TW201311682A - Fused heteroaryls and their uses - Google Patents
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本發明係關於一類稠合雜芳基化合物、其組合物及其用途方法。 This invention relates to a class of fused heteroaryl compounds, compositions thereof, and methods of use thereof.
磷脂醯肌醇3-激酶(Phosphoinositide 3-kinases，也稱為PI3K激酶或PI3Ks)家族在細胞生長、增殖、分化、遷移、存活和胞內轉運等多種細胞功能中至關重要，因而其在腫瘤發生發展中的作用變得不容忽視。 Phosphoinositide 3-kinases (also known as PI3K kinases or PI3Ks) are critical for cell function in cell growth, proliferation, differentiation, migration, survival, and intracellular transport, and thus are in tumors. The role of development has become impossible to ignore.
根據結構和功能特點，PI3K激酶家族成員可歸為四類，即I至IV類。目前瞭解最為全面的應屬I類PI3K激酶。I類含有三個亞型，即PI3Kα、PI3Kβ，PI3Kγ和PI3Kδ。研究發現，PI3Kα與人類腫瘤密切相關，其在多種人類腫瘤中高度表達。 According to the structural and functional characteristics, PI3K kinase family members can be classified into four categories, namely, I to IV. The most comprehensive understanding of this class is the class I PI3K kinase. Class I contains three subtypes, namely PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ. The study found that PI3Kα is closely related to human tumors and is highly expressed in a variety of human tumors.
哺乳動物雷帕黴素靶蛋白(mTOR，Mammalian target of rapamycin)為PI3K激酶家族的下游信號分子，抑制mTOR可以進一步抑制PI3K的活性，因而PI3K/mTOR信號通路有望成為新型抗癌藥物研發的靶點。 The mammalian target of rapamycin (mTOR) is a downstream signaling molecule of the PI3K kinase family. Inhibition of mTOR can further inhibit the activity of PI3K, and thus the PI3K/mTOR signaling pathway is expected to become a target for the development of novel anticancer drugs. .
本發明提供了至少一種式(1)的化合物：
和/或其至少一種醫藥上可接受的鹽，其中A1選自N或CH；A4和A5獨立地為N或CR2； A2、A3連同B環一起為含有1至4個選自N、O、和S的雜原子的五員雜芳基或五員雜環基，且該五員雜芳基或五員雜環基可以視需要經一個或多個獨立選自下列的基團所取代：烷基、烯基、炔基、芳基、環烷基、氧代(oxo)、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、鹵代烷基、雜芳基、和雜環基； 條件是A2、A3連同B環一起的五員環，不是 表示單鍵或雙鍵； R1是雜芳基，視需要經一個或多個獨立選自下列的基團所取代：烷基、烯基、炔基、芳基、環烷基、氧代、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、鹵代烷基、雜芳基、和雜環基；R和R2獨立地選自氫、烷基、烯基、炔基、芳基、環烷基、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-OC(O)Ra、-OC(O)NRcRd、-S(O)nRe、-S(O)nNRcRd、鹵素、鹵代烷基、雜芳基、和雜環基；且上述烷基、烯基、炔基、芳基、環烷基、鹵代烷基、雜芳基和雜環基可各自視需要經一個或多個獨立選自下列的基團所取代：視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的芳基、視需要經取代的環烷基、-OH、氧代、- C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、視需要經取代的鹵代烷基、視需要經取代的雜芳基、和視需要經取代的雜環基；Ra、Rb、Rc、Rd、Re、Rf和Rg係各自獨立地選自氫、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的芳基、視需要經取代的環烷基、視需要經取代的鹵代烷基、視需要經取代的雜芳基和視需要經取代的雜環基；或Ra和Rc、和/或Rc和Rd、和/或Rc和Re、和/或Rc和Rf、和/或Rd和Re、和/或Rg和Rf與它們所連接的原子一起形成3至10員的視需要經取代的雜環；以及n在每次出現時獨立地為0、1、或2；其中，上述各視需要經取代的基團可以是未取代的、或獨立地經一個或多個基團如一個、兩個、或三個取代基取代，取代基獨立地選自C1-C4烷基、環烷基、氧代、芳基、雜環基、雜芳基、芳基-C1-C4烷基-、雜芳基-C1-C4烷基-、C1-C4鹵代烷基-、-OC1-C4烷基、-OC1-C4烷基苯基、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4鹵代烷基、鹵素、-OH、-NH2、-C1-C4烷基-NH2、-N(C1-C4烷基)(C1-C4烷基)、-NH(C1-C4烷基)、-N(C1-C4烷基)(C1-C4烷基苯基)、-NH(C1-C4烷基苯基)、氰基、硝基、氧代、-CO2H、-C(O)OC1-C4烷基、-C(O)O環烷基、-C(O)O芳基、-C(O)O雜芳基、-C(O)O雜環基、-CON(C1-C4烷基)(C1-C4烷基)、-CONR’R”(其中R’和R”與它們所連接的N原子可形成雜環)、-CON(環烷基)(環烷基)、-CON(雜環基)(雜環基)、-CONH(C1-C4烷 基)、-CONH(環烷基)、-CONH(雜環基)、-CONH2、-NHC(O)(C1-C4烷基)、-NHC(O)(環烷基)、-NHC(O)(雜環基)、-NHC(O)(芳基)如-NHC(O)(苯基)、-NHC(O)(雜芳基)、-N(C1-C4烷基)C(O)(C1-C4烷基)、-N(C1-C4烷基)C(O)(環烷基)、-N(C1-C4烷基)C(O)(雜環基)、-N(C1-C4烷基)C(O)(芳基)如-N(C1-C4烷基)C(O)(苯基)、-N(C1-C4烷基)C(O)(雜芳基)、-C(O)C1-C4烷基、-C(O)(環烷基)、-C(O)(雜環基)、-C(O)(芳基)(如-C(O)苯基、-C(O)(雜芳基))、-C(O)C1-C4鹵代烷基、-OC(O)C1-C4烷基、-OC(O)(環烷基)、-OC(O)(雜環基)、-OC(O)(雜芳基)、-OC(O)(芳基)(如-OC(O)苯基)、-SO2(C1-C4烷基)、-SO2(環烷基)、-SO2(雜環基)、-SO2(芳基)如-SO2(苯基)、-SO2(雜芳基)、-SO2(C1-C4鹵代烷基)、-SO2NH2、-SO2NR’R”(其中R’和R”與它們所連接的N原子可形成雜環基)、-SO2NH(C1-C4烷基)、-SO2NH(環烷基)、-SO2NH(雜環基)、-SO2NH(芳基)如-SO2NH(苯基)、-SO2NH(雜芳基)、-NHSO2(C1-C4烷基)、-NHSO2(環烷基)、-NHSO2(雜環基)、-NHSO2(芳基)如-NHSO2(苯基)、-NHSO2(雜芳基)和-NHSO2(C1-C4鹵代烷基)，其中各烷基、苯基、芳基、環烷基、雜環基、和雜芳基可視需要經一個或多個獨立選自下列基團所取代：-OH、鹵素、環烷基、雜環基、C1-C4烷基、C1-C4鹵代烷基、-OC1-C4烷基、C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4鹵代烷基、氰基、硝基、-NH2、-CO2H、-C(O)OC1-C4烷基、-CON(C1-C4烷基)(C1-C4烷基)、-CONH(C1-C4烷基)、-CONH2、-NHC(O)(C1-C4烷基)、和-N(C1-C4烷基)C(O)(C1-C4烷基)。 And/or at least one pharmaceutically acceptable salt thereof, wherein A 1 is selected from N or CH; A 4 and A 5 are independently N or CR 2 ; A 2 , A 3 together with B ring are 1 to 4 a five-membered heteroaryl or a five-membered heterocyclic group selected from the group consisting of N, O, and S, and the five-membered heteroaryl or five-membered heterocyclic group may be optionally selected from one or more selected from the group consisting of Substituted by: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oxo, -C(O)R a , -C(O)OR b , -CN, -C(O )NR c R d , -NR c R d , -NR c C(O)R a , -NR c S(O) n R e , -NR c S(O) n NR f R g , -NR c C (O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b , -S(O) n R e , -S(O) n NR c R d , halogen, haloalkyl , heteroaryl, and heterocyclic; conditional is a five-membered ring of A 2 , A 3 together with ring B, not Represents a single bond or a double bond; R 1 is a heteroaryl group, optionally substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oxo, -C(O)R a , -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S( O) n R e , -NR c S(O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b ,- S(O) n R e , -S(O) n NR c R d , halogen, haloalkyl, heteroaryl, and heterocyclic; R and R 2 are independently selected from hydrogen, alkyl, alkenyl, alkyne Base, aryl, cycloalkyl, -C(O)R a , -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O R a , -NR c S(O) n R e , -NR c S(O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b , -OC(O)R a , -OC(O)NR c R d , -S(O) n R e , -S(O) n NR c R d , halogen, haloalkyl a heteroaryl group, and a heterocyclic group; and the above alkyl group, alkenyl group, alkynyl group, aryl group, cycloalkyl group, haloalkyl group, heteroaryl group and heterocyclic group may each be optionally independently selected from one or more Substituted by the following group: alkane which is optionally substituted , An optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, -OH, oxo, - C (O) R a , -C (O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S(O) n R e , -NR c S (O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , OR b , -S(O) n R e , -S( O) n NR c R d , halogen, optionally substituted haloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclic; R a , R b , R c , R d , R e , R f and R g are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally Substituted cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl; or R a and R c , and/or R c and R d , and / Or R c and R e , and/or R c and R f , and/or R d and R e , and/or R g and R f together with the atom to which they are attached form an optionally substituted 3 to 10 member Heterocycle n is independently 0, 1, or 2 at each occurrence; wherein each of the above optionally substituted groups may be unsubstituted or independently one or more groups such as one, two, or Substituted by three substituents, the substituents are independently selected from C 1 -C 4 alkyl, cycloalkyl, oxo, aryl, heterocyclyl, heteroaryl, aryl-C 1 -C 4 alkyl-, Heteroaryl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl-, -OC 1 -C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C 4 alkyl -OH, -C 1 -C 4 alkyl-OC 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, halogen, -OH, -NH 2 , -C 1 -C 4 alkyl-NH 2 , -N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl)(C 1 -C 4 Alkylphenyl), -NH(C 1 -C 4 alkylphenyl), cyano, nitro, oxo, -CO 2 H, -C(O)OC 1 -C 4 alkyl, -C( O) O cycloalkyl, -C(O)O aryl, -C(O)O heteroaryl, -C(O)O heterocyclyl, -CON(C 1 -C 4 alkyl) (C 1 -C 4 alkyl), -CONR'R" (wherein R' and R" may form a heterocyclic ring with the N atom to which they are attached), -CON(cycloalkyl)(cycloalkyl), -CON(heterocyclic ring) ()heterocyclyl), -CONH(C 1 -C 4 alkyl), -CO NH(cycloalkyl), -CONH(heterocyclyl), -CONH 2 , -NHC(O)(C 1 -C 4 alkyl), -NHC(O)(cycloalkyl), -NHC(O) (heterocyclyl), -NHC(O)(aryl) such as -NHC(O)(phenyl), -NHC(O)(heteroaryl), -N(C 1 -C 4 alkyl)C( O) (C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl)C(O)(cycloalkyl), -N(C 1 -C 4 alkyl)C(O) (hetero Cyclo), -N(C 1 -C 4 alkyl)C(O)(aryl) such as -N(C 1 -C 4 alkyl)C(O)(phenyl), -N(C 1 - C 4 alkyl)C(O)(heteroaryl), -C(O)C 1 -C 4 alkyl, -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(aryl) (such as -C(O)phenyl, -C(O)(heteroaryl)), -C(O)C 1 -C 4 haloalkyl, -OC(O)C 1- C 4 alkyl, -OC(O)(cycloalkyl), -OC(O)(heterocyclyl), -OC(O)(heteroaryl), -OC(O)(aryl)( Such as -OC(O)phenyl), -SO 2 (C 1 -C 4 alkyl), -SO 2 (cycloalkyl), -SO 2 (heterocyclyl), -SO 2 (aryl) such as - SO 2 (phenyl), -SO 2 (heteroaryl), -SO 2 (C 1 -C 4 haloalkyl), -SO 2 NH 2 , -SO 2 NR'R" (wherein R' and R" and The N atom to which they are attached may form a heterocyclic group), -SO 2 NH(C 1 -C 4 alkyl), -SO 2 NH(cycloalkyl), -SO 2 NH(heterocyclic group), -SO 2 NH(aryl) such as -SO 2 NH(phenyl), -SO 2 NH (heteroaryl), - NHSO 2 (C 1 -C 4 alkyl), - NHSO 2 (cycloalkyl), - NHSO 2 (heterocyclyl), - NHSO 2 (aryl), such as -NHSO 2 ( Phenyl), -NHSO 2 (heteroaryl) and -NHSO 2 (C 1 -C 4 haloalkyl), wherein each alkyl, phenyl, aryl, cycloalkyl, heterocyclic, and heteroaryl group is visible It is required to be substituted by one or more groups independently selected from: -OH, halogen, cycloalkyl, heterocyclyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OC 1 -C 4 Alkyl, C 1 -C 4 alkyl-OH, -C 1 -C 4 alkyl-OC 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, cyano, nitro, -NH 2 , - CO 2 H, -C(O)OC 1 -C 4 alkyl, -CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), -CONH(C 1 -C 4 alkyl), -CONH 2 , -NHC(O)(C 1 -C 4 alkyl), and -N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl).
本發明也提供一種醫藥組合物，包含本文所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽，以及至少一種醫藥上可接受的載劑。 The invention also provides a pharmaceutical composition comprising at least one compound described herein and/or at least one pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
本發明也提供一種抑制PI3K和/或mTOR活性的方法，包括將有效量所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽與文所述的酵素接觸。 The invention also provides a method of inhibiting PI3K and/or mTOR activity comprising contacting an effective amount of said at least one compound and/or at least one pharmaceutically acceptable salt thereof with an enzyme as described herein.
本發明也提供一種治療對抑制PI3K和/或mTOR有回應之癌症的方法，包括給予需要治療癌症的個體有效量的所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽。 The invention also provides a method of treating a cancer responsive to inhibition of PI3K and/or mTOR comprising administering to the individual in need of treatment of the cancer an effective amount of the at least one compound and/or at least one pharmaceutically acceptable salt thereof.
本發明也提供本文所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽於製備用於抑制PI3K和/或mTOR活性的藥物的用途。 The invention also provides the use of at least one compound described herein and/or at least one pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting PI3K and/or mTOR activity.
本發明也提供本文所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽於製備用於治療癌症的藥物的用途。 The invention also provides the use of at least one compound described herein and/or at least one pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.
本說明書中所用的下列單詞、短語和符號，除非另有說明，一般按如下定義。下列說明縮寫和術語在全文中表示的意義：不在兩個字母和符號之間的短線「-」表示取代基連接的位點。例如，-CONH2係透過碳原子與別的基團相連。 The following words, phrases and symbols used in the specification are generally defined as follows unless otherwise indicated. The following abbreviations and terms are used throughout the meaning of the meaning: a short line "-" between two letters and symbols means a site to which a substituent is attached. For example, -CONH 2 is attached to another group through a carbon atom.
術語「烷基」指的是含有1至18個碳原子(如1至12個碳原子，再例如1至6個碳原子)的直鏈或支鏈烴類。例如，烷基包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基和三級丁基。「短鏈烷基」是指含有1至6個碳原子(例如1至4個碳原子)的直鏈或支鏈烷烴。 The term "alkyl" refers to a straight or branched chain hydrocarbon having from 1 to 18 carbon atoms (e.g., from 1 to 12 carbon atoms, such as from 1 to 6 carbon atoms). For example, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. "Short chain alkyl group" means a straight or branched chain alkane having 1 to 6 carbon atoms (for example, 1 to 4 carbon atoms).
術語「烷氧基」指的是透過一個氧橋連接的指定數目的碳原子的直鏈或支鏈烷基基團，例如，甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、二級丁氧基、三級丁氧基、戊氧基、2-戊氧基、異戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基、3-甲基戊氧基以及類似的基團。烷氧基通常有透過氧橋連接的1至6個碳原子。「短鏈烷氧基」指的是直鏈或支鏈烷氧基，其中烷基部分包括1至4個碳原子。 The term "alkoxy" refers to a straight or branched alkyl group of the specified number of carbon atoms attached through an oxygen bridge, for example, methoxy, ethoxy, propoxy, isopropoxy, n-Butoxy, 2,4-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyl Oxyl, 3-methylpentyloxy and the like. Alkoxy groups typically have from 1 to 6 carbon atoms attached through an oxygen bridge. "Short chain alkoxy" refers to a straight or branched alkoxy group wherein the alkyl moiety includes from 1 to 4 carbon atoms.
術語「烯基」指的是含有一個或一個以上C=C雙鍵、碳原子數在2至10之間(例如2至6個碳原子)的直鏈或支鏈烴類。例如，烯基包括但不限於乙烯基、2-丙烯基、2-丁烯基。 The term "alkenyl" refers to a straight or branched chain hydrocarbon containing one or more C=C double bonds having between 2 and 10 carbon atoms (e.g., 2 to 6 carbon atoms). For example, alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, 2-butenyl.
術語「炔基」指的是含一個或一個以上C≡C三鍵、碳原子數在2-10之間(例如2至6個碳原子)的直鏈或支鏈烷烴。例如，炔基包括但不限於乙炔基、2-丙炔基、2-丁炔基。 The term "alkynyl" refers to a straight or branched chain alkane containing one or more C≡C triple bonds having between 2 and 10 carbon atoms (e.g., 2 to 6 carbon atoms). For example, alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl.
術語「環烷基」指的是含有3至12個碳原子(例如3至8個碳原子)的飽和或部分不飽和的環狀烴類基團。例如，環烷基包括但不限於環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基和環辛基。環可以是飽和的，也可以含有一個或多個雙鍵(即部分不飽和)，但不是完全共軛的，也不是芳香的，如本文所定義。 The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon group containing from 3 to 12 carbon atoms, for example from 3 to 8 carbon atoms. For example, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The ring may be saturated or may contain one or more double bonds (ie, partially unsaturated), but is not fully conjugated, nor aromatic, as defined herein.
「芳基」包括：5-和6-員碳環芳香環，例如，苯基；雙環系統至少一個環是碳環和芳香環，例如，萘、二氫化茚和1,2,3,4-四氫喹啉；三環系統至少一個環是碳環和芳香環，例如，芴。 "Aryl" includes: 5- and 6-membered carbocyclic aromatic rings, for example, phenyl; at least one ring of the bicyclic system is a carbocyclic ring and an aromatic ring, for example, naphthalene, indane, and 1,2,3,4- Tetrahydroquinoline; at least one ring of the tricyclic system is a carbocyclic ring and an aromatic ring, for example, hydrazine.
例如，芳基係包括5和6-員碳芳香環稠合至一個5至7員環烷基或雜環(包含零個或多個選自氮、氧和硫的雜原子)，當碳芳香環與雜 環稠合時，連接位點在碳芳香環上；當碳芳香環與環烷基稠合時，連接位點可在碳芳香環或環烷基上。由經取代的苯的衍生物所形成、且環上原子具有自由價態的二價自由基，其命名為經取代的亞苯基自由基。由命名以「基」結尾的單價多環烴自由基透過減少一個自由價態的氫原子衍生而來的二價自由基，其命名就是在相應的單價自由基的名稱加上「亞」，例如，有兩個連接點的萘基被稱為亞萘基。但是，芳基不包含、也不透過任何方式與下面分別定義的雜環芳基重疊。因此，在此定義，如果一個或多個碳芳香環與一個雜芳香環稠合，由此產生的環系統是雜芳基，而不是芳基。 For example, an aryl group includes a 5- and 6-membered carbon aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocyclic ring (containing zero or more heteroatoms selected from nitrogen, oxygen, and sulfur) when carbon aromatic Ring and miscellaneous When the ring is fused, the attachment site is on the carbon aromatic ring; when the carbon aromatic ring is fused to the cycloalkyl group, the attachment site may be on the carbon aromatic ring or the cycloalkyl group. A divalent radical formed from a derivative of substituted benzene and having a free valence on the ring, which is designated as a substituted phenylene radical. A divalent free radical derived from a monovalent polycyclic hydrocarbon radical named after a "base" through a hydrogen atom that reduces a free valence state, which is named after the name of the corresponding monovalent radical, for example, A naphthyl group having two points of attachment is referred to as a naphthylene group. However, the aryl group does not contain, and does not in any way overlap with, the heterocyclic aryl groups respectively defined below. Thus, as defined herein, if one or more carbon aromatic rings are fused to a heteroaromatic ring, the resulting ring system is a heteroaryl group rather than an aryl group.
術語「鹵素」包括氟、氯、溴和碘，所述的「鹵代」包括氟代、氯代、溴代和碘代。 The term "halogen" includes fluoro, chloro, bromo and iodo, and the term "halo" includes fluoro, chloro, bromo and iodo.
術語「雜芳基」是指：5至7-員芳香的單環，包括一個或多個(例如，1至4個，或在某些實施態樣中，1至3個)選自N、O和S的雜原子，環上其餘的原子是碳原子；8至12-員的雙環，包括一個或多個(例如，1至4個，或在某些實施態樣中，1至3個)選自N、O和S的雜原子，環上其餘的原子是碳原子。其中至少一個環是芳香環且至少一個雜原子在芳香環中；11至14-員的三環包括一個或多個(例如，1至4個，或在某些實施態樣中，1至3個)選自N、O和S的雜原子，環上其餘的原子是碳原子。其中至少一個環是芳香環且至少一個雜原子在芳香環中； 例如，雜芳基包括一個5至7員雜環芳香環稠合至一個5至7員環烷基，對於這樣的雙環稠合的雜芳基，其中只有一個環含有一個或多個雜原子，鏈結位元點可在雜芳環或環烷基環上。 The term "heteroaryl" refers to a 5- to 7-membered aromatic monocyclic ring comprising one or more (eg, 1 to 4, or in certain embodiments, 1 to 3) selected from N, Heteroatoms of O and S, the remaining atoms on the ring are carbon atoms; 8 to 12-membered bicyclic rings, including one or more (for example, 1 to 4, or in some embodiments, 1 to 3) a hetero atom selected from N, O and S, and the remaining atoms on the ring are carbon atoms. Wherein at least one ring is an aromatic ring and at least one heteroatom is in the aromatic ring; the 11 to 14-membered three ring includes one or more (eg, 1 to 4, or in certain embodiments, 1 to 3) a hetero atom selected from N, O and S, the remaining atoms on the ring being carbon atoms. Wherein at least one ring is an aromatic ring and at least one hetero atom is in the aromatic ring; For example, a heteroaryl group includes a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl group, and for such a bicyclic fused heteroaryl group, wherein only one ring contains one or more heteroatoms, The linker sites can be on a heteroaryl or cycloalkyl ring.
當雜芳基上的硫原子和氧原子總數超過1時，這些雜原子不會彼此相鄰。在一些實施態樣中，硫原子和氧原子在雜芳基中的總數不超過2。在一些實施態樣中，硫原子和氧原子在雜芳基中的總數不超過1。 When the total number of sulfur atoms and oxygen atoms on the heteroaryl group exceeds 1, these hetero atoms are not adjacent to each other. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed two. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed one.
