Inhibitors of cyclin-dependent kinase

Abstract

Provided herein are inhibitors of CDK2 / 4 / 6 kinase, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said CDK2 / 4 / 6 kinase inhibitory compounds for the treatment of disease.

Description

WSGR Ref: 54004-768.601 INHIBITORS OF CYCLIN-DEPENDENT KINASE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Patent Application No.63 / 515,795, filed on July 26, 2023; US Patent Application No.63 / 595,916, filed on November 3, 2023; and US Patent Application No.63 / 613,595, filed on December 21, 2023, each of which is hereby incorporated by reference in its entirety. BACKGROUND

[0002] Cyclin-dependent kinases (CDKs) are a conserved family of proline-directed serine / threonine kinases that perform critical roles in the regulation of cell division and proliferation. Dysregulation of CDK2, CDK4 and CDK6 (CDK2 / 4 / 6) has been demonstrated to be a key driver of many cancers, and inhibition of CDK2 / 4 / 6 has become a validated treatment modality in some disease, such as breast cancer. Accordingly, therapies that target CDK2 / 4 / 6 kinase activity are desired for use in the treatment of cancer and other disorders characterized by aberrant CDK2 / 4 / 6 pathway signaling. BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are inhibitors of CDK2 / 4 / 6 kinase, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said inhibitory compounds for the treatment of disease.

[0004] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein, R1is selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, C3-C4 optionally substituted cycloalkyl, or optionally substituted C2-C8 alkynyl; R3is selected from L-G, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C3-C10 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl;WSGR Ref: 54004-768.601 L is selected from -O-, -NR10-, an optionally substituted arylene or optionally substituted heteroarylene; G is selected from an optionally substituted C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl; R5is selected from hydrogen, halogen, -OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy; R6is selected from hydrogen or halogen; or optionally, R5and R6together form an oxo; each R7is independently selected from hydrogen or halogen; X is -O-, -S-, -SO2-, -P(=O)-, N-R8, CH2, CF2, or C-SO2-R9; R8is selected from hydrogen, -SO2R9, SO(=NR9)R9, -COR9, -CO2R9, -CONHR9, - CON(R9)2, or P(=O)(R11)2; each R9is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl alkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; R10is selected from hydrogen or optionally substituted C1-C6 alkyl; and R11is optionally substituted C1-C6 alkyl; provided that the compound of Formula (I) is not:.

[0005] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):wherein, R1is selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, C3-C4 optionally substituted cycloalkyl, or optionally substituted C2-C8 alkynyl;WSGR Ref: 54004-768.601 R3is selected from L-G, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; L is selected from -O-, -NR10-, an optionally substituted arylene or optionally substituted heteroarylene; G is selected from an optionally substituted C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl; R5is selected from hydrogen, halogen, -OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy; R6is selected from hydrogen or halogen; or optionally, R5and R6together form an oxo; each R7is independently selected from hydrogen or halogen; X is -O-, -S-, -SO2-, -P(=O)-, N-R8, CH2, CF2, or C-SO2-R9; R8is selected from hydrogen, -SO2R9, SO(=NR9)R9, -COR9, -CO2R9, -CONHR9, - CON(R9)2, or P(=O)(R11)2; each R9is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl alkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; R10is selected from hydrogen or optionally substituted C1-C6 alkyl; and R11is optionally substituted C1-C6 alkyl; provided that the compound of Formula (Ia) is not:.

[0006] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0007] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), or pharmaceuticallyWSGR Ref: 54004-768.601 acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figures 1-46 provides a structure of a CDK2 / 4 / 6 inhibitory compound as described herein. INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0010] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of" or "consist essentially of" the described features. Definitions

[0011] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0012] "Amino" refers to the –NH2radical.

[0013] "Cyano" refers to the -CN radical.

[0014] "Nitro" refers to the -NO2radical.

[0015] "Oxa" refers to the -O- radical.

[0016] "Oxo" refers to the =O radical.

[0017] "Thioxo" refers to the =S radical.

[0018] "Imino" refers to the =N-H radical.

[0019] "Oximo" refers to the =N-OH radical.WSGR Ref: 54004-768.601

[0020] "Hydrazino" refers to the =N-NH2 radical.

[0021] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1- C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.WSGR Ref: 54004-768.601

[0022] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.

[0023] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0024] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy,WSGR Ref: 54004-768.601 methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylWSGR Ref: 54004-768.601 (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to theWSGR Ref: 54004-768.601 radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0028] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, - Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-WSGR Ref: 54004-768.601 N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0029] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0030] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0031] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0032] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0033] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes spiro, fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five toWSGR Ref: 54004-768.601 seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb- N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0034] "Carbocyclylalkyl" refers to a radical of the formula –Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0035] "Carbocyclylalkynyl" refers to a radical of the formula –Rc-carbocyclyl where Rcis an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.WSGR Ref: 54004-768.601

[0036] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O- Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0038] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0039] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, - Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionallyWSGR Ref: 54004-768.601 substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0040] "N-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0041] "C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0042] "Heterocyclylalkyl" refers to a radical of the formula –Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0043] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O- Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0044] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance withWSGR Ref: 54004-768.601 the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb- OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb- O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), - Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen,WSGR Ref: 54004-768.601 hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0045] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0047] "Heteroarylalkyl" refers to a radical of the formula –Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0048] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O- Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0049] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated byWSGR Ref: 54004-768.601 this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0050] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0051] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0052] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium,WSGR Ref: 54004-768.601 or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0053] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O, 17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0054] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0055] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0056] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0057] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3(CD3I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.WSGR Ref: 54004-768.601

[0058] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4is illustrated, by way of example only, in the reaction schemes below.

[0059] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0060] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0061] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the CDK2 / 4 / 6 kinase inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0062] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphaticWSGR Ref: 54004-768.601 mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1- 19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0063] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0064] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formedWSGR Ref: 54004-768.601 when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0065] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0066] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. CDK2 / 4 / 6 Kinase

[0067] Cyclin-dependent kinases (CDKs) are a conserved family of proline-directed serine / threonine kinases that perform critical roles in the regulation of cell division and proliferation. CDKs are members of the CMGC kinase family, which encompasses 63 family members including mitogen-activated protein kinase (MAPK), glycogen synthase kinase (GSK) and CDC-like kinase (CLK). The activity of CDKs is regulated through phosphorylation by interaction with cyclin proteins and other upstream kinases such as CDK-activating kinases (CAKs). At least 21 CDKs have been identified to date, including CDK1, 2, 4, and 6 (which regulate the transition of the cell cycle steps), CDK7, 8, 9, 12 and 13 (which regulate gene transcription through phosphorylation of the heptad repeats that comprise the C-terminal tail of RNA polymerase II), and CDK3 (which regulates the transition from G0 (quiescence) into G1 phase of cell division). CDKs regulate the transition between the four distinct phases of the eukaryotic cell cycle, i.e., the G1, S (DNA synthesis), G2 and M phases. Furthermore, CDKs are implicated in the progression of many different types of cancer. In particular, dysregulation of CDK2, CDK4 and CDK6 (CDK2 / 4 / 6) has been demonstrated to be a key driver of many cancers, and inhibition of CDK2 / 4 / 6 has become a validated treatment modality in some disease, such as breast cancer.WSGR Ref: 54004-768.601

[0068] Structurally, CDK4 and 6 have a bilobal structure typically seen in other kinases, comprising a 5-stranded β-sheet on the N-terminal side of the protein and a predominantly helical C-terminal domain The ATP binding site is located in the cleft between the domains. Although a structure for a CDK6 with its primary cyclin partner (cyclin D) has not yet been determined, the crystal structure of CDK6 bound to a viral cyclin has been solved and provides some structural insight to the function of CDK6. Furthermore, the structures of non-phosphorylated and phosphorylated CDK4 bound to cyclin D3 or cyclin D1 have been solved. The kinase binding sites of CDK4 and 6 are highly conserved and the structural similarity between these kinases is likely the reason that highly selective ATP-competitive inhibitors of both CDK4 and CDK6 (CDK4 / 6 inhibitors) have been developed.

[0069] CDK4 and CDK6 associate with the D-type cyclins, activating the CDK4 / 6 and causing them to phosphorylate and inactivate the retinoblastoma (Rb) protein family members. Cyclin D possesses a tertiary structure that is common to other cyclins, known as the cyclin fold. The cyclin fold contains a core of two compact domains, with each domain having five alpha helices. The first five-helix bundle is a conserved cyclin box, a region of about 100 amino acid residues shared by all cyclins. The cyclin box functions by binding to and activating CDKs. The second five-helix bundle is composed of the same arrangement of helices but comprises several differences in the primary sequence. All three D-type cyclins (D1, D2, D3) share a common alpha 1 helix hydrophobic patch, and each of these D-type cyclins bind to and activate CDK4 and 6, leading to cell cycle progression. Cell Cycle

[0070] The eukaryotic cell division cycle is divided into two basic parts: mitosis and interphase. Mitosis (nuclear division) corresponds to the separation of daughter chromosomes and usually ends with cell division (cytokinesis). The period between mitoses is interphase, which generally accounts for approximately 95% of the cell cycle time (e.g., 23 hours of a 24-hour cycle). During interphase, the chromosomes are decondensed and distributed throughout the nucleus, and the cell prepares itself for mitosis by regulating both cell growth and DNA replication. The cell grows at a steady rate throughout interphase, with most dividing cells doubling in size between mitosis cycles. In contrast, DNA is synthesized during only a relatively short portion of interphase.

[0071] The timing of the cycle of eukaryotic cells into four discrete phases based on DNA synthesis and cell division. The M phase of the cycle corresponds to mitosis, which is usually followed by cytokinesis (cell division). This phase is followed by the G1 phase (gap 1), which corresponds to the interval between mitosis and initiation of DNA synthesis. During G1, the cell is metabolically active and continuously grows but does not replicate its DNA. Following G1, theWSGR Ref: 54004-768.601 cell enters the S phase (synthesis phase), during which DNA replication takes place. After completion of DNA synthesis, the cell contains two identical chromosome sets and enters the G2 phase (gap 2) of cell division. During the G2 phase, the cell continues to grow, and proteins are synthesized in preparation for the next round of mitosis (i.e., the next M cycle).

[0072] In some cell types, including many embryonic cells, cell division is perpetual and the cells continuously cycle between the M, G1, S, and G2 phases. In contrast, many cells in adult animals either cease division altogether (e.g., nerve cells) and or divide only as needed to replace cells that have been lost due to injury. Such intermittently dividing cells include skin fibroblasts and cells of many internal organs, including the liver, kidney, and lung. Such cells exit G1 to enter a quiescent stage of the cycle called G0, where they remain metabolically active but no longer proliferate unless called on to do so by appropriate extracellular signals, such as those resulting from an injury to the local tissue. However, in cancer, a relatively large subpopulation of the cells remain cycling through the four phases of cell division, driving tumor proliferation and disease progression.

[0073] To enter the cell cycle, a cell must progress from G1 to S phase via a restriction point, and most cells will only do so in the presence of the appropriate growth factors. Once the cell has passed through the restriction point, the cell is committed to proceed through S phase and the rest of the cell cycle, even in the absence of further growth factor stimulation. However, if appropriate growth factors are not available in G1, progression through the cell cycle generally stops at the restriction point, and the cell will enter G0 (the quiescent stage) until a signal is received to resume cell division. The transition from G1 to S phase is mediated in part by the retinoblastoma protein (RB), which is usually regulated through a delicate balance of pro- and anti-mitotic signals. In healthy cells, the balance of pro- and anti-mitotic signals is tightly regulated, and specific mitogenic signals (e.g., growth factors) are necessary for normal cells to enter the cell division cycle. Cell Signaling Networks

[0074] CDK4 and 6 are directly involved with mediating the transition from the G1 to S phase, with activated CDK4 / 6 initiating a downstream pathway that advances the cell into the S phase of cell division. According to the “classical” cell cycle model, the G1 / S transition begins in early G1 when the balance between mitogenic stimulation (via growth factor receptor activation) and inhibition tips in favor of the former, triggering an increase in the levels of D-type cyclins (Dl, D2, and D3). The expression level of the D type cyclins is controlled by growth factor signaling, with transcription, turnover and nuclear transport of D type cyclins all dependent on this signaling. D-type cyclins bind to CDK4 or CDK6, and the cyclin-CDK complexesWSGR Ref: 54004-768.601 subsequently enter the nucleus where the cyclin-CDK complexes are phosphorylated by the CDK-activating kinase (CAK) complex.

[0075] Once activated, CDK4 / 6 complexes phosphorylate the retinoblastoma (RB) tumor suppressor protein, as well as the related p107 and p130 proteins. RB phosphorylation by CDK4 / 6 partially inhibits activity of the E2F family of transcription factors, which, in turn, increases the expression of E2F target genes including those for the E-type cyclins (cyclins E1 and E2). Cyclin E then binds to and activates CDK2, which hyper-phosphorylates RB. Hyper- phosphorylation of RB further increases the expression of E2F target genes, which are critical for initiation of DNA synthesis and entry into S-phase. This creates a positive feedback loop, as the E2Fs promote transcription of the E type cyclins, activating CDK2 and other proteins important for initiation of S phase and DNA synthesis.

[0076] Regulation of CDK4 / 6 is primarily achieved by two families of endogenous inhibitory proteins. The first is the INK4 family, comprising the p16INK4A, p15INK4B, p18INK4C, and p19INK4D proteins, which bind to CDKs 4 and 6, forming binary complexes that lack kinase activity. The second is the CIP / KIP family, which includes p27KIP1, p21CIP1, and p57KIP2. These proteins bind to a variety of CDKs having more diverse functions, potently inhibiting a number of CDKs (including CDK4 / 6, CDK2, and CDK1). However, in some circumstances, these proteins bind to and stabilize the cyclin D-CDK4 / 6 holoenzyme. These divergent functions may be regulated by the extent of phosphorylation of the CIP / KIP proteins. Prior Art CDK2 / 4 / 6 Kinase Inhibitors

[0077] Several CDK inhibitors have been developed and tested in many different types of cancer. The first generation of CDK inhibitors, including flavopiridol (inhibitor of at least CDKs 1, 2, 4, and 9 inhibitor) and roscovitine (inhibitor of at least CDKs 1, 2, 5, 7, and 9), were pan inhibitors that acted on several kinases. These first-generation CDK inhibitors has limited clinical success due to an inadequate balance between efficacy and toxicity. The second generation of inhibitors, such as dinaciclib (inhibitor of CDKs 1, 2, 5, and 9) were developed with the aim to increase potency and selectivity for CDKs over other kinases. However, these compounds demonstrated limited efficacy and considerable toxicity in clinical studies. The toxicity of these compounds results from their broad-spectrum activity against numerous CDK isoforms, including CDK1 and CDK9, which are required for the proliferation (CDK1) and survival (CDK9) of normal cells. More recently, selective CDK2 / 4 / 6 inhibitors have been developed, which exhibit more targeted action on tumor cells and reduced toxicity. This third generation of CDK inhibitors selectively inhibit CDK4 and CDK6 with potent efficacy and reduced toxicity, selectively binding to the CDK2 / 4 / 6 ATP-binding pockets.WSGR Ref: 54004-768.601

[0078] To date, three CDK2 / 4 / 6 inhibitors have received FDA approval: palbociclib, ribociclib, and abemaciclib. Palbociclib (Ibrance®) received accelerated FDA approval in 2015 in combination with letrozole for the treatment of estrogen receptor positive (ER+) advanced breast cancer. In 2017, palbociclib in combination with an aromatase inhibitor received full FDA approval for use in hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic breast cancer. Ribociclib (Kisqali ®) was approved in 2017 for use in combination with an aromatase inhibitor (such as letrozole) to treat HR-positive, HER2-negative advanced or metastatic breast cancers. Abemaciclib (Verzenio®) was FDA approved in 2017 for use as a monotherapy or in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- negative advanced or metastatic breast cancer with disease progression following endocrine therapy. In 2018 abemaciclib received a second approval for use in combination with an aromatase inhibitor as an initial endocrine based therapy for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. More recently, in 2021, abemaciclib was approved in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer.

[0079] The development of selective CDK2 / 4 / 6 inhibitor agents has radically changed the approach to managing this disease hormone receptor-positive, HER2-negative advanced breast cancer, approximately doubling the progression-free survival (PFS) for most patients. However, resistance to CDK2 / 4 / 6 inhibitors is considered to be nearly inevitable in most patients. Although mechanisms of resistance to these agents are multifactorial and research in this field is ongoing, several mechanisms of resistance to CDK2 / 4 / 6 inhibitors have been identified to date.

[0080] First, overexpression of CDK6 (and potentially CDK4) is a major mechanism of resistance to CDK2 / 4 / 6 inhibitors. Studies in human cell lines have shown that increased expression of CDK6 reduced the response of CDK2 / 4 / 6 inhibitors, and subsequent knockdown of CDK6 rescued the therapy sensitivity, indicating that CDK6-mediated drug resistance may be independent of CDK4 expression. However, both increased and decreased expression of CDK4 has been detected in CDK4 / 6 inhibitor–resistant breast cancer cells, indicating that the role of CDK4 expression in CDK4 / 6 inhibitor resistance requires further investigation. Second, loss of Rb has been implicated as a driver of resistance to CDK4 / 6 inhibitors in several preclinical studies. Without the inhibitory influence of Rb, transcription factors of the E2F family continue unchecked, thus facilitating unregulated cellular progression to S-phase entry independently of CDK4 / 6 activity. Acquired CDK4 / 6 inhibitor resistance due to RB1 mutations has beenWSGR Ref: 54004-768.601 identified in several patients treated with CDK 4 / 6 inhibitors. Third, decrease in cyclin D1 expression can lead to CDK4 / 6 inhibitor resistance. Cyclin D1 expression is regulated by the estrogen receptor (ER), and decreased ER expression results in reduced expression of cyclin D1. In preclinical trials, resistance to abemaciclib was associated with the loss of cyclin D1 and concomitant loss of ER / PR expression. Resistance in these patients may be related to the decrease in cyclin D1 due to the loss of ER. Additional possible mechanisms of action include overexpression of Brk (breast tumor-related kinase), overexpression of the E2F2 transcription factor, and overexpression of cyclins E1 or E2. Thus, there exists a need for a new generation of CDK inhibitors that are not susceptible to one or more of these resistance mechanisms and provide longer progression-free survival. CDK2 / 4 / 6 Kinase Inhibitory Compounds

[0081] In one aspect, provided herein is a CDK2 / 4 / 6 inhibitory compound. In another aspect, provided herein is a selective CDK2 inhibitory compound. In another aspect, provided herein is a selective CDK4 inhibitory compound. In another aspect, provided herein is a selective CDK6 inhibitory compound. In another aspect, provided herein is a selective CDK2 / 4 / 6 inhibitory compound.

[0082] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein, R1is selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, C3-C4 optionally substituted cycloalkyl, or optionally substituted C2-C8 alkynyl; R3is selected from L-G, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C3-C10 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; L is selected from -O-, -NR10-, an optionally substituted arylene or optionally substituted heteroarylene;WSGR Ref: 54004-768.601 G is selected from an optionally substituted C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl; R5is selected from hydrogen, halogen, -OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy; R6is selected from hydrogen or halogen; or optionally, R5and R6together form an oxo; each R7is independently selected from hydrogen or halogen; X is -O-, -S-, -SO2-, -P(=O)-, N-R8, CH2, CF2, or C-SO2-R9; R8is selected from hydrogen, -SO2R9, SO(=NR9)R9, -COR9, -CO2R9, -CONHR9, - CON(R9)2, or P(=O)(R11)2; each R9is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl alkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; R10is selected from hydrogen or optionally substituted C1-C6 alkyl; and R11is optionally substituted C1-C6 alkyl; provided that the compound of Formula (I) is not:.

[0083] One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):wherein, R1is selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, C3-C4 optionally substituted cycloalkyl, or optionally substituted C2-C8 alkynyl; R3is selected from L-G, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl,WSGR Ref: 54004-768.601 optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; L is selected from -O-, -NR10-, an optionally substituted arylene or optionally substituted heteroarylene; G is selected from an optionally substituted C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl; R5is selected from hydrogen, halogen, -OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy; R6is selected from hydrogen or halogen; or optionally, R5and R6together form an oxo; each R7is independently selected from hydrogen or halogen; X is -O-, -S-, -SO2-, -P(=O)-, N-R8, CH2, CF2, or C-SO2-R9; R8is selected from hydrogen, -SO2R9, SO(=NR9)R9, -COR9, -CO2R9, -CONHR9, - CON(R9)2, or P(=O)(R11)2; each R9is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl alkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; R10is selected from hydrogen or optionally substituted C1-C6 alkyl; and R11is optionally substituted C1-C6 alkyl; provided that the compound of Formula (Ia) is not:.

[0084] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, provided that if R3is phenyl, then at least one of R5, R6and R7are not hydrogen.

[0085] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, provided that if all of R5, R6and each R7are hydrogen, and X is -CH2- or -O-, then R3is not phenyl.

[0086] One embodiment provides a CDK2 / 4 / 6 kinase inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.WSGR Ref: 54004-768.601 Table 1WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601WSGR Ref: 54004-768.601

[0087] Another embodiment provides a CDK2 / 4 / 6 kinase inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in any one of Figures 1-46. Numbered Embodiments Embodiment 1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):WSGR Ref: 54004-768.601wherein, R1is selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, C3-C4 optionally substituted cycloalkyl, or optionally substituted C2-C8 alkynyl; R3is selected from L-G, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C3-C10 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; L is selected from -O-, -NR10-, an optionally substituted arylene or optionally substituted heteroarylene; G is selected from an optionally substituted C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl; R5is selected from hydrogen, halogen, -OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy; R6is selected from hydrogen or halogen; or optionally, R5and R6together form an oxo; each R7is independently selected from hydrogen or halogen; X is -O-, -S-, -SO2-, -P(=O)-, N-R8, CH2, CF2, or C-SO2-R9; R8is selected from hydrogen, -SO2R9, SO(=NR9)R9, -COR9, -CO2R9, -CONHR9, - CON(R9)2, or P(=O)(R11)2; each R9is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl alkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; R10is selected from hydrogen or optionally substituted C1-C6 alkyl; and R11is optionally substituted C1-C6 alkyl; provided that the compound of Formula (I) is not:WSGR Ref: 54004-768.601. Embodiment 2. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):wherein, R1is selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, C3-C4 optionally substituted cycloalkyl, or optionally substituted C2-C8 alkynyl; R3is selected from L-G, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; L is selected from -O-, -NR10-, an optionally substituted arylene or optionally substituted heteroarylene; G is selected from an optionally substituted C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl; R5is selected from hydrogen, halogen, -OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy; R6is selected from hydrogen or halogen; or optionally, R5and R6together form an oxo; each R7is independently selected from hydrogen or halogen; X is -O-, -S-, -SO2-, -P(=O)-, N-R8, CH2, CF2, or C-SO2-R9; R8is selected from hydrogen, -SO2R9, SO(=NR9)R9, -COR9, -CO2R9, -CONHR9, - CON(R9)2, or P(=O)(R11)2; each R9is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl,WSGR Ref: 54004-768.601 optionally substituted heteroaryl, optionally substituted carbocyclyl alkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; R10is selected from hydrogen or optionally substituted C1-C6 alkyl; and R11is optionally substituted C1-C6 alkyl; provided that the compound of Formula (Ia) is not:. Embodiment 3. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the stereochemistry indicated in Formula (Ib):Embodiment 4. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the stereochemistry indicated in Formula (Ic):Embodiment 5. The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-. Embodiment 6. The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N-R8.WSGR Ref: 54004-768.601 Embodiment 7. The compound of embodiment 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is -SO2R9. Embodiment 8. The compound of embodiment 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is -P(=O)(R11)2. Embodiment 9. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen. Embodiment 10. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. Embodiment 11. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is fluoro. Embodiment 12. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is chloro. Embodiment 13. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted C1-C4 alkyl. Embodiment 14. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted C1 alkyl. Embodiment 15. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1 alkyl substituted with at least one fluoro. Embodiment 16. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted C1-C8 alkyl. Embodiment 17. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted C3-C7 carbocyclyl. Embodiment 18. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heterocyclyl. Embodiment 19. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aryl.WSGR Ref: 54004-768.601 Embodiment 20. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heteroaryl. Embodiment 21. The compound of embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted pyridine. Embodiment 22. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted carbocyclylalkyl. Embodiment 23. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heterocyclylalkyl. Embodiment 24. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aralkyl. Embodiment 25. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heteroaralkyl. Embodiment 26. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from L-G. Embodiment 27. The compound of embodiment 26, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -O-; and G is optionally substituted C1-C8 alkyl. Embodiment 28. The compound of any one of embodiments 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each R7is hydrogen. Embodiment 29. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen. Embodiment 30. The compound of any one of embodiments 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen. Embodiment 31. The compound of embodiment 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen. Embodiment 32. The compound of embodiment 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen.WSGR Ref: 54004-768.601 Embodiment 33. The compound of embodiment 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is -OH. Embodiment 34. The compound of embodiment 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is fluoro. Embodiment 35. The compound of embodiment 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is -OH. Embodiment 36. The compound of embodiment 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is fluoro. Embodiment 37. A compound, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1. Embodiment 38. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of embodiments 1-37 and a pharmaceutically acceptable excipient. Embodiment 39. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of embodiments 1- 37, and a pharmaceutically acceptable carrier. Embodiment 40. A compound of any one of embodiments 1-37, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. Embodiment 41. A compound of any one of embodiments 1-37, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. Embodiment 42. Use of a compound of any one of embodiments 1-37, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. Embodiment 43. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of embodiments 1-37, or pharmaceutically acceptable salt or solvate thereof. Embodiment 44. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as describedWSGR Ref: 54004-768.601 in any one of embodiments 1-37, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. Embodiment 45. The use of embodiments 41 or 42, or the method of embodiments 43 or 44, wherein the cancer is selected from breast cancer, skin cancer, melanoma, or leukemia. Embodiment 46. A method of inhibiting a CDK2, CDK4, or CDK6 kinase enzyme comprising contacting the enzyme with a compound of any one of embodiments 1-37, wherein the CDK2, CDK4 or CDK6 kinase is contacted in an in vitro setting. Embodiment 47. A method of inhibiting a CDK2, CDK4, or CDK6 kinase enzyme comprising contacting the enzyme with a compound of any one of embodiments 1-37, wherein the CDK2, CDK4, or CDK6 kinase is contacted in an in vivo setting. Preparation of Compounds

[0088] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0089] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley &WSGR Ref: 54004-768.601 Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0090] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. General Synthetic SchemesWSGR Ref: 54004-768.601 SCHEME 1

[0091] One common route for 5-chloro analogs is illustrated in Scheme 1. In the presence of acid 2 and a coupling reagent such as HATU, amine hydrochloride 1 can be converted to corresponding amide 3, which can be treated with POCl3 to afford ring-closed intermediate 4. Chlorination followed by oxidation then generates sulfoxide 6, which when treated with an appropriate amine 7, like tert-butyl (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate, in the presence of a base, such as DIEA, affords compound 8. Removal of the Boc group of compound 8 is accomplished with HCl in DCM, subsequent sulfonylation with a suitably substituted sulfonic anhydride in the presence of a base, such as sodium bicarbonate, affords compound 9. Alternatively, intermediate 4 is treated with m-CPBA in DCM to afford sulfoxide 10. Compound 11 is generated through substitution with corresponding amine 7 in the presence of DIEA. Chlorination with NCS in DMF affords compound 8.WSGR Ref: 54004-768.601 SCHEME 2

[0092] One common route for 5-Me / CF3analogs is illustrated in Scheme 2. Protection of hydroxyl in compound 11 is accomplished with Ac2O in DCM and a base such as TEA to afford compound 12, which is treated with NBS to afford bromide 13, followed by palladium mediated cross- coupling with a corresponding boronic acid to generate compound 15. Removal of the Boc group is accomplished with HCl in DCM, subsequent sulfonylation with a suitably substituted sulfonic anhydride in the presence of a base such as sodium bicarbonate affords compound 16. De-protection of Ac generated compound 17. Similarly, compound 12 is treated with NIS to afford iodide 18, which is converted to CF3compound 20 by copper mediated cross-coupling with reagent 19. Removal of the Boc group followed by sulfonylation and de-protection of Ac affords CF3 compound 22.

