BROM DOMAIN HOMES

Description

CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 61 / 893,133, filed October 18, 2013, and U.S. Provisional Application No. 61 / 931,467, filed January 24, 2014.BACKGROUND

[0002] A need exists in the art for an effective treatment of cancer and neoplastic disease. US 2008 / 269234 A1 describes inhibitors of poly(ADP-ribose)polymerase, ways to make them and compositions comprising them for treating patients using them.BRIEF SUMMARY OF THE INVENTION

[0003] The invention is defined by the appended claims.DETAILED DESCRIPTION OF THE INVENTION

[0004] 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 may vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of" or "consist essentially of" the described features.Definitions

[0005] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0006] "Amino" refers to the -NH 2 radical.

[0007] "Cyano" refers to the -CN radical.

[0008] "Nitro" refers to the -NO 2 radical.

[0009] "Oxa" refers to the -O- radical.

[0010] "Oxo" refers to the =O radical.

[0011] "Thioxo" refers to the =S radical.

[0012] "Imino" refers to the =N-H radical.

[0013] "Oximo" refers to the =N-OH radical.

[0014] "Hydrazino" refers to the =N-NH 2 radical.

[0015] "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., C 1 -C 15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a< , -SR a< , -OC(O)-R a< , -N(R a< ) 2 , -C(O)R a< , -C(O)OR a< , -C(O)N(R a< ) 2 , -N(R a< )C(O)OR a< , -OC(O)- N(R a< ) 2 , -N(R a< )C(O)R a< , -N(R a< )S(O) t R a< (where t is 1 or 2), -S(O) t OR a< (where t is 1 or 2), -S(O) t R a< (where t is 1 or 2) and -S(O) t N(R a< ) 2 (where t is 1 or 2) where each R a< is 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).

[0016] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0017] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a< , -SR a< , -OC(O)-R a< , -N(R a< ) 2 , -C(O)R a< , -C(O)OR a< , -C(O)N(R a< ) 2 , -N(R a< )C(O)OR a< , -OC(O)-N(R a< ) 2 , -N(R a< )C(O)R a< , -N(R a< )S(O) t R a< (where t is 1 or 2), -S(O) t OR a< (where t is 1 or 2), -S(O) t R a< (where t is 1 or 2) and -S(O) t N(R a< ) 2 (where t is 1 or 2) where each R a< is 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).

[0018] "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 has 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, -OR a< , -SR a< , -OC(O)-R a< , -N(R a< ) 2 , -C(O)R a< , -C(O)OR a< , -C(O)N(R a< ) 2 , -N(R a< )C(O)OR a< , -OC(O)- N(R a< ) 2 , -N(R a< )C(O)R a< , -N(R a< )S(O) t R a< (where t is 1 or 2), -S(O) t OR a< (where t is 1 or 2), -S(O) t R a< (where t is 1 or 2) and -S(O) t N(R a< ) 2 (where t is 1 or 2) where each R a< is 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).

[0019] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be 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., C 1 -C 8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C 5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C 1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C 5 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, -OR a< , -SR a< , -OC(O)-R a< , -N(R a< ) 2 , -C(O)R a< , -C(O)OR a< , -C(O)N(R a< ) 2 , -N(R a< )C(O)OR a< , -OC(O)-N(R a< ) 2 , -N(R a< )C(O)R a< , -N(R a< )S(O) t R a< (where t is 1 or 2), -S(O) t OR a< (where t is 1 or 2), -S(O) t R a< (where t is 1 or 2) and -S(O) t N(R a< ) 2 (where t is 1 or 2) where each R a< is 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).

[0020] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C 2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C 3 -C 5 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, -OR a< , -SR a< , -OC(O)-R a< , -N(R a< ) 2 , -C(O)R a< , -C(O)OR a< , -C(O)N(R a< ) 2 , -N(R a< )C(O)OR a< , -OC(O)- N(R a< ) 2 , -N(R a< )C(O)R a< , -N(R a< )S(OlR a< (where t is 1 or 2), -S(O) t OR a< (where t is 1 or 2), -S(O) t R a< (where t is 1 or 2) and -S(O) t N(R a< ) 2 (where t is 1 or 2) where each R a< is 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).

[0021] "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) π-electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b< -OR a< , -R b< -OC(O)-R a< , -R b< -OC(O)-OR a< , -R b< -OC(O)-N(R a< ) 2 , -R b< -N(R a< ) 2 , -R b< -C(O)R a< , -R b< -C(O)OR a< , -R b< -C(O)N(R a< ) 2 , -R b< -O-R c< -C(O)N(R a< ) 2 , -R b< -N(R a< )C(O)OR a< , -R b< -N(R a< )C(O)R a< , -R b< -N(R a< )S(O) t R a< (where t is 1 or 2), -R P< -S(O) t R a< (where t is 1 or 2), -R b< -S(O) t OR a< (where t is 1 or 2) and -R b< -S(O) t N(R a< ) 2 (where t is 1 or 2), where each R a< is 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 R b< is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c< is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0022] "Aralkyl" refers to a radical of the formula -R c< -aryl where R c< is 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.

[0023] "Aralkenyl" refers to a radical of the formula -R d< -aryl where R d< is 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.

[0024] "Aralkynyl" refers to a radical of the formula -R e< -aryl, where R e< is 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.

[0025] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula - O-R c< -aryl where R c< is 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.

[0026] "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 may be saturated, (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b< -OR a< , -R b< -OC(O)-R a< , -R b< -OC(O)-OR a< , -R b< -OC(O)-N(R a< ) 2 , -R b< -N(R a< ) 2 , -R b< -C(O)R a< , -R b< -C(O)OR a< , -R b< -C(O)N(R a< ) 2 , -R b< -O-R c< -C(O)N(R a< ) 2 , -R b< -N(R a< )C(O)OR a< , -R b< -N(R a< )C(O)R a< , -R b< -N(R a< )S(O) t R a< (where t is 1 or 2), -R b< -S(O) t R a< (where t is 1 or 2), -R b< -S(O) t OR a< (where t is 1 or 2) and -R b< -S(O) t N(R a< ) 2 (where t is 1 or 2), where each R a< is 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 R b< is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c< is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0027] "Carbocyclylalkyl" refers to a radical of the formula -R c< -carbocyclyl where R c< is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0028] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-R c< -carbocyclyl where R c< is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0029] "Carbocyclylalkynyl" refers to a radical of the formula -R c< -carbocyclyl, where R c< is an alkynylene chain as defined above. The carbocyclyl part of the carbocyclylalkynyl radical is optionally substituted as described above for an carbocyclyl group. In some embodiments the carbocyclyl group is a cycloalkyl group. The alkynylene chain part of the carbocyclylalkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0030] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological and / or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to, and the like.

[0031] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0032] "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. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0033] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b< -OR a< , -R b< -OC(O)-R a< , -R b< -OC(O)-OR a< , -R b< -OC(O)-N(Ra) 2 , -R b< -N(R a< ) 2 , -R b< -C(O)R a< , -R b< -C(O)OR a< ,-R b< -C(O)N(R a< ) 2 , -R b< -O-R c< -C(O)N(R a< ) 2 , -R b< -N(R a< )C(O)OR a< , -R b< -N(R a< )C(O)R a< , -R b< -N(R a< )S(O) t R a< (where t is 1 or 2), -R b< -S(O) t R a< (where t is 1 or 2), -R b< -S(O) t OR a< (where t is 1 or 2) and -R b< -S(O) t N(R a< ) 2 (where t is 1 or 2), where each R a< is 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 R b< is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c< is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0034] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0035] "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.

[0036] "Heterocyclylalkyl" refers to a radical of the formula -R c< -heterocyclyl where R c< is 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.

[0037] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-R c< -heterocyclyl where R c< is 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.

[0038] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical may be 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) π-electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b< -OR a< , -R b< -OC(O)-R a< , -R b< -OC(O)-OR a< , -R b< -OC(O)-N(Ra) 2 , -R b< -N(R a< ) 2 , -R b< -C(O)R a< , -R b< -C(O)OR a< ,-R b< -C(O)N(R a< ) 2 , -R b< -O-R c< -C(O)N(R a< ) 2 , -R b< -N(R a< )C(O)OR a< , -R b< -N(R a< )C(O)R a< , -R b< -N(R a< )S(O) t R a< (where t is 1 or 2), -R b< -S(O) t R a< (where t is 1 or 2), -R b< -S(O) t OR a< (where t is 1 or 2) and -R b< -S(O) t N(R a< ) 2 (where t is 1 or 2), where each R a< is 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 R b< is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c< is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0039] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0040] "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.

[0041] "Heteroarylalkyl" refers to a radical of the formula -R c< -heteroaryl, where R c< is 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.

[0042] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-R c< -heteroaryl, where R c< is 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.

[0043] The compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated 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.

[0044] 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 may, 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:

[0045] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0046] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the substituted heterocyclic derivative 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.

[0047] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds may be 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.

[0048] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0049] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably herein. These terms refers 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 may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be 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 may not have been made.

[0050] "Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0051] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C. S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0052] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.

[0053] 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 by 13< C- or 14< C-enriched carbon are within the scope of the present disclosure.

[0054] 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 ( 2< H), tritium ( 3< H), iodine-125 ( 125< I) or carbon-14 ( 14< C). Isotopic substitution with 2< H, 11< C, 13< C, 14< C, 15< C, 12< N, 13< N, 15< N, 16< N, 16< O, 17< O, 14< F, 15< F, 16< F, 17< F, 18< F, 33< S, 34< S, 35< S, 36< S, 35< Cl, 37< Cl, 79< Br, 81< Br, 125< I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0055] In certain embodiments, the compounds disclosed herein have some or all of the 1< H atoms replaced with 2< H atoms. The methods of synthesis for deuterium-containing substituted heterocyclic derivative compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

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

[0057] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d 3 (CD 3 I), 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 CD 3 I is illustrated, by way of example only, in the reaction schemes below.

[0058] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD 4 ), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD 4 is illustrated, by way of example only, in the reaction schemes below.

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

[0060] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1< H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.Substituted Heterocyclic Derivative Compounds

[0061] Disclosed is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein, R 2< is CH 3 , CH 2 CH 3 , CH 2 CF 3 , CH 2 F, CHF 2 , CF 3 , CH 2 D, CHD 2 , or CD 3 ; X1 is C-H or N; ring B is an optionally substituted 5- or 6-membered heterocyclic ring containing at least one oxygen or nitrogen atom; R A< is X2 is N or C-R 12< , wherein R 12< is hydrogen, halogen, alkyl, or alkoxy; R 13< is -Y-Z; Y is selected from a bond, -CH 2 -, or -CH(C 1 -C 4 alkyl)-; Z is selected from -SO 2 R 21< , -N(R 22< )SO 2 R 21< , -SO 2 N(R 22< ) 2 , -N(R 22< )SO 2 N(R 22< ) 2 , - CON(R 22< ) 2 , -N(R 22< )CO 2 R 21< , -N(R 22< )CON(R 22< ) 2 , -N(R 22< )COR 21< , -OC(O)N(R 22< ) 2 , - OSO 2 N(R 22< ) 2 , or -N(R 22< )SO 3 R 21< ; X3 is N or C-R 14< , wherein R 14< is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; or optionally when X4 is C-R 15< , R 14< and R 15< connect to form a ring; X4 is N or C-R 15< , wherein R 15< is hydrogen, halogen, -CN, alkyl, or alkoxy; R 16< is hydrogen, halogen, or -W-X, wherein W is a bond, -O-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when X4 is C-R 15< , R 16< and R 15< connect to form a ring; each R 21< is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R 22< is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0062] Another disclosure provides a compound of Formula (III), wherein X2 is N. Another disclosure provides a compound of Formula (III), wherein X3 is N. Another disclosure provides a compound of Formula (III), wherein X4 is N. Another disclosure provides a compound of Formula (III), wherein X2 and X3 are N. Another disclosure provides a compound of Formula (III), wherein X2 is C-R 12< , X3 is C-R 14< , and X4 is C-R 15< .

[0063] Another disclosure provides a compound of Formula (III), having the structure of Formula (IIIa): wherein, ring B is a 6-membered ring having one nitrogen atom; R 23< is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, -COR 24< , -CO 2 R 24< , - CONH(R 24< ), -CON(R 24< ) 2 , or SO 2 R 24< ; and each R 24< is independently selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0064] Another disclosure provides a compound of Formula (III), wherein R 2< is CH 3 . Another disclosure provides a compound of Formula (III), wherein X1 is C-H. Another disclosure provides a compound of Formula (III), wherein X1 is N.

[0065] Another disclosure provides a compound of Formula (III), wherein Y is a bond. Another disclosure provides a compound of Formula (III), wherein Y is a -CH 2 -. Another disclosure provides a compound of Formula (III), wherein Z is -SO 2 R 21< . Another disclosure provides a compound of Formula (III), wherein Z is -N(R 22< )SO 2 R 21< . Another disclosure provides a compound of Formula (III), wherein Z is -SO 2 N(R 22< ) 2 . Another disclosure provides a compound of Formula (III), wherein Z is - N(R 22< )SO 2 N(R 22< ) 2 . Another disclosure provides a compound of Formula (III), wherein Z is -CON(R 22< ) 2 . Another disclosure provides a compound of Formula (III), wherein Z is - N(R 22< )CO 2R 21< . Another disclosure provides a compound of Formula (III), wherein Z is - N(R 22< )CON(R 22< ) 2 . Another disclosure provides a compound of Formula (III), wherein R 21< is alkyl, cycloalkyl, or cycloalkylalkyl. Another disclosure provides a compound of Formula (III), wherein R 21< is alkyl. Another disclosure provides a compound of Formula (III), wherein R 14< is hydrogen, halogen, or alkyl. Another disclosure provides a compound of Formula (III), wherein X4 is C-R 15< . Another disclosure provides a compound of Formula (III), wherein W is -O-. Another disclosure provides a compound of Formula (III), wherein W is -NH-. Another disclosure provides a compound of Formula (III), wherein X is alkyl. Another disclosure provides a compound of Formula (III), wherein X is alkynyl. Another disclosure provides a compound of Formula (III), wherein X is aryl. Another disclosure provides a compound of Formula (III), wherein X is cycloalkylalkyl. Another disclosure provides a compound of Formula (III), wherein X is cycloalkylalkynyl. Another disclosure provides a compound of Formula (III), wherein W is -O- and X is alkyl. Another disclosure provides a compound of Formula (III), wherein W is -O- and X is alkynyl. Another disclosure provides a compound of Formula (III), wherein W is -O- and X is aryl. Another disclosure provides a compound of Formula (III), wherein W is -O- and X is cycloalkylalkyl. Another disclosure provides a compound of Formula (III), wherein W is -O- and X is cycloalkylalkynyl.

[0066] In some embodiments, the substituted heterocyclic derivative compound disclosed herein has the structure provided in Table 1. TABLE 1 Chemical Synthesis Example Structure Name 2 4-(3-methoxyphenyl)-2-methylisoquinolin-1-one3 4-(2-fluorophenyl)-2-methylisoquinolin-1-one4 4-(2-methoxyphenyl)-2-methylisoquinolin-1-one5 4-(3-aminophenyl)-2-methylisoquinolin-1-one6 N-cyclopropyl-3-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide7 2-methyl-4-(3-pyrrolidin-1-ylsulfonylphenyl)isoquinolin-1-one8 N-[[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methyl]methanesulfon amide9 N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide10 N-ethyl-3-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide11 4-(3-ethylsulfonylphenyl)-2-methylisoquinolin-1-one12 4-[3-(dimethylsulfamoylamino)pheny 1]-2-methyl-1-oxoisoquinoline13 N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide14 2-methyl-4-(3-morpholin-4-ylsulfonylphenyl)isoquinolin-1-one15 N-benzyl-2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide16 2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide17 N-[2-methyl-5-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide18 N-benzyl-2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl)benzamide19 4-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-methylisoquinolin-1-one20 2-methyl-4-(2-oxo-1,3-dihydroindol-6-yl)isoquinolin-1-one21 3-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide22 N-(2-hydroxyethyl)-3-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide23 4-(5-amino-2-fluorophenyl)-2-methylisoquinolin-1-one24 4-(5-amino-2,4-difluorophenyl)-2-methylisoquinolin-1-one25 4-(3-amino-5-fluorophenyl)-2-methylisoquinolin-1-one26 4-(3-amino-4-fluorophenyl)-2-methylisoquinolin-1-one27 N-benzyl-3-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide28 N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]propane-1-sulfonamide29 N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]butane-1-sulfonamide30 N-[2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide31 tert-butyl N-methyl-N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]carbamate32 2-methyl-4-[3-(methylamino)phenyl]isoquinoli n-1-one33 N-methyl-N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide34 N-[4-fluoro-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide35 N-[2,4-difluoro-5-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide36 N-[3-fluoro-5-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide37 N-[2-fluoro-5-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide38 N-[4-chloro-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide39 N-[4-methyl-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide40 N-[3-(2-methyl-1-oxoisoquinolin-4-yl)-5-(trifluoromethyl)phenyl]methane sulfonamide41 N-[4-fluoro-3-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]methanesulfonamide42 N-[3-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]methanesulfonamide43 N-[2,4-difluoro-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]methanesulfonamide44 4-(3-ethylsulfonylphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one45 N-[4-chloro-3-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide46 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one47 N-[3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide48 3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide49 N-ethyl-3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide50 N-[4-chloro-3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide51 N-[3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methanesulfonamide52 N-[3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]ethanesulfonamide53 N-ethyl-3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzenesulfonamide54 N-benzyl-2-methoxy-5-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzenesulfonamide55 3 -(2-methyl-1-oxo-2, 7-naphthyridin-4-yl)benzenesulfonamide56 2-methoxy-5-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzenesulfonamide57 N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]ethanesulfonamide58 N-[3-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide59 N-ethyl-3-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide60 N-benzyl-5-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)-2-methoxybenzenesulfonamide61 3-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide62 N-[3-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide63 4-(3-ethylsulfonylphenyl)-7-fluoro-2-methylisoquinolin-1-one64 5-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)-2-methoxybenzenesulfonamide65 2-methyl-4-(1-methylpyrazol-4-yl)isoquinolin-1-one66 4-(furan-2-yl)-2-methylisoquinolin-1-one67 2-methyl-4-(1,3-oxazol-2-yl)isoquinolin-1-one68 2-methyl-4-(1H-pyrazol-5-yl)isoquinolin-1-one69 2-methyl-4-(1-methylimidazol-2-yl)isoquinolin-1-one70 2-methyl-4-pyridin-2-ylisoquinolin-1-one71 2-methyl-4-pyrimidin-2-ylisoquinolin-1-one72 N-[3-[2-methyl-6-(6-methylpyridin-3-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide73 N-[3-(2-methyl-1-oxo-6-phenylisoquinolin-4-yl)phenyl]ethanesulfonamide74 N-[3-(2-methyl-1-oxo-6-phenylisoquinolin-4-yl)phenyl]methanesulfonamide75 N-[3-(2,6-dimethyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide76 N-[3-(6-ethyl-2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide77 N-[3-(6-ethyl-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide78 N-[3-(2,6-dimethyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide79 4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one80 4-(5-ethylsulfonyl-2-hydroxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one81 4-(2-ethoxy-5-ethylsulfonylphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one82 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one83 4-(5-ethylsulfonyl-2-propoxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one84 4-[5-ethylsulfonyl-2-(2-hydroxyethoxy)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one85 4-[2-(2-aminoethoxy)-5-ethylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one86 N-[2-fluoro-4-methoxy-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide87 N-[3-(2-methyl-1-oxo-6-pyridin-2-ylisoquinolin-4-yl)phenyl]ethanesulfonamide88 4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one89 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one90 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one91 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one92 4-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one93 N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide94 N-[3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide95 N-[3-(1,4-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide96 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide97 N-[3-(1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide98 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one99 N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide100 N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide101 N-[4-(2,4-difluorophenoxy)-3-(1,4-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide102 N-[4-(2,4-difluorophenoxy)-3-(1, 5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide103 N-[4-(2,4-difluorophenoxy)-3-(1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide104 3-amino-1-methyl-5-(3-methylsulfonylphenyl)pyrazin-2-one105 3-amino-5-(3-ethylsulfonylphenyl)-1-methylpyrazin-2-one106 N-[5-(6-amino-4-methyl-5-oxopyrazin-2-yl)-2-methoxyphenyl]methanesulfona mide107 3-amino-1-methyl-5-(3-methylsulfonylphenyl)pyridin-2-one108 3-amino-5-(3-ethylsulfonylphenyl)-1-methylpyridin-2-one109 N-[5-(5-amino-1-methyl-6-oxopyridin-3-yl)-2-methoxyphenyl]methanesulfona mide110 N-[2-methoxy-5-[1-methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl]methanesulfonamide111 N-[5-[5-(ethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfona mide112 N-[5-[5-(cyclopropylmethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfona mide113 N-[5-[5-(dimethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfona mide114 N-[5-[5-(diethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfona mide115 N-[3-(5-amino-1-methyl-6-oxopyridin-3 -yl)-4-(2,4-difluorophenoxy)phenyl]ethanes ulfonamide116 3-amino-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one117 4-ethoxy-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamide118 4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamide119 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one120 5-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one121 5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one122 N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide123 N-[3-(2-methyl-1-oxo-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide124 N-ethyl-3-(2-methyl-1-oxo-2,6-naphthyridin-4-yl)benzenesulfonamide125 N-[3-(2-methyl-1-oxo-2,6-naphthyridin-4-yl)phenyl]methanesulfonamide126 4-(3-ethylsulfonylphenyl)-2-methyl-2,6-naphthyridin-1-one127 N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide128 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one129 N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]ethanesulfonamide130 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one131 7-methyl-5-(3-methylsulfonylphenyl)imidazo[1 ,5-a]pyrazin-8-one132 N-[2-methoxy-5-(7-methyl-8-oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]methanesulfonamide133 5-(3-ethylsulfonylphenyl)-7-methylimidazo[1,5-a]pyrazin-8-one134 N-[3-(5-chloro-1-methyl-6-oxopyridin-3 -yl)-4-(2,4-difluorophenoxy)phenyl]ethanes ulfonamide135 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one136 6-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,4-dimethylpyridazin-3-one137 6-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,5-dimethylpyridazin-3-one138 N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(trifluoromethyl)pyridin-3-yl]phenyl]ethanesulfonamide139 N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide140 N-[3-(5-cyclopropyl-1-methyl-6-oxopyridin-3 -yl)-4-(2,4-difluorophenoxy)phenyl]ethanes ulfonamide141 N-{ 4-(2,4-difluorophenoxy)-3-[1-( 2< H 3 )methyl-6-oxopyridin-3-yl]phenyl}ethanesulfonamide142 N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide143 4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidi n-4-yl]-2-methylisoquinolin-1-one144 5-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidi n-4-yl]-1,3-dimethylpyridin-2-one145 4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidi n-4-yl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one146 5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidi n-4-yl]-3-methoxy-1-methylpyridin-2-one147 5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidi n-4-yl]-1,3-dimethylpyridin-2-one148 4-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidi n-4-yl]-2-methylisoquinolin-1-one149 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-1,3-dimethylpyridin-2-one150 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-3-methoxy-1-methylpyridin-2-one151 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin-1-one152 N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide153 N-[5-(cyclopropylmethoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide154 N-[5-(cyclopropylmethoxy)-4-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]pyrimidin-2-yl]methanesulfonamide155 N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide156 4-[5-(cyclopropylmethoxy)-2-(1,1-dioxo-1,2-thiazolidin-2-yl)pyrimidin-4-yl]-2-methylisoquinolin-1-one157 N-[5-(cyclopropylmethoxy)-4-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide158 N-[5-(cyclopropylmethoxy)-4-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide159 N-[5-(cyclopropylmethoxy)-4-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide160 N-[5-(cyclopropylmethoxy)-4-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide161 N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]-N-ethylmethanesulfonamide162 N-[5-(cyclopropylmethoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]-N-ethylmethanesulfonamide163 N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxo-5, 6,7, 8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide164 N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxo-5, 6,7, 8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide165 N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide166 N-[5-(2,4-difluorophenoxy)-4-(1, 5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide167 N-[5-(2,4-difluorophenoxy)-4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide168 N-[5-(2,4-difluorophenoxy)-4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide169 N-[5-(2,4-difluorophenoxy)-4-(1, 5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide170 N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide171 4-[5-(2,4-difluorophenoxy)-2-(1,1-dioxo-1,2-thiazolidin-2-yl)pyrimidin-4-yl]-2-methylisoquinolin-1-one172 N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxo-5, 6,7, 8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide173 N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxo-5, 6,7, 8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide174 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one175 2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-yloxy)phenyl]isoquinolin-1-one176 2-methyl-4-[5-methylsulfonyl-2-(oxan-4-yloxy)phenyl]isoquinolin-1-one177 4-(2-ethoxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one178 2-methyl-4-(5-methylsulfonyl-2-propoxyphenyl)isoquinolin-1-one179 2-methyl-4-[5-methylsulfonyl-2-(oxan-3-yloxy)phenyl]isoquinolin-1-one180 4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one181 4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-2-methylisoquinolin-1-one182 4-[2-(trans-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one183 4-[2-(cis-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one184 4-(2-but-2-ynoxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one185 4-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-2-methylisoquinolin-1-one186 6-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one187 7-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one188 4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-6-fluoro-2-methylisoquinolin-1-one189 4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-7-fluoro-2-methylisoquinolin-1-one190 2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-ylamino)phenyl]isoquinolin-1-one191 2-methyl-4-[5-methylsulfonyl-2-(oxan-4-ylamino)phenyl]isoquinolin-1-one192 4-[2-[(trans-4-hydroxycyclohexyl)amino]-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one193 4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one194 4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one195 4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one196 4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one197 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(trifluoromethyl)isoquinolin-1-one198 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methoxy-2-methylisoquinolin-1-one199 4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-2-methylisoquinolin-1-one200 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyridin-4-yl]-2-methylisoquinolin-1-one201 4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-7-fluoro-2-methylisoquinolin-1-one202 4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-6-fluoro-2-methylisoquinolin-1-one203 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyridin-4-yl]-7-fluoro-2-methylisoquinolin-1-one204 4-(2-ethoxy-5-ethylsulfonylthiophen-3-yl)-2-methylisoquinolin-1-one205 4-[2-(cyclopropylmethylamino)-5-ethylsulfonylthiophen-3-yl]-2-methylisoquinolin-1-one206 4-[3-(cyclopropylmethoxy)-6-ethylsulfonylpyridin-2-yl]-2-methylisoquinolin-1-one207 4-[5-(cyclopropylmethoxy)-2-ethylsulfonylpyridin-4-yl]-2-methylisoquinolin-1-one208 4-[5-(2-hydroxyethylsulfonyl)-2-methoxyphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one209 N-[4-(cyclopropylmethoxy)-2-fluoro-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide210 4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(1H-pyrazol-4-yl)isoquinolin-1-one211 4-(2-ethoxy-5-methylsulfonylphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one212 2-methyl-6-(1-methylpyrazol-4-yl)-4-(5-methylsulfonyl-2-propoxyphenyl)isoquinolin-1-one213 N-[2-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]pyridin-4-yl]ethanesulfonamide214 [4-(cyclopropylmethoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl] sulfamate215 [4-(cyclopropylmethoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl] sulfamate216 4-(2-ethoxy-5-methylsulfonylphenyl)-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one217 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one218 N-[4-(cyclopropylmethoxy)-2-fluoro-5-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)phenyl]methanesulfonamide219 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one220 N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]cycloprop anecarboxamide221 N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]propanam ide222 N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]acetamide223 4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one224 8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one225 8-(5-ethylsulfonyl-2-propoxyphenyl)-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one226 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one227 8-(2-ethoxy-5-ethylsulfonylphenyl)-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one228 6-methyl-2-(1-methylpyrazol-4-yl)-8-(5-methylsulfonyl-2-propoxyphenyl)pyrido[4,3-d]pyrimidin-5-one229 N-[4-(2,4-difluorophenoxy)-3-(1, 5-dimethyl-6-oxopyridin-3-yl)phenyl]-N-methylmethanesulfonamide230 N-[4-(2,4-difluorophenoxy)-3-(1, 5-dimethyl-6-oxopyridin-3-yl)phenyl]-N-(oxetan-3-yl)methanesulfonamide231 8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one232 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one233 8-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one234 8-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one235 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-one236 N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxo-[1,2,4]triazolo[4,3-a]pyrazin-5-yl)phenyl]ethanesulfonamide237 7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-5-methyl-[1,3]oxazolo[4,5-c]pyridin-4-one238 7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,5-dimethyl-[1,3]oxazolo[4,5-c]pyridin-4-one239 5-methyl-7-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-[1,3]oxazolo[4,5-c]pyridin-4-one240 N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-[1,3]oxazolo[4,5-c]pyridin-7-yl)phenyl]ethanesulfonamide241 N-[4-(2,4-difluorophenoxy)-3-(2,5-dimethyl-4-oxo-[1,3]oxazolo[4,5-c]pyridin-7-yl)phenyl]ethanesulfonamide242 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-(cyclopropylmethyl)-3-methylpyridin-2-one243 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methyl-1-(2-methylpropyl)pyridin-2-one244 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-(2-methoxyethyl)-3-methylpyridin-2-one245 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methyl-1-(oxetan-3-ylmethyl)pyridin-2-one246 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methyl-1-(1,3-oxazol-4-ylmethyl)pyridin-2-one247 N-[3-[1-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-4-(2,4-difluorophenoxy)phenyl]ethanes ulfonamide248 N-[4-[1-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide249 N-[4-[1-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide250 1-(cyclopropylmethyl)-5-[4-(2,4-difluorophenoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-3-methylpyridin-2-one251 1-cyclopropyl-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-methylpyridin-2-one252 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one253 N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide254 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one255 N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide256 N-[6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3-yl]ethanesulfonamide257 N-[6-(cyclopropylmethoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3-yl]ethanesulfonamide258 6-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]furo[2,3-c]pyridin-7-one259 4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-6-methylfuro[2,3-c]pyridin-7-one260 2-chloro-4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one261 N-[6-(cyclopropylmethoxy)-5-(2-fluoro-6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3-yl]ethanesulfonamide262 N-[5-(2,4-difluorophenoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]methanesulfonamide263 N-[5-(2,4-difluorophenoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]ethanesulfonamide264 N-[5-(cyclopropylmethoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]ethanesulfonamide265 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide266 4-[2-(cyclopropylmethoxy)-5-(ethylsulfonylamino)phenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide267 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide268 4-[2-(cyclopropylmethoxy)-5-(ethylsulfonylamino)pyridin-3-yl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide269 N-[4-(2,4-difluorophenoxy)-3-(2,6-dimethyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide270 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2,6-dimethylfuro[2,3-c]pyridin-7-one271 N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide272 3-chloro-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methylpyridin-2-one273 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-1-methyl-3-propan-2-ylpyridin-2-one274 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one275 3-chloro-5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-1-methylpyridin-2-one276 5-[2-(2,4-difluorophenoxy)-5-(methanesulfonylmethyl)phenyl] -3-( 2< H 3 )methyl-1-methyl-1,2-dihydropyridin-2-one277 N-[4-(2,4-difluorophenoxy)-3-[5-( 2< H 3 )methyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]phenyl]methanesulfonamide278 N-[4-(2,4-difluorophenoxy)-3-[5-( 2< H 3 )methyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]phenyl]ethane-1-sulfonamide279 N-[3-(5-cyclopropyl-1-methyl-6-oxopyridin-3 -yl)-4-(2,4-difluorophenoxy)phenyl]methan esulfonamide280 3-cyclopropyl-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methylpyridin-2-one281 N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxo-5-pyrrolidin-1-ylpyridin-3-yl)phenyl]methanesulfonamide282 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methyl-3-pyrrolidin-1-ylpyridin-2-one283 N-[4-(2,4-difluorophenoxy)-3-(5-ethynyl-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide284 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-ethynyl-1-methylpyridin-2-one285 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-ethynyl-1-methylpyridin-2-one286 N-[4-(2,4-difluorophenoxy)-3-(5-ethynyl-1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide287 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-(difluoromethoxy)-1-methylpyridin-2-one288 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one289 N-[3-[5-(difluoromethoxy)-1-methyl-6-oxopyridin-3-yl]-4-(2,4-difluorophenoxy)phenyl]ethanes ulfonamide290 N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenyl]ethanesulfonamide291 3-(difluoromethoxy)-5-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-1-methylpyridin-2-one292 5-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one293 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methyl-3-(1-methylpyrazol-4-yl)oxypyridin-2-one294 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methyl-3-(1-propan-2-ylpyrazol-4-yl)oxypyridin-2-one295 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methyl-3-phenoxypyridin-2-one296 N-[4-(1-butyl-5-methyl-6-oxopyridin-3 -yl)-5 -(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide297 N-[4-(1-butyl-5-methyl-6-oxopyridin-3 -yl)-5 -(2,4-difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide298 N-[4-[1-(cyclobutylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide299 N-[4-[1-(cyclobutylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide300 N-[5-ethyl-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide301 2-methyl-4-(2-methylsulfonyl-5-propylpyrimidin-4-yl)isoquinolin-1-one302 5-(5-ethyl-2-methylsulfonylpyrimidin-4-yl)-1,3-dimethylpyridin-2-one303 1,3-dimethyl-5-(2-methylsulfonyl-5-propylpyrimidin-4-yl)pyridin-2-one304 4-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-2-methylisoquinolin-1-one305 5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-1,3-dimethylpyridin-2-one306 N-[4-(2-methyl-1-oxoisoquinolin-4-yl)-5-propylpyrimidin-2-yl]ethanesulfonamide307 N-[4-(1,5-dimethyl-6-oxopyridin-3-yl)-5-ethylpyrimidin-2-yl]ethanesulfonamide308 N-[4-(1,5-dimethyl-6-oxopyridin-3-yl)-5-propylpyrimidin-2-yl]ethanesulfonamide309 N-[5-butyl-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide310 N-[5-butyl-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide311 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin-1-one312 5-(2-ethyl-5-methylsulfonylphenyl)-1-methylpyridin-2-one313 1-methyl-5-(5-methylsulfonyl-2-propylphenyl)pyridin-2-one314 2-methyl-4-(5-methylsulfonyl-2-propylphenyl)isoquinolin-1-one315 5-[2-(2-cyclopropylethyl)-5-methylsulfonylphenyl]-1-methylpyridin-2-one316 4-(2-ethyl-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one317 5-(2-butyl-5-methylsulfonylphenyl)-1-methylpyridin-2-one318 4-(2-butyl-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one319 4-[2-(2-cyclopropylethyl)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one320 N-[6-(cyclopropylmethoxy)-5-(2-methyl-1-oxoisoquinolin-4-yl)pyridin-3-yl]ethanesulfonamide321 4-[2-(cyclopropylmethoxy)-5-methylsulfonylpyridin-3-yl]-2-methylisoquinolin-1-one322 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylpyridin-3-yl]-2-methylisoquinolin-1-one323 5-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one324 1,3-dimethyl-5-(3-methylsulfonyl-5-phenylmethoxyphenyl)pyridin-2-one325 5-[3-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one326 1,3-dimethyl-5-[3-methylsulfonyl-5-(2-phenylethoxy)phenyl]pyridin-2-one327 5-[3-(2-cyclopropylethoxy)-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one328 1,3-dimethyl-5-[3-methylsulfonyl-5-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one329 1,3-dimethyl-5-[3-[(3-methyloxetan-3-yl)methoxy]-5-methylsulfonylphenyl]pyridin-2-one330 1,3-dimethyl-5-[3-methylsulfonyl-5-(pyridin-2-ylmethoxy)phenyl]pyridin-2-one331 5-[3-[(2,6-dimethylphenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one332 5-[3-[(2-chlorophenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one333 5-[3-[[2-(difluoromethoxy)phenyl]metho xy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one334 2-[[3-(1,5-dimethyl-6-oxopyridin-3-yl)-5-methylsulfonylphenoxy]methyl] benzonitrile335 5-[3-[(2,4-difluorophenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one336 1,3-dimethyl-5-[3-methylsulfonyl-5-(1-phenylethoxy)phenyl]pyridin-2-one337 5-[3-[(2,3-dichlorophenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one338 1,3-dimethyl-5-[3-methylsulfonyl-5-(pyridin-3-ylmethoxy)phenyl]pyridin-2-one339 3-[[3-(1,5-dimethyl-6-oxopyridin-3-yl)-5-methylsulfonylphenoxy]methyl] benzonitrile340 5-(3-but-2-ynoxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one341 1,3-dimethyl-5-[3-methylsulfonyl-5-(1-phenylethoxy)phenyl]pyridin-2-one342 N-[3-(2,4-difluorophenoxy)-5-(1, 5-dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide343 4-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one344 2-methyl-4-(3-methylsulfonyl-5-phenylmethoxyphenyl)isoquinoli n-1-one345 4-[3-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one346 N-[4-(2,4-difluorophenoxy)-6-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide347 N-[2-(2,4-difluorophenoxy)-6-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-4-yl]ethanesulfonamide348 4-[3-[[2-(difluoromethoxy)phenyl]metho xy]-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one349 6-methyl-4-(3-methylsulfonyl-5-phenylmethoxyphenyl)furo[2,3-c]pyridin-7-one350 4-[3-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one351 1-methyl-5-(2-methylsulfonyl-5-propylpyrimidin-4-yl)pyridin-2-one352 5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-1-methylpyridin-2-one353 3-chloro-1-methyl-5-(2-methylsulfonyl-5-propylpyrimidin-4-yl)pyridin-2-one354 5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-3-chloro-1-methylpyridin-2-one355 3-methoxy-1-methyl-5-(2-methylsulfonyl-5-propylpyrimidin-4-yl)pyridin-2-one356 5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-3-methoxy-1-methylpyridin-2-one357 N-[4-(1-methyl-6-oxopyridin-3-yl)-5-propylpyrimidin-2-yl]ethanesulfonamide358 N-[5-butyl-4-(1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide359 N-[4-(5-chloro-1-methyl-6-oxopyridin-3-yl)-5-propylpyrimidin-2-yl]ethanesulfonamide360 N-[5-butyl-4-(5-chloro-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide361 N-[4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-5-propylpyrimidin-2-yl]ethanesulfonamide362 N-[5-butyl-4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide363 N-[5-butyl-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide364 4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-2-methylisoquinolin-1-one365 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-4H-pyrido[4,3-b][1,4]oxazine-3,5-dione366 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-5-one367 N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]methanesulfonamide368 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one369 5-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one370 7-methyl-5-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]imidazo[ 1,5-a]pyrazin-8-one371 5-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one372 5-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one373 5-[2-(4,4-difluorocyclohexyl)oxy-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one374 5-(2-cyclopentyloxy-5-ethylsulfonylphenyl)-7-methylimidazo[1,5-a]pyrazin-8-one375 5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one376 5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one377 7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-5-methylfuro[3,2-c]pyridin-4-one378 7-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-5-methylfuro[3,2-c]pyridin-4-one379 N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxofuro[3,2-c]pyridin-7-yl)phenyl]ethanesulfonamide380 N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxofuro[3,2-c]pyridin-7-yl)phenyl]methanesulfonamide381 4-(cyclopropylmethoxy)-5-(1-methyl-6-oxopyridin-3-yl)-1-(methylsulfonylmethyl)pyridin-2-one382 5-[4-(cyclopropylmethoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-1,3-dimethylpyridin-2-one383 4-[4-(cyclopropylmethoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-7-fluoro-2-methylisoquinolin-1-one384 4-[4-(cyclopropylmethoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-2-methylisoquinolin-1-one385 5-[4-(2,4-difluorophenoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-1,3-dimethylpyridin-2-one386 4-(2,4-difluorophenoxy)-5-(1-methyl-6-oxopyridin-3-yl)-1-(methylsulfonylmethyl)pyridin-2-one387 4-[4-(2,4-difluorophenoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-2-methylisoquinolin-1-one388 5-(2-but-2-ynoxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one389 5-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-3-methoxy-1-methylpyridin-2-one390 5-(5-ethylsulfonyl-2-pent-2-ynoxyphenyl)-3-methoxy-1-methylpyridin-2-one391 5-[2-(3-cyclopropylprop-2-ynoxy)-5-ethylsulfonylphenyl]-3-methoxy-1-methylpyridin-2-one392 5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-1-methyl-3-(trifluoromethyl)pyridin-2-one393 4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-6-methoxy-2-methylisoquinolin-1-one394 5-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-1,3-dimethylpyridin-2-one395 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-5-phenylmethoxyphenyl]ethanesul fonamide396 5-[2-(2,4-difluoroanilino)-5-ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one397 5-[2-[(4,4-difluorocyclohexyl)amino]-5-ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one398 5-[2-(2,4-difluoroanilino)-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one399 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-methoxy-1-methylpyridin-2-one400 5-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-3-methoxy-1-methylpyridin-2-one401 5-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one402 N-[4-(2,4-difluorophenoxy)-3-(1-methyl-5-methylsulfanyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide403 5-[2-(cis-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one404 5-[2-(trans-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one405 1,3-dimethyl-5-[5-methylsulfonyl-2-(3,3,3-trifluoropropoxy)phenyl]pyridin-2-one406 5-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-1-(2-hydroxyethyl)-3-methylpyridin-2-one407 5-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-1-(2-hydroxyethyl)-3-methylpyridin-2-one408 5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-1-methyl-3-(methylamino)pyridin-2-one409 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methyl-3-(methylamino)pyridin-2-one410 N-[4-(2,4-difluorophenoxy)-3-[1-methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl]ethanesulfonamide411 5-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-1,3-dimethylpyridin-2-one412 N-[4-(2,4-difluorophenoxy)-3-[1-methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl]methanesulfonamide413 5-[2-[(4,4-difluorocyclohexyl)amino]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one414 5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-3-methoxy-1-methylpyridin-2-one415 5-[2-(4,4-difluorocyclohexyl)oxy-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one416 5-[2-(cyclopentylamino)-5-ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one417 5-[2-(cyclopentylamino)-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one418 3-chloro-1-methyl-5-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one419 5-(2-cyclopentyloxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one420 1,3-dimethyl-5-[5-methylsulfonyl-2-(oxan-4-yloxy)phenyl]pyridin-2-one421 3-fluoro-1-methyl-5-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one422 5-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-1,4-dimethylpyridin-2-one423 5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-1,4-dimethylpyridin-2-one424 N-[4-(1-methyl-6-oxopyridin-3-yl)-5-phenylthiophen-2-yl]ethanesulfonamide425 1,3-dimethyl-5-[5-methylsulfonyl-2-(oxolan-3-ylamino)phenyl]pyridin-2-one426 1,3-dimethyl-5-[5-methylsulfonyl-2-(oxolan-3-yloxy)phenyl]pyridin-2-one427 1,3-dimethyl-5-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one428 5-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-1-ethyl-3-methylpyridin-2-one429 5-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-1-ethyl-3-methylpyridin-2-one430 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(trans-4-hydroxycyclohexyl)oxyphenyl]et hanesulfonamide431 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(cis-4-hydroxycyclohexyl)oxyphenyl]et hanesulfonamide432 N-[4-(1-methyl-6-oxopyridin-3-yl)-5-(2-methylphenyl)thiophen-2-yl]ethanesulfonamide433 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(trans-4-hydroxycyclohexyl)oxyphenyl] methanesulfonamide434 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(cis-4-hydroxycyclohexyl)oxyphenyl] methanesulfonamide435 N-[5-(2-ethylphenyl)-4-(1-methyl-6-oxopyridin-3-yl)thiophen-2-yl]ethanesulfonamide436 1,3-dimethyl-5-[5-methylsulfonyl-2-(oxan-4-ylamino)phenyl]pyridin-2-one437 5-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-3-fluoro-1-methylpyridin-2-one438 5-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-3-(dimethylamino)-1-methylpyridin-2-one439 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxan-4-yloxy)phenyl]methanesulfonami de440 5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-3-(dimethylamino)-1-methylpyridin-2-one441 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxan-4-yloxy)phenyl]ethanesulfonamide442 N-[4-(2,4-difluorophenoxy)-3-(5-methoxy-1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide443 N-[4-(2,4-difluorophenoxy)-3-(5-methoxy-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide444 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxolan-3-yloxy)phenyl]methanesulfonami de445 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxolan-3-yloxy)phenyl]ethanesulfonamide446 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxan-3-yloxy)phenyl]methanesulfonami de447 N-[4-(4,4-difluorocyclohexyl)oxy-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide448 N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxan-3-yloxy)phenyl]ethanesulfonamide449 N-[4-(4,4-difluorocyclohexyl)oxy-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide450 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one451 N-[4-(2,4-difluorophenoxy)-3-(5-hydroxy-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide452 4-(cyclopropylmethylamino)-3-(1,5-dimethyl-6-oxopyridin-3-yl)benzenesulfonamide453 4-(cyclopropylmethylamino)-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamide454 5-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-1,4-dimethylpyridin-2-one455 5-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-1,3-dimethylpyridin-2-one456 5-(2-ethoxy-5-ethylsulfonylphenyl)-1-( 2< H 3 )methyl-4-methylpyridin-2-one457 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]- 1-( 2< H 3 )methyl-4-methylpyridin-2-one458 5-(2-ethoxy-5-ethylsulfonylphenyl)-1,4-dimethylpyridin-2-one459 5-[2-(cyclobutylmethoxy)-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one460 5-[2-(cyclobutylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one461 5-(5-ethylsulfonyl-2-methoxyphenyl)-3-hydroxy-1-methylpyridin-2-one462 5-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one463 N-[4-(2,4-difluorophenoxy)-3-[5-(dimethylamino)-1-methyl-6-oxopyridin-3-yl]phenyl]methanesulfonamide464 N-[4-(2,4-difluorophenoxy)-3-[5-(dimethylamino)-1-methyl-6-oxopyridin-3-yl]phenyl]ethanesulfonamide465 5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one466 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1,4-dimethylpyridin-2-one467 N-[3-(5-hydroxy-1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide468 5-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-1-methylpyridin-2-one469 3-(dimethylamino)-5-(2-ethoxy-5-ethylsulfonylphenyl)-1-methylpyridin-2-one470 5-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-1-methylpyridin-2-one471 N-[3-(1-methyl-6-oxo-5-phenylmethoxypyridin-3-yl)phenyl]methanesulfonamide472 N-[4-(2,4-difluorophenoxy)-3-(1, 5-dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide473 5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-1-methylpyridin-2-one474 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-(dimethylamino)-1-methylpyridin-2-one475 5-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-1-methylpyridin-2-one476 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one477 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1,4-dimethylpyridin-2-one478 N-[6-[3-(methanesulfonamido)phenyl]-4-methyl-3-oxopyrazin-2-yl]acetamide479 N-[3-(1,4-dimethyl-6-oxopyridazin-3-yl)phenyl]ethanesulfonamide480 N-[3-(1,5-dimethyl-6-oxopyridazin-3-yl)phenyl]ethanesulfonamide481 N-[5-[3-(methanesulfonamido)phenyl]-1-methyl-2-oxopyridin-3-yl]propanamide482 N-[5-[3-(methanesulfonamido)phenyl]-1-methyl-2-oxopyridin-3-yl]acetamide483 1-cyclobutyl-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methylpyridin-2-one484 N-[3-(1-cyclobutyl-5-methyl-6-oxopyridin-3 -yl)-4-(2,4-difluorophenoxy)phenyl]methan esulfonamide485 1-benzyl-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methylpyridin-2-one486 1,3-dimethyl-5-(2-methyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)pyridin-2-one487 4-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-2-methylisoquinolin-1-one488 2-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]isoquinol in-1-one489 1,3-dimethyl-5-(7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl)pyridin-2-one490 N-[2-ethyl-8-(2-methyl-1-oxoisoquinolin-4-yl)-3,4-dihydro-2H-chromen-6-yl]methanesulfonamide491 N-[2-ethyl-8-(2-methyl-1-oxoisoquinolin-4-yl)-3,4-dihydro-2H-chromen-6-yl]ethanesulfonamide492 N-[8-(1,5-dimethyl-6-oxopyridin-3 -yl)-2-ethyl-3,4-dihydro-2H-chromen-6-yl]ethanesulfonamide493 4-(2-cyclopropyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)-2-methylisoquinolin-1-one494 4-(2-ethyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)-2-methylisoquinolin-1-one495 N-[7-(1,5-dimethyl-6-oxopyridin-3-yl)-2-propyl-2,3-dihydro-1-benzofuran-5-yl]ethanesulfonamide496 N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-2,3-dihydro-1-benzofuran-5-yl]ethanesulfonamide497 4-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2-methylisoquinolin-1-one498 5-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-1,3-dimethylpyridin-2-one499 4-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2-methylisoquinolin-1-one500 5-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-1,3-dimethylpyridin-2-one501 4-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2-methylisoquinolin-1-one502 5-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-1,3-dimethylpyridin-2-one503 4-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2-methylisoquinolin-1-one504 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-one505 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-one506 N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)phenyl]methanesulfonamide507 N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)phenyl]ethanesulfonamide508 5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-3-methyl-1-propan-2-ylpyridin-2-one509 N-[5-(2,4-difluorophenoxy)-4-(5-methyl-6-oxo-1-propan-2-ylpyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide510 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-3-methyl-1-propan-2-ylpyridin-2-one511 N-[5-butyl-4-(5-methyl-6-oxo-1-propan-2-ylpyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide512 N-[5-butyl-4-(1-methyl-6-oxo-5-propan-2-ylpyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide513 5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-1-methyl-3-propan-2-ylpyridin-2-one514 N-[5-(2,4-difluorophenoxy)-4-(1-methyl-6-oxo-5-propan-2-ylpyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide

[0067] In some embodiments, the substituted heterocyclic derivative compound disclosed herein has the structure provided in Table 2. Preparation of the Substituted Heterocyclic Derivative Compounds

[0068] 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).

[0069] Methods known to one of ordinary skill in the art are identified through various reference books and databases. 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.

[0070] Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be 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 for the preparation and selection of pharmaceutical salts of the substituted heterocyclic derivative compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0071] General methods for the synthesis of substituted heterocyclic derivatives are provided in, but not limited to, the following references: WO 2009 / 158396; WO 2005 / 63768; WO 2006 / 112666; Briet et. al., Tetrahedron (2002), 58(29), 5761-5766; WO 2008 / 77550; WO 2008 / 77551; WO 2008 / 77556; WO 2007 / 12421; WO 2007 / 12422; US 2007 / 99911; WO 2008 / 77550; Havera et al., J. Med. Chem. (1999), 42, 3860-3873; WO 2004 / 29051; and US 2009 / 0054434. Additional examples of the synthesis of substituted heterocyclic derivatives are found in the following references: WO 2012 / 171337; WO 2011 / 044157; WO 2009 / 097567; WO 2005 / 030791; EP 203216; Becknell et al., Bioorganic & Medicinal Chemistry Letters (2011), 21(23), 7076-7080; Svechkarev et al., Visnik Kharkivs'kogo Natsional'nogo Universitetu im. V. N. Karazina (2007), 770, 201-207; Coskun et al., Synthetic Communications (2005), 35(18), 2435-2443; Alvarez et al., Science of Synthesis (2005), 15, 839-906; Kihara et al., Heterocycles (2000), 53(2), 359-372; Couture et al., Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1999), (7), 789-794; Kihara et al., Heterocycles (1998), 48(12), 2473-2476; Couture et al., Tetrahedron (1996), 52(12), 4433-48; Couturre et al., Tetrahedron Letters (1996), 37(21), 3697-3700; Natsugari et al., Journal of Medicinal Chemistry (1995), 38(16), 3106-20; Moehrle et al., Archiv der Pharmazie (Weinheim, Germany) (1988), 321(10), 759-64; Gore et al., Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1988), (3), 481-3; Narasimhan et al., Journal of the Chemical Society, Chemical Communications (1987), (3), 191-2; Henry et al., Journal of Organic Chemistry (1975), 40(12), 1760-6; Berti, Gazzetta Chimica Italiana (1960), 90, 559-72; Berti et al., Annali di Chimica (Rome, Italy) (1959), 49, 2110-23; Berti et al., Annali di Chimica (Rome, Italy) (1959), 49, 1253-68; WO 2012 / 000595; Couture et al., Tetrahedron (1996), 52(12), 4433-48; WO 2010 / 069504; WO 2010 / 069504; WO 2006 / 030032; WO 2005 / 095384; US 2005 / 0222159; WO 2013 / 064984; Mishra et al., European Journal of Organic Chemistry (2013), 2013(4), 693-700; Vachhani et al., Tetrahedron (2013), 69(1), 359-365; Xie et al., European Journal of Medicinal Chemistry (2010), 45(1), 210-218; Mukaiyama et al., Bioorganic & Medicinal Chemistry (2007), 15(2), 868-885; JP 2005 / 089352; Wang et al., Molecules (2004), 9(7), 574-582; WO 2000 / 023487; US 2006 / 0287341; CN 103183675 ; Hares et al., Egyptian Journal of Pharmaceutical Sciences (1991), 32(1-2), 303-14; DE 2356005 ; DE 2133898 ; DE 2133998; US 3816422; DE 2011970; and Staehle et al., Justus Liebigs Annalen der Chemie (1973), (8), 1275-81.

[0072] In some embodiments, the substituted heterocyclic derivative compounds disclosed herein are prepared by the general synthetic routes described below in Schemes 1-6. These schemes are intended to exemplary to one of skill in the art and are not limiting. Additional methods for the synthesis of the substituted heterocyclic derivative compounds disclosed herein are readily available to one of skill in the art.

[0073] A method for preparing compounds of Formula (I) is provided in Scheme 1. 6-Bromo-2-methylisoquinolin-1(2H)-one (1-1) is subjected to a palladium-catalyzed cross coupling reaction to provide isoquinolinone 1-2. Bromination under acidic conditions provides compound 1-3. Further palladium-catalyzed cross coupling reaction with a boronic acid, or ester, provides the isoquinolinone 1-4. Alternatively, palladium-catalyzed cross coupling of compound 1-3 with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane under the conditions described by Miyaura (Ishiyama et al., J. Org. Chem. 1995, 60, 7508-7510) provides the boron ester 1-5. Further palladium-catalyzed cross coupling reaction of compound 1-5 with a suitable halide provides the isoquinolinone 1-6.

[0074] A method for preparing compounds of Formula (I) is provided in Scheme 2. 6-Bromo-2-methylisoquinolin-1(2H)-one (2-1) is subjected to a palladium-catalyzed cross coupling reaction with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane to provide boron ester 2-2. Further palladium-catalyzed cross coupling reaction of compound 2-2 with a suitable halide provides compound 2-3. Bromination under acidic conditions provides compound 2-4. Further palladium-catalyzed cross coupling reaction with a boronic acid, or ester, provides the isoquinolinone 2-5.

[0075] A method for preparing compounds of Formula (II) is provided in Scheme 3. 5-Bromopyridin-2-ol derivative (3-1) is subjected to alkylation with methyl iodide under basic conditions to provide the related 5-bromo-1-methylpyridin-2(1H)-one derivative (3-2). Further palladium-catalyzed cross coupling reaction of compound 3-2 with a suitable halide provides compound 3-3.

[0076] A method for preparing compounds of Formula (II) is provided in Scheme 4. 3-Amino-5-bromo-1-methylpyridin-2(1H)-one derivative 4-1 is used as a starting material for several routes. In one route, compound 4-1 is directly subjected to a palladium-catalyzed cross coupling reaction to provide pyridone 4-3. The amino group of compound 4-3 is subjected to a reductive amination with an aldehyde and a reducing agent, such as sodium cyanoborohydride, to provide the substituted amino derivative compound 4-7. A second route involving selective alkylation of the amino group of compound 4-1 begins with protection of the amino group as the BOC carbamate. Alkylation of the carbamate under basic conditions followed by removal of the BOC carbamate under acidic conditions provides the secondary amine compound 4-5. Treatment of 4-5 with a suitable halide under palladium-catalyzed cross coupling conditions affords compound 4-6.

[0077] A method for preparing compounds of Formula (IV) is provided in Scheme 5. 5-Bromo-1-methylpyrazin-2(1H)-one (5-1) is subjected to an imidazole annulation reaction by treatment with tosylmethisocyanide (TosMIC) under basic conditions (Hoogenboom et al., Organic Syntheses, Coll. Vol. 6, p. 987 (1988)) to provide 5-bromo-7-methylimidazo[1,5-a]pyrazin-8(7H)-one (5-2). Palladium-catalyzed cross coupling reaction of compound 5-2 with a suitable halide provides the compound 5-3.

[0078] A method for preparing compounds of Formula (III) is provided in Scheme 6. 2,6-Naphthyridin-1-ol (6-1) is subjected to alkylation with methyl iodide under basic conditions to provide 2-methyl-2,6-naphthyridin-1(2H)-one (6-2). Chlorination of 6-2 with N-chlorosuccinimide provides chloro compound 6-3. Treatment of 6-3 under palladium-catalyzed cross coupling conditions with a suitable halide provides compound 6-4. Selective reduction of the 2,6-naphthyridinone derivative provides the 5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one derivative 6-5.

[0079] In each of the above reaction procedures or schemes, the various substituents may be selected from among the various substituents otherwise taught herein.Pharmaceutical Compositions

[0080] In certain embodiments, the substituted heterocyclic derivative compound as described herein is administered as a pure chemical. In other embodiments, the substituted heterocyclic derivative 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, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0081] Accordingly, provided herein is a pharmaceutical composition comprising at least one substituted heterocyclic derivative compound, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide 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) of the composition.

[0082] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (III), or (IIIa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (V), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (VIa), (VIb), (VIc), (VId), or (VIe), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (VII), or (VIIa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (VIII), or (VIIIa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XIII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XIV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XVI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XVII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XVIII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XIX), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XX), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XXI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XXII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XXIII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0083] In certain embodiments, the substituted heterocyclic derivative compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.

[0084] 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. 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, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0085] The dose of the composition comprising at least one substituted heterocyclic derivative compound as described herein may differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.

[0086] Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts. 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 may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the patient.

[0087] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Bromodomain Inhibition

[0088] Chromatin is the complex of DNA and protein that makes up chromosomes. Histones are the major protein component of chromatin, acting as spools around which DNA winds. Changes in chromatin structure are affected by covalent modifications of histone proteins and by non-histone binding proteins. Several classes of enzymes are known which modify histones at various sites.

[0089] Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than the underlying DNA sequence. Molecular mechanisms that play a role in epigenetic regulation include DNA methylation and chromatin / histone modifications.

[0090] The genomes of eukaryotic organisms are highly organized within the nucleus of the cell. Tremendous compaction is required to package the 3 billion nucleotides of the human genome into the nucleus of a cell.

[0091] Histones are the chief protein components of chromatin. There are a total of six classes of histones (H1, H2A, H2B, H3, H4, and H5) organized into two classes: core histones (H2A, H2B, H3, and H4) and linker histones (H1 and H5). The basic unit of chromatin is the nucleosome, which consists of about 147 base pairs of DNA wrapped around the core histone octamer, consisting of two copies each of the core histones H2A, H2B, H3, and H4.

[0092] Basic nucleosome units are then further organized and condensed by the aggregation and folding of nucleosomes to form a highly condensed chromatin structure. A range of different states of condensation are possible, and the tightness of chromatin structure varies during the cell cycle, being most compact during the process of cell division.

[0093] Chromatin structure plays a critical role in regulating gene transcription, which cannot occur efficiently from highly condensed chromatin. The chromatin structure is controlled by a series of post translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the histone tails which extend beyond the core nucleosome structure. These modifications include acetylation, methylation, phosphorylation, ribosylation sumoylation, ubiquitination, citrullination, deimination, and biotinylation. The core of histones H2A and H3 can also be modified. Histone modifications are integral to diverse biological processes such as gene regulation, DNA repair, and chromosome condensation.Histone Acetylation and Bromodomains

[0094] Histone acetylation is generally associated with the activation of gene transcription, as the modification is known to loosen the interaction of the DNA and the histone octamer by changing the electrostatics. In addition to this physical change, specific proteins are known to bind to acetylated lysine residues within histones in order to read the epigenetic code. Bromodomains are small ( ~< 110 amino acid) distinct domains within proteins that are known to bind to acetylated lysine residues commonly, but not exclusively, in the context of histones. Around 50 proteins are known to contain bromodomains, and they have a range of functions within the cell.

[0095] The BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t) which contain tandem bromodomains capable of binding to two acetylated lysine resides in close proximity, increasing the specificity of the interaction.

[0096] Bromodomain-containing proteins that recognize acetylated lysines on histones (such as BET proteins and non-BET proteins) have been implicated in proliferative disease. BRD4 knockout mice die shortly after implantation and are compromised in their ability to maintain an inner cell mass, and heterozygotes display pre- and postnatal growth defects associated with reduced proliferation rates. BRD4 regulates genes expressed during M / Gl, including growth-associated genes, and remains bound to chromatin throughout the cell cycle (Dey, et al. (2009) Mol. Biol. Cell 20:4899-4909). BRD4 also physically associates with Mediator and P-TEFb (CDK9 / cyclin Tl) to facilitate transcriptional elongation (Yang, et al. (2005) Oncogene 24:1653-1662; Yang, et al. (2005) Mol. Cell 19:535-545). CDK9 is a validated target in chronic lymphocytic leukemia (CLL), and is linked to c-Myc-dependent transcription (Phelps, et al. Blood 113:2637-2645; Rahl, et al. (2010) Cell 141:432-445).

[0097] BRD4 is translocated to the NUT protein in patients with lethal midline carcinoma, an aggressive form of human squamous carcinoma (French, et al. (2001) Am. J. Pathol. 159:1987-1992; French, et al. (2003) Cancer Res. 63:304-307). In vitro analysis with RNAi supports a causal role for BRD4 in this recurrent t(15; 19) chromosomal translocation. Also, inhibition of the BRD4 bromodomains has been found to result in growth arrest / differentiation of BRD4-NUT cell lines in vitro and in vivo (Filippakopoulos, et al. "Selective Inhibition of BET Bromodomains," Nature (published online September 24, 2010)).

[0098] Bromodomain-containing proteins (such as BET proteins) have also been implicated in inflammatory diseases. BET proteins (e.g., BRD2, BRD3, BRD4, and BRDT) regulate assembly of histone acetylation-dependent chromatin complexes that control inflammatory gene expression (Hargreaves, et al. (2009) Cell 138:129-145; LeRoy, et al. (2008) Mol. Cell 30:51-60; Jang, et al. (2005) Mol. Cell 19:523-534; Yang, et al. (2005) Mol. Cell 19:535-545). Key inflammatory genes (secondary response genes) are down-regulated upon bromodomain inhibition of the BET subfamily, and non-responsive genes (primary response genes) are poised for transcription. BET bromodomain inhibition protects against LPS-induced endotoxic shock and bacteria-induced sepsis in vivo (Nicodeme, et al. "Suppression of Inflammation by a Synthetic Histone Mimic," Nature (published online November 10, 2010)).

[0099] Bromodomain-containing proteins (such as BET proteins) have also been found to play a role in viral infection. For example, BRD4 is implicated in the primary phase of human papilloma virus (HPV) infection, in which the viral genome is maintained in an extra-chromosomal episome in basal epithelia. In some strains of HPV, BRD4 binding to the HPV E2 protein functions to tether the viral genome to chromosomes. E2 is critical for both the repression of E6 / E7 and the activation of HPV viral genes. Disruption of BRD4 or the BRD4-E2 interaction blocks E2-dependent gene activation. BRD4 also functions to tether other classes of viral genomes to host chromatin (e.g., Herpes virus, Epstein-Barr virus).

[0100] Bromodomain-containing proteins has also been found to bind to acetylated lysine residues on proteins other than histones. For example, the bromodomain of CREB binding protein transcriptional coactivator (CBP) allows for recognition of p53 with acetylated Lys382. The interaction between the bromodomain and acetyl-p53 follows DNA damage and promotes p53-induced transcriptional activation of the CDK inhibitor p21 and cell cycle arrest.

[0101] Another novel bromodomain-containing protein is BAZ2B, whose biological function, is believed to function similarly to ACF1, the Drosophila BAZ2B ortholog. ACF complexes play roles in establishing regular nucleosome spacing during chromatin assembly and influencing different remodeling outcomes at target loci.

[0102] One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (I), (Ia), or (Ib). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (II), (IIa), or (IIb). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (III), or (IIIa). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (IV). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (V). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (VIa), (VIb), (VIc), (VId), or (VIe). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (VII) or (VIIa). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (VIII), or (VIIIa). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (IX). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XIII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XIV). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XV). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XVI). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XVII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XVIII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XIX). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XX). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XXI). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XXII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XXIII). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XXIV). One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain containing protein to a compound of Formula (XXV).

[0103] One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (I), (Ia), or (Ib). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (II), (IIa), or (IIb). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (III), or (IIIa). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (IV). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (V). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (VIa), (VIb), (VIc), (VId), or (VIe). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (VII), or (VIIa). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (VIII), or (VIIIa). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (IX). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XII). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XIII). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XIV). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XV). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XVI). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XVII). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XVIII). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XIX). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XX). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XXI). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XXII). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XXIII). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XXIV). One embodiment provides a method of inhibiting bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XXV).

[0104] One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain-containing protein to a compound of Formula (X), or a pharmaceutically acceptable salt thereof, wherein, R 2< is selected from CH 3 , CH 2 CH 3 , CH 2 CF 3 , CH 2 F, CHF 2 , CF 3 , CH 2 D, CHD 2 , or CD 3 ; X5 is C-R 5< or N; X6 is C-R 6< or N; X7 is C-R 7< or N; X8 is C-R 8< or N; wherein no more than two of X5, X6, X7, or X8 may be N; R 5< is hydrogen, halogen, -OH,-CN, -OR 61< , -NHR 61< , -N(R 61< ) 2 , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R 61< is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R 6< is hydrogen, halogen, -OH,-CN, -OR 61< , -NHR 61< , -N(R 61< ) 2 , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R 61< is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R 7< is hydrogen, halogen, -OH,-CN, -OR 61< , -NHR 61< , -N(R 61< ) 2 , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R 61< is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R 8< is hydrogen, halogen, or alkyl; and R A< is an aryl group or a heteroaryl group.

[0105] Another embodiment provides the method of regulating gene transcription in a cell, wherein the compound of Formula (X) has the structure wherein R A< is a substituted phenyl group.

[0106] Another embodiment provides a method of inhibiting of bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (X). Another embodiment provides the method of inhibiting of bromodomain-mediated recognition of an acetyl lysine region of a protein, wherein the compound of Formula (X) has the structure wherein R A< is a substituted phenyl group.

