Piperazinone based modulators for the treatment of disease

Abstract

The disclosure herein provides compounds of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), and pharmaceutical compositions of any one thereof. Further, the compounds and pharmaceutical compositions disclosed herein, are useful in methods for killing cancer cells or the inhibition of cancer cell proliferation.

Description

Attorney Docket No.60185-706601 PIPERAZINONE BASED MODULATORS FOR THE TREATMENT OF DISEASE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. US 63 / 655,882filed on June 4, 2024, the entirety of which is incorporated herein by reference. BACKGROUND OF THE INVENTION

[0002] In 2020, there were an estimated 19.3 million new cancer cases around the world. Thisnumber is expected to increase to 30.2 million by 2040. In 2022, there will be an estimated 2.0 million new cancer cases diagnosed and 611,720 cancer deaths in the United States. Although medical advances have improved cancer survival rates, certain patient populations and particular cancers still require further research. Thus, there exists an unmet need for new and more effective treatments for cancer patients. SUMMARY OF THE INVENTION

[0003] In some aspects, the present disclosure provides a compound represented by the structureof Formula (I-A), (I-B), (I-C), (I-D), or (I-E):-1-Attorney Docket No.60185-706601or a pharmaceutically acceptable salt thereof, wherein: each X1is selected from N or C(R10); R10is selected from:, and - CN; and C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =NR11, and -CN; R1is selected from: hydrogen, halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, - N(R12)C(O)R12, -C(O)OR12, -OC(O)R12, -N(R12)C(O)OR12, -OC(O)N(R12)2, - N(R12)C(O)N(R12)2, -S(O)R12, -S(O)2R12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -NO2, and - CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12,CN; or R1and R10may come together with the atom to which they are attached, to form a C3-6 carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =NR13, -NO2, and -CN; and -2-Attorney Docket No.60185-706601 C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, =NR13, and -CN; R2is independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, - S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, - S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, =O, =S, =NR14, and -CN; R3is independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, - S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, - SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, - SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; and (iii) C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, -CN; and -3-Attorney Docket No.60185-706601 C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; or two R3may come together with the atom to which they are attached, to form a C3-6 carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, - C(O)OR16, -OC(O)R16, -N(R16)C(O)OR16, -OC(O)N(R16)2, -N(R16)C(O)N(R16)2, - S(O)R16, -S(O)2R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -NO2, =O, =S, =NR16, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -N(R16)C(O)OR16, -OC(O)N(R16)2, -N(R16)C(O)N(R16)2, - S(O)R16, -S(O)2R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -NO2, =O, =S, =NR16, and -CN; wherein when one R3is n-butyl, R4is methyl, and R1is NH2; then each of X1are C(R10); R4is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -C(O)R17, -C(O)N(R17)2, -N(R17)C(O)R17, -C(O)OR17, -OC(O)R17, -N(R17)C(O)OR17, -OC(O)N(R17)2, -N(R17)C(O)N(R17)2, - S(O)R17, -S(O)2R17, -N(R17)S(O)2R17, -S(O)2N(R17)2, -NO2, =O, =S, =NR17, and -CN; R5is independently selected at each occurrence from: halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -N(R18)C(O)R18, - C(O)OR18, -OC(O)R18, -N(R18)C(O)OR18, -OC(O)N(R18)2, -N(R18)C(O)N(R18)2, - S(O)R18, -S(O)2R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -NO2, =O, =S, =NR18, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -N(R18)C(O)R18, -C(O)OR18, -OC(O)R18, -N(R18)C(O)OR18, -OC(O)N(R18)2, -N(R18)C(O)N(R18)2, - S(O)R18, -S(O)2R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -NO2, =O, =S, =NR18, and -CN; R11, R12, R13, R14, R15, R16, R17, and R18are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents -4-Attorney Docket No.60185-706601 independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4.

[0004] In one aspect, the present disclosure provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formulas (I-A), (I-B), (I-C), (I-D), (I- E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), or a pharmaceutically acceptable salt thereof.

[0005] In one aspect the present disclosure provides methods of killing a cancer cell or inhibitingcell proliferation, comprising contacting a cell with a compound of Formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer cell is a Cal 27 cell or a HeLa cell. In some embodiments, the cancer cell is a squamous cell carcinoma or a hepatocellular carcinoma cell.

[0006] In one aspect, the present disclosure provides methods of treating a carcinoma, themethods comprising administering to a subject in need thereof a compound of Formulas (I-A), (I- B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), or a pharmaceutically acceptable salt thereof. In some embodiments, the carcinoma is a squamous cell carcinoma or a hepatocellular carcinoma cell.

[0007] In another aspect the present disclosure provides methods of killing a cancer cell orinhibiting cell proliferation, comprising contacting a cell with a pharmaceutical composition comprising a compound of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I- A4), (I-A5), or (I-A6), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer cell is a Cal 27 cell or a HeLa cell. In some embodiments, the cancer cell is a squamous cell carcinoma or a hepatocellular carcinoma cell.

[0008] In another aspect, the present disclosure provides methods of treating a carcinoma, themethods comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formulas (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I- A4), (I-A5), or (I-A6), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the carcinoma is a squamous cell carcinoma or a hepatocellular carcinoma cell. -5-Attorney Docket No.60185-706601 INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification areherein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. DETAILED DESCRIPTION OF THE INVENTION

[0010] While preferred embodiments of the present invention have been shown and describedherein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0011] Definitions

[0012] Unless defined otherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0013] As used in the specification and claims, the singular form “a”, “an” and “the” includesplural references unless the context clearly dictates otherwise.

[0014] "Alkyl" refers to a straight or branched hydrocarbon chain monovalent radical consistingsolely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-C12alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises -6-Attorney Docket No.60185-706601 three to five carbon atoms (i.e., C3-C5 alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bind, such as, 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), and the like.

[0015] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consistingsolely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4alkenyl). 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.

[0016] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consistingsolely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0017] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl,or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.

[0018] The terms “Cx-y alkenyl” and “Cx-y alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0019] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring inwhich each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro- ring systems. In some embodiments, the bicyclic carbocycle is selected from a fused carbocycle, a bridged carbocycle, and a spirocyclic carbocycle. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a -7-Attorney Docket No.60185-706601 saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0020] "Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbonradical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7cycloalkyl). The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl 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. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0021] "Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C3-12cycloalkenyl). In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkenyl). In other embodiments, a cycloalkenyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkenyl). The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0022] The term “carbocyclene” as used herein refers to a divalent saturated, unsaturated oraromatic ring in which each atom of the ring is carbon. The carbocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A carbocyclene may be optionally substituted by one or more substituents such as those substituents described herein. Carbocyclene includes divalent 3- to 10-membered monocyclic rings and divalent polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic carbocyclene may be selected from saturated, unsaturated, and aromatic rings. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. The single bond connecting the carbocyclene to the -8-Attorney Docket No.60185-706601 rest of the molecule and the single bond connecting the carbocyclene to the radical group may be located on the same ring or different rings of a polycyclic carbocyclene. In some embodiments, the carbocycle is an arylene, for example, a phenylene. A “phenylene” as used herein refers to a divalent benzene group. The phenylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A phenylene may be optionally substituted by one or more substituents such as those substituents described herein. In some embodiments, the carbocyclene is attached to the rest of the molecule through the divalent radical group on a single carbon atom, wherein the divalent group is connected to rest of the molecule through two single bonds or one double bond. ((for example, the carbocyclene is cyclopentylene and isrepresented bysome embodiments, the carbocyclene is attached to the restof the molecule through the divalent radical group on a single carbon atom, wherein the divalent group on the carbocyclene is connected by a double bond to one atom to the rest of the molecule (for example, the carbocyclene is cyclopentylene and is represented byIn some embodiments, the carbocyclene is attached to the rest of the molecule through the divalent radical group, wherein the divalent group on the carbocyclene is connected by a two single bonds to two separate atoms on rest of the molecule (for example, the carbocyclene is cyclopentylene and is represented

[0023] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclichydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p–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. Aryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0024] A “Cx-y carbocycle” is meant to include groups that contain from x to y carbons in a ring.For example, the term “C3-6carbocycle” can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms―any of which is optionally substituted as provided herein.

[0025] The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic oraromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, -9-Attorney Docket No.60185-706601 B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In some embodiments, the bicyclic heterocycle is selected from a fused heterocycle, a bridged heterocycle, and a spirocyclic heterocycle. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0026] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical thatcomprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, -10-Attorney Docket No.60185-706601decahydroisoquinolyl, 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. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0027] The term “heteroaryl” refers to a radical derived from a 5- to 12-membered aromatic ringradical whose ring structure comprise at least one heteroatom, preferably between one to four heteroatoms. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.

[0028] As used herein, the heteroaryl ring may be selected from monocyclic or polycyclic(bicyclic and fused or bridged) systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p–electron system in accordance with the Hückel theory. Heteroaryl includes aromatic single ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein. Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic.

[0029] An “X-membered heterocycle” refers to the number of endocyclic atoms, i.e., X, in thering. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0030] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl,where alkyl is an alkyl chain as defined above. -11-Attorney Docket No.60185-706601

[0031] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodosubstituents.

[0032] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as definedabove, that is substituted by one or more halogen radicals, for example, trifluoromethyl,dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected for example, 1-chloro,2-fluoroethane.

[0033] The term “substituted” refers to moieties having substituents replacing a hydrogen on oneor more carbons or substitutable heteroatoms, e.g., an NH or NH2of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0034] In some embodiments, substituents may include any substituents described herein, forexample: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb- N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, -12-Attorney Docket No.60185-706601 alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo(=N-OH), hydrazine(=N-NH2), -Rb-ORa, -Rb-OC(O)- Ra, -Rb-OC(O)- ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb- C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (- CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine(=N-NH2), -Rb-ORa, -Rb-OC(O)- Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0035] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from avariety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0036] The phrase “pharmaceutically acceptable” is employed herein to refer to thosecompounds, materials, compositions, and / or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0037] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptablecarrier” as used herein means a pharmaceutically acceptable material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier -13-Attorney Docket No.60185-706601 must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0038] The terms "subject," "individual," and "patient" may be used interchangeably and refer tohumans, as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0039] As used herein, the phrase "a subject in need thereof" refers to a subject, as describedinfra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0040] The terms “administer”, “administered”, “administers” and “administering” are defined asproviding a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certainembodiments, oral routes of administering a composition can be used. The terms ““administer”,“administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0041] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial ordesired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some -14-Attorney Docket No.60185-706601 level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0042] In certain embodiments, the term “prevent” or “preventing” as related to a disease ordisorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0043] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefitand / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0044] Without wishing to be limited by this statement, it is understood that, while variousoptions for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0045] Compounds

[0046] Compounds of Formula (I-A), (I-B), (I-C), (I-D), or (I-E).

[0047] In some aspects, the present disclosure provides a compound represented by the structureof Formula (I-A), (I-B), (I-C), (I-D), or (I-E):Attorney Docket No.60185-706601or a pharmaceutically acceptable salt thereof, wherein: each X1is selected from N or C(R10); R10is selected from:, and - CN; and C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =NR11, and -CN; R1is selected from: hydrogen, halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, - N(R12)C(O)R12, -C(O)OR12, -OC(O)R12, -N(R12)C(O)OR12, -OC(O)N(R12)2, - N(R12)C(O)N(R12)2, -S(O)R12, -S(O)2R12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -NO2, and - CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12,CN; or R1and R10may come together with the atom to which they are attached, to form a C3-6 carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =NR13, -NO2, and -CN; and -16-Attorney Docket No.60185-706601 C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, =NR13, and -CN; R2is independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, - S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, - S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, =O, =S, =NR14, and -CN; R3is independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and - CN; C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, - N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; and (iii) C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: -17-Attorney Docket No.60185-706601 halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, - OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, - S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; or two R3may come together with the atom to which they are attached, to form a C3-6carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, - C(O)OR16, -OC(O)R16, -N(R16)C(O)OR16, -OC(O)N(R16)2, -N(R16)C(O)N(R16)2, - S(O)R16, -S(O)2R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -NO2, =O, =S, =NR16, and -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -N(R16)C(O)OR16, -OC(O)N(R16)2, -N(R16)C(O)N(R16)2, - S(O)R16, -S(O)2R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -NO2, =O, =S, =NR16, and -CN; wherein when one R3is n-butyl, R4is methyl, and R1is NH2; then each of X1are C(R10); R4is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -C(O)R17, -C(O)N(R17)2, -N(R17)C(O)R17, -C(O)OR17, -OC(O)R17, -N(R17)C(O)OR17, -OC(O)N(R17)2, -N(R17)C(O)N(R17)2, - S(O)R17, -S(O)2R17, -N(R17)S(O)2R17, -S(O)2N(R17)2, -NO2, =O, =S, =NR17, and -CN; R5is independently selected at each occurrence from: halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -N(R18)C(O)R18, - C(O)OR18, -OC(O)R18, -N(R18)C(O)OR18, -OC(O)N(R18)2, -N(R18)C(O)N(R18)2, - S(O)R18, -S(O)2R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -NO2, =O, =S, =NR18, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -N(R18)C(O)R18, -C(O)OR18, -OC(O)R18, -N(R18)C(O)OR18, -OC(O)N(R18)2, -N(R18)C(O)N(R18)2, - S(O)R18, -S(O)2R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -NO2, =O, =S, =NR18, and -CN; R11, R12, R13, R14, R15, R16, R17, and R18are each independently selected at each occurrence from: hydrogen; -18-Attorney Docket No.60185-706601 C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O- C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4.

[0048] In some embodiments, the compound or salt is represented by the structure of Formulas(I-B), (I-C), (I-D), or (I-E):-19-Attorney Docket No.60185-706601

[0049] In some embodiments, the compound or salt is represented by the structure of Formulas

[0050] In some embodiments, the compound or salt is represented by the structure of Formulas(I-B):

[0051] In some embodiments, the compound or salt of Formula (I-B) is represented by thestructure of Formula (I-B1), (I-B2), (I-B3), or (I-B4): -20-Attorney Docket No.60185-706601

[0052] In some embodiments, the compound or salt is represented by the structure of Formulas(I-C):

[0053] In some embodiments, the compound or salt of Formula (I-C) is represented by thestructure of Formula (I-C1), (I-C2), (I-C3), or (I-C4): -21-Attorney Docket No.60185-706601

[0054] In some embodiments, the compound or salt is represented by the structure of Formulas(I-D):

[0055] In some embodiments, the compound or salt of Formula (I-D) is represented by thestructure of Formula (I-D1), (I-D2), (I-D3), or (I-D4): -22-Attorney Docket No.60185-706601

[0056] In some embodiments, the compound or salt is represented by the structure of Formulas(I-E):

[0057] In some embodiments, the compound or salt of Formula (I-E) is represented by thestructure of Formula (I-E1), (I-E2), (I-E3), or (I-E4): -23-Attorney Docket No.60185-706601

[0058] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), or(I-E), one of X1is N.

[0059] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), or(I-E), each of X1is N.

[0060] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), or(I-E), one of X1is C(R10).

[0061] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), or(I-E), each of X1is C(R10).

[0062] In some aspects, the present disclosure provides a compound represented by the structureof Formula (I-A):or a pharmaceutically acceptable salt thereof, wherein: each X1is selected from N or C(R10); -24-Attorney Docket No.60185-706601 R10is selected from:, and - CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =NR11, and -CN; R1is selected from: hydrogen, halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, - N(R12)C(O)R12, -C(O)OR12, -OC(O)R12, -N(R12)C(O)OR12, -OC(O)N(R12)2, - N(R12)C(O)N(R12)2, -S(O)R12, -S(O)2R12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -NO2, and - CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -C(O)OR12, -OC(O)R12, -N(R12)C(O)OR12, -OC(O)N(R12)2, -N(R12)C(O)N(R12)2, - S(O)R12, -S(O)2R12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -NO2, =O, =S, =NR12, and -CN; or R1and R10may come together with the atom to which they are attached to form a C3-6carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =NR13, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, =NR13, and -CN; R2is independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, - S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -25-Attorney Docket No.60185-706601 -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, - S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, =O, =S, =NR14, and -CN; R3is independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, - SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, - SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; and (iii) C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; or two R3may come together with the atom to which they are attached, to form a C3-6carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, - C(O)OR16, -OC(O)R16, -N(R16)C(O)OR16, -OC(O)N(R16)2, -N(R16)C(O)N(R16)2, - S(O)R16, -S(O)2R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -NO2, =O, =S, =NR16, and -CN; and-26-Attorney Docket No.60185-706601 C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -N(R16)C(O)OR16, -OC(O)N(R16)2, -N(R16)C(O)N(R16)2, - S(O)R16, -S(O)2R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -NO2, =O, =S, =NR16, and -CN; wherein when one R3is n-butyl, R4is methyl, and R1is NH2; then each of X1are C(R10); R4is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -C(O)R17, -C(O)N(R17)2, -N(R17)C(O)R17, -C(O)OR17, -OC(O)R17, -N(R17)C(O)OR17, -OC(O)N(R17)2, -N(R17)C(O)N(R17)2, - S(O)R17, -S(O)2R17, -N(R17)S(O)2R17, -S(O)2N(R17)2, -NO2, =O, =S, =NR17, and -CN; R5is independently selected at each occurrence from: halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -N(R18)C(O)R18, - C(O)OR18, -OC(O)R18, -N(R18)C(O)OR18, -OC(O)N(R18)2, -N(R18)C(O)N(R18)2, - S(O)R18, -S(O)2R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -NO2, =O, =S, =NR18, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -N(R18)C(O)R18, -C(O)OR18, -OC(O)R18, -N(R18)C(O)OR18, -OC(O)N(R18)2, -N(R18)C(O)N(R18)2, - S(O)R18, -S(O)2R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -NO2, =O, =S, =NR18, and -CN; R11, R12, R13, R14, R15, R16, R17, and R18are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O- C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4.

[0063] In some aspects, the compound or salt of Formula (I-A) is represented by the structure ofFormula (I-A1): -27-Attorney Docket No.60185-706601wherein R1, R2, each R3, R4, R5, R10, m, and n, are as defined as in Formula (I-A).

[0064] In some embodiments, for the compound or salt of Formula (I-A), each of X1 is N.

[0065] In some embodiments, for the compound or salt of Formula (I-A), one of X1 is N. In someembodiments, one X1is C(R10) and the X1is other is N.

[0066] In some aspects, the compound or salt of Formula (I-A) is represented by the structure ofFormula (I-A2):, wherein R1, R2, each R3, R4, R5, R10, m, and n, are as defined as in Formula (I-A).

[0067] In some aspects, the compound or salt of Formula (I-A) is represented by the structure ofFormula (I-A3):, wherein X1, R1, R2, each R3, R4, R5, R10, m, and n, are as defined as in Formula (I-A).

[0068] In some aspects, the compound or salt of Formula (I-A) is represented by the structure ofFormula (I-A4): -28-Attorney Docket No.60185-706601, wherein X1, R1, R2, each R3, R4, R5, R10, m, and n, are as defined as in Formula (I-A).

[0069] In some aspects, the compound or salt of Formula (I-A) is represented by the structure ofFormula (I-A5):wherein R1, R2, each R3, R4, R5, R10, m, and n, are as defined as in Formula (I-A).

[0070] In some aspects, the compound or salt of Formula (I-A) is represented by the structure ofFormula (I-A6):wherein R1, R2, each R3, R4, R5, each R10, m, and n, are as defined as in Formula (I-A).

[0071] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R10is selected from:, and - CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - -29-Attorney Docket No.60185-706601CN.

[0072] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R10of C(R10) is selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, - OC(O)R11, -NO2, and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -CN.

[0073] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R10is selected from hydrogen, halogen, - OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -NO2, -CN; and C1-6alkyl, C2-3 alkenyl, and C2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -some embodiments, R10is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - C(O)OR11, -OC(O)R11, -NO2, -CN; and C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, =O, and -CN. In some embodiments, R10of C(R10) is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN; and C1-3 alkyl, C2-3 alkenyl, and C2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -NO2, =O, and -CN. In some embodiments, R10is selected from hydrogen, fluoro, methyl, chloro,-C=C, -CHF2, -CN, -OCH3, and -CF3.

[0074] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R10of C(R10) is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11,some embodiments, R10is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, - C(O)OR11, -OC(O)R11, -NO2, -CN; and C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, =NR11, and -CN. In some embodiments, R10is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN; and C1-6 alkyl optionally substituted with -30-Attorney Docket No.60185-706601 one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -NO2, =O, =S, and -CN. In some embodiments, R10is selected from hydrogen, halogen, -OR11, -SR11, - N(R11)2, -NO2, -CN; and C1-3alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -NO2, =O, =S, and -CN. In some embodiments, R10is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN, C1-6 alkyl, and C1-6haloalkyl. In some embodiments, R10is selected from hydrogen, halogen, -OR11, - SR11, -N(R11)2, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R10is selected from hydrogen, halogen, -OR11, -N(R11)2, -CN, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R10is selected from hydrogen, halogen, -OR11, -CN, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R10is selected from hydrogen, fluoro, methyl, chloro, -CHF2, -CN, - OCH3, and -CF3. In some embodiments, R10is selected from hydrogen, halogen, and C1-6 alkyl. In some embodiments, R10is selected from hydrogen, halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R10is selected from hydrogen, fluoro, and methyl. In some embodiments, R10is hydrogen. In some embodiments, R10is fluoro. In some embodiments, R10is methyl.

[0075] In some embodiments, for the compound or salt of Formula (I-A), (I-A1), (I-A2), (I-A3),(I-A4), (I-A5), or (I-A6), n is selected 0, 1, 2, and 3. In some embodiments, n is 0. In some embodiments, n is selected from 1 and 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 1, 2, and 3.

[0076] In some embodiments, for the compound or salt of Formula (I-B), (I-C), (I-D), or (I-E), nis selected from 0, 1, 2, and 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is selected from 0 and 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0077] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), each R2is independently selected at eachoccurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -NO2, -CN;and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -NO2, =O, =S, =NR14, and - CN. In some embodiments, each R2is independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -NO2, -CN; and C1-6 alkyl optionallysubstituted with one or more substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -C(O)R14, -C(O)OR14, -NO2, =O, and -CN. In some embodiments, each R2is independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -NO2, -CN; and C1-3 alkyl optionally substituted with one or more-31-Attorney Docket No.60185-706601 substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -NO2, =O, and -CN. In some embodiments, each R2is independently selected at each occurrencefrom: halogen, -OR14, -N(R14)2, -C(O)R14, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In someembodiments, each R2is independently selected at each occurrence from: halogen, -OR14, -N(R14)2, -C(O)R14, -NO2, -CN, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, each R2 isindependently selected at each occurrence from: halogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, each R2is independently selected at each occurrence from halogen. In some embodiments, each R2is independently selected at each occurrence from fluoro.

[0078] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), m is 0. In some embodiments, m is selected from 1 and 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is selected from 1, 2, and 3. In some embodiments, m is selected from 0, 1, 2, and 3.

[0079] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R5is independently selected at each occurrence from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)OR18, -OC(O)R18, -NO2, =O, =S, =NR18, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)OR18, -OC(O)R18, -NO2, =O, =S, =NR18, and -CN. In some embodiments, R5is independently selected at each occurrence from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)OR18, -OC(O)R18, -NO2, =O, =S, =NR18, -CN; and C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)OR18, -OC(O)R18, -NO2, =O, =S, =NR18, and -CN. In some embodiments, R5is independently selected at each occurrence from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)OR18, -NO2, -CN; C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R5is independently selected at each occurrence from halogen, - OR18, -N(R18)2, -C(O)R18, -C(O)OR18, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R5is independently selected at each occurrence from halogen, -OR18, -N(R18)2, - C(O)R18, -C(O)OR18, -NO2, -CN; C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R5is independently selected at each occurrence from halogen, -OR18, -N(R18)2, -NO2, -CN, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R5is independently selected at each occurrence from halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R5is independently selected at each occurrence from C1-3 alkyl. In some embodiments, R5is independently selected at each occurrence from methyl.

[0080] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R4is C1-6 alkyl optionally substituted with -32-Attorney Docket No.60185-706601 one or more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -C(O)R17, -C(O)N(R17)2, -C(O)OR17, -OC(O)R17, -S(O)R17, -S(O)2R17, -NO2, =O, =S, =NR17, and -CN. In some embodiments, R4is C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -NO2, =O, and -CN. In some embodiments, R4is C1-3 alkyl optionally substituted with halogen, -OR17, -SR17, -N(R17)2, -NO2, =O, and -CN. In some embodiments, R4is selected from methyl, ethyl, propyl, n-butyl, and isobutyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -C(O)R17, -C(O)N(R17)2, -C(O)OR17, -OC(O)R17, -S(O)R17, -S(O)2R17, -NO2, =O, =S, =NR17, and -CN. In some embodiments, R4is selected from methyl, ethyl, propyl, n-butyl, and isobutyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -C(O)R17, - C(O)N(R17)2, -C(O)OR17, -NO2, =O, =S, and -CN. In some embodiments, R4is selected from methyl, ethyl, propyl, n-butyl, and isobutyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -NO2, =O, =S, and -CN. In some embodiments, R4is selected from methyl, ethyl, propyl, n-butyl, and isobutyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR17, -N(R17)2, and -CN. In some embodiments, R4is selected from methyl, ethyl, propyl, n-butyl, and isobutyl, each of which is optionally substituted with one or more fluorosubstituents. In some embodiments, R4 is selected from, , , .In some embodiments, R4is selected from methyl, ethyl, propyl, n-butyl, and isobutyl. In some embodiments, R4is selected from methyl, ethyl, and isopropyl. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is isopropyl. In someembodiments, R4 is selected from, , .

[0081] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R1is selected from hydrogen, halogen, - OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -and -CN. In some embodiments, R1is selected from hydrogen, halogen, -OR12, -SR12, -N(R12)2, - C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, - C(O)R12, -C(O)OR12, -NO2, =O, =S, and -CN. In some embodiments, R1is selected from hydrogen, halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, - -33-Attorney Docket No.60185-706601 NO2, -CN; and C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, and -CN. In some embodiments, R1is selected from hydrogen, halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -NO2, and -CN; and each R12is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1is selected from hydrogen, halogen, - OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -NO2, and -CN; and each R12is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R1is selected from hydrogen, halogen, -OR12, -SR12, and -N(R12)2; and each R12is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R1is selected from hydrogen, halogen, -OR12, -SR12, and -N(R12)2; and each R12is selected from hydrogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R1is -N(R12)2; and each R12is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1is -N(R12)2; and each R12is selected from hydrogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R1is -N(R12)2; and each R12is selected from hydrogen and C1-3 alkyl. In some embodiments, R1is -N(R12)2; and each R12is selected from hydrogen and methyl. In some embodiments, R1is selected from amino, methylamino, and dimethylamino. In some embodiments, R1is selected from , , and . In some embodiments, R1is . In some embodiments, R1is selected from.

[0082] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to which they are attached, to form a C3-6 carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, - OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

[0083] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to which they are attached, to form a C3-6carbocycle, optionally substituted with one or more substituents independently selected from: -34-Attorney Docket No.60185-706601 halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =NR13, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, =NR13, and -CN.

[0084] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to which they are attached, to form a C3-6carbocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

[0085] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to which they are attached, to form a C3-6carbocycle, optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -NO2, =O, =S, and -CN.

[0086] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to which they are attached, to form a 3- to 6-membered heterocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =NR13, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, =NR13, and -CN. -35-Attorney Docket No.60185-706601

[0087] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to which they are attached, to form a 3- to 6-membered heterocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

[0088] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

[0089] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle has at least one nitrogen heteroatom, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

[0090] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -C(O)OR13, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -NO2, =O, =S, and -CN. -36-Attorney Docket No.60185-706601

[0091] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -C(O)OR13, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -NO2, =O, =S, and -CN. In some embodiments, R1and R10come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -C(O)OR13, -NO2, -CN, C1-6alkyl and C1-6haloalkyl. In some embodiments, R1and R10come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R1and R10come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R1and R10come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN, C1-3alkyl, and C1-3haloalkyl.

[0092] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10come together with the atom to which they are attached to form a 5-membered heterocycle, optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -NO2, =O, =S, and -CN. In some embodiments, R1and R10come together with the atom to which they are attached to form 4,5,-dihydro-1H-pyrazolylene, optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -NO2, =O, =S, and -CN. In some embodiments, R1and R10come together with the atom to which they are attached to form 4,5- dihydro-1H-pyrazolylene, optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -NO2, -CN, C1-6alkyl, and C1-6 haloalkyl. In some embodiments, R1and R10come together with the atom to which they are -37-Attorney Docket No.60185-706601 attached to form 4,5-dihydro-1H-pyrazolylene, optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

[0093] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10come together with the atom to which they are attached, to form:.

[0094] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle has at least one nitrogen heteroatom, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, =O, =S, and - CN. In some embodiments, R1and R10may come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle has at least one nitrogen heteroatom, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1and R10may come together with the atom to which they are attached to form 4,5-dihydro-1H-pyrazolyl or pyrrolidinyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1and R10may come together with the atom to which they are attached to formeach of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R1and R10may come together with the atom to which they are attached to form, each of which is optionally substituted with one or more substituents independently selected from fluoro, chloro, amino, and methyl. In some embodiments, R1and R10may come together with the atom to which they are attached to form-38-Attorney Docket No.60185-706601 some embodiments, R1and R10may come together with the atom to which they are attached to form or , each of which is optionally substituted with one or more substituents independently selected from chloro, amino, and methyl. In some embodiments, R1and R10may come together with the atom to which they are attached to form, , ,, . In some embodiments, R1and R10may come together with the atom to which they are attached to form.

[0095] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to

[0096] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle has two nitrogen heteroatoms, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, =O, =S, and - CN. In some embodiments, R1and R10may come together with the atom to which they are attached to form a 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle has two nitrogen heteroatoms, wherein the 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, - NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0097] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A3), (I-A4), (I-A5), or (I-A6), R1and R10may come together with the atom to -39-Attorney Docket No.60185-706601 which they are attached, to form 4,5-dihydro-1H-pyrazolylene optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, =O, =S, and -CN. In some embodiments, R1and R10may come together with the atom to which they are attached, to form 4,5-dihydro-1H-pyrazolylene optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1and R10may come together with the atom to which they are attached, to form 4,5-dihydro-1H-pyrazolylene optionally substituted with one or more substituents independently selected from halogen, - N(R13)2,C1-6alkyl, and C1-6haloalkyl. In some embodiments, R1and R10may come together with the atom to which they are attached, to form 4,5-dihydro-1H-pyrazolylene optionally substituted with one or more substituents independently selected from amino, chloro, and methyl. In some embodiments, R1and R10may come together with the atom to which they are attached, to form optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1and R10may come together with the atom to which they are attached, to form optionally substituted with one or more substituents independently selected from amino, chloro, and methyl. In some embodiments, R1and R10may come together with the atom to which they

[0098] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I--40-Attorney Docket No.60185-706601

[0099] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15,-C(O)OR15, -OC(O)R15, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted withone or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN, C3-6carbocycle and 3- to 6- membered heterocycle, the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - NO2, =O, =S, and -CN; and (iii) C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - NO2, =O, =S, and -CN.

[0100] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -NO2, and -CN;-41-Attorney Docket No.60185-706601 (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted withone or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -NO2, =O, =S, - CN, C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, - C(O)R15, -C(O)OR15, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, =S, and -CN; and (iii) C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -NO2, =O, =S, and -CN.

[0101] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -NO2, and -CN;(ii) C1-6 alkyl and C2-6 alkenyl, each of which is optionally substituted with one or moresubstituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -NO2, =O, =S, - CN, C3-6 carbocycle, the C3-6 carbocycle is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, - C(O)R15, -C(O)OR15, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, =S, and -CN; and (iii) C3-6 carbocycle, optionally substituted with one or more substituents independentlyselected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -NO2, =O, =S, - CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -NO2, =O, =S, and -CN.

[0102] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen;-42-Attorney Docket No.60185-706601 (ii) C1-6 alkyl and C2-6 alkenyl, each of which is optionally substituted with one or moresubstituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -CN, and C3-6carbocycle, the C3-6carbocycle is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, =S, -CN, C1-6 alkyl, and C1-6haloalkyl; and (iii) C3-6 carbocycle, optionally substituted with one or more substituents independentlyselected from: halogen, -OR15, -SR15, -N(R15)2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0103] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from (i) and (ii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15,-C(O)OR15, -OC(O)R15, -NO2, and -CN; and (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted withone or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN, C3-6 carbocycle and 3- to 6- membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - NO2, =O, =S, and -CN.

[0104] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from (i) and (ii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, and -CN; and(ii) C1-6 alkyl and C2-6 alkenyl, each of which is optionally substituted with one or moresubstituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -CN, and C3-6 carbocycle, the C3-6 carbocycle is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, =S, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, =S, and -CN. -43-Attorney Docket No.60185-706601

[0105] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C3-6carbocycle, the C1-6alkyl, C2-6alkenyl, and C3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, - N(R15)2, -NO2, =O, -CN; and C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, and -CN.

[0106] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C2-6 alkenyl, the C1-6 alkyl, and C2-6 alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN, and C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C2-6 alkenyl, the C1-6 alkyl, and C2-6 alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, and C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6 haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C2-6 alkenyl, the C1-6 alkyl, and C2-6 alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, - C(O)R15, -NO2, -CN, and C3-6 carbocycle optionally substituted with C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen, C1-6alkyl, and C2-6alkenyl, the C1-6alkyl, and C2-6alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, and C3-6 carbocycle. In some embodiments, R3is independently selected at each occurrenceis independently selected at each occurrence from hydrogen, , ,-44-Attorney Docket No.60185-706601, , and . In some embodiments, R3 is independently selected at each occurrencefrom hydrogen,, , , , . In some embodiments, R3is independently selected at each occurrence from hydrogen,, , . Insome embodiments, R3is independently selected at each occurrence from hydrogen and. In some embodiments, R3is independently selected at each occurrence from hydrogen and. In some embodiments, R3is independently selected at each occurrence from hydrogen, some em 3bodiments, R isindependently selected at each occurrence from hydrogen and.

