EA046488B1 - IMIDAZO[2,1-f][1,2,4]TRIAZINE-4-AMINE DERIVATIVES AS TLR7 AGONISTS - Google Patents

Description

Field of technology

Disclosed herein is an imidazo[2,1-:1][1,2,4]triazin-4-amine derivative or a pharmaceutically acceptable salt thereof useful as a TLR7 agonist and a pharmaceutical composition containing the same. Also disclosed herein is a method of treating cancer using an imidazo[2,1-:1][1,2,4]triazin-4-amine derivative or a pharmaceutically acceptable salt thereof as a TLR7 agonist.

Prior Art

Toll-like receptors (TLRs) belong to the family of pattern recognition receptors (PRRs) that play a critical role in the early innate immune response by sensing highly conserved molecular patterns of various pathogens (pathogen-associated molecular patterns, PAMPs), as well as endogenous molecular patterns, damage-associated molecular patterns (DAMPs) (Barton, G. M. and R. Medzhitov (2002). Toll-like receptors and their ligands. Curr Top Microbiol Immunol 270: 81-92).

Ten different TLRs have been identified in humans. These include TLR7, TLR8, and TLR9, which belong to the same TLR subfamily based on their genomic structures, sequence similarity, and endosomal localization. They have a limited expression pattern, limited to specific types of immune cells. TLR7 is expressed in B cells and plasmacytoid dendritic cells (PDCs); TLR8 is expressed in monocytes and myeloid dendritic cells (MDCs) (Iwasaki, A. and R. Medzhitov (2004). Toll-like receptor control of the adaptive immune responses. Nat Immunol 5(10): 987-995).

In addition, TLR7 and/or 8 single-stranded RNA natural ligand activation, imidazoquinolones (or imiquime-like ligands) and guanosine analogues with varying specificities have been shown. Activation of TLR7 and/or TLR8 induces dendritic cell (DC) maturation and secretion of proinflammatory cytokines (van Duin, D., et al. (2006). Triggering TLR signaling in vaccination. Trends Immunol 27(1): 49-55). CTLs (cytotoxic T lymphocytes) and NK cells (natural killer cells) are further activated and proliferate as a result of stimulation of DCs by cytokines and antigen presentation. Thus, the properties of TLR agonists underlie an effective strategy for stimulating antitumor immunity (Adams, S. (2009). Toll-like receptor agonists in cancer therapy. Immunotherapy 1(6): 949-964).

Imiquimod (a TLR7 agonist) has been successfully used to treat many primary skin tumors and skin metastases as a single antitumor agent with immunostimulatory properties (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 3: e29179).

WO 2016023511 discloses pyrrolopyrimidine compounds as a TLR7 agonist for antiviral drug treatment.

Currently, much effort is being devoted to preclinical and clinical studies of TLR agonists for anticancer therapy. Thus, there is a need to develop more potent TLR agonists for the treatment of cancer.

Brief description of the invention

Surprisingly, the inventors have discovered that the imidazo|2,14']|1,2,4]'griazin-4amine derivatives disclosed herein exhibit stronger TLR7 agonist activity, particularly when ring A in formula (I) is additionally directly substituted with a heterocyclyl ring. We also discovered that branching the alkyl group at position 2 of imidazo[2,1-:1][1,2,4]triazin-4-amine derivatives unexpectedly improves TLR7 agonist activity.

In a first aspect, this document discloses a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X represents N;

L ¹ represents -(CR ^a R ^b ) _m -, -O- or -S-, where m is a number from 1 to 8;

R ^a and R ^b are each independently hydrogen or -C _1-8 alkyl;

R ¹ is -OR ^1a , -SR ^1a or -NR ^1a R ^1b ;

R ^1a and R ^1b are independently hydrogen, -C1 _-8 alkyl, alkenyl or alkynyl, each of said alkyl, alkenyl or alkynyl being optionally substituted with one, two or three substituents selected from halogen, -C1 _-8 alkyl, optionally substituted R ^1e , cycloalkyl, optional

- 1046488 optionally substituted with ^R1e , heterocyclyl, optionally substituted with ^R1e , aryl, optionally substituted with ^R1e , heteroaryl, optionally substituted with ^R1e , or ^-OR1f ;

where R ^1e represents halogen, hydroxy, amino (-NH2), alkylamino, dialkylamino or -C _1-6 alkyl, optionally substituted with halogen;

where R ^1f represents -C _1-8 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with -C _1-4 alkyl or halogen;

R ¹ in each occurrence is independently hydrogen, oxo, amino (-NH2), alkylamino, dialkylamino, halogen, haloalkyl, -C _1-8 alkyl, haloalkoxy, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl;

R2 and ^R3 are each independently hydrogen or _-C1-8 alkyl;

R ⁴ represents hydrogen, halogen, -C _1-8 alkyl, alkenyl or alkynyl;

Ring A is aryl or heteroaryl;

R ⁵ is halogen, hydroxy, -C1-8alkyl, haloalkyl, alkoxy, haloalkoxy, -oxo or -C(=O)OR ^5a , where R ^5a is hydrogen, -C1-8alkyl or haloalkyl;

p represents the number 0, 1, 2 or 3;

L ² represents a direct bond, -(CR ^f R ^g )r, -O-, -S-, -S(O)-, -SO2- or -NR ^d -, where R ^d represents -C|-6alkyl . where t represents a number from 1 to 8;

R ^f and R ^g are each independently hydrogen, -C _1-8 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl;

R ⁶ is -NR ^6a R ^6b , -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is -C _1-8 alkyl , -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl is independently and optionally substituted with one, two or three R ^6c substituents;

R ^6a and R ^6bl independently represent hydrogen or -C _1-8 alkyl;

R ^6c is independently hydrogen, halogen, -OR ^6d , -SR ^6d , -NR ^6d R ^6e , -COR ^6d , -SO2R ^6d , -C(=O)NR ^6d R ^6e or -C1-8alkyl, wherein said - The C _1-8 alkyl is independently and optionally substituted with one, two or three R ^6g substituents;

R ^6d and R ^6e are independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, heterocyclyl or aryl, each of which is optionally -C _1-8 alkyl, -C _2-8 alkenyl, heterocyclyl or aryl substituted with one, two or three R ^6g substituents;

R ^6g is in each case independently hydrogen, halogen, -OR ^6h , -SR ^6h , -NR ^6h R ⁶¹ , -N(R ^6h )C(=O)OR ⁶¹ , -C1-8alkyl, heterocyclyl, aryl or heteroaryl where R ⁶¹ ' and R ⁶¹ independently represent hydrogen or -C1-8alkyl;

said alkenyl is a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and from 2 to 8 carbon atoms;

said alkynyl is a hydrocarbon group selected from a linear and branched hydrocarbon group containing at least one C=C triple bond and from 2 to 8 carbon atoms;

said cycloalkyl group is a hydrocarbon group selected from saturated cyclic hydrocarbon groups containing monocyclic and bicyclic and tricyclic groups and containing from 3 to 12 carbon atoms;

said aryl is phenyl;

said heteroaryl represents a group selected from:

5-, 6- or 7-membered aromatic, monocyclic rings containing from 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, the remaining ring members being carbon;

7-12 membered bicyclic rings containing from 1 to 3 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), wherein the remaining ring members are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present on the aromatic ring; And

11-14 membered tricyclic rings containing from 1 to 3 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), wherein the remaining ring members are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present on the aromatic ring;

said heterocyclyl is a non-aromatic heterocyclyl group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon, including monocyclic 4-9 membered heterocyclyl, 5-20- a membered fused ring, a 5-14 membered bridged ring, and a 5-20 membered spiro ring;

said cycloalkenyl is a non-aromatic cyclic alkyl group containing from 3 to 10 carbon atoms, having one or more rings and 1 to 2 double bonds;

- 2 046488 said cycloalkynyl is a non-aromatic cycloalkyl group containing from 5 to 10 carbon atoms, having one or more rings and one triple bond;

the specified alkylamino represents -ISH^^alkyl);

said dialkylamino is -I(-C _1-8 alkyl) ₂ ;

said haloalkyl represents a -C _1-8 alkyl group in which one or more hydrogens are replaced by halogen atoms; and said alkoxy represents a -C _1-8 alkyl group attached to the parent molecular group via an oxygen atom.

Definition of X.

In some embodiments, X is N.

Definition of L ¹ .

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

In some embodiments, L ¹ is -CR ^a R ^b -, -O-, or -S-, wherein R ^a and R ^b are each independently hydrogen or -C1-8 alkyl. In other embodiments, L ¹ is -CR ^a R ^b -, wherein R ^a and R ^b are each independently hydrogen or -C1-8 alkyl (preferably -C _1-4 alkyl, more preferably methyl). In some embodiments, L ¹ is -CH2- or -CH( _CH3 )-. In other embodiments, L ¹ is -CH2-.

Definition of ^R1 .

In some embodiments, R ¹ is -OR ^1a or -NR ^1a R ^1b , where R ^1a and R ^1b are defined by formula (I).

In some embodiments, R ¹ is -OR ^1a or -NR ^1a R ^1b ; wherein R ^1a , R ^1b are independently hydrogen, -C1-8alkyl or -C2-8alkenyl, each of said -C1-8alkyl optionally substituted with one, two or three substituents selected from heterocyclyl, optionally substituted with ^R1e , aryl, optionally substituted R ^1e , CH3-(OCH ₂ CH ₂ )n- (where n is a number from 3 to 10, preferably 4 to 8, more preferably 5 to 7) or -OR ^1f ;

where R ^1e represents halogen or -C _1-6 alkyl, optionally substituted with halogen;

where R ^1f represents -C _1-8 alkyl, aryl or heteroaryl, each of which is optionally substituted with -C _1-4 alkyl or halogen.

In some embodiments, R ¹ is -OR ^1a , where R ^1a is hydrogen. In some embodiments, R ¹ is -OR ^1a , where R ^1a is -C1-8 alkyl, optionally substituted with one, two or three substituents selected from halogen, -C1-8 alkyl, optionally substituted with R ^1e , cycloalkyl, optionally substituted with R ^1e , heterocyclyl, optionally substituted with R ^1e , aryl, optionally substituted with R ^1e , heteroaryl, optionally substituted with R ^1e , CH3(OCH2CH ₂ ) _n - (where n is the number 3 to 10) or -OR ^1f , where R ^1e and R ^1f defined by formula (I).

In some embodiments, R ¹ is -OR ^1a , where R ^1a is unsubstituted C1-8 alkyl. In some embodiments, R ¹ is -OR ^1a , where R ^1a is straight. In some embodiments, R ¹ is -OR ^1a , where R ^1a is a branched -C1-8 alkyl. In some embodiments, R ¹ is -OR ^1a , where R ^1a is a branched -C _1-8 alkyl, preferably -C _4-8 alkyl, where the branched substituent is in the alpha position with respect to the oxygen atom, including but not limited to butane -2-yl, pentan-2-yl, pentan-3-yl, heptan-2yl, heptan-3-yl, heptan-4-yl, octan-2-yl, octan-3-yl, octan-4-yl or octan-5-yl. In some embodiments, R ¹ is methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octoxy. In some embodiments, R ¹ is preferably propoxy, isopropoxy, nbutoxy, isobutoxy, butan-2-yloxy (sec-butoxy), pentan-2-yloxy, pentan-3-yloxy, 2-methylbutoxy, heptan-2-yloxy, heptane -3-yloxy, heptan-4-yloxy, octan-2-yloxy, octan-3-yloxy, octan-4-yloxy or octan-5-yloxy. In some embodiments, R ¹ is n-butoxy, butan-2-yloxy (sec-butoxy), pentan-2-yloxy, pentan-3-yloxy, heptan-2-yloxy, heptan-3-yloxy, heptan-4-yloxy, octan2-yloxy, octan-3-yloxy, octan-4-yloxy or octan-5-yloxy.

In some embodiments, R ¹ is -OR ^1a , where R ^1a is -C _1-8 alkyl, preferably -C _4-5 alkyl, said alkyl being substituted with 1 to 3 halogens, for example fluorine.

In some embodiments, R ¹ is -OR ^1a , where R ^1a is -C _1-8 alkyl, preferably -C _1-3 alkyl, said alkyl is substituted with cycloalkyl, optionally substituted with R ^1e , heterocyclyl, optionally substituted with R ^1e , aryl, optionally substituted with R ^1e , or heteroaryl, optionally substituted with R ^1e , wherein R ^1e is defined by formula (I).

In some embodiments, R ¹ is -OR ^1a , where R ^1a is -C _1-8 alkyl, preferably -C _1-3 alkyl, said alkyl being substituted with a heteroaryl, for example, a 5- to 6-membered heteroaryl containing one, two or three heteroatoms selected from oxygen, nitrogen or optionally oxidized sulfur as ring members, said heteroaryl being optionally substituted with -C _1-6 alkyl, preferably -C _1-4 alkyl, more preferably methyl. In some embodiments, the heteroaryl is pyridinyl or imidazolyl or isoxazolyl. In some embodiments, R ¹ is pyridin-3-ylmethoxy, 2-(N-imidazol-1-yl)ethoxy, or (5-methylisoxazol-3yl)methoxy.

- 3 046488

In some embodiments, R ¹ is -OR ^1a , where R ^1a is -C _1-8 alkyl, preferably -C ^ alkyl, said alkyl being substituted with phenyl. In some embodiments, R ¹ is 2-phenethoxy or 3-phenylpropoxy.

In some embodiments, R ¹ is -OR ^1a , where R ^1a is -C1-8 alkyl, preferably -C1-3 alkyl, said alkyl being substituted with -OR ^1f , where R ^1f is -C1-8 alkyl or phenyl. In some embodiments, R ¹ is 2-methoxyethoxy or 2-phenoxyethoxy.

In some embodiments, R ¹ is -OR ^1a , where R ^1a is -C _1-8 alkyl, preferably -C _1-3 alkyl, said alkyl is substituted with CH ₃ -(OCH ₂ CH ₂ ) _n- , where n is a number from 3 to 10, preferably 3 or 4 or 5. In some embodiments, R ¹ is 2,5,8,11tetraoxatridecan-13-yloxy.

In some embodiments, R ¹ is -OR ^1a , where R ^1a is -C _2-8 alkenyl; preferably -C _2-6 alkenyl; most preferably -C _4-6 alkenyl. For example, R ¹ represents but-3-enyloxy.

In some embodiments, R ¹ is -NR ^1a R ^1b , where R ^1a and R ^1b are each hydrogen or -C1-8 alkyl, preferably -C1-6 alkyl, said alkyl optionally substituted with one, two or three substituents selected from halogen, -C1-8alkyl, optionally substituted with ^R1e , cycloalkyl, optionally substituted with ^R1e , heterocyclyl, optionally substituted with ^R1e , aryl, optionally substituted with ^R1e , or heteroaryl, optionally substituted with ^R1e , where ^R1e is -C1-6alkyl, for example , methyl.

In some embodiments, R ¹ is -NR ^1a R ^1b , where R ^1a is hydrogen and R ^1b is straight or branched -C1-8 alkyl. In some embodiments, R ¹ is -NR ^1a R ^1b , where R ^1a is hydrogen, R ¹ is a branched -C1-8 alkyl, preferably -C _4-8 alkyl, where the branched substituent is in the alpha position relative to the oxygen atom including, without limitation, butan-2-yl, pentan-2-yl, pentan-3-yl, heptan-2-yl, heptan-3yl, heptan-4-yl, octan-2-yl, octan-3-yl, octan-4-yl or octan-5-yl.

In some embodiments, R ¹ is butylamino, N-butyl-N-methylamino, or isopentylamino.

In some embodiments, R ¹ is optionally partially or completely deuterated, i.e. one or more hydrogen bonded to carbon in the definition of R ¹ is replaced by one or more deuterium.

Definition of R ² and R ³ .

In some embodiments, R ² and R ³ are each independently hydrogen or C _1-8 alkyl, preferably C _1-6 alkyl. In some embodiments, R ² and R ³ are both hydrogen.

Definition of ^R4 .

In some embodiments, R ⁴ is hydrogen.

Definition of ^R5 .

In some embodiments, R ⁵ is halogen, hydroxy, C1-8alkyl, haloC1-8alkyl, C1-8alkkoxy, haloC1-8alkkoxy or -C(=O)OR ^5a , where R ^5a is hydrogen, C1-8alkyl or _{haloC1- 8} alkyl; and p represents the number 0, 1 or 2.

In some embodiments, R ⁵ is halogen, C _1-3 alkyl, haloC _1-3 alkyl, C _1-3 alkoxy, or haloC _1-8 alkoxy. In some embodiments, R ⁵ is methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, or trifluoromethyl. In some embodiments, R ⁵ is methyl.

In some embodiments, p is the number 1.

In some embodiments, R ⁵ and L2-R ⁶ are in the ortho position on the A ring.

Definition of ring A.

In some embodiments, ring A is phenyl.

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

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.

Definition of L ² -R ⁶ .

In some embodiments, L is a direct bond, -(CH ₂ )t, -O-, -S-, -S(O)-, -SO ₂ - or -NR ^d -, where R ^d is -C1-6alkyl where t is a number from 1 to 8, preferably from 1 to 5, more preferably 1 or 2 or 3; and R ^d represents -C1-6alkyl.

In some embodiments, L ² is a direct bond -CH2-, -CH2CH2-, -CH2CH2CH2-, -Oi or -NR ^d -, where R ^d is -C1-6 alkyl, preferably -C _1-4 alkyl, more preferably

- 4 046488 methyl.

Definition of L2-R ⁶ where L ² is -(CRfR ^g )t and R ⁶ is heterocyclyl.

In some embodiments, L ² is -(CR ^f R ^g )t- (where t, R ^f and R ^g are defined by formula (I)), preferably -CH2- or -CH ₂ CH ₂ -, and R ⁶ is heterocyclyl , optionally substituted with one or two R ^6c substituents, where R ^6c is defined by formula (I).

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

In some embodiments, a heterocyclyl such as R ⁶ is pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl), triazolyl (e.g. 1H-1,2,4triazol-1-yl), azepanil (e.g. azepan-2-yl, azepan-3- yl, azepan-4-yl, azepan-5-yl), piperazinil (eg piperazin-1-yl, piperazin-2-yl, piperazin-3-yl) or morpholino. In some embodiments, the heterocyclyl is a bicyclic ring containing one, two, or three heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur as ring members. In some examples, the heterocyclyl is (^^)-2,5-diazabicyclo[2.2.1]heptan-2-yl. In the above embodiments, a heterocyclyl such as R ⁶ is optionally further substituted with one or two R ^6c substituents. In some embodiments, R ^6c is -NR ^6d R ^6e , -COR ^6d , -OR ^6d , or -C^alkyl, optionally substituted with hydroxy, wherein R ^6d and R ^6e are independently hydrogen or -C1-8 alkyl (preferably -C1- 3alkyl) or phenyl, where said alkyl is optionally substituted with NH2-, alkylamino or dialkylamino. In some embodiments, R ^6c is amino, dimethylamino, 2-(dimethylamino)acetyl, methyl, 3-hydroxypropyl, or phenoxy. In some embodiments, L ² is -CH2- or -CH ₂ CH ₂ -. In some embodiments, R ⁶ is pyrrolidin1-yl, morpholino, piperidin-1-yl, 4-methylpiperazin-1-yl, piperazin-1-yl, piperidin-4-yl, 4-(2(dimethylamino)acetyl)piperazin- 1-yl, (^^)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 4-aminopiperidin1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 4-phenoxypiperidin-1-yl, 1H-1,2,4-triazol-1-yl, 4-(3hydroxypropyl)piperazin-1-yl or piperidin-3-yl.

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

Definition of L2-R ⁶ where L ² represents -(CR ^f R ^g ) _r and R ⁶ represents -NR ^6a R ^6b

In some embodiments, L ² is -(CR ^f R ^g )t- (where t, Rf and R ^g are defined by formula (I)), preferably -CH2- or -CH ₂ CH ₂ - and R ⁶ is -NR ^6a R ^6b where R ^6a and R ^6b are defined by formula (I). In some embodiments, L ² is -(CH2)t- (where t is a number from 1 to 8, preferably 1 to 5, more preferably 1, 2 or 3), preferably -CH2- or -CH2CH2- and R ⁶ is -NR ^6a R ^6b where R ^6a and R ^6b are independently hydrogen or C1-8 alkyl, preferably _C1-6 alkyl. In some embodiments, L2-R ⁶ is aminomethyl.

Definition of L2-R ⁶ where L ² represents a direct bond and R ⁶ represents _-C1-8 alkyl, -C _2-8 alkenyl or -C _2-8 alkynyl.

Definition of L2- ^R6 , where ^L2 is -O- or ^-NRd- , and ^R6 is _-C1-8 alkyl, _-C2-8 alkenyl, _-C2-8 alkynyl, heterocyclyl, aryl or heteroaryl .

In some embodiments, L is -O-, and R ⁶ is -C1-8 alkyl or heterocyclyl, wherein said -C1-8 alkyl and heterocyclyl are optionally substituted with one or two R ^6c . In some embodiments, R ^6c is -C1-8 alkyl, -NR ^6d R ^6e and -COR ^6d , wherein R ^6d and R ^6e are independently -C _1-8 alkyl (preferably _-C1-3 alkyl), optionally substituted with NH2- , alkylamino or dialkylamino. In some embodiments, L2-R ⁶ is 3-(methylamino)propoxy, 3-(dimethylamino)propoxy, 3-(diethylamino)propoxy, 2-aminoethoxy, 3-(dimethylamino)-2,2dimethylpropoxy, methoxy, 2-(methylamino )ethoxy, 2-(Nmethylacetamido)ethoxy, 3-(piperidin-1yl)propoxy, 3-morpholinopropoxy, 3-(pyrrolidin-1-yl)propoxy, 3-aminopropoxy, (1R,5S)-8azabicyclo[3.2.1 ]octan-3-yloxy, piperidin-4-yloxy, (N^)-8-ethyl-8-azabicyclo[3.2.1]octan-3yloxy, 1-ethylpyrrolidin-3-yloxy or pyrrolidin-3-yloxy.

In some embodiments, L ² is -NR ^d -, where R ^d is -C1-6 alkyl, and R ⁶ is -C1-8 alkyl, -C _2-8 alkenyl, or -C _2-8 alkynyl, each of which is optional substituted with one or two R ^6c . In some embodiments, R ^6c is -C1-8 alkyl or -NR ^6d R ^6e , wherein R ^6d and R ^6e are independently -C1-8 alkyl (preferably _-C1-3 alkyl). In some cases

- 5 046488 L2-R ⁶ is (2-(dimethylamino)ethyl)(methyl)amino.

Definition of L2-R ⁶ where L ² represents a direct bond and R ⁶ represents cycloalkyl, heterocyclyl, aryl or heteroaryl.

In some embodiments, L ² is a direct bond and R ⁶ is cycloalkyl, heterocyclyl, aryl or heteroaryl, each independently and optionally substituted with one, two or three R ^6c substituents.

In some embodiments, L ² is a direct bond and R ⁶ is a heterocyclyl which is optionally substituted with one, two or three R ^6c substituents.

As R, in some embodiments the heterocyclyl is monocyclic; in some embodiments, the heterocyclyl is a fused bicyclic heterocyclyl; and in some embodiments the heterocyclyl is a spirobicyclic heterocyclyl.

In some embodiments, the heterocyclyl is saturated. In some embodiments, the heterocyclyl is a 4-, 5-, 6-, 7-, or 8-membered monocyclic ring containing one, two, or three heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur as ring members. In some embodiments, the heterocyclyl is a 5-, 6-, 7-, or 8-membered saturated monocyclic ring containing one or two or three nitrogen heteroatoms as ring members. In some embodiments, the heterocyclyl is a 5- or 6-membered saturated monocyclic ring containing one or two nitrogen heteroatoms as ring members. In some embodiments, the heterocyclyl is pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3yl, piperidine -4-yl, piperidin-5-yl), triazolyl (for example, Ш-1,2,4-triazol-1-yl), azepanil (for example, azepan-2-yl, azepan-3-yl, azepan-4 -yl, azepan-5-yl), diazepanil (e.g. 1,4-diazepan-1-yl, 1,4diazepan-2-yl, 1,4-diazepan-3-yl, 1,4-diazepan-4- yl), piperazinil (eg piperazin-1-yl, piperazin-2-yl, piperazin-3-yl) or morpholino.

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

In some embodiments, the heterocyclyl is a 6-14 membered, and more preferably a 7-10 membered spirobicyclic heterocyclyl. In some embodiments, the heterocyclyl is spiroheptanyl, spirodecanyl, or spirononanyl containing one or two nitrogen atoms as ring members. In some embodiments, the heterocyclyl is 8-azaspiro[4.5]decan-8-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 2,8-diazaspiro[4.5]decan-2-yl, 2,7diazaspiro[3.5] nonan-2-yl, 2,8-diazaspiro[4.5]decan-8-yl.

In the above embodiments, the heterocyclyl as R ⁶ is optionally further substituted with one or two R ^6c substituents.

In some embodiments, R ^6c is -COR ^6d , where R ^6d is -C1-8alkyl, optionally substituted with one or two R ^6g substituents, where R ^6g is -NR ^6h R ⁶¹ , -N(R ^6h )C(= O)R ⁶¹ , -C1.8alkyl, aryl or heteroaryl, where R ^6h and R ⁶ i are defined by formula (I). In some embodiments, R ^6c is -COR ^6d , where R ^6d is -C1-8 alkyl (preferably _C1-6 alkyl, more preferably C _1-4 alkyl), optionally substituted with one or two R ^6g substituents, where R ^6g is -NR ^6h R ⁶¹ , -N(R ^6h )C(=O)R ⁶¹ , -C1-8alkyl, aryl or heteroaryl, where R ^6h and R ⁶¹ are each independently hydrogen or -C1-8alkyl (preferably _{C1- 6} alkyl, more preferably C _1-4 alkyl).

In some embodiments, R ^6c is -COR ^6d , where R ^6d is -C _2-8 alkenyl.

In some embodiments, R ^6c is -COR ^6d , where R ^6d is heterocyclyl.

In some embodiments, R ^6c is acetyl, 2-(dimethylamino)acetyl, 2(dimethylamino)acetyl, aminoacetyl, 2-(methylamino)acetyl, 3-(dimethylamino)propanoyl, 4(dimethylamino)butanoyl, 5-(dimethylamino)pentanoyl , (2S,3S)-2-amino-3-methylpentanoyl, 2(methylamino)acetyl, 2-amino-4-methylpentanoyl, 2-amino-3-methylbutanoyl, 2-(dimethylamino)acetyl, phenylpropanoyl, 2-(piperazine -1-yl)acetyl, acryloyl, piperazine-2-carbonyl, piperidin-4-carbonyl, pyrrolidin-2-carbonyl or 2-(Nimethylacetamido)acetyl.

In some embodiments, R ^6c is -C _1-8 alkoxy, preferably -C _1-6 alkoxy, eg methoxy.

In some embodiments, R ^6c is -C1-8alkyl, preferably -C1-6alkyl, optionally substituted with one or two R ^6g substituents, where R ^6g is -OR ^6h , -NR ^6h R ⁶¹ , heterocyclyl, aryl, where R ^6h and R ⁶¹ are defined by formula (I). In some aspects, R ^6c is -C1-8 alkyl, preferably -C _1-6 alkyl, optionally substituted with one or two R ^6g substituents, where R ^6g is -OR ^6h , -NR ^6h R ⁶¹ , heterocyclyl (e.g., morpholino) , phenyl, where R ^6h and R ⁶¹ represent -C _1-4 alkyl, preferably methyl. In some embodiments, R ^6c is methyl, ethyl, isobutyl, methoxymethyl, 2-methoxyethyl, (methylamino)methyl, 2-(dimethylamino)ethyl,

- 6 046488 (dimethylamino)methyl, 2-aminoethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, morpholinomethyl, or phenethyl.

In some embodiments, R ^6c is -C(=O)NR ^6d R ^6e , wherein R ^6d and R ^6e are independently hydrogen, -C1-8alkyl (preferably -C1-Zalkyl) or aryl, said -C1-8alkyl or aryl independently and optionally substituted with halogen or -C1-4alkyl. In some embodiments, R ^6c is -C(=O)NR ^6d R ^6e , where R ^6d and R ^6e are independently hydrogen and -C1-4 alkyl. In some embodiments, R ^6c is -C(=O)NR ^6d R ^6e , wherein R ^6d and R ^6e are independently hydrogen and aryl, optionally substituted with halogen. In some embodiments, R ^6c is dimethylcarbamoyl, isopropylcarbamoyl, or 2,4,5-trifluorophenylcarbamoyl.

In some embodiments, R ^6c is -NR ^6d R ^6e , wherein 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 is dimethylamino or amino.

In some embodiments, R ^6c is -SO2R ^6d , where R ^6d is -C1-8 alkyl, -C _2-8 alkenyl, heterocyclyl or aryl. In some embodiments, R ^6c is -SO2R ⁶ where R ^6d is -C _1-8 alkyl (preferably -C _1-6 alkyl). In some embodiments, R ^6c is propylsulfonyl.

In some embodiments, L ² is a direct bond, R ⁶ is pyrrolidinyl, optionally substituted with one, two or three substituents selected from methyl, (dimethylamino)methyl or dimethylamino. In some embodiments, L2-R ⁶ is 1methylpyrrolidin-3-yl, pyrrolidin-1-yl, 3-((dimethylamino)methyl)pyrrolidin-1-yl, or 3(dimethylamino)pyrrolidin-1-yl.

In some embodiments, L ² is a direct bond, R ⁶ is piperazinyl, optionally substituted with one, two or three substituents selected from acryloyl, 2(dimethylamino)acetyl, aminoacetyl, 2-(methylamino)acetyl, 3-(dimethylamino)propanoyl , 2(piperazin-1-yl)acetyl, piperazin-2-carbonyl, 4-(dimethylamino)butanoyl, 5(dimethylamino)pentanoyl, methyl, piperidin-4-carbonyl, acetyl, 2-(Nmethylacetamido)acetyl, isopropylcarbamoyl, 2,4,5-trifluorophenylcarbamoyl, ^^)-2-amino-3-methylpentanoyl, 2-methoxyethyl, 2-(methylamino)acetyl, ethyl, isobutyl, pyrrolidine-2-carbonyl, 2-amino-4methylpentanoyl, 2-amino-3 -methylbutanoyl, 2-(dimethylamino)acetyl, 2-(methylamino)ethyl, 2(dimethylamino)ethyl, amino, phenylpropanoyl, propylsulfonyl or 2-aminoethyl. In some embodiments, L ² -R ⁶ 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-(piperazin1-yl)acetyl) piperazin-1-yl, 4-(piperazin-2-carbonyl)piperazin-1-yl, 4-acryloyl piperazin-1-yl, 4-(4(dimethylamino)butanoyl)piperazin-1-yl, 4-(5- (dimethylamino)pentanoyl)piperazin-1-yl, 3,5dimethylpiperazin-1-yl, 4-(piperidin-4-carbonyl)piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-(2-(Nmethylacetamido) acetyl)piperazin-1-yl, 4-(isopropylcarbamoyl)piperazin-1-yl, 4-(2,4,5trifluorophenylcarbamoyl)piperazin-1-yl, 4-(3,5-dimethylpiperazin-1-yl, 4-( ^^)-2-amino-3 methylpentanoyl)piperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl, 4-(2-(methylamino)acetyl)piperazin1-yl, 4-ethylpiperazin-1- yl, 4-isobutylpiperazin-1-yl, 4-(pyrrolidin-2-carbonyl)piperazin-1-yl, 4-(2-amino-4-methylpentanoyl)piperazin-1-yl, 4-(2-amino-3-methylbutanoyl) )piperazin-1-yl, 4-(2(dimethylamino)acetyl)piperazin-1-yl, ^)-2-methylpiperazin-1-yl, ^)-2-methylpiperazin-1-yl, 4-(2(methylamino )ethyl)piperazin-1-yl, 4-(2-(dimethylamino)ethyl)piperazin-1-yl, 4-(2-amino-3phenylpropanoyl)piperazin-1-yl, 4-(propylsulfonyl)piperazin-1-yl , 4-(2-aminoethyl)piperazin-1-yl, or 3-methylpiperazin-1-yl.

In some embodiments, L ² is a direct bond, R ⁶ is piperidinyl, optionally substituted with one, two or three substituents selected from 2(dimethylamino)acetyl, methoxy, methoxymethyl, (methylamino)methyl, 4-morpholinopiperidin-1-yl, morpholinomethyl, 2-(dimethylamino)ethyl, phenethyl, (dimethylamino)methyl, amino, dimethylamino or dimethylcarbamoyl. In some embodiments, L ² -R ⁶ is piperidin-4-yl, 4-(2(dimethylamino)acetyl)piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, piperidin-1-yl, piperidin4 -yl, 4-methoxypiperidin-1-yl, 4-(methoxymethyl)piperidin-1-yl, 4-((methylamino)methyl)piperidin-1yl, (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-1yl, 4-aminopiperidin-1 -yl, 4-(dimethylamino)piperidin-1-yl, or 4-(dimethylcarbamoyl)piperidin-1yl.

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

In some embodiments, L2-R ⁶ is octahydro-2H-isoindol-2-yl.

In some embodiments, L ² -R ⁶ is a morpholino.

In some embodiments, L2-R ⁶ is 8-azaspiro[4.5]decan-8-yl, 2,7diazaspiro[3.5]nonan-7-yl, 2,8-diazaspiro[4.5]decan-2-yl, 2,7 -diazaspiro[3.5]nonan-2-yl, 2,8diazaspiro[4.5]decan-8-yl, (1Р4К)-2.5-diazabicyclo[2.2.1|heptan-2-i.t.

- 7 046488

In some embodiments, ring A is phenyl, and ^L1 and L2- ^R6 are at the para positions of the phenyl ring, and said phenyl ring is further substituted by one ^R5 , wherein ^L1 , ^L2 , ^R5 , and ^R6 are defined in each of the above embodiments . In some embodiments, ring A is pyridyl, and L ¹ and L2-R ⁶ are in the para positions of the pyridyl ring, and said pyridyl ring is further optionally substituted with one R ⁵ , wherein L ¹ , L ² , R ⁵ and R ⁶ are defined in each of the above embodiments.

In some embodiments, disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, selected from the specific compounds set forth herein:

- 8 046488

- 9 046488

- 10 046488

- 11 046488

In a third aspect, a pharmaceutical composition is disclosed containing a compound disclosed in

- 12 046488 herein, including a compound of formula (I) or specific compounds provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

In a fourth aspect, this document discloses a method of modulating TLR7, which includes administering to an individual a compound disclosed herein, or a pharmaceutically acceptable salt thereof, including a compound of formula (I) or specific compounds provided herein.

In a fifth aspect, a method of treating a disease or disorder in a patient is disclosed, 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 (I) or specific compounds disclosed herein. In some embodiments, the disease or disorder is associated with modulation of a TLR, such as TLR-7, eg, TLR-7 agonizing activity. In some embodiments, the disease or disorder is melanoma, non-small cell lung carcinoma, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD (chronic obstructive pulmonary disease), ulcerative colitis, liver fibrosis, HBV (hepatitis virus) B), HCV (hepatitis C virus), HPV (human papillomavirus), RSV (respiratory syncytial virus), SARS (severe acute respiratory syndrome), HIV (human immunodeficiency virus) or influenza.

Detailed Description of the Invention

The following terms have the indicated meanings throughout the description.

As set forth herein, including the appended claims, the singular forms of words include their corresponding plural forms unless the context indicates otherwise.

The term or is used to mean, and is used interchangeably with the term and/or, unless the context indicates otherwise.

The term alkyl as used herein refers to a hydrocarbon group selected from linear or branched hydrocarbon groups containing from 1 to 8 carbon atoms. Examples of alkyl groups containing from 1 to 6 carbon atoms (i.e., C1.6alkyl) 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 (sec-Bu), 1,1-dimethylethyl or tert-butyl (tertBu) , 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl1-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, 2,3dimethyl-2 -butyl and 3,3-dimethyl-2-butyl groups.

The terms alkoxy or alkyloxy refers to an alkyl group, as previously defined, attached to the parent molecular group via an oxygen atom.

The term amino refers to -NH ₂ . The term alkylamino refers to -NH(-C _1-8 alkyl). The term dialkylamino refers to -N(-C _1-8 alkyl) ₂ . The term halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

The term haloalkyl as used herein refers to a -C _1-8 alkyl group in which one or more hydrogens are replaced by one or more halogen atoms such as fluorine, chlorine, bromine and iodine. Examples of haloalkyl include haloC1 _-8 alkyl, haloC1 _-6 alkyl or haloC1 _-4 alkyl, but are not limited to -CF ₃ , -CH ₂ Cl, -CH2CF ₃ , -CCI2, CF ₃ and the like.

The term alkenyl as used herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C=C double bond and 2 to 8, such as 2 to 6 carbon atoms. Examples of the alkenyl group, for example, C _2-6 alkenyl, include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1enyl, but-1-enyl, but-2-enyl, but -3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl groups.

The term alkynyl as used herein refers to a hydrocarbon group selected from a straight or branched hydrocarbon group containing at least one C=C triple bond and from 2 to 8, for example from 2 to 6 carbon atoms. Examples of the alkynyl group, for example, C _2-6 alkynyl, include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl and 3-butynyl groups.

The term alkyloxy or alkoxy as used herein refers to a _-C1-8 alkyl group as defined above attached to the parent molecular group via an oxygen atom. Examples of alkyloxy, for example, _C1-6 alkyloxy or _C1-4 alkyloxy include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, t-butoxy, pentoxy and hexoxy and the like.

The term alkoxy-alkyl- refers to an alkyl group as defined above, in addition to

- 13 046488 substituted alkoxy, as defined above. Examples of alkoxy-alkyl-, for example, C _1-8 alkoxy-C _1-8 alkyl or C _1-6 alkoxy-C _1-6 alkyl-, include, but are not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl or propoxymethyl and the like.

The term cycloalkyl refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups containing monocyclic and bicyclic and tricyclic) groups, including fused, bridged or spirocycloalkyl.

For example, a cycloalkyl group may contain from 3 to 12, such as 3 to 10, such as 3 to 8, such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. In a further example, the cycloalkyl group may be selected from a monocyclic group containing 3 to 12, eg 3 to 10, eg 3 to 8, eg 3 to 6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1enyl, 1-cyclohex-2-enyl, 1 -cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups. In particular, examples of a saturated monocyclic cycloalkyl group, such as C ₃₈ cycloalkyl, include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. In a preferred embodiment, cycloalkyl is a monocyclic ring containing from 3 to 6 carbon atoms (abbreviated C _3-6 cycloalkyl), including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of bicyclic cycloalkyl groups include groups having from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] and [6 ,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include, as the bicyclic ring, groups selected from the [5,6] and [6,6] ring systems.

The term cycloalkenyl refers to non-aromatic cyclic alkyl groups of 3 to 10 carbon atoms, having one or more rings and 1 to 2 double bonds. In one embodiment, the cycloalkenyl is cyclopentenyl or cyclohexenyl, preferably cyclohexenyl.

The term cycloalkynyl refers to non-aromatic cycloalkyl groups containing from 5 to 10 carbon atoms, having one or more rings and one triple bond.

The term deuterated is used herein to modify a chemical structure, or organic group, or radical, where one or more carbon-bonded hydrogen(s) is replaced by one or more deuterium(s), e.g., deuterated-alkyl, deuterated-cycloalkyl, deuterated-heterocycloalkyl, deuterated-aryl, deuterated-morpholinyl, etc. For example, the term deuterated-alkyl as defined above refers to an alkyl group as defined herein where at least one hydrogen atom bonded to a carbon atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium; and optionally the carbon atom is bonded to more than one deuterium; also, optionally, more than one carbon atom in the alkyl group is associated with deuterium.

The term aryl, used alone or in combination with other terms, refers to a group selected from phenyl.

The terms aromatic hydrocarbon ring and aryl are used interchangeably in the description of this document. The term heteroaryl as used herein refers to a group selected from: 5-, 6-, or 7-membered aromatic, monocyclic rings containing 1 to 3, in some embodiments 1 to 2, heteroatoms selected from nitrogen (N), sulfur (S) and oxygen (O), with the remaining atoms of the ring being carbon; 7-12 membered bicyclic rings containing from 1 to 3, or in other embodiments, 1 or 2 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), the remaining ring atoms being carbon, and where at least one ring is aromatic and at least one heteroatom is present on the aromatic ring; and 11 to 14 membered tricyclic rings containing from 1 to 3, or in other embodiments 1 or 2 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present on the aromatic ring.

In the case when the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no more than 1. In the case where the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.

The term optionally oxidized sulfur as used herein refers to S, SO or SO2.

- 14 046488

The terms aromatic heterocyclic ring and heteroaryl are used interchangeably in the description of this invention. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring contains 5, 6, 7, 8, 9, or 10 ring-forming members, with 1, 2, or 3 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining members of the ring are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 5-6 membered heteroaryl ring that is monocyclic and contains 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is an 8-10 membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

Examples of a heteroaryl group, or a monocyclic or bicyclic aromatic heterocyclic ring include, but are not limited to (numbered based on the position of the priority 1 bond) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl or 1,3,4-thiadiazolyl) , thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1, 2,4oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as 1Hpyrazolo^D-^pyridin^-yl), benzoxazolyl (such as benzoxazol-6- yl), 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl , 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanil (such as furazan-2-yl, furazan-3-yl), benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzothiazol-6-yl), indazolyl (such as N-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

The terms heterocyclyl, heterocycle or heterocyclic are interchangeable and refer to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon, including monocyclic, fused, bridged ring and spiro ring, i.e. containing a monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

The term monocyclic heterocyclyl refers to monocyclic groups in which at least one ring member is a heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

Examples of monocyclic 4-9 membered heterocyclic groups include, but are not limited to (numbered based on bond position with priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4- yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranil, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranil, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranil, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanil, thiethanyl, 1,2-dithiethanyl, 1,3-dithiethanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanil, piperazinil, homopiperazinil, homopiperidinil, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanil, tiepanil, 1,4-oxathianil, 1,4-dioxepanil, 1,4- oxathiepanil, 1,4oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazoline silt, pyrimidinonyl or 1,1-dioxothiomorpholinyl.

The term spiroheterocyclyl refers to a 5-20 membered polycyclic heterocyclyl with rings connected by one common carbon atom (called a spiroate) containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members are carbon. One or more rings of a spiroheterocyclyl group may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. Preferably the spiroheterocyclyl is 6-14 membered, and more preferably 7-12 membered. Depending on the number of common spiro atoms, spiroheterocyclyl is classified as monospiroheterocyclyl, dispyrogeterocyclyl, or polyspiro.

- 15 046488 heterocyclyl and preferably refers to monospiroheterocyclyl or dispyroheterocyclyl, and more preferably 4-membered/4-membered, 3-membered/5-membered, 4-membered/5-membered, 4-membered/6-membered 5-membered/5- membered or 5-membered/6-membered monospiroheterocyclyl.

The term fused heterocyclic group refers to a 5-20 membered polycyclic heterocyclyl group, where each ring in the system has a pair of adjacent atoms (carbon and carbon atoms or carbon and nitrogen atoms) in common with another ring containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon. One or more rings of a fused heterocyclic group may contain one or more double bonds, but none of the rings has a fully fused pi electron system. Preferably the fused heterocyclyl is 6-14 membered and more preferably 7-10 membered. Depending on the number of ring members, the fused heterocycle is classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycle, preferably refers to a bicyclic or tricyclic fused heterocycle, and more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocycle. Representative examples of fused heterocycles include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl) , octahydro-benzo[b][1,4]dioxin.

The term bridged heterocyclyl refers to a 5-14 membered polycyclic heterocyclic alkyl group wherein each two rings in the system have two common dissociated atoms containing one or more heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with In this case, the remaining members of the ring are carbon. One or more rings of a bridged heterocyclyl group may contain one or more double bonds, but none of the rings has a fully fused pieletron system. Preferably the bridged heterocyclyl is 6-14 membered and more preferably 7-10 membered. Depending on the number of ring members, the bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyls include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

The compounds disclosed herein may contain a center of asymmetry and may thus exist as enantiomers. The term enantiomers refers to two stereoisomers of a compound that are non-matching mirror images of each other. In cases where the compounds disclosed herein have two or more centers of asymmetricity, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to the broader class of stereoisomers. All such possible stereoisomers are intended to be included, such as substantially pure separated enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and/or their pharmaceutically acceptable salts are intended to be included. Unless specifically stated otherwise, reference to one isomer includes any of the possible isomers. In the case where the composition of isomers is not determined, all possible isomers are included.

The term substantially pure as used herein means that the desired stereoisomer contains no more than 35 wt.%, for example, no more than 30 wt.%, preferably no more than 25 wt.%, preferably, e.g., no more than 20 wt.%, relative to the mass of any other stereoisomer. In some embodiments, the term substantially pure means that the desired stereoisomer contains no more than 10 wt.%, for example, no more than 5 wt.%, no more than 1 wt.% based on the weight of any other stereoisomer.

Where the compounds disclosed herein contain olefinic double bonds, unless otherwise indicated, such double bonds include both E- and Z-geometric isomers.

In the case where the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents located on the cyclohexyl or cyclobutyl ring may assume cis and trans positions. The cis position means that both substituents are located on the top side of the two substituted positions on the carbon, while trans means that they are located on opposite sides.

It may be promising to separate the reaction products from one another and/or from the starting materials. The desired products in each step or series of steps are separated and/or purified (hereinafter separated) to the desired degree of homogeneity using methods known in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or mixture of solvents, distillation, sublimation or chromatography. Chromatography

- 16 046488 may include any number of methods, including, for example, reversed phase and normal phase; exclusive; ion exchange; methods and equipment of high, medium and low pressure liquid chromatography; analytical on a small scale; pseudo-moving bed (SMB) and preparative thin- and thick-layer chromatography, as well as small-scale thin-layer chromatography and flash chromatography methods. Those skilled in the art will employ methods likely to achieve the desired separation.

The term diastereomers refers to stereoisomers of a compound with two or more chiral centers, but they are not mirror images of each other. Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods known to those skilled in the art, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting an enantiomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher acid chloride), separating the diastereomers, and converting (e.g., hydrolysis) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

A single stereoisomer, for example, a substantially pure enantiomer, can be obtained by resolving a racemic mixture using a method such as the formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. Chromatographic resolution of enantiomers: Selective review. J. Chromatogr., 113(3) (1975): pp. 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 resolution by fractional crystallization or other means, (2) formation of diastereomeric compounds by chiral derivatization reagents, resolution diastereomers and conversion to pure stereoisomers, and (3) separation of substantially pure and enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

The term pharmaceutically acceptable salts refers to those salts that are approved for medical use, are acceptable for use in contact with tissues of humans and lower animals without non-specific toxicity, irritation, allergic reaction, etc., and have an acceptable benefit-risk ratio. The pharmaceutically acceptable salt may 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.

In addition, if the compound disclosed in this invention is obtained as an acid addition salt, the free base can be obtained by increasing the basicity of the acid salt solution. Alternatively, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional methods for preparing salts, by adding the acid from the basic connections. Various synthetic methods are known to those skilled in the art that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable acid addition salts.

As defined herein, a pharmaceutically acceptable salt includes salts of at least one compound of formula (I).

The terms administration, administered, treatment and treatment as used herein, when applied to an animal, human, test subject, tissue, organ or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent or composition with an animal, human, test subject, cell, tissue , organ or biological fluid. Cell processing covers reagent-cell contact as well as reagent-liquid contact, where the liquid is in contact with the cell. The term administration and treatment also means in vitro and ex vivo treatment, for example, of a cell, a reagent, a diagnostic agent, a binding compound, or another cell. The term subject as used herein includes any organism, preferably an animal, more preferably a mammal (eg, rat, mouse, dog, cat, rabbit), and most preferably human.

The term effective amount or therapeutically effective amount refers to an amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to provide such treatment of the disease, disorder or symptom. The therapeutically effective amount may vary depending on the compound, the disease, disorder and/or symptoms of the disease or disorder, the severity of the disease, disorder and/or symptoms

- 17 046488 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 example may be apparent to those skilled in the art or can be determined by routine experimentation. In some embodiments, a therapeutically effective amount is an amount of at least one compound and/or at least one pharmaceutically acceptable salt thereof disclosed herein effective for treating, as described above, a disease or disorder in a subject. In the case of combination therapy, a therapeutically effective amount refers to the total amount of the combined entities to effectively treat the disease, disorder or condition.

A pharmaceutical composition containing a compound disclosed in this invention can be administered by oral, inhalation, rectal, parenteral and/or topical administration to a subject in need thereof. For oral administration, the pharmaceutical composition may be a conventional solid dosage form such as tablets, powder, granules, capsules and the like, a liquid dosage form such as an aqueous or oily suspension, or other liquid dosage form such as a syrup, solution, suspension, etc. for parenteral administration, the pharmaceutical composition may be a solution, an aqueous solution, an oily suspension concentrate, a lyophilized powder, or the like. Preferably, the form of the pharmaceutical composition is selected from tablet, film-coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule. The pharmaceutical composition may be intended for single use in a precise dose. In addition, the pharmaceutical composition may additionally contain additional active ingredients.

All forms of the pharmaceutical composition disclosed herein can be prepared using conventional pharmaceutical techniques. For example, the active ingredient may be mixed with one or more excipients to obtain the desired form. Pharmaceutically acceptable excipient refers to conventional pharmaceutical carriers acceptable for the desired pharmaceutical form, for example: a diluent, a carrier such as water, various organic solvents, etc., a filler such as starch, sucrose, etc., a binder, such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); a humectant such as glycerin; a leavening agent such as agar, calcium carbonate and sodium bicarbonate; an absorption enhancer such as a quaternary ammonium compound; a surfactant such as hexadecanol; an absorbent carrier such as kaolin and soap clay; lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition further contains other pharmaceutically acceptable excipients, such as a disintegrant, stabilizer, thickener, complexing agent, buffering agent, penetration enhancer, polymerizing agent, flavorings, sweetener and coloring agent.

The term disease refers to any disease, discomfort, illness, symptom or indicator, and can be used interchangeably with the term disorder or condition.

Throughout this specification and the claims below, unless the context otherwise requires, the term contain and its various variations such as contains and containing are intended to indicate the presence of subsequent features, but does not exclude the presence or addition of one or more other features. When used herein, the term containing may be replaced by the term containing, including, or sometimes having.

Throughout this description and the following claims, the term Cn _-m means a range that includes end values, where n and m are integers and denote the number of carbon atoms. Examples include C _1-8 , C _1-6 , and the like.

Unless specifically stated otherwise herein, all other technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the invention relates.

Basic synthesis.

The compounds disclosed herein, including their salts, can be prepared using known organic synthesis methods according to any of numerous possible synthetic methods.

The reaction to prepare the compounds disclosed herein can be carried out in suitable solvents, which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may not be substantially reactive with the starting materials, intermediates, or products at the temperatures at which the reaction is carried out, for example, temperatures ranging from room temperature to the boiling point of the solvent. This reaction can be carried out in a solvent or mixture of solvents.

The selection of appropriate protecting groups can be easily made by those skilled in the art.

The reaction can be monitored by any suitable method known in the art, such as NMR, UV, HPLC, LC-MS and TLC. Connections can be cleaned by

- 18 046488 various methods, including HPLC and normal phase chromatography on silicon.

Chiral analytical HPLC can be used to analyze the retention time of various chiral examples, the conditions can be divided into the methods below, according to the column used, the mobile phase, the solvent ratio.

The compounds disclosed herein can be prepared according to the following Scheme I.

Scheme I

Removing protection

hydrisipshi grutttty \ν= Ν o

where -WR ^1a is -OR ^1a or

-NR ^1a R ^1b , and L ² , R ⁵ , R ⁶ , R ^1a and R ^1b are defined by formula (I),

X and Y independently represent CH or N; W is independently N or O.

In Scheme I, commercially available ethyl 1H-imidazole-2-carboxylate was reacted with 2-O-(4nitrobenzoyl)hydroxylamine to form compound 2, which reacted with ethyl chloroformate, then the ring was closed in the presence of ammonium hydroxide to give imidazo[2,1£ ][1,2,4]triazine-2,4(1H,3H)-dione. Intermediate 5 was prepared by introducing one Br atom using a brominating reagent and then the dione was chlorinated to form intermediate 6. One chlorine atom was replaced with a protected amine to give intermediate 7, which reacted with R ^1a -W to give the key intermediate 8, which then reacted with various aldehydes under basic conditions to form intermediate 10. The protecting groups on the amine and hydroxyl group were removed to give the compound of formula I.

Intermediate 10 can also be prepared using Scheme II.

Scheme II

In Scheme II, compound 4 was chlorinated to form intermediate 6'. One chlorine atom was replaced with a protecting amine to produce intermediate 7', which reacted with R ^1a -W to form the key intermediate 8', which then reacted with various aldehydes under basic conditions to form intermediate 10.

Examples

The following examples are for illustrative purposes only and should not be construed as limiting. Unless otherwise specified, the experimental methods in the examples below are conventional methods. Unless otherwise stated, reagents and materials are commercially available. All solvents and chemicals used are analytically or chemically pure. Solvents are redistilled before use. All anhydrous solvents are prepared using standard methods or reference methods. Silica gel (100-200 mesh) for column chromatography and silica gel (GF254) for thin layer chromatography (TLC), commercially available from Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd. of China; eluted with petroleum ether (60-90°C)/ethyl acetate (v/v) and visualized with iodine or molybdophosphoric acid in ethanol unless otherwise stated. All extracts

- 19 046488 Solvents, unless otherwise indicated, are dried over anhydrous Na2SO4. The ¹ H NMR spectrum was recorded on a Bruck-400 nuclear resonance magnetic spectrometer with TMS (tetramethylsilane) as an internal standard. LC/MS data are acquired using an Agilent1100 HPLC 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, excluding reagents, are generated using ChemDraw®.

In the following examples the following abbreviations are used

AcOH Acetic acid aq. Water BINAP 2,2'-bis(diphenylphosphino)-1, G-dinaphthyl Saline solution Bn Saturated aqueous sodium chloride solution Benzyl VpVg Benzyl bromide BPO Benzoyl peroxide B.S.A. N, O-bis(trimethylsilyl)acetamide CH ₂ C1 ₂ or DXM DIAD DMF Dppf DBU Dichloromethane Diisopropyl azodicarboxylate N,N-Dimethylformamide 1, G-bis(diphenylphosphino)ferrocene 1,8-diazabicyclo[5.4.0]undec-7-ene DIEA or DIPEA N,N-diisopropylethylamine DMAP DMF DMSO EtOAc or EA 4-Ν,Ν-dimethyl aminopyridine Ν,Ν-d imethyl formamide Dimethyl sulfoxide Ethyl acetate EtOH Ethanol Et ₂ O or ether Diethyl ether G Grams h Watch) HATU O-(7-Azabenzotriazol-1-yl)-X,Ν,Ν',Ν' -tetramethyluronium hexafluorophosphate Hex Hexane NS1 Hydrochloric acid GMDS HPLC Hexamethyldisilazane High performance liquid chromatography IBX 2-Iodoxybenzoic acid ANN Isopropyl alcohol i-PrOH Isopropyl alcohol

- 20 046488

zhms Liquid chromatography-mass spectrometry mg Milligrams ml Milliliters mmol Millimole MeCN Acetonitrile MeOH Methanol min minutes ms or ms Mass spectrum MTBE Methyl tert-butyl ether _{Na2SO4 ​} Sodium sulfate N.B.S. N-Bromosuccinimide NMP N-Methyl pyrrole ide RE petroleum ether RMV (4-methoxyphenyl)methanamine prey Preparative CT or CT Room temperature us. Saturated TBAF Tetrabutyl ammonium fluoride TV SCI tert-butyldimethylsilyl chloride t-BuOK Potassium tert-butoxide TFU Trifluoroacetic acid THF Tetrahydrofuran those Thin column chromatography µl Microliters

Synthesis of intermediate I.

7-bromo-2-butoxy-U,U-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine.

Step A: ethyl 1-amino-III-imidazole-2-carboxylate hydrochloride.

