TW202317570A - Tricyclic compounds - Google Patents

Abstract

Disclosed herein are tricyclic compounds, together with pharmaceutical compositions and methods for treating a cancer described herein.

Description

tricyclic compound

This application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are tricyclic compounds of formula (I), and pharmaceutically acceptable salts thereof, which are useful in the treatment of cancers as described herein.

Cancer kills more than 7 million people every year. Breast, lung, prostate, and colorectal cancers account for almost 50% of all new cancers in the United States. Lung, colorectal, pancreatic, and breast cancers account for nearly 50% of all deaths. Gene mutations are the cause of cancer.

Some embodiments provide a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relate to a pharmaceutical composition, which may include an effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient form, or a combination thereof.

Some embodiments described herein pertain to a method for treating a cancer described herein, which may comprise administering to a subject having a cancer described herein an effective amount of a compound described herein (e.g., A compound of formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to or include an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or include a compound described herein (e.g., Use of a pharmaceutical composition of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer as described herein. Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) or include a compound described herein (e.g., a compound of formula (I) ), or a pharmaceutically acceptable salt thereof), for use in the treatment of the cancers described herein. In some embodiments, the cancer may have a KRAS mutation.

definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. If a term in this article has multiple definitions, unless otherwise stated, the definition in this section prevails.

Whenever a group is described as being "optionally substituted," that group can be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "unsubstituted or substituted", if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituent is indicated, it means that the indicated "optionally substituted" or "substituted" groups may be individually and independently selected from one or more of the following group (such as 1, 2, or 3 groups) substitution: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl ), cycloalkyl (alkyl), heteroaryl (alkyl), heterocyclyl (alkyl), hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-aminoformyl, N-aminoformyl, O-thiamineformyl, N-thiamineformyl, C-amido, N-amido, S-sulfonamide, N-sulfonamide, C -carboxyl, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, amino, monosubstituted amine, and disubstituted amine.

As used herein, "a" and "b" in "C _a to C _b " are integers which refer to the number of carbon atoms in the group. Indicated groups may be inclusive and contain "a" to "b" carbon atoms. Thus, "C ₁ to C ₄ alkyl" refers to all alkyl groups having 1 to 4 carbons, ie CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, (CH ₃ ) ₂ CH -, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH(CH ₃ )-, and (CH ₃ ) ₃ C-. If "a" and "b" are not specified, the broadest range described in these definitions is assumed.

If two "R" groups are described as being "taken together," the R groups and the atoms to which they are attached can form cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycles. For example, without limitation, if R ^a and R ^b of an NR ^a R ^b group are described as "together", it means that they are covalently bonded to each other to form a ring:

As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety can be branched or straight chain. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, secondary butyl, tertiary butyl, and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as "1 to 30" refers to each integer within the given range; e.g., "1 to 30 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although this definition also covers the term "alkyl" when no numerical range is specified) . The alkyl group can also be a medium size alkyl group having 1 to 12 carbon atoms. The alkyl group can also be a lower alkyl group having 1 to 6 carbon atoms. Alkyl groups can be substituted or unsubstituted.

The term "alkenyl" as used herein refers to a monovalent linear or branched chain group of 2 to 20 carbon atoms containing a carbon double bond(s), including but not limited to 1-propenyl, 2 -propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl groups can be unsubstituted or substituted.

The term "alkynyl" as used herein refers to a monovalent linear or branched chain group of 2 to 20 carbon atoms containing a carbon triple bond(s), including but not limited to 1-propynyl, 1-butynyl, 2-butynyl, and the like. Alkynyl groups can be unsubstituted or substituted.

As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bond) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be fused, bridged, or joined together in a helical fashion. As used herein, the term "fused" refers to two rings that share two atoms and a bond. As used herein, the term "bridged cycloalkyl" refers to a compound in which the cycloalkyl contains a linkage to one or more atoms that are not adjacent atoms. As used herein, the term "spiro" refers to two rings that share an atom and are not joined by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), ) containing 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring(s). Cycloalkyl groups can be unsubstituted or substituted. Examples of monocycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthyl, dodecahydro-1H-propenyl naphthyl, and tetrahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantyl , and norbornyl (norbornanyl); and examples of spirocycloalkyl include spiro[3.3]heptane and spiro[4.5]decane.

As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one is present, the double bonds cannot A fully delocalized π-electron system is formed in all rings (otherwise the group would be an "aryl" as defined herein). For example, a cycloalkenyl group can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). When two or more rings are included, the rings can be joined together by fused, bridged or spiro-connected. Cycloalkenyl groups can be unsubstituted or substituted.

As used herein, "carbocyclyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or helical fashion as described herein. Carbocyclyl can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), ) containing 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring(s). A carbocyclyl can be unsubstituted or substituted. Examples of carbocyclyl include, but are in no way limited to, cycloalkyl and cycloalkenyl as defined herein, and 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, 5,6 , 7,8-tetrahydroquinoline, and the non-aromatic moiety of 6,7-dihydro-5H-cyclopenta[b]pyridine.

As used herein, "aryl" means a carbocyclic (full carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbocyclic rings share a chemical bond) having Fully delocalized π-electron systems. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C ₆ -C ₁₄ aryl group, a C ₆ -C ₁₀ aryl group, or a C ₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups can be substituted or unsubstituted.

、吡咯、

唑、苯并

唑、1,2,3-

二唑、1,2,4-

二唑、噻唑、1,2,3-噻二唑、1,2,4-噻二唑、苯并噻唑、咪唑、苯并咪唑、吲哚、吲唑、吡唑、苯并吡唑、異

唑、苯并異

唑、異噻唑、三唑、苯并三唑、噻二唑、四唑、吡啶、嗒

、嘧啶、吡

、嘌呤、喋啶、喹啉、異喹啉、喹唑啉、喹

啉、

啉、及三

。雜芳基可係經取代或未經取代的。 As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system with a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), that is, elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring(s) of a heteroaryl can vary. For example, a heteroaryl group may contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s), or 5 to 6 atoms in the ring(s), such as Nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atom and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms atom and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings (such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings) share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furan, thiophene, benzothiophene, thiophene,

, pyrrole,

Azole, benzo

Azole, 1,2,3-

Oxadiazole, 1,2,4-

Oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, iso

azoles, benziso

Azole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridine

, pyrimidine, pyrimidine

, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoline

phylloline,

phylloline, and three

. Heteroaryl groups can be substituted or unsubstituted.

烷、1,4-二

烷、1,2-二氧雜環戊烷、1,3-二氧雜環戊烷、1,4-二氧雜環戊烷、1,3-氧硫雜環己烷(1,3-oxathiane)、1,4-氧硫雜環己二烯(1,4-oxathiin)、1,3-氧硫雜環戊烷(1,3-oxathiolane)、1,3-二硫雜環戊烯(1,3-dithiole)、1,3-二硫雜環戊烷(1,3-dithiolane)、1,4-氧硫雜環己烷、四氫-1,4-噻

、2H-1,2-

、馬來醯亞胺、琥珀醯亞胺、巴比妥酸、硫巴比妥酸、二氧哌

、乙內醯脲、二氫尿嘧啶、三

烷、六氫-1,3,5-三

、咪唑啉、咪唑啶、異

唑啉、異

唑啶、

唑啉、

唑啶、

唑啶酮、噻唑啉、噻唑啶、嗎啉、環氧乙烷、哌啶N-氧化物、哌啶、哌

、吡咯啶、氮

、吡咯啶酮、吡咯啶二酮、4-哌啶酮、吡唑啉、吡唑啶、2-側氧基吡咯啶、四氫哌喃、4H-哌喃、四氫噻喃、硫嗎啉、硫嗎啉亞碸、硫嗎啉碸、及其苯并稠合類似物（例如，苯并咪唑啶酮、四氫喹啉、及/或3,4-亞甲基二氧基苯基）。螺雜環基之實例包括2-氮雜螺[3.3]庚烷、2-氧雜螺[3.3]庚烷、2-氧雜-6-氮雜螺[3.3]庚烷、2,6-二氮雜螺[3.3]庚烷、2-氧雜螺[3.4]辛烷、及2-氮雜螺[3.4]辛烷。 As used herein, "heterocyclyl" refers to three, four, five, six, seven, eight, nine, ten to up to 18 membered monocyclic, bicyclic, and tricyclic ring systems in which the carbon atoms are From 1 to 5 heteroatoms together form the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned in this manner, however, fully delocalized π-electron systems do not occur in all rings. Heteroatom(s) are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. The heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities such that the definition includes pendant oxygen systems as well as thio systems such as lactamides, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be fused, bridged, or joined together in a helical fashion. As used herein, the term "fused" refers to two rings that share two atoms and a bond. As used herein, the term "bridged heterocyclyl" refers to a compound in which the heterocyclyl contains a linkage to one or more atoms that are not adjacent atoms. As used herein, the term "spiro" refers to two rings that share an atom and are not joined by a bridge. A heterocyclyl group can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), ) containing 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogen in the heterocyclyl group may be quaternary ammonium. A heterocyclyl group can be unsubstituted or substituted. Examples of such "heterocyclyl" include, but are not limited to, 1,3-dioxin, 1,3-di

Alkane, 1,4-bis

alkane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiolane (1,3- oxathiane), 1,4-oxathiin (1,4-oxathiin), 1,3-oxathiolane (1,3-oxathiolane), 1,3-dithiolane (1,3-dithiole), 1,3-dithiolane (1,3-dithiolane), 1,4-oxathiolane, tetrahydro-1,4-thiolane

, 2H-1,2-

, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopane

, hydantoin, dihydrouracil, three

Alkane, hexahydro-1,3,5-tri

, imidazoline, imidazolidine, iso

oxazoline, iso

Azolidine,

oxazoline,

Azolidine,

Pazolidone, thiazoline, thiazolidine, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperidine

, pyrrolidine, nitrogen

, pyrrolidone, pyrrolidinone, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine , thiomorpholinoline, thiomorpholinoline, and benzo-fused analogs thereof (e.g., benzimidazolidinone, tetrahydroquinoline, and/or 3,4-methylenedioxyphenyl) . Examples of spiroheterocyclyl include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-di Azaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane.

As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group as a substituent attached via a lower alkylene group. The lower alkylene and aryl groups of the aralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

唑基烷基、及咪唑基烷基、及其苯并稠合類似物。 As used herein, "heteroaralkyl" and "heteroaryl (alkyl)" refer to a heteroaryl group as a substituent linked via a lower alkylene group. The lower alkylene and heteroaryl groups of heteroaralkyl may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, iso

Azolylalkyl, and imidazolylalkyl, and benzofused analogs thereof.

"Heterocyclyl (alkyl)" refers to a heterocyclic group linked via a lower alkylene group as a substituent. The lower alkylene and heterocyclyl groups of heterocyclyl (alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiopyran -4-yl (methyl) and 1,3-thiazinan-4-yl (methyl) (1,3-thiazinan-4-yl (methyl)).

）來取代。 As used herein, a "lower alkylene group" is a straight-chain _-CH2 -tethering group that forms a bond to connect molecular fragments via its terminal carbon atoms. Examples include _, but _are not _limited to, methylene ( _-CH2- ), ethylenyl ( _-CH2CH2- ), propylenyl ( _-CH2CH2CH2- ), and butylene ( _{-CH2CH 2CH2CH2- ) .} A lower alkylene group can be obtained by replacing one or more hydrogens of the lower alkylene group and/or by replacing two hydrogens on the same carbon with a cycloalkyl group (for example,

) to replace.

As used herein, the term "hydroxy" refers to an -OH group.

As used herein, "alkoxy" refers to the formula -OR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl as defined herein radical, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A non-limiting list of alkoxy groups are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, secondary butoxy group, tertiary butoxy, phenoxy, and benzyloxy. Alkoxy groups can be substituted or unsubstituted.

As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle attached as a substituent through a carbonyl group radical, aryl (alkyl), heteroaryl (alkyl) and heterocyclyl (alkyl). Examples include formyl, acetyl, propionyl, benzyl, and acryl. Acyl groups can be substituted or unsubstituted.

"cyano" refers to a "-CN" group.

The term "halogen atom" or "halogen" as used herein means any radioactive stable atom in column 7 of the periodic table of elements, such as fluorine, chlorine, bromine, and iodine.

"thiocarbonyl" refers to a "-C(=S)R" group, where R may be the same as defined for O-carboxy. Thiocarbonyl groups can be substituted or unsubstituted.

"O-carbamyl" refers to the "-OC(=O)N( _RA R _B )" group, where R _A and R _B can be independently hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl (alkyl). An O-aminoformyl group can be substituted or unsubstituted.

"N-carbamyl" refers to the "ROC(=O)N( _RA )-" group, where R and _RA can be independently hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl ). The N-aminoformyl group can be substituted or unsubstituted.

"O-thiocarbamyl (O-thiocarbamyl)" refers to the group "-OC(=S)-N( _RA R _B )", wherein R _A and R _B can be independently hydrogen, alkyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heteroaryl Cyclic (alkyl). The O-thiacarbamoyl group can be substituted or unsubstituted.

"N-thiocarbamyl" refers to the group "ROC(=S)N( _RA )-", wherein R and _RA can be independently hydrogen, alkyl, alkenyl, alkyne radical, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl base). The N-thiacarbamoyl group can be substituted or unsubstituted.

"C-amido" refers to a "-C(=O)N( _RA R _B )" group, wherein R _A and R _B can be independently hydrogen, alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl( alkyl). A C-amido group can be substituted or unsubstituted.

"N-amido" refers to the group "RC(=O)N( _RA )-", wherein R and _RA can be independently hydrogen, alkyl, alkenyl, alkynyl, Cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) . N-amido groups can be substituted or unsubstituted.

"S-sulfonamido (S-sulfonamido)" refers to the "-SO ₂ N( _RA R _B )" group, where R _A and R _B can be independently hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl ). The S-sulfonylamino group can be substituted or unsubstituted.

"N-sulfonamido (N-sulfonamido)" refers to the "RSO ₂ N( _RA )-" group, where R and _RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkane radical, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The N-sulfonylamino group can be substituted or unsubstituted.

"O-carboxy" refers to the group "RC(=O)O-", wherein R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, Heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy can be substituted or unsubstituted.

The terms "ester" and "C-carboxy" refer to a "-C(=O)OR" group, where R may be the same as defined for O-carboxy. Esters and C-carboxy groups can be substituted or unsubstituted.

As used herein, "urea (urea)" refers to "-NH-C(=O)-N( _RA R _B )", wherein RA _{and RB} can be independently hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl (alkyl). Ureas can be substituted or unsubstituted.

"Nitro" refers to a -NO ₂ "group.

A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, Heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A sulfenyl group can be substituted or unsubstituted.

"Sulfinyl" refers to a "-S(=O)-R" group, where R may be the same as defined for sulfenyl. A sulfinyl group can be substituted or unsubstituted.

"Sulfonyl" refers to a "-SO ₂ R" group, wherein R may be the same as defined for sulfenyl. A sulfonyl group can be substituted or unsubstituted.

As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl). haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl groups can be substituted or unsubstituted.

As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy) alkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy can be substituted or unsubstituted.

As used herein, the term "amino" refers to a -NH ₂ group.

A "mono-substituted amine" group refers to a " _-NHRA " group, where _RA can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, hetero Aryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. _RA can be substituted or unsubstituted. Examples of monosubstituted amine groups include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

A "di-substituted amine" group refers to a "-NR _A R _B " group, wherein R _A and R _B can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, Alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as described herein definition. _RA and _RB can independently be substituted or unsubstituted. Examples of disubstituted amine groups include, but are not limited to, −N(methyl) ₂ , −N(phenyl)(methyl), −N(ethyl)(methyl), and the like.

When the number of substituents is not specified (eg, haloalkyl), then one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C ₁ -C ₃ alkoxyphenyl (C ₁ -C ₃ alkoxyphenyl)" may include one or more same or different alkoxy groups containing one, two, or three atoms.

As used herein, a group means a species with a single unpaired electron such that the species containing the group can covalently bond to another species. Therefore, radicals are not necessarily free radicals in this context. In contrast, a group denotes a specific portion of a larger molecule. The term "radical" is used interchangeably with the term "group".

The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not invalidate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of a compound. Pharmaceutical salts can be obtained by reacting compounds with inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acids), sulfuric acid, nitric acid, and phosphoric acids (such as 2,3-dihydroxypropyl phosphate di hydrogen salt). Pharmaceutical salts can also be obtained by reacting compounds with organic acids, such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic acid, Alkaline acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxoglutaric acid or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as ammonium salt, alkali metal salt (such as sodium, potassium, or lithium salt), alkaline earth metal salt (such as calcium or magnesium salt), Carbonates, bicarbonates, organic bases such as dicyclohexylamine, N-methyl-D-glucosamine, ginseng(hydroxymethyl)methylamine, C ₁ -C ₇ alkylamines, cyclohexylamine , triethanolamine, ethylenediamine), and salts with amino acids (such as arginine and lysine). Those of ordinary skill in the art understand that when a salt is formed by protonation of a nitrogen-based group (e.g., _NH2 ), the nitrogen-based group can associate with a positive charge (e.g., _NH2 can become NH ₃ ⁺ ), and this positive charge can be balanced by a negatively charged counterion such as Cl ⁻ .

It is understood that in any compound described herein having one or more chiral centers, unless absolute stereochemistry is explicitly indicated, each center may independently have the R-configuration, or the S-configuration, or mixtures thereof . Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixture. Furthermore, it should be understood that in any of the compounds described herein having one or more double bonds yielding geometric isomers (which may be defined as E or Z), each double bond may independently be E or Z or a mixture thereof. Likewise, it is to be understood that in any such compound, all tautomeric forms are also intended to be included.

It is understood that where compounds disclosed herein have unfilled valencies, then the valences should be filled with hydrogen or isotopes thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

It is understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. Wherever a hydrogen atom may be present in a compound, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, references herein to compounds encompass all potential isotopic forms, unless the context clearly dictates otherwise.

It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal-packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated form with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed with pharmaceutically acceptable solvents such as water, ethanol, or the like during the crystallization process. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Where a range of values is provided, it is understood that the upper and lower limits of the range, as well as each intervening value therebetween, are encompassed in the examples.

Unless expressly stated otherwise, the terms and phrases used in this application, and variations thereof (particularly in the appended claims), should be interpreted as open-ended and not limiting. As an example of the foregoing, the term "including" should be read to mean "including, without limitation/including but not limited to" or the like; as used herein, the term "comprising )" is synonymous with "including", "containing", or "characterized by", and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; The term "having" should be read as "having at least"; the term "include" should be read as "including but not limited to"; the term "example" is used to provide discussion items illustrative examples rather than an exhaustive or limiting list thereof; and the use of terms such as "preferably", "preferred", or "desired/desirable" and words of similar meaning , should not be interpreted as implying that certain features are critical, necessary, or even important to the structure or function, but merely intended to emphasize alternative or additional features that may or may not be utilized in a specific embodiment. Furthermore, the term "comprising" should be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

With respect to the use of substantially any plural and/or singular terms herein, one of ordinary skill in the art may switch from the plural to the singular and/or from the singular to the plural as appropriate to the context and/or application. Various singular/plural permutations may be explicitly set forth herein for clarity. The indefinite article "one (a or an)" does not exclude the plural. The mere fact that certain measures are listed in mutually different subparagraphs does not indicate that a combination of these measures cannot be used to advantage. Any element symbols in claims should not be construed as limiting the scope. compound

(I) 其中： ----------可各自獨立地係單鍵或雙鍵；其中X ³與X ⁴之間之鍵可係雙鍵；X ⁴與X ⁵之間之鍵可係單鍵；X ⁵與X ⁶之間之鍵可係雙鍵；且X ²與X ⁶之間之鍵可係單鍵；其中X ³與X ⁴之間之鍵可係單鍵；X ⁴與X ⁵之間之鍵可係雙鍵；X ⁵與X ⁶之間之鍵可係單鍵；且X ²與X ⁶之間之鍵可係雙鍵；或其中X ³與X ⁴之間之鍵可係單鍵；X ⁴與X ⁵之間之鍵可係單鍵；X ⁵與X ⁶之間之鍵可係單鍵；且X ²與X ⁶之間之鍵可係雙鍵；X ¹可係N（氮）或C（碳），前提係當X ¹係N（氮）時，則R ¹不存在；X ²、X ³、X ⁴、X ⁵及X ⁶可各自獨立地係N（氮）或C（碳），前提係X ²、X ³、X ⁴、X ⁵及X ⁶係C（碳）；且前提係R ²、R ³及R ⁴經選擇使得X ²、X ³、X ⁴、X ⁵及X ⁶係不帶電的；R ¹可係不存在或氫；R ²、R ³及R ⁴可各自獨立地係不存在、氫、鹵素、羥基、胺基、氰基、未經取代C _1-4烷基、未經取代C _1-4鹵烷基、未經取代或經取代醯基、未經取代或經取代C-羧基、未經取代或經取代C-醯胺基、未經取代或經取代脲、未經取代C _1-4烷氧基、未經取代或經取代N-胺甲醯基、未經取代或經取代環烷基、未經取代或經取代芳基、未經取代或經取代雜芳基或未經取代或經取代雜環基，其中該經取代醯基、該經取代C-羧基、該經取代C-醯胺基、該經取代脲、該經取代N-胺甲醯基、該經取代環烷基、該經取代芳基、該經取代雜芳基及該可選地經取代雜環基可經一或多個獨立地選自下列之取代基取代：鹵素、OH、CN、未經取代C _1-4烷基、未經取代C _1-4烷氧基、未經取代C _1-4鹵烷基、未經取代C _1-4羥基烷基及未經取代C-羧基；環A及環B可各自獨立地係未經取代或經取代C _6-8環烷基、未經取代或經取代芳基、未經取代或經取代雜芳基或未經取代或經取代雜環基，其中該經取代C _6-8環烷基、該經取代芳基、該經取代雜芳基及該經取代雜環基可經一或多個獨立地選自下列之部分取代：鹵素、羥基、胺基、氰基、未經取代C _1-4烷基、未經取代C _1-4鹵烷基、未經取代或經取代醯基、未經取代或經取代C-羧基、未經取代或經取代C-醯胺基、未經取代或經取代脲、未經取代烷氧基、未經取代或經取代N-胺甲醯基、未經取代或經取代環烷基、未經取代或經取代芳基、未經取代或經取代雜芳基及未經取代或經取代雜環基，其中該經取代醯基、該經取代C-羧基、該經取代C-醯胺基、該經取代脲、該經取代N-胺甲醯基、該經取代環烷基、該經取代芳基、該經取代雜芳基及該經取代雜環基可經一或多個獨立地選自下列之取代基取代：鹵素、OH、CN、未經取代C _1-4烷基、未經取代烷氧基、未經取代C _1-4鹵烷基、未經取代C _1-4羥基烷基及未經取代C-羧基。 Some embodiments disclosed herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, which has the following structure:

(I) wherein: ---------- can be single bond or double bond independently; wherein the bond between ^X3 and ^X4 can be a double bond; the bond between ^X4 and ^X5 Can be a single bond; the bond between ^X5 and ^X6 can be a double bond; and the bond between ^X2 and ^X6 can be a single bond; the bond between ^X3 and ^X4 can be a single bond; X The bond between ⁴ and ^X5 can be a double bond; the bond between ^X5 and ^X6 can be a single bond; and the bond between ^X2 and ^X6 can be a double bond; or wherein the bond between ^X3 and ^X4 The bond between X and X can be a single bond; the bond between ^X and ^X can be a single bond; the bond between ^X and ^X can be a single bond; and the bond between X ^{and X} can be a double bond ; X ¹ can be N (nitrogen) or C (carbon), the premise is that when X ¹ is N (nitrogen), then R ¹ does not exist; X ² , X ³ , X ⁴ , X ⁵ and X ⁶ can be independent is N (nitrogen) or C (carbon), the premise is that X ² , X ³ , X ⁴ , X ⁵ and X ⁶ are C (carbon); and the premise is that R ² , R ³ and R ⁴ are selected such that X ² , X ³ , X ⁴ , X ⁵ and X ⁶ are uncharged; R ¹ can be absent or hydrogen; R ² , R ³ and R ⁴ can be independently absent, hydrogen, halogen, hydroxyl, amino , cyano, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, unsubstituted or substituted C-amido, unsubstituted or substituted urea, unsubstituted C _1-4 alkoxy, unsubstituted or substituted N-aminoformyl, unsubstituted or substituted cycloalkyl, unsubstituted Substituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted heterocyclyl, wherein the substituted acyl, the substituted C-carboxy, the substituted C-amido, The substituted urea, the substituted N-aminoformyl group, the substituted cycloalkyl group, the substituted aryl group, the substituted heteroaryl group, and the optionally substituted heterocyclic group can be modified by one or more Substituents independently selected from the following substituents: halogen, OH, CN, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkyl, unsubstituted Substituted C _1-4 hydroxyalkyl and unsubstituted C-carboxyl; ring A and ring B can be independently unsubstituted or substituted C _6-8 cycloalkyl, unsubstituted or substituted aryl, unsubstituted Substituted or substituted heteroaryl or unsubstituted or substituted heterocyclic group, wherein the substituted C _6-8 cycloalkyl, the substituted aryl, the substituted heteroaryl and the substituted heterocyclic group Can be substituted with one or more moieties independently selected from the group consisting of halogen, hydroxyl, amino, cyano, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, unsubstituted or Substituted acyl, unsubstituted or substituted C-carboxy, unsubstituted or substituted C-amido, unsubstituted or substituted urea, unsubstituted alkoxy, unsubstituted or substituted N- Carbamoyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heterocyclyl, wherein the substituted acyl , the substituted C-carboxy, the substituted C-amido, the substituted urea, the substituted N-aminoformyl, the substituted cycloalkyl, the substituted aryl, the substituted heteroaryl and the substituted heterocyclic group may be substituted by one or more substituents independently selected from the group consisting of halogen, OH, CN, unsubstituted C _1-4 alkyl, unsubstituted alkoxy, unsubstituted C _1-4 haloalkyl, unsubstituted C _1-4 hydroxyalkyl and unsubstituted C-carboxy.

。在本段之一些實施例中，X ¹、X ²、X ⁴及X ⁵可各自係N（氮）；X ³及X ⁶可各自係C（碳），且式(I)之化合物、或其醫藥上可接受之鹽可係式(Ia)之化合物、或其醫藥上可接受之鹽。在本段之一些實施例中，X ¹、X ²、X ⁴、X ⁵及X ⁶可各自係N（氮）；X ³可係C（碳），且式(I)之化合物、或其醫藥上可接受之鹽可係式(Ib)之化合物、或其醫藥上可接受之鹽。如本文中所提供，當X ¹係N（氮）時，則R ¹不存在。亦如本文中所提供，R ²、R ³及R ⁴經選擇，使得X ⁴、X ⁵及X ⁶係不帶電的。舉例而言，當X ⁴係N（氮）時，則R ²不存在。同樣，當X ⁵係N（氮）時，則R ³不存在，且當X ⁶係N（氮）時，則R ⁴不存在。

(Ia)

(Ib) Rings comprising ^X2 , ^X3 , ^X4 , ^X5 and ^X6 may comprise single and/or double bonds as described herein. In some embodiments, the bond between X ^{and X} can be a double bond; the bond between ^X and X can be a single bond ^; the bond between ^X and ^X can be a double bond; and X The bond between ² and ^X can be a single bond such that a ring comprising X ² , X ³ , X ⁴ , X ⁵ and X ⁶ can have the following structure:

. In some embodiments of this paragraph, X ¹ , X ² , X ⁴ , and X ⁵ can each be N (nitrogen); X ³ and X ⁶ can each be C (carbon), and the compound of formula (I), or Its pharmaceutically acceptable salt can be the compound of formula (Ia), or its pharmaceutically acceptable salt. In some embodiments of this paragraph, X ¹ , X ² , X ⁴ , X ⁵ and X ⁶ can each be N (nitrogen); X ³ can be C (carbon), and the compound of formula (I), or A pharmaceutically acceptable salt may be a compound of formula (Ib), or a pharmaceutically acceptable salt thereof. As provided herein, when X ¹ is N (nitrogen), then R ¹ is absent. Also as provided herein, ^R2 , ^R3 and ^R4 are selected such that ^X4 , ^X5 and ^X6 are uncharged. For example, when X ⁴ is N (nitrogen), then R ² is absent. Likewise, when ^X5 is N (nitrogen), then ^R3 is absent, and when ^X6 is N (nitrogen), then ^R4 is absent.

(Ia)

(Ib)

In some embodiments of formula (Ia), or a pharmaceutically acceptable salt thereof, R ⁴ can be hydrogen. In other embodiments of formula (Ia), or a pharmaceutically acceptable salt thereof, R ⁴ can be unsubstituted C _1-4 alkyl. Examples of C _1-4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, and tertiary butyl. In yet other embodiments of formula (Ia), or a pharmaceutically acceptable salt thereof, R ⁴ may be unsubstituted C _1-4 haloalkyl, such as —CF ₃ , —CHF ₂ , —CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -CCl ₃ , -CHCl ₂ and -CH ₂ Cl.

。在本段之一些實施例中，X ²及X ⁴可各自係C（碳）；且X ¹、X ³、X ⁵及X ⁶可各自係N（氮），使得式(I)之化合物、或其醫藥上可接受之鹽可係式(Ic)之化合物、或其醫藥上可接受之鹽。在本段之其他實施例中，X ²、X ⁴及X ⁵各自係C（碳）；且X ¹、X ³及X ⁶各自係N（氮），使得式(I)之化合物、或其醫藥上可接受之鹽可係式(Id)之化合物、或其醫藥上可接受之鹽。在本段之又其他實施例中，X ²、X ⁴、X ⁵及X ⁶可各自係C（碳）；且X ¹及X ³可各自係N（氮），使得式(I)之化合物、或其醫藥上可接受之鹽可係式(Ie)之化合物、或其醫藥上可接受之鹽。在本段之再其他實施例中，X ²、X ⁵及X ⁶可各自係C（碳）；且X ¹、X ³及X ⁴可各自係N（氮），且式(I)之化合物、或其醫藥上可接受之鹽可係式(If)之化合物、或其醫藥上可接受之鹽。

(Ic)

(Id)

(Ie)

(If) In some embodiments, the bond between X ^and X can be a single bond; the bond between ^X and ^X can be a double bond; the bond ^{between X} and ^X can be a single bond; and X The bond between ² and ^X6 may be a double bond, and the ring comprising ^X2 , ^X3 , ^X4 , ^X5 and ^X6 may have the following structure:

. In some embodiments of this paragraph, X ² and X ⁴ can each be C (carbon); and X ¹ , X ³ , X ^{5 ,} and X ⁶ can each be N (nitrogen), such that the compound of formula (I), Or a pharmaceutically acceptable salt thereof may be a compound of formula (Ic), or a pharmaceutically acceptable salt thereof. In other embodiments of this paragraph, X ² , X ⁴ , and X ⁵ are each C (carbon); and X ¹ , X ^{3 ,} and X ⁶ are each N (nitrogen), such that the compound of formula (I), or A pharmaceutically acceptable salt may be a compound of formula (Id), or a pharmaceutically acceptable salt thereof. In yet other embodiments of this paragraph, X ² , X ⁴ , X ⁵ , and X ⁶ can each be C (carbon); and X ¹ and X ³ can each be N (nitrogen), such that the compound of formula (I) , or a pharmaceutically acceptable salt thereof may be a compound of formula (Ie), or a pharmaceutically acceptable salt thereof. In yet other embodiments of this paragraph, X ² , X ⁵ , and X ⁶ can each be C (carbon); and X ¹ , X ³ , and X ⁴ can each be N (nitrogen), and the compound of formula (I) , or a pharmaceutically acceptable salt thereof may be a compound of formula (If), or a pharmaceutically acceptable salt thereof.

(Ic)

(Id)

(Ie)

(If)

In some embodiments of formula (Ic), or a pharmaceutically acceptable salt thereof, ^R2 can be hydrogen. In other embodiments of formula (Ic), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted C _1-4 alkyl. In yet other embodiments of formula (Ic), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted C _1-4 haloalkyl. For example, for formula (Ic), or a pharmaceutically acceptable salt thereof, R can be ^methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl tertiary butyl group, –CF ₃ , –CHF ₂ , –CH ₂ F, –CH ₂ CF ₃ , –CH ₂ CHF ₂ , –CH ₂ CH ₂ F, –CCl ₃ , –CHCl ₂ , –CH ₂ Cl, -C(=O)OH, -C(=O)O(unsubstituted C _1-4 alkyl) (such as -C(=O)OCH ₃ , -C(=O)OCH ₂ CH ₃ , –C(=O)OCH ₂ CH ₂ CH ₃ , –C(=O)O(isopropyl), –C(=O)OCH ₂ CH ₂ CH ₂ CH ₃ , –C(=O)O(isopropyl) butyl), —C(=O)O (secondary butyl) and —C(=O)O (tertiary butyl)), and —C(=O)NH ₂ .

In some embodiments of formula (Id), or a pharmaceutically acceptable salt thereof, ^R2 can be hydrogen. In other embodiments of Formula (Id), or a pharmaceutically acceptable salt thereof, R ² can be cyano. In yet other embodiments of formula (Id), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted C _1-4 alkyl. In still other embodiments of formula (Id), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted C _1-4 haloalkyl. In some embodiments of Formula (Id), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted or substituted aryl. As an example, for formula (Id), ^R2 can be unsubstituted or substituted phenyl. In other embodiments of formula (Id), or a pharmaceutically acceptable salt thereof, ^R2 can be unsubstituted or substituted C-carboxy.

For compounds of formula (Id), or pharmaceutically acceptable salts thereof, various substituents may also be present at ^R3 . In some embodiments of formula (Id), or a pharmaceutically acceptable salt thereof, ^R3 can be hydrogen. In other embodiments of formula (Id), or a pharmaceutically acceptable salt thereof, ^R3 can be cyano. In yet other embodiments of formula (Id), or a pharmaceutically acceptable salt thereof, R ³ can be unsubstituted C _1-4 alkyl. In still other embodiments of formula (Id), or a pharmaceutically acceptable salt thereof, R ³ can be unsubstituted C _1-4 haloalkyl. In some embodiments of formula (Id), or a pharmaceutically acceptable salt thereof, ^R3 can be unsubstituted or substituted aryl, such as unsubstituted or substituted phenyl. Exemplary unsubstituted C _1-4 alkyl and unsubstituted C _1-4 haloalkyl are set forth herein, and an exemplary C-carboxy for R ^and /or ^R may be -C(=O)OH and -C(=O)O(unsubstituted C _1-4 alkyl) (such as -C(=O)OCH ₃ , -C(=O)OCH ₂ CH ₃ , -C(=O)OCH ₂ CH ₂ CH ₃ , –C(=O)O(isopropyl), –C(=O)OCH ₂ CH ₂ CH ₂ CH ₃ , –C(=O)O(isobutyl), –C(=O )O (secondary butyl) and –C(=O)O (tertiary butyl)). An example of a C-amido group is -C(=O) _NH2 .

