡啶-1(2H
)-基)乙-1-酮-2,2-d2
，依照通用程序C來製備標題化合物。mp：145至147℃：1
H NMR (400 MHz, DMSO-d 6
) δ 13.20 (s, 1H), 9.98 (m, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 7.9 (d,J
= 8.4 Hz, 1H), 7.86 (d,J
= 8.4 Hz, 1H), 7.70 (d,J
= 8.0 Hz, 1H), 7.68-7.60 (m, 1H), 7.50-7.40 (m, 4H), 6.30-6.20 (m, 1H), 4.40-4.10 (m, 3H), 4.08 (s, 3H), 3.91 (s, 4H), 3.74-3.70 (m, 1H), 3.68-3.64 (m, 1H), 3.50-3.43 (m, 1H), 2.80-2.70 (m, 3H), 2.70-2.60 (m, 2H), 2.05 (s, 3H), 2.02-1.93(m, 1H), 0.83-0.70 (m, 4H)。MS (ESI)m/z
722.60 [M+H]+
。實例10 (S
)-N
-(3-(5- 環丙氧基-6- 甲氧基吡啶-2- 基)-1H
- 吲唑-5- 基)-1-(2-(4-(3- 氟-4-(1- 甲基-1H
-1,2,4- ***-3- 基) 苯基)-3,6- 二氫吡啶-1(2H
)- 基)-2- 側氧乙基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用(S
)-N
-(3-(5-環丙氧基吡啶-6-甲氧基吡啶-2-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(3-氟-4-(1-甲基-1H
-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H
)-基)乙酮(參見WO 2016/161160)，依照通用程序C來製備標題化合物。mp：146至148℃；1
H NMR (400 MHz, DMSO-d 6
) δ 13.02 (s, 1H), 9.89 (s,
1H), 9.07 (s,
1H), 8.54 (s, 1H), 7.98-7.82 (m, 1H), 7.73-7.59 (m, 2H), 7.47-7.41 (m, 2H), 7.37 –7.23 (m, 2H), 6.38-6.28 (m, 1H), 4.32-4.06 (m, 2H), 4.08 (s, 3H), 3.93 (s, 3H), 3.74-3.62 (m,
2H), 3.48-3.41 (m, 3H), 2.81-2.71 (m, 3H), 2.68-2.61 (m, 3H), 2.04 (s, 3H), 2.02-1.94 (m, 1H), 0.83-0.68 (m, 4H)。MS (ESI)m/z
738.56 [M+H]+
。實例 11 (S
)-N
-(3-(6- 環丙氧基吡啶 -3- 基 )-1H
- 吲唑 -5- 基 )-1-(2-(4-(3- 氟 -4-(1- 甲基 -1H
-1,2,4- *** -3- 基 ) 苯基 )-3,6- 二氫吡啶 -1(2H
)- 基 )-2- 側氧乙基 )-3-( 甲基硫基 ) 吡咯啶 -3- 羧醯胺 
使用(S
)-N
-(3-(6-環丙氧基吡啶-3-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(3-氟-4-(1-甲基-1H
-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H
)-基)乙酮，依照通用程序C來製備標題化合物。mp：133至135℃；1
H NMR (400 MHz, DMSO-d 6
) δ 13.25 (s, 1H), 9.97-9.93 (m, 1H), 8.74 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.25-8.15 (m, 1H), 8.00-7.85 (m, 1H), 7.76 (d,J
= 9.2 Hz, 1H), 7.52 (d,J
= 8.8 Hz, 1H), 7.40-7.20 (m, 2H), 7.10-6.99 (m, 1H), 6.40-6.25 (m, 1H), 4.27-4.10 (m, 3H), 3.93 (s, 3H), 3.72-3.66 (m, 2H), 3.50-3.46 (m, 3H), 2.85-2.45 (m, 6H), 2.05 (s, 3H), 2.02-1.93(m, 1H), 0.83-0.70 (m, 4H)。MS (ESI)m/z
708.55 [M+H]+
。實例 12 (S
)-N
-(3-(6- 環丙氧基吡啶 -3- 基 )-1H
- 吲唑 -5- 基 )-1-(2-(4-(3- 氟 -4-(1- 甲基 -1H
-1,2,4- *** -3- 基 ) 苯基 )-3,6- 二氫吡啶 -1(2H
)- 基 )-2- 側氧乙基 -1,1-d2
)-3-( 甲基硫基 ) 吡咯啶 -3- 羧醯胺 
使用(S
)-N
-(3-(6-環丙氧基吡啶-3-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(3-氟-4-(1-甲基-1H
-1,2,4-***-3-基)苯基)-3,6-二氫吡啶-1(2H
)-基)乙-1-酮-2,2-d2
