Indazole compounds and azaindazole compounds as inhibitors of RAF kinases

Abstract

Provided herein are inhibitors of receptor tyrosine kinase effector (RAF), pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of disease.

Description

INDAZOLE COMPOUNDS AND AZAINDAZOLE COMPOUNDS AS INHIBITORS OF RAF KINASESBACKGROUND

[0001] RAF kinase functions in the Ras-Raf-MEK-ERK mitogen activated protein kinase (MAPK) pathway (also known as MAPK / ERK pathway) by phosphorylating and activating MEK. By altering the levels and activities of transcription factors, MAPK leads to altered transcription of genes that are important for the cell cycle. Deregulation of MAPK activity occurs frequently in tumors. Accordingly, therapies that target RAF kinase activity are desired for use in the treatment of cancer and other disorders characterized by aberrant MAPK / ERK pathway signaling.BRIEF SUMMARY OF THE INVENTION

[0002] Provided herein are inhibitors of the receptor tyrosine kinase effector Raf (RAF), pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.

[0003] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein,R is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; andW is an optionally substituted nitrogen-containing heterocyclyl, optionally substituted nitrogen-containing heteroaryl, optionally substituted aryl, optionally substituted nitrogencontaining heterocyclyl further substituted with an optionally substituted cycloalkyl, optionally substituted nitrogen-containing heteroaryl further substituted with an optionallysubstituted cycloalkyl, or optionally substituted aryl further substituted with an optionally substituted cycloalkyl.

[0004] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or any RAF kinase inhibitory compound disclosed below, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0005] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), or any RAF kinase inhibitory compound disclosed below, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer.

[0006] The invention also relates to a compound of Formula (I), or any RAF kinase inhibitory compound disclosed below, or pharmaceutically acceptable salt or solvate thereof for use as a medicament or in a method of treatment of the human or animal body, in particular for treating a disease or disorder such as cancer or neoplastic disease, in particular cancer.

[0007] The invention also relates to the use of a compound of Formula (I), or any RAF kinase inhibitory compound disclosed below, or pharmaceutically acceptable salt or solvate thereof as a medicament, in particular for treating a disease or disorder such as cancer.

[0008] The invention also relates to the use of a compound of Formula (I), or any RAF kinase inhibitory compound disclosed below, or pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a disease or disorder such as cancer.

[0009] The present invention also relates to the following objects.

[0010] Object 1 : A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein,R is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; andW is an optionally substituted nitrogen-containing heterocyclyl, optionally substituted nitrogencontaining heteroaryl, optionally substituted aryl, optionally substituted nitrogen-containing heterocyclyl further substituted with an optionally substituted cycloalkyl, optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl, or optionally substituted aryl further substituted with an optionally substituted cycloalkyl.

[0011] Object 2: The compound of object 1, or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted alkyl.

[0012] Object 3: The compound of object 1, or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted cycloalkyl.

[0013] Object 4: The compound of object 1, or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted cycloalkylalkyl.

[0014] Object 5: The compound of object 1, or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted heterocyclyl.

[0015] Object 6: The compound of object 1, or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted heterocyclylalkyl.

[0016] Object 7: The compound of object 5, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl is nitrogen-containing optionally substituted heterocyclyl.

[0017] Object 8: The compound of object 7, or pharmaceutically acceptable salt or solvate thereof, wherein the nitrogen-containing optionally substituted heterocyclyl is a 4-, 5-, or 6- membered nitrogen-containing optionally substituted heterocyclyl.

[0018] Object 9: The compound of object 8, or pharmaceutically acceptable salt or solvate thereof, wherein the 4-, 5-, or 6-membered nitrogen-containing optionally substituted heterocyclyl is substituted with an optionally substituted alkyl.

[0019] Object 10: The compound of any one of objects 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted nitrogen-containing heterocyclyl.

[0020] Object 11 : The compound of any one of objects 1 -9, or pharmaceutically acceptable salt or solvate thereof, wherein W is optionally substituted nitrogen-containing heteroaryl.

[0021] Object 12: The compound of any one of objects 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein W is optionally substituted aryl.

[0022] Object 13: The compound of any one of objects 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein W is optionally substituted nitrogen-containing heterocyclyl further substituted with an optionally substituted cycloalkyl.

[0023] Object 14: The compound of any one of objects 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein W is optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl.

[0024] Object 15: The compound of any one of objects 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein W is optionally substituted aryl further substituted with an optionally substituted cycloalkyl.

[0025] Object 16: The compound of object 10, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from an optionally substituted pyrrolidine, an optionally substituted 2,5-dihydro-lH-pyrrole, an optionally substituted piperidine, or an optionally substituted 1 ,2,3,6-tetrahydropyridine.

[0026] Object 17: The compound of object 16, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from:; and wherein R5 is selected from -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CH2CF3, - CH(CH3)CF3, -CH2CHF2, or -C(CH3)2CF3.

[0027] Object 18: The compound of object 11, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted nitrogen-containing heteroaryl.

[0028] Object 19: The compound of object 18, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted triazinyl, or optionally substituted pyrrolyl.

[0029] Object 20: The compound of object 19, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from:wherein R5 is selected from -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CH2CF3, - CH(CH3)CF3, -CH2CHF2, or -C(CH3)2CF3.

[0030] Object 21: The compound of object 18, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted pyrazyl, optionally substituted imidazyl, optionally substituted triazyl, optionally substituted oxazyl, or optionally substituted tetrazyl.

[0031] Object 22: The compound of object 18, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted pyraz-3-yl, optionally substituted pyraz-4-yl, optionally substituted pyraz-5-yl, optionally substituted imidaz-4-yl, or optionally substituted imidaz-5-yl.

[0032] Object 23: The compound of object 18, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted l,2,3-triaz-4-yl, optionally substituted 1,2,3-triaz- 5-yl, or optionally substituted l,2,4-oxadiaz-5-yl.

[0033] Object 24: The compound of object 18, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted oxaz-2-yl, optionally substituted oxaz-4-yl, or optionally substituted oxaz-5-yl.

[0034] Object 25: The compound of object 18, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted thiaz-2-yl, optionally substituted thiaz-4-yl, or optionally substituted thiaz-5-yl.

[0035] Object 26: The compound of object 13, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted nitrogen-containing heterocyclyl further substituted with an optionally substituted cycloalkyl.

[0036] Object 27: The compound of object 26, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from:; and R5 is 1 -trifluoromethylcyclopropyl, or a cyclopropyl substituted with at least one fluorine.

[0037] Object 28: The compound of object 13, or pharmaceutically acceptable salt or solvate thereof, wherein W is optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl.

[0038] Object 29: The compound of object 14, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from:trifluoromethylcyclopropyl, or a cyclopropyl substituted with at least one fluorine.

[0039] Object 30: The compound of object 12, or pharmaceutically acceptable salt or solvate thereof, wherein W is optionally substituted aryl.

[0040] Object 31: The compound of object 30, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted phenyl.

[0041] Object 32: The compound of object 31, or pharmaceutically acceptable salt or solvate thereof, whereinselected from -CH3, -CH2CH3, -CH(CH3)2, - C(CH3)3, -CF3, -CH2CF3, -CH(CH3)CF3, -CH2CHF2, or -C(CH3)2CF3.

[0042] Object 33: The compound of object 15, or pharmaceutically acceptable salt or solvate thereof, whereinselected from is 1 -trifluoromethylcyclopropyl, or a cyclopropyl substituted with at least one fluorine.

[0043] Object 34: The compound of object 10, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from an optionally substituted pyrrolidine, an optionally substituted 2,5-dihydro-lH-pyrrole, an optionally substituted piperidine, or an optionally substituted 1 ,2,3,6-tetrahydropyridine.

[0044] Object 35: The compound of object 11, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted l,2,3-triaz-4-yl, optionally substituted 1,2,3-triaz- 5-yl, or optionally substituted l,2,4-oxadiaz-5-yl.

[0045] Object 36: The compound of object 11, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted oxaz-2-yl, optionally substituted oxaz-4-yl, or optionally substituted oxaz-5-yl.

[0046] Object 37: The compound of object 11, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted thiaz-2-yl, optionally substituted thiaz-4-yl, or optionally substituted thiaz-5-yl.

[0047] Object 38: The compound of any one of objects 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from:

[0048] Object 39: The compound of any one of objects 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from:

[0049] Object 40: The compound of any one of objects 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from:

[0050] Object 41 : A compound, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1.

[0051] Object 42: A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of objects 1 - 41, and a pharmaceutically acceptable excipient.

[0052] Object 43: A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of objects 1 - 41, and a pharmaceutically acceptable carrier.

[0053] Object 44: A compound of any one of objects 1 - 41, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0054] Object 45: A compound of any one of objects 1 - 41, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0055] Object 46: Use of a compound of any one of objects 1 - 41, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0056] Object 47: A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of objects 1 - 41, or pharmaceutically acceptable salt or solvate thereof.

[0057] Object 48: A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of objects 1 - 41, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.INCORPORATION BY REFERENCE

[0058] 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

[0059] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended toexclude 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

[0060] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0061] " Amino" refers to the -NH2 radical.

[0062] "Cyano" refers to the -CN radical.

[0063] " Nitro" refers to the -NO2 radical.

[0064] " Oxa" refers to the -O- radical.

[0065] " Oxo" refers to the =0 radical.

[0066] " Thioxo" refers to the =S radical.

[0067] " Imino" refers to the =N-H radical.

[0068] " Oximo" refers to the =N-0H radical.

[0069] "Hydrazino" refers to the =N-NH2 radical.

[0070] "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 alkyl comprises 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 (w-propyl), 1 -methylethyl (Ao-propyl), 1 -butyl ( / ?-butyl), 1- methylpropyl (sec-butyl), 2-methylpropyl ( / .so-butyl), 1 , 1 -dimethylethyl (tert-butyl), 1 -pentyl (n- pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless statedotherwise 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, tnmethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.

[0071] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0072] "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, tnmethylsilanyl, -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, ortrifluoromethyl), 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) .

[0073] "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) .

[0074] "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, ^-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., 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).

[0075] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-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., C2 alkenylene). 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) .

[0076] "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 bondand to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 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., C2 alkynylene). 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 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) .

[0077] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) 7t-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-R°-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.

[0078] "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.

[0079] "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.

[0080] "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.

[0081] "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.

[0082] "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), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb- ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-R°-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 (optionallysubstituted 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.

[0083] "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. A fully saturated carbocyclylalkyl radical is also referred to as "cycloalkylalkyl."

[0084] "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.

[0085] "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.

[0086] " Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0087] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0088] "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. A “nitrogen-containing heterocyclyl” contains at least one heteroatom being a nitrogen. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to,dioxolanyl, thienyl[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-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-R°-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.

[0089] " / V-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 / V-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such / V-heterocyclyl radicals include, but are not limited to, 1 -morpholinyl, 1- piperidinyl, 1 -piperazinyl, 1 -pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0090] "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.

[0091] "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.

[0092] "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.

[0093] "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. A “nitrogen-containing heteroaryl” contains at least one heteroatom being a nitrogen. 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 Hiickel 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[ / >][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[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-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 1 / 7-pyrroly 1, 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- R°-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.

[0094] " / V-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 / V-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0095] "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.

[0096] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0097] "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.

[0098] 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 statedotherwise, 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.

[0099] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0100] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H (or D),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. Asdescribed 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.

[0101] 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.

[0102] 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,160,170,14F,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.

[0103] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0104] 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.

[0105] 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.

[0106] 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 deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.

[0107] Deuterium-transfer reagents, such as lithium aluminum deuteride (UAID4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of UAID4 is illustrated, by way of example only, in the reaction schemes below.

[0108] Deuterium gas and palladium catalyst are employed to reduce unsaturated carboncarbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0109] 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-exchangeable H hydrogen atoms. In one embodiment, the level of deuteriumincorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0110] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the RAF 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.

[0111] "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. etal., "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.

[0112] "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 tothe free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0113] "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 optionally exist in unsolvated as well as solvated forms. 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.

[0114] 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 underlyingdisorder. 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. The RAF Family of Kinases

[0115] The RAF kinases are a family of serine / thronine protein kinases constitute core components of the RAS-RAF-MEK-ERK mitogen activated protein kinase (MAPK) signalling cascade (also known as the MAPK / ERK pathway), a pathway that mediates signals from cell surface receptors to the nucleus to regulate cell growth, differentiation, and survival. The RAF proteins are related to retroviral oncogenes and are structurally conserved from metazoans to mammals, as is the MAPK / ERK pathway. Their dysregulation leads to uncontrolled cellular proliferation, survival, and dedifferentiation. Consequently, RAF kinases are altered or inappropriately activated in a majority of cancers.