The compound of formula (Ie), or a pharmaceutically acceptable salt thereof, may have various substituents at R ² , R ³ and R ⁴ . In some embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, R ² can be hydrogen. In other embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, R ² can be cyano. In yet other embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted C _1-4 alkyl. In still other embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted C _1-4 haloalkyl. In some embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, ^R2 can be unsubstituted or substituted aryl, such as unsubstituted or substituted phenyl. In other embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, ^R can be unsubstituted or substituted C-carboxy, such as having the formula -C(=O)OH or -C(=O )O(unsubstituted C _1-4 alkyl) unsubstituted or substituted C-carboxy. In yet other embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, ^R can be unsubstituted or substituted C-amido (e.g., of formula -C(=O)NH _or - unsubstituted or substituted C-amido group of C(=O)N(unsubstituted C _1-4 alkyl) ₂ ). In some embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, ^R3 can be hydrogen. In other embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, R ³ can be cyano. In yet other embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, R ³ can be unsubstituted C _1-4 alkyl. In still other embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, R ³ may be an unsubstituted C _1-4 haloalkyl. In some embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, ^R can be unsubstituted or substituted aryl (eg, unsubstituted or substituted phenyl). In other embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, ^R can be unsubstituted or substituted C-carboxy (for example, having the formula -C(=O)OH or -C(= O) unsubstituted or substituted C-carboxy for O(unsubstituted C _1-4 alkyl)). In yet other embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, R ³ may be unsubstituted or substituted C-amido, such as having the formula -C(=O)NH ₂ or - C(=O)N(unsubstituted C _1-4 alkyl) ₂ ) unsubstituted or substituted C-amido group. For example, R ³ can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, —CF ₃ , —CHF ₂ , —CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -CCl ₃ , -CHCl ₂ , -CH ₂ Cl, unsubstituted phenyl, substituted phenyl, -C(= O)OH, -C(=O)O(unsubstituted C _1-4 alkyl) (such as -C(=O)OCH ₃ , -C(=O)OCH ₂ CH ₃ , -C(=O) OCH ₂ CH ₂ CH ₃ , –C(=O)O(isopropyl), –C(=O)OCH ₂ CH ₂ CH ₂ CH ₃ , –C(=O)O(isobutyl), –C (=O)O (secondary tablet) and —C(=O)O (tertiary butyl)), and —C(=O)NH ₂ . In some embodiments of formula (Ie), or a pharmaceutically acceptable salt thereof, R ⁴ can be hydrogen.

For formula (If), or a pharmaceutically acceptable salt thereof, in some embodiments, ^R3 can be hydrogen. In other embodiments of formula (If), or a pharmaceutically acceptable salt thereof, R ³ can be cyano. In yet other embodiments of formula (If), or a pharmaceutically acceptable salt thereof, R ³ can be unsubstituted C _1-4 alkyl. In yet other embodiments of formula (If), or a pharmaceutically acceptable salt thereof, R ³ may be an unsubstituted C _1-4 haloalkyl. In some embodiments of formula (If), or a pharmaceutically acceptable salt thereof, ^R3 can be unsubstituted or substituted aryl, such as unsubstituted or substituted phenyl. In other embodiments of formula (If), or a pharmaceutically acceptable salt thereof, ^R3 can be unsubstituted or substituted C-carboxy. For example, R ³ can be -C(=O)O(unsubstituted C _1-4 alkyl). In some embodiments of formula (If), or a pharmaceutically acceptable salt thereof, R ⁴ can be hydrogen.

。在本段之一些實施例中，X ²及X ⁴可各自係C（碳）；且X ¹、X ³、X ⁵及X ⁶可各自係N（氮），使得式(I)之化合物、或其醫藥上可接受之鹽可係式(Ig)之化合物、或其醫藥上可接受之鹽。在本段之其他實施例中，X ²、X ⁴及X ⁵可各自係C（碳）；且X ¹、X ³及X ⁶可各自係N（氮），使得式(I)之化合物、或其醫藥上可接受之鹽可係式(Ih)之化合物、或其醫藥上可接受之鹽。

(Ig)

(Ih) In some embodiments, the bond between ^X3 and ^X4 can be a single bond; the bond between ^X4 and ^X5 can be a single bond; the bond between ^X5 and ^X6 can be a single bond; and X The bond between ² and ^X6 may be a double bond, and the ring comprising ^X2 , ^X3 , ^X4 , ^X5 and ^X6 may have the following structure:

. In some embodiments of this paragraph, X ² and X ⁴ can each be C (carbon); and X ¹ , X ³ , X ^{5 ,} and X ⁶ can each be N (nitrogen), such that the compound of formula (I), Or a pharmaceutically acceptable salt thereof may be a compound of formula (Ig), or a pharmaceutically acceptable salt thereof. In other embodiments of this paragraph, X ² , X ^{4 ,} and X ⁵ can each be C (carbon); and X ¹ , X ^{3 ,} and X ⁶ can each be N (nitrogen), such that the compound of formula (I), Or a pharmaceutically acceptable salt thereof may be a compound of formula (Ih), or a pharmaceutically acceptable salt thereof.

(Ig)

(Ih)

The compound of formula (Ig), or a pharmaceutically acceptable salt thereof, may have various substituents at R ² and R ³ . In some embodiments of Formula (Ig), or a pharmaceutically acceptable salt thereof, ^R2 can be hydrogen. In other embodiments of Formula (Ig), or a pharmaceutically acceptable salt thereof, R ² can be cyano. In yet other embodiments of formula (Ig), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted C _1-4 alkyl. In still other embodiments of formula (Ig), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted C _1-4 haloalkyl. In some embodiments of Formula (Ig), or a pharmaceutically acceptable salt thereof, ^R3 can be hydrogen. In other embodiments of Formula (Ig), or a pharmaceutically acceptable salt thereof, R ³ can be cyano. In yet other embodiments of formula (Ig), or a pharmaceutically acceptable salt thereof, R ³ can be unsubstituted C _1-4 alkyl. In still other embodiments of formula (Ig), or a pharmaceutically acceptable salt thereof, R ³ can be unsubstituted C _1-4 haloalkyl. For compounds of formula (Ig), or pharmaceutically acceptable salts thereof, exemplary ^R2 and/or ^R3 substituents include, but are not limited to, which can be methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, –CF ₃ , –CHF ₂ , –CH ₂ F, –CH ₂ CF ₃ , –CH ₂ CHF ₂ , –CH ₂ CH ₂ F, —CCl ₃ , —CHCl ₂ , or —CH ₂ Cl.

For compounds of formula (Ih), or pharmaceutically acceptable salts thereof, various substituents may be present for ^R2 and ^R3 . In some embodiments of formula (Ih), or a pharmaceutically acceptable salt thereof, R ² can be hydrogen. In some embodiments of formula (Ih), or a pharmaceutically acceptable salt thereof, ^R3 can be hydrogen. In other embodiments of formula (Ih), or a pharmaceutically acceptable salt thereof, R ² and/or R ³ may be non-hydrogen substituents, such as those described herein. In some embodiments of formula (Ih), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted C _1-4 alkyl. In other embodiments of formula (Ih), or a pharmaceutically acceptable salt thereof, R ² can be unsubstituted C _1-4 haloalkyl. In some embodiments of formula (Ih), or a pharmaceutically acceptable salt thereof, R ³ can be unsubstituted C _1-4 alkyl. In other embodiments of formula (Ih), or a pharmaceutically acceptable salt thereof, R ³ can be unsubstituted C _1-4 haloalkyl. In some embodiments of formula (Ih), or a pharmaceutically acceptable salt thereof, ^R2 and ^R3 can each be hydrogen. For the compound of formula (Ih), or a pharmaceutically acceptable salt thereof, examples of R ^and /or ^R substituents include, but are not limited to, methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, –CF ₃ , –CHF ₂ , –CH ₂ F, –CH ₂ CF ₃ , –CH ₂ CHF ₂ , –CH ₂ CH ₂ F, —CCl ₃ , —CHCl ₂ , or —CH ₂ Cl.

When present, ^R2 , ^R3 and ^R4 can be various substituents. In some embodiments, R ² , R ³ and/or R ⁴ can be hydrogen. In other embodiments, R ² , R ³ and/or R ⁴ may be halogen, such as F or Cl. In yet other embodiments, R ² , R ³ and/or R ⁴ can be hydroxyl. In still other embodiments, R ² , R ³ and/or R ⁴ may be amine groups. In some embodiments, R ² , R ³ and/or R ⁴ may be cyano. In other embodiments, R ² , R ³ and/or R ⁴ can be unsubstituted C _1-4 alkyl, such as those described herein. In still other embodiments, R ² , R ³ and/or R ⁴ can be unsubstituted C _1-4 haloalkyl. For example, R ² , R ³ and/or R ⁴ may be selected from -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, - _CCl3 , _-CHCl2 and _-CH2Cl . In still other embodiments, R ² , R ³ and/or R ⁴ can be unsubstituted or substituted acyl groups. In some embodiments, R ² , R ³ and/or R ⁴ can be unsubstituted or substituted C-carboxy. In other embodiments, R ² , R ³ and/or R ⁴ can be unsubstituted or substituted C-amido. In yet other embodiments, R ² , R ³ and/or R ⁴ can be unsubstituted or substituted ureas. In still other embodiments, R ² , R ³ and/or R ⁴ may be unsubstituted C _1-4 alkoxy. In some embodiments, R ² , R ³ and/or R ⁴ can be unsubstituted or substituted N-carbamoyl. In other embodiments, R ² , R ³ and/or R ⁴ may be unsubstituted or substituted cycloalkyl, such as unsubstituted or substituted monocyclic C _3-6 cycloalkyl. In yet other embodiments, R ² , R ³ and/or R ⁴ can be unsubstituted or substituted aryl. As an example, ^R2 , ^R3 and/or ^R4 can be unsubstituted or substituted phenyl. In still other embodiments, R ² , R ³ and/or R ⁴ can be unsubstituted or substituted heteroaryl, such as unsubstituted or substituted 5 or 6 membered monocyclic heteroaryl. In some embodiments, R ² , R ³ and/or R ⁴ can be unsubstituted or substituted heterocyclyl, such as unsubstituted or substituted 5- or 6-membered monocyclic heterocyclyl.

When R ² , R ³ and/or R ⁴ are substituted acyl, substituted C-carboxy, substituted C-amido, substituted urea, substituted N-carbamoyl, substituted cycloalkyl, When a substituted aryl group, a substituted heteroaryl group or a substituted heterocyclic group, the substituted acyl group, the substituted C-carboxyl group, the substituted C-amido group, the substituted urea group, the substituted N- The carbamoyl group, the substituted cycloalkyl group, the substituted aryl group, the substituted heteroaryl group and the optionally substituted heterocyclyl group may be substituted with one or more substituents independently selected from the following: Halogen, OH, CN, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkyl, unsubstituted C _1-4 hydroxyalkyl and unsubstituted Substituted C-carboxy. Exemplary substituents that may be present on substituted groups of ^R2 , ^R3 and/or ^R4 include, but are not limited to, F, Cl, OH, CN, methyl, ethyl, n-propyl, isopropyl base, n-butyl, isobutyl, secondary butyl, tertiary butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary Butoxy, tertiary butoxy, –CF ₃ , –CHF ₂ , –CH ₂ F, –CH ₂ CF ₃ , –CH ₂ CHF ₂ , –CH ₂ CH ₂ F, –CCl ₃ , –CHCl ₂ , –CH ₂ Cl, –CH ₂ –OH, –CH ₂ CH ₂ –OH, –CH ₂ CH ₂ CH ₂ –OH, –CH ₂ CH ₂ CH ₂ CH ₂ –OH, –C(=O)OH and – C(=O)O(unsubstituted C _1-4 alkyl) (such as -C(=O)OCH ₃ , -C(=O)OCH ₂ CH ₃ , -C(=O)OCH ₂ CH ₂ CH _3. –C(=O)O(isopropyl), –C(=O)OCH ₂ CH ₂ CH ₂ CH ₃ , –C(=O)O(isobutyl), –C(=O)O (secondary butyl) and –C(=O)O (tertiary butyl)).

For ring B, various ring structures can exist. In some embodiments, Ring B can be unsubstituted or substituted aryl. An example of a suitable aryl group is phenyl. In some embodiments, Ring B can be unsubstituted phenyl. In other embodiments, Ring B can be a substituted phenyl. The phenyl group of ring B may be substituted 1 time, 2 times or 3 times. For example, ring B can be monosubstituted phenyl or disubstituted phenyl. When ring B is a monosubstituted phenyl group, the phenyl ring may be substituted at the para-position, meta-position or ortho-position. In some embodiments, ring B can be 2,3-substituted phenyl or 3,5-substituted phenyl. In other embodiments, ring B can be 2,4-substituted phenyl, 2,5-substituted phenyl or 2,6-substituted phenyl, 3,4-substituted phenyl or 3,6-substituted phenyl. In yet other embodiments, Ring B can be 2, 3 or 5-substituted phenyl.

In some embodiments, Ring B can be unsubstituted or substituted C _6-8 cycloalkyl. For example, ring B can be unsubstituted or substituted monocyclic C _6-8 cycloalkyl such as cyclohexyl, cycloheptyl and cyclooctyl. In some embodiments, Ring B can be unsubstituted or substituted bicyclic C _6-8 cycloalkyl. Unsubstituted or substituted bicyclic C _6-8 cycloalkyl can be fused bicyclic C _6-8 cycloalkyl, bridged bicyclic C _6-8 cycloalkyl or spiro bicyclic C _6-8 cycloalkyl, both Can be unsubstituted or substituted.

二唑、咪唑、呔

、吲哚基、吲唑基及2,3-二氫苯并呋喃（上文提及之每一者可未經取代或經取代）。 In some embodiments, Ring B can be an unsubstituted heteroaryl. In other embodiments, Ring B can be a substituted heteroaryl. In yet other embodiments, Ring B can be an unsubstituted heterocyclyl. In yet other embodiments, Ring B can be an unsubstituted heterocyclyl. The heteroaryl and/or heterocyclic group may contain 1, 2 or 3 heteroatoms selected from O (oxygen), S (sulfur) and N (nitrogen). The heteroaryl and/or heterocyclic group can be monocyclic, such as 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered monocyclic heterocyclic group or 6-membered monocyclic heterocyclic group. Exemplary cyclic groups for Ring B include, but are not limited to, pyridyl, pyrimidinyl,

Oxadiazole, imidazole, thiamine

, indolyl, indazolyl and 2,3-dihydrobenzofuran (each of the above mentioned may be unsubstituted or substituted).

As provided herein, ring B may be substituted one or more times (1, 2 or 3 times) with groups independently selected from the group consisting of halogen, hydroxyl, amine, cyano, unsubstituted C _{1- 4} Alkyl, unsubstituted C _1-4 haloalkyl, unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, unsubstituted or substituted C-amido, unsubstituted or Substituted urea, unsubstituted alkoxy, unsubstituted or substituted N-aminoformyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted hetero Aryl, unsubstituted or substituted heterocyclic group and unsubstituted or substituted heterocyclic group (C _1-4 alkyl). In some embodiments, ring B can be substituted once or twice, wherein each group can be independently selected from halogen, amine, cyano, unsubstituted C _1-4 alkyl, unsubstituted C _{1-4 -4} haloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted heterocyclic group, such as unsubstituted or substituted Substituted monocyclic heterocyclyl. In some embodiments, ring B can be substituted once or twice with groups, each of which can be independently selected from halogen, amine, cyano, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl and unsubstituted or substituted heterocyclic group, such as unsubstituted or substituted monocyclic heterocyclic group. Exemplary groups that may be present on ring B include fluoro, chloro, amine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary Butyl, –CF ₃ , –CCl ₃ , –CHF ₂ , –C(CH ₃ )F ₂ , –C(CH ₃ )F ₂ , –CHCl ₂ , –CH ₂ F, –CH(CH ₃ )F, –CH ₂ CF ₃ , –CH ₂ Cl, –CH ₂ CH ₂ F, –CH ₂ CH ₂ Cl, –CH ₂ CH ₂ CH ₂ F, –CH ₂ CH ₂ CH ₂ Cl and unsubstituted 5-6 members Monocyclic heterocyclic group, the unsubstituted 5-6 membered monocyclic heterocyclic group includes 1, 2 or 3 heteroatoms selected from O (oxygen), S (sulfur) and N (nitrogen). In some embodiments, ring B can be substituted once or twice with groups, each of which can be independently selected from fluorine, amine, cyano, methyl, —CF ₃ , —CHF ₂ , —C (CH ₃ )F ₂ , and an unsubstituted 5-6 membered monocyclic heterocyclic group, the unsubstituted 5-6 membered monocyclic heterocyclic group includes 1 or 2 members selected from O (oxygen) and N (nitrogen ) of heteroatoms.

、

、

、

、

、

、

、

、

、

、

、

、

、

及

。 Exemplary Ring B groups include the following:

,

,

,

,

,

,

,

,

,

,

,

,

,

and

.

，其中R ^1a、R ^1b、R ^1c及R ^1d可係獨立地選自氫、鹵素（例如，F或Cl）、OH、CN、未經取代C _1-4烷基、未經取代烷氧基（諸如未經取代C _1-4烷氧基、–O(單環4至6員雜環基)及–O(單環C _3-6環烷基(C _1-4烷基))）、未經取代C _1-4鹵烷基（諸如–CF ₃、–CHF ₂、–CH ₂F、–CH ₂CF ₃、–CH ₂CHF ₂、–CH ₂CH ₂F、–CCl ₃、–CHCl ₂及–CH ₂Cl）、未經取代C _1-4羥基烷基（諸如–(CH ₂) _1-4–OH)及未經取代C-羧基（例如，–C(=O)O(未經取代C _1-4烷基)）。在一些實施例中，R ^1a及R ^1d可各自係氫；且R ^1b及R ^1c可選自本文中提供之取代基，諸如本段之彼等取代基。在一些實施例中，R ^1a、R ^1b及R ^1d可各自係氫；且R ^1c可選自本文中提供之取代基，諸如本段之彼等取代基。在一些實施例中，R ^1a及R ^1d可各自係氫；且R ^1b及R ^1c可各自係未經取代C _1-4烷氧基，諸如甲氧基。 For ring A, various ring structures can exist. In some embodiments, Ring A can be unsubstituted or substituted aryl. As an example, ring A can be unsubstituted phenyl. As another example, Ring A can be a substituted phenyl. When a phenyl group is present for ring A, the phenyl ring may be substituted 1, 2 or 3 times. In some embodiments, ring A may be monosubstituted phenyl, such as p-substituted phenyl, m-substituted phenyl, and ortho-substituted phenyl. In other embodiments, Ring A can be a disubstituted phenyl group. For example, ring A can be

, wherein R ^1a , R ^1b , R ^1c and R ^1d can be independently selected from hydrogen, halogen (eg, F or Cl), OH, CN, unsubstituted C _1-4 alkyl, unsubstituted alkoxy (such as unsubstituted C _1-4 alkoxy, -O (monocyclic 4 to 6-membered heterocyclic group) and -O (monocyclic C _3-6 cycloalkyl (C _1-4 alkyl))), Unsubstituted C _1-4 haloalkyl (such as -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -CCl ₃ , -CHCl ₂ and –CH ₂ Cl), unsubstituted C _1-4 hydroxyalkyl groups (such as –(CH ₂ ) _1-4 –OH) and unsubstituted C-carboxy groups (for example, –C(=O)O(unsubstituted Substituted C _1-4 alkyl)). In some embodiments, R ^1a and R ^1d can each be hydrogen; and R ^1b and R ^1c can be selected from substituents provided herein, such as those in this paragraph. In some embodiments, R ^1a , R ^1b , and R ^1d can each be hydrogen; and R ^1c can be selected from substituents provided herein, such as those in this paragraph. In some embodiments, R ^1a and R ^1d can each be hydrogen; and R ^1b and R ^1c can each be unsubstituted C _1-4 alkoxy, such as methoxy.

In some embodiments, Ring A can be a non-aromatic carbocyclyl, such as unsubstituted or substituted C _6-8 cycloalkyl. In some embodiments, Ring A can be an unsubstituted C _6-8 cycloalkyl. In other embodiments, Ring A can be a substituted C _6-8 cycloalkyl. C _6-8 cycloalkyl can be monocyclic C _6-8 cycloalkyl, fused bicyclic C _6-8 cycloalkyl, bridged bicyclic C _6-8 cycloalkyl or spiro bicyclic C _6-8 cycloalkyl .

、

、

、

、

、

、

、

、

、

、

、

、及

。 In other embodiments, Ring A can be unsubstituted or substituted heteroaryl. In yet other embodiments, Ring A can be unsubstituted or substituted heterocyclyl. The heteroaryl and/or heterocyclyl of Ring A may include 1, 2 or 3 heteroatoms selected from nitrogen, sulfur and oxygen. In some embodiments, Ring A can be an unsubstituted or substituted monocyclic heteroaryl, such as a 5 or 6 membered monocyclic heteroaryl. For example, ring A can be pyridyl. In other embodiments, Ring A can be an unsubstituted or substituted bicyclic heteroaryl, such as a 9 or 10 membered bicyclic heteroaryl. In yet other embodiments, Ring A can be unsubstituted or substituted monocyclic heterocyclyl (eg, 4, 5 or 6 membered monocyclic heterocyclyl). In still other embodiments, Ring A can be unsubstituted or substituted bicyclic heterocyclyl (eg, 9 or 10 membered bicyclic heterocyclyl). Examples of suitable Ring A heterocyclyl groups include, but are not limited to, unsubstituted or substituted acridine, unsubstituted or substituted pyrrolidine, and unsubstituted or substituted piperidine. Exemplary compounds of formula (I), including pharmaceutically acceptable salts thereof, include the following:

,

,

,

,

,

,

,

,

,

,

,

,and

.

In some embodiments, Ring A can be monosubstituted. In other embodiments, Ring A can be disubstituted. In some embodiments, Ring A may be substituted with a substituent selected from the group consisting of hydroxyl, amine, cyano, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, and unsubstituted alkoxy. For example, ring A may be substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tri Butyl, –CF ₃ , –CHF ₂ , –CH ₂ F, –CH ₂ CF ₃ , –CH ₂ CHF ₂ , –CH ₂ CH ₂ F, –CCl ₃ , –CHCl ₂ , –CH ₂ Cl, formazan Oxygen, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy and tertiary butoxy. In some embodiments, Ring A may be substituted with a substituent selected from unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, unsubstituted or substituted C-amido, unsubstituted Substituted or substituted urea and unsubstituted or substituted N-aminoformyl. In some embodiments, Ring A can be substituted with unsubstituted C _1-4 alkyl. In some embodiments, Ring A may be substituted with a substituent selected from unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, unsubstituted or substituted heterocyclyl, and unsubstituted Or a substituted heterocyclyl (C _1-4 alkyl).

In some embodiments, Ring A can be substituted with unsubstituted alkoxy. For example, ring A can be unsubstituted by C _1-4 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy and tertiary butoxy), –O–(4 to 6 membered monocyclic heterocyclic group) or –O–(monocyclic C _3-6 cycloalkyl (C _1-4 alkyl)) substitution.

In some embodiments, Ring A can be substituted with unsubstituted or substituted acyl groups. Exemplary unsubstituted or substituted acyl groups that may be present on Ring A include, but are not limited to, -C(=0) (unsubstituted C _1-4 alkyl), -C(=0) (unsubstituted Substituted C _1-4 haloalkyl), –C(=O) (unsubstituted or substituted monocyclic C _3-6 cycloalkyl), –C(=O) (unsubstituted or substituted bicyclic C _{3 -6} cycloalkyl) (for example, unsubstituted or substituted bridging C _3-6 cycloalkyl), –C(=O) (unsubstituted or substituted monocyclic heteroaryl), –C(=O ) (unsubstituted or substituted bicyclic heteroaryl), –C(=O) (unsubstituted or substituted monocyclic heterocyclyl) and –C(=O) (unsubstituted or substituted bicyclic heterocyclic base). For example, ring A can be substituted with the following groups: -C(=O)CH ₃ , -C(=O)-C(CH ₃ ) ₃ , -C(=O) (unsubstituted cyclopropyl) , –C(=O)(C _1-4 alkyl substituted cyclopropyl) (for example, –C(=O)(H ₃ C substituted cyclopropyl)), –C(=O)(C _1-4 alkoxy substituted cyclopropyl) (e.g., –C(=O)(H ₃ CO substituted cyclopropyl)), –C(=O)(C _1-4 haloalkyl substituted cyclopropyl) (such as – C(=O) (FCH ₂ substituted cyclopropyl)), –C(=O) (C _1-4 hydroxyalkyl substituted cyclopropyl) (such as –C(=O) (HOCH ₂ substituted cyclopropyl) ), –C(=O) (unsubstituted bicyclo[1.1.1]pent-1-yl), –C(=O) (halogen substituted bicyclo[1.1.1]pent-1-yl), –C( =O)(C _1-4 alkyl substituted bicyclo[1.1.1]pent-1-yl) (such as –C(=O)(H ₃ C substituted bicyclo[1.1.1]pent-1-yl)), –C(=O)(C _1-4 -carboxy substituted bicyclo[1.1.1]pent-1-yl) (such as –C(=O)(H ₃ COC(=O) substituted bicyclo[1.1.1]pentan-1-yl) -1-yl)), –C(=O)(C _1-4 -hydroxyalkyl substituted bicyclo[1.1.1]pentan-1-yl) (for example, –C(=O)(HOCH ₂ substituted bicyclo[ 1.1.1]pent-1-yl)), –C(=O)(C _1-4 haloalkyl substituted bicyclo[1.1.1]pent-1-yl) (such as –C(=O)(F ₃ C-substituted bicyclo[1.1.1]pent-1-yl)), –C(=O) (unsubstituted 4 to 6 including 1 or 2 heteroatoms selected from O (oxygen) and N (nitrogen) membered monocyclic heterocycles, such as propylene oxide, tetrahydro-2H-pyran and morpholine; -C(=O) (including 1 or 2 heteroatoms selected from O (oxygen) and N (nitrogen) C _1-4 alkyl substituted 4 to 6 membered monocyclic heterocyclic groups, such as propylene oxide, tetrahydro-2H-pyran and morpholine (for example, -C(=O) (including 1 or 2 selected from O (oxygen) and N (nitrogen) heteroatoms H ₃ C substituted 4 to 6-membered monocyclic heterocyclic group), and -C (=O) (including 1 or 2 selected from O (oxygen) and N C _1-4 alkoxyl substituted 4 to 6 membered monocyclic heterocyclic groups with (nitrogen) heteroatoms, such as propylene oxide, tetrahydro-2H-pyran and morpholine (for example, –C(=O)( H ₃ CO including 1 or 2 heteroatoms selected from O (oxygen) and N (nitrogen) substituted 4 to 6 membered monocyclic heterocyclyl).

As described herein, in some embodiments, Ring A can be substituted with unsubstituted or substituted C-carboxy. As an example, Ring A may be substituted with -C(=O)O(unsubstituted C _1-4 alkyl). In some embodiments, Ring A can be substituted with —C(=O)O(CH ₂ CH ₃ ) or —C(=O)O(C(CH ₃ ) ₃ ).

In some embodiments, Ring A can be substituted with unsubstituted or substituted heterocyclyl. In other embodiments, Ring A can be substituted with unsubstituted or substituted heterocyclyl(C _1-4 alkyl). For the unsubstituted or substituted heterocyclic group, and the unsubstituted or substituted heterocyclic group(C _1-4 alkyl) substituted on ring A, various heterocyclic groups may exist. For example, heterocyclyl and heterocyclyl(C _1-4 alkyl) substituted on ring A may be 4 including 1 or 2 heteroatoms selected from N (nitrogen) and O (oxygen). to 6-membered monocyclic heterocyclyl. Exemplary heterocyclyl groups include propylene oxide, tetrahydrofuran, tetrahydro-2H-pyran and morpholine. When the heterocyclyl and/or heterocyclyl (C _1-4 alkyl) is substituted on ring A, the heterocyclyl and/or heterocyclyl (C _1-4 alkyl) may be unsubstituted C _{1 -4} alkyl, unsubstituted C _1-4 alkoxy and/or unsubstituted C-carboxy, such as -C(=0)(C _1-4 alkyl) substituted.

及1,2,3,6-四氫吡啶。 In some embodiments, ring A may be substituted with ring moieties such as unsubstituted or substituted aryl (e.g., unsubstituted or substituted phenyl), unsubstituted or substituted cycloalkyl (such as unsubstituted Substituted or substituted monocyclic C _3-6 cycloalkyl), unsubstituted or substituted heteroaryl (for example, unsubstituted or substituted monocyclic heteroaryl) and unsubstituted or substituted heterocyclic group ( For example, unsubstituted or substituted monocyclic heterocyclyl). Exemplary monocyclic heteroaryl and/or monocyclic heterocyclyl groups that may be substituted on ring A include 1, 2 or 3 heterocyclic groups selected from N (nitrogen), O (oxygen) and S (sulfur). atom. In some embodiments, monocyclic heteroaryl and/or monocyclic heterocyclyl can include 1 nitrogen and/or 1 oxygen. Examples of unsubstituted or substituted monocyclic heteroaryl and monocyclic heterocyclyl groups that may be substituted on ring A include 1,2,3,6-tetrahydropyridine, 3,6-dihydro-2H- pyran, morpholine, tetrahydro-2H-pyran, 3,6-dihydro-2H-pyran, piperidine, piperidine

and 1,2,3,6-tetrahydropyridine.

As described herein, substituted C _6-8 cycloalkyl, substituted aryl, substituted heteroaryl and substituted heterocyclyl may be substituted with one or two groups selected from the group consisting of halogen, OH, CN, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, and unsubstituted or substituted heterocyclic group. For example, substituted C _6-8 cycloalkyl, substituted aryl, substituted heteroaryl and substituted heterocyclyl may be substituted with one or two groups selected from the group consisting of F, Cl, OH, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, –CF ₃ , –CHF ₂ , –CH ₂ F, –CH ₂ CF ₃ , —CH ₂ CHF ₂ , —CH ₂ CH ₂ F, —CCl ₃ , —CHCl ₂ , —CH ₂ Cl, and unsubstituted or substituted monocyclic heterocyclyl.

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、及

。 Examples of suitable groups that may be substituted on ring A include the following:

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Those of ordinary skill in the art should understand that the carbon-based chiral center indicated by an asterisk in formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, carbons indicated with an asterisk may be in the (R)-configuration. In other embodiments, carbons indicated with an asterisk may be in the (S)-configuration.

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、及

，或前述中任一者之醫藥上可接受之鹽。 Examples of compounds of formula (I) include the following:

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,and

, or a pharmaceutically acceptable salt of any of the foregoing.

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，或前述中任一者之醫藥上可接受之鹽。 Additional examples of compounds of formula (I) include the following:

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, or a pharmaceutically acceptable salt of any of the foregoing.

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，或前述中任一者之醫藥上可接受之鹽。 Exemplary compounds of formula (I) include the following:

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, or a pharmaceutically acceptable salt of any of the foregoing.

、或其醫藥上可接受之鹽。 Examples of compounds of formula (I) are

, or a pharmaceutically acceptable salt thereof.

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、及

，或前述中任一者之醫藥上可接受之鹽。 Examples of compounds of formula (I) include the following:

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,and

, or a pharmaceutically acceptable salt of any of the foregoing.

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，或前述中任一者之醫藥上可接受之鹽。 Additional examples of compounds of formula (I) include the following:

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, or a pharmaceutically acceptable salt of any of the foregoing.

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，或前述中任一者之醫藥上可接受之鹽。 Exemplary compounds of formula (I) include the following:

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,and

, or a pharmaceutically acceptable salt of any of the foregoing.

、或其醫藥上可接受之鹽。 Examples of compounds of formula (I) are

, or a pharmaceutically acceptable salt thereof.

(II) 其中： ---------、X ¹、X ²、X ³、X ⁴、X ⁵、X ⁶、R ¹、R ²、R ³、R ⁴、環A及環B可如關於式(I)所提供，且R ^N可與R ²相同，或R ^N可係未經取代或經取代C _1-4烷基、未經取代C _1-4鹵烷基、未經取代C _1-4烷氧基、未經取代或經取代環烷基、未經取代或經取代芳基、未經取代或經取代雜芳基、或未經取代或經取代雜環基，其中該經取代C _1-4烷基經一或多個獨立地選自下列之取代基取代：鹵素、OH、CN、未經取代C _1-4烷氧基、未經取代C _1-4鹵烷基、未經取代C _1-4羥基烷基及未經取代C-羧基，且其中該經取代環烷基、該經取代芳基、該經取代雜芳基及該可選地經取代雜環基經一或多個獨立地選自下列之取代基取代：鹵素、OH、CN、未經取代C _1-4烷基、未經取代C _1-4烷氧基、未經取代C _1-4鹵烷基、未經取代C _1-4羥基烷基及未經取代C-羧基。 Some embodiments disclosed herein relate to a compound of formula (II) or a pharmaceutically acceptable salt thereof, which has the following structure:

(II) Among them: --------- , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , R ¹ , R ² , R ³ , R ⁴ , ring A and ring B may be as provided for formula (I), and R ^N may be the same as R ² , or R ^N may be unsubstituted or substituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, unsubstituted Substituted C _1-4 alkoxy, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted heterocyclyl, wherein The substituted C _1-4 alkyl is substituted by one or more substituents independently selected from the group consisting of halogen, OH, CN, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkane group, unsubstituted C _1-4 hydroxyalkyl and unsubstituted C-carboxy, and wherein the substituted cycloalkyl, the substituted aryl, the substituted heteroaryl and the optionally substituted heterocycle The group is substituted by one or more substituents independently selected from the following: halogen, OH, CN, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 Haloalkyl, unsubstituted C _1-4 hydroxyalkyl and unsubstituted C-carboxy.