[0107] One embodiment provides a method of regulating gene transcription in a cell comprising exposing a bromodomain-containing protein to a compound of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein, R 2< is CH 3 , CH 2 CH 3 , CH 2 CF 3 , CH 2 F, CHF 2 , CF 3 , CH 2 D, CHD 2 , or CD 3 ; X3 is C-H or N; X5 is C-R 5< or N; provided that if X3 is N, then X5 is C-R 5< , and if X5 is N, then X3 is CH; R 5< is hydrogen, halogen, -OH,-CN, -OR 61< , -NHR 61< , -N(R 61< ) 2 , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R 61< is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R 6< is hydrogen, halogen, -OH,-CN, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, cycloalkylalkylamino, alkoxy, or cycloalkylalkoxy; and R A< is an aryl group or a heteroaryl group.

[0108] Another embodiment provides the method of regulating gene transcription in a cell, wherein the compound of Formula (XI) has the structure wherein R A< is a substituted phenyl group.

[0109] Another embodiment provides a method of inhibiting of bromodomain-mediated recognition of an acetyl lysine region of a protein comprising exposing the bromodomain to a compound of Formula (XI). Another embodiment provides the method of inhibiting of bromodomain-mediated recognition of an acetyl lysine region of a protein, wherein the compound of Formula (XI) has the structure wherein R A< is a substituted phenyl group.Methods of Treatment

[0110] Compounds and compositions described herein are generally useful for the inhibition of activity of one or more proteins involved in epigenetic regulation. Thus, one embodiment provides a method of modulating epigenetic regulation mediated by one or more proteins containing acetyl-lysine recognition motifs, also known as bromodomains (e.g., BET proteins, such as BRD2, BRD3, BRD4, and / or BRDT, and non-BET proteins, such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1, and / or BRPF1), by administering a substituted heterocyclic derivative compound as described herein.

[0111] In some embodiments, the substituted heterocyclic derivative compounds as described herein are capable of inhibiting the activity of a bromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4 and / or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1, and / or BRPF1) or a mutant thereof, in a biological sample in manner useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0112] In some embodiments is provided a method of inhibiting the activity of a bromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4 and / or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1, and / or BRPF 1) or a mutant thereof, in a patient comprising the step of administering to said patient a substituted heterocyclic derivative compound as described herein, or a composition comprising said compound.

[0113] In some embodiments is provided a method of inhibiting the activity of a bromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4 and / or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1, and / or BRPF1) or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a substituted heterocyclic derivative compound as described herein. In some embodiments, the bromodomain-containing protein is a BET protein. In some embodiments, the BET protein is BRD4.

[0114] In some embodiments is provided a method of inhibiting the activity of a bromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4 and / or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1, and / or BRPF1) or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a substituted heterocyclic derivative compound as described herein. In some embodiments, the bromodomain-containing protein is a BET protein. In some embodiments, the BET protein is BRD4.EXAMPLES I. Chemical Synthesis

[0115] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ) and coupling constants (J) are reported in Hertz. For 1< H NMR spectra, the solvent peak was used as the reference peak.

[0116] Chemistry Example 1 is 2-methyl-4-phenylisoquinolin-1-one which was purchased from a commercial vendor.Example 2: 4-(3-methoxyphenyl)-2-methylisoquinolin-1-one

[0117]

[0118] A mixture of 4-bromo-2-methylisoquinolin-1(2H)-one (100 mg, 0.42 mmol), and (3-methoxyphenyl)boronic acid (70 mg, 0.46 mmol), PPh 3 (66 mg, 0.25 mmol), Na 2 CO 3 (133 mg, 1.26 mmol), and Pd(dppf)Cl 2 (62 mg,0.084 mmol) in dioxane (2.5 mL) and water (0.5 mL) was heated overnight at 90 0< C. Extractive work up with ethyl acetate followed by preparative TLC (PE:EA=1:1) gave the title compound (18 mg, 0.07 mmol) as a white solid in 17% yield. 1< H NMR (DMSO, 400 MHz): δ 8.30 (d, 1H, J=7.68), 7.68 (t, 1H, J=7.56), 7.50-7.55 (m, 3H), 7.40 (t, 1H, J= 7.44), 6.97-7.00 (m, 3H), 3.78 (s, 3H), 3.54 (s, 3H). MS (m / z, relative intensity): 266 (M +< , 1).

[0119] Examples 3-14 in Table 3 were prepared from 4-bromo-2-methylisoquinolin-1(2H)-one and the appropriate boronic acid / ester in a manner similar to Example 2. Table 3 Ex . No .R 1< Name 1< H NMR (ppm (δ), 400 MHz) MS (M+H) 3 4-(2-fluorophenyl)-2-methylisoquinoli n-1-one(DMSO-d 6 ) 3.57 (s, 3 H) 7.20 (d, J=7.42 Hz, 1 H) 7.31 - 7.41 (m, 2 H) 7.42 - 7.61 (m, 4 H) 7.64 - 7.73 (m, 1 H) 8.32 (d, J=7.81 Hz, 1 H)2544 4-(2-methoxyphenyl)-2-methylisoquinoli n-1-one(DMSO-d 6 ) 3.54 (s, 3 H) 3.67 (s, 3 H) 7.00 - 7.11 (m, 2 H) 7.15 (d, J=8.20 Hz, 1 H) 7.25 (d, J=6.83 Hz, 1 H) 7.40 (s, 1 H) 7.48 (dt, J=15.91, 7.86 Hz, 2 H) 7.61 (d, J=7.42 Hz, 1 H) 8.28 (d, J=8.20 Hz, 1 H)2665 4-(3-aminophenyl)-2-methylisoquinoli n-1-one(DMSO-d 6 ) 3.55 (s, 3 H) 5.19 (br. s., 2 H) 6.55 (d, J=7.33 Hz, 1 H) 6.60 - 6.64 (m, 2 H) 7.12 (t, J=7.83 Hz, 1 H) 7.43 (s, 1 H) 7.51 - 7.62 (m, 2 H) 7.66 - 7.72 (m, 1 H) 8.31 (d, J=7.83 Hz, 1 H)2516 N-cyclopropyl-3-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfon amide(DMSO-d 6 ) 0.36 - 0.41 (m, 2 H) 0.47 - 0.52 (m, 2 H) 2.16 (br. s., 1 H) 3.57 (s, 3 H) 7.44 (d, J=8.20 Hz, 1 H) 7.54 - 7.61 (m, 2 H) 7.68 - 7.77 (m, 3 H) 7.83 - 7.88 (m, 2 H) 7.96 (br. s., 1 H) 8.34 (d, J=7.81 Hz, 1 H)3557 2-methyl-4-(3-pyrrolidin-1-ylsulfonylphenyl )isoquinolin-1-one(DMSO-d 6 ) 1.67 (t, J=6.64 Hz, 4 H) 3.18 (t, J=6.44 Hz, 4 H) 3.57 (s, 3 H) 7.42 (d, J=8.20 Hz, 1 H) 7.56 (t, J=7.61 Hz, 1 H) 7.61 (s, 1 H) 7.68 - 7.80 (m, 4 H) 7.85 (d, J=6.83 Hz, 1 H) 8.33 (d, J=8.20 Hz, 1 H).3698 N-[[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methyl ]methanesulfona mide(DMSO-d 6 ) 2.87 (s, 3 H) 3.56 (s, 3 H) 4.22 (d, J=6.05 Hz, 2 H) 7.31 - 7.44 (m, 3 H) 7.45 - 7.62 (m, 5 H) 7.64 - 7.72 (m, 1 H) 8.32 (d, J=7.61 Hz, 1 H)3439 N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]metha nesulfonamide(DMSO-d 6 ) 3.03 (s, 3 H) 3.55 (s, 3 H) 7.16 (d, J=7.61 Hz, 1 H) 7.23 - 7.28 (m, 2 H) 7.45 (t, J=8.30 Hz, 1 H) 7.48 - 7.57 (m, 3 H) 7.67 - 7.72 (m, 1 H) 8.31 (d, J=7.03 Hz, 1 H) 9.88 (br. s., 1 H)32910 N-ethyl-3-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfon amide(DMSO-d 6 ) 0.92 - 1.02 (m, 3 H) 2.76 - 2.86 (m, 2 H) 3.56 (s, 3 H) 7.43 (d, J=8.20 Hz, 1 H) 7.53 - 7.60 (m, 2 H) 7.64 (t, J=5.66 Hz, 1 H) 7.68 - 7.75 (m, 3 H) 7.80 - 7.88 (m, 2 H) 8.29 - 8.36 (m, 1 H)34311 4-(3-ethylsulfonylphe nyl)-2-methylisoquinoli n-1-one(CHLOROFORM-d) 1.33 (t, J=7.42 Hz, 3 H) 3.18 (q, J=7.42 Hz, 2 H) 3.65 - 3.69 (m, 3 H) 7.10 (s, 1 H) 7.43 (d, J=8.01 Hz, 1 H) 7.51 - 7.57 (m, 1 H) 7.60 - 7.76 (m, 3 H) 7.93 - 7.98 (m, 2 H) 8.53 (dd, J=8.01, 0.98 Hz, 1 H)32812 4-[3-(dimethylsulfam oylamino)phenyl ]-2-methyl-1-oxoisoquinoline(DMSO-d 6 ) 2.71 (s, 6 H) 3.55 (s, 3 H) 7.10 (d, J=7.03 Hz, 1 H) 7.22 - 7.25 (m, 2 H) 7.41 (t, J=7.71 Hz, 1 H) 7.48 (s, 1 H) 7.50 - 7.56 (m, 2 H) 7.67 - 7.72 (m, 1 H) 8.31 (d, J=7.81 Hz, 1 H) 10.02 (br. s., 1 H)35813 N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethane sulfonamide(DMSO-d 6 ) 1.20 (t, J=7.13 Hz, 3 H) 3.13 (q, J=7.29 Hz, 2 H) 3.55 (s, 3 H) 7.14 (d, J=7.03 Hz, 1 H) 7.25 (br. s., 2 H) 7.38 - 7.59 (m, 4 H) 7.69 (t, J=7.61 Hz, 1 H) 8.31 (d, J=8.01 Hz, 1 H) 9.92 (s, 1 H)34314 2-methyl-4-(3-morpholin-4-ylsulfonylphenyl )isoquinolin-1-one(DMSO-d 6 ) 3.02 - 3.09 (m, 4 H) 3.68 (s, 3 H) 3.73 - 3.80 (m, 4 H) 7.09 (s, 1 H) 7.43 (d, J=7.81 Hz, 1 H) 7.53 - 7.58 (m, 1 H) 7.61 - 7.73 (m, 3 H) 7.78 - 7.84 (m, 2 H) 8.55 (d, J=7.03 Hz, 1 H)385 Example 15: N-benzyl-2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide

[0120]

[0121] For about 3 min, N 2 was bubbled through the mixture of 4-bromo-2-methylisoquinolin-1(2H)-one (56 mg, 0.24 mmol), [3-(benzylsulfamoyl)-4-methoxyphenyl]boronic acid (83 mg, 0.26 mmol), aqueous 2M Na 2 CO 3 (0.375 mL) and Pd(dppf)Cl 2 (9 mg,0.001 mmol) in dioxane (1.5 mL) which was then microwaved at 120 0< C for 1 h and then filtered through a plug of anhydrous Na 2 SO 4 using ethyl acetate to transfer and rinse. Silica gel chromatography, eluting with 0-60% EA in hexane over 6 min and continuing 60% isocratic EA gave the title compound (60 mg, 0.14 mmol) as a white solid in 58% yield. 1< H NMR (400 MHz, DMSO-d 6 ) δ 3.57 (s, 3 H), 3.89 (s, 3 H), 4.11 (d, J=6.32 Hz, 2 H), 7.16 - 7.23 (m, 6 H), 7.34 (d, J=8.08 Hz, 1 H), 7.47 (s, 1 H), 7.53 - 7.59 (m, 2 H), 7.65 (d, J=2.27 Hz, 1 H), 7.72 - 7.77 (m, 1 H), 7.94 (t, J=6.32 Hz, 1 H), 8.34 (d, J=7.33 Hz, 1 H). LCMS (M+H) +< 435.

[0122] Examples 16-17 in Table 4 were prepared from 4-bromo-2-methylisoquinolin-1(2H)-one and the appropriate boronic acid / ester in a manner similar to Example 15. Table 4 Ex. No. R 1< Name 1< H NMR (ppm (δ), 400 MHz) MS (M+H) 16 2-methoxy-5-(2-methyl-1-oxoisoquinoli n-4-yl)benzenesul fonamide(DMSO-d 6 ) 3.57 (s, 3 H) 3.97 (s, 3 H) 7.18 (s, 2 H) 7.35 (d, J=8.59 Hz, 1 H) 7.44 (d, J=8.08 Hz, 1 H) 7.50 (s, 1 H) 7.57 (t, J=7.45 Hz, 1 H) 7.65 (dd, J=8.46, 2.15 Hz, 1 H) 7.71 (t, J=7.58 Hz, 1 H) 7.76 (d, J=2.27 Hz, 1 H) 8.34 (d, J=8.34 Hz, 1 H)34517 N-[2-methyl-5-(2-methyl-1-oxoisoquinoli n-4-yl)phenyl]me thanesulfona mide(DMSO-d 6 ) 2.38 (s, 3 H) 3.02 (s, 3 H) 3.57 (s, 3 H) 7.24 (dd, J=7.83, 1.77 Hz, 1 H) 7.34 (d, J=1.52 Hz, 1 H) 7.38 (d, J=7.83 Hz, 1 H) 7.50 (s, 1 H) 7.53 - 7.58 (m, 2 H) 7.67 - 7.72 (m, 1 H) 8.30 - 8.36 (m, 1 H) 9.18 (s, 1 H)343 Example 18: N-benzyl-2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl)benzamide Step 1: N-benzyl-5-bromo-2-methoxybenzamide

[0123]

[0124] To an ice bath cooled mixture of 5-bromo-2-methoxybenzoic acid (439 mg, 1.9 mmol) in 1:1 CH 2 Cl 2 :DMF (4 mL) was added benzylamine (0.228 mL, 2.1 mmol), EDCI (438mg, 2.3 mmol), HOBt (311 mg, 2.3 mmol) and NEtiPr 2 (0.496 mL, 2.85 mmol). The mixture was then stirred at room temperature until the reaction was complete. Extractive work up with ethyl acetate, washing with saturated aqueous NaHCO 3 , H 2 O, saturated aqueous KHSO 4 and brine, gave the title compound (550 mg) after isolation which was carried forward without purification. LCMS (M+H) +< 320, 322.Step 2: N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[0125]

[0126] For about 3 min, N 2 was bubbled through a mixture of the title compound of N-benzyl-5-bromo-2-methoxybenzamide (174 mg, 0.54 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (166 mg, 0.65 mmol), potassium acetate (159 mg, 1.62 mmol) and Pd(dppf)Cl 2 (20 mg,0.03 mmol) in anhydrous DMF (4.2 mL). After heating at 90 0< C for about 2 h under N 2 , silica gel chromatography, eluting with 0-40% EA in hexane over 7 min and continuing 40% isocratic EA gave the title compound (138 mg, 0.38 mmol) as a white solid in 70% yield. LCMS (M+H) +< 368.Step 3: N-benzyl-2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl)benzamide

[0127]

[0128] For about 3 min, N 2 was bubbled through a mixture of N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (51 mg, 0.14 mmol), 4-bromo-2-methylisoquinolin-1(2H)-one (30 mg, 0.13 mmol), aqueous 1M K 3 PO 4 (0.3 mL) and Pd(dppf)Cl 2 (10 mg,0.013 mmol) in dioxane (1.15 mL) which was then microwaved at 100 0< C for 1 h. Work up similar to Example 15 and purification by silica gel chromatography, eluting with 5-50% EA in hexane over 4 min and continuing 50% isocratic EA gave the title compound (37 mg, 0.14 mmol) as a tan solid in 71% yield. 1< H NMR (400 MHz, DMSO-d 6 ) δ 3.57 (s, 3 H), 3.97 (s, 3 H), 4.52 (d, J=6.06 Hz, 2 H), 7.21 - 7.37 (m, 6 H), 7.47 - 7.51 (m, 2 H), 7.56 (td, J=5.37, 2.15 Hz, 2 H), 7.68 - 7.73 (m, 1 H), 7.79 (d, J=2.27 Hz, 1 H), 8.33 (d, J=7.83 Hz, 1 H), 8.79 (t, J=6.06 Hz, 1 H). LCMS (M+H) +< 399.

[0129] Examples 19-31 in Table 5 were prepared from 4-bromo-2-methylisoquinolin-1(2H)-one and the appropriate boronic acid / ester in a manner similar to Example 18, step 3. For Examples 20-26 the microwave temperature was increased to 120 0< C. Aniline hydrochlorides were prepared by treating the aniline with anhydrous HCl in methanol as the final step. Table 5 Ex. No. R 1< Name 1< H NMR (ppm (δ), 400 MHz) MS (M+H) 19 4-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-methylisoqui nolin-1-one(DMSO-d 6 ) 3.50 - 3.59 (m, 3 H) 4.14 - 4.19 (m, 2 H) 5.87 (br. s., 1 H) 6.51 (dd, J=8.08, 2.02 Hz, 1 H) 6.61 (d, J=2.02 Hz, 1 H) 6.74 (d, J=8.08 Hz, 1 H) 7.38 (s, 1 H) 7.50 - 7.55 (m, 1 H) 7.58 (d, J=7.83 Hz, 1 H) 7.66 - 7.72 (m, 1 H) 8.30 (d, J=8.08 Hz, 1 H)29320 2-methyl-4-(2-oxo-1,3-dihydroindol-6-yl)isoquinolin -1-one(DMSO-d 6 ) 3.55 (s, 2 H) 3.56 (s, 3 H) 6.85 (s, 1 H) 7.00 (dd, J=7.58, 1.52 Hz, 1 H) 7.32 (d, J=7.58 Hz, 1 H) 7.49 (s, 1 H) 7.53 - 7.58 (m, 2 H) 7.67 - 7.72 (m, 1 H) 8.31 - 8.35 (m, 1 H) 10.47 (s, 1 H)29121 3-(2-methyl-1-oxoisoquinoli n-4-yl)benzenesul fonamide(DMSO-d 6 ) 3.59 (s, 3 H) 7.43 (s, 2 H) 7.48 (d, J=8.08 Hz, 1 H) 7.56 - 7.61 (m, 2 H) 7.67 - 7.75 (m, 3 H) 7.87 - 7.92 (m, 2 H) 8.36 (d, J=8.08 Hz, 1 H)31522 N-(2-hydroxyethyl )-3-(2-methyl-1-oxoisoquinoli n-4-yl)benzenesul fonamide(DMSO-d 6 ) 2.85 (q, J=6.06 Hz, 2 H) 3.39 (q, J=6.06 Hz, 2 H) 3.59 (s, 3 H) 4.70 (t, J=5.56 Hz, 1 H) 7.47 (d, J=8.08 Hz, 1 H) 7.56 - 7.59 (m, 1 H) 7.61 (s, 1 H) 7.66 - 7.77 (m, 4 H) 7.83 - 7.88 (m, 2 H) 8.36 (d, J=8.08 Hz, 1 H)35923 4-(5-amino-2-fluorophenyl) -2-methylisoqui nolin-1-one hydrochloride(DMSO-d 6 ) 3.57 (s, 3 H partially obscured) 7.08 - 7.22 (m, 2 H) 7.24 (d, J=9.60 Hz, 1 H) 7.32 (t, J=9.09 Hz, 1 H) 7.54 - 7.60 (m, 2 H) 7.67 - 7.73 (m, 1 H) 8.32 (d, J=7.83 Hz, 1 H26924 4-(5-amino-2,4-difluorophen yl)-2-methylisoqui nolin-1-one hydrochloride(DMSO-d 6 ) 3.55 (s, 3 H) 6.83 (dd, J=9.73, 7.96 Hz, 1 H) 7.19 - 7.28 (m, 2 H) 7.51 - 7.58 (m, 2 H) 7.67 - 7.72 (m, 1 H) 8.30 (d, J=8.08 Hz, 1 H)28725 4-(3-amino-5-fluorophenyl) -2-methylisoqui nolin-1-one hydrochloride(DMSO-d 6 ) 3.55 (s, 3 H) 6.47 - 6.56 (m, 2 H) 6.59 (s, 1 H) 7.51 (s, 1 H) 7.52 - 7.62 (m, 2 H) 7.69 - 7.75 (m, 1 H) 8.32 (d, J=8.08 Hz, 1 H)26926 4-(3-amino-4-fluorophenyl) -2-methylisoqui nolin-1-one hydrochloride(DMSO-d 6 ) 3.55 (s, 3 H) 6.64 (d, J=2.53 Hz, 1 H) 6.89 (dd, J=8.59, 2.02 Hz, 1 H) 7.13 (dd, J=11.49, 8.21 Hz, 1 H) 7.45 (s, 1 H) 7.52 - 7.58 (m, 2 H) 7.67 - 7.74 (m, 1 H) 8.32 (d, J=7.07 Hz, 1 H)26927 N-benzyl-3-(2-methyl-1-oxoisoquinoli n-4-yl)benzenesul fonamide(DMSO-d 6 ) 3.59 (s, 3 H) 4.08 (d, J=6.06 Hz, 2 H) 7.17 - 7.29 (m, 5 H) 7.40 (d, J=7.83 Hz, 1 H) 7.54 (s, 1 H) 7.58 (t, J=7.58 Hz, 1 H) 7.68 - 7.76 (m, 3 H) 7.80 (s, 1 H) 7.85 (td, J=4.48, 1.89 Hz, 1 H) 8.26 (t, J=6.32 Hz, 1 H) 8.35 (d, J=8.08 Hz, 1 H)40528 N-[3-(2-methyl-1-oxoisoquinoli n-4-yl)phenyl]pro pane-1-sulfonamide(DMSO-d 6 ) 0.96 (t, J=7.45 Hz, 3 H) 1.72 (sxt, J=7.48 Hz, 2 H) 3.10 - 3.15 (m, 2 H) 3.57 (s, 3 H) 7.16 (d, J=7.58 Hz, 1 H) 7.26 - 7.30 (m, 2 H) 7.43 - 7.59 (m, 4 H) 7.68 - 7.73 (m, 1 H) 8.34 (d, J=7.83 Hz, 1 H) 9.91 (s, 1 H)35729 N-[3-(2-methyl-1-oxoisoquinoli n-4-yl)phenyl]butane-1-sulfonamide(DMSO-d 6 ) 0.84 (t, J=7.33 Hz, 3 H) 1.37 (sxt, J=7.38 Hz, 2 H) 1.67 (dt, J=15.35, 7.61 Hz, 2 H) 3.10 - 3.18 (m, 2 H) 3.57 (s, 3 H) 7.16 (d, J=7.58 Hz, 1 H) 7.24 - 7.33 (m, 2 H) 7.41 - 7.60 (m, 4 H) 7.64 - 7.74 (m, 1 H) 8.34 (d, J=8.08 Hz, 1 H) 9.91 (s, 1 H)37130 N-[2-methoxy-5-(2-methyl-1-oxoisoquinoli n-4-yl)phenyl]me thanesulfona mide(DMSO-d 6 ) 3.00 (s, 3 H) 3.57 (s, 3 H) 3.90 (s, 3 H) 7.18 - 7.23 (m, 1 H) 7.24 - 7.30 (m, 1 H) 7.33 (d, J=2.27 Hz, 1 H) 7.47 (s, 1 H) 7.55 (dd, J=7.58, 5.05 Hz, 2 H) 7.65 - 7.73 (m, 1 H) 8.31 - 8.37 (m, 1 H) 9.04 (s, 1 H)35931 tert-butyl N-methyl-N-[3-(2-methyl-1-oxoisoquinoli n-4-yl)phenyl]car bamate(DMSO-d 6 ) 1.41 (s, 9 H) 3.24 (s, 3 H) 3.57 (s, 3 H) 7.25 (d, J=7.33 Hz, 1 H) 7.32 - 7.38 (m, 2 H) 7.44 - 7.60 (m, 4 H) 7.67 - 7.73 (m, 1 H) 8.34 (d, J=7.83 Hz, 1 H)365 Example 32: 2-methyl-4-[3-(methylamino)phenyl]isoquinolin-1-one hydrochloride

[0130]

[0131] To the title compound of Example 31 (48 mg, 0.13 mmol) was added 4 M HCl in dioxane (3 mL). After stirring about 1 h, the volatile components were removed under vacuum. Hexane was added and evaporated (x2). The resulting white solid was dried under vacuum to give the title compound (39 mg, 0.13 mmol) in quantitative yield. 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.85 (s, 3 H), 3.57 (s, 3 H), 7.10 (br. s., 3 H), 7.44 (br. s., 1 H), 7.51 - 7.60 (m, 3 H), 7.68 - 7.74 (m, 1 H), 8.34 (d, J=7.58 Hz, 1 H). LCMS (M+H) +< 265.Example 33: N-methyl-N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide

[0132]

[0133] To the title compound of Example 32 (35 mg, 0.12 mmol) in anhydrous CH 2 Cl 2 (0.3 mL), pyridine (0.1 mL) and NEtiPr 2 (0.021 mL, 0.12 mmol) was added methanesulfonyl chloride (0.011 mL, 0.14 mmol). After 0.5-1 h, ice was added to the mixture followed by water and ethyl acetate. Extractive work up, washing with H 2 O, a 1:1 aqueous saturated KHSO 4 :H 2 O, and brine, and purification on silica gel eluting with 35-80% EA in hexane over 6 min and continuing 80% isocratic EA gave the title compound (22 mg, 0.06 mmol) as a cream solid in 54% yield. 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.00 (s, 3 H), 3.30 (s, 3 H), 3.58 (s, 3 H), 7.40 (d, J=7.58 Hz, 1 H), 7.45 - 7.61 (m, 6 H), 7.71 (td, J=7.58, 1.26 Hz, 1 H), 8.34 (dd, J=8.21, 1.14 Hz, 1 H). LCMS (M+H) +< 343.

[0134] Examples 34-40 in Table 6 were prepared in one step by sulfonylation of the aniline Examples 23-26 from Table 5 using methanesulfonyl chloride in a manner similar to Example 33 (1 step from the indicated Example No.) or in two steps from 4-bromo-2-methylisoquinolin-1(2H)-one and the appropriate aniline boronic acid / ester in a manner similar to Example 23 followed by sulfonylation of the aniline with methanesulfonyl chloride in a manner similar to Example 33 (2 steps). Table 6 Ex. No. R 1< Name No. of steps (from Ex. No.) 1< H NMR (ppm (δ), 400 MHz) MS (M+H ) 34 N-[4-fluoro-3-(2-methyl-1-oxoisoquinol in-4-yl)phenyl]m ethanesulfon amide1 step (from Ex. 23) 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.04 (s, 3 H) 3.57 (s, 3 H) 7.22 - 7.27 (m, 2 H) 7.30 - 7.40 (m, 2 H) 7.53 - 7.59 (m, 1 H) 7.61 (s, 1 H) 7.66 - 7.74 (m, 1 H) 8.32 (d, J=8.08 Hz, 1 H) 9.83 (s, 1 H)34735 N-[2,4-difluoro-5-(2-methyl-1-oxoisoquinol in-4-yl)phenyl]m ethanesulfon amide1 step (from Ex. 24) 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.08 (s, 3 H) 3.57 (s, 3 H) 7.24 (d, J=8.08 Hz, 1 H) 7.45 (t, J=8.21 Hz, 1 H) 7.53 - 7.60 (m, 2 H) 7.62 (s, 1 H) 7.70 (t, J=7.58 Hz, 1 H) 8.32 (d, J=7.83 Hz, 1 H) 9.70 (s, 1 H)36536 N-[3-fluoro-5-(2-methyl-1-oxoisoquinol in-4-yl)phenyl]m ethanesulfon amide1 step (from Ex. 25) 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.12 (s, 3 H) 3.57 (s, 3 H) 7.01 - 7.13 (m, 3 H) 7.54 - 7.63 (m, 3 H) 7.70 - 7.77 (m, 1 H) 8.33 (d, J=8.08 Hz, 1 H) 10.16 (s, 1 H)34737 N-[2-fluoro-5-(2-methyl-1-oxoisoquinol in-4-yl)phenyl]m ethanesulfon amide1 step (from Ex. 26) 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.09 (s, 3 H) 3.57 (s, 3 H) 7.28 - 7.36 (m, 1 H) 7.39 - 7.48 (m, 2 H) 7.49 - 7.60 (m, 3 H) 7.67 - 7.74 (m, 1 H) 8.34 (d, J=8.08 Hz, 1 H) 9.75 (s, 1 H)34738 N-[4-chloro-3-(2-methyl-1-oxoisoquinol in-4-yl)phenyl]m ethanesulfon amide2 steps 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.08 (s, 3 H) 3.56 (s, 3 H) 7.07 (d, J=7.83 Hz, 1 H) 7.23 (d, J=2.78 Hz, 1 H) 7.33 (dd, J=8.72, 2.65 Hz, 1 H) 7.51 - 7.62 (m, 3 H) 7.64 - 7.70 (m, 1 H) 8.28 - 8.36 (m, 1 H) 10.04 (s, 1 H)363, 36539 N-[4-methyl-3-(2-methyl-1-oxoisoquinol in-4-yl)phenyl]m ethanesulfon amide2 steps 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 2.01 (s, 3 H) 3.00 (s, 3 H) 3.56 (s, 3 H) 7.02 (d, J=8.08 Hz, 1 H) 7.06 (d, J=2.53 Hz, 1 H) 7.22 (dd, J=8.21, 2.40 Hz, 1 H) 7.33 (d, J=8.34 Hz, 1 H) 7.45 (s, 1 H) 7.51 - 7.56 (m, 1 H) 7.63 - 7.68 (m, 1 H) 8.32 (d, J=8.08 Hz, 1 H) 9.71 (s, 1 H)34340 N-[3-(2-methyl-1-oxoisoquinol in-4-yl)-5-(trifluoromet hyl)phenyl] methanesulf onamide2 steps 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.14 (s, 3 H) 3.58 (s, 3 H) 7.49 - 7.52 (m, 2 H) 7.54 - 7.61 (m, 3 H) 7.64 (s, 1 H) 7.70 - 7.76 (m, 1 H) 8.35 (d, J=8.08 Hz, 1 H) 10.29 (s, 1 H)397 Example 41: N-[4-fluoro-3-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]methanesulfonamideStep 1: 2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0135]

[0136] A mixture of 6-bromo-2-methylisoquinolin-1-one (3.8 g, 16 mmol), 1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.69 g, 32 mmol), CsF (7.29 g, 48 mmol), Pd(PPh 3 ) 2 Cl 2 (0.4 g, 1mmol) in dioxane / H 2 O (60 / 10 mL) was stirred at 90 °C for 12 h under N 2 . The mixture was concentrated and the residue was purified by silica gel chromatography (PE:EA = 2:1) to give the title compound (3.1 g, 81%) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.40 (d, J = 12 Hz, 1 H), 7.87 (s, 1 H), 7.74 (s, 1 H), 7.59-7.56 (dt, J 1 = 4 Hz, J 2 = 8 Hz, 2 H), 7.07 (d, J = 4 Hz, 1 H), 6.48 (d, J = 8 Hz, 1 H) 3.98 (s, 3 H), 3.61 (s, 3 H). LCMS: 240.0 (M+H) +< Step 2: 4-bromo-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0137]

[0138] Bromine (1.8 g, 11.25 mmol) in HOAc (6 mL) was added to the title compound of 2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (3 g, 12.5 mmol) in HOAc (24 mL) at 0 °C. The mixture was stirred at 30 °C for 15 min, quenched with H 2 O (100 mL), and the resulting yellow solid was collected by filtration to give the title compound (2.04 g, 56%). 1< H NMR (CDCl 3 , 400 MHz) δ 8.42 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 28.8 Hz, 2 H), 7.82(d, J = 15.6 Hz, 2 H), 7.65 (d, J = 8 Hz, 2 H), 7.38 (s, 1 H), 4.00 (s, 3 H), 3.61 (s, 3 H). LCMS: 318.0 (M+H) +< Step 3: 4-(5-amino-2-fluorophenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0139]

[0140] 4-Bromo-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (35 mg, 0.11 mmol), 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (29 mg, 0.12 mmol), Pd(dppf)Cl 2 (8 mg, 0.01 mmol) and aqueous 1 M K 3 PO 4 (0.3 mL) in dioxane (1.2 mL) were microwaved at 120 °C for 1.25 h. Work up was similar to that described for Example 18, step 3. Silica gel chromatography, eluting with 100% EA followed by 10% methanol in EA, gave the title compound (25 mg, 0.07 mmol) as a cream solid in 64% yield. LCMS (M+H) +< 349.Step 4: N-[4-fluoro-3-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]methanesulfonamide

[0141]

[0142] 4-(5-Amino-2-fluorophenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (25 mg, 0.07 mmol) in pyridine (0.1 mL) and anhydrous CH 2 Cl 2 (0.3 mL) was treated with methanesulfonyl chloride (0.007 mL, 0.09 mmol) in a manner similar to Example 33. After a similar work up, silica gel chromatography, eluting with 50-100% EA in heaxane over 4 min and continuing isocratic 100% EA, gave the title compound (24 mg, 0.06 mmol) as a white solid in 78% yield. 1< H NMR (400 MHz, DMSO-d 6 ) δ 3.06 (s, 3 H), 3.56 (s, 3 H), 3.85 (s, 3 H), 7.22 - 7.45 (m, 4 H), 7.59 (s, 1 H), 7.76 (dd, J=8.34, 1.52 Hz, 1 H), 7.85 (s, 1 H), 8.16 (s, 1 H), 8.29 (d, J=8.34 Hz, 1 H), 9.82 (s, 1 H). LCMS (M+H) +< 427.