To a mixed solution of ethyl-III-imidazole-2-carboxylate (56 g, 0.4 mol) in NMP (1.2 L), tertBuOK (1 M in THF, 440 ml, 0.44 mol) was added at 20~30° WITH. The mixture was stirred for 0.5 hours. A solution of O-(4-nitrobenzoyl)hydroxylamine (80.08 g, 0.44 mol) in NMP (0.4 L) was added dropwise at less than 30°C. The solution was stirred at rt for 2 hours. The solution was diluted with MTBE (500 ml). HCl (4 M in EA, 100 ml) was added to stop the reaction. Diatomite (20 g) was added to the above mixture and then stirred for 0.5 hours. The mixture was filtered. The filtrate was diluted with MTBE (2 L) and HCl (4 M in EA, 200 ml) dropwise. The suspension was stirred for 0.5 h and filtered. The filter cake was washed with MTBE and oven dried to obtain the product (70 g, 91%). MS: m/e 156 (M+1)+.

Step B: mixture of ethyl 1-((ethoxycarbonyl)amino)-III-imidazole-2-carboxylate and ethyl 1(di(ethoxycarbonyl)amino)-III-imidazole-2-carboxylate (1:1).

To a stirred solution of ethyl 1-amino-III-imidazole-2-carboxylate hydrochloride (80 g, 0.42 mol) in THF (900 ml) and H2O (900 ml), several portions of NaHCO ₃ (178.9 g, 2.1 mol). Ethyl chloroformate (98.55 g, 0.9 mol) was added dropwise at less than 30°C. The mixture was stirred at rt for 4 hours. The mixture was diluted with EA (1 L) and then separated. The aqueous layer was extracted with EA (800 ml). The collected organic layer was washed with brine, dried over Na ₂ SO ₄ , 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) ⁺ .

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

A mixture of ethyl 1-((ethoxycarbonyl)amino)-III-imidazole-2-carboxylate and ethyl 1-(di(ethoxycarbonyl)amino)-III-imidazole-2-carboxylate (110 g) in ammonium hydroxide was placed in a sealed tube. (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 washed with MeOH. The filtrate was concentrated under reduced pressure. The resulting precipitate was suspended in MeOH, filtered and washed with MeOH. The resulting filter cake and the previous filter cake were mixed and dried in an oven to obtain the product (56 g) as a white solid. MS: m/e 153 (M+1) ⁺ .

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

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), NBS (nbromosuccinimide ) (24.6 g, 0.14 mol) was added in several portions at less than 25°C. The mixture was stirred at rt for 1 hour. The mixture was filtered. The filtrate was concentrated to remove

- 21 046488 solvent. The resulting cake and the previous filter cake were mixed and suspended in MeOH (20 V) and then MeOH:H ₂ O (1:1, 20 V) to obtain the product (30.4 g, 94%) as a white solid. MS: m/e 231 (M+1)+.

Step E: 7-bromo-2.4-dichloroimidazo[2.1-G|[1.2.4|triazine.

7-bromimidazo[2.1-G|[1.2.4|triazine-2.4(1H.3H)-dione (10 g, 43 mmol), triethylamine hydrochloride (12 g, 88 mmol) and POCl ₃ ( 100 ml). The mixture was stirred at 120°C overnight. The mixture was concentrated to remove POCl ₃ . The precipitate was diluted with EA (200 ml) and at a temperature below 20°C, sodium was added dropwise. NaHCO ₃ (aq) to a pH above 7. The solution was separated. The organic layer was washed with H2O, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by 0-20% EA in PE column chromatography to obtain the product (8.5 g, 73%) as a white solid. MS: m/e 267 (M+1)+.

Step F: 7-bromo-2-chloro-^Nibis(4-methoxybenzyl)imidazo[2,1-G][1,2,4]triazin-4-amine.

To a stirred solution of 7-bromo-2,4-dichloroimidazo[2,1-G|[1,2,4]triazine (30 g, 0.11 mol) in THF (500 ml) was added dropwise TEA (22.6 g, 0.22 mol). 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 hours. The solution was quenched with H2O (300 ml) and then extracted with EA (200 mlx2). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting precipitate was suspended in PE (300 ml) and filtered to give the product (41.4 g, 76%) as a white solid. MS:M/e 488 (M+1) ⁺ .

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

Mixture.

7-bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (35 g, 71.6 mmol) and H- BuONa/n-ViOH (20%, 200 ml) was stirred at 80°C under N2 for 1 hour. The solution was quenched with H2O (200 ml). The aqueous solution was extracted with EA (150 mlx2). The collected organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by 0-20% EA in PE column chromatography to give the product (33 g, 88%) as a colorless oil which solidified after a few hours. MS: m/e 526 (M+1)+.

Compound A1: 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-G] [1.2.4|triazin-4amine.

Step A: 7-bromo-2-chlorimidazo[2,1-G][1,2,4]triazin-4-amine.

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

Step B: 7-bromo-2-butoxyimidazo[2,1-G][1,2,4]triazin-4-amine.

A mixture of the product from step A (1.7 g, 6.84 mmol) and sodium butanolate (50 ml, 1M in 1-butanol) was stirred at 70°C overnight. The mixture was evaporated and the precipitate was diluted with methanol. The precipitate was filtered to obtain the crude product (1 g, 51%).

1H NMR (400 MHz, DMSOO δ 8.31 (s, 1H), 8.24 (s, 1H), 7.60 (s, 1H), 4.24 (t, J=6.5 Hz, 2H) , 1.81-1.62 (m, 2H), 1.53-1.34 (m, 2H), 0.94 (t, J=7.4 Hz, 3H) ppm MS: m/e 286 (M+1)+.

Step C: tert-butyl(7-bromo-2-butoxyimidazo[2.1-G|[1,2,4|triazin-4-yl)(tert-butoxycarbonyl)carbamate.

To a solution of the product from step B (525 mg, 1.84 mmol) and DMAP (224 mg, 1.84 mmol) in dichloromethane (20 ml) was added di-tert-butyl dicarbonate (1.2 g, 5.51 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (20 ml), washed with water and saline, and dried over Na ₂ SO _4; filtered and evaporated to obtain the crude product (650 mg, 72%), which was used in the next step without further purification. MS: m/e 486 (M+1)+.

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

To a solution of the product from step C (650 mg, 1.33 mmol) in THF (30 ml) under nitrogen was added nBuLi (0.8 ml, 2.00 mmol, 2.5 M in hexane) at -78°C and stirred for 0.5 hours. After adding 4(pyrrolidin-1-ylmethyl)benzaldehyde (378 mg, 2.00 mmol). The mixture was warmed to room temperature overnight. The reaction was quenched with an aqueous saturated solution of NH4C1 and the resulting mixture was extracted with ethyl acetate (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by column chromatography (eluent: MeOH/DCM = 0.1% to 5%) to give the product (200 mg, 30%). MS: m/e 597 (M+1)+.

Step E: 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (compound A1).

The reaction mixture of the product of step D (140 mg, 0.28 mmol), trifluoroacetic acid (2 ml), triethylsilane (2 ml) and dichloromethane (1 ml) was stirred at 40°C overnight. Once complete, the mixture was evaporated and made alkaline. The precipitate was purified using the CombiFlash system (eluent: MeOH/DCM =

- 22 046488

0% to 10%) to obtain the product (50 mg, 47%).

1H NMR (400 MHz, DMSO-dg) δ 8.15 (s, 1H), 8.04 (s, 1H), 7.30 (s, 1H), 7.29-7.18 (m, 4H) , 4.19 (t, J=6.6 Hz, 2H), 4.11 (s, 2H), 3.59 (s, 2H), 2.49-2.33 (m, 4H), 1, 70-1.61 (m, 6H), 1.50-1.32 (m, 2H), 0.92 (t, J=7.4 Hz, 3H) ppm. MS: m/e 381 (M+1)+.

Compound A2: 2-butoxy-7-(4-(3 -(dimethylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4amine.

Step A: 4-(3-(dimethylamino)propoxy)benzaldehyde.

DIAD (2.5 g, 12.3 mmol) was added dropwise to a solution of 4-hydroxybenzaldehyde (1 g, 8.2 mmol), 3-(dimethylamino)propan-1-ol (1.2 g, 12.3 mmol ) and triphenylphosphane (3.2 g, 12.3 mmol) in THF (20 ml) at 0°C under N2. The mixture was heated to rt and stirred for 6 hours. The reaction was quenched with water (20 ml), extracted with ethyl acetate (20 ml) and washed with brine (10 ml). The organic layers were dried, concentrated and purified using CombiFlash to give the product (1.1 g, 65%) as a colorless oil.

1H NMR (400 MHz, CDCl ₃ ) δ 9.88 (s, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz, 2H) , 4.11 (t, J=8.0 Hz, 2H), 2.46 (t, J=8.0 Hz, 2H), 2.26 (s, 6H), 2.02-1.96 ( m, 2H) ppm. MS: m/e 208 (M+1) ⁺ .

Step B: tert-butyl-(2-butoxy-7-((4-(3 -(dimethylamino)propoxy)phenyl)(hydroxy)methyl)imidazo[2,1-f][1,2,4]triazine- 4-yl)(tert-butoxycarbonyl)carbamate.

A cooled solution of bromide (100 mg, 0.2 mmol) in THF (3 ml) at -78°C was purged with N2, and then n-BuLi (1.6 M, 0.3 ml) was added dropwise. After stirring at -78°C for 30 min, 4-(3-(dimethylamino)propoxy)benzaldehyde (83 mg, 0.4 mmol) in THF (1 ml) was added. The resulting mixture was stirred at this temperature for 30 minutes, and then heated to rt 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 layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified by pre-TLC (DCM:MeOH=10:1) to give the pure product as a white solid (35 mg, 33%) . MS: m/e 615 (M+1)+.

Step C: 2-butoxy-7-(4-(3 -(dimethylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (compound A2).

Triethylsilane (0.5 ml) and trifluoroacetic acid (0.5 ml) were added to a solution of the product from step B (35 mg, 0.07 mmol) in DCM (2 ml). The mixture was heated at 40°C for 1 hour and then concentrated. Water (5 ml) was added to the precipitate, extracted with ethyl acetate (5 ml), washed with NaHCO ₃ (5 ml) and brine (5 ml). The organic layer was dried, concentrated and purified by pre-TLC (DCM:MeOH=6:1) to give the product (9 mg, 33%).

1H NMR (400 MHz, DMSO-ph;) δ 9.75 (br,s, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 7.25 (s, 1H), 7.23 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.0 Hz, 2H), 4.20 (t, J=8.0 Hz, 2H), 4, 07 (s, 2H), 3.99 (t, J=8.0 Hz, 2H), 3.11 (t, J=4.0 Hz, 2H), 2.74 (s, 6H), 2, 10-2.03 (m, 2H), 1.71-1.64 (m, 2H), 1.45-1.36 (m, 2H), 0.93 (t, J=8.0 Hz, 3H) ppm. MS: m/e 399 (M+1)+.

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

Step A: 4-(bromomethyl)benzaldehyde.

To the stirred solution was added 4-(hydroxymethyl)benzaldehyde (7 g, 50.7 mmol) in DCM (400 mL), NBS (17.8 g, 100 mmol) and PPh ₃ (27.3 g, 104 mmol). After addition, the reaction mixture was stirred at rt for 4 hours. The reaction mixture was washed with H2O (150 mlx3). The organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc = 5:1) to give 4-(bromomethyl)benzaldehyde (9.5 g, 95%) as white solid. MS: m/e 199 (M+1)+.

Step B: 4-(morpholinomethyl)benzaldehyde.

To a stirred solution of 4-(bromomethyl)benzaldehyde (3 g, 15 mmol) in MeCN (40 ml) was added morpholine (1.39 g, 16 mmol) and K ₂ CO ₃ (4.17 g, 30 mmol). After addition, the reaction mixture was stirred at rt overnight. The mixture was filtered. The filtrate was poured into H ₂ O and extracted with EtOAc (15 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether/ESAAc=1:1) to give 4-(morpholinomethyl)benzaldehyde (2 g, 66.7%) as a yellow oil.

1H NMR (400 MHz, DMSOO δ 10.00 (s, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 3 .74-3.67 (m, 4H), 3.57 (s, 2H), 2.50-2.42 (m, 4H) ppm MS: m/e 206 (M+1)+.

Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1T][1,2,4]triazin-7-yl)(4(morpholinomethyl)phenyl)methanol.

To a stirred solution of 7-bromo-2-butoxy-VNbis(4-methoxybenzyl)imidazo[2,1Al,2,4]triazin-4-amine (150 mg, 0.3 mmol) in THF (10 ml), cooled to -78°C under nitrogen, n-BuLi (1.6 M in hexane, 0.75 mmol, 0.47 ml) was added dropwise. After stirring for 20 min, a solution of 4-(morpholinomethyl)benzaldehyde (114 mg, 0.45 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly heated to rt and stirred for 2 hours. The reaction mixture was poured

- 23 046488 into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , and concentrated to give the title product (220 mg, 100%), which was used directly in the next step without further purification. MS: m/e 653 (M+1)+.

Step D: 2-butoxy-7-(4-(morpholinomethyl)benzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (compound A3).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4(morpholinomethyl)phenyl)methanol (220 mg, 0 .3 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by column chromatography (DCM/MeOH=5:1) to give the product (40 mg, 33.6%).

1H NMR (400 MHz, DMSO<) δ 8.13 (s, 1H), 8.04 (s, 1H), 7.57-7.25 (m, 5H), 4.23-4.15 (m , 2H), 3.833.65 (m, 2H), 3.62-3.49 (m, 4H), 2.43-2.29 (m, 4H), 1.71-1.57 (m, 2H ), 1.47-1.33 (m, 2H), 0.90 (t, J=7.6 3H) ppm. MS: m/e 397 (M+1) ⁺ .

Compound A4: N ¹ -(5-((4-amino-2-butoxyimidazo [2,1-f][1,2,4]triazin-7-yl)methyl)pyridin-2-yl)N ¹ X2X ² -trimethylethane-1,2-diamine.

Step A: 6-((2-(dimethylamino)ethyl)amino)nicotinaldehyde.

A mixture of 6-chloronicotinaldehyde (1 g, 7.1 mmol), X,X^2-trimethylethane-1,2-diamine (0.87 g, 8.5 mmol) and DIEA (1.8 g, 14.2 mmol) in DMSO (10 ml) was heated at 90°C overnight. The solution was cooled and water (10 ml) was added, extracted with ethyl acetate (10 ml) and washed with brine (10 ml). The organic layer was dried, concentrated and purified using CombiFlash (DCM:MeOH=4%) to give the product as a red oil (0.8 g, 57%).

1H NMR (400 MHz, CDCl ₃ ) δ 9.76 (s, 1H), 8.54 (d, J=4.0 Hz, 1H), 7.90 (dd, J=8.0, 4.0 Hz, 1H), 6.55 (d, J=4.0 Hz, 1H), 3.77 (t, J=8.0 Hz, 2H), 3.17 (s, 3H), 2.53 ( t, J=8.0 Hz, 2H), 2.30 (s, 6H) ppm. MS:M/e 208 (M+1)+.

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

To a cooled solution of 7-bromo-2-butoxy-NX-bis(4-methoxybenzyl)imidazo[2,1P|1.2.4]triazin-4-amine (150 mg, 0.29 mmol) in THF (8 ml) at -78°C (purged with N2), n-BuLi (1.6 M, 0.5 ml) was added dropwise. After stirring at -78°C for 30 min, 6-((2(dimethylamino)ethyl)amino)nicotinaldehyde (88 mg, 0.43 mmol) in THF (2 ml) was added. The resulting mixture was stirred at this temperature for 30 minutes and heated to rt for 1 hour. 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 Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified using Combiflash (DCM:MeOH=20%) to give the pure product as a white solid (130 mg, 70%). MS: m/e 655 (M+1)+.

Step C: N ¹ -(5-((4-amino-2-butoxyimidazo [2,1-f][1,2,4]triazin-7 -yl)methyl)pyridin-2-yl)-N1,N ² ,N ² trimethylethane-1,2-diamine (compound A4).

Triethylsilane (1 ml) and trifluoroacetic acid (1 ml) were added to the solution of (4-(bis(4methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)( 6-((2(dimethylamino)ethyl)(methyl)amino)pyridin-3-yl)methanol (130 mg, 0.2 mmol) in DCM (2 ml). The mixture was heated at 80°C overnight. The solvent was evaporated to a residue, which was treated with NaHCO ₃ (5 ml), extracted with ethyl acetate (5 ml), washed with brine (5 ml). The organic layers were dried, concentrated and purified using CombiFlash (DCM:MeOH=8:1) to give the product (28 mg, 35%).

1H NMR (400 MHz, DMSO<) δ 8.13-8.05 (m, 3H), 7.52 (dd, J=8.0, 4.0 Hz, 1H), 7.27 (s, 1H ), 6.85 (d, J=8.0 Hz, 1H), 4.22 (t, J=8.0 Hz, 2H), 4.01 (s, 2H), 3.83 (t, J =8.0 Hz, 2H), 3.22 (s, 2H), 2.95 (s, 3H), 2.79 (s, 6H), 1.70-1.67 (m, 2H), 1 .44-1.39 (m, 2H), 0.93 (t, J=8.0 Hz, 3H) ppm. MS: m/e 399 (M+1)+.

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

Step A: 4-(piperidin-1-ylmethyl)benzaldehyde.

Piperidine (1.36 g, 16 mmol) and K2CO3 (4.17 g, 30 mmol) were added to a stirred solution of 4-(bromomethyl)benzaldehyde (3 g, 15 mmol) in MeCN (40 mL). After addition, the reaction mixture was stirred at rt overnight. The mixture was filtered. The filtrate was poured into H2O and extracted with EtOAc (15 mlx3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether/EAAc=1:1) to give the title product (2.7 g, 88%) as a yellow oil.

1H NMR (400 MHz, DMSO<) δ 9.99 (s, 1H), 7.83 (d, J=7.9 Hz, 2H), 7.50 (d, J=7.9 Hz, 2H) , 3.53 (s, 2H), 2.38 (s, 4H), 1.62-1.54 (m, 4H), 1.45 (d, J=4.9 Hz, 2H) ppm. MS:M/e 204 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7 -yl)(4- 24 046488 (piperidin-1 -ylmethyl )phenyl)methanol.

To a stirred solution of 7-bromo-2-butoxy-H,H-bis(4-methoxybenzyl)imidazo[2,1P|1,2,4|triazin-4-amine (150 mg, 0.3 mmol) in THF ( 10 ml), cooled to -78°C under nitrogen, n-BuLi (1.6 M in hexane, 0.75 mmol, 0.47 ml) was added dropwise. After stirring for 20 min, a solution of 4-(piperidin-1-ylmethyl)benzaldehyde (114 mg, 0.45 mmol) in THF (2 ml) was slowly added. The reaction mixture was warmed slowly to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated to give the product (270 mg, 100%), which was directly used in the next step without further purification. MS: m/e 651 (M+1)+.

Step C: 2-butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (compound A5).

A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4(piperidin-1-ylmethyl)phenyl)methanol ( 270 mg, 0.3 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) were stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (50 mg, 42%).

Ή NMR (400 MHz, DMSO-dg) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.30 (s, 1H), 7.24-7.17 (m, 4H) , 4.19 (t, J=6.5 Hz, 2H), 4.11 (s, 2H), 3.35 (s, 2H), 2.31-2.21 (m, 4H), 1, 70-1.61 (m, 2H), 1.45 (m, 4H), 1.42-1.31 (m, 4H), 0.91 (t, J=7.3 Hz, 3H) ppm. MS: m/e 395 (M+1)+.

Compound A6: 2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)imidazo[2.1G|[1.2.4|triazin-4-amine.

Step A: 4-((4-methylpiperazin-1-yl)methyl)benzaldehyde.

To a stirred solution of 4-(bromomethyl)benzaldehyde (3 g, 15 mmol) in MeCN (40 ml) was added piperidine (1.6 g, 16 mmol) and K ₂ CO ₃ (4.17 g, 30 mmol). After addition, the reaction mixture was stirred at rt overnight. The mixture was filtered. The filtrate was poured into H2O and extracted with EtOAc (15 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether/EAAc=1:1) to give 4-((4-methylpiperazin-1-yl)methyl)benzaldehyde (2.3 g, 71.8%) as a yellow oil colors. MS: m/e 219 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4-((4-methylpyrazine-1 -yl)methyl)phenyl)methanol.

To a stirred solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1G][1,2,4]triazin-4-amine (150 mg, 0.3 mmol) in THF ( 10 ml), cooled to -78°C, and n-BuLi (1.6 M in hexane, 0.75 mmol, 0.47 ml) was added dropwise under nitrogen atmosphere. After stirring for 20 minutes, a solution of 4-((4-methylpiperazin-1-yl)methyl)benzaldehyde (122 mg, 0.45 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated to give the product (300 mg, 100%), which was directly used in the next step without further purification. MS: m/e 666 (M+1)+.

Step C: 2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (compound A6) .

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4-((4-methylpiperazin-1-yl )methyl)phenyl)methanol (300 mg, 0.3 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (60 mg, 49.1%).

Ή NMR (400 MHz, DMSOD ₆ ) δ 8.13 (s, 1H), 8.03 (s, 1H), 7.30 (s, 1H), 7.24 (d, J=7.9 Hz, 2H), 7.19 (d, J=7.9 Hz, 2H), 4.19 (t, J=6.5 Hz, 2H), 4.11 (s, 2H), 3.38 (s, 2H), 3.21-2.17 (m, 8H), 2.12 (s, 3H), 1.71-1.59 (m, 2H), 1.45-1.33 (m, 2H) , 0.92 (t, J=7.4 Hz, 3H) ppm. MS: m/e 410 (M+1)+.

Compound A7: 2-butoxy-7 -(3 -(piperidin-1-ylmethyl)benzyl)imidazo[2,1-G][1,2,4]triazin-4-amine.

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(3(piperidin-1-ylmethyl)phenyl) methanol

To a stirred solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,11][1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF ( 10 ml) at -78°C under N2 atmosphere, n-BuLi (1.6 M, 0.60 ml, 0.96 mmol) was added. The solution was stirred at -78°C for 30 minutes. 3-(piperidin-1ylmethyl)benzaldehyde (116 mg, 0.57 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was heated to rt and then stirred for 3 hours. After completion

- 25 046488 the reaction mixture was quenched with H2O (20 ml) and extracted with DCM (20 mlx3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow oil, which was directly used in the next step without further purification. MS: m/e 651 (M+1)+.

Step B: 2-butoxy-7-(3-(piperidin-1-ylmethyl)benzyl)imidazo[2,1-£][1,2,4]triazin-4-amine (compound A7).

A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(3(piperidin-1-ylmethyl)phenyl)methanol ( crude) in TFA (2 ml) and triethylsilane (2 ml) were stirred at 80°C for 15 hours. The solution was concentrated under reduced pressure to remove triethylsilane. The precipitate was dissolved in TFA (2 ml) and stirred at 80°C overnight. After completion, the reaction mixture was quenched with aq. NaHCO ₃ (sat, 25 ml) and then extracted with DCM (20 ml x 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by pre-TLC with DCM:MeOH (10:1) to give the product (81.54 mg).

¹ H NMR (400 MHz, DMSOO δ 8.16 (s, 1H), 8.07 (s, 1H), 7.40 (d, J=8 Hz, 4H), 7.32 (s, 1H), 4.31-4.09 (m, 6H), 3.31-3.12 (m, 2H), 2.90-2.70 (m, 2H), 1.87-1.60 (m, 7H ), 1.45-1.28 (m, 3H), 0.91 (t, J=8 Hz, 3H) ppm MS: m/e 395 (M+1)+.

Compound A8: 2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)imidazo[2,1C[1,2,4]triazin-4-amine.

Step A: 6-bromo-2-isopropyl-1,2,3,4-tetrahydroisoquinoline.

Acetone (3 ml) and AcOH (10 drops) were added to a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (1.06 g, 5 mmol) in MeOH (3 ml). The mixture was then stirred at 80°C for 1.5 hours. The mixture was cooled to room temperature. NaBH ₃ CN (0.93 g, 15 mmol) was added in several portions and the resulting mixture was stirred at room temperature for 3 hours. The reaction was concentrated, diluted water (30 ml), extracted with EtOAc (50 mlx2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified using CombiFlash to obtain the title compound (450 mg, 36%) as an oil. MS: m/e 254 (M+1)+.

Step B: 2-isopropyl-1,2,3,4-tetrahydroisoquinoline-6-carbaldehyde.

To a solution of the product from step A (450 mg, 1.77 mmol) in THF (5 mL), n-BuLi (2.2 mL, 1.6 mol/L, 3.54 mmol) was added dropwise, maintaining the temperature between -75 to -65°C. After 30 minutes, DMF (258 mg, 3.54 mmol) was added dropwise and the resulting mixture was stirred at -65°C for 30 minutes. The reaction was quenched with saturated NH ₄ Cl solution, extracted with EtOAc (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography to give the title compound (250 mg, 69%) as an oil.

1H NMR (400 MHz, CDCl ₃ ) δ 9.94 (s, 1H), 7.68-7.60 (m, 2H), 7.20 (d, J=8.0 Hz, 1H), 3, 90-3.78 (m, 2H), 3.11-2.95 (m, 3H), 2.90-2.80 (m, 2H), 1.18 (d, J=6.4 Hz, 6H) ppm. MS: m/e 204 (M+1)+.

Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(2-isopropyl 1,2,3,4 -tetrahydroisoquinolin-6-yl)methanol.

To a solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (150 mg, 0.285 mmol) in THF (5 ml) n-BuLi (0.44 ml, 0.71 mmol) was added dropwise, maintaining the temperature between -75 and -65°C. After 30 minutes, a mixture of the product from step B (87 mg, 0.423 mmol) in THF (4 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature over 1 hour. The reaction was quenched with saturated NH ₄ Cl solution, extracted with EtOAc (80 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by column chromatography ₍ ΠΧΜΜόΟΗ=50/1) to obtain the title compound (60 mg, 32%). MS: m/e 651 (M+1)+.

Step D: 2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)imidazo[2,1C[1,2,4]triazin-4-amine (compound A8).

To a mixture of the product of step C (60 mg, 0.092 mmol) in TFA (2 ml) was added Et ₃ SiH (2 ml). The reaction was heated at 80°C for 2 hours. The mixture was concentrated to dryness and the residue was treated with TFA (4 ml). The reaction was heated at 85°C overnight. The mixture was concentrated and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the product (20 mg, 55%).

1H NMR (400 MHz, _DMSOD6 ) δ 8.11 (s, 1H), 8.02 (s, 1H), 7.27 (s, 1H), 6.85-6.15 (m, 3H), 4.20 (t, J=6.4 Hz, 2H), 4.05 (s, 2H), 3.57 (s, 2H), 2.91-2.76 (m, 1H), 2.74 - 2.60 (m, 4H), 1.74-1.62 (m, 2H), 1.47-1.34 (m, 2H), 1.03 (d, J=5.6 Hz, 6H ), 0.92 (t, J=7.2 Hz, 3H) ppm. MS: m/e 395 (M+1)+.

Compound A9: 2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)imidazo[2,1C[1,2,4]triazin-4-amine.

Step A: 7-bromo-2-isopropyl-1,2,3,4-tetrahydroisoquinoline.

Acetone (3 ml) and AcOH (10 drops) were added to a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (1.06 g, 5 mmol) in MeOH (3 ml). The mixture was then stirred at 80°C for 1.5 hours. The mixture was cooled to

- 26 046488 room temperature NaBH3CN (0.93 g, 15 mmol) was added in several portions and the resulting mixture was stirred at room temperature for 3 hours. The reaction was concentrated, diluted with water (30 ml), extracted with EtOAc (50 mlx2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and the residue purified by flash chromatography to give the title compound (930 mg, 73%) as an oil. MS: m/e 254 (M+1)+.

Step B: 2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-carbaldehyde.

To a solution of the product from step A (930 mg, 3.64 mmol) in THF (20 ml), a solution of n-BuLi (4.5 ml, 7.2 mmol) was added dropwise, maintaining the temperature in the range of -75 to -65° WITH. After 30 minutes, DMF (532 mg, 7.3 mmol) was added dropwise and the resulting mixture was stirred at -65°C for 30 minutes. The reaction was quenched with saturated NH ₄ Cl solution, extracted with EtOAc (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography to give the title compound (80 mg, 11%) as an oil. MS: m/e 204 (M+1)+.

Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(2-isopropyl 1,2,3,4 -tetrahydroisoquinolin-7-yl)methanol.

To a solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (150 mg, 0.285 mmol) in THF (5 ml) n-BuLi solution (0.44 ml, 0.71 mmol) was added dropwise, maintaining the temperature in the range from -75 to -65°C. After 30 minutes, a mixture of the product from step B (80 mg, 0.42 mmol) in THF (4 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature over 1 hour. The reaction was quenched with saturated NH ₄ Cl solution, extracted with EtOAc (80 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (DCM/MeOH = 40/1) to give the title compound (50 mg, crude). MS: m/e 651 (M+1)+.

Step D: 2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)imidazo[2,1Al,2,4]triazin-4-amine (compound A9) .

To a mixture of the product from step C (50 mg, crude) in TFA (3 ml) was added Et3SiH (1 ml). The reaction was heated at 85°C overnight. The mixture was concentrated and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the product (20 mg, 12% in the water step).

1H NMR (400 MHz, DMSO-de) δ 8.19-7.98 (m, 2H), 7.28 (s, 1H), 7.10-6.65 (m, 3H), 4.20 ( t, J=6.4 Hz, 2H), 4.05 (s, 2H), 3.56 (s, 2H), 2.85-2.76 (m, 1H), 2.74-2.62 (m, 4H), 1.74-1.62 (m, 2H), 1.49-1.34 (m, 2H), 1.02 (d, J=6.4 Hz, 6H), 0, 92 (t, J=7.6 Hz, 3H) ppm. MS: m/e 395 (M+1)+.

Compound A10: 2-butoxy-7-(4-(piperazin-1-ylmethyl)benzyl)imidazo[2,1-1][1,2,4]triazin-4amine.

Step A: tert-butyl 4-(4-formylbenzyl)piperazine-1-carboxylate.

To a stirred solution of 4-(bromomethyl)benzaldehyde (4 g, 20 mmol) in THF (40 mL) was added tert-butylpiperazine-1-carboxylate (4.6 g, 25 mmol) and DIEA (5.04 g, 40 mmol) . After addition, the reaction mixture was stirred at rt overnight. The mixture was filtered. The filtrate was poured into H2O and extracted with EtOAc (15 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether/ESAAc=1:1) to give tert-butyl 4-(4formylbenzyl)piperazine-1-carboxylate (4.1 g, 68%) as a yellow oil. MS: m/e 305 (M+1)+.

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

To a stirred solution of 7-bromo-2-butoxy-H,Nbis(4-methoxybenzyl)imidazo[2,1E][1,2,4]triazin-4-amine (150 mg, 0.3 mmol) in THF ( 10 ml), cooled to -78°C and under nitrogen, n-BuLi (1.6 M in hexane, 0.75 mmol, 0.47 ml) was added dropwise. After stirring for 20 min, a solution of 4-(4-formylbenzyl)piperazine-1-carboxylate (137 mg, 0.45 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated to give the product (270 mg, 100%), which was directly used in the next step without further purification. MS: m/e 752 (M+1)+.

Step C: 2-butoxy-7-(4-(piperazin-1-ylmethyl)benzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (compound A10).

Solution of tert-butyl-4-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7yl)(hydroxy)methyl) benzyl)piperazine-1-carboxylate (270 mg, 0.3 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified using pre-HPLC with

- 27 046488 by obtaining the product (40 mg, 33.8%).

¹ H NMR (400 MHz, DMSO-dg) δ 8.13 (s, 1H), 8.03 (s, 1H), 7.30 (s, 1H), 7.24 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 4.19 (t, J=6.4 Hz, 2H), 4.11 (s, 2H), 3.40 (s, 2H) , 2.71-2.61 (m, 4H), 2.32-2.28 (m, 4H), 1.65 (dd, J=14.2, 6.8 Hz, 2H), 1.42 -1.36 (m, 2H), 0.92 (t, J=7.3 Hz, 3H) ppm. MS: m/e 396 (M+1)+.

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

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1T][1,2,4]triazin-7-yl)(3(pyrrolidin-1 -ylmethyl)phenyl) methanol

To a stirred solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1H[1.2.4|triazin-4-amine (170 mg, 0.32 mmol) in THF (10 ml) n-BuLi (1.6 M, 0.51 mL, 0.82 mmol) was added at -78°C under N2. The solution was stirred at -78°C for 30 minutes. 3-(pyrrolidin-1ylmethyl)benzaldehyde (92 mg, 0.49 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was warmed to rt and then stirred for 3 hours. Once complete, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml x 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure. The precipitate was purified by pre-TLC PE:EA (1:1) to give the product (120 mg, 58%) as an off-white oil. MS: m/e 637 (M+1)+.

Step B: 2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (compound A11).

A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1T][1,2,4]triazin-7-yl)(3(pyrrolidin-1-ylmethyl)phenyl)methanol ( 120 mg, 0.19 mmol) in TFA (2 ml) and triethylsilane (2 ml) were stirred at 80°C for 15 hours. The solution was concentrated under reduced pressure to remove triethylsilane. The precipitate was dissolved in TFA (2 ml) and stirred at 80°C overnight. After completion, the reaction mixture was quenched with aq. NaHCO ₃ (sat, 25 ml) and then extracted with DCM (20 ml x 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by pre-TLC with DCM:MeOH (10:1) to give the product (15.11 mg, 21%).

1H NMR (400 MHz, DMSOD ₆ ) δ 8.11 (s, 1H), 8.02 (s, 1H), 7.43-7.11 (m, 5H), 4.26 (s, 2H), 4.18 (t, J=8 Hz, 2H), 3.65 (s, 2H), 2.40 (s, 4H), 1.73-1.60 (m, 6H), 1.42-1 .35 (m, 2H), 0.91 (t, J=8 Hz, 3H) ppm. MS: m/e 381 (M+1)+.

Connection A12:

2-butoxy-7-(3-(morpholinomethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine.

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1T][1,2,4]triazin-7-yl)(3(morpholinomethyl)phenyl)methanol.

To a stirred solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1L[1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF (10 ml) at -78°C under N2 atmosphere, n-BuLi (1.6 M, 0.60 ml, 0.96 mmol) was added. The solution was stirred at -78°C for 30 minutes. 3(morpholinomethyl)benzaldehyde (117 mg, 0.57 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was warmed to rt and then stirred for 3 hours. Once complete, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml x 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow oil, which was directly used in the next step without further purification. MS: m/e 653 (M+1)+.

Step B: 2-butoxy-7-(3-(morpholinomethyl)benzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (compound A12).

A solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1T][1,2,4]triazin-7-yl)(3(morpholinomethyl)phenyl)methanol (crude) in TFA (2 ml) and triethylsilane (2 ml) were stirred at 80°C for 15 hours. The solution was concentrated under reduced pressure to remove triethylsilane. The precipitate was dissolved in TFA (2 ml) and stirred at 80°C overnight. After completion, the reaction mixture was quenched with aq. NaHCO ₃ (sat., 25 ml) and then extracted with DCM (20 ml x 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by pre-TLC DCM:MeOH (10:1) to give the product (59.43 mg).

1H NMR (400 MHz, DMSO^) δ 8.13 (s, 1H), 8.04 (s, 1H), 7.30-7.13 (m, 5H), 4.19 (t, J=8 Hz, 2H), 4.13 (s, 2H), 3.53 (s, 4H), 3.40 (s, 2H), 2.30 (s, 4H), 1.74-1.63 (m , 2H), 1.45-1.34 (m, 2H), 0.92 (t, J=8 Hz, 3H) ppm. MS: m/e 397 (M+1)+.

Compound A13: 2-butoxy-7 -(3 -((4-methylpiperazin-1 -yl)methyl)benzyl)imidazo[2,1L[1,2,4]triazin-4-amine.

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1T][1,2,4]triazin-7-yl)(3-((4-methylpiperazine-1 -yl)methyl)phenyl)methanol.

To a stirred solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1L[1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF (10 ml) at -78°C under N2 atmosphere, n-BuLi (1.6 M, 0.60 ml, 0.96 mmol) was added. The solution was stirred at -78°C for 30 minutes. 3-((4-methylpiperazine-1

- 28 046488 yl)methyl)benzaldehyde (124 mg, 0.57 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was warmed to rt and then stirred for 3 hours. Once complete, the reaction mixture was quenched with H ₂ O (20 ml) and then extracted with DCM (20 ml x 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a green oil, which was directly used in the next step without further purification. MS: m/e 666 (M+1)+.

Step B: 2-butoxy-7-(3 -((4-methylpiperazin-1 -yl)methyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (compound A13) .

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(3-((4-methylpiperazin-1-yl )Methyl)phenyl)methanol (crude) in TFA (2 ml) and triethylsilane (2 ml) was stirred at 80°C for 15 hours. The solution was concentrated under reduced pressure to remove triethylsilane. The precipitate was dissolved in TFA (2 ml) and stirred at 80°C overnight. After completion, the reaction mixture was quenched with aq. NaHCO ₃ (sat, 25 ml) and then extracted with DCM (20 ml x 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by pre-TLC DCM:MeOH (10:1) to give the product (49.03 mg).

¹ H NMR (400 MHz, DMSO-b6) δ 8.13 (s, 1H), 8.06 (s, 1H), 7.31-7.15 (m, 5H), 4.20 (t, J =8 Hz, 2H), 4.13 (s, 2H), 3.50 (s, 2H), 3.31-2.82 (m, 6H), 2.72 (s, 3H), 2.43 - 2.13 (m, 2H), 1.73-1.61 (m, 2H), 1.48-1.34 (m, 2H), 0.92 (t, J=8 Hz, 3H) ppm . MS: m/e 410 (M+1)+.

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

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1T][1,2,4]triazin-7-yl)(2(morpholinomethyl)phenyl)methanol.

To a solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1-1G][1,2,4]triazin-4-amine (150 mg, 0.29 mmol) in THF (5 ml) was added dropwise n-butyllithium (0.27 ml, 0.43 mmol) at -78°C and stirred for 1 hour. Then a solution of 2-(morpholinomethyl)benzaldehyde ( 88 mg, 0.43 mmol) in THF (2 ml), after addition the mixture was stirred at 60°C overnight. The mixture was quenched with saturated ammonium chloride solution (5 ml), extracted with DCM (30 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (.3XM/MeOH=20:1~5:1) to give the title product (83 mg, 44.6%) in in the form of a yellow oil. MS: m/e 653 (M+1)+.

Step B: 2-butoxy-7-(2-(morpholinomethyl)benzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (compound A14).

Mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(2(morpholinomethyl)phenyl)methanol (83 mg, 0 .13 mmol) and triethylsilane (1 ml) in TFA (2 ml) were stirred at 90°C overnight. The mixture was concentrated and purified by pre-HPLC to give the desired product (23 mg, 46%).

1H NMR (400 MHz, DMSOO δ 8.12 (s, 1H), 8.02 (s, 1H), 7.29-7.15 (m, 4H), 7.09 (s, 1H), 4, 27 (s, 2H), 4.18 (t, J=6.6 Hz, 2H), 3.51 (s, 2H), 3.40 (s, 4H), 2.28 (s, 4H), 1.71-1.60 (m, 2H), 1.46-1.32 (m, 2H), 0.91 (t, J=7.4 Hz, 3H) ppm MS: m/e 397 ( M+1)+.

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

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1T][1,2,4]triazin-7-yl)(2(piperidin-1-ylmethyl)phenyl) methanol

To a solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (150 mg, 0.29 mmol) in THF (5 ml), n-butyllithium (0.27 ml, 0.43 mmol) was added dropwise at -78°C and stirred for 1 hour. Then a solution of 2-(piperidin-1ylmethyl) was added dropwise at -78°C )benzaldehyde (87 mg, 0.43 mmol) in THF (2 ml), after addition the mixture was heated to 60°C and stirred overnight. The mixture was quenched with saturated ammonium chloride solution (5 ml), extracted with DCM (30 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by ^XM/MeOH=20:1~5:1 column chromatography to give the product (79 mg, 43%) as a yellow oil. . MS: m/e 651 (M+1)+.

Step B: 2-butoxy-7-(2-(piperidin-1-ylmethyl)benzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (compound A15).

Mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(2-(piperidin1-ylmethyl)phenyl)methanol (79 mg, 0.12 mmol) and triethylsilane (1 ml) in TFA (2 ml) were stirred at 90°C overnight. The mixture was concentrated and purified by pre-HPLC to give the title product (19 mg, 40%).

1H NMR (400 MHz, DMSOO δ 8.10 (s, 1H), 8.01 (s, 1H), 7.25-7.15 (m, 4H), 7.09 (s, 1H), 4, 26 (s, 2H), 4.18 (t, J=6.3 Hz, 2H), 3.45 (s, 2H), 2.28-2.13 (m, 4H), 1.70-1 .62 (m, 2H), 1.47-1.30 (m, 8H), 0.91 (t, J=7.3 Hz, 3H) ppm MS: m/e 395 (M+1)+ .

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

- 29 046488 amin.

Step A: (4-(bis(4-methoxybenzyl)amino)-2-isobutoxyimidazo[2,1-P[1,2,4|triazin-7-yl)(3-(pyrrolidin-1 -ylmethyl)phenyl )methanol.

To a stirred solution of 7-bromo-2-isobutoxy-H.H-bis(4-methoxybenzyl)imidazo[2.11][1,2,4]triazin-4-amine (180 mg, 0.34 mmol) in THF (10 ml) at -78°C under N2 atmosphere, n-BuLi (1.6 M, 0.54 ml, 0.86 mmol) was added. The solution was stirred at -78°C for 30 minutes. 3-(pyrrolidin-1ylmethyl)benzaldehyde (97 mg, 0.51 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was warmed to rt and then stirred for 3 hours. Once complete, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml x 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow oil, which was directly used in the next step without further purification. MS: m/e 637 (M+1)+.

Step B: 2-isobutoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (compound A16).

Solution (4-(bis(4-methoxybenzyl)amino)-2-isobutoxyimidazo[2,1-G|[1,2,4]triazin-7-yl)(3-(pyrrolidin-1-ylmethyl)phenyl) methanol (crude) in TFA (2 ml) and triethylsilane (2 ml) were stirred at 80°C for 15 hours. The solution was concentrated under reduced pressure to remove triethylsilane. The precipitate was dissolved in TFA (2 ml) and stirred at 80°C overnight. After completion, the reaction mixture was quenched with aq. NaHCO ₃ (sat, 25 ml) and then extracted with DCM (20 ml x 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by pre-TLC with DCM:MeOH (10:1) to give the product (24.30 mg).

Ή NMR (400 MHz, DMSO-dg) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.32-7.14 (m, 5H), 4.27 (s, 2H) , 3.96 (d, J=4 Hz, 2H), 3.67 (s, 2H), 2.41 (s, 4H), 2.05-1.94 (m, 1H), 1.63 ( s, 4H), 0.96 (s, 3H), 0.94 (s, 3H) ppm. MS: m/e 381 (M+1)+.

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

Step A: 7-bromo-N,N-bis(4-methoxybenzyl)-2-(2-methoxyethoxy)imidazo[2,1-f][1,2,4]triazin-4-amine.

Na (approximately 0.6 g) was added in small pieces to a solution of 2-methoxyethan-1-ol (6 g, 79 mmol). To the resulting mixture (5 ml) was added 7-bromo-2-chloro-N,Nbis(4methoxybenzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (250 mg, 0.51 mmol). The mixture was then stirred at 80°C for 3 hours. The mixture was concentrated, diluted with water (30 ml), extracted with EtOAc (80 ml), washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and the residue was purified using CombiFlash with obtaining the target compound (200 mg, 75%).

Ή NMR (400 MHz, CDC13) δ 7.47 (s, 1H), 7.20 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 4H), 5.60 (s, 2H), 4.86 (s, 2H), 4.52 (t, J=4.8 Hz, 2H), 3.80 (s, 6H), 3.77 (t, J=4.8 Hz, 2H), 3.42 (s, 3H) ppm. MS: m/e 528 (M+1)+.

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

To a solution of the product from step A (200 mg, 0.38 mmol) in THF (10 ml), a solution of n-BuLi (0.6 ml, 0.9 mmol) was added dropwise, maintaining the temperature in the range from -75 to -65° WITH. After 1.5 h, a solution of 3-(pyrrolidin-1-ylmethyl)benzaldehyde (107 mg, 0.57 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature over 1 hour. The reaction was quenched with saturated NH4C1 solution, extracted with EtOAc (50 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated . The precipitate was purified using CombiFlash to give a solid (150 mg, 62%). MS: m/e 639 (M+1)+.

Step C: 2-(2-methoxyethoxy)-7 -(3 -(pyrrolidin-1 -ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4amine (compound A17).

To a mixture of the product of step B (150 mg, 0.235 mmol) in TFA (6 ml) was added Et ₃ SiH (2 ml). The reaction was heated at 80°C for 16 hours. The mixture was concentrated to dryness and the residue was treated with TFA (6 ml). The reaction was heated at 85°C overnight. The mixture was concentrated and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the product (48 mg, 53%).

Ή NMR (400 MHz, CD3OD) δ 7.37 (t, J=6.0 Hz, 1H), 7.30-7.15 (m, 4H), 4.42 (t, J=4.8 Hz , 2H), 4.33 (s, 2H), 4.05-3.88 (m, 2H), 3.69 (t, J=4.8 Hz, 2H), 3.38 (s, 3H) , 3.01-2.61 (m, 4H), 1.95-1.71 (m, 4H) ppm. MS: m/e 383 (M+1)+.

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

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

To a stirred solution of 7-bromo-N^-bis(4-methoxybenzyl)-2-(4,4,4-trifluorobutoxy)

- 30 046488 uMuga3o[2,1-f][1,2,4]ipua3UH-4-amine (130 mg, 0.22 mmol) in THF (10 ml) at -78°C in an atmosphere of N ₂ was added n- BuLi (1.6 M, 0.35 ml, 0.56 mmol). The solution was stirred at -78°C for 30 minutes. 3(pyrrolidin-1-ylmethyl)benzaldehyde (64 mg, 0.34 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was warmed to rt and then stirred for 3 hours. Once complete, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml x 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow oil, which was directly used in the next step without further purification. MS: m/e 691 (M+1)+.

Step B: 7-(3 -(pyrrolidin-1 -ylmethyl)benzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1,2,4]triazin4-amine (compound A18 ).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-G|[1,2,4]triazin-7yl)(3-(pyrrolidin- 1-ylmethyl)phenyl)methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) was stirred at 80°C for 24 hours. Once complete, the reaction mixture was quenched with aq. NaHCO ₃ (sat, 25 ml) and then extracted with DCM (20 ml x 3). The organic phase was concentrated under reduced pressure and the resulting mixture was purified by pre-TLC DCM:MeOH (10:1) to give the product (19.75 mg).

1H NMR (400 MHz, DMSO<) δ 8.18 (s, 1H), 8.08 (s, 1H), 7.28-7.13 (m, 5H), 4.26 (s, 4H), 3.63 (s, 2H), 2.48-2.25 (m, 6H), 2.01-1.89 (m, 2H), 1.88-1.51 (m, 4H) ppm. MS: m/e 435 (M+1)+.

Compound A19: 2-butoxy-7-(2-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-(][1,2,4]triazin-4amine.

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

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) at -78°C, n-butyllithium (0.27 ml, 0.43 mmol) was added dropwise and stirred for 1 hour. Then a solution of 2-(pyrrolidin-1ylmethyl) was added dropwise at -78°C )benzaldehyde (81 mg, 0.43 mmol) in THF (2 ml), after addition the mixture was heated to 60°C and stirred overnight. The mixture was quenched with saturated ammonium chloride solution (5 ml), extracted with DCM (30 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (DCM/MeOH=20:1~5:1) to give the title product (67 mg, 37%) as a yellow oil colors. MS: m/e 637 (M+1)+.

Step B: 2-butoxy-7-(2-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-(][1,2,4]triazin-4-amine (compound A19).

Mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(2-(pyrrolidin1-ylmethyl)phenyl)methanol (67 mg, 0.11 mmol) and triethylsilane (1 ml) in TFA (2 ml) were stirred at 90°C overnight. The mixture was concentrated and purified by pre-HPLC to give the title product (15 mg, 38%).

1H NMR (400 MHz, DMSO-de) δ 8.22-8.03 (m, 2H), 7.44-7.15 (m, 5H), 4.55 (s, 1H), 4.28 ( s, 2H), 4.17 (t, J=6.6 Hz, 2H), 3.71-3.38 (m, 2H), 3.17 (s, 1H), 2.42-2.32 (m, 2H), 2.05-1.74 (m, 2H), 1.70-1.56 (m, 4H), 1.38 (dt, J=14.6, 7.4 Hz, 2H ), 0.91 (t, J=7.4 Hz, 3H) ppm. MS: m/e 381 (M+1)+.

Compound A20: 2-butoxy-7 -(2-fluoro-4-(pyrrolidin-1 -ylmethyl)benzyl)imidazo[2,1GC1,2,4]triazin-4-amine.

Step A: 2-fluoro-4-(pyrrolidin-1-ylmethyl)benzonitrile.

To a stirred solution of 2-fluoro-4-formylbenzonitrile (447 mg, 3 mmol) in MeOH (5 ml) was added pyrrolidine (234 mg, 3.3 mmol), then the mixture was stirred for 2 hours followed by the addition of NaBH ₃ CN (378 mg, 6 mmol). After addition, the reaction mixture was concentrated to give a precipitate, which was purified by column chromatography (petroleum ether/EAAc=2:1) to give the title compound (400 mg, 65.4%) as a yellow oil. MS: m/e 205 (M+1)+.

Step B: 2-fluoro-4-(pyrrolidin-1-ylmethyl)benzaldehyde.

To a stirred solution of the product from step A (400 mg, 1.96 mmol) in dry THF (10 ml) was added dropwise DIBAL-H (1.2 M, 4 ml, 4.9 mmol) at -20°C. After addition, the reaction was stirred for 3 hours at room temperature. The reaction was quenched with aq. NH4C1, extracted with EtOAc (20 mlx3) and filtered. The filtrate was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=3:1~1:1) to obtain the title compound (182 mg, 44.3%) as an oil light yellow color. MS: m/e 208 (M+1) ⁺ .

Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(2-fluoro-4(pyrrolidin-1- ylmethyl)phenyl)methanol.

To a stirred solution of 7-bromo-2-butoxy-NiNbis(4-methoxybenzyl)imidazo[2,1HZ1,2,4]triazin-4-amine (150 mg, 0.285 mmol) in THF (10 ml) at -78 °C n-BuLi (0.44 ml, 0.71 mmol) was added dropwise. After stirring for an hour, a solution of the product from step B (88.7 mg, 0.428 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then heated

- 31 046488 brought to room temperature for 1 hour. The reaction was quenched by us. aq. NH ₄ Cl solution, extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by pre-TLC (petroleum ether/EAAc=1:1) to give the title compound (60 mg, 32%). MS: m/e 655 (M+1)+.

Step D: 2-butoxy-7-(2-fluoro-4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (compound A20).

A mixture of the product from step C (60 mg, 0.092 mmol) in Et ₃ SiH/TFA (0.5 ml/2 ml) was stirred at 80° C. overnight. The reaction mixture was concentrated to give the product, which was purified by pre-HPLC to give the title compound (23 mg, 62.8).

^1H NMR (400 MHz, DMSO-b6) δ 8.16 (s, 1H), 8.05 (s, 1H), 7.27 (s, 1H), 7.23-7.19 (m, 1H ), 7.11-7.04 (m, 2H), 4.19-4.13 (m, 4H), 3.53 (s, 2H), 2.42-2.31 (m, 4H), 1.72-1.61 (m, 6H), 1.42-1.36 (m, 2H), 0.91 (t, J=7.6 Hz, 3H) ppm. MS: m/e 399 (M+1)+.

Compound A21: 2-butoxy-7-(4-(3 -(piperidin-1-yl)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin4-amine.

Step A: 4-(3-bromopropoxy)benzaldehyde.

A solution of 4-hydroxybenzaldehyde (2 g, 16 mmol), 3-bromopropan-1-ol (2.3 g, 16 mmol) and triphenylphosphane (6.3 g, 24 mmol) in dry THF (60 ml) at 0°C treated with DTAD (5.5 g, 24 mmol) in portions. The reaction mixture was slowly warmed to rt overnight. The solution was quenched with water (20 ml), extracted with ethyl acetate (20 ml) and washed with brine (20 ml). The organic layers were dried, concentrated and purified using CombiFlash (PE:EA=15:1) to give the product (1.3 g, 33%).

1H NMR (400 MHz, DMSOO δ 9.88 (s, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.16 (d, J=12.0 Hz, 2H), 4 .21 (t, J=8.0 Hz, 2H), 3.68 (t, J=8.0 Hz, 2H), 2.32-2.27 (m, 2H) ppm. MS: m/e 243 (M+1)+.

Step B: 4-(3-(piperidin-1-yl)propoxy)benzaldehyde.

A mixture of 4-(3-bromopropoxy)benzaldehyde (200 mg, 0.8 mmol), piperidine (136 mg, 1.6 mmol), sodium carbonate (170 mg, 1.6 mmol) and potassium iodide (17 mg, 0. 1 mmol) in n-BuOH (5 ml) was heated at 105°C for 4 hours. The solution was cooled, quenched with water (10 ml) and extracted with dichloromethane (10 ml). The organic layer was dried, concentrated and purified using CombiFlash (DCM:MeOH=8%) to give the product (190 mg, 93%). MS: m/e 248 (M+1)+.

Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4-(3(piperidin-1-yl )propoxy)phenyl)methanol.

To a cooled solution of 7-bromo-2-butoxy-XNibis(4-methoxybenzyl)imidazo[2,1Al,2,4]triazin-4-amine (200 mg, 0.4 mmol) in THF (8 ml) at -78°C (purged with N2), n-BuLi (1.6 M, 0.7 ml) was added dropwise. After stirring at -78°C for 30 min, 4-(3(piperidin-1-yl)propoxy)benzaldehyde (148 mg, 0.6 mmol) in THF (2 ml) was added. The resulting mixture was stirred at this temperature for 30 min and then heated to rt for 1 h. The solution was quenched with NH4Cl solution (5 ml), extracted with ethyl acetate (10 ml) and washed with brine (10 ml). The organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified using Combiflash (DCM:MeOH=5%) to give the pure product (140 mg, 37%). MS: m/e 695 (M+1)+.

Step D: 2-butoxy-7-(4-(3 -(piperidin-1-yl)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (compound A21) .

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(4-(3(piperidin-1-yl)propoxy )phenyl)methanoltriethylsilane (140 mg, 0.2 mmol) in trifluoroacetic acid (3 ml) and triethylsilane (1 ml) were heated at 80°C overnight. The solvent was evaporated to obtain a precipitate, which was made alkaline with a solution of NaHCO ₃ , extracted with ethyl acetate (5 ml), washed with saline solution (5 ml). The organic layer was dried, concentrated and purified using CombiFlash (DCM:MeOH=8%) to give the product (35 mg, 40%).

1H NMR (400 MHz, DMSOL) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.25 (s, 1H), 7.21 (d, J=8.0 Hz, 2H ), 6.84 (d, J=8.0 Hz, 2H), 4.20 (t, J=8.0 Hz, 2H), 4.06 (s, 2H), 3.97-3.95 (m, 2H), 2.49-2.20 (m, 4H), 2.18-1.75 (m, 3H), 1.67-1.38 (m, 11H), 0.91 (t , J=7.6 Hz, 3H) ppm. MS: m/e 439 (M+1)+.

Compound A22: 2-butoxy-7-(4-(3-morpholinopropoxy)benzyl)imidazo[2,1-1][1,2,4]triazin-4amine.

Step A: 4-(3-morpholinopropoxy)benzaldehyde.

A mixture of 4-(3-bromopropoxy)benzaldehyde (300 mg, 1.2 mmol), morpholine (209 mg, 2.4 mmol) and potassium carbonate (193 mg, 2.4 mmol) in acetonitrile (10 ml) was heated at 80 °C overnight. The solution was cooled, concentrated, water (10 ml) was added and extracted with ethyl acetate (10 ml). The organic layer was dried, concentrated and purified using CombiFlash (DCM:MeOH=8%) to give the product as a colorless oil (260 mg, 84%).

1H NMR (400 MHz, DMSOO δ 9.87 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 4 .13 (t, J=8.0 Hz, 2H), 3.59-3.51 (m, 4H), 2.44-2.36 (m, 6H), 1.99-1.87 (m , 2H) ppm MS: m/e 250 (M+1)+.

- 32 046488

Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(4-(3morpholinopropoxy)phenyl)methanol.