雜芳基的例子包括但不限於(連接點優先標記為1)：吡啶基(如2-吡啶基、3-吡啶基或4-吡啶基)、吡嗪基、2,4-嘧啶基、3,5-嘧啶基、2,4-咪唑基、異惡唑基、惡唑基、噻唑基、噻二唑基、四唑基、噻吩基、苯並噻吩基、呋喃基、苯並呋喃基、苯並咪唑基、吲哚基、二氫吲哚基、吡啶嗪基、***基、喹啉基、吡唑基、吡咯吡啶基(如1H-。吡咯[2,3-b]吡啶-5-基)、吡唑吡啶基(如1H-吡唑[3,4-b]吡啶-5-基)、苯並惡唑基(如苯並[d]惡唑-6-基)、苯並噻唑基(如苯並[d]噻唑-6-基)、吲唑基(如1H-吲唑-5-基)和5,6,7,8-四氫異喹啉。 Examples of heteroaryl groups include, but are not limited to, (the point of attachment is preferentially labeled as 1): pyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl), pyrazinyl, 2,4-pyrimidinyl, 3 , 5-pyrimidinyl, 2,4-imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuranyl, Benzimidazolyl, indenyl, indanyl, pyridazolidinyl, triazolyl, quinolyl, pyrazolyl, pyrrolidinyl (eg 1H-.pyrrole[2,3-b]pyridine-5 -yl), pyrazolidine (such as 1H-pyrazole [3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), benzo Thiazolyl (such as benzo[d]thiazol-6-yl), oxazolyl (such as 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.
由命名以「基」結尾的一價自由基透過減少一個自由價態的氫原子衍生而來的二價自由基，其命名是透過在相應的一價自由基的名稱加上「亞」。例如，吡啶基有兩個連接位點則稱為亞吡啶基。雜芳基不包括、也不與前面所述的芳基重疊。 A divalent radical derived from a hydrogen atom whose name is terminated by a "base" is reduced by a hydrogen atom of a free valence state, and is named by adding "sub" to the name of the corresponding monovalent radical. For example, a pyridyl group having two attachment sites is referred to as a pyridylene group. The heteroaryl group does not include or overlap with the aryl groups previously described.
經取代的雜芳基也包括經一個或多個氧(-O-)取代的環系統，如N-氧化吡啶基。 Substituted aryl groups also include heteroaryl with one or more oxygen (-O -) substituted ring systems, such as N- oxidopyridyl.
「雜環(heterocycle)」或「雜環(heterocyclic ring)」是指4至12-員的飽和或部分不飽和的單環、雙環或三環，所述環除含有1至3個獨立選自氧、硫和氮的雜原子外，還包括至少2個碳原子。 「雜環(heterocycle)」也指包含一個或多個選自N、O和S的雜原子的5至7員的雜環與5、6和/或7員的環烷基、碳芳環或雜芳環稠合所得的雜環，條件為當雜環與碳芳基環或雜芳環稠合時連接點係位於雜環；當雜環與環烷基稠合時連接點可位於環烷基或雜環基。「雜環(heterocycle)」也指含一個或多個選自N、O和S的雜原子的脂肪螺環，條件為連接點係位於雜環上。這些環可以是飽和的或含有一個或多個雙鍵(即部分不飽和的)。雜環可以經氧取代。連接點可以是雜環的碳原子或雜原子。雜環不是本文所定義的雜芳基。 "Heterocycle" or "heterocyclic ring" means a 4 to 12-membered saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 1 to 3 independently selected from the group consisting of In addition to the heteroatoms of oxygen, sulfur and nitrogen, it also includes at least 2 carbon atoms. "Heterocycle" also refers to a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, and a 5, 6 and/or 7 membered cycloalkyl, carbocyclic ring or a heterocyclic ring obtained by condensing a heteroaromatic ring, provided that when the heterocyclic ring is fused to a carbon aryl ring or a heteroaryl ring, the point of attachment is at the heterocyclic ring; when the heterocyclic ring is fused to the cycloalkyl group, the point of attachment may be at the naphthenic ring. Base or heterocyclic group. "Heterocycle" also refers to a fatty spiro ring containing one or more heteroatoms selected from N, O and S, provided that the point of attachment is on the heterocycle. These rings may be saturated or contain one or more double bonds (ie, partially unsaturated). The heterocyclic ring can be substituted by oxygen. The point of attachment can be a carbon atom or a hetero atom of a heterocyclic ring. A heterocyclic ring is not a heteroaryl group as defined herein.
合適的雜環包括，例如(連接點優先標記為1)、1-吡咯啉基、2-吡咯啉基、2,4-咪唑烷基、2,3-吡唑烷基、1-呱啶基、2-呱啶基、3-呱啶基、4-呱啶基和2,5-呱嗪基、呱喃基、2-嗎啉基、和3-嗎啉基。經取代的雜環基也包括具有一個或一個以上氧代基團的環系統，例如，N-氧化呱啶基、N-氧化嗎啉基、1-氧代-1-硫代嗎啉基和1,1-二氧代-1-硫代嗎啉基。 Suitable heterocycles include, for example, (the point of preference is preferably 1), 1-pyrolinyl, 2-pyrroline, 2,4-imidazolidinyl, 2,3-pyrazolyl, 1-acridinyl 2-oxaridinyl, 3-acridinyl, 4-acridinyl and 2,5-pyridazinyl, indolyl, 2-morpholinyl, and 3-morpholinyl. Substituted heterocyclic groups also include ring systems having one or more oxo groups, for example, N-oxaridinyl, N-oxymorpholinyl, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.
所謂「視需要(optional)」或「視需要地(optionally)」的意思是指後續描述的事件或情形可能會也可能不會發生，並且該描述包括事物或情形發生和不發生兩種情況。例如，「視需要經取代的烷基」包括下文定義的「烷基」和「經取代的烷基」。關於任一包含一個或多個取代基的基團，本領域之技藝人士均可理解，但不包括不切實際的高位阻、合成上不可行的和(或)內在不穩定的取代基。 By "optional" or "optionally" is meant that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence or non-occurrence of the thing or situation. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined below. Any group containing one or more substituents will be understood by those skilled in the art, but does not include impractical high steric hindrance, synthetically unfeasible, and/or inherently labile substituents.
所用的術語「經取代」是指在特定的原子或基團中的一個或多個氫原子被從指定範圍選出的基團替換，前提是特定原子的價態正常。當取代基是氧代(例如：=O)即意味著指定原子上的兩個氫經取代。只要組合能得到穩定的化合物或有用的合成中間體，取代基的組合和 /或變化是允許的。穩定的化合物或穩定的結構意味著它穩定到能從反應混合物中分離出來，並至少在隨後的製劑過程中有實用價值。除特別說明，取代基被命名進母核結構。例如，可理解當(環烷基)烷基是作為一個可能的取代基，母核上這個取代基的連接位點在烷基上。 The term "substituted" as used herein refers to the replacement of one or more hydrogen atoms in a particular atom or group by a group selected from a specified range, provided that the valence of the particular atom is normal. When the substituent is oxo (for example: =O), it means that two hydrogens on the designated atom are substituted. As long as the combination provides stable compounds or useful synthetic intermediates, combinations of substituents and / or change is allowed. A stable compound or stable structure means that it is stable enough to be separated from the reaction mixture and at least useful in subsequent formulation processes. Unless otherwise stated, the substituents are named into the parent core structure. For example, it will be understood that when a (cycloalkyl)alkyl group is used as a possible substituent, the attachment site for this substituent on the parent nucleus is on the alkyl group.
在一些實施態樣中，「經一個或多個基團取代」是指在特定的原子或基團中的兩個氫原子分別被指定範圍的基團中選出的相同或不同的基團替換。在一些實施態樣中，「經一個或多個基團取代」是指在特定的原子或基團中的三個氫原子分別被指定範圍的基團中選出的相同或不同的基團替換。在一些實施態樣中，「經一個或多個基團取代」是指在特定的原子或基團中的四個氫原子分別被指定範圍的基團中選出的相同或不同的基團替換。 In some embodiments, "substituting one or more groups" means that two hydrogen atoms in a particular atom or group are replaced by the same or different groups selected from the specified range of groups, respectively. In some embodiments, "substituted with one or more groups" refers to the replacement of three hydrogen atoms in a particular atom or group by the same or different groups selected from the specified range of groups. In some embodiments, "substituting one or more groups" means that four hydrogen atoms in a particular atom or group are replaced by the same or different groups selected from the specified range of groups, respectively.
本文所述的化合物包括但不限於：它們的光學異構體，如對映異構體和非對映異構體、對映異構體的混合物包括外消旋體、非對映異構體的混合物以及其他本領域之技藝人士通過常規實驗能夠合成的混合物。在這些情況下，單一對映異構體或非對映異構體，例如具有光學活性的結構，可以通過不對稱合成或由外消旋體或非對映異構體混合物拆分(resolution)得到。對於消旋混合物或非對映體混合物的拆分，可以用傳統的方法分離，例如使用拆分試劑結晶；也可以用色譜法分離，例如對掌性高效液相層析(HPLC)管柱。此外，這些化合物也包括具有Z-和E-構型(或順-和反-式)的含C=C雙鍵化合物。所述的化合物存在各種互變異構體，術語「化合物」包括本領域之技藝人士無須透過過度實驗能夠合成的該化合物的所有互變異構形式。這裏化合物也包括本領域之技藝人士透過常規實驗能夠合成之其晶體 形式，包含多晶和包合物。同樣，術語「鹽」也包括了本領域之技藝人士通過常規實驗能夠合成的該化合物的鹽的所有異構體、消旋體、其他混合物、Z-和E-型、互變異構體和晶體形式。 The compounds described herein include, but are not limited to, their optical isomers, such as enantiomers and diastereomers, mixtures of enantiomers including racemates, diastereomers. Mixtures and other mixtures which can be synthesized by routine experimentation by those skilled in the art. In these cases, a single enantiomer or diastereomer, such as an optically active structure, can be resolved by asymmetric synthesis or by a racemic or diastereomeric mixture. get. Resolution of the racemic mixture or mixture of diastereomers can be carried out by conventional methods, for example by crystallization using a resolving agent, or by chromatography, for example, on a palm chromatography high performance liquid chromatography (HPLC) column. In addition, these compounds also include C=C double bond containing compounds having the Z- and E-configurations (or cis- and trans-forms). The compounds are present in a variety of tautomers, and the term "compound" includes all tautomeric forms of the compound which will be synthesized by those skilled in the art without undue experimentation. The compounds herein also include crystals which can be synthesized by those skilled in the art through routine experimentation. Form, containing polycrystals and inclusion complexes. Similarly, the term "salt" also encompasses all isomers, racemates, other mixtures, Z- and E-forms, tautomers and crystals of salts of such compounds which can be synthesized by those skilled in the art by routine experimentation. form.
術語「醫藥上可接受的鹽」包括但不限於與無機酸形成的鹽，如鹽酸鹽、磷酸鹽、二磷酸鹽、氫溴酸鹽、硫酸鹽、亞硫酸鹽、硝酸鹽、及其類似鹽；也包括與有機酸形成的鹽，如蘋果酸鹽、馬來酸鹽、富馬酸鹽、酒石酸鹽、琥珀酸鹽、檸檬酸鹽、乳酸鹽、甲磺酸鹽、對甲苯磺酸鹽、2-羥乙基磺酸鹽、安息香酸鹽、水楊酸鹽、硬脂酸鹽和鏈烷酸鹽如醋酸鹽、以及與HOOC-(CH2)n-COOH所成的鹽，其中n=0-4、及其類似鹽。同樣地，醫藥上可接受的陽離子包括但不限於鈉、鉀、鈣、鋁、鋰和銨。 The term "pharmaceutically acceptable salts" includes, but is not limited to, salts formed with inorganic acids such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfites, nitrates, and the like. Salt; also includes salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate , 2-hydroxyethyl sulfonate, benzoate, salicylate, stearate and alkanoates such as acetate, and salts with HOOC-(CH 2 ) n -COOH, wherein =0-4, and similar salts. Likewise, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
此外，如果所述的化合物是一種與酸形成的酸加成鹽，其游離鹼可以透過鹼化該酸鹽溶液獲得。相反地，如果化合物是游離鹼，則其加成鹽特別是醫藥上可接受的加成鹽可以透過由鹼化合物製備酸加成鹽的常規程序製得，即將游離鹼溶於合適的有機溶劑後用酸處理。本領域之技藝人士無須過度的實驗，可識別各種可能用來製備無毒的醫藥上可接受的加成鹽的合成方法。 Further, if the compound is an acid addition salt formed with an acid, the free base thereof can be obtained by alkalizing the acid salt solution. Conversely, if the compound is a free base, the addition salt thereof, especially a pharmaceutically acceptable addition salt, can be prepared by conventional procedures for preparing an acid addition salt from an alkali compound, i.e., after dissolving the free base in a suitable organic solvent. Treated with acid. Those skilled in the art will be able to identify various synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.
「溶劑化物」如「水合物」，是化合物與溶劑相互作用形成的。術語「化合物」意指包含化合物的溶劑化物(包括化合物的水合物)，本領域之技藝人士能透過常規實驗來製備。同樣，「鹽」也包括了鹽的溶劑化物(如鹽的水合物)，本領域之技藝人士能透過常規實驗來製備。合適的溶劑化物是醫藥上可接受的，例如水合物，它包括了單水合物和半水合物，本領域之技藝人士能透過常規實驗來製備。 "Solvate" such as "hydrate" is formed by the interaction of a compound with a solvent. The term "compound" means a solvate comprising a compound (including a hydrate of a compound), which can be prepared by those skilled in the art by routine experimentation. Similarly, "salts" also include solvates of salts (e.g., hydrates of salts) which can be prepared by those skilled in the art by routine experimentation. Suitable solvates are pharmaceutically acceptable, such as hydrates, which include monohydrates and hemihydrates, and can be prepared by those skilled in the art by routine experimentation.
「螯合物」是由化合物與金屬離子在兩個(或更多的)點配位而成。術語「化合物」應該包括化合物的螯合物。同樣，「鹽」也包括鹽的螯合物。 A "chelate" is formed by the coordination of a compound with a metal ion at two (or more) points. The term "compound" shall include a chelate of the compound. Similarly, "salt" also includes a salt chelate.
「非共價複合物」是由一化合物與另外一分子透過非共價鍵相互作用形成的。比如，複合物可以透過凡得瓦力、氫鍵和靜電相互作用(也稱為離子鍵)形成。這些非共價複合物也包含在術語「化合物」的概念中。 A "non-covalent complex" is formed by the interaction of a compound with another molecule through a non-covalent bond. For example, a composite can be formed by van der Waals, hydrogen bonds, and electrostatic interactions (also known as ionic bonds). These non-covalent complexes are also included in the term "compound".
術語「氫鍵」是指電負性原子(也稱為氫鍵受體)與一個連接在另一相對電負性原子上的氫原子(也稱為氫鍵給體)作用的形式。合適的氫鍵給體和受體見於各種著名的藥物化學書籍(G.C.Pimentel and A.L.McClellan,The Hydrogen Bond,Freeman,San Francisco,1960；R.Taylor and O.Kennard,"Hydrogen Bond Geometry in Organic Crystals",Accounts of Chemical Research,17,pp.320-326(1984))。 The term "hydrogen bond" refers to a form in which an electronegative atom (also known as a hydrogen bond acceptor) interacts with a hydrogen atom (also referred to as a hydrogen bond donor) attached to another relatively electronegative atom. Suitable hydrogen bond donors and acceptors are found in various well-known books on medicinal chemistry (GC Pimentel and ALMcClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic Crystals" , Accounts of Chemical Research, 17, pp. 320-326 (1984)).
本文所使用的術語「基團」、「基」或「片段」為同義詞，用於代表功能基團或連接於某一根鍵的片段或其他分子片段。 The term "group", "base" or "fragment" as used herein is synonymous and is used to refer to a functional group or a fragment or other molecular fragment attached to a certain bond.
術語「活性成分」是指具有生物活性的化學物質。在一些具體態樣中，一個「活性成分」是具有醫藥效用的化學物質。 The term "active ingredient" refers to a biologically active chemical. In some specific aspects, an "active ingredient" is a chemical substance that has a medicinal effect.
「處理(treating)」、「治療(treat)」或「治療(treatment)」或「減緩」(alleviation)」是指給予一患有癌症、或具有癌症的症狀、或有易患癌症體質的個體所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽，以用於治癒(cure)、治療(heal)、緩和(alleviate)、紓解(relieve)、改變(alter)、醫 治(remedy)、改善(ameliorate)、改良(improve)或影響(affect)癌症、癌症的症狀或易患癌症的體質。 "treating", "treat" or "treatment" or "alleviation" refers to the administration of an individual who has cancer, or has symptoms of cancer, or is susceptible to cancer. Said at least one compound and / or at least one pharmaceutically acceptable salt thereof for use in cure, heal, alleviate, relieve, alter, medical Remedy, ameliorate, improve, or affect cancer, symptoms of cancer, or susceptibility to cancer.
術語「有效量」指的是，所述至少一種化合物和/或其至少一種醫藥上可接受的鹽對於能有效「治療」個體的一種疾病或不適的用量。如果是癌症時，有效量可在一個體中引起如上述定義之「處理」、「治療」和「減緩」中任何一種可見的或可檢測的變化。例如，有效量係能減少癌症或腫瘤細胞的數目；縮小腫瘤的大小；抑制或阻止腫瘤細胞向周邊器官的侵入，例如，腫瘤蔓延入軟組織或骨骼中；抑制或阻止腫瘤的轉移；抑制或阻止腫瘤的生長；一定程度上減輕一種或多種與癌症相關的症狀；減少發病率和死亡率；提高生活品質；或者是上述效果的結合。有效量可以是抑制PI3K和/或mTOR的活性來減少疾病症狀的用量。對於癌症治療，體內實驗的效果可以透過評估如存活期、疾病進展時間(Time to Disease Progression，TTP)、反應率(Response Rates，RR)、持續反應期和/或生活品質來測量。專業人員已經意識到，有效量可以隨著給藥的途徑、賦形劑的劑量、以及與其他藥物的合用而變化。 The term "effective amount" refers to an amount of the at least one compound and/or at least one pharmaceutically acceptable salt thereof that is effective to "treat" a disease or discomfort to the individual. In the case of cancer, an effective amount can cause any visible or detectable change in "treatment", "treatment" and "mitigation" as defined above in one body. For example, an effective amount can reduce the number of cancer or tumor cells; reduce the size of the tumor; inhibit or prevent the invasion of tumor cells into peripheral organs, for example, tumors spread into soft tissues or bones; inhibit or prevent tumor metastasis; inhibit or prevent Tumor growth; to some extent alleviate one or more cancer-related symptoms; reduce morbidity and mortality; improve quality of life; or a combination of the above effects. An effective amount can be an amount that inhibits the activity of PI3K and/or mTOR to reduce the symptoms of the disease. For cancer treatment, the effects of in vivo experiments can be measured by assessing, for example, survival, time to disease progression (TTP), response rate (RR), duration of response, and/or quality of life. The skilled person has recognized that an effective amount can vary with the route of administration, the dosage of the excipient, and the combination with other drugs.
術語「抑制」是指一種生物活動或生物過程的基礎活性的降低。「抑制PI3K和/或mTOR活性」是相對於在沒有所述至少一種化合物和/或其至少一種醫藥上可接受的鹽時PI3K和/或mTOR的活性，由所述至少一種化合物和/或其至少一種醫藥上可接受的鹽直接或間接的作用導致PI3K和/或mTOR的活性降低。活性的降低不受理論的限制且可以是所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽與PI3K和/或mTOR直接的相互作用引起的，或者是由於所述至少一種化合物和/或其至少一種醫藥上可接受的鹽與其他一種或 多種因素的相互作用進而最終影響了PI3K和/或mTOR的活性引起的。例如，所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽，可透過直接與PI3K和/或mTOR結合而降低其活性，可透過直接或間接地影響其他因素來降低PI3K和/或mTOR活性，或透過直接或間接地降低細胞或器官中PI3K和/或mTOR的數量，來降低PI3K和/或mTOR的活性。 The term "inhibition" refers to a decrease in the basal activity of a biological activity or biological process. "inhibiting PI3K and/or mTOR activity" is relative to the activity of PI3K and/or mTOR in the absence of the at least one compound and/or at least one pharmaceutically acceptable salt thereof, from the at least one compound and/or The direct or indirect action of at least one pharmaceutically acceptable salt results in a decrease in the activity of PI3K and/or mTOR. The reduction in activity is not limited by theory and may be due to direct interaction of the at least one compound and/or at least one pharmaceutically acceptable salt thereof with PI3K and/or mTOR, or due to the at least one compound And/or at least one pharmaceutically acceptable salt thereof and the other or The interaction of multiple factors ultimately affects the activity of PI3K and/or mTOR. For example, the at least one compound and/or at least one pharmaceutically acceptable salt thereof can reduce its activity by directly binding to PI3K and/or mTOR, and can reduce PI3K and/or by directly or indirectly affecting other factors. Or mTOR activity, or by directly or indirectly reducing the amount of PI3K and/or mTOR in a cell or organ to reduce the activity of PI3K and/or mTOR.
本發明的一個或多個具體實施態樣的細節會在下文闡明。 Details of one or more embodiments of the invention are set forth below.