[0107] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from hydrogen and C1-6 alkyl, each C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, and C3-6carbocycle optionally substituted with C1-6alkyl, and C1-6haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen and C1-6 alkyl, each C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -NO2, and -CN. In some embodiments, R3is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen and C1-6 alkyl. In someembodiments, R3 is independently selected at each occurrence from hydrogen,, ,.

[0108] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from hydrogen, C1-6alkyl, and C2-6alkenyl, the C1-6alkyl, and C2-6alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, and C3-6 carbocycle optionally substituted with C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen, C1-6alkyl, and C2-6alkenyl, the C1-6alkyl, and C2-6alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, - C(O)R15, -NO2, and -CN. In some embodiments, R3is independently selected at each occurrence -45-Attorney Docket No.60185-706601 from hydrogen, C1-6 alkyl, and C2-6 alkenyl. In some embodiments, R3is independently selectedat each occurrence from hydrogen,, , , . In someembodiments, R3is independently selected at each occurrence from hydrogen, and C2-6 alkenyl, the C2-6 alkenyl is each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, and C3-6carbocycle optionally substituted with C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen and C2-6 alkenyl, the C2-6 alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, - C(O)R15, -NO2, and -CN. In some embodiments, R3is independently selected at each occurrence from hydrogen and C2-6 alkenyl. In some embodiments, R3is independently selected at each occurrence from hydrogen and prop-1-enyl. In some embodiments, R3is independently selected at each occurrence from hydrogen and.

[0109] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C2-6 alkenyl, the C1-6 alkyl, and C2-6 alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN, and C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen, C1-6alkyl, and C2-6alkenyl, the C1-6 alkyl, and C2-6 alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -CN, and C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, - N(R15)2, -NO2, =O, =S, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen, C1-6 alkyl, the C1-6 alkyl is each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -CN, and C3-6carbocycle. In some embodiments, R3is independently selected at each occurrence from hydrogen, C1-3 alkyl, the C1-3 alkyl is each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -CN, and C3-6carbocycle. In some embodiments, R3is independently selected at each occurrence from hydrogen, C1-3 alkyl, the C1-3 alkyl is each optionally substituted with C3-6 carbocycle. In some embodiments, R3is independently selected at each occurrence from hydrogen, C1-3alkyl, the C1-3alkyl is each optionally substituted with saturated C3-6carbocycle. In some embodiments, R3is -46-Attorney Docket No.60185-706601 independently selected at each occurrence from hydrogen and methylcyclopropyl. In someembodiments, R3 is independently selected at each occurrence from hydrogen and .

[0110] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from hydrogen and C1-6alkyl, each C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -NO2, and -CN. In some embodiments, R3is independently selected at each occurrence from hydrogen, methyl, and ethyl, each methyl and ethyl are optionally substituted with -OR15. In some embodiments, R3is independently selected at each In some embodiments, R3is independently selected at eachoccurrence from hydrogen and.

[0111] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each occurrence from hydrogen and C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, C1-6alkyl, and C1-6 haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen and C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -CN, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen and saturated C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -CN, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen and cyclopropyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -CN, C1-3 alkyl, and C1-3haloalkyl. In some embodiments, R3is independently selected at each occurrence from hydrogen and cyclopropyl. In some embodiments, R3is independently selected at each occurrence from hydrogen and.

[0112] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at eachoccurrence from hydrogen,, , , , , , .

[0113] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), R3is independently selected at each -47-Attorney Docket No.60185-706601occurrence from hydrogen, , , , , , , ,

[0114] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), two R3may come together with the atom to which they are attached, to form a C3-6carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN; and C1-6 alkyl optionally substituted with one or moresubstituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, - C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN.

[0115] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), two R3may come together with the atom to which they are attached, to form a 3- to 6-membered heterocycle, optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN.

[0116] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), two R3may come together with the atom to which they are attached, to form a C3-6carbocycle, optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN.

[0117] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), , two R3may come together with the atom to which they are attached, to form a saturated C3-6carbocycle, optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - -48-Attorney Docket No.60185-706601 OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN.

[0118] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), two R3may come together with the atom to which they are attached, to form a C5-6 carbocycle, optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN.

[0119] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), two R3may come together with the atom to which they are attached, to form a saturated C3-6carbocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -NO2, =O, =S,=NR16, and -CN; and C1-6 alkyl optionally substituted with one or more substituentsindependently selected from halogen, -OR16, -SR16, -N(R16)2, -NO2, =O, =S, =NR16, and -CN. In some embodiments, two R3may come together with the atom to which they are attached, to form a saturated C3-6 carbocycle, optionally substituted with one or more substituents independentlyselected from: halogen, -OR16, -SR16, -N(R16)2, -NO2, =O, =S, =NR16, -CN, C1-6 alkyl and C1-6haloalkyl. In some embodiments, two R3may come together with the atom to which they are attached, to form a saturated C5-6 carbocycle, optionally substituted with one or more substituentsindependently selected from: halogen, -OR16, -SR16, -N(R16)2, -NO2, =O, =S, =NR16, and -CN;and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -NO2, =O, =S, =NR16, and -CN. In some embodiments, two R3may come together with the atom to which they are attached, to form a saturated C5-6 carbocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -NO2, =O, =S, =NR16, -CN, C1-6 alkyl and C1-6 haloalkyl. In someembodiments, two R3may come together with the atom to which they are attached, to form a saturated C5-6carbocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -CN, C1-3alkyl and C1-3haloalkyl. In some embodiments, two R3may come together with the atom to which they are attached, to form a cyclopentylene, optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -CN, C1-3alkyl and C1-3haloalkyl. In some embodiments, two R3may come together with the atom to which they are attached, to form a cyclopentylene. In -49-Attorney Docket No.60185-706601 some embodiments, two R3may come together with the atom to which they are attached, to form.

[0120] In some embodiments, for the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), when one R3is n-butyl, R4is methyl, and R1is NH2; then each R10is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -CN. In some embodiments, when one R3is n-butyl, R4is methyl, and R1is NH2; then each R10is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -NO2, =O, =S, and -CN. In some embodiments, when one R3is n-butyl, R4is methyl, and R1is NH2; then R10is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, - C(O)R11, -NO2, -CN; and C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -NO2, =O, =S, and -CN. In some embodiments, when one R3is n-butyl, R4is methyl, and R1is NH2; then each R10is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, when one R3is n-butyl, R4is methyl, and R1is NH2; then each R10is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN, C1-3 alkyl, and C1-3haloalkyl.

[0121] In some aspects, Formula (I-A) is represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: each X1is selected from N or C(R10); R10is selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -NO2, -CN, C1-6 alkyl, and C1-6haloalkyl; -50-Attorney Docket No.60185-706601 R1is selected from hydrogen, halogen, -OR12, -N(R12)2, -C(O)R12, -NO2, -CN, C1-6 alkyl, and C1- 6 haloalkyl; R2is independently selected at each occurrence from halogen, -OR14, -N(R14)2, -C(O)R14, -NO2, - CN, C1-6 alkyl, and C1-6 haloalkyl; R3is independently selected at each occurrence from: hydrogen, halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: hydrogen, halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected hydrogen, halogen, - OR15, -N(R15)2, -C(O)R15, -NO2, and-CN; and wherein when one R3is n-butyl, R4is methyl, and R1is NH2; then each of X1are C(R10); R4is C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR17, -N(R17)2, -C(O)R17, -NO2, and -CN; R5is independently selected at each occurrence from halogen, -OR18, -N(R18)2, -C(O)R18, -NO2, and -CN, C1-6alkyl, and C1-6haloalkyl; R11, R12, R13, R14, R15, R16, R17, and R18are each independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; n is selected from 0, 1, and 2; and m is selected from 0, 1, and 2.

[0122] In some aspects, Formula (I-A) is represented by the structure of Formula (III):-51-Attorney Docket No.60185-706601or a pharmaceutically acceptable salt thereof, wherein: each X1is selected from N or C(R10); R10is selected from hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl; R1is selected from hydrogen, halogen, -OR12, -N(R12)2, -C(O)R12, -NO2,-CN, C1-6alkyl, and C1-6haloalkyl; R2is independently selected at each occurrence from halogen, -OR14, -N(R14)2, -C(O)R14, -NO2, - CN, C1-6alkyl, and C1-6haloalkyl; R3is independently selected at each occurrence from: hydrogen, halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; and C1-3alkyl optionally substituted with one or more substituents independently selected from: hydrogen, halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected hydrogen, halogen, - OR15, -N(R15)2, -C(O)R15, -NO2, and -CN; and R4is C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR17, -N(R17)2, -C(O)R17, -NO2, and -CN; R5is independently selected at each occurrence from halogen, -OR18, -N(R18)2, -C(O)R18, -NO2, and -CN, C1-6 alkyl, and C1-6 haloalkyl; R11, R12, R13, R14, R15, R16, R17, and R18are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents -52-Attorney Docket No.60185-706601 independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; n is selected from 0, 1, and 2; and m is selected from 0, 1, and 2.

[0123] In some embodiments, the compound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E),(I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), is selected from a compound or salt of Table 1. * Denotes a stereocenter with undetermined absolute stereochemistry of a single isolated isomer.

[0124] Table 1. Selected Compounds-53-Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601Attorney Docket No.60185-706601

[0125] While preferred embodiments of the present invention have been shown and describedherein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0126] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds mayexist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of the Formulas provided herein, are intended to include all Z-, E- and tautomeric forms as well.

[0127] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers”are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which canAttorney Docket No.60185-706601 be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0128] The compounds or salts for the Formulas provided herein, herein may in some cases exist asdiastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0129] In certain embodiments, compounds or salts for the Formulas provided herein, may comprisetwo or more enantiomers or diatereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283- 302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under -67-Attorney Docket No.60185-706601 chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0130] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule toanother atom of the same molecule is possible. In certain embodiments, the compounds or salts for the Formulas provided herein, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non– limiting examples of tautomeric equilibrium include:

[0131] The compounds disclosed herein, in some embodiments, are used in different enrichedisotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0132] In certain embodiments, the compounds disclosed herein have some or all of the 1H atomsreplaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.Attorney Docket No.60185-706601

[0133] Deuterium substituted compounds are synthesized using various methods such as describedin: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0134] Deuterated starting materials are readily available and are subjected to the synthetic methodsdescribed herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0135] Unless otherwise stated, compounds described herein are intended to include compoundswhich differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0136] The compounds of the present disclosure optionally contain unnatural proportions of atomicisotopes at one or more atoms that constitute such compounds. For example, the compounds may belabeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) orcarbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I 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.

[0137] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, ofthe compounds of the Formulas provided herein. The compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0138] Synthetic chemistry transformations and methodologies useful in synthesizing thecompounds described herein are known in the art and include, for example, those described in R.Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser andAttorney Docket No.60185-706601Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis (1995).

[0139] Pharmaceutical Formulations

[0140] In some aspects, the present disclosure provides a pharmaceutical composition comprising acompound or salt of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6), and at least one pharmaceutically acceptable excipient.

[0141] Pharmaceutical compositions can be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.

[0142] Preparations for such pharmaceutical composition are well-known in the art. See, e.g.,Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0143] Methods of Treatment

[0144] The compounds described herein can be used in the preparation of medicaments for theprevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0145] The compositions containing the compound(s) described herein can be administered forprophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for thisAttorney Docket No.60185-706601 use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0146] In prophylactic applications, compositions containing the compounds described herein areadministered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0147] In some aspects, the present disclosure provides a method of killing a cancer cell ormodulating cell proliferation, comprising contacting a cell with a compound or salt of any one of Formulas disclosed herein or a pharmaceutical composition as disclosed herein. In some embodiments, the compound or salt is a compound of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I- A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6). In some embodiments, the cancer cell is a Cal 27 cell or a HeLa cell. In some embodiments, the cancer cell is a Cal 27 cell. In some embodiments, the cancer cell is a HeLa cell. In some embodiments, the cancer cell is a squamous cell carcinoma or a hepatocellular carcinoma cell. In some embodiments, the cancer cell is a squamous cell carcinoma. In some embodiments, the cancer cell is a hepatocellular carcinoma cell.

[0148] In some aspects, the present disclosure provides a method of modulating cell proliferation,comprising contacting a cell with a compound or salt of any one of Formulas disclosed herein, or a pharmaceutical composition as disclosed herein. In some embodiments, the compound or salt is a compound of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I- A6). In some embodiments, the cancer cell is a Cal 27 cell or a HeLa cell. In some embodiments, the cancer cell is a Cal 27 cell. In some embodiments, the cancer cell is a HeLa cell. In some embodiments, the cancer cell is a squamous cell carcinoma or a hepatocellular carcinoma cell. In some embodiments, the cancer cell is a squamous cell carcinoma. In some embodiments, the cancer cell is a hepatocellular carcinoma cell.

[0149] In some aspects, the present disclosure provides a method of killing a cancer cell orinhibiting cell proliferation, comprising contacting a cell with a compound or salt of any one of Formulas disclosed herein, or a pharmaceutical composition as disclosed herein. In some embodiments, the compound or salt is a compound of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I- A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6). In some embodiments, the cancer cell is a Cal 27 cell or a HeLa cell. In some embodiments, the cancer cell is a Cal 27 cell. In some embodiments, the -71-Attorney Docket No.60185-706601 cancer cell is a HeLa cell. In some embodiments, the cancer cell is a squamous cell carcinoma or a hepatocellular carcinoma cell. In some embodiments, the cancer cell is a squamous cell carcinoma. In some embodiments, the cancer cell is a hepatocellular carcinoma cell.

[0150] In some aspects, the present disclosure provides a method of killing a cancer cell, comprisingcontacting the cancer cell with a compound or salt of any one of Formulas disclosed herein or a pharmaceutical composition as disclosed herein. In some embodiments, the compound or salt is a compound of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I- A6). In some embodiments, the cancer cell is a Cal 27 cell or a HeLa cell. In some embodiments, the cancer cell is a Cal 27 cell. In some embodiments, the cancer cell is a HeLa cell. In some embodiments, the cancer cell is a squamous cell carcinoma or a hepatocellular carcinoma cell. In some embodiments, the cancer cell is a squamous cell carcinoma. In some embodiments, the cancer cell is a hepatocellular carcinoma cell.

[0151] In some aspects, the present disclosure provides a method of treating a carcinomacomprising, administering to a subject in need thereof a compound or salt of any one of Formulas disclosed herein, or a pharmaceutical composition as disclosed herein. In some embodiments, the compound or salt is a compound of Formula (I-A), (I-B), (I-C), (I-D), (I-E), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), or (I-A6). In some embodiments, the carcinoma is a squamous cell carcinoma or a hepatocellular carcinoma cell. In some embodiments, the carcinoma is a squamous cell carcinoma. In some embodiments, the carcinoma is a hepatocellular carcinoma cell.

[0152] EXAMPLES

[0153] The invention now being generally described, it will be more readily understood by referenceto the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.

[0154] The following synthetic schemes are provided for purposes of illustration, not limitation. Thefollowing examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein. The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise:Attorney Docket No.60185-706601

[0155] When given, 1H NMR spectra was recorded on Bruker Avance 300 (300 MHz), BrukerAvance 400 (400 MHz) or Bruker Avance 500 (500 MHz). Either the central peaks of the chloroform-d (CDCl3; ^H 7.27 ppm), dimethylsulfoxide-d6 (DMSO-d6; ^H 2.50 ppm) or methanol-d4 (CD3OD; ^H3.31 ppm), or an internal standard of tetramethylsilane (TMS; ^H0.00 ppm) were used as references.

[0156] Mass spectra were recorded on an Agilent MSD (+ve and –ve electrospray) or a FisonsInstrument VG Platform following analytical HPLC. Where values for m / z are given, generally only ions which indicate the parent mass are reported, and the mass ions quoted are the positive and negative mass ions: [M+H]+or [M+H]-.

[0157] Unless stated otherwise, starting materials were commercially available. All solvents andcommercial reagents were of laboratory grade and were used as received. All operations were carried out at ambient temperature, i.e. in the range 16 to 28°C and, where appropriate, under an atmosphere of an inert gas such as nitrogen.

[0158] Table 2. Table of AbbreviationsAttorney Docket No.60185-706601

[0159] Table 3. Instrument Parameters by Method codeAttorney Docket No.60185-706601Attorney Docket No.60185-706601

[0160] Example 1: Synthesis of 3-Butyl-1-methyl-4-[3-[2-(methylamino)pyrimidin-5-yl]benzoyl]piperazin-2-one (Compound 1)

[0161] Step a) 5-Bromo-N-methyl-pyrimidin-2-amine hydrochloride

[0162] A screw-cap tube was charged with 5-bromo-2-chloro-pyrimidine (500 mg, 2.6 mmol).Ethanol (2.0 mL) and methyl amine (2 M solution in methanol, 2.6 mL, 65.5 mmol) was subsequently added. The reaction mixture was stirred at 80ºC for 16 h. The reaction mixture was concentrated affording 5-bromo-N-methyl-pyrimidin-2-amine hydrochloride (1.03 g, crude) as a solid.1H NMR (400 MHz, CDCl3) δ 8.28 (s, 2H), 5.22 (s, 1H), 3.48 (s, 3H). LCMS (Method A): [M+H]+= 188.0, 190.0

[0163] Step b) tert-Butyl N-(5-bromopyrimidin-2-yl)-N-methyl-carbamate

[0164] To a solution of 5-bromo-N-methyl-pyrimidin-2-amine (589 mg, 3.1 mmol), TEA (1.9 mL,13.9 mmol) and DMAP (188 mg, 1.5 mmol) in DCM (10 mL), tert-butoxycarbonyl tert-butyl carbonate (2.8 mL, 12.3 mmol) was added. The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and water was added. The product was extracted withAttorney Docket No.60185-706601 EtOAc (3x), and the combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give tert-butyl N-(5-bromopyrimidin-2-yl)-N-methyl-carbamate (327 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 8.64 (s, 2H), 3.41 (s, 3H), 1.53 (s, 9H). LCMS (Method C): [M- BOC+H]+= 188.0, 190.0

[0165] Step c) Methyl 3-[2-[tert-butoxycarbonyl(methyl)amino]pyrimidin-5-yl]benzoate

[0166] A screw-cap tube was charged with tert-butyl N-(5-bromopyrimidin-2-yl)-N-methyl-carbamate (327 mg, 1.1 mmol), (3-methoxycarbonylphenyl)boronic acid (250 mg, 1.4 mmol) and Na2CO3(241 mg, 0.3 mmol). Toluene (10.0 mL) and water (2.5 mL) were added and the reaction mixture was sparged with nitrogen for 10 minutes. Pd(dppf)Cl2 (93 mg, 0.1 mmol) was added and the reaction mixture stirred at 85°C for 1 h. The reaction mixture was cooled to RT and diluted with water. The product was extracted with EtOAc (3x), and the combined organics washed with brine, dried over MgSO4, filtered, and concentrated to give a red oil. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded methyl 3-[2-[tert-butoxycarbonyl(methyl)amino]pyrimidin-5- yl]benzoate (235 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 8.87 (s, 2H), 8.23 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 3.96 (s, 3H), 3.49 (s, 3H), 1.56 (s, 9H). LCMS (Method A): [M+H]+= 344.2

[0167] Step d) 3-[2-[tert-Butoxycarbonyl(methyl)amino]pyrimidin-5-yl]benzoic acid

[0168] An RBF was charged with methyl 3-[2-[tert-butoxycarbonyl(methyl)amino]pyrimidin-5-yl]benzoate (235 mg, 0.7 mmol). THF (3.0 mL) and water (3.0 mL) were added. Lithium hydroxide hydrate (86 mg, 2.1 mmol) was added and the reaction was stirred at RT for 5 h. The reaction mixture was adjusted to pH 7 by using HCl (3 M, aqueous solution). The reaction mixture wasAttorney Docket No.60185-706601 concentrated in vacuo affording 3-[2-[tert-butoxycarbonyl(methyl)amino]pyrimidin-5-yl]benzoic acid (235 mg, crude) as a solid. LCMS (Method A): [M-tBu+H]+= 274.1

[0169] Step e) tert-Butyl N-[5-[3-(2-butyl-4-methyl-3-oxo-piperazine-1-carbonyl)phenyl]pyrimidin-2-yl]-N-methyl-carbamate

[0170] A screw-cap tube was charged with 3-[2-[tert-butoxycarbonyl(methyl)amino]pyrimidin-5-yl]benzoic acid (235 mg, 0.4 mmol). Anhydrous DMF (7 mL), 3-butyl-1-methyl-piperazin-2-one (73 mg, 0.4 mmol) and DIPEA (249 μL, 1.4 mmol) were added and the reaction mixture was sparged with nitrogen for 5 minutes. HATU (271 mg, 0.7 mmol) was added and the reaction mixture was stirred at RT for 48 h. The reaction mixture was diluted with water. The product was extracted with EtOAc (3x), and the combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded tert-butyl N- [5-[3-(2-butyl-4-methyl-3-oxo-piperazine-1-carbonyl)phenyl]pyrimidin-2-yl]-N-methyl-carbamate (220 mg) as a solid. LCMS (Method A): [M-BOC+H]+= 382.3

[0171] Step f) 3-Butyl-1-methyl-4-[3-[2-(methylamino)pyrimidin-5-yl]benzoyl]piperazin-2-one

[0172] An RBF was charged with tert-butyl N-[5-[3-(2-butyl-4-methyl-3-oxo-piperazine-1-carbonyl)phenyl]pyrimidin-2-yl]-N-methyl-carbamate (200 mg, 0.3 mmol). Dioxane (1.8 mL) and HCl (4M in dioxane, 343 μL, 1.4 mmol) were subsequently added. The reaction mixture was stirred at RT for 16 h. The reaction mixture was adjusted to pH 7 by using NaOH (1 M aqueous solution) and diluted with water. The product was extracted with DCM (3x), and the combined organics wereAttorney Docket No.60185-706601 washed with brine, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-100% EtOAc in DCM) afforded 3-butyl-1-methyl-4-[3-[2-(methylamino)pyrimidin-5- yl]benzoyl]piperazin-2-one (17 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 6.86 (s, 1H), 4.66 (s, 1H), 3.88 (s, 1H), 3.57 – 3.42 (m, 2H), 3.26 – 3.17 (m, 1H), 2.91 (d, J = 4.9 Hz, 3H), 2.88 (s, 3H), 1.86 (ddt, J = 21.9, 14.2, 7.0 Hz, 2H), 1.35 (ddd, J = 25.4, 16.7, 9.3 Hz, 4H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (Method B): [M+H]+= 382.2281

[0173] Example 2: Synthesis of 3-allyl-4-[3-(2-aminopyrimidin-5-yl)benzoyl]-1-methyl-piperazin-2-one (Compound 2)

[0174] Step a) tert-Butyl 4-methyl-3-oxo-piperazine-1-carboxylate

[0175] To a solution of 1-methylpiperazin-2-one (5.0 g, 43.8 mmol) and DMAP (535 mg, 4.4 mmol)in DCM (5.0 mL), tert-butoxycarbonyl tert-butyl carbonate (10.1 mL, 43.8 mmol) was added. The reaction mixture was stirred at RT for 16 h. Water was added to the reaction mixture. The product was extracted with DCM (3x), and the combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give an oil. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded tert-butyl 4-methyl-3-oxo-piperazine-1-carboxylate (5.2 g) as an oil.1H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 2H), 3.55 (t, J = 5.4 Hz, 2H), 3.30 (d, J = 5.3 Hz, 2H), 2.85 (s, 3H), 1.41 (s, 9H). LCMS (Method C): [M+H]+= 215.2

[0176] Step b) tert-Butyl 2-allyl-4-methyl-3-oxo-piperazine-1-carboxylate

[0177] A solution of diisopropylamine (1.1 mL, 7.9 mmol) in anhydrous THF (10.0 mL) was cooledto –78ºC. n-BuLi (2.5 M in hexanes, 2.6 mL, 6.4 mmol) was added dropwise over 15 minutes. Then, a solution of tert-butyl 4-methyl-3-oxo-piperazine-1-carboxylate (500 mg, 2.3 mmol) andAttorney Docket No.60185-706601 hexamethylphosphoramide (1.2 mL, 7.0 mmol) in anhydrous THF (5.0 mL) was added dropwise. The reaction mixture was stirred at -78ºC under nitrogen for 15 minutes before a solution of 3- bromoprop-1-ene (609 μL, 7.0 mmol) in anhydrous THF (5.0 mL) was added dropwise. The reaction mixture was allowed to warm to RT and stirred for 16 h. NH4Cl (saturated aqueous solution) was added and the aqueous phase was extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give a dark yellow oil. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded tert-butyl 2-allyl-4-methyl-3-oxo- piperazine-1-carboxylate (210 mg) as an oil.1H NMR (400 MHz, CDCl3) δ 5.67 - 5.85 (m, 1 H), 4.96 - 4.97 (m, 1 H), 4.92 - 5.08 (m, 1 H), 4.46 - 4.63 (m, 1 H), 4.11 (br d, J=3.43 Hz, 1 H), 3.42 (td, J=11.63, 4.48 Hz, 1 H), 3.00 - 3.25 (m, 2 H), 2.91 (s, 3 H), 2.59 - 2.73 (m, 1 H), 2.48 (dt, J=14.09, 8.50 Hz, 1 H), 1.39 (s, 9 H). LCMS (Method D): [M+H]+= 255.2

[0178] Step c) 3-Allyl-1-methyl-piperazin-2-one hydrochloride

[0179] Following the procedure in example 1 step f but concentrating the crude reaction, tert-butyl2-allyl-4-methyl-3-oxo-piperazine-1-carboxylate (210 mg, 0.8 mmol) was used to prepare 3-allyl-1- methyl-piperazin-2-one hydrochloride (157 mg, crude) as an oil.1H NMR (400 MHz, DMSO-d6) δ 5.69 - 5.99 (m, 1 H), 5.13 - 5.32 (m, 2 H), 3.97 (br s, 1 H), 3.61 - 3.75 (m, 1 H), 3.40 - 3.53 (m, 4 H), 2.89 (s, 3 H), 2.75 - 2.86 (m, 1 H), 2.54 - 2.66 (m, 1 H). LCMS (Method D): [M+H]+= 155.0

[0180] Step d) Ethyl 3-[2-[bis(tert-butoxycarbonyl)amino]pyrimidin-5-yl]benzoate

[0181] Following the procedure in example 1 step c, tert-butyl N-(5-bromopyrimidin-2-yl)-N-tert-butoxycarbonyl-carbamate (8.5 g, 15.9 mmol) and (3-ethoxycarbonylphenyl)boronic acid (3.7 g, 19.1 mmol) was used to prepare ethyl 3-[2-[bis(tert-butoxycarbonyl)amino]pyrimidin-5-yl]benzoate (5.9 g) as a solid.1H NMR (400 MHz, CDCl3) δ 8.98 - 9.01 (m, 2 H), 8.27 - 8.30 (m, 1 H), 8.16 (dt,Attorney Docket No.60185-706601 J=7.80, 1.25 Hz, 1 H), 7.78 (dt, J=7.77, 1.45 Hz, 1 H), 7.59 - 7.65 (m, 1 H), 4.44 (q, J=7.12 Hz, 2 H), 1.51 (s, 18 H), 1.44 (t, J=7.15 Hz, 3 H). LCMS (Method C): [M-2BOC+H]+= 244.2

[0182]

[0183] Following the procedure in example 1 step d, ethyl 3-[2-[bis(tert-butoxycarbonyl)amino]pyrimidin-5-yl]benzoate (9.3 g, 20.9 mmol) was used to prepare 3-[2-(tert- butoxycarbonylamino)pyrimidin-5-yl]benzoic acid (10.1 g, crude) as a solid.1H NMR (400 MHz, DMSO-d6) δ 10.11 - 10.19 (m, 1 H), 8.88 (s, 2 H), 8.14 - 8.20 (m, 1 H), 7.87 - 7.94 (m, 1 H), 7.62 - 7.67 (m, 1 H), 7.40 (t, J=7.58 Hz, 1 H), 1.48 (s, 9 H). LCMS (Method C): [M-tBu+H]+= 260.1

[0184] Step f) tert-Butyl N-[5-[3-(2-allyl-4-methyl-3-oxo-piperazine-1-carbonyl)phenyl]pyrimidin-2-yl]carbamate

[0185] Following the procedure in example 1 step e, 3-[2-(tert-butoxycarbonylamino)pyrimidin-5-yl]benzoic acid (308 mg, 0.7 mmol) and 3-allyl-1-methyl-piperazin-2-one hydrochloride was used to prepare (143 mg) as an oil.1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1 H), 8.95 (s, 2 H), 7.86 (d, J=7.92 Hz, 1 H), 7.75 (s, 1 H), 7.60 (t, J=7.68 Hz, 1 H), 7.40 (d, J=7.63 Hz, 1 H), 5.77 - 5.96 (m, 1 H), 5.01 - 5.29 (m, 2 H), 4.94 (br d, J=4.01 Hz, 1 H), 3.57 - 3.67 (m, 1 H), 3.43 - 3.69 (m, 2 H), 3.09 - 3.16 (m, 2 H), 2.88 (s, 3 H), 2.61 - 2.74 (m, 2 H), 1.49 (s, 9 H). LCMS (Method D): [M+H]+= 452.2

[0186] Step g) 3-Allyl-4-[3-(2-aminopyrimidin-5-yl)benzoyl]-1-methyl-piperazin-2-oneAttorney Docket No.60185-706601

[0187] Following the procedure in example 1 step f, but basifying with NaHCO3 instead of NaOHsolution and purification by FCC (irregular silica, 0-7% MeOH in DCM), tert-butyl N-[5-[3-(2-allyl- 4-methyl-3-oxo-piperazine-1-carbonyl)phenyl]pyrimidin-2-yl]carbamate (237 mg, 0.5 mmol) was used to prepare 3-allyl-4-[3-(2-aminopyrimidin-5-yl)benzoyl]-1-methyl-piperazin-2-one (100 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.57 (s, 2 H), 7.65 - 7.73 (m, 1 H), 7.48 - 7.59 (m, 2 H), 7.31 (dt, J=7.58, 1.26 Hz, 1 H), 6.41 (br s, 2 H), 5.75 - 5.93 (m, 1 H), 5.03 - 5.21 (m, 2 H), 4.76 (br s, 1 H), 3.75 - 3.93 (m, 1 H), 3.43 - 3.59 (m, 2 H), 3.17 - 3.24 (m, 1 H), 2.89 (s, 3 H), 2.62 - 2.72 (m, 2 H). LCMS (Method E): [M+H]+= 352.1736

[0188] Example 3: Synthesis of 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 3)

[0189] Step a) tert-Butyl 4-methyl-3-oxo-2-propyl-piperazine-1-carboxylate

[0190] Following the procedure in example 2 step b, tert-butyl 4-methyl-3-oxo-piperazine-1-carboxylate (500 mg, 2.3 mmol) and 1-bromopropane (636 μL, 7.0 mmol) were used to prepare tert- butyl 4-methyl-3-oxo-2-propyl-piperazine-1-carboxylate (275 mg) as an oil.1H NMR (400 MHz, CDCl3) δ 4.54 (br s, 1 H), 4.15 - 4.30 (m, 1 H), 3.49 (td, J=11.56, 4.43 Hz, 1 H), 3.06 - 3.34 (m, 2 H), 2.97 (s, 3 H), 1.84 - 1.99 (m, 1 H), 1.55 - 1.79 (m, 3 H), 1.33 - 1.53 (m, 9 H), 0.95 (t, J=7.34 Hz, 3 H). LCMS (Method A): [M-tBu+H]+= 201.1

[0191] Step b) 1-Methyl-3-propyl-piperazin-2-one hydrochlorideAttorney Docket No.60185-706601

[0192] Following the procedure in example 2 step c, tert-butyl 4-methyl-3-oxo-2-propyl-piperazine-1-carboxylate (275 mg, 1.1 mmol) was used to prepare 1-methyl-3-propyl-piperazin-2-one hydrochloride (250 mg, crude) as an oil.1H NMR (400 MHz, DMSO-d6) δ 9.98 (br d, J=1.33 Hz, 1 H), 9.63 - 9.83 (m, 1 H), 3.57 - 3.70 (m, 1 H), 3.36 - 3.48 (m, 2 H), 3.26 - 3.35 (m, 1 H), 2.87 (s, 3 H), 1.88 - 2.01 (m, 1 H), 1.68 - 1.82 (m, 1 H), 1.47 (sxt, J=7.57 Hz, 2 H), 0.89 (t, J=7.30 Hz, 3 H). LCMS (Method D): [M+H]+= 157.0

[0193] Step c) tert-Butyl N-[5-[3-(4-methyl-3-oxo-2-propyl-piperazine-1-carbonyl)phenyl]pyrimidin-2-yl]carbamate

[0194] Following the procedure in example 1 step e but purification by FCC (irregular silica, 0-4%MeOH in DCM), 3-[2-(tert-butoxycarbonylamino)pyrimidin-5-yl]benzoic acid (643 mg, 1.4 mmol) and 1-methyl-3-propyl-piperazin-2-one hydrochloride (250 mg, 1.3 mmol) were used to prepare tert- butyl N-[5-[3-(4-methyl-3-oxo-2-propyl-piperazine-1-carbonyl)phenyl]pyrimidin-2-yl]carbamate (588 mg) as an oil.1H NMR (400 MHz, DMSO-d6) δ 10.18 - 10.22 (m, 1 H), 8.94 - 8.98 (m, 2 H), 7.83 - 7.88 (m, 1 H), 7.77 - 7.82 (m, 1 H), 7.57 - 7.62 (m, 1 H), 7.45 (br d, J=7.06 Hz, 1 H), 4.82 - 4.99 (m, 1 H), 3.40 - 3.66 (m, 4 H), 2.82 - 2.88 (m, 3 H), 1.80 - 1.89 (m, 2 H), 1.48 (s, 10 H), 1.37 - 1.45 (m, 1 H), 0.94 (br s, 3 H). LCMS (Method A): [M-tBu+H]+= 398.2