To a cooled solution of 7-bromo-2-butoxy-H,H-bis(4-methoxybenzyl)imidazo[2,1P[1,2,4|triazin-4-amine (200 mg, 0.4 mmol) in THF ( 8 ml) at -78°C (purged with N2), n-BuLi (1.6 M, 0.7 ml) was added dropwise. After stirring at -78°C for 30 min, 4-(3morpholinopropoxy)benzaldehyde (150 mg, 0.6 mmol) in THF (2 ml) was added. The resulting mixture was stirred at this temperature for 30 min, and then heated to rt for 1 h. The solution was quenched with NH4C1 solution (5 ml), extracted with ethyl acetate (10 ml) and washed with brine (10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified using Combiflash (DCM:MeOH=6%) to give the pure product (190 mg, 71%). MS: m/e 697 (M+1)+.

Step C: 2-butoxy-7-(4-(3-morpholinopropoxy)benzyl)imidazo[2,1-£][1,2,4]triazin-4-amine (compound A22).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(4-(3morpholinopropoxy)phenyl)methanol (190 mg, 0.27 mmol) in trifluoroacetic acid (2 ml) and triethylsilane (2 ml) were heated at 80°C for 1 hour. After concentration, trifluoroacetic acid (2 ml) was added to the precipitate and the mixture was heated at 80°C overnight. The solvent was evaporated to obtain a precipitate, which was made alkaline with a solution of NaHCO ₃ , ethyl acetate (5 ml), and washed with saline solution (5 ml). The organic layer was dried, concentrated and purified using CombiFlash (DCM:MeOH=8%) to give the product (84 mg, 70%).

Ή NMR (400 MHz, DMSO-de) δ 8.12 (s, 1H), 8.02 (s, 1H), 7.25 (s, 1H), 7.20 (d, J=8.0 Hz , 2H), 6.83 (d, J=8.0 Hz, 2H), 4.20 (t, J=8.0 Hz, 2H), 4.05 (s, 2H), 3.95 (t , J=8.0 Hz, 2H), 3.55 (t, J=4.0 Hz, 4H), 2.40-2.34 (m, 6H), 1.87-1.81 (m, 2H), 1.68-1.63 (m, 2H), 1.43-1.37 (m, 2H), 0.92 (t, J=8.0 Hz, 3H) ppm. MS: m/e 441 (M+1)+.

Compound A23: 2-butoxy-7-(3 -(3 -(dimethylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin4-amine.

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(3 -(3 (dimethylamino)propoxy)phenyl )methanol.

To a stirred solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1P[1.2.4|triazin-4-amine (180 mg, 0.34 mmol) in THF (10 ml) at -78°C under N2, n-BuLi (1.6 M, 0.54 mL, 0.86 mmol) was added. The solution was stirred at -78°C for 30 minutes. 3-(3(dimethylamino)propoxy)benzaldehyde (71 mg, 0.34 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was warmed to rt and then stirred for 3 hours. Once complete, the reaction mixture was quenched with H ₂ O (20 ml) and extracted with DCM (20 ml x 3 ). The organic phase was washed with H ₂ O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow oil, which was directly used in the next step without further purification. MS: m/e 655 (M+1)+.

Step B: 2-butoxy-7-(3 -(3 -(dimethylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine.

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(3-(3(dimethylamino)propoxy)phenyl)methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) was stirred at 80°C for 24 hours. After completion, the reaction mixture was quenched with aq. NaHCO ₃ (sat, 25 ml) and then extracted with DCM (20 ml x 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by pre-TLC with DCM:MeOH (10:1) to give the product (18.32 mg).

Ή NMR (400 MHz, DMSO-b6) δ 8.15 (s, 1H), 8.08 (s, 1H), 7.31 (s, 1H), 7.23 (t, J=8 Hz, 1H ), 6.91 (d, J=8 Hz, 1H), 6.85 (s, 1H), 6.80 (d, J=8 Hz, 1H), 4.21 (t, J=8 Hz, 2H), 4.12 (s, 2H), 4.00 (t, J=8 Hz, 2H), 3.17 (t, J=8 Hz, 2H), 2.78 (s, 6H), 2 ,13-2.03 (m, 2H), 1.72-1.64 (m, 2H), 1.45-1.36 (m, 2H), 0.93 (t, J=8 Hz, 3H ) ppm. MS: m/e 399 (M+1)+.

Compound A24: 2-butoxy-7 -(3 -(3 -(dimethylamino)propoxy)-4-fluorobenzyl)imidazo[2,1£][1,2,4]triazin-4-amine.

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

To a stirred solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1£][1,2,4]triazin-4-amine (257 mg, 0.49 mmol in THF ( 10 ml) at -78°C under N2 atmosphere, n-BuLi (1.6 M, 0.76 ml, 1.22 mmol) was added. The solution was stirred at -78°C for 30 minutes. 3-(3(dimethylamino )propoxy)-4-fluorobenzaldehyde (110 mg, 0.49 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was heated to rt and then stirred for 3 hours. Once complete, the reaction mixture was quenched with H ₂ O (20 ml) and then extracted with DCM (20 ml x 3) The organic phase was washed with H ₂ O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow oil, which was directly used in the next step without further purification MS: m/e 673 (M+1)+.

Step B: 2-butoxy-7-(3 -(3 -(dimethylamino)propoxy)-4-fluorobenzyl)imidazo[2,1-f][1,2,4]triazine-4

- 33 046488 amine (compound A24).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(3-(3(dimethylamino)propoxy)-4- fluorophenyl)methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) were stirred at 80°C for 24 hours. After completion, the reaction mixture was quenched with aq. NaHCO ₃ (sat, 25 ml) and then extracted with DCM (20 ml x 3). The organic phase was concentrated under reduced pressure and the resulting residue was purified by pre-TLC DCM:MeOH (10:1) to give the product (43.52 mg).

^1H NMR (400 MHz, DMSO-de) δ 8.14 (s, 1H), 8.06 (s, 1H), 7.29 (s, 1H), 7.22-7.08 (m, 2H ), 6.92-6.83 (m, 1H), 4.20 (t, J=8 Hz, 2H), 4.11 (s, 2H), 4.08 (t, J=8 Hz, 2H ), 3.15 (t, J=8 Hz, 2H), 2.75 (s, 6H), 2.18-2.06 (m, 2H), 1.72-1.61 (m, 2H) , 1.45-1.34 (m, 2H), 0.92 (t, J=8 Hz, 3H) ppm. MS: m/e 417 (M+1)+.

Compound A25: 2-butoxy-7-((4'-(pyrrolidin-1 -ylmethyl)-[1,1'-biphenyl]-3 -yl)methyl)imidazo [2,1G][1,2,4] triazine-4-amine.

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

To a solution of 7-bromo-2-butoxy-Nibis(4-methoxybenzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (150 mg, 0.29 mmol) in THF ( 5 ml), n-butyllithium (0.27 ml, 0.43 mmol) was added dropwise at -78°C under N2 and stirred for 1 hour. Then a solution of 4'-( pyrrolidin-1ylmethyl)-[1,1'-biphenyl]-3-carbaldehyde (114 mg, 0.4278 mmol) in THF (2 ml) after addition the mixture was warmed to rt and stirred for 3 hours. The mixture was quenched with saturated chloride solution ammonium (5 ml), extracted with DCM (30 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (DCM/MeOH=20:1~5:1) to give the title product (103 mg, 51%) as a yellow oil colors. MS: m/e 713 (M+1)+.

Step B: 2-butoxy-7-((4'-(pyrrolidin-1 -ylmethyl)-[1,1'-biphenyl]-3 -yl)methyl)imidazo [2.1G]|1.2.4]triazin- 4-amine (compound A25).

Mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4'(pyrrolidin-1-ylmethyl)-[1 ,1'-biphenyl]-3-yl)methanol (103 mg, 0.1447 mmol) and triethylsilane (1 ml) in TFA (2 ml) were stirred at 90°C overnight. The mixture was concentrated and purified by pre-HPLC to give the target product (50 mg, 75.63%).

¹ H NMR (400 MHz, DMSOO δ 9.80 (br,s, 1H), 8.13 (1H), 8.09 (s, 1H), 7.73-7.54 (m, 6H), 7 ,39-7.28 (m, 3H), 4.39 (d, J=5.5 Hz, 2H), 4.23 (s, 2H), 4.18 (t, J=6.5 Hz, 2H), 3.43-3.35 (m, 2H), 3.16-3.11 (m, 2H), 2.082.03 (m, 2H), 1.94-1.78 (m, 2H) , 1.69-1.57 (m, 2H), 1.41-1.28 (m, 2H), 0.88 (t, J=7.4 Hz, 3H) ppm MS: m/e 457 (M+1)+.

Compound A26: 2-butoxy-7-(2-fluoro-5-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1G][1,2,4]triazin-4-amine.

Step A: 2-fluoro-5-(pyrrolidin-1-ylmethyl)benzonitrile.

To a stirred solution of 2-fluoro-5-formylbenzonitrile (447 mg, 3 mmol) in MeOH (5 ml) was added pyrrolidine (234 mg, 3.3 mmol), then the mixture was stirred for 2 hours followed by the addition of NaBH ₃ CN (378 mg, 6 mmol). After addition, the reaction mixture was concentrated to give a precipitate, which was purified by column chromatography (petroleum ether/EAAc=2:1) to give the title compound (350 mg, 57.2%) as a yellow oil. MS: m/e 205 (M+1)+.

Step B: 2-fluoro-5-(pyrrolidin-1-ylmethyl)benzaldehyde.

To a stirred solution of the product from step A (350 mg, 1.7 mmol) in dry THF (10 ml) at -20°C was added dropwise DIBAL-H (1.2 M, 3.57 ml, 4.3 mmol). After addition, the reaction was stirred for 3 hours at room temperature. The reaction was quenched with aq. NH4C1, extracted with EtOAc (20 mlx3) and filtered. The filtrate was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=3:1~2:1) to obtain the title compound (180 mg, 51.1%) as an oil light yellow color. MS: m/e 208 (M+1)+.

Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(2-fluoro p-5(pyrrolidin-1 -ylmethyl)phenyl)methanol.

To a solution of 7-bromo-2-butoxy-Nibis(4-methoxybenzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (150 mg, 0.285 mmol) in THF (10 ml ) at -78°C, n-BuLi (0.44 ml, 0.71 mmol) was added dropwise. After stirring for an hour, a solution of the product from step B (88.7 mg, 0.428 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature for 1 hour. The reaction was quenched. aq. NH4C1 solution, extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by pre-TLC (petroleum ether/EAAc=1:1) to give the title compound (55 mg, 29.4%). MS: m/e 655 (M+1)+.

Step D: 2-butoxy-7-(2-fluoro-5-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (compound A26).

A mixture of product C (55 mg, 0.084 mmol) in Et ₃ SiH/TOy (0.5 ml/3 ml) was stirred at 85°C for

- 34 046488 night. The reaction mixture was concentrated to give a residue, which was purified by pre-HPLC to give the title compound (20 mg, 59.8%).

^1H NMR (400 MHz, DMSO-de) δ 8.13 (s, 1H), 8.03 (s, 1H), 7.26 (s, 1H), 7.24-7.04 (m, 3H ), 4.18-4.13 (m, 4H), 3.45 (s, 2H), 2.35-2.28 (m, 4H), 1.66-1.61 (m, 6H), 1.37-1.29 (m, 2H), 0.90 (t, J=7.2 Hz, 3H) ppm. MS: m/e 399 (M+1)+.

Compound A27: 2-butoxy-7 -(2-fluoro-5-(pyrrolidin-1 -ylmethyl)benzyl)imidazo [2,1P|1.2.4|triazin-4-amine.

Step A: 2-(3-(dimethylamino)propoxy)benzaldehyde.

A mixture of 2-hydroxybenzaldehyde (1.73 g, 10 mmol), 3-chloro-NX-dimethylpropan-1-amine hydrochloride (1.74 g, 1.1 mmol) and K ₂ CO ₃ (2.76 g, 20 mmol ) in DMF (10 ml) was stirred at 60°C overnight. The reaction mixture was poured into H2O (50 ml) and extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=5:1~100% EtOAc) to give the title compound (1.96 g, 76%) in in the form of a light yellow oil. MS: m/e 208 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(2-(3(dimethylamino)propoxy)phenyl )methanol.

To a solution of 7-bromo-2-butoxy-NX-bis(4-methoxybenzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (150 mg, 0.285 mmol) in THF (10 ml ) at -78°C, n-BuLi (1.6 M, 0.44 ml, 0.71 mmol) was added dropwise. After stirring for an hour, a solution of the product from step A (88.7 mg, 0.428 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature for 1 hour. The reaction was quenched. aq. NH4C1 solution, extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC (CH ₂ Cl ₂ /MeOH=10:1) to give the title compound (62 mg, 33%) as a white solid. MS: m/e 655 (M+1)+.

Step C: 2-butoxy-7-(2-(3 -(dimethylamino)propoxy)benzyl)imidazo[2,1-f|[1,2,4]triazin-4-amine (compound A27).

A mixture of the product from step B (62 mg, 0.095 mmol) in E1 ₃ 81I/HFC (0.5 ml/3 ml) was stirred at 85°C overnight. The reaction mixture was concentrated to give a residue, which was purified by pre-HPLC to give the title compound (24 mg, 63.4%).

1H NMR (400 MHz, DMSOSH ₆ ) δ 8.09 (s, 1H), 8.00 (s, 1H), 7.22-7.18 (m, 2H), 7.10 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.85 (t, J=7.6 Hz, 1H), 4.21 (t, J=6.4 Hz, 2H), 4, 07 (s, 2H), 3.96 (t, J=6.4 Hz, 2H), 2.23 (t, J=7.2 Hz, 2H), 2.08 (s, 6H), 1, 85-1.61 (m, 4H), 1.48-1.35 (m, 2H), 0.92 (t, J=7.2 Hz, 3H) ppm. MS: m/e 399 (M+1)+.

Compound A28: 2-butoxy-7 -(4-(3 -(pyrrolidin-1 -yl)propoxy)benzyl)imidazo [2,11][1,2,4]triazin-4-amine.

Step A: 4-(3-(pyrrolidin-1-yl)propoxy)benzaldehyde.

A solution of 4-(3-bromopropoxy)benzaldehyde (300 mg, 1.2 mmol), pyrrolidine (170 mg, 2.4 mmol), sodium carbonate (254 mg, 2.4 mmol) and potassium iodide (17 mg, 0. 1 mmol) in acetonitrile (10 ml) was heated at 80°C overnight. The solution was concentrated, treated with water (10 ml) and extracted with dichloromethane (10 ml). The organic layer was dried, concentrated and purified using CombiFlash (DCM:MeOH=8%) to give the product (200 mg, 70%) as a colorless oil. MS: m/e 234 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(4-(3(pyrrolidin-1-yl )propoxy)phenyl)methanol.

To a cooled solution of 7-bromo-2-butoxy-NX-bis(4-methoxybenzyl)imidazo[2,11][1,2,4]triazin-4-amine (210 mg, 0.4 mmol) in THF (8 ml) at -78°C (purged with N2), n-BuLi (1.6 M, 0.7 ml) was added dropwise. After stirring at -78°C for 30 min, 4-(3(pyrrolidin-1-yl)propoxy)benzaldehyde (140 mg, 0.6 mmol) in THF (2 ml) was added. The resulting mixture was stirred at this temperature for 30 min and then heated to rt for 1 h. The solution was quenched with NH4C1 solution (5 ml), extracted with ethyl acetate (10 ml) and washed with brine (10 ml). The organic layer was dried with Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified using Combiflash (DCM:MeOH=7%) and prep-TLC (DCM:MeOH=6:1) to give the pure product (108 mg, 40%). MS: m/e 681 (M+1)+.

Step C: 2-butoxy-7-(4-(3-(pyrrolidin-1-yl)propoxy)benzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (compound A28) .

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(4-(3-(pyrrole idin-1-yl )propoxy)phenyl)methanol (108 mg, 0.16 mmol) in trifluoroacetic acid (2 ml) and triethylsilane (2 ml) were heated at 80°C for 1 hour. After concentration, trifluoroacetic acid (1 ml) was added to the precipitate, and the mixture was heated at 80°C overnight. The solvent was evaporated to leave a residue, which was made alkaline with NaHCO ₃ , extracted with ethyl acetate (5 ml), washed with brine (5 ml). The organic layer was dried, concentrated and purified using CombiFlash (DCM:MeOH=18%) to give the product (25 mg, 37%).

- 35 046488 ¹ H NMR (400 MHz, DMSO-dg) δ 8.11 (s, 1H), 8.02 (s, 1H), 7.25 (s, 1H), 7.20 (d, J= 8.0 Hz, 2H), 6.83 (d, J=8.0 Hz, 2H), 4.20 (t, J=8.0 Hz, 2H), 4.05 (s, 2H), 3 .95 (t, J=8.0 Hz, 2H), 2.51 (s, 2H), 2.43 (s, 4H), 1.88-1.81 (m, 2H), 1.70- 1.63 (m, 6H), 1.43-1.37 (m, 2H), 0.92 (t, J=8.0 Hz, 3H) ppm. MS: m/e 425 (M+1)+.

Compound A29: 2-butoxy-7-(4-(3 -(diethylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4amine.

Step A: 4-(3-(diethylamino)propoxy)benzaldehyde.

DEAD (1 g, 6 mmol) was added dropwise to a solution of 4-hydroxybenzaldehyde (0.5 g, 4 mmol), 3(diethylamino)propan-1-ol (0.5 g, 4 mmol) and triphenylphosphane (1.6 g, 6 mmol) in THF (10 ml) at 0°C in an N2 atmosphere. The mixture was heated to rt and stirred overnight. The solution was concentrated and purified using CombiFlash (PE:EA=80%) to give the product (0.4 g, 42%) as a colorless oil. MS: m/e 236 (M+1) ⁺ .

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

To a cooled solution of 7-bromo-2-butoxy-NX-bis(4-methoxybenzyl)imidazo[2,1L[1,2,4]triazin-4-amine (200 mg, 0.4 mmol) in THF (8 ml ) (purged with N2) at -78°C, n-BuLi (1.6 M, 0.6 ml) was added dropwise. After stirring at -78°C for 30 min, 4-(3(diethylamino)propoxy)benzaldehyde (134 mg, 0.6 mmol) in THF (2 ml) was added. The resulting mixture was stirred at this temperature for 30 minutes, and then heated to rt for 1 hour. 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 with Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified using Combiflash (DCM:MeOH=8%) and prep-TLC (DCM:MeOH=7:1) to give the pure product (150 mg, 58%). MS: m/e 683 (M+1) ⁺ .

Step C: 2-butoxy-7-(4-(3-(diethylamino)propoxy)benzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (compound A29).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(4-(3(diethylamino)propoxy)phenyl)methanol (150 mg, 0.22 mmol) in trifluoroacetic acid (2 ml) and triethylsilane (2 ml) were heated at 80°C for 1 hour. After concentration, trifluoroacetic acid (2 ml) was added to the precipitate and the mixture was heated at 80° C during the night. The solvent was evaporated to leave a residue, which was made alkaline with NaHCO ₃ , extracted with ethyl acetate (5 ml), washed with brine (5 ml). The organic layer was dried, concentrated and purified by pre-TLC (DCM:MeOH=7:1) to give the product (50 mg, 54%).

1H NMR (400 MHz, DMSO-bb) δ 8.12 (s, 1H), 8.04 (s, 1H), 7.25 (s, 1H), 7.23 (d, J=8.0 Hz , 2H), 6.86 (d, J=12.0 Hz, 2H), 4.20 (t, J=8.0 Hz, 2H), 4.07 (s, 2H), 4.02 (t , J=8.0 Hz, 2H), 3.13 (s, 6H), 2.08 (br,s, 2H), 1.711.64 (m, 2H), 1.45-1.36 (m, 2H), 1.20 (t, J=8.0 Hz, 6H), 0.93 (t, J=8.0 Hz, 3H) ppm. MS: m/e 427 (M+1)+.

Compound A30: 2-butoxy-7-((4'-(pyrrolidin-1 -ylmethyl)-[1,1'-biphenyl]-4-yl)methyl)imidazo [2,11][1,2,4] triazine-4-amine.

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

To a solution of 7-bromo-2-butoxy-NX-bis(4-methoxybenzyl)imidazo[2,1-1T][1,2,4]triazin-4-amine (150 mg, 0.23 mmol) in THF ( 5 ml) at -78°C, n-butyllithium (0.27 ml, 0.43 mmol) was added dropwise and stirred for 1 hour. Then, at -78°C, a solution of 4'-(pyrrolidine-1- ylmethyl)-[1,1'biphenyl]-4-carbaldehyde (114 mg, 0.43 mmol) in THF (2 ml) after addition the mixture was heated to rt and stirred for 3 hours. The mixture was quenched with saturated ammonium chloride solution (5 ml), extracted with DCM (30 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (3ΧΜΜόΟΗ=20:1~5:1) to obtain the title product (124 mg, 61%) as a yellow oil . MS: m/e 713 (M+1) ⁺ .

Step B: 2-butoxy-7-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methyl)imidazo[2,11][1,2,4] triazin-4-amine (compound A30).

Mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(4'(pyrrolidin-1-ylmethyl)-[1 ,1'-biphenyl]-4-yl)methanol (124 mg, 0.17 mmol) and triethylsilane (1 ml) in TFA (2 ml) were stirred at 90°C overnight. The mixture was concentrated and purified by pre-HPLC to give 2-butoxy-7-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4yl)methyl)imidazo[2,1-1 ][1,2,4]triazin-4-amine (58 mg, 73%).

1H NMR (400 MHz, DMSO-ph;) δ 9.74 (br,s, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.78-7.75 (m , 2H), 7.64-7.53 (m, 4H), 7.43-7.38 (m, 2H), 7.36 (s, 1H), 4.38 (d, J=5.7 Hz, 2H), 4.26-4.18 (m, 4H), 3.42-3.35 (m, 2H), 3.213.12 (m, 2H), 2.14-2.02 (m, 2H), 1.92-1.83 (m, 2H), 1.72-1.61 (m, 2H), 1.42-1.33 (m, 2H), 0.91 (t, J= 7.4 Hz, 3H) ppm. MS: m/e 457 (M+1) ⁺ .

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

Step A: tert-butyl (3-(4-formylphenoxy)propyl)carbamate.

To a solution of 4-hydroxybenzaldehyde (1.22 g, 10 mmol), tert-butyl(3-hydroxypropyl)carbamate (2.62 g, 15 mmol) and PPh3 (3.93 g, 15 mmol) in THF (15 ml) DIAD (7.57 g, 15 mmol,

- 36 046488

40% in toluene solution). The mixture was then stirred at room temperature for 5 hours. The mixture was diluted with water (50 ml), extracted with EtOAc (60 mlx2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and the residue was purified using CombiFlash to give the title compound (2.53 g, 90%). MS: m/e 224 (M+H-tBu) ⁺ .

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

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

Step C: 7-(4-(3-aminopropoxy)benzyl)-2-butoxyimidazo[2,1-N1,2,4]triazin-4-amine (compound A31).

To a mixture of the product of step B (100 mg, crude) in TFA (3 ml) was added Et ₃ SiH (1 ml). The reaction was heated at 85°C overnight. The mixture was cooled to room temperature and concentrated to dryness. TFA (3 ml) was added to the precipitate and the resulting mixture was heated at 85°C overnight. The mixture was concentrated to dryness and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (50 mlx2), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to obtain the target compound (30 mg, 15% in two steps).

1H NMR (400 MHz, DMSOL) δ 8.11 (s, 1H), 8.02 (s, 1H), 7.25 (s, 1H), 7.20 (d, J=8.8 Hz, 2H ), 6.84 (d, J=8.4 Hz, 2H), 4.20 (t, J=6.0 Hz, 2H), 4.05 (s, 2H), 3.97 (t, J =6.4 Hz, 2H), 3.05-2.90 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 1.86-1.59 (m, 4H) , 1.49-1.35 (m, 2H), 0.92 (t, J=7.6 Hz, 3H) ppm. MS: m/e 371 (M+1)+.

Compound A32: 2-butoxy-7-((6-(3 -(dimethylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1A[1,2,4]triazin-4-amine.

Step A: 6-(3-(dimethylamino)propoxy)nicotinaldehyde.

DEAD (2.1 g, 12 mmol) was added dropwise to a solution of 6-hydroxynicotinaldehyde (1 g, 8.1 mmol), 3-(dimethylamino)propan-1-ol (837 mg, 8.1 mmol) and triphenylphosphane ( 3.1 g, 12 mmol) in THF (20 ml) at 0°C under N ₂ atmosphere. The mixture was heated to rt and stirred overnight. The solution was quenched with water (20 ml), extracted with ethyl acetate (20 ml) and washed with brine (10 ml). The organic layer was dried, concentrated and purified using CombiFlash (EA to DCM:MeOH=10%) to give the product (0.5 g, 30%) as a colorless oil.

1H NMR (400 MHz, DMSOL) δ 9.95 (s, 1H), 8.74 (d, J=4.0 Hz, 1H), 8.10 (dd, J=8.0, 4.0 Hz , 1H), 6.96 (d, J=8.0 Hz, 1H), 4.40 (t, J=8.0 Hz, 2H), 2.37-2.35 (m, 2H), 2 .13 (s, 6H), 1.88-1.85 (m, 2H) ppm. MS: m/e 209 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(6-(3(dimethylamino)propoxy)pyridine -3-yl)methanol.

To a cooled solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1A[1,2,4]triazin-4-amine (420 mg, 0.8 mmol) in THF (12 ml) at -78°C (purged with N2), n-BuLi (1.6 M, 1.3 ml) was added dropwise. After stirring at -78°C for 30 min, 6-(3(dimethylamino)propoxy)nicotinaldehyde (250 mg, 1.2 mmol) in THF (3 ml) was added. The resulting mixture was stirred at this temperature for 30 minutes, and then heated to rt 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 with Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified using CombiFlash (DCM:MeOH=8%) to give the pure product as a white solid (133 mg, 46%). MS: m/e 656 (M+1)+.

Step C: 2-butoxy-7-((6-(3 -(dimethylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1A[1,2,4]triazin-4-amine (compound A32) .

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(6-(3(dimethylamino)propoxy)pyridin-3 -yl)methanol (78 mg, 0.12 mmol) in trifluoroacetic acid (2 ml) and triethylsilane (2 ml) were heated at 80°C for 1 hour. After concentration, trifluoroacetic acid (2 ml) was added to the precipitate, and the mixture heated at 80°C overnight. The solvent was evaporated to leave a residue, which was made alkaline with NaHCO ₃ , extracted with ethyl acetate (5 ml), washed with brine (5 ml). The organic layer was dried, concentrated and purified by pre-TLC (DCM:MeOH=8:1) to give the product (10 mg, 21%).

1H NMR (400 MHz, DMSOL) δ 8.13 (s, 2H), 8.06 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.30 (s, 1H ), 6.75 (d,

- 37 046488

J=8.0 Hz, 1H), 4.27 (t, J=8.0 Hz, 2H), 4.20 (t, J=8.0 Hz, 2H), 4.09 (s, 2H) , 3.14 (t, J=8.0 Hz, 2H), 2.74 (s, 6H), 2.12-2.05 (m, 2H), 1.71-1.64 (m, 2H ), 1.45-1.36 (m, 2H), 0.93 (t, J=8.0 Hz, 3H) ppm. MS: m/e 400 (M+1)+.

Compound A3 3: 2-butoxy-7-(4-(piperidin-4-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4amine.

Step A: methyl 4-((diethoxyphosphoryl)methyl)benzoate.

A solution of methyl 4-(bromomethyl)benzoate (5.5 g, 24 mmol) in triethylphosphite (15 ml) was stirred at 115°C for 4 hours. The mixture was cooled to room temperature, concentrated and the residue was purified using CombiFlash to give the target compounds (6.16 g, 90%). MS: m/e 287 (M+1) ⁺ .

Step B: tert-butyl 4-(4-(methoxycarbonyl)benzylidene)piperidine-1-carboxylate.

To a solution of the product of step A (6.16 g, 21.54 mmol) in THF (60 ml) was added dropwise LDA (12 ml, 23.69 mmol) at -70°C. After stirring at this temperature for 30 minutes, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (4.7 g, 23.69 mmol) in THF (10 ml) was added. The resulting mixture was slowly warmed to room temperature overnight. The reaction was quenched with a saturated solution of NH ₄ Cl and extracted with EtOAc (80 mlx2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified using CombiFlash to obtain the title compound (4.5 g, 63%). MS: m/e 276 (M+H-tBu)+.

Step C: tert-butyl 4-(4-(methoxycarbonyl)benzyl)piperidine-1-carboxylate.

To a solution of the product from step B (4.5 g, 13.6 mmol) in MeOH (40 ml) was added 10% Pd/C (450 mg). The reaction was stirred at room temperature under H ₂ (balloon) for 4 hours. The catalyst was filtered off and the filtrate was concentrated to give the title compound (4 g, 88%). MS: m/e 278 (M+H-tBu)+.

Step D: tert-butyl 4-(4-(hydroxymethyl)benzyl)piperidine-1-carboxylate.

To a solution of LiAlH ₄ (273 mg, 7.2 mmol) in THF (10 ml) at 0°C, the product of step C (2 g, 6 mmol) in THF (10 ml) was added dropwise. After addition, the resulting mixture was slowly warmed to room temperature overnight. The reaction was quenched with saturated aqueous (0.3 ml), 10% NaOH (0.3 ml) and water (0.9 ml). The resulting mixture was filtered and the filtrate was concentrated to give the title compound (1.65 g, 90%).

1H NMR (400 MHz, CD ₃ Cl) δ 7.28 (d, J=7.6 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 4.66 (s, 2H ), 4.06 (d, J=12.8 Hz, 2H), 2.71-2.57 (m, 2H), 2.53 (d, J=6.4 Hz, 2H), 1.73 -1.54 (m, 5H), 1.44 (s, 9H) ppm.

Step E: tert-butyl 4-(4-formylbenzyl)piperidine-1-carboxylate.

To a solution of the product of step D (1.65 g, 5.4 mmol) in THF (30 ml) was added Dess-Martin reagent (4.58 g, 10.8 mmol) at 0° C. in several parts. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with a saturated solution of K ₂ CO ₃ , filtered through a celite pad, and washed with EA (50 ml). The filtrate was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified using CombiFlash to obtain the target compound (475 mg, 29%). MS: m/e 248 (M+H-tBu)+.

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

To a solution of 7-bromo-2-butoxy-UNbis(4-methoxybenzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF ( 8 ml) n-BuLi solution (0.6 ml, 0.95 mmol) was added dropwise, maintaining the temperature in the range from -75 to -65°C. After 1 hour, a mixture of the product from step E (172 mg, 0.57 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 0.5 hours and then warmed to room temperature overnight. The reaction was quenched with saturated NH ₄ Cl solution, extracted with EtOAc (50 ml), washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC (EA/PE=1/2) to give the title compound (60 mg, crude). MS: m/e 751 (M+1)+.

Step G: 2-butoxy-7-(4-(piperidin-4-ylmethyl)benzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (compound A33).

To a mixture of the product of step F (60 mg, 0.08 mmol) in TFA (3 ml) was added Et ₃ SiH (0.5 ml). The reaction was heated at 85°C overnight. The mixture was concentrated to dryness and the residue was purified by pre-HPLC. The collected phrase was made alkaline with NaHCO ₃ solution, extracted with DCM (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the target compound (4 mg, 3% in two steps).

1H NMR (400 MHz, DMSO-06) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.29 (s, 1H), 7.21 (d, J=8.0 Hz , 2H), 7.07 (d, J=8.0 Hz, 2H), 4.19 (t, J=6.0 Hz, 2H), 4.09 (s, 2H), 3.00 (d , J=12.0 Hz, 2H), 2.53-2.49 (m, 2H), 2.44 (d, J=7.2 Hz, 2H), 1.75-1.49 (m, 5H), 1.48-1.34 (m, 2H), 1.18-1.04 (m, 2H), 0.92 (t, J=7.2 Hz, 3H) ppm. MS: m/e 395 (M+1)+.

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

Step A: 5-chloro-6-(3-(dimethylamino)propoxy)nicotinaldehyde.

To a solution of 5,6-dichloronicotinaldehyde (1.76 g, 10 mmol) and K ₂ CO ₃ (1.65 g, 12 mmol) in DMF (20

- 38046488 ml) 3-(dimethylamino)propan-1-ol (1.13 g, 11 mmol) was added. The mixture was then stirred at 80°C overnight under N2 atmosphere. The mixture was cooled to room temperature, diluted with water (50 ml), extracted with EtOAc (50 mlx2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and the residue purified by flash chromatography to give the title compound (0.5 g, 21%).

1H NMR (400 MHz, CDCl ₃ ) δ 9.93 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.11 (d, J=2.2 Hz, 1H) , 4.56 (t, J=6.0 Hz, 2H), 2.56 (t, J=7.6 Hz, 2H), 2.33 (s, 6H), 2.15-2.03 ( m, 2H) ppm. MS: m/e 243 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimcdazo[2,1-£][1,2,4]triazin-7-yl)(5-chloro-6-(3(dimethylamino )propoxy)pyridin-3-yl)methanol.

To a solution of 7-bromo-2-butoxy-Nibis(4-methoxybenzyl)imidazo[2,1-N1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF (8 ml) n-BuLi solution (0.6 mL, 0.95 mmol) was added dropwise, maintaining the temperature between -75 and -65°C. After 1 hour, a mixture of the product from step A (138 mg, 0.57 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature overnight. The reaction was quenched with a saturated solution of NH ₄ Cl, extracted with EtOAc (50 mlx2), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC (DCM/MeOH=10/1) to give the title compound (60 mg, crude). MS: m/e 690 (M+1) ⁺ .

Step C: 2-butoxy-7-((5-chloro-6-(3 -(dimethylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1P[1.2.4|triazin-4-amine (compound A34).

To a mixture of the product of step B (60 mg, crude) in TFA (3 ml) was added Et ₃ SiH (0.5 ml) and the resulting mixture was heated at 80° C. overnight. The mixture was cooled to room temperature and concentrated to dryness. TFA (3 ml) was added to the precipitate and the resulting mixture was heated at 85°C overnight. The mixture was concentrated to dryness and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (50 mlx2), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to obtain the target compound (8 mg, 5% in two steps).

1H NMR (400 MHz, CD3OD) δ 8.02 (d, J=2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.36 (s, 1H), 4.38 (t, J=6.0 Hz, 2H), 4.28 (t, J=6.4 Hz, 2H), 4.15 (s, 2H), 2.59 (t, J=8 .0 Hz, 2H), 2.32 (s, 6H), 2.05-1.94 (m, 2H), 1.82-1.70 (m, 2H), 1.56-1.43 ( m, 2H), 0.98 (t, J=7.2 Hz, 3H) ppm. MS: m/e 434 (M+1)+.

Compound A3 5: 2-butoxy-7 -(4-(3 -(dimethylamino)propoxy)-3-fluorobenzyl)imidazo[2,1Al,2,4]triazin-4-amine.

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(4-(3(dimethylamino)propoxy)- 3-fluorophenyl)methanol.

To a solution of 7-bromo-2-butoxy-Nibis(4-methoxybenzyl)imidazo[2,1-N1,2,4]triazin-4-amine (150 mg, 0.29 mmol) in THF (5 ml) at -78°C, n-butyllithium (0.27 ml, 0.43 mmol) was added dropwise under N ₂ and stirred for 1 hour. Then a solution of 4-(3-(dimethylamino)propoxy)-3fluorobenzaldehyde (96 mg , 0.43 mmol) in THF (2 ml) was added dropwise at -78°C, then the mixture was heated to rt and stirred for 3 hours. The mixture was quenched with saturated ammonium chloride solution (5 ml), extracted with DCM (30 mlx3) . The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (DCM/MeOH=20:1~5:1) to give the product (136 mg, 70.86%) as an oil yellow color. MS: m/e 673 (M+1)+.

Step B: 2-butoxy-7-(4-(3-(dimethylamino)propoxy)-3-fluorobenzyl)imidazo[2,1-f][1,2,4]triazin-4amine (compound A35).

Mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7 -yl)(4-(3 (dimethylamino)propoxy)-3- fluorophenyl)methanol (136 mg, 0.2 mmol) and triethylsilane (1 ml) in TFA (2 ml) were stirred at 90°C overnight. The mixture was concentrated and purified by pre-HPLC to give the product (34 mg, 40%).

1H NMR (400 MHz, DMSOO δ 9.36 (br,s, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.30 (s, 1H), 7.19 ( d, J=12.6 Hz, 1H), 7.13-7.02 (m, 2H), 4.20 (t, J=6.5 Hz, 2H), 4.11-4.02 (m , 4H), 3.20 (dd, J=15.2, 5.5 Hz, 2H), 2.81 (d, J=4.8 Hz, 6H), 2.09 (dt, J=12, 3, 6.1 Hz, 2H), 1.76-1.57 (m, 2H), 1.47-1.33 (m, 2H), 0.92 (t, J=7.4 Hz, 3H ) ppm MS: m/e 417 (M+1)+.

Compound A36: 2-butoxy-7-(4-(3-(dimethylamino)propoxy)-2-fluorobenzyl)imidazo[2,11][1,2,4]triazin-4-amine.

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(4-(3(dimethylamino)propoxy)- 2-fluorophenyl)methanol.

To a solution of 7-bromo-2-butoxy-Nibis(4-methoxybenzyl)imidazo[2,1-1T][1,2,4]triazin-4-amine (150 mg, 0.29 mmol) in THF ( 5 ml), at -78°C, n-butyllithium (0.27 ml, 0.43 mmol) was added dropwise and stirred for 1 hour. Then, at -78°C, a solution of 4-(3-(dimethylamino) )propoxy)-2fluorobenzaldehyde (96 mg, 0.43 mmol) in THF (2 ml), after addition the mixture was warmed to rt and stirred for 3 hours. The mixture was quenched with a saturated solution of ammonium chloride (5 ml), extracted

- 39 046488 li DXM (30 mlx3). The combined organic layers were washed with brine, dried over _Na2SO4 , concentrated and purified by column chromatography (ΠΧΜ/ΜόΟΗ=20:1~5:1) to give the product (107 mg, 55.8%) as a yellow oil colors. MS: m/e 673 (M+1)+.

Step B: 2-butoxy-7-(4-(3 -(dimethylamino)propoxy)-2-fluorobenzyl)imidazo[2,1-f][1,2,4]triazin-4amine (compound A36).

Mixture of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(3 (dimethylamino)propoxy)-2- fluorophenyl)methanol (107 mg, 0.16 mmol) and triethylsilane (1 ml) in TFA (2 ml) were stirred at 90°C overnight. The mixture was concentrated and purified by pre-HPLC to give the title product (48 mg, 72.6%).

1H NMR (400 MHz, DMSO-de) δ 9.32 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.37-7.07 (m, 2H) , 6.82 (dd, J=11.9, 2.1 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 4.19 (t, J=6.5 Hz, 2H), 4.08 (s, 2H), 4.02 (t, J=5.9 Hz, 2H), 3.253.17 (m, 2H), 2.80 (s, 6H), 2.12- 2.00 (m, 2H), 1.74-1.59 (m, 2H), 1.47-1.34 (m, 2H), 0.92 (t, J=7.4 Hz, 3H) ppm MS: m/e 417 (M+1)+.

Compound A37: 7-((6-(2-aminoethoxy)pyridin-3-yl)methyl)-2-butoxyimidazo[2,1P|1.2.4|triazin-4-amine.

Step A: tert-butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)carbamate. K2CO ₃ (2.76 g, 20 mmol) was added to a solution of 6-chloronicotinaldehyde (1.41 g, 10 mmol) and tert-butyl(2-hydroxyethyl)carbamate (1.61 g, 10 mmol) in DMA (20 ml ), the reaction mixture was stirred at 80°C overnight and cooled to room temperature. The solution was quenched with H2O (10 ml). The aqueous solution was extracted with EA (20 mlx4). The collected organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography to give the product (120 mg, 4%). MS: m/e 267 (M+1)+.

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

To a solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1T|[1,2,4]triazin-4-amine (158 mg, 0.3 mmol) in THF (2 ml) n-BuLi solution (0.38 ml, 0.6 mmol) was added dropwise, maintaining the temperature between -75 and -65°C. After 10 min, a solution of the product from step A (120 mg, 0.45 mmol) in THF (3 ml) was added dropwise. The resulting mixture was stirred at -70°C for 20 minutes. The reaction was quenched with a saturated solution of NH4C1, extracted with EtOAc (5 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to give the title compound (80 mg, 37%). MS: m/e 714 (M+1)+.

Step C: 7-((6-(2-aminoethoxy)pyridin-3-yl)methyl)-2-butoxyimidazo[2,1-f|[1,2,4]triazin-4-amine (compound A37).

To a mixture of the product of step B (80 mg, 0.11 mmol) in TFA (1 ml) was added Et ₃ SiH (1 ml). The reaction was heated at 80°C for 3 hours. The mixture was concentrated to dryness and the residue was treated with TFA (2 ml). The reaction was heated at 80°C overnight. The mixture was concentrated and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (30 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title product (12 mg, 33%).

1H NMR (400 MHz, CDCl ₃ ) δ 8.12 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.25 (s, 1H), 6.70 (d, J=8.0 Hz, 1H), 4.35-4.21 (m, 4H), 4.11 (s, 2H), 3.06 (t, J=6.0 Hz, 2H), 1, 62-1.51 (m, 2H), 1.47-1.35 (m, 4H), 0.98 (t, J=8.0 Hz, 3H) ppm. MS: m/e 358 (M+1)+.

Compound A38: 7-(4-(((N^)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzyl)-2butoxyimidazo[2,1-f|[1,2, 4]triazine-4-amine.

Step A: tert-butyl(N^)-3-(3-fluoro-4-formylphenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate.

DIAD (3.8 mL, 7.2 mmol) was added dropwise to a solution of 2-fluoro-4-hydroxybenzaldehyde (500 mg, 3.6 mmol), tert-butyl(N^)-3-hydroxy-8-azabicyclo[ 3.2.1]octane-8-carboxylate (817 mg, 3.6 mmol) and triphenylphosphane (1.8 g, 7.2 mmol) in THF (20 ml) at 0°C under N2. The mixture was heated to rt and stirred overnight. The solution was quenched with water (20 ml), extracted with ethyl acetate (20 ml) and washed with brine (10 ml). The organic layer was dried, concentrated and purified using CombiFlash (PE:EA=10%) to give the product (330 mg, 27%) as a colorless oil.

1H NMR (400 MHz, CDCl ₃ ) δ 10.21 (s, 1H), 7.83 (t, J=8.0 Hz, 1H), 6.72 (dd, J=8.0, 4.0 Hz, 1H), 6.57 (dd, J=12, 4.0 Hz, 1H), 4.70 (t, J=4.0 Hz, 1H), 4.24 (s, 2H), 2, 20 (d, J=12.0 Hz, 2H), 2.08-1.94 (m, 6H), 1.49 (s, 9H) ppm. MS: m/e 350 (M+1)+.

Step B: tert-butyl(Ni^)-3-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2.1A1,2.4]triazin-7-yl)(hydroxy )methyl)-3-fluorophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate.

To a cooled solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1Al,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF (8 ml) at -78°C (purged with N2), n-BuLi (1.6 M, 0.6 ml) was added dropwise. After stirring at -78°C for 30 min, tert-butyl(N^)-3-(3-fluoro-4-formylphenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (199 mg, 0. 57 mmol) in THF (2 ml). The resulting mixture was stirred at this temperature for 30 minutes and then heated

- 40 046488 get to CT 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 Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified using CombiFlash (PE:EA=30%) to give the pure product as a red oil (190 mg, 63%). MS: m/e 797 (M+1)+.

Step C: 7-(4-(((^^)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzyl)-2-butoxyimidazo[2,1G][1,2, 4]triazin-4-amine (compound A38).

A mixture of tert-butyl(^^)-3 -(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1G][1,2,4]triazin-7-yl)( Hydroxy)methyl)-3-fluorophenoxy)-8-azabicyclo[3.2.1]octane-8carboxylate triethylsilane (190 mg, 0.24 mmol) in triethylsilane (3 ml) and trifluoroacetic acid (3 ml) was heated at 80°C for 2 hours. The solution was concentrated, trifluoroacetic acid (2 ml) was added and heated at 80°C overnight. The solvent was evaporated to obtain a precipitate, which was made alkaline with aq. NaHCO ₃ (5 ml), extracted with ethyl acetate (5 ml), washed with brine (5 ml). The organic layer was dried, concentrated and purified by pre-HPLC to give the product (30 mg, 33%).

1H NMR (400 MHz, DMSO-de) δ 8.14 (s, 1H), 8.04 (s, 1H), 7.25 (s, 1H), 7.18 (t, J=8.0 Hz , 1H), 6.72 (d, J=12.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.59 (s, 1H), 4.19 (t , J=8.0 Hz, 2H), 4.06 (s, 2H), 3.37 (s, 2H), 1.99-1.91 (m, 4H), 1.77 (s, 1H) , 1.74 (s, 1H), 1.68-1.64 (m, 4H), 1.44-1.35 (m, 2H), 0.92 (t, J=8.0 Hz, 3H ) ppm. MS: m/e 441 (M+1)+.

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

To a mixture of 2-butoxy-7-(4-(piperazin-1-ylmethyl)benzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (20 mg, 0.052 mmol), dimethylglycine ( 5 mg, 0.05 mmol) and DIEA (12 mg, 0.1 mmol) in THF (4 ml) was added HATU (19 mg, 0.05 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with DCM (20 mlx2), washed with brine, dried over Na2SO4, filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (2 mg, 8.3%).

1H NMR (400 MHz, CD3OD) δ 7.34-7.24 (m, 5H), 4.28 (t, J=6.4 Hz, 2H), 4.19 (s, 2H), 4.09 (s, 2H), 3.663.58 (m, 2H), 3.54 (s, 2H), 3.43-3.36 (m, 2H), 2.84 (s, 6H), 2.55- 2.40 (m, 4H), 1.83-1.70 (m, 2H), 1.55-1.45 (m, 2H), 0.98 (t, J=7.6 Hz, 3H) ppm MS: m/e 481 (M+1)+.

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

Step A: tert-butyl 4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidine-1-carboxylate.

To a solution of NaH (0.6 g, 15 mmol) in DMA (15 ml) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (2.2 g, 11 mmol). The mixture was stirred at room temperature for 1 hour. A solution of 5-bromo-2,3-dichloropyridine (2.26 g, 10 mmol) in DMA (5 ml) was then added and the resulting mixture was stirred at 80°C overnight under protection N2. The mixture was cooled to room temperature, diluted with water (50 ml), extracted with EtOAc (60 mlx2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and the residue purified using CombiFlash to give the title compound (2.23 g, 57%). MS: m/e 335 ^+^^^+.

Step B: tert-butyl 4-((3-chloro-5-formylpyridin-2-yl)oxy)piperidine-1-carboxylate.

To a solution of the product from step A (2.23 g, 5.7 mmol) in THF (15 ml), a solution of n-BuLi (5.3 ml, 8.55 mmol) was added dropwise, maintaining the temperature between -75 and - 65°C. After 1 hour, DMF (500 mg, 6.3 mmol) was added dropwise and the resulting mixture was stirred at -70°C for 2 hours. The reaction was quenched with saturated NH ₄ Cl solution, extracted with EtOAc (40 mlx2), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified using CombiFlash to obtain the title compound (350 mg, 18%) as an oil.

1H NMR (400 MHz, CDCl ₃ ) δ 9.93 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H) , 5.49-5.41 (m, 1H), 3.79-3.65 (m, 2H), 3.49-3.38 (m, 2H), 2.05-1.92 (m, 2H), 1.91-1.78 (m, 2H), 1.47 (s, 9H) ppm. MS: m/e 341 (M+1) ⁺ .

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

To a solution of 7-bromo-2-butoxy-Nibis(4-methoxybenzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF ( 8 ml) n-BuLi solution (0.6 ml, 0.95 mmol) was added dropwise while maintaining the temperature in the range from -75 to -65°C. After 1 hour, a mixture of the product from step B (155 mg, 0.456 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature over 5 hours. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated . The residue was purified by pre-TLC (EA/PE=1/2) to give the title compound (80 mg, crude). MS: m/e 788 (M+1) ⁺ .

Step D: 2-butoxy-7 -((5-chloro-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo [2,1- 41 046488

P|1,2,4|triazin-4-amine (compound A40).

To a mixture of the product of step C (80 mg, crude) in TFA (3 ml) was added Et ₃ SiH (0.5 ml) and the resulting mixture was stirred at 85°C overnight. The mixture was cooled to room temperature and concentrated to dryness. The precipitate was purified using pre-HPLC. The collected fractions were made alkaline with NaHCO ₃ solution, extracted with DCM (50 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the target compound (20 mg, 45% in two steps).

Ή NMR (400 MHz, DMSO-dg) δ 8.15 (s, 1H), 8.10-8.01 (m, 2H), 7.84 (d, J=2.0 Hz, 1H), 7 .34 (s, 1H), 5.15-5.04 (m, 1H), 4.19 (t, J=6.4 Hz, 2H), 4.09 (s, 2H), 3.02- 2.90 (m, 2H), 2.64-2.53 (m, 2H), 1.98-1.86 (m, 2H), 1.72-1.60 (m, 2H), 1, 59-1.46 (m, 2H), 1.44-1.32 (m, 2H), 0.92 (t, J=7.2 Hz, 3H) ppm. MS: m/e 432 (M+1)+.

Compound A41: 7-(4-(((^^)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzyl)-2butoxyimidazo [2,1-f|[ 1,2,4 ]triazine-4-amine.

Step A: tert-butyl(^^)-5-(4-formylbenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate.

A mixture of 4-(chloromethyl)benzaldehyde (2 g, 12.9 mmol), tert-butyl(^^)-2,5diazabicyclo[2.2.1]heptane-2-carboxylate (3.06 g, 15.5 mmol) and K ₂ CO ₃ (3.56 g, 25.8 mmol) in CH3CN (30 ml) was stirred at 50°C overnight. The reaction was cooled to room temperature. The mixture was diluted with water (50 ml) and extracted with EA (30 mlx3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The precipitate was purified using CombiFlash to give the title compound (3.8 g, yield: 93.1%) as a brown oil.

Ή NMR (400 MHz, DMSOO δ 9.98 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 3 .79 (s, 2H), 3.42-3.37 (m, 2H), 3.19-3.00 (m, 1H), 2.83-2.70 (m, 1H), 2.53 -2.38 (m, 1H), 1.85-1.75 (m, 1H), 1.72-1.55 (m, 1H), 1.48-1.32 (m, 10H) ppm. MS: m/e 317 (M+1) ⁺ .

Step B: tert-butyl(^^)-5-(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,11G][1,2,4]triazin-7-yl )(hydroxy)methyl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate.

To a stirred solution of 7-bromo-2-butoxy-NY-bis(4-methoxybenzyl)imidazo[2,11G][1,2,4]triazin-4-amine (150 mg, 0.29 mmol) in THF (10 ml) n-BuLi (1.6 M, 0.45 ml) was added at -78°C under N2 atmosphere. The mixture was stirred at -78°C for 1 hour. Then the product of step A (135 mg, 0.43 mmol) in THF (0.5 ml) was added to the system at -78°C. The reaction was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl at room temperature. The mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The precipitate was purified using CombiFlash to obtain the title compound (140 mg, yield: 63.3%) as a yellow oil. MS: m/e 764 (M+1)+.

Step C: 7-(4-(((^^)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzyl)-2-butoxyimidazo[2,1A[1,2,4] triazin-4-amine (compound A41).

To a stirred solution of the product from step B (140 mg, 0.18 mmol) in Et ₃ SiH (4 ml) was added CF ₃ COOH (4 ml) at room temperature. The mixture was stirred at 80°C for 1 hour. The reaction was cooled to room temperature and concentrated under reduced pressure. The precipitate was dissolved with CF3COOH (4 ml). And 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 pre-HPLC to give the title compound (12 mg, yield: 16.1%).

Ή NMR (400 MHz, DMSO-dQ δ 8.19-7.97 (m, 2H), 7.30 (s, 1H), 7.25-7.19 (m, 4H), 4.20 (t , J=6.4 Hz, 2H), 4.11 (s, 2H), 3.67-3.55 (m, 2H), 3.31-3.18 (m, 2H), 3.03 ( d, J=9.6 Hz, 1H), 2.68 (t, J=8.4 Hz, 2H), 2.36 (d, J=9.6 Hz, 1H), 1.77-1, 60 (m, 3H), 1.49-1.33 (m, 3H), 0.92 (t, J=7.2 Hz, 3H) ppm MS: m/e 408 (M+1)+.

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

Step A: 4-bromophenethyl 4-methylbenzenesulfonate.

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

Step B: 1-(4-bromophenethyl)pyrrolidine.

To a stirred solution of 4-bromophenethyl-4-methylbenzenesulfonate (7 g, 20 mmol) in MeCN (50 mL) was added pyrrole (5.6 g, 77 mmol) and Et ₃ N (8 g, 80 mmol). The reaction mixture was stirred at rt overnight. The mixture was concentrated in vacuo. H2O (40 ml) was added to the precipitate and extracted with DCM (20 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography to give the product (4.3 g, 86%) as a yellow oil. MS: m/e 254 (M+1)+.

Step C: 4-(2-(pyrrolidin-1-yl)ethyl)benzaldehyde.

- 42 046488

To a stirred solution of 1-(4-bromophenethyl)pyrrolidine (1 g, 4 mmol) in THF (20 ml), cooled to -78°C, n-BuLi (1.6 M in hexane, 4 .4 mmol, 2.7 ml). After stirring for 60 min, a solution of DMF (876 mg, 12 mmol) in THF (3 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography to give the title product (600 mg, 73.8%). MS: m/e 204 (M+1)+.

Step D: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4-(2-(pyrrole idin-1 -yl)ethyl)phenyl)methanol.

To a stirred solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1G][1,2,4]triazin-4-amine (150 mg, 0.29 mmol) in THF ( 10 ml), cooled to -78°C under nitrogen, n-BuLi (1.6 M in hexane, 0.71 mmol, 0.47 ml) was added dropwise. After stirring for 20 min, a solution of 4-(2-(pyrrolidin-1-yl)ethyl)benzaldehyde (87.5 mg, 0.43 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred overnight. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography to give the title product (80 mg, 43%). MS: m/e 651 (M+1)+.

Step E: 2-butoxy-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (compound A42) .

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4-(2-(pyrrole idin-1-yl )ethyl)phenyl)methanol (80 mg, 0.123 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (14 mg, 29%).

¹ H NMR (400 MHz, DMSO-de) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.28 (s, 1H), 7.21 (d, J=7.8 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 4.20 (t, J=6.5 Hz, 2H), 4.09 (s, 2H), 2.71- 2.59 (m, 2H), 2.65 (s, 2H), 2.50 (s, 4H), 1.68-l.57 (m, 6H), 1.45-1.36 (m, 2H), 0.92 (t, J=7.3 Hz, 3H) ppm. MS: m/e 395 (M+1)+.

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

Step A: tert-butyl (1-(4-formylbenzyl)piperidin-4-yl)carbamate.

To a solution of 4-(bromomethyl)benzaldehyde (0.4 g, 2 mmol) and DIEA (0.52 g, 4 mmol) in THF (10 ml) was added tert-butylpiperidin-4-ylcarbamate (0.44 g, 2. 2 mmol). The mixture was then stirred at room temperature overnight. The mixture was diluted with water (50 ml), extracted with EtOAc (80 ml), washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and the residue purified using CombiFlash to give the title compound (0.6 g, 94%). MS: m/e 319 (M+1)+.

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

To a solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (380 mg, 0.72 mmol) in THF (12 ml) n-BuLi solution (1 ml, 1.6 mmol) was added dropwise, maintaining the temperature in the range from -75 to -65°C. After 1 hour, a mixture of the product from step A (276 mg, 0.868 mmol) in THF (3 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature overnight. The reaction was quenched with saturated NH ₄ Cl solution, extracted with EtOAc (50 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC to give the title compound (60 mg, crude). MS: m/e 766 (M+1)+.

Step C: 7-(4-((4-aminopiperidin-1-yl)methyl)benzyl)-2-butoxyimidazo[2,1-G][1,2,4]triazin-4-amine (compound A43) .

To a mixture of the product of step B (60 mg, crude) in TFA (3 ml) was added Et ₃ SiH (0.5 ml). The resulting mixture was heated at 85°C overnight. The mixture was concentrated to dryness and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (50 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the target compound (7 mg, 2.3% in two steps).