本發明提供至少一種式(1)化合物：
和/或其至少一種醫藥上可接受的鹽，其中A1選自N或CH；A4和A5獨立地為N或CR2；A2、A3連同B環一起為含有1至4個選自N、O、和S的雜原子的五員雜芳基或五員雜環基，以及所述五員雜芳基或五員雜環基係視需要經一個或多個獨立選自下列的基團所取代：烷基、烯基、炔基、芳基、環烷基、氧代、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、鹵代烷基、雜芳基、和雜環基； 條件是A2、A3連同B環一起的五員環，不是 表示單鍵或雙鍵； R1是雜芳基，視需要經一個或多個獨立選自下列的基團所取代：烷基、烯基、炔基、芳基、環烷基、氧代、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、鹵代烷基、雜芳基、和雜環基；R和R2獨立地選自氫、烷基、烯基、炔基、芳基、環烷基、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-OC(O)Ra、-OC(O)NRcRd、-S(O)nRe、-S(O)nNRcRd、鹵素、鹵代烷基、雜芳基和雜環基；且上述的烷基、烯基、炔基、芳基、環烷基、鹵代烷基、雜芳基、和雜環基可各自視需要經一個或多個獨立選自下列的基團取代：視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的芳基、視需要經取代的環烷基、-OH、氧代、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、視需要經取代的鹵代烷基，視需要經取代的雜芳基、和視需要經取代的雜環基；Ra、Rb、Rc、Rd、Re、Rf和Rg各自獨立地選自氫、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的芳基、視需要經取代的環烷基、視需要經取代的鹵代烷基、視需要經取代的雜芳基、和視需要經取代的雜環基； 或Ra和Rc、和/或Rc和Rd、和/或Rc和Re、和/或Rc和Rf、和/或Rd和Re、和/或Rg和Rf與它們所連接的原子一起形成3至10員的視需要經取代的雜環基；n在每次出現時獨立地為0、1或2；上述各視需要經取代的基團可以是未經取代的，或者經一個或多個基團，例如、一個、兩個、或三個獨立選自下列的基團所取代：C1-C4烷基、環烷基、氧代、芳基、雜環、雜芳基、芳基-C1-C4烷基、雜芳基-C1-C4烷基、C1-C4鹵代烷基、-OC1-C4烷基、-OC1-C4烷基苯基、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4鹵代烷基、鹵素、-OH、-NH2、-C1-C4烷基-NH2、-N(C1-C4烷基)(C1-C4烷基)、-NH(C1-C4烷基)、-N(C1-C4烷基)(C1-C4烷基苯基)、-NH(C1-C4烷基苯基)、氰基、硝基、氧代、-CO2H、-C(O)OC1-C4烷基、-C(O)O環烷基、-C(O)O芳基、-C(O)O雜芳基、-C(O)O雜環基、-CON(C1-C4烷基)(C1-C4烷基)、-CONR’R”，其中R’和R”與它們所連接的N原子形成雜環、-CON(環烷基)(環烷基)、-CON(雜環基)(雜環基)、-CONH(C1-C4烷基)、-CONH(環烷基)、-CONH(雜環基)、-CONH2、-NHC(O)(C1-C4烷基)、-NHC(O)(環烷基)、-NHC(O)(雜環基)、-NHC(O)(芳基)如-NHC(O)(苯基)、-NHC(O)(雜芳基)、-N(C1-C4烷基)C(O)(C1-C4烷基)、-N(C1-C4烷基)C(O)(環烷基)、-N(C1-C4烷基)C(O)(雜環基)、-N(C1-C4烷基)C(O)(芳基)如-N(C1-C4烷基)C(O)(苯基)、-N(C1-C4烷基)C(O)(雜芳基)、-C(O)C1-C4烷基，-C(O)(環烷基)、-C(O)(雜環基)，-C(O)(芳基)如-C(O)苯基、-C(O)(雜芳基)、-C(O)C1-C4鹵代烷基、-OC(O)C1-C4烷基、-OC(O)(環烷 基)、-OC(O)(雜環基)、-OC(O)(雜芳基)、-OC(O)(芳基)如-OC(O)苯基、-SO2(C1-C4烷基)、-SO2(環烷基)、-SO2(雜環基)、-SO2(芳基)如-SO2(苯基)、-SO2(雜芳基)、-SO2(C1-C4鹵代烷基)、-SO2NH2、-SO2NR’R”，其中R’和R”與它們所連接的N原子形成雜環基、-SO2NH(C1-C4烷基)、-SO2NH(環烷基)、-SO2NH(雜環基)，-SO2NH(芳基)如-SO2NH(苯基)、-SO2NH(雜芳基)、-NHSO2(C1-C4烷基)、-NHSO2(環烷基)、-NHSO2(雜環基)、-NHSO2(芳基)如-NHSO2(苯基)、-NHSO2(雜芳基)、和-NHSO2(C1-C4鹵代烷基)，其中各烷基、苯基、芳基、環烷基、雜環基、和雜芳基係視需要經一個或多個獨立選自下列的基團所取代：-OH、鹵素、環烷基、雜環基、C1-C4烷基、C1-C4鹵代烷基-、-OC1-C4烷基、C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4鹵代烷基、氰基、硝基、-NH2、-CO2H、-C(O)OC1-C4烷基、-CON(C1-C4烷基)(C1-C4烷基)、-CONH(C1-C4烷基)、-CONH2,-NHC(O)(C1-C4烷基)、和-N(C1-C4烷基)C(O)(C1-C4烷基)。 And/or at least one pharmaceutically acceptable salt thereof, wherein A 1 is selected from N or CH; A 4 and A 5 are independently N or CR 2 ; A 2 and A 3 together with B ring contain 1 to 4 a five-membered heteroaryl or five-membered heterocyclic group selected from heteroatoms of N, O, and S, and the five-membered heteroaryl or five-membered heterocyclic group are optionally selected from one or more selected from the group consisting of Substituted by: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oxo, -C(O)R a , -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S(O) n R e , -NR c S(O) n NR f R g , -NR c C(O )OR b , -NR c C(O)NR d R e , -NO 2 , -OR b , -S(O) n R e , -S(O) n NR c R d , halogen, haloalkyl, hetero An aryl group, and a heterocyclic group; the condition is a five-membered ring of A 2 , A 3 together with the B ring, not Represents a single bond or a double bond; R 1 is a heteroaryl group, optionally substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oxo, -C(O)R a , -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S( O) n R e , -NR c S(O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b ,- S(O) n R e , -S(O) n NR c R d , halogen, haloalkyl, heteroaryl, and heterocyclic; R and R 2 are independently selected from hydrogen, alkyl, alkenyl, alkyne Base, aryl, cycloalkyl, -C(O)R a , -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O R a , -NR c S(O) n R e , -NR c S(O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b , -OC(O)R a , -OC(O)NR c R d , -S(O) n R e , -S(O) n NR c R d , halogen, haloalkyl a heteroaryl group and a heterocyclic group; and the above alkyl, alkenyl, alkynyl, aryl, cycloalkyl, haloalkyl, heteroaryl, and heterocyclic groups may each be independently selected by one or more Substituted from the following groups: optionally substituted alkane , An optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, -OH, oxo, -C (O) R a, -C (O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S(O) n R e , -NR c S (O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , OR b , -S(O) n R e , -S( O) n NR c R d , halogen, optionally substituted haloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclic; R a , R b , R c , R d , R e , R f and R g are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted Cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; or R a and R c , and/or R c and R d , and / Or R c and R e , and/or R c and R f , and/or R d and R e , and/or R g and R f together with the atom to which they are attached form an optionally substituted 3 to 10 member Heterocyclic group; n Each occurrence is independently 0, 1 or 2; the above-mentioned optionally substituted groups may be unsubstituted or independently selected via one or more groups, for example, one, two, or three Substituted from the following groups: C 1 -C 4 alkyl, cycloalkyl, oxo, aryl, heterocyclic, heteroaryl, aryl-C 1 -C 4 alkyl, heteroaryl-C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OC 1 -C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C 4 alkyl-OH, -C 1 -C 4- alkyl-OC 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, halogen, -OH, -NH 2 , -C 1 -C 4 alkyl-NH 2 , -N (C 1 -C 4 Alkyl)(C 1 -C 4 alkyl), -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), -NH (C 1 -C 4 alkylphenyl), cyano, nitro, oxo, -CO 2 H, -C(O)OC 1 -C 4 alkyl, -C(O)O cycloalkyl, - C(O)O aryl, -C(O)Oheteroaryl, -C(O)Oheterocyclyl, -CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), - CONR'R", wherein R' and R" form a heterocyclic ring with the N atom to which they are attached, -CON(cycloalkyl)(cycloalkyl), -CON(heterocyclyl)(heterocyclyl), -CONH (C 1 -C 4 alkyl), -CONH (cycloalkyl), -CON H(heterocyclyl), -CONH 2 , -NHC(O)(C 1 -C 4 alkyl), -NHC(O)(cycloalkyl), -NHC(O)(heterocyclyl), -NHC (O) (aryl) such as -NHC(O)(phenyl), -NHC(O)(heteroaryl), -N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl)C(O)(cycloalkyl), -N(C 1 -C 4 alkyl)C(O)(heterocyclyl), -N(C 1 -C 4 alkyl)C(O)(aryl) such as -N(C 1 -C 4 alkyl)C(O)(phenyl), -N(C 1 -C 4 alkyl)C(O (heteroaryl), -C(O)C 1 -C 4 alkyl, -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(aryl) ) such as -C(O)phenyl, -C(O)(heteroaryl), -C(O)C 1 -C 4 haloalkyl, -OC(O)C 1 -C 4 alkyl, -OC ( O) (cycloalkyl), -OC(O) (heterocyclyl), -OC(O)(heteroaryl), -OC(O)(aryl) such as -OC(O)phenyl, -SO 2 (C 1 -C 4 alkyl), -SO 2 (cycloalkyl), -SO 2 (heterocyclyl), -SO 2 (aryl) such as -SO 2 (phenyl), -SO 2 (hetero Aryl), -SO 2 (C 1 -C 4 haloalkyl), -SO 2 NH 2 , -SO 2 NR'R", wherein R' and R" form a heterocyclic group with the N atom to which they are attached, - SO 2 NH(C 1 -C 4 alkyl), -SO 2 NH(cycloalkyl), -SO 2 NH(heterocyclyl), -SO 2 NH(aryl) such as -SO 2 NH(phenyl) , -SO 2 NH(heteroaryl), -NHSO 2 (C 1 -C 4 alkyl), - NHSO 2 (cycloalkyl), - NHSO 2 (heterocyclyl), - NHSO 2 (aryl), such as -NHSO 2 (phenyl), - NHSO 2 (heteroaryl) And -NHSO 2 (C 1 -C 4 haloalkyl), wherein each alkyl, phenyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl is optionally selected from one or more selected from the group consisting of Substituted by: -OH, halogen, cycloalkyl, heterocyclyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl-, -OC 1 -C 4 alkyl, C 1 -C 4 Alkyl-OH, -C 1 -C 4 alkyl-OC 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, cyano, nitro, -NH 2 , -CO 2 H, -C(O OC 1 -C 4 alkyl, -CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), -CONH(C 1 -C 4 alkyl), -CONH 2 , -NHC(O (C 1 -C 4 alkyl), and -N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl).
在一些實施態樣中，本發明提供了式(1)化合物：
其中，t為1、2或3；且R3係獨立選自H、C1-C6烷基、C2-C8烯基、C2-C8炔基、C6-C14芳基、C3-C9員環烷基、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-CC(O)Ra、-OC(O)NRcRd、-S(O)nRe、-S(O)nNRcRd、鹵素、鹵代烷基、雜芳基、和雜環基；上述的烷基、烯基，炔基、芳基、環烷基、雜芳基、和雜環基可各自視需要經一個或多個獨立選自下列的基團所取代：視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的芳基、視需要經取代的環烷基、-OH、氧代、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、視需要經取代的鹵代烷基、視需要經取代的雜芳基、和視需要經取代的雜環基；條件為，當A4是CR2、A2和A3與B環一起形成結構式(3)、(5)或(6)的結構； 表示單鍵或雙鍵； R1為雜芳基，視需要經一個或多個獨立選自下列的基團所取代：烷基、烯基、炔基、芳基、環烷基、氧代、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、- NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、鹵代烷基、雜芳基、和雜環基；R2獨立地選自氫、烷基、烯基、炔基、芳基、環烷基、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-OC(O)Ra、-OC(O)NRcRd、-S(O)nRe、-S(O)nNRcRd、鹵素、鹵代烷基、雜芳基和雜環基；且上述的烷基、烯基、炔基、芳基、環烷基、鹵代烷基、雜芳基、和雜環基可各自視需要經一個或多個獨立選自下列的基團所取代：視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的芳基、視需要經取代的環烷基、-OH、氧代、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、視需要經取代的鹵代烷基、視需要經取代的雜芳基、和視需要經取代的雜環基；Ra、Rb、Rc、Rd、Re、Rf和Rg各自獨立地選自氫、視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的芳基、視需要經取代的環烷基、視需要經取代的鹵代烷基、視需要經取代的雜芳基、和視需要經取代的雜環基；或Ra和Rc、和/或Rc和Rd、和/或Rc和Re、和/或Rc和Rf、和/或Rd和Re、和/或Rg和Rf與它們所連接的原子一起形成3至10員的視需要經取代的雜環基；n在每次出現時獨立地為0、1或2。 Wherein t is 1, 2 or 3; and R 3 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 14 aryl , C 3 -C 9 membered cycloalkyl, -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S(O) n R e , -NR c S(O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b , -CC(O)R a , -OC(O)NR c R d , -S(O) n R e , -S(O) n NR c R d , halogen, haloalkyl, heteroaryl, and Heterocyclyl; the above alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic groups may each be optionally substituted with one or more groups independently selected from the group consisting of: A substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted cycloalkyl group, -OH, oxo, -C(O) are required. R a , -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S(O) n R e , -NR c S(O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b , -S(O) n R e, -S (O) n NR c R d, halogen, optionally substituted Substituted alkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; with the proviso that, when A 4 is CR 2, A 2, and A 3 and B form a cyclic structure of formula (3) together with ( 5) or (6) structure; Represents a single bond or a double bond; R 1 is a heteroaryl group, optionally substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oxo, -C(O)R a , -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S( O) n R e , - NR c S(O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b ,- S(O) n R e , -S(O) n NR c R d , halogen, haloalkyl, heteroaryl, and heterocyclic; R 2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, Aryl, cycloalkyl, -C(O)R a , -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S(O) n R e , -NR c S(O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b , -OC(O)R a , -OC(O)NR c R d , -S(O) n R e , -S(O) n NR c R d , halogen, haloalkyl, hetero An aryl group and a heterocyclic group; and the above alkyl group, alkenyl group, alkynyl group, aryl group, cycloalkyl group, haloalkyl group, heteroaryl group, and heterocyclic group may each independently be selected from one or more selected from the following Substituted by a group: an alkyl group substituted as needed , An optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, -OH, oxo, -C (O) R a, -C (O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S(O) n R e , -NR c S (O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , OR b , -S(O) n R e , -S( O) n NR c R d , halogen, optionally substituted haloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclic; R a , R b , R c , R d , R e , R f and R g are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted Cycloalkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; or R a and R c , and/or R c and R d , and / Or R c and R e , and/or R c and R f , and/or R d and R e , and/or R g and R f together with the atom to which they are attached form an optionally substituted 3 to 10 member Heterocyclic group; n At each occurrence is independently 0, 1 or 2.
在一些實施態樣中，A2和A3連同B環一起為含有1至3個雜原子(選自N、O、和S)的五員雜芳基或雜環基。在一些實施態樣中，A2和A3連同B環一起為含有1至3個氮原子的五員雜芳環基或雜環基。 In some embodiments, A 2 and A 3 together with the B ring are a five-membered heteroaryl or heterocyclic group containing from 1 to 3 heteroatoms (selected from N, O, and S). In some embodiments, A 2 and A 3 together with the B ring are a five membered heteroaryl or heterocyclic group containing from 1 to 3 nitrogen atoms.
在一些實施態樣中，A2和A3連同B環一起為選自結構(2)至(6)
其中，t為1、2或3；以及R3係獨立選自H、C1-C6烷基、C2-C8烯基、C2-C8炔基、C6-C14芳基、C3-C9環烷基、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-OC(O)Ra、-OC(O)NRcRd、-S(O)nRe、-S(O)nNRcRd、鹵素、鹵代烷基、雜芳基、和雜環基；且上述的烷基、烯基，炔基、芳基、環烷基、雜芳基、和雜環基係可各自視需要經一個或多個獨立選自下列的基團所取代：視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的芳基、視需要經取代的環烷基、-OH、氧代、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、視需要經取代的鹵代 烷基、視需要經取代的雜芳基、視需要經取代的雜環基；以及Ra、Rb、Rc、Rd、Re、Rf和Rg係如上所述定義。 Wherein t is 1, 2 or 3; and R 3 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 14 aryl , C 3 -C 9 cycloalkyl, -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S(O) n R e , -NR c S(O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b , -OC(O)R a , -OC(O)NR c R d , -S(O) n R e , -S(O) n NR c R d , halogen, haloalkyl, heteroaryl, and hetero a cyclic group; and the above alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclic groups may each be optionally substituted with one or more groups independently selected from the group consisting of: Optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, -OH, oxo, -C ( O) R a , -C(O)OR b , -CN, -C(O)NR c R d , -NR c R d , -NR c C(O)R a , -NR c S(O) n R e , -NR c S(O) n NR f R g , -NR c C(O)OR b , -NR c C(O)NR d R e , -NO 2 , -OR b , -S(O ) n R e, -S (O ) n NR c R d, halogen, an optionally taken Haloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl group; and R a, R b, R c , R d, R e, R f and R g are as defined above lines.
條件為，當A2和A3連同B環一起為結構式(4)的結構時，A4不是CR2，而R2的定義同前述。 The condition is that when A 2 and A 3 together with the B ring are the structures of the structural formula (4), A 4 is not CR 2 , and R 2 has the same meaning as defined above.
例如，R3獨立選自H、-OH、-CN、-NO2、鹵素、C1-C6烷基、C2-C8烯基、C2-C8炔基、C6-C14芳基、C3-C9環烷基、雜芳基、和雜環、其中該烷基、烯基、炔基、芳基、環烷基、雜芳基、和雜環可各自視需要經一個或多個獨立選自下列的基團所取代：視需要經取代的烷基、視需要經取代的烯基、視需要經取代的炔基、視需要經取代的芳基、視需要經取代的環烷基、-OH、氧代、-C(O)Ra、-C(O)ORb、-CN、-C(O)NRcRd、-NRcRd、-NRcC(O)Ra、-NRcS(O)nRe、-NRcS(O)nNRfRg、-NRcC(O)ORb、-NRcC(O)NRdRe、-NO2、-ORb、-S(O)nRe、-S(O)nNRcRd、鹵素、視需要經取代的鹵代烷基、視需要經取代的雜芳基、視需要經取代的雜環基；在一些實施態樣中，A2和A3連同B環一起為選自結構(2)至(5)，其中R3和t的定義同前述：
在一些實施態樣中，A2和A3連同B環一起為選自結構(3)至(4)，其中R3和t的定義同前述：
在一些實施態樣中，A4為N或CH。 In some embodiments, A 4 is N or CH.
在一些實施態樣中，A5為N或CH。 In some embodiments, A 5 is N or CH.
在一些實施態樣中，A1、A4、和A5為CH。 In some embodiments, A 1 , A 4 , and A 5 are CH.
在一些實施態樣中，A1和A5為CH,A4為N。 In some embodiments, A 1 and A 5 are CH and A 4 is N.
在一些實施態樣中，R1為選自下列結構的雜芳基：
例如，R1為選自下列的雜芳基：
在一些實施態樣中，R1為
本發明亦提供了至少一種選自化合物1至184的化合物和/或其至少一種醫藥上可接受的鹽。 The invention also provides at least one compound selected from the group consisting of compounds 1 to 184 and/or at least one pharmaceutically acceptable salt thereof.
本發明所述的化合物和/或其醫藥上可接受的鹽均可以從商業上可獲得的原料，透過已知的方法，結合本專利申請案所公開的內容合成得到。下列的反應路線顯示了大部分化合物的合成方法。 The compounds of the present invention and/or their pharmaceutically acceptable salts can be synthesized from commercially available starting materials by known methods in conjunction with the disclosure of the present patent application. The following reaction schemes show the synthesis of most of the compounds.
在使用前，所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽可以通過管柱層析、高效液相層析、結晶或其他適當的方法進行純化。 The at least one compound and/or at least one pharmaceutically acceptable salt thereof may be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods prior to use.
本發明亦提供一種組合物，包含本文所述的至少一種化合物和/或其醫藥學上可接受的鹽，以及至少一種醫藥上可接受的載劑。 The invention also provides a composition comprising at least one compound described herein and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
包括所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽的組合物，可以各種習知的方法如口服、非腸道式、吸入劑噴霧、或是植入式貯器等方式投藥。術語「非腸道式」，指的是包括皮下、皮內、靜脈、肌肉、關節內、動脈內、滑膜內、胸骨內、脊椎內、患處內、以及顱內注射或輸注技術。 The composition comprising the at least one compound and/or at least one pharmaceutically acceptable salt thereof can be administered by various conventional methods such as oral, parenteral, inhalation spray, or implantable reservoirs. Dosing. The term "parenteral" refers to subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intraspinal, intralesional, and intracranial injection or infusion techniques.
口服用的組合物可以是任何一種可接受的口服劑型，包括但不限於：錠劑、膠囊、乳劑、以及水相懸浮劑、分散劑以及溶液。常用的錠劑載劑包括乳糖和玉米澱粉。錠劑中也常加入如硬脂酸鎂之類的潤滑劑。以膠囊形式口服時，有效的稀釋劑包括乳糖以及乾燥的玉米澱粉。當水相懸浮液或乳劑以口服投藥時，可用乳化劑或懸浮劑使活性成分懸浮或溶解於一油相中。若有需要，可添加特定的甜味、香料、或色素。 The compositions for oral administration can be any of the acceptable oral dosage forms including, but not limited to, lozenges, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. Common lozenge carriers include lactose and corn starch. Lubricants such as magnesium stearate are also often added to tablets. When administered orally in a capsule form, effective diluents include lactose and dried corn starch. When the aqueous suspension or emulsion is administered orally, the active ingredient may be suspended or dissolved in an oil phase using an emulsifying or suspending agent. Add specific sweetness, flavor, or color if needed.
無菌可注射組合物(如水狀或油狀懸浮液)可按照任何一種已知技術，使用適合的分散劑或潤濕劑(如：Tween 80)以及懸浮劑來完成製備。無菌可注射組合物也可製備成無菌的可注射溶液或懸浮液，溶於一無毒性的可用於非腸道式的稀釋劑或溶劑中，例如，1,3-丁二醇溶液。在可接受的載劑與溶劑中，可使用的是甘露糖醇、水、林格爾氏液、以及生理鹽水。此外，無菌的低沸點油，如合成的單-或雙-甘油酯，通常用作溶劑或懸浮介質。脂肪酸，例如油酸以及其甘油酯衍生物，以及天然的醫藥可接受的油，例如橄欖油或蓖麻油，尤其是聚乙氧基化的形態，常用於製備可注射溶液。這些油溶液或懸浮液亦可含有一長鏈的醇類稀釋劑或分散劑、或羧甲基纖維素、或其類似的分散劑。 Sterile injectable compositions (e.g., aqueous or oily suspensions) can be prepared according to any of the known techniques using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable compositions can also be prepared in a sterile injectable solution or dispersion in a non-toxic parenteral diluent or solvent, for example, a 1,3-butanediol solution. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution, and physiological saline. In addition, sterile low boiling oils, such as synthetic mono- or di-glycerides, are commonly employed as solvents or suspending media. Fatty acids, such as oleic acid and its glyceride derivatives, as well as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially polyethoxylated forms, are commonly used in the preparation of injectable solutions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose, or a similar dispersing agent.
吸入組合物可以使用醫藥製劑領域眾所周知的技術製備，也可製成溶於食鹽水中的溶液，採用苯甲醇或其他適宜的防腐劑，採用吸收促進劑提高生物可利用度，採用碳氟化合物和或其他該領域已知的增溶劑或分散劑。 The inhalation composition can be prepared using techniques well known in the art of pharmaceutical preparations, or can be prepared in a solution in saline, using benzyl alcohol or other suitable preservatives, using an absorption enhancer to increase bioavailability, using fluorocarbons and/or Other solubilizers or dispersants known in the art.
用於局部的組合物可配製為油脂、霜劑、乳液、軟膏、以及類似的產品。適於該組合物的載劑包括植物油或礦物油、白凡士林(白軟石蠟)、支鏈脂肪或油、動物脂肪和高分子量的醇類(碳數大於12)。在一些實施態樣中，醫藥上可接受的載劑為活性成分能溶解於其中者。此外，在添加增加顏色或香味成分之外，亦可依需要加入乳化劑、穩定劑、保濕劑、以及抗氧化劑。而外皮滲透促進劑也可添加於這些局部配方中。這類促進劑的例子可見於美國專利3,989,816和4,444,762。 The topical compositions can be formulated as oils, creams, lotions, ointments, and the like. Carriers suitable for the composition include vegetable oils or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (carbon number greater than 12). In some embodiments, a pharmaceutically acceptable carrier is one in which the active ingredient is soluble. In addition, emulsifiers, stabilizers, humectants, and antioxidants may be added as needed in addition to adding color or aroma components. Skin penetration enhancers can also be added to these topical formulations. Examples of such accelerators can be found in U.S. Patents 3,989,816 and 4,444,762.
霜劑配方可將礦物油、自體乳化之蜂蠟、以及水混合後之混合物，其中混合之活性成分係溶解於一小量的油脂中，例如杏仁油，再摻雜於其中。此類霜劑的一例子是包括約40重量份的水、約20重量份的蜂蠟、約40重量份的礦物油、以及約1重量份的杏仁油。可混合一活性成分溶於一植物油中(例如杏仁油)的溶液以及溫的軟石蠟，並讓混合物冷卻而製備軟膏。這類軟膏的一例子，是包括約30%重量百分比的杏仁油和約70%重量百分比的白軟石蠟。 The cream formulation may be a mixture of mineral oil, self-emulsified beeswax, and water, wherein the mixed active ingredients are dissolved in a small amount of oil, such as almond oil, and then doped therein. An example of such a cream is comprising about 40 parts by weight of water, about 20 parts by weight of beeswax, about 40 parts by weight of mineral oil, and about 1 part by weight of almond oil. A solution in which an active ingredient is dissolved in a vegetable oil (for example, almond oil) and warm soft paraffin can be mixed, and the mixture is allowed to cool to prepare an ointment. An example of such an ointment is about 30% by weight of almond oil and about 70% by weight of white soft paraffin.