[0143] Examples 42-45 in Table 7 were prepared from title compound of Example 41, step 2, in one step using the appropriate phenyl boronic acid / ester in a manner similar to Example 18, step 3, (1 step) or in two steps from the aniline boronic acid / ester followed sulfonylation of the aniline with the either methanesulfonyl chloride or ethanesulfonyl chloride in a manner similar to Example 41, steps 3 and 4, (2 steps). Table 7 Ex. No. R 1< Name No. of steps (from Ex. No.) 1< H NMR (ppm (δ), 400 MHz) MS (M+H) 42 N-[3-[2-methyl-6-(1-methylpyrazol -4-yl)-1-oxoisoquinoli n-4-yl]phenyl]met hanesulfonam ide1 step(DMSO-d 6 ) 3.07 (s, 3 H) 3.56 (s, 3 H) 3.85 (s, 3 H) 7.23 (d, J=7.83 Hz, 1 H) 7.28 (d, J=8.08 Hz, 1 H) 7.34 (s, 1 H) 7.41 - 7.54 (m, 2 H) 7.66 (s, 1 H) 7.72 - 7.80 (m, 1 H) 7.86 (s, 1 H) 8.16 (s, 1 H) 8.30 (d, J=8.34 Hz, 1 H) 9.87 (s, 1 H)40943 N-[2,4-difluoro-5-[2-methyl-6-(1-methylpyrazol -4-yl)-1-oxoisoquinoli n-4-yl]phenyl]met hanesulfonam ide2 steps(DMSO-d 6 ) 3.10 (s, 3 H) 3.55 (s, 3 H) 3.85 (s, 3 H) 7.33 (s, 1 H) 7.44 - 7.63 (m, 3 H) 7.77 (dd, J=8.59, 1.52 Hz, 1 H) 7.89 (s, 1 H) 8.19 (s, 1 H) 8.28 (d, J=8.34 Hz, 1 H) 9.71 (s, 1 H)44544 4-(3-ethylsulfonylp henyl)-2-methyl-6-(1-methylpyrazol -4-yl)isoquinolin -1-one1 step(DMSO-d 6 ) 1.17 (t, J=7.33 Hz, 3 H) 3.40 (q, J=7.41 Hz, 2 H) 3.58 (s, 3 H) 3.85 (s, 3 H) 7.56 (s, 1 H) 7.63 (s, 1 H) 7.75 - 8.00 (m, 6 H) 8.16 (s, 1 H) 8.32 (d, J=8.34 Hz, 1 H)40945 N-[4-chloro-3-[2-methyl-6-(1-methylpyrazol -4-yl)-1-oxoisoquinoli n-4-yl]phenyl]etha nesulfonamid e2 steps(DMSO-d 6 ) 1.14 - 1.28 (m, 3 H) 3.11 - 3.28 (m, 2 H) 3.55 (s, 3 H) 3.84 (s, 3 H) 7.13 (s, 1 H) 7.26 (d, J=2.53 Hz, 1 H) 7.36 (dd, J=8.72, 2.65 Hz, 1 H) 7.54 (s, 1 H) 7.61 (d, J=8.84 Hz, 1 H) 7.72 - 7.77 (m, 1 H) 7.81 (s, 1 H) 8.12 (s, 1 H) 8.28 (d, J=8.34 Hz, 1 H) 10.08 (s, 1 H)457, 459 Example 46: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-oneStep 1: 2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene

[0144]

[0145] A mixture of 2-bromo-4-methanesulfonylphenol (7.2 g, 29 mmol), (chloromethyl)cyclopropane (4.3 g, 32 mmol) and K 2 CO 3 (8 g, 58 mmol) in acetone (80 mL) was stirred at 80 °C for 5 h. The mixture was quenched with water (40 mL). Extractive work up with ethyl acetate and purification by preparative HPLC gave the title compound (2.5 g, 28.6%). 1< H NMR (CDCl 3 , 400 MHz) δ 8.12 (d, J=2.3 Hz, 1 H), 7.84 (dd, J 1 = 2.3 Hz, J 2 = 8.7 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 1 H), 3.99 (d, J = 6.7 Hz, 2 H), 3.05 (s, 3 H), 1.23-1.43 (m, 1 H), 0.70 (d, J = 7.9 Hz, 2 H), 0.44 (d, J = 5.4 Hz, 2 H). Step 2: 2-methyl-6-(1-methylpyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

[0146] A mixture of the title compound of Example 41, step 2 (1.4 g, 4.41 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.24 g, 8.83 mmol), KOAc (1.08 g, 11.08mmol), Pd(dppf)Cl 2 (100 mg, 0.137 mmol) in dioxane (50 mL) was stirred at 90 °C for 12 h under N 2 . Purification by column chromatography on silica gel (PE:EA = 3:1) gave the title compound (200 mg, 12%) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.55 (d, J = 1.5 Hz,1 H), 8.40 (d, J = 8.4 Hz, 1 H), 7.90 (s,1 H), 7.71 (d, J = 16.8 Hz, 2 H), 4.00 (s, 3 H), 3.63 (s, 3 H), 1.40 (s, 12 H)Step 3: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0147]

[0148] A mixture of 2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene (20.8 mg, 0.068 mmol), 2-methyl-6-(1-methylpyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (30 mg, 0.08 mmol), NaHCO 3 (14.28 mg, 0.17 mmol), and Pd(dppf)Cl 2 (10 mg, 0.014 mmol) in dioxane (2.0 mL) and H 2 O (0.5 mL) was microwaved under N 2 at 100 °C for 30 min. Purification by preparative HPLC gave the title compound (11 mg, 28%) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.48 (d, J =8.4 Hz, 1 H), 7.98-8.04 (m, 1 H), 7.89 (d, J=2.4 Hz, 1 H), 7.68 (s, 1 H), 7.63 (s, 1 H), 7.58-7.62 (m, 1 H), 7.19-7.21 (m, 1 H), 7.11-7.15 (m, 1 H), 7.09 (s, 1 H), 3.93 (s, 3 H), 3.83-3.91 (m, 2 H), 3.66 (s, 3 H), 3.12 (s, 3 H), 0.94-1.04 (m, 1 H), 0.30-0.40 (m, 2 H), 0.00-0.12 (m, 2 H). LCMS: 464.1 (M+H) +< Example 47: N-[3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamideStep 1: 6-fluoro-2-methylisoquinolin-1-one

[0149]

[0150] Sodium hydride (60% in mineral oil) (211 mg, 5.27 mmol) was added to 6-fluoro-1,2-dihydroisoquinolin-1-one (716 mg, 4.39 mmol) in anhydrous DMF (6 mL) cooled in an ice bath. The mixture was stirred for about 30 min at room temperature and methyl iodide (0.328 mL, 5.27 mmol) was added dropwise. After 1 h, the reaction was judged to be about 60% complete and additional methyl iodide (0.2 mL, 3.2 mmol) was added. After about 1 h, ice and water and ethyl acetate were added to the mixture. After extractive work up with ethyl acetate, the title compound (836 mg) was obtained as a cream solid and carried on without purification.Step 2: 4-bromo-6-fluoro-2-methylisoquinolin-1-one

[0151]

[0152] Bromine (232 mg, 1.45 mmol, 0.097 mL) in acetic acid (1.0 mL) was added dropwise, quickly to 6-fluoro-2-methylisoquinolin-1-one (283 mg, 1.61 mmol) in acetic acid (7.0 mL) under N 2 and cooled in an ice bath. The ice bath was removed and the thick suspension was stirred for 10 min at room temperature. Ice and water and ethyl acetate were added. Extractive work up with ethyl acetate, washing with aqueous 0.5 N NaOH, H 2 O, saturated aqueous KHSO 4 and brine, gave the title compound as a cream solid (313 mg) which was carried on without purification.Step 3: N-[3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide

[0153]

[0154] For about 3 min N 2 was bubbled through a mixture of 4-bromo-6-fluoro-2-methylisoquinolin-1-one (41 mg, 0.16 mmol), (3-methanesulfonamidophenyl)boronic acid (38 mg, 0.18 mmol), aqueous 1 M K 3 PO 4 (0.3 mL) and Pd(dppf)Cl 2 (12 mg,0.016 mmol) in dioxane (1.2 mL) which was then microwaved for 1 h at 120 0< C. Work up was similar to that described for Example 18, step 3. Purification using silica gel chromatography, eluting with 40-80% EA in hexane over 5 min and continuing 80% isocratic EA gave the title compound (28 mg, 0.08 mmol) as a cream solid in a combined yield of 38% over steps 1-3. 1< H NMR (400 MHz, DMSO-d 6 ) δ 3.06 (s, 3 H), 3.56 (s, 3 H), 7.15 - 7.22 (m, 2 H), 7.25 - 7.31 (m, 2 H), 7.41 (td, J=8.65, 2.65 Hz, 1 H), 7.45 - 7.52 (m, 1 H), 7.61 (s, 1 H), 8.40 (dd, J=9.09, 6.06 Hz, 1 H), 9.88 (s, 1 H). LCMS (M+H) +< 347.

[0155] Examples 48-50 in Table 8 were prepared from title compound of Example 47, step 2, in one step using the appropriate phenyl boronic acid / ester in a manner similar to Example 47, step 3 (1 step) or in two steps from the appropriate aniline boronic acid / ester in a manner similar to Example 47, step 3 followed by sulfonylation of the aniline with either methanesulfonyl chloride or ethanesulfonyl chloride in a manner similar to Example 41, step 4 (2 steps). Table 8 Ex. No. R 1< Name No. of steps (fro m Ex. No.) 1< H NMR (ppm (δ), 400 MHz) MS (M+H ) 48 3-(6-fluoro-2-methyl-1-oxoisoquinol in-4-yl)benzenesu lfonamide1(DMSO-d 6 ) 3.58 (s, 3 H) 7.11 (dd, J=10.61, 2.53 Hz, 1 H) 7.41 - 7.49 (m, 3 H) 7.65 - 7.76 (m, 3 H) 7.87 - 7.93 (m, 2 H) 8.42 (dd, J=8.84, 6.06 Hz, 1 H)33349 N-ethyl-3-(6-fluoro-2-methyl-1-oxoisoquinol in-4-yl)benzenesu lfonamide1(DMSO-d 6 ) 1.00 (t, J=7.33 Hz, 3 H) 2.81 - 2.89 (m, 2 H) 3.58 (s, 3 H) 7.09 (dd, J=10.36, 2.53 Hz, 1 H) 7.44 (td, J=8.65, 2.40 Hz, 1 H) 7.65 (t, J=5.68 Hz, 1 H) 7.69 (s, 1 H) 7.72 - 7.79 (m, 2 H) 7.82 - 7.90 (m, 2 H) 8.42 (dd, J=9.09, 6.06 Hz, 1 H)36150 N-[4-chloro-3-(6-fluoro-2-methyl-1-oxoisoquinol in-4-yl)phenyl]eth anesulfonami de2(DMSO-d 6 ) 1.22 (t, J=7.33 Hz, 3 H) 3.16 - 3.24 (m, 2 H) 3.56 (s, 3 H) 6.72 (dd, J=10.23, 2.40 Hz, 1 H) 7.24 (d, J=2.53 Hz, 1 H) 7.34 (dd, J=8.59, 2.78 Hz, 1 H) 7.40 (td, J=8.72, 2.53 Hz, 1 H) 7.60 (d, J=8.84 Hz, 1 H) 7.65 (s, 1 H) 8.38 (dd, J=8.84, 5.81 Hz, 1 H) 9.86 - 10.28 (m, 1 H)395, 397 Example 51: N-[3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methanesulfonamide Step 1: 2-methyl-2,7-naphthyridin-1-one

[0156]

[0157] Sodium hydride (2.9 g, 72.5 mmol, 60% in oil) was added in portions to 2H-2,7-naphthyridin-1-one (3.5 g, 24.0 mmol) in dry DMF (50 mL) at 0 °C. After stirring at 0 °C for 30 min, MeI (17.0 g, 118.7 mmol) was added and the mixture was stirred for an additional 30 min. Saturated aqueous NH 4 Cl (250 mL) and ethyl acetate (100 mL) were added. Extractive work up with ethyl acetate and purification by silica gel chromatography (DCM:MeOH = 100:1 to 10:1) gave the title compound (0.5 g, 13.1 %) as a yellow solid. 1< H NMR (CDCl3, 400 MHz) δ 9.54 (1 H, s), 8.64-8.62 (1 H, d, J = 5.6 Hz), 7.27-7.26 (1 H, d, J = 5.2 Hz), 7.22-7.20 (1 H, d, J = 5.6 Hz), 6.37-6.35 (1 H, d, J = 7.2 Hz), 3.54 (3 H, s).Step 2: 4-bromo-2-methyl-2,7-naphthyridin-1-one

[0158]

[0159] Bromine (1.1 g, 6.87 mmol) in acetic acid (10 mL) was added dropwise to2-methyl-2,7-naphthyridin-1-one (1.1 g, 6.87 mmol) in acetic acid (60 mL) at 10-15 °C. After stirring at 15 °C for 1 h, the mixture was concentrated under vacuum. Purification by silica gel chromatography (DCM: MeOH = 50:1 to 10: 1) gave the title compound (0.45 g, 27.4 %) as a yellow solid.

[0160] 1< H NMR (CDCl3, 400 MHz) δ 9.61 (1 H, s), 8.86-8.85 (1 H, d, J = 5.6 Hz), 7.62-7.60 (1 H, d, J = 5.6 Hz), 7.56 (1 H, s), 3.63 (3 H, s).Step 3: N-[3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methanesulfonamide

[0161]

[0162] A mixture of 4-bromo-2-methyl-2,7-naphthyridin-1-one (50 mg, 0.21 mmol), [3-(methanesulfonamido)phenyl]boronic acid (68 mg, 0.31 mmol), Pd(dppf)Cl 2 (15.3 mg, 0.021 mmol) and aqueous K 3 PO 4 (1 M, 0.3 mL, 0.3 mmol) in dioxane (3 mL) was microwaved at 90 °C for 40 min. Purification by silica gel chromatography (PE:EA = 100:1 to 1:1) followed by preparative HPLC gave the title compound (48.1 mg, 69.8 %) as a white solid. 1< H NMR (400 MHz, Methanol-d4) δ 9.56 (s, 1 H), 8.68 (d, J = 6.4 Hz, 1 H), 7.96 (s, 1 H), 7.81 (d, J = 6.4 Hz, 1 H), 7.51 (t, J = 7.6 Hz, 1 H), 7.37 (d, J = 2.0 Hz, 1 H), 7.34 (d, J = 1.6 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 1 H), 3.71 (s, 3 H), 3.03 (s, 3 H). LCMS: 330.0 (M+H) +<

[0163] Examples 52-56 in Table 9 were prepared from title compound of Example 51, step 2, in one step using the appropriate phenyl boronic acid / ester in a manner similar to Example 51, step 3. Table 9 Ex. No. R 1< Name 1< H NMR (ppm (δ), 400 MHz) MS (M+H ) 52 N-[3-(2-methyl-1-oxo-2,7-naphthyridin -4-yl)phenyl]eth anesulfonami de 1< H NMR (400 MHz, CDCl 3 ) δ 9.71 (s, 1 H), 8.72 (d, J = 6.0 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.37 (d, J = 6.0 Hz, 1 H), 7.29-7.26 (m, 3 H), 7.20 (d, J = 7.6 Hz, 1 H), 6.74 (s, 1 H), 3.69 (s, 3 H), 3.21 (q, J = 7.6 Hz, 2 H), 1.43 (t, J = 7.6 Hz, 3 H)34453 N-ethyl-3-(2-methyl-1-oxo-2,7-naphthyridin -4-yl)benzenesu lfonamide 1< H NMR (400 MHz, CDCl 3 ) δ 9.72 (s, 1 H), 8.73 (d, J = 5.6 Hz, 1 H), 7.95 (d, J = 7.2 Hz, 1 H), 7.92 (s, 1 H), 7.67-7.62 (m, 2 H), 7.33 (s, 1 H), 7.30 (d, J = 5.6 Hz, 1 H), 4.48 (s, 1 H), 3.70 (s, 3 H), 3.13-3.12 (m, 2 H), 1.18 (t, J = 7.2 Hz, 3 H)34454 N-benzyl-2-methoxy-5-(2-methyl-1-oxo-2,7-naphthyridin -4-yl)benzenesu lfonamide 1< H NMR (400 MHz, CDCl 3 ) δ 9.72 (s, 1 H), 8.74 (d, J = 5.6 Hz, 1 H), 7.93 (s, 1 H), 7.54 (dd, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1 H), 7.27-7.26 (s, 6 H), 7.19 (d, J = 3.2 Hz, 1 H) 7.06 (d, J = 8.4 Hz, 1 H), 5.26 (s, 1 H), 4.20 (d, J = 5.2 Hz, 2 H), 3.96 (s, 3 H), 3.70 (s, 3 H)43655 3-(2-methyl-1-oxo-2,7-naphthyridin -4-yl)benzenesu lfonamide 1< H NMR (400 MHz, DMSO-d6) δ 9.46 (d, J = 9.2 Hz,1 H), 8.73 (d, J = 5.6 Hz, 1 H), 7.89-7.88 (m, 3 H), 7.73-7.69 (m, 2 H), 7.39-7.38 (d, J = 5.2 Hz, 1 H), 3.60 (s, 3 H)31656 2-methoxy-5-(2-methyl-1-oxo-2,7-naphthyridin -4-yl)benzenesu lfonamide 1< H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1 H), 8.72 (d, J = 5.6 Hz, 1 H), 7.80 (s, 1 H), 7.77 (d, J = 2.4 Hz, 1 H), 7.65-7.63 (dd, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 7.33 (d, J = 5.2 Hz, 1 H), 3.97 (s, 3 H), 3.59 (s, 3 H)346 Example 57: N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]ethanesulfonamideStep 1: 4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0164]

[0165] A mixture of 3-bromo-4-(2,4-difluorophenoxy)aniline (300 mg, 1 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (518 mg, 2 mmol), KOAc (300 mg, 3 mmol) and Pd(dppf)Cl 2 (73.2 mg, 0.1 mmol) in dioxane (6 mL) was microwaved at 100 °C for 2 h. Purification by silica gel chromatography (PE:EA = 10:1 to 5:1) gave the title compound (200 mg, 56 %). LCMS: 348.0 (M+H) +< Step 2: 4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-2-methyl-2,7-naphthyridin-1-one

[0166]

[0167] For 5 min, N 2 was bubbled through a mixture of 4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (64.8 mg, 0.187 mmol), the title compound of Example 51, step 2 (30.0 mg, 0.124 mmol), K 2 CO 3 (51.6 mg, 0.374 mmol) and Pd(dppf)Cl 2 (18.3 mg, 0.025 mmol) in dioxane (2.0 mL) and water (0.2 mL) which was then microwaved at 100 °C for 1 h. Purification by preparative TLC (DCM:MeOH = 20: 1, Rf = 0.5) gave the title compound (25.0 mg, 53 %) as yellow gum. LCMS: 380.0 (M+H) +< Step 3: N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]ethanesulfonamide

[0168]

[0169] Ethanesulfonyl chloride (25.4 mg, 0.198 mmol) was added to 4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-2-methyl-2,7-naphthyridin-1-one (25.0 mg, 0.066 mmol) and TEA (20.0 mg, 0.198 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at room temperature for 18 h and then purified by preparative HPLC to give the title compound (8.5 mg, 27.4 %) as yellow gum. 1< H NMR (Methanol-d4, 400 MHz) δ 9.54 (s, 1 H), 8.68 (d, J = 4.4 Hz, 1 H), 8.00 (s, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.38 - 7.33 (m, 2 H), 7.09 - 6.99 (m, 2 H), 6.96 - 6.94 (d, J = 8.4 Hz, 1 H), 6.91 - 6.85 (m, 1 H), 3.70 (s, 3 H), 3.15 (q, J = 7.6 Hz, 2 H), 1.35 (t, J = 7.6 Hz, 3 H). LCMS: 472.1 (M+H) +< Example 58: N-[3-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamideStep 1: 7-fluoro-2-methylisoquinolin-1-one

[0170]

[0171] Under N 2 , sodium hydride (710 mg, 29.4 mmol) was added to 7-fluoro-2H-isoquinolin-1-one (4 g, 24.55 mmol) in dry DMF (40 mL) at 0 °C. After stirring at 0 °C for 20 min, CH 3 I (5.2 g, 36.7 mmol) was added. The mixture was stirred at 26 °C for 2 h. Saturated aqueous NH 4 Cl (20 mL) was added and after extractive work up with ethyl acetate, purification by silica gel chromatography (PE:EA = 10:1) gave the title compound (2.2 g, 50 %) as an off-white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.06 (dd, J 1 = 9.6 Hz, J 2 = 2.8 Hz, 1 H), 7.50 (dd, J 1 = 8.8 Hz, J 2 = 5.2 Hz, 1 H), 7.38-7.36 (m, 1 H), 7.03 (d, J = 7.6 Hz, 1 H), 6.48 (d, J = 7.2 Hz, 1 H), 3.61 (s, 3 H). LCMS: 178.1 [M+H] +< Step 2: 4-bromo-7-fluoro-2H-isoquinolin-1-one

[0172] Bromine (3.8 g, 24 mmol) in acetic acid (6 mL) was added slowly to a mixture of 7-fluoro-2-methylisoquinolin-1-one (4 g, 22.4 mmol) in acetic acid (8 mL) at 0 °C. After stirring at 26 °C for 2 h, the mixture was poured into water (100 mL) and the solid was collected by filtration. Purification by silica gel chromatography (PE:EA = 20:1) gave the title compound (1.4 g, 44%) as an off-white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.11 (d, J = 9.2 Hz, 1 H), 7.84 (dd, J 1 = 9.6 Hz, J 2 = 4.8 Hz, 1 H), 7.49-7.45 (m, 1 H), 7.34 (s, 1 H), 3.62 (3 H, s). LCMS: 255.9 [M+H] +< Step 3: N-[3-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide

[0173]

[0174] 4-Bromo-7-fluoro-2H-isoquinolin-1-one was treated with [3-(methanesulfonamido)phenyl]boronic acid in a manner similar to Example 51, step 3. Isolation and purification also in a similar manner gave the title compound (18 mg, 26.5 %) a white solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.17 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1 H), 7.52 (dd, J1 = 8.0 Hz, J2 = 4.0 Hz 1 H), 7.50-7.45 (m, 1 H), 7.38-7.32 (m, 1 H), 7.31-7.27 (m, 2 H), 7.26-7.21 (m, 1 H), 7.03 (s, 1 H), 6.72 (brs, 1 H), 3.67 (s, 3 H), 3.09 (s, 3 H). LCMS: 347.0 (M+H) +< .

[0175] Examples 59-64 in Table 10 were prepared from title compound of Example 58, step 2 using the appropriate phenyl boronic acid / ester in a manner similar to Example 18, step 3. Table 10 Ex. No. R 1< Name 1< H NMR (ppm (δ), 400 MHz) MS (M+H ) 59 N-ethyl-3-(7-fluoro-2-methyl-1-oxoisoquinol in-4-yl)benzenesu lfonamide(CDCl 3 ) 8.17 (dd, J 1 = 9.6 Hz, J 2 = 2.4 Hz, 1 H), 7.93-7.92 (m, 2 H), 7.64-7.63 (s, 2 H), 7.46-7.45 (m, 1 H), 7.36-7.35 (m, 1 H), 7.06 (s, 1 H), 4.58 (brs, 1 H), 3.14-3.07 (m, 2 H), 1.16 (t, J = 7.2 Hz, 3 H)36160 N-benzyl-5-(7-fluoro-2-methyl-1-oxoisoquinol in-4-yl)-2-methoxybenz enesulfonami de(CDCl 3 ) 8.20 (dd, J 1 = 9.3 Hz, J 2 = 2.8 Hz, 1 H), 7.96 (d, J = 2.4 Hz, 1 H), 7.54 (dd, J 1 = 8.5 Hz, J 2 = 2.3 Hz, 1 H), 7.47-7.44 (m, 1 H), 7.41-7.36 (m, 1H), 7.30-7.25 (m, 3H), 7.22-7.20 (m, 2H), 7.06 (d, J = 8.5 Hz, 1 H), 7.04 (s, 1 H), 5.34 (t, J = 6.0 Hz, 1 H), 4.21 (d, J = 6.3 Hz, 2 H), 3.97 (s, 3 H), 3.70 (s, 3 H)45361 3-(7-fluoro-2-methyl-1-oxoisoquinol in-4-yl)benzenesu lfonamide(CDCl 3 ) 7.13 (dd, J 1 = 9.6 Hz, J 2 = 2.8 Hz, 1 H), 7.03-7.01 (m, 2 H), 6.84-6.82 (m, 2 H), 6.76-6.74 (m, 1 H), 6.69 (s, 1 H), 6.67-6.66 (m, 1 H), 6.58-6.56 (m, 2 H), 2.71 (s, 3 H)33362 N-[3-(7-fluoro-2-methyl-1-oxoisoquinol in-4-yl)phenyl]eth anesulfonami de(CDCl 3 ) 8.17 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1 H), 7.53 (dd, J 1 = 8.8 Hz, J 2 = 3.6 Hz, 1 H), 7.44 (t, J = 8.4 Hz, 1 H), 7.28-7.27 (m, 3 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.03 (s, 1 H), 6.79 (s, 1 H), 3.67 (s, 3 H), 3.20 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H)36163 4-(3-ethylsulfonyl phenyl)-7-fluoro-2-methylisoqui nolin-1-one(CDCl 3 ) 1.15 (t, J=7.45 Hz, 3 H) 3.38 (q, J=7.41 Hz, 2 H) 3.60 (s, 3 H) 7.52 - 7.57 (m, 1 H) 7.61 - 7.67 (m, 2 H) 7.78 - 7.87 (m, 2 H) 7.91 - 8.03 (m, 3 H)34664 5-(7-fluoro-2-methyl-1-oxoisoquinol in-4-yl)-2-methoxybenz enesulfonami de(DMSO-d6) 7.98 (d, J = 7.2 Hz, 1 H), 7.74 (s, 1 H), 7.65-7.61 (m, 2 H), 7.51-7.48 (m, 2 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.18 (s, 2 H), 3.97 (s, 3 H), 3.57 (s, 3 H)363 Example 65: 2-methyl-4-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0176]

[0177] For 3 min, N 2 was bubbled through a mixture of 4-bromo-2-methylisoquinolin-1(2H)-one (54 mg, 0.23 mmol), (1-methylpyrazol-4-yl)boronic acid (31 mg, 0.25 mmol), aqueous 2M Na 2 CO 3 (0.375 mL) and Pd(dppf)Cl 2 (8 mg, 0.01 mmol) in 1,4-dioxane (1.5 mL) which was then microwaved at 120 °C for 1 h. Work up in a manner similar to Example 18, step 3, and two successive silica gel chromatographies, eluting with 15-80% EA in hexane over 6 min and continuing 80% isocratic EA followed by a second chromatography 15-100% EA in hexane over 6 min and continuing 100% isocratic EA gave the title compound (28 mg, 0.12 mmol) as a cream solid in 51% yield. 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.54 (s, 3 H) 3.92 (s, 3 H) 7.50 (s, 1 H) 7.55 (ddd, J=8.02, 5.87, 2.27 Hz, 1 H) 7.60 - 7.64 (m, 1 H) 7.70 - 7.80 (m, 2 H) 7.95 (s, 1 H) 8.31 (d, J=7.83 Hz, 1 H). LCMS (M+H) +< 240.

[0178] Examples 66-71 in Table 11 were prepared from 4-bromo-2-methylisoquinolin-1(2H)-one in a similar manner to Example 65 using commercially available boronic acids / esters or from commercially available tin compounds using standard Stille-type coupling conditions. Table 11 Ex. No. R 1< Name 1< H NMR (ppm (δ), 400 MHz) MS (M+H ) 66 4-(furan-2-yl)-2-methylisoqu inolin-1-one(CHLOROFORM-d) 3.61 - 3.70 (m, 3 H) 6.50 - 6.57 (m, 2 H) 7.37 (s, 1 H) 7.50 - 7.58 (m, 2 H) 7.69 (ddd, J=8.30, 7.03, 1.46 Hz, 1 H) 7.93 (d, J=8.20 Hz, 1 H) 8.51 (dd, J=8.01, 0.98 Hz, 1 H)22667 2-methyl-4-(1,3-oxazol-2-yl)isoquinoli n-1-one(CHLOROFORM-d) 3.72 (s, 3 H) 7.30 (s, 1 H) 7.56 - 7.61 (m, 1 H) 7.74 (s, 1 H) 7.79 (ddd, J=8.40, 7.03, 1.37 Hz, 1 H) 7.99 (s, 1 H) 8.52 (dd, J=8.01, 0.98 Hz, 1 H) 8.93 (d, J=8.40 Hz, 1 H)22768 2-methyl-4-(1H-pyrazol-5-yl)isoquinoli n-1-one(CHLOROFORM-d) 3.61 - 3.71 (m, 3 H) 6.66 (br. s., 1 H) 7.34 (s, 1 H) 7.57 (t, J=7.42 Hz, 1 H) 7.68 (t, J=7.52 Hz, 1 H) 7.76 (d, J=8.01 Hz, 1 H) 7.83 (br. s., 1 H) 8.52 (d, J=7.81 Hz, 1 H)22669 2-methyl-4-(1-methylimida zol-2-yl)isoquinoli n-1-one(METHANOL-d 4 ) 3.55 (s, 3 H) 3.65 (s, 3 H) 7.10 (br. s., 1 H) 7.17 (br. s., 1 H) 7.28 (s, 1 H) 7.54 - 7.62 (m, 2 H) 7.71 (t, J=7.61 Hz, 1 H) 8.41 (d, J=8.20 Hz, 1 H)24070 2-methyl-4-pyridin-2-ylisoquinolin -1-one(METHANOL-d 4 ) 3.69 (s, 3 H) 7.48 (d, J=5.86 Hz, 1 H) 7.58 (br. s., 2 H) 7.65 (d, J=7.81 Hz, 1 H) 7.71 (t, J=7.22 Hz, 1 H) 7.76 - 7.80 (m, 1 H) 7.98 (t, J=7.03 Hz, 1 H) 8.42 (d, J=7.81 Hz, 1 H) 8.68 (d, J=3.32 Hz, 1 H)23771 2-methyl-4-pyrimidin-2-ylisoquinolin -1-one(METHANOL-d 4 ) 3.73 (s, 3 H) 7.41 (t, J=4.88 Hz, 1 H) 7.59 (t, J=7.71 Hz, 1 H) 7.76 (t, J=7.71 Hz, 1 H) 8.27 (s, 1 H) 8.42 (d, J=8.20 Hz, 1 H) 8.82 (d, J=8.40 Hz, 1 H) 8.90 (d, J=4.88 Hz, 2 H)238 Example 72: N-[3-[2-methyl-6-(6-methylpyridin-3-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamideStep 1: 2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one

[0179]

[0180] A mixture of 6-bromo-2-methylisoquinolin-1-one (160 mg, 0.67 mmol), (6-methylpyridin-3-yl)boronic acid (166 mg, 0.32 mmol), Pd(dppf)Cl 2 (60 mg, 0.08 mmol) and saturated aqueous NaHCO 3 (0.6 mL) in dioxane (6.5 mL) was microwaved at 110 °C for 1.5 h. Purification using silica gel chromatography (PE:EA = 3:1 to 2:3) gave the title compound (160 mg, 95.2 %) as a yellow solid. LCMS: 251.2 (M+H) +< Step 2: 4-bromo-2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one

[0181]

[0182] Bromine (97 mg, 0.61 mmol) in acetic acid (0.61 mL) was added dropwise to 2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one (160 mg, 0.64 mmol) in acetic acid (6 mL) at 0 °C. After stirring at room temperature for 17 min, water (22 mL) was added and the pH was adjusted to 7-8 with 1M NaOH. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE:EA = 2:1 to 3:2) gave the title compound (135 mg, 64.3 %) as a yellow solid. LCMS: 329.0 (M+H) +< Step 3: N-[3-[2-methyl-6-(6-methylpyridin-3-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide

[0183]

[0184] A mixture of 4-bromo-2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one (135 mg, 0.41 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (141 mg, 0.62 mmol), Pd(dppf)Cl 2 (35 mg, 0.05 mmol) and aqueous 1M K 3 PO 4 (1.03 mL) in dioxane (6 mL) was microwaved at 100 °C for 1 h. Purification by silica gel chromatography (PE:EA = 3:1 to 1:2) followed by preparative HPLC gave the title compound (25 mg, 14.1 %) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.74 (d, J = 2.0 Hz, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.75 (s, 1 H), 7.58 (s, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.39 (s, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 3.59 (s, 3 H), 3.59 (s, 3 H), 3.15 (q, J= 7.2 Hz, 2 H), 1.19 (t, J = 7.2 Hz, 3 H). LCMS: 434.1 (M+H) +< .

