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 discovered that the imidazo[2,1-f][1,2,4]triazine-4-amine derivatives disclosed herein exhibit more potent TLR7 agonist activity when Ring A in Formula (II) is directly substituted with a heterocyclyl ring. The inventors also discovered that branching of the alkyl moiety at position 2 of the imidazo[2,1-f][1,2,4]triazine-4-amine derivatives unexpectedly improves TLR7 agonist activity.

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

[0010]

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

[0012] 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;

[0013] 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 ;

[0014] where R 1e is halogen, nitro, cyano, hydroxy, amino (-NH2), alkylamino, dialkylamino, or -C optionally substituted by halogen 1-6 alkyl;

[0015] where R 1f is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted by -C 1-4 Alkyl or halogen substituted;

[0016] 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;

[0017] Ring A is an aryl group or a heteroaryl group;

[0018] Het is a heterocyclic group;

[0019] R 5 is halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, -oxo, or -C(=O)OR 5a , where R 5a is hydrogen, alkyl, or haloalkyl;

[0020] p is a number among 0, 1, 2 or 3;

[0021] 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;

[0022] 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;

[0023] 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,

[0024] 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.

[0025] R 1 Definition of

[0026] In some embodiments, R 1 Yes-OR 1a or -NR 1a R 1b , where R 1a and R 1b is as defined for formula (II).

[0027] 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 ;

[0028] where R 1e is halogen, or -C optionally substituted by halogen 1-6 alkyl;

[0029] 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.

[0030] In some embodiments, R 1 Yes-OR 1a , where R 1a It's hydrogen.

[0031] 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 (II).

[0032] 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 4-8Alkyl 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 1 Preferably, 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.

[0033] 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).

[0034] 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 (II).

[0035] In some embodiments, R 1 Yes-OR 1a , where R 1a Yes-C 1-8 Alkyl, preferably -C 1-3Alkyl, 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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 1It is but-3-enyloxy.

[0040] 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 1-8 Alkyl, 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.

[0041] 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.

[0042] In some embodiments, R 1 It is butylamino, n-butyl-N-methylamino, or isopentylamino.

[0043] 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.

[0044] R 5 Definition of

[0045] In some embodiments, R 5 Halogen, hydroxyl, C1-8 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.

[0046] 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.

[0047] In some embodiments, p is the number 1.

[0048] In some embodiments, R 5 and Het-R 6c Located at the ortho position on ring A.

[0049] Definition of Ring A

[0050] In some embodiments, Ring A is phenyl.

[0051] 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.

[0052] 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.

[0053] Definition of Het

[0054] In some embodiments, Het is a monocyclic heterocyclyl; in some embodiments, Het is a fused bicyclic heterocyclyl; and in some embodiments, Het is a spiro bicyclic heterocyclyl.

[0055] In some embodiments, Het is a saturated heterocyclyl. In some embodiments, Het is a 4-, 5-, 6-, 7-, or 8-membered saturated monocyclic heterocyclyl ring containing one, two, or three heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur as ring members. In some embodiments, Het is a 5-, 6-, 7-, or 8-membered saturated monocyclic heterocyclyl ring containing one, two, or three nitrogen heteroatoms as ring members. In some embodiments, Het is a 5- or 6-membered saturated monocyclic heterocyclyl ring containing one or two nitrogen heteroatoms as ring members. In some embodiments, Het 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.

[0056] In some embodiments, Het is a bicyclic heterocyclyl ring comprising one, two, or three heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur as ring members. In some instances, Het is 2,5-diazabicyclo[2.2.1]heptan-2-yl.

[0057] In some embodiments, Het 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.

[0058] R 6c Definition of

[0059] In some embodiments, Het is optionally substituted with one or two or three substituents R 6c In some embodiments, Het is optionally replaced by one R 6c replace.

[0060] In some embodiments, 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;

[0061] R 6d 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;

[0062] 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 an alkyl group, a heterocyclic group, an aryl group, or a heteroaryl group,

[0063] R 6h and R 6i are independently hydrogen or -C 1-8 alkyl.

[0064] 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 (II). In some embodiments, R 6c Yes-COR 6d , where R 6dis 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).

[0065] In some embodiments, R 6c Yes-COR 6d , where R 6d Yes-C 2-8 Alkenyl.

[0066] In some embodiments, R 6c Yes-COR 6d , where R 6d It is a heterocyclic group.

[0067] 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.

[0068] In some embodiments, R 6c Yes-C 1-8 Alkoxy, preferably -C 1-6 Alkoxy groups, such as methoxy groups.

[0069] In some embodiments, R 6c is optionally substituted by one or two substituents R 6g Substituted -C 1-8 Alkyl, preferably -C 1-6 Alkyl, where R 6g Yes-OR6h 、-NR 6h R 6i , heterocyclic group, aryl group, where R 6h and R 6i is as defined for formula (II). 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 6c is methyl, ethyl, isobutyl, methoxymethyl, 2-methoxyethyl, (methylamino)methyl, 2-(dimethylamino)ethyl, (dimethylamino)methyl, 2-aminoethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, morpholinomethyl, or phenethyl.

[0070] 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.

[0071] 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 R6e , 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.

[0072] 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.

[0073] 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.

[0074] In some embodiments, Het is pyrrolidinyl optionally substituted with one or two or three substituents selected from methyl, (dimethylamino)methyl, or dimethylamino. In some embodiments, Het is 1-methylpyrrolidin-3-yl, pyrrolidin-1-yl, 3-((dimethylamino)methyl)pyrrolidin-1-yl, or 3-(dimethylamino)pyrrolidin-1-yl.

[0075] In some embodiments, Het is piperazinyl 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. , isopropylcarbamoyl, 2,4,5-trifluorophenylcarbamoyl, (2S,3S)-2-amino-3-methylpentanoyl, 2-methoxyethyl, 2-(methylamino)acetyl, ethyl, isobutyl, pyrrolidine-2-carbonyl, 2-amino-4-methylpentanoyl, 2-amino-3-methylbutanoyl, 2-(dimethylamino)acetyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, amino, phenylpropionyl, propylsulfonyl, or 2-aminoethyl.In some embodiments, Het is piperazin-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)propanoyl)piperazin-1-yl, 4-(2-(piperazin-1-yl)acetyl)piperazin-1-yl, 4-(piperazine-2-carbonyl)piperazin-1-yl, 4-acryloyl ... acylpiperazin-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 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.

[0076] In some embodiments, Het is piperidinyl 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, Het is 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.

[0077] In some embodiments, Het is azepan-1-yl or 1,4-diazepan-1-yl.

[0078] In some embodiments, Het is octahydro-2H-isoindol-2-yl.

[0079] In some embodiments, Het is morpholino.

[0080] In some embodiments, Het is 8-azaspiro[4.5]decan-8-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 2,8-diazaspiro[4.5]decan-2-yl, 2,7-diazaspiro[3.5]nonan-2-yl, 2,8-diazaspiro[4.5]decan-8-yl, (1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl.

[0081] In some embodiments, ring A is phenyl, and the methylene group and Het on the phenyl ring are located in the para position of the phenyl ring, and the phenyl ring is further optionally substituted with one R 5 Substituted, where R 5 In other embodiments, ring A is pyridyl, and the methylene group and Het on the pyridyl ring are located in the para position of the pyridyl ring, and the pyridyl ring is further optionally substituted with one R 5 Substituted, where R 5 is as defined in each of the above embodiments. In some embodiments, Ring A is pyridin-2-yl or pyridin-3-yl.

[0082] In some embodiments, disclosed herein are compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, selected from the specific compounds exemplified herein:

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099] In a second aspect, disclosed herein are pharmaceutical compositions comprising a compound disclosed herein (including a compound of formula (II) or a specific compound exemplified herein), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0100] In a third aspect, disclosed herein are methods of modulating TLR7, comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, including a compound of formula (II) or a specific compound exemplified herein.

[0101] In a fourth 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 comprises a compound of formula (II) 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

[0102] The following terms have the indicated meanings throughout this specification:

[0103] 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.

[0104] Unless the context clearly indicates otherwise, the term "or" means and is used interchangeably with the term "and / or."

[0105] 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.

[0106] The term "alkoxy" or "alkyloxy" means an alkyl group, as previously defined, appended to the parent molecular moiety through an oxygen atom.

[0107] 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).

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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 3-6Examples 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).

[0115] 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.

[0116] 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.

[0117] 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.

[0118] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0119] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0120] - 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

[0121] - 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.

[0122] 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.

[0123] The term "heteroaryl" as used herein refers to a group selected from:

[0124] - 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;

[0125] - 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

[0126] - 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.

[0127] 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.

[0128] As used herein, the term "optionally oxidized sulfur" refers to S, SO or SO2.

[0129] 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.

[0130] 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.

[0131] "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.

[0132] 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.

[0133] 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,

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0140] 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.

[0141] 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.

[0142] "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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] As defined herein, "pharmaceutically acceptable salts thereof" include salts of at least one compound of formula (II), and salts of stereoisomers of the compound of formula (II), such as enantiomeric salts and / or diastereomeric salts.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] The term "disease" refers to any illness, ailment, disease, symptom, or indication and is interchangeable with the terms "disorder" or "condition."

[0152] 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."

[0153] 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.

[0154] 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.

[0155] Universal synthesis

[0156] 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.

[0157] 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.

[0158] The selection of appropriate protecting groups can be readily determined by one skilled in the art.

[0159] 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.

[0160] 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.

[0161] The compounds disclosed herein can be prepared according to Scheme 1 below.

[0162] Plan I

[0163]

[0164] Among them -WR 1A Yes-OR 1a or -NR 1a R 1b , and R 1a 、R 1b 、R 5 and R 6c is as defined for formula (II); R 8 、R 9 、R 10 and R 11 Independently C 1-6 alkyl. X, Y and Z are independently CH or N. W is independently N or O. m is 0, 1, 2, or 3, and n is 1, 2, or 3.

[0165] In Scheme I, commercially available ethyl 1H-imidazole-2-carboxylate is reacted with 2-O-(4-nitrobenzoyl)hydroxylamine to form intermediate 2, which is reacted with ethyl chloroformate and then ring-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 agent, and the diketone is then chlorinated to form compound 6. One chlorine atom is replaced by a protected amine, and the other chlorine atom reacts with RW to give intermediate 8, which is then reacted with different aldehydes under alkaline conditions to form intermediate 10. The protected group on the amine and the hydroxyl group are removed to give intermediate 11. After deprotection and coupling with different acids under alkaline conditions, a compound of formula (II) is obtained.

[0166] Intermediate 10 can also be prepared by Scheme II below.

[0167] Option II

[0168]

[0169] In Scheme II, intermediate 4 is 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 subsequently reacted with different aldehydes under basic conditions to form intermediate 10.

[0170] Examples

[0171] 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.

[0172] In the following examples, the following abbreviations are used:

[0173] AcOH acetic acid

[0174] Aq. Water-based

[0175] BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0176] Brine saturated sodium chloride aqueous solution

[0177] Bn benzyl

[0178] BnBr benzyl bromide

[0179] BPO Benzoyl Peroxide

[0180] BSA N,O-Bis(trimethylsilyl)acetamide

[0181] CH2Cl2 or DCM dichloromethane

[0182] DIAD Diisopropyl azodicarboxylate

[0183] DMF N,N-dimethylformamide

[0184] Dppf 1,1'-bis(diphenylphosphino)ferrocene

[0185] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0186] DIEA or DIPEA N,N-diisopropylethylamine

[0187] DMAP 4-N,N-dimethylaminopyridine

[0188] DMF N,N-dimethylformamide

[0189] DMSO dimethyl sulfoxide

[0190] EtOAc or EA Ethyl acetate

[0191] EtOH

[0192] Et2O or ether

[0193] g grams

[0194] h or hr hours

[0195] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0196] Hexane

[0197] HCl

[0198] HMDS Hexamethyldisilazane

[0199] HPLC high-performance liquid chromatography

[0200] IBX 2-iodoacylbenzoic acid

[0201] IPA Isopropyl alcohol

[0202] i-PrOH isopropyl alcohol

[0203] LCMS liquid chromatography-mass spectrometry

[0204] mg milligrams

[0205] mL milliliters

[0206] mmol millimole

[0207] MeCN Acetonitrile

[0208] MeOH methanol

[0209] Min minutes

[0210] ms or MS mass spectrometry

[0211] MTBE methyl tert-butyl ether

[0212] Na2SO4 sodium sulfate

[0213] NBS N-bromosuccinimide

[0214] NMP N-Methylpyrrolidone

[0215] PE petroleum ether

[0216] PMB (4-methoxyphenyl)methylamine

[0217] prep

[0218] Rt or rt room temperature

[0219] sat. saturated

[0220] TBAF Tetrabutylammonium fluoride

[0221] TBSCl tert-Butyldimethylsilyl chloride

[0222] t-BuOK Potassium tert-butoxide

[0223] TFA trifluoroacetic acid

[0224] THF Tetrahydrofuran

[0225] TLC thin layer chromatography

[0226] μL microliter

[0227] Synthesis of Intermediate-I

[0228] 7-Bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0229] Step A: Ethyl 1-amino-1H-imidazole-2-carboxylate hydrochloride

[0230] 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) + .

[0231] Step B: A mixture of ethyl 1-((ethoxycarbonyl)amino)-1H-imidazole-2-carboxylate and ethyl 1-(di(ethoxycarbonyl)amino)-1H-imidazole-2-carboxylate (1:1)

[0232] 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) + .

[0233] Step C: Imidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione

[0234] 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) + .

[0235] Step D: 7-Bromoimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione

[0236] 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) + .

[0237] Step E: 7-Bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine

[0238] 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) + .

[0239] Step F: 7-Bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0240] 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) + .

[0241] Step G: 7-Bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0242] 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) + .

[0243] Compound B1: 2-Butoxy-7-((5-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0244] Step A: Methyl 5-chloro-6-(4-methylpiperazin-1-yl)nicotinate

[0245] To a solution of methyl 5,6-dichloronicotinate (2 g, 10 mmol) and DIPEA (1.93 g, 15 mmol) in DMA (20 mL) was added 1-methylpiperazine (1.1 g, 11 mmol). The mixture was then stirred at 100°C for 3 h. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was triturated with EA / PE = 1 / 4 to give the target compound (1.2 g, 36%). MS: M / e 270 (M+1) + .

[0246] Step B: (5-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)methanol

[0247] To a solution of the product of step A (0.87 g, 3.23 mmol) in EtOH (10 mL) was added NaBH4 (370 mg, 9.7 mmol). The reaction was heated at 80 ° C overnight. The mixture was cooled to room temperature and concentrated, diluted with water, and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the target compound (560 mg, crude) as an oil. MS: M / e 242 (M+1) + .

[0248] Step C: 5-chloro-6-(4-methylpiperazin-1-yl)nicotinaldehyde

[0249] To a solution of the product of step B (0.56 g, 2.32 mmol) in THF (10 mL) was added Dess-Martin reagent (2.1 mg, 5 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated KCO solution (10 mL) and diluted with EtOAc (40 mL). The mixture was filtered through a pad of celite. The organic layer was collected, washed with brine, dried over NaSO, filtered and concentrated. The residue was purified by combi flash to give the title compound (250 mg, 32% for 2 steps). 1 HNMR (400MHz, CDCl3) δ9.88 (s, 1H), 8.54 (d, J = 2.0Hz, 1H), 8.01 (d, J = 2.0Hz, 1H), 3.79 (t, J = 4.4Hz, 4H), 2.75 (t, J = 4.8Hz, 4H), 2.46 (s, 3H) ppm. MS:M / e 240(M+1) + .

[0250] Step D: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(5-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)methanol

[0251] 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, 0.285 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 from Step C (100 mg, 0.43 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 x 2), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the target compound (60 mg, crude). MS:M / e 687(M+1) + .

[0252] Step E: 2-Butoxy-7-((5-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0253] To a mixture of the product of step D (60 mg, 0.092 mmol) in TFA (3 mL) was added Et3SiH (1 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 product (10 mg, 8% for both steps). 1 HNMR(400MHz,CD3OD)δ8.16(s,1H),7.72(s,1H),7.38(s,1H),4.32-4.24(m,2H),4.16(s,2H),2 .91-2.42(m,8H),2.35(s,3H),1.81-1.66(m,2H),1.56-1.41(m,2H),0.98(t,J=6.8Hz,3H)ppm. MS:M / e 431(M+1) + .

[0254] Compound B2: 2-Butoxy-7-((5-chloro-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0255] Step A: tert-Butyl 4-(3-chloro-5-formylpyridin-2-yl)piperazine-1-carboxylate

[0256] To a solution of 5,6-dichloronicotinaldehyde (1.76 g, 10 mmol) and DIEA (1.93 g, 15 mmol) in DMA (20 mL) was added tert-butyl piperazine-1-carboxylate (2 g, 11 mmol). The mixture was then stirred at 80°C overnight. 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 combi-flash to give the title compound (1.9 g, 58%). 1 HNMR (400MHz, CDCl3) δ9.86 (s, 1H), 8.54 (d, J = 2.0Hz, 1H), 8.01 (d, J = 2.0Hz, 1H), 3.66-3.54 (m, 8H), 1.48 (s, 9H) ppm. MS:M / e 270(M+Ht-Bu) + .

[0257] Step B: 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)piperazine-1-carboxylate

[0258] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-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) while maintaining the temperature between -75°C and -65°C. After 1 h, the product of Step A (278 mg, 0.855 mmol) in THF (4 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then allowed to warm 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 (EA / PE = 1 / 3) to give the title compound (150 mg, crude). MS: M / e 773 (M+1) + .

[0259] Step C: 2-Butoxy-7-((5-chloro-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0260] To a stirred solution of the product of step B (150 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. 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 NaHCO3 solution, extracted with DCM (50 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to give the target compound (46 mg, 20% for two steps). 1 HNMR (400MHz, DMSO-d6) δ8.18(d,J=2.0Hz,1H),8.16(s,1H),8.07(s,1H),7.76(d,J=2.0Hz,1H),7.35(s,1H),4.20(t,J=6.0Hz, 2H), 4.10 (s, 2H), 3.13 (t, J = 5.2Hz, 4H), 2.85 (t, J = 5.2Hz, 4H), 1.74-1.62 (m, 2H), 1.46-1.34 (m, 2H), 0.92 (t, J = 7.2Hz, 3H) ppm. MS:M / e 417(M+1) + .

[0261] Compound B3: 2-Butoxy-7-(4-(piperidin-4-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0262] Step A: tert-Butyl 4-(4-formylphenyl)piperidine-1-carboxylate

[0263] To a solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (3.4 g, 10 mmol) in THF (30 mL) was added a solution of n-butyllithium (10 mL, 16 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 1 h, DMF (814 mg, 11 mmol) was added dropwise, and the resulting mixture was stirred at -65°C for 1 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (60 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (eluting with EA / PE = 1 / 8) to give the title compound (1.35 g, 46%) as an oil. 1HNMR (400MHz, CDCl3) δ9.98 (s, 1H), 7.83 (d, J = 8.4Hz, 2H), 7.37 (d, J = 8.4Hz, 2H), 4.34- 4.20(m,2H),2.91-2.66(m,3H),1.91-1.80(m,2H),1.91-1.58(m,2H),1.49(s,9H)ppm. MS:M / e 234(M+H-tBu) + .

[0264] Step B: tert-Butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)phenyl)piperidine-1-carboxylate

[0265] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-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 from step A (164 mg, 0.57 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70°C for 1 h and then allowed to warm 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 / 3) to give the title compound (63 mg, 23%). MS: M / e 737 (M+1) + .

[0266] Step C: 2-Butoxy-7-(4-(piperidin-4-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0267] To a mixture of the product from step B (63 mg, 0.086 mmol) in TFA (3 mL) was added Et3SiH (0.5 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 (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (15 mg, 39%). 1HNMR (400MHz, DMSO-d6) δ8.12(s,1H),8.03(s,1H),7.30(s,1H),7.25(d,J=8.4Hz,2H),7.13(d,J=8.4Hz,2H),4.20(t,J=6.4Hz,2H),4.10(s,2H ),3.27-3.18(m,2H),2.91-2.77(m,2H),2.76-2.64(m,1H),1.86-1.74( m,2H),1.73-1.56(m,4H),1.47-1.33(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 381(M+1) + .

[0268] Compound B4: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-chloropyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0269] To a stirred solution of 2-butoxy-7-((5-chloro-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.05 mmol) in CH 3 CN (2 mL) was added saturated aqueous NaHCO 3 solution (0.5 mL) at 0° C., and then a solution of acryloyl chloride (4.5 mg, 0.05 mmol) in CH 3 CN (0.1 mL) was added. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with water, extracted with DCM (40 mL x 2), washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (12 mg, 51%). 1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.16(s,1H),8.06(s,1H),7.81(s,1 H),7.35(s,1H),6.90-6.77(m,1H),6.13(d,J=16.8Hz,1H),5.70(d,J=11. 6Hz,1H),4.20(t,J=6.0Hz,2H),4.11(s,2H),3.80-3.61(m,4H),3.26-3.1 4(m,4H),1.75-1.60(m,2H),1.46-1.33(m,2H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 471(M+1) + .

[0270] Compound B5: 7-((5-chloro-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(2-methoxyethoxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0271] Compound B5 was synthesized from the corresponding starting materials according to a procedure similar to that described for compound B2. 1H NMR (400 MHz, CD3OD) δ 8.23 ​​(s, 1H), 7.79 (s, 1H), 7.39 (s, 1H), 4.41 (t, J = 4 Hz, 2H), 4.19 (s, 2H), 3.73 (t, J = 4 Hz, 2H), 3.52 (t, J = 8 Hz, 4H), 3.40 (s, 3H), 3.34 (t, J = 8 Hz, 4H) ppm. MS: M / e 419 (M+1)+.

[0272] Compound B6: 2-Butoxy-7-((6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0273] Compound B6 was synthesized according to a similar procedure as described for compound B2 starting from the corresponding starting materials. 1 HNMR(400MHz, DMSO-d6)δ8.06(s,1H),7.76(s,2H),7.45-7.36(m,1H),7.24(s,1H),6.66(d,J=8.8Hz,1H),4.23(t,J=6.8H z,2H),3.99(s,2H),3.39-3.25(m,4H),2.84-2.70(m,4H),1.75-1.62(m,2H),1.46-1.32(m,2H),0.93(t,J=7.2Hz,3H)ppm. MS:M / e 383(M+1) + .

[0274] Compound B7: 2-Butoxy-7-((4-chloro-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0275] Compound B7 was synthesized according to a similar procedure as described for compound B2 starting from the corresponding starting materials. 1HNMR(400MHz,DMSO-d6)δ8.14(s,1H),8.12(s,1H),8.04(s,1H),7.21(s,1H),6.87(s,1H),4.21(t,J=6.4Hz,2H),4.08 (s,2H),3.37(t,J=4.8Hz,4H),2.73(t,J=4.8Hz,4H),1.76-1.56(m,2H),1.50-1.35(m,2H),0.93(t,J=7.2Hz,3H)ppm. MS:M / e 417(M+1)+.

[0276] Compound B8: 2-Butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0277] Step A: tert-Butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0278] To a solution of 6-chloro-5-methylnicotinaldehyde (0.93 g, 6 mmol) and DIEA (0.93 g, 7.2 mmol) in DMA (15 mL) was added tert-butyl piperazine-1-carboxylate (1.12 g, 6 mmol). The mixture was then stirred at 115° C. under N2 overnight. The mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (60 mL), washed with brine, dried over Na2SO4, concentrated, and the residue was purified by combi-flash to give the title compound (1.05 g, 58%). 1 HNMR (400MHz, CDCl3) δ9.91 (s, 1H), 8.53 (d, J = 2.0Hz, 1H), 7.85 (s, 1H), 3.58 (t, J = 4.4Hz, 4H), 3.37 (t, J = 4.4Hz, 4H), 2.33 (s, 3H), 1.49 (s, 9H) ppm. MS:M / e 306(M+1) + .

[0279] Step B: 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)piperazine-1-carboxylate

[0280] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (2.62 g, 5 mmol) in THF (25 mL) was added dropwise a solution of n-butyllithium (4.7 mL, 7.5 mmol) while maintaining the temperature between -75°C and -65°C. After 1 h, a mixture of the product from step A (2.28 g, 7.5 mmol) in THF (7 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 (100 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (EA / PE = 1 / 2) to give the title compound (2.1 g, 56%). MS: M / e 753 (M+1) + .

[0281] Step C: 2-Butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0282] To a mixture of the product of step B (2.1 g, crude) in TFA (15 mL) was added Et3SiH (5 mL), and the resulting mixture was stirred at 85 ° C overnight. The mixture was cooled to room temperature and concentrated to dryness. TFA (10 mL) was added to the residue and the resulting mixture was heated at 85 ° C overnight. The mixture was concentrated to dryness. The crude product was diluted with water, alkalized with NaHCO3 solution, extracted with DCM (60 mL x 8), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (eluted with the following: DCM: (7M NH3, in MeOH) = 15: 1) to give the target compound (600 mg, 30% for two steps). 1 HNMR(400MHz,DMSO-d6)δ8.13(s,1H),8.06(s,1H),8.04(s,1H),7.43(s,1H),7.31(s,1H),4.21(t,J=6.8Hz,2H),4.04(s ,2H),2.98-2.86(m,4H),2.84-2.74(m,4H),2.17(s,3H),1.75-1.62(m,2H),1.48-1.32(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 397(M+1) + .

[0283] Compound B9: 2-Butoxy-7-((5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0284] Compound B9 was synthesized according to a similar procedure as described for compound B2 starting from the corresponding starting materials. 1 HNMR(400MHz, DMSO-d6)δ8.16(s,1H),8.06(s,1H),7.98(s,1H),7.45(d,J=9.6Hz,1H),7.31(s,1H),4.20(t,J=6.4Hz,2H), 4.07(s,2H),3.22(t,J=4.4Hz,4H),2.78(t,J=4.4Hz,4H),1.75-1.62(m,2H),1.46-1.34(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 401(M+1) + .

[0285] Compound B10: 2-Butoxy-7-((6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0286] Compound B10 was synthesized according to a similar procedure as described for compound B2 starting from the corresponding starting materials. 1 HNMR(400MHz,DMSO-d6))δ8.47(s,1H),8.17(s,1H),8.07(s,1H),8.02(s,1H),7.38(s,1H),4.26-4.12( m,4H),3.06-3.00(m,4H),2.81-2.72(m,4H),1.70-1.58(m,2H),1.39(m,2H),0.91(t,J=7.1Hz,3H)ppm. MS:M / e 451(M+1) + .

[0287] Compound B11: 2-Butoxy-7-((5-methoxy-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0288] Compound B11 was synthesized according to a similar procedure as described for compound B2 starting from the corresponding starting materials. 1HNMR(400MHz, DMSO-d6))δ8.13(s,1H),8.04(s,1H),7.73(s,1H),7.29(s,1H),7.21(s,1H),4.22(t,J=6.4Hz,2H),4.05( s,2H),3.74(s,3H),3.13(s,4H),2.77(s,4H),1.72-1.64(m,2H),1.40(dd,J=14.8,7.4Hz,2H),0.92(t,J=7.3Hz,3H)ppm. MS:M / e 413(M+1) + .

[0289] Compound B12: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

[0290] To a mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.5 mmol), dimethylglycine (52 mg, 0.5 mmol), and DIPEA (129 mg, 1 mmol) in THF (10 mL) was added HATU (190 mg, 0.5 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with EA (60 mL x 2), washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (eluting with DCM:(7M NH in MeOH) = 20:1) and further recrystallized from MeOH to give the title compound (55 mg, 22%). 1 HNMR(400MHz,DMSO-d6)δ8.13(s,1H),8.08(s,1H),8.04(s,1H),7.46(s,1H),7.31(s,1H),4.20(t,J=6.0Hz,2H),4.05(s,2H),3.70-3 .49(m,4H),3.09(s,2H),3.05-2.90(m,4H),2.21(s,3H),2.18(s,6H),1.75-1.62(m,2H),1.50-1.34(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 482(M+1) + .