，依照通用程序C來製備標題化合物。1
H NMR (400 MHz, DMSO-d6
) δ 13.18 (s, 1H), 9.97-9.93 (m, 1H), 8.74 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.24-8.18 (m, 1H), 7.92-7.85 (m, 1H), 7.76 (d,J
= 8.4 Hz, 1H), 7.52 (d,J
= 8.8 Hz, 1H), 7.36-7.24 (m, 2H), 7.04-7.00 (m, 1H), 6.35-6.30 (m, 1H), 4.28-4.14 (m, 3H), 3.93 (s, 3H), 3.76-3.68 (m, 3H), 3.47-3.45 (m, 2H), 2.81-2.73 (m, 4H), 2.05 (s, 3H), 2.00-1.98 (m, 1H), 0.79-0.71 (m, 4H)；MS (ESI)m/z
710.23 [M+H]+
。實例13 (S
)-N
-(3-(5- 環丙氧基-6-( 甲氧基-d3
) 吡啶-2- 基)-1H
- 吲唑-5- 基)-1-(2-(4-(4-(1- 甲基-1H
-1,2,4- ***-3- 基) 苯基)-3,6- 二氫吡啶-1(2H
)- 基)-2- 側氧乙基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用(S
)-N
-(3-(5-環丙氧基-6-甲氧基-d3
-吡啶-2-基)-1H-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(4-(1-甲基-1H-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H
)-基)乙酮，依照通用程序C來製備標題化合物。1
H NMR (400 MHz, DMSO-d6
) δ 13.08 (s, 1H), 9.63 (s, 1H), 9.98 (s, 1H), 8.41 (s, 1H), 7.90 (d,J
= 11.2 Hz, 2H), 7.68 (d,J
= 10.8 Hz, 1H), 7.60 (d,J
= 10.8 Hz, 1H), 7.45– 7.41 (m, 4H), 6.19 (s,
1H), 4.25-4.13 (m, 2H), 3.95-3.90 (m, 4H), 3.74-3.68 (m, 2H), 3.50-3.45 (m, 3H), 2.84-2.77 (m, 3H), 2.68-2.61 (m, 3H), 2.07 (s, 3H), 2.05-1.97 (m, 1H), 0.79-0.73 (m, 4H)；MS (ESI)m/z
723.39 [M+H]+
。實例14 (S
)-N
-(3-(5- 環丙氧基-6- 甲基吡啶-2- 基)-1H
- 吲唑-5- 基)-1-(2-(4-(4-(1- 甲基-1H
-1,2,4- ***-3- 基) 苯基)-3,6- 二氫吡啶-1(2H
)- 基)-2- 側氧乙基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用(S
)-N
-(3-(5-環丙氧基-6-甲基吡啶-2-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(4-(1-甲基-1H
-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H
)-基)乙酮，依照通用程序C來製備標題化合物。mp：141至143℃；1
H NMR (DMSO–d6
, 400 MHz) δ 13.10 (s, 1H), 9.92 (s, 1H), 8.83 (s, 1H), 8.49 (s, 1H), 8.00-7.80 (m, 3H), 7.72-7.65 (m, 1H), 7.62-7.56 (m, 1H), 7.50-7.39 (m, 3H), 6.31-6.20 (m, 1H), 4.35-4.00 (m, 2H), 3.95-3.93 (m, 1H), 3.91 (s, 3H), 3.80-3.60 (m, 2H), 3.50-3.30 (m, 3H), 2.83-2.60 (m, 3H), 2.59-2.52 (m, 3H), 2.46-2.40 (m, 3H), 2.07 (m, 3H), 2.06-1.95 (m, 1H), 0.86-0.80 (m, 2H), 0.73-0.68 (m, 2H)。MS (ESI)m/z
: 704.51 [M+H]+
。實例 15 (S
)-N
-(3-(5- 環丙氧基 -6-( 二甲基胺基 ) 吡啶 -2- 基 )-1H
- 吲唑 -5- 基 )-1-(2-(4-(4-(1- 甲基 -1H
-1,2,4- *** -3- 基 ) 苯基 )-3,6- 二氫吡啶 -1(2H
)- 基 )-2- 側氧乙基 )-3-( 甲基硫基 ) 吡咯啶 -3- 羧醯胺 
使用(S
)-N
-(3-(5-環丙氧基-6-(二甲基胺基)吡啶-2-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(4-(1-甲基-1H-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H
)-基)乙酮，依照通用程序C來製備標題化合物。mp：146至148℃；1
H NMR (400 MHz, DMSO-d6