、或其醫藥上可接受之鹽。 合成 Exemplary compounds of formula (II), and pharmaceutically acceptable salts thereof, include the following:

, or a pharmaceutically acceptable salt thereof. synthesis

Compounds of formula (I), or pharmaceutically acceptable salts thereof, and those compounds described herein can be prepared in a variety of ways. Some compounds of formula (I), or pharmaceutically acceptable salts thereof, can be obtained using known synthetic procedures. Some examples of general synthetic routes for compounds of formula (I), or pharmaceutically acceptable salts thereof, and starting materials for the synthesis of compounds of formula (I), or pharmaceutically acceptable salts thereof, are shown herein and elaboration. An example is shown in Scheme 1 below. The approaches shown and described herein are exemplary only and are not intended or construed as limiting the scope of the claimed patent scope in any way. Those of ordinary skill in the art will recognize modifications to the disclosed syntheses and devise alternative routes based on the disclosure herein and knowledge of the art; all such modifications and alternative routes are within the scope of the claims.

plan 1

Compounds of formula (I), including pharmaceutically acceptable salts thereof, can be prepared by reacting compounds of general formula (A) with compounds of general formula (B), wherein LG ₁ may be a suitable leaving group. Compounds of general formula (B) may include additional leaving groups on ring A as well as at ^R2 , ^R3 and ^R4 . Using methods known to those of ordinary skill in the art, the leaving group may be converted to a moiety corresponding to those set forth as present on ring A, ^R2 , ^R3 , and ^R4 , or may be converted to a moiety corresponding to that set forth are substituted for part of those present on ring A, ^R2 , ^R3 and ^R4 . Pharmaceutical composition

Some embodiments described herein relate to a pharmaceutical composition, which may include an effective amount of one or more compounds described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutical The above acceptable carrier, diluent, excipient, or a combination thereof.

The term "pharmaceutical composition" refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components such as diluents, carriers, and/or excipients. Pharmaceutical compositions facilitate the administration of compounds to organisms. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid . Pharmaceutical compositions will generally be designed for a particular intended route of administration.

As used herein, "carrier" refers to a compound that facilitates the incorporation of the compound into cells or tissues. For example, but not limited to, dimethylsulfoxide (DMSO) is a frequently utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that lacks significant pharmacological activity but may be medically necessary or desirable. For example, diluents can be used to increase the volume of an effective drug whose mass is too small to manufacture and/or administer. It can also be a liquid used to dissolve a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, but not limited to, phosphate buffered saline that mimics the pH and isotonicity of human blood.

As used herein, "excipient" means a substantially inert substance added to a pharmaceutical composition to provide, but not limited to, volume, consistency, stability, binding capacity to the composition , lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelating agents are excipients. In one embodiment, the pharmaceutical composition includes antioxidants and/or metal chelating agents. A "diluent" is a type of excipient.

In some embodiments, Compound (B) (together with pharmaceutically acceptable salts thereof) may be provided in a pharmaceutical composition comprising Compound (A) (including pharmaceutically acceptable salts thereof). In other embodiments, Compound (B) (together with pharmaceutically acceptable salts thereof) may be administered in a pharmaceutical composition separate from a pharmaceutical composition comprising Compound (A) (including pharmaceutically acceptable salts thereof) .

The pharmaceutical compositions described herein may be administered to human patients by themselves, or may be pharmaceutical compositions in which they are admixed with other active ingredients (as in combination therapy), or carriers, diluents, excipients, or combinations thereof administered to human patients. Proper formulation depends upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those of ordinary skill in the art.

The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or tableting processes. Furthermore, the active ingredient is contained in an amount effective for its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein can be provided as salts with pharmaceutically compatible counterions.

Various techniques for administering compounds, salts, and/or compositions exist in the art, including but not limited to oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, Intravenous, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injections. In some embodiments, Compound (A), including pharmaceutically acceptable salts thereof, can be administered orally. In some embodiments, Compound (A) (including pharmaceutically acceptable salts thereof) may be provided to a subject by the same route of administration as Compound (B) (together with pharmaceutically acceptable salts thereof). In other embodiments, Compound (A) (including pharmaceutically acceptable salts thereof) may be provided to a subject by a different route of administration than Compound (B) (together with pharmaceutically acceptable salts thereof).

Compounds, salts, and/or compositions can also be administered locally rather than systemically, for example, by direct injection or implantation of the compound, usually in a depot or sustained release formulation, into the affected area. Additionally, the compounds can be administered in a targeted drug delivery system such as liposomes coated with tissue-specific antibodies. The liposomes will be targeted to and selectively taken up by the organ. For example, intranasal or pulmonary delivery may be desired to target respiratory diseases or conditions.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms (containing the active ingredient). The pack may eg comprise metal or plastic foil, eg a blister pack. The pack or dispenser unit may be accompanied by administration instructions. The package or dispenser may also be accompanied by a notice associated with the container regulating the manufacture, use, or sale of the drug in a form prescribed by a government agency reflecting the agency's approval of the drug form for human or veterinary administration. give. For example, the notification could be a label or a product leaflet approved by the Food and Drug Administration for a prescription drug. Compositions, which may include compounds described herein and/or salts formulated in a compatible pharmaceutical carrier, may also be prepared, placed in an appropriate container and labeled for treatment of the indicated condition. Therapeutic uses and methods

Some embodiments described herein relate to a method of treating cancer, which may comprise administering to a subject identified as suffering from cancer an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or comprising A pharmaceutical composition of an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof , which is used in the preparation of medicines for treating cancer. Yet other embodiments described herein relate to compounds as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising an effective amount of compounds as described herein, or pharmaceutically acceptable salts thereof purposes, it is used for the treatment of cancer. In some embodiments, the cancer may be selected from lung cancer, colorectal cancer, and pancreatic cancer. Lung cancer can be non-small cell lung cancer. In some embodiments, the cancer can be associated with a KRAS mutation (eg, a G12C mutation).

As used herein, "subject" refers to an animal that is the object of treatment, observation, or experimentation. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates such as fish, crustaceans, reptiles and especially mammals. "Mammal" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as monkeys, chimpanzees, and apes, and especially humans . In some embodiments, the subject may be a person. In some embodiments, the subject may be a child and/or an infant, such as a child or infant with a fever. In other embodiments, the subject can be an adult.

As used herein, the terms "treat, treating, treatment, therapeutic" and "therapy" do not necessarily mean complete cure or elimination of a disease or condition. Any alleviation to any degree of any undesirable sign or symptom of a disease or condition may be considered treatment and/or therapy. Additionally, treatment can include actions that can worsen a subject's overall sense of well-being or appearance.

The term "effective amount" is used to indicate the amount of an active compound or pharmaceutical preparation that elicits an indicated biological or pharmaceutical response. For example, an effective amount of a compound, salt, or composition may be that amount required to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or prolong the survival of a treated subject. The response can occur in a tissue, system, animal, or human, and includes alleviation of signs or symptoms of the disease or condition being treated. In view of the disclosure provided herein, determination of an effective amount is well within the ability of one of ordinary skill in the art. The effective amount of a compound disclosed herein required as a dosage will depend on the route of administration, the type of animal (including humans) being treated, and the physical characteristics of the particular animal under consideration. Dosage can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concomitant drugs, and other factors as will be recognized by those of ordinary skill in the medical art.

As will be apparent to those of ordinary skill in the art, useful in vivo doses to be administered and the particular mode of administration will vary depending on the age, body weight, severity of affliction, and the species of mammal being treated, the particular compound employed, and The particular use for which these compounds are employed will vary. Determination of effective dosage levels (ie, dosage levels required to achieve the desired effect) can be achieved by those of ordinary skill in the art using routine methods, for example, human clinical trials, in vivo studies, and in vitro studies. For example, a useful dosage of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined by comparing its in vitro activity with its in vivo activity in animal models. This comparison can be done by comparison with established drugs such as cisplatin and/or gemcitabine

Dosage and intervals may be adjusted individually to provide plasma levels or minimum effective concentration (MEC) of the active moiety sufficient to maintain a modulating effect. The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC values. The composition should be administered using a regimen that maintains plasma levels above the MEC for 10 to 90% of the time, preferably between 30 to 90% of the time, and optimally between 50 to 90% of the time . In cases of local administration or selective uptake, the local effective concentration of the drug may not be related to plasma concentration.

It should be noted that the attending physician will know how and when to terminate, interrupt or adjust administration due to toxicity or abnormal organ function. Conversely, the attending physician will also know to adjust treatment to higher levels if the clinical response is insufficient (excluding toxicity). The magnitude of the dosage administered in the management of the condition of interest will vary depending on the severity of the disease or condition being treated and the route of administration. The severity of a disease or condition can be assessed, for example, based in part on standard prognostic assessment methods. In addition, the dosage and possibly the frequency of administration will also vary according to the age, weight and response of the individual patient. Programs similar to those discussed above are available in veterinary medicine.

The efficacy and toxicity of the compounds, salts, and compositions disclosed herein can be assessed using known methods. For example, the toxicology of a particular compound or a subgroup of compounds sharing certain chemical moieties can be established by determining in vitro toxicity on cell lines, such as mammalian and preferably human cell lines. The results of such studies are generally predictive of toxicity in animals (eg, mammals) or, more specifically, humans. Alternatively, known methods can be used to determine the toxicity of a particular compound in animal models such as mice, rats, rabbits, dogs, or monkeys. The therapeutic effect of a particular compound can be established using several recognized methods such as in vitro methods, animal models or human clinical trials. When selecting a model to determine efficacy, one skilled in the art can be guided by the best current techniques to select the appropriate model, dose, route of administration and/or regimen. example

Additional embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way. Example 1 [1-(3-amino-5-trifluoromethyl-phenyl)-ethyl]-(8,9-dimethoxy-3-methyl-[1,2,4]triazole And[3,4-a]phthalazin-6-yl)-amine

To 5,6-dimethoxyisobenzofuran-1(3 H )-one ( 1 ) (10 g, 5.1498 mmol) in demineralized water (100 mL, 10 V) over a period of 3 h To the cold (0° C.) magnetically stirred suspension was added a solution of powdered KMnO ₄ (20 g, 12.87 mmol) in aqueous NaOH (7%, 7 g in 100 mL H ₂ O). The mixture was slowly warmed to room temperature (rt) and stirred overnight (TLC eluent: 10% MeOH in EtOAc, UV active). After complete consumption of the starting material, the mixture was filtered through ^Celite® and the diatomaceous earth bed was washed with cold water. The filtrate was then acidified to pH~1-3, and the product was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to furnish 2 . Yield: 6.8 g (50%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.83 (bs, 2H), 7.16 (s, 2H), 3.81 (s, 6H).

A solution of 2 (6.8 g, 3.00 mmol) in acetic anhydride (68 mL, 10 V) was refluxed at 150 °C for 2 h (TLC eluent: EtOAc, UV active). Upon completion, the mixture was concentrated under reduced pressure to remove acetic anhydride. The obtained crude was then triturated with n-hexane (70 mL), and the resulting product was dried under vacuum to supply 3 . Yield: 6.5 g (61%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.36 (s, 2H), 4.03 (s, 6H).

To a solution of 3 (6.5 g, 3.12 mmol) in ethanol (300 mL) was added hydrazine hydrate (64% aq.) (32.5 mL), and the mixture was refluxed for 60 min (TLC eluent: EtOAc, UV active ). After the reaction was complete, the mixture was cooled and filtered. The residue was triturated with ethanol (65 mL) to provide 4 . Yield: 6 g (86%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.41 (s, 2H), 3.90 (s, 6H).

A solution of 4 (6 g, 2.700 mmol) in POCl ₃ (30 mL, 5 V) was stirred at 115 °C for 2 h (TLC eluent: 70% EtOAc in n-hexane, UV active). After the reaction was complete, the mixture was concentrated on a rotary evaporator to remove _POCl3 . The obtained residue was poured into ice water (100 mL). The precipitate was filtered and dried under reduced pressure to give 5 . Yield: 6 g (87%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.49 (s, 2H), 4.14 (s, 6H).

To a solution of 5 (4.5 g, 16.48 mmol) in DMSO (45 mL, 10 V) was added 6 (3-(1-amino-ethyl)-5-trifluoromethyl-phenylamine) (4.4 g, 16.48 mmol) and DIPEA (5.1 g, 39.55 mmol), and the mixture was stirred at 120 °C for 24 h (TLC eluent: 50% EtOAc in hexane). Upon completion, the mixture was cooled to ambient temperature, diluted with water, and extracted with DCM (3 x 45 mL). The combined organic layers were dried over anhydrous _Na2SO4 and concentrated under _reduced pressure to give crude. The crude was purified by ^Combiflash® purification technique (eluent: 35-45% EtOAc in hexanes) to give the crude product which was purified by reverse phase ^Combiflash® purification technique (50% CH ₃ CN in 0.01 M CH ₃ COONH ₄ solution) was further purified a second time to provide 7 . Yield: 500 mg (6.3%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.35-8.25 (m, 2H), 7.90-7.80 (m, 2H), 7.31 (s, 1H), 5.70-5.50 (m , 1H), 4.05 (s, 3H), 3.97 (s, 3H), 1.66 (d, J= 7.2 Hz , 3H).

To a solution of 7 (150 mg, 0.328 mmol) in n-BuOH (7.5 mL, 50 V) was added acetylhydrazine (49 mg, 0.657 mmol), and the mixture was refluxed at 120 °C for 24 h (TLC eluent : 10% MeOH in DCM, UV active). Upon completion, the mixture was evaporated to afford a crude residue. The crude residue was subjected to purification using reverse phase ^Combiflash® purification technique to provide 8 . Yield: 55 mg (35%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (s, 1H), 8.39, (s, 1H), 8.32 (s, 1H), 8.02 (d, J =6.4 Hz, 1H), 7.87 (s , 1H), 7.70 (s, 1H), 5.40-5.25 (m, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 2.39 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H).

To a solution of 8 (50 mg, 0.046 mmol) in THF (5 mL) was added Pd/C (10%, 50 wet) (50 mg, W/W) in one portion at ambient temperature, and the mixture was Stir at ambient temperature under _H2 atmosphere (balloon) for 6 h. After completion of the reaction (TLC eluent: 10% MeOH in DCM), the mixture was filtered through a bed of celite. The obtained filtrate was concentrated under reduced pressure at 45°C. The obtained residue was dried to obtain [1-(3-amino-5-trifluoromethyl-phenyl)-ethyl]-(8,9-dimethoxy-3-methyl-[1 ,2,4]triazolo[3,4-a]phthalazin-6-yl)-amine (40 mg, 79% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (s, 1H), 7.75 (d, J = 6.8 Hz , 1H), 7.71 (s, 1H), 6.95-6.85 (m, 2H), 6.67 ( s, 1H), 5.52 (s, 2H), 5.10-5.05 (m, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 2.42 (s, 3H), 1.59 (d, J = 7.04 Hz , 3H).

Example 2 ( R )-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-methyl-6,8-dihydro-7H -pyrrolo[3,4-e][1,2,4]triazolo[4,3-a]pyrimidin-7-yl)(bicyclo[1.1.1]pent-1-yl)methanone

To a solution of 1 (3 g, 10.34 mmol) and 2 (2.79 g, 10.34 mmol) in DMSO (30 mL, 10 V) at ambient temperature was added DIPEA (5.33 g, 41.36 mmol) in one portion. The mixture was stirred at 120 °C for 16 h at ambient temperature. Upon completion as indicated by TLC, the mixture was added to water (150 mL), extracted with EtOAc (150 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure at 45 °C to afford the crude product. The residue was purified by ^Combiflash® (product eluting in (30-35% EtOAc in hexanes)). The collected fractions were concentrated under pressure to give 3 (3.5 g, 69%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 8.35-8.26 (m, 3H), 5.46-5.41 (m, 1H), 4.49-4.39 (m, 2H), 4.04-3.98 (m, 2H) 1.53 (d, J = 6.8 Hz, 3H), 1.49-1.41 (m, 9H). MS m/z (M+H): 488.223.

To a solution of 3 (500 mg, 1.03 mmol) in EtOH (5 mL, 10 V) at ambient temperature was added hydrazine hydrate (1.5 mL, 3 V) in one portion. The solution was stirred at 65 °C for 16 h. Upon completion as indicated by TLC, the mixture was concentrated under reduced pressure at 45 °C to provide 4 (580 mg, crude). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 8.31 (d, J = 15.6 Hz, 2H), 7.57-7.52 (m, 1H), 5.51-5.46 (m, 1H), 4.35-4.30 (m, 2H), 4.19-4.16 (m, 2H), 1.76 (d, J = 15.6 Hz, 3H), 1.51-1.53 (m, 9H). MS m/z (M+H): 484.37.

To a solution of 4 (500 mg, 1.035 mmol) in EtOH (0.25 mL, 0.5 V) was added xylene (5 mL) and triethyl orthoacetate (1.5 mL, 3 V) at ambient temperature. The solution was stirred at 140 °C for 10 h. Upon completion as indicated by TLC, the mixture was concentrated under reduced pressure at 50 °C to afford the crude product. The residue was purified by ^Combiflash® (product eluting in (6-7% MeOH in DCM)). The collected fractions were concentrated under pressure to obtain 6 (230 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 8.35 (d, J = 13.6 Hz, 2H), 8.11-8.07 (m, 1H), 5.58-5.22 (m, 1H), 5.00 (s , 2H), 4.62-4.44 (m, 2H), 2.54 (d, J = 6.8 Hz, 3H), 1.56 (d, J = 9.2 Hz, 3H), 1.50-1.48 (m, 9H).

烷(2.5 mL, 10 V)中之懸浮液中，以逐滴方式添加於1,4-二

烷中之4 M (HCl) (2.5 mL, 5V)。將懸浮液在環境溫度下攪拌16 h。在如藉由TLC指示完成時，將混合物在45℃下在減壓下濃縮，以提供殘餘物。將獲得之殘餘物與MTBE (2.5 mL)一起研磨，且過濾。將獲得之殘餘物乾燥，以給出 7（180 mg，粗製物）。 ¹H NMR (400 MHz, DMSO-d ₆) δ 11.18 (bs, 2H), 9.96 (bs, 1H), 8.67 (s, 1H), 8.41 (s, 2H), 5.61-5.56 (m, 1H), 5.05 (bs, 2H), 4.80-4.75 (d, J= 19 Hz,1H), 4.65-4.60 (d, J= 22 Hz, 1H), 2.65 (s, 3H), 1.67 (d, J= 9.2 Hz, 3H)。 6 (220 mg, 1.28 mmol) in 1,4-bis

A suspension in alkanes (2.5 mL, 10 V) was added dropwise to 1,4-bis

4 M (HCl) in alkanes (2.5 mL, 5V). The suspension was stirred at ambient temperature for 16 h. Upon completion as indicated by TLC, the mixture was concentrated under reduced pressure at 45 °C to provide a residue. The obtained residue was triturated with MTBE (2.5 mL) and filtered. The obtained residue was dried to give 7 (180 mg, crude). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.18 (bs, 2H), 9.96 (bs, 1H), 8.67 (s, 1H), 8.41 (s, 2H), 5.61-5.56 (m, 1H), 5.05 (bs, 2H), 4.80-4.75 (d, J = 19 Hz, 1H), 4.65-4.60 (d, J = 22 Hz, 1H), 2.65 (s, 3H), 1.67 (d, J = 9.2 Hz , 3H).

To a suspension of 7 (40 mg, 0.09 mmol) and 8 (10.1 mg, 0.09 mmol) in DMF (0.8 mL, 10 V) at 0-5°C was added successively EDCI (25.7 mg, 0.135 mmol), HOBt (12 mg, 0.09 mmol) and DIPEA (46 mg, 0.36 mmol). The mixture was stirred at ambient temperature for 12 h. Upon completion as indicated by TLC, the mixture was added to water (5 mL), extracted with EtOAc (2 x 5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C to afford 9 . The residue was purified by ^Combiflash® (product eluting in (6.5-7.5% MeOH in DCM)). The collected fractions were concentrated under pressure to provide 9 (23 mg, 51%). ¹ H NMR (400 MHz, CD ₃ OD) 8.56-8.55 (m, 1H), 8.39-8.38 (m, 1H), 8.18-8.17 (m, 1H), 5.56-5.59 (m, 1H), 5.43-5.42 (m, 1H), 5.12-5.10 (m, 1H), 4.97-4.94 (m, 1H), 4.71-4.69 (m, 1H), 2.67-2.65 (m, 3H), 2.55-2.53 (m, 1H) , 2.32-2.29 (m, 6H), 1.70-1.64 (m, 3H) (mixture of rotamers).

啉-5-胺

To a solution of 9 (23 mg, 0.046 mmol) in THF:H ₂ O (2:1) (0.46 mL, 20 V), NH ₄ Cl (29 mg, 0.552 mmol) and Zn powder (18 mg, 0.276 mmol). The mixture was stirred at ambient temperature for 16 h. Upon completion as indicated by TLC, the mixture was filtered through a bed of celite. The obtained filtrate was concentrated under reduced pressure at 45°C. The residue was extracted with DCM (3 x 5 mL), dried over anhydrous sodium sulfate and concentrated to give ( R )-(5-((1-(3-amino-5-(trifluoromethyl)benzene Base) ethyl) amino) -1-methyl-6,8-dihydro-7H-pyrrolo[3,4-e][1,2,4]triazolo[4,3-a]pyrimidine -7-yl)(bicyclo[1.1.1]pentan-1-yl)methanone (12 mg, 55%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.01-7.85 (m, 1H), 6.82-6.79 (m, 2H), 6.70-6.66 (m, 1H), 5.56-5.52 (m, 2H), 5.33- 5.31 (m, 2H), 5.01 (s, 1H), 4.81-4.72 (m, 1H), 2.59-2.56 (m, 3H), 2.20 (s, 3H), 2.15 (s, 1H) 1.50-1.42 (m , 3H). Example 3 (R)-7,8-dimethoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]quinone

Lin-5-amine

啉(1.8 g, 6.95 mmol)、1N NaOH (28 mL)及THF (15 mL)之混合物於rt下在N ₂下攪拌15 h。將溶液冷卻至0℃且用AcOH調整至pH 5。過濾沉澱，以給出2-氯-6,7-二甲氧基喹

啉-4(3H)-酮(1.4 g, 84%)。MS (APCI) m/z 241.0 [M+H] ⁺。 2,4-dichloro-6,7-dimethoxyquin

A mixture of morphine (1.8 g, 6.95 mmol), 1N NaOH (28 mL) and THF (15 mL) was stirred at rt under N ₂ for 15 h. The solution was cooled to 0 °C and adjusted to pH 5 with AcOH. The precipitate was filtered to give 2-chloro-6,7-dimethoxyquin

Lin-4(3H)-one (1.4 g, 84%). MS (APCI) m/z 241.0 [M+H] ⁺ .

啉-4(3H)-酮(0.88 g, 3.66 mmol)及2,2-二甲氧基乙胺(1.922 g, 18.28 mmol)之混合物回流16 h，且然後冷卻且過濾，以給出2-((2,2-二甲氧基乙基)胺基)-6,7-二甲氧基喹

啉-4(3H)-酮(1 g, 88%)。MS (APCI) m/z 310.1 [M+H] ⁺。 2-chloro-6,7-dimethoxyquin

A mixture of lin-4(3H)-one (0.88 g, 3.66 mmol) and 2,2-dimethoxyethylamine (1.922 g, 18.28 mmol) was refluxed for 16 h, and then cooled and filtered to give 2- ((2,2-dimethoxyethyl)amino)-6,7-dimethoxyquin

Lin-4(3H)-one (1 g, 88%). MS (APCI) m/z 310.1 [M+H] ⁺ .

啉-4(3H)-酮(1 g, 3.23 mmol)在乙酸(7.2 mL)中加熱16小時。將混合物冷卻，過濾且用己烷洗滌，以獲得7,8-二甲氧基咪唑并[1,2-a]喹

啉-5(4H)-酮(0.62 g, 78%)。MS (APCI) m/z 246.1 [M+H] ⁺。 2-((2,2-dimethoxyethyl)amino)-6,7-dimethoxyquin

Lin-4(3H)-one (1 g, 3.23 mmol) was heated in acetic acid (7.2 mL) for 16 hours. The mixture was cooled, filtered and washed with hexane to obtain 7,8-dimethoxyimidazo[1,2-a]quinone

Lin-5(4H)-one (0.62 g, 78%). MS (APCI) m/z 246.1 [M+H] ⁺ .

啉-5(4H)-酮(0.30 g, 1.223 mmol)及磷醯氯(1.716 mL, 18.35 mmol)之混合物在回流下加熱16 h。將產物冷卻，過濾且用己烷洗滌，以獲得5-氯-7,8-二甲氧基咪唑并[1,2-a]喹

啉(0.14 g, 43%)。MS (APCI) m/z 264.0 [M+H] ⁺。 7,8-dimethoxyimidazo[1,2-a]quinone

A mixture of lin-5(4H)-one (0.30 g, 1.223 mmol) and phosphoryl chloride (1.716 mL, 18.35 mmol) was heated at reflux for 16 h. The product was cooled, filtered and washed with hexanes to obtain 5-chloro-7,8-dimethoxyimidazo[1,2-a]quinone

phenoline (0.14 g, 43%). MS (APCI) m/z 264.0 [M+H] ⁺ .

啉(0.07 g, 0.265 mmol)於DMSO (1.3 mL)中之攪拌溶液中，添加(R)-1-(2-甲基-3-(三氟甲基)苯基)乙胺(0.059 g, 0.292 mmol)及三乙胺(0.10 mL, 0.796 mmol)。在125℃下加熱14 h后，將混合物冷卻且藉由反相HPLC使用於水（含有0.1%甲酸）中10-40% CH ₃CN（含有0.1%甲酸）來純化，以提供(R)-7,8-二甲氧基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)咪唑并[1,2-a]喹

啉-5-胺(20.6 mg, 18.0%)。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ1.57 (d, J= 7.1 Hz, 3 H), 2.62 (s, 3 H), 3.97 (d, J= 8.6 Hz, 6 H), 5.73 (quin, J= 7.0 Hz, 1 H), 7.13 (d, J= 1.5 Hz, 1 H), 7.37 (t, J= 7.8 Hz, 1 H), 7.58-7.53 (m, 2 H), 7.81 (d, J= 7.58 Hz, 1 H), 7.94 (s, 1 H), 8.10-8.05 (m, 2 H), 8.17 (s, 1 H)。 實例4 (R)-7-(1-甲基-1,2,3,6-四氫吡啶-4-基)-N-(1-(2-甲基-3 (三氟甲基)苯基)乙基)咪唑并[1,2-a]喹

啉-5-胺

5-Chloro-7,8-dimethoxyimidazo[1,2-a]quine at rt

To a stirred solution of morphine (0.07 g, 0.265 mmol) in DMSO (1.3 mL), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethylamine (0.059 g, 0.292 mmol) and triethylamine (0.10 mL, 0.796 mmol). After heating at 125 °C for 14 h, the mixture was cooled and purified by reverse phase HPLC using 10-40% CH ₃ CN (containing 0.1% formic acid) in water (containing 0.1% formic acid) to provide (R)- 7,8-Dimethoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]quinone

Lin-5-amine (20.6 mg, 18.0%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.57 (d, J = 7.1 Hz, 3 H), 2.62 (s, 3 H), 3.97 (d, J = 8.6 Hz, 6 H), 5.73 (quin , J = 7.0 Hz, 1 H), 7.13 (d, J = 1.5 Hz, 1 H), 7.37 (t, J = 7.8 Hz, 1 H), 7.58-7.53 (m, 2 H), 7.81 (d, J = 7.58 Hz, 1 H), 7.94 (s, 1 H), 8.10-8.05 (m, 2 H), 8.17 (s, 1 H). Example 4 (R)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(1-(2-methyl-3 (trifluoromethyl)benzene Base) ethyl) imidazo [1,2-a] quinone

Lin-5-amine

啉(3 g, 10.79 mmol)、NaOH (1N, 43 mL)及THF (24 mL)之混合物於rt下在N ₂下攪拌15 h。將溶液冷卻至0 ^oC且用AcOH調整至pH 5。沉澱係6-溴-2-氯喹

啉-4(3H)-酮(2.70 g, 96%)。MS (APCI) m/z 258.9, 259.9 [M+H] ⁺。 6-bromo-2,4-dichloroquine

A mixture of morphine (3 g, 10.79 mmol), NaOH (1N, 43 mL) and THF (24 mL) was stirred at rt under N ₂ for 15 h. The solution was cooled to 0 ^° C and adjusted to pH 5 with AcOH. Precipitating system 6-bromo-2-chloroquine

Lin-4(3H)-one (2.70 g, 96%). MS (APCI) m/z 258.9, 259.9 [M+H] ⁺ .

啉-4(3H)-酮(2 g, 7.71 mmol)及2,2-二甲氧基乙胺(4.05 g, 38.5 mmol)之混合物回流16 h，且然後冷卻且過濾，以給出6-溴-2-((2,2-二甲氧基乙基)胺基)喹

啉-4(3H)-酮(1.7 g, 67%)。MS (APCI) m/z 330.0, 331.0 [M+H] ⁺。 6-bromo-2-chloroquine

A mixture of lin-4(3H)-one (2 g, 7.71 mmol) and 2,2-dimethoxyethylamine (4.05 g, 38.5 mmol) was refluxed for 16 h, and then cooled and filtered to give 6- Bromo-2-((2,2-dimethoxyethyl)amino)quinone

Lin-4(3H)-one (1.7 g, 67%). MS (APCI) m/z 330.0, 331.0 [M+H] ⁺ .

啉-4(3H)-酮(1 g, 3.05 mmol)在氫溴酸(20 mL)中在100℃下加熱16 h。將混合物冷卻，過濾且用己烷洗滌，以獲得7-溴咪唑并[1,2-a]喹

啉-5(4H)-酮(0.78 g, 97%)。MS (APCI) m/z 265, 265.9 [M+H] ⁺。 6-bromo-2-((2,2-dimethoxyethyl)amino)quinone

Lin-4(3H)-one (1 g, 3.05 mmol) was heated in hydrobromic acid (20 mL) at 100 °C for 16 h. The mixture was cooled, filtered and washed with hexane to obtain 7-bromoimidazo[1,2-a]quinone

Lin-5(4H)-one (0.78 g, 97%). MS (APCI) m/z 265, 265.9 [M+H] ⁺ .

啉-5(4H)-酮(1.09 g, 4.13 mmol)及磷醯氯(3.86 mL, 41.3 mmol)之混合物在90℃下加熱16 h。將所得產物冷卻，過濾且用己烷洗滌，以獲得7-溴-5-氯咪唑并[1,2-a]喹

啉(0.54 g, 46.3%)。MS (APCI) m/z 281.9, 283 [M+H] ⁺。 7-bromoimidazo[1,2-a]quinone

A mixture of lin-5(4H)-one (1.09 g, 4.13 mmol) and phosphoryl chloride (3.86 mL, 41.3 mmol) was heated at 90 °C for 16 h. The resulting product was cooled, filtered and washed with hexanes to obtain 7-bromo-5-chloroimidazo[1,2-a]quinone

morphine (0.54 g, 46.3%). MS (APCI) m/z 281.9, 283 [M+H] ⁺ .

啉(0.124 g, 0.439 mmol)於DMSO (2.2 mL)中之攪拌溶液中，添加(R)-1-(2-甲基-3-(三氟甲基)苯基)乙胺(0.116 g, 0.571 mmol)及三乙胺(0.184 mL, 1.317 mmol)。在120℃下加熱15 h后，將混合物冷卻至rt。將反應用水(15 mL)淬熄，並用EtOAc (3 × 10 mL)萃取。將合併之有機層用鹽水(10 mL)洗滌，以Na ₂SO ₄乾燥且在減壓下濃縮，以提供(R)-7-溴-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)咪唑并[1,2-a]喹

啉-5-胺(0.11 g, 56%)。將粗化合物直接用於下個一步驟中而未進行進一步純化。MS (APCI) m/z 449.0, 450.1 [M+H] ⁺。 To 7-bromo-5-chloroimidazo[1,2-a]quine at rt

To a stirred solution of morphine (0.124 g, 0.439 mmol) in DMSO (2.2 mL), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethylamine (0.116 g, 0.571 mmol) and triethylamine (0.184 mL, 1.317 mmol). After heating at 120 °C for 15 h, the mixture was cooled to rt. The reaction was quenched with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to provide (R)-7-bromo-N-(1-(2-methyl-3-( Trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]quinone

Lin-5-amine (0.11 g, 56%). The crude compound was used directly in the next step without further purification. MS (APCI) m/z 449.0, 450.1 [M+H] ⁺ .

啉-5-胺(0.05 g, 0.111 mmol)、1,2,3,6-四氫-1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(0.030 g, 0.134 mmol)、磷酸鉀鹽(0.094 g, 0.445 mmol)、Xphos (10.61 mg, 0.022 mmol)及參(二亞苄基丙酮)二鈀(0) (10.19 mg, 0.011 mmol)於二

烷:H ₂O（脫氣, 4:1, 1.5 mL）中之混合物在100℃下加熱3 h。將混合物冷卻，用5 mL水處理，用EtOAc萃取，濃縮且藉由反相HPLC使用水（含有0.1%甲酸）中之10-40% CH ₃CN（含有0.1%甲酸）純化，以獲得(R)-7-(1-甲基-1,2,3,6-四氫吡啶-4-基)-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)咪唑并[1,2-a]喹

啉-5-胺(16 mg, 0.034 mmol, 31%)。 ¹H NMR (400 MHz, DMSO- d ₆) δ1.59 (d, J= 7.1 Hz, 3 H), 2.33 (s, 3 H), 2.72-2.60 (m, 6 H), 3.14-3.08 (m, 2 H), 5.74 (quin, J= 6.9 Hz, 1 H), 6.39 (t, J= 3.6 Hz, 1 H), 7.13 (d, J= 1.6 Hz, 1 H), 7.36, (t, J= 7.8 Hz, 1 H), 7.55 (d, J= 7.2 Hz, 1 H), 7.82 (d, J= 7.8 Hz, 1 H), 7.92 (dd, J= 8.7, 1.8 Hz, 1 H), 8.01 (d, J= 1.71 Hz, 1 H), 8.06 (d, J= 8.9 Hz, 1 H), 8.19 (s, 1 H), 8.33 (d, J=7.1 Hz, 1 H), 8.50 (d, J= 1.7 Hz, 1 H)。 實例5 (R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7,8-二甲氧基吡咯并[1,2-a]喹

啉-2-甲酸甲酯

(R)-7-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]quinone

Phenyl-5-amine (0.05 g, 0.111 mmol), 1,2,3,6-tetrahydro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)pyridine (0.030 g, 0.134 mmol), potassium phosphate salt (0.094 g, 0.445 mmol), Xphos (10.61 mg, 0.022 mmol) and ginseng (dibenzylideneacetone) Dipalladium(0) (10.19 mg, 0.011 mmol) in di

A mixture in alkanes:H ₂ O (degassed, 4:1, 1.5 mL) was heated at 100°C for 3 h. The mixture was cooled, treated with 5 mL of water, extracted with EtOAc, concentrated and purified by reverse phase HPLC using 10-40% _CH3CN (containing 0.1% formic acid) in water (containing 0.1% formic acid) to obtain (R )-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl base) imidazo[1,2-a]quinone

Lin-5-amine (16 mg, 0.034 mmol, 31%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.59 (d, J = 7.1 Hz, 3 H), 2.33 (s, 3 H), 2.72-2.60 (m, 6 H), 3.14-3.08 (m, 2 H), 5.74 (quin, J = 6.9 Hz, 1 H), 6.39 (t, J = 3.6 Hz, 1 H), 7.13 (d, J = 1.6 Hz, 1 H), 7.36, (t, J = 7.8 Hz, 1 H), 7.55 (d, J = 7.2 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.92 (dd, J = 8.7, 1.8 Hz, 1 H), 8.01 ( d, J = 1.71 Hz, 1 H), 8.06 (d, J = 8.9 Hz, 1 H), 8.19 (s, 1 H), 8.33 (d, J =7.1 Hz, 1 H), 8.50 (d, J = 1.7 Hz, 1 H). Example 5 (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7,8-dimethoxypyrrolo[1,2- a]quinoline

Phenyl-2-carboxylic acid methyl ester

Into a dry and clean 250 mL round bottom flask, succinonitrile (20 g, 0.249 mol) was taken up in a solvent mixture of toluene (168 mL, 8.4 V) and t -butanol (33.4 mL, 1.67 V). The resulting solution was treated with ethyl formate (22.2 g, 0.299 mol) in one portion at rt. The solution was cooled to -5 °C, and a solution of potassium tert-butoxide (28.5 g, 0.254 mol) in tert-butanol (220 mL) was added dropwise. After the addition was complete, the resulting suspension was warmed to room temperature and then stirred for 3 h. The thick suspension was filtered. The wet cake was collected, stirred with ethanol (200 mL, 10 V) for 15 min and filtered. The wet cake was collected, stirred with methyl tert-butyl ether (250 mL, 12.5 V) for 15 min, filtered and dried under vacuum to afford 2-formylsuccinonitrile (20 g, 55%). ¹ H-NMR (DMSO- d ₆ ): 3.05 (s, 2H), 8.26 (s, 1H).