1H NMR (400 MHz, DMSO-de) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.30 (s, 1H), 7.23 (d, J=7.6 Hz , 2H), 7.18 (d, J=7.6 Hz, 2H), 4.19 (t, J=6.0 Hz, 2H), 4.11 (s, 2H), 3.36 (s , 2H), 3.15-2.80 (m, 2H), 2.74-2.61 (m, 2H), 2.60-2.51 (m, 1H), 1.89 (t, J =10.4 Hz, 2H), 1.72-1.58 (m, 4H), 1.49-1.34 (m, 2H), 1.29-1.15 (m, 2H), 0, 92 (t, J=7.6 Hz, 3H) ppm. MS: m/e 410 (M+1)+.

Compound A44: 2-butoxy-7-(4-((3 -(dimethylamino)pyrrolidin-1-yl)methyl)benzyl)imidazo [2,1G][1,2,4]triazin-4-amine.

- 43 046488

Step A: 4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)benzaldehyde.

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

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

To a stirred solution of 4-((4-(bis(4-methoxybenzyl)amino)-7-bromimidazo[2,1-1][1,2,4]triazin2-yl)oxy)butan-2-ylium (150 mg , 0.28 mmol) in THF (10 ml), cooled to -78°C, n-BuLi (1.6 M in hexane, 0.7 mmol, 0.43 ml) was added dropwise under nitrogen atmosphere. After stirring for 60 min, a solution of 4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)benzaldehyde (80 mg, 0.34 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo to give the crude product (110 mg, 57.8%), which was directly used in the next step without further purification. MS: m/e 680 (M+1)+.

Step C: 2-butoxy-7 -(4-((3 -(dimethylamino)pyrrolidin-1 -yl)methyl)benzyl)imidazo[2,1P[1.2.4|triazin-4-amine (compound A44).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(4-((3(dimethylamino)pyrrolidin-1- yl)methyl)phenyl)methanol (110 mg, 0.162 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et 3 SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (30 mg, 43.5%).

1H NMR (400 MHz, DMSO^) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.30 (s, 1H), 7.25-7.19 (m, 4H), 4.19 (t, J=6.5 Hz, 2H), 4.11 (s, 2H), 3.52-3.38 (m, 2H), 2.74-2.65 (m, 1H) , 2.61 (t, J=8.0 Hz, 1H), 2.53 (d, J=8.4 Hz, 1H), 2.38 (dd, J=14.7, 8.5 Hz, 1H), 2.27-2.16 (m, 1H), 2.07 (s, 6H), 1.81 (dd, J=13.3, 6.0 Hz, 1H), 1.72-1 .53 (m, 3H), 1.421.33 (m, 2H), 0.91 (t, J=7.4 Hz, 3H) ppm. MS: m/e 424 (M+1)+.

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

Step A: 3 -((5-bromo-3-chloropyridin-2-yl)oxy)-H,^2,2-tetramethylpropan-1-amine.

To a stirred suspension of NaH (60%, 600 mg, 15 mmol) in DMA (15 ml) was added a solution of 3(dimethylamino)-2,2-dimethylpropan-1-ol (1.44 g, 1.1 mmol) in DMA ( 2 ml). After stirring for 30 min, a solution of 5-bromo-2,3-dichloropyridine (2.26 g, 10 mmol) in DMA (2 ml) was added. After addition, the reaction was stirred at 80°C overnight. The reaction was quenched with H2O (10 ml) and extracted with EtOAc (20 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=20:1~5:1) to give the title compound (2.3 g, 71.5% ) in the form of a colorless oil. MS: m/e 321 (M+1)+.

Step B: 5-chloro-6-(3-(dimethylamino)-2,2-dimethylpropoxy)nicotinaldehyde.

To a stirred solution of the product from step A (961.5 mg, 3 mmol) in dry THF (10 ml) at -78°C, n-BuLi (1.6 M, 2.8 ml, 4.5 ml) was added dropwise. After stirring for 30 minutes, DMF (337 mg, 4.5 mmol) was added and stirred for 2 hours. The reaction was quenched with aq. NH4C1, and extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=5:1~1:1) to obtain the title compound (550 mg, 68%) as a colorless oils MS: m/e 271 (M+1)+.

Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimcdazo[2,1-£][1,2,4]triazin-7-yl)(5-chloro-6-(3(dimethylamino )-2,2-dimethylpropoxy)pyridin-3-yl)methanol.

To a solution of 7-bromo-2-butoxy-Nibis(4-methoxybenzyl)imidazo[2,1-1T][1,2,4]triazin-4-amine (150 mg, 0.286 mmol) in THF (10 ml ) at -78°C, n-BuLi (1.6 M, 0.44 ml, 0.71 mmol) was added dropwise. After stirring for 1 hour, a solution of the product from step B (115 mg, 0.428 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred overnight. The reaction was extinguished by us. aq. NH4C1 solution, extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The precipitate was purified by prepTLC (100% EtOAc) to give the title compound (60 mg, 29.3%). MS: m/e 718 (M+1)+.

Step D: 2-butoxy-7-((5-chloro-6-(3 -(dimethylamino)-2,2-dimethylpropoxy)pyridin-3 yl)methyl)imidazo[2,1-!T][1,2 ,4]triazin-4-amine (compound A45).

A mixture of the product from step C (70 mg, 0.095 mmol) in Et ₃ SiH/^y (0.5 ml/3 ml) was stirred at 85°C overnight. The reaction mixture was concentrated to give a residue, which was purified by pre-HPLC to give the title compound (20 mg, 54.1%).

- 44 046488 ¹ H NMR (400 MHz, DMSO-dg) δ 8.15 (s, 1H), 8.07 (s, 2H), 7.85 (d, J=2.0 Hz, 1H), 7 .34 (s, 1H), 4.19 (t, J=6.4 Hz, 2H), 4.10 (s, 2H), 4.04 (s, 2H), 2.30-2.15 ( m, 8H), 1.73-1.61 (m, 2H), 1.44-1.35 (m, 2H), 0.98-0.88 (m, 9H) ppm. MS: m/e 462 (M+1)+.

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

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

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

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

To a mixture of the product of step A (90 mg, crude) in TFA (3 ml) was added Et ₃ SiH (0.5 ml). The reaction was heated at 85°C overnight. The mixture was concentrated to dryness and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the product (10 mg, 10% in two steps).

1H NMR (400 MHz, DMSO^) δ 8.11 (s, 1H), 8.03 (s, 1H), 7.27 (s, 1H), 7.25-7.22 (m, 4H), 4.42 (t, J=6.4 Hz, 2H), 4.10 (s, 2H), 3.67 (s, 2H), 1.75-1.60 (m, 2H), 1.50 -1.30 (m, 2H), 0.93 (t, J=7.6 Hz, 3H) ppm. MS: m/e 327 (M+1)+.

Compound A47: 2-butoxy-7-(4-((4-phenoxypiperidin-1-yl)methyl)benzyl)imidazo[2,1P[1,2,4]triazin-4-amine.

Step A: 4-((4-phenoxypiperidin-1-yl)methyl)benzaldehyde.

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

Step B: tert-butyl(4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4((4-phenoxypiperidin- 1-yl)methyl)phenyl)methanol.

To a solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,14][1,2,4]triazin-4-amine (150 mg, 0.285 mmol) in THF (5 ml) n-BuLi solution (0.4 ml, 0.64 mmol) was added dropwise, maintaining the temperature in the range from -75 to -65°C. After 1 hour, a mixture of the product from step A (100 mg, 0.34 mmol) in THF (1 ml) was added. 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 (50 ml), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by pre-TLC (EA/PE=1/1) to give the title compound (95 mg, crude). MS: m/e 743 (M+1)+.

Step C: 2-butoxy-7-(4-((4-phenoxypiperidin-1-yl)methyl)benzyl)imidazo[2,1-1][1,2,4]triazin-4amine (compound A47).

To a mixture of the product of step B (95 mg, crude) in TFA (3 ml) was added Et ₃ SiH (1 ml) and the resulting mixture was stirred at 85°C overnight. The mixture was cooled to room temperature and concentrated to dryness. TFA (3 ml) was added to the precipitate and the resulting mixture was heated at 85°C overnight. The mixture was concentrated to dryness and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO3 solution, extracted with DCM (60 ml), washed with brine, dried over Na2SO4, filtered and concentrated to give the target compound (15 mg, 11% in two steps).

1H NMR (400 MHz, _DMSOD6 ) δ 8.13 (s, 1H), 8.03 (s, 1H), 7.31 (s, 1H), 7.29-7.18 (m, 6H), 6.96-6.85 (m, 3H), 4.42-4.28 (m, 1H), 4.19 (t, J=6.4 Hz, 2H), 4.12 (s, 2H) , 3.43 (s, 2H), 2.70-2.58 (m, 2H), 2.25-2.10 (m, 2H), 1.98-1.82 (m, 2H), 1 .72-1.50 (m, 4H), 1.46-1.32 (m, 2H), 0.91 (t, J=7.8 Hz, 3H) ppm. MS: m/e 487 (M+1)+.

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

Step A: 7-bromo-N^-bis(4-methoxybenzyl)-2-((5-methylisoxazol-3-yl)methoxy)imidazo[2,1-1][1,2,4]triazin-4- amine.

To a suspension of NaH (80 mg, 2 mmol) in THF (5 ml) was added (5-methylisoxazol-3-yl)methanol (226 mg, 2 mmol). After stirring at room temperature for 30 min, a solution of 7bromo-2-chloro-N^-bis(4-methoxybenzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (240 mg) was added , 0.5 mmol) in THF (2 ml). The mixture was then stirred at 80°C for 6 hours. The mixture was cooled to room temperature,

- 45 046488 was diluted with water (30 ml), extracted with EtOAc (60 ml), washed with saline, dried over Na2SO ₄ . filtered, concentrated and the precipitate was purified using CombiFlash to give the title compound (200 mg, 71%).

1H NMR (400 MHz, CDCI3) δ 7.50 (s, 1H), 7.18 (d, J=8.4 Hz, 4H), 6.88-6.82 (m, 4H), 6.18 (s, 1H), 5.61 (s, 2H), 5.43 (s, 2H), 4.85 (s, 2H), 3.80 (s, 6H), 2.40 (s, 3H) ppm MS: m/e 565 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-((5-methylisoxazol-3-yl)methoxy)imidazo[2,1-f][1,2,4]t riazin-7- yl)(4-(pyrrolidin-1-ylmethyl)phenyl)methanol.

To a solution of the product from step A (100 mg, 0.177 mmol) in THF (3 mL), a solution of n-BuLi (0.3 mL, 0.44 mmol) was added dropwise, maintaining the temperature between -75 and -65°C. After 1 hour, a solution of 4-(pyrrolidin-1-ylmethyl)benzaldehyde (80 mg, 0.424 mmol) in THF (1 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature over 4 hours. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (50 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated . The precipitate was purified by prepTLC to give the title compound (50 mg, crude). MS: m/e 676 (M+1) ⁺ .

Step C: 2-((5-methylisoxazol-3-yl)methoxy)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1G][1,2,4]triazin-4-amine (connection A48).

To a mixture of the product of step B (50 mg, crude) in TFA (3 ml) was added Et ₃ SiH (0.5 ml). The reaction was heated at 85°C for 16 hours. The mixture was concentrated to dryness and the residue was treated with TFA (3 ml). The reaction was heated at 85°C overnight. The mixture was concentrated and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the target compound (10 mg, 13% in two steps).

1H NMR (400 MHz, DMSOO δ 8.28 (s, 1H), 8.19 (s, 1H), 7.34 (s, 1H), 7.30-7.15 (m, 4H), 6, 27 (s, 1H), 5.31 (s, 2H), 4.12 (s, 2H), 3.51 (s, 2H), 2.44-2.33 (m, 7H), 1.75 -1.62 (m, 4H) ppm MS: m/e 420 (M+1)+.

Compound A49: 2-butoxy-7-(4-(((t^)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2fluorobenzyl)imidazo[2,1-G] [1,2,4]triazin-4-amine.

Step A: 4-(((t^)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzaldehyde hydrochloride.

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

Step B: 4-(((t^)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzaldehyde.

Iodoethane (156 mg, 1 mmol) was added to a solution of 4-(((t^)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2fluorobenzaldehyde hydrochloride (150 mg, 0.5 mmol) and K ₂ CO ₃ (138 mg, 1 mmol) in THF (3 ml) and DMF (3 ml). The solution was stirred at rt overnight, water (10 ml) was added, extracted with ethyl acetate (10 ml) and washed with brine (10 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by pre-TLC (DCM:MeOH=7:1) to give the pure product (60 mg, 41%). MS: m/e 278 (M+1)+.

Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4-(((t^)-8 ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorophenyl)methanol.

To a cooled solution of 7-bromo-2-butoxy-NiNbis(4-methoxybenzyl)imidazo[2,1G][1,2,4]triazin-4-amine (100 mg, 0.19 mmol) in THF (8 ml) at -78°C (purged with N2), n-BuLi (1.6 M, 0.3 ml) was added dropwise. After stirring at -78°C for 30 min, 4-(((1R,5S)-8ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorobenzaldehyde (58 mg, 0. 21 mmol) in THF (2 ml). The resulting mixture was stirred at this temperature for 30 min and then heated to rt for 2 h. The solution was quenched with NH4Cl solution (5 ml), extracted with ethyl acetate (5 ml) and washed with brine (5 ml). The organic layer was dried with Na2SO4, filtered and concentrated to give the crude product, which was further purified by pre-TLC (DCM:MeOH=8:1) to give the product (30 mg, 22%). MS: m/e 725 (M+1)+.

Step D: 2-butoxy-7-(4-(((t^)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2fluorobenzyl)imidazo[2,1-G| [1,2,4]triazin-4-amine (compound A49).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4-(((t^)-8-ethyl -8-azabicyclo[3.2.1]octan-3-yl)oxy)-2-fluorophenyl)methanol (28 mg, 0.04 mmol) in triethylsilane (2 ml) and trifluoroacetic acid (2 ml) were heated at 80°C during the night. The solvent was evaporated to leave a residue, which was purified by pre-HPLC to give the product (15 mg, 83%).

1H NMR (400 MHz, DMSO<) δ 9.22 (s, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.28 (s,lH), 7.24 ( t, J=8.0 Hz, 1H), 6.91 (dd, J=12.0, J=4.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 4.71 (s, 1H), 4.20 (t, J=8.0 Hz, 2H), 4.08 (s, 2H), 3.96 (s, 2H), 3.03-2.96 (m, 2H), 2.34-2.30 (m, 2H), 2.21-2.08 (m, 6H), 1.70-1.63 (m, 2H), 1.45-1 .36 (m, 2H), 1.24-1.21 (m, 3H), 0.92 (t, J=8.0 Hz, 3H) ppm. MS: m/e 469 (M+1)+.

Compound A50: 2-butoxy-7-((5-methoxypyridin-2-yl)methyl)imidazo[2,1-G][1,2,4]triazin-4-amine.

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(5

- 46 046488 methoxypyridin-2-yl)methanol.

To a stirred solution of 7-bromo-2-butoxy-K^bis(4-methoxybenzyl)imidazo[2.1P[1,2,4|triazin-4-amine (150 mg, 0.28 mmol) in THF (10 ml) , cooled to -78°C and under a nitrogen atmosphere, n-BuLi (1.6 M in hexane, 0.7 mmol, 0.43 ml) was added dropwise. After stirring for 60 min, a solution of 5-methoxypicolinaldehyde (50 mg, 0.34 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo to give the title product (200 mg, 100%), which was directly used in the next step without further purification. MS: m/e 585 (M+1)+.

Step B: 2-butoxy-7-((5-methoxypyridin-2-yl)methyl)imidazo[2,1-1][1,2,4]triazin-4-amine (compound A50).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(5methoxypyridin-2-yl)methanol (200 mg, 0 .28 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (10 mg, 10.8%).

Ή NMR (400 MHz, DMSO-dg) δ 8.18 (d, J=2.8 Hz, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.31 (dd , J=8.5, 2.8 Hz, 1H), 7.28 (s, 1H), 7.24 (d, J=8.6 Hz, 1H), 4.23 (s, 2H), 4 .15 (t, J=6.5 Hz, 2H), 3.78 (s, 3H), 1.68-1.57 (m, 2H), 1.43-1.30 (m, 2H), 0.90 (t, J=7.4 Hz, 3H) ppm. MS: m/e 329 (M+1)+.

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

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(6methoxypyridin-2-yl)methanol.

To a stirred solution of 7-bromo-2-butoxy-XNbis(4-methoxybenzyl)imidazo[2,11][1,2,4]triazin-4-amine (150 mg, 0.28 mmol) in THF (10 ml), cooled to -78°C under nitrogen, n-BuLi (1.6 M in hexane, 0.7 mmol, 0.43 ml) was added dropwise. After stirring for 60 min, a solution of 6-methoxypicolinaldehyde (50 mg, 0.34 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo to give the title product (250 mg, 100%) which was directly used in the next step without further purification. MS: m/e 585 (M+1)+.

Step B: 2-butoxy-7-((6-methoxypyridin-2-yl)methyl)imidazo[2,1-1][1,2,4]triazin-4-amine (compound A51).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(6methoxypyridin-2-yl)methanol (250 mg, 0 .28 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (25 mg, 27.2%).

Ή NMR (400 MHz, DMSOO δ 8.15 (s, 1H), 8.05 (s, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.35 (s, 1H) , 6.80 (d, J=7.3 Hz, 1H), 6.65 (d, J=8.2 Hz, 1H), 4.21 (s, 2H), 4.15 (t, J= 6.5 Hz, 2H), 3.79 (s, 3H), 1.68-1.56 (m, 2H), 1.37 (dd, J=15.0, 7.5 Hz, 2H), 0.90 (t, J=7.4 Hz, 3H) ppm MS: m/e 329 (M+1)+.

Compound A52: 7-(4-(pyrrolidin-1 -ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2,4-diamine.

Step A: 7-bromo-N2-(furan-2-ylmethyl)-H4,N-bis(4-methoxybenzyl)imidazo[2,1-1][1,2,4]triazin-2, 4-diamine.

A solution of 7-bromo-2-chloro-N,Nbis(4-methoxybenzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (200 mg, 0.41 mmol), furan- 2-ylmethanamine (80 mg, 0.28 mmol) and DIEA (106 mg, 0.82 mmol) in n-BuOH (5 ml) were heated at 120°C in a sealed tube for 48 hours. The solution was cooled, concentrated and further purified by pre-TLC (PE:EA=2:1) to obtain pure product (70 mg, 31%). MS: m/e 549 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-((furan-2-ylmethyl)amino)imidazo[2,1-f][1,2,4]triazin7-yl)(4- (pyrrolidin-1-ylmethyl)phenyl)methanol.

To a cooled solution of (4-(bis(4-methoxybenzyl)amino)-2-((furan-2ylmethyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)(4- (pyrrolidin-1-ylmethyl)phenyl)methanol (70 mg, 0.13 mmol) in THF (5 ml) at -78°C (purged with N2) n-BuLi (1.6 M, 0.2 ml) was added dropwise ). After stirring at -78°C for 30 min, 4-(pyrrolidin-1-ylmethyl)benzaldehyde (37 mg, 0.20 mmol) in THF (1 ml) was added. The resulting mixture was stirred at this temperature for 30 minutes, and then heated to rt overnight. The solution was quenched with NH4C1 solution (2 ml), extracted with ethyl acetate (10 ml) and washed with brine (10 ml). The organic layer was dried using

- 47 046488

Na ₂ SO ₄ was filtered and concentrated to give the crude product, which was further purified by pre-TLC (DCM:MeOH=7:1) to give the product (15 mg, 18%). MS: m/e 660 (M+1)+.

Step C: 7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-£][1,2,4]triazine-2,4-diamine (compound A52).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-((furan-2-ylmethyl)amino)imidazo[2,1-f][1,2,4]triazin7-yl)(4-(pyrrolidine -1-ylmethyl)phenyl)methanol (15 mg, 0.02 mmol) in triethylsilane (2 ml) and trifluoroacetic acid (2 ml) were heated at 80°C overnight. The solution was evaporated to a residue, which was purified by pre-HPLC to give the product (5 mg, 50%).

1H NMR (400 MHz, DMSOO δ 9.86 (br,s, 1H), 7.86 (br,s, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.35 ( d, J=8.0 Hz, 2H), 7.31 (s, 1H), 4.31 (d, J=8.0 Hz, 2H), 4.15 (s, 2H), 3.35- 3.31 (m, 2H), 3.12-3.05 (m, 2H), 2.05-2.02 (m, 2H), 1.86-1.81 (m, 2H) ppm MS : m/e 324 (M+1)+.

Compound A53: 2-butoxy-7-((6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3yl)methyl)imidazo[2,1-f][1,2,4]triazine-4 -amine.

Step A: 6-(3-(dimethylamino)-2,2-dimethylpropoxy)nicotinonitrile.

To a stirred suspension of NaH (60%, 600 mg, 15 mmol) in DMA (15 ml) was added a solution of 3(dimethylamino)-2,2-dimethylpropan-1-ol (1.44 g, 1.1 mmol) in DMA ( 2 ml). After stirring for 30 min, a solution of 6-chloronicotinonitrile (1.38 g, 10 mmol) in DMA (2 ml) was added. After addition, the reaction was stirred at 80°C overnight, the reaction was quenched with aq. NH ₄ Cl and extracted with EtOAc (20 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=20:1) to give the title compound (240 mg, 10.3%) as a white solid. . MS: m/e 234 (M+1)+.

Step B: 6-(3-(dimethylamino)-2,2-dimethylpropoxy)nicotinaldehyde.

To a stirred solution of the product from step A (233 mg, 1 mmol) in dry THF (10 ml) was added dropwise DIBAL-H (1.2 M, 2 ml, 2.5 mmol) at -20°C. After addition, the reaction was stirred for 3 hours. The reaction was quenched with aq. NH ₄ Cl and extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=10:1~2:1) to give the title compound (120 mg, 50.8%) in as a white solid. MS: m/e 237 (M+1)+.

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

To a solution of 7-bromo-2-butoxy-Nibis(4-methoxybenzyl)imidazo[2,1-1T][1,2,4]triazin-4-amine (150 mg, 0.286 mmol) in THF (10 ml ) n-BuLi (1.6 M, 0.44 ml, 0.71 mmol) was added dropwise at -78°C. After stirring for an hour, a solution of the product from step B (115 mg, 0.428 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred overnight. The reaction was extinguished by us. aq. NH ₄ Cl solution, extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC (100% EtOAc) to give the title compound (45 mg, 23%) as a colorless oil. MS: m/e 684 (M+1)+.

Step D: 2-butoxy-7-((5-chloro-6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3yl)methyl)imidazo[2,1-!T][1,2, 4]triazin-4-amine (compound A53).

A mixture of the product from step C (45 mg, 0.066 mmol) in EbSiH/TFA (0.5 ml/3 ml) was stirred at 85°C overnight. The reaction mixture was concentrated to give a residue, which was purified by pre-HPLC to give the title compound (10 mg, 35.4%).

1H NMR (400 MHz, DMSO<) δ 8.14 (s, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 7.59 (dd, J=8.4, 2 ,4 Hz, 1H), 7.30 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.19 (t, J=6.5 Hz, 2H), 4, 07 (s, 2H), 3.94 (s, 2H), 2.18 (s, 8H), 1.72-1.59 (m, 2H), 1.47-1.34 (m, 2H) , 0.96-0.86 (m, 9H) ppm. MS: m/e 428 (M+1)+.

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

Stage A:

7-bromo-2-isobutoxy-^Nbis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine.

Sodium (1 g) was added to the stirred 2-methylpropan-1-ol (10 g) in several portions. The mixture was stirred at 80°C for 2 hours. The above pure solution was added to 7-bromo-2chloro-VNbis(4-methoxybenzyl)imidazo[2,14][1,2,4]triazin-4-amine (0 .25 g, 0.51 mmol). The mixture was heated to 80°C and stirred for 1 hour. Once complete, the mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml x 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on a 0-20% EA in PE column to give the product (0.18 g, 67%) as a white solid. MS: m/e 526 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-isobutoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(pyrrho

- 48 046488 lidin-1 -ylmethyl)phenyl)methanol.

To a stirred solution of 7-bromo-2-isobutoxy-X.X-bis(4-methoxybenzyl)imidazo[2.1P|1,2,4|triazin-4-amine (180 mg, 0.34 mmol) in THF (10 ml) at -78°C under N2 atmosphere, n-BuLi (1.6 M, 0.54 ml, 0.86 mmol) was added. The solution was stirred at -78°C for 30 minutes. 4-(pyrrolidin-1ylmethyl)benzaldehyde (97 mg, 0.51 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was warmed to rt and then stirred for 3 hours. Once complete, the reaction mixture was quenched with H2O (20 ml) then extracted with DCM (20 ml x 3). The organic phase was washed with H2O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow oil, which was directly used in the next step without further purification. MS: m/e 637 (M+1)+.

Step C: 2-isobutoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-£][1,2,4]triazin-4-amine (compound A54).

Solution (4-(bis(4-methoxybenzyl)amino)-2-isobutoxyimidazo[2,1-G|[1,2,4]triazin-7-yl)(4-(pyrrolidin-1-ylmethyl)phenyl) methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) were stirred at 80°C for 24 hours. Once complete, the reaction mixture was concentrated under reduced pressure. The precipitate was dissolved in EA (30 ml) and washed with aq. NaHCO ₃ (us, 25 ml) and saline (20 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by pre-TLC with DCM:MeOH (10:1) to give the product (13.83 mg).

¹ 1 NMR (400 MHz, CD3OD) δ 7.49-7.42 (m, 4H), 7.33 (s, 1H), 4.65 (s, 1H), 4.38-4.34 (m , 1H), 4.33 (s, 2H), 4.26 (s, 2H), 4.04 (d, J=4 Hz, 2H), 2.16-1.98 (m, 7H), 1 .02 (d, J=8 Hz, 6H) ppm. MS: m/e 381 (M+1)+.

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

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

To a solution of tert-butyl(2-butoxy-7 -(hydroxy(3-methoxypyridin-2-yl)methyl)imidazo[2,1D[1,2,4]triazin-4-yl)(tert-butoxycarbonyl)carbamate ( 150 mg, 0.3 mmol) in THF (5 ml), a solution of n-BuLi (0.4 ml, 0.6 mmol) was added dropwise, maintaining the temperature between -75 and -65°C. After 1 hour, a solution of 3-methoxypicolinaldehyde (55 mg, 0.45 mmol) in THF (1 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature overnight. The reaction was quenched with saturated NH4C1 solution, extracted with EtOAc (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC to give the title compound (20 mg, crude). MS: m/e 545 (M+1)+.

Step B: 2-butoxy-7-((3-methoxypyridin-2-yl)methyl)imidazo[2,1-!][1,2,4]triazin-4-amine (compound A55).

To a mixture of the product of step A (20 mg, crude) in TFA (3 ml) was added Et ₃ SiH (0.5 ml). The reaction was heated at 85°C overnight. The mixture was concentrated to dryness and the residue was purified by pre-HPLC to give the title product (8 mg, 6% in two steps).

¹ 1 NMR (400 MHz, CD3OD) δ 8.23 (d, J=5.4 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.80 (dd, J= 8.0, 5.4, Hz, 1H), 7.54 (s, 1H), 4.60 (s, 2H), 4.14 (t, J=6.4 Hz, 2H), 4.03 (s, 3H), 175-1.62 (m, 2H), 1.50-1.38 (m, 2H), 0.96 (t, J=7.6 Hz, 3H) ppm. MS: m/e 329 (M+1)+.

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

To a mixture of tert-butyl(2-butoxy-7 -(hydroxy(3-methoxypyridin-2-yl)methyl)imidazo[2,1:C[1,2,4]triazin-4-yl)(tert-butoxycarbonyl) carbamate (35 mg, crude) in DCM (3 ml) was added TFA (1 ml) and Et ₃ SiH (1 ml). The reaction was heated at 40°C overnight. The mixture was concentrated to dryness and the residue was purified by pre-HPLC to give the title product (20 mg, 68%).

¹ 1 NMR (400 MHz, DMSOO δ 8.25 (d, J=4.0 Hz, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.81 (d, J =6.0 Hz, 1H), 7.66 (d, J=3.2 Hz, 1H), 7.43 (s, 1H), 6.43 (s, 1H), 4.10-3.98 (m, 1H), 3.96-3.86 (m, 1H), 3.82 (s, 3H), 1.66-1.52 (m, 2H), 1.45-1.26 (m , 2H), 0.91 (t, J=7.6 Hz, 3H) ppm MS: m/e 345 (M+1)+.

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

Step A: Methyl 2-(3-(dimethylamino)propoxy)-5-formyl benzoate.

A mixture of methyl 5-formyl-2-hydroxybenzoate (500 mg, 2.7 mmol), 3-chloro-N,Ni-dimethylpropan-1amine hydrochloride (512 mg, 3.2 mmol) and Cs ₂ CO ₃ (1.7 g, 5.4 mmol) in DMF (20 ml) was heated at 80°C overnight. The solution was eluted with water (20 ml), extracted with ethyl acetate (20 ml) and washed with brine (10 ml). The organic layer was dried, concentrated and purified using CombiFlash (DCM:MeOH=10%, with 10% NH ₃ .MeOH) to give the product (400 mg, 54%).

¹ 1 NMR (400 MHz, DMSO^) δ 9.91 (s, 1H), 8.20 (s, 1H), 8.06 (dd, J=8.0, 4.0 Hz, 1H), 7 .35 (d, J=12.0 Hz, 1H), 4.20 (t, J=8.0 Hz, 2H), 3.84 (s, 3H), 2.42 (t, J=8, 0 Hz, 2H), 2.16 (s, 6H), 1.91-1.85 (m, 2H) ppm. MS: m/e 266 (M+1) ⁺ .

Step B: methyl 5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-£][1,2,4]triazin-7yl)(hydroxy)methyl)-2- (3-(dimethylamino)propoxy)benzoate.

- 49 046488

To a cooled solution of 7-bromo-2-butoxy-H,H-bis(4-methoxybenzyl)imidazo[2,1P[1,2,4|triazin-4-amine (150 mg, 0.29 mmol) in THF ( 8 ml) at -78°C (purged with N2), n-BuLi (1.6 M, 0.5 ml) was added dropwise. After stirring at -78°C for 30 min, methyl 2-(3(dimethylamino)propoxy)-5-formyl benzoate (115 mg, 0.44 mmol) in THF (2 ml) was added. The resulting mixture was stirred at this temperature for 30 minutes and then heated to rt for 2 hours. 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 with Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified by pre-TLC (DCM:MeOH=7:1) to give the product (54 mg, 27%). MS: m/e 713 (M+1)+.

Step C: methyl 5-((4-amino-2-butoxyimidazo [2,1-f|[1,2,4]triazin-7-yl)methyl)-2-(3 (dimethylamino)propoxy)benzoate ( connection A57).

Solution of methyl 5-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(hydroxy)methyl)-2 -(3-(dimethylamino)propoxy)benzoate (54 mg, 0.08 mmol) in triethylsilane (2 ml) and trifluoroacetic acid (2 ml) were heated at 80°C overnight. The solvent was evaporated to leave a residue which was purified by pre-HPLC to give the product (23 mg, 67%).

Ή NMR (400 MHz, DMSO-dg) δ 9.50 (br,s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.73 (s,1H), 7 .50 (d, J=8.0 Hz, 1H), 7.33 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 4.20 (t, J=8, 0 Hz, 2H), 4.12-4.09 (m, 4H), 3.80 (s, 3H), 3.27-3.23 (m, 2H), 2.82 (d, J=4 .0 Hz, 6H), 2.14-2.10 (m, 2H), 1.70-1.65 (m, 2H), 1.43-1.38 (m, 2H), 0.92 ( t, J=8.0 Hz, 3H) ppm. MS: m/e 457 (M+1)+.

Compound A58: 2-butoxy-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1P[1.2.4|triazin-4-amine.

Step A: tert-butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate.

K ₂ CO ₃ (5.52 g, 40 mmol) was added to a solution of 6-chloronicotinaldehyde (2.82 g, 20 mmol) and tert-butyl(2-hydroxyethyl)(methyl)carbamate (4.2 g, 24 mmol) in DMA (40 ml), the reaction mixture was heated at 80°C overnight, cooled to room temperature. The solution was quenched with H2O (40 ml). The aqueous solution was extracted with EA (40 mlx3). The collected organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography to give the product (560 mg, 10%) MS: m/e 281 (M+1)+.

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

To a solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1-1G][1,2,4]triazin-4-amine (158 mg, 0.3 mmol) in THF (1 ml), n-BuLi solution (0.28 ml, 0.45 mmol) was added dropwise, maintaining the temperature between -75 and -65°C. After 10 min, a solution of the product from step A (126 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 a saturated solution of NH4C1, extracted with EtOAc (10 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to obtain the title compound (200 mg, 91%). MS: m/e 728 (M+1)+.

Step C: 2-butoxy-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4amine (compound A58 ).

To a mixture of the product of step B (180 mg, 0.25 mmol) in TFA (1 ml) was added Et ₃ SiH (1 ml). The reaction was heated at 80°C overnight. The mixture was concentrated to dryness and the residue was treated with TFA (1 ml). The reaction was heated at 80°C overnight. The mixture was concentrated and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (30 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title product (20 mg, 22%).

Ή NMR (400 MHz, CDC13) δ 8.11 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.25 (s, 1H), 6.70 (d, J =8.0 Hz, 1H), 4.40 (t, J=6.0 Hz, 2H), 4.28 (t, J=6.0 Hz, 2H), 4.11 (s, 2H), 2.99 (t, J=8.3 Hz, 2H), 2.52 (s, 3H), 1.82-1.71 (m, 4H), 1.53-1.42 (m, 2H) , 0.98 (t, J=6.2 Hz, 3H) ppm. MS: m/e 372 (M+1)+.

Compound A59: No.(2-((5-((4-amino-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)methyl)pyridin-2yl)oxy)ethyl) -N-methylacetamide.

Ac2O (4 mg, 0.04 mmol) was added to a solution of 2-butoxy-7-((6-(2-(methylamino)ethoxy)pyridin-3yl)methyl)imidazo[2,1-C[1,2,4 ]triazin-4-amine (11 mg, 0.03 mmol) and Et ₃ N in DCM (0.5 ml), the reaction mixture was stirred at 0° C. for 2 hours. The mixture was concentrated and the residue was purified using pre-HPLC. The collected fraction was made alkaline with NaHCO3 solution, extracted with DCM (30 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title product (10 mg, 80%).

Ή NMR (400 MHz, CDC13) δ 8.11 (s, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.31 (s, 1H), 6.69 (d, J =8.2 Hz, 1H), 4.45 (t, J=6.4 Hz, 2H), 4.33 (t, J=8.0 Hz, 2H), 4.15 (s, 2H), 3.74-3.68 (m, 2H), 3.11 (s, 2H), 2.99 (s, 2H), 2.152.10 (m, 3H), 1.78-1.69 (m, 2H), 1.39-1.26 (m, 2H), 0.98 (t, J=6.0 Hz, 3H) ppm. MS: m/e 414 (M+1)+.

Compound A60: 2-butoxy-7-(4-((1-ethylpyrrolidin-3-yl)oxy)-2-fluorobenzyl)imidazo[2,1P[1,2,4]triazin-4-amine.

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Step A: 2-fluoro-4-(pyrrolidin-3-yloxy)benzaldehyde hydrochloride.

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

Step B: 4-((1-ethylpyrrolidin-3-yl)oxy)-2-fluorobenzaldehyde.

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

Step C: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(4-((1ethylpyrrolidin-3-yl) hydroxy)-2-fluorophenyl)methanol.

To a cooled solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,11][1,2,4]triazin-4-amine (100 mg, 0.2 mmol) in THF ( 8 ml) at -78°C (purged with N2), n-BuLi (1.6 M, 0.3 ml) was added dropwise. After stirring at -78°C for 30 min, 4-((1ethylpyrrolidin-3-yl)oxy)-2-fluorobenzaldehyde (68 mg, 0.3 mmol) in THF (2 ml) was added. The resulting mixture was stirred at this temperature for 30 min and then heated to rt for 2 h. 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 Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified by pre-TLC (DCM:MeOH=8:1) to give the product (78 mg, 60%). MS: m/e 685 (M+1)+.

Step D: 2-butoxy-7-(4-((1-ethylpyrrolidin-3-yl)oxy)-2-fluorobenzyl)imidazo[2,1-f][1,2,4]triazin4-amine (compound A60 ).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(( 1 ethylpyrrolidin-3-yl)oxy )-2-fluorophenyl)methanol (78 mg, 0.1 mmol) in triethylsilane (2 ml) and trifluoroacetic acid (2 ml) were heated at 80°C overnight. The solvent was evaporated to a residue, which was purified by pre-TLC (DCM:MeOH=8:1) to give the product (18 mg, 38%).

¹ H NMR (400 MHz, DMSOHO δ 8.15 (s, 1H), 8.05 (s, 1H), 7.24 (s, 1H), 7.18 (t, J=8.0 Hz, 1H ), 6.75 (dd, J=12.0 Hz, J ₂ =4.0 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 4.84 (s, 1H) , 4.19 (t, J=8.0 Hz, 2H), 4.07 (s, 2H), 2.79 (s, 1H), 2.71-2.65 (m, 2H), 2, 44-2.30 (m, 3H), 2.29-2.21 (m, 1H), 1.75-1.63 (m, 3H), 1.44-1.35 (m, 2H), 1.02 (t, J=8.0 Hz, 3H), 0.92 (t, J=8.0 Hz, 3H) ppm MS: m/e 429 (M+1)+.

Compound A61: 2-butoxy-7-(2-fluoro-4-(pyrrolidin-3-yloxy)benzyl)imidazo[2,1!T][1,2,4]triazin-4-amine.

Step A: tert-butyl 3-(3-fluoro-4-formylphenoxy)pyrrolidine-1-carboxylate.

A solution of 2-fluoro-4-hydroxybenzaldehyde (1 g, 7.1 mmol), tert-butyl-3-bromopyrrolidine-1carboxylate (2.7 g, 10.7 mmol) and Cs ₂ CO ₃ (4.6 g, 14 .2 mmol) in DMF (20 ml) was heated at 80°C overnight. The solution was filtered and water (10 ml) was added to the filtrate, extracted with ethyl acetate (20 ml) and washed with brine (10 ml). The organic layer was dried, concentrated and purified using CombiFlash (PE:EA=20%) to give the product as a colorless oil (1.1 g, 50%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.21 (s, 1H), 7.83 (t, J=8.0 Hz, 1H), 6.75 (dd, J=8.0, 4, 0 Hz, 1H), 6.62 (dd, J=12.0, 4.0 Hz, 1H), 4.95 (s, 1H), 3.67-3.50 (m, 4H), 2, 20 (d, J=8.0 Hz, 2H), 1.48 (s, 9H) ppm. MS: m/e 310 (M+1)+.

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

To a cooled solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1Al,2,4]triazin-4-amine (150 mg,

0.29 mmol) in THF (8 ml) at -78°C (purged with N2) n-BuLi (1.6 M, 0.5 ml) was added dropwise. After stirring at -78°C for 30 min, tert-butyl 3-(3-fluoro-4formylphenoxy)pyrrolidine-1-carboxylate (132 mg, 0.43 mmol) in THF (2 ml) was added. The resulting mixture was stirred at this temperature for 30 minutes, and then heated to rt 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 with Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified by CombiFlash (PE:EA=1:1) to give the product (110 mg, 51%). MS: m/e 757 (M+1)+.

Step C: 2-butoxy-7-(2-fluoro-4-(pyrrolidin-3-yloxy)benzyl)imidazo[2,14][1,2,4]triazin-4-amine (compound A61).

Solution of tert-butyl-3 -(4-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7yl)(hydroxy)methyl) -3-fluorophenoxy)pyrrolidine-1-carboxylate (110 mg, 0.15 mmol) in triethylsilane (2 ml) and trifluoroacetic acid (2 ml) were heated at 80°C overnight. The solvent was evaporated until

- 51 046488 to obtain a precipitate, which was purified using pre-HPLC to obtain the product (33 mg, 57%).

1H NMR (400 MHz, DMSO-dg) δ 8.15 (s, 1H), 8.04 (s, 1H), 7.23 (s, 1H), 7.18 (t, J=8.0 Hz , 1H), 6.77-6.66 (m, 2H), 4.81 (s, 1H), 4.19 (t, J=8.0 Hz, 2H), 4.06 (s, 2H) , 3.04-3.01 (m, 1H), 2.82-2.71 (m, 3H), 1.98-1.95 (m, 1H), 1.72-1.63 (m, 3H), 1.41-1.37 (m, 2H), 0.92 (t, J=8.0 Hz, 3H) ppm. MS: m/e 401 (M+1)+.

Compound A62: 7-(4-((III-1,2,4-triazol-1-yl)methyl)benzyl)-2-butoxyimidazo[2,1C[1,2,4|triazin-4-amine.

Step A: 4-((1H-1,2,4-triazol-1-yl)methyl)benzaldehyde.

To a solution of 4-(bromomethyl)benzaldehyde (200 mg, 1 mmol) and K2CO3 (200 mg, 1.5 mmol) in acetone (5 ml) was added 1H-1,2,4-triazole (75 mg, 2.2 mmol ). The mixture was then stirred at room temperature overnight. The mixture was diluted with water (50 ml), extracted with EtOAc (60 ml), washed with saline, dried over Na ₂ SO ₄ and filtered. Concentrate and purify the residue using CombiFlash to give the title compound (130 mg, 69%). MS: m/e 188 (M+1) ⁺ .

Step B: (4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)(4-(bis(4-methoxybenzyl)amino)-2-butoxyimidase o[2.1-G|[1.2 .4|triazin-7-yl)methanol.

To a solution of 7-bromo-2-butoxy-H,Nbis(4-methoxybenzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF (8 ml), n-BuLi solution (0.48 ml, 1.6 mmol) was added dropwise, maintaining the temperature in the range of -75 to -65°C. After 1 hour, a mixture of the product from step A (107 mg, 0.57 mmol) in THF (1 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature overnight. The reaction was quenched with a saturated solution of NH4C1, extracted with EtOAc (40 mlx2), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC to give the title compound (130 mg, crude). MS: m/e 635 (M+1)+.

Step C: 7-(4-((1H-1,2,4-triazol-1-yl)methyl)benzyl)-2-butoxyimidazo[2,1-G|[1,2,4]triazin-4- amine (compound A62).

To a mixture of the product of step B (60 mg, crude) in TFA (3 ml) was added Et ₃ SiH (0.5 ml). The resulting mixture was heated at 85°C overnight. The mixture was concentrated to dryness and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (50 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the target compound (25 mg, 17% in two steps).

1H NMR (400 MHz, DMSOO δ 8.62 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.34-7, 27 (m, 3H), 7.19 (d, J=8.4 Hz, 2H), 5.36 (s, 2H), 4.17 (t, J=6.4 Hz, 2H), 4, 12 (s, 2H), 1.72-1.59 (m, 2H), 1.46-1.30 (m, 2H), 0.91 (t, J=7.2 Hz, 3H) ppm. MS: m/e 379 (M+1)+.

Compound A63: 2-butoxy-7-(4-(3 -(methylamino)propoxy)benzyl)imidazo[2,1-G][1,2,4]triazin-4amine.

Step A: tert-butyl (3-(4-formylphenoxy)propyl)(methyl)carbamate.

To a solution of 4-hydroxybenzaldehyde (0.61 g, 5 mmol), tert-butyl(3hydroxypropyl)(methyl)carbamate (0.95 g, 5 mmol) and PPh ₃ (1.96 g, 7.5 mmol) in THF (8 ml) was added dropwise 40% DIAD in toluene solution (3.7 g, 7.5 mmol). The mixture was then stirred at room temperature overnight. The mixture was diluted with water (50 ml), extracted with EtOAc (40 mlx2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and the residue purified using CombiFlash to give the title compound (0.71 g, 48%). MS: m/e 238 (M+N-TVi)+.

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

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

Step C: 2-butoxy-7-(4-(3-(methylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (compound A63).

To a mixture of the product of step B (130 mg, crude) in TFA (3 ml) was added Et ₃ SiH (1 ml). The reaction was heated at 85°C overnight. The mixture was cooled to room temperature and concentrated to dryness. The precipitate was purified using pre-HPLC. The collected fraction was made alkaline with NaHCO3 solution, extracted with DCM (60 mlx2), washed with brine, dried over Na2SO4, filtered and concentrated to obtain the target compound (36 mg, 25% in two steps).

1H NMR (400 MHz, DMSO^) δ 8.12 (s, 1H), 8.02 (s, 1H), 7.25 (s, 1H), 7.20 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.20 (t, J=6.4 Hz, 2H), 4.05 (s, 2H), 3.96 (t, J=6.4 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.30 (s, 3H),

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1.90-1.79 (m, 2H), 1.73-1.62 (m, 2H), 1.46-1.34 (m, 2H), 0.92 (t, J=7.6 Hz, 3H) ppm. MS: m/e 385 (M+1)+.

Compound A64: Na-(furan-2-ylmethyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1P[1,2,4|triazin-2,4-diamine.

Step A: 7-bromo-N-((|)uran-2-ylmethyl)imidazo[2.1-G|[1.2.4|triazin-2.4-diamine.

A solution of 7-bromo-2-chloroimidazo[2,1-G|[1,2,4]triazin-4-amine (500 mg, 2 mmol), furan-2ylmethanamine (388 mg, 4 mmol) and DIEA (516 mg , 4 mmol) in n-BuOH (10 ml) in a sealed tube was heated at 120°C overnight. After concentration under reduced pressure, the precipitate was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). The organic layer was dried, concentrated and purified using CombiFlash (PE:EA=50%) to give the product (180 mg, 29%).

1H NMR (400 MHz, DMSOD ₆ ) δ 7.86 (br,s, 2H), 7.54 (s, 1H), 7.44 (s, 1H), 7.02 (t, J=8.0 Hz, 1H), 6.37 (d, J=4.0 Hz, 1H), 6.30 (d, J=4.0 Hz, 1H), 4.38 (d, J=4.0 Hz, 2H) ppm. MS: m/e 309 (M+1)+.

Step B: tert-butyl(7-bromo-2-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)imidazo [2,1G][1,2,4]triazin-4-yl)(tert- butoxycarbonyl)carbamate.

Solution of 7-bromo-N2-(furan-2-ylmethyl)imidazo[2,1-G][1,2,4]triazine-2,4-diamine (150 mg, 0.5 mmol), (Boc) ₂ O (327 mg, 1.5 mmol) and DMAP (31 mg, 0.25 mmol) in DCM (10 ml) were stirred at rt overnight. The solution was concentrated and purified using CombiFlash (PE:EA=20%) to obtain pure product (270 mg, 91%). MS: m/e 609 (M+1)+.

Step C: tert-butyl(tert-butoxycarbonyl)(2-(((uran-2-ylmethyl)amino)-7-(hydroxy(4-(pyrrolidin n-1 -ylmethyl)phenyl)methyl)imidazo [2,1 -G|[1,2,4]triazin-4-yl)carbamate.

To a cooled solution of tert-butyl(7-bromo-2-((tert-butoxycarbonyl)(furan-2ylmethyl)amino)imidazo[2,1-f][1,2,4]triazin-4-yl)(tert- butoxycarbonyl)carbamate (150 mg, 0.25 mmol) in THF (8 ml) at -78°C (purged with N2) was added dropwise n-BuLi (1.6 M, 0.4 ml). After stirring at -78°C for 30 min, 4-(pyrrolidin-1-ylmethyl)benzaldehyde (70 mg, 0.37 mmol) in THF (2 ml) was added. The resulting mixture was stirred at this temperature for 30 minutes and then heated to rt overnight. The solution was quenched with NH4C1 solution (5 ml), extracted with ethyl acetate (10 ml) and washed with brine (10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified using CombiFlash (DCM:MeOH=7:1) to give the pure product (15 mg, 10%). MS: m/e 620 (M+1)+.

Step D: ^-(furan-2-ylmethyl)-7-(4-(pyrrolidin-1 -ylmethyl)benzyl)imidazo [2,1-G|[1,2,4|triazin2,4-diamine (compound A64 ).

Triethylsilane (0.5 ml) and trifluoroacetic acid (0.5 ml) were added to the mixture of tert-butyl(tertbutoxycarbonyl)(2-((furan-2-ylmethyl)amino)-7-(hydroxyl(4-(pyrrolidine-1 ylmethyl)phenyl)methyl)imidazo[2,1-G][1,2,4]triazin-4-yl)carbamate (15 mg, 0.02 mmol) in DCM (1 ml) and heated at 40°C in for 2 hours. The solvent was evaporated to leave a residue, which was purified by pre-HPLC to give the product (3 mg, 31%).

1H NMR (400 MHz, CD ₃ OD) δ 7.47-7.41 (m, 6H), 6.32 (d, J=4.0 Hz, 1H), 6.21 (d, J=4, 0 Hz, 1H), 4.46 (s, 2H), 4.33 (s, 2H), 4.26 (s, 2H), 3.19-3.44 (m, 2H), 3.17- 3.13 (m, 2H), 2.22-2.15 (m, 2H), 2.02-1.93 (m, 2H) ppm. MS: m/e 404 (M+1)+.

Compound A65: 4-amino-7-(4-(pyrrolidin-1 -ylmethyl)benzyl)imidazo[2,1-G|[TD^triazin^-ol.

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

NaH (80 mg, 2 mmol, 60% in oil) was added to a stirred solution of furan-2-ylmethanol (73 mg, 0.75 mmol) in THF (20 ml) at 0°C. The reaction mixture was stirred at 0°C for 0.5 h.

7-Bromo-2-chloro-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (243 mg, 0.5 mmol) was added to the mixture , and the reaction mixture was stirred at 70°C for 6 hours. The mixture was diluted with H ₂ O (20 ml) and extracted with EtOAc (10 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography to give the product (150 mg, 57.4%) as a white solid. MS: m/e 550 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-(furan-2-ylmethoxy)imidazo[2,1-G|[1,2,4|triazin-7yl)(4-(pyrrolidin- 1-ylmethyl)phenyl)methanol.

To a stirred solution of 7-bromo-2-(furan-2-ylmethoxy)-Nibis(4-methoxybenzyl)imidazo[2,1G][1,2,4]triazin-4-a min (120 mg, 0. 22 mmol) in THF (10 ml), cooled to -78°C under nitrogen, n-BuLi (1.6 M in hexane, 0.55 mmol, 0.34 ml) was added dropwise. After stirring for 50 min, a solution of 4-(pyrrolidin-1-ylmethyl)benzaldehyde (66 mg, 0.33 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography to give the title product (30 mg, 20.6%). MS: m/e 661 (M+1)+.

Step C: 4-amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-G|[1,2,4|triazin-2-ol.

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A solution of 4-(ois(4-methoxybenzyl)amino)-2-((|)uran-2-ylmethoxy)imidazo[2,1T|[1,2,4|triazin-7yl)(4-(pyrrolidin-1- ylmethyl)phenyl)methanol (30 mg, 0.045 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (13 mg, 88%).

Ή NMR (400 MHz, DMSO-dg) δ 9.83 (s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.44 (d, J=7.6 Hz , 2H), 7.34 (d, J=7.6 Hz, 2H), 7.26 (s, 1H), 4.32 (s, 2H), 4.17 (s, 2H), 3.34 (s, 2H), 3.07 (s, 2H), 1.96-1.91 (m, 2H), 1.86-1.75 (m, 2H) ppm. MS: m/e 325 (M+1)+.

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

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-( 1 -methyl irrolidin-3 - yl)phenyl)methanol.

To a stirred solution of 7-bromo-2-butoxy-NiNbis(4-methoxybenzyl)imidazo[2,1Al,2,4]triazin-4-amine (105 mg, 0.2 mmol) in THF (10 ml), cooled to -78°C under nitrogen, n-BuLi (1.6 M in hexane, 0.5 mmol, 0.31 ml) was added dropwise. After stirring for 50 min, a solution of 4-(1-methylpyrrolidin-3-yl)benzaldehyde (43 mg, 0.2 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo to give the product (30 mg, 23.5%). MS: m/e 638 (M+1) ⁺ .

Step B: 2-butoxy-7-(4-(1-methylpyrrolidin-3-yl)benzyl)imidazo[2,1-£][1,2,4]triazin-4-amine (compound A66).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(4-(1-methylpyrrolidin-3-yl) phenyl)methanol (30 mg, 0.047 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et 3 SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (5 mg, 28%).

Ή NMR (400 MHz, DMSO^) δ 8.12 (s, 1H), 8.03 (s, 1H), 7.29 (s, 1H), 7.25-7.19 (m, 4H), 4.20 (t, J=6.4 Hz, 2H), 4.09 (s, 2H), 3.11-2.95 (m, 1H), 2.82-2.75 (m, 2H) , 2.59-5.52 (m, 2H), 2.44 (s, 3H), 2.26-2.18 (m, 1H), 1.79-1.61 (m, 3H), 1 .42-1.37 (m, 2H), 0.92 (t, J=7.4 Hz, 3H) ppm. MS: m/e 381 (M+1)+.

Compound A67: H2-butyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2.1T|[1.2.4|triazin-2.4diamine.

Stage A:

(4-(bis(4-methoxybenzyl)amino)-2-(butylamino)imidazo[2,1-f|[1,2,4]triazin-7-yl)(4-(pyrrolidin1 -ylmethyl)phenyl) methanol

To a stirred solution of 7-bromo-H2-butyl-N4,N-bis(4-methoxybenzyl)imidazo[2,1f][1,2,4]triazine-2,4-diamine (150 mg, 0.285 mmol) in THF (10 ml) was added dropwise n-BuLi (1.6 M, 0.35 ml, 0.428 mmol) at -78°C. After stirring for an hour under N2 at -78°C, a solution of 4-(pyrrolidin-1-ylmethyl)benzaldehyde (87.4 mg, 0.428 mmol) in THF (2 ml) was added dropwise. After addition, the reaction was stirred for 3 hours. The reaction was quenched with aq. NH4C1, extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by pre-TLC (CH ₂ Cl ₂ :MeOH=10:1) to give the title compound (65 mg, 35.8%) as white solid matter. MS: m/e 636 (M+1)+.

Step B: Na-butyl-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f|[1,2,4|triazin-2,4-diamine.

A mixture of the product from step A (65 mg, 0.102 mmol) in EbSiH/TFA (0.5 ml/3 ml) was stirred at 85°C overnight. The reaction mixture was concentrated to give a residue, which was purified by pre-HPLC to give the title compound (26 mg, 67.1%).

¹ H NMR (400 MHz, DMSOD ₆ ) δ 9.72 (br,s, 1H), 7.69 (s, 2H), 7.46-7.37 (m, 4H), 7.36-7, 28 (m, 1H), 6.45 (s, 1H), 4.30 (d, J=5.6 Hz, 2H), 4.14 (s, 2H), 3.38-3.26 (m , 2H), 3.16 (t, J=6.8 Hz, 2H), 3.15-3.02 (m, 2H), 2.051.96 (m, 2H), 1.90-1.76 ( m, 2H), 1.56-1.45 (m, 2H), 1.39-1.26 (m, 2H), 0.89 (t, J=7.2 Hz, 3H) ppm. MS: m/e 380 (M+1)+.

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

Step A: 7-bromo-^Nibis(4-methoxybenzyl)-2-(pyridin-3-ylmethoxy)imidazo[2,1-f|[1,2,4|triazin-4amine.

To a suspension of NaH (80 mg, 2 mmol) in THF (8 ml) was added pyridin-3-ylmethanol (218 mg, 2 mmol). After stirring at room temperature for 30 min, a solution of 7-bromo-2-chloro-Ni bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (240 mg, 0.5 mmol) in THF (2 ml). Then the mixture was stirred at 80°C for 4 hours. The mixture was cooled to room temperature and diluted with water

- 54 046488 (30 ml), extracted with EtOAc (50 mlx2), washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and the precipitate was purified using CombiFlash to obtain the title compound (250 mg, 89%).

1H NMR (400 MHz, CDCl ₃ ) δ 8.84 (s, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.07 (d, J=6.8 Hz, 1H) , 7.51-7.45 (m, 2H), 7.17 (d, J=8.4 Hz, 4H), 6.85 (d, J=8.0 Hz 4H), 5.60 (s , 2H), 5.46 (s, 2H), 4.83 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H) ppm. MS: m/e 561 (M+1)+.

