Inhibitors of cdk2 / 4 / 6 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

INHIBITORS OF CDK2 / 4 / 6 KINASECROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of US Patent Application No. 63 / 515,748, filed on July 26, 2023, 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 CDK2 / 4 / 6 kinase inhibitory compound, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, having a structure presented in Table 1.

[0005] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or pharmaceutically acceptable salt or solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0006] 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 Table 1, or pharmaceutically acceptable salt or solvate, or stereoisomer thereof Another embodiment provides the method wherein the disease or disorder is cancer.INCORPORATION BY REFERENCE

[0007] 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

[0008] 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 toone 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

[0009] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0010] "Amino" refers to the -NH2 radical.

[0011] "Cyano" refers to the -CN radical.

[0012] "Nitro" refers to the -NO2radical.

[0013] "Oxa" refers to the -O- radical.

[0014] "Oxo" refers to the =0 radical.

[0015] " Thioxo" refers to the =S radical.

[0016] " Imino" refers to the =N-H radical.

[0017] " Oximo" refers to the =N-0H radical.

[0018] "Hydrazino" refers to the =N-NH2 radical.

[0019] "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., Ci- Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). 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-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). 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., Cs-Cs alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C2-C5 alkyl). 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 ( / / -propyl), 1 -methylethyl (zso-propyl), 1 -butyl ( / / -butyl), 1 -methylpropyl (sec-butyl), 2-methyl propyl (zso-butyl), 1,1 -dimethyl ethyl (Zc / 7-butyl). 1 -pentyl ( / / -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, -SIU, -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.

[0020] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0021] "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-l-enyl (i.e., allyl), but-l-enyl, pent-l-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 eachRais 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).

[0022] "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, 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).

[0023] "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, w-butylene, and the like. The alkylene chain is attached to therest 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., Ci-Cs 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-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms e.g., C1-C3 alkylene). 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., Ci alkylene) In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). 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), 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] "Alkenylene" or "alkenyl ene 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-C8 alkenylene). 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-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments,an alkenylene comprises two carbon atoms (e.g., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). 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).

[0025] "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 the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-Cs alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). 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., Cs-Cs 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 eachRais 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).

[0026] "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, z.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Hiickel 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- 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 oralkenylene 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.

[0027] "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.

[0028] "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.

[0029] "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.

[0030] "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.

[0031] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes 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 to 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), norbomenyl, 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-0Ra, -Rh-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb- N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)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.

[0032] "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.

[0033] "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.

[0034] "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.

[0035] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0036] "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, l-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.

[0037] "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. Oneor more nitrogen atoms, if present, are optionally quatemized. 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[l,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-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-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.

[0038] "A-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 A-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limited to, 1 -morpholinyl, 1- piperidinyl, 1 -piperazinyl, 1 -pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0039] "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.

[0040] "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.

[0041] "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.

[0042] "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) 7t-electron system in accordance with the Huckel 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[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,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[l,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-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 177-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 is1 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.

[0043] "A-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 A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0044] " 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.

[0045] "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 heteroaryl alkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroaryl alkyl radical is optionally substituted as defined above for a heteroaryl group.

[0046] "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.

[0047] 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 (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by 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.

[0048] 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 severalfactors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0049] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,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.

[0050] 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, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0051] 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,nC,13C,14C,15C,12N,13N,15N,16N,16O, 17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,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.

[0052] 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 areknown in the art and include, by way of non-limiting example only, the following synthetic methods.

[0053] 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.

[0054] 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.

[0055] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-ds (CD3I), are readily available and may be employed to transfer a deuteriumsubstituted 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.

[0056] Deuterium-transfer reagents, such as lithium aluminum deuteride (Li AID4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.

[0057] 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.

[0058] 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.

[0059] "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.

[0060] "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 aliphatic 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.

[0061] "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, tri ethyl amine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, .V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0062] "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 formed 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.

[0063] 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.

[0064] 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

[0065] 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 GO (quiescence) into G1 phase of cell division). CDKs regulate the transition between the four distinct phases of the eukaryotic cell cycle, i.e., the Gl, 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.

[0066] Structurally, CDK4 and 6 have a bilobal structure typically seen in other kinases, comprising a 5-stranded P-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 DI have been solved. The kinase binding sites of CDK4 and 6 are highly conserved and the structural similarity between these kinases islikely the reason that highly selective ATP-competitive inhibitors of both CDK4 and CDK6 (CDK4 / 6 inhibitors) have been developed.

[0067] 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 (DI, 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

[0068] 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.

[0069] 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 Gl, the cell is metabolically active and continuously grows but does not replicate its DNA. Following Gl, the 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).

[0070] In some cell types, including many embryonic cells, cell division is perpetual and the cells continuously cycle between the M, Gl, 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 skinfibroblasts 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 GO, 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.

[0071] 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 Gl, progression through the cell cycle generally stops at the restriction point, and the cell will enter GO (the quiescent stage) until a signal is received to resume cell division. The transition from Gl 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

[0072] CDK2, 4 and 6 are directly involved with mediating the transition from the Gl to S phase, with activated CDK2 / 4 / 6 initiating a downstream pathway that advances the cell into the S phase of cell division. According to the “classical” cell cycle model, the Gl / S transition begins in early Gl 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 (DI, 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 complexes subsequently enter the nucleus where the cyclin-CDK complexes are phosphorylated by the CDK-activating kinase (CAK) complex.

[0073] Once activated, CDK4 / 6 complexes phosphorylate the retinoblastoma (RB) tumor suppressor protein, as well as the related pl07 and pl30 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 El and E2). Cyclin E then binds to and activates CDK2, which hyper-phosphorylates RB. Hyperphosphorylation 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, asthe E2Fs promote transcription of the E type cyclins, activating CDK2 and other proteins important for initiation of S phase and DNA synthesis.

[0074] Regulation of CDK4 / 6 is primarily achieved by two families of endogenous inhibitory proteins. The first is the INK4 family, comprising the pl6INK4A, pl5INK4B, pl8INK4C, and pl9INK4D proteins, which bind to CDKs 4 and 6, forming binary complexes that lack kinase activity The second is the CIP / KIP family, which includes p27KIPl, p21CIPl, 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

[0075] 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 CDK4 / 6 ATP -binding pockets.

[0076] To date, three CDK4 / 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.

[0077] The development of selective CDK4 / 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 CDK4 / 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 CDK 4 / 6 inhibitors have been identified to date.

[0078] First, overexpression of CDK6 (and potentially CDK4) is a major mechanism of resistance to CDK4 / 6 inhibitors. Studies in human cell lines have shown that increased expression of CDK6 reduced the response of CDK4 / 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 RBI mutations has been identified in several patients treated with CDK 4 / 6 inhibitors. Third, decrease in cyclin DI expression can lead to CDK4 / 6 inhibitor resistance. Cyclin DI expression is regulated by the estrogen receptor (ER), and decreased ER expression results in reduced expression of cyclin DI. In preclinical trials, resistance to abemaciclib was associated with the loss of cyclin DI and concomitant loss of ER / PR expression. Resistance in these patients may be related to the decrease in cyclin DI 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 El 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

[0079] In one aspect, provided herein is a CDK2 / 4 / 6 kinase inhibitory compound.

[0080] 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.Table 1Numbered EmbodimentsEmbodiment 1. A compound, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, having a structure selected from the group consisting of:Embodiment 2. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, as described in embodiment 1 and a pharmaceutically acceptable excipient.Embodiment 3. A method of preparing a pharmaceutical composition comprising mixing a compound, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, of embodiment 1, and a pharmaceutically acceptable carrierEmbodiment 4. A compound of embodiment 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, for use in a method of treatment of the human or animal body.Embodiment 5. A compound of embodiment 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, for use in a method of treatment of cancer or neoplastic disease.Embodiment 6. Use of a compound of embodiment 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.Embodiment 7. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in embodiment 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof.Embodiment 8. 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 embodiment 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.Embodiment 9. The use of embodiment any one of embodiments 4 to 6, or the method of embodiment 7 or 8, wherein the cancer is selected from breast cancer, skin cancer, melanoma, or leukemia.Embodiment 10. A method of inhibiting a CDK2, CDK4 or CDK6 kinase enzyme comprising contacting the enzyme with a compound of embodiment 1, or a stereoisomer thereof, wherein the CDK2, CDK4 or CDK6 kinase is contacted in an in vitro setting.Embodiment 11. A method of inhibiting a CDK2, CDK4 or CDK6 kinase enzyme comprising contacting the enzyme with a compound of embodiment 1, or a stereoisomer thereof, wherein the CDK2, CDK4 or CDK6 kinase is contacted in an in vivo setting.Preparation of Compounds

[0081] 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 commerciallyavailable 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).

[0082] 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 & 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) "Modem 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'sEncyclopedia" (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.

[0083] 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 SchemesSCHEME 1

[0084] One common route is illustrated in Scheme 1. Treatment of bromide 1 with 4, 4, 4', 4', 5, 5, 5', 5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) in the presence of a palladium catalyst generated boronic acid 2, which was further converted to intermediate 3 by treatment with an appropriate substituted bromide in the presence of a palladium catalyst. Alternatively, bromide 1 could be treated with a substituted tin reagent in the presence of a palladium catalyst, or an alkyl bromide under metal catalyzed photo-redox conditions, to generate intermediate 3 directly. Intermediate 3 can be brominated, such as with NBS, to generate bromide 4, which can then be converted to intermediate 5 by the treatment with a methylating agent, such as tetramethylstannane or 2,4,6- trimethyl-l,3,5,2,4,6-trioxatriborinane. Sulfone 10 is then made by the treatment of intermediate 5 with an oxidizing agent, such as hydrogen peroxide and sodium tungstate. Sulfone 10 is reacted with a substituted amine and a base, such as DIEA, to make compound 11. Alternatively, intermediate 3 can be oxidized to sulfone 6, such as with hydrogen peroxide and sodium tungstate, and sulfone 6 is reacted directly with a substituted amine and a base, such as DIEA, to generate compound 9. Alternatively, hydrolysis with aqueous sodium base to form intermediate 7 followed by conversion to triflate 8 and reaction with a substituted amine and a base such as DIEA provides compound 9.SCHEME 2

[0085] Another common route is illustrated in Scheme 2. Bromide 1 is oxidized, such as with hydrogen peroxide and sodium tungstate, to form sulfone 2, which is treated with an appropriate amine, such as tert-butyl (3R,4R)-4-amino-3 -hydroxypiperidine- 1 -carboxylate, in the presence of a base such as DIEA, to afford intermediate 3. Removal of the Boc group is accomplished with TFA in DCM. Subsequent sulfonylation with a substituted sulfonyl chloride in the presence of a base, such as sodium bicarbonate, affords bromide 4. Conversion of bromide 4 to boronic acid 6, followed by palladium-mediated cross-coupling with a suitably substituted aryl bromide generates compound 5. Bromide 4 can be converted to compound 5 by direct palladium- mediated cross-coupling with an appropriately substituted aryl boronic acid ester or substituted aryl tin reagent. Compound 5 can also be generated through palladium-mediated cross-coupling of intermediate 3 with an appropriately substituted aryl boron reagent or substituted aryl tin reagent to form intermediate 9. Removal of the Boc group of intermediate 9 is accomplished with TFA in DCM. Subsequent sulfonylation with a suitably substituted sulfonyl chloride in the presence of a base, such as sodium bicarbonate, would afford compound 5. Alternatively, sulfone 2 could be treated with an amine, such as (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol, in the presence of a base, such as DIEA, to afford bromide 8. Conversion of bromide 8 to boronic acid 7 followed by palladium-mediated cross-coupling with a suitably substituted aryl bromide generates compound 10. Bromide 8 can also be converted to compound 10 by direct coupling with an appropriately substituted aryl boronic acid ester or substituted aryl tin reagent.SCHEME 35 6

[0086] Another common route is illustrated in Scheme 3. Bromide 1 is treated with a suitably substituted amine in the presence of a palladium catalyst to afford intermediate 2, which is oxidized, such as with hydrogen peroxide and sodium tungstate, to form sulfone 3. Treatment of sulfone 3 with an appropriate amine, such as (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol, in the presence of an appropriate base, such as DIEA, would then generate compound 4. Alternatively, bromide 1 can be oxidized, such as with hydrogen peroxide and sodium tungstate, to form sulfone 5 which can be reacted with a suitable amine, such as (3S,4R)-4-aminotetrahydro-2H- pyran-3-ol, in the presence of an appropriate base, such as DIEA, to afford intermediate 6. Treatment of compound 6 with a suitably substituted amine in the presence of a palladium catalyst would then generate compound 4.SCHEME 4

[0087] Another common route is illustrated in Scheme 4. Bromide 1 is esterified, such as with carbon monoxide under palladium-catalyzed conditions to afford ester 2, which could then be treated with hydrazine in an appropriate solvent, e.g., ethanol, to generate intermediate 3. Treatment of intermediate 3 with triethyl orthoformate and toluene sulfonic acid produced compound 4. Ester 2 can also be hydrolyzed, such as with aqueous sodium hydroxide, to acid 5. This is followed by amide bond formation, such as via HATU mediated amide coupling, to afford intermediate 6.Compound 7 can be generated from intermediate 6 by cyclizing under acidic conditions, such as toluene sulfonic acid in a solvent such as toluene.SCHEME 5

[0088] One common route is illustrated in Scheme 5. Bromide 1 is reacted under palladium-catalyzed conditions with a suitably substituted metal reagent to afford intermediate 2 which can be subsequently brominated, such as with NBS, to generate bromide 3. Palladium-mediated crosscoupling of bromide 3 with an appropriately substituted aryl boronic acid ester or substituted aryl tin reagent forms intermediate 4, which is then oxidized to sulfone 5, such as with hydrogen peroxide and sodium tungstate. Compound 6 is then generated by the addition of an appropriate amine, such as (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol, with an appropriate base, such as DIEA. Bromide 7 is reacted with an appropriate amine, such as tert-butyl (3R,4R)-4-amino-3- hydroxypiperidine-1 -carboxylate, using an appropriate base, such as DIEA, to afford bromide 8. Removal of the Boc group under acidic conditions, such as with TFA, in dichloromethane followed by mesylation with methanesulfonyl chloride then generates bromide 9, which is reacted under palladium-catalyzed conditions with a substituted metal reagent to afford intermediate 10. Bromination of intermediate 10, such as with NBS, afforded two regioisomers which could be directly coupled to a suitably substituted aryl boron reagent or substituted aryl tin reagent under palladium mediated cross-coupling conditions to afford compound 13 and compound 14.SCHEME 6

[0089] One common route is illustrated in Scheme 6. Sulfone 1 can be treated with a suitably substituted amine using an appropriate base, such as DIEA, to afford bromide 2. Palladium- mediated cross-coupling with a suitably substituted vinyl boronic acid is then carried out to generate intermediate 3. Reduction of the intermediate 3 olefin is carried out with a catalyst such as palladium hydroxide on carbon to afford compound 4.SCHEME 7

[0090] Another common route is illustrated in Scheme 7. Pyrrole 1 is deprotonated with base, such as sodium hydride, followed by the addition of O-(2,4-dinitrophenyl)hydroxylamine to afford intermediate 2, which is then treated with benzoyl isothiocyanate in THF to afford intermediate 3. Treatment of intermediate 3 with base, such as aqueous sodium hydroxide, followed by methylation with iodomethane generated intermediate 5. Treatment of intermediate 5 with phosphorus oxychloride followed by bromination, such as with NBS, would afford chloride 7. Removal of the chlorine group could be accomplished by the treatment with sodium borohydride followed by oxidation with DDQ to afford bromide 8. Bromide 8 is converted to intermediate 9 via boron intermediate 12 by the palladium-catalyzed coupling with suitably substituted bromide, or by a palladium-catalyzed coupling with a suitably substituted metal reagent. Oxidation of intermediate 9 is carried out using hydrogen peroxide and sodium tungstate to form sulfone 10 which is reacted with an appropriate amine, such as (3S,4R)-4-aminotetrahydro-2H- pyran-3-ol, using an appropriate base, such as DIEA, to afford compound 11. Alternatively, sulfone 10 could be reacted with an appropriate amine, such as tert-butyl (3R,4R)-4-amino-3- hydroxypiperidine-1 -carboxylate, to generate key intermediate 13. Compound 14 is generated by removing the Boc group of intermediate 13 followed by sulfonylation with a suitably substituted sulfonyl chloride in the presence of a base, such as sodium bicarbonate. An alternative route to key intermediate 13 is also provided. Bromide 8 is oxidized to sulfone 15, such as by using hydrogen peroxide and sodium tungstate, followed by treatment with an appropriate amine, such as tert-butyl (3R,4R)-4-amino-3-hydroxypiperidine-l-carboxylate, using an appropriate base, such as DIEA, to afford intermediate 16. Intermediate 13 could also be generated either by direct treatment of compound 16 with a suitably substituted metal reagent under palladium catalyzed conditions, or via a boron reagent 17 and a suitably substituted bromide under palladium-catalyzed conditions. Dichloride 21 can be converted to the monochloride through a reduction and oxidation sequence, such as treatment with sodium borohydride, followed by oxidation with DDQ to afford chloride 22 which is brominated, such as with NBS, to generate bromide 23. Fluorination with Selectfluor produces intermediate 24 which is reacted with an appropriate amine, such as tert-butyl (3R,4R)-4-amino-3- hydroxypiperidine-1 -carboxylate, using an appropriate base, such as DIEA, to afford intermediate 16, or reacted with a suitably substituted amine using an appropriate base, such as DIEA, to generate intermediate 18. Intermediate 18 can also be made by treating sulfone 15 with a suitable amine, such as (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol, using an appropriate base, such as DIEA. Intermediate 19 is made from intermediate 18 by palladium-catalyzed coupling conditions using a suitably substituted metal reagent. Halogenation, such as with either NBS or NIS, affords compound 20a or 20b.SCHEME 8

[0091] One common route is illustrated in Scheme 8. Bromide 1 is reacted under photo-redox conditions using an iridium catalyst to afford alkyl substituted intermediate 2 which is oxidized to sulfone 3, such as with hydrogen peroxide and sodium tungstate. Treatment of sulfone 3 with an appropriate amine, such as (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol, using a base, such as DIEA, would generate compound 4. Alternatively, sulfone 3 could be treated with an appropriate amine, such as tert-butyl (3R,4R)-4-amino-3-hydroxypiperidine-l-carboxylate, using a base, such as DIEA, to generate intermediate 5. Removal of the Boc group under acidic conditions, such as TFA in dichloromethane, followed by sulfonylation with a suitably substituted sulfonyl chloride using a base, such as sodium bicarbonate, generates compound 6.SCHEME 9

[0092] One common route is illustrated in Scheme 9. Chloride 1 is treated with a suitably substituted amine using a base, such as DIEA, to afford bromide 2. Palladium-mediated cross-coupling with a suitably substituted vinyl boron reagent is carried out to generate intermediate 3. Hydrogenation of intermediate 3 is carried out with a catalyst, such as palladium-on-carbon, followed by subsequent oxidation with DDQ to afford intermediate 4. Halogenation of intermediate 4, such as with either NCS, NBS, or NIS, produces compounds 5a, 5b, or 5c.Palladium-catalyzed coupling with a suitably substituted metal reagent is carried out to afford compound 6.SCHEME 10

[0093] One common route is illustrated in Scheme 10. Di chloride 1 is treated with a suitably substituted carboxylic acid in the presence of a silver salt, such as silver nitrate, to afford intermediate 2, which is subsequently fluorinated with a reagent, such as Selectfluor to generate fluoride 4. Removal of a chloride from compound 4 is accomplished by treatment with sodium borohydride followed by oxidation with DDQ to generate intermediate 5. Alternatively, removal of a chloride from intermediate 2 is accomplished by treatment with sodium borohydride followed by oxidation with DDQ to produce intermediate 3 which is fluorinated with a reagent like Selectfluor to generate intermediate 5. Intermediate 5 is converted to compound 6 by the addition of a suitably substituted amine and using a base, such as DIEA. Pyrrole 7 is treated with a base, like sodium hydride, followed by the addition of O-(2,4-dinitrophenyl)hydroxylamine to afford intermediate 8 which is treated with ammonia in methanol to afford primary amide 9. Cyclization of primary amide 9 is accomplished by treatment with oxalyl chloride in a suitable solvent, such as toluene, affords intermediate 10 which is chlorinated, such as by using phosphorus oxychloride and a base such as DIEA, to afford dichloride 11. Fluoride 4 is made from di chloride 11 by treatment with a suitably substituted carboxylic acid in the presence of a silver salt, such as silver nitrate.SCHEME 11

[0094] One common route is illustrated in Scheme 11. Intermediate 1 can be treated with NBS or 1,3- dichloro-5,5-dimethylimidazolidine-2, 4-dione to afford compound 2. Dimethylphosphoryl compound 5 can be generated through palladium mediated cross-coupling of bromide 2 with dimethylphosphine oxide 3. Bromide 2 could also be converted to compound 6 by direct coupling with an appropriately substituted aryl boronic acid ester or substituted aryl tin reagent. Protection of hydroxy intermediate 7 could be accomplished with acetic anhydride and TEA in DCM. Intermediate 8 could be treated with iodine in DMF to generate iodide 9, followed by palladium mediated cross-coupling with alkynyl tin reagent or ethynyltrimethylsilane, and deprotection of Ac or TMS group in the presence of K2CO3in MeOH to afford compound 10. Removal of the Boc group of compound 10 can be accomplished with TFA in DCM. Subsequent sulfonylation with a suitably substituted sulfonyl chloride in the presence of a base such as sodium bicarbonate would afford compound 11.SCHEME 12

[0095] One common route is illustrated in Scheme 12. Bromide 1 can be converted to olefin 3 by direct palladium mediated cross-coupling with borate ester 2. The catalytic hydrogenation followed by oxidation with DDQ generated trifluoroisopropyl intermediate 4. Chiral separation (column: CHIRAL ART Cellulose-SB, Hexane / EtOH / DCM = 8 / 1 / 1) of intermediate 4 afforded diastereoisomers 5 (Peakl) and 6 (Peak 2), which could be halogenated in the presence of NBS and l,3-dichloro-5,5-dimethylimidazolidine-2, 4-dione or iodinated with iodine to generate intermediate 7 (Peak 1) and 8 (Peak 2). Subsequent palladium-copper mediated cross-coupling with ethynyltrimethylsilane, followed by removal of the TMS group would generate ethynyl compound 9 (Peak 1) and 10 (Peak 2).SCHEME 13

[0096] One common route is illustrated in Scheme 13. Bromide 1 could convert to olefin 3 by direct palladium mediated cross-coupling with borate ester 2, followed by catalytic hydrogenation to generate trifluoroisopropyl intermediate 4, which could be then treated with sodium nitrite and bromine in the presence of HBr to afford bromide 5. Chiral separation (column: CHIRAL ART Cellulose-SB, CCL / 'PrOH = 8 / 2) of 5 would afford enantiomers 6 (Peak 1) and 7 (Peak 2). Conversion of bromide 6 (Peak 1) and 7 (Peak 2) to tin reagent 9 (Peak 1) and 10 (Peak 2) through palladium mediated cross-coupling with hexabutyl di stannane 8, followed by palladiumcopper mediated cross-coupling with bromide 11 would generate compound 12 (Peak 1) and 13 (Peak 2).SCHEME 14

[0097] One common route is illustrated in Scheme 14. Corresponding intermediate 1 can be treated with NBS to afford bromide 2, which could be converted to olefin compound 4 by direct coupling with vinyl borate ester. Compound 4 could be treated with potassium osmate and sodium periodate to generate aldehyde 5, followed by fluoronation with DAST in DCM to afford compound 6. Removal of the Boc group of compound 6 can be accomplished with TFA in DCM, subsequent sulfonylation with a suitably substituted sulfonyl chloride in the presence of a base such as sodium bicarbonate would afford compound 7. Alternatively, methylthio intermediate 8 can be treated with NBS to afford bromide 9. Conversion of intermediate 9 to aldehyde 10 can be accomplished with butyl lithium in THF and DMF. Dz-fluoromethyl 11 could be generated through fluoronation of intermediate 10 with DAST in DCM. Oxidation ofmethylthio such as with hydrogen peroxide and sodium tungstate forms sulfone 12, which could be then treated with an appropriate amine like (35',4R)-4-aminotetrahydro-2 / / -pyran-3-ol in the presence of a base such as DIEA to afford compound 13.SCHEME 15

[0098] One common route is illustrated in Scheme 15. Methylthio intermediate 1 can be treated with iodine in DMF to afford iodide 2. Subsequent trifluoromethylation with a reagent such as methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of copper iodide and HMPA to afford intermediate 4. Oxidation of methylthio group of intermediate 4 could be accomplished such as with hydrogen peroxide and sodium tungstate to form sulfone 5, which could be then treated with an appropriate amine 6 like (3S,4R)-4-aminotetrahydro-27 / -pyran-3-ol in the presence of a base such as DIEA to afford intermediate compound 7.SCHEME 16

[0099] One common route is illustrated in Scheme 16. Protection of hydroxy intermediate 1 could be accomplished with acetic anhydride and TEA in DCM. Intermediate 2 could be treated with iodine in DMF to generate iodide 3, followed by palladium mediated cross-coupling with zinc cyanide. Subsequent removal of acetyl group in the presence of K2CO3and MeOH would afford compounds 5 and 6.SCHEME 17

[0100] One common route is illustrated in Scheme 17. Bromide 1 can be fluorinated such as with selectfluor to form a mixture of 5-fluoro intermediate 2 and 6-fluoro intermediate 3.Intermediate 3 could be treated with an appropriate amine like terZ-butyl (3R,4R)-4-amino-3- fluoropiperidine-1 -carboxylate in the presence of a base such as DIEA to afford intermediate 5. Removal of the Boc group could be accomplished with TFA in DCM. Subsequent sulfonylation with a substituted sulfonyl chloride in the presence of a base such as sodium bicarbonate would afford bromide 6. Conversion of bromide 6 to corresponding boronic acid 15 followed by palladium mediated cross-coupling with a suitably substituted aryl bromide would generate compound 8. Bromide 6 could also be converted to compound 8 by direct palladium mediated cross-coupling with an appropriately substituted aryl boronic acid ester. Intermediate 3 could also be treated with an appropriate amine like tert-butyl (3R,4A)-4-amino-3-hydroxypiperidine- 1 -carboxylate in the presence of a base such as DIEA, then converted to bromide 13 in the sequence involved removal of the Boc group and methylsulfonylation in the presence of sodium bicarbonate. Boronic acid 14 could be generated by employing sequentially protection of hydroxy with acetyl and Miyaura borylation reaction. Subsequent direct palladium mediated cross-coupling with an appropriately substituted aryl bromide, followed by removal of acetyl group accomplished with potassium carbonate in methanol would generate compound 17. Alternatively, bromide 13 could also be converted to compound 17 by direct palladium mediated cross-coupling with an appropriately substituted aryl boronic acid ester. Olefin 11 could be generated through palladium mediated cross-coupling of bromide 13 with an appropriately substituted alkenyl boronic acid ester. Subsequent hydrogenation followed by oxidation in the presence of DDQ would generate alkyl compound 16.SCHEME 18

[0101] One common route is illustrated in Scheme 18. Asymmetric hydroxylation of ketone 1 could be accomplished with nitrosobenzene in the presence of corresponding proline to afford chiral a- hydroxyketone 3. Protection of hydroxy with SEM, followed by asymmetric reduction of carbonyl in the presence of an appropriately reductive reagent such as L-selectride would generate (R,R) or (S,S) mono protected diols 5. Subsequent methanesulfonylation in the presence of DIEA would afford mesylate 6, which could be converted to azide 7, followed by Staudinger reaction in the presence of trimethylphosphane to afford amine 8. Removal of SEM group could be accomplished with hydrogen chloride in methanol to afford corresponding (R,S) or (S, R) hydramine hydrochloride 9. Bromide 11 could be converted to intermediate 12 by direct palladium mediated cross-coupling with cyclopentenyl boronic acid ester 10. Intermediate 12 could be treated with corresponding hydramine hydrochloride 9 in the presence of a base such as DIEA to afford olefin 13. Subsequent hydrogenation followed by oxidation in the presence of DDQ would generate compound 14.SCHEME 19

[0102] One common route is illustrated in Scheme 19. Methanesulfonylation of cis or trans alcohol 1 in the presence of TEA would afford mesylate 2, which could be converted to methylthio 3, followed by oxidation in the presence of metachloroperbenzoic acid to afford methyl sulfonyl 4. Removal of Boc group could be accomplished with hydrogen chloride in ethyl acetate and methanol to afford corresponding trans or cis amine hydrochloride 5. Chloride 6 could be treated with corresponding amine hydrochloride 5 in the presence of a base such as DIEA to afford olefin 7. Subsequent hydrogenation followed by oxidation in the presence of DDQ would generate compound 8.SCHEME 20

[0103] One common route is illustrated in Scheme 20. Bromide 1 could be treated with an appropriate amine like / / Z-butyl (3A,4R)-4-amino-3-fluoropiperidine-l-carboxylate in the presence of a base such as DIEA to afford intermediate 3. Then direct palladium mediated cross-coupling with an appropriately vinyl borate ester 4 to afford olefin compound 5. Subsequent hydrogenation followed by oxidation in the presence of DDQ would generate 6, which could be treated with iodine in DMF to form iodide 7, followed by palladium mediated cross-coupling with zincI l lcyanide. Removal of the Boc group could be accomplished with TFA in DCM. Subsequent sulfonylation with a substituted sulfonyl chloride in the presence of a base such as sodium bicarbonate would afford compound 9.

[0104] Alternatively, intermediate 10 could also be converted to dichloride 12 by direct sliver mediatedMinisci reaction with an appropriately substituted acid. It could be converted to mono chloride13 in the sequence involved reduction by NaBFU and oxidation in the presence of DDQ. Intermediate 6 could be generated by employing substitution with an appropriate amine like tert- butyl (3R,4A)-4-amino-3-fluoropiperidine-l -carboxylate in the presence of a base such as DIEA.Intermediate 6 could also be generated through photoredox cross-coupling of intermediate 10 with corresponding active ester of substituted acid 11 in the presence of catalyst 16.SCHEME 21

[0105] Another route is illustrated in Scheme 21. In the presence of DIC and DMAP, alkyl carboxylic acid 1 can be converted to active esters 2, then direct iridium mediated cross-coupling with chloride triazine core 3 to afford trichloride intermediate 4. Alternatively, Minisci reaction of alkyl carboxylic acid 1 and chloride triazine core 3 could also form intermediate 4. One chlorine was removed in the sequence involved reduction by NaBIHU and oxidation in the presence of DDQ to afford di chloride intermediate 5. Intermediate 7 could be generated by employing substitution with an appropriate amine like / e / 7-butyl (3 R, 4A)-4-amino-3 -hydroxypiperidine- 1- carboxylate in the presence of a base such as DIEA. Iodide 9 would be generated by employing sequentially protection of hydroxy with acetyl and iodination, which could be converted to cyano or trifluoromethyl intermediate 11 and trifluoroethyl or difluoroethyl intermediate 13 through metal mediated cross-coupling. Removal of the Boc group could be accomplished with HC1 (gas) in DCM. Subsequent sulfonylation or acylation with a substituted sulfonyl chloride or acyl chloride, followed by removal of acetyl group could afford 6-cyano or 6-trifluoromethyl compound 12 and 6-trifluoroethyl or 6-difluoroethyl compound 14.

[0106] Iodide 16 could be generated from chloride 11 through subsequent palladium-catalyzed reduction accomplished with triethyl silicane, followed by iodination. Copper mediated crosscoupling in the presence of fluorinated reagent 10 would give intermediate 17. Removal of the Boc group could be accomplished with HC1 (gas) in DCM. Subsequent sulfonylation or acylation with a substituted sulfonyl chloride or acyl chloride, followed by removal of acetyl group could afford 5-trifluoromethyl-6-cyano compound 18.

