Imidazolo[2,1-F][1,2,4]triazine-4-amine derivatives as TLR7 agonists

Abstract

Disclosed herein are imidazo[2,1-f][1,2,4]triazine-4-amine derivatives or stereoisomers thereof, or pharmaceutically acceptable salts thereof, which can be used as TLR7 agonists, and pharmaceutical compositions comprising the imidazo[2,1-f][1,2,4]triazine-4-amine derivatives or stereoisomers thereof, or pharmaceutically acceptable salts thereof. Also disclosed herein are methods for treating cancer using the imidazo[2,1-f][1,2,4]triazine-4-amine derivatives or stereoisomers thereof, or pharmaceutically acceptable salts thereof as TLR7 agonists.

Description

Technical Field

[0001] Disclosed herein are imidazo[2,1-f][1,2,4]triazine-4-amine derivatives or stereoisomers thereof, or pharmaceutically acceptable salts thereof, that can be used as TLR7 agonists, and pharmaceutical compositions comprising the same. Also disclosed herein are methods for treating cancer using the imidazo[2,1-f][1,2,4]triazine-4-amine derivatives or stereoisomers thereof, or pharmaceutically acceptable salts thereof, as TLR7 agonists. Background Art

[0002] Toll-like receptors (TLRs) belong to the family of pattern recognition receptors (PRRs) that play a key role in early innate immune responses by sensing highly conserved molecular patterns (PAMPs) of different pathogens as well as endogenous danger-associated molecular patterns (DAMPs) (Barton, GM and R. Medzhitov (2002) “Toll-like receptors and their ligands.” Curr Top Microbiol Immunol 270:81-92).

[0003] Ten different TLRs have been identified in humans. Among them, TLR7, TLR8 and TLR9 belong to the same subfamily of TLRs based on their genomic structure, sequence similarity and endosomal localization. They have a restricted expression pattern (restricted to certain types of immune cells). TLR7 is expressed in B cells and plasmacytoid dendritic cells (pDC); TLR8 is expressed in monocytes and myeloid dendritic cells (mDC) (Iwasaki, A. and R. Medzhitov (2004). "Toll-like receptor control of the adaptive immune responses." Nat Immunol [Natural Immunity] 5(10): 987-995).

[0004] In addition to the natural ligand single-stranded RNA, imidazoquinolones (or "imiquimod-like" ligands) and guanosine analogs have also been shown to activate TLR7 and / or 8 with varying specificity. Activation of TLR7 and / or TLR8 triggers maturation of dendritic cells (DCs) and secretion of proinflammatory cytokines (van Duin, D. et al. (2006). "Triggering TLR signaling invaccination." Trends Immunol 27(1):49-55). CTLs and NK cells are further activated and proliferate by DCs stimulated by cytokines and antigen presentation. Therefore, the properties of TLR agonists constitute an effective strategy to enhance anti-cancer immunity (Adams, S. (2009). "Toll-like receptor agonists in cancer therapy." Immunotherapy 1(6):949-964).

[0005] Imiquimod (TLR7 agonist) is a single antineoplastic agent with immunostimulatory properties and has been successfully used in the treatment of many primary skin tumors and skin metastases (Stary, G. et al. (2007). “Tumoricidal activity of TLR7 / 8-activated inflammatory dendritic cells.” J Exp Med 204(6):1441-1451., Aranda, F. et al. (2014). “Trial Watch: Toll-like receptor agonists in oncological indications.” Oncoimmunology [Tumor Immunology] 3:e29179).

[0006] WO 2016023511 discloses pyrrolopyrimidine compounds as TLR7 agonists for use as antiviral drugs.

[0007] Currently, a great deal of effort has been invested in the preclinical and clinical development of TLR agonists for cancer therapy. Therefore, there is a need to develop more effective TLR agonists for the treatment of cancer. Summary of the Invention

[0008] Unexpectedly and surprisingly, the inventors have found that the imidazo[2,1-f][1,2,4]triazin-4-amine derivatives disclosed herein exhibit more potent TLR7 agonist activity, particularly when Ring A in Formula (I) is further directly substituted with a heterocyclyl ring. The inventors have also found that branching of the alkyl moiety at position 2 of the imidazo[2,1-f][1,2,4]triazin-4-amine derivatives unexpectedly improves TLR7 agonist activity.

[0009] In a first aspect, disclosed herein are compounds of formula (I),

[0010]

[0011] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein

[0012] X is N or CR 7 ;

[0013] where R 7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl;

[0014] L 1 Yes-(CR a R b ) m -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, -C(O)O-, -OC(O)-, -NR a -、-C(O)NR a -、-NR a C(O)-、-NR a C(O)O-、-NR a C(O)NR b -, -SO2NR a -、-NR a SO2-、-NR a S(O)2NR b -、-NR a S(O)NR b -、-C(O)NR a SO2-、-C(O)NR a SO-, or -C(=NR a )NR b -,

[0015] Where m is a number from 1 to 8, and -(CR a R b ) m -One or both CR a R bThe moiety is unsubstituted or replaced by one or more moieties selected from the group consisting of O, S, SO, SO2, C(O) and NR a ;

[0016] R a and R b is independently at each occurrence hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, or -OR c ;

[0017] where R c is hydrogen, alkyl, alkoxy-alkyl-, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl;

[0018] R 1 Yes-OR 1a 、-SR 1a 、-NR 1a R 1b 、-COR 1a 、-SO2R 1a 、-C(=O)OR 1a 、-C(=O)NR 1a R 1b 、-C(=NR 1a )NR 1b R 1c 、-N(R 1a )C(=O)R 1b 、-N(R 1a )C(=O)OR 1b 、-N(R 1a )C(O)NR 1b R 1c 、-N(R 1a )S(O)NR 1b R 1c 、-N(R 1a )S(O)2NR 1b R 1c 、-NR 1a SO2R 1b , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, each of which is independently and optionally substituted by one or two or three substituents R 1d replace;

[0019] R 1a 、R 1b , and R 1care independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or two or three substituents selected from halogen, optionally substituted with R 1e Substituted -C 1-8 Alkyl, optionally replaced by R 1e Substituted cycloalkyl, optionally R 1e substituted heterocyclic group, optionally substituted by R 1e substituted aryl, optionally substituted by R 1e Substituted heteroaryl, CH3-(OCH2CH2) n -(where n is a number from 3 to 10) or -OR 1f ;

[0020] where R 1e is halogen, nitro, cyano, hydroxy, amino (-NH2), alkylamino, dialkylamino, or -C optionally substituted by halogen 1-6 alkyl;

[0021] where R 1f is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted by -C 1-4 Alkyl or halogen substituted;

[0022] R 1d is independently at each occurrence hydrogen, oxo, -CN, -NO2, amino (-NH2), alkylamino, dialkylamino, halo, haloalkyl, alkyl, haloalkoxy, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl;

[0023] R 2 and R 3 is independently at each occurrence hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 substituents selected from oxo, -CN, -NO2, amino (-NH2), alkylamino, dialkylamino, halogen, hydroxy, haloalkyl, alkyl, haloalkoxy, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl;

[0024] R 4 It is hydrogen, halogen, cyano, -NO2, -OR 4a 、-SR 4a 、-NR 4a R 4b 、-COR4a 、-SO2R 4a 、-C(=O)OR 4a 、-C(=O)NR 4a R 4b 、-C(=NR 4a )NR 4b R 4c 、-N(R 4a )C(=O)R 4b 、-N(R 4a )C(=O)OR 4b 、-N(R 4a )C(O)NR 4b R 4c 、-N(R 4a )S(O)NR 4b R 4c 、-N(R 4a )S(O)2NR 4b R 4c 、-NR 4a SO2R 4b , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, each of which is independently and optionally substituted by one or two or three substituents R 4d replace;

[0025] R 4a 、R 4b , and R 4c are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with halogen, hydroxy, NH2-, alkylamino, dialkylamino, or alkoxy;

[0026] R 4d is independently at each occurrence hydrogen, oxo, -CN, -NO2, halogen, NH2-, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with halogen, hydroxy, NH2-, alkylamino, dialkylamino, or alkoxy;

[0027] Ring A is aryl or heteroaryl;

[0028] R 5 is halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, -oxo-, or -C(=O)OR5a , where R 5a is hydrogen, alkyl, or haloalkyl;

[0029] p is a number among 0, 1, 2 or 3;

[0030] L 2 Is a direct key, -(CR f R g ) t -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, -C(O)O-, -OC(O)-, or -NR d -, where R d Yes-C 1-6 Alkyl, wherein t is a number from 1 to 8, and -(CR f R g ) t -One or both CR f R g The moiety is unsubstituted or replaced by one or more moieties selected from the group consisting of O, S, SO, SO2, C(O) and NR f ;

[0031] R f and R g is independently at each occurrence hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl;

[0032] R 6 Yes-NR 6a R 6b , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, each of which is independently and optionally substituted by one or two or three substituents R 6c replace;

[0033] R 6a and R 6b are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with halogen, hydroxy, NH2-, alkylamino, dialkylamino, or alkoxy;

[0034] R 6c are independently hydrogen, halogen, cyano, -NO2, -OR 6d 、-SR 6d 、-NR 6d R 6e 、-COR6d 、-SO2R 6d 、-C(=O)OR 6d 、-C(=O)NR 6d R 6e 、-C(=NR 6d )NR 6e R 6f 、-N(R 6d )C(=O)R 6e 、-N(R 6d )C(=O)OR 6e 、-N(R 6d )C(O)NR 6e R 6f 、-N(R 6d )S(O)NR 6e R 6f 、-N(R 6d )S(O)2NR 6e R 6f 、-NR 6d SO2R 6e , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, each of which is independently and optionally substituted by one or two or three substituents R 6g replace;

[0035] R 6d 、R 6e and R 6f R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or two or three substituents R 6g replace;

[0036] R 6g is independently at each occurrence hydrogen, halogen, cyano, -NO2, -OR 6h 、-SR 6h 、-NR 6h R 6i 、-COR 6h 、-SO2R 6h 、-C(=O)OR 6h 、-C(=O)NR 6h R 6i 、-C(=NR 6h )NR 6i R 6j 、-N(R 6h )C(=O)R6i 、-N(R 6h )C(=O)OR 6i 、-N(R 6h )C(O)NR 6i R 6j 、-N(R 6h )S(O)NR 6i R 6j 、-N(R 6h )S(O)2NR 6i R 6h 、-NR 6h SO2R 6i , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl,

[0037] R 6h 、R 6i and R 6j is independently hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, each of which is independently and optionally substituted with one or two or three substituents selected from halogen, -C 1-4 Alkyl, -C 1-4 alkoxy, hydroxy, nitro, -NH2, alkylamino, dialkylamino, or cyano.

[0038] Definition of X

[0039] In some embodiments, X is N. In some embodiments, X is CR 7 , where R 7 is as defined for formula (I). In some embodiments, X is CH.

[0040] L 1 Definition of

[0041] In some embodiments, m is a number from 1 to 5, or a number from 1 to 3, or the number 1.

[0042] In some embodiments, L 1 Yes-CR a R b -, -O-, -S-, -S(O)-, -SO2-, or -C(O)-, where R a and R b is independently at each occurrence hydrogen, -C 1-8 Alkyl, or -OR c , where R c is hydrogen or -C 1-4In other embodiments, L 1 Yes-CR a R b -, where R a and R b is independently at each occurrence hydrogen, -C 1-8 Alkyl (preferably -C 1-4 In some embodiments, L 1 is -CH2-, -CH(OH)- or -CH(CH3)-. In other embodiments, L 1 It is -CH2-.

[0043] R 1 Definition of

[0044] In some embodiments, R 1 Yes-OR 1a or -NR 1a R 1b , where R 1a and R 1b is as defined for formula (I).

[0045] In some embodiments, R 1 Yes-OR 1a , or -NR 1a R 1b ; where R 1a 、R 1b are independently hydrogen, -C 1-8 Alkyl, or -C 2-8 alkenyl, the-C 1-8 Each of the alkyl groups is optionally substituted with one or two or three substituents selected from the group consisting of optionally substituted with R 1e substituted heterocyclic group, optionally substituted by R 1e Substituted aryl, CH3-(OCH2CH2) n -(wherein n is a number from 3 to 10, preferably 4-8, more preferably 5-7) or -OR 1f ;

[0046] where R 1e is halogen, or -C optionally substituted by halogen 1-6 alkyl;

[0047] where R 1f Yes-C 1-8 Alkyl, aryl, or heteroaryl, each of which is optionally substituted by -C 1-4 Alkyl or halogen substituted.

[0048] In some embodiments, R 1 Yes-OR 1a , where R1a It's hydrogen.

[0049] In some embodiments, R 1 Yes-OR 1a , where R 1a is -C optionally substituted by one or two or three substituents 1-8 Alkyl, the substituents are selected from halogen, optionally R 1e Substituted -C 1-8 Alkyl, optionally replaced by R 1e Substituted cycloalkyl, optionally R 1e substituted heterocyclic group, optionally substituted by R 1e substituted aryl, optionally substituted by R 1e Substituted heteroaryl, CH3-(OCH2CH2) n -(where n is a number from 3 to 10) or -OR 1f , where R 1e and R 1f is as defined for formula (I).

[0050] In some embodiments, R 1 Yes-OR 1a , where R 1a is unsubstituted C 1-8 In some embodiments, R 1 Yes-OR 1a , where R 1a In some embodiments, R 1 Yes-OR 1a , where R 1a In some embodiments, R 1 Yes-OR 1a , where R 1a is a branched alkyl group, preferably -C 4-8 Alkyl groups (wherein the branched substituents are located alpha to the oxygen atom) include, but are not limited to, butane-2-yl, pentane-2-yl, pentane-3-yl, heptane-2-yl, heptane-3-yl, heptane-4-yl, octane-2-yl, octane-3-yl, octane-4-yl, or octane-5-yl. In some embodiments, R 1 is methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy. In some embodiments, R 1Preferably, it is propoxy, isopropoxy, n-butoxy, isobutoxy, butan-2-yloxy (sec-butoxy), pentan-2-yloxy, pentan-3-yloxy, 2-methylbutoxy, heptan-2-yloxy, heptan-3-yloxy, heptan-4-yloxy, octane-2-yloxy, octane-3-yloxy, octane-4-yloxy, or octane-5-yloxy. In some embodiments, R 1 It is n-butoxy, butan-2-yloxy (sec-butoxy), pentan-2-yloxy, pentan-3-yloxy, heptan-2-yloxy, heptan-3-yloxy, heptan-4-yloxy, octane-2-yloxy, octane-3-yloxy, octane-4-yloxy, or octane-5-yloxy.

[0051] In some embodiments, R 1 Yes-OR 1a , where R 1a Yes-C 1-8 Alkyl, preferably -C 4-5 Alkyl, wherein the alkyl is substituted by 1 to 3 halogens (eg, fluorine).

[0052] In some embodiments, R 1 Yes-OR 1a , where R 1a Yes-C 1-8 Alkyl, preferably -C 1-3 Alkyl, said alkyl being substituted by: optionally by R 1e Substituted cycloalkyl, optionally R 1e substituted heterocyclic group, optionally substituted by R 1e substituted aryl, or optionally substituted by R 1e Substituted heteroaryl, wherein R 1e is as defined for formula (I).

[0053] In some embodiments, R 1 Yes-OR 1a , where R 1a Yes-C 1-8 Alkyl, preferably -C 1-3 Alkyl, said alkyl being substituted by heteroaryl (for example 5- to 6-membered heteroaryl containing one or two or three heteroatoms selected from oxygen, nitrogen or optionally oxidized sulfur as ring members), said heteroaryl being optionally substituted by -C 1-6 Alkyl, preferably -C 1-4 In some embodiments, heteroaryl is pyridyl, imidazolyl, or isoxazolyl. In some embodiments, R 1 It is pyridin-3-ylmethoxy, 2-(1H-imidazol-1-yl)ethoxy, or (5-methylisoxazol-3-yl)methoxy.

[0054] In some embodiments, R 1 Yes-OR 1a , where R 1a Yes-C 1-8 Alkyl, preferably -C 1-3 In some embodiments, R 1 It is 2-phenylethoxy or 3-phenylpropoxy.

[0055] In some embodiments, R 1 Yes-OR 1a , where R 1a Yes-C 1-8 Alkyl, preferably -C 1-3 Alkyl, the alkyl group is -OR 1f Substituted, where R 1f Yes-C 1-8 In some embodiments, R 1 It is 2-methoxyethoxy or 2-phenoxyethoxy.

[0056] In some embodiments, R 1 Yes-OR 1a , where R 1a Yes-C 1-8 Alkyl, preferably -C 1-3 Alkyl, said alkyl being replaced by CH3-(OCH2CH2) n -substituted, wherein n is a number from 3 to 10, preferably 3 or 4 or 5. In some embodiments, R 1 It is 2,5,8,11-tetraoxatridecan-13-yloxy.

[0057] In some embodiments, R 1 Yes-OR 1a , where R 1a Yes-C 2-8 Alkenyl; preferably -C 2-6 Alkenyl; most preferably -C 4-6 In the example, R 1 It is but-3-enyloxy.

[0058] In some embodiments, R 1 Yes-NR 1a R 1b , where R 1a and R 1b Each is hydrogen, or -C 1-8 Alkyl, preferably -C 1-6 Alkyl, said alkyl being optionally substituted by one or two or three substituents selected from halogen, optionally substituted by R 1e Substituted -C 1-8Alkyl, optionally replaced by R 1e Substituted cycloalkyl, optionally R 1e substituted heterocyclic group, optionally substituted by R 1e substituted aryl, or optionally substituted by R 1e Substituted heteroaryl, wherein R 1e Yes-C 1-6 Alkyl groups, such as methyl groups.

[0059] In some embodiments, R 1 Yes-NR 1a R 1b , where R 1a is hydrogen, and R 1b Is a straight chain or branched-C 1-8 In some embodiments, R 1 Yes-NR 1a R 1b , where R 1a is hydrogen, R 1b is a branched alkyl group, preferably -C 4-8 Alkyl groups (wherein the branched substituent is located alpha to the oxygen atom) include, but are not limited to, butan-2-yl, pentan-2-yl, pentan-3-yl, heptan-2-yl, heptan-3-yl, heptan-4-yl, octane-2-yl, octane-3-yl, octane-4-yl, or octane-5-yl.

[0060] In some embodiments, R 1 It is butylamino, n-butyl-N-methylamino, or isopentylamino.

[0061] In some embodiments, R 1 is optionally partially or fully deuterated, i.e., R 1 The definition of wherein one or more carbon-bonded hydrogens are replaced by one or more deuteriums.

[0062] R 2 and R 3 Definition of

[0063] In some embodiments, R 2 and R 3 is independently hydrogen or C 1-8 Alkyl, preferably C 1-6 In some embodiments, R 2 and R 3 All are hydrogen.

[0064] R 4 Definition of

[0065] In some embodiments, R 4 It's hydrogen.

[0066] R 5 Definition of

[0067] In some embodiments, R 5 Halogen, hydroxyl, C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkoxy, or -C(=O)OR 5a , where R 5a It is hydrogen, C 1-8 Alkyl or halogenated C 1-8 and p is a number selected from 0, 1, or 2.

[0068] In some embodiments, R 5 Halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-8 In some embodiments, R 5 is methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, or trifluoromethyl. In some embodiments, R 5 It's methyl.

[0069] In some embodiments, p is the number 1.

[0070] In some embodiments, R 5 and L 2 -R 6 Located at the ortho position on ring A.

[0071] Definition of Ring A

[0072] In some embodiments, Ring A is phenyl.

[0073] In some embodiments, Ring A is a 5- to 8-membered, preferably 5- to 6-membered heteroaryl group containing one, two, or three heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur as ring members, preferably a 5- to 6-membered heteroaryl group containing one or two nitrogen atoms as ring members. In some embodiments, Ring A is a pyridyl group, such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, or pyridin-6-yl, preferably pyridin-2-yl or pyridin-3-yl. In some embodiments, Ring A is a pyrazolyl group, i.e., 1H-pyrazol-4-yl.

[0074] In some embodiments, Ring A is 1,2,3,4-tetrahydroisoquinolinyl, such as 1,2,3,4-tetrahydroisoquinolin-6-yl or 1,2,3,4-tetrahydroisoquinolin-7-yl.

[0075] L 2 -R 6 Definition of

[0076] In some embodiments, L2 Is a direct bond, -(CH2) t -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, -C(O)O-, -OC(O)-, or -NR d -, where R d Yes-C 1-6 Alkyl, wherein t is a number from 1 to 8, preferably from 1 to 5, more preferably 1 or 2 or 3; and R d Yes-C 1-6 alkyl.

[0077] In some embodiments, L 2 Is a direct bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-, or -NR d -, where R d Yes-C 1-6 Alkyl, preferably -C 1-4 Alkyl, more methyl.

[0078] In some embodiments, R 6 Yes-NR 6a R 6b 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is independently and optionally substituted with one or two or three substituents R 6c replace;

[0079] R 6a and R 6b are independently hydrogen or -C 1-8 alkyl;

[0080] R 6c are independently hydrogen, halogen, -OR 6d 、-SR 6d 、-NR 6d R 6e 、-COR 6d 、-SO2R 6d 、-C(=O)NR 6d R 6e , or -C 1-8 Alkyl, the -C 1-8 The alkyl groups are independently and optionally substituted by one or two or three substituents R 6g replace;

[0081] R6d and R 6e are independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, heterocyclic, or aryl, the -C 1-8 Alkyl, -C 2-8 Each of the alkenyl, heterocyclyl, or aryl groups is optionally substituted with one, two, or three substituents R 6g replace;

[0082] R 6g is independently at each occurrence hydrogen, halogen, -OR 6h 、-SR 6h 、-NR 6h R 6i 、-N(R 6h )C(=O)OR 6i 、-C 1-8 Alkyl, heterocyclyl, aryl, or heteroaryl, wherein R 6h and R 6i are independently hydrogen or -C 1-8 alkyl.

[0083] L 2 -R 6 The definition of L 2 Yes-(CR f R g ) t - and R 6 is a heterocyclic group

[0084] In some embodiments, L 2 Yes-(CR f R g ) t -(where t, R f and R g is as defined for formula (I), preferably -CH2- or -CH2CH2-, and R 6 is optionally substituted by one or two substituents R 6c Substituted heterocyclic group, wherein R 6c is as defined for formula (I).

[0085] In some embodiments, the heterocyclic group (such as R 6 ) is a monocyclic ring. In some embodiments, the heterocyclyl is a bicyclic ring. In some embodiments, the heterocyclyl is saturated. In some embodiments, the heterocyclyl is a 5- to 8-membered saturated monocyclic ring containing one, two, or three heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur as ring members. In some embodiments, the heterocyclyl is a 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing one, two, or three nitrogen heteroatoms as ring members.

[0086] In some embodiments, the heterocyclic group (such as R 6) is pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl), triazolyl (e.g., 1H-1,2,4-triazol-1-yl), azepanyl (e.g., azepan-2-yl, azepan-3-yl, azepan-4-yl, azepan-5-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3-yl), or morpholino. In some embodiments, the heterocyclyl group is a bicyclic ring containing one, two, or three heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur as ring members. In some instances, the heterocyclyl group is (1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl. In the above embodiments, the heterocyclic group (such as R 6 ) is further optionally substituted by one or two substituents R 6c In some embodiments, R 6c Yes-NR 6d R 6e 、-COR 6d 、-OR 6d , or -C optionally substituted by hydroxy 1-8 Alkyl, where R 6d and R 6e are independently hydrogen or -C 1-8 Alkyl (preferably -C 1-3 alkyl) or phenyl, wherein the alkyl is optionally substituted with NH2-, alkylamino, or dialkylamino. In some embodiments, R 6c L is amino, dimethylamino, 2-(dimethylamino)acetyl, methyl, 3-hydroxypropyl or phenoxy. 2 In some embodiments, R 6 is pyrrolidin-1-yl, morpholino, piperidin-1-yl, 4-methylpiperazin-1-yl, piperazin-1-yl, piperidin-4-yl, 4-(2-(dimethylamino)acetyl)piperazin-1-yl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 4-aminopiperidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 4-phenoxypiperidin-1-yl, 1H-1,2,4-triazol-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl, or piperidin-3-yl.

[0087] In some embodiments, L 2 -R 6It is pyrrolidin-1-ylmethyl, morpholinomethyl, piperidin-1-ylmethyl, (4-methylpiperazin-1-yl)methyl, piperazin-1-ylmethyl, piperidin-4-ylmethyl, (4-(2-(dimethylamino)acetyl)piperazin-1-yl)methyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-ylmethyl, 2-(pyrrolidin-1-yl)ethyl, (4-aminopiperidin-1-yl)methyl, (3-(dimethylamino)pyrrolidin-1-yl)methyl, (4-phenoxypiperidin-1-yl)methyl, (1H-1,2,4-triazol-1-yl)methyl, (4-(3-hydroxypropyl)piperazin-1-yl)methyl, or piperidin-3-ylmethyl.

[0088] L 2 -R 6 The definition of L 2 Yes-(CR f R g ) t - and R 6 Yes-NR 6a R 6b

[0089] In some embodiments, L 2 Yes-(CR f R g ) t -(where t, R f and R g is as defined for formula (I), preferably -CH2- or -CH2CH2- and R 6 Yes-NR 6a R 6b , where R 6a and R 6b is as defined for formula (I). In some embodiments, L 2 Yes - (CH2) t -(wherein t is a number from 1 to 8, preferably from 1 to 5, more preferably 1 or 2 or 3), preferably -CH2- or -CH2CH2-, and R 6 Yes-NR 6a R 6b , where R 6a and R 6b are independently hydrogen or C 1-8 Alkyl, preferably C 1-6 In some embodiments, L 2 -R 6 It is an aminomethyl group.

[0090] L 2 -R 6 The definition of L 2 is a direct key and R 6 is an alkyl, alkenyl, or alkynyl group

[0091] In some embodiments, L 2 is a direct key and R 6 Yes-C 1-8 Alkyl, -C 2-8 Alkenyl, or -C 2-8 Alkynyl.

[0092] L 2 -R 6 The definition of L 2 Is -O- or -NR d - and R 6 is an alkyl, alkenyl, alkynyl, heterocyclic, aryl or heteroaromatic base

[0093] In some embodiments, L 2 Yes-O- and R 6 Yes-C 1-8 Alkyl or heterocyclic group, the -C 1-8 Alkyl and heterocyclic groups are optionally substituted by one or two R 6c In some embodiments, R 6c Yes-C 1-8 Alkyl, -NR 6d R 6e and-COR 6d , where R 6d and R 6e is independently -C optionally substituted by NH2-, alkylamino, or dialkylamino 1-8 Alkyl (preferably -C 1-3 In some embodiments, L 2 -R 6 is 3-(methylamino)propoxy, 3-(dimethylamino)propoxy, 3-(diethylamino)propoxy, 2-aminoethoxy, 3-(dimethylamino)-2,2-dimethylpropoxy, methoxy, 2-(methylamino)ethoxy, 2-(N-methylacetamido)ethoxy, 3-(piperidin-1-yl)propoxy, 3-morpholinopropoxy, 3-(pyrrolidin-1-yl)propoxy, 3-aminopropoxy, (1R,5S)-8-azabicyclo[3.2.1]octan-3-yloxy, piperidin-4-yloxy, (1R,5S)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yloxy, 1-ethylpyrrolidin-3-yloxy, or pyrrolidin-3-yloxy.

[0094] In some embodiments, L 2 Yes-NR d -, where R d Yes-C 1-6 Alkyl, and R 6 Yes-C 1-8 Alkyl, -C 2-8 Alkenyl, or -C 2-8 Alkynyl, each of which is optionally substituted by one or two R 6c In some embodiments, R 6c Yes-C 1-8 Alkyl or -NR 6d R 6e , where R 6d and R 6e Independently -C 1-8 Alkyl (preferably -C 1-3 In some embodiments, L 2 -R 6It is (2-(dimethylamino)ethyl)(methyl)amino.

[0095] L 2 -R 6 The definition of L 2 is a direct key and R 6 is a cycloalkyl, heterocyclyl, aryl, or heteroaryl

[0096] In some embodiments, L 2 is a direct key and R 6 is a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, each of which is independently and optionally substituted by one or two or three substituents R 6c replace.

[0097] In some embodiments, L 2 is a direct key and R 6 is a heterocyclic group, which is optionally substituted by one, two or three substituents R 6c replace.

[0098] Such as R 6 , in some embodiments, the heterocyclyl is a monocyclic ring; in some embodiments, the heterocyclyl is a fused bicyclic heterocyclyl; and in some embodiments, the heterocyclyl is a spiro bicyclic heterocyclyl.

[0099] In some embodiments, the heterocyclic radical is saturated. In some embodiments, the heterocyclic radical is a 4-, 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing one, two, or three heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur as ring members. In some embodiments, the heterocyclic radical is a 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing one, two, or three nitrogen heteroatoms as ring members. In some embodiments, the heterocyclic radical is a 5- or 6-membered saturated monocyclic ring containing one or two nitrogen heteroatoms as ring members. In some embodiments, the heterocyclyl group is pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl), triazolyl (e.g., 1H-1,2,4-triazol-1-yl), azepanyl (e.g., azepan-2-yl, azepan-3-yl, azepan-4-yl, azepan-5-yl), diazepanyl (e.g., 1,4-diazepan-1-yl, 1,4-diazepan-2-yl, 1,4-diazepan-3-yl, 1,4-diazepan-4-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3-yl), or morpholino.

[0100] In some embodiments, the heterocyclyl group is a bicyclic ring comprising one, two, or three heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur as ring members. In some instances, the heterocyclyl group is 2,5-diazabicyclo[2.2.1]heptan-2-yl.

[0101] In some embodiments, the heterocyclic radical is a 6- to 14-membered, and more preferably a 7- to 10-membered, spirobicyclic heterocyclic radical. In some embodiments, the heterocyclic radical is a spiroheptyl, spirodecanyl, or spirononyl radical comprising one or two nitrogen atoms as ring members. In some embodiments, the heterocyclic radical is an 8-azaspiro[4.5]decane-8-yl, a 2,7-diazaspiro[3.5]nonane-7-yl, a 2,8-diazaspiro[4.5]decane-2-yl, a 2,7-diazaspiro[3.5]nonane-2-yl, a 2,8-diazaspiro[4.5]decane-8-yl radical.

[0102] In the above embodiments, the heterocyclic group (such as R 6 ) is further optionally substituted by one or two substituents R 6c replace.

[0103] In some embodiments, R 6c Yes-COR 6d , where R 6d is optionally substituted by one or two substituents R 6g Substituted -C 1-8 Alkyl, where R 6g Yes-NR 6h R 6i 、-N(R 6h )C(=O)R 6i 、-C 1-8 Alkyl, aryl or heteroaryl, where R 6h and R 6i is as defined for formula (I). In some embodiments, R 6c Yes-COR 6d , where R 6d is optionally substituted by one or two substituents R 6g Substituted -C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-4 alkyl), where R 6g Yes-NR 6h R 6i 、-N(R 6h )C(=O)R 6i 、-C 1-8 Alkyl, aryl or heteroaryl, where R 6h and R 6i are each independently hydrogen or -C 1-8 Alkyl (preferably C 1-6 Alkyl, more preferably C 1-4 alkyl).

[0104] In some embodiments, R 6c Yes-COR 6d , where R 6d Yes-C2-8 Alkenyl.

[0105] In some embodiments, R 6c Yes-COR 6d , where R 6d It is a heterocyclic group.

[0106] In some embodiments, R 6c is acetyl, 2-(dimethylamino)acetyl, 2-(dimethylamino)acetyl, aminoacetyl, 2-(methylamino)acetyl, 3-(dimethylamino)propionyl, 4-(dimethylamino)butyryl, 5-(dimethylamino)pentanoyl, (2S,3S)-2-amino-3-methylpentanoyl, 2-(methylamino)acetyl, 2-amino-4-methylpentanoyl, 2-amino-3-methylbutyryl, 2-(dimethylamino)acetyl, phenylpropionyl, 2-(piperazin-1-yl)acetyl, acryloyl, piperazine-2-carbonyl, piperidine-4-carbonyl, pyrrolidine-2-carbonyl, or 2-(N-methylacetylamino)acetyl.

[0107] In some embodiments, R 6c Yes-C 1-8 Alkoxy, preferably -C 1-6 Alkoxy groups, such as methoxy groups.

[0108] In some embodiments, R 6c Yes-C 1-8 Alkyl, preferably -C 1-6 Alkyl, which is optionally substituted by one or two substituents R 6g Substituted, where R 6g Yes-OR 6h 、-NR 6h R 6i , heterocyclic group, aryl group, where R 6h and R 6i is as defined for formula (I). In some aspects, R 6c is optionally substituted by a substituent R 6g Substituted -C 1-8 Alkyl, preferably -C 1-6 Alkyl, where R 6g Yes-OR 6h 、-NR 6h R 6i , heterocyclic group (such as morpholino), aryl group (such as phenyl), wherein R 6h and R 6i Yes-C 1-4 In some embodiments, R 6cis methyl, ethyl, isobutyl, methoxymethyl, 2-methoxyethyl, (methylamino)methyl, 2-(dimethylamino)ethyl, (dimethylamino)methyl, 2-aminoethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, morpholinomethyl, or phenethyl.

[0109] In some embodiments, R 6c is optionally substituted by a substituent R 6g In some embodiments, R 6c is optionally substituted by a substituent R 6g In some embodiments, R 6c It is 4-morpholinopiperidin-1-yl.

[0110] In some embodiments, R 6c is -C(=O)NR 6d R 6e , where R 6d and R 6e are independently hydrogen, -C 1-8 Alkyl (preferably -C 1-3 alkyl), or aryl, the -C 1-8 Alkyl or aryl is independently and optionally substituted with halogen or -C 1-4 In some embodiments, R 6c is -C(=O)NR 6d R 6e , where R 6d and R 6e are independently hydrogen and -C 1-4 In some embodiments, R 6c is -C(=O)NR 6d R 6e , where R 6d and R 6e are independently hydrogen and aryl optionally substituted halogen. In some embodiments, R 6c It is a dimethylcarbamoyl group, an isopropylcarbamoyl group, or a 2,4,5-trifluorophenylcarbamoyl group.

[0111] In some embodiments, R 6c Yes-NR 6d R 6e (where R 6d and R 6e are independently hydrogen), or -C 1-8 Alkyl (preferably -C 1-6 Alkyl, more preferably -C 1-3 alkyl, most preferably methyl). In some embodiments, R 6c It is dimethylamino or amino.