[0195] Step d) 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-oneAttorney Docket No.60185-706601

[0196] Following the procedure in example 2 step g but purification by FCC (irregular silica, 0-3%MeOH in DCM) followed by RP purification (Phenomenex Gemini C1830x100mm 5µm Column, from 95% [25mM NH4HCO3] - 5% [MeCN: MeOH 1:1] to 63% [25mM NH4HCO3] - 37% [MeCN: MeOH 1:1]), tert-butyl N-[5-[3-(4-methyl-3-oxo-2-propyl-piperazine-1-carbonyl)phenyl]pyrimidin- 2-yl]carbamate (588 mg, 1.3 mmol) was used to prepare 4-[3-(2-aminopyrimidin-5-yl)benzoyl]-1- methyl-3-propyl-piperazin-2-one (192 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 2 H), 7.68 - 7.72 (m, 1 H), 7.59 - 7.62 (m, 1 H), 7.50 - 7.56 (m, 1 H), 7.31 - 7.37 (m, 1 H), 6.41 - 6.48 (m, 2 H), 4.58 - 4.80 (m, 1 H), 3.77 - 3.97 (m, 1 H), 3.42 - 3.58 (m, 2 H), 3.17 - 3.25 (m, 1 H), 2.87 - 2.91 (m, 3 H), 1.76 - 1.95 (m, 2 H), 1.33 - 1.51 (m, 2 H), 0.91 (t, J=7.34 Hz, 3 H). LCMS (Method E): [M+H]+= 354.1868

[0197] Example 4: Synthesis of 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-(ethoxymethyl)-1-methyl-piperazin-2-one (Compound 4)

[0198] Step a) tert-Butyl 2-(ethoxymethyl)-4-methyl-3-oxo-piperazine-1-carboxylate

[0199] Following the procedure in example 2 step b but at -50ºC for 1 h and purification by FCC(irregular silica, 0-100% EtOAc in DCM), tert-butyl 4-methyl-3-oxo-piperazine-1-carboxylate (250 mg, 1.2 mmol) and chloromethoxyethane (325 μL, 3.5 mmol) were used to prepare tert-butyl 2- (ethoxymethyl)-4-methyl-3-oxo-piperazine-1-carboxylate (156 mg) as an oil.1H NMR (400 MHz, CDCl3) δ 4.03 (dd, J = 9.8, 3.7 Hz, 1H), 3.74 – 3.67 (m, 1H), 3.46 (dd, J = 13.9, 7.0 Hz, 3H), 3.25 – 3.12 (m, 1H), 3.00 (s, 3H), 1.61 (d, J = 19.4 Hz, 3H), 1.46 (s, 9H), 1.14 (q, J = 6.8 Hz, 3H). LCMS (Method D): [M+H]+= 273.2

[0200] Step b) 3-(Ethoxymethyl)-1-methyl-piperazin-2-one hydrochlorideAttorney Docket No.60185-706601

[0201] Following the procedure in example 2 step c, tert-butyl 2-allyl-4-methyl-3-oxo-piperazine-1-carboxylate (210 mg, 0.8 mmol) was used to prepare 3-allyl-1-methyl-piperazin-2-one hydrochloride (157 mg) as an oil. LCMS (Method D): [M+H]+= 173.1

[0202] Step c) tert-Butyl N-[5-[3-[2-(ethoxymethyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]pyrimidin-2-yl]carbamate

[0203] Following the procedure in example 1 step e, but purification by FCC (irregular silica, 0-10%MeOH in DCM), 3-[2-(tert-butoxycarbonylamino)pyrimidin-5-yl]benzoic acid (358 mg, 0.9 mmol) and 3-(ethoxymethyl)-1-methyl-piperazin-2-one (148 mg, 0.7 mmol) were used to prepare tert-butyl N-[5-[3-[2-(ethoxymethyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]pyrimidin-2-yl]carbamate (118 mg) as an oil.1H NMR (400 MHz, CDCl3) δ 8.80 (s, 2H), 7.7-7.8 (m, 1H), 7.5-7.7 (m, 4H), 3.5-3.6 (m, 3H), 3.1-3.3 (m, 1H), 3.04 (s, 3H), 1.6-1.8 (m, 5H), 1.6-1.6 (m, 9H), 1.18 (t, J=6.9 Hz, 3H). LCMS (Method D): [M+H]+= 470.2

[0204] Step d) 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-(ethoxymethyl)-1-methyl-piperazin-2-one

[0205] Following the procedure in example 2 step g, by using DCM as solvent, purification by FCC(irregular silica, 0-4% MeOH in DCM) followed by trituration with DIPE:pentane 1:1, tert-butyl N- [5-[3-[2-(ethoxymethyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]pyrimidin-2-yl]carbamate (133 mg, 0.3 mmol) was used to prepare 4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-(ethoxymethyl)-1- methyl-piperazin-2-one (47 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 2H), 7.75 – 7.59 (m, 1H), 7.55 – 7.45 (m, 1H), 7.34 (d, J = 7.3 Hz, 1H), 6.83 (s, 2H), 4.04 – 3.57 (m, 2H), 3.57 –Attorney Docket No.60185-706601 3.31 (m, 6H), 3.20 – 3.06 (m, 1H), 2.92 – 2.82 (m, 4H), 2.10 – 2.02 (m, 1H), 1.17 – 1.01 (m, 4H). LCMS (Method B): [M+H]+= 370.1845

[0206] Example 5: Synthesis of 4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl-piperazin-2-one (Compound 5)

[0207] Step a) 3-Butylpiperazin-2-one

[0208] In a two-neck RBF, a solution of methyl 2-bromohexanoate (1.9 mL, 12.0 mmol) in EtOH(17.0 mL) was dropwise added over 2.5 h to a stirred refluxing solution of ethane-1,2-diamine (15.0 mL, 223.9 mmol) in EtOH (68.0 mL). The resulting mixture was stirred for another 2.5h at reflux. Then, sodium ethoxide solution (4.6 mL, 12.3 mmol, 21 wt. %) in ethanol was added to the mixture. The resulting mixture was stirred for 1.5 h at reflux. The reaction mixture was cooled and the solvent was concentrated in vacuo to give an orange residue. The residue was triturated with Et2O, filtered and the filtrate was concentrated in vacuo to afford 3-butylpiperazin-2-one (1.4 g) as a solid.1H NMR (400 MHz, DMSO-d6) δ 3.19 – 2.98 (m, 4H), 2.93 – 2.83 (m, 2H), 2.73 – 2.63 (m, 1H), 1.78 – 1.64 (m, 1H), 1.54 – 1.39 (m, 1H), 1.37 – 1.20 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H). LCMS (Method A): [M+H]+= 157.1

[0209] Step b) 4-(3-Bromobenzoyl)-3-butyl-piperazin-2-one

[0210] In an RBF, 3-bromobenzoyl chloride (355 μL, 2.7 mmol) was added dropwise to a stirredsolution of 3-butylpiperazin-2-one (500 mg, 2.6 mmol) and TEA (535 μL, 3.8 mmol) in CHCl3(10.0 mL) at 0°C. The resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with NaHCO3 (saturated aqueous solution) and the product was extracted with DCM (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow solid. Purification by FCC (irregular silica, 0-1% MeOH in DCM) afforded 4-(3-bromobenzoyl)-3- butyl-piperazin-2-one (703 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 7.61 – 7.56 (m, 1H), 7.54Attorney Docket No.60185-706601 (s, 1H), 7.31 (d, J = 4.8 Hz, 2H), 6.08 (s, 1H), 5.23 (s, 1H), 4.74 (s, 1H), 3.69 (d, J = 48.3 Hz, 1H), 3.59 – 3.07 (m, 3H), 1.88 (s, 1H), 1.54 – 1.14 (m, 4H), 0.91 (s, 3H). LCMS (Method A): [M+H]+= 339.2, 341.1

[0211] Step c) 4-(3-Bromobenzoyl)-3-butyl-1-ethyl-piperazin-2-one

[0212] In an RBF, sodium hydride (28 mg, 0.7 mmol, 60% dispersion in mineral oil) was addedportion-wise to a stirred solution of 4-(3-bromobenzoyl)-3-butyl-piperazin-2-one (200 mg, 0.6 mmol) in anhydrous THF (3.0 mL) at 0ºC. The resulting mixture was stirred at RT for 30 minutes. Then, iodoethane (56 μL, 0.7 mmol) was added dropwise to the mixture at RT. The resulting mixture was stirred at RT for 16 h. The mixture was quenched with water. The aqueous phase was extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow solid. Purification by FCC (irregular silica, 0-2% MeOH in DCM) afforded 4-(3-bromobenzoyl)-3-butyl-1-ethyl-piperazin-2-one (174 mg) as an oil.1H NMR (400 MHz, DMSO-d6) δ 7.67 (dt, J = 7.5, 1.8 Hz, 1H), 7.58 (s, 1H), 7.46 – 7.38 (m, 2H), 4.68 – 3.71 (m, 2H), 3.56 – 3.16 (m, 5H), 1.99 – 1.69 (m, 2H), 1.43 – 1.24 (m, 4H), 1.07 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H). LCMS (Method C): [M+H]+= 367.3, 369.3

[0213] Step d) 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl-piperazin-2-one

[0214] Following the procedure in example 1 step c but during 2 h, using Pd(dppf)Cl2·DCM anddioxane, and purification by FCC (irregular silica, 0-10% MeOH in DCM) followed by trituration with DIPE:pentane 1:1, (2-aminopyrimidin-5-yl)boronic acid (70 mg, 0.5 mmol) and 4-(3- bromobenzoyl)-3-butyl-1-ethyl-piperazin-2-one (165 mg, 0.5 mmol) were used to prepare 4-[3-(2- aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl-piperazin-2-one (65 mg) as a solid.1H NMR (400Attorney Docket No.60185-706601 MHz, DMSO-d6, 100ºC) δ 8.58 (s, 2H), 7.69 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.43 (s, 2H), 4.65 (s, 1H), 3.87 (s, 1H), 3.54 – 3.15 (m, 5H), 1.95 – 1.75 (m, 2H), 1.44 – 1.23 (m, 4H), 1.08 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H). LCMS (Method E): [M+H]+= 382.2257

[0215] Example 6: Synthesis of 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-butyl-1-isopropyl-piperazin-2-one (Compound 6)

[0216] Step a) 4-(3-Bromobenzoyl)-3-butyl-1-isopropyl-piperazin-2-one

[0217] Following the procedure in example 5 step c, 4-(3-bromobenzoyl)-3-butyl-piperazin-2-one(200 mg, 0.6 mmol) and 2-iodopropane (117 μL, 1.2 mmol) were used to prepare 4-(3- bromobenzoyl)-3-butyl-1-isopropyl-piperazin-2-one (230 mg) as an oil.1H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.65 (m, 1H), 7.63 (s, 1H), 7.47 – 7.39 (m, 2H), 4.78 (s, 1H), 4.69 – 4.54 (m, 1H), 3.65 – 3.41 (m, 2H), 3.28 – 2.97 (m, 2H), 1.82 (s, 2H), 1.46 – 1.15 (m, 5H), 1.04 (dd, J = 15.1, 6.6 Hz, 6H), 0.88 (s, 3H). LCMS (Method C): [M+H]+= 381.2, 383.2

[0218] Step b) 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-butyl-1-isopropyl-piperazin-2-one

[0219] Following the procedure in example 5 step d, 4-(3-bromobenzoyl)-3-butyl-1-isopropyl-piperazin-2-one (220 mg, 0.6 mmol) and (2-aminopyrimidin-5-yl)boronic acid (90 mg, 0.6 mmol) were used to prepare 4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-butyl-1-isopropyl-piperazin-2-one (100 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.58 (s, 2H), 7.69 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.43 (s, 2H), 4.65 (s, 1H), 3.87 (s,Attorney Docket No.60185-706601 1H), 3.54 – 3.15 (m, 5H), 1.95 – 1.75 (m, 2H), 1.44 – 1.23 (m, 4H), 1.08 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H). LCMS (Method E): [M+H]+= 396.2301

[0220] Example 7: Synthesis of 3-Butyl-1-methyl-4-[3-(1H-pyrazolo[3,4-b]pyridin-6-yl)benzoyl]piperazin-2-one (Compound 7)

[0221] Step a) 4-(3-Bromobenzoyl)-3-butyl-1-methyl-piperazin-2-one

[0222] Following the procedure in example 5 step b but during 2 h and without purification by FCC,3-bromobenzoyl chloride (129 mg, 0.6 mmol) and 3-butyl-1-methyl-piperazin-2-one (100 mg, 0.6 mmol) were used to prepare 4-(3-bromobenzoyl)-3-butyl-1-methyl-piperazin-2-one (150 mg).1H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.66 (m, 1H), 7.63 (s, 1H), 7.44 (t, J = 6.6 Hz, 2H), 4.82 (s, 1H), 3.60 – 3.36 (m, 3H), 3.13 (td, J = 8.1, 4.0 Hz, 1H), 2.84 (s, 3H), 1.95 – 1.67 (m, 2H), 1.40 – 1.25 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H). LCMS (Method C): [M+H]+= 353.2, 355.2 Step b) 3-Butyl-1-methyl-4-[3-(1H-pyrazolo[5,4-b]pyridin-5-yl)benzoyl]piperazin-2-one

[0223] Following the procedure in example 5 step d without trituration with DIPE:pentane 1:1, 4-(3-bromobenzoyl)-3-butyl-1-methyl-piperazin-2-one (84 mg, 0.2 mmol) and 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (64 mg, 0.3 mmol) were used to prepare 3- butyl-1-methyl-4-[3-(1H-pyrazolo[3,4-b]pyridin-6-yl)benzoyl]piperazin-2-one (10 mg) as an oil.1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 7.87 – 7.80 (m, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 4.70 (s, 1H), 3.90 (s, 1H), 3.63 – 3.41 (m, 2H), 3.26 – 3.17 (m, 1H), 2.88 (s, 3H), 2.01 – 1.78 (m, 2H), 1.47 – 1.24 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (Method B): [M+H]+= 392.2162

[0224] Example 8: Synthesis of 4-[3-(6-Amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one (Compound 8)

[0225] Step a) 4-[3-(6-Amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one-89-Attorney Docket No.60185-706601

[0226] Follow the procedure in example 5 step d, 4-(3-bromobenzoyl)-3-butyl-1-methyl-piperazin-2-one (170 mg, 0.5 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- amine (124 mg, 0.5 mmol) were used to prepare 4-[3-(6-amino-5-methyl-3-pyridyl)benzoyl]-3- butyl-1-methyl-piperazin-2-one (22 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.3 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.54 (s, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 5.56 (s, 2H), 4.67 (s, 1H), 3.90 (s, 1H), 3.58 – 3.40 (m, 2H), 3.26 – 3.13 (m, 1H), 2.88 (s, 3H), 2.16 (s, 3H), 1.97 – 1.75 (m, 2H), 1.43 – 1.35 (m, J = 12.0, 6.0 Hz, 2H), 1.34 – 1.26 (m, 2H), 0.88 (t, J = 7.1 Hz, 3H). LCMS (Method B): [M+H]+= 381.2429

[0227] Example 9: Synthesis of 4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one (Compound 9)

[0228] Step a) tert-Butyl 2-(cyclopropylmethyl)-4-methyl-3-oxo-piperazine-1-carboxylate

[0229] Following the procedure in example 2 step b but purification by FCC (irregular silica, 0-60%EtOAc in DCM), tert-butyl 4-methyl-3-oxo-piperazine-1-carboxylate (500 mg, 2.3 mmol) and bromomethylcyclopropane (1.9 g, 14.0 mmol) were used to prepare tert-butyl 2- (cyclopropylmethyl)-4-methyl-3-oxo-piperazine-1-carboxylate (405 mg) as an oil.1H NMR (400 MHz, DMSO-d6) δ 4.62 (s, 1H), 4.23 (t, J = 20.3 Hz, 1H), 3.50 (td, J = 11.7, 4.6 Hz, 1H), 3.28 (t, J = 25.4 Hz, 1H), 3.18 – 3.10 (m, 1H), 2.97 (s, 3H), 1.77 (s, 2H), 1.46 (s, 9H), 0.82 – 0.70 (m, 1H), 0.52 – 0.40 (m, 2H), 0.18 – 0.08 (m, 2H). GCMS (Method GC1): [M+] = 268.1

[0230] Step b) 3-(Cyclopropylmethyl)-1-methyl-piperazin-2-one hydrochlorideAttorney Docket No.60185-706601

[0231] Following the procedure in example 2 step c but using DCM as solvent, tert-butyl 2-(cyclopropylmethyl)-4-methyl-3-oxo-piperazine-1-carboxylate (400 mg, 1.5 mmol) was used to prepare 3-(cyclopropylmethyl)-1-methyl-piperazin-2-one hydrochloride (400 mg, crude) as an oil.1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.62 (s, 1H), 3.91 (s, 1H), 3.71 – 3.61 (m, 1H), 3.51 – 3.40 (m, 2H), 2.88 (s, 3H), 1.91 (ddd, J = 14.6, 7.2, 4.8 Hz, 1H), 1.72 – 1.59 (m, 1H), 0.95 – 0.83 (m, 1H), 0.58 – 0.39 (m, 2H), 0.28 – 0.19 (m, 1H), 0.11 (dq, J = 9.7, 4.7 Hz, 1H). LCMS (Method A): [M+H]+= 169.2

[0232] Step c) tert-Butyl N-[5-[3-[2-(cyclopropylmethyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]pyrimidin-2-yl]carbamate

[0233] A screw-cap tube was charged with 3-[2-(tert-butoxycarbonylamino)pyrimidin-5-yl]benzoicacid (363 mg, 0.8 mmol). MeCN (2.0 mL) was added and the reaction mixture was sparged with nitrogen for 5 minutes.1-Methylimidazole (204 μL, 2.6 mmol) and TCFH (247 mg, 0.9 mmol) were added. The reaction mixture was stirred at RT for 10 minutes before the addition of 3- (cyclopropylmethyl)-1-methyl-piperazin-2-one hydrochloride (200 mg, 0.7 mmol). The mixture was stirred at RT for 16 h. The reaction mixture was diluted with water. The product was extracted with EtOAc (3x), and the combined organics washed with brine, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-20% EtOAc in heptane) afforded tert-butyl N- [5-[3-[2-(cyclopropylmethyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]pyrimidin-2- yl]carbamate (320 mg) as a solid. LCMS (Method A): [M+H]+= 466.4Attorney Docket No.60185-706601

[0234] Step d) 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one

[0235] Following the procedure in example 2 step g, but using DCM as solvent and purification byFCC (irregular silica, 0-4% MeOH in DCM) followed by RP purification (Phenomenex Gemini C18 30x100mm 5µm Column, from 81% [25mM NH4HCO3] - 19% MeCN to 45% [25mM NH4HCO3] - 55% MeCN), tert-butyl N-[5-[3-[2-(cyclopropylmethyl)-4-methyl-3-oxo-piperazine-1- carbonyl]phenyl]pyrimidin-2-yl]carbamate (320 mg, 0.7 mmol) was used to prepare 4-[3-(2- aminopyrimidin-5-yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one (94 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.58 (s, 2H), 7.69 (d, J = 8.3 Hz, 1H), 7.60 (s, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 6.43 (s, 2H), 4.76 (s, 1H), 3.91 (s, 1H), 3.62 – 3.45 (m, 2H), 3.27 – 3.16 (m, 1H), 2.89 (s, 3H), 1.86 – 1.75 (m, 2H), 0.81 (s, 1H), 0.52 – 0.35 (m, 2H), 0.18 – 0.09 (m, 1H), 0.08 – 0.01 (m, 1H). LCMS (Method E): [M+H]+= 366.1900

[0236] Example 10: Synthesis of 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-cyclopropyl-1-methyl-piperazin-2-one (Compound 10)

[0237] Step a) tert-Butyl N-(2-bromoethyl)carbamate

[0238] Following the procedure in example 1 step b but without DMAP and purification by FCC(irregular silica, 0-10% EtOAc in heptane), 2-bromoethanamine hydrobromide (2.2 g, 10.2 mmol) and tert-butoxycarbonyl tert-butyl carbonate (3.5 mL, 15.3 mmol) were used to prepare tert-butyl N- (2-bromoethyl)carbamate (2.3 g) as an oil.1H NMR (300 MHz, CDCl3) δ 4.94 (br s, 1 H), 3.33 - 3.67 (m, 4 H), 1.46 (s, 9 H). LCMS not performed; product did not show UV absorbanceL.

[0239] Step b) Methyl 2-[2-(tert-butoxycarbonylamino)ethylamino]-2-cyclopropyl-acetateAttorney Docket No.60185-706601

[0240] In an RBF, methyl 2-amino-2-cyclopropyl-acetate hydrochloride (300 mg, 1.8 mmol) wasadded and dissolved in MeCN (15.0 mL). tert-Butyl N-(2-bromoethyl)carbamate (600 mg, 2.5 mmol) and KHCO3(544 mg, 5.4 mmol) were added and the reaction mixture was stirred at 80ºC for 4 h, after which it was stirred at RT for 4 days. The reaction mixture was then stirred at 80ºC for 1 day. The excess MeCN was removed under reduced pressure, the residue was dissolved in EtOAc and extracted with NaHCO3 (saturated aqueous solution). The product was extracted with EtOAc (3x), and the combined organics washed with brine, dried over MgSO4, filtered, and concentrated to give an oil. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded methyl 2-[2- (tert-butoxycarbonylamino)ethylamino]-2-cyclopropyl-acetate (56 mg) as an oil.1H NMR (400 MHz, DMSO-d6) δ 6.72 (m, 1 H), 3.63 (s, 3 H), 2.98 - 2.93 (m, 2 H), 2.66 (m, 1 H), 2.48 - 2.39 (m, 1 H), 1.37 (s, 9 H), 0.84 (m, 4 H), 0.45 - 0.39 (m, 2 H), 0.27 (br d, J=4.77 Hz, 2 H). LCMS (Method D): [M+H]+= 273.1

[0241] Step c) Methyl 2-(2-aminoethylamino)-2-cyclopropyl-acetate dihydrochloride

[0242] Following the procedure in example 2 step c, methyl 2-[2-(tert-butoxycarbonylamino)ethylamino]-2-cyclopropyl-acetate (56 mg, 0.2 mmol) was used to prepare methyl 2-(2-aminoethylamino)-2-cyclopropyl-acetate dihydrochloride (50 mg, crude) as a solid.1H NMR (300 MHz, DMSO-d6) δ 9.94 (m, 2 H), 8.29 (m, 3 H), 3.80 (s, 3 H), 3.66 (m, 2 H), 3.22 (m, 3 H), 1.21 - 1.09 (m, 1 H), 0.64 - 0.82 (m, 3 H), 0.46 - 0.60 (m, 1 H). LCMS (Method D): [M+H]+= 173.0

[0243] Step d) 3-Cyclopropylpiperazin-2-oneAttorney Docket No.60185-706601

[0244] To an RBF was added methyl 2-(2-aminoethylamino)-2-cyclopropyl-acetate dihydrochloride(50 mg, 0.2 mmol) and EtOH (1.5 mL), followed by TEA (71 μL, 0.5 mmol). The reaction mixture was stirred at RT for 16 h. The solvent was removed and the product was purified by FCC (irregular silica, 0-10% MeOH in DCM) afforded 3-cyclopropylpiperazin-2-one (22 mg) as an oil.1H NMR (300 MHz, DMSO-d6) δ 7.66 (br s, 1 H), 3.02 (m, 3 H), 2.83 (s, 2 H), 1.06 - 1.15 (m, 1 H), 0.47 - 0.58 (m, 1 H), 0.37 - 0.46 (m, 1 H), 0.27 - 0.37 (m, 2 H). LCMS (Method D): [M+H]+= 141.1

[0245] Step e) 4-(3-Bromobenzoyl)-3-cyclopropyl-piperazin-2-one

[0246] Following the procedure in example 1 step e, 3-cyclopropylpiperazin-2-one (110 mg, 0.8mmol) and 3-bromobenzoic acid (174 mg, 0.9 mmol) was used to prepare 4-(3-bromobenzoyl)-3- cyclopropyl-piperazin-2-one (187 mg) as an oil.1H NMR (400 MHz, DMSO-d6) δ 7.98 - 8.03 (m, 1 H), 7.69 - 7.74 (m, 1 H), 7.64 - 7.68 (m, 1 H), 7.43 - 7.48 (m, 2 H), 4.42 (br s, 1 H), 3.46 - 3.73 (m, 2 H), 3.33 (br s, 1 H), 3.07 - 3.23 (m, 1 H), 1.36 - 1.36 (m, 1 H), 1.33 - 1.42 (m, 1 H), 0.37 - 0.75 (m, 4 H). LCMS (Method D): [M+H]+= 323.0, 325.0

[0247] Step f) 4-(3-Bromobenzoyl)-3-cyclopropyl-1-methyl-piperazin-2-one

[0248] Following the procedure in example 5 step c, with purification by FCC (irregular silica, 0-100% EtOAc in heptane), 4-(3-bromobenzoyl)-3-cyclopropyl-piperazin-2-one (187 mg, 0.6 mmol) and iodomethane (47 μL, 1.4 mmol) were used to prepare 4-(3-bromobenzoyl)-3-cyclopropyl-1- methyl-piperazin-2-one (125 mg) as an oil.1H NMR (300 MHz, DMSO-d6) δ 7.66 - 7.74 (m, 1 H), 7.61 - 7.65 (m, 1 H), 7.44 (d, J=4.94 Hz, 2 H), 4.25 - 4.56 (m, 1 H), 3.38 - 3.81 (m, 3 H), 3.11 - 3.28Attorney Docket No.60185-706601 (m, 1 H), 2.86 (s, 3 H), 1.26 - 1.46 (m, 1 H), 0.30 - 0.71 (m, 4 H). LCMS (Method D): [M+H]+= 337.0, 339.0

[0249] Step g) 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-cyclopropyl-1-methyl-piperazin-2-one

[0250] Following procedure in example 1 step c but using dioxane instead of toluene, 100ºC during16 h and purification by FCC (irregular silica, 0-5% MeOH in DCM), (2-aminopyrimidin-5- yl)boronic acid (57 mg, 0.4 mmol) and 4-(3-bromobenzoyl)-3-cyclopropyl-piperazin-2-one (120 mg, 0.4 mmol) were used to prepare 4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-cyclopropyl-1-methyl- piperazin-2-one (100 mg) as a foam.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.58 (s, 2 H), 7.66 - 7.73 (m, 1 H), 7.60 (t, J=1.48 Hz, 1 H), 7.52 (t, J=7.72 Hz, 1 H), 7.34 (dt, J=7.61, 1.25 Hz, 1 H), 6.44 (br s, 2 H), 4.34 (m, 1 H), 3.68 (m, 1 H), 3.60 - 3.72 (m, 1 H), 3.48 (td, J=11.59, 5.05 Hz, 1 H), 3.21 - 3.32 (m, 1 H), 2.88 (s, 3 H), 1.24 - 1.39 (m, 1 H), 0.57 - 0.68 (m, 1 H), 0.37 - 0.57 (m, 3 H). LCMS (Method E): [M+H]+= 352.1691

[0251] Example 11: Synthesis of 4-[3-[2-(dimethylamino)pyrimidin-5-yl]benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 11)

[0252] Step a) 4-(3-Bromobenzoyl)-1-methyl-3-propyl-piperazin-2-one

[0253] Following the procedure in example 5 step b but during 1 h and purification by FCC(irregular silica, 0-10% EtOAc in heptane), 1-methyl-3-propyl-piperazin-2-one hydrochloride (597 mg, 3.1 mmol) and 3-bromobenzoyl chloride (430 μL, 3.3 mmol) were used to prepare 4-(3- bromobenzoyl)-1-methyl-3-propyl-piperazin-2-one (568 mg) as an oil.1H NMR (300 MHz, DMSO-d6) δ 7.69 (m, 1 H), 7.64 (m, 1 H), 7.44 (br s, 2 H), 4.85 (m, 1 H), 3.53 (m, 2 H), 3.43 (m, 1 H), 3.18 (s, 1 H), 2.84 (s, 3 H), 1.85 (m, 2 H), 1.40 (m, 2 H), 0.93 (br s, 3 H). LCMS (Method A): [M+H]+= 339.4, 341.4

[0254] Step b) 4-[3-[2-(Dimethylamino)pyrimidin-5-yl]benzoyl]-1-methyl-3-propyl-piperazin-2-oneAttorney Docket No.60185-706601

[0255] Following the procedure in example 10 step g and purification by RP (Phenomenex GeminiC1830x100mm 5µm Column, from 70% [25mM NH4HCO3] - 30% [MeCN: MeOH 1:1] to 27% [25mM NH4HCO3] - 73% [MeCN: MeOH 1:1]), 4-(3-bromobenzoyl)-1-methyl-3-propyl-piperazin- 2-one (150 mg, 0.4 mmol) and [2-(dimethylamino)pyrimidin-5-yl]boronic acid (81 mg, 0.5 mmol) were used to prepare 4-[3-[2-(dimethylamino)pyrimidin-5-yl]benzoyl]-1-methyl-3-propyl-piperazin- 2-one (85 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.65 - 8.73 (m, 2 H), 7.69 - 7.75 (m, 1 H), 7.60 - 7.64 (m, 1 H), 7.49 - 7.57 (m, 1 H), 7.31 - 7.37 (m, 1 H), 4.66 - 4.77 (m, 1 H), 3.81 - 3.99 (m, 1 H), 3.43 - 3.57 (m, 2 H), 3.21 - 3.24 (m, 1 H), 3.19 - 3.22 (m, 6 H), 2.87 - 2.91 (m, 3 H), 1.76 - 1.93 (m, 2 H), 1.36 - 1.54 (m, 2 H), 0.86 - 0.96 (m, 3 H). LCMS (Method E): [M+H]+= 382.2620

[0256] Example 12: Synthesis of 4-[3-(6-Amino-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 12)

[0257] Step a) 4-[3-(6-Amino-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0258] Following the procedure in example 10 step g and purification by RP (Phenomenex GeminiC1830x100mm 5µm Column, from 81% [25mM NH4HCO3] - 19% [MeCN:MeOH (1:1)] to 45% [25mM NH4HCO3] - 55% [MeCN:MeOH (1:1)]), 4-(3-bromobenzoyl)-1-methyl-3-propyl-piperazin- 2-one (150 mg, 0.4 mol) and (6-amino-3-pyridyl)boronic acid (71 mg, 0.5 mmol) were used to prepare 4-[3-(6-amino-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (48 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.28 (d, J=2.10 Hz, 1 H), 7.71 (dd, J=8.68, 2.48 Hz, 1 H), 7.66 (d, J=7.82 Hz, 1 H), 7.55 (qq, J=1.00 Hz, 1 H), 7.49 (t, J=7.68 Hz, 1 H), 7.28 (d, J=7.44 Hz, 1Attorney Docket No.60185-706601 H), 6.59 (d, J=1.00 Hz, 1 H), 5.77 (s, 2 H), 4.54 - 4.80 (m, 1 H), 3.81 - 3.93 (m, 1 H), 3.35 - 3.60 (m, 2 H), 3.16 - 3.25 (m, 1 H), 2.88 (s, 3 H), 1.86 (sxt, J=1.00 Hz, 2 H), 1.42 (sxt, J=2.00 Hz, 1 H), 0.91 (t, J=1.00 Hz, 3 H). LCMS (Method E): [M+H]+= 353.2461

[0259] Example 13: Synthesis of 1-Methyl-4-[3-[2-(methylamino)pyrimidin-5-yl]benzoyl]-3-propyl-piperazin-2-one (Compound 13)

[0260] Step a) 1-Methyl-4-[3-[2-(methylamino)pyrimidin-5-yl]benzoyl]-3-propyl-piperazin-2-one

[0261] Following the procedure in example 10 step g at 90ºC and purification by RP (PhenomenexGemini C1830x100mm 5µm Column, from 81% [25mM NH4HCO3] - 19% [MeCN: MeOH 1:1] to 45% [25mM NH4HCO3] - 55% [MeCN: MeOH 1:1]), 4-(3-bromobenzoyl)-1-methyl-3-propyl- piperazin-2-one (150 mg, 0.4 mmol) and N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidin-2-amine (114 mg, 0.5 mmol) were used to prepare 1-methyl-4-[3-[2- (methylamino)pyrimidin-5-yl]benzoyl]-3-propyl-piperazin-2-one (43 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.52 (s, 2 H), 7.60 (d, J=7.82 Hz, 1 H), 7.50 (s, 1 H), 7.43 (t, J=7.68 Hz, 1 H), 7.23 (d, J=7.53 Hz, 1 H), 6.72 - 6.85 (m, 1 H), 4.60 (br s, 1 H), 3.67 - 3.87 (m, 1 H), 3.32 - 3.47 (m, 2 H), 3.05 - 3.17 (m, 1 H), 2.82 (d, J=4.86 Hz, 3 H), 2.78 (s, 3 H), 1.66 - 1.87 (m, 2 H), 1.27 - 1.39 (m, 2 H), 0.81 (t, J=7.30 Hz, 3 H). LCMS (Method B): [M+H]+= 368.2195

[0262] Example 14: Synthesis of (3*)-4-[3-(2-aminopyrimidin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 14) and (3*)-4-[3-(2-aminopyrimidin-5-yl)benzoyl]-1-methyl-3-propyl- piperazin-2-one (Compound 15)

[0263] Step a) (3*)-4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one and(3*)-4-[3-(2-aminopyrimidin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0264] 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (100 mg, 0.3mmol) as racemic mixture, was subjected to preparative SFC (Stationary phase: Whelk-01250x30Attorney Docket No.60185-706601 mm, 5 μm, Mobile phase: 5-60% EtOH + 0.1% DEA) to afford two yellow oils. Both oils were partitioned between a solution of NaHCO3 saturated and EtOAc. The products were extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give two solids. Both solids were lyophilised to afford single enantiomers of 4-[3-(2- aminopyrimidin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (isomer 1 : 25 mg and isomer 2 : 25 mg) as foams.