[0107] Hydroxymethyl intermediate 20 could be generated through palladium mediated cross-coupling with tin reagent 19. Subsequent oxidation in the presence of Dess-Martin reagent followed by fluorination with DAST would generate difluoromethyl intermediate 21. Removal of the Boc group could be accomplished with HC1 (gas) in DCM. Subsequent sulfonylation or acylation with a substituted sulfonyl chloride or acyl chloride, followed by removal of acetyl group could afford 5-difluoromethyl-6-cyano compound 22.

[0108] Using appropriate starting materials, the CDK2 / 4 / 6 kinase inhibitory compounds described herein within Table 1, were synthesized using the methods described above in Schemes 1-21. Pharmaceutical Compositions

[0109] 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,for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0110] 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.

[0111] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof.

[0112] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0113] In certain embodiments, the CDK2 / 4 / 6 kinase inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer 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.

[0114] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof.

[0115] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0116] In certain embodiments, the CDK2 / 4 / 6 kinase inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer 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.

[0117] 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, forexample, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium 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)).

[0118] In some embodiments, the CDK2 / 4 / 6 kinase inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer 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

[0119] The dose of the composition comprising at least one CDK2 / 4 / 6 kinase inhibitory compound as described in Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, 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.

[0120] 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.

[0121] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0122] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, for use in a method of treatment of the human or animal body.

[0123] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, for use in a method of treatment of cancer or neoplastic disease.

[0124] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0125] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0126] 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, or stereoisomer 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, or stereoisomer thereof, and a pharmaceutically acceptable excipient

[0127] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, for use in a method of treatment of the human or animal body.

[0128] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, for use in a method of treatment of cancer or neoplastic disease.

[0129] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0130] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0131] 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, or stereoisomer 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.

[0132] 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.

[0133] 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.

[0134] One embodiment provides a method of inhibiting a CDK2 / 4 / 6 kinase comprising contacting the CDK2 / 4 / 6 kinase with a compound of Table 1. Another embodiment provides the method of inhibiting a CDK2 / 4 / 6 kinase, wherein the CDK2 / 4 / 6 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.

[0135] 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

[0136] 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: °C degrees CelsiusOn chemical shift in parts per million downfield from tetramethylsilaneDCM dichloromethane (CH2CI2)DMF dimethylformamideDMSO dimethylsulfoxideEA ethyl acetateESI electrospray ionizationEt ethyl g gram(s) h hour(s)HPLC high performance liquid chromatographyHz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometry / z micro m multiplet (spectral); meter(s); milliM molarM+parent molecular ionMe methylMHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliterMS mass spectrometry nm nanometer(s)NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solutionPE petroleum etherRT room temperature s singlet (spectral) t triplet (spectral)T temperatureTFA trifluoroacetic acidTHF tetrahydrofuran

[0137] Common intermediates are provided below in Table 4:Table 4Common intermediate 1:2,5-dichloro-7-(3-fluoro-3-methylbutan-2-yl)Dyrrolo[2,1-f][l,2,41triazineStep 1 : methyl 3 -hydroxy-2, 2-dimethylbutanoate

[0138] A solution of methyl 2,2-dimethyl-3-oxobutanoate (4.00 g, 27.745 mmol) and NaBH4 (1.05 g, 27.745 mmol) in MeOH (50 mL) was stirred for 2 h at 0 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE / EtOAc (2 / 1) to afford methyl 3 -hydroxy-2, 2- dimethylbutanoate (2.10 g, 51%) as colorless oil.1H XVIR (300 MHz, Chloroform-<7) 3 3.89- 3.83 (m, 1H), 3.70 (s, 3H), 1.20-1.09 (m, 9H). Step 2: 3-hydroxy-2.2-dimethylbutanoic acid

[0139] A solution of methyl 3-hydroxy-2,2-dimethylbutanoate (2.10 g, 14.365 mmol) and LiOHH2O (1.21 g, 28.730 mmol) in MeOH (15 mL) and H2O (15 mL) were stirred for 16 h at room temperature. The reaction was diluted with water (200 mL). The mixture was acidified to pH 3 with HC1 (aq., 1 M). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3 -hydroxy -2,2- dimethylbutanoic acid (1.70 g, 89%) as colorless oil.1H NMR (300 MHz, Chloroform-d ) 3 3.97- 3.90 (m, 1H), 1.24-1.20 (m, 9H).Step 3: 3-methyl-3-12,4,5-trichloropyrrolor2,1-f1[L2,41triazin-7-yllbutan-2-ol

[0140] To a stirred solution of 2,4,5-trichloropyrrolo[2,l- / |[l,2,4]triazine (1.00 g, 4.495 mmol), 3- hydroxy-2,2-dimethylbutanoic acid (1.78 g, 13.485 mmol) and AgNCh (1.53 g, 8.990 mmol) in CH3CN (60 mL) and H2O (30 mL) was added (NH4)2S2O8 (5.13 g, 22.475 mmol) in H2O (30 mL) dropwise at 50 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 °C. The mixture was allowed to cool down to room temperature. The reaction was diluted with NaHCO, (15 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic 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 (5 / 1) to afford 3-methyl-3-{2,4,5- trichloropyrrolo[2, !- / ][!, 2, 4]triazin-7-yl}butan-2-ol (0.47 g, 29%) as a yellow solid. MS ESI calculated for C11H12CI3N3O [M + H]+, 308.00, found 307.85. *HNMR (400 MHz, Chloroform- d) 8 6.83 (s, 1H), 4.56 (q, J= 6.4 Hz, 1H), 1.50 (s, 3H), 1.46 (s, 3H), 1.07 (d, J = 6.4 Hz, 3H). Step 4: 3-12,5-dichloropyrrolor2,1-f][L2,4]triazin-7-yll-3-methylbutan-2-ol

[0141] To a stirred solution of 3-methyl-3-{2,4,5-trichloropyrrolo[2,l-;][l,2,4]triazin-7-yl}butan-2-ol (440 mg, 1.426 mmol) in z-PrOH (0.7 mL) and THF (17 mL) was added NaBH4(86 mg, 2.282 mmol). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with sat. NH4C1 (20 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To this was added DDQ (485 mg, 2.139 mmol) in DCM (14 mL). The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched with sat. NaHCO3(20 mL) at 0 °C. The resulting mixture was extracted with DCM (3 x 40 mL). The combined organic layers werewashed with brine (2 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 (5 / 1) to afford 3-{2,5-dichloropyrrolo[2,l- / |[l,2,4]triazin-7-yl}-3-methylbutan-2-ol (270 mg, 69%) as a yellow solid. MS ESI calculated for C11H13CI2N3O [M + H]+, 274.04, found 274.05.1H NMR (400 MHz, Chloroform-d ) δ 8.77 (s, 1H), 6.82 (s, 1H), 4.53 (q, J= 6.4 Hz, 1H), 1.52 (s, 3H), 1.48 (s, 3H), 1.07 (d, J= 6.4 Hz, 3H).Step 5: 2,5-dichloro-7-(3-fluoro-3-methylbutan-2-yl)pyrrolor2,1-f1[E2,41triazine

[0142] To a stirred solution of 3-{2,5-dichloropyrrolo[2,l- / |[l,2,4]triazin-7-yl}-3-methylbutan-2-ol (270 mg, 0.985 mmol) in DCM (40 mL) was added DAST (317 mg, 1.970 mmol) dropwise at- 78 °C under nitrogen atmosphere. The reaction mixture was stirred for 30 min. The mixture was allowed to warm to at 0 °C. The reaction was quenched with EtOH (15 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10 / 1) to afford 2,5-dichloro-7-(3-fluoro-3- methylbutan-2-yl)pyrrolo[2,l- / |[l,2,4]triazine (240 mg, 74%) as yellow oil. MS ESI calculated for C11H12CI2FN3 [M + H]+, 276.04, found 275.901H NMR (400 MHz, Chloroform-d S 8.77 (s, 1H), 6.89 (s, 1H), 3.88-3.79 (m, 1H), 1.48 (d, 21.2 Hz, 3H), 1.40 (d, . / - 7.2 Hz, 3H), 1.26 (d,J= 21.2 Hz, 3H).Common intermediate 2;(35,41?)-4-{[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6-iodopyrrolo[2,l- / ][l,2,4]triazin-2- yl]amino}oxan-3-yl acetateStep 1 : (3A4R)-4-([5-chloro-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,1-firL2,41triazin-2- yllaminoloxan-3-ol

[0143] To a stirred solution of 2,5-dichloro-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- / |[l,2,4]triazine (240 mg, 0.869 mmol) in NMP (4 mL) were added (3S,4R)-4-aminooxan-3-ol hydrochloride (200 mg, 1.304 mmol) and DIEA (562 mg, 4.345 mmol) at room temperature. The resulting mixture was stirred for 16 h at 80 °C. The resulting mixture was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 30% to 70%; detector, UV 254 nm to afford (3S,4R)-4-{[5-chloro-7-(3- fluoro-3-methylbutan-2-yl)pyrrolo[2,l: / ][l,2,4]triazin-2-yl]amino}oxan-3-ol (174 mg, 56%) as yellow oil. MS ESI calculated for C16H22CIFN4O2[M + H]+, 357.14, found 357.10.1H NMR (400 MHz, Chloroform^ / ) δ 8.57 (s, 1H), 6.54 (s, 1H), 4.87-4.84 (m, 1H), 4.09-3.96 (m, 2H), 3.75-3.62 (m, 3H), 3.52-3.45 (m, 1H), 3.26-3.20 (m, 1H), 2.11-2.06 (m, 1H), 1.77-1.62 (m, 1H), 1.44-1.26 (m, 9H).Step 2: -4-l[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l - / ][!, 2,4]triazin-2-yl1amino !oxan-3-yl acetate

[0144] To a stirred solution of (3S,4R)-4-{[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-ol (93 mg, 0.261 mmol) in DCM (3 mL) were added AC2O (53 mg, 0.522 mmol) and TEA (132 mg, 1.305 mmol) at room temperature. The resulting mixture was stirred for 16 h at 50 °C. The mixture was allowed to cool down to room temperature. The resulting was purified by Prep-TLC (PE / EtOAc = 1 / 1) to afford (3S,4R)-4-{[5- chloro-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (70 mg, 67%) as a yellow solid. MS ESI calculated for C18H24CIFN4O3[M + H]+, 399.15, found 399.40.1HNMR (400 MHz, Chloroform-d ) δ 8.58 (s, 1H), 6.54 (d, J= 6.4 Hz, 1H), 5.10-4.90 (m, 2H), 4.07-3.91 (m, 3H), 3.91-3.73 (m, 1H), 3.67-3.58 (m, 1H), 3.51-3.45 (m, 1H), 2.42-2.38 (m, 1H), 2.06 (s, 3H), 1.74-1.61 (m, 1H), 1.47-1.25 (m, 9H).Step 3: (3S,4R)-4-ir5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6-iodopyrrolor2,1-fin,2,41triazin- 2-yl |amino ! oxan-3-Yl acetate

[0145] A solution of (3S,4R)-4-{[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- / |[l,2,4]triazin- 2-yl]amino}oxan-3-yl acetate (70 mg, 0.176 mmol) and I2 (178 mg, 0.704 mmol) in DMF (3 mL) was stirred for 16 h at room temperature. The resulting mixture was purified by reversed - phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 35% to 70%; detector, UV 254 nm to afford (3S,4R)-4-{[5-chloro-7- (3-fluoro-3-methylbutan-2-yl)-6-iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (72 mg, 78%) as yellow oil. MS ESI calculated for C18H23CIFIN4O3[M + H]+, 525.05 found 524.95.1HNMR (400 MHz, Chloroform-d ) δ 8.56 (s, 1H), 5.12-4.84 (m, 2H), 4.08-3.80 (m, 3H), 3.59-3.40 (m, 3H), 2.40-2.37 (m, 1H), 2.04 (s, 3H), 1.65-1.25 (m, 10H).Common intermediate 3;(3R,4R)-4-I[6-cvano-7-(3-fluoro-3-methylbutan-2-yl)Dyrrolo[2,1-f][l,2,4]triazin-2- yZlaminoloxan-3-yl acetateStep 1 : -4-l r5-chloro-6-cvano-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2.1- / ]|T,2,41triazin-2-yl1aminoloxan-3-yl acetate

[0146] To a stirred solution of (3S,4R)-4-{[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6- iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (72 mg, 0.137 mmol) in DMF (7 mL) were added Zn(CN)2 (19.33 mg, 0.164 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol) under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 130 °C under nitrogen atmosphere. The reaction was quenched with water (50 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 fdtration, the fdtrate was concentrated under reducedpressure. The residue was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% formic acid), 25% to 55%; detector, UV 254 nm to afford (3 ,4J?)-4-{[5-chloro-6-cyano-7-(3-fluoro-3-methylbutan-2- yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (50 mg, 85%) as a yellow solid. MS ESI calculated for C19H23CIFN5O3[M + H]+, 424.15 found 424.25. ’H NMR (400 MHz, Chloroform-d) δ 8 68 (s, 1H), 5.28-5.24 (m, 1H), 5.00-4 96 (m, 1H), 4.05-3.96 (m, 4H), 3.65- 3.53 (m, 1H), 3.48-3.45 (m, 1H), 2.42-2.36 (m, 1H), 2.05 (s, 3H), 1.62-1.59 (m, 4H), 1.52-1.34 (m, 6H).Step 2: -4-([6-cyano-7-(3-fluoro-3-methylbutan-2-yl)pyrrolor2J- / iri,2,41triazin-2-y / ]amino)oxan-3-yl acetate

[0147] A solution of (3S,4R)-4-{[5-chloro-6-cyano-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- _ / ][!, 2, 4]triazin-2-yl]amino}oxan-3-yl acetate (127 mg, 0.300 mmol), EtaSiH (105 mg, 0.900 mmol), EtaN (121 mg, 1.200 mmol), Pd(dba)? (17 mg, 0.030 mmol) and / -BuXPhos (25 mg, 0.060 mmol) in 1,4-dioxane (2 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaaSOa. 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-{[6-cyano-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- / ][l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (110 mg, 94%) as a light yellow solid. MS ESI calculated for C19H24FN5O3[M + H]+, 390.19, found 390.00. ‘H NMR (400 MHz, Chloroform- d) δ 8.65 (s, 1H), 7.05 (s, 1H), 5.31 (brs, 1H), 5.03-4.96 (m, 1H), 4.02-3.95 (m, 4H), 3.63-3.59 (m, 1H), 3.51-3.45 (m, 1H), 2.45-2.40 (m, 1H), 2.06 (s, 3H), 1.64 (d, J= 6.8 Hz, 3H), 1.50-1.34 (m, 6H).Common intermediate 4: l-d-fluoroethyDcvclobutane-l-carboxylic acidStep 1 : benzyl l-( l-[(carboxycarbonyl)oxy1ethvHcvclobutane-l-carboxylate

[0148] To a stirred mixture of (COC1)2 (42.68 mL, 85.362 mmol) was added benzyl 1-(1- hydroxyethyl)cyclobutane-l -carboxylate (10 g, 42.681 mmol) in DCM (10 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. To the above mixture was added H2O (6.50 g, 360.654 mmol) dropwise over 3 min at 0 °C. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reducedpressure to afford benzyl l-{l-[(carboxycarbonyl)oxy]ethyl}cyclobutane-l-carboxylate (12.4 g, 94%) as brown oil. MS ESI calculated for CI6HIXO6[M - H]+, 305.11, found 305.15.1H NMR (400 MHz, Chloroform-d ) 5 7.41-7.31 (m, 5H), 5.43 (q, J= 6.4 Hz, 1H), 5.27-5.13 (m, 2H), 2.60-2.37 (m, 2H), 2.29-2.13 (m, 2H), 2.01-1.91 (m, 2H), 1.31 (d, J= 6.4 Hz, 3H). Step 2: benzyl 1 -f l -11 uorocthyl level obutanc- 1 -carboxylate

[0149] To a stirred mixture of benzyl l-{l-[(carboxycarbonyl)oxy]ethyl}cyclobutane-l-carboxylate (12 g, 39.175 mmol), Selectfluor (31.23 g, 88.144 mmol) in acetone (576 mL) and H2O (144 m ) was added Na2HPO4 (11.12 g, 78.350 mmol), Ir[dF(CFs)ppy]2(dtbbpy)PF6 (2.2 g, 1.959 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was irradiated with Blue LED for 60 min at room temperature under nitrogen atmosphere. The resulting mixture was extracted with pentane (3 x 100 mL). The combined organic layers were washed with brine (3 x 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: Cl 8 column; mobile phase, CH3CN in water (0.1% TFA), 45% to 75%; detector, UV 220 nm to afford benzyl l-(l-fluoroethyl)cyclobutane-l-carboxylate (3.1 g, 33%) as yellow oil. MS ESI calculated for C14H17FO2[M + H]+, 237.12, found 237.15. ’H NMR (400 MHz, Chloroform^ / ) 5 7.41-7.35 (m, 5H), 5.19 (s, 2H), 4.99-4.83 (m, 1H), 2.51-2.21 (m, 4H), 2.05-1.81 (m, 2H), 1.24 (dd, J= 24.0, 6.0 Hz, 3H).19F NMR (377 MHz, Chloroform-d ) δ - 184.35 (IF).Step 3: l-(l-fluoroethyl)cvclobutane-l-carboxylic acid

[0150] To a solution of benzyl l-(l-fluoroethyl)cyclobutane-l-carboxylate (3 g, 12.696 mmol) in MeOH (60 mL) was added Pd / C (3.11 g, 2.920 mmol, 10%) under nitrogen atmosphere. The mixture was stirred for 1 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered through a Celite pad and concentrated under reduced pressure to afford 1 - (l-fluoroethyl)cyclobutane-l-carboxylic acid (1.5 g, 80%) as yellow oil. MS ESI calculated for C7H11FO2[M - H]+, 145.07, found 145.00.1H NMR (400 MHz, Chloroform-d ) 8 5.01-4.85 (m, 1H), 2.54-2.20 (m, 4H), 2.05-1.90 (m, 2H), 1.35 (dd, J= 24.0, 6.0 Hz, 3H).19F NMR (377 MHz, Chloroform-d ) δ -184.32 (IF).Common intermediate 5;2-chloro-7-(l-ethylcvdobutyl)Dyrrolo[2.1- / ][1.2,4]triazineStep 1 : 2,4-dichloro-7-(l-ethylcvclobutyl)pyrrolor2,1-f] triazine

[0151] To a stirred solution of 2,4-dichloropyrrolo[2,l-y][l,2,4]triazine (8 g, 42.551 mmol), 1- ethylcyclobutane-1 -carboxylic acid (16.36 g, 127.653 mmol) and AgNCh (14.46 g, 85.102 mmol) in CH3CN (80 mL) and H2O (40 mL) was added (NH4)2S20s (48.55 g, 212.755 mmol) in H2O (40 mL) dropwise at 50 °C . The resulting mixture was stirred for 2 h at 50 °C. Theresulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10 / 1) to afford 2,4-dichloro-7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazine (7.3 g, 63%) as yellow oil. MS ESI calculated for C12H13CI2N3 [M + H]+, 270.05, found 270.10; ' H NMR (400 MHz, Chloroform-d ) 5 7.01 (d, J= 4.8 Hz, 1H), 6.77 (d, J= 4.8 Hz, 1H), 2.47-2.45 (m, 2H), 2.29-2.25 (m, 2H), 2.11-2.06 (m, 2H), 1.93-1.89 (m, 2H), 0.60 (t, J= 7.2 Hz, 3H). Step 2: 2-chloro-7-(l-ethylcyclobutyl)pyrrolor2J- / ][L2A1triazine

[0152] To a stirred mixture of 2,4-dichloro-7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazine (1 g, 3.702 mmol) in z-PrOH (1 mL) and THF (10 mL) was added NaBH4 (224.05 mg, 5.923 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of sat. NH4CI (aq.) (10 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To this was added DCM (10 mL) and DDQ (1.26 g, 5.553 mmol). The reaction mixture was stirred for 1 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 brine (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 (2 / 1) to afford 2-chloro-7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazine (630 mg, 72%) as a light yellow oil; MS ESI calculated for C12H14CIN3 [M + H]+, 236.09, found 236.10; *HNMR (400 MHz, Chloroform-d ) δ 8.71 (s, 1H), 6.92 (d, J= 4.8 Hz, 1H), 6.80 (d, J= 4.8 Hz, 1H), 2.57-2.44 (m, 2H), 2.37-2.25 (m, 2H), 2.19-2.04 (m, 3H), 1.96-1.89 (m, 1H), 0.61 (t, J= 7.2 Hz, 3H).Common intermediate 6:2-chloroDyrrolo [2.1-M [ 1.2,411 riazineStep 1 : 2,4-dichloro-7-isopropylpyrrolor2,1-fl[l,2,41triazine

[0153] To a stirred solution of 2,4-dichloropyrrolo[2,l- / |[l,2,4]triazine (24 g, 127.65 mmol) and isobutyric acid (33.74 g, 382.96 mmol) and AgNCh (43.37 g, 255.31 mmol) in CH3CN (960 mL) was added (NH4)2S20s (145.65 g, 638.27 mmol) in H2O (480 mL) dropwise at 50 °C. The resulting mixture was stirred for 3 h at 50 °C. The resulting mixture was extracted with EtOAc (2 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. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (8 / 1) to afford 2,4-dichloro-7-isopropylpyrrolo[2,l- / |[l,2,4]triazine (8 g, 27%) as a yellow solid. MS ESI calculated for C9H9CI2N3 [M + H]+, 230.02, found 230.00.1H NMR (400 MHz, Chloroform-d 8 7.03 (d, .7 = 4.8 Hz, 1H), 6 86-6.80 (m, 1H), 3.60-3.54 (m, 1H), 1.40-1.37 (m, 6H) Step 2: 2-chloropyrrolor2,1-firi,2,41triazine

[0154] A solution of 2,4-dichloropyrrolo[2,l- / |[l,2,4]triazine (9.2 g, 48.93 mmol) and NaBH4 (3.70 g, 97.87 mmol) in THF (92 mL) and z-PrOH (10 ml) was stirred for 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (500 mL). The filtrate was concentrated under reduced pressure. To the residue was added DDQ (17.51 g, 77.13 mmol) in DCM (200 mL). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with sat. NaHCO3(aq., 500 mL) at 0 °C. The resulting mixture was extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SC>4. 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 afford2-chloropyrrolo[2,l: / ][l,2,4]triazine (7.4 g, 93%) as a yellow oil. MS ESI calculated for C9H10CIN3 [M + H]+, 196.06, found 195.95.1H NMR (400 MHz, Chloroform-tT) δ 8.72 (s, 1H), 6.93 (d, .7= 4.8 Hz, 1H), 6.83 (d, J= 4.8 Hz, 1H), 3.60-3.58 (m, 1H), 1.41-1.37 (m, 6H).Common intermediate 7;3-f2,5-dichloropyrrolo[2.1- / l[l,2,4]triazin-7-yl)-2-methylbutan-2-olStep 1 : ethyl 3 -hydroxy-2, 3 -dimethylbutanoate

[0155] To a mixture of Zn (11.70 g, 178.978 mmol) in THF (200 mL) was added TMSC1 (2.0 mL, 15.648 mmol) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 20 min at 75 °C under nitrogen atmosphere. To this was added ethyl 2- bromopropanoate (20 g, 110.480 mmol) and acetone (5.77 g, 99.432 mmol) dropwise at 75 °C. The resulting mixture was stirred for additional 2 h at 75 °C. The mixture was allowed to cool down to 0 °C. The mixture was acidified to pH 3 with cone. HC1. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford ethyl 3-hydroxy-2,3-dimethylbutanoate (10.3 g, 58%) as yellow oil. 1H NMR (400 MHz, Chloroform^ / ) 8 4.23-4.19 (m, 2H), 2.53-2.49 (m, 1H), 1.34-1.26 (m, 6H), 1.25-1.21 (m, 6H).Step 2: 3-hydroxy-2,3-dimethylbutanoic acid

[0156] A mixture of ethyl 3 -hydroxy-2, 3 -dimethylbutanoate (10 g, 62.417 mmol) and NaOH (4.99 g, 124.834 mmol) in THF (100 mL) and H2O (100 mL) was stirred for 16 h at room temperature. The mixture was acidified to pH 2 with cone. HC1. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), driedover anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-hydroxy-2,3-dimethylbutanoic acid (3.6 g, 43%) as yellow oil.!H NMR (400 MHz, Chloroform-cZ) 62 58 (q, J= 7.2 Hz, 1H), 1.34 (s, 3H), 1.28 (d, J= 6.8 Hz, 6H).Step 3: 1.3-dioxoisoindol-2-yl 3-hydroxy-2,3-dimethylbutanoate

[0157] To a stirred solution of 3-hydroxy-2,3-dimethylbutanoic acid (1 g, 7.567 mmol, 1 equiv) and N- hydroxyphthalimide (1.36 g, 8.324 mmol), DMAP (92 mg, 0.757 mmol) in DCM (15 mL) was added DIC (1.05 g, 8.324 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford l,3-dioxoisoindol-2-yl 3-hydroxy-2,3-dimethylbutanoate (1.6 g, 76%) as colorless oil.1H NMR (400 MHz, DMSO-zL) 8 7.93-7.89 (m, 2H), 7.85-7.80 (m, 2H), 2.95 (q, . / - 7.2 Hz, 1H), 1.47-1.35 (m, 9H).Step 4: 2-methyl-3-12.4.5-trichloropyrrolor2.1- / 1[1.2.41triazin-7-yllbutan-2-ol

[0158] To a mixture of l,3-dioxoisoindol-2-yl 3-hydroxy-2,3-dimethylbutanoate (1 g, 3.607 mmol), 2,4,5-trichloropyrrolo[2,l- / |[l,2,4]triazine (1.60 g, 7.214 mmol), TFA (1.23 g, 10.821 mmol) in DMA (25 mL) was added Ir[dF(CF3)PPy]2(dtbpy)PFe (81 mg, 0.072 mmol) under nitrogen atmosphere. The reaction mixture was irradiated with Blue LED for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 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 (3 / 1) to afford 2-methyl-3-{2,4,5-trichloropyrrolo[2,l- / |[l,2,4]triazin-7-yl}butan-2-ol (100 mg, 8%) as a yellow solid. MS ESI calculated for C11H12CI3N3O [M + H]+, 308.00; found 308.00.Step 5: 3-12.5-dichloropyrrolor2.l- / 11L2.41triazin-7-vn-2-methylbutan-2-ol

[0159] Amixture of 2-methyl-3-{2,4,5-trichloropyrrolo[2,l- / |[l,2,4]triazin-7-yl}butan-2-ol (150 mg, 0.486 mmol) and NaBH4 (30 mg, 0.793 mmol) in z-PrOH (2 mL) was stirred for 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 20 mL). The filtrate was concentrated under reduced pressure. To this was added DDQ (132 mg, 0.581 mmol, 1.46 equiv) in DCM (3 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of sat. NallCO3(aq.) (20 mL). The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (3 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 (3 / 1) to afford 3-{2,5-dichloropyrrolo[2,l- / ][l,2,4]triazin-7-yl}-2-methylbutan-2-ol (80 mg, 73%) as yellow oil. MS ESI calculated forC11H13CIN3O [M + H]+, 274.04; found 274.05.1H NMR (Chloroform-z / ) S 8.76 (s, 1H), 6.88 (s, 1H), 3.72-3.69 (m, 1H), 1.38 (d, J= 7.2 Hz, 3H), 1.28 (s, 3H), 1.22 (s, 3H).Common intermediate 8:2,5-dichloro-7-isoDropylpyrrolo[2,1-f][l,2,4]triazineStep 1 : 2A5-trichloro-7-isopropylpyrrolor2.1- / iri.2.41triazine

[0160] To a stirred mixture of 2,4,5-trichloropyrrolo[2, l- / |[l,2,4]triazine (1 g, 4.495 mmol) and isobutyric acid (1.19 g, 13.485 mmol) in CH3CN (40 mL) and water (10 mL) was added AgNCh (1.53 g, 8.99 mmol) at room temperature. The resulting mixture was stirred for 10 min at room temperature. To this was added (NH4)2S20s (5.15 g, 22 475 mmol) in water (10 mL) over 10 min at room temperature. The resulting mixture was stirred for additional 2 h at 50 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of sat. NH4CI (aq.) (120 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 30% to 95%; detector, UV 254 nm to afford 2,4,5-trichloro-7-isopropylpyrrolo[2,l- / |[l,2,4]triazine (560 mg, 42%) as a yellow oil. MS ESI calculated for C9H8CI3N3 [M + H]+, 263.98, found 263.95. ‘H NMR (400 MHz, Chloroform-d 5 6.77 (s, 1H), 3.60-3.50 (m, 1H), 1.38-1.36 (m, 6H).Step 2: 2,5-dichloro-7-isopropylpyrrolor2,1-fl[L2,4]triazine

[0161] To a stirred mixture of 2,4,5-trichloro-7-isopropylpyrrolo[2,l- / |[l,2,4]triazine (560 mg, 2.117 mmol) in THF (5.6 mL) and z-PrOH (0.28 mL) was added NaBH4 (128 mg, 3.388 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (6 mL). To this was added DDQ (721 mg, 3.175 mmol). The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched by the addition of sat. NaHCCL (aq.) (20 mL). The resulting mixture was extracted with EtOAc (2 x 15 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 (0-40%) to afford 2,5-dichloro-7-isopropylpyrrolo[2,l- / |[l,2,4]triazine (430 mg, 77%) as yellow oil. MS ESI calculated for C9H9CI2N3 [M + H]+, 230.02, found 230.05.1H NMR (400 MHz, Chloroform-d ) δ 8.76 (s, 1H), 6.75 (s, 1H), 3.62-3.52 (m, 1H), 1.38-1.37 (m, 6H).Common intermediate 9;2-(l-bromoethenyl)-2-methyl-l,3-dioxolaneStep 1 : 2-(l-chloroethyl)-2-methyl-L3-dioxolane

[0162] To a stirred solution of 3-chloro-2-butanone (15.45 g, 145.002 mmol) and ethylene glycol (8.63 g, 139.041 mmol) in cyclohexane (150 mL) was added -TsOH (0.21 g, 1.249 mmol) at room temperature. The resulting mixture was stirred for 16 h at 95 °C. The resulting mixture was concentrated under reduced pressure to afford 2-(l-chloroethyl)-2-methyl-l,3-dioxolane (18.0 g, 82%) as brown oil. CeHuClCh, *HNMR (300 MHz, Chloroform-d ) 5 4.07-3.96 (m, 5H), 1.54 (d, 6.9 Hz, 3H), 1.45 (s, 3H).Step 2: 2-ethenyl-2-methyl- 1,3 -di oxolane

[0163] To a stirred solution of 2-(l-chloroethyl)-2-methyl-l,3-dioxolane (18.0 g, 119.522 mmol) in DMSO (100 mL) was added KOH (44.00 g, 784.244 mmol) at room temperature. The reaction mixture was stirred for 3 h at 120 °C. The resulting mixture was purified by distillation and the fraction was collected at 110-115 °C at atmospheric pressure to afford 2-ethenyl-2-methyl-l,3- dioxolane (13.8 g, crude) as colorless liquid. C6H10O2, H NMR (300 MHz, Chloroform-d ) 5 5.81 (dd, J= 17.2, 10.5 Hz, 1H), 5.39 (dd, J= 17.2, 1.8 Hz, 1H), 5.15 (dd, J= 10.5, 1.8 Hz, 1H), 4.03-3.82 (m, 4H), 1.48 (s, 3H).Step 3: 2-(l-bromoethenyl)-2-m ethyl- 1,3 -di oxolane