[0093] Using the methods described in Scheme 1 and Scheme 2, the CDK2 / 4 / 6 inhibitory compound described herein, or a pharmaceutically acceptable salt or solvate thereof, may be prepared. Pharmaceutical Compositions

[0094] In certain embodiments, the CDK2 / 4 / 6 kinase inhibitory compound described herein is administered as a pure chemical. In other embodiments, the CDK2 / 4 / 6 kinase inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described,WSGR Ref: 54004-768.601 for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0095] Provided herein is a pharmaceutical composition comprising at least one CDK2 / 4 / 6 kinase inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0096] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (Ia), Table 1, or Figures 1-46, or a pharmaceutically acceptable salt or solvate thereof.

[0097] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), (Ia), Table 1, or Figures 1-46, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0098] In certain embodiments, the CDK2 / 4 / 6 kinase inhibitory compound as described by Formula (I), (Ia), Table 1, or Figures 1-46, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0099] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0100] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0101] In certain embodiments, the CDK2 / 4 / 6 kinase inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0102] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodiumWSGR Ref: 54004-768.601 saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0103] In some embodiments, the CDK2 / 4 / 6 kinase inhibitory compound as described by Formula (I), (Ia), Table 1, or Figures 1-46, or a pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0104] The dose of the composition comprising at least one CDK2 / 4 / 6 kinase inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0105] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0106] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Methods of Treatment

[0107] One embodiment provides a compound of Formula (I), (Ia), Table 1, or Figures 1-46, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0108] One embodiment provides a compound of Formula (I), (Ia), Table 1, or Figures 1-46, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0109] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (Ia), Table 1, or Figures 1-46, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.WSGR Ref: 54004-768.601

[0110] One embodiment provides a use of a compound of Formula (I), (Ia), Table 1, or Figures 1-46, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0111] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (Ia), Table 1, or Figures 1- 46, or a pharmaceutically acceptable salt or solvate thereof.

[0112] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), (Ia), Table 1, or Figures 1-46, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0113] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0114] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0115] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0116] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0117] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0118] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is leukemia.

[0119] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0120] One embodiment provides a method of inhibiting a CDK2 / 4 / 6 kinase comprising contacting the CDK2 / 4 / 6 kinase with a compound of Formula (I), (Ia), Table 1, or Figures 1-46. Another embodiment provides the method of inhibiting a CDK2 / 4 / 6 kinase, wherein the CDK2 / 4 / 6WSGR Ref: 54004-768.601 kinase is contacted in an in vivo setting. Another embodiment provides the method of inhibiting a CDK2 / 4 / 6 kinase, wherein the CDK2 / 4 / 6 kinase is contacted in an in vitro setting.

[0121] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. EXAMPLES I. Chemical Synthesis

[0122] In some embodiments, the CDK2 / 4 / 6 kinase inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: oC degrees Celsius δHchemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate ESI electrospray ionization Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertz J coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry μ micro m multiplet (spectral); meter(s); milli M molar M+parent molecular ion Me methyl MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliterWSGR Ref: 54004-768.601 MS mass spectrometry nm nanometer(s) NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether RT room temperature s singlet (spectral) t triplet (spectral) T temperature TFA trifluoroacetic acid THF tetrahydrofuran

[0123] Common intermediates are provided below in Table 2: Table 2WSGR Ref: 54004-768.601

[0124] Common intermediate 1: 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochloride Step 1: tert-butyl N-[2-(1,3-dithian-2-yl)-2-oxoethyl]carbamateWSGR Ref: 54004-768.601 To a solution of 1,3-dithiane (397 g, 3298.92 mmol) in THF (2 L) was added n-BuLi in hexanes (1.25 L, 2.5 M, 3115.65 mmol) dropwise with stirring at room temperature under N2atmosphere. After 30 min, to this was added tert-butyl N- {[methoxy(methyl)carbamoyl]methyl}carbamate (200 g, 916.37 mmol) in THF (2 L) at -78 °C. The resulting solution was then warmed to around -10 °C over 2 h, then was poured into a stirred mixture of ethyl ether (10 L) and sodium dihydrogen phosphate (5 L, 1 M in water). The organic layer was washed with sodium dihydrogen phosphate (2 x 1 L, 1 M in water) and brine (1 L), then dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5 / 1) to afford tert-butyl N-[2-(1,3-dithian-2-yl)-2-oxoethyl]carbamate (171 g, 67%) as a yellow solid. MS ESI calculated for C11H19NO3S2 [M + H]+, 278.08, no MS signal;1H NMR (400 MHz, Chloroform-d) δ 5.16 (s, 1H), 4.34-4.25 (m, 2H), 4.24 (s, 1H), 3.33-3.21 (m, 2H), 2.66-2.55 (m, 2H), 2.21-1.96 (m, 2H), 1.48 (s, 9H). Step 2: tert-butyl N-[(2Z)-2-[(carbamothioylamino)imino]-2-(1,3-dithian-2-yl)ethyl]carbamate A solution of tert-butyl N-[2-(1,3-dithian-2-yl)-2-oxoethyl]carbamate (171 g, 616.44 mmol), thiosemicarbazide (61.8 g, 678.08 mmol) and TsOH (4.25 g, 24.66 mmol) in EtOH (1.8 L) was stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure then diluted with Et2O (1.5 L). The solid was filtered out and washed with Et2O (3 x 200 mL). The combined filtrate was dried under reduced pressure to afford tert-butyl N-[(2Z)-2- [(carbamothioylamino)imino]-2-(1,3-dithian-2-yl)ethyl]carbamate (190 g, crude) as a yellow solid which was used for next step without any further purification. MS ESI calculated for C12H22N4O2S3[M + H]+, 351.09 found 351.10. Step 3: tert-butyl N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}carbamate To a solution of tert-butyl N-[(2Z)-2-[(carbamothioylamino)imino]-2-(1,3-dithian-2- yl)ethyl]carbamate (50 g, 142.65 mmol) in acetone (900 mL) and H2O (110 mL) was added CaCO3(42.8 g, 427.95 mmol), followed by methyl iodide (202.5 g, 1426.49 mmol). The resulting mixture was stirred for 16 h at 40 °C. The reaction was quenched by the addition of water (1 L) at room temperature. The resulting mixture was extracted with EtOAc (2 x 700 mL). The combined organic layers were washed with brine (2 x 600 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford tert-butyl N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}carbamate (7 g, 19%) as a yellow solid. MS ESI calculated for C10H16N4O2S [M + H]+, 257.10 found 257.10;1H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H), 5.38 (brs, 1H), 4.59 (d, J = 6.0 Hz, 2H), 2.69 (s, 3H), 1.48 (s, 9H). Step 4: 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochlorideWSGR Ref: 54004-768.601 A mixture of tert-butyl N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}carbamate (7 g, 27.310 mmol) and HCl (gas) in 1,4-dioxane (70 mL, 4 M) in DCM (70 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was triturated with ethyl ether (50 mL) and filtered to afford 1-[3-(methylsulfanyl)-1,2,4-triazin-6- yl]methanamine hydrochloride (5.2 g, 98%) as a brown solid. MS ESI calculated for C5H9ClN4S [M – Cl]+, 157.21 found 157.10.1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 6.38 (br, 2H), 4.35 (q, J = 5.8 Hz, 2H), 3.68-3.56 (m, 1H), 2.64 (s, 3H).

[0125] Common intermediate 2: 7-(1-ethylcyclobutyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine Step 1: 1-ethyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}cyclobutane-1-carboxamide To a stirred solution of 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochloride (700 mg, 3.63 mmol) and 1-ethylcyclobutane-1-carboxylic acid (699 mg, 5.45 mmol) in CH3CN (25 mL) was added was added HATU (1.66 g, 4.36 mmol) followed by Et3N (1.10 g, 10.90 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diulted with water (100 mL), extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 1-ethyl-N-{[3-(methylsulfanyl)-1,2,4- triazin-6-yl]methyl}cyclobutane-1-carboxamide (900 mg, 93%) as a yellow solid. MS ESI calculated for C12H18N4OS [M + H]+, 267.12 found 267.05.1H-NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.27 (brs, 1H), 4.49 (d, J = 5.6 Hz, 2H), 2.62 (s, 3H), 2.29-2.20 (m, 2H), 1.88-1.63 (m, 6H), 0.69 (t, J = 7.2 Hz, 3H). Step 2: 7-(1-ethylcyclobutyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine To a stirred solution of 1-ethyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}cyclobutane-1- carboxamide (700 mg, 2.62 mmol) and 1H-1,2,4-triazole (726 mg, 10.51 mmol) in pyridine (15 mL) was added POCl3(0.98 mL, 10.51 mmol) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was basified to pH 7 with saturated sat. NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 30% to 50%; detector, UV 254 nm to afford 7-(1- ethylcyclobutyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (460 mg, 70%) as a yellow solid. MS ESI calculated for C12H16N4S [M + H]+, 249.11 found 249.15.1H NMR (400 MHz,WSGR Ref: 54004-768.601 Chloroform-d) δ 8.92 (s, 1H), 7.81 (s, 1H), 2.87-2.75 (m, 2H), 2.56 (s, 3H), 2.37-2.30 (m, 2H), 2.23-2.08 (m, 3H), 2.05-1.90 (m, 1H), 0.71 (t, J = 7.5 Hz, 3H).

[0126] Common intermediate 3: 7-isopropyl-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine Step 1: 2-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}propanamide To a stirred solution of 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochloride (600 mg, 3.114 mmol) and isobutyric acid (0.43 mL, 4.671 mmol) in CH3CN (6 mL) was added HATU (1.42 g, 3.737 mmol) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2-methyl-N-{[3- (methylsulfanyl)-1,2,4-triazin-6-yl]methyl}propanamide (700 mg, 98%) as yellow oil. MS ESI calculated for C9H14N4OS [M + H]+, 227.09, found 227.10.1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 8.50-8.47 (m, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.61 (s, 3H), 2.46-2.40 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H). Step 2: 7-isopropyl-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine To a stirredmixture of 2-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}propanamide (350 mg, 1.547 mmol) and 1H-1,2,4-triazole (427 mg, 6.188 mmol) in pyridine (7 mL) was added POCl3(0.58 mL, 6.188 mmol) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The mixture was neutralized to pH 7 with saturated sat. NaHCO3 (aq.) and HCl (aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 20% to 55% gradient in 25 min; detector, UV 254 nm to afford 7-isopropyl-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (120 mg, 37%) as a yellow solid. MS ESI calculated for C9 H12N4S [M + H]+, 209.08, found 209.10.1H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 7.74 (s, 1H), 3.93-3.62 (m, 1H), 2.59 (s, 3H), 1.47 (d, J = 6.8 Hz, 6H). Step 3: 7-isopropyl-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine To a stirred mixture of 7-isopropyl-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (300 mg, 1.440 mmol) in DCM (4 mL) was added m-CPBA (497 mg, 2.880 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with sat. NaHCO3 (aq., 50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organicWSGR Ref: 54004-768.601 layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc / EtOH (4 / 3 / 1) to afford 7-isopropyl-2- methanesulfinylimidazo[4,3-f][1,2,4]triazine (150 mg, 45%) as a yellow solid. MS ESI calculated for C9H12N4OS [M + H]+, 225.07, found 225.05.1H NMR (400 MHz, Chloroform-d) δ 9.11 (s, 1H), 7.99 (s, 1H), 3.86-3.79 (m, 1H), 3.06 (s, 3H), 1.50-1.47 (m, 6H).

[0127] Common intermediate 4: 2-methanesulfinyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine Step 1: 3-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}butanamide To a stirred solution of 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochloride (1.13 g, 5.839 mmol) and isovaleric acid (0.89 g, 8.759 mmol) in CH3CN (20 mL) was added HATU (2.66 g, 7.007 mmol) and Et3N (1.77 g, 17.517 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 2) to afford 3-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}butanamide (1.3 g, 92%) as light brown oil. MS ESI calculated for C10H16N4OS [M + H]+, 241.10, found 241.05.1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 4.48 (d, J = 5.6 Hz, 2H), 2.61 (s, 3H), 2.07-1.99 (m, 3H), 0.86 (d, J = 6.4 Hz, 6H). Step 2: 7-(2-methylpropyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine To a stirred solution of 3-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}butanamide (1.7 g, 7.074 mmol) and 1,2,4-1H-Triazole (1.95 g, 28.296 mmol) in pyridine (2 mL) was added POCl3 (2.64 mL, 28.296 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with sat. NaHCO3 (aq.) (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 20% to 50%; detector, UV 254 nm to afford 7-(2-methylpropyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (800 mg, 50%) as light yellow oil. MS ESI calculated for C10H14N4S [M + H]+, 223.09, found 223.05.1H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 7.77 (s, 1H), 3.03 (d, J = 7.2 Hz, 2H), 2.60 (s, 3H), 2.40-2.30 (m, 1H), 1.00 (d, J = 6.8 Hz, 6H). Step 3: 2-methanesulfinyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazineWSGR Ref: 54004-768.601 To a stirred solution of 7-(2-methylpropyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (800 mg, 3.599 mmol) in DCM (10 mL) was added m-CPBA (1.46 g, 7.198 mmol, 85%). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with saturated sat. NaHCO3 (aq.) (100 mL) and extracted with DCM (2 x 80 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc / EtOH (3 / 5 / 1) to afford 2-methanesulfinyl-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazine (400 mg, 46%) as a light yellow solid. MS ESI calculated for C10H14N4OS [M + H]+, 239.09, found 238.90.1H NMR (400 MHz, Chloroform-d) δ 9.12 (s, 1H), 8.01 (s, 1H), 3.13 (d, J = 7.2 Hz, 2H), 3.05 (s, 3H), 2.44-2.35 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H).

[0128] Common intermediate 5: 7-(4-chlorophenyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine Step 1: 4-chloro-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}benzamide To a stirred solution of 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochloride (450 mg, 2.336 mmol), 4-chlorobenzoic acid (549 mg, 3.504 mmol) and HATU (1066 mg, 2.803 mmol) in CH3CN (9 mL) was added Et3N (709 mg, 7.008 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 40% to 60%; detector, UV 254 nm to afford 4-chloro-N-{[3- (methylsulfanyl)-1,2,4-triazin-6-yl]methyl}benzamide (480 mg, 69%) as a light yellow solid. MS ESI calculated for C12H11ClN4OS [M + H]+, 295.03, found 295.10.1H NMR (400 MHz, DMSO-d6) δ 9.30 (t, J = 5.6 Hz, 1H), 8.69 (s, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 7.6 Hz, 2H), 4.70 (d, J = 5.6 Hz, 2H), 2.62 (s, 3H). Step 2: 7-(4-chlorophenyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine To a solution of 4-chloro-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}benzamide (400 mg, 1.357 mmol) in pyridine (8 mL) were added 1,2,4-triazole (375 mg, 5.428 mmol) and POCl3(832 mg, 5.428 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was basified to pH 7 with sat. NaHCO3 (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted withWSGR Ref: 54004-768.601 PE / EtOAc / EtOH (3 / 5 / 1) to afford 7-(4-chlorophenyl)-2-(methylsulfanyl)imidazo[4,3- f][1,2,4]triazine (110 mg, 29%) as a light yellow solid. MS ESI calculated for C12H9ClN4S [M + H]+, 277.02, found 277.05.1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.49-8.44 (m, 2H), 8.09 (s, 1H), 7.66-7.62 (m, 2H), 2.63 (s, 3H). Step 3: 7-(4-chlorophenyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine To a stirred solution of 7-(4-chlorophenyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (110 mg, 0.397 mmol) in DCM (3 mL) was added m-CPBA (137 mg, 0.794 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with sat. NaHCO3(aq.) (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 7-(4- chlorophenyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (65 mg, 55%) as a light yellow solid. MS ESI calculated for C12H9ClN4OS [M + H]+, 293.02, found 293.00.1H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 8.60-8.54 (m, 2H), 8.17 (s, 1H), 7.57-7.51 (m, 2H), 3.09 (s, 3H).

[0129] Common intermediate 6: 2-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazine Step 1: 2-isopropyl-4-(trifluoromethyl)-3H-imidazole A stirred solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (20 g, 74.12 mmol) and sodium acetate trihydrate (12.20 g, 89.68 mmol) in water (40 mL) was stirred for 1 h at reflux. The resulting mixture was allowed to cool down to room temperature. To this was added isobutyraldehyde (5.34 g, 74.12 mmol) and NH3.H2O (81 mL) in MeOH (120 mL). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-isopropyl-4-(trifluoromethyl)-3H-imidazole (12.7 g, 96%) as a yellow solid. MS ESI calculated for C7H9F3N2[M + H]+, 179.07, found 179.15;1H NMR (400 MHz, DMSO-d6) δ 12.33 (brs, 1H), 7.60 (s, 1H), 3.03-2.92 (m, 1H), 1.23 (d, J = 9.6 Hz, 6H). Step 2: methyl 2-isopropyl-3H-imidazole-4-carboxylate To a stirred solution of 2-isopropyl-4-(trifluoromethyl)-3H-imidazole (12.67 g, 71.12 mmol) in MeOH (102 mL) was added NaOH (8.53 g, 213.35 mmol) in water (77 mL) at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was adjust to pH 3 with conc. HCl. The resulting mixture was stirred for 4 h at room temperature. TheWSGR Ref: 54004-768.601 resulting mixture was to pH 8 with sat. K2CO3. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2-isopropyl-3H-imidazole-4-carboxylate (11.04 g, 92%) as a brown solid. MS ESI calculated for C8H12N2O2 [M + H]+, 169.09, found 169.15;1H NMR (400 MHz, DMSO-d6) δ 12.30 (brs, 1H), 7.73 (s, 1H), 3.72 (s, 3H), 2.97-2.90 (m, 1H), 1.23 (d, J = 6.8 Hz, 6H). Step 3: methyl 3-amino-2-isopropylimidazole-4-carboxylate To a stirred solution of NaH (856 mg, 35.67 mmol) in DMF (40 mL) was added methyl 2- isopropyl-3H-imidazole-4-carboxylate (5 g, 29.73 mmol) in DMF (40 mL) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. To this was added amino 4-nitrobenzoate (6.50 g, 35.67 mmol) in DMF (40 mL) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford methyl 3-amino-2-isopropylimidazole-4-carboxylate (1.7 g, 31%) as light yellow oil. MS ESI calculated for C8H13N3O2 [M + H]+, 184.10, found 184.15;1H NMR (400 MHz, Chloroform-d) δ 7.66 (s, 1H), 5.28 (brs, 2H), 3.90 (s, 3H), 3.49-3.38 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H). Step 4: methyl 2-isopropyl-3-{[(2,2,2-trichloroacetyl)carbamoyl]amino}imidazole-4-carboxylate To a stirred mixture of methyl 3-amino-2-isopropylimidazole-4-carboxylate (1.75 g, 9.55 mmol) in THF (20 mL) was added trichloroethanecarbonyl isocyanate (1.80 g, 9.55 mmol) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by trituration with EtOAc / Et2O (1 / 4, 30 mL). The precipitated solids were collected by filtration and washed with EtOAc / Et2O (1 / 4, 3 x 5 mL) to afford methyl 2-isopropyl-3-{[(2,2,2- trichloroacetyl)carbamoyl]amino}imidazole-4-carboxylate (2.6 g, 73%) as an off-white solid. MS ESI calculated for C11H13Cl3N4O4 [M + H]+, 371.00, found 371.05.1H NMR (400 MHz, DMSO-d6) δ 12.00 (brs, 1H), 10.79 (s, 1H), 7.61 (s, 1H), 3.74 (s, 3H), 3.07-3.00 (m, 1H), 1.24- 1.15 (m, 6H). Step 5: 7-isopropyl-1H,3H-imidazo[4,3-f][1,2,4]triazine-2,4-dione To a stirred mixture of methyl 2-isopropyl-3-{[(2,2,2- trichloroacetyl)carbamoyl]amino}imidazole-4-carboxylate (1.75 g, 4.71 mmol) in MeOH (20 mL) was added KOH (0.53 g, 9.42 mmol) at room temperature. The resulting mixture was stirred for 16 h at 60 °C. The resulting mixture was allowed to cool down to room temperature.WSGR Ref: 54004-768.601 The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by trituration with PE / EtOAc (5 / 1, 10 mL). The precipitated solids were collected by filtration and washed with PE / EtOAc (5 / 1, 3 x 3 mL) to afford 7-isopropyl-1H,3H-imidazo[4,3- f][1,2,4]triazine-2,4-dione (2.6 g, crude) as an off-white solid. MS ESI calculated for C8H10N4O2 [M + H]+, 195.08, found 195.05.1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.20 (s, 1H), 3.30-3.21 (m, 1H), 1.21 (d, J = 7.2 Hz, 6H). Step 6: 2,4-dichloro-7-isopropylimidazo[4,3-f][1,2,4]triazine To a stirred solution of 7-isopropyl-1H,3H-imidazo[4,3-f][1,2,4]triazine-2,4-dione (6 g, 30.90 mmol) and POCl3(36 mL) was added 2,6-diethylaniline (3.6 mL, 1.15 mmol) at 0 °C. The resulting mixture was stirred for 3 h at 120 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (50 mL). The resulting mixture was basified to pH 8 with sat. NaHCO3(aq.30 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (10 / 1) to afford 2,4-dichloro-7- isopropylimidazo[4,3-f][1,2,4]triazine (1.86 g, 26%) as a green solid. MS ESI calculated for C8H8Cl2N4 [M + H]+, 231.01, found 230.95;1H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 1H), 3.70-3.59 (m, 1H), 1.45 (d, J = 6.8 Hz, 6H). Step 7: 2-Chloro-7-isopropyl- triazineTo a stirred solution of 2,4-dichloro-7-isopropylimidazo[4,3-f][1,2,4]triazine (1.3 g, 5.63 mmol) and i-PrOH (0.65 mL, 8.51 mmol) in CH3CN (13 mL) was added NaBH4(0.32 g, 8.44 mmol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with sat. NH4Cl (aq.) at room temperature. The resulting mixture was extracted with DCM (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2-chloro-7-isopropyl-3H,4H-imidazo[4,3-f][1,2,4]triazine (1 g, 89%) as a white solid. MS ESI calculated for C8H11ClN4 [M + H]+, 199.07, found 198.95;1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 6.52 (s, 1H), 4.56 (s, 2H), 3.17-3.10 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H). Step 8: 2-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazine A stirred solution of 2-chloro-7-isopropyl-3H,4H-imidazo[4,3-f][1,2,4]triazine (400 mg, 2.01 mmol) and DDQ (1.83 g, 8.06 mmol) in toluene (20 mL) was stirred for 4 h at 110 °C. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was diluted with NaHCO3 (aq.) (50 mL), extracted with DCM (3 x 50 mL), and dried over anhydrousWSGR Ref: 54004-768.601 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (2 / 1) to afford 2-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazine (250 mg, 63%) as a brown solid. MS ESI calculated for C8H9ClN4 [M + H]+, 197.05, found 197.10;1H NMR (400 MHz, Chloroform- d) δ 8.97 (s, 1H), 7.92 (s, 1H), 3.73-3.63 (m, 1H), 1.47 (d, J = 6.8 Hz, 6H).