[0265] Single enantiomer isomer 1 (Compound 14): (3*)-4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one:1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.57 - 8.60 (m, 2 H), 7.68 - 7.72 (m, 1 H), 7.59 - 7.63 (m, 1 H), 7.50 - 7.56 (m, 1 H), 7.34 (d, J=7.53 Hz, 1 H), 6.41 - 6.48 (m, 2 H), 4.70 (br d, J=1.05 Hz, 1 H), 3.80 - 3.93 (m, 1 H), 3.41 - 3.61 (m, 2 H), 3.15 - 3.27 (m, 1 H), 2.89 (s, 3 H), 1.75 - 1.98 (m, 2 H), 1.35 - 1.56 (m, 2 H), 0.91 (t, J=7.30 Hz, 3 H). LCMS (Method E): [M+H]+= 354.2489. SFC: RT = 7.21 min, 99% ee. Mass: 1.06 mg. Solvent: MeOH. Concentration: 0.0707 w / v %. OR: -0.0728. SOR: -86.7. * Denotes a stereocenter with undetermined absolute stereochemistry of a single enantiomer.

[0266] Single enantiomer isomer 2 (Compound 15): (3*)-4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one:1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.59 (s, 2 H), 7.70 (d, J=7.92 Hz, 1 H), 7.61 (s, 1 H), 7.53 (t, J=7.68 Hz, 1 H), 7.31 - 7.38 (m, 1 H), 6.45 (br s, 2 H), 4.61 - 4.78 (m, 1 H), 3.75 - 3.94 (m, 1 H), 3.41 - 3.56 (m, 2 H), 3.17 - 3.25 (m, 1 H), 2.89 (s, 3 H), 1.76 - 1.94 (m, 2 H), 1.39 - 1.49 (m, 2 H), 0.91 (t, J=7.30 Hz, 3 H). LCMS (Method B): [M+H]+= 354.2046. SFC: RT = 8.06 min, 99% ee. Mass: 1.25 mg. Solvent: MeOH. Concentration: 0.0833 w / v %. OR: +0.0486. SOR: +72.2. * Denotes a stereocenter with undetermined absolute stereochemistry of a single enantiomer.

[0267] Example 15: Synthesis of (3*)-4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one (Compound 16) and (3*)-4-[3-(2-aminopyrimidin-5- yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one (Compound 17)

[0268] Step a) (3*)-4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one and (3*)-4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl- piperazin-2-oneAttorney Docket No.60185-706601

[0269] 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one (75mg, 0.2 mmol), as racemic mixture, was subjected to preparative SFC (Stationary phase: Whelk-01 250x30 mm, 5μm, Mobile phase: 5-60% EtOH + 0.1% DEA) to afford two yellow oils. Both oils were partitioned between a solution of NaHCO3saturated and EtOAc. The products were extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give two solids. Both solids were lyophilised to afford single enantiomers of 4-[3-(2- aminopyrimidin-5-yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one (isomer 1 : 25 mg and isomer 2 : 27 mg) as foams.

[0270] Single enantiomer isomer 1 (Compound 16): (3*)-4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one:1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.58 (s, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.60 (s, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 6.44 (s, 2H), 4.76 (s, 1H), 3.91 (s, 1H), 3.63 – 3.43 (m, 2H), 3.28 – 3.16 (m, 1H), 2.89 (s, 3H), 1.87 – 1.74 (m, 2H), 0.91 – 0.73 (m, 1H), 0.53 – 0.35 (m, 2H), 0.18 – 0.09 (m, 1H), 0.09 – 0.00 (m, 1H). LCMS (Method E): [M+H]+= 366.2345. SFC: RT = 7.43 min, 99% ee. Mass: 1.08 mg. Solvent: MeOH. Concentration: 0.0720 w / v %. OR: -0.0733. SOR: -85.7. * Denotes a stereocenter with undetermined absolute stereochemistry of a single enantiomer.

[0271] Single enantiomer isomer 2 (Compound 17): (3*)-4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one:1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.58 (s, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.60 (s, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 6.44 (s, 2H), 4.89 – 4.65 (m, 1H), 4.04 – 3.79 (m, 1H), 3.64 – 3.43 (m, 2H), 3.22 (dd, J = 11.2, 2.8 Hz, 1H), 2.89 (s, 3H), 1.87 – 1.75 (m, 2H), 0.89 – 0.74 (m, 1H), 0.53 – 0.35 (m, 2H), 0.18 – 0.09 (m, 1H), 0.08 – -0.01 (m, 1H). LCMS (Method E): [M+H]+= 366.2363. SFC: RT = 8.46 min, 99% ee. Mass: 1.13 mg. Solvent: MeOH. Concentration: 0.0867 w / v %. OR: 0.0507. SOR: +71.8. * Denotes a stereocenter with undetermined absolute stereochemistry of a single enantiomer.

[0272] Example 16: Synthesis of (3*)-4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl-piperazin-2-one (Compound 18) and (3*)-4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl- piperazin-2-one (Compound 19)Attorney Docket No.60185-706601

[0273] Step a) (3*)-4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl-piperazin-2-one and(3*)-4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl-piperazin-2-one

[0274] 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl-piperazin-2-one (57 mg, 0.1 mmol),as racemic mixture, was subjected to preparative SFC (Stationary phase: Whelk-01250x30 mm, 5μm, Mobile phase: 5-60% EtOH + 0.1% DEA) to afford two yellow oils. Both oils were partitioned between a solution of NaHCO3 saturated and EtOAc. The products were extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give two solids. Both solids were lyophilised to afford single enantiomers of 4-[3-(2- aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl-piperazin-2-one (isomer 1 : 15 mg and isomer 2: 10 mg) as a foam.

[0275] Single enantiomer isomer 1 (Compound 18): (3*)-4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl-piperazin-2-one:1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.58 (s, 2H), 7.70 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.44 (s, 2H), 4.64 (s, 1H), 3.88 (s, 1H), 3.55 – 3.15 (m, 5H), 1.99 – 1.76 (m, 2H), 1.47 – 1.25 (m, 4H), 1.08 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H). LCMS (Method E): [M+H]+= 382.2599. SFC: RT = 6.81 min, 99% ee. Mass: 1.3 mg. Solvent: MeOH. Concentration: 0.0867 w / v %. OR: -0.0644. SOR: -67.0. * Denotes a stereocenter with undetermined absolute stereochemistry of a single enantiomer.

[0276] Single enantiomer isomer 2 (Compound 19): (3*)-4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-butyl-1-ethyl-piperazin-2-one:1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.58 (s, 2H), 7.70 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 6.44 (s, 2H), 4.65 (s, 1H), 3.89 (s, 1H), 3.57 – 3.16 (m, 5H), 1.95 – 1.73 (m, 2H), 1.46 – 1.25 (m, 4H), 1.08 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H). LCMS (Method E): [M+H]+= 382.2658. SFC: RT = 7.32 min, 99% ee. Mass: 1.2 mg. Solvent: MeOH. Concentration: 0.0800 w / v %. OR: 0.0509. SOR: +71.4. * Denotes a stereocenter with undetermined absolute stereochemistry of a single enantiomer.

[0277] Example 17: Synthesis of 4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-ethyl-1-methyl-piperazin-2-one (Compound 20)

[0278] Step a) 4-(3-Bromobenzoyl)-3-ethyl-1-methyl-piperazin-2-oneAttorney Docket No.60185-706601

[0279] Following the procedure in example 5 step b and purification by FCC (irregular silica, 0-1%MeOH in DCM), 3-ethyl-1-methyl-piperazin-2-one hydrochloride (150 mg, 0.8 mmol) and 3- bromobenzoyl chloride (108 μL, 0.8 mmol) were used to prepare 4-(3-bromobenzoyl)-3-ethyl-1- methyl-piperazin-2-one (230 mg) as an oil.1H NMR (400 MHz, DMSO-d6) δ 7.60 - 7.74 (m, 2 H), 7.33 - 7.54 (m, 2 H), 4.77 (br s, 1 H), 3.53 (br s, 1 H), 3.39 - 3.48 (m, 1 H), 3.12 - 3.21 (m, 1 H), 2.85 (s, 3 H), 1.94 - 2.03 (m, 1 H), 1.79 - 1.90 (m, 1 H), 0.78 - 1.01 (m, 3 H). LCMS (Method D): [M+H]+= 325.0, 327.0.

[0280] Step b) 4-[3-(2-Aminopyrimidin-5-yl)benzoyl]-3-ethyl-1-methyl-piperazin-2-one

[0281] Following the procedure in example 10 step g and purification by RP (Phenomenex GeminiC1830x100mm 5µm Column, from 81% [25mM NH4HCO3] - 19% [MeCN:MeOH (1:1)] to 45% [25mM NH4HCO3] - 55% [MeCN:MeOH (1:1)]), 4-(3-bromobenzoyl)-3-ethyl-1-methyl-piperazin- 2-one (230 mg, 0.7 mmol) and (2-aminopyrimidin-5-yl)boronic acid (108 mg, 0.8 mmol) were used to prepare 4-[3-(2-aminopyrimidin-5-yl)benzoyl]-3-ethyl-1-methyl-piperazin-2-one (63 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.59 (s, 2 H), 7.70 (d, J=7.92 Hz, 1 H), 7.61 (s, 1 H), 7.53 (t, J=7.68 Hz, 1 H), 7.35 (d, J=7.63 Hz, 1 H), 6.44 (br s, 2 H), 4.52 - 4.71 (m, 1 H), 3.78 - 3.98 (m, 1 H), 3.43 - 3.58 (m, 2 H), 3.18 - 3.25 (m, 1 H), 2.89 (s, 3 H), 1.83 - 2.04 (m, 2 H), 0.98 (t, J=7.44 Hz, 3 H). LCMS (Method B): [M+H]+= 340.1799.

[0282] Example 18: Synthesis of (3*)-4-[3-(6-amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one (Compound 21) and (3R)-4-[3-(6-amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1- methyl-piperazin-2-one (Compound 22)

[0283] Step a) (3*)-4-[3-(6-Amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-oneand (3*)-4-[3-(6-amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one -101-Attorney Docket No.60185-706601

[0284] Following the procedure in example 8, 4-(3-bromobenzoyl)-3-butyl-1-methyl-piperazin-2-one (200 mg, 0.6 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- amine (146 mg, 0.6 mmol) were used to prepare 4-[3-(6-amino-5-methyl-3-pyridyl)benzoyl]-3- butyl-1-methyl-piperazin-2-one (81 mg).

[0285] As racemic mixture, the product was subjected to preparative SFC (Stationary phase: i-Amylose-A, Mobile phase: ISOC 50% EtOH + 0.1% DEA) to give two oils. Both oils were partitioned between a solution of NaHCO3saturated and EtOAc. The products were extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give two white solids. Both solids were lyophilised to afford (3R)-4-[3-(6-amino-5- methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one (12 mg) and (3S)-4-[3-(6-amino-5- methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one (16 mg) as foams.

[0286] Single enantiomer isomer 1 (Compound 21): (3*)-4-[3-(6-Amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one:1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.16 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 5.55 (s, 2H), 4.66 (s, 1H), 3.88 (s, 1H), 3.61 – 3.40 (m, 2H), 3.26 – 3.15 (m, 1H), 2.88 (s, 3H), 2.16 (s, 3H), 1.98 – 1.76 (m, 2H), 1.33 (ddd, J = 26.7, 12.9, 6.8 Hz, 4H), 0.88 (t, J = 7.1 Hz, 3H). LCMS (Method B): [M+H]+= 381.2424. SFC: RT = 1.25 min, 99% ee. Mass: 1.5 mg. Solvent: MeOH. Concentration: 0.1000 w / v %. OR: 0.1286. SOR: + 59.2. * Denotes a stereocenter with undetermined absolute stereochemistry of a single enantiomer.

[0287] Single enantiomer isomer 2 (Compound 22) (3R)-4-[3-(6-Amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one:1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.15 (d, J = 2.1 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 5.54 (s, 2H), 4.67 (s, 1H), 3.89 (s, 1H), 3.56 – 3.41 (m, 2H), 3.21 (d, J = 8.5 Hz, 1H), 2.88 (s, 3H), 2.16 (s, 3H), 2.09 – 1.77 (m, 2H), 1.38 – 1.27 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H). LCMS (Method B): [M+H]+= 381.2435. SFC: RT = 1.65 min, 99% ee. Mass: 1.9 mg. Solvent: MeOH. Concentration: 0.1267 w / v %. OR: -0.2577. SOR: - 55.3. Stereochemistry was determined via chiral synthesis below.Attorney Docket No.60185-706601

[0288] Alternative chiral synthesis of Single enantiomer isomer 2 (Compound 22): of (3R)-[3-(6-Amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one.

[0289] Step a) tert-butyl N-(2-oxoethyl)carbamate

[0290] To a solution of oxalyl dichloride (259.84 mg, 2.05 mmol, 178.58 μL) in dry DCM (4.31mL) at -78ºC, DMSO (319.90 mg, 4.09 mmol, 290.56 μL) was added dropwise. After 15 mins at - 78ºC, a solution of tert-butyl N-(2-hydroxyethyl)carbamate (300 mg, 1.86 mmol, 287.91 μL) in dry DCM (2.15 mL) was added dropwise and stirred for 45 mins. After this time, N,N- diethylethanamine (941.60 mg, 9.31 mmol, 1.30 mL) was added and the reaction was brought to rt for 30 mins. The reaction was extracted with HCl 1N and sat. NaHCO3, the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to form tert-butyl N-(2-oxoethyl)carbamate (457 mg, crude) as an oil.1H NMR (300 MHz, DMSO-d6) δ ppm 9.46 (s, 1 H), 7.21 (br s, 1 H), 3.73 (br d, J=5.59 Hz, 2 H), 1.39 (br s, 9 H).

[0291] Step b) methyl (2R)-2-[2-(tert-butoxycarbonylamino)ethylamino]hexanoate

[0292] tert-butyl N-(2-oxoethyl)carbamate (457 mg, 1.87 mmol) and methyl (2R)-2-aminohexanoate;hydrochloride (406.79 mg, 2.24 mmol) were dissolved in MeOH (14.87 mL) and the solution was brought to 0ºC for 5 minutes before the addition of sodium;cyanoboranuide (117.27 mg, 1.87 mmol) and AcOH (134.47 mg, 2.24 mmol, 128.07 μL) . Excess solvent was evaporated before extracting with sat. NaHCO3 and brine, the combined organic fractions were dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by column chromatography (12g, Hept:EtOAc 100:00 to 50:50) to obtain methyl (2R)-2-[2-(tert- butoxycarbonylamino)ethylamino]hexanoate (200 mg).1H NMR (300 MHz, DMSO-d6) δ ppm 6.62 - 6.76 (m, 1 H), 3.62 (s, 3 H), 3.14 - 3.14 (m, 1 H), 3.08 - 3.22 (m, 1 H), 2.85 - 3.03 (m, 2 H), 2.32 - 2.45 (m, 1 H), 1.43 - 1.59 (m, 2 H), 1.37 (s, 9 H), 1.17 - 1.31 (m, 5 H), 0.78 - 0.93 (m, 4 H). LCMS (Method D): [M+H]+= 289.2.Attorney Docket No.60185-706601

[0293] Step c) methyl (2R)-2-(2-aminoethylamino)hexanoate;hydrochloridemethyl (2R)-2-[2-(tert-butoxycarbonylamino)ethylamino]hexanoate (200 mg, 693.52 μmol) was added to an RBF and dissolved in DCM (2 mL) and hydrogen chloride (4 M, 3.47 mmol, 866.91 μL) was added. The reaction was stirred at 25°C for 16h. Excess solvent was removed under reduced pressure to afford methyl (2R)-2-(2-aminoethylamino)hexanoate;hydrochloride (172 mg, crude) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 - 8.60 (m, 3 H), 4.10 - 4.32 (m, 1 H), 3.79 (s, 3 H), 3.22 (br s, 4 H), 1.80 - 2.01 (m, 2 H), 1.30 (br d, J=6.8 Hz, 4 H), 0.88 (t, J=6.8 Hz, 3 H). LCMS (Method D): [M+H]+= 189.0

[0294] Step d) (3R)-3-butylpiperazin-2-one

[0295] methyl (2R)-2-(2-aminoethylamino)hexanoate;hydrochloride (150 mg, 667.48 μmol) wasadded into an RBF, dissolved in EtOH (4.5 mL) and N,N-diethylethanamine (168.85 mg, 1.67 mmol, 232.58 μL) was added. After 16 h the excess solvent was removed under reduced pressure to afford (3R)-3-butylpiperazin-2-one (130 mg, crude). LCMS (Method D): [M+H]+= 157.0

[0296] Step e) (3R)-4-(3-bromobenzoyl)-3-butyl-piperazin-2-one

[0297] 3-bromobenzoyl chloride (168.57 mg, 768.12 μmol, 101.43 μL) was added to a solutionof (3R)-3-butylpiperazin-2-one (100 mg, 640.10 μmol) in CHCl3 (4.99 mL) and N,N- diethylethanamine (97.16 mg, 960.15 μmol, 133.83 μL). After 1h, the crude was extracted with NaHCO3 and water. The combined organic phases were dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by column chromatography (12 g, Hept:EtOAc 100:0 to 0:100 DCM:MeOH 100:0 to 0:100) to obtain (3R)-4-(3-bromobenzoyl)-3-butyl-piperazin-2-one (212 mg) as an orange oil.1H NMR (300 MHz, DMSO-d6) δ ppm 7.98 (br d, 1 H), 7.69 (m, 1 H), 7.43 -104-Attorney Docket No.60185-706601 (br d, 2 H), 4.85 (m, 1 H), 3.78 (br d, J=4.07 Hz, 1 H), 3.45 (m, 2 H), 3.07 (m, H), 1.84 (m, 2 H), 1.35 (m, 3 H), 0.88 (m, 3 H). LCMS (Method D): [M+H]+= 341.1

[0298] Step f) (3R)-4-(3-bromobenzoyl)-3-butyl-1-methyl-piperazin-2-one

[0299] To a solution of (3R)-4-(3-bromobenzoyl)-3-butyl-piperazin-2-one (120 mg, 353.75μmol) and dicesium;carbonate (230.51 mg, 707.49 μmol) in MeCN (4.01 mL) in a 25 ml screw cap vial, iodomethane (75.32 mg, 530.62 μmol, 33.03 μL) was added under nitrogen atmosphere. The reaction was stirred at 60°C for 72h . The reaction mixture was vacuum filtered and purified by column chromatography (12 g, EtOAc:Hept 0:100 to 100:0) to obtain (3R)-4-(3-bromobenzoyl)-3- butyl-1-methyl-piperazin-2-one (97 mg) as a yellow oil.1H NMR (400 MHz, DMSO-d6, 100ºC) δ ppm 7.67 (dt, J=7.34, 1.34 Hz, 1 H), 7.59 (d, J=1.34 Hz, 1 H), 7.38 - 7.47 (m, 2 H), 4.53 - 4.68 (m, 1 H), 3.82 (br dd, J=5.87, 1.86 Hz, 1 H), 3.39 - 3.58 (m, 2 H), 3.17 - 3.28 (m, 1 H), 2.88 (s, 3 H), 1.76 - 1.97 (m, 2 H), 1.27 - 1.44 (m, 4 H), 0.82 - 0.98 (m, 3 H). LCMS (Method D): [M+H]+= 353.1, 355.1

[0300] Step g) (3R)-4-[3-(6-amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one

[0301] Pd(dppf)Cl2 (20.81 mg, 25.48 μmol) was added to a previously degassed screw cap vialcontaining (3R)-4-(3-bromobenzoyl)-3-butyl-1-methyl-piperazin-2-one (90 mg, 254.77 μmol) , 3- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (71.57 mg, 305.73 μmol) and tripotassium;carbonate (77.46 mg, 560.50 μmol) dissolved in Water (0.5 mL) and Dioxane (2 mL) . The reaction mixture was stirred at 85°C for 3h and then concentrated to dryness. The crude was subjected to silica gel chromatography (4 g, DCM:MeOH 100:0 to 90:10) to obtain (3R)-4-[3-(6-amino-5-methyl-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one as a brown solid. The product was washed with HCl 1M, then the aqueous phase was then brought to basic pH and the product extracted with EtOAc to obtain (3R)-4-[3-(6-amino-5-methyl-3- pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one (50 mg) as an off-white solid.1H NMR (400Attorney Docket No.60185-706601 MHz, d6-DMSO) δ ppm 8.16 (s, 1 H), 7.66 (br d, J=7.72 Hz, 1 H), 7.58 (s, 1 H), 7.53 - 7.56 (m, 1 H), 7.49 (t, J=7.72 Hz, 2 H), 7.28 (br d, J=7.53 Hz, 1 H), 5.52 (br s, 2 H), 4.60 - 4.74 (m, 1 H), 3.90 (br d, J=7.44 Hz, 1 H), 3.40 - 3.58 (m, 2 H), 3.18 - 3.25 (m, 1 H), 2.88 (s, 4 H), 2.17 (s, 3 H), 1.29 (m, H), 1.25 - 1.44 (m, 4 H), 0.89 (t, J=7.01 Hz, 3 H). LCMS (Method E): [M+H]+= 381.1920 SFC: RT = 6.21 min, 94% ee. SOR: - 58.

[0302] Example 19: Synthesis of 4-[3-(5-amino-6-methyl-pyrazin-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 23)

[0303] Step a) 1-Methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0304] Following the procedure in example 1 step e but using anhydrous THF as solvent andpurification by FCC (irregular silica, 0-73% EtOAc in heptane), 1-methyl-3-propyl-piperazin-2-one hydrochloride (391 mg, 2.0 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (503 mg, 2.0 mmol) were used to prepare 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoyl]piperazin-2-one (393 mg, 3:1 mixture of boronic ester and boronic acid) as an oil.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 7.78 (d, J=7.06 Hz, 1 H), 7.62 - 7.72 (m, 1 H), 7.45 - 7.55 (m, 2 H), 3.84 (br s, 1 H), 3.38 - 3.61 (m, 2 H), 3.12 - 3.30 (m, 1 H), 2.97 (s, 3 H), 1.77 - 1.94 (m, 2 H), 1.39 - 1.46 (m, 2 H), 1.34 (s, 12 H), 1.21 (t, J=7.06 Hz, 1 H), 0.91 (t, J=7.30 Hz, 3 H). LCMS (Method F): [M+H]+= 386.9.

[0305] Step b) 4-[3-(5-Amino-6-methyl-pyrazin-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-oneAttorney Docket No.60185-706601

[0306] Following the procedure in example 10 step g at 90ºC and using K2CO3, 5-bromo-3-methyl-pyrazin-2-amine (65 mg, 0.3 mmol) and 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoyl]piperazin-2-one (134 mg, 0.3 mmol) were used to prepare 4-[3-(5-amino- 6-methyl-pyrazin-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (62 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.39 (s, 1 H), 8.00 (d, J=7.45 Hz, 1 H), 7.93 (s, 1 H), 7.50 (t, J=7.72 Hz, 1 H), 7.32 (d, J=7.26 Hz, 1 H), 5.99 (br s, 2 H), 4.62 - 4.77 (m, 1 H), 3.79 - 4.01 (m, 1 H), 3.42 - 3.57 (m, 2 H), 3.14 - 3.31 (m, 1 H), 2.89 (s, 3 H), 2.36 - 2.48 (m, 3 H), 1.76 - 1.99 (m, 2 H), 1.45 (dq, J=14.76, 7.35 Hz, 2 H), 0.92 (t, J=7.30 Hz, 3 H). LCMS (Method E): [M+H]+= 368.1699.

[0307] Example 20: Synthesis of 3-(cyclopropylmethyl)-1-methyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]piperazin-2-one (Compound 24)

[0308] Step a) 3-(Cyclopropylmethyl)-1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0309] Following the procedure in example 19 step a and purification by FCC (irregular silica, 0-70% EtOAc in heptane), 3-(cyclopropylmethyl)-1-methyl-piperazin-2-one;hydrochloride (543 mg, 2.7 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (658 mg, 2.7 mmol) were used to prepare 3-(cyclopropylmethyl)-1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzoyl]piperazin-2-one (1.5 g) as an oil. LCMS (Method C): [M+H]+= 399.3

[0310] Step b) 3-(Cyclopropylmethyl)-1-methyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]piperazin-2-oneAttorney Docket No.60185-706601

[0311] Following the procedure in example 19 step b but purification by FCC (irregular silica, 0-7%MeOH in DCM) followed by RP purification (Phenomenex Gemini C1830x100mm 5µm Column [73% [25mM NH4HCO3] - 28% [MeCN: MeOH 1:1] to 36% [25mM NH4HCO3] - 64% [MeCN: MeOH 1:1]), 3-(cyclopropylmethyl)-1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoyl]piperazin-2-one (300 mg, 0.5 mmol) and 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (112 mg, 0.5 mmol) were used to prepare 3-(cyclopropylmethyl)-1-methyl-4-[3-(3-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)benzoyl]piperazin-2-one (71 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 12.99 (s, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H), 3.96 (s, 1H), 3.68 – 3.43 (m, 2H), 3.24 (d, J = 11.7 Hz, 1H), 2.89 (s, 3H), 2.57 (s, 3H), 1.91 – 1.72 (m, 2H), 0.83 (s, 1H), 0.55 – 0.35 (m, 2H), 0.21 – 0.09 (m, 1H), 0.09 – -0.01 (m, 1H). LCMS (Method E): [M+H]+= 404.1480.

[0312] Example 21: Synthesis of 4-[3-(6-amino-5-methyl-3-pyridyl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one (Compound 25)

[0313] Step a) 4-[3-(6-Amino-5-methyl-3-pyridyl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one

[0314] Following the procedure in example 19 step b and purification by RP (Phenomenex GeminiC1830x100mm 5µm Column [72% [25mM NH4HCO3] - 28% [MeCN: MeOH 1:1] to 36% [25mM NH4HCO3] - 64% [MeCN: MeOH 1:1]), 3-(cyclopropylmethyl)-1-methyl-4-[3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (300 mg, 0.5 mmol) and 5-bromo-3-methyl- pyridin-2-amine (99 mg, 0.5 mmol) were used to prepare 4-[3-(6-amino-5-methyl-3- pyridyl)benzoyl]-3-(cyclopropylmethyl)-1-methyl-piperazin-2-one (71 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.15 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 9.6 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 5.53 (s, 2H), 4.78 (s, 1H), 3.91 (s, 1H), 3.64 – 3.41 (m, 2H), 3.32 – 3.13 (m, 1H), 2.89 (s, 3H), 2.16 (s, 3H), 1.85 – 1.75 (m, 2H), 0.93 – 0.72Attorney Docket No.60185-706601 (m, 1H), 0.51 – 0.32 (m, 2H), 0.18 – 0.09 (m, 1H), 0.09 – 0.00 (m, 1H). LCMS (Method E): [M+H]+= 379.1616.

[0315] Example 22: Synthesis of 4-[3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 26)

[0316] Step a) 4-[3-(3-Chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0317] Following the procedure in example 19 step b at 80ºC and purification by RP (PhenomenexGemini C1830x100mm 5µm Column, from 81% [0.1% HCOOH] - 19% MeCN to 45% [0.1% HCOOH] - 55% MeCN), 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoyl]piperazin-2-one (133 mg, 0.3 mmol) and 5-bromo-3-chloro-1H-pyrazolo[3,4-b]pyridine (80 mg, 0.3 mmol) were used to prepare 4-[3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-1- methyl-3-propyl-piperazin-2-one (13 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.93 (d, J=2.10 Hz, 1 H), 8.35 - 8.40 (m, 1 H), 7.88 (d, J=8.01 Hz, 1 H), 7.78 - 7.81 (m, 1 H), 7.58 - 7.65 (m, 1 H), 7.43 - 7.47 (m, 1 H), 4.65 - 4.83 (m, 1 H), 3.81 - 4.02 (m, 1 H), 3.45 - 3.62 (m, 2 H), 3.20 - 3.29 (m, 1 H), 2.89 (s, 3 H), 1.84 - 1.93 (m, 2 H), 1.41 - 1.51 (m, 2 H), 0.92 (t, J=7.30 Hz, 3 H). LCMS (Method E): [M+H]+= 412.0864.

[0318] Example 23: Synthesis of 4-[3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 27)

[0319] Step a) 4-[3-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-oneAttorney Docket No.60185-706601

[0320] Following the procedure in example 19 step b at 80ºC during 48 h and purification by RP(Phenomenex Gemini C1830x100mm 5µm Column, from 75% [25mM NH4HCO3] - 25% [MeCN:MeOH (1:1)] to 38% [25mM NH4HCO3] - 62% [MeCN:MeOH (1:1)]), 1-methyl-3-propyl- 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (127 mg, 0.3 mmol) and 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (65 mg, 0.3 mmol) were used to prepare 4-[3-(2,3- dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (27 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.01 - 8.05 (m, 1 H), 7.61 - 7.64 (m, 1 H), 7.55 - 7.58 (m, 1 H), 7.51 - 7.53 (m, 1 H), 7.45 - 7.50 (m, 1 H), 7.25 - 7.29 (m, 1 H), 6.15 - 6.27 (m, 1 H), 4.62 - 4.77 (m, 1 H), 3.80 - 3.94 (m, 1 H), 3.54 - 3.60 (m, 2 H), 3.39 - 3.52 (m, 2 H), 3.16 - 3.24 (m, 1 H), 3.02 - 3.10 (m, 2 H), 2.86 - 2.90 (m, 3 H), 1.79 - 1.92 (m, 2 H), 1.37 - 1.49 (m, 2 H), 0.87 - 0.94 (m, 3 H). LCMS (Method E): [M+H]+= 379.1662.

[0321] Example 24: Synthesis of 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 28)

[0322] Step a) 4-[3-(6-Amino-5-fluoro-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0323] Following the procedure in example 10 step g at 80ºC, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (200 mg, 0.5 mmol) and 5-bromo-3- fluoro-pyridin-2-amine (89 mg, 0.5 mmol) were used to prepare 4-[3-(6-amino-5-fluoro-3-Attorney Docket No.60185-706601 pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (36 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.15 - 8.21 (m, 1 H), 7.76 - 7.83 (m, 1 H), 7.71 - 7.75 (m, 1 H), 7.65 (br s, 1 H), 7.50 (t, J=7.68 Hz, 1 H), 7.27 - 7.36 (m, 1 H), 6.36 - 6.45 (m, 2 H), 4.83 - 4.98 (m, 1 H), 3.42 - 3.68 (m, 3 H), 3.06 - 3.18 (m, 1 H), 2.85 (s, 3 H), 1.76 - 1.91 (m, 2 H), 1.37 - 1.49 (m, 2 H), 0.95 (br s, 3 H). LCMS (Method E): [M+H]+= 371.1419.

[0324] Example 25: Synthesis of 4-[3-(3-amino-2H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 29)

[0325] Step a) 4-[3-(3-Amino-2H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0326] Following the procedure in example 10 step g at 90ºC and purification FCC (irregular silica,0-55% EtOAc in heptane), 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoyl]piperazin-2-one (127 mg, 0.3 mmol) and 5-bromo-2H-pyrazolo[3,4-b]pyridin-3-amine (70 mg, 0.3 mmol) were used to prepare 4-[3-(3-amino-2H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-1- methyl-3-propyl-piperazin-2-one (34 mg) as a solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.69 (d, J=2.19 Hz, 1 H), 8.44 (d, J=2.19 Hz, 1 H), 7.79 (br d, J=8.11 Hz, 1 H), 7.69 (s, 1 H), 7.58 (t, J=7.72 Hz, 1 H), 7.39 (d, J=7.53 Hz, 1 H), 5.23 - 5.41 (m, 1 H), 4.73 (br s, 1 H), 3.82 - 3.97 (m, 1 H), 3.43 - 3.58 (m, 2 H), 3.24 (br d, J=12.02 Hz, 1 H), 2.89 (s, 3 H), 1.88 (br dd, J=10.44, 6.34 Hz, 2 H), 1.39 - 1.52 (m, 2 H), 0.92 (t, J=7.34 Hz, 3 H). LCMS (Method E): [M+H]+= 393.1467.

[0327] Example 26: Synthesis of 4-[3-(6-amino-5-methyl-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 30)

[0328] Step a) 4-[3-(6-amino-5-methyl-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-oneAttorney Docket No.60185-706601

[0329] Following procedure in example 1 step c, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one, (57 mg, 0.4 mmol) and 5-bromo-3-methyl-pyridin-2- amine (97 mg, 0.5 mmol) in dioxane:H2O were stirred at 80ºC for 16 h. Purification by FCC (irregular silica, 50% EtOAc in DCM, then 0-5% MeOH in DCM) afforded 4-[3-(6-amino-5-methyl- 3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (60 mg) as a slightly brown solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.13 - 8.18 (m, 1 H), 7.65 (d, J=7.82 Hz, 1 H), 7.58 (d, J=1.24 Hz, 1 H), 7.54 (s, 1 H), 7.48 (t, J=7.63 Hz, 1 H), 7.24 - 7.30 (m, 1 H), 5.54 (br s, 2 H), 4.69 (br d, J=6.77 Hz, 1 H), 3.77 - 3.95 (m, 1 H), 3.40 - 3.55 (m, 2 H), 3.17 - 3.25 (m, 1 H), 2.86 - 2.89 (m, 3 H), 2.13 - 2.19 (m, 3 H), 1.89 (s, 2 H), 1.37 - 1.48 (m, 2 H), 0.86 - 0.95 (m, 3 H). LCMS (Method E): [M+H]+= 367.1664.