[0116] The MAPK / ERK signalling pathway is a network of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division. The pathway includes many proteins, which communicate by adding phosphate groups to a neighboring protein, which acts as a molecular "on" or "off1switch, and overall, the pathway can be divided into 3 steps: (i) Ras activation, (ii) a kinase signal transduction cascade, and (iii) regulation of translation and transcription. Briefly, an extracellular mitogen or a signaling molecule binds to the membrane receptor. This allows Ras (a small GTPase) to swap its GDP for a GTP and become active. Activated Ras activates the protein kinase activity of RAF kinase. RAF kinase phosphorylates and activates MEK (MEK1 and MEK2). MEK then phosphorylates and activates a MAPK (also known as ERK). MAPK activation regulates activities of several transcription factors and also alters the translation of mRNA to proteins. By altering the levels and activities of transcription factors, MAPK leads to altered transcription of genes that are important for the cell cycle.

[0117] There are three known mammalian RAF isoforms: C-RAF (also known as RAF-1, or c- RAF-1), B- RAF, and A-RAF. All RAF kinases share a common modular structure consisting of 3 conserved regions (CR1, CR2, and CR3) with distinct functions. CR1 contains (i) a Ras- binding domain (RBD), which is necessary for the interaction with Ras and with membranephospholipids required for membrane recruitment, and (ii) a cysteine-rich domain (CRD), which is a secondary Ras-binding site and also necessary for the interaction of CR1 with the kinase domain for RAF autoinhibition. CR2 contains important inhibitory phosphorylation sites participating in the negative regulation of Ras binding and RAF activation. CR3 features the kinase domain, including the activation segment, whose phosphorylation is crucial for kinase activation.

[0118] Functionally, the RAF structure can be split into a regulatory N-terminal region, containing the RBD, which is critical for activation as well as inhibitory phosphorylation sites, and a catalytic C-terminal region, which includes phosphorylation sites necessary for the kinase activation. The regulatory domain restrains the activity of the kinase domain, and its removal results in constitutive oncogenic activation. However, the activity of the isolated C-RAF kinase domain is subjected to further regulation and can be stimulated by phorbol esters, v-Src, and phosphorylation.

[0119] The common and key step in the activation of all 3 RAF kinase isoforms is membrane recruitment by a Ras family protein. The RAF kinases are located in the cytosol in their inactive state when bound to 14-3-3 proteins. In the presence of active Ras, they translocate to the plasma membrane. Membrane translocation triggers further activation events, such as the binding of PP2A to dephosphorylate the inhibitory pS259 site in RAF-1 (and presumably the corresponding sites in A-RAF and B-RAF) and the co-localization with the kinases responsible for the multiple activating phosphorylations. The sequences forming the binding interface are well conserved in the RAF as well as Ras family indicating that several members of the Ras family have the ability to bind RAF kinases. H-Ras, N-Ras, and K-Ras stimulate all 3 RAF isoforms and are the only Ras proteins that activate B-RAF. In contrast, A-RAF is also activated by R-Ras3, while C-RAF responds weakly to R-Ras3, Rit, and TC21as well. But all RAF kinases share MEK1 / 2 kinases as substrates. MEK1 / 2 in turn activate ERK1 / 2, and this pathway regulates many cellular functions such as cell proliferation, differentiation, migration, or apoptosis.C-RAF

[0120] C-RAF was first to be identified and is a ubiquitously expressed isoform. In humans, C- RAF is encoded by the RAFI gene. C-RAF also has a known splice variant preferentially expressed in the muscle and brain. C-RAF plays a critical role in mediating the cellular effects of growth factor signals. In the inactive state, C-RAF exists in a closed conformation in which theN-terminal regulatory region folds over and occludes the catalytic region. This conformation is stabilized by a 14-3-3 dimer binding to an N-terminal site, phospho-S259 (pS259), and a C- terminal site, pS621. Dephosphorylation of pS259 at the cell membrane by specific phosphatases (PP2A, PPI) releases 14-3-3 from its N-terminal binding site in C-RAF, thereby allowing conformational changes to occur that unmask the RBD and CRD domains in the CR1 region to enable Ras binding and membrane recruitment.B-RAF

[0121] B-RAF is encoded in humans by the BRAF gene, also known as proto-oncogene B-RAF and v-RAF murine sarcoma viral oncogene homolog B. Alternative splicing gives rise to multiple B-RAF isoforms which are differentially expressed in various tissues. Whereas activation of A-RAF and C-RAF requires both phosphorylation and dephosphorylation of certain residues, as well as binding to other proteins, B-RAF becomes activated immediately upon translocation to the plasma membrane. B-RAF exhibits higher basal kinase activity than A-RAF and C-RAF. B-RAF requires Ras and 14-3-3 binding for its activation and is inhibited or activated by PKA depending on the levels of 14-3-3 expression, which need to be high for permitting activation. B-RAF activity is also regulated by splicing. B-RAF isoforms containing exon 8b are more phosphorylated on the inhibitory S365 site, leading to an increased interaction with 14-3-3 and strengthening the inhibitory interaction between N-terminal regulatory domain and kinase domain, altogether resulting in lower kinase activity.A-RAF

[0122] Serine / threonine-protein kinase A-RAF or A-RAF is an enzyme encoded by the ARAF gene in humans. There are 2 known splice isoforms of A-RAF - DA-RAF1 and D-RAF2. They lack the kinase domain and act as dominant inhibitory mutants of Ras and ARF GTPases. DARAF 1 is a positive regulator of myogenic differentiation by mediating the inhibition of the ERK pathway required for differentiation. There are several ways A-RAF is different from the other RAF kinases. A-RAF is the only steroid hormone-regulated Raf isoform. In addition, the A- RAFprotein has amino acid substitutions in a negatively charged region upstream of the kinase domain (N-region), which contributes to its low basal activity. A-RAF is also only weakly activated by oncogenic H-Ras and Src and also displays low kinase activity towards MEK (the lowest kinase activity towards MEK proteins in the Raf kinase family). In addition to phosphorylating MEK, A-RAF also inhibits MST2, a tumor suppressor and pro-apoptotic kinasenot found in the MAPK pathway. By inhibiting MST2, A-RAF prevents apoptosis from occurring. However, this inhibition only occurs when the splice factor heterogenous nuclear ribonucleoprotein H (hnRNP H) maintains the expression of a full-length A-RAF protein. Tumorous cells often overexpress hnRNP H which leads to full-length expression of A-Raf which then inhibits apoptosis, allowing cancerous cells that should be destroyed to stay alive. A- RAF also binds to pyruvate kinase M2 (PKM2), again outside the MAPK pathway. PKM2 is an isozyme of pyruvate kinase that is responsible for the Warburg effect in cancer cells. A-RAF upregulates the activity of PKM2 by promoting a conformational change in PKM2. This causes PKM2 to transition from its low-activity dimeric form to a highly active tetrameric form. This causes more glucose carbons to be converted to pyruvate and lactate, producing energy for the cell, linking A-Raf to energy metabolism regulation and cell transformation, both of which are very important in tumorigenesis.BRAF-targeted therapy in CNS tumors and / or brain metastases

[0123] Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. In the case of melanoma, brain metastases are frequently the first site of disease-progression (Cohn-Cedermark, G. el al. Central nervous system metastases of cutaneous malignant melanoma — A population-based study. Acta Oncol. 1998, 37, 463-470). Metastatic CNS invasion is a multistep process. Primary tumor cells initially enter the circulation and then undergo hematogenous spread until they arrest within capillary beds of organs, where they proliferate and form the metastasis. (Redmer, T. Deciphering mechanisms of brain metastasis in melanoma — The gist of the matter. Mol. Cancer 2018, 17, 106; Tawbi, H. A.; et al. New era in the management of melanoma brain metastases. Am. Soc. Clin. Oncol. Educ. Book 2018, 38, 741-750). One shortcoming of current therapies is the inability of a small molecule RAF kinase inhibitor to cross the blood-brain barrier and provide a therapeutically effective amount of inhibitor at the location of the CNS tumor and / or brain metastatic tissue.Determination of blood-brain barrier penetration by small molecules

[0124] In drug development, CNS drug candidates have lower success rates and longer development times than those in the other therapeutic areas. (Di, L. et al. Expert Opinion on Drug Discovery (2008) 3:6, 677-687. DOI: 10.1517 / 17460441.3.6.677) Low brain penetration of small molecules can be due to several factors, including, but not limited to, low blood-brain barrier (BBB) permeability, P-glycoprotein (Pgp) efflux, or high plasma protein binding.

[0125] There are multiple mechanisms that affect brain penetration of molecules. Compounds may enter the brain by transcellular passive diffusion, which is driven by a concentration gradient between the blood and the brain. Brain penetration of compounds may be enhanced by influx transporters, such as the large neutral amino acid transporter 1 (LAT1) for L-dopa and gabapentin (Ohtsuki,et al. Pharm. Res. 2007, 24, 1745-58; Gynther, et al. J. Med. Chem. 2008, 51(4), 932-936). This requires that the compounds have a certain structural motif to bind to the transporter. Only a few examples have been reported in which this pathway was purposely used to increase brain penetration. Efflux transporters move molecules out of cells. Of primary importance for brain penetration is the efflux transporter Pgp. Plasma protein binding, which reduces the free drug concentration available for BBB penetration, and metabolism and renal excretion, which reduces the total blood concentration, also affect brain penetration. Overall, passive diffusion is the major driving force moving most molecules into the brain; however, the other mechanisms discussed above can reduce brain penetration, depending on the structure and properties of the compound.

[0126] Bioanalytical methods and screening strategies provide the rationale for design and evaluation of compounds with desirable BBB distribution properties. (Di, L. et al. Expert Opinion on Drug Discovery (2008) 3:6, 677-687; Summerfield et al. J. Pharmacol. Exp. Ther. (2016) 358:294-305) A superior representation of brain distribution is based on the ratio of unbound compound in the brain extracellular fluid to the unbound blood concentration, represented as Kp,uu. (Liu and Chen, Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs (2015), p. 42- 65, Wiley & Sons). Kp,uu is a steady-state distribution term denoting the unbound concentration gradient across the BBB. If Kp,uu is lower than 1, then drug passage across the BBB is restricted by some factor. If Kp, uu is larger than 1 , then drug passage across the BBB is assisted by some factor. Kp, uu value of about 1 indicates passive diffusion across the BBB is predominate, or that active pathways (e.g., influx and efflux) are balanced. (Summerfield et al. vide supra) RAF Kinase Inhibitors

[0127] Aberrant activation of the MAPK / ERK pathway is frequently found in various cancers and is a target for cancer therapeutics. In particular, B-RAF has emerged as one of the most attractive molecular targets for cancer therapeutics because somatic mutations of B-RAF have frequently been found in human tumors. Approximately 20% of all cancer samples tested to dateharbor mutations in B-RAF. B-RAF-V600E, a missense mutation in the kinase domain generated by the substitution of glutamic acid with valine at position 600 is the most common B-RAF mutation. C-RAF is mutated in ~ 1% of the various tumor types tested and the rate of mutations in A-RAF is even lower. B-RAF and C-RAF form both homo- and heterodimers as part of their activation mechanism and A-RAF stabilizes the B-RAF: C-RAF complexes to sustain signaling efficiency. Also, it is C-RAF, not B-RAF, that transmits signals from oncogenic RAS to MEK. Therefore, in different contexts, each of the RAF isoforms act as a potential therapeutic target.

[0128] Sorafenib was the first RAF inhibitor to enter clinical trials. Sorafenib is a broad specificity drug that inhibits additional kinases, including vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3), platelet-derived growth factor receptor family (PDGFR-b and KIT) and FLT3. Clinical trials showed no correlation between the clinical responses with B-RAF mutation status, indicating it is a poor inhibitor of B-RAF. This led to the development of a new generation of B-RAF inhibitors, including, but not limited to vemurafenib, SB-590885, and dabrafenib (GSK2118436). Although the initial results of the clinical studies in B-RAF -mutant melanoma were encouraging, as clinical testing began in other B-RAF-mutated cancers (such as thyroid and colorectal cancers) it became apparent that tumors of different cell types harboring B-RAF mutations responded differently to selective B-RAF inhibition.Moreover, the existence of both primary and secondary resistance to RAF inhibition poses as one of the greatest challenge to the progress of RAF kinase inhibitor therapy. The mechanisms of resistance fall into two broad categories. Intrinsic / primary resistance is displayed by approximately 50% of patients. The other 50% of the patients initially respond (>30% tumor shrinkage) to RAF inhibitor but subsequently develop progressive disease associated with acquired / secondary resistance to RAF inhibitor. These two categories are not mutually exclusive because nearly all responders have remaining disease and, thus, may display intrinsic resistance. The determinants of primary RAF inhibitor resistance seem to vary with tumor type, with alteration in RTK signaling also being involved. Potential mechanisms of secondary B-RAF inhibitor resistance include, but are not limited to, reactivation of ERK1 / 2 pathways, upregulation of RTK signaling, the upregulation of receptor tyrosine kinases, mutations in RAS, and upregulation of COT. B-Raf alternative splicing and amplification of B-RAF -V600E have also been implicated in ~ 30 and 20% of patients, respectively. Moreover, RAF kinase inhibitors cause paradoxical activation of the MAPK pathway, which, in some instances, leads to thedevelopment of secondary RAS mutation-driven malignancies. As such, there is a need in the field for new RAF kinase inhibitors that overcome the existing pitfalls and challenges posed by the current inhibitors.RAF Inhibitory Compounds

[0129] In one aspect, provided herein is a RAF inhibitory compound.