[0185] Examples 73-74 in Table 12 were prepared from 6-bromo-2-methylisoquinolin-1-one and phenylboronic acid in three steps in a manner similar to Example 72, steps 1-3. For Example 74, [3-(methanesulfonamido)phenyl]boronic acid was substituted for [3-(ethylsulfonylamino)phenyl]boronic acid in step 3. Table 12 Ex. No.R 1< Name 1< H NMR (ppm (δ), 400 MHz)MS (M+H)73EthylN-[3-(2-methyl-1-oxo-6-phenylisoquinol in-4-yl)phenyl]ethan esulfonamide(DMSO-d 6 ) 9.94 (brs, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.74 (s, 1 H), 7.67 (d, J = 7.6 Hz, 2 H), 7.57 (s, 1 H), 7.50-7.45 (m, 3 H), 7.42 (d, J = 7.6 Hz, 1 H), 7.38 (s, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 3.59 (s, 3 H), 3.14 (q, J = 7.2 Hz, 2 H), 1.19 (t, J = 7.2 Hz, 3 H).41974Meth ylN-[3-(2-methyl-1-oxo-6-phenylisoquinol in-4-yl)phenyl]meth anesulfonamide(CHLOROFORM-d) 8.60 (d, J = 8.4 Hz, 1 H), 7.78 (dd, J 1 = 8.4 Hz, J 2 = 1.6 Hz, 1 H), 7.72 (d, J = 1.2 Hz, 1 H), 7.60-7.58 (m, 2 H), 7.49-7.36 (m, 5 H), 7.31 (d, J = 7.6 Hz, 1 H), 7.26-7.23 (m, 1 H), 7.10 (s, 1 H), 6.47 (s, 1 H), 3.70 (s, 3 H), 3.08 (s, 3 H)405 Example 75: N-[3-(2,6-dimethyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide Step 1: 2,6-dimethylisoquinolin-1-one

[0186]

[0187] A mixture of 6-bromo-2-methylisoquinolin-1-one (200.0 mg, 0.84 mmol), methylboronic acid (251.0 mg, 4.2 mmol), Pd(PPh 3 ) 4 (93.0 mg, 0.08 mmol), K 2 CO 3 (232.0 mg, 1.68 mmol) and H 2 O (2 drops) in dioxane (10.0 mL) was microwaved at 120 °C for 1 h. Purification by silica gel chromatography (PE:EA = 5:1) gave the title compound (120.0 mg, 82.8 %) as a light yellow solid. LCMS: 174.3 (M+H) +< .Step 2: 4-bromo-2,6-dimethylisoquinolin-1-one

[0188]

[0189] 2,6-Dimethylisoquinolin-1-one (120.0 mg, 0.60 mmol) in acetic acid (4 mL) was treated with Br 2 (96 mg, 0.6 mmol) in acetic acid (0.6 mL) at 0 °C in a manner similar to Example 72, step 2. Isolation, also in a similar manner, gave the title compound (145.0 mg, 82.9 %) as a white yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.33 (d, J = 8.0 Hz, 1 H), 7.60 (s, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.35 (s, 1 H), 3.60 (s, 3 H), 2.54 (s, 3 H). LCMS: 252.1 (M+H) +< Step 3: N-[3-(2,6-dimethyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide

[0190]

[0191] 4-Bromo-2,6-dimethylisoquinolin-1-one (75.0 mg, 0.30 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (82.0 mg, 0.36 mmol), Pd(dppf)Cl 2 (22 mg, 0.03 mmol) and aqueous 1M K 3 PO 4 (0.75 mL) in dioxane (4 mL) were reacted in a manner similar to Example 72, step 3. Isolation, also in a similar manner, gave the title compound (60.0 mg, 48.1 %) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.42 (d, J = 8.4 Hz, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.29-7.27 (m, 2 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.03 (s, 1 H), 6.68 (s, 1 H), 3.65 (s, 3 H), 3.21 (q, J = 7.2 Hz, 2 H), 2.42 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H). LCMS: 357.0 (M+H) +<

[0192] Examples 76-78 in Table 13 were prepared in three steps in a similar manner to Example 75 steps 1-3. For Examples 76 and 77, ethylboronic acid was substituted for methylboronic acid in step 1. For Examples 77 and 78, [3-(methanesulfonamido)phenyl]boronic acid was substituted for [3-(ethylsulfonylamino)phenyl]boronic acid in step 3. Table 13 Ex. No. R 1< R 2< Name 1< H NMR (ppm (δ), 400 MHz) MS (M+H) 76EthylEthylN-[3-(6-ethyl-2-methyl-1-oxoisoquino lin-4-yl)phenyl]et hanesulfona mide(CDCl 3 ) 8.41 (d, J = 8.4 Hz, 1 H), 7.42 (t, J = 8.4 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1 H), 7.29-7.25 (m, 2 H), 7.19 (d, J = 7.6 Hz, 1 H), 7.00 (s, 1 H), 6.90 (s, 1 H), 3.61 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H ), 2.67 (q, J = 7.6 Hz, 2 H), 1.39 (t, J = 7.6 Hz, 3 H), 1.19 (t, J = 7.6 Hz, 3 H)37177EthylMeth ylN-[3-(6-ethyl-2-methyl-1-oxoisoquino lin-4-yl)phenyl]m ethanesulfon amide(CDCl 3 ) 8.45 (d, J = 8.4 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.32-7.26 (m, 5 H), 7.04 (s, 1 H), 6.66 (s, 1 H), 3.65 (s, 3 H), 3.10 (s, 3 H), 2.70 (q, J = 7.6 Hz, 2 H), 1.23 (t, J = 7.6 Hz, 3 H)35778Methy lMeth ylN-[3-(2,6-dimethyl-1-oxoisoquino lin-4-yl)phenyl]m ethanesulfon amide(DMSO-d 6 ) 9.88 (brs, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 7.49-7.45 (m, 2 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.33 (s, 1 H), 7.28-7.24 (m, 2 H), 7.19 (d, J = 8.0 Hz, 1 H), 3.55 (s, 3 H), 3.06 (s, 3 H), 2.39 (s, 3 H)343 Example 79: 4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-oneStep 1: 2-bromo-4-ethylsulfanyl-1-fluorobenzene

[0193]

[0194] To a mixture of 3-bromo-4-fluorobenzenethiol (2.07 g, 10 mmol) and K 2 CO 3 (4.14 g, 30 mmol) in acetone (20 mL) was added EtI (3.12 g, 20 mmol). The mixture was stirred at room temperature for 12 h, filtered, and the volatile components were removed under vacuum to give the title compound (2.34 g) as light yellow oil which was carried on without purification. 1< H NMR (CDCl 3 , 400 MHz): d 7.54 (dd, J 1 = 6.4 Hz, J 2 = 2.4 Hz, 1 H), 7.26-7.25 (m, 1 H), 7.05 (t, J = 8.4 Hz, 1 H), 2.91 (q, J = 7.6 Hz, 2 H), 1.30 (t, J = 7.6 Hz, 3 H).Step 2: 2-bromo-4-ethylsulfonyl-1-fluorobenzene

[0195]

[0196] To 2-bromo-4-ethylsulfanyl-1-fluorobenzene (2.2 g, 9.36 mmol) in DCM (20 mL) was added m-CPBA (6.47 g, 37.4 mmol). The mixture was stirred at room temperature for 12 h. Aqueous saturated Na 2 S 2 O 3 (100 mL) was added, and extractive work up with CH 2 Cl 2 gave the title compound (1.5 g, 50 %) as a yellow solid which was carried on without purification. 1< H NMR (CDCl 3 , 400 MHz) δ 8.15 (dd, J 1 = 6.4 Hz, J 2 = 2.4 Hz, 1 H), 7.88-7.85 (m, 1 H), 7.32 (t, J = 8.4 Hz, 1 H), 3.14 (q, J = 7.2 Hz, 2 H), 1.31 (t, J = 7.6 Hz, 3 H).Step 3: 2-bromo-4-ethylsulfonyl-1-methoxybenzene

[0197]

[0198] A mixture of 2-bromo-4-ethylsulfonyl-1-fluorobenzene (0.6 g, 2.25 mmol) and sodium methoxide (1.2 g, 22.2 mmol) in THF (20 mL) was stirred at room temperature for 18 h. Water (30 mL) was added and extractive work up with ethyl acetate followed by silica gel chromatography (PE:EA = 10:1 to 1:1) gave the title compound (0.5 g, 79.4 %) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.08 (d, J = 2.4 Hz, 1 H), 7.87-7.84 (dd, J 1 = 8.6 Hz, J 2 = 2.4 Hz, 1 H), 7.04 (d, J = 8.8 Hz, 1 H), 3.99 (s, 3 H), 3.11 (q, J = 7.4 Hz, 2 H), 1.30 (t, J = 7.4 Hz, 3 H).Step 4: 4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0199]

[0200] For 5 min N 2 was bubbled into a mixture of 2-bromo-4-ethylsulfonyl-1-methoxybenzene (300 mg, 1.07 mmol), the title compound of Example 46, step 2 (300 mg, 0.82 mmol), K 3 PO 4 (435.6 mg, 2.05 mmol) and Pd(dppf)Cl 2 (120.2 mg, 0.16 mmol) in dioxane (8 mL) and water (0.8 mL) which was then microwaved at 110 °C for 30 min. Purification by silica gel chromatography (DCM:MeOH = 100:0 to 20:1) gave the title compound (200 mg, 55.7 %) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.51 (d, J = 8.4 Hz, 1 H), 8.03 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.72 (s, 1 H), 7.64 (s, 1 H), 7.63-7.61 (m, 1H), 7.19 (d, J = 8.8 Hz, 1 H), 7.15 (d, J = 1.2 Hz, 1 H), 7.09 (s, 1 H), 3.97 (s, 3 H), 3.85 (s, 3 H), 3.68 (s, 3 H), 3.18 (q, J = 7.6 Hz, 2 H), 1.35 (t, J = 7.6 Hz, 3 H). LCMS: 438.1 (M+H) +< Example 80: 4-(5-ethylsulfonyl-2-hydroxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0201]

[0202] At -78 °C, a 4 M solution of BBr 3 (2.3 mL, 9.2 mmol) in CH 2 Cl 2 was added to the title compound of Example 79 (200.0 mg, 0.458 mmol) in dry CH 2 Cl 2 (8 mL). The mixture was refluxed for 18 h. Extractive work up with CH 2 Cl 2 and purification by silica gel chromatography (DCM:MeOH = 100:1 to 20:1) gave the title compound (70 mg, 36.1 %) as a brown solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.39 (d, J = 8.4 Hz, 1 H), 7.99 (s, 1 H), 7.87 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 7.80 (s, 1 H), 7.79 (s, 1 H), 7.76 (d, J = 1.6 Hz, 1 H), 7.39 (s, 1 H), 7.35 (d, J = 1.2 Hz, 1 H), 7.18 (d, J = 8.8 Hz, 1 H), 3.91 (s, 3 H), 3.67 (s, 3 H), 3.25 (q, J = 7.6 Hz, 2 H), 1.27 (t, J = 7.6 Hz, 3 H). LCMS: 424.0 (M+H) +< Example 81: 4-(2-ethoxy-5-ethylsulfonylphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0203]

[0204] A mixture of the title compound of Example 80 (25.0 mg, 0.059 mmol), ethyl iodide (27.7 mg, 0.177 mmol), and K 2 CO 3 (24.5 mg, 0.177 mmol) in acetone (2 mL) was stirred at room temperature for 18 h. After CH 2 Cl 2 extractive work up, purification by preparative TLC (PE:EA = 2:1) gave the title compound (15.8 mg, 60%) as a white solid. 1< H NMR: (CDCl 3 , 400 MHz) δ 8.48 (d, J = 8.4 Hz, 1 H), 7.97 (dd, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.68 (s, 1 H), 7.62 (s, 1 H), 7.61 (dd, J 1 = 8.4 Hz, J 2 = 1.6 Hz, 1 H), 7.17 (d, J = 1.2 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 7.08 (s, 1 H), 4.3 (q, J = 7.2 Hz, 2 H), 3.94 (s, 3 H), 3.66 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H), 1.35 (t, J = 7.6 Hz, 3 H), 1.18 (t, J = 7.2 Hz, 3 H). LCMS: 452.1 (M+H) +<

[0205] Examples 82-84 in Table 14, the title compound of Example 80 was O-alkylated with the appropriate alkyl halide in a similar manner to Example 81. Example 85 in Table 14 was prepared in two steps by O-alkylation with tert-butyl N-(2-bromoethyl)carbamate in a similar manner to Example 81 followed by deprotection of the the Boc group in a manner similar to Example 32. Table 14 Ex. No. R 1< Name 1< H NMR (ppm (δ), 400 MHz) MS (M+H) 82 4-[2-(cyclopropylm ethoxy)-5-ethylsulfonylp henyl]-2-methyl-6-(1-methylpyrazol -4-yl)isoquinolin -1-one(CDCl 3 ) 8.51 (d, J = 8.4 Hz, 1 H), 7.97 (dd, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1 H), 7.88 (d, J = 2.8 Hz, 1 H), 7.70 (s, 1 H), 7.64 (s, 1 H), 7.62 (dd, J 1 = 8.4 Hz, J 2 = 1.6 Hz, 1 H), 7.21 (d, J = 1.6 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.11 (s, 1 H), 3.96 (s, 3 H), 3.91-3.86 (m, 2 H), 3.67 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H ), 1.34 (t, J = 7.6 Hz, 3 H), 0.99-0.96 (m, 1 H), 0.38-0.35 (m, 2 H), 0.10-0.02 (m, 2 H).47883 4-(5-ethylsulfonyl-2-propoxypheny l)-2-methyl-6-(1-methylpyrazol -4-yl)isoquinolin -1-one(CDCl 3 ) 8.51 (d, J = 8.4 Hz, 1 H), 7.97 (dd, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1 H), 7.88 (d, J = 2.8 Hz, 1 H), 7.70 (s, 1 H), 7.64 (s, 1 H), 7.62 (dd, J 1 = 8.4 Hz, J 2 = 1.6 Hz, 1 H), 7.21 (d, J = 1.6 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.11 (s, 1 H), 3.96 (s, 3 H), 3.91-3.86 (m, 2 H), 3.67 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H ), 1.34 (t, J = 7.6 Hz, 3 H), 0.99-0.96 (m, 1 H), 0.38-0.35 (m, 2 H), 0.10-0.02 (m, 2 H).46684 4-[5-ethylsulfonyl-2-(2-hydroxyethox y)phenyl]-2-methyl-6-(1-methylpyrazol -4-yl)isoquinolin -1-one(CDCl 3 ) 8.51 (d, J = 8.4 Hz, 1 H), 7.97 (dd, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1 H), 7.88 (d, J = 2.8 Hz, 1 H), 7.70 (s, 1 H), 7.64 (s, 1 H), 7.62 (dd, J 1 = 8.4 Hz, J 2 = 1.6 Hz, 1 H), 7.21 (d, J = 1.6 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.11 (s, 1 H), 3.96 (s, 3 H), 3.91-3.86 (m, 2 H), 3.67 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H ), 1.34 (t, J = 7.6 Hz, 3 H), 0.99-0.96 (m, 1 H), 0.38-0.35 (m, 2 H), 0.10-0.02 (m, 2 H).46885 4-[2-(2-aminoethoxy)-5-ethylsulfonylp henyl]-2-methyl-6-(1-methylpyrazol -4-yl)isoquinolin -1-one(Methanol-d4) 8.38 (d, J = 8.4 Hz, 1 H), 8.06 (dd, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1 H), 8.05 (s, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.83 (s, 1 H), 7.76 (dd, J 1 = 8.4 Hz, J 2 = 1.2 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.44 (s, 1 H), 7.27 (d, J = 1.2 Hz, 1 H), 4.46-4.32 (m, 2 H), 3.92 (s, 3 H), 3.67 (s, 3 H), 3.27 (q, J = 7.2 Hz, 2 H), 3.25-3.17 (m, 1 H), 3.04-2.96 (m, 1 H), 1.28 (t, J = 7.2 Hz, 3 H) Example 86: N-[2-fluoro-4-methoxy-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamideStep 1: 1-bromo-4-fluoro-2-methoxy-5-nitrobenzene and 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene

[0206]

[0207] At 0 °C, sodium methoxide (344 mg, 6.3 mmol) in dry MeOH (7 mL) was added dropwise to 1-bromo-2,4-difluoro-5-nitrobenzene (1 g, 4.2 mmol) in dry MeOH (18 mL). The mixture was stirred at room temperature for 10 h and then refluxed for 8 h. After extractive work up, purification by silica gel chromatography (PE:EA = 1:0 to 10: 1) gave a mixture of the two title compounds (765 mg, 72.9 %) in about a 2:1 ratio as a yellow solid. LCMS: 249.9 (M+H) +< Step 2: 5-bromo-2-fluoro-4-methoxyaniline

[0208]

[0209] Zinc dust (0.95 g, 14.5 mmol) was added to the mixture of two title compounds from step 1 (725 mg, 2.9 mmol) in 2:1 MeOH:saturated aqueous NH 4 Cl (10 mL) at 0 °C. After stirring at room temperature for 30 min, extractive work upwith ethyl acetate and purification by silica gel chromatography (PE:EA = 1:0 to 10:1) gave the title compound (260 mg, 41 %) as a yellow solid free of the corresponding regioisomer. 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.00 (d, J = 9.6 Hz, 1 H), 6.94 (d, J = 13.2 Hz, 1 H), 4.88 (s, 2 H), 3.72 (s, 3 H). LCMS: 219.9 (M+H) +< Step 3: N-(5-bromo-2-fluoro-4-methoxyphenyl)ethanesulfonamide

[0210]

[0211] At 0 °C, ethansulfonylchloride (1.4 g, 10.9 mmol) was added dropwise to a solution of 5-bromo-2-fluoro-4-methoxyaniline (3.5 g, 24.0 mmol) in pyridine (1.3 g, 16.4 mmol) and dry CH 2 Cl 2 (20 mL). After stirring at room temperature for 10 h, CH 2 Cl 2 extractive work up and purification by silica gel chromatography (PE:EA = 10:0 to 3:1) gave the title compound (2.5 g, 73.5 %) as a yellow solid. 1< H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J = 8.4 Hz, 1 H), 6.73 (d, J = 11.6 Hz, 1 H), 6.27 (s, 1 H), 3.89 (s, 3 H), 3.10 (q, J = 7.6 Hz, 2 H), 1.40 (t, J = 7.6 Hz, 3 H). LCMS: 334.0 (M+Na) +< Step 4: N-[2-fluoro-4-methoxy-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide

[0212]

[0213] A mixture of N-(5-bromo-2-fluoro-4-methoxyphenyl)ethanesulfonamide (63 mg, 0.20 mmol), the title compound of Example 46, step 2 (75 mg, 0.21 mmol), Pd(dppf)Cl 2 (19 mg, 0.03 mmol) and aqueous K 3 PO 4 (1 M, 0.5 mL, 0.5 mmol) in dioxane (3 mL) was microwaved at 100 °C for 1 h. Purification by silica gel chromatography (PE:EA = 1:1 to 1:4) followed by preparative HPLC gave the title compound (25 mg, 26.3 %) as a white solid. 1< H NMR (400 MHz, CDCl 3 ) δ 8.48 (d, J = 8.4 Hz, 1 H), 7.72 (s, 1 H), 7.69 (s, 1 H), 7.58 (d, J = 7.2 Hz, 1 H), 7.49 (d, J = 9.2 Hz, 1 H), 7.25 (s, 1 H), 7.04 (s, 1 H), 6.85 (d, J = 12.0 Hz, 1 H), 6.37 (s, 1 H), 3.94 (s, 3 H), 3.75 (s, 3 H), 3.65 (s, 3 H), 3.17 (q, J = 7.2 Hz, 2 H), 1.46 (t, J = 7.2 Hz, 3 H). LCMS: 471.1 (M+H) +< Example 87: N-[3-(2-methyl-1-oxo-6-pyridin-2-ylisoquinolin-4-yl)phenyl]ethanesulfonamideStep 1: 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

[0214]

[0215] For 5 min N 2 was bubbled through a mixture of 6-bromo-2-methylisoquinolin-1-one (0.5 g, 2.1 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.8 g, 3.1 mmol), Pd(dppf)Cl 2 (153.6 mg, 0.21 mmol) and KOAc (0.51 g, 5.2 mmol) in dioxane (5 mL) which was then microwaved at 110 °C for 40 min. Purification by silica gel chromatography (PE:EA = 20:1 to 5:1) gave the title compound (0.45 g, 75.0 %) as yellow gum.Step 2: 2-methyl-6-pyridin-2-ylisoquinolin-1-one

[0216]

[0217] A mixture of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (420 mg, 1.47 mmol), 2-bromopyridine (698 mg, 4.42 mmol), Pd(dppf)Cl 2 (107 mg, 0.15 mmol) and saturated aqueous NaHCO 3 (3.5 mL) in DMSO (25 mL) was microwaved at 150 °C for 45 min. After extractive work up with ethyl acetate, purification by silica gel chromatography (PE:EA = 3:1 to 3:2) gave the title compound (160 mg, 46.0 %) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.76 (d, J = 4.8 Hz, 1 H), 8.53 (d, J = 8.0 Hz, 1 H), 8.20 (d, J = 1.2 Hz, 1 H), 8.07 (dd, J 1 = 8.4 Hz, J 2 = 1.6 Hz, 1 H), 7.85- 7.82 (m, 2 H), 7.34- 7.30 (m, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 6.6 (d, J = 7.2 Hz, 1 H), 3.64 (s, 3 H). LCMS: 237.2 (M+H) +< Step 3: 4-bromo-2-methyl-6-pyridin-2-ylisoquinolin-1-one

[0218]

[0219] At 0 °C, bromine (78 mg, 0.49 mmol) in acetic acid (0.3 mL) was added dropwise to 2-methyl-6-pyridin-2-ylisoquinolin-1-one (115 mg, 0.49 mmol) in acetic acid (20 mL). The mixture was stirred at room temperature for 20 min. Extractive work up with CH 2 Cl 2 and purification by silica gel chromatography (PE:EA = 5:1~1:1) gave the title compound (73.0 mg, 47.7 %) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.79 (d, J = 4.4 Hz, 1 H), 8.55 (d, J = 8.4 Hz, 1 H), 8.44 (s, 1 H), 8.19 (d, J = 8.8 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.85 (t, J = 7.2 Hz, 1 H), 7.42 (s, 1 H), 7.36-7.34 (m, 1 H), 3.64 (s, 3 H). LCMS: 314.9 (M+H) +< Step 4: N-[3-(2-methyl-1-oxo-6-pyridin-2-ylisoquinolin-4-yl)phenyl]ethanesulfonamide

[0220]

[0221] For 5 min, N 2 was bubbled through a mixture of 4-bromo-2-methyl-6-pyridin-2-ylisoquinolin-1-one (48.1 mg, 0.153 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (35.0 mg, 0.153 mmol), Pd(dppf)Cl 2 (22.3 mg, 0.03 mmol) and aqueous 1M K 3 PO 4 (0.38 mL, 0.38 mmol, 1 M) in dioxane (5 mL) which was then microwaved at 80 °C for 20 min. Purification by silica gel chromatography (PE:EA = 3:1 to 1:2) followed by preparative HPLC gave the title compound (2.5 mg, 3.9 %) as a white solid. 1< H NMR (Methanol-d4, 400 MHz) δ 8.69 (d, J = 8.4 Hz, 1 H), 8.59 (d, J = 8.4 Hz, 1 H), 8.23 (d, J = 1.2 Hz, 1 H), 8.15-8.22 (m, 1 H), 8.10 (dd, J 1 = 8.4 Hz, J 2 = 1.6 Hz, 2 H), 7.65-7.62 (m, 1 H), 7.50-7.45 (m, 3 H), 7.38-7.30 (m, 2 H), 3.71 (s, 3 H), 3.16 (q, J = 7.2 Hz, 2 H), 1.32 (t, J = 7.2 Hz, 3 H). LCMS: 420.1 (M+H) +< Example 88: 4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-oneStep 1: 4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0222]

[0223] At 0-10 °C, Br 2 (24 g, 150 mmol) in acetic acid (100 mL) was added drop-wise to a solution of methyl 2-fluoro-4-hydroxybenzoate (25.5 g, 150 mmol) in acetic acid (600 mL). The mixture was stirred at room temperature overnight. Extractive work up with ethyl acetate and purification by silica gel chromatography (100 % DCM) gave the title compound (32.0 g, 86.5 %) as a white solid. 1< H NMR (Methanol-d4, 400 MHz) δ 8.03 (d, J = 7.2 Hz, 1 H), 6.68 (d, J = 12.0 Hz, 1 H), 3.86 (s, 3 H). LCMS: 249.1 (M+H) +< Step 2: 5- methyl 5-bromo-2-fluoro-4-methoxybenzoate

[0224] Methyl iodide (10.6 g, 74.9 mmol) was added drop-wise to 4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (6.0 g, 24.1 mmol) and K 2 CO 3 (9.98 g, 72.3 mmol) in MeCN (120 mL). The mixture was heated at 80 °C overnight. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE:EA = 60:1 to 40:1) gave the title compound (5.1 g, 80.4 %) as a white solid which was carried on without purification. 1< H NMR (CDCl 3 , 400 MHz) δ 8.15 (d, J = 7.6 Hz, 1 H), 6.66 (d, J = 12.0 Hz, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H). LCMS: 263.0 (M+H) +< Step 3: (5-bromo-2-fluoro-4-methoxyphenyl)methanol

[0225]

[0226] DIBAL-H (45.6 mL, 1M in toluene) was added drop-wise to a solution of 5-methyl 5-bromo-2-fluoro-4-methoxybenzoate (5.0 g, 19.0 mmol) in anhydrous CH 2 Cl 2 (300 mL) at -78 °C. The mixture was stirred at -78 °C for 3 h and then quenched with MeOH and water. The mixture was filtered and the filter cake rinsed with CH 2 Cl 2 . The filtrate was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (4.18 g, 94.4 %) as a white solid which was carried on without purification. 1< H NMR (DMSO-d6, 400 MHz) δ 7.59 (d, J = 7.6 Hz, 1 H), 7.02 (d, J = 12.4 Hz, 1 H), 5.25 (t, J = 5.6 Hz, 1 H), 4.45 (d, J = 5.6 Hz, 2 H), 3.84 (s, 3 H).Step 4: 1-bromo-5-(bromomethyl)-4-fluoro-2-methoxybenzene

[0227]

[0228] PBr 3 (4.7 g, 17.4 mmol) was added drop-wise to a solution of (5-bromo-2-fluoro-4-methoxyphenyl)methanol (4.1 g, 17.4 mmol) in anhydrous CH 2 Cl 2 (40 mL) at 0 °C. The mixture was stirred at room temperature for 3 h and poured into ice water. The pH was adjusted to 8 with saturated aqueous NaHCO 3 . Extractive work up with CH 2 Cl 2 gave the title compound (4.9 g, 94.8 %) as a white solid which was carried on without purification. 1< H NMR (DMSO-d 6 , 400 MHz) δ 7.56 (d, J = 8.0 Hz, 1 H), 6.65 (d, J = 11.6 Hz, 1 H), 4.46 (s, 2 H), 3.89 (s, 3 H).Step 5: 1-bromo-4-fluoro-2-methoxy-5-(methylsulfanylmethyl)benzene

[0229]

[0230] Thiomethoxide (1.19 g, 17.0 mmol) was added to a solution of 1-bromo-5-(bromomethyl)-4-fluoro-2-methoxybenzene (4.9 g, 16.4 mmol) in anhydrous DMF (25 mL) at 0 °C. The mixture was stirred at room temperature for 5 h, and then poured into water (40 mL). Extractive work up with ethyl acetate gave the title compound (4.3 g, 99.0 %) as colorless oil which was carried on without purification. 1< H NMR (CDCl 3 , 400 MHz) δ 7.50 (d, J = 8.0 Hz, 1 H), 6.64 (d, J = 11.2 Hz, 1 H), 3.88 (s, 3 H), 3.63 (s, 2 H), 2.04 (s, 3 H).Step 6: 1-bromo-4-fluoro-2-methoxy-5-(methylsulfonylmethyl)benzene

[0231]

[0232] Oxone (20.9 g, 34.1 mmol) in H 2 O (100 mL) was added drop-wise to a solution of 1-bromo-4-fluoro-2-methoxy-5-(methylsulfanylmethyl)benzene (4.3 g, 16.2 mmol) in MeOH (100 mL) at 0 °C. The mixture was then stirred at room temperature for 3 h and then poured into water. Extractive work up with ethyl acetate, washing with saturated aqueous Na 2 SO 3 (40 mL) and brine, gave a solid that was triturated with 1:10 / EA:MTBE to give the title compound (4.40 g, 93.0 %) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 7.66 (d, J = 8.0 Hz, 1 H), 6.72 (d, J = 11.2 Hz, 1 H), 4.22 (s, 2 H), 3.92 (s, 3 H), 2.83 (s, 3 H). LCMS: 318.9 (M+Na) +< Step 7: 4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0233]

[0234] 1-Bromo-4-fluoro-2-methoxy-5-(methylsulfonylmethyl)benzene (34.0 mg, 0.114 mmol), the title compound of Example 46, step 2 (50.0 mg, 0.137 mmol), Pd(dppf)Cl 2 (20.0 mg, 0.027 mmol) and 1 M aqueous K 3 PO 4 (0.47 mL, 0.47 mmol) in dioxane (3.0 mL) were microwaved at 100 °C for 40 min. Preparative HPLC gave the title compound (10.0 mg, 18 %) as a light yellow solid. 1H NMR: (CDCl 3 , 400 MHz) δ 8.47 (d, J = 8.0 Hz, 1 H), 7.74 (s, 1 H), 7.73 (s, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 7.27 (s, 1 H), 7.05 (s, 1 H), 6.85 (d, J = 12.0 Hz, 1 H), 4.32 (d, J = 6.4 Hz, 2 H), 3.93 (s, 3 H), 3.77 (s, 3 H), 3.64 (s, 3 H), 2.93 (s, 3 H). LCMS: 456.1 (M+H) +.Example 89: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-oneStep 1: 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

[0235]

[0236] A suspension of 4-bromo-2-methylisoquinolin-1-one (100 mg, 0.42 mmol), bis(pinacolato)diboron (214 mg, 0.84 mmol), Pd(dppf)Cl 2 (31 mg, 0.04 mmol) and potassium acetate (104 mg, 1.05 mmol) in dioxane (2 mL) under nitrogen was warmed up to 90 °C for 135 minutes. It was then cooled down to room temperature and diluted with ethyl acetate (8 mL). The mixture was washed with aqueous saturated solution of NaHCO 3 (8 mL) and brine (8 mL). The organic phase was separated, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purifed by normal phase column chromatography (10-90% EtOAc / Hexanes) to give the title compound (44 mg, 37%). 1< H NMR (CDCl 3 , 400 MHz) δ 8.43 (d, J = 7.9 Hz, 1 H), 8.40 (dd, J = 8.2 Hz, 0.9 Hz, 1 H), 7.68 (s, 1 H), 7.65 (ddd, J = 8.2, 8.2, 1.1 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 3.63 (s, 3H), 1.38 (s, 12H). LCMS (M+H) +< 286.Step 2: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

[0237]

[0238] The title compound was prepared in a manner similar to Example 18, step 3, substituting 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene for 4-bromo-2-methylisoquinolin-1(2H)-one and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one for N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. 1< H NMR (DMSO-d6, 400 MHz) δ 0.09 (m, 2 H), 0.29 (m, 1H), 0.35 (m, 1H), 0.94 (m, 1H), 3.22 (s, 3H), 3.57 (s, 3H), 3.95 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.53 (m, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.8, 2.4 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H). LCMS (M+H) +< 384.