[0330] Example 27: Synthesis of 1-methyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-3-propyl-piperazin-2-one (Compound 31)

[0331] Step a) 1-methyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-3-propyl-piperazin-2-one

[0332] A RBF was charged with 1-methyl-3-propyl-piperazin-2-one hydrochloride (125 mg, 0.5mol) and 3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoic acid (150 mg, 0.3 mmol). DMF (1.5 mL), T3P (210 μL, 0.3 mmol) and DIPEA (155 μL, 0.9 mmol) were added and the reaction mixture was stirred at RT for 48 h. The reaction mixture was diluted with water. The product was extracted with EtOAc (3x), and the combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-5% DCM in MeOH) afforded impure 1- methyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-3-propyl-piperazin-2-one which was further purified by RP HPLC (Phenomenex Gemini C1830x100mm 5µm Column, from 72% [25mM NH4HCO3] - 28% [MeCN:MeOH (1:1)] to 36% [25mM NH4HCO3] - 64% [MeCN:MeOH (1:1)]). Resulting solution was lyophilized to afford 1-methyl-4-[3-(3-methyl-1H-pyrazolo[3,4- b]pyridin-5-yl)benzoyl]-3-propyl-piperazin-2-one (29 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.79 - 8.83 (m, 1 H), 8.42 - 8.47 (m, 1 H), 7.83 - 7.89 (m, 1 H), 7.76 (s, 1 H), 7.57 - 7.63 (m, 1 H), 7.40 - 7.44 (m, 1 H), 4.65 - 4.81 (m, 1 H), 3.84 - 3.99 (m, 1 H), 3.43 - 3.62 (m, 2 H), 3.19 - 3.27 (m, 1 H), 2.88 - 2.92 (m, 3 H), 2.58 (s, 3 H), 1.83 - 1.93 (m, 2 H), 1.42 - 1.51 (m, 2Attorney Docket No.60185-706601 H), 0.92 (br t, J=7.20 Hz, 3 H), N-H signal not observed, 1H signal overlaps with water peak. LCMS (Method E): [M+H]+= 392.1875.

[0333] Example 28: Synthesis of 3-(cyclopropylmethyl)-1-methyl-4-[3-[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoyl]piperazin-2-one (Compound 32)

[0334] Step a) 3-(cyclopropylmethyl)-1-methyl-4-[3-[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoyl]piperazin-2-one

[0335] Following procedure in example 1 step c, 3-(cyclopropylmethyl)-1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (184 mg, 0.5 mmol), 5-bromo-3- (trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (123 mg, 0.5 mmol), and potassium carbonate (140 mg, 1 mmol) in dioxane:H2O were stirred at 90ºC for 16 h. Purification by FCC (irregular silica, 0- 50% EtOAc in DCM, then 0-5% MeOH in DCM) afforded impure 3-(cyclopropylmethyl)-1-methyl- 4-[3-[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoyl]piperazin-2-one which was further purified by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 70% [25mM NH4HCO3] - 30% [MeCN:MeOH (1:1)] to 27% [25mM NH4HCO3] - 73% [MeCN:MeOH (1:1)]).Resulting solution was lyophilized to afford 3-(cyclopropylmethyl)-1-methyl-4-[3-[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoyl]piperazin-2-one (15 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.92 (d, J=2.10 Hz, 1 H), 8.37 (s, 1 H), 7.82 (d, J=7.82 Hz, 1 H), 7.73 (s, 1 H), 7.55 (t, J=7.68 Hz, 1 H), 7.40 (d, J=7.63 Hz, 1 H), 4.64 - 4.78 (m, 1 H), 3.74 - 4.00 (m, 1 H), 3.40 - 3.60 (m, 2 H), 3.14 - 3.20 (m, 1 H), 2.83 (s, 3 H), 1.75 (br t, J=7.10 Hz, 2 H), 0.76 (br s, 1 H), 0.28 - 0.45 (m, 2 H), -0.09 - 0.13 (m, 2 H), N-H signal not observed. LCMS (Method B): [M+H]+= 458.1616.

[0336] Example 29: Synthesis of 1-methyl-3-propyl-4-[3-[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoyl]piperazin-2-one (Compound 33)

[0337] Step a) 1-methyl-3-propyl-4-[3-[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoyl]piperazin-2-oneAttorney Docket No.60185-706601

[0338] Following procedure in example 1 step c, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (200 mg, 0.5 mmol), 5-bromo-3-(trifluoromethyl)-1H- pyrazolo[3,4-b]pyridine (139 mg, 0.5 mmol) and potassium carbonate (158 mg, 1.1 mmol) in dioxane:H2O were stirred at 90ºC for 40 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded impure 1-methyl-3-propyl-4-[3-[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5- yl]benzoyl]piperazin-2-one which was further purified by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 81% [25mM NH4HCO3] - 19% [MeCN:MeOH (1:1)] to 45% [25mMNH4HCO3] - 55% [MeCN:MeOH (1:1)]). Resulting solution was lyophilized to afford 1-methyl-3-propyl-4-[3-[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]benzoyl]piperazin-2-one (16 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.99 (d, J=2.10 Hz, 1 H), 8.44 (s, 1 H), 7.88 (d, J=7.54 Hz, 1 H), 7.79 (s, 1 H), 7.62 (t, J=7.68 Hz, 1 H), 7.46 (d, J=7.44 Hz, 1 H), 4.57 - 4.83 (m, 1 H), 3.77 - 3.99 (m, 1 H), 3.45 - 3.57 (m, 2 H), 3.19 - 3.26 (m, 1 H), 2.88 (s, 3 H), 1.82 - 1.93 (m, 2 H), 1.40 - 1.50 (m, 2 H), 0.91 (t, J=7.25 Hz, 3 H), N-H signal not observed. LCMS (Method B): [M+H]+= 446.1542.

[0339] Example 30: Synthesis of 4-[3-[6-amino-5-(trifluoromethyl)-3-pyridyl]benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 34)

[0340] Step a) 4-[3-[6-amino-5-(trifluoromethyl)-3-pyridyl]benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0341] Following procedure in example 1 step c, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (200 mg, 0.5 mmol), 5-bromo-3- (trifluoromethyl)pyridin-2-amine (125 mg, 0.5 mmol) in dioxane:H2O were stirred at 80ºC for 16 h. Purification by FCC (irregular silica, 50% EtOAc in DCM, then 0-5% MeOH in DCM) afforded 4- [3-[6-amino-5-(trifluoromethyl)-3-pyridyl]benzoyl]-1-methyl-3-propyl-piperazin-2-one (69 mg) as a beige solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ ppm 8.57 (s, 1 H), 8.01 (d, J=1.91 Hz, 1 H), 7.74 (d, J=7.92 Hz, 1 H), 7.65 (s, 1 H), 7.54 (t, J=7.68 Hz, 1 H), 7.36 (d, J=7.53 Hz, 1 H), 6.24 (br s, 2 H), 3.43 - 3.54 (m, 2 H), 3.23 (s, 1 H), 2.88 (s, 3 H), 1.81 - 1.93 (m, 2 H), 1.39 - 1.49 (m, 2 H), 0.91 (t, J=7.34 Hz, 3 H). LCMS (Method E): [M+H]+= 421.1636.

[0342] Example 31: Synthesis of 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 35)Attorney Docket No.60185-706601

[0343] Step a) 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0344] Following procedure in example 1 step c, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (230 mg, 0.6 mol), 5-bromo-3-chloro-pyridin-2-amine (124 mg, 0.6 mol) in dioxane:H2O were stirred at 80ºC for 16 h . Purification by FCC (irregular silica, 50% EtOAc in DCM, then 0-5% MeOH in DCM) afforded impure 4-[3-(6-amino-5-chloro-3- pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one which was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3(sat. sol.) and extracted with CHCl3:IPA (3:1). Organics were combined, dried over MgSO4, filtered, and concentrated. Resulting oil was lyophilized to afford 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (17 mg) as an off-white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.28 (d, J=2.10 Hz, 1 H), 7.90 (d, J=2.00 Hz, 1 H), 7.67 - 7.72 (m, 1 H), 7.63 (br d, J=0.86 Hz, 1 H), 7.47 - 7.54 (m, 1 H), 7.29 - 7.35 (m, 1 H), 5.85 - 6.25 (m, 2 H), 4.56 - 4.79 (m, 1 H), 3.76 - 3.96 (m, 1 H), 3.39 - 3.60 (m, 2 H), 3.16 - 3.24 (m, 1 H), 2.88 (s, 3 H), 1.78 - 1.94 (m, 2 H), 1.38 - 1.50 (m, 2 H), 0.91 (t, J=7.30 Hz, 3 H). LCMS (Method E): [M+H]+= 387.1346.

[0345] Example 32: Synthesis of 4-[3-(5-aminopyrazin-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 36)

[0346] Step a) 4-[3-(5-aminopyrazin-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0347] Following procedure in example 1 step c, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (333 mg, 0.9 mmol), 5-bromopyrazin-2-amine (150 mg, 0.9 mmol), and potassium carbonate (262 mg, 1.9 mmol) in dioxane:H2O were stirred at 80ºC for 16 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded impure 4-[3-(5- aminopyrazin-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one which was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3 (sat. sol.) and extracted with EtOAc. Organics were combined, dried over MgSO4, filtered, and concentrated. Resulting oil was lyophilized to afford 4-[3-(5-aminopyrazin-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (57Attorney Docket No.60185-706601 mg) as an off-white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.52 (d, J=1.34 Hz, 1 H), 7.99 - 8.04 (m, 2 H), 7.92 (t, J=1.53 Hz, 1 H), 7.52 (t, J=7.72 Hz, 1 H), 7.34 (dt, J=7.58, 1.26 Hz, 1 H), 6.28 (br s, 2 H), 4.71 (br s, 1 H), 3.88 (br s, 1 H), 3.41 - 3.57 (m, 2 H), 3.17 - 3.27 (m, 1 H), 2.89 (s, 3 H), 1.79 - 1.94 (m, 2 H), 1.44 (dq, J=14.85, 7.32 Hz, 2 H), 0.91 (t, J=7.30 Hz, 3 H). LCMS (Method B): [M+H]+= 354.2073.

[0348] Example 33: Synthesis of 4-[3-(5-amino-6-methyl-pyrazin-2-yl)benzoyl]-1-methyl-3-(3,3,3-trifluoropropyl)piperazin-2-one (Compound 37)

[0349] Step a) 4-[3-(5-amino-6-methyl-pyrazin-2-yl)benzoyl]-1-methyl-3-(3,3,3-trifluoropropyl)piperazin-2-one

[0350] Following procedure in example 1 step c, 1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-3-(3,3,3-trifluoropropyl)piperazin-2-one (178 mg, 0.4 mmol) and 5- bromo-3-methyl-pyrazin-2-amine (76 mg, 0.4 mmol) in dioxane:H2O were stirred at 80ºC for 16 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded 4-[3-(5-amino-6-methyl- pyrazin-2-yl)benzoyl]-1-methyl-3-(3,3,3-trifluoropropyl)piperazin-2-one (86 mg) as a beige solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.57 (s, 1 H), 8.01 (d, J=1.91 Hz, 1 H), 7.74 (d, J=7.92 Hz, 1 H), 7.65 (s, 1 H), 7.54 (t, J=7.68 Hz, 1 H), 7.36 (d, J=7.53 Hz, 1 H), 6.24 (br s, 2 H), 3.43 - 3.54 (m, 2 H), 3.23 (s, 1 H), 2.88 (s, 3 H), 1.81 - 1.93 (m, 2 H), 1.39 - 1.49 (m, 2 H), 0.91 (t, J=7.34 Hz, 3 H), 1H signal overlaps with DMSO peak. LCMS (Method E): [M+H]+= 422.1912.

[0351] Example 34: Synthesis of 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1-methyl-3-(3,3,3-trifluoropropyl)piperazin-2-one (Compound 38)

[0352] Step a) 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1-methyl-3-(3,3,3-trifluoropropyl)piperazin-2-one

[0353] Following procedure in example 1 step c, 1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-3-(3,3,3-trifluoropropyl)piperazin-2-one (178 mg, 0.4 mmol) and 5-Attorney Docket No.60185-706601 bromo-3-fluoro-pyridin-2-amine (77 mg, 0.4 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded impure 4-[3-(5-amino-6- methyl-pyrazin-2-yl)benzoyl]-1-methyl-3-(3,3,3-trifluoropropyl)piperazin-2-one which was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3(sat. sol.), extracted with DCM, dried over MgSO4, filtered, and concentrated to afford 4-[3-(6-amino-5-fluoro- 3-pyridyl)benzoyl]-1-methyl-3-(3,3,3-trifluoropropyl)piperazin-2-one (34 mg) as an off-white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.12 - 8.22 (m, 1 H), 7.69 - 7.77 (m, 2 H), 7.63 - 7.68 (m, 1 H), 7.47 - 7.57 (m, 1 H), 7.37 (br d, J=7.82 Hz, 1 H), 5.93 - 6.08 (m, 2 H), 4.65 - 4.89 (m, 1 H), 3.71 - 3.93 (m, 1 H), 3.44 - 3.64 (m, 2 H), 3.14 - 3.30 (m, 1 H), 2.91 (s, 3 H), 2.33 - 2.48 (m, 2 H), 2.01 - 2.29 (m, 2 H). LCMS (Method B): [M+H]+= 425.1877.

[0354] Example 35: Synthesis of 4-[3-(6-amino-2,5-dimethyl-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 39)

[0355] Step a) 4-[3-(6-amino-2,5-dimethyl-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0356] Following procedure in example 1 step c, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (75 mg, 0.2 mmol), 5-bromo-3,6-dimethyl-pyridin-2- amine (39 mg, 0.2 mmol), and potassium carbonate (59 mg, 0.4 mmol) in dioxane:H2O were stirred at 90ºC for 16 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded impure 4-[3- (6-amino-2,5-dimethyl-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one was further purified by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 72% [25mM NH4HCO3] - 28% [MeCN:MeOH (1:1)] to 36% [25mM NH4HCO3] - 64% [MeCN:MeOH (1:1)]). Resulting solution was lyophilized to afford 4-[3-(6-amino-2,5-dimethyl-3-pyridyl)benzoyl]-1-methyl-3-propyl- piperazin-2-one (15 mg) as white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 7.45 - 7.51 (m, 1 H), 7.38 (d, J=7.82 Hz, 1 H), 7.31 (d, J=7.53 Hz, 1 H), 7.27 (s, 1 H), 7.11 (s, 1 H), 5.36 (s, 2 H), 4.68 (br s, 1 H), 3.81 - 3.98 (m, 1 H), 3.35 - 3.62 (m, 2 H), 3.16 - 3.26 (m, 1 H), 2.87 (s, 3 H), 2.23 (s, 3 H), 2.08 (s, 3 H), 1.73 - 1.95 (m, 2 H), 1.31 - 1.50 (m, 2 H), 0.88 (t, J=7.30 Hz, 3 H). LCMS (Method B): [M+H]+= 381.2468.

[0357] Example 36: Synthesis of 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1-ethyl-3-propyl-piperazin-2-one (Compound 40)

[0358] Step a) tert-Butyl 4-ethyl-3-oxo-2-propyl-piperazine-1-carboxylateAttorney Docket No.60185-706601

[0359] Following procedure in example 2 step b, tert-butyl 4-ethyl-3-oxo-piperazine-1-carboxylate(2.0 g, 8.8 mmol) and 1-bromopropane (2.4 mL, 26.6 mmol) were used to prepare tert-butyl 4-ethyl- 3-oxo-2-propyl-piperazine-1-carboxylate. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded tert-butyl 4-ethyl-3-oxo-2-propyl-piperazine-1-carboxylate (870 mg) was recovered as a yellow oil.1H NMR (300 MHz, DMSO-d6) δ 4.18 - 4.33 (m, 1 H), 3.81 - 3.99 (m, 1 H), 3.36 (br d, J=4.31 Hz, 1 H), 3.26 - 3.31 (m, 2 H), 3.17 - 3.25 (m, 2 H), 1.63 - 1.78 (m, 2 H), 1.41 (s, 9 H), 1.26 - 1.37 (m, 2 H), 0.97 - 1.07 (m, 3 H), 0.85 - 0.93 (m, 3 H). LCMS (Method C): [M+H]+= 271.2.

[0360] Step b) 1-Ethyl-3-propyl-piperazin-2-one hydrochloride

[0361] Following procedure in example 2 step c, tert-butyl 4-ethyl-3-oxo-2-propyl-piperazine-1-carboxylate (413 mg, 1.5 mmol) was used to prepare 1-ethyl-3-propyl-piperazin-2-one hydrochloride (371 mg, crude) as a light pink oil.1H NMR (400 MHz, D2O) δ 3.90 - 3.97 (m, 1 H), 3.62 - 3.68 (m, 1 H), 3.52 - 3.60 (m, 2 H), 3.28 - 3.45 (m, 3 H), 1.92 - 2.09 (m, 1 H), 1.69 - 1.81 (m, 1 H), 1.39 (br d, J=8.01 Hz, 2 H), 1.07 (t, J=7.20 Hz, 3 H), 0.89 (t, J=7.30 Hz, 3 H). LCMS (Method C): [M+H]+= 171.32.

[0362] Step c) 1-Ethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0363] Following procedure in example 1 step e, 1-ethyl-3-propyl-piperazin-2-one hydrochloride(823 mg, 2.6 mmol) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (814 mg, 2.7 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-30% EtOAc in heptane)Attorney Docket No.60185-706601 afforded 1-ethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (600 mg) as a colourless oil.1H NMR (400 MHz, DMSO-d6) δ 7.74 - 7.80 (m, 1 H), 7.61 - 7.69 (m, 1 H), 7.53 - 7.61 (m, 1 H), 7.45 - 7.52 (m, 1 H), 4.75 - 4.96 (m, 1 H), 3.39 - 3.67 (m, 3 H), 3.08 - 3.22 (m, 1 H), 1.62 - 1.90 (m, 10 H), 1.31 - 1.46 (m, 2 H), 1.03 (t, J=7.06 Hz, 3 H), 0.92 (t, J=7.34 Hz, 15 H), 2H overlap with water signal. LCMS (Method D): [M+H]+= 457.3.

[0364] Step d) 4-[3-(6-Amino-5-fluoro-3-pyridyl)benzoyl]-1-ethyl-3-propyl-piperazin-2-one

[0365] Following procedure in example 1 step c, 1-ethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (150 mg, 0.3 mmol) and 5-bromo-3-fluoro-pyridin-2- amine (66 mg, 0.3 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. The crude mixture was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3(sat. sol.), extracted with DCM, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-3% MeOH in DCM) afforded 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1-ethyl-3-propyl- piperazin-2-one (65 mg) as an off-white solid after lyophilization.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.13 - 8.19 (m, 1 H), 7.67 - 7.73 (m, 2 H), 7.59 (s, 1 H), 7.47 - 7.55 (t, 1 H), 7.29 - 7.36 (dt, 1 H), 5.98 (br s, 2 H), 4.59 - 4.74 (m, 1 H), 3.82 - 3.97 (m, 1 H), 3.41 - 3.56 (m, 2 H), 3.29 - 3.41 (m, 2 H), 3.19 - 3.28 (m, 1 H), 1.75 - 1.96 (m, 2 H), 1.44 (br d, J=7.53 Hz, 2 H), 1.09 (t, J=7.10 Hz, 3 H), 0.91 (t, J=7.30 Hz, 3 H). LCMS (Method E): [M+H]+= 385.2050.

[0366] Example 37: Synthesis of 4-[3-(5-amino-6-methyl-pyrazin-2-yl)benzoyl]-1-ethyl-3-propyl-piperazin-2-one (Compound 41)

[0367] Step a) 4-[3-(5-amino-6-methyl-pyrazin-2-yl)benzoyl]-1-ethyl-3-propyl-piperazin-2-one

[0368] Following procedure in example 1 step c, 1-ethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (150 mg, 0.3 mmol) and 5-bromo-3-methyl-pyrazin-2- amine (65 mg, 0.3 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Crude was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3(sat. sol.), extracted withAttorney Docket No.60185-706601 DCM, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-4% MeOH in DCM) afforded 4-[3-(5-amino-6-methyl-pyrazin-2-yl)benzoyl]-1-ethyl-3-propyl- piperazin-2-one (75 mg) as a white solid after lyophilization.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.39 (s, 1 H), 7.96 - 8.05 (m, 1 H), 7.88 - 7.95 (m, 1 H), 7.47 - 7.54 (m, 1 H), 7.32 (d, J=7.53 Hz, 1 H), 5.95 - 6.04 (m, 2 H), 4.59 - 4.73 (m, 1 H), 3.83 - 3.99 (m, 1 H), 3.43 - 3.56 (m, 2 H), 3.31 - 3.43 (m, 2 H), 3.20 - 3.29 (m, 1 H), 2.42 (s, 3 H), 1.76 - 1.95 (m, 2 H), 1.36 - 1.50 (m, 2 H), 1.09 (t, J=7.10 Hz, 3 H), 0.91 (t, J=7.30 Hz, 3 H). LCMS (Method E): [M+H]+= 382.2396.

[0369] Example 38: 4-[3-[6-amino-5-(difluoromethyl)-3-pyridyl]benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 42)

[0370] Step a) 2-chloro-3-(difluoromethyl)pyridine

[0371] DAST (8 mL, 60.6 mmol) was added to a solution of 2-chloropyridine-3-carbaldehyde (3 g,21.2 mmol) in DCM (18 mL). The mixture was stirred at RT for 4 h and was quenched with H2O. Product was extracted with DCM (3x20 mL), and the combined organics washed with brine, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-3% EtOAc in heptane) afforded 2-chloro-3-(difluoromethyl)pyridine (1.09 g) as an orange oil.1H NMR (400 MHz, DMSO-d6) δ 8.60 (br d, J=4.77 Hz, 1 H), 8.17 (d, J=7.63 Hz, 1 H), 7.62 (dd, J=7.49, 5.01 Hz, 1 H), 7.04 - 7.42 (m, 1 H). LCMS (Method D): [M+H]+= 164.1.

[0372] Step b) N-[3-(Difluoromethyl)-2-pyridyl]-1,1-diphenyl-methanimine

[0373] Diphenylmethanimine (1.5 mL, 8.7 mmol), potassium tert-butoxide (1.50 g, 13.3 mmol), and2-chloro-3-(difluoromethyl)pyridine (1.09 g, 6.7 mmol) were solubilized in toluene (14 mL). Pd2(dba)3(305 mg, 0.33. mmol), Xantphos (193 mg, 0.33 mmol) were added, and the reaction mixture was stirred at 90°C for 3 h. Reaction mixture was concentrated and partitioned between water and EtOAc. The product was extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0- 10% EtOAc in heptane) afforded N-[3-(difluoromethyl)-2-pyridyl]-1,1-diphenyl-methanimine (706 -120-Attorney Docket No.60185-706601 mg) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J=4.48 Hz, 1 H), 7.92 (d, J=7.63 Hz, 1 H), 7.38 - 7.80 (m, 7 H), 7.28 - 7.38 (m, 3 H), 6.92 - 7.25 (m, 4 H). LCMS (Method D): [M+H]+= 309.1.

[0374] Step c) 3-(difluoromethyl)pyridin-2-amine

[0375] Hydrogen chloride (4M in dioxane, 3 mL, 12 mmol), was added to a solution of N-[3-(difluoromethyl)-2-pyridyl]-1,1-diphenyl-methanimine (700 mg, 2.3 mmol) in THF (500 μL). The mixture was stirred at 40°C for 16 h. Reaction mixture was concentrated and partitioned between NaHCO3(sat. sol.) and EtOAc. The product was extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-30% EtOAc in heptane) afforded 3-(difluoromethyl)pyridin-2-amine (181 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.08 (br d, J=4.10 Hz, 1 H), 7.61 (d, J=7.44 Hz, 1 H), 7.00 (t, J=54.74 Hz, 1 H), 6.63 (dd, J=7.39, 4.91 Hz, 1 H), 6.19 (br s, 2 H). LCMS (Method D): [M+H]+= 145.1.

[0376] Step d) 5-Bromo-3-(difluoromethyl)pyridin-2-amine

[0377] N-Bromosuccinimide (279 mg, 1.6 mmol) was added portion wise to a solution of 3-(difluoromethyl)pyridin-2-amine (181 mg, 1.3 mmol) in ACN (2.5 mL) at 0ºC. The reaction mixture was stirred at 0ºC for 40 min. Reaction mixture was concentrated and partitioned between water and EtOAc. The product was extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-10% EtOAc in heptane) afforded 5-bromo-3-(difluoromethyl)pyridin-2-amine (83 mg) as a red solid.1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J=0.95 Hz, 1 H), 7.76 (s, 1 H), 6.77 - 7.28 (t, J=54 Hz, 1 H), 6.50 (s, 2 H). LCMS (Method D): [M+H]+= 223.0 / 225.0.

[0378] Step e) 1-Methyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-oneAttorney Docket No.60185-706601

[0379] Following procedure in example 1 step e, 1-methyl-3-propyl-piperazin-2-one (317 mg, 2.0mmol) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (648 mg, 2.1 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded 1- methyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (203 mg) as a white foam.1H NMR (400 MHz, DMSO-d6) δ 7.73 - 7.87 (m, 1 H), 7.69 (s, 1 H), 7.46 - 7.56 (m, 2 H), 4.62 (br s, 1 H), 3.86 (br s, 1 H), 3.37 - 3.56 (m, 2 H), 3.18 - 3.26 (m, 1 H), 2.88 (s, 3 H), 1.69 - 1.87 (m, 10 H), 1.42 (dq, J=14.82, 7.39 Hz, 2 H), 0.97 (t, J=7.44 Hz, 12 H), 0.87 - 0.93 (m, 3 H). LCMS (Method D): [M+H]+= 443.3.

[0380] Step f) 4-[3-[6-Amino-5-(difluoromethyl)-3-pyridyl]benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0381] Following procedure in example 1 step c, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (200 mg, 0.5 mmol), 5-bromo-3- (difluoromethyl)pyridin-2-amine (101 mg 0.5 mmol), and potassium carbonate (137 mg, 1.0 mmol in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-45% EtOAc in heptane) afforded impure 4-[3-[6-amino-5-(difluoromethyl)-3-pyridyl]benzoyl]-1-methyl-3-propyl- piperazin-2-one was further purified by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 72% [25mM NH4HCO3] - 28% MeCN to 36% [25mM NH4HCO3] - 64% MeCN). Resulting solution was lyophilized to afford4-[3-[6-amino-5-(difluoromethyl)-3-pyridyl]benzoyl]-1-methyl-3- propyl-piperazin-2-one (58 mg) as white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.46 (s, 1 H), 7.93 (d, J=1.05 Hz, 1 H), 7.71 (d, J=7.92 Hz, 1 H), 7.60 (s, 1 H), 7.53 (t, J=7.68 Hz, 1 H), 7.34 (d, J=7.53 Hz, 1 H), 7.06 (t, J=54.69 Hz, 1 H), 6.08 (br s, 2 H), 4.60 - 4.84 (m, 1 H), 3.77 - 4.00 (m, 1 H), 3.40 - 3.62 (m, 2 H), 3.17 - 3.27 (m, 1 H), 2.88 (s, 3 H), 1.79 - 1.93 (m, 2 H), 1.44 (sxt, J=7.34 Hz, 2 H), 0.91 (t, J=7.34 Hz, 3 H). LCMS (Method E): [M+H]+= 403.1409.

[0382] Example 39: Synthesis 2-amino-5-[3-(4-methyl-3-oxo-2-propyl-piperazine-1-carbonyl)phenyl]pyridine-3-carbonitrile (Compound 43) -122-Attorney Docket No.60185-706601

[0383] Step a) 4-[3-(6-amino-2,5-dimethyl-3-pyridyl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0384] Following procedure in example 1 step c, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (147 mg, 0.3 mmol), 2-amino-5-bromo-pyridine-3- carbonitrile (66 mg, 0.3 mmol), and potassium carbonate (101 mg, 0.7 mmol) in dioxane:H2O were stirred at 90ºC for 16 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded impure 2-amino-5-[3-(4-methyl-3-oxo-2-propyl-piperazine-1-carbonyl)phenyl]pyridine-3-carbonitrile which was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3 (sat. sol.), extracted with EtOAc, dried over MgSO4, filtered, and concentrated to afford 2-amino-5-[3-(4- methyl-3-oxo-2-propyl-piperazine-1-carbonyl)phenyl]pyridine-3-carbonitrile (60 mg) as an off- white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.58 (d, J=2.48 Hz, 1 H), 8.20 (d, J=2.38 Hz, 1 H), 7.73 (d, J=7.92 Hz, 1 H), 7.65 (s, 1 H), 7.53 (t, J=7.72 Hz, 1 H), 7.35 (d, J=7.63 Hz, 1 H), 6.68 (br s, 2 H), 4.60 - 4.78 (m, 1 H), 3.78 - 3.93 (m, 1 H), 3.43 - 3.55 (m, 2 H), 3.15 - 3.27 (m, 1 H), 2.89 (s, 3 H), 1.80 - 1.93 (m, 2 H), 1.39 - 1.50 (m, 2 H), 0.92 (t, J=7.25 Hz, 3 H). LCMS (Method E): [M+H]+= 378.2793.

[0385] Example 40: Synthesis of 5-[3-[2-(cyclopropylmethyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2-one (Compound 44)

[0386] Step a) 5-Bromospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2-one

[0387] Sodium hydride (540 mg, 14 mmol) was added portion-wise to a stirring solution of 5-bromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one (500 mg, 2.3 mmol) and 1,2-dibromoethane (610 μL, 7.0 mmol) in DMF (5.5 mL) at 0ºC. The mixture was stirred at RT for 2 h. The reaction was cooledto 0ºC and then quenched NaHCO3 (sat. sol.) and extracted with EtOAc (x3). Organic layers werecombined, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0- 80% EtOAc in heptane) afforded 5-bromospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2-one (294 mg,) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 11.34 (br s, 1 H), 8.16 (d, J=2.22Attorney Docket No.60185-706601 Hz, 1 H), 7.67 (d, J=2.22 Hz, 1 H), 1.68 - 1.79 (m, 2 H), 1.55 (q, J=3.95 Hz, 2 H). LCMS (Method D): [M+H]+= 239.0 / 241.0.

[0388] Step b) 5-[3-[2-(Cyclopropylmethyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2-one

[0389] Following procedure in example 1 step c, 3-(cyclopropylmethyl)-1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (181 mg, 0.3 mmol) and 5- bromospiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2-one (80 mg, 0.3 mmol) in dioxane:H2O were stirred at 80ºC for 16 h. Purification by FCC (irregular silica, 0-50% EtOAc in DCM, then 0- 5% MeOH in DCM) afforded impure 5-[3-[2-(cyclopropylmethyl)-4-methyl-3-oxo-piperazine-1- carbonyl]phenyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2- which was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3(sat. sol.), extracted with EtOAc, dried over MgSO4, filtered, and concentrated to afford 35-[3-[2-(cyclopropylmethyl)-4- methyl-3-oxo-piperazine-1-carbonyl]phenyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,1'-cyclopropane]-2- one (61 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 10.64 - 10.92 (m, 1 H), 8.22 - 8.26 (m, 1 H), 7.60 - 7.64 (m, 1 H), 7.51 - 7.55 (m, 2 H), 7.39 - 7.45 (m, 1 H), 7.23 - 7.28 (m, 1 H), 4.48 - 4.76 (m, 1 H), 3.71 - 3.89 (m, 1 H), 3.30 - 3.53 (m, 2 H), 3.07 - 3.15 (m, 1 H), 2.75 - 2.78 (m, 3 H), 1.65 - 1.72 (m, 2 H), 1.60 - 1.64 (m, 2 H), 1.43 - 1.51 (m, 2 H), 0.62 - 0.77 (m, 1 H), 0.22 - 0.40 (m, 2 H), -0.13 - 0.05 (m, 2 H). LCMS (Method E): [M+H]+= 431.3144.

[0390] Example 41: Synthesis of 3-(cyclopropylmethyl)-1-methyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzoyl]piperazin-2-one (Compound 45)

[0391] Step a) 3-(Cyclopropylmethyl)-1-methyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzoyl]piperazin-2-one

[0392] Following procedure in example 1 step c, 3-(cyclopropylmethyl)-1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (133.55 mg, 0.2 mmol) and 5-bromo-Attorney Docket No.60185-706601 3-methyl-1H-pyrazolo[3,4-b]pyrazine (50 mg, 0.2 mmol) in dioxane:H2O were stirred at 80ºC for 16 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded 3-(cyclopropylmethyl)-1- methyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)benzoyl]piperazin-2-one (16 mg) as a white solid after lyophilization.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 13.17 - 13.31 (br s, 1 H), 8.93 - 9.02 (s, 1 H), 8.07 - 8.13 (d, 1 H), 8.01 - 8.07 (br s, 1 H), 7.49 (t, J=7.72 Hz, 1 H), 7.34 - 7.38 (br d, 1 H), 4.57 - 4.70 (m, 1 H), 3.74 - 3.91 (m, 1 H), 3.31 - 3.51 (m, 2 H), 3.05 - 3.14 (m, 1 H), 2.73 - 2.76 (m, 3 H), 2.47 (s, 3 H), 1.63 - 1.75 (m, 2 H), 0.65 - 0.75 (m, 1 H), 0.24 - 0.41 (m, 2 H), -0.13 - 0.03 (m, 2 H). LCMS (Method E): [M+H]+= 405.2101.

[0393] Example 42: Synthesis of 4-[3-(5-amino-6-methyl-pyrazin-2-yl)benzoyl]-3-[(2,2-difluorocyclopropyl)methyl]-1-methyl-piperazin-2-one (Compound 46)

[0394] Step a) 3-[(2,2-Difluorocyclopropyl)methyl]-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0395] Following procedure in example 1 step e, 3-[(2,2-difluorocyclopropyl)methyl]-1-methyl-piperazin-2-one hydrochloride (example 73 step b, 100 mg, 0.4 mmol) and 3-(4,4,5,5-tetraethyl- 1,3,2-dioxaborolan-2-yl)benzoic acid (151 mg, 0.5 mmol) were used to prepare 3-[(2,2- difluorocyclopropyl)methyl]-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2- yl)benzoyl]piperazin-2-one (138 mg) as a brown oil.1H NMR (400 MHz, DMSO-d6) δ 7.75 - 7.80 (m, 1 H), 7.54 - 7.59 (m, 1 H), 7.46 - 7.52 (m, 1 H), 4.85 - 5.10 (m, 1 H), 3.39 - 3.69 (m, 2 H), 3.06 - 3.20 (m, 1 H), 2.86 (d, J=8.96 Hz, 3 H), 2.69 (s, 7 H), 1.66 - 1.78 (m, 8 H), 0.92 (t, J=7.39 Hz, 12 H). LCMS (Method D): [M+H]+= 491.6.