[0130] Common intermediate 7: 2-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine Step 1: 2-(2-methylpropyl)-4-(trifluoromethyl)-3H-imidazole A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (80 g, 296.47 mmol) and NaOAc (48.64 g, 592.94 mmol) in water (160 mL) was stirred for 1 h in reflux. The resulting mixture was allowed to cool down to room temperature. To this was added isovaleraldehyde (51.07 g, 592.94 mmol) and NH3.H2O (435 mL) in MeOH (1000 mL). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 700 mL). The combined organic layers were washed with brine (1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(2-methylpropyl)-4-(trifluoromethyl)-3H- imidazole (54.5 g, 96%) as a yellow solid. MS ESI calculated for C8H11F3N2 [M + H]+, 193.09, found 193.05.1H NMR (400 MHz, Chloroform-d) δ 11.92 (brs, 1H), 7.32 (s, 1H), 2.64 (d, J = 7.2 Hz, 2H), 2.13-2.02 (m, 1H), 0.94 (d, J = 6.8 Hz, 6H).19F NMR (376 MHz, Chloroform-d) δ - 62.04 (3F). Step 2: methyl 2-(2-methylpropyl)-3H-imidazole-4-carboxylate A mixture of NaOH (34.21 g, 855.43 mmol) in water (800 mL) and 2-(2-methylpropyl)-4- (trifluoromethyl)-3H-imidazole (54.80 g, 285.14 mmol) in MeOH (300 mL) was stirred for 16 h at room temperature. The resulting mixture was adjust to pH 3 with conc. HCl. The resulting mixture was stirred for 4 h at room temperature. The resulting mixture was to pH 8 with sat. K2CO3. The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2-(2-methylpropyl)-3H-imidazole-4-carboxylate (37.6 g, 72%) as a yellow oil. MS ESI calculated for C9H14N2O2[M + H]+, 183.11, found 183.25.1H NMR (400 MHz, Chloroform-d) δ 11.68 (brs, 1H), 7.68 (s, 1H), 3.84 (s, 3H), 2.64 (d, J = 7.2 Hz, 2H), 2.13-2.02 (m, 1H), 0.90 (d, J = 6.8 Hz, 6H). Step 3: methyl 3-amino-2-(2-methylpropyl)imidazole-4-carboxylate To a stirred mixture of NaH (9.75 g, 243.66 mmol, 60%) in DMF (1 L) were added methyl 2-(2- methylpropyl)-3H-imidazole-4-carboxylate (37 g, 203.05 mmol) in DMF (1 L) dropwise atWSGR Ref: 54004-768.601 0 °C. The resulting mixture was stirred for 1 h at room temperature. To this was added amino 4- nitrobenzoate (44.38 g, 243.66 mmol) in DMF (1 L) dropwise min at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. NH4Cl (aq.) (3 L) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 3 L). The combined organic layers were washed with brine (5 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford methyl 3- amino-2-(2-methylpropyl)imidazole-4-carboxylate (13 g, 32%) as a yellow solid. MS ESI calculated for C9H15N3O2[M + H]+, 198.12, found 198.30.1H NMR (400 MHz, Chloroform-d) δ 7.63 (s, 1H), 5.23 (brs, 2H), 3.90-3.86 (m, 3H), 2.75 (d, J = 7.2 Hz, 2H), 2.24-2.17 (m, 1H), 0.99 (d, J = 6.8 Hz, 6H). Step 4: 7-(2-methylpropyl)- triazine-2,4-dioneA mixture of methyl 3-amino-2-(2-methylpropyl)imidazole-4-carboxylate (13 g, 65.91 mmol) and trichloroethanecarbonyl isocyanate (24.83 g, 131.82 mmol) in THF (300 mL) was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (5 / 1). The resulting mixture was concentrated under reduced pressure. To this was added K2CO3 (21.50 g, 155.59 mmol) in MeOH (400 mL). The resulting mixture was stirred for 16 h at 60 °C. The resulting mixture was allowed to cool down to room temperature and acidified to pH 4 with HCl (3 M). The precipitated solids were collected by filtration and washed with acetonitrile (3 x 130 mL) to afford 7-(2-methylpropyl)-1H,3H-imidazo[4,3-f][1,2,4]triazine-2,4-dione (10 g, crude) as a white solid. MS ESI calculated for C9H12N4O2[M + H]+, 209.10, found 209.05.1H NMR (400 MHz, DMSO-d6) δ 13.70 (brs, 1H), 10.98 (brs, 1H), 7.82 (s, 1H), 2.76 (d, J = 7.2 Hz, 2H), 2.21-2.10 (m, 1H), 0.90 (d, J = 6.8 Hz, 6H). Step 5: 2,4-dichloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine To a stirred mixture of 7-(2-methylpropyl)-1H,3H-imidazo[4,3-f][1,2,4]triazine-2,4-dione (6 g, 28.82 mmol) in POCl3(60 mL) was added 2,6-diethylaniline (6 mL) dropwise at 0 °C. The resulting mixture was stirred for 8 h at 120 °C. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by the addition of sat. aqueous NaHCO3(100 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with sat. brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2,4- dichloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine (500 mg, 7%) as a light yellow solid. MS ESI calculated for C9H10Cl2N4 [M + H]+, 245.03, found 245.15.1H NMR (400 MHz,WSGR Ref: 54004-768.601 Chloroform-d) δ 7.97 (s, 1H), 3.02 (d, J = 7.2 Hz, 2H), 2.38-2.28 (m, 1H), 0.99 (d, J = 6.8 Hz, 6H). Step 6: 2-chloro-7-(2-methylpropyl)- triazineTo a stirred mixture of 2,4-dichloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine (700 mg, 2.86 mmol) and i-PrOH (0.2 mL) in CH3CN (8 mL) was added NaBH4 (216 mg, 5.71 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was quenched with water (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with sat. brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-chloro-7-(2- methylpropyl)-3H,4H-imidazo[4,3-f][1,2,4]triazine (400 mg, 65%) as a light yellow solid. MS ESI calculated for C9H13ClN4 [M + H]+, 213.08, found 213.05.1H NMR (400 MHz, Chloroform-d) δ 6.69 (s, 1H), 5.40 (brs, 1H), 4.70 (s, 2H), 2.67 (d, J = 7.2 Hz, 2H), 2.22-2.12 (m, 1H), 0.96 (d, J = 6.8 Hz, 6H). Step 7: 2-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine To a stirred mixture of 2-chloro-7-(2-methylpropyl)-3H,4H-imidazo[4,3-f][1,2,4]triazine (400 mg, 1.88 mmol) in toluene (4 mL) was added DDQ (1.28 g, 5.64 mmol) at room temperature. The resulting mixture was stirred for 10 h at 120 °C. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was quenched with water (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with sat. brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine (180 mg, 45%) as a light brown solid. MS ESI calculated for C9H11ClN4[M + H]+, 211.07, found 211.10.1H NMR (400 MHz, Chloroform-d) δ 8.96 (s, 1H), 7.93 (s, 1H), 3.03 (d, J = 7.2 Hz, 2H), 2.40-2.29 (m, 1H), 0.99 (d, J = 6.8 Hz, 6H).

[0131] Common intermediate 8: 2-methanesulfinyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazine Step 1: 2-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}butanamide To a solution of 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochloride (2 g, 10.380 mmol) in CH3CN (40 mL) was added 2-methylbutyrate (1.59 g, 15.570 mmol) and HATU (7.89 g, 20.760 mmol), and TEA (3.15 g, 31.140 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of ice / water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gelWSGR Ref: 54004-768.601 column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2-methyl-N-{[3- (methylsulfanyl)-1,2,4-triazin-6-yl]methyl}butanamide (1.2 g, 48%) as yellow oil. MS ESI calculated for C10H16N4OS [M + H]+, 241.10; found 240.95.1H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H), 6.57 (brs, 1H), 4.69 (d, J = 5.6 Hz, 2H), 2.67 (s, 3H), 2.25-2.20 (m, 1H), 1.73- 1.64 (m, 1H), 1.52-1.41 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). Step 2: 2-(methylsulfanyl)-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazine To a solution of 2-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}butanamide (1.6 g, 6.658 mmol) in pyridine (32 mL) was added 1,2,4-triazole (1.84 g, 26.632 mmol), followed by the addition of POCl3(4.08 g, 26.632 mmol) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was basified to pH 8 with sat. NaHCO3(aq.). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2-(methylsulfanyl)-7-(sec- butyl)imidazo[4,3-f][1,2,4]triazine (900 mg, 60%) as yellow oil. MS ESI calculated for C10H14N4S [M + H]+, 223.09; found 223.05.1H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 7.76 (s, 1H), 3.54-3.47 (m, 1H), 2.59 (s, 3H), 2.06-1.93 (m, 1H), 1.88-1.76 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H). Step 3: 2-methanesulfinyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazine A mixture of 2-(methylsulfanyl)-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazine (900 mg, 4.048 mmol) and m-CPBA (1.40 g, 8.096 mmol) in DCM (18 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2-methanesulfinyl-7-(sec- butyl)imidazo[4,3-f][1,2,4]triazine (580 mg, 60%) as yellow oil. MS ESI calculated for C10H14N4OS [M + H]+, 239.09; found 239.05.1H NMR (400 MHz, Chloroform-d) δ 9.11 (s, 1H), 8.01 (s, 1H), 3.64-3.54 (m, 1H), 3.06 (s, 3H), 1.98-1.85 (m, 2H), 1.44-1.40 (m, 3H), 0.91- 0.87 (m, 3H).

[0132] Common intermediate 9: 2-methanesulfinyl-7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triazine Step 1: 1-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}cyclobutane-1-carboxamide To a stirred mixture of 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochloride (1.1 g, 5.709 mmol), 1-methylcyclobutane-1-carboxylic acid (980 mg, 8.563 mmol) and HATU (2.6WSGR Ref: 54004-768.601 g, 6.864 mmol) in CH3CN (20 mL) was added TEA (2.4 mL, 17.070 mmol). The resulting mixture was stirred for 4 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with EtOAc / PE (0~70%) to afford 1-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}cyclobutane-1-carboxamide (980 mg, 64%) as brown oil. MS ESI calculated for C11H16N4OS [M + H]+, 253.10, found 253.10. Step 2: 7-(1-methylcyclobutyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine To a stirred mixture of 1-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}cyclobutane- 1-carboxamide (950 mg, 3.765 mmol) and 1H-1,2,4-triazole (1 g, 15.060 mmol) in pyridine (10 mL) were added POCl3(1.4 mL, 15.098 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was acidified to pH 2 with HCl (6 M). The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with EtOAc / PE (0~60%) to afford 7-(1-methylcyclobutyl)-2- (methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (830 mg, 84%) as a yellow solid. MS ESI calculated for C11H14N4S [M + H]+, 235.09, found 235.15.1H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 7.74 (s, 1H), 2.89-2.80 (m, 2H), 2.56 (s, 3H), 2.25-2.18 (m, 3H), 1.99-1.96 (m, 1H), 1.70 (s, 3H). Step 3: 2-methanesulfinyl-7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triazine To a stirred mixture of 7-(1-methylcyclobutyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (695 mg, 2.966 mmol) in DCM (10 mL) was added 3-chlorobenzene-1-carboperoxoic acid (1.2 g, 5.902 mmol, 85%) in portions at 0 °C. The resulting mixture was stirred for 4 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (100 mL). The resulting mixture was extracted with DCM (2 x 100 mL). The combined organic layerswere dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with (EtOAc / EtOH = 3 / 1) / PE (0~60%) to afford 2-methanesulfinyl-7-(1- methylcyclobutyl)imidazo[4,3-f][1,2,4]triazine (390 mg, 47%) as yellow oil. MS ESI calculated for C11H14N4OS [M + H]+, 251.09, found 251.05.1H NMR (400 MHz, Chloroform-d) δ 9.15 (s, 1H), 7.97 (s, 1H), 3.03 (s, 3H), 2.86-2.82 (m, 2H), 2.30-2.26 (m, 3H), 2.00-1.93 (m, 1H), 1.72 (s, 3H).WSGR Ref: 54004-768.601

[0133] Common intermediate 10: 7-(1-ethylcyclopropyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine Step 1: 1-ethyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}cyclopropane-1-carboxamide To a stirred solution of 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochloride (1.9 g, 9.86 mmol), 1-ethylcyclopropane-1-carboxylic acid (1.69 g, 14.79 mmol) and HATU (4.50 g, 11.83 mmol) in CH3CN (40 mL) was added TEA (2.99 g, 29.58 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 1-ethyl-N-{[3- (methylsulfanyl)-1,2,4-triazin-6-yl]methyl}cyclopropane-1-carboxamide (1.9 g, 76%) as yellow oil. MS ESI calculated for C11H16N4OS [M + H]+, 253.10, found 253.20. Step 2: 7-(1-ethylcyclopropyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine To a stirred solution of 1-ethyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}cyclopropane- 1-carboxamide (300 mg, 1.19 mmol) and 1H-1,2,3-triazole (328 mg, 4.76 mmol) in pyridine (6 mL) was added POCl3 (729 mg, 4.76 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with HCl (0.5 M) (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 7-(1-ethylcyclopropyl)-2-(methylsulfanyl)imidazo[4,3- f][1,2,4]triazine (200 mg, 71%) as yellow oil. MS ESI calculated for C11H14N4S [M + H]+, 235.09, found 235.05.1H NMR (400 MHz, Chloroform-d) δ 8.84 (s, 1H), 7.72 (s, 1H), 2.60 (s, 3H), 1.93 (q, J = 7.2 Hz, 2H), 1.35-1.31 (m, 2H), 0.95-0.88 (m, 5H). Step 3: 7-(1-ethylcyclopropyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine To a stirred solution of 7-(1-ethylcyclopropyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (200 mg, 0.85 mmol) in DCM (5 mL) was added m-CPBA (347 mg, 1.71 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was quenched with sat. NaHCO3(aq.) (20 mL). The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford 7-(1- ethylcyclopropyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (100 mg, 46%) as yellow oil. MS ESI calculated for C11H14N4OS [M + H]+, 251.09, found 251.05.1H NMR (400 MHz,WSGR Ref: 54004-768.601 Chloroform-d) δ 9.11 (s, 1H), 7.94 (s, 1H), 3.05 (s, 3H), 1.97 (q, J = 7.2 Hz, 2H), 1.37-1.34 (m, 2H), 0.98-0.87 (m, 3H).

[0134] Common intermediate 11: 2-methanesulfinyl-7-(3-methylbutan-2-yl)imidazo[4,3-f][1,2,4]triazine Step 1: 2,3-dimethyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}butanamide To a stirred mixture of 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochloride (1 g, 5.190 mmol), 2,3-dimethylbutanoic acid (0.90 g, 7.785 mmol) and HATU (2.37 g, 6.228 mmol) in CH3CN (10 mL) was added TEA (2 mL, 15.570 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with sat. NaHCO3(50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2,3-dimethyl-N-{[3- (methylsulfanyl)-1,2,4-triazin-6-yl]methyl}butanamide (900 mg, 66%) as yellow oil. MS ESI calculated for C11H18N4OS [M + H]+, 255.12, found 255.10. Step 2: 7-{bicyclo[2.2.2]octan-1-yl}-2-chloro-5-fluoropyrrolo[2,1-f][1,2,4]triazine To a stirred mixture of 2,3-dimethyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6- yl]methyl}butanamide (850 mg, 3.342 mmol) and 1H-1,2,4-triazole (0.92 g, 13.368 mmol) in pyridine (9 mL) was added POCl3(1.25 mL, 13.368 mmol) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of HCl (0.01 M, 50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 7-(3- methylbutan-2-yl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (600 mg, 75%) as yellow oil. MS ESI calculated for C11H16N4S [M + H]+, 237.11, found 237.10.1H NMR (400 MHz, Chloroform-d) δ 8.84 (s, 1H), 7.76 (s, 1H), 3.42-3.35 (m, 1H), 2.59 (s, 3H), 2.25-2.16 (m, 1H), 1.42 (d, J = 7.2 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H). Step 3: 2-methanesulfinyl-7-(3-methylbutan-2-yl)imidazo[4,3-f][1,2,4]triazine To a stirred mixture of 7-(3-methylbutan-2-yl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (550 mg, 2.327 mmol) in DCM (6 mL) was added m-CPBA (944 mg, 4.654 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resultingWSGR Ref: 54004-768.601 mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2-methanesulfinyl-7-(3-methylbutan-2-yl)imidazo[4,3-f][1,2,4]triazine (250 mg, 41%) as yellow oil. MS ESI calculated for C11H16N4OS [M + H]+, 253.10, found 253.10.1H NMR (400 MHz, Chloroform-d) δ 9.11 (s, 1H), 8.01 (s, 1H), 3.57-3.49 (m, 1H), 3.05 (s, 3H), 2.27-2.18 (m, 1H), 1.44-1.41 (m, 3H), 1.02-1.00 (m, 3H), 0.86-0.82 (m, 3H).

[0135] Common intermediate 12: 5-chloro-2-methanesulfinyl-7-(1-methylcyclopropyl)imidazo[4,3-f][1,2,4]triazine Step 1: 1-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methyl}cyclopropane-1-carboxamide To a stirred mixture of 1-[3-(methylsulfanyl)-1,2,4-triazin-6-yl]methanamine hydrochloride (500 mg, 2.595 mmol), 1-methylcyclopropane-1-carboxylic acid (390 mg, 3.893 mmol) and HATU (1.18 g, 3.103 mmol) in CH3CN (5 mL) was added TEA (1.1 mL, 7.770 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was diluted with sat. NaHCO3(50 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 1-methyl-N-{[3-(methylsulfanyl)-1,2,4- triazin-6-yl]methyl}cyclopropane-1-carboxamide (260 mg, 39%) as yellow oil. MS ESI calculated for C10H14N4OS [M+H]+, 239.09, found 239.00.1H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H), 6.75 (brs, 1H), 4.70 (d, J = 5.6 Hz, 2H), 2.69 (s, 3H), 1.39 (s, 3H), 1.25-1.22 (m, 2H), 0.66-0.63 (m, 2H). Step 2: 7-(1-methylcyclopropyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine To a stirred solution of 1-methyl-N-{[3-(methylsulfanyl)-1,2,4-triazin-6- yl]methyl}cyclopropane-1-carboxamide (260 mg, 1.091 mmol) and 1H-1,2,4-triazole (301 mg, 4.364 mmol) in pyridine (3 mL) was added POCl3 (0.4 mL, 4.364 mmol) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was basified by sat. NaHCO3(50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 7-(1- methylcyclopropyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (210 mg, 87%) as yellow oil. MS ESI calculated for C10H12N4S [M+H]+, 221.08, found 221.05.1H NMR (400 MHz, Chloroform-d) δ 8.84 (s, 1H), 7.70 (s, 1H), 2.59 (s, 3H), 1.65 (s, 3H), 1.52-1.48 (m, 2H), 0.91- 0.88 (m, 2H). Step 3: 5-chloro-7-(1-methylcyclopropyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazineWSGR Ref: 54004-768.601 A mixture of 7-(1-methylcyclopropyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (210 mg, 0.953 mmol) and NCS (191 mg, 1.430 mmol) in DMF (2 mL) was stirred for 16 h at room temperature. The reaction was quenched water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 5-chloro-7-(1- methylcyclopropyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (170 mg, 66%) as a yellow solid. MS ESI calculated for C10H11ClN4S [M+H]+, 255.04, found 255.05.1H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H), 2.58 (s, 3H), 1.63 (s, 3H), 1.48-1.45 (m, 2H), 0.90-0.87 (m, 2H). Step 4: 5-chloro-2-methanesulfinyl-7-(1-methylcyclopropyl)imidazo[4,3-f][1,2,4]triazine To a stirred mixture of 5-chloro-7-(1-methylcyclopropyl)-2-(methylsulfanyl)imidazo[4,3- f][1,2,4]triazine (100 mg, 0.393 mmol) in DCM (1.5 mL) was added m-CPBA (160 mg, 0.785 mmol, 85%) in portions at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3 (30 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 5-chloro-2-methanesulfinyl-7-(1-methylcyclopropyl)imidazo[4,3-f][1,2,4]triazine (40 mg, 37%) as yellow oil. MS ESI calculated for C10H11ClN4OS [M+H]+, 271.03, found 271.15.1H NMR (400 MHz, Chloroform-d) δ 9.02 (s, 1H), 3.04 (s, 3H), 1.68 (s, 3H), 1.52-1.49 (m, 2H), 0.99-0.96 (m, 2H).

[0136] Example 1: (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol Step 1: 5-chloro-7-(1-ethylcyclobutyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine To a stirred solution of 7-(1-ethylcyclobutyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (100 mg, 0.403 mmol) in DMF (1 mL) was added NCS (54 mg, 0.403 mmol). The resulting mixture was stirred for 16 h at room temperature, then was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 55% to 80%; detector, UV 254 nm to afford 5-chloro-7-(1-ethylcyclobutyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (80 mg, 68%) as yellow oil. MS ESI calculated for C12H15ClN4S [M + H]+, 283.07, found 283.15.1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 2.77-2.71 (m, 2H), 2.52 (s, 3H), 2.25-2.22 (m, 2H), 2.19-2.03 (m, 3H), 1.99-1.90 (m, 1H), 0.71 (t, J = 7.5 Hz, 3H). Step 2: 5-chloro-7-(1-ethylcyclobutyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazineWSGR Ref: 54004-768.601 To a stirred mixture of 5-chloro-7-(1-ethylcyclobutyl)-2-(methylsulfanyl)imidazo[4,3- f][1,2,4]triazine (80 mg, 0.283 mmol) in DCM (1 mL) was added m-CPBA (98 mg, 0.566 mmol). The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (15 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 5-chloro-7-(1-ethylcyclobutyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (55 mg, 63%) as yellow oil. MS ESI calculated for C12H15ClN4OS [M + H]+, 299.07, found 299.00. 1H NMR (400 MHz, Chloroform-d) δ 9.07 (s, 1H), 3.02 (s, 3H), 2.80-2.67 (m, 2H), 2.35-2.30 (m, 2H), 2.22-2.05 (m, 3H), 2.03-1.90 (m, 1H), 0.71 (t, J = 7.5 Hz, 3H). Example 1: (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol To a stirred mixture of 5-chloro-7-(1-ethylcyclobutyl)-2-methanesulfinylimidazo[4,3- f][1,2,4]triazine (50 mg, 0.167 mmol) and (3S,4R)-4-aminooxan-3-ol hydrochloride (129 mg, 0.835 mmol) in NMP (2 mL) was added DIEA (0.17 mL, 1.002 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 0.1% formic acid), 35% to 60%; detector, UV 254 nm to afford (3S,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}oxan-3-ol (8.1 mg, 13%) as a yellow solid. MS ESI calculated for C16H22ClN5O2 [M + H]+, 352.15, found 351.95.1H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 5.04 (d, J = 5.2 Hz, 1H), 4.11-4.06 (m, 1H), 4.01-3.98 (m, 1H), 3.78-3.63 (m, 2H), 3.56- 3.45 (m, 2H), 3.25-3.22 (m, 1H), 2.80-2.69 (m, 1H), 2.67-2.58 (m, 1H), 2.28-2.01 (m, 6H), 2.00- 1.85 (m, 1H), 1.76-1.62 (m, 1H), 0.71 (t, J = 7.2 Hz, 3H).