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

To a solution of the product from step A (250 mg, 0.44 mmol) in THF (8 ml), a solution of n-BuLi (0.41 ml, 0.66 mmol) was added dropwise, maintaining the temperature between -75 and -65° WITH. After 1 hour, a solution of 4-(pyrrolidin-1-ylmethyl)benzaldehyde (100 mg, 0.53 mmol) in THF (1 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature over 5 hours. The reaction was quenched with saturated NH ₄ Cl solution, extracted with EtOAc (50 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by prepTLC to give the title compound (80 mg, crude). MS: m/e 672 (M+1)+.

Step C: 2-(pyridin-3 -ylmethoxy)-7-(4-(pyrrolidin-1 -ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin4-amine (compound A68).

To a mixture of the product of step B (80 mg, crude) in TFA (3 ml) was added Et ₃ SiH (1 ml). The reaction was heated at 85°C overnight. The mixture was concentrated and the residue was purified by pre-HPLC. The collected fraction was made alkaline with NaHCO ₃ solution, extracted with DCM (60 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the target compound (8 mg, 5% in two steps).

1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8.49 (d, J=4.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.50-7.39 (m, 1H), 7.37-7.20 (m, 5H), 5.39 (s, 2H), 4.21 (s, 2H), 3.67 (s, 2H), 2.71-2.50 (m, 4H), 1.91-1.75 (m, 4H) ppm. MS: m/e 416 (M+1) ⁺ .

Compound A69: 7 -(4-(pyrrolidin-1-ylmethyl)benzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1C[1,2,4]triazin-4-amine.

Step A: 7-bromo-H/N-bis(4-methoxybenzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-1][1,2,4]triazine-4 amine.

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

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

To a stirred solution of 7-bromo-N^-bis(4-methoxybenzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,14][1,2,4]triazin-4-amine (200 mg, 0.34 mmol) n-BuLi (1.6 M, 0.54 mL, 0.86 mmol) was added to THF (15 mL) at -78°C under N2. The solution was stirred at -78°C for 30 minutes. 4(pyrrolidin-1-ylmethyl)benzaldehyde (97 mg, 0.51 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was warmed to rt and then stirred for 3 hours. Once complete, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml x 3). The organic phase was washed with H ₂ O (10 ml), dried and concentrated under reduced pressure to give the crude product as a yellow oil, which was directly used in the next step without further purification. MS: m/e 691 (M+1)+.

Step C: 7-(4-(pyrrolidin-1 -ylmethyl)benzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-f][1,2,4]triazin4-amine (compound A69 ).

Solution of (4-(bis(4-methoxybenzyl)amino)-2-(4,4,4-trifluorobutoxy)imidazo[2,1-1][1,2,4]triazin-7yl)(4-(pyrrolidin- 1-ylmethyl)phenyl)methanol (crude) in TFA (6 ml) and triethylsilane (2 ml) was stirred at 80°C for 24 hours. Once complete, the reaction mixture was concentrated under reduced pressure. The precipitate was dissolved in EA (30 ml) and washed with aq. NaHCO ₃ (us, 25 ml) and saline (20 ml). The organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by pre-TLC with DCM:MeOH (10:1) to give the product (15.11 mg).

1H NMR (400 MHz, DMSOO δ 8.21 (s, 1H), 8.11 (s, 1H), 7.55-7.30 (m, 5H), 4.47-3.86 (m, 6H ), 3.302.70 (m, 4H), 2.46-2.32 (m, 2H), 2.03-1.71 (m, 6H) ppm MS: m/e 435 (M+1)+ .

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

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

- 55 046488

To a stirred solution of 7-bromo-2-butoxy-X.X-bis(4-methoxybenzyl)imidazo[2.1P|1,2,4|triazin-4-amine (150 mg, 0.29 mmol) in THF (15 ml) at -78°C under N2 atmosphere, n-BuLi (1.6 M, 0.22 ml, 0.35 mmol) was added. The solution was stirred at -78°C for 30 minutes. 3-formylbenzonitrile (37.4 mg, 0.29 mmol) in THF (2 ml) was added dropwise to the above solution. After addition, the solution was warmed to rt and then stirred for 3 hours. Once complete, the reaction mixture was quenched with H2O (20 ml) and then extracted with DCM (20 ml x 3). The organic phase was washed with H2O (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product as an off-white semi-solid (180 mg), which was directly used in the next step without further purification. MS: m/e 579 (M+1)+.

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

To a stirred solution of 3-((4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1G|[1,2,4]triazin-7-yl)(hydroxy)methyl)benzonitrile (180 mg, 0.31 mmol) in THF (15 ml) was added LiAlH ₄ (24 mg, 0.63 mmol). The mixture was stirred at 66°C overnight. Once complete, the reaction mixture was poured into ice water and then extracted with EA (15 mlx2). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product as a light yellow semi-solid, which was directly used in the next step without further purification. MS: m/e 583 (M+1)+.

Step C: 7-(3-(aminomethyl)benzyl)-2-butoxyimidazo[2,1T|[1,2,4]triazin-4-amine (compound A70).

A solution of (3-(aminomethyl)phenyl)(4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1G|[1,2,4]triazin-7-yl)methanol (crude) in TFA( 6 ml) and triethylsilane (2 ml) were stirred at 80°C for 24 hours. After completion, the reaction mixture was concentrated under reduced pressure. The precipitate was dissolved in EA (30 ml) and washed with aq. NaHCO ₃ (sat., 25 ml) and saline solution (20 ml). The organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by pre-TLC with DCM:MeOH (10:1) and then pre-HPLC to give the product (5.04 mg).

Ή NMR (400 MHz, DMSOO δ 8.25-7.98 (m, 4H), 7.41-7.27 (m, 5H), 4.20 (t, J=8 Hz, 2H), 4, 16 (s, 2H), 4.02-3.94 (m, 2H), 1.72-1.53 (m, 2H), 1.47-1.28 (m, 2H), 0.97- 0.84 (m, 3H) ppm MS: m/e 327 (M+1)+.

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

Step A: Ethyl tert-butyl 4-(4-formylbenzyl)piperazine-1-carboxylate.

A mixture of 4-(chloromethyl)benzaldehyde (1.8 g, 11.6 mmol), tert-butylpiperazine-1-carboxylate (2.6 g, 13.9 mmol) and K ₂ CO ₃ (3.2 g, 23. 2 mmol) in CH3CN (50 ml) was stirred at 50°C overnight. The reaction was cooled to room temperature. The mixture was diluted with water (100 ml) and extracted with EA (80 mlx3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The precipitate was purified using CombiFlash to obtain the title compound (2 g, yield: 56.7%) as a yellow oil. MS: m/e 305 (M+1)+.

Step B: 4-(piperazin-1-ylmethyl)benzaldehyde hydrochloride.

The product from step A (2 g, 6.6 mmol) was dissolved in HCl/EA (4 M, 20 ml) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The precipitate (2HC1 salt) appears as a yellow solid, which is used directly in the next step. MS: m/e 205 (M+1)+.

Step C: 4-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)piperazin-1-yl)methyl)benzaldehyde.

Mixture of product from step B (508 mg, 1.84 mmol), tert-butyl(3-chloropropoxy)dimethylsilane (574 mg, 2.76 mmol), K ₂ CO ₃ (1.02 g, 7.36 mmol) and KI (61 mg, 0.37 mmol) in DMF (10 ml) was stirred at 100°C for 12 hours. The reaction was cooled to room temperature. The mixture was quenched with water (20 ml) and extracted with EA (20 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The precipitate was purified using CombiFlash to obtain the title compound (440 mg, yield: 63.6%) as a yellow oil. MS: m/e 377 (M+1)+.

Step D: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4-((4-(3-( (t-butyldimethylsilyl)oxy)propyl)piperazin-1-yl)methyl)phenyl)methanol.

To a stirred solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1G][1,2,4]triazin-4-amine (140 mg, 0.27 mmol) in THF ( 2 ml) n-BuLi (1.6 M, 0.21 ml) was added at -78°C under N2 atmosphere. The mixture was stirred at -78°C for 1 hour. Then the product of step C (150 mg, 0.40 mmol) in THF (0.3 ml) was added to the system at -78°C. The reaction was stirred at -78°C for 0.5 hours. The reaction was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4C1 at room temperature. The mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The precipitate was purified using CombiFlash to obtain the title compound (160 mg, yield: 72.1%) as a yellow oil. MS: m/e 824 (M+1)+.

Step E: 3-(4-(4-((4-amino-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)methyl)benzyl)piperazine-1

- 56 046488 yl)propan-1-ol (compound A71).

The product of step D (80 mg, 0.10 mmol) was dissolved in Et3SiH (0.5 ml) and CF3COOH (0.1 ml). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The precipitate was dissolved in CF3COOH (0.5 ml) at room temperature. The mixture was stirred at 80°C for 3 hours. The reaction was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC to give the title compound (6.5 mg, yield: 14.4%).

1H NMR (400 MHz, DMSO-dg) δ 8.25-7.95 (m, 2H), 7.36-7.13 (m, 5H), 4.31-4.17 (m, 2H), 4.12 (s, 2H), 3.51-3.41 (m, 4H), 2.50-2.28 (m, 8H), 1.73-1.54 (m, 4H), 1. 46-1.34 (m, 2H), 1.29-1.06 (m, 2H), 0.92 (t, J=7.2 Hz, 3H) ppm. MS: m/e 454 (M+1)+.

Compound A72: 2-butoxy-7-((5-methyl-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo[2.1G][1,2,4]triazin-4-amine .

Step A: tert-butyl 4-((5-bromo-3-methylpyridin-2-yl)oxy)piperidine-1-carboxylate.

To a solution of NaH (0.3 g, 7.5 mmol) in DMA (15 ml) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (1.1 g, 5.5 mmol). The mixture was stirred at room temperature for 1 hour. A solution of 5-bromo-2-chloro-3-methylpyridine (1.1 g, 5 mmol) in DMA (5 ml) was then added and the resulting mixture was stirred at 80°C overnight under the protection of N2. The mixture was cooled to room temperature, diluted with water (50 ml), extracted with EtOAc (60 mlx2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and the residue purified using CombiFlash to give the title compound (1.3 g, 70%). MS: m/e 371 (M+H)+.

Step B: tert-butyl 4-((5-formyl-3-methylpyridin-2-yl)oxy)piperidine-1-carboxylate.

To a stirred solution of the product from step A (1.1 g, 3 mmol) in THF (15 ml), a solution of n-BuLi (2.81 ml, 4.5 mmol) was added dropwise, maintaining the temperature between -75 and -65 °C. After 1 hour, a solution of DMF (266 mg, 3.6 mmol) in THF (1 ml) was added dropwise and the resulting mixture was stirred at -70°C for 2 hours. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (60 ml), washed with saline, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified using CombiFlash to obtain the target compound (900 mg, 93%). MS: m/e 321 (M+H)+.

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

To a solution of 7-bromo-2-butoxy-NX-bis(4-methoxybenzyl)imidazo[2,1-G][1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF ( 8 ml) n-BuLi solution (0.6 ml, 0.95 mmol) was added dropwise, maintaining the temperature in the range from -75 to -65°C. After 1 hour, a mixture of the product from step B (150 mg, 0.456 mmol) in THF (1 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature over 5 hours. The reaction was quenched with saturated NH ₄ Cl solution, extracted with EtOAc (50 ml), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified using CombiFlash to obtain the target compound (180 mg, crude). MS: m/e 768 (M+1)+.

Step D: 2-butoxy-7-((5-methyl-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo[2,1G][1,2,4]triazin-4-amine (connection A72).

To a mixture of the product of step C (180 mg, crude) in TFA (12 ml) was added Et ₃ SiH (4 ml) and the resulting mixture was stirred at 85°C overnight. The mixture was cooled to room temperature and concentrated to dryness. The precipitate was added with TFA (8 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 pre-HPLC to give the title compound (120 mg, 60% in two steps).

1H NMR (400 MHz, DMSOO δ 8.71-8.35 (m, 2H), 8.17 (s, 2H), 7.94 (d, J=1.6 Hz, 1H), 7.51 ( s, 1H), 7.45-7.30 (m, 1H), 5.31-5.16 (m, 1H), 4.21 (t, J=6.4 Hz, 2H), 4.06 (s, 2H), 3.35-3.05 (m, 4H), 2.11 (s, 3H), 2.112.01 (m, 2H), 1.95-1.80 (m, 2H), 1.74-1.60 (m, 2H), 1.44-1.32 (m, 2H), 0.92 (t, J=7.6 Hz, 3H) ppm MS: m/e 412 ( M+1)+.

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

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1T][1,2,4]triazin-7-yl)(4methoxypyridin-2-yl)methanol.

To a stirred solution of 7-bromo-2-butoxy-NX-bis(4-methoxybenzyl)imidazo[2,1L[1,2,4]triazin-4-amine (150 mg, 0.286 mmol) in THF (10 ml) was added dropwise n-BuLi (1.6 M, 0.45 ml, 0.715 mmol) at -78°C. After stirring for an hour under N2, a solution of 4-methoxypicolinaldehyde (58.6 mg, 0.48 mmol) in THF (2 mL) was added dropwise at -78° C. and the reaction was stirred for 4 hours. The reaction was quenched with aq. NH ₄ Cl, extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by pre-TLC (petroleum ether/EAAc=2:1) to give the title compound (42 mg, 25%) as a colorless oil. MS: m/e 585 (M+1)+.

Step B: (4-amino-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(4-methoxypyridin-2-yl)methanol (co

- 57 046488 association A73).

A mixture of the product from step A (42 mg, 0.072 mmol) in TFA/Et ₃ SiH (3 ml/0.5 ml) was stirred at 85°C overnight. The reaction mixture was concentrated to give a residue, which was purified by pre-HPLC to give the title compound (5 mg, 20%).

1H NMR (400 MHz, DMSO-de) δ 8.25 (d, J=5.6 Hz, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.26 (d , J=2.4 Hz, 1H), 7.21 (s, 1H), 6.88-6.86 (m, 1H), 6.14 (d, J=5.6 Hz, 1H), 6 .02 (d, J=5.6 Hz, 1H), 4.18-4.04 (m, 2H), 3.85 (s, 3H), 1.71-1.53 (m, 2H), 1.43-1.31 (m, 2H), 0.91 (t, J=7.2 Hz, 3H) ppm. MS: m/e 345 (M+1)+.

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

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1][1,2,4]triazin-7-yl)(pyridin-2yl)methanol.

To a stirred solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1P[1.2.4|triazin-4-amine (300 mg, 0.572 mmol) in THF (15 ml) at - At 78°C, n-BuLi (1.6 M, 0.9 mL, 1.43 mmol) was added dropwise. After stirring for an hour under N2, a solution of picolinaldehyde (92 mg, 0.856 mmol) in THF (2 ml) was added dropwise at -78°C and the reaction was stirred for 3 hours. The reaction was quenched with aq. NH4C1, extracted with EtOAc (30 mlx2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=3:1) to give the title compound (240 mg, 75.7%) as a colorless syrup. MS: m/e 585 (M+1)+.

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

A mixture of the product from step A (100 mg, 0.18 mmol) in TFA/E^SiH (3 ml/0.5 ml) was stirred at 85°C overnight. The reaction mixture was concentrated to give a residue, which was purified by pre-HPLC to give the title compound (6 mg, 10.6%).

1H NMR (400 MHz, DMSOO 8.45 (d, J=4.4 Hz, 1H), 8.17-8.09 (m, 2H), 7.84 (t, J=7.6 Hz, 1H ), 7.68 (d, J=7.6 Hz, 1H), 7.31-7.25 (m, 1H), 7.22 (s, 1H), 6.17 (d, J=5, 6 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 4.16-4.02 (m, 2H), 1.69-1.52 (m, 2H), 1, 47-1.29 (m, 2H), 0.91 (t, J=7.4 Hz, 3H) ppm MS: m/e 315 (M+1)+.

Compound A75: 2-butoxy-7-(1-(4-(pyrrolidin-1-ylmethyl)phenyl)ethyl)imidazo[2,1Al,2,4]triazin-4-amine.

Step A: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)(4(pyrrolidin-1-ylmethyl)phenyl) methanol

To a cooled solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,11][1,2,4]triazin-4-amine (200 mg, 0.38 mmol) in THF ( 8 ml) at -78°C (purged with N2), n-BuLi (1.6 M, 0.6 ml) was added dropwise. After stirring at -78°C for 30 min, 4-(pyrrolidin-1ylmethyl)benzaldehyde (100 mg, 0.57 mmol) in THF (2 ml) was added. The resulting mixture was stirred at this temperature for 30 min and then heated to rt for 2 h. The reaction was quenched with NH4C1 solution (2 ml), extracted with ethyl acetate (10 ml) and washed with brine (10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified by CombiFlash (DCM:MeOH=6%) to give the pure product (170 mg, 70%). MS: m/e 637 (M+1)+.

Step B: (4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-f][1,2,4]triazin-7 -yl)(4(pyrrolidin-1-ylmethyl)phenyl) methanone.

Dess-Martin reagent (229 mg, 0.54 mmol) was added portionwise to a solution of the product from step A (170 mg, 0.27 mmol) in THF (3 mL) at 0°C. After stirring at rt for 4 hours, TLC indicated that the reaction was complete. The solution was quenched with NH ₄ Cl solution (5 ml) and extracted with ethyl acetate (10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified using CombiFlash (DCM:MeOH=5%) to give the product (130 mg, 76%). MS: m/e 635 (M+1)+.

Step C: 1-(4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-G][1,2,4]triazin-7-yl)-1-(4(pyrrolidin-1 -ylmethyl)phenyl)ethan-1-ol.

A solution of the product from step B (30 mg, 0.05 mmol) in THF (3 ml) at 0°C under N2 was treated dropwise with CH ₃ MgBr (3M in ether, 0.2 ml). The reaction mixture was stirred at rt for 3 hours and then quenched with NH ₄ Cl solution (5 ml). The solution was extracted with ethyl acetate (10 ml), washed with brine (10 ml), dried and concentrated to obtain the crude product, which was directly used in the next step without further purification. MS: m/e 651 (M+1)+.

Step D: 2-butoxy-7-(1 -(4-(pyrrolidin-1-ylmethyl)phenyl)ethyl)imidazo[2,1-f][1,2,4]triazin-4-amine (compound A75) .

A solution of 1-(4-(bis(4-methoxybenzyl)amino)-2-butoxyimidazo[2,1-1T][1,2,4]triazin-7-yl)-1-(4-(pyrrolidin-1 -ylmethyl)phenyl)ethan-1-ol (25 mg, 0.04 mmol) in triethylsilane (1 ml) and trifluoroacetic acid (1 ml) were heated at 80°C for 1 hour. The solution was concentrated, trifluoroacetic acid (1 ml) and heated at 80°C overnight. The solvent was evaporated to obtain a precipitate, which was made alkaline with NaHCO3, extracted with ethyl acetate (5 ml), washed with brine (5 ml).

- 58 046488

The organic layer was dried, concentrated and purified by pre-HPLC to give the product (6 mg, 40%).

1H NMR (400 MHz, DMSOO δ 9.74 (br,s, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.46-7.37 (m, 5H), 4.48 (q, J=8.0 Hz, 1H), 4.29 (s, 2H), 4.14-4.08 (m, 2H), 3.33 (s, 2H), 3.07 -3.04 (m, 2H), 2.03-2.01 (m, 2H), 1.85-1.82 (m, 2H), 1.68-1.59 (m, 5H), 1 .42-1.32 (m, 2H), 0.91 (t, J=8.0 Hz, 3H) ppm MS: m/e 395 (M+1)+.

Compound A76: 2-butoxy-7-((1-(piperidin-3-ylmethyl)-III-pyrazol-4-yl)methyl)imidazo [2,1P[1,2,4|triazin-4-amine.

Step A: tert-butyl 3-(bromomethyl)piperidine-1-carboxylate.

Tert-butyl-3-(hydroxymethyl)piperidine-1-carboxylate (2.15 g, 10 mmol) and CBr ₄ (4.98 g, 15 mmol) were dissolved in CH ₂ Cl ₂ (50 ml), PPh ₃ was added ( 3.1 g, 12 mmol) at room temperature. After addition, the reaction mixture was concentrated to give a precipitate, which was purified by column chromatography (petroleum ether/EAAc=20:1) to give the title compound (2.3 g, 82.7%) as a colorless oil. MS: m/e 278 (M+1)+.

Step B: tert-butyl 3-((4-formyl-III-pyrazol-1-yl)methyl)piperidine-1-carboxylate.

To a stirred suspension of NaH (60%, 0.6 g, 5 mmol) in DMF (5 ml) was added a solution of N-pyrazole4-carbaldehyde (0.32 g, 3.3 mmol) in DMF (3 ml) at 0°C . After stirring for 30 minutes, a solution of the product from step A (1.1 g, 4 mmol) in DMF (3 ml) was added. The mixture was then stirred overnight. The reaction mixture was quenched with H2O (20 ml) and extracted with EtOAc (20 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=10:1~1:1) to give the title compound (420 mg, 43.4%) in in the form of a colorless oil. MS: m/e 294 (M+1)+.

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

To a solution of 7-bromo-2-butoxy-N,Nbis(4-methoxybenzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (150 mg, 0.286 mmol) in THF (10 ml) at -78°C, n-BuLi (1.6 M, 0.44 ml, 0.71 mmol) was added dropwise. After stirring for an hour, a solution of the product from step B (125 mg, 0.428 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 1 hour and then warmed to room temperature for 1 hour. The reaction was quenched with sat.aq. NH4C1 solution, extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC (petroleum ether/EAAc=2:1) to give the title compound (70 mg, 33%) as an off-white solid. MS: m/e 741 (M+1)+.

Step D: 2-butoxy-7-((1-(piperidin-3-ylmethyl)-1H-pyrazol-4-yl)methyl)imidazo[2,11][1,2,4]triazin-4-amine ( connection A76).

A mixture of the product from step C (70 mg, 0.095 mmol) in ELSiH/TFA (0.5 ml/3 ml) was stirred at 85°C overnight. The reaction mixture was concentrated to give a residue, which was purified by pre-HPLC to give the title compound (24 mg, 63.4%).

1H NMR (400 MHz, _DMSOD6 ) δ 8.10 (s, 1H), 8.02 (s, 1H), 7.55 (s, 1H), 7.34 (s, 1H), 7.21 ( s, 1H), 4.22 (t, J=6.4 Hz, 2H), 3.93 (s, 2H), 3.88 (d, J=7.2 Hz, 2H), 2.80- 2.76 (m, 1H), 2.70-2.66 (m, 1H), 2.44-2.34 (m, 1H), 2.23-2.13 (m, 1H), 1, 92-1.83 (m, 1H), 1.75-1.63 (m, 2H), 1.56-1.46 (m, 2H), 1.48-1.36 (m, 2H), 1.33-1.22 (m, 1H), 1.06-0.96 (m, 1H), 0.93 (t, J=7.2 Hz, 3H) ppm. MS: m/e 385 (M+1)+.

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

Step A: tert-butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-yloxy)imidazo[2,1f][1,2,4]triazine -7 -yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate.

To a stirred solution of N-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1Al,2,4]triazin-4-amine (754 mg, 1.64 mmol) in dry THF (15 ml) at -78°C, n-BuLi (2.05 ml, 3.28 mmol) was added dropwise. After stirring for half an hour, a solution of tert-butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (550 mg, 1.96 mmol) in THF (5 ml) was added dropwise. After addition, the reaction was stirred for 2 hours. The reaction was quenched with aq. NH4Cl, extracted with EtOAc (30 mlx2). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether/ESAAc=2:1) to give the title compound (256 mg, 21%) as a brown syrup. MS: m/e 742 (M+1)+.

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

A mixture of the product from step A (256 mg, 0.345 mmol) in TFA/EbSiH (3 ml/3 ml) was stirred at 90°C overnight. The reaction mixture was concentrated to give a residue, which was purified by pre-HPLC to give the title compound (20 mg).

1H NMR (400 MHz, DMSOO δ 8.21-7.94 (m, 4H), 7.65 (dd, J=8.5, 2.0 Hz, 1H), 7.31 (s, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.03-4.89 (m, 1H), 4.41 (t, J=5.2 Hz, 2H), 4.09 (s , 2H), 3.24-3.12 (m, 2H), 2.55 (s, 3H), 1.70-1.47

- 59 046488 (m, 2H), 1.43-1.29 (m, 2H), 1.25 (d, J=6.0 Hz, 3H), 0.89 (t, J=7.2 Hz , 3H) ppm. MS: m/e 386 (M+1)+.

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

Step A: tert-butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-(pentan-2-yloxy)imidazo[2,1f][1,2,4]triazine -7 -yl)(hydroxy)methyl)-3-methylpyridin-2-yl)oxy)ethyl)(methyl)carbamate.

To a stirred solution of HH-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2.1P[1,2,4|triazin-4-amine (461 mg, 1 mmol) in dry THF ( 10 ml) n-BuLi (1.25 ml, 2 mmol) was added dropwise at -78°C. After stirring for half an hour, a solution of tert-butyl (2((5-formyl-3-methylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (353 mg, 1.2 mmol) in THF (2 ml) was added dropwise ). After addition, the reaction was stirred overnight. The reaction was quenched with aq. NH4C1, extracted with EtOAc (30 mlx2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=5:1-2:1) to obtain the title compound (340 mg, 45%) as a syrup Brown color. MS: m/e 756 (M+1)+.

Step B: 7-((5-methyl-6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2yloxy)imidazo[2,1-G][1,2, 4]triazin-4-amine (compound A78).

A mixture of the product from step A (340 mg, 0.45 mmol) in TFA/Et3SiH (3 ml/3 ml) was stirred at 90°C overnight. The reaction mixture was concentrated to give a residue, which was purified by pre-HPLC to give the title compound (42 mg).

1H NMR (400 MHz, DMSO-dg) δ 8.58 (br,s, 2H), 8.16 (s, 1H), 8.11 (s, 1H), 7.95 (d, J=1, 6 Hz, 1H), 7.51 (d, J=1.4 Hz, 1H), 7.37 (s, 1H), 5.03-4.94 (m, 1H), 4.49-4, 44 (m, 2H), 4.07 (s, 2H), 3.38-3.29 (m, 2H), 2.64 (t, J=5.6 Hz, 3H), 2.15 (s , 3H), 1.71-1.48 (m, 2H), 1.45-1.30 (m, 2H), 1.26 (d, J=6.0 Hz, 3H), 0.89 ( t, J=7.2 Hz, 3H) ppm. MS: m/e 400 (M+1) ⁺ .

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

Step A: hexane-1,3-diol.

To a stirred suspension of LAH (lithium aluminum hydride) (0.76 g, 20 mmol) in THF (10 ml) was added dropwise a solution of methyl 3-hydroxyhexanoate (1.46 g, 10 mmol) in THF (5 ml) at 0° WITH. After addition, the reaction was stirred for 2 hours. The reaction was quenched with H2O (0.76 ml), aq. NaOH (15%, 0.76 ml), then H ₂ O (2.28 ml), then filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether/EAAc=2:1~1:1) to obtain the target compound (634 mg, 53.7%) as a colorless oil.

Step B: 1-((tert-butyldimethylsilyl)oxy)hexan-3-ol.

To a stirred solution of the product from step A (634 mg, 5.37 mmol) in CH ₂ Cl ₂ (15 ml) was added imidazole (730 mg, 10.74 mmol), then a solution of TBS-Cl (730 mg, 4. 83 mmol) in CH ₂ Cl ₂ (3 ml) at 0°C. After addition, the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated to obtain a residue, which was purified by column chromatography (petroleum ether/ESAAc = 1:1) to obtain the title compound (1.1 g, 88.2%) in the form of a colorless oil.

Step C: 7-bromo-2-((1-((tert-butyldimethylsilyl)oxy)hexan-3-yl)oxy)-N^-bis(4methoxybenzyl)imidazo [2,1-f][1,2, 4]triazine-4-amine.

NaH (60%, 80 mg) was added to a stirred solution of the product from step B (464 mg, 2 mmol) in THF (10 mL). After stirring for 30 min, 7-bromo-2-chloro-N,Nbis(4methoxybenzyl)imidazo[2,1-1][1,2,4]triazin-4-amine (488 mg, 1 mmol) was added. After addition, the reaction was stirred at 60°C overnight. The reaction mixture was treated with H ₂ O (20 ml), extracted with EtOAc (15 mlx2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether/EAAc=10:1) to give the title compound (530 mg, 77.5%) as a colorless oil. MS: m/e 684 (M+1)+.

Step D: tert-butyl (2-((5-((4-(bis(3,4-dimethoxybenzyl)amino)-2-((1-((tertbutyldimethylsilyl)oxy)hexan-3-yl)oxy)imidazo [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin2-yl)oxy)ethyl)(methyl)carbamate.

To a solution of 7-bromo-2-(( 1 -((tert-butyldimethylsilyl)oxy)hexan-3-yl)oxy)-N,Nbis(2,4dimethoxybenzyl)imidazo[2,1-G][1, 2,4]triazin-4-amine (700 mg, 0.939 mmol) in THF (10 ml) was added n-BuLi (1.8 ml, 2.88 mmol) under N2 at -78°C. After stirring for 0.5 h at -78°C, tert-butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (400 mg, 1.429 mmol) was added. The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH4C1 (30 ml) and extracted with DCM (3x30 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (60%) to give the title compound (590 mg, 66%). MS: m/e 946 (M+1)+.

Step E: 3 -((4-amino-7-(hydroxy(6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo [2,1- 60 046488

f][1,2,4]triazin-2-yl)oxy)hexan-1-ol.

The product from step D (800 mg, 0.846 mmol) was dissolved in TFA (9 mL) and H ₂ O (1 mL) under N2. The reaction mixture was stirred for 12 hours at 35°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to adjust the pH to a value in the range of 2 to 3. The aqueous phase was washed with DCM (3x30 ml) and alkalinized with 2 N NaOH to pH value equal to 13 to 14 and extracted with DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (320 mg, crude). MS: m/e 432 (M+1)+.

Step F: 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin2- yl)oxy)hexan-1-ol (compound A79).

The product from step E (320 mg) was dissolved in TFA (5 ml) and Et ₃ SiH (5 ml) under N2. The reaction mixture was stirred for 12 hours at 90°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 2 to 3. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted with DCM/i-PrOH (5/1, 3x60 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by pre-HPLC to give the title compound (15 mg).

¹ H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 6.77 (d, J=8.4 Hz, 1H), 5.24-5.10 (m, 1H), 4.37 (s, 2H), 4.15 (s, 2H), 3.70-3.56 (m , 2H), 2.99 (s, 2H), 2.47 (s, 3H), 1.98-1.79 (m, 2H), 1.77-1.53 (m, 2H), 1, 50-1.33 (m, 2H), 0.91 (t, J=7.2 Hz, 3H) ppm. MS: m/e 416 (M+1) ⁺ .

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

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

To a solution of 7-bromo-N^-bis(4-methoxybenzyl)-2-((tetrahydrofuran-3-yl)methoxy)imidazo[2,11^[1,2,4]triazin-4-amine (134 mg, 0.24 mmol) in THF (8 ml), a solution of n-BuLi (1.6 M, 0.3 ml, 0.48 mmol) was added dropwise, maintaining the temperature between -75 and -65°C. After 1 hour, a suspension of tert-butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (100 mg, 0.36 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 2 hours and then warmed to room temperature overnight. The reaction was quenched with saturated NH ₄ Cl solution, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC to give the title compound (160 mg, 88%). MS: m/e 756.9 (M+1) ⁺ .

Step B: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-((tetrahydrofuran-3yl)methoxy)imidazo[2,1-10[1,2,4] triazin-4-amine (compound A80).

To a mixture of the product of step A (160 mg, 0.21 mmol) in TFA (4 ml) was added Et ₃ SiH (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 precipitate and the reaction was heated at 80°C overnight. The mixture was concentrated and the residue was purified by pre-HPLC to give the title compound (19 mg, 22.6%).

1H NMR (400 MHz, DMSO^) δ 8.18 (s, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.29 (s, 1H), 6.74 (d, J=8.4 Hz, 1H), 4.27 (t, J=5.5 Hz, 2H), 4.23-4, 16 (m, 1H), 4.13-4.08 (m, 3H), 3.77 (t, J=7.6 Hz, 2H), 3.68-3.61 (m, 1H), 3 ,54-3.48 (m, 1H), 2.86 (d, J=5.3 Hz, 2H), 2.64 (dd, J=13.6, 6.9 Hz, 1H), 2, 34 (s, 3H), 2.031.95 (m, 1H), 1.66-1.61 (m, 1H), ppm. MS: m/e 400 (M+1) ⁺ .

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

Compound A79 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,110[1,2,4]triazin-2-yl)oxy) hexan-1-ol (70 mg, 0.168 mmol) was separated into two optical isomers Compound A81 and Compound A82 by prep-SCPC to give Compound A81 (18 mg), and Compound A82 (38 mg). The conditions for pre-SKFH are given below.___________________________

Column Chiral CANCER AD-H Column size 3 cm*25 cm, 5 microns Mobile phase Hexane (2 mM NH ₃ -MeOH): IPA = 75:25 Current speed 45 ml/min Wavelength UV: 220 nm Temperature 25°C

Compound A81 (R or S optical isomer 1): 1H NMR (400 MHz, CD ₃ OD) δ 8.09 (s, 1H), 7.62 (d,

- 61 046488

J=8.4 Hz, 1H), 7.33 (s, 1H), 6.77 (d, J=8.4 Hz, 1H), 5.24-5.08 (m, 1H), 4, 37 (t, J=5.2 Hz, 2H), 4.15 (s, 2H), 3.65 (d, J=4.8 Hz, 2H), 2.99 (s, 2H), 2, 45 (s, 3H), 1.95-1.82 (m, 2H), 1.78-1.56 (m, 2H), 1.49-1.32 (m, 2H), 0.91 ( t, J=7.2 Hz, 3H) ppm. MS: m/e 416 (M+1)+.

Compound A82 (S or R optical isomer 2): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.09 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7. 33 (s, 1H), 6.77 (d, J=8.4 Hz, 1H), 5.22-5.13 (m, 1H), 4.36 (t, J=5.2 Hz, 2H ), 4.15 (s, 2H), 3.66 (d, J=4.8 Hz, 2H), 2.96 (s, 2H), 2.45 (s, 3H), 1.97-1 .77 (m, 2H), 1.77-1.54 (m, 2H), 1.49-1.32 (m, 2H), 0.91 (t, J=7.2 Hz, 3H) ppm . MS: m/e 416 (M+1) ⁺ .

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

Step A: H,H-bis(4-methoxybenzyl)-2-(pentan-3-yloxy)imidazo[2,1T|[1,2,4|triazin-4-amine.

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

Step B: tert-butyl(2-((5-((4-(bis(4-methoxybenzyl)amino)-2-(pentan-3-yloxy)imidazo [2,1f| [1,2,4]triazine -7 -yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate.

To a solution of YNbis(4-methoxybenzyl)-2-(pentan-3-yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine (220 mg, 0.48 mmol) in THF (8 mL) was added dropwise to n-BuLi solution (1.6 M, 0.44 mL, 0.72 mmol), maintaining the temperature between -75 and -65°C. After 1 hour, a suspension of tert-butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (200 mg, 0.72 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 2 hours and then warmed to room temperature overnight. The reaction was quenched with a saturated solution of NH4C1, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC to give the title compound (120 mg, 47%). MS: m/e 742 (M+1) ⁺ .

Step C: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-3-yloxy)imidazo [2,1!T][1,2,4] triazin-4-amine (compound A83).

To a mixture of the product of step B (120 mg, 0.161 mmol) in TFA (4 ml) was added Et ₃ SiH (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 precipitate and the reaction was heated at 80°C overnight. The mixture was concentrated in vacuo and the residue was purified by pre-HPLC to give the title compound (25 mg, 38.6%).

1H NMR (400 MHz, DMSOL) δ 8.11 (s, 2H), 8.00 (s, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.30 (s, 1H ), 6.74 (d, J=8.4 Hz, 1H), 4.82-4.74 (m, 1H), 4.28 (t, J=5.5 Hz, 2H), 4.07 (s, 2H), 2.89 (t, J=5.4 Hz, 2H), 2.37 (s, 3H), 1.641.58 (m, 4H), 0.87 (t, J=7, 3 Hz, 6H) ppm. MS: m/e 386 (M+1)+.

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

Step A: 2-(hexan-3-yloxy)-N,Nbis(4-methoxybenzyl)imidazo[2,1-1T][1,2,4]triazin-4-amine.

NaH (60%, 80 mg, 2 mmol) was added to a solution of hexan-3-ol (102 mg, 1 mmol) in THF (10 ml) at 0 degrees. The reaction mixture was stirred at room temperature for 20 minutes.

2-chloro-N,Nbis(4-methoxybenzyl)imidazo[2,1-1G][1,2,4]triazin-4-amine (204 mg, 0.5 mmol) was added to the mixture. The reaction mixture was stirred at 70 degrees overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (260 mg, 100%). MS: m/e: 476 (M+1)+.

Step B: tert-butyl(2-((5-((4-(bis(4-methoxybenzyl)amino)-2-(hexan-3-yloxy)imidazo [2,1f] [1,2,4]triazine -7 -yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate.

To a solution of 2-(hexan-3-yloxy)-NY-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (260 mg, 0.5 mmol) in THF (8 mL) was added dropwise to n-BuLi solution (1.6 M, 0.44 mL, 0.72 mmol), maintaining the temperature between -75 and -65°C. After 1 hour, a suspension of tert-butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (200 mg, 0.72 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 2 hours and then warmed to room temperature overnight. The reaction was quenched with a saturated solution of NH4C1, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (130 mg, 34.4%). MS: m/e 756 (M+1)+.

Step C: 2-(hexan-3-yloxy)-7 -((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo [2,1!T][1,2,4] triazin-4-amine (compound A84).

To a mixture of the product of step B (130 mg, 0.172 mmol) in TFA (4 ml) was added Et ₃ SiH (4 ml) and obtained

- 62 046488 The 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 precipitate and the reaction was heated at 80°C overnight. The mixture was concentrated in vacuo and the residue was purified by pre-HPLC to give the title compound (12 mg, 16.9%).

1H NMR (400 MHz, DMSO^b) δ 8.11 (s, 2H), 8.00 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.31 (s , 1H), 6.74 (d, J=8.6 Hz, 1H), 4.89-4.83 (m, 1H), 4.30 (t, J=5.5 Hz, 2H), 4 .07 (s, 2H), 2.94 (s, 2H), 2.39 (s, 3H), 1.61-1.54 (m, 4H), 1.38-1.26 (m, 2H ), 0.87 (t, J=6.9 Hz, 6H) ppm. MS: m/e 400 (M+1)+.

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

Step A: 2-((tert-butoxycarbonyl)(methyl)amino)ethyl methanesulfonate.

To a 0°C solution of tert-butyl-(2-hydroxyethyl)(methyl)carbamate (3.5 g, 20 mmol) in THF (40 ml) was added DIEA (7.8 g, 60 mmol), and then added dropwise MsCl (3.4 g, 30 mmol). The resulting mixture was stirred at rt for 2 hours. The suspension was filtered and the filtrate was diluted with EA (100 ml), washed with saline (100 mlx3), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=3:1) to give the title compound (3.1 g, crude). MS: m/e 254 (M+1)+.

Step B: tert-butyl (2-(4-formylphenoxy)ethyl)(methyl)carbamate.

A mixture of 2-((tert-butoxycarbonyl)(methyl)amino)ethylmethanesulfonate (1.5 g, crude), 4-hydroxybenzaldehyde (800 mg, 6.5 mmol) and K2CO3 (2.5 g, 18.1 mmol) in DMF ( 10 ml) was stirred at 60°C for 16 hours. The mixture was diluted with EA (50 ml) and filtered. The filtrate was washed with brine (20 mlx3), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=4:1) to give the title compound (105 mg, yield: 4% in two steps). MS: m/e 280 (M+1)+.

Step C: tert-butyl(2-(4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4-dimethoxybenzyl)amino)imidazo [2,1 -f][1,2,4]triazin-7-yl)(hydroxy)methyl)phenoxy)ethyl)(methyl)carbamate.

To a solution of 2-(( 1 -(benzyloxy)hexan-3-yl)oxy)-N,Nbis(2,4-dimethoxybenzyl)imidazo[2,1D[1,2,4]triazin-4-amine (156 mg, 0.24 mmol) n-BuLi (1.6 M, 0.3 mL, 0.48 mmol) was added to THF (2 mL) at -78°C under N2. The mixture was stirred at -78°C for 20 minutes. A solution of tert-butyl (2-(4-formylphenoxy)ethyl)(methyl)carbamate (102 mg, 0.36 mmol) in THF (2 ml) was then added to the system at -78°C. The reaction was stirred for 30 minutes and then warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated NH ₄ Cl (20 ml) at room temperature and extracted with EA (10 ml x 3 ). The combined organic phase was washed with brine (10 mlx3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (80 mg, yield: 36%). MS: m/e 921 (M+1)+.

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

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

Step E: 3 -((4-amino-7 -(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2yl)oxy)hexane-1 -ol (compound A85).

Tert-butyl-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3-yl)o xy)imndazo[2,1-1T][ 1,2,4]triazin-7-yl)methyl)phenoxy)ethyl)(methyl)carbamate (50 mg, 0.06 mmol) in TFA/H ₂ O (9:1, 5 ml) was stirred at rt for 16 hours. The reaction was concentrated under reduced pressure. 2 ml of H ₂ O were added. The mixture was stirred at RT for 20 minutes, then filtered. The filtrate was extracted with DCM (20 mlx2) to remove impurities. The aqueous layer was made alkaline with aq. NaOH(4M) to pH greater than 10, extracted with DCM/IPA (5:1, 3 mlx5). The combined extracts were washed with saline (5 mlx3), dried over Na2SO4, concentrated and purified by pre-TLC (DCM/MeOH( _CN3 )=10:1) to give the title compound (5 mg, yield: 12%).

1H NMR (400 MHz, CD3OD) δ 7.32-7.23 (m, 3H), 6.94 (d, J=8.8 Hz, 2H), 5.26-5.11 (m, 1H) , 4.26-4.19 (m, 2H), 4.18-4.11 (m, 2H), 3.75-3.54 (m, 2H), 3.46-3.37 (m, 2H), 2.77 (s, 3H), 1.95-1.82 (m, 2H), 1.77-1.61 (m, 2H), 1.49-1.37 (m, 2H) , 0.92 (t, J=7.2 Hz, 3H) ppm. MS: m/e 415 (M+1)+.

Compound A86: 3 -((4-amino-7 -((6-(3 -(methylamino)propoxy)pyridin-3-yl)methyl)imidazo [2,1C|1.2.4|triazin-2-yl] oxy)hexan-1-ol.

Step A: tert-butyl (3-((5-formylpyridin-2-yl)oxy)propyl)(methyl)carbamate.

Mixture of 6-chloronicotinaldehyde (400 mg, 2.84 mmol), tert-butyl (3hydroxypropyl)(methyl)carbamate (600 mg, 3.17 mmol), Pd ₂ (dba) ₃ (180 mg, 0.20 mmol), RuPhos (187 mmol, 0.40 mmol) and Cs ₂ CO ₃ (2.3 g, 7.0 mmol) in dioxane (5 ml) were stirred at 100°C for 4 hours.

- 63 046488

The mixture was treated with 20 ml EA and 20 ml H ₂ O. The mixture was filtered through a celite pad. The aqueous layer was extracted with EA (20 mlx2). The combined organics were washed with saline (30 mlx3), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=2:1) to obtain the title compound (490 mg, yield: 59%). MS: m/e 295 (M+1)+.

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

To a solution of 2-(( 1 -(benzyloxy)hexan-3-yl)oxy)-N,Nbis(2,4-dimethoxybenzyl)imidazo[2,1G][1,2,4]triazin-4-amine ( 642 mg, 1.0 mmol) in THF (5 ml) was added n-BuLi (1.6 M, 1.5 ml, 2.4 mmol) at -78°C under N ₂ atmosphere. The mixture was stirred at -78°C for 20 minutes. A solution of tert-butyl-(3-((5-formylpyridin-2-yl)oxy)propyl)(methyl)carbamate (480 mg, 1.6 mmol) in THF (3 ml) was then added to the system at -78°C. . The reaction was stirred for 30 min, and then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated NH ₄ Cl (20 ml) at room temperature and extracted with EA (10 ml x 3 ). The combined organic phase was washed with brine (10 mlx3), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (510 mg, yield: 54%). MS: m/e 936 (M+1) ⁺ .

Step C: tert-butyl(3 -((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-(( 1 -hydroxyhexan-3 yl)oxy)imidazo [2,1-f] [1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)propyl)(methyl)carbamate.

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

Step D: 3-((4-amino-7-(hydroxy(6-(3-(methylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1f][1,2,4]triazine-2 -yl)oxy)hexane-1-ol.

Tert-butyl(3-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3-yl)o xy)imidazo[2,1-!T] [1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)propyl)(methyl)carbamate (100 mg, crude) in TFA/ _H2O (9:1.5 ml) was stirred at rt for 16 hours. The reaction mixture was concentrated under reduced pressure. 2 ml H2O was added. The mixture was stirred at RT for 30 min, then filtered. The filtrate was extracted with DCM (5 mlx2) to remove impurities. The aqueous layer was made alkaline with aq. NaOH (4M) to pH greater than 10, extracted with DCM/IPA (5:1, 10 mlx3). The combined extracts were washed with saline (10 mlx3), dried over Na ₂ SO ₄ , concentrated to give the title compound (45 mg, crude). MS: m/e 446 (M+1) ⁺ .

Step E: 3-((4-amino-7-((6-(3-(methylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1-1T][1,2,4]triazine -2-yl)oxy)hexan-1-ol (compound A86).

Mixture of 3 -((4-amino-7-(hydroxy(6-(3 -(methylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1!T][1,2,4]triazin-2 -yl)oxy)hexan-1-ol (45 mg, crude), TFA (2.5 ml) and Et ₃ SiH (2.5 ml) were stirred at 70°C for 20 hours. The reaction mixture was concentrated under reduced pressure . The precipitate was dissolved in H2O (2 ml) and extracted with DCM (2 mlx2). The organic phase was discarded. The inorganic phase was alkalinized with aq. NaOH (4 M) to pH greater than 10. The mixture was extracted with DCM/iPrOH (5:1, 3 mlx3). The combined organic phase was washed with brine (5 mlx2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by pre-TLC (DCM/MeOH(HH3)=9:1) to give the title compound (3.2 mg, yield: 6% in two steps).

^1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 6.78 (d, J=8.8 Hz, 1H), 5.23-5.11 (m, 1H), 4.37 (t, J=5.6 Hz, 2H), 4.16 (s, 2H), 3, 69-3.60 (m, 2H), 3.20-3.12 (m, 2H), 2.71 (s, 3H), 2.212.10 (m, 2H), 1.95-1.83 ( m, 2H), 1.76-1.62 (m, 2H), 1.49-1.36 (m, 2H), 0.92 (t, J=7.6 Hz, 3H) ppm. MS: m/e 430 (M+1) ⁺ .

Compound A87: 2-(heptan-4-yloxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3yl)methyl)imidazo[2,1-1T][1,2,4]triazine- 4-amine

Stage A:

2-(heptan-4-yloxy)-N,Nbis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine.

NaH (60%, 80 mg, 2 mmol) was added to a solution of heptan-4-ol (116 mg, 1 mmol) in THF (10 ml) at 0 degrees. The reaction mixture was stirred at room temperature for 20 minutes.

2-chloro-H,Nbis(4-methoxybenzyl)imidazo[2,1-1T][1,2,4]triazin-4-amine (204 mg, 0.5 mmol) was added to the mixture. The reaction mixture was stirred at 70 degrees overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (160 mg, 65.5%). MS: m/e: 490

- 64 046488 (M+1)+.

Step B: tert-butyl (2-((5-((4-(bis(4-methoxybenzyl)amino)-2-(heptan-4-yloxy)imidazo[2,1f][1,2,4]triazine -7 -yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate.

To a solution of 2-(heptan-4-yloxy)-KH-bis(4-methoxybenzyl)imidazo[2,1T|[1,2,4|triazin-4-amine (160 mg, 0.327 mmol) in THF (8 ml ) n-BuLi solution (1.6 M, 0.31 mL, 0.5 mmol) was added dropwise, maintaining the temperature between -75 and -65°C. After 1 hour, a suspension of tert-butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (130 mg, 0.46 mmol) in THF (2 ml) was added dropwise. The resulting mixture was stirred at -70°C for 2 hours and then warmed to room temperature overnight. The reaction was quenched with a saturated solution of NH ₄ Cl, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (100 mg, 39.8%). MS: m/e 770 (M+1)+.

Step C: 2-(heptan-4-yloxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f|[1,2,4 ] triazin-4-amine (compound A87).

To a mixture of the product of step B (100 mg, 0.13 mmol) in TFA (4 ml) was added Et ₃ SiH (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 precipitate and the reaction was heated at 80°C overnight. The mixture was concentrated in vacuo and the residue was purified by pre-HPLC to give the title compound (3 mg, 5.4%).

1H NMR (400 MHz, DMSO-dg) δ 8.69 (s, 2H), 8.13 (s, 2H), 8.01 (s, 1H), 7.65 (d, J=8.3 Hz , 1H), 7.31 (s, 1H), 6.78 (d, J=8.6 Hz, 1H), 5.04-4.92 (m, 1H), 4.44 (s, 2H) , 4.09 (s, 2H), 2.98 (s, 2H), 2.60 (s, 3H), 1.61-1.54 (m, 4H), 1.42-1.33 (m , 4H), 0.87 (t, J=7.3 Hz, 6H) ppm. MS: m/e 414 (M+1)+.

Compound A88: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-((tetrahydrofuran-2yl)methoxy)imidazo [2,1-f][1,2,4 ]triazine-4-amine.

Step A: 7-bromo-NX-bis(4-methoxybenzyl)-2-((tetrahydrofuran-2-yl)methoxy)imidazo[2,1^[1,2,4]triazin-4-amine.

To a solution of (tetrahydrofuran-2-yl)methanol (204 mg, 2 mmol) in THF (10 ml) was added NaH (60%, 160 mg, 4 mmol) at 0 degrees. The reaction mixture was stirred at room temperature for 20 minutes.

7-Bromo-2-chloro-H/N-bis(4-methoxybenzyl)imidazo[2,1-£][1,2,4]triazin-4-amine (487 mg, 1 mmol) was added to the mixture. The reaction mixture was stirred at 70 degrees overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (440 mg, 79.4%). MS: m/e: 554 (M+1)+.

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

To a solution of 7-bromo-NX-bis(4-methoxybenzyl)-2-((tetrahydrofuran-2-yl)methoxy)imidazo[2,1^[1,2,4]triazin-4-amine (220 mg, 0 .39 mmol) in THF (8 ml), a solution of n-BuLi (1.6 M, 0.45 ml, 0.72 mmol) was added dropwise, maintaining the temperature in the range of -75 to -65°C. After 1 hour, a suspension of tert-butyl-(2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (151 mg, 0.54 mmol) in THF (2 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 a saturated solution of NH ₄ Cl, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (130 mg, 44.2%). MS: m/e 756 (M+1)+.

Step C: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-((tetrahydrofuran-2yl)methoxy)imidazo[2,1-1G][1,2,4 ]triazine-4-amine (compound A88).

To a mixture of the product of step B (130 mg, 0.172 mmol) in TFA (4 ml) was added Et ₃ SiH (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 precipitate and the reaction was heated at 80°C overnight. The mixture was concentrated and the residue was purified by pre-HPLC to give the title compound (5 mg, 7.2%).

1H NMR (400 MHz, DMSO-de) δ 8.18 (s, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.66 (d, J=8.2 Hz , 1H), 7.30 (s, 1H), 6.78 (d, J=8.5 Hz, 1H), 4.38 (t, J=4.9 Hz, 2H), 4.17 (t , J=8.3 Hz, 2H), 4.14 (s, 1H), 4.10 (s, 2H), 3.76 (t, J=7.3 Hz, 1H), 3.72-3 .62 (m, 1H), 3.14 (s, 2H), 2.51 (s, 3H), 1.99 (s, 1H), 1.84 (dd, J=13.9, 6.8 Hz, 2H), 1.66 (d, J=8.0 Hz, 1H), ppm. MS: m/e 400 (M+1)+.

Compound A89: ^)-2-(sec-butoxy)-7 -((6-(2-(methylamino)ethoxy)pyridin-3 yl)methyl)imidazo [2,1-f][1,2,4] triazine-4-amine.

Step A: 2-chloro-H,Nbis(2,4-dimethoxybenzyl)imidazo[2,1-1T][1,2,4]triazin-4-amine.

To a mixture of imidazo[2,1-1T][1,2,4]triazine-2,4(1H,3H)-dione (10 g, 65.8 mmol), POCl ₃ (50 g, 0.33 mol) And

- 65 046488 toluene (60 ml) DIPEA (25.5 g, 0.20 mmol) was added over 30 min at 60°C. In this case, an exothermic effect was observed, and the temperature was increased to 90°C. (The solid was gradually dissolved.) After addition, the reaction was heated to 100°C (internal temperature approximately 95°C) and stirred overnight. The reaction was then cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was dissolved in THF (100 ml), then DIPEA (25.5 g, 0.20 mmol) was added dropwise to the mixture. This mixture was added to a solution of bis(2,4dimethoxybenzyl)amine (31.3 g, 0.10 mol), K ₂ CO ₃ (18 g, 1.32 mol), THF (260 ml) and water (260 ml) at 0°C for 1 hour. After addition, the mixture was extracted with EA (300 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The precipitate was dissolved in EA (400 ml), the mixture was stirred under reflux for 1 hour and filtered at this temperature. The filtrate was concentrated under reduced pressure. EA was replaced by MeOH, and the mixture was stirred at room temperature overnight. The mixture was filtered and the solid (off-white) was collected. The product was directly used in the next step (20 g, HPLC: 98.87%, Yield: 54.4%).

Step B: ^)-2-(sec-butoxy)-H^-bis(2,4-dimethoxybenzyl)imidazo[2,1-£][1,2,4]triazin-4-amine.

To a solution of N-butan-2-ol (236 mg, 3.19 mmol) in THF (20 mL) was added NaH (128 mg, 3.2 mmol) under N2 at 0°C. After stirring for 0.5 h at 25°C, 2-chloro-KH-bis(2.4dimethoxybenzyl)imidazo[2,1-£][1,2,4]triazin-4-amine (500 mg, 1. 06 mmol). The reaction mixture was stirred for 6 hours at 70°C. Once complete, the reaction mixture was quenched with water (20 ml) and extracted with EtOAc (3x30 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (40%) to give the title compound (540 mg, crude). MS: m/e 508 (M+1)+.

Step C: tert-butyl(2-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-(^)-sec-butoxy)imidazo[2,1f] [1,2, 4]triazin-7 -yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate.

To a solution of the product from step B (540 mg, 1.06 mmol) in THF (15 ml) was added n-BuLi (1.4 ml, 2.24 mmol) under N2 at -78°C. After stirring for 0.5 h at -78°C, tert-butyl (2-((5-formylpyridin-2-yl)oxy)ethyl)(methyl)carbamate (445 mg, 1.59 mmol) was added. The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH4C1 (30 ml) and extracted with DCM (3x30 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (70%) to give the title compound (340 mg, 41%). MS: m/e 788 (M+1)+.

Step D: (4-amino-2-(^)-sec-butoxy)imidazo[2,1-£][1,2,4]triazin-7-yl)(6-(2(methylamino)ethoxy)pyridine -3-yl)methanol.

The product from step C (340 mg, 0.431 mmol) was dissolved in TFA (6 mL) and H2O (0.6 mL) under N2. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (120 mg, crude). MS: m/e 388 (M+1)+.

Step E: ^)-2-(sec-butoxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1C[1,2,4]triazin- 4-amine (compound A89).

The product of step D (120 mg, 0.31 mmol) was dissolved in TFA (4 ml) and Et ₃ SiH (4 ml) under N2. The reaction mixture was stirred for 12 hours at 90°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by pre-TLC (DCM/CH ₃ OH(CI ₃ )=15/1) to give the title compound (17 mg).

1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.34 (s, 1H), 6.82 (d, J =8.4 Hz, 1H), 4.99-4.94 (m, 1H), 4.55-4.44 (m, 2H), 4.16 (s, 2H), 3.32 (s, 2H), 2.68 (s, 3H), 1.80-1.59 (m, 2H), 1.31 (d, J=6.0 Hz, 3H), 0.97 (t, J=7 .2 Hz, 3H) ppm. MS: m/e 372 (M+1) ⁺ .

Compound A90: (S)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2yloxy)imidazo[2,1-C[1,2,4 ]triazine-4-amine.