[0112] In some embodiments, R 6c Yes-SO2R 6d , where R 6d Yes-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 In some embodiments, R 6c Yes-SO2R 6d , where R 6d Yes-C 1-8 Alkyl (preferably -C 1-6 In some embodiments, R 6c It is propylsulfonyl.

[0113] In some embodiments, L 2 is a direct key, R 6 is pyrrolidinyl, said pyrrolidinyl being optionally substituted with one or two or three substituents selected from methyl, (dimethylamino)methyl, or dimethylamino. In some embodiments, L 2 -R 6 It is 1-methylpyrrolidin-3-yl, pyrrolidin-1-yl, 3-((dimethylamino)methyl)pyrrolidin-1-yl, or 3-(dimethylamino)pyrrolidin-1-yl.

[0114] In some embodiments, L 2 is a direct key, R 6 is piperazinyl, said piperazinyl being optionally substituted with one or two or three substituents selected from acryloyl, 2-(dimethylamino)acetyl, aminoacetyl, 2-(methylamino)acetyl, 3-(dimethylamino)propanoyl, 2-(piperazin-1-yl)acetyl, piperazine-2-carbonyl, 4-(dimethylamino)butanoyl, 5-(dimethylamino)pentanoyl, methyl, piperidine-4-carbonyl, acetyl, 2-(N-methylacetamido)acetyl, isopropyl In some embodiments, L is 1-(4-amino-5-methyl-2-oxo-2-nitro-1-oxo-2-nitro-2-nitro-4-nitro-2-nitro-3-nitro-4-nitro-2-nitro-3-nitro-2 ... 2 -R 6piperazin-1-yl, 4-acryloylpiperazin-1-yl, 4-(2-(dimethylamino)acetyl)piperazin-1-yl, (4-aminoacetyl)piperazin-1-yl, piperazin-1-yl, 4-(2-(methylamino)acetyl)piperazin-1-yl), 4-(3-(dimethylamino)propionyl)piperazin-1-yl, 4-(2-(piperazin-1-yl)acetyl)piperazin-1-yl, 4-(piperazine-2-carbonyl)piperazin-1-yl, 4-acryloylpiperazin-1-yl , 4-(4-(dimethylamino)butyryl)piperazin-1-yl, 4-(5-(dimethylamino)pentanoyl)piperazin-1-yl, 3,5-dimethylpiperazin-1-yl, 4-(piperidine-4-carbonyl)piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-(2-(N-methylacetylamino)acetyl)piperazin-1-yl, 4-(isopropylcarbamoyl)piperazin-1-yl, 4-(2,4,5-trifluorophenylcarbamoyl)piperazin-1-yl, 4-(3, 5-dimethylpiperazin-1-yl, 4-((2S,3S)-2-amino-3-methylpentanoyl)piperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl, 4-(2-(methylamino)acetyl)piperazin-1-yl, 4-ethylpiperazin-1-yl, 4-isobutylpiperazin-1-yl, 4-(pyrrolidine-2-carbonyl)piperazin-1-yl, 4-(2-amino-4-methylpentanoyl)piperazin-1-yl, 4-(2-amino-3-methylbutanoyl)piperazin- 1-yl, 4-(2-(dimethylamino)acetyl)piperazin-1-yl, (S)-2-methylpiperazin-1-yl, (R)-2-methylpiperazin-1-yl, 4-(2-(methylamino)ethyl)piperazin-1-yl, 4-(2-(dimethylamino)ethyl)piperazin-1-yl, 4-(2-amino-3-phenylpropanoyl)piperazin-1-yl, 4-(propylsulfonyl)piperazin-1-yl, 4-(2-aminoethyl)piperazin-1-yl, or 3-methylpiperazin-1-yl.

[0115] In some embodiments, L 2 is a direct key, R 6 is piperidinyl, said piperidinyl being optionally substituted with one or two or three substituents selected from 2-(dimethylamino)acetyl, methoxy, methoxymethyl, (methylamino)methyl, 4-morpholinopiperidin-1-yl, morpholinomethyl, 2-(dimethylamino)ethyl, phenethyl, (dimethylamino)methyl, amino, dimethylamino, or dimethylcarbamoyl. In some embodiments, L 2 -R 6

[00145] Piperidin-4-yl, 4-(2-(dimethylamino)acetyl)piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, piperidin-1-yl, piperidin-4-yl, 4-methoxypiperidin-1-yl, 4-(methoxymethyl)piperidin-1-yl, 4-((methylamino)methyl)piperidin-1-yl, (4-morpholinopiperidin-1-yl)pyridin-3-yl, 4-(morpholinomethyl)piperidin-1-yl, 4-(2-(dimethylamino)ethyl)piperidin-1-yl, 1-phenethylpiperidin-4-yl, 4-((dimethylamino)methyl)piperidin-1-yl, 4-aminopiperidin-1-yl, 4-(dimethylamino)piperidin-1-yl, or 4-(dimethylcarbamoyl)piperidin-1-yl.

[0116] In some embodiments, L 2 -R 6 It is azepan-1-yl or 1,4-diazepan-1-yl.

[0117] In some embodiments, L 2 -R 6 It is octahydro-2H-isoindol-2-yl.

[0118] In some embodiments, L 2 -R 6 It's a morpholino.

[0119] In some embodiments, L 2 -R 6 8-Azaspiro[4.5]Decan-8-yl, 2,7-Diazaspiro[3.5]Nonane-7-yl, 2,8-Diazaspiro[4.5]Decan-2-yl, 2,7-Diazaspiro[3.5]Nonane-2-yl, 2,8-Diazaspiro[4.5]Decan-8-yl, (1R,4R)-2,5-Diazabicyclo[2.2.1]Heptane-2-yl.

[0120] In some embodiments, Ring A is phenyl, and L 1 and L 2 -R 6 Located in the para position of the phenyl ring, and the phenyl ring is further optionally supported by an R 5 Substituted, where L 1 , L 2 、R 5 and R 6 is as defined in each of the above embodiments. In some embodiments, Ring A is pyridinyl, and L 1 and L 2 -R 6 Located in the para position of the pyridyl ring, and the pyridyl ring is further optionally supported by an R 5 Substituted, where L 1, L 2 、R 5 and R 6 is as defined in each of the above embodiments.

[0121] In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the specific compounds exemplified herein:

[0122]

[0123]

[0124]

[0125]

[0126]

[0127] In a third aspect, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein (including a compound of formula (I) or a specific compound exemplified herein), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0128] In a fourth aspect, disclosed herein is a method of modulating TLR7, comprising administering to a subject a compound disclosed herein or a pharmaceutically acceptable salt thereof, including a compound of formula (I) or a specific compound exemplified herein.

[0129] In a fifth aspect, disclosed herein is a method for treating a disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof as a TLR7 agonist, wherein the compound disclosed herein includes a compound of formula (I) or a specific compound exemplified herein. In some embodiments, the disease or disorder is associated with regulation of a TLR (e.g., TLR-7) (e.g., stimulating TLR-7). In some embodiments, the disease or disorder comprises a viral infection caused by a virus selected from the group consisting of: dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, and hepatitis C. In some embodiments, the disease or disorder comprises melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis, liver fibrosis, HBV, HCV, HPV, RSV, SARS, HIV or influenza. Preferably, the disease or disorder is cancer. DETAILED DESCRIPTION

[0130] The following terms have the indicated meanings throughout this specification:

[0131] As used herein, including the appended claims, singular forms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0132] Unless the context clearly indicates otherwise, the term "or" means and is used interchangeably with the term "and / or."

[0133] The term "alkyl" herein refers to a hydrocarbon group selected from straight and branched saturated hydrocarbon groups containing from 1 to 18 (e.g., from 1 to 12, further for example, from 1 to 10, further for example, from 1 to 8, or from 1 to 6, or from 1 to 4) carbon atoms. Examples of alkyl groups containing from 1 to 6 carbon atoms (i.e., C1-6 alkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu") ”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups.

[0134] The term "alkoxy" or "alkyloxy" means an alkyl group, as previously defined, appended to the parent molecular moiety through an oxygen atom.

[0135] The term "amino" refers to -NH2. The term "alkylamino" refers to -NH(alkyl). The term "dialkylamino" refers to -N(alkyl). The term "halogen" as used herein refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0136] The term "haloalkyl" herein refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (e.g., fluorine, chlorine, bromine, and iodine). Examples of haloalkyl groups include halo-C 1-8 Alkyl, halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl groups include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0137] The term "alkenyl" herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C=C double bond and from 2 to 18 (e.g., from 2 to 8, further e.g., from 2 to 6) carbon atoms. Examples of alkenyl groups (e.g., C2-6 alkenyl) include, but are not limited to, vinyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, butane-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups.

[0138] The term "alkynyl" herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C≡C triple bond and from 2 to 18 (e.g., from 2 to 8, further e.g., 2 to 6) carbon atoms. Examples of alkynyl groups (e.g., C2-6 alkynyl) include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0139] The term "alkyloxy" or "alkoxy" as used herein refers to an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom. Examples of alkyloxy groups (e.g., C1-6 alkyloxy or C1-4 alkyloxy) include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy groups.

[0140] The term "alkoxy-alkyl-" refers to an alkyl group as defined above that is further substituted by an alkoxy group as defined above. Examples of alkoxy-alkyl- (e.g., C1-8 alkoxy-C1-8 alkyl- or C1-6 alkoxy-C1-6 alkyl-) include, but are not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl, or propoxymethyl.

[0141] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused, bridged or spiro cycloalkyl groups.

[0142] For example, cycloalkyl group can comprise from 3 to 12, for example from 3 to 10, further for example 3 to 8, further for example 3 to 6, 3 to 5 or 3 to 4 carbon atoms.Even further for example, cycloalkyl group can be selected from and comprise from 3 to 12, for example from 3 to 10, further for example 3 to 8, the monocyclic group of 3 to 6 carbon atoms.The example of monocyclic cycloalkyl group comprises cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl group.Especially, saturated monocyclic cycloalkyl group (for example C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl groups are monocyclic rings (abbreviated as C 3-6 Examples of bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms, fused bicyclic ring arrangements (selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems), or bridged bicyclic ring arrangements (selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane). Additional examples of bicyclic cycloalkyl groups include those having bicyclic ring arrangements (selected from [5,6] and [6,6] ring systems).

[0143] The term "cycloalkenyl" refers to a non-aromatic cycloalkyl group of from 3 to 10 carbon atoms having a single ring or multiple rings and at least one double bond and preferably from 1 to 2 double bonds. In one embodiment, the cycloalkenyl is a cyclopentenyl or cyclohexenyl, preferably a cyclohexenyl.

[0144] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having a single ring or multiple rings and having at least one triple bond.

[0145] The term "deuterated" is used herein to modify a chemical structure or organic group (group or radical) in which one or more carbon-bonded hydrogens are replaced by one or more deuteriums, such as "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated-aryl," "deuterated morpholinyl," and the like. For example, the term "deuterated alkyl" as defined above refers to an alkyl group as defined herein in which at least one carbon-bonded hydrogen atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium; and a carbon atom may be bonded to no more than one deuterium; more than one carbon atom in the alkyl group may also be bonded to deuterium.

[0146] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0147] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0148] - bicyclic ring systems, for example 7- to 12-membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl; and

[0149] - a tricyclic ring system, for example a 10- to 15-membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0150] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In certain embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, etc. In certain embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In certain embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0151] The term "heteroaryl" as used herein refers to a group selected from:

[0152] - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, in some embodiments, from 1 to 2 heteroatoms) selected from nitrogen (N), sulfur (S), and oxygen (O), wherein the remaining ring atoms are carbon;

[0153] - a 7- to 12-membered bicyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) chosen from nitrogen, oxygen, or optionally oxidized sulfur as a ring member, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0154] - an 11- to 14-membered tricyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from nitrogen, oxygen, or optionally oxidized sulfur as a ring member, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0155] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. The nitrogen atom in the ring of the heteroaryl group can be oxidized to form an N-oxide.

[0156] As used herein, the term "optionally oxidized sulfur" refers to S, SO or SO2.

[0157] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure herein. In some embodiments, monocyclic or bicyclic aromatic heterocycles have 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulphur (S) and oxygen (O), and the remaining ring members are carbon. In some embodiments, monocyclic or bicyclic aromatic heterocycles are monocyclic or bicyclic rings comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulphur (S) and oxygen (O). In some embodiments, monocyclic or bicyclic aromatic heterocycles are 5 to 6 membered heteroaryl rings, which are monocyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulphur (S) and oxygen (O). In some embodiments, monocyclic or bicyclic aromatic heterocycles are 8 to 10 membered heteroaryl rings, which are bicyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen, sulphur and oxygen.

[0158] Examples of heteroaryl groups, or monocyclic or bicyclic aromatic heterocycles, include, but are not limited to, (numbering starting from the attachment position designated as priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4- 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-oxadiazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furanyl, or furanyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), 4-triazolyl), quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thiophene hetero-2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, fluoropyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0159] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon, including monocyclic, fused, bridged, and spiro rings, i.e., containing monocyclic heterocyclyls, bridged heterocyclyls, spiroheterocyclyls, and fused heterocyclic groups.

[0160] The term "monocyclic heterocyclyl" refers to a monocyclic group wherein at least one ring member is a heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0161] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to, (numbering from the attachment position designated as priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidinon-2-yl, imidazolidinon-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridine-1-yl, aziridine-2-yl, azetin-1-yl, azetin-2-yl, azetin-3-yl, azetin-4-yl, azetin-5-yl, thiirane, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, azetidin-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, thiiran ... -2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-thiocyclobutane, 1,3-thiocyclobutane, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, oxathianyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxetanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxetanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepanyl Base, diazepine thiazolinone 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone,

[0162] The term " spiro heterocyclic radical " refers to a 5 to 20 yuan polycyclic heterocyclic radical with a ring connected by a shared carbon atom (called spiral atom), which includes one or more heteroatoms selected from nitrogen, oxygen or the optionally oxidized sulphur as ring members, and remaining ring members are carbon. One or more rings of spiro heterocyclic radical groups can contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, spiro heterocyclic radical is 6 to 14 yuan and more preferably 7 to 12 yuan. According to the shared spiral atom number, spiro heterocyclic radical is divided into monospiro heterocyclic radical, two-spiro heterocyclic radical or many spiral heterocyclic radicals, and preferably refers to monospiro heterocyclic radical or two-spiro heterocyclic radical, and more preferably 4 yuan / 4 yuan, 3 yuan / 5 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic radical.

[0163] The term "fused heterocyclic group" refers to a 5 to 20 membered polycyclic heterocyclic radical group (wherein each ring in the system shares adjacent pairs of atoms (carbon and carbon atoms, or carbon and nitrogen atoms) with another ring), comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulphur as ring members, and the remaining ring members are carbon. The one or more rings of the fused heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the fused heterocyclic group is 6 to 14 members and more preferably 7 to 10 members. According to the number of member rings, the fused heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, and more preferably a 5 yuan / 5 yuan or 5 yuan / 6 yuan bicyclic fused heterocyclic group. Representative examples of fused heterocycles include, but are not limited to, the following: octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolyl (e.g., isoindolyl-2-yl), octahydro-benzo[b][1,4]dioxin.

[0164] The term "bridged heterocyclic group" refers to a 5 to 14-membered polycyclic heterocycloalkyl group (wherein every two rings in the system share two discontinuous atoms), comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon. One or more rings of the bridged heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the bridged heterocyclic group is 6 to 14 members and more preferably 7 to 10 members. Depending on the number of member rings, the bridged heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, and more preferably a bicyclic or tricyclic bridged heterocyclic group. Representative examples of bridged heterocyclic groups include, but are not limited to, the following: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0165] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more chiral centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. It is intended to include all possible stereoisomers, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include stereoisomers of all compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically stated, a reference to an isomer applies to any possible isomer. Whenever the composition of the isomers is not specified, all possible isomers are included.

[0166] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, and even further such as no more than 20% of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, such as no more than 5%, such as no more than 1% of any other one or more stereoisomers.

[0167] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0168] When the compounds disclosed herein contain disubstituted cyclohexyl or cyclobutyl groups, the substituents found on the cyclohexyl or cyclobutyl ring can be in cis and trans forms. The cis form means that both substituents are located on the upper side of the carbon 2 substituent positions, while the trans form means that they are located on opposite sides.

[0169] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) to the desired uniformity by common techniques in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including: reverse phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. Those skilled in the art will apply the technology most likely to achieve the desired separation.

[0170] "Diastereoisomers" refer to stereoisomers of compounds with two or more chiral centers but that are not mirror images of each other. Diastereoisomers can be separated into their individual diastereoisomers based on their physicochemical differences by methods well known to those skilled in the art (e.g., by chromatography and / or fractional crystallization). Enantiomers can be separated as follows: by reacting the enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acidchlorid), converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereoisomers, and converting the individual diastereoisomers (e.g., hydrolyzing) into the corresponding pure enantiomers. Enantiomers can also be separated using chiral HPLC columns.

[0171] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolution of the racemic mixture using an optically active resolving agent to form the diastereomers (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): 283-302). Racemic mixtures of the chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers and conversion to pure stereoisomers; and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0172] The term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base group with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0173] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt (e.g., a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize that a variety of synthetic methods can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0174] As defined herein, "pharmaceutically acceptable salts thereof" include salts of at least one compound of formula (I), and salts of stereoisomers, such as salts of enantiomers, and / or salts of diastereomers, of compounds of formula (I).

[0175] The terms "administration," "administering," and "treating," "treatment," as used herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells encompasses contact of an agent with a cell and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treating" also refer to in vitro and ex vivo treatment of a cell, such as by a reagent, diagnostic agent, binding compound, or another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human.

[0176] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a compound) that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or disorder, is sufficient to affect the treatment of such a disease, disorder, or symptom. A "therapeutically effective amount" can vary with the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, as defined above, that is effective to treat the disease or disorder of the subject. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination subject used to effectively treat the disease, disorder, or condition.

[0177] The pharmaceutical compositions comprising the compounds disclosed herein can be administered orally, by inhalation, rectally, parenterally, or topically to a subject in need thereof. For oral administration, the pharmaceutical composition can be a conventional solid formulation, such as a tablet, powder, granule, capsule, etc.; a liquid formulation, such as an aqueous or oily suspension; or other liquid formulations, such as a syrup, solution, suspension, etc.; for parenteral administration, the pharmaceutical composition can be a solution, an aqueous solution, an oily suspension concentrate, a lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition can be a single unit administration with a precise dosage. In addition, the pharmaceutical composition may further comprise other active ingredients.

[0178] All formulations of the pharmaceutical composition disclosed herein can be produced by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients and then made into the desired formulation. "Pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers suitable for desired pharmaceutical formulations, such as: diluents, vehicles (such as water, various organic solvents, etc.), fillers (such as starch, sucrose, etc.), adhesives (such as cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone (PVP)); Wetting agents, such as glycerol; Disintegrants, such as agar, calcium carbonate and sodium bicarbonate; Absorption enhancers, such as quaternary ammonium compounds; Surfactants, such as hexadecanol; Absorption carriers, such as kaolin and bentonite; Lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition also includes other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners and dyes.

[0179] The term "disease" refers to any illness, ailment, disease, symptom, or indication and is interchangeable with the terms "disorder" or "condition."

[0180] Throughout this specification and the appended claims, unless the context requires otherwise, the term "comprise" and variations such as "include" and "comprising" are intended to specify the presence of the following features, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced with the terms "contain" or "includes," or sometimes "having."

[0181] Throughout the specification and the appended claims, the term "Cn-m" indicates a range including endpoints, where n and m are integers and indicate the number of carbons. Examples include C1-8, C1-6, etc.

[0182] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0183] Universal synthesis

[0184] The compounds disclosed herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0185] The reaction for preparing the compound disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting material (intermediate) or product at the temperature at which the reaction is carried out (e.g., a temperature that can range from room temperature to the boiling temperature of the solvent). A given reaction can be carried out in a solvent or a mixture of more than one solvent.

[0186] The selection of appropriate protecting groups can be readily determined by one skilled in the art.

[0187] The reaction can be monitored according to any suitable method known in the art (e.g., NMR, UV, HPLC, LC-MS, and TLC).The compound can be purified by a variety of methods including HPLC and normal phase silica gel chromatography.

[0188] Chiral analytical HPLC was used for retention time analysis of different chiral examples, and the conditions were divided into the following methods based on the column, mobile phase, and solvent ratio used.

[0189] The compounds disclosed herein can be prepared according to Scheme 1 below.

[0190] Plan I

[0191]

[0192] Among them -WR 1A Yes-OR 1a or -NR 1a R 1b , and L2, R 5 、R 6 、R 1a and R 1b is as defined for formula (I), X and Y are independently CH or N; W is independently N or O.

[0193] In Scheme 1, commercially available ethyl 1H-imidazole-2-carboxylate is reacted with 2-O-(4-nitrobenzoyl)hydroxylamine to form compound 2, which is reacted with ethyl chloroformate and then the ring is closed in the presence of ammonium hydroxide to give imidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione. Intermediate 5 is obtained after the introduction of a Br atom using a brominating reagent, and the diketone is then chlorinated to form intermediate 6. One chlorine atom is replaced by a protected amine to obtain intermediate 7, which is reacted with R 1A -W reaction to give the key intermediate 8, which is then reacted with different aldehydes under basic conditions to form intermediate 10. The protected groups on the amine and the hydroxyl group are removed to give formula I.

[0194] Intermediate 10 can also be prepared by the following Scheme II.

[0195] Option II

[0196]

[0197] In Scheme II, compound 4 is chlorinated to form intermediate 6'. One chlorine atom is replaced by a protected amine to obtain intermediate 7', which is then reacted with R 1A -W reaction to give the key intermediate 8', which is then reacted with different aldehydes under basic conditions to form intermediate 10.

[0198] Examples

[0199] The following examples are intended to be purely illustrative and should not be construed as limiting in any way. Unless otherwise stated, the experimental methods in the following examples are conventional methods. Unless otherwise stated, reagents and materials are commercially available. All solvents and chemicals used are of analytical grade or chemical purity. All solvents were redistilled before use. Anhydrous solvents were prepared according to standard methods or reference methods. Silica gel (100-200 mesh) for column chromatography and silica gel (GF254) for thin layer chromatography (TLC) are commercially available from Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd. in China; unless otherwise stated, all were eluted with petroleum ether (60°C-90°C) / ethyl acetate (v / v) and developed with a solution of iodine or phosphomolybdic acid in ethanol. Unless otherwise stated, all extraction solvents were dried over anhydrous Na2SO4. Recorded on a Bruck-400 nuclear magnetic resonance spectrometer with TMS (tetramethylsilane) as the internal standard 1 H NMR spectra. LC / MS data were recorded using an Agilent 1100 high performance liquid chromatograph-ion trap mass spectrometer (LC-MSD trap) equipped with a diode array detector (DAD) detecting at 214 nm and 254 nm and an ion trap (ESI source). All compound names except those of the reagents are given by generate.

[0200] In the following examples, the following abbreviations are used:

[0201] AcOH acetic acid

[0202] Aq. Water-based

[0203] BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0204] Brine saturated sodium chloride aqueous solution

[0205] Bn benzyl

[0206] BnBr benzyl bromide

[0207] BPO Benzoyl Peroxide

[0208] BSA N,O-Bis(trimethylsilyl)acetamide

[0209] CH2Cl2 or DCM dichloromethane

[0210] DIAD Diisopropyl azodicarboxylate

[0211] DMF N,N-dimethylformamide

[0212] Dppf 1,1'-bis(diphenylphosphino)ferrocene

[0213] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0214] DIEA or DIPEA N,N-diisopropylethylamine

[0215] DMAP 4-N,N-dimethylaminopyridine

[0216] DMF N,N-dimethylformamide

[0217] DMSO dimethyl sulfoxide

[0218] EtOAc or EA Ethyl acetate

[0219] EtOH

[0220] Et2O or ether

[0221] g grams

[0222] h or hr hours

[0223] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0224] Hexane

[0225] HCl

[0226] HMDS Hexamethyldisilazane

[0227] HPLC high-performance liquid chromatography

[0228] IBX 2-iodoacylbenzoic acid

[0229] IPA Isopropyl alcohol

[0230] i-PrOH isopropyl alcohol

[0231] LCMS liquid chromatography-mass spectrometry

[0232] mg milligrams

[0233] mL milliliters

[0234] mmol millimole

[0235] MeCN Acetonitrile

[0236] MeOH methanol

[0237] Min minutes

[0238] ms or MS mass spectrometry

[0239] MTBE methyl tert-butyl ether

[0240] Na2SO4 sodium sulfate

[0241] NBS N-bromosuccinimide

[0242] NMP N-Methylpyrrolidone

[0243] PE petroleum ether

[0244] PMB (4-methoxyphenyl)methylamine

[0245] prep

[0246] Rt or rt room temperature

[0247] sat. saturated

[0248] TBAF Tetrabutylammonium fluoride

[0249] TBSCl tert-Butyldimethylsilyl chloride

[0250] t-BuOK Potassium tert-butoxide

[0251] TFA trifluoroacetic acid

[0252] THF Tetrahydrofuran

[0253] TLC thin layer chromatography

[0254] μL microliter

[0255] Synthesis of Intermediate-I

[0256] 7-Bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0257] Step A: Ethyl 1-amino-1H-imidazole-2-carboxylate hydrochloride

[0258] To a stirred solution of ethyl 1H-imidazole-2-carboxylate (56 g, 0.4 mol) in NMP (1.2 L) was added t-BuOK (1 M in THF, 440 ml, 0.44 mol) at 20°C to 30°C. The mixture was stirred for 0.5 h. Below 30°C, a solution of O-(4-nitrobenzoyl)hydroxylamine (80.08 g, 0.44 mol) in NMP (0.4 L) was added dropwise. The solution was stirred at rt for 2 h. The solution was diluted with MTBE (500 ml). HCl (4 M in EA, 100 ml) was added to quench the reaction. Celite (20 g) was added to the mixture and then stirred for 0.5 h. The mixture was filtered. The filtrate was diluted with MTBE (2 L) and HCl (4 M in EA, 200 ml) was added dropwise. The suspension was stirred for 0.5 h and filtered. The filter cake was rinsed with MTBE and microwave dried to give the product (70 g, 91%). MS: M / e 156 (M+1) + .

[0259] Step B: Ethyl 1-((ethoxycarbonyl)amino)-1H-imidazole-2-carboxylate and ethyl 1-(bis(ethoxycarbonyl)amino)-1H-imidazole-2-carboxylate A mixture of 1H-imidazole-2-carboxylate (1:1)

[0260] To a stirred solution of ethyl 1-amino-1H-imidazole-2-carboxylate hydrochloride (80 g, 0.42 mol) in THF (900 ml) and H2O (900 ml) was added NaHCO3 (178.9 g, 2.1 mol) in several batches. Below 30°C, ethyl chloroformate (98.55 g, 0.9 mol) was added dropwise. The mixture was stirred at rt for 4 h. The mixture was diluted with EA (1 L) and then separated. The aqueous layer was extracted with EA (800 ml). The collected organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product (113 g) as a yellow oil, which was used directly in the next step without further purification. MS: M / e 228 (M+1) + &M / e 300(M+1) + .

[0261] Step C: Imidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione

[0262] A sealed tube was filled with a mixture of ethyl 1-((ethoxycarbonyl)amino)-1H-imidazole-2-carboxylate and ethyl 1-(di(ethoxycarbonyl)amino)-1H-imidazole-2-carboxylate (110 g) in ammonium hydroxide (400 ml, 3.6 V) and IPA (200 ml, 1.8 V). The mixture was stirred at 120 ° C. overnight. After cooling, the mixture was filtered. The filter cake was rinsed with MeOH. The filtrate was concentrated under reduced pressure. The resulting residue was made into a slurry in MeOH, filtered and rinsed with MeOH. The resulting filter cake and the previous filter cake were mixed and microwave-dried to give the product (56 g) as a white solid. MS: M / e 153 (M + 1) + .

[0263] Step D: 7-Bromoimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione

[0264] To a solution of imidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (30 g, 0.20 mol) in H2O (1.2 L) was added NBS (24.6 g, 0.14 mol) in several batches below 25°C. The mixture was stirred at rt for 1 h. The mixture was filtered. The filtrate was concentrated to remove the solvent. The resulting residue was mixed with the previous filter cake and slurried in MeOH (20 V) and then in MeOH:H2O (1:1, 20 V) to give the product (30.4 g, 94%) as a white solid. MS: M / e 231 (M+1) + .

[0265] Step E: 7-Bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine

[0266] A 350ml sealed tube was filled with 7-bromoimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (10g, 43mmol), triethylamine hydrochloride (12g, 88mmol) and POCl3 (100ml). The mixture was stirred at 120°C overnight. The mixture was concentrated to remove POCl3. The residue was diluted with EA (200ml) and saturated NaHCO3 (aqueous) was added dropwise below 20°C until the pH value was greater than 7. The solution was separated. The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography using 0-20% EA in PE to give the product (8.5g, 73%) as a white solid. MS: M / e267 (M+1) + .

[0267] Step F: 7-Bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0268] To a stirred solution of 7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine (30 g, 0.11 mol) in THF (500 ml) was added TEA (22.6 g, 0.22 mol) dropwise. The mixture was stirred at rt for 10 min. A solution of bis(4-methoxybenzyl)amine (31.6 g, 0.12 mol) in THF (80 ml) was added dropwise to the above solution. The mixture was stirred at rt for 2 h. The solution was quenched with H2O (300 ml) and then extracted with EA (200 ml x 2). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was slurried in PE (300 ml) and filtered to give the product (41.4 g, 76%) as a white solid. MS: M / e 488 (M+1) + .

[0269] Step G: 7-Bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0270] Under N2, a mixture of 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (35 g, 71.6 mmol) and n-BuONa / n-BuOH (20%, 200 ml) was stirred at 80 ° C for 1 h. The solution was quenched with H2O (200 ml). The aqueous solution was extracted with EA (150 ml × 2). The collected organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography using 0-20% EA in PE to give the product (33 g, 88%) as a colorless oil that solidified after several hours. MS: M / e 526 (M+1) + .

[0271] Compound A1: 2-Butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0272] Step A: 7-Bromo-2-chloroimidazo[2,1-f][1,2,4]triazin-4-amine

[0273] The reaction mixture of 7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine (2.37 g, 8.84 mmol) and ammonium hydroxide (30 mL) was stirred at 80° C. overnight. The mixture was cooled to room temperature and the precipitate was filtered to give the crude product (1.7 g, 77%). MS: M / e 248 (M+1) + .

[0274] Step B: 7-Bromo-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0275] A mixture of the product of step A (1.7 g, 6.84 mmol) and sodium butanoate (50 mL, 1 M in 1-butanol) was stirred at 70° C. overnight. The mixture was evaporated and the residue was diluted with methanol. The precipitate was filtered to give the crude product (1 g, 51%). 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H),8.24(s,1H),7.60(s,1H),4.24(t,J=6.5Hz,2H),1.81-1.62(m,2H),1.53-1.34(m,2H),0.94(t,J=7.4Hz,3H)ppm. MS:M / e 286(M+1) + .

[0276] Step C: tert-butyl (7-bromo-2-butoxyimidazo [2, 1-f] [1, 2, 4] triazin-4-yl) (tert-butyloxycarbonyl) methyl) carbamate

[0277] To a solution of the product of step B (525 mg, 1.84 mmol) and DMAP (224 mg, 1.84 mmol) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate (1.2 g, 5.51 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (20 mL), washed with water and brine, dried over Na2SO4, filtered and evaporated to give the crude product (650 mg, 72%), which was used in the next step without further purification. MS: M / e 486 (M+1) + .

[0278] Step D: tert-Butyl (2-butoxy-7-(hydroxy (4-(pyrrolidin-1-ylmethyl)phenyl)methyl) imidazo [2, 1-f][1,2,4]triazin-4-yl)(tert-butoxycarbonyl)carbamate

[0279] At -78 ° C, under nitrogen, to a solution of the product of step C (650 mg, 1.33 mmol) in THF (30 mL) was added n-butyl lithium (0.8 mL, 2.00 mmol, 2.5 M in hexane) and stirred for 0.5 hr. After adding 4- (pyrrolidin-1-ylmethyl) benzaldehyde (378 mg, 2.00 mmol), the mixture was warmed to room temperature overnight. The reaction was quenched with aqueous saturated NH4Cl solution and the resulting mixture was extracted with ethyl acetate (30 mL X 3). The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography (eluent: MeOH / DCM=0.1% to 5%) to give the product (200 mg, 30%). MS: M / e 597 (M+1) + .

[0280] Step E: 2-Butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-4- Amine (Compound A1)

[0281] The reaction mixture of the product of step D (140 mg, 0.28 mmol), trifluoroacetic acid (2 mL), triethylsilane (2 mL) and dichloromethane (1 mL) was stirred at 40 ° C overnight. After completion, the mixture was evaporated and alkalized. The residue was purified by combi-flash (eluent: MeOH / DCM=0% to 10%) to give the product (50 mg, 47%). 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),8.04(s,1H),7.30(s,1H),7.29-7.18(m,4H),4.19(t,J=6.6Hz,2H),4. 11(s,2H),3.59(s,2H),2.49-2.33(m,4H),1.70-1.61(m,6H),1.50-1.32(m,2H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e 381(M+1) + .

[0282] Compound A2: 2-Butoxy-7-(4-(3-(dimethylamino)propyloxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0283] Step A: 4-(3-(Dimethylamino)propoxy)benzaldehyde

[0284] Under N2 atmosphere, at 0 DEG C, DIAD (2.5g, 12.3mmol) was added dropwise to a solution of 4-hydroxybenzaldehyde (1g, 8.2mmol), 3-(dimethylamino)propan-1-ol (1.2g, 12.3mmol) and triphenylphosphine (3.2g, 12.3mmol) in THF (20mL). The mixture was warmed to rt and stirred for 6hr. The reaction was quenched with water (20mL), extracted with ethyl acetate (20mL) and washed with brine (10mL). The organic layer was dried, concentrated and purified by CombiFlash to obtain the product (1.1g, 65%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ9.88 (s, 1H), 7.82 (d, J = 8.0Hz, 2H), 7.00 (d, J = 8.0Hz, 2H), 4.11(t,J=8.0Hz,2H),2.46(t,J=8.0Hz,2H),2.26(s,6H),2.02-1.96(m,2H)ppm. MS:M / e 208(M+1) + .