[0239] Alternatively, 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one can be prepared as described below.Step 1: 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

[0240]

[0241] A mixture of 4-bromo-2-methylisoquinolin-1-one (8.0 g, 33.6 mmol), bis(pinacolato)diboron (17.1 g, 67.2 mmol), KOAc (6.6 g, 67.2 mmol), Pd 2 (dba) 3 (3.1 g, 3.36 mmol) and X-Phos (1.6 g, 3.36 mmol) in anhydrous dioxane (200 mL) was stirred at 60 °C for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (PE : EA = 15 : 1) to give the title compound (6.0 g, 62 %) as a solid.Step 2: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

[0242] The title compound from Step 1 (5.0 g, 17.5 mmol), 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene (6.4 g, 21 mmol), K 3 PO 4 (9.3 g, 43.9 mmol) and Pd(dppf)Cl 2 (1.4 g, 1.75 mmol) in a dioxane / water (100 mL / 10 mL) mixture were stirred at 60 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EA : DCM = 1 : 4). Appropriate fractions were combined and concentrated under reduce pressure. The resultant solid was recrystallized from DCM / MTBE (1 : 1, 50 mL) to give the title compound (4.0 g, 60 %) as a white solid. 1< H NMR: (CDCl 3 , 400 MHz) δ 8.51 (dd, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1 H), 7.98 (dd, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.53 (m, 2 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.10 (m, 2 H), 3.88 (m, 2 H), 3.66 (s, 3 H), 3.09 (s, 3 H), 1.02-0.98 (m, 1 H), 0.44-0.38 (m, 2 H), 0.11-0.09 (m, 2 H). LCMS: 384.1 (M+H) +< Example 90: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-oneStep 1: 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0243]

[0244] The title compound was prepared in a manner similar to Example 89, step 1, substituting 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene for 4-bromo-2-methylisoquinolin-1-one. 1< H NMR (CDCl 3 , 400 MHz) δ 0.46 (m, 2 H), 0.60 (m, 2H), 1.24 (m, 1H), 1.35 (s, 12H), 3.02 (s, 3H), 3.97 (d, J = 6.0, 2H), 6.91 (d, J = 8.7 Hz, 1H), 7.92 (dd, J = 8.7, 2.5 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H). LCMS (M+H) +< 353.Step 2: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one

[0245]

[0246] The title compound was prepared in a manner similar to Example 18, step 3, substituting the title compound of Example 47, step 2 for 4-bromo-2-methylisoquinolin-1(2H)-one and 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. 1< H NMR (DMSO-d6, 400 MHz) δ 0.12 (m, 2 H), 0.32 (m, 1H), 0.39 (m, 1H), 0.99 (m, 1H), 3.22 (s, 3H), 3.56 (s, 3H), 3.97 (m, 2H), 6.82 (dd, J = 10.5, 2.4 Hz, 1H), 7.39 (m, 2H), 7.61 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 8.74, 2.4 Hz, 1H), 8.36 (dd, J = 8.9, 6.1 Hz, 1H). LCMS (M+H) +< 402.Example 91: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one

[0247]

[0248] The title compound was prepared in a manner similar to Example 18, step 3, substituting the title compound of Example 58, step 2 for 4-bromo-2-methylisoquinolin-1(2H)-one and 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. 1< H NMR (DMSO-d6, 400 MHz) δ 0.10 (m, 2 H), 0.30 (m, 1H), 0.39 (m, 1H), 0.94 (m, 1H), 3.22 (s, 3H), 3.58 (s, 3H), 3.95 (m, 2H), 7.24 (dd, J = 9, 5.3 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.56 (m, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.96 (m, 2H). LCMS (M+H) +< 402.Example 92: 4-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

[0249]

[0250] The title compound was prepared in a manner similar to Example 18, step 3, substituting 1-(2-bromo-4-methylsulfonylphenoxy)-2,4-difluorobenzene for 4-bromo-2-methylisoquinolin-1(2H)-one and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one for N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. 1< H NMR (DMSO-d6, 400 MHz) δ 3.27 (s, 3H), 3.58 (s, 3H), 7.03 (d, J = 9.2 Hz, 1H), 7.13 (m, 1H), 7.35 (m, 2H), 7.48 (m, 1H), 7.54 (t, J = 7.5, 1H), 7.67 (s, 1H), 7.69 (m, 1H), 7.97 (m, 1H), 7.98 (s, 1H), 8.30 (d, J = 8.1, 1H). LCMS (M+H) +< 442. Example 93: N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide

[0251] The title compound was prepared in a manner similar to Example 18, step 3, substituting N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide for 4-bromo-2-methylisoquinolin-1(2H)-one and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one for N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. 1< H NMR (DMSO-d6, 400 MHz) δ 1.23 (t, J = 7.3 Hz, 3H), 3.13 (q, J = 7.8 Hz, 2H), 3.53 (s, 3H), 6.95 (m, 2H), 7.09 (m, 1H), 7.28 (m, 3H), 7.51 (m, 2H), 7.65 (t, J = 6.9 Hz, 1H), 8.26 (d, J = 0.8 Hz, 1H), 9.83 (s, 1H). LCMS (M+H) +< 471.Example 94: N-[3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

[0252]

[0253] A mixture of 5-bromo-1-methylpyridin-2-one (100 mg, 0.532 mmol), [3-(methanesulfonamido)phenyl]boronic acid (171.1 mg, 0.798 mmol), KOAc (130.0 mg, 1.326 mmol) and Pd(dppf)Cl 2 (38.9 mg, 0.05 mmol) in dioxane / H 2 O (2 mL / 0.5 mL) was stirred at 90 °C for 20 min. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA = 1:1) to give the title compound (30.0 mg, 20 %) as a brown solid. 1< H NMR (CDCl 3 , 400 MHz) δ 7.65-7.60 (dd, J 1 = 7.6 Hz, J 2 = 2.4 Hz, 1 H), 7.54 (d, J = 2.4 Hz, 1 H), 7.41 (t, J= 8.0 Hz, 1 H), 7.33 (s, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 7.17 (d, J = 7.6 Hz, 1 H), 6.86 (brs, 1 H), 6.67 (d, J = 9.2 Hz, 1 H), 3.65 (s, 3 H), 3.05 (s, 3 H). LCMS (M+H) +< 279.Example 95: N-[3-(1,4-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamideStep 1: 5-bromo-1,4-dimethylpyridin-2-one

[0254]

[0255] To a solution of 5-bromo-4-methylpyridin-2-ol (1.12 g, 6.0 mmol) in anhydrous THF (20 mL) was added NaH (288.0 mg, 12.0 mmol) and the reaction mixture was stirred at 0 °C for 30 min. Then, methyl iodide (1.7 g, 12.0 mmol) was added and stirred at room temperature for 3 h. Saturated NH 4 Cl (100 mL) was added and the resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1 to 2:1) to give the title compound (1.0 g, 83.3 %) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 7.44 (s, 1 H), 6.94 (s, 1 H), 3.51 (s, 3 H), 2.24 (s, 3 H). LCMS (M+H) +< 202.Step 2: N-[3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

[0256]

[0257] 5-Bromo-1,4-dimethylpyridin-2-one was treated with [3-(methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 7.43 (t, J = 8.0 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 7.16 (s, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.71 (s, 1 H), 6.69 (s, 1 H), 3.67 (s, 3 H), 3.07 (s, 3 H), 2.16 (s, 3 H). LCMS (M+H) +< 293.Example 96: N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamideStep 1: 5-bromo-1,3-dimethylpyridin-2-one

[0258]

[0259] The title compound of step 1 was prepared in a manner similar to Example 95, step 1 using 5-bromo-3-methylpyridin-2-ol instead of 5-bromo-4-methylpyridin-2-ol to give 5-bromo-1,3-dimethylpyridin-2-one. 1< H NMR (CDCl 3 , 400 MHz): 7.30 (d, J = 2.0 Hz, 1 H), 7.26 (d, J = 1.6 Hz, 1 H), 3.53 (s, 3 H), 2.16 (s, 3 H). LCMS (M+H) +< 202. Step 2: N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

[0260] 5-Bromo-1,3-dimethylpyridin-2-one was treated with [3-(methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1< H NMR (DMSO-d6, 400 MHz): 9.74 (s, 1 H), 7.91 (d, J = 2.4 Hz, 1 H), 7.62 (s, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.32 (s, 1 H), 7.29 (d, J = 7.6 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 3.52 (s, 3 H), 3.02 (s, 3 H), 2.08 (s, 3 H). LCMS (M+H) +< 293.Example 97: N-[3-(1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamideStep 1: 5-bromo-3,4-dimethyl-1H-pyridin-2-one

[0261]

[0262] To a mixture of 5-bromo-3,4-dimethylpyridin-2-amine (0.6 g, 3.0 mmol) and H 2 SO 4 (98 %, 1.62 mL) and H 2 O (18 mL) is added a solution of NaNO 2 (243.6 mg, 4.2 mmol) in H 2 O (1.6 mL) drop-wise at 0 °C. Then, it was stirred at 31 °C for 30 minutes and filtered. The resulting solid is washed with water to provide the title compound (375.0 mg, 62 %) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 7.48 (s, 1 H), 2.32 (s, 3 H), 2.19 (s, 3 H). LCMS (M+H) +< 202.Step 2: 5-bromo-1,3,4-trimethylpyridin-2-one

[0263]

[0264] To a solution of 5-bromo-3,4-dimethyl-1H-pyridin-2-one (402.0 mg, 2.0 mmol) in anhydrous THF (20 mL) was added NaH (96.0 mg, 2.4 mmol). The resulting mixture was stirred at 0 °C for 30 min. Methyl iodide (568.0 mg, 4.0 mmol) was added and the reaction was stirred at 32 °C for 3 h. Then, saturated aqueous NH 4 Cl (100 mL) was added and the mixture extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1 to 2:1) to give the title compound (350.0 mg, 80 %) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 7.38 (s, 1 H), 3.52 (s, 3 H), 2.27 (s, 3 H), 2.20 (s, 3 H). LCMS (M+H) +< 216.Step 3: N-[3-(1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

[0265]

[0266] 5-Bromo-1,3,4-trimethylpyridin-2-one was treated with [3-(methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 7.42 (s, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.24 (s, 1 H), 7.16 (s, 1 H), 7.08 (s, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 3.59 (s, 3 H), 3.06 (s, 3 H), 2.19 (s, 3 H), 2.06 (s, 3 H). LCMS (M+H) +< 307.Example 98: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-oneStep 1: 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one

[0267]

[0268] A solution of 5-bromo-1-methylpyridin-2-one (200.0 mg, 1.06 mmol), bis(pinacolato)diboron (410.0 mg, 1.61 mmol), potassium acetate (270 mg, 2.67 mmol), Pd (dppf)Cl 2 (80 mg, 0.11 mmol) in dioxane (5 mL) was heated at 100 °C for 2 h under microwave. The mixture was filtered, washed with water and extracted with ethyl acetate (20 mL x 3). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to give the crude title compound (59.0 mg, 23.6%). LCMS (M+H) +< 236.Step 2: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one

[0269]

[0270] 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one was treated with 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene in a manner similar to Example 94 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz): δ 7.86 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.68-765 (m, 2 H), 7.03 (d, J = 8.4 Hz, 1 H), 6.66 (d, J = 8.8 Hz, 1 H), 3.95 (d, J = 6.8 Hz, 2 H), 3.64 (s, 3 H), 3.07 (s, 3 H), 1.28-1.25 (m, 1 H), 0.69-0.65 (m, 2 H), 0.34-0.38 (m, 2 H). LCMS (M+H) +< 334.Example 99: N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamideStep 1: 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-1-methylpyridin-2-one

[0271]

[0272] A mixture of the title compound of step 1 in Example 57 (100 mg, 0.289 mmol), 5-bromo-1-methylpyridin-2-one (45.27 mg, 0.240 mmol), K 3 PO 4 (127.6 mg, 0.60 mmol) and Pd(dppf)Cl 2 (20 mg, 0.027 mmol) in dioxane / H 2 0 (4 / 0.5 mL) was stirred at 100 °C for 40 min under microwave. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA =1:2) to give the title compound (60 mg, 76 %). LCMS (M+H) +< 328.Step 2: N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide

[0273]

[0274] To a solution of 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-1-methylpyridin-2-one (30 mg, 0.09 mmol) in DCM (4 mL) was added TEA (27.3 mg, 0.27 mmol) and EtSO 2 Cl (35.39 mg, 0.27 mmol). The mixture was stirred at 30 °C for 12 h. Water (4 mL) was added and the mixture was extracted with DCM (4 mL x 3). The organic layer was concentrated and the residue was purified by prep-HPLC to give the title compound (10 mg, 26 %) as light yellow gum. 1< H NMR (CDCl 3 , 400 MHz) δ7.68-7.66 (m, 2 H), 7.28 (d, J = 2.4 Hz, 1 H), 7.13-7.10 (m, 1 H), 7.09 (s, 1 H), 7.00-6.92 (m, 2 H), 6.84-6.86 (m, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 6.73 (d, J = 9.2 Hz, 1 H), 3.65 (s, 3 H), 3.14 (q, J = 7.2 Hz, 2 H), 1.41 (t, J = 7.2 Hz, 3 H). LCMS (M+H) +< 421.Example 100: N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

[0275]

[0276] Preparation was carried out in a manner similar to Example 99, substituting methanesulfonyl chloride for ethanesulfonyl chloride in step 2 to give the title compound as a light yellow gum. 1< H NMR (CDCl 3 , 400 MHz) δ 7.64-7.62 (m, 2 H), 7.29 (d, J = 4.8 Hz, 1 H), 7.13-7.12 (m, 1 H), 6.69-6.95 (m, 2 H), 6.79 (m, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 9.4 Hz, 1 H), 3.61 (s, 3 H), 3.04 (s, 3 H). LCMS (M+H) +< 407.Example 101: N-[4-(2,4-difluorophenoxy)-3-(1,4-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

[0277]

[0278] Preparation was carried out in a manner similar to Example 100, substituting 5-bromo-1,4-dimethylpyridin-2-one for 5-bromo-1-methylpyridin-2-one in step 1 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz) δ 7.21-7.16 (m, 4 H), 6.95-6.93 (m, 2 H), 6.86-6.80 (m, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 6.53 (s, 1 H), 3.57 (s, 3 H), 3.04 (s, 3 H), 2.10 (s, 3 H). LCMS (M+H) +< 421.Example 102: N-[4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

[0279]

[0280] Preparation was carried out in a manner similar to Example 100, substituting 5-bromo-1,3-dimethylpyridin-2-one for 5-bromo-1-methylpyridin-2-one to give the title compound. 1< H NMR (CDCl 3 , 400 MHz) δ 7.53 (s, 2 H), 7.40 (s., 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 7.17 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 6.99-6.90 (m, 2 H), 6.87-6.80 (m, 1 H), 6.80 (d, J = 8.8 Hz, 1 H ), 3.63 (s, 3 H), 3.03 (s, 3 H), 2.19 (s, 3 H). LCMS (M+H) +< 421.Example 103: N-[4-(2,4-difluorophenoxy)-3-(1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

[0281]

[0282] Preparation was carried out in a manner similar to Example 100, substituting 5-bromo-1,3,4-trimethylpyridin-2-one for 5-bromo-1-methylpyridin-2-one to give the title compound. 1< H NMR (Methanol-d4, 400 MHz) δ 7.65 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 7.58 (d, J = 2.8 Hz, 1 H), 7.39 (s, 1 H), 7.05-7.01 (m, 2 H), 6.94-6.91 (m, 2 H), 3.55 (s, 3 H), 3.31 (s, 3 H), 2.13 (s, 3 H), 2.08 (s, 3 H). LCMS (M+18+H) +< 453.Example 104: 3-amino-1-methyl-5-(3-methylsulfonylphenyl)pyrazin-2-oneStep 1: 3-amino-5-bromo-1-methylpyrazin-2-one

[0283]

[0284] A solution of 3,5-dibromo-1-methylpyrazin-2-one (500.0 mg, 2.46 mmol), NH 3 H 2 O (5.0 mL) in dioxane (30.0 mL) was heated at 105 °C for 20 h. The mixture was concentrated, diluted with EtOAc (50 mL) and filtrated to give the title compound (300.0 mg, 79.0 %) which was carried on without purification. LCMS (M+H) +< 204.Step 2: 3-amino-1-methyl-5-(3-methylsulfonylphenyl)pyrazin-2-one

[0285]

[0286] A solution of 3-amino-5-bromo-1-methylpyrazin-2-one (81.0 mg, 0.4 mmol), (3-methylsulfonylphenyl)boronic acid (120.0 mg, 0.6 mmol), Cs 2 CO 3 (391.0 mg, 1.2 mmol), Pd(PPh 3 ) 4 (20.0 mg, 0.017 mmol) in dioxane (20.0 mL) and water (2.0 mL) was stirred at 95 °C for 12 h under N 2 . The mixture was concentrated and purified by silica gel chromatography (PE: EA = 3:2) to give the title compound (20.0 mg, 18 %). 1< H NMR (DMSO-d 6 400 MHz): δ 8.35 (s, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.73 (s, 1 H), 7.66 (t, J = 8.0 Hz, 1 H), 6.93 (brs, 2 H), 3.50 (s, 3 H), 3.24 (s, 3 H).. LCMS (M+H) +< 280.Example 105: 3-amino-5-(3-ethylsulfonylphenyl)-1-methylpyrazin-2-one

[0287]

[0288] Preparation was carried out in a manner similar to Example 104, step 2, substituting (3-ethylsulfonylphenyl)boronic acid for (3-methylsulfonylphenyl)boronic acid to give the title compound. 1< H NMR (DMSO-d 6 400 MHz): δ 8.30 (t, J = 1.6 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.71 (s, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 6.90 (brs, 2 H), 3.48 (s, 3 H), 3.29 (q, J = 7.2 Hz, 2 H), 1.11 (t, J = 7.2 Hz, 3 H). LCMS (M+H) +< 294.Example 106: N-[5-(6-amino-4-methyl-5-oxopyrazin-2-yl)-2-methoxyphenyl]methanesulfonamide

[0289]

[0290] Preparation was carried out in a manner similar to Example 104, step 2, substituting [3-(methanesulfonamido)-4-methoxyphenyl]boronic acid for (3-methylsulfonylphenyl)boronic acid to give the title compound. 1< H NMR (DMSO-d 6 400 MHz): δ 8.91 (s, 1 H), 7.68 (d, J = 2.4 Hz, 1 H), 7.61 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 7.38 (s, 1 H), 7.08 (d, J = 8.8 Hz, 1 H), 6.88-6.64 (m, 2 H), 3.84 (s, 3 H), 3.46 (s, 3 H), 2.95 (s, 3 H). LCMS (M+H) +< 325.Example 107: 3-amino-1-methyl-5-(3-methylsulfonylphenyl)pyridin-2-one

[0291]

[0292] Preparation was carried out in a manner similar to Example 104, step 2, substituting 3-amino-5-bromo-1-methylpyridin-2-one for 3-amino-5-bromo-1-methylpyrazin-2-one to give the title compound. 1< H NMR (Methanol-d4, 400 MHz) δ 8.06 (t, J = 2.0 Hz, 1 H), 7.89-7.85 (m, 2 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 2.0 Hz ,1 H), 7.03 (d, J = 2.4 Hz ,1 H), 3.67 (s, 3 H), 3.17 (s, 3 H). LCMS (M+H) +< 279.Example 108: 3-amino-5-(3-ethylsulfonylphenyl)-1-methylpyridin-2-one

[0293]

[0294] Preparation was carried out in a manner similar to Example 105, substituting 3-amino-5-bromo-1-methylpyridin-2-one for 3-amino-5-bromo-1-methylpyrazin-2-one to give the title compound. 1< H NMR (Methanol-d4, 400MHz) δ 8.01 (t, J = 2.0 Hz, 1 H), 7.88-7.83 (m, 2 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 2.0 Hz ,1 H), 7.03 (d, J = 2.4 Hz ,1 H), 3.67 (s, 3 H), 3.26 (q, J = 7.6 Hz, 2 H), 1.25 (t, J = 7.6 Hz, 3 H). LCMS (M+H) +< 293.Example 109: N-[5-(5-amino-1-methyl-6-oxopyridin-3-yl)-2-methoxyphenyl]methanesulfonamide

[0295]

[0296] Preparation was carried out in a manner similar to Example 106, substituting 3-amino-5-bromo-1-methylpyridin-2-one for 3-amino-5-bromo-1-methylpyrazin-2-one to give the title compound. 1< H NMR (Methanol-d4, 400 MHz) δ 7.53 (d, J = 2.4 Hz, 1 H), 7.34 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 7.18 (d, J = 2.4 Hz, 1 H), 7.09 (d, J = 8.8 Hz, 1 H), 6.96 (d, J = 2.4 Hz, 1 H), 3.92 (s, 3 H), 3.64 (s, 3 H), 2.94 (s, 3 H). LCMS (M+H) +< 324.Example 110: N-[2-methoxy-5-[1-methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl]methanesulfonamideStep 1: tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)carbamate

[0297]

[0298] To a solution of 3-amino-5-bromo-1-methylpyridin-2-one (404.0 mg, 2.0 mmol) in DCM (30 mL) was added (Boc) 2 O (654.0 mg, 3.0 mmol), Et 3 N (606.0 mg, 6.0 mmol) dropwise and DMAP (123.0 mg, 1.0 mmol). The reaction mixture was stirred for 12 h at 30 °C, quenched with saturated aqueous NH 4 Cl (50 mL), extracted with EA (50 mL), dried over Na 2 SO 4 , filtered and concentrated. Silica gel chromatography (PE:EA = 2:1) gave the impure title compound (400.0 mg) as a green solid, which was carried on to the next step. LCMS (M-55) +< 247.Step 2: tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-methylcarbamate

[0299]

[0300] To a solution of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)carbamate (150.0 mg, impure) in DMF (10 mL) was added NaH (60.0 mg, 1.5 mol, 60 % in oil) in portions at 0 °C. It was stirred for 30 min. Then CH 3 I (231.0 mg, 1.5 mmol) was added dropwise at 0 °C. The reaction mixture was stirred for 2 h at 30 °C. The reaction was quenched with saturated aqueous NH 4 Cl (15 mL), extracted with EA (20 mL), washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated to give the title compound (120.0 mg, crude) as a green solid, which was used directly in the next step without purification.Step 3: 5-bromo-1-methyl-3-(methylamino)pyridin-2-one

[0301]

[0302] To a solution of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-methylcarbamate (94.8 mg, crude) in DCM (10 mL) was added HCl / dioxane (1 mL, 4 M) dropwise with stirring at 30 °C. The reaction mixture was stirred at 30 °C for 30 min. The mixture was filtered and the filter cake collected. The filtrate was adjusted to pH = 9 with saturated aqueous NaHCO 3 , extracted with ethyl acetate (20 mL), dried over Na 2 SO 4 , filtered and concentrated to give a green solid which was combined with the filter cake to give the title compound (43.2 mg). 1< H NMR (CDCl 3 400MHz): δ 6.74 (d, J = 2.4 Hz, 1 H), 6.18 (d, J =2.4 Hz, 1 H), 5.15 (s, 1 H), 3.53 (s, 3 H), 2.83 (s, 3 H). LCMS (M+H) +< 217.Step 4: N-[2-methoxy-5-[1-methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl]methanesulfonamide

[0303]

[0304] The title compound was prepared in a manner similar to Example 106, substituting the title compound of step 3 for 3-amino-5-bromo-1-methylpyrazin-2-one. 1< H NMR (Methanol-d4, 400 MHz): δ 7.55 (d, J = 2.0 Hz, 1 H), 7.38 (dd, J 1 = 8.8, J 2 = 2.4 Hz, 1 H), 7.13-7.08 (m, 2 H), 6.52 (d, J = 2.0 Hz, 1 H), 3.93 (s, 3 H), 3.63 (s, 3 H), 2.94 (s, 3 H), 2.88 (s, 3 H).. LCMS (M+H) +< 338.Example 111: N-[5-[5-(ethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamideStep 1: tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-ethylcarbamate

[0305]

[0306] To a solution of the title compound from Example 110, step 1 (150.0 mg, crude) in DMF (10 mL) was added NaH (60.0 mg, 1.5 mmol, 60 % in oil) in portions at 0 °C and stirred for 30 min. Then iodoethane (234.0 mg, 1.5 mmol) was added dropwise at 0 °C. The reaction mixture was stirred for 2 h at 30 °C. It was then quenched with saturated aqueous NH 4 Cl (15 mL), extracted with ethyl acetate (20 mL), washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated to give the title compound (120.0 mg, crude) as a light green solid which was carried forward without purification.Step 2: 5-bromo-3-(ethylamino)-1-methylpyridin-2-one

[0307]

[0308] To a solution of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-ethylcarbamate (99.0 mg, crude) in DCM (10 mL) was added HCl / dioxane (1 mL, 4 M) dropwise with stirring at 30 °C. The reaction mixture was stirred for 30 min at 30 °C. Then the mixture was filtered and the filter cake collected. The filtrate was adjusted to pH = 9 with saturated aqueous NaHCO 3 , extracted with EA (20 mL), dried over Na 2 SO 4 , filtered and concentrated to give a light green solid which is combined with the filter cake to give the title compound (46.0 mg) which was carried forward without purification. 1< H NMR (CDCl 3 400MHz): δ 6.72 (d, J = 2.4 Hz, 1 H), 6.20 (d, J = 1.6 Hz, 1 H), 3.51 (s, 3 H), 3.09 (q, J = 7.2 Hz, 2 H), 1.27 (t, J = 7.2 Hz, 3 H). LCMS (M+H) +< 231. thStep 3: N-[5-[5-(ethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide

[0309] The title compound was prepared in a manner similar to Example 106, substituting the title compound of step 2 for 3-amino-5-bromo-1-methylpyrazin-2-one. 1< H NMR (CDCl 3 400MHz): δ 7.63 (d, J = 2.0 Hz, 1 H), 6.16 (dd, J 1 = 8.4 Hz, J 1 = 2.4 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 6.82-6.80 (m, 1 H), 6.39 (d, J = 2.4 Hz, 1 H), 3.93 (s, 3 H), 3.64 (s, 3 H), 3.19 (q, J = 7.2 Hz, 2 H), 2.98 (s, 3 H), 1.32 (t, J = 7.2 Hz, 3 H). LCMS (M+H) +< 352.Example 112: N-[5-[5-(cyclopropylmethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide

[0310]

[0311] To a solution of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 mL) and AcOH (0.3 mL) was added cyclopropanecarbaldehyde (14.0 mg, 0.2 mmol) dropwise with stirring at 30 °C. NaBH 3 CN (24.5 mg, 0.4 mol) was added in portions at 30 °C. The reaction mixture was stirred for 2 h at 30 °C. It was then quenched with saturated aqueous NH 4 Cl (5 mL), extracted with EtOAc (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (10.0 mg, 13.2%) as a light green solid. 1< H NMR (Methanol-d4 400 MHz): δ 7.55 (d, J = 2.4 Hz, 1 H), 7.36 (dd, J = 8.4, 2.4 Hz, 1 H), 7.16-7.07 (m, 2 H), 6.61 (d, J = 2.4 Hz, 1 H), 3.94 (s, 3 H), 3.66 (s, 3 H), 3.05 (s, 2 H), 2.95 (s, 3 H), 1.21-1.14 (m, 1 H), 0.64-0.56 (m, 2 H), 0.35-0.28 (m, 2 H). LCMS (M+H) +< 378.Example 113: N-[5-[5-(dimethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide

[0312]

[0313] To a solution of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 mL) and AcOH (0.3 mL) was added HCHO (30.0 mg, 1.0 mmol) dropwise with stirring at 30 °C. NaBH 3 CN (61 mg, 1.0 mol) was added in portions at 30 °C. The reaction mixture was stirred for 2 h at 30 °C. It was then quenched with saturated aqueous NH 4 Cl (5 mL), extracted with EtOAc (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 2:3) to give the title compound (30 mg , 43%) as a light green solid. 1< H NMR (Methanol-d4 400 MHz): δ 7.54 (d, J = 2.4 Hz, 1 H), 7.47 (d, J = 2.4 Hz, 1 H), 7.37 (dd, J 1 = 2.4, J 2 = 8.4 Hz, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 2.4 Hz, 1 H), 3.93 (s, 3 H), 3.63 (s, 3 H), 2.94 (s, 3 H), 2.86 (s, 6 H). LCMS (M+H) +< 352.Example 114: N-[5-[5-(diethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide

[0314]

[0315] The title compound was prepared in a manner similar to Example 113, substituting acetaldehyde for formaldehyde. 1< H NMR (Methanol-d4 400 MHz): δ 7.55 (d, J = 2.4 Hz, 1 H), 7.49 (d, J = 2.4 Hz, 1 H), 7.37 (dd, J 1 = 8.4 Hz, J 2 =2.4 Hz, 1 H), 7.17-7.11 (m, 1 H), 7.06 (d, J = 2.4 Hz, 1 H), 3.95 (s, 3 H), 3.65 (s, 3 H), 3.34 (m, 4H), 2.97 (s, 3 H), 1.11 (t, J = 7.2 Hz, 6 H). LCMS (M+H) +< 380.Example 115: N-[3-(5-amino-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamideStep 1: 3-amino-5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-1-methylpyridin-2-one

[0316]

[0317] The title compound of step 1 was prepared in a manner similar to Example 107, substituting the title compound of Example 57, step 1 for (3-methylsulfonylphenyl)boronic acid. LCMS (M+H) +< 344.Step 2: N-[3-(5-amino-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

[0318]

[0319] The title compound was prepared in a manner similar to Example 99, step 2. 1< H NMR (DMSO-d6, 400 MHz) δ 9.78 (s, 1 H), 7.45-7.39 (m, 1 H), 7.23-7.22 (m, 2 H), 7.14 (dd, J 1 = 7.2 Hz, J 2 = 1.6 Hz, 1 H), 7.10-7.02 (m, 2 H), 6.85 (d, J = 8.8 Hz, 1 H), 6.79 (d, J = 2.0 Hz, 1 H), 3.49 (s, 3 H), 3.09 (q, J = 7.2 Hz, 2 H), 1.21 (t, J = 7.6 Hz, 3 H). LCMS (M+H) +< 436.Example 116: 3-amino-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one

[0320]

[0321] The title compound was prepared in a manner similar to Example 107, substituting the title compound of Example 90, step 1 for (3-methylsulfonylphenyl)boronic acid. 1< H NMR (CDCl 3 , 400 MHz) δ 7.84-7.81 (m, 2 H), 7.11 (d, J = 2.0 Hz, 1 H), 7.02 (d, J = 2.4 Hz, 1 H), 6.84 (d, J = 2.4 Hz, 1 H), 3.95 (d, J = 6.8 Hz, 2 H), 3.65 (s, 3 H), 3.06 (s, 3 H), 1.31-1.27 (m, 1 H), 0.68 (q, J = 5.6 Hz, 2 H), 0.37 (q, J =5.2 Hz, 2 H). LCMS (M+H) +< 349.Example 117: 4-ethoxy-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamide

[0322]

[0323] A mixture of the title compound of Example 98, step 1 (40 mg, 0.17 mmol), Pd(dppf)Cl 2 (10 mg, 8%) and 3-bromo-4-ethoxybenzene-1-sulfonamide (48 mg, 0.17 mmol) was suspended in 1,4-dioxane (880 µL) and saturated bicarbonate solution (aq) (220 µL). The mixture was heated to 95 °C using microwave irradiation (normal) for 60 min. The crude reaction mixture was filtered through a short plug of celite, the plug was washed with additional 1,4-dioxane (1 ml), and the combined filtrate was purified by prep-HPLC. The fractions were combined and lyophilized to give the title compound (14 mg, 27%) as a white solid. 1HNMR (DMSO, 400 MHz): δ 1.33 (t, J=6.9, 3 H), 3.49 (s, 3H), 4.15 (q, J=6.9, 2H), 6.45 (d, J=9.4 Hz, 1 H), 7.20-7.23 (m, 3H), 7.64 (dd, J=2.6, 9.4 Hz, 1 H), 7.72-7.74 (m, 2 H), 7.89 (d, J=2.6 Hz, 1 H). LCMS (M+H) +< = 309.Example 118: 4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamideStep 1: 3-bromo-4-fluorobenzenesulfonamide

[0324]

[0325] A solution of 3-bromo-4-fluorobenzenesulfonyl chloride (1g, 3.3 mmol, 90% pure) stirred at 0 °C in THF (15 ml) and DCM (5 ml) was treated with aqueous ammonium hydroxide (28%) by dropwise addition over 15 min. After stirring at 0 °C for 210 min, the mixture was acidified (pH = 1) by addition of 1 N HCl (aq). After the mixture was concentrated in vacuo to near dryness, it was treated with water (50 ml), sonicated for 3 min and filtered. After the filter cake was washed sequentially with water (50 ml) and hexanes (100 ml), it was dried in vacuo to afford the title compound (503 mg, 60%) as a white solid which was carried forward without purification. LCMS (M-H) -< = 253.Step 2: 3-bromo-4-(2,4-difluorophenoxy)benzenesulfonamide

[0326]

[0327] A solution of 3-bromo-4-fluorobenzenesulfonamide (400 mg, 1.6 mmol) and 2,4-difluorophenol (228 mg, 1.76 mmol) in DMSO (16 ml) was treated with cesium carbonate (1 g, 3.2 mmol). The resulting mixture was heated to 120 °C for 20 min by microwave irridation (normal). The mixture was treated with water (100 ml) and extracted with EtOAc (3 X 50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan solid. The solid was purified by silica gel chromatography (12 g ISCO, 30% EtOAc in hexanes 30 ml / min) to give the title compound (340 mg, 58%) as a tan solid LCMS (M-H) -< = 362.Step 3: 4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamide

[0328]

[0329] 3-Bromo-4-(2,4-difluorophenoxy)benzenesulfonamide (1 eq., 62 mg), the title compound of Example 98, step 1 (40 mg, 0.17 mmol), Pd(dppf)Cl 2 (10 mg, 8%) in 1,4-dioxane (880 µL) and saturated bicarbonate solution (aq) (220 µL) were reacted at 105 °C for 30 min in a manner similar to Example 117. Work up and preparative HPLC, also in a similar manner, gave the title compound (12 mg, 18%) as a white solid. 1H NMR (DMSO, 400 MHz): δ3.51 (s, 3 H), 6.49 (d, J=9.4, 1H), 4.15 (q, J=6.9, 2H), 6.45 (d, J=9.4 Hz, 1 H), 7.20-7.23 (m, 3H), 7.64 (dd, J=2.6, 9.4 Hz, 1 H), 7.72-7.74 (m, 2 H), 7.89 (d, J=2.6 Hz, 1 H). LCMS (M+H) +< = 393.Example 119: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-oneStep 1: 5-bromo-3-fluoro-1-methylpyridin-2-one

[0330]

[0331] A mixture of 5-bromo-3-fluoropyridin-2-ol (1 g, 5.2 mmol), iodomethane (356 mg, 5.7 mmol) and K 2 CO 3 (1.4 g, 10.4 mmol) in DMF (10 mL) was stirred at rt for 12 h. The mixture was treated with water (70 ml) and extracted with EtOAc (3 X 50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1 g, 93 %) as a white solid which was carried forward without purification. LCMS (M+H) +< = 207.Step 2: 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one

[0332]