Methyl-2-amino-4,5 dimethoxybenzoate (10 g, 0.0473 mol) and 2-formyl succinonitrile (6.9 g, 0.0473 mol) were added to water-acetic acid mixture (100 mL, 1:1, 10 V). The solution was heated to 100 °C and then stirred for 10 min. The thick suspension was diluted with ethanol (100 mL, 10 V) and filtered. The wet cake was stirred with ethanol (100 mL, 10 V) for 10 min at rt and filtered. The wet cake was collected, stripped with toluene (3 x 100 mL) and dried under reduced pressure to afford 2-(2,3-dicyano-propenylamino)-4,5-dimethoxy-benzene Methyl formate (11 g, 55%). ¹ H-NMR (DMSO- d ₆ ) [mixture of isomers]: 8.24 (d, 0.3H), 8.15 (d, 0.7H), 7.34 (s, 1H), 7.14 (s, 0.3H), 6.96 (s, 0.7H), 3.89 (s, 3H), 3.85 (s, 3H), 3.74 (s, 3H), 3.32-3.61 (d, J =14 Hz, 2H).

啉-2-甲腈(7.5 g, 76%)。 ¹H-NMR (DMSO- d ₆): 11.84 (s, 1H), 8.53 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 5.88 (s, 1H), 3.94 (s, 3H), 3.84 (s, 3H)。 By dissolving in ethanol (85 mL, 7.8 V) at 0-5 °C, 2-(2,3-dicyano-propenylamino)-4,5-dimethoxy-benzoic acid To an ice-cooled suspension of the base ester (11 g, 0.0365 mol) in ethanol (190 mL, 17.3 V) was added sodium ethoxide (6.2 g, 0.0912 mol) dropwise. After the addition was complete, the mixture was warmed to room temperature and then stirred for 3 h. The thick suspension was diluted with 1N hydrochloric acid solution (132 mL, 12 V), filtered, washed with water (154 mL, 14 V) and dried. The product was suspended in ethanol (154 mL, 14 V), stirred at rt for 15 min, filtered and dried. The product was collected, stripped with toluene (3 x 100 mL) and dried under high vacuum to give 7,8-dimethoxy-5-oxo-4,5-dihydro-pyrrolo[1, 2-a]quinoline

Phenyl-2-carbonitrile (7.5 g, 76%). ¹ H-NMR (DMSO- d ₆ ): 11.84 (s, 1H), 8.53 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 5.88 (s, 1H), 3.94 (s, 3H), 3.84 (s, 3H).

啉-2-甲腈(2.5 g, 9.285 mmol)吸收於氧氯化磷(42.5 mL, 17 V)中。將懸浮液在110℃下攪拌48 h。將混合物在減壓下濃縮。將殘餘物用冷的10%碳酸氫鈉水溶液(40 mL)處理。將材料研磨，過濾，用水(5 mL)洗滌且乾燥。收集材料，用甲苯(3 × 25 mL)汽提且在高真空下乾燥，以獲得5-氯-7,8-二甲氧基-吡咯并[1,2-a]喹

啉-2-甲腈(6 g, 60%)。LCMS: m/z 288 [M+1]。 7,8-dimethoxy-5-oxo-4,5-dihydro-pyrrolo[1,2-a]quinone

Phenyl-2-carbonitrile (2.5 g, 9.285 mmol) was taken up in phosphorus oxychloride (42.5 mL, 17 V). The suspension was stirred at 110 °C for 48 h. The mixture was concentrated under reduced pressure. The residue was treated with cold 10% aqueous sodium bicarbonate (40 mL). The material was ground, filtered, washed with water (5 mL) and dried. The collected material was stripped with toluene (3 x 25 mL) and dried under high vacuum to obtain 5-chloro-7,8-dimethoxy-pyrrolo[1,2-a]quinone

Phenyl-2-carbonitrile (6 g, 60%). LCMS: m/z 288 [M+1].

啉-2-甲腈(750 mg, 2.606 mmol)及1-(3-二氟甲基-2-氟-苯基)-乙胺(493 mg, 2.606 mmol)一起加入二甲亞碸(20 mL)中。將懸浮液用N, N二異丙基乙胺(1.01 g, 7.820 mmol)處理，加熱至125℃且攪拌36 h。將混合物冷卻至rt，且然後傾倒至冰冷水(50 mL)中且用乙酸乙酯(EA) (3 × 75 mL)萃取。將合併之有機層用水(1 × 50 mL)洗滌，以硫酸鈉乾燥且濃縮，以提供粗產物。經由反相HPLC純化粗製物。收集純部分且濃縮。將殘餘物用EA (50 mL)稀釋，用10%碳酸氫鈉溶液(1 × 25 mL)洗滌，以硫酸鈉乾燥且濃縮，以給出5-[1-(3-二氟甲基-2-氟-苯基)-乙基胺基]-7,8-二甲氧基-吡咯并[1,2-a]喹

啉-2-甲腈(300 mg, 26%)。 ¹H-NMR (DMSO- d ₆): 8.49 (s, 1H), 7.87-7.83 (m, 2H), 7.65-7.63 (m, 2H), 7.49-7.46 (m, 1H), 7.37-7.10 (m, 2H), 6.07 (s, 1H), 5.72-5.65 (m, 1H), 3.95 (s, 6H), 1.60 (d, J= 6.4 Hz, 3H)。 In a sealed tube, 5-chloro-7,8-dimethoxy-pyrrolo[1,2-a]quinone

Phenyl-2-carbonitrile (750 mg, 2.606 mmol) and 1-(3-difluoromethyl-2-fluoro-phenyl)-ethylamine (493 mg, 2.606 mmol) were added together in dimethylsulfoxide (20 mL )middle. The suspension was treated with N,N diisopropylethylamine (1.01 g, 7.820 mmol), heated to 125 °C and stirred for 36 h. The mixture was cooled to rt, and then poured into ice cold water (50 mL) and extracted with ethyl acetate (EA) (3 x 75 mL). The combined organic layers were washed with water (1 x 50 mL), dried over sodium sulfate and concentrated to provide the crude product. The crude was purified via reverse phase HPLC. Pure fractions were collected and concentrated. The residue was diluted with EA (50 mL), washed with 10% sodium bicarbonate solution (1 x 25 mL), dried over sodium sulfate and concentrated to give 5-[1-(3-difluoromethyl-2 -fluoro-phenyl)-ethylamino]-7,8-dimethoxy-pyrrolo[1,2-a]quinone

Phenyl-2-carbonitrile (300 mg, 26%). ¹ H-NMR (DMSO- d ₆ ): 8.49 (s, 1H), 7.87-7.83 (m, 2H), 7.65-7.63 (m, 2H), 7.49-7.46 (m, 1H), 7.37-7.10 (m , 2H), 6.07 (s, 1H), 5.72-5.65 (m, 1H), 3.95 (s, 6H), 1.60 (d, J = 6.4 Hz, 3H).

啉-2-甲腈(2 × 50 mg, 0.227 mmol)且然後添加14 M甲醇HCl (5 mL)。將混合物在50℃下攪拌4 h，且然後於rt下保持36h。將混合物冷卻至rt且然後在減壓下完全濃縮。將殘餘物用飽和碳酸氫鹽溶液(10 mL)稀釋且用EA (2 × 15 mL)萃取。將合併之有機層以硫酸鈉乾燥，濃縮，且經受反相HPLC純化。收集純部分且濃縮。將所得殘餘物用EA (50 mL)稀釋，用10%碳酸氫鈉溶液(1 × 25 mL)洗滌，以硫酸鈉乾燥且濃縮，以提供(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7,8-二甲氧基吡咯并[1,2-a]喹

啉-2-甲酸甲酯(20 mg, 20%)。 ¹H-NMR (DMSO- d ₆): 7.85 (s, 1H), 7.56-7.60 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.15 (m, 2H), 7.21-6.79 (m, 2H), 6.43 (s, 1H), 5.71-5.68 (m , 1H), 5.25 (d, J= 8.8 Hz,1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.87 (s, 3H), 1.70 (d, J= 6.8 Hz, 3H)。 實例6 (R)-2-甲基-3-(1-((7-嗎啉基咪唑并[1,2-a]喹

啉-5-基)胺基)乙基)芐腈

In the seal, take 5-[1-(3-difluoromethyl-2-fluoro-phenyl)-ethylamino]-7,8-dimethoxy-pyrrolo[1,2-a] Quinoa

Phenyl-2-carbonitrile (2 x 50 mg, 0.227 mmol) and then 14 M methanolic HCl (5 mL) was added. The mixture was stirred at 50 °C for 4 h, and then kept at rt for 36 h. The mixture was cooled to rt and then completely concentrated under reduced pressure. The residue was diluted with saturated bicarbonate solution (10 mL) and extracted with EA (2 x 15 mL). The combined organic layers were dried over sodium sulfate, concentrated, and subjected to reverse phase HPLC purification. Pure fractions were collected and concentrated. The resulting residue was diluted with EA (50 mL), washed with 10% sodium bicarbonate solution (1 x 25 mL), dried over sodium sulfate and concentrated to provide (R)-5-((1-(3-( Difluoromethyl)-2-fluorophenyl)ethyl)amino)-7,8-dimethoxypyrrolo[1,2-a]quinone

Methyl phenoline-2-carboxylate (20 mg, 20%). ¹ H-NMR (DMSO- d ₆ ): 7.85 (s, 1H), 7.56-7.60 (m, 1H), 7.46-7.49 (m, 1H), 7.27-7.15 (m, 2H), 7.21-6.79 (m , 2H), 6.43 (s, 1H), 5.71-5.68 (m , 1H), 5.25 (d, J = 8.8 Hz,1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.87 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H). Example 6 (R)-2-methyl-3-(1-((7-morpholinoimidazo[1,2-a]quinone

Lin-5-yl)amino)ethyl)benzonitrile

To a solution of methyl 2-amino-5-morpholinylbenzoate (1 g, 4.23 mmol) in THF (17 mL) was added trichloroacetylisocyanate (0.84 g, 4.44 mmol). The mixture was stirred at rt for 2 h, and then the solvent was removed. _Et2O (25 mL) was added to the residue. The resulting white precipitate was collected by filtration to obtain methyl 5-morpholino-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate (1.75 g, 97%). MS m/z: 425.7 [M+1].

啉-2,4(1H,3H)-二酮(0.83 g, 81%)。MS m/z: 248.3 [M+1]。 To a solution of methyl 5-morpholino-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate (1.75 g, 4.12 mmol) in MeOH (21 mL), Ammonia (7N in MeOH) (1.177 mL, 8.24 mmol) was added. The mixture was stirred at rt under _N2 for 2 h. The solution was heated at reflux for an additional 2 h. The mixture was cooled to rt. The mixture was filtered off to give 6-morpholinoquinone

Phenyl-2,4(1H,3H)-dione (0.83 g, 81%). MS m/z: 248.3 [M+1].

啉-2,4(1H,3H)-二酮(0.83 g, 3.36 mmol)於磷醯氯(3.13 mL, 33.6 mmol)中之懸浮液中，逐滴添加N,N-二乙基苯胺(1.068 mL, 6.71 mmol)。將混合物在回流下加熱15 h。去除過量磷醯氯。向殘餘物中添加冰水，且將混合物攪拌30 min。將所得沉澱過濾，用水及己烷洗滌，且在真空爐中乾燥，以獲得呈褐色粉末之4-(2,4-二氯喹

啉-6-基)嗎啉(0.84 g, 88%)。MS m/z: 285.2 [M+1]。 6-Morpholinylquinoline was stirred at 0°C

To a suspension of phenoline-2,4(1H,3H)-dione (0.83 g, 3.36 mmol) in phosphoryl chloride (3.13 mL, 33.6 mmol), N,N-diethylaniline (1.068 mL, 6.71 mmol). The mixture was heated at reflux for 15 h. Remove excess phosphoryl chloride. Ice water was added to the residue, and the mixture was stirred for 30 min. The resulting precipitate was filtered, washed with water and hexane, and dried in a vacuum oven to obtain 4-(2,4-dichloroquine as a brown powder

morpholin-6-yl)morpholine (0.84 g, 88%). MS m/z: 285.2 [M+1].

啉-6-基)嗎啉(0.25 g, 0.880 mmol)於DMSO (4.5 mL)中之溶液中，添加(R)-1-(3-溴-2-甲基苯基)乙胺鹽酸鹽(0.231 g, 0.924 mmol)及三乙胺(2.70 mL, 19.41 mmol)。將混合物在110℃下加熱16 h。將混合物冷卻至rt，且然後傾倒至冰冷水(50 mL)中。將混合物用EA (3 × 35 mL)萃取。將合併之有機層用水(1 × 50 mL)洗滌，以硫酸鈉乾燥且濃縮。將粗產物藉由矽膠層析法(0-70% EA純化，以獲得(R)-N-(1-(3-溴-2-甲基苯基)乙基)-2-氯-6-嗎啉基喹

啉-4-胺(0.28 g, 69%)。MS m/z: 462.8 [M+1]。 4-(2,4-Dichloroquine

To a solution of phen-6-yl)morpholine (0.25 g, 0.880 mmol) in DMSO (4.5 mL) was added (R)-1-(3-bromo-2-methylphenyl)ethanamine hydrochloride (0.231 g, 0.924 mmol) and triethylamine (2.70 mL, 19.41 mmol). The mixture was heated at 110 °C for 16 h. The mixture was cooled to rt, and then poured into ice-cold water (50 mL). The mixture was extracted with EA (3 x 35 mL). The combined organic layers were washed with water (1 x 50 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (0-70% EA to obtain (R)-N-(1-(3-bromo-2-methylphenyl)ethyl)-2-chloro-6- Morpholinoquine

Lin-4-amine (0.28 g, 69%). MS m/z: 462.8 [M+1].

啉-4-胺(0.28 g, 0.61 mmol)及2,2-二甲氧基乙-1-胺(1.9 g, 18.2 mmol)之混合物在100℃下加熱18 h。將混合物冷卻至rt且然後傾倒至冰冷水(20 mL)中。過濾掉沉澱，用水及己烷洗滌且在真空爐中乾燥，以獲得(R)-N-4-(1-(3-溴-2-甲基苯基)乙基)-N2-(2,2-二甲氧基乙基)-6-嗎啉基喹

啉-2,4-二胺(0.32 g, 99%)。MS m/z: 531.6 [M+1]。 (R)-N-(1-(3-bromo-2-methylphenyl)ethyl)-2-chloro-6-morpholinoquinoline

A mixture of phenin-4-amine (0.28 g, 0.61 mmol) and 2,2-dimethoxyethan-1-amine (1.9 g, 18.2 mmol) was heated at 100°C for 18 h. The mixture was cooled to rt and then poured into ice cold water (20 mL). The precipitate was filtered off, washed with water and hexane and dried in a vacuum oven to obtain (R)-N-4-(1-(3-bromo-2-methylphenyl)ethyl)-N2-(2, 2-dimethoxyethyl)-6-morpholinoquinoline

Phenyl-2,4-diamine (0.32 g, 99%). MS m/z: 531.6 [M+1].

啉-2,4-二胺(0.40 g, 0.754 mmol)溶解於甲酸(2.84 mL, 75 mmol)中，且然後在100℃下加熱17 h。將混合物冷卻至rt，用碳酸氫鈉水溶液中和，且用EA (3 × 30 mL)萃取。將合併之有機層用水(1 × 20 mL)洗滌，以硫酸鈉乾燥且濃縮。將粗產物藉由矽膠層析法（DCM中之0-70% (9:1 DCM : MeOH)）純化，以獲得(R)-N-(1-(3-溴-2-甲基苯基)乙基)-7-嗎啉基咪唑并[1,2-a]喹

啉-5-胺(0.16 g, 45%)。MS m/z: 467.4 [M+1]。 (R)-N4-(1-(3-bromo-2-methylphenyl)ethyl)-N2-(2,2-dimethoxyethyl)-6-morpholinoquinoline

Phenyl-2,4-diamine (0.40 g, 0.754 mmol) was dissolved in formic acid (2.84 mL, 75 mmol) and then heated at 100 °C for 17 h. The mixture was cooled to rt, neutralized with aqueous sodium bicarbonate and extracted with EA (3 x 30 mL). The combined organic layers were washed with water (1 x 20 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (0-70% (9:1 DCM:MeOH) in DCM) to obtain (R)-N-(1-(3-bromo-2-methylphenyl ) ethyl) -7-morpholino imidazo [1,2-a] quinone

Lin-5-amine (0.16 g, 45%). MS m/z: 467.4 [M+1].

啉-5-胺(0.095 g, 0.204 mmol)於脫氣DMF (1 mL)中之溶液中，添加氰化鋅(0.029 g, 0.244 mmol)及四(三苯基膦)鈀(0) (0.024 g, 0.020 mmol)。將混合物脫氣且在110℃下加熱3 h。將混合物冷卻至rt。添加水(5 mL)及EtOAc (10 mL)，且然後沉澱出，且過濾。將產物溶解於DMSO (2 mL)中，且藉由反相HPLC管柱使用水中之10-50% CH ₃CN純化，以獲得(R)-2-甲基-3-(1-((7-嗎啉基咪唑并[1,2-a]喹

啉-5-基)胺基)乙基)芐腈(10 mg, 12%)。MS m/z: 413.5 [M+1]。 實例7 (R)-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-3-(四氫-2H-哌喃-4-基)咪唑并[1,2-a]吡啶并[4,3-e]嘧啶-5-胺

To (R)-N-(1-(3-bromo-2-methylphenyl)ethyl)-7-morpholino imidazo[1,2-a]quinone

To a solution of phenin-5-amine (0.095 g, 0.204 mmol) in degassed DMF (1 mL), zinc cyanide (0.029 g, 0.244 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.020 mmol). The mixture was degassed and heated at 110 °C for 3 h. The mixture was cooled to rt. Water (5 mL) and EtOAc (10 mL) were added and then precipitated out and filtered. The product was dissolved in DMSO (2 mL) and purified by reverse phase HPLC column using 10-50% CH ₃ CN in water to obtain (R)-2-methyl-3-(1-((7 -Morpholinylimidazo[1,2-a]quinone

(olin-5-yl)amino)ethyl)benzonitrile (10 mg, 12%). MS m/z: 413.5 [M+1]. Example 7 (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[ 1,2-a]pyrido[4,3-e]pyrimidin-5-amine

烷:H ₂O (4:1, 1.5 mL)中之混合物在100℃下加熱2 h。將混合物冷卻至rt，用水(20 mL)處理，用EtOAc萃取，且然後濃縮。將所得粗製物藉由反相HPLC管柱使用水中之10-50% CH ₃CN純化，以獲得(R)-3-(3,6-二氫-2H-哌喃-4-基)-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)咪唑并[1,2-a]吡啶并[4,3-e]嘧啶-5-胺(36 mg, 53.7%)。MS m/z : 454.5 [M+1]。 (R)-3-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]pyrido[4,3- e] pyrimidin-5-amine (0.06 g, 0.148 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3 , 2-dioxaborolane (0.037 g, 0.177 mmol), potassium phosphate salt (0.126 g, 0.591 mmol), Xphos (0.014 g, 0.030 mmol) and ginseng (dibenzylideneacetone) dipalladium ( 0) (0.014 g, 0.015 mmol) in degassed di

A mixture in alkanes: _H2O (4:1, 1.5 mL) was heated at 100 °C for 2 h. The mixture was cooled to rt, treated with water (20 mL), extracted with EtOAc, and then concentrated. The resulting crude was purified by reverse phase HPLC column using 10-50% CH ₃ CN in water to obtain (R)-3-(3,6-dihydro-2H-pyran-4-yl)-N -(1-(2-Methyl-3-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]pyrido[4,3-e]pyrimidin-5-amine (36 mg , 53.7%). MS m/z: 454.5 [M+1].

(R)-3-(3,6-dihydro-2H-pyran-4-yl)-N-(1-(2-methyl-3-(trifluoromethyl)benzene) in degassed methanol Pd/C (10 w%, 0.014 g, 0.013 mmol) was added to ethyl) ethyl) imidazo[1,2-a]pyrido[4,3-e]pyrimidin-5-amine (0.06 g, 0.132 mmol) ). The solution was degassed a second time and then stirred at rt under an atmosphere of hydrogen. After 15 h, LCMS showed exclusive formation of product. The mixture was filtered through celite and then concentrated. The crude product was purified by reverse phase HPLC column using 10-50% _CH3CN in water to obtain (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl) ethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyrido[4,3-e]pyrimidin-5-amine (25.4 mg, 41.3%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.59 (d, J = 4 Hz, 3H), 1.93-1.82 (m, 4H), 2.61 (s, 3H), 3.10 (quint, J = 8 Hz, 1H), 3.57-3.46 (m, 2H), 4.06-3.99 (m, 2H), 5.70 (quint, J = 8 Hz, 1H) 7.18 (d, J = 4 Hz, 1H) 7.39 (t, J = 8 Hz, 1H) 7.56 (d, J = 8 Hz, 1H) 7.80 (d, J = 8 Hz, 1H) 8.16 (d, J = 1.71 Hz, 1H) 8.36 (s, 1H), 8.48 (d, J = 8 Hz, 1H) 9.47 (s, 1H). Example 8 (R)-(8-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-1,3-dihydro-2H -imidazo[1,2-a]pyrrolo[3,4-e]pyrimidin-2-yl)(1-methylcyclopropyl)methanone

To (R)-8-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2,3-dihydro-1H-imidazole at 0°C And[1,2-a]pyrrolo[3,4-e]pyrimidin-4-amine (0.060 g, 0.160 mmol) and 1-methylcyclopropanecarboxylic acid (0.019 g, 0.192 mmol) in DMF (1.066 mL) Add 1H-benzo[d][1,2,3]triazol-1-ol (0.026 g, 0.192 mmol), N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide (0.037 g, 0.240 mmol) and N,N-diisopropylethylamine (0.111 mL, 0.639 mmol). The mixture was stirred at rt for 12 h. Upon completion as indicated by LCMS, the mixture was added to water (20 mL), extracted with EtOAc (2 x 5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by reverse phase HPLC using 10-50% CH ₃ CN in water to obtain (R)-(8-methyl-4-((1-(2-methyl-3-(tri Fluoromethyl)phenyl)ethyl)amino)-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidin-2(3H)-yl)(1-methylcyclopropane base) Methanone (0.017 g, 23%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 0.62 (br s, 2H), 0.95 (br s, 2H), 1.36 (br s, 3H) 1.48 (br s, 3H) 2.46-2.39 (m, 3H ) 2.56 (br s, 3H), 4.65-4.33 (m, 1H), 4.87 (br s, 1H) 5.05 (br s, 1H) 5.42 (br s, 1H) 5.54 (br s, 1H) 6.84 (s, 1H) 7.37 (br s, 1H) 7.67-7.50 (m, 2H) 7.75 (s, 1H). Example 9 (R)-(4-methoxytetrahydro-2H-pyran-4-yl)(8-methyl-4-((1-(2-methyl-3-(trifluoromethyl) Phenyl)ethyl)amino)-1,3-dihydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidin-2-yl)methanone

To a solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (0.90 g, 3.10 mmol) in DMSO (16 mL), Add (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethanamine (0.693 g, 3.41 mmol) and triethylamine (2.70 mL, 19.41 mmol). The mixture was heated at 120 °C for 15 h. The mixture was cooled to rt. The mixture was poured into ice water (100 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with water (1 x 50 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (0-70% EA in hexane) to obtain (R)-2-chloro-4-((1-(2-methyl-3-(trifluoro Methyl)phenyl)ethyl)amino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (1.20 g, 85%). MS m/z: 457.9 [M+1].

To (R)-2-chloro-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-5H-pyrrolo[3,4-d] In a solution of pyrimidine-6(7H)-tertiary butyl carboxylate (1.26 g, 2.76 mmol), add 3-amino-1-propyne (0.759 g, 13.79 mmol) and N,N-diisopropyl Ethylamine (1.441 mL, 8.27 mmol), and then heated at 100 °C for 4 days. The mixture was cooled to rt. The mixture was poured into cold water (25 mL) and extracted with EA (3 x 35 mL). The combined organic layers were washed with water (1 x 20 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (0-60% EA in hexane) to obtain (R)-4-((1-(2-methyl-3-(trifluoromethyl)benzene Base) ethyl) amino)-2-(prop-2-yn-1-ylamino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylic acid tertiary butyl ester ( 0.63 g, 48%). MS m/z: 476.6 [M+1].

(R)-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2-(propan-2- Alkyn-1-ylamino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylic acid tert-butyl ester ( _0.44 g, 0.925 mmol) was deoxygenated with N for 10 min, and then added Silver triflate (0.071 g, 0.278 mmol). The mixture was heated at 85 °C for 18 h. After the reaction was complete, the mixture was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EA in hexane) to obtain (R)-8-methyl-4-((1-(2-methyl-3-(trifluoro Methyl)phenyl)ethyl)amino)-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine-2(3H)-carboxylic acid tertiary butyl ester (0.25 g, 57 %). MS m/z: 476.6 [M+1].

To (R)-8-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-1H-imidazo[1,2-a To a solution of ]pyrrolo[3,4-e]pyrimidine-2(3H)-carboxylic acid tert-butyl ester (0.14 g, 0.294 mmol) in DCM (1.963 mL), trifluoroacetic acid was added dropwise at 0 °C (0.676 mL, 8.83 mmol). The mixture was stirred at rt for 4 h. After the reaction was complete, the mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% 9:1 DCM:methanol (7N ammonia) in DCM) to obtain (R)-8-methyl-N-(1-(2 -Methyl-3-(trifluoromethyl)phenyl)ethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine-4- Amine (0.08 g, 72%). MS m/z: 376.6 [M+1].

烷-4-甲酸(0.028 g, 0.176 mmol)於DMF (0.90 mL)中之懸浮液中，連續添加1H-苯并[d][1,2,3]三唑-1-醇(0.026 g, 0.192 mmol)、N-(3-二甲基胺基丙基)-N'-乙基碳二亞胺(0.037 g, 0.240 mmol)及N,N-二異丙基乙胺(0.111 mL, 0.639 mmol)。將混合物於rt下攪拌12 h。在如藉由LCMS指示完成時，將混合物添加至水(20 mL)中，用EtOAc (2 × 5 mL)萃取，以無水硫酸鈉乾燥且在減壓下濃縮。將獲得之殘餘物藉由反相HPLC使用水中之10-50% CH ₃CN純化，以獲得(R)-(4-甲氧基四氫-2H-哌喃-4-基)(8-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)-1H-咪唑并[1,2-a]吡咯并[3,4-e]嘧啶-2(3H)-基)甲酮(0.016 g, 19%)。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ1.47 (t, J= 7.21 Hz, 3H), 2.02-1.88 (m, 4H), 2.42 (bs, 4H), 2.58 (br s, 3H) 3.24-3.14 (m, 2H), 3.75-3.58 (m, 4H), 4.64 (br d, J= 12.47 Hz, 1H), 4.90 (bs, 1H) 5.18 (br s, 1H), 5.41 (bs, 1H), 5.49-5.59 (m, 1H), 6.84 (dd, J= 2.08, 1.10 Hz, 1H) 7.39-7.34 (m, 1H) 7.53 (dd, J= 7.3, 4.9 Hz, 1H), 7.71-7.61 (m, 1H) 7.72-7.78 (m, 1H)。MS m/z: 518.6 [M+1]。 實例10 (R)-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-3-嗎啉基-8,9-二氫咪唑并[1,2-a]吡啶并[4,3-e]嘧啶-5-胺

To (R)-8-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2,3-dihydro-1H-imidazole at 0°C And[1,2-a]pyrrolo[3,4-e]pyrimidin-4-amine (0.060 g, 0.160 mmol) and 4-methoxy

To a suspension of alkane-4-carboxylic acid (0.028 g, 0.176 mmol) in DMF (0.90 mL), 1H-benzo[d][1,2,3]triazol-1-ol (0.026 g, 0.192 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.037 g, 0.240 mmol) and N,N-diisopropylethylamine (0.111 mL, 0.639 mmol). The mixture was stirred at rt for 12 h. Upon completion as indicated by LCMS, the mixture was added to water (20 mL), extracted with EtOAc (2 x 5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by reverse phase HPLC using 10-50% CH ₃ CN in water to obtain (R)-(4-methoxytetrahydro-2H-pyran-4-yl)(8-methyl Base-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-1H-imidazo[1,2-a]pyrrolo[3,4- e] pyrimidin-2(3H)-yl)methanone (0.016 g, 19%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.47 (t, J = 7.21 Hz, 3H), 2.02-1.88 (m, 4H), 2.42 (bs, 4H), 2.58 (br s, 3H) 3.24- 3.14 (m, 2H), 3.75-3.58 (m, 4H), 4.64 (br d, J = 12.47 Hz, 1H), 4.90 (bs, 1H) 5.18 (br s, 1H), 5.41 (bs, 1H), 5.49-5.59 (m, 1H), 6.84 (dd, J = 2.08, 1.10 Hz, 1H) 7.39-7.34 (m, 1H) 7.53 (dd, J = 7.3, 4.9 Hz, 1H), 7.71-7.61 (m, 1H) 7.72-7.78 (m, 1H). MS m/z: 518.6 [M+1]. Example 10 (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-3-morpholinyl-8,9-dihydroimidazo[1,2 -a]pyrido[4,3-e]pyrimidin-5-amine

To (R)-2,6-dichloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidine-4- To a solution of the amine (0.90 g, 2.243 mmol) in EtOH (3 mL) was added 2-aminoethanol (1.370 g, 22.43 mmol). The mixture was heated at 80 °C for 3 h. The mixture was cooled to rt and then concentrated. To the residue, water (20 mL) was added, and the mixture was stirred for 15 min. The resulting precipitate was filtered, washed with water and hexane, and dried in a vacuum oven to obtain (R)-2-((6-chloro-4-((1-(2-methyl-3-(trifluoromethane yl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)ethanol (0.86 g, , 90%). MS m/z: 426.9 [M+1].

To (R)-2-((6-chloro-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d ]pyrimidin-2-yl)amino)ethanol (0.44 g, 1.033 mmol) in DCM (5.17 mL) was added methanesulfonyl chloride (0.096 mL, 1.240 mmol) and triethylamine ( 0.216 mL, 1.550 mmol). The mixture was stirred at the same temperature for 2 h. The progress of the reaction was monitored by LCMS. The mixture was diluted with water (10 mL) followed by dichloromethane (10 mL). The layers were separated. The organic layer was dried over sodium sulfate and concentrated to obtain (R)-methanesulfonic acid 2-((6-chloro-4-((1-(2-methyl-3-(trifluoromethyl )phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)ethyl ester (0.51 g, 98%, crude).

To R)-methanesulfonic acid 2-((6-chloro-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4 -d] To a solution of pyrimidin-2-yl)amino)ethyl ester (0.27 g, 0.536 mmol) in DMF (2.143 mL) was added N,N-diisopropylethylamine (0.187 mL, 1.072 mmol) . The mixture was stirred at 75 °C for 14 h. The progress of the reaction was monitored by LCMS. The mixture was cooled to rt. The mixture was cooled to rt, and then ice water (15 mL) was added. The mixture was stirred for 15 min. The resulting precipitate was filtered, washed with water and hexanes, and dried in a vacuum oven to obtain (R)-3-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl) ethyl)-8,9-dihydroimidazo[1,2-a]pyrido[4,3-e]pyrimidin-5-amine (0.17 g, 78%). MS m/z: 408.9 [M+1].