[0137] Example 2: (3S,4R)-4-{[7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol Step 1: 7-(1-ethylcyclobutyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine To a stirred solution of 7-(1-ethylcyclobutyl)-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (100 mg, 0.40 mmol) in DCM (3 mL) was added m-CPBA (139 mg, 0.80 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL), dried over anhydrous Na2SO4.WSGR Ref: 54004-768.601 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 20% to 45%; detector, UV 254 nm to afford 7-(1- ethylcyclobutyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (80 mg, 75%) as yellow oil. MS ESI calculated for C12H16N4OS [M + H]+, 265.10 found 265.15.1H-NMR (400 MHz, Chloroform-d) δ 9.16 (s, 1H), 7.99 (s, 1H), 3.01 (s, 3H), 2.84-2.70 (m, 2H), 2.41-2.30 (m, 2H), 2.26-2.07 (m, 3H), 2.04-1.89 (m, 1H), 0.68 (t, J = 7.2 Hz, 3H). Example 2: (3S,4R)-4-{[7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol A mixture of 7-(1-ethylcyclobutyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (90 mg, 0.340 mmol), (3S,4R)-4-aminooxan-3-ol hydrochloride (261 mg, 1.700 mmol) and DIEA (0.36 mL, 2.040 mmol) in NMP (2 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% formic acid), 10% to 50%; detector, UV 254 nm to afford (3S,4R)-4-{[7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol (14.3 mg, 13%) as a light yellow solid. MS ESI calculated for C16H23N5O2 [M + H]+, 318.19, found 318.20.1H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 7.69 (s, 1H), 4.97 (d, J = 5.2 Hz, 1H), 4.12-4.08 (m, 1H), 4.05-3.99 (m, 1H), 3.81-3.67 (m, 3H), 3.54-3.48 (m, 1H), 3.28-3.23 (m, 1H), 2.81-2.76 (m, 1H), 2.69-2.65 (m, 1H), 2.29-2.22 (m, 2H), 2.21-2.01 (m, 4H), 2.00-1.94 (m, 1H), 1.77-1.65 (m, 1H), 0.69 (t, J = 7.2 Hz, 3H).

[0138] Example 3: (3S,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-ol Step 1: 5-chloro-7-isopropyl-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine To a stirred mixture of 7-isopropyl-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (250 mg, 1.200 mmol) and DMF (3 mL) was added NCS (160 mg, 1.200 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with sat. NaHCO3 (aq., 100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 20% to 55%; detector, UV 254 nm to afford 5-chloro-7-isopropyl-2- (methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (150 mg, 51%) as a yellow solid. MS ESI calculated for C9H11ClN4S [M + H]+, 243.04, found 243.00.1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 3.64-3.57 (m, 1H), 2.58 (s, 3H), 1.44 (d, J = 6.8 Hz, 6H). Step 2: 5-chloro-7-isopropyl-2-methanesulfinylimidazo[4,3-f][1,2,4]triazineWSGR Ref: 54004-768.601 To a stirred mixture of 5-chloro-7-isopropyl-2-(methylsulfanyl)imidazo[4,3-f][1,2,4]triazine (150 mg, 0.618 mmol) in DCM (1.5 mL) was added m-CPBA (213 mg, 1.236 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with sat. NaHCO3 (aq., 100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 10% to 60%; detector, UV 254 nm to afford 5- chloro-7-isopropyl-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (90 mg, 43%) as a yellow solid. MS ESI calculated for C9H11ClN4OS[M + H]+, 259.03, found 259.00.1H NMR (400 MHz, Chloroform-d) δ 9.03 (s, 1H), 3.82-3.73 (m, 1H), 3.05 (s, 3H), 1.46 (d, J = 6.8 Hz, 6H). Example 3: (3S,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-ol To a stirred mixture of 5-chloro-7-isopropyl-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (80 mg, 0.309 mmol) and (3S,4R)-4-aminooxan-3-ol hydrochloride (237 mg, 1.545 mmol) in NMP (1 mL) was added DIEA (0.32 mL, 1.854 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (plus 10 mM NH4HCO3), Mobile Phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 16% B to 41% B; Wave Length: 254 nm / 220 nm to afford (3S,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)oxan-3-ol (62.2 mg, 64%) as a yellow solid. MS ESI calculated for C13H18ClN5O2 [M + H]+, 312.11, found 312.15.1H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 5.39 (brs, 1H),4.15-4.05 (m, 1H), 4.03-3.99 (m, 1H), 3.86-3.80 (m, 1H), 3.76-3.66 (m, 1H), 3.59-3.42 (m, 2H), 3.34-3.25 (m, 1H), 2.22-2.13 (m, 1H), 1.79-1.65 (m, 1H), 1.43-1.40 (m, 6H).

[0139] Example 4: (3R,4R)-N-{5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}-3-fluoro-1- methanesulfonylpiperidin-4-amine Step 1: tert-butyl (3R,4R)-3-fluoro-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)piperidine- 1-carboxylate To a stirred mixture of 7-isopropyl-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (50 mg, 0.223 mmol) and tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate (29 mg, 0.135WSGR Ref: 54004-768.601 mmol) in NMP (1 mL) was added DIEA (0.23 mL, 1.338 mmol). The resulting mixture was stirred for 16 h at 40 °C. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% formic acid), 10% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)-3-fluoro-4-({7-isopropylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (70 mg, 82%) as a yellow solid. MS ESI calculated for C18H27FN6O2[M + H]+, 379.22, found 379.30.1H NMR (400 MHz, Chloroform- d) δ 8.79 (s, 1H), 7.69 (s, 1H), 5.07 (brs, 1H), 4.66-4.49 (m, 1H), 4.29-4.00 (m, 2H), 3.84-3.81 (m, 1H), 3.60-3.53 (m, 1H), 3.30-3.10 (m, 2H), 2.40-2.34 (m, 1H), 1.73-1.55 (m, 1H), 1.50 (s, 9H), 1.47-1.42 (m, 6H).19F NMR (376 MHz, Chloroform-d) δ -189.41 (1F). Step 2: tert-butyl (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-3- fluoropiperidine-1-carboxylate To a stirred mixture of tert-butyl (3R,4R)-3-fluoro-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate (40 mg, 0.106 mmol) in DMF (0.5 mL) was added NCS (17 mg, 0.127 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with sat. NaHCO3(aq., 30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 2) to afford tert-butyl (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)-3-fluoropiperidine-1-carboxylate (27 mg, 58%) as a yellow solid. MS ESI calculated for C18H26ClFN6O2 [M + H]+, 413.18, found 413.30. Step 3: 2-chloro-7-(1-ethynylcyclopropyl)-5-fluoropyrrolo[2,1-f][1,2,4]triazine hydrochloride To a stirred mixture of tert-butyl (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin- 2-yl}amino)-3-fluoropiperidine-1-carboxylate (27 mg, 0.065 mmol) in DCM (0.5 mL) was added HCl (gas) in 1,4-dioxane (1 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature, then concentrated under reduced pressure to afford 2-chloro-7-(1- ethynylcyclopropyl)-5-fluoropyrrolo[2,1-f][1,2,4]triazine hydrochloride (20 mg, 98%) which was used in the next step directly without further purification. MS ESI calculated for C13H19Cl2FN6 [M – Cl]+, 313.13, found 313.10.1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 5.07-4.92 (m, 1H), 4.18-4.14 (m, 1H), 3.46-3.35 (m, 2H), 3.32-3.19 (m, 2H), 3.13-3.09 (m, 1H),WSGR Ref: 54004-768.601 2.25-2.18 (m, 1H), 1.88-1.80 (m, 1H), 1.30 (d, J = 7.2 Hz, 6H).19F NMR (377 MHz, DMSO-d6) δ -188.16 (1F). Example 4: (3R,4R)-N-{5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}-3-fluoro-1- methanesulfonylpiperidin-4-amine To a stirred mixture of (3R,4R)-N-{5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}-3- fluoropiperidin-4-amine hydrochloride (20 mg, 0.064 mmol) and methanesulfonic anhydride (13 mg, 0.077 mmol) in EtOAc (1.5 mL) was added sat. Na2CO3 (2 mL) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL). The organic layer was washed with water (15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 0.1% NH3.H2O), 10% to 55%; detector, UV 254 nm to afford (3R,4R)-N-{5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}-3-fluoro-1- methanesulfonylpiperidin-4-amine (15.7 mg, 62%) as a yellow solid. MS ESI calculated for C14H20ClFN6O2S [M + H]+, 391.10, found 391.20.1H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 5.15 (d, J = 6.8 Hz, 1H), 4.81-4.60 (m, 1H), 4.17-4.04 (m, 1H), 3.99-3.87 (m, 1H), 3.70- 3.62 (m, 1H), 3.54-3.46 (m, 1H), 3.33-3.17 (m, 2H), 2.92 (s, 3H), 2.51-2.42 (m, 1H), 1.84-1.76 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H).19F NMR (376 MHz, Chloroform-d) δ -188.64 (1F).

[0140] Example 5: (3R,4R)-3-fluoro-N-{7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}-1- methanesulfonylpiperidin-4-amine Step 1: tert-butyl (3R,4R)-4-({5-bromo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-3- fluoropiperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-fluoro-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin- 2-yl}amino)piperidine-1-carboxylate (80 mg, 0.211 mmol) in DMF (1 mL) was added NBS (56 mg, 0.317 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (2 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3 / 1) to afford tert-butyl (3R,4R)-4-({5-bromo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-3- fluoropiperidine-1-carboxylate (100 mg, 98%) as a yellow solid. MS ESI calculated for C18H26BrFN6O2 [M + H]+, 457.13, 459.13, found 457.25, 459.25.WSGR Ref: 54004-768.601 Step 2: tert-butyl (3R,4R)-3-fluoro-4-({7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate A mixture of tert-butyl (3R,4R)-4-({5-bromo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)-3-fluoropiperidine-1-carboxylate (75 mg, 0.164 mmol), trimethyl-1,3,5,2,4,6- trioxatriborinane (31 mg, 0.250 mmol), Pd(dppf)Cl2.CH2Cl2(17 mg, 0.021 mmol) and Cs2CO3(203 mg, 0.624 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) at room temperature and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford tert-butyl (3R,4R)-3-fluoro-4-({7-isopropyl-5- methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (80 mg, 98%) as brown oil. MS ESI calculated for C19H29FN6O2 [M + H]+, 393.23, found 393.15.1H NMR (400 MHz, Chloroform-d) δ 8.70 (s, 1H), 4.95 (brs, 1H), 4.72-4.46 (m, 1H), 4.17-4.07 (m, 2H), 3.86-3.77 (m, 1H), 3.57-3.51 (m, 1H), 3.27-3.20 (m, 2H), 2.58 (s, 3H), 2.40-2.33 (m, 1H), 1.60-1.52 (m, 1H), 1.50 (s, 9H), 1.44 (d, J = 6.8 Hz, 6H).19F NMR (376 MHz, Chloroform-d) δ -189.45 (1F). Example 5: (3R,4R)-3-fluoro-N-{7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}-1- methanesulfonylpiperidin-4-amine To a stirred mixture of tert-butyl (3R,4R)-3-fluoro-4-({7-isopropyl-5-methylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (80 mg, 0.204 mmol) in DCM (1 mL) was added HCl (gas) in 1,4-dioxane (1 mL, 4 M) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. To this was added methanesulfonyl methanesulfonate (43 mg, 0.246 mmol) in EtOAc (1 mL), followed by the addition of sat. Na2CO3 (1.5 mL) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (100 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc / EtOH = 8 / 3 / 1) to afford (3R,4R)-3- fluoro-N-{7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}-1-methanesulfonylpiperidin- 4-amine (15.9 mg, 20%) as a yellow solid. MS ESI calculated for C15H23FN6O2S [M + H]+, 371.16, found 371.10.1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 5.08 (brs, 1H), 4.84- 4.67 (m, 1H), 4.12-4.07 (m, 1H), 3.97-3.90 (m, 1H), 3.70-3.55 (m, 2H), 3.29-3.21 (m, 2H), 2.92 (s, 3H), 2.62 (s, 3H), 2.49-2.44 (m, 1H), 1.81-1.76 (m, 1H), 1.49-1.45 (m, 6H).19F NMR (376 MHz, Chloroform-d) δ -188.62 (1F).WSGR Ref: 54004-768.601

[0141] Example 6: (3R,4R)-N-[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine Step 1: tert-butyl (3R,4R)-3-fluoro-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate To a stirred solution of 2-methanesulfinyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine (20 mg, 0.084 mmol) and tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate (92 mg, 0.420 mmol) in NMP (1 mL) was added DIEA (65 mg, 0.504 mmol). The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 25% to 60%; detector, UV 254 nm to afford tert-butyl (3R,4R)-3- fluoro-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (19 mg, 57%) as a light yellow solid. MS ESI calculated for C19H29FN6O2 [M + H]+, 393.23, found 393.20.1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 7.66 (s, 1H), 5.06 (d, J = 6.8 Hz, 1H), 4.64-4.50 (m, 1H), 4.08-4.01 (m, 2H), 3.82-3.78 (m, 1H), 3.39-3.20 (m, 2H), 2.90 (d, J = 7.2 Hz, 2H), 2.40-2.28 (m, 2H), 1.98-1.80 (m, 1H), 1.49 (s, 9H), 0.99 (d, J = 6.8 Hz, 6H).19F NMR (377 MHz, Chloroform-d) δ -189.50 (1F). Step 2: tert-butyl (3R,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- fluoropiperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-fluoro-4-{[7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (19 mg, 0.048 mmol) in DMF (1 mL) was added NCS (8 mg, 0.058 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 30% to 55%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (11 mg, 53%) as a light yellow solid. MS ESI calculated for C19H28ClFN6O2[M + H]+, 427.19, found 427.15.1H NMR (400 MHz, Chloroform-d) δ 8.70 (s, 1H), 5.08 (d, J = 6.8 Hz, 1H), 4.61-4.48 (m, 1H), 4.18-4.01 (m, 2H), 3.85-3.78 (m, 1H), 3.28-3.20 (m, 2H), 2.87-2.83 (m, 2H), 2.38-2.23 (m, 2H), 1.52-1.49 (m, 10H), 0.99-0.96 (m, 6H).19F NMR (377 MHz, Chloroform-d) δ -189.44 (1F). Step 3: (3R,4R)-N-[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoropiperidin-4- amine hydrochlorideWSGR Ref: 54004-768.601 To a stirred solution of tert-butyl (3R,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (11 mg, 0.026 mmol) in DCM (1 mL) was added HCl (gas) in 1,4-dioxane (1 mL) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-N-[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin- 2-yl]-3-fluoropiperidin-4-amine hydrochloride (8 mg, 95%) as a yellow solid. MS ESI calculated for C14H21Cl2FN6 [M – Cl]+, 327.14, found 327.05. Example 6: (3R,4R)-N-[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine To a stirred solution of (3R,4R)-N-[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]-3-fluoropiperidin-4-amine hydrochloride (8 mg, 0.024 mmol) in EtOAc (1 mL) and sat. NaHCO3(1 mL) was added methanesulfonyl methanesulfonate (7 mg, 0.038 mmol). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 8 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 30% to 50%; detector, UV 254 nm to afford (3R,4R)-N-[5-chloro-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1-methanesulfonylpiperidin-4-amine (6 mg, 62%) as a light yellow solid. MS ESI calculated for C15H22ClFN6O2S [M + H]+, 405.12, found 405.10.1H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 5.50 (brs, 1H), 4.82-4.65 (m, 1H), 4.11-4.09 (m, 1H), 3.94-3.86 (m, 1H), 3.68-3.62 (m, 1H), 3.34-3.21 (m, 2H), 2.92 (s, 3H), 2.88 (d, J = 7.2 Hz, 2H), 2.47-2.43 (m, 1H), 2.32-2.26 (m, 1H), 1.84-1.77 (m, 1H), 1.00 (d, J = 6.8 Hz, 6H).19F NMR (376 MHz, Chloroform-d) δ -188.57 (1F).

[0142] Example 7: (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]piperidin-4-amine Step 1: tert-butyl (3R,4R)-4-{[5-bromo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- fluoropiperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-fluoro-4-{[7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (70 mg, 0.178 mmol) in DMF (2 mL) was added NBS (47 mg, 0.267 mmol). The resulting mixture was stirred for 16 h at 30 °C. The resulting mixture was purified by reversed phase chromatography with the following conditions:WSGR Ref: 54004-768.601 C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 30% to 55%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[5-bromo-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (55 mg, 65%) as a light yellow solid. MS ESI calculated for C19H28BrFN6O2 [M + H]+, 471.14, 473.14, found 471.15, 473.15.1H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 5.02 (d, J = 6.8 Hz, 1H), 4.62-4.48 (m, 1H), 4.20-4.03 (m, 2H), 3.84-3.81 (m, 1H), 3.35-3.23 (m, 2H), 2.88 (d, J = 7.2 Hz, 2H), 2.38-2.25 (m, 2H), 1.57-1.49 (m, 10H), 0.99 (d, J = 6.8 Hz, 6H).19F NMR (377 MHz, Chloroform-d) δ - 189.48 (1F). Step 2: tert-butyl (3R,4R)-3-fluoro-4-{[5-methyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate To a solution of tert-butyl (3R,4R)-4-{[5-bromo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin- 2-yl]amino}-3-fluoropiperidine-1-carboxylate (55 mg, 0.117 mmol) and trimethyl-1,3,5,2,4,6- trioxatriborinane (59 mg, 0.468 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) were added Pd(dppf)Cl2.CH2Cl2 (9 mg, 0.012 mmol) and Cs2CO3 (76 mg, 0.234 mmol). The reaction mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc / EtOH (3 / 5 / 1) to afford tert-butyl (3R,4R)-3-fluoro-4- {[5-methyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (29 mg, 61%) as a light yellow solid. MS ESI calculated for C20H31FN6O2[M + H]+, 407.25, found 407.25.1H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 5.04 (brs, 1H), 4.63-4.50 (m, 1H), 4.13-4.01 (m, 2H), 3.79-3.75 (m, 1H), 3.48-3.25 (m, 2H), 2.84 (d, J = 7.2 Hz, 2H), 2.51 (s, 3H), 2.38-2.22 (m, 2H), 1.56-1.48 (m, 10H), 0.97 (d, J = 6.8 Hz, 6H).19F NMR (377 MHz, Chloroform-d) δ -189.48 (1F). Step 3: (3R,4R)-3-fluoro-N-[5-methyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4- amine hydrochloride To a stirred solution of tert-butyl (3R,4R)-3-fluoro-4-{[5-methyl-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (29 mg, 0.071 mmol) in DCM (1 mL) was added HCl (gas) in 1,4-dioxane (1 mL) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-3-fluoro-N-[5-methyl-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine hydrochloride (20 mg, 91%) as light yellow oil. MS ESI calculated for C15H24ClFN6 [M – Cl]+, 307.20, found 307.10. Example 7:WSGR Ref: 54004-768.601 (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]piperidin-4-amine To a stirred solution of (3R,4R)-3-fluoro-N-[5-methyl-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]piperidin-4-amine hydrochloride (20 mg, 0.065 mmol) in EtOAc (2 mL) and sat. NaHCO3 (3 mL) was added methanesulfonyl methanesulfonate (18 mg, 0.104 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 20% to 50%; detector, UV 254 nm to afford (3R,4R)-3-fluoro-1- methanesulfonyl-N-[5-methyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4- amine (12 mg, 46%) as a light yellow solid. MS ESI calculated for C16H25FN6O2S [M + H]+, 385.17, found 385.15.1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 5.02 (brs, 1H), 4.80- 4.64 (m, 1H), 4.07-4.02 (m, 1H), 3.96-3.90 (m, 1H), 3.66-3.62 (m, 1H), 3.27-3.15 (m, 2H), 2.94- 2.89 (m, 5H), 2.61 (s, 3H), 2.46-2.42 (m, 1H), 2.35-2.31 (m, 1H), 1.81-1.72 (m, 1H), 1.01-0.98 (m, 6H).19F NMR (377 MHz, Chloroform-d) δ -188.67 (1F).

[0143] Example 8: (3R,4R)-3-fluoro-1-methanesulfonyl-N-[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]piperidin-4-amine Step 1: tert-butyl (3R,4R)-3-fluoro-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate A solution of tert-butyl (3R,4R)-3-fluoro-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (140 mg, 0.357 mmol) and I2 (362 mg, 1.428 mmol) in DMF (3 mL) was stirred for 16 h at room temperature. The reaction was quenched with sat. Na2S2O3(aq.) (25 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3 / 1) to afford tert-butyl (3R,4R)-3- fluoro-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1- carboxylate (130 mg, 70%) as a yellow solid. MS ESI calculated for C19H28FIN6O2 [M + H]+519.13, found 519.35.1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 5.03 (d, J = 6.8 Hz, 1H), 4.64-4.43 (m, 1H), 4.15-4.03 (m, 2H), 3.83-3.80 (m, 1H), 3.30-3.22 (m, 2H), 2.89 (d, J =WSGR Ref: 54004-768.601 7.2 Hz, 2H), 2.44-2.14 (m, 2H), 1.51-1.48 (m, 10H) 0.98 (d, J = 6.8 Hz, 6H).19F NMR (376 MHz, Chloroform-d) δ -189.50 (1F). Step 2: tert-butyl (3R,4R)-3-fluoro-4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate To a stirred mixture of tert-butyl (3R,4R)-3-fluoro-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (130 mg, 0.251 mmol), CuI (48 mg, 0.251 mmol) and KF (44 mg, 0.753 mmol) in DMF (3 mL) was added methyl 2,2-difluoro-2- sulfoacetate (241 mg, 1.255 mmol). The resulting mixture was stirred for 1.5 h at 80 °C under nitrogen atmosphere. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: column, C18; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 30% to 60%; detector, UV 254 nm to afford tert-butyl (3R,4R)-3-fluoro-4-{[7-(2-methylpropyl)- 5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (70 mg, 60%) as a yellow solid. MS ESI calculated for C20H28F4N6O2 [ M + H]+461.22, found 461.25.1H NMR (400 MHz, Chloroform-d) δ 9.06 (s, 1H), 5.14 (brs, 1H), 4.62-4.49 (m, 1H), 4.22-4.05 (m, 2H), 3.90-3.86 (m, 1H), 3.26-3.18 (m, 2H), 2.93 (d, J = 7.2 Hz, 2H), 2.45-2.22 (m, 2H), 1.52-1.49 (m, 10H), 1.01 (d, J = 6.8 Hz, 6H).19F NMR (376 MHz, Chloroform-d) δ -60.72 (3F), -189.46 (1F). Step 3: -3-fluoro-N-[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine hydrochloride To a stirred solution of tert-butyl (3R,4R)-3-fluoro-4-{[7-(2-methylpropyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (70 mg, 0.152 mmol) in DCM (2 mL) was added HCl (gas) in 1,4-dioxane (2 mL) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-3-fluoro-N-[7-(2-methylpropyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine hydrochloride (60 mg, 80%) as light yellow oil. MS ESI calculated for C15H21ClF4N6[M – Cl]+361.17, found 361.20. Example 8: -3-fluoro-1-methanesulfonyl-N-[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine A mixture of (3R,4R)-3-fluoro-N-[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]piperidin-4-amine hydrochloride (70 mg, 0.143 mmol) and methanesulfonic anhydride (37 mg, 0.214 mmol) in EtOAc (3 mL) and sat. NaHCO3 (aq.) (2 mL) was stirred forWSGR Ref: 54004-768.601 1 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: column, C18; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 30% to 50%; detector, UV 254 nm to afford (3R,4R)-3-fluoro-1- methanesulfonyl-N-[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2- yl]piperidin-4-amine (15.8 mg, 25%) as a white solid. MS ESI calculated for C16H22F4N6O2S [M + H]+, 439.15, found 439.30.1H NMR (400 MHz, Chloroform-d) δ 8.96 (s, 1H), 5.16 (d, J = 6.8 Hz, 1H), 4.81-4.63 (m, 1H), 4.13-4.03 (m, 1H), 3.98-3.92 (m, 1H), 3.74-3.61 (m, 1H), 3.29-3.13 (m, 2H), 2.97-2.90 (m, 5H), 2.60-2.44 (m, 1H), 2.32-2.25 (m, 1H), 1.82-1.74 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H).19F NMR (377 MHz, Chloroform-d) δ -60.73 (3F), -188.72 (1F).