[0130] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein, R is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; andW is an optionally substituted nitrogen-containing heterocyclyl, optionally substituted nitrogencontaining heteroaryl, optionally substituted aryl, optionally substituted nitrogen-containing heterocyclyl further substituted with an optionally substituted cycloalkyl, optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl, or optionally substituted aryl further substituted with an optionally substituted cycloalkyl.

[0131] In formula (I), R is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl. Preferably, R is optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, most preferably optionally substituted heterocyclyl. The heterocyclyl (including in the heterocyclylalkyl group) may be substituted with one or several, in particular 1, 2, 3, or 4, preferably 1, or 2, substituants selected fom halo (e.g. fluoro), optionally substituted alkyl, and optionally substituted fluoroalkyl, preferably from optionally substituted alkyl. Most preferably, the heterocyclyl (including in the heterocyclylalkyl group) may besubstituted with one or several, in particular 1, 2, 3, or 4, preferably 1, or 2, substituants selected fom halo (e.g. fluoro), alkyl, and fluoroalkyl, preferably from alkyl. The alkyl (including in the heterocyclylalkyl group) may be substituted with one or several, in particular 1, 2, 3, or 4, substituants selected fom halo (e.g. fluoro). In the definition of R, alkyl (including in the heterocyclylalkyl group) has preferably 1 to 6 carbon atoms; cycloalkyl has preferably 3 to 8 carbon atoms; and heterocyclyl (including in the heterocyclylalkyl group) is preferably a nitrogen-containing heterocyclyl, in particular a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl most preferably a saturated 4-, 5-, or 6-membered nitrogen-containing heterocyclyl such as piperidine, pyrrolidine, or azetidine.

[0132] Preferably, R is a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl, in particular a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl such as piperidine, pyrrolidine, or azetidine, optionally substituted (and preferably substituted) with one or several, in particular 1, or 2, substituants selected fom halo (e.g. fluoro), optionally substituted (and preferably substituted) alkyl, and optionally substituted fluoroalkyl, preferably from optionally substituted alkyl.

[0133] Preferably, R is a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl, in particular a 4-, 5-, or 6-membered nitrogen-containing heterocyclyl such as piperidine, pyrrolidine, or azetidine, optionally substituted (and preferably substituted) with one or several, in particular 1, or 2, substituants selected fom halo (e.g. fluoro), alkyl, and fluoroalkyl, preferably from alkyl.

[0134] In formula (I), W is an optionally substituted nitrogen-containing heterocyclyl, optionally substituted nitrogen-containing heteroaryl, optionally substituted aryl, optionally substituted nitrogen-containing heterocyclyl further substituted with an optionally substituted cycloalkyl, optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl, or optionally substituted aryl further substituted with an optionally substituted cycloalkyl. Preferably, W is an optionally substituted nitrogen-containing heterocyclyl, optionally substituted nitrogen-containing heteroaryl, optionally substituted nitrogen-containing heterocyclyl further substituted with an optionally substituted cycloalkyl, or optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl. In the definition of W, “optionally substituted” preferably means optionally substituted with one or several, in particular 1, 2, 3, or 4, preferably 1, or 2, substituants selected from halo (e.g. fluoro), optionally substituted alkyl, and optionallysubstituted fluoroalkyl, preferably selected from halo (e.g. fluoro), alkyl, and fluoroalkyl, the alkyl and fluoralkyl having preferably 1 to 5 carbon atoms. In the definition of W, nitrogencontaining heterocyclyl is preferably a 3- to 18-membered, saturated or instaurated (preferely saturated), heterocyclyl containing 1 to 6 heteroatoms, at least one heteroatom being N, the other being preferably selected from N, O and S, preferably from O and N, and preferably the heterocyclyl is a 5-, 6-, or 7-membered (preferably 5- or 6-membered), saturated or instaurated (preferely saturated), heterocyclyl in which at least one heteroatom is nitrogen, preferably the heterocyclyl contains 1 to 4, preferably 1, or 2, heteroatoms, preferably selected from N and O (at least one heteroatom being N), preferably contains 1 heteroatom being N; nitrogen-containing heteroaryl is preferably a 3- to 18-membered heteroaryl containing 1 to 6 heteroatoms, at least one heteroatom being N, the other being preferably selected from N, O and S, preferably from O and N, and preferably the heteroaryl is a 5- or 6-membered heteroaryl in which at least one heteroatom is nitrogen, preferably the heteroaryl contains 1 to 4, preferably 1, 2, or 3, heteroatoms, preferably selected from N and O (at least one heteroatom being N); aryl has preferably 5 to 18, in particular 6 to 10, carbon atoms; cycloalkyl has preferably 3 to 10, in particular 5 to 7, carbon atoms. Preferably, the nitrogen-containing heterocyclyl is pyrrolidine,2.3-dihydro-lH-pyrrole, 2,5-dihydro-lH-pyrrole, piperidine, 1,2,3,4-tetrahydropyridine, 1, 2,3,6- tetrahydropyridine, morpholine, or piperazine; and the nitrogen-containing heteroaryl is a pyridyl, pyrimidyl, triazinyl, pyrazyl, pyrrolyl, imidazyl, triazyl, oxazyl, tetrazyl, oxadiazyl, or a thiazyl, preferably pyrazyl, or oxazyl, such as pyraz-4-yl, or oxaz-5-yl.

[0135] According to a preferred embodiment, W is an optionally substituted nitrogencontaining heterocyclyl, optionally substituted nitrogen-containing heteroaryl, optionally substituted nitrogen-containing heterocyclyl further substituted with an optionally substituted cycloalkyl, or optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl, wherein the nitrogen-containing heterocyclyl is selected from pyrrolidine, 2,3-dihydro-lH-pyrrole, 2,5-dihydro-lH-pyrrole, piperidine, 1,2,3,4- tetrahydropyridine, 1,2,3,6-tetrahydropyridine, morpholine, and piperazine; and the nitrogencontaining heteroaryl is selected from pyridyl, pyrimidyl, triazinyl, pyrazyl (e.g. pyraz-3-yl, pyraz-4-yl, or pyraz-5-yl), pyrrolyl, imidazyl (e.g. imidaz-4-yl, or imidaz-5-yl), triazyl (e.g.1.2.3-triazyl such as l,2,3-triaz-4-yl, or l,2,3-triaz-5-yl), oxazyl (e.g. oxaz-2-yl, oxaz-4-yl, or oxaz-5-yl), tetrazyl, oxadiazyl (e.g. 1 ,2,4-oxadiazyl such as l,2,4-oxadiaz-5-yl), and a thiazyl(e.g. thiaz-2-yl, thiaz-4-yl, or thiaz-5-yl). Preferably, W is an optionally substituted nitrogencontaining heteroaryl, or optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl, wherein the nitrogen-containing heteroaryl is selected from pyridyl, pyrimidyl, triazinyl, pyrazyl (e.g. pyraz-3-yl, pyraz-4-yl, or pyraz-5-yl), pyrrolyl, imidazyl (e.g. imidaz-4-yl, or imidaz-5-yl), triazyl (e.g. 1,2,3-triazyl such as l,2,3-triaz-4-yl, or l,2,3-triaz-5-yl), oxazyl (e.g. oxaz-2-yl, oxaz-4-yl, or oxaz-5-yl), tetrazyl, oxadiazyl (e.g. 1,2,4- oxadiazyl such as l,2,4-oxadiaz-5-yl), and a thiazyl (e.g. thiaz-2-yl, thiaz-4-yl, or thiaz-5-yl); preferably from pyrazyl (e.g. pyraz-3-yl, pyraz-4-yl, or pyraz-5-yl), pyrrolyl, imidazyl (e.g. imidaz-4-yl, or imidaz-5-yl), triazyl (e.g. 1,2,3-triazyl such as l,2,3-triaz-4-yl, or l,2,3-triaz-5- yl), oxazyl (e.g. oxaz-2-yl, oxaz-4-yl, or oxaz-5-yl), tetrazyl, oxadiazyl (e.g. 1,2,4-oxadiazyl such as l,2,4-oxadiaz-5-yl), and a thiazyl (e.g. thiaz-2-yl, thiaz-4-yl, or thiaz-5-yl); preferably from pyrazyl (e.g. pyraz-3-yl, pyraz-4-yl, or pyraz-5-yl), and oxazyl (e.g. oxaz-2-yl, oxaz-4-yl, or oxaz-5-yl); in particular from pyraz-4-yl, and oxaz-5-yl. In this embodiment, “optionally substituted” preferably means optionally substituted with one or several, in particular 1 , or 2, substituants selected from halo (e.g. fluoro), alkyl, and fluoroalkyl, the alkyl and fluoralkyl having preferably 1 to 5 carbon atoms, in particular selected from -F, -CH3, -CH2CH3, - CH(CH3)2, -C(CH3)3, -CF3, -CH2CF3, -CH(CH3)CF3, -CH2CHF2, and -C(CH3)2CF3.

[0136] According to a particular embodiment, W is selected from:wherein R5is selected from halo (e.g. fluoro), alkyl, and fluoroalkyl, the alkyl and fluoralkyl having preferably 1 to 5 carbon atoms, in particular selected from -CH3, -CH2CH3, -CH(CH,)2, - C(CH3)3, -CF3, -CH2CF3, -CH(CH3)CF3, -CH2CHF2, -C(CH3)2CF3, 1 -trifluoromethylcyclopropyl, and a cyclopropyl substituted with at least one fluorine.

[0137] According to another particular embodiment, W is selected from:wherein R5is selected from halo (e.g. fluoro), alkyl, and fluoroalkyl, the alkyl and fluoralkyl having preferably 1 to 5 carbon atoms, in particular selected from -CH3, -CH2CH3, -CH(CH,)2, -C(CH3)3, -CF3, -CH2CF3, -CH(CH3)CF3J-CH2CHF2, -C(CH3)2CF3, 1 -trifluoromethylcyclopropyl, and a cyclopropyl substituted with at least one fluorine.

[0138] According to another particular embodiment, W is selected from:wherein Ri, R2, and R3independently are selected from hydrogen, halo (e.g. fluoro), alkyl, fluoroalkyl and optionally substituted cycloalkyl, wherein the optionally substituted cycloalkyl is a cycloalkyl optionally substituted with one or several, in particular 1, or 2, substituents selected from halo (e.g. fluoro), alkyl, and fluoroalkyl. In particular, the alkyl and fluoralkyl have 1 to 5 carbon atoms, and the cycloalkyl has 3 to 7 carbon atoms.Preferably, Ri and R3are independently hydrogen, or halo such as fluoro; and R3is selected from halo (e.g. fluoro), alkyl, fluoroalkyl and optionally substituted cycloalkyl, wherein the optionally substituted cycloalkyl is a cycloalkyl optionally substituted with one or several, in particular 1, or 2, substituents selected from halo (e.g. fluoro), alkyl, and fluoroalkyl. In particular, the alkyl and fluoralkyl have 1 to 5 carbon atoms, and the cycloalkyl has 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, or bicyclo[l.l.l]pentan-l-yl.R2may be, -F, -CH3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CH2F, -CH2CHF2, -CH2CF3, - CH(CH3)2, -CH(CH3)CH2F, -CH(CH3)CHF2, -CH(CH3)CF3, -C(CH3)3, -C(CH3)2CH2F, - C(CH3)2CHF2, -C(CH3)2CF3, -C(CH3)2CH2CH3, -C(CH3)2CH2CH2F, -C(CH3)2CH2CHF2, - C(CH3)2CH2CF3, cyclopropyl, 1 -methylcyclopropyl, 1 -fluoromethylcyclopropyl, 1- difluoromethylcyclopropyl, 1 -trifluoromethylcyclopropyl, cyclobutyl, 1 -methylcyclobutyl, bicyclo[l.l.l]pentan-l-yl, and 3-fluorobicyclo[l.l.l]pentan-l-yl.

[0139] In some embodiments, the RAF kinase inhibitory compound as described herein has a structure provided in Table 1. It can also be a pharmaceutically acceptable salt or solvate thereof.Table 1Preparation of Compounds

[0140] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co.(Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0141] 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) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0142] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, whichare 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.Pharmaceutical Compositions

[0143] In certain embodiments, the RAF kinase inhibitory compound described herein is administered as a pure chemical. In other embodiments, the RAF 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)).

[0144] Provided herein is a pharmaceutical composition comprising at least one RAF 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.

[0145] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0146] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0147] In certain embodiments, the RAF kinase inhibitory compound as described by Formula (I), Table 1, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organicsmall 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.

[0148] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, 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)).

[0149] In some embodiments, the RAF kinase inhibitory compound as described by Formula (I), Table 1, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0150] The dose of the composition comprising at least one RAF kinase inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0151] 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.

[0152] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0153] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0154] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0155] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0156] One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0157] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0158] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0159] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

[0160] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.

[0161] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.