[0164] To a stirred solution of 2-ethenyl-2-methyl-l,3-dioxolane (39 g, 256.255 mmol, 75% purity) in DCM (100 mL) was added Br2 (9.19 mL, 179.378 mmol) in DCM (100 mL) dropwise at 0°C. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and dissolved in THF (400 mL). To this was added DBU (58.52 g, 384.382 mmol). The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with DCM (3 x 400mL). The combined organic layers were washed with brine (200 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 (10 / 1) to afford 2-(l-bromoethenyl)-2-methyl- 1,3 -di oxolane (18.7 g, 38%) as colorless oil. C6H9BrO2,1H NMR (400 MHz, Chloroform-d ) 5 6.06 (d, J= 1.6 Hz, 1H), 5.61 (d, J= 1.6 Hz, 1H), 4.05-3.88 (m, 4H), 1.63 (s, 3H).Common intermediate 10: 4,4,5,5-tetramethyl-2-[l-(2-methyl-l.,3-dioxolan-2-yl)ethenyl1-l,3-,2-dioxaborolane Step 1 : 4,4,5, 5-tetramethyl-2-[ l-(2-methyl-l,3-dioxolan-2-yl)ethenyl1-L3,2-dioxaborolane

[0165] To a mixture of 2-ethynyl-2-methyl-l,3-dioxolane (20 g, 178.368 mmol) and bis(pinacolato)diboron (49.8 g, 196.205 mmol) in toluene (340 mL) was added CuCl (1.77 g, 17.837 mmol), / -BuONa (2.57 g, 26.755 mmol, 0.15 equiv), tri-ter / -butylphosphane (43.30 g,10%, 21.404 mmol) and MeOH (11.43 g, 356.736 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for 16 h at room temperature under a nitrogen atmosphere. The reaction was diluted with MeOH (200 mL). The resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10 / 1) to afford 4,4,5,5-tetramethyl-2-[l-(2-methyl-l,3-dioxolan-2-yl)ethenyl]-l,3,2- dioxaborolane (16 g, 37%) as light yellow liquid.1H NMR (400 MHz, C h loro form -<7) 5.97 (dδ, J= 3.6 Hz, 1H), 5.84 (d, J= 3.6 Hz, 1H), 3.98-3.94 (m, 2H), 3.85-3.79 (m, 2H), 1.56 (s, 3H), 1.29 (s, 12H).Common intermediate 11: (3R,41?)-4-G5-chloro-6-cyano-7-isopropylpyrrolo[2,1-f][l,2,4]triazin-2-yl}amino)piperidin- 3-yl acetate hydrochlorideStep 1 : tert-butyl (3A.4A)-4-(15-chloro-7-isopropylpyrrolo[2.1- / irL2.41triazin-2-vHamino)-3- hydroxypiperidine- 1 -carboxylate

[0166] A mixture of 2,5-dichloro-7-isopropylpyrrolo[2,l- / |[l,2,4]triazine (430 mg, 1.869 mmol), tertbutyl (3A,4R)-4-amino-3-hydroxypiperidine-l -carboxylate (1.62 g, 7.490 mmol) and DIEA (1.6 mL, 9.358 mmol) in NMP (4 mL) was stirred for 16 h at 120 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 10% to 80%; detector, UV 254 nm to afford tert-butyl (3R,4A)-4-({5- chloro-7-isopropylpyrrolo[2, 1 -f\ [ 1 ,2,4]triazin-2-yl }amino)-3 -hydroxypiperidine- 1 -carboxylate (760 mg, 89%) as a yellow solid. MS ESI calculated for C19H28CIN5O3[M + H]+, 410.19, found 410.35.1HNMR (400 MHz, Chloroform-d δ 8.56 (s, 1H), 6.49 (s, 1H), 5.06 (m, 1H), 4.34-4.28 (m, 1H), 4.21-4.16 (m, 1H), 3.75-3.71 (m, 1H), 3.62-3.58 (m, 1H), 3.42-3.39 (m, 1H), 2.89-2.85 (m, 1H), 2.79-2.73 (m, 1H), 2.13-2.09 (m, 1H), 1.60-1.53 (m, 1H), 1.49 (s, 9H), 1.35-1.33 (m, 6H).Step 2: tert-butyl (3A.4A)-3-(acetyloxy)-4-(f 5-cliloro-7-isopropylpyrrolol2,1-f]rL2,41triazin-2- yllamino)piperidine-l -carboxylate

[0167] To a stirred mixture of tert-butyl (3R,4R)-4-({5-chloro-7-isopropylpyrrolo[2,l: / ][l,2,4]triazin-2- yl}amino)-3-hydroxypiperidine-l-carboxylate (500 mg, 1.220 mmol) and TEA (0.85 mL, 6.115 mmol) in DCM (5 mL) was added AC2O (0.17 mL, 1.830 mmol) at room temperature. The resulting mixture was stirred for 16 h at 50 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (0~60%) to afford tert-butyl (3R,4R)-3-(acetyloxy)-4-({5-chloro-7- isopropylpyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)piperidine-l-carboxylate (630 mg, 97%) as a yellow solid. MS ESI calculated for C21H30CIN5O4 [M + H]+, 452.20, found 452.15.!H NMR(400 MHz, Chloroform-d) δ 8.56 (s, 1H), 6.42 (s, 1H), 4.98-4.88 (m, 2H), 3.99-3.90 (m, 2H), 3.85-3.80 (m, 1H), 3.44-3.40 (m, 1H), 3.26-3.23 (m, 2H), 2.37-2.33 (m, 1H), 2.06 (s, 3H), 1.51- 1.48 (m, 10H), 1.35-1.32 (m, 6H).Step 3: tert-butyl (3A.4A)-3-(acetyloxy)-4-((5-chloro-6-iodo-7-isopropylpyrrolor2,l- f\ 11 ,2,41triazin-2-yl ! aminolpiperidine- 1 -carboxylate

[0168] A mixture of tert-butyl (3R,4A)-3-(acetyloxy)-4-({5-chloro-7-isopropylpyrrolo[2,l- / |[1, 2, 4]triazin-2-yl}amino)piperi dine- 1 -carboxylate (300 mg, 0.664 mmol) and I2 (674 mg, 2.656 mmol) in DMF (3 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat Na2S2O3(aq.) (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SC>4. 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 (3A,4R)-3-(acetyloxy)-4-({5-chloro-6-iodo-7- isopropylpyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)piperidine-l-carboxylate (400 mg, 93%) as a yellow solid. MS ESI calculated for C21H29CIIN5O4 [M + H]+, 578.10, found 578.15.1HNMR (400 MHz, Chloroform-d ) δ 8.55 (s, 1H), 5.10-4.92 (m, 2H), 4.16-4.12 (m, 1H), 3.91-3.83 (m, 2H), 3.59-3.55 (m, 1H), 3.30-3.22 (m, 2H), 2.34-2.25 (m, 1H), 2.07 (s, 3H), 1.49-1.45 (m, 16H). Step 4: tert-butyl (3R.4R)-3-(acetyloxy)-4-(15-chloro-6-cyano-7-isopropylpyrrolo[2,l- f\ 11 ,2,41triazin-2-yl 1 amino)piperidine- 1 -carboxylate

[0169] A mixture of tert-butyl (3A,4R)-3-(acetyloxy)-4-({5-chloro-6-iodo-7-isopropylpyrrolo[2,l- _ / ][!, 2, 4]triazin-2-yl}amino)piperi dine- 1 -carboxylate (400 mg, 0.692 mmol), Zn(CN)2 (98 mg, 0.830 mmol) and Pd(PPh3)4 (80 mg, 0.069 mmol) in DMA (4 mL) was stirred for 2 h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water / ice (20 mL). The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were 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-(acetyloxy)-4-({5-chloro-6-cyano-7-isopropylpyrrolo[2,l-: / ][l,2,4]triazin-2- yl}amino)piperidine-l -carboxylate (270 mg, 77%) as a yellow solid. MS ESI calculated for C22H29CIN6O4 [M + H]+, 477.19, found 477.20.1HNMR (400 MHz, Chloroform-d ) δ 8.66 (s, 1H), 5.19 (s, 1H), 4.93-4.92(m, 1H) 4.08-4.04 (m, 1H), 3.95-3.87 (m, 3H), 3.68-3.63 (m, 1H), 3.17-3.12 (m, 1H), 2.36-2.32 (m, 1H), 2.08-2.06 (m, 3H), 1.79-1.75 (m, 1H), 1.50-1.47 (m, 15H).Step 5: (3R,4R)-4-(15-chloro-6-cyano-7-isopropylpyrrolo[2,1-f][L2,41triazin-2- yHamino)piperi din-3 -yl acetate hydrochloride

[0170] To a stirred mixture of / c / 7-butyl (3R,4A)-3-(acetyloxy)-4-({5-chloro-6-cyano-7- isopropylpyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)piperidine-l-carboxylate (70 mg, 0.147 mmol) in DCM (1 mL) was added HC1 (gas) in 1,4-dioxane (1 mb) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3A,4R)-4-({5-chloro-6-cyano-7-isopropylpyrrolo[2,l: / ][l,2,4]triazin-2- yl}amino)piperi din-3 -yl acetate hydrochloride (60 mg, 89%) (crude) as yellow oil. MS ESI calculated for C17H22CI2N6O2[M - Cl]+, 377.14, found 377.20.Common intermediate 12:2,5-dichloro-7-(sec-butyl)pyrrolo[2,1-f]|l,2,4]triazineStep 1 : 2,4,5-trichloro-7-(sec-butyl)pyrrolo[2, !- / ][ l,2,41triazine

[0171] To a stirred mixture of 2,4,5-trichloropyrrolo[2, l - / ][ l,2,4]triazine (700 mg, 3.147 mmol) and 2- methylbutanoic acid (964 mg, 9.441 mmol) and CH3CN (8 mL) was added AgNCh (1.07 g, 6.294 mmol) at room temperature. To this was added (NH4)2S2C>8 (3.59 g, 15.735 mmol) in water (4 mL) at 50 °C. The reaction mixture was stirred for 16 h at 50 °C. The resulting mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL), dried over anhydrous Na2SC>4. 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 2,4,5-trichloro-7-( ec-butyl)pyrrolo[2,l: / ][l,2,4]triazine (450 mg, 51%) as a yellow solid; MS ESI calculated for C10H10CI3N3 [M + H]+, 277.99, found 278.05.1H NMR (400 MHz, Chloroform-d ) 5 6.75 (s, 1H), 3.44-3.40 (m, 1H), 1.87-1.73 (m, 2H), 1.33 (d, J= 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H).Step 2: 2,5-dichloro-7- butyl)pyrrolo[2.1- / irL2,41triazine

[0172] To a stirred mixture of 2,4,5-trichloro-7-(sec-butyl)pyrrolo[2,l- / |[l,2,4]triazine (450 mg, 1.615 mmol) in z-PrOH (0.25 mL) and THF (5 mL) was added NaBH4 (92 mg, 2.422 mmol) in portions at 0 °C. The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of sat. NH4CI (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 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. To this was added DCM (5 mL) and DDQ (692 mg, 3.046 mmol) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (5 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 3 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10 / 1) to afford 2,5-dichloro-7- (sec-butyl)pyrrolo[2,l- / |[l,2,4]triazine (370 mg, 75%) as yellow oil. MS ESI calculated for C10H11CI2N3 [M + H]+, 244.03, found 244.05. ' H NMR (400 MHz, Chloroform-d ) δ 8.75 (s,1H), 6.74 (s, 1H), 3.49-3.40 (m, 1H), 1.88-1.69 (m, 2H), 1.34 (d, J= 7.2 Hz, 4H), 0.92 (t, J= 7.2 Hz, 3H).Common intermediate 13:2,5-dichloro-6-iodo-7-(2-methylpropyl)pyrrolo[2,l-f|[l,2,41triazineStep 1 : L3-dioxoisoindol-2-yl 3-methylbutanoate

[0173] To a stirred solution of isovaleric acid (1.1 g, 10 770 mmol), isovaleric acid (1.1 g, 10.770 mmol) and DMAP (0.13 g, 1.077 mmol) in DCM (15 mL) was added DIC (1.50 g, 11.847 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was fdtered, the filter cake was washed with EtOAc (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2 / 1) to afford l,3-dioxoisoindol-2-yl 3- methylbutanoate (1.8 g, 67.59%) as a white solid.1HNMR (400 MHz, Chloroform-d ) 5 7.92- 7.87 (m, 2H), 7.83-7.78 (m, 2H), 2.56 (d, J= 7.2 Hz, 2H), 2.33-2.22 (m, 1H), 1.12 (d, J = 6.8 Hz, 6H).Step 2: 2.4-dichloro-7-(2-methylpropyl)pyrrolor2. l- / 1[L2.41triazine

[0174] A mixture of 2,4-dichloropyrrolo[2,l- / |[l,2,4]triazine (3 g, 15.957 mmol), l,3-dioxoisoindol-2- yl 3-methylbutanoate (7.89 g, 31.914 mmol) and TFA (5.46 g, 47.871 mmol) in DMA (48 mL) was added Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.90 g, 0.798 mmol) under nitrogen atmosphere. The reaction mixture was irradiated with Blue LED for 48 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (300 mL) and 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. The residue was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in Water (0.1% formic acid), 20% to 50%; detector, UV 254 nm to afford 2,4-dichloro-7-(2-methylpropyl)pyrrolo[2,l- / |[l,2,4]triazine (1.5 g, 27%) as brown oil. MS ESI calculated for C10H11CI2N3 [M + H]+, 244.03, found 244.10.1H NMR (400 MHz, Chloroform-d ) δ 7.05 (d, J= 4.8 Hz, 1H), 6.82 (d, J= 4.8 Hz, 1H), 2.91 (d, J= 7.2 Hz, 2H), 2.20-2.17 (m, 1H), 0.99 (d, J= 6.8 Hz, 6H).Step 3: 2-chloro-7-(2-methylpropyl)pyrrolor2,1-f1[l,2,4]triazine

[0175] To a stirred mixture of 2,4-dichloro-7-(2-methylpropyl)pyrrolo[2,l- / |[l,2,4]triazine (1.64 g, 4.703 mmol) in THF (20 mL) and z-PrOH (1 mL) was added NaBH4 (284.64 mg, 7.525 mmol) in portions at 0 °C. The resulting mixture was stirred for 4 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL). To this was added DDQ (1.77 g, 7.794 mmol).

[0176] The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 100 mL). The combined filtrare was extracted with water (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 (5 / 1) to afford 2-chloro-7-(2-methylpropyl)pyrrolo[2,l- / |[l,2,4]triazine (700 mg, 64%) as light yellow oil. MS ESI calculated for C10H12CIN3 [M + H]+, 210.07, found 210.10.1H NMR (400 MHz, Chloroform-d δ 8.73 (s, 1H), 6.99 (d, J = 4.8 Hz, 1H), 6.85 (d, . / - 4.8 Hz, 1H), 2.93 (d, J = 7.2 Hz, 2H), 2.25-2.19 (m, 1H), 1.00 (d, J= 6.8 Hz, 6H).Step 4: 2,5-dichloro-7-(2-methylpropyl)pyrrolor2, l- / ][l,2,4]triazine

[0177] To a stirred mixture of 2-chloro-7-(2-methylpropyl)pyrrolo[2,l^][l,2,4]triazine (110 mg, 0.525 mmol) in DMF (1.5 mL) was added NCS (63.05 mg, 0.473 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The residue was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, MeOH in water (0.1% NH3.H2O), 50% to 95%; detector, UV 254 nm to afford 2,5-dichloro-7- (2-methylpropyl)pyrrolo[2,l-: / ][l,2,4]triazine (100 mg, 72%) as yellow oil. MS ESI calculated for C10H11CI2N3 [M + H]+, 244.03, found 244.05.Step 5: 2.5-dichloro-6-iodo-7-(2-methylpropyl)pyrrolo[2.1- / l[1.2.41triazine

[0178] To a stirred mixture of 2,5-dichloro-7-(2-methylpropyl)pyrrolo[2,l- / |[l,2,4]triazine (50 mg, 0.205 mmol) in DMF (1 mL) was added I2 (208 mg, 0.820 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. Na2S2C>3 (aq.) (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10 / 1) to afford 2,5-dichloro-6-iodo-7-(2-methylpropyl)pyrrolo[2,l- / |[l,2,4]triazine (20 mg, 25%) as brown yellow oil. MS ESI calculated for C10H10CI2IN3 [M + H]+, 369.93, found 370.00.1H NMR (400 MHz, Chloroform-d ) δ 8.75 (s, 1H), 2.88 (d, J= 7.2 Hz, 2H), 2.21-2.11 (m, 1H), 1.00-0.97 (m, 6H).Common intermediate 14:2,5-dichloro-7-(3-methylbutan-2-yl)pyrrolo[2,1-f] [l,2,41triazineStep 1 : 2,4,5-trichloro-7-(3-methylbutan-2-yl)pyrrolor2,1-f][l,2,4]triazine

[0179] To a stirred mixture of 2,4,5-trichloropyrrolo[2,l- / |[l,2,4]triazine (350 mg, 1.573 mmol) and 2,3 -dimethylbutanoic acid (548 mg, 4.71 mmol) in CH3CN (10 mL) were added (NH4)2S2O8 (1.80 g, 7.86 mmol) and water (7 mL) at room temperature. The resulting mixture was stirred for2 h at 50 °C. The mixture was allowed to cool down to room temperature. The reaction was diluted with sat. NH4CI (aq.) (20 mL. 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 reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% TFA), 10% to 50%; detector, UV 254 nm to afford 2,4,5- trichloro-7-(3-methylbutan-2-yl)pyrrolo[2,l- / |[l,2,4]triazine (310 mg, 67%) as yellow oil. MS ESI calculated for C11H12CI3N3 [M + H]+, 292.01 found 292.00.1H-NMR (400 MHz, Chloroform-d ) 5 6 74 (s, 1H), 3.40-3.35 (m, 1H), 2.06-2 00 (m, 1H), 1.29 (d, J= 7.2 Hz, 3H), 0.94 (d, J= 6.8 Hz, 3H), 0.89 (d, J= 6.8 Hz, 3H).Step 2: 2,5-dichloro-7-(3-methylbutan-2-yl)pyrrolor2,1-fir L2,4]triazine

[0180] To a stirred mixture of 2,4,5-trichloro-7-(3-methylbutan-2-yl)pyrrolo[2,l: / ][l,2,4]triazine (310 mg, 1.06 mmol) and z-PrOH (0.2 mL) in THF (4 mL) was added NaBH4 (64 mg, 1.69 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure. To this was added DDQ (360 mg, 1.59 mmol) and DCM (4 mL) at 0 °C. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (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 (3 / 1) to afford 2,5-dichloro-7-(3-methylbutan-2-yl)pyrrolo[2,l- / |[l,2,4]triazine (220 mg, 80%) as yellow oil. MS ESI calculated for C11H13Q2N3 [M + H]+, 258.05 found 258.05.1H-NMR (400 MHz, Chloroform-z / ) δ 8.75 (s, 1H), 6.74 (d, J= 1.6 Hz, 1H), 3.41-3.36 (m, 1H), 2.08-2.02 (m, 1H), 1.30 (d, J= 7.2 Hz, 3H), 0.95 (d, J= 6.8 Hz, 3H), 0.89 (d, J= 6.8 Hz, 3H).Common intermediate 15: -4-f[5-chloro-6-cvano-7-(3-methylbutan-2-yl)pyrrolo[2,1-f][l,2,41triazin-2-yl]amino}piperidin-3-yl acetate hydrochlorideStep 1 : tert-butyl (3R.4A)-3-(acetyloxy)-4-H5-chloro-6-iodo-7-(3-methylbutan-2-yl)pyrrolor2.1- f\ [ 1 ,2,41triazin-2-yl1aminolpiperidine- 1 -carboxylate

[0181] To a stirred mixture of tert-butyl (3A,4R)-3-(acetyloxy)-4-{[5-chloro-7-(3-methylbutan-2- yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}piperidine-l-carboxylate (150 mg, 0.3 mmol) in DMF (3 mL) was added I2 (317 mg, 1.24 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. Na2S2Ch (aq.) (20 mL) at roomtemperature. 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 NazSC . 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 Zc / 7-butyl (3R,4R)-3- (acetyloxy)-4-{ [5-chl oro-6-iodo-7-(3-methylbutan-2-yl)pyrrolo[2,l- / |[l, 2, 4]tri azin-2- yl]amino}piperidine-l -carboxylate (175 mg, 92%) as a yellow solid. MS ESI calculated for C23H33CIIN5O4 [M + H]+, 606.13, found 606.20.Step 2: tert-butyl (3R.4A)-3-(acetyloxy)-4-f [5-chloro-6-cvano-7-(3-methylbutan-2- yl jpyrrol o[2, 1 - / ] [ 1 ,2,41triazin-2-yl1amino)piperidine- 1 -carboxylate

[0182] To a stirred mixture of tert-butyl (3R,4R)-3-(acetyloxy)-4-{[5-chloro-6-iodo-7-(3-methylbutan- 2-yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}piperidine-l-carboxylate (175 mg, 0.28 mmol) and Zn(CN)2 (15 mg, 0.23 mmol) in DMA (3 mL) was added Pd(PPh3)4 (66 mg, 0.05 mmol). The resulting mixture was stirred for 2 h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (20 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 reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 10% to 50%; detector, UV 254 nm to afford / / Z-butyl (3A,4R)-3-(acetyloxy)-4-{[5-chloro-6-cyano-7-(3-methylbutan-2- yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}piperidine-l-carboxylate (98 mg, 67%) as a yellow solid. MS ESI calculated for C27H33CIN6O4 [M + H]+, 505.23, found 505.25.1H NMR (400 MHz, Chloroform-d ) δ 8.52 (s, 1H), 5.48 (brs, 1H), 4.95-4.91 (m, 1H), 3.90-3.86 (m, 2H), 3.77- 3.73 (m, 1H), 3.38-3.34 (m, 2H), 3.10-3.00 (m, 1H), 2.54-2.43 (m, 1H), 2.35-2.30 (m, 1H), 2.08- 2.07 (m, 3H), 1.62-1.56 (m, 1H), 1.49 (s, 9H), 1.45-1.41 (m, 3H), 1.11-1.07 (m, 3H), 0.72-068 (m, 3H).Step 3 : -4-( r5-chloro-6-cvano-7-(3-methylbutan-2-yl)pyrrolor2. l- / irL2.41triazin-2-yllaminolpiperidin-3-yl acetate hydrochloride

[0183] To a stirred mixture of te / 7-butyl (3R,4R)-3-(acetyloxy)-4-{[5-chloro-6-cyano-7-(3- methylbutan-2-yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}piperidine-l-carboxylate (98 mg, 0.194 mmol) in DCM (4 mL) was added HC1 (gas) in 1,4-dioxane (4 mL) 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-6-cyano-7-(3-methylbutan- 2-yl)pyrr°l°[2,l- / |[l,2,4]triazin-2-yl]amino}piperidin-3-yl acetate hydrochloride (80 mg, 93%) as a yellow solid. MS ESI calculated for CisTEgCENeCLfM - Cl]+, 405.17, found 405.20.Common intermediate 16:(31?.,4R)-4-f[5-chloro-6-cvano-7-(l-ethylcvclobutyl)pyrrolo[2,1-f][l.,2.,41triazin-2- yllaminolpiperidin-3-yl acetate hydrochlorideStep 1 : 2,5-dichloro-7-(l-ethylcyclobutyl)pyrrolor2,1-f1[l,2,41triazine

[0184] Amixture of 2-chloro-7-(l-ethylcyclobutyl)pyrrolo[2,l-;][l,2,4]triazine (3.3 g, 14.000 mmol) and NCS (1.96 g, 14.700 mmol) in DMF (50 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of water (100 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 residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2,5-dichloro-7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazine (3.0 g, 79%) as a yellow solid. MS ESI calculated for C12H13CI2N3 [M + H]+, 270.05; found 270.05.1HNMR (400 MHz, Chloroform-d δ 8.75 (s, 1H), 6.72 (s, 1H), 2.51-2.40 (m, 2H), 2.34-2.24 (m, 2H), 2.14-2.06 (m, 3H), 1.97-1.87 (m, 1H), 0.63 (t, 7.2 Hz, 3H).Step 2: 2.5-dichloro-7-(l-ethylcvclobutyl)-6-iodopyrrolo[2.1- / iri.2.41triazine

[0185] Amixture of 2,5-dichloro-7-(l-ethylcyclobutyl)pyrrolo[2,l: / ][l,2,4]triazine (3.0 g, 11.105 mmol) and I2 (11.27 g, 44.420 mmol) in DMF (60 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. Na2S20s (aq.) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 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 residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford 2,5-dichloro-7-(l-ethylcyclobutyl)-6- iodopyrrolo[2,l- / ][l,2,4]triazine (3.0 g, 68%) as a yellow solid. MS ESI calculated for C12H12CI2IN3 [M + H]+, 395.95; found 395.95.1H NMR (400 MHz, Chloroform-d ) δ 8.71 (s, 1H), 2.79-2.62 (m, 2H), 2.56-2.40 (m, 2H), 2.20-2.05 (m, 3H), 1.91-1.82 (m, 1H), 0.88-0.74 (m, 3H).Step 3 : tert-butyl (3A.4A)-4-( r5-chloro-7-(l-ethylcvclobutyl)-6-iodopyrrolo[2. !- / ][ L2.41triazin- 2-yl1aminol-3-hvdroxypiperidine-l-carboxylate

[0186] Amixture of 2,5-dichloro-7-(l-ethylcyclobutyl)-6-iodopyrrolo[2,l: / ][l,2,4]triazine (2.5 g, 6.312 mmol), tert-butyl (3A,4R)-4-amino-3-hydroxypiperidine-l-carboxylate (1.64 g, 7.574 mmol) and DIEA (3.26 g, 25.248 mmol) in NMP (50 mL) was stirred for 16 h at 80 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (100 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 residue waspurified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford / c / 7-butyl (3R,4A)-4-{[5-chloro-7-(l-ethylcyclobutyl)-6-iodopyrrolo[2,l:][l,2,4]triazin-2-yl]amino}-3- hydroxypiperidine- 1 -carboxylate (3.3 g, 90%) as a yellow solid. MS ESI calculated for C22H31CIIN5O3[M + H]+, 576.12; found 576.15.1H NMR (400 MHz, Chloroform-d δ 8.51 (s, 1H), 4.94 (brs, 1H), 4.32-4.25 (m, 1H), 4.15-4.11 (m, 2H), 3.66-3.47 (m, 3H), 2.89-2.84 (m, 1H), 2.80-2.66 (m, 3H), 2.42-2.38 (m, 2H), 2.25-1.99 (m, 6H), 1.87-1.83 (m, 1H), 1.48 (s, 9H), 0.83-0.79 (m, 3H).Step 4: tert-butyl (37 4A)-3-(acetyloxy)-4-f [5-chloro-7-(l-ethylcyclobutyl)-6-iodopyrrolo[2,l- f\ 11 ,2,41triazin-2-yl1aminolpiperidine- 1 -carboxylate

[0187] A mixture of tert-butyl (3R,4R)-4-{[5-chloro-7-(l-ethylcyclobutyl)-6-iodopyrrolo[2,l- / ][l,2,4]triazin-2-yl]amino}-3-hydroxypiperidine-l-carboxylate (3.3 g, 5.730 mmol), AC2O (0.88 g, 8.595 mmol) and TEA (2.32 g, 22.920 mmol) in DCM (50 mL) was stirred for 16 h at 50 °C. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (2 / 1) to afford tert-butyl (3R,4R)-3-(acetyloxy)-4- | [5-chloro-7-( l-ethylcyclobutyl)-6- iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}piperidine-l-carboxylate (3.3 g, 93%) as a yellow solid. MS ESI calculated for C24H33CIIN5O4 [M + H]+, 618.13; found 618.15.Step 5: tert-butyl (3R.4A)-3-(acetyloxy)-4-n5-chloro-6-cyano-7-(l-ethylcyclobutyl)pyrrolo[2,l- f\ [ 1.2.41triazin-2-yl1aminolpiperidine- 1 -carboxylate

[0188] A mixture of tert-butyl (3R,4R)-3-(acetyloxy)-4-{[5-chloro-7-(l-ethylcyclobutyl)-6- iodopyrrolo[2, !- / ][!, 2, 4]triazin-2-yl]amino}piperidine-l-carboxylate (3.3 g, 5.341 mmol), Zn(CN)2 (345 mg, 2.938 mmol) and Pd(PPhs)4 (617 mg, 0.534 mmol) in DMF (40 mL) was stirred for 2 h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (100 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 Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2 / 1) to afford Ze / 7-butyl (3R,4R)-3-(acetyloxy)- 4-{[5-chloro-6-cyano-7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}piperidine-l- carboxylate (2.3 g, 83%) as a yellow solid. MS ESI calculated for C25H33CIN6O4 [M + H]+, 517.23; found 517.30.1HNMR (400 MHz, Chloroform / ) δ 8.65 (s, 1H), 5.25 (brs, 1H), 4.92- 4.88 (m, 1H), 4.14-4.10 (m, 1H), 3.94-3.87 (m, 1H), 3.79-3.76 (m, 1H), 3.13-3.09 (m, 2H), 2.73- 2.69 (m, 2H), 2.37-2.28 (m, 3H), 2.23-2.15 (m, 1H), 2.13-2.04 (m, 5H), 2.01-1.92 (m, 1H), 1.53- 1.49 (m, 10H), 0.81 (t, J = 7.2 Hz, 3H).Step 6: -4-l r5-chloro-6-cyano-7-(l-ethylcyclobutyl)pyrrolor2,1-f1[L2,41triazin-2-yl]aminolpiperidin-3-yl acetate hydrochloride

[0189] A mixture of tert-butyl (3R,4R)-3-(acetyloxy)-4-{[5-chloro-6-cyano-7-(l- ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}piperidine-l-carboxylate (1 g, 1.934 mmol) and HC1 (gas)in 1,4-di oxane (10 mL) in DCM (10 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (3R,4R)~ 4-{[5-chloro-6-cyano-7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}piperidin-3- yl acetate hydrochloride (800 mg, 91%) as a yellow solid. MS ESI calculated for C20H26CI2N6O2[M - Cl]+, 417.17; found 417.25.Example 1: -((5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6-(trifluoromethyl)pyrrolo[2.,l-f][l,2,4]triazin-2-yl)amino)tetrahydro-2H-pyran-3-oI (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRALPAK ID, Hexane / TrOH = 93 / 7, 1stpeak)Example 2: -4-((5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6-(trifluoromethyl)pyrrolo[2,l-f][1.2,4]triazin-2-yl)amino)tetrahydro-2J / -pyran-3-ol (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRALPAK ID, Hcxanc / 'PrOH = 93 / 7, 2ndpeak)Step 1 : (3S, 4R)-4-([5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6-(trifluoromethyl)pyrrolo[2.1- / ]|T,2,41triazin-2-yl1aminoloxan-3-yl acetate

[0190] To a stirred solution of (3S,4A)-4-{[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6- iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (200 mg, 0.38 mmol) and KF (66 mg, 1.14 mmol), Cui (72 mg, 0.38 mmol) in DMF (3 mL) was added methyl 2,2-difluoro-2- sulfoacetate (366 mg, 1.91mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 50 °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% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford (3S,4R)-4-{[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6- (trifluoromethyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (177 mg, 79%) as a yellow solid. MS ESI calculated for C19H23CIF4N4O3[M + H]+, 467.14, found 467.30. Step 2: (3S.4R)-4-([5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6-(trifluoromethyl)pyrrolo[2.1- / ] triazin-2-yl1aminoloxan-3-ol

[0191] A solution of (3S,4R)-4-{[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6- (trifluoromethyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (177 mg, 0.38 mmol) and K2CO3(105 mg, 0.76mmol) in MeOH (3 mL, 1.14 mmol) was stirred for 20 min at room temperature. The resulting mixture was purified by reversed-phase chromatography with thefollowing conditions: C18 column; mobile phase, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford (35',4R)-4-{[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6- (trifluoromethyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-ol (90 mg, 56%) as yellow oil. MS ESI calculated for C17H21CIF4N4O2[M + H]+, 425.13 found 425.30.Example 1: (3A,4R)-4-((5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6-(trifluoromethyl)pyrrolo[2,l- / ni,2,4]triazin-2-yl)amino)tetrahydro-2H-pyran-3-oI (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRALPAK ID, Hexane / 'PrOH = 93 / 7, 1stpeak)Example 2: (3S,4R)-4-((5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6- (trit1uoroinethyl)pyrrolo|2.1- / ] 11.2.4|triazin-2-yl)aniino)tetrahvdro-2 / / -pyran-3-ol (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRALPAK ID, Hexane / 'PrOH = 93 / 7, 2ndpeak)

[0192] (3S,4R)-4-{[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6-(trifluoromethyl)pyrrolo[2,l-_ / ][!, 2, 4]triazin-2-yl]amino}oxan-3-ol (40 mg, 0.09 mmol) was purified by Chiral-HPLC with the following conditions (Column: CHIRALPAK ID, 2*25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: 'PrOH; Flow rate: 20 mL / min; Gradient: A:B = 93:7; Wave Length: 254 / 220 nm;

[0193] RTi: 14.81 min to afford (3S,4R)-4-((5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6- (trifluorornethyl)pyrrolo[2, l - / ][ l,2,4]triazin-2-yl)amino)tetrahydro-2 / / -pyran-3-ol (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRALPAK ID, Hexane / 'PrOH = 93 / 7, 1stpeak) (8.1 mg, 20%) as a off-white solid. MS ESI calculated for C17H21CIF4N4O2[M + H]+, 425.13, found 425.15. ‘HNMR (400 MHz, DMSO-t / s) δ 8.96 (s, 1H), 7.32 (brs, 1H), 4.98 (brs, 1H), 3.86-3.81 (m, 2H), 3.66-3.49 (m, 3H), 3.31-3.24 (m, 1H), 3.09-3.04 (m, 1H), 2.05-1.98 (m, 1H), 1.62 (d, J= 7.2 Hz, 3H), 1.49- 1.37 (m, 4H), 1.36-1.28 (m, 3H).19F NMR (377 MHz, DMSO-fifc) δ -52.37 (3F), -130.12 (IF).