) δ 13.05 (s, 1H), 9.90-9.75 (m, 1H), 9.01-8.90 (m, 1H), 8.49 (s, 1H), 8.01-7.80 (m, 2H), 7.60-7.49 (m, 2H), 7.40-7.30 (m, 4H), 6.30-6.10 (m, 1H), 4.30-4.00 (m, 3H), 3.91 (s, 3H), 3.90-3.87 (m, s1H), 3.74-3.60 (m, 2H), 3.51-3.20 (m, 4H), 3.00 (s, 6H), 2.80-2.70 (m, 3H), 2.68-2.60 (m, 1H), 2.06 (s, 3H), 2.00-1.90 (m, 1H), 0.85-0.72 (m, 4H)。MS (ESI)m/z
733.7 [M+H]+
。實例 16 (S
)-N
-(3-(6- 環丙氧基吡啶 -3- 基 )-1H
- 吲唑 -5- 基 )-1-(2-(4-(4-(1- 乙基 -1H
-1,2,4- *** -3- 基 ) 苯基 )-3,6- 二氫吡啶 -1(2H
)- 基 )-2- 側氧乙基 )-3-( 甲基硫基 ) 吡咯啶 -3- 羧醯胺 
使用(S
)-N
-(3-(6-環丙氧基吡啶-3-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(4-(1-乙基-1H
-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H
)-基)乙酮(參見WO 2016/161160)，依照通用程序C來製備標題化合物。1
H NMR (400 MHz, DMSO-d6
) δ 13.19 (s, 1H), 9.97-9.93 (m, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 8.21 (d,J
= 8.0 Hz, 1H), 7.93 (d,J
= 8.4 Hz, 1H), 7.87 (d,J
= 8.4 Hz, 1H), 7.76 (d,J
= 9.2 Hz, 1H), 7.54-7.47 (m, 2H), 7.41 (d,J
= 8 Hz, 1H), 7.03-7.00 (m, 1H), 6.26-6.19 (m, 1H), 4.26-4.12 (m, 5H), 3.72-3.67 (m, 2H), 3.48-3.46 (m, 3H), 2.81-2.73 (m, 3H), 2.66-2.59 (m, 3H), 2.05 (s, 3H), 2.03-1.98 (m, 1H), 1.44 (t,J
= 7.2 Hz, 3H), 0.79-0.71 (m, 4H)。MS (ESI)m/z
704.55 [M+H]+
。實例17 (S
)-N
-(3-(6- 環丙氧基-5- 氟吡啶-2- 基)-1H
- 吲唑-5- 基)-1-(2-(4-(4-(1- 甲基-1H
-1,2,4- ***-3- 基) 苯基)-3,6- 二氫吡啶-1(2H
)- 基)-2- 側氧乙基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用(S
)-N
-(3-(6-環丙氧基-5-氟吡啶-2-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(4-(1-甲基-1H
-1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H
)-基)乙酮，依照通用程序C及D來製備標題化合物。HCl鹽：1
H NMR (400 MHz, DMSO-d6
) δ 13.39 (s, 1H), 10.45 (d, 1H), 10.06 (d, 1H), 9.18 (s, 1H), 8.52 (s, 1H), 8.00-7.97 (m, 2H), 7.81-7.73 (m, 2H), 7.58-7.53 (m, 3H), 7.46-7.44 (dd, 1H), 7.18 (t, 1H), 6.32 (br, 1H), 4.77-4.75 (m, 1H), 3.92 (s, 3H), 3.87-3.78 (m, 3H), 3.63-3.57 (m, 2H), 2.68-2.66 (m, 2H), 2.56-2.55 (m, 1H), 2.46-2.45 (m, 1H), 2.39-2.33 (br, 1H), 2.13-2.12 (m, 3H), 1.30-1.24 (m, 1H), 1.00-0.99 (m, 2H), 0.83 (br, 2H)；MS (ESI)m/z
708.30 [M+H]+
。實例18 (S
)-N
-(3-(5- 環丙氧基-6- 甲氧基吡啶-2- 基)-1H
- 吲唑-5- 基)-1-(2-(4-(5-(1- 甲基-1H
-1,2,4- ***-3- 基) 噻唑-2- 基)-3,6- 二氫吡啶-1(2H
)- 基)-2- 側氧乙基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺 
使用(S
)-N
-(3-(5-環丙氧基-6-甲氧基吡啶-2-基)-1H
-吲唑-5-基)-3-(甲基硫基)吡咯啶-3-羧醯胺、及2-氯-1-(4-(5-(1-甲基-1H
-1,2,4-***-3-基)噻唑-2-基)-5,6-二氫吡啶-1(2H
)-基)乙酮，依照通用程序C及D來製備標題化合物。HCl鹽：1
H NMR (400 MHz, DMSO-d6