[0285] Step B: tert-Butyl (2-butoxy-7-((4-(3-(dimethylamino)propoxy)phenyl)(hydroxy)methyl)imidazole Azo[2,1-f][1,2,4]triazin-4-yl)(tert-butoxycarbonyl)carbamate

[0286] At -78 ° C, a cooled solution of bromide (100 mg, 0.2 mmol) in THF (3 mL) was purged with N2, and then n-butyl lithium (1.6 M, 0.3 mL) was added dropwise. After stirring for 30 min at -78 ° C, 4- (3- (dimethylamino) propoxy) benzaldehyde (83 mg, 0.4 mmol) in THF (1 mL) was added. The resulting mixture was stirred at this temperature for 30 min, and then heated to rt overnight. The solution was quenched with NH4Cl solution (5 mL), extracted with ethyl acetate (10 mL) and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to obtain a crude product, which was further purified by preparative TLC (DCM: MeOH = 10: 1) to obtain the pure product (35 mg, 33%) as a white solid. MS: M / e 615 (M+1) + .

[0287] Step C: 2-Butoxy-7-(4-(3-(dimethylamino)propyloxy)benzyl)imidazo[2,1-f][1,2,4]triazol Oxazine-4-amine (Compound A2)

[0288] Triethylsilane (0.5mL) and trifluoroacetic acid (0.5mL) are added to a solution of the product of step B (35mg, 0.07mmol) in DCM (2mL). The mixture is heated at 40°C for 1hr and then concentrated. Water (5mL) is added to the residue, extracted with ethyl acetate (5mL), washed with NaHCO (5mL) and brine (5mL). The organic layer is dried, concentrated and purified by preparative TLC (DCM: MeOH=6:1) to obtain product (9mg, 33%). 1 H NMR(400MHz,DMSO-d6)δ9.75(br.s,1H),8.12(s,1H),8.04(s,1H),7.25(s, 1H),7.23(d,J=8.0Hz,2H),6.86(d,J=8.0Hz,2H),4.20(t,J=8.0Hz,2H),4.0 7(s,2H),3.99(t,J=8.0Hz,2H),3.11(t,J=4.0Hz,2H),2.74(s,6H),2.10-2 .03(m,2H),1.71-1.64(m,2H),1.45-1.36(m,2H),0.93(t,J=8.0Hz,3H)ppm. MS:M / e 399(M+1) + .

[0289] Compound A3: 2-Butoxy-7-(4-(morpholinomethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0290] Step A: 4-(Bromomethyl)benzaldehyde

[0291] To a stirred solution of 4-(hydroxymethyl)benzaldehyde (7 g, 50.7 mmol) in DCM (400 mL) was added NBS (17.8 g, 100 mmol) and PPh (27.3 g, 104 mmol). After addition, the reaction mixture was stirred at rt for 4 hr. The reaction mixture was washed with H2O (150 mL x 3). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether / EtOAc=5:1) to give 4-(bromomethyl)benzaldehyde (9.5 g, 95%) as a white solid. MS: M / e199 (M+1) + .

[0292] Step B: 4-(Morpholinomethyl)benzaldehyde

[0293] To a stirred solution of 4- (bromomethyl) benzaldehyde (3g, 15mmol) in MeCN (40mL) was added morpholine (1.39g, 16mmol) and KCO (4.17g, 30mmol). After addition, the reaction mixture was stirred overnight at Rt. The mixture was filtered. The filtrate was poured into HO and extracted with EtOAc (15mL x 3). The combined organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether / EtOAc=1:1) to give 4- (morpholinomethyl) benzaldehyde (2g, 66.7%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ10.00(s,1H),7.84(d,J=8.2Hz,2H),7.52(d,J=8.2Hz,2H),3.74-3.67(m,4H),3.57(s,2H),2.50-2.42(m,4H)ppm. MS:M / e 206(M+1) + .

[0294] Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- methyl)(4-(morpholinomethyl)phenyl)methanol

[0295] To a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.3 mmol) in THF (10 mL) cooled to -78 ° C under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.75 mmol, 0.47 mL). After stirring for 20 min, a solution of 4-(morpholinomethyl)benzaldehyde (114 mg, 0.45 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give the title product (220 mg, 100%), which was used directly in the next step without further purification. MS: M / e 653 (M+1) + .

[0296] Step D: 2-Butoxy-7-(4-(morpholinomethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Chemical Compound A3)

[0297] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(morpholinomethyl)phenyl)methanol (220 mg, 0.3 mmol) in TFA (3 mL) and Et3SiH (3 mL) was stirred at 80 ° C for 2 h. The reaction mixture was concentrated in vacuo to remove TFA and Et3SiH. TFA (5 mL) was added to the residue and stirred at 85 ° C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by column chromatography (DCM / MeOH=5:1) to give the product (40 mg, 33.6%). 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),8.04(s,1H),7.57-7.25(m,5H),4.23-4.15(m,2H),3.83-3.65(m,2H),3.62-3.49(m,4H),2.43-2.29(m,4H). 1.71-1.57(m,2H),1.47-1.33(m,2H),0.90(t,J=7.6 3H)ppm. MS:M / e 397(M+1) + .

[0298] Compound A4:N 1 -(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)pyridin-2-yl)-N 1 ,N 2 ,N 2 -Trimethylethane-1,2-diamine

[0299] Step A: 6-((2-(dimethylamino)ethyl)amino)nicotinaldehyde

[0300] 6-Chloronicotinaldehyde (1 g, 7.1 mmol), N 1 ,N 1 ,N 2 A mixture of -trimethylethane-1,2-diamine (0.87 g, 8.5 mmol) and DIEA (1.8 g, 14.2 mmol) in DMSO (10 mL) was heated at 90 ° C overnight. The solution was cooled and water (10 mL) was added, extracted with ethyl acetate (10 mL), and washed with brine (10 mL). The organic layer was dried, concentrated and purified by CombiFlash (DCM:MeOH=4%) to give the product (0.8 g, 57%) as a red oil. 1 H NMR (400MHz, CDCl3) δ9.76 (s, 1H), 8.54 (d, J = 4.0Hz, 1H), 7.90 (dd, J = 8.0, 4.0Hz, 1H), 6.55 ( d,J=4.0Hz,1H),3.77(t,J=8.0Hz,2H),3.17(s,3H),2.53(t,J=8.0Hz,2H),2.30(s,6H)ppm. MS:M / e 208(M+1) + .

[0301] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-(6-((2-(dimethylamino)ethyl)(methyl)amino)pyridin-3-yl)methanol

[0302] At -78°C (with N 2 To a cooled solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.29 mmol) in THF (8 mL) was added n-butyl lithium (1.6 M, 0.5 mL) dropwise under 4% CO 2 (purging). After stirring at -78 ° C for 30 min, 6-((2-(dimethylamino)ethyl)amino)nicotinaldehyde (88 mg, 0.43 mmol) in THF (2 mL) was added. The resulting mixture was stirred at this temperature for 30 min and then warmed to rt for 1 hour. The solution was quenched with NH4Cl solution (5 mL), extracted with ethyl acetate (10 mL), and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by Combiflash (DCM:MeOH=20%) to give the pure product (130 mg, 70%) as a white solid. MS: M / e 655 (M+1) + .

[0303] Step C: N 1 -(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)pyridine-2-methyl)-N 1 ,N 2 ,N 2 -Trimethylethane-1,2-diamine (Compound A4)

[0304] Triethylsilane (1 mL) and trifluoroacetic acid (1 mL) were added to a solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(6-((2-(dimethylamino)ethyl)(methyl)amino)pyridin-3-yl)methanol (130 mg, 0.2 mmol) in DCM (2 mL). The mixture was heated at 80° C. overnight. The solvent was evaporated to give a residue, which was treated with NaHCO 3 (5 mL), extracted with ethyl acetate (5 mL), and washed with brine (5 mL). The organic layer was dried, concentrated, and purified by CombiFlash (DCM:MeOH=8:1) to give the product (28 mg, 35%). 1 H NMR (400MHz, DMSO-d6) δ8.13-8.05(m,3H),7.52(dd,J=8.0,4.0Hz,1H),7.27(s,1H),6.85(d,J=8.0Hz,1H),4.22(t,J=8.0Hz,2H),4.01 (s,2H),3.83(t,J=8.0Hz,2H),3.22(s,2H),2.95(s,3H),2.79(s,6H),1.70-1.67(m,2H),1.44-1.39(m,2H),0.93(t,J=8.0Hz,3H)ppm. MS:M / e 399(M+1) + .

[0305] Compound A5: 2-Butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0306] Step A: 4-(Piperidin-1-ylmethyl)benzaldehyde

[0307] To a stirred solution of 4-(bromomethyl)benzaldehyde (3g, 15mmol) in MeCN (40mL) was added piperidine (1.36g, 16mmol) and KCO (4.17g, 30mmol). After addition, the reaction mixture was stirred overnight at Rt. The mixture was filtered. The filtrate was poured into HO and extracted with EtOAc (15mL x 3). The combined organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether / EtOAc=1:1) to give the title product (2.7g, 88%) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),7.83(d,J=7.9Hz,2H),7.50(d,J=7.9Hz ,2H),3.53(s,2H),2.38(s,4H),1.62-1.54(m,4H),1.45(d,J=4.9Hz,2H)ppm. MS:M / e 204(M+1) + .

[0308] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(4-(piperidin-1-ylmethyl)phenyl)methanol

[0309] To a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.3 mmol) in THF (10 mL) cooled to -78 ° C and under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.75 mmol, 0.47 mL). After stirring for 20 min, a solution of 4-(piperidin-1-ylmethyl)benzaldehyde (114 mg, 0.45 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly heated to rt and stirred for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give the product (270 mg, 100%), which was used directly in the next step without further purification. MS:M / e 651(M+1) + .

[0310] Step C: 2-Butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Compound A5)

[0311] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(piperidin-1-ylmethyl)phenyl)methanol (270 mg, 0.3 mmol) in TFA (3 mL) and Et3SiH (3 mL) was stirred at 80 ° C for 2 h. The reaction mixture was concentrated in vacuo to remove TFA and Et3SiH. TFA (5 mL) was added to the residue and stirred at 85 ° C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (50 mg, 42%). 1H NMR (400MHz, DMSO-d6) δ8.12(s,1H),8.03(s,1H),7.30(s,1H),7.24-7.17(m,4H),4.19(t,J=6.5Hz,2H),4.11(s, 2H),3.35(s,2H),2.31-2.21(m,4H),1.70-1.61(m,2H),1.45(m,4H),1.42-1.31(m,4H),0.91(t,J=7.3Hz,3H)ppm. MS:M / e 395(M+1) + .

[0312] Compound A6: 2-Butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0313] Step A: 4-((4-Methylpiperazin-1-yl)methyl)benzaldehyde

[0314] To a stirred solution of 4-(bromomethyl)benzaldehyde (3g, 15mmol) in MeCN (40mL) was added piperidine (1.6g, 16mmol) and KCO (4.17g, 30mmol). After addition, the reaction mixture was stirred at Rt overnight. The mixture was filtered. The filtrate was poured into H2O and extracted with EtOAc (15mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether / EtOAc=1:1) to give 4-((4-methylpiperazine-1-yl)methyl)benzaldehyde (2.3g, 71.8%) as a yellow oil. MS:M / e 219 (M+1) + .

[0315] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-((4-methylpiperazin-1-yl)methyl)phenyl)methanol

[0316] To a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.3 mmol) in THF (10 mL) cooled to -78 ° C and under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.75 mmol, 0.47 mL). After stirring for 20 min, a solution of 4-((4-methylpiperazin-1-yl)methyl)benzaldehyde (122 mg, 0.45 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly heated to rt and stirred for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give the product (300 mg, 100%), which was used directly in the next step without further purification. MS:M / e 666(M+1) + .

[0317] Step C: 2-Butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)imidazo[2,1-f][1,2,4] Triazine-4-amine (Compound A6)

[0318] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-((4-methylpiperazin-1-yl)methyl)phenyl)methanol (300 mg, 0.3 mmol) in TFA (3 mL) and Et3SiH (3 mL) was stirred at 80 ° C for 2 h. The reaction mixture was concentrated in vacuo to remove TFA and Et3SiH. TFA (5 mL) was added to the residue and stirred at 85 ° C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (60 mg, 49.1%). 1 H NMR (400MHz, DMSO-d6)) δ8.13(s,1H),8.03(s,1H),7.30(s,1H),7.24(d,J=7.9Hz,2H),7.19(d,J=7.9Hz,2H),4.19(t,J=6.5Hz, 2H),4.11(s,2H),3.38(s,2H),3.21-2.17(m,8H),2.12(s,3H),1.71-1.59(m,2H),1.45-1.33(m,2H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e 410(M+1) + .

[0319] Compound A7: 2-Butoxy-7-(3-(piperidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0320] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-Methyl-2-piperidin-1-ylmethylphenyl)methanol

[0321] Under N2 atmosphere, at -78 ° C, to a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.38 mmol) in THF (10 ml) was added n-butyl lithium (1.6 M, 0.60 ml, 0.96 mmol). The solution was stirred at -78 ° C for 30 min. 3-(piperidin-1-ylmethyl)benzaldehyde (116 mg, 0.57 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was naturally warmed to rt and then stirred for 3 hr. After completion, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml × 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to obtain a crude product in the form of a yellow oil, which was directly used in the next step without further purification. MS:M / e651(M+1) + .

[0322] Step B: 2-Butoxy-7-(3-(piperidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Compound A7)

[0323] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(3-(piperidin-1-ylmethyl)phenyl)methanol (crude) in TFA (2 ml) and triethylsilane (2 ml) was stirred at 80 ° C for 15 hr. The solution was concentrated under reduced pressure to remove triethylsilane. The residue was dissolved in TFA (2 ml) and stirred at 80 ° C overnight. After completion, the reaction mixture was quenched with aqueous NaHCO (saturated, 25 ml) and then extracted with DCM (20 ml × 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by preparative TLC using DCM:MeOH (10: 1) to give the product (81.54 mg). 1 H NMR (400MHz, DMSO-d6) δ8.16 (s, 1H), 8.07 (s, 1H), 7.40 (d, J = 8Hz, 4H), 7.32 (s, 1H), 4.31-4.09 (m, 6H) ,3.31-3.12(m,2H),2.90-2.70(m,2H),1.87-1.60(m,7H),1.45-1.28(m,3H),0.91(t,J=8Hz,3H)ppm. MS:M / e 395(M+1) + .

[0324] Compound A8: 2-Butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0325] Step A: 6-Bromo-2-isopropyl-1,2,3,4-tetrahydroisoquinoline

[0326] To a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (1.06 g, 5 mmol) in MeOH (3 mL) was added acetone (3 mL) and AcOH (10 drops). The mixture was then stirred at 80 ° C for 1.5 h. The mixture was cooled to room temperature, NaBH3CN (0.93 g, 15 mmol) was added in several batches, and the resulting mixture was stirred at room temperature for 3 h. The reaction was concentrated, diluted with water (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (450 mg, 36%) as an oil. MS: M / e 254 (M + 1) + .

[0327] Step B: 2-Isopropyl-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde

[0328] To a solution of the product of step A (450 mg, 1.77 mmol) in THF (5 mL) was added n-butyl lithium (2.2 mL, 1.6 mol / L, 3.54 mmol) dropwise, and the temperature was maintained between -75°C and -65°C. After 30 min, DMF (258 mg, 3.54 mmol) was added dropwise and the resulting mixture was stirred at -65°C for 30 min. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give the target compound (250 mg, 69%) as an oil. 1 H NMR (400MHz, CDCl3) δ9.94 (s, 1H), 7.68-7.60 (m, 2H), 7.20 (d, J = 8.0Hz, 1H), 3.9 0-3.78(m,2H),3.11-2.95(m,3H),2.90-2.80(m,2H),1.18(d,J=6.4Hz,6H)ppm. MS:M / e 204(M+1) + .

[0329] Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)(2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methanol

[0330] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.285 mmol) in THF (5 mL) was added n-butyllithium (0.44 mL, 0.71 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 30 min, a mixture of the product of step B (87 mg, 0.423 mmol) in THF (4 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature for 1 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (80 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH=50 / 1) to give the target compound (60 mg, 32%). MS: M / e 651 (M+1) + .

[0331] Step D: 2-Butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)imidazo[2,1- f][1,2,4]triazine-4-amine (Compound A8)

[0332] To the mixture of the product of step C (60 mg, 0.092 mmol) in TFA (2 mL), Et3SiH (2 mL) was added. The reaction was heated at 80 ° C for 2 h. The mixture was concentrated to dryness, and the residue was treated with TFA (4 mL). The reaction was heated at 85 ° C overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The collected fractions were alkalized with NaHCO3 solution, extracted with DCM (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give product (20 mg, 55%). 1 HNMR(400MHz,DMSO-d6)δ8.11(s,1H),8.02(s,1H),7.27(s,1H),6.85-6.15(m,3H),4.20(t,J=6.4Hz,2H),4.05(s,2H),3.57(s,2 H),2.91-2.76(m,1H),2.74-2.60(m,4H),1.74-1.62(m,2H),1.47-1.34(m,2H),1.03(d,J=5.6Hz,6H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 395(M+1) + .

[0333] Compound A9: 2-Butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0334] Step A: 7-Bromo-2-isopropyl-1,2,3,4-tetrahydroisoquinoline

[0335] To a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (1.06 g, 5 mmol) in MeOH (3 mL) was added acetone (3 mL) and AcOH (10 drops). The mixture was then stirred at 80 ° C for 1.5 h. The mixture was cooled to room temperature, NaBH3CN (0.93 g, 15 mmol) was added in several batches, and the resulting mixture was stirred at room temperature for 3 h. The reaction was concentrated, diluted with water (30 mL), and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by flash chromatography to give the target compound (930 mg, 73%) as an oil. MS: M / e 254 (M + 1) + .

[0336] Step B: 2-Isopropyl-1,2,3,4-tetrahydroisoquinoline-7-carbaldehyde

[0337] To a solution of the product of step A (930 mg, 3.64 mmol) in THF (20 mL) was added a solution of n-butyllithium (4.5 mL, 7.2 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 30 min, DMF (532 mg, 7.3 mmol) was added dropwise and the resulting mixture was stirred at -65°C for 30 min. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give the target compound (80 mg, 11%) as an oil. MS: M / e 204 (M+1) + .

[0338] Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-Isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methanol

[0339] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.285 mmol) in THF (5 mL) was added dropwise a solution of n-butyllithium (0.44 mL, 0.71 mmol), maintaining the temperature between -75°C and -65°C. After 30 min, a mixture of the product of step B (80 mg, 0.42 mmol) in THF (4 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature for 1 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (80 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH=40 / 1) to give the target compound (50 mg, crude). MS: M / e 651 (M+1) +.

[0340] Step D: 2-Butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)imidazo[2,1- f][1,2,4]triazine-4-amine (Compound A9)

[0341] To the mixture of the product of step C (50 mg, crude) in TFA (3 mL) was added Et3SiH (1 mL). The reaction was heated at 85 ° C overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The collected fractions were alkalized with NaHCO3 solution, extracted with DCM (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the product (20 mg, 12% for two steps). 1 H NMR (400MHz, DMSO-d6) δ8.19-7.98(m,2H),7.28(s,1H),7.10-6.65(m,3H),4.20(t,J=6.4Hz,2H),4.05(s,2H),3.56(s,2H), 2.85-2.76(m,1H),2.74-2.62(m,4H),1.74-1.62(m,2H),1.49-1.34(m,2H),1.02(d,J=6.4Hz,6H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 395(M+1) + .

[0342] Compound A10: 2-Butoxy-7-(4-(piperazin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0343] Step A: tert-Butyl 4-(4-formylbenzyl)piperazine-1-carboxylate

[0344] To a stirred solution of 4-(bromomethyl)benzaldehyde (4g, 20mmol) in THF (40mL) was added tert-butylpiperazine-1-carboxylate (4.6g, 25mmol) and DIEA (5.04g, 40mmol). After addition, the reaction mixture was stirred at Rt overnight. The mixture was filtered. The filtrate was poured into H2O and extracted with EtOAc (15mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether / EtOAc=1:1) to give tert-butyl 4-(4-formylbenzyl)piperazine-1-carboxylate (4.1g, 68%) as a yellow oil. MS:M / e 305 (M+1) + .

[0345] Step B: tert-butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1, 2,4]triazin-7-yl)(hydroxy)methyl)benzyl)piperazine-1-carboxylate

[0346] To a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.3 mmol) in THF (10 mL) cooled to -78 ° C and under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.75 mmol, 0.47 mL). After stirring for 20 min, a solution of 4-(4-formylbenzyl)piperazine-1-carboxylate (137 mg, 0.45 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly heated to rt and stirred for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give the product (270 mg, 100%), which was used directly in the next step without further purification. MS:M / e 752(M+1) + .

[0347] Step C: 2-Butoxy-7-(4-(piperazin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Compound A10)

[0348] A solution of tert-butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)benzyl)piperazine-1-carboxylate (270 mg, 0.3 mmol) in TFA (3 mL) and EtSiH (3 mL) was stirred at 80 ° C for 2 h. The reaction mixture was concentrated in vacuo to remove TFA and EtSiH. TFA (5 mL) was added to the residue and stirred at 85 ° C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (40 mg, 33.8%). 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),8.03(s,1H),7.30(s,1H),7.24(d,J=8Hz,2H),7.19(d,J=8Hz,2H),4.19(t,J=6.4Hz,2H),4.11( s,2H),3.40(s,2H),2.71-2.61(m,4H),2.32-2.28(m,4H),1.65(dd,J=14.2,6.8Hz,2H),1.42-1.36(m,2H),0.92(t,J=7.3Hz,3H)ppm. MS:M / e 396(M+1) + .

[0349] Compound A11: 2-Butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0350] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-Methylphenyl)(3-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0351] Under N2 atmosphere, at -78 ℃, to a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (170mg, 0.32mmol) in THF (10ml) was added n-butyllithium (1.6M, 0.51ml, 0.82mmol). The solution was stirred at -78 ℃ for 30min. 3-(pyrrolidin-1-ylmethyl)benzaldehyde (92mg, 0.49mmol) in THF (2ml) was added dropwise to the above solution. After addition, the solution was naturally warmed to rt and then stirred for 3hr. After completion, the reaction mixture was quenched with H2O (20ml) and then extracted with DCM (20ml x 3). The organic phase was washed with H2O (10ml), dried and concentrated under reduced pressure. The residue was purified by preparative TLC with PE:EA (1:1) to give the product as an off-white oil (120 mg, 58%). MS: M / e 637 (M+1) + .

[0352] Step B: 2-Butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-4- Amine (Compound A11)

[0353] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(3-(pyrrolidin-1-ylmethyl)phenyl)methanol (120 mg, 0.19 mmol) in TFA (2 ml) and triethylsilane (2 ml) was stirred at 80 ° C for 15 hr. The solution was concentrated under reduced pressure to remove triethylsilane. The residue was dissolved in TFA (2 ml) and stirred at 80 ° C overnight. After completion, the reaction mixture was quenched with aqueous NaHCO (saturated, 25 ml) and then extracted with DCM (20 ml × 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by preparative TLC with DCM:MeOH (10: 1) to give the product (15.11 mg, 21%). 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),8.02(s,1H),7.43-7.11(m,5H),4.26(s,2H),4.18(t,J=8H z,2H),3.65(s,2H),2.40(s,4H),1.73-1.60(m,6H),1.42-1.35(m,2H),0.91(t,J=8Hz,3H)ppm. MS:M / e 381(M+1) + .

[0354] Compound A12: 2-Butoxy-7-(3-(morpholinomethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0355] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- methyl)(3-(morpholinomethyl)phenyl)methanol

[0356] Under N2 atmosphere, at -78 DEG C, to a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200mg, 0.38mmol) in THF (10ml) was added n-butyllithium (1.6M, 0.60ml, 0.96mmol). The solution was stirred at -78 DEG C for 30min. 3-(morpholinomethyl)benzaldehyde (117mg, 0.57mmol) in THF (2ml) was added dropwise to the above solution. After addition, the solution was naturally warmed to rt and then stirred for 3hr. After completion, the reaction mixture was quenched with H2O (20ml) and then extracted with DCM (20ml × 3). The organic phase was washed with H2O (10ml), dried and concentrated under reduced pressure to obtain a crude product in the form of a yellow oil, which was directly used in the next step without further purification. MS:M / e653(M+1) + .

[0357] Step B: 2-Butoxy-7-(3-(morpholinomethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Chemical Compound A12)

[0358] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(3-(morpholinomethyl)phenyl)methanol (crude) in TFA (2 ml) and triethylsilane (2 ml) was stirred at 80 ° C for 15 hr. The solution was concentrated under reduced pressure to remove triethylsilane. The residue was dissolved in TFA (2 ml) and stirred at 80 ° C overnight. After completion, the reaction mixture was quenched with aqueous NaHCO (saturated, 25 ml) and then extracted with DCM (20 ml × 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by preparative TLC using DCM:MeOH (10: 1) to give the product (59.43 mg). 1H NMR (400MHz, DMSO-d6) δ8.13(s,1H),8.04(s,1H),7.30-7.13(m,5H),4.19(t,J=8Hz,2H),4.13(s,2H) ,3.53(s,4H),3.40(s,2H),2.30(s,4H),1.74-1.63(m,2H),1.45-1.34(m,2H),0.92(t,J=8Hz,3H)ppm. MS:M / e 397(M+1) + .

[0359] Compound A13: 2-Butoxy-7-(3-((4-methylpiperazin-1-yl)methyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0360] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-Methylpiperazin-1-yl)(3-((4-methylpiperazin-1-yl)methyl)phenyl)methanol

[0361] Under N2 atmosphere, at -78 ℃, to 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200mg, 0.38mmol) in THF (10ml) stirred solution, n-butyllithium (1.6M, 0.60ml, 0.96mmol) was added. The solution was stirred at -78 ℃ for 30min. 3-((4-methylpiperazine-1-yl)methyl)benzaldehyde (124mg, 0.57mmol) in THF (2ml) was added dropwise to the above solution. After addition, the solution was naturally warmed to rt and then stirred for 3hr. After completion, the reaction mixture was quenched with H2O (20ml) and then extracted with DCM (20ml × 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a green oil, which was used directly in the next step without further purification. MS: M / e 666 (M+1) + .

[0362] Step B: 2-Butoxy-7-(3-((4-methylpiperazin-1-yl)methyl)benzyl)imidazo[2,1-f][1,2,4] Triazine-4-amine (Compound A13)

[0363] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(3-((4-methylpiperazin-1-yl)methyl)phenyl)methanol (crude) in TFA (2ml) and triethylsilane (2ml) was stirred at 80°C for 15hr. The solution was concentrated under reduced pressure to remove triethylsilane. The residue was dissolved in TFA (2ml) and stirred at 80°C overnight. After completion, the reaction mixture was quenched with aqueous NaHCO (saturated, 25ml) and then extracted with DCM (20ml x 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by preparative TLC using DCM:MeOH (10:1) to give the product (49.03mg). 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),8.06(s,1H),7.31–7.15(m,5H),4.20(t,J=8Hz,2H),4.13(s,2H),3.50(s,2H) ,3.31–2.82(m,6H),2.72(s,3H),2.43–2.13(m,2H),1.73–1.61(m,2H),1.48–1.34(m,2H),0.92(t,J=8Hz,3H)ppm. MS:M / e 410(M+1) + .

[0364] Compound A14: 2-Butoxy-7-(2-(morpholinomethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0365] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- methyl)(2-(morpholinomethyl)phenyl)methanol

[0366] To a solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.29 mmol) in THF (5 mL) was added n-butyllithium (0.27 ml, 0.43 mmol) at -78 ° C and stirred for 1 h. A solution of 2-(morpholinomethyl)benzaldehyde (88 mg, 0.43 mmol) in THF (2 mL) was then added dropwise at -78 ° C. After addition, the mixture was stirred at 60 ° C overnight. The mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (DCM / MeOH=20:1~5:1) to give the target product (83 mg, 44.6%) as a yellow oil. MS:M / e 653(M+1) + .

[0367] Step B: 2-Butoxy-7-(2-(morpholinomethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Chemical Compound A14)

[0368] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(2-(morpholinomethyl)phenyl)methanol (83 mg, 0.13 mmol) and triethylsilane (1 mL) in TFA (2 mL) was stirred at 90° C. overnight. The mixture was concentrated and purified by preparative HPLC to give the desired product (23 mg, 46%). 1 H NMR (400MHz, DMSO-d6) δ8.12(s,1H),8.02(s,1H),7.29-7.15(m,4H),7.09(s,1H),4.27(s,2H),4.18(t,J=6.6H z,2H),3.51(s,2H),3.40(s,4H),2.28(s,4H),1.71-1.60(m,2H),1.46-1.32(m,2H),0.91(t,J=7.4Hz,3H)ppm. MS:M / e397(M+1) + .

[0369] Compound A15: 2-Butoxy-7-(2-(piperidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0370] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-Methyl)(2-(piperidin-1-ylmethyl)phenyl)methanol

[0371] To a solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.29 mmol) in THF (5 mL) was added n-butyl lithium (0.27 ml, 0.43 mmol) at -78 ° C and stirred for 1 h. A solution of 2-(piperidin-1-ylmethyl)benzaldehyde (87 mg, 0.43 mmol) in THF (2 mL) was then added dropwise at -78 ° C. After addition, the mixture was stirred to 60 ° C and stirred overnight. The mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (DCM / MeOH=20:1~5:1) to give the product (79 mg, 43%) as a yellow oil. MS:M / e 651(M+1) + .

[0372] Step B: 2-Butoxy-7-(2-(piperidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Compound A15)

[0373] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(2-(piperidin-1-ylmethyl)phenyl)methanol (79 mg, 0.12 mmol) and triethylsilane (1 mL) in TFA (2 mL) was stirred at 90° C. overnight. The mixture was concentrated and purified by preparative HPLC to give the desired product (19 mg, 40%). 1 HNMR(400MHz, DMSO-d6)δ8.10(s,1H),8.01(s,1H),7.25-7.15(m,4H),7.09(s,1H),4.26(s,2H),4.18(t,J= 6.3Hz,2H),3.45(s,2H),2.28-2.13(m,4H),1.70-1.62(m,2H),1.47-1.30(m,8H),0.91(t,J=7.3Hz,3H)ppm. MS:M / e 395(M+1) + .

[0374] Compound A16: 2-isobutoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0375] Step A: (4-(bis(4-methoxybenzyl)amino)-2-isobutoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-Methylphenyl)(3-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0376] Under N2 atmosphere, at -78 ° C, to a stirred solution of 7-bromo-2-isobutoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (180 mg, 0.34 mmol) in THF (10 ml) was added n-butyl lithium (1.6 M, 0.54 ml, 0.86 mmol). The solution was stirred at -78 ° C for 30 min. 3-(pyrrolidin-1-ylmethyl)benzaldehyde (97 mg, 0.51 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was naturally warmed to rt and then stirred for 3 hr. After completion, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml × 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to obtain a crude product in the form of a yellow oil, which was directly used in the next step without further purification. MS:M / e 637(M+1) + .

[0377] Step B: 2-isobutoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine- 4-Amine (Compound A16)

[0378] A solution of (4-(bis(4-methoxybenzyl)amino)-2-isobutoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(3-(pyrrolidin-1-ylmethyl)phenyl)methanol (crude) in TFA (2 ml) and triethylsilane (2 ml) was stirred at 80 ° C for 15 hr. The solution was concentrated under reduced pressure to remove triethylsilane. The residue was dissolved in TFA (2 ml) and stirred at 80 ° C overnight. After completion, the reaction mixture was quenched with aqueous NaHCO (saturated, 25 ml) and then extracted with DCM (20 ml × 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by preparative TLC with DCM:MeOH (10: 1) to give the product (24.30 mg). 1 H NMR (400MHz, DMSO-d6) δ8.12(s,1H),8.03(s,1H),7.32-7.14(m,5H),4.27(s,2H),3.96(d,J=4H z,2H),3.67(s,2H),2.41(s,4H),2.05-1.94(m,1H),1.63(s,4H),0.96(s,3H),0.94(s,3H)ppm. MS:M / e 381(M+1) + .

[0379] Compound A17: 2-(2-methoxyethoxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0380] Step A: 7-Bromo-N,N-bis(4-methoxybenzyl)-2-(2-methoxyethoxy)imidazo[2,1-f][1,2, 4]Triazine-4-amine

[0381] To a solution of 2-methoxyethane-1-ol (6 g, 79 mmol) was added some small pieces of Na (about 0.6 g). To the resulting mixture (5 mL) was added 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (250 mg, 0.51 mmol). The mixture was then stirred at 80 ° C for 3 h. The mixture was concentrated, diluted with water (30 mL), extracted with EtOAc (80 mL), washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by combi-flash to give the target compound (200 mg, 75%). 1HNMR (400MHz, CDCl3) δ7.47(s,1H),7.20(d,J=8.8Hz,2H),7.17(d,J=8.8Hz,2H),6.85(d,J=8.8Hz,4H) ,5.60(s,2H),4.86(s,2H),4.52(t,J=4.8Hz,2H),3.80(s,6H),3.77(t,J=4.8Hz,2H),3.42(s,3H)ppm. MS:M / e 528(M+1) + .

[0382] Step B: (4-(bis(4-methoxybenzyl)amino)-2-(2-methoxyethoxy)imidazo[2,1-f][1,2, 4]Triazin-7-yl)(3-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0383] To a solution of the product of step A (200 mg, 0.38 mmol) in THF (10 mL) was added dropwise a solution of n-butyllithium (0.6 mL, 0.9 mmol) and the temperature was maintained between -75°C and -65°C. After 1.5 h, a solution of 3-(pyrrolidin-1-ylmethyl)benzaldehyde (107 mg, 0.57 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature for 1 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by combi flash to give a solid (150 mg, 62%). MS: M / e639 (M+1) + .

[0384] Step C: 2-(2-methoxyethoxy)-7-(3-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1, 2,4]Triazine-4-amine (Compound A17)

[0385] To the mixture of the product of step B (150mg, 0.235mmol) in TFA (6mL), Et3SiH (2mL) was added. The reaction was heated at 80°C for 16h. The mixture was concentrated to dryness, and the residue was treated with TFA (6mL). The reaction was heated at 85°C overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The collected fractions were alkalized with NaHCO3 solution, extracted with DCM (60mL), washed with salt water, dried over Na2SO4, filtered, and concentrated to give product (48mg, 53%). 1HNMR(400MHz,CD3OD)δ7.37(t,J=6.0Hz,1H),7.30-7.15(m,4H),4.42(t,J=4.8Hz,2H),4.33(s,2H ),4.05-3.88(m,2H),3.69(t,J=4.8Hz,2H),3.38(s,3H),3.01-2.61(m,4H),1.95-1.71(m,4H)ppm. MS:M / e 383(M+1) + .