[0333] A mixture of 5-bromo-3-fluoro-1-methylpyridin-2-one (1 g, 4.9 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.5 g, 9.8 mmol), KOAc(1.2 g, 12.3 mmol), and Pd(dppf)Cl 2 (286 mg, 8%) was suspended in 1,4-dioxane (15 mL). After purging the reaction vial with nitrogen for 5 min, the capped vial was stirred at 80 °C for 1 h. The mixture was treated with water (70 ml) and extracted with EtOAc (3 X 40 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark residue. The residue was purified by silica gel chromatography (12 g ISCO, gradient 05-75 % EtOAc in hexanes) to give the title compound (682 mg, 55%) as a reddish brown solid.Step 3: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one

[0334]

[0335] 3-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (40 mg, 0.16 mmol), 2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene (49 mg, 0.16mmol), and Pd(dppf)Cl 2 (12 mg, 10%) in 1,4-dioxane (880 µL) and saturated bicarbonate solution (aq) (220 µL) were reacted, worked up, and purified in a manner similar to Example 117. The title compound (22 mg, 46%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 0.31 - 0.42 (m, 2 H) 0.53 - 0.63 (m, 2 H) 1.17 - 1.34 (m, 1 H) 3.20 (s, 3 H) 3.58 (s, 3 H) 3.95 - 4.06 (m, 2 H) 7.24 - 7.33 (m, 1 H) 7.72 - 7.79 (m, 1 H) 7.80 - 7.87 (m, 1 H) 7.84 (s, 1 H) 7.88 - 7.93 (m, 1 H) LCMS (M+H) +< = 351.Example 120: 5-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one

[0336]

[0337] The title compound of Example 119, step 2 (40 mg, 0.16 mmol), 1-(2-bromo-4-methylsulfonylphenoxy)-2,4-difluorobenzene (58 mg, 0.16mmol) and Pd(dppf)Cl 2 (12 mg, 10%) in 1,4-dioxane (880 µL) and saturated bicarbonate solution (aq) (220 µL) were reacted, worked up and purified in a manner similar to Example 117. The title compound (26 mg, 46%) was obtained as a tan solid. 1< H NMR (400 MHz, DMSO-d6) δ 3.25 (s, 3 H) 3.60 (s, 3 H) 6.91 - 6.99 (m, 1 H) 7.16 - 7.30 (m, 1 H) 7.49 - 7.62 (m, 2 H) 7.76 - 7.86 (m, 2 H) 8.00 (m, 2 H) LCMS (M+H) +< = 410.Example 121: 5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one

[0338]

[0339] The title compound of Example 119, step 2 (40 mg, 0.16 mmol), 1-(2-bromo-4-ethylsulfonylphenoxy)-2,4-difluorobenzene (60 mg, 0.16mmol), and Pd(dppf)Cl 2 (12 mg, 10%) in 1,4-dioxane (880 µL) and saturated bicarbonate solution (aq) (220 µL) were reacted, worked up and purified in a manner similar to Example 117. The title compound (18 mg, 27%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.13 (t, J=7.33 Hz, 3 H) 3.34 (q, J=7.33 Hz, 2 H) 3.59 (s, 3 H) 6.92 - 6.98 (m, 1 H) 7.19 - 7.27 (m, 1 H) 7.50 - 7.61 (m, 2 H) 7.76 - 7.84 (m, 2 H) 7.92 - 7.96 (m, 1 H) 7.97 - 8.01 (m, 1 H)LCMS (M+H) +< = 424.Example 122: N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamideStep 1: N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

[0340]

[0341] Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 3-bromo-4-(2,4-difluorophenoxy)aniline ( 328 mg, 1.1 mmol) and pyridine ( 178 µL, 2.2 mmol) in dichloromethane (2 ml) at 0 °C under nitrogen. After the mixture was allowed to warm to rt and stir overnight, it was treated with 1N HCl (10 ml) and extracted with dichloromethane (3 X 10 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (430 mg, 99 %) as a tan solid which was carried forward without purification. LCMS (M-H) -< = 391.Step 2: N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide

[0342]

[0343] N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide (77 mg, 0.2 mmol), the title compound of Example 119, step 2 (50 mg, 0.2 mmol), and Pd(dppf)Cl 2 (14 mg, 10%) in 1,4-dioxane (1 mL) and saturated bicarbonate solution (aq) (333 µL) were reacted, worked up and purified in a manner similar to Example 117. The title compound (31 mg, 27%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.22 (t, J=7.3, 3 H) 3.11 (q, J=7.3 Hz, 2 H) 3.55 (s, 3 H) 6.86 (d, J=8.6 Hz, 1 H) 7.02 - 7.12 (m, 1 H) 7.13 - 7.23 (m, 2 H) 7.26 (d, J=2.8 Hz, 1 H) 7.35 - 7.52 (m, 1 H) 7.60 (m, 1 H) 7.79 (s, 1 H) 9.48 - 9.96 (m, 1 H). LCMS (M+H) +< = 439.Example 123: N-[3-(2-methyl-1-oxo-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide Step 1: 4-chloro-2-methyl-2,6-naphthyridin-1-one

[0344]

[0345] N-chlorosuccinimide (0.8 g, 6.2 mmol) was added in portions to a solution of 2-methyl-2,6-naphthyridin-1-one (1.0 g, 6.2 mmol) in acetonitrile (25 mL) which was then heated at 65 °C for 18 h. Extractive work up with ethyl acetate and purification by silica gel chromatography (PE: EA = 5:1~1:1) gave the title compound of step 1 (0.6 g, 56 %) as a yellow solid. 1< H NMR: (CDCl3, 400 MHz) δ 9.29 (s, 1 H), 8.81 (d, J = 3.6 Hz, 1 H), 8.21 (d, J = 5.2 Hz, 1 H), 7.31 (s, 1 H), 3.63 (s, 3 H). LCMS: 195.0 (M+H)+.Step 2: N-[3-(2-methyl-1-oxo-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide

[0346]

[0347] A mixture of 4-chloro-2-methyl-2,6-naphthyridin-1-one (50.0 mg, 0.26 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (88.0 mg, 0.38 mmol), Pd(dppf)Cl 2 (15.3 mg, 0.026 mmol) and K 3 PO 4 (190 mg, 0.9 mmol) in dioxane (3 mL) and water (0.5 mL) was microwaved at 120 °C under microwave for 2 h. Purification by silica gel chromatography on (PE:EA = 10:1 to 1:1) followed by preparative HPLC gave the title compound (5.9 mg, 6.8 %) as a yellow solid. 1< H NMR (Methanol-d4, 400 MHz) δ 8.99 (brs, 1 H), 8.71 (d, J = 6.0 Hz, 1 H), 8.39 (d, J = 5.6 Hz, 1H), 7.62 (s, 1 H), 7.51 (t, J = 8.0 Hz,,1 H), 7.41-7.40 (m, 1 H), 7.36 (dd, J 1 = 8.0 Hz, J 2 = 1.2 Hz, 1 H), 7.29 (d, J = 5.6 Hz, 1 H), 3.72 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H), 1.35 (t, J = 7.6 Hz, 3 H). LCMS: 344.1 (M+H) +< .

[0348] Examples 124-126 in Table 15 were prepared from title compound of Example 123, step 1, using the appropriate phenyl boronic acid / ester in a manner similar to Example 123, step 2. Example 127 in Table 15 was prepared in two steps from the title compound of Example 123, step 1, and the the title compound of Example 57, step 1, by coupling the aniline boronic ester in a manner similar to Example 123, step 1, except that the temperature was raised from 120 °C to 150 °C and NMP was used instead of dioxane (step 1), followed by sulfonylation of the aniline in a manner similar to Example 57, step 3 (step 2). Table 15 Ex. No. R 1< Name 1< H NMR (ppm (δ), 400 MHz) MS (M+H ) 124 N-ethyl-3-(2-methyl-1-oxo-2,6-naphthyridin -4-yl)benzenesu lfonamide(Methanol-d4) 8.86 (d, J = 0.8 Hz, 1 H), 8.70 (d, J = 5.6 Hz, 1 H), 8.28 (dd, J 1 = 5.6 Hz, J 2 = 0.8 Hz, 1 H), 7.98-7.95 (m, 2 H), 7.78-7.75 (m, 2 H), 7.60 (s, 1 H), 3.71 (s, 3 H), 2.98 (q, J = 7.2 Hz, 2 H), 1.10 (t, J = 7.2 Hz, 3 H)344125 N-[3-(2-methyl-1-oxo-2,6-naphthyridin -4-yl)phenyl]me thanesulfona mide(CD 3 OD) 8.98 (s, 1 H), 8.70 (d, J = 5.2 Hz, 1 H), 8.34 (d, J = 5.2 Hz, 1 H), 7.60 (s, 1 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.40 (s, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 3.71 (s, 3 H), 3.04 (s, 3 H)330126 4-(3-ethylsulfonyl phenyl)-2-methyl-2,6-naphthyridin -1-one(CD 3 OD) 9.02 (s, 1 H), 8.78 (d, J = 5.2 Hz, 1 H), 8.57 (d, J = 5.2 Hz, 1 H), 8.09 (s, 1 H), 8.06 (d, J = 7.6 Hz, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.85 (t, J = 7.6 Hz, 1 H), 7.80 (s, 1 H), 3.74 (s, 3 H), 3.33 (q, J = 7.6 Hz, 2 H), 1.29 (t, J = 7.6 Hz, 3 H)329127 N-[4-(2,4-difluorophen oxy)-3-(2-methyl-1-oxo-2,6-naphthyridin -4-yl)phenyl]eth anesulfonami de(CD 3 OD) 9.02 (s, 1 H), 8.78 (d, J = 5.2 Hz, 1 H), 8.57 (d, J = 5.2 Hz, 1 H), 8.09 (s, 1 H), 8.06 (d, J = 7.6 Hz, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.85 (t, J = 7.6 Hz, 1 H), 7.80 (s, 1 H), 3.74 (s, 3 H), 3.33 (q, J = 7.6 Hz, 2 H), 1.29 (t, J = 7.6 Hz, 3 H)472 Example 128: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-oneStep 1: 2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one

[0349]

[0350] 6-Bromo-2-methylisoquinolin-1-one (300.0 mg, 1.27 mmol), 4-methyl-1H-pyrazole (210.0 mg, 2.54 mmol), CuI (30.0 mg, 0.127 mmol) and K 2 CO 3 (360.0 mg, 2.54 mmol) in NMP (3.0 mL) were microwaved at 195 °C for 5 h. Extractive work up with ethyl acetate followed by silica gel chromatography (PE:EA = 5:1) gave the title compound of step 1 (160.0 mg, 52 %) as a light yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.49 (d, J = 8.8 Hz, 1 H), 7.84 (s, 1 H), 7.83 (d, J = 2.0 Hz, 1 H), 7.74 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.59 (s, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 6.52 (d, J = 7.6 Hz, 1 H), 3.62 (s, 3 H), 2.19 (s, 3 H). LCMS: 240.0 (M+H)+.Step 2: 4-bromo-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one

[0351]

[0352] Bromine (94 mg, 0.59 mmol) in acetic acid (2 mL) was added drop-wise to a solution of 2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one (140.0 mg, 0.583 mmol) in acetic acid (4 mL) at 0 °C. The mixture was then stirred at room temperature for 17 min and quenched with water (10 mL). The pH was adjusted to about 7-8 with aqueous 1M NaOH. Extractive work up with ethyl acetate followed by purification using silica gel chromatography (PE:EA = 1:1) gave the title compound of step 2 (120.0 mg, 56 %) as a light yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.51 (d, J = 8.8 Hz, 1 H), 8.06 (d, J = 2.0 Hz, 1 H), 7.89 (s, 1 H), 7.87 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1 H), 7.63 (s, 1 H), 7.42 (s, 1 H), 3.62 (s, 3 H), 2.20 (s, 3 H). LCMS: 319.8 (M+H)+.Step 3: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one

[0353]

[0354] 4-Bromo-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one (40.0 mg, 0.126 mmol), the title compound of Example 90, step 1 (53.2 mg, 0.152 mmol), Pd(dppf)Cl 2 (200.0 mg, 0.05 mmol) and aqueous 1M K 3 PO 4 (0.38 mL, 0.38 mmol) in dioxane (3 mL) were heat in a microwave at 100 °C for 1 h. Purification by preparative HPLC gave the title compound (15.0 mg, 25 %) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.57 (d, J = 8.4 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.90 (s, 1 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.73 (s, 1 H), 7.54 (s, 1 H), 7.50 (s, 1 H), 7.14 (s, 1 H), 7.12 (s, J = 9.2 Hz, 1 H), 3.96-3.83 (m, 2 H), 3.68 (s, 3 H), 3.13 (s, 3 H), 2.15 (s, 3 H), 1.01-0.94 (m, 1 H), 0.38-0.28 (m, 2 H), 0.08-0.02 (m, 2 H). LCMS: 464.1 (M+H)+.Example 129: N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]ethanesulfonamideStep 1: 5-bromo-7-methylimidazo[1,5-a]pyrazin-8-one

[0355]

[0356] To a solution of 5-bromo-1-methylpyrazin-2-one (500.0 mg, 2.65 mmol) and (p-tolylsulfonyl)methyl isocyanide (573.0 mg, 2.94 mmol) in THF (4 mL) was added a suspension of NaH (235.0 mg, 5.9 mmol) in THF (2 mL) at 0 °C under N 2 . After stirring at 0 °C for 30 min, the mixture was stirred at 30 °C for another 1.5 h. The reaction mixture was quenched with H 2 O (20 mL) at 0 °C, and extracted with EtOAc (30 mL x 2). The organic phases were combined, washed with brine (30 mL), dried over Na 2 SO 4 , filtered and evaporated. The crude product was purified by column chromatography (PE:EA = 1 / 1) to give the title compound (300.0 mg, 50 %) as a light yellow solid. 1< H NMR (CDCl 3 400 MHz) δ 8.06 (d, J=4.4 Hz, 1 H), 6.61 (s, 1 H), 3.48 (s, 3 H). LCMS (M+H) +< 228.Step 2: 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one

[0357]

[0358] A solution of 5-bromo-7-methylimidazo[1,5-a]pyrazin-8-one (114.0 mg, 0.5 mmol), the title compound of Example 57, step 1 (208.0 mg, 0.6 mmol), Pd(dppf) 2 Cl 2 (37.0 mg, 0.05 mmol), NaHCO 3 (126.0 mg, 1.5 mmol) in dioxane (10 mL) and H 2 O (1 mL) was stirred in microwave at 110 °C with N 2 atmosphere for 3 hours. The solvent was evaporated to give the crude product, which was purified by column chromatography (PE:EA = 3 / 1) to give the title compound (110 mg, 60 %) as a yellow solid. 1< H NMR (CDCl 3 400 MHz) δ 7.94 (s, 1 H), 7.82 (s, 1 H), 6.93-6.82 (m, 2 H), 6.79-6.74 (m, 4 H), 6.41 (s, 1 H), 3.50 (s, 3 H). LCMS (M+H) +< 369.Step 3: N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]ethanesulfonamide

[0359]

[0360] The title compound was prepared in a manner similar to Example 99, step 2, substituting the title compound of step 2 for the title compound of Example 99, step 1. 1< H NMR (CDCl 3 400 MHz) δ 8.57 (s, 1 H), 8.14 (s, 1 H), 7.50 (d, J = 2.4 Hz, 1 H), 7.30 (dd, J 1 = 8.8 Hz, J 2 = 2.4, 1 H), 7.20-7.16 (m, 1 H), 6.99-6.87 (m, 2 H), 6.83 (s, 1 H), 6.55 (d, J = 8.8 Hz, 1 H), 3.59 (s, 3 H), 3.13 (q, J = 7.2 Hz, 2 H), 1.39 (t, J = 7.2 Hz, 3 H). LCMS (M+H) +< 461.Example 130: 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one

[0361]

[0362] The title compound was prepared in a manner similar to Example 129, step 2, substituting 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for 4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to give the title compound. 1< H NMR (CDCl 3 400 MHz) δ 8.08 (dd, J 1 = 8.8 Hz, J 2 = 2.4, 1 H), 8.03 (s, 1 H), 7.98 (d, J = 2.4 Hz, 1 H), 7.58 (s, 1 H), 7.16 (d, J = 8.8 Hz, 1 H), 6.50 (s, 1 H), 3.97 (d, J = 7.2 Hz, 2 H), 3.54 (s, 3 H), 3.11 (s, 3 H), 1.15-1.02 (m, 1 H), 0.59-0.49 (m, 2 H), 0.26 -0.17 (m, 2 H). LCMS (M+H) +< 374.Example 131: 7-methyl-5-(3-methylsulfonylphenyl)imidazo[1,5-a]pyrazin-8-one

[0363]

[0364] A solution of compound from Example 129, step 1 (80 mg, 0.35 mmol), (3-methylsulfonylphenyl)boronic acid (77 mg, 0.6 mmol), Na 2 CO 3 (106 mg, 1 mmol), Pd(PPh 3 ) 2 Cl 2 (30.0 mg) in dioxane (3 mL) and water (0.5 mL) was stirred at 120 °C for 18 h under N 2 . After cooling to room temperature, the mixture was filtered, concentrated and purified by prep-HPLC to give the title compound (20.0 mg, 20 %). 1< H NMR (Methanol-d 4 400 MHz): δ 8.70-8.65 (m, 1 H), 8.30-8.20 (m, 2 H), 8.16 (d, J = 8.0 Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.88 (t, J = 8.0 Hz, 1 H), 7.22 (s, 1 H), 3.56 (s, 3 H), 3.24 (s, 3 H). LCMS (M+H) +< 304.Example 132: N-[2-methoxy-5-(7-methyl-8-oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]methanesulfonamide

[0365]

[0366] The title compound was prepared in a manner similar to Example 131, substituting [3-(methanesulfonamido)-4-methoxyphenyl]boronic acid for (3-methylsulfonylphenyl)boronic acid to give the title compound. 1< H NMR (Methanol-d 4 400 MHz): δ 8.81 (s, 1 H), 8.29 (s, 1 H), 7.70 (s, 1 H), 7.50 (m, 2 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.12 (s, 1 H), 4.01 (s, 3 H), 3.56 (s, 3 H), 3.08 (s, 3 H). LCMS (M+H) +< 349.Example 133: 5-(3-ethylsulfonylphenyl)-7-methylimidazo[1,5-a]pyrazin-8-one

[0367]

[0368] The title compound was prepared in a manner similar to Example 131, substituting (3-ethylsulfonylphenyl)boronic acid for (3-methylsulfonylphenyl)boronic acid to give the title compound. 1< H NMR (Methanol-d4 400 MHz): δ 8.83 (s, 1 H), 8.27 (s, 1 H), 8.21 (s, 1 H), 8.10 (d, J = 7.6 Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.89 (t, J = 8.0 Hz, 1 H), 7.24 (s, 1 H), 3.56 (s, 3 H), 3.31 (q, J = 7.6 Hz, 2 H), 1.28 (t, J = 7.6 Hz, 3 H). LCMS (M+H) +< 318.Example 134: N-[3-(5-chloro-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

[0369]

[0370] The title compound was prepared in a manner similar to Example 122, substituting 3-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one. LCMS (M+H) +< 455.Example 135: 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one

[0371]

[0372] The title compound was prepared in a manner similar to Example 89, substituting 2-bromo-1-(cyclopropylmethoxy)-4-ethylsulfonylbenzene for 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene. LCMS (M+H)+ 398.Example 136: 6-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,4-dimethylpyridazin-3-one

[0373]

[0374] The title compound was prepared in a manner similar to Example 90, substituting 6-chloro-2,4-dimethylpyridazin-3-one for 4-bromo-6-fluoro-2-methylisoquinolin-1-one.. LCMS (M+H) +< 349.Example 137: 6-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,5-dimethylpyridazin-3-one

[0375]

[0376] The title compound was prepared in a manner similar to Example 90, substituting 6-chloro-2,5-dimethylpyridazin-3-one for 4-bromo-6-fluoro-2-methylisoquinolin-1-one. LCMS (M+H) +< 349.Example 138: N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(trifluoromethyl)pyridin-3-yl]phenyl]ethanesulfonamide

[0377]

[0378] The title compound was prepared in a manner similar to Example 122, substituting 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-one for 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one. LCMS (M+H) +< 489.Example 139: N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide

[0379] Step 1: 2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine

[0380]

[0381] A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (170 mg, 0.66 mmol), 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene (326 mg, 0.98 mmol), Pd 2 (dba) 3 (30 mg, 5%), and tricyclohexylphosphine (280 mg, 10%) was suspended in 1,4-dioxane (4 mL) and aqueous 1M K 3 PO 4 (2 mL). The mixture was heated to 70 °C using microwave irradiation (normal) for 45 min. The crude reaction mixture was filtered through a short plug of celite and the celite plug was washed with EtOAc (~ 50 mL). The filtrate was washed with water (2 x 30 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (12 g ISCO, gradient 05-75 % EtOAc in hexanes) to afford the free base of the desired product, 2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine as a yellow solid (144 mg, 57%). LCMS (M+H) +< = 381. Step 2: 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro-1-methylpyridin-2-one

[0382] A mixture of 2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine (140 mg, 0.37 mmol), KOH (62 mg, 1.11 mmol), Pd 2 (dba) 3 (17 mg, 5%), and XPhos (18 mg, 10%) was suspended in 1,4-dioxane (1.9 mL) and water (316 µL). After purging the reaction vial with nitrogen for 5 min, the capped vial was stirred at 100 °C for 1 h. After the mixture cooled to rt, it was treated with 1N HCl (aq) (1 mL) and EtOAc (5 mL). The biphasic mixture was filtered through a short plug of celite and the celite plug was washed with EtOAc (~ 50 mL). The filtrate was washed with water (2 x 30 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a orange solid, 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridin-2-ol ( LCMS (M+H) +< = 363). After the solid was diluted with DMF (2.4 mL), it was treated with K 2 CO 3 (112 mg) and MeI (23 µL). After stirring at rt for 5 h, the mixture was treated with water (10 mL) and extracted with EtOAc (3 x 10 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered, concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (4 g ISCO, gradient 05-95 % EtOAc in hexanes) to afford the desired product, 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro-1-methylpyridin-2-one as a tan solid (95 mg). LCMS (M+H) +< = 377.Step 3: 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-4-fluoro-1-methylpyridin-2-one

[0383]

[0384] A mixture of 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro-1-methylpyridin-2-one (90 mg, 0.24 mmol), ammonium chloride (26 mg, 0.48 mmol), iron powder (67 mg, 1.2 mmol) suspended in THF (500 µL), water (180 µL) and ethanol (500 µL) was heated to 100 °C using microwave irradiation (normal) for 3 h. The crude reaction mixture was filtered through a short plug of celite and the celite plug was washed with heated (50 °C) MeOH (~ 10 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (20 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-4-fluoro-1-methylpyridin-2-one (75 mg, 90%). LCMS (M+H) +< = 347. The material was carried forward without any further purification.Step 4: N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide

[0385]

[0386] Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-4-fluoro-1-methylpyridin-2-one (72 mg, 0.21 mmol) and pyridine (50 µL, 0.63 mmol) in dichloromethane (500 µL) at 0 °C under nitrogen. After the mixture was allowed to warm to rt and stir for 2 h, it was treated with 1N HCl (3 mL) and extracted with dichloromethane (3 x 10 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (4 g ISCO, gradient 0-10 % MeOH in dichloromethane) to afford the desired product, N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide (66 mg, 72 %) as a white solid. 1< H NMR (400 MHz, DMSO-d6) δ 1.18 - 1.26 (m, 3 H), 3.07 - 3.16 (m, 2 H), 3.45 (s, 3 H), 6.22 - 6.33 (m, 1 H), 6.82 - 6.93 (m, 1 H), 7.01 - 7.16 (m, 2 H), 7.18 - 7.28 (m, 2 H), 7.38 - 7.49 (m, 1 H), 7.95 - 8.05 (m, 1 H), 9.77 - 9.87 (s, 1 H). LCMS (M+H) +< = 439.Example 140: N-[3-(5-cyclopropyl-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

[0387]

[0388] The title compound was prepared in a manner similar to Example 122, substituting 3-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one. LCMS (M+H) +< 461.Example 141: N-{4-(2,4-difluorophenoxy)-3-[1-( 2< H 3 )methyl-6-oxopyridin-3-yl]phenyl}ethanesulfonamide

[0389]

[0390] The title compound was prepared in a manner similar to Example 122, substituting 1-( 2< H 3 )methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one. LCMS (M+H) +< 424.Example 142: N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide

[0391]

[0392] The title compound of Example 127 (240 mg, 0.5 mmol) was hydrogenated (50 psi) at room temperature in anhydrous EtOH (30 mL) for 18 h using PtO 2 (0.1 g). Purification by preparative HPLC gave the title compound (40 mg, 16.7 %) as a white solid. 1< H NMR (Methanol-d4, 400 MHz) δ 7.36 (s., 1 H), 7.23 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz 1 H), 7.14 (d, J = 2.8 Hz, 1 H), 7.06-6.96 (m, 2 H), 6.91-6.86 (m, 2 H), 3.83-3.49 (m, 2 H), 3.53 (s, 3 H), 3.16-2.89 (m, 2 H), 3.08 (q, J = 7.2 Hz, 2 H), 2.55 (t, J = 6.0 Hz, 2 H), 2.55 (t, J = 7.2 Hz, 3 H). LCMS (M+H) +< 476.Example 143: 4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin-1-oneStep 1: 5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-ol

[0393]

[0394] To the title compound of Example 152, step 1 (5.00 g, 31.6 mmol) in THF (50 mL) at 0°C was added NaH (1.26 g, 31.6 mmol, 60% in mineral oil). Ethyl formate (2.57 g, 34.76 mmol) was added at 0°C and the mixture was heated at 70°C for 2 h. The mixture was then cooled to r.t and a pre-mixed solution of 2-(methylsulfonyl)-ethanimidamide (6.44 g 47.4 mmol) and EtONa (4.3 g, 63.2 mmol) in ethanol (50mL) was added dropwise. The mixture was heated at 90°C for 12 h, cooled to room temperature, and the solvent was removed under vacuum. Water (50 mL) was added to the residue and the pH was adjusted to 5 with 1M HCl. The resulting precipitate was collected and washed with water (100 ml), ethanol (50 ml) and methanol (30 mL) to give the title compound (1.9 g, yield: 23.4%) as a white solid. 1< H NMR (DMSO-d6, 400 MHz) δ 11.49 (s, 1 H), 6.83 (s, 1 H), 6.49 (s, 2 H), 3.63 (d, J = 6.8 Hz, 2 H), 3.04 (s, 3 H), 1.14-1.10 (m, 1 H), 0.52-0.49 (m,2 H), 0.27-0.24 (m, 2 H). LCMS: 259.0 (M+1) +< Step 2: 4-chloro-5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidine

[0395] To the title compound of step 1 (1.9 g, 7.36 mmol) in MeCN (30 mL) was added Me 4 NCl (1.6 g, 14.72 mmol) and POCl 3 (6.8 g, 44.16 mmol). The mixture was heated at 80°C for 6 h. After concentration under vacuum, the residue was subjected to EA extractive work up. Trituration with methanol (20 mL) gave the title compound (1 g, yield: 49.3%) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 7.60 (s, 1 H), 5.50 (s, 2 H), 3.85 (d, J = 6.8 H z, 2 H), 3.09 (s, 3 H), 1.31-1.28 (m, 1 H), 0.70-0.65 (m, 2 H), 0.39-0.36 (m, 2 H). LCMS: 277.1 (M+1) +< Step 3: 4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin-1-one

[0396]

[0397] The title compound of step 2 (100 mg, 0.36 mmol), the title compound of Example 89, step 1 (124 mg, 0.43 mmol), Pd(dppf)Cl 2 (27 mg, 0.03 mmol ) and K 3 PO 4 (154 mg, 0.72 mmol) in dioxane (5 mL) and water (5 drops) were N 2 purged and heated to 70 °C for 18 h. After concentration under vacuum, the residue was purified using silica gel chromatography followed by prep-HPLC to give the title compound (61.7 mg, 42.7%) as a yellow solid. 1< H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, J = 7.2 Hz, 1 H), 7.69-7.65(m, 3 H), 7.53(t, J= 7.2 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 3.76 (d, J = 6.8 Hz, 2 H), 3.58 (s, 3 H), 3.26 (s, 3 H), 0.94-0.88 (m, 1 H), 0.35-0.31 (m, 2 H), 0.10-0.08 (m, 2 H). LCMS: 400.1 (M+1) +< Example 144: 5-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-1,3-dimethylpyridin-2-one

[0398]

[0399] The title compound of Example 143, step 2 was reacted with 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 143, step 3 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz) δ 8.49 (d, J = 2.0 Hz, 1 H), 8.18 (s, 1 H), 7.60 (s, 1 H), 3.86 (d, J = 6.8 Hz, 2 H), 3.67 (s, 3 H), 3.11 (s, 3 H), 2.24 (s, 3 H), 1.29-1.27 (m, 1 H), 0.72-0.67 (m, 2 H), 0.39-0.35 (m, 2 H). LCMS: 364.1(M+1) +< Example 145: 4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

[0400]

[0401] The title compound of Example 143, step 2 was reacted with the title compound of Example 46, step 2 in a manner similar to Example 143, step 3 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 8.26 (d, J = 8.4 Hz, 1 H), 8.23 (s, 1 H), 7.91 (s, 1 H), 7.5 (d, J = 8.4 Hz, 1 H), 7.70 (s, 1 H), 7.66 (s, 1 H), 7.52 (s, 1 H), 3.87 (s, 3 H), 3.85-3.80 (m, 4 H), 3.57 (s, 3 H), 3.28 (s, 3 H), 0.88-0.87 (m, 1 H), 0.30-0.25 (m, 2 H), 0.07-0.04 (m, 2 H). LCMS: 480.2 (M+1) +< Example 146: 5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-3-methoxy-1-methylpyridin-2-one Step 1: 5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-ol

[0402]

[0403] To a stirred suspension of NaH (960 mg, 24 mmol, 60% in mineral oil) in anhydrous THF (33 mL) was added ethyl formate (1.8 g, 24.3 mmol) and 2-(2,4-difluorophenoxy)acetic acid ethyl ester (4.3 g, 19.9 mmol) in anhydrous THF (10 mL). The suspension was stirred at room temperature for 0.5 h and then refluxed for 3 h, cooled, and concentrated under vacuum. The residue was dissolved in EtOH (50 mL) and 2-(methylsulfonyl)-ethanimidamide (3.0 g, 22.1 mmol) was added and the mixture was refluxed for 18 h. After concentration under vacuum, water (50 mL) was added and the pH was adjusted to 5 with acetic acid. After EA extractive work up, the residue was dissolved in EA (20 mL) and PE (150 mL) was added. The resulting precipitate (3.0 g, crude) was collected as a grey solid to give the title compound. LCMS: 317.1 (M+1) +< Step 2: 4-chloro-5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidine

[0404] To the title compound of step 1 (3.0 g) and N(CH 3 ) 4 Cl (1.6 g, 14.2 mmol) in anhydrous MeCN (30 mL), POCl 3 (8.7 g, 56.9 mmol) was added dropwise. The mixture was stirred at r.t. for 0.5 h and then at 70°C for 6 h. After concentration under vacuum, water was added and EA extractive work up was carried out to give the title compound (3.0 g) as a light yellow solid. LCMS: 335.1 (M+1) +< Step 3: 5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-3-methoxy-1-methylpyridin-2-one

[0405]

[0406] The title compound of Example 287, step 1 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a maner similar to that outlined for Example 119, step 2 to give 3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one which was then reacted with the title compound of step 2 in a manner similar to Example 143, step 3 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 8.37 (s, 1 H), 8.36 (d, J = 2.0 Hz, 1 H), 7.62 (d, J = 2.0 Hz, 1 H), 7.60-7.54 (m, 1 H), 7.51-7.45 (m, 1 H), 7.22-7.18 (m, 1 H), 4.78 (s, 2 H), 3.77 (s, 3 H), 3.56 (s, 3 H), 3.20 (s, 3 H). LCMS: 438.1 (M+1) +< Example 147: 5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-1,3-dimethylpyridin-2-one

[0407]

[0408] The title compound of Example 146, step 2 was reacted with 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 143, step 3 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 8.58 (d, J = 2.0 Hz, 1 H), 8.35 (s, 1 H), 8.13 (s, 1 H), 7.60-7.54 (m, 1 H), 7.52-7.46 (m, 1 H), 7.22-7.17 (m, 1 H), 4.76 (s, 2 H), 3.56 (s, 3 H), 3.18 (s, 3 H), 2.08 (s, 3 H). LCMS: 422.1 (M+1) +< Example 148: 4-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin-1-one

[0409]

[0410] The title compound of Example 146, step 2 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 143, step 3 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 8.62 (s, 1 H), 8.28 (d, J = 8.0 Hz, 1 H), 7.91 (s, 1 H), 7.69-7.68 (m, 2 H), 7.58-7.54 (m, 1 H), 7.45-7.34 (m, 2 H), 7.07-7.03 (m, 1 H), 4.83 (s, 2 H), 3.58 (s, 3 H), 3.17 (s, 3 H). LCMS: 458.1 (M+1) +< Example 149: 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-1,3-dimethylpyridin-2-oneStep 1: 5-(2,4-difluorophenoxy)-2-methylsulfanylpyrimidin-4-ol

[0411]