[0162] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceuticalcomposition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0163] In some embodiments described herein, the compound of Formula (I) or Table 1 partitions across the blood-brain barrier (BBB) with a Kp, uu of greater than 1. In some embodiments described herein, the compound of Formula (I) or Table 1 exhibits a Kp,uu greater than 0.3. In some embodiments described herein, the compound of Formula (I) or Table 1 exhibits a Kp,uu greater than 0.4. In some embodiments described herein, the compound of Formula (I) or Table 1 exhibits a Kp,uu greater than 0.6. In some embodiments described herein, the compound of Formula (I) or Table 1 exhibits a Kp,uu greater than 0.8. In some embodiments described herein, the compound of Formula (I) or Table 1 exhibits aKp,uu greater than 1.0. In some embodiments described herein, the compound of Formula (I) or Table 1 exhibits a Kp,uu greater than 1.2. In some embodiments described herein, the compound of Formula (I) or Table 1 exhibits a Kp,uu greater than 1.4. In some embodiments described herein, the compound of Formula (I) or Table 1 exhibits a Kp,uu greater than 1.6. In some embodiments described herein, the compound of Formula (I) or Table 1 exhibits a Kp,uu greater than 1.8. In some embodiments described herein, the compound of Formula (I) or Table 1 exhibits aKp,uu greater than 2.0. In some embodiments, the Kp, uu value is determined in a rat. In some embodiments, the Kp, uu value is determined in a mouse. In some embodiments, the Kp, uu value is determined in a rodent. In some embodiments, the Kp, uu value is determined in a dog. In some embodiments, the Kp, uu value is determined in a primate. In some embodiments, the Kp,uu value is determined in a human.

[0164] 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.

[0165] 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.EXAMPLESI. Chemical Synthesis

[0166] In some embodiments, the RAF kinase inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the descriptionof the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:°C degrees Celsius8H chemical shift in parts per million downfield from tetramethylsilaneDCM dichloromethane (CH2Q2)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 / / 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

[0167] Example 3: N-(l-(tert-butyl)-5-fluoro-lH-pyrazol-4-yl)-2-fluoro-4-methyl-5-(2-(methyl-d3)-5-morpholino-[l,2,4]triazolo[l,5-a]pyridin-7-yl)benzamide

[0168] Step 1: To a stirred solution of l,2-diamino-4,6-dichloropyridin-l-ium 2,4,6- trimethylbenzenesulfonate (1.5 g, 3.97 mmol) and TsOH (136.57 mg, 0.7 mmol) in dioxane (4.3 mL) were added acetic-2,2,2-<73 anhydride (1.29 g, 11.90 mmol) drop wise at room temperature. The resulting mixture was stirred for 2 h at 100 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (2 x 30 mL) and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO-i, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1). The fractions contained desired product were combined and concentrated to afford 5,7-dichloro-2-(methyl-<A)- [l,2,4]triazolo[l,5-a]pyridine (450 mg, 55%) as a white solid. MS ESI calculated for C7H2D3CI2N3 [M + H]+, 205.00, 207.00, found 205.25,207.25. ' H NMR (400 MHz, DMSO-t / 6) 8 8.00 (d, J= 1.9 Hz, 1H), 7.66 (d, J= 2.0 Hz, 1H).

[0169] Step 2: To a stirred solution of 5,7-dichloro-2-(methyl-r / 3)-[l ,2,4]triazolo[l ,5-a]pyridine (450 mg, 2.19 mmol) and morpholine (191.19 mg, 2.19 mmol) in DMSO (4.5 mL) was added DIEA (1.15 mL, 6.58 mmol) dropwise at room temperature. The reaction mixture was stirred for 2 h at 130 °C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (2 x 30 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL) and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1). The fractions contained desired product were combined and concentrated to afford 4-(7-chloro-2- (methyl-<73)-[l,2,4]triazolo[l,5-a]pyridin-5-yl)morpholine (400 mg, 71%) as a white solid. MS ESI calculated for C11H10D3CIN4O [M + H]+, 256.10, 258.10, found 256.20, 258.20. 'H NMR (400 MHz, DMSO-c / ) 8 7.43 (d, J= 2.0 Hz, 1H), 6.52 (d, J= 2.1 Hz, 1H), 3.81 (t, J= 4.0, Hz, 4H), 3.49 (t, J = 4.0 Hz, 4H).

[0170] Step 3: A solution of 4-(7-chloro-2-(methyl-<73)-[l,2,4]triazolo[l,5-a]pyridin-5- yl)morpholine (500 mg, 1.96 mmol), methyl 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (690.12 mg, 2.35 mmol) and 2nd Generation XPhos Precatalyst (153.84 mg, 0.20 mmol) in THF (4 mL) was added K3PO4 (2 mL) dropwise at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 16 h at 40 °C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 30 mL) and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 2). The fractions contained desired product were combined and concentrated to afford methyl 2-fluoro-4-methyl-5-(2-(methyl-<A)-5-morpholino- [l,2,4]triazolo[l,5-a]pyridin-7-yl)benzoate (500 mg, 66%) as a white solid. MS ESI calculated for C20H18D3FN4O3 [M + H]+, 388.18, found 388.45. ' H NMR (400 MHz, CDCh) 8 7.86 (d, J = 7.3 Hz, 1H), 7.24 (s, 1H), 7.10 (d, J= 11.4 Hz, 1H), 6.23 (s, 1H), 4.00 (t, J = 4.6 Hz, 4H), 3.94 (s, 3H), 3.53 (t, J= 4.6 Hz, 4H), 2.33 (s, 3H).

[0171] Step 4. To a stirred solution of methyl 2-fluoro-4-methyl-5-(2-(methyl-<73)-5- morpholino-[l,2,4]triazolo[l,5-a]pyridin-7-yl)benzoate (450 mg, 1.16 mmol) in MeOH (4.5 mL) and THF (4.5 mL) was added NaOH (0.23 g, 5.81 mmol) in H2O (4.5 mL) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The PH value ofresulting mixture was adjusted to 6 with diluted HC1. The resulting mixture was extracted with EtOAc (2 x 30 mL) and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 2-fluoro-4- methyl-5-(2-(methyl-r / 3)-5-morpholino-[l,2,4]triazolo[l,5-a]pyridin-7-yl)benzoic acid (840 mg, crude) as a light yellow solid. MS ESI calculated for C19H16D3FN4O3 [M + H]+, 374.16 , found 374.30.

[0172] Step 5: To a stirred solution of 2-fluoro-4-methyl-5-(2-(methyl-<73)-5-morpholino-[1.2.4]triazolo[l,5-a]pyridin-7-yl)benzoic acid (740 mg, 1.09 mmol, 55%), EDCI (313.42 mg, 1.64 mmol), HOBT (220.93 mg, 1.64 mmol) and NH4C1 (291.51 mg, 5.45 mmol) in DMF (14 mL) was added DIEA (1.90 mL, 10.90 mmol) dropwise at room temperature. The reaction mixture was stirred for 2 h at 50 °C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CFECh / MeOH (25 / 1). The fractions contained desired product were combined and concentrated to afford 2-fluoro-4- methyl-5-(2-(methyl-<73)-5-morpholino-[l,2,4]triazolo[l,5-a]pyridin-7-yl)benzamide (210 mg, 51 %) as a white solid. MS ESI calculated for C19H17D3FN5O2 [M + H]+, 373.18 , found 373.15. ' H NMR (400 MHz, CDCI3) 8 8.05 (d, J= 8.1 Hz, 1H), 7.20 (d, J= 1.6 Hz, 1H), 7.10 (d, J= 12.6 Hz, 1H), 6.70 (d, J= 11.5 Hz, 1H), 6.21 (d, J= 1.4 Hz, 1H), 5.90 (s, 1H), 4.00 (t, J = 4.0 Hz, 4H), 3.52 (t, J= 4.0 Hz, 4H), 2.34 (s, 3H).

[0173] Step 6: To a stirred solution of 2-fluoro-4-methyl-5-(2-(methyl-<73)-5-morpholino-[1.2.4]triazolo[l,5-a]pyridin-7-yl)benzamide (150 mg, 0.40 mmol), methyl[2- (methylamino)ethyl]amine (35.51 mg, 0.40 mmol,), Cui (76.71 mg, 0.40 mmol) and K3PO4 (179.54 mg, 0.85 mmol) in dioxane (2.0 mL) was added 4-bromo-l-(tert-butyl)-5-fluoro-l / 7- pyrazole (178.08 mg, 0.81 mmol) dropwise at room temperature. The reaction mixture was stirred for 16 h at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with CH2C12 / MeOH (10 / 1) to afford the crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD Cl 8 Column, 30 x 150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 62% B in 7 min; Wave Length: 254nm / 220nm. Thefractions containing the desired product were combined and concentrated to afford the title compound (75.5 mg, 36%) as a white solid. MS ESI calculated for C26H26D3F2N7O2 [M + H]+, 513.25 , found 513.40. 'H NMR (400 MHz, CDCh) 8 8.11 (d, J= 8.0 Hz, 1H), 7.98 (d, J= 15.5 Hz, 1H), 7.77 (d, J= 2.2 Hz, 1H), 7.23-7.11 (m, 2H), 6.21 (s, 1H), 4.00 (t, J= 4.6 Hz, 4H), 3.51 (t, J= 4.7 Hz, 4H), 2.36 (s, 3H), 1.62 (s, 9H).

[0174] Example 6: l-(Tert-butyl)-N-(5-(2-cyclopropyl-5-morpholino-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-2-fluoro-4-methylphenyl)-5-fluoro-lH-pyrazole-4-carboxamide

[0175] Step 1: A mixture of l,2-diamino-4,6-dichloropyridin-l-ium 2,4,6- trimethylbenzenesulfonate (1 g, 2.64 mmol) and Cu(OAc)2 (0.24 g, 1.32 mmol) in AcOH (8 mL) and MeOH (4 mL) was added cyclopropanecarbaldehyde (0.56 g, 7.93 mmol) dropwise at room temperature. The reaction mixture was degassed with nitrogen three times and stirred for 1 h at 70 °C under nitrogen atmosphere. The resulting mixture was neutralized pH 7 with NaOH (aq.) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO-i. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1). The fractions contained desired product were combined and concentrated to afford 5,7-dichloro-2-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridine (390 mg, 63%) as a white solid. MS ESI calculated for C9H7CI2N3. [M + H]+, 228.00, found 228.20; ' H NMR (400 MHz, CDCh) 8 7.56 (d, J= 1.9 Hz, 1H), 7.06 (d, J= 1.9 Hz, 1H), 2.31-2.27 (m, 1H), 1.23-1.09 (m, 4H).

[0176] Step 2: A mixture of 5,7-dichloro-2-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridine (370 mg, 1.62 mmol) and K2CO3 (448.40 mg, 3.24 mmol) in DMSO (0.5 mL, 1.62 mmol) was added morpholine (141.33 mg, 1.62 mmol) dropwise at room temperature. The reaction mixture wasstirred for 1 h at 100 °C. The resulting mixture was allowed to cool down to room temperature and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (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 / EA (1 / 1). The fractions contained desired product were combined and concentrated to afford 4-{7-chloro-2-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-5-yl}morpholine (300 mg, 64%) as a white solid. MS ESI calculated for C13H15CIN4O. [M + H]+, 279.30, found 279.20; 'H NMR (400 MHz, CDCh) 8 7.26 (d, J= 1.9 Hz, 1H), 6.25 (d, J= 1.9 Hz, 1H), 4.03-3.96 (m, 4H), 3.55-3.49 (m, 4H), 2.30-2.16 (m, 1H), 1.19-1.04 (m, 4H).

[0177] Step 3: A mixture of 4-{7-chloro-2-cyclopropyl-[l,2,4]triazolo[l,5-a]pyridin-5- yl}morpholine (280 mg, 1.00 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (302.69 mg, 1.21 mmol) and K3PO4 (639.67 mg, 0.5 M in water) in THF (3 mL) was added 2nd Generation XPhos precatalyst (79.04 mg, 0.10 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen three times and stirred for 1 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1). The fractions contained desired product were combined and concentrated to afford 5-[2-cyclopropyl-5-(morpholin-4-yl)- [l,2,4]triazolo[l,5-a]pyridin-7-yl]-2-fluoro-4-methylaniline (230 mg, 62%) as a light yellow solid. MS ESI calculated for C20H22FN5O. [M + H]+, 368.18, found 368.35; ' H NMR (400 MHz, CDCh) 8 7.18 (s, 1H), 6.93 (d, J= 11.8 Hz, 1H), 6.71 (d, J= 9.0 Hz, 1H), 6.21 (d, J= 1.6 Hz, 1H), 4.01 (t, J= 4.7 Hz, 4H), 3.72 (s, 2H), 3.52 (t, J= 5.7 Hz, 4H), 2.28 (d, J= 8.2 Hz, 1H), 2.18 (s, 3H), 1.19 (d, J = 5.4 Hz, 2H), 1.11 (d, J= 8.6 Hz, 2H);19F NMR (376 MHz, CDCh) 8 - 135.80.