[0194] RT2: 20.14 min to afford (3S,4R)-4-((5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6- (trifluoromethyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl)amino)tetrahydro-2 / / -pyran-3-ol (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRALPAK ID, Hexane / 'PrOH = 93 / 7, 2ndpeak) (8.5 mg, 21%) as a off-white solid. MS ESI calculated for C17H21CIF4N4O2[M + H]+, 425.13, found 425.15. ‘HNMR (400 MHz, DMSO-4) δ 8.91 (s, 1H), 7.28 (brs, 1H), 4.98 (brs, 1H), 3.86-3.81 (m, 2H), 3.65-3.50 (m, 3H), 3.31-3.24 (m, 1H), 3.09-3.04 (m, 1H), 2.05-1.98 (m, 1H), 1.59-1.56 (m, 3H), 1.53-1.40 (m, 4H), 1.35-1.29 (m, 3H).19F NMR (377 MHz, DMSO-4) -52.37 (3F), -128.68 (IF).Example 3: -4-(15-chloro-7-[5-(2.,2,2-trifluoroethyl)pyridiii-2-yl]pyrrolo[2,1-f] [L2.,41triazin-2-yl)amino)oxan-3-ol

[0195] To a stirred solution of 2-bromo-5-(2,2,2-trifluoroethyl)pyridine (104 mg, 0.432 mmol) and Pd(OAc)2 (5 mg, 0.020 mmol) in hexabutyldistannane (275 mg, 0.475 mmol) was added PCya (12 mg, 0.043 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 24 h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. To this was added (3S,4R)-4-({7-bromo-5-chloropyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-ol (100 mg, 0.288 mmol), Cui (22 mg, 0 115 mmol) and Pd(PPhs)4 (17 mg, 0.014 mmol). The resulting mixture was stirred for an additional 16 h at 120 °C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 20 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 resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 2). The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: CH3CN; Flow rate: 60 mL / min mL / min; Gradient: 33% B to 63 % B; Wave Length: 254nm / 220 nm to afford (3S,4R)-4-({5-chloro-7-[5-(2,2,2- trifluoroethyl)pyri din-2 -yl]pyrrolo[2,1-f][1, 2, 4]triazin-2-yl}amino)oxan-3-ol (10 mg, 8%) as a light yellow solid. MS ESI calculated for C18H17CIF3N5O2[M + H]+, 428.10, found 428.10.JH NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.81 (d, J= 8.0 Hz, 1H), 8.65 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.28 (d, J= 7.2 Hz, 1H), 5.02 (d, J= 5.2 Hz, 1H), 4.03-3.75 (m, 5H), 3.60-3.58 (m, 1H), 3.51-3.47 (m, 1H), 3.17-3.12 (m, 1H), 2.16-2.12 (m, 1H), 1.63-1.41 (m, 1H). 19F NMR (376 MHz, DMSO-d6)δ -64.35 (3F).Example 4:5-fluoro-7-[l-(l-fluoroethyl)cvclobutyl1-2-n(3S,4R)-3-hvdroxyoxan-4- yl1aminolpyrrolo[2.1-f][1,2.,4]triazine-6-carboiiitrileStep 1 : 2A-dichloro-5-fluoro-7-ri-(l-fluoroethyl)cyclobutyllpyrrolor2,l-f][12,41triazine

[0196] To a stirred mixture of 2,4-dichloro-5-fluoropyrrolo[2,l- / |[l,2,4]triazine (1.6 g, 7.767 mmol), 1- (l-fluoroethyl)cyclobutane-l-carboxylic acid (2.27 g, 15.534 mmol) and Ag2CO3(4.28 g, 15.534 mmol) in CH3CN (40 mL) was added (NH4)2S2O8(8.86 g, 38.835 mmol) in H2O (32 mL) dropwise at 50 °C under nitrogen atmosphere. The resulting mixture was stirred for 3.5 h at 50 °C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue waspurified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% formic acid), 60% to 80%; detector, UV 220 nm to afford 2,4- dichloro-5-fluoro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazine (85 mg, 3%) as a yellow green solid. MS ESI calculated for C12H11CI2F2N3 [M + H]+, , 306.03, found 305.90.1H NMR (400 MHz, Chloroform-d ) 5 6.55 (s, 1H), 5.26-5.09 (m, 1H), 2.67-2.61 (m, 2H), 2.55-2.39 (m, 2H), 2.15-2.01 (m, 1H), 1.97-1.86 (m, 1H), 1.15 (dd, J = 24.0, 6 4 Hz, 3H).19F NMR (377 MHz, Chloroform^ / ) δ -151.08 (IF), 181.60 (IF).Step 2: 2-chloro-5-fluoro-7-[l -(l-fluoroethyl)cy cl obutyl1pyrrolor2, 1- / 11 l,2,41triazine

[0197] To a stirred mixture of 2,4-dichloro-5-fluoro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazine (70 mg, 0.229 mmol) in THF (2 mL) and / -PrOH (0.1 mL) was added NaBH> (13.84 mg, 0.366 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. The resulting mixture was filtered, and the filter cake was washed with THF (3 x 1 mL). The filtrate was concentrated under reduced pressure. To this were added DDQ (77.86 mg, 0.344 mmol) and DCM (2 mL) at room temperature. The resulting mixture was stirred for an additional 1 h at room temperature. The reaction was quenched by the addition of sat. Na2S20s (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 3 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-chloro-5-fluoro-7-[l-(l- fluoroethyl)cyclobutyl]pyrrolo[2,l: / ][l,2,4]triazine (55 mg, 88%) as a yellow green solid. MS ESI calculated for C12H12CIF2N3 [M + H]+, 272.07, found 272.00.1HNMR (400 MHz, Chloroform-d ) δ 8.79 (s, 1H), 6.53 (s, 1H), 5.29-5.12 (m, 1H), 2.71-2.60 (m, 2H), 2.59-2.38 (m, 2H), 2.16-1.86 (m, 2H), 1.15 (dd, J= 24.0, 6.4 Hz, 3H).19F NMR (377 MHz, Chloroform^ / ) δ - 157.15 (IF), 181.75 (IF).Step 3: (3S,4A)-4-((5-fluoro-7-|T-(l-fluoroethyl)cyclobutyl1pyrrolo[2,1-firL2,41triazin-2- yl 1 amino)oxan-3 -ol

[0198] To a stirred mixture of 2-chloro-5-fluoro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazine (55 mg, 0.202 mmol) and (3S,4R)-4-aminooxan-3 -ol hydrochloride (93 mg, 0.606 mmol) in NMP (2.5 mL) was added DIEA (157 mg, 1.212 mmol). The resulting mixture was stirred for 16 h at 80 °C. The resulting mixture was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 40% to 60%; detector, UV 254 nm to afford (3S,4R)-4-({5-fluoro-7-[l-(l- fluoroethyl)cyclobutyl]pyrrolo[2,l-: / ][l,2,4]triazin-2-yl}amino)oxan-3-ol (50 mg, 70%) as a yellow green solid. MS ESI calculated for C17H22F2N4O2[M + H]+, , 353.17, found 353.00.1H NMR (400 MHz, Chloroform-d ) δ 8.58 (s, 1H), 6.23 (d, J= 7.2 Hz, 1H), 5.44-5.03 (m, 1H),4.11-4.07 (m, 1H), 4.01-3.96 (m, 1H), 3.73-3.70 (m, 1H), 3.50-3.46 (m, 1H), 3.28-3.25 (m, 2H), 2.70-2.44 (m, 4H), 2.20-2.07 (m, 2H), 1.89-1.85 (m, 1H), 1.69-1.58 (m, 1H), 1.22-1.09 (m, 3H). Step 4: (3,S'.4R)-4-( {5-lluoro-7-r i -(' I -lluoroetliyl )cvclobiityl1pyrrolo[2, l - / ]i 1 ,2,411riazin-2- yl ;amino)oxan-3-yl acetate

[0199] To a stirred mixture of (3S,4R)-4-({5-fluoro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-ol (50 mg, 0.142 mmol) and TEA (86 15 mg, 0.852 mmol) in DCM (2 mL) was added AC2O (28.97 mg, 0.284 mmol) at room temperature. The resulting mixture was stirred for 16 h at 50 °C. The reaction was quenched by the addition of water / ice (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (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: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 50% to 65%; detector, UV 254 nm to afford (3S,4R)-4-({5- fluoro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (48 mg, 85%) as a yellow green solid. MS ESI calculated for C19H24F2N4O3[M + H]+, 395.18, found 395.00.Step 5: (3S,4R)-4-(f5-fluoro-7-ri-(l-fluoroethyl)cyclobutyl1-6-iodopyrrolor2,1-firL2,41triazin- 2-yllamino)oxan-3-yl acetate

[0200] A mixture of (3S,4R)-4-({5-fluoro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazin-2- yl}amino)oxan-3-yl acetate (50 mg, 0.127 mmol) and I2 (161 mg, 0.635 mmol) in DMF (2 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. Na2S2C>3 (20 mL) The resulting mixture was extracted with EtOAc (2 x 10 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% formic acid), 60% to 75%; detector, UV 254 nm to afford (3S,4R)-4-({5- fluoro-7-[l-(l-fluoroethyl)cyclobutyl]-6-iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (55 mg, 83%) as a yellow green solid. MS ESI calculated for C19H23F2IN4O3[M + H]+, , 521.08, found 520.85.Step 6: (3S.4R)-4-(16-cyano-5-fluoro-7-[l-(l-fluoroethyl)cyclobutyl1pyrrolo[2.1 - / ][!, 2,41triazin- 2-yllamino)oxan-3-yl acetate

[0201] To a stirred mixture of (3S,4R)-4-({5-fluoro-7-[l-(l-fluoroethyl)cyclobutyl]-6-iodopyrrolo[2,l- _ / ][!, 2, 4]triazin-2-yl}amino)oxan-3-yl acetate (50 mg, 0.096 mmol) and Zn(CN)2 (15.71 mg, 0.240 mmol) in DMF (2 mL) was added Pd(PPh3)4 (11 mg, 0.010 mmol) under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 130 °C under nitrogen atmosphere. Thereaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (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: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 50% to 65%; detector, UV 254 nm to afford (3S,4R)-4-({6-cyano-5-fluoro-7-[l-(l- fluoroethyl)cyclobutyl]pyrrolo[2,l:][l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (17 mg, 42%) as a yellow green solid. MS ESI calculated for C20H23F2N5O3[M + H]+, , 420.18, found 420.00. 1HNMR (400 MHz, Chloroform-d ) δ 8.69 (s, 1H), 5.29 (brs, 1H), 5 21-5.03 (m, 1H), 4.96-4.92 (m, 1H), 4.08-3.94 (m, 2H), 3.83-3.79 (m, 1H), 3.54-3.51 (m, 1H), 3.43-3.39 (m, 1H), 2.91-2.64 (m, 4H), 2.53-2.31 (m, 2H), 2.24-2.19 (m, 1H), 2.08 (s, 3H), 1.73-1.68 (m, 1H), 1.33-1.25 (m, 3H).Example 4:5-fluoro-7-[1(1-fluoroethyl)cvclobutyl1-2-{[(3R,4R)-3-hydroxyoxan-4- yl] aminol pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0202] A mixture of (3S,4A)-4-({6-cyano-5-fluoro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / ][l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (12 mg, 0.029 mmol) and K2CO3(11.86 mg, 0.087 mmol) in MeOH (1 mL) was stirred for 30 min at 0 °C. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 45% to 60%; detector, UV 254 nm to afford 5-fluoro- 7-[l-(l-fluoroethyl)cyclobutyl]-2-{[(3S,4A)-3-hydroxyoxan-4-yl]amino}pyrrolo[2,l- / |[l,2,4]triazine-6-carbonitrile (8.4 mg, 77%) as an off-white solid. MS ESI calculated for C18H21F2N5O2[M + H]+, , 378.17, found 378.20.1H NMR (400 MHz, DMSO-d6) 5 9.02 (s, 1H), 7.33 (brs, 1H), 5.26-5.10 (m, 1H), 4.93 (brs, 1H), 3.85-3.78 (m, 2H), 3.53-3.49 (m, 2H), 3.47- 3.25 (m, 1H), 3.05-3.02 (m, 1H), 2.81-2.62 (m, 3H), 2.42-2.37 (m, 1H), 2.16-1.98 (m, 2H), 1.90- 1.87 (m, 1H), 1.48-1.27 (m, 1H), 1.19 (dd, J= 24.0, 6.4 Hz, 3H).19F NMR (376 MHz, DMSO- d6) δ -156.18 (IF), -178.00 (IF).Example 5:5-chloro-7-[l-(l-fluoroethyl)cvclobutyl1-2-I[(3S,4R)-3-hvdroxyoxan-4- yl1aminolpyrrolo[2,1-f][1,2,4]triazine-6-carbonitrileStep 1 : 2,4,5-trichloro-7-|T-(l-fluoroethyl)cvclobutyl1pyrrolor2,1-fl|T,2,4]triazine

[0203] To a stirred mixture of 2,4,5-trichloropyrrolo[2,l- / |[l,2,4]triazine (1.2 g, 5.394 mmol), Ag2CC>3 (2.97 g, 10.788 mmol), and l-(l-fluoroethyl)cyclobutane-l -carboxylic acid (1.58 g, 10.788 mmol) in CH3CN (60 mL) was added (NH4)2S20g (6.15 g, 26.970 mmol) in H2O (48 mL) dropwise over 2 min at 50 °C. The resulting mixture was stirred for 2.5 h at 50 °C. The resultingmixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 200 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: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 50% to 80%; detector, UV 254 nm to afford 2,4,5-trichloro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l:][l,2,4]triazine (60 mg, 3%) as a yellow solid. MS ESI calculated for C12H11CI3FN3 [M + H]+, , 321.00, found 321.85.JH NMR (400 MHz, Chloroform-d ) 6δ.82 (s, 1H), 5.27-5.10 (m, 1H), 2.72-2.60 (m, 2H), 2.50-2.41 (m, 2H), 2.15-2.04 (m, 1H). 1.97-1.84 (m, 1H), 1.15 (dd, J = 24.0, 6.4 Hz, 3H).19F NMR (377 MHz, Chloroform-d ) 3 181.88 (IF).Step 2: 2,5-dichloro-7-ri-(l-fluoroethyl)cvclobutyl1pyrrolor2,1-f1[L2,41triazine

[0204] To a stirred mixture of 2,4,5-trichloro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazine (80 mg, 0.248 mmol) in THF (2 mL) and / -PrOH (0.1 mL) was added NaBHi (15.01 mg, 0.397 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. The resulting mixture was filtered, the filter cake was washed with THF (3 x 1 mL). The combined filtrate was concentrated under reduced pressure. To the residue were added DDQ (84.44 mg, 0.372 mmol) and DCM (2 mL) at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched by the addition of sat. Na2S20s (aq.) (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 3 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 2,5-dichloro-7-[l-(l- fluoroethyl)cyclobutyl]pyrrolo[2,l: / ][l,2,4]triazine (60 mg, 83%) as a yellow green solid. MS ESI calculated for C12H12CI2FN3 [M + H]+, 288.04, found 287.90.1HNMR (400 MHz, Chloroform-d δ 8.79 (s, 1H), 6.81 (s, 1H), 5.28-5.12 (m, 1H), 2.71-2.61 (m, 2H), 2.56-2.41 (m, 2H), 2.09-2.03 (m, 1H), 1.97-1.91 (m, 1H), 1.14 (dd, J = 24.0, 6.4 Hz, 3H).19F NMR (377 MHz, Chloroform-d ) δ 181.89 (IF).Step 3 : (3S,4A)-4-((5-chloro-7-ri-(l-fluoroethyl)cvclobutyl1pyrrolo[2, l triazin-2-yl 1 amino)oxan-3 -ol

[0205] A mixture of 2,5-dichloro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazine (60 mg, 0.208 mmol), (35',4A)-4-aminooxan-3-ol hydrochloride (38 mg, 0.250 mmol) and DIEA (81 mg, 0.624 mmol) in NMP (2 mL) was stirred for 16 h at 80 °C. The resulting mixture was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 50% to 70%; detector, UV 254 nm to afford (3S,4A)-4-({5- chloro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-ol (55 mg,71%) as a yellow green solid. MS ESI calculated for C17H22CIFN4O2[M + H]+, , 369.14, found 369.00.1HNMR (400 MHz, Chloroform-d δ 8.58 (s, 1H), 6.54-6.52 (m, 1H), 5.29-5.09 (m, 1H), 4.11-4.07 (m, 1H), 4.04-3.94 (m, 1H), 3.72-3.67 (m, 2H), 3.52-3.47 (m, 1H), 3.30-3.23 (m, 1H), 2.70-2.36 (m, 4H), 2.19-2.03 (m, 2H), 1.97-1.92 (m, 1H), 1.74-1.66 (m, 1H), 1.21-1.09 (m, 3H).19F NMR (377 MHz, Chloroform-d ) 8 181.54 (IF).Step 4: (3S,4R)-4-((5-chloro-7-ri-(l-fluoroethyl)cyclobutyl1pyrrolor2,1-firE2,41triazin-2- vnamino)oxan-3-yl acetate

[0206] To a stirred mixture of (3S,4R)-4-({5-chloro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-ol (55 mg, 0.149 mmol) and TEA (90 54 mg, 0.894 mmol) in DCM (2 mL) was added AC2O (30.45 mg, 0.298 mmol). The resulting mixture was stirred for 16 h at 50 °C. The reaction was quenched by the addition of water / ice (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 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 (0.1% formic acid), 50% to 70%; detector, UV 254 nm to afford (3S,4R)-4-({5- chloro-7-[l -(1 -fluoroethyl)cyclobutyl]pyrrolo[2, 1 - / |[ 1 , 2, 4]tri azin-2 -yl }amino)oxan-3-yl acetate (40 mg, 65%) as a yellow green solid. MS ESI calculated for C19H24CIFN4O3[M + H]+, 411.15, found 411.05.Step 5: (3S,4R)-4-(f5-chloro-7-ri-(l-fluoroethyl)cvclobutyl1-6-iodopyrrolor2,1-f11L2,41triazin- 2-yllamino)oxan-3-yl acetate

[0207] A mixture of (3S,4R)-4-({5-chloro-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazin-2- yl}amino)oxan-3-yl acetate (40 mg, 0.097 mmol) and I2 (123.55 mg, 0.485 mmol) in DMF (2 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. Na2S2C>3 (aq.) (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 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: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 55% to 75%; detector, UV 254 nm to afford (3S,4R)-4-({5- chloro-7-[l -(l-fluoroethyl)cyclobutyl]-6-iodopyrrolo[2,l- / |[l, 2, 4]tri azin-2 -yl}amino)oxan-3-yl acetate (45 mg, 86%) (crude) as a yellow green solid. MS ESI calculated for C19H23CIFIN4O3[M + H]+, , 537.05, found 536.85.Step 6: -4-((5-chloro-6-cyano-7-ri-(l-fluoroethyl)cyclobutyl1pyrrolo[2.1- / HT,2,41triazin-2-yHamino)oxan-3-yl acetate

[0208] To a stirred mixture of (3S,4R)-4-({5-chloro-7-[l-(l-fluoroethyl)cyclobutyl]-6-iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (40 mg, 0.075 mmol) and Zn(CN)2 (5.25 mg, 0.045 mmol) in DMF (1.5 mL) was added Pd(PPhs)4 (8 mg, 0.007 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1.5 h at 130 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (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: Cl 8 column, mobile phase, CH3CN in water (0.1% formic acid), 50% to 65%; detector, UV 254 nm to afford (3S,4R)-4-({5-chloro-6-cyano- 7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (13 mg, 40%) as a yellow green solid. MS ESI calculated for C20H23CIFN5O3[M + H]+, , 436.15, found 436.00.1HNMR (400 MHz, Chloroform-d δ 8.68 (s, 1H), 5.45 (brs, 1H), 5.22-5.04 (m, 1H), 4.99-4.94 (m, 1H), 4.06-3.96 (m, 2H), 3.84-3.80 (m, 1H), 3.56-3.50 (m, 1H), 3.44-3.39 (m, 1H), 2.88-2.70 (m, 3H), 2.57-2.51 (m, 1H), 2.38-2.31 (m, 1H), 2.24-2.19 (m, 1H), 2.08-2.05 (m, 3H), 2.03-1.97 (m, 1H), 1.48-1.40 (m, 1H), 1.30 (dd, J= 23.6, 6.0 Hz, 3H).Example 5:5-chlor o-7- [l-( l-fluoroethyl)cvclobutyl] -2- -3-hvdroxyoxan-4-y 11 amino) pyrrolo [2 ,1- / 1 [ 1 ,2,41triazine-6-carbonitrile

[0209] A mixture of (3S,4A)-4-({5-chloro-6-cyano-7-[l-(l-fluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (15 mg, 0.034 mmol) and K2CO3(14.27 mg, 0.102 mmol) in MeOH (1 mL) was stirred for 30 min at 0 °C. The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 40% to 60%; detector, UV 254 nm to afford 5-chloro- 7-[l-(l-fluoroethyl)cyclobutyl]-2-{[(3S,4R)-3-hydroxyoxan-4-yl]amino}pyrrolo[2,l- / ][l,2,4]triazine-6-carbonitrile (10.6 mg, 77%) as an off-white solid. MS ESI calculated for C18H21CIFN5O2[M + H]+, , 394.14, found 394.15.1H NMR (400 MHz, DMSO-cL) 8.96 (δs, 1H), 7.40 (brs, 1H), 5.31-5.06 (m, 1H), 4.94 (brs, 1H), 3.84-3.80 (m, 2H), 3.53-3.49 (m, 2H), 3.34-3.30 (m, 1H), 3.07-3.02 (m, 1H), 2.81-2.64 (m, 3 H), 2.42-2.33 (m, 1H), 2.20-1.96 (m, 2H), 1.91-1.85 (m, 1H), 1.48-1.38 (m, 1H), 1.19 (dd, J = 24.0, 6.0 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -177.98 (IF).Example 6:5-chloro-7-| 1 -( 1.1 -dinii()roethyl)cvdobiityl|-2- !l(3S,4R)-3-hvdroxyoxan-4- yl] amino) pyrrolo [2, 1- / 1 [ 1 ,2,41triazine-6-carbonitrileStep 1 : benzyl cyclobutanecarboxylate

[0210] To a stirred mixture of cyclobutanecarboxylic acid (100 g, 998.831 mmol, 1 equiv) and KHCO3(200 g, 1997.662 mmol) in DMF (1 L) was added BnBr (118.8 mL, 998.831 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched with water (10 L). The resulting mixture was extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (3 x 2 L), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (50 / 1) to afford benzyl cyclobutanecarboxylate (121 g, 57%) as colorless oil. C12H14O2, ^HNMR (400 MHz, Chloroform-d ) 5 7.41-7.32 (m, 5H), 5.14 (s, 2H), 3.23-3 17 (m, 1H), 2.38-2.18 (m, 4H), 2.03- 1.90 (m, 2H).Step 2: benzyl l-(l-hydroxyethyl)cyclobutane-l -carboxylate

[0211] To a stirred mixture of bis(propan-2-yl)amine (38.6 mL, 273.330 mmol) in THF (120 mL) was added w-BuLi (100.9 mL, 2.5 M, 252.300 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. To this was added benzyl cyclobutanecarboxylate (40.0 g, 210.259 mmol) dropwise over 30 min at -78 °C. The resulting mixture was stirred for 1 h at -78 °C. To this was added acetaldehyde (84.1 mL, 420.518 mmol) dropwise over 30 min at -78 °C. The resulting mixture was stirred for additional 16 h at room temperature. The reaction was quenched by the addition of sat. NH4CI (aq.) (800 mL) at 0 °C. The resulting mixture was extracted with EtOAc / PE (1 / 1) (2 x 1000 mL). The combined organic layers were washed with brine (1000 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). The resulting crude product was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% TFA), 50% to 95%; detector, UV 254 nm to afford benzyl l-(l-hydroxyethyl)cyclobutane-l -carboxylate (10.3 g, 19%) as yellow oil. MS ESI calculated for C14H18O3[M + H]+, 235.13, found 235.25.1H NMR (400 MHz, Chloroform-d ) 5 7.40-7.36 (m, 5H), 5.24-5.20 (m, 2H), 4.02 (q, J= 6.4 Hz, 1H), 2.70 (brs, 1H), 2.53-2.49 (m, 1H), 2.34- 2.28 (m, 2H), 2.00-1.93 (m, 3H), 1.16 (d, J= 6.4 Hz, 3H). Step 3: benzyl 1 -acetylcyclobutane- 1 -carboxylate

[0212] To a stirred solution of oxalic dichloride (10.9 mL, 128.043 mmol) in DCM (100 mL) was added DMSO (15 mL) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C. To this was added benzyl 3-hydroxy-2,2-dimethylpropanoate (10 g, 42.681 mmol) dropwise over 30 min at -78 °C. The resulting mixture was stirred for additional 1 h at -78 °C. To this was added EtsN (59 mL, 426.810 mmol) dropwise over 30 min at -78 °C. The mixture was allowed to warm up to room temperature. The resulting mixture was stirred foradditional 16 h at room temperature. The reaction was diluted with water (100 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brinw (100 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (7 / 1) to afford benzyl 1 -acetylcyclobutane- 1- carboxylate (7.0 g, 71%) as yellow oil. MS ESI calculated for C14H16O3[M + H]+, 233.11 found 232.95.1HNMR (400 MHz, Chloroform-d 8 7.44-7.31 (m, 5H), 5.21 (s, 2H), 2.53-2.48 (m, 4H), 2.07 (s, 3H), 2.00-1.96 (m, 1H), 1.90-1.83 (m, 1H).Step 4: enzyl l-(Ll-difluoroethyl)cyclobutane-l-carboxylate

[0213] To benzyl 1-acetylcyclobutane-l-carboxylate (3.8 g, 16.360 mmol) was added DAST (20 mL) at 0 °C. The resulting mixture was stirred for 2 days at room temperature. The reaction was quenched with EtOH (50 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (8 / 1) to afford benzyl l-(l,l-difluoroethyl)cy cl obutane-1 -carboxylate (2.5 g, 60%) as colorless oil. MS ESI calculated for C14H16F2O2[M + H]+, 255.11 found 255.05. ‘H NMR (400 MHz, Chloroform-d ) 8 7.42-7.34 (m, 5H), 5.23 (s, 2H), 2.53-2.42 (m, 4H), 1.99-1.91 (m, 2H), 1.59 (t, J = 20.0 Hz, 3H).19F NMR (377 MHz, Chloroform-d ) δ -99.00 (2F).Step 5: l-(Ll-difluoroethyl)cyclobutane-l-carboxylic acid

[0214] To a solution of benzyl l-(l,l-difluoroethyl)cyclobutane-l-carboxylate (3.0 g, 11.798 mmol) in 30 mL MeOH was added Pd / C (10%, 2.00 g) under nitrogen atmosphere. The mixture was hydrogenated for 1 h at room temperature under hydrogen atmosphere. The solid was filtered out and washed with DCM (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford l-(l,l-difluoroethyl)cyclobutane-l-carboxylic acid (1.4 g, 72%) as colorless oil. MS ESI calculated for C7H10F2O2[M + H]+, 165.06 found 165.10.1HNMR (400 MHz, DMSO-r / ,) 8 13.08 (s, 1H), 2.47-2.15 (m, 4H), 1.92-1.71 (m, 2H), 1.62 (t, J= 19.2 Hz, 3H).19F NMR (376 MHz, DMSO- ) δ -97.34 (2F).Step 6: L3-dioxoisoindol-2-yl l-(Ll-difluoroethyl)cv cl obutane-1 -carboxylate

[0215] To a stirred solution of l-(l,l-difluoroethyl)cy cl obutane-1 -carboxylic acid (2.20 g, 13.402 mmol) and A-hydroxyphthalimide (2.40 g, 14.742 mmol), DMAP (0.16 g, 1.340 mmol) in DCM (30 mL) was added A V-diisopropylcarbodiimide (1.86 g, 14.742 mmol) at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (6 / 1) to afford l,3-dioxoisoindol-2-yl 1- (l,l-difluoroethyl)cyclobutane-l-carboxylate (4.00 g, 96%) as a white solid. C15H13F2NO4, 'l l NMR (400 MHz, Chloroform-d ) 8 7.94-7.85 (m, 2H), 7.85-7.74 (m, 2H), 2.80-2.56 (m, 4H), 2.23-1.97 (m, 2H), 1.81 (t, J= 18.8 Hz, 3H).19F NMR (376 MHz, Chloroform^ / ) δ -99.56 (2F).Step 7: 2,4,5-trichloro-7-[l-(l,l-difhioroethyl)cyclobutyl1pyrrolor2,1-f][l,2,4]triazine