Step A: tert-butyl(2-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((^)-pentan-2yl)oxy)imidazo [2,1-f] [1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2 yl)oxy)ethyl)(methyl)carbamate.

To a solution of N)-H,Ni-bis(2,4-dimethoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-N1,2,4]triazin-4amine (600 mg, 1.15 mmol ) n-BuLi (1.4 mL, 2.24 mmol) was added to THF (10 mL) under N2 at -78°C. After stirring for 0.5 h at -78°C, tert-butyl (2-((5-formylpyridine-2

- 66 046488 yl)oxy)ethyl)(methyl)carbamate (480 mg, 1.71 mmol). The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (30 ml) and extracted with DCM (3x30 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a residue. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (40%) to give the title compound (720 mg, 78%). MS: m/e 802 (M+1)+.

Step B: (4-amino-2-((^)-pentan-2-yl)oxy)imidazo[2,1-G][1,2,4]triazin-7-yl)(6-(2( methylamino)ethoxy)pyridin-3-yl)methanol.

Tert-butyl(2-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((^)-pentan-2-yl)oxy)imidazo[2,1G][1, 2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)ethyl)(methyl)carbamate (720 mg, 0.898 mmol) was dissolved in TFA (9 ml) and H2O (1 ml) in atmosphere N2. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (30 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x120 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound (290 mg, crude). MS: m/e 402 (M+1)+.

Step C: (S)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2-yloxy)imidazo [2,1G][1,2, 4]triazin-4-amine (compound A90).

(4-amino-2-((^)-pentan-2-yl)oxy)imidazo[2,1-G][1,2,4]triazin-7-yl)(6-(2(methylamino)ethoxy )pyridin-3-yl)methanol (290 mg, crude) was dissolved in TFA (5 ml) and Et ₃ SiH (5 ml) under nitrogen N ₂ atmosphere. The reaction mixture was stirred for 12 hours at 90°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x120 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a residue. The residue was purified by pre-TLC (DCM/CH ₃ OH (NH ₃ ) = 20/1 to 15/1) to give the title compound (70 mg).

¹ H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.24 (s, 1H), 6.69 (d, J=8.4 Hz, 1H), 4.95 (qt, J=12.0, 6.4 Hz, 1H), 4.37-4.27 (m, 2H), 4.05 (s, 2H ), 3.08-2.98 (m, 2H), 2.47 (s, 3H), 1.71-1.55 (m, 1H), 1.54-1.25 (m, 3H), 1.21 (d, J=6.0 Hz, ZN), 0.84 (t, J=7.2 Hz, ZN) ppm. MS: m/e 386 (M+1)+.

Connection A91:

3-((4-amino-7-(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-1][1,2,4]triazin-2yl)oxy)hexane- 1-ol.

Step A: tert-butyl (2-(2-fluoro-4-formylphenoxy)ethyl)(methyl)carbamate.

To a solution of 3-fluoro-4-hydroxybenzaldehyde (280 mg, 2 mmol) in THF (10 ml) was added tert-butyl (2-hydroxyethyl)(methyl)carbamate (350 mg, 2 mmol) and PPh3 (628 mg, 2.4 mmol ). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (552 mg, 2.4 mmol) in THF (2 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (400 mg, 67.3%). MS: m/e: 298 (M+1)+.

Step B: tert-butyl (2-(4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(4-methoxybenzyl)amino)imidazo [2,1-f ][1,2,4]triazin-7-yl)(hydroxy)methyl)-2-fluorophenoxy)ethyl)(methyl)carbamate.

To a solution of 2-((1-(benzyloxy)hexan-3-yl)oxy)-N,Nbis(4-methoxybenzyl)imidazo[2,1G][1,2,4]triazin-4-amine (291 mg , 0.5 mmol) in THF (8 ml), a solution of n-BuLi (1.6 M, 0.44 ml, 0.72 mmol) was added dropwise, maintaining the temperature in the range from -75 to -65°C. After 1 hour, a suspension of tert-butyl (2-(2-fluoro-4-formylphenoxy)ethyl)(methyl)carbamate (400 mg, 1.3 mmol) in THF (2 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 NH ₄ Cl solution, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC to give the title compound (340 mg, 77%). MS: m/e 879 (M+1)+.

Step C: tert-butyl (2-(4-((4-(bis(4-methoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1-f][1,2 ,4]triazin-7-yl)(hydroxy)methyl)-2-fluorophenoxy)ethyl)(methyl)carbamate.

Pd/C (800 mg) was added to a solution of the product from step B (340 mg, 0.38 mmol) in MeOH (20 mL). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (230 mg, 75.4%). MS: m/e: 789 (M+1)+.

Step D: 3-((4-amino-7-(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-G][1,2,4]triazin-2yl)oxy )hexan-1-ol (compound A91).

To a mixture of the product from step C (230 mg, 0.291 mmol) in TFA (4 ml) was added Et ₃ SiH (4 ml) and the resulting mixture was stirred at 85°C for 4 hours. The mixture was cooled to room temperature and conc.

- 67 046488 triried until dry. TFA (5 ml) was added to the precipitate and the reaction was heated at 80°C overnight. The mixture was concentrated in vacuo and the residue was purified by pre-HPLC to give the title compound (8 mg, 6.4%).

1H NMR (400 MHz, DMSO^) δ 8.13 (s, 1H), 8.02 (s, 1H), 7.31 (s, 1H), 7.19 (d, J=12.2 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 5.04 (d, J=5.3 Hz, 1H), 4.17 (d, J=4.8 Hz, 2H) , 4.08 (s, 2H), 3.55-3.39 (m, 5H), 3.11 (s, 2H), 1.82-1.70 (m, 2H), 1.61 (d , J=6.2 Hz, 2H), 1.31 (dd, J=14.8, 7.3 Hz, 2H), 1.23 (s, 1H), 0.86 (t, J=7, 2 Hz, 3H) ppm. MS: m/e 433 (M+1)+.

Compound A92 and Compound A93: (R or S) 3-((4-amino-7-(4-(2(methylamino)ethoxy)benzyl)imidazo[2,1-:1][1,2,4]triazine -2-yl)o xy)hexan-1-oli (S or R) 3-((4-amino7-(4-(2-(methylamino)ethoxy)benzyl)imidazo [2,1-f][1, 2,4]triazin-2-yl)o xy)hexan-1-ol.

Connection A85. 3-((4-amino-7-(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-1 ^: ][1,2,4]triazin-2yl)oxy)hexan-1-ol (1.1 g, 2.66 mmol) was separated into two optical isomers, compound A92 (441 mg) and compound A93 (410 mg), prep-SCPC. The conditions for pre-SKFH are given below.________

Column CHIRAL ART Amylose-C ΝΕΟ Column size 3cm χ 25 cm, 5 µm Injection 3.0 ml Mobile phase CO ₂ :IPA (2 mM NH3-MeOH) = 60:40 Current speed 50 ml/min Wavelength UV 220 nm Temperature 35°C Sample solution 19.6 mg/ml in ANN: MeOH=3:1

Compound A92 (R or S optical isomer 1): 1H NMR (400 MHz, CD ₃ OD) δ 7.25 (s, 1H), 7.20 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 5.27-5.08 (m, 1H), 4.12 (s, 2H), 4.04 (t, J=5.2 Hz, 2H) , 3.65 (t, J=6.0 Hz, 2H), 2.92 (t, J=5.2 Hz, 2H), 2.43 (s, 3H), 1.98-1.81 ( m, 2H), 1.78-1.57 (m, 2H), 1.51-1.32 (m, 2H), 0.91 (t, J=7.2 Hz, 3H) ppm. MS: m/e 415 (M+1) ⁺ .

Compound A93: (S or R optical isomer 2): 1H NMR (400 MHz, CD ₃ OD) δ 7.25 (s, 1H), 7.20 (d, J=8.4 Hz, 2H), 6, 87 (d, J=8.4 Hz, 2H), 5.24-5.09 (m, 1H), 4.12 (s, 2H), 4.05 (t, J=5.2 Hz, 2H ), 3.65 (t, J=6.4 Hz, 2H), 2.92 (t, J=5.2 Hz, 2H), 2.44 (s, 3H), 2.00-1.82 (m, 2H), 1.80-1.58 (m, 2H), 1.50-1.31 (m, 2H), 0.91 (t, J=7.2 Hz, 3H) ppm. MS: m/e 415 (M+1) ⁺ .

Compound A94: 3-((4-amino-7-(4-(methyl(2-(methylamino)ethyl)amino)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy )hexane-1-ol.

Step A: tert-butyl(2-((4-formylphenyl)(methyl)amino)ethyl)(methyl)carbamate.

Pd(OAc) ₂ (100 mg, 0.446 mmol), BINAP (350 mg, 0.562 mmol) and Cs ₂ CO ₃ (2.4 g, 7.36 mmol) under N2 atmosphere. The reaction mixture was stirred for 1 hour at 90°C. Once complete, the reaction mixture was quenched with water (30 ml) and extracted with EtOAc (3x30 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a residue. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (50%) to give the title compound (510 mg, 49%). MS: m/e 293. (M+H) ⁺ .

Step B: tert-butyl(2-((4-((2-(( 1 -(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo[2,1- f][1,2,4]triazin-7 yl)(hydroxy)methyl)phenyl)(methyl)amino)ethyl)(methyl)carbamate.

To a solution of 2-((1-(benzyloxy)hexan-3-yl)oxy)-M,Nbis(2,4-dimethoxybenzyl)imidazo[2,1£][1,2,4]triazin-4-amine (480 mg, 0.748 mmol) in THF (20 ml) was added n-BuLi (0.7 ml, 1.12 mmol) under N2 at -78°C. After stirring for 0.5 h at -78°C, a solution of tert-butyl(2-((4-formylphenyl)(methyl)amino)ethyl)(methyl)carbamate (260 mg, 0.89 mmol) in THF (5 ml). The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (30 ml) and extracted with DCM (3x30 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (50%) to give the title compound (470 mg, 67%). MS: m/e 934 (M+1) ⁺ .

Step C: tert-butyl (2-((4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo[2,1-:1] [1,2,4]triazin-7 yl)methyl)phenyl)(methyl)amino)ethyl)(methyl)carbamate.

To a solution of tert-butyl (2-((4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo[2,1-: 1][1,2,4]triazin-7yl)(hydroxy)methyl)phenyl)(methyl)amino)ethyl)(methyl)carbamate (470 mg, 0.503 mmol) in MeOH (20 ml) was added Pd/C (500 mg). The reaction mixture was stirred for 48 hours at 40°C in an H2 atmosphere (1 atm). The mixture was filtered and the filtrate was combined together and concentrated in vacuo. Sediment eyes

- 68 046488 was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (80%) to give the title compound (90 mg, 22%). MS: m/e 828 (M+1)+.

Step D: 3 -((4-amino-7 -(4-(methyl(2-(methylamino)ethyl)amino)benzyl)imidazo[2,1-f][1,2,4]triazin-2yl)oxy )hexan-1-ol (compound A94).

Tert-butyl (2-((4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1-f][1,2 ,4]triazin-7-yl)methyl)phenyl)(methyl)amino)ethyl)(methyl)carbamate (90 mg, 0.109 mmol) was dissolved in TFA (4 ml) and H2O (0.4 ml) under N2 atmosphere. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x30 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by pre-TLC (DCM/CH3OH( _NH3 ) = 20/1 to 10/1) to give the title compound (16 mg, 35%).

^1H NMR (400 MHz, CD3OD) δ 7.23 (s, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H) , 5.25-5.13 (m, 1H), 4.07 (s, 2H), 3.65 (t, J=6.4 Hz, 2H), 3.44 (t, J=6.8 Hz, 2H), 2.90 (s, 3H), 2.83 (t, J=6.8 Hz, 2H), 2.46 (s, 3H), 1.95-1.84 (m, 2H ), 1.79-1.59 (m, 2H), 1.51-1.32 (m, 2H), 0.92 (t, J=7.2 Hz, 3H) ppm. MS: m/e 428 (M+1)+.

Compound A95: 3 -((4-amino-7-(4-(2-(methylamino)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2yl)oxy)hex an- 1-ol.

Step A: methyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)benzoate.

To a solution of 4-(2-((tert-butoxycarbonyl)amino)ethyl)benzoic acid (2.5 g, 9.43 mmol) in DMF (30 ml) was added NaH (l.5 g, 37.5 mmol) in N2 atmosphere at 0°C. After stirring for 0.5 h at 25°C, CH3I (5.4 g, 38.03 mmol) in DMF (10 ml) was added dropwise. The reaction mixture was stirred for 16 hours at 25°C. Once complete, the reaction mixture was quenched with ice water (50 ml) at 0°C and extracted with EtOAc (3x100 ml). The combined organic layers were washed with water (3x50 ml), brine (3x50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product (2.2 g).

1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 3.91 (s, 3H), 3.45 (t, J=7.2 Hz, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.80 (s, 3H), 1.41 (s, 9H) ppm . MS: m/e 316. (M+H) ⁺ .

Step B: tert-butyl (4-(hydroxymethyl)phenethyl)(methyl)carbamate.

To a solution of methyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)benzoate (2.1 g, 7.17 mmol) in THF (20 ml) was added LiAlH ₄ (1.1 g, 28 .94 mmol) in an N2 atmosphere at 0°C. The reaction mixture was stirred for 0.5 h at 25°C. Once complete, the reaction mixture was quenched with water (1.1 ml), 15% NaOH (1.1 ml) and water (3.3 ml) at 0°C and Na2SO4 was added. The mixture was filtered and the filtrate was combined together and concentrated in vacuo to give the crude product (2.2 g). MS: m/e 288. (M+Na)+.

Step C: tert-butyl(4-formylphenethyl)(methyl)carbamate.

To a solution of tert-butyl(4-(hydroxymethyl)phenethyl)(methyl)carbamate (2.15 g, 8.11 mmol) in DCM (20 mL) was added DMP (4.1 g, 9.67 mmol) under N ₂ at 0°C. The reaction mixture was stirred for 1 hour at 25°C. After completion, the reaction mixture was quenched with aq. Na ₂ S ₂ O ₃ (50 ml) and extracted with DCM (3x50 ml). The combined organic layers were washed with aq. NaHCO3 (50 ml), brine (50 ml) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (40%) to give the title compound (1.1 g, 44% dnhb'nfgf).

1H NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 7.84 (d, J=7.6 Hz, 2H), 7.43 (d, J=6.8 Hz, 2H), 3.43 (t, J=6.0 Hz, 2H), 2.86 (t, J=7.2 Hz, 2H), 2.74 (s, 3H), 1.43-1.16 (m , 9H) ppm.

Step D: tert-butyl (4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f][1 ,2,4]triazin-7-yl)(hydroxy)methyl)phenethyl)(methyl)carbamate.

To a solution of 2-(( 1 -(benzyloxy)hexan-3-yl)oxy)-N,Nbis(2,4-dimethoxybenzyl)imidazo[2,1P[1,2,4]triazin-4-amine (500 mg, 0.78 mmol) in THF (15 ml) was added n-BuLi (0.73 ml, 1.17 mmol) under N ₂ atmosphere at -78°C. After stirring for 0.5 h at -78°C, a solution of tert-butyl(4-formylphenethyl)(methyl)carbamate (246 mg, 0.935 mmol) in THF (5 ml) was added dropwise. The reaction mixture was stirred for 2.5 hours at -78°C. Once complete, the reaction mixture was quenched with aqueous NH ₄ Cl (50 ml) and extracted with DCM (3x50 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (50%) to give the title compound (430 mg, 61%). MS: m/e 905 (M+1)+.

Step E: tert-butyl (4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1-f][1,2, 4]triazin-7-yl)methyl)phenethyl)(methyl)carbamate.

To a solution of tert-butyl(4-((2-(( 1 -(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f][1, 2,4]triazin-7-yl)(hydroxy)methyl)phenethyl)(methyl)carbamate (430 mg, 0.475 mmol) in MeOH (20 ml) was added to Pd/C (500 mg). The reaction mixture was stirred

- 69 046488 for 16 hours at 40°C in an H2 atmosphere (1 atm). The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (80%) to give the title compound (190 mg, 50%). MS: m/e 799 (M+1)+.

Step F: 3 -((4-amino-7 -(4-(2-(methylamino)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2yl)oxy)hexane-1 -ol (compound A95).

Tert-butyl(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-(( 1 -hydroxyhexan-3-yl)oxy)imidazo [2,1P[1,2,4]triazin- 7-yl)methyl)phenethyl)(methyl)carbamate (190 mg, 0.238 mmol) was dissolved in TFA (4 ml) and H2O (0.4 ml) under N2. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x30 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a residue. The residue was purified by pre-TLC (DCM/CH ₃ OH (NH ₃ ) = 20/1 to 15/1) to give the title compound (50 mg, 53%).

1H NMR (400 MHz, CD3OD) δ 7.31-7.25 (m, 3H), 7.18 (d, J=7.6 Hz, 2H), 5.24-5.11 (m, 1H) , 4.18 (s, 2H), 3.68-3.58 (m, 2H), 3.00 (d, J=7.6 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H), 2.54 (s, 3H), 1.95-1.88 (m, 2H), 1.78-1.56 (m, 2H), 1.51-1.31 (m, 2H), 0.92 (t, J=7.2 Hz, 3H) ppm. MS: m/e 399 (M+1)+.

Compound A96: 3-((4-amino-7-(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-£][1,2,4]triazin-2yl)oxy)hexane-1 -ol.

Step A: tert-butyl (2-((5-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1- f][1,2,4]triazin-7-yl)(hydroxy)methyl)-6-methoxypyridin-2yl)oxy)ethyl)(methyl)carbamate.

To a solution of 2-((1-(benzyloxy)hexan-3-yl)oxy)-N,Nbis(2,4-dimethoxybenzyl)imidazo[2,1P[1,2,4]triazin-4-amine (250 mg, 0.39 mmol) n-BuLi (1.6 M, 1.0 mL, 1.6 mmol) was added to THF (3 mL) at -78°C under N2. The mixture was stirred at -78°C for 30 minutes. A solution of tert-butyl(2((5-formyl-6-methoxypyridin-2-yl)oxy)ethyl)(methyl)carbamate (170 mg, 0.55 mmol) in THF (2 ml) was then added to the system at -78 °C. The reaction was stirred for 30 min and then warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated NH4Cl (10 ml) at room temperature and extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (120 mg, yield: 32%). MS: m/e 952 (M+1)+.

Step B: tert-butyl (2-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1-f][ 1,2,4]triazin-7-yl)methyl)-6-methoxypyridin-2-yl)oxy)ethyl)(methyl)carbamate.

A mixture of tert-butyl (2-((5-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f] [1,2,4]triazin-7-yl)(hydroxy)methyl)-6-methoxypyridin-2yl)oxy)ethyl)(methyl)carbamate (120 mg, 0.126 mmol) and Pd/C (wet, 200 mg) in MeOH (5 ml) was stirred under H ₂ at rt for 16 hours. The mixture was filtered and the filtrate was concentrated. The resulting residue was purified by pre-TLC (PE/EA=1:1) to give the title product (65 mg, yield: 60%). MS: m/e 846 (M+1)+.

Step C: 3-((4-amino-7-((2-methoxy-6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2,1-f][1, 2, 4]triazin-2-yl)oxy)hexan-1-ol (compound A96).

Tert-butyl(2-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3-yl)o xy)imidazo [2,1-f][ 1,2,4]triazin-7-yl)methyl)-6-methoxypyridin-2-yl)oxy)ethyl)(methyl)carbamate (65 mg, 0.077 mmol) in TFA (2 ml) stirred at rt for 24 h. The reaction mixture was concentrated under reduced pressure. The precipitate was treated with NaOH (2 ml, 4M), extracted with DCM/IPA (5:1, 3 mlx3). The combined organics were washed with brine (5 mlx3), dried over Na ₂ SO ₄ , concentrated and purified by pre-TLC (DCM/MeOH(NH ₃ )=8:1) to give the title compound (5 mg, yield: 15 %).

1H NMR (400 MHz, CD3OD) δ 7.51 (d, J=8.0 Hz, lH), 7.24 (s, 1H), 6.37 (d, J=8.0 Hz, 1H), 5.24-5.15 (m, 1H), 4.60-4.54 (m, 2H), 4.07 (s, 2H), 3.96 (s, 3H), 3.68-3, 61 (m, 2H), 3.46-3.42 (m, 2H), 2.76 (s, 3H), 2.07-1.98 (m, 2H), 1.96-1.82 ( m, 2H), 1.75-1.64 (m, 2H), 0.94-0.89 (m, 3H) ppm. MS: m/e 446 (M+1)+.

Compound A97: 3-((4-amino-7-(2-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy )hexane-1-ol.

Step A: tert-butyl (2-(3-fluoro-4-formylphenoxy)ethyl)(methyl)carbamate.

To a solution of 2-fluoro-4-hydroxybenzaldehyde (1.4 g, 10 mmol) in THF (20 ml) was added tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.75 g, 10 mmol) and PPh ₃ (3, 1 g, 12 mmol), the mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (2.4 g, 12 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. Combined organic extracts

- 70 046488 stirred over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (867 mg, 29.2%). MS: m/e: 298 (M+1)+.

Step B: tert-butyl (2-(4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f ][1,2,4]triazin-7-yl)(hydroxy)methyl)-3 fluorophenoxy)ethyl)(methyl)carbamate.

To a solution of 2-(( 1 -(benzyloxy)hexan-3-yl)oxy)-N,Nbis(2,4-dimethoxybenzyl)imidazo[2,1L[1,2,4]triazin-4-amine (867 mg, 1.35 mmol) in THF (10 ml), a solution of n-BuLi (1.6 M, 2.1 ml, 3.3 mmol) was added dropwise, maintaining the temperature between -75 and -65°C. After 1 hour, a suspension of tert-butyl (2-(3-fluoro-4-formylphenoxy)ethyl)(methyl)carbamate (400 mg, 1.34 mmol) in THF (2 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 a saturated solution of NH ₄ Cl, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by pre-TLC to give the title compound (670 mg, 52.9%). MS: m/e 939 (M+1) ⁺ .

Step C: tert-butyl(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-(( 1 -hydroxyhexan-3yl)oxy)imidazo [2,1-f][ 1,2,4]triazin-7-yl)methyl)-3-fluorophenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f] [1,2,4]triazin-7-yl)(hydroxy)methyl)-3 fluorophenoxy)ethyl)(methyl)carbamate (670 mg, 0.71 mmol) in MeOH (20 ml) was added Pd/C (600 mg ). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (100 mg, 16.9%). MS: m/e: 834 (M+1)+.

Step D: 3-((4-amino-7-(2-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-G][1,2,4]triazin-2yl)oxy )hexan-1-ol (compound A97).

To a mixture of the product of step C (100 mg, 0.12 mmol) in TFA (9 ml) was added H2O (1 ml) and the resulting mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2 N solution of NaOH (10 ml) and DCM (20 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (10 mg, 19.2%).

1H NMR (400 MHz, DMSOO δ 8.11 (s, 1H), 8.00 (s, 1H), 7.29-7.14 (m, 2H), 6.82 (d, J=11.7 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 5.04 (s, 1H), 4.43 (s, 1H), 4.03 (dd, J=14.1 , 8.4 Hz, 4H), 3.48 (d, J=6.0 Hz, 2H), 2.89 (s, 2H), 2.37 (s, 3H), 1.77 (d, J =6.1 Hz, 2H), 1.59 (s, 2H), 1.37-1.26 (m, 2H), 0.86 (t, J=7.3 Hz, 3H) ppm MS: m/e 433 (M+1)+.

Compound A98: 3 -((4-amino-7-(3-methoxy-4-(2-(methylamino)ethoxy)benzyl)imidazo [2,1f] [1,2,4]triazin-2-yl)oxy )hexane-1-ol.

Step A: tert-butyl (2-(4-formyl-2-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of 4-hydroxy-3-methoxybenzaldehyde (1.52 g, 10 mmol) in THF (20 ml) was added tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.75 g, 10 mmol) and PPh ₃ (3, 4 g, 13 mmol), the mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (2.6 g, 13 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (1.6 g, 51.7%). MS: m/e: 310 (M+1)+.

Step B: tert-butyl(2-(4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f ][1,2,4]triazin-7 -yl)(hydroxy)methyl)-2methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of 2-(( 1 -(benzyloxy)hexan-3-yl)oxy)-N,Nbis(2,4-dimethoxybenzyl)imidazo[2,1L[1,2,4]triazin-4-amine (867 mg, 1.35 mmol) in THF (10 ml) was added dropwise a solution of n-BuLi (1.6 M, 2.1 ml, 3.3 mmol), maintaining the temperature in the range from -75 to -65°C. After 1 hour, a suspension of tert-butyl (2-(4-formyl-2-methoxyphenoxy)ethyl)(methyl)carbamate (618 mg, 2 mmol) in THF (2 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 NH ₄ Cl solution, extracted with EtOAc (20 mlx3), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the title compound (650 mg, 50.7%). MS: m/e 951 (M+1)+.

Step C: tert-butyl(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1-f][1 ,2,4]triazin-7-yl)methyl)-2-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f] [1,2,4]triazin-7-yl)(hydroxy)methyl)-2methoxyphenoxy)ethyl)(methyl)carbamate (650 mg, 0.68 mmol) in MeOH (20 ml) was added Pd/C (600 mg) . The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified using chromatography

- 71 046488 graphs on a column to obtain the title product (200 mg, 34.7%). MS: m/e: 845 (M+1)+.

Step D: 3-((4-amino-7-(3-methoxy-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-£][1,2,4]triazin-2yl)oxy )hexan-1-ol (compound A98).

To a mixture of the product of step C (200 mg, 0.24 mmol) in TFA (9 ml) was added H ₂ O (1 ml) and the resulting mixture was stirred at 40° C. overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2 N solution of NaOH (10 ml) and DCM (20 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (50 mg, 47.6%).

1H NMR (400 MHz, DMSOL) δ 8.09 (s, 1H), 7.97 (s, 1H), 7.27 (s, 1H), 6.95 (s, 1H), 6.86 (d , J=8.4 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 5.06-5.01 (m, 1H), 4.44 (s, 1H), 4 .05 (s, 2H), 3.95 (t, J=5.5 Hz, 2H), 3.72 (s, 3H), 3.48 (s, 2H), 2.82 (s, 2H) , 2.34 (s, 3H), 1.78 (d, J=6.5 Hz, 2H), 1.60 (s, 2H), 1.41-1.26 (m, 2H), 0, 86 (t, J=7.3 Hz, 3H) ppm. MS: m/e 445 (M+1) ⁺ .

Compound A99: (S)-7-(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)-2-(pentan-2-yloxy)imidazo[2,1P[1.2.4|triazin-4- amine.

Step A: tert-butyl(2-(4-((4-(bis(4-methoxybenzyl)amino)-2-((^)-pentan-2-yl)oxy)imidazo[2,1А1,2,4 ]triazin-7-yl)(hydroxy)methyl)-2-fluorophenoxy)ethyl)(methyl)carbamate.

To a solution of ^)-N^-bis(4-methoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-f|[1,2,4]triazin-4-amine (234 mg, 0. 5 mmol) in THF (10 ml) a solution of n-BuLi (1.6 M, 0.9 ml, 1.5 mmol) was added dropwise maintaining the temperature in the range from -75 to -65°C. After 1 hour, a suspension of tert-butyl (2-(2-fluoro-4-formylphenoxy)ethyl)(methyl)carbamate (297 mg, 1 mmol) in THF (2 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 a saturated solution of NH4C1, extracted with EtOAc (20 mlx3), washed with brine, dried over Na2SO4, filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (120 mg, 31.6%). MS: m/e 759 (M+1)+.

Step B: (S)-7-(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)-2-(pentan-2-yloxy)imidazo[2,1N1,2,4]triazin-4- amine (compound A99).

To a mixture of the product of step C (120 mg, 0.158 mmol) in TFA (4 ml) was added Et ₃ SiH (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 precipitate and the reaction was heated at 80°C overnight. The mixture was concentrated in vacuo and the residue was purified by pre-HPLC to give the title compound (22 mg, 34.9%).

1H NMR (400 MHz, DMSOHO δ 8.11 (s, 1H), 7.99 (s, 1H), 7.30 (s, 1H), 7.16 (m, 1H), 7.09 (t, J=8.5 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 5.03-4.88 (m, 1H), 4.07 (s, 4H), 2, 90 (t, J=5.3 Hz, 2H), 2.38 (s, 3H), 1.62 (d, J=6.8 Hz, 1H), 1.51 (d, J=5.9 Hz, 1H), 1.35 (dd, J=14.8, 7.5 Hz, 2H), 1.24 (d, J=6.0 Hz, 3H), 0.88 (t, J=7 .2 Hz, 3H) ppm MS: m/e 403 (M+1)+.

Compound A100: ^)-7-(4-(2-(methylamino)ethoxy)benzyl)-2-(pentan-2-yloxy)imidazo[2,1N1,2,4]triazin-4-amine.

Step A: tert-butyl(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((^)-pentan-2yl)oxy)imidazo [2,1-1T][ 1,2,4]t riazin-7 -yl)(hydroxy)methyl)phenoxy)ethyl)(methyl)carbamate.

To a solution of N)-N,Nbis(2,4-dimethoxybenzyl)-2-(pentan-2-yloxy)imidazo[2,1-1G][1,2,4]triazin-4amine (521 mg, 1 .0 mmol) in THF (5 ml) was added n-BuLi (1.6 M, 3.1 ml, 5.0 mmol) at -78°C under N ₂ atmosphere. The mixture was stirred at -78°C for 30 minutes. A solution of tert-butyl(2-(4formylphenoxy)ethyl)(methyl)carbamate (500 mg, 2.0 mmol) in THF (5 ml) was added to the system at -78°C. The reaction was stirred for 30 min and then warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated NH ₄ Cl (10 ml) at room temperature and extracted with EA (10 ml x 3 ). The combined organic phase was washed with brine (10 mlx3), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (265 mg, yield: 33%). MS: m/e 801 (M+1)+.

Step B: tert-butyl^)-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-(pentai-2-yloxy)imidazo[2,1А1,2,4] triazin-7-yl)methyl)phenoxy)ethyl)(methyl)carbamate.

A mixture of tert-butyl(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((^)-pentan-2-yl)oxy)imidazo[2,1Al,2,4 ]triazin-7-yl)(hydroxy)methyl)phenoxy)ethyl)(methyl)carbamate (210 mg, 0.26 mmol), Pd/C (wet, 200 mg) and AcOH (0.5 ml) in MeOH ( 20 ml) was stirred under H2 at rt for 24 hours. The mixture was filtered and the filtrate was concentrated under high vacuum to give the title product (205 mg, crude). MS: m/e 785 (M+1)+.

Step C: ^)-7-(4-(2-(methylamino)ethoxy)benzyl)-2-(pentan-2-yloxy)imidazo[2,1-£][1,2,4]triazin-4 amine (connection A100).

Tert-butyl^)-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-(pentan-2-yloxy)imidazo[2,11T][1,2,4] triazin-7-yl)methyl)phenoxy)ethyl)(methyl)carbamate (205 mg, 0.26 mmol) in TFA (5 ml) was stirred at rt for 16 hours. The reaction mixture was concentrated under reduced pressure. Sediment about

- 72 046488 treated with NaOH (2 ml, 4M), extracted with DCM/IPA (5:1, 3 mlx3). The combined organics were washed with brine (5 mlx3), dried over Na ₂ SO ₄ , concentrated and purified by pre-TLC (DCM/MeOH(CI ₃ )=10:1) to give the title compound (5 mg, yield: 15 %).

1H NMR (400 MHz, CD3OD) δ 7.26 (s, 1H), 7.20 (d J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 2H), 5 ,13-4.99 (m, 1H), 4.12 (s, 2H), 4.05 (t, J=4.8 Hz, 2H), 2.98-2.88 (m, 2H), 2.44 (s, 3H), 1.80-1.66 (m, 1H), 1.64-1.50 (m, 1H), 1.50-1.35 (m, 2H), 1. 30 (d, J=6.0 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H) ppm. MS: m/e 385 (M+1)+.

Compound A101: (R or S)-3-((4-amino-7-(2-methoxy-4-(2(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4] triazin -2-yl)oxy)hexan-1-ol.

Step A: (R or S)-2-(2-(benzyloxy)ethyl)oxirane.

The R-1 reactor with a mixer was started. (Note: R-1 reactor: 500 ml bottle). Reactor R-1 was filled with NaH (19.1 g, 0.54 X w/w, 60% purity). Reactor R-1 was charged with THF (210 ml, 6.00 X by volume). Reactor R-1 at 0°C was charged with (R or S)-2-(oxiran-2-yl)ethan-1-ol (35.0 g, 1.00 X w/w). The mixture was stirred at 0°C for 0.5 hours. BnBr (81.5 g, 2.33 X relative weight) and TBAI (14.7 g, 0.42 X relative weight) were loaded into reactor R-1 at 0°C masses). The mixture was stirred at 25°C for 16 hours. TLC (petroleum ether/ethyl acetate = 3/1, R _f = 0.42) indicated completion of the reaction. H2O (150 ml, 4.29 X v/v) was added to the mixture. The mixture was extracted with EtOAc (200 mlx2, 11.4 X v/v). The organic layer was mixed and washed with brine. The organic layer was dried using Na ₂ SO ₄ . The organic layer was concentrated to obtain the crude product. The precipitate was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 5/1). The title compound (40.0 g, 56.5% yield) was obtained as a yellow oil. ^1H NMR: 400 MHz CDCl ₃ : δ 7.30-7.36 (m, 5H), 4.55 (s, 2H), 3.62-3.66 (m, 2H), 3.08-3 .09 (m, 1H), 2.78-2.81 (m, 1H), 2.532.55 (m, 1H), 1.90-1.92 (m, 1H), 1.81-1.82 (m, 1H) ppm.

Step B: (R or S)-1-(benzyloxy)hexan-3-ol.

The R-1 reactor with a mixer was started. (Note: R-1 reactor: 1L bottle). EtMgBr (150 ml, 3.75 X v/v) was charged into reactor R-1. Reactor R-1 was charged with THF (240 ml, 6.00 X by volume). CuI (0.85 g, 0.02 X relative to weight) was loaded into reactor R-1 at 0°C. The mixture was stirred at 0°C for 0.5 h. Reactor R-1 was charged with (R or S)-2-(2-(benzyloxy)ethyl)oxirane (40.0 g, 1.00 X w/w). The mixture was stirred at 25°C for 1 hour. TLC (petroleum ether/ethyl acetate = 3/1, _Rf = 0.35) showed completion of the reaction. Aq. was added to the mixture. NH ₄ Cl (200 ml, 5.00 X by volume). The mixture was extracted with EtOAc (200 mlx2, 10.0 X v/v). The organic layer was mixed and washed with brine. The organic layer was dried using Na2SO4. The organic layer was concentrated to obtain the crude product. The precipitate was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 5/1). The title compound was obtained (22.7 g, 47.1% yield, 97.0% purity) as a yellow oil. 1H NMR: 400 MHz CDCl _3: δ 7.30-7.38 (m, 5H), 4.54 (s, 2H), 3.74-3.83 (m, 1H), 3.69-3, 73 (m, 1H), 3.65-3.67 (m, 1H), 2.87 (s, 1H), 1.75-1.77 (m, 2H), 1.36-1.48 ( m, 4H), 0.92-0.95 (m, 3H) ppm.

Step C: (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4-dimethoxybenzyl)imidazo[2,1D[1,2,4 ]triazine-4-amine.

To a solution of (R or S)-1-(benzyloxy)hexan-3-ol (10.0 g, 48.07 mmol) in DMF (100 mL) was added NaH (3.8 g, 95.0 mmol) under atmosphere N2 at 0°C. After stirring for 0.5 h at 25°C, 2-chloro-N,Nbis(2,4-dimethoxybenzyl)imidazo[2,1-1G][1,2,4]triazin-4-amine ( 18.8 g, 40.0 mmol). The reaction mixture was stirred for 0.5 h at 80°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (80 ml) and extracted with EtOAc (3x 100 ml). The combined organic layers were washed with water (3x50 ml), brine (3x50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to leave a residue. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (50%) to give the title compound (24.9 g, 97%). MS: m/e 642 (M+1)+.

Step D: tert-butyl (2-(4-formyl-3-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of 4-hydroxy-2-methoxybenzaldehyde (304 g, 2 mmol) in THF (20 ml) was added tert-butyl (2-hydroxyethyl)(methyl)carbamate (350 g, 2 mmol) and PPh ₃ (665 g, 2.5 mmol). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (505 mg, 2.5 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (300 mg, 48.5%). MS: m/e: 310 (M+1)+.

Step E: tert-butyl (2-(4-((2-(((R or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3 methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4

- 73 046488 dimethoxybenzyl)imidazo[2,1-0[1,2,4|triazin-4-amine (237 mg, 0.37 mmol) in THF (10 ml) a solution of n-BuLi (1.6) was added dropwise M, 0.7 ml, 1.1 mmol), maintaining the temperature in the range from -75 to -65°C. After 1 hour, a suspension of tert-butyl (2-(4-formyl-3methoxyphenoxy)ethyl)(methyl)carbamate (340 mg, 1 mmol) in THF (2 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 a saturated solution of NH4C1, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (100 mg, 28.4%). MS: m/e 951 (M+1)+.

Step F: tert-butyl^ or S)-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)-3-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3 methoxyphenoxy)ethyl)(methyl)carbamate (100 mg, 0.105 mmol) in MeOH (20 ml) was added Pd/C (200 mg). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (60 mg, 67.6%). MS: m/e: 845 (M+1) ⁺ .

Step G: (R or S)-3-((4-amino-7-(2-methoxy-4-(2-(methylamino)ethoxy)benzyl)imidazo[2.1G|[1.2.4|lriazin -2 -yl)oxy)hexan-1-ol (compound A101).

To a mixture of the product from step F (60 mg, 0.071 mmol) in TFA (9 ml) was added H2O (1 ml) and the resulting mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2 N solution of NaOH (10 ml) and DCM (20 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (8 mg, 25.3%).

Ή NMR (400 MHz, DMSOD ₆ ) δ 8.88 (br,s, 2H), 8.38 (s, 1H), 8.25 (s, 1H), 7.35 (s, 1H), 7, 10 (d, J=8.1 Hz, 1H), 6.61 (s, 1H), 6.49 (d, J=8.2 Hz, 1H), 5.08 (m, 1H), 4, 21 (s, 2H), 4.00 (s, 2H), 3.80 (s, 3H), 3.49 (d, J=6.0 Hz, 2H), 3.30 (s, 2H), 2.62 (s, 3H), 1.78 (s, 2H), 1.62 (s, 2H), 1.41-1.28 (m, 2H), 0.87 (t, J=7, 1 Hz, 3H) ppm. MS: m/e 445 (M+1)+.

Compound A102: 3-((4-amino-7-(3-chloro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4]triazin-2-yl)oxy )hexane-1-ol.

Step A: tert-butyl (2-(2-chloro-4-formylphenoxy)ethyl)(methyl)carbamate.

To a solution of 3-chloro-4-hydroxybenzaldehyde (1.56 g, 10 mmol) in THF (20 ml) was added tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.75 g, 10 mmol) and PPh ₃ (3, 4 g, 13 mmol). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (2.6 g, 13 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (1.6 g, 49.8%). MS: m/e: 314 (M+1)+.

Step B: tert-butyl(2-(4-((2-((1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(4methoxybenzyl)amino)imidazo [2,1-G][ 1,2,4]triazin-7-yl)(hydroxy)methyl)-2chlorophenoxy)ethyl)(methyl)carbamate.

To a solution of 2-((1-(benzyloxy)hexan-3-yl)oxy)-Nbis(4-methoxybenzyl)imidazo[2,1G][1,2,4]triazin-4-amine (288 mg, 0.5 mmol) in THF (10 ml), a solution of n-BuLi (1.6 M, 1.25 ml, 2 mmol) was added dropwise, maintaining the temperature between -75 and -65°C. After 1 hour, a suspension of tert-butyl (2-(2-chloro-4-formylphenoxy)ethyl)(methyl)carbamate (313 mg, 1 mmol) in THF (2 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 a saturated solution of NH4C1, extracted with EtOAc (20 mlx3), washed with brine, dried over Na2SO4, filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (320 mg, 71.8%). MS: m/e 896 (M+1)+.

Step C: 3-((4-amino-7-(3-chloro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-G][1,2,4]triazin-2yl)oxy )hexan-1-ol (compound A102).

To a mixture of the product of step C (320 mg, 0.357 mmol) in TFA (4 ml) was added Et ₃ SiH (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 precipitate and the reaction was heated at 80°C overnight. The mixture was concentrated in vacuo and the residue was purified by pre-HPLC to give the title compound (25 mg, 15.6%).

Ή NMR (400 MHz, DMSO^6) δ 8.12 (s, 1H), 8.00 (s, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 5.07-5.01 (m, 1H), 4.44 (s, 1H) , 4.07 (s, 4H), 3.49 (s, 2H), 2.93 (d, J=4.5 Hz, 2H), 2.41 (s, 3H), 1.83-1, 71 (m, 2H), 1.60 (d, J=6.3 Hz, 2H), 1.38-1.25 (m, 2H), 0.85 (t, J=7.1 Hz, 3H ) ppm. MS: m/e 449 (M+1)+.

Compound A103: (R or S)-3-((4-amino-7-(3-methyl-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1- 74 046488

P[1,2,4|triazin-2-yl)oxy)hexan-1-ol.

Step A: tert-butyl (2-(4-formyl-2-methylphenoxy)ethyl)(methyl)carbamate.

To a solution of 4-hydroxy-3-methylbenzaldehyde (1.36 g, 10 mmol) in THF (20 ml) was added tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.75 g, 10 mmol) and PPh ₃ (3, 4 g, 13 mmol). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (2.6 g, 13 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (1.7 g, 58%). MS: m/e: 294 (M+1)+.

Step B: tert-butyl(2-(4-((2-((U or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [ 2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2methylphenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4dimethoxybenzyl)imidazo[2,1-G|[1,2,4 ]triazin-4-amine (384 mg, 0.6 mmol) in THF (10 ml), a solution of n-BuLi (1.6 M, 0.75 ml, 1.2 mmol) was added dropwise, maintaining the temperature between -75 to -65°C. After 1 hour, a suspension of tert-butyl (2-(4-formyl-2methylphenoxy)ethyl)(methyl)carbamate (300 mg, 1 mmol) in THF (2 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 a saturated solution of NH4C1, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC to give the title compound (400 mg, 71.4%). MS: m/e 935 (M+1) ⁺ .

Step C: tert-butyl or S)-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1- f][1,2,4]triazin-7-yl)methyl)-2-methylphenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(4-((2-((U or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7 -yl)(hydroxy)methyl)-2methylphenoxy)ethyl)(methyl)carbamate (400 mg, 0.428 mmol) in MeOH (20 ml) was added Pd/C ( 400 mg). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (200 mg, 56.4%). MS: m/e: 829 (M+1)+.

Step D: (R or S)-3-((4-amino-7-(3-methyl-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4]triazine -2-yl)oxy)hexan-1-ol (compound A103).

To a mixture of the product of step C (200 mg, 0.24 mmol) in TFA (9 ml) was added H2O (1 ml) and the resulting mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2 N solution of NaOH (10 ml) and DCM (20 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (40 mg, 38.8%).

Ή NMR (400 MHz, DMSO-de) δ 8.08 (s, 1H), 7.97 (s, 1H), 7.26 (s, 1H), 7.07 (d, J=10.3 Hz , 2H), 6.82 (d, J=8.1 Hz, 1H), 5.11-5.02 (m, 1H), 4.45 (s, 1H), 4.01 (s, 2H) , 3.96 (t, J=5.5 Hz, 2H), 3.49 (d, J=5.0 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H), 2 .35 (s, 3H), 2.10 (s, 3H), 1.79 (dd, J=12.5, 6.1 Hz, 2H), 1.65-1.58 (m, 2H), 1.33 (dt, J=14.5, 7.1 Hz, 2H), 0.86 (t, J=7.3 Hz, 3H) ppm. MS: m/e 429 (M+1)+.

Compound A104: (R or S)-3-((4-amino-7-(3-(2-(methylamino)ethoxy)benzyl)imidazo[2.1GC1,2,4]triazin-2-yl)oxy) hexan-1-ol.

Step A: tert-butyl (2-(3-formylphenoxy)ethyl)(methyl)carbamate.

To a solution of 3-hydroxybenzaldehyde (2 g, 16.39 mmol), tert-butyl(2hydroxyethyl)(methyl)carbamate (2.9 g, 16.57 mmol) and PPh ₃ (6.4 g, 24.4 mmol) in THF (60 ml) a solution of DTAD (4.1 g, 17.83 mmol) in THF (20 ml) was added under N2 at 0°C. The reaction mixture was stirred for 16 hours at 25°C. Once complete, the reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3x80 ml). The combined organic layers were washed with aq. NaHCO ₃ (3x50 ml), brine (50 ml), dried over Na2SO4 and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (20%) to give the title compound (4.3 g, crude). MS: m/e 302 (M+Na)+.

Step B: tert-butyl(2-(3-((2-((U or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [ 2,1-f][1,2,4]triazin-7 yl)(hydroxy)methyl)phenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4dimethoxybenzyl)imidazo[2,1-G][1,2,4 ]triazin-4-amine (500 mg, 0.78 mmol) in THF (20 ml) was added nBuLi (2 ml, 3.2 mmol) under N ₂ atmosphere at -78°C. After stirring for 0.5 h at -78°C, tert-butyl (2-(3-formylphenoxy)ethyl)(methyl)carbamate (870 mg, crude) was added. The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (30 ml) and extracted with DCM (3x30 ml). The combined organic layers were dried over

- 75 046488

Na2SO4 and concentrated in vacuo to obtain a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (50%) to give the title compound (150 mg, 21%). MS: m/e 921 (M+1)+.

Step C: tert-butyl^ or S)-(2-(3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)phenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(3-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7yl)(hydroxy)methyl)phenoxy)ethyl)(methyl)carbamate (150 mg, 0.163 mmol) in MeOH (20 ml) was added Pd/C (150 mg) and AcOH (0.1 ml). The reaction mixture was stirred for 24 hours at 40°C in an atmosphere of H ₂ (1 atm). The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (90%) to give the title compound (120 mg, 90%). MS: m/e 815 (M+1) ⁺ .

Step D: (R or S)-3-((4-amino-7-(3-(2-(methylamino)ethoxy)benzyl)imudazo[2,1-f][1,2,4]triazin-2yl )oxy)hexan-1-ol (compound A104).

Tert-butyl^ or S)-(2-(3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo[2,1-B] [1,2,4]triazin-7-yl)methyl)phenoxy)ethyl)(methyl)carbamate (120 mg, 0.147 mmol) was dissolved in TFA (3 ml) and H2O (0.3 ml) under N2 atmosphere. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x30 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a precipitate. The residue was purified by pre-TLC (DCM/CH ₃ OH (NH ₃ ) = 15/1 to 10/1) to give the title compound (30 mg).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.29 (s, 1H), 7.23 (t, J=7.6 Hz, 1H), 6.99-6.79 (m, 3H), 5.17 (s, 1H), 4.18 (s, 2H), 4.13 (s, 2H), 3.64 (d, J=6.8 Hz, 2H), 3.19 (s, 2H ), 2.61 (s, 3H), 1.96-1.83 (m, 2H), 1.77-1.56 (m, 2H), 1.48-1.31 (m, 2H), 0.90 (t, J=7.2 Hz, 3H) ppm. MS: m/e 415 (M+1) ⁺ .

Compound A105 and compound A106: (R or S)-3-((4-amino-7-(3-fluoro-4-(2(methylamino)ethoxy)benzyl)imidazo[2,1-:А1,2,4 ]triazin-2-yl)oxy)hexan-1-ol, and (S or R)-3-((4-amino7-(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo [2 ,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-oli compound A91 3 -((4-amino-7-(3-fluoro-4-(2-(methylamino) Ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2yl)oxy)hexan-1-ol was separated into two optical isomers, compound A105 and compound A106, using prep-SCPC. The conditions for pre-SKFH are given below.

Column CHIRALPAK AD-H Column size 5 cm x 25 cm, 5 microns Injection 4.8 ml Mobile phase CO ₂ :IPA (2 mM MNH3-MeOH) = 55:45 Current speed 200 ml/min Wavelength UV 220 nm Temperature 35°C Sample solution 36.5 mg/ml in MeOH:DCM=3:1

Compound A105 (R or S optical isomer 1): 1H NMR (400 MHz, CD3OD) δ 7.31 (s, 1H), 7.126.99 (m, 3H), 5.21-5.10 (m, 1H) , 4.18-4.08 (m, 4H), 3.70-3.58 (m, 2H), 3.03-2.92 (m, 2H), 2.47 (s, 3H), 1 .96-

1.82 (m, 2H), 1.80-1.60 (m, 2H), 1.45-1.30 (m, 2H), 0.90 (t, J=6.8 Hz, 3H) ppm MS: m/e 433 (M+1)+.

Compound A106 (S or R optical isomer 2): 1H NMR (400 MHz, CD ₃ OD) δ 7.31 (s, 1H), 7.126.98 (m, 3H), 5.22-5.12 (m, 1H), 4.19-4.11 (m, 4H), 3.70-3.59 (m, 2H), 3.04-2.97 (m, 2H), 2.49 (s, 3H) , 1.96-

1.81 (m, 2H), 1.79-1.58 (m, 2H), 1.50-1.30 (m, 2H), 0.90 (t, J=7.2 Hz, 3H) ppm MS: m/e 433 (M+1)+.

Compound A107: (R or S)-3-((4-amino-7-(2-methyl-4-(2-(methylamino)ethoxy)benzyl)imudazo[2,1f][1,2,4]triazine -2 -yl)oxy)hexane-1-ol.

Step A: tert-butyl (2-(4-formyl-3-methylphenoxy)ethyl)(methyl)carbamate.

To a solution of 4-hydroxy-2-methylbenzaldehyde (1.36 g, 10 mmol) in THF (20 ml) was added tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.7 g, 10 mmol) and PPh ₃ (3, 4 g, 13 mmol). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (2.6 g, 13 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (1.5 g, 51.2%). MS: m/e: 294 (M+1)+.

Step B: tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [ 2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3 methylphenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4

- 76 046488 dimethoxybenzyl)imidazo[2,1T|[1,2,4|triazin-4-amine (530 mg, 0.82 mmol) in THF (10 ml) a solution of n-BuLi (1.6 M) was added dropwise , 1 ml, 1.6 mmol), maintaining the temperature in the range from -75 to -65°C. After 1 hour, a suspension of tert-butyl (2-(4-formyl-3methylphenoxy)ethyl)(methyl)carbamate (400 mg, 1.36 mmol) in THF (2 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 a saturated solution of NH4C1, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (400 mg, 52.2%). MS: m/e 935 (M+1)+.

Step C: tert-butyl^ or S)-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)-3-methylphenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3 methylphenoxy)ethyl)(methyl)carbamate (400 mg, 0.42 mmol) in MeOH (20 ml) was added Pd /C (400 mg). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (200 mg, 57.6%). MS: m/e: 829 (M+1) ⁺ .

Step D: (R or S)-3-((4-amino-7-(2-methyl-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4]triazine -2-yl)oxy)hexan-1-ol (compound A107).

To a mixture of the product of step C (200 mg, 0.24 mmol) in TFA (9 ml) was added H2O (1 ml) and the resulting mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2 N solution of NaOH (10 ml) and DCM (20 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (36 mg, 34.9%).

Ή NMR (400 MHz, DMSOL) δ 8.10 (s, 1H), 7.98 (s, 1H), 7.13 (s, 1H), 7.08 (d, J=8.1 Hz, 1H ), 6.77 (s, 1H), 6.68 (d, J=7.9 Hz, 1H), 5.06 (s, 1H), 4.5 (br,s, 1H), 4.02 (s, 2H), 3.96 (s, 2H), 3.48 (s, 2H), 2.83 (d, J=3.3 Hz, 2H), 2.34 (d, J=2, 7 Hz, 3H), 2.27 (s, 3H), 1.77 (s, 2H), 1.60 (s, 2H), 1.39-1.26 (m, 2H), 0.86 ( t, J=7.1 Hz, 3H) ppm. MS: m/e 429 (M+1)+.

Compound A108: (R or S)-3-((4-amino-7-(2-chloro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f][1,2,4]triazine -2-yl)oxy)hexane-1-ol.

Step A: tert-butyl (2-(3-chloro-4-formylphenoxy)ethyl)(methyl)carbamate.

To a solution of 2-chloro-4-hydroxybenzaldehyde (1.56 g, 10 mmol) in THF (20 ml) was added tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.75 g, 10 mmol) and PPh ₃ (3, 4 g, 13 mmol). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (2.6 g, 13 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (0.8 g, 25.6%). MS: m/e: 314 (M+1)+.

Step B: tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(4methoxybenzyl)amino)imidazo [2, 1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3 chlorophenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(4-methoxybenzyl)imidazo[2.1G][1,2,4]triazine -4-amine (288 mg, 0.5 mmol) in THF (10 ml), a solution of n-BuLi (1.6 M, 1.25 ml, 2 mmol) was added dropwise, maintaining the temperature between -75 and - 65°C. After 1 hour, a suspension of tert-butyl (2-(3-chloro-4-formylphenoxy)ethyl)(methyl)carbamate (313 mg, 1 mmol) in THF (2 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 a saturated solution of NH4C1, extracted with EtOAc (20 mlx3), washed with brine, dried over Na2SO4, filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (120 mg, 26.8%). MS: m/e 895 (M+1)+.

Step C: (R or S)-3-((4-amino-7-(2-chloro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4]triazine -2-yl)oxy)hexan-1-ol (compound A108).

To a mixture of the product of step C (120 mg, 0.134 mmol) in TFA (4 ml) was added Et ₃ SiH (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 precipitate and the reaction was heated at 80°C overnight. The mixture was concentrated in vacuo and the residue was purified by pre-HPLC to give the title compound (15 mg, 25%).

Ή NMR (400 MHz, DMSO-de) δ 8.13 (s, 1H), 8.00 (s, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.21 (s , 1H), 7.05 (s, 1H), 6.86 (d, J=8.6 Hz, 1H), 5.09-5.01 (m, 1H), 4.5 (br,s, 2H), 4.14 (s, 2H), 4.02 (t, J=4.9 Hz, 2H), 3.48 (d, J=5.3 Hz, 2H), 2.85 (d, J=5.1 Hz, 2H), 2.35 (s, 3H), 1.77 (d, J=6.0 Hz, 2H), 1.59 (d, J= 4.6 Hz, 2H) , 1.31 (dt, J=14.5, 7.0 Hz, 2H), 0.85 (t, J=7.2 Hz, 3H) ppm. MS: m/e 449 (M+1)+.

Compound A109: (3R or S)-3-((4-amino-7-((6-((1-(methylamino)propan-2-yl)oxy)pyridin-3

- 77 046488 yl)methyl)imidazo[2,1-G][1,2,4]triazin-2-yl)oxy)hexan-1-ol.

Step A: tert-butyl(2-hydroxypropyl)(methyl)carbamate.

To a solution of tert-butyl-methyl(2-oxoethyl)carbamate (3.9 g, 22.5 mmol) in THF (80 ml) was added CH ₃ BrMg (24.8 ml, 24.8 mmol) under N ₂ at -0°C. The reaction mixture was stirred for 1 hour at 25°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a residue. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (50%) to give the title compound (3.87 g, 91%).

1H NMR (400 MHz, DMSO-de) δ 4.64 (s, 1H), 3.77 (d, J=5.6 Hz, 1H), 3.14 (dd, J=13.6, 5, 2 Hz, 1H), 2.97 (dd, J=13.6, 6.8 Hz, 1H), 2.89-2.75 (m, 3H), 1.36 (s, 9H), 1, 00 (d, J=5.6 Hz, 3H) ppm.

Step B: tert-butyl (2-(4-formylphenoxy)propyl)(methyl)carbamate.

To a solution of 6-chloronicotinaldehyde (500 mg, 3.52 mmol), tert-butyl(2hydroxypropyl)(methyl)carbamate (800 mg, 4.23 mmol), Pd ₂ (dba) ₃ (240 mg, 0.262 mmol) and Cs ₂ CO ₃ (2.3 g, 7.05 mmol) in dioxane (10 ml) was added RuPhos (247 g, 0.528 mmol) under N2. The reaction mixture was stirred for 12 hours at 95°C. The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (30%) to give the title compound (600 mg, 58%).