「醫藥上可接受的載劑」，指的是能與組合物中的活性成分相容(甚至在一些實施態樣中能穩定活性成分)，而且不能對於欲治療的個體有危害。例如環糊精(能與所述至少一種化合物和/或其至少一種醫藥上可接受的鹽形成特定的、溶解性更強的複合物)之類的增溶劑，可作為醫藥用的賦形劑來傳送活性成分。其他載劑的例子包括膠態二氧化矽、硬脂酸鎂、纖維素、十二烷基硫酸鈉、以及色素如D&C黃色10號(D&C Yellow # 10)。 "Pharmaceutically acceptable carrier" means that it is compatible with the active ingredients of the composition (even in some embodiments to stabilize the active ingredient) and is not hazardous to the individual to be treated. For example, a cyclodextrin (a solubilizing agent capable of forming a specific, more soluble complex with the at least one compound and/or at least one pharmaceutically acceptable salt thereof) can be used as a pharmaceutical excipient To deliver the active ingredient. Examples of other carriers include colloidal cerium oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10.
合適的體外實驗可用於早期評價所述至少一種化合物和/或其至少一種醫藥上可接受的鹽抑制PI3K和/或mTOR活性的效果，其治療癌症的效果可進一步通過體內實驗檢驗。例如，所述化合物和/或其醫學上可接受的鹽可給予患有癌症的動物(如小鼠模型)，然後檢測其治療效果。一個或多個此類測試所獲得的陽性結果足以擴充科學知識的寶庫，且因此也足以說明經測試的化合物和/或鹽的實用性。基於上述結果，還可以決定其對動物(如，人)的適合的劑量和給藥方式。 Suitable in vitro assays can be used to early evaluate the effect of the at least one compound and/or at least one pharmaceutically acceptable salt thereof inhibiting PI3K and/or mTOR activity, and the effect of treating cancer can be further tested by in vivo experiments. For example, the compound and/or its medically acceptable salt can be administered to an animal having a cancer (such as a mouse model) and then tested for its therapeutic effect. Positive results obtained by one or more such tests are sufficient to expand the treasure trove of scientific knowledge and are therefore sufficient to demonstrate the utility of the tested compounds and/or salts. Based on the above results, it is also possible to determine the appropriate dosage and mode of administration for the animal (e.g., human).
本發明也提供一種抑制PI3K和/或mTOR的活性的方法，該方法包括使有效量的所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽與酵素接觸以抑制PI3K和/或mTOR的活性。 The invention also provides a method of inhibiting the activity of PI3K and/or mTOR, the method comprising contacting an effective amount of the at least one compound and/or at least one pharmaceutically acceptable salt thereof with an enzyme to inhibit PI3K and/or The activity of mTOR.
所述的至少一種化合物和/或其至少一種醫藥學上可接受的鹽用來達到一種有益的治療或預防效果，例如，在患有癌症的個體中。這裡所用的術語「癌症(或腫瘤)」指的是細胞紊亂，其特徵為不可控或不可調的細胞增殖、細胞分化的減少、不恰當的侵入周圍組織的能力、和/或在異常部位建立新的生長的能力。術語「癌症」包括但不限於固態腫瘤和血源性腫瘤。術語「癌症」包括皮膚癌、組織癌、器官癌、骨癌、軟骨癌、血液癌和血管癌。術語「癌症」也包括原發性和轉移性的癌症。 The at least one compound and/or at least one pharmaceutically acceptable salt thereof is used to achieve a beneficial therapeutic or prophylactic effect, for example, in an individual having cancer. The term "cancer (or tumor)" as used herein refers to a cellular disorder characterized by uncontrolled or non-adjustable cell proliferation, decreased cell differentiation, inappropriate ability to invade surrounding tissues, and/or establishment at abnormal sites. New ability to grow. The term "cancer" includes, but is not limited to, solid tumors and blood-borne tumors. The term "cancer" includes skin cancer, tissue cancer, organ cancer, bone cancer, cartilage cancer, blood cancer, and vascular cancer. The term "cancer" also includes primary and metastatic cancers.
固態腫瘤的非限定性例子包括胰腺癌、膀胱癌、結腸直腸癌、乳腺癌(包括轉移性乳腺癌)、***癌(包括雄激素依賴和非雄激素依賴的***癌)、腎癌(包括如轉移性腎細胞癌)、肝細胞癌、肺癌(包括如非小細胞肺癌(NSCLC)、細支氣管肺泡癌(BAC)和肺腺癌)、卵巢癌(包括如漸進上皮癌或原發性腹膜癌)、宮頸癌、胃癌、食道癌、頭頸部癌(包括如頭部和頸部的鱗狀細胞癌)、皮膚癌(包括例如惡性黑色素瘤)、神經內分泌癌包括轉移性神經內分泌腫瘤、腦瘤(包括例如神經膠質瘤、間變性少突神經膠質瘤、成人多形性膠質母細胞癌和成人間變性星型細胞瘤)、骨癌、軟組織肉瘤和甲狀腺癌。例如，這些固態腫瘤包括胰腺癌、膀胱癌、結腸直腸癌、乳腺癌和卵巢癌。 Non-limiting examples of solid tumors include pancreatic cancer, bladder cancer, colorectal cancer, breast cancer (including metastatic breast cancer), prostate cancer (including androgen-dependent and non-androgen-dependent prostate cancer), and renal cancer (including Metastatic renal cell carcinoma), hepatocellular carcinoma, lung cancer (including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma), ovarian cancer (including, for example, progressive epithelial cancer or primary peritoneal cancer) ), cervical cancer, gastric cancer, esophageal cancer, head and neck cancer (including squamous cell carcinoma such as head and neck), skin cancer (including, for example, malignant melanoma), neuroendocrine cancer including metastatic neuroendocrine tumor, brain tumor (including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme and adult metaplastic astrocytoma), bone cancer, soft tissue sarcoma, and thyroid cancer. For example, these solid tumors include pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, and ovarian cancer.
血液惡性腫瘤(hematologic malignancies)的非限定性例子包括急性骨髓性白血病(AML)；慢性骨髓性白血病(CML)，包括不 斷發展的CML和急變的CML(CML-BP)；急性淋巴細胞白血病(ALL)；慢性淋巴細胞白血病(CLL)；霍奇金氏病(HD)；非霍奇金淋巴瘤(NHL)，包括濾泡型淋巴瘤和地幔細胞淋巴瘤；B-細胞淋巴瘤；T-細胞淋巴瘤；多發性骨髓瘤(MM)；瓦爾登斯特倫氏巨球蛋白血症；骨髓增生異常綜合症(MDS)，包括難治性貧血(RA)、伴有環狀鐵幼粒細胞增多的難治性貧血(RARS)、伴有原始細胞增多的難治性貧血(RAEB)、和轉變中的伴有原始細胞增多的難治性貧血(RAEB-T)；以及骨髓增生綜合症。 Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myelogenous leukemia (CML), including no Broken CML and rapidly changing CML (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including Follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS) ), including refractory anemia (RA), refractory anemia associated with annular iron granulocytosis (RARS), refractory anemia with primordial augmentation (RAEB), and primordial cell proliferation with transformation Refractory anemia (RAEB-T); and myeloproliferative syndrome.
在一些實施態樣中，能夠治療的癌症的例子，包括但不限於肺癌、頭頸部癌、結腸直腸癌、胰腺癌、結腸癌、乳腺癌、卵巢癌、***癌、胃癌、腎癌、肝癌、腦癌、骨癌和白血病。 In some embodiments, examples of cancers that can be treated include, but are not limited to, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, Brain cancer, bone cancer and leukemia.
在一些實施態樣中，所述的至少一種化合物和/或其至少一種醫藥學上可接受的鹽係與其他治療藥劑聯合用藥。在一些實施態樣中，其他的治療藥劑是一種患有受治療的疾病或症狀的病人通常服用的藥劑。所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽，可與其他的治療藥劑以單一劑量的形式服用，或以分開的劑量形式服用。當以分開的劑量形式服用時，其他的治療藥劑可以在所述的至少一種化合物和/或其至少一種醫藥上可接受的鹽服用之前、同時或之後服用。 In some embodiments, the at least one compound and/or at least one pharmaceutically acceptable salt thereof is administered in combination with other therapeutic agents. In some embodiments, the additional therapeutic agent is an agent that is typically administered to a patient suffering from a disease or condition being treated. The at least one compound and/or at least one pharmaceutically acceptable salt thereof may be administered in a single dose with other therapeutic agents or in separate dosage forms. When administered in separate dosage forms, other therapeutic agents can be administered prior to, concurrently with, or subsequent to administration of the at least one compound and/or at least one pharmaceutically acceptable salt thereof.
在一些實施態樣中，本文所述的至少一種化合物和/或其至少一種醫藥學上可接受的鹽，可與其他抗瘤藥劑(anti-neoplastic agent)聯合用藥。這裡所用的術語「抗瘤藥劑」指得是任何一種用於癌症患者治療癌症的藥劑。抗瘤製劑的非限定性例子包括：放療藥劑、免疫療法藥劑、DNA損傷的化療藥劑和干擾細胞複製的化療藥劑。 DNA損傷的化療藥劑的非限定性例子包括，拓撲異構酶I的抑制劑(如，伊立替康(irinotecan)、拓撲替康(topotecan)和喜樹鹼(camptothecin)以及他們的類似物或代謝物、以及阿黴素(doxorubicin))；拓撲異構酶Ⅱ抑制劑(如，依妥普賽(etoposide)、替尼泊苷(teniposide)、和道諾黴素(daunorubicin))；烷化劑(如，左旋溶肉瘤素(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、三胺硫磷(thiotepa)、異環磷醯胺(ifosfamide)、亞硝基脲氮芥(carmustine)、環己亞硝脲(lomustine)、甲基環己亞硝脲(semustine)、鏈脲黴素(streptozocin)、氨烯咪胺(decarbazine)、甲氨蝶呤(methotrexate)、絲裂黴素C(mitomycin C)和環磷醯胺(cyclophosphamide))；DNA***劑(如，順鉑(cisplatin)、奧沙利鉑(oxaliplatin)和卡波鉑(carboplatin))；DNA***劑和自由基產生劑，如博來黴素(bleomycin)；以及核苷模仿劑(如5-氟尿嘧啶(5-fluorouracil)、卡培他濱(capecitibine)、2、2-二氟去氧胞嘧啶核苷(gemcitabine)、氟達拉濱(fludarabine)、阿糖胞苷(cytarabine)、巰基嘌呤(mercaptopurine)、硫鳥嘌呤(thioguanine)、噴司他丁(pentostatin)和羥基脲(hydroxyurea)。 In some embodiments, at least one compound described herein and/or at least one pharmaceutically acceptable salt thereof can be administered in combination with other anti-neoplastic agents. The term "anti-tumor agent" as used herein refers to any agent for treating cancer in a cancer patient. Non-limiting examples of anti-tumor agents include: radiotherapeutic agents, immunotherapeutic agents, chemotherapeutic agents for DNA damage, and chemotherapeutic agents that interfere with cell replication. Non-limiting examples of chemotherapeutic agents for DNA damage include inhibitors of topoisomerase I (eg, irinotecan, topotecan, and camptothecin, and their analogs or metabolism) And doxorubicin); topoisomerase II inhibitors (eg, etoposide, teniposide, and daunorubicin); alkylating agents (eg, melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosourea mustard (carmustine), lomustine, semustine, streptozocin, decarbazine, methotrexate, mitosis Molecular C (mitomycin C) and cyclophosphamide; DNA inserts (eg, cisplatin, oxaliplatin, and carboplatin); DNA inserts and freedom Base generators, such as bleomycin; and nucleoside mimics (eg 5-fluorouracil, capecitabine) ), 2, 2-difluorodeoxycytidine (gemcitabine), fludarabine (cydarabine), cytarabine, mercaptopurine, thioguanine, pentazostat Pentostatin and hydroxyurea.
干擾細胞複製的化療藥劑包括：紫杉醇(paclitaxel)、紫杉萜(docetaxel)、及其相關類似物；長春新鹼(vincristine)、長春鹼(vinblastin)，及其相關類似物；沙立度胺(thalidomide)及其相關類似物(如：CC-5013和CC-4047)；蛋白酪氨酸激酶抑制劑 (如，甲磺酸伊馬替尼(imatinib mesylate)和吉非替尼(gefitinib))；蛋白酶抑制劑(如，硼替佐米(bortezomib))；NF-kB抑制劑，包括IKB(I kappa B)激酶抑制劑；與腫瘤中過度表現的蛋白結合，從而下調細胞複製的抗體(如曲妥單抗(trastuzumab)、利妥昔單抗(rituximab)、西妥昔單抗(cetuximab)和貝伐單抗(bevacizuma))；以及其他蛋白或酶的抑制劑，已知這些蛋白或酶在癌症中會被調高、過度表現或啟動，能夠抑制細胞複製。 Chemotherapeutic agents that interfere with cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide ( Thalidomide) and related analogs (eg CC-5013 and CC-4047); protein tyrosine kinase inhibitors (eg, imatinib mesylate and gefitinib); protease inhibitors (eg, bortezomib); NF-kB inhibitors, including IKB (I kappa B) Kinase inhibitors; antibodies that bind to overexpressed proteins in tumors, thereby downregulating cellular replication (eg trastuzumab, rituximab, cetuximab, and bevacizumab) Anti- (bevacizuma); and other protein or enzyme inhibitors, these proteins or enzymes are known to be elevated, overexpressed or activated in cancer, inhibiting cell replication.
下列實施例應確定為純粹地作為示例，而不應當是以任何方式對本發明的限制。用到的資料(如，量、溫度等)會力爭保證其準確性，但是仍會有一些實驗誤差和偏移。除非另有說明，份數是重量份數，溫度為攝氏溫度，壓力為或接近大氣壓。所有的質譜資料運用安捷倫(Agilent)6120和/或1100測定。氫核磁共振光譜(1H NMR)係以瓦裡安(Varian)400 MHz核磁共振儀測定，使用CDCl3或DMSO-d6為溶劑，TMS為內標準品。相較於內標準品TMS往低磁場之化學位移以ppm表示，偶合常數(J values)係以Hz為單位。本發明所用的所有試劑(除了中間體物以外)均為商業管道獲得。所有化合物的名字(除了試劑以外)皆由軟體Chemdraw 10產生。 The following examples are to be considered as illustrative and not restrictive. The data used (eg, volume, temperature, etc.) will strive to ensure its accuracy, but there will still be some experimental errors and offsets. Unless otherwise indicated, parts are parts by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. All mass spectral data were measured using an Agilent 6120 and/or 1100. Hydrogen nuclear magnetic resonance spectroscopy ( 1 H NMR) was measured on a Varian 400 MHz NMR spectrometer using CDCl 3 or DMSO-d 6 as the solvent and TMS as the internal standard. The chemical shift to the low magnetic field is expressed in ppm compared to the internal standard TMS, and the coupling constant ( J values) is in Hz. All reagents (other than intermediates) used in the present invention are obtained commercially. The names of all compounds (except reagents) were generated by the software Chemdraw 10.
以下實施例中，使用到的縮寫列表： In the following examples, the list of abbreviations used is:
室溫下，將K2CO3(17.4公克，126毫莫耳)和2-氰基乙酸三級丁基酯(10.7公克，76毫莫耳)加入2-氯-5-硝基吡啶(10公克，63毫莫耳)的THF(150毫升)溶液中，反應混合液加熱回流並攪拌過夜。濾去固體，所得濾液濃縮，乾燥得到中間體I-1b(16.6公克)。m/z 208(M+H)+。 K 2 CO 3 (17.4 g, 126 mmol) and 2-butyl cyanoacetate (10.7 g, 76 mmol) were added to 2-chloro-5-nitropyridine (10 ° C) A solution of gram (63 mL) in THF (150 mL). The solid was filtered off, and the obtained filtrate was concentrated and dried to afford Intermediate I-1b (16.6 g). m/z 208 (M+H) + .
將粗產品2-氰基-2-(5-硝基吡啶-2-基)乙酸三級丁基酯(I-1b，12公克，47毫莫耳)溶於100毫升HCl/EtOH(v/v 1：5)中，於80℃攪拌反應4小時，然後濃縮，加水稀釋。混合液用EtOAc(4 x 40毫升)萃取。萃取液合併，濃縮，經矽膠管柱層析(PE：EtOAc=3：1)純化得2-(5-硝基吡啶-2-基)乙腈(I-1c)固體(7.7克，收率42.0%)。 The crude product 2-cyano-2-(5-nitropyridin-2-yl)acetic acid tert-butyl ester (I-1b, 12 g, 47 mmol) was dissolved in 100 mL HCl/EtOH (v/ In v 1:5), the reaction was stirred at 80 ° C for 4 hours, then concentrated and diluted with water. The mixture was extracted with EtOAc (4×40 mL). The extracts were combined, concentrated and purified with EtOAc EtOAc EtOAc EtOAc EtOAc %).
室溫下將碘甲烷(7.5毫升，120毫莫耳)滴入上述2-(5-硝基吡啶-2-基)乙腈(I-1c，8公克，46毫莫耳)和K2CO3(18公克，110毫莫耳)的CH3CN(200毫升)混合液中，升溫至40℃，攪拌反應過夜。然後過濾，濾液濃縮，經矽膠管柱層析(PE：EtOAc=5：1)純化，得到2-甲基-2-(5-硝基吡啶-2-基)丙腈(I-1d)(4.2公克，收率48%)。m/z 192(M+H)+。 Methyl iodide (7.5 ml, 120 mmol) was added dropwise to the above 2-(5-nitropyridin-2-yl)acetonitrile (I-1c, 8 g, 46 mmol) and K 2 CO 3 at room temperature. (18 g, 110 mmol) in CH 3 CN (200 mL) mixture was heated to 40 ℃, the reaction was stirred overnight. Then it was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE:EtOAc = 5:1) to give 2-methyl-2-(5-nitropyridin-2-yl)propionitrile (I-1d) ( 4.2 grams, yield 48%). m/z 192 (M+H) + .
將2-甲基-2-(5-硝基吡啶-2-基)丙腈(I-1d，2公克，10.4毫莫耳)和SnCl2．2H2O(9.3公克，41.6毫莫耳)的EtOAc(10毫升)溶液回流攪拌反應4小時，冷卻至室溫，加入2莫耳濃度NaOH(80毫升)調節pH=8~9，濾去固體所得濾液用乙酸乙酯(3 x 40毫升)萃取，合併後的有機相用無水硫酸鈉乾燥，濃縮得2-(5-胺基吡啶-2-基)-2-甲基丙腈(I-1，1.7公克，收率65.3%)。 2-Methyl-2-(5-nitropyridin-2-yl)propanenitrile (I-1d, 2 g, 10.4 mmol) and SnCl 2 . 2H 2 O (9.3 g, 41.6 mmol) in EtOAc (10 mL) EtOAc (10 mL) EtOAc EtOAc EtOAc EtOAc. The filtrate was extracted with EtOAc (3×40 mL). 1,1.7 grams, yield 65.3%).
將2-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2取代)吡啶(300毫克，1.1毫莫耳濃度)和Raney-Ni(10毫克)的甲醇(10毫升)混合液，在氫氣下攪拌2小時。過濾，濾液濃縮得一白色固體，為目標化合物(261毫克，收率95%)。 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-substituted)pyridine (300 mg, 1.1 mmol) A mixture of ear concentration and Raney-Ni (10 mg) in methanol (10 ml) was stirred under hydrogen for 2 hr. Filtration and concentration of the filtrate gave a white solid (yield: 261 mg, yield 95%).
在-20℃下，將三氟甲基磺酸酐(147毫克，0.52毫莫耳)慢慢滴加至2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2取代)吡啶-3-胺(100毫克，0.4毫莫耳)和2，6-二-三級丁基-4-甲基吡啶(115毫克，0.56毫莫耳)的DCM(5毫升)混合液中，並在此溫度下繼續攪拌2小時。真空除去溶劑得到1,1,1-三氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-3-)甲磺醯胺(141毫克，收率92.0%)，無需進一步純化可直接用於以後的反應。 Trifluoromethanesulfonic anhydride (147 mg, 0.52 mmol) was slowly added dropwise to 2-methoxy-5-(4,4,5,5-tetramethyl-1 at -20 °C. 3,2-dioxaborolan-2 substituted)pyridin-3-amine (100 mg, 0.4 mmol) and 2,6-di-tert-butyl-4-methylpyridine (115 mg, 0.56 m) Mix a mixture of DCM (5 mL) and continue stirring at this temperature for 2 hours. The solvent was removed in vacuo to give 1,1,1-trifluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 Pyridyl-3-)methanesulfonamide (141 mg, yield 92.0%) was used in the next reaction without further purification.
將6-氯-3-胺基吡啶(5.0公克，38.8毫莫耳)和5-(甲氧基甲烯)-2,2-二甲基-1,3-二氧-4,6-二酮(7.2公克，38.8毫莫耳)的異丙醇(60毫升)混合液，回流攪拌反應2小時。蒸乾溶劑得到10公克固體為5-((6-氯吡啶-3-胺基)甲基烯)-2,2-二甲基-1,3-二氧-4,6-二酮(產率91%)，m/z 283(M+H)+。 6-Chloro-3-aminopyridine (5.0 g, 38.8 mmol) and 5-(methoxymethyl)-2,2-dimethyl-1,3-dioxo-4,6-di A mixture of ketone (7.2 g, 38.8 mmol) in isopropanol (60 ml) was stirred and refluxed for 2 hours. Evaporation of the solvent gave 10 g of solid as 5-((6-chloropyridin-3-amino)methylene)-2,2-dimethyl-1,3-dioxo-4,6-dione. Rate 91%), m/z 283 (M+H) + .
向加熱至200℃的Dowtherm A(200毫升)中分批加入5-((6-氯吡啶-3-胺基)甲基烯)-2,2-二甲基-1,3-二氧-4,6-二酮(3.5公克，12.4毫莫耳)後繼續攪拌5分鐘，冷卻至室溫後，向反應液中加石油醚，過濾收集沉澱，真空乾燥後得到灰白色固體產物6-氯-1,5-萘啶-4-醇，產率42%(0.94公克)。m/z 183(M+H)+。 5-((6-chloropyridin-3-amino)methylene)-2,2-dimethyl-1,3-dioxos was added in portions to Dowtherm A (200 mL) heated to 200 °C. After 4,6-diketone (3.5 g, 12.4 mmol), stirring was continued for 5 minutes. After cooling to room temperature, petroleum ether was added to the reaction mixture, and the precipitate was collected by filtration. 1,5-naphthyridin-4-ol, yield 42% (0.94 g). m/z 183 (M+H) + .
將6-氯-1,5-萘啶4-醇(1.45公克，8毫升)加入到冰冷卻的濃硫酸(15毫升)中，接著慢慢於0℃下分批加入KNO3(1.62公克，16毫莫耳)。混合液加熱至100℃攪拌反應一小時後，倒入冰水中，收集沉澱，真空乾燥得6-氯-3-硝基-1,5-萘啶-4-醇，產率90%(1.97公克)。 6-chloro-1,5-naphthyridin-4- ol (1.45 g, 8 ml) was added to an ice-cooled concentrated sulfuric acid (15 ml), followed by the slow portionwise at 0 ℃ was added KNO 3 (1.62 g, 16 millimoles). The mixture was heated to 100 ° C and stirred for one hour, poured into ice water, and the precipitate was collected and dried in vacuo to give 6-chloro-3-nitro-1,5-naphthyridin-4-ol, yield 90% (1.97 g) ).
將5-溴-2甲氧基-3-硝基吡啶(5公克，21.5毫莫耳)、4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧硼戊環)(6.6公克，25.8毫莫耳)、PdCl2(dppf)-CH2Cl2(500毫克)和乙酸鉀(6.3公克，64.5毫莫耳)的無水二氧六環(200毫升)混合液，回流攪拌反應2小時。濃縮，經矽膠管柱層析純化(PE：EtOAc=10：1)，得到5克2-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2)吡啶(產率81%)。m/z 281(M+H)+。 5-Bromo-2methoxy-3-nitropyridine (5 g, 21.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2 , 2'-bis(1,3,2-dioxaborolan) (6.6 g, 25.8 mmol), PdCl 2 (dppf)-CH 2 Cl 2 (500 mg) and potassium acetate (6.3 g, 64.5 A mixture of anhydrous dioxane (200 ml) was stirred and refluxed for 2 hours. Concentrate and purify by column chromatography (PE:EtOAc = 10:1) to give 5 g of 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2)pyridine (yield 81%). m/z 281 (M+H) + .