[0386] Compound A18: 7-(3-(pyrrolidin-1-ylmethyl)benzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0387] Step A: (4-(bis(4-methoxybenzyl)amino)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1, 2,4]triazin-7-yl)(3-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0388] Under N2 atmosphere, at -78°C, 7-bromo-N,N-bis(4-methoxybenzyl)-2-(4,4,4-trifluoromethyl)benzyl

[0389] To a stirred solution of 2-(4-(2-pyrrolidin-1-ylmethyl)benzaldehyde (64 mg, 0.34 mmol) in THF (2 ml) was added n-butyllithium (1.6 M, 0.35 ml, 0.56 mmol). The solution was stirred at -78 ° C for 30 min. 3-(Pyrrolidin-1-ylmethyl)benzaldehyde (64 mg, 0.34 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was naturally warmed to rt and then stirred for 3 hr. After completion, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml × 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give a crude product as a yellow oil, which was used directly in the next step without further purification. MS: M / e 691 (M+1) + .

[0390] Step B: 7-(3-(pyrrolidin-1-ylmethyl)benzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f] [1,2,4]triazine-4-amine ( Compound A18 )

[0391] A solution of (4-(bis(4-methoxybenzyl)amino)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(3-(pyrrolidin-1-ylmethyl)phenyl)methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) was stirred at 80 ° C for 24 hr. After completion, the reaction mixture was quenched with aqueous NaHCO (saturated, 25 ml) and then extracted with DCM (20 ml × 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by preparative TLC using DCM:MeOH (10:1) to give the product (19.75 mg). 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.08(s,1H),7.28-7.13(m,5H),4.26(s, 4H),3.63(s,2H),2.48-2.25(m,6H),2.01-1.89(m,2H),1.88-1.51(m,4H)ppm. MS:M / e 435(M+1) + .

[0392] Compound A19: 2-Butoxy-7-(2-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0393] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-(Pyrrolidin-1-ylmethyl)phenyl)methanol

[0394] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.29 mmol) in THF (5 mL) was added n-butyllithium (0.27 mL, 0.43 mmol) dropwise at -78°C and stirred for 1 hour. A solution of 2-(pyrrolidin-1-ylmethyl)benzaldehyde (81 mg, 0.43 mmol) in THF (2 mL) was then added dropwise at -78°C. After addition, the mixture was warmed to 60°C and stirred overnight. The mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (DCM / MeOH = 20:1 to 5:1) to give the desired product (67 mg, 37%) as a yellow oil. MS:M / e 637(M+1) + .

[0395] Step B: 2-Butoxy-7-(2-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-4- Amine (Compound A19)

[0396] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(2-(pyrrolidin-1-ylmethyl)phenyl)methanol (67 mg, 0.11 mmol) and triethylsilane (1 mL) in TFA (2 mL) was stirred at 90° C. overnight. The mixture was concentrated and purified by preparative HPLC to give the desired product (15 mg, 38%). 1 HNMR(400MHz,DMSO-d6)δ8.22-8.03(m,2H),7.44-7.15(m,5H),4.55(s,1H),4.28(s,2H),4.17(t,J=6.6Hz,2H),3.71-3.38(m,2H ),3.17(s,1H),2.42-2.32(m,2H),2.05-1.74(m,2H),1.70-1.56(m,4H),1.38(dt,J=14.6,7.4Hz,2H),0.91(t,J=7.4Hz,3H)ppm. MS:M / e 381(M+1) + .

[0397] Compound A20: 2-Butoxy-7-(2-fluoro-4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0398] Step A: 2-Fluoro-4-(pyrrolidin-1-ylmethyl)benzonitrile

[0399] To a stirred solution of 2-fluoro-4-formylbenzonitrile (447 mg, 3 mmol) in MeOH (5 mL) was added pyrrolidine (234 mg, 3.3 mmol), and the mixture was stirred for 2 hours before the addition of NaBH3CN (378 mg, 6 mmol). After the addition, the reaction mixture was concentrated to give a residue, which was purified by column chromatography (petroleum ether / EtOAc=2:1) ​​to give the target compound (400 mg, 65.4%) as a yellow oil. MS: M / e 205 (M+1) + .

[0400] Step B: 2-Fluoro-4-(pyrrolidin-1-ylmethyl)benzaldehyde

[0401] To a stirred solution of the product of step A (400 mg, 1.96 mmol) in dry THF (10 mL) was added DIBAL-H (1.2 M, 4 mL, 4.9 mmol) at -20 ° C. After addition, the reaction was stirred at room temperature for 3 hours. The reaction was quenched with aqueous NH4Cl, extracted with EtOAc (20 mL × 3) and filtered. The filtrate was washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether / EtOAc=3:1~1:1) to give the target compound (182 mg, 44.3%) as a light yellow oil. MS: M / e 208 (M+1) + .

[0402] Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-Methyl)(2-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0403] At -78 ° C, to a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.285 mmol) in THF (10 mL) was added n-butyl lithium (0.44 mL, 0.71 mmol). After stirring for 1 hour, a solution of the product of step B (88.7 mg, 0.428 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 ° C for 1 hour and then warmed to room temperature for 1 hour. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the target compound (60 mg, 32%). MS:M / e655(M+1) + .

[0404] Step D: 2-Butoxy-7-(2-fluoro-4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazol Oxazine-4-amine (Compound A20)

[0405] A mixture of the product of step C (60 mg, 0.092 mmol) in Et3SiH / TFA (0.5 mL / 2 mL) was stirred overnight at 80° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the target compound (23 mg, 62.8 g). 1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.05(s,1H),7.27(s,1H),7.23-7.19(m,1H),7.11-7.04(m,2H),4.19-4 .13(m,4H),3.53(s,2H),2.42-2.31(m,4H),1.72-1.61(m,6H),1.42-1.36(m,2H),0.91(t,J=7.6Hz,3H)ppm. MS:M / e 399(M+1) + .

[0406] Compound A21: 2-Butoxy-7-(4-(3-(piperidin-1-yl)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0407] Step A: 4-(3-bromopropoxy)benzaldehyde

[0408] At 0 ℃, a solution of 4-hydroxybenzaldehyde (2g, 16mmol), 3-bromopropan-1-ol (2.3g, 16mmol) and triphenylphosphine (6.3g, 24mmol) in dry THF (60mL) is dropwise treated with DTAD (5.5g, 24mmol). The reaction mixture is slowly heated to rt overnight. The solution is quenched with water (20mL), extracted with ethyl acetate (20mL), and washed with brine (20mL). The organic layer is dried, concentrated and purified by CombiFlash (PE:EA=15:1) to obtain product (1.3g, 33%). 1 HNMR (400MHz, DMSO-d6) δ9.88 (s, 1H), 7.88 (d, J = 8.0Hz, 2H), 7.16 (d, J = 12.0Hz, 2H), 4.21 (t, J = 8.0Hz, 2H), 3.68 (t, J = 8.0Hz, 2H), 2.32-2.27 (m, 2H) ppm. MS:M / e 243(M+1) + .

[0409] Step B: 4-(3-(Piperidin-1-yl)propoxy)benzaldehyde

[0410] A mixture of 4-(3-bromopropoxy)benzaldehyde (200 mg, 0.8 mmol), piperidine (136 mg, 1.6 mmol), sodium carbonate (170 mg, 1.6 mmol) and potassium iodide (17 mg, 0.1 mmol) in n-BuOH (5 mL) was heated at 105 ° C for 4 hours. The solution was cooled, quenched with water (10 mL) and extracted with dichloromethane (10 mL). The organic layer was dried, concentrated and purified by CombiFlash (DCM:MeOH=8%) to give the product (190 mg, 93%). MS: M / e 248 (M+1) + .

[0411] Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(3-(piperidin-1-yl)propyloxy)phenyl)methanol

[0412] At -78°C (with N 2 To a cooled solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.4 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.7 mL) under 4% purging. After stirring at -78 ° C for 30 min, 4-(3-(piperidin-1-yl)propoxy)benzaldehyde (148 mg, 0.6 mmol) in THF (2 mL) was added. The resulting mixture was stirred at this temperature for 30 min and then warmed to rt for 1 hour. The solution was quenched with NH4Cl solution (5 mL), extracted with ethyl acetate (10 mL), and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by Combiflash (DCM:MeOH=5%) to give the pure product (140 mg, 37%). MS:M / e 695(M+1) + .

[0413] Step D: 2-Butoxy-7-(4-(3-(piperidin-1-yl)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazol Oxazine-4-amine (Compound A21)

[0414] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(3-(piperidin-1-yl)propoxy)phenyl)methanoltriethylsilane (140 mg, 0.2 mmol) in trifluoroacetic acid (3 mL) and triethylsilane (1 mL) was heated at 80° C. overnight. The solvent was evaporated to give a residue, which was basified with NaHCO solution, extracted with ethyl acetate (5 mL), and washed with brine (5 mL). The organic layer was dried, concentrated, and purified by CombiFlash (DCM:MeOH=8%) to give the product (35 mg, 40%). 1H NMR (400MHz, DMSO-d6) δ8.12(s,1H),8.03(s,1H),7.25(s,1H),7.21(d,J=8.0Hz,2H),6.84(d,J=8.0Hz,2H),4.20(t,J=8.0H z,2H),4.06(s,2H),3.97-3.95(m,2H),2.49-2.20(m,4H),2.18-1.75(m,3H),1.67-1.38(m,11H),0.91(t,J=7.6Hz,3H)ppm. MS:M / e 439(M+1) + .

[0415] Compound A22: 2-Butoxy-7-(4-(3-morpholinopropoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0416] Step A: 4-(3-morpholinopropoxy)benzaldehyde

[0417] A mixture of 4-(3-bromopropoxy)benzaldehyde (300 mg, 1.2 mmol), morpholine (209 mg, 2.4 mmol) and potassium carbonate (193 mg, 2.4 mmol) in acetonitrile (10 mL) was heated at 80 ° C overnight. The solution was cooled, concentrated, water (10 mL) was added thereto and extracted with ethyl acetate (10 mL). The organic layer was dried, concentrated and purified by CombiFlash (DCM:MeOH=8%) to give the product (260 mg, 84%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ9.87(s,1H),7.86(d,J=8.0Hz,2H),7.12(d,J=8.0Hz,2H), 4.13(t,J=8.0Hz,2H),3.59-3.51(m,4H),2.44-2.36(m,6H),1.99-1.87(m,2H)ppm. MS:M / e 250(M+1) + .

[0418] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- methyl)(4-(3-morpholinopropoxy)phenyl)methanol

[0419] At -78°C (with N 2Under 4 ℃ of purging, to 7- bromo-2-butoxy-N, N- bis (4-methoxybenzyl) imidazo [2,1-f] [1,2,4] triazine -4- amine (200mg, 0.4mmol) in THF (8mL) cooling solution was added dropwise n-butyl lithium (1.6M, 0.7mL). After stirring at -78 ℃ for 30min, 4- (3-morpholinopropoxy) benzaldehyde (150mg, 0.6mmol) in THF (2mL) was added. The resulting mixture was stirred at this temperature for 30min, and then heated to rt for 1 hour. The solution was quenched with NH4Cl solution (5mL), extracted with ethyl acetate (10mL), and washed with brine (10mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by Combiflash (DCM: MeOH = 6%) to give pure product (190mg, 71%). MS:M / e 697(M+1) + .

[0420] Step C: 2-Butoxy-7-(4-(3-morpholinopropoxy)benzyl)imidazo[2,1-f][1,2,4]triazine-4- Amine (Compound A22)

[0421] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(3-morpholinopropoxy)phenyl)methanol (190 mg, 0.27 mmol) in trifluoroacetic acid (2 mL) and triethylsilane (2 mL) was heated at 80 ° C for 1 hour. After concentration, trifluoroacetic acid (2 mL) was added to the residue and the mixture was heated at 80 ° C overnight. The solvent was evaporated to give a residue, which was basified with NaHCO3 solution, extracted with ethyl acetate (5 mL), and washed with brine (5 mL). The organic layer was dried, concentrated and purified by CombiFlash (DCM:MeOH=8%) to give the product (84 mg, 70%). 1 H NMR (400MHz, DMSO-d6) δ8.12(s,1H),8.02(s,1H),7.25(s,1H),7.20(d,J=8.0Hz,2H),6.83(d,J=8.0Hz,2H),4.20(t,J=8.0Hz,2H),4.05(s,2H),3 .95(t,J=8.0Hz,2H),3.55(t,J=4.0Hz,4H),2.40-2.34(m,6H),1.87-1.8 1(m,2H),1.68-1.63(m,2H),1.43-1.37(m,2H),0.92(t,J=8.0Hz,3H)ppm. MS:M / e 441(M+1) + .

[0422] Compound A23: 2-Butoxy-7-(3-(3-dimethylamino)propyloxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0423] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-(3-(dimethylamino)propyloxy)phenyl)methanol

[0424] Under N2 atmosphere, at -78 ° C, to a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (180 mg, 0.34 mmol) in THF (10 ml) was added n-butyl lithium (1.6 M, 0.54 ml, 0.86 mmol). The solution was stirred at -78 ° C for 30 min. 3-(3-(dimethylamino)propoxy)benzaldehyde (71 mg, 0.34 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was naturally warmed to rt and then stirred for 3 hr. After completion, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml × 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to obtain a crude product in the form of a yellow oil, which was directly used in the next step without further purification. MS:M / e 655(M+1) + .

[0425] Step B: 2-Butoxy-7-(3-(3-(dimethylamino)propyloxy)benzyl)imidazo[2,1-f][1,2,4]triazol Oxazine-4-amine

[0426] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(3-(3-(dimethylamino)propoxy)phenyl)methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) was stirred at 80 ° C for 24 hr. After completion, the reaction mixture was quenched with aqueous NaHCO (saturated, 25 ml) and then extracted with DCM (20 ml × 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by preparative TLC using DCM:MeOH (10: 1) to give the product (18.32 mg). 1H NMR (400MHz, DMSO-d6) δ8.15(s,1H),8.08(s,1H),7.31(s,1H),7.23(t,J=8H z,1H),6.91(d,J=8Hz,1H),6.85(s,1H),6.80(d,J=8Hz,1H),4.21(t,J=8Hz, 2H),4.12(s,2H),4.00(t,J=8Hz,2H),3.17(t,J=8Hz,2H),2.78(s,6H),2.13 -2.03(m,2H),1.72-1.64(m,2H),1.45-1.36(m,2H),0.93(t,J=8Hz,3H)ppm. MS:M / e 399(M+1) + .

[0427] Compound A24: 2-Butoxy-7-(3-(3-(dimethylamino)propoxy)-4-fluorobenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0428] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(3-(dimethylamino)propoxy)-4-fluorophenyl)methanol

[0429] Under N2 atmosphere, at -78 ℃, to 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (257mg, 0.49mmol) in THF (10ml) stirring solution, n-butyllithium (1.6M, 0.76ml, 1.22mmol) was added. The solution was stirred at -78 ℃ for 30min. 3-(3-(dimethylamino)propoxy)-4-fluorobenzaldehyde (110mg, 0.49mmol) in THF (2ml) was added dropwise to the above solution. After addition, the solution was naturally heated to rt and then stirred for 3hr. After completion, the reaction mixture was quenched with H2O (20ml) and then extracted with DCM (20ml × 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow oil, which was used directly in the next step without further purification. MS: M / e 673 (M+1) + .

[0430] Step B: 2-Butoxy-7-(3-(3-(dimethylamino)propoxy)-4-fluorobenzyl)imidazo[2,1-f][1, 2,4]Triazine-4-amine (Compound A24)

[0431] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(3-(3-(dimethylamino)propoxy)-4-fluorophenyl)methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) was stirred at 80° C. for 24 hr. Upon completion, the reaction mixture was quenched with aqueous NaHCO (saturated, 25 ml) and then extracted with DCM (20 ml×3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by preparative TLC using DCM:MeOH (10:1) to afford the product (43.52 mg). 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),8.06(s,1H),7.29(s,1H),7.22-7.08(m,2H),6.92-6.83(m,1H),4.20(t,J=8Hz,2H),4.11(s,2H), 4.08(t,J=8Hz,2H),3.15(t,J=8Hz,2H),2.75(s,6H),2.18-2.06(m,2H),1.72-1.61(m,2H),1.45-1.34(m,2H),0.92(t,J=8Hz,3H)ppm. MS:M / e 417(M+1) + .

[0432] Compound A25: 2-Butoxy-7-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0433] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-(4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-3-yl)methanol

[0434] Under N2, n-butyllithium (0.27 ml, 0.43 mmol) was added dropwise to a solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.29 mmol) in THF (5 mL) at -78 ° C and stirred for 1 h. Then, a solution of 4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-3-carbaldehyde (114 mg, 0.4278 mmol) in THF (2 mL) was added dropwise at -78 ° C. After addition, the mixture was warmed to rt and stirred for 3 h. The mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (DCM / MeOH=20:1-5:1) to give the title product (103 mg, 51%) as a yellow oil. MS: M / e 713 (M+1) + .

[0435] Step B: 2-Butoxy-7-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-3-yl)methyl)imidazole 4-[2,1-f][1,2,4]triazine-3-amine (Compound A25)

[0436] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-3-yl)methanol (103 mg, 0.1447 mmol) and triethylsilane (1 mL) in TFA (2 mL) was stirred at 90 °C overnight. The mixture was concentrated and purified by preparative HPLC to give the desired product (50 mg, 75.63%). 1 H NMR(400MHz,DMSO-d6)δ9.80(br.s,1H),8.13(1H),8.09(s,1H),7.73-7.54 (m,6H),7.39-7.28(m,3H),4.39(d,J=5.5Hz,2H),4.23(s,2H),4.18(t,J=6 .5Hz,2H),3.43-3.35(m,2H),3.16-3.11(m,2H),2.08-2.03(m,2H),1.94-1 .78(m,2H),1.69-1.57(m,2H),1.41-1.28(m,2H),0.88(t,J=7.4Hz,3H)ppm. MS:M / e 457(M+1) + .

[0437] Compound A26: 2-Butoxy-7-(2-fluoro-5-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0438] Step A: 2-Fluoro-5-(pyrrolidin-1-ylmethyl)benzonitrile

[0439] To a stirred solution of 2-fluoro-5-formylbenzonitrile (447 mg, 3 mmol) in MeOH (5 mL) was added pyrrolidine (234 mg, 3.3 mmol), and the mixture was stirred for 2 hours before the addition of NaBH3CN (378 mg, 6 mmol). After addition, the reaction mixture was concentrated to give a residue, which was purified by column chromatography (petroleum ether / EtOAc=2:1) ​​to give the target compound (350 mg, 57.2%) as a yellow oil. MS: M / e 205 (M+1) + .

[0440] Step B: 2-Fluoro-5-(pyrrolidin-1-ylmethyl)benzaldehyde

[0441] To a stirred solution of the product of step A (350 mg, 1.7 mmol) in dry THF (10 mL) was added DIBAL-H (1.2 M, 3.57 mL, 4.3 mmol) at -20 ° C. After addition, the reaction was stirred at room temperature for 3 hours. The reaction was quenched with aqueous NH4Cl, extracted with EtOAc (20 mL × 3) and filtered. The filtrate was washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether / EtOAc=3:1~2:1) to give the target compound (180 mg, 51.1%) as a light yellow oil. MS: M / e 208 (M+1) + .

[0442] Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-Methyl)(2-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0443] At -78 ° C, to 7-bromo-2-butoxy-N, N-bis (4-methoxybenzyl) imidazo [2,1-f] [1,2,4] triazine -4-amine (150 mg, 0.285 mmol) in THF (10 mL) was added dropwise n-butyl lithium (0.44 mL, 0.71 mmol). After stirring for 1 hour, a solution of the product of step B (88.7 mg, 0.428 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 ° C for 1 h and then warmed to room temperature for 1 h. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the target compound (55 mg, 29.4%). MS:M / e 655(M+1) + .

[0444] Step D: 2-Butoxy-7-(2-fluoro-5-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazol Oxazine-4-amine (Compound A26)

[0445] A mixture of the product of step C (55 mg, 0.084 mmol) in Et3SiH / TFA (0.5 mL / 3 mL) was stirred overnight at 85° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the title compound (20 mg, 59.8%). 1 H NMR(400MHz,DMSO-d6)δ8.13(s,1H),8.03(s,1H),7.26(s,1H),7.24-7.04(m,3H),4.18-4.13(m,4H ), 3.45 (s, 2H), 2.35-2.28 (m, 4H), 1.66-1.61 (m, 6H), 1.37-1.29 (m, 2H), 0.90 (t, J = 7.2Hz, 3H) ppm. MS:M / e399(M+1) + .

[0446] Compound A27: 2-Butoxy-7-(2-fluoro-5-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0447] Step A: 2-(3-(Dimethylamino)propoxy)benzaldehyde

[0448] A mixture of 2-hydroxybenzaldehyde (1.73 g, 10 mmol), 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (1.74 g, 1.1 mmol) and K2CO3 (2.76 g, 20 mmol) in DMF (10 mL) was stirred at 60 ° C overnight. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether / EtOAc=5:1~100% EtOAc) to give the target compound (1.96 g, 76%) as a light yellow oil. MS: M / e 208 (M+1) + .

[0449] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-(3-(dimethylamino)propyloxy)phenyl)methanol

[0450] At -78 ° C, to a solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.285 mmol) in THF (10 mL) was added n-butyllithium (1.6 M, 0.44 mL, 0.71 mmol) dropwise. After stirring for 1 hour, a solution of the product of step A (88.7 mg, 0.428 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 ° C for 1 h and then warmed to room temperature for 1 h. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the target compound (62 mg, 33%) as a white solid. MS:M / e 655(M+1) + .

[0451] Step C: 2-Butoxy-7-(2-(3-(dimethylamino)propyloxy)benzyl)imidazo[2,1-f][1,2,4]triazol Oxazine-4-amine (Compound A27)

[0452] A mixture of the product of step B (62 mg, 0.095 mmol) in Et3SiH / TFA (0.5 mL / 3 mL) was stirred overnight at 85° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the title compound (24 mg, 63.4%). 1 H NMR (400MHz, DMSO-d6) δ8.09(s,1H),8.00(s,1H),7.22-7.18(m,2H),7.10(s,1H),6.95(d,J=8.4Hz,1H),6.85(t,J=7.6Hz,1H),4.21(t,J=6.4H z,2H),4.07(s,2H),3.96(t,J=6.4Hz,2H),2.23(t,J=7.2Hz,2H),2.08(s,6H),1.85-1.61(m,4H),1.48-1.35(m,2H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 399(M+1) + .

[0453] Compound A28: 2-Butoxy-7-(4-(3-(pyrrolidin-1-yl)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0454] Step A: 4-(3-(Pyrrolidin-1-yl)propoxy)benzaldehyde

[0455] A solution of 4-(3-bromopropoxy)benzaldehyde (300 mg, 1.2 mmol), pyrrolidine (170 mg, 2.4 mmol), sodium carbonate (254 mg, 2.4 mmol) and potassium iodide (17 mg, 0.1 mmol) in acetonitrile (10 mL) was heated at 80 ° C overnight. The solution was concentrated, treated with water (10 mL) and extracted with dichloromethane (10 mL). The organic layer was dried, concentrated and purified by CombiFlash (DCM:MeOH=8%) to give the product (200 mg, 70%) as a colorless oil. MS: M / e 234 (M+1) + .

[0456] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(3-(Pyrrolidin-1-yl)propyloxy)phenyl)methanol

[0457] At -78°C (with N 2 Under 4 ℃ of purging, to 7- bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (210mg, 0.4mmol) in THF (8mL) cooling solution, n-butyllithium (1.6M, 0.7mL) was added dropwise. After stirring at -78 ℃ for 30min, 4-(3-(pyrrolidin-1-yl)propoxy)benzaldehyde (140mg, 0.6mmol) in THF (2mL) was added. The resulting mixture was stirred at this temperature for 30min, and then heated to rt for 1 hour. The solution was quenched with NH4Cl solution (5mL), extracted with ethyl acetate (10mL), and washed with brine (10mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by Combiflash (DCM:MeOH=7%) and preparative TLC (DCM:MeOH=6:1) to give the pure product (108 mg, 40%). MS: M / e 681 (M+1) + .

[0458] Step C: 2-Butoxy-7-(4-(3-(pyrrolidin-1-yl)propoxy)benzyl)imidazo[2,1-f][1,2,4] Triazine-4-amine (Compound A28)

[0459] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)methanol (108 mg, 0.16 mmol) in trifluoroacetic acid (2 mL) and triethylsilane (2 mL) was heated at 80 ° C for 1 hour. After concentration, trifluoroacetic acid (1 mL) was added to the residue and the mixture was heated at 80 ° C overnight. The solvent was evaporated to give a residue, which was basified with NaHCO 3 , extracted with ethyl acetate (5 mL), and washed with brine (5 mL). The organic layer was dried, concentrated and purified by CombiFlash (DCM:MeOH=18%) to give the product (25 mg, 37%). 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),8.02(s,1H),7.25(s,1H),7.20(d,J=8.0Hz,2H),6.83(d,J=8.0Hz,2H),4.20(t,J=8.0Hz,2H),4.05(s ,2H),3.95(t,J=8.0Hz,2H),2.51(s,2H),2.43(s,4H),1.88-1.81(m,2H),1.70-1.63(m,6H),1.43-1.37(m,2H),0.92(t,J=8.0Hz,3H)ppm. MS:M / e 425(M+1) + .

[0460] Compound A29: 2-Butoxy-7-(4-(3-(diethylamino)propyloxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0461] Step A: 4-(3-(Diethylamino)propoxy)benzaldehyde

[0462] Under N2 atmosphere, DEAD (1 g, 6 mmol) was added dropwise to a solution of 4-hydroxybenzo-aldehyde (0.5 g, 4 mmol), 3-(diethylamino)propan-1-ol (0.5 g, 4 mmol) and triphenylphosphine (1.6 g, 6 mmol) in THF (10 mL) at 0 ° C. The mixture was warmed to rt and stirred overnight. The solution was concentrated and purified by CombiFlash (PE:EA=80%) to give the product (0.4 g, 42%) as a colorless oil. MS: M / e 236 (M+1) + .

[0463] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(3-(diethylamino)propoxy)phenyl)methanol

[0464] At -78°C (with N 2Under 4 ℃ of purging, to 7- bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200mg, 0.4mmol) in THF (8mL) cooling solution, n-butyllithium (1.6M, 0.6mL) was added dropwise. After stirring at -78 ℃ for 30min, 4-(3-(diethylamino)propoxy)benzaldehyde (134mg, 0.6mmol) in THF (2mL) was added. The resulting mixture was stirred at this temperature for 30min, and then heated to rt for 1 hour. The solution was quenched with NH4Cl solution (5mL), extracted with ethyl acetate (10mL), and washed with brine (10mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by Combiflash (DCM:MeOH=8%) and preparative TLC (DCM:MeOH=7:1) to give the pure product (150 mg, 58%). MS: M / e 683 (M+1) + .

[0465] Step C: 2-Butoxy-7-(4-(3-(diethylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazol Oxazine-4-amine (Compound A29)

[0466] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(3-(diethylamino)propoxy)phenyl)methanol (150 mg, 0.22 mmol) in trifluoroacetic acid (2 mL) and triethylsilane (2 mL) was heated at 80 ° C for 1 hour. After concentration, trifluoroacetic acid (2 mL) was added to the residue and the mixture was heated at 80 ° C overnight. The solvent was evaporated to give a residue, which was basified with NaHCO 3 , extracted with ethyl acetate (5 mL), and washed with brine (5 mL). The organic layer was dried, concentrated and purified by preparative TLC (DCM:MeOH=7:1) to give the product (50 mg, 54%). 1 H NMR (400MHz, DMSO-d6) δ8.12(s,1H),8.04(s,1H),7.25(s,1H),7.23(d,J=8.0Hz,2H),6.86(d,J=12.0Hz,2H),4.20(t,J=8.0Hz,2H),4.07(s,2 H),4.02(t,J=8.0Hz,2H),3.13(s,6H),2.08(br.s,2H),1.71-1.64(m,2H),1.45-1.36(m,2H),1.20(t,J=8.0Hz,6H),0.93(t,J=8.0Hz,3H)ppm. MS:M / e 427(M+1) + .

[0467] Compound A30: 2-Butoxy-7-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0468] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-(4-pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methanol

[0469] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.23 mmol) in THF (5 mL) was added n-butyl lithium (0.27 ml, 0.43 mmol) dropwise at -78 ° C and stirred for 1 h. A solution of 4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-carbaldehyde (114 mg, 0.43 mmol) in THF (2 mL) was then added dropwise at -78 ° C. After addition, the mixture was warmed to rt and stirred for 3 h. The mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (DCM / MeOH = 20:1 to 5:1) to give the title product (124 mg, 61%) as a yellow oil. MS: M / e 713 (M+1) + .

[0470] Step B: 2-Butoxy-7-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methyl)imidazole 4-[2,1-f][1,2,4]triazine-3-amine (Compound A30)

[0471] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methanol (124 mg, 0.17 mmol) and triethylsilane (1 mL) in TFA (2 mL) was stirred at 90° C. overnight. The mixture was concentrated and purified by preparative HPLC to give 2-butoxy-7-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (58 mg, 73%). 1H NMR(400MHz,DMSO-d6)δ9.74(br.s,1H),8.17(s,1H),8.06(s,1H),7.78-7.75(m ,2H),7.64-7.53(m,4H),7.43-7.38(m,2H),7.36(s,1H),4.38(d,J=5.7Hz,2H), 4.26-4.18(m,4H),3.42-3.35(m,2H),3.21-3.12(m,2H),2.14-2.02(m,2H),1.9 2-1.83(m,2H),1.72-1.61(m,2H),1.42-1.33(m,2H),0.91(t,J=7.4Hz,3H)ppm. MS:M / e457(M+1) + .

[0472] Compound A31: 7-(4-(3-aminopropyloxy)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0473] Step A: tert-Butyl (3-(4-formylphenoxy)propyl)carbamate

[0474] To a solution of 4-hydroxybenzaldehyde (1.22 g, 10 mmol), tert-butyl (3-hydroxypropyl) carbamate (2.62 g, 15 mmol) and PPh 3 (3.93 g, 15 mmol) in THF (15 mL) was added DIAD (7.57 g, 15 mmol, 40% in toluene solution) dropwise. The mixture was then stirred at room temperature for 5 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, concentrated, and the residue was purified by combiflash to give the target compound (2.53 g, 90%). MS: M / e 224 (M + Ht-Bu) + .

[0475] Step B: tert-butyl (3-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1, 2,4]triazin-7-yl)(hydroxy)methyl)phenoxy)propyl)carbamate

[0476] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (300 mg, 0.57 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium (0.9 mL, 1.42 mmol) and the temperature was maintained between -75°C and -65°C. After 1 h, a mixture of the product of step A (238 mg, 0.855 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70°C for 0.5 h and then warmed to room temperature for 2 hours. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (EA / PE=1 / 3) to give the target compound (100 mg, crude). MS: M / e 727 (M+1) + .

[0477] Step C: 7-(4-(3-aminopropyloxy)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine (Compound A31)

[0478] To the mixture of the product of step B (100mg, crude) in TFA (3mL), Et3SiH (1mL) is added. The reaction is heated at 85°C overnight. The mixture is cooled to room temperature and concentrated to dryness. TFA (3mL) is added to the residue, and the resulting mixture is heated at 85°C overnight. The mixture is concentrated to dryness and the residue is purified by preparative HPLC. The collected fractions are alkalized with NaHCO3 solution, extracted with DCM (50mL x 2), washed with salt water, dried over Na2SO4, filtered, and concentrated to give the target compound (30mg, 15% for two steps). 1 HNMR (400MHz, DMSO-d6) δ8.11(s,1H),8.02(s,1H),7.25(s,1H),7.20(d,J=8.8Hz,2H),6.84(d,J=8.4Hz,2H),4.20(t,J=6.0Hz,2H),4.05 (s,2H),3.97(t,J=6.4Hz,2H),3.05–2.90(m,2H),2.68(t,J=7.2Hz,2H),1.86–1.59(m,4H),1.49–1.35(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 371(M+1) + .

[0479] Compound A32: 2-Butoxy-7-((6-(3-(dimethylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]pyridin-4-amine

[0480] Step A: 6-(3-(dimethylamino)propoxy)nicotinaldehyde

[0481] Under N2 atmosphere, at 0 ° C, DEAD (2.1 g, 12 mmol) was added dropwise to a solution of 6-hydroxynicotinaldehyde (1 g, 8.1 mmol), 3-(dimethylamino)propan-1-ol (837 mg, 8.1 mmol) and triphenylphosphine (3.1 g, 12 mmol) in THF (20 mL). The mixture was warmed to rt and stirred overnight. The solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL), and washed with brine (10 mL). The organic layer was dried, concentrated and purified by CombiFlash (EA to DCM: MeOH = 10%) to give the product (0.5 g, 30%) as a colorless oil. 1 H NMR(400MHz, DMSO-d6)δ9.95(s,1H),8.74(d,J=4.0Hz,1H),8.10(dd,J=8.0,4.0Hz,1H),6.96( d,J=8.0Hz,1H),4.40(t,J=8.0Hz,2H),2.37-2.35(m,2H),2.13(s,6H),1.88-1.85(m,2H)ppm. MS:M / e 209(M+1) + .

[0482] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)methanol

[0483] At -78°C (with N 2 To a cooled solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (420 mg, 0.8 mmol) in THF (12 mL) was added n-butyllithium (1.6 M, 1.3 mL) under 4% CO 2 purging. After stirring at -78 ° C for 30 min, 6-(3-(dimethylamino)propoxy)nicotinaldehyde (250 mg, 1.2 mmol) in THF (3 mL) was added. The resulting mixture was stirred at this temperature for 30 min and then warmed to rt overnight. The solution was quenched with NH4Cl solution (5 mL), extracted with ethyl acetate (10 mL) and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by Combiflash (DCM:MeOH=8%) to give the pure product (133 mg, 46%) as a white solid. MS:M / e 656(M+1) + .

[0484] Step C: 2-Butoxy-7-((6-(3-(dimethylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1- f][1,2,4]triazine-4-amine (Compound A32)

[0485] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(6-(3-(dimethylamino)propoxy)pyridin-3-yl)methanol (78 mg, 0.12 mmol) in trifluoroacetic acid (2 mL) and triethylsilane (2 mL) was heated at 80 ° C for 1 hour. After concentration, trifluoroacetic acid (2 mL) was added to the residue and the mixture was heated at 80 ° C overnight. The solvent was evaporated to give a residue, which was basified with NaHCO 3 , extracted with ethyl acetate (5 mL), and washed with brine (5 mL). The organic layer was dried, concentrated and purified by preparative TLC (DCM:MeOH=8:1) to give the product (10 mg, 21%). 1 H NMR (400MHz, DMSO-d6) δ8.13(s,2H),8.06(s,1H),7.65(d,J=8.0Hz,1H),7.30(s,1H),6.75(d,J=8.0Hz,1H),4.27(t,J=8.0Hz,2H),4.20(t,J=8 .0Hz,2H),4.09(s,2H),3.14(t,J=8.0Hz,2H),2.74(s,6H),2.12-2.05( m,2H),1.71-1.64(m,2H),1.45-1.36(m,2H),0.93(t,J=8.0Hz,3H)ppm. MS:M / e 400(M+1) + .