[0144] Example 9: (3R,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-1- methanesulfonylpiperidin-3-ol Step 1: tert-butyl (3R,4R)-3-hydroxy-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate A solution of 2-methanesulfinyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine (60 mg, 0.252 mmol), DIEA (195 mg, 1.512 mmol) and tert-butyl (3R,4R)-4-amino-3-hydroxypiperidine-1- carboxylate (272 mg, 1.260 mmol) in NMP (0.6 mL) was stirred for 16 h at 80 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature and purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 40% to 60%; detector, UV 254 nm to afford tert-butyl (3R,4R)-3-hydroxy-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (71 mg, 72%) as a light yellow solid. MS ESI calculated for C19H30N6O3[M + H]+, 391.24, found 391.20.1H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 1H), 7.81 (s, 1H), 5.35 (brs, 1H), 4.34-3.30 (m, 1H), 4.21-4.15 (m, 1H), 3.76 (m, 1H), 3.68-3.66 (m, 1H), 3.01 (d, J = 7.2 Hz, 2H), 2.95-2.76 (m, 2H), 2.41-2.30 (m, 1H), 2.23-2.15 (m, 1H), 1.54- 1.47 (m, 10H), 1.02 (d, J = 6.8 Hz, 6H). Step 2: tert-butyl (3R,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- hydroxypiperidine-1-carboxylate A solution of tert-butyl (3R,4R)-3-hydroxy-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin- 2-yl]amino}piperidine-1-carboxylate (68 mg, 0.174 mmol) and NCS (28 mg, 0.209 mmol) in DMF (0.7 mL) was stirred for 16 h at room temperature. The mixture was purified by reversedWSGR Ref: 54004-768.601 phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 40% to 60%; detector, UV 254 nm to afford tert-butyl (3R,4R)- 4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-hydroxypiperidine- 1-carboxylate (60 mg, 81%) as a light yellow solid. MS ESI calculated for C19H29ClN6O3 [M + H]+, 425.20, found 425.20.1H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 5.23 (brs, 1H), 4.32-4.29 (m, 1H), 4.16-4.10 (m, 1H), 3.78-3.74 (m, 1H), 3.65-3.61 (m, 1H), 2.97-2.77 (m, 4H), 2.31-2.24 (m, 1H), 2.19-2.15 (m, 1H), 1.56-1.49 (m, 10H), 1.00 (d, J = 6.8 Hz, 6H). Step 3: (3R,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidin-3-ol hydrochloride A solution of tert-butyl (3R,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-hydroxypiperidine-1-carboxylate (60 mg, 0.141 mmol) in HCl (gas) in 1,4-dioxane (0.6 mL) and DCM (0.6 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-4-{[5-chloro-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidin-3-ol hydrochloride (50 mg, 98%) which was used in the next step directly without further purification. MS ESI calculated for C14H22Cl2N6O [M – Cl]+, 325.15, found 325.20. Example 9: (3R,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-1- methanesulfonylpiperidin-3-ol A solution of (3R,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidin-3-ol hydrochloride (60 mg, 0.166 mmol), methanesulfonyl methanesulfonate (46 mg, 0.266 mmol) and NaHCO3(42 mg, 0.498 mmol) in EtOAc (1.2 mL) was stirred for 1 h at room temperature. The reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 40% to 60%; detector, UV 254 nm to afford (3R,4R)-4-{[5-chloro-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-1-methanesulfonylpiperidin-3-ol (25 mg, 38%) as a light yellow solid. MS ESI calculated for C15H23ClN6O3S [M + H]+, 403.12; found 403.20.1H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 5.42 (brs, 1H), 4.02-3.91 (m, 1H), 3.90-3.77 (m, 3H), 2.98-2.92 (m, 1H), 2.90-2.76 (m, 6H), 2.32-2.25 (m, 2H), 1.84-1.70 (m, 1H), 1.00 (d, J = 6.8 Hz, 6H).

[0145] Example 10:WSGR Ref: 54004-768.601 (3S,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol Step 1: (3S,4R)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol A mixture of 2-methanesulfinyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine (20 mg, 0.084 mmol), (3S,4R)-4-aminooxan-3-ol hydrochloride (64 mg, 0.417 mmol) and DIEA (66 mg, 0.511 mmol) in NMP (1 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase: CH3CN in water (plus 5 mM formic acid); 10% to 30%; Detector: 220 / 254 nm to afford (3S,4R)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol (10 mg, 40%) as a yellow solid. MS ESI calculated for C14H21N5O2[M + H]+, 292.17; found 292.10.1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 7.69 (s, 1H), 5.09 (d, J = 6.4 Hz, 1H), 4.23 (brs, 1H), 4.12-4.08 (m, 1H), 4.03-3.98 (m, 1H), 3.82-3.78 (m, 1H), 3.70-3.67 (m, 1H), 3.55-3.52 (m, 1H), 3.30-3.25 (m, 1H), 2.88 (d, J = 7.2 Hz, 2H), 2.32-2.23 (m, 1H), 2.20-2.14 (m, 1H), 1.76-1.65 (m, 1H), 0.99 (d, J = 6.8 Hz, 6H). Example 10: (3S,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol A mixture of (3S,4R)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol (40 mg, 0.137 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (16 mg, 0.081 mmol) in CH3CN (1 mL) was stirred for 1 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; CH3CN in water (plus 5 mM formic acid); 20% to 45%; detector: 220 / 254 nm to afford (3S,4R)-4-{[5- chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol (13.5 mg, 30%) as a yellow solid. MS ESI calculated for C14H20ClN5O2[M + H]+, 326.13; found 326.05.1H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 5.11 (brs, 1H), 4.14-4.06 (m, 1H), 4.05-3.96 (m, 1H), 3.83-3.78 (m, 1H), 3.75-3.65 (m, 1H), 3.57-3.48 (m, 1H), 3.32-3.24 (m, 1H), 2.83 (d, J = 7.2 Hz, 2H), 2.30-2.21 (m, 1H), 2.20-2.12 (m, 1H), 1.76-1.65 (m, 1H), 0.99 (d, J = 6.4 Hz, 6H).

[0146] Example 11: (3S,4R)-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol Example 11: (3S,4R)-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol To a stirred solution of (3S,4R)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}oxan-3-ol (15 mg, 0.051 mmol) in DMF (1 mL) was added NIS (58 mg, 0.258 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% formic acid), 40% to 60%; detector, UV 254WSGR Ref: 54004-768.601 nm to afford (3S,4R)-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}oxan-3-ol (1 mg, 4%) as a light yellow solid. MS ESI calculated for C14H20IN5O2[M + H]+, 418.07 found 418.15.1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 5.04 (d, J = 6.4 Hz, 1H), 4.10-4.06 (m, 1H), 4.00-3.97 (m, 1H), 3.91-3.78 (m, 1H), 3.69-3.65 (m, 1H), 3.58-3.47 (m, 1H), 3.28-3.23 (m, 1H), 2.84 (d, J = 7.2 Hz, 2H), 2.28-2.21 (m, 1H), 2.17-2.12 (m, 1H), 1.74-1.66 (m, 1H), 0.98-0.95 (m, 6H).

[0147] Example 12: -3-fluoro-N-[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-1-methanesulfonylpiperidin-4-amine Step 1: tert-butyl (3R,4R)-3-fluoro-4-({5-iodo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate A solution of tert-butyl (3R,4R)-3-fluoro-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate (110 mg, 0.29 mmol) and I2 (369 mg, 1.46 mmol) in DMF (2 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 10% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)- 3-fluoro-4-({5-iodo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)piperidine-1- carboxylate (100 mg, 68%) as a yellow solid. MS ESI calculated for C18H26FIN6O2[M + H]+, 505.11, found 505.10.1H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 1H), 5.19 (s, 1H), 4.62-4.48 (m, 1H), 4.10-4.04 (m, 2H), 3.87-3.83 (m, 1H), 3.59-3.53 (m, 1H), 3.28-3.21 (m, 2H), 2.37-2.33 (m, 1H), 1.61-1.58 (m, 1H), 1.50 (s, 9H), 1.45 (d, J = 6.4 Hz, 6H).19F NMR (377 MHz, Chloroform-d) δ -189.34 (1F). Step 2: tert-butyl (3R,4R)-3-fluoro-4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate A mixture of tert-butyl (3R,4R)-3-fluoro-4-({5-iodo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate (100 mg, 0.20 mmol), methyl 2,2-difluoro-2-sulfoacetate (191 mg, 0.99 mmol), KF (35 mg, 0.59 mmol), and CuI (38 mg, 0.20 mmol) in DMF (2 mL) was stirred for 3 h at 80 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature, then was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)-3-fluoro-4-{[7-isopropyl-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (90 mg, 99%) as a yellow solid. MS ESI calculated for C19H26F4N6O2 [M + H]+, 447.21, found 447.15.1HWSGR Ref: 54004-768.601 NMR (400 MHz, Chloroform-d) δ 8.95 (s, 1H), 5.11 (d, J = 6.8 Hz, 1H), 4.64-4.49 (m, 1H), 4.17-4.08 (m, 2H), 3.89-3.86 (m, 1H), 3.59-3.52 (m, 1H), 3.23-3.17 (m, 2H), 2.38-2.34 (m, 1H), 1.53-1.51 (m, 10H), 1.45 (d, J = 6.8 Hz, 6H).19F NMR (377 MHz, Chloroform-d) δ -60.62 (3F), -189.40 (1F). Example 12: -3-fluoro-N-[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-1-methanesulfonylpiperidin-4-amine A solution of tert-butyl (3R,4R)-3-fluoro-4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (90 mg, 0.20 mmol) and HCl (gas) in 1,4- dioxane (2 mL, 4 M) in DCM (1 mL) was stirred for 40 min at room temperature. The resulting mixture was concentrated under reduced pressure. To this was added methanesulfonyl methanesulfonate (91 mg, 0.52 mmol) in EtOAc (2 mL), followed by the addition of NaHCO3(84 mg, 1.00 mmol) in H2O (1 mL) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (30 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford (3R,4R)-3- fluoro-N-[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-1- methanesulfonylpiperidin-4-amine (43.5 mg, 51%) as a white solid. MS ESI calculated for C15H20F4N6O2S [M + H]+, 425.13, found 425.05.1H NMR (400 MHz, Chloroform-d) δ 8.96 (s, 1H), 5.17 (d, J = 6.8 Hz, 1H), 4.84-4.63 (m, 1H), 4.15-4.07 (m, 1H), 4.02-3.92 (m, 1H), 3.75- 3.65 (m, 1H), 3.62-3.47 (m, 1H), 3.28-3.14 (m, 2H), 2.93 (s, 3H), 2.53-2.42 (m, 1H), 1.87-1.73 (m, 1H), 1.45 (d, J = 6.8 Hz, 6H).19F NMR (377 MHz, Chloroform-d) δ -60.61 (3F), -188.68 (1F).

[0148] Example 13: (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-1- methanesulfonylpiperidin-3-ol Step 1: tert-butyl (3R,4R)-3-hydroxy-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate To a stirred mixture of 7-isopropyl-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (250 mg, 1.115 mmol) and tert-butyl (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (1.21 g, 5.575 mmol) in NMP (2.5 mL) was added DIEA (1.16 mL, 6.690 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was quenched with water (100 mL)WSGR Ref: 54004-768.601 and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford tert-butyl (3R,4R)-3-hydroxy-4-({7-isopropylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (400 mg, 95%) as a yellow solid. MS ESI calculated for C18H28N6O3[M + H]+, 377.22, found 377.25.1H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 7.70 (s, 1H), 5.01 (brs, 1H), 4.34-4.31 (m, 1H), 4.20-4.10 (m, 2H), 3.81-3.75 (m, 1H), 3.65-3.60 (m, 1H), 3.54-3.47 (m, 1H), 2.93-2.86 (m, 1H), 2.80-2.75 (m, 1H), 2.18-2.15 (m, 1H), 1.57-1.54 (m, 1H), 1.50 (s, 9H), 1.50-1.42 (m, 6H). Step 2: tert-butyl (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-3- hydroxypiperidine-1-carboxylate To a stirred mixture of tert-butyl (3R,4R)-3-hydroxy-4-({7-isopropylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (50 mg, 0.133 mmol) in CH3CN (1 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (26 mg, 0.132 mmol) in portions at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was quenched with sat. NaHCO3 (aq., 30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford tert-butyl (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-3-hydroxypiperidine- 1-carboxylate. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 30% to 80%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)-3-hydroxypiperidine-1-carboxylate (19 mg, 30%) as a yellow solid. MS ESI calculated for C18H27ClN6O3[M + H]+, 411.18, found 411.20. Step 3: (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)piperidin-3-ol hydrochloride A mixture of tert-butyl (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)-3-hydroxypiperidine-1-carboxylate (100 mg, 0.243 mmol) and HCl (gas) in 1,4- dioxane (1 mL, 1.000 mmol) in DCM (1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-4-({5-chloro-7- isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)piperidin-3-ol hydrochloride (60 mg, 71%, crude) as a yellow solid. MS ESI calculated for C13H19ClN6O [M – Cl]+, 311.13; found 311.30.WSGR Ref: 54004-768.601 Example 13: (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-1- methanesulfonylpiperidin-3-ol To a stirred mixture of (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidin-3-ol (20 mg, 0.064 mmol) and methanesulfonyl methanesulfonate (13 mg, 0.077 mmol) in EtOAc (0.5 mL) was added sat. Na2CO3(1.5 mL) dropwise at 0 °C. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was diluted with EtOAc (50 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford (3R,4R)-4-({5-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-1- methanesulfonylpiperidin-3-ol (12.2 mg, 47%) as a yellow solid. MS ESI calculated for C14H21ClN6O3S [M + H]+, 389.11, found 389.10.1H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 5.03 (d, J = 6.4 Hz, 1H), 4.02-3.97 (m, 1H), 3.89-3.75 (m, 3H), 3.51-3.41 (m, 1H), 2.99- 2.91 (m, 1H), 2.89 (s, 3H), 2.83-2.73 (m, 1H), 2.35-2.25 (m, 1H), 1.85-1.71 (m, 1H), 1.43-1.37 (m, 6H).

[0149] Example 14: (3R,4R)-4-({7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-1- methanesulfonylpiperidin-3-ol Step 1: tert-butyl (3R,4R)-3-(acetyloxy)-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate To a stirred mixture of tert-butyl (3R,4R)-3-hydroxy-4-({7-isopropylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (350 mg, 0.930 mmol) and TEA (0.52 mL, 3.720 mmol) in DCM (3.5 mL) was added Ac2O (0.13 mL, 1.395 mmol) dropwise at room temperature. The resulting mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc / EtOH (4 / 3 / 1) to afford tert-butyl (3R,4R)-3-(acetyloxy)-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate (260 mg, 66%) as yellow oil. MS ESI calculated for C22H30N6O4[M + H]+, 419.23, found 419.30. Step 2:WSGR Ref: 54004-768.601 tert-butyl (3R,4R)-3-(acetyloxy)-4-({5-bromo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-(acetyloxy)-4-({7-isopropylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (130 mg, 0.311 mmol) in DMF (2 mL) was added NBS (83 mg, 0.467 mmol). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with sat. Na2S2O3(aq.) (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc / EtOH 2 / 5 / 1) to afford tert-butyl (3R,4R)-3-(acetyloxy)-4-({5- bromo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (110 mg, 71%) as a light yellow solid. MS ESI calculated for C20H29BrN6O4 [M + H]+, 497.14, 499.14, found 497.10, 499.10.1H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 5.34 (brs, 1H), 4.95- 4.91 (m, 1H), 4.11-4.06 (m, 1H), 3.93-3.89 (m, 2H), 3.56-3.49 (m, 1H), 3.19-3.13 (m, 2H), 2.37- 2.33 (m, 1H), 2.08 (s, 3H), 1.57-1.49 (m, 10H), 1.43-1.40 (m, 6H). Step 3: tert-butyl (3R,4R)-3-hydroxy-4-({7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate To a solution of tert-butyl (3R,4R)-3-(acetyloxy)-4-({5-bromo-7-isopropylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (110 mg, 0.221 mmol) and trimethyl- 1,3,5,2,4,6-trioxatriborinane (111 mg, 0.442 mmol, 50%) in 1,4-dioxane (2 mL) and H2O (0.5 mL) were added Pd(dppf)Cl2.CH2Cl2 (18 mg, 0.022 mmol) and Cs2CO3 (144 mg, 0.442 mmol). The reaction mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with PE / EtOAc / EtOH (1 / 5 / 1) to afford tert-butyl (3R,4R)-3-hydroxy-4-({7-isopropyl-5- methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (27 mg, 31%) as a light yellow solid. MS ESI calculated for C19H30N6O3[M + H]+, 391.24, found 391.25. Example 14: (3R,4R)-4-({7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-1- methanesulfonylpiperidin-3-ol A solution of tert-butyl (3R,4R)-3-hydroxy-4-({7-isopropyl-5-methylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (27 mg, 0.069 mmol) and HCl (gas) in 1,4- dioxane (1.5 mL) in DCM (1.5 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. To this were added EtOAc (2 mL) and sat. NaHCO3 (2 mL), followed by methanesulfonyl methanesulfonate (22 mg, 0.124 mmol) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature.WSGR Ref: 54004-768.601 The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 10% to 50%; detector, UV 254 nm to afford (3R,4R)- 4-({7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)-1-methanesulfonylpiperidin- 3-ol (12.7 mg, 55%) as a light yellow solid. MS ESI calculated for C15H24N6O3S [M + H]+, 369.16, found 369.10.1H NMR (400 MHz, Chloroform-d) δ 8.70 (s, 1H), 4.99 (brs, 1H), 4.12 (brs, 1H), 4.03-3.98 (m, 1H), 3.86-3.74 (m, 3H), 3.50-3.46 (m, 1H), 2.93-2.88 (m, 4H), 2.77- 2.72 (m, 1H), 2.58 (s, 3H), 2.30-2.25 (m, 1H), 1.82-1.73 (m, 1H), 1.44-1.42 (m, 6H).

[0150] Example 15: (3R,4R)-4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-1- methanesulfonylpiperidin-3-ol Step 1: tert-butyl (3R,4R)-3-(acetyloxy)-4-({5-iodo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)piperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-(acetyloxy)-4-({7-isopropylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (130 mg, 0.311 mmol) in DMF (2 mL) was added I2(315 mg, 1.244 mmol). The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched with sat. Na2S2O3(aq.) (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc / EtOH 2 / 5 / 1) to afford tert-butyl (3R,4R)-3-(acetyloxy)-4-({5- iodo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (130 mg, 76%) as a light yellow solid. MS ESI calculated for C20H29IN6O4 [M + H]+, 545.13, found 545.10.1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 5.29 (brs, 1H), 4.96-4.90 (m, 1H), 4.10-4.03 (m, 1H), 3.97-3.91 (m, 2H), 3.58-3.51 (m, 1H), 3.16-3.10 (m, 2H), 2.37-2.33 (m, 1H), 2.07 (s, 3H), 1.56-1.49 (m, 10H), 1.44-1.42 (m, 6H). Step 2: tert-butyl (3R,4R)-3-(acetyloxy)-4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin- 2-yl]amino}piperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-(acetyloxy)-4-({5-iodo-7-isopropylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (130 mg, 0.239 mmol) and methyl 2,2- difluoro-2-sulfoacetate (229 mg, 1.195 mmol) in DMF (2 mL) were added CuI (45 mg, 0.239 mmol) and KF (42 mg, 0.717 mmol) under nitrogen atmosphere. The reaction mixture wasWSGR Ref: 54004-768.601 stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature and purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 20% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)-3-(acetyloxy)-4-{[7-isopropyl-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (60 mg, 51%) as a light yellow solid. MS ESI calculated for C21H29F3N6O4[M + H]+, 487.22, found 487.20.1H NMR (400 MHz, Chloroform-d) δ 8.97 (s, 1H), 5.32 (brs, 1H), 4.95-4.94 (m, 1H), 4.15-3.95 (m, 2H), 4.00-3.93 (m, 1H), 3.57-3.52 (m, 1H), 3.15-3.09 (m, 2H), 2.40-2.35 (m, 1H), 2.08 (s, 3H), 1.55-1.48 (m, 10H), 1.46-1.43 (m, 6H).19F NMR (377 MHz, Chloroform-d) δ -60.33 (3F). Step 3: (3R,4R)-4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-1- methanesulfonylpiperidin-3-yl acetate A solution of tert-butyl (3R,4R)-3-hydroxy-4-({7-isopropyl-5-methylimidazo[4,3- f][1,2,4]triazin-2-yl}amino)piperidine-1-carboxylate (27 mg, 0.069 mmol) and HCl (gas) in 1,4- dioxane (1.5 mL) in DCM (1.5 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. To this were added EtOAc (2 mL) and sat. NaHCO3 (2 mL), followed by methanesulfonyl methanesulfonate (41 mg, 0.232 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (3R,4R)-4-{[7- isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-1- methanesulfonylpiperidin-3-yl acetate (50 mg, 92%) as a light yellow solid. MS ESI calculated for C17H23F3N6O4S [M + H]+, 465.15, found 465.10.1H NMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 5.50 (brs, 1H), 5.11-5.10 (m, 1H), 3.92-3.89 (m, 2H), 3.76-3.73 (m, 1H), 3.55-3.51 (m, 1H), 3.08-3.03 (m, 2H), 2.89 (s, 3H), 2.50-2.45 (m, 1H), 2.07 (s, 3H), 1.86-1.68 (m, 1H), 1.44- 1.41 (m, 6H).19F NMR (377 MHz, Chloroform-d) δ -60.55 (3F).

[0151] Example 15: (3R,4R)-4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-1- methanesulfonylpiperidin-3-ol To a stirred solution of (3R,4R)-4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin- 2-yl]amino}-1-methanesulfonylpiperidin-3-yl acetate (50 mg, 0.108 mmol) in MeOH (2 mL) was added K2CO3(44 mg, 0.324 mmol). The reaction mixture was stirred for 30 min at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3),WSGR Ref: 54004-768.601 20% to 50%; detector, UV 254 nm to afford (3R,4R)-4-{[7-isopropyl-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-1-methanesulfonylpiperidin-3-ol (22.5 mg, 49%) as a white solid. MS ESI calculated for C15H21F3N6O3S [M + H]+, 423.13, found 423.10.1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 5.15 (d, J = 6.4 Hz, 1H), 4.00-3.95 (m, 1H), 3.88-3.76 (m, 3H), 3.53-3.45 (m, 1H), 2.97-2.91 (m, 1H), 2.87 (s, 3H), 2.82-2.76 (m, 1H), 2.37-2.31 (m, 1H), 1.83-1.73 (m, 1H), 1.45-1.41 (m, 6H).19F NMR (377 MHz, Chloroform-d) δ -60.66 (3F).

[0152] Example 16: (3R,4R)-1-methanesulfonyl-4-{[5-methyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidin-3-ol Step 1: tert-butyl (3R,4R)-3-(acetyloxy)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-hydroxy-4-{[7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (380 mg, 0.97 mmol) and Ac2O (149 mg, 1.46 mmol) in DCM (5 mL) was added TEA (394 mg, 3.89 mmol). The reaction mixture was stirred for 16 h at 50 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EtOAc (6 / 1) to afford tert-butyl (3R,4R)-3-(acetyloxy)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (360 mg, 85%) as an yellow oil. MS ESI calculated for C21H32N6O4 [M + H]+, 433.25, found 433.20. Step 2: tert-butyl (3R,4R)-3-(acetyloxy)-4-{[5-bromo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate A solution of tert-butyl (3R,4R)-3-(acetyloxy)-4-{[7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (87 mg, 0.201 mmol) and NBS (53 mg, 0.301 mmol) in DMF (2 mL) was stirred for 2 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: column, C18; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 10% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)-3-(acetyloxy)-4-{[5-bromo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (100 mg, 97%) as a yellow solid. MS ESI calculated for C21H31BrN6O4 [M + H]+, 511.16513.16, found 511.20, 513.20.1H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 5.27 (brs, 1H), 4.95-4.91 (m, 1H), 4.13-3.97 (m, 1H), 3.96-3.83 (m, 2H), 3.26-3.10 (m, 2H), 2.89 (d, J = 7.2 Hz, 2H), 2.39-2.23 (m, 2H), 2.07 (s, 3H), 1.55-1.47 (m, 10H), 0.99 (d, J = 6.8 Hz, 6H).WSGR Ref: 54004-768.601 Step 3: tert-butyl (3R,4R)-3-hydroxy-4-{[5-methyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-(acetyloxy)-4-{[5-bromo-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (110 mg, 0.215 mmol) and trimethyl-1,3,5,2,4,6-trioxatriborinane (0.12 mL, 0.430 mmol) in dioxane (2 mL) and H2O (0.4 mL) were added Pd(dppf)Cl2.CH2Cl2 (18 mg, 0.022 mmol) and Cs2CO3 (140 mg, 0.430 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford tert-butyl (3R,4R)-3-hydroxy-4-{[5-methyl-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (50 mg, 57%) as a yellow solid. MS ESI calculated for C20H32N6O3[M + H]+, 405.25, found 405.20.1H NMR (400 MHz, Chloroform-d) δ 8.67 (s, 1H), 5.01-4.98 (m, 1H), 4.92 (brs, 1H), 4.22-4.09 (m, 1H), 3.83-3.70 (m, 1H), 3.66-3.54 (m, 1H), 2.93-2.82 (m, 3H), 2.80-2.71 (m, 1H), 2.55 (s, 3H), 2.38- 2.22 (m, 1H), 2.19-2.04 (m, 1H), 1.77-1.72 (m, 1H), 1.50 (s, 9H), 0.99 (d, J = 6.8 Hz, 6H). Example 16: (3R,4R)-1-methanesulfonyl-4-{[5-methyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidin-3-ol To a stirred solution of tert-butyl (3R,4R)-3-hydroxy-4-{[5-methyl-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (50 mg, 0.124 mmol) in DCM (1.5 mL) was added HCl (gas) in 1,4-dioxane (1.5 mL) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. To this were added EtOAc (2 mL) and sat. NaHCO3 (aq.) (2 mL), followed by the addition of methanesulfonyl methanesulfonate (46 mg, 0.264 mmol). The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: column, C18; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 10% to 50%; detector, UV 254 nm to afford (3R,4R)-1-methanesulfonyl-4-{[5-methyl-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidin-3-ol (21.7 mg, 41%) as a light yellow solid. MS ESI calculated for C16H26N6O3S [M + H]+, 383.18, found 383.10.1H NMR (400 MHz, Chloroform- d) δ 8.64 (s, 1H), 4.97 (d, J = 6.0 Hz, 1H), 4.01-3.97 (m, 1H), 3.84-3.68 (m, 3H), 2.94-2.85 (m,WSGR Ref: 54004-768.601 4H), 2.81 (d, J = 7.2 Hz, 2H), 2.76-2.69 (m, 1H), 2.51 (s, 3H), 2.30-2.21 (m, 2H), 1.83-1.72 (m, 1H), 0.99 (d, J = 6.8 Hz, 6H).