[0291] Compound B13: 2-butyl-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0292] Step A: 7-Bromo-N2-butyl-N4,N4-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0293] A mixture of 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (244 mg, 0.5 mmol), butane-1-amine (365 mg, 5 mmol) and DIPEA (645 mg, 5 mmol) in NMP (3 mL) was stirred at 220° C. in a sealed tube for 6 hours. The mixture was poured into H 2 O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated and purified by column chromatography (petroleum ether / EtOAc=20:1 to 5:1) to give the target compound (220 mg, 83.8%). MS: M / e 525 / 527 (M+1) + .

[0294] Step B: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(butylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0295] To a stirred solution of the product of step A (200 mg, 0.38 mmol) in dry THF (10 mL) was added n-butyl lithium (1.6 M, 0.59 mL, 0.95 mmol) dropwise at -78°C. After stirring for 30 min, a solution of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (232 mg, 0.76 mmol) in THF (2 mL) was added dropwise. The reaction was then stirred overnight. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the target compound (80 mg, 28%). MS: M / e 753 (M+1) + .

[0296] Step C: N2-butyl-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0297] A mixture of the product of step B (80 mg, 0.106 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 (32 mg, 76.9%). 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.50(br.s,2H),7.43(s,1H),7.15(s,1H),6.24(t,J=5.6Hz,1H),3.97(s,2H),3.20-3.1 3(m,3H),2.92-2.87(m,4H),2.82-2.76(m,4H),2.17(s,3H),1.58-1.44(m,2H),1.36-1.28(m,2H),0.90(t,J=7.6Hz,3H)ppm. MS:M / e 396(M+1) + .

[0298] Compound B14: 1-(4-(4-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)phenyl)piperidin-1-yl)-2-(dimethylamino)ethan-1-one

[0299] To a mixture of 2-butoxy-7-(4-(piperidin-4-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.052 mmol, crude), dimethylglycine (4 mg, 0.04 mmol), and DIPEA (12 mg, 0.1 mmol) in THF (3 mL) was added HATU (15 mg, 0.04 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with DCM (40 mL x 2), washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (5 mg, 21%). 1HNMR(400MHz,DMSO-d6)δ9.47(br.s,1H),8.13(s,1H),8.06(s,1H),7.31(s,1H) ,7.25(d,J=8.0Hz,2H),7.15(d,J=8.4Hz,2H),4.55-4.41(m,1H),4.37-4.25(m,2 H),4.20(t,J=6.4Hz,2H),4.10(s,2H),3.25-3.08(m,2H),2.86-2.70(m,8H),1. 86-1.73(m,2H),1.73-1.56(m,3H),1.50-1.29(m,3H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e466(M+1) + .

[0300] Compound B15: 2-Butoxy-7-((5-(piperidin-4-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0301] Step A: (5-Bromopyridin-2-yl)methanol

[0302] At 0 ° C, sodium borohydride (380 mg, 10 mmol) was added portionwise to a solution of 5-bromopicolinaldehyde (2 g, 10 mmol) in methanol. After stirring at rt for 1 hour, TLC showed that the reaction was complete. The solution was quenched with water (5 mL), extracted with ethyl acetate (20 mL) and washed with brine (10 mL). The organic layer was dried, concentrated and purified by Combi-Flash (PE:EA=25%) to give the product (1.8 g, 90%). 1 H NMR (400MHz, DMSO-d6) δ 8.59 (d, J = 4.0 Hz, 1H), 8.04 ( d, J = 8.0 Hz, 1H), 7.45 ( d, J = 8.0 Hz, 1H), 5.52 ( t, J = 8.0 Hz, 1H), 4.52 ( d, J = 4.0 Hz, 2H) ppm. MS:M / e 188(M+1) + .

[0303] Step B: tert-Butyl 6-(hydroxymethyl)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-carboxylate

[0304] A solution of (5-bromopyridin-2-yl)methanol (300 mg, 1.6 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (545 mg, 1.8 mmol), Pd(dppf)2Cl2 (147 mg, 0.18 mmol) and Cs2CO3 (1 g, 3.2 mmol) in DMF / THF (1:1, 10 mL) was heated at 90 ° C. under an N2 atmosphere overnight. The solution was cooled, diluted with water (10 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 (PE:EA=80%) to give the pure product (280 mg, 60%) as a yellow oil. MS:M / e 291(M+1) + .

[0305] Step C: tert-Butyl 4-(6-(hydroxymethyl)pyridin-3-yl)piperidine-1-carboxylate

[0306] A solution of tert-butyl 6-(hydroxymethyl)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-carboxylate (280 mg, 1.0 mmol) and PtO2 (30 mg) in methanol (10 mL) was stirred at rt under a H2 balloon overnight. The catalyst was filtered and the filtrate was concentrated to give the crude product, which was used directly in the next step without further purification (280 mg, crude). MS: M / e 293 (M+1) + .

[0307] Step D: tert-Butyl 4-(6-formylpyridin-3-yl)piperidine-1-carboxylate

[0308] At 0 ° C, Dess-Martin reagent (636 mg, 1.5 mmol) was added in portions to a solution of tert-butyl 4-(6-(hydroxymethyl)pyridin-3-yl)piperidine-1-carboxylate (280 mg, 1.0 mmol) in THF (5 mL). After stirring at rt for 1 hour, TLC showed that the reaction was complete. The solution was quenched with water (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 (PE:EA=30%) to give the product as an oil (60 mg, 21%). MS: M / e 291 (M+1) + .

[0309] Step E: tert-Butyl 4-(6-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-3-yl)piperidine-1-carboxylate

[0310] To a cooled solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.19 mmol) in THF (8 mL) was added dropwise n-butyllithium (1.6 M, 0.3 mL) at -78°C (with N purging). After stirring at -78°C for 30 minutes, tert-butyl 4-(6-formylpyridin-3-yl)piperidine-1-carboxylate (60 mg, 0.20 mmol) in THF (2 mL) was added. The resulting mixture was stirred at this temperature for 30 minutes and then allowed to warm to room temperature overnight. The solution was quenched with NH 4 Cl 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 Combi-Flash (PE:EA=60%) to give the pure product (40 mg, 29%). MS: M / e 738 (M+1) + .

[0311] Step F: 2-Butoxy-7-((5-(piperidin-4-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0312] A mixture of tert-butyl 4-(6-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-3-yl)piperidine-1-carboxylate (40 mg, 0.05 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (2 mL) was heated at 100° C. overnight. The solvent was evaporated to give a residue, to which water (5 mL) was added, extracted with ethyl acetate (5 mL), washed with NaHCO (5 mL) and brine (5 mL). The organic layer was dried, concentrated and purified by preparative HPLC to give the product (6 mg, 30%). 1H NMR (400MHz, CD3OD) δ8.61(s,1H),8.17(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.57(s,1H),4.60(s,2H),4.19(t,J=8.0Hz,2H),3.53(d,J= 12.0Hz,2H),3.19-3.09(m,3H),2.13(d,J=12.0Hz,2H),1.99-1.89(m,2H),1.73-1.66(m,2H),1.50-1.41(m,2H),0.95(t,J=8.0Hz,3H)ppm. MS:M / e 382(M+1) + .

[0313] Compound B16: 2-Butoxy-7-((5-(piperazin-1-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0314] Step A: tert-Butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate

[0315] A solution of 5-bromopicolinaldehyde (500 mg, 2.7 mmol), tert-butyl piperazine-1-carboxylate (600 mg, 3.2 mmol), Pd2(dba)3 (80 mg, 0.16 mmol), BINAP (187 mg, 0.3 mmol) and Cs2CO3 (2.2 g, 6.8 mmol) in toluene (20 mL) was purged with N2 at 100°C and heated overnight. The solution was cooled, concentrated, diluted with water (10 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 (PE:EA=40%) to give the pure product (130 mg, 17%). MS: M / e 292 (M+1) + .

[0316] Step B: tert-Butyl 4-(6-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-3-yl)piperazine-1-carboxylate

[0317] 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]triazin-4-amine (150 mg, 0.28 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.44 mL) dropwise under a 4% CO purging (pH 7.0). After stirring at -78°C for 30 minutes, tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (125 mg, 0.43 mmol) in THF (2 mL) was added. The resulting mixture was stirred at this temperature for 30 minutes and then allowed to warm to room temperature 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 preparative TLC (EA) to yield the pure product (75 mg, 36%). MS:M / e 739(M+1) + .

[0318] Step C: 2-Butoxy-7-((5-(piperazin-1-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0319] A solution of tert-butyl 4-(6-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-3-yl)piperazine-1-carboxylate (75 mg, 0.1 mmol) in triethylsilane (1 mL) and trifluoroacetic acid (1 mL) was heated at 80° C. overnight and then at 100° C. for 4 hours. The solvent was evaporated to give a residue, which was purified by preparative HPLC to give the product (15 mg, 39%). 1 H NMR (400MHz, CD3OD) δ8.38(d,J=4.0Hz,1H),8.03(dd,J=8.0Hz,4.0Hz,1H),7.71(d,J=12.0Hz,1H),7.59(s,1H),4.58(s,2H),4.2 0(t,J=8.0Hz,2H),3.65(t,J=4.0Hz,4H),3.40(t,J=4.0Hz,4H),1.72-1.67(m,2H),1.47-1.43(m,2H),0.96(t,J=8.0Hz,3H)ppm. MS:M / e 383(M+1) + .

[0320] Compound B17: 2-Butoxy-7-((5-methoxy-6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0321] Compound B17 was prepared according to the general procedure for the preparation of compound B15 to give the target product (20 mg). 1 HNMR(400MHz,DMSO-d6)δ8.15(s,1H),8.04(br.s,2H),7.34(s,1H),7.32(s,1H),4.21(t,J=6.4Hz,2H),4.13(s,2H),3 .77(s,3H),3.19-3.03(m,3H),2.61(t,J=11.3Hz,2H),1.73-1.51(m,6H),1.42-1.36(m,2H),0.92(t,J=7.3Hz,3H)ppm. MS:M / e 412(M+1) + .

[0322] Compound B18: N2-butyl-7-(4-(piperidin-4-yl)benzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0323] Step A: tert-Butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-(butylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)phenyl)piperidine-1-carboxylate

[0324] 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) at -78°C was added n-butyllithium (1.6 M, 0.35 mL, 0.428 mmol) dropwise. After stirring under N2 for one hour, a solution of tert-butyl 4-(4-formylphenyl)piperidine-1-carboxylate (123 mg, 0.428 mmol) in THF (2 mL) was added dropwise at -78°C. Following the 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 (petroleum ether / EtOAc=2:1) ​​to give the target compound (98 mg, 47.8%). MS: M / e 736 (M+1) + .

[0325] Step B: N2-butyl-7-(4-(piperidin-4-yl)benzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0326] To a mixture of the product of step B (98 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 (45 mg, 87.2%). 1 H NMR(400MHz,DMSO-d6)δ8.71-8.63(m,1H),8.50-8.32(m,1H),7.81(br.s,2H),7.42(s,1 H),7.29(d,J=8.0Hz,2H),7.14(d,J=8.0Hz,2H),6.58(s,1H),4.09(s,2H),3.36(d,J=12. 4Hz,2H),3.17(t,J=7.2Hz,2H),3.05-2.92(m,2H),2.82-2.72(m,1H),1.89(d,J=13.2Hz ,2H),1.82-1.66(m,2H),1.56-1.44(m,2H),1.38-1.24(m,2H),0.89(t,J=7.2Hz,3H)ppm. MS:M / e 380(M+1) + .

[0327] Compound B19: 2-Butoxy-7-((6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0328] Compound B19 was prepared according to the general procedure for the preparation of compound B15 to give the product (19 mg). 1 H NMR(400MHz,DMSO-d6 with D2O)δ8.78(d,J=4.0Hz,1H),8.30(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.66(s,1H),4.44(s,2H),4.28(t,J=8.0Hz,2H),3.56(d,J=12.0Hz,2 H),3.35-3.32(m,1H),3.30-3.14(m,2H),2.19-2.11(m,2H),2.08-2.04 (m,2H),1.75-1.71(m,2H),1.50-1.46(m,2H),0.97(t,J=8.0Hz,3H)ppm. MS:M / e 382(M+1) + .

[0329] Compound B20: 2-Butoxy-7-(4-(piperidin-3-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0330] Compound B20 was prepared according to the general procedure for the preparation of compound B15 to give the target product (37 mg). 1 HNMR(400MHz,DMSO-d6)δ8.76(br.s,1H),8.44(s,1H),8.14(s,1H),8.08( s,1H),7.33(s,1H),7.29(d,J=7.4Hz,2H),7.20(d,J=7.5Hz,2H),4.20(t,J =6.3Hz,2H),4.12(s,2H),3.33-3.23(m,2H),2.98-2.88(m,4H),1.86(t,J =12.2Hz,2H),1.67-1.59(m,4H),1.42-1.34(m,2H),0.92(t,J=7.2Hz,3H). MS:M / e 381(M+1) + .

[0331] Compound B21: 2-Butoxy-7-((2-fluoro-6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0332] Compound B21 was prepared according to the general procedure for the preparation of compound B15 to give the target product (10 mg). 1 HNMR(400MHz,CD3OD)δ7.76(s,1H),7.42(s,1H)7.16(d,J=8Hz,1H),4.28-4.21(m,4H),3.35-3.27(m,2H ),3.14-2.99(m,3H),2.10-1.87(m,4H),1.78-1.69(m,2H),1.52-1.41(m,2H),0.98(t,J=6.0Hz,3H)ppm. MS:M / e 400(M+1) + .

[0333] Compound B22: 2-(Isopentyloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0334] Compound B22 was synthesized according to a similar procedure to that described for compound B2 starting from the corresponding starting materials. 1HNMR(400MHz,CD3OD)δ8.15(s,1H),7.61(s,1H),7.43(s,1H),4.38-4.28(m,2H),4.19(s,2H), 3.42-3.33(m,8H),2.29(s,3H),1.92-1.76(m,1H),1.72-1.63(m,2H)0.97(d,J=6.8Hz,6H)ppm. MS:M / e 411(M+1) + .

[0335] Compound B23: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentyloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0336] Compound B23 was synthesized according to a similar procedure as described for compound B2 starting from the corresponding starting materials. 1 HNMR(400MHz,CD3OD)δ8.15(s,1H),7.62(s,1H),7.45(s,1H),4.29(t,J=6.4Hz,2H),4.19(s,2H) ,3.41-3.33(m,8H),2.30(s,3H),1.84-1.72(m,2H),1.51-1.34(m,4H),0.95(t,J=6.8Hz,3H)ppm. MS:M / e 411(M+1) + .

[0337] Compound B24: 2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)ethan-1-one

[0338] Step A: tert-Butyl (2-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)carbamate

[0339] To a mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol), (tert-butyloxycarbonyl)glycine (18 mg, 0.1 mmol), and DIEA (25 mg, 0.2 mmol) in THF (5 mL) was added HATU (38 mg, 0.1 mmol). The reaction was stirred at room temperature overnight. The reaction solution was diluted with water, extracted with EA (50 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (60 mg, crude). MS: M / e 554 (M+1) + .

[0340] Step B: 2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)ethan-1-one

[0341] To a mixture of the product of step A (60 mg, crude) in DCM (5 mL) was added a 4M solution of HCl in EA (0.5 mL). The reaction was stirred at room temperature for 5 h. The mixture was concentrated and purified by preparative HPLC to give the title compound (18 mg, 32%). 1 H NMR (400MHz, CD3OD) δ8.12(s,1H),7.94(s,1H),7.52(s,1H),4.30(t,J=6.8Hz,2H),4.26(s,2H),4.00(s,2H),3.81(t,J=4.8H z,2H),3.63(t,J=4.8Hz,2H),3.43-3.31(m,4H),2.39(s,3H),1.82-1.70(m,2H),1.57-1.42(m,2H),0.98(t,J=7.6Hz,3H)ppm. MS:M / e 454(M+1) + .

[0342] Compound B25: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(2-phenoxyethoxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0343] Compound B25 was synthesized according to a similar procedure as described for compound B2 starting from the corresponding starting materials. 1HNMR(400MHz,CD3OD)δ8.19(s,1H),7.74(s,1H),7.56(s,1H),7.31-7.22(m,2H),7.00-6.87(m,3 H), 4.64 (t, J = 4.0Hz, 2H), 4.30 (t, J = 4.0Hz, 2H), 4.23 (s, 2H), 3.47-3.31 (m, 8H), 2.31 (s, 3H) ppm. MS:M / e 461(M+1) + .

[0344] Compound B26: 2-Butoxy-7-(3-ethoxy-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0345] Compound B26 was synthesized according to a similar procedure to that described for compound B16 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),8.02(s,1H),7.27(s,1H),6.91(s,1H),6.80-6.74(m,2H),4.22(t,J=8.0Hz,2H),4.04(s ,2H),3.98-3.94(m,2H),2.84(s,8H),1.70-1.64(m,2H),1.45-1.36(m,2H),1.31(t,J=8.0Hz,3H),0.93(t,J=8.0Hz,3H)ppm. MS:M / e 426(M+1) + .

[0346] Compound B27: 2-Butoxy-7-(4-(piperazin-1-yl)-3-(trifluoromethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0347] Compound B27 was synthesized according to a similar procedure to that described for compound B16 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),8.05(s,1H),7.33(s,1H),7.25-7.21(m,2H),7.03(d,J=12.0Hz,1H),4.19( t,J=8.0Hz,2H),4.11(s,2H),2.86-2.80(m,8H),1.70-1.63(m,2H),1.41-1.37(m,2H),0.92(t,J=8.0Hz,3H)ppm. MS:M / e 466(M+1) + .

[0348] Compound B28: 2-Butoxy-7-((6-(piperidin-4-yl)-5-(trifluoromethyl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0349] Compound B28 was prepared according to the general procedure for the preparation of compound B15 to give the target product (10 mg). 1 HNMR (400MHz, DMSO-d6)) δ8.77(s,1H),8.18(s,1H),8.07(s,2H),7.42(s,1H),4.26(s,2H),4.16(t,J=6.4Hz,2H),3.12-2.92(m ,4H),2.65-2.58(m,1H),1.84(d,J=11.2Hz,2H),1.70-1.60(m,2H),1.55-1.50(m,2H),1.41-1.36(m,2H),0.91(t,J=7.4Hz,3H). MS:M / e412(M+1) + .

[0350] Compound B29: 4-amino-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-ol

[0351] Step A: tert-Butyl (7-bromo-2-(furan-2-ylmethoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)carbamate

[0352] To a stirred solution of furan-2-ylmethanol (112 mg, 1.16 mmol) in THF (20 mL) was added NaH (88 mg, 2.32 mmol, 60% in oil) at 0°C. The reaction mixture was stirred at 0°C for 0.5 h. Tert-butyl (7-bromo-2-chloroimidazo[2,1-f][1,2,4]triazin-4-yl)carbamate (200 mg, 0.58 mmol) was added to the mixture, and the reaction mixture was stirred at 70°C for 6 h. H2O (20 mL) was added to the mixture 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 (140 mg, 59%). MS: M / e 410 (M+1) + .

[0353] Step B: tert-Butyl 4-(5-((4-((tert-butoxycarbonyl)amino)-2-(furan-2-ylmethoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0354] To a stirred solution of tert-butyl (7-bromo-2-(furan-2-ylmethoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)carbamate (210 mg, 0.51 mmol) in THF (10 mL) cooled to -78°C under a nitrogen atmosphere was added dropwise n-butyllithium (1.6 M in hexanes, 1.25 mmol, 0.78 mL). After stirring for 50 min, a solution of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (156 mg, 0.5 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 saturated ammonium chloride solution and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by column chromatography to give the title product (70 mg, 22%). MS: M / e 637 (M+1) + .

[0355] Step C: 4-amino-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-ol

[0356] A solution of tert-butyl 4-(5-((4-((tert-butoxycarbonyl)amino)-2-(furan-2-ylmethoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate (70 mg, 0.11 mmol) in TFA (3 mL) and EtSiH (3 mL) was stirred at rt overnight. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (15 mg, 40%). 1 H NMR (400MHz, DMSO-d6)) δ8.71(br.s,2H),8.08(s,2H),8.00(s,1H),7.48(s,1H),7.28(s,1H),4.05(s,2H),3.21(s,8H),2.21(s,3H)ppm. MS:M / e 341(M+1) + .

[0357] Compound B30: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-phenylethoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0358] Compound B30 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,DMSO-d6)δ8.70(br.s,2H),8.19(s,2H),8.10(s,1H),7.52(s,1H),7.43-7.26(m,5H),7.2 6-7.18(m,1H),4.40(t,J=8Hz,2H),4.09(s,2H),3.26-3.16(m,8H),3.02(t,J=8Hz,2H),2.17(s,3H)ppm. MS:M / e 445(M+1) + .

[0359] Compound B31: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(3-phenylpropyloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0360] Compound B31 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,CD3OD)δ8.14(s,1H),7.70-7.42(m,2H),7.30-7.12(m,5H),4.31(t,J=8Hz,2H),4.1 8(t,J=8Hz,2H),3.44-3.32(m,8H),2.78(t,J=8Hz,2H),2.29-2.24(m,3H),2.11-2.03(m,2H)ppm. MS:M / e 459(M+1) + .

[0361] Compound B32: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0362] Step A: tert-Butyl (2-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate

[0363] To a mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol), N-(tert-butyloxycarbonyl)-N-methylglycine (20 mg, 0.1 mmol), and DIEA (25 mg, 0.2 mmol) in THF (5 mL) was added HATU (38 mg, 0.1 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with EA (40 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (60 mg, crude). MS: M / e 568 (M+1) + .

[0364] Step B: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0365] To a mixture of the product of step A (60 mg, crude) in DCM (5 mL) was added a 4M HCl solution in EA (0.5 mL). The reaction was stirred at room temperature for 5 h. The mixture was concentrated and purified by preparative HPLC to give the title product (35 mg, 60% for two steps). 1 HNMR (400MHz, CD3OD) δ8.12(s,1H),7.93(s,1H),7.51(s,1H),4.30(t,J=6.4Hz,2H),4.25(s,2H),4.13(s,2H),3.80(t,J=4.8Hz,2H) ,3.62(t,J=4.8Hz,2H),3.43-3.31(m,4H),2.75(s,3H),2.38(s,3H),1.82-1.68(m,2H),1.57-1.42(m,2H),0.98(t,J=7.6Hz,3H)ppm. MS:M / e 468(M+1) + .

[0366] Compound B33: 2-Butoxy-7-((4-methyl-5-(piperazin-1-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0367] Step A: tert-Butyl 4-(6-(methoxycarbonyl)-4-methylpyridin-3-yl)piperazine-1-carboxylate

[0368] To a flask containing methyl 5-bromo-4-methylpicolinate (1.15 g, 5 mmol), tert-butyl piperazine-1-carboxylate (1.12 g, 6 mmol), BINAP (311 mg, 0.5 mmol), Pd2(dba)3 (575 mg, 1 mmol) and Cs2CO3 (3.26 g, 10 mmol) was added toluene (10 mL) under nitrogen. The mixture was stirred at 100°C overnight. After cooling to room temperature, the solvent was removed by rotary evaporation. The residue was dissolved in EA (20 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give the target compound (593 mg, 35%). MS: M / e 336 (M+1) + .

[0369] Step B: tert-Butyl 4-(6-(hydroxymethyl)-4-methylpyridin-3-yl)piperazine-1-carboxylate

[0370] To a solution of the product of step A (590 mg, 1.76 mmol) in THF (5 mL) was added LiAlH4 (134 mg, 3.52 mmol). After stirring at 0°C for 30 min, the mixture was then stirred at room temperature for another 2 hours. 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 (288 mg, 53%). MS: M / e 308 (M+1) + .

[0371] Step C: tert-Butyl 4-(6-formyl-4-methylpyridin-3-yl)piperazine-1-carboxylate

[0372] To a solution of the product from step B (288 mg, 0.94 mmol) in DCM (5 mL) was added Dess-Martin periodinane (796 mg, 1.88 mmol). After stirring at room temperature for 1 hour, the solution was quenched with saturated NaHCO solution (5 mL). The aqueous solution was extracted with DCM (15 ml x 3). The collected organic layer was washed with brine, dried over NaSO, filtered and concentrated. The resulting residue was purified by column chromatography to give the product (220 mg, 78%). MS: M / e 306 (M+1) + .

[0373] Step D: tert-Butyl 4-(6-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-4-methylpyridin-3-yl)piperazine-1-carboxylate

[0374] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (211 mg, 0.4 mmol) in THF (2 mL) was added a solution of n-butyllithium (0.38 mL, 0.6 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 10 min, a solution of the product from step C (183 mg, 0.6 mmol) in THF (3 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 4), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the title compound (127 mg, 42%). MS: M / e 753 (M+1) + .

[0375] Step E: 2-Butoxy-7-((4-methyl-5-(piperazin-1-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0376] To a mixture of the product from step D (127 mg, 0.17 mmol) in TFA (5 mL) was added Et3SiH (1 mL). The reaction was heated at 80°C for 2 days. 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 product (4 mg, 6%). 1H NMR(400MHz,DMSO-d6)δ9.17(br.s,2H),8.17(s,1H),8.06(s,1H),7.33(s,1H),7.21(s,1H),4.24(s,2H),4.15(t,J=6.3Hz,2H) ,3.24-3.19(m,4H),3.14-3.07(m,4H),2.24(s,3H),1.74-1.53(m,3H),1.38(dq,J=14.6,7.2Hz,3H),0.90(t,J=7.3Hz,3H).ppm. MS:M / e 398(M+1)+.

[0377] Compound B34: 2-Butoxy-7-((5-methyl-6-(piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0378] Compound B34 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1HNMR(400MHz, DMSO-d6))δ8.13(s,1H),8.05(s,2H),7.41(d,J=2.0Hz,1H),7.31(s,1H),4.21(t,J=6.5Hz,2H),4.03(s,2H),2.98-2.89(m, 4H), 2.17 (s, 3H), 1.68 (dd, J = 14.1, 7.4Hz, 2H), 1.61 (t, J = 7.9Hz, 4H), 1.53 (d, J = 4.6Hz, 2H), 1.45-1.34 (m, 2H), 0.92 (t, J = 7.4Hz, 3H) ppm. MS:M / e 396(M+1) + .

[0379] Compound B35: 7-((6-(azepan-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0380] Compound B35 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 HNMR (400MHz, DMSO-d6)) δ8.13(s,1H),8.03(s,1H),7.97(d,J=1.8Hz,1H),7.33(d,J=1.8Hz,1H),7.30(s,1H),4.21(t,J=6.5Hz,2H ),3.99(s,2H),3.37-3.28(m,4H),2.18(s,3H),1.75-1.63(m,6H),1.59-1.51(m,4H),1.46-1.35(m,2H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e 410(M+1) + .

[0381] Compound B36: 2-Butoxy-7-(3-methyl-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0382] Step A: tert-Butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-methylphenyl)piperazine-1-carboxylate

[0383] 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 tert-butyl 4-(4-formyl-2-methylphenyl)piperazine-1-carboxylate (130 mg, 0.43 mmol) in THF (2 mL) was then added dropwise at -78°C. After addition, the mixture was warmed to room temperature and stirred for 3 hours. 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 (85 mg, 39.7%) as a yellow oil. MS: M / e 752 (M+1) + .

[0384] Step B: 2-Butoxy-7-(3-methyl-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0385] A mixture of tert-butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-methylphenyl)piperazine-1-carboxylate (85 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 title product (17 mg, 38%). 1 H NMR (400MHz, DMSO-d6) δ8.72(br.s,2H),8.14(s,1H),8.08(s,1H),7.32(s,1H),7.16(s,1H),7.11(d,J=8.4Hz,1H),6.96(d,J=8.4Hz,1H),4.22( t,J=6.5Hz,2H),4.05(s,2H),3.25-3.12(m,4H),3.13-2.97(m,4H),2.21 (s,3H),1.75-1.61(m,2H),1.48-1.34(m,2H),0.93(t,J=7.4Hz,3H)ppm. MS:M / e 396(M+1) + .