[0216] To a stirred solution of l,3-dioxoisoindol-2-yl l-(l,l-difluoroethyl)cyclobutane-l-carboxylate (2 g, 6.467 mmol) and 2,4,5-trichloropyrrolo[2,l- / |[l,2,4]triazine (2.88 g, 12 934 mmol) in DMA (60 m ) were added Ir[dF(CF3)PPy]2(dtbpy)PFe (0.15 g, 0.129 mmol) and TFA (2.21 g, 19.401 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was irradiated with Blue LED for 16 h at room temperature under nitrogen atmosphere The resulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% formic acid), 70% to 90%; detector, UV 254 nm to afford 2,4,5- trichloro-7-[l-(l,l-difluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazine (187 mg, 8%) as a yellow solid. MS ESI calculated for C12H10CI3F2N3 [M + H]+, 339.99 found 340.20. ’H NMR (400 MHz, Chloroform-d ) δ 6.84 (s, 1H), 2.86-2.74 (m, 2H), 2.70-2.64 (m, 2H), 2.19-2.13 (m, 1H), 1.94-1.88 (m, 1H), 1.51 (t, J= 18.8 Hz, 3H).19F NMR (376 MHz, Chloroform-d ) δ -100.27 (2F).Step 8: 2,5-dichloro-7-[l-(Ll-difluoroethyl)cyclobutyl1pyrrolo[2,1-f][L2,41triazine

[0217] To a stirred solution of 2,4,5-trichloro-7-[l-(l,l-difluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazine (187 mg, 0.549 mmol) in THF (5 mL) and / -PrOH (0.25 mL) was added NaBH4 (33 mg, 0.872 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. To the residue was added DCM (5 mL) and DDQ (150 mg, 0.661 mmol) at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 20 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (9 / 1) to afford 2,5-dichloro-7-[l-(l,l-difluoroethyl)cyclobutyl]pyrrolo[2,l:][l,2,4]triazine (160 mg, 95%) as a light yellow solid. MS ESI calculated for C12H11CI2F2N3 [M + H]+, 306.03 found 305.90.1HNMR (400 MHz, Chloroform-d ) δ 8.82 (s, 1H), 6.83 (s, 1H), 2.87-2.78 (m, 2H), 2.76-2.65 (m, 2H), 2.23-2.11 (m, 1H), 1.98-1.89 (m, 1H), 1.51 (t, J= 18.8 Hz, 3H).19F NMR (376 MHz, Chloroform-d ) δ -100.41 (2F).Step 9: -4-((5-chloro-7-[l-(Ll-difluoroethyl)cvclobutyl1pyrrolor2,1-f][L2,4]triazin-2-yl 1 amino)oxan-3 -ol

[0218] To a stirred solution of 2,5-dichloro-7-[l-(l,l-difluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazine (160 mg, 0.523 mmol) and (3S, 4R)-4-aminooxan-3-ol hydrochloride (120 mg, 0.781 mmol) in NMP (3 mL) was added DIEA (270 mg, 2.089 mmol). The resulting mixture was stirred for 16 h at 80 °C. The resulting mixture was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water(0.1% formic acid), 40% to 55%; detector, UV 254 nm to afford (3S,4R)-4-({5-chloro-7-[l-(l,l- difluoroethyl)cyclobutyl]pyrrolo[2,l-:][l,2,4]triazin-2-yl}amino)oxan-3-ol (90 mg, 44%) as a yellow solid. MS ESI calculated for C17H21CIF2N4O2[M + H]+, 387 13 found 386.95.1HNMR (400 MHz, Chloroform-d ) δ 8.59 (s, 1H), 6.48 (s, 1H), 5.09 (brs, 1H), 4.09-4.05 (m, 1H), 3.99- .394 (m, 1H), 3.67-3.63 (m, 2H), 3.51-3.46 (m, 1H), 3.42 -3.36 (m, 1H), 3.2δ -3.18 (m, 1H), 2.78-2.69 (m, 3H), 2.65-2.58 (m, 1H), 2.20-2 10 (m, 1H), 2.08-2.01 (m, 1H), 1.95-1 85 (m, 1H), 1.69-1.58 (m, 1H), 1.46 (t, J= 18.8 Hz, 3H).19F NMR (376 MHz, Chloroform-d ) δ -100.19 (2F).Step 10: (3 ,4R)-4-((5-chloro-7-ri-(El-difluoroethyl)cyclobutyl1pyrrolor2J- / irE2,41triazin-2- yHamino)oxan-3-yl acetate

[0219] To a stirred solution of (3S,4R)-4-({5-chloro-7-[l-(l,l-difluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-ol (90 mg, 0.233 mmol) and AC2O (38.00 mg, 0.373 mmol) in DCM (3 mL) was added TEA(141 mg, 1.393 mmol) at room temperature. The resulting 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 PE / EtOAc (3 / 1) to afford (3S,4R)-4-({5-chloro-7-[l-(l,l-difluoroethyl)cyclobutyl]pyrrolo[2,l- / ][l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (96 mg, 96%) as yellow oil. MS ESI calculated for C19H23CIF2N4O3[M + H]+, 429.14 found 429.05.Step 11: (3A4R)-4-(f 5-chloro-7-ri-(El-difluoroethyl)cvclobutyl1-6-iodoDyrrolor2,l- / irE2,41triazin-2-YHamino)oxan-3-yl acetate

[0220] To a stirred solution of (3S,4R)-4-({5-chloro-7-[l-(l,l-difluoroethyl)cyclobutyl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (96 mg, 0.224 mmol) in DMF (2 mL) was added I2 (227.26 mg, 0.896 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 254 nm to afford (3S,4R)-4-({5-chloro-7-[l-(l,l- difluoroethyl)cyclobutyl]-6-iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (70 mg, 56%) as a yellow solid. MS ESI calculated for C19H22CIF2IN4O3[M + H]+, 555.04 found 555.00.Step 12: (3 AR)-4-(f 5-chloro-6-cyano-7-^l-(Ll-difluoroethyl)cyclobutyl1pyrrolo[2.1- / l[L2A1triazin-2-v^amino)oxan-3-yl acetate

[0221] To a stirred solution of (3S,4A)-4-({5-chloro-7-[l-(l,l-difluoroethyl)cyclobutyl]-6- iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (70 mg, 0.126 mmol) and Zn(CN)2 (12 mg, 0.184 mmol) in DMF (2 mL) was added Pd(PPh3)4 (15 mg, 0.013 mmol) at room temperature. The resulting mixture was stirred for 2 h at 130 °C under nitrogenatmosphere. The mixture was allowed to cool down to room temperature. The residue was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% formic acid), 40% to 55%; detector, UV 254 nm to afford (3S, 4R)-4-({5-chloro-6-cyano-7-[l-(l,l-difluoroethyl)cyclobutyl]pyrrolo[2,l: / ][l,2,4]triazin-2- yl}amino)oxan-3-yl acetate (40 mg, 69%) as a yellow solid. MS ESI calculated for C20H22CIF2N5O3[M + H]+, 454.14 found 454.05.Example 6: 5-chloro-7-[l-(l,l-difluoroethyl)cvclobutyl1-2-I[(3ty.,4R)-3-hvdroxyoxan-4- yl] amino) pyrrolo [2, 1- / 1 [ 1 ,2,4]triazine-6-carbonitrile

[0222] To a stirred solution of (3S,4R)-4-({5-chloro-6-cyano-7-[l-(l,l- difluoroethyl)cyclobutyl]pyrrolo[2,l: / ][l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (40 mg, 0.088 mmol) in MeOH (2 mL) was added K2CO3(36.54 mg, 0.264 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 35% to 50%; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XselectCSH Prep Fluoro-Phenyl OBD Cl 8 Column, 30*150 mm, 5 pm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 36% B to 43% B; Wave Length: 254nm / 220nm nm to afford 5-chloro-7-[l-(l,l-difluoroethyl)cyclobutyl]-2-{[(3S,4R)-3- hydroxyoxan-d-yljaminojpyrrolopj^fl^djtriazine-b-carbonitrile (10.4 mg, 28%) as a white solid. MS ESI calculated for C18H20CIF2N5O2[M + H]+, 412.13 found 411.95.1H NMR (400 MHz, DMSO-fifc) δ 8.99 (s, 1H), 7.45 (d, J= 6.8 Hz, 1H), 4.94 (d, J= 4.8 Hz, 1H), 3.85-3.77 (m, 2H), 3.55-3.50 (m, 2H), 3.35-3.30 (m, 1H), 3.09-3.04 (m, 1H), 2.90-2.84 (m, 2H), 2.70-2.65 (m, 2H), 2.15-2.00 (m, 2H), 1.98-1.92 (m, 1H), 1.58 (t, J = 19.2 Hz, 3H), 1.47-1.41 (m, 1H).19F NMR (376 MHz, DMSO-<76) δ -73.45 (2F).Example 7: 5-chloro-7-I3-fluorobicvclo[1.1.11pentan-l-yB-2-f[f3tS,,41?)-3-hydroxyoxan-4- yl] amino) pyrrolo [2, 1- / 1 [ 1 ,2,4]triazine-6-carbonitrileStep 1 : L3-dioxoisoindol-2-yl 3 -fluorobicyclo|T.1.11pentane-l -carboxylate

[0223] A solution of 3 -fluorobicyclo[ 1.1.1 ]pentane-l -carboxylic acid (1 g, 7.685 mmol), N- hydroxyphthalimide (1 g, 8.454 mmol) and DMAP (0.09 g, 0.768 mmol) in DCM (10 mL) was stirred for 5 min at 0 °C. To this was added DIC (1.07 g, 8.454 mmol) at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (5 x 40 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3 / 1) toafford l,3-dioxoisoindol-2-yl 3 -fluorobicyclo[l.l. l]pentane-l -carboxylate (1.7 g, 80%) as a white solid. MS ESI calculated for C14H10FNO4 [M + H]+, 276.06, found 276.05. ’H NMR (400 MHz, Chloroform-d ) 8 7.91 (d, J= 5.6 Hz, 2H), 7.82 (d, J= 5.6 Hz, 2H), 2 63 (s, 6H). Step 2: 2,4,5-trichloro-7-13-fluorobicvclori.l.l1pentan-l-vnpyrrolor2,1-fl[l,2,41triazine

[0224] To a stirred solution of l,3-dioxoisoindol-2-yl 3-fluorobicyclo[l. l.l]pentane-l-carboxylate (1.9 g, 6.903 mmol), 2,4,5-trichloropyrrolo[2,l:][l,2,4]triazine (3.07 g, 13.806 mmol) and TFA (2.36 g, 20.709 mmol) in DMA (58 m ) was added Ir[dF(CFa)PPy]2(dtbpy)PF6 (0.16 g, 0.138 mmol) under nitrogen atmosphere. The reaction mixture was irradiated with Blue LED for 16 h at 60 °C under nitrogen atmosphere. The resulting mixture was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 70% to 85%; detector, UV 254 nm to afford 2,4,5-trichloro-7-{3- fluorobicyclo[l.l. l]pentan-l-yl}pyrrolo[2,l- / |[l,2,4]triazine (160 mg, 7%) as a light yellow solid. MS ESI calculated for C11H7CI3FN3 [M + H]+, 305.97, found 305.90. ' H NMR (400 MHz, Chloroform-d ) 5 6.74 (s, 1H), 2.61 (d, J = 2.4 Hz, 6H).Step 3 : 2.5-dichloro-7-13-fluorobicvclori.1.11pentan-l-vnpyrrolor2.1- / irE2.41triazine

[0225] A solution of 2,4,5-trichloro-7-{3-fluorobicyclo[l.l.l]pentan-l-yl}pyrrolo[2,l- / |[l,2,4]triazine (60 mg, 0.196 mmol) and NaBH4(12 mg, 0.314 mmol) in THF (2 mL) and z-PrOH (0.1 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (5 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (2 mL). To this was added DDQ (67 mg, 0.294 mmol). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 50% to 70%; detector, UV 254 nm to afford 2,5-dichloro-7-{3- fluorobicyclo[l.l. l]pentan-l-yl}pyrrolo[2,l- |[l,2,4]triazine (41 mg, 76%) as a light yellow solid. MS ESI calculated for C11H8CI2FN3[M + H]+, 272.01, found 271.85.1H NMR (400 MHz, Chloroform-dδ) 8.80 (s, 1H), 6.72 (s, 1H), 2.62 (d, J= 2.4 Hz, 6H).Step 4: (3S,4R)-4-[(5-chloro-7-(3-fluorobicyclo[ 1.1. Hpentan-l-vH pyrrolo[2, 1- / 1 [L2,41triazin-2- yl)amino1oxan-3-ol

[0226] A solution of 2,5-dichloro-7-{3-fluorobicyclo[LLl]pentan-l-yl}pyrrolo[2,l-: / ][l,2,4]triazine (42 mg, 0.154 mmol), (3S,4R)-4-aminooxan-3-ol hydrochloride (57 mg, 0.370 mmol) and DIEA (100 mg, 0.770 mmol) in NMP (1 mL) was stirred for 16 h at 80 °C under nitrogen atmosphere. 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 65%;detector, UV 254 nm to afford (3S,4A)-4-[(5-chloro-7-{3-fluorobicyclo[l.l. l]pentan-l- yl}pyrrolo[2,l- / |[l,2,4]triazin-2-yl)amino]oxan-3-ol (30 mg, 55%) as a light yellow solid. MS ESI calculated for C16H18ClFN4O2[M + H]+, 353.11, found 352.95.1H NMR (400 MHz, Chloroform-d ) δ 8.59 (s, 1H), 6.41 (s, 1H), 4.94 (d, J= 6.4 Hz, 1H), 4.13-4.09 (m, 1H), 4.06- 3.97 (m, 1H), 3.79-3.73 (m, 1H), 3.71-3.68 (m, 1H), 3.55-3.51 (m, 1H), 3.30-2.26 (m, 1H), 2.56 (d, .7= 2.4 Hz, 6H), 2 17-2.11 (m, 1H), 1.74-1.65 (m, 1H).Step 5: (3S, 4R)-4-[(5-chloro-7-(3-fluorobicvclo

[0111] pentan-l-vnpyrrolo[2 - / l[L2,41triazin-2- vDaminoloxan-3-yl acetate

[0227] A solution of (3S, 4R)-4-[(5-chloro-7-{3-fluorobicyclo[l l. l]pentan-l-yl}pyrrolo[2,l- / |[l,2,4]triazin-2-yl)amino]oxan-3-ol (102 mg, 0.289 mmol), Ac2O (44 mg, 0.433 mmol) and TEA (117 mg, 1.156 mmol) in DCM (2 mL) 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 PE / EtOAc (1 / 1) to afford (3S,4R)-4-[(5-chloro-7-{3- fluorobicyclo[l.l. l]pentan-l-yl}pyrrolo[2,l- |[l,2,4]triazin-2-yl)amino]oxan-3-yl acetate (103 mg, 90%) as a light yellow solid. MS ESI calculated for C18H2OC1FN4O3[M + H]+, 395.12, found 395.00.Step 6: (3s.4R)-4-[(5-chl oro-7-13-fluorobicyclo[ 1.1.11pentan-l-yH-6-iodopyrrolor2.1- f]T,2.41triazin-2-yl)amino1oxan-3-yl acetate

[0228] A solution of (3S,4R)-4-[(5-chloro-7-{3-fluorobicyclo[l.l. l]pentan-l-yl}pyrrolo[2,l- f][l,2,4]triazin-2-yl)amino]oxan-3-yl acetate (103 mg, 0.261 mmol) and l2(265 mg, 1.044 mmol) in DMF (2 mL) was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. Na2S2Ch (aq.) (40 mL). The resulting mixture was extracted with EtOAc (3 x 30 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 (1 / 1) to afford (3S,4R)-4-[(5-chloro-7-{3-fluorobicyclo[l. l.l]pentan-l-yl}-6-iodopyrrolo[2,l- _ / ][!, 2, 4]triazin-2-yl)amino]oxan-3-yl acetate (110 mg, 80%) as a light yellow solid. MS ESI calculated for CI8HI9C1FIN4O3[M + H]+, 521.02, found 520.85.1HNMR (400 MHz, Chloroform-d ) δ 8.57 (s, 1H), 5.09 (d, J= 7.2 Hz, 1H), 4.97-4.92 (m, 1H), 4.08-3.98 (m, 1H), 3.98-3.86 (m, 2H), 3.64-3.56 (m, 1H), 3.53-3.46 (m, 1H), 2.75 (d, J= 3.2 Hz, 6H), 2.44-2.38 (m, 1H), 2.10 (s, 3H), 1.72-1.67 (m, 1H).Step 7 : (3S, 4R)-4-[( 5 -chi oro-6-cyano-7 - 13 -fluorobicyclol 1.1.1 Ipentan- 1 -yl 1 pyrrolo[2, 1 - / H1,2.4]triazin-2-yl)amino1oxan-3-yl acetate

[0229] A solution of (3S,4R)-4-[(5-chloro-7-{3-fluorobicyclo[l.l. l]pentan-l-yl}-6-iodopyrrolo[2,l- / ][l,2,4]triazin-2-yl)amino]oxan-3-yl acetate (100 mg, 0.192 mmol), Zn(CN)2(20 mg, 0.173mmol) and Pd(PPha)4 (22 mg, 0.019 mmol) in DMA (1.5 mL) was stirred for 2 h at 130 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (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 residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4R)-4-[(5-chloro-6-cyano-7-{3-fluorobicyclo[l.l. l]pentan-l- yl}pyrrolo[2,l- / |[l,2,4]triazin-2-yl)amino]oxan-3-yl acetate (44 mg, 54 %) as a light yellow solid. MS ESI calculated for C19H19CIFN5O3, [M + H]+, 420.12, found 419 90.Example 7: 5-chloro-7-I3-fluorobicyclo[l.l.l]pentan-l-yl}-2-{[ -3-hydroxyoxan-4-yl] amino} pyrrolo [2.1-f ] 1 ,2.,41triazine-6-carbonitrile

[0230] A solution of (3S,4R)-4-[(5-chloro-6-cyano-7-{3-fluorobicyclo[l. l.l]pentan-l-yl}pyrrolo[2,l- / ][l,2,4]triazin-2-yl)amino]oxan-3-yl acetate (40 mg, 0.095 mmol) and K2CO3(40 mg, 0.285 mmol) in MeOH (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 (10 mmol / L NH4HCO3), 10% to 50%; detector, UV 254 nm to afford 5- chl oro-7 - { 3 -fluorobicy clo[ 1.1.1 ]pentan- 1 -yl } -2- { [(3S,4R)-3 -hydroxy oxan-4- yljaminojpyrrolopj^ lfl^djtriazine-b-carbonitrile (17.3 mg, 45%) as a white solid. MS ESI calculated for C17H17CIFN5O2[M + H]+, 378.11; found 377.95. ‘HNMR (400 MHz, Chloroform-d ) δ 8.71 (s, 1H), 5.08 (d, J= 6.8 Hz, 1H), 4.14-4.08 (m, 1H), 4.03-3.99 (m, 1H), 3.83-3.79 (m, 1H), 3.75-3.67 (m, 1H), 3.58-3.53 (m, 1H), 3.34-3.26 (m, 1H), 2.73 (d, J= 2.0 Hz, 6H), 2.30-2.22 (m, 1H), 1.74-1.64 (m, 1H).19F NMR (376 MHz, Chloroform-d ) δ -145.53 (IF).Example 8:7-[3-(l,l-difluoroethyl)oxetan-3-yl]-5-fluoro-2- -3-hydroxyoxan-4-yl] amino} pyrrolo [2.1- / 1 [ 1.,2.,4]triazine-6-carbonitrileStep 1 : L3-dioxoisoindol-2-yl 3-(Ll-difluoroethyl)oxetane-3-carboxylate

[0231] To a mixture of 3 -(l,l-difluoroethyl)oxetane-3 -carboxylic acid (780 mg, 4.695 mmol) in DCM (8 mL) were added A-hydroxyphthalimide (843 mg, 5.165 mmol) and DMAP (58 mg, 0.470 mmol), followed by the addition of DIC (652 mg, 5.165 mmol) at 0 °C. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford l,3-dioxoisoindol-2-yl 3-(l,l-difluoroethyl)oxetane-3-carboxylate (1.3 g, 80%) as an off-white solid. C14H11F2NO5,1HNMR (400 MHz, Chloroform-d ) 8 7.97-7.92 (m, 2H), 7.88-7.84 (m,2H), 5.15-5.13 (m, 2H), 5.03-4.97 (m, 2H), 1.89 (t, J = 18.4 Hz, 3H).19F NMR (376 MHz, Chloroform-d ) δ -99.96 (2F).Step 2: 2,4-dichloro-7-r3-(Fl-difluoroethyl)oxetan-3-yl]-5-fluoropyrrolor24- / irF2,41triazine

[0232] A mixture of 2,4-dichloro-5-fluoropyrrolo[2,l- / |[l,2,4]triazine (821 mg, 3.984 mmol), 1,3- dioxoisoindol-2-yl 3-(l,l-difluoroethyl)oxetane-3-carboxylate (620 mg, 1.992 mmol), Ir[dF(CF3)PPy]2(dtbpy)PFs (45 mg, 0.040 mmol) and TFA (0.4 mL, 5.924 mmol) in DMA (18.6 m ). The reaction mixture was irradiated with Blue LED for 16 h at room temperature under nitrogen atmosphere. 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 70%; detector, UV 254 nm to afford 2,4-dichloro-7-[3-(l,l-difluoroethyl)oxetan-3-yl]-5- fluoropyrrolo[2,l- / |[l,2,4]triazine (45 mg, 6%) as yellow oil. MS ESI calculated for C11H8CI2F3N3O [M + H]+, 326.00, found 326.20.1HNMR (400 MHz, Chloroform-d ) 8 6.55 (s, 1H), 5.11 (s, 4H), 1.67-1.62 (m, 3H).19F NMR (376 MHz, Chloroform-d ) δ -100.57 (2F), - 149.92 (IF).Step 3 : 2-chloro-7-[3 -(LI -difluoroethyl)oxetan-3 -yll-5-fluoropyrrolor 2.1 - / I [1 ,2.41tri azine

[0233] To a stirred mixture of 2,4-dichloro-7-[3-(l,l-difluoroethyl)oxetan-3-yl]-5-fluoropyrrolo[2,l- / ][l,2,4]triazine (40 mg, 0.123 mmol) in z-PrOH (50 uL) and THF (1 mL) was added NaBH4 (9.3 mg, 0.246 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. To the resudue was added DDQ (42 mg, 0.184 mmol) in DCM (1 mL). The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 15 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with sat. NaHCCL (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SC>4. 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-chloro-7-[3-(l,l- difluoroethyl)oxetan-3-yl]-5-fluoropyrrolo[2,l- / |[l,2,4]triazine (22 mg, 55%) as a yellow solid. MS ESI calculated for C11H9CIF3N3O [M + H]+, 292.04, found 292.00. ’H NMR (400 MHz, Chloroform-d ) δ 8.90 (s, 1H), 6.53 (s, 1H), 5.12 (s, 4H), 1.64 (t, J= 18.8 Hz, 3H).19F NMR (376 MHz, Chloroform-d ) δ -100.81 (2F), -156.22 (IF).Step 4: (3S.4R)-4-(I7-[3-(l.l-difluoroethyl)oxetan-3-yl1-5-fluoropyrrolor2.1- / iri.2.41triazin-2- yl ) amino)oxan-3 -ol

[0234] A mixture of 2-chloro-7-[3-(l,l-difluoroethyl)oxetan-3-yl]-5-fluoropyrrolo[2,l- / |[l,2,4]triazine (20 mg, 0.069 mmol), (3S,4R)-4-aminooxan-3-ol hydrochloride (53 mg, 0.345 mmol) and DIEA (72 uL, 0.411 mmol) in NMP (1 mL) was stirred for 16 h at 80 °C 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 70%; detector, UV 254 nm to afford (3S,4R)-4-({7-[3-(l,l-difhioroethyl)oxetan-3-yl]-5-fluoropyrrolo[2,l- / |[l,2,4]triazin-2- yl}amino)oxan-3-ol (10 mg, 35%) (crude) as yellow oil. MS ESI calculated for C16H19F3N4O3[M + H]+, 373.14, found 373.15.Step 5: -4-(f7-[3-(El-difluoroethyl)oxetan-3-yl1-5-fluoropyrrolor2J- / iri,2,4]triazin-2-yl)amino)oxan-3-yl acetate

[0235] A mixture of (3S,4R)-4-({7-[3-(l,l-difluoroethyl)oxetan-3-yl]-5-fluoropyrrolo[2,l-_ / ][!, 2, 4]triazin-2-yl}amino)oxan-3-ol (10 mg, 0.027 mmol), AC2O (4 uL, 0.041 mmol) and TEA (19 uL, 0.135 mmol) in DCM (0.5 mL) was stirred for 16 h at 50 °C. The reaction was quenched by the addition of sat. NaHCCh (aq.) (3 mL) at 0 °C. The resulting mixture was extracted with DCM (2 x 3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SC>4. 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-[3-(l,l-difhioroethyl)oxetan-3-yl]-5-fhioropyrrolo[2,l- / |[l,2,4]triazin-2- yl}amino)oxan-3-yl acetate (10 mg, 80%) as a yellow solid. MS ESI calculated for C18H21F3N4O4 [M + H]+, 415.15, found 415.25.Step 6: (3S.4A)-4-((7-[3-(l.l-difluoroethyl)oxetan-3-yl1-5-fluoro-6-iodopyrrolo[2.1- / HT,2,41triazin-2-yl)amino)oxan-3-yl acetate

[0236] A mixture of (3S,4R)-4-({7-[3-(l,l-difluoroethyl)oxetan-3-yl]-5-fluoropyrrolo[2,l-_ / ][!, 2, 4]triazin-2-yl}amino)oxan-3-yl acetate (10 mg, 0.024 mmol) and I2 (49 mg, 0.192 mmol) in DMF (0.5 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. Na2S20s (aq.) (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous IXfeSCU. 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)-44X?-[3-(l J-difh^oroethyl)oxetan<Lyl]-5-fluoro-6-iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (13 mg, 74%) as a yellow solid. MS ESI calculated for C18H20F3IN4O4 [M + H]+, 541.05, found 541.00.

[0237] Step 7: (3S.4R)-4-(16-cyano-7-[3-(Ll-difluoroethyl)oxetan-3-yl1-5-fluoropyrrolor2.1- / ]|T,2,41triazin-2-yllamino)oxan-3-yl acetate

[0238] A mixture of (3S,4R)-4-({7-[3-(l,l-difluoroethyl)oxetan-3-yl]-5-fluoro-6-iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (13 mg, 0.024 mmol), Zn(CN)2 (3.4 mg, 0.029 mmol) and Pd(PPli3)4 (2.8 mg, 0.002 mmol) in DMA (0.5 mL) was stirred for 1 h at 130 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC with PE / EtOAc (2 / 1) to afford (3S,4R)-4-({6-cyano-7-[3-(l,l-difluoroethyl)oxetan-3- yl]-5-fluoropyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (8 mg, 68%) as an off- white solid. MS ESI calculated for C19H20F3N5O4 [M + H]+, 440.15, found 440.25.

[0239] Example 8: 7-[3-(Ll-difluoroethyl)oxetan-3-yl]-5-fluoro-2-l[(3S,4R)-3-hydroxyoxan-4- yl1aminolpyrrolor2. l- / irL2.41triazine-6-carbonitrile

[0240] A solution of (3S,4R)-4-({6-cyano-7-[3-(l,l-difluoroethyl)oxetan-3-yl]-5-fluoropyrrolo[2,l- / ][l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (3.5 mg, 0.008 mmol) and K2CO3(3.30 mg, 0.024 mmol) in MeOH (0.5 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 (0.1% formic acid), 30% to 50%; detector, UV 254 nm to afford 7- [3 -(1 , 1 -difluoroethyl)oxetan-3 -yl] -5 -fluoro-2- { [(3S,4R)-3 -hy droxy oxan-4- yljaminojpyrrolopj^ / lfl^djtriazine-b-carbonitrile (1.2 mg, 37%) as a light yellow solid. MS ESI calculated for C17H18F3N5O3[M + H]+, 398.14; found 398.05. H WIR (400 MHz, Chloroform-d ) δ 8.79 (s, 1H), 5.32-5.27 (m, 2H), 5.08-5.02 (m, 3H), 4.06-3.96 (m, 2H), 3.69- 3.63 (m, 2H), 3.53-3.47 (m, 1H), 3.29-3.23 (m, 1H), 2.19-2.13 (m, 1H), 1.82 (t, J= 18.8 Hz, 3H), 1.68-1.63 (m, 1H).19F NMR (376 MHz, Chloroform-d ) δ -99.66 (2F), -151.86 (IF).Example 9:5-fluoro-2-I[(35,4.R)-3-hvdroxyoxan-4-yl]amino}-7-(l,l,2-trifluoro-2- methylpropyl)pyrrolo[2,1-f] [l,2.,41triazine-6-carbonitrileStep 1 : (3S.4R)-4-l[5-fluoro-7-(2-methylprop-l-en-l-yl)pyrrolol2.1- / irL2.41triazin-2- yllaminoloxan-3-ol

[0241] A mixture of (3S,4R)-4-({7-bromo-5-fluoropyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-ol (200 mg, 0.604 mmol), 4,4,5,5-tetramethyl-2-(2-methylprop-l-en-l-yl)-l,3,2-dioxaborolane (165 mg, 0.906 mmol), Pd(dppf)C12.CH2C12 (49.20 mg, 0.060 mmol) and CS2CO3(393 mg, 1.208 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was stirred for 2 h at 100 °C under a nitrogen atmosphere. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3A',4 / ?)-4-{ [5-fluoro-7-(2-methylprop-l- en-l-yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-ol (180 mg, 97%) as a light yellow solid. MS ESI calculated for C15H19FN4O2[M + H]+, 307.15, found 307.10. *HNMR (400 MHz, Chloroform-d ) δ 8.59 (s, 1H), 6.51 (s, 1H), 6.37 (s, 1H), 4.98 (brs, 1H), 4.17-4.04 (m, 2H), 3.81- 3.76 (m, 1H), 3.67-3.61 (m, 1H), 3.53-3.48 (m, 1H), 3 28-3.22 (m, 1H), 2.08-2.01 (m, 4H), 1 98 (s, 3H), 1.72-1.64 (m, 1H).Step 2: (3S,4R)-4-l[5-fluoro-7-(2-methylprop-l-en-l-yl)pyrrolol2,1-firL2,41triazin-2- yl1amino)oxan-3-yl acetate

[0242] To a stirred solution of (3S,4R)-4-{[5-fluoro-7-(2-methylprop-l-en-l-yl)pyrrolo[2,l- / ][l,2,4]triazin-2-yl]amino}oxan-3-ol (280 mg, 0.914 mmol) in DCM (5 mL) were added AC2O (140 mg, 1.371 mmol) and TEA (370 mg, 3.656 mmol) at room temperature. The resulting 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 PE / EtOAc (1 / 1) to afford (3S,4R)-4-{ [5-fluoro-7-(2-methylprop-l-en-l-yl)pyrrolo[2,l: / ][l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (290 mg, 91%) as a yellow solid. MS ESI calculated for C17H21FN4O3[M + H]+, 349.16, found 349.10. *HNMR (400 MHz, Chloroform-d ) δ 8.54 (s, 1H), 6.69 (s, 1H), 6.41 (s, 1H), 5.21 (brs, 1H), 5.03-4.99 (m, 1H), 4.09-4.04 (m, 2H), 3.98-3.93 (m, 1H), 3.67-3.62 (m, 1H), 3.53-3.47 (m, 1H), 2.46-2.41 (m, 1H), 2.14-2.04 (m, 6H), 2.01 (s, 3H), 1.72-1.64 (m, 1H).19F NMR (377 MHz, Chloroform^ / ) δ -159.69 (IF).Step 3: (3S.4A)-4-l[7-(1.2-dihydroxy-2-methylpropyl)-5-fluoropyrrolo[2,1-firL2.41triazin-2- yl]amino |oxan-3-yl acetate