[0486] Compound A33: 2-Butoxy-7-(4-(piperidin-4-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0487] Step A: Methyl 4-((diethoxyphosphoryl)methyl)benzoate

[0488] A solution of methyl 4-(bromomethyl)benzoate (5.5 g, 24 mmol) in triethyl phosphite (15 mL) was stirred at 115° C. for 4 h. The mixture was cooled to room temperature, concentrated, and the residue was purified by combi flash to give the title compound (6.16 g, 90%). MS: M / e 287 (M+1) + .

[0489] Step B: tert-Butyl 4-(4-(methoxycarbonyl)benzylidene)piperidine-1-carboxylate

[0490] To a solution of the product of step A (6.16 g, 21.54 mmol) in THF (60 mL) was added LDA (12 mL, 23.69 mmol) dropwise at -70 ° C. After stirring at this temperature for 30 min, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (4.7 g, 23.69 mmol) in THF (10 mL) was added. The resulting mixture was slowly warmed to room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc (80 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (4.5 g, 63%). MS: M / e 276 (M+H-tBu) + .

[0491] Step C: tert-Butyl 4-(4-(methoxycarbonyl)benzyl)piperidine-1-carboxylate

[0492] To a solution of the product of step B (4.5 g, 13.6 mmol) in MeOH (40 mL) was added 10% Pd / C (450 mg). The reaction was stirred at room temperature for 4 h under a H2 atmosphere (balloon). The catalyst was filtered off and the filtrate was concentrated to give the title compound (4 g, 88%). MS: M / e 278 (M+H-tBu) + .

[0493] Step D: tert-Butyl 4-(4-(hydroxymethyl)benzyl)piperidine-1-carboxylate

[0494] At 0 ° C, to a solution of LiAlH4 (273 mg, 7.2 mmol) in THF (10 mL) was added dropwise the product of step C (2 g, 6 mmol) in THF (10 mL). After addition, the resulting mixture was slowly warmed to room temperature overnight. The reaction was quenched with saturated water (0.3 mL), 10% NaOH solution (0.3 mL) and water (0.9 mL). The resulting mixture was filtered and the filtrate was concentrated to give the target compound (1.65 g, 90%). 1 HNMR (400MHz, CD3Cl) δ7.28(d,J=7.6Hz,2H),7.13(d,J=8.4Hz,2H),4.66(s,2H),4.06(d,J =12.8Hz,2H),2.71-2.57(m,2H),2.53(d,J=6.4Hz,2H),1.73-1.54(m,5H),1.44(s,9H)ppm.

[0495] Step E: tert-Butyl 4-(4-formylbenzyl)piperidine-1-carboxylate

[0496] To a solution of the product of step D (1.65 g, 5.4 mmol) in THF (30 mL) was added Dess-Martin reagent (4.58 g, 10.8 mmol) in several batches at 0°C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated K2CO3 solution, filtered through a celite pad, and washed with EA (50 mL). The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by combi flash to give the target compound (475 mg, 29%). MS: M / e 248 (M+H-tBu) + .

[0497] Step F: tert-butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1, 2,4]triazin-7-yl)(hydroxy)methyl)benzyl)piperidine-1-carboxylate

[0498] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.38 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium (0.6 mL, 0.95 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a mixture of the product of step E (172 mg, 0.57 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70°C for 0.5 h and then warmed to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (EA / PE=1 / 2) to give the target compound (60 mg, crude). MS: M / e 751 (M+1) + .

[0499] Step G: 2-Butoxy-7-(4-(piperidin-4-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Compound A33)

[0500] To a mixture of the product of step F (60 mg, 0.08 mmol) in TFA (3 mL) was added Et3SiH (0.5 mL). The reaction was heated at 85 ° C overnight. The mixture was concentrated to dryness and the residue was purified by preparative HPLC. The collected fractions were basified with NaHCO3 solution, extracted with DCM (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the target compound (4 mg, 3% for both steps). 1HNMR(400MHz,DMSO-d6)δ8.12(s,1H),8.03(s,1H),7.29(s,1H),7.21(d,J=8.0Hz,2H),7.07(d,J=8.0Hz,2H),4.19(t,J=6.0Hz,2H),4.09(s,2H),3 .00(d,J=12.0Hz,2H),2.53-2.49(m,2H),2.44(d,J=7.2Hz,2H),1.75-1.4 9(m,5H),1.48-1.34(m,2H),1.18-1.04(m,2H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 395(M+1) + .

[0501] Compound A34: 2-Butoxy-7-((5-chloro-6-(3-(dimethylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0502] Step A: 5-chloro-6-(3-(dimethylamino)propoxy)nicotinaldehyde

[0503] To a solution of 5,6-dichloronicotinaldehyde (1.76 g, 10 mmol) and K2CO3 (1.65 g, 12 mmol) in DMF (20 mL) was added 3-(dimethylamino)propan-1-ol (1.13 g, 11 mmol). The mixture was then stirred at 80°C overnight under N2. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by flash chromatography to give the target compound (0.5 g, 21%). 1 HNMR(400MHz, CDCl3)δ9.93(s,1H),8.50(d,J=2.2Hz,1H),8.11(d,J=2.2Hz,1H), 4.56(t,J=6.0Hz,2H), 2.56(t,J=7.6Hz,2H), 2.33(s,6H), 2.15-2.03(m,2H)ppm. MS:M / e243(M+1) + .

[0504] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 5-Chloro-6-(3-(dimethylamino)propoxy)pyridin-3-yl)methanol

[0505] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.38 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium (0.6 mL, 0.95 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a mixture of the product of step A (138 mg, 0.57 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give the target compound (60 mg, crude). MS: M / e 690 (M+1) + .

[0506] Step C: 2-Butoxy-7-((5-chloro-6-(3-(dimethylamino)propoxy)pyridin-3-yl)methyl)imidazolyl [2,1-f][1,2,4]triazine-4-amine (Compound A34)

[0507] To the mixture of the product (60mg, rough) of step B in TFA (3mL), Et is added SiH (0.5mL) and the gained mixture is heated at 80 ℃ and spent the night.The mixture is cooled to room temperature and concentrated to dryness.In residue, TFA (3mL) is added, and the gained mixture is heated at 85 ℃ and spent the night.The mixture is concentrated to dryness and residue is passed through preparation HPLC purification.The fractions collected are alkalized with NaHCO solution, extracted with DCM (50mL x 2), washed with salt water, through Na SO dried, filtered, and concentrated to give target compound (8mg, 5% for two steps). 1 HNMR (400MHz, CD3OD) δ8.02(d,J=2.0Hz,1H),7.75(d,J=2.0Hz,1H),7.36(s,1H),4.38(t,J=6.0Hz,2H),4.28(t,J=6.4Hz,2H),4. 15(s,2H),2.59(t,J=8.0Hz,2H),2.32(s,6H),2.05-1.94(m,2H),1.82-1.70(m,2H),1.56-1.43(m,2H),0.98(t,J=7.2Hz,3H)ppm. MS:M / e 434(M+1) + .

[0508] Compound A35: 2-Butoxy-7-(4-(3-(dimethylamino)propoxy)-3-fluorobenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0509] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(3-(dimethylamino)propoxy)-3-fluorophenyl)methanol

[0510] Under N2, to a solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.29 mmol) in THF (5 mL) was added n-butyllithium (0.27 ml, 0.43 mmol) dropwise at -78 ° C and stirred for 1 h. Then, at -78 ° C, a solution of 4-(3-(dimethylamino)propoxy)-3-fluorobenzaldehyde (96 mg, 0.43 mmol) in THF (2 mL) was added dropwise, and the mixture was warmed to rt and stirred for 3 h. The mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (DCM / MeOH=20:1-5:1) to give the product as a yellow oil (136 mg, 70.86%). MS: M / e 673 (M+1) + .

[0511] Step B: 2-Butoxy-7-(4-(3-(dimethylamino)propoxy)-3-fluorobenzyl)imidazo[2,1-f][1, 2,4]Triazine-4-amine (Compound A35)

[0512] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(3-(dimethylamino)propoxy)-3-fluorophenyl)methanol (136 mg, 0.2 mmol) and triethylsilane (1 mL) in TFA (2 mL) was stirred at 90° C. overnight. The mixture was concentrated and purified by preparative HPLC to give the product (34 mg, 40%). 1 H NMR(400MHz,DMSO-d6)δ9.36(br.s,1H),8.14(s,1H),8.07(s,1H),7.30(s,1H ),7.19(d,J=12.6Hz,1H),7.13-7.02(m,2H),4.20(t,J=6.5Hz,2H),4.11-4.0 2(m,4H),3.20(dd,J=15.2,5.5Hz,2H),2.81(d,J=4.8Hz,6H),2.09(dt,J=12. 3,6.1Hz,2H),1.76-1.57(m,2H),1.47-1.33(m,2H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e 417(M+1) + .

[0513] Compound A36: 2-Butoxy-7-(4-(3-(dimethylamino)propoxy)-2-fluorobenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0514] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(3-(dimethylamino)propoxy)-2-fluorophenyl)methanol

[0515] To a solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.29 mmol) in THF (5 mL) was added n-butyllithium (0.27 ml, 0.43 mmol) at -78 ° C and stirred for 1 h. A solution of 4-(3-(dimethylamino)propoxy)-2-fluorobenzaldehyde (96 mg, 0.43 mmol) in THF (2 mL) was then added dropwise at -78 ° C. After addition, the mixture was warmed to rt and stirred for 3 hr. The mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (DCM / MeOH=20:1~5:1) to give the product (107 mg, 55.8%) as a yellow oil. MS:M / e673(M+1) + .

[0516] Step B: 2-Butoxy-7-(4-(3-(dimethylamino)propoxy)-2-fluorobenzyl)imidazo[2,1-f][1, 2,4]Triazine-4-amine (Compound A36)

[0517] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(3-(dimethylamino)propoxy)-2-fluorophenyl)methanol (107 mg, 0.16 mmol) and triethylsilane (1 mL) in TFA (2 mL) was stirred at 90 °C overnight. The mixture was concentrated and purified by preparative HPLC to give the title product (48 mg, 72.6%). 1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.14(s,1H),8.06(s,1H),7.37-7.07(m ,2H),6.82(dd,J=11.9,2.1Hz,1H),6.72(d,J=8.4Hz,1H),4.19(t,J=6.5Hz,2 H),4.08(s,2H),4.02(t,J=5.9Hz,2H),3.25-3.17(m,2H),2.80(s,6H),2.12- 2.00(m,2H),1.74-1.59(m,2H),1.47-1.34(m,2H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e 417(M+1) + .

[0518] Compound A37: 7-((6-(2-aminoethoxy)pyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0519] Step A: tert-Butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)carbamate

[0520] K2CO3 (2.76 g, 20 mmol) was added to a solution of 6-chloronicotinaldehyde (1.41 g, 10 mmol) and tert-butyl (2-hydroxyethyl) carbamate (1.61 g, 10 mmol) in DMA (20 mL), and the reaction mixture was stirred at 80°C overnight and cooled to room temperature. The solution was quenched with H2O (10 ml). The aqueous solution was extracted with EA (20 ml x 4). The collected organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography to give the product (120 mg, 4%). MS: M / e 267 (M+1) + .

[0521] Step B: tert-butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f] [1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)carbamate

[0522] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (158 mg, 0.3 mmol) in THF (2 mL) was added dropwise a solution of n-butyllithium (0.38 mL, 0.6 mmol), maintaining the temperature between -75°C and -65°C. After 10 min, a solution of the product of step A (120 mg, 0.45 mmol) in THF (3 mL) was added dropwise. The resulting mixture was stirred at -70°C for 20 min. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (5 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the target compound (80 mg, 37%). MS: M / e714 (M+1) + .

[0523] Step C: 7-((6-(2-aminoethoxy)pyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2, 4] Triazine-4-amine (Compound A37)

[0524] To the mixture of the product of step B (80 mg, 0.11 mmol) in TFA (1 mL), Et3SiH (1 mL) was added. The reaction was heated at 80 ° C for 3 h. The mixture was concentrated to dryness, and the residue was treated with TFA (2 mL). The reaction was heated at 80 ° C overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The collected fractions were alkalized with NaHCO3 solution, extracted with DCM (30 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (12 mg, 33%). 1 H NMR (400MHz, CDCl3) δ8.12(s,1H)7.51(d,J=8.0Hz,1H),7.25(s,1H),6.70(d,J=8.0Hz,1H),4.35-4.21(m ,4H),4.11(s,2H),3.06(t,J=6.0Hz,2H),1.62-1.51(m,2H),1.47-1.35(m,4H),0.98(t,J=8.0Hz,3H)ppm. MS:M / e 358(M+1) + .

[0525] Compound A38: 7-(4-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0526] Step A: tert-butyl (1R, 5S)-3-(3-fluoro-4-formylphenoxy)-8-azabicyclo[3.2.1]octane-8- Formate

[0527] Under N2 atmosphere, at 0 ° C, DIAD (3.8 mL, 7.2 mmol) was added dropwise to a solution of 2-fluoro-4-hydroxybenzaldehyde (500 mg, 3.6 mmol), tert-butyl (1R, 5S) -3-hydroxy-8-azabicyclo [3.2.1] octane -8- carboxylate (817 mg, 3.6 mmol) and triphenylphosphine (1.8 g, 7.2 mmol) in THF (20 mL). The mixture was warmed to rt and stirred overnight. The solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL), and washed with brine (10 mL). The organic layer was dried, concentrated and purified by CombiFlash (PE: EA = 10%) to give the product (330 mg, 27%) as a colorless oil. 1 HNMR (400MHz, CDCl3) δ10.21(s,1H),7.83(t,J=8.0Hz,1H),6.72(dd,J=8.0,4.0Hz,1H),6.57(dd,J=12,4 .0Hz,1H),4.70(t,J=4.0Hz,1H),4.24(s,2H),2.20(d,J=12.0Hz,2H),2.08-1.94(m,6H),1.49(s,9H)ppm. MS:M / e 350(M+1) + .

[0528] Step B: tert-butyl (1R,5S)-3-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2, 1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-fluorophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0529] At -78°C (with N 2 Under 40 ℃ of purging, to 7- bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200mg, 0.38mmol) in THF (8mL) cooling solution, n-butyllithium (1.6M, 0.6mL) was added dropwise. After stirring at -78 ℃ for 30min, tert-butyl (1R, 5S)-3-(3-fluoro-4-formylphenoxy)-8-azabicyclo[3.2.1]octane-8-formate (199mg, 0.57mmol) in THF (2mL) was added. The resulting mixture was stirred at this temperature for 30min, and then heated to rt overnight. The solution was quenched with NH4Cl solution (5mL), extracted with ethyl acetate (10mL) and washed with brine (10mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by CombiFlash (PE:EA=30%) to give the pure product (190 mg, 63%) as a red oil. MS: M / e797 (M+1) + .

[0530] Step C: 7-(4-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzyl)-2-butane Oxyimidazo[2,1-f][1,2,4]triazin-4-amine (Compound A38)

[0531] A mixture of tert-butyl (1R, 5S) -3- (4- ( (4- (bis (4-methoxybenzyl) amino) -2- butoxyimidazo [2, 1-f] [ 1, 2, 4] triazin-7-yl) (hydroxy) methyl) -3-fluorophenoxy) -8- azabicyclo [3.2.1] octane -8- carboxylate triethylsilane (190 mg, 0.24 mmol) in triethylsilane (3 mL) and trifluoroacetic acid (3 mL) was heated at 80 ° C for 2 hr. The solution was concentrated, trifluoroacetic acid (2 mL) was added thereto and heated at 80 ° C overnight. The solvent was evaporated to give a residue, which was basified with NaHCO3 water (5 mL), extracted with ethyl acetate (5 mL), and washed with brine (5 mL). The organic layer was dried, concentrated and purified by preparative HPLC to give the product (30 mg, 33%). 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),8.04(s,1H),7.25(s,1H),7.18(t,J=8 .0Hz,1H),6.72(d,J=12.0Hz,1H),6.62(d,J=8.0Hz,1H),4.59(s,1H),4.19( t,J=8.0Hz,2H),4.06(s,2H),3.37(s,2H),1.99-1.91(m,4H),1.77(s,1H),1 .74(s,1H),1.68-1.64(m,4H),1.44-1.35(m,2H),0.92(t,J=8.0Hz,3H)ppm. MS:M / e 441(M+1) + .

[0532] Compound A39: 1-(4-(4-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)benzyl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

[0533] To a mixture of 2-butoxy-7-(4-(piperazin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.052 mmol), dimethylglycine (5 mg, 0.05 mmol) and DIEA (12 mg, 0.1 mmol) in THF (4 mL) was added HATU (19 mg, 0.05 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with DCM (20 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (2 mg, 8.3%).1 HNMR (400MHz, CD3OD) δ7.34-7.24(m,5H),4.28(t,J=6.4Hz,2H),4.19(s,2H),4.09(s,2H),3.66-3.58(m,2H),3.54(s,2 H),3.43-3.36(m,2H),2.84(s,6H),2.55-2.40(m,4H),1.83-1.70(m,2H),1.55-1.45(m,2H),0.98(t,J=7.6Hz,3H)ppm. MS:M / e 481(M+1) + .

[0534] Compound A40: 2-Butoxy-7-((5-chloro-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0535] Step A: tert-Butyl 4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidine-1-carboxylate

[0536] To a solution of NaH (0.6 g, 15 mmol) in DMA (15 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (2.2 g, 11 mmol). The mixture was stirred at room temperature for 1 h. A solution of 5-bromo-2,3-dichloropyridine (2.26 g, 10 mmol) in DMA (5 mL) was then added, and the resulting mixture was stirred at 80 ° C overnight under N2 protection. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by combi-flash to give the target compound (2.23 g, 57%). MS: M / e335 (M+Ht-Bu) + .

[0537] Step B: tert-Butyl 4-((3-chloro-5-formylpyridin-2-yl)oxy)piperidine-1-carboxylate

[0538] To a solution of the product of step A (2.23 g, 5.7 mmol) in THF (15 mL) was added n-butyllithium (5.3 mL, 8.55 mmol) solution, the temperature being maintained between -75°C and -65°C. After 1 h, DMF (500 mg, 6.3 mmol) was added dropwise and the resulting mixture was stirred at -70°C for 2 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (40 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by combi flash to give the target compound (350 mg, 18%) as an oil. 1H NMR(400MHz, CDCl3) δ9.93(s,1H),8.49(d,J=2.0Hz,1H),8.12(d,J=2.0Hz,1H),5.49-5.41(m,1 H),3.79-3.65(m,2H),3.49-3.38(m,2H),2.05-1.92(m,2H),1.91-1.78(m,2H),1.47(s,9H)ppm. MS:M / e 341(M+1) + .

[0539] Step C: tert-butyl 4-((5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1, 2,4]triazin-7-yl)(hydroxy)methyl)-3-chloropyridin-2-yl)oxy)piperidine-1-carboxylate

[0540] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.38 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium (0.6 mL, 0.95 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a mixture of the product of step B (155 mg, 0.456 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature for 5 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (EA / PE=1 / 2) to give the target compound (80 mg, crude). MS: M / e 788 (M+1) + .

[0541] Step D: 2-Butoxy-7-((5-chloro-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo[2,1-f] [1,2,4]triazine-4-amine (Compound A40)

[0542] To a mixture of the product of step C (80 mg, crude) in TFA (3 mL) was added Et3SiH (0.5 mL) and the resulting mixture was stirred at 85°C overnight. The mixture was cooled to room temperature and concentrated to dryness. The residue was purified by preparative HPLC. The collected fractions were basified with NaHCO3 solution, extracted with DCM (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the target compound (20 mg, 45% for two steps). 1HNMR(400MHz, DMSO-d6)δ8.15(s,1H),8.10-8.01(m,2H),7.84(d,J=2.0Hz,1H),7.34(s,1H),5.15-5.04(m,1H),4.19(t,J=6.4Hz,2H),4.09(s,2 H),3.02-2.90(m,2H),2.64-2.53(m,2H),1.98-1.86(m,2H),1.72-1.60 (m,2H),1.59-1.46(m,2H),1.44-1.32(m,2H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 432(M+1) + .

[0543] Compound A41: 7-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0544] Step A: tert-Butyl (1S,4S)-5-(4-formylbenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid ester

[0545] A mixture of 4-(chloromethyl)benzaldehyde (2 g, 12.9 mmol), tert-butyl (1S, 4S)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (3.06 g, 15.5 mmol) and KCO (3.56 g, 25.8 mmol) in CHCN (30 mL) was stirred at 50 ° C overnight. The reaction was cooled to room temperature. The mixture was diluted with water (50 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by combiflash to obtain the title compound (3.8 g, yield: 93.1%) as a brown oil. 1 H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H), 7.86 (d, J = 8.0Hz, 2H), 7.56 (d, J = 8.0Hz, 2H), 3.79 (s, 2H), 3.42-3.37 (m, 2H), 3. 19-3.00(m,1H),2.83-2.70(m,1H),2.53-2.38(m,1H),1.85-1.75(m,1H),1.72-1.55(m,1H),1.48-1.32(m,10H)ppm. MS:M / e 317(M+1) + .

[0546] Step B: tert-butyl (1S, 4S)-5-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2, 1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0547] Under N2 atmosphere, at -78 ° C, to a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.29 mmol) in THF (10 mL) was added n-butyllithium (1.6 M, 0.45 mL). The mixture was stirred at -78 ° C for 1 hour. The product of step A (135 mg, 0.43 mmol) in THF (0.5 mL) was then added to the system at -78 ° C. The reaction was warmed to room temperature and stirred overnight. At room temperature, the reaction was quenched with saturated aqueous NH4Cl. The mixture was extracted with EA (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by combiflash to obtain the title compound (140 mg, yield: 63.3%) as a yellow oil. MS:M / e 764(M+1) + .

[0548] Step C: 7-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl)benzyl)-2-butoxy Imidazolo[2,1-f][1,2,4]triazin-4-amine (Compound A41)

[0549] To a stirred solution of the product of step B (140 mg, 0.18 mmol) in Et3SiH (4 mL) was added CF3COOH (4 mL) at room temperature. The mixture was stirred at 80 ° C for 1 hour. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CF3COOH (4 mL). The mixture was stirred at 80 ° C overnight. The reaction was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (12 mg, yield: 16.1%). 1 H NMR (400MHz, DMSO-d6) δ8.19-7.97(m,2H),7.30(s,1H),7.25-7.19(m,4H),4.20(t,J=6.4Hz,2H),4.11(s,2H),3.67-3.55(m,2H),3.31-3.18 (m,2H),3.03(d,J=9.6Hz,1H),2.68(t,J=8.4Hz,2H),2.36(d,J=9.6Hz,1H),1.77-1.60(m,3H),1.49-1.33(m,3H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e408(M+1) + .

[0550] Compound A42: 2-Butoxy-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0551] Step A: 4-Bromophenethyl 4-methylbenzenesulfonate

[0552] To a stirred solution of 2-(4-bromophenyl)ethane-1-ol (4 g, 20 mmol) in DCM (40 mL) was added 4-methylbenzenesulfonyl chloride (4.12 g, 20.14 mmol) and EtN (2.18 g, 20.14 mmol). The reaction mixture was stirred overnight at rt. 1N HCl aqueous solution (40 mL) was added to the mixture and extracted with DCM (20 ml x 3). The combined organic phases were washed with brine, dried over NaSO and concentrated in vacuo to give the product (7.7 g, 100%) as a yellow oil, which was used in the next step without further purification.

[0553] Step B: 1-(4-bromophenethyl)pyrrolidine

[0554] To a stirred solution of 4-bromophenethyl 4-methylbenzenesulfonate (7g, 20mmol) in MeCN (50mL) was added pyrrole (5.6g, 77mmol) and EtN (8g, 80mmol). The reaction mixture was stirred at rt overnight. The mixture was concentrated in vacuo. H2O (40mL) was added to the residue and extracted with DCM (20ml x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography to give the product (4.3g, 86%) as a yellow oil. MS: M / e 254 (M+1) + .

[0555] Step C: 4-(2-(Pyrrolidin-1-yl)ethyl)benzaldehyde

[0556] To a stirred solution of 1-(4-bromophenethyl)pyrrolidine (1 g, 4 mmol) in THF (20 mL) cooled to -78 ° C and under a nitrogen atmosphere was added n-butyl lithium (1.6 M in hexane, 4.4 mmol, 2.7 mL). After stirring for 60 min, a solution of DMF (876 mg, 12 mmol) in THF (3 mL) was slowly added. The reaction mixture was slowly heated to rt and stirred for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography to give the title product (600 mg, 73.8%). MS: M / e 204 (M+1) + .

[0557] Step D: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-(2-(pyrrolidin-1-yl)ethyl)phenyl)methanol

[0558] To a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.29 mmol) in THF (10 mL) cooled to -78 ° C under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.71 mmol, 0.47 mL). After stirring for 20 min, a solution of 4-(2-(pyrrolidin-1-yl)ethyl)benzaldehyde (87.5 mg, 0.43 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly heated to rt and stirred overnight. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography to give the title product (80 mg, 43%). MS:M / e 651(M+1) + .

[0559] Step E: 2-Butoxy-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazol Oxazine-4-amine (Compound A42)

[0560] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(2-(pyrrolidin-1-yl)ethyl)phenyl)methanol (80 mg, 0.123 mmol) in TFA (3 mL) and Et3SiH (3 mL) was stirred at 80 ° C for 2 h. The reaction mixture was concentrated in vacuo to remove TFA and Et3SiH. TFA (5 mL) was added to the residue and stirred at 85 ° C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (14 mg, 29%). 1 H NMR (400MHz, DMSO-d6)) δ8.12(s,1H),8.03(s,1H),7.28(s,1H),7.21(d,J=7.8Hz,2H),7.13(d,J=7.8Hz,2H),4.20(t,J=6.5Hz, 2H),4.09(s,2H),2.71-2.59(m,2H),2.65(s,2H),2.50(s,4H),1.68-1.57(m,6H),1.45-1.36(m,2H),0.92(t,J=7.3Hz,3H)ppm. MS:M / e 395(M+1) + .

[0561] Compound A43: 7-(4-((4-aminopiperidin-1-yl)methyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0562] Step A: tert-Butyl (1-(4-formylbenzyl)piperidin-4-yl)carbamate

[0563] To a solution of 4-(bromomethyl)benzaldehyde (0.4 g, 2 mmol) and DIEA (0.52 g, 4 mmol) in THF (10 mL) was added tert-butylpiperidin-4-ylcarbamate (0.44 g, 2.2 mmol). The mixture was then stirred at room temperature overnight. The mixture was diluted with water (50 mL), extracted with EtOAc (80 mL), washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by combi-flash to give the target compound (0.6 g, 94%). MS: M / e 319 (M+1) +

[0564] Step B: tert-butyl (1-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1, 2,4]triazin-7-yl)(hydroxy)methyl)benzyl)piperidin-4-yl)carbamate

[0565] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (380 mg, 0.72 mmol) in THF (12 mL) was added dropwise a solution of n-butyllithium (1 mL, 1.6 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a mixture of the product of step A (276 mg, 0.868 mmol) in THF (3 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (60 mg, crude). MS: M / e 766 (M+1) + .

[0566] Step C: 7-(4-((4-aminopiperidin-1-yl)methyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4] Triazine-4-amine (Compound A43)

[0567] To a mixture of the product of step B (60 mg, crude) in TFA (3 mL) was added Et3SiH (0.5 mL). The resulting mixture was heated at 85 ° C overnight. The mixture was concentrated to dryness and the residue was purified by preparative HPLC. The collected fractions were basified with NaHCO3 solution, extracted with DCM (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the target compound (7 mg, 2.3% for two steps). 1HNMR(400MHz,DMSO-d6)δ8.12(s,1H),8.03(s,1H),7.30(s,1H),7.23(d,J=7.6H z,2H),7.18(d,J=7.6Hz,2H),4.19(t,J=6.0Hz,2H),4.11(s,2H),3.36(s,2H),3. 15-2.80(m,2H),2.74-2.61(m,2H),2.60-2.51(m,1H),1.89(t,J=10.4Hz,2H),1. 72-1.58(m,4H),1.49-1.34(m,2H),1.29-1.15(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 410(M+1) + .

[0568] Compound A44: 2-Butoxy-7-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0569] Step A: 4-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)benzaldehyde

[0570] To a stirred solution of 4-(bromomethyl)benzaldehyde (459 mg, 2.3 mmol) in MeCN (15 mL) was added N,N-dimethylpyrrolidin-3-amine (319 mg, 2.8 mmol) and Et3N (929 mg, 9.2 mmol). The reaction mixture was stirred overnight at rt. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give the product (100 mg, 18.7%) as a yellow oil. MS: M / e 233 (M+1) + .

[0571] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)methanol

[0572] To a stirred solution of 4-((4-(bis(4-methoxybenzyl)amino)-7-bromoimidazo[2,1-f][1,2,4]triazin-2-yl)oxy)butane-2-pyrrole (150 mg, 0.28 mmol) in THF (10 mL) cooled to -78 ° C under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.7 mmol, 0.43 mL) dropwise. After stirring for 60 min, a solution of 4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)benzaldehyde (80 mg, 0.34 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product (110 mg, 57.8%), which was used directly in the next step without further purification. MS: M / e 680 (M+1) + .

[0573] Step C: 2-Butoxy-7-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)benzyl)imidazo[2,1- f][1,2,4]triazine-4-amine (Compound A44)

[0574] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)methanol (110 mg, 0.162 mmol) in TFA (3 mL) and Et3SiH (3 mL) was stirred at 80°C for 2 h. The reaction mixture was concentrated in vacuo to remove TFA and Et3SiH. TFA (5 mL) was added to the residue and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (30 mg, 43.5%). 1 H NMR(400MHz, DMSO-d6))δ8.12(s,1H),8.03(s,1H),7.30(s,1H),7.25-7.19(m,4H),4.19( t,J=6.5Hz,2H),4.11(s,2H),3.52-3.38(m,2H),2.74-2.65(m,1H),2.61(t,J=8.0Hz,1H) ,2.53(d,J=8.4Hz,1H),2.38(dd,J=14.7,8.5Hz,1H),2.27-2.16(m,1H),2.07(s,6H),1.8 1(dd,J=13.3,6.0Hz,1H),1.72-1.53(m,3H),1.42-1.33(m,2H),0.91(t,J=7.4Hz,3H)ppm. MS:M / e 424(M+1)+ .

[0575] Compound A45: 2-Butoxy-7-((5-chloro-6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0576] Step A: 3-((5-bromo-3-chloropyridin-2-yl)oxy)-N,N,2,2-tetramethylpropan-1-amine

[0577] To a stirred suspension of NaH (60%, 600 mg, 15 mmol) in DMA (15 mL) was added a solution of 3-(dimethylamino)-2,2-dimethylpropan-1-ol (1.44 g, 1.1 mmol) in DMA (2 mL). After stirring for 30 min, a solution of 5-bromo-2,3-dichloropyridine (2.26 g, 10 mmol) in DMA (2 mL) was added. After addition, the reaction was stirred at 80 ° C overnight. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether / EtOAc=20:1~5:1) to give the target compound (2.3 g, 71.5%) as a colorless oil. MS: M / e 321 (M+1) + .

[0578] Step B: 5-chloro-6-(3-(dimethylamino)-2,2-dimethylpropoxy)nicotinaldehyde

[0579] At -78 ° C, n-butyl lithium (1.6 M, 2.8 mL, 4.5 mL) was added dropwise to a stirred solution of the product of step A (961.5 mg, 3 mmol) in dry THF (10 mL). After stirring for 30 min, DMF (337 mg, 4.5 mmol) was added and stirred for 2 hours. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether / EtOAc=5:1~1:1) to give the target compound (550 mg, 68%) as a colorless oil. MS: M / e 271 (M+1) + .

[0580] Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-(5-chloro-6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3-yl)methanol

[0581] At -78 ° C, to a solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.286 mmol) in THF (10 mL) was added dropwise n-butyllithium (1.6 M, 0.44 mL, 0.71 mmol). After stirring for 1 hour, a solution of the product of step B (115 mg, 0.428 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred overnight. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (100% EtOAc) to give the target compound (60 mg, 29.3%). MS: M / e 718 (M+1) + .

[0582] Step D: 2-Butoxy-7-((5-chloro-6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3-yl) Methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Compound A45)

[0583] A mixture of the product of step C (70 mg, 0.095 mmol) in Et3SiH / TFA (0.5 mL / 3 mL) was stirred overnight at 85° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the title compound (20 mg, 54.1%). 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),8.07(s,2H),7.85(d,J=2.0Hz,1H),7.34(s,1H),4.19(t,J=6.4Hz,2H) ,4.10(s,2H),4.04(s,2H),2.30-2.15(m,8H),1.73-1.61(m,2H),1.44-1.35(m,2H),0.98-0.88(m,9H)ppm. MS:M / e 462(M+1) + .

[0584] Compound A46: 7-(4-(aminomethyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0585] Step A: tert-butyl (4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2, 4]triazin-7-yl)(hydroxy)methyl)benzyl)carbamate

[0586] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.38 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium (0.5 mL, 0.76 mmol), maintaining the temperature between -75°C and -65°C. After 1.5 h, a solution of tert-butyl(4-formylbenzyl)carbamate (107 mg, 0.456 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature for 1 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (90 mg, crude). MS: M / e 683 (M+1) + .

[0587] Step B: 7-(4-(aminomethyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine (compound Object A46)

[0588] To the mixture of the product of step A (90 mg, crude) in TFA (3 mL), Et3SiH (0.5 mL) was added. The reaction was heated at 85 ° C overnight. The mixture was concentrated to dryness and the residue was purified by preparative HPLC. The collected fractions were alkalized with NaHCO3 solution, extracted with DCM (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the product (10 mg, 10% for both steps). 1 HNMR(400MHz,DMSO-d6)δ8.11(s,1H),8.03(s,1H),7.27(s,1H),7.25-7.22(m,4H),4.42(t,J=6.4 Hz,2H),4.10(s,2H),3.67(s,2H),1.75-1.60(m,2H),1.50-1.30(m,2H),0.93(t,J=7.6Hz,3H)ppm. MS:M / e 327(M+1) + .