烷中之脫氣溶液中，添加碳酸銫(0.399 g, 1.226 mmol)、嗎啉(0.043 g, 0.490 mmol)及Pd PEPPSI-IHEPT Cl 3-氯吡啶(0.024 g, 0.025 mmol)。將混合物在100℃下攪拌15 h。將混合物冷卻至rt且然後用水(20 mL)處理。將混合物用EA (3 × 20 mL)萃取。將合併之有機層用水(20 mL)洗滌，以硫酸鈉乾燥，且濃縮。將粗產物經矽膠管柱層析法（DCM中之0-100% 9:1 DCM:甲醇（7N氨））純化，以獲得(R)-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-3-嗎啉基-8,9-二氫咪唑并[1,2-a]吡啶并[4,3-e]嘧啶-5-胺(44 mg, 39%)。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ1.37 (br d, J= 4 Hz, 3H), 2.47 (br s, 3H), 3.42-3.37 (m, 4H) 3.76-3.60 (m, 7H), 4.09-3.96 (m, 2H), 5.62 (q, J= 8 Hz, 1H), 7.37 (t, J= 8 Hz, 1H), 7.45 (br s, 1H), 7.52 (d, J= 8 Hz, 1H), 7.98 (br d, J= 8 Hz, 1H), 8.05 (s, 1H)。 實例11 N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S)-四氫呋喃-3-基)氧基)-1,2-二氫咪唑并[1,2-a]喹

啉-5-胺

To (R)-3-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-8,9-dihydroimidazo[1,2-a] Pyrido[4,3-e]pyrimidin-5-amine (0.10 g, 0.245 mmol) in di

To the degassed solution in alkanes, cesium carbonate (0.399 g, 1.226 mmol), morpholine (0.043 g, 0.490 mmol) and Pd PEPPSI-IHEPT Cl 3-chloropyridine (0.024 g, 0.025 mmol) were added. The mixture was stirred at 100 °C for 15 h. The mixture was cooled to rt and then treated with water (20 mL). The mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (20 mL), dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (0-100% 9:1 DCM:methanol (7N ammonia) in DCM) to obtain (R)-N-(1-(2-methyl-3- (Trifluoromethyl)phenyl)ethyl)-3-morpholinyl-8,9-dihydroimidazo[1,2-a]pyrido[4,3-e]pyrimidin-5-amine (44 mg, 39%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.37 (br d, J = 4 Hz, 3H), 2.47 (br s, 3H), 3.42-3.37 (m, 4H) 3.76-3.60 (m, 7H) , 4.09-3.96 (m, 2H), 5.62 (q, J = 8 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.45 (br s, 1H), 7.52 (d, J = 8 Hz , 1H), 7.98 (br d, J = 8 Hz, 1H), 8.05 (s, 1H). Example 11 N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)- 1,2-Dihydroimidazo[1,2-a]quinone

Lin-5-amine

啉-4-胺(1.4 g, 3.54 mmol)於EtOH (2 mL)中之溶液中，添加2-胺基乙醇(3.24 g, 53.1 mmol)。將混合物在80℃下加熱3 h。將混合物冷卻至rt且然後濃縮。向殘餘物中添加水(30 mL)，且然後攪拌15 min。將所得沉澱過濾，用水及己烷洗滌，且在真空爐中乾燥，以獲得(R)-2-((6-甲氧基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)喹

啉-2-基)胺基)乙醇(1.2 g, 81%)。MS m/z: 421.5 [M+1]。 To (R)-2-chloro-6-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)quinone

To a solution of phenin-4-amine (1.4 g, 3.54 mmol) in EtOH (2 mL) was added 2-aminoethanol (3.24 g, 53.1 mmol). The mixture was heated at 80 °C for 3 h. The mixture was cooled to rt and then concentrated. Water (30 mL) was added to the residue, and then stirred for 15 min. The resulting precipitate was filtered, washed with water and hexane, and dried in a vacuum oven to obtain (R)-2-((6-methoxy-4-((1-(2-methyl-3-(tri Fluoromethyl)phenyl)ethyl)amino)quinoline

(olin-2-yl)amino)ethanol (1.2 g, 81%). MS m/z: 421.5 [M+1].

啉-2-基)胺基)乙醇(1.1 g, 2.62 mmol)於DCM (13.08 mL)中之溶液中，逐滴添加甲烷磺醯氯(0.243 mL, 3.14 mmol)及三乙胺(0.912 mL, 6.54 mmol)。將混合物在0℃下攪拌2 h。TLC顯示起始材料完全消耗。將混合物用水(10 mL)稀釋，之後用二氯甲烷(20 mL)稀釋。將混合物攪拌10 min。分離各層。將有機層以硫酸鈉乾燥且濃縮，以獲得(R)-甲烷磺酸2-((6-甲氧基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)喹

啉-2-基)胺基)乙酯(0.41 g, 31%)，將其用於下一個步驟中而未進行純化。 To (R)-2-((6-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinone at 0°C

To a solution of olin-2-yl)amino)ethanol (1.1 g, 2.62 mmol) in DCM (13.08 mL), methanesulfonyl chloride (0.243 mL, 3.14 mmol) and triethylamine (0.912 mL, 6.54 mmol). The mixture was stirred at 0 °C for 2 h. TLC showed complete consumption of starting material. The mixture was diluted with water (10 mL) followed by dichloromethane (20 mL). The mixture was stirred for 10 min. Separate the layers. The organic layer was dried over sodium sulfate and concentrated to obtain (R)-methanesulfonic acid 2-((6-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)benzene base) ethyl) amino) quinone

(0.41 g, 31%) ethyl ester (0.41 g, 31%) which was used in the next step without purification.

啉-2-基)胺基)乙酯(0.50 g, 1.003 mmol)於DMF (4.01 mL)中之溶液中，添加N,N-二異丙基乙胺(0.349 mL, 2.006 mmol)。將混合物在75℃下攪拌14 h。藉由LCMS監測反應進程。在反應完成後，將混合物冷卻至rt。添加冰水(15 mL)且將混合物攪拌15 min。將所得沉澱過濾，用水及己烷洗滌，且在真空爐中乾燥，以獲得(R)-7-甲氧基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-1,2-二氫咪唑并[1,2-a]喹

啉-5-胺(0.17 g, 42.1%)。MS m/z: 403.3 [M+1]。 To (R)-methanesulfonic acid 2-((6-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinone

To a solution of phenin-2-yl)amino)ethyl ester (0.50 g, 1.003 mmol) in DMF (4.01 mL) was added N,N-diisopropylethylamine (0.349 mL, 2.006 mmol). The mixture was stirred at 75 °C for 14 h. The progress of the reaction was monitored by LCMS. After the reaction was complete, the mixture was cooled to rt. Ice water (15 mL) was added and the mixture was stirred for 15 min. The resulting precipitate was filtered, washed with water and hexane, and dried in a vacuum oven to obtain (R)-7-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)benzene Base) ethyl) -1,2-dihydroimidazo[1,2-a]quinone

Lin-5-amine (0.17 g, 42.1%). MS m/z: 403.3 [M+1].

啉-5-胺(0.40 g, 0.994 mmol)於DCM (4.97 mL)中之溶液中，添加三溴化硼(1.690 mL, 1.690 mmol)。將混合物在55℃下攪拌15 h。在反應完成後，將混合物冷卻至rt，且然後用飽和碳酸氫鈉中和。將所得沉澱過濾，用水及己烷洗滌，且在真空爐中乾燥，以獲得(R)-5-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)-1,2-二氫咪唑并[1,2-a]喹

啉-7-醇(0.26 g, 67%產率）。MS m/z: 398.2 [M+1]。 To (R)-7-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-1,2-dihydroimidazo[1,2- a]quinoline

To a solution of olin-5-amine (0.40 g, 0.994 mmol) in DCM (4.97 mL) was added boron tribromide (1.690 mL, 1.690 mmol). The mixture was stirred at 55 °C for 15 h. After the reaction was complete, the mixture was cooled to rt, and then neutralized with saturated sodium bicarbonate. The resulting precipitate was filtered, washed with water and hexanes, and dried in a vacuum oven to obtain (R)-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) Amino)-1,2-dihydroimidazo[1,2-a]quinone

Lin-7-ol (0.26 g, 67% yield). MS m/z: 398.2 [M+1].

啉-7-醇(0.10 g, 0.257 mmol)於DMF (1.3 mL)中之溶液中，添加碳酸銫(0.168 g, 0.515 mmol)及(R)-4-甲基苯磺酸四氫呋喃-3-基酯(0.094 g, 0.386 mmol)。將混合物於rt下在N ₂氣氛下攪拌24 h。起始材料消耗後，添加水(10 mL)。將混合物用EA (3 × 15 mL)萃取。將合併之有機層用水(10 mL)洗滌，以硫酸鈉乾燥且濃縮。將粗產物在HPLC管柱上使用水（含有0.1%甲酸）中之10-50% CH ₃CN（含有0.1%甲酸）純化。將產物凍乾，以提供N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S)-四氫呋喃-3-基)氧基)-1,2-二氫咪唑并[1,2-a]喹

啉-5-胺(25 mg, 21%)。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ1.56 (d, J= 4 Hz, 3H), 2.03-1.93 (m, 1H), 2.35-2.24 (m, 1H), 2.55 (s, 3H), 4.02–3.72 (m, 6H), 4.36-4.21 (m, 2H), 5.25-5.22 (m, 1H), 5.72 (q, J= 8 Hz, 1H) 7.29 (d, J= 8 Hz, 1H) 7.39 (t, J= 8 Hz, 1H) 7.48 (t, J= 8 Hz, 1H) 7.58 (d, J= 4 Hz, 1H) 7.87 (d, J= 4 Hz, 1H) 8.18 (s, 1H) 8.53 (s, 1H)。 實例12 N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S)-四氫呋喃-3-基)氧基)咪唑并[1,2-a]喹

啉-5-胺

To (R)-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-1,2-dihydroimidazo[1,2-a] Quinoa

To a solution of phenin-7-ol (0.10 g, 0.257 mmol) in DMF (1.3 mL) was added cesium carbonate (0.168 g, 0.515 mmol) and (R)-4-tetrahydrofuran-3-ylmethylbenzenesulfonate Ester (0.094 g, 0.386 mmol). The mixture was stirred at rt under _N2 atmosphere for 24 h. After the starting material was consumed, water (10 mL) was added. The mixture was extracted with EA (3 x 15 mL). The combined organic layers were washed with water (10 mL), dried over sodium sulfate and concentrated. The crude product was purified on a HPLC column using 10-50% _CH3CN (containing 0.1% formic acid) in water (containing 0.1% formic acid). The product was lyophilized to provide N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl )Oxy)-1,2-dihydroimidazo[1,2-a]quinone

Lin-5-amine (25 mg, 21%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.56 (d, J = 4 Hz, 3H), 2.03-1.93 (m, 1H), 2.35-2.24 (m, 1H), 2.55 (s, 3H), 4.02–3.72 (m, 6H), 4.36-4.21 (m, 2H), 5.25-5.22 (m, 1H), 5.72 (q, J = 8 Hz, 1H) 7.29 (d, J = 8 Hz, 1H) 7.39 (t, J = 8 Hz, 1H) 7.48 (t, J = 8 Hz, 1H) 7.58 (d, J = 4 Hz, 1H) 7.87 (d, J = 4 Hz, 1H) 8.18 (s, 1H) 8.53 (s, 1H). Example 12 N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)imidazole And[1,2-a]quinone

Lin-5-amine

啉(0.81 g, 3.54 mmol)於DMSO (17.68 mL)中之溶液中，添加(R)-1-(2-甲基-3-(三氟甲基)苯基)乙胺(1.1 g, 5.41 mmol)及三乙胺(1.971 mL, 14.14 mmol)。將混合物在110℃下加熱16 h。將混合物冷卻至rt，且然後傾倒至冰冷水(150 mL)中。將混合物用EA (3 × 60 mL)萃取。將合併之有機層用水(1 × 50 mL)洗滌，以硫酸鈉乾燥且濃縮。將粗產物經矽膠層析法（己烷中之0-50% EA）純化，以獲得(R)-2-氯-6-甲氧基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹

啉-4-胺(1.30 g, 93%)。MS m/z: 396.9 [M+1]。 2,4-dichloro-6-methoxyquin

To a solution of morphine (0.81 g, 3.54 mmol) in DMSO (17.68 mL), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethylamine (1.1 g, 5.41 mmol) and triethylamine (1.971 mL, 14.14 mmol). The mixture was heated at 110 °C for 16 h. The mixture was cooled to rt, and then poured into ice-cold water (150 mL). The mixture was extracted with EA (3 x 60 mL). The combined organic layers were washed with water (1 x 50 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (0-50% EA in hexane) to obtain (R)-2-chloro-6-methoxy-N-(1-(2-methyl-3- (Trifluoromethyl)phenyl)ethyl)quinone

Lin-4-amine (1.30 g, 93%). MS m/z: 396.9 [M+1].

啉-4-胺(0.35 g, 0.884 mmol)及2,2-二甲氧基乙胺(1.859 g, 17.69 mmol)之混合物在100℃下加熱18 h。將混合物冷卻至rt，且然後傾倒至冰冷水(30 mL)中。將所得沉澱過濾，用水及己烷洗滌，且在真空爐中乾燥，以獲得(R)-N2-(2,2-二甲氧基乙基)-6-甲氧基-N4-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹

啉-2,4-二胺(0.38 g, 93%)。MS m/z: 465.4 [M+1]。 (R)-2-chloro-6-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)quinone

A mixture of phenin-4-amine (0.35 g, 0.884 mmol) and 2,2-dimethoxyethylamine (1.859 g, 17.69 mmol) was heated at 100°C for 18 h. The mixture was cooled to rt, and then poured into ice-cold water (30 mL). The resulting precipitate was filtered, washed with water and hexane, and dried in a vacuum oven to obtain (R)-N2-(2,2-dimethoxyethyl)-6-methoxy-N4-(1- (2-Methyl-3-(trifluoromethyl)phenyl)ethyl)quinone

Phenyl-2,4-diamine (0.38 g, 93%). MS m/z: 465.4 [M+1].

啉-2,4-二胺(0.30 g, 0.646 mmol)溶解於甲酸(2.437 mL, 64.6 mmol)中，且在100℃下加熱16 h。將混合物冷卻至rt，濃縮且用飽和碳酸氫鈉中和。將沉澱過濾，用水及己烷洗滌，且在真空下乾燥，以獲得(R)-7-甲氧基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)咪唑并[1,2-a]喹

啉-5-胺(0.25 g, 97%)。MS m/z: 401.0 [M+1]。 (R)-N2-(2,2-dimethoxyethyl)-6-methoxy-N4-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl ) quinone

Phenyl-2,4-diamine (0.30 g, 0.646 mmol) was dissolved in formic acid (2.437 mL, 64.6 mmol) and heated at 100 °C for 16 h. The mixture was cooled to rt, concentrated and neutralized with saturated sodium bicarbonate. The precipitate was filtered, washed with water and hexanes, and dried under vacuum to obtain (R)-7-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl) Ethyl)imidazo[1,2-a]quinone

Lin-5-amine (0.25 g, 97%). MS m/z: 401.0 [M+1].

啉-5-胺(0.25 g, 0.624 mmol)於DCM (3.12 mL)中之混合物中，添加三溴化硼(1.061 mL, 1.061 mmol)。將混合物在55℃下加熱15 h。將混合物冷卻至0 ^oC且用飽和碳酸氫鈉中和。將所得沉澱過濾，用水及己烷洗滌，且在真空下乾燥，以獲得(R)-5-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)咪唑并[1,2-a]喹

啉-7-醇(0.22 g, 91%)。MS m/z: 386.9 [M+1]。 To (R)-7-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]quinone

To a mixture of olin-5-amine (0.25 g, 0.624 mmol) in DCM (3.12 mL) was added boron tribromide (1.061 mL, 1.061 mmol). The mixture was heated at 55 °C for 15 h. The mixture was cooled to 0 ^° C and neutralized with saturated sodium bicarbonate. The resulting precipitate was filtered, washed with water and hexanes, and dried under vacuum to obtain (R)-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amine base) imidazo[1,2-a]quinone

Lin-7-ol (0.22 g, 91%). MS m/z: 386.9 [M+1].

啉-7-醇(0.06 g, 0.155 mmol)於DMF (0.776 mL)中之溶液中，添加(R)-4-甲基苯磺酸四氫呋喃-3-基酯(0.041 g, 0.171 mmol)及碳酸銫(0.091 g, 0.280 mmol)。將混合物在環境溫度下在N ₂氣氛下攪拌18 h。添加水(5 mL)。將混合物用EA (3 × 15 mL)萃取。將合併之有機層用水(10 mL)洗滌，以硫酸鈉乾燥，且濃縮。將粗產物藉由反相HPLC使用水（含有0.1%甲酸）中之10-50% CH ₃CN（含有0.1%甲酸）純化。將產物凍乾，以提供N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7-(((S)-四氫呋喃-3-基)氧基)咪唑并[1,2-a]喹

啉-5-胺(16 mg, 23%)。 ¹H NMR (400 MHz, DMSO-d6) δ1.56 (d, J= 4.0 Hz, 3H), 1.95-2.11 (m, 1H), 2.10 – 1.98 (m, 1H), 2.31-2.24 (m, 1H), 3.89-3.71 (m, 3H), 4.03-3.90 (m, 4H), 5.32-5.24 (m, 1H), 7.11 (s, 1H), 7.36 (t, J= 8 Hz, 1H), 7.58-7.47 (m, 2H), 7.80 (d, J= 8 Hz, 1H), 7.99 (s, 1H), 8.04-8.13 (m, 2H), 8.20 (d, J= 4.0 Hz, 1H)。 實例13 (R)-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-3-嗎啉基咪唑并[1,2-a]吡啶并[4,3-e]嘧啶-5-胺

To (R)-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)imidazo[1,2-a]quinone

To a solution of phenin-7-ol (0.06 g, 0.155 mmol) in DMF (0.776 mL) was added (R)-4-methylbenzenesulfonic acid tetrahydrofuran-3-yl ester (0.041 g, 0.171 mmol) and carbonic acid Cesium (0.091 g, 0.280 mmol). The mixture was stirred at ambient temperature under _N2 atmosphere for 18 h. Water (5 mL) was added. The mixture was extracted with EA (3 x 15 mL). The combined organic layers were washed with water (10 mL), dried over sodium sulfate, and concentrated. The crude product was purified by reverse phase HPLC using 10-50% _CH3CN (with 0.1% formic acid) in water (with 0.1% formic acid). The product was lyophilized to provide N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl )Oxy)imidazo[1,2-a]quinone

Lin-5-amine (16 mg, 23%). ¹ H NMR (400 MHz, DMSO-d6) δ 1.56 (d, J = 4.0 Hz, 3H), 1.95-2.11 (m, 1H), 2.10 – 1.98 (m, 1H), 2.31-2.24 (m, 1H) , 3.89-3.71 (m, 3H), 4.03-3.90 (m, 4H), 5.32-5.24 (m, 1H), 7.11 (s, 1H), 7.36 (t, J = 8 Hz, 1H), 7.58-7.47 (m, 2H), 7.80 (d, J = 8 Hz, 1H), 7.99 (s, 1H), 8.04-8.13 (m, 2H), 8.20 (d, J = 4.0 Hz, 1H). Example 13 (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-3-morpholinoimidazo[1,2-a]pyrido[4 ,3-e]pyrimidin-5-amine

To a solution of methyl 5-amino-2-chloroisonicotinate (5 g, 26.8 mmol) in THF (107 mL) was added trichloroacetyl isocyanate (5.30 g, 28.1 mmol). The mixture was stirred at rt for 2 h. Solvent was removed. _Et2O (25 mL) was added to the residue. The white precipitate was collected by filtration to obtain methyl 2-chloro-5-(3-(2,2,2-trichloroacetyl)ureido)isonicotinate (9.3 g, 93%). MS m/z: 457.0 [M+1].

To a solution of methyl 2-chloro-5-(3-(2,2,2-trichloroacetyl)ureido)isonicotinate (9.3 g, 24.80 mmol) in MeOH (100 mL), Ammonia (7N in MeOH) (7.09 mL, 49.6 mmol) was added. The mixture was stirred at rt under _N2 for 2 h. The solution was heated at reflux for an additional 2 h. The mixture was cooled to rt. The precipitate was filtered off to give 6-chloropyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (4.5 g, 92%). MS m/z: 198.9 [M+1].

To a suspension of 6-chloropyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (4.75 g, 24.04 mmol) in phosphoryl chloride (42.7 mL, 457 mmol), N,N-Diisopropylethylamine (4.40 mL, 25.2 mmol) and DMF (0.30 mL) were added dropwise with stirring at 0 °C. The mixture was heated at reflux for 10 h. Remove excess phosphoryl chloride. Ice water was added to the residue, and the mixture was stirred for 30 min. The precipitate was filtered, washed with water and hexane, and dried in a vacuum oven to obtain 2,4,6-trichloropyrido[3,4-d]pyrimidine (4.23 g, 75% yield). MS m/z: 235.5 [M+1].

To a solution of 2,4,6-trichloropyrido[3,4-d]pyrimidine (1.30 g, 5.54 mmol) in DMSO (27.7 mL) was added (R)-1-(2-methyl- 3-(Trifluoromethyl)phenyl)ethanamine (1.127 g, 5.54 mmol) and triethylamine (2.70 mL, 19.41 mmol). The mixture was heated at 80 °C for 2.5 h. The mixture was cooled to rt, and then poured into ice-cold water (150 mL). The mixture was extracted with EA (3 x 75 mL). The combined organic layers were washed with water (1 x 50 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (0-50% EA in hexane) to obtain (R)-2,6-dichloro-N-(1-(2-methyl-3-(trifluoro Methyl)phenyl)ethyl)pyrido[3,4-d]pyrimidin-4-amine (1.60 g, 72%). MS m/z: 402.2 [M+1].

(R)-2,6-dichloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidine-4- A mixture of amine (0.90 g, 2.24 mmol) and 2,2-dimethoxyethan-1-amine (4.7 g, 44.9 mmol) was heated at 100 °C for 18 h. LCMS showed exclusive formation of product. The mixture was cooled to rt, and then poured into ice-cold water (20 mL). The resulting precipitate was filtered, washed with water and hexane, and dried in a vacuum oven to obtain (R)-6-chloro-N2-(2,2-dimethoxyethyl)-N4-(1-(2 -Methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyrimidine-2,4-diamine (0.80 g, 76%). MS m/z: 470.9 [M+1].

(R)-6-chloro-N2-(2,2-dimethoxyethyl)-N4-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyridine Do[3,4-d]pyrimidine-2,4-diamine (0.40 g, 0.851 mmol) was dissolved in formic acid (3.21 mL, 85 mmol). The mixture was heated at 100°C for 7 days. The mixture was cooled to rt, neutralized with aqueous sodium bicarbonate and extracted with EA (3 x 30 mL). The combined organic layers were washed with water (1 x 30 mL), dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (0-70% (9:1 DCM:MeOH) in DCM) to obtain (R)-3-chloro-N-(1-(2-methyl-3- (Trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]pyrido[4,3-e]pyrimidin-5-amine (0.20 g, 0.493 mmol, 58%). MS m/z: 406.10 [M+1].

烷(0.887 mL)中之溶液中，添加碳酸銫(0.361 g, 1.109 mmol)、嗎啉(0.023 g, 0.266 mmol)及Pd PEPPSI-IHEPT Cl 3-氯吡啶(0.022 g, 0.022 mmol)。將混合物脫氣且在100℃下攪拌12 h。將混合物冷卻至rt且用EA (3 × 30 mL)萃取。將合併之有機層用水(1 × 30 mL)洗滌，以硫酸鈉乾燥且濃縮。將粗產物藉由反相HPLC使用水中之10-50% CH ₃CN純化，以獲得R)-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-3-嗎啉基咪唑并[1,2-a]吡啶并[4,3-e]嘧啶-5-胺(16.7 mg, 17%)。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ1.58 (d, J= 4.0 Hz, 3H), 2.60 (s, 3 H) 3.61-3.53 (m, 4H), 3.83-3.76 (m, 4H), 5.70 (quin, J= 8.0 Hz, 1H), 7.10 (s, 1H), 7.38 (t, J= 8.0 Hz, 1H) 7.56 (d, J= 8.0 Hz, 1H), 7.68 (s, 1H), 7.77 (d, J= 8.0 Hz, 1H), 8.04 (s, 1H) 8.34 (d, 1H) 9.13 (s, 1H)。 實例14 ( R)-(4-((1-(5-胺基-2-甲基-3-(三氟甲基)苯基)乙基)胺基)-8-甲基-1,3-二氫-2 H-咪唑并[1,2- a]吡咯并[3,4- e]嘧啶-2-基)(4-甲氧基四氫-2 H-哌喃-4-基)甲酮

To (R)-3-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]pyrido[4,3- e] pyrimidine-5-amine (0.09 g, 0.222 mmol) in di

To a solution in alkanes (0.887 mL), cesium carbonate (0.361 g, 1.109 mmol), morpholine (0.023 g, 0.266 mmol) and Pd PEPPSI-IHEPT Cl 3-chloropyridine (0.022 g, 0.022 mmol) were added. The mixture was degassed and stirred at 100 °C for 12 h. The mixture was cooled to rt and extracted with EA (3 x 30 mL). The combined organic layers were washed with water (1 x 30 mL), dried over sodium sulfate and concentrated. The crude product was purified by reverse phase HPLC using 10-50% _CH3CN in water to obtain R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) -3-Morpholinylimidazo[1,2-a]pyrido[4,3-e]pyrimidin-5-amine (16.7 mg, 17%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.58 (d, J = 4.0 Hz, 3H), 2.60 (s, 3 H) 3.61-3.53 (m, 4H), 3.83-3.76 (m, 4H), 5.70 (quin, J = 8.0 Hz, 1H), 7.10 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H) 7.56 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H) 8.34 (d, 1H) 9.13 (s, 1H). Example 14 ( R )-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-1,3 -Dihydro- 2H -imidazo[1,2- a ]pyrrolo[3,4- e ]pyrimidin-2-yl)(4-methoxytetrahydro- 2H -pyran-4-yl) ketone

N,N -Diisopropylethylamine (0.45 mL, 2.58 mmol, 3.0 eq.) was added to 1 (0.25 g, 0.86 mmol, 1.0 eq.) and 2 (0.25 g, 0.86 mmol, 1.0 eq.) in solution in anhydrous acetonitrile (7.0 mL). The mixture was stirred at 80 °C for 17 h, at which time LCMS analysis indicated the reaction was complete. The solvent was evaporated under reduced pressure at 29°C. The yellow crude was purified on a Teledyne ISCO automated chromatography system (40 g RediSepRf silica gel column) with gradient elution from 0 to 30% EA in hexane to give 3 (0.41 g, 94% yield , >99% LCMS purity). LCMS m/z: 502.10 [M+H] ⁺ .

Propargylamine (0.38 mL, 5.98 mmol, 10.0 eq.) and N,N -diisopropylethylamine (0.31 mL, 1.79 mmol, 3.0 eq.) were sequentially added to 3 (0.30 g, 0.60 mmol, 1.0 eq.) in anhydrous 2-propanol (5.0 mL). The mixture was stirred at 105 °C for 2.5 days, at which time LCMS analysis indicated the reaction was complete. The solvent was evaporated under reduced pressure at 29°C. The yellow crude was purified on a Teledyne ISCO automated chromatography system (40 g RediSepRf silica gel column) with gradient elution from 0 to 100% EA in hexane to give 4 (0.08 g, 26% yield , >99% LCMS purity). LCMS m/z: 521.10 [M+H] ⁺ .

A mixture of 4 (65 mg, 0.13 mmol, 1.0 eq.) and 10% palladium on carbon (10.0 mg, 50% wet) in methanol (1.0 mL) was hydrogenated at 1 psi for 18 h, at which time LCMS analysis indicated a reaction completely. The mixture was filtered through celite (2 g), which was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure at 29°C to give 5 (60 mg, 98% yield, >90% LCMS purity), which was subsequently used without any purification. LCMS m/z: 491.20 [M+H] ⁺ .

烷(1.0 mL)中之溶液中，逐滴添加於1,4-二

烷中之4M HCl (0.31 mL, 1.22 mmol, 10.0 eq.)。將混合物升溫至rt，且然後在此溫度下攪拌17 h，此時LCMS分析指示反應完全。將混合物在29℃下在減壓下濃縮，以給出 6（95 mg, 95%產率，＞90% LCMS純度），其隨後使用而未進行任何純化。LCMS m/z: 391.20 [M+H] ⁺（游離鹼）。 5 (60 mg, 0.122 mmol, 1.0 eq.) in anhydrous 1,4-bis

a solution in alkane (1.0 mL), add dropwise in 1,4-bis

4M HCl in alkanes (0.31 mL, 1.22 mmol, 10.0 eq.). The mixture was warmed to rt and then stirred at this temperature for 17 h at which time LCMS analysis indicated the reaction was complete. The mixture was concentrated under reduced pressure at 29°C to give 6 (95 mg, 95% yield, >90% LCMS purity), which was subsequently used without any purification. LCMS m/z: 391.20 [M+H] ⁺ (free base).

Azabenzotriazol-1-yl) -N , N - N' , N' -tetramethyluronium hexafluorophosphate (HATU) (44 mg, 0.12 mmol, 1.1 eq.) Add to a solution of 4-methoxytetrahydro- 2H -pyran-4-carboxylic acid (17 mg, 0.11 mmol, 1.0 eq.) in dry dimethylformamide (1.2 mL). The mixture was stirred for 10 min. Compound 6 (45 mg, 0.11 mmol, 1.0 eq.) and N,N -diisopropylethylamine (0.06 mL, 0.32 mmol, 3.0 eq.) were added sequentially at 0°C. The mixture was stirred at 0 °C for 20 min, at which time LCMS analysis indicated the reaction was complete. Sat. sodium bicarbonate and sat. brine (4.0 mL, 1:1) were added, and then extracted with EA (2 x 20 mL). The combined organic extracts were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure at 30 °C. The yellow crude was purified on a Teledyne ISCO automated chromatography system (40 g RediSepRf Gold silica gel column) with a gradient elution of 0 to 8% methanol in dichloromethane to give ( R )-(4- ((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-1,3-dihydro-2 H -imidazo [1,2- a ]pyrrolo[3,4- e ]pyrimidin-2-yl)(4-methoxytetrahydro- 2H -pyran-4-yl)methanone (15 mg, 27% yield yield, 96% LCMS purity). ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 7.29 (s, 1H), 6.90-6.84 (m, 1H), 6.80 (dd, 1H), 5.51-5.38 (m, 2H), 5.36-5.21 ( m, 3H), 4.95 (br d, 1H), 3.76-3.56 (m, 5H), 3.29-3.26 (m, 1H), 3.24-3.13 (m, 4H), 2.34-2.32 (m, 1H), 2.32 (s, 3H), 2.03-1.84 (m, 4H), 1.46 (t, 3H). Example 15 ( R )-(4-((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-1,3,7,8-tetrahydro -2H -imidazo[1,2- a ]pyrrolo[3,4- e ]pyrimidin-2-yl)(4-methoxytetrahydro- 2H -pyran-4-yl)methanone

N,N -Diisopropylethylamine (0.36 mL, 2.07 mmol, 3.0 eq.) was added to compounds 1 (0.2 g, 0.69 mmol, 1.0 eq.) and 2 (0.17 g, 0.69 mmol, 1.0 eq.) In solution in anhydrous acetonitrile (5.0 mL). The mixture was stirred at 80 °C for 17 h, at which time LCMS analysis indicated the reaction was complete. The mixture was cooled to rt. The solvent was evaporated under reduced pressure at 29°C. The yellow crude was purified on a Teledyne ISCO automated chromatography system (24 g RediSepRf silica gel column) with gradient elution from 0 to 30% EA in hexane to give 3 (0.28 g, 89% yield , >95% LCMS purity). LCMS m/z: 457.10 [M+H] ⁺ .

烷(2.0 mL)中之溶液中，逐滴添加於1,4-二

烷中之4M HCl (0.82 mL, 3.28 mmol, 6.0 eq.)。將混合物升溫至rt，且然後在此溫度下攪拌17 h，此時LCMS分析指示反應完全。將混合物在29℃下在減壓下濃縮，以給出 4（210 mg, 98%產率，＞90% LCMS純度），其隨後使用而未進行任何純化。LCMS m/z: 357.10 [M+H] ⁺（游離鹼）。 3 (250 mg, 0.55 mmol, 1.0 eq.) in anhydrous 1,4-bis

a solution in alkane (2.0 mL), add dropwise in 1,4-bis

4M HCl in alkanes (0.82 mL, 3.28 mmol, 6.0 eq.). The mixture was warmed to rt and then stirred at this temperature for 17 h at which time LCMS analysis indicated the reaction was complete. The mixture was concentrated under reduced pressure at 29°C to give 4 (210 mg, 98% yield, >90% LCMS purity), which was subsequently used without any purification. LCMS m/z: 357.10 [M+H] ⁺ (free base).

Azabenzotriazol-1-yl) -N , N - N' , N' -tetramethyluronium hexafluorophosphate (HATU) (223 mg, 0.59 mmol, 1.1 eq.) Add to a solution of 4-methoxytetrahydro- 2H -pyran-4-carboxylic acid (86 mg, 0.53 mmol, 1.0 eq.) in dry dimethylformamide (5.0 mL). The mixture was stirred at rt for 10 min. Compound 4 (210 mg, 0.53 mmol, 1.0 eq.) and N,N -diisopropylethylamine (0.28 mL, 1.60 mmol, 3.0 eq.) were added sequentially at rt. The mixture was stirred at rt for 1 h at which time LCMS analysis indicated the reaction was complete. Water (10 mL) was added. The mixture was extracted with EA (3 x 100 mL). The combined organic extracts were washed with saturated brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure at 29 °C. The yellow crude was purified on a Teledyne ISCO automated chromatography system (24 g RediSepRf silica gel column) with gradient elution from 0 to 70% EA in hexane to give 5 (210 mg, 79% yield , >95% LCMS purity). LCMS m/z: 499.10 [M+H] ⁺ .

To 5 (100 mg, 0.20 mmol, 1.0 eq.) was slowly added ethanolamine (1.0 mL). After the addition, the clear brown solution was stirred at 80 °C for 2 h at which time LCMS analysis indicated the reaction was complete. The mixture was cooled at rt, and then cold water (3.0 mL) was added. The mixture was precipitated and filtered. The filter cake was washed with water (2 x 10 mL) and dried in a high vacuum oven at 35 °C for 18 h to give 6 (60 mg, 57% yield, >90% LCMS purity), which was subsequently used with No purification was performed. LCMS m/z: 524.10 [M+H] ⁺ .

To a solution of 6 (60 mg, 0.12 mmol, 1.0 eq.) in anhydrous dichloromethane (0.6 mL) was added sequentially triethylamine (24 µL, 0.17 mmol, 1.5 eq.) and methanesulfonate at 0°C Acyl chloride (11 µL, 0.14 mmol, 1.2 eq.). The mixture was stirred at 0 °C for 2 h, at which time LCMS analysis indicated the reaction was complete. Ice-cold water (10 mL) was added, and the mixture was extracted with dichloromethane (3 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure below 29 °C to give 7 (60 mg, 87% yield, >70% LCMS purity), which was subsequently used with No purification was performed. LCMS m/z: 602.10 [M+H] ⁺ .