[0153] Example 17: (3R,4R)-1-methanesulfonyl-4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidin-3-ol Step 1: tert-butyl (3R,4R)-3-(acetyloxy)-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate A solution of tert-butyl (3R,4R)-3-(acetyloxy)-4-{[7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (360 mg, 0.83 mmol) and I2(1.06 g, 4.16 mmol) in DMF (5 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)-3-(acetyloxy)-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (280 mg, 60%) as a yellow solid. MS ESI calculated for C21H31IN6O4[M + H]+, 559.15, found 559.15.1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 7.66 (s, 1H), 5.10 (brs, 1H), 4.97-4.92 (m, 1H), 4.05-3.85 (m, 3H), 3.25-3.14 (m, 2H), 2.92 (d, J = 7.2 Hz, 2H), 2.41-2.25 (m, 2H), 2.07 (s, 3H), 1.56-1.49 (m, 10H), 0.99 (d, J = 6.8 Hz, 6H). Step 2: tert-butyl (3R,4R)-3-(acetyloxy)-4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-(acetyloxy)-4-{[5-iodo-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (140 mg, 0.25 mmol), KF (44 mg, 0.75 mmol) and methyl 2,2-difluoro-2-sulfoacetate (241 mg, 1.25 mmol) in DMF (2 mL) was added CuI (48 mg, 0.25 mmol). The reaction mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature and purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% formic acid), 10% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)-3-(acetyloxy)-4-{[7-(2-methylpropyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (120 mg, 96%) as a yellow solid. MS ESI calculated for C22H31F3N6O4 [M + H]+,501.24, found 501.25. 1H NMR (400 MHz, Chloroform-d) δ 8.95 (s, 1H), 5.30 (brs, 1H), 4.97-4.94 (m, 1H), 4.08-3.90 (m, 3H), 3.19-3.13 (m, 2H), 2.93 (d, J = 7.2 Hz, 2H), 2.41-2.26 (m, 2H), 2.09 (s, 3H), 1.55-1.50 (m, 10H), 1.00 (d, J = 6.8 Hz, 6H).19F NMR (377 MHz, Chloroform-d) δ -60.67 (3F).WSGR Ref: 54004-768.601 Step 3: -4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidin-3-yl acetate hydrochloride A solution of tert-butyl (3R,4R)-3-(acetyloxy)-4-{[7-(2-methylpropyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (120 mg, 0.24 mmol) and HCl (gas) in 1,4-dioxane (2 mL) in DCM (1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)- 4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidin-3- yl acetate hydrochloride (90 mg, 93%) which was used in the next step directly without further purification. MS ESI calculated for C17H24ClF3N6O2[M – Cl]+, 401.18, found 401.20. Step 4: (3R,4R)-1-methanesulfonyl-4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidin-3-yl acetate To a stirred solution of (3R,4R)-4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidin-3-yl acetate hydrochloride (90 mg, 0.20 mmol) and methanesulfonyl methanesulfonate (63 mg, 0.36 mmol) in EtOAc (2 mL) was added NaHCO3(52 mg, 0.62 mmol) in H2O (1 mL) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5 / 1) to afford (3R,4R)-1-methanesulfonyl-4-{[7-(2- methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidin-3-yl acetate (80 mg, 92%) as a white solid. MS ESI calculated for C18H25F3N6O4S [M + H]+, 479.16, found 479.15.1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 5.31 (d, J = 7.2 Hz, 1H), 5.15-5.10 (m, 1H), 3.99-3.87 (m, 2H), 3.76-3.73 (m, 1H), 3.13-3.05 (m, 2H), 2.93 (d, J = 7.2 Hz, 2H), 2.91 (s, 3H), 2.53-2.49 (m, 1H), 2.35-2.25 (m, 1H), 2.10 (s, 3H), 1.81-1.72 (m, 1H), 1.00 (d, J = 6.8 Hz, 6H).19F NMR (377 MHz, Chloroform-d) δ -60.78 (3F). Example 17: (3R,4R)-1-methanesulfonyl-4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidin-3-ol A solution of (3R,4R)-1-methanesulfonyl-4-{[7-(2-methylpropyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidin-3-yl acetate (60 mg, 0.13 mmol) and K2CO3(35 mg, 0.25 mmol) in MeOH (2 mL) was stirred for 20 min at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% NH3.H2O), 35% toWSGR Ref: 54004-768.601 50%; detector, UV 254 nm to afford (3R,4R)-1-methanesulfonyl-4-{[7-(2-methylpropyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidin-3-ol (31.1 mg, 56%) as a white solid. MS ESI calculated for C16H23F3N6O3S [M + H]+, 437.15, found 437.20.1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 5.14 (d, J = 6.4 Hz, 1H), 4.01-3.96 (m, 1H), 3.88-3.74 (m, 3H), 2.97-2.88 (m, 6H), 2.81-2.76 (m, 1H), 2.40-2.22 (m, 2H), 1.85-1.71 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H).19F NMR (377 MHz, Chloroform-d) δ -60.79 (3F).

[0154] Example 18: (3S,4R)-4-({7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-ol Step 1: triazin-2-yl}amino)oxan-3-olA mixture of 7-isopropyl-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (150 mg, 0.669 mmol), (3S,4R)-4-aminooxan-3-ol hydrochloride (771 mg, 5.016 mmol) and DIEA (1.05 mL, 6.028 mmol) in NMP (2.5 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 5% to 70%; detector, UV 254 nm to afford (3S,4R)-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-ol (117 mg, 56%) as a yellow solid. MS ESI calculated for C13H19N5O2 [M + H]+, 278.15, found 278.20.1H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H), 7.68 (s, 1H), 5.03 (d, J = 6.4 Hz, 1H), 4.17-4.06 (m, 2H), 4.04-3.96 (m, 1H), 3.84-3.77 (m, 1H), 3.71-3.65 (m, 1H), 3.56-3.44 (m, 2H), 3.30-3.25 (m, 1H), 2.20-2.10 (m, 1H), 1.79-1.66 (m, 1H), 1.44-1.41 (m, 6H). Step 2: triazin-2-yl}amino)oxan-3-yl acetateTo a stirred mixture of (3S,4R)-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3- ol (110 mg, 0.397 mmol) and TEA (276 uL, 1.983 mmol) in DCM (2 mL) were added Ac2O (56 uL, 0.596 mmol) dropwise at room temperature. The resulting mixture was stirred for 16 h at 50 °C. The resulting mixture concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4R)-4-({7- isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-yl acetate (100 mg, 78%) as yellow oil. MS ESI calculated for C15H21N5O3[M + H]+, 320.16, found 320.20.1H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 7.65 (s, 1H), 5.17 (d, J = 7.2 Hz, 1H), 5.03-4.95 (m, 1H), 4.07- 3.97 (m, 3H), 3.60-3.56 (m, 2H), 3.47-3.42 (m, 1H), 2.51-2.42 (m, 1H), 2.07 (s, 3H), 1.75-1.63 (m, 1H), 1.46-1.43 (m, 6H). Step 3: (3S,4R)-4-({5-bromo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-yl acetateWSGR Ref: 54004-768.601 A mixture of (3S,4R)-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-yl acetate (50 mg, 0.157 mmol) and NBS (42 mg, 0.235 mmol) in DMF (1 mL) was stirred for 3 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (10 mL) . The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4R)-4-({5-bromo-7- isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-yl acetate (50 mg, 76%) as yellow oil. MS ESI calculated for C15H20BrN5O3[M + H]+, 398.07, 400.07, found 398.00, 400.00.1H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 5.30 (brs, 1H), 5.01-4.96 (m, 1H), 4.07-3.97 (m, 3H), 3.60-3.40 (m, 3H), 2.48-2.40 (m, 1H), 2.08 (s, 3H), 1.75-1.65 (m, 1H), 1.44-1.40 (m, 6H). Step 4: ((3S,4R)-4-({7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-yl acetate A mixture of (3S,4R)-4-({5-bromo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3- yl acetate (50 mg, 0.126 mmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (43 uL, 0.151 mmol), Pd(dppf)Cl2.CH2Cl2(10 mg, 0.013 mmol) and Cs2CO3(123 mg, 0.378 mmol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4R)-4-({7-isopropyl-5- methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-yl acetate (20 mg, 33%) as brown oil. MS ESI calculated for C16H23N5O3[M + H]+, 334.18, found 334.20.1H NMR (400 MHz, Chloroform-d) δ 8.69 (s, 1H), 5.02-4.95 (m, 1H), 4.06-3.95 (m, 3H), 3.62-3.42 (m, 3H), 2.57 (s, 3H), 2.50-2.40 (m, 1H), 2.07 (s, 3H), 1.70-1.62 (m, 1H), 1.48-1.43 (m, 6H). Example 18: (3S,4R)-4-({7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-ol A mixture of (3S,4R)-4-({7-isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3- yl acetate (20 mg, 0.060 mmol) and K2CO3(16 mg, 0.120 mmol) in MeOH (1 mL) and THF (1 mL) was stirred for 30 min at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 5% to 70%; detector, UV 254 nm to afford (3S,4R)-4-({7- isopropyl-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-ol (9.6 mg, 54%) as a yellow solid. MS ESI calculated for C14H21N5O2 [M + H]+, 292.17, found 292.15.1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 5.04 (brs, 1H), 4.12-4.08 (m, 1H), 4.01-3.90 (m, 1H), 3.82-3.78WSGR Ref: 54004-768.601 (m, 1H), 3.73-3.69 (m, 1H), 3.56-3.52 (m, 2H), 3.31-3.28 (m, 1H), 2.62 (s, 3H), 2.18-2.12 (m, 1H), 1.74-1.69 (m, 1H), 1.62-1.58 (m, 6H).

[0155] Example 19: -4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-olStep 1: (3S,4R)-4-({5-iodo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-yl acetate A mixture of (3S,4R)-4-({7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-yl acetate (50 mg, 0.157 mmol) and I2 (159 mg, 0.628 mmol) in DMF (1 mL) was stirred for 2 h at room temperature. The reaction was quenched by the addition of sat. Na2S2O3(aq.) (15 mL). The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4R)-4-({5-iodo-7- isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-yl acetate (50 mg, 68%) as colorless oil. MS ESI calculated for C15H20IN5O3 [M + H]+, 446.06, found 446.05.1H NMR (400 MHz, Chloroform-d) δ 8.52 (s, 1H), 5.23 (d, J = 7.2 Hz, 1H), 5.00-4.96 (m, 1H), 4.07-3.97 (m, 3H), 3.61-3.52 (m, 2H), 3.47-3.41 (m, 1H), 2.47-2.41 (m, 1H), 2.07 (s, 3H), 1.71-1.66 (m, 1H), 1.44- 1.41 (m, 6H). Step 2: (3S,4R)-4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-yl acetate To a stirred mixture of (3S,4R)-4-({5-iodo-7-isopropylimidazo[4,3-f][1,2,4]triazin-2- yl}amino)oxan-3-yl acetate (60 mg, 0.135 mmol), CuI (26 mg, 0.135 mmol) and KF (24 mg, 0.404 mmol) in DMF (1 mL) was added methyl 2,2-difluoro-2-sulfoacetate (130 mg, 0.675 mmol). The resulting mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) / NH4OH (9 / 1, 50 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4R)-4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}oxan-3-yl acetate (44 mg, 80%) as colorless oil. MS ESI calculated for C16H20F3N5O3 [M + H]+, 388.15, found 388.30.1H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 1H), 5.03-4.97 (m, 1H), 4.09-3.99 (m, 3H), 3.61-3.54 (m, 2H), 3.47-3.42 (m, 1H), 2.47-2.42 (m, 1H), 2.08 (s, 3H), 1.75-1.65 (m, 1H), 1.47-1.43 (m, 6H).19F NMR (376 MHz, Chloroform- d) δ -60.62 (3F).WSGR Ref: 54004-768.601 Example 19: -4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-olA mixture of (3S,4R)-4-{[7-isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}oxan-3-yl acetate (44 mg, 0.114 mmol) and K2CO3 (31 mg, 0.227 mmol) in MeOH (1 mL) was stirred for 30 min at room temperature. The resuting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 5% to 70%; detector, UV 254 nm to afford (3S,4R)-4-{[7- isopropyl-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol (22 mg, 55%) as an off-white solid. MS ESI calculated for C14H18F3N5O2[M + H]+, 346.14, found 346.15.1H NMR (400 MHz, Chloroform-d) δ 8.97 (s, 1H), 5.15 (d, J = 6.0 Hz, 1H), 4.13-4.08 (m, 1H), 4.04-3.99 (m, 1H), 3.88-3.82 (m, 1H), 3.76-3.70 (m, 1H), 3.59-3.48 (m, 2H), 3.33-3.28 (m, 1H), 2.24-2.19 (m, 1H), 1.78-1.68 (m, 1H), 1.45-1.42 (m, 6H).19F NMR (376 MHz, Chloroform-d) δ -60.65 (3F).

[0156] Example 20: (3S,4R)-4-{[5-methyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol Step 1: (3S,4R)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-yl acetate To a stirred solution of (3S,4R)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}oxan-3-ol (210 mg, 0.721 mmol) and TEA (291 mg, 2.884 mmol) in DCM (4 mL) was added Ac2O (110 mg, 1.081 mmol) at room temperature. The reaction mixture was stirred for 16 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford (3S,4R)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-yl acetate (190 mg, 79%) as yellow oil. MS ESI calculated for C16H23N5O3 [M + H]+, 334.18, found 334.20.1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 7.69 (s, 1H), 5.22 (d, J = 6.8 Hz, 1H), 5.05-4.95 (m, 1H), 4.10-3.94 (m, 3H), 3.63-3.57 (m, 1H), 3.49-3.43 (m, 1H), 2.96 (d, J = 7.2 Hz, 2H), 2.50-2.42 (m, 1H), 2.39-2.27 (m, 1H), 2.08 (s, 3H), 1.75-1.62 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H). Step 2: (3S,4R)-4-{[5-bromo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-yl acetate A solution of (3S,4R)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-yl acetate (90 mg, 0.270 mmol) and NBS (72 mg, 0.405 mmol, 1.5 equiv) in DMF (2 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: column, C18; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 10% to 50%; detector, UV 254 nm to afford (3S,4R)-4-{[5-bromo-7-WSGR Ref: 54004-768.601 (2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-yl acetate (100 mg, 89%) as a yellow solid. MS ESI calculated for C16H22BrN5O3[M + H]+, 412.09, 414.09, found 412.00, 414.00.1H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 5.24 (d, J = 7.2 Hz, 1H), 5.02-4.94 (m, 1H), 4.07-3.94 (m, 3H), 3.62-3.56 (m, 1H), 3.48-3.42 (m, 1H), 2.88 (d, J = 7.2 Hz, 2H), 2.47-2.39 (m, 1H), 2.35-2.21 (m, 1H), 2.08 (s, 3H), 1.74-1.61 (m, 1H), 1.00 (d, J = 6.8 Hz, 6H). Example 20: (3S,4R)-4-{[5-methyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol To a stirred solution of (3S,4R)-4-{[5-bromo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}oxan-3-yl acetate (50 mg, 0.121 mmol) and trimethyl-1,3,5,2,4,6-trioxatriborinane (0.07 mL, 0.245 mmol) in dioxane (1 mL) and H2O (0.2 mL) were added Cs2CO3(79 mg, 0.242 mmol) and Pd(dppf)Cl2.CH2Cl2 (10 mg, 0.012 mmol). The reaction mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 10% to 50%; detector, UV 254 nm to afford (3S,4R)-4-{[5-methyl-7- (2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol (9.8 mg, 26%) as a yellow solid. MS ESI calculated for C15H23N5O2[M + H]+, 306.19, found 306.25.1H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 4.95 (d, J = 6.4 Hz, 1H), 4.32 (brs, 1H), 4.13-4.08 (m, 1H), 4.03- 3.98 (m, 1H), 3.82-3.75 (m, 1H), 3.71-3.65 (m, 1H), 3.55-3.47 (m, 1H), 3.29-3.23 (m, 1H), 2.84 (d, J = 7.2 Hz, 2H), 2.54 (s, 3H), 2.29-2.23 (m, 1H), 2.15-2.10 (m, 1H), 1.76-1.68 (m, 1H), 1.01- 0.98 (m, 6H).

[0157] Example 21: (3S,4R)-4-{[5-bromo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol Example 1: (3S,4R)-4-{[5-bromo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol A solution of (3S,4R)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol (20 mg, 0.069 mmol) and NBS (18 mg, 0.104 mmol) in DMF (0.5 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: column, C18; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 10% to 50%; detector, UV 254 nm to afford (3S,4R)-4-{[5-bromo-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol (3.9 mg, 15%) as a yellow solid. MS ESI calculated for C14H20BrN5O2 [M + H]+, 370.08, 372.08, found 370.05; 372.05.1H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 5.20 (brs, 1H), 4.11-4.08 (m, 1H), 4.04-3.96 (m,WSGR Ref: 54004-768.601 1H), 3.87-3.76 (m, 1H), 3.73-3.67 (m, 1H), 3.57-3.49 (m, 1H), 3.31-3.25 (m, 1H), 2.86 (d, J = 7.2 Hz, 2H), 2.32-2.22 (m, 1H), 2.20-2.13 (m, 1H), 1.76-1.64 (m, 1H), 0.99 (dd, J = 6.8, 2.4 Hz, 6H).

[0158] Example 22: -4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol Step 1: (3S,4R)-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-yl acetate To a stirred solution of (3S,4R)-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}oxan-3-yl acetate (90 mg, 0.270 mmol) in DMF (2 mL) was added I2(274 mg, 1.080 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: column, C18; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 10% to 50%; detector, UV 254 nm to afford (3S,4R)-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-yl acetate (110 mg, 88%) as a yellow solid. MS ESI calculated for C16H22IN5O3 [M + H]+, 460.08, found 460.05.1H NMR (400 MHz, Chloroform-d) δ 8.52 (s, 1H), 5.22 (d, J = 7.2 Hz, 1H), 5.02- 4.93 (m, 1H), 4.06-3.95 (m, 3H), 3.62-3.51 (m, 1H), 3.47-3.42 (m, 1H), 2.91-2.88 (m, 2H), 2.46- 2.36 (m, 1H), 2.34-2.20 (m, 1H), 2.07 (s, 3H), 1.74-1.60 (m, 1H), 1.00-0.97 (m, 6H). Step 2: -4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-yl acetate To a stirred solution of (3S,4R)-4-{[5-iodo-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}oxan-3-yl acetate (100 mg, 0.218 mmol) and CuI (41 mg, 0.218 mmol) in DMF (2 mL) were added KF (38 mg, 0.654 mmol) and methyl 2,2-difluoro-2-sulfoacetate (209 mg, 1.090 mmol) at room temperature. The resulting mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4R)-4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}oxan-3-yl acetate (60 mg, 68%) as a yellow solid. MS ESI calculated for C17H22F3N5O3 [M + H]+, 402.17, found 402.20.1H NMR (400 MHz, Chloroform-d) δ 8.99 (s, 1H), 5.35 (brs, 1H), 5.06-4.92 (m, 1H), 4.08-3.92 (m, 3H), 3.62-3.56 (m, 1H), 3.48-3.43 (m, 1H), 2.93 (d, J = 7.2 Hz, 2H), 2.50-2.41 (m, 1H), 2.35-2.27 (m, 1H), 2.08 (s, 3H), 1.72-1.62 (m, 1H), 1.02-0.99 (m, 6H).19F NMR (376 MHz, Chloroform-d) δ -60.68 (3F).WSGR Ref: 54004-768.601 Example 22: (3S,4R)-4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}oxan-3-ol A solution of (3S,4R)-4-{[7-(2-methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}oxan-3-yl acetate (60 mg, 0.149 mmol) and K2CO3 (62 mg, 0.447 mmol) in MeOH (1 mL) was stirred for 1 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: column, C18; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 10% to 50%; detector, UV 254 nm to afford (3S,4R)-4-{[7-(2- methylpropyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}oxan-3-ol (33.6 mg, 62%) as an off-white solid. MS ESI calculated for C15H20F3N5O2[M + H]+, 360.16, found 360.10.1H NMR (400 MHz, Chloroform-d) δ 8.96 (s, 1H), 5.17 (brs, 1H), 4.13-4.09 (m, 1H), 4.05-3.97 (m, 1H), 3.87-3.83 (m, 1H), 3.77-3.71 (m, 1H), 3.57-3.51 (m, 1H), 3.33-3.28 (m, 1H), 2.91 (d, J = 7.2 Hz, 2H), 2.33-2.18 (m, 2H), 1.77-1.66 (m, 1H), 1.02-0.99 (m, 6H).19F NMR (376 MHz, Chloroform-d) δ -60.77 (3F).

[0159] Example 23: (3R,4R)-N-[5-chloro-7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine Step 1: tert-butyl (3R,4R)-4-{[7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- fluoropiperidine-1-carboxylate A solution of 7-(4-chlorophenyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (54 mg, 0.184 mmol), tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate (201 mg, 0.920 mmol) and DIEA (143 mg, 1.104 mmol) in NMP (1 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 70% to 95%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (35 mg, 42%) as a light yellow solid. MS ESI calculated for C21H24ClFN6O2 [M + H]+, 447.17, found 447.20.1H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 1H), 8.55-8.48 (m, 2H), 7.90 (s, 1H), 7.55-7.51 (m, 2H), 5.22 (d, J = 6.8 Hz, 1H), 4.71-4.52 (m, 1H), 4.24-4.08 (m, 2H), 3.92-3.88 (m, 1H), 3.30-3.22 (m, 2H), 2.43- 2.37 (m, 1H), 1.68-1.60 (m, 1H), 1.51 (s, 9H). Step 2: tert-butyl (3R,4R)-4-{[5-chloro-7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- fluoropiperidine-1-carboxylateWSGR Ref: 54004-768.601 A solution of tert-butyl (3R,4R)-4-{[7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (70 mg, 0.157 mmol) and 1,3-dichloro-5,5- dimethylimidazolidine-2,4-dione (25 mg, 0.126 mmol) in CH3CN (2 mL) was stirred for 2 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (plus 10 mM NH4HCO3), 70% to 95%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[5- chloro-7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1- carboxylate (35 mg, 46%) as a light yellow solid. MS ESI calculated for C21H23Cl2FN6O2 [M + H]+, 481.12, found 481.10.1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.45-8.42 (m, 2H), 7.96 (s, 1H), 7.63-7.60 (m, 2H), 4.70-4.54 (m, 1H), 4.06-3.99 (m, 2H), 3.76-3.73 (m, 1H), 3.26- 3.21 (m, 1H), 3.19-3.16 (m, 1H), 2.56-2.51 (m, 1H), 1.58-1.52 (m, 1H), 1.43 (s, 9H). Step 3: (3R,4R)-N-[5-chloro-7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoropiperidin-4- amine hydrochloride A solution of tert-butyl (3R,4R)-4-{[5-chloro-7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (35 mg, 0.073 mmol) in HCl (gas) in 1,4-dioxane (1 mL) and DCM (1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-N-[5-chloro-7-(4- chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoropiperidin-4-amine hydrochloride (30 mg, crude) which was used in the next step directly without further purification. MS ESI calculated for C16H16Cl3FN6 [M – Cl]+, 381.07, found 381.05. Example 23: (3R,4R)-N-[5-chloro-7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine A solution of (3R,4R)-N-[5-chloro-7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3- fluoropiperidin-4-amine hydrochloride (35 mg, 0.084 mmol) and methanesulfonyl methanesulfonate (29 mg, 0.168 mmol) in sat. NaHCO3(3 mL) and EtOAc (2 mL) was stirred for 30 min at room temperature. The reaction was quenched by the addition of water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with CH3CN (3 mL) to afford (3R,4R)-N-[5-chloro-7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-WSGR Ref: 54004-768.601 fluoro-1-methanesulfonylpiperidin-4-amine (10.6 mg, 26%) as a yellow solid. MS ESI calculated for C17H17Cl2FN6O2S [M + H]+, 459.05; found 459.15.1H NMR (400 MHz, DMSO- d6) δ 9.15 (s, 1H), 8.44 (d, J = 7.6 Hz, 2H), 8.02 (s, 1H), 7.63 (d, J = 7.2 Hz, 2H), 4.87-4.73 (m, 1H), 4.07-4.03 (m, 1H), 3.81-3.74 (m, 1H), 3.55-3.52 (m, 1H), 3.22-3.12 (m, 2H), 3.00 (s, 3H), 2.23-2.20 (m, 1H), 1.73-1.69 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -186.45 (1F).