[0589] Compound A47: 2-Butoxy-7-(4-((4-phenoxypiperidin-1-yl)methyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0590] Step A: 4-((4-phenoxypiperidin-1-yl)methyl)benzaldehyde

[0591] To a solution of 4-(bromomethyl)benzaldehyde (0.4 g, 2 mmol) and DIPEA (0.36 g, 3 mmol) in THF (10 mL) was added 4-phenoxypiperidine (0.35 g, 2 mmol). The mixture was then stirred at room temperature overnight. The reaction was diluted with water (50 mL), extracted with EtOAc (60 mL), washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by flash chromatography to give the target compound (0.22 g, 37%). MS: M / e 296 (M+1) + .

[0592] Step B: tert-Butyl (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazol Oxazin-7-yl)(4-((4-phenoxypiperidin-1-yl)methyl)phenyl)methanol

[0593] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.285 mmol) in THF (5 mL) was added dropwise a solution of n-butyllithium (0.4 mL, 0.64 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a mixture of the product of step A (100 mg, 0.34 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 2 h and then warmed to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (EA / PE=1 / 1) to give the target compound (95 mg, crude). MS: M / e 743 (M+1) + .

[0594] Step C: 2-Butoxy-7-(4-((4-phenoxypiperidin-1-yl)methyl)benzyl)imidazo[2,1-f][1,2, 4] Triazine-4-amine (Compound A47)

[0595] To the mixture of the product of step B (95 mg, crude) in TFA (3 mL), Et was added SiH (1 mL) and the resulting mixture was stirred at 85 ° C overnight. The mixture was cooled to room temperature and concentrated to dryness. TFA (3 mL) was added to the residue, and the resulting mixture was heated at 85 ° C overnight. The mixture was concentrated to dryness and the residue was purified by preparative HPLC. The collected fractions were alkalized with NaHCO solution, extracted with DCM (60 mL), washed with brine, dried over Na SO, filtered, and concentrated to give the target compound (15 mg, 11% for two steps). 1HNMR(400MHz,DMSO-d6)δ8.13(s,1H),8.03(s,1H),7.31(s,1H),7.29-7.18(m,6H),6.96-6.85(m,3H),4.42-4.28(m,1H),4.19(t,J=6.4Hz,2H),4 .12(s,2H),3.43(s,2H),2.70-2.58(m,2H),2.25-2.10(m,2H),1.98-1.8 2(m,2H),1.72-1.50(m,4H),1.46-1.32(m,2H),0.91(t,J=7.8Hz,3H)ppm. MS:M / e 487(M+1) + .

[0596] Compound A48: 2-((5-methylisoxazol-3-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0597] Step A: 7-Bromo-N,N-bis(4-methoxybenzyl)-2-((5-methylisoxazol-3-yl)methoxy)imidazolyl [2,1-f][1,2,4]triazine-4-amine

[0598] To a suspension of NaH (80 mg, 2 mmol) in THF (5 mL) was added (5-methylisoxazol-3-yl) methanol (226 mg, 2 mmol). After stirring at room temperature for 30 min, a solution of 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (240 mg, 0.5 mmol) in THF (2 mL) was added. The mixture was then stirred at 80 ° C for 6 h. The mixture was cooled to room temperature, diluted with water (30 mL), extracted with EtOAc (60 mL), washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by combi-flash to give the target compound (200 mg, 71%). 1 HNMR (400MHz, CDCl3) δ7.50 (s, 1H), 7.18 (d, J = 8.4Hz, 4H), 6.88-6.82 (m, 4H), 6. 18(s,1H),5.61(s,2H),5.43(s,2H),4.85(s,2H),3.80(s,6H),2.40(s,3H)ppm. MS:M / e 565(M+1) + .

[0599] Step B: (4-(bis(4-methoxybenzyl)amino)-2-((5-methylisoxazol-3-yl)methoxy)imidazolyl [2,1-f][1,2,4]triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0600] To a solution of the product of step A (100 mg, 0.177 mmol) in THF (3 mL) was added dropwise a solution of n-butyllithium (0.3 mL, 0.44 mmol) and the temperature was maintained between -75°C and -65°C. After 1 h, a solution of 4-(pyrrolidin-1-ylmethyl)benzaldehyde (80 mg, 0.424 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature for 4 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (50 mg, crude). MS: M / e676 (M+1) + .

[0601] Step C: 2-((5-methylisoxazol-3-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazolyl [2,1-f][1,2,4]triazine-4-amine (Compound A48)

[0602] To the mixture of the product of step B (50 mg, crude) in TFA (3 mL), Et3SiH (0.5 mL) was added. The reaction was heated at 85 ° C for 16 h. The mixture was concentrated to dryness, and the residue was treated with TFA (3 mL). The reaction was heated at 85 ° C overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The collected fractions were alkalized with NaHCO3 solution, extracted with DCM (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the target compound (10 mg, 13% for two steps). 1 H NMR(400MHz,DMSO-d6)δ8.28(s,1H),8.19(s,1H),7.34(s,1H),7.30-7.15(m,4H),6.27( s,1H),5.31(s,2H),4.12(s,2H),3.51(s,2H),2.44-2.33(m,7H),1.75-1.62(m,4H)ppm. MS:M / e 420(M+1) + .

[0603] Compound A49: 2-Butoxy-7-(4-(((1R,5S)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0604] Step A: 4-(((1R,5S)-8-Azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzaldehyde hydrochloride

[0605] A solution of tert-butyl (1R,5S)-3-(3-fluoro-4-formylphenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (330 mg, 1 mmol) in HCl / dioxane (4 M, 4 mL) was stirred overnight at rt. The solution was concentrated to give the product as a white solid HCl salt (250 mg, 92%). MS: M / e 252 (M+1) + .

[0606] Step B: 4-(((1R,5S)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzaldehyde

[0607] Iodoethane (156 mg, 1 mmol) was added to a solution of 4-(((1R, 5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzaldehyde hydrochloride (150 mg, 0.5 mmol) and KCO (138 mg, 1 mmol) in THF (3 mL) and DMF (3 mL). The solution was stirred at rt overnight, water (10 mL) was added, extracted with ethyl acetate (10 mL), and washed with brine (10 mL). The organic layer was dried over NaSO, filtered and concentrated to give the crude product, which was further purified by preparative TLC (DCM:MeOH=7:1) to give the pure product (60 mg, 41%). MS: M / e 278 (M+1) + .

[0608] Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(((1R,5S)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorophenyl)methanol

[0609] At -78°C (with N 2 To the cooled solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (100 mg, 0.19 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.3 mL) under purging. After stirring at -78 ° C for 30 min, 4-(((1R, 5S)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzaldehyde (58 mg, 0.21 mmol) in THF (2 mL) was added. The resulting mixture was stirred at this temperature for 30 min, and then heated to rt for 2 hr. The solution was quenched with NH4Cl solution (5 mL), extracted with ethyl acetate (5 mL) and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude product, which was further purified by preparative TLC (DCM:MeOH=8:1) to give the product (30 mg, 22%). MS: M / e 725 (M+1) + .

[0610] Step D: 2-Butoxy-7-(4-(((1R,5S)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy 2-(2-fluorobenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Compound A49)

[0611] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(((1R,5S)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorophenyl)methanol (28 mg, 0.04 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (2 mL) was heated at 80 °C overnight. The solvent was evaporated to give a residue, which was purified by preparative HPLC to give the product (15 mg, 83%). 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.16(s,1H),8.09(s,1H),7.28(s,1H),7.24(t,J=8 .0Hz,1H),6.91(dd,J=12.0,J=4.0Hz,1H),6.75(d,J=8.0Hz,1H),4.71(s,1H),4.20(t,J= 8.0Hz,2H),4.08(s,2H),3.96(s,2H),3.03-2.96(m,2H),2.34-2.30(m,2H),2.21-2.08(m ,6H),1.70-1.63(m,2H),1.45-1.36(m,2H),1.24-1.21(m,3H),0.92(t,J=8.0Hz,3H)ppm. MS:M / e 469(M+1) + .

[0612] Compound A50: 2-Butoxy-7-((5-methoxypyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0613] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-Methyl)(5-methoxypyridin-2-yl)methanol

[0614] To a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.28 mmol) in THF (10 mL) cooled to -78 ° C and under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.7 mmol, 0.43 mL). After stirring for 60 min, a solution of 5-methoxypicolinaldehyde (50 mg, 0.34 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title product (200 mg, 100%), which was used directly in the next step without further purification. MS: M / e 585 (M+1) + .

[0615] Step B: 2-Butoxy-7-((5-methoxypyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazine-4- Amine (Compound A50)

[0616] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(5-methoxypyridin-2-yl)methanol (200 mg, 0.28 mmol) in TFA (3 mL) and EtSiH (3 mL) was stirred at 80 ° C for 2 h. The reaction mixture was concentrated in vacuo to remove TFA and EtSiH. TFA (5 mL) was added to the residue and stirred at 85 ° C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (10 mg, 10.8%). 1 H NMR (400MHz, DMSO-d6)) δ8.18(d,J=2.8Hz,1H),8.13(s,1H),8.03(s,1H),7.31(dd,J=8.5,2.8Hz,1H),7.28(s,1H),7.24(d,J =8.6Hz,1H),4.23(s,2H),4.15(t,J=6.5Hz,2H),3.78(s,3H),1.68-1.57(m,2H),1.43-1.30(m,2H),0.90(t,J=7.4Hz,3H)ppm. MS:M / e 329(M+1) + .

[0617] Compound A51: 2-Butoxy-7-((6-methoxypyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0618] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-Methyl)(6-methoxypyridin-2-yl)methanol

[0619] To a stirred solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.28 mmol) in THF (10 mL) cooled to -78 ° C and under a nitrogen atmosphere was added n-butyl lithium (1.6 M in hexane, 0.7 mmol, 0.43 mL). After stirring for 60 min, a solution of 6-methoxypicolinaldehyde (50 mg, 0.34 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title product (250 mg, 100%), which was used directly in the next step without further purification. MS: M / e585 (M+1) + .

[0620] Step B: 2-Butoxy-7-((6-methoxypyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazine-4- Amine (Compound A51)

[0621] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(6-methoxypyridin-2-yl)methanol (250 mg, 0.28 mmol) in TFA (3 mL) and EtSiH (3 mL) was stirred at 80 ° C for 2 h. The reaction mixture was concentrated in vacuo to remove TFA and EtSiH. TFA (5 mL) was added to the residue and stirred at 85 ° C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (25 mg, 27.2%). 1 H NMR (400MHz, DMSO-d6)) δ8.15(s,1H),8.05(s,1H),7.60(t,J=7.8Hz,1H),7.35(s,1H),6.80(d,J=7.3Hz,1H),6.65(d,J=8.2Hz, 1H), 4.21 (s, 2H), 4.15 (t, J = 6.5Hz, 2H), 3.79 (s, 3H), 1.68-1.56 (m, 2H), 1.37 (dd, J = 15.0, 7.5Hz, 2H), 0.90 (t, J = 7.4Hz, 3H) ppm. MS:M / e 329(M+1) + .

[0622] Compound A52: 7-(4-(Pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0623] Step A: 7-Bromo-N2-(furan-2-ylmethyl)-N4,N4-bis(4-methoxybenzyl)imidazo[2,1-f][1, 2,4]triazine-2,4-diamine

[0624] A solution of 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.41 mmol), furan-2-ylmethylamine (80 mg, 0.28 mmol) and DIEA (106 mg, 0.82 mmol) in n-BuOH (5 mL) was heated in a sealed tube at 120° C. for 48 hr. The solution was cooled, concentrated and further purified by preparative TLC (PE:EA=2:1) ​​to give the pure product (70 mg, 31%). MS: M / e 549 (M+1) + .

[0625] Step B: (4-(bis(4-methoxybenzyl)amino)-2-((furan-2-ylmethyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0626] At -78°C (with N 2 To a cooled solution of (4-(bis(4-methoxybenzyl)amino)-2-((furan-2-ylmethyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol (70 mg, 0.13 mmol) in THF (5 mL) was added n-butyllithium (1.6 M, 0.2 mL) dropwise under a 4% (5% purging) column. After stirring at -78 ° C. for 30 min, 4-(pyrrolidin-1-ylmethyl)benzaldehyde (37 mg, 0.20 mmol) in THF (1 mL) was added. The resulting mixture was stirred at this temperature for 30 min and then warmed to rt overnight. The solution was quenched with NH4Cl solution (2 mL), extracted with ethyl acetate (10 mL), and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude product, which was further purified by preparative TLC (DCM:MeOH=7:1) to give the product (15 mg, 18%). MS: M / e 660 (M+1) + .

[0627] Step C: 7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (Chemical Compound A52)

[0628] A solution of (4-(bis(4-methoxybenzyl)amino)-2-((furan-2-ylmethyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol (15 mg, 0.02 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (2 mL) was heated at 80° C. overnight. The solution was evaporated to give a residue, which was purified by preparative HPLC to give the product (5 mg, 50%). 1 H NMR(400MHz,DMSO-d6)δ9.86(br.s,1H),7.86(br.s,1H),7.44(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),7.31(s,1H), 4.31(d,J=8.0Hz,2H),4.15(s,2H),3.35-3.31(m,2H),3.12-3.05(m,2H),2.05-2.02(m,2H),1.86-1.81(m,2H)ppm. MS:M / e 324(M+1) + .

[0629] Compound A53: 2-Butoxy-7-((6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0630] Step A: 6-(3-(dimethylamino)-2,2-dimethylpropoxy)nicotinonitrile

[0631] To a stirred suspension of NaH (60%, 600 mg, 15 mmol) in DMA (15 mL) was added a solution of 3-(dimethylamino)-2,2-dimethylpropan-1-ol (1.44 g, 1.1 mmol) in DMA (2 mL). After stirring for 30 min, a solution of 6-chloronicotinonitrile (1.38 g, 10 mmol) in DMA (2 mL) was added. After addition, the reaction was stirred at 80 ° C overnight. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether / EtOAc=20:1) to give the target compound (240 mg, 10.3%) as a white solid. MS: M / e 234 (M+1) + .

[0632] Step B: 6-(3-(dimethylamino)-2,2-dimethylpropoxy)nicotinaldehyde

[0633] To a stirred solution of the product of step A (233 mg, 1 mmol) in dry THF (10 mL) was added DIBAL-H (1.2 M, 2 mL, 2.5 mmol) at -20 ° C. After addition, the reaction was stirred for 3 hours. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether / EtOAc=10:1~2:1) to give the target compound (120 mg, 50.8%) as a white solid. MS: M / e 237 (M+1) + .

[0634] Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-(6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3-yl)methanol

[0635] At -78 ° C, to a solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.286 mmol) in THF (10 mL) was added dropwise n-butyllithium (1.6 M, 0.44 mL, 0.71 mmol). After stirring for 1 hour, a solution of the product of step B (115 mg, 0.428 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred overnight. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (100% EtOAc) to give the target compound (45 mg, 23%) as a colorless oil. MS: M / e 684 (M+1) + .

[0636] Step D: 2-Butoxy-7-((5-chloro-6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3-yl) Methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (Compound A53)

[0637] A mixture of the product of step C (45 mg, 0.066 mmol) in Et3SiH / TFA (0.5 mL / 3 mL) was stirred overnight at 85° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the title compound (10 mg, 35.4%). 1H NMR (400MHz, DMSO-d6) δ8.14(s,1H),8.11(s,1H),8.05(s,1H),7.59(dd,J=8.4,2.4Hz,1H),7.30(s,1H),6.73(d,J=8.4Hz,1H ), 4.19(t,J=6.5Hz,2H),4.07(s,2H),3.94(s,2H),2.18(s,8H),1.72-1.59(m,2H),1.47-1.34(m,2H),0.96-0.86(m,9H)ppm. MS:M / e 428(M+1) + .

[0638] Compound A54: 2-isobutoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0639] Step A: 7-Bromo-2-isobutoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4- amine

[0640] Sodium (1g) was added to the stirred 2-methylpropan-1-ol (10g) in several batches. The mixture was stirred at 80°C for 2h. The above clear solution was added to 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (0.25g, 0.51mmol). The mixture was heated to 80°C and stirred for 1h. After completion, the mixture was quenched with H2O (20ml) and then extracted with DCM (20ml x 3). The organic phase was washed with H2O (10ml), dried and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography with 0-20% EA in PE to obtain the product (0.18g, 67%) as a white solid. MS: M / e 526 (M+1) + .

[0641] Step B: (4-(bis(4-methoxybenzyl)amino)-2-isobutoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(Pyrrolidin-1-ylmethyl)phenyl)methanol

[0642] Under N2 atmosphere, at -78 ° C, to a stirred solution of 7-bromo-2-isobutoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (180 mg, 0.34 mmol) in THF (10 ml) was added n-butyl lithium (1.6 M, 0.54 ml, 0.86 mmol). The solution was stirred at -78 ° C for 30 min. 4-(pyrrolidin-1-ylmethyl)benzaldehyde (97 mg, 0.51 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was naturally warmed to rt and then stirred for 3 hr. After completion, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml × 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to obtain a crude product in the form of a yellow oil, which was directly used in the next step without further purification. MS:M / e 637(M+1) + .

[0643] Step C: 2-isobutoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine- 4-Amine (Compound A54)

[0644] A solution of (4-(bis(4-methoxybenzyl)amino)-2-isobutoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) was stirred at 80 ° C for 24 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EA (30 ml) and washed with aqueous NaHCO (saturated, 25 ml) and brine (20 ml). The organic phase was dried over Na SO, filtered and concentrated. The resulting residue was purified by preparative TLC using DCM:MeOH (10: 1) to give the product (13.83 mg). 1 H NMR(400MHz,CD3OD)δ7.49-7.42(m,4H),7.33(s,1H),4.65(s,1H),4.38-4.34(m,1H),4 .33(s,2H),4.26(s,2H),4.04(d,J=4Hz,2H),2.16-1.98(m,7H),1.02(d,J=8Hz,6H)ppm. MS:M / e 381(M+1) + .

[0645] Compound A55: 2-Butoxy-7-((3-methoxypyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0646] Step A: tert-butyl (2-butoxy-7-(hydroxy(3-methoxypyridin-2-yl)methyl)imidazo[2,1-f][1, 2,4]triazin-4-yl)(tert-butoxycarbonyl)carbamate

[0647] To a solution of tert-butyl (2-butoxy-7-(hydroxy (3-methoxypyridin-2-yl) methyl) imidazo [2, 1-f] [1, 2, 4] triazine -4- yl) (tert-butoxycarbonyl) carbamate (150 mg, 0.3 mmol) in THF (5 mL) was added dropwise a solution of n-butyl lithium (0.4 mL, 0.6 mmol) and the temperature was maintained between -75 ° C and -65 ° C. After 1 h, a solution of 3-methoxypicolinaldehyde (55 mg, 0.45 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70 ° C for 1 h and then warmed to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (20 mg, crude). MS:M / e 545(M+1) + .

[0648] Step B: 2-Butoxy-7-((3-methoxypyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazine-4- Amine (Compound A55)

[0649] To a mixture of the product of step A (20 mg, crude) in TFA (3 mL) was added EtSiH (0.5 mL). The reaction was heated at 85° C. overnight. The mixture was concentrated to dryness and the residue was purified by preparative HPLC to give the title product (8 mg, 6% for two steps). 1 HNMR(400MHz,CD3OD)δ8.23(d,J=5.4Hz,1H),8.04(d,J=8.0Hz,1H),7.80(dd,J=8.0,5.4,Hz,1H),7.54(s,1H), 4.60(s,2H),4.14(t,J=6.4Hz,2H),4.03(s,3H),175-1.62(m,2H),1.50-1.38(m,2H),0.96(t,J=7.6Hz,3H)ppm. MS:M / e329(M+1) + .

[0650] Compound A56: (4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(3-methoxypyridin-2-yl)methanol

[0651] To a mixture of tert-butyl (2-butoxy-7-(hydroxy (3-methoxypyridin-2-yl) methyl) imidazo [2, 1-f] [1, 2, 4] triazine -4- base) (tert-butoxycarbonyl) carbamate (35 mg, crude) in DCM (3 mL) was added TFA (1 mL) and EtSiH (1 mL). The reaction was heated at 40 ° C overnight. The mixture was concentrated to dryness and the residue was purified by preparative HPLC to give the title product (20 mg, 68%). 1 HNMR (400MHz, DMSO-d6) δ8.25(d,J=4.0Hz,1H),8.20(s,1H),8.14(s,1H),7.81(d,J=6.0Hz,1H),7.66(d,J=3.2Hz,1H),7.43(s,1H ),6.43(s,1H),4.10-3.98(m,1H),3.96-3.86(m,1H),3.82(s,3H),1.66-1.52(m,2H),1.45-1.26(m,2H),0.91(t,J=7.6Hz,3H)ppm. MS:M / e 345(M+1) + .

[0652] Compound A57: Methyl 5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-2-(3-(dimethylamino)propoxy)benzoate

[0653] Step A: Methyl 2-(3-(dimethylamino)propoxy)-5-formylbenzoate

[0654] A mixture of methyl 5-formyl-2-hydroxybenzoate (500 mg, 2.7 mmol), 3-chloro-N, N-dimethylpropan-1-amine hydrochloride (512 mg, 3.2 mmol) and CsCO (1.7 g, 5.4 mmol) in DMF (20 mL) was heated at 80° C. overnight. The solution was eluted with water (20 mL), extracted with ethyl acetate (20 mL), and washed with brine (10 mL). The organic layer was dried, concentrated, and purified by CombiFlash (DCM:MeOH=10%, with 10% NH.MeOH) to give the product (400 mg, 54%). 1H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 8.20 (s, 1H), 8.06 (dd, J = 8.0, 4.0Hz, 1H), 7.35 (d, J = 12.0Hz, 1H), 4.20 (t, J = 8.0Hz, 2H), 3.84 (s, 3H), 2.42 (t, J = 8.0Hz, 2H), 2.16 (s, 6H), 1.91-1.85 (m, 2H)ppm. MS:M / e 266(M+1) + .

[0655] Step B: Methyl 5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazol-2-yl)-1-nitropropene (2-(3-(dimethylamino)propyloxy)benzoate)

[0656] At -78°C (with N 2 Under 40 ℃ of purging, to 7- bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150mg, 0.29mmol) in THF (8mL) cooling solution, n-butyllithium (1.6M, 0.5mL) was added dropwise. After stirring at -78 ℃ for 30min, methyl 2-(3-(dimethylamino)propoxy)-5-formylbenzoate (115mg, 0.44mmol) in THF (2mL) was added. The resulting mixture was stirred at this temperature for 30min, and then heated to rt for 2hr. The solution was quenched with NH4Cl solution (5mL), extracted with ethyl acetate (10mL) and washed with brine (10mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude product, which was further purified by preparative TLC (DCM:MeOH=7:1) to give the product (54 mg, 27%). MS: M / e 713 (M+1) +

[0657] Step C: Methyl 5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-2- (3-(Dimethylamino)propyloxy)benzoate (Compound A57)

[0658] A solution of methyl 5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-(3-(dimethylamino)propoxy)benzoate (54 mg, 0.08 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (2 mL) was heated at 80° C. overnight. The solvent was evaporated to give a residue, which was purified by preparative HPLC to give the product (23 mg, 67%). 1H NMR(400MHz,DMSO-d6)δ9.50(br.s,1H),8.14(s,1H),8.06(s,1H),7.73(s,1H) ,7.50(d,J=8.0Hz,1H),7.33(s,1H),7.10(d,J=8.0Hz,1H),4.20(t,J=8.0Hz,2H ),4.12-4.09(m,4H),3.80(s,3H),3.27-3.23(m,2H),2.82(d,J=4.0Hz,6H),2.1 4-2.10(m,2H),1.70-1.65(m,2H),1.43-1.38(m,2H),0.92(t,J=8.0Hz,3H)ppm. MS:M / e 457(M+1) + .

[0659] Compound A58: 2-Butoxy-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0660] Step A: tert-Butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate

[0661] K2CO3 (5.52 g, 40 mmol) was added to a solution of 6-chloronicotinaldehyde (2.82 g, 20 mmol) and tert-butyl (2-hydroxyethyl) (methyl) carbamate (4.2 g, 24 mmol) in DMA (40 mL). The reaction mixture was heated at 80°C overnight and cooled to room temperature. The solution was quenched with H2O (40 ml). The aqueous solution was extracted with EA (40 ml x 3). The collected organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography to give the product (560 mg, 10%). MS: M / e 281 (M+1) +

[0662] Step B: tert-butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f] [1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate

[0663] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (158 mg, 0.3 mmol) in THF (1 mL) was added dropwise a solution of n-butyllithium (0.28 mL, 0.45 mmol), maintaining the temperature between -75°C and -65°C. After 10 min, a solution of the product of step A (126 mg, 0.45 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 30 min. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (10 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the target compound (200 mg, 91%). MS: M / e728 (M+1) + .

[0664] Step C: 2-Butoxy-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f] [1,2,4]triazine-4-amine (Compound A58)

[0665] To the mixture of the product of step B (180 mg, 0.25 mmol) in TFA (1 mL), Et3SiH (1 mL) was added. The reaction was heated at 80 ° C overnight. The mixture was concentrated to dryness, and the residue was treated with TFA (1 mL). The reaction was heated at 80 ° C overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The collected fractions were alkalized with NaHCO3 solution, extracted with DCM (30 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (20 mg, 22%). 1 H NMR (400MHz, CDCl3) δ8.11(s,1H)7.52(d,J=8.0Hz,1H),7.25(s,1H),6.70(d,J=8.0Hz,1H),4.40(t,J=6.0Hz,2H),4.28(t,J= 6.0Hz,2H),,4.11(s,2H),2.99(t,J=8.3Hz,2H),2.52(s,3H),1.82-1.71(m,4H),1.53-1.42(m,2H),0.98(t,J=6.2Hz,3H)ppm. MS:M / e 372(M+1) + .

[0666] Compound A59: N-(2-((5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)pyridin-2-yl)oxy)ethyl)-N-methylacetamide

[0667] Ac2O (4 mg, 0.04 mmol) was added to a solution of 2-butoxy-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-4-amine (11 mg, 0.03 mmol) and Et3N in DCM (0.5 mL), and the reaction mixture was stirred at 0 ° C for 2 hours. The mixture was concentrated and the residue was purified by preparative HPLC. The collected fractions were basified with NaHCO3 solution, extracted with DCM (30 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (10 mg, 80%). 1 H NMR (400MHz, CDCl3) δ8.11(s,1H)7.50(d,J=8.2Hz,1H),7.31(s,1H),6.69(d,J=8.2Hz,1H),4.45(t,J=6.4Hz,2H),4.33(t,J=8.0Hz,2H),4. 15(s,2H),3.74-3.68(m,2H),3.11(s,2H),2.99(s,2H),2.15-2.10(m,3H),1.78-1.69(m,2H),1.39-1.26(m,2H),0.98(t,J=6.0Hz,3H)ppm. MS:M / e 414(M+1) + .

[0668] Compound A60: 2-Butoxy-7-(4-((1-ethylpyrrolidin-3-yl)oxy)-2-fluorobenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0669] Step A: 2-Fluoro-4-(pyrrolidin-3-yloxy)benzaldehyde hydrochloride

[0670] A solution of tert-butyl 3-(3-fluoro-4-formylphenoxy)pyrrolidine-1-carboxylate (500 mg, 1.6 mmol) in HCl / dioxane (4 M, 3 mL) was stirred overnight at rt. The solution was concentrated to give the product as a white solid HCl salt (400 mg, 100%). MS: M / e 210 (M+1) + .

[0671] Step B: 4-((1-ethylpyrrolidin-3-yl)oxy)-2-fluorobenzaldehyde

[0672] Iodoethane (500 mg, 1.6 mmol) was added to a mixture of 2-fluoro-4-(pyrrolidin-3-yloxy)benzaldehyde hydrochloride (400 mg, 1.6 mmol) and KCO (442 mg, 3.2 mmol) in DMF (10 mL). The solution was stirred at rt overnight, eluted with water (10 mL), extracted with ethyl acetate (10 mL), and washed with brine (10 mL). The organic layer was dried over NaSO, filtered and concentrated to give the crude product, which was further purified by CombiFlash (PE:EA=1:1 to EA) to give the pure product (133 mg, 34%). MS: M / e 238 (M+1) + .

[0673] Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-(4-((1-ethylpyrrolidin-3-yl)oxy)-2-fluorophenyl)methanol

[0674] At -78 ° C (with N2 purging), to 7- bromo-2-butoxy-N, N- bis (4-methoxybenzyl) imidazo [2,1-f] [1,2,4] triazine -4- amine (100mg, 0.2mmol) in THF (8mL) in the cooling solution was added n-butyl lithium (1.6M, 0.3mL). After stirring at -78 ° C for 30min, 4- ((1-ethylpyrrolidin-3-yl) oxy) -2-fluorobenzaldehyde (68mg, 0.3mmol) in THF (2mL) was added. The resulting mixture was stirred at this temperature for 30min, and then heated to rt for 2hr. The solution was quenched with NH4Cl solution (5mL), extracted with ethyl acetate (10mL) and washed with brine (10mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude product, which was further purified by preparative TLC (DCM:MeOH=8:1) to give the product (78 mg, 60%). MS: M / e 685 (M+1) + .

[0675] Step D: 2-Butoxy-7-(4-((1-ethylpyrrolidin-3-yl)oxy)-2-fluorobenzyl)imidazo[2,1-f] [1,2,4]triazine-4-amine (Compound A60)

[0676] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-((1-ethylpyrrolidin-3-yl)oxy)-2-fluorophenyl)methanol (78 mg, 0.1 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (2 mL) was heated at 80° C. overnight. The solvent was evaporated to give a residue, which was purified by preparative TLC (DCM:MeOH=8:1) to give the product (18 mg, 38%). 1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),8.05(s,1H),7.24(s,1H),7.18(t,J=8.0Hz,1H),6 .75(dd,J=12.0Hz,J2=4.0Hz,1H),6.66(d,J=8.0Hz,1H),4.84(s,1H),4.19(t,J=8.0Hz, 2H),4.07(s,2H),2.79(s,1H),2.71-2.65(m,2H),2.44-2.30(m,3H),2.29-2.21(m,1H) ,1.75-1.63(m,3H),1.44-1.35(m,2H),1.02(t,J=8.0Hz,3H),0.92(t,J=8.0Hz,3H)ppm. MS:M / e 429(M+1) + .

[0677] Compound A61: 2-Butoxy-7-(2-fluoro-4-(pyrrolidin-3-yloxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0678] Step A: tert-Butyl 3-(3-fluoro-4-formylphenoxy)pyrrolidine-1-carboxylate

[0679] A solution of 2-fluoro-4-hydroxybenzaldehyde (1 g, 7.1 mmol), tert-butyl 3-bromopyrrolidine-1-carboxylate (2.7 g, 10.7 mmol) and CsCO (4.6 g, 14.2 mmol) in DMF (20 mL) was heated at 80 ° C overnight. The solution was filtered and water (10 mL) was added to the filtrate, extracted with ethyl acetate (20 mL), and washed with brine (10 mL). The organic layer was dried, concentrated and purified by CombiFlash (PE:EA=20%) to give the product (1.1 g, 50%) as a colorless oil. 1 HNMR (400MHz, CDCl3) δ10.21(s,1H),7.83(t,J=8.0Hz,1H),6.75(dd,J=8.0,4.0Hz,1H),6.62( dd,J=12.0,4.0Hz,1H),4.95(s,1H),3.67-3.50(m,4H),2.20(d,J=8.0Hz,2H),1.48(s,9H)ppm. MS:M / e 310(M+1) + .

[0680] Step B: tert-butyl 3-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1, 2,4]triazin-7-yl)(hydroxy)methyl)-3-fluorophenoxy)pyrrolidine-1-carboxylate

[0681] At -78°C (with N 2Under 40 ℃ of purging, to 7- bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150mg, 0.29mmol) in THF (8mL) cooling solution, n-butyllithium (1.6M, 0.5mL) was added dropwise. After stirring at -78 ℃ for 30min, tert-butyl 3-(3-fluoro-4-formylphenoxy)pyrrolidine-1-formate (132mg, 0.43mmol) in THF (2mL) was added. The resulting mixture was stirred at this temperature for 30min, and then heated to rt overnight. The solution was quenched with NH4Cl solution (5mL), extracted with ethyl acetate (10mL) and washed with brine (10mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by CombiFlash (PE:EA=1:1) to give the product (110 mg, 51%). MS: M / e 757 (M+1) + .

[0682] Step C: 2-Butoxy-7-(2-fluoro-4-(pyrrolidin-3-yloxy)benzyl)imidazo[2,1-f][1,2,4]triazol Oxazine-4-amine (Compound A61)

[0683] A solution of tert-butyl 3-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-fluorophenoxy)pyrrolidine-1-carboxylate (110 mg, 0.15 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (2 mL) was heated at 80° C. overnight. The solvent was evaporated to give a residue, which was purified by preparative HPLC to give the product (33 mg, 57%). 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),8.04(s,1H),7.23(s,1H),7.18(t,J=8.0Hz,1H),6.77-6.66(m,2H),4.81(s,1H),4.19(t,J=8.0Hz,2 H),4.06(s,2H),3.04-3.01(m,1H),2.82-2.71(m,3H),1.98-1.95(m,1H),1.72-1.63(m,3H),1.41-1.37(m,2H),0.92(t,J=8.0Hz,3H)ppm. MS:M / e 401(M+1) + .

[0684] Compound A62: 7-(4-((1H-1,2,4-triazol-1-yl)methyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0685] Step A: 4-((1H-1,2,4-triazol-1-yl)methyl)benzaldehyde

[0686] To a solution of 4-(bromomethyl)benzaldehyde (200 mg, 1 mmol) and K2CO3 (200 mg, 1.5 mmol) in acetone (5 mL) was added 1H-1,2,4-triazole (75 mg, 2.2 mmol). The mixture was then stirred at room temperature overnight. The mixture was diluted with water (50 mL), extracted with EtOAc (60 mL), washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by combi-flash to give the target compound (130 mg, 69%). MS: M / e 188 (M+1) + .

[0687] Step B: (4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)(4-(bis(4-methoxybenzyl)amino)-2- Butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methanol

[0688] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.38 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium (0.48 mL, 1.6 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a mixture of the product of step A (107 mg, 0.57 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (40 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (130 mg, crude). MS: M / e 635 (M+1) + .