[0396] Step b) 4-[3-(5-Amino-6-methyl-pyrazin-2-yl)benzoyl]-3-[(2,2-difluorocyclopropyl)methyl]-1-methyl-piperazin-2-one

[0397] Following procedure in example 1 step c, 3-[(2,2-difluorocyclopropyl)methyl]-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (90 mg, 0.2 mmol), 5-bromo-Attorney Docket No.60185-706601 3-methyl-pyrazin-2-amine (36 mg, 0.2 mmol), and cesium carbonate (120 mg, 0.4 mmol) in dioxane:H2O were stirred at 85ºC for 4 h. Purification by FCC (irregular silica, 0-3% MeOH in DCM) afforded 4-[3-(5-amino-6-methyl-pyrazin-2-yl)benzoyl]-3-[(2,2-difluorocyclopropyl)methyl]- 1-methyl-piperazin-2-one (41 mg) as a yellow solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.36 - 8.39 (m, 1 H), 7.98 - 8.03 (m, 1 H), 7.95 (br d, J=4.96 Hz, 1 H), 7.48 - 7.54 (m, 1 H), 7.34 (dd, J=7.58, 1.10 Hz, 1 H), 6.01 (br s, 2 H), 5.67 (s, 1 H), 4.76 - 4.93 (m, 1 H), 3.81 - 3.93 (m, 1 H), 3.45 - 3.59 (m, 2 H), 3.17 - 3.26 (m, 1 H), 2.90 (d, J=5.63 Hz, 3 H), 2.41 (s, 3 H), 2.09 - 2.20 (m, 1 H), 1.98 - 2.08 (m, 1 H), 1.72 - 1.85 (m, 1 H), 1.49 - 1.61 (m, 1 H). LCMS (Method B): [M+H]+= 416.2116.

[0398] Example 43: Synthesis of 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-1-ethyl-3-propyl-piperazin-2-one (Compound 47)

[0399] Step a) 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-1-ethyl-3-propyl-piperazin-2-one

[0400] Following procedure in example 1 step c, 1-ethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (200 mg, 0.4 mol) and 5-bromo-3-chloro-pyridin-2- amine (95 mg, 0.4 mmol) in dioxane:H2O were stirred at 85ºC for 2 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-1-ethyl-3-propyl- piperazin-2-one (101 mg) as a yellow solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.28 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 6.07 (s, 1H), 4.67 (s, 1H), 3.88 (s, 1H), 3.28 – 3.54 (m, 4H), 3.25 (t, J = 10.9 Hz, 1H), 1.76 – 1.94 (m, 2H), 1.43 (dd, J = 14.9, 7.4 Hz, 2H), 1.08 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H). LCMS (Method B): [M+H]+= 401.2355.

[0401] Example 44: Synthesis of 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one (Compound 48)

[0402] Step a) 3-[(2,2-Difluorocyclopropyl)methyl]-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-oneAttorney Docket No.60185-706601

[0403] Following procedure in example 1 step e, 3-butyl-1-methylpiperazin-2-one (250 mg, 1.5mmol) and 33-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (536 mg, 1.7 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-25% EtOAc in heptane) afforded 3- butyl-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (677 mg) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J=7.34 Hz, 1 H), 7.65 (br s, 1 H), 7.53 - 7.58 (m, 1 H), 7.46 - 7.52 (m, 1 H), 4.86 (br s, 1 H), 3.35 - 3.62 (m, 3 H), 3.12 (br s, 1 H), 2.84 (s, 3 H), 2.69 (s, 3 H), 1.79 - 1.94 (m, 2 H), 1.66 - 1.78 (m, 8 H), 1.22 - 1.41 (m, 4 H), 0.89 - 0.96 (m, 12 H). LCMS (Method D): [M+H]+= 457.4.

[0404] Step b) 4-[3-(6-Amino-5-chloro-3-pyridyl)benzoyl]-3-butyl-1-methyl-piperazin-2-one

[0405] Following procedure in example 1 step c, 3-butyl-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (200 mg, 0.4 mmol) and 5-bromo-3-chloro-pyridin-2- amine (95 mg, 0.5 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-2.5% MeOH in DCM) afforded 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-3- butyl-1-methyl-piperazin-2-one (125 mg) as a light-yellow foam.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.28 (d, J=2.19 Hz, 1 H), 7.90 (d, J=2.19 Hz, 1 H), 7.70 (d, J=7.92 Hz, 1 H), 7.59 (s, 1 H), 7.51 (t, J=7.68 Hz, 1 H), 7.31 (d, J=7.53 Hz, 1 H), 6.10 (br s, 2 H), 4.66 (br s, 1 H), 3.79 - 3.94 (m, 1 H), 3.41 - 3.56 (m, 2 H), 3.17 - 3.23 (m, 1 H), 2.88 (s, 3 H), 1.78 - 1.96 (m, 2 H), 1.29 - 1.40 (m, 4 H), 0.85 - 0.92 (m, 3 H). LCMS (Method B): [M+H]+= 401.1808.

[0406] Example 45: Synthesis of 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-3-(cyclobutylmethyl)-1-methyl-piperazin-2-one (Compound 49)

[0407] Step a) tert-Butyl 2-(cyclobutylmethyl)-4-methyl-3-oxo-piperazine-1-carboxylate

[0408] Following procedure in example 2 step b, tert-butyl 4-methyl-3-oxo-piperazine-1-carboxylate (301 mg, 1.4 mmol) and bromomethylcyclobutane (175 mg, 1.2 mmol) were used to prepare tert-butyl 2-(cyclobutylmethyl)-4-methyl-3-oxo-piperazine-1-carboxylate. Purification byAttorney Docket No.60185-706601 FCC (irregular silica, 0-5% DCM in MeOH) afforded tert-butyl 2-(cyclobutylmethyl)-4-methyl-3- oxo-piperazine-1-carboxylate (133 mg) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 4.11 - 4.29 (m, 1 H), 3.79 - 3.99 (m, 1 H), 3.34 - 3.41 (m, 1 H), 3.09 - 3.27 (m, 2 H), 2.81 (s, 3 H), 2.21 - 2.38 (m, 1 H), 1.90 - 2.15 (m, 2 H), 1.73 - 1.90 (m, 4 H), 1.52 - 1.67 (m, 2 H), 1.34 - 1.46 (m, 9 H). LCMS (Method D): [M+H]+= 283.3.

[0409] Step b) 3-(Cyclobutylmethyl)-1-methyl-piperazin-2-one hydrochloride

[0410] Following procedure in example 2 step c, tert-butyl 2-(cyclobutylmethyl)-4-methyl-3-oxo-piperazine-1-carboxylate (130 mg, 0.5 mmol) was used to prepare 3-(cyclobutylmethyl)-1-methyl- piperazin-2-one hydrochloride (97 mg, crude) as a brown solid.1H NMR (300 MHz, DMSO-d6) δ 3.80 – 3.97 (m, 1H), 3.65 – 3.52 (m, 1H), 3.38 – 3.52 (m, 2H), 3.17 – 3.35. LCMS (Method C): [M+H]+= 183.2.

[0411] Step c) 3-(Cyclobutylmethyl)-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0412] Following procedure in example 1 step e, 3-(cyclobutylmethyl)-1-methyl-piperazin-2-onehydrochloride (94 mg, 0.4 mmol) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (141 mg, 0.5 mmol) were stirred RT at for 16 h. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded 3-(cyclobutylmethyl)-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2- dioxaborolan-2-yl)benzoyl]piperazin-2-one (43 mg) as a brown oil.1H NMR (400 MHz, DMSO- d6) δ 7.77 (d, J = 7.5 Hz, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 7.49 (t, J = 7.4 Hz, 1H), 4.79 (s, 1H), 3.43 – 3.73 (m, 2H), 3.20 – 3.30 (m, 2H), 3.05 – 3.20 (m, 1H), 2.45 – 2.36 (m, 1H), 1.89 – 2.12 (m, 3H), 1.55 – 1.85 (m, 14H), 1.02 (t, J = 7.0 Hz, 3H), 0.92 (t, J = 7.3 Hz, 12H). LCMS (Method D): [M+H]+= 469.4.

[0413] Step d) 4-[3-(6-Amino-5-chloro-3-pyridyl)benzoyl]-3-(cyclobutylmethyl)-1-methyl-piperazin-2-oneAttorney Docket No.60185-706601

[0414] Following procedure in example 1 step c, 3-(cyclobutylmethyl)-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (40 mg, 0.1 mmol) and 5-bromo-3- chloro-pyridin-2-amine (18 mg, 0.1 mmol) in dioxane:H2O were stirred at 85ºC for 4 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded 4-[3-(6-amino-5-chloro-3- pyridyl)benzoyl]-3-(cyclobutylmethyl)-1-methyl-piperazin-2-one (9 mg) as a slightly yellow solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.28 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 6.09 (s, 2H), 4.63 (s, 1H), 3.85 (s, 1H), 3.39 – 3.56 (m, 2H), 3.16 – 3.23 (m, 1H), 2.87 (s, 3H), 2.39 – 2.48 (m, 1H), 1.92 – 2.11 (m, 4H), 1.73 – 1.88 (m, 2H), 1.54 – 1.72 (m, 2H). LCMS (Method E): [M+H]+= 413.2290.

[0415] Example 46: Synthesis of 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-1-cyclopropyl-3-propyl-piperazin-2-one (Compound 50)

[0416] Step a) tert-Butyl 4-cyclopropyl-3-oxo-piperazine-1-carboxylate

[0417] A RBF was charged with tert-butyl 3-oxopiperazine-1-carboxylate (1 g, 5.0 mmol),cyclopropylboronic acid (858 mg, 10 mmol), copper(II) acetate (227 mg, 1.2 mmol), DMAP (1.83 g, 15 mmol) and NaHDMS 1M solution in THF (5 mmol, 5 mL). The mixture was sparged with O2 for 5 minutes, and stirred at 95ºC for 16 h. The reaction mixture was cooled to RT and quenched with NH4Cl. The product was extracted with EtOAc (3x), and the combined organics washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow oil. Purification by FCC (irregular silica, 0-2% DCM in MeOH) afforded tert-butyl 4-cyclopropyl-3-oxo-piperazine-1-carboxylate (1.16 g) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 4.05 (s, 2H), 3.53 – 3.64 (m, 2H), 3.25 – 3.33 (m, 2H), 2.69 – 2.80 (m, 1H), 1.46 (s, 9H), 0.81 – 0.90 (m, 2H), 0.63 – 0.70 (m, 2H). LCMS (Method E): [M+H]+= 392.1875.

[0418] Step b) tert-Butyl 4-cyclopropyl-3-oxo-2-propyl-piperazine-1-carboxylateAttorney Docket No.60185-706601

[0419] Following procedure in example 2 step b, tert-butyl 4-cyclopropyl-3-oxo-piperazine-1-carboxylate (1.1 g, 4.3 mmol) and 1-bromopropane (1.3 mL, 13.7 mmol) were used to prepare tert- butyl 4-cyclopropyl-3-oxo-2-propyl-piperazine-1-carboxylate. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded tert-butyl 4-cyclopropyl-3-oxo-2-propyl-piperazine-1- carboxylate (458 mg) as a yellow oil.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 4.27 (dd, J = 7.8, 5.8 Hz, 1H), 3.79 – 3.90 (m, 1H), 3.14 – 3.30 (m, 3H), 2.72– 2.81 (m, 1H), 1.61 – 1.82 (m, 2H), 1.43 (s, 9H), 1.31 – 1.40 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H), 0.67 – 0.77 (m, 2H), 0.58 – 0.67 (m, 2H). LCMS (Method D): [M+H]+= 283.2.

[0420] Step c) 1-Cyclopropyl-3-propyl-piperazin-2-one hydrochloride

[0421] Following procedure in example 2 step c, tert-butyl 4-cyclopropyl-3-oxo-2-propyl-piperazine-1-carboxylate (455 mg, 1.6 mmol) was used to prepare 1-cyclopropyl-3-propyl-piperazin- 2-one hydrochloride (400 mg, crude) as a brown solid.1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 3.76 (dd, J = 7.4, 5.3 Hz, 1H), 3.49 – 3.58 (m, 1H), 3.32 – 3.46 (m, 2H), 3.22 – 3.32 (m, 1H), 2.77 (ddd, J = 11.3, 7.4, 4.2 Hz, 1H), 1.87 – 2.05 (m, 1H), 1.73 – 1.84 (m, 1H), 1.43 – 1.59 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H), 0.70 – 0.82 (m, 2H), 0.55 – 0.69 (m, 2H). LCMS (Method D): [M+H]+= 183.2.

[0422] Step d) 1-Cyclopropyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0423] Following procedure in example 1 step e, 1-cyclopropyl-3-propyl-piperazin-2-onehydrochloride (400 mg, crude) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (600 -130-Attorney Docket No.60185-706601 mg, 2.0 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-45% EtOAc in heptane) afforded 1-cyclopropyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2- yl)benzoyl]piperazin-2-one (687 mg) as a colourless oil.1H NMR (400 MHz, CDCl3) δ 7.81 (br d, J=6.60 Hz, 1 H), 7.74 (br s, 1 H), 7.28 - 7.42 (m, 2 H), 4.96 - 5.21 (m, 1 H), 3.60 - 3.86 (m, 1 H), 2.96 - 3.51 (m, 3 H), 2.73 (s, 1 H), 2.66 (dt, J=7.29, 3.42 Hz, 1 H), 1.88 - 2.06 (m, 1 H), 1.59 - 1.83 (m, 10 H), 1.30 - 1.45 (m, 1 H), 0.89 (t, J=7.43 Hz, 12 H), 0.77 (br d, J=6.42 Hz, 4 H), 0.52 - 0.63 (m, 2 H). LCMS (Method D): [M+H]+= 469.3.

[0424] Step e) 4-[3-(6-Amino-5-chloro-3-pyridyl)benzoyl]-1-cyclopropyl-3-propyl-piperazin-2-one

[0425] Following procedure in example 1 step c, 1-cyclopropyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (250 mg, 0.5 mmol), 5-bromo-3-chloro-pyridin-2- amine (100 mg, 0.5 mmol), and cesium carbonate (474 mg, 1.5 mmol) in dioxane:H2O were stirred at 85ºC for 5 h. Purification by FCC (irregular silica, 0-2.5% MeOH in DCM) afforded 4-[3-(6- amino-5-chloro-3-pyridyl)benzoyl]-1-cyclopropyl-3-propyl-piperazin-2-one (140 mg) as a slightly brown foam.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.28 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.06 (s, 2H), 4.61 – 4.68 (m, 1H), 3.82 (s, 1H), 3.39 – 3.54 (m, 1H), 3.27 – 3.39 (m, 1H), 3.16 (d, J = 12.4 Hz, 1H), 2.78 (ddd, J = 11.2, 7.4, 4.2 Hz, 1H), 1.74 – 1.93 (m, 2H), 1.42 (dd, J = 14.9, 7.5 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H), 0.56 – 0.80 (m, 4H). LCMS (Method E): [M+H]+= 413.2296.

[0426] Example 47: Synthesis of 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1-ethyl-3-(3,3,3-trifluoropropyl)piperazin-2-one (Compound 51)

[0427] Step a) tert-Butyl 4-cyclopropyl-3-oxo-2-propyl-piperazine-1-carboxylate

[0428] Following procedure in example 2 step b, tert-butyl 4-ethyl-3-oxo-piperazine-1-carboxylate(1.5 g, 7.0 mmol) and 1,1,1-trifluoro-3-iodo-propane (2.5 mL, 21.0 mmol) were used to prepare tert- butyl 4-cyclopropyl-3-oxo-2-propyl-piperazine-1-carboxylate. Purification by FCC (irregular silica, -131-Attorney Docket No.60185-706601 0-100% EtOAc in heptane) afforded tert-butyl 4-ethyl-3-oxo-2-(3,3,3-trifluoropropyl)piperazine-1- carboxylate (1.38 g) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 4.27 – 4.34 (m, 1H), 3.92 (d, J = 14.2 Hz, 1H), 3.33 – 3.44 (m, 3H), 3.23 (dd, J = 12.2, 3.1 Hz, 2H), 2.32 – 2.45 (m, 1H), 2.25 (ddd, J = 20.8, 15.4, 10.6 Hz, 1H), 2.05 (dtd, J = 15.9, 10.6, 5.2 Hz, 1H), 1.90 (ddd, J = 19.1, 12.2, 5.3 Hz, 1H), 1.43 (s, 9H), 1.03 (t, J = 7.1 Hz, 3H). LCMS (Method H): [M+H-tBu]+= 269.1.

[0429] Step b) 1-Ethyl-3-(3,3,3-trifluoropropyl)piperazin-2-one hydrochloride

[0430] Following procedure in example 2 step c, tert-butyl 4-ethyl-3-oxo-2-(3,3,3-trifluoropropyl)piperazine-1-carboxylate (1.38 g, 4.2 mmol) was used to prepare 1-ethyl-3-(3,3,3- trifluoropropyl)piperazin-2-one hydrochloride (1.32 g, crude) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 10.31 - 10.77 (m, 2 H), 3.90 - 4.01 (m, 1 H), 3.70 - 3.80 (m, 1 H), 3.39 - 3.50 (m, 2 H), 3.35 (br dd, J=7.01, 3.19 Hz, 3 H), 2.64 - 2.81 (m, 1 H), 2.54 - 2.63 (m, 1 H), 2.18 - 2.36 (m, 1 H), 2.00 - 2.14 (m, 1 H), 1.05 (t, J=7.10 Hz, 3 H). LCMS (Method H): [M+H]+= 225.2.

[0431] Step c) 1-Ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-3-(3,3,3-trifluoropropyl)piperazin-2-one

[0432] Following procedure in example 1 step e, 1-ethyl-3-(3,3,3-trifluoropropyl)piperazin-2-onehydrochloride (1.32 g, crude) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.25 g, 4.1 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-80% EtOAc in heptane) afforded 1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-3-(3,3,3- trifluoropropyl)piperazin-2-one (1.32 g) as a colourless oil.1H NMR (400 MHz, CDCl3) δ 7.84 (br d, J=6.77 Hz, 1 H), 7.71 - 7.78 (m, 1 H), 7.39 (s, 2 H), 4.89 - 5.28 (m, 1 H), 3.30 - 3.50 (m, 4 H), 3.01 - 3.18 (m, 1 H), 2.11 - 2.50 (m, 3 H), 1.90 - 2.02 (m, 1 H), 1.60 - 1.81 (m, 9 H), 1.09 (t, J=7.20 Hz, 3 H), 0.87 - 0.92 (m, 12 H). LCMS (Method H): [M+H]+= 511.3.Attorney Docket No.60185-706601

[0433] Step d) 4-[3-(6-Amino-5-fluoro-3-pyridyl)benzoyl]-1-ethyl-3-(3,3,3-trifluoropropyl)piperazin-2-one

[0434] Following procedure in example 1 step c, 1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-3-(3,3,3-trifluoropropyl)piperazin-2-one (250 mg, 0.4 mmol), 5-bromo-3-fluoro- pyridin-2-amine (70mg, 0.4 mmol), and cesium carbonate (360 mg, 1.1 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded 4- [3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1-ethyl-3-(3,3,3-trifluoropropyl)piperazin-2-one (145 mg) as a brown solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.19 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.70 – 7.73 (m, 1H), 7.67 (s, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 6.02 (s, 2H), 4.79 (s, 1H), 3.85 (d, J = 12.7 Hz, 1H), 3.45 – 3.64 (m, 2H), 3.36 – 3.43 (m, 2H), 3.22 – 3.29 (m, 1H), 2.34 – 2.49 (m, 2H), 2.03 – 2.28 (m, 2H), 1.11 (t, J = 7.1 Hz, 3H). LCMS (Method B): [M+H]+= 439.1939.

[0435] Example 48: Synthesis of 4-[3-(5-amino-6-methyl-pyrazin-2-yl)benzoyl]-1-ethyl-3-(3,3,3-trifluoropropyl)piperazin-2-one (Compound 52)

[0436] Step a) 4-[3-(6-Amino-5-fluoro-3-pyridyl)benzoyl]-1-ethyl-3-(3,3,3-trifluoropropyl)piperazin-2-one

[0437] Following procedure in example 1 step c, 1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-3-(3,3,3-trifluoropropyl)piperazin-2-one (250 mg, 0.4 mmol), 5-bromo-3-methyl- pyrazin-2-amine (69 mg, 0.4 mmol), and cesium carbonate (360 mg, 1.1 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded 4-[3-(5-amino-6-methyl-pyrazin-2-yl)benzoyl]-1-ethyl-3-(3,3,3-trifluoropropyl)piperazin- 2-one (45 mg) as a brown solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.40 (s, 1 H), 8.02 (dd, J=7.87, 1.19 Hz, 1 H), 7.93 - 7.98 (m, 1 H), 7.52 (t, J=7.72 Hz, 1 H), 7.37 (d, J=7.63 Hz, 1 H), 6.03Attorney Docket No.60185-706601 (s, 2 H), 4.68 - 4.85 (m, 1 H), 3.81 - 3.93 (m, 1 H), 3.51 (s, 2 H), 3.39 (d, J=7.15 Hz, 2 H), 3.26 (s, 1 H), 2.42 (s, 5 H), 2.03 - 2.25 (m, 2 H), 1.10 (t, J=7.15 Hz, 3 H). LCMS (Method B): [M+H]+= 436.2051.

[0438] Example 49: Synthesis of 4-[3-(3-fluoro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 53)

[0439] Step a) 4-[3-(3-Fluoro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0440] Following procedure in example 1 step c, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (180 mg, 0.4 mmol) and 5-bromo-3-fluoro-1H- pyrazolo[3,4-b]pyridine (92 mg, 0.4 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Crude was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3 (sat. sol.), extracted with EtOAc, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-3% MeOH in DCM) afforded 4-[3-(3-fluoro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-1- methyl-3-propyl-piperazin-2-one (21 mg) as an off-white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 12.84 - 13.20 (m, 1 H), 8.92 (d, J=2.19 Hz, 1 H), 8.47 (d, J=1.33 Hz, 1 H), 7.87 (d, J=7.72 Hz, 1 H), 7.78 (s, 1 H), 7.61 (t, J=7.68 Hz, 1 H), 7.44 (d, J=7.53 Hz, 1 H), 4.65 - 4.79 (m, 1 H), 3.83 - 3.97 (m, 1 H), 3.44 - 3.63 (m, 2 H), 3.23 (br d, J=11.16 Hz, 1 H), 2.89 (s, 3 H), 1.82 - 1.94 (m, 2 H), 1.40 - 1.51 (m, 2 H), 0.92 (t, J=7.30 Hz, 3 H). LCMS (Method B): [M+H]+= 396.1846.

[0441] Example 50: Synthesis of 1-methyl-4-[3-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)benzoyl]-3-propyl-piperazin-2-one (Compound 54)

[0442] Step a) 1-Methyl-4-[3-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)benzoyl]-3-propyl-piperazin-2-one

[0443] Following procedure in example 1 step c, 1-methyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (162 mg, 0.4 mmol) and 6-bromo-2-methyl-1H- imidazo[4,5-b]pyridine (82 mg, 0.4 mmol) in dioxane:H2O were stirred at 85ºC for 40 h. Purification -134-Attorney Docket No.60185-706601 by FCC (irregular silica, 0-3% MeOH in DCM) afforded impure 1-methyl-4-[3-(2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)benzoyl]-3-propyl-piperazin-2-one which was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3(sat. sol.), extracted with EtOAc, dried over MgSO4, filtered, and concentrated to afford 1-methyl-4-[3-(2-methyl-1H- imidazo[4,5-b]pyridin-6-yl)benzoyl]-3-propyl-piperazin-2-one (18 mg) as a white solid after lyophilization.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 12.5 (br s, 1 H), 8.56 (br s, 1 H), 7.99 - 8.15 (m, 1 H), 7.81 (br d, J=7.82 Hz, 1 H), 7.71 (s, 1 H), 7.54 - 7.61 (m, 1 H), 7.40 (d, J=7.63 Hz, 1 H), 4.73 (br s, 1 H), 3.91 (br s, 1 H), 3.45 - 3.60 (m, 2 H), 3.18 - 3.26 (m, 1 H), 2.89 (s, 3 H), 2.57 (s, 3 H), 1.80 - 1.93 (m, 2 H), 1.45 (dq, J=14.70, 7.28 Hz, 2 H), 0.92 (br t, J=7.30 Hz, 3 H). LCMS (Method B): [M+H]+= 392.2140.

[0444] Example 51: Synthesis of 4-[3-(6-amino-5-chloro-3-pyridyl)-4-fluoro-benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 55)

[0445] Step a) 2-Fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid

[0446] A RBF was charged with 3-borono-4-fluoro-benzoic acid (300 mg, 1.6 mmol), 3,4-diethylhexane-3,4-diol (370 μL, 2.0 mmol), and anhydrous toluene (6 mL). The mixture was stirred at 100°C for 16h. Solvent was removed and purification by FCC (irregular silica, 0-30% EtOAc in heptane) afforded 2-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (322 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.95 - 13.24 (m, 1 H), 8.24 (dd, J=5.72, 2.29 Hz, 1 H), 8.10 (ddd, J=8.34, 5.53, 2.34 Hz, 1 H), 7.28 (t, J=8.77 Hz, 1 H), 1.65 - 1.80 (m, 8 H), 0.92 (t, J=7.39 Hz, 12 H). LCMS (Method D): [M+H]+= 323.2.

[0447] Step b) 4-[4-Fluoro-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0448] Following procedure in example 1 step e, 1-methyl-3-propyl-piperazin-2-one hydrochloride(200 mg, 0.8 mmol) and 4-fluoro-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (321 mg, 1 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-25% EtOAc inAttorney Docket No.60185-706601 heptane) afforded 4-[4-fluoro-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3- propyl-piperazin-2-one (323 mg) as a light-yellow foam.1H NMR (400 MHz, DMSO-d6) δ 7.60 - 7.67 (m, 2 H), 7.23 - 7.29 (m, 1 H), 4.75 - 4.94 (m, 1 H), 3.38 - 3.64 (m, 3 H), 3.06 - 3.19 (m, 1 H), 2.83 (s, 3 H), 1.78 - 1.88 (m, 2 H), 1.67 - 1.76 (m, 8 H), 1.30 - 1.45 (m, 2 H), 0.92 (t, J=7.39 Hz, 15 H). LCMS (Method D): [M+H]+= 461.3.

[0449] Step c) 4-[3-(6-Amino-5-chloro-3-pyridyl)-4-fluoro-benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0450] Following procedure in example 1 step c, 4-[4-fluoro-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (323 mg, 0.7 mmol) and 5-bromo-3- chloro-pyridin-2-amine (218 mg, 1.0 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-2% MeOH in DCM) afforded impure 1-methyl-4-[3-(2- methyl-1H-imidazo[4,5-b]pyridin-6-yl)benzoyl]-3-propyl-piperazin-2-one which was further purified by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 90% [0.1% HCOOH] - 10% MeCN to 54% [0.1% HCOOH] - 46% MeCN). Resulting solution was extracted, organics were lyophilized to afford 4-[3-(6-amino-5-chloro-3-pyridyl)-4-fluoro-benzoyl]-1-methyl-3-propyl- piperazin-2-one (147 mg) as a beige foam.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.15 - 8.18 (m, 1 H), 7.78 - 7.81 (m, 1 H), 7.55 (dd, J=7.63, 2.10 Hz, 1 H), 7.38 - 7.44 (m, 1 H), 7.31 - 7.37 (m, 1 H), 6.18 (br s, 2 H), 4.69 (br s, 1 H), 3.87 (br d, J=10.78 Hz, 1 H), 3.42 - 3.57 (m, 2 H), 3.15 - 3.26 (m, 1 H), 2.87 (s, 3 H), 1.79 - 1.92 (m, 2 H), 1.42 (sxt, J=7.40 Hz, 2 H), 0.90 (t, J=7.34 Hz, 3 H). LCMS (Method E): [M+H]+= 405.2154.

[0451] Example 52: Synthesis of 4-[5-(6-amino-5-chloro-3-pyridyl)-2-fluoro-benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 56)

[0452] Step a) 2-Fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid

[0453] Following procedure in example 51 step a, 5-borono-2-fluoro-benzoic acid (0.3 g, 1.6 mmol)was used to prepare 2-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. PurificationAttorney Docket No.60185-706601 by FCC (irregular silica, 0-30% EtOAc in heptane) afforded 2-fluoro-5-(4,4,5,5-tetraethyl-1,3,2- dioxaborolan-2-yl)benzoic acid (368 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.19 - 13.49 (m, 1 H), 8.17 (dd, J=7.96, 1.67 Hz, 1 H), 7.87 - 7.92 (m, 1 H), 7.33 (dd, J=11.21, 8.25 Hz, 1 H), 1.64 - 1.79 (m, 8 H), 0.91 (t, J=7.39 Hz, 12 H). LCMS (Method D): [M+H]+= 323.2.

[0454] Step b) 4-[2-Fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3-

[0455] Following procedure in example 1 step e, 1-methyl-3-propyl-piperazin-2-one hydrochloride(225 mg, 0.9 mmol) and 2-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (361 mg, 1.1 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-25% EtOAc in heptane) afforded 4-[2-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3- propyl-piperazin-2-one (333 mg) as a yellow gum.1H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.85 (m, 2 H), 7.34 (s, 1 H), 4.83 - 4.91 (m, 1 H), 3.51 - 3.62 (m, 1 H), 3.34 - 3.50 (m, 2 H), 3.06 - 3.17 (m, 1 H), 2.80 - 2.88 (m, 3 H), 1.80 - 1.90 (m, 2 H), 1.67 - 1.75 (m, 8 H), 1.33 - 1.44 (m, 2 H), 0.86 - 0.98 (m, 15 H). LCMS (Method D): [M+H]+= 461.2.

[0456] Step c) 4-[5-(6-Amino-5-chloro-3-pyridyl)-2-fluoro-benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0457] Following procedure in example 1 step c, 4-[2-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (333 mg, 0.7 mmol) and 5-bromo-3- chloro-pyridin-2-amine (225 mg, 1.1 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-2% MeOH in DCM) afforded impure 1-methyl-4-[3-(2- methyl-1H-imidazo[4,5-b]pyridin-6-yl)benzoyl]-3-propyl-piperazin-2-one which was further purified by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 72% [0.1% HCOOH] - 28% MeCN to 36% [0.1% HCOOH] - 64% MeCN). Resulting solution was extracted, organics werelyophilized to afford 4-[5-(6-amino-5-chloro-3-pyridyl)-2-fluoro-benzoyl]-1-methyl-3-propyl-piperazin-2-one (142 mg) as a beige foam.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.26 (d,Attorney Docket No.60185-706601 J=1.91 Hz, 1 H), 7.90 (d, J=1.81 Hz, 1 H), 7.70 - 7.75 (m, 1 H), 7.61 - 7.68 (m, 1 H), 7.32 (t, J=9.01 Hz, 1 H), 6.09 (br s, 2 H), 4.66 - 5.09 (m, 1 H), 3.37 - 3.65 (m, 3 H), 3.17 - 3.27 (m, 1 H), 2.88 (s, 3 H), 1.84 (br d, J=6.29 Hz, 2 H), 1.44 (br s, 2 H), 0.92 (br s, 3 H). LCMS (Method E): [M+H]+= 405.2088.

[0458] Example 53: Synthesis of 4-[3-(6-amino-5-chloro-3-pyridyl)-5-fluoro-benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 57)

[0459] Step a) 3-Fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid

[0460] Following procedure in example 51 step a, 3-borono-5-fluoro-benzoic acid (0.3 g, 1.6 mmol)was used to prepare 3-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. Purification by FCC (irregular silica, 0-20% EtOAc in heptane) afforded 3-fluoro-5-(4,4,5,5-tetraethyl-1,3,2- dioxaborolan-2-yl)benzoic acid (524 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.06 - 13.43 (m, 1 H), 7.96 (td, J=7.49, 1.91 Hz, 1 H), 7.83 (ddd, J=7.25, 5.25, 1.91 Hz, 1 H), 7.31 (t, J=7.49 Hz, 1 H), 1.65 - 1.78 (m, 8 H), 0.92 (t, J=7.44 Hz, 12 H). LCMS (Method D): [M+H]+= 323.2.

[0461] Step b) 4-[3-Fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0462] Following procedure in example 1 step e, 1-methyl-3-propyl-piperazin-2-one hydrochloride(324 mg, 1.3 mmol) and 3-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (520 mg, 1.6 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-25% EtOAc in heptane) afforded 4-[3-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3- propyl-piperazin-2-one (538 mg) as an orange gum.1H NMR (400 MHz, DMSO-d6) δ 7.71 - 7.77 (m, 1 H), 7.50 - 7.66 (m, 1 H), 7.29 - 7.35 (m, 1 H), 4.83 - 4.91 (m, 1 H), 3.49 - 3.59 (m, 1 H), 3.06 -Attorney Docket No.60185-706601 3.16 (m, 1 H), 2.81 - 2.88 (m, 3 H), 2.68 - 2.70 (m, 2 H), 1.80 - 1.89 (m, 2 H), 1.64 - 1.77 (m, 8 H), 1.33 - 1.45 (m, 2 H), 0.87 - 0.97 (m, 15 H). LCMS (Method D): [M+H]+= 461.3.