[0386] Compound B37: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-3-(dimethylamino)propan-1-one

[0387] A mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.05 mmol), 3-(dimethylamino)propanoic acid (6 mg, 0.05 mmol), HATU (23 mg, 0.06 mmol) and DIPEA (19 mg, 0.15 mmol) in DCM (3 mL) was stirred at rt for 2 h. The mixture was extracted with DCM (10 mL) and washed with water (5 ml), dried over Na2SO4, concentrated, and purified by preparative HPLC to give the product (12 mg, 47.88%). 1 H NMR(400MHz,DMSO-d6)δ9.12(br.s,1H),8.16(s,1H),8.10(s,2H),7.54(s, 1H),7.35(d,J=2.4Hz,1H),4.21(t,J=6.5Hz,2H),4.08(s,2H),3.64-3.56(m ,4H),3.35-3.01(m,6H),2.87(t,J=6.7Hz,2H),2.79(s,3H),2.78(s,3H),2 .24(s,3H),1.73-1.62(m,2H),1.47-1.35(m,2H),0.93(t,J=7.4Hz,3H)ppm. MS:M / e 496(M+1) + .

[0388] Compound B38: 2-Butoxy-7-((5-methyl-6-(octahydro-2H-isoindol-2-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0389] Compound B38 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1HNMR(400MHz,DMSO-d6)δ8.12(s,1H),8.03(s,1H),7.88(s,1H),7.27(s,1H),7.25(s,1H),4.22(t,J=8.0Hz,2H),3.95(s,2H),3 .44-3.39(m,2H),3.37-3.33(m,2H),2.23(s,3H),2.16(s,2H),1.68-1.67(m,2H),1.51-1.33(m,10H),0.93(t,J=8.0Hz,3H)ppm. MS:M / e 436(M+1) + .

[0390] Compound B39: 7-((6-(1,4-diazepan-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0391] Compound B39 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,DMSO-d6)δ8.67(br.s,2H),8.16(s,1H),8.10(s,1H),8.04(s ,1H),7.51(s,1H),7.34(s,1H),4.22(t,J=8.0Hz,2H),4.06(s,2H),3.57(d, J=4.0Hz,2H),3.37(t,J=4.0Hz,2H),3.28-3.24(m,4H),2.22(s,2H),2.02-2 .00(m,2H),1.69-1.65(m,2H),1.42-1.39(m,2H),0.93(t,J=8.0Hz,3H)ppm. MS:M / e 411(M+1) + .

[0392] Compound B40: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(piperazin-1-yl)ethan-1-one

[0393] Step A: tert-Butyl 4-(2-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)piperazine-1-carboxylate

[0394] A mixture of 2-butoxy-7-((5-methyl-6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.05 mmol), 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (15 mg, 0.06 mmol), HATU (23 mg, 0.06 mmol), and DIPEA (12.9 mg, 0.1 mmol) in THF (3 mL) was stirred overnight. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the target compound (crude, 100%), which was used directly in the next step. MS: M / e 623 (M+1) + .

[0395] Step B: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(piperazin-1-yl)ethan-1-one

[0396] To a stirred solution of the product of step A (0.05 mmol) in CH2Cl2 (5 mL) was added dioxane / HCl (g) (4.0 M, 2 mL). After addition, the reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the title compound (12 mg, 45.9%). 1 H NMR(400MHz,DMSO-d6)δ9.20(br.s,2H),8.19(s,1H),8.14(s,1H),8.10(s,1H),7 .56(s,1H),7.38(s,1H),4.29(s,2H),4.21(t,J=6.4Hz,2H),4.09(s,2H),3.66-3. 62(m,2H),3.49-3.45(m,2H),3.43-3.30(m,7H),3.12-3.09(m,2H),3.07-3.01(m, 2H), 2.24 (s, 3H), 1.76-1.63 (m, 2H), 1.49-1.34 (m, 2H), 0.90 (t, J = 7.2Hz, 3H) ppm. MS:M / e 523(M+1) + .

[0397] Compound B41: (4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)(piperazin-2-yl)methanone

[0398] Step A: Di-tert-butyl 2-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazine-1-carbonyl)piperazine-1,4-dicarboxylate

[0399] A mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.05 mmol), 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (20 mg, 0.06 mmol), HATU (23 mg, 0.06 mmol), DIPEA (12.9 mg, 0.1 mmol) in THF (3 mL) was stirred overnight. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the target compound (crude, 100%), which was used directly in the next step. MS: M / e 709 (M+1) + .

[0400] Step B: (4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)(piperazin-2-yl)methanone

[0401] To a stirred solution of the product of step A (0.05 mmol) in CH2Cl2 (5 mL) was added dioxane / HCl (g) (4.0 M, 2 mL). After addition, the reaction mixture was concentrated to give a residue, which was purified by preparative HPLC to give the title compound (10 mg, 39.3%). 1 H NMR (400MHz, DMSO-d6) δ8.20 (s, 1H), δ8.16 (s, 1H), 8.11 (d, J = 1.6Hz, 1H), 7.57 (d,J=1.6Hz,1H),7.39(s,1H),4.80(d,J=10.8Hz,1H),4.22(t,J=6.6Hz,2H),4. 09(s,2H),3.780-3.72(m,2H),3.65-3.50(m,5H),3.29-2.95(m,7H),2.24(s,3H ), 2.08 (s, 1H), 1.74-1.62 (m, 2H), 1.48-1.35 (m, 2H), 0.93 (t, J = 7.2Hz, 3H) ppm. MS:M / e509(M+1) + .

[0402] Compound B42: 2-(2-(1H-imidazol-1-yl)ethoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0403] Step A: 2-(2-(1H-imidazol-1-yl)ethoxy)-7-bromo-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0404] To a suspension of NaH (80 mg, 2 mmol) in THF (8 mL) was added 2-(1H-imidazol-1-yl)ethane-1-ol (224 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]triazin-4-amine (240 mg, 0.5 mmol) in THF (1 mL) was added. The mixture was then stirred at 80°C overnight. 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 (170 mg, 60%) as a solid. MS: M / e 564 (M+1) + .

[0405] Compound B42 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,CD3OD)δ9.06(s,1H),8.17(s,1H),7.76(d,J=1.2Hz,1H),7.64(s,1H),7.60 (m,1H),7.39(s,1H),4.75-4.68(m,4H),4.19(s,2H),3.41-3.36(m,8H),2.31(s,3H)ppm. MS:M / e 435(M+1) + .

[0406] Compound B43: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(octyloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0407] Compound B43 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1HNMR(400MHz,DMSO-d6)δ8.67(br.s,2H),8.16(s,1H),8.10(d,J=2.0Hz,1H),8.09(s,1H),7.52(s,1H),7.34(m,1H),4.20(t, J=6.4Hz,2H),4.07(s,2H),3.30-3.10(m,8H),2.21(s,3H),1.75-1.64(m,2H),1.45-1.15(m,10H),0.85(t,J=6.8Hz,3H)ppm. MS:M / e 453(M+1) + .

[0408] Compound B44: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0409] To a mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol) in CH 3 CN (3 mL) at 0° C. was added saturated NaHCO 3 (0.5 mL) and then a solution of acryloyl chloride (9 mg, 0.1 mmol) in CH 3 CN (0.1 mL). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with water, extracted with EA (40 mL x 2), washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (16 mg, 36%). 1 HNMR(400MHz,DMSO-d6)δ8.14(s,1H),8.08(d,J=1.6Hz,1H),8.04(s,1H),7.41(d,J= 1.6Hz,1H),7.31(s,1H),6.90-6.75(m,1H),6.13(dd,J=16.8,2.4Hz,1H),5.69(dd,J =10.8,2.4Hz,1H),4.20(t,J=6.4Hz,2H),4.05(s,2H),3.80-3.55(m,4H),3.06-2.94 (m,4H),2.22(s,3H),1.75-1.60(m,2H),1.46-1.33(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 451(M+1) + .

[0410] Compound B45: 2-Butoxy-7-(3-methoxy-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0411] Compound B45 was synthesized according to a similar procedure as described for compound B2 starting from the corresponding starting materials. 1 HNMR(400MHz,DMSO-d6)δ8.23-7.85(m,2H),7.28(s,1H),6.94(s,1H),6.82-6.75(m,2H),4.22(t,J=6.4Hz,2H) ,4.06(s,2H),3.74(s,3H),2.91-2.78(m,8H),1.76-1.59(m,2H),1.48-1.35(m,2H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 412(M+1) + .

[0412] Compound B46: 2-Butoxy-7-(3-isopropoxy-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0413] Compound B46 was synthesized according to a similar procedure to that described for compound B16 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.21-7.87(m,2H),7.21(s,1H),6.82(s,1H),6.77-6.63(m,2H),4.59-4.35(m,1H),4.26-4.08(m ,2H),3.97(s,2H),2.99-2.66(m,8H),1.74-1.53(m,2H),1.45-1.27(m,2H),1.24-1.06(m,6H),0.85(t,J=7.2Hz,3H)ppm. MS:M / e 440(M+1) + .

[0414] Compound B47: 2-Butoxy-7-((4-methyl-5-(piperidin-4-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0415] Step A: (5-Bromo-4-methylpyridin-2-yl)methanol

[0416] BH3·THF (20 mL, 20 mmol) was added to a solution of 5-bromo-4-methylpicolinic acid (2.16 g, 10 mmol) in THF (10 mL). The reaction mixture was heated at 80°C for 2 hours and cooled to room temperature. The solution was quenched with CH3OH (10 mL) and H2O (10 ml). The aqueous solution was extracted with EA (20 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 (515 mg, 25%). MS: M / e 203 (M+1) + .

[0417] Step B: tert-Butyl 6-(hydroxymethyl)-4-methyl-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-carboxylate

[0418] Under nitrogen, to a flask containing (5-bromo-4-methylpyridin-2-yl)methanol (515 mg, 2.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.01 g, 3.3 mmol), dppf·PdCl2 (368 mg, 0.5 mmol) and K2CO3 (696 mg, 5 mmol) were added 1,4-dioxane (10 ml) and H2O (1 mL). The mixture was stirred at 80°C overnight. After cooling to room temperature, the solvent was removed by rotary evaporation. The residue was dissolved in EA (20 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give the target compound (300 mg, 39%). MS: M / e 305 (M+1) + .

[0419] Step C: tert-Butyl 4-(6-(hydroxymethyl)-4-methylpyridin-3-yl)piperidine-1-carboxylate

[0420] The product of step B (300 mg, 0.98 mmol) was dissolved in CH3OH (5 mL), Pd / C (30 mg) was added and saturated with hydrogen from a balloon and stirred at room temperature for 3 days. The hydrogen was removed and the reaction mixture was filtered through a pad of celite, the solid was washed with methanol and the filtrate was concentrated to dryness. The residue was purified by column chromatography to give the title compound (90 mg, 30%). MS: M / e 307 (M+1) + .

[0421] Step D: tert-Butyl 4-(6-formyl-4-methylpyridin-3-yl)piperidine-1-carboxylate

[0422] To a solution of the product from step C (90 mg, 0.29 mmol) in DCM (2 mL) was added Dess-Martin periodinane (124 mg, 0.58 mmol). After stirring at room temperature for 1 hour, the solution was quenched with saturated NaHCO solution (5 mL). The aqueous solution was extracted with DCM (10 ml x 4). The collected organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The resulting residue was purified by column chromatography to obtain the product (75 mg, 83%).

[0423] Step E: tert-Butyl 4-(6-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-4-methylpyridin-3-yl)piperidine-1-carboxylate

[0424] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (131 mg, 0.25 mmol) in THF (1 mL) was added dropwise a solution of n-butyllithium (0.19 mL, 0.3 mmol), maintaining the temperature between -75°C and -65°C. After 10 min, a solution of the product from step D (75 mg, 0.25 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 4), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the title compound (20 mg, 11%). MS: M / e 753 (M+1) + .

[0425] Step F: 2-Butoxy-7-((4-methyl-5-(piperidin-4-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0426] To a mixture of the product of step E (20 mg, 0.026 mmol) in TFA (2 mL) was added Et3SiH (0.5 mL). The reaction was heated at 80°C for 2 days. The mixture was concentrated, and the residue was purified by preparative HPLC and concentrated to give the product (5 mg, 45%). 1H NMR (400MHz, CD3OD) δ8.89-8.20(m,1H),7.90-7.16(m,2H),4.61-4.41(m,2H),4.19(s,2H),3.57-3.51(m,2H),3.20(t,J=12.5H z,2H),2.78-2.65(m,1H),2.63-2.36(m,3H),2.21-1.93(m,4H),1.80-1.63(m,2H),1.51-1.41(m,2H),0.96(t,J=7.4Hz,3H)ppm. MS:M / e 396(M+1) + .

[0427] Compound B48: 2-Butoxy-7-((4-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0428] Step A: tert-Butyl 4-(5-(methoxycarbonyl)-4-methylpyridin-2-yl)piperazine-1-carboxylate

[0429] DIPEA (1.7 g, 13 mmol) was added to a solution of methyl 6-chloro-4-methylnicotinate (1.85 g, 10 mmol) and tert-butyl piperazine-1-carboxylate (2.24 g, 12 mmol) in DMA (15 mL). The reaction mixture was heated at 120 ° C for 3 hours and then cooled to room temperature. The solution was quenched with H2O (10 ml). The aqueous solution was extracted with EA (20 ml × 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 (2.4 g, 72%). MS: M / e 336 (M+1) + .

[0430] Step B: tert-Butyl 4-(5-(hydroxymethyl)-4-methylpyridin-2-yl)piperazine-1-carboxylate

[0431] To a solution of the product from step A (670 mg, 2 mmol) in THF (5 mL) was added LiAlH4 (112 mg, 4 mmol). After stirring at 0°C for 2 hours, the reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (10 mL x 5), washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was used in the next step without further purification (614 mg). MS: M / e 308 (M+1) + .

[0432] Step C: tert-Butyl 4-(5-formyl-4-methylpyridin-2-yl)piperazine-1-carboxylate

[0433] To a solution of the product of step A (307 mg, 1 mmol) in EA (10 mL) was added IBX (560 mg, 2 mmol). After stirring at 80°C for 2 hours, the reaction was cooled to room temperature, the resulting mixture was filtered through celite, and the solid was washed with EtOAc (10 mL x 4). The filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography to give the product (220 mg, 72%). MS: M / e 306 (M+1) + .

[0434] Step D: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-4-methylpyridin-2-yl)piperazine-1-carboxylate

[0435] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (158 mg, 0.3 mmol) in THF (1 mL) was added dropwise a solution of n-butyllithium (0.3 mL, 0.45 mmol), maintaining the temperature between -75°C and -65°C. After 10 minutes, a solution of the product from step C (138 mg, 0.45 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 30 minutes. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (10 mL x 4), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the title compound (80 mg, 78%). MS: M / e 754 (M+1) + .

[0436] Step E: 2-Butoxy-7-((4-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0437] To a mixture of the product from step D (180 mg, 0.24 mmol) in TFA (5 mL) was added Et3SiH (1 mL). The reaction was heated at 80°C for 2 days. 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 product (25 mg, 26%). 1H NMR (400MHz, CD3OD) δ8.01(s,1H),7.19(s,1H),6.74(s,1H),4.29(t,J=6.5Hz,2H),4.11(s,2H),3.68-3.5 1(m,4H),3.20-3.04(m,4H),2.30(s,3H),1.92-1.68(m,2H),1.59-1.39(m,2H),0.98(t,J=7.4Hz,3H)ppm. MS:M / e 397(M+1) + .

[0438] Compound B49: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-4-(dimethylamino)butan-1-one

[0439] A mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.05 mmol), 4-(dimethylamino)butanoic acid (6 mg, 0.05 mmol), HATU (23 mg, 0.06 mmol) and DIPEA (19 mg, 0.15 mmol) in DCM (3 mL) was stirred at rt for 2 h. The mixture was extracted with DCM (10 mL) and washed with water (5 ml), dried over Na2SO4, concentrated and purified by preparative HPLC to give the title product (13 mg, 50.4%). 1 H NMR(400MHz,DMSO-d6)δ9.33(br.s,1H),8.15(s,1H),8.09(s,2H),7.53(s,1H),7.3 4(s,1H),4.21(t,J=6.6Hz,2H),4.07(s,2H),3.57(d,J=14.8Hz,4H),3.05(t,J=7.6 Hz,4H),2.98(s,2H),2.78(s,3H),2.77(s,3H),2.46(t,J=7.0Hz,2H),2.23(s,3H), 1.92-1.78(m,2H),1.73-1.61(m,2H),1.47-1.34(m,2H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e510(M+1) + .

[0440] Compound B50: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-5-(dimethylamino)pentan-1-one

[0441] A mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.05 mmol), 5-(dimethylamino)pentanoic acid (7 mg, 0.05 mmol), HATU (23 mg, 0.06 mmol) and DIPEA (19 mg, 0.15 mmol) in DCM (3 mL) was stirred at rt for 2 h. The mixture was extracted with DCM (10 mL) and washed with water (5 ml), dried over Na2SO4, concentrated and purified by preparative HPLC to give the title product (10 mg, 37.8%). 1 H NMR(400MHz,DMSO-d6)δ9.22(br.s,1H),8.15(s,1H),8.08(s,2H),7.52(s,1H ),7.33(s,1H),4.21(t,J=6.5Hz,2H),4.07(s,2H),3.62-3.51(m,4H),3.12-2. 95(m,6H),2.76(s,3H),2.75(s,3H),2.40(t,J=6.9Hz,2H),2.22(s,3H),1.74 -1.58(m,4H),1.58-1.49(m,2H),1.46-1.34(m,2H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e 524(M+1) + .

[0442] Compound B51: 2-Butoxy-7-((5-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0443] Compound B51 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1HNMR(400MHz, DMSO-d6)))δ8.17(s,1H),8.08(s,1H),7.81(s,1H),7.63(s,1H),7.32(s,1H),4.21(t,J=6.4Hz,2H), 4.04(s,2H),3.61(s,4H),2.40(s,3H),1.91(s,4H),1.75-1.61(m,2H),1.48-1.35(m,2H),0.93(t,J=7.4Hz,3H)ppm. MS:M / e 382(M+1) + .

[0444] Compound B52: 2-Butoxy-7-((5-methyl-6-morpholinopyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0445] Compound B52 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz, DMSO-d6))δ8.17(s,1H),8.14(s,1H),8.10(s,1H),7.63(s,1H),7.38-7.34(m,1H),4.21(t,J=6.4Hz,2H),4 .10(s,2H),3.76-3.67(m,4H),3.10(s,4H),2.23(s,3H),1.76-1.61(m,2H),1.48-1.31(m,2H),0.93(t,J=7.3Hz,3H)ppm. MS:M / e 398(M+1) + .

[0446] Compound B53: 2-Butoxy-7-((2-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0447] Compound B53 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1HNMR(400MHz,DMSO-d6)δ8.88(br.s,2H),8.19(s,2H),7.55(d,J=8.0Hz,1H),7.33(s,1H),6.79(d,J=8.0Hz,1H),4.20(t,J=8.0Hz, 2H), 4.06 (s, 2H), 3.68 (t, J = 4.0Hz, 4H), 3.19 (s, 4H), 2.44 (s, 3H), 1.70-1.64 (m, 2H), 1.44-1.37 (m, 2H), 0.93 (t, J = 8.0Hz, 3H) ppm. MS:M / e 397(M+1) + .

[0448] Compound B54: 2-Butoxy-7-((2-methyl-6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0449] Step A: tert-Butyl 5-formyl-6-methyl-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate

[0450] A solution of 6-chloro-2-methylnicotinaldehyde (500 mg, 3.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 3.5 mmol), Pd(dppf)Cl (224 mg, 0.30 mmol) and KCO (662 mg, 4.8 mmol) in dioxane / water (1:1, 10 mL) was heated at 80° C. under a N atmosphere overnight. The solution was cooled, evaporated, water (10 mL) was added thereto and extracted with ethyl acetate (20 mL). The organic layer was dried over NaSO, filtered and concentrated to give the crude product, which was further purified by CombiFlash (PE:EA=25%) to give the pure product (718 mg, 74%) as a colorless oil. MS:M / e 303(M+1) + .

[0451] Step B: tert-Butyl 5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-6-methyl-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate

[0452] 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]triazin-4-amine (200 mg, 0.38 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.60 mL) dropwise under a purging (1 mL / min). After stirring at -78°C for 30 minutes, tert-butyl 5-formyl-6-methyl-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate (173 mg, 0.57 mmol) in THF (2 mL) was added. The resulting mixture was stirred at this temperature for 30 minutes and then allowed to warm to room temperature overnight. 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 (PE:EA=35%) to give the product (123 mg, 43%). MS: M / e 750 (M+1) + .

[0453] Step C: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-6-methylpyridin-2-yl)piperidine-1-carboxylate

[0454] A solution of tert-butyl 5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-6-methyl-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate (123 mg, 0.16 mmol) and Pd / C (27 mg) in ethyl acetate (10 mL) was stirred at rt under a H2 balloon for 48 h. The catalyst was filtered and the filtrate was concentrated to give the crude product, which was used directly in the next step (110 mg, 89%). MS: M / e 752 (M+1) + .

[0455] Step D: 2-Butoxy-7-((2-methyl-6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0456] A solution of tert-butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-6-methylpyridin-2-yl)piperidine-1-carboxylate (110 mg, 0.15 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (2 mL) was heated at 85 ° C overnight, then concentrated, 2 mL of trifluoroacetic acid was added thereto, and heated at 90 ° C for 6 hours. The solvent was evaporated to give a residue, which was basified with NaHCO (5 mL), extracted with ethyl acetate (5 mL), and washed with brine. The organic layer was dried, concentrated, and purified by preparative HPLC to give the product (40 mg, 69%). 1 H NMR(400MHz,DMSO-d6)δ8.72(br.s,1H),8.41(br.s,1H),8.21(s,1H),8.14(s,1H ),7.80(br.s,1H),7.37(s,1H),7.27(br.s,1H),4.22(s,2H),4.16(t,J=8.0Hz,2 H),3.39(d,J=12.0Hz,2H),3.02-2.97(m,3H),2.62(s,3H),2.03-2.00(m,2H),1. 91-1.82(m,2H),1.69-1.62(m,2H),1.44-1.35(m,2H),0.91(t,J=8.0Hz,3H)ppm. MS:M / e 396(M+1) + .

[0457] Compound B55: 2-Butoxy-7-((6-(3,5-dimethylpiperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0458] Compound B55 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,DMSO-d6)δ8.95(br.s,1H),8.31(br.s,1H),8.15(s,1H),8.11(s,2H),7.52(s,1H),7.34(s,1H),4.21(t,J=8.0Hz,2H),4.08(s, 2H),3.48-3.45(m,4H),2.75-2.69(m,2H),2.24(s,3H),1.68-1.64(m,2 H), 1.44-1.38 (m, 2H), 1.22 (d, J = 4.0Hz, 6H), 0.93 (t, J = 8.0Hz, 3H) ppm. MS:M / e 425(M+1)+ .

[0459] Compound B56: (4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)(piperidin-4-yl)methanone

[0460] Step A: tert-Butyl 4-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0461] To a mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (23 mg, 0.1 mmol), and DIEA (25 mg, 0.2 mmol) in THF (5 mL) was added HATU (38 mg, 0.1 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with EA (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (60 mg, crude). MS: M / e 608 (M+1) + .

[0462] Step B: (4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)(piperidin-4-yl)methanone

[0463] To a mixture of the product of step A (60 mg, crude) in DCM (5 mL) was added a 4M solution of HCl in EA (0.5 mL). The reaction was stirred at room temperature for 3 h. The mixture was concentrated and purified by preparative HPLC to give the title compound (20 mg, 32%). 1 HNMR (400MHz, CD3OD) δ8.15(d,J=1.6Hz,1H),8.08(s,1H),7.68(d,J=2.0Hz,1H),4.32(t,J=6.8Hz,2H),4.31(s,2H),3.90-3.75(m,4H) ,3.55-3.38(m,6H),3.18-3.03(m,3H),2.43(s,3H),2.06-1.84(m,4H),1.81-1.71(m,2H),1.57-1.42(m,2H),0.98(t,J=7.6Hz,3H)ppm. MS:M / e508(M+1)+ .

[0464] Compound B57: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)ethan-1-one

[0465] To a mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol) in THF (4 mL) was added DIEA (25 mg, 0.2 mmol). A solution of acetyl chloride in DCM (0.1 mL, 1 mol / L) was then added dropwise. The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with EA (50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the title compound (20 mg, 46%). 1 HNMR(400MHz,DMSO-d6)δ8.14(s,1H),8.08(d,J=1.6Hz,1H),8.05(s,1H),7.47(s,1H),7.31(s,1H),4.20(t,J=6.8Hz,2H),4.05(s,2H),3.61-3.5 0(m,4H),3.01(t,J=4.8Hz,2H),2.93(t,J=4.8Hz,2H),2.21(s,3H),2.03 (s,3H),1.74-1.60(m,2H),1.51-1.34(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 439(M+1) + .

[0466] Compound B58: N-(2-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)-N-methylacetamide

[0467] To a mixture of 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one hydrochloride (60 mg, crude) in THF (4 mL) was added DIEA (129 mg, 1 mmol). A solution of acetyl chloride in DCM (0.1 mL, 1 mol / L) was then added dropwise. The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with EA (40 mL x 2), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the title product (10 mg, 20% for three steps). 1 H NMR(400MHz,CD3OD)δ8.08(d,J=2.4Hz,1H),7.55(s,1H),7.34(s,1H),4.40-4.31( m,2H),4.28(t,J=6.0Hz,2H),4.15(s,2H),3.78-3.69(m,2H),3.68-3.59(m,2H),3. 18-3.12(m,2H),3.11-3.06(m,2H),3.09(s,2H),2.92(s,1H),2.29(s,3H),2.15(s ,2H),2.00(s,1H),1.82-1.68(m,2H),1.57-1.42(m,2H),0.98(t,J=7.6Hz,3H)ppm. MS:M / e 510(M+1) + .

[0468] Compound B59: 2-Butoxy-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0469] Step A: 6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylnicotinaldehyde

[0470] DIPEA (2.6 g, 20 mmol) was added to a solution of methyl 6-chloro-4-methylnicotinate (1.87 g, 12 mmol) and N,N-dimethyl-1-(piperidin-4-yl)methanamine (1.42 g, 10 mmol) in DMA (10 mL), and the reaction mixture was heated at 120 ° C. overnight and cooled to room temperature. The solution was quenched with H2O (10 ml). The aqueous solution was extracted with EA (25 ml × 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 (720 mg, 27%). MS: M / e261 (M+1)+ .

[0471] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0472] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (158 mg, 0.3 mmol) in THF (1 mL) was added a solution of n-butyllithium (0.28 mL, 0.45 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 10 minutes, a solution of the product from step A (118 mg, 0.45 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 30 minutes. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (10 mL x 4), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the title compound (100 mg, 47%). MS: M / e 709 (M+1) + .

[0473] Step C: 2-Butoxy-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0474] To a mixture of the product from step B (100 mg, 0.24 mmol) in TFA (4 mL) was added Et3SiH (1 mL). The reaction was heated at 80°C for 24 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 product (55 mg, 77%). 1H NMR(400MHz,CD3OD)δ8.03(d,J=1.6Hz,1H),7.47(s,1H),7.32(s,1H),4.27(t,J =6.5Hz,2H),4.11(s,2H),3.35(d,J=12.6Hz,2H),2.74(t,J=11.5Hz,2H),2.28(s ,2H),2.26(s,6H),2.23(s,3H),1.83(d,J=11.6Hz,2H),1.77-1.61(m,3H),1.49 (dt,J=15.0,7.4Hz,2H), 1.33(qd,J=12.4,3.6Hz,2H), 0.97(t,J=7.4Hz,3H)ppm. MS:M / e 453(M+1) + .