將Raney-Ni(50毫克)加入2-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2)吡啶(500毫克，1.79毫莫耳)的甲醇(50毫升)溶液中，混合物在氫氣下，室溫攪拌反應兩小時。濾去固體，去 除溶劑，得2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2)吡啶-3-胺(400毫克，產率89%)。m/z 251(M+H)+。 Add Raney-Ni (50 mg) to 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2)pyridine (500 mg, 1.79 mmol) in methanol (50 mL). The solid was filtered off and the solvent was removed to give 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2)pyridin-3-amine (400 Mg, yield 89%). m/z 251 (M+H) + .
將2,4-二氟苯磺醯氯(407毫克，1.9毫莫耳)慢慢加入2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2)吡啶-3-胺(400毫克，1.6毫莫耳)的吡啶(5毫升)溶液中，混合物室溫攪拌，反應過夜，真空蒸去溶劑，剩餘物加鹽水(5毫升)稀釋，EtOAc(3×10毫升)萃取。合併有機相，真空蒸乾，以管柱層析(PE：EtOAc=5：1)純化得到400毫克白色固體產物2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶-3-)苯磺醯胺(產率59%)。m/z 427(M+H)+。 2,4-Difluorobenzenesulfonium chloride (407 mg, 1.9 mmol) was slowly added to 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2- A solution of dioxonol-2)pyridin-3-amine (400 mg, 1.6 mmol) in pyridine (5 mL). Diluted with EtOAc (3 x 10 mL). The combined organic phases were evaporated to dryness purified eluting elut elut elut elut elut elut eluting 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-)benzenesulfonamide (yield 59%). m/z 427 (M+H) + .
將溴(0.895毫升，15.5毫莫耳)加入喹喔啉-2-醇(1.5公克，10.3毫莫耳)的乙酸(15毫升)溶液中，混合物室溫攪拌反應6小時，收集沉澱。沉澱用乙酸乙酯洗滌，乾燥得固體7-溴-喹喔啉-2-醇(2公克，收率90%)。 Bromine (0.895 ml, 15.5 mmol) was added to a solution of quinoxaline-2-ol (1.5 g, 10.3 mmol) in acetic acid (15 ml), and the mixture was stirred at room temperature for 6 hr. The precipitate was washed with ethyl acetate and dried to give solid 7-bromo-quinoxaline-2-ol (2 g, yield: 90%).
在7-溴-喹喔啉-2-醇(2公克，8.88毫莫耳)的三氯氧膦(7毫升)混懸液中，滴加2滴DMF，混合物升溫至100℃，反應3小時。冷卻，真空除去三氯氧膦，剩餘物溶解於EtOAc中，在攪拌 下，滴加至冰水中。然後，用乙酸乙酯萃取三次，合併萃取液，萃取液用飽和碳酸氫鈉溶液洗滌，有機相濃縮，乾燥得固體7-溴-2-氯-喹喔啉(2公克，產率93%)。 In a suspension of 7-bromo-quinoxalin-2-ol (2 g, 8.88 mmol) in phosphorus oxychloride (7 ml), 2 drops of DMF were added dropwise, and the mixture was warmed to 100 ° C for 3 hours. . Cooled, the phosphorus oxychloride was removed in vacuo and the residue was dissolved in EtOAc. Next, add to the ice water. Then, it was extracted with ethyl acetate three times, and the extracts were combined, and the extract was washed with saturated sodium hydrogen carbonate solution, and the organic phase was concentrated and dried to give solid 7-bromo-2-chloro-quinoxaline (2 g, yield 93%) .
將水合肼(85%，4.5毫升，32.8毫莫耳)加入7-溴-2-氯-喹喔啉(2公克，8.2毫莫耳)的乙醇(20毫升)溶液中，混合液在78℃下反應2小時。冷卻，過濾，收集沉澱，得到固體7-溴-2-肼基-喹喔啉(1.7公克，產率87%)。 Add hydrazine hydrate (85%, 4.5 ml, 32.8 mmol) to a solution of 7-bromo-2-chloro-quinoxaline (2 g, 8.2 mmol) in ethanol (20 mL) at EtOAc. The reaction was carried out for 2 hours. After cooling, filtration, the precipitate was collected to give solid 7-bromo-2-mercapto-quinoxaline (1.7 g, yield 87%).
將7-溴-2-肼基-喹喔啉(200毫克，0.83毫莫耳)的原甲酸三乙酯(3毫升)溶液升溫至100℃，反應4小時。冷卻，混合液用乙酸乙酯稀釋，過濾，收集沉澱，乾燥得到黃色固體8-溴-[1,2,4]***並[4,3-a]喹喔啉(180毫克，產率87%).m/z 251(M+H)+。 A solution of 7-bromo-2-indolyl-quinoxaline (200 mg, 0.83 mmol) in triethyl orthoformate (3 ml) was warmed to 100 ° C and allowed to react for 4 hours. After cooling, the mixture was diluted with ethyl acetate, filtered, and then evaporated and evaporated, then evaporated %).m/z 251(M+H) + .
在7-溴-2-肼基喹喔啉(200毫克，0.83毫莫耳)的DMF(3毫升)溶液中，加入HATU(380毫克，1毫莫耳)、DIPEA(0.205毫升，1毫莫耳)和環丙基甲酸(71毫克，0.83毫莫耳)。混合物室溫攪拌反應5小時後，用乙酸乙酯稀釋。水洗三次有機相，然後濃縮 得黃色固體N'-(7-溴喹喔啉-2-)環丙基碳醯肼，該固體直接用於下步反應。m/z 309(M+H)+。 In a solution of 7-bromo-2-indolyl quinoxaline (200 mg, 0.83 mmol) in DMF (3 mL), HATU (380 mg, 1 mmol), DIPEA (0.205 ml, 1 mmol) Ear) and cyclopropyl formate (71 mg, 0.83 mmol). The mixture was stirred at room temperature for 5 hours and then diluted with ethyl acetate. The organic phase was washed three times with water, then concentrated to give a yellow solid N--(7-bromoquinoxaline-2-)cyclopropylcarbazide which was used directly in the next step. m/z 309 (M+H) + .
上述粗產物N'-(7-溴喹喔啉-2-)環丙基碳醯肼溶於乙酸(5毫升)中，在100℃下反應過夜。真空除去溶劑，剩餘物水洗，真空乾燥得到8-溴-1-環丙基-[1,2,4]***並[4,3-a]喹喔啉(100毫克，產率42%)。m/z 291(M+H)+。 The above crude N'-(7-bromoquinoxaline-2-)cyclopropylcarbazide was dissolved in acetic acid (5 ml) and then reacted at 100 ° C overnight. The solvent was removed in vacuo and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ . m/z 291 (M+H) + .
將三乙胺(0.175毫升，1.2毫莫耳)加入7-溴-2-肼基喹喔啉(200毫克，0.83毫莫耳)的二氯甲烷(5毫升)溶液中，然後在氮氣下，於0℃滴加光氣(0.055毫升，0.46毫莫耳)的二氯甲烷溶液。滴加完光氣溶液後，升溫至室溫，繼續攪拌反應5小時。真空除去溶劑，剩餘物水洗，真空乾燥得黃色固體8-溴-[1,2,4]***並[4,3-a]喹喔啉-1(2H)-酮(180毫克，產率82%)。m/z 265(M+H)+。 Add triethylamine (0.175 ml, 1.2 mmol) to a solution of 7-bromo-2-mercaptoquinoxaline (200 mg, 0.83 mmol) in dichloromethane (5 mL). A solution of phosgene (0.055 ml, 0.46 mmol) in dichloromethane was added dropwise at 0 °C. After the phosgene solution was added dropwise, the temperature was raised to room temperature, and the reaction was further stirred for 5 hours. The solvent was removed in vacuo and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 82%). m/z 265 (M+H) + .
將5-溴-3-(三氟甲基)吡啶-2-胺(4公克，16.60毫莫耳)，4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧硼戊環)(5.90公克，23.24毫莫耳)、KOAc(4.07公克，41.5毫莫耳)和PdCl2(dppf).CH2Cl2(0.678公克，0.830毫莫耳)的二氧六環(60毫升)橙色混懸液，在氮氣下加熱至110℃反應10小時。真空濃縮，除去溶劑，粗產品經矽膠管柱純化(洗脫劑PE/EtOAc)得到淡黃色固體純產物5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2)-3-(三氟甲基)吡啶-2-胺(4.5公克，產率94%)。MS(m/z)：289(M+H)+。 5-Bromo-3-(trifluoromethyl)pyridin-2-amine (4 g, 16.60 mmol), 4,4,4',4',5,5,5',5'-octa Base-2,2'-bis(1,3,2-dioxaborolan) (5.90 g, 23.24 mmol), KOAc (4.07 g, 41.5 mmol) and PdCl 2 (dppf).CH 2 An orange suspension of dioxane (60 ml) of Cl 2 (0.678 g, 0.830 mmol) was heated to 110 ° C under nitrogen for 10 hours. Concentrated in vacuo, the solvent was evaporated and purified eluted eluted elut elut elut elut elut elut Borapentane-2)-3-(trifluoromethyl)pyridin-2-amine (4.5 g, yield 94%). MS (m/z): 289 (M+H) + .
將三氯氧膦(2.7毫升，28.8毫莫耳)的無水DMF(10毫升)溶液在3分鐘內加至6-氯-3-硝基-1,5-萘啶-4-醇(5公克，22.1毫莫耳)的DMF(15毫升)混懸液中，混合物室溫攪拌，反應過夜。把反應液倒入碎冰中，過濾，收集沉澱，水洗，真空乾燥，得黃色固體2,8-二氯-7-硝基-1,5-萘啶(4公克，產率74.0%)。MS(m/z)：244(M+H)+。 A solution of phosphorus oxychloride (2.7 ml, 28.8 mmol) in dry DMF (10 mL) was added to 6-chloro-3-nitro-1,5-naphthyridin-4-ol (5 g) over 3 min. In a suspension of 22.1 mmol of DMF (15 mL), the mixture was stirred at room temperature overnight. The reaction solution was poured into crushed ice, filtered, and the precipitate was collected, washed with water, and dried in vacuo to give a white solid, 2,8-dichloro-7-nitro-1,5-naphthyridine (4 g, yield 74.0%). MS (m/z): 244 (M+H) + .
將2,8-二氯-7-硝基-1,5-萘啶(4公克，16.4毫莫耳)、4-胺基-呱啶-1-羧酸三級丁酯(4公克，19.7毫莫耳)和三乙胺(3.5毫升)的DMF(15毫升)的混合液，室溫攪拌，反應過夜。反應液倒入250毫升水中，過濾，收集沉澱，水洗，真空乾燥得黃色固體，為4-(6-氯-3-硝基-1,5-萘啶-4-胺基)呱啶-1-羧酸三級丁酯(6.54公克，產率97.8%).MS(m/z)：408(M+H)+。粗產物不需進一步純化直接用於下步反應。 2,8-Dichloro-7-nitro-1,5-naphthyridine (4 g, 16.4 mmol), 4-amino-acridine-1-carboxylic acid tert-butyl ester (4 g, 19.7) A mixture of millimolar and triethylamine (3.5 mL) in DMF (15 mL) was stirred at room temperature overnight. The reaction solution was poured into 250 ml of water, filtered, and the precipitate was collected, washed with water and dried in vacuo to give 4-(6-chloro-3-nitro-1,5-naphthyridin-4-amino) acridine-1 - carboxylic acid tert-butyl acrylate (6.54 g, yield 97.8%). MS (m/z): 408 (M+H) + . The crude product was used in the next step without further purification.
將SnCl2．2H2O(18公克，78.8毫莫耳)加入4-(6-氯-3-硝基-1,5-萘啶-4-胺基)呱啶-1-羧酸三級丁酯(6.43公克，15.7毫莫耳)的乙酸乙酯(250 mL)溶液，混合物室溫攪拌3小時，然後用飽和碳酸氫鈉溶液調節至pH=8，濾去固體，濾液濃縮，經矽膠管柱層析(洗脫劑EtOAc：PE)純化得黃色固體，為4-(3-胺基-6-氯-1,5-萘啶-4-胺基)呱啶-1-羧酸三級丁酯(5.1公克，產率85.6%)。MS(m/z)：378(M+H)+。 Will SnCl 2 . 2H 2 O (18 g, 78.8 mmol) was added 4-(6-chloro-3-nitro-1,5-naphthyridin-4-amino)acridine-1-carboxylic acid tert-butyl ester (6.43) A solution of gram (15.7 mmol) in ethyl acetate (250 mL), EtOAc EtOAc (EtOAc)EtOAc. (Eluent EtOAc: PE) was purified to give a yellow solid (4-(3-amino-6-chloro-1,5-naphthyridin-4-amino) acridine-1-carboxylic acid tert-butyl ester ( 5.1 grams, yield 85.6%). MS (m/z): 378 (M+H) + .
將NaNO2(460毫克，6.6毫莫耳)在0℃下加入4-(3-氨基-6-氯-1,5-萘啶-4-氨基)呱啶-1-羧酸三級丁酯(2.5公克，6.6毫莫耳)的醋酸(8毫升)溶液中，然後在室溫下，攪拌反應2小時，加入飽和碳酸鈉溶液和冰水。混合液用二氯甲烷提取。有機相經無水硫酸鈉乾 燥，濃縮，矽膠柱層析(洗脫劑：EtOAc：PE)純化得黃色固體為4-(8-氯-1H-[1,2,3]***並[4,5-c][1,5]萘啶-1-)呱啶-1-羧酸三級丁酯(1.9公克，收率73.8%)。MS(m/z)：388.8(M+H)+。 Add NaNO 2 (460 mg, 6.6 mmol) to 4-(3-amino-6-chloro-1,5-naphthyridin-4-amino)acridine-1-carboxylic acid tert-butyl ester at 0 °C (2.5 g, 6.6 mmol) in acetic acid (8 ml), then the reaction was stirred at room temperature for 2 hours, and saturated sodium carbonate solution and ice water were added. The mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate (MgSO4)EtOAc. 5-c][1,5]naphthyridine-1-)acridine-1-carboxylic acid tert-butyl ester (1.9 g, yield 73.8%). MS (m/z): 388.8 (M+H) + .
在4-(8-氯-1H-[1,2,3]***[4,5-c][1,5]萘啶-1-)呱啶-1-羧酸三級丁酯(4公克)的二氯甲烷-甲醇溶液中加入3毫升濃鹽酸，反應完全後，濃縮得到黃色固體，為8-氯-1-(呱啶-4-)-1H-[1,2,3]***並[4,5-c][1,5]萘啶鹽酸鹽(3.81公克，產率100%)。MS(m/z)：289(M+H)+。 3-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-)acridine-1-carboxylic acid tert-butyl ester (4 Add 3 ml of concentrated hydrochloric acid to a dichloromethane-methanol solution. After the reaction is completed, concentrate to give a yellow solid as 8-chloro-1-(azidine-4-)-1H-[1,2,3] Zoxao[4,5-c][1,5]naphthyridine hydrochloride (3.81 g, yield 100%). MS (m/z): 289 (M+H) + .
將乙酸(S)-1-氯-1-氧代丙-2-基酯(1.4公克，9.23毫莫耳)和Et3N(2.2毫升)加入8-氯-1-(呱啶-4-)-1H-[1,2,3]***並[4,5-c][1,5]萘啶鹽酸鹽(1公克，3.08毫莫耳)的二氯甲烷(10mL)溶液中，混合液室溫攪拌，反應2小時，加水(10毫升)淬滅。然後用CH2Cl2(2 x 20毫升)萃取，有機相合併，無水硫酸鈉乾燥，真空濃縮得乙酸(S)-1-(4-(8-氯-1H-[1,2,3]***並[4,5-c][1,5]萘啶-1-)呱啶-1-)-1-氧代丙-2-基酯(1.2公克)。MS(m/z)：403(M+H)+。 Add (-)-1-chloro-1-oxopropan-2-yl acetate (1.4 g, 9.23 mmol) and Et 3 N (2.2 ml) to 8-chloro-1-(acridine-4- a solution of -1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine hydrochloride (1 g, 3.08 mmol) in dichloromethane (10 mL) The mixture was stirred at rt for 2 h and quenched with water (10 mL). It is then extracted with CH 2 Cl 2 (2 x 20 mL). EtOAcjjjjjjjjjjjjjjjjj Triazolo[4,5-c][1,5]naphthyridin-1-)acridin-1-)-1-oxopropan-2-yl ester (1.2 g). MS (m/z): 403 (M+H) + .
將LiOH(650毫克，14.9毫莫耳)加入乙酸(S)-1-(4-(8-氯-1H-[1,2,3]***並[4,5-c][1,5]萘啶-1-)呱啶-1-)-1-氧代丙-2-基酯(1.2公克，2.97毫莫耳)的THF(30毫升)和MeOH(30毫升)混合液中，室溫攪拌，反應3小時。真空濃縮，加水稀釋，用2N鹽酸調節pH至7。所得混合物濃縮，過濾以收集沉澱，水洗，真空乾燥得黃色固體，為(S)-1-(4-(8-氯-1H-[1,2,3]***並[4,5-c][1,5]萘啶-1-)呱啶-1-)-2-羥丙基-1-酮(918毫克，產率85.4%)。MS(m/z)：361(M+H)+。該粗產物不需進一步純化直接用於下述反應。 Add LiOH (650 mg, 14.9 mmol) to acetic acid (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5 a mixture of naphthyridine-1-)azetidin-1-)-1-oxopropan-2-yl ester (1.2 g, 2.97 mmol) in THF (30 mL) and MeOH (30 mL) Stir under temperature for 3 hours. Concentrated in vacuo, diluted with water and adjusted to pH 7 with 2N hydrochloric acid. The resulting mixture was concentrated, filtered to give a crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs [1,5]naphthyridine-1-)acridin-1-)-2-hydroxypropyl-1-one (918 mg, yield 85.4%). MS (m/z): 361 (M+H) + . This crude product was used in the next reaction without further purification.
將5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-)-3-(三氟甲基)吡啶-2-胺(120毫克，0.42毫莫耳)、Pd(dppf)Cl2(20毫克，0.02毫莫耳)和Na2CO3(100毫克，0.84毫莫耳)加入(S)-1-(4-(8-氯-1H-[1,2,3]***並[4,5-c][1,5]萘啶-1-)呱啶-1-)-2-羥丙基-1-酮(150毫克，0.42毫莫耳)的二氧六環(20毫升)與水(2毫升)的混合溶液中，通入氮氣，在100℃下攪拌反應過夜。經矽膠管柱層析純化(洗脫劑MeOH/H2O)，得黃色固體，為化合物1(59.1毫克)。1H NMR(400 MHz,DMSO-d6)δ 9.60(s,1H),9.20(s,1H),8.67(s,1H),8.64(d,J=8.8 Hz,1H),8.54(d,J=8.8Hz,1H),7.09(s,2H),6.23-6.02(m,1H),5.17-5.01(m,1H),4.75-4.50(m,2H),4.46-4.27(m,1H),3.00-2.79(m,1H),2.39-1.90(m,3H),1.36-1.16(m,6H)。MS(m/z)：487(M+H)+。 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-)-3-(trifluoromethyl)pyridin-2-amine (120 mg, 0.42) Millol), Pd(dppf)Cl 2 (20 mg, 0.02 mmol) and Na 2 CO 3 (100 mg, 0.84 mmol) were added to (S)-1-(4-(8-chloro-1H) -[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-)acridin-1-)-2-hydroxypropyl-1-one (150 mg, 0.42 A mixture of dioxane (20 ml) and water (2 ml) was passed through a nitrogen atmosphere, and the mixture was stirred at 100 ° C overnight. Purified by silica gel column chromatography (eluent MeOH / H 2 O), thus obtaining a yellow solid, Compound 1 (59.1 mg). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.60 (s, 1H), 9.20 (s, 1H), 8.67 (s, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 7.09 (s, 2H), 6.23 - 6.02 (m, 1H), 5.17 - 5.01 (m, 1H), 4.75 - 4.50 (m, 2H), 4.46 - 4.27 (m, 1H) , 3.00-2.79 (m, 1H), 2.39-1.90 (m, 3H), 1.36-1.16 (m, 6H). MS (m/z): 487 (M+H) + .
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體和硼酸或酯，採用化合物1的程序，合成以下化合物2至20。 The following compounds 2 to 20 were synthesized using the corresponding intermediate and boric acid or ester under the appropriate conditions recognized by those skilled in the art using the procedure of Compound 1.
將(R)-2-羥基丙酸(540毫克，1.85毫莫耳)、HATU(850毫克，2.21毫莫耳)DIEA(0.8毫升，3.70毫莫耳)加入8-氯-1-(呱啶-4-)-1H-[1,2,3]***並[4,5-c][1,5]萘啶鹽酸鹽(600毫克，1.85毫 莫耳)的DMF(15毫升)溶液中，混合物室溫攪拌，反應過夜。經HPLC-MS檢測，反應不完全，補加3倍量HATU和2倍量DIEA。繼續反應30分鐘，加水稀釋。乙酸乙酯萃取兩次，有機相合併，無水硫酸鈉乾燥，濃縮得到粗產物。粗產物經矽膠柱層析(洗脫劑EtOAc：PE)純化得到黃色固體(R)-1-(4-(8-氯-1H-[1,2,3]***並[4,5-c][1,5]萘啶-1-)呱啶-1-)-2-羥丙基-1-酮(136毫克，產率20.4%)。MS(m/z)：361(M+H)+。 Add (R)-2-hydroxypropionic acid (540 mg, 1.85 mmol), HATU (850 mg, 2.21 mmol) DIEA (0.8 mL, 3.70 mmol) to 8-chloro-1-(acridine) -4-)-1H-[1,2,3]Triazolo[4,5-c][1,5]naphthyridine hydrochloride (600 mg, 1.85 mmol) in DMF (15 mL) The mixture was stirred at room temperature and allowed to react overnight. The reaction was incomplete by HPLC-MS, and 3 times the amount of HATU and 2 times the amount of DIEA were added. Continue the reaction for 30 minutes and dilute with water. The organic layer was combined and dried over anhydrous sodium sulfate. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc) c] [1,5]naphthyridine-1-)acridin-1-)-2-hydroxypropyl-1-one (136 mg, yield 20.4%). MS (m/z): 361 (M+H) + .
餘下合成化合物21的方法與合成化合物1相似。 The remaining method of synthesizing the compound 21 is similar to the synthesis of the compound 1.
化合物21：為一固體，31.0毫克。1H NMR(400 MHz,dmso)δ 9.59(s,1H),9.19(s,1H),8.66(s,1H),8.63(d,J=8.9 Hz,1H),8.53(d,J=8.9 Hz,1H),7.07(s,2H),6.09(m,1H),5.02(m,1H),4.74-4.27(m,2H),2.87(m,1H),2.44-1.90(m,3H),1.27-1.21(m,4H)。MS(m/z)：487(M+H)+。 Compound 21: a solid, 31.0 mg. 1 H NMR (400 MHz, dmso) δ 9.59 (s, 1H), 9.19 (s, 1H), 8.66 (s, 1H), 8.63 (d, J = 8.9 Hz, 1H), 8.53 (d, J = 8.9) Hz,1H),7.07(s,2H),6.09(m,1H),5.02(m,1H),4.74-4.27(m,2H),2.87(m,1H),2.44-1.90(m,3H) , 1.27.21.21 (m, 4H). MS (m/z): 487 (M+H) + .