[0689] Step C: 7-(4-((1H-1,2,4-triazol-1-yl)methyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine (Compound A62)

[0690] To a mixture of the product of step B (60 mg, crude) in TFA (3 mL) was added Et3SiH (0.5 mL). The resulting mixture was heated at 85 ° C overnight. The mixture was concentrated to dryness and the residue was purified by preparative HPLC. The collected fractions were basified with NaHCO3 solution, extracted with DCM (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the target compound (25 mg, 17% for two steps). 1HNMR(400MHz,DMSO-d6)δ8.62(s,1H),8.13(s,1H),8.03(s,1H),7.95(s,1H),7.34-7.27(m,3H),7.19(d,J=8.4Hz,2 H), 5.36 (s, 2H), 4.17 (t, J = 6.4Hz, 2H), 4.12 (s, 2H), 1.72-1.59 (m, 2H), 1.46-1.30 (m, 2H), 0.91 (t, J = 7.2Hz, 3H) ppm. MS:M / e379(M+1) + .

[0691] Compound A63: 2-Butoxy-7-(4-(3-(methylamino)propyloxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0692] Step A: tert-Butyl (3-(4-formylphenoxy)propyl)(methyl)carbamate

[0693] To a solution of 4-hydroxybenzaldehyde (0.61 g, 5 mmol), tert-butyl (3-hydroxypropyl) (methyl) carbamate (0.95 g, 5 mmol) and PPh 3 (1.96 g, 7.5 mmol) in THF (8 mL) was added dropwise 40% DIAD in a toluene solution (3.7 g, 7.5 mmol). The mixture was then stirred at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL x2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, concentrated, and the residue was purified by combiflash to give the target compound (0.71 g, 48%). MS: M / e 238 (M + Ht-Bu) + .

[0694] Step B: tert-butyl (3-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1, 2,4]triazin-7-yl)(hydroxy)methyl)phenoxy)propyl)(methyl)carbamate

[0695] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.38 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium (0.4 mL, 0.57 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a mixture of the product of step A (168 mg, 0.57 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 0.5 h and then warmed to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (EA / PE=1 / 2) to give the target compound (130 mg, crude). MS: M / e 741 (M+1) + .

[0696] Step C: 2-Butoxy-7-(4-(3-(methylamino)propyloxy)benzyl)imidazo[2,1-f][1,2,4]triazol Oxazine-4-amine (Compound A63)

[0697] To the mixture of the product of step B (130 mg, crude) in TFA (3 mL), Et3SiH (1 mL) was added. The reaction was heated at 85 ° C overnight. The mixture was cooled to room temperature and concentrated to dryness. The residue was purified by preparative HPLC. The collected fractions were alkalized with NaHCO3 solution, extracted with DCM (60 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to give the target compound (36 mg, 25% for two steps). 1 HNMR (400MHz, DMSO-d6) δ8.12(s,1H),8.02(s,1H),7.25(s,1H),7.20(d,J=8.4Hz,2H),6.83(d,J=8.4Hz,2H),4.20(t,J=6.4Hz,2H),4.05(s,2H ),3.96(t,J=6.4Hz,2H),2.63(t,J=7.2Hz,2H),2.30(s,3H),1.90-1.79 (m,2H),1.73-1.62(m,2H),1.46-1.34(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 385(M+1) + .

[0698] Compound A64:N 2 -(Furan-2-ylmethyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0699] Step A: 7-Bromo-N 2 -(Furan-2-ylmethyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0700] A solution of 7-bromo-2-chloroimidazo[2,1-f][1,2,4]triazine-4-amine (500 mg, 2 mmol), furan-2-ylmethylamine (388 mg, 4 mmol) and DIEA (516 mg, 4 mmol) in n-BuOH (10 mL) in a sealed tube was heated at 120 ° C overnight. After concentration under reduced pressure, the residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried, concentrated and purified by CombiFlash (PE:EA=50%) to give the product (180 mg, 29%). 1 H NMR (400MHz, DMSO-d6) δ7.86(br.s,2H),7.54(s,1H),7.44(s,1H),7.02(t,J=8. 0Hz, 1H), 6.37 (d, J = 4.0Hz, 1H), 6.30 (d, J = 4.0Hz, 1H), 4.38 (d, J = 4.0Hz, 2H) ppm. MS:M / e 309(M+1) +

[0701] Step B: tert-Butyl(7-bromo-2-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)imidazo[2,1-f] [1,2,4]triazin-4-yl)(tert-butoxycarbonyl)carbamate

[0702] 7-Bromo-N 2 A solution of -(furan-2-ylmethyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (150 mg, 0.5 mmol), (Boc)2O (327 mg, 1.5 mmol) and DMAP (31 mg, 0.25 mmol) in DCM (10 mL) was stirred overnight at rt. The solution was concentrated and purified by CombiFlash (PE:EA=20%) to give the pure product (270 mg, 91%). MS: M / e 609 (M+1) + .

[0703] Step C: tert-Butyl(tert-butoxycarbonyl)(2-((furan-2-ylmethyl)amino)-7-(hydroxy(4-(pyrrolidine- imidazo[2,1-f][1,2,4]triazin-4-yl)carbamate

[0704] At -78°C (with N 2To a cooled solution of tert-butyl (7-bromo-2-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)imidazo[2,1-f][1,2,4]triazine-4-yl)(tert-butoxycarbonyl)carbamate (150 mg, 0.25 mmol) in THF (8 mL) was added n-butyl lithium (1.6 M, 0.4 mL) under a 4- (pyrrolidin-1-ylmethyl) benzaldehyde (70 mg, 0.37 mmol) column (TFA) at -78 ° C. The mixture was stirred for 30 min at this temperature and then heated to rt overnight. The solution was quenched with NH4Cl solution (5 mL), extracted with ethyl acetate (10 mL) and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by CombiFlash (DCM:MeOH=7:1) to give the pure product (15 mg, 10%). MS: M / e 620 (M+1) + .

[0705] Step D:N 2 -(furan-2-ylmethyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1, 2,4]Triazine-2,4-diamine (Compound A64)

[0706] Triethylsilane (0.5 mL) and trifluoroacetic acid (0.5 mL) were added to a mixture of tert-butyl(tert-butoxycarbonyl)(2-((furan-2-ylmethyl)amino)-7-(hydroxy(4-(pyrrolidin-1-ylmethyl)phenyl)methyl)imidazo[2,1-f][1,2,4]triazin-4-yl)carbamate (15 mg, 0.02 mmol) in DCM (1 mL) and heated at 40° C. for 2 hr. The solvent was evaporated to give a residue, which was purified by preparative HPLC to give the product (3 mg, 31%). 1 H NMR (400MHz, CD3OD) δ7.47-7.41(m,6H),6.32(d,J=4.0Hz,1H),6.21(d,J=4.0Hz,1H),4.46(s,2H),4.3 3(s,2H),4.26(s,2H),3.19-3.44(m,2H),3.17-3.13(m,2H),2.22-2.15(m,2H),2.02-1.93(m,2H)ppm. MS:M / e 404(M+1) + .

[0707] Compound A65: 4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2-ol

[0708] Step A: 7-bromo-2-(furan-2-ylmethoxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2, 4]Triazine-4-amine

[0709] To a stirred solution of furan-2-ylmethanol (73 mg, 0.75 mmol) in THF (20 mL) was added NaH (80 mg, 2 mmol, 60% in oil) at 0 ° C. The reaction mixture was stirred at 0 ° C for 0.5 h. 7-Bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (243 mg, 0.5 mmol) was added to the mixture and the reaction mixture was stirred at 70 ° C for 6 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 ml X 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography to give the product as a white solid (150 mg, 57.4%). MS: M / e 550 (M + 1) + .

[0710] Step B: (4-(bis(4-methoxybenzyl)amino)-2-(furan-2-ylmethoxy)imidazo[2,1-f][1,2, 4]Triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0711] To a stirred solution of 7-bromo-2-(furan-2-ylmethoxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (120 mg, 0.22 mmol) in THF (10 mL) cooled to -78 ° C and under a nitrogen atmosphere was added n-butyl lithium (1.6 M in hexane, 0.55 mmol, 0.34 mL). After stirring for 50 min, a solution of 4-(pyrrolidin-1-ylmethyl)benzaldehyde (66 mg, 0.33 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly heated to rt and stirred for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo.

[0712] The crude product was purified by column chromatography to give the title product (30 mg, 20.6%). MS: M / e 661 (M+1) + .

[0713] Step C: 4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2-ol

[0714] A solution of (4-(bis(4-methoxybenzyl)amino)-2-(furan-2-ylmethoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol (30 mg, 0.045 mmol) in TFA (3 mL) and Et3SiH (3 mL) was stirred at 80 ° C for 2 h. The reaction mixture was concentrated in vacuo to remove TFA and Et3SiH. TFA (5 mL) was added to the residue and stirred at 85 ° C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (13 mg, 88%). 1 H NMR (400MHz, DMSO-d6)) δ9.83(s,1H),8.08(s,1H),7.95(s,1H),7.44(d,J=7.6Hz,2H),7.34(d,J=7.6Hz,2H) ,7.26(s,1H),4.32(s,2H),4.17(s,2H),3.34(s,2H),3.07(s,2H),1.96-1.91(m,2H),1.86-1.75(m,2H)ppm. MS:M / e 325(M+1) + .

[0715] Compound A66: 2-Butoxy-7-(4-(1-methylpyrrolidin-3-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0716] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-Methyl)(4-(1-methylpyrrolidin-3-yl)phenyl)methanol

[0717] To a stirred solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (105 mg, 0.2 mmol) in THF (10 mL) cooled to -78 ° C under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.5 mmol, 0.31 mL). After stirring for 50 min, a solution of 4-(1-methylpyrrolidin-3-yl)benzaldehyde (43 mg, 0.2 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the product (30 mg, 23.5%). MS: M / e 638 (M+1) + .

[0718] Step B: 2-Butoxy-7-(4-(1-methylpyrrolidin-3-yl)benzyl)imidazo[2,1-f][1,2,4]triazine- 4-Amine (Compound A66)

[0719] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(1-methylpyrrolidin-3-yl)phenyl)methanol (30 mg, 0.047 mmol) in TFA (3 mL) and Et3SiH (3 mL) was stirred at 80 ° C for 2 h. The reaction mixture was concentrated in vacuo to remove TFA and Et3SiH. TFA (5 mL) was added to the residue and stirred at 85 ° C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (5 mg, 28%). 1 H NMR (400MHz, DMSO-d6)) δ8.12(s,1H),8.03(s,1H),7.29(s,1H),7.25-7.19(m,4H),4.20(t,J=6.4Hz,2H),4.09(s,2H),3.11-2.95(m,1H ),2.82-2.75(m,2H),2.59-5.52(m,2H),2.44(s,3H),2.26-2.18(m,1H),1.79-1.61(m,3H),1.42-1.37(m,2H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e381(M+1) + .

[0720] Compound A67: N2-butyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0721] Step A: (4-(bis(4-methoxybenzyl)amino)-2-(butylamino)imidazo[2,1-f][1,2,4]triazine- 7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0722] At -78 ° C, to a stirred solution of 7-bromo-N2-butyl-N4,N4-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (150 mg, 0.285 mmol) in THF (10 mL) was added dropwise n-butyllithium (1.6 M, 0.35 mL, 0.428 mmol). After stirring under N2 for one hour, a solution of 4-(pyrrolidin-1-ylmethyl)benzaldehyde (87.4 mg, 0.428 mmol) in THF (2 mL) was added dropwise at -78 ° C. After addition, the reaction was stirred for 3 hours. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by preparative TLC (CH2Cl2:MeOH=10:1) to give the target compound (65 mg, 35.8%) as a white solid. MS: M / e636 (M+1) + .

[0723] Step B: N2-butyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-2, 4-Diamine

[0724] A mixture of the product of step A (65 mg, 0.102 mmol) in Et3SiH / TFA (0.5 mL / 3 mL) was stirred overnight at 85° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the title compound (26 mg, 67.1%). 1 H NMR(400MHz,DMSO-d6)δ9.72(br.s,1H),7.69(s,2H),7.46-7.37(m,4H),7. 36-7.28(m,1H),6.45(s,1H),4.30(d,J=5.6Hz,2H),4.14(s,2H),3.38-3.26 (m,2H),3.16(t,J=6.8Hz,2H),3.15-3.02(m,2H),2.05-1.96(m,2H),1.90-1 .76(m,2H),1.56-1.45(m,2H),1.39-1.26(m,2H),0.89(t,J=7.2Hz,3H)ppm. MS:M / e 380(M+1) + .

[0725] Compound A68: 2-(pyridin-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0726] Step A: 7-Bromo-N,N-bis(4-methoxybenzyl)-2-(pyridin-3-ylmethoxy)imidazo[2,1-f][1,2, 4]Triazine-4-amine

[0727] To a suspension of NaH (80 mg, 2 mmol) in THF (8 mL) was added pyridin-3-ylmethanol (218 mg, 2 mmol). After stirring at room temperature for 30 min, a solution of 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (240 mg, 0.5 mmol) in THF (2 mL) was added. The mixture was then stirred at 80 ° C for 4 h. The mixture was cooled to room temperature, diluted with water (30 mL), extracted with EtOAc (50 mL x 2), washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by combi-flash to give the target compound (250 mg, 89%). 1H NMR (400MHz, CDCl3) δ8.84(s,1H),8.59(d,J=2.4Hz,1H),8.07(d,J=6.8Hz,1H),7.51-7.45(m,2H),7.17(d,J=8.4Hz,4H),6.85(d,J=8.0Hz 4H),5.60(s,2H),5.46(s,2H),4.83(s,2H),3.81(s,3H),3.80(s,3H)ppm. MS:M / e 561(M+1) + .

[0728] Step B: (4-(bis(4-methoxybenzyl)amino)-2-(pyridin-3-ylmethoxy)imidazo[2,1-f][1,2, 4]Triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0729] To a solution of the product of step A (250 mg, 0.44 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium (0.41 mL, 0.66 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a solution of 4-(pyrrolidin-1-ylmethyl)benzaldehyde (100 mg, 0.53 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature for 5 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (80 mg, crude). MS: M / e672 (M+1) + .

[0730] Step C: 2-(pyridin-3-ylmethoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1, 2,4]Triazine-4-amine (Compound A68)

[0731] To a mixture of the product of step B (80 mg, crude) in TFA (3 mL) was added Et3SiH (1 mL). The reaction was heated at 85 ° C overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The collected fractions were basified with NaHCO3 solution, extracted with DCM (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the target compound (8 mg, 5% for both steps). 1 HNMR(400MHz,CD3OD)δ8.66(s,1H),8.49(d,J=4.4Hz,1H),7.94(d,J=8.4Hz,1H),7.50-7.39(m,1H), 7.37-7.20(m,5H),5.39(s,2H),4.21(s,2H),3.67(s,2H),2.71-2.50(m,4H),1.91-1.75(m,4H)ppm. MS:M / e 416(M+1)+ .

[0732] Compound A69: 7-(4-(Pyrrolidin-1-ylmethyl)benzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0733] Step A: 7-Bromo-N,N-bis(4-methoxybenzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1, 2,4]triazine-4-amine

[0734] Sodium (0.4 g) was added to the stirred 4,4,4-trifluorobutane-1-ol (5 g) in several batches. The mixture was stirred at 80 ° C for 2 hours. The above clear solution was taken and 7-bromo-2-chloro-N, N-bis (4-methoxybenzyl) imidazo [2,1-f] [1,2,4] triazine-4-amine (0.3 g, 0.61 mmol) was added. The mixture was heated to 80 ° C and stirred for 1 hour. After completion, the mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml × 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography with 0-15% EA in PE to obtain the product (0.2 g, 56%) as a light yellow solid. MS: M / e 580 (M + 1) + .

[0735] Step B: (4-(bis(4-methoxybenzyl)amino)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1, 2,4]triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol

[0736] Under N2 atmosphere, at -78 ℃, to 7-bromo-N, N-bis(4-methoxybenzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1,2,4]triazine-4-amine (200mg, 0.34mmol) in THF (15ml) stirred solution, n-butyllithium (1.6M, 0.54ml, 0.86mmol) was added. The solution was stirred at -78 ℃ for 30min. 4-(pyrrolidin-1-ylmethyl)benzaldehyde (97mg, 0.51mmol) in THF (2ml) was added dropwise to the above solution. After addition, the solution was naturally warmed to rt and then stirred for 3hr. After completion, the reaction mixture was quenched with H2O (20ml) and then extracted with DCM (20ml × 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow oil, which was used directly in the next step without further purification. MS: M / e 691 (M+1) + .

[0737] Step C: 7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f] [1,2,4]triazine-4-amine (Compound A69)

[0738] A solution of (4-(bis(4-methoxybenzyl)amino)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) was stirred at 80 ° C for 24 hr. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EA (30 ml) and washed with aqueous NaHCO (saturated, 25 ml) and brine (20 ml). The organic phase was dried over Na SO, filtered and concentrated. The resulting residue was purified by preparative TLC using DCM:MeOH (10: 1) to give the product (15.11 mg). 1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.11(s,1H),7.55-7.30(m,5H),4.47 -3.86(m,6H),3.30-2.70(m,4H),2.46-2.32(m,2H),2.03-1.71(m,6H)ppm. MS:M / e 435(M+1) + .

[0739] Compound A70: 7-(3-(aminomethyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0740] Step A: 3-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1f][1,2,4]triazine-7-yl)- (hydroxy)methyl)benzonitrile

[0741] Under N2 atmosphere, at -78 ℃, to a stirred solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150mg, 0.29mmol) in THF (15ml) was added n-butyllithium (1.6M, 0.22ml, 0.35mmol). The solution was stirred at -78 ℃ for 30min. 3-formylbenzonitrile (37.4mg, 0.29mmol) in THF (2ml) was added dropwise to the above solution. After addition, the solution was naturally warmed to rt and then stirred for 3hr. After completion, the reaction mixture was quenched with H2O (20ml) and then extracted with DCM (20ml x 3). The organic phase was washed with H2O (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product (180 mg) as an off-white semi-solid, which was used directly in the next step without further purification. MS: M / e 579 (M+1) + .

[0742] Step B: (3-(aminomethyl)phenyl)(4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1- f][1,2,4]triazin-7-yl)methanol

[0743] To a stirred solution of 3-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)benzonitrile (180 mg, 0.31 mmol) in THF (15 ml) was added LiAlH 4 (24 mg, 0.63 mmol). The mixture was stirred at 66° C. overnight. Upon completion, the reaction mixture was poured into ice water and then extracted with EA (15 ml×2). The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the crude product as a light yellow semisolid, which was used directly in the next step without further purification. MS: M / e 583 (M+1) + .

[0744] Step C: 7-(3-(aminomethyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine (compound Object A70)

[0745] A solution of (3-(aminomethyl)phenyl)(4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) was stirred at 80 ° C for 24 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EA (30 ml) and washed with aqueous NaHCO (saturated, 25 ml) and brine (20 ml). The organic phase was dried over Na SO, filtered and concentrated. The resulting residue was purified by preparative TLC using DCM:MeOH (10: 1) and then by preparative HPLC to give the product (5.04 mg). 1 H NMR (400MHz, DMSO-d6) δ8.25-7.98(m,4H),7.41-7.27(m,5H),4.20(t,J=8Hz,2H),4.16 (s,2H),4.02-3.94(m,2H),1.72-1.53(m,2H),1.47-1.28(m,2H),0.97-0.84(m,3H)ppm. MS:M / e327(M+1) + .

[0746] Compound A71: 3-(4-(4-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)benzyl)piperazin-1-yl)propan-1-ol

[0747] Step A: Ethyl tert-butyl 4-(4-formylbenzyl)piperazine-1-carboxylate

[0748] A mixture of 4-(chloromethyl)benzaldehyde (1.8 g, 11.6 mmol), tert-butylpiperazine-1-carboxylate (2.6 g, 13.9 mmol) and K2CO3 (3.2 g, 23.2 mmol) in CH3CN (50 mL) was stirred at 50 ° C overnight. The reaction was cooled to room temperature. The mixture was diluted with water (100 mL) and extracted with EA (80 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by combiflash to obtain the title compound (2 g, yield: 56.7%) as a yellow oil. MS: M / e 305 (M+1) + .

[0749] Step B: 4-(Piperazin-1-ylmethyl)benzaldehyde hydrochloride

[0750] The product of step A (2 g, 6.6 mmol) was dissolved in HCl / EA (4 M, 20 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The yellow solid residue (2HCl salt) was used directly in the next step. MS: M / e 205 (M+1) + .

[0751] Step C: 4-((4-(3-((tert-Butyldimethylsilyl)oxy)propyl)piperazin-1-yl)methyl)benzaldehyde

[0752] A mixture of the product of step B (508 mg, 1.84 mmol), tert-butyl (3-chloropropoxy) dimethylsilane (574 mg, 2.76 mmol), K2CO3 (1.02 g, 7.36 mmol) and KI (61 mg, 0.37 mmol) in DMF (10 mL) was stirred at 100 ° C for 12 hours. The reaction was cooled to room temperature. The mixture was quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by combiflash to obtain the title compound (440 mg, yield: 63.6%) as a yellow oil. MS: M / e 377 (M+1) + .

[0753] Step D: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-((4-(3-((tert-Butyldimethylsilyl)oxy)propyl)piperazin-1-yl)methyl)phenyl)methanol

[0754] Under N2 atmosphere, at -78 ℃, to 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (140mg, 0.27mmol) in THF (2mL) stirring solution, n-butyllithium (1.6M, 0.21mL) was added dropwise. The mixture was stirred at -78 ℃ for 1 hour. Then at -78 ℃, the product of step C (150mg, 0.40mmol) in THF (0.3mL) was added to the system. The reaction was stirred at -78 ℃ for 0.5 hour. The reaction was warmed to room temperature and stirred overnight. At room temperature, the reaction was quenched with saturated aqueous NH4Cl. The mixture was extracted with EA (10mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by combiflash to give the title compound as a yellow oil (160 mg, yield: 72.1%). MS: M / e 824 (M+1) + .

[0755] Step E: 3-(4-(4-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)benzyl 1-[4-[(1-[(2 ...piperazin-1-yl)piperazin-1-yl)propan-1-ol

[0756] The product of step D (80 mg, 0.10 mmol) was dissolved in Et3SiH (0.5 mL) and CF3COOH (0.1 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in CF3COOH (0.5 mL) at room temperature. The mixture was stirred at 80 ° C for 3 hours. The reaction was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (6.5 mg, yield: 14.4%). 1 H NMR (400MHz, DMSO-d6) δ8.25-7.95(m,2H),7.36-7.13(m,5H),4.31-4.17(m,2H),4.12(s,2H),3.51-3.41(m ,4H),2.50-2.28(m,8H),1.73-1.54(m,4H),1.46-1.34(m,2H),1.29-1.06(m,2H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 454(M+1) + .

[0757] Compound A72: 2-Butoxy-7-((5-methyl-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0758] Step A: tert-Butyl 4-((5-bromo-3-methylpyridin-2-yl)oxy)piperidine-1-carboxylate

[0759] To a solution of NaH (0.3 g, 7.5 mmol) in DMA (15 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (1.1 g, 5.5 mmol). The mixture was stirred at room temperature for 1 h. A solution of 5-bromo-2-chloro-3-methylpyridine (1.1 g, 5 mmol) in DMA (5 mL) was then added, and the resulting mixture was stirred at 80 ° C overnight under N2 protection. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by combi-flash to give the target compound (1.3 g, 70%). MS: M / e 371 (M + H) + .

[0760] Step B: tert-Butyl 4-((5-formyl-3-methylpyridin-2-yl)oxy)piperidine-1-carboxylate

[0761] To a stirred solution of the product of step A (1.1 g, 3 mmol) in THF (15 mL) was added a solution of n-butyllithium (2.81 mL, 4.5 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 1 h, a solution of DMF (266 mg, 3.6 mmol) in THF (1 mL) was added dropwise and the resulting mixture was stirred at -70°C for 2 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by combi-flash to give the target compound (900 mg, 93%). MS: M / e 321 (M+H) + .

[0762] Step C: tert-butyl 4-((5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1, 2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)oxy)piperidine-1-carboxylate

[0763] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.38 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium (0.6 mL, 0.95 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a mixture of the product of step B (150 mg, 0.456 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then warmed to room temperature for 5 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by combi-flash to give the target compound (180 mg, crude). MS: M / e 768 (M+1) + .

[0764] Step D: 2-Butoxy-7-((5-methyl-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo[2,1- f][1,2,4]triazine-4-amine (Compound A72)

[0765] To a mixture of the product of step C (180 mg, crude) in TFA (12 mL), Et3SiH (4 mL) was added and the resulting mixture was stirred at 85 ° C overnight. The mixture was cooled to room temperature and concentrated to dryness. TFA (8 mL) was added to the residue and the resulting mixture was stirred at 85 ° C overnight. The mixture was cooled to room temperature and concentrated to dryness. The residue was purified by preparative HPLC to give the target compound (120 mg, 60% for two steps). 1 HNMR(400MHz,DMSO-d6)δ8.71-8.35(m,2H),8.17(s,2H),7.94(d,J=1.6Hz, 1H),7.51(s,1H),7.45-7.30(m,1H),5.31-5.16(m,1H),4.21(t,J=6.4Hz,2 H),4.06(s,2H),3.35-3.05(m,4H),2.11(s,3H),2.11-2.01(m,2H),1.95-1 .80(m,2H),1.74-1.60(m,2H),1.44-1.32(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 412(M+1) + .

[0766] Compound A73: (4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-methoxypyridin-2-yl)methanol

[0767] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-Methyl)(4-methoxypyridin-2-yl)methanol

[0768] To a stirred solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.286 mmol) in THF (10 mL) was added n-butyllithium (1.6 M, 0.45 mL, 0.715 mmol) dropwise at -78 ° C. After stirring under N2 for one hour, a solution of 4-methoxypicolinaldehyde (58.6 mg, 0.48 mmol) in THF (2 mL) was added dropwise at -78 ° C. and the reaction was stirred for 4 hours. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by preparative TLC (petroleum ether / EtOAc=2:1) ​​to give the target compound (42 mg, 25%) as a colorless oil. MS:M / e 585(M+1) + .

[0769] Step B: (4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-methoxypyridine-2- methyl)methanol (Compound A73)

[0770] A mixture of the product of step A (42 mg, 0.072 mmol) in TFA / Et3SiH (3 mL / 0.5 mL) was stirred overnight at 85° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the title compound (5 mg, 20%). 1 H NMR (400MHz, DMSO-d6) δ8.25(d,J=5.6Hz,1H),8.16(s,1H),8.06(s,1H),7.26(d,J=2.4Hz,1H),7.21(s,1H),6.88-6.86(m,1H),6.14(d ,J=5.6Hz,1H),6.02(d,J=5.6Hz,1H),4.18-4.04(m,2H),3.85(s,3H),1.71-1.53(m,2H),1.43-1.31(m,2H),0.91(t,J=7.2Hz,3H)ppm. MS:M / e 345(M+1) + .

[0771] Compound A74: (4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(pyridin-2-yl)methanol

[0772] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 2-Methyl)(pyridin-2-yl)methanol

[0773] To a stirred solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (300 mg, 0.572 mmol) in THF (15 mL) was added n-butyl lithium (1.6 M, 0.9 mL, 1.43 mmol) dropwise at -78 ° C. After stirring under N2 for one hour, a solution of picolinaldehyde (92 mg, 0.856 mmol) in THF (2 mL) was added dropwise at -78 ° C. and the reaction was stirred for 3 hours. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (petroleum ether / EtOAc=3:1) to give the target compound (240 mg, 75.7%) as a colorless syrup. MS: M / e 585 (M+1) + .

[0774] Step B: (4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(pyridin-2-yl)methanol (Compound A74)

[0775] A mixture of the product of step A (100 mg, 0.18 mmol) in TFA / Et3SiH (3 mL / 0.5 mL) was stirred overnight at 85° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the title compound (6 mg, 10.6%). 1 H NMR (400MHz, DMSO-d6)8.45(d,J=4.4Hz,1H),8.17-8.09(m,2H),7.84(t,J=7.6Hz,1H),7.68(d,J=7.6Hz,1H),7.31-7.25(m,1H),7.22( s,1H),6.17(d,J=5.6Hz,1H),6.06(d,J=5.6Hz,1H),4.16-4.02(m,2H),1.69-1.52(m,2H),1.47-1.29(m,2H),0.91(t,J=7.4Hz,3H)ppm. MS:M / e 315(M+1) + .

[0776] Compound A75: 2-Butoxy-7-(1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0777] Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(Pyrrolidin-1-ylmethyl)phenyl)methanol

[0778] At -78°C (with N 2To a cooled solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.38 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.6 mL) under 4% purging. After stirring at -78 ° C for 30 min, 4-(pyrrolidin-1-ylmethyl)benzaldehyde (100 mg, 0.57 mmol) in THF (2 mL) was added. The resulting mixture was stirred at this temperature for 30 min and then warmed to rt for 2 hr. The reaction was quenched with NH4Cl solution (2 mL), extracted with ethyl acetate (10 mL) and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by Combi-Flash (DCM:MeOH=6%) to give the pure product (170 mg, 70%). MS:M / e 637(M+1) + .

[0779] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 4-(Pyrrolidin-1-ylmethyl)phenyl)methanone

[0780] At 0 ° C, Dess-Martin reagent (229 mg, 0.54 mmol) was added in batches to a solution of the product of step A (170 mg, 0.27 mmol) in THF (3 mL). After stirring at rt for 4 hours, TLC showed that the reaction was complete. The solution was quenched with NH4Cl solution (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by CombiFlash (DCM:MeOH=5%) to give the product (130 mg, 76%). MS: M / e 635 (M+1) + .

[0781] Step C: 1-(4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazine-7-yl)- 1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethan-1-ol

[0782] Under N2 atmosphere, a solution of the product of step B (30 mg, 0.05 mmol) in THF (3 mL) was treated dropwise with CH3MgBr (3 M in ether, 0.2 mL) at 0°C. The reaction mixture was stirred at rt for 3 hr and then quenched with NH4Cl solution (5 mL). The solution was extracted with ethyl acetate (10 mL), washed with brine (10 mL), dried and concentrated to give the crude product, which was used directly in the next step without further purification. MS: M / e 651 (M+1) + .

[0783] Step D: 2-Butoxy-7-(1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethyl)imidazo[2,1-f][1,2, 4] Triazine-4-amine (Compound A75)

[0784] A solution of 1-(4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)-1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethan-1-ol (25 mg, 0.04 mmol) in triethylsilane (1 mL) and trifluoroacetic acid (1 mL) was heated at 80 ° C for 1 hr. The solution was concentrated, trifluoroacetic acid (1 mL) was added and heated at 80 ° C overnight. The solvent was evaporated to give a residue, which was basified with NaHCO 3 , extracted with ethyl acetate (5 mL) and washed with brine (5 mL). The organic layer was dried, concentrated and purified by preparative HPLC to give the product (6 mg, 40%). 1 H NMR (400MHz, DMSO-d6) δ9.74(br.s,1H),8.15(s,1H),8.06(s,1H),7.46-7.37(m,5H),4.48(q,J=8.0Hz,1H),4.29(s,2H),4.14-4.08(m,2 H),3.33(s,2H),3.07-3.04(m,2H),2.03-2.01(m,2H),1.85-1.82(m,2H),1.68-1.59(m,5H),1.42-1.32(m,2H),0.91(t,J=8.0Hz,3H)ppm. MS:M / e395(M+1) + .

[0785] Compound A76: 2-Butoxy-7-((1-(piperidin-3-ylmethyl)-1H-pyrazol-4-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0786] Step A: tert-Butyl 3-(bromomethyl)piperidine-1-carboxylate

[0787] Tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (2.15 g, 10 mmol) and CBr (4.98 g, 15 mmol) were dissolved in CH Cl (50 mL) at room temperature, and PPh (3.1 g, 12 mmol) was added. After addition, the reaction mixture was concentrated to give a residue, which was purified by column chromatography (petroleum ether / EtOAc=20:1) to give the target compound (2.3 g, 82.7%) as a colorless oil. MS: M / e 278 (M+1) + .

[0788] Step B: tert-Butyl 3-((4-formyl-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

[0789] At 0 ° C, to a stirred suspension of NaH (60%, 0.6 g, 5 mmol) in DMF (5 mL) was added a solution of 1H-pyrazole-4-carboxaldehyde (0.32 g, 3.3 mmol) in DMF (3 mL). After stirring for 30 min, a solution of the product of step A (1.1 g, 4 mmol) in DMF (3 mL) was added. The mixture was then stirred overnight. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether / EtOAc=10: 1~1: 1) to give the target compound (420 mg, 43.4%) as a colorless oil. MS: M / e294 (M+1) + .

[0790] Step C: tert-butyl 3-((4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1, 2,4]triazin-7-yl)(hydroxy)methyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

[0791] At -78 ° C, to a solution of 7-bromo-2-butoxy-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (150 mg, 0.286 mmol) in THF (10 mL) was added n-butyllithium (1.6 M, 0.44 mL, 0.71 mmol). After stirring for 1 hour, a solution of the product of step B (125 mg, 0.428 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 ° C for 1 h and then warmed to room temperature for 1 h. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=2:1) ​​to give the target compound (70 mg, 33%) as an off-white solid. MS:M / e 741(M+1) + .

[0792] Step D: 2-Butoxy-7-((1-(piperidin-3-ylmethyl)-1H-pyrazol-4-yl)methyl)imidazo[2,1-f] [1,2,4]triazine-4-amine (Compound A76)

[0793] A mixture of the product of step C (70 mg, 0.095 mmol) in Et3SiH / TFA (0.5 mL / 3 mL) was stirred overnight at 85° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the title compound (24 mg, 63.4%). 1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),8.02(s,1H),7.55(s,1H),7.34(s,1H),7.21(s,1H),4 .22(t,J=6.4Hz,2H),3.93(s,2H),3.88(d,J=7.2Hz,2H),2.80-2.76(m,1H),2.70-2.66(m,1 H),2.44-2.34(m,1H),2.23-2.13(m,1H),1.92-1.83(m,1H),1.75-1.63(m,2H),1.56-1.46 (m,2H),1.48-1.36(m,2H),1.33-1.22(m,1H),1.06-0.96(m,1H),0.93(t,J=7.2Hz,3H)ppm. MS:M / e 385(M+1) + .

[0794] Compound A77: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0795] Step A: tert-Butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-yloxy)imidazolyl) [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate

[0796] To a stirred solution of N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (754 mg, 1.64 mmol) in dry THF (15 mL) was added n-butyllithium (2.05 mL, 3.28 mmol) dropwise at -78 ° C. After stirring for half an hour, a solution of tert-butyl(2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (550 mg, 1.96 mmol) in THF (5 mL) was added dropwise. After addition, the reaction was stirred for 2 hours. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (petroleum ether / EtOAc=2:1) ​​to give the target compound (256 mg, 21%) as a brown syrup. MS:M / e 742(M+1) + .