1H NMR (400 MHz, DMSO^) δ 9.95 (s, 1H), 8.72 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 6.91 (s, 1H), 5.57 (s, 1H), 3.43 (s, 2H), 2.80 (d, J=9.2 Hz, 3H), 1.35 (s, 9H), 1.27 ( d, J=5.6 Hz, 3H) ppm. MS: m/e 295 (M+H)+.

Step C: tert-butyl (2-((5-((2-(((R or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino) imidazo [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2yl)oxy)propyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4dimethoxybenzyl)imidazo[2,1-G][1,2,4 ]triazin-4-amine (600 mg, 0.934 mmol) in THF (15 ml) was added nBuLi (0.88 ml, 1.41 mmol) under N2 at -78°C. After stirring for 0.5 h at -78°C, tert-butyl (2-(4-formylphenoxy)propyl)(methyl)carbamate (328 mg, 1.12 mmol) was added. The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (30 ml) and extracted with DCM (3x50 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (50%) to give the title compound (510 mg, 58%). MS: m/e 936 (M+H)+.

Step D: tert-butyl(2-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((U or S)-1-hydroxyhexan-3yl)oxy)imidazo [2, 1-f][1,2,4]triazin-7-yl)methyl)pyridin-2-yl)oxy)propyl)(methyl)carbamate.

To a solution of tert-butyl(2-((5-((2-(((I or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2yl)oxy)propyl)(methyl)carbamate (410 mg, 0.438 mmol) in MeOH (30 ml) Pd/C (410 mg) and AcOH (0.4 ml) were added. The reaction mixture was stirred for 12 hours at 40°C in an atmosphere of H ₂ (1 atm). The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (70%) to give the title compound (180 mg, 50%). MS: m/e 830 (M+H)+.

Step E: (3R or S)-3-((4-amino-7-((6-((1-(methylamino)propan-2-yl)oxy)pyridin-3yl)methyl)imidazo[2,1- G ][1,2,4]triazin-2-yl)oxy)hexan-1-ol (compound A109).

Tert-butyl(2-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((U or S)-1-hydroxyhexan-3 yl)oxy)imidazo [2,1- f][1,2,4]triazin-7-yl)methyl)pyridin-2-yl)oxy)propyl)(methyl)carbamate (180 mg, 0.217 mmol) was dissolved in TFA (3 ml) and H2O (0. 3 ml) in N2 atmosphere. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a residue. The residue was purified by pre-TLC (DCM/CH ₃ OH(KH ₃ )=15/1) to give the title compound (50 mg, 53%).

1H NMR (400 MHz, CD3OD) δ 8.09 (d, J=13.6 Hz, 1H), 7.66-7.54 (m, 1H), 7.33 (s, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.30-5.13 (m, 2H), 4.14 (s, 2H), 3.65 (s, 2H), 2.94-2, 69 (m, 2H), 2.41 (s, 3H), 1.98-1.80 (m, 2H), 1.80-1.55 (m, 2H), 1.53-1.34 ( m, 2H), 1.29 (d, J=6.0 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H) ppm. MS: m/e 430 (M+H)+.

Compound A110: (R or S)-3-((4-amino-7-(4-(3-(methylamino)propyl)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl )oxy)hexane-1-ol.

Step A: 3-(4-bromophenyl)-N-methylpropanamide.

To a solution of 3-(4-bromophenyl)propanoic acid (2 g, 8.73 mmol) and CH3NH2 HCl (712 mg, 10.47 mmol) and HATU (3.98 g, 10.47 mmol) in DMF (20 ml ) DIEA (2.7 g, 20.93 mmol) was added under N2 at -0°C. The reaction mixture was stirred for 12 hours at 25°C. Once complete, the reaction mixture was quenched with ice water (50 ml) and extracted with EtOAc (3x80 ml). Combined organic

- 78 046488 the layers were washed with water (50 ml), saline (3x50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to obtain a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (60%) to give the title compound (3 g, crude). MS: m/e 242, 244. (M+H)+.

Step B: 3-(4-bromophenyl)-N-methylpropan-1-amine.

To a solution of 3-(4-bromophenyl)-N-methylpropanamide (2.6 g, crude) in THF (50 ml) was added BH ₃ in THF (42 ml, 42.0 mmol) under N2 at 0°C. The reaction mixture was stirred for 0.5 h at 0°C and the next 4 hours at 70°C. After completion, the reaction mixture was cooled to 0°C and MeOH (20 ml) and 6 N HCl (20 ml) were added dropwise. The mixture was returned for 0.5 h and the solvent was removed in vacuo. The aqueous phase was made alkaline with 50% NaOH and extracted with MTBE (3x80 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product (2.5 g). MS: m/e 228, 230. (M+H) ⁺ .

Step C: tert-butyl(3-(4-bromophenyl)propyl)(methyl)carbamate.

To a solution of 3-(4-bromophenyl)-N-methylpropan-1-amine (2.5 g, crude) in DCM (30 ml) was added Et ₃ N (1.8 g, 17.82 mmol) and (Boc) ₂ O (2.3 g, 10.55 mmol) in an N2 atmosphere at 0°C. The reaction mixture was stirred for 12 hours at 25°C. Once complete, the reaction mixture was quenched with water (30 ml) and extracted with DCM (3x50 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (20%) to give the title compound (1.8 g, 63% in three steps).

1H NMR (400 MHz, DMSOO δ 7.46 (d, J=6.8 Hz, 2H), 7.19 (d, J=6.8 Hz, 2H), 3.15 (s, 2H), 2 .76 (s, 3H), 2.52 (s, 2H), 1.73 (s, 2H), 1.35 (s, 9H) ppm MS: m/e 350, 352 (M+H)+ .

Step D: tert-butyl(3-(4-formylphenyl)propyl)(methyl)carbamate.

To a solution of tert-butyl(3-(4-bromophenyl)propyl)(methyl)carbamate (1.7 g, 5.18 mmol) in THF (25 ml) was added n-BuLi (4.8 ml, 7.68 mmol ) in an N2 atmosphere at -78°C. After stirring for 0.5 h at -78°C, DMF (570 mg, 7.8 mmol) was added dropwise. The reaction mixture was heated to 25°C and stirred for 0.5 hours. After completion, the reaction mixture was quenched with aq. NH4Cl (50 ml) and extracted with DCM (3x50 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (40%) to give the title compound (1.2 g, 84%).

1H NMR (400 MHz, DMSOO δ 9.97 (s, 1H), 7.84 (d, J=7.2 Hz, 2H), 7.46 (d, J=7.2 Hz, 2H), 3 .18 (s, 2H), 2.77 (s, 3H), 2.64 (s, 2H), 1.80 (s, 2H), 1.36 (s, 9H) ppm MS: m/e 300 (M+Na)+.

Step E: tert-butyl(3-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo[ 2,1-f][1,2,4]triazin-7 yl)(hydroxy)methyl)phenyl)propyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4dimethoxybenzyl)imidazo[2,1-G][1,2,4 ]triazin-4-amine (600 mg, 0.934 mmol) in THF (15 ml) was added nBuLi (0.88 ml, 1.41 mmol) under N ₂ atmosphere at -78°C. After stirring for 0.5 h at -78°C, tert-butyl (3-(4-formylphenyl)propyl)(methyl)carbamate (310 mg, 1.12 mmol) was added. The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (30 ml) and extracted with DCM (3x50 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (50%) to give the title compound (660 mg, 77%). MS: m/e 919 (M+H)+.

Step F: tert-butyl^ or S)-(3-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)phenyl)propyl) (methyl)carbamate.

To a solution of tert-butyl(3-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7 yl)(hydroxy)methyl)phenyl)propyl)(methyl)carbamate (560 mg, 0.609 mmol) in MeOH (30 ml) was added Pd/C (560 mg ) and AcOH (0.5 ml). The reaction mixture was stirred for 12 hours at 40°C in an atmosphere of H ₂ (1 atm). The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (60%) to give the title compound (470 mg, 94%). MS: m/e 813 (M+H)+.

Step G: (R or S)-3-((4-amino-7-(4-(3-(methylamino)propyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2yl )oxy)hexan-1-ol (compound A110).

Tert-butyl(T or S)-(3 -(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-(( 1 -hydroxyhexan-3 yl)oxy)imidazo[2,1- G][1,2,4]triazin-7-yl)methyl)phenyl)propyl)(methyl)carbamate (470 mg, 0.578 mmol) was dissolved in TFA (5 ml) and H2O (0.5 ml) under N2 atmosphere . The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20

- 79 046488 ml) and alkalinized with 2 N NaOH to pH 13 to 14 and extracted with DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by pre-TLC (DCM/CH3OH (NH ₃ )=15/1) to give the title compound (125 mg, 53%).

1H NMR (400 MHz, CD3OD) δ 7.27 (s, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.13 (d, J=7.6 Hz, 2H), 5.18 (s, 1H), 4.16 (s, 2H), 3.65 (s, 2H), 2.63 (dd, J=13.6, 6.8 Hz, 4H), 2.41 (s, 3H), 1.95-1.76 (m, 4H), 1.76-1.58 (m, 2H), 1.41 (s, 2H), 0.91 (t, J=7 .2 Hz, 3H) ppm. MS: m/e 413 (M+H)+.

Compound A111: (R or S)-3-((4-amino-7-(2,3-difluor-4-(2(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2, 4]triazin-2-yl)oxy)hexan-1-ol.

Step A: tert-butyl (2-(2,3-difluoro-4-formylphenoxy)ethyl)(methyl)carbamate.

To a solution of 2,3-difluoro-4-hydroxybenzaldehyde (1.58 g, 10 mmol) in THF (20 ml) was added tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.75 g, 10 mmol) and PPh ₃ ( 3.4 g, 13 mmol). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (2.6 g, 13 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (1.1 g, 34.9%). MS: m/e: 316 (M+1) ⁺ .

Step B: tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [ 2,1-f][1,2,4]triazin-7 -yl)(hydroxy)methyl)-2,3difluorophenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4dimethoxybenzyl)imidazo[2,14][1,2,4]triazine -4-amine (320 mg, 0.5 mmol) in THF (10 ml) was added dropwise with a solution of n-BuLi (1.6 M, 0.7 ml, 1.1 mmol) maintaining the temperature in the range from -75 to -65°C. After 1 hour, a suspension of tert-butyl(2-(2,3-difluoro-4formylphenoxy)ethyl)(methyl)carbamate (315 mg, 1 mmol) in THF (2 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 a saturated solution of NH ₄ Cl, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC to give the title compound (100 mg, 23.3%). MS: m/e 957 (M+1)+.

Step C: tert-butyl^ or S)-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)-2,3-difluorophenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7 -yl)(hydroxy)methyl)-2,3difluorophenoxy)ethyl)(methyl)carbamate (100 mg, 0.104 mmol) in MeOH (20 ml) was added Pd/ C (100 mg). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (60 mg, 68.1%). MS: m/e: 851 (M+1)+.

Step D: (R or S)-3-((4-amino-7-(2,3-difluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1D[1,2,4] triazin-2-yl)oxy)hexan-1-ol (compound A111).

To a mixture of the product of step C (60 mg, 0.07 mmol) in TFA (9 ml) was added H2O (1 ml) and the resulting mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2N solution of NaOH (10 ml) and DCM (20 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (4 mg, 12.9%).

1H NMR (400 MHz, CD3OD) δ 7.32 (s, 1H), 6.98 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 5.17 (s, 1H ), 4.20 (s, 4H), 3.63 (s, 2H), 3.14 (s, 2H), 2.57 (s, 3H), 1.89 (s, 2H), 1.68 (d, J=5.7 Hz, 2H), 1.40 (s, 2H), 0.91 (t, J=7.1 Hz, 3H) ppm. MS: m/e 451 (M+1)+.

Compound A112: (R or S)-3-((4-amino-7-(2,5-difluoro-4-(2(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2, 4]triazin-2-yl)oxy)hexan-1-ol.

Step A: tert-butyl (2-(2,5-difluoro-4-formylphenoxy)ethyl)(methyl)carbamate.

To a solution of 2,5-difluoro-4-hydroxybenzaldehyde (316 mg, 2 mmol) in THF (20 ml) was added tert-butyl(2-hydroxyethyl)(methyl)carbamate (350 mg, 2 mmol) and PPh3 (655 mg, 2. 5 mmol). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (505 mg, 2.5 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (448 g, 71.1%). MS: m/e: 316 (M+1)+.

Step B: tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [ 2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2,5

- 80 046488 difluorophenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(6eH3n.TOKCn)reKcaH-3-ni)OKCn)-N,N-6nc(2,4dimethoxybenzyl)imidazo[2,1T|[1,2,4 |triazin-4-amine (448 mg, 0.7 mmol) in THF (10 ml), a solution of n-BuLi (1.6 M, 0.9 ml, 1.4 mmol) was added dropwise, maintaining the temperature in the range from -75 to -65°C. After 1 hour, a suspension of tert-butyl (2-(2,5-difluoro-4formylphenoxy)ethyl)(methyl)carbamate (310 mg, 1 mmol) in THF (2 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 a saturated solution of NH4C1, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC to give the title compound (280 mg, 41.8%). MS: m/e 957 (M+1)+.

Step C: tert-butyl^ or S)-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)-2,5-difluorophenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7 -yl)(hydroxy)methyl)-2,5difluorophenoxy)ethyl)(methyl)carbamate (280 mg, 0.295 mmol) in MeOH (20 ml) was added Pd/ C (300 mg). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (110 mg, 44%). MS: m/e: 851 (M+1) ⁺ .

Step D: (R or S)-3-((4-amino-7-(2,5-difluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4 ]triazin-2-yl)oxy)hexan-1-ol (compound A112).

To a mixture of the product of step C (110 mg, 0.129 mmol) in TFA (9 ml) was added H2O (1 ml) and the resulting mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2 N solution of NaOH (10 ml) and DCM (20 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (22 mg, 37.9%).

^1H NMR (400 MHz, CD3OD) δ 7.30 (s, 1H), 7.09-7.01 (m, 1H), 7.01-6.88 (m, 1H), 5.25-5 .10 (m, 1H), 4.14 (s, 4H), 3.65 (s, 2H), 2.99 (s, 2H), 2.47 (s, 3H), 1.91 (d, J=5.9 Hz, 2H), 1.74-1.63 (m, 2H), 1.40 (s, 2H), 0.90 (d, J=7.2 Hz, 3H) ppm. MS: m/e 451 (M+1)+.

Compound A113: (R or S)-3-((4-amino-7-(2-methoxy-5-(2(methylamino)ethoxy)benzyl)imidazo [2,1-f][1,2,4] triazin -2-yl)oxy)hexan-1-ol.

Step A: tert-butyl (2-(3-formyl-4-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of 5-hydroxy-2-methoxybenzaldehyde (1 g, 6.58 mmol), tert-butyl(2hydroxyethyl)(methyl)carbamate (1.15 g, 6.57 mmol) and PPh ₃ (2.6 g, 9 .92 mmol) in THF (20 mL), a solution of DTAD (1.7 g, 7.39 mmol) in THF (20 mL) was added under N2 at 0°C. The reaction mixture was stirred for 16 hours at 25°C. Once complete, the reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with aq. NaHCO ₃ (3x50 ml), water (30 ml), brine (50 ml), dried over Na2SO4 and concentrated in vacuo to leave a residue. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (20%) to give the title compound (1.7 g, crude). MS: m/e 332 (M+Na)+.

Step B: tert-butyl(2-(3-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [ 2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-4methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4dimethoxybenzyl)imidazo[2,1-1T][1,2,4 ]triazin-4-amine (500 mg, 0.78 mmol) in THF (20 ml) was added nBuLi (2.4 ml, 3.84 mmol) under N ₂ at -78°C. After stirring for 0.5 h at -78°C, tert-butyl (2-(3-formyl-4-methoxyphenoxy)ethyl)(methyl)carbamate (720 mg, crude) was added. The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (50 ml) and extracted with DCM (3x50 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (60%) to give the title compound (370 mg, 50%). MS: m/e 952 (M+1)+.

Step C: tert-butyl^ or S)-(2-(3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)-4-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(3-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-4methoxyphenoxy)ethyl)(methyl)carbamate (370 mg, 0.389 mmol) in MeOH (20 ml) was added Pd/C ( 370 mg) and AcOH (0.3 ml). The reaction mixture was stirred for 12 hours at 40°C in an atmosphere of H ₂ (1 atm). The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The precipitate was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (80%) with

- 81 046488 by obtaining the title compound (200 mg, 61%). MS: m/e 845 (M+1)+.

Step D: (R or S)-3-((4-amino-7-(2-methoxy-5-(2-(methylamino)ethoxy)benzyl)imidazo[2,1P[1,2,4|triazine- 2-yl)oxy)hexan-1-ol (compound A113).

Tert-butyl^ or S)-(2-(3 -((4-(bis(2,4-dimethoxybenzyl)amino)-2-(( 1 -hydroxyhexan-3 yl)oxy)imidazo[2.1-G| [ 1,2,4]triazin-7-yl)methyl)-4-methoxyphenoxy)ethyl)(methyl)carbamate (200 mg, 0.237 mmol) was dissolved in TFA (5 ml) and H ₂ O (0.5 ml) in atmosphere N2. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a residue. The residue was purified by pre-TLC (DCM/CH ₃ OH (NH ₃ ) = 15/1) to give the title compound (60 mg, 57%).

1H NMR (400 MHz, CD3OD) δ 7.20 (s, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.84-6.78 (m, 1H), 6.75 (s, 1H), 5.275.09 (m, 1H), 4.20-4.04 (m, 2H), 3.99 (t, J=5.2 Hz, 2H), 3.80 (s, 3H), 3.65 (t, J=6.4 Hz, 2H), 2.95 (t, J=5.2 Hz, 2H), 2.45 (s, 3H), 1.90 (d, J=5.2 Hz, 2H), 1.81-1.56 (m, 2H), 1.52-1.30 (m, 2H), 0.91 (t, J=7.2 Hz, 3H ) ppm. MS: m/e 445 (M+1) ⁺ .

Compound A114: (R or S)-3-((4-amino-7-(3,5-difluoro-4-(2(methylamino)ethoxy)benzyl)imidazo [2,1-G][1,2, 4]triazin-2-yl)oxy)hexan-1-ol.

Step A: tert-butyl (2-(2,6-difluoro-4-formylphenoxy)ethyl)(methyl)carbamate.

To a solution of 3,5-difluoro-4-hydroxybenzaldehyde (1.58 g, 10 mmol) in THF (20 ml) was added tert-butyl(2-hydroxyethyl)(methyl)carbamate (1.7 g, 10 mmol) and PPh ₃ ( 3.4 g, 13 mmol). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (2.6 g, 13 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (1 g, 31.7%). MS: m/e: 316 (M+1) ⁺ .

Step B: tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(3,4dimethoxybenzyl)amino)imidazo [ 2,1-G][1,2,4]triazin-7-yl)(hydroxy)methyl)-2,6difluorophenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4dimethoxybenzyl)imidazo[2,1-G][1,2,4 ]triazine-4-amine (300 mg, 0.5 mmol) in THF (10 ml), a solution of n-BuLi (1.6 M, 0.9 ml, 1.5 mmol) was added dropwise, maintaining the temperature between -75 to -65°C. After 1 hour, a suspension of tert-butyl (2-(2,6-difluoro-4formylphenoxy)ethyl)(methyl)carbamate (315 mg, 1 mmol) in THF (2 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 a saturated solution of NH4C1, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (280 mg, 58.5%). MS: m/e 957 (M+1) ⁺ .

Step C: tert-butyl^ or S)-(2-(4-((4-(bis(3,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -G][1,2,4]triazin-7-yl)methyl)-2,6-difluorophenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(3,4dimethoxybenzyl)amino)imidazo [2 ,1-G][1,2,4]triazin-7-yl)(hydroxy)methyl)-2,6difluorophenoxy)ethyl)(methyl)carbamate (280 mg, 0.292 mmol) in MeOH (20 ml) was added Pd/ C (300 mg). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (140 mg, 56.4%). MS: m/e: 851 (M+1) ⁺ .

Step D: (R or S)-3-((4-amino-7-(3,5-difluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4 ]triazin-2-yl)oxy)hexan-1-ol (compound A114).

To a mixture of the product of step C (140 mg, 0.164 mmol) in TFA (9 ml) was added H2O (1 ml) and the resulting mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2 N solution of NaOH (10 ml) and DCM (20 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (9 mg, 12.1%).

1H NMR (400 MHz, CD3OD) δ 7.38 (s, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 5.20-5.15 (m, 1H), 4 .19 (d, J=9.4 Hz, 4H), 3.64 (s, 2H), 3.00 (s, 2H), 2.52 (s, 3H), 1.96-1.84 ( m, 2H), 1.75-1.59 (m 2H), 1.52-1.39 (m, 2H), 0.91 (t, J=7.4 Hz, 3H) ppm. MS: m/e 451 (M+1)+.

Compound A115: (R or S)-3-((4-amino-7-(2-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4]triazine -2-yl)oxy)hexane-1-ol.

Step A: tert-butyl (2-(3-fluoro-4-formylphenoxy)ethyl)(methyl)carbamate.

To a solution of 2-fluoro-4-hydroxybenzaldehyde (1.4 g, 10 mmol) in THF (20 ml) was added tert

- 82 046488 butyl (2-hydroxyethyl)(methyl)carbamate (1.75 g, 10 mmol) and PPh3 (3.4 g, 13 mmol). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (2.6 g, 13 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (0.9 g, 30.3%). MS: m/e: 298 (M+1)+.

Step B: tert-butyl(2-(4-((2-((U or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(3,4dimethoxybenzyl)amino)imidazo [ 2,1-f][1,2,4]triazin-7 -yl)(hydroxy)methyl)-3 fluorophenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(4-methoxybenzyl)imidazo[2.1G][1,2,4]triazine -4-amine (641 mg, 1 mmol) in THF (10 ml) was added dropwise with a solution of n-BuLi (1.6 M, 1.25 ml, 2 mmol), maintaining the temperature in the range from -75 to -65° WITH. After 1 hour, a suspension of tert-butyl (2-(3-fluoro-4-formylphenoxy)ethyl)(methyl)carbamate (450 mg, 1.5 mmol) in THF (2 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 a saturated solution of NH ₄ Cl, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (700 mg, 74.6%). MS: m/e 939 (M+1)+.

Step C: tert-butyl or S)-(2-(4-((4-(bis(3,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1- f][1,2,4]triazin-7-yl)methyl)-3-fluorophenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(4-((2-((U or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(3,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3 fluorophenoxy)ethyl)(methyl)carbamate (700 mg, 0.746 mmol) in MeOH (20 ml) was added Pd/C (700 mg). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (350 mg, 56.4%). MS: m/e: 833 (M+1)+.

Step D: (R or S)-3-((4-amino-7-(2-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4]triazine -2-yl)oxy)hexan-1-ol (compound A115).

To a mixture of the product of step C (2.2 g, 2.6 mmol) in TFA (18 ml) was added H2O (2 ml) and the resulting mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2 N solution of NaOH (20 ml) and DCM (60 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (0.8 g, 70%).

^1H NMR (400 MHz, CD3OD) δ 7.25 (s, 1H), 7.19-7.14 (m, 1H), 6.78-6.64 (m, 2H), 5.25-5 .13 (m, 1H), 4.14-4.06 (m, 4H), 3.76-3.59 (m, 2H), 2.94 (d, J=4.3 Hz, 2H), 2.44 (d, J=3.1 Hz, 3H), 1.90 (s, 2H), 1.75-1.56 (m, 2H), 1.48-1.36 (m, 2H) , 0.92 (t, J=7.3 Hz, 3H) ppm. MS: m/e 433 (M+1)+.

Compound A116: (R or S)-3-((4-amino-7-(3-methoxy-5-(2(methylamino)ethoxy)benzyl)imidazo [2,1-f][1,2,4] triazin -2-yl)oxy)hexan-1-ol.

Step A: tert-butyl (2-(3-formyl-5-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of 3-hydroxy-5-methoxybenzaldehyde (1 g, 6.58 mmol), tert-butyl(2hydroxyethyl)(methyl)carbamate (1.15 g, 6.57 mmol) and PPh3 (2.6 g, 9. 92 mmol) in THF (20 ml), a solution of DTAD (1.7 g, 7.39 mmol) in THF (20 ml) was added under N2 at 0°C. The reaction mixture was stirred for 16 hours at 25°C. Once complete, the reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with aq. NaHCO ₃ (3x50 ml), water (50 ml), brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (33%) to give the title compound (2 g, crude). MS: m/e 332 (M+Na)+.

Step B: tert-butyl(2-(3-((2-((U or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [ 2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-5methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4dimethoxybenzyl)imidazo[2,1-L[1,2,4] triazin-4-amine (500 mg, 0.78 mmol) in THF (20 ml) was added nBuLi (3.2 ml, 5.12 mmol) under N2 at -78°C. After stirring for 0.5 h at -78° C., tert-butyl (2-(3-formyl-5-methoxyphenoxy)ethyl)(methyl)carbamate (1.1 g, crude) was added. The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (30 ml) and extracted with DCM (3x50 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (60%) to give the title compound (250 mg, 34%). MS: m/e 951 (M+1)+.

Step C: tert-butyl or S)-(2-(3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexane-3

- 83 046488 yl)oxy)imidazo [2,1-f][1,2,4]triazin-7-yl)methyl)-5-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(3-((2-(((K. or S)-1-(6eH3n.TOKCn)reKcaH-3-ni)OKCn)-4-(6nc(2,4dimethoxybenzyl)amino )imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-5methoxyphenoxy)ethyl)(methyl)carbamate (250 mg, 0.263 mmol) in MeOH (20 ml) was added Pd/C (250 mg) and AcOH (0.26 ml). The reaction mixture was stirred for 12 hours at 40°C in an atmosphere of H ₂ (1 atm). The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (80%) to give the title compound (120 mg, 54%). MS: m/e 845 (M+1)+.

Step D: (R or S)-3-((4-αmino-7-(3-methoxy-5-(2-(methylαmino)ethoxy)benzyl)imidazo[2,1G][1,2,4]triazine -2-yl)oxy)hexan-1-ol (compound A116).

Tert-butyl^ or S)-(2-(3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1-f] [1,2,4]triazin-7-yl)methyl)-5-methoxyphenoxy)ethyl)(methyl)carbamate (120 mg, 0.142 mmol) was dissolved in TFA (4 ml) and H2O (0.4 ml) in atmosphere N2. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by pre-TLC (DCM/CH3OH (NH ₃ ) = 15/1) to give the title compound (45 mg, 71%).

^1H NMR (400 MHz, CD3OD) δ 7.31 (s, 1H), 6.56 (s, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 5.21- 5.13 (m, 1H), 4.15 (s, 4H), 3.75 (s, 3H), 3.64 (t, J=6.0 Hz, 2H), 3.32 (s, 2H ), 2.70 (s, 3H), 1.96-1.79 (m, 2H), 1.78-1.56 (m, 2H), 1.49-1.31 (m, 2H), 0.90 (t, J=7.2 Hz, 3H) ppm. MS: m/e 445 (M+1) ⁺ .

Compound A117: (R or S)-3-((4-amino-7-(4-methoxy-3-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4 ]triazin -2-yl)oxy)hexan-1-ol.

Step A: tert-butyl (2-(5-formyl-2-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of 3-hydroxy-4-methoxybenzaldehyde (1 g, 6.58 mmol), tert-butyl(2hydroxyethyl)(methyl)carbamate (1.15 g, 6.57 mmol) and PPh ₃ (2.6 g, 9 .92 mmol) in THF (20 ml) was added a solution of DIAD (1.7 g, 8.42 mmol) in THF (20 ml) under N2 atmosphere at 0°C. The reaction mixture was stirred for 16 hours at 25°C. Once complete, the reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with aq. Na ₂ CO ₃ (3x50 ml), water (50 ml), brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (33%) to give the title compound (2.8 g, crude). MS: m/e 332. (M+Na)+.

Step B: tert-butyl(2-(5-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo[ 2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4-dimethoxybenzyl)imidazo[2,1-G][1,2 ,4]triazin-4-amine (500 mg, 0.78 mmol) in THF (20 ml) was added n-BuLi (3.2 ml, 5.12 mmol) under N2 at -78°C. After stirring for 0.5 h at -78°C, tert-butyl (2-(5-formyl-2-methoxyphenoxy)ethyl)(methyl)carbamate (830 mg, crude) was added. The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH4Cl (30 ml) and extracted with DCM (3x30 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (60%) to give the title compound (240 mg, 32%). MS: m/e 951 (M+1)+.

Step C: tert-butyl^ or S)-(2-(5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)-2-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(5-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2methoxyphenoxy)ethyl)(methyl)carbamate (240 mg, 0.252 mmol) in MeOH (20 ml) was added Pd/C ( 240 mg) and AcOH (0.24 ml). The reaction mixture was stirred for 12 hours at 40°C in an atmosphere of H ₂ (1 atm). The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (80%) to give the title compound (100 mg, 54%). MS: m/e 845 (M+1)+.

Step D: (R or S)-3-((4-αmino-7-(4-methoxy-3-(2-(methylαmino)ethoxy)benzyl)imidazo[2,1G][1,2,4]triazine -2-yl)oxy)hexan-1-ol (compound A117).

Tert-butyl^ or S)-(2-(5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1-f] [1,2,4]triazin-7-yl)methyl)-2-methoxyphenoxy)ethyl)(methyl)carbamate (100 mg, 0.118 mmol) was dissolved in TFA (4 ml) and H2O (0.4 ml) in atmosphere N2. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The sediment was diluted with water (20 ml)

- 84 046488 and DCM (20 ml) and the aqueous phase were acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted with DCM/i- PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by pre-TLC (DCM/CH3OH (NH ₃ ) = 15/1) to give the title compound (30 mg, 58%).

^1H NMR (400 MHz, CD3OD) δ 7.27 (s, 1H), 6.99-6.86 (m, 3H), 5.22-5.18 (m, 1H), 4.18-4 .04 (m, 4H), 3.83 (s, 3H), 3.70-3.61 (m, 2H), 3.08 (s, 2H), 2.61-2.49 (m, 3H ), 1.96-1.79 (m, 2H), 1.78-1.54 (m, 2H), 1.51-1.34 (m, 2H), 0.90 (t, J=7 .2 Hz, 3H) ppm. MS: m/e 445 (M+1)+.

Compound A118: (R or S)-3-((4-amino-7-(2-methoxy-3-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4 ]triazin -2-yl)oxy)hexan-1-ol.

Step A: tert-butyl(2-(3-formyl-2-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of 3-hydroxy-2-methoxybenzaldehyde (1 g, 6.58 mmol), tert-butyl(2hydroxyethyl)(methyl)carbamate (1.15 g, 6.57 mmol) and PPh ₃ (2.6 g, 9 .92 mmol) in THF (20 ml), a solution of DTAD (1.7 g, 7.39 mmol) in THF (20 ml) was added under N2 at 0°C. The reaction mixture was stirred for 16 hours at 25°C. Once complete, the reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with aq. NaHCO ₃ (3x50 ml), water (50 ml), brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (20%) to give the title compound (2.3 g, crude). MS: m/e 332 (M+Na)+.

Step B: tert-butyl(2-(3-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo[ 2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4dimethoxybenzyl)imidazo[2,1-G][1,2,4 ]triazin-4-amine (500 mg, 0.78 mmol) in THF (20 ml) was added nBuLi (3.2 ml, 5.12 mmol) under N2 at -78°C. After stirring for 0.5 h at -78° C., tert-butyl (2-(3-formyl-2-methoxyphenoxy)ethyl)(methyl)carbamate (1.1 g, crude) was added. The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (30 ml) and extracted with DCM (3x30 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (60%) to give the title compound (260 mg, 35%). MS: m/e 951 (M+1)+.

Step C: tert-butyl^ or S)-(2-(3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)-2-methoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(3-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-2methoxyphenoxy)ethyl)(methyl)carbamate (260 mg, 0.273 mmol) in MeOH (20 ml) was added Pd/C ( 260 mg) and AcOH (0.26 ml). The reaction mixture was stirred for 12 hours at 40°C in an atmosphere of H ₂ (1 atm). The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (80%) to give the title compound (150 mg, 65%). MS: m/e 845 (M+1)+.

Step D: (R or S)-3-((4-amino-7-(2-methoxy-3-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4]triazine -2-yl)oxy)hexan-1-ol (compound A118).

Tert-butyl^ or S)-(2-(3-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1-f] [1,2,4]triazin-7-yl)methyl)-2-methoxyphenoxy)ethyl)(methyl)carbamate (150 mg, 0.177 mmol) was dissolved in TFA (5 ml) and H2O (0.5 ml) in atmosphere N2. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a residue. The residue was purified by pre-TLC (DCM/ _CH3OH ( _NH3 )=15/1) to give the title compound (48 mg, 61%).

1H NMR (400 MHz, CD3OD) δ 7.20 (s, 1H), 7.02-6.91 (m, 2H), 6.85 (d, J=6.8 Hz, 1H), 5.25 -5.15 (m, 1H), 4.24-4.11 (m, 4H), 3.79 (s, 3H), 3.65 (t, J=6.0 Hz, 2H), 3, 10 (t, J=4.8 Hz, 2H), 2.56 (s, 3H), 1.97-1.81 (m, 2H), 1.79-1.57 (m, 2H), 1 .50-1.22 (m, 2H), 0.91 (t, J=7.2 Hz, 3H) ppm. MS: m/e 445 (M+1)+.

Compound A119 and Compound A120: (R or S)-3-((4-amino-7-(4-(2(methylamino)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazine -2-yl)oxy)hexan-1-oli (S or R)-3 -((4-amino-7(4-(2-(methylamino)ethyl)benzyl)imidazo [2,1-f][ 1 ,2,4]triazin-2-yl)oxy)hexan-1-ol.

Compound A95 3 -((4-amino-7 -(4-(2-(methylamino)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2yl)oxy)hex an-1 -ol (45 mg, 0.168 mmol) was purified using prep-SCPC (chiral column PAK AD-H, 3 cm * 25 cm, 5 μm, flow rate 45 ml/min phase: Hexane (2 mM H2H ₃ -MeOH): IPS = 80:20, UV:

- 85 046488

220 nm, 25°C) to obtain compound A119 (20 mg) and compound A120 (23 mg).

Compound A119 (optical isomer 1): 1H NMR (400 MHz, CD ₃ OD) δ 7.29 (s,

1H), 7.24 (d, J=7.6 Hz, 2H), 7.16 (d, J=7.6 Hz, 2H), 5.18 (s, 1H), 4.17 (s, 2H), 3.64 (s, 2H), 2.80 (s, 4H), 2.40 (s, 3H), 1.90 (s, 2H), 1.78-1.55 (m, 2H ), 1.49-1.34 (m, 2H), 0.91 (t, J=7.2 Hz, 3H) ppm. MS: m/e 399 (M+1)+.

Compound A120 (optical isomer 2): ^1H NMR (400 MHz, CD3OD) δ 7.31-7.25 (m, 3H), 7.19 (d, J=7.6 Hz, 2H), 5.25 -5.10 (m, 1H), 4.18 (s, 2H), 3.62 (s, 2H), 3.04 (t, J=7.6 Hz, 2H), 2.87 (t, J=7.6 Hz, 2H), 2.56 (s, 3H), 1.94-1.81 (m, 2H), 1.79-1.56 (m, 2H), 1.49-1 .34 (m, 2H), 0.92 (t, J=7.2 Hz, 3H) ppm. MS: m/e 399 (M+1)+.

Compound A121: (R or S)-3-((4-amino-7-(2-ethoxy-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f][1,2,4]triazine -2-yl)oxy)hexane-1-ol.

Step A: 4-chloro-2-ethoxybenzaldehyde.

To a mixture of 4-chloro-2-hydroxybenzaldehyde (1.56 g, 10 mmol) and K ₂ CO ₃ (3.45 g, 25 mmol) in DMF (10 ml) was added iodoethane (2.34 g, 15 mmol) at rt and the resulting mixture was stirred at rt for 16 hours. The mixture was diluted with EA (50 ml) and filtered. The filtrate was washed with saline (50 mlx3), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give the title product (1.70 g, yield: 92%). MS: m/e 185 (M+1)+.

Step B: tert-butyl (2-(3-ethoxy-4-formylphenoxy)ethyl)(methyl)carbamate.

Mixture of 4-chloro-2-ethoxybenzaldehyde (736 mg, 4 mmol), tert-butyl(2hydroxyethyl)(methyl)carbamate (1.05 g, 6 mmol), Pd ₂ (dba) ₃ (183 mg, 0.2 mmol ), RuPhos (186 mg, 0.4 mmol) and Cs ₂ CO ₃ (2.6 g, 8 mmol) in dioxane (10 ml) were stirred at 100°C under N2 for 16 hours. The mixture was cooled and diluted with EA (20 ml), filtered and the filtrate was washed with brine (10 ml x 3), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give the title product (500 mg, yield: 38%). MS: m/e 324 (M+1)+.

Step C: tert-butyl(2-(4-((2-(^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2 ,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3 ethoxyphenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4dimethoxybenzyl)imidazo[2,1-G][1,2,4 ]triazin-4-amine (340 mg, 0.53 mmol) in THF (5 ml) was added nBuLi (1.6 M, 2.0 ml, 3.2 mmol) at -78°C under N2 atmosphere. The mixture was stirred at -78°C for 30 minutes. A solution of tert-butyl(2-(3-ethoxy-4-formylphenoxy)ethyl)(methyl)carbamate (340 mg, 1.05 mmol) in THF (3 ml) was then added to the system at -78°C. The reaction was stirred for 30 min and then warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated NH ₄ Cl (00 ml) at room temperature and extracted with EA (10 ml x 3 ). The combined organic phase was washed with brine (10 mlx3), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (125 mg, yield: 25%). MS: m/e 965 (M+1) ⁺ .

Step D: tert-butyl^ or S)-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)-3-ethoxyphenoxy)ethyl)(methyl)carbamate.

A mixture of tert-butyl(2-(4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2, 1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3 ethoxyphenoxy)ethyl)(methyl)carbamate (180 mg, 0.187 mmol), Pd/C (wet, 200 mg) and AcOH (5 drops) in MeOH (5 ml) was stirred at 40°C under H2 at rt for 16 hours. The mixture was filtered and the filtrate was concentrated under high vacuum to give the title product (85 mg, crude). MS: m/e 859 (M+1)+.

Step E: (R or S)-3-((4-amino-7-(2-ethoxy-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4]triazine -2-yl)oxy)hexan-1-ol (compound A121).

Tert-butyl^ or S)-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-(( 1 -hydroxyhexan-3 yl)oxy)imidazo [2,1-f ][1,2,4]triazin-7-yl)methyl)-3-ethoxyphenoxy)ethyl)(methyl)carbamate (85 mg, crude) in TFA (3 ml) was stirred at rt for 6 hours. The reaction mixture was concentrated at reduced pressure. The precipitate was diluted with MeOH (3 ml), purified with NaOH (1 ml, 4 M), stirred at rt for 1 hour and concentrated to remove MeOH. The resulting aqueous solution was extracted with DCM (3 mlx3). The resulting organics were washed with brine (5 mlx2), dried over Na ₂ SO ₄ , concentrated and purified by pre-HPLC to give the title compound (5.5 mg, yield: 6% in two steps).

1H NMR (400 MHz, CD3OD) 7.20-7.11 (m, 2H), 6.59 (s, 1H), 6.50 (d, J=8.0 Hz, 1H), 5.29- 5.13 (m, 1H), 4.25-4.16 (m, 2H), 4.09 (s, 2H), 4.07-3.97 (m, 2H), 3.70-3, 60 (m, 2H), 3.41-3.34 (m, 2H), 2.73 (s, 3H), 1.961.85 (m, 2H), 1.78-1.61 (m, 2H) , 1.51-1.39 (m, 2H), 1.37 (t, J=6.8 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H) ppm. MS: m/e 459 (M+1)+.

Compound A122: (R or S)-3-((4-amino-7-((6-(2-(methylamino)propoxy)pyridin-3yl)methyl)imidazo[2,1-G] [1,2, 4]t riazin-2-yl)oxy)hexan-1-ol.

- 86 046488

Step A: tert-butyl(1-hydroxypropan-2-yl)(methyl)carbamate.

To a solution of H-(tert-butoxycarbonyl)-N-methylalanine (1 g, 4.93 mmol) in THF (20 ml) was added BH ₃ (7.5 ml, 7.5 mmol) under an atmosphere of N ₂ at -0° WITH. The reaction mixture was stirred for 2 hours at 0°C. Then water (5 ml) was added dropwise at 0°C. After stirring for 10 minutes, 10% Na ₂ CO ₃ (10 ml) was added dropwise. The reaction mixture was stirred for 1 hour at 25°C. Once complete, the reaction mixture was extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (3x20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product (900 mg, 96%).

1H NMR (400 MHz, DMSO-de) δ 4.66 (s, 1H), 4.14-3.86 (m, 1H), 3.43-3.26 (m, 2H), 2.64 ( s, 3H), 1.39 (s, 9H), 0.97 (s, 3H).

Step B: tert-butyl (1-((5-formylpyridin-2-yl)oxy)propan-2-yl)(methyl)carbamate.

To a solution of 6-chloronicotinaldehyde (570 mg, 4.01 mmol), tert-butyl (1-hydroxypropan-2yl)(methyl)carbamate (900 mg, 4.76 mmol), Pd ₂ (dba) ₃ -CHCl ₃ (311 mg, 0.3 mmol) and Cs ₂ CO ₃ (2.6 g, 7.97 mmol) in dioxane (20 ml) was added RuPhos (280 mg, 0.599 mmol) under N2. The reaction mixture was stirred for 12 hours at 95°C. The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (25%) to give the title compound (1 g, 85%).

1H NMR (400 MHz, DMSO<) δ 9.97 (s, 1H), 8.76 (s, 1H), 8.12 (s, 1H), 6.95 (s, 1H), 4.60- 4.16 (m, 3H), 2.69 (s, 3H), 1.47-1.06 (m, 12H) ppm, MS: m/e 295, (M+H)+.

Step C: tert-butyl(1-((5-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)propan2-yl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4-dimethoxybenzyl)imidazo[2,1-G][1,2 ,4]triazin-4-amine (600 mg, 0.934 mmol) in THF (10 ml) was added n-BuLi (0.88 ml, 1.41 mmol) under N ₂ atmosphere at -78°C. After stirring for 0.5 h at -78°C, tert-butyl (1-((5-formylpyridin-2-yl)oxy)propan-2-yl)(methyl)carbamate (328 mg, 1.12 mmol) was added. The reaction mixture was stirred for 2.5 hours at -78°C. After completion, the reaction mixture was quenched with aq. NH ₄ Cl (30 ml) and extracted with DCM (3x30 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a precipitate. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (70%) to give the title compound (700 mg, 80%). MS: m/e 936 (M+H)+.

Step D: tert-butyl(1-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((^ or S)-1-hydroxyhexan-3yl)oxy)imidazo [2, 1-f][1,2,4]triazin-7-yl)methyl)pyridin-2-yl)oxy)propan-2-yl)(methyl)carbamate.

To a solution of tert-butyl(1-((5-((2-(((I or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)pyridin-2-yl)oxy)propan2-yl)(methyl)carbamate (700 mg, 0.748 mmol) in MeOH (40 ml) Pd/C (700 mg) and AcOH (0.8 ml) were added. The reaction mixture was stirred for 12 hours at 40°C in an atmosphere of H ₂ (1 atm). The mixture was filtered and the filtrate was combined together and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (70%) to give the title compound (200 mg, 32%). MS: m/e 830 (M+H)+.

Step E: (R or S)-3-((4-amino-7-((6-(2-(methylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1G][1,2, 4]triazin-2-yl)oxy)hexan-1-ol (compound A122).

Tert-butyl(1-((5-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((^ or S)-1-hydroxyhexan-3yl)oxy)imidazo[2,1-G ][1,2,4]triazin-7-yl)methyl)pyridin-2-yl)oxy)propan-2-yl) (methyl)carbamate (200 mg, 0.241 mmol) was dissolved in TFA (4 ml) and H2O (0.4 ml) under N2 atmosphere. The reaction mixture was stirred for 12 hours at 40°C. Once complete, the solvent was removed in vacuo. The precipitate was diluted with water (20 ml) and DCM (20 ml) and the aqueous phase was acidified with 1 N HCl to a pH value of 1 to 2. The aqueous phase was washed with DCM (3x20 ml) and alkalinized with 2 N NaOH to a pH value of 13 to 14 and extracted DCM/i-PrOH (5/1, 3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to leave a residue. The residue was purified by pre-TLC (DCM/CH ₃ OH(MH ₃ )=15/1) to give the title compound (60 mg, 58%).

1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.67 (s, 1H), 7.36 (s, 1H), 6.81 (d, J=4.8 Hz, 1H ), 5.20 (s, 1H), 4.32 (s, 1H), 4.18 (s, 3H), 3.67 (s, 2H), 3.16 (s, 1H), 2.51 (s, 3H), 1.91 (s, 2H), 1.80-1.60 (m, 2H), 1.54-1.31 (m, 2H), 1.23 (s, 3H), 0.94 (s, 3H) ppm. MS: m/e 430 (M+H)+.

Compound A123: (R or S)-3-((4-amino-7-(2,6-difluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-G][1,2 ,4]triazin-2-yl)oxy)hexan-1-ol.

Step A: tert-butyl (2-(3,5-difluoro-4-formylphenoxy)ethyl)(methyl)carbamate.

To a solution of 3,5-difluoro-4-hydroxybenzaldehyde (316 mg, 2 mmol) in THF (10 ml) was added tert-butyl(2-hydroxyethyl)(methyl)carbamate (350 mg, 2 mmol) and PPh3 (655 mg, 2. 5 mmol). The mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (505 mg, 2.5 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. Added water race

- 87 046488 ammonium chloride solution and the mixture were extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (180 mg, 28.5%). MS: m/e: 316 (M+1)+.

Step B: tert-butyl(2-(4-((2-(((K. or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino) imidazo [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3,5difluorophenoxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(2,4-dimethoxybenzyl)imidazo[2,1-G][1,2 ,4]triazin-4-amine (300 mg, 0.5 mmol) in THF (10 ml), a solution of nBuLi (1.6 M, 0.9 ml, 1.5 mmol) was added dropwise, maintaining the temperature between -75 to -65°C. After 1 hour, tert-butyl (2-(3,5-difluoro-4-formylphenoxy)ethyl)(methyl)carbamate (180 mg, 0.57 mmol) in THF (2 ml) was added dropwise to the suspension. The resulting mixture was stirred at -70°C for 2 hours and then warmed to room temperature overnight. The reaction was quenched with a saturated solution of NH ₄ Cl, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (120 mg, 25.1%). MS: m/e 957 (M+1)+.

Step C: tert-butyl^ or S)-(2-(4-((4-(bis(2,4-dimethoxybenzyl)amino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2,1 -f][1,2,4]triazin-7-yl)methyl)-3,5-difluorophenoxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-(4-((2-(((K. or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-3,5difluorophenoxy)ethyl)(methyl)carbamate (120 mg, 0.125 mmol) in MeOH (20 ml) was added Pd/C (200 mg). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (60 mg, 56.2%). MS: m/e: 851 (M+1)+.

Step D: (R or S)-3-((4-amino-7-(2,6-difluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1G][1,2,4 ]triazin-2-yl)oxy)hexan-1-ol (compound A123).

To a mixture of the product of step C (60 mg, 0.07 mmol) in TFA (9 ml) was added H2O (1 ml) and the resulting mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2 N solution of NaOH (10 ml) and DCM (20 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (8 mg, 25.2%).

1H NMR (400 MHz, CD ₃ OD) δ 7.21 (s, 1H), 6.68 (d, J=9.2 Hz, 2H), 5.26 (s, 1H), 4.15 (dd , J=12.0, 7.3 Hz, 4H), 3.67 (s, 2H), 3.09 (s, 2H), 2.56 (s, 3H), 1.94 (d, J= 6.4 Hz, 2H), 1.72 (s, 2H), 1.45 (s, 2H), 0.97 (t, J=7.4 Hz, 3H) ppm. MS: m/e 451 (M+1)+.

Compound A124: (R or S)-3-((4-αmino-7-((4-(2-(methylαmino)ethoxy)naphthalen-1yl)methyl)imidazo [2,1-f][1,2, 4]triazin-2-yl)oxy)hexan-1-ol.

Step A: tert-butyl (2-((4-formylnaphthalen-1-yl)oxy)ethyl)(methyl)carbamate.

To a solution of 4-hydroxy-1-naphthaldehyde (344 mg, 2 mmol) in THF (10 ml) was added tert-butyl(2hydroxyethyl)(methyl)carbamate (350 mg, 2 mmol) and PPh ₃ (655 mg, 2.5 mmol), the mixture was protected with nitrogen and cooled to 0 degrees. A solution of DIAD (505 mg, 2.5 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography to give the title product (400 mg, 60.7%). MS: m/e: 330 (M+1)+.

Step B: tert-butyl(2-((4-((2-((^ or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)naphthalen-1yl)oxy)ethyl)(methyl)carbamate.

To a solution of (R or S)-2-((1-(benzyloxy)hexan-3-yl)oxy)-N,N-bis(4-methoxybenzyl)imidazo[2.1G][1,2,4]triazine -4-amine (519 mg, 0.8 mmol) in THF (10 ml), a solution of n-BuLi (1.6 M, 1.5 ml, 2.4 mmol) was added dropwise, maintaining the temperature between -75 up to -65°C. After 1 hour, a suspension of tert-butyl(2-((4-formylnaphthalen-1-yl)oxy)ethyl)(methyl)carbamate (400 mg, 1.2 mmol) in THF (2 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 a saturated solution of NH ₄ Cl, extracted with EtOAc (20 mlx3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The precipitate was purified by pre-TLC to give the title compound (220 mg, 22.6%). MS: m/e 971 (M+1)+.

Step C: tert-butyl^ or S)-(2-((4-((4-(bis(2,4-dimethoxybenzyl)αmino)-2-((1-hydroxyhexan-3yl)oxy)imidazo [2, 1-f][1,2,4]triazin-7-yl)methyl)naphthalen-1-yl)oxy)ethyl)(methyl)carbamate.

To a solution of tert-butyl(2-((4-((2-(((I or S)-1-(benzyloxy)hexan-3-yl)oxy)-4-(bis(2,4dimethoxybenzyl)amino)imidazo [2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)naphthalene-1

- 88 046488 yl)oxy)ethyl)(methyl)carbamate (220 mg, 0.226 mmol) in MeOH (20 ml) was added Pd/C (300 mg). The mixture was protected with hydrogen and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to give the title product (60 mg, 30%). MS: m/e: 865 (M+1)+.

Step D: (R or S)-3-((4-amino-7-((4-(2-(methylamino)ethoxy)naphthalen-1-yl)methyl)imidazo[2,1f] [1,2, 4]triazin-2-yl)oxy)hexan-1-ol.

To a mixture of the product of step C (60 g, 0.069 mmol) in TFA (18 ml) was added H2O (2 ml) and the resulting mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated to dryness. A 2 N solution of NaOH (20 ml) and DCM (60 ml) was added to the precipitate and stirred at rt for 30 min. The mixture was separated. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by pre-HPLC to give the title compound (10 mg, 31.1%).

1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.06 (s, 1H), 7.53 (s, 2H), 7.33 (s, 1H), 7.12 (s , 1H), 6.91 (s, 1H), 5.22 (s, 1H), 4.58 (s, 2H), 4.33 (s, 2H), 3.68 (s, 2H), 3 .23 (s, 2H), 2.61 (s, 3H), 1.93 (s, 2H), 1.74 (s, 2H), 1.41 (s, 2H), 0.91 (s, 3H) ppm. MS: m/e 465 (M+1)+.

Compound C1: 2-butoxy-8-(3-(pyrrolidin-1-ylmethyl)benzyl)pyrazolo[1,5-a][1,3,5]triazin-4amine.

Step A: tert-butyl(2-butoxypyrazolo[1,5-a][1,3,5]triazin-4-yl)carbamate.

Di-tert-butydicarbonate (130 mg, 0.6 mmol) and DMAP (10 mg, 0.08 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with H2O (20 ml) and extracted with EtOAc (10 mlx3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography to give the product (100 mg, 100%) as white solids. MS: m/e 308 (M+1)+.

Step B: tert-butyl(8-bromo-2-butoxypyrazolo[1,5-a][1,3,5]triazin-4-yl)carbamate.

To the stirred solution was added tert-butyl(2-butoxypyrazolo[1,5-a][1,3,5]triazin-4yl)carbamate (100 mg, 0.3 mmol) in MeCN (10 ml), NBS (115 mg , 0.6 mmol). The reaction mixture was stirred at rt for 2 hours. The mixture was concentrated in vacuo. The crude product was purified by column chromatography to give the product (150 mg, 100%) as a white solid. MS: m/e 386 (M+1)+.

Step C: tert-butyl (2-butoxy-8-(hydroxy(3-(pyrrolidin-1-ylmethyl)phenyl)methyl)pyrazolo[1,5a][1,3,5]triazin-4-yl)carbamate .

To a stirred solution of tert-butyl(8-bromo-2-butoxypyrazolo[1,5-a][1,3,5]triazin-4yl)carbamate (150 mg, 0.3 mmol) in THF (10 ml), cooled to -78°C and under a nitrogen atmosphere, n-BuLi (1.6 M in hexane, 0.75 mmol, 0.47 ml) was added dropwise. After stirring for 20 min, a solution of 3-(pyrrolidin-1-ylmethyl)benzaldehyde (85 mg, 0.45 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography to give the title product (100 mg, 67%). MS: m/e 498 (M+1)+.

Step D: 2-butoxy-8-(3-(pyrrolidin-1-ylmethyl)benzyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine.

Solution of tert-butyl(2-butoxy-8-(hydroxy(3-(pyrrolidin-1-ylmethyl)phenyl)methyl)pyrazolo[1,5a][1,3,5]triazin-4-yl)carbamate (100 mg , 0.2 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (10 mg, 13.1%).

1H NMR (400 MHz, DMSOO δ 8.45 (s, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 7.35-7.02 (m, 4H), 4, 27 (s, 2H), 3.95 (s, 2H), 3.67 (s, 2H), 2.38-2.32 (m, 4H), 1.68-1.62 (m, 4H) , 1.40 (s, 2H), 1.19-1.15 (m, 2H), 0.90-0.85 (m, 3H) ppm MS: m/e 381 (M+1)+.

Compound C2: 2-butoxy-8-(4-(pyrrolidin-1-ylmethyl)benzyl)pyrazolo[1,5-a][1,3,5]triazin-4amine.

Step A: tert-butyl-(2-butoxy-8-(hydroxy(4-(pyrrolidin-1-ylmethyl)phenyl)methyl)pyrazolo[1,5a][1,3,5]triazin-4-yl)carbamate .

To a stirred solution of tert-butyl(8-bromo-2-butoxypyrazolo[1,5-a][1,3,5]triazin-4yl)carbamate (100 mg, 0.26 mmol) in THF (10 ml), cooled to -78°C and under a nitrogen atmosphere, n-BuLi (1.6 M in hexane, 0.75 mmol, 0.47 ml) was added dropwise. After stirring for 20 min, a solution of 4-(pyrrolidin-1-ylmethyl)benzaldehyde (100 mg, 0.52 mmol) in THF (2 ml) was slowly added. The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). Combined organic

- 89 046488 The phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo to obtain the crude product (220 mg, 100%), which was directly used in the step. MS: m/e 497 (M+1)+.

Step B: 2-butoxy-8-(4-(pyrrolidin-1 -ylmethyl)benzyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine.

Tert-butyl(2-butoxy-8-(hydroxy(4-(pyrrolidin-1-ylmethyl)phenyl)methyl)pyrazolo[1,5a][1,3,5]triazin-4-yl)carbamate solution (220 mg , 0.26 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. TFA (5 ml) was added to the precipitate and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (10 mg, 10.1%).

1H NMR (400 MHz, DMSOHO δ 8.47 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.19 (s, 4H), 4.26 (t, J=6.4 Hz, 2H), 3.82 (s, 2H), 3.50 (s, 2H), 2.39-2.31 (m, 4H), 1.72-1.61 (m , 6H), 1.40 (dq, J=14.3, 7.2 Hz, 2H), 0.98-0.87 (m, 3H) ppm MS: m/e 381 (M+1)+ .

Compound C3: 5-butoxy-3-((5-chloro-6-(piperazin-1-yl)pyridin-3-yl)methyl)pyrazolo[1,5c]pyrimidin-7-amine.

Step A: methyl 7-amino-5-hydroxypyrazolo[1,5-c]pyrimidine-3-carboxylate.