) δ 13.22 (s, 1H), 10.50 (br, 1H), 10.02 (d, 1H), 9.12 (br, 2H), 8.59-8.57 (m, 1H), 8.22-8.15 (m, 1H), 7.74-7.65 (m, 2H), 7.55-7.44 (m, 2H), 6.74 (br, 1H), 4.64-4.53 (m, 3H), 4.26 (br, 1H), 4.16-4.10 (m, 3H), 3.95-3.91 (m, 5H), 3.77 (t, 1H), 3.59-3.47 (m, 3H), 2.76-2.73 (m, 2H), 2.67-2.66 (m, 1H), 2.43-2.31 (m, 1H), 2.16 (m, 3H), 0.83-0.81 (m, 2H), 0.72 (m, 2H)；MS (ESI)m/z
727.30 [M+H]+
。實例19 (S
)-N
-(3-(6- 環丙氧基吡啶-3- 基)-7- 氟-1H
- 吲唑-5- 基)-1-(2-(4-(4-(1- 甲基-1H
-1,2,4- ***-3- 基) 苯基)-3,6- 二氫吡啶-1(2H
)- 基)-2- 側氧乙基)-3-( 甲基硫基) 吡咯啶-3- 羧醯胺： 
使用3-(6-環丙氧基吡啶-3-基)-7-氟-1-(四氫-2H -哌喃-2-基)-1H -吲唑-5-胺、(S )-1-(三級丁氧羰基)-3-(甲基硫基)吡咯啶-3-羧酸(參見Boga et al.,ACS Med Chem Lett (2018) 9(7): 761-767)、及2-氯-1-(4-(4-(1-甲基-1H -1,2,4-***-3-基)苯基)-5,6-二氫吡啶-1(2H )-基)乙酮，依照通用程序A、B、及C來製備標題化合物。1 H NMR (400 MHz, DMSO-d 6 ), δ 10.20-10.10 (m, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 8.21-8.17 (m, 2H), 7.95-7.85 (m, 2H), 7.74 (d,J = 13.2 Hz, 1H), 7.43 (d,J = 8.0 Hz, 2H), 7.00 (d,J = 8.8 Hz, 1H), 6.20 (brs, 1H), 4.31-4.25 (m, 2H), 4.19 (brs, 2H), 3.91 (s, 3H), 3.75-3.70 (m, 2H), 3.55-3.45 (m, 3H), 2.90-2.82 (m, 1H), 2.82-2.75 (m, 2H), 2.70-2.60 (m, 1H), 2.60-2.45 (m, 2H，與溶劑峰合併), 2.10-1.95 (m, 4H), 0.82-0.70 (m, 4H)；MS (ESI)m/z 708.20 [M+H]+ 。實例A 活性ERK1 及ERK2 激酶檢定 Using 3- (6-cyclopropyloxy-3-yl) -7-fluoro-1- (tetrahydro -2 H - pyran-2-yl) -1 H - indazol-5-amine, (S )-1-(tertiary butoxycarbonyl)-3-(methylthio)pyrrolidine-3-carboxylic acid (see Boga et al., ACS Med Chem Lett (2018) 9(7): 761-767) , And 2-chloro-1-(4-(4-(1-methyl-1 H -1,2,4-triazol-3-yl)phenyl)-5,6-dihydropyridine-1( 2 H )-yl) ethyl ketone, according to general procedures A, B, and C to prepare the title compound. 1 H NMR (400 MHz, DMSO- d 6 ) , δ 10.20-10.10 (m, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 8.21-8.17 (m, 2H), 7.95-7.85 ( m, 2H), 7.74 (d, J = 13.2 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.20 (brs, 1H), 4.31- 4.25 (m, 2H), 4.19 (brs, 2H), 3.91 (s, 3H), 3.75-3.70 (m, 2H), 3.55-3.45 (m, 3H), 2.90-2.82 (m, 1H), 2.82- 2.75 (m, 2H), 2.70-2.60 (m, 1H), 2.60-2.45 (m, 2H, combined with solvent peak), 2.10-1.95 (m, 4H), 0.82-0.70 (m, 4H); MS ( ESI) m/z 708.20 [M+H] + . Example A Activity ERK1 and ERK2 kinase assay