烷-4-羰基)-12-甲基-N-[(1R)-1-[3-(三氟甲基)苯基]乙基]-1,4,8,10-四氮雜三環[7.3.0.02,⁶]十二-2(6),7,9,11-四烯-7-胺

N,N -Diisopropylethylamine (36 µL, 0.20 mmol, 2.0 eq.) was added to 7 (60 mg, 0.10 mmol, 1.0 eq.) in dry dimethylformamide (0.5 mL) in solution. The mixture was stirred at 70 °C for 1 h at which time LCMS analysis indicated the reaction was complete. The mixture was cooled to rt. The crude was purified directly on a reverse phase Teledyne ISCO automated chromatography system with a gradient of 0 to 60% acetonitrile in water. The desired fractions were collected and dried via lyophilization to give ( R )-(4-((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amine base)-1,3,7,8-tetrahydro- 2H -imidazo[1,2- a ]pyrrolo[3,4- e ]pyrimidin-2-yl)(4-methoxytetrahydro- 2H -pyran-4-yl)methanone (30 mg, 60% yield, 98.4% LCMS purity). LCMS m/z: 506.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.50 (br s, 1H), 7.62 (dd, 1H), 7.48 (t, 1H), 7.30 (dt, 1H), 5.65-5.53 (m, 1H) , 5.02-4.90 (m, 1H), 4.84 (s, 1H), 4.71 (d, 1H), 4.57 (d, 1H), 4.34-4.19 (m, 2H), 3.79-3.56 (m, 6H), 3.53 -3.43 (m, 2H), 3.23-3.11 (m, 4H), 1.95-1.83 (m, 4H), 1.51 (t, 3H). Example 16 4-(4-methoxy

Alkane-4-carbonyl)-12-methyl-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-1,4,8,10-tetraazatricyclic [7.3.0.02,⁶]Dodeca-2(6),7,9,11-tetraen-7-amine

To a solution of 1 (8 g, 27.57 mmol) in dimethyloxide (80 mL, 10 V) was added 2 (5.7 g, 30.33 mmol), N,N-diisopropylethylamine (7.2 mL , 41.36 mmol). The mixture was refluxed at 120 °C for 12 h. After complete consumption of the starting material, the reaction was quenched with water (3 x 50 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were separated, dried (anhydrous Na ₂ SO ₄ ), and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography to afford 3 (10 g, 81.9%). LCMS m/z: 443.2 [M+H] ⁺ .

To a solution of 3 (5 g, 11.29 mmol) in dimethyloxide (31 mL, 6.2 V) was added propargylamine ( 4 , 2.1 mL, 33.87 mmol), and N,N-diisopropyl Ethylamine (6.2 mL, 33.87 mmol) was refluxed at 105°C for 36 h. The reaction was quenched with water (3 x 50 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were separated, dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure to give crude product, which was purified by column chromatography to give 5 (0.7 g, 13%). LCMS m/z: 462.32 [M+H] ⁺ .

To a solution of 5 (0.7 g, 1.51 mmol) in acetonitrile (7 mL, 10 V) was added AgoTf (38.9 mg, 0.151 mmol). The mixture was refluxed at 85 °C for 16 h. The reaction was quenched with water (3 x 50 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were separated, dried (anhydrous Na ₂ SO ₄ ), and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography to afford 6 (0.55 g, 79.7%). LCMS m/z: 463.27 [M+H] ⁺ .

烷(2.75 mL, 5 V)中之溶液中，添加於二

烷中之4M HCl (2.75 mL, 5V)。將混合物於rt下攪拌16 h。將混合物在減壓下蒸發，以去除最少量之溶劑。將混合物用二乙醚(20 mL)洗滌，且將殘餘物在減壓下乾燥，以獲得 7(0.4 g, 93%)。 Xiang 6 (0.55 g, 1.193 mmol) in 1,4-di

In a solution in alkane (2.75 mL, 5 V), add in two

4M HCl in alkanes (2.75 mL, 5V). The mixture was stirred at rt for 16 h. The mixture was evaporated under reduced pressure to remove the minimum amount of solvent. The mixture was washed with diethyl ether (20 mL), and the residue was dried under reduced pressure to obtain 7 (0.4 g, 93%).

烷-4-羰基)-12-甲基-N-[(1R)-1-[3-(三氟甲基)苯基]乙基]-1,4,8,10-四氮雜三環[7.3.0.02,⁶]十二-2(6),7,9,11-四烯-7-胺。 ¹H NMR (400 MHz, DMSO-d ₆) δ 8.55 (s, 1H), 8.35-8.25 (m, 2H), 7.90-7.80 (m, 2H), 7.31 (s, 1H), 5.70-5.50 (m, 1H), 4.05 (s, 3H), 3.97 (s, 3H), 1.66 (d, J=7.2 Hz, 3H), NH質子由於交換而未觀察到。 實例17 (1-甲氧基-環丙基)-{8-甲基-4-[1-(3-三氟甲基-苯基)-乙基胺基]-1,3-二氫-2,5,6,8a-四氮雜-不對稱二環戊二烯并苯-2-基}-甲酮

To a solution of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid (0.04 g, 0.252 mmol) in dichloromethane (1 mL, 10 V) was added EDC·HCl (0.0725 g, 0.378 mmol ), HOBT (0.034 g, 0.252 mmol) and DIPEA (0.176 mL, 1.0 mmol). The mixture was stirred for 15 min, and then 7 (0.1 g, 0.252 mmol) was added. The mixture was stirred at rt for 12 h. The mixture was diluted with water, and then extracted with DCM (3 x 30 mL). The combined organic layers were separated, dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure to provide crude product. The crude product was purified by column chromatography to obtain 4-(4-methoxy

Alkane-4-carbonyl)-12-methyl-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]-1,4,8,10-tetraazatricyclic [7.3.0.02,⁶]Dodeca-2(6),7,9,11-tetraen-7-amine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.35-8.25 (m, 2H), 7.90-7.80 (m, 2H), 7.31 (s, 1H), 5.70-5.50 (m , 1H), 4.05 (s, 3H), 3.97 (s, 3H), 1.66 (d, J= 7.2 Hz , 3H), NH protons were not observed due to exchange. Example 17 (1-methoxy-cyclopropyl)-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro- 2,5,6,8a-Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-methanone

(1-methoxy-cyclopropyl)-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2, 5,6,8a-tetraaza-asymmetric dicyclopentadienenen-2-yl}-methanone using 1-methoxycyclopropane-1-carboxylic acid using a similar method as provided in Example 17 (0.029 g, 0.252 mmol) was prepared instead of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid. (1-Methoxy-cyclopropyl)-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2 ,5,6,8a-Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-methanone. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.35-8.25 (m, 2H), 7.90-7.80 (m, 2H), 7.31 (s, 1H), 5.70-5.50 (m , 1H), 4.05 (s, 3H), 3.97 (s, 3H), 1.66 (d, J= 7.2 Hz , 3H), NH protons were not observed due to exchange. Example 18 (1-fluoromethyl-cyclopropyl)-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro- 2,5,6,8a-Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-methanone

(1-fluoromethyl-cyclopropyl)-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2, 5,6,8a-tetraaza-asymmetric dicyclopentadienenen-2-yl}-methanone using 1-(fluoromethyl)cyclopropane-1 using a method similar to that provided in Example 17 - Formic acid (0.029 g, 0.252 mmol) was prepared instead of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid. (1-Fluoromethyl-cyclopropyl)-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2 ,5,6,8a-Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-methanone. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.35-8.25 (m, 2H), 7.90-7.80 (m, 2H), 7.31 (s, 1H), 5.70-5.50 (m , 1H), 4.05 (s, 3H), 3.97 (s, 3H), 1.66 (d, J= 7.2 Hz , 3H), NH protons were not observed due to exchange. Example 19 (1-methyl-cyclopropyl)-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2 ,5,6,8a-tetraaza-asymmetric dicyclopentadienen-2-yl}-methanone

(1-Methyl-cyclopropyl)-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2,5 , 6,8a-Tetraaza-asymmetric dicyclopentadienen-2-yl}-methanone using 1-methylcyclopropane-1-carboxylic acid (0.025 g, 0.252 mmol) was prepared instead of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid. (1-Methyl-cyclopropyl)-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2, 5,6,8a-Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-methanone. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.35-8.25 (m, 2H), 7.90-7.80 (m, 2H), 7.31 (s, 1H), 5.70-5.50 (m , 1H), 4.05 (s, 3H), 3.97 (s, 3H), 1.66 (d, J= 7.2 Hz , 3H), NH protons were not observed due to exchange. Example 20 Bicyclo[1.1.1]pent-1-yl-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro- 2,5,6,8a-Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-methanone

Bicyclo[1.1.1]pent-1-yl-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2, 5,6,8a-Tetraaza-asymmetric dicyclopentadienenen-2-yl}-methanone using a similar method as provided in Example 17 using bicyclo[1.1.1]pentane-1- Formic acid (0.028 g, 0.252 mmol) was prepared in place of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid. Bicyclo[1.1.1]pent-1-yl-{8-methyl-4-[1-(3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2 ,5,6,8a-Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-methanone. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.35-8.25 (m, 2H), 7.90-7.80 (m, 2H), 7.31 (s, 1H), 5.70-5.50 (m , 1H), 4.05 (s, 3H), 3.97 (s, 3H), 1.66 (d, J= 7.2 Hz , 3H), NH protons were not observed due to exchange.

Example 21 (4-methoxy-tetrahydro-pyran-4-yl)-{4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-1 ,3-Dihydro-2,5,6,8a-tetraaza-asymmetric dicyclopentadienen-2-yl}-methanone

烷(50 mL)中之冷卻(0℃)溶液中，緩慢添加於1,4-二

烷中之4M HCl (50 mL)。將混合物於rt下攪拌12 h。將混合物在減壓下蒸發，以去除1,4-二

烷。將殘餘物用DCM (10 mL)洗滌，且在減壓下乾燥，以得到 2(8 g, 95.12%)。LCMS m/z: 190 [M+H] ⁺。 1 (10 g, 34.02 mmol) to 1,4-di

To a cooled (0°C) solution in alkane (50 mL), slowly add 1,4-bis

4M HCl in alkanes (50 mL). The mixture was stirred at rt for 12 h. The mixture was evaporated under reduced pressure to remove 1,4-di

alkyl. The residue was washed with DCM (10 mL) and dried under reduced pressure to give 2 (8 g, 95.12%). LCMS m/z: 190 [M+H] ⁺ .

To a solution of 2 (8 g, 0.3539 mmol) in DCM (160 mL, 20 V) was added DIPEA (18.54 mL, 0.1061 mmol) and ethyl chloroformate (3.47 mL, 0.03539 mmol). The mixture was stirred at rt for 2 h. The mixture was diluted with purified water (10 mL), and extracted with DCM (3 x 10 mL). The organic layer was dried over Na ₂ SO ₄ , concentrated, and purified by column chromatography (10% EA:Hex) to obtain 3 (8 g 86.29%). LCMS m/z: 262.2 [M+H] ⁺ .

A solution of 3 (2.5 g, 9.5778 mmol) and 4 (2.33 mg, 11.49 mmol) in DMSO (25 mL) was stirred at rt for 5 min, and then DIPEA (5.1 mL, 28.73 mmol) was added. The mixture was stirred at 90 °C for 12 h. The mixture was cooled to rt and ice-cold water (25 mL) was added. The mixture was extracted with EA (3 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography (5% EA:Hex) to obtain 5 (3.6 g, 87.80%). LCMS m/z: 429.2 [M+H] ⁺ .

A solution of 5 (3.6 g, 8.394 mmol) and 6 (1.37 mL, 12.59 mmol) in DMSO (36 mL) was stirred at rt for 5 min, and then DIPEA (5.1 mL, 28.73 mmol) was added. The mixture was stirred at 130 °C for 18 h. The mixture was cooled to rt and then ice-cold water (25 mL) was added. The mixture was extracted with EA (3 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (5% EA:Hex) to obtain 7 (2.3 g, 55% ). LCMS m/z: 498.00 [M+H] ⁺ .

A solution of 7 (2.5 g, 5.0525 mmol) dissolved in HBr (25 mL, 10 V) in acetic acid was stirred at 100 °C for 12 h. The mixture was cooled to rt, and then concentrated to remove HBr in AcOH. The reaction was quenched with saturated NaHCO ₃ solution (pH maintained at 8-9), and then extracted with 10% MeOH:DCM. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography (5% MeOH:DCM) to obtain 8 (620 mg, 34.15%). LCMS m/z: 362.3 [M+H] ⁺ .

To a stirred solution of 8 (80 mg, 0.2216 mmol) and 9 (35.4 mg, 0.2216 mmol) in DCM (4.2 mL, 62 V) was added DIPEA (0.09 mL, 0.5540 mmol), EDC HCl (63.2 mg, 0.3324 mmol) and HOBT (29.9 mg, 0.2216 mmol). The mixture was stirred at rt for 12 h. The mixture was diluted with purified water (10 mL), and extracted with DCM (3 x 10 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated (1% MeOH:DCM) to provide (4-methoxy-tetrahydro-pyran-4-yl)-{4-[1-(2-methyl -3-Trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2,5,6,8a-tetraaza-asymmetric dicyclopentadienen-2-yl }-methanone (35 mg, 31%). LCMS m/z: 504.4 [M+H] ⁺ . Example 22 (1-fluoromethyl-cyclopropyl)-{4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro- 2,5,6,8a-Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-methanone

(1-fluoromethyl-cyclopropyl)-{4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2, 5,6,8a-Tetraaza-asymmetric dicyclopentadienenen-2-yl}-methanone using 1-(fluoromethyl)cyclopropane-1 using a method similar to that provided in Example 21 - Formic acid (22.9 mg, 0.1939 mmol) was prepared instead of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid. (1-Fluoromethyl-cyclopropyl)-{4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2 ,5,6,8a-tetraaza-unsymmetric dicyclopentadienen-2-yl}-methanone (25 mg, 28%). LCMS m/z: 462.3 [M+H] ⁺ . Example 23 (1-methyl-cyclopropyl)-{4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2 ,5,6,8a-tetraaza-asymmetric dicyclopentadienen-2-yl}-methanone

(1-methyl-cyclopropyl)-{4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2,5 , 6,8a-Tetraaza-asymmetric dicyclopentadienenen-2-yl}-methanone using 1-methylcyclopropane-1-carboxylic acid (27.7 mg, 0.2768 mmol) instead of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid. (1-Methyl-cyclopropyl)-{4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2, 5,6,8a-Tetraaza-unsymmetric dicyclopentadienen-2-yl}-methanone (25 mg, 20%). LCMS m/z: 444.25 [M+H] ⁺ . Example 24 (1-methoxy-cyclopropyl)-{4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro- 2,5,6,8a-Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-methanone

(1-methoxy-cyclopropyl)-{4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2, 5,6,8a-Tetraaza-asymmetric dicyclopentadienenen-2-yl}-methanone using 1-methoxycyclopropane-1-carboxylic acid using a similar method as provided in Example 21 (32.14 mg, 0.2768 mmol) was prepared instead of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid. (1-Methoxy-cyclopropyl)-{4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2 ,5,6,8a-Tetraaza-unsymmetric dicyclopentadienenen-2-yl}-methanone (26 mg, 21%). LCMS m/z: 460.3 [M+H] ⁺ . Example 25 ((2,3-dihydro-1H-2,5,6,8a-tetraaza-unsymmetrical dicyclopentadiene-4-yl)-[1-(2-methyl-3 -trifluoromethyl-phenyl)-ethyl]-amine

A solution of 7 (2.5 g, 5.0525 mmol) in HBr in acetic acid (25 mL, 10 V) was stirred at 100 °C for 12 h. The mixture was cooled to rt, and then concentrated to remove HBr in AcOH. The reaction was quenched with saturated NaHCO ₃ solution (pH maintained at 8-9). The mixture was extracted with 10% MeOH:DCM. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography (5% MeOH:DCM) to obtain ((2,3-dihydro-1H-2,5,6,8a-tetraaza-asymmetric dicyclopentadiene Alkenen-4-yl)-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethyl]-amine (620 mg, 34.15%). LCMS m/z: 362.3 [M +H] ⁺ . Example 26 ([1-(2-methyl-3-trifluoromethyl-phenyl)-ethyl]-[2-(tetrahydro-pyran-4-ylmethyl)-2 ,3-Dihydro-1H-2,5,6,8a-tetraaza-unsymmetrical dicyclopentadienen-4-yl]-amine

([1-(2-Methyl-3-trifluoromethyl-phenyl)-ethyl]-[2-(tetrahydro-pyran-4-ylmethyl)-2,3-dihydro-1H -2,5,6,8a-Tetraaza-asymmetric dicyclopentadienen-4-yl]-amine using a similar method as provided in Example 21 using tetrahydro-2H-pyran-4 -Formaldehyde (22.1 mg, 0.1938 mmol) was prepared instead of 4-methoxytetrahydro-2H-pyran-4-carboxylic acid. Obtained ([1-(2-methyl-3-trifluoromethyl-phenyl) -Ethyl]-[2-(tetrahydro-pyran-4-ylmethyl)-2,3-dihydro-1H-2,5,6,8a-tetraaza-asymmetric dicyclopentadiene Acene-4-yl]-amine (29 mg, 32%). LCMS m/z: 460.4 [M+H] ⁺ . Example 27 {4-[1-(3-amino-5-trifluoromethyl -phenyl)-ethylamino]-1,3-dihydro-2,5,6,8a-tetraaza-asymmetric dicyclopentadienecene-2-yl}-(1-methoxy yl-cyclopropyl)-methanone

A solution of 3 (3 g, 11.45 mmol) and 4 (3.7 g, 16.48 mmol) in DMSO (30 mL) was stirred at rt for 5 min, and then DIPEA (7.9 mL, 45.80 mmol) was added. The mixture was stirred at 120 °C for 12 h. The mixture was cooled to rt and ice-cold water (25 mL) was added. The mixture was extracted with EA (3 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography (5% EA:Hex) to obtain 5 (3.6 g, 69%). LCMS m/z: 460.3 [M+H] ⁺ .

A solution of 5 (3.2 g, 6.9595 mmol) and 6 (1.13 mL, 10.43 mmol) in DMSO (32 mL) was stirred at rt for 5 min, and DIPEA (4.25 mL, 24.35 mmol) was added. The mixture was stirred at 120 °C for 12 h. The mixture was cooled to rt and ice-cold water (25 mL) was added. The mixture was extracted with EA (3 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography (10% EA:Hex) to obtain 7 (3.2 g, 88%).

To a solution of 7 (3.2 g, 6.5057 mmol) in HBr (32 mL, 10 V) in acetic acid. The mixture was stirred at 100 °C for 12 h. The mixture was cooled to rt, and then concentrated to remove HBr in AcOH. The reaction was quenched with saturated NaHCO ₃ solution (pH maintained at 8-9), and then extracted with 10% MeOH:DCM. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography (5% MeOH:DCM) to obtain 8 (790 mg, 33.3%).

To a solution of 8 (800 mg, 2.03 mmol) in THF:water (7:3, 56 mL:24 mL) was added zinc powder (2.4 g, 3 × W/W) and NH ₄ Cl (2.4 g, 3 x W/W). The mixture was stirred at rt for 12 h. The mixture was filtered through a bed of celite, and then concentrated to remove THF. The mixture was extracted with 10% MeOH:DCM (3 x 10 V). The organic layer was dried over Na ₂ SO ₄ and concentrated to provide crude product. The crude product was purified via prep-TLC to obtain 9 (350 mg, 47%). LCMS m/z: 363.3 [M+H] ⁺ .

To a stirred solution of 9 (80 mg, 0.2207 mmol) and 10 (25.6 mg, 0.2207 mmol) in DCM (4.9 mL, 62 V) was added DIPEA (0.0.09 mL, 0.5517 mmol), EDC·HCl (62.9 mg, 0.3311 mmol) and HOBT (29.8 mg, 0.2207 mmol). The mixture was stirred at rt for 12 h. The mixture was diluted with purified water (10 mL), and extracted with DCM (3 x 10 mL). The organic layer was dried over _Na2SO4 and concentrated (1% MeOH:DCM) to obtain {4-[1-(3-amino-5-trifluoromethyl _- phenyl)-ethylamino]- 1,3-Dihydro-2,5,6,8a-tetraaza-asymmetric dicyclopentadienen-2-yl}-(1-methoxy-cyclopropyl)-methanone (9 mg, 8.85%). LCMS m/z: 461.3 [M+H] ⁺ . Example 28 (R)-(1-methoxycyclopropyl)(4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-1,3 ,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidin-2-yl)methanone

To a stirred solution of 1 (4 g, 1 eq.) in dimethyloxide (20 mL, 5 V) at rt was added dropwise 2 (2.51 g, 0.9 eq.) followed by dropwise addition of N, N diisopropylethylamine (8.32 mL, 3.5 eq.). The resulting solution was heated to 90 °C and stirred for 12 h. The mixture was cooled to rt, and the resultant was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (100 mL) and extracted with EA (2 x 70 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified via ^Combiflash® with 20-25% EA in hexane as eluent. Pure fractions were collected and concentrated to provide 3 (4.4 g, 70%). LCMS m/z: 457.3 [M+H] ⁺ .

烷(1.5 mL, 3 V)中之攪拌溶液中，逐滴添加二

烷中之4M HCl (2.5 mL, 5V)。將混合物攪拌15 min。將溫度緩慢增加至環境溫度。將混合物攪拌12 h。將混合物在減壓下濃縮。將混合物用甲苯洗滌，以提供 4（0.84 g, HCl鹽），將其用於下一個步驟中。LCMS m/z: 357.16 [M+H] ⁺。 3 (0.5 g, 1 eq.) in 1,4-di

To a stirred solution in alkane (1.5 mL, 3 V), add two

4M HCl in alkanes (2.5 mL, 5V). The mixture was stirred for 15 min. The temperature was slowly increased to ambient temperature. The mixture was stirred for 12 h. The mixture was concentrated under reduced pressure. The mixture was washed with toluene to provide 4 (0.84 g, HCl salt), which was used in the next step. LCMS m/z: 357.16 [M+H] ⁺ .

To a solution of 4 (0.42 g, 1 eq.) in dichloromethane (4.2 mL, 10 V) was added N,N diisopropylethylamine (0.63 mL, 5 eq.) dropwise at rt, followed by EDC·HCl (0.28 g, 1.5 eq.), HOBt (0.13 g, 1 eq.) and 5 (0.11 g, 1 eq.) were added dropwise at rt. The mixture was stirred at ambient temperature for 12 h. The reaction was quenched with ice-cold water, and then extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by ^Combiflash® using 3-4% dichloromethane in methanol as eluent. The pure fractions were collected and concentrated to provide 6 (0.35 g, 79%). LCMS m/z: 455.26 [M+H] ⁺ .

Compound 6 (0.35 g, 1 eq.) was taken up in 2-aminoethanol (0.46 mL, 10 eq.). The mixture was heated to 70 °C and then stirred for 6 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to rt. The reaction was quenched with cooling and extracted with EA (2 x 40 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by ^Combiflash® using dichloromethane in methanol as eluent. Pure fractions were collected and concentrated to provide 8 (0.25 g, 69%). LCMS m/z: 480.41 [M+H] ⁺ .

To a suspension of 8 (0.15 g, 1 eq.) in chloroform (0.75 mL, 5 V) was added phosphorus oxychloride (0.75 mL, 5 V) dropwise at rt. The resulting solution was heated to 65 °C and then stirred for 4 h. The mixture was cooled to rt and concentrated under reduced pressure. The mixture was stripped with toluene (2 x 5 mL) to provide 9 (0.17 g, crude), which was used in the next step. LCMS m/z: 498.4 [M+H] ⁺ .

To a solution of 9 (0.17 g, 1 eq.) in DMF (3.4 mL, 20 V) degassed with Ar at rt was added N,N-diisopropylethylamine (0.12 mL, 2 eq.). The resulting solution was heated to 70 °C and stirred for 3 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The aqueous layer was concentrated under reduced pressure. The resulting crude was purified by using RP-HPLC. The pure fractions were concentrated and lyophilized to give (R)-(1-methoxycyclopropyl)(4-((1-(2-methyl-3-(trifluoromethyl)benzene) as TFA salt Base) ethyl) amino)-1,3,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidin-2-yl)methanone (32 mg, 20.38%). LCMS m/z: 462.3 [M+H] ⁺ . Example 29 {4-[1-(3-amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3,7,8-tetrahydro-2,5,6,8a- Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-(4-methoxy-tetrahydro-pyran-4-yl)-methanone

A solution of 1 (1 g, 3.44 mmol) and 2 (930 mg, 3.44 mmol) in DMSO (10 mL) was stirred at rt for 5 min, and DIPEA (2.1 mL, 12.00 mmol) was added. The mixture was stirred at 90 °C for 12 h, and then cooled to rt. Ice-cold water (10 mL) was added to the mixture. The mixture was extracted with EA (3 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography (7% EA:Hex) to obtain 3 (1.5 g, 93.5%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.40-8.20 (m, 3H), 5.50-5.35 (m, 1H), 4.50-4.30 (m, 4H), 1.54 (d , J =6.9 Hz , 3H), 1.50-1.40 (m, 9H).

A solution of 3 (1.5 g, 2.45 mmol) and 4 (1.5 mL 24.5 mmol) was refluxed at 70 °C for 6 h. The mixture was cooled at rt, and then ice-cold water (15 mL) was added. The mixture was filtered to obtain a residue. The residue was washed with n-hexane (15 mL). The resulting product was dried under vacuum to furnish 5 (1.4 g, 89.17%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 8.30 (s, 1H), 8.188 (s, 1H), 7.44 (d, J =6.4 Hz , 1H), 6.40 (bs, 1H), 5.50-5.35 (m, 1H), 4.45-4.10 (m, 6H), 3.10 (s, 2H), 1.44-1.40 (m, 12H).

烷(7 mL)中之冷卻(0℃)溶液中，緩慢添加1,4-二

烷中之4M HCl (7 mL)。將混合物於rt下攪拌12 h，且然後在減壓下蒸發，以去除1,4-二

烷。將殘餘物用DCM (10 mL)收集，且在減壓下乾燥，以提供 6(1.1 g, 91.23%)。 ¹H NMR (300 MHz, DMSO-d ₆): ¹H NMR (400 MHz, DMSO-d ₆) δ 10.55 (s, 1H), 10.34 (s, 1H), 9.65 (s, 1H), 8.60 (s, 1H), 8.40-8.35 (m, 2H), 7.20-7.10 (m, 2H), 5.50-5.45 (m, 1H), 4.40-4.15 (m, 6H), 3.65-3.15 (m, 4H), 2.85-2.80 (m, 1H), 1.55 (d, J=6.4 Hz, 1H)。 5 (1.4 g, 2.70 mmol) in 1,4-di

To a cooled (0°C) solution in alkanes (7 mL), slowly add 1,4-bis

4M HCl in alkanes (7 mL). The mixture was stirred at rt for 12 h, and then evaporated under reduced pressure to remove 1,4-di

alkyl. The residue was collected with DCM (10 mL) and dried under reduced pressure to provide 6 (1.1 g, 91.23%). ¹ H NMR (300 MHz, DMSO-d ₆ ): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 10.34 (s, 1H), 9.65 (s, 1H), 8.60 (s , 1H), 8.40-8.35 (m, 2H), 7.20-7.10 (m, 2H), 5.50-5.45 (m, 1H), 4.40-4.15 (m, 6H), 3.65-3.15 (m, 4H), 2.85 -2.80 (m, 1H), 1.55 (d, J =6.4 Hz , 1H).

To a stirred solution of 6 (400 mg, 0.8958 mmol) and 7 (85 mg, 0.5357) in DCM (4 mL, 10 V) was added DIPEA (0.77 mL, 4.4642 mmol), EDC HCl (254 mg, 1.3392 mmol) and HOBT (120 mg, 0.8928 mmol). The mixture was stirred at rt for 12 h, diluted with purified water (10 mL) and extracted with DCM (3 x 10 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated (1% MeOH:DCM) to provide 8 (250 mg, 50%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 7.60-7.50 (m, 1H), 5.40-5.35 (m, 1H ), 4.80-4.70 (m, 1H), 4.60-4.50 (m, 4H), 4.35 (s, 1H), 3.70-3.60 (m, 6H), 3.20-3.10 (m, 6H), 1.98-1.90 (m , 6H), 1.52-1.50 (m, 4H).

To a solution of 8 (250 mg, 0.651 mmol) in CHCl ₃ (1.75 mL, 5 V) was added thionyl chloride (1.75 mL, 5 V). The mixture was refluxed at 65 °C for 3 h. The mixture was cooled to rt, and then concentrated to remove thionyl chloride. The residue was collected with toluene (5 mL) to give 9 (150 mg, 57.03%, crude), which was used in the next step. LCMS m/z: 573.3 [M+H] ⁺ .

To a solution of 9 (150 mg, 0.2613 mmol) in DMF (1.5 mL) was added DIPEA (0.09 mL, 0.5226 mmol). The mixture was stirred at 75 °C for 3 h, and then concentrated to remove DMF to give 10 (50 mg, 35.03%, crude), which was used in the next step. LCMS m/z: 537.3 [M+H] ⁺ .

To a solution of 10 (50 mg, 0.09328 mmol) in THF:water (7:3, 3.5 mL:1.5 mL), zinc powder (150 mg, 3 × W/W) and NH ₄ Cl (150 mg, 3 x W/W). The mixture was stirred at rt for 12 h, and then filtered through a bed of celite. The mixture was concentrated to remove THF. The mixture was extracted with 10% MeOH:DCM (3 x 10 V). The organic layer was dried over _Na2SO4 and concentrated to give _the crude product, which was purified via preparative TLC to give 11 {4-[1-(3-amino-5-trifluoromethyl-phenyl )-Ethylamino]-1,3,7,8-tetrahydro-2,5,6,8a-tetraaza-asymmetric dicyclopentadienen-2-yl}-(4-methyl Oxy-tetrahydro-pyran-4-yl)-methanone (15 mg, 31.92%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.88 (m, 3H), 5.53 (m, 1H), 5.52-4.96 (m, 4H), 4.31 (t,J-18.3 Hz, 2H), 3.9 ( t, J-9 Hz, 2H), 3.77-3.69 (m, 4H), 3.26 (s, 3H), 1.61 (d, J-12.6 Hz, 3H), 1.37-1.30 (m, 4H). Example 30 {4{4-[1-(3-amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2,5,6,8a-tetraazepine Hetero-unsymmetrical dicyclopentadienen-2-yl}-(1-methyl-cyclopropyl)-methanone

{4{4-[1-(3-Amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2,5,6,8a-tetraaza- Unsymmetrical dicyclopentadienenen-2-yl}-(1-methyl-cyclopropyl)-methanone (51 mg, 68.05%) was obtained using a procedure similar to that provided in Example 29. LCMS m/z: 445.2 [M+H] ⁺ . Example 31 {4-[1-(3-amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2,5,6,8a-tetraaza- Unsymmetrical dicyclopentadienen-2-yl}-bicyclo[1.1.1]pent-1-yl-methanone

{{4-[1-(3-Amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2,5,6,8a-tetraaza-no The symmetrical dicyclopentadienen-2-yl}-bicyclo[1.1.1]pentan-1-yl-methanone (53 mg, 75.3%) was obtained using a procedure similar to that provided in Example 29. LCMS m/z: 457.3 [M+H] ⁺ . Example 32 {4-[1-(3-amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2,5,6,8a-tetraaza- Unsymmetrical dicyclopentadienen-2-yl}-(4-methoxy-tetrahydro-pyran-4-yl)-methanone

{4-[1-(3-Amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3-dihydro-2,5,6,8a-tetraaza-asymmetric Dicyclopentadienen-2-yl}-(4-methoxy-tetrahydro-pyran-4-yl)-methanone (31 mg, 43.98%) was used similar to that provided in Example 29 program to obtain. LCMS m/z: 505.3 [M+H] ⁺ . Example 33 [1-(3-amino-5-trifluoromethyl-phenyl)-ethyl]-[2-(tetrahydro-pyran-4-ylmethyl)-2,3-dihydro- 1H-2,5,6,8a-tetraaza-unsymmetrical dicyclopentadienen-4-yl]-amine

啉-5-胺

{[1-(3-amino-5-trifluoromethyl-phenyl)-ethyl]-[2-(tetrahydro-pyran-4-ylmethyl)-2,3-dihydro-1H -2,5,6,8a-Tetraaza-asymmetric dicyclopentadienen-4-yl]-amine (54 mg, 63.89%) was obtained using a procedure similar to that provided in Example 29. LCMS m/z: 461.3 [M+H] ⁺ . Example 34 N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-8-methoxy-7-(((S)-tetrahydrofuran-3- Base) oxy) imidazo [1,2-a] quinone

Lin-5-amine

A solution of 4,5-dimethoxy-2-nitro-benzoic acid ( 1 ) (25 g, 0.11 mol) in sodium hydroxide (aqueous solution, 20%, 125 mL, 5V) was stirred at 100°C 48 h. The progress of the reaction was monitored by TLC. After consumption of the starting material, the mixture was cooled to ambient temperature and acidified to pH 2 using (6 M aq) HCl. By maintaining the temperature at 10-20°C, the product was formed and then filtered off. The product was washed with water and dried under high vacuum to give 2 (22 g, 92%). Product formation was confirmed by LCMS and ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.24 (s, 1H), 6.76 (s, 1H), 3.75 (s, 3H).

To a suspension of 5-hydroxy-4-methoxy-2-nitro-benzoic acid (22 g, 7.959 mmol) in MeOH (1100 mL, 50 V) was added Pd/C (10%, 50 V) in one portion. % wet) (2.2 g). The mixture was stirred at ambient temperature under _H2 atmosphere (1.5 Kg/ ^cm2 ) for 4 h. The reaction was monitored by TLC (20% MeOH in DCM, and after the reaction, non-polar spot formation was observed). After the starting material was consumed, the mixture was filtered through a bed of celite and concentrated to give 3 (17.5 g, 92%). ¹ H NMR (400 MHz, DMSO3) δ 7.65 (bs, 1H), 7.20 (s, 1H), 6.23 (bs, 2H), 6.06 (s, 1H), 3.65 (s, 3H).

To a solution of 3 (17.5 g, 0.082 mol) in MeOH (175 mL, 10 V) at ambient temperature was added acetic acid (8.75 mL, 0.5 V) in one portion. A solution of KOCN (10.0 g, 0.124 mol) in water (60 mL) was added dropwise at rt for 20 min. The mixture was stirred at ambient temperature for 2 h. The resulting slurry was added dropwise to a hot solution of aqueous sodium hydroxide (25%) (350 mL, 20 V) by maintaining the internal temperature at 90 °C (internal) while simultaneously distilling the solvent at the slurry addition rate with a distillation condenser middle. The mixture was cooled to ambient temperature over 30 min and diluted with water (90 mL). The resulting solution was acidified with formic acid (pH 3). The mixture was stirred at rt for 2 h. The mixture was filtered, washed with water (150 mL) and dried under vacuum to give 4 (14.5 g, 71%). ¹ H NMR (400 MHz, DMSO) δ 10.99 (bs, 1H), 10.82 (bs, 1H), 9.36 (bs, 1H), 7.17 (s, 1H), 6.62 (s, 1H), 3.80 (s, 3H ).