[0243] A solution of (3S,4R)-4-{[5-fluoro-7-(2-methylprop-l-en-l-yl)pyrrolo[2,l- / |[l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (430 mg, 1.234 mmol), NMO (289 mg, 2.468 mmol) and K2OSO4.2H2O (45 mg, 0.123 mmol,) in acetone (7.5 mL) and H2O (2.5 mL) was stirred for 2 h at room temperature. The reaction was quenched by the addition of NajSiO? (10 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO / . 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-(l,2-dihydroxy-2- methylpropyl)-5-fluoropyrrolo[2,l:][l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (470 mg, 99%) as a yellow solid. MS ESI calculated for C17H23FN4O5 [M + H]+, 383.17, found 383.95.1H NMR (400 MHz, Chloroform-d ) δ 8.61 (d, J= 3.2 Hz, 1H), 6.34 (d, J= 9.6 Hz, 1H), 5.09-4.87 (m, 2H), 4.04-3.86 (m, 4H), 3.73-3.67 (m, 1H), 3.57-3.51 (m, 1H), 2.40-2.35 (m, 1H), 2.11 (d, J= 5.6 Hz, 3H), 1.78-1.60 (m, 1H), 1.37 (d, J= 8.0 Hz, 3H), 1.20 (s, 3H).19F NMR (377 MHz, Chloroform-d ) δ -159.15 (IF).Step 4: (3S, 4R)-4-([5-fluoro-7-(2-hvdroxy-2-methylpropanoyl)pyrrolo[2J- / ]|T,2,41triazin-2- yl]amino !oxan-3-yl acetate

[0244] A solution of (3S,4R)-4-{[7-(l,2-dihydroxy-2-methylpropyl)-5-fluoropyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (460 mg, 1.203 mmol) and IBX (673 mg, 2406 mmol) in CH3CN (10 mL) was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4A)-4-{[5-fluoro-7-(2-hydroxy-2- methylpropanoyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (325 mg, 71%) as a yellow solid. MS ESI calculated for C17H21FN4O5[M + H]+, 381.15, found 381.20. NMR (400 MHz, Chloroform-d ) δ 8.82 (s, 1H), 6.98 (s, 1H), 5.51 (d, J= 8.0 Hz, 1H), 4.96-4.90 (m, 1H), 4.11-3.89 (m, 3H), 3.59-3.54 (m, 1H), 3.49-3.34 (m, 1H), 2.40-2.31 (m, 1H), 2.05 (s, 3H), 1.79-1.66 (m, 1H), 1.57 (d, J= 7.2 Hz, 6H).19F NMR (377 MHz, Chloroform-d δ -159.03 (IF). Step 5: (3S.4A)-4-l[5-fluoro-7-(1.1.2-trifluoro-2-methylpropyl)pyrrolo[2.1- / irE2,41triazin-2- yl1amino !oxan-3-yl acetate

[0245] To a stirred solution of (3S,4A)-4-{[5-fhioro-7-(2-hydroxy-2-methylpropanoyl)pyrrolo[2,l- _ / ][!, 2, 4]triazin-2-yl]amino}oxan-3-yl acetate (310 mg, 0.815 mmol) in DCM (10 mL) was added DAST (525 mg, 3.260 mmol) in DCM (10 mL) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at -30 °C under nitrogen atmosphere. The reaction was quenched by the addition of NaHCO3(20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SC>4. 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 (3S,4R)-4-{[5-fluoro-7-(l,l,2-trifluoro-2-methylpropyl)pyrrolo[2,l- / ][l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (40 mg, 12%) as yellow oil. MS ESI calculated for C17H20F4N4O3[M + H]+, 405.15, found 405.20.1HNMR (400 MHz, Chloroform-d ) δ 8.73 (s, 1H), 6.48 (s, 1H), 5.18 (d, J= 7.2 Hz, 1H), 4.97-4.89 (m, 1H), 4.06-4.01 (m, 1H), 3.99-3.88 (m, 2H), 3.56-3.51 (m, 1H), 3.45-3.40 (m, 1H), 2.51-2.41 (m, 1H), 2.06 (s, 3H), 1.70-1.61 (m, 1H), 1.58 (d, J= 6.4 Hz, 3H), 1.53 (d, J= 6.4 Hz, 3H).19F NMR (377 MHz, Chloroform / ) δ - 106.86-103.36 (2F), -152.81 (IF), -161.36 (IF).Step 6: (3S,4R)-4-l[5-fluoro-6-iodo-7-(112-trifluoro-2-methylpropyl)pyrrolor2,l- / l[1.2.41triazin-2-yl1aminoloxan-3-yl acetate

[0246] A solution of (3S,4R)-4-{[5-fluoro-7-(l,l,2-trifluoro-2-methylpropyl)pyrrolo[2,l- / ][l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (40 mg, 0.099 mmol) and I2 (200 mg, 0.792 mmol)in DMF (2 mL) was stirred for 48 h at 80 °C. The resulting mixture was purified by reversed- phase chromatography with the following conditions: column, Cl 8; mobile phase, CH3CN in water (0.1% formic acid), 20% to 70%; detector, UV 254 nm to afford (3S,4R)-4-{[5-fluoro-6- iodo-7-(l,l,2-trifluoro-2-methylpropyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (12 mg, 22%) as a yellow solid. MS ESI calculated for C17H19F4IN4O3[M + H]+, 531.04, found 530.85.Step 7: (3S,4A)-4-([6-cyano-5-fluoro-7- trifluoro-2-methylpropyl)pyrrolo[2,l- / iri,2,41triazin-2-yl1aminoloxan-3-yl acetate

[0247] To a stirred solution of (3S,4R)-4-{[5-fluoro-6-iodo-7-(l,l,2-trifluoro-2- methylpropyl)pyrrolo[2,l:][l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (10 mg, 0.019 mmol) and Zn(CN)2 (3 mg, 0.028 mmol) in DMF (0.5 mL) was added Pd(PPh3)4 (2 mg, 0.002 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 130 °C under nitrogen atmosphere. The resulting mixture was purified by reversed-phase chromatography with the following conditions: column, C18; mobile phase, CH3CN in water (0.1% formic acid), 20% to 65%; detector, UV 254 nm to afford (3S,4R)-4-{[6-cyano-5-fluoro- 7-(l,l,2-trifluoro-2-methylpropyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (4 mg, 49%) as a yellow solid. MS ESI calculated for C18H19F4N5O3[M + H]+, 430.14, found 430.20.1HNMR (400 MHz, Chloroform-r / ) δ 8.82 (s, 1H), 5.51 (d, J= 6.8 Hz, 1H), 4.96-4.92 (m, 1H), 4.11-3.93 (m, 2H), 3.92-3.80 (m, 1H), 3.53-3.48 (m, 1H), 3.44-3.38 (m, 1H), 2.48-2.39 (m, 1H), 2.07 (s, 3H), 1.70-1.54 (m, 7H).19F NMR (376 MHz, Chloroform-d ) δ -105.86-107.71 (2F), -152.55 (IF), -153.01 (IF).Example 9: 5-fluoro-2- -hvdroxyoxan-4-yl]amino}-7-(l,l.,2-trifluoro-2-methylpropyl)pyrrolo[2,1-f] [l,2.,41triazine-6-carbonitrile

[0248] A mixture of (3S,4R)-4-{[6-cyano-5-fluoro-7-(l,l,2-trifluoro-2-methylpropyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (4 mg, 0.009 mmol) and K^CCL (4 mg, 0.027 mmol) in MeOH (0.5 mL) was stirred for 30 min at room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: column, Cl 8; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 10% to 50%; detector, UV 254 nm to afford 5-fluoro-2-{[(3S,4R)-3-hydroxyoxan-4-yl]amino}-7-(l,l,2-trifluoro-2- methylpropyl)pyrrolo[2,l-: / ][l,2,4]triazine-6-carbonitrile (2.6 mg, 71%) as a white solid. MS ESI calculated for C16H17F4N5O2[M + H]+, 388.13, found 387.90. *HNMR (400 MHz, Chloroform- d) δ 8.83 (s, 1H), 5.17 (brs, 1H), 4.10-3.94 (m, 2H), 3.81-3.63 (m, 2H), 3.53-3.46 (m, 1H), 3.28- 3.20 (m, 1H), 3.14-3.08 (m, 1H), 2.20-2.11 (m, 1H), 1.72-1.49 (m, 7H).19F NMR (376 MHz, Chloroform-d ) δ -105.77-107.73 (2F), -152.45 (IF), -152.63 (IF).Example 10: 5-(difluoromethyl)-7-(3-fluoro-3-methylbutan-2-yl)-2-(((3S,4R)-3-hvdroxytetrahvdro-2H- pyran-4-yl)amino)pyrrolo[2,1-f] [l,2,4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH = 70 / 30, 1stpeak) Example 11: 5-(difluoromethyl)-7-(3-fluoro-3-methylbutan-2-yl)-2-(((35,4R)-3-hvdroxytetrahydro-2Zf- pyran-4-yl)amino)pyrrolo[2, 1- / ] [1,2, 4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH = 70 / 30, 2ndpeak)Step 1 : (3S,4R)-4-([6-cvano-7-(3-fluoro-3-methylbutan-2-yl)-5-iodopyrrolo[2,1-f1[l,2,41triazin- 2-yl1amino !oxan-3-yl acetate

[0249] To a stirred solution of (3S,4R)-4-{[6-cyano-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- / ][l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (160 mg, 0.411 mmol) in DMF (2.5 mL) was added h (417 mg, 1.644 mmol). The reaction mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. Na2S20s (aq.) (5 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 3 mL). The combined organic layers were 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 (2 / 1) to afford (3S,4R)-4-{[6-cyano-7-(3-fluoro-3-methylbutan-2-yl)-5-iodopyrrolo[2,l- _ / ][!, 2, 4]triazin-2-yl]amino}oxan-3-yl acetate (190 mg, 89%) as an off-white solid. MS ESI calculated for C19H23FIN5O3[M + H]+, 516.08, found 516.25; *HNMR (400 MHz, Chloroform- d) δ 8.50 (s, 1H), 5.47 (brs, 1H), 5.04-4.93 (m, 1H), 4.06-3.95 (m, 4H), 3.62-3.59 (m, 1H), 3.50- 3.45 (m, 1H), 2.43-2.38 (m, 1H), 2.07 (s, 3H), 1.73-1.61 (m, 4H), 1.50-1.34 (m, 6H).Step 2: -4-l[6-cyano-7-(3-fluoro-3-methylbutan-2-yl)-5-(hydroxymethyl)pyrrolo[2,l- / l[l,2,41triazin-2-yl1aminoloxan-3-yl acetate

[0250] To a solution of (3S,4R)-4-{[6-cyano-7-(3-fluoro-3-methylbutan-2-yl)-5-iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (74 mg, 0.144 mmol) in dioxane (10 mL) were added 2nd Generation XPhos Precatalyst (11 mg, 0.014 mmol) and (tributyl stannyl)methanol (92 mg, 0.288 mmol). The reaction mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The reaction was quenched with sat. KF (aq.) (5 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 15 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: column, C18; mobile phase, CH3CN in water (0.1% formic acid), 25% to60%; detector, UV 254 nm to afford (3S,4R)-4-{[6-cyano-7-(3-fluoro-3-methylbutan-2-yl)-5- (hydroxymethyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (25 mg, 41%) as a yellow solid. MS ESI calculated for C20H26FN5O4 [M + H]+, 420.20, found 420.35.!H NMR (400 MHz, Chloroform-d ) δ 8.93 (s, 1H), 5.20-5.14 (m, 1H), 5.02 (s, 2H), 4.97-4.93 (m, 1H), 4.00-3.91 (m, 4H), 3.63-3.56 (m, 1H), 3.49-3.44 (m, 1H), 2.43-2.39 (m, 1H), 2.07 (d, J= 8.4 Hz, 3H), 1.78-1.66 (m, 1H), 1.62-1.60 (m, 3H), 1.49-1.41 (m, 3H), 1.39-1.33 (m, 3H).Step 3: (3S,4A)-4-l[6-cvano-7-(3-fluoro-3-methylbutan-2-yl)-5-formylpyrrolor2,l- / irE2,41triazin-2-yl]aminoloxan-3-yl acetate

[0251] A solution of (3S,4R)-4-{[6-cyano-7-(3-fluoro-3-methylbutan-2-yl)-5- (hydroxymethyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (25 mg, 0.060 mmol) and DMP (50 mg, 0.120 mmol) in DCM (1 mL) was stirred for 2 h at room temperature. The reaction was quenched with sat. NaHCO3(aq.) (2 mL) at 0 °C. The resulting mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine (2 x 2 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC with PE / EtOAc / EtOH (6 / 5 / 1) to afford (3S,4R)- 4-{[6-cyano-7-(3-fluoro-3-methylbutan-2-yl)-5-formylpyrrolo[2,l - |[1, 2, 4]tri azin-2- yl]amino}oxan-3-yl acetate (17 mg, 68%) as a light yellow solid. MS ESI calculated for C20H24FN5O4 [M + H]+, 418.18, found 418.30.Step 4 : (3SAR -4-{ j 6-cyano-5 -(difluoromethyl)-7 -(3 -fluoro-3 -methylbutan-2-yl)pyrrolor 2,1- / l[L2,41triazin-2-yl1aminoloxan-3-yl acetate

[0252] To a stirred mixture of (3S,4A)-4-{[6-cyano-7-(3-fluoro-3-methylbutan-2-yl)-5- formylpyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (17 mg, 0.041 mmol) in DCM (1.5 mL) was added DAST (52 mg, 0.328 mmol) dropwise at 0 °C. The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (2 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 3 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-{[6-cyano-5-(difluoromethyl)-7-(3-fluoro-3-methylbutan-2- yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (11 mg, 61%) as a light yellow solid. MS ESI calculated for C20H24F3N5O3[M + H]+, 440.18, found 440.05.Step 5: 5-(difluoromethyl)-7-(3-fluoro-3-methylbutan-2-yl)-2-ir(3A4A)-3-hydroxyoxan-4- yllaminolpyrroloR, l- / ]ri,2,41triazine-6-carbonitrile

[0253] A solution of (3S,4R)-4-{[6-cyano-5-(difluoromethyl)-7-(3-fluoro-3-methylbutan-2- yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (10 mg, 0.023 mmol) and K2CO3(9.44 mg, 0.069 mmol, 3 equiv) in MeOH (1 mL) was stirred for 1 h at room temperature. Theresulting mixture was purified by reversed-phase chromatography with the following conditions: column, Cl 8; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 25% to 50%; detector, UV 254 nm to afford 5-(difluoromethyl)-7-(3-fluoro-3-methylbutan-2-yl)-2-{[(3S, 4R)-3- hydroxyoxan-4-yl]amino}pyrrolo[2,l: / ][l,2,4]triazine-6-carbonitrile (6 mg, 66%) as a light yellow oil. MS ESI calculated for C18H22F3N5O2[M + H]+, 398.17, found 398.20.Example 10: 5-(difluoromethyl)-7-(3-fluoro-3-methylbutan-2-yl)-2-(( -3-hvdroxytetrahvdro-2H-pyran-4-yl)amino)pyrroIo[2,1-f] [l,2,4]triazine-6-carbonitriIe (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH = 70 / 30, 1stpeak) Example 11: 5-(difluoromethyl)-7-(3-fluoro-3-methylbutan-2-yl)-2-(( -3-hvdroxytetrahvdro-2H-pyran-4-yl)amino)pyrrolo[2, 1- / 1 [1,2, 4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH = 70 / 30, 2ndpeak)

[0254] 5-(difhioromethyl)-7-(3-fluoro-3-methylbutan-2-yl)-2-{[(3S,4R)-3-hydroxyoxan-4- yl]amino}pyrrolo[2,l^][l,2,4]triazine-6-carbonitrile (6 mg) was purified by Chiral-HPLC with the following conditions: Column: CHIRAL ART Amylose-SA, 2 x 25 cm, 5 pm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: A:B = 70:30; Wave Length: 254 / 220 nm;

[0255] RTi: 9.29 min to afford 5-(difluoromethyl)-7-(3-fluoro-3-methylbutan-2-yl)-2-(((3S,4R)-3- hydroxytetrahydro-2 / / -pyran-4-yl)amino)pyrrolo[2,l- / |[l,2,4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH = 70 / 30, 1stpeak) (2.2 mg, 36%) as a light yellow solid MS ESI calculated for C18H22F3N5O2[M + H]+, 398.17, found 398.20.1H NMR (400 MHz, Chloroform-d ) δ 8.97 (s, 1H), 7.02 (t, J= 54.8 Hz,lH), 5.36 (brs, 1H), 5.18 (brs, 1H), 4.11-4.06 (m, 1H), 4.04-3.91 (m, 1H), 3.86-3.83 (m, 1H), 3.71-3.66 (m, 1H), 3.56- 3.50 (m, 1H), 3.30-3.25 (m, 1H), 3.19-3.15 (m, 1H), 2.26-2.14 (m, 1H), 1.76-1.62 (m, 4H), 1.51 - 1.38 (m, 3H), 1.35-1.28 (m, 3H).19F NMR (377 MHz, Chloroform-d δ -105.54-107.92 (2F), - 138.97 (IF).

[0256] RT2: 15.38 min to afford 5-(difluoromethyl)-7-(3-fluoro-3-methylbutan-2-yl)-2-(((3S,4R)-3- hydroxytetrahydro-2 / / -pyran-4-yl)amino)pyrrolo[2, L / ][ l,2,4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH = 70 / 30, 2ndpeak) (1.3 mg, 21%) as an off-white solid MS ESI calculated for C18H22F3N5O2[M + H]+, 398.17, found 398.20. ' H NMR(400 MHz, Chloroform-d ) δ 8.96 (s, 1H), 7.02 (t, J= 54.8 Hz,lH), 5.36 (brs, 1H), 5.13 (brs, 1H), 4.12-4.08 (m, 1H), 4.01-3.96 (m, 1H), 3.92-3.81 (m, 1H), 3.73-3.70 (m, 1H), 3.56-3.50 (m, 1H), 3.32-3.27 (m, 1H), 3.03-2.99 (m, 1H), 2.26-2.18 (m, 1H), 1.73-1.62 (m, 4H), 1.50-1.27 (m, 6H).19F NMR (377 MHz, Chloroform-d ) δ -106.76 (2F), -140.40 (IF).Example 12:5-(difluoromethyl)-7-(l-ethylcyclobutyl)-2- -3-hydroxyoxan-4-y 11 amino} pyrrolo [2, 1- / 1 [ 1 ,2,41triazine-6-carbonitrileStep 1 : (3S,4R)-4-n7-(l-ethylcvclobutyl)Dyrrolo[2,1-firF2,4]triazin-2-yl]amino}oxan-3-ol

[0257] A mixture of 2-chloro-7-(l-ethylcyclobutyl)pyrrolo[2,l-: / ][l,2,4]triazine (1.3 g, 5 515 mmol), (3S,4R)-4-aminooxan-3-ol (2.59 g, 22.109 mmol) and DIEA (4.28 g, 33.090 mmol) in NMP (30 mL) was stirred for 16 h at 80 °C. 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 (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EtOAc (1 / 2) to afford (3S,4R)-4-{ [7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-ol (1.5 g, 86%) as a yellow solid. MS ESI calculated for C17H24N4O2[M + H]+, 317.19, found 317.10Step 2: (3S, 4R)-4-l [7-(l-ethylcyclobutyl)pyrrolo[2.1- / irL2.41triazin-2-yl1aminoloxan-3-yl acetate

[0258] To a solution of (3S,4A)-4-{[7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan- 3-ol (130 mg, 0.411 mmol) and AC2O (50 mg, 0.493 mmol) in DCM (4 mL) was added TEA (249 mg, 2.466 mmol) at room temperature. The resulting mixture was stirred for 5 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4A)-4-{ [7-(l - ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (140 mg, 95%) as light yellow oil. MS ESI calculated for C19H26N4O3[M + H]+, 359.20, found 359.15. *HNMR (400 MHz, Chloroform-d ) δ 8.50 (s, 1H), 6.65 (d, J= 4.4 Hz, 1H), 6.45 (d, J= 4.4 Hz, 1H), 4.94-4.77 (m, 2H), 4.05-3.99 (m, 1H), 3.98-3.85 (m, 2H), 3.63-3.53 (m, 1H), 3.47-3.40 (m, 1H), 2.54-2.48 (m, 2H), 2.19-2.12 (m, 2H), 2.12-1.99 (m, 7H), 1.95-1.87 (m, 1H), 1.65 (m, 1H), 0.62 (t, J= 7.2 Hz, 3H).Step 3: (3S,4A)-4-l[5-chloro-7-(l-ethylcvclobutyl)pyrrolor2J- / irL2,41triazin-2-yl1amino}oxan- %yl

[0259] To a stirred solution of (3S,4A)-4-{[7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (1 g, 2.790 mmol) in DMF (10 mL) was added NCS (0.75 g, 5.580 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. Thereaction was quenched by the addition of sat. Na2S20a (aq.) (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic 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 (1 / 1) to afford (3S,4R)-4-{ [5-chloro-7-(l- ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (800 mg, 69%) as a yellow solid. MS ESI calculated for C19H25CIN4O3[M + H]+, 393.16, found 393.30.!H NMR (400 MHz, Chloroform-d ) δ 8.54 (s, 1H), 6.42 (s, 1H), 5.26 (brs, 1H), 4.99-4.92 (m, 1H), 4.07- 4.00 (m, 1H), 3.99-3.92 (m, 1H), 3.91-3.83 (m, 1H), 3 60-3.52 (m, 1H), 3.48-3.41 (m, 1H), 2.52- 2.38 (m, 3H), 2.23-2.13 (m, 2H), 2.13-1.99 (m, 6H), 1.97-1.86 (m, 1H), 1.76-1.94 (m, 1H), 0.70- 0.63 (m, 3H).Step 4 : (3S,4R)-4-l [5-chloro-7-(l -ethylcvclobutyl)-6-iodopyrrolor2.1- / 111 ,2.41tri azin-2 - yl]amino)oxan-3-yl acetate

[0260] To a stirred solution of (3S,4A)-4-{[5-chloro-7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (800 mg, 2.036 mmol) in DMF (8 mL) was added I2 (2.07 g, 8.144 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. Na2S20s (aq.) (500 mL) 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 residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3 / 1) to afford (3S,4R)-4-{ [5-chloro-7-(l- ethylcyclobutyl)-6-iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (900 mg, 82%) as a yellow solid. MS ESI calculated for C19H24CIIN4O3[M + H]+, 519.06, found 519.30.1H NMR (400 MHz, Chloroform-d ) δ 8.52 (s, 1H), 5.09 (s, 1H), 4.97-4.90 (m, 1H), 4.06-4.00 (m, 1H), 3.99-3.92 (m, 1H), 3.90-3.81 (m, 1H), 3.59-3.50 (m, 1H), 3.47-3.40 (m, 1H), 2.81-2.63 (m, 2H), 2.44-2.32 (m, 3H), 2.19-2.08 (m, 2H), 2.07-2.02 (m, 4H), 1.91-1.81 (m, 1H), 1.72-1.61 (m, 1H), 0.84-0.78 (m, 3H).Step 5: (3S,4A)-4-l[5-chloro-6-cvano-7-(l-ethylcvclobutyl)pyrrolol2,1-f]rL2,4]triazin-2- yllaminoloxan-3-yl acetate

[0261] To a stirred solution of (3S,4A)-4-{[5-chloro-7-(l-ethylcyclobutyl)-6-iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (750 mg, 1.446 mmol) and Zn(CN)2 (102 mg, 0.868 mmol) in DMF (8 mL) was added Pd(PPh3)4 (334 mg, 0.289 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at 140 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3 x100 mL). The combined organic layers were washed with brine (2 x 100 mb), 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 (3S,4R)-4-{[5-chloro-6-cyano-7-(l-ethylcyclobutyl)pyrrolo[2,l: / ][l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (480 mg, 80%) as a yellow solid. MS ESI calculated for C20H24CIN5O3[M + H]+, 418 16, found 418.10.1H NMR (400 MHz, Chloroform-d ) δ 8 65 (s, 1H), 5.28 (s, 1H), 4.99-4.91 (m, 1H), 4.07-4.01 (m, 2H), 3.87-3.77 (m, 1H), 3.56-3.48 (m, 1H), 3.44-3.71 (m, 1H), 2.79-2.62 (m, 2H), 2.44-2.27 (m, 3H), 2.25-2.06 (m, 6H), 2.02-1.91 (m, 1H), 1.94-1.61 (m, 1H), 0.85-0.77 (m, 3H).Step 6: -4-l [6-cyano-7-(l-ethylcyclobutyl)pyrrolo[2,1-firi,2,41triazin-2-yl1aminoloxan-3-yl acetate

[0262] To a stirred solution of (3S,4A)-4-{[5-chloro-6-cyano-7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (600 mg, 1.436 mmol) and Pd(dba)2 (82.56 mg, 0.144 mmol) and t-BuXPhos (121.94 mg, 0.287 mmol, 0.2 equiv) in dioxane (6 mL) were added EtaSiH (0.70 mL, 4.308 mmol) and TEA (0.60 mL, 4.308 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 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 (3 / 1) to afford (3S,4R)-4- {[6-cyano-7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (440 mg, 79%) as a yellow solid. MS ESI calculated for C20H25N5O3[M + H]+, 384.20, found 384.30. Step 7: (3S.4A)-4-l[6-cyano-7-(l-ethylcyclobutyl)-5-iodopyrrolo[2.1- / irL2.41triazin-2- yl]amino |oxan-3-yl acetate

[0263] To a stirred mixture of (3S,4R)-4-{[6-cyano-7-(l-ethylcyclobutyl)pyrrolo[2,l: / ][l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (440 mg, 1.147 mmol) in DMF (5 mL) was added I2 (1.16 g, 4.588 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. Na2S20s (aq.) (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 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 (3 / 1) to afford (35',4R)-4-{[6-cyano-7-(l-ethylcyclobutyl)-5-iodopyrrolo[2,l- / |[l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (400 mg, 66%) as a yellow solid. MS ESI calculated for C20H24IN5O3[M + H]+, 510.09, found 510.10.NMR (400 MHz, Chloroform-d ) δ 8.44 (s, 1H), 5.29-5.20 (m, 1H) 5.00-4.91 (m, 1H), 4.09-3.94 (m, 2H), 3.86-3.77 (m, 1H), 3.57-3.48 (m, 1H), 3.45-3.67 (m, 1H), 2.79-2.63 (m, 2H), 2.42-2.28 (m, 3H), 2.24-2.10 (m, 2H), 2.09-2.04 (m, 4H), 2.00-1.88 (m, 1H), 0.97-0.86 (m, 1H), 0.84-0.77 (m, 3H).Step 8: -4-l[6-cyano-7-(l-ethylcyclobutyl)-5-(hydroxymethyl)pyrrolo[2,l- / iri.2,41triazin-2-yl1aminoloxan-3-yl acetate

[0264] To a solution of (3S,4R)-4-{[6-cyano-7-(l-ethylcyclobutyl)-5-iodopyrrolo[2,l: / ][l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (200 mg, 0.393 mmol, 1 equiv)in dioxane (5 mL) were added 2nd Generation XPhos Precatalyst (30.90 mg, 0.039 mmol) and (tributyl stannyl)methanol (252.16 mg, 0.786 mmol) The reaction mixture was stirred for 4 h at 80 °C under nitrogen atmosphere. The reaction was quenched with sat. KF (aq.) (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 15 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-{[6-cyano-7-(l-ethylcyclobutyl)-5-(hydroxymethyl)pyrrolo[2,l- _ / ][!, 2, 4]triazin-2-yl]amino}oxan-3-yl acetate (35 mg, 19%) as a yellow solid. MS ESI calculated for C21H27N5O4 [M + H]+, 414.21, found 414.15.1H NMR (400 MHz, Chloroform-d ) δ 8.99 (s, 1H), 5.81 (s, 1H), 5.04 (s, 2H), 5.00-4.93 (m, 1H), 4.09-4.02 (m, 1H), 4.00-3.94 (m, 1H), 3.88- 3.81 (m, 1H), 3.61-3.51 (m, 1H), 3.47-3.38 (m, 1H), 2.77-2.64 (m, 1H), 2.41-2.30 (m, 3H), 2.25- 2.11 (m, 2H), 2.10-2.06 (m, 4H), 1.99-1.91 (m, 1H), 1.79-1.70 (m, 1H), 1.01-0.91 (m, 1H), 0.85- 0.79 (m, 3H).Step 9: (3S,4R)-4-l r6-cyano-7-(l-ethylcyclobutyl)-5-formylpyrrolor2.1- / in,2.41triazin-2- yllaminoloxan-3-yl acetate

[0265] A solution of (3S,4R)-4-{[6-cyano-7-(l-ethylcyclobutyl)-5-(hydroxymethyl)pyrrolo[2,l- _ / ][!, 2, 4]triazin-2-yl]amino}oxan-3-yl acetate (30 mg, 0.073 mmol) and DMP (61.55 mg, 0.146 mmol) in DCM (1 mL) was stirred for 2 h at room temperature. The reaction was quenched with sat. NaHCO3(aq.) (2 mL). The resulting mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine (2 x 2 mL), dried over anhydrous Na2SC>4. 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-{ [6- cyano-7-(l-ethylcyclobutyl)-5-formylpyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (24 mg, 77%) as a yellow solid. MS ESI calculated for C21H25N5O4 [M + H]+, 412.19, found 412.25. ‘HNMR (400 MHz, Chloroform-d 5 10.09 (s, 1H), 9.34 (s, 1H), 5.45-5.39 (m, 1H), 5.01-4.93 (m, 1H), 4.08-3.96 (m, 2H), 3.90-3.81 (m, 1H), 3.56-3.48 (m, 1H), 3.44-3.38 (m, 1H), 2.82-2.67 (m, 2H), 2.42-3.34 (m, 3H), 2.20-2.09 (m, 2H), 2.208-2.06 (m, 3H), 2.03-1.96 (m, 1H), 1.76-1.63 (m, 1H), 1.31-1.25 (m, 1H), 0.85-0.80 (m, 3H).Step 10: -4-ir6-cyano-5-(difluoromethyl)-7-(l-ethylcyclobutyl)pyrrolo[2.1- / l[L2,41triazin-2-yl1aminoloxan-3-yl acetate

[0266] To a stirred mixture of (3S,4R)-4-{[6-cyano-7-(l-ethylcyclobutyl)-5-formylpyrrolo[2,l-_ / ][!, 2, 4]triazin-2-yl]amino}oxan-3-yl acetate (24 mg, 0.058 mmol) in DCM (1 mL) was added DAST (61 15 uL, 0.464 mmol) dropwise at 0 °C . The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (3 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC with PE / EtOAc (3 / 1) to afford (3S,4R)-4-{[6-cyano-5- (difluoromethyl)-7-(l-ethylcyclobutyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (20 mg, 77%) as an off-white solid. MS ESI calculated for C21H25F2N5O3[M + H]+, 434.19, found 434.35.Example 12:5-(difluoromethyl)-7-(l-ethylcyclobutyl)-2- [(3S, 4R)-3-hydroxyoxan-4-yl] amino} pyrrolo [2, 1- / 1 [ 1 ,2,4]triazine-6-carbonitrile