[0178] Step 4: A solution of 5-[2-cyclopropyl-5-(morpholin-4-yl)-[l,2,4]triazolo[l,5-a]pyridin- 7-yl]-2-fluoro-4-methylaniline (100 mg, 0.27 mmol) in LiHMDS (3 mL, 1 M in THF) was stirred for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added propyl 1- (terZ-butyl)-5-fluoro-lH-pyrazole-4-carboxylate (93.19 mg, 0.41 mmol) in THF (3 mL) dropwise over 5 min at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was quenched by the addition of sat. NH4CI (aq.) (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried overanhydrous Na2SC>4 and filted. The filtrate was concentrated under reduced pressure and the residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD Cl 8 Column, 30 x 150 mm, 5 pm; Mobile Phase A: Water (Plus 10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 36% B to 66% B in 7 min; Wave Length: 254 nm / 220 nm; RT1: 6.7 min. The fractions containing the desired product were combined and concentrated to afford the title compound (23.1 mg, 15%) as a white solid. MS ESI calculated for C28H31F2N7O2. [M + H]+, 536.25, found 536.40; 'H NMR (400 MHz, DMSO-t / 6) 8 9.72 (s, 1H), 8.00 (d, J= 2.4 Hz, 1H), 7.54 (d, J= 7.9 Hz, 1H), 7.29 (d, J= 11.4 Hz, 1H), 7.20 (d, J= 1.5 Hz, 1H), 6.37 (d, J= 1.6 Hz, 1H), 3.83 (t, J= 4.5 Hz, 4H), 3.48 (t, J= 4.7 Hz, 4H), 2.29 (s, 3H), 2.25-2.15 (m, 1H), 1.59 (d, J= 1.4 Hz, 9H), 1.04-0.96 (m, 4H);19F NMR (376 MHz, DMSO-t / 6) 8 -121.41, -122.98.

[0179] Example 13: N-(2-tert-butyl-l,2,3-triazol-4-yl)-2-fluoro-4-methyl-5-[2-methyl-8-(morpholin-4-yl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]benzamide

[0180] Step 1 : To a stirred mixture of ethyl 2- / / 7-butyl- l ,2,3-triazole-4-carboxylate (200 mg, 1.01 mmol) in THF (0.7 mL), MeOH (0.7 mL) and H2O (0.7 mL) was added L1OH H2O (148.92 mg, 3.55 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was acidified to pH 5 with diluted HC1 (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, ACN in Water (Plus 0.1% FA), 15% to 35% gradient in 10 min; detector, UV 254 nm. The fractions contained desired product were combined and contained to afford 2- / / 7-butyl- l ,2,3-triazole-4- carboxylic acid (139 mg, 73%) as a white solid. MS ESI calculated for C7H11N3O2 [M + H]+,170.09, found 170.18;JH NMR (400 MHz, Chloroform-^ / ) 8 8.12 (d, J= 1.8 Hz, 1H), 7.26 (d, J = 1.9 Hz, 1H), 1.73 (s, 9H).

[0181] Step 2: A solution of 2-terZ-butyl-l,2,3-triazole-4-carboxylic acid (500 mg, 2.96 mmol) in t-BuOH (6 mL) was added DPPA (1219.99 mg, 4.43 mmol) and TEA (1196.25 mg, 11.82 mmol) dropwise at room temperature. The reaction mixture was stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1). The fractions contained desired product were combined and concentrated to afford tert-butyl A-(2-tert-butyl-l ,2,3-triazol-4-yl)carbamate (600 mg, 68%) as a light yellow oil. MS ESI calculated for C11H20N4O2 [M + H]+, 241.16, found 241.20; 'H NMR (400 MHz, Chloroform- ) 8 7.75 (s, 1H), 6.97 (s, 1H), 1.62 (s, 9H), 1.53 (s, 9H).

[0182] Step 3: A solution of tert-butyl A-(2-tert-butyl-l,2,3-triazol-4-yl)carbamate (150 mg, 0.62 mmol) in DCM (0.5 mL) was added HC1 in EA (0.5 mL, 2.00 mmol, 4 M) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-tert-butyl-l,2,3-triazol-4-amine (130 mg, crude). The crude product was used in the next step directly without further purification. MS ESI calculated for C6H13CIN4 [M + H]+, 141.19, found 141.10.

[0183] Step 4: A solution of methyl 2-fluoro-4-methyl-5-[2-methyl-8-(morpholin-4-yl)- [l,2,4]triazolo[l,5-a]pyridin-6-yl]benzoate (200 mg, 0.52 mmol) in THF (1.5 mL), MeOH (1.5 ml) and water (1.5 mL) was added LiOH H2O (65.49 mg, 1.56 mmol) in portions at room temperature. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to afford 2-fluoro-4-methyl-5-[2-methyl-8- (morpholin-4-yl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]benzoic acid (280 mg, 87%) as an off-white solid. The crude product was used in the next step directly without further purification. MS ESI calculated for Cl 9H19FN4O3. [M + H]+, 371.38, found 371.30.

[0184] Step 5: A mixture of 2- / / 7-butyl- l ,2,3-triazol-4-amine (30 mg, 0.21 mmol) in Pyridine (2 mL) were added 2-fluoro-4-methyl-5-[2-methyl-8-(morpholin-4-yl)-[l,2,4]triazolo[l,5- a]pyridin-6-yl]benzoic acid (90 mg) in T3P (2 mL, 50% in EA) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel;mobile phase, MeCN in Water (plus 0.1% NH3 H2O), 35% to 65% gradient in 10 min; detector, UV 254 nm. The fractions containing the desired product were combined and concentrated to afford the title compound (15mg, 12%) as an off-white solid. MS ESI calculated for C25H29FN8O2. [M + H]+, 493.55, found 493.35; ' H NMR (400 MHz, DMSO-d6) 8 11.31 (s, 1H), 8.47 (d, J= 1.4 Hz, 1H), 7.99 (s, 1H), 7.67 (d, J= 7.4 Hz, 1H), 7.34 (d, J= 11.4 Hz, 1H), 6.77 (d, J= 1.5 Hz, 1H), 3.87-3.77 (m, 4H), 3.56 (t, J= 4.8 Hz, 4H), 2.48 (s, 3H), 2.36 (s, 3H), 1.60 (s, 9H), 1.24 (s, 1H);19F NMR (376 MHz, DMSO) 8 -115.97.

[0185] Example 16: l-(Tert-butyl)-N-(5-(2-ethyl-5-morpholino-[l,2,4]triazolo[l,5-a]pyridin-7- yl)-2-fluoro-4-methylphenyl)-5-fluoro-lH-pyrazole-4-carboxamide

[0186] Step 1: A mixture of l,2-diamino-4,6-dichloropyridin-l-ium 2,4,6- trimethylbenzenesulfonate (1.5 g, 3.97 mmol) and Cu(OAc)2 (0.36 g, 1.98 mmol) in AcOH (8 mL) and MeOH (4 mL) was added propionaldehyde (0.69 g, 11.90 mmol) drop wise at room temperature. The reaction mixture was degassed with nitrogen three times and stirred for 1 h at 70 °C under nitrogen atmosphere. The PH value of resulting mixture was adjusted to 7 with NaOH (IM aquoues solution). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (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 / EA (3 / 1). The fractions contained desired product were combined and concentrated to afford 5,7-dichloro-2-ethyl-[l,2,4]triazolo[l,5- a]pyridine (340 mg, 40%) as a yellow solid. MS ESI calculated for C8H7Q2N3 [M + H]+, 216.07, 218.07 found 216.25, 218.25.

[0187] Step 2: A solution of 5,7-dichloro-2-ethyl-[l ,2,4]triazolo[l ,5-a]pyridine (320 mg, 1.48 mmol) and K2CO3 (410 mg, 2.96 mmol) in DMSO (4 mL, 1.48 mmol) was added morpholine (130 mg, 1.48 mmol) at room temperature. The reaction mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash TM Cl 8-1, 20-40 pm, 80 g; Eluent A: Water (plus 10 mmol / L NH4HCO3); Eluent B: ACN; Gradient: 5% - 95% B in 30 min; Flow rate: 50 mL / min; Detector: 220 / 254 nm. The fractions contained desired product were combined and concentrated to afford 4-{7-chloro-2- ethyl-[l,2,4]triazolo[l,5-a]pyridin-5-yl}morpholine (230 mg, 58%) as a white solid. MS ESI calculated for C12H15CIN4O [M + H]+, 267.73, found 267.15; [M + H + 2]+, 269.73, found 269.15. 'H NMR (400 MHz, DMSO-t / 6) 8 7.45 (s, 1H), 6.52 (s, 1H), 3.81 (t, J = 4.4 Hz, 4H), 3.49 (t, J = 4.8 Hz, 4H), 2.82-2.69 (m, 2H), 1.30 (t, J = 7.6 Hz, 3H).

[0188] Step 3: A solution of 4-{7-chloro-2-ethyl-[l,2,4]triazolo[l,5-a]pyridin-5-yl}morpholine (175 mg, 0.66 mmol), K3PO4 (418 mg, 1.97 mmol) and 2-fhroro-4-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (198 mg, 0.79 mmol) in THF (2.5 mL) was added 2nd Generation XPhos precatalyst (52 mg, 0.07 mmol) at room temperature. The reaction mixture was degassed with nitrogen for 3 times and stirred for 2 h at 80 °C. The resulting mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 3). The fractions contained desired product were combined and concentrated to afford 5-[2- ethyl-5-(morpholin-4-yl)-[l,2,4]triazolo[l,5-a]pyridin-7-yl]-2-fluoro-4-methylaniline (150 mg, 64%) as a yellow solid. MS ESI calculated for C19H22FN5O [M + H]+, 356.18, found 356.35;1H NMR (400 MHz, Chloroform- ) 8 7.24 (d, J= 1.6 Hz, 1H), 6.94 (d, J= 11.6 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H), 6.24 (d, J= 1.6 Hz, 1H), 4.02 (t, J= 4.8 Hz, 4H), 3.56-3.49 (m, 4H), 3.00 (q, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.47 (t, J= 7.6 Hz, 3H).19F NMR (376 MHz, CDCI3) 8 -135.76 (IF).

[0189] Step 4: A solution of 5-[2-ethyl-5-(morpholin-4-yl)-[l,2,4]triazolo[l,5-a]pyridin-7-yl]- 2-fluoro-4-methylaniline (100 mg, 0.28 mmol) and propyl l-(tert-butyl)-5-fluoro-l / 7-pyrazole-4- carboxylate (78 mg, 0.34 mmol) in THF (1 mL) was added LiHMDS (1 mL, IM in THF) at 0 °C . The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched by add sat. NH4CI (aq.) at room temperature. The resulting mixturewas diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous ISfeSCE and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Prep-TLC with PE / EA / EtOH (8 / 3 / 1) to afford the crude product. The crude product was further purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash TM Cl 8-1, 20-40 pm, 40 g; Eluent A: Water (plus 10 mmol / L NH4HCO3); Eluent B: ACN; Gradient: 5%-95% B in 30 min; Flow rate: 30 mL / min; Detector: 220 / 254 nm; desired fractions were collected at 60% B and concentrated under reduced pressure. The fractions containing the desired product were combined and concentrated to afford the title compound (34.1 mg, 23%) as a white solid. MS ESI calculated for C27H3IF2N7O2 [M + H]+, 524.25, found 524.40; ' H NMR (400 MHz, DMSO- <7s) 8 9.72 (s, 1H), 8.00 (d, J= 2.4 Hz, 1H), 7.55 (d, J= 7.8 Hz, 1H), 7.30 (d, J= 11.6 Hz, 1H), 7.25 (d, J= 1.6 Hz, 1H), 6.39 (d, J= 1.6 Hz, 1H), 3.83 (t, J= 4.4 Hz, 4H), 3.49 (t, J= 4.8 Hz, 4H), 2.85 (q, J= 7.6 Hz, 2H), 2.30 (s, 3H), 1.57 (d, J= 1.4 Hz, 9H), 1.33 (t, J= 7.6 Hz, 3H).19F NMR (376 MHz, DMSO) 8 -121.40 (IF), -122.96 (IF).