[0463] Step c) 4-[3-(6-Amino-5-chloro-3-pyridyl)-5-fluoro-benzoyl]-1-methyl-3-propyl-piperazin-

[0464] Following procedure in example 1 step c, 4-[3-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (250 mg, 0.5 mmol) and 5-bromo-3- chloro-pyridin-2-amine (169 mg, 0.8 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-2% MeOH in DCM) afforded impure 1-methyl-4-[3-(2- methyl-1H-imidazo[4,5-b]pyridin-6-yl)benzoyl]-3-propyl-piperazin-2-one which was further purified by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 90% [0.1% HCOOH] - 10% MeCN to 54% [0.1% HCOOH] - 46% MeCN). Resulting solution was extracted, organics were lyophilized to afford 4-[3-(6-amino-5-chloro-3-pyridyl)-5-fluoro-benzoyl]-1-methyl-3-propyl- piperazin-2-one (129 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.15 (s, 1 H), 7.78 (s, 1 H), 7.58 - 7.63 (m, 1 H), 7.35 (d, J=4.96 Hz, 2 H), 6.19 (br s, 2 H), 4.76 - 5.05 (m, 1 H), 3.36 - 3.62 (m, 3 H), 3.15 - 3.29 (m, 1 H), 2.88 (s, 3 H), 1.76 - 1.93 (m, 2 H), 1.33 - 1.54 (m, 2 H), 0.80 - 1.01 (m, 3 H). LCMS (Method B): [M+H]+= 405.1595.

[0465] Example 54: Synthesis of 4-[3-(6-amino-5-chloro-3-pyridyl)-2-fluoro-benzoyl]-1-methyl-3-propyl-piperazin-2-one (Compound 58)

[0466] Step a) 2-Fluoro-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid

[0467] Following procedure in example 51 step a, 3-borono-2-fluoro-benzoic acid (0.3 g, 1.6 mmol)was used to prepare 2-fluoro-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. Purification by FCC (irregular silica, 0-30% EtOAc in heptane) afforded 2-fluoro-5-(4,4,5,5-tetraethyl-1,3,2- dioxaborolan-2-yl)benzoic acid (494 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.23Attorney Docket No.60185-706601 - 13.51 (m, 1 H), 8.07 (s, 1 H), 7.75 - 7.80 (m, 1 H), 7.57 - 7.63 (m, 1 H), 1.65 - 1.80 (m, 8 H), 0.88 - 0.96 (m, 12 H). LCMS (Method H): [M+H]+= 323.1.

[0468] Step b) 4-[2-Fluoro-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0469] Following procedure in example 1 step e, 1-methyl-3-propyl-piperazin-2-one hydrochloride(370 mg, 1.5 mmol) and 2-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (494 mg, 1.5 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-25% EtOAc in heptane) afforded 4-[2-fluoro-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3- propyl-piperazin-2-one (573 mg) as a yellow gum.1H NMR (400 MHz, DMSO-d6) δ 7.42 - 7.51 (m, 3 H), 4.79 - 4.89 (m, 1 H), 3.47 - 3.59 (m, 2 H), 2.83 (s, 3 H), 2.68 - 2.70 (m, 2 H), 1.79 - 1.90 (m, 2 H), 1.66 - 1.76 (m, 8 H), 1.32 - 1.48 (m, 2 H), 0.91 (t, J=7.34 Hz, 15 H). LCMS (Method H): [M+H]+= 461.3.

[0470] Step c) 4-[3-(6-Amino-5-chloro-3-pyridyl)-2-fluoro-benzoyl]-1-methyl-3-propyl-piperazin-2-one

[0471] Following procedure in example 1 step c, 4-[2-fluoro-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1-methyl-3-propyl-piperazin-2-one (250 mg, 0.5 mmol) and 5-bromo-3- chloro-pyridin-2-amine (169 mg, 0.8 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-10% MeOH in DCM) afforded impure 1-methyl-4-[3-(2- methyl-1H-imidazo[4,5-b]pyridin-6-yl)benzoyl]-3-propyl-piperazin-2-one which was further purified by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 90% [0.1% HCOOH] - 10% MeCN to 54% [0.1% HCOOH] - 46% MeCN). Resulting solution was extracted, organics werelyophilized to afford 4-[5-(6-amino-5-chloro-3-pyridyl)-2-fluoro-benzoyl]-1-methyl-3-propyl-piperazin-2-one (142 mg) as a beige foam.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.33 (d, J=2.19 Hz, 1 H), 7.97 (d, J=2.19 Hz, 1 H), 7.53 - 7.58 (m, 1 H), 7.47 (t, J=1.43 Hz, 1 H), 7.12 - 7.16 (m, 1 H), 6.18 (br s, 2 H), 4.60 - 4.76 (m, 1 H), 3.76 - 3.92 (m, 1 H), 3.44 - 3.57 (m, 2 H), 3.16 - 3.24Attorney Docket No.60185-706601 (m, 1 H), 2.88 (s, 3 H), 1.79 - 1.92 (m, 2 H), 1.37 - 1.50 (m, 2 H), 0.91 (t, J=7.30 Hz, 3 H). LCMS (Method B): [M+H]+= 405.1576.

[0472] Example 55: Synthesis of 4-[3-(6-amino-5-chloro-3-pyridyl)benzoyl]-1-(2,2-difluoroethyl)-3-propyl-piperazin-2-one (Compound 59)

[0473] Step a) tert-Butyl 4-(2,2-difluoroethyl)-3-oxo-piperazine-1-carboxylate

[0474] Following procedure in example 10 step f, tert-butyl 3-oxopiperazine-1-carboxylate (500 mg,2.5 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (1.7 mL, 12.6 mmol) were used to prepare tert-butyl 4-(2,2-difluoroethyl)-3-oxo-piperazine-1-carboxylate. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded tert-butyl 4-(2,2-difluoroethyl)-3-oxo- piperazine-1-carboxylate (596 mg) as a light yellow oil.1H NMR (400 MHz, CDCl3) δ 5.97 (tt, J = 56.1, 4.5 Hz, 1H), 4.12 (s, 2H), 3.73 (dd, J = 14.1, 4.4 Hz, 2H), 3.63 – 3.69 (m, 2H), 3.48 (t, J = 5.3 Hz, 2H), 1.47 (s, 9H). LCMS (Method D): [M+H-tBu]+= 209.0.

[0475] Step b) tert-Butyl 4-(2,2-difluoroethyl)-3-oxo-2-propyl-piperazine-1-carboxylate

[0476] Following procedure in example 2 step b, tert-butyl 4-(2,2-difluoroethyl)-3-oxo-piperazine-1-carboxylate (596 mg, 1.8 mmol) and 1-bromopropane (615 μL, 6.8 mmol) were used to prepare tert-butyl 4-(2,2-difluoroethyl)-3-oxo-2-propyl-piperazine-1-carboxylate. Purification by FCC (irregular silica, 0-3% MeOH in DCM) afforded tert-butyl 4-(2,2-difluoroethyl)-3-oxo-2-propyl- piperazine-1-carboxylate (960 mg) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 5.81 - 6.12 (m, 1 H), 4.46 - 4.68 (m, 1 H), 4.13 (s, 1 H), 3.69 - 3.84 (m, 2 H), 3.59 (br s, 2 H), 3.27 - 3.36 (m, 1 H), 3.13 - 3.27 (m, 1 H), 1.70 - 1.81 (m, 3 H), 1.47 (s, 9 H), 0.96 (t, J = 7.34 Hz, 3 H). LCMS (Method D): [M+H-tBu]+= 251.1.

[0477] Step c) 1-(2,2-Difluoroethyl)-3-propyl-piperazin-2-one hydrochlorideAttorney Docket No.60185-706601

[0478] Following procedure in example 2 step c, tert-butyl 4-(2,2-difluoroethyl)-3-oxo-2-propyl-piperazine-1-carboxylate (960 mg, 2.2 mmol) was used to prepare 1-(2,2-difluoroethyl)-3-propyl- piperazin-2-one hydrochloride (1 g, crude) as brown oil. LCMS (Method D): [M+H]+= 207.1.

[0479] Step d) 1-(2,2-Difluoroethyl)-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0480] Following procedure in example 1 step e, 1-(2,2-difluoroethyl)-3-propyl-piperazin-2-onehydrochloride (300 mg, 0.80 mmol) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (289 mg, 1.0 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-25% EtOAc in heptane) afforded 1-(2,2-difluoroethyl)-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2- yl)benzoyl]piperazin-2-one (114 mg) as a yellow gum.1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 6.77 Hz, 1 H), 7.70 (s, 1 H), 7.50 - 7.55 (m, 2 H), 6.15 (tt, J = 55.81, 4.03 Hz, 1 H), 4.65 - 4.77 (m, 1 H), 3.84 - 3.97 (m, 1 H), 3.76 (br d, J = 4.01 Hz, 2 H), 3.47 - 3.61 (m, 2 H), 3.36 - 3.44 (m, 1 H), 1.83 - 1.95 (m, 2 H), 1.77 (t, J=7.44 Hz, 8 H), 1.43 (br d, J = 7.34 Hz, 2 H), 0.97 (t, J = 7.44 Hz, 12 H), 0.91 (t, J = 7.34 Hz, 3 H). LCMS (Method D): [M+H]+= 492.3.

[0481] Step e) 4-[3-(6-Amino-5-chloro-3-pyridyl)benzoyl]-1-(2,2-difluoroethyl)-3-propyl-piperazin-2-one

[0482] Following procedure in example 1 step c, 1-(2,2-difluoroethyl)-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (91 mg, 0.2 mmol) and 5-bromo-3-Attorney Docket No.60185-706601 chloro-pyridin-2-amine (36 mg, 0.2 mmol) in dioxane:H2O were stirred at 85ºC for 4 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded 4-[3-(6-amino-5-chloro-3- pyridyl)benzoyl]-1-(2,2-difluoroethyl)-3-propyl-piperazin-2-one (30 mg) as a brown oil.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.31 (s, 1 H), 7.98 (br s, 1 H), 7.74 (d, J=8.01 Hz, 1 H), 7.59 - 7.69 (m, 1 H), 7.51 (s, 1 H), 7.33 (br d, J = 7.06 Hz, 1 H), 6.49 (s, 2 H), 6.00 - 6.41 (m, 1 H), 4.97 (br d, J = 3.24 Hz, 1 H), 3.59 (s, 5 H), 1.80 - 1.99 (m, 2 H), 1.40 - 1.61 (m, 3 H), 0.95 (br s, 3 H). LCMS (Method B): [M+H]+= 437.1328.

[0483] Example 56: Synthesis of trans-4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1,6-dimethyl-3-propyl-piperazin-2-one and cis-4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1,6-dimethyl-3-propyl- piperazin-2-one (Compounds 60 and 61)

[0484] Step a) tert-Butyl 4-(2,2-difluoroethyl)-3-oxo-piperazine-1-carboxylate

[0485] Following procedure in example 2 step a, 6-methylpiperazin-2-one (300 mg, 2.6 mmol),DIPEA (1.4 mL, 7.9 mmol), and tert-butoxycarbonyl tert-butyl carbonate (725 μL, 3.2 mmol) were used to prepare tert-butyl 3-methyl-5-oxo-piperazine-1-carboxylate (428 mg) as a white solid that was used without further purification.1H NMR (400 MHz, CDCl3) δ 6.00 (br s, 1 H), 4.24 (d, J = 18.41 Hz, 1 H), 3.86 - 4.02 (m, 2 H), 3.60 - 3.70 (m, 1 H), 2.89 - 3.08 (m, 1 H), 1.48 (s, 9 H), 1.20 - 1.23 (m, 3 H). LCMS (Method G): [M+H-tBu]+= 159.2.

[0486] Step b) tert-Butyl 3,4-dimethyl-5-oxo-piperazine-1-carboxylate

[0487] Following procedure in example 10 step f, tert-butyl 3-methyl-5-oxo-piperazine-1-carboxylate (375 mg, 1.7 mmol) was used to prepare tert-butyl 3,4-dimethyl-5-oxo-piperazine-1- carboxylate (390 mg) as a light yellow oil.1H NMR (400 MHz, CDCl3) δ 4.19 - 4.43 (m, 1 H), 3.75 - 3.95 (m, 2 H), 3.31 - 3.52 (m, 2 H), 2.94 - 3.00 (m, 3 H), 1.45 - 1.50 (m, 9 H), 1.21 - 1.29 (m, 3 H). LCMS (Method G): [M+H-tBu]+= 173.1.

[0488] Step c) tert-Butyl 4,5-dimethyl-3-oxo-2-propyl-piperazine-1-carboxylateAttorney Docket No.60185-706601

[0489] Following procedure in example 2 step b, tert-butyl 3,4-dimethyl-5-oxo-piperazine-1-carboxylate (385 mg, 1.7 mmol) and 1-bromopropane (460 μL, 5.1 mmol) were used to prepare tert- butyl 4,5-dimethyl-3-oxo-2-propyl-piperazine-1-carboxylate. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded tert-butyl 4,5-dimethyl-3-oxo-2-propyl-piperazine-1-carboxylate (217 mg) as a yellow oil.1H NMR (300 MHz, DMSO-d6) δ 4.22 - 4.37 (m, 1 H), 3.72 - 4.08 (m, 1 H), 3.41 - 3.53 (m, 1 H), 3.26 (s, 1 H), 2.78 - 2.83 (m, 3 H), 1.64 - 1.78 (m, 2 H), 1.39 - 1.45 (m, 9 H), 1.23 - 1.34 (m, 2 H), 1.06 - 1.15 (m, 3 H), 0.85 - 0.97 (m, 3 H). LCMS (Method D): [M+H-tBu]+= 215.2.

[0490] Step d) 1,6-Dimethyl-3-propyl-piperazin-2-one hydrochloride

[0491] Following procedure in example 2 step c, tert-butyl 4,5-dimethyl-3-oxo-2-propyl-piperazine-1-carboxylate (210 mg, 0.8 mmol) was used to prepare 1,6-dimethyl-3-propyl-piperazin-2-one hydrochloride (158 mg) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.94 - 10.55 (m, 2 H), 3.66 - 3.93 (m, 2 H), 3.40 - 3.60 (m, 1 H), 2.98 - 3.25 (m, 1 H), 2.78 - 2.92 (m, 3 H), 1.88 - 2.11 (m, 1 H), 1.60 - 1.87 (m, 1 H), 1.42 - 1.56 (m, 2 H), 1.19 - 1.37 (m, 3 H), 0.85 - 0.98 (m, 3 H). LCMS (Method G): [M+H]+= 171.2.

[0492] Step e) 1,6-Dimethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0493] Following procedure in example 1 step e, 1,6-dimethyl-3-propyl-piperazin-2-onehydrochloride (155 mg, 0.6 mmol) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (228 mg, 0.7 mmol) were stirred at RT for 16 h. Purification by FCC (irregular silica, 0-50% EtOAcAttorney Docket No.60185-706601 in heptane) afforded 1,6-dimethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2- yl)benzoyl]piperazin-2-one (246 mg) as a colourless oil.1H NMR (400 MHz, CDCl3) δ 7.79 (t, J = 4.4 Hz, 1H), 7.67 (s, 1H), 7.49 (d, J = 5.1 Hz, 2H), 3.54 – 3.63 (m, 1H), 3.46 (s, 1H), 2.84 (s, 3H), 2.72 (s, 3H), 1.66 – 1.91 (m, 10H), 1.31 – 1.45 (m, 2H), 1.09 (d, J = 5.9 Hz, 2H), 0.96 (t, J = 7.4 Hz, 12H), 0.83 – 0.90 (m, 3H). LCMS (Method D): [M+H]+= 457.4.

[0494] Step f) trans-4-[3-(6-Amino-5-fluoro-3-pyridyl)benzoyl]-1,6-dimethyl-3-propyl-piperazin-2-one and cis-4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1,6-dimethyl-3-propyl-piperazin-2-one

[0495] Following procedure in example 1 step c, 1,6-dimethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (245 mg, 0.5 mmol), 5-bromo-3-fluoro-pyridin-2- amine (93 mg, 0.5 mmol) and cesium carbonate (476 mg, 1.5 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-2.5% MeOH in DCM) afforded the isomer mixture of 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1,6-dimethyl-3-propyl-piperazin-2-one which were separated by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 90% [0.1% HCOOH] - 10% [MeCN:MeOH (1:1)] to 54% [0.1% HCOOH] - 46% [MeCN:MeOH (1:1)]). The products were extracted with EtOAc (3x). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give two solids. Both solids were lyophilised to afford single isomers 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1,6-dimethyl-3-propyl-piperazin-2-one (isomer 1) : 95 mg and isomer 2 : 10 mg as yellow solids.

[0496] Single isomer 1: trans-4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1,6-dimethyl-3-propyl-piperazin-2-one:1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.14 (d, J = 1.14 Hz, 1 H), 7.64 - 7.73 (m, 2 H), 7.55 - 7.58 (m, 1 H), 7.52 (t, J = 7.82 Hz, 1 H), 7.32 (d, J=7.53 Hz, 1 H), 5.98 (br d, J = 1.33 Hz, 2 H), 4.71 (s, 1 H), 3.71 - 3.94 (m, 1 H), 3.58 - 3.69 (m, 1 H), 3.47 (br d, J = 2.86 Hz, 1 H), 2.86 (s, 3 H), 1.80 - 1.95 (m, 2 H), 1.37 - 1.50 (m, 2 H), 1.11 (br d, J=6.29 Hz, 3 H), 0.90 (br t, J=6.29 Hz, 3 H). LCMS (Method E): [M+H]+= 385.2062.Attorney Docket No.60185-706601

[0497] Single isomer 2: cis-4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-1,6-dimethyl-3-propyl-piperazin-2-one:1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.15 (s, 1H), 7.73 – 7.65 (m, 2H), 7.59 (s, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.00 (s, 2H), 4.68 (s, 1H), 3.95 (d, J = 11.9 Hz, 1H), 3.69 – 3.52 (m, 1H), 3.18 (dd, J = 14.1, 10.8 Hz, 1H), 2.85 (s, 3H), 1.93 – 1.79 (m, 2H), 1.41 (dt, J = 20.8, 7.0 Hz, 2H), 1.13 (d, J = 6.2 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H). LCMS (Method E): [M+H]+= 385.2011.

[0498] Example 57: Synthesis of 2-amino-5-[3-(4-ethyl-3-oxo-2-propyl-piperazine-1-carbonyl)phenyl]pyridine-3-carbonitrile (Compound 62)

[0499] Step a) 2-Amino-5-[3-(4-ethyl-3-oxo-2-propyl-piperazine-1-carbonyl)phenyl]pyridine-3-carbonitrile

[0500] Following procedure in example 1 step c, 1-ethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (113 mg, 0.3 mol) and 2-amino-5-bromo-pyridine-3- carbonitrile (51 mg, 0.3 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Crude was diluted in EtOAc and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3 (sat. sol.), extracted with EtOAc, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-4% MeOH in DCM) afforded 2-amino-5-[3-(4-ethyl-3-oxo-2-propyl-piperazine-1- carbonyl)phenyl]pyridine-3-carbonitrile (56 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.57 - 8.59 (m, 1 H), 8.20 (d, J=2.58 Hz, 1 H), 7.73 (ddd, J=7.89, 1.84, 1.05 Hz, 1 H), 7.64 (t, J=1.57 Hz, 1 H), 7.53 (t, J=7.72 Hz, 1 H), 7.33 - 7.38 (m, 1 H), 6.68 (br s, 2 H), 4.71 (m, 1 H), 3.88 (m, 1 H), 3.30 (m, 5 H), 1.81 - 1.92 (m, 2 H), 1.38 - 1.50 (m, 2 H), 1.09 (s, 4 H), 0.91 (t, J=7.25 Hz, 3 H). LCMS (Method B): [M+H]+= 392.1910.

[0501] Example 58: Synthesis of 4-[3-[5-amino-6-(trifluoromethyl)pyrazin-2-yl]benzoyl]-1-ethyl-3-propyl-piperazin-2-one (Compound 63)

[0502] Step a) 4-[3-[5-Amino-6-(trifluoromethyl)pyrazin-2-yl]benzoyl]-1-ethyl-3-propyl-piperazin-2-oneAttorney Docket No.60185-706601

[0503] Following procedure in example 1 step c, 1-ethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (100 mg, 0.2 mol) and 5-chloro-3- (trifluoromethyl)pyrazin-2-amine (45 mg, 0.2 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Crude was diluted in EtOAc and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3 (sat. sol.), extracted with EtOAc, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded 4-[3-[5-amino-6- (trifluoromethyl)pyrazin-2-yl]benzoyl]-1-ethyl-3-propyl-piperazin-2-one (74 mg) as a light yellow solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.90 (s, 1 H), 8.05 (dt, J = 7.89, 1.39 Hz, 1 H), 7.96 (t, J = 1.62 Hz, 1 H), 7.57 (t, J = 7.72 Hz, 1 H), 7.41 (d, J = 7.63 Hz, 1 H), 6.65 (br s, 2 H), 4.66 (br s, 1 H), 3.84 - 3.94 (m, 1 H), 3.47 (s, 2 H), 3.36 (dd, J = 8.11, 7.25 Hz, 2 H), 3.20 - 3.27 (m, 1 H), 1.80 - 1.92 (m, 2 H), 1.43 (sxt, J=7.44 Hz, 2 H), 1.08 (t, J = 7.15 Hz, 3 H), 0.89 - 0.94 (m, 3 H). LCMS (Method B): [M+H]+= 436.1715.

[0504] Example 59: Synthesis of 3-amino-6-[3-[2-(cyclobutylmethyl)-4-ethyl-3-oxo-piperazine-1-carbonyl]phenyl]pyrazine-2-carbonitrile (Compound 64)

[0505] Step a) tert-Butyl 2-(cyclobutylmethyl)-4-ethyl-3-oxo-piperazine-1-carboxylate

[0506] Following procedure in example 2 step b, tert-butyl 4-ethyl-3-oxo-piperazine-1-carboxylate(3.0 g, 13.2 mmol) and bromomethylcyclobutane (1.2 mL, 11 mmol) were used to prepare tert-butyl 2-(cyclobutylmethyl)-4-ethyl-3-oxo-piperazine-1-carboxylate. Purification by FCC (irregular silica, 0-3% DCM in MeOH) afforded tert-butyl 2-(cyclobutylmethyl)-4-ethyl-3-oxo-piperazine-1- carboxylate (3.6 g, crude) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 4.16 (s, 1H), 3.85 (s, 1H), 3.12 – 3.32 (m, 4H), 2.50 – 2.47 (m, 1H), 2.14 – 2.38 (m, 1H), 2.00 (s, 2H), 1.70 – 1.92 (m, 4H), 1.50 – 1.69 (m, 2H), 1.40 (s, 9H), 1.00 (t, J = 7.1 Hz, 3H), 2H signals overlap with water signal. LCMS (Method D): [M+H]+= 297.2.Attorney Docket No.60185-706601

[0507] Step b) 3-(Cyclobutylmethyl)-1-ethyl-piperazin-2-one hydrochloride

[0508] Following procedure in example 2 step c, tert-butyl 2-(cyclobutylmethyl)-4-ethyl-3-oxo-piperazine-1-carboxylate (3.6 g, 7.3 mmol) was used to prepare 3-(cyclobutylmethyl)-1-ethyl- piperazin-2-one hydrochloride (4.6 g, crude) as a crude as a brown solid. LCMS (Method D): [M+H]+= 197.1.

[0509] Step c) 3-(Cyclobutylmethyl)-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0510] Following procedure in example 1 step e, 3-(cyclobutylmethyl)-1-ethyl-piperazin-2-onehydrochloride (2.6 g, 5.6 mmol) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (3.40 g, 11.2 mmol) were stirred RT at for 16 h. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded 3-(cyclobutylmethyl)-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2- yl)benzoyl]piperazin-2-one (2.1 g) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 7.5 Hz, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 7.49 (t, J = 7.4 Hz, 1H), 4.79 (s, 1H), 3.43 – 3.73 (m, 2H), 3.20 – 3.30 (m, 2H), 3.20 – 3.05 (m, 1H), 2.36 – 2.45 (m, 1H), 1.89 – 2.12 (m, 3H), 1.55 – 1.85 (m, 14H), 1.02 (t, J = 7.0 Hz, 3H), 0.92 (t, J = 7.3 Hz, 12H). LCMS (Method G): [M+H]+= 483.3.

[0511] Step d) 3-Amino-6-[3-[2-(cyclobutylmethyl)-4-ethyl-3-oxo-piperazine-1-carbonyl]phenyl]pyrazine-2-carbonitrile

[0512] Following procedure in example 1 step c, 3-(cyclobutylmethyl)-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (250 mg, 0.5 mmol), 3-amino-6-bromo- pyrazine-2-carbonitrile (113 mg, 0.6 mmol), and cesium carbonate (506 mg, 1.6 mmol) in -148-Attorney Docket No.60185-706601 dioxane:H2O were stirred at 85ºC for 4 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded 3-amino-6-[3-[2-(cyclobutylmethyl)-4-ethyl-3-oxo-piperazine-1- carbonyl]phenyl]pyrazine-2-carbonitrile (35 mg) as a yellow solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.89 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.93 (s, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.12 (s, 2H), 4.60 (s broad, 1H), 3.87 (s broad, 1H), 3.27 – 3.55 (m, 4H), 3.27 – 3.18 (m, 1H), 2.38 – 2.47 (m, 1H), 1.92 – 2.11 (m, 4H), 1.73 – 1.89 (m, 2H), 1.53 – 1.73 (m, 2H), 1.08 (t, J = 7.1 Hz, 3H). LCMS (Method E): [M+H]+= 419.2851.

[0513] Example 60: Synthesis of 2-amino-5-[3-[2-(cyclobutylmethyl)-4-ethyl-3-oxo-piperazine-1-carbonyl]phenyl]pyridine-3-carbonitrile (Compound 65)

[0514] Step a) 2-Amino-5-[3-[2-(cyclobutylmethyl)-4-ethyl-3-oxo-piperazine-1-carbonyl]phenyl]pyridine-3-carbonitrile

[0515] Following procedure in example 1 step c, 3-(cyclobutylmethyl)-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (250 mg, 0.5 mmol), 2-amino-5-bromo- pyridine-3-carbonitrile (103 mg, 0.5 mmol), and cesium carbonate (506 mg, 1.6 mmol) in dioxane:H2O were stirred at 85ºC for 3 h. Purification by FCC (irregular silica, 0-40% EtOAc in DCM) afforded 2-amino-5-[3-[2-(cyclobutylmethyl)-4-ethyl-3-oxo-piperazine-1- carbonyl]phenyl]pyridine-3-carbonitrile (67 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.58 (d, J = 2.48 Hz, 1 H), 8.20 (d, J = 2.67 Hz, 1 H), 7.70 - 7.77 (m, 1 H), 7.64 (t, J = 1.62 Hz, 1 H), 7.54 (t, J = 7.63 Hz, 1 H), 7.35 (dt, J = 7.58, 1.26 Hz, 1 H), 6.69 (s, 2 H), 4.62 (br s, 1 H), 3.79 - 3.94 (m, 1 H), 3.19 - 3.52 (m, 5 H), 2.46 (br d, J = 0.76 Hz, 1 H), 2.10 (s, 2 H), 1.99 (br s, 2 H), 1.76 - 1.87 (m, 2 H), 1.57 - 1.70 (m, 2 H), 1.08 (t, J = 7.15 Hz, 3 H). LCMS (Method E): [M+H]+= 418.2890.

[0516] Example 61: Synthesis of 1-ethyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-3-propyl-piperazin-2-one (Compound 66)

[0517] Step a) 1-Ethyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoyl]-3-propyl-piperazin-2-oneAttorney Docket No.60185-706601

[0518] Following procedure in example 1 step c, 1-ethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (113 mg, 0.3 mol) and 5-bromo-3-methyl-1H- pyrazolo[3,4-b]pyridine (55 mg, 0.3 mmol)in dioxane:H2O were stirred at 85ºC for 16 h. Crude was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3 (sat. sol.), extracted with DCM, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded 1-ethyl-4-[3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5- yl)benzoyl]-3-propyl-piperazin-2-one (38 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 13.01 (br s, 1 H), 8.80 (d, J = 2.10 Hz, 1 H), 8.44 (d, J = 2.10 Hz, 1 H), 7.86 (d, J = 7.82 Hz, 1 H), 7.76 (s, 1 H), 7.60 (t, J = 7.72 Hz, 1 H), 7.41 (d, J = 7.53 Hz, 1 H), 4.59 - 4.82 (m, 1 H), 3.80 - 4.05 (m, 1 H), 3.19 - 3.60 (m, 5 H), 2.58 (s, 3 H), 1.81 - 1.94 (m, 2 H), 1.38 - 1.52 (m, 2 H), 1.06 - 1.13 (m, 3 H), 0.87 - 0.95 (m, 3 H). LCMS (Method E): [M+H]+= 406.2983.

[0519] Example 62: Synthesis 3-amino-6-[3-(4-ethyl-3-oxo-2-propyl-piperazine-1-carbonyl)phenyl]pyrazine-2-carbonitrile (Compound 67)

[0520] Step a) 3-Amino-6-[3-(4-ethyl-3-oxo-2-propyl-piperazine-1-carbonyl)phenyl]pyrazine-2-carbonitrile

[0521] Following procedure in example 1 step c, 1-ethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (113 mg, 0.3 mol) and 3-amino-6-bromo-pyrazine-2- carbonitrile (52 mg, 0.3 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Crude was diluted in EtOAc and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3 (sat. sol.), extracted with EtOAc, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-4% MeOH in DCM) afforded 3-amino-6-[3-(4-ethyl-3-oxo-2-propyl-piperazine-1- carbonyl)phenyl]pyrazine-2-carbonitrile (47 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.87 - 8.93 (m, 1 H), 7.99 - 8.09 (m, 1 H), 7.91 - 7.96 (m, 1 H), 7.54 - 7.61 (m, 1 H), 7.43 (br d, J = 7.53 Hz, 1 H), 7.13 (br s, 2 H), 4.57 - 4.76 (m, 1 H), 3.82 - 3.94 (m, 1 H), 3.15 - 3.64 (m, 5 -150-Attorney Docket No.60185-706601 H), 1.78 - 1.96 (m, 2 H), 1.38 - 1.52 (m, 2 H), 1.05 - 1.14 (m, 3 H), 0.87 - 0.96 (m, 3 H). LCMS (Method B): [M+H]+= 393.1729.

[0522] Example 63: Synthesis 4-[3-(6-amino-5-methoxy-3-pyridyl)benzoyl]-1-ethyl-3-propyl-piperazin-2-one (Compound 68)

[0523] Step a) 4-[3-(6-Amino-5-methoxy-3-pyridyl)benzoyl]-1-ethyl-3-propyl-piperazin-2-one

[0524] Following procedure in example 1 step c, 1-ethyl-3-propyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (100 mg, 0.2 mol) and 5-bromo-3-methoxy-pyridin-2- amine (47 mg, 0.2 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Crude was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3(sat. sol.), extracted with DCM, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded impure 4-[3-(6-amino-5-methoxy-3-pyridyl)benzoyl]-1-ethyl-3-propyl- piperazin-2-one which was further purified by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 72% [25mM NH4HCO3] - 28% [MeCN:MeOH (1:1)] to 36% [25mM NH4HCO3] -64% [MeCN:MeOH (1:1)]). Resulting solution was lyophilized to afford 4-[3-(6-amino-5-methoxy-3-pyridyl)benzoyl]-1-ethyl-3-propyl-piperazin-2-one (37 mg) as a white powder.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 7.90 (d, J = 1.91 Hz, 1 H), 7.71 (d, J = 7.82 Hz, 1 H), 7.59 (s, 1 H), 7.51 (t, J = 7.68 Hz, 1 H), 7.26 - 7.35 (m, 2 H), 5.55 (s, 2 H), 4.60 - 4.74 (m, 1 H), 3.91 (s, 4 H), 3.20 - 3.57 (m, 5 H), 1.79 - 1.93 (m, 2 H), 1.43 (br d, J = 7.53 Hz, 2 H), 1.09 (t, J = 7.10 Hz, 3 H), 0.87 - 0.96 (m, 3 H). LCMS (Method E): [M+H]+= 397.3071.

[0525] Example 64: Synthesis of 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-3-(cyclobutylmethyl)-1-ethyl-piperazin-2-one (Compound 69)

[0526] Step a) 4-[3-(6-Amino-5-fluoro-3-pyridyl)benzoyl]-3-(cyclobutylmethyl)-1-ethyl-piperazin-2-oneAttorney Docket No.60185-706601

[0527] Following procedure in example 1 step c, 3-(cyclobutylmethyl)-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (250 mg, 0.5 mmol), 5-bromo-3-fluoro- pyridin-2-amine (99 mg, 0.5 mmol), and cesium carbonate (506 mg, 1.6 mmol) in dioxane:H2O were stirred at 85ºC for 6 h. Purification by FCC (irregular silica, 0-10% MeOH in DCM) afforded impure 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-3-(cyclobutylmethyl)-1-ethyl-piperazin-2-one which was further purified by RP (Phenomenex Gemini C1830x100mm 5µm Column, from 70% [25mM NH4HCO3] - 30% [MeCN:MeOH (1:1)] to 27% [25mM NH4HCO3] - 73% [MeCN:MeOH (1:1)]).Resulting solution was concentrated to afford 4-[3-(6-amino-5-fluoro-3-pyridyl)benzoyl]-3-(cyclobutylmethyl)-1-ethyl-piperazin-2-one (41 mg) as a white solid.NMR (400 MHz, DMSO- d6, 100ºC) δ 8.16 (s, 1 H), 7.66 - 7.73 (m, 2 H), 7.59 (s, 1 H), 7.48 - 7.56 (m, 1 H), 7.31 (d, J = 7.53 Hz, 1 H), 5.98 (br s, 2 H), 4.61 (br dd, J = 7.10, 2.72 Hz, 1 H), 3.80 - 3.98 (m, 1 H), 3.23 - 3.52 (m, 5 H), 2.45 (br d, J = 7.72 Hz, 1 H), 1.93 - 2.04 (m, 4 H), 1.81 (br d, J = 9.82 Hz, 2 H), 1.55 - 1.68 (m, 2 H), 1.09 (t, J = 7.15 Hz, 3 H). LCMS (Method B): [M+H]+= 411.2179.