啉-2,4-二酮( 5) (14 g, 0.355 mol)於吡啶(280 mL)中之溶液中，以逐滴方式添加乙酸酐(36 mL, 2V)。將混合物在120℃下攪拌18 h。藉由TLC監測反應進程。在反應完成後，將混合物在45℃下在減壓下濃縮至40 mL。藉由過濾收集所獲得之產物。將殘餘物用水(100 mL)洗滌，之後用丙酮(50 mL)洗滌，以得到 5(14 g, 80%)。 ¹H NMR (400 MHz, DMSO) δ 11.21 (bs, 1H), 11.09 (bs, 1H), 7.52 (s, 1H), 6.75 (s, 1H), 3.82 (s, 3H), 2.25 (s, 3 H)。 6-Hydroxy-7-methoxy-1 H -quinone

To a solution of phenoline-2,4-dione ( 5 ) (14 g, 0.355 mol) in pyridine (280 mL), acetic anhydride (36 mL, 2V) was added dropwise. The mixture was stirred at 120 °C for 18 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated to 40 mL at 45 °C under reduced pressure. The obtained product was collected by filtration. The residue was washed with water (100 mL) followed by acetone (50 mL) to give 5 (14 g, 80%). ¹ H NMR (400 MHz, DMSO) δ 11.21 (bs, 1H), 11.09 (bs, 1H), 7.52 (s, 1H), 6.75 (s, 1H), 3.82 (s, 3H), 2.25 (s, 3 h).

啉-6-基酯( 5) (14 g, 0.056 mol)於POCl ₃(28 mL, 2V)及N,N-二乙基苯胺(16.7 g, 0.112 mol)之懸浮液加熱回流3 h。藉由TLC監測反應進程。在反應完成後，將混合物在45℃下在減壓下濃縮，以去除POCl ₃。將殘餘物傾倒至冰水(300 mL)中。將漿液在0-5℃下攪拌1 h。將漿液過濾，用水洗滌且乾燥，以給出6 (11.5 g, 72%)。 ¹H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 7.64 (s, 1H), 4.02 (s, 3H), 2.27 (s, 3 H)。 acetic acid 7-methoxy-2,4-dipentoxy-1,2,3,4-tetrahydro-quinone

A suspension of phenin-6-yl ester ( 5 ) (14 g, 0.056 mol) in POCl ₃ (28 mL, 2V) and N,N-diethylaniline (16.7 g, 0.112 mol) was heated under reflux for 3 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure at 45°C to remove POCl ₃ . The residue was poured into ice water (300 mL). The slurry was stirred at 0-5 °C for 1 h. The slurry was filtered, washed with water and dried to give 6 (11.5 g, 72%). ¹ H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 7.64 (s, 1H), 4.02 (s, 3H), 2.27 (s, 3 H).

啉-6-基酯( 6) (100 mg, 0.35 mmol)於THF (2 mL, 20V)及MeOH (0.2 mL, 2 V)中之溶液中，以逐滴方式添加甲基氯化鎂（3 M，於THF中, 0.37 mL, 1.12 mmol）。將所得混合物在回流下攪拌3 h。藉由TLC監測反應進程。在起始材料消耗後，將混合物冷卻至rt，且然後逐滴添加乙酸(0.11 mL, 1.75 mol)。將所得溶液濃縮且用EA (15 mL)萃取。將溶液用水(10 mL)及鹽水(10 mL)洗滌，以Na ₂SO ₄乾燥，過濾且蒸發溶劑，以給出7 (60 mg, 83%)。 ¹H NMR (400 MHz, DMSO) δ10.59 (s, 1H), 7.42 (s, 1H), 7.38 (s, 1H), 4.01 (s, 3H)。 to 2,4-dichloro-7-methoxy-quinone at ambient temperature

To a solution of phenin-6-yl ester ( 6 ) (100 mg, 0.35 mmol) in THF (2 mL, 20 V) and MeOH (0.2 mL, 2 V), methylmagnesium chloride (3 M, in THF, 0.37 mL, 1.12 mmol). The resulting mixture was stirred at reflux for 3 h. The progress of the reaction was monitored by TLC. After the starting material was consumed, the mixture was cooled to rt, and then acetic acid (0.11 mL, 1.75 mol) was added dropwise. The resulting solution was concentrated and extracted with EA (15 mL). The solution was washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give 7 (60 mg, 83%). ¹ H NMR (400 MHz, DMSO) δ 10.59 (s, 1H), 7.42 (s, 1H), 7.38 (s, 1H), 4.01 (s, 3H).

啉-6-醇( 7) (800 mg, 3.29 mmol)及1-(3-硝基-5-三氟甲基-苯基)-乙胺( 8) (690 mg , 2.96 mmol)於DMSO (8 mL, 10 V)中之溶液中，逐滴添加DIPEA (2.4 mL, 13.16 mmol)。將所得溶液在90℃下攪拌4 h。藉由TLC監測反應進程。在起始材料消耗後，將混合物冷卻至環境溫度，用EA稀釋且用水洗滌。分離有機層，以Na ₂SO ₄乾燥，且在高真空下濃縮，以得到粗產物，將粗產物藉由Combiflash ^®（產物以己烷中之60-70% EA溶析）純化，以得到 9(730 mg, 49%)。 ¹H NMR (400 MHz, CD ₃OD) δ8.57 (S, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.18 (d, J= 8.4 Hz, 1H), 7.54 (s, 1H), 6.96 (s, 1H), 5.61-5.56 (m, 1H), 3.96 (s, 3H) 1.70 (d, J= 7.2 Hz, 3H)。 2,4-dichloro-7-methoxy-quinone at rt

Lin-6-ol ( 7 ) (800 mg, 3.29 mmol) and 1-(3-nitro-5-trifluoromethyl-phenyl)-ethylamine ( 8 ) (690 mg, 2.96 mmol) in DMSO ( 8 mL, 10 V), DIPEA (2.4 mL, 13.16 mmol) was added dropwise. The resulting solution was stirred at 90 °C for 4 h. The progress of the reaction was monitored by TLC. After the starting material was consumed, the mixture was cooled to ambient temperature, diluted with EA and washed with water. The organic layer was separated _, dried over _Na2SO4 , and concentrated under high vacuum to give the crude product, which was purified by ^Combiflash® (product was eluted with 60-70% EA in hexane) to give 9 (730 mg, 49%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (S, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 6.96 (s, 1H), 5.61-5.56 (m, 1H), 3.96 (s, 3H) 1.70 (d, J = 7.2 Hz, 3H).

啉-6-醇( 9) (700 mg, 1.58 mmol)於DMF (7 mL, 10 V)中之溶液中，添加Cs ₂CO ₃(1.8 g, 5.54 mmol)，之後添加甲苯-4-磺酸四氫-呋喃-3-基酯( 10) (575 mg, 2.37 mmol)。將混合物在環境溫度下在N ₂氣氛下攪拌24 h。藉由TLC（己烷中之70% EA）監測反應進程。在起始材料消耗後，將混合物用EA (10 mL)稀釋且濃縮，以得到粗產物。將粗產物藉由Combiflash ^®（產物以己烷中之60% EA）純化，以獲得 11(615 mg, 75%)。 ¹H NMR (400 MHz, CD ₃OD) δ8.57 (d, J= 1.6 Hz, 1H), 8.37 (S, 1H), 8.19-8.17 (m, 1H), 7.62 (s, 1H), 6.99 (s, 1H), 5.62-5.60 (m, 1H), 5.18-5.16 (m, 1H), 4.04-3.84 (m, 7H), 1.74-1.68 (m, 2H), 1.46 (d, J= 6.8 Hz, 3H)。 To 2-chloro-7-methoxy-4-[1-(3-nitro-5-trifluoromethyl-phenyl)-ethylamino]-quinone

To a solution of lin-6-ol ( 9 ) (700 mg, 1.58 mmol) in DMF (7 mL, 10 V) was added Cs ₂ CO ₃ (1.8 g, 5.54 mmol) followed by toluene-4-sulfonic acid Tetrahydro-furan-3-yl ester ( 10 ) (575 mg, 2.37 mmol). The mixture was stirred at ambient temperature under _N2 atmosphere for 24 h. The progress of the reaction was monitored by TLC (70% EA in hexane). After the starting material was consumed, the mixture was diluted with EA (10 mL) and concentrated to give crude product. The crude product was purified by ^Combiflash® (product in 60% EA in hexanes) to afford 11 (615 mg, 75%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (d, J = 1.6 Hz, 1H), 8.37 (S, 1H), 8.19-8.17 (m, 1H), 7.62 (s, 1H), 6.99 (s , 1H), 5.62-5.60 (m, 1H), 5.18-5.16 (m, 1H), 4.04-3.84 (m, 7H), 1.74-1.68 (m, 2H), 1.46 (d, J = 6.8 Hz, 3H ).

啉-4-基]-[1-(3-硝基-5-三氟甲基-苯基)-乙基]-胺( 11) (600 mg, 1.17 mmol)於胺基乙醛二甲基縮醛(6 mL, 10 V)中之溶液加熱至90℃并保持24 h。藉由TLC監測反應進程。在起始材料消耗後，將混合物冷卻至環境溫度且在高真空下濃縮，以得到粗產物。將粗產物藉由Combiflash ^®（產物以己烷中之65-70% EA溶析）純化，以獲得 13（420 mg，不純）。LCMS m/z: 582.3 [M+H] ⁺。 [2-Chloro-7-methoxy-6-(tetrahydro-furan-3-yloxy)-quinone

Phenyl-4-yl]-[1-(3-nitro-5-trifluoromethyl-phenyl)-ethyl]-amine ( 11 ) (600 mg, 1.17 mmol) in aminoacetaldehyde dimethyl A solution in acetal (6 mL, 10 V) was heated to 90 °C for 24 h. The progress of the reaction was monitored by TLC. After the starting material was consumed, the mixture was cooled to ambient temperature and concentrated under high vacuum to give the crude product. The crude product was purified by ^Combiflash® (product eluted with 65-70% EA in hexanes) to afford 13 (420 mg, impure). LCMS m/z: 582.3 [M+H] ⁺ .

啉-2,4-二胺( 13) (400 mg, 0.688 mmol)於甲酸(4 mL, 10 V)中之溶液在100℃下攪拌24 h。藉由TLC監測反應進程。在起始材料消耗後，將混合物冷卻至環境溫度且在高真空下濃縮，以得到粗產物。將粗產物藉由RP- HPLC純化，且將收集之部分在減壓下濃縮，以提供 14(180 mg)。 ¹H NMR (300 MHz, DMSO) δ9.21 (d, J= 7.2 Hz, 1H), 8.89 (S, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 8.33, 8.08 (s, 1H), 7.85 (S, 1H), 7.71 (s, 1H), 5.80-5.65 (m, 1H), 5.35-5.20 (m, 1H), 4.05-3.85 (m, 7H), 2.49-2.39, (m, 2H), 1.80-1.75 (m, 3H)。 N2-(2,2-dimethoxy-ethyl)-7-methoxy- N 4-[1-(3-nitro-5-trifluoromethyl-phenyl)-ethyl]- 6-(tetrahydro-furan-3-yloxy)-quinone

A solution of phenoline-2,4-diamine ( 13 ) (400 mg, 0.688 mmol) in formic acid (4 mL, 10 V) was stirred at 100°C for 24 h. The progress of the reaction was monitored by TLC. After the starting material was consumed, the mixture was cooled to ambient temperature and concentrated under high vacuum to give the crude product. The crude product was purified by RP-HPLC, and the collected fractions were concentrated under reduced pressure to provide 14 (180 mg). ¹ H NMR (300 MHz, DMSO) δ 9.21 (d, J = 7.2 Hz, 1H), 8.89 (S, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 8.33, 8.08 (s, 1H ), 7.85 (S, 1H), 7.71 (s, 1H), 5.80-5.65 (m, 1H), 5.35-5.20 (m, 1H), 4.05-3.85 (m, 7H), 2.49-2.39, (m, 2H), 1.80-1.75 (m, 3H).

啉-5-基]-[1-(3-硝基-5-三氟甲基-苯基)-乙基]-胺( 14) (48 mg, 0.093 mmol)於THF:水(1:1, 4 mL)中之溶液中，連續添加Zn (144 mg, 3x w/w)及Zn (144 mg, 3x w/w)。將混合物在環境溫度下攪拌16 h。藉由TLC及IPC LCMS監測反應進程。在起始材料消耗後，將混合物用EA稀釋且經由矽藻土床過濾。分離有機層，濃縮，藉由RP HPLC純化，且藉由凍乾乾燥，以得到N-((R)-1-(3-胺基-5-(三氟甲基)苯基)乙基)-8-甲氧基-7-(((S)-四氫呋喃-3-基)氧基)咪唑并[1,2-a]喹

啉-5-胺(21 mg, 47%)。 ¹H NMR (400 MHz, CD ₃OD) δ8.83 (d, J= 8.8 Hz 1H), 8.24 (d, J= 2.4 Hz, 1H), 7.99 (s, 1H), 7.69 (s, 1H), 7.48 (d, J= 2.4 Hz, 1H), 6.97 (d, J= 5.6 Hz, 1H), 6.81 (S, 1H), 5.59-5.56 (m, 1H), 5.25-5.24 (m, 1H), 4.87 (S, 3H) 4.07-3.85 (m, 4H), 2.31-2.28 (m, 1H), 2.23-2.22 (m, 1H), 1.69 (d, J= 7.2 Hz, 1H)。 實例35 {4-[1-(3-胺基-5-三氟甲基-苯基)-乙基胺基]-1,3,7,8-四氫-2,5,6,8a-四氮雜-不對稱二環戊二烯并苯-2-基}-雙環[1.1.1]戊-1-基-甲酮

To [8-methoxy-7-(tetrahydro-furan-3-yloxy)-imidazo[1,2-a]quinone

Phylin-5-yl]-[1-(3-nitro-5-trifluoromethyl-phenyl)-ethyl]-amine ( 14 ) (48 mg, 0.093 mmol) in THF:water (1:1 , 4 mL), Zn (144 mg, 3x w/w) and Zn (144 mg, 3x w/w) were added successively. The mixture was stirred at ambient temperature for 16 h. The progress of the reaction was monitored by TLC and IPC LCMS. After the starting material was consumed, the mixture was diluted with EA and filtered through a bed of celite. The organic layer was separated, concentrated, purified by RP HPLC, and dried by lyophilization to give N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) -8-methoxy-7-(((S)-tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]quinone

Lin-5-amine (21 mg, 47%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.83 (d, J = 8.8 Hz 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.99 (s, 1H), 7.69 (s, 1H), 7.48 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 5.6 Hz, 1H), 6.81 (S, 1H), 5.59-5.56 (m, 1H), 5.25-5.24 (m, 1H), 4.87 ( S, 3H) 4.07-3.85 (m, 4H), 2.31-2.28 (m, 1H), 2.23-2.22 (m, 1H), 1.69 (d, J = 7.2 Hz, 1H). Example 35 {4-[1-(3-amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3,7,8-tetrahydro-2,5,6,8a- Tetraaza-unsymmetrical dicyclopentadienen-2-yl}-bicyclo[1.1.1]pentan-1-yl-methanone

A solution of 1 (1 g, 3.44 mmol) and 2 (930 mg, 3.44 mmol) in DMSO (10 mL) was stirred at rt for 5 min and DIPEA (2.1 mL, 12.00 mmol) was added. The mixture was stirred at 90 °C for 12 h. The mixture was cooled to rt, and then ice-cold water (10 mL) was added. The mixture was extracted with EA (3 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography (7% EA:Hex) to obtain 3 (1.5 g, 93.50%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.40-8.20 (m, 3H), 5.50-5.35 (m, 1H), 4.50-4.30 (m, 4H), 1.54 (d , J =6.9 Hz , 3H), 1.50-1.40 (m, 9H).

A solution of 3 (1.5 g, 2.45 mmol) and 4 (1.5 mL 24.5 mmol) was refluxed at 70 °C for 6 h. The mixture was cooled at rt and ice-cold water (15 mL) was added. The mixture was filtered to obtain a residue. The residue was washed with n-hexane (15 mL). The resulting product was dried under vacuum to furnish 5 (1.4 g, 89.17%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 8.30 (s, 1H), 8.188 (s, 1H), 7.44 (d, J =6.4 Hz , 1H), 6.40 (bs, 1H), 5.50-5.35 (m, 1H), 4.45-4.10 (m, 6H), 3.10 (s, 2H), 1.44-1.40 (m, 12H).

烷(7 mL)中之冷卻(0℃)溶液中緩慢添加於1,4-二

烷中之4M HCl (7 mL)。將混合物於rt下攪拌12 h。將混合物在減壓下蒸發，以去除1,4-二

烷。將殘餘物用DCM (10 mL)洗滌且在減壓下乾燥，以提供 6(1.1 g, 91.23%)。 ¹H NMR (300 MHz, DMSO-d ₆) δ 10.55 (s, 1H), 10.34 (s, 1H), 9.65 (s, 1H), 8.60 (s, 1H), 8.40-8.35 (m, 2H), 7.20-7.10 (m, 2H), 5.50-5.45 (m, 1H), 4.40-4.15 (m, 6H), 3.65-3.15 (m, 4H), 2.85-2.80 (m, 1H), 1.55 (d, J=6.4 Hz, 1H)。 5 (1.4 g, 2.70 mmol) in 1,4-bis

A cooled (0°C) solution in alkanes (7 mL) was slowly added to 1,4-bis

4M HCl in alkanes (7 mL). The mixture was stirred at rt for 12 h. The mixture was evaporated under reduced pressure to remove 1,4-di

alkyl. The residue was washed with DCM (10 mL) and dried under reduced pressure to afford 6 (1.1 g, 91.23%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 10.34 (s, 1H), 9.65 (s, 1H), 8.60 (s, 1H), 8.40-8.35 (m, 2H), 7.20-7.10 (m, 2H), 5.50-5.45 (m, 1H), 4.40-4.15 (m, 6H), 3.65-3.15 (m, 4H), 2.85-2.80 (m, 1H), 1.55 (d, J =6.4 Hz , 1H).

To a stirred solution of 6 (500 mg, 1.1140 mmol) and 7 (74.8 mg, 0.6684) in DCM (5 mL, 10 V) was added DIPEA (0.97 mL, 5.5704 mmol), EDC HCl (317.7 mg, 1.6711 mmol) and HOBT (150.05 mg, 1.1140 mmol). The mixture was stirred at rt for 12 h. The mixture was diluted with purified water (10 mL), and extracted with DCM (3 x 10 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated (1% MeOH:DCM) to obtain 8 (240 mg, 42.53$). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.52 (d, J-16.5 Hz, 1H), 5.39 (m, 1H), 4.66-4.21 (m, 4H), 3.15-3.13 (m, 2H), 2.27 (m, 2H), 1.28 (d, J-6.3 Hz, 3H), 0.84 (m, 6H).

To a solution of 8 (250 mg, 0.4940 mmol) and DCM (2.5 mL, 10 V) was added triethylamine (0.172 mL, 1.2351 mmol). To the mixture was added methanesulfonyl chloride (0.04 mL, 0.5928 mmol), and the resulting mixture was stirred at 0 °C for 2 h. The mixture was diluted with purified water (10 mL) and extracted with 10% MeOH:DCM (3×10 V). The organic layer was dried over Na ₂ SO ₄ and concentrated to give 9 (270 mg, 93.52%, crude).

To a solution of 9 (260 mg, 0.4448 mmol) in DMF (2.7 mL) was added DIPEA (0.15 mL, 0.8896 mmol). The mixture was stirred at 75 °C for 3 h, and then concentrated to remove DMF to give crude product. The crude product was purified by column chromatography to afford 10 (150 mg, 69.12%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (s, 1H), 8.53 (s, 1H), 8.38 (s, 1H), 5.51 (m, 1H), 4.98-4.45 (m, 4H), 4.28-4.13 (m, 2H), 3.72 (m, 2H), 2.13 (d, J-18.6 Hz, 3H), 1.55 (m, 6H).

To a solution of 10 (150 mg, 0.3070 mmol) in THF:water (7:3, 10.5 mL:4.5 mL) was added zinc powder (450 mg, 3x, w/w) and NH ₄ Cl (450 mg, 3x , w/w). The mixture was stirred at rt for 12 h. The mixture was filtered through a bed of celite, and then concentrated to remove THF. The mixture was extracted with 10% MeOH:DCM (3 x 10 V). The organic layer was dried over Na ₂ SO ₄ and concentrated to obtain crude product. The crude product was purified via preparative TLC to give {4-[1-(3-amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3,7,8-tetrahydro -2,5,6,8a-Tetraaza-asymmetric dicyclopentadienen-2-yl}-bicyclo[1.1.1]pentan-1-yl-methanone (26.2 mg, 19.28%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.86-6.80 (m, 3H), 5.40 (m, 1H), 4.97-4.56 (m, 4H), 4.35-4.31 (m, 2H), 3.90-3.85 (m, 2H), 2.28-2.21 (m, 6H), 1.55 (d, J-7.2 Hz, 3H). Example 36 {4-[1-(3-amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3,7,8-tetrahydro-2,5,6,8a tetra Aza-unsymmetrical dicyclopentadienen-2-yl}-(1-methoxy-cyclopropyl)-methanone

{4-[1-(3-Amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3,7,8-tetrahydro-2,5,6,8a tetraaza -Unsymmetrical dicyclopentadienenen-2-yl}-(1-methoxy-cyclopropyl)-methanone (35.3 mg, 31.25%) was obtained using a procedure similar to that provided in Example 35 . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.83-6.78 (s, 3H), 5.35 (m, 1H), 5.07-4.35 (m, 4H), 4.34-4.28 (m, 2H), 3.86-3.82 (m, 2H), 3.28 (s, 3H), 1.56 (d, J-9.2 Hz, 3H), 1.16-1.11 (m, 2H), 1.09-1.04 (m, 2H). Example 37 {4-[1-(3-amino-5-trifluoromethyl-phenyl)-ethylamino]-1,3,7,8-tetrahydro-2,5,6,8a tetra Aza-unsymmetrical dicyclopentadienen-2-yl}-(1-methoxy-cyclopropyl)-methanone

To a stirred solution of 1 (4 g, 1 eq.) in dimethyloxide (20 mL, 5 V) at rt was added dropwise 2 (2.51 g, 0.9 eq.) followed by dropwise addition of N, N diisopropylethylamine (8.32 mL, 3.5 eq.). The resulting solution was heated to 90 °C and stirred for 12 h. The mixture was cooled to rt. The resulting solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (100 mL) and extracted with EA (2 x 70 mL). The combined organic layers were dried over sodium sulfate and concentrated to provide crude product. The crude product was purified by ^Combiflash® with 20-25% EA in hexane as eluent. The pure fractions were collected and concentrated to provide 3 (4.4 g, 70%). LCMS m/z: 457.3 [M+H] ⁺ .

烷(1.5 mL, 3 V)中之攪拌溶液中，逐滴添加二

烷中之4M HCl (2.5 mL, 5V)。將混合物攪拌15 min，且將溫度緩慢增加至環境溫度。將混合物攪拌12 h，且然後在減壓下濃縮。將混合物用甲苯洗滌，以提供4（0.84 g, HCl鹽），將其用於下一個步驟中。 3 (0.5 g, 1 eq.) in 1,4-di

To a stirred solution in alkane (1.5 mL, 3 V), add two

4M HCl in alkanes (2.5 mL, 5V). The mixture was stirred for 15 min, and the temperature was slowly increased to ambient temperature. The mixture was stirred for 12 h, and then concentrated under reduced pressure. The mixture was washed with toluene to provide 4 (0.84 g, HCl salt), which was used in the next step.

To a solution of 4 (0.45 g, 1 eq.) in dichloromethane (4.5 mL, 10 V) was added N,N diisopropylethylamine (0.67 mL, 5 eq.) dropwise at rt. Then EDC•HCl (0.3 g, 1.5 eq.), HOBt (0.14 g, 1 eq.) and Int-5 (0.11 g, 1 eq.) were added at rt. The mixture was stirred at ambient temperature for 12 h. The reaction was quenched with ice-cold water, and then extracted with dichloromethane (3 x 20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by ^Combiflash® using EtOAc in hexane as eluent. The pure fractions were collected and concentrated to provide 6 (0.24 g, 51%).

Compound 6 (0.24 g, 1 eq.) was taken up in 2-aminoethanol (0.32 mL, 10 eq.). The mixture was heated to 70 °C and then stirred for 16 h. The reaction was monitored via TLC. After the reaction was complete, the mixture was cooled to rt. The reaction was quenched with cold water, filtered and washed with diethyl ether to provide 8 (0.19 g, 76%).

啉-2-基胺基]-乙醇

To a suspension of 8 (0.2 g, 1 eq.) in DCM (2 mL, 10 V) at 0-5 °C was added triethylamine (0.1 g, 2.5 eq.) dropwise followed by methanesulfonate Acyl chloride (0.04 mL g, 1.2 eq.). The mixture was stirred for 12 h. The reaction mixture was monitored via TLC. After completion of the reaction, the mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude product, which was purified by RP-HPLC to obtain 9 (22.7 mg, 9.78%). LCMS m/z: 458.3 [M+H] ⁺ . Example 38 2-[7-methoxy-4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-6-(tetrahydro-furan-3-yl Oxy)-quinone

Phenyl-2-ylamino]-ethanol

啉-6-基酯( 6) (4 g, 0.0139 mol)於二甲亞碸(20 mL , 5V)中之溶液中，一次性添加N,N-二異丙基乙基胺(7.2 g, 0.0557 mol)，之後添加1-(2-甲基-3-三氟甲基-苯基)-乙胺(7)。將混合物在85℃下攪拌3 h。藉由TLC監測反應進程。將混合物冷卻至rt，且然後用水(100 mL, 5 V)稀釋。將混合物用EA (1 × 200 mL)萃取。將層分離。將有機層用水(1 × 100 mL)洗滌，以硫酸鈉乾燥且濃縮，以提供粗產物。將粗產物藉由Combiflash ^®以30% EA/己烷純化。收集純部分且濃縮，以提供 8(2.3 g, 36%)。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ1.52 (d, J=7.2 Hz, 3H), 2.33 (s, 3H), 2.58 (s, 3H), 3.87 (s, 3H), 5.58-5.61 (m, 1H), 7.21 (s, 1H), 7.32-7.38 (m, 1H), 7.54 (d, J=7.6 Hz ,1H), 7.73 (d, J=7.2 Hz, 1H), 8.24 (s, 1H), 8.85 (d, J=7.2 Hz, 1H)。 acetic acid 2,4-dichloro-7-methoxy-quinone

To a solution of phenin-6-yl ester ( 6 ) (4 g, 0.0139 mol) in dimethylsulfoxide (20 mL, 5V), N,N-diisopropylethylamine (7.2 g, 0.0557 mol), followed by the addition of 1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamine (7). The mixture was stirred at 85 °C for 3 h. The progress of the reaction was monitored by TLC. The mixture was cooled to rt, and then diluted with water (100 mL, 5 V). The mixture was extracted with EA (1 x 200 mL). The layers were separated. The organic layer was washed with water (1 x 100 mL), dried over sodium sulfate and concentrated to provide crude product. The crude product was purified by ^Combiflash® in 30% EA/hexanes. Pure fractions were collected and concentrated to provide 8 (2.3 g, 36%). ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 1.52 (d, J =7.2 Hz, 3H), 2.33 (s, 3H), 2.58 (s, 3H), 3.87 (s, 3H), 5.58-5.61 (m, 1H), 7.21 (s, 1H), 7.32-7.38 (m, 1H), 7.54 (d, J =7.6 Hz ,1H), 7.73 (d, J =7.2 Hz, 1H), 8.24 (s, 1H), 8.85 (d, J =7.2 Hz, 1H).

啉-6-基酯( 8) (100 mg, 0.2206 mmol)於四氫呋喃(10 mL, 20 V)及甲醇(4 mL, 8 V)中之溶液中，一次性添加碳酸鉀(304 mg, 0.4413 mmol)。將混合物於rt下攪拌2 h。將混合物用水(25 mL)稀釋且用EA (1 × 50 mL)萃取。將合併之有機層以硫酸鈉乾燥且濃縮。分離各層，以硫酸鈉乾燥且濃縮，以提供9 (72 mg, ,80%)。粗製物進行至下一個步驟中而未進行進一步純化。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ1.52 (d, J=7.2 Hz, 3H), 2.59 (s, 3H), 3.90 (s, 3H), 5.55-5.62 (m, 1H), 7.05 (s, 1H), 7.32-7.36 (m, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.72 (s, 1H) 7.67 (d, J=7.6 Hz, 1H), 8.59 (d, J=7.2 Hz, 1H), 9.56 (bs, 1H)。 To acetic acid 2-chloro-7-methoxy-4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-quinone at rt

To a solution of phenin-6-yl ester ( 8 ) (100 mg, 0.2206 mmol) in tetrahydrofuran (10 mL, 20 V) and methanol (4 mL, 8 V), potassium carbonate (304 mg, 0.4413 mmol ). The mixture was stirred at rt for 2 h. The mixture was diluted with water (25 mL) and extracted with EA (1 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The layers were separated, dried over sodium sulfate and concentrated to provide 9 (72 mg, , 80%). The crude was carried on to the next step without further purification. ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 1.52 (d, J =7.2 Hz, 3H), 2.59 (s, 3H), 3.90 (s, 3H), 5.55-5.62 (m, 1H), 7.05 (s, 1H), 7.32-7.36 (m, 1H), 7.53 (d, J =7.6 Hz, 1H), 7.72 (s, 1H) 7.67 (d, J =7.6 Hz, 1H), 8.59 (d, J =7.2 Hz, 1H), 9.56 (bs, 1H).

啉-6-醇( 9) (300 mg, 0.7284 mmol)於N,N-二甲基甲醯胺(5 mL, 15V)中之溶液中，一次性添加碳酸銫(831 mg, 2.5497 mmol)及碘化鉀(12 mg, 0.0728 mmol)，之後一次性添加甲苯磺醯基-四氫呋喃( 10) (441 mg, 1.8212 mmol)。將混合物於rt下攪拌16 h。將混合物在水(50 mL)中稀釋且用EA (1 × 100 mL)萃取。分離各層且用水(3 × 5 0 mL)洗滌。將有機層以硫酸鈉乾燥且濃縮。將粗產物經由Combiflash ^®以40% EA/己烷純化。收集純部分且在減壓下濃縮，以提供 11(225 mg, 64%)。將粗產物用於下一個步驟中而未進行進一步純化。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ1.55 (d, J=6.8 Hz, 3H), 1.98-2.50 (m, 1H), 2.28-2.38 (m, 1H), 2.57 (s, 3H), 3.78-3.9 (m,61H), 3.95-4.02 (m, 1H), 5.18-5.22 (m, 1H), 5.60-5.65 (m, 1H), 7.06 (s, 1H), 7.32-7.38 (m, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.75 (s, 1H), 8.64 (d, J= 6.8 Hz, 1H)。 2-Chloro-7-methoxy-4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-quinone at rt

To a solution of phenin-6-ol ( 9 ) (300 mg, 0.7284 mmol) in N,N-dimethylformamide (5 mL, 15V), cesium carbonate (831 mg, 2.5497 mmol) and Potassium iodide (12 mg, 0.0728 mmol), followed by tosyl-tetrahydrofuran ( 10 ) (441 mg, 1.8212 mmol) in one portion. The mixture was stirred at rt for 16 h. The mixture was diluted in water (50 mL) and extracted with EA (1 x 100 mL). The layers were separated and washed with water (3 x 50 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified via ^Combiflash® in 40% EA/hexanes. The pure fractions were collected and concentrated under reduced pressure to provide 11 (225 mg, 64%). The crude product was used in the next step without further purification. ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 1.55 (d, J =6.8 Hz, 3H), 1.98-2.50 (m, 1H), 2.28-2.38 (m, 1H), 2.57 (s, 3H) , 3.78-3.9 (m,61H), 3.95-4.02 (m, 1H), 5.18-5.22 (m, 1H), 5.60-5.65 (m, 1H), 7.06 (s, 1H), 7.32-7.38 (m, 1H), 7.53 (d, J =7.6 Hz, 1H), 7.70 (d, J =7.6 Hz, 1H), 7.75 (s, 1H), 8.64 (d, J = 6.8 Hz, 1H).

啉-4-基]-[1-(2-甲基-3-三氟甲基-苯基)-乙基]-胺( 11) (200 mg, 0.4565 mmol)於2-胺基乙醇(2 mL, 10 V)中之溶液中，一次性添加。將混合物在85℃下攪拌4 h。將混合物冷卻至rt，用水(40 mL)稀釋且用EA (1 × 80 mL)萃取。分離有機層，用水(1 × 20 mL)洗滌，以硫酸鈉乾燥且濃縮，以提供 13(130 mg, 62%)。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ1.51 (d, J=6.9 Hz, 3H), 1.95-2.05 (m, 1H), 2.15-2.30 (m, 1H), 2.55 (s, 3H), 3.17-3.25 (m, 2H), 3.40-3.50 (m, 2H), 3.75-4.00 (m, 7H), 5.00-5.12 (m, 1H), 5.6-5.75 (m, 1H), 5.95-6.0 (m, 1H), 6.67 (s, 1H), 7.32-7.42 (m, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.64 (s, 1H),7.74 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.2 Hz, 1H)。 [2-Chloro-7-methoxyl-6-(tetrahydro-furan-3-yloxy)-quinone at rt

Phenyl-4-yl]-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethyl]-amine ( 11 ) (200 mg, 0.4565 mmol) in 2-aminoethanol (2 mL, 10 V), add in one go. The mixture was stirred at 85 °C for 4 h. The mixture was cooled to rt, diluted with water (40 mL) and extracted with EA (1 x 80 mL). The organic layer was separated, washed with water (1 x 20 mL), dried over sodium sulfate and concentrated to provide 13 (130 mg, 62%). ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 1.51 (d, J =6.9 Hz, 3H), 1.95-2.05 (m, 1H), 2.15-2.30 (m, 1H), 2.55 (s, 3H) , 3.17-3.25 (m, 2H), 3.40-3.50 (m, 2H), 3.75-4.00 (m, 7H), 5.00-5.12 (m, 1H), 5.6-5.75 (m, 1H), 5.95-6.0 ( m, 1H), 6.67 (s, 1H), 7.32-7.42 (m, 1H), 7.53 (d, J =7.8 Hz, 1H), 7.64 (s, 1H),7.74 (d, J =7.5 Hz, 1H ), 7.87 (d, J =7.2 Hz, 1H).