[0475] Compound B60: 7-((6-(4-aminopiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0476] Step A: tert-Butyl (1-(5-formyl-3-methylpyridin-2-yl)piperidin-4-yl)carbamate

[0477] DIPEA (2.6 g, 20 mmol) was added to a solution of methyl 6-chloro-4-methylnicotinate (1.56 g, 10 mmol) and tert-butylpiperidin-4-ylcarbamate (2.4 g, 12 mmol) in DMA (10 mL), and the reaction mixture was heated at 120 ° C. overnight and cooled to room temperature. The solution was quenched with H2O (10 ml). The aqueous solution was extracted with EA (25 ml × 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 (1.3 g, 41%). MS: M / e 320 (M+1) + .

[0478] Step B: tert-Butyl (1-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperidin-4-yl)carbamate

[0479] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (158 mg, 0.3 mmol) in THF (1 mL) was added a solution of n-butyllithium (0.28 mL, 0.45 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 10 minutes, a solution of the product from step A (144 mg, 0.45 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 30 minutes. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (10 mL x 4), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the title compound (140 mg, 61%). MS: M / e 767 (M+1) + .

[0480] Step C: 7-((6-(4-aminopiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0481] To a mixture of the product from step B (140 mg, 0.18 mmol) in TFA (4 mL) was added Et3SiH (1 mL). The reaction was heated at 80°C for 24 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 (40 mg, 54%). 1 H NMR (400MHz, CD3OD) δ=8.03(s,1H),7.48(s,1H),7.32(s,1H),4.27(t,J=6.5,2H),4.11(s,2H),3.36(d,J=13.0,2H),2.96-2.87(m,1H),2.79(t, J=11.8,2H),2.24(s,3H),1.95(d,J=11.1,2H),1.80-1.68(m,2H),1.59( qd,J=12.1,3.8,2H), 1.47(dt,J=14.6,7.4,2H), 0.97(t,J=7.4,3H)ppm. MS:M / e 411(M+1) + .

[0482] Compound B61: 2-Butoxy-7-(4-(3,5-dimethylpiperazin-1-yl)-3-methylbenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0483] Compound B61 was synthesized according to a similar procedure as described for compound B16 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.10(s,1H),8.01(s,1H),7.28(s,1H),7.10(s,1H),7.05(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H),4.21(t,J=8.0 Hz,2H),4.02(s,2H),2.87-2.80(m,4H),2.18(s,3H),2.12-2.07(m,2H),1.71-1.64(m,2H),1.43-1.38(m,2H),0.94(t,J=8.0Hz,9H)ppm. MS:M / e 424(M+1) + .

[0484] Compound B62: 2-methoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0485] Step A: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-chloroimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0486] At -78°C (with N 2 To a cooled solution of 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (1 g, 2 mmol) in THF (20 mL) was added dropwise n-butyllithium (1.6 M, 3.2 mL) under a purging (pressure). After stirring at -78°C for 30 min, tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (915 mg, 3.0 mmol) in THF (10 mL) was added. The resulting mixture was stirred at this temperature for 30 min and then allowed to warm to room temperature overnight. The solution was quenched with NH4Cl solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford the crude product, which was further purified by Combi-Flash (PE:EA = 40%) to yield the pure product (790 mg, 54%). MS:M / e715(M+1) + .

[0487] Step B: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-methoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0488] Sodium methoxide (38 mg, 0.7 mmol) was added to a solution of tert-butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-chloroimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate (50 mg, 0.07 mmol) in methanol (10 mL). The reaction mixture was heated at 70° C. overnight, cooled, concentrated and further purified by Combi-Flash (PE:EA=50%) to give the pure product (40 mg, 82%). MS: M / e 711 (M+1) + .

[0489] Step C: 2-methoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0490] A solution of tert-butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-methoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate (40 mg, 0.06 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (2 mL) was heated at 85° C. overnight, then concentrated, 2 mL of trifluoroacetic acid was added and heated at 90° C. for 4 hours. The solvent was evaporated to give a residue, which was purified by preparative HPLC to give the product (14 mg, 70%). 1 H NMR (400MHz, CD3OD) δ8.08 (s, 1H), 7.57 (s, 1H), 7.35 (d, J = 4.0Hz, 1H), 4.11 (s, 2H), 3.86 (s, 3H), 3.27 (s, 8H), 2.21 (s, 3H) ppm. MS:M / e 355(M+1) + .

[0491] Compound B63: 2-Ethoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0492] Compound B63 was synthesized according to a similar procedure to that described for compound B62 starting from the corresponding starting materials. 1H NMR (400MHz, CD3OD) δ8.06(s,1H),7.55(s,1H),7.37(s,1H),4.26-4.23(m,2H),4.10(s,2H),3.27(s,8H),2.20(s,3H),1.29(t,J=8.0Hz,3H)ppm. MS:M / e 369(M+1) + .

[0493] Compound B64: 2-Butoxy-7-(3-methyl-4-(piperidin-4-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0494] Step A: tert-Butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0495] 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. Then, a solution of tert-butyl 4-(4-formyl-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (129 mg, 0.43 mmol) in THF (2 mL) was added dropwise at -78°C. After the addition, the mixture was warmed to room temperature and stirred for 3 hours. 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 product as a yellow oil (101 mg, 47.3%). MS: M / e 749 (M+1) + .

[0496] Step B: tert-Butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-methylphenyl)piperidine-1-carboxylate

[0497] To 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)-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (101 mg, 0.135 mmol) in THF (5 mL) was added Pd / C (10%, 50 mg) and stirred at rt overnight under a H2 (1 atm) atmosphere. The mixture was filtered to give a filtrate, concentrated and purified by column chromatography (DCM / MeOH=20:1 to 5:1) to give the title product (97 mg, 95.8%) as a yellow oil. MS: M / e 751 (M+1) + .

[0498] Step C: 2-Butoxy-7-(3-methyl-4-(piperidin-4-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0499] A mixture of tert-butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-methylphenyl)piperidine-1-carboxylate (97 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 title product (38 mg, 74.5%). 1 H NMR(400MHz,DMSO-d6)δ8.68-8.65(m,1H),8.40-8.38(m,1H),8.13(s,1H),8.05 (s,1H),7.32(s,1H),7.12(d,J=8.1Hz,2H),7.05(d,J=7.8Hz,1H),4.21(t,J=6.5 Hz,2H),4.06(s,2H),3.36(d,J=12.3Hz,2H),3.05-2.94(m,3H),2.27(s,3H),1. 85-1.70(m,4H),1.70-1.65(m,2H),1.47-1.35(m,2H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e395(M+1) + .

[0500] Compound B65: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0501] Step A: 7-Bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0502] NaH (100 mg, 2.5 mmol) was added to a solution of pentane-2-ol (220 mg, 2.5 mmol) in THF (15 mL). After stirring at rt under an N2 atmosphere for 30 min, 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (300 mg, 0.62 mmol) was added and the resulting mixture was heated at 60 ° C overnight. The solution was cooled, diluted with water (10 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 Combi-Flash (PE:EA = 25%) to give the pure product (265 mg, 85%). MS: M / e540 (M+1) + .

[0503] Step B: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0504] At -78°C (with N 2 To a cooled solution of 7-bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (265 mg, 0.5 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.8 mL) dropwise under a purging (1% CO). After stirring at -78°C for 30 minutes, tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (225 mg, 0.75 mmol) in THF (2 mL) was added. The resulting mixture was stirred at this temperature for 30 minutes and then allowed to warm to room temperature overnight. 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 Combi-Flash (PE:EA=30%) to give the pure product (180 mg, 48%). MS: M / e 767 (M+1) + .

[0505] Step C: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0506] A solution of tert-butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate (180 mg, 0.23 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (2 mL) was heated at 85° C. overnight and then stirred at 90° C. for 4 hours. The solvent was evaporated to give a residue, which was purified by preparative HPLC to give the product (56 mg, 58%). 1 H NMR(400MHz,DMSO-d6)δ8.88(br.s,2H),8.23(br.s,2H),8.12(s,1H),7.53(s,1H),7.47(s,1H),5.01-4.95(m,1H),4.10(s, 2H),3.25-3.21(m,8H),2.21(s,3H),1.66-1.49(m,2H),1.39-1.29(m,2H),1.25(d,J=4.0Hz,3H),0.88(t,J=8.0Hz,3H)ppm. MS:M / e 411(M+1) + .

[0507] Compound B66: 2-Isopropoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0508] Compound B66 was synthesized according to a similar procedure to that described for compound B65 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),8.05(d,J=4.0Hz,1H),7.99(s,1H),7.40(d,J=4.0Hz,1H),7.32(s,1H), 5.08-5.02(m,2H),4.03(s,2H),2.96-2.91(m,4H),2.86-2.75(m,4H),2.17(s,3H),1.27(d,J=8.0Hz,6H)ppm. MS:M / e 383(M+1) + .

[0509] Compound B67: (2S,3S)-2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-3-methylpentan-1-one

[0510] Step A: tert-Butyl ((2S,3S)-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate

[0511] To a stirred solution of (tert-butyloxycarbonyl)-L-isoleucine (23.4 mg, 0.088 mmol), HATU (33.6 mg, 0.088 mmol) and DIEA (22.8 mg, 0.18 mmol) in THF (10 ml) was added 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (35 mg, 0.088 mmol). The mixture was stirred at rt for 1 h. Upon completion, the solution was quenched with H2O (10 ml) and then extracted with DCM (15 ml x 2). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product (100 mg) as an off-white film, which was used directly in the next step without further purification. MS: M / e 610 (M+1) + .

[0512] Step B: (2S,3S)-2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-3-methylpentan-1-one

[0513] To a stirred solution of tert-butyl ((2S,3S)-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate (100 mg, crude) in EA (10 ml) was added a solution of HCl in EA (4 M, 5 ml). The mixture was stirred at rt for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product (37.31 mg). 1H NMR(400MHz,DMSO-d6)δ8.24-8.01(m,6H),7.64-7.51(m,1H),7.42-7.33(m,1H), 4.41-4.30(m,1H),4.21(t,J=8Hz,2H),4.09(s,2H),3.85-3.53(m,4H),3.15-2.9 6(m,4H),2.24(s,3H),1.87-1.75(m,1H),1.73-1.62(m,2H),1.52-1.35(m,3H),1 .22-1.07(m,1H),0.97(d,J=8Hz,3H),0.92(t,J=8Hz,3H),0.87(t,J=8Hz,3H)ppm. MS:M / e 510(M+1) + .

[0514] Compound B68: (S)-4-amino-2-butoxy-7-((5-methyl-6-(4-prolylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine

[0515] Compound B68 was synthesized according to a similar procedure to that described for compound B67 starting from the corresponding starting materials. 1 H NMR(400MHz,DMSO-d6)δ9.45-9.21(m,1H),8.62-8.44(m,1H),8.32-8.05(m,3H),7.65-7.51(m ,1H),7.48-7.33(m,1H),4.72-4.58(m,1H),4.21(t,J=8Hz,2H),4.08(s,2H),3.72-3.69(m,1H) ,3.68-3.53(m,3H),3.33-3.24(m,1H),3.22-3.14(m,1H),3.13-2.98(m,4H),2.46-2.32(m,1H) ,2.23(s,3H),1.98-1.75(m,3H),1.73-1.61(m,2H),1.47-1.34(m,2H),0.92(t,J=8Hz,3H)ppm. MS:M / e 494(M+1) + .

[0516] Compound B69: (S)-2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-4-methylpentan-1-one

[0517] Compound B69 was synthesized according to a similar procedure to that described for compound B67 starting from the corresponding starting materials. 1 H NMR(400MHz,DMSO-d6)δ8.22-8.03(m,6H),7.61-7.49(m,1H),7.43-7.32(m,1H) ,4.49-4.37(m,1H),4.21(t,J=8Hz,2H),4.08(s,2H),3.84-3.74(m,1H),3.69-3. 59(m,1H),3.58-3.46(m,2H),3.20-3.12(m,1H),3.11-3.03(m,2H),3.01-2.95( m,1H),2.23(s,3H),1.78-1.55(m,4H),1.52-1.35(m,3H),0.98-0.87(m,9H)ppm. MS:M / e 510(M+1) + .

[0518] Compound B70: (S)-2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-3-methylbutan-1-one

[0519] Compound B70 was synthesized according to a similar procedure to that described for compound B67 starting from the corresponding starting materials. 1 H NMR(400MHz,DMSO-d6)δ8.23-7.99(m,6H),7.64-7.47(m,1H),7.42-7.32(m ,1H),4.37-4.31(m,1H),4.21(t,J=8Hz,2H),4.08(s,2H),3.81-3.74(m,1H) ,3.72-3.53(m,3H),3.17-3.01(m,4H),2.24(s,3H),2.13-2.02(m,1H),1.75 -1.60(m,2H),1.48-1.33(m,2H),1.00(d,J=8Hz,3H),0.96-0.87(m,6H)ppm. MS:M / e 496(M+1) + .

[0520] Compound B71: 1-(4-(5-((4-amino-2-(butylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

[0521] A mixture of N2-butyl-7-((5-methyl-6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (200 mg, 0.5 mmol), dimethylglycine (62 mg, 0.6 mmol), HATU (230 mg, 0.6 mmol), DIPEA (129 mg, 1 mmol) in THF (20 mL) was stirred overnight. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (CH2Cl2 / MeOH=15:1 to 10:1, containing NH3(g)) to give a crude product, which was further purified by preparative TLC (CH2Cl2 / MeOH(NH3)=15:1) to give the target compound (100 mg, 41.5%). 1 H NMR (400MHz, DMSO-d6) δ8.08(s,1H),7.50(br.s,2H),7.47(s,1H),7.15(s,1H),6.24(t,J=5.6Hz,1H),3.98(s,2H),3.65-3.55(m,4 H),3.27-3.13(m,4H),3.03-2.92(m,4H),2.26(s,6H),2.21(s,3H),1.59-1.44(m,2H),1.36-1.21(m,2H),0.89(t,J=7.2Hz,3H)ppm. MS:M / e 481(M+1) + .

[0522] Compound B72: 2-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide

[0523] A mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.05 mmol) and 2-bromo-N,N-dimethylacetamide (10 mg, 0.06 mmol) and K2CO3 (14 mg, 0.1 mmol) was stirred at rt overnight, diluted with water (5 mL) and extracted with EA (5 mL x 3), and dried over N2SO4, filtered and concentrated, the residue was purified by preparative HPLC to give the title product (15 mg, 63%). 1H NMR (400MHz, CD3OD) δ8.16(d,J=1.7Hz,1H),7.63(s,1H),7.47(d,J=1.7Hz,1H),4.39-4.26(m,4H),4.19(s,2H),3.68 -3.37(m,8H),3.00(s,3H),2.99(s,3H),2.29(s,3H),1.87-1.68(m,2H),1.59-1.41(m,2H),0.98(t,J=7.4Hz,3H)ppm. MS:M / e 482(M+1) + .

[0524] Compound B73: (S)-2-Butoxy-7-((5-methyl-6-(2-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine.

[0525] Step A: 2,4-Dichloroimidazo[2,1-f][1,2,4]triazine.

[0526] A mixture of imidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (5.0 g, 32.9 mmol) and triethylamine hydrochloride (9.0 g, 65.7 mmol) in POCl3 (50 mL) was heated at 120 ° C in a sealed tube for 16 hours. The mixture was concentrated to dryness under high vacuum, and the resulting residue was diluted with 200 mL of EA, suspended and poured into 500 mL of aqueous NaHCO3. The mixture was stirred at rt for 30 min. The organic layer was separated and the aqueous layer was extracted with EA (200 mL x 2). The combined organics were washed with aqueous NaHCO3 (200 mL), brine (200 mL x 3), dried over Na2SO4 and concentrated to dryness to give the title product (4.9 g, yield: 80%) as a yellow solid. MS: M / e 189 (M+1) + .

[0527] Step B: 2-Chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine.

[0528] At 0 ° C, DIEA (10.0 g, 77.7 mmol) was added to a stirred solution of 2,4-dichloroimidazo[2,1-f][1,2,4]triazine (4.9 g, 25.9 mmol) in THF (30 mL), and then a solution of bis(4-methoxybenzyl)amine (7.4 g, 28.7 mmol) in THF (40 mL) was added. The resulting mixture was stirred at rt for 2 hours. The mixture was concentrated to dryness and diluted with 200 mL of EA, washed with NaHCO (50 mL x 2), brine (50 mL x 2), dried, and concentrated to dryness. The resulting solid was slurried in a mixed solvent of PE / EA (10: 1, 200 mL) for 2 hours. The suspension was filtered. The filter cake was dried under high vacuum to give the title product (8.7 g, yield: 82%) as a light yellow solid. MS: M / e 410 (M+1) + .

[0529] Step C: 2-Butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0530] A mixture of 2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (8.7 g, 21.2 mmol) and sodium butanoate solution in n-BuOH (20%, 80 mL) was heated at 80 ° C for 1 hour. The mixture was treated with 200 mL of EA and 200 mL of aqueous NaHCO 3 . The aqueous layer was extracted with EA (100 mL x 2). The combined organic layers were washed with brine (200 mL x 3), dried over Na 2 SO 4 and concentrated. The resulting residue was purified by column chromatography (eluted with PE / EA (10: 1 to 5: 1)) to give the title product (7.6 g, yield: 80%) as a light yellow solid. MS: M / e 448 (M + 1) + .

[0531] Step D: tert-Butyl (3S)-4-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)-3-methylpiperazine-1-carboxylate.

[0532] Under N₂, n-butyllithium solution (1.6 M, 0.65 mL, 1.0 mmol) was added dropwise to a -78°C solution of 2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (300 mg, 0.67 mmol) in THF (5 mL) using a syringe, and the resulting mixture was stirred at -78°C for 15 min. A solution of tert-butyl (S)-4-(5-formyl-3-methylpyridin-2-yl)-3-methylpiperazine-1-carboxylate (250 mg, 0.78 mmol) in THF (3 mL) was added dropwise at -78°C using a syringe. The resulting mixture was stirred at this temperature for 1 hour, allowed to warm to rt, and stirred for an additional 1 hour. The mixture was quenched with 20 mL of aqueous NH₄Cl and extracted with EA (20 mL x 2). The combined layers were washed with brine (20 mL x 2), dried over Na2SO4 and concentrated, and purified by column chromatography (eluted with PE / EA (5:1 to 3:1)) to give the title product (230 mg, crude) as a light yellow oil. MS: M / e 767 (M+1) + .

[0533] Step E: (S)-2-Butoxy-7-((5-methyl-6-(2-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine.

[0534] A mixture of tert-butyl (3S)-4-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)-3-methylpiperazine-1-carboxylate (230 mg, 0.3 mmol), TFA (5 mL) and EtSiH (3 mL) was heated at 85° C. for 16 hours. The mixture was concentrated, and the resulting residue was treated with 10 mL of aqueous NaHCO and extracted with a mixed solvent (DCM / MeOH=5:1, 10 mL×3). The combined layers were washed with brine (10 mL x 2), dried over Na2SO4 and concentrated, purified by column chromatography (eluted with DCM / MeOH-NH3 (15:1, 5 mol / L of NH3 in MeOH) to give 75 mg of crude product, which was purified by preparative TLC (DCM / MeOH-NH3, 10:1, 5 mol / L of NH3 in MeOH) to give the title product (15 mg, 5.5% yield for 2 steps). 1H NMR (400MHz, DMSO-d6) δ8.19-8.04(m,3H),7.48(s,1H),7.33(s,1H),4.19(t,J=6.4Hz,2H),4.07(s,2H),3.47-3.39(m,1H),3.05-2.81(m,4H),2. 75-2.63(m,1H),2.56(dd,J=12.0,8.0Hz,1H),2.18(s,3H),1.73-1.61(m ,2H),1.48-1.32(m,2H),0.92(t,J=7.2Hz,3H),0.80(d,J=6.4Hz,3H)ppm. MS:M / e 411(M+1) + .

[0535] Compound B74: (R)-2-butoxy-7-((5-methyl-6-(2-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine.

[0536] Compound B74 was synthesized according to a similar procedure to that described for compound B73 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.19-8.04(m,3H),7.46(s,1H),7.33(s,1H),4.19(t,J=6.4Hz,2H),4.06(s,2H),3.45-3.30(m,1H),2.98-2.88(m,2H ),2.87-2.76(m,2H),2.70-2.58(m,1H),2.18(s,3H),1.72-1.62(m,2H),1.47-1.33(m,2H),0.92(t,J=7.6Hz,3H),0.79(d,J=6.0Hz,3H)ppm. MS:M / e 411(M+1) + .

[0537] Compound B75: 2-Butoxy-7-((5-methyl-6-(4-(2-(methylamino)ethyl)piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0538] Step A: tert-Butyl (2-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)ethyl)(methyl)carbamate

[0539] To a mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol), tert-butylmethyl(2-oxoethyl)carbamate (16 mg, 0.12 mmol) in DCM (4 mL) was added NaBH(OAc)3 (32 mg, 0.15 mmol) and AcOH (one drop). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with DCM (60 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (40 mg, crude). MS: M / e 554 (M+1) + .

[0540] Step B: 2-Butoxy-7-((5-methyl-6-(4-(2-(methylamino)ethyl)piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0541] To a mixture of the product of step A (40 mg, crude) in DCM (5 mL) was added a 4M HCl solution in EA (0.5 mL). The reaction was stirred at room temperature overnight. The mixture was concentrated and purified by preparative HPLC to give the title product (8 mg, 16% for two steps). 1 HNMR(400MHz,DMSO-d6)δ8.32(s,1H),8.13(s,1H),8.06(s,1H),8.04(s,1H),7.44(s,1H),7.31(s,1H),4.21(t,J=6.8Hz,2H),4.04(s,2H),3.10- 2.95(m,4H),2.84(t,J=6.0Hz,2H),2.62-2.51(m,6H),2.45(s,3H),2.18 (s,3H),1.75-1.61(m,2H),1.46-1.31(m,2H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 454(M+1) + .

[0542] Compound B76: 2-Butoxy-7-((6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0543] Step A: 6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-5-methylnicotinaldehyde

[0544] To a solution of 6-chloro-5-methylnicotinaldehyde (0.46 g, 3 mmol) and DIEA (0.77 g, 6 mmol) in DMA (5 mL) was added N,N-dimethyl-2-(piperazin-1-yl)ethan-1-amine (0.46 g, 3 mmol). The mixture was then stirred at 115° C. under N2 overnight. The mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (60 mL x 2), washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by combi-flash to give the title compound (110 mg, 13%). 1 HNMR (400MHz, CDCl3) δ9.88(s,1H),8.51(d,J=2.0Hz,1H),7.81(d,J=2.0Hz,1H),3.46( t,J=5.2Hz,4H),2.64(t,J=4.4Hz,4H),2.61-2.50(m,4H),2.34(s,6H),2.31(s,3H)ppm. MS:M / e 277(M+1) + .

[0545] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-5-methylpyridin-3-yl)methanol

[0546] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF (6 mL) was added a solution of n-butyllithium (0.35 mL, 0.57 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After stirring for 1 hour, a mixture of the product of step A (105 mg, 0.38 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70°C for 2 hours 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 to give the target compound (200 mg, crude). MS: M / e724 (M+1) + .

[0547] Step C: 2-Butoxy-7-((6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0548] To a mixture of the product of step B (200 mg, crude) in TFA (6 mL) was added EtSiH (2 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 to give the title compound as a FA salt (22 mg, 11% for two steps). 1 HNMR(400MHz,DMSO-d6)δ8.14-8.05(m,4H),7.45(s,1H),7.31(s,1H),4.21(t,J=6.4Hz,2H),4.05(s,2H),3.15-2.96 (m,6H),2.69(s,6H),2.67-2.56(m,6H),2.18(s,3H),1.75-1.64(m,2H),1.48-1.35(m,2H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 468(M+1) + .

[0549] Compound B77: 2-Butoxy-7-((5-(piperidin-4-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0550] Compound B77 was prepared according to the general procedure for the preparation of compound B15 to give the target product (15 mg). 1 HNMR(400MHz,DMSO-d6+D2O)δ8.37(s,1H),8.33(d,J=1.6Hz,1H),7.49(d,J=1 .6Hz,1H),7.39(s,1H),4.20(t,J=6.4Hz,2H),4.12(s,2H),3.39-3.28(m,2H) ,3.20-3.10(m,1H),3.06-2.91(m,2H),2.28(s,3H),2.03-1.86(m,2H),1.84- 1.74(m,2H),1.72-1.60(m,2H),1.46-1.31(m,2H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 396(M+1) + .

[0551] Compound B78: 2-Butoxy-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0552] Step A: 6-(4-(dimethylamino)piperidin-1-yl)-5-methylnicotinaldehyde

[0553] DIPEA (1.3 g, 10 mmol) was added to a solution of methyl 6-chloro-4-methylnicotinate (778 mg, 5 mmol) and N,N-dimethylpiperidin-4-amine (1.42 g, 10 mmol) in DMA (10 mL), and the reaction mixture was stirred at 120 ° C for 4 hours and cooled to room temperature. The solution was quenched with H2O (10 ml). The aqueous solution was extracted with EA (10 ml × 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 (560 mg, 47%), MS: M / e 248 (M+1). +

[0554] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0555] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-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 from step A (112 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 title compound (55 mg, 26%). MS: M / e 695 (M+1) + .

[0556] Step C: 2-Butoxy-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0557] To a mixture of the product from step B (55 mg, 0.08 mmol) in TFA (5 mL) was added Et3SiH (1 mL). The reaction was heated at 80°C for 24 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 (18 mg, 51%). 1H NMR (400MHz, DMSO-d6) δ8.13(s,1H),8.05(s,1H),8.04(s,1H),7.42(s,1H),7.30(s,1H),4.20(t,J=6.5Hz,2H),4.03(s,2H),3.41-3.25(m,3 H),2.63(t,J=11.9Hz,2H),2.19(s,6H),2.17(s,3H),1.80(d,J=11.0Hz,2H),1.72-1.59(m,2H),1.53-1.31(m,4H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e 439(M+1) + .

[0558] Compound B79: 7-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0559] Compound B79 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,CD3OD)δ7.90(s,1H),7.33(s,1H),7.21(s,1H),4.26-4.11(m,3H),3.99(s,2H),3.74(d,J=10.2Hz,1H),3.57(s,1H),3.37- 3.00(m,3H),2.12(s,3H),2.07(d,J=10.8Hz,1H),1.84(d,J=10.6Hz,1H),1.74-1.59(m,2H),1.52-1.32(m,2H),0.90(t,J=7.2Hz,3H)ppm. MS:M / e 409(M+1) + .

[0560] Compound B80: 2-(But-3-en-1-yloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0561] Compound B80 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1HNMR(400MHz,DMSO-d6)δ8.15(s,1H),8.11-8.00(m,2H),7.45-7.41(m,1H),7.31(s,1H),5.93-5.79(m,1H),5.19-5. 04(m,2H),4.25(t,J=8Hz,2H),4.04(s,2H),2.97-2.90(m,4H),2.89-2.81(m,4H),2.49-2.42(m,2H),2.17(s,3H)ppm. MS:M / e 395(M+1) + .

[0562] Compound B81: (S)-2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-3-phenylpropan-1-one

[0563] Compound B81 was synthesized according to a similar procedure to that described for compound B67 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.31-8.04(m,6H),7.55-7.47(m,1H),7.39-7.31(m,3H),7.31-7.21(m,3H),4.75-4.65(m,1H),4.21(t,J=8Hz,2H),4. 06(s,2H),3.73-3.60(m,1H),3.57-3.38(m,2H),3.13-2.80(m,7H),2.1 6(s,3H),1.73-1.62(m,2H),1.46-1.34(m,2H),0.92(t,J=8Hz,3H)ppm. MS:M / e 544(M+1) + .