[0160] Example 24: -4-({5-fluoro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-ol Step 1: 2-Chloro-5-fluoro-7-isopropylimidazo[4,3-f][1,2,4]triazine A solution of 2-chloro-7-isopropylimidazo[4,3-f][1,2,4]triazine (170 mg, 0.87 mmol) and Selectfluor (613 mg, 1.73 mmol) in CH3CN (1 mL) was stirred for 48 h at 80 °C. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2-chloro-5-fluoro-7- isopropylimidazo[4,3-f][1,2,4]triazine (20 mg, crude) as a yellow solid. MS ESI calculated for C8H8ClFN4 [M + H]+, 215.04, found 215.15. Example 24: (3S,4R)-4-({5-fluoro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-ol To a stirred solution of 2-chloro-5-fluoro-7-isopropylimidazo[4,3-f][1,2,4]triazine (18 mg, 0.08 mmol) and (3S,4R)-4-aminooxan-3-ol hydrochloride (16 mg, 0.10 mmol) in NMP (1 mL) was added DIEA (33 mg, 0.25 mmol) at room temperature. The reaction mixture was stirred for 2 h at 60 °C. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by Prep-TLC with PE / EtOAc (2 / 1). The crude product was purified by Prep-HPLC with the following conditions: Column: XselectCSH Prep Fluoro-Phenyl OBD C18 Column, 30 x 150 mm, 5 μm; CH3CN in water (0.1% formic acid), Flow rate: 60 mL / min; 18% to 33%; Wave Length: 254 nm / 220 nm to afford (3S,4R)-4-({5-fluoro-7-isopropylimidazo[4,3-f][1,2,4]triazin-2-yl}amino)oxan-3-ol (4.4 mg, 17%) as an off-white solid. MS ESI calculated for C13H18FN5O2 [M + H]+, 296.14, found 296.15.1H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 4.99 (d, J = 6.0 Hz, 1H), 4.10-4.06 (m, 1H), 4.01-3.96 (m, 1H), 3.82-3.78 (m, 1H), 3.70-3.64 (m, 1H), 3.58-3.36 (m, 2H), 3.27-3.22 (m, 1H), 2.15-2.11 (m, 1H), 1.71-1.67 (m, 1H), 1.36-1.33 (m, 6H).19F NMR (377 MHz, Chloroform-d) δ -122.32 (1F).

[0161] Example 25:WSGR Ref: 54004-768.601 (3R,4R)-N-[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec- butyl was not determined) (CHIRALPAK AD-H, Hexane / i-PrOH = 90 / 10, 1stpeak)

[0162] Example 28: (3R,4R)-N-[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec- butyl was not determined) (CHIRALPAK AD-H, Hexane / i-PrOH = 90 / 10, 2ndpeak) Step 1: (3R,4R)-3-fluoro-4-{[7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1- carboxylate A mixture of 2-methanesulfinyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazine (580 mg, 2.434 mmol), tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate (2.66 g, 12.170 mmol) and DIEA (1.89 g, 14.604 mmol) in NMP (12 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford tert-butyl (3R,4R)-3-fluoro-4-{[7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (460 mg, 48%) as a yellow solid. MS ESI calculated for C19H29FN6O2[M + H]+, 393.23; found 393.25.1H NMR (Chloroform-d) δ 8.76 (s, 1H), 7.68 (s, 1H), 5.00 (brs, 1H), 4.68-4.51 (m, 1H), 4.17-4.02 (m, 2H), 3.82-3.78 (m, 1H), 3.40-3.25 (m, 3H), 2.39-2.35 (m, 1H), 1.98-1.94 (m, 1H), 1.81-1.75 (m, 1H), 1.61-1.55 (m, 1H), 1.50 (s, 9H), 1.43-1.39 (m, 3H), 0.91-0.87 (m, 3H).19F NMR (377 MHz, Chloroform-d) δ -189.48 (1F). Step 2: (3R,4R)-4-{[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine- 1-carboxylate A mixture of tert-butyl (3R,4R)-3-fluoro-4-{[7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (50 mg, 0.127 mmol) and NCS (25 mg, 0.187 mmol) in DMF (1 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford tert-butyl (3R,4R)-4-{[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (40 mg, 73%) as a yellow solid. MS ESI calculatedWSGR Ref: 54004-768.601 for C19H28ClFN6O2 [M + H]+, 427.19; found 427.20.1H NMR (Chloroform-d) δ 8.71 (s, 1H), 5.01 (d, J = 6.4 Hz, 1H), 4.65-4.46 (m, 1H), 4.18-4.02 (m, 2H), 3.84-3.80 (m, 1H), 3.39-3.17 (m, 3H), 2.39-2.33 (m, 1H), 1.97-1.87 (m, 1H), 1.78-1.71 (m, 1H), 1.60-1.49 (m, 10H), 1.40-1.36 (m, 3H), 0.91-0.87 (m, 3H).19F NMR (377 MHz, Chloroform-d) δ -189.32 (1F). Step 3: 7-(sec-butyl)-5-chloro-N-((3R,4R)-3-fluoropiperidin-4-yl)imidazo[5,1-f][1,2,4]triazin-2-amine hydrochloride A mixture of tert-butyl (3R,4R)-4-{[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (40 mg, 0.094 mmol) and HCl (gas) in 1,4-dioxane (1 mL) in DCM (1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 7-(sec-butyl)-5-chloro-N-((3R,4R)-3- fluoropiperidin-4-yl)imidazo[5,1-f][1,2,4]triazin-2-amine hydrochloride (30 mg, crude) as a yellow solid. MS ESI calculated for C14H21Cl2FN6[M – Cl]+, 327.14; found 327.25. Step 4: (3R,4R)-N-[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine To mixture of (3R,4R)-N-[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3- fluoropiperidin-4-amine hydrochloride (780 mg, 2.147 mmol) in EtOAc (10 mL) was added sat. NaHCO3(5 mL), followed by the addition of methanesulfonic anhydride (748 mg, 4.294 mmol) at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC with PE / EtOAc (1 / 1) to afford (3R,4R)-N-[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3- fluoro-1-methanesulfonylpiperidin-4-amine (800 mg, 92%) as a yellow solid. MS ESI calculated for C15H22ClFN6O2S [M + H]+, 405.12; found 405.10.1H NMR (Chloroform-d) δ 8.72 (s, 1H), 5.27 (brs, 1H), 4.82-4.65 (m, 1H), 4.11-4.07 (m, 1H), 3.93-3.89 (m, 1H), 3.67-3.63 (m, 1H), 3.40-3.17 (m, 3H), 2.92 (s, 3H), 2.48-2.44 (m, 1H), 1.97-1.89 (m, 1H), 1.80-1.72 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H). Example 25: (3R,4R)-N-[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec- butyl was not determined) (CHIRALPAK AD-H, Hexane / i-PrOH = 90 / 10, 1stpeak) Example 28:WSGR Ref: 54004-768.601 (3R,4R)-N-[5-chloro-7-(sec-butyl)imidazo[4,3- triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec- butyl was not determined) (CHIRALPAK AD-H, Hexane / i-PrOH = 90 / 10, 2ndpeak) (3R,4R)-N-[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine (400 mg) was purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK AD-H, 2 x 25 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: i-PrOH; Flow rate: 20 mL / min; A:B = 90:10; Wave Length: 254 / 220 nm; RT1: 34.83 min to afford (3R,4R)-N-[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3- fluoro-1-methanesulfonylpiperidin-4-amine (single diastereoisomer, absolute chiral configuration of butyl was not determined) (CHIRALPAK AD-H, Hexane / i-PrOH = 90 / 10,1stpeak) (100.3 mg, 25%) as a yellow solid. MS ESI calculated for C15H22ClFN6O2S [M + H]+, 405.12; found 405.10.1H NMR (Chloroform-d) δ 8.72 (s, 1H), 5.29-5.25 (m, 1H), 4.78-4.63 (m, 1H), 4.09-4.05 (m, 1H), 3.91-3.85 (m, 1H), 3.65-3.60 (m, 1H), 3.40-3.17 (m, 3H), 2.92 (s, 3H), 2.46-2.41 (m, 1H), 1.93-1.87 (m, 1H), 1.81-1.70 (m, 2H), 1.36 (d, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H).19F NMR (377 MHz, Chloroform-d) δ -188.62 (1F). Also RT2: 40.30 min to (3R,4R)-N-[5-chloro-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3- fluoro-1-methanesulfonylpiperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / i-PrOH = 90 / 10, 2ndpeak) (100 mg, 25%) as a yellow solid. MS ESI calculated for C15H22ClFN6O2S [M + H]+, 405.12; found 405.05.1H NMR (Chloroform-d) δ 8.72 (s, 1H), 5.11 (brs, 1H), 4.82-4.65 (m, 1H), 4.09-4.03 (m, 1H), 3.95-3.87 (m, 1H), 3.68-3.62 (m, 1H), 3.36-3.17 (m, 3H), 2.90 (s, 3H), 2.46-2.42 (m, 1H), 1.93-1.87 (m, 1H), 1.78-1.69 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H).19F NMR (377 MHz, Chloroform-d) δ -188.65 (1F).

[0163] Example 26: (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / EtOH = 85 / 15, 1stpeak)

[0164] Example 29: (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / EtOH = 85 / 15, 2ndpeak) Step 1: tert-butyl (3R,4R)-4-{[5-bromo-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- fluoropiperidine-1-carboxylateWSGR Ref: 54004-768.601 A mixture of tert-butyl (3R,4R)-3-fluoro-4-{[7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (150 mg, 0.382 mmol) and NBS (102 mg, 0.573 mmol) in DMF (2 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford tert-butyl (3R,4R)-4-{[5-bromo-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}- 3-fluoropiperidine-1-carboxylate (120 mg, 66 %) as a yellow solid. MS ESI calculated for C19H28BrFN6O2[M + H]+, 471.14, 473.14; found 471.15, 473.15. Step 2: tert-butyl (3R,4R)-3-fluoro-4-{[5-methyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate A mixture of tert-butyl (3R,4R)-4-{[5-bromo-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (100 mg, 0.212 mmol), trimethyl-1,3,5,2,4,6- trioxatriborinane (54 mg, 0.428 mmol), Cs2CO3(138 mg, 0.422 mmol) and Pd(dppf)Cl2DCM (17 mg, 0.021 mmol) in dioxane (1 mL) and water (0.25 mL) was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (2 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by Prep-TLC with PE / EtOAc (1 / 1) to afford tert-butyl (3R,4R)-3-fluoro-4-{[5-methyl-7-(sec-butyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (20 mg, 51%) as a yellow solid. MS ESI calculated for C20H31FN6O2 [M + H]+, 407.25; found 407.20. Step 3: (3R,4R)-3-fluoro-N-[5-methyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine hydrochloride A mixture of tert-butyl (3R,4R)-3-fluoro-4-{[5-methyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin- 2-yl]amino}piperidine-1-carboxylate (60 mg, 0.025 mmol) and HCl (gas) in 1,4-dioxane (1 mL) in DCM (1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-3-fluoro-N-[5-methyl-7-(sec-butyl)imidazo[4,3- f][1,2,4]triazin-2-yl]piperidin-4-amine hydrochloride (40 mg, crude) as a yellow solid. MS ESI calculated for C15H23FN6 [M + H]+, 307.20; found 307.10. Step 4:WSGR Ref: 54004-768.601 (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]piperidin-4-amine A mixture of (3R,4R)-3-fluoro-N-[5-methyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]piperidin-4-amine hydrochloride (55 mg, 0.160 mmol) in EtOAc (1 mL) was added sat. NaHCO3 (0.5 mL) followed by tha addition of methanesulfonic anhydride (56 mg, 0.321 mmol) at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by Prep- TLC with PE / EtOAc (1 / 1) to afford (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(sec- butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine (40 mg, 64%) as a yellow solid. MS ESI calculated for C16H25FN6O2S [M + H]+, 385.17; found 385.20. Example 26: (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / EtOH = 85 / 15, 1stpeak) Example 29: (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / EtOH = 85 / 15, 2ndpeak) (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]piperidin-4-amine (30 mg) was purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK AD-H, 2 x 25 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL / min; A:B = 85:15; Wave Length: 254 / 220 nm; RT1: 27.85 min to afford (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(sec- butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / EtOH = 85 / 15, 1stpeak) (5.1 mg, 16%) as a yellow solid as a yellow solid. MS ESI calculated for C16H25FN6O2S [M + H]+, 385.17; found 385.15.1H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 4.90 (brs, 1H), 4.82-4.65 (m, 1H), 4.10-4.05 (m, 1H), 3.90-3.83 (m, 1H), 3.63-3.57 (m, 1H), 3.35-3.20 (m, 3H), 2.94-2.90 (s, 3H), 2.54 (s, 3H), 2.52-2.43 (m, 1H), 2.00-1.89 (m, 1H), 1.82-1.71 (m, 2H), 1.38 (d, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H).19F NMR (377 MHz, Chloroform-d) δ -188.67 (1F). RT2: 32.36 min to afford (3R,4R)-3-fluoro-1-methanesulfonyl-N-[5-methyl-7-(sec- butyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine (single diastereoisomer, absolute chiralWSGR Ref: 54004-768.601 configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / EtOH = 85 / 15, 2ndpeak) (5.1 mg, 16%) as a yellow solid as a yellow solid. MS ESI calculated for C16H25FN6O2S [M + H]+, 385.17; found 385.20.1H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 4.91 (brs, 1H), 4.83-4.67 (m, 1H), 4.11-4.03 (m, 1H), 3.91-3.84 (m, 1H), 3.67-3.58 (m, 1H), 3.39-3.18 (m, 3H), 2.90 (s, 3H), 2.54 (s, 3H), 2.48-2.43 (m, 1H), 1.97-1.89 (m, 1H), 1.78- 1.71 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H), 0.88-0.84 (m, 3H).19F NMR (377 MHz, Chloroform-d) δ -188.66 (1F).

[0165] Example 27: (3R,4R)-3-fluoro-1-methanesulfonyl-N-[7- butyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / i-PrOH = 90 / 10, 1stpeak)

[0166] Example 30: -3-fluoro-1-methanesulfonyl-N-[7-(sec-butyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / i-PrOH = 90 / 10, 2ndpeak) Step 1: tert-butyl(3R,4R)-3-fluoro-4-{[5-iodo-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-fluoro-4-{[7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin- 2-yl]amino}piperidine-1-carboxylate (75 mg, 0.191 mmol) in DMF (1 mL) was added I2(194 mg, 0.764 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with sat. sodium thiosulfate (aq.) (30 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by Prep-TLC with PE / EtOAc / EtOH (12 / 5 / 1) to afford tert- butyl (3R,4R)-3-fluoro-4-{[5-iodo-7-(sec-butyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (55 mg, 55%) as a light yellow solid. MS ESI calculated for C19H28FIN6O2 [M + H]+, 519.13, found 519.25. Step 2: tert-butyl(3R,4R)-3-fluoro-4-{[7-(sec-butyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-3-fluoro-4-{[5-iodo-7-(sec-butyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (55 mg, 0.106 mmol) and methyl 2,2- difluoro-2-sulfoacetate (102 mg, 0.530 mmol) in DMF (2 mL) were added CuI (20 mg, 0.106 mmol) and KF (18 mg, 0.318 mmol). The resulting mixture was stirred for 2 h at 80 °C underWSGR Ref: 54004-768.601 nitrogen atmosphere. The reaction was quenched with sat. Na2S2O3 (aq.) (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by Prep-TLC with PE / EtOAc / EtOH (6 / 5 / 1) to afford tert- butyl (3R,4R)-3-fluoro-4-{[7-(sec-butyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (40 mg, 81%) as a light yellow solid. MS ESI calculated for C20H28F4N6O2 [M + H]+, 461.22, found 461.35.1H NMR (400 MHz, Chloroform-d) δ 8.96 (s, 1H), 5.16 (brs, 1H), 4.65-4.46 (m, 1H), 4.25-4.13 (m, 2H), 3.87-3.85 (m, 1H), 3.40-3.38 (m, 1H), 3.22-3.20 (m, 2H), 2.40-2.31 (m, 1H), 2.00-1.97 (m, 1H), 1.79-1.72 (m, 2H), 1.62 (s, 9H), 1.48-1.45 (m, 3H), 0.88-0.85 (m, 3H).19F NMR (377 MHz, Chloroform-d) δ -60.59 (3F), - 189.41 (1F). Step 3: (3R,4R)-3-fluoro-1-methanesulfonyl-N-[7-(sec-butyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]piperidin-4-amine A solution of tert-butyl (3R,4R)-3-fluoro-4-{[7-(sec-butyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (40 mg, 0.087 mmol) and HCl (gas) in 1,4- dioxane (1 mL) in DCM (1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced. To this were added EtOAc (2 mL) and sat.NaHCO3 (2 mL), followed by the addition of methanesulfonyl methanesulfonate (29 mg, 0.166 mmol). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (10 mmol / L NH4HCO3), 20% to 50%; detector, UV 254 nm to afford (3R,4R)-3-fluoro-1-methanesulfonyl- N-[7-(sec-butyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine (15 mg, 41%) as a yellow solid. MS ESI calculated for C16H22F4N6O2S [M + H]+, 439.15, found 439.10. Example 27: (3R,4R)-3-fluoro-1-methanesulfonyl-N-[7-(sec-butyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of butyl was not determined) (CHIRALPAK AD-H, Hexane / i-PrOH = 90 / 10, 1stpeak) Example 30: (3R,4R)-3-fluoro-1-methanesulfonyl-N-[7-(sec-butyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / i-PrOH = 90 / 10, 2ndpeak)WSGR Ref: 54004-768.601 (3R,4R)-3-fluoro-1-methanesulfonyl-N-[7-(sec-butyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]piperidin-4-amine (15 mg) was purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK AD-H, 2 x 25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: i-PrOH; Flow rate: 20 mL / min; A:B = 90:10; Wave Length: 254 / 220 nm; RT1: 24.55 min to afford (3R,4R)-3-fluoro-1-methanesulfonyl-N-[7-(sec-butyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / i- PrOH = 90 / 10, 1stpeak) (3.2 mg, 21%) as a white solid. MS ESI calculated for C16H22F4N6O2S [M + H]+, 439.15, found 439.15.1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 5.14 (d, J = 6.4 Hz, 1H), 4.78-4.64 (m, 1H), 4.10-4.05 (m, 1H), 3.96-3.94 (m, 1H), 3.69-3.65 (m, 1H), 3.39-3.33 (m, 1H), 3.24-3.15 (m, 2H), 2.91 (s, 3H), 2.46-2.44 (m, 1H), 1.99-1.92 (m, 1H), 1.83-1.73 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H).19F NMR (377 MHz, Chloroform-d) δ -60.63 (3F), -188.70 (1F). RT2: 28.80 min to afford (3R,4R)-3-fluoro-1-methanesulfonyl-N-[7-(sec-butyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]piperidin-4-amine (single diastereoisomer, absolute chiral configuration of sec-butyl was not determined) (CHIRALPAK AD-H, Hexane / i- PrOH = 90 / 10, 2ndpeak) (2.4 mg, 15%) as a white solid. MS ESI calculated for C16H22F4N6O2S [M + H]+, 439.15, found 439.15.1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 5.14 (d, J = 6.4 Hz, 1H), 4.80-4.65 (m, 1H), 4.09-4.06 (m, 1H), 3.97-3.93 (m, 1H), 3.69-3.66 (m, 1H), 3.38- 3.35 (m, 1H), 3.25-3.16 (m, 2H), 2.91 (s, 3H), 2.47-2.43 (m, 1H), 1.99-1.92 (m, 1H), 1.82-1.72 (m, 2H), 1.40 (d, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H).19F NMR (377 MHz, Chloroform-d) δ -60.63 (3F), -188.70 (1F).

[0167] Example 31: (3R,4R)-N-[7-(4-chlorophenyl)-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine Step 1: tert-butyl (3R,4R)-4-((5-bromo-7-(4-chlorophenyl)imidazo[5,1-f][1,2,4]triazin-2-yl)amino)-3- fluoropiperidine-1-carboxylate To a stirred mixture of tert-butyl (3R,4R)-4-{[7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (120 mg, 0.27 mmol) in DMF (2 mL) was added NBS (52 mg, 0.30 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified byWSGR Ref: 54004-768.601 trituration with EtOAc (40 mL) to afford tert-butyl (3R,4R)-4-{[5-bromo-7-(4- chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (105 mg, 74 %) as a yellow solid. MS ESI calculated for C21H23BrClFN6O2[M + H]+, 525.05, 527.07, found 525.10, 527.10. Step 2: tert-butyl (3R,4R)-4-((7-(4-chlorophenyl)-5-methylimidazo[5,1-f][1,2,4]triazin-2-yl)amino)-3- fluoropiperidine-1-carboxylate To a stirred mixture of tert-butyl (3R,4R)-4-{[5-bromo-7-(4-chlorophenyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (100 mg, 0.19 mmol), Pd(dppf)Cl2DCM (15 mg, 0.02 mmol) and Cs2CO3(124 mg, 0.38 mmol) in dioxane (4 mL) and water (0.8 mL) was added trimethyl-1,3,5,2,4,6-trioxatriborinane (0.11 mL, 0.38 mmol under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford tert-butyl (3R,4R)-4-{[7-(4-chlorophenyl)-5-methylimidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (57 mg, 65%) as a yellow solid. MS ESI calculated for C22H26ClFN6O2[M + H]+, 461.18, found 461.25.1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.52-8.46 (m, 2H), 7.68-7.55 (m, 3H), 4.69-4.55 (m, 1H), 4.08-3.96 (m, 2H), 3.75-3.71 (m, 1H), 3.33-3.17 (m, 2H), 2.51 (s, 3H), 2.10-2.02 (m, 1H), 1.58-1.52 (m, 1H), 1.42 (s, 9H). Step 3: (3R,4R)-N-[7-(4-chlorophenyl)-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoropiperidin-4- amine hydrochloride To a stirred mixture of tert-butyl (3R,4R)-4-{[7-(4-chlorophenyl)-5-methylimidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (57 mg, 0.12 mmol) in DCM (1 mL) was added HCl (gas) in 1,4-dioxane (1 mL) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-N-[7-(4-chlorophenyl)-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl]-3- fluoropiperidin-4-amine hydrochloride (44 mg, 98 %) as a yellow solid. MS ESI calculated for C17H19Cl2FN6 [M – Cl]+, 361.13, found 361.20. Example 31: (3R,4R)-N-[7-(4-chlorophenyl)-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amineWSGR Ref: 54004-768.601 To a stirred mixture of (3R,4R)-N-[7-(4-chlorophenyl)-5-methylimidazo[4,3-f][1,2,4]triazin-2- yl]-3-fluoropiperidin-4-amine hydrochloride (40 mg, 0.11 mmol) in EtOAc (1 mL) was added sat. NaHCO3(1 mL), followed by the addition of methanesulfonic anhydride (39 mg, 0.22 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (10 mmol / L NH4HCO3), 40% to 60%; detector, UV 254 nm to afford (3R,4R)-N-[7-(4- chlorophenyl)-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1-methanesulfonylpiperidin- 4-amine (33 mg, 67%) as a yellow solid. MS ESI calculated for C18H20ClFN6O2S [M + H]+, 439.10, found 439.30.1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.50 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 6.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 4.87-4.73 (m, 1H), 4.07-4.04 (m, 1H), 3.79- 3.71 (m, 1H), 3.53-3.50 (m, 1H), 3.25-3.10 (m, 2H), 2.99 (s, 3H), 2.51-2.50 (m, 3H), 2.22-2.16 (m, 1H), 1.77-1.73 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -186.46 (1F).