啉-2-基胺基]-乙醇( 13) (130 mg, 0.2569 mmol)於二氯甲烷(2.5 mL, 20 V)中之溶液中，添加甲烷磺醯氯(35.2 mg, 0.3079 mmol)，且在0℃下添加三乙胺(65 mg, 0.6416 mmol)。將混合物在0℃下攪拌3 h。將混合物用水(10 mL)稀釋，之後用二氯甲烷(20 mL)稀釋。將混合物攪拌10 min，且分離各層。將有機層以硫酸鈉乾燥且濃縮，以獲得粗產物，殘餘物。將粗產物溶解於N,N二甲基甲醯胺(2.5 mL, 20 V)中，且添加N,N二異丙基乙胺(66 mg, 0.5138 mmol)。將混合物在70℃下攪拌過夜。將混合物冷卻至rt且在減壓下濃縮。將所得殘餘物用RP-HPLC純化。收集所欲的部分且濃縮並凍乾，以提供2-[7-甲氧基-4-[1-(2-甲基-3-三氟甲基-苯基)-乙基胺基]-6-(四氫-呋喃-3-基氧基)-喹

啉-2-基胺基]-乙醇(30 mg, 24%)。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ1.63 (d, J= 6.8 Hz, 3H), 2.10-2.30 (m, 1H), 2.56 (s, 1H), 3.88-4.02 (m, 8H), 4.35-4.50 (m, 2H), 5.11-5.13 (m, 1H), 5.78-5.88 (m, 1H), 7.30 -7.36 (m, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.86 (s, 1H), 9.12 (d, J= 6.4 Hz, 1H)。 實例39 1-(3-胺基-5-三氟甲基-苯基)-乙基]-[8-甲氧基-7-(四氫-呋喃-3-基氧基)-1,2-二氫-咪唑并[1,2-a]喹

啉-5-基]-胺

To 2-[7-methoxy-4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]-6-(tetrahydro-furan-3-yloxy base)-quinone

To a solution of phenin-2-ylamino]-ethanol ( 13 ) (130 mg, 0.2569 mmol) in dichloromethane (2.5 mL, 20 V) was added methanesulfonyl chloride (35.2 mg, 0.3079 mmol), and Triethylamine (65 mg, 0.6416 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 3 h. The mixture was diluted with water (10 mL) followed by dichloromethane (20 mL). The mixture was stirred for 10 min, and the layers were separated. The organic layer was dried over sodium sulfate and concentrated to obtain crude product, residue. The crude product was dissolved in N,N dimethylformamide (2.5 mL, 20 V), and N,N diisopropylethylamine (66 mg, 0.5138 mmol) was added. The mixture was stirred overnight at 70 °C. The mixture was cooled to rt and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC. The desired fractions were collected and concentrated and lyophilized to provide 2-[7-methoxy-4-[1-(2-methyl-3-trifluoromethyl-phenyl)-ethylamino]- 6-(tetrahydro-furan-3-yloxy)-quinone

Lin-2-ylamino]-ethanol (30 mg, 24%). ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 1.63 (d, J = 6.8 Hz, 3H), 2.10-2.30 (m, 1H), 2.56 (s, 1H), 3.88-4.02 (m, 8H) , 4.35-4.50 (m, 2H), 5.11-5.13 (m, 1H), 5.78-5.88 (m, 1H), 7.30 -7.36 (m, 1H), 7.55 (d, J =7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 9.12 (d, J = 6.4 Hz, 1H). Example 39 1-(3-amino-5-trifluoromethyl-phenyl)-ethyl]-[8-methoxy-7-(tetrahydro-furan-3-yloxy)-1,2 -Dihydro-imidazo[1,2-a]quinone

Lin-5-yl]-amine

啉-6-基酯二鹽酸鹽(7) (6 g, 16.662 mmol)於二甲亞碸(15 mL, 5 V)中之溶液中，依序添加1-(3-硝基-5-三氟甲基-苯基)-乙胺鹽酸鹽( 8) (3.38 g, 12.496 mmol)及N,N-二異丙基乙胺(8.61 g, 66.650 mmol)。將混合物在80℃下在Ar氣氛下攪拌4 h。將混合物冷卻至rt且然後傾倒至冰冷水(200 mL)中。將懸浮液用EA (2 × 50 mL)萃取。將合併之有機層用水(1 × 100 mL)洗滌且以硫酸鈉乾燥。將有機層在減壓下濃縮，以提供粗產物。將粗產物藉由Combiflash ^®以35-40% EA/己烷純化。收集純部分且濃縮，以提供9 (3.3 g, 41%)。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ1.65 (d, J=6.9 Hz, 3H), 1.98 (s, 3H), 3.90 (s, 3H), 5.63-5.59 (m, 1H), 7.25 (s, 1H), 8.18 (s, 1H), 8.37-8.32 (m, 2H), 8.59 (s, 1H), 8.84-8.82 (m, 1H)。 2,4-dichloro-7-methoxy-quinone to acetic acid

To a solution of phenin-6-yl ester dihydrochloride (7) (6 g, 16.662 mmol) in dimethylsulfoxide (15 mL, 5 V), 1-(3-nitro-5- Trifluoromethyl-phenyl)-ethylamine hydrochloride ( 8 ) (3.38 g, 12.496 mmol) and N,N-diisopropylethylamine (8.61 g, 66.650 mmol). The mixture was stirred at 80 °C for 4 h under Ar atmosphere. The mixture was cooled to rt and then poured into ice cold water (200 mL). The suspension was extracted with EA (2 x 50 mL). The combined organic layers were washed with water (1 x 100 mL) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to provide crude product. The crude product was purified by ^Combiflash® at 35-40% EA/hexanes. The pure fractions were collected and concentrated to provide 9 (3.3 g, 41%). ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 1.65 (d, J =6.9 Hz, 3H), 1.98 (s, 3H), 3.90 (s, 3H), 5.63-5.59 (m, 1H), 7.25 (s, 1H), 8.18 (s, 1H), 8.37-8.32 (m, 2H), 8.59 (s, 1H), 8.84-8.82 (m, 1H).

啉-6-基酯( 9) (3.3 g, 6.818 mmol)於四氫呋喃(22 mL) –甲醇(11 mL) (10 V)混合物中之溶液中，一次性添加碳酸鉀(1.88 g, 13.636 mmol)。將混合物在於rt下攪拌2 h。將混合物用EA (100 mL)稀釋，用水(1 × 50 mL)洗滌且以硫酸鈉乾燥。將有機層在減壓下濃縮，以提供 10（0.9 g, 98%,粗製物），將其用於下一個步驟中而未進行進一步純化。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ1.63 (d, J=7.2 Hz, 3H), 3.91 (s, 3H), 5.63-5.54 (m, 1H), 7.08 (s, 1H), 7.66 (s, 1H), 8.35 -5.32 (m, 2H), 8.60-8.55 (m, 2H), 9.69 (bs, 1H)。 To acetic acid 2-chloro-7-methoxy-4-[1-(3-nitro-5-trifluoromethyl-phenyl)-ethylamino]-quinone at rt

To a solution of phenin-6-yl ester ( 9 ) (3.3 g, 6.818 mmol) in a mixture of tetrahydrofuran (22 mL)-methanol (11 mL) (10 V), potassium carbonate (1.88 g, 13.636 mmol) was added in one portion . The mixture was stirred at rt for 2 h. The mixture was diluted with EA (100 mL), washed with water (1 x 50 mL) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to provide 10 (0.9 g, 98%, crude), which was used in the next step without further purification. ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 1.63 (d, J =7.2 Hz, 3H), 3.91 (s, 3H), 5.63-5.54 (m, 1H), 7.08 (s, 1H), 7.66 (s, 1H), 8.35-5.32 (m, 2H), 8.60-8.55 (m, 2H), 9.69 (bs, 1H).

啉-6-醇( 10) (2.9 g, 6.549 mmol)於DMF (21 mL, 7 V)中之溶液中，添加碳酸銫(7.46 g, 22.923 mmol)，之後添加甲苯-4-磺酸四氫-呋喃-3-基酯( 12) (3.96 g, 16.373 mmol)。將所得懸浮液在氮氣氛下攪拌24 h。將混合物用EA (200 mL)稀釋，用水(3 × 100 mL)洗滌，以硫酸鈉乾燥且在減壓下濃縮，以提供粗產物。將粗產物藉由Combiflash ^®以45-50% EA/己烷純化。收集純部分且濃縮，以提供 13(.2 g, 66%)。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ1.65 (d, J=7.2 Hz, 3H), 2.08-2.02 (m, 1H), 2.38-2.31 (m, 1H), 3.99-3.81 (m, 2H), 4.03-4.01 (m, 1H), 5.65-5.62 (m, 1H), 5.67-5.62 (m, 1H), 7.13-7.11 (m, 1H), 7.74 (s, 1H), 8.37 -8.31 (m, 2H), 8.66-8.57 (m, 2H)。 To 2-chloro-7-methoxy-4-[1-(3-nitro-5-trifluoromethyl-phenyl)-ethylamino]-quinone

To a solution of lin-6-ol ( 10 ) (2.9 g, 6.549 mmol) in DMF (21 mL, 7 V) was added cesium carbonate (7.46 g, 22.923 mmol) followed by toluene-4-sulfonic acid tetrahydro -furan-3-yl ester ( 12 ) (3.96 g, 16.373 mmol). The resulting suspension was stirred under nitrogen atmosphere for 24 h. The mixture was diluted with EA (200 mL), washed with water (3 x 100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by ^Combiflash® at 45-50% EA/hexanes. The pure fractions were collected and concentrated to provide 13 (.2 g, 66%). ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 1.65 (d, J =7.2 Hz, 3H), 2.08-2.02 (m, 1H), 2.38-2.31 (m, 1H), 3.99-3.81 (m, 2H), 4.03-4.01 (m, 1H), 5.65-5.62 (m, 1H), 5.67-5.62 (m, 1H), 7.13-7.11 (m, 1H), 7.74 (s, 1H), 8.37 -8.31 ( m, 2H), 8.66-8.57 (m, 2H).

啉-4-基]-[1-(3-硝基-5-三氟甲基-苯基)-乙基]-胺( 12) (500 mg, 0.976 mmol)懸浮於2-胺基乙醇(5 mL, 10 V)中。將混合物在70℃下攪拌6 h。將混合物用EA (75 mL)稀釋，用水(2 × 30 mL)洗滌，以硫酸鈉乾燥且濃縮，以提供粗產物。將粗產物與甲基-三級丁基醚一起研磨，以提供 13(320 mg, 61%)，將其用於下一個步驟中而未進行進一步純化。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ1.73 (d, J=7.2 Hz, 3H), 2.14-2.12 (m, 1H), 2.29-2.27 (m, 1H), 3.16 (bs, 2H), 3.5 (bs, 2H), 4.04-3.82 (m, 7H), 5.15 (m, 1H), 5.80 -5.60 (m, 1H), 6.19-6.16 (m, 1H), 6.78 (s, 1H), 7.67 (s, 1H), 8.07 -8.04 (m, 1H), 8.35 (s, 1H), 8.43 (s, 1H), 8.64 (s, 1H)。 [2-Chloro-7-methoxy-6-(tetrahydro-furan-3-yloxy)-quinone

Phenyl-4-yl]-[1-(3-nitro-5-trifluoromethyl-phenyl)-ethyl]-amine ( 12 ) (500 mg, 0.976 mmol) was suspended in 2-aminoethanol ( 5 mL, 10 V). The mixture was stirred at 70 °C for 6 h. The mixture was diluted with EA (75 mL), washed with water (2 x 30 mL), dried over sodium sulfate and concentrated to afford the crude product. The crude product was triturated with methyl-tert-butyl ether to provide 13 (320 mg, 61%) which was used in the next step without further purification. ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 1.73 (d, J =7.2 Hz, 3H), 2.14-2.12 (m, 1H), 2.29-2.27 (m, 1H), 3.16 (bs, 2H) , 3.5 (bs, 2H), 4.04-3.82 (m, 7H), 5.15 (m, 1H), 5.80 -5.60 (m, 1H), 6.19-6.16 (m, 1H), 6.78 (s, 1H), 7.67 (s, 1H), 8.07 -8.04 (m, 1H), 8.35 (s, 1H), 8.43 (s, 1H), 8.64 (s, 1H).

啉-2-基胺基]-乙醇(300 mg, 0.558 mmol)於二氯甲烷(10 mL)中之冰冷卻懸浮液中，逐滴添加三甲胺(142 mg, 1.396 mmol)。然後逐滴添加甲烷磺醯氯(80 mg, 0.698 mmol)。將混合物在相同溫度下攪拌2 h。將混合物用二氯甲烷(100 mL)稀釋且用水(1 × 50 mL)洗滌。將有機層以硫酸鈉乾燥且在減壓下濃縮，以提供粗產物。將粗產物溶解於N,N-二甲基甲醯胺(2.5 mL, 8 V)中。將溶液用Ar吹掃5 min。將溶液用N,N二異丙基乙胺(180 mg, 1.396 mmol)處理，在70℃下攪拌過夜。將混合物在減壓下濃縮，以提供粗產物。將粗產物藉由製備型HPLC純化。收集純部分且濃縮，以提供 14(100 mg, 34%)。 ¹H-NMR (400 MHz, CDCl ₃) δ1.74 (d, J=7.2 Hz, 3H), 2.05-2.10 (m, 1H), 2.29 -2.34 (m, 1H), 3.86-3.80 (m, 1H), 4.02-3.91 (m, 7H), 4.28-4.22 (m, 1H), 5.30 -5.26 (m , 1H), 5.59-5.57 (m, 1H), 6.32 (S, 1H), 8.16 (s, 1H), 8.26 (m, 2H), 8.52 (s, 1H)。 To 2-[7-methoxy-4-[1-(3-nitro-5-trifluoromethyl-phenyl)-ethylamino]-6-(tetrahydro-furan-3-yloxy base)-quinone

To an ice-cooled suspension of phenin-2-ylamino]-ethanol (300 mg, 0.558 mmol) in dichloromethane (10 mL), trimethylamine (142 mg, 1.396 mmol) was added dropwise. Methanesulfonyl chloride (80 mg, 0.698 mmol) was then added dropwise. The mixture was stirred at the same temperature for 2 h. The mixture was diluted with dichloromethane (100 mL) and washed with water (1 x 50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to provide crude product. The crude product was dissolved in N,N-dimethylformamide (2.5 mL, 8 V). The solution was purged with Ar for 5 min. The solution was treated with N,N diisopropylethylamine (180 mg, 1.396 mmol) and stirred at 70 °C overnight. The mixture was concentrated under reduced pressure to provide crude product. The crude product was purified by preparative HPLC. Pure fractions were collected and concentrated to provide 14 (100 mg, 34%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.74 (d, J =7.2 Hz, 3H), 2.05-2.10 (m, 1H), 2.29 -2.34 (m, 1H), 3.86-3.80 (m, 1H) , 4.02-3.91 (m, 7H), 4.28-4.22 (m, 1H), 5.30 -5.26 (m , 1H), 5.59-5.57 (m, 1H), 6.32 (S, 1H), 8.16 (s, 1H) , 8.26 (m, 2H), 8.52 (s, 1H).

啉-5-基]-[1-(3-硝基-5-三氟甲基-苯基)-乙基]-胺( 14) (50 mg)於THF:水(3:1) (4 mL)中之溶液中，連續添加Zn (150 mg, 3x, w/w)及氯化銨(150 mg, 3x, w/w)。將混合物在環境溫度下攪拌24 h。在起始材料消耗後，將混合物用EA (50 mL)稀釋且經由矽藻土床過濾。將有機層分離，濃縮且藉由RP-HPLC純化。收集純部分且濃縮，以提供1-(3-胺基-5-三氟甲基-苯基)-乙基]-[8-甲氧基-7-(四氫-呋喃-3-基氧基)-1,2-二氫-咪唑并[1,2-a]喹

啉-5-基]-胺(20 mg, 47%)。 ¹H-NMR (400 MHz, CD ₃OD): δ= 1.62 (d, J=7.2 Hz ,3H), 2.24 – 2.19 (m, 2H), 4.02-3.89 (m, 9H), 4.32- 4.30 (m, 1H), 5.10 (m, 1H),5.58 -5.56 (m, 1H), 6.72 (S, 1H), 6.80 (m, 1H), 6.92-6.90 (m, 2H), 7.79 (S, 1H)。 To [8-methoxy-7-(tetrahydro-furan-3-yloxy)-1,2-dihydro-imidazo[1,2-a]quinone

Phenyl-5-yl]-[1-(3-nitro-5-trifluoromethyl-phenyl)-ethyl]-amine ( 14 ) (50 mg) in THF:water (3:1) (4 mL), Zn (150 mg, 3x, w/w) and ammonium chloride (150 mg, 3x, w/w) were added successively. The mixture was stirred at ambient temperature for 24 h. After the starting material was consumed, the mixture was diluted with EA (50 mL) and filtered through a bed of celite. The organic layer was separated, concentrated and purified by RP-HPLC. The pure fractions were collected and concentrated to provide 1-(3-amino-5-trifluoromethyl-phenyl)-ethyl]-[8-methoxy-7-(tetrahydro-furan-3-yloxy base)-1,2-dihydro-imidazo[1,2-a]quinone

Lin-5-yl]-amine (20 mg, 47%). ¹ H-NMR (400 MHz, CD ₃ OD): δ = 1.62 (d, J =7.2 Hz ,3H), 2.24 – 2.19 (m, 2H), 4.02-3.89 (m, 9H), 4.32- 4.30 (m , 1H), 5.10 (m, 1H), 5.58 -5.56 (m, 1H), 6.72 (S, 1H), 6.80 (m, 1H), 6.92-6.90 (m, 2H), 7.79 (S, 1H).

Additional compounds of formula (I), including pharmaceutically acceptable salts thereof, are prepared by applying the starting and intermediate compounds described herein and analogous procedures. Examples of such additional compounds include those compounds provided in Table 1. Additionally, one of ordinary skill in the art will be able to synthesize other compounds of formula (I) and pharmaceutically acceptable salts thereof using routine experimentation by using compounds and procedures analogous to the specific compounds and procedures disclosed herein. Example A KRAS/SOS1 Nucleotide Exchange HTRF Analysis Protocol

Reaction buffer was prepared using 10 mM HEPES 7.4, 150 mM NaCl, 5 mM MgCl ₂ , 1 mM DTT, 0.05% BSA, 0.0025% NP40 and 0.5% DMSO. Recombinant KRAS G12C protein (recombinant human KRAS G12C mutant; wt Genbank accession number NM_033360.3; aa 2-169, expressed in E. coli with an N-terminal GST fusion; MW 46 kDa) was combined with an anti-GST Tb antibody ( Cisbio, catalog number 61GSTTLB) were pre-incubated at rt for 1 h. SOS1 (recombinant human SOS1; Genbank accession number NM_005633.3; aa 564-1049, expressed in E. coli with C-terminal StrepII; MW=60.6 kDa) was prepared in reaction buffer. Compounds in 100% DMSO along with SOS1 reaction mixture (10 µL per well) were added to assay wells using acoustic liquid dispensing (Echo ^® 550 series, Labcyte) and incubated for 15 min at rt. GTP-DY-647P1 was added to the GST-KRAS/anti-GST Tb antibody mixture and 5 uL of the mixture was added to the assay wells for a final assay volume of 15 µL. The mixture consists of recombinant KRAS G12C (30 nM final concentration), recombinant SOS1 (20 nM final concentration), and GTP-DY-647P1 (150 nM final concentration). The reaction was monitored for 40 minutes at rt using an Envision plate reader (Perkin Elmer; Ex/Em = (320-75/665-7.5; 615-8.5). Data analysis was performed when the reaction was linear, corresponding to the addition of GTP-DY - HTRF signal about 20 min after 647P1 and GST-Kras/anti-GST Tb antibody mixture. Background (well with buffer only; no SOS1 protein added) subtracted signal was converted to % activity relative to DMSO control. Use with GraphPad Prism 4 analysis data for sigmoidal dose-response (variable slope); 4 parameters with Hill Slope.

The results are provided in Table 1. In Table 1, "A" indicates IC ₅₀ < 15 nM, "B" indicates IC ₅₀ ≥ 15 to < 25 nM, "C" indicates IC ₅₀ > 25 and < 500 nM, and "D" indicates IC ₅₀ > 500 nM. As shown by the results in Table 1, compounds of formula (I), including pharmaceutically acceptable salts thereof, are potent inhibitors of KRAS mutations.

C

D

D

D

D

D

C

D

D

D

D

D

D

C

D

C

C

C

C

C

C

C

D

C

D

D

D

D

C

C

D

C

D

D

C

C

D

D

C

C

D

B

C

C

D

B

C

D

D

D

C

C

D

D

D

D

D

D

C

D

D

D

C

D

C

C

C

C

C

C

C

C

C

B

C

C

C

C

D

D

D

C

C

D

C

C

C

C

C

C

D

D

A

A

A

C

C

D

A

C

C

C

A

C

C

C

A

D

D

C

A

C

A

A

A

A

A

A

A

A

B

A

A

C

C

B

A

C

A

A

A

C

A

A

A

A

A

A

A

A

A

A

A

B

A

C

A

A

B

D

c

D

D

A

A

A

A

D

C

C

C

C

D

D

D

D

B

C

D

C

C

C

C

D

C

C

D

A

A

A

B

B

B

A

A

A

A

D

D

C

b

a

C

B

B

C

A

A

A

A

A

A

A

A

C

A

B

A

A

B

A

A

C

A

C

A

A

A

C

C

A

A

A

A

A

A

A

D

A

A [Table 1] compound SOS1: KRAS IC ₅₀

C

D.

D.

D.

D.

D.

C

D.

D.

D.

D.

D.

D.

C

D.

C

C

C

C

C

C

C

D.

C

D.

D.

D.

D.

C

C

D.

C

D.

D.

C

C

D.

D.

C

C

D.

B

C

C

D.

B

C

D.

D.

D.

C

C

D.

D.

D.

D.

D.

D.

C

D.

D.

D.

C

D.

C

C

C

C

C

C

C

C

C

B

C

C

C

C

D.

D.

D.

C

C

D.

C

C

C

C

C

C

D.

D.

A

A

A

C

C

D.

A

C

C

C

A

C

C

C

A

D.

D.

C

A

C

A

A

A

A

A

A

A

A

B

A

A

C

C

B

A

C

A

A

A

C

A

A

A

A

A

A

A

A

A

A

A

B

A

C

A

A

B

D.

c

D.

D.

A

A

A

A

D.

C

C

C

C

D.

D.

D.

D.

B

C

D.

C

C

C

C

D.

C

C

D.

A

A

A

B

B

B

A

A

A

A

D.

D.

C

b

a

C

B

B

C

A

A

A

A

A

A

A

A

C

A

B

A

A

B

A

A

C

A

C

A

A

A

C

C

A

A

A

A

A

A

A

D.

A

A

Furthermore, while the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, those skilled in the art will appreciate that various modifications can be made without departing from the spirit of the disclosure. Therefore, it should be clearly understood that the forms disclosed herein are for illustration only, and are not intended to limit the scope of the disclosure, but also cover all modifications and alternatives accompanying the true scope and spirit of the disclosure.

Claims (95)

A compound of formula (I), or a pharmaceutically acceptable salt thereof, which has the following structure

(I) wherein: ---------- each independently is a single bond or a double bond; wherein the bond between X ³ and X ⁴ is a double bond; the bond between X ⁴ and X ⁵ is a single bond bond; the bond between X ⁵ and X ⁶ is a double bond; and the bond between X ² and X ⁶ is a single bond; the bond between X ³ and X ⁴ is a single bond; the bond between X ⁴ and X ⁵ The bond between X ⁵ and X ⁶ is a single bond; and the bond between X ² and X ⁶ is a double bond; or the bond between X ³ and X ⁴ is a single bond; X ⁴ The bond between X5 and ^X5 is a single bond; the bond between ^X5 and ^X6 is a single bond; and the bond between ^X2 and ^X6 is a double bond; ^X1 is N or C, and the premise is that ^X1 When it is N, then R ¹ does not exist; X ² , X ³ , X ⁴ , X ⁵ , and X ⁶ are each independently N or C, provided that X ² , X ³ , X ⁴ , X ⁵ , and X ⁶ at least one of which is C; and provided that R ² , R ³ , and R ⁴ are selected such that X ² , X ³ , X ⁴ , X ⁵ , and X ⁶ are uncharged; R ¹ is absent or Hydrogen; R ² , R ³ , and R ⁴ are independently absent, hydrogen, halogen, hydroxyl, amino, cyano, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl , unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, unsubstituted or substituted C-amido, unsubstituted or substituted urea, unsubstituted C _1-4 alkoxy , unsubstituted or substituted N-aminoformyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted Heterocyclyl, wherein the substituted acyl group, the substituted C-carboxyl group, the substituted C-amido group, the substituted urea, the substituted N-aminoformyl group, the substituted cycloalkyl group, the The substituted aryl, the substituted heteroaryl, and the optionally substituted heterocyclyl are substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, Substituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkyl, unsubstituted C _1-4 hydroxyalkyl, and unsubstituted C-carboxyl; Ring A and ring B are each independently unsubstituted or substituted C _6-8 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted heterocycle wherein the substituted C _6-8 cycloalkyl, the substituted aryl, the substituted heteroaryl, and the substituted heterocyclic group are one or more independently selected from the group consisting of Partially substituted: halogen, hydroxyl, amino, cyano, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, unsubstituted or substituted acyl, unsubstituted or substituted C -Carboxyl, unsubstituted or substituted C-amido, unsubstituted or substituted urea, unsubstituted alkoxy, unsubstituted or substituted N-aminoformyl, unsubstituted or substituted ring Alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl, and unsubstituted or substituted heterocyclyl(C _1-4 alkyl) , wherein the substituted acyl group, the substituted C-carboxyl group, the substituted C-amido group, the substituted urea, the substituted N-aminoformyl group, the substituted cycloalkyl group, the substituted aryl group, the substituted heteroaryl group, and the substituted heterocyclic group are substituted by one or more substituents independently selected from the group consisting of: halogen, OH, CN, unsubstituted C _1-4 alkane group, unsubstituted alkoxy group, unsubstituted C _1-4 haloalkyl group, unsubstituted C _1-4 hydroxyalkyl group, unsubstituted acyl group, and unsubstituted C-carboxy group. The compound as claimed in item 1, wherein the bond between X ³ and X ⁴ is a double bond; the bond between X ⁴ and X ⁵ is a single bond; the bond between X ⁵ and X ⁶ is a double bond; and X ² The bond between X6 and ^X6 is a single bond. The compound according to claim 2, wherein each of X ¹ , X ² , X ⁴ , and X ⁵ is N; each of X ³ and X ⁶ is C. The compound as claimed in item 3, wherein R ⁴ is hydrogen. The compound as claimed in item 3, wherein R ⁴ is an unsubstituted C _1-4 alkyl group. The compound as claimed in item 3, wherein R ⁴ is an unsubstituted C _1-4 haloalkyl group. The compound according to claim 2, wherein each of X ¹ , X ² , X ⁴ , X ⁵ , and X ⁶ is N; X ³ is C. The compound as claimed in item 1, wherein the bond between X ³ and X ⁴ is a single bond; the bond between X ⁴ and X ⁵ is a double bond; the bond between X ⁵ and X ⁶ is a single bond; and X ² The bond with ^X6 is a double bond. The compound according to claim 8, wherein each of X ² and X ⁴ is C; and each of X ¹ , X ³ , X ⁵ , and X ⁶ is N. The compound as claimed in item 9, wherein R ² is hydrogen. The compound as claimed in item 9, wherein R ² is an unsubstituted C _1-4 alkyl group. The compound as claimed in item 9, wherein R ² is an unsubstituted C _1-4 haloalkyl group. The compound according to claim 8, wherein each of X ² , X ⁴ , and X ⁵ is C; and each of X ¹ , X ³ , and X ⁶ is N. The compound as claimed in item 13, wherein R ² is hydrogen. As the compound of claim 13, wherein R ² is a cyano group. The compound as claimed in item 13, wherein R ² is an unsubstituted C _1-4 alkyl group. The compound of claim 13, wherein R ² is an unsubstituted C _1-4 haloalkyl group. The compound as claimed in claim 13, wherein R ² is unsubstituted or substituted aryl. The compound of claim 13, wherein R ² is unsubstituted or substituted C-carboxy. The compound as claimed in any one of items 13 to 19, wherein R ³ is hydrogen. The compound according to any one of claims 13 to 19, wherein R ³ is a cyano group. The compound as claimed in any one of claims 13 to 19, wherein R ³ is an unsubstituted C _1-4 alkyl group. The compound according to any one of claims 13 to 19, wherein R ³ is an unsubstituted C _1-4 haloalkyl group. The compound according to any one of claims 13 to 19, wherein R ³ is unsubstituted or substituted aryl. The compound according to any one of claims 13 to 19, wherein R ³ is unsubstituted or substituted C-carboxy. The compound according to claim 8, wherein each of X ² , X ⁴ , X ⁵ , and X ⁶ is C; and each of X ¹ and X ³ is N. The compound as claimed in item 26, wherein R ² is hydrogen. As the compound of claim 26, wherein R ² is a cyano group. The compound as claimed in item 26, wherein R ² is an unsubstituted C _1-4 alkyl group. The compound as claimed in item 26, wherein R ² is an unsubstituted C _1-4 haloalkyl group. The compound as claimed in claim 26, wherein R ² is unsubstituted or substituted aryl. The compound as claimed in item 26, wherein R ² is unsubstituted or substituted C-carboxy. The compound according to any one of claims 26 to 32, wherein R ³ is hydrogen. The compound as claimed in any one of items 26 to 32, wherein R ³ is a cyano group. The compound according to any one of claims 26 to 32, wherein R ³ is an unsubstituted C _1-4 alkyl group. The compound according to any one of claims 26 to 32, wherein R ³ is an unsubstituted C _1-4 haloalkyl group. The compound according to any one of claims 26 to 32, wherein R ³ is unsubstituted or substituted aryl. The compound as claimed in any one of claims 26 to 32, wherein R ³ is unsubstituted or substituted C-carboxy. The compound according to any one of claims 26 to 38, wherein R ⁴ is hydrogen. The compound according to claim 8, wherein each of X ² , X ⁵ , and X ⁶ is C; and each of X ¹ , X ³ , and X ⁴ is N. The compound as claimed in item 40, wherein R ³ is hydrogen. As the compound of claim 40, wherein R ³ is a cyano group. The compound of claim 40, wherein R ³ is an unsubstituted C _1-4 alkyl group. The compound of claim 40, wherein R ³ is an unsubstituted C _1-4 haloalkyl group. The compound according to any one of claims 40 to 44, wherein R ³ is unsubstituted or substituted aryl. The compound as claimed in any one of claims 40 to 44, wherein R ³ is unsubstituted or substituted C-carboxy. The compound according to any one of claims 40 to 46, wherein R ⁴ is hydrogen. The compound as claimed in item 1, wherein the bond between X ³ and X ⁴ is a single bond; the bond between X ⁴ and X ⁵ is a single bond; the bond between X ⁵ and X ⁶ is a single bond; and X ² The bond with ^X6 is a double bond. The compound of claim 48, wherein each of X ² and X ⁴ is C; and each of X ¹ , X ³ , X ⁵ , and X ⁶ is N. The compound as claimed in item 49, wherein R ² is hydrogen. As the compound of claim 49, wherein R ² is a cyano group. The compound as claimed in item 49, wherein R ² is an unsubstituted C _1-4 alkyl group. The compound of claim 49, wherein R ² is an unsubstituted C _1-4 haloalkyl group. The compound as claimed in any one of items 49 to 53, wherein R ³ is hydrogen. The compound as claimed in any one of items 49 to 53, wherein R ³ is an unsubstituted C _1-4 alkyl group. The compound according to any one of claims 1 to 55, wherein ring B is unsubstituted or substituted aryl. The compound as claimed in item 56, wherein ring B is an unsubstituted phenyl group. The compound of claim 56, wherein ring B is a substituted phenyl group. The compound as claimed in item 58, wherein ring B is a monosubstituted phenyl group. The compound as claimed in item 58, wherein ring B is a disubstituted phenyl group. The compound according to any one of claims 1 to 55, wherein ring B is unsubstituted or substituted C _6-8 cycloalkyl. The compound according to any one of claims 1 to 55, wherein ring B is unsubstituted or substituted heteroaryl. The compound according to any one of claims 1 to 55, wherein ring B is an unsubstituted or substituted heterocyclic group. The compound according to any one of claims 1 to 63, wherein ring A is unsubstituted or substituted aryl. The compound as claimed in item 64, wherein ring A is an unsubstituted phenyl group. The compound as claimed in item 64, wherein ring A is a substituted phenyl group. The compound as claimed in item 66, wherein ring A is a monosubstituted phenyl group. The compound as claimed in item 66, wherein ring A is a disubstituted phenyl group. A compound as claimed in any one of claims 1 to 63, wherein ring A is unsubstituted or substituted C _{6- 8} cycloalkyl. The compound according to any one of claims 1 to 63, wherein ring A is unsubstituted or substituted heteroaryl. The compound according to any one of claims 1 to 63, wherein ring A is an unsubstituted or substituted heterocyclic group. The compound of claim 71, wherein ring A is an unsubstituted or substituted 4-6 membered monocyclic heterocyclic group. The compound as claimed in item 72, wherein ring A is unsubstituted or substituted acridine. The compound of claim 72, wherein ring A is unsubstituted or substituted pyrrolidine. The compound of claim 72, wherein ring A is unsubstituted or substituted piperidine. The compound according to any one of claims 64 or 66 to 75, wherein ring A is monosubstituted. The compound according to any one of claims 64 or 66 to 75, wherein ring A is disubstituted. The compound according to any one of claims 64 or 66 to 77, wherein ring A is substituted by one or more substituents independently selected from the group consisting of: hydroxyl, amino, cyano, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, and unsubstituted alkoxy. The compound according to any one of claims 64 or 66 to 77, wherein ring A is substituted by one or more substituents independently selected from the group consisting of: unsubstituted or substituted acyl, unsubstituted or substituted C-carboxy, unsubstituted or substituted C-amido, unsubstituted or substituted urea, and unsubstituted or substituted N-carbamoyl. The compound according to any one of claims 64 or 66 to 77, wherein ring A is substituted by one or more substituents independently selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl. The compound according to any one of claims 64 or 66 to 77, wherein ring A is substituted by one or more substituents independently selected from the group consisting of: unsubstituted alkoxy and unsubstituted or substituted Substituted acyl group. The compound of claim 1, wherein the compound is selected from the group consisting of:

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, or a pharmaceutically acceptable salt of any of the foregoing. The compound of claim 1, wherein the compound is selected from the group consisting of:

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, or a pharmaceutically acceptable salt thereof. A compound having the following structure:

, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 86 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof . A method for treating cancer, comprising administering an effective amount of the compound according to any one of Claims 1 to 86 or a pharmaceutically acceptable salt thereof, or the medicine according to Claim 87, to a subject suffering from the cancer Composition. The method of claim 88, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, and pancreatic cancer. The method according to claim 89, wherein the lung cancer is non-small cell lung cancer. The method of claim 89 or 90, wherein the cancer is associated with a KRAS mutation. Use of a compound according to any one of claims 1 to 86 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 87 for preparing a drug for treating cancer. The use of claim 92, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, and pancreatic cancer. The use according to claim 93, wherein the lung cancer is non-small cell lung cancer. The use according to claim 93 or 94, wherein the cancer is associated with a KRAS mutation.