[0267] A solution of (3S,4R)-4-{[6-cyano-5-(difluoromethyl)-7-(l-ethylcyclobutyl)pyrrolo[2,l-_ / ][!, 2, 4]triazin-2-yl]amino}oxan-3-yl acetate (20 mg, 0.046 mmol) and K2CO3(12.75 mg, 0.092 mmol) in MeOH (1 mL) was stirred for 1 h at 0 °C. The resulting mixture was purified by reversed-phase chromatography with the following conditions: column, C18; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 25% to 50%; detector, UV 254 nm to afford 5- (difl uoromethyl)-7-( l -ethyl cyclobutyl )-2-{ [(3A'.4A’)-3-hydroxyoxan-4-yl]aminojpyrrolo[2, l - / ][l,2,4]triazine-6-carbonitrile (8.6 mg, 47%) as an off-white solid. MS ESI calculated for C19H23F2N5O2[M + H]+, 392.18, found 392.20. ‘HNMR (400 MHz, Chloroform-d ) δ 8.92 (s, 1H), 7.00 (t, J= 54.8 Hz, 1H), 5.21 (brs, 1H), 4.12-4.06 (m, 1H), 4.03-3.96 (m, 1H), 3.78- 3.67(m, 2H), 3.57-3.48 (m, 1H), 3.34-3.25 (m, 1H), 2.78-2.65 (m, 2H), 2.46-2.32 (m, 2H), 2.28- 2.18 (m, 2H), 2.17-1.95 (m, 3H), 1.76-1.62 (m, 1H), 0.85-0.78 (m, 3H).19F NMR (376 MHz, Chloroform-d ) δ -106.62-106.77 (2F).Example 13: (3tS,,41?)-4-((5-chloro-7-(5-(1.2-difluoro-2-methylpropyl)pyridin-2-yl)pyrrolo[2.1- / II L2.4|lriazin-2-yl)amino)tetrahvdro-2 / / -pyran-3-ol (single diastereoisomer, absolute chiral configuration of l,2-difluoro-2-methylpropyl was not determined) (CHIRALPAK IG, Hexane / EtOH = 50 / 50, 1stpeak) Example 14;(35,4R)-4-((5-chloro-7-(5-(l,2-difluoro-2-methylpropyl)pyridin-2-yl)pyrrolo[2,l- / II 1 ■2.4|triazin-2-yl)aniino)tetrahvdro-2 / / -pyran-3-ol (single diastereoisomer, absolute chiral configuration of l,2-difluoro-2-methylpropyl was not determined) (CHIRALPAK IG, Hexane / EtOH = 50 / 50, 2ndpeak)Step 1 : 2-bromo-5-(2-methylprop-l-en-l-yl)pyridine

[0268] To a stirred mixture of isopropyltriphenylphosphanium iodide (72 g, 166.649 mmol) in DMF (200 mL) was added / -BuOK (179 mL, 178.490 mmol). The resulting mixture was stirred for 30 min at room temperature. To this was added 6-bromopyridine-3-carbaldehyde (20 g, 107.522 mmol) in DMF (200 mL). The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. NH4CI (aq.) (3000 mL). The resulting mixture was extracted with EtOAc (2 x 2000 mL). The combined organic layers were washed with brine (2000 mL), dried over anhydrous Na2SC>4. 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-bromo-5-(2-methylprop-l-en-l-yl)pyridine (9.9 g, 41%) as a yellow oil. MS ESI calculated for C9Hi0BrN [M + H]+, 212.00, 214.00, found 212.00, 214.00.1HNMR (400 MHz, Chloroform-d ) δ 8.27 (s, 1H), 7.48-7.43 (m, 2H), 6.16-6.15 (m, 1H), 1.96-1.94 (m, 3H), 1.87-1.85 (m, 3H).Step 2: 2-bromo-5-(L2-difluoro-2-methylpropyl)pyridine

[0269] To a stirred mixture of 2-bromo-5-(2-methylprop-l-en-l-yl)pyridine (1 g, 4.715 mmol), 1-iodo- 4-methylbenzene (206 mg, 0.943 mmol) and HF-Pyridine (13 mL, 532.182 mmol, 70%) was added m-CPBA (1.24 g, 6.130 mmol, 85%) in portions at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with DCM (100 mL) and was cooled to -78 °C. The resulting mixture was quenched by the addition of sat. NaOH (aq.) (4 M) (150 mL) at -78 °C. The mixture was allowed to warm to room temperature. The aqueous layers was extracted with DCM (2 x 100 mL). The combined organic layers were washed with aqueous copper sulfate solution (100 mL) and brine (100 mL), dried over anhydrous Na2SC>4. 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-bromo-5-(l,2-difluoro-2-methylpropyl)pyridine (650 mg, 52%) as an off-white solid. MS ESI calculated for C9Hi0BrF2N [M + H]+, 250.00, 252.00, found 249.95, 251.95.1H NMR (400 MHz, Chloroform-d ) δ 8.37 (s, 1H), 7.64-7.62 (m, 1H), 7.56-7.47 (m, 1H), 5.39-5.24 (m, 1H), 1.45-1.42 (m, 3H), 1.40-1.34 (m, 3H).19F NMR (376 MHz, Chloroform-d ) δ -152.84 (IF), - 190.38 (IF).Step 3: (3S.4R)-4-(15-chloro-7-r5-(L2-difluoro-2-methylpropyl)pyridin-2-yl1pyrrolo[2,l- / irL2,41triazin-2-vHamino)oxan-3-ol

[0270] A mixture of (3S,4A)-4-({7-bromo-5-chloropyrrolo[2,l: / ][l,2,4]triazin-2-yl}amino)oxan-3-ol (382 mg, 1.100 mmol), 2-bromo-5-(l,2-difluoro-2-methylpropyl)pyridine (250 mg, 1.000 mmol), pyridine-2-carboximidamide hydrochloride (16 mg, 0.100 mmol), nickel(II) iodide (31 mg, 0.100 mmol), Nal (37 mg, 0.250 mmol), Mn (110 mg, 2.000 mmol) and TFA (11.40 mg,0.100 mmol) in DMA (5 mL) was stirred for 24 h at 60 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 30 mL). The filtrate was washed with 3 x 20 mL of NH4CI / NH4OH (9 / 1) and 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 / EtOH (4 / 3 / 1). The crude product was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (0.1% formic acid), 10% to 70%; detector, UV 254 nm to afford (3S,4R)-4-({5- chloro-7-[5-(l,2-difluoro-2-methylpropyl)pyridin-2-yl]pyrrolo[2,l- / |[l,2,4]tri azin-2- yl}amino)oxan-3-ol (40 mg, 9%) as a yellow solid. MS ESI calculated for C20H22CIF2N5O2[M + H]+, 438.14 found 438.00.1H NMR (400 MHz, Chloroform-d ) δ 8.72 (s, 1H), 8.67 (s, 1H), 8.57-8.51 (m, 1H), 7.90-7.83 (m, 1H), 7.39 (s, 1H), 5.48-5.32 (m, 1H), 5.09-4.92 (m, 1H), 4.17- 4.09 (m, 1H), 4.05-3.98 (m, 1H), 3.93-3.85 (m, 1H), 3.77-3.69 (m, 1H), 3.58-3.49 (m, 1H), 3.34- 3.26 (m, 1H), 2.39-2.07 (m, 1H), 2.24-2.16 (m, 1H), 1.80-1.68 (m, 1H), 1.51-1.40 (m, 6H).19F NMR (376 MHz, Chloroform-d ) δ -152.34 (IF), -190.18 (IF).Example 13;(3ty,4R)-4-((5-chloro-7-(5-(l,2-difluoro-2-methylpropyl)pyridin-2-yl)pyrrolo[2,l- M[1.2,4]triazin-2-yl)amino)tetrahydro-2H-pyran-3-ol (single diastereoisomer, absolute chiral configuration of l,2-difluoro-2-methylpropyl was not determined) (CHIRALPAK IG, Hexane / EtOH = 50 / 50, 1stpeak) Example 14; -4-((5-chloro-7-(5-(l,2-difluoro-2-methylpropyl)pyridin-2-yl)pyrrolo[2,l- / II 1 ■2.4|triazin-2-yl)aniino)tetrahvdro-2 / / -pyran-3-ol (single diastereoisomer, absolute chiral configuration of 1.2-difluoro-2-methylpropyl was not determined) (CHIRALPAK IG, Hexane / EtOH = 50 / 50, 2ndpeak)

[0271] (35, 4R)-4-({5-chloro-7-[5-(l,2-difluoro-2-methylpropyl)pyri din-2 -yl]pyrrolo[2, 1- / |[l,2,4]triazin-2-yl}amino)oxan-3-ol (40 mg) was purified by Prep-Chiral -HPLC with the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: A:B = 50:50; Wave Length: 254 / 220 nm;

[0272] RTi: 8.57 min to afford (3S,4R)-4-((5-chloro-7-(5-(l,2-difluoro-2-methylpropyl)pyridin-2- yl)pyrrolo[2, 1 -f\ [ 1 ,2,4]tri azi n-2-yl )ami no)tetrahydro-2 / / -pyran-3 -ol (single diastereoisomer, absolute chiral configuration of l,2-difluoro-2-methylpropyl was not determined) (CHIRALPAK IG, Hexane / EtOH = 50 / 50, 1stpeak) (23.9 mg, 57%). MS ESI calculated for C20H22CIF2N5O2[M + H]+, 438.14 found 438.00. *HNMR (400 MHz, DMSO- ) δ 8.94 (s, 1H),8.86 (d, J= 8.4 Hz, 1H), 8.67 (s, 1H), 7.99 (d, J= 8.4 Hz, 1H), 7.39-7.37 (m, 1H), 7.28 (d, J = 7.6 Hz, 1H), 5.80-5.60 (m, 1H), 5.02-4.98 (m, 1H), 3.89-3.81 (m, 2H), 3.79-3.70 (m, 1H), 3.63- 3.53 (m, 1H), 3.49-3.41 (m, 1H), 3.19-3.10 (m, 1H), 2 17-2.10 (m, 1H), 1.59-1.40 (m, 4H), 1 35- 1.25 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -151.59 (IF), -188.28 (IF).

[0273] RT2: 12.04 min to afford ((3S,4R)-4-((5-chloro-7-(5-(l,2-difluoro-2-methylpropyl)pyridin-2- yl)pyrrolo[2, 1 -f\ [ 1 ,2,4]tri azi n-2-yl )am i no)tetrahy dro-27 / -py ran-3 -ol (single diastereoisomer, absolute chiral configuration of l,2-difluoro-2-methylpropyl was not determined) (CHIRALPAK IG, Hexane / EtOH = 50 / 50, 2ndpeak) (16.5 mg, 41%) as a yellow solid. MS ESI calculated for C20H22CIF2N5O2[M + H]+, 438.14 found 438.05.1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.86 (d, J= 8.4 Hz, 1H), 8.67 (s, 1H), 7.99 (d, J= 8.4 Hz, 1H), 7.39-7.37 (m, 1H), 7.28 (d, J= 7.6 Hz, 1H), 5.80-5.60 (m, 1H), 5.02-4.98 (m, 1H), 3.89-3.81 (m, 2H), 3.79- 3.70 (m, 1H), 3.63-3.53 (m, 1H), 3.49-3.41 (m, 1H), 3.19-3.10 (m, 1H), 2.17-2.10 (m, 1H), 1.59- 1.40 (m, 4H), 1.35-1.25 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -151.65 (IF), -188.39 (IF). Example 15;5-fluoro-2-I[(3S,4R)-3-hvdroxyoxan-4-yl]amino)-7-[3- (trifluoromethyl)bicvclo[l.l.llpentan-l-yl1pyrrolo[2,l-f|[l,2,41triazine-6-carbonitrileStep 1 : 2,4-dichloro-5-fluoro-7-r3-(trifluoromethyl)bicyclor 1.1 11pentan-l-yl1pyrrolo[2,l- / 111.2.41tri azine

[0274] A solution of 2,4-dichloro-5-fluoropyrrolo[2,l: / ][l,2,4]triazine (500 mg, 2.427 mmol) and Ag2CO3(669 mg, 2.427 mmol) in CH3CN (5 m ) and H2O (2.5 mL) was treated with TFA (276.75 mg, 2.427 mmol) for 5 min at 50 °C under nitrogen atmosphere, followed by the addition of 3-(trifluoromethyl)bicyclo[l.l.l]pentane-l-carboxylic acid (874 mg, 4.854 mmol), (NH4)2S20S (1772 mg, 7.766 mmol) in CH3CN (2.5 mL) and H2O (5 mb). The resulting mixture was stirred for 48 h at 50 °C under nitrogen atmosphere. The reaction 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 (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: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 50% to 70%; detector, UV 254 nm to afford 2,4-dichloro-5-fluoro-7-[3- (trifluoromethyl)bicyclo[l. l.l]pentan-l-yl]pyrrolo[2,l-: / ][l,2,4]triazine (60 mg, 7 %) as a light yellow solid. MS ESI calculated for C12H7CI2F4N3 [M + H]+, 340.00, found 339.85. *HNMR (400 MHz, Chloroform^) 8 6.46 (s, 1H), 2.52 (s, 6H).Step 2: 2-chloro-5-fluoro-7-[3-(trifluoromethyl)bicyclol 1.1.1 lpentan-1 -yl1pyrrolo[2.1- / HL2,41tri azine

[0275] A solution of 2,4-dichloro-5-fluoro-7-[3-(trifluoromethyl)bicyclo[LL l]pentan-l-yl]pyrrolo[2,l- _ / ][!, 2, 4]triazine (160 mg, 0.470 mmol) and NaBt (28 mg, 0.752 mmol) in THF (2 mL) and i- PrOH (0.1 mL) was stirred for 1 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (5 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (2 mL). To this was added DDQ (160 mg, 0.705 mmol). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with the following conditions: Cl 8 column, mobile phase, CH3CN in water (0.1% formic acid), 50% to 70%; detector, UV 254 nm to afford 2-chloro-5-fluoro-7-[3- (trifluoromethyl)bicyclo[l. l.l]pentan-l-yl]pyrrolo[2,l^][l,2,4]triazine (104 mg, 72%) as a light yellow solid. MS ESI calculated for CI2H8C1F4N3[M + H]+, 306.03, found 305.90.1HNMR (400 MHz, Chloroform-d ) δ 8.81 (s, 1H), 6.44 (s, 1H), 2.53 (s, 6H).Step 3 : (3S,4R)-4-(f 5-fluoro-7-l 3 -(trifluorom ethyl )bicyclo[ 1.1.1 Ipentan- 1 -yl1pyrrolol2, 1 - / iri,2.41triazin-2-yllamino)oxan-3-ol

[0276] A solution of 2-chloro-5-fhioro-7-[3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl]pyrrolo[2,l- / ][l,2,4]triazine (102 mg, 0.334 mmol), (3S,4R)-4-aminooxan-3-ol hydrochloride (128 mg, 0.835 mmol) and DIEA (216 mg, 1.670 mmol) in NMP (2 mL) was stirred for 16 h at 60 °C under nitrogen atmosphere. The resulting mixture was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% formic acid), 40% to 65%; detector, UV 254 nm to afford (3S,4R)-4-({5-fluoro-7-[3- (trifluoromethyl)bicy clo[l.l.l]pentan-l-yl]pyrrolo[2,l-: / ][l, 2, 4]tri azin-2 -yl}amino)oxan-3-ol (110 mg, 85%) as a light yellow solid. MS ESI calculated for C17H18F4N4O2[M + H]+, 387.14, found 387.00.1HNMR (400 MHz, Chloroform-d ) δ 8.57 (s, 1H), 6.08 (s, 1H), 5.23 (d, J= 6.4 Hz, 1H), 4.92 (br, 1H), 4.11-4.17 (m, 1H), 4.04-3.98 (m, 1H), 3.72-3.67 (m, 2H), 3.53-3.49 (m, 1H), 3.31-3.25 (m, 1H), 2.48-2.42 (m, 6H), 2.18-2.14 (m, 1H), 1.71-1.63 (m, 1H).Step 4: (3SAR)-4-(15-fluoro-7-[3-(trifhioromethyl)bicvclorLLllpentan-l-yl1pyrrolo[2.1- / irL2,41triazin-2-vHamino)oxan-3-yl acetate

[0277] A solution of (3S,4R)-4-({5-fluoro-7-[3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl]pyrrolo[2,l- _ / ][!, 2, 4]triazin-2-yl}amino)oxan-3-ol (32 mg, 0.083 mmol), Ac2O (12.68 mg, 0.124 mmol, 1.5 equiv) and TEA (34 mg, 0.332 mmol) in DCM (1 mL) was stirred for 16 h at 50 °C under nitrogen atmosphere. 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 (3S,4R)-4-({5-fluoro-7-[3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (34 mg, 95%) as a light yellow solid. MS ESI calculated for C19H20F4N4O3[M + H]+, 429.15, found 429.15.Step 5: (3S,4R)-4-((5-fluoro-6-iodo-7-r3-(trifluoromethyl)bicvclo[ 1.1.11pentan-l-yl1pyrrolor2J- / iri,2,41triazin-2-vnamino)oxan-3-yl acetate

[0278] A solution of (3 ,4A)-4-({5-fhjoro-7-[3-(trifhioromethyl)bicyclo[l.l.l]pentan-l-yl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (36 mg, 0.084 mmol) and I2 (85 mg, 0.336 mmol) in DMF (0.5 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. Na2S2Ch (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 silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4R)-4- ({5-fluoro-6-iodo-7-[3 -(tri fluoromethyl)bicyclo[l.l.l]pentan-l-yl]pyrrolo[2,l - |[1, 2, 4]tri azin-2- yl}amino)oxan-3-yl acetate (34 mg, 72%) as a light yellow solid. MS ESI calculated for C19H19F4IN4O3[M + H]+, 555.04, found 554.90.Step 6: (3S.4A)-4-((6-cvano-5-fluoro-7-[3-(trifluoromethyl)bicvclori.L 11pentan-l- yl1pyrrolo / l[L2,41triazin-2-ynamino)oxan-3-yl acetate

[0279] A solution of (3S,4R)-4-({5-fhioro-6-iodo-7-[3-(trifhioromethyl)bicyclo[l. l.l]pentan-l- yl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (30 mg, 0.054 mmol), Zn(CN)2 (8 mg, 0.065 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol) in DMA (1 mL) was stirred for 2 h at 130 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (15 mL) at room temperature. The resulting mixture was 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 silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4R)-4-({6-cyano-5-fluoro-7- [3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (14 mg, 57%) as a light yellow solid. MS ESI calculated for C20H19F4N5O3[M + H]+, 454.14, found 453.95.1HNMR (400 MHz, Chloroform-d ) δ 8.71 (s, 1H), 5.36 (d, J= 7.2 Hz, 1H), 4.99-4.94 (m, 1H), 4.06-3.83 (m, 3H), 3.62-3.47 (m, 2H), 2.64-2.57 (m, 6H), 2.45-2.39 (m, 2H), 2.13-2.06 (m, 3H), 1.71-1.67 (m, 1H).Example 15:5-fluoro-2- -hvdroxyoxan-4-yl]amino}-7-[3-(trifluoromethyl)bicvclo[l.l.llpentan-l-yl1pyrrolo[2,l-f|[l,2,41triazine-6-carbonitrile

[0280] A solution of (3S,4R)-4-({6-cyano-5-fluoro-7-[3-(trifluoromethyl)bicyclo[l.l.l]pentan-l- yl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (14 mg, 0.031 mmol) and K2CO3(13 mg, 0.093 mmol) in MeOH (0.5 mL) was stirred for 30 min at room temperature. Theresulting mixture was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 10% to 50%; detector, UV 254 nm to afford 5-fluoro-2-{[(3S,4R)-3-hydroxyoxan-4-yl]amino}-7-[3- (trifluoromethyl)bicyclo[l.l.l]pentan-l-yl]pyrrolo[2,l-: / ][l,2,4]triazine-6-carbonitrile (4.8 mg, 34%) as a light yellow solid. MS ESI calculated for C18H17F4N5O2[M + H]+, 412.13; found 412.10.1H NMR (400 MHz, Chloroform-d δ 8.73 (s, 1H), 5.11 (brs, 1H), 4.13-3.95 (m, 2H), 3.81-3.68 (m, 2H), 3.56-3.50 (m, 1H), 3.33-3.27 (m, 1H), 2.67 (s, 6H), 2.26-2.15 (m, 1H), 1.71- 1.66 (m, 1H).19F NMR (376 MHz, Chloroform-<7) -73δ.19 (3F), -152.79 (IF).Example 16: -4-(I5-chloro-7-[5-(2,2-difluoroethyl)pyridin-2-yl1pyrrolo[2,1-f][l,2,41triazin-2-yl}amino)oxan-3-olStep 1 : 2-(6-chl oropyri din-3 -vDethanol

[0281] To a stirred mixture of (6-chl oropyri din-3 -yl)acetic acid (50 g, 291.40 mmol) in THF (125 mL) was added BH3-THF (400 mL, 400.00 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of MeOH (500 mL) at 0 °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 2-(6-chl oropyri din-3 -yl)ethanol (41.5 g, 90%) as yellow oil. MS ESI calculated for C7H8C1NO [M + H]+, 157.03 found 158.151H NMR (400 MHz, Chloroform- d) δ 8.22 (dd, J= 9.6, 2.8 Hz, 1H), 7.57 (dd, J= 8.0, 2.4 Hz, 1H), 7.25 (dd, J= 8.0, 5.2 Hz, 1H), 3.88 (t, J= 6.4 Hz, 2H), 2.85 (t, J= 6.4 Hz, 2H).Step 2: 2-(6-chl oropyri din-3 -yDacetaldehyde

[0282] To a stirred solution of 2-(6-chl oropyri din-3 -yl)ethanol (2.00 g, 12.690 mmol) in DCM (40 mL) was added Dess-Martin (6.46 g, 15.228 mmol). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (2 x 80 mL). The filtrate was concentrated under reduced pressure to afford 2-(6-chloropyridin-3- yl)acetaldehyde (1.9 g, crude) as colorless oil which was used in the next step directly without further purification. MS ESI calculated for CvHeCINO [M + H]+, 156.01, found 156.10. Step 3: 2-chloro-5-(2,2-difluoroethyl)pyridine

[0283] To a stirred solution of 2-(6-chloropyridin-3-yl)acetaldehyde (2.00 g, 12.855 mmol) in DCM (100 mL) was added DAST (3.40 mL, 25.710 mmol) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (5 / 1) to afford 2-chloro-5-(2,2-difluoroethyl)pyridine (130 mg, 4%) as colorless oil. MS ESI calculated for C7H6CIF2N [M + H]+, 178.02, found 177.95.1H NMR (400 MHz, Chloroform-d )δ 8.32 (d, J= 2.4 Hz, 1H), 7.62 (dd, J= 8.4, 2.4 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 5.97 (t, J = 56.0 Hz, 1H), 3.22-3.12 (m, 2H).19F NMR (376 MHz, Chloroform-d) δ -115.69 (2F). Step 4: (3SAR)-4-((7-[5-(2,2-difluoroethyl)pyridin-2-yl]pyrrolol2,1-firL2A1triazin-2- yl ;amino)oxan-3-yl acetate

[0284] To a stirred solution of (3S,4R)-4-({7-bromopyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (200 mg, 0 56 mmol) and bis(pinacolato)diboron (286 mg, 1 12 mmol) in dioxane (12 mL) was added Pd(PPha)2C12 (40 mg, 0.05 mmol) and KOAc (166 mg, 1.68 mmol) under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere To this was added 2-chloro-5-(2,2-difluoroethyl)pyridine (200 mg, 1.12 mmol) and Pd(dppf)C12.DCM (46 mg, 0.05 mmol) and CS2CO3(367 mg, 1.12 mmol) and water (3 mL) at room temperature. The resulting mixture was stirred for additional 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (150 mL). The organic layers were washed with water (3 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 (1 / 1) to afford (3S,4R)-4-({7-[5-(2,2- difluoroethyl)pyridin-2-yl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (100 mg, 42%) as yellow oil. MS ESI calculated for C20 H2IF2N5O3[M + H]+, 418.16 found 418.20.Step 5: -4-(15-chloro-7-r5-(2.2-difluoroethyl)pyridin-2-yl1pyrrolor2.1- / l[L2.41triazin-2-vHamino)oxan-3-yl acetate

[0285] A solution of (3S,4R)-4-({7-[5-(2,2-difluoroethyl)pyridin-2-yl]pyrrolo[2,l- / |[l,2,4]triazin-2- yl}amino)oxan-3-yl acetate (110 mg, 0.264 mmol) and l,3-dichloro-5,5-dimethylimidazolidine- 2, 4-dione (36 mg, 0.185 mmol) in CH3CN (2 mL) was stirred for 20 min at room temperature. The reaction was quenched by the addition of sat. NaHCO3(aq.) (30 mL). The resulting mixture was extracted with EtOAc (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 residue was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in Water (0.1% formic acid), 40% to 60%; detector, UV 254 nm to afford (3S,4R)-4-({5-chloro-7-[5-(2,2-difluoroethyl)pyridin-2- yl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (55 mg, 46%) as a light yellow solid. MS ESI calculated for C2OH2OC1F2N503 [M + H]+, 452.12, found 452.20.Example 16;(3ty,4R)-4-(T5-chloro-7-[5-(2.,2-difluoroethyl)pyridin-2-yl]DviTolo[2.,l- / |[l.,2,4]triazin-2- vUamino)oxan-3-ol

[0286] To a stirred mixture of (3S,4R)-4-({5-chloro-7-[5-(2,2-difluoroethyl)pyridin-2-yl]pyrrolo[2,l- / ][l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (40 mg, 0.089 mmol) in MeOH (1 mL) was addedK2CO3(24 mg, 0.177 mmol) at 0 °C. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was purified by reversed-phase chromatography with the following conditions: Cl 8 column, mobile phase, CH3CN in water (0.1% formic acid), 30% to 75%; detector, UV 254 nm to afford (3S,4R)-4-({5-chloro-7-[5-(2,2-difluoroethyl)pyridin-2- yl]pyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-ol (10.3 mg, 28%) as a yellow solid. MS ESI calculated for C18H18CIF2N5O2[M + H]+, 410.11, found 410.20. ’H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.78 (d, J= 4.4 Hz, 1H), 8.59 (d, J= 1.6 Hz, 1H), 7.91 (d, J= 6.4 Hz, 1H), 7.34 (s, 1H), 7.25 (d, J= 7.2 Hz, 1H), 6.49-6.21 (m, 1H), 5.00-4.99 (m, 1H), 3.88-3.84 (m, 2H), 3.76- 3.71 (m, 1H), 3.60-3.58 (m, 1H), 3.57-3.43 (m, 1H), 3 32-3.24 (m, 2H), 3.16-3.10 (m, 1H), 2.21- 2.13 (m, 1H), 1.60-1.40 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -115.44 (2F).Example 17: 2-(((31S,,41?)-3-hvdroxytetrahvdro-2H-pyran-4-yl)amino)-7-(l.l,l-trifluoropropan-2- yl)pyrrolo[2, 1- / 1 [1,2, 4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of l,l,l-trifluoropropan-2-yl was not determined) (CHIRALPAK IG, Hexane / EtOH = 70 / 30, 1stpeak) Example 18;2-(( -3-hydroxytetrahydro-2H-pyran-4-yl)amino)-7-(l,l,l-trifluoropropan-2-yl)pyrrolo[2,1-f][1.2,41triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of l,l,l-trifluoropropan-2-yl was not determined) (CHIRALPAK IG, Hexane / EtOH = 70 / 30, 2ndpeak)Step 1 : (3S.4R)-4-(17-bromopyrrolo[2.1- / irE2.41triazin-2-yllamino)oxan-3-ol

[0287] A solution of 7-bromo-2-chloropyrrolo[2,l- / |[l,2,4]triazine (1.00 g, 4.302 mmol), (3S, 4R)-4- aminooxan-3-ol (0.60 g, 5.162 mmol) and DIEA (2.22 g, 17.208 mmol) in NMP (10 mL) was stirred for 16 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in Water (10 mM NH4HCO3), 30% to 60%; detector, UV 254 nm to afford (3S,4R)-4-({7-bromopyrrolo[2,l-; / ][l,2,4]triazin-2- yl}amino)oxan-3-ol (1.10 g, 81%) as a brown solid. MS ESI calculated for CnHnBrN^ [M + H]+, 313.02, 315.02, found 313.00, 315.00.1H NMR (400 MHz, Chloroform-d δ 8.53 (s, 1H), 6.80 (d, J = 4.8 Hz, 1H), 6.71 (d, J= 4.8 Hz, 1H), 5.04 (d, J= 5.6 Hz, 1H), 4.13-4.09 (m, 1H), 4.04-4.00 (m, 1H), 3.86-3.79 (m, 1H), 3.70-3.66 (m, 1H), 3.54-3.48 (m, 1H), 3.29-3.24 (m, 1H), 2.16-2.04 (m, 1H), 1.77-1.71 (m, 1H).Step 2: .41triazin-2-yllamino)oxan-3-yl acetate

[0288] A solution of (3S,4R)-4-({7-bromopyrrolo[2,l: / ][l,2,4]triazin-2-yl}amino)oxan-3-ol (1.10 g,3.513 mmol), AC2O (0.54 g, 5.269 mmol, 1.5 equiv) and TEA (1.42 g, 14.052 mmol) in DCM(15 mL) was stirred for 16 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2 / 1 ) to afford (3S,4R)-4-({7-bromopyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (1.20 g, 96%) as light yellow oil. MS ESI calculated for CnHisBrN^a [M + H]+, 355.03, 357,03, found 355.00, 357.00. ’H NMR (400 MHz, Chloroform-d ) 8δ.52 (s, 1H), 6.79 (d, J= 4.8 Hz, 1H), 6.71 (d, J= 4.8 Hz, 1H), 5.32 (brs, 1H), 4.99-4.96 (m, 1H), 4.15-4.04 (m, 2H), 4.00-3.96 (m, 1H), 3.64-3.60 (m, 1H), 3.48-3.43 (m, 1H), 2.53-2.48 (m, 1H), 2.06 (s, 3H), 1.72-1.68 (m, 1H). Step 3: (3,S'.4R)-4-l [7-(3.3,3-tri fluoroprop-1 -en-2-yl)pyrrolol2,l - / 111.2,41lriazin-2- yl]amino !oxan-3-yl acetate

[0289] A solution of (3S,4R)-4-({7-bromopyrrolo[2,l^][l,2,4]triazin-2-yl}amino)oxan-3-yl acetate (1.20 g, 3.378 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-l-en-2-yl)-l,3,2-dioxaborinane (0.90 g, 4.054 mmol), Cs2CO3(2.20 g, 6.756 mmol) and Pd(dppf)Cl2CH2C12(0.28 g, 0.338 mmol) in 1,4-dioxane (12 mL) and H2O (2 mL) were stirred for 2 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to 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 silica gel column chromatography, eluted with PE / EtOAc (1 / 1) to afford (3S,4R)-4-{[7-(3,3,3-trifluoroprop-l-en-2-yl)pyrrolo[2,l: / ][l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (1.23 g, 98%) as a light yellow solid. MS ESI calculated for C16H17F3N4O3[M + H]+, 371.13, found 371.05.1H NMR (300 MHz, Chloroform-d ) δ 8.67 (s, 1H), 7.16-7.12 (m, 1H), 6.91-6.88 (m, 1H), 6.79-6.77 (m, 1H), 6.29-6.28 (m, 1H), 5.23 (br, 1H), 4.99-4.95 (m, 1H), 4.31- 4.22 (m, 1H), 4.08-3.93 (m, 2H), 3.60-3.54 (m, 1H), 3.49-3.42 (m, 1H), 2.45-2.41 (m, 1H), 2.05 (s, 3H), 1.74-1.70 (m, 1H).Step 4: (3£4R)-4-{[7-(LLldrifluoropropan-2-yl)pyrrolo[2,1-f][L2,4]triazin-2-yl]amino}oxan- 3-yl acetate