To a solution of dimethyl 3-oxopentanedioate (50 g, 0.29 mol) in ethanol (500 ml), DMF-DMA (34.5 g, 0.29 mol) was added and the mixture was stirred at rt for 2 hours. Then added hydrazinecarboximidamide hydrochloride (35.4 g, 0.32 mol) and the solution was heated at 80°C for 3 hours. After cooling to rt, the precipitated solid was filtered and dried to give the product as a yellow solid (24 g, 40%) .

1H NMR (400 MHz, DMSO-de) δ 10.99 (br,s, 1H), 8.24 (s, 1H), 7.82 (br,s, 2H), 6.27 (s, 1H) , 3.76 (s, 3H) ppm. MS: m/e 209 (M+1)+.

Step B: methyl 7-amino-5-butoxypyrazolo[1,5-c]pyrimidine-3-carboxylate.

1-iodobutane (6.6 g, 36 mmol) was added to a solution of methyl 7-amino-5-hydroxypyrazolo[1,5c]pyrimidine-3-carboxylate (5 g, 24 mmol) in DMF (100 ml). The solution was stirred at rt overnight. Water (50 ml) was added and the precipitated solid was filtered and dried to give the desired product as a yellow solid (6.1 g, 96%).

1H NMR (400 MHz, DMSO-de) δ 8.30 (s, 1H), 8.01 (br,s, 1H), 6.35 (s, 1H), 4.20 (t, J=8, 0 Hz, 2H), 3.77 (s, 3H), 1.71-1.66 (m, 2H), 1.45-1.38 (m, 2H), 0.89 (t, J=8 .0 Hz, 3H) ppm. MS: m/e 265 (M+1)+.

Step C: methyl 7-(bis(tert-butoxycarbonyl)amino)-5-butoxypyrazolo[1,5-c]pyrimidine-3 carboxylate.

(Boc) _2O (7.7 g, 35.2 mmol) was added dropwise to a solution of methyl 7-amino-5-butoxypyrazolo[1,5c]pyrimidine-3-carboxylate (3.1 g, 11.7 mmol ) and DMAP (714 mg, 5.9 mmol) in THF (250 ml). After addition, the suspension became transparent. Continue stirring at rt for 2 hours, then concentrate and purify using CombiFlash (PE:EA=25%) to give product (4.2 g, 78%).

1H NMR (400 MHz, DMSOD6) δ 8.37 (s, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 4.30 (t, J=8.0 Hz, 2H ), 3.91 (s, 3H), 1.80-1.76 (m, 2H), 1.54-1.45 (m, 2H), 1.29 (s, 9H), 0.97 ( t, J=8.0 Hz, 3H) ppm. MS: m/e 465 (M+1)+.

Step D: tert-butyl(5-butoxy-3-(hydroxymethyl)pyrazolo[1,5-c]pyrimidin-7-yl)carbamate.

To a solution of lithium aluminum hydride (782 mg, 20.6 mmol) in THF (60 ml) at 0°C was added dropwise methyl 7-(bis(tert-butoxycarbonyl)amino)-5-butoxypyrazolo[1,5-c] pyrimidine-3-carboxylate (4.2 g, 10.3 mmol) in THF (20 ml). The resulting mixture was stirred gradually at rt for 2 hours. Then the mixture was quenched with 0.8 ml of water, then 0.8 ml of NaOH solution (15%) and 2.4 ml of water. The solid was filtered and the cake was suspended with 100 ml of methanol for 1 hour. After filtration, the filter cake was again suspended with 100 ml of methanol. After filtration, the combined filtrate was evaporated to obtain the desired product (1.9 g, 50%).

1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 6.14 (s, 1H), 4.64 (s, 1H), 4.04 (t, J=8.0 Hz, 2H ), 1.79-1.75 (m, 2H), 1.54-1.44 (m, 12H), 0.97 (t, J=8.0 Hz, 3H) ppm. MS: m/e 337 (M+1)+.

Step E: tert-butyl(5-butoxy-3-formylpyrazolo[1,5-c]pyrimidin-7-yl)carbamate.

To a cooled solution of tert-butyl(5-butoxy-3-(hydroxymethyl)pyrazolo[1,5-c]pyrimidip-7yl)carbamate (1.2 g, 3.6 mmol) in THF (110 ml) at 0°C , Dess-Martin reagent (3.1 g, 7.2 mmol) was added. The solution was stirred at 0°C for 30 min and then gradually warmed to rt over 30 min. The solution was quenched with water at 0°C to a clear solution and extracted with ethyl acetate (80 ml). The organic layer was concentrated and purified using CombiFlash (PE:EA=25%) to obtain the product as a colorless oil (270 mg, 23%).

1H NMR (400 MHz, _DMSOD6 ) δ 10.19 (s, 1H), 9.91 (s, 1H), 8.60 (s, 1H), 7.01 (s, 1H), 4.31 ( t, J=8.0 Hz, 2H), 1.76-1.70 (m, 2H), 1.52-1.40 (m, 12H), 0.95 (t, J=8.0 Hz , 3H) ppm. MS: m/e 335 (M+1)+.

Step F: tert-butyl-4-(5-((5-butoxy-7-((tert-butoxycarbonyl)amino)pyrazolo[1,5-c]pyrimidin-3 yl)(hydroxy)methyl)-3-chloropyridine -2-yl)piperazine-1-carboxylate.

To the cooled solution was added dropwise tert-butyl 4-(5-bromo-3-chloropyridin-2yl)piperazine-1-carboxylate (289 mg, 0.8 mmol) in THF (15 ml) at -78°C (purged N2), n-BuLi (1.6

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M, 1.2 ml). After stirring at -78°C for 30 min, tert-butyl (5-butoxy-3formylpyrazolo[1,5-c]pyrimidin-7-yl)carbamate (270 mg, 0.8 mmol) in THF (5 ml) was added ). The resulting mixture was stirred at this temperature for 30 minutes and then heated to rt for 2 hours. The solution was quenched with NH ₄ Cl solution (10 ml) and extracted with ethyl acetate (10 ml). The organic layer was dried with Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was further purified using CombiFlash (PE:EA=50%) and prep-TLC (PE:EA=1:1) to give the pure product (80 mg, 16%). MS: m/e 632 (M+1)+.

Step G: 5-butoxy-3-((5-chloro-6-(piperazin-1-yl)pyridin-3-yl)methyl)pyrazolo[1,5-c]pyrimidin-7 amine.

A mixture of tert-butyl-4-(5 -((5-butoxy-7-((tert-butoxycarbonyl)amino)pyrazolo[1,5-c]pyrimidin-3 yl)(hydroxy)methyl)-3-chloropyridine-2 -yl)piperazine-1-carbo xylate (20 mg, 0.03 mmol) in triethylsilane (0.5 ml) and trifluoroacetic acid (0.5 ml) was heated at 30°C for 2 hours. Then concentrated with butyric acid pump at 60°C to obtain the crude product, which was purified using pre-TLC (DCM:MeOH=7:1) to obtain the product (5 mg, 38%).

1H NMR (400 MHz, CD3OD) δ 8.12 (t, J=8.0 Hz, 1H), 7.75 (d, J=4.0 Hz, 1H), 7.64 (s, 1H), 6.97 (d, J=4.0 Hz, 1H), 5.97 (d, J=8.0 Hz, 1H), 4.12-4.09 (m, 3H), 3.51-3 .38 (m, 4H), 2.91-2.65 (m, 4H), 1.76-1.72 (m, 2H), 1.49-1.45 (m, 2H), 0.98 (t, J=8.0 Hz, 3H) ppm. MS: m/e 416 (M+1)+.

Compound C4: 6-propoxy-3-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo [1 D-^pyridazin^-amine.

Step A: 6-chloro-N,N-bis(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine.

To a stirred solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.7 mmol) in DMF (20 ml), added bis(4-methoxybenzyl)amine (2.7 g, 10. 44 mmol) and DIEA (2.3 g, 17.4 mmol). The reaction mixture was stirred at 90°C overnight. The mixture was diluted with H2O (50 ml) and extracted with EtOAc (20 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography to give the product (2.8 mg, 80%) as a white solid. MS: m/e 308 (M+1)+.

Step B: N,N-bis(4-methoxybenzyl)-6-propoxyimugazo[1,2-b]pyridazin-8-amine.

To a stirred solution of 6-chloro-N,N-bis(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine (2.2 g, 5.4 mmol) in butyl alcohol (10 ml) was added sodium butanolate (50 ml, 4 M in butyl alcohol). The reaction mixture was stirred at 95°C overnight. The mixture was concentrated in vacuo. The precipitate was added with H2O (50 ml) and extracted with EtOAc (20 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography to give the product (2 g, 85.8%) as a white solid. MS: m/e 437 (M+1)+.

Step C: 8-(bis(4-methoxybenzyl)amino)-6-propoxyimidazo[1,2-b]pyridazine-3-carbaldehyde.

DMF (5 ml) was added to a 100 ml round bottom flask, POCl ₃ (900 mg, 5.88 mmol) was added to DMF at 0°C. The reaction was stirred at 0°C for 30 minutes. N,Nbis(4-methoxybenzyl)-6-propoxyimidazo[1,2-b]pyridazin-8-amine (300 mg, 0.69 mmol) was added to this solution. The reaction was stirred at rt overnight. The mixture was diluted with H2O (50 ml) and extracted with EtOAc (20 mlx3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography to give the product (300 mg, 94%) as a yellow solid. MS: m/e 475 (M+1)+.

Step D: (8-(bis(4-methoxybenzyl)amino)-6-propoxyimidazo [N-^pyridazinD -yl)(4-(pyrrolidin n-1-ylmethyl)phenyl)methanol.

n-BuLi (1.6 M in hexane, 0.93 mmol, 0.58 ml). After stirring for 50 min, a solution of 8-(bis(4methoxybenzyl)amino)-6-n-propoxyimidazo[1,2-b]pyridazine-3-carbaldehyde (150 mg, 0.37 mmol) in THF (2 ml) was slowly added. . The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo to give the product (60 mg, 25.6%). MS: M/e: 636 (M+1)+.

Step E: 6-butoxy-3-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo [1 D-^pyridazin^-amine.

Solution of (8-(bis(4-methoxybenzyl)amino)-6-propoxyimidazo[1,2-b]pyridazin-3-yl)(4-(pyrrolidin n-1-ylmethyl)phenyl)methanol (60 mg, 0. 09 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. The precipitate was added with TFA (5 ml) and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (5 mg, 14.2%).

1H NMR (400 MHz, DMSO-de) δ 9.83 (s, 1H), 8.04 (s, 1H), 7.74 (s, 1H), 7.39 (d, J=7.5 Hz , 2H), 7.30 (d, J=7.7 Hz, 2H), 7.04 (s, 2H), 4.29 (d, J=5.4 Hz, 2H), 4.20 (t , J=6.1 Hz, 2H), 3.95 (s, 2H), 3.30 (s, 2H), 3.06 (s, 2H), 2.01 (s, 2H), 1.91 -1.77 (m, 2H), 1.69-1.56 (m, 2H), 1.35-1.19 (m, 2H), 0.85 (t, J=7.3 Hz, 3H ) ppm. MS: m/e 380 (M+1)+.

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Compound C5: 6-butoxy-3-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[1,2-b]pyride azin-8-amine.

Step A: tert-butyl-4-(5-((8-(bis(4-methoxybenzyl)amino)-6-butoxyimidazo[1,2-b]pyridazi n-3yl)(hydroxy)methyl)-3-methylpyridine -2-yl)piperazine-1-carboxylate.

To a stirred solution of tert-butyl 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylate (180 mg, 0.44 mmol) in THF (10 ml), cooled to -78°C and under a nitrogen atmosphere, nBuLi (1.6 M in hexane, 0.99 mmol, 0.618 ml) was added dropwise. After stirring for 50 min, a solution of 8-(bis(4-methoxybenzyl)αmino)-6-n-propoxyimidazo[1,2-b]pyridazine-3-carbaldehyde (201 mg, 0.66 mmol) in THF (2 ml) was slowly added ). The reaction mixture was slowly warmed to rt and stirred for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (15 mlx3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo to give the product (120 mg, 24.2%). MS: m/e: 752 (M+1)+.

Step B: 6-butoxy-3-((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)imidazo[1,2-b]pyridαzin-8amine.

A solution of tert-butyl-4-(5-((8-(bis(4-methoxybenzyl)amino)-6-butoxyimidazo[1,2-b]pyridazin-3yl)(hydroxy)methyl)-3-methylpyridin-2- yl)piperazine-1-carboxylate (120 mg, 0.16 mmol) in TFA (3 ml) and Et ₃ SiH (3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to remove TFA and Et ₃ SiH. The precipitate was added with TFA (5 ml) and stirred at 85°C overnight. The mixture was cooled to rt and concentrated in vacuo. The crude product was purified by pre-HPLC to give the product (10 mg, 15.8%).

1H NMR (400 MHz, DMSOO δ 8.68 (br,s, 2H), 8.14-8.10 (m, 1H), 8.05 (s, 1H), 7.89-7.83 (m , 1H), 7.39 (s, 1H), 7.16-7.11 (m, 2H), 4.24 (br,s, 2H), 3.84 (s, 2H), 3.26- 3.14 (m, 8H), 2.18 (s, 3H), 1.72-1.59 (m, 2H), 1.33-1.27 (m, 2H), 0.86 (t, J=7.6, 3H) ppm MS: m/e 396 (M+1)+.

Compound C6: 2-butoxy-7 -((5-methyl-6-(piperazin-1-yl)pyridin-3-yl)methyl)-5H-pyrrolo[3,2d]pyrimidin-4-amine.

Step A: 2,4-dichloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2D]pyrimidine.

To a solution of 2,4-dichloro-5H-pyrrolo[3,2D]pyrimidine (3.76 g, 20 mmol) in DMF (40 ml), add DIPEA (4.2 ml, 24 mmol) and (2-(chloromethoxy )ethyl)trimethylsilane (4.3 ml, 24 mmol). The mixture was stirred at room temperature overnight. The reaction was concentrated, diluted with water (5 ml), extracted with EtOAc (30 mlx5). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and the residue purified by flash chromatography to give the title compound (3 g, 47%) as a white solid. MS: m/e 318 (M+1)+.

Step B: 2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2D]pyrimidin-4-amine.

Aqueous ammonium (20 ml) was added to a solution of 2,4-dichloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5Hpyrrolo[3,2D]pyrimidine (5 g, 15.8 mmol) in propane-2- ole (20 ml), the reaction mixture was stirred in an autoclave at 95°C for 7 hours, extracted with EtOAc (25 mlx4). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and the residue was purified by flash chromatography to give the title compound (3.2 g, 68%) as a white solid. MS: m/e 299 (M+1)+.

Step C: 2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2D]pyrimidin-4-amine.

A mixture of 2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2D]pyrimidin-4-amine (3 g, 10 mmol) and n-BuONa/n-BuOH (20% , 9.6 ml) was stirred at 80°C for 5 hours. The solution was quenched with H2O (10 ml). The aqueous solution was extracted with EA (20 mlx4). The collected organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography to give the product (3.3 g, 95%). MS: m/e 337 (M+1)+.

Step D: 2-butoxy-5H-pyrrolo[3,2D]pyrimidin-4-amine.

A mixture of 2-butoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2D]pyrimidin-4-amine (3.3 g, 10 mmol) and CF3COOH was stirred at room temperature overnight . The reaction was quenched with a saturated NaHCO ₃ solution. The aqueous solution was extracted with EA (20 mlx3). The collected organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography to give (1.53 g, 74%). MS: m/e 207 (M+1)+.

Step E: tert-butyl-4-(5-((4-amino-2-butoxy-5H-pyrrolo[3,2D]pyrimidin-7-yl)(hydroxy)methyl)3-methylpyridin-2-yl)piperazine -1-carboxylate.

Mixture of 2-butoxy-5H-pyrrolo[3,2D]pyrimidin-4-amine (206 mg, 1 mmol), tert-butyl 4-(5-formyl3-methylpyridin-2-yl)piperazine-1-carboxylate (458 mg, 1.5 mmol) and K ₂ CO ₃ (166 mg, 1.5 mmol) in CH3OH (1 ml) m H2O (1 ml) was stirred at room temperature for two days. The reaction was quenched with a saturated NaHCO ₃ solution. The aqueous solution was extracted with EA (25 mlx4). The collected organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography to give the product (203 mg, 40%) MS: m/e 512 (M+1)+.

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Step F: 2-butoxy-7 -((5-methyl-6-(piperazin-1 -yl)pyridin-3 -yl)methyl)-5H-pyrrolo[3,2d]pyrimidip-4-amine.

To a stirred solution of the product of step A (206 mg, 0.5 mmol) in DCM (5 ml) at -15°C, Et ₃ SiH (0.5 ml) and TFA (0.5 ml) were added. The reaction mixture was stirred at 0°C overnight. The solution was quenched with saturated NaHCO ₃ (5 ml). The aqueous solution was extracted with EA (10 mlx4). The collected organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by column chromatography to give the product (82 mg, 41%).

1H NMR (400 MHz, CDCl ₃ ) δ 10.45 (s, 1H), 8.04 (d, J=4 Hz, 1H), 7.46 (s, 1H), 7.16 (d, J= 4 Hz, 1H), 6.65 (s, 2H), 4.19 (t, J=4 Hz, 2H), 3.77 (s, 2H), 2.91-2.75 (m, 8H) , 1.68-1.61 (m, 2H), 1.42-1.35 (m, 2H), 0.93 (t, J=8.0 Hz, 3H) ppm. MS: m/e 396 (M+1)+.

HEK293-Blue hTLR7 reporter gene assay.

The HEK-Blue-hTLR7 cell line (Invivogen, Cat. No. hkb-htlr7) was engineered so that secreted embryonic alkaline phosphatase (SEAP) expression could be induced by activated NF-κ and AP-1 through stimulation of human TLR7 with TLR7 agonists.

HEK-Blue-hTLR7 cells were seeded at a density of 4x104 cells/well in a volume of 180 μl in 96-well DMEM plates (Cat. No. 11965-092), supplemented with 10% (v/v) heat-killed fetal bovine serum (FBS) ( Gibco, 10099-1441), 100 U/ml penicillin and 100 μg/ml streptomycin (Gibco, 15140122), containing 50 U/ml penicillin and 50 mg/ml streptomycin and 10% (v/v) heat-killed fetal bovine serum. Cells were left for 5 hours, then treated with increasing amounts of test compounds at 37°C for 24 hours. Then, 20 μl of supernatant from each well was incubated with 180 μl of Quanti-blue substrate solution at 37°C for 10-30 minutes until activity was determined. SEAP at 620-655 nm using a spectrophotometer. The EC50 value for each compound was calculated using GraphPad Prism software using a sigmoidal dose-response function.

Determination of TLR7 stimulation by HEK-Blue.

This study is designed to examine the stimulation of TLR7 protein in the HEKBlue hTLR7 cell line by NF-κB activation. HEK-Blue hTLR7 cells were generated by cotransfecting the hTLR7 gene and an optimized secreted embryonic alkaline phosphatase (SEAP) reporter gene into HEK293 cells. The SEAP reporter gene was placed under the control of an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. TLR7 ligand stimulation activates NF-κB and AP-1, which induce SEAP expression. SEAP levels can be easily determined using HEK-Blue detection medium, a cell culture medium that allows real-time SEAP detection. HEK-Blue detection medium contains all substances necessary for cell growth and a colored substrate specific for SEAP. SEAP hydrolyzes the substrate, resulting in a purple/blue color that can be measured using a spectrophotometer.

When grown to 50-80% confluence, HEK-Blue hTLR7 cells were plated in a 96-well plate (costar 3599) at a density of 40,000 cells/well. Compounds were then added in serial dilutions at 10 points ranging from 0.04 nM to a final concentration of 10 μM in 0.1% DMSO/HEK-Blue Detection. The plates were then incubated for 16 hours at 37°C in 5% CO ₂ and vortexed for 30 seconds before measurement. Optical density was read at 620-655 nm using BMG PHERAstar FSX equipment. The EC50 for each compound was determined by calculating the percentage of maximum activation identified with resiquimod.

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Table 1

Series A compounds (D refers to EC50 >10 µmol; A1-A76 tested with QUANTIBLUE, A77-A124 tested with HEK-Blue detection medium)

Connection number EU 50 (nmol) Connection number EU 50 (nmol) A1 900 A2 920 AZ D A4 1846 A5 1271 Ab 1507 A7 D A8 3029 A9 D AY 1174 AP D A12 D A13 D A14 D A15 D A16 D A17 D A18 D A19 D A20 1749 A21 2866 A22 5708 A23 D A24 D A25 D A26 D A27 D A28 1789 A29 2601 AZO 3519 A31 D A32 861 AZZ 1059 A34 3369 AZ 5 2068 AZ 6 880 AZ 7 D AZ 8 1858 AZ 9 543 A40 602

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A41 1591 A42 1380 A43 822 A44 1012 A45 3845 A46 D A47 D A48 D A49 4319 A50 D A51 D A52 D A53 1432 A54 D A55 D A56 D A57 375 A58 246 A59 D A60 246 A61 183 A62 D A63 996 A64 3998 A65 D A66 387 A67 585 A68 D A69 1238 A70 D A71 1174 A72 462 A73 D A74 D A75 D A76 D A77 19.2 A78 23 A79 10 A80 446 A81 310 A82 5 A83 42.6 A84 6.9 A85 4.5 A86 57.7 A87 10.5 A88 D A89 10 A90 8.9 A91 2.1 A92 122 A93 1.7 A94 13.8 A95 8.0 A96 4.3 A97 1.0 A98 eleven A99 14.4 A100 15 A101 0.78 A102 3.7 A103 2.4 A104 10 A105 61 A106 1.6 A107 1.3 A108 0.8 A109 3.4 APO 4.0 AS 1.9 A112 0.93 APZ 24 A114 1 A115 0.72 A116 37.8 A117 13 A118 eleven A119 146 A120 3.9 A121 0.63 A122 6.0 APZ 0.7 A124 1.2

table 2

Compound series C (D refers to EC50 greater than 10 µmol;

_____С1-С6 were tested using QUANTI-BLUE)_____

Connection number EU 50 (nmol) Connection number EC50 (nmol) C1 D C2 D nw D C4 D C5 D C6 1075

- 95 046488

Determination of TLR8 stimulation using HEK-Blue detection.

This study is designed to investigate the stimulation of human TLR8 protein in the HEK-Blue hTLR8 cell line by monitoring NF-κB activation. HEK-Blue hTLR8 cells were generated by cotransforming the hTLR8 gene and the optimized secreted embryonic alkaline phosphatase (SEAP) reporter gene in HEK293 cells. The SEAP reporter gene was placed under the control of a minimal IFN-β promoter fused to five NF-κB and AP-1 binding sites. Stimulation of TLR ligand 8 activates NF-κB and AP-1, which induce SEAP expression. SEAP levels can be determined using HEK-Blue detection medium, a cell culture medium that allows real-time SEAP detection. HEK-Blue detection medium contains all substances necessary for cell growth and a colored SEAP-specific substrate. SEAP hydrolyzes the substrate, resulting in a purple/blue color that can be measured using a spectrophotometer.

When grown to 50-80% confluence, HEK-Blue hTLR7/8 cells were plated in a 96-well plate (costar 3599) at a density of 40,000 cells/well. Compounds were then added in serial dilutions at 10 points ranging from 1 nM to a final concentration of 10 μM in 0.1% DMSO/HEK-Blue detection medium. The plates were then incubated for 16 hours at 37°C in 5% CO ₂ . Optical density at 620-655 nm was read on a BMG PHERAstar FSX instrument. The EC50 for each compound was determined by calculating the percentage of maximum activation identified with resiquimod and motolimod.

Table 3

Connections for HEK-Blue hTLR8 cells (D refers to EC50 greater than 10 µmol)

Connection number EU 50 (nmol) Connection number EU 50 (nmol) A8 187 AY 572 A43 255 A58 183 A77 293 A78 1135 A79 69 A80 D A81 6246 A82 22 A83 458 A84 192 A85 41 A86 541 A87 434 A88 D A89 199 A90 112 A91 15 A92 872 A93 13.5 A94 146 A95 19 A96 29 A97 10 A98 163 A99 129 AY0 195 A101 8.6 AYU2 134 A103 47 AYU4 24 A105 622 AYU6 12 A107 16 AYU8 21 A109 47 APO 65 AS 47 AP2 9 A113 98 AP4 6.8 A115 7 AP6 51 A117 532 AP8 21 A119 2972 A120 59 A121 19 A122 113 A123 15 A124 105

Although the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations will be apparent to those skilled in the art. All such alternatives, modifications and variations are within the spirit and scope of the present invention.

Claims (19)

1. Compound of formula (I) nr ² r ³ or a pharmaceutically acceptable salt thereof, wherein X represents N; L ¹ represents -(CR ^a R ^b )m-, -O- or -S-, where m is a number from 1 to 8; R ^a and R ^b are each independently hydrogen or -C _1-8 alkyl; R ¹ is -OR ^1a , -SR ^1a or -NR ^1a R ^1b ; R ^1a and R ^1b are independently hydrogen, -C _1-8 alkyl, alkenyl or alkynyl, each of said alkyl, alkenyl or alkynyl being optionally substituted with one, or two, or three substituents selected from halogen, -C _1-8 alkyl, optionally substituted with R ^1e , cycloalkyl, optionally substituted with R ^1e , heterocyclyl, optionally substituted with R ^1e , aryl, optionally substituted with R ^1e , heteroaryl, optionally substituted with R ^1e , or -OR ^1f ; where R ^1e represents halogen, hydroxy, amino (-NH2), alkylamino, dialkylamino or -C _1-6 alkyl, optionally substituted with halogen; where R ^1f represents -C _1-8 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with -C _1-4 alkyl or halogen; R ^1d in each occurrence is independently hydrogen, oxo, amino (-NH2), alkylamino, dialkylamino, halogen, haloalkyl, -C _1-8 alkyl, haloalkoxy, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl; R ² and R ³ are each independently hydrogen or -C _1-8 alkyl; R ⁴ represents hydrogen, halogen, -C _1-8 alkyl, alkenyl or alkynyl; ring A is aryl or heteroaryl; R ⁵ is halogen, hydroxy, -C1-8alkyl, haloalkyl, alkoxy, haloalkoxy, -oxo- or -C(=O)OR ^5a , where R ^5a is hydrogen, -C1-8alkyl or haloalkyl; p represents the number 0, 1, 2 or 3; L ² represents a direct bond, -(CR ^f R ^g )r, -O-, -S-, -S(O)-, -SO2- or -NR ^d -, where R ^d represents -C1-6alkyl, where t represents a number from 1 to 8; R ^f and R ^g are each independently hydrogen, -C _1-8 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl; R ⁶ is -NR ^6a R ^6b , -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is -C _1-8 alkyl , -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl is independently and optionally substituted with one, two or three R ^6c substituents; R ^6a and R ^6b independently represent hydrogen or -C _1-8 alkyl; R ^6c is independently hydrogen, halogen, -OR ^6d , -SR ^6d , -NR ^6d R ^6e , -COR ^6d , -SO2R ^6d , -C(=O)NR ^6d R ^6e or -C1-8alkyl, wherein said - The C _1-8 alkyl is independently and optionally substituted with one, two or three R ^6g substituents; R ^6d and R ^6e are independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, heterocyclyl or aryl, each of which is optionally -C _1-8 alkyl, -C _2-8 alkenyl, heterocyclyl or aryl substituted with one, two or three R ^6g substituents; R ^6g is in each instance independently hydrogen, halogen, -OR ^6h , -SR ^6h , -NR ^6h R ⁶¹ , -N(R ^6h )C(=O)OR ⁶¹ , -C1-8alkyl, heterocyclyl, aryl or heteroaryl where R ^6h and R ⁶ i independently represent hydrogen or -C1-8alkyl; said alkenyl is a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and from 2 to 8 carbon atoms; said alkynyl is a hydrocarbon group selected from a linear and branched hydrocarbon group containing at least one C=C triple bond and from 2 to 8 carbon atoms; said cycloalkyl group is a hydrocarbon group selected from saturated cyclic hydrocarbon groups containing monocyclic and bicyclic and tricyclic groups and containing from 3 to 12 carbon atoms; said aryl is phenyl; said heteroaryl represents a group selected from: - 97 046488 5-, 6- or 7-membered aromatic, monocyclic rings containing from 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, the remaining ring members being carbon; 7-12 membered bicyclic rings containing from 1 to 3 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), wherein the remaining ring members are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present on the aromatic ring; And 11-14 membered tricyclic rings containing from 1 to 3 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), wherein the remaining ring members are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present on the aromatic ring; said heterocyclyl is a non-aromatic heterocyclyl group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon, including monocyclic 4-9 membered heterocyclyl, 5-20- a membered fused ring, a 5-14 membered bridged ring, and a 5-20 membered spiro ring; said cycloalkenyl is a non-aromatic cyclic alkyl group containing from 3 to 10 carbon atoms, having one or more rings and 1 to 2 double bonds; said cycloalkynyl is a non-aromatic cycloalkyl group containing from 5 to 10 carbon atoms, having one or more rings and one triple bond; said alkylamino is -MSN^^alkyl); said dialkylamino is -M-C _1-8 alkyl) ₂ ; said haloalkyl is a _-C1-8 alkyl group in which one or more hydrogens are replaced by halogen atoms; and said alkoxy is a _-C1-8 alkyl group attached to the parent molecular group via an oxygen atom. 2. The compound according to claim 1, where R ¹ represents -OR ^1a or -NR ^1a R ^1b ; wherein R ^1a , R ^1b are independently hydrogen, -C1-8alkyl or -C2-8alkenyl, each of said -C1-8alkyl optionally substituted with one, two or three substituents selected from heterocyclyl, optionally substituted with ^R1e , aryl, optionally substituted R ^1e , CH3-(OCH ₂ CH ₂ ) _n - (where n is a number from 3 to 10) or -OR ^1f ; where R ^1e represents halogen or -C _1-6 alkyl, optionally substituted with halogen; where R ^1f represents -C _1-8 alkyl, aryl or heteroaryl, each of which is optionally substituted with -C _1-4 alkyl or halogen. 3. A compound according to claim 1, wherein R ¹ is -OR ^1a , where R ^1a is -C1-8alkyl, optionally substituted with one, two or three substituents selected from halogen, -C1-8alkyl, optionally substituted with ^R1e , cycloalkyl, optionally substituted with ^R1e , heterocyclyl, optionally substituted with ^R1e , aryl, optionally substituted with ^R1e , heteroaryl, optionally substituted with ^R1e , _CH3- ( _OCH2CH2 ) _n- (where n is a number from 3 to 10) or -OR ^1f , where R ^1e and R ^1f are defined in paragraph 1. 4. A compound according to claim 1, where R ¹ represents -OR ^1a or -NHR ^1a , where R ^1a represents a branched -C _4-8 alkyl, where the branched substituent is in the alpha position relative to the oxygen atom. 5. A compound according to claim 1, where R ¹ represents -OR ^1a or -NHR ^1a , where R ^1a represents butan-2-yl, pentan-2-yl, pentan-3-yl, heptan-2-yl, heptan-3-yl, heptan-4-yl, octan-2-yl, octan-3-yl, octan4-yl or octan-5-yl. 6. A compound according to any one of claims 1 to 5, where R ⁵ represents halogen, hydroxy, -C1-8alkyl, -haloC1-8alkyl, -C1-8alkoxy, -haloC1-8alkoxy or -C(=O)OR ^5a . where R ^5a represents hydrogen, -C1-8 alkyl or -haloC _1-8 alkyl; and p represents the number 0, 1 or 2. 7. A compound according to any one of claims 1 to 6, wherein ring A is phenyl or a 5-8 membered heteroaryl containing one, or two, or three heteroatoms selected from oxygen, nitrogen or optionally oxidized sulfur as ring members . 8. A compound according to any one of claims 1 to 7, where L ² represents a direct bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O- or -NR ^d -, where R ^d represents -C _{1- 6} alkyl. 9. Connection according to claim 1, where L2-R ⁶ is selected from: a) L ² is -CH2- or -CH2CH2-, and R ⁶ is a 5-, 6-, 7- or 8-membered saturated monocyclic ring containing one, two or three nitrogen heteroatoms as ring members, or a bicyclic a ring containing one, two or three heteroatoms selected from oxygen, nitrogen or optionally oxidized sulfur as ring members, each of which is optionally substituted with one or two R ^6c substituents, where R ^6c is -NR ^6d R ^6e , -COR ^6d , -OR ^6d or -C18 alkyl, optionally substituted with hydroxy, where R ^6d and R ^6e independently represent hydrogen, or -C _1-8 alkyl, or phenyl, wherein said alkyl is optionally substituted with NH2-, alkylamino or dialkyls - 98 046488 but; b) L ² is -CH2- or -CH2CH2-, and R ⁶ is -NR ^6a R ^6b , where R ^6a and R ^6b independently represent hydrogen or C1-8alkyl; c) L ² represents a direct bond and R ⁶ represents -C _1-8 alkyl, -C _2-8 alkenyl or -C _2-8 alkynyl; d) L ² represents -O-, and R ⁶ represents -C1-8 alkyl or heterocyclyl, said -C1-8 alkyl and heterocyclyl are optionally substituted with one or two R ^6c , where R ^6c represents -C1-8 alkyl, -NR ^6d R ^6e and -COR ^6d , wherein R ^6d and R ^6e independently represent -C _1-8 alkyl, optionally substituted with NH2-, alkylamino or dialkylamino; e) L ² represents -NR ^d -, where Rd represents -C1-6 alkyl, and R ⁶ represents -C1-8 alkyl, -C _2-8 alkenyl or -C _1-8 alkynyl, each of which is optionally substituted with one or two R ^6c where R ^6c is -C1-8alkyl or -NR ^6d R ^6e where R ^6d and R ^6e are independently -C1-8alkyl; or f) L ² represents a direct bond, and R ⁶ represents cycloalkyl, aryl or heteroaryl, each of which is independently and optionally substituted with one, two or three R ^6c substituents. 10. A compound according to claim 9, where L ² represents -CH2- or -CH2CH2-, and R ⁶ represents pyrrolidinyl, piperidinyl, triazolyl, azepanyl, piperazinyl or morpholino, or (1S,4S)-2,5diazabicyclo[2.2 .1]heptan-2-yl, each of which is additionally optionally substituted with one or two R ^6c substituents, where R ^6c represents -NR ^6d R ^6e , -COR ^6d , -OR ^6d or -C1-8alkyl, optionally substituted with hydroxy, wherein R ^6d and R ^6e independently represent hydrogen, or -C _1-8 alkyl, or phenyl, wherein said alkyl is optionally substituted with NH2-, alkylamino or dialkylamino. 11. A compound according to claim 9, where L ² represents -CH ₂ - or -CH ₂ CH ₂ -, and R ⁶ represents pyrrolidin-1-yl, morpholino, piperidin-1-yl, 4-methylpiperazin-1- yl, piperazin-1-yl, piperidin-4yl, 4-(2-(dimethylamino)acetyl)piperazin-1-yl, (N^)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 4aminopiperidine -1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 4-phenoxypiperidin-1-yl, 1H-1,2,4-triazol1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or piperidine -3-il. 12. The connection according to claim 9, where L2-R ⁶ is selected from: a) pyrrolidin-1-ylmethyl, morpholinomethyl, piperidin-1-ylmethyl, (4-methylpiperazin-1yl)methyl, piperazin-1-ylmethyl, piperidin-4-ylmethyl, (4-(2-(dimethylamino)acetyl)piperazin- 1yl)methyl, (N^)-2,5-diazabicyclo[2.2.1]heptan-2-ylmethyl, 2-(pyrrolidin-1-yl)ethyl, (4-aminopiperidin-1-yl)methyl, (3- (dimethylamino)pyrrolidin-1-yl)methyl, (4-phenoxypiperidin-1yl)methyl, (1H-1,2,4-triazol-1-yl)methyl, (4-(3-hydroxypropyl)piperazin-1-yl )methyl or piperidin3-ylmethyl; b) aminomethyl; d) 3-(methylamino)propoxy, 3-(dimethylamino)propoxy, 3-(diethylamino)propoxy, 2-aminoethoxy, 3-(dimethylamino)-2,2-dimethylpropoxy, methoxy, 2-(methylamino)ethoxy, 2- (N-methylacetamido)ethoxy, 3-(piperidin-1-yl)propoxy, 3-morpholinopropoxy, 3-(pyrrolidin-1-yl)propoxy, 3-aminopropoxy, (III^)-8-azabicyclo[3.2.1] octan-3-yloxy, piperidin-4-yloxy, (1R,5S)-8-3th3-8-azabicyclo[3.2.1]octan-3-yloxy, 1-ethylpyrrolidin-3-yloxy or pyrrolidin-3-yloxy; or e) (2-(dimethylamino)ethyl)(methyl)amino. 13. A compound according to any one of claims 1 to 7, wherein ring A represents phenyl, and L ¹ and L2-R ⁶ are in the para positions of the phenyl ring, and said phenyl ring is further optionally substituted with one R ⁵ , where L ¹ , L ² , R ⁵ and R ⁶ are defined in paragraph 1. 14. A compound according to any one of claims 1 to 7, wherein ring A is pyridyl, and the methylene group and Het of the pyridyl ring are in the para positions of the pyridyl ring, and L ¹ and L2-R ⁶ are in the para positions of the pyridyl ring, and said pyridyl ring is further optionally substituted with one R ⁵ , where L ¹ , L ² , R ⁵ and R ⁶ are defined in claim 1. 15. A compound or a pharmaceutically acceptable salt thereof selected from: compound A1: 2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-1][1,2,4]triazin-4amine, compound A2: 2-butoxy-7-( 4-(3 -(dimethylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4amine, compound A3: 2-butoxy-7-(4-(morpholinomethyl)benzyl)imidazo[ 2,1-G][1,2,4]triazin-4-amine, compound A4: N ¹ -(5-((4-amino-2-butoxyimidazo [2,1-f][1,2,4 ]triazin-7-yl)methyl)pyridin-2-yl)N ¹ X ² ^ ² -trimethylethane-1,2-diamine, compound A5: 2-butoxy-7-(4-(piperidin-1 -ylmethyl)benzyl )imidazo [2,1-f][1,2,4]triazin-4-amine, compound A6: 2-butoxy-7-(4-((4-methylpiperazin-1 -yl)methyl)benzyl)imidazo [ 2.1- f] [1,2,4]triazin-4-amine, compound A7: 2-butoxy-7-(3 -(piperidin-1-ylmethyl)benzyl)imidazo [2,1-f][1,2,4 ]triazin-4-amine, compound A8: 2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)imidazo[2,1f] [1,2,4 ]triazin-4-amine, compound A9: 2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)imidazo[2,1 - 99 046488 f] [1,2,4]triazin-4-amine, compound A10: 2-butoxy-7-(4-(piperazin-1-ylmethyl)benzyl)imidazo [2,1-f][1,2,4 ]triazin-4-amine, compound A11: 2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-0 [1,2,4]triazin-4 amine, compound A12: 2-butoxy-7-(3-(mor(|yulinomethyl)benzyl)imidazo[2,1T][1,2,4]triazin-4-amine, compound A13: 2-butoxy-7-(3 -(( 4-methylpiperazin-1-yl)methyl)benzyl)imidazo[2,1f][1,2,4]triazin-4-amine, compound A14: 2-butoxy-7-(2-(morpholinomethyl)benzyl)imidazo[ 2,14][1,2,4]triazin-4-amine, compound A15: 2-butoxy-7-(2-(piperidin-1 -ylmethyl)benzyl)imidazo[2,1-f][1,2 ,4]triazin-4-amine, compound A16: 2-isobutoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,14] [1,2,4]triazin-4amine, compound A17: 2-(2-methoxyethoxy)-7-(3 -(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1f][1,2,4]triazin-4-amine, compound A18: 7-(3 -( pyrrolidin-1-ylmethyl)benzyl)-2-(4,4,4-trifluorobutoxy)imidazo[2,1f][1,2,4]triazin-4-amine, compound A19: 2-butoxy-7-(2 -(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,14][1,2,4]triazin-4 amine, compound A20: 2-butoxy-7-(2-fluoro-4-(pyrrolidin-1-ylmethyl )benzyl)imidazo[2,1f] [ 1,2,4]triazin-4-amine, compound A21: 2-butoxy-7-(4-(3 -(piperidin-1 -yl)propoxy)benzyl)imidazo [ 2,1-f][1,2,4]triazin4-amine, compound A22: 2-butoxy-7-(4-(3-morpholinopropoxy)benzyl)imidazo[2,1-£][1,2,4 ]triazin-4 amine, compound A23: 2-butoxy-7-(3 -(3 -(dimethylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-4 amine, compound A24 : 2-butoxy-7 -(3 -(3 -(dimethylamino)propoxy)-4-fluorobenzyl)imidazo [2,1 f] [1,2,4]triazin-4-amine, compound A25: 2-butoxy-7-((4'-(pyrrolidin-1 -ylmethyl)-[1,1'-biphenyl]-3 -yl) methyl)imidazo[2,1f][1,2,4]triazin-4-amine, compound A26: f] [1,2,4]triazin-4-amine, compound A27: f] [1,2,4]triazin-4-amine, compound A28: f] [1,2,4]triazin-4-amine, 2-butoxy-7-(2-fluoro-5-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,12-butoxy-7-(2-fluoro-5-(pyrrolidin-1-ylmethyl)benzyl)imidazo[ 2,12-butoxy-7-(4-(3 -(pyrrolidin-1-yl)propoxy)benzyl)imidazo [2,1 compound A29: 2-butoxy-7-(4-(3 -(diethylamino)propoxy)benzyl )imidazo[2,1-f][1,2,4]triazin-4 amine, compound A30: 2-butoxy-7-((4'-(pyrrolidin-1 -ylmethyl)-[1,1'-biphenyl ] -4-yl)methyl)imidazo [2,1f] [1,2,4]triazin-4-amine, compound A31: 7-(4-(3-aminopropoxy)benzyl)-2-butoxyimidazo [2,1 -f][ 1,2,4]triazin-4-amine, compound A32: 2-butoxy-7-((6-(3 -(dimethylamino)propoxy)pyridin-3-yl)methyl)imidazo [2,10 [1.2.4|triazin-4-amine. compound A3 3: 2-butoxy-7-(4-(piperidin-4-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine, compound A34: 2-butoxy- 7-((5-chloro-6-(3 -(dimethylamino)propoxy)pyridin-3 yl)methyl)imidazo[2,14][1,2,4]triazin-4-amine, compound A3 5: 2- butoxy-7 -(4-(3 -(dimethylamino)propoxy)-3-fluorobenzyl)imidazo[2,1А1,2,4]triazin-4-amine, compound A36: 2-butoxy-7 -(4-(3 -(dimethylamino)propoxy)-2-fluorobenzyl)imidazo[2,1Al,2,4]triazin-4-amine, compound A37: 7-((6-(2-aminoethoxy)pyridin-3-yl)methyl)- 2-butoxyimidazo[2,1-f][1,2,4]triazin4-amine, compound A38: 7-(4-(((N^)-8-azabicyclo[3.2.1]octan-3-yl) oxy)-2-fluorobenzyl)-2butoxyimidazo[2,1-f][1,2,4]triazin-4-amine, compound A39: 1-(4-(4-((4-amino-2-butoxyimidazo[ 2,1-£][1,2,4]triazin-7yl)methyl)benzyl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one, compound A40: 2-butoxy-7 -(( 5-chloro-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo[2,1Al,2,4]triazin-4-amine, compound A41: 7-(4-(((^^ )-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzyl)-2butoxyimidazo[2,1-f][1,2,4]triazin-4-amine, compound A42: 2-butoxy -7-(4-(2-(pyrrolidin-1 -yl)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4amine, compound A43: 7-(4-((4 -aminopiperidin-1-yl)methyl)benzyl)-2-butoxyimidazo [2,1 - 100 046488 f] [1,2,4]triazin-4-amine, compound A44: 2-butoxy-7 -(4-((3 -(dimethylamino)pyrrolidin-1-yl)methyl)benzyl)imidazo [2,1f] [1,2,4]triazin-4-amine, compound A45: 2-butoxy-7-((5-chloro-6-(3 -(dimethylamino)-2,2-dimethylpropoxy)pyridin-3 yl)methyl) imidazo[2,1-f][1,2,4]triazin-4-amine, compound A46: 7-(4-(aminomethyl)benzyl)-2-butoxyimidazo[2,1-f][1,2, 4]triazin-4-amine, compound A47: 2-butoxy-7-(4-((4-phenoxypiperidin-1-yl)methyl)benzyl)imidazo[2,1f] [1,2,4]triazin-4 -amine, compound A48: 2-((5 -methylisoxazol-3 -yl)methoxy)-7-(4 -(pyrrolidin-1 ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine -4-amine, compound A49: 2-butoxy-7-(4-(((^^)-8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-2fluorobenzyl)imidazo [2 ,1-f][1,2,4]triazin-4-amine, compound A50: 2-butoxy-7-((5-methoxypyridin-2-yl)methyl)imidazo [2,1-f][ 1, 2,4]triazin-4-amine, compound A51: 2-butoxy-7-((6-methoxypyridin-2-yl)methyl)imidazo [2,1-f][1,2,4]triazin-4- amine, compound A52: 7-(4-(pyrrolidin-1 -ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-2,4-diamine, compound A53: 2-butoxy-7 -((6-(3-(dimethylamino)-2,2-dimethylpropoxy)pyridin-3yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine, compound A54: 2- isobutoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4amine, compound A55: 2-butoxy-7-((3-methoxypyridin- 2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine, compound A56: (4-amino-2-butoxyimidazo[2,1-f][1,2, 4]triazin-7 -yl)(3-methoxypyridin-2yl)methanol, compound A57: methyl-5-((4-amino-2-butoxyimidazo[2,1-1][1,2,4]triazin-7 -yl)methyl)-2-(3(dimethylamino)propoxy)benzoate, compound A58: 2-butoxy-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)imidazo[2, 1f][1,2,4]triazin-4-amine, compound A59: No(2-((5-((4-amino-2-butoxyimidazo [2,1-f][1,2,4]triazine -7-yl)methyl)pyridin-2yl)oxy)ethyl)-N-methylacetamide, compound A60: 2-butoxy-7-(4-(( 1 -ethylpyrrolidin-3 -yl)oxy)-2-fluorobenzyl)imidazo [2,1f] [1,2,4]triazin-4-amine, compound A61: 2-butoxy-7-(2-fluoro-4-(pyrrolidin-3 -yloxy)benzyl)imidazo [2,1-f ][ 1,2,4]triazin4-amine, compound A62: 7-(4-((1H-1,2,4-triazol-1-yl)methyl)benzyl)-2-butoxyimidazo[2,1-1 ][1,2,4]triazin4-amine, compound A63: 2-butoxy-7-(4-(3 -(methylamino)propoxy)benzyl)imidazo[2,1-f][1,2,4]triazine -4amine, compound A64: N(furan-2-ylmethyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)imidazo[2.1P|1.2.4|triazin-2.4-diamine. compound A65: 4-amino-7-(4-(pyrrolidin-1 -ylmethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2-ol, compound A66: 2-butoxy-7 -(4-( 1 -methylpyrrolidin-3 -yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4amine, compound A67: N-butyl-7-(4-(pyrrolidin-1 -ylmethyl)benzyl)imidazo[2,14][1,2,4]triazin-2,4diamine, compound A68: 2-(pyridin-3 -ylmethoxy)-7 -(4-(pyrrolidin-1 -ylmethyl)benzyl )imidazo [2,1f] [1,2,4]triazin-4-amine, compound A69: 7-(4-(pyrrolidin-1-ylmethyl)benzyl)-2-(4,4,4-trifluorobutoxy)imidazo [2,1f][1,2,4]triazin-4-amine, compound A70: 7-(3-(aminomethyl)benzyl)-2-butoxyimidazo[2,14][1,2,4]triazine-4 -amine, compound A71: 3-(4-(4-((4-amino-2-butoxyimidazo[2,14][1,2,4]triazin-7yl)methyl)benzyl)piperazin-1-yl)propane -1-ol, compound A72: 2-butoxy-7-((5-methyl-6-(piperidin-4-yloxy)pyridin-3-yl)methyl)imidazo[2,1f] [1,2,4] triazin-4-amine, compound A73: (4-amino-2-butoxyimidazo[2,1-£][1,2,4]triazin-7-yl)(4-methoxypyridin-2yl)methanol, compound A74: ( 4-amino-2-butoxyimidazo[2,1-f][1,2,4]triazin-7-yl)(pyridin-2-yl)methanol, compound A7 5: 2-butoxy-7-(1 -( 4-(pyrrolidin-1 -ylmethyl)phenyl)ethyl)imidazo [2,1f] [1,2,4]triazin-4-amine, compound A76: 2-butoxy-7-((1 -(piperidine-3 - ylmethyl)-1H-pyrazol-4-yl)methyl)imidazo [2,1f] [1,2,4]triazin-4-amine, compound A77: 7-((6-(2-(methylamino)ethoxy)pyridine -3-yl)methyl)-2-(pentan-2yloxy)imidazo[2,1-f][1,2,4]triazin-4-amine, compound A78: 7-((5-methyl-6-( 2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentane-2 - 101 046488 yloxy)imidazo [2,1-f][1,2,4]triazin-4-amine, compound A79: 3 -((4-amino-7-((6-(2-(methylamino)ethoxy )pyridin-3 -yl)methyl)imidazo [2,1f] [1,2,4]triazin-2-yl)oxy)hexan-1 -ol, compound A80: 7-((6-(2-(methylamino )ethoxy)pyridin-3-yl)methyl)-2-((tetrahydrofuran-3 yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-amine, compound A81: (R or S) 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3yl)methyl)imidazo[2,1-f][1,2,4]triazin-2-yl )oxy)hexan-1-ol, compound A82: (S or R) 3-((4-amino-7-((6-(2-(methylamino)ethoxy)pyridin-3yl)methyl)imidazo [2,1 -f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A83: 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)- 2-(pentan-3yloxy)imidazo[2,14] [1,2,4]triazin-4-amine, compound A84: 2-(hexan-3-yloxy)-7 -((6-(2-(methylamino )ethoxy)pyridin-3 yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine, compound A85: 3 -((4-amino-7 -(4-(2- (methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2yl)oxy)hexan-1-ol, compound A86: 3 -((4-amino-7 -((6 -(3 -(methylamino)propoxy)pyridin-3-yl)methyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A87: 2-( heptan-4-yloxy)-7-((6-(2-(methylamino)ethoxy)pyridin-3yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine, compound A88 : 7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-((tetrahydrofuran-2yl)methoxy)imidazo[2,1-f][1,2,4]triazine -4-amine, compound A89: ^)-2-(sec-butoxy)-7 -((6-(2-(methylamino)ethoxy)pyridin-3 yl)methyl)imidazo [2,1-f][ 1 ,2,4]triazin-4-amine, compound A90: (S)-7-((6-(2-(methylamino)ethoxy)pyridin-3-yl)methyl)-2-(pentan-2yloxy)imidazo[ 2,1-1][1,2,4]triazin-4-amine, compound A91: 3 -((4-amino-7 -(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo [2,1f] [1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A92: (R or S) 3-((4-amino-7-(4-(2- (methylamino)ethoxy)benzyl)imidazo[2,1f] [1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A93: (S or R) 3-((4-amino- 7-(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A94: 3-((4 -amino-7-(4-(methyl(2-(methylamino)ethyl)amino)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A95: 3 -((4-amino-7 -(4-(2-(methylamino)ethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-2yl)oxy)hexane-1- ol, compound A96: 3-((4-amino-7-(4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1-1] [1,2,4]triazin-2yl)oxy)hexane -1-ol, compound A97: 3 -((4-amino-7-(2-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo [2,1f] [1,2,4]triazine- 2-yl)oxy)hexan-1-ol, compound A98: 3 -((4-amino-7-(3-methoxy-4-(2-(methylamino)ethoxy)benzyl)imidazo [2,1f] [1 ,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A99: (S)-7-(3-fluoro-4-(2-(methylamino)ethoxy)benzyl)-2-(pentane -2-yloxy)imidazo[2,1f][1,2,4]triazin-4-amine, compound A100: ^)-7-(4-(2-(methylamino)ethoxy)benzyl)-2-(pentane -2-yloxy)imidazo[2,1f] [1,2,4]triazin-4-amine, compound A101: (R or S)-3-((4-amino-7-(2-methoxy-4- (2-(methylamino)ethoxy)benzyl)imidazo[2,1f] [1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A102: 3 -((4-amino-7- (3-chloro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A103: (R or S)-3-((4-amino-7-(3-methyl-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f] [1,2,4]triazin-2-yl)oxy )hexan-1-ol, compound A104: (R or S)-3-((4-amino-7-(3-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f] [1,2, 4]triazin-2-yl)oxy)hexan-1-ol, compound A105: (R or S)-3-((4-amino-7-(3-fluoro-4-(2-(methylamino)ethoxy) benzyl)imidazo[2,1f] [1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A106: (S or R)-3-((4-amino-7-(3 -fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A107: (R or S) -3-((4-amino-7-(2-methyl-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f] [1,2,4]triazin-2-yl)oxy)hexane -1-ol, compound A108: (R or S)-3-((4-amino-7-(2-chloro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f] [1, 2,4]triazin-2-yl)oxy)hexan-1-ol, compound A109: (3R or S)-3-((4-amino-7-((6-((1-(methylamino)propan- 2-yl)oxy)pyridine-3 - 102 046488 yl)methyl)imidazo[2,1-0 [1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A110: (R or S)-3-((4- amino-7-(4-(3-(methylamino)propyl)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A111: (R or S)-3-((4-amino-7-(2,3-difluoro-4-(2(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazine-2- yl)oxy)hexan-1-ol, compound A112: (R or S)-3-((4-amino-7-(2,5-difluoro-4-(2(methylamino)ethoxy)benzyl)imidazo [2 ,1-f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A113: (R or S)-3-((4-amino-7-(2-methoxy- 5-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A114: (R or S)-3- ((4-amino-7-(3,5-difluoro-4-(2(methylamino)ethoxy)benzyl)imidazo[2,1-f][1,2,4]triazin-2-yl)oxy)hexane -1-ol, compound A115: (R or S)-3-((4-amino-7-(2-fluoro-4-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f] [1, 2,4]triazin-2-yl)oxy)hexan-1-ol, compound A116: (R or S)-3-((4-amino-7-(3-methoxy-5-(2-(methylamino) ethoxy)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A117: (R or S)-3-((4-amino-7- (4-methoxy-3-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A118: (R or S)-3-((4-amino-7-(2-methoxy-3-(2-(methylamino)ethoxy)benzyl)imidazo[2,1f] [1,2,4]triazin-2-yl)oxy )hexan-1-ol, compound A119: (R or S)-3-((4-amino-7-(4-(2-(methylamino)ethyl)benzyl)imidazo[2,1f] [1,2, 4]triazin-2-yl)oxy)hexan-1-ol, compound A120: (S or R)-3-((4-amino-7-(4-(2-(methylamino)ethyl)benzyl)imidazo[ 2.1- f] [1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A121: (R or S)-3-((4-amino-7-(2-ethoxy-4-( 2-(methylamino)ethoxy)benzyl)imidazo[2,1f][1,2,4]triazin-2-yl)oxy)hexan-1-ol, compound A122: (R or S)-3-((4 -amino-7-((6-(2-(methylamino)propoxy)pyridin-3yl)methyl)imidazo[2,1-1][1,2,4]triazin-2-yl)oxy)hexane-1- ol, compound A123: (R or S)-3-((4-amino-7-(2,6-difluoro-4-(2(methylamino)ethoxy)benzyl)imidazo [2,1-f][ 1, 2,4]triazin-2-yl)oxy)hexan-1-ol, or compound A124: (R or S)-3-((4-amino-7-((4-(2-(methylamino)ethoxy) naphthalen-1yl)methyl)imidazo[2,1-1][1,2,4]triazin-2-yl)oxy)hexan-1-ol. 16. A pharmaceutical composition containing a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient. 17. A method of modulating TLR7 (Toll-like receptor 7), comprising administering to an individual a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof. 18. A method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as a TLR7 agonist. 19. The method of claim 18, wherein the disease or disorder is melanoma, non-small cell lung carcinoma, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD (chronic obstructive pulmonary disease), ulcerative colitis, liver fibrosis, HBV (hepatitis B virus), HCV (hepatitis C virus), HPV (human papillomavirus), RSV (respiratory syncytial virus), SARS (severe acute respiratory syndrome), HIV (human immunodeficiency virus) or influenza.