以遷移率變動檢定(Mobility Shift Assay, MSA)方式，判定活化ERK1及ERK2活性如下：將化合物及激酶溶液用檢定緩衝液(20 mM HEPES, 0.01% Triton X-100, 2 mM DTT, pH7.5)來製備，並在rt下混合及培養30 min。然後，添加Fl-受質、ATP、以及金屬溶液，以活化ERK1及ERK2，並將ERK1及ERK2在rt下培養1 h。1 h後，將70 mL的終止緩衝液(QuickScout Screening Assist MSA; Carna Biosciences)添加至孔中，以終止反應。將反應混合物施加至LabChip™系統(PerkinElmer)，並對產物及受質的肽峰值進行分離、分析及定量。自產物(P)及受質(S)肽(P/(P+S))的峰高，計算產物比，以評估激酶反應。實例B 增生檢定 Use the Mobility Shift Assay (MSA) method to determine the activity of activated ERK1 and ERK2 as follows: Use the assay buffer (20 mM HEPES, 0.01% Triton X-100, 2 mM DTT, pH 7.5). ) To prepare, and mix and incubate for 30 min at rt. Then, Fl-substrate, ATP, and metal solution were added to activate ERK1 and ERK2, and ERK1 and ERK2 were cultured at rt for 1 h. After 1 h, 70 mL of stop buffer (QuickScout Screening Assist MSA; Carna Biosciences) was added to the well to stop the reaction. The reaction mixture was applied to the LabChip™ system (PerkinElmer), and the peptide peaks of the product and substrate were separated, analyzed and quantified. From the peak heights of the product (P) and the substrate (S) peptide (P/(P+S)), the product ratio was calculated to evaluate the kinase reaction. Case B hyperplasia test
使A375(黑色素瘤)、Colo-205(結腸癌)、Miapaca(胰臟)、HPAFII(胰臟)、sNF02.0(神經纖維瘤第1型)、sNF96.2(神經纖維瘤第1型)、及8505(甲狀腺)細胞，在RPMI-1640培養基中生長並加以維持，該培養基含有100 U/mL青黴素-鏈黴素、及10%胎牛血清。處理前，使細胞處於96孔不透明壁之透明底盤中之生長培養基內，並在CO2 培養箱中培養過夜。將細胞用稀釋於DMSO中之化合物處理，並進行10點3倍連續稀釋。將盤置於37℃、5% CO2 中培養3天。在藉由向檢定盤中添加100 µL CellTiter-Glo試劑(Promega)使該等細胞發育之前，將盤短暫振盪2 min且使其在室溫下培養10 min。將盤底貼上白色背密封材，並以Flexstation3用發光設定(積分時間500 ms)來記錄發光。Make A375 (melanoma), Colo-205 (colon cancer), Miapaca (pancreas), HPAFII (pancreas), sNF02.0 (neurofibromas type 1), sNF96.2 (neurofibromas type 1) , And 8505 (thyroid) cells are grown and maintained in RPMI-1640 medium, which contains 100 U/mL penicillin-streptomycin, and 10% fetal bovine serum. Before treatment, the cells were placed in a 96-well growth medium in a transparent bottom plate with opaque walls, and cultured in a CO 2 incubator overnight. The cells were treated with compounds diluted in DMSO, and a 10-point 3-fold serial dilution was performed. The dish was incubated at 37°C and 5% CO 2 for 3 days. Before the cells were developed by adding 100 µL CellTiter-Glo reagent (Promega) to the assay plate, the plate was briefly shaken for 2 min and allowed to incubate at room temperature for 10 min. A white backing sealing material was attached to the bottom of the disk, and the luminescence was recorded with Flexstation3 with luminescence setting (integration time 500 ms).