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體和硼酸或酯，採用化合物21的程序，合成以下化合物22至29。 The following compounds 22 to 29 were synthesized using the corresponding intermediate and boronic acid or ester under the appropriate conditions recognized by those skilled in the art using the procedure of Compound 21.
將8-氯-1-(呱啶-4-)-1H-[1,2,3]***並[4,5-c][1,5]萘啶(200毫克，0.69毫莫耳)、異丁酸(67毫克，0.76毫莫耳)、HATU(315毫克，0.83毫莫耳)、DIEA(133毫克，1.04毫莫耳)的DMF(5毫升)混合液室溫攪拌，過夜。加入10毫升水，收集沉 澱，真空乾燥得固體，為1-(4-(8-氯-1H-[1,2,3]***並[4,5-c][1,5]萘啶-1-)呱啶-1-)-2-甲基丙基-1-酮(200毫克)。 8-Chloro-1-(acridin-4-)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine (200 mg, 0.69 mmol) A mixture of isobutyric acid (67 mg, 0.76 mmol), HATU (315 mg, 0.83 mmol), DIEA (133 mg, 1.04 mmol) in DMF (5 mL). Add 10 ml of water and collect the sink Precipitate and dry in vacuo to give 1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-) acridine 1-)-2-methylpropyl-1-one (200 mg).
將1-(4-(8-氯-1H-[1,2,3]***並[4,5-c][1,5]萘啶-1-)呱啶-1-)-2-甲基丙基-1-酮(60毫克，0.17毫莫耳)、5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-)-3-(三氟甲基)吡啶-2-(53毫克，0.18毫莫耳)，、碳酸鉀(70毫克，0.51毫莫耳)、Pd(dppf)Cl2(6毫克)、dioxane/H2O(3：1，4毫升)混合，混合液在160℃下，於微波反應器中，反應0.5小時。除去溶劑，剩餘物經快速層析ISCO(洗脫劑：MeOH/H2O=20%至80%)純化，得到白色固體，1-(4-(8-(6-胺基-5-(三氟甲基)吡啶-3-)-1H-[1,2,3]***並[4,5-c][1,5]萘啶-1-)呱啶-1-)-2-甲基丙基-1-酮(46毫克)。1H NMR(400 MHz,dmso)δ 9.61(s,1H),9.21(d,J=2.1 Hz,1H),8.66(dd,J=12.5,5.5 Hz,2H),8.55(d,J=8.9 Hz,1H),7.10(s,2H),6.17-6.01(m,1H),4.78-4.59(m,1H),4.35-4.26(m,1H),3.40-3.37(m,2H),3.05-2.97(m,1H),2.93-2.82(m,1H),2.64-2.52(m,1H),2.39-2.21(m,1H),2.16-1.96(m,1H),1.07(s,6H).MS(m/z)：485(M+H)+。 1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-)pyridin-1-)-2- Methylpropyl-1-one (60 mg, 0.17 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)-3 -(trifluoromethyl)pyridine-2-(53 mg, 0.18 mmol), potassium carbonate (70 mg, 0.51 mmol), Pd(dppf)Cl 2 (6 mg), dioxane/H 2 O (3:1, 4 ml) was mixed, and the mixture was reacted at 160 ° C for 0.5 hour in a microwave reactor. The solvent was removed, the residue was purified by flash chromatography on ISCO (eluent: MeOH / H 2 O = 20 % to 80%) to give a white solid, 1- (4- (8- (6-amino-5- ( Trifluoromethyl)pyridine-3-)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-)pyridin-1-)-2- Methyl propyl-1-one (46 mg). 1 H NMR (400 MHz, dmso) δ 9.61 (s, 1H), 9.21. (d, J = 2.1 Hz, 1H), 8.66 (dd, J = 12.5, 5.5 Hz, 2H), 8.55 (d, J = 8.9 Hz, 1H), 7.10 (s, 2H), 6.17-6.01 (m, 1H), 4.78-4.59 (m, 1H), 4.35-4.26 (m, 1H), 3.40-3.37 (m, 2H), 3.05- 2.97 (m, 1H), 2.93-2.82 (m, 1H), 2.64-2.52 (m, 1H), 2.39-2.21 (m, 1H), 2.16.16.96 (m, 1H), 1.07 (s, 6H). MS (m/z): 485 (M+H) + .
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體和硼酸或酯，採用化合物30的程序，合成以下化合物31至42。 The following compounds 31 to 42 were synthesized using the corresponding intermediate and boric acid or ester under the appropriate conditions recognized by those skilled in the art using the procedure of Compound 30.
將8-氯-1-(呱啶-4-)-1H-[1,2,3]***並[4,5-c][1,5]萘啶(100毫克，0.35毫莫耳)、2-氯-N,N-二甲基乙醯胺(46毫克，0.38毫莫耳)、碳酸鉀(97毫克，1.04毫莫耳)的DMF(5毫升)混合液室溫攪拌，反應過夜。除去溶劑，乙酸乙酯(3x10毫升)萃取，合併乙酸乙酯相，硫酸鈉乾燥濃縮得到粗2-(4-(8-氯-1H-[1,2,3]***並 [4,5-c][1,5]萘啶-1-)呱啶-1-)-N,N-二甲基乙醯胺，該產物不需進一步純化直接用於下述反應。 8-Chloro-1-(acridin-4-)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine (100 mg, 0.35 mmol) , a mixture of 2-chloro-N,N-dimethylacetamide (46 mg, 0.38 mmol), potassium carbonate (97 mg, 1.04 mmol) in DMF (5 mL) . The solvent was removed, and ethyl acetate (3×10 mL) was evaporated. [4,5-c][1,5]naphthyridin-1-)acridin-1-)-N,N-dimethylacetamide, the product was used in the next reaction without further purification.
將上述產物、5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-)-3-(三氟甲基)吡啶-2-胺(109毫克，0.38毫莫耳)、碳酸鉀(145毫克，1.05毫莫耳)、Pd(dppf)Cl2(10毫克)、二氧六環/H2O(3：1，4毫升)混合，在微波反應器中，於160℃反應0.5小時。除去溶劑，經層析純化，得灰黃色固體，為化合物43(50毫克)。1H NMR(400 MHz,dmso-d6)δ 9.60(s,1H),9.20(d,J=2.0 Hz,1H),8.66(dd,J=16.5,5.4 Hz,2H),8.54(d,J=8.9 Hz,1H),7.12(s,2H),5.97-5.77(m,1H),3.40(s,2H),3.29-3.14(m,4H),3.10(s,3H),2.86(s,3H),2.44-2.35(m,4H)。MS(m/z)：500(M+H)+。 The above product, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)-3-(trifluoromethyl)pyridin-2-amine (109 Mg, 0.38 mmol, potassium carbonate (145 mg, 1.05 mmol), Pd(dppf)Cl 2 (10 mg), dioxane/H 2 O (3:1, 4 mL), The reaction was carried out at 160 ° C for 0.5 hours in a microwave reactor. The solvent was removed and purified by EtOAcqqqqqq 1 H NMR (400 MHz, dmso-d 6 ) δ 9.60 (s, 1H), 9.20 (d, J = 2.0 Hz, 1H), 8.66 (dd, J = 16.5, 5.4 Hz, 2H), 8.54 (d, J = 8.9 Hz, 1H), 7.12 (s, 2H), 5.97-5.77 (m, 1H), 3.40 (s, 2H), 3.29-3.14 (m, 4H), 3.10 (s, 3H), 2.86 (s , 3H), 2.44 - 2.35 (m, 4H). MS (m/z): 500 (M+H) + .
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體 和硼酸或酯，採用化合物43的程序，合成以下化合物44至47。 The appropriate intermediates are used under appropriate conditions as recognized by those skilled in the art The following compounds 44 to 47 were synthesized using the procedure of Compound 43 with a boronic acid or ester.
在氮氣下，將8-氯-1-(呱啶-4-)-1H-[1,2,3]***並[4,5-c][1,5]萘啶(130毫克，0.450毫莫耳)、4-(溴甲基)四氫-2H-吡喃(97毫克，0.540毫莫耳)、碳酸鉀(124毫克，0.900毫莫耳)、乙腈(15毫升)混合，混合液加熱，回流4小時。冷卻至室溫，混合物加EtOAc 20毫升稀釋。布氏漏斗抽濾，收集有機相，濃縮，得到粗產物(35毫克)，MS(m/z)：387(M+H)+。不須進一步純化直接用於下述反應。 8-Chloro-1-(acridin-4-)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine (130 mg, 0.450 under nitrogen) Mixture of 4-(bromomethyl)tetrahydro-2H-pyran (97 mg, 0.540 mmol), potassium carbonate (124 mg, 0.900 mmol), acetonitrile (15 ml), mixture Heat and reflux for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL). Buchner funnel under suction, the organic phase was collected and concentrated to give the crude product (35 mg), MS (m / z) : 387 (M + H) +. It was used in the following reaction without further purification.
在氮氣下，將8-氯-1-(1-((四氫-2H-吡喃-4-)甲基)呱啶-4-)-H-[1,2,3]***並[4,5-c][1,5]萘啶(35毫克，0.090毫莫耳)、5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-)-3-(三氟甲基)呱啶-2-胺(26.1 毫克，0.090毫莫耳)、碳酸鈉(19.18毫克，0.181毫莫耳)、PdCl2(dppf).CH2Cl2(3.69毫克，4.52微莫耳)、二氧六環(20毫升)和H2O(2毫升)的混合液攪拌10分鐘，然後加熱升溫至120℃反應2小時。混合物濃縮後經快速柱層析ISCO純化，使用12公克矽膠(PE/EtOAc)得到灰黃色固體(10毫克)。1H NMR(400 MHz,dmso)δ 9.53(s,1H),9.15(d,J=2.1,1H),8.65(s,1H),8.61(d,J=8.9,1H),8.51(d,J=8.9,1H),7.07(s,2H),5.99-5.80(m,1H),3.91-3.85(m,4H),3.22-3.08(m,4H),2.41-2.15(m,10H),1.73-1.58(m,2H)。MS(m/z)：513(M+H)+。 8-Chloro-1-(1-((tetrahydro-2H-pyran-4-)methyl)acridin-4-)-H-[1,2,3]triazolo[ under nitrogen] 4,5-c][1,5]naphthyridine (35 mg, 0.090 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-)-3-(Trifluoromethyl)acridin-2-amine (26.1 mg, 0.090 mmol), sodium carbonate (19.18 mg, 0.181 mmol), PdCl 2 (dppf).CH 2 Cl 2 A mixture of (3.69 mg, 4.52 micromolar), dioxane (20 ml) and H 2 O (2 ml) was stirred for 10 minutes and then heated to 120 ° C for 2 hours. The mixture was concentrated and purified with EtOAc EtOAc (EtOAc) 1 H NMR (400 MHz, dmso) δ 9.53 (s, 1H), 9.15 (d, J = 2.1, 1H), 8.65 (s, 1H), 8.61 (d, J = 8.9, 1H), 8.51 (d, J=8.9,1H),7.07(s,2H),5.99-5.80(m,1H),3.91-3.85(m,4H),3.22-3.08(m,4H),2.41-2.15(m,10H), 1.73-1.58 (m, 2H). MS (m/z): 513 (M+H) + .
將HATU(2.4公克，0.063莫耳)和DIEA(1.2公克，0.095莫耳)加入7-溴-2-肼基喹喔啉(1.5公克，0.063莫耳)，4-(2-氰基丙基-2-)苯甲酸(1.1公克，0.063莫耳)的DMF(5毫升)溶液中混 合，室溫攪拌，反應過夜。加5毫升水稀釋，過濾，收集黃色固體，為N'-(7-溴喹喔啉-2-)-4-(2-氰基丙基-2-)苯醯肼(2.2公克，產率85.0%)。MS(m/z)：412(M+H)+。 Add HATU (2.4 g, 0.063 mol) and DIEA (1.2 g, 0.095 mol) to 7-bromo-2-indolyl quinoxaline (1.5 g, 0.063 mol), 4-(2-cyanopropyl) 2-) A solution of benzoic acid (1.1 g, 0.063 mol) in DMF (5 ml) was stirred and stirred at room temperature overnight. Dilute with 5 ml of water, filter, and collect a yellow solid as N'-(7-bromoquinoxaline-2-)-4-(2-cyanopropyl-2-)phenylhydrazine (2.2 g, yield 85.0%). MS (m/z): 412 (M + H) + .
在攪拌下，將N'-(7-溴喹喔啉-2-)-4-(2-氰基丙基-2-)苯醯肼(2.2公克，0.054莫耳)的3毫升AcOH溶液於100℃反應過夜。冷卻至室溫，加水(5毫升)稀釋，過濾，飽和碳酸氫鈉(5毫升)洗滌，得到黃色固體，為2-(4-(8-溴-[1,2,4]***並[4,3-a]喹喔啉-1-)苯基)-2-甲基丙腈(1.8公克，產率85.0%)。MS(m/z)：392(M+H)+。 N'-(7-bromoquinoxalin-2-)-4-(2-cyanopropyl-2-)phenylhydrazine (2.2 g, 0.054 mol) in 3 ml of AcOH was stirred with stirring. The reaction was carried out at 100 ° C overnight. It was cooled to room temperature, diluted with water (5 ml), filtered and evaporated with NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 4,3-a]quinoxaline-1-)phenyl)-2-methylpropanenitrile (1.8 g, yield 85.0%). MS (m/z): 392 (M+H) + .
將2-(4-(8-溴-[1,2,4]***並[4,3-a]喹喔啉-1-)苯基)-2-甲基丙腈睛(80毫克，0.21毫莫耳)、5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-)-3-(三氟甲基)吡啶-2-(59毫克，0.21毫莫耳)、K2CO3(87毫克，0.63毫莫耳)、二氧六環(3毫升)的H2O(1毫升)的混合，加入Pd(dppf)Cl2(3毫克)。混合物在150℃，於微波反應器中反應30分鐘。冷卻至室溫，濃縮，層析純化得黃色固體，為化合物49(52毫克)。1H NMR(400 MHz,dmso)δ 9.38(s,1H),8.26(s,1H),8.11(d,J=8.5,1H),7.99-7.95(m,1H),7.92(d,J=8.3,2H),7.83(d,J=8.4,2H),7.63(m,1H),7.52(d,J=1.5,1H),6.77(s,2H),1.77(s,6H)。MS(m/z)：474(M+H)+。 2-(4-(8-Bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1-)phenyl)-2-methylpropionitrile (80 mg, 0.21 mmol, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)-3-(trifluoromethyl)pyridine-2-( Mixing 59 mg (0.21 mmol), K 2 CO 3 (87 mg, 0.63 mmol), dioxane (3 mL) in H 2 O (1 mL), and adding Pd(dppf)Cl 2 ( 3 mg). The mixture was reacted in a microwave reactor at 150 ° C for 30 minutes. It was cooled to room temperature, concentrated and purified to purified crystall 1 H NMR (400 MHz, dmso) δ 9.38 (s, 1H), 8.26 (s, 1H), 8.11 (d, J = 8.5, 1H), 7.99-7.95 (m, 1H), 7.92 (d, J = 8.3, 2H), 7.83 (d, J = 8.4, 2H), 7.63 (m, 1H), 7.52 (d, J = 1.5, 1H), 6.77 (s, 2H), 1.77 (s, 6H). MS (m/z): 474 (M+H) + .
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體和硼酸或酯，採用化合物49的程序，合成以下化合物50至78。 The following compounds 50 to 78 were synthesized using the corresponding intermediate and boric acid or ester under the appropriate conditions recognized by those skilled in the art using the procedure of compound 49.
將呱啶-1,4-二羧酸1-三級丁基酯4-甲基酯(4.84公克，20毫莫耳)、LiOH(2.52公克，60毫莫耳)的THF(90毫升)/MeOH(90毫升)/H2O(30毫升)的混合，室溫攪拌，反應過夜。除去溶劑，用2N鹽酸調節pH至2，然後用EtOAc(3 x 20毫升)萃取，有機相合併，硫酸鈉乾燥，濃縮得到1-(三級丁氧基羰基)呱啶-4-羧酸(4.6公克，產率100.0%)。 Acridine-1,4-dicarboxylic acid 1-tert-butyl 4-methyl ester (4.84 g, 20 mmol), LiOH (2.52 g, 60 mmol) in THF (90 mL) / MeOH (90 mL) / H 2 O (30 mL) were mixed at room temperature with stirring overnight. The solvent was removed, the pH was taken to EtOAc (EtOAc) (EtOAcjjjjjjjjjjj 4.6 grams, yield 100.0%).
將7-溴-2-肼基喹喔啉(3公克，12.55毫莫耳)、1-(三級丁氧基羰基)呱啶-4-羧酸(3.16公克，13.81毫莫耳)、EDCI(2.89公克，15.06毫莫耳)、HOBt(2.03公克，15.06毫莫耳)TEA(1.9公克，18.83毫莫耳)的DMF(100毫升)混合液攪拌，室溫反應過夜。加水(10毫升)稀釋，EtOAc(3 x 100毫升)萃取。合併有機相，硫酸鈉乾燥，真空濃縮，得到灰黃色固體，為4-(2-(7-溴喹喔啉-2-)肼羰基)呱啶-1-羧酸三級丁基酯(3.5公克，產率62%)。 7-Bromo-2-indolyl quinoxaline (3 g, 12.55 mmol), 1-(tertiary butoxycarbonyl) acridine-4-carboxylic acid (3.16 g, 13.81 mmol), EDCI (2.89 g, 15.06 mmol), HOBt (2.03 g, 15.06 mmol) TEA (1.9 g, 18.83 mmol) in DMF (100 mL) was stirred and allowed to react overnight at room temperature. Diluted with water (10 mL) and EtOAc (3 x 100 mL). The combined organics were dried with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Gram, yield 62%).
將4-(2-(7-溴喹喔啉-2-)肼羰基)呱啶-1-羧酸三級丁基酯(900毫克，2.0毫莫耳)和AcOH(10毫升)混合，回流反應過夜。除去溶劑，經快速層析ISCO純化(MeOH/H2O=20%至90%)得灰黃色固體，為8-溴-1-(呱啶-4-)-[1,2,4]***並[4,3-a]喹喔啉(550毫克，收率83.0%)。MS(m/z)：332(M+H)+。 Mixing 4-(2-(7-bromoquinoxalin-2-)indolecarbonyl)acridine-1-carboxylic acid tert-butyl ester (900 mg, 2.0 mmol) with AcOH (10 mL), reflux The reaction was overnight. The solvent was removed and purified by flash chromatography ISCO (MeOH/H 2 O = 20% to 90%) to give a pale yellow solid as 8-bromo-1-(azidine-4-)-[1,2,4] Zoxao[4,3-a]quinoxaline (550 mg, yield 83.0%). MS (m/z): 332 (M+H) + .
將8-溴-1-(呱啶-4-)-[1,2,4]***並[4,3-a]喹喔啉(250毫克，0.75毫莫耳)、(S)-2-羥基丙酸(75毫克，0.83毫莫耳)、HATU(346毫克，0.90毫莫耳)、DIEA(116毫克，0.90毫莫耳)和DMF(5毫升)的混合液，室溫攪拌，反應6小時。除去溶劑，剩餘物經快速層析ISCO純化(洗脫劑MeOH/H2O=20%-90%)得到灰黃色固體，為(S)-1-(4-(8-溴-[1,2,4]***[4,3a]喹喔啉-1-)呱啶-1-)-2-羥丙基-1-酮(200毫克，產率66.0%)。MS(m/z)：404(M+H)+。 8-Bromo-1-(acridin-4-)-[1,2,4]triazolo[4,3-a]quinoxaline (250 mg, 0.75 mmol), (S)-2 a mixture of hydroxypropionic acid (75 mg, 0.83 mmol), HATU (346 mg, 0.90 mmol), DIEA (116 mg, 0.90 mmol) and DMF (5 mL). 6 hours. The solvent was removed, the residue was purified by flash chromatography on ISCO (eluent MeOH / H 2 O = 20% -90%) was obtained as a pale yellow solid as (S) -1- (4- (8- bromo - [1, 2,4] Triazolo[4,3a]quinoxaline-1-)acridin-1-)-2-hydroxypropyl-1-one (200 mg, yield 66.0%). MS (m/z): 404 (M+H) + .
將(S)-1-(4-(8-溴-[1,2,4]***[4,3a]喹喔啉-1-)呱啶-1-)-2-羥丙基-1-酮(65毫克，0.16毫莫耳)、5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-)-3-(三氟甲基)吡啶-2-胺(51毫克，0.18毫莫耳)、K2CO3(67毫克，0.48毫莫耳)、Pd(dppf)Cl2(5毫克)的二氧六環/H2O(3：1，4毫升)混合液在微波反應器中，於150℃下反應0.5小時。除去溶劑，剩餘物經快速層析ISCO(MeOH/H2O=20%-80%)純化得到黃色固體，為化合物79(30毫克)。1H NMR(400 MHz,dmso)δ 9.28(s,1H),8.72(d,J=2.0 Hz,1H),8.32(s,1H),8.16-8.12(m,2H),8.05(dd,J=8.5,1.5 Hz,1H),6.82(s,2H),4.91(dd,J=7.2,6.5 Hz,1H),4.47(dd,J=17.8,11.8 Hz,2H),4.29(t,J=10.6 Hz,1H),4.15(t,J=11.2 Hz,1H),3.09-2.97(m,1H),2.27(dd,J= 15.6,14.5 Hz,2H),1.97(dd,J=12.0,4.5 Hz,1H),1.78(dd,J=7.1,5.0 Hz,1H),1.25-1.15(m,3H)。MS(m/z)：486(M+H)+。 (S)-1-(4-(8-Bromo-[1,2,4]triazolo[4,3a]quinoxalin-1-)pyridin-1-)-2-hydroxypropyl-1 -ketone (65 mg, 0.16 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)-3-(trifluoromethyl) Pyridin-2-amine (51 mg, 0.18 mmol), K 2 CO 3 (67 mg, 0.48 mmol), Pd(dppf)Cl 2 (5 mg) of dioxane/H 2 O ( The 3:1, 4 ml) mixture was reacted in a microwave reactor at 150 ° C for 0.5 hours. The solvent was removed, the residue was purified by flash chromatography on ISCO (MeOH / H 2 O = 20% -80%) to give a yellow solid, Compound 79 (30 mg). 1 H NMR (400 MHz, dmso) δ 9.28 (s, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.32 (s, 1H), 8.16-8.12 (m, 2H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H), 6.82 (s, 2H), 4.91 (dd, J = 7.2, 6.5 Hz, 1H), 4.47 (dd, J = 17.8, 11.8 Hz, 2H), 4.29 (t, J = 10.6 Hz, 1H), 4.15 (t, J = 11.2 Hz, 1H), 3.09-2.97 (m, 1H), 2.27 (dd, J = 15.6, 14.5 Hz, 2H), 1.97 (dd, J = 12.0, 4.5) Hz, 1H), 1.78 (dd, J = 7.1, 5.0 Hz, 1H), 1.25-1.15 (m, 3H). MS (m/z): 486 (M+H) + .
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體和硼酸或酯，採用化合物79的程序，合成以下化合物80至87。 The following compounds 80 to 87 were synthesized using the corresponding intermediate and boronic acid or ester under the appropriate conditions recognized by those skilled in the art using the procedure of Compound 79.
將2,8-二氯-7-硝基-1,5-萘啶(3.55公克，14.55毫莫耳)及碳酸鉀(6.02公克，43.65毫莫耳)的DMF(8毫升)混合液室溫攪拌，反應過夜，倒入20毫升的冰水混合液中，收集沉澱，水洗三次，真空乾燥得到黃色固體，為4-(6-氯-3-硝基-1,5-萘啶-4-氨基)呱啶-1-羧酸三級丁基酯(5.22公克，產率88%)，不需進一步純化直接用於下步反應。MS(m/z)：409(M+H)+。 a mixture of 2,8-dichloro-7-nitro-1,5-naphthyridine (3.55 g, 14.55 mmol) and potassium carbonate (6.02 g, 43.65 mmol) in DMF (8 mL) at room temperature Stir, react overnight, pour into 20 ml of ice water mixture, collect the precipitate, wash three times with water, and dry in vacuo to give 4-(6-chloro-3-nitro-1,5-naphthyridin-4- Amino) acridine-1-carboxylic acid tert-butyl ester (5.22 g, yield 88%) was used in the next step without further purification. MS (m/z): 409 (M+H) + .