[0564] Compound B82: 2-Butoxy-7-((5-methyl-6-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0565] Compound B82 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1HNMR(400MHz,DMSO-d6)δ8.84(br.s,2H),8.17(s,1H),8.12(s,1H),8.08(s ,1H),7.64(d,J=14.8Hz,1H),7.36(d,J=4.8Hz,1H),4.21(t,J=6.3Hz,2H), 4.10(s,2H),3.36-3.21(m,2H),3.20-2.98(m,6H),2.23(s,3H),1.84(t,J= 7.2Hz,2H),1.72-1.58(m,6H),1.44-1.38(m,2H),0.93(t,J=7.3Hz,3H)ppm. MS:M / e 451(M+1) + .

[0566] Compound B83: 2-Butoxy-7-((5-methyl-6-(8-azaspiro[4.5]decan-8-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0567] Compound B83 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,DMSO-d6)δ8.13(s,1H),8.05(s,2H),7.42(s,1H),7.30(s,1H),4.20(t,J=6.5Hz,2H),4.03(s,2H),2.97-2.88 (m,4H),2.17(s,3H),1.73-1.62(m,2H),1.59-1.57(m,4H),1.55-1.47(m,4H),1.47-1.35(m,6H),0.92(t,J=7.4Hz,3H)ppm. MS:M / e 450(M+1) + .

[0568] Compound B84: N2-methyl-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-propylimidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0569] Step A: 7-Bromo-N2-butyl-N4,N4-bis(4-methoxybenzyl)-N2-methylimidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0570] To a stirred solution of 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (300 mg, 0.62 mmol) in NMP (8 mL) was added N-methylbutane-1-amine (174 mg, 2 mmol). The reaction mixture was sealed and heated at 200 ° C for 6 h. The mixture was cooled to rt, H2O (20 mL) was added 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 (250 mg, 71.4%). MS: M / e 539 (M + 1) + .

[0571] Step B: tert-Butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-(butyl(methyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-methylphenyl)piperazine-1-carboxylate

[0572] To a stirred solution of 7-bromo-N2-butyl-N4,N4-bis(4-methoxybenzyl)-N2-methylimidazo[2,1-f][1,2,4]triazine-2,4-diamine (210 mg, 0.39 mmol) in THF (10 mL) cooled to -78°C under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.9 mmol, 0.6 mL) dropwise. After stirring for 50 min, a solution of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (210 mg, 0.58 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 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 (130 mg, 44.5%). MS: M / e 765 (M+1) + .

[0573] Step C: N 2 -Butyl-N 2 -methyl-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0574] A solution of tert-butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-(butyl(methyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-methylphenyl)piperazine-1-carboxylate (130 mg, 0.17 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, 35.9%). 1 H NMR (400MHz, DMSO-d6) δ8.08(s,1H),7.61(s,2H),7.44(s,1H),7.19(s,1H),3.98(s,2H),3.49(t,J=7.2Hz,2H ), 2.99 (s, 3H), 2.99-2.81 (m, 8H), 2.17 (s, 3H), 1.56-1.45 (m, 2H), 1.3-1.24 (m, 2H), 0.90 (t, J = 7.3Hz, 3H) ppm. MS:M / e 410(M+1) + .

[0575] Compound B85:N 2 -Isopentyl-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0576] Compound B85 was synthesized according to a similar procedure to that described for compound B13 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.79(br.s,2H),8.12(s,1H),7.93(m,2H),7.51(s,2H),4.05(d,J=5.5Hz,2H),3.24-3. 15(m,6H),2.50-2.47(m,4H),2.22(s,3H),1.65-1.57(m,1H),1.45-1.39(m,2H),0.89(s,3H),0.88(s,3H)ppm. MS:M / e 410(M+1) + .

[0577] Compound B86: 2-Butoxy-7-((5-methyl-6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0578] Compound B86 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,DMSO-d6)δ8.79(br.s,1H),8.68(s,1H),8.15(s,2H),8.07(s,1 H),7.66-7.53(m,1H),7.36(d,J=12.8Hz,1H),4.21(t,J=6.2Hz,2H),4.08(d,J =6.6Hz,2H),3.75-3.70(m,4H),3.08-2.88(m,4H),2.21(d,J=5.1Hz,3H),1.92 -1.84(m,4H),1.73-1.61(m,2H),1.51-1.32(m,2H),0.93(t,J=7.2Hz,3H)ppm. MS:M / e451.0(M+1) + .

[0579] Compound B87: 2-Butoxy-7-((6-(3-(dimethylamino)pyrrolidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0580] Compound B87 was synthesized according to a similar procedure to that described for compound B78 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ10.32(br.s,1H),8.14(s,2H),7.96(s,1H),7.65(s,1H),7.42-7.26(m,1H),4.22(t,J=6.3Hz,2H),4.07(s,2H),3. 95-3.71(m,4H),2.86(s,6H),2.36(s,3H),2.35-2.28(m,2H),2.23-1.14(m,1H),1.77-1.62(m,2H),1.43(m,2H),0.93(t,J=7.2Hz,3H)ppm. MS:M / e 425(M+1) + .

[0581] Compound B88: 7-((6-(4-aminopiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-butylimidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0582] Step A: tert-Butyl (1-(5-((4-(bis(4-methoxybenzyl)amino)-2-(butylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperidin-4-yl)carbamate

[0583] 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 (160 mg, 0.3 mmol) in THF (10 mL) at -78°C was added n-butyllithium (1.6 M, 0.375 mL, 0.6 mmol) dropwise. After stirring under N2 for one hour, a solution of tert-butyl (1-(5-formyl-3-methylpyridin-2-yl)piperidin-4-yl)carbamate (144 mg, 0.45 mmol) in THF (2 mL) was added dropwise at -78°C and the reaction was 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 preparative TLC (petroleum ether / EtOAc=1:1) to give the target compound (60 mg, 26.1%). MS: M / e766 (M+1) + .

[0584] Step B: 7-((6-(4-aminopiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-butylimidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0585] To a mixture of the product of step B (60 mg, 0.078 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, 62.5%). 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.84(s,2H),7.63(s,1H),7.49(s,1H ),7.35-7.25(m,1H),6.44(s,1H),4.01(s,2H),3.39(d,J=13.2Hz,2H),3.2 3-3.12(m,3H),2.81-2.71(m,2H),2.17(s,3H),1.98-1.90(m,2H),1.71-1. 57(m,2H),1.55-1.46(m,2H),1.36-1.28(m,2H),0.89(t,J=7.2Hz,3H)ppm. MS:M / e 410(M+1) + .

[0586] Compound B89: 2-Butoxy-7-((5-methyl-6-(4-(propylsulfonyl)piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0587] To a mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol) and TEA (20 mg, 0.2 mmol) in DCM (5 mL) was added a solution of propane-1-sulfonyl chloride (14 mg, 0.1 mmol) in DCM (0.1 mL). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with DCM (50 mL), washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (22 mg, 44%). 1 HNMR(400MHz,DMSO-d6)δ8.14(s,1H),8.10(d,J=2.0Hz,1H),8.07(s,1H),7.50(s,1H),7.33(s,1H),4.21(t,J=6.8Hz,2H),4.07(s,2H),3 .32-3.24(m,4H),3.14-3.02(m,6H),2.21(s,3H),1.80-1.61(m,4H),1.46-1.34(m,2H),0.99(t,J=7.6Hz,3H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 503(M+1) + .

[0588] Compound B90: 2-Butoxy-7-(3-isopropyl-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0589] Step A: tert-Butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-(prop-1-en-2-yl)phenyl)piperazine-1-carboxylate

[0590] 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, 0.4278 mmol) dropwise at -78°C and stirred for 1 hour. A solution of tert-butyl 4-(4-formyl-2-(prop-1-en-2-yl)phenyl)piperazine-1-carboxylate (141 mg, 0.43 mmol) in THF (2 mL) was then added dropwise at -78°C. After addition, the mixture was warmed to room temperature and stirred for 3 hours. 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 (85 mg, 38.31%) as a yellow oil. MS: M / e 778 (M+1) + .

[0591] Step B: tert-Butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-isopropylphenyl)piperazine-1-carboxylate

[0592] To 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)-2-(prop-1-en-2-yl)phenyl)piperazine-1-carboxylate (85 mg, 0.11 mmol) in THF (5 mL) was added Pd / C (10%, 50 mg) and stirred at rt under H2 (1 atm) atmosphere overnight. The mixture was filtered to give a filtrate, concentrated and purified by column chromatography (DCM / MeOH = 20:1 to 5:1) to give the title product (79 mg, 92.70%) as a yellow oil. MS: M / e 780 (M+1) + .

[0593] Step C: 2-Butoxy-7-(3-isopropyl-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0594] A mixture of tert-butyl 4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-isopropylphenyl)piperazine-1-carboxylate (79 mg, 0.10 mmol) and triethylsilane (1 mL) in TFA (2 mL) was stirred at 90° C. overnight. The mixture was concentrated and purified with preparative HPLC to give the title product. 1 H NMR (400MHz, DMSO-d6) δ8.75 (s, 2H), 8.13 (s, 1H), 8.10 (s, 1H), 7.35 (d, J = 4.0Hz, 1H),7.31(s,1H),7.09(d,J=8.0Hz,1H),7.03(d,J=8.0Hz,1H),4.23(t,J=6.0Hz, 2H),4.09(s,2H),3.43-3.32(m,1H),3.23-3.18(m,4H),3.03-2.82(m,4H),1.73- 1.64(m,2H),1.43-1.34(m,2H),1.14(d,J=6.3Hz,6H),0.93(t,J=7.0Hz,3H)ppm. MS:M / e 424(M+1) + .

[0595] Compound B91: 7-((6-(4-(2-aminoethyl)piperazin-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0596] Step A: tert-Butyl (2-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)ethyl)carbamate

[0597] To a mixture of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol), tert-butyl(2-oxoethyl)carbamate (19 mg, 0.12 mmol) in DCM (4 mL) was added NaBH(OAc)3 (32 mg, 0.15 mmol) and one drop of AcOH. The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with DCM (30 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (25 mg, crude). MS: M / e 540 (M+1) + .

[0598] Step B: 7-((6-(4-(2-aminoethyl)piperazin-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0599] To a mixture of the product of step A (25 mg, crude) in DCM (5 mL) was added a 4M HCl solution in EA (0.5 mL). The reaction was stirred at room temperature overnight. The mixture was concentrated and purified by preparative HPLC to give the title product (6 mg, 10% for both steps). 1 HNMR (400MHz, DMSO-d6) δ8.15(s,1H),8.12(s,1H),8.09(s,1H),7.99(br.s,2H),7.53(s,1H),7.34(s,1H),4.21(t,J=6. 4Hz,2H),4.08(s,2H),3.62-2.95(m,12H),2.22(s,3H),1.75-1.61(m,2H),1.46-1.32(m,2H),0.93(t,J=7.6Hz,3H)ppm. MS:M / e 440(M+1) + .

[0600] Compound B92: 2-Butoxy-7-(3-ethyl-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0601] Compound B92 was synthesized according to a similar procedure as described for compound B90 starting from the corresponding starting materials. 1 H NMR(400MHz,DMSO-d6)δ8.71(br.s,2H),8.13(s,1H),8.07(s,1H),7.33(d,J=3.6 Hz,1H),7.24(s,1H),7.11(d,J=8.1Hz,1H),7.01(d,J=8.1Hz,1H),4.22(t,J=6.4 Hz,2H),4.08(s,2H),3.25-3.18(m,4H),3.05-2.86(m,4H),2.66-2.57(m,2H),1. 75-1.64(m,2H),1.46-1.35(m,2H),1.16(t,J=7.4Hz,3H),0.93(t,J=7.3Hz,3H). MS:M / e 410(M+1) + .

[0602] Compound B93: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-propoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0603] Compound B93 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,DMSO-d6)δ8.13(s,1H),8.06(s,2H),7.43(s,1H),7.30(s,1H),4.16(d,J=8.0Hz, 2H), 4.03 (s, 2H), 2.87-2.77 (m, 8H), 2.17 (s, 3H), 1.71-1.68 (m, 2H), 0.96 (t, J = 8.0Hz, 3H) ppm. MS:M / e 383(M+1) + .

[0604] Compound B94: 1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

[0605] A solution of 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentane-2-yloxy)imidazo[2,1-f][1,2,4]triazine-4-amine (53 mg, 0.1 mmol), dimethylglycine (13 mg, 0.12 mmol), HATU (57 mg, 0.15 mmol) and DIEA (26 mg, 0.2 mmol) in THF (5 mL with 1 mL of DMF) was stirred for 2 hours at rt. The reaction mixture was quenched with water (5 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 preparative HPLC to give the pure product (15 mg, 24%). 1H NMR(400MHz,DMSO-d6)δ9.51(br.s,1H),8.14(s,2H),8.09(s,1H),7.55(s,1H),7. 41(s,1H),4.99-4.95(m,1H),4.30(d,J=4.0Hz,2H),4.09(s,2H),3.72-3.65(m,2H) ,3.49-3.41(m,2H),3.12-3.06(m,4H),2.82(s,3H),2.82(s,3H),2.24(s,3H),1.6 3-1.52(m,2H),1.41-1.31(m,2H),1.24(d,J=4.0Hz,3H),0.88(t,J=8.0Hz,3H)ppm. MS:M / e496(M+1) + .

[0606] Compound B95: 1-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide

[0607] Step A: tert-Butyl 4-(dimethylcarbamoyl)piperidine-1-carboxylate

[0608] To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (830 mg, 3.6 mmol), dimethylamine hydrochloride (350 mg, 4.3 mmol) and DIEA (2.0 g, 15.5 mmol) in DMF (10 mL) was added HATU (1.6 g, 4.3 mmol) at rt, and the mixture was stirred at rt for 16 hours. The mixture was diluted with 30 mL of EA, washed with brine (20 mL x 3), dried over Na2SO4, and concentrated to give the title product (1.5 g, crude) as a light yellow oil. MS: M / e 257 (M+1) + .

[0609] Step B: N,N-dimethylpiperidine-4-carboxamide hydrochloride

[0610] A suspension of tert-butyl 4-(dimethylcarbamoyl)piperidine-1-carboxylate (1.5 g, 5.85 mmol) in HCl / EA (4 M, 20 mL) was stirred at rt for 3 days. The resulting suspension was filtered, and the filter cake was washed with EA (10 mL) and dried under high vacuum to give the title product as a white solid (380 mg, 56% yield for 2 steps). MS: M / e 157 (M+1) + .

[0611] Step C: 1-(5-Formyl-3-methylpyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide.

[0612] A mixture of 6-chloro-5-methylnicotinaldehyde (310 mg, 2 mmol), N,N-dimethylpiperidine-4-carboxamide hydrochloride (380 mg, 2 mmol) and DIEA (1.2 g, 9.3 mmol) in DMA (5 mL) was heated at 120 ° C for 5 hours. The mixture was diluted with 20 mL of aqueous NaHCO 3 and extracted with EA (20 mL x 3). The combined organics were washed with brine (20 mL x 3), dried, concentrated, and purified by column chromatography (eluted with PE / EA / DCM (2:2:0 to 2:2:1) to give the title product (350 mg, yield: 64%) as a brown oil. MS: M / e 276 (M+1) + .

[0613] Step D: 1-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide.

[0614] Under N₂, to a -78°C solution of 2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (350 mg, 0.78 mmol) in THF (3 mL) was added n-butyllithium solution (1.6 M, 0.6 mL, 0.96 mmol) dropwise via syringe, and the resulting mixture was stirred at -78°C for 15 min. A solution of 1-(5-formyl-3-methylpyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide (300 mg, 1.1 mmol) in THF (2 mL) was added dropwise via syringe at -78°C. The resulting mixture was stirred at this temperature for 0.5 h, allowed to warm to rt, and stirred for 16 h. The mixture was quenched with 10 mL of aqueous NH₄Cl and extracted with EA (10 mL x 3). The combined extracts were washed with brine (10 mL x 3), dried over Na2SO4 and concentrated, and purified by column chromatography (eluted with DCM / MeOH(NH3)) (50:1 to 30:1, 2M NH3 in MeOH) to give the title product as a light yellow solid (290 mg, yield: 51%). MS: M / e 723 (M+1) + .

[0615] Step E: 1-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide.

[0616] A mixture of 1-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)-N,N-dimethylpiperidine-4-carboxamide (290 mg, 0.4 mmol), TFA (10 mL) and Et3SiH (5 mL) was heated at 85°C for 16 hours. The mixture was concentrated, and the resulting residue was treated with 10 mL of aqueous NaHCO3 and extracted with a mixed solvent (DCM / MeOH=5:1, 10 mL x 2). The combined extracts were washed with brine (10 mL x 2), dried over Na2SO4 and concentrated, purified by column chromatography (eluted with DCM / MeOH-NH3 (20:1, 2 mol / L of NH3 in MeOH) to give 185 mg of crude product, which was purified by preparative TLC (DCM / MeOH-NH3, 15:1, 2 mol / L of NH3 in MeOH) to give the title product (95 mg, yield: 51%). 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),8.06(s,2H),7.48(s,1H),7.32(s,1H),4.21(t,J=6.4Hz,2H),4.05(s,2H),3.37(d,J=12.4H z,2H),3.04(s,3H),2.82(s,3H),2.80-2.69(m,3H),2.19(s,3H),1.75-1.61(m,6H),1.49-1.34(m,2H),0.93(t,J=7.6Hz,3H)ppm. MS:M / e467(M+1) + .

[0617] Compound B96: N2-butyl-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0618] Step A: (4-(bis(4-methoxybenzyl)amino)-2-(butylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0619] 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 (160 mg, 0.3 mmol) in THF (10 mL) at -78°C was added n-butyllithium (1.6 M, 0.375 mL, 0.6 mmol) dropwise. After stirring under N2 for one hour, a solution of 6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylnicotinaldehyde (120 mg, 0.45 mmol) in THF (2 mL) was added dropwise at -78°C and the reaction was 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 Na 2 SO 4 , concentrated, and purified by preparative TLC (CH 2 Cl 2 / MeOH=10:1) to give the target compound (80 mg, 37.7%) as a colorless oil. MS: M / e 708 (M+1) + .

[0620] Step B: N2-butyl-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0621] A mixture of the product of step B (80 mg, 0.113 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, 19.6%). 1 H NMR(400MHz,DMSO-d6)δ9.14(br.s,1H),8.06(s,1H),7.70(s,2H),7.54(s,1H),7.33( s,1H),6.48(s,1H),4.02(s,2H),3.42-3.34(m,2H),3.17(t,J=6.4Hz,2H),3.02(t,J= 6.4Hz,2H),2.81(s,3H),2.80(s,3H),2.75-2.65(m,2H),2.19(s,3H),1.98-1.88(m,1 H),1.82-1.74(m,2H),1.57-1.45(m,2H),1.36-1.24(m,4H),0.89(t,J=7.2Hz,3H)ppm. MS:M / e 452(M+1) + .

[0622] Compound B97: (R)-2-Butoxy-7-((5-methyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0623] Compound B97 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,DMSO-d6)δ8.13(br.s,1H),8.10-7.99(m,2H),7.43(s,1H),7. 35-7.23(m,1H),4.21(t,J=6.0Hz,2H),4.04(s,2H),3.19(d,J=12.0Hz,2H), 3.03-2.79(m,3H),2.75-2.63(m,1H),2.46-2.36(m,1H),2.18(s,3H),1.76- 1.61(m,2H),1.46-1.34(m,2H),1.11-0.99(m,3H),0.92(t,J=7.2Hz,3H)ppm. MS:M / e 411(M+1) + .

[0624] Compound B98: (R)-2-Butoxy-7-(3-methyl-4-(3-methylpiperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0625] Compound B98 was synthesized according to a similar procedure as described for compound B16 starting from the corresponding starting materials. 1 H NMR(400MHz,DMSO-d6)δ8.20-7.97(m,2H),7.28(s,1H),7.12(s,1H),7.07(d, J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),4.22(t,J=6.4Hz,2H),4.03(s,2H),3.06- 2.81(m,5H),2.67-2.55(m,1H),2.31(t,J=10.4Hz,1H),2.19(s,3H),1.77-1. 60(m,2H),1.51-1.33(m,2H),1.04(d,J=6.0Hz,3H),0.93(t,J=7.2Hz,3H)ppm. MS:M / e 410(M+1) + .

[0626] Compound B99: 2-Butoxy-7-(4-(piperazin-1-yl)-3-propoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0627] Compound B99 was synthesized according to a similar procedure as described for compound B16 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.20-7.95(m,2H),7.28(s,1H),6.94(s,1H),6.85-6.73(m,2H),4.22(t,J=6.4Hz,2H),4.05(s,2H) ,3.88(t,J=6.4Hz,2H),3.01(s,8H),1.78-1.58(m,4H),1.51-1.33(m,2H),0.99(t,J=7.2Hz,3H),0.93(t,J=7.2Hz,3H)ppm. MS:M / e 440(M+1) + .

[0628] Compound B100: 2-((2,5,8,11-tetraoxatridecan-13-yl)oxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0629] Compound B100 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1 H NMR (400MHz, CD3OD) δ8.16(s,1H),7.64(s,1H),7.47(s,1H),4.43(t,J=4Hz,2H),4.20(s,2H),3.82(t,J=4Hz, 2H),3.69-3.66(m,2H),3.65-3.57(m,8H),3.52-3.48(m,2H),3.39-3.36(m,8H),3.32(s,3H),2.30(s,3H)ppm. MS:M / e 531(M+1) + .

[0630] Compound B101: 2-Butoxy-7-((5-methyl-6-(2,8-diazaspiro[4.5]decan-2-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0631] Compound B101 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1H NMR (400MHz, DMSO-d6) δ8.58(br.s,2H),8.19(s,1H),8.12(s,1H),7.83(s,1H),7.77(s,1H),7.35(d,J=3.8Hz,1H),4.22(t,J=6.3Hz,2H),4.08(s ,2H),3.79(s,2H),3.62(s,2H),3.11(s,4H),2.48(s,3H),1.92(t,J=6.3 Hz, 2H), 1.83-1.62 (m, 6H), 1.42-1.33 (m, 2H), 0.93 (t, J = 7.3Hz, 3H) ppm. MS:M / e 451(M+1) + .

[0632] Compound B102: 2-Butoxy-7-((5-methyl-6-(2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0633] Compound B102 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1 H NMR(400MHz,DMSO-d6)δ8.63(br.s,1H),8.49(s,1H),8.18(s,1H),8.14(s,1H),7.85(s,1H),7.69(s,1H),7.42-7.33(m,1H),4.25-4.17 (m,6H),4.06(s,2H),3.17-2.98(m,4H),2.31(s,3H),2.03-1.85(m,4H),1.76-1.62(m,2H),1.45-1.36(m,2H),0.94(t,J=7.3Hz,3H)ppm. MS:M / e 437(M+1) + .

[0634] Compound B103: 2-Butoxy-7-((6-(4-methoxypiperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0635] Compound B103 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1H NMR (400MHz, DMSO-d6) δ8.17(br.s,2H),8.06(s,1H),7.82(s,1H),7.44-7.30(m,1H),4.21(t,J=6.4Hz,2H),4.13(s,2H),3.40(s,3H),3.2 8(s,3H),3.03(s,2H),2.26(s,3H),2.04-1.88(m,2H),1.74-1.63(m,2H),1.61-1.52(m,2H),1.46-1.36(m,2H),0.93(t,J=7.4Hz,3H)ppm. MS:M / e 426(M+1) + .

[0636] Compound B104: 2-Butoxy-7-((6-(4-(methoxymethyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0637] Compound B104 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1 H NMR(400MHz,DMSO-d6)δ8.25-8.10(m,2H),8.07(s,1H),7.94-7.77(m,1H),7. 47-7.32(m,1H),4.21(t,J=6.5Hz,2H),4.14(s,2H),3.56(d,J=11.9Hz,2H),3 .25(s,3H),3.24(d,J=6.3Hz,2H),2.98-2.87(m,2H),2.27(s,3H),1.77(d,J= 10.5Hz,3H),1.73-1.62(m,2H),1.49-1.24(m,4H),0.93(t,J=7.4Hz,3H)ppm. MS:M / e 440(M+1) + .

[0638] Compound B105: 2-Butoxy-7-((6-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0639] Compound B105 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1HNMR(400MHz,DMSO-d6)δ9.65(br.s,1H),8.18(s,1H),8.11(s,1H),7.86(s,1H),7.74(s,1H) ,7.34(d,J=2.0Hz,1H),4.22(t,J=6.8Hz,2H),4.07(s,2H),3.96-3.80(m,1H),3.75-3.59(m,2 H),3.56-3.42(m,1H),3.21(t,J=5.2Hz,2H),2.83(s,3H),2.81(s,3H),2.74-2.61(m,1H),2. 43(s,3H),2.25-2.10(m,1H),1.85-1.60(m,3H),1.50-1.35(m,2H),0.94(t,J=7.6Hz,3H)ppm. MS:M / e 439(M+1) + .

[0640] Compound B106: 2-Butoxy-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0641] Step A: tert-Butyl ((1-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperidin-4-yl)methyl)(methyl)carbamate

[0642] 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, 0.286 mmol) in THF (10 mL) at -78°C was added n-butyllithium (1.6 M, 0.375 mL, 0.6 mmol) dropwise. After stirring under N2 for one hour, a solution of tert-butyl ((1-(5-formyl-3-methylpyridin-2-yl)piperidin-4-yl)methyl)(methyl)carbamate (165 mg, 0.475 mmol) in THF (2 mL) was added dropwise at -78°C and the reaction was stirred overnight. 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 combi-flash (petroleum ether / EtOAc=2:1 to 1:1) to give the target compound (170 mg, 74.8%) as a colorless oil. MS: M / e 795 (M+1) + .

[0643] Step B: 2-Butoxy-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0644] A mixture of the product of step B (170 mg, 0.214 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, 19.6%). 1 H NMR (400MHz, DMSO-d6) δ8.44(br.s,2H),8.13(br.s,2H),8.09(s,1H),7.69(s,1H),7.38-7.32(m,1H),4.21(t,J=6.4Hz,2H),4.10(s,2H),3.46(s, 2H),2.89-2.70(m,4H),2.59(t,J=5.2Hz,3H),2.23(s,3H),1.80(d,J=11. 6Hz, 3H), 1.74-1.60 (m, 2H), 1.51-1.27 (m, 4H), 0.93 (t, J = 7.2Hz, 3H) ppm. MS:M / e 439(M+1) + .

[0645] Compound B107: 2-Butoxy-7-((6-(4-(2-methoxyethyl)piperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0646] Compound B107 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1 H NMR(400MHz, DMSO-d6)δ9.63(br.s,1H),8.19-8.04(m,3H),7.52(s,1H),7.34(s,1H),4.21(t,J=6.5Hz,2H),4.08(s,2H),3.72-3.66(m,2H), 3.57-3.42(m,4H),3.38(s,2H),3.33(s,3H),3.25-3.11(m,4H),2.21( s,3H),1.73-1.63(m,2H),1.47-1.34(m,2H),0.93(t,J=7.4Hz,3H)ppm. MS:M / e 455(M+1) + .

[0647] Compound B108: 2-Butoxy-7-((5-methyl-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0648] Compound B108 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 H NMR(400MHz,DMSO-d6)δ9.69(br.s,1H),8.17(s,1H),8.11(s,1H),8.09(s,1H),7.54(s,1H), 7.35(s,1H),4.21(t,J=6.5Hz,2H),4.08(s,2H),4.02(d,J=12.1Hz,2H),3.67(t,J=11.6Hz,2 H),3.61-3.44(m,4H),3.42-3.34(m,1H),3.18-3.06(m,2H),2.75(t,J=12.4Hz,2H),2.21(s, 3H), 2.13 (d, J = 10.4Hz, 2H), 1.82-1.63 (m, 4H), 1.49-1.35 (m, 2H), 0.93 (t, J = 7.2Hz, 3H) ppm. MS:M / e 481(M+1) + .