[0797] Step B: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazole 4-[2,1-f][1,2,4]triazine-3-amine (Compound A77)

[0798] A mixture of the product of step A (256 mg, 0.345 mmol) in TFA / Et3SiH (3 mL / 3 mL) was stirred overnight at 90° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the target compound (20 mg). 1 H NMR (400MHz, DMSO-d6) δ8.21–7.94(m,4H),7.65(dd,J=8.5,2.0Hz,1H),7.31(s,1H),6.78(d,J=8.4Hz,1H),5.03–4.89(m,1H),4.41(t,J=5.2 Hz,2H),4.09(s,2H),3.24–3.12(m,2H),2.55(s,3H),1.70–1.47(m,2H),1.43–1.29(m,2H),1.25(d,J=6.0Hz,3H),0.89(t,J=7.2Hz,3H)ppm. MS:M / e 386(M+1) + .

[0799] Compound A78: 7-((5-methyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0800] Step A: tert-Butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-yloxy)imidazolyl) [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)oxy)ethyl)(methyl)carbamic acid ester

[0801] To a stirred solution of N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (461 mg, 1 mmol) in dry THF (10 mL) at -78°C was added n-butyllithium (1.25 mL, 2 mmol) dropwise. After stirring for half an hour, a solution of tert-butyl(2-((5-formyl-3-methylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (353 mg, 1.2 mmol) in THF (2 mL) was added dropwise. After addition, the reaction was stirred overnight. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography (petroleum ether / EtOAc = 5:1 to 2:1) to afford the title compound (340 mg, 45%) as a brown syrup. MS:M / e 756(M+1) + .

[0802] Step B: 7-((5-methyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2-yloxy base)

[0803] Imidazo[2,1-f][1,2,4]triazine-4-amine (Compound A78)

[0804] A mixture of the product of step A (340 mg, 0.45 mmol) in TFA / Et3SiH (3 mL / 3 mL) was stirred overnight at 90° C. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the target compound (42 mg). 1 H NMR(400MHz,DMSO-d6)δ8.58(br.s,2H),8.16(s,1H),8.11(s,1H),7.95(d,J=1 .6Hz,1H),7.51(d,J=1.4Hz,1H),7.37(s,1H),5.03-4.94(m,1H),4.49–4.44(m, 2H),4.07(s,2H),3.38–3.29(m,2H),2.64(t,J=5.6Hz,3H),2.15(s,3H),1.71–1 .48(m,2H),1.45–1.30(m,2H),1.26(d,J=6.0Hz,3H),0.89(t,J=7.2Hz,3H)ppm. MS:M / e 400(M+1) + .

[0805] Compound A79: 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol

[0806] Step A: Hexane-1,3-diol

[0807] At 0 ° C, a solution of methyl 3-hydroxyhexanoate (1.46 g, 10 mmol) in THF (5 mL) was added dropwise to a stirred suspension of LAH (0.76 g, 20 mmol) in THF (10 mL). After addition, the reaction was stirred for 2 hours. The reaction was quenched with H2O (0.76 mL), aqueous NaOH (15%, 0.76 mL), followed by H2O (2.28 mL), and then filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether / EtOAc=2: 1 to 1: 1) to give the target compound (634 mg, 53.7%) as a colorless oil.

[0808] Step B: 1-((tert-Butyldimethylsilyl)oxy)hexan-3-ol

[0809] To a stirred solution of the product of step A (634 mg, 5.37 mmol) in CHCl (15 mL) was added imidazole (730 mg, 10.74 mmol) at 0°C, followed by a solution of TBS-Cl (730 mg, 4.83 mmol) in CHCl (3 mL) was added dropwise. After addition, the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated to give a residue, which was purified by column chromatography (petroleum ether / EtOAc=1:1) to give the target compound (1.1 g, 88.2%) as a colorless oil.

[0810] Step C: 7-Bromo-2-((1-((tert-butyldimethylsilyl)oxy)hexan-3-yl)oxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0811] To a stirred solution of the product of step B (464 mg, 2 mmol) in THF (10 mL) was added NaH (60%, 80 mg). After stirring for 30 min, 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (488 mg, 1 mmol) was added. After addition, the reaction was stirred at 60 ° C. overnight. The reaction mixture was treated with H2O (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether / EtOAc=10:1) to give the target compound (530 mg, 77.5%) as a colorless oil. MS: M / e684 (M+1) + .

[0812] Step D: tert-butyl (2-((5-((4-(bis(3,4-dimethoxybenzyl)amino)-2-((1-((tert-butyldimethoxy) (1,2,4]triazin-7-yl)(hydroxy)methyl)pyridine- 2-amino)ethyl)oxy)ethyl)(methyl)carbamate

[0813] To a solution of 7-bromo-2-((1-((tert-butyldimethylsilyl)oxy)hexane-3-yl)oxy)-N,N-bis(2,4-dimethoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (700 mg, 0.939 mmol) in THF (10 mL) was added n-butyllithium (1.8 mL, 2.88 mmol) at -78 ° C under N2. After stirring at -78 ° C for 0.5 h, tert-butyl(2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (400 mg, 1.429 mmol) was added. The reaction mixture was stirred at -78 ° C for 2.5 h. Upon completion, the reaction mixture was quenched with aqueous NH4Cl (30 mL) and extracted with DCM (3x30 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (60%) to give the title compound (590 mg, 66%). MS: M / e 946 (M+1) + .

[0814] Step E: 3-((4-amino-7-(hydroxy(6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazolyl [2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol

[0815] Under N2, the product of step D (800mg, 0.846mmol) was dissolved in TFA (9mL) and H2O (1mL). The reaction mixture was stirred at 35°C for 12h. After completion, the solvent was removed in vacuo. The residue was diluted with water (20mL) and DCM (20mL) and the aqueous phase was acidified with 1N HCl to adjust pH=2 to 3. The aqueous phase was washed with DCM (3x30mL) and basified with 2N NaOH to adjust pH=13~14 and extracted with DCM / i-PrOH (5 / 1, 3x100mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (320mg, crude). MS: M / e 432 (M+1) + .

[0816] Step F: 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1- f) [1,2,4]triazin-2-yl)oxy)hexane-1-ol (Compound A79)

[0817] Under N2, the product (320mg) of step E is dissolved in TFA (5mL) and Et3SiH (5mL) in.Reactant mixture is stirred at 90 ℃ for 12h.After completion, solvent is removed in vacuo.Residue is diluted with water (20mL) and DCM (20mL) and aqueous phase is acidified with 1N HCl to regulate pH=2 to 3.Aqueous phase is washed with DCM (3x20mL) and alkalized with 2N NaOH to regulate pH=13~14 and extracted with DCM / i-PrOH (5 / 1,3x60mL).The organic layer merged is through Na2SO4 dry and concentrated under vacuum to obtain residue.Residue is purified by preparative HPLC to obtain title compound (15mg). 1 H NMR (400MHz, CD3OD) δ8.09(s,1H),7.62(d,J=8.4Hz,1H),7.33(s,1H),6.77(d,J=8.4Hz,1H),5.24-5.10(m,1H),4.37(s,2H),4.15(s, 2H),3.70-3.56(m,2H),2.99(s,2H),2.47(s,3H),1.98-1.79(m,2H),1.77-1.53(m,2H),1.50-1.33(m,2H),0.91(t,J=7.2Hz,3H)ppm. MS:M / e 416(M+1) + .

[0818] Compound A80: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-((tetrahydrofuran-3-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0819] Step A: tert-Butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-((tetrahydrofuran-3-yl)methoxy) yl)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)amino acid esters

[0820] To a solution of 7-bromo-N,N-bis(4-methoxybenzyl)-2-((tetrahydrofuran-3-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-amine (134 mg, 0.24 mmol) in THF (8 mL) was added dropwise a solution of n-butyllithium (1.6 M, 0.3 mL, 0.48 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a suspension of tert-butyl(2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (100 mg, 0.36 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70°C for 2 h and then allowed to warm to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (20 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (160 mg, 88%). MS: M / e 756.9 (M+1) + .

[0821] Step B: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-((tetrahydrofuran-3-yl)methane Oxy)imidazo[2,1-f][1,2,4]triazine-4-amine (Compound A80)

[0822] To a mixture of the product of step A (160 mg, 0.21 mmol) in TFA (4 mL) was added Et3SiH (4 mL) and the resulting mixture was stirred at 85°C for 4 hours. The mixture was cooled to room temperature and concentrated to dryness. TFA (5 mL) was added to the residue and the reaction was heated at 80°C overnight. The mixture was concentrated and the residue was purified by preparative HPLC to give the target compound (19 mg, 22.6%). 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.29 (s, 1H), 6.74 (d, J = 8.4 Hz, 1H), 4.27 (t, J = 5.5 Hz, 2H), 4.23–4.16 (m, 1H), 4.13–4.08 ( m,3H),3.77(t,J=7.6Hz,2H),3.68–3.61(m,1H),3.54–3.48(m,1H),2.86(d,J=5.3Hz,2 H), 2.64 (dd, J=13.6, 6.9Hz, 1H), 2.34 (s, 3H), 2.03–1.95 (m, 1H), 1.66–1.61 (m, 1H)ppm. MS:M / e 400(M+1) + .

[0823] Compound A81 and Compound A82: (R or S) 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, and (S or R) 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol

[0824] Compound A79 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol (70 mg, 0.168 mmol) was separated into two optical isomers, Compound A81 and Compound A82, by preparative SFC to give Compound A81 (18 mg) and Compound A82 (38 mg). The conditions for preparative SFC were as follows.

[0825]

[0826] Compound A81 (R or S optical isomer 1): 1 H NMR (400MHz, CD3OD) δ8.09(s,1H),7.62(d,J=8.4Hz,1H),7.33(s,1H),6.77(d,J=8.4Hz,1H),5.24-5.08(m,1H),4.37(t,J=5.2Hz,2H),4.15 (s,2H),3.65(d,J=4.8Hz,2H),2.99(s,2H),2.45(s,3H),1.95-1.82(m,2H),1.78-1.56(m,2H),1.49-1.32(m,2H),0.91(t,J=7.2Hz,3H)ppm. MS:M / e416(M+1) + .

[0827] Compound A82 (S or R optical isomer 2): 1H NMR (400MHz, CD3OD) δ8.09(s,1H),7.62(d,J=8.4Hz,1H),7.33(s,1H),6.77(d,J=8.4Hz,1H),5.22-5.13(m,1H),4.36(t,J=5.2Hz,2H),4.15 (s,2H),3.66(d,J=4.8Hz,2H),2.96(s,2H),2.45(s,3H),1.97-1.77(m,2H),1.77-1.54(m,2H),1.49-1.32(m,2H),0.91(t,J=7.2Hz,3H)ppm. MS:M / e416(M+1) + .

[0828] Compound A83: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0829] Step A: N,N-bis(4-methoxybenzyl)-2-(pentan-3-yloxy)imidazo[2,1-f][1,2,4]triazine- 4-Amine

[0830] To a solution of pentane-3-ol (88 mg, 1 mmol) in THF (10 mL) was added NaH (60%, 80 mg, 2 mmol) at 0 degrees. The reaction mixture was stirred at room temperature for 20 min. 2-Chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (204 mg, 0.5 mmol) was added to the mixture. The reaction mixture was stirred at 70 degrees overnight. An aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (220 mg, 95.6%). MS: m / e: 462 (M+1) + .

[0831] Step B: tert-Butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-(pentan-3-yloxy)imidazolyl) [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate

[0832] To a solution of N,N-bis(4-methoxybenzyl)-2-(pentan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (220 mg, 0.48 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.44 mL, 0.72 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 1 h, a suspension of tert-butyl(2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (200 mg, 0.72 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70°C for 2 h and then allowed to warm to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (20 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (120 mg, 47%). MS: M / e 742 (M+1) + .

[0833] Step C: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-3-yloxy)imidazole 4-[2,1-f][1,2,4]triazine-3-amine (Compound A83)

[0834] To a mixture of the product of step B (120 mg, 0.161 mmol) in TFA (4 mL) was added EtSiH (4 mL) and the resulting mixture was stirred at 85 ° C for 4 hours. The mixture was cooled to room temperature and concentrated to dryness. TFA (5 mL) was added to the residue and the reaction was heated at 80 ° C overnight. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give the target compound (25 mg, 38.6%). 1H NMR (400MHz, DMSO-d6) δ8.11(s,2H),8.00(s,1H),7.60(d,J=8.5Hz,1H),7.30(s,1H),6.74(d,J=8.4Hz,1H),4.82–4.74(m ,1H),4.28(t,J=5.5Hz,2H),4.07(s,2H),2.89(t,J=5.4Hz,2H),2.37(s,3H),1.64–1.58(m,4H),0.87(t,J=7.3Hz,6H)ppm. MS:M / e386(M+1) + .

[0835] Compound A84: 2-(hexan-3-yloxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0836] Step A: 2-(Hexane-3-yloxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine- 4-Amine

[0837] At 0 degrees, NaH (60%, 80 mg, 2 mmol) was added to a solution of hexane-3-ol (102 mg, 1 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 20 min. 2-Chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (204 mg, 0.5 mmol) was added to the mixture. The reaction mixture was stirred at 70 degrees overnight. Aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (260 mg, 100%). MS: m / e: 476 (M+1) + .

[0838] Step B: tert-Butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-(hexane-3-yloxy)imidazolyl) [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate

[0839] To a solution of 2-(hexan-3-yloxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (260 mg, 0.5 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.44 mL, 0.72 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 1 h, a suspension of tert-butyl(2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (200 mg, 0.72 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70°C for 2 h and then allowed to warm to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (20 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (130 mg, 34.4%). MS: M / e 756 (M+1) + .

[0840] Step C: 2-(Hexan-3-yloxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazole 4-[2,1-f][1,2,4]triazine-3-amine (Compound A84)

[0841] To a mixture of the product of step B (130 mg, 0.172 mmol) in TFA (4 mL) was added EtSiH (4 mL) and the resulting mixture was stirred at 85 ° C for 4 hours. The mixture was cooled to room temperature and concentrated to dryness. TFA (5 mL) was added to the residue and the reaction was heated at 80 ° C overnight. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give the target compound (12 mg, 16.9%). 1H NMR (400MHz, DMSO-d6) δ8.11(s,2H),8.00(s,1H),7.60(d,J=8.4Hz,1H),7.31(s,1H),6.74(d,J=8.6Hz,1H),4.89–4.83(m,1H) ,4.30(t,J=5.5Hz,2H),4.07(s,2H),2.94(s,2H),2.39(s,3H),1.61–1.54(m,4H),1.38–1.26(m,2H),0.87(t,J=6.9Hz,6H)ppm. MS:M / e 400(M+1) + .

[0842] Compound A85: 3-((4-amino-7-(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol.

[0843] Step A: 2-((tert-Butoxycarbonyl)(methyl)amino)ethyl methanesulfonate.

[0844] At 0 ° C, DIEA (7.8 g, 60 mmol) and MsCl (3.4 g, 30 mmol) were added dropwise to a solution of tert-butyl (2-hydroxyethyl) (methyl) carbamate (3.5 g, 20 mmol) in THF (40 mL). The resulting mixture was stirred for 2 hours at rt. The suspension was filtered, and the filtrate was diluted with EA (100 mL), washed with brine (100 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=3:1) to obtain the title compound (3.1 g, crude). MS: M / e 254 (M+1) + .

[0845] Step B: tert-Butyl (2-(4-formylphenoxy)ethyl)(methyl)carbamate.

[0846] A mixture of 2-((tert-butoxycarbonyl)(methyl)amino)ethyl methanesulfonate (1.5 g, crude), 4-hydroxybenzaldehyde (800 mg, 6.5 mmol) and K2CO3 (2.5 g, 18.1 mmol) in DMF (10 mL) was stirred at 60°C for 16 hr. The mixture was diluted with EA (50 mL) and filtered. The filtrate was washed with brine (20 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=4:1) to obtain the title compound (105 mg, yield: 4% for 2 steps). MS: M / e 280 (M+1) + .

[0847] Step C: tert-Butyl (2-(4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4-dimethoxy) (4-(2-(4-(2-methyl-1-thiazolyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)phenoxy)ethyl)(methyl)amino acid esters.

[0848] Under N2 atmosphere, at -78 ℃, to 2-((1-(benzyloxy)hexane-3-yl)oxy)-N, N-bis(2,4-dimethoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (156mg, 0.24mmol) in THF (2mL) was added n-butyllithium (1.6M, 0.3mL, 0.48mmol). The mixture was stirred at -78 ℃ for 20min. Then at -78 ℃, a solution of tert-butyl(2-(4-formylphenoxy)ethyl)(methyl)carbamate (102mg, 0.36mmol) in THF (2mL) was added to the system. The reaction was stirred for 30min, and then warmed to room temperature and stirred for 2hr. At room temperature, the reaction was quenched with saturated NH4Cl (20mL) and extracted with EA (10mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (80 mg, yield: 36%). MS: M / e 921 (M+1) + .

[0849] Step D: tert-Butyl (2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3-yl) [1,2,4]triazin-7-yl](methyl)-1,4-dimethyl-2-thiazolyloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)phenoxy)ethyl)(methyl)carbamate.

[0850] A mixture of tert-butyl (2-(4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4-dimethoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)phenoxy)ethyl)(methyl)carbamate (60 mg, 0.065 mmol) and Pd / C (wet, 60 mg) in MeOH (2 mL) was stirred under H at rt for 2 days. The mixture was filtered and the filtrate was concentrated to afford the title product (50 mg, yield: 94%). MS: M / e 815 (M+1) + .

[0851] Step E: 3-((4-amino-7-(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazol

[0147] The compound prepared was methyl-1-oxazin-2-yl)oxy)hexan-1-ol (Compound A85).

[0852] Tert-butyl (2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexane-3-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)phenoxy)ethyl)(methyl)carbamate (50 mg, 0.06 mmol) in TFA / H2O (9:1, 5 mL) was stirred at rt for 16 hr. The reaction was concentrated under reduced pressure. 2 mL of H2O was added. The mixture was stirred at RT for 20 min and then filtered. The filtrate was extracted with DCM (20 mL x 2) to remove impurities. The aqueous layer was basified with aqueous NaOH (4 M) to pH>10 and extracted with DCM / IPA (5:1, 3 mL x 5). The combined extracts were washed with brine (5 mL x 3), dried over Na 2 SO 4 , concentrated and purified by preparative TLC (DCM / MeOH(NH 3 )=10:1) to obtain the title compound (5 mg, yield: 12%). 1 H NMR (400MHz, CD3OD) δ7.32–7.23(m,3H),6.94(d,J=8.8Hz,2H),5.26–5.11(m,1H),4.26–4.19(m,2H),4.18–4.11(m,2H),3.75–3 .54(m,2H),3.46–3.37(m,2H),2.77(s,3H),1.95–1.82(m,2H),1.77–1.61(m,2H),1.49–1.37(m,2H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 415(M+1) + .

[0853] Compound A86: 3-((4-amino-7-((6-(3-(methylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol.

[0854] Step A: tert-Butyl (3-((5-formylpyridin-2-yl)oxy)propyl)(methyl)carbamate.

[0855] A mixture of 6-chloronicotinaldehyde (400 mg, 2.84 mmol), tert-butyl (3-hydroxypropyl) (methyl) carbamate (600 mg, 3.17 mmol), Pd2(dba)3 (180 mg, 0.20 mmol), RuPhos (187 mmol, 0.40 mmol) and Cs2CO3 (2.3 g, 7.0 mmol) in dioxane (5 mL) was stirred at 100 ° C for 4 hr. The mixture was treated with 20 mL of EA and 20 mL of H2O. The mixture was filtered through a celite pad. The aqueous layer was extracted with EA (20 mL x 2). The combined organics were washed with brine (30 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=2:1) ​​to obtain the title compound (490 mg, yield: 59%). MS: M / e 295 (M+1) + .

[0856] Step B: tert-Butyl (3-((5-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4-dimethoxy) 1-[4-(2-[4-(2-(4-phenyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)propyl)(methyl yl) carbamate.

[0857] Under N2 atmosphere, at -78 ℃, to 2-((1-(benzyloxy)hexane-3-yl)oxy)-N,N-bis(2,4-dimethoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (642mg, 1.0mmol) in THF (5mL) was added n-butyllithium (1.6M, 1.5mL, 2.4mmol). The mixture was stirred at -78 ℃ for 20min. Then at -78 ℃, a solution of tert-butyl(3-((5-formylpyridin-2-yl)oxy)propyl)(methyl)carbamate (480mg, 1.6mmol) in THF (3mL) was added to the system. The reaction was stirred for 30min, and then warmed to room temperature and stirred for 2hr. At room temperature, the reaction mixture was quenched with saturated NH4Cl (20mL) and extracted with EA (10mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (510 mg, yield: 54%). MS: M / e 936 (M+1) + .

[0858] Step C: tert-butyl (3-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexane-3- 1-yl)(hydroxy)methyl)pyridin-2-yl)oxy)propyl)(methyl)amino methyl formate.

[0859] A mixture of tert-butyl (3-((5-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4-dimethoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)propyl)(methyl)carbamate (120 mg, 0.128 mmol) and Pd / C (wet, 120 mg) in MeOH (4 mL) was stirred under H at rt for 5 days. The mixture was filtered and the filtrate was concentrated to give the title product (100 mg, crude), which was used directly in the next step. MS: M / e 846 (M+1) + .

[0860] Step D: 3-((4-amino-7-(hydroxy(6-(3-(methylamino)propoxy)pyridin-3-yl)methyl)imidazolyl [2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol.

[0861] Tert-butyl (3-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexane-3-yl)oxy)imidazo[2,1-f][1,2,4]triazine-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)propyl)(methyl)carbamate (100 mg, crude) in TFA / H2O (9:1, 5 mL) was stirred at rt for 16 hr. The reaction mixture was concentrated under reduced pressure. 2 mL of H2O was added. The mixture was stirred at RT for 30 min and then filtered. The filtrate was extracted with DCM (5 mL x 2) to remove impurities. The aqueous layer was basified to pH>10 by aqueous NaOH (4 M) and extracted with DCM / IPA (5:1, 10 mL x 3). The combined extracts were washed with brine (10 mL x 3), dried over Na2SO4, and concentrated to obtain the title compound (45 mg, crude). MS:M / e446(M+1) + .

[0862] Step E: 3-((4-amino-7-((6-(3-(methylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1- f) [1,2,4]triazin-2-yl)oxy)hexan-1-ol (Compound A86).

[0863] A mixture of 3-((4-amino-7-(hydroxy(6-(3-(methylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2-yl)oxy)hexane-1-ol (45 mg, crude), TFA (2.5 mL) and EtSiH (2.5 mL) was stirred at 70 ° C for 20 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in H2O (2 mL) and extracted with DCM (2 mL x 2). The organic phase was discarded. The inorganic phase was basified to pH>10 by aqueous NaOH (4 M). The mixture was extracted with DCM / iPrOH (5: 1, 3 mL x 3). The combined organic phases were washed with brine (5 mL x 2), dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (DCM / MeOH(NH 3 )=9:1) to obtain the title compound (3.2 mg, yield: 6% for 3 steps). 1 H NMR (400MHz, CD3OD) δ8.12 (s, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.36 (s, 1H), 6.78 (d,J=8.8Hz,1H),5.23–5.11(m,1H),4.37(t,J=5.6Hz,2H),4.16(s,2H),3. 69–3.60(m,2H),3.20–3.12(m,2H),2.71(s,3H),2.21–2.10(m,2H),1.95–1 .83(m,2H),1.76–1.62(m,2H),1.49–1.36(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 430(M+1) + .

[0864] Compound A87: 2-(heptane-4-yloxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0865] Step A: 2-(Heptan-4-yloxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine- 4-Amine

[0866] At 0 degrees, NaH (60%, 80 mg, 2 mmol) was added to a solution of heptane-4-ol (116 mg, 1 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 20 min. 2-Chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (204 mg, 0.5 mmol) was added to the mixture. The reaction mixture was stirred at 70 degrees overnight. Aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (160 mg, 65.5%). MS: m / e: 490 (M+1) + .

[0867] Step B: tert-Butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-(heptane-4-yloxy)imidazolyl) [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate

[0868] To a solution of 2-(heptan-4-yloxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (160 mg, 0.327 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.31 mL, 0.5 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 1 h, a suspension of tert-butyl(2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (130 mg, 0.46 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70°C for 2 h and then allowed to warm to room temperature overnight. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (20 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (100 mg, 39.8%). MS: M / e 770 (M+1) + .

[0869] Step C: 2-(heptan-4-yloxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazole 4-Chloro[2,1-f][1,2,4]triazine-4-amine (Compound A87)

[0870] To a mixture of the product of step B (100 mg, 0.13 mmol) in TFA (4 mL) was added EtSiH (4 mL) and the resulting mixture was stirred at 85 ° C for 4 hours. The mixture was cooled to room temperature and concentrated to dryness. TFA (5 mL) was added to the residue and the reaction was heated at 80 ° C overnight. The mixture was concentrated in vacuo and the residue was ...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is N; L 1 is -CH2-, R 1 Yes-OR 1a , where R 1a It is a branched-C 4-8 Alkyl, wherein the branched-C 4-8 The alkyl group is located in the alpha position relative to the oxygen atom; R 2 and R 3 In independently it is hydrogen; R 4 It is hydrogen; Ring A is phenyl or pyridyl; R 5 Halogen, C 1-8 Alkyl or halogenated C 1-8 alkyl; p is a number among 0, 1, 2 or 3; L 2 is-O-; R 6 It is C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally substituted by one, two or three substituents R 6c replace; R 6c is hydrogen, halogen, -OR 6d 、-SR 6d 、-NR 6d R 6e 、-COR 6d 、-SO2R 6d 、-C(=O)NR 6d R 6e or C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally substituted by one, two or three substituents R 6g replace; R 6d and R 6e It is hydrogen, C 1-8 Alkyl, C 2-8 alkenyl, heterocyclic or aryl, wherein the C 1-8 Alkyl, C 2-8 The alkenyl, heterocyclic or aryl groups are optionally substituted by one, two or three substituents R 6g replace; R 6g is hydrogen, halogen, -OR 6h 、-SR 6h 、-NR 6h R 6i 、-N(R 6h )C(=O)OR 6i , C 1-8 an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, R 6h and R 6i are independently hydrogen or C 1-8 alkyl, in: The term "heterocyclyl" refers to a non-aromatic monocyclic 4 to 9 membered heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon; The term "heteroaryl" refers to a 5-, 6-, or 7-membered aromatic monocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen (N), sulfur (S) and oxygen (O), the remaining ring members being carbon; and The term "aryl" refers to phenyl or naphthyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Yes-OR 1a , where R 1a It is butane-2-yl, pentane-2-yl, pentane-3-yl, heptane-2-yl, heptane-3-yl, heptane-4-yl, octane-2-yl, octane-3-yl, octane-4-yl, or octane-5-yl.

3. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein R 5 It is halogen, -C 1-8 Alkyl, or -halogenated C 1-8 and p is a number selected from 0, 1, or 2.

4. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein R 6 Yes-C 1-8 Alkyl, wherein the -C 1-8 The alkyl group is optionally substituted by one, two or three substituents R 6c replace; R 6c is hydrogen, halogen, -OR 6d 、-SR 6d 、-NR 6d R 6e 、-COR 6d 、-SO2R 6d 、-C(=O)NR 6d R 6e , or -C 1-8 Alkyl, the -C 1-8 The alkyl group is independently and optionally substituted by one or two or three substituents R 6g replace; R 6d and R 6e are independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, heterocyclic, or aryl, wherein the -C 1-8 Alkyl, -C 2-8 The alkenyl, heterocyclic, or aryl groups are optionally substituted by one, two, or three substituents R 6g replace; R 6g is hydrogen, halogen, -OR 6h 、-SR 6h 、-NR 6h R 6i 、-N(R 6h )C(=O)OR 6i , -C 1-8 Alkyl, heterocyclyl, aryl, or heteroaryl, wherein R 6h and R 6i is hydrogen or -C 1-8 alkyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein L 2 -R 6 Selected from: d) L 2 is -O-, and R 6 Yes-C 1-8 Alkyl, the -C 1-8 The alkyl group is optionally replaced by one or two R 6c Substitution, where R 6c Yes-C 1-8 Alkyl, -NR 6d R 6e and-COR 6d , where R 6d and R 6e is optionally NH2-, C 1-8 Alkylamino, or di-C 1-8 Alkylamino substituted-C 1-8 alkyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein L 2 -R 6 Selected from: d) 3-(methylamino)propoxy, 3-(dimethylamino)propoxy, 3-(diethylamino)propoxy, 2-aminoethoxy, 3-(dimethylamino)-2,2-dimethylpropoxy, methoxy, 2-(methylamino)ethoxy, or 3-aminopropoxy.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein ring A is phenyl, and L 1 and L 2 -R 6 Located in the para position of the phenyl ring, and the phenyl ring is further optionally supported by an R 5 Substitution, where L 1 , L 2 , R 5 and R 6 As defined in claim 1.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein Ring A is pyridyl, and L 1 and L 2 -R 6 is located in the para position of the pyridyl ring, and the pyridyl ring is further optionally represented by an R 5 Substitution, where L 1 , L 2 , R 5 and R 6 As defined in claim 1.

9. A compound, or a pharmaceutically acceptable salt thereof, selected from: Compound A1: 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A2: 2-butoxy-7-(4-(3-(dimethylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A4: N 1 -(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)pyridin-2-yl)-N 1 ,N 2 ,N 2 -trimethylethane-1,2-diamine; Compound A5: 2-butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A6: 2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A8: 2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A10: 2-butoxy-7-(4-(piperazin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A20: 2-butoxy-7-(2-fluoro-4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A21: 2-butoxy-7-(4-(3-(piperidin-1-yl)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A22: 2-butoxy-7-(4-(3-morpholinopropoxy)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A28: 2-butoxy-7-(4-(3-(pyrrolidin-1-yl)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A29: 2-butoxy-7-(4-(3-(diethylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A30: 2-butoxy-7-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A32: 2-butoxy-7-((6-(3-(dimethylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]pyridin-4-amine; Compound A33: 2-butoxy-7-(4-(piperidin-4-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A34: 2-butoxy-7-((5-chloro-6-(3-(dimethylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A35: 2-butoxy-7-(4-(3-(dimethylamino)propoxy)-3-fluorobenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A36: 2-butoxy-7-(4-(3-(dimethylamino)propoxy)-2-fluorobenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A38: 7-(4-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazine-4-amine; Compound A39: 1-(4-(4-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)benzyl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound A40: 2-butoxy-7-((5-chloro-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A41: 7-(4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)methyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazine-4-amine; Compound A42: 2-butoxy-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A43: 7-(4-((4-aminopiperidin-1-yl)methyl)benzyl)-2-butoxyimidazo[2,1-f][1,2,4]triazine-4-amine; Compound A44: 2-butoxy-7-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A45: 2-butoxy-7-((5-chloro-6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A49: 2-butoxy-7-(4-(((1R,5S)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A53: 2-butoxy-7-((6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A57: methyl 5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-2-(3-(dimethylamino)propoxy)benzoate; Compound A58: 2-butoxy-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A60: 2-butoxy-7-(4-((1-ethylpyrrolidin-3-yl)oxy)-2-fluorobenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A61: 2-butoxy-7-(2-fluoro-4-(pyrrolidin-3-yloxy)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A63: 2-butoxy-7-(4-(3-(methylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A64:N 2 -(Furan-2-ylmethyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound A66: 2-butoxy-7-(4-(1-methylpyrrolidin-3-yl)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound A67: N2-butyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound A69: 7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A71: 3-(4-(4-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)benzyl)piperazin-1-yl)propan-1-ol; Compound A72: 2-butoxy-7-((5-methyl-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A77: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A78: 7-((5-methyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A79: 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A81: (R or S) 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A82: (S or R) 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A83: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A84: 2-(hexan-3-yloxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A85: 3-((4-amino-7-(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A86: 3-((4-amino-7-((6-(3-(methylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A87: 2-(heptane-4-yloxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A89: (S)-2-(sec-butoxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A90: (S)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A91: 3-((4-amino-7-(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A92: (R or S) 3-((4-amino-7-(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A93: (S or R) 3-((4-amino-7-(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A94: 3-((4-amino-7-(4-(methyl(2-(methylamino)ethyl)amino)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A95: 3-((4-amino-7-(4-(2-(methylamino)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A96: 3-((4-amino-7-(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A97: 3-((4-amino-7-(2-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A98: 3-((4-amino-7-(3-methoxy-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A99: (S)-7-(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A100: (S)-7-(4-(2-(methylamino)ethoxy)benzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound A101: (R or S)-3-((4-amino-7-(2-methoxy-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A102: 3-((4-amino-7-(3-chloro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A103: (R or S)-3-((4-amino-7-(3-methyl-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A104: (R or S)-3-((4-amino-7-(3-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A105: (R or S)-3-((4-amino-7-(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A106: (S or R)-3-((4-amino-7-(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A107: (R or S)-3-((4-amino-7-(2-methyl-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A108: (R or S)-3-((4-amino-7-(2-chloro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A109: (3R or S)-3-((4-amino-7-((6-((1-(methylamino)propan-2-yl)oxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A110: (R or S)-3-((4-amino-7-(4-(3-(methylamino)propyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A111: (R or S)-3-((4-amino-7-(2,3-difluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A112: (R or S)-3-((4-amino-7-(2,5-difluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A113: (R or S)-3-((4-amino-7-(2-methoxy-5-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A114: (R or S)-3-((4-amino-7-(3,5-difluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A115: (R or S)-3-((4-amino-7-(2-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A116: (R or S)-3-((4-amino-7-(3-methoxy-5-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A117: (R or S)-3-((4-amino-7-(4-methoxy-3-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A118: (R or S)-3-((4-amino-7-(2-methoxy-3-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A119: (R or S)-3-((4-amino-7-(4-(2-(methylamino)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A120: (S or R)-3-((4-amino-7-(4-(2-(methylamino)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A121: (R or S)-3-((4-amino-7-(2-ethoxy-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane-1-ol; Compound A122: (R or S)-3-((4-amino-7-((6-(2-(methylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound A123: (R or S)-3-((4-amino-7-(2,6-difluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; and Compound A124: (R or S)-3-((4-amino-7-((4-(2-(methylamino)ethoxy)naphthalen-1-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

11. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 10 in the preparation of a medicament for agonizing TLR7.

12. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating a disease or disorder associated with TLR7.

13. The use according to claim 12, wherein the disease or disorder is cancer.

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