將4-(6-氯-3-硝基-1,5-萘啶-4-氨基)呱啶-1-羧酸三級丁基酯(600毫克，1.47毫莫耳)及SnCl2.H2O(996毫克，4.41毫莫耳)混合於乙酸乙酯(20毫升)，室溫攪拌2小時，然後用5% NaOH鹼化。混合物經矽藻土過濾，濾液用乙酸乙酯(3 x 15毫升)萃取，有機相合併，鹽水(10毫升)洗，無水硫酸鈉乾燥，得到黃色固體，為4-(3-胺基-6-氯-1,5-萘啶-4-氨基)呱啶-1-羧酸三級丁基酯(499毫克，產率90%)，不需進一步純化可直接用於下步反應，MS(m/z)：378(M+H)+。 4-(6-Chloro-3-nitro-1,5-naphthyridin-4-amino)acridine-1-carboxylic acid tert-butyl ester (600 mg, 1.47 mmol) and SnCl 2 .H 2 O (996 mg, 4.41 mmol) was combined in ethyl acetate (20 ml), stirred at room temperature for 2 hr and then basified with 5% NaOH. The mixture was filtered over EtOAc (EtOAc) (EtOAc (EtOAc) -Chloro-1,5-naphthyridin-4-amino)acridine-1-carboxylic acid tert-butyl ester (499 mg, yield 90%), used directly in the next step without further purification, MS ( m/z): 378 (M+H) + .
將4-(3-胺基-6-氯-1,5-萘啶-4-胺基)呱啶-1-羧酸三級丁基酯(200毫克，0.53毫莫耳)、原甲酸三乙酯(94毫克，0,64毫莫耳)、吡 啶鹽酸鹽(6毫克，0.053毫莫耳)的甲苯(5毫升)混合液回流3.5小時。真空除去溶劑，加入鹽酸甲醇溶液(6 N，3毫升)，繼續在室溫下攪拌3小時，真空濃縮。剩餘物溶於20毫升二氯甲烷，然後依次用飽和碳酸氫鈉溶液(10毫升)，鹽水(10毫升)洗滌，無水硫酸鈉乾燥，過濾，濃縮得到黃色固體，為8-氯-1-(呱啶-4-)-1H-咪唑[4,5-c][1,5]萘啶(110毫克，產率72%)，不需進一步純化可直接用於下步反應。 4-(3-Amino-6-chloro-1,5-naphthyridin-4-amino)acridine-1-carboxylic acid tert-butyl ester (200 mg, 0.53 mmol), orthoformic acid A mixture of ethyl ester (94 mg, 0, 64 mmol), pyridine hydrochloride (6 mg, 0.053 mmol) in toluene (5 ml) was refluxed for 3.5 hours. The solvent was removed in vacuo. The residue was dissolved in EtOAc (EtOAc (EtOAcMeOHMeOHMeOHMeOH Acridine-4-)-1 H -imidazole [4,5- c ][1,5]naphthyridine (110 mg, yield 72%) was used in the next step without further purification.
在冰浴下，將環丙基甲醯氯(38微升，0.420毫莫耳)加入8-氯-1-(呱啶-4-)-1H-咪唑[4,5-c][1,5]萘啶(110毫克，0.382毫莫耳)、Et3N(106微升，0.764毫莫耳)的THF(15毫升)溶液中，然後在室溫下攪拌，反應3小時，真空濃縮。加20毫升乙酸乙酯溶解，依次用飽和碳酸氫鈉溶液(10毫升)，鹽水(10毫升)洗滌，無水硫酸鈉乾燥，過濾，濃縮得到黃色固體，為(4-(8-氯-1H-咪唑[4,5-c][1,5]萘啶-1-)呱啶-1-)(環丙基)甲基酮(100毫克，產率73%)。不需進一步純化可直接用於下步反應。MS(m/z)：356(M+H)+。 Cyclopropylformamidine chloride (38 μl, 0.420 mmol) was added to 8-chloro-1-(acridin-4-)-1 H -imidazole [4,5- c ][1] , 5] naphthyridine (110 mg, 0.382 mmol), Et 3 N (106 μL, 0.764 mmol) in THF (15 ml), then stirred at room temperature for 3 hours, concentrated in vacuo . Dissolved with 20 ml of ethyl acetate, washed with saturated sodium bicarbonate solution (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid as (4- (8-chloro -1 H -Imidazole [4,5- c ][1,5]naphthyridin-1-)acridin-1-)(cyclopropyl)methyl ketone (100 mg, yield 73%). It can be used directly in the next step without further purification. MS (m/z): 356 (M+H) + .
將(4-(8-氯-1H-咪唑[4,5-c][1,5]萘啶-1-)呱啶-1-)(環丙基)甲基酮(100毫克，0.281毫莫耳)、PdCl2(dppf)2(12毫克，0.014毫莫耳)、5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-)-3-(三氟甲基)吡啶-2-胺(97毫克，0.337毫莫耳)、2 N K2CO3溶液(1毫升)的二氧六環(4毫升)混合溶液，在微波反應器中，於150℃反應30分鐘。除去溶劑，剩餘物經快速層析ISCO(MeOH/H2O：0%至100%)純化得黃色固體，為化合物88(70毫克)。1H NMR(400 MHz,dmso)δ 9.20(s,1H),9.13(d,J=1.9,1H),8.71(s,1H),8.59(d,J=2.0,1H),8.49(d,J=8.9,1H),8.32(d,J=8.9,1H),6.99(s,2H),5.98- 5.92(m,1H),4.66(s,1H),4.58(s,1H),3.25(s,2H),2.35(s,2H),2.09-2.01(m,2H),2.01-1.90(m,1H),0.80-0.71(m,4H)。MS(m/z)：482(M+H)+。 (4-(8-Chloro-1 H -imidazo[4,5- c ][1,5]naphthyridin-1-)acridin-1-)(cyclopropyl)methyl ketone (100 mg, 0.281 Millol), PdCl 2 (dppf) 2 (12 mg, 0.014 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- a mixed solution of -3-(trifluoromethyl)pyridin-2-amine (97 mg, 0.337 mmol), 2 NK 2 CO 3 solution (1 ml) in dioxane (4 ml), in a microwave reaction In the apparatus, the reaction was carried out at 150 ° C for 30 minutes. The solvent was removed, the residue was purified by flash chromatography on ISCO (MeOH / H 2 O: 0% to 100%) is purified to give a yellow solid, Compound 88 (70 mg). 1 H NMR (400 MHz, dmso) δ 9.20 (s, 1H), 9.13 (d, J = 1.9, 1H), 8.71 (s, 1H), 8.59 (d, J = 2.0, 1H), 8.49 (d, J = 8.9, 1H), 8.32 (d, J = 8.9, 1H), 6.99 (s, 2H), 5.98 - 5.92 (m, 1H), 4.66 (s, 1H), 4.58 (s, 1H), 3.25 ( s, 2H), 2.35 (s, 2H), 2.09-2.01 (m, 2H), 2.01-1.90 (m, 1H), 0.80-0.71 (m, 4H). MS (m/z): 482 (M+H) + .
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體和硼酸或酯，採用與化合物88的程序，合成以下化合物89至118。 The following compounds 89 to 118 were synthesized using the corresponding intermediates and boronic acids or esters under the appropriate conditions recognized by those skilled in the art using the procedure of Compound 88.
將4-(3-胺基-6-氯-1,5-萘啶-4-氨基)呱啶-1-羧酸三級丁酯(200毫克，0.53毫莫耳)與乙酸(3毫升)混合，於100℃攪拌，反應過夜。真空除去溶劑，加入3毫升6 N鹽酸甲醇溶液，室溫繼續攪拌2小時，真空濃縮。剩餘物溶於20毫升二氯甲烷，依次經飽和碳酸氫鈉溶液(10毫升)，鹽水(10毫升)洗滌，無水硫酸鈉乾燥，濃 縮，得到黃色固體，為8-氯-甲基-1-(呱啶-4-)-1H-咪唑[4,5-c][1,5]萘啶(110毫克，收率68%)。不需進一步純化可直接用於下列反應。 4-(3-Amino-6-chloro-1,5-naphthyridin-4-amino)acridine-1-carboxylic acid tert-butyl ester (200 mg, 0.53 mmol) with acetic acid (3 mL) Mix and stir at 100 ° C and react overnight. The solvent was removed in vacuo and aq. The residue was dissolved in EtOAc (EtOAc (EtOAcMeOHMeOHMeOHMeOH (Acridine-4-)-1 H -imidazole [4,5- c ][1,5]naphthyridine (110 mg, yield 68%). It can be directly used in the following reactions without further purification.
在冰浴下，將環丙基甲醯氯(36微升，0.401毫莫耳)加入8-氯-甲基-1-(呱啶-4-)-1H-咪唑[4,5-c][1,5]萘啶(110毫克，0.364毫莫耳)，Et3N(101微升，0.728毫莫耳)的THF(15毫升)溶液，混合液室溫攪拌，反應3小時，然後真空濃縮。濃縮物加入二氯甲烷(10毫升)和水(10毫升)，所得混合液用乙酸乙酯(2 x 10毫升)萃取，合併有機相，濃縮得到黃色固體，為粗(4-(8-氯-2-甲基-1H-咪唑[4,5-c][1,5]萘啶-1-)呱啶-1-)(環丙基)甲基酮(105毫克，產率80%)，不需進一步純化可直接用於下步反應。MS(m/z)：370(M+H)+。 Cyclopropylformamidine chloride (36 μl, 0.401 mmol) was added to 8-chloro-methyl-1-(acridin-4-)-1 H -imidazole [4,5- c ] on ice. [1,5]naphthyridine (110 mg, 0.364 mmol), Et 3 N (101 μL, 0.728 mmol) in THF (15 mL), and the mixture was stirred at room temperature for 3 hours, then Concentrate in vacuo. The concentrate was added to dichloromethane (10 mL) and EtOAc (EtOAc)EtOAc. -2-methyl-1 H -imidazole [4,5- c ][1,5]naphthyridin-1-)acridin-1-)(cyclopropyl)methyl ketone (105 mg, yield 80%) ) can be used directly in the next step without further purification. MS (m/z): 370 (M+H) + .
將上述(4-(8-氯-2-甲基-1H-咪唑[4,5-c][1,5]萘啶-1-)呱啶-1-)(環丙基)甲基酮(105毫克，0.284毫莫耳)、PdCl2(dppf)2(12毫克，0.014mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-)-3-(三氟甲基)吡啶-2-胺(98毫克，0.340毫莫耳)、2 N K2CO3溶液(1毫升)加入二氧六環(4毫升)中混合，混合液在150℃下，於微波反應器中反應30分鐘。除去溶劑，剩餘物經快速層析ISCO(MeOH/H2O 0%至100%)純化，得到黃色固體，為化合物119(57毫克)。1H NMR(400 MHz,dmso)δ 9.11(d,J=6.8,2H),8.58(s,1H),8.48(d,J=8.8,1H),8.29(d,J=8.3,1H),6.97(s,2H),4.67-4.58(m,2H),4.06(s,1H),2.75(m,5H),2.11-2.04(m,4H),0.81(s,1H),0.71(m,4H)。MS(m/z)：496(M+H)+。 The above (4-(8-chloro-2-methyl-1 H -imidazole [4,5- c ][1,5]naphthyridin-1-)acridin-1-)(cyclopropyl)methyl Ketone (105 mg, 0.284 mmol), PdCl 2 (dppf) 2 (12 mg, 0.014 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane Cyclo-2-)-3-(trifluoromethyl)pyridin-2-amine (98 mg, 0.340 mmol), 2 NK 2 CO 3 solution (1 mL) was added to dioxane (4 mL). The mixture was reacted in a microwave reactor at 150 ° C for 30 minutes. The solvent was removed and the residue was purified EtOAcjjjjjjjjj 1 H NMR (400 MHz, dmso) δ 9.11 (d, J = 6.8, 2H), 8.58 (s, 1H), 8.48 (d, J = 8.8, 1H), 8.29 (d, J = 8.3, 1H), 6.97 (s, 2H), 4.67-4.58 (m, 2H), 4.06 (s, 1H), 2.75 (m, 5H), 2.11-2.04 (m, 4H), 0.81 (s, 1H), 0.71 (m, 4H). MS (m/z): 496 (M+H) + .
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體和硼酸或酯，採用化合物119的程序，合成以下化合物120至146。 The following compounds 120 to 146 were synthesized using the corresponding intermediate and boric acid or ester under the appropriate conditions recognized by those skilled in the art using the procedure of Compound 119.
將7-溴-2-肼基喹喔啉(200毫克，0.84毫莫耳)和AcOH(5毫升)混合，混合液回流，反應過夜。冷卻至室溫，加入10毫升水，過濾收集所得沉澱，真空乾燥得灰色固體，為8-溴-1-甲基-[1,2,4]***並[4,3-a]喹喔啉(200毫克，產率91.0%)。 7-Bromo-2-indolylquinoxaline (200 mg, 0.84 mmol) and AcOH (5 mL) were combined, and the mixture was refluxed and allowed to react overnight. After cooling to room temperature, 10 ml of water was added, and the obtained precipitate was collected by filtration and dried in vacuo to give a white solid as 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quine. Porphyrin (200 mg, yield 91.0%).
將8-溴-1-甲基-[1,2,4]***並[4,3-a]喹喔啉(60毫克，0.23毫莫耳)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-)吡啶-3-)苯磺醯胺(107毫克，0.25毫莫耳)、K2CO3(95毫克，0.69毫莫耳)、Pd(dppf)Cl2(6毫克)和二氧六環/水(3：1，4毫升)混合，混合液160℃在微波反應器反應0.5小時。除去溶劑，剩餘物經快速層析ISCO(MeOH/H2O=20%至80%)純化，得到白色固體，為化合物147(60毫克)。1H NMR(400 MHz,dmso)δ 10.44(s,1H),9.26(s,1H),8.47(d,J=1.7 Hz,1H),8.34(d,J=1.5 Hz,1H),8.13(t,J=10.3 Hz,1H),8.02(d,J=2.1 Hz,1H),7.92(dd,J=8.4,1.5 Hz,1H),7.76(dd,J=14.9,8.5 Hz,1H),7.51(dd,J=14.2,5.4 Hz,1H),7.18(t,J=7.5 Hz,1H),3.68(s,3H),3.17(s,3H)。MS(m/z)：483(M+H)+。 8-Bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline (60 mg, 0.23 mmol), 2,4-difluoro-N- ( 2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)pyridine-3-)benzenesulfonamide (107 mg, 0.25 Mix of K 2 CO 3 (95 mg, 0.69 mmol), Pd (dppf) Cl 2 (6 mg) and dioxane/water (3:1, 4 ml), mixture 160 ° C The reaction was carried out in a microwave reactor for 0.5 hours. The solvent was removed, the residue was purified by flash chromatography on ISCO (MeOH / H 2 O = 20% to 80%) to give a white solid, Compound 147 (60 mg). 1 H NMR (400 MHz, dmso) δ 10.44 (s, 1H), 9.26 (s, 1H), 8.47 (d, J = 1.7 Hz, 1H), 8.34 (d, J = 1.5 Hz, 1H), 8.13 ( t, J = 10.3 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.92 (dd, J = 8.4, 1.5 Hz, 1H), 7.76 (dd, J = 14.9, 8.5 Hz, 1H), 7.51 (dd, J = 14.2, 5.4 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 3.68 (s, 3H), 3.17 (s, 3H). MS (m/z): 483 (M+H) + .
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體和硼酸或酯，採用化合物147的程序，合成以下化合物148至178。 The following compounds 148 to 178 were synthesized using the corresponding intermediates and boronic acid or esters under the appropriate conditions recognized by those skilled in the art using the procedure of compound 147.
將7-溴-2-肼基喹喔啉(1公克，4.18毫莫耳)和醋酸(10毫升)混合，回流反應18小時。真空除去一半醋酸，把剩餘物倒入冰水中，過濾，收集沉澱，水洗，真空乾燥，得到深紅色固體，為8-溴-1-甲基-[1,2,4]***並[4,3-a]喹喔啉(1公克，產率90%)，不需進一步純化可直接用於下步反應。MS(m/z)：263(M+H)+。 7-Bromo-2-indolylquinoxaline (1 g, 4.18 mmol) and acetic acid (10 ml) were combined and refluxed for 18 hours. Half of the acetic acid was removed in vacuo, the residue was poured into ice water, filtered, and the precipitate was collected, washed with water and dried in vacuo to give a dark red solid as 8-bromo-1-methyl-[1,2,4]triazolo[4 , 3-a] quinoxaline (1 g, yield 90%) was used in the next step without further purification. MS (m/z): 263 (M+H) + .
將粗8-溴-1-甲基-[1,2,4]***並[4,3-a]喹喔啉(809毫克，3.07毫莫耳)、PdCl2(dppf)2(132.6毫克，0.153毫莫耳)、2-甲氧基-5-(4,4,5,5-四甲基1-1,3,2-二氧硼戊環-2-)吡啶-3-胺(1公克，4.3毫莫耳)，碳酸鉀(1.7公克，12.28毫莫耳)，DMF(40毫升)和水(15毫升)混合，混合液在100℃下，攪拌反應過夜。除去一半溶 劑，冷卻至室溫，混合液倒入冰水中，收集沉澱，水洗三次，真空乾燥得到灰色固體，為2-甲氧基-5-(1-甲基-[1,2,4]***[4,3-a]喹喔啉-8-)吡啶-3-胺(730毫克，產率77%)。無需進一步純化可直接用於下步反應。MS(m/z)：307(M+H)+。 Crude 8-bromo-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline (809 mg, 3.07 mmol), PdCl 2 (dppf) 2 (132.6 mg) , 0.153 mmol, 2-methoxy-5-(4,4,5,5-tetramethyl1-1,3,2-dioxaborolan-2-)pyridin-3-amine ( 1 g, 4.3 mmol, potassium carbonate (1.7 g, 12.28 mmol), DMF (40 ml) and water (15 ml) were mixed, and the mixture was stirred at 100 ° C overnight. Remove half of the solvent, cool to room temperature, pour the mixture into ice water, collect the precipitate, wash three times with water, and dry in vacuo to give a white solid as 2-methoxy-5-(1-methyl-[1,2,4] Triazolo[4,3-a]quinoxaline-8-)pyridin-3-amine (730 mg, yield 77%). It can be used directly in the next step without further purification. MS (m/z): 307 (M+H) + .
將4-甲基苯基-1-磺醯氯(31.3毫克，0.164毫莫耳)加入2-甲氧基-5-(1-甲基-[1,2,4]***[4,3-a]喹喔啉-8-)吡啶-3-胺(50毫克，0.163毫莫耳)和吡啶(2毫升)混合液中，混合液室溫攪拌，反應過夜。然後在50℃反應5小時。除去溶劑，經製備薄層色譜板純化，得到灰色固體，為化合物179(22毫克)。1H NMR(400 MHz,dmso)δ 10.00(s,1H),9.27(s,1H),8.44(d,J=2.3,1H),8.32(d,J=1.8,1H),8.15(d,J=8.4,1H),7.98(d,J=2.3,1H),7.89(dd,J=8.4,1.8,1H),7.68(dd,J=8.4,1.8,2H),7.35(d,J=8.0,2H),3.71(s,3H),3.17(s,3H),2.33(s,3H)。MS(m/z)：461(M+H)+。 4-Methylphenyl-1-sulfonium chloride (31.3 mg, 0.164 mmol) was added to 2-methoxy-5-(1-methyl-[1,2,4]triazole [4,3 -a] A mixture of quinoxaline-8-)pyridin-3-amine (50 mg, 0.163 mmol) and pyridine (2 ml), and the mixture was stirred at room temperature overnight. It was then reacted at 50 ° C for 5 hours. The solvent was removed and purified by preparative EtOAc EtOAc (EtOAc) 1 H NMR (400 MHz, dmso) δ 10.00 (s, 1H), 9.27 (s, 1H), 8.44 (d, J = 2.3, 1H), 8.32 (d, J = 1.8, 1H), 8.15 (d, J = 8.4, 1H), 7.98 (d, J = 2.3, 1H), 7.89 (dd, J = 8.4, 1.8, 1H), 7.68 (dd, J = 8.4, 1.8, 2H), 7.35 (d, J = 8.0, 2H), 3.71 (s, 3H), 3.17 (s, 3H), 2.33 (s, 3H). MS (m/z): 461 (M+H) + .
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體和硼酸或酯，採用化合物179的程序，合成以下化合物180至182。 The following compounds 180 to 182 are synthesized using the corresponding intermediate and boric acid or ester under the appropriate conditions recognized by those skilled in the art using the procedure of Compound 179.
在0℃下，將乙醯氯(15.70毫升，222毫莫耳)的25毫升DCM溶液滴加至1-(2-胺基苯基)乙酮(25公克，185毫升)、Et3N(33.4毫升，240毫莫耳)的DCM白色混懸液中，室溫攪拌，反應2小時。待LC-MS監控顯示反應完成，將反應液冷卻至0℃，加100毫升水淬滅。分出有機相，水相用二氯甲烷萃取，合併有機相，依次水洗，鹽水洗，無水硫酸鎂乾燥，過濾，濃縮，乾燥得到粗N-(2-乙醯苯基)乙醯胺(30公克，收率92%)，無需進一步純化直接用於下步反應。MS(m/z)：136(M+H)+。 A solution of acetamidine chloride (15.70 ml, 222 mmol) in 25 mL of DCM was added dropwise to 1-(2-aminophenyl)ethanone (25 g, 185 mL), Et 3 N 33.4 ml, 240 mmol of DCM in a white suspension was stirred at room temperature for 2 hours. After LC-MS monitoring showed the reaction was complete, the reaction was cooled to 0 ° C and quenched with 100 mL water. The organic phase is separated, the aqueous phase is extracted with dichloromethane, and the organic phase is combined, washed successively, washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated and dried to give crude N-(2-ethylphenylphenyl)acetamide (30) Gram, yield 92%), used in the next step without further purification. MS (m/z): 136 (M+H) + .
在氮氣下，將上述粗N-(2-乙醯苯基)乙醯胺(28公克，158毫莫耳)、AcOH(300毫升)的淡黃色混懸液攪拌5分鐘，然後，室溫下一小時內加入Br2(12.95毫升，253毫莫耳)。繼續攪拌反應75分鐘，待LC-MS監控顯示反應完成，加200毫升水淬滅，布氏漏斗 過濾，收集沉澱，得到N-(2-乙醯-4-溴苯基l)乙醯胺(35公克，產率86%)。MS(m/z)：216(M+H)+。 The above crude N-(2-acetamidophenyl)acetamide (28 g, 158 mmol), AcOH (300 mL) was stirred for 5 min under nitrogen, then at room temperature Br 2 (12.95 ml, 253 mmol) was added over one hour. Stirring reaction was continued for 75 minutes. After completion of LC-MS monitoring, the reaction was completed, quenched with water (200 ml), filtered with a Buchner funnel, and the precipitate was collected to give N-(2- ethane- 4-bromophenyl-l) acetamide ( 35 grams, yield 86%). MS (m/z): 216 (M+H) + .