[0190] Example 38: l-{Bicyclo[l. l.l]pentan-l-yl}-N-{5-[2-ethyl-5-(morpholin-4-yl)- [1 ,2,4]triazolo[l ,5-a]pyridin-7-yl]-2-fluoro-4-methylphenyl} -5-fluoropyrazole-4-carboxamide

[0191] Step 1: A solution of 1- {bicyclo [1.1.1 ] pentan- 1-yl} -5 -fhioropyrazole-4-carboxylic acid (8 mg, 0.04 mmol) in T3P (0.1 mL, 50% in EA) was added 5-[2-ethyl-5-(morpholin-4-yl)- [l,2,4]triazolo[l,5-a]pyridin-7-yl]-2-fluoro-4-methylaniline (15 mg, 0.04 mmol) and Pyridine (0.1 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XB ridge Prep OBD Cl 8 Column, 30 x 150mm, 5 m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 38% B to 68% B in 7 min; Wave Length: 254 nm / 220 nm; RT: 6.4 min. The fractions containing the desired product were combined and concentrated to afford the title compound (3.2 mg, 14%) as a white solid. MS ESI calculated for C28H29F2N7O2 [M + H]+, 534.24, found 534.40; 'H NMR (400 MHz, Chloroform- ) 8 8.34 (d, J= 4.2 Hz, 1H), 7.89-7.81 (m, 1H), 7.64 (s, 1H), 7.29-7.26 (m, 1H), 7.09 (s, 1H), 6.29-6.21 (m, 1H), 4.07-3.97 (m, 4H), 3.58-3.50 (m, 4H), 3.01-2.98 (m, 2H), 2.71-2.70 (m, 1H), 2.45-2.37 (m, 6H), 2.28-2.27 (m, 3H), 1.49-1.44 (m, 3H).19F NMR (376 MHz, CDCh) 8 -129.15 (IF), -132.77 (IF).

[0192] Example 88: l-Tert-butyl-5-fluoro-N-{2-fluoro-4-methyl-5-[l-(l-methylazetidin-3-yl)- 7-(morpholin-4-yl)indazol-5-yl]phenyl}pyrazole-4-carboxamide

[0193] Step 1: A mixture of 5-chloro-7-(morpholin-4-yl)-27 / -indazole (1 g, 4.21 mmol) and CS2CO3 (2.74 g, 8.41 mmol) in DMF (14 mL) was added tert-butyl 3 -iodoazetidine- 1 - carboxylate (1.19 g, 4.21 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 80 °C. The resulting mixture was diluted with water (70 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SC>4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1). The fractions contained desired product were combined and concentrated to afford tertbutyl 3-[5-chloro-7-(morpholin-4-yl)indazol-l-yl]azetidine-l-carboxylate (700 mg, 42%) as a white solid. MS ESI calculated for C19H25CIN4O3. [M + H]+, 393.16, found 393.20. 'H NMR (400 MHz, CDCh) 8 8.06 (d, J= 0.6 Hz, 1H), 7.46 (d, J= 1.8 Hz, 1H), 7.02 (d, J= 1.8 Hz, 1H),6.30 (t, J= 5.6 Hz, 1H), 4.50 (dd, J= 8.8, 5.6 Hz, 2H), 4.40-4.31 (m, 2H), 4.04 (d, J= 11.3 Hz, 2H), 3.89 (d, J= 10.4 Hz, 2H), 3.08-2.97 (m, 4H), 1.50 (s, 9H).

[0194] Step 2: A solution of tert-butyl 3-[5-chloro-7-(morpholin-4-yl)indazol-l-yl]azetidine-l- carboxylate (350 mg, 0.89 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0 °C . The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford l-(azetidin-3-yl)-5-chloro-7-(morpholin-4-yl)indazole (250 mg, 95%) as a light yellow solid that was used in the next step without further purification. MS ESI calculated for C14H17CIN4O. [M + H]+, 293.11, found 293.15.

[0195] Step 3: A mixture of l-(azetidin-3-yl)-5-chloro-7-(morpholin-4-yl)indazole (150 mg, 0.51 mmol), l-tert-butyl-5-fluoro-A-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]pyrazole-4-carboxamide (150.37 mg, 0.36 mmol) and K3PO4 (217.51 mg, 1.02 mmol) in THF (2 mL) and water (0.2 mL) was added 2nd Generation XPhos precatalyst (40.31 mg, 0.05 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen three times and stirred for 1 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 CTECh / MeOH (5 / 1). The fractions containing the desired product were combined and concentrated to afford the title compound (220 mg, 73%) as a brown solid. MS ESI calculated for C29H33F2N7O2. [M + H]+, 550.27, found 550.30.XH NMR (400 MHz, CDC13) 8 8.31 (d, J= 8.1 Hz, 1H), 8.14 (s, 1H), 7.83 (d, J= 2.6 Hz, 1H), 7.68 (s, 1H), 7.41 (s, 1H), 7.07 (d, J= 13.1 Hz, 2H), 6.68 (s, 1H), 4.66 (s, 2H), 4.41-4.22 (m, 2H), 4.03 (s, 4H), 3.04 (s, 5H), 2.24 (s, 3H), 1.77-1.53 (m, 9H).19F NMR (377 MHz, CDCI3) 8 -122.79, -134.37.

[0196] Step 4: A mixture of 7V-{5-[l-(azetidin-3-yl)-7-(morpholin-4-yl)indazol-5-yl]-2-fluoro- 4-methylphenyl}- l - / / 7-butyl-5-fluoropyrazole-4-carboxamide (80 mg, 0.15 mmol) and NaBH(OAc)3 (61.70 mg, 0.25 mmol) in THF (1.5 mL) was added formaldehyde (17.72 mg, 0.45 mmol, 37%) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (Plus 10 mmol / L NH4HCO3), 50% to 70% gradient in 10 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford l-tert-butyl-5-fluoro-7V-{2-fluoro-4-methyl-5-[l-(l-methylazetidin-3-yl)-7-(morpholin-4-yl)indazol-5-yl]phenyl}pyrazole-4-carboxamide as a white solid. The crude product (60 mg) was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 pm; Mobile Phase A: Water (Plus 10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 67% B in 7 min; Wave Length: 220 nm; RT1: 6.5 min. The fractions containing the desired product were combined and concentrated to afford the title compound (32.7 mg, 39.26%) as a white solid. MS ESI calculated for C30H35F2N7O2. [M + H]+, 564.28, found 564.50. ' H NMR (400 MHz, DMSO- d6) 5 9.66 (s, 1H), 8.21 (s, 1H), 8.00 (d, J= 2.5 Hz, 1H), 7.49-7.40 (m, 2H), 7.25 (d, J= 11.5 Hz, 1H), 7.01 (d, J= 1.5 Hz, 1H), 6.12 (d, J= 7.2 Hz, 1H), 3.94 (s, 2H), 3.79 (t, J= Hz, 4H), 3.56 (t, J= 7.2 Hz, 2H), 3.02 (s, 2H), 2.94 (d, J= 11.5 Hz, 2H), 2.40 (s, 3H), 2.24 (s, 3H), 1.57 (d, J= 1.5 Hz, 9H).19F NMR (377 MHz, DMSO-6) 8 -121.48, -124.71.

[0197] Example 89: l-Tert-butyl-5-fluoro-N-{2-fluoro-4-methyl-5-[l-(l-methylpiperidin-4-yl)- 7-(morpholin-4-yl)indazol-5-yl]phenyl}pyrazole-4-carboxamide

[0198] Step 1: A solution of 4-(5-chloro-lTLindazol-7-yl)morpholine (1 g, 4.21 mmol) and CS2CO3 (0.96 g, 12.62 mmol) in DMF (12 mL) was added Tert-butyl 4-iodopiperidine-l- carboxylate (1.57 g, 5.05 mmol) at room temperature. The reaction mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 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 / EA (2 / 1) to afford Tert-butyl 4-[5-chloro-7-(morpholin-4-yl)indazol-l-yl]piperidine-l-carboxylate (420 mg,23.72%) as a white solid and Tert-butyl 4-[5-chloro-7-(morpholin-4-yl)indazol-2-yl]piperidine- 1 -carboxylate (1 g, 56.47%) as a pink solid. MS ESI calculated for C21H29CIN4O3. [M + H]+, 421.19, found 421.20;1H NMR (400 MHz, CDCl3-t / ) 8 7.92 (s, 1H), 7.42 (d, J= 1.7 Hz, 1H), 7.01 (d, J= 1.8 Hz, 1H), 5.39 (t, J = 11.5, 1H), 4.31 (d, J= 12.5 Hz, 2H), 4.01-3.89 (m, 2H), 3.81-3.76 (m, 2H), 3.06-2.99 (m, 4H), 2.89 (t, J= 13.1 Hz, 2H), 2.18-2.01 (m, 2H), 1.93-1.82 (m, 2H), 1.47 (s, 9H).

[0199] Step 2: A solution of Tert-butyl 4-[5-chloro-7-(morpholin-4-yl)indazol-l-yl]piperidine- 1 -carboxylate (150 mg, 0.356 mmol), 1 -Ter / -butyl-5-fluoro- / V-[2-fluoro-4-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carboxamide (149.41 mg, 0.356 mmol) and K3PO4 (151.28 mg, 0.712 mmol) in THF (2 mL) and H2O (0.2 mL) was added 2nd Generation XPhos Precatalyst / X-Phos aminobiphenyl palladium chloride precatalyst (28.04 mg, 0.036 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 3 times and stirred for 16 h at 80 °C. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (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 / EA (1 / 1) to afford Tert-butyl 4- [5-[5-( l - / e / 7-butyl-5- fluoropyrazole-4-amido)-4-fluoro-2-methy Ipheny 1] -7 -(morpholin-4-yl)indazol- 1 -yl } piperidine- 1 -carboxylate (200 mg, 83%) as an off-white solid. MS ESI calculated for C36H45F2N7O4. [M + H - B°C ]+, 578.35, found 578.35; 'H-NMR (400 MHz, CDCh-t / ) 8 8.32 (d, J= 8.2 Hz, 1H), 8.04 (s, 1H), 7.84 (d, J= 2.6 Hz, 1H), 7.68 (t, J= 4.1 Hz, 1H), 7.48-7.40 (m, 1H), 7.14-7.03 (m, 2H), 5.54-5.47(m, 1H), 4.37 (s, 2H), 4.09-4.00 (m, 2H), 3.94-3.76 (m, 2H), 3.17-3.04 (m, 4H), 2.96 (s, 2H), 2.27 (s, 4H), 1.99 (d, J= 12.7 Hz, 2H), 1.68 (d, J= 1.6 Hz, 9H), 1.52 (s, 10H).

[0200] Step 3: A solution of Tert-butyl 4-{5-[5-(l-tert-butyl-5-fluoropyrazole-4-amido)-4- fluoro-2-methylphenyl]-7-(morpholin-4-yl)indazol-l-yl}piperidine-l-carboxylate (180 mg, 0.27 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with DCM (10 mL). The resulting mixture was washed with saturated NaHCO? (aq.) (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford I - / c / 7-butyl-5-fluoro-A- [2-fluoro- 4-methyl-5-[7-(morpholin-4-yl)-l-(piperidin-4-yl)indazol-5-yl]phenyl}pyrazole-4-carboxamide(130 mg) as a yellow solid which was used in the next step directly without further purification. MS ESI calculated for C31H37F2N7O2. [M + H]+, 578.30, found 578.35.

[0201] Step 4: A solution of l -7l77-butyl-5-fluoro-A- [2-fluoro-4-methyl-5-[7-(morpholin-4- yl)-l-(piperidin-4-yl)indazol-5-yl]phenyl}pyrazole-4-carboxamide (130 mg, 0.23 mmol) and NaBH(OAc)3 (71.54 mg, 0.34 mmol) in THF (2 mL) was stirred for 15 min at room temperature under nitrogen atmosphere. To the above reaction mixture was added formaldehyde (67.57 mg, 0.68 mmol, 30%) dropwise over 1 min at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 2). The fractions containing the desired product were combined and concentrated to afford the title compound (75.5 mg, 55.74%) as a white solid. MS ESI calculated for C32H39F2N7O2. [M + H]+, 592.31, found 592.55;1H-NMR (400 MHz, DMSO-6) 8 9.66 (s, 1H), 8.13 (s, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.25 (d, J= 11.5 Hz, 1H), 7.08 (d, J= 1.5 Hz, 1H), 5.32 (s, 1H), 3.94 (d, J= 10.8 Hz, 2H), 3.76 (m, 2H), 3.09-2.93 (m, 6H), 2.30 (s, 3H), 2.25 (s, 3H), 2.19 (t, J= 8.8 Hz, 4H), 1.92 (d, J= 8.8 Hz, 2H), 1.57 (d, J = 1.4 Hz, 9H).19F NMR (376 MHz, DMSO-t / g) 8 -121.53, -122.97.

[0202] Example 90: l-Tert-butyl-5-fluoro-N-(2-fluoro-4-methyl-5-{l-[(3S)-l-methylpiperidin- 3-yl]-7-(morpholin-4-yl)indazol-5-yl}phenyl)pyrazole-4-carboxamide

[0203] Step 1 : A mixture of 7-bromo-5-chloro-17 / -indazole (10 g, 43.20 mmol) in LiHMDS (150 mL) was added morpholine (3.76 g, 43.20 mmol) and l-chloro-l-[dicyclohexyl([2-[2,4,6- tris(propan-2-yl)phenyl]phenyl])-lA[5]-phosphanyl]-2 / 7,3 / 7,4 / 7-benzo[c] l -aza-2- palladacyclohexane (1.28 g, 1.73 mmol) at room temperature under nitrogen atmosphere. Thereaction mixture was degassed with nitrogen 3 times and stirred for 1 h at 65 °C. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0% to 50% EtOAc in PE. The fractions contained desired product were combined and concentrated to afford 5-chloro-7-(morpholin-4-yl)- l / / -indazole (8 g, 76%) as a brown solid. MS ESI calculated for C11H12CIN3O. [M + H]+, 238.69, found 238.10.