[0649] Compound B109: 2-Butoxy-7-((5-methyl-6-(4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0650] Compound B109 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1 HNMR(400MHz,DMSO-d6)δ9.48(br.s,1H),8.17(s,1H),8.11(s,1H),8.08(s,1H),7.62(s,1H ),7.35(s,1H),4.21(t,J=6.8Hz,2H),4.09(s,2H),4.02-3.92(m,2H),3.72(t,J=11.6Hz,2H ),3.46(t,J=12.8Hz,4H),3.15-3.00(m,4H),2.79(t,J=11.6Hz,2H),2.21(s,3H),2.06-1.9 4(m,1H),1.90-1.76(m,2H),1.71-1.60(m,2H),1.51-1.24(m,4H),0.93(t,J=7.6Hz,3H)ppm. MS:M / e 495(M+1)+ .

[0651] Compound B110: 2-Butoxy-7-((6-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0652] Step A: 6-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-5-methylnicotinaldehyde

[0653] To a solution of 6-chloro-5-methylnicotinaldehyde (155 mg, 1 mmol) and DIEA (260 mg, 2 mmol) in DMA (5 mL) was added N,N-dimethyl-2-(piperidin-4-yl)ethan-1-amine (170 mg, 1.1 mmol). The mixture was then stirred at 115° C. overnight under N 2 . The mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (40 mL x 2), washed with brine, dried over Na 2 SO 4 , filtered, concentrated, and the residue was purified by preparative TLC to give the title compound (50 mg, 18%). MS: M / e 276 (M+1) + .

[0654] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0655] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (85 mg, 0.16 mmol) in THF (5 mL) was added dropwise a solution of n-butyllithium (0.15 mL, 0.24 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a suspension of the product of step A (50 mg, 0.182 mmol) in THF (2 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 (60 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 / e 723 (M+1) + .

[0656] Step C: 2-Butoxy-7-((6-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0657] To a mixture of the product of step B (50 mg, crude) in TFA (3 mL) was added Et3SiH (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 reaction was heated at 85°C overnight. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (16 mg, 17% for two steps). 1 HNMR(400MHz,DMSO-d6)δ9.45(br.s,1H),8.19(s,1H),8.13(s,1H),8.08(s,1H ),7.72(s,1H),7.37(s,1H),4.21(t,J=6.8Hz,2H),4.11(s,2H),3.55-3.40(m, 2H),3.15-3.03(m,2H),2.91-2.70(m,8H),2.24(s,3H),1.84-1.72(m,2H),1.7 1-1.59(m,4H),1.55-1.45(m,1H),1.44-1.25(m,4H),0.92(t,J=7.6Hz,3H)ppm. MS:M / e 467(M+1) + .

[0658] Compound B111: 1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0659] Step A: tert-Butyl (2-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate

[0660] A solution of 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.24 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (55 mg, 0.29 mmol), HATU (137 mg, 0.36 mmol) and DIEA (62 mg, 0.48 mmol) in DMF (5 mL) was stirred for 2 hours at rt. The reaction mixture was quenched with water (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 used directly in the next step without further purification (140 mg, crude). MS: M / e 582 (M+1) + .

[0661] Step B: 1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0662] To a solution of tert-butyl (2-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (140 mg, crude) in EA (5 mL) was added HCl / EA (2M, 3 mL). The solution was stirred at rt overnight. After concentration, the residue was dissolved in DCM (10 mL) and washed with NaHCO (10 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the crude product, which was further purified by preparative HPLC to give the pure product (20 mg, 17%). 1 H NMR(400MHz,DMSO-d6)δ8.09(s,1H),8.07(s,1H),7.98(s,1H),7.44(s,1H),7.32(s,1H),4.98-4.94(m,1H),4.05(s,2H),3.58-3.51(m,4H),3. 39(s,2H),3.00-2.95(m,4H),2.30(s,3H),2.20(s,3H),1.62-1.51(m,2 H), 1.41-1.33 (m, 2H), 1.23 (d, J = 4.0Hz, 3H), 0.87 (t, J = 8.0Hz, 3H) ppm. MS:M / e482(M+1) + .

[0663] Compound 112: 2-(sec-Butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0664] Step A: 7-Bromo-2-(sec-butoxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0665] NaH (96 mg, 2.4 mmol) was added to a solution of butane-2-ol (178 mg, 2.4 mmol) in THF (10 mL). After stirring at rt under an N2 atmosphere for 30 min, 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (300 mg, 0.60 mmol) was added and the resulting mixture was heated at 65 ° C overnight. The solution was cooled, quenched with water (10 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 Combi-Flash (PE:EA=15%) to give the product (225 mg, 75%). MS: M / e 526 (M+1) + .

[0666] Step B: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0667] At -78°C (with N 2 To a cooled solution of 7-bromo-2-(sec-butoxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (225 mg, 0.43 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.4 mL) dropwise under a purging (1 mL). After stirring at -78°C for 30 minutes, tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (157 mg, 0.51 mmol) in THF (2 mL) was added. The resulting mixture was stirred at this temperature for 30 minutes and then allowed to warm to room temperature overnight. 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 Combi-Flash (PE:EA=50%) to give the pure product (266 mg, 82%). MS: M / e 753 (M+1) + .

[0668] Step C: 2-(sec-Butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0669] A solution of tert-butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate (266 mg, 0.35 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (10 mL) was heated at 88° C. overnight. The solvent was evaporated under an oil pump to give a residue, to which DCM (10 mL) was added and basified with NaHCO 3 solution (5 mL). The organic layer was dried, concentrated and purified by Combi-Flash (DCM:MeOH=25%, 40% NH 3 ·MeOH was added) and preparative TLC (DCM:NH 3 ·MeOH=7:1) to give the product (15 mg, 11%). 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),8.05(s,1H),7.99(s,1H),7.41(s,1H),7.32(s,1H),4.90-4.85(m,1H),4. 03(s,2H),2.92-2.83(m,8H),2.17(s,3H),1.63-1.57(m,2H),1.24(d,J=8.0Hz,3H),0.90(t,J=4.0Hz,3H)ppm. MS:M / e 397(M+1) + .

[0670] Compound B113: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(2-methylbutyloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0671] Compound B113 was synthesized according to a similar procedure to that described for compound B8 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),8.06(s,2H),7.43(s,1H),7.30(s,1H),4.10-3.99(m,4H),2.91-2. 82(m,8H),2.17(s,3H),1.81-1.78(m,1H),1.47-1.42(m,1H),1.21-1.15(m,1H),0.95-0.88(m,6H)ppm. MS:M / e 411(M+1) + .

[0672] Compound B114: 2-Butoxy-7-((6-(4-ethylpiperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0673] To a stirred solution of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol) in DCM (5 mL) and MeOH (5 mL) was added acetaldehyde (10.8 mg, 0.1 mmol) and NaBH3CN (18 mg, 0.3 mmol). The reaction mixture was stirred at RT overnight. The mixture was poured into H2O (50 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 preparative HPLC to give the product (32 mg, 59.4%). 1 H NMR (400MHz, DMSO-d6) δ9.40(br.s,1H),8.16-8.05(m,3H),7.53(s,1H),7.35(d,J=3.5Hz,1H),4.21(t,J=6.5Hz,2H),4.08(s,2H),3.53-3 .42(m,4H),3.24-2.93(m,6H),2.21(s,3H),1.74-1.59(m,2H),1.41(dd,J=14.9,7.4Hz,2H),1.32-1.21(m,3H),0.93(t,J=7.4Hz,3H)ppm. MS:M / e 425(M+1) + .

[0674] Compound B115: 2-Butoxy-7-((6-(4-ethylpiperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0675] To a stirred solution of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol) in DCM (5 mL) and MeOH (5 mL) was added isobutyraldehyde (13.7 mg, 0.1 mmol) and NaBH3CN (18 mg, 0.3 mmol). The reaction mixture was stirred at RT overnight. The mixture was poured into H2O (50 mL) and extracted with EtOAc (10 ml x 3). The combined layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (32 mg, 35.3%). 1 H NMR (400MHz, DMSO-d6) δ9.14(br.s,1H),8.20-8.03(m,3H),7.52(s,1H),7.35(s,1H),4.22(t,J=6.4Hz,2H),4.08(s,2H),3.62-3.34(m,4H),3. 23-3.06(m,4H),3.01(d,J=5.5Hz,2H),2.21(s,3H),2.11(dt,J=13.0,6 .8Hz,1H),1.74-1.63(m,2H),1.48-1.33(m,2H),1.04-0.86(m,9H)ppm. MS:M / e 453(M+1) + .

[0676] Compound B116: 2-Butoxy-7-((5-methyl-6-(4-phenethylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0677] To a stirred solution of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol) in DCM (5 mL) and MeOH (5 mL) was added 2-phenylacetaldehyde (18.5 mg, 0.1 mmol) and NaBH3CN (18 mg, 0.3 mmol). The reaction mixture was stirred at RT overnight. The mixture was poured into H2O (50 mL) and extracted with EtOAc (10 ml x 3). The combined layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (30 mg, 48.8%). 1H NMR (400MHz, DMSO-d6) δ9.93 (br.s, 1H), 8.25-8.04 (m, 3H), 7.55 (s, 1H), 7.43-7.25 (m, 6H), 4.22 (t, J = 6.2Hz, 2H), 4.10 (s, 2H), 3.6 4-3.54(m,4H),3.47-3.22(m,4H),3.17-2.96(m,4H),2.23(s,3H),1.74-1.63(m,2H),1.41-1.32(m,2H),0.93(t,J=7.3Hz,3H)ppm. MS:M / e 501(M+1) + .

[0678] Compound B117: (R)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0679] Step A: (R)-7-Bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0680] NaH (984 mg, 24.6 mmol) was added to a solution of (R)-pentane-2-ol (2.2 g, 24.6 mmol) in THF (20 mL). After stirring at rt under N2 atmosphere for 30 min, 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (3 g, 6.2 mmol) was added and the resulting mixture was heated at 60 ° C overnight. The solution was cooled, diluted with water (10 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 Combi-Flash (PE:EA=15%) to give the pure product (3 g, 90%). MS: M / e 540 (M+1) + .

[0681] Step B: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(((R)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0682] To (R)-7-bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yl

[0683] A solution of 2-(4-(2-(2-oxy)imidazo[2,1-f][1,2,4]triazin-4-amine (1 g, 1.8 mmol) in THF (15 mL) was stirred at -78 °C (with N 2 To the mixture was added n-butyllithium (1.6 M, 1.7 mL) (purged). After stirring at -78 ° C for 30 min, tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (659 mg, 2.2 mmol) in THF (5 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 (10 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 Combi-Flash (PE:EA=50%) to give the pure product (800 mg, 56%). MS: M / e 767 (M+1) +

[0684] Step C: (R)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0685] A solution of tert-butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(((R)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate (800 mg, 1 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (8 mL) was heated at 80° C. overnight. The solvent was evaporated to give a residue, which was dissolved in EA (10 mL) and washed with NaHCO solution (10 mL). The organic layer was dried, concentrated, and purified by Combi-Flash (DCM:NH·MeOH=35%) and preparative TLC (DCM:NH·MeOH=9:1) to give the product (65 mg, 15%). 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),8.05(s,1H),7.99(s,1H),7.39(s,1H),7.32(s,1H),4.98-4.94(m,1H),4.03(s,2H ), 2.95-2.74(m,8H),2.16(s,3H),1.63-1.52(m,2H),1.48-1.30(m,2H),1.24(d,J=4.0,3H),0.88(t,J=8.0Hz,3H)ppm. MS:M / e411(M+1) + .

[0686] Compound B118: (S)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0687] Step A: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(((S)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0688] At -78°C (with N 2 To a cooled solution of (S)-7-bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (300 mg, 0.56 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.5 mL) dropwise under a 4% CO purging (1% CO purging). After stirring at -78°C for 30 minutes, tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (204 mg, 0.67 mmol) in THF (2 mL) was added. The resulting mixture was stirred at this temperature for 30 minutes and then warmed to room temperature for 2 hours. The solution was quenched with NH4Cl solution (10 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 Combi-Flash (PE:EA=50%) to give the pure product (300 mg, 70%). MS: M / e 767 (M+1) + .

[0689] Step B: (S)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0690] A solution of tert-butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(((S)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate (300 mg, 0.39 mmol) in triethylsilane (2 mL) and trifluoroacetic acid (8 mL) was heated at 85 ° C. overnight. The solvent was evaporated to give a residue, which was dissolved in EA (10 mL) and washed with NaHCO solution (10 mL). The organic layer was dried, concentrated, and purified by preparative TLC (DCM:NH ·MeOH=9:1) to give the product (20 mg, 13%).1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),8.05(s,1H),7.99(s,1H),7.40(s,1H),7.32(s,1H),4.98-4.94(m,1H),4.03(s,2H ),2.98-2.76(m,8H),2.16(s,3H),1.65-1.48(m,2H),1.42-1.30(m,2H),1.24(d,J=4.0,3H),0.88(t,J=8.0Hz,3H)ppm. MS:M / e 411(M+1) + .

[0691] Compound B119: 2-(2-(2-methoxyethoxy)ethoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0692] Compound B119 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.68(br.s,2H),8.21(s,1H),8.14(s,1H),8.11(s,1H),7.52(s,1H),7.36(s,1H),4.32(t,J=4 Hz, 2H), 4.08 (s, 2H), 3.71 (t, J = 4Hz, 2H), 3.57 (t, J = 4Hz, 2H), 3.45 (t, J = 4Hz, 2H), 3.34-3.11 (m, 11H), 2.21 (s, 3H) ppm. MS:M / e 443(M+1) + .

[0693] Compound B120: 2-((2,5,8,11,14,17-hexaoxonadecan-19-yl)oxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0694] Compound B120 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1H NMR(400MHz,DMSO-d6)δ8.73(br.s,2H),8.22(s,1H),8.17(s,1H),8.12(s,1H),7.54(s,1H),7.38(s,1H),4.33(t,J=4Hz,2H),4.09(s,2H) ,3.72(t,J=4Hz,2H),3.57(t,J=4Hz,2H),3.53(t,J=4Hz,2H),3.51-3.46(m,14H),3.42-3.80(m,2H),3.29-3.16(m,11H),2.21(s,3H)ppm. MS:M / e 619(M+1) + .

[0695] Compound B121: 2-Butoxy-7-((5-methyl-6-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0696] Step A: 5-methyl-6-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)nicotinaldehyde

[0697] To a solution of 6-chloro-5-methylnicotinaldehyde (155 mg, 1 mmol) and DIEA (560 mg, 4 mmol) in DMA (5 mL) was added 4-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride (265 mg, 1.1 mmol). The mixture was then stirred at 115° C. overnight under N 2 . The mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (50 mL x 2), washed with brine, dried over Na 2 SO 4 , filtered, concentrated, and the residue was purified by preparative TLC to give the title compound (80 mg, 28%). MS: M / e 288 (M+1) + .

[0698] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(5-methyl-6-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-3-yl)methanol

[0699] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (116 mg, 0.22 mmol) in THF (5 mL) was added dropwise a solution of n-butyllithium (0.21 mL, 0.33 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a suspension of the product of step A (70 mg, 0.243 mmol) in THF (2 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 to give the target compound (60 mg, crude). MS: M / e 735 (M+1) + .

[0700] Step C: 2-Butoxy-7-((5-methyl-6-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0701] To a mixture of the product of step B (60 mg, crude) in TFA (2 mL) was added Et3SiH (2 mL), and the resulting mixture was stirred at 85°C for 3 hours. The mixture was cooled to room temperature and concentrated to dryness. TFA (3 mL) was added to the residue and the reaction was heated at 85°C overnight. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (15 mg, 12% for two steps). 1 HNMR(400MHz,DMSO-d6)δ9.24(br.s,1H),8.16(s,1H),8.09(s,1H),8.07(s,1H),7.57(s,1 H),7.34(s,1H),4.21(t,J=6.8Hz,2H),4.07(s,2H),3.66-3.52(m,2H),3.46-3.31(m,2H), 3.31(t,J=6.0Hz,2H),3.06-2.95(m,2H),2.76(t,J=11.6Hz,2H),2.20(s,3H),2.10-1.95( m,2H),1.94-1.75(m,5H),1.72-1.60(m,2H),1.50-1.24(m,4H),0.93(t,J=7.6Hz,3H)ppm. MS:M / e 479(M+1) + .

[0702] Compound B122: (S)-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0703] Step A: (S)-7-Bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0704] To a solution of (S)-pentane-2-ol (5.4 g, 64.35 mmol) in THF (30 mL) was added NaH (2.4 g, 61.35 mmol) in portions at 0 ° C and stirred at rt for 1 h. A solution of 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (10 g, 20.45 mmol) in THF (20 mL) was then added dropwise at 0 ° C. After addition, the mixture was heated to 60 ° C and stirred overnight. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (PE / EA=5:1 to 1:1) to give the title product (10.74 g, 97.26%) as a yellow oil. MS:M / e 540(M+1) + .

[0705] Step B: (4-(bis(4-methoxybenzyl)amino)-2-(((S)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0706] To a solution of (S)-7-bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.37 mmol) in THF (5 mL) was added n-butyllithium (0.35 mL, 0.56 mmol) dropwise at -78°C and stirred for 1 hour. A solution of 6-(4-(dimethylamino)piperidin-1-yl)-5-methylnicotinaldehyde (137 mg, 0.56 mmol) in THF (2 mL) was then added dropwise at -78°C. After addition, the mixture was warmed to room temperature and stirred for 3 hours. 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 (175 mg, 66.64%) as a yellow oil. MS: M / e709 (M+1) + .

[0707] Step C: (S)-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0708] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-(((S)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methanol (175 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 title product (41 mg, 36.75%). 1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.14(s,1H),8.07(s,2H),7.51(s,1H),7.37(s,1H),4.9 9-4.94(m,1H),4.07(s,2H),3.50(d,J=12.2Hz,2H),3.37-3.25(m,1H),2.79(s,3H),2.78(s, 3H),2.75-2.66(m,2H),2.20(s,3H),2.05(d,J=10.9Hz,2H),1.79-1.66(m,2H),1.67-1.58(m ,1H),1.57-1.47(m,1H),1.42-1.29(m,2H),1.25(d,J=6.1Hz,3H),0.88(t,J=7.3Hz,3H)ppm. MS:M / e 453(M+1) + .

[0709] Compound B123: (S)-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0710] Step A: (4-(bis(4-methoxybenzyl)amino)-2-(((S)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0711] To a solution of (S)-7-bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.37 mmol) in THF (5 mL) was added n-butyllithium (0.35 mL, 0.56 mmol) dropwise at -78°C and stirred for 1 hour. A solution of 6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylnicotinaldehyde (145 mg, 0.56 mmol) in THF (2 mL) was then added dropwise at -78°C. After addition, the mixture was warmed to room temperature and stirred for 3 hours. 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 (201 mg, 75.06%) as a yellow oil. MS: M / e 723 (M+1) + .

[0712] Step B: (S)-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0713] A mixture of the product of step A (201 mg, 0.28 mmol) and triethylsilane (1 mL) in TFA (2 mL) was stirred overnight at 90° C. The mixture was concentrated and purified by preparative HPLC to give the title product (33 mg, 25.47%). 1 HNMR(400MHz,DMSO-d6)δ9.33(br.s,1H),8.17(s,1H),8.11(s,1H),8.07(s,1H),7.64(s ,1H),7.39(s,1H),5.03-4.89(m,1H),4.10(s,2H),3.46(d,J=12.6Hz,2H),3.05-3.01(m ,2H),2.87-2.81(m,8H),2.22(s,3H),1.98(s,1H),1.80(d,J=11.5Hz,2H),1.69-1.59(m ,1H),1.58-1.46(m,1H),1.42-1.28(m,4H),1.25(d,J=5.0Hz,3H),0.88(t,J=6.8Hz,3H). MS:M / e 467(M+1) + .

[0714] Compound B124: (R)-1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

[0715] A solution of (R)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (67 mg, 0.16 mmol), dimethylglycine (21 mg, 0.2 mmol), HATU (91 mg, 0.24 mmol) and DIEA (42 mg, 0.32 mmol) in DMF (5 mL) was stirred at rt for 2 hours. The reaction mixture was diluted with water (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 purified by preparative TLC (DCM:NH3.MeOH=10:1) to give the product (29 mg, 36%). 1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.07(s,1H),7.99(s,1H),7.44(s,1H) ,7.33(s,1H),4.98-4.94(m,1H),4.05(s,2H),3.62(s,2H),3.57(s,2H),3. 25(s,2H),3.01(s,2H),2.94(s,2H),2.26(s,6H),2.20(s,3H),1.53-1.37( m, 2H), 1.35-1.25 (m, 2H), 1.24 (d, J = 4.0Hz, 3H), 0.88 (t, J = 8.0Hz, 3H) ppm. MS:M / e 496(M+1) +

[0716] Compound B125: (S)-1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

[0717] A solution of (S)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (43 mg, 0.10 mmol), dimethylglycine (13 mg, 0.12 mmol), HATU (57 mg, 0.15 mmol) and DIEA (26 mg, 0.20 mmol) in DMF (5 mL) was stirred for 2 hours at rt. The reaction mixture was diluted with water (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 purified by preparative TLC (DCM:NH3.MeOH=10:1) to give the product (10 mg, 20%). 1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),8.07(s,1H),7.99(s,1H),7.44(s,1H),7.33(s,1H),4.98-4.94(m,1H),4.05(s,2H),3.59(s,4H),3.47(s, 2H),3.02(s,2H),2.95(s,2H),2.33(s,6H),2.21(s,3H),1.53-1.35(m, 2H), 1.33-1.26 (m, 2H), 1.24 (d, J = 4.0Hz, 3H), 0.88 (t, J = 8.0Hz, 3H) ppm. MS:M / e 496(M+1)+ .

[0718] Compound B126: 2-Butoxy-7-((6-(4-((diethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0719] Step A: 6-(4-((diethylamino)methyl)piperidin-1-yl)-5-methylnicotinaldehyde

[0720] To a solution of 6-chloro-5-methylnicotinaldehyde (155 mg, 1 mmol) and DIEA (258 mg, 2 mmol) in DMA (5 mL) was added N-ethyl-N-(piperidin-4-ylmethyl)ethanamine (190 mg, 1.1 mmol). The mixture was then stirred at 115° C. overnight under N 2 . The mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (50 mL x 2), washed with brine, dried over Na 2 SO 4 , filtered, concentrated, and the residue was purified by preparative TLC to give the title compound (110 mg, 38%). MS: M / e 290 (M+1) + .

[0721] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-((diethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0722] To a solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (175 mg, 0.22 mmol) in THF (8 mL) was added a solution of n-butyllithium (0.31 mL, 0.5 mmol) dropwise, maintaining the temperature between -75°C and -65°C. After 1 h, a suspension of the product of step A (110 mg, 0.38 mmol) in THF (2 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 to give the target compound (100 mg, crude). MS: M / e 737 (M+1) + .

[0723] Step C: 2-Butoxy-7-((6-(4-((diethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0724] To a mixture of the product of step B (100 mg, crude) 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 85°C overnight. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (30 mg, 15% for two steps). 1 HNMR(400MHz,DMSO-d6)δ8.92(br.s,1H),8.20(s,1H),8.15(s,1H),8.09(s,1H),7.73( s,1H),7.38(d,J=4.0Hz,1H),4.21(t,J=6.4Hz,2H),4.11(s,2H),3.57-3.36(m,2H),3. 26-3.05(m,4H),3.06-2.94(m,2H),2.91-2.75(m,2H),2.23(s,3H),2.05-1.76(m,3H), 1.74-1.60(m,2H),1.51-1.29(m,4H),1.21(t,J=7.2Hz,6H),0.93(t,J=7.6Hz,3H)ppm. MS:M / e 481(M+1) + .

[0725] Compound B127: (R)-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0726] Step A: (R)-7-Bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0727] To a solution of (R)-pentane-2-ol (5.4 g, 64.35 mmol) in THF (30 mL) was added NaH (2.4 g, 61.35 mmol) in portions at 0 ° C and stirred at rt for 1 h. A solution of 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (10 g, 20.45 mmol) in THF (20 mL) was then added dropwise at 0 ° C. After addition, the mixture was heated to 60 ° C and stirred overnight. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (PE / EA=5:1 to 1:1) to give the title product (10.25 g, 92.63%) as a yellow oil. MS:M / e 540(M+1) + .

[0728] Step B: (4-(bis(4-methoxybenzyl)amino)-2-(((R)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0729] To a solution of (R)-7-bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.37 mmol) in THF (5 mL) was added n-butyl lithium (0.35 mL, 0.56 mmol) dropwise at -78°C and stirred for 1 hour. A solution of 6-(4-(dimethylamino)piperidin-1-yl)-5-methylnicotinaldehyde (137 mg, 0.56 mmol) in THF (2 mL) was then added dropwise at -78°C. After addition, the mixture was warmed to room temperature and stirred for 3 hours. 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 (156 mg, 59.41%) as a yellow oil. MS: M / e709 (M+1) + .

[0730] Step C: (R)-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0731] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-(((R)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methanol (156 mg, 0.22 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 (54 mg, 54.30%). 1 H NMR(400MHz,DMSO-d6)δ9.52(br.s,1H),8.14(s,1H),8.07(s,2H),7.49(s,1H),7.35(s,1H ),4.99-2.94(m,1H),4.06(s,2H),3.49(d,J=11.9Hz,2H),3.31(s,1H),2.78(s,3H),2.77(s ,3H),2.75-2.67(m,2H),2.20(s,3H),2.04(d,J=10.4Hz,2H),1.79-1.67(m,2H),1.66-1.59 (m,1H),1.57-1.48(m,1H),1.42-1.29(m,2H),1.25(d,J=6.1Hz,3H),0.88(t,J=7.3Hz,3H). MS:M / e 453(M+1) + .

[0732] Compound B128: (R)-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0733] Step A: (4-(bis(4-methoxybenzyl)amino)-2-(((R)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0734] To a solution of (R)-7-bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.37 mmol) in THF (5 mL) was added n-butyllithium (0.35 mL, 0.56 mmol) dropwise at -78°C and stirred for 1 hour. A solution of 6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylnicotinaldehyde (145 mg, 0.56 mmol) in THF (2 mL) was then added dropwise at -78°C. After addition, the mixture was warmed to room temperature and stirred for 3 hours. 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 (201 mg, 75.06%) as a yellow oil. MS: M / e 723 (M+1) + .

[0735] Step B: (R)-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0736] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-(((R)-pentan-2-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol (201 mg, 0.28 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 (54 mg, 41.89%). 1H NMR(400MHz,DMSO-d6)δ9.15(br.s,1H),8.14(s,1H),8.06(s,2H),7.55(s,1H),7.36( s,1H),4.98-4.94(m,1H),4.07(s,2H),3.39(s,2H),3.02(t,J=5.9Hz,2H),2.80(s,6H ),2.79(s,2H),2.20(s,3H),1.94(s,1H),1.78(d,J=11.9Hz,2H),1.67-1.58(m,1H),1 .56-1.46(m,1H),1.44-1.28(m,4H),1.25(d,J=6.1Hz,3H),0.88(t,J=7.3Hz,3H)ppm. MS:M / e 467(M+1) + .

[0737] Compound B129: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)octadecane-1-one

[0738] To a stirred solution of 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.1 mmol) in DMF (5 mL) was added stearic acid (35 mg, 0.12 mmol), HATU (116 mg, 0.3 mmol), and DIEA (25.8 mg, 0.2 mmol). The reaction mixture was stirred at RT overnight. The mixture was poured into H2O (50 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 (10 mg, 15.1%). 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),7.37(s,1H),7.28(s,1H),4.29(t,J=6.1H z,2H),4.11(s,2H),3.74(s,2H),3.60(s,2H),3.17(s,2H),3.04(s,2H),2.36 (t,J=7.4Hz,2H),2.26(s,3H),1.82-1.73(m,2H),1.63(d,J=6.2Hz,2H),1.54 -1.46(m,2H),1.25(s,28H),0.97(t,J=7.2Hz,3H),0.87(t,J=6.7Hz,3H)ppm. MS:M / e 663(M+1)+ .