[0290] A solution of (35',4R)-4-{[7-(3,3,3-trifluoroprop-l-en-2-yl)pyrrolo[2,l- |[l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (1.23 g, 3.321 mmol), 2-nitrobenzenesulfonohydrazide (2.89 g, 13.284 mmol) and K3PO4 (1.41 g, 6.642 mmol) in CH3CN (20 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of water (100 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 residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2 / 1) to afford (3S,4R)-4-{ [7-(l ,1 ,1 -trifluoropropan-2-yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (0.43 g, 34%) as a light yellow solid. MS ESI calculated for C16H19F3N4O3[M + H]+, 373.14, found 373.10.1H NMR (300 MHz, C h loro form -<7) δ 8.63 (s, 1H), 7.20 (d, J= 4.8 Hz, 1H), 6 98 (d, J= 4.8 Hz, 1H), 5.10-5.06 (m, 1H), 4.53-4.44 (m, 1H), 4.06-4.01 (m, 3H), 3.73-3.69 (m, 1H), 3.59-3.51 (m, 1H), 2.40-2.35 (m, 1H), 2.08 (s, 3H), 1.89-1.86 (m, 1H), 1.62-1.58 (m, 3H).Step 5 : )-4- 1 [5-clil oro-7-(L 1 , 1 -tri fl uoropropan-2-yl (pyrrol o[2.1- / 111 ,2,41triazin-2- yl]amino |oxan-3-yl acetate

[0291] A solution of (35, 4A)-4-{[7-( 1,1,1 -trifhioropropan-2-yl)pyrrolo[2,l- / |[ 1,2, 4]triazin-2- yl]amino}oxan-3-yl acetate (400 mg, 1.074 mmol) and NCS (143 mg, 1.074 mmol) in DMF (5 mL) was stirred for 2 h at room temperature. The mixture was purified by reversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in Water (10 mM NH4HCO3), 40% to 65%; detector, UV 254 nm to afford (3S, 4R)-4-{[5-chloro-7-(l,l,l- trifluoropropan-2-yl)pyrrolo[2,l-: / ][l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (430 mg, 98%) as a light yellow solid. MS ESI calculated for C16H18CIF3N4O3[M + H]+, 407.11, found 407.05.1H NMR (400 MHz, Chloroform-d ) δ 8.64 (d, J= 2.0 Hz, 1H), 6.61 (s, 1H), 5.14-5.06 (m, 1H), 5.02-4.96 (m, 1H), 4.40-4.31 (m, 1H), 4.06-3.92 (m, 3H), 3.67-3.58 (m, 1H), 3.50-3.42 (m, 1H), 2.46-2.33 (m, 1H), 2.07 (d, J= 11.2 Hz, 3H), 1.69-1.62 (m, 1H), 1.54-1.48 (m, 3H).Step 6: (35.4R)-4-l[5-chloro-6-iodo-7-(LLl-trifluoropropan-2-yl)pyrrolo[2.1- / irL2.41triazin-2- yllaminoloxan-3-yl acetate

[0292] A solution of (3S,4R)-4-{[5-chloro-7-(l,l,l-trifluoropropan-2-yl)pyrrolo[2,l- / |[l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (0.41 g, 1.008 mmol) and I2 (1.02 g, 4.032 mmol) in DMF (5 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of sat. sodium hyposulfite (50 mL) at room temperature. 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 residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2 / 1) to afford (3S,4R)-4-{ [5-chloro-6-iodo-7-( 1,1,1 -trifhioropropan-2-yl)pyrrolo[2, 1 -f\ [ 1 , 2, 4]tri azin-2 - yl]amino}oxan-3-yl acetate (0.42 g, 78%) as a light yellow solid. MS ESI calculated for C16H17CIF3IN4O3[M + H]+, 533.00, found 533.10. *HNMR (300 MHz, Chloroform-d ) 3 8.63 (s, 1H), 5.18-5.15 (m, 1H), 4.98-4.93 (m, 1H), 4.47-4.17 (m, 1H), 4.07-3.85 (m, 3H), 3.63-3.39 (m, 2H), 2.42-2.37 (m, 1H), 2.10-2.02 (m, 3H), 1.82-1.73 (m, 3H), 1.68-1.64 (m, 1H). Step 7 : (35,4R)-4-l [5-chloro-6-cyano-7-( 1, L 1 -trifluoropropan-2-yl)pyrrolor2, 1 - / ] [ 1 ,2,4]triazin- 2-yl]amino !oxan-3-yl acetate

[0293] A mixture of (3S, 4R)-4-{[5-chloro-6-iodo-7-(l,l,l-trifluoropropan-2-yl)pyrrolo[2,l- / ][l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (400 mg, 0.751 mmol), Zn(CN)2 (98 mg, 1.502mmol) and Pd(PPha)4 (87 mg, 0.075 mmol) in DMF (5 mL) was irradiated with microwave radiation for 2 h at 120 °C under nitrogen atmosphere. The mixture was purified by reversed - phase chromatography with the following conditions: Cl 8 column; mobile phase, CHjCN in Water (10 mM NH4HCO3), 30% to 60% gradient in 15 min; detector, UV 254 nm to afford (3S,4R)-4-{[5-chloro-6-cyano-7-(l,l,l-trifluoropropan-2-yl)pyrrolo[2,l- / |[l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (270 mg, 83%) as a light yellow solid. MS ESI calculated for C17H17CIF3N5O3[M + H]+, 432.10, found 432.10.Step 8 : -4- 1 [ 6-cyano-7-( 1,1,1 -trifIuoropropan-2-yl)pyrrolo[2, 1- / 111 ,2,41triazin-2-yllaminoloxan-3-yl acetate

[0294] Amixture of (3S,4A)-4-{[5-chloro-6-cyano-7-(l,l,l-trifluoropropan-2-yl)pyrrolo[2,l- / ][l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (300 mg, 0.695 mmol), EtsSiH (242 mg, 2.081 mmol), EtsN (281 mg, 2.777 mmol), Pd(dba)2 (40 mg, 0.070 mmol) and di-ferZ-butyl[2',4',6'- tris(propan-2-yl)-[l,l'-biphenyl]-2-yl]phosphane (59 mg, 0.139 mmol) in dioxane (5 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 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 / 1) to afford (3S,4R)-4- {[6-cyano-7-(l,l,l-trifluoropropan-2-yl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (260 mg, 94%) as a yellow solid. MS ESI calculated for C17H18F3N5O3[M + H]+, 398.14; found 398.15.1HNMR (400 MHz, Chloroform-tT) δ 8.71 (d, J= 2.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 5.32 (brs, 1H), 5.03-4.98 (m, 1H), 4.56-4.51 (m, 1H), 4.04-3.99 (m, 3H), 3.63- 3.59 (m, 1H), 3.48-3.44 (m, 1H), 2.44-2.39 (m, 1H), 2.06 (d, J= 4.8 Hz, 3H), 1.83-1.78 (m, 3H), 1.71-1.66 (m, 1H).Step 9: 2-1 r(3S,4R)-3-hydroxyoxan-4-yl1aminol-7-(l,L l-trifluoropropan-2-yl)pyrrolo[2,l- / ] [ 1 ,2,41triazine-6-carbonitrile

[0295] A mixture of (3S,4R)-4-{ [6-cyano-7-(l,l,l-trifluoropropan-2-yl)pyrrolo[2, l- / |[l,2,4]triazin-2- yl]amino}oxan-3-yl acetate (260 mg, 0.654 mmol) and K2CO3(271 mg, 1.961 mmol) in MeOH (3 mL) was stirred for 1 h at room temperature. The reaction was quenched by the addition of water (10 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 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 2- {[(3S,4R)-3-hydroxyoxan-4-yl]amino}-7-(l,l,l-trifluoropropan-2-yl)pyrrolo[2,l- / |[l,2,4]triazine-6-carbonitrile (200 mg, 86%) as a yellow solid. MS ESI calculated for C15H16FN5O2[M + H]+, 356.13; found 356.05.Example 17:2-(((3.S'.4R)-3-livdr()xytetralivdi()-2 / / -i)yraii-4-yl)aniino)-7-(l ,1.l-triniioropropan-2- yl)pyrrolo[2,1-f][l,2,41triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of l,l,l-trifluoropropan-2-yl was not determined) (CHIRALPAK IG, Hexane / EtOH = 70 / 30, 1stpeak) Example 18: 2-(((35,41?)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-7-(l,l,l-trifluoropropan-2- yl)pyrrolo[2, 1- / 1 [1,2, 4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of l,l,l-trifluoropropan-2-yl was not determined) (CHIRALPAK IG, Hexane / EtOH = 70 / 30, 2ndpeak)

[0296] 2-{[(3S, 4R)-3-hydroxyoxan-4-yl]amino}-7-(l,l,l-trifluoropropan-2-yl)pyrrolo[2,l- / ][l,2,4]triazine-6-carbonitrile (100 mg) was purified by Prep-HPLC with the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: A:B = 70:30; Wave Length: 254 / 220 nm;

[0297] RTi: 6.80 min to afford 2-(((3S,4R)-3-hydroxytetrahydro-277-pyran-4-yl)amino)-7-(l,l,l- trifluoropropan-2-yl)pyrrolo[2,l: / ][l,2,4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 1 , 1 , 1 -tri fluoropropan -2-y I was not determined) (CHIRALPAK IG, Hexane / EtOH = 70 / 30, 1stpeak) (29.6 mg, 29%) as a white solid. MS ESI calculated for C15H16FN5O2[M + H]+, 356.13; found 356.15. *HNMR (400 MHz, DMSO-c / s) δ 8.99 (s, 1H),7.39-7.35 (m, 2H), 4.95 (brs, 1H), 4.69-4.64 (m, 1H), 3.85-3.81 (m, 2H), 3.71-3.66 (m, 1H), 3.56-3.51 (m, 1H), 3.41-3.36 (m, 1H), 3.10-3.06 (m, 1H), 2.10-1.96 (m, 1H), 1.71-1.67 (m, 3H), 1.48-1.43 (m, 1H).19F NMR (377 MHz, DMSO-t76) δ -69.74 (3F).

[0298] RT2: 9.04 min to afford 2-(((3S, 4R)-3-hydroxytetrahydro-2 / / -pyran-4-yl)amino)-7-(l,l,l- trifluoropropan-2-yl)pyrrolo[2,l: / ][l,2,4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 1 , 1 , 1 -tri fluoropropan -2-y I was not determined) (CHIRALPAK IG, Hexane / EtOH = 70 / 30, 2ndpeak) (29.1 mg, 28%) as a white solid. MS ESI calculated for C15H16FN5O2[M + H]+, 356.13; found 356.10. *HNMR (400 MHz, DMSO-fifc) δ 8.99 (s, 1H),7.39-7.34 (m, 2H), 4.92 (brs, 1H), 4.69-4.64 (m, 1H), 3.85-3.81 (m, 2H), 3.71-3.66 (m, 1H), 3.56-3.51 (m, 1H), 3.41-3.36 (m, 1H), 3.10-3.06 (m, 1H), 2.10-2.00 (m, 1H), 1.72-1.67 (m, 3H), 1.48-1.43 (m, 1H).19F NMR (377 MHz, DMSO-<76) δ -69.41 (3F).Example 19: 2-f[(3J?,4R)-3-fluoro-l-methanesulfonylpiperidin-4-yl1aminol-7-isopropyl-5- (triflnoromethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrileStep 1 : tert-butyl (3R.4A)-3-fluoro-4-(17-isopropylpyrrolor2,1-f1[L2,41triazin-2- ynamino piperidine-l -carboxylate

[0299] To a stirred solution of 2-chloro-7-isopropylpyrrolo[2,l- / |[l,2,4]triazine (7.4 g, 37.82 mmol) and tert-butyl (3A,4R)-4-amino-3-fluoropiperidine-l-carboxylate (93 mg, 0.43 mmol) in NMP (74 mL) was added DIEA (19.55 g, 151.29 mmol). The resulting mixture was stirred for 16 h at 150 °C under nitrogen atmosphere. The resulting mixture was purified by reversed-phase chromatography with the following conditions: Cl 8 column; mobile phase, CH3CN in water (0.1% NH3.H2O), 10% to 50%; detector, UV 254 nm to afford tert-butyl (3R,4A)-3-fluoro-4-({7- isopropylpyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)piperidine-l-carboxylate as a yellow solid. MS ESI calculated for C19H28FN5O2[M + H]+, 378.22, found 378.25.1H NMR (400 MHz, Chloroform-r / ) δ 8.53 (s, 1H), 6.68 (d, J = 4.8 Hz, 1H), 6.52 (d, J = 4.8 Hz, 1H), 4.94-4.88 (m, 1H), 4.72-4.69 (m, 1H), 4.60-4.57 (m, 1H), 4.15-4.10 (m, 1H), 3.73-3.69 (m, 1H), 3.47-3.44 (m, 1H), 3.36-3.33 (m, 1H), 2.41-2.37 (m, 1H), 1.53-1.48 (m, 9H), 1.38-1.35 (m, 6H).19F NMR (377 MHz, Chloroform-d ) -δ189.50 (IF).Step 2: tert-butyl (3A.4A)-4-(15-chloro-7-isopropylpyrrolo[2.1- / llL2.41triazin-2-yllamino)-3- fluoropiperidine-1 -carboxylate

[0300] A solution of tert-butyl (3R,4R)-3-fluoro-4-({7-isopropylpyrrolo[2,l^][l,2,4]triazin-2- yl}amino)piperidine-l -carboxylate (100 mg, 0.27 mmol) and NCS (6.37 g, 47.69 mmol) in DMF (120 mL) was stirred for 16 h at room temperature. The resulting mixture was diluted with EtOAc (400 mL), washed with brine (200 mL), and 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), 80% to 90%; detector, UV 254 nm to afford tert-butyl (3R,4R)-4-({5-chloro-7-isopropylpyrrolo[2,l-y][l,2,4]triazin-2-yl}amino)-3-fluoropiperidine-l- carboxylate as a yellow solid. MS ESI calculated for C19H27CIFN5O2[M + H]+, 412.18, found 412.20.1HNMR (400 MHz, Chloroform-d ) δ 8.58 (s, 1H), 6.44 (s, 1H), 4.89-4.86 (m, 1H), 4.69-4.65 (m, 1H), 4.57-4.54 (m, 1H), 4.09-4.05 (m, 2H), 3.77-3.69 (m, 1H), 3.44-3.40 (m, 1H), 3.34-3.31 (m, 1H), 2.38-2.33 (m, 1H), 1.53-1.48 (m, 9H), 1.36-1.33 (m, 6H).19F NMR (377 MHz, Chloroform-d ) δ -189.50 (IF).Step 3: tert-butyl (3R.4A)-4-((5-chloro-6-iodo-7-isopropylpyrrolor2.1- / irL2.41triazin-2- yl 1 amino)-3 -fluoropiperidine- 1 -carboxylate

[0301] A solution of tert-butyl (3R,4R)-4-({5-chloro-7-isopropylpyrrolo[2,l-y][l,2,4]triazin-2- yl}amino)-3-fluoropiperidine-l -carboxylate (100 mg, 0.24 mmol) and I2 (18.49 g, 72.83 mmol) in DMF (60 mL) was stirred for 3 h at room temperature. The reaction was quenched by the addition of sat. Na2S20s (aq.) (50 mL). The resulting mixture was extracted with EtOAc (3 x100 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 (8 / 1) to afford tert-butyl (3R,4A)-4-({ 5-chloro-6-iodo-7-isopropylpyrrolo[2, 1 -f\ [ 1 ,2,4]triazin-2-yl } amino)-3 - fluoropiperidine- 1 -carboxylate (7.2 g, 91%) as a yellow solid. MS ESI calculated for C19H26CIFIN5O2[M + H]+, 538.08, found 538 25.1H NMR (400 MHz, Cliloroform- ) δ 8.56 (s, 1H), 4.95-4.91 (m, 1H), 4.66-4.62 (m, 1H), 4.53-4.49 (m, 1H), 4.05-4.01 (m, 2H), 3.59-3.56 (m, 1H), 3.44-3.40 (m, 1H), 3.33-3.30 (m, 1H), 2.38-2.33 (m, 1H), 1.52-1.43 (m, 9H), 1.31-1.26 (m 6H).19F NMR (376 MHz, Chloroform-d ) δ -18946 (IF).Step 4: tert-butyl (3R,4R)-4-(15-chloro-6-cyano-7-isopropylpyrrolor2,1-f][l,2,41triazin-2- yl ) amino)-3 -fluoropiperidine- 1 -carboxylate

[0302] To a stirred solution of tert-butyl (3R,4R)-4-({5-chloro-6-iodo-7-isopropylpyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)-3-fluoropiperidine-l-carboxylate (6.0 g, 11.157 mmol) and Zn(CN)2 (0.44 g, 6.69 mmol) in DMF (60 mL) was added Pd(PPha)4 (1.29 g, 1.12 mmol) under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 120 °C under nitrogen atmosphere. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EtOAc (7 / 1) to afford tert-butyl (3R,4A)-4-({5-chloro-6-cyano-7-isopropylpyrrolo[2,l- / |[l,2,4]triazin-2- yl}amino)-3 -fluoropiperidine- 1 -carboxylate (4.4 g, 90%) as a yellow solid. MS ESI calculated for C20H26CIFN6O2[M + H]+, 437.18, found 437.25.1H NMR (400 MHz, Chloroform-d ) δ 8.67 (s, 1H), 5.18-5.16 (m, 1H), 4.63-4.59 (m, 1H), 4.49-4.46 (m, 1H), 4.06-4.02 (m, 1H), 3.89-3.79 (m, 1H), 3.67-3.64 (m, 1H), 3.29-3.25 (m, 1H), 3.23-3.19 (m, 1H), 2.39-2.26 (m, 1H), 1.48 (m, 15H).19F NMR (377 MHz, Chloroform-d ) δ -189.28 (IF).Step 5: tert-butyl (3R,4R)-4-(16-cvano-7-isopropylpyrrolor2,1-f triazin-2-yHamino)-3-fluoropiperidine-1 -carboxylate

[0303] To a stirred solution of tert-butyl (3R,4R)-4-({5-chloro-6-cyano-7-isopropylpyrrolo[2,l- / ][l,2,4]triazin-2-yl}amino)-3-fluoropiperidine-l-carboxylate (6.02 g, 13.78 mmol) and EtsSiH (4.81 g, 41.33 mmol), TEA (6.97 g, 68.89 mmol) in dioxane (60 mL) was added Pd(dba)2 (0.79 g, 1.38 mmol). The resulting mixture was stirred for 2 h at 80 °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 (1 / 1) to afford tert-butyl (3R,4R)-4- ({6-cyano-7-isopropylpyrrolo[2, 1- / |[ 1, 2, 4]triazin-2-yl}amino)-3-fluoropiperidine-l -carboxylate (5.5 g, 99%) as a yellow solid. MS ESI calculated for C20H27FN6O2[M + H]+, 403.22, found 403.25.1HNMR (400 MHz, Chloroform^ / ) δ 8.64 (s, 1H), 6.96 (s, 1H), 5.02-4.98 (m, 1H), 4.64-4.61 (m, 1H), 4.53-4.48 (m, 1H), 4.18-4.13 (m, 1H), 4.08-4.05 (m, 1H), 3.87-3.76 (m, 1H),3.70-3.67 (m, 1H), 3.33-3.22 (m, 2H), 2.38-2.34 (m, 1H), 1.53-1.47 (m, 15H).19F NMR (377 MHz, Chloroform-d ) 3 -189.35 (IF).Step 6: tert-butyl (3R,4A)-4-((6-cvano-5-iodo-7-isopropylpyrrolo[24- / lll,2,41triazin-2- yl ) amino)-3 -fluoropiperidine- 1 -carboxylate

[0304] A solution of tert-butyl (3A,4R)-4-({6-cyano-7-isopropylpyrrolo[2,l- / |[l,2,4]triazin-2- yl}amino)-3 -fluoropiperidine- 1 -carboxylate (5.5 g, 13 67 mmol) and I2 (17.34 g, 68.33 mmol) in DMF (55 m ) was stirred for 16 h at room temperature. The resulting mixture was quenched with Na2S20s (200 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 (5 / 1) to afford tert-butyl (3R,4R)-4- ({6-cyano-5-iodo-7-isopropylpyrrolo[2,l- / |[l,2,4]triazin-2-yl}amino)-3-fluoropiperidine-l- carboxylate (6.14 g, 85%) as a yellow solid. MS ESI calculated for C20H26FIN6O2[M + H]+, 529.11, found 529.25.1H NMR (400 MHz, Chloroform-d ) 8.δ49 (s, 1H), 5.10-5.08 (m, 1H), 4.62-4.57 (m, 1H), 4.49-4.45 (m, 1H), 4.08-4.03 (m, 1H), 3.89-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.32-3.28 (m, 1H), 3.23-3.18 (m, 1H), 2.39-2.28 (m, 1H), 1.51-1.46 (m, 15H).19F NMR (377 MHz, Chloroform^ / ) δ -189.28 (IF).Step 7: tert-butyl (3A.4A)-4-(r6-cyano-7-isopropyl-5-(trifluoromethyl)pyrrolor2.1- / irL2,41triazin-2-yl1amino)-3-fluoropiperidine-l -carboxylate

[0305] To a stirred solution of tert-butyl (3R,4A)-4-({6-cyano-5-iodo-7-isopropylpyrrolo[2,l- _ / ][!, 2, 4]triazin-2-yl}amino)-3-fluoropiperidine-l-carboxylate (100 mg, 0.19 mmol) and KF (0.68 g, 11.68 mmol), Cui (1.84 g, 9.65 mmol) in DMF (51 mL) was added methyl 2,2-difluoro- 2-(fluorosulfonyl)acetate (9.27 g, 48.26 mmol,) under nitrogen atmosphere. The resulting mixture was stirred for 3h at 80°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (200 mL). The resulting mixture was washed with brine (500 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 (3A,4R)-4-{[6-cyano-7-isopropyl-5- (trifluoromethyl)pyrrolo[2,l- / |[l, 2, 4]triazin-2-yl]amino}-3-fluoropiperidine-l -carboxylate (3.4 g, 74%) as a yellow solid. MS ESI calculated for C21H26F4N6O2[M + H]+, 471.21, found 471.25. 1H NMR (400 MHz, Chloroform-d ) δ 8.89 (d, J= 1.2 Hz, 1H), 5.21 (m, 1H), 4.62-4.57 (m, 1H), 4.49-4.45 (m, 1H), 4.21-4.19 (m, 1H), 4.06-4.03 (m, 1H), 3.94-3.84 (m, 1H), 3.72-3.69 (m, 1H), 3.20-3.15 (m, 1H), 2.39-2.27 (m, 1H), 1.61-1.59 (m, 1H), 1.52-1.49 (m, 15H).19F NMR (377 MHz, Chloroform-d ) δ -54.96 (3F), -189.23 (IF).Example 19:2-f[(3R,41?)-3-fluoro-l-methanesulfonylpiperidin-4-yl1amino}-7-isopropyl-5- (trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0306] A solution of tert-butyl (3A,4R)-4-{[6-cyano-7-isopropyl-5-(trifluoromethyl)pyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}-3-fluoropiperidine-l-carboxylate (3.4 g, 7.23 mmol) and HCl (gas) in 1,4-dioxane (60 mb) in DCM (34 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. To this was added methanesulfonic anhydride (2.63 g, 15.12 mmol) in EtOAc (28 mL). The mixture was basified to pH 7 with saturated NaHCCL (aq ). The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with EtOAc (100 mL), washed with brine (100 mL), and 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: Cl 8 column; mobile phase, CH3CN in water (0.1% NH3.H2O), 40% to 70%; detector, UV 254 nm to afford 2-{[(3R,4A)-3-fluoro-l-methanesulfonylpiperidin-4-yl]amino}-7-isopropyl-5- (trifluoromethyl)pyrrolo[2,l- / |[l,2,4]triazine-6-carbonitrile (2.96 g, 86%) as a white solid. MS ESI calculated for C17H20F4N6O2S [M + H]+, 449.13, found 449.15. *HNMR (400 MHz, DMSO-d6) δ 8.91 (d, J= 1.6 Hz, 1H), 5.19 (d, . / ~ 7.2 Hz, 1H), 4.77-4.70 (m, 1H), 4.11-4.07 (m, 1H), 4.01-3.96 (m, 1H), 3.74-3.70 (m, 2H), 3.21-3.17 (m, 2H), 2.96-2.90 (m, 3H), 2.46-2.44 (m, 1H), 1.83-1.79 (m, 1H), 1.55-1.50 (m, 6H).19F NMR (377 MHz, CDCI3) δ -54.98 (3F), -188.55 (IF).Example 20;7-(3-fluoro-3-methylbutan-2-yl)-2-f[(35,4R)-3-hydroxyoxan-4-yl]amino)pyrrolo[2,l- / ][l,2,4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3- fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH / DCM = 80 / 10 / 10, 1stpeak) Example 21: 7-(3-fluoro-3-methylbutan-2-yl)-2-f[(31S,.4R)-3-hydroxyoxan-4-yllamino)pyrrolo[2,l- / ][l,2,4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3- fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH / DCM = 80 / 10 / 10, 2ndpeak)Step 1 : 7-(3-fluoro-3-methylbutan-2-yl)-2-n(3A4^)-3-hvdroxyoxan-4-yl1aminolpyrrolor2,l- f\ 11 ,2,41triazine-6-carbonitrile

[0307] A solution of (35',4R)-4-{[6-cyano-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- / |[l,2,4]triazin- 2-yl]amino}oxan-3-yl acetate (180 mg, 0.462 mmol) and K2CO3(96 mg, 0.693 mmol) in MeOH (2 mL) was stirred for 30 min at room temperature. The resulting mixture was purified byreversed-phase chromatography with the following conditions: C18 column; mobile phase, CH3CN in water (10 mmol / L NH4HCO3), 40% to 60%; detector, UV 254 nm to afford 7-(3- fluoro-3-methylbutan-2-yl)-2-{[(31S',4R)-3-hydroxyoxan-4-yl]amino}pyrrolo[2,l- / |[l,2,4]triazine-6-carbonitrile (110 mg, 68%) as an off-white solid. MS ESI calculated for C17H22FN5O2[M + H]+, 348.18, found 348.20.Example 20:7-(3-fluoro-3-methylbutan-2-yl)-2 -3-hydroxyoxan-4-yl]amino)pyrrolo[2,l- / ][l,2,41triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3- fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH / DCM = 80 / 10 / 10, 1stpeak) Example 21: 7-(3-fluoro-3-methylbutan-2-yl)-2-f[(31S,.4R)-3-hydroxyoxan-4-yllamino)pyrrolo[2,l- / ][l,2,41triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3- fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH / DCM = 80 / 10 / 10, 2ndpeak)

[0308] 7-(3-fluoro-3-methylbutan-2-yl)-2-{[(3S,4R)-3-hydroxyoxan-4-yl]amino}pyrrolo[2,l- / ][l,2,4]triazine-6-carbonitrile (110 mg) was purified by Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 pm; Mobile Phase A: Hexane, Mobile Phase B: EtOH / DCM (1 / 1); Flow rate: 20 mL / min; Gradient: A:B = 80;20; Wave Length: 254 / 220 nm;

[0309] RTi: 14.06 min to afford 7-(3-fluoro-3-methylbutan-2-yl)-2-{[(3S,4R)-3-hydroxyoxan-4- yl]amino}pyrrolo[2,l-f][l,2,4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH / DCM = 80 / 10 / 10, 1stpeak) (37.1 mg, 33%) as a white solid. MS ESI calculated for C17H22FN5O2[M + H]+, 348.18; found 348.05.1H NMR (400 MHz, Chloroform-d ) δ 8.67 (s, 1H), 7.07 (s, 1H), 5.06 (s, 1H), 4.12-4.09 (m, 1H), 4.02-3.94 (m, 2H), 3.85-3.83 (m, 1H), 3.71- 3.66 (m, 1H), 3.56-3.47 (m, 1H), 3.31-3.25 (m, 1H), 2.16-2.12 (m, 1H), 1.77-1.66 (m, 1H), 1.65- 1.61 (m, 3H), 1.47-1.44 (m, 6H).19F NMR (376 MHz, Chloroform -d) -13δ8.64 (IF).

[0310] RT2 : 7 -(3 -fluoro-3 -methylbutan-2-yl)-2-{ [(3 S,4R)-3 -hydroxy oxan-4-yl] amino } pyrrolo[2, 1 - f][l,2,4]triazine-6-carbonitrile (single diastereoisomer, absolute chiral configuration of 3-fluoro- 3-methylbutan-2-yl was not determined) (CHIRAL ART Amylose-SA, Hexane / EtOH / DCM = 80 / 10 / 10, 2ndpeak) (37.8 mg, 34%) as a white solid. MS ESI calculated for C17H22FN5O2[M + H]+, 348.18; found 348.20. ‘HNMR (400 MHz, Chloroform-d ) δ 8.67 (s, 1H), 7.07 (s, 1H), 5.06 (s, 1H), 4.10 (m, 1H), 4.02-3.94 (m, 2H), 3.86-3.82 (m, 1H), 3.71-3.66 (m, 1H), 3.56-3.47 (m,1H), 3.31-3.25 (m, 1H), 2.16-2.12 (m, 1H), 1.77-1.66 (m, 1H), 1.63 (m, 3H), 1.45 (m, 6H).19F NMR (376 MHz, Chloroform -d) δ -140.14 (IF).Example 22: (35,4R)-4-((5-chloro-6-(2,2-difluoroethyl)-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- / 1[l,2,4]triazin-2-yl)amino)tetrahydro-2H-pyran-3-ol (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRALPAK IF, Hexane / EtOH = 90 / 10, 1stpeak) Example 23: (35,4R)-4-((5-chloro-6-(2,2-difluoroethyl)-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- / II 1.2.4|triaziii-2-yl)aniiiio)tetrahvdro-2 / / -pyran-3-ol (single diastereoisomer, absolute chiral configuration of 3-fluoro-3-methylbutan-2-yl was not determined) (CHIRALPAK IF, Hexane / EtOH = 90 / 10, 2ndpeak)Step 1 : (3S,4R)-4-( [5-chloro-6-(2,2-difluoroethyl)-7-(3-fluoro-3-methylbutan-2-yl)pyrrolo[2,l- / iri,2,41triazin-2-yl1amino)oxan-3-yl acetate

[0311] To a stirred solution of (3S,4R)-4-{[5-chloro-7-(3-fluoro-3-methylbutan-2-yl)-6- iodopyrrolo[2,l- / |[l,2,4]triazin-2-yl]amino}oxan-3-yl acetate (500 mg, 0.953 mmol), nickel(II) iodide (30 mg, 0.095 mmol), dppf (105 mg, 0.191 mmol), dtbpy (51 mg, 0.191 mmol) and Mn (183 mg, 3.335 mmol) in DMA (5 mL) was added l,l-difluoro-2-iodoethane (549 mg, 2.859 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirr...

Claims

CLAIMSWe claim:

1. A compound, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, having a structure selected from the group consisting of:

2. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, as described in claim 1 and a pharmaceutically acceptable excipient.

3. A method of preparing a pharmaceutical composition comprising mixing a compound, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, of claim 1, and a pharmaceutically acceptable carrier.

4. A compound of claim 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, for use in a method of treatment of the human or animal body.

5. A compound of claim 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, for use in a method of treatment of cancer or neoplastic disease.

6. Use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

7. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in claim 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof.

8. 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 claim 1, or a pharmaceutically acceptable salt or solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

9. The use of claim any one of claims 4 to 6, or the method of claim 7 or 8, wherein the cancer is selected from breast cancer, skin cancer, melanoma, or leukemia.

10. A method of inhibiting a CDK2, CDK4 or CDK6 kinase enzyme comprising contacting the enzyme with a compound of claim 1, or a stereoisomer thereof, wherein the CDK2, CDK4 or CDK6 kinase is contacted in an in vitro setting.

1. A method of inhibiting a CDK2, CDK4 or CDK6 kinase enzyme comprising contacting the enzyme with a compound of claim 1, or a stereoisomer thereof, wherein the CDK2, CDK4 or CDK6 kinase is contacted in an in vivo setting.

Images