如表1所示，式(I)化合物在此檢定中具活性，其中針對ERK2酶IC50
：A =單一IC50
≤50 nM；B =單一IC50
≥50 nM且≤ 250 nM；C =單一IC50
≥250 nM；針對A375 IC50
：A =單一IC50
≤100 nM；B =單一IC50
≥100 nM且≤ 1.0 µM；C =單一IC50
≥1.0 µM。〔表1 〕
此外，雖然前述已藉由說明和示例之方式稍微詳細地描述以達清晰及理解之目的，所屬技術領域中具有通常知識者將理解可進行各式各樣的改良而不背離本揭露之精神。因此，應清楚理解在本文中揭示之形式僅為示範，且並非意圖限制本揭露之範圍，而是亦涵蓋伴隨本發明之真實範圍及精神而來的所有改良及替代方案。In addition, although the foregoing has been described in some detail by way of illustration and examples for the purpose of clarity and understanding, those with ordinary knowledge in the art will understand that various improvements can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed in this text are only exemplary, and are not intended to limit the scope of the disclosure, but also cover all improvements and alternatives that accompany the true scope and spirit of the present invention.
Claims (61)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962908736P | 2019-10-01 | 2019-10-01 | |
| US62/908,736 | 2019-10-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW202126639A true TW202126639A (en) | 2021-07-16 |
Family
ID=75337427
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW109134237A TW202126639A (en) | 2019-10-01 | 2020-09-30 | Pyrrolidinyl-based compounds |
Country Status (2)
| Country | Link |
|---|---|
| TW (1) | TW202126639A (en) |
| WO (1) | WO2021067266A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2260031B1 (en) * | 2008-02-21 | 2015-10-07 | Merck Sharp & Dohme Corp. | Compounds that are erk inhibitors |
| EP2316031B1 (en) * | 2008-08-19 | 2016-09-14 | Merck Sharp & Dohme Corp. | IL-8 biomarker for monitoring cancer treatment |
| US20140309234A1 (en) * | 2013-03-10 | 2014-10-16 | Angion Biomedica Corp | Small molecule anti-fibrotic compounds and uses thereof |
-
2020
- 2020-09-29 WO PCT/US2020/053270 patent/WO2021067266A1/en active Application Filing
- 2020-09-30 TW TW109134237A patent/TW202126639A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021067266A1 (en) | 2021-04-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6949952B2 (en) | Spiro ring compound | |
| RU2652638C2 (en) | Substituted pyrazolo-quinazoline derivatives as kinase inhibitors | |
| WO2023081209A1 (en) | Pi3k inhibitors and methods of treating cancer | |
| US10493060B2 (en) | Spirocyclic compounds | |
| KR20050040814A (en) | Amide derivatives as glycogen synthase kinase 3-beta inhibitors | |
| US20220144854A1 (en) | Macrocyclic compounds | |
| TW202102474A (en) | Pyrrole compounds | |
| KR20180003614A (en) | Bicyclic compound | |
| TW202241886A (en) | Estrogen receptor modulators | |
| WO2020167984A1 (en) | Bicyclic sulfonamides | |
| WO2023131690A1 (en) | Substituted heterocycles as hset inhibitors | |
| TW202126639A (en) | Pyrrolidinyl-based compounds | |
| WO2023049691A1 (en) | Cdk7 inhibitors and methods of treating cancer | |
| WO2023147531A1 (en) | Inhibitors of protein tyrosine phosphatase, compositions, and methods of use | |
| NZ751398B2 (en) | Spirocyclic compounds | |
| WO2023141522A2 (en) | Multicyclic compounds | |
| WO2021030278A1 (en) | Bicyclic compounds |