[0204] Step 2: A mixture of 5-chloro-7-(morpholin-4-yl)-l / 7-indazole (1 g, 4.21 mmol) and tert-butyl (3A)-3-(methanesulfonyloxy)piperidine-l -carboxylate (2.35 g, 8.41 mmol) in DMF (10 mL) was added CS2CO3 (4.11 g, 12.62 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 2 h. The resulting mixture was extracted with EtOAc (3 x 100 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 / EA (2 / 1). The fractions contained desired product were combined and concentrated to afford tert-butyl (3S)-3-[5-chloro-7-(morpholin-4- yl)indazol-l-yl]piperidine-l-carboxylate (320 mg, 17%) as a white solid. MS ESI calculated for C21H29CIN4O3. [M + H]+, 421.94, found 421.30. 'H NMR (400 MHz, Chloroform- ) 8 7.96 (s, 1H), 7.46 (d, J= 1.8 Hz, 1H), 7.04 (d, J= 1.8 Hz, 1H), 5.44-5.29 (m, 1H), 4.19 (d, J= 12.5 Hz, 1H), 4.08-3.93 (m, 2H), 3.89-3.71 (m, 4H), 3.17-2.96 (m, 4H), 2.89-2.75 (m, 1H), 2.24 (m, 1H), 2.15-2.06 (m, 1H), 1.92-1.84 (m, 1H), 1.66-1.59 (m, 1H), 1.47 (s, 9H).

[0205] Step 3: A mixture of tert-butyl (35)-3-[5-chloro-7-(morpholin-4-yl)indazol-l- yl]piperidine-l -carboxylate (100 mg, 0.24 mmol) and l-tert-butyl-5-fluoro-A-[2-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carboxamide (109.57 mg, 0.26 mmol) in THF (2 mL) and H2O (0.2 mL) was added X-Phos aminobiphenyl palladium chloride precatalyst (37.38 mg, 0.05 mmol) and K3PO4 (151.28 mg, 0.71 mmol) at room temperature. The reaction mixture was degassed with nitrogen three times and stirred at 80 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1). The fractions contained desired product were combined and concentrated to afford tert-butyl (38)-3-{5-[5-(l-tert-butyl-5- fluoropyrazole-4-amido)-4-fluoro-2-methy Ipheny 1] -7 -(morpholin-4-yl)indazol- 1 -yl } piperidine- 1 -carboxylate (190 mg, 96%) as a yellow solid. MS ESI calculated for C36H45F2N7O4. [M + H]+,678.79, found 678.35; 'H NMR (400 MHz, Chloroform-^ / ) 8 8.32 (d, J= 8.2 Hz, 1H), 8.04 (s, 1H), 7.84 (d, J= 2.6 Hz, 1H), 7.67 (s, 1H), 7.43 (d, J= 1.4 Hz, 1H), 7.07 (dd, J= 6.7, 5.2 Hz, 2H), 4.22 (s, 1H), 4.01 (d, J= 11.2 Hz, 2H), 3.90-3.76 (m, 2H), 3.30 (s, 1H), 3.18-3.01 (m, 3H), 2.85 (t, J= 12.8 Hz, 1H), 2.26 (s, 1H), 2.18 (d, J= 12.7 Hz, 1H), 2.07 (s, 1H), 1.96 (s, 4H), 1.49 (s, 10H), 1.29 (d, J= 7.1 Hz, 1H), 1.26 (s, 10H).

[0206] Step 4: A solution of tert-butyl (35)-3-{5-[5-(l-tert-butyl-5-fluoropyrazole-4-amido)-4- fluoro-2-methylphenyl]-7-(morpholin-4-yl)indazol-l-yl}piperidine-l-carboxylate (10 mg, 0.02 mmol) in DCM (2 mL) was added HC1 (gas) in 1,4-dioxane (2 mL, 65.83 mmol) dropwise at room temperature. The reaction mixture was stirred at rt for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water and basified to pH 8 with saturated NaHCO? (aq.). The resulting mixture was extracted with CH2Q2 (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous ISfeSCL. After filtration, the filtrate was concentrated under reduced pressure. The fractions contained desired product were combined and concentrated to afford l - / r 7-butyl-5-fluoro-A- [2-fluoro-4- methyl-5-[7-(morpholin-4-yl)-l-[(35)-piperidin-3-yl]indazol-5-yl]phenyl}pyrazole-4- carboxamide (120 mg, 66%) as an off-white solid. MS ESI calculated for C31H37F2N7O2. [M + H]+, 578.68, found 578.30.

[0207] Step 5: A solution of l-tert-butyl-5-fluoro-A-{2-fluoro-4-methyl-5-[7-(morphohn-4-yl)- l-[(35)-piperidin-3-yl]indazol-5-yl]phenyl}pyrazole-4-carboxamide (120 mg, 0.21 mmol) and NaBH(OAc)3 (66.04 mg, 0.31 mmol) in THF (2 mL) was added formaldehyde (9.36 mg, 0.31 mmol) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with QLCh / MeOH (10 / 1). The fractions containing the desired product were combined and concentrated to afford the title compound (59.8 mg, 47%) as a white solid. MS ESI calculated for C32H39F2N7O2. [M + H]+, 592.70, found 592.55;XH NMR (400 MHz, DMSO-t / 6) 8 9.66 (s, 1H), 8.12 (s, 1H), 8.00 (d, J= 2.5 Hz, 1H), 7.50-7.41 (m, 2H), 7.25 (d, J= 11.6 Hz, 1H), 7.07 (d, J= 1.5 Hz, 1H), 5.47 (s, 1H), 3.93 (d, J = 10.9 Hz, 2H), 3.74 (t, J= 11.0 Hz, 2H), 3.11-3.00 (m, 3H), 2.97 (s, 3H), 2.85 (s, 1H), 2.26 (s, 4H), 2.02 (s, 1H), 1.95-1.84 (m, 2H), 1.82 (s, 1H), 1.76-1.63 (m, 1H), 1.57 (d, J= 1.4 Hz, 9H), 1.24 (s, 1H);19F NMR (377 MHz, DMSO) 8 -121.48, -124.60, -124.84;19F NMR (376 MHz, DMSO-t / g) 8 -121.48, -121.84.

[0208] Example 91: (R)-l-(tert-butyl)-5-fluoro-N-(2-fluoro-4-methyl-5-(l-(l-methylpiperidin-3 -yl)-7-morpholino- 1 H-indazol-5 -yl)phenyl)- 1 H-pyrazole-4-carboxamide

[0209] Step 1: A mixture of tert-butyl (35)-3-(methanesulfonyloxy)piperidine-l -carboxylate (2.35 g, 8.41 mmol), 5-chloro-7-(morpholin-4-yl)-177-indazole (1 g, 4.20 mmol) and CS2CO3 (4.11 g, 12.62 mmol) in DMF (10 mL) was stirred for 4 h at 80 °C under air atmosphere. The resulting mixture was poured into H2O (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1). Fractions containing Peak 1 were combined and concentrated to afford tert-butyl ( / ?)-3-(5-chloro-7-morpholino-2H-indazol-2- yl)piperidine-l -carboxylate (760 mg, 42%) as a light-pink solid. MS ESI calculated for C21H31CIN4O3 [M + H]+, 423.21, found 423.40; The slower peak 2 contained desired product were combined and concentrated to afford tert-butyl ( / ?)-3-(5-chloro-7-morpholino-l / 7-indazol- l-yl)piperidine-l -carboxylate (360 mg, 19%) as a yellow solid. MS ESI calculated for C21H31CIN4O3 [M + H]+, 421.21, found 421.40.

[0210] Step 2: To a mixture of tert-butyl (37?)-3-[5-chloro-7-(morpholin-4-yl)indazol-l- yl]piperidine-l -carboxylate (100 mg, 0.24 mmol), l-tert-butyl-5-fluoro-N-[2-fluoro-4-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carboxamide (99.61 mg, 0.24 mmol), in THF (1.2 mL) and H2O (0.3 mL) were added 2nd Generation XPhos Precatalyst / X- Phos aminobiphenyl palladium chloride precatalyst (18.69 mg, 0.02 mmol) and K3PO4 (151.28 mg, 0.71 mmol). The resulting mixture was degassed with nitrogen for three times and stirred for 1 h at 80 °C. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3x 10 mL). The combined organic layers were washed with brine (3 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 / EA (1 / 1) and concentrated under reduce pressure to afford tert-butyl ( / ?)-3-(5-(5-( l -( / c / 7-butyl)-5-fluoro-l / 7- pyrazole-4-carboxamido)-4-fluoro-2-methylphenyl)-7-morpholino-l / f-indazol-l-yl)piperidine-l- carboxylate (180 mg) as a light yellow solid. MS ESI calculated for C36H45F2N7O4 [M + H]+, 678.35, found 678.60.

[0211] Step 3: To a solution of tert-butyl (A)-3-(5-(5-(l-(tert-butyl)-5-fluoro-l / 7-pyrazole-4- carboxamido)-4-fluoro-2-methylphenyl)-7-morpholino-l / 7-indazol- l -yl)piperidine-l -carboxylate (180 mg, 0.27 mmol) in DCM (2 mL) was added HC1 (gas) in 1,4-di oxane (2 mL, 65.83 mmol) dropwised for 1 min at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was poured into NaHCO? (sat. aq. 5 mL) and extracted with CH2Q2 (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford (7?)-l-(terZ-butyl)-5-fluoro-7V-(2-fluoro-4-methyl-5-(7-morpholino-l-(piperidin-3-yl)-l / 7- indazol-5-yl)phenyl)-17 / -pyrazole-4-carboxamide (110 mg, 71%) as a colorless solid. MS ESI calculated for C31H37F2N7O2 [M + H]+, 578.55, found 578.55. 'H NMR (400 MHz, Chloroform- d) 8 8.32 (d, J= 8.2 Hz, 1H), 8.03 (s, 1H), 7.84 (d, J= 2.6 Hz, 1H), 7.68 (s, 1H), 7.43 (d, J= 1.4 Hz, 1H), 7.12-7.04 (m, 2H), 5.58 (s, 1H), 4.03 (d, J= 10.8 Hz, 3H), 3.95-3.89 (m, 1H), 3.44 (d, J = 9.4 Hz, 2H), 3.22 (d, J= 12.3 Hz, 1H), 3.09 (d, J= 5.0 Hz, 4H), 2.98 (s, 1H), 2.27 (s, 3H), 2.20 (d, J= 4.7 Hz, 1H), 1.96 (d, J= 14.0 Hz, 2H), 1.86-1.76 (m, 2H), 1.68 (d, J= 1.6 Hz, 9H).

[0212] Step 4: To a mixture of l-tert-butyl-5-fluoro-A-{2-fluoro-4-methyl-5-[7-(morphohn-4- yl)-l-[(3A)-piperidin-3-yl]indazol-5-yl]phenyl}pyrazole-4-carboxamide (100 mg, 0.17 mmol) and NaBH(OAc)3 (73.38 mg, 0.35 mmol) in THF (0.5 mL) was added formaldehyde (0.78 mg, 0.03 mmol) dropwise at room temperature. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CTECh / MeOH (10 / 1) to afford the crude product (95 mg) as a light-yellow solid which was further purified by reverse-phase flash chromatography with following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 50% to 80% gradient in 10 min; detector, UV 254 nm. The fractions containing the desired product were combined and concentrated to afford the titlecompound (50 mg, 47%) as a white solid. MS ESI calculated for C32H39F2N7O2 [M + H]+, 592.55, found 592.55. 'H NMR (400 MHz, DMSO-t / 6) 8 9.66 (s, 1H), 8.11 (s, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.50-7.41 (m, 2H), 7.25 (d, J= 11.6 Hz, 1H), 7.07 (d, J= 1.4 Hz, 1H), 5.47 (t, J = 11.0 Hz, 1H), 3.93 (d, J= 11.0 Hz, 2H), 3.74 (t, J= 10.9 Hz, 2H), 3.10-2.91 (m, 5H), 2.85 (d, J = 10.9 Hz, 1H), 2.34 (t, J= 10.5 Hz, 1H), 2.25 (d, J = 7.6 Hz, 6H), 2.03 (d, J= 11.9 Hz, 1H), 1.97- 1.79 (m, 3H), 1.70 (t, J= 12.8 Hz, 1H), 1.57 (d, J= 1.5 Hz, 9H).