[0412] To a solution of 2-(2,4-difluorophenoxy)acetic acid ethyl ester (8.0 g, 37.01 mmol) and ethyl formate (4.11 g, 55.51 mmol) in dry THF (200 mL) was added NaH (1.55 g, 38.75 mmol) slowly at 0°C. The mixture was then refluxed for 2 h. In a separate flask, sodium ethoxide (3.02 g, 44.41 mmol) and S-methylthiopseudourea hemisulfate (6.17 g, 44.41 mmol) in EtOH (100 mL) were stirred at 20 ° C for 2 h and then the resulting mixture was added to the above THF solution. The combined mixture was refluxed for 12 h. After concentration under vacuum, water (20 mL) and HCl (10 mL, aq. 1N) were added. The suspended solids were collected and washed with water (50 mL x 3) and EtOH (50 mL x 3) and dried to give the title compound (6.0 g, 60.0 % yield) as a light yellow solid. 1< H NMR (DMSO-d6, 400 MHz) δ 7.84 (s, 1H), 7.42-7.34 (m, 1H), 7.04-7.01 (m, 1H), 6.95 (t, J = 9.6 Hz, 1H), 2.47 (s, 3H). LCMS: 271.1 (M+1) +< Step 2: 4-chloro-5-(2,4-difluorophenoxy)-2-methylsulfanylpyrimidine

[0413]

[0414] The title compound of step 1 (5.30 g, 19.63 mmol), POCl 3 (18.06 g, 117.78 mmol), (Me) 4 NCl (3.23 g, 29.47 mmol) in dry CH 3 CN (60 mL) was refluxed for 12 h. The mixture was poured into ice-water (50 mL) and subjected to EA extractive work up. Concentration under vacuum gave impure title compound (4.0 g), which was carried on to the next step. LCMS: 288.99 (M+1) +< Step 3: 4-chloro-5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidine

[0415]

[0416] To a solution of the title compound of step 2 (4.60 g, 15.93 mmol) in CH 2 Cl 2 (200 mL) was added mCPBA (13.75 g, 79.68 mmol) slowly at 0°C. The mixture was stirred at 20°C for 12 h and then sat. aq. Na 2 SO 3 (200 mL) was added. EA extractive work up and silica gel chromatography gave the title compound (2.0 g, 39.1% yield) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.18 (s, 1 H), 7.31-7.27 (m, 1 H), 7.10-7.01 (m, 2 H), 3.36 (s, 3 H). LCMS: 320.8 (M+1) +< Step 4: 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-1,3-dimethylpyridin-2-one

[0417]

[0418] A mixture of the title compound from step 3 (100 mg, 0.31 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (93 mg, 0.37 mmol), Pd(dppf)Cl 2 (23 mg, 0.31 mmol) and K 3 PO 4 (199 mg, 0.94 mmol) in dioxane / water (3 mL / 0.5 mL) was N 2 purged and heated at 70 ° C for 12 h. Concentration under vacuum and silica gel chromatography (PE: EA= 3:1~0:1) followed by prep-HPLC gave the title compound (45 mg, 35.4%). 1< H NMR (CDCl 3 , 400 MHz) δ 8.57 (s, 1 H), 8.25 (s, 1 H), 8.15 (s, 1 H), 7.25-7.24 (m, 1 H), 7.12-7.07 (m, 1 H), 7.03 (t, J = 8.0 Hz, 1 H), 3.68 (s, 3 H), 3.38 (s, 3 H), 2.25 (s, 3 H). LCMS: 407.9 (M+1) +< Example 150: 5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-3-methoxy-1-methylpyridin-2-one

[0419]

[0420] The title compound of Example 149, step 3 was reacted with 3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (see Example 146, step 3) in a manner similar to Example 149, step 4 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz) δ 8.35 (d, J = 2.0 Hz, 1 H), 8.18 (s, 1 H), 7.70 (d, J = 2.0 Hz, 1 H), 7.25-7.22 (m, 1 H), 7.12-7.08 (m, 1 H), 7.08-7.04 (m, 1 H), 3.93 (s, 3 H), 3.70 (s, 3 H), 3.38 (s, 3 H). LCMS: 423.9 (M+1) +< Example 151: 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin-1-one

[0421]

[0422] The title compound of Example 149, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 149, step 4 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz) δ 8.52 (d, J = 8.0 Hz, 1 H), 8.32 (s, 1 H), 7.68 (s, 3 H), 7.59-7.56 (m, 1 H), 7.14-7.08 (m, 1 H), 7.05-7.00 (m, 1 H), 6.96-6.92 (m, 1 H), 3.72 (s, 3 H), 3.39 (s, 3 H). LCMS: 443.9 (M+1) +< Example 152: N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamideStep 1: ethyl 2-(cyclopropylmethoxy)acetate

[0423]

[0424] Diazoacetic acid ethyl ester (80.00 g, 0.70 mol) was added dropwise to cyclopropanemethanol (60.66 g, 0.84 mol) and [Rh(Ac 2 O) 2 ] 2 (3.1 g, 7.02 mmol) in anhydrous CH 2 Cl 2 (800 mL) at 0°C. The mixture was stirred at 0°C for 30 min and at room temperature for 4 h. CH 2 Cl 2 extractive work up and silica gel chromatography (PE: EA = 100:1~50:1) gave the title compound (100 g, 90.4% yield) as a colorless oil. 1< H NMR: (CDCl 3 , 400 MHz) δ 4.23-4.19 (m, 2 H), 4.09 (s, 2 H), 3.38-3.36 (m, 2 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.10-1.07 (m, 1 H), 0.57-0.52 (m, 2 H), 0.24-0.20 (m, 2 H). Step 2: 5-(cyclopropylmethoxy)-2-methylsulfanylpyrimidin-4-ol

[0425] To a stirred suspension of NaH (35.20 g, 0.88 mol, 60% in mineral oil) in anhydrous THF (1000 mL) was added ethyl formate (88.80 g, 0.90 mol) and the title compound of step 1 (126.0 g, 0.80 mol) in anhydrous THF (100 mL). The mixture was stirred at r.t. for 0.5 hour and refluxed for 3 h. In a separate flask, S-methylthiopseudourea hemisulfate (133.44 g, 0.96 mol) and sodium ethoxide (65.28 g, 0.96 mol) in EtOH (200 mL) were stirred at r.t. for 1 h, whereupon this mixture was added to the above mixture. There combined mixture was refluxed for 15 h, cooled, and the pHwas adjusted to 5 with acetic acid. After concentration under vacuum, silica gel chromatography (DCM: MeOH=50 / 1~10 / 1) gave the title compound (30.00 g, 17.7% yield) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 12.08 (s, 1 H), 7.49 (s, 1 H), 3.83-3.80 (m, 2 H), 2.55 (s, 3 H), 1.37-1.28 (m, 1 H), 0.65-0.62 (m, 2 H), 0.37-0.34 (m, 2 H). Step 3: 4-chloro-5-(cyclopropylmethoxy)-2-methylsulfanylpyrimidine

[0426] To the title compound of step 2 (29.00 g, 136.79 mmol) and N(CH 3 ) 4 Cl (22.47 g, 205.19 mmol) in anhydrous MeCN (300 mL), was added POCl 3 (123.93 g, 820.74 mmol). The mixture was stirred at r.t. for 30 min and at 70°C for 1 h. After concentration under vacuum, EA extractive work up and silica gel chromatography (PE: EA = 50:1~5:1) gave the title compound (20 g, 63.6% yield) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.16 (s, 1 H), 3.95 (d, J = 6.8Hz, 2 H), 2.56 (s, 3 H), 1.33-1.28 (m, 1 H), 0.72-0.70 (m, 2 H), 0.41-0.37 (m, 2 H). LCMS: 230.9 (M+1) +< Step 4: 4-chloro-5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidine

[0427]

[0428] To the title compound of step 3 (19.0 g, 82.60 mmol) in dry CH 2 Cl 2 (200 mL) at 0°C, m-CPBA (42.62 g, 247.80 mmol) was added over 15 min. The mixture was stirred at 0°C for 30 min and at r.t. overnight. Sat.aq. Na 2 SO 3 (100 mL) was added and CH 2 Cl 2 extractive work up was carried out. Trituration with MTBE (300 mL) gave the title compound (17 g, 78.3% yield) as a white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.37 (s, 1 H), 4.13 (d, J = 6.8 Hz, 2 H), 3.33 (s, 3 H), 1.39-1.35 (m, 1 H), 0.79-0.74 (m, 2 H), 0.49-0.45 (m, 2 H). LCMS: 263.0 (M+1) +< Step 5: 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin-1-one

[0429]

[0430] The title compound of step 4 (5.00 g, 19.08 mmol), the title compound of Example 89, step 1 (5.98 g, 20.99 mmol), K 3 PO 4 (12.13 g, 57.24mmol), and Pd(dppf)Cl 2 (1.40 g, 1.91 mmol) in dioxane / H 2 O (50 mL / 5 mL) were N 2 purged and heated at 80 ° C for 8 h. Silica gel chromatography (PE: EA=10 / 1~1 / 1) to gave the title compound (5.01 g, yield: 68%) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ8.53 (s, 2 H), 7.67-7.63 (m, 2 H), 7.57-7.52 (m, 2 H), 4.06 (d, J = 6.8 Hz, 2 H), 3.71 (s, 3 H), 3.37 (s, 3 H), 1.17 (m, 1 H), 0.61 (m, 2 H), 0.30 (m, 2 H). LCMS: 386.1 (M+1) +< Step 6: N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

[0431]

[0432] Sodium hydride (0.93 g, 23.37 mmol, 60% in mineral oil) was added to MeSO 2 NH 2 (2.22 g, 23.37 mmol) in dry DMF (30 mL) at 0°C over 15 min. The mixture was stirred at 0°C for 1 h and the title compound of step 5 (3.00 g, 7.79 mmol) was added. The mixture was heated at 60 ° C for 6 h. After cooling, ice water was added and the pH was adjusted to 5 with acetic acid. The suspended solids were collected and washed with MTBE (50 mL) to afford the title compound (3 g, yield: 96.7%) as an off-white solid. 1< H NMR (CDCl 3 , 400 MHz) δ 9.80 (s, 1 H), 8.53 (d, J = 8.0 Hz, 1 H), 8.42 (s, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.70 (m, 2 H), 7.56 (t, J = 7.6 Hz , 1 H), 3.87 (d, J = 7.2 Hz, 2 H), 3.70 (s, 3 H), 3.39 (s, 3 H), 1.12 (m, 1 H), 0.58 (m, 2 H), 0.24 (m, 2 H). LCMS: 401.1 (M+1) +< Example 153: N-[5-(cyclopropylmethoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide

[0433]

[0434] The title compound of Example 152, step 4 was reacted with 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 152, step 5 and the resulting product was treated with MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 10.97 (s, 1 H), 8.67 (s, 1 H), 8.42 (s, 1 H), 8.14 (s, 1 H), 4.03 (d, J = 6.4 Hz, 2 H), 3.54 (s, 3 H), 3.35 (s, 3 H), 2.08 (s, 3 H), 1.33-1.31 (m, 1 H), 0.63-0.61 (m, 2 H), 0.38-0.37 (m, 2 H). LCMS: 365.0 (M+1) +< Example 154: N-[5-(cyclopropylmethoxy)-4-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]pyrimidin-2-yl]methanesulfonamide

[0435]

[0436] The title compound of Example 152, step 4 was reacted with the title compound of Example 46 step 2 in a manner similar to Example 152, step 5 and the resulting product was treated with MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz) δ 11.15 (s, 1 H), 8.56 (s, 1 H), 8.27 (s, 1 H), 8.25 (d, J = 7.6 Hz, 1 H), 7.98 (s, 1 H), 7.79 (s, 1 H), 7.77 (d, J = 9.6 Hz, 1 H), 7.70 (s, 1 H), 3.95 (d, J = 7.2 Hz, 2 H), 3.85 (s, 3 H), 3.57 (s, 3 H), 3.32 (s, 3 H), 1.00-0.99 (m, 1 H), 0.37-0.32 (m, 2 H), 0.14-0.12 (m, 2 H). LCMS: 481.0 (M+1) +< Example 155: N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

[0437]

[0438] The title compound of Example 152, step 5 was treated with EtSO 2 NH 2 instead of MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz) δ 9.00 (s, 1 H), 8.53 (d, J = 8.0 Hz, 1 H), 8.38 (s, 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.69 (m, 2 H), 7.57 (t, J = 7.6 Hz , 1 H), 3.86 (d, J = 6.8 Hz, 2 H), 3.70 (s, 3 H), 3.63 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.13 (m, 1 H), 0.57 (m, 2 H), 0.25 (m, 2 H). LCMS: 415.0 (M+1) +< Example 156: 4-[5-(cyclopropylmethoxy)-2-(1,1-dioxo-1,2-thiazolidin-2-yl)pyrimidin-4-yl]-2-methylisoquinolin-1-one

[0439]

[0440] The title compound of Example 152, step 5 was treated with 1,1-dioxidoisothiazolidine instead of MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 8.56 (s, 1H), 8.30 (d, J = 8.0 Hz, 1 H), 7.86 (s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.67 (t, J = 7.6 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 3.93-3.91 (m, 4 H), 3.59 (s, 3 H), 2.38-2.31 (m, 2 H), 1.06-1.01 (m, 1 H), 0.44-0.39 (m, 2 H), 0.20-0.16 (m, 2 H). LCMS: 427.1 (M+H) +< Example 157: N-[5-(cyclopropylmethoxy)-4-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

[0441]

[0442] The title compound of Example 47, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-fluoro-2-methylisoquinolin-1-one was treated with EtSO 2 NH 2 instead of MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 11.04 (brs, 1 H), 8.54 (s, 1 H), 8.36 (dd, J 1 = 9.2 Hz, J 2 = 2.4 Hz, 1 H), 8.01 (s, 1 H), 7.65 (dd, J 1 = 11.2 Hz, J 2 = 2.4 Hz, 1 H), 7.45-7.38 (m, 1 H), 3.95 (d, J = 6.8 Hz, 2 H), 3.58 (s, 3 H), 3.48 (q, J = 7.2 Hz, 2 H), 1.22 (t, J = 7.2 Hz, 3 H), 1.16-1.04 (m, 1 H), 0.50-0.42 (m, 2 H), 0.27-0.20 (m, 2 H). LCMS: 433.0 (M+1) +< Example 158: N-[5-(cyclopropylmethoxy)-4-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

[0443]

[0444] The title compound of Example 58, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-7-fluoro-2-methylisoquinolin-1-one was treated with MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 11.15 (s, 1 H), 8.55 (s, 1 H), 8.36 (dd, J 1 = 9.2 Hz, J 2 = 6.0 Hz, 1 H), 8.00 (s, 1 H), 7.60 (dd, J 1 = 11.2 Hz, J 2 = 2.4 Hz, 1 H), 7.44-7.37 (m, 1 H), 3.95 (d, J = 7.2 Hz, 2 H), 3.58 (s, 3 H), 3.32 (s, 3 H), 1.15-1.03 (m, 1 H), 0.49-0.42 (m, 2 H), 0.26-0.20 (m, 2 H). LCMS: 419.0 (M+1) +< Example 159: N-[5-(cyclopropylmethoxy)-4-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

[0445]

[0446] The title compound of Example 47, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-fluoro-2-methylisoquinolin-1-one was treated with MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 11.14 (brs, 1 H), 8.56 (s, 1 H), 7.96 (dd, J 1 = 9.2 Hz, J 2 = 3.2 Hz, 1 H), 7.88 (s, 1 H), 7.85 (dd, J 1 = 9.2 Hz, J 2 = 3.6 Hz, 1 H), 7.62-7.55 (m, 1 H), 3.94 (d, J = 6.8 Hz, 2 H), 3.60 (s, 3 H), 3.32 (s, 3 H), 1.11-0.99 (m, 1 H), 0.47-0.40 (m, 2 H), 0.23-0.16 (m, 2 H). LCMS: 419.0 (M+1) +< Example 160: N-[5-(cyclopropylmethoxy)-4-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

[0447]

[0448] The title compound of Example 58, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-7-fluoro-2-methylisoquinolin-1-one was treated with with EtSO 2 NH 2 instead of MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (CDCl3 400MHz) δ 8.53 (dd, J 1 = 8.8 Hz, J 2 = 6.0 Hz, 1 H), 8.40 (s, 1 H), 7.77 (s, 1 H), 7.69 (dd, J = 8.8 Hz, 1 H), 7.27-7.23 (m, 1 H), 3.88 (d, J = 6.8 Hz, 2 H), 3.69 (s, 3 H), 3.60 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.16-1.13 (m, 1 H), 0.62-0.56 (m, 2 H), 0.27-0.26 (m, 2 H). LCMS: 433.2 (M+1) +< Example 161: N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]-N-ethylmethanesulfonamide

[0449]

[0450] Ethyl iodide (95 mg, 0.6 mmol) and K 2 CO 3 (55 mg, 0.4 mmol) were added to a solution of the title compound of Example 152 (80 mg, 0.2 mmol) in MeCN (5 mL). After refluxing 1 h, the mixture was cooled, concentrated under vacuum and subjected to CH 2 Cl 2 extractive work up. HPLC purification gave the title compound (13.42 mg, yield: 15.2%) as a yellow solid. 1< H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.32 (d, J = 8.0 Hz, 1 H), 7.90 (s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 4.02 (q, J = 6.8 Hz, 2 H), 3.97 (d, J = 7.2 Hz, 1 H), 3.60 (s, 3 H), 3.43 (s, 3 H), 1.25 (t, J = 6.8 Hz, 1 H), 1.10-1.07 (m, 1 H), 0.46-0.42 (m, 2 H), 0.24-0.20 (m, 2 H). LCMS: 429.1 (M+H) +< Example 162: N-[5-(cyclopropylmethoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]-N-ethylmethanesulfonamide

[0451]

[0452] The title compound of Example 153 was treated with ethyl iodide in a manner similar to Example 161 to give the title compound. 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm 0.36-0.42 (m, 2 H) 0.60-0.66 (m, 2 H) 1.25 (t, J=6.82 Hz, 3 H) 1.29-1.40 (m, 1 H) 2.09 (s, 3 H) 3.48 (s, 3 H) 3.56 (s, 3 H) 3.88 - 4.20 (m, 4 H) 8.13 (s, 1 H) 8.49 (s, 1 H) 8.69 (s, 1 H). ). LCMS: 393 (M+H) +< Example 163: N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide Step 1: 2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

[0453]

[0454] The title compound was prepared from the N-methylation of 5,6,7,8-tetrahydroisoquinolin-1(2H)-one in a manner similar to Example 47, step 1. 1< H NMR (CDCl 3 , 400 MHz): δ 7.02 (d, J = 7.2 Hz, 1 H), 5.90 (d, J = 7.2 Hz, 1 H), 3.49 (s, 3 H), 2.54-2.45 (m, 4H), 1.74-1.69 (m, 4H).Step 2: 4-bromo-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

[0455]

[0456] The title compound was prepared from the bromination of the title compound of step 1 in a manner similar to Example 47, step 2. LCMS: 241.9(M+H) +< Step 3: 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydroisoquinolin-1-one

[0457]

[0458] The title compound of step 2 (3.3 g, 13.7 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.96 g, 27.4 mmol), Pd 2 (dba) 3 (400 mg, 0.43 mmol), X-phos (400 mg, 0.84 mmol) and anhydrous KOAc (1.02 g, 41.1 mmol) in anhydrous dioxane (50 mL) were heated at 50 ° C under N 2 for 12 h. Silica gel chromatography (PE: EA = 5:1) gave the title compound (1.5 g, yield: 38 %) as a yellow solid. 1< H NMR (CDCl 3 , 400 MHz): δ 7.62 (s, 1 H), 5.28 (s, 3 H), 2.82-2.76 (m, 2 H), 2.55-2.33 (m, 2 H), 1.72-1.70 (m, 4 H), 1.31 (s, 12 H). LCMS: 290.0(M+H) +< Step 4: 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

[0459] The title compound of step 3 (200 mg, 0.69 mmol), the title compound of Example 152, step 4 (218 mg, 0.83 mmol), K 3 PO 4 (440 mg, 2.07 mmol) and Pd(dppf)Cl 2 (51 mg, 0.7 mmol) in 6:1 dioxane / water (7 mL) were purged with nitrogen and heated at 70 ° C for 8 h. After silica gel chromatography (PE: EA=1:1), the title compound (180 mg, yield: 67%) was obtained as a light yellow solid. 1< H NMR (CDCl 3 , 400 MHz): δ 8.42 (s, 1 H), 7.48 (s, 1 H), 4.04 (d, J = 7.2 Hz, 2 H), 3.60 (s, 3 H), 3.35 (s, 3 H), 2.65-2.62 (m, 2 H), 2.54-2.50 (m, 2 H), 1.80-1.78 (m, 2 H), 1.77-1.67 (m, 2H), 1.28-1.25 (m, 1 H), 0.73-0.71 (m, 2 H), 0.41-0.38 (m, 2 H).Step 5: N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

[0460]

[0461] The title compound of step 4 was treated with MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz): δ 8.18 (s, 1 H), 7.38 (s, 1 H), 3.74 (d, J = 6.4 Hz, 2 H), 3.51 (s, 3 H), 3.28 (s, 3 H), 2.60-2.53 (m, 2H), 2.50-2.46 (m, 2 H), 1.74-1.71 (m, 2 H), 1.64-1.59 (m, 2 H), 1.13-1.10 (m, 1 H), 0.60-0.58 (m, 2 H), 0.25-0.24 (m, 2 H). LCMS: 405.1(M+H) +< Example 164: N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

[0462]

[0463] The title compound of Example 163, step 4 was treated with treated with EtSO 2 NH 2 instead of MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz): δ 8.32 (s, 1 H), 7.64 (s, 1 H), 3.83 (d, J = 6.8 Hz, 2 H), 3.44 (s, 3 H), 3.30-3.20 (m, 2 H), 2.47-2.41 (m, 4 H), 1.67-1.57 (m, 4 H), 1.19-1.13 (m, 4 H), 0.51-0.49 (m, 2 H), 0.24-0.22 (m, 2 H). LCMS: 419.1(M+H) +< Example 165: N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

[0464] The title compound of Example 151 was treated with MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 11.50 (s, 1 H), 8.59 (s, 1 H), 8.25 (s, J = 8.0 Hz, 1 H), 7.87 (s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.54 (t, J = 7.2 Hz, 1 H), 7.34-7.28 (m, 1 H), 7.20-7.13 (m, 1 H), 6.90 (t, J = 8.8 Hz, 1 H), 3.54 (s, 3 H), 3.35 (s, 3 H). LCMS: 459.0 (M+1) +< Example 166: N-[5-(2,4-difluorophenoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide

[0465] The title compound of Example 149, step 4 was treated with MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz) δ 8.42 (s, 1 H), 8.36 (s, 1 H), 8.10-8.12 (m, 2 H), 6.98-7.05 (m, 2 H), 6.87-6.92 (m, 1 H), 3.64 (s, 3 H), 3.45 (s, 3 H), 2.22 (s, 3 H). LCMS: 423.0 (M+1) +< Example 167: N-[5-(2,4-difluorophenoxy)-4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide

[0466]

[0467] The title compound of Example 150 was treated with MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 11.37 (s, 1 H), 8.34 (s, 1 H), 8.26 (s, 1 H), 7.58 (s, 1 H), 7.54-7.50 (m, 1 H), 7.28-7.23 (m, 1 H), 7.10-7.06 (m, 1 H), 3.74 (s, 3 H), 3.52 (s, 3 H), 3.39 (s, 3 H). LCMS: 439.0 (M+1) +< Example 168: N-[5-(2,4-difluorophenoxy)-4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide

[0468]

[0469] The title compound of Example 150 was treated with EtSO 2 NH 2 instead of MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz) δ 8.35 (d, J = 2.0 Hz, 1 H), 8.18 (s, 1 H), 7.70 (d, J = 2.0 Hz, 1 H), 7.25-7.22 (m, 1 H), 7.12-7.07 (m, 1 H), 7.04-7.01 (m, 1 H), 3.93 (s, 3 H), 3.70 (s, 3 H), 3.38 (s, 3 H). LCMS: 423.9 (M+1) +< Example 169: N-[5-(2,4-difluorophenoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide

[0470]

[0471] The title compound of Example 149, step 4 was treated with EtSO 2 NH 2 instead of MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 9.07 (s, 1 H), 8.42 (s, 1 H), 8.15 (s, 1 H), 8.11 (s, 1 H), 7.03-6.97 (m, 1 H), 6.91-6.87 (m, 1 H), 3.66-3.61 (m, 5 H), 2.22 (s, 3 H), 1.44 (t, J = 7.6 Hz, 3 H). LCMS: 437.0 (M+1) +< Example 170: N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

[0472]

[0473] The title compound of Example 151 was treated with with EtSO 2 NH 2 instead of MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (CDCl 3 , 400 MHz) δ 9.15 (s, 1 H), 8.49 (d, J = 7.6 Hz, 1 H), 8.34 (s, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.71-7.67 (m, 2 H), 7.54 (t, J = 7.6 Hz, 1 H), 6.92-6.86 (m, 2 H), 6.79-6.75 (m, 1 H), 3.67 (s, 3 H), 3.58 (q, J = 7.6 Hz, 2 H), 1.39 (t, J = 7.6 Hz, 3 H). LCMS: 473.0 (M+1) +< Example 171: 4-[5-(2,4-difluorophenoxy)-2-(1,1-dioxo-1,2-thiazolidin-2-yl)pyrimidin-4-yl]-2-methylisoquinolin-1-one

[0474]

[0475] The title compound of Example 151 was treated with 1,1-dioxidoisothiazolidine instead of MeSO 2 NH 2 in a manner similar to Example 152, step 6 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.24 (d, J = 8.0 Hz, 1 H), 7.86 (s, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.65 (t, J = 7.2 Hz, 1 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.31-7.26 (m, 1 H), 7.13-7.07 (m, 1 H), 6.89-6.87 (m, 1 H), 3.97 (t, J = 6.4 Hz, 2 H), 3.57 (t, J = 7.2 Hz, 2 H), 3.54 (s, 3 H), 2.40-2.33 (m, 2 H). LCMS: 485.2 (M+H) +< Example 172: N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

[0476]

[0477] The title compound of Example 149, step 3 was reacted with the title compound of Example 163, step 3 in a manner similar to Example 163, step 4 and the resulting product was treated with MeSO 2 NH 2 in a manner similar to Example 163, step 5 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz): δ 8.16 (s, 1 H), 7.46 (s, 1 H), 7.25-7.20 (m, 1 H), 6.90-6.84 (m, 2 H), 3.34 (s, 3 H), 2.80 (s, 3 H), 2.41-2.29 (m, 4 H), 1.60-1.48 (m, 4 H). LCMS: 463.1(M+H) +< Example 173: N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

[0478]

[0479] The title compound of Example 149, step 3 was reacted with the title compound of Example 163, step 3 in a manner similar to Example 163, step 4 and the resulting 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one was treated with EtSO 2 NH 2 instead of MeSO 2 NH 2 in a manner similar to Example 163, step 5 to give the title compound. 1< H NMR (DMSO-d6, 400 MHz): δ 8.38 (s, 1 H), 7.61 (s, 1 H), 7.35-7.31 (m, 1 H), 7.04-6.95 (m, 2 H), 3.41 (s, 3 H), 3.30-3.20 (m, 2 H), 2.42-2.40 (m, 2 H), 2.32-2.30 (m, 2 H), 1.61-1.51 (m, 4 H), 1.18 (t, J = 7.2 Hz, 3 H). LCMS: 477.1(M+H) +< Example 174: 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one

[0480]

[0481] A mixture of 4-bromo-6-fluoro-2-methylisoquinolin-1-one (500.00 mg, 1.95 mmol), 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.07 g, 2.92 mmol), K 3 PO 4 (1.24 g, 5.85 mmol) and Pd(dppf)Cl 2 (0.1 g, cat.) in dioxane / H 2 O (30 mL / 4 mL) was stirred at 70 ° C for 12 hrs under Ar. The mixture was concentrated and the residue purified by column chromatography (PE: EA = 1:1) to give a pink solid. The pink solid was further purified by column chromatography (DCM : EA = 4:1) to afford the title compound (0.13 g, 16%) as a light yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.54 (brs, 1 H), 7.96 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.22-7.20 (m,1 H), 7.15-7.13 (m, 1 H), 7.1 (d, J = 8.8 Hz, 1 H), 6.78 (dd, J 1 = 10.4 Hz, J 2 = 2.4 Hz, 1 H), 3.90 (t, J = 7.6 Hz, 2 H), 3.68 (s, 3 H), 3.15 (q, J = 7.6 Hz, 2 H), 1.33 (t, J = 7.6 Hz, 3 H), 1.06 - 1.02 (m, 1 H), 0.50-0.43 (m, 2 H), 0.15-0.14 (m, 2 H). LCMS (M+H) +< = 416.0 (M+1) +< Example 175: 2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-yloxy)phenyl]isoquinolin-1-oneStep 1: 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one

[0482]

[0483] A mixture of compound 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (4.1 g, 14.5 mmol), 2-bromo-4-methylsulfonyl-1-fluorobenzene (3.5 g, 13.8 mmol) prepared in a similar manner to Example 79 steps 1-2, CsF (6.3 g, 41.3 mmol), and Pd(dppf)Cl 2 (1.0 g, 1.38 mmol) in DME (70 mL) and MeOH (35 ml) was stirred at 70 ° C for 12 h under N 2 . The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EA = 2:1~0:1) to give the title compound (3.4 g, 74.4%) as a red solid. LCMS (M+H) +< = 331.9 (M+1) +< Step 2: 2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-yloxy)phenyl]isoquinolin-1-one

[0484]

[0485] To a solution of oxolan-3-ol (175.0 mg, 1.99 mmol) in anhydrous DMF (3 mL) was added NaH (66.0 mg, 1.65 mmol, 60% in mineral oil) at 0 ° C and then stirred at 0 ° C for 0.5 hrs. 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (110.0 mg, 0.33 mmol) was added. The mixture was stirred at 0 ° C for 0.5 h and then at r.t. for 3 hrs. It was then quenched with aqueous sat. NH 4 Cl (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure to afford a crude product which was purified by prep-HPLC to give the title compound (62.0 mg, 39.7 %) as a light yellow solid. 1< H NMR (CDCl 3 , 400 MHz) δ 8.51 (d, J = 7.6 Hz, 1 H), 8.00 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.58-7.51 (m, 2 H), 7.11-7.03 (m, 3 H), 5.01-4.98 (m, 1 H), 3.97 (dd, J 1 = 10.4 Hz, J 2 = 4.8 Hz, 1 H), 3.76-3.70 (m, 2 H), 3.67 (s, 3 H), 3.61-3.42 (m, 1 H), 3.11 (s, 3 H), 2.18-1.88 (m, 2 H). LCMS (M+H) +< = 400.0 (M+1) +< Example 176: 2-methyl-4-[5-methylsulfonyl-2-(oxan-4-yloxy)phenyl]isoquinolin-1-one

[0486]

[0487] The title compound was prepared in a manner similar to Example 175, by substituting oxan-4-ol for oxolan-3-ol in step 2. 1< H NMR (CDCl 3 , 400 MHz) δ 8.52 (d, J = 7.6 Hz, 1 H), 8.00 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.63-7.50 (m, 2 H), 7.19 (d, J = 7.6 Hz, 1 H), 7.11 (d, J = 8.8 Hz, 1 H), ...

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (III): wherein, R2 is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3; X1 is C-H or N; ring B is an optionally substituted 6-membered heterocyclic ring containing at least one oxygen or nitrogen atom; RA is X2 is N or C-R12, wherein R12 is hydrogen, halogen, alkyl, or alkoxy; R13 is -Y-Z; Y is selected from a bond, -CH2-, or -CH(C1-C4 alkyl)-; Z is selected from -SO2R21, -N(R22)SO2R21, -SO2N(R22)2, -N(R22)SO2N(R22)2, - CON(R22)2, -N(R22)CO2R21, -N(R22)CON(R22)2, -N(R22)COR21, -OC(O)N(R22)2, - OSO2N(R22)2, or -N(R22)SO3R21; X3 is N or C-R14, wherein R14 is hydrogen, halogen, -CN, alkyl, cycloalkyl, or alkoxy; or optionally when X4 is C-R15, R14 and R15 connect to form a ring; X4 is N or C-R15, wherein R15 is hydrogen, halogen, -CN, alkyl, or alkoxy; R16 is hydrogen, halogen, or -W-X, wherein W is a bond, -O-, -S-, or -NH-, and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or optionally when X4 is C-R15, R16 and R15 connect to form a ring; each R21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

2. The compound of claim 1, wherein X2 and X3 are N.

3. The compound of claim 1, wherein X2 is C-R12, X3 is C-R14, and X4 is C-R15.

4. The compound of claim 1, having the structure of Formula (IIIa): wherein, ring B is a 6-membered ring having one nitrogen atom; R23 is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, -COR24, -CO2R24, -CONH(R24), -CON(R24)2, or SO2R24; and each R24 is independently selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

5. The compound of claim 1, wherein W is -O- and X is alkyl.

6. The compound of claim 1, wherein W is -O- and X is alkynyl.

7. The compound of claim 1, wherein W is -O- and X is aryl.

8. The compound of claim 1, wherein W is -O- and X is cycloalkylalkyl.

9. The compound of claim 1, wherein W is -O- and X is cycloalkylalkynyl.

10. A compound or pharmaceutical acceptable salt thereof, selected from: 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-4H-pyrido[4,3-b][1,4]oxazine-3,5-dione; and 8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-5-one.

11. A pharmaceutical composition comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising a compound of claim 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.