[0168] Example 32: (3R,4R)-N-[7-(4-chlorophenyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine Step 1: tert-butyl(3R,4R)-4-{[7-(4-chlorophenyl)-5-iodoimidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- fluoropiperidine-1-carboxylate To a stirred solution of tert-butyl (3R, 4R)-4-{[7-(4-chlorophenyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (80 mg, 0.17 mmol) in DMF (3 mL) was added I2(182 mg, 0.71 mmol) at room temperature. The resulting mixture was stirred for 16 h at at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was re-crystallized from PE / EtOAc (15 / 1) (20 mL) to afford tert-butyl (3R,4R)-4-{[7-(4- chlorophenyl)-5-iodoimidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (87 mg, 84%) as a white solid. MS ESI calculated for C21H23ClFIN6O2 [M + H]+, 573.06; found 573.20. Step 2: tert-butyl(3R,4R)-4-{[7-(4-chlorophenyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate To a stirred mixture of tert-butyl (3R,4R)-4-{[7-(4-chlorophenyl)-5-iodoimidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (120 mg, 0.20 mmol) and KF (37 mg, 0.62 mmol) in DMF (2 mL) was added methyl 2,2-difluoro-2-sulfoacetate (201 mg, 1.04WSGR Ref: 54004-768.601 mmol) under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature. The reaction was quenched with sat. Na2S2O3(30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (3 / 1) to afford tert-butyl (3R,4R)-4-{[7-(4-chlorophenyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (80 mg, 74 %) as a white solid. MS ESI calculated for C22H23ClF4N6O2[M + H]+, 515.15; found 515.40.1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.48 (d, J = 8.8 Hz, 2H), 8.16 (brs, 1H), 7.69-7.63 (m, 2H), 4.70-4.57 (m, 1H), 4.06-4.03 (m, 2H), 3.76-3.74 (m, 1H), 3.33-3.28 (m, 2H), 2.11-2.08 (m, 1H), 1.56-1.53 (m, 1H), 1.43 (s, 9H). Step 3: (3R,4R)-N-[7-(4-chlorophenyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3- fluoropiperidin-4-amine hydrochloride A solution of tert-butyl (3R,4R)-4-{[7-(4-chlorophenyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (80 mg, 0.15 mmol) and HCl (gas)in 1,4-dioxane (1 mL) in DCM (1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-N-[7-(4- chlorophenyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoropiperidin-4-amine hydrochloride (80 mg, crude) as a yellow solid. MS ESI calculated for C17H16Cl2F4N6 [M – Cl]+, 415.10 found 415.25. Example 32: (3R,4R)-N-[7-(4-chlorophenyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine To a stirred solution of (3R,4R)-N-[7-(4-chlorophenyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]-3-fluoropiperidin-4-amine hydrochloride (54 mg, 0.13 mmol) in EtOAc (2 mL) and sat. NaHCO3 (2 mL) was added methanesulfonyl methanesulfonate (23 mg, 0.13 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (10 mmol / L NH4HCO3), 20% to 50%; detector, UV 254 nm to afford (3R,4R)-N-[7-(4-chlorophenyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1-methanesulfonylpiperidin-4-amineWSGR Ref: 54004-768.601 (24.4 mg, 35%) as a white solid. MS ESI calculated for C18H17ClF4N6O2S [M + H]+, 493.08; found 493.20.1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.48 (d, J = 7.2 Hz, 2H), 8.21 (brs, 1H), 7.66 (d, J = 7.2 Hz, 2H), 4.88-4.75 (m, 1H), 4.07-4.04 (m, 1H), 3.82-3.74 (m, 1H), 3.56-3.52 (m, 1H), 3.30-3.22 (m, 1H) 3.19-3.10 (m, 1H), 3.00 (s, 3H), 2.25-2.20 (m, 1H), 1.76- 1.70 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -59.45 (3F), -186.51 (1F) .

[0169] Example 33: [5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1-methanesulfonylpiperidin-4-amine Step 1: tert-butyl (3S,4R)-3-fluoro-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate To a stirred solution of 2-methanesulfinyl-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazine (50 mg, 0.210 mmol) and tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (228 mg, 1.050 mmol) in NMP (1 mL) was added DIEA (162 mg, 1.260 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (10 mmol / L NH4HCO3), 20% to 60%; detector, UV 254 nm to afford tert-butyl (3S,4R)-3-fluoro-4-{[7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (50 mg, 60%) as a yellow solid. MS ESI calculated for C19H29FN6O2[M + H]+, 393.23, found 393.35.1H NMR (400 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.72 (s, 1H), 5.20 (brs, 1H), 4.95-4.82 (m, 1H), 4.60- 4.52 (m, 1H), 4.36-4.30 (m, 1H), 4.07-3.98 (m, 1H), 3.20-3.08 (m, 1H), 2.97-2.84 (m, 3H), 2.37- 2.29 (m, 1H), 1.98-1.82 (m, 2H), 1.50 (s, 9H), 1.00 (d, J = 6.8 Hz, 6H).19F NMR (376 MHz, Chloroform-d) δ -204.60 (1F). Step 2: tert-butyl (3S,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- fluoropiperidine-1-carboxylate A solution of tert-butyl (3S,4R)-3-fluoro-4-{[7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate (50 mg, 0.127 mmol) and NCS (25 mg, 0.191 mmol) in DMF (1 mL) was stirred for 4 h at 50 °C. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (10 mmol / L NH4HCO3), 20% to 70%; detector, UV 254 nm to afford tert-butyl (3S,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (40 mg, 73%) as a yellow solid. MS ESI calculated for C19H28ClFN6O2 [M + H]+, 427.19, found 427.25. Step 3:WSGR Ref: 54004-768.601 (3S,4R)-N-[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoropiperidin-4- amine hydrochloride To a stirred solution of tert-butyl (3S,4R)-4-{[5-chloro-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (40 mg, 0.094 mmol) in DCM (1 mL) was added HCl (gas) in 1,4-dioxane (1 mL) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford (3S,4R)-N-[5-chloro-7-(2- methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoropiperidin-4-amine hydrochloride (33 mg, crude) as a yellow solid. MS ESI calculated for C14H21Cl2FN6[M – Cl]+, 327.14, found 327.10. Example 33: (3S,4R)-N-[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine To a stirred solution of (3S,4R)-N-[5-chloro-7-(2-methylpropyl)imidazo[4,3-f][1,2,4]triazin-2- yl]-3-fluoropiperidin-4-amine hydrochloride (30 mg, 0.083 mmol) and NaHCO3 (28 mg, 0.332 mmol) in EtOAc (1 mL) and water (1 mL) was added methanesulfonyl methanesulfonate (28 mg, 0.166 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (10 mmol / L NH4HCO3), 20% to 70%; detector, UV 254 nm to afford (3S,4R)-N-[5-chloro-7-(2-methylpropyl)imidazo[4,3- f][1,2,4]triazin-2-yl]-3-fluoro-1-methanesulfonylpiperidin-4-amine (17.7 mg, 52%) as a light yellow solid. MS ESI calculated for C15H22ClFN6O2S [M + H]+, 405.12, found 405.15.1H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 5.27 (d, J = 8.4 Hz, 1H), 4.96 (d, J = 48.8 Hz, 1H), 4.31-4.23 (m, 1H), 4.10-3.99 (m, 2H), 3.28-3.08 (m, 2H), 2.97 (s, 3H), 2.84 (d, J = 7.2 Hz, 2H), 2.31-2.21 (m, 1H), 2.10-1.91 (m, 2H), 1.02-0.99 (m, 6H).19F NMR (376 MHz, Chloroform-d) δ -201.83 (1F).

[0170] Example 34: (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-1- methanesulfonylpiperidin-3-ol Step 1: tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- hydroxypiperidine-1-carboxylateWSGR Ref: 54004-768.601 To a stirred solution of 7-(1-ethylcyclobutyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (50 mg, 0.189 mmol) and tert-butyl (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (204 mg, 0.945 mmol) in NMP (1 mL) was added DIEA (146 mg, 1.134 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (0.1% formic acid), 20% to 70%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[7-(1- ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-hydroxypiperidine-1-carboxylate (50 mg, 63%) as a yellow solid. MS ESI calculated for C21H32N6O3 [M + H]+, 417.25, found 417.25.1H NMR (400 MHz, Chloroform-d) δ 8.82 (s, 1H), 7.77 (s, 1H), 5.21 (brs, 1H), 4.33-4.29 (m, 1H), 4.17-4.12 (m, 1H), 3.68-3.62 (m, 2H), 2.88-2.67 (m, 4H), 2.31-2.26 (m, 2H), 2.21-2.04 (m, 4H), 1.99-1.92 (m, 1H), 1.58-1.41 (m, 10H), 0.72-0.68 (m, 3H). Step 2: tert-butyl (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- hydroxypiperidine-1-carboxylate A solution of tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-hydroxypiperidine-1-carboxylate (50 mg, 0.120 mmol) and 1,3-dichloro-5,5- dimethylimidazolidine-2,4-dione (14 mg, 0.072 mmol) in DMF (1 mL) was stirred for 2 h at room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (10 mmol / L NH4HCO3), 20% to 70%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[5-chloro-7-(1- ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-hydroxypiperidine-1-carboxylate (22 mg, 40%) as a yellow solid. MS ESI calculated for C21H31ClN6O3[M + H]+, 451.21, found 451.20. Step 3: (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidin-3- ol hydrochloride To a stirred solution of tert-butyl (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-hydroxypiperidine-1-carboxylate (22 mg, 0.049 mmol) in DCM (1 mL) was added HCl (gas) in 1,4-dioxane (1 mL) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidin-3-ol hydrochloride (18 mg, crude). MS ESI calculated for C16H24Cl2N6O [M – Cl]+, 351.16, found 351.10. Example 34:WSGR Ref: 54004-768.601 (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-1- methanesulfonylpiperidin-3-ol To a stirred solution of (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin- 2-yl]amino}piperidin-3-ol hydrochloride (18 mg, 0.046 mmol) and NaHCO3 (16 mg, 0.184 mmol) in EtOAc (1 mL) and water (1 mL) was added methanesulfonyl methanesulfonate (16 mg, 0.092 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (10 mmol / L NH4HCO3), 20% to 60%; detector, UV 254 nm to afford (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-1-methanesulfonylpiperidin-3-ol (10 mg, 50%) as a yellow solid. MS ESI calculated for C17H25ClN6O3S [M + H]+, 429.14, found 429.15.1H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 5.22 (s, 1H), 4.01-3.95 (m, 1H), 3.87-3.79 (m, 2H), 3.72-3.61 (m, 1H), 2.95-2.84 (m, 4H), 2.80-2.61 (m, 4H), 2.36-2.28 (m, 1H), 2.26-2.17 (m, 2H), 2.15-2.01 (m, 3H), 1.99-1.89 (m, 1H), 1.81-1.68 (m, 1H), 0.74-0.70 (m, 3H).

[0171] Example 35: (3R,4R)-N-[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine Step 1: tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- fluoropiperidine-1-carboxylate To a stirred solution of 7-(1-ethylcyclobutyl)-2-methanesulfinylimidazo[4,3-f][1,2,4]triazine (240 mg, 0.91 mmol) and tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate (33 mg, 0.15 mmol) in NMP (2 mL) was added DIEA (469 mg, 3.63 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[7-(1- ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (170 mg, 44%) as a yellow solid. MS ESI calculated for C21H31FN6O2 [M + H]+, 419.25, found 419.25.1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 7.66 (s, 1H), 5.06 (brs, 1H), 4.67- 4.52 (m, 1H), 3.99-3.92 (m, 1H), 3.81-3.77 (m, 1H), 3.35-3.20 (m, 3H), 2.81-2.67 (m, 2H), 2.39- 2.36 (m, 1H), 2.27-2.20 (m, 2H), 2.17-2.02 (m, 3H), 2.00-1.85 (m, 1H), 1.57-1.48 (m, 10H), 0.72-0.66 (m, 3H).19F NMR (377 MHz, Chloroform-d) δ -189.21 (1F).WSGR Ref: 54004-768.601 Step 2: tert-butyl(3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- fluoropiperidine-1-carboxylate A solution of tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (40 mg, 0.10 mmol) and NCS (26 mg, 0.19 mmol) in DMF (1 mL) was stirred for 16 h at 30 °C. The resulting mixture was purified by reversed- phase chromatography with the following conditions: C18 column, CH3CN in water (0.1% NH3.H2O), 30 % to 50 %; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[5-chloro-7-(1- ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (15 mg, 34%) as a yellow solid. MS ESI calculated for C21H30ClFN6O2[M + H]+, 453.21, found 453.45. Example 35: (3R,4R)-N-[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine A solution of tert-butyl (3R,4R)-4-{[5-chloro-7-(1-ethylcyclobutyl) imidazo [4,3-f][1,2,4]triazin- 2-yl]amino}-3-fluoropiperidine-1-carboxylate (15 mg, 0.033 mmol) and HCl (gas) in 1,4- dioxane (2 mL, 8.00 mmol) in DCM (1 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. To this were added EtOAc (1 mL), sat. NaHCO3(1 mL) and methanesulfonyl methanesulfonate (15 mg, 0.09 mmol). The resulting mixture was stirred for 2 h at at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford (3R,4R)-N-[5-chloro-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2- yl]-3-fluoro-1-methanesulfonylpiperidin-4-amine (6 mg, 3%) as a light yellow solid. MS ESI calculated for C17H24ClFN6O2S [M + H]+, 431.14, found 431.20.1H NMR (400 MHz, DMSO- d6) δ 9.00 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 4.83-4.69 (m, 1H), 3.94-3.86 (m, 1H), 3.68-3.64 (m, 1H), 3.50-3.42 (m, 1H), 3.23-3.19 (m, 1H), 3.11-3.07 (m, 1H), 2.96 (s, 3H), 2.62-2.57 (m, 2H), 2.16-2.01 (m, 6H), 1.86-1.80 (m, 1H), 1.71-1.64 (m, 1H), 0.65-0.59 (m, 3H).19F NMR (377 MHz, DMSO-d6) δ -186.67 (1F).

[0172] Example 36: (3R,4R)-N-[7-(1-ethylcyclobutyl)-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine Step 1:WSGR Ref: 54004-768.601 tert-butyl(3R,4R)-4-{[5-bromo-7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3- fluoropiperidine-1-carboxylate A solution of tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (65 mg, 0.16 mmol) and NBS (41 mg, 0.23 mmol) in DMF (2 mL) was stirred for 2 h at room temperature.The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (0.1% NH3.H2O), 30% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[5-bromo- 7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (50 mg, 64%) as a yellow solid. MS ESI calculated for C21H30BrFN6O2[M + H]+, 497.16, 499.16 found 497.35, 499.35. Step 2: tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl]amino}- 3-fluoropiperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-4-{[5-bromo-7-(1-ethylcyclobutyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (65 mg, 0.13 mmol) and trimethyl- 1,3,5,2,4,6-trioxatriborinane (33 mg, 0.26 mmol), Cs2CO3(85 mg, 0.26 mmol) in dioxane (1 mL) and water (1 mL, 0.06 mmol) was added Pd(dppf)Cl2 (10 mg, 0.02 mmol) at room temperature under nitrogen atmosphere.The resulting mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)-5- methylimidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (50 mg, 88%) as a yellow solid. MS ESI calculated for C22H33FN6O2[M + H]+, 433.26, found 433.35. Example 36: (3R,4R)-N-[7-(1-ethylcyclobutyl)-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine A solution of tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)-5-methylimidazo[4,3-f][1,2,4]triazin- 2-yl]amino}-3-fluoropiperidine-1-carboxylate (50 mg, 0.12 mmol) and HCl (gas) in 1,4-dioxane (2 mL) in DCM (1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. To this were added EtOAc (2 mL), sat. NaHCO3(2 mL), and methanesulfonyl methanesulfonate (24 mg, 0.14 mmol). The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with the following conditions: C18WSGR Ref: 54004-768.601 column, CH3CN in water (0.1% NH3.H2O), 40% to 70%; detector, UV 254 nm to afford (3R,4R)-N-[7-(1-ethylcyclobutyl)-5-methylimidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine (9.7 mg, 32%) as a light yellow solid. MS ESI calculated for C18H27FN6O2S [M + H]+, 411.19, found 411.30.1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 4.85-4.69 (m, 1H), 3.94-3.88 (m, 1H), 3.66-3.60 (m, 1H), 3.45-3.42 (m, 1H), 3.26-3.21 (m, 1H), 3.12-3.07 (m, 1H), 2.95 (s, 3H), 2.65-2.55 (m, 2H), 2.42 (s, 3H), 2.13- 2.04 (m, 3H), 2.16-1.99 (m, 3H), 1.86-1.80 (m, 1H), 1.71-1.65 (m, 1H), 0.62-0.57 (m, 3H).19F NMR (377 MHz, DMSO-d6) δ -186.60 (1F).

[0173] Example 37: -N-[7-(1-ethylcyclobutyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1-methanesulfonylpiperidin-4-amine Step 1: tert-butyl -4-{[7-(1-ethylcyclobutyl)-5-iodoimidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate A solution of tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (65 mg, 0.16 mmol) and I2(197 mg, 0.78 mmol) in DMF (2 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[7-(1- ethylcyclobutyl)-5-iodoimidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1- carboxylate (50 mg, 59%) as a yellow solid. MS ESI calculated for C21H30FIN6O2 [M + H]+, 545.15, found 545.40. Step 2: tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate To a stirred solution of tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)-5-iodoimidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (10 mg, 0.02 mmol) and methyl 2,2-difluoro-2-sulfoacetate (88 mg, 0.46 mmol) in DMF (2 mL) were added CuI (17 mg, 0.09 mmol) and KF (16 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (0.1% NH3.H2O), 40% to 60%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (33 mg, 73%) as a yellow solid. MS ESI calculated for C22H30F4N6O2 [M + H]+, 487.24, found 487.30.WSGR Ref: 54004-768.601 Example 37: [7-(1-ethylcyclobutyl)-5-(trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1-methanesulfonylpiperidin-4-amine A solution of tert-butyl (3R,4R)-4-{[7-(1-ethylcyclobutyl)-5-(trifluoromethyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (50 mg, 0.05 mmol) and HCl (gas)in 1,4-dioxane (2 mL) in DCM (1 mL) was stirred for 50 min at room temperature. The resulting mixture was concentrated under reduced pressure. To this were added EtOAc (2 mL), sat. NaHCO3 (2 mL), and methanesulfonyl methanesulfonate (24 mg, 0.14 mmol). The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford (3R,4R)-N-[7-(1-ethylcyclobutyl)-5- (trifluoromethyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1-methanesulfonylpiperidin-4-amine (18.5 mg, 58%) as a white solid. MS ESI calculated for C18H24F4N6O2S [M + H]+, 465.16, found 465.10.1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), 4.84-4.69 (m, 1H), 3.95-3.92 (m, 1H), 3.72-3.64 (m, 1H), 3.49-3.45 (m, 1H), 3.26-3.19 (m, 1H), 3.13-3.08 (m, 1H), 2.96 (s, 3H), 2.65-2.60 (m, 2H), 2.20-2.03 (m, 6H), 1.89-1.81 (m, 1H), 1.72-1.66 (m, 1H), 0.62-0.58 (m, 3H).19F NMR (377 MHz, DMSO-d6) δ -58.97 (3F), -186.72 (1F).

[0174] Example 38: (3R,4R)-N-[5-chloro-7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoro-1- methanesulfonylpiperidin-4-amine Step 1: tert-butyl (3R,4R)-3-fluoro-4-{[7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}piperidine-1-carboxylate A mixture of 2-methanesulfinyl-7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triazine (100 mg, 0.399 mmol), DIEA (278 uL, 1.596 mmol) and tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1- carboxylate (262 mg, 1.197 mmol) in NMP (1.5 mL) was stirred for 16 h at 40 °C. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column, CH3CN in water (10 mmol / L NH4HCO3), 10% to 80%; detector, UV 254 nm to afford tert-butyl (3R,4R)-3- fluoro-4-{[7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}piperidine-1- carboxylate (94 mg, 55%) as a yellow solid. MS ESI calculated for C20H29FN6O2 [M + H]+, 405.23, found 405.25.1H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 7.65 (s, 1H), 4.98 (brs,WSGR Ref: 54004-768.601 1H), 4.70-4.55 (m, 1H), 4.03-3.95 (m, 1H), 3.81-3.75 (m, 1H), 3.29-3.20 (m, 3H), 2.87-2.83 (m, 2H), 2.40-2.33 (m, 1H), 2.21-2.13 (m, 3H), 1.99-1.91 (m, 1H), 1.68-1.53 (m, 4H), 1.50 (s, 9H).19F NMR (376 MHz, Chloroform-d) δ -189.69 (1F). Step 2: tert-butyl (3R,4R)-4-{[5-chloro-7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]amino}- 3-fluoropiperidine-1-carboxylate To a stirred mixture of tert-butyl (3R,4R)-3-fluoro-4-{[7-(1-methylcyclobutyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}piperidine-1-carboxylate (90 mg, 0.223 mmol) in DMF (1.5 mL) was added NCS (45 mg, 0.334 mmol). The resulting mixture was stirred for 4 h at 50 °C. The resulting mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (20 mL. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford tert-butyl (3R,4R)-4-{[5-chloro-7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2- yl]amino}-3-fluoropiperidine-1-carboxylate (82 mg, 75%) as yellow oil. MS ESI calculated for C20H28ClFN6O2 [M + H]+, 439.19, found 439.35. Step 3: (3R,4R)-N-[5-chloro-7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]-3-fluoropiperidin- 4-amine hydrochloride To a stirred mixture of tert-butyl (3R,4R)-4-{[5-chloro-7-(1-methylcyclobutyl)imidazo[4,3- f][1,2,4]triazin-2-yl]amino}-3-fluoropiperidine-1-carboxylate (80 mg, 0.182 mmol) in DCM (1.5 mL) was added HCl (gas) in 1,4-dioxane (1.5 mL) dropwise at 0 °C. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)-N-[5-chloro-7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triazin-2-yl]- 3-fluoropiperidin-4-amine hydrochloride (89 mg, 97%) (crude) as yellow oil. MS ESI calculated for C15H21Cl2FN6[M – Cl]+, 339.14, found 339.20. Example 38: (3R,4R)-N-[5-chloro-7-(1-methylcyclobutyl)imidazo[4,3-f][1,2,4]triaz...

Claims

WSGR Ref: 54004-768.601 CLAIMS We claim:

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein, R1is selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, C3-C4 optionally substituted cycloalkyl, or optionally substituted C2-C8 alkynyl; R3is selected from L-G, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C3-C10 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; L is selected from -O-, -NR10-, an optionally substituted arylene or optionally substituted heteroarylene; G is selected from an optionally substituted C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl; R5is selected from hydrogen, halogen, -OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy; R6is selected from hydrogen or halogen; or optionally, R5and R6together form an oxo; each R7is independently selected from hydrogen or halogen; X is -O-, -S-, -SO2-, -P(=O)-, N-R8, CH2, CF2, or C-SO2-R9; R8is selected from hydrogen, -SO2R9, SO(=NR9)R9, -COR9, -CO2R9, -CONHR9, - CON(R9)2, or P(=O)(R11)2; each R9is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl alkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; R10is selected from hydrogen or optionally substituted C1-C6 alkyl; andWSGR Ref: 54004-768.601 R11is optionally substituted C1-C6 alkyl; provided that the compound of Formula (I) is not:. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):wherein, R1is selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, C3-C4 optionally substituted cycloalkyl, or optionally substituted C2-C8 alkynyl; R3is selected from L-G, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; L is selected from -O-, -NR10-, an optionally substituted arylene or optionally substituted heteroarylene; G is selected from an optionally substituted C1-C8 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl; R5is selected from hydrogen, halogen, -OH, optionally substituted C1-C4 alkyl, and optionally substituted C1-C4 alkoxy; R6is selected from hydrogen or halogen; or optionally, R5and R6together form an oxo; each R7is independently selected from hydrogen or halogen; X is -O-, -S-, -SO2-, -P(=O)-, N-R8, CH2, CF2, or C-SO2-R9; R8is selected from hydrogen, -SO2R9, SO(=NR9)R9, -COR9, -CO2R9, -CONHR9, - CON(R9)2, or P(=O)(R11)2;WSGR Ref: 54004-768.601 each R9is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl alkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; R10is selected from hydrogen or optionally substituted C1-C6 alkyl; and R11is optionally substituted C1-C6 alkyl; provided that the compound of Formula (Ia) is not:.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the stereochemistry indicated in Formula (Ib):

4. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the stereochemistry indicated in Formula (Ic):

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N-R8.WSGR Ref: 54004-768.601 7. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is -SO2R9.

8. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is -P(=O)(R11)2.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is hydrogen.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen.

11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is fluoro.

12. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is chloro.

13. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted C1-C4 alkyl.

14. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted C1 alkyl.

15. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1 alkyl substituted with at least one fluoro.

16. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted C1-C8 alkyl.

17. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted C3-C7 carbocyclyl.

18. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heterocyclyl.

19. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aryl.WSGR Ref: 54004-768.601 20. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heteroaryl.

21. The compound of claim 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted pyridine.

22. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted carbocyclylalkyl.

23. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heterocyclylalkyl.

24. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted aralkyl.

25. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is optionally substituted heteroaralkyl.

26. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from L-G.

27. The compound of claim 26, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -O-; and G is optionally substituted C1-C8 alkyl.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each R7is hydrogen.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R5and R6are hydrogen.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen.

31. The compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen.

32. The compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen.WSGR Ref: 54004-768.601 33. The compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is -OH.

34. The compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is fluoro.

35. The compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is -OH.

36. The compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is fluoro.

37. A compound, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1.

38. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1-37 and a pharmaceutically acceptable excipient.

39. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims 1-37, and a pharmaceutically acceptable carrier.

40. A compound of any one of claims 1-37, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

41. A compound of any one of claims 1-37, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

42. Use of a compound of any one of claims 1-37, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

43. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 1-37, or pharmaceutically acceptable salt or solvate thereof.

44. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-37, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.WSGR Ref: 54004-768.601 45. The use of claims 41 or 42, or the method of claims 43 or 44, wherein the cancer is selected from breast cancer, skin cancer, melanoma, or leukemia.

46. A method of inhibiting a CDK2, CDK4, or CDK6 kinase enzyme comprising contacting the enzyme with a compound of any one of claims 1-37, wherein the CDK2, CDK4 or CDK6 kinase is contacted in an in vitro setting.

47. A method of inhibiting a CDK2, CDK4, or CDK6 kinase enzyme comprising contacting the enzyme with a compound of any one of claims 1-37, wherein the CDK2, CDK4, or CDK6 kinase is contacted in an in vivo setting.

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