[0739] Compound B130: 2-Butoxy-7-((5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0740] Step A: 5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)nicotinaldehyde

[0741] To a stirred solution of 6-chloro-5-methylnicotinaldehyde (310 mg, 2 mmol) in DMA (10 mL) was added 1-methyl-4-(piperidin-4-yl)piperazine (439 mg, 2.4 mmol) and DIEA (516 mg, 4 mmol). The reaction mixture was protected with N2 and stirred at 120 ° C for 4 hours. The mixture was cooled to rt, H2O (50 mL) was added and extracted with DCM (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 yellow solid (130 mg, 21.5%). MS: M / e 303 (M+1) + .

[0742] Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)methanol

[0743] 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) cooled to -78 ° C and under a nitrogen atmosphere was added n-butyl lithium (1.6 M in hexane, 0.95 mmol, 0.59 mL). After stirring for 50 min, a solution of 5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)nicotinaldehyde (130 mg, 0.43 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. The crude product was purified by column chromatography to give the title product (110 mg, 38.7%). MS: M / e 750 (M+1) + .

[0744] Step C: 2-Butoxy-7-((5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0745] A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)methanol (110 mg, 0.15 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 80 ° C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give the product (15 mg, 21%). 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),8.11(s,1H),8.08(s,1H),7.56(s,1H),7.34(s,1H),4.21(t,J=6.1Hz,2H),4.08(s,2H),3.52(br .s,6H),3.08(br.s,4H),2.83-2.75(m,6H),2.21(s,3H),2.04(s,2H),1.75-1.61(m,4H),1.43-1.35(m,2H),0.93(t,J=7.2Hz,3H)ppm. MS:M / e 494(M+1) + .

[0746] Compound B131: 2-Butoxy-7-((5-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0747] Step A: tert-Butyl-9-(5-formyl-3-methylpyridin-2-yl)-3,9-diazaspiro[5.5]

[0748] Undecane-3-carboxylate

[0749] To a stirred solution of 6-chloro-5-methylnicotinaldehyde (310 mg, 2 mmol) in DMA (10 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (500 mg, 2 mmol) and DIEA (487 mg, 3 mmol). The reaction mixture was protected by N2 and stirred at 120 ° C for 4 h. The mixture was cooled to rt, H2O (50 mL) was added 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 (260 mg, 34.8%). MS: M / e 374 (M+1) + .

[0750] Step B: tert-Butyl-9-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0751] To a stirred solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF (10 mL) cooled to -78°C under nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.95 mmol, 0.59 mL) dropwise. After stirring for 50 min, tert-butyl 9-(5-formyl)-1,2-diol was slowly added.

[0752] -3-methylpyridin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (212 mg, 0.57 mmol) in THF (2 mL). The reaction mixture was slowly warmed to rt and stirred for 2 h. The reaction mixture was poured into 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 (120 mg, 38.6%). MS: M / e 821 (M+1) + .

[0753] Step C: 2-Butoxy-7-((5-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0754] A solution of tert-butyl 9-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (120 mg, 0.146 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 (55 mg, 51.4%). 1 H NMR (400MHz, DMSO-d6) δ8.44(br.s,2H),8.20(s,1H),8.15(s,1H),8.08(s,1H),7.73(s,1H),7.36(s,1H),4.21(t,J=6. 3Hz,2H),4.11(s,2H),3.22-3.05(m,8H),2.23(s,3H),1.79-1.51(m,10H),1.50-1.33(m,2H),0.92(t,J=7.3Hz,3H)ppm. MS:M / e 465(M+1) + .

[0755] Compound B132: (S)-2-Butoxy-7-((5-methyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0756] Step A: tert-Butyl (S)-4-(5-formyl-3-methylpyridin-2-yl)-2-methylpiperazine-1-carboxylate

[0757] A mixture of 6-chloro-5-methylnicotinaldehyde (500 mg, 3.2 mmol), tert-butyl (S)-2-methylpiperazine-1-carboxylate (645 mg, 3.2 mmol) and DIEA (832 mg, 6.4 mmol) in DMAc (10 mL) was stirred at 100 ° C overnight. The reaction was diluted with water (30 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 combi-flash to obtain the title compound (350 mg, yield: 34.3%) as a yellow oil. MS: M / e 320 (M+1) + .

[0758] Step B: tert-Butyl (2S)-4-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)-2-methylpiperazine-1-carboxylate

[0759] 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-butyl lithium (1.6 M, 0.36 mL). The mixture was stirred at -78 ° C for 1 hour. The product of step A (137 mg, 0.44 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 combi-flash to obtain the title compound (190 mg, yield: 85.6%) as a yellow oil. MS:M / e767(M+1) + .

[0760] Step C: (S)-2-Butoxy-7-((5-methyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (TLR-281)

[0761] To a stirred solution of the product from step B (190 mg, 0.25 mmol) in Et3SiH (4 mL) was added CF3COOH (2 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 (35 mg, yield: 34.1%). 1H NMR (400MHz, DMSO-d6) δ8.14(br.s,1H),8.10-7.98(m,2H),7.42(s,1H),7.31(s,1H),4.21(t,J=6.4Hz,2H),4.03(s,2H),3.14(d,J=11.6H z,2H),2.97-2.72(m,3H),2.67-2.57(m,1H),2.38-2.26(m,1H),2.17(s,3H),1.79-1.60(m,2H),1.53-1.35(m,2H),1.08-0.83(m,6H)ppm. MS:M / e 411(M+1) + .

[0762] Compound B133: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0763] Step A: 7-Bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0764] To a solution of pentane-2-ol (5.4 g, 64.35 mmol) in THF (30 mL) was added NaH (2.4 g, 61.35 mmol) in portions at 0 ° C and stirred at rt for 1 h. A solution of 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (10 g, 20.45 mmol) in THF (20 mL) was then added dropwise at 0 ° C. After addition, the mixture was heated to 60 ° C and stirred overnight. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (PE / EA=5:1 to 1:1) to give the title product (10.54 g, 95.25%) as a yellow oil. MS:M / e 540(M+1) + .

[0765] Step B: (4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0766] To a solution of 7-bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.37 mmol) in THF (5 mL) was added n-butyllithium (0.35 mL, 0.56 mmol) dropwise at -78°C and stirred for 1 hour. A solution of 6-(4-(dimethylamino)piperidin-1-yl)-5-methylnicotinaldehyde (137 mg, 0.56 mmol) in THF (2 mL) was then added dropwise at -78°C. After addition, the mixture was warmed to room temperature and stirred for 3 hours. 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 (187 mg, 71.21%) as a yellow oil. MS: M / e709 (M+1) + .

[0767] Step C: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0768] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methanol (187 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 title product (68 mg, 57.04%). 1 H NMR(400MHz,DMSO-d6)δ9.71(br.s,1H),8.19(s,1H),8.14(s,1H),8.08(s,1H),7.57( s,1H),7.39(d,J=4.0Hz,1H),4.99-4.94(m,1H),4.09(s,2H),3.53(d,J=12.1Hz,2H),3 .33(s,1H),2.82-2.65(m,8H),2.21(s,3H),2.06(d,J=11.5Hz,2H),1.78-1.58(m,3H), 1.58-1.47(m,1H),1.45-1.27(m,2H),1.25(d,J=6.1Hz,3H),0.88(t,J=7.3Hz,3H)ppm. MS:M / e 453(M+1) + .

[0769] Compound B134: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0770] Step A: (4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0771] To a solution of 7-bromo-N,N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.37 mmol) in THF (5 mL) was added n-butyllithium (0.35 mL, 0.56 mmol) dropwise at -78°C and stirred for 1 hour. A solution of 6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylnicotinaldehyde (145 mg, 0.56 mmol) in THF (2 mL) was then added dropwise at -78°C. After addition, the mixture was warmed to room temperature and stirred for 3 hours. 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 (156 mg, 58.25%) as a yellow oil. MS: M / e 723 (M+1) + .

[0772] Step B: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine

[0773] A mixture of (4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol (156 mg, 0.21 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 (62 mg, 61.53%). 1H NMR(400MHz,DMSO-d6)δ9.28(br.s,1H),8.18(s,1H),8.11(s,1H),8.07(s,1H),7.63(s,1H),7 .38(s,1H),4.98-4.94(m,1H),4.10(s,2H),3.45(d,J=12.5Hz,2H),3.03(t,J=6.2Hz,2H),2.85 (s,2H),2.81(s,3H),2.80(s,3H),2.21(s,3H),1.97(s,1H),1.80(d,J=12.4Hz,2H),1.69-1.59 (m,1H),1.58-1.48(m,1H),1.46-1.28(m,4H),1.25(d,J=6.1Hz,3H),0.88(t,J=7.3Hz,3H)ppm. MS:M / e476(M+1) + .

[0774] Compound B135: N2-butyl-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0775] Step A: (4-(bis(4-methoxybenzyl)amino)-2-(butylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0776] 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 (160 mg, 0.3 mmol) in THF (10 mL) at -78°C was added n-butyllithium (1.6 M, 0.47 mL, 0.76 mmol) dropwise. After stirring under N2 for one hour, a solution of 6-(4-(dimethylamino)piperidin-1-yl)-5-methylnicotinaldehyde (111.6 mg, 0.45 mmol) in THF (2 mL) was added dropwise at -78°C and the reaction was stirred overnight. 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 (102 mg, 49%) as a brown oil. MS: M / e694 (M+1) + .

[0777] Step B: N2-butyl-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0778] A mixture of the product of step A (102 mg, 0.147 mmol) in Et3SiH / TFA (2 mL / 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 (32 mg, 72.9%). 1 H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.09(s,1H),7.84(br.s,2H),7.53(s,1H),7.44(s ,1H),6.63(s,1H),4.04(s,2H),3.49(d,J=12.4Hz,2H),3.36-3.26(m,1H),3.17(t,J=6. 8Hz,2H),2.79(s,3H),3.77(s,3H),2.73(t,J=12.4Hz,2H),2.19(s,3H),2.08-2.00(m, 2H),1.72-1.64(m,2H),1.60-1.45(m,2H),1.39-1.24(m,2H),0.89(t,J=7.3Hz,3H)ppm. MS:M / e 438(M+1) + .

[0779] Compound B136: 7-((6-(3-aminoazetidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0780] Compound B136 was synthesized according to a similar procedure as described for compound B8 starting from the corresponding starting materials. 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.34(s,2H),8.17(s,1H),8.11(s,1H),7.97(s,1H),7.55(d,J=14.9Hz,1H),7.32(s,1 H),4.44(d,J=8.5Hz,2H),4.28-3.99(m,7H),2.17(s,3H),1.74-1.63(m,2H),1.48-1.35(m,2H),0.94(t,J=7.2Hz,3H)ppm. MS:M / e 383(M+1) + .

[0781] Compound B137: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0782] Step A: 7-Bromo-N 4 ,N 4 -Bis(4-methoxybenzyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0783] To a stirred solution of 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (1 g, 2.05 mmol) in NMP (10 mL) was added pentane-2-amine (1 g, 11.5 mmol) and DIEA (400 mg, 3.1 mmol). The reaction mixture was sealed and heated at 220 ° C for 6 h. The mixture was cooled to rt, H2O (20 mL) was added 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 (250 mg, 22.7%). MS: M / e 539 (M+1) + .

[0784] Step B: (4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(4-(4-((dimethylamino)methyl)piperidin-1-yl)-3-methylphenyl)methanol

[0785] The 7-bromo-N 4 ,N 4 -bis(4-methoxybenzyl)-N 2To a stirred solution of 2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (110 mg, 0.2 mmol) in THF (8 mL) was added n-butyllithium (1.6 M in hexanes, 0.56 mmol, 0.35 mL) dropwise. After stirring for 50 min, a solution of 6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylnicotinaldehyde (90 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 saturated ammonium chloride solution and extracted with EA (15 mL 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 to give the title product (80 mg, 55.6%). MS: M / e 722 (M+1) + .

[0786] Step C: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N 2 -(Pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0787] A solution of (4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(4-(4-((dimethylamino)methyl)piperidin-1-yl)-3-methylphenyl)methanol (80 mg, 0.11 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 (20 mg, 38.8%). 1H NMR(400MHz,DMSO-d6)δ9.40(br.s,1H),8.08(s,1H),7.90(s,2H),7.60(s,1H),7. 51(s,1H),6.47(br.s,1H),4.06(s,2H),3.79(s,1H),3.42(d,J=11.5Hz,2H),3.03 (s,2H),2.91-2.75(m,8H),2.21(s,3H),1.96(s,1H),1.80(d,J=12.1Hz,2H),1.52 -1.48(m,1H),1.46-1.33(m,5H),1.10(d,J=6.3Hz,3H),0.85(t,J=6.8Hz,3H)ppm. MS:M / e 466(M+1) + .

[0788] Compound B138: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N 2 -(Pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0789] Step A: (4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(4-(4-(dimethylamino)piperidin-1-yl)-3-methylphenyl)methanol

[0790] The 7-bromo-N 4 ,N 4 -bis(4-methoxybenzyl)-N 2 To a stirred solution of 2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (200 mg, 0.37 mmol) in THF (8 mL) was added n-butyllithium (1.6 M in hexanes, 0.93 mmol, 0.58 mL) dropwise. After stirring for 50 min, a solution of 6-(4-(dimethylamino)piperidin-1-yl)-5-methylnicotinaldehyde (162 mg, 0.56 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 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 (100 mg, 0.38%). MS: M / e 708 (M+1) + .

[0791] Step C: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0792] A solution of (4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(4-(4-(dimethylamino)piperidin-1-yl)-3-methylphenyl)methanol (100 mg, 0.14 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 (70 mg, 88%). 1 H NMR(400MHz,DMSO-d6)δ9.60(br.s,1H),8.07(s,1H),7.81(br.s,2H),7.51( s,2H),6.42(s,1H),4.04(s,2H),3.80(s,1H),3.48(d,J=10.6Hz,2H),3.30( s,1H),2.75(m,8H),2.19(s,3H),2.04(d,J=10.3Hz,2H),1.71(d,J=10.7Hz, 2H), 1.51 (s, 1H), 1.43-1.17 (m, 3H), 1.10 (d, J = 5.5Hz, 3H), 0.85 (s, 3H) ppm. MS:M / e 452(M+1) + .

[0793] Compound B139: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-propylimidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0794] Step A: 7-Bromo-N4,N4-bis(4-methoxybenzyl)-N2-propylimidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0795] To a stirred solution of 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (1 g, 2.05 mmol) in NMP (5 mL) was added propan-1-amine (1 g, 12.8 mmol) and DIEA (1 g, 7.8 mmol). The reaction mixture was sealed and heated at 230 ° C for 6 h. The mixture was cooled to rt, H2O (20 mL) was added 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 (700 mg, 67%). MS: M / e 511 (M + 1) + .

[0796] Step B: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(propylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0797] To a stirred solution of 7-bromo-N4,N4-bis(4-methoxybenzyl)-N2-propylimidazo[2,1-f][1,2,4]triazine-2,4-diamine (200 mg, 0.39 mmol) in THF (8 mL) cooled to -78°C and under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.59 mmol, 0.37 mL) dropwise. After stirring for 50 min, a solution of the product of step A (180 mg, 0.39 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. The crude product was purified by column chromatography to give the title product (120 mg, 41.8%). MS: M / e 738 (M+1) + .

[0798] Step C: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-propylimidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0799] The product of step B (120mg, 0.163mmol) in TFA (3mL) and Et3SiH (3mL) was stirred at 80 ℃ for 2h. The reaction mixture was concentrated in vacuo to remove TFA and Et3SiH. TFA (5mL) was added to the residue and stirred at 85 ℃ overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give product (35mg, 56.4%). 1 H NMR(400MHz,DMSO-d6)δ8.70(br.s,2H),8.12(s,1H),7.78(br.s,2H),7.53(s,1H),7.44-7.41(m,1H),6.59(br .s,1H),4.05(s,2H),3.27-3.08(m,8H),3.13(s,2H),2.21(s,3H),1.61-1.43(m,2H),0.88(t,J=7.0Hz,3H)ppm. MS:M / e 382(M+1) + .

[0800] Compound B140: 2-(Hexan-3-yloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0801] Step A: 7-Bromo-2-(hexan-3-yloxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0802] At 0 degrees, NaH (60%, 164 mg, 4.1 mmol) was added to a solution of hexane-3-ol (314 mg, 3.07 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 20 minutes, then 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (1000 mg, 2.05 mmol) was added and the resulting mixture was stirred at 70 ° C 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 title product (450 mg) was purified by preparative TLC (silica gel, EA: PE = 1: 10) to give a yellow oil. MS: m / e554 (M + 1) + .

[0803] Step B: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(hexan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0804] To a solution of 7-bromo-2-(hexan-3-yloxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (250 mg, 0.45 mmol) in THF (4 mL) was added dropwise a solution of n-butyllithium (1.6 M, 0.69 mL, 1.1 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a suspension of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (207 mg, 0.68 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 (300 mg, crude yellow oil). MS: M / e 781 (M+1) + .

[0805] Step C: 2-(Hexan-3-yloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0806] To a mixture of the product of step B (250 mg, crude) 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 title compound (12.5 mg, 15% for two steps). 1H NMR(400MHz,DMSO-d6)δ8.67(br.s,2H),8.13-8.04(m,3H),7.46(s,1H),7.36(s,1H),4.88(br.s,1H),4. 07(s,2H),3.20(br.s,8H),2.19(s,3H),1.62-1.53(m,4H),1.37-1.24(m,2H),0.86(t,J=7.0Hz,6H)ppm. MS:M / e 425(M+1) + .

[0807] Compound B141: 2-butyl-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0808] Step A: 2-Butyl-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0809] A mixture of 2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (0.5 g, 1.22 mmol), butylboronic acid (0.37 g, 3.63 mmol), sodium hydroxide (0.098 g, 2.45 mmol) and Pd(PPh 3 ) 4 (0.14 g, 0.12 mmol) in dioxane (10 ml) and H 2 O (2 ml) was stirred at 80 ° C under N 2 overnight. After completion, the mixture was diluted with EA (30 ml) and then washed with brine (10 ml). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure to remove the solvent. The residue was purified by flash column chromatography using 0-15% EA in PE to give the product (0.16 g, 30%) as a colorless oil. MS: M / e 432 (M + 1) + .

[0810] Step B: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-butylimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0811] To a stirred solution of 2-butyl-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (0.22 g, 0.51 mmol) in THF (15 ml) was added dropwise n-butyllithium (1.6 M, 0.48 ml, 0.77 mmol) at -78°C under N₂. The solution was stirred at -78°C for 30 min. A solution of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (230 mg, 0.75 mmol) in THF (2 ml) was added dropwise at -78°C. The resulting solution was allowed to warm to rt and then stirred at rt for 1 h. Upon completion, the solution was quenched with H₂O (10 ml) and then extracted with DCM (15 ml x 2). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a red oil, which was used directly in the next step without further purification. MS: M / e 737 (M+1) + .

[0812] Step C: 2-butyl-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0813] The mixture of the product (rough) of step B, TFA (6ml) and triethylsilane (2ml) was stirred at 80 ℃ and spent the night. After completing, the reaction mixture was concentrated under reduced pressure to remove TFA. Residue was diluted with EA (20ml), and then washed twice with aqueous NaHCO (saturated, 15ml). With the organic phase through Na SO Drying and under reduced pressure concentrated. Residue is passed through preparation TLC purification and then through preparation HPLC purification to obtain product (105mg). 1 H NMR(400MHz,DMSO-d6)δ8.76(br.s,2H),8.22(br.s,2H),8.11(s,1H),7.53(s,1H),7.45-7.32(m,1H),4.13(s,2H ), 3.22(br.s,8H),2.60(t,J=8Hz,2H),2.21(s,3H),1.73-1.65(m,2H),1.35-1.27(m,2H),0.89(t,J=8Hz,3H)ppm. MS:M / e 381(M+1) + .

[0814] Compound B142: N-(1-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperidin-4-yl)-2-(dimethylamino)acetamide

[0815] A mixture of 7-((6-(4-aminopiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine (60 mg, 0.146 mmol), dimethylglycine (19 mg, 1.77 mmol) and DIPEA (38 mg, 0.292 mmol) in DCM (2 mL) was stirred at room temperature for 2 hours, then the reaction was quenched with H2O, extracted with DCM (10 mL×3), the combined layers were washed with brine, dried over Na2SO4 and concentrated, and the residue was purified by preparative HPLC to give the product (5 mg, 21%). 1H NMR (400MHz, CD3OD) δ8.10-7.89(m,2H),7.46(s,1H),4.29(t,J=6.4Hz,2H),4.25(s,2H),4.03-3.95(m,1H),3.94(s,2H),3.71-3.62(m,2 H),3.26-3.12(m,2H),2.94(s,6H),2.38(s,3H),2.08(d,J=11.9Hz,2H),1.83-1.60(m,4H),1.55-1.47(m,2H),0.98(t,J=7.4Hz,3H)ppm. MS:M / e 496(M+1)+.

[0816] Compound B143: 2-(Heptan-4-yloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0817] Step A: 7-Bromo-2-(heptane-4-yloxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0818] To a solution of heptane-4-ol (174 mg, 1.5 mmol) in THF (5 mL) was added NaH (60%, 80 mg, 2.0 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 20 minutes, then 7-bromo-2-chloro-N, N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (487 mg, 1.0 mmol) was added and the resulting mixture was stirred at 70 ° C 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 title product (400 mg, 67%) was obtained by purification by preparative TLC (silica gel, EA: PE = 1: 10) as a yellow oil. MS: m / e 568 (M + 1) + .

[0819] Step B: tert-Butyl tert-butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(heptan-4-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0820] To a solution of 7-bromo-2-(heptan-4-yloxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (200 mg, 0.35 mmol) in THF (4 mL) was added dropwise a solution of n-butyllithium (1.6 M, 0.55 mL, 0.88 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a suspension of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (161 mg, 0.53 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*3), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (240 mg, crude yellow oil). MS: M / e 795 (M+1) + .

[0821] Step C: 2-(Heptan-4-yloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0822] To a mixture of the product of step B (240 mg, crude) in TFA (2 mL) was added Et3SiH (2 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 (4 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 title compound (8.2 mg, 6% for two steps). 1 H NMR(400MHz,DMSO-d6)δ8.67(br.s,2H),8.12(s,,1H),8.09(s,1H),8.03(s,1H),7.46(s,1H),7.36(s,1H),4.97(b r.s,1H),4.07(s,2H),3.25-3.0(m,8H),2.23(s,3H),1.59-1.50(m,4H),1.43-1.25(m,4H),0.86(t,J=8.0,6H)ppm. MS:m / e439(M+1) + .

[0823] Compound B144: 7-((6-(4-(aminomethyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0824] Step A: tert-Butyl ((1-(5-formyl-3-methylpyridin-2-yl)piperidin-4-yl)methyl)carbamate

[0825] A mixture of 6-chloro-5-methylnicotinaldehyde (500 mg, 3.21 mmol), tert-butyl (piperidin-4-ylmethyl) carbamate (792 mg, 3.70 mmol) and DIEA (829 mg, 6.43 mmol) in DMA (15 ml) was stirred at 100 ° C under N2 overnight. After completion, the mixture was poured into water and then extracted twice with EA (20 ml). The organic layer was washed with water, dried and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography with 20%-50% EA in PE to give the product (950 mg, 89%) as a white solid. MS: M / e 334 (M+1) + .

[0826] Step B: tert-Butyl ((1-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperidin-4-yl)methyl)carbamate

[0827] To a stirred solution of 7-bromo-2-butoxy-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (0.2 g, 0.38 mmol) in THF (15 ml) was added dropwise n-butyllithium (1.6 M, 0.60 ml, 0.96 mmol) at -78°C under N₂. The solution was stirred at -78°C for 30 min. A solution of tert-butyl((1-(5-formyl-3-methylpyridin-2-yl)piperidin-4-yl)methyl)carbamate (190 mg, 0.57 mmol) in THF (2 ml) was added dropwise at -78°C. The resulting solution was allowed to warm to rt and then stirred at rt for 1 h. Upon completion, the solution was quenched with H₂O (10 ml) and then extracted with DCM (15 ml x 2). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow semisolid, which was used directly in the next step without further purification. MS: M / e 781 (M+1) + .

[0828] Step C: 7-((6-(4-(aminomethyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine

[0829] A mixture of tert-butyl ((1-(5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperidin-4-yl)methyl)carbamate (crude), TFA (6 ml) and triethylsilane (2 ml) was stirred at 80 ° C overnight. After completion, the reaction mixture was concentrated under reduced pressure to remove TFA. The residue was diluted with EA (20 ml) and then washed twice with aqueous NaHCO (saturated, 15 ml). The organic phase was dried over Na SO and concentrated under reduced pressure. The residue was purified by preparative TLC and then by preparative HPLC to give the product (62.23 mg). 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),8.07(s,2H),7.72(s,3H),7.63-7.42(m,1H),7.33(s,1H),4.21(t,J=8Hz,2H),4.06(s,2H),3.45-3.35 (m,2H),2.80-2.74(m,2H),2.73-2.64(m,2H),2.19(s,3H),1.83-1.75(m,2H),1.73-1.62(m,3H),1.47-1.26(m,4H),0.93(t,J=8Hz,3H)ppm. MS:M / e 425(M+1) + .

[0830] Compound B145: (S)-1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

[0831] A solution of (S)-2-(sec-butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (280 mg, 0.73 mmol), dimethylglycine (91 mg, 0.88 mmol), HATU (416 mg, 1.1 mmol) and DIEA (188 mg, 0.46 mmol) in DMF (10 mL) was stirred at rt for 2 hours. Water (10 mL) was added to the reaction mixture, 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 purified by Combi-Flash (DCM:NH3·MeOH=30%) to give the product (115 mg, 34%). 1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),8.08(s,1H),8.00(s,1H),7.45(s,1H),7.33(s,1H),4.90-4.87(m,1H),4.05(s,2H),3.59(br.s,4H ),3.44(s,2H),3.02(s,2H),2.96(s,2H),2.36(s,6H),2.21(s,3H),1.62-1.57(m,2H),1.24(d,J=8.0Hz,3H),0.90(t,J=8.0Hz,3H)ppm. MS:M / e 482(M+1) + .

[0832] Compound B146: (S)-1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0833] Step A: tert-Butyl (S)-(2-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate

[0834] A solution of (S)-2-(sec-butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (400 mg, 1.0 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (227 mg, 1.2 mmol), HATU (570 mg, 1.5 mmol) and DIEA (258 mg, 2.0 mmol) in DMF (10 mL) was stirred at rt for 2 hours. Water (10 mL) was added to the reaction mixture, 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 used in the next step (500 mg, 87%). MS: M / e 568 (M+1) + .

[0835] Step B: (S)-1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0836] To a solution of tert-butyl (S)-(2-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (500 mg, 0.9 mmol) in EA (8 mL) was added HCl / EA (2 M, 3 mL). The solution was stirred at rt for 3 hours. After concentration, the residue was dissolved in DCM (10 mL) and washed with NaHCO (10 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the crude product, which was further purified by Combi-Flash (DCM:NH·MeOH=35%) to give the pure product (160 mg, 39%). 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),8.07(s,1H),8.00(s,1H),7.45(s,1H),7.32(s,1H),4.92-4.83(m,1H),4.05(s,2H),3.58-3.52(m, 4H),3.33-3.31(m,2H),3.00-2.95(m,4H),2.28(s,3H),2.20(s,3H),1.62-1.59(m,2H),1.23(d,J=4.0Hz,3H),0.89(t,J=8.0Hz,3H)ppm. MS:M / e468(M+1) + .