在氮氣下，將-(2-乙醯-4-溴苯基)乙醯胺(35公克，137毫莫耳)、HCl(100毫升，600毫莫耳)和THF(400毫升)的混合液，加熱回流1小時。真空濃縮除去溶劑，加EtOAc(100毫升)處理。水相進一步濃縮，除去四氫呋喃，然後室溫加入6 N HCl(100毫升，600毫莫耳)。冷卻至0℃，滴加NaNO2(9.43公克，137毫莫耳)的20毫升H2O溶液，混合液繼續室溫攪拌，反應15小時。 然後回流反應6小時，冷卻至室溫，過濾，收集固體，真空乾燥，得到白色固體產物(19.5公克，產率63.4%)，無需進一步純化可直接用於下步反應。MS(m/z)：227(M+H)+。 a mixture of -(2-acetamido-4-bromophenyl)acetamide (35 g, 137 mmol), HCl (100 mL, 600 mmol) and THF (400 mL) under nitrogen. Heated to reflux for 1 hour. The solvent was removed in vacuo <RTI ID=0.0> The aqueous phase was further concentrated to remove the tetrahydrofuran, then 6 N HCl (100 mL, 600 m. After cooling to 0 ° C, NaNO 2 (9.43 g, 137 mmol) in 20 mL of H 2 O was added dropwise, and the mixture was stirred at room temperature for 15 hours. The reaction was then refluxed for 6 h, cooled to EtOAcqqqqqqqm MS (m/z): 227 (M+H) + .
在氮氣下，將6-溴噌啉-4-醇(18.5公克，82毫莫耳)的HNO3(90毫升，82毫莫耳)溶液冷卻至0℃，然後加入H2SO4(30毫升)。所得混合液加熱至60℃反應3小時，待LC-MS監控顯示反應完成，冷卻至0℃，加水(20毫升)淬滅。混合液加入EtOAc(25毫升)，按常規後處理，粗產物經矽膠管柱層析，PE/EtOAc洗脫，得到灰黃色固體，為6-溴-3-硝基噌啉-4-醇(13公克，產率58.6%)。 A solution of 6-bromoporphyrin-4-ol (18.5 g, 82 mmol) in HNO 3 (90 mL, 82 mmol) was cooled to 0 ° C under nitrogen then H 2 SO 4 (30 mL) ). The resulting mixture was heated to 60 ° C for 3 hours. The reaction was completed by LC-MS and was cooled to 0 ° C. The mixture was taken up in EtOAc (EtOAc (EtOAc)EtOAc. 13 grams, yield 58.6%).
在氮氣下，將6-溴-3-硝基噌啉-4-醇(2公克，7.41毫莫耳)的的DMF(10毫升)溶液冷卻至0℃，然後滴加POCl3(0.897毫升，9.63毫莫耳)。混合液室溫攪拌，反應5小時。待LC-MS監控顯示反應完成，將反應液冷卻至0℃，加50毫升水淬滅。布氏漏斗抽濾，收集固體，得到粗6-溴-4-氯-3-硝基噌啉(1.75公克，產率 82%)。MS(m/z)：290(M+H)+。不需進一步純化直接用於下步反應。 A solution of 6-bromo-3-nitroporphyrin-4-ol (2 g, 7.41 mmol) in DMF (10 mL) was cooled to 0 ° C, then POCI 3 (0.897 mL, 9.63 millimoles). The mixture was stirred at room temperature for 5 hours. After LC-MS monitoring showed the reaction was complete, the reaction was cooled to 0 ° C and quenched with 50 mL water. The mixture was suction filtered with a Buchner funnel, and solid was collected to give crude 6-bromo-4-chloro-3-nitro porphyrin (1.75 g, yield 82%). MS (m/z): 290 (M+H) + . It was used in the next step without further purification.
將6-溴-4-氯-3-硝基噌啉(1.75公克，6.07毫莫耳)、2-(4-氨基苯基)-2-甲基丙腈(1.069公克，6.67毫莫耳)、K2CO3(1.677公克，12.13毫莫耳)和MeCN(2毫升)混合，黃色混懸液加熱回流反應5分鐘。按常規後處理，經矽膠管柱層析純化，PE/EtOAc洗脫，得到黃色固體，為2-(4-(6-溴-3-硝基噌啉-4-氨基)苯基)-2-甲基丙腈(2.5公克，產率100%)。MS(m/z)：414(M+H)+。 6-Bromo-4-chloro-3-nitroporphyrin (1.75 g, 6.07 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (1.069 g, 6.67 mmol) K 2 CO 3 (1.677 g, 12.13 mmol) was mixed with MeCN (2 mL), and the yellow suspension was heated and refluxed for 5 minutes. After work-up, it was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) - Methylpropionitrile (2.5 g, yield 100%). MS (m/z): 414 (M+H) + .
在氮氣下，將2-(4-(6-溴-3-硝基噌啉-4-氨基)苯基)-2-甲基丙腈(2.5公克，6.06毫莫耳)、SnCl2.2H2O(5.21公克，24,26毫莫耳)和EtOAc(50毫升)橙色混合液加熱至45℃反應3小時。冷卻至室溫，用飽和碳酸鈉溶液調節pH至8，布氏漏斗抽濾，收集濾液，濃縮得到2-(4-(3-氨基-6-溴噌啉-4-氨基)苯基)-2-甲基丙腈(1.6公克，產率69%)。MS(m/z)：384(M+H)+。 2-(4-(6-Bromo-3-nitroporphyrin-4-amino)phenyl)-2-methylpropanenitrile (2.5 g, 6.06 mmol), SnCl 2 .2H under nitrogen An orange mixture of 2 O (5.21 g, 24, 26 mmol) and EtOAc (50 mL) was warmed to 45 ° C for 3 hours. After cooling to room temperature, the pH was adjusted to 8 with a saturated sodium carbonate solution, suction filtered with a Buchner funnel, and the filtrate was collected and concentrated to give 2-(4-(3-amino-6-bromo porphyrin-4-amino)phenyl)- 2-methylpropionitrile (1.6 g, yield 69%). MS (m/z): 384 (M + H) + .
在氮氣下，將2-(4-(3-氨基-6-溴噌啉-4-氨基)苯基)-2-甲基丙腈(250毫克，0.654毫莫耳)的HCO2H(3毫升)混合液加熱回流4小時。反應液加水淬滅，然後濃縮，粗產物(250毫克，產率97%)。MS(m/z)：394(M+H)+。無需進一步純化可直接用於下步反應。 2-(4-(3-Amino-6-bromoporphyrin-4-amino)phenyl)-2-methylpropanenitrile (250 mg, 0.654 mmol) of HCO 2 H (3) The mixture was heated to reflux for 4 hours. The reaction mixture was quenched with water and then evaporated and evaporated. MS (m/z): 394 (M+H) + . It can be used directly in the next step without further purification.
在氮氣下，將2-(4-(8-溴-1H-咪唑[4,5-c]噌啉-1-)苯基)-2-甲基丙腈(100m公克，0.255毫莫耳)、5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-)-3-(三氟甲基)吡啶-2-胺(95毫克，0.331毫莫耳)、Na2CO3(54.0毫克，0.510毫莫耳)、PdCl2(dppf).CH2Cl2(10.41毫克，0.013毫莫耳)和二氧六環(20毫升)、H2O(2毫升)混合，橙色 混合液室溫攪拌10分鐘，然後加熱至120℃繼續反應2小時。反應液真空濃縮，剩餘物柱層析純化得到灰黃色粉末，為化合物183(50毫克)。1H NMR(400 MHz,dmso)δ 8.87(s,1H),8.63(d,J=8.9,1H),8.48(d,J=2.0,1H),8.22(dd,J=9.0,1.9,1H),7.95(d,J=8.6,2H),7.88(d,J=8.6,2H),7.76(d,J=2.1,1H),7.52(d,J=1.8,1H),6.84(s,2H),1.78(s,6H)。MS(m/z)：474(M+H)+。 2-(4-(8-Bromo-1H-imidazo[4,5-c]porphyrin-1-ylphenyl)-2-methylpropanenitrile (100 m g, 0.255 mmol) under nitrogen , 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-)-3-(trifluoromethyl)pyridin-2-amine (95 mg, 0.331 Millol), Na 2 CO 3 (54.0 mg, 0.510 mmol), PdCl 2 (dppf). CH 2 Cl 2 (10.41 mg, 0.013 mmol) and dioxane (20 mL), H 2 O (2 ml) was mixed, and the orange mixture was stirred at room temperature for 10 minutes, then heated to 120 ° C to continue the reaction for 2 hours. The reaction mixture was concentrated in vacuo. 1 H NMR (400 MHz, dmso) δ 8.87 (s, 1H), 8.63 (d, J = 8.9, 1H), 8.48 (d, J = 2.0, 1H), 8.22 (dd, J = 9.0, 1.9, 1H) ), 7.95 (d, J = 8.6, 2H), 7.88 (d, J = 8.6, 2H), 7.76 (d, J = 2.1, 1H), 7.52 (d, J = 1.8, 1H), 6.84 (s, 2H), 1.78 (s, 6H). MS (m/z): 474 (M+H)+.
在此技術領域之技藝人士所認知的適當條件下，使用相應的中間體和硼酸或酯，採用化合物183的程序，合成以下化合物184。 The following compound 184 is synthesized using the corresponding intermediate and boronic acid or ester under the appropriate conditions recognized by those skilled in the art using the procedure of compound 183.
本實驗使用的是螢光偏振方法。最終的激酶反應是在10微莫耳濃度的ATP、0.2奈克/微升的PI3Kα激酶、30微莫耳濃度的脂質基質以及含有50毫莫耳濃度HEPES(pH 7.5)、100毫莫耳濃度NaCl、 1毫莫耳濃度EGTA、3毫莫耳濃度毫克Cl2、1毫莫耳濃度DTT和0.03%的CHAPS和2% DMSO的反應緩衝液中進行的。 This experiment used a fluorescence polarization method. The final kinase reaction was ATP at 10 micromolar, 0.2 ng/μl of PI3K alpha kinase, 30 micromolar lipid matrix and a concentration of 50 millimolar HEPES (pH 7.5), 100 millimolar The reaction was carried out in a reaction buffer of NaCl, 1 mM concentration of EGTA, 3 millimolar milligrams of Cl 2 , 1 millimolar of DTT, and 0.03% of CHAPS and 2% DMSO.
含10%DMSO的5微升的測試化合物和10微升的0.5奈克/微升的PI3K激酶(invitrogen，PV4788)分別加入96孔盤(Greiner，Cat.675076)，然後加入10微升的75微莫耳濃度PIP2脂質基質(invitrogen，PV5100)和25微莫耳濃度ATP的混合物啟動反應，混合後，在室溫下反應60分鐘。然後加入25微升的ADP檢測試劑(Bellbrook Labs公司，Transcreener Kinase試劑盒)，繼續反應1.5小時。反應結束後，在Tecan infinite F500儀器在610奈米激發，檢測670奈米處的發射值。 5 μl of test compound containing 10% DMSO and 10 μl of 0.5 Ng/μl of PI3K kinase (invitrogen, PV4788) were added to a 96-well plate (Greiner, Cat. 675076), respectively, followed by 10 μL of 75 The reaction was initiated by a mixture of micromolar concentration PIP2 lipid matrix (invitrogen, PV5100) and 25 micromolar concentration ATP, and after mixing, reacted at room temperature for 60 minutes. Then, 25 μl of ADP detection reagent (Bellbrook Labs, Transcreener Kinase kit) was added, and the reaction was continued for 1.5 hours. After the reaction was completed, the Tecan infinite F500 instrument was excited at 610 nm, and the emission value at 670 nm was detected.
ADP標準曲線藉由分別以DMSO與反應緩衝液替換化合物與PI3Kα以平行方式獲得。在標準曲線實驗裡，0至10微莫耳濃度濃度的ADP和10至0微莫耳濃度濃度的ATP混合物替代了反應中固定的10微莫耳濃度ATP濃度(ATP+ADP相加總濃度是10微莫耳濃度)，其他反應條件和前面描述的相同，最後標準曲線用Origin 8.0軟體作圖。測試化合物對ADP生成的抑制率根據標準曲線算出生成的ADP濃度獲得，IC50用XLfit 2.0軟體計算得到。 The ADP standard curve was obtained in parallel by replacing the compound with PI3Kα with DMSO and reaction buffer, respectively. In the standard curve experiment, ADP with a concentration of 0 to 10 micromolar and an ATP mixture with a concentration of 10 to 0 micromolar replaced the ATP concentration of 10 micromolar concentration fixed in the reaction (the total concentration of ATP + ADP is 10 micromolar concentration), other reaction conditions were the same as described above, and the final standard curve was plotted with Origin 8.0 software. The inhibition rate of the test compound for ADP production was obtained by calculating the ADP concentration generated from the standard curve, and the IC 50 was calculated using XLfit 2.0 software.
以上化合物1、2、3、5、6、7、8、9、10、11、12、13、14、15、16、17、18、20、21、22、23、24、25、26、28、29、30、31、33、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、79、80、81、82、83、84、85、87、88、89、90、92、94、95、96、97、98、99、100、101、102、103、104、105、 106、107、108、109、110、111、112、113、119,120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、142、143、144、145、147、148、149、150、151、152、153、154、155、156、157、158、159、160、161、162、163、164、165、166、167、168、169、170、171、172、173、174、175、176、177、178、179、180、181、182、183、184抑制PI3Kα激酶受體，並且IC50<100奈莫耳濃度。 The above compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 28, 29, 30, 31, 33, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 52, 53, 54, 55 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 81, 82, 83, 84, 85, 87, 88, 89, 90, 92, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 142, 143, 144, 145, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184 PI3Kα kinase receptor inhibition, and the IC 50 concentration ear <100 nemorubicin.
化合物抑制細胞的活性是用p-Akt Acumen方法檢測的。人的***癌細胞系PC3(ATCC)用含10%FBS的F-12培養基培養後，以每個孔5000個細胞的密度種90微升在有多聚賴氨酸結合的96孔盤裡(BD公司，356692)。孵育培養24小時後，加入10微升的不同濃度梯度的測試化合物，繼續孵育2小時。然後加入100微升的平衡到室溫的4%的多聚甲醛，室溫下固定細胞45分鐘。移除多聚甲醛後，再加入100微升的0.1%的Triton X-100，在室溫下再孵育30分鐘。然後用160微升的PBS洗兩次，再加入100微升的溶解在PBS裏的1% BSA，繼續孵育2至3小時。然後再用160微升的PBS洗兩次，加入30微升的以1：250比例稀釋在0.1% BSA裏的Ser473-p-Akt抗體(Cell signaling，CAT：4060)，在4℃孵育過夜。然後用160微升的PBS洗兩次後，加入35微升的以1：1000比例稀釋在0.1% BSA裏的Alexa Fluor 488山羊抗-兔子抗體(Invitrogen， A11034)，避光孵育1.5小時。用160微升的PBS洗兩次後，加入35微升的1.5微莫耳濃度濃度的碘化丙啶(Sigma，P4170)，37℃，5% CO2下繼續孵育30分鐘，然後在Acumen eX3(TTP LabTech)儀器上讀板。 The inhibition of cell activity by the compounds was detected by the p-Akt Acumen method. Human prostate cancer cell line PC3 (ATCC) was cultured in F-12 medium containing 10% FBS and seeded at a density of 5000 cells per well in a 96-well plate with polylysine binding ( BD, 356692). After incubation for 24 hours, 10 microliters of test compound of different concentration gradients were added and incubation continued for 2 hours. Then 100 microliters of 4% paraformaldehyde equilibrated to room temperature was added and the cells were fixed for 45 minutes at room temperature. After removal of paraformaldehyde, 100 microliters of 0.1% Triton X-100 was added and incubated for an additional 30 minutes at room temperature. Then wash twice with 160 microliters of PBS, then add 100 microliters of 1% BSA dissolved in PBS and continue to incubate for 2 to 3 hours. Then, it was washed twice with 160 μl of PBS, and 30 μl of Ser473-p-Akt antibody (Cell signaling, CAT: 4060) diluted 1:250 in 0.1% BSA was added, and incubated at 4 ° C overnight. After washing twice with 160 microliters of PBS, 35 microliters of Alexa Fluor 488 goat anti-rabbit antibody (Invitrogen, A11034) diluted 1:1000 in 0.1% BSA was added and incubated for 1.5 hours in the dark. After washing twice with 160 μl of PBS, 35 μl of 1.5 μmol concentration of propidium iodide (Sigma, P4170) was added, incubation was continued for 30 minutes at 37 ° C, 5% CO 2 , and then at Acumen eX3 (TTP LabTech) The instrument is read on the instrument.
測試化合物的抑制率用化合物處理過和未處理過的細胞的比值得到，IC50用XLfit 2.0軟體計算得到。 The inhibition rate of the test compound was obtained as the ratio of the compound treated to the untreated cells, and the IC 50 was calculated using XLfit 2.0 software.
每一個例舉的化合物對PI3Kα受體的抑制IC50均小於1.0微莫耳濃度。 Each exemplified compound of PI3Kα receptor inhibition IC 50 less than 1.0 micromolar.
化合物用LanthaScreen TR-FRET方法檢測。激酶反應是在384孔盤(Corning，Cat.3676)上進行的。最終的激酶反應條件是：10微莫耳濃度的ATP、0.2奈克/微升的mTOR激酶、0.4微莫耳濃度的GFP-4EBP1基質，並且在含有50毫莫耳濃度的pH7.5的HEPES、0.01%的Tween 20、1毫莫耳濃度的EGTA、10毫莫耳濃度的MnCl2、2毫莫耳濃度的DTT和1%DMSO緩衝液中進行的。 Compounds were detected by the LanthaScreen TR-FRET method. The kinase reaction was performed on a 384 well plate (Corning, Cat. 3676). The final kinase reaction conditions were: 10 micromolar ATP, 0.2 ng/μl mTOR kinase, 0.4 micromolar GFP-4 EBP1 matrix, and HEPES at pH 7.5 containing 50 mM concentration , 0.01% Tween 20, 1 mM molar concentration of EGTA, 10 millimolar concentration of MnCl 2 , 2 millimolar DTT and 1% DMSO buffer.
2.5微升的含4%DMSO的測試化合物和稀釋在緩衝液中的0.8奈克/微升濃度的2.5微升mTOR激酶(invitrogen，PV4753)分別加入384孔盤中，然後加入5微升的0.8微莫耳濃度公克FP-4EBP1基質(invitrogen，PV4759)和20微莫耳濃度ATP的混合物啟動反應，在室溫下孵育60分鐘。然後加入10微升包含有20毫莫耳濃度的EDTA和4奈莫耳濃度的Tb-anti-p4EBP1[pThr46]抗體(invitrogen，PV4755)的TR-FRET稀釋液，繼續孵育1小時。最 後在BioTek Synergy2儀器上，在340奈米激發，490奈米和528奈米發射波長下讀板。 2.5 μl of test compound containing 4% DMSO and 2.5 μl of mTOR kinase (invitrogen, PV4753) diluted to a concentration of 0.8 Ng/μl in buffer were added to a 384-well plate, respectively, and then 5 μL of 0.8 was added. The reaction was initiated by a mixture of micromolar concentrations of FP-4EBP1 matrix (invitrogen, PV4759) and 20 micromolar concentrations of ATP, and incubated for 60 minutes at room temperature. Ten microliters of TR-FRET dilution containing Tb-anti-p4EBP1 [pThr46] antibody (invitrogen, PV4755) at a concentration of 20 millimolar EDTA and 4 nanomolar was then added and incubation continued for 1 hour. most Plates were then read on a BioTek Synergy 2 instrument at 340 nm excitation, 490 nm and 528 nm emission wavelengths.
測試化合物的抑制率通過528奈米/490奈米的比值計算得到。IC50用XLfit 2.0軟體計算獲得。 The inhibition rate of the test compound was calculated from the ratio of 528 nm / 490 nm. The IC 50 was calculated using the XLfit 2.0 software.
結果：以上化合物1、6、7、9、10、12、14、16、17、21、25、26、30、33、35、42、43、44、45、46、49、50、52、53、55、56、58、63、66、72、75、88、96、98、102、103、105、106、107、119、120、121、122、123、129、131、147、148、149、151、152、153、154、155、156、157、158、159、160、165、166、178、180、181對mTOR的抑制IC50<100奈莫耳濃度。 Results: the above compounds 1, 6, 7, 9, 10, 12, 14, 16, 17, 21, 25, 26, 30, 33, 35, 42, 43, 44, 45, 46, 49, 50, 52, 53, 55, 56, 58, 63, 66, 72, 75, 88, 96, 98, 102, 103, 105, 106, 107, 119, 120, 121, 122, 123, 129, 131, 147, 148, 149,151,152,153,154,155,156,157,158,159,160,165,166,178,180,181 of mTOR inhibition IC 50 <100 nemorubicin concentration ear.
化合物抑制細胞的活性是用p-S6 Acumen方法檢測的。人的***癌細胞系PC3(ATCC)用含10%FBS的F-12培養基培養後，以每個孔5000個細胞的密度接種90微升至經多聚賴氨酸結合的96孔盤裡(BD公司，356692)。孵育培養24小時後，加入10微升的不同濃度梯度的測試化合物，繼續孵育2小時。然後加入100微升的平衡到室溫的4%的多聚甲醛，室溫下固定細胞45分鐘。移除多聚甲醛後，再加入100微升的0.1%的Triton X-100，在室溫下再孵育30分鐘。然後用160微升的PBS洗兩次，再加入100微升的溶解在PBS裡的1% BSA，繼續孵育2至3小時。然後再用160微升的PBS洗兩次，加入30微升的以1：250比例稀釋在0.1% BSA裏的p-S6抗體(Cell signalin公克，CAT：4858)，在4℃孵育過夜。然後用160 微升的PBS洗兩次後，加入35微升的以1：1000比例稀釋在0.1% BSA裏的Alexa Fluor 488山羊抗兔子抗體(Invitrogen，A11034)，避光孵育1.5小時。用160微升的PBS洗兩次後，加入35微升的1.5微莫耳濃度濃度的碘化丙啶(Sigma，P4170)，37℃，5% CO2下繼續孵育30分鐘，然後在Acumen eX3(TTP LabTech)儀器上讀板。 The inhibition of cell activity by the compounds was detected by the p-S6 Acumen method. After human prostate cancer cell line PC3 (ATCC) was cultured in F-12 medium containing 10% FBS, 90 μl was seeded at a density of 5000 cells per well into a poly-lysine-conjugated 96-well plate ( BD, 356692). After incubation for 24 hours, 10 microliters of test compound of different concentration gradients were added and incubation continued for 2 hours. Then 100 microliters of 4% paraformaldehyde equilibrated to room temperature was added and the cells were fixed for 45 minutes at room temperature. After removal of paraformaldehyde, 100 microliters of 0.1% Triton X-100 was added and incubated for an additional 30 minutes at room temperature. Then wash twice with 160 microliters of PBS, then add 100 microliters of 1% BSA dissolved in PBS and continue to incubate for 2 to 3 hours. Then, it was washed twice with 160 μl of PBS, and 30 μl of p-S6 antibody (Cell signalin gram, CAT: 4858) diluted 1:250 in 0.1% BSA was added, and incubated at 4 ° C overnight. After washing twice with 160 microliters of PBS, 35 microliters of Alexa Fluor 488 goat anti-rabbit antibody (Invitrogen, A11034) diluted 1:1000 in 0.1% BSA was added and incubated for 1.5 hours in the dark. After washing twice with 160 μl of PBS, 35 μl of 1.5 μmol concentration of propidium iodide (Sigma, P4170) was added, incubation was continued for 30 minutes at 37 ° C, 5% CO 2 , and then at Acumen eX3 (TTP LabTech) The instrument is read on the instrument.
測試化合物的抑制率用化合物處理過和未處理過的細胞的比值得到，IC50用XLfit 2.0軟體計算得到。每一個例舉的化合物對mTOR的抑制IC50均小於10微莫耳濃度。 The inhibition rate of the test compound was obtained as the ratio of the compound treated to the untreated cells, and the IC 50 was calculated using XLfit 2.0 software. Each exemplified compound of mTOR inhibition IC 50 of less than 10 micromolar.
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