[0213] Example 93 and 94: l-(tert-butyl)-5-fluoro-N-(2-fluoro-4-methyl-5-(l-(l- methylpyrrolidin-3-yl)-7-morpholino-lH-indazol-5-yl)phenyl)-lH-pyrazole-4-carboxamide

[0214] Step 1: To a mixture of tert-butyl 3 -bromopyrrolidine- 1 -carboxylate (1.58 g, 6.31 mmol), 5-chloro-7-(morpholin-4-yl)-17 / -indazole (1 g, 4.21 mmol) in DMF (15 mL) was added CS2CO3 (4.11 g, 12.62 mmol) and ther reaction mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 60 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 / EA (1 / 1) to afford tert-butyl 3-[5-chloro-7-(morpholin-4-yl)indazol-l-yl]pyrrolidine-l-carboxylate (520 mg, 27%) as a colorless oil and tert-butyl 3-[5-chloro-7-(morpholin-4-yl)indazol-2-yl]pyrrolidine-l- carboxylate (1.06 g, 55%) as a colorless oil. MS ESI calculated for C20H27C1N4O3 [M + H]+, 407.35, found 407.20, 407.15.

[0215] Step 2: To a mixture of tert-butyl 3-[5-chloro-7-(morpholin-4-yl)indazol-l- yl]pyrrolidine-l -carboxylate (300 mg, 0.74 mmol), l-tert-butyl-5-fluoro-A-[2-fluoro-4-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carboxamide (309.12 mg, 0.74mmol) in THF (1.6 mL) and H2O (0.4 mL) were added 2nd Generation XPhos Precatalyst / X- Phos aminobiph (58.01 mg, 0.07 mmol) and KsPO4 (312.99 mg, 1.47 mmol). The reaction mixture was degassed with nitrogen three times and stirred for 1 h at 80 °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 Na2SO-i. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) and concentrated under reduced pressure. The fractions contained desired product were combined and concentrated to afford tert-butyl 3-{5-[5-(l-tert-butyl-5- fluoropyrazole-4-amido)-4-fluoro-2-methylphenyl]-7-(morphohn-4-yl)indazol-l-yl} pyrrolidine- 1 -carboxylate (480 mg, 88%) as a light yellow solid. MS ESI calculated for C35H43F2N7O4 [M + H]+, 664.05, found 664.20; ' H NMR (400 MHz, DMSO-t / 6) 8 9.66 (s, 1H), 8.15 (s, 1H), 8.00 (d, J= 2.5 Hz, 1H), 7.50-7.44 (m, 2H), 7.25 (d, J= 11.5 Hz, 1H), 7.11 (d, J= 1.5 Hz, 1H), 6.07 (s, 1H), 3.89 (d, J= 7.9 Hz, 2H), 3.83-3.71 (m, 3H), 3.58 (d, J= 10.7 Hz, 2H), 3.47 (s, 1H), 3.12- 2.90 (m, 4H), 2.45-2.34 (m, 1H), 2.25 (s, 4H), 1.57 (d, J = 1.5 Hz, 9H), 1.41 (d, J= 17.8 Hz, 9H).

[0216] Step 3: To a solution of tert-butyl 3-{5-[5-(l-tert-butyl-5-fluoropyrazole-4-amido)-4- fluoro-2-methylphenyl]-7-(morpholin-4-yl)indazol-l-yl}pyrrolidine-l -carboxylate (460 mg, 0.69 mmol) in DCM (6 mL) was added TFA (3 mL, 40.39 mmol) dropwise at room temperature under air atmosphere. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 mL) and neutralized to pH 7 with saturated NaHCO? (aq.). 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 to afford l-tert-butyl-5-fluoro-A-{2-fluoro-4-methyl-5-[7-(morpholin-4-yl)-l- (pyrrolidin-3-yl)indazol-5-yl]phenyl}pyrazole-4-carboxamide (400 mg, 92%) as a light yellow solid. MS ESI calculated for C30H35F2N7O2 [M + H]+, 564.45, found 564.28.

[0217] Step 4: To a solution of l-tert-butyl-5-fluoro-A-{2-fluoro-4-methyl-5-[7-(morpholin-4- yl)-l-(pyrrolidin-3-yl)indazol-5-yl]phenyl}pyrazole-4-carboxamide (380 mg, 0.67 mmol) in THF (0.5 mL) was added NaBH(OAc)3 (285.77 mg, 1.35 mmol) for 1 min at room temperature. To the above mixture was added formaldehyde (82.07 mg, 1.01 mmol) dropwise. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CThCb / MeOH (10 / 1) to afford the crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: XB ridge Prep OBD Cl 8 Column, 30 x 150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 47% B to 61% B in 10 min; Wave Length: 220 nm; RT1: 9.65 min. The fractions contained desired product were combined and concentrated to afford l-tert-butyl-5-fluoro-A-{2-fluoro-4-methyl-5-[l-(l-methylpyrrohdin-3- yl)-7-(morpholin-4-yl)indazol-5-yl]phenyl}pyrazole-4-carboxamide (160 mg, 39%) as a white solid. MS ESI calculated for C31H37F2N7O2 [M + H]+, 578.55, found 578.26.

[0218] Step 5: l-tert-butyl-5-fluoro-A-{2-fluoro-4-methyl-5-[l-(l-methylpyrrolidin-3-yl)-7- (morpholin-4-yl)indazol-5-yl]phenyl}pyrazole-4-carboxamide (160 mg) was sepatated by Prep- SFC with the following conditions: Column: CHIRAL ART Cellulose-SZ 3 x 25 cm, 5 m; Mobile Phase A: CO2, Mobile Phase B: MeOH(l%-2 M-NHs-MeOH); Flow rate: 85 mL / min; Gradient: isocratic 46% B; Column Temperature: 35 °C ; Back Pressure(bar): 100; Wave Length: 220 nm; RT1 : 11.83 min; Sample Solvent: MEOH.

[0219] The fractions containing peak 1 were concentrated to afford the title compound (64 mg, 39%) as a white solid. MS ESI calculated for C31H37F2N7O2 [M + H]+, 578.30, found 578.55. ' H NMR (400 MHz, DMSO-t / 6) 8 9.66 (s, 1H), 8.16 (s, 1H), 8.00 (d, J= 2.5 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.25 (d, J= 11.5 Hz, 1H), 7.04 (d, J= 1.4 Hz, 1H), 6.12 (p, J= 6.6 Hz, 1H), 3.94 (d, J = 11.1 Hz, 2H), 3.73-3.65 (m, 2H), 3.16-3.03 (m, 3H), 2.95-2.84 (m, 2H), 2.81-2.70 (m, 1H), 2.69 (dd, J= 8.9, 6.6 Hz, 2H), 2.33 (s, 4H), 2.25 (s, 3H), 2.22-2.14 (m, 1H), 1.57 (d, J= 1.4 Hz, 9H).

[0220] The fractions containing peak 2 were concentrated to afford the title compound (60.2 mg, 37%) as a white solid. MS ESI calculated for C31H37F2N7O2 [M + H]+, 578.55, found 578.60.1H NMR (400 MHz, DMSO-d6) 8 9.66 (s, 1H), 8.16 (s, 1H), 8.00 (d, J= 2.5 Hz, 1H), 7.50-7.41 (m, 2H), 7.25 (d, J= 11.5 Hz, 1H), 7.04 (d, J= 1.4 Hz, 1H), 6.12-6.09 (m, 1H), 3.94 (d, J= 11.1 Hz, 2H), 3.73-3.69 (m, 2H), 3.16-3.03 (m, 3H), 2.95-2.86 (m, 2H), 2.79-2.70 (m, 1H), 2.69 (dd, J= 8.9, 6.6 Hz, 2H), 2.33 (s, 4H), 2.25 (s, 3H), 2.22-2.14 (m, 1H), 1.57 (d, J= 1.4 Hz, 9H).

[0221] Examples 1, 2, 4, 5, 7-12, 14, 15, 17-37, 39-87, and 92 were prepared following the examples provided above with the substitution of the appropriate starting materials. Mass spectrum data for these compounds is provided in Table 1.II. Biological Evaluation

[0222] Example 1 : Kinase assay protocol

[0223] Small molecule inhibition of the BRAF kinase was measured using ADP-Glo assay. In the assay, ADP is converted to ATP in the presence of test kinase and substrate, resulting in luciferase reaction and luminescent readout with light generated proportional to the relative kinase activity. Compounds diluted in DMSO were used in 10-point, 3-fold dose curve for both assays. Final concentrations of 6 nM BRAF (CarnaBio, Cat. 09-122) and 30 nMMEKl substrate (Millipore, Cat. 14-420) were incubated with 3 pM ATP, 10 mM MgCh, 0.003% Brij-35, 2 mM DTT, 0.05% BSA, 1 mM EGTA, and 50 mM HEPES for 90 minutes at room temp prior to addition of ADP-Glo reagent (Promega, Cat. V9102) for 40 minutes, and detection reagent for 45 minutes. Luminescence was read on an Envision plate reader (PerkinElmer) and percent remaining activity was used to calculate IC50 using a four-parameter fit model using Dotmatics Knowledge Solutions Studies curve fitting (Dotmatics, Bishops Stortford, UK, CM23). Representative data for exemplary compounds is presented in Table 2. Table 2Note: Biochemical assay IC50data are designated within the following ranges:A: < 0.001 pM C: > 0.010 pM to < 0.100 pMB: > 0.001 pM to < 0.010 pM D: > 0.100 pM to < 1 pMIII. Preparation of Pharmaceutical Dosage Forms

[0224] Example 1 : Oral capsule

[0225] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

[0226] Example 2: Solution for injection

[0227] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq / mL.

[0228] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS1. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein,R is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; andW is an optionally substituted nitrogen-containing heterocyclyl, optionally substituted nitrogen-containing heteroaryl, optionally substituted aryl, optionally substituted nitrogencontaining heterocyclyl further substituted with an optionally substituted cycloalkyl, optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl, or optionally substituted aryl further substituted with an optionally substituted cycloalkyl.

2. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted heterocyclyl.

3. The compound of claim 2, or pharmaceutically acceptable salt or solvate thereof, wherein R is a nitrogen-containing optionally substituted heterocyclyl, preferably a 4-, 5-, or 6- membered nitrogen-containing optionally substituted heterocyclyl.

4. The compound of claim 3, or pharmaceutically acceptable salt or solvate thereof, wherein the 4-, 5-, or 6-membered nitrogen-containing optionally substituted heterocyclyl is a 4-, 5- , or 6-membered nitrogen-containing heterocyclyl substituted with an optionally substituted alkyl, preferably an alkyl.

5. The compound of any one of claims 1 to 4, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted nitrogen-containing heterocyclyl, optionally substituted nitrogen-containing heteroaryl, optionally substituted nitrogen-containing heterocyclyl further substituted with an optionally substituted cycloalkyl, or optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl.

6. The compound of claim 5, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted nitrogen-containing heteroaryl, or optionally substituted nitrogen-containing heteroaryl further substituted with an optionally substituted cycloalkyl, wherein the nitrogen-containing heteroaryl is selected from pyridyl, pyrimidyl, triazinyl, pyrazyl, pyrrolyl, imidazyl, triazyl, oxazyl, tetrazyl, oxadiazyl, and thiazyl.

7. The compound of of claim 6, or pharmaceutically acceptable salt or solvate thereof, wherein the nitrogen-containing heteroaryl is selected from pyrazyl, and oxazyl, in particular from pyraz-4-yl, and oxaz-5-yl.

8. The compound of claim 5, or pharmaceutically acceptable salt or solvate thereof, wherein W is an optionally substituted nitrogen-containing heterocyclyl, or optionally substituted nitrogen-containing heterocyclyl further substituted with an optionally substituted cycloalkyl, wherein the nitrogen-containing heterocyclyl is selected from pyrrolidine, 2,3- dihydro-lH-pyrrole, 2,5-dihydro-lH-pyrrole, piperidine, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, morpholine, and piperazine.

9. The compound of claim 5, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from:wherein Ri, R2, and R3 independently are selected from hydrogen, halo, alkyl, fluoroalkyl and optionally substituted cycloalkyl, wherein the optionally substituted cycloalkyl is a cycloalkyl optionally substituted with one or several, in particular 1, or 2, substituents selected from halo, alkyl, and fluoroalkyl.

10. The compound of claim 9, or pharmaceutically acceptable salt or solvate thereof, wherein Ri and R3 are independently hydrogen, or halo such as fluoro; and R3 is selected from halo,alkyl, fluoroalkyl and optionally substituted cycloalkyl, wherein the optionally substituted cycloalkyl is a cycloalkyl optionally substituted with one or several, in particular 1, or 2, substituents selected from halo, alkyl, and fluoroalkyl.

11. The compound of claim 5, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from:; and wherein R5is selected from -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CH2CF3, -CH(CH3)CF3;-CH2CHF2, -C(CH3)2CF3, 1 -trifluoromethylcyclopropyl, and a cyclopropyl substituted with at least one fluorine.

12. The compound of claim 5, or pharmaceutically acceptable salt or solvate thereof, wherein W is selected from:wherein R5is selected from -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CH2CF3, - CH(CH3)CF3;-CH2CHF2, -C(CH3)2CF3, 1 -trifluoromethylcyclopropyl, and a cyclopropyl substituted with at least one fluorine.

13. A compound, or pharmaceutically acceptable salt or solvate thereof, selected from:

14. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1 to 13, and a pharmaceutically acceptable excipient.

15. A compound of any one of claims 1 to 13, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

16. A compound of any one of claims 1 to 13, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.

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