[0837] Compound B147: (S)-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0838] Step A: (S)-7-Bromo-N4,N4-bis(4-methoxybenzyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0839] To a stirred solution of 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazine-4-amine (800 mg, 1.65 mmol) in NMP (5 mL) was added (S)-pentane-2-amine (1 g, 8.1 mmol) and DIEA (1 g, 8 mmol). The reaction mixture was sealed and heated at 230 ° C for 6 h. The mixture was cooled to rt, H2O (20 mL) was added 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 (485 mg, 54.6%). MS: M / e 539 (M+1) + .

[0840] Step B: (4-(bis(4-methoxybenzyl)amino)-2-(((S)-pentan-2-yl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol

[0841] To a stirred solution of (S)-7-bromo-N4,N4-bis(4-methoxybenzyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (210 mg, 0.39 mmol) in THF (8 mL) cooled to -78°C under a nitrogen atmosphere was added dropwise n-butyllithium (1.6 M in hexane, 0.56 mmol, 0.35 mL). After stirring for 50 minutes, a solution of 6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylnicotinaldehyde (179 mg, 0.58 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into 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 (120 mg, 42.8%). MS: M / e 722 (M+1)+ .

[0842] Step C: (S)-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridine

[0843] -3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0844] A solution of (4-(bis(4-methoxybenzyl)amino)-2-(((S)-pentan-2-yl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methanol (120 mg, 0.166 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 (5 mg, 6.2%). 1 H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.47(br.s,2H),7.41(s,1H),7.14(s,1 H),5.98(d,J=8.4Hz,1H),3.96(s,2H),3.81(br.s,1H),3.28-3.23(m,4H),2 .64(t,J=11.9Hz,2H),2.24-2.03(m,8H),1.75(d,J=12.3Hz,2H),1.61-1.48 (m,2H),1.43-1.19(m,6H),1.10(d,J=6.1Hz,3H),0.87(t,J=7.0Hz,3H)ppm. MS:M / e 486(M+1) + .

[0845] Compound B148: (S)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0846] Step A: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(((S)-pentan-2-yl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0847] To a stirred solution of (S)-7-bromo-N4,N4-bis(4-methoxybenzyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (180 mg, 0.34 mmol) in THF (8 mL) cooled to -78°C under a nitrogen atmosphere was added n-butyllithium (1.6 M in hexane, 0.75 mmol, 0.48 mL) dropwise. After stirring for 50 min, a solution of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (153 mg, 0.5 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 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 (110 mg, 46.1%). MS: M / e 766 (M+1) + .

[0848] Step B: (S)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0849] A solution of tert-butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(((S)-pentan-2-yl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate (110 mg, 0.14 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, 67.8%). 1 H-NMR(400MHz,DMSO-d6)δ8.70(br.s,2H),8.11(s,1H),7.64(s,1H),7.50(s,1H),7.26(s,1H),6.19(s,1H),4.02(s,2H),3.8 0(s,1H),3.19(br.s,8H),2.20(s,3H),1.56-1.47(m,1H),1.43-1.21(m,3H),1.09(d,J=5.9Hz,3H),0.86(t,J=6.8Hz,3H)ppm. MS:M / e 410(M+1) + .

[0850] Compound B149: 1-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0851] Step A: tert-Butyl (2-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate

[0852] To a stirred solution of 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (80 mg, 0.2 mmol) in DMF (5 mL) was added N-(tert-butyloxycarbonyl)-N-methylglycine (60 mg, 0.316 mmol), HATU (116 mg, 0.3 mmol) and DIEA (51 mg, 0.395 mmol). The reaction mixture was stirred at RT overnight. The mixture was poured into H2O (50 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 (60 mg, 51.7%) as a white solid. MS: M / e 581 (M+1) + .

[0853] Step B: 1-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0854] To a stirred solution of 4M HCl in EA (10 ml) was added tert-butyl (2-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (60 mg, 0.1 mmol). The reaction mixture was stirred at RT overnight. The mixture was poured into saturated NaHCO solution (20 mL) and extracted with DCM (10 ml x 3). The combined organic phases were washed with brine, dried over NaSO and concentrated in vacuo. The crude product was purified by column chromatography to give the product (30 mg, 62.5%). 1H NMR(400MHz,DMSO-d6)δ8.70(br.s,2H),8.09(s,1H),7.78(br.s,1H),7.50(s ,1H),7.41(s,1H),6.34(br.s,1H),4.09(s,2H),4.03(s,2H),3.80(s,1H),3.6 4(s,2H),3.48(s,2H),3.06(s,2H),3.00(s,2H),2.57(s,3H),2.22(s,3H),1. 51(s,1H),1.47-1.21(m,3H),1.10(d,J=5.7Hz,3H),0.86(t,J=6.7Hz,3H)ppm. MS:M / e 481(M+1) + .

[0855] Compound B150: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0856] Step A: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0857] To a stirred solution of 7-bromo-N4,N4-bis(4-methoxybenzyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (1 g, 1.87 mmol) in THF (15 mL) cooled to -78°C under a nitrogen atmosphere was added dropwise n-butyllithium (1.6 M in hexane, 3.74 mmol, 2.3 mL). After stirring for 50 minutes, a solution of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (854 mg, 2.8 mmol) in THF (2 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into 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 (750 mg, 53.5%). MS: M / e 766 (M+1) + .

[0858] Step B: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine

[0859] The product of step A (750mg, 0.98mmol) in TFA (6mL) and Et3SiH (6mL) was stirred at 80 ℃ for 2h. The reaction mixture was concentrated in vacuo to remove TFA and Et3SiH. TFA (10mL) was added to the residue and stirred at 85 ℃ overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by preparative HPLC to give product (240mg, 60%). 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H),7.46(br.s,2H),7.41(s,1H),7.14(s,1H),5.98(d,J=8.6Hz,1H),3.96(s,2H),3.81(s,1H),2. 90(br.s,4H),2.81(br.s,4H),2.16(s,3H),1.61-1.42(m,1H),1.40-1.22(m,3H),1.10(d,J=6.3Hz,3H),0.87(t,J=7.1Hz,3H)ppm. MS:M / e 410(M+1) + .

[0860] Compound B151: 1-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

[0861] To a stirred solution of 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine (60 mg, 0.147 mmol) in DMF (5 mL) was added dimethylglycine (30 mg, 0.291 mmol), HATU (70 mg, 0.183 mmol), and DIPEA (80 mg, 0.62 mmol). The reaction mixture was stirred at RT overnight. The mixture was poured into H2O (50 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 (11 mg, 15.1%). 1HNMR(400MHz, CDCl3)δ8.08(s,1H),7.46(br.s,3H),7.15(s,1H),5.99(d,J=8.1Hz,1H),3.98(s,2H),3.80(s,1H),3.61(s,2H),3.57(s,2H),3.27( s,2H),2.99(s,2H),2.93(s,2H),2.27(s,6H),2.20(s,3H),1.53-1.47(m ,1H),1.43-1.25(m,3H),1.09(d,J=6.4Hz,3H),0.86(t,J=7.1Hz,3H)ppm. MS:M / e 495(M+1) + .

[0862] Compound B152: (R)-2-(sec-Butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0863] Step A: (R)-7-Bromo-2-(sec-butoxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0864] NaH (656 mg, 16.4 mmol) was added to a solution of (R)-butan-2-ol (1.2 g, 16.4 mmol) in THF (20 mL). After stirring at rt under N2 atmosphere for 30 min, 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (2 g, 4.1 mmol) was added.

[0865] The resulting mixture was heated at 60°C overnight. The solution was cooled, water (10 mL) was added thereto and extracted with ethyl acetate (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude product, which was further purified by Combi-Flash (PE:EA=15%) to give the product (2 g, 95%). MS: M / e526 (M+1) + .

[0866] Step B: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-((R)-sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0867] At -78°C (with N 2To a cooled solution of (R)-7-bromo-2-(sec-butoxy)-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (1.1 g, 2.1 mmol) in THF (35 mL) was added n-butyllithium (1.6 M, 2 mL) dropwise under a purging (1% CO). After stirring at -78°C for 30 minutes, tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (769 mg, 2.5 mmol) in THF (5 mL) was added. The resulting mixture was stirred at this temperature for 30 minutes and then allowed to warm to room temperature overnight. The solution was quenched with NH4Cl solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by CombiFlash (PE:EA=50%) to give the pure product (430 mg, 27%). MS: M / e 753 (M+1) + .

[0868] Step C: (R)-2-(sec-Butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0869] A solution of tert-butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-((R)-sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate (430 mg, 0.57 mmol) in triethylsilane (1 mL) and trifluoroacetic acid (4 mL) was heated at 80 ° C. overnight. The solvent was evaporated under an oil pump to give a residue, which was dissolved in EA (10 mL) and washed with NaHCO solution (10 mL). The organic layer was dried, concentrated and purified by preparative TLC (DCM:NH ·MeOH=7:1) to give the product (100 mg, 44%). 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),8.05(s,1H),7.99(s,1H),7.41(s,1H),7.32(s,1H),4.92-4.83(m,1H),4. 03(s,2H),2.95-2.74(m,8H),2.17(s,3H),1.65-1.59(m,2H),1.24(d,J=8.0Hz,3H),0.90(t,J=8.0Hz,3H)ppm. MS:M / e397(M+1) + .

[0870] Compound B153: (R)-1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

[0871] A solution of (R)-2-(sec-butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.10 mmol), dimethylglycine (12 mg, 0.12 mmol), HATU (57 mg, 0.15 mmol) and DIEA (26 mg, 0.20 mmol) in DMF (5 mL) was stirred at rt for 2 hours. Water (5 mL) was added to the reaction mixture, 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 purified by preparative TLC (DCM:NH3.MeOH=7:1) to give the product (12 mg, 25%). 1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),8.08(s,1H),8.00(s,1H),7.45(s,1H),7.33(s,1H),4.92-4.83(m,1H),4.05(s,2H),3.5 8(br.s,6H),3.06-2.92(m,4H),2.42(s,6H),2.21(s,3H),1.65-1.59(m,2H),1.24(d,J=4.0Hz,3H),0.90(t,J=8.0Hz,3H)ppm. MS:M / e482(M+1) + .

[0872] Compound B154: (S)-1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0873] Step A: tert-Butyl (S)-(2-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate

[0874] A solution of (S)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (375 mg, 0.90 mmol), N-(tert-butyloxycarbonyl)-N-methylglycine (207 mg, 1.1 mmol), HATU (513 mg, 1.4 mmol) and DIEA (232 mg, 1.8 mmol) in DMF (10 mL) was stirred at rt for 2 hours. Water (10 mL) was added to the reaction mixture, 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 used in the next step (120 mg, 23%). MS: M / e 582 (M+1) + .

[0875] Step B: (S)-1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0876] To a solution of tert-butyl (S)-(2-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (120 mg, 0.2 mmol) in EA (5 mL) was added HCl / EA (2 M, 2 mL). The solution was stirred at rt for 3 hours. After concentration, the residue was dissolved in DCM (10 mL) and washed with NaHCO (5 mL). The organic layer was dried over Na, filtered, and concentrated to give the crude product, which was further purified by preparative TLC (DCM:NH·MeOH=7:1) to give the pure product (25 mg, 25%). 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),8.07(s,1H),7.99(s,1H),7.44(s,1H),7.33(s,1H),5.01-4.87(m,1H),4.05(s,2H),3.58-3.52(m,4H),3. 32(s,2H),2.99-2.94(m,4H),2.27(s,3H),2.20(s,3H),1.65-1.50(m,2 H), 1.38-1.33 (m, 2H), 1.24 (d, J = 4.0Hz, 3H), 0.87 (t, J = 8.0Hz, 3H) ppm. MS:M / e 482(M+1) + .

[0877] Compound B155: 1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one

[0878] A solution of 2-(sec-butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (30 mg, 0.08 mmol), dimethylglycine (10 mg, 0.09 mmol), HATU (46 mg, 0.12 mmol) and DIEA (21 mg, 0.16 mmol) in DMF (5 mL) was stirred at rt for 2 hours. Water (5 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL) and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC (DCM:NH3·MeOH=8:1) to give the product (16 mg, 44%). 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),8.07(s,1H),8.00(s,1H),7.44(s,1H),7.32(s,1H),4.92-4.83(m,1H),4.05(s,2H),3.63-3.57(m, 4H),3.21-3.14(m,2H),3.02-2.92(m,4H),2.23(s,6H),2.20(s,3H),1.65-1.58(m,2H),1.24(d,J=4.0Hz,3H),0.89(t,J=8.0Hz,3H)ppm. MS:M / e 482(M+1) + .

[0879] Compound B156: 1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0880] Step A: tert-Butyl (2-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate

[0881] A solution of 2-(sec-butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine (30 mg, 0.08 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (17 mg, 0.09 mmol), HATU (46 mg, 0.12 mmol) and DIEA (21 mg, 0.16 mmol) in DMF (5 mL) was stirred at rt for 2 hours. Water (5 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL) and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was used in the next step (40 mg, crude). MS: M / e 568 (M+1) + .

[0882] Step B: 1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one

[0883] To a solution of tert-butyl (2-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (40 mg, crude) in EA (2 mL) was added HCl / EA (2 M, 1 mL). The solution was stirred at rt for 2 hours. After concentration, the residue was dissolved in DCM (10 mL) and washed with NaHCO (5 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the crude product, which was further purified by preparative TLC (DCM:NH·MeOH=8:1) to give the pure product (15 mg, 47%). 1 H NMR(400MHz,DMSO-d6)δ8.73(br.s,2H),8.12(s,1H),8.08(s,1H),8.01(s, 1H),7.47(s,1H),7.27(s,1H),7.14-7.02(m,1H),4.92-4.83(m,1H),4.09-4 .06(m,2H),3.63(s,2H),3.47(s,2H),3.05-2.99(m,4H),2.57(s,2H),2.22 (s,3H),1.62-1.59(m,2H),1.24(d,J=4.0Hz,3H),0.90(t,J=8.0Hz,3H)ppm. MS:M / e 468(M+1) + .

[0884] Compound B157: 1-((4-amino-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-3-ol

[0885] Step A: tert-Butyl 4-(5-((4-(bis(4-methoxybenzyl)amino)-2-chloroimidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3-methylpyridin-2-yl)piperazine-1-carboxylate

[0886] To a solution of 7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (2000 mg, 4.1 mmol) in THF (20 mL) was added dropwise a solution of n-butyllithium (1.6 M, 3.84 mL, 6.15 mmol), maintaining the temperature between -75°C and -65°C. After 1 h, a suspension of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (1500 mg, 4.9 mmol) in THF (15 mL) was added dropwise. The resulting mixture was stirred at -70°C for 2 h and then warmed to room temperature for 4 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to give the target compound (1.9 g, yellow oil). MS: m / e 715 (M+1) + .

[0887] Step B: 2-chloro-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine

[0888] To a mixture of the product of step A (1500 mg, 2.1 mmol) in TFA (5 mL) was added EtSiH (5 mL), and the resulting mixture was stirred at 85 ° C for 4 hours. The mixture ...

Claims

1. A compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R 1 Yes - NHR 1a , where R 1a It is a branched-C 4-8 Alkyl, wherein the branched substituent is located alpha to the nitrogen atom; wherein ring A is pyridyl, and the methylene group and Het on the pyridyl ring are located in the para position of the pyridyl ring, and the pyridyl ring is further optionally substituted by one R 5 replace; Het is piperidinyl or piperazinyl; R 5 It is C 1-8 alkyl; p is 0 or 1; R 6c are independently hydrogen, -COR 6d or C 1-8 Alkyl, the C 1-8 The alkyl group is optionally substituted by a substituent R 6g replace; R 6d It is C 1-8 Alkyl, the C 1-8 The alkyl group is optionally substituted by a substituent R 6g replace; R 6g -OR independently at each occurrence 6h or -NR 6h R 6i , R 6h and R 6i independently hydrogen and C 1-8 Alkyl, the C 1-8 The alkyl group is optionally substituted with a substituent selected from hydroxyl or C 1-8 Alkylamino.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Yes - NHR 1a , where R 1a It is butan-2-yl, pentan-2-yl, heptan-2-yl or octane-2-yl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 Yes-C 1-6 alkyl, and p is 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 and Het-R 6c Located at the ortho position on ring A.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Het is piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperazin-1-yl, piperazin-2-yl or piperazin-3-yl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6c Yes-COR 6d , where R 6d is optionally substituted by a substituent R 6g Replaced-C 1-8 Alkyl, where R 6g Yes - NR 6h R 6i , where R 6h and R 6i are independently hydrogen or -C 1-8 alkyl.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6c Yes-COR 6d , where R 6d is optionally substituted by a substituent R 6g Replaced-C 1-6 Alkyl, where R 6g Yes - NR 6h R 6i , where R 6h and R 6i are independently hydrogen or -C 1-6 alkyl.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6c Yes-COR 6d , where R 6d is optionally substituted by a substituent R 6g Replaced-C 1-4 Alkyl, where R 6g Yes - NR 6h R 6i , where R 6h and R 6i are independently hydrogen or -C 1-4 alkyl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6c is optionally substituted by a substituent R 6g Replaced-C 1-8 Alkyl, where R 6g Yes OR 6h or -NR 6h R 6i , where R 6h and R 6i As defined in claim 1.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6c yes aminoacetyl, 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 or 2-(dimethylamino)acetyl; methyl, ethyl, isobutyl, (methylamino)methyl, (dimethylamino)methyl, 2-aminoethyl, 2-(methylamino)ethyl or 2-(dimethylamino)ethyl; or dimethylamino, or amino.

11. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: Compound B1: 2-butoxy-7-((5-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B2: 2-butoxy-7-((5-chloro-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B3: 2-butoxy-7-(4-(piperidin-4-yl)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound B6: 2-butoxy-7-((6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B8: 2-butoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B9: 2-butoxy-7-((5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B10: 2-butoxy-7-((6-(piperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B11: 2-butoxy-7-((5-methoxy-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B12: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B13: 2-butyl-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B14: 1-(4-(4-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)phenyl)piperidin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B15: 2-butoxy-7-((5-(piperidin-4-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B17: 2-butoxy-7-((5-methoxy-6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B18: N2-butyl-7-(4-(piperidin-4-yl)benzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B19: 2-butoxy-7-((6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B21: 2-butoxy-7-((2-fluoro-6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B22: 2-(isopentyloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B23: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentyloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B24: 2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)ethan-1-one; Compound B26: 2-butoxy-7-(3-ethoxy-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B27: 2-butoxy-7-(4-(piperazin-1-yl)-3-(trifluoromethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B28: 2-butoxy-7-((6-(piperidin-4-yl)-5-(trifluoromethyl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B32: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B33: 2-butoxy-7-((4-methyl-5-(piperazin-1-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B36: 2-butoxy-7-(3-methyl-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B37: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-3-(dimethylamino)propan-1-one; Compound B39: 7-((6-(1,4-diazepan-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazine-4-amine; Compound B40: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(piperazin-1-yl)ethan-1-one; Compound B41: (4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)(piperazin-2-yl)methanone; Compound B45: 2-butoxy-7-(3-methoxy-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B46: 2-butoxy-7-(3-isopropoxy-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B47: 2-butoxy-7-((4-methyl-5-(piperidin-4-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B49: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-4-(dimethylamino)butan-1-one; Compound B50: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-5-(dimethylamino)pentan-1-one; Compound B53: 2-butoxy-7-((2-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B54: 2-butoxy-7-((2-methyl-6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B55: 2-butoxy-7-((6-(3,5-dimethylpiperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B56: (4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)(piperidin-4-yl)methanone; Compound B59: 2-butoxy-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B60: 7-((6-(4-aminopiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine; Compound B61: 2-butoxy-7-(4-(3,5-dimethylpiperazin-1-yl)-3-methylbenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B63: 2-ethoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B64: 2-butoxy-7-(3-methyl-4-(piperidin-4-yl)benzyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound B65: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B66: 2-isopropoxy-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B67: (2S,3S)-2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-3-methylpentan-1-one; Compound B68: (S)-4-amino-2-butoxy-7-((5-methyl-6-(4-prolylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine; Compound B69: (S)-2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-4-methylpentan-1-one; Compound B70: (S)-2-amino-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-3-methylbutan-1-one; Compound B71: 1-(4-(5-((4-amino-2-(butylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B72: 2-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-N,N-dimethylacetamide; Compound B73: (S)-2-butoxy-7-((5-methyl-6-(2-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B74: (R)-2-butoxy-7-((5-methyl-6-(2-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B75: 2-butoxy-7-((5-methyl-6-(4-(2-(methylamino)ethyl)piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B76: 2-butoxy-7-((6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B77: 2-butoxy-7-((5-(piperidin-4-yl)pyridin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B78: 2-butoxy-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B79: 7-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine; Compound B80: 2-(but-3-en-1-yloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B82: 2-butoxy-7-((5-methyl-6-(2,8-diazaspiro[4.5]decane-8-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B86: 2-butoxy-7-((5-methyl-6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B87: 2-butoxy-7-((6-(3-(dimethylamino)pyrrolidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B88: 7-((6-(4-aminopiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-butylimidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B91: 7-((6-(4-(2-aminoethyl)piperazin-1-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazin-4-amine; Compound B92: 2-butoxy-7-(3-ethyl-4-(piperazin-1-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B93: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-propoxyimidazo[2,1-f][1,2,4]triazin-4-amine; Compound B94: 1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B96: N2-butyl-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B97: (R)-2-butoxy-7-((5-methyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B99: 2-butoxy-7-(4-(piperazin-1-yl)-3-propoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B101: 2-butoxy-7-((5-methyl-6-(2,8-diazaspiro[4.5]decane-2-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-4-amine; Compound B102: 2-butoxy-7-((5-methyl-6-(2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B105: 2-butoxy-7-((6-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B106: 2-butoxy-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B107: 2-butoxy-7-((6-(4-(2-methoxyethyl)piperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B108: 2-butoxy-7-((5-methyl-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B109: 2-butoxy-7-((5-methyl-6-(4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B110: 2-butoxy-7-((6-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B111: 1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound 112: 2-(sec-butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B113: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(2-methylbutyloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B114: 2-butoxy-7-((6-(4-ethylpiperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B115: 2-butoxy-7-((6-(4-ethylpiperazin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B117: (R)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B118: (S)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B121: 2-butoxy-7-((5-methyl-6-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B122: (S)-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B123: (S)-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B124: (R)-1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B125: (S)-1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B126: 2-butoxy-7-((6-(4-((diethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B127: (R)-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B128: (R)-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B130: 2-butoxy-7-((5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B131: 2-butoxy-7-((5-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B132: (S)-2-butoxy-7-((5-methyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B133: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B134: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B135: N2-butyl-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B137: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B138: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N 2 -(Pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B139: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-propylimidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B140: 2-(hexan-3-yloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B141: 2-butyl-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B142: N-(1-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperidin-4-yl)-2-(dimethylamino)acetamide; Compound B143: 2-(heptane-4-yloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B145: (S)-1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B146: (S)-1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B147: (S)-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B148: (S)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B149: 1-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B150: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B151: 1-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B152: (R)-2-(sec-butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B153: (R)-1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B154: (S)-1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B155: 1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B156: 1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B157: 1-((4-amino-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-3-ol; Compound B158: (S)-2-(sec-butoxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B159: (R)-1-(4-(5-((4-amino-2-(sec-butoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B160: (R)-1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B161: 2-butoxy-7-((5-methyl-6-(4-(methylamino)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B162: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B163: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(hexan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B164: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(hexan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B165: 3-((4-amino-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound B166: 7-((5-methyl-6-(4-(methylamino)piperidin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B167: 2-(cyclohexyloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B168: 7-((6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-methylpyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f][1,2,4]triazine-4-amine; Compound B169: 1-(4-(5-((4-amino-2-(hexan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B170: 1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(diethylamino)ethan-1-one; Compound B172: 2-(cyclopentyloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B173: (S)-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B174: 2-((1-methoxypropan-2-yl)oxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B175: 1-(4-(5-((4-amino-2-(pentan-3-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B176: 1-(4-(5-((4-amino-2-((1-hydroxyhexan-3-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B178: (R)-7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B179: (S)-1-(4-(5-((4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)-2-methylpiperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B180: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-pentylimidazo[2,1-f][1,2,4]triazin-4-amine; Compound B181: 1-(4-(5-((4-amino-2-(hexan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B183: 2-butoxy-7-((5-ethyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B184: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(heptane-4-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B185: (R)-7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B186: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(heptan-4-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B187: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B188: 1-(4-(5-((4-amino-2-(heptane-4-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B189: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B190: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(heptane-4-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B191: N2-(heptane-4-yl)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B193: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-((tetrahydrofuran-3-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B194: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B195: 1-(4-(5-((4-amino-2-(heptane-4-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B196: 1-(4-(5-((4-amino-2-(heptane-4-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B197: 1-(4-(5-((4-amino-2-(heptane-4-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B198: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(heptan-4-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B199: (S)-2-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)ethan-1-ol; Compound B200: 1-(4-(5-((4-amino-2-(pentan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B201: 1-(4-(5-((4-amino-2-(pentan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B202: 2-(1-cyclopropylbutyloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B204: 7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B205: 7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B207: (R)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B208: 7-((6-(4-((dimethylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(pentan-3-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B209: 7-((6-(4-(dimethylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N2-(pentan-3-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B210: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-3-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B211: 1-(4-(5-((4-amino-2-(pentan-3-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B212: (S)-1-(4-(5-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(isobutylamino)ethan-1-one; Compound B213: (S)-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B214: (R)-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B215: (S)-7-((6-(4-(isobutylamino)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B218: 1-(4-(5-((4-amino-2-((1-hydroxyhexan-3-yl)oxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B219: (S)-1-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one; Compound B220: N2-(heptane-4-yl)-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B221: (S)-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B222: (R)-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B223: N2-(hexan-3-yl)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B224: (S)-2-(hexan-3-yloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B225: (R)-2-(hexan-3-yloxy)-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B226: (S)-3-((4-amino-7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)hexan-1-ol; Compound B227: 7-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-N2-(1,1,1-trifluoropentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B228: (S)-3-((4-amino-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)hexan-1-ol; Compound B229: 3-((4-amino-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound B230: (S)-1-(4-(5-((4-amino-2-(hexan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B231: (S)-1-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methylamino)ethan-1-one; Compound B232: 2-((4-amino-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)pentan-1-ol; Compound B233: 2-((S)-4-(5-((4-amino-2-(((S)-pentan-2-yl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-2-yl)acetonitrile; Compound B234: 7-((6-(4-((isobutylamino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B235: 2-((4-amino-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)pentan-1-ol; Compound B236: 1-((4-amino-7-((5-methyl-6-(4-((methylamino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)pentan-2-ol; Compound B237: 7-((6-(4-(((2-methoxyethyl)amino)methyl)piperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B238: 7-((2-fluoro-6-(piperidin-4-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B239: (S)-7-((2-fluoro-6-(piperidin-4-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B240: (S)-7-((5-methyl-6-(piperidin-4-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B241: (S)-7-((5-methoxy-6-(piperazin-1-yl)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine; Compound B242: 3-((4-amino-7-((2-fluoro-6-(piperidin-4-yl)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol; Compound B243: (S)-4-((4-amino-2-(pentan-2-yloxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-1-(piperidin-4-yl)pyridin-2(1H)-one; Compound B244: (S)-1-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)-2-(methyl(2-(methylamino)ethyl)amino)ethan-1-one; Compound B245: (S)-7-((5-methyl-6-(4-((methyl(2-(methylamino)ethyl)amino)methyl)piperidin-1-yl)pyridin-3-yl)methyl)-N2-(pentan-2-yl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine; Compound B246: (S)-2-amino-1-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)ethan-1-one; and Compound B247: (S)-2-(4-(5-((4-amino-2-(pentan-2-ylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-3-methylpyridin-2-yl)piperazin-1-yl)ethan-1-ol.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

13. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for agonizing TLR7.

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