[0528] Example 65: Synthesis of 2-amino-5-[3-[2-(cyclobutylmethyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]pyridine-3-carbonitrile (Compound 70)

[0529] Step a) 2-Amino-5-[3-[2-(cyclobutylmethyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]pyridine-3-carbonitrile

[0530] Following procedure in example 1 step c, 3-(cyclobutylmethyl)-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (250 mg, 0.5 mmol), 2-amino-5-bromo- pyridine-3-carbonitrile (159 mg, 0.8 mmol), and cesium carbonate (696 mg, 2.1mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-5% MeOH in DCM) afforded 2-amino-5-[3-[2-(cyclobutylmethyl)-4-methyl-3-oxo-piperazine-1- carbonyl]phenyl]pyridine-3-carbonitrile (72 mg) as a beige solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.57 (d, J = 2.48 Hz, 1 H), 8.19 (d, J = 2.48 Hz, 1 H), 7.72 (dd, J = 7.87, 1.10 Hz, 1 H), 7.61 - 7.65 (m, 1 H), 7.52 (t, J = 7.72 Hz, 1 H), 7.34 (d, J = 7.63 Hz, 1 H), 6.67 (s, 2 H), 4.51 - 4.72 (m, 1 H), 3.75 - 3.93 (m, 1 H), 3.41 - 3.53 (m, 2 H), 3.20 (br d, J = 11.06 Hz, 1 H), 2.87 (s, 3 H), 2.41 - 2.47 (m, 1 H), 1.91 - 2.08 (m, 4 H), 1.73 - 1.87 (m, 2 H), 1.62 (br, 2 H). LCMS (Method E): [M+H]+= 404.2740.Attorney Docket No.60185-706601

[0531] Example 66: Synthesis of 2-amino-5-[3-(4-ethyl-2-isobutyl-3-oxo-piperazine-1-carbonyl)phenyl]pyridine-3-carbonitrile (Compound 71)

[0532] Step a) tert-Butyl 4-ethyl-2-isobutyl-3-oxo-piperazine-1-carboxylate

[0533] Following procedure in example 2 step b, tert-butyl 4-ethyl-3-oxo-piperazine-1-carboxylate(500 mg, 2.2 mmol) and 1-iodo-2-methyl-propane (760 μL, 6.6 mmol) were used to prepare tert- butyl 4-ethyl-2-isobutyl-3-oxo-piperazine-1-carboxylate. Purification by FCC (irregular silica, 0- 50% EtOAc in heptane) afforded tert-butyl 4-ethyl-2-isobutyl-3-oxo-piperazine-1-carboxylate (295 mg) as a pale-yellow oil.1H NMR (400 MHz, DMSO-d6) δ 4.17 - 4.45 (m, 1 H), 3.78 - 4.07 (m, 1 H), 3.05 - 3.29 (m, 4 H), 1.47 - 1.69 (m, 3 H), 1.41 (s, 9 H), 1.24 (s, 1 H), 1.01 (t, J=7.10 Hz, 3 H), 0.86 - 0.96 (m, 6 H). LCMS (Method D): [M+H]+= 285.1.

[0534] Step b) 1-Ethyl-3-isobutyl-piperazin-2-one hydrochloride

[0535] Following procedure in example 2 step c, tert-butyl 4-ethyl-2-isobutyl-3-oxo-piperazine-1-carboxylate (295 mg, 1.0 mmol) was used to prepare 1-ethyl-3-isobutyl-piperazin-2-one hydrochloride (272 mg) as a brown oil.1H NMR (400 MHz, D2O) δ 3.90 - 4.03 (m, 1 H), 3.66 (br d, J = 5.72 Hz, 2 H), 3.52 - 3.63 (m, 2 H), 3.31 - 3.47 (m, 3 H), 1.82 - 1.97 (m, 1 H), 1.58 - 1.77 (m, 2 H), 1.08 (t, J = 7.25 Hz, 3 H), 0.90 (t, J = 6.29 Hz, 6 H). LCMS (Method C): [M+H]+= 185.2.

[0536] Step c) 1-Ethyl-3-isobutyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0537] Following procedure in example 1 step e, 1-ethyl-3-isobutyl-piperazin-2-one hydrochloride(252.19 mg, 1.0 mmol) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (390 mg, 1.3Attorney Docket No.60185-706601 mmol) were stirred RT at for 16 h. Purification by FCC (irregular silica, 0-40% EtOAc in heptane) afforded 1-ethyl-3-isobutyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (320 mg) as a colourless oil.1H NMR (400 MHz, DMSO-d6) δ 7.77 - 7.84 (m, 1 H), 7.68 (s, 1 H), 7.46 - 7.55 (m, 2 H), 4.50 - 4.85 (m, 1 H), 3.69 - 4.06 (m, 1 H), 3.16 - 3.58 (m, 5 H), 1.68 - 1.85 (m, 12 H), 1.02 - 1.14 (m, 3 H), 0.93 - 1.01 (m, 12 H), 0.83 - 0.92 (m, 6 H). LCMS (Method C): [M+H]+= 471.5.

[0538] Step d) 2-Amino-5-[3-(4-ethyl-2-isobutyl-3-oxo-piperazine-1-carbonyl)phenyl]pyridine-3-carbonitrile

[0539] Following procedure in example 1 step c, 1-ethyl-3-isobutyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (150 mg, 0.3 mol) and 2-amino-5-bromo-pyridine-3- carbonitrile (66 mg, 0.3 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Crude was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3 (sat. sol.), extracted with DCM, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0- 100% EtOAc in heptane) afforded 2-amino-5-[3-(4-ethyl-2-isobutyl-3-oxo-piperazine-1- carbonyl)phenyl]pyridine-3-carbonitrile (50 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.55 - 8.59 (m, 1 H), 8.17 - 8.20 (m, 1 H), 7.73 (br d, J = 7.82 Hz, 1 H), 7.63 (d, J = 1.62 Hz, 1 H), 7.53 (td, J = 7.72, 2.00 Hz, 1 H), 7.34 (br d, J = 7.53 Hz, 1 H), 6.68 (br s, 2 H), 4.77 (br s, 1 H), 3.85 (br s, 1 H), 3.20 - 3.59 (m, 6 H), 1.75 (br d, J = 4.58 Hz, 3 H), 1.08 (td, J = 7.18, 2.15 Hz, 3 H), 0.93 (br d, J = 4.20 Hz, 6 H). LCMS (Method E): [M+H]+= 406.3330.

[0540] Example 67: Synthesis of 2-amino-5-[3-[2-(2,2-dimethylpropyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]pyridine-3-carbonitrile (Compound 72)

[0541] Step a) tert-Butyl 2-(2,2-dimethylpropyl)-4-methyl-3-oxo-piperazine-1-carboxylate

[0542] Following procedure in example 2 step b, tert-butyl 4-methyl-3-oxo-piperazine-1-carboxylate (500 mg, 2.3 mmol) and 1-iodo-2,2-dimethyl-propane (930 μL, 7.0 mmol) were used to -154-Attorney Docket No.60185-706601 prepare tert-butyl 2-(2,2-dimethylpropyl)-4-methyl-3-oxo-piperazine-1-carboxylate. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded tert-butyl 2-(2,2-dimethylpropyl)-4- methyl-3-oxo-piperazine-1-carboxylate (57 mg) as a pale yellow oil.1H NMR (400 MHz, DMSO- d6) δ 4.34 - 4.55 (m, 1 H), 3.79 - 4.01 (m, 1 H), 3.35 (br s, 1 H), 3.13 - 3.19 (m, 1 H), 2.81 (s, 3 H), 1.66 - 1.80 (m, 1 H), 1.54 (br d, J=14.21 Hz, 1 H), 1.41 (s, 9 H), 1.24 (br s, 1 H), 0.92 (br s, 9 H). LCMS (Method D): [M+H]+= 285.2.

[0543] Step b) 3-(2,2-Dimethylpropyl)-1-methyl-piperazin-2-one hydrochloride

[0544] Following procedure in example 2 step c, tert-butyl 2-(2,2-dimethylpropyl)-4-methyl-3-oxo-piperazine-1-carboxylate (57 mg, 0.2 mmol) was used to prepare 3-(2,2-dimethylpropyl)-1-methyl- piperazin-2-one hydrochloride (67 mg, crude) as a brown oil.1H NMR (400 MHz, D2O) δ 4.56 - 4.63 (m, 1 H), 4.32 - 4.41 (m, 1 H), 4.24 (s, 4 H), 3.58 - 3.59 (m, 1 H), 3.59 (s, 2 H), 2.74 (dd, J = 15.40, 3.67 Hz, 1 H), 2.24 (dd, J = 15.35, 6.20 Hz, 1 H), 1.58 (s, 9 H). LCMS (Method D): [M+H]+= 185.1.

[0545] Step c) 3-(2,2-Dimethylpropyl)-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0546] Following procedure in example 1 step e, 3-(2,2-dimethylpropyl)-1-methyl-piperazin-2-onehydrochloride (140 mg, 0.7 mol) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (202 mg, 0.7 mmol) were stirred RT at for 16 h. Purification by FCC (irregular silica, 0-40% EtOAc in heptane) afforded 3-(2,2-dimethylpropyl)-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2- yl)benzoyl]piperazin-2-one (146 mg) as a colourless oil.1H NMR (400 MHz, DMSO-d6) δ 7.78 (dd, J=8.49, 1.05 Hz, 1 H), 7.65 (s, 1 H), 7.45 - 7.55 (m, 2 H), 5.05 - 5.14 (m, 1 H), 3.63 - 3.76 (m, 1 H), 3.51 - 3.63 (m, 1 H), 3.25 (br d, J=4.39 Hz, 1 H), 3.03 - 3.12 (m, 1 H), 2.81 (s, 3 H), 1.65 - 1.78 (m, 9 H), 1.06 - 1.35 (m, 2 H), 0.98 (s, 8 H), 0.92 (t, J=7.39 Hz, 12 H). LCMS (Method D): [M+H]+= 471.4.Attorney Docket No.60185-706601

[0547] Step d) 2-Amino-5-[3-[2-(2,2-dimethylpropyl)-4-methyl-3-oxo-piperazine-1-carbonyl]phenyl]pyridine-3-carbonitrile

[0548] Following procedure in example 1 step c, 3-(2,2-dimethylpropyl)-1-methyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (146 mg, 0.3 mol) and 2-amino-5- bromo-pyridine-3-carbonitrile (61 mg, 0.3 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Crude was diluted in DCM and extracted with HCl (1 N). Aqueous phase was basified with NaHCO3 (sat. sol.), extracted with DCM, dried over MgSO4, filtered, and concentrated. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded 2-amino-5-[3-[2-(2,2-dimethylpropyl)-4- methyl-3-oxo-piperazine-1-carbonyl]phenyl]pyridine-3-carbonitrile (66 mg).1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.56 (d, J = 2.48 Hz, 1 H), 8.18 (d, J = 2.57 Hz, 1 H), 7.73 (dt, J = 7.87, 1.41 Hz, 1 H), 7.61 (t, J = 1.53 Hz, 1 H), 7.53 (t, J = 7.72 Hz, 1 H), 7.31 (d, J = 7.63 Hz, 1 H), 6.68 (br s, 2 H), 4.95 - 5.11 (m, 1 H), 3.60 - 3.75 (m, 2 H), 3.34 - 3.43 (m, 1 H), 3.13 - 3.24 (m, 1 H), 2.86 (s, 3 H), 1.88 (dd, J = 14.45, 9.20 Hz, 1 H), 1.71 - 1.80 (m, 1 H), 0.99 (s, 9 H). LCMS (Method E): [M+H]+= 406.2905.

[0549] Example 68: Synthesis of 2-amino-5-[3-[2-(2-cyclopropylethyl)-4-ethyl-3-oxo-piperazine-1-carbonyl]phenyl]pyridine-3-carbonitrile (Compound 73)

[0550] Step a) tert-Butyl 2-(2-cyclopropylethyl)-4-ethyl-3-oxo-piperazine-1-carboxylate

[0551] Following procedure in example 2 step b, tert-butyl 4-ethyl-3-oxo-piperazine-1-carboxylate(307 mg, 1.3 mmol) and iodoethylcyclopropane (220 mg, 1.1 mmol) were used to prepare tert-butyl 2-(2-cyclopropylethyl)-4-ethyl-3-oxo-piperazine-1-carboxylate. Purification by FCC (irregular silica, 0-4% MeOH in DCM) afforded tert-butyl 2-(2-cyclopropylethyl)-4-ethyl-3-oxo-piperazine-1- carboxylate (455 mg) as a yellow oil.1H NMR (300 MHz, CDCl3) δ .40 - 4.58 (m, 1 H), 4.07 - 4.18 (m, 1 H), 3.43 (br d, J = 4.03 Hz, 5 H), 3.15 (s, 2 H), 1.99 - 2.14 (m, 1 H), 1.81 (br s, 1 H), 1.44 (s, 9Attorney Docket No.60185-706601 H), 1.12 (s, 3 H), 0.58 - 0.73 (m, 1 H), 0.21 - 0.45 (m, 2 H), -0.08 - 0.06 (m, 2 H). LCMS (Method D): [M+H]+= 297.2.

[0552] Step b) 3-(2-Cyclopropylethyl)-1-ethyl-piperazin-2-one hydrochloride

[0553] Following procedure in example 2 step c, tert-butyl 2-(2-cyclopropylethyl)-4-ethyl-3-oxo-piperazine-1-carboxylate (455 mg, 0.8 mmol) was used to prepare 33-(2-cyclopropylethyl)-1-ethyl- piperazin-2-one hydrochloride (455 mg, crude) as a brown oil. LCMS (Method D): [M+H]+= 197.0.

[0554] Step c) 3-(2-Cyclopropylethyl)-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0555] Following procedure in example 1 step e, 3-(2-cyclopropylethyl)-1-ethyl-piperazin-2-onehydrochloride (455 mg, 0.8 mmol) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (305 mg, 0.8 mmol) were stirred RT at for 16 h. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded 3-(2-cyclopropylethyl)-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2- dioxaborolan-2-yl)benzoyl]piperazin-2-one (243 mg) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.74 - 7.93 (m, 2 H), 7.37 - 7.53 (m, 2 H), 4.65 - 5.31 (m, 1 H), 3.21 - 3.61 (m, 4 H), 1.87 - 2.00 (m, 1 H), 1.65 - 1.85 (m, 9 H), 1.16 (br t, J = 7.06 Hz, 4 H), 0.97 (t, J = 7.44 Hz, 12 H), 0.88 (br d, J = 6.87 Hz, 4 H), 0.23 - 0.51 (m, 2 H), 0.08 (s, 2 H). LCMS (Method D): [M+H]+= 483.3.

[0556] Step d) 2-Amino-5-[3-[2-(2-cyclopropylethyl)-4-ethyl-3-oxo-piperazine-1-carbonyl]phenyl]pyridine-3-carbonitrileAttorney Docket No.60185-706601

[0557] Following procedure in example 1 step c, 3-(2-cyclopropylethyl)-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (100 mg, 0.2 mol), 2-amino-5-bromo- pyridine-3-carbonitrile (49 mg, 0.2 mmol), and cesium carbonate (203 mg, 0.6 mmol) in dioxane:H2O were stirred at 85ºC for 16 h. Purification by FCC (irregular silica, 0-100% MeOH in DCM) afforded 2-amino-5-[3-[2-(2-cyclopropylethyl)-4-ethyl-3-oxo-piperazine-1- carbonyl]phenyl]pyridine-3-carbonitrile (37 mg) as a white foam.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.54 - 8.61 (m, 1 H), 8.15 - 8.21 (m, 1 H), 7.70 - 7.75 (m, 1 H), 7.60 - 7.66 (m, 1 H), 7.50 - 7.55 (m, 1 H), 7.31 - 7.36 (m, 1 H), 6.57 - 6.72 (m, 2 H), 4.56 - 4.78 (m, 1 H), 3.79 - 3.97 (m, 1 H), 3.43 - 3.51 (m, 2 H), 3.38 - 3.42 (m, 1 H), 3.28 - 3.35 (m, 1 H), 3.21 - 3.27 (m, 1 H), 1.89 - 2.05 (m, 2 H), 1.37 (br s, 3 H), 1.06 - 1.11 (m, 3 H), 0.34 - 0.41 (m, 2 H), 0.00 - 0.07 (m, 2 H). LCMS (Method B): [M+H]+= 418.2207.

[0558] Example 69: Synthesis of 2-amino-5-[3-(2-benzyl-4-ethyl-3-oxo-piperazine-1-carbonyl)phenyl]pyridine-3-carbonitrile (Compound 74)

[0559] Step a) tert-Butyl 2-benzyl-4-ethyl-3-oxo-piperazine-1-carboxylate

[0560] Following procedure in example 2 step b, tert-butyl 4-ethyl-3-oxo-piperazine-1-carboxylate(400 mg, 1.8 mmol) and bromomethylbenzene (174 μL, 1.5 mmol) were used to prepare tert-butyl 2- benzyl-4-ethyl-3-oxo-piperazine-1-carboxylate. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded tert-butyl 2-benzyl-4-ethyl-3-oxo-piperazine-1-carboxylate (179 mg) as a colourless oil.1H NMR (300 MHz, DMSO-d6) δ 7.19 - 7.31 (m, 3 H), 7.13 - 7.13 (m, 1 H), 7.10 - 7.18 (m, 1 H), 4.46 (br s, 1 H), 3.81 - 4.03 (m, 1 H), 3.20 - 3.31 (m, 2 H), 3.07 (br d, J = 5.87 Hz, 4 H), 0.93 - 1.33 (m, 13 H). LCMS (Method D): [M+H]+= 319.2.

[0561] Step b) 3-Benzyl-1-ethyl-piperazin-2-one hydrochlorideAttorney Docket No.60185-706601

[0562] Following procedure in example 2 step c, tert-butyl 2-benzyl-4-ethyl-3-oxo-piperazine-1-carboxylate (179 mg, 0.6 mmol) was used to prepare 3-benzyl-1-ethyl-piperazin-2-one hydrochloride (0.140 g, crude) as a brown oil.1H NMR (300 MHz, DMSO-d6) δ 7.22 - 7.43 (m, 5 H), 4.12 (dd, J = 7.72, 5.15 Hz, 1 H), 3.68 (ddd, J = 13.28, 8.42, 5.10 Hz, 1 H), 3.25 - 3.53 (m, 7 H), 3.16 - 3.22 (m, 1 H), 1.11 (t, J = 7.10 Hz, 3 H). LCMS (Method D): [M+H]+= 219.1.

[0563] Step c) 3-Benzyl-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one

[0564] Following procedure in example 1 step e, 3-benzyl-1-ethyl-piperazin-2-one hydrochloride(0.140 g, 0.6 mmol) and 3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (167 mg, 0.6 mmol) were stirred RT at for 16 h. Purification by FCC (irregular silica, 0-100% EtOAc in heptane) afforded 3-benzyl-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (133 mg) as a beige solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 7.74 (d, J = 7.44 Hz, 1 H), 7.48 (s, 1 H), 7.41 (t, J = 7.58 Hz, 1 H), 7.13 - 7.31 (m, 6 H), 4.87 (br d, J = 5.82 Hz, 1 H), 3.70 (br s, 1 H), 3.07 - 3.49 (m, 7 H), 1.70 - 1.86 (m, 8 H), 1.09 (t, J=7.15 Hz, 3 H), 0.98 (td, J = 7.41, 0.81 Hz, 12 H). LCMS (Method D): [M+H]+= 505.2.

[0565] Step d) 2-Amino-5-[3-(2-benzyl-4-ethyl-3-oxo-piperazine-1-carbonyl)phenyl]pyridine-3-carbonitrile

[0566] Following procedure in example 1 step c, 3-benzyl-1-ethyl-4-[3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-2-one (0.133 g, 0.3 mol), 2-amino-5-bromo-pyridine-3- carbonitrile (63 mg, 0.3 mmol), and cesium carbonate (257 mg, 0.8 mmol) in dioxane:H2O were stirred at 85ºC for 2 h. Purification by FCC (irregular silica, 0-50% EtOAc in heptane) afforded 2- amino-5-[3-(2-benzyl-4-ethyl-3-oxo-piperazine-1-carbonyl)phenyl]pyridine-3-carbonitrile (43 mg)Attorney Docket No.60185-706601 as a beige solid.1H NMR (400 MHz, DMSO-d6, 100ºC) δ 8.51 (d, J = 2.57 Hz, 1 H), 8.10 (d, J = 2.48 Hz, 1 H), 7.65 - 7.71 (m, 1 H), 7.45 (t, J = 7.72 Hz, 1 H), 7.15 - 7.34 (m, 6...

Claims

Attorney Docket No.60185-706601 CLAIMS WHAT IS CLAIMED IS:

1. A compound represented by the structure of Formula (I-A), (I-B), (I-C), (I-D), or (I-E):or a pharmaceutically acceptable salt thereof, wherein: each of X1is selected from N or C(R10); R10is selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, - N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, - N(R11)C(O)N(R11)2, -S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, and - CN; and C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - -248-Attorney Docket No.60185-706601 N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -R1is selected from: hydrogen, halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, - N(R12)C(O)R12, -C(O)OR12, -OC(O)R12, -N(R12)C(O)OR12, -OC(O)N(R12)2, - N(R12)C(O)N(R12)2, -S(O)R12, -S(O)2R12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -NO2, and - CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -C(O)OR12, -OC(O)R12, -N(R12)C(O)OR12, -OC(O)N(R12)2, -N(R12)C(O)N(R12)2, - S(O)R12, -S(O)2R12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -NO2, =O, =S, =NR12, and -CN; or R1and R10may come together with the atom to which they are attached to form a C3-6carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =NR13, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, =NR13, and -CN; R2is independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, - S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, - S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, =O, =S, =NR14, and -CN; R3is independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, and -CN; -249-Attorney Docket No.60185-706601 (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, - SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, - SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; and (iii) C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; or two R3may come together with the atom to which they are attached, to form a C3-6 carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, - C(O)OR16, -OC(O)R16, -N(R16)C(O)OR16, -OC(O)N(R16)2, -N(R16)C(O)N(R16)2, - S(O)R16, -S(O)2R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -NO2, =O, =S, =NR16, and -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -N(R16)C(O)OR16, -OC(O)N(R16)2, -N(R16)C(O)N(R16)2, - S(O)R16, -S(O)2R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -NO2, =O, =S, =NR16, and -CN; wherein when one R3is n-butyl, R4is methyl, and R1is NH2; then each of X1are C(R10); R4is selected from: -250-Attorney Docket No.60185-706601 C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -C(O)R17, -C(O)N(R17)2, -N(R17)C(O)R17, -C(O)OR17, -OC(O)R17, -N(R17)C(O)OR17, -OC(O)N(R17)2, -N(R17)C(O)N(R17)2, - S(O)R17, -S(O)2R17, -N(R17)S(O)2R17, -S(O)2N(R17)2, -NO2, =O, =S, =NR17, and -CN; R5is independently selected at each occurrence from: halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -N(R18)C(O)R18, - C(O)OR18, -OC(O)R18, -N(R18)C(O)OR18, -OC(O)N(R18)2, -N(R18)C(O)N(R18)2, - S(O)R18, -S(O)2R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -NO2, =O, =S, =NR18, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -N(R18)C(O)R18, -C(O)OR18, -OC(O)R18, -N(R18)C(O)OR18, -OC(O)N(R18)2, -N(R18)C(O)N(R18)2, - S(O)R18, -S(O)2R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -NO2, =O, =S, =NR18, and -CN; R11, R12, R13, R14, R15, R16, R17, and R18are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O- C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4.

2. The compound or salt of claim 1, wherein the structure is (I-B), (I-C), (I-D), or (I-E):-251-Attorney Docket No.60185-7066013. The compound or salt of claim 2, wherein the structure is (I-B) or (I-C):

4. The compound or salt of claims 2 or 3, wherein n is 0.

5. The compound or salt of claims 2 or 3, wherein n is selected from 1 and 2.

6. The compound or salt of claim 5, wherein each R2 is independently selected at eachoccurrence from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -NO2, -CN;and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -NO2, =O, =S, =NR14, and - CN. -252-Attorney Docket No.60185-7066017. The compound or salt of claim 6, wherein each R2 is independently selected at eachoccurrence from halogen, -OR14, -N(R14)2, -C(O)R14, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

8. The compound or salt of any one of claims 2 to 7, wherein m is 0.

9. The compound or salt of any one of claims 2 to 7, wherein m is selected from 1 and 2.

10. The compound or salt of claim 9, wherein R5 is independently selected at each occurrencefrom halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)OR18, -OC(O)R18, -NO2, =O, =S, =NR18, - CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)OR18, -OC(O)R18, -NO2, =O, =S, =NR18, and -CN.

11. The compound or salt of claim 10, wherein R5 is independently selected at eachoccurrence from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)OR18, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

12. The compound or salt of any one of claims 2 to 11, wherein R4 is C1-6 alkyl optionallysubstituted with one or more substituents independently selected from halogen, -OR17, -SR17, - N(R17)2, -C(O)R17, -C(O)N(R17)2, -C(O)OR17, -OC(O)R17, -S(O)R17, -S(O)2R17, -NO2, =O, =S, =NR17, and -CN.

13. The compound or salt of claim 12, wherein R4 is C1-6 alkyl optionally substituted with oneor more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -NO2, =O, and -CN.

14. The compound or salt of claim 13, wherein R4 is methyl.

15. The compound or salt of any one of claims 2 to 14, wherein one of X1 is N.

16. The compound or salt of any one of claims 2 to 14, wherein each of X1 is C(R10).

17. The compound or salt of any one of claims 1 to 16, wherein R10 is selected fromhydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, - C(O)OR11, -OC(O)R11, -NO2, =O, =S, =NR11, and -CN.

18. The compound or salt of claim 17, wherein R10 is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN; and C1-3alkyl, C2-3alkenyl, and C2-3alkynyl, each of which is -253-Attorney Docket No.60185-706601 optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -NO2, =O, =S, and -CN.

19. The compound or salt of claim 18, wherein R10 is selected from hydrogen, fluoro, methyl,chloro,-C=C, -CHF2, -CN, -OCH3, and -CF3.

20. The compound or salt of any one of claims 1 to 16, wherein R1 and R10 may cometogether with the atom to which they are attached, to form a C3-6carbocycle or a 3- to 6- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

21. The compound or salt of claim 20, wherein R1 and R10 may come together with the atomto which they are attached to form a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

22. The compound or salt of claim 21, wherein R1 and R10 may come together with the atomto which they are attached to form a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -C(O)OR13, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -NO2, =O, =S, and -CN.

23. The compound or salt of claim 22, wherein R1 and R10 may come together with the atomto which they are attached, to form:. -254-Attorney Docket No.60185-70660124. The compound or salt of any one of claims 2 to 23, wherein R3 is independently selectedat each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 carbocycle; the C1-6 alkyl, C2-6 alkenyl, and C3-6carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, -CN; and C1-3alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, and - CN.

25. The compound or salt of claim 24, wherein R3 is independently selected at eachoccurrence from hydrogen and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, and C3-6 carbocycle optionally substituted with C1-6 alkyl and C1-6 haloalkyl.

26. The compound or salt of claim 25, wherein R3 is independently selected at eachoccurrence from hydrogen and.

27. The compound or salt of claim 1, wherein the structure is Formula (I-A):or a pharmaceutically acceptable salt thereof, wherein: each of X1is selected from N or C(R10); R10is selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -and - CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -255-Attorney Docket No.60185-706601 -C(O)OR11, -OC(O)R11, -N(R11)C(O)OR11, -OC(O)N(R11)2, -N(R11)C(O)N(R11)2, - S(O)R11, -S(O)2R11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -NO2, =O, =S, =NR11, and -CN; R1is selected from: hydrogen, halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, - N(R12)C(O)R12, -C(O)OR12, -OC(O)R12, -N(R12)C(O)OR12, -OC(O)N(R12)2, - N(R12)C(O)N(R12)2, -S(O)R12, -S(O)2R12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -NO2, and - CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -C(O)OR12, -OC(O)R12, -N(R12)C(O)OR12, -OC(O)N(R12)2, -N(R12)C(O)N(R12)2, - S(O)R12, -S(O)2R12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -NO2, =O, =S, =NR12, and -CN; or R1and R10may come together with the atom to which they are attached to form a C3-6 carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, =O, =S, =NR13, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)C(O)OR13, -OC(O)N(R13)2, -N(R13)C(O)N(R13)2, - S(O)R13, -S(O)2R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, =NR13, and -CN; R2is independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, - S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -N(R14)C(O)OR14, -OC(O)N(R14)2, -N(R14)C(O)N(R14)2, - S(O)R14, -S(O)2R14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -NO2, =O, =S, =NR14, and -CN; R3is independently selected at each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: -256-Attorney Docket No.60185-706601 halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, - SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, - SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, -S(O)R15, -S(O)2R15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; and (iii) C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -N(R15)C(O)OR15, -OC(O)N(R15)2, -N(R15)C(O)N(R15)2, - S(O)R15, -S(O)2R15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -NO2, =O, =S, =NR15, and -CN; or two R3may come together with the atom to which they are attached, to form a C3-6 carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, - C(O)OR16, -OC(O)R16, -N(R16)C(O)OR16, -OC(O)N(R16)2, -N(R16)C(O)N(R16)2, - S(O)R16, -S(O)2R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -NO2, =O, =S, =NR16, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -N(R16)C(O)OR16, -OC(O)N(R16)2, -N(R16)C(O)N(R16)2, - S(O)R16, -S(O)2R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -NO2, =O, =S, =NR16, and -CN; wherein when one R3is n-butyl, R4is methyl, and R1is NH2; then each of X1are C(R10); R4is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -C(O)R17, -C(O)N(R17)2, -N(R17)C(O)R17, -257-Attorney Docket No.60185-706601 -C(O)OR17, -OC(O)R17, -N(R17)C(O)OR17, -OC(O)N(R17)2, -N(R17)C(O)N(R17)2, - S(O)R17, -S(O)2R17, -N(R17)S(O)2R17, -S(O)2N(R17)2, -NO2, =O, =S, =NR17, and -CN; R5is independently selected at each occurrence from: halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -N(R18)C(O)R18, - C(O)OR18, -OC(O)R18, -N(R18)C(O)OR18, -OC(O)N(R18)2, -N(R18)C(O)N(R18)2, - S(O)R18, -S(O)2R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -NO2, =O, =S, =NR18, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)N(R18)2, -N(R18)C(O)R18, -C(O)OR18, -OC(O)R18, -N(R18)C(O)OR18, -OC(O)N(R18)2, -N(R18)C(O)N(R18)2, - S(O)R18, -S(O)2R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -NO2, =O, =S, =NR18, and -CN; R11, R12, R13, R14, R15, R16, R17, and R18are each independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4.

28. The compound or salt of claim 27, wherein n is 0.

29. The compound or salt of claim 27, wherein n is selected from 1 and 2.

30. The compound or salt of claim 29, wherein n is 1.

31. The compound or salt of any one of claims 1, 27, 29, or 30, wherein each R2 isindependently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -NO2, -CN; and C1-6 alkyl optionally substituted with one or moresubstituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -NO2, =O, =S, =NR14, and -CN. -258-Attorney Docket No.60185-70660132. The compound or salt of claim 31, wherein each R2 is independently selected at eachoccurrence from: halogen, -OR14, -N(R14)2, -C(O)R14, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

33. The compound or salt of claim 32, wherein each R2 is independently selected at eachoccurrence from fluoro.

34. The compound or salt of any one of claims 27 to 33, wherein m is 0.

35. The compound or salt of any one of claims 27 to 33, wherein m is selected from 1 and 2.

36. The compound or salt of claim 35, wherein m is 1.

37. The compound or salt of claims 35 or 36, wherein R5 is independently selected at eachoccurrence from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)OR18, -OC(O)R18, -NO2, =O, =S, =NR18, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)R18, -C(O)OR18, -OC(O)R18, -NO2, =O, =S, =NR18, and -CN.

38. The compound or salt of claim 37, wherein R5 is independently selected at eachoccurrence from halogen, -OR18, -N(R18)2, -C(O)R18, -C(O)OR18, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl.

39. The compound or salt of claim 38, wherein R5 is independently selected at eachoccurrence from methyl.

40. The compound or salt of any one of claims 27 to 39, wherein R4 is C1-6 alkyl optionallysubstituted with one or more substituents independently selected from halogen, -OR17, -SR17, - N(R17)2, -C(O)R17, -C(O)N(R17)2, -C(O)OR17, -OC(O)R17, -S(O)R17, -S(O)2R17, -NO2, =O, =S, =NR17, and -CN.

41. The compound or salt of claim 40, wherein R4 is C1-6 alkyl optionally substituted with oneor more substituents independently selected from halogen, -OR17, -SR17, -N(R17)2, -NO2, =O, and -CN.

42. The compound or salt of claim 41, wherein R4 is C1-3 alkyl optionally substituted withhalogen, -OR17, -SR17, -N(R17)2, -NO2, =O, and -CN.

43. The compound or salt of claim 41, wherein R4 is selected from methyl, ethyl, propyl, n-butyl, and isobutyl, each of which is optionally substituted with one or more substituents -259-Attorney Docket No.60185-706601 independently selected from halogen, -OR17, -SR17, -N(R17)2, -C(O)R17, -C(O)N(R17)2, - C(O)OR17, -OC(O)R17, -S(O)R17, -S(O)2R17, -NO2, =O, =S, =NR17, and -CN.

44. The compound or salt of claim 43, wherein R4 is selected from methyl, ethyl, propyl, n-butyl, and isobutyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR17, -N(R17)2, and -CN.

45. The compound or salt of claim 44, wherein R4 is selected from methyl, ethyl, propyl, n-butyl, and isobutyl, each of which is optionally substituted with one or more fluoro substituents.

46. The compound or salt of claim 45, wherein R4 is selected from methyl, ethyl, propyl, n-butyl, and isobutyl.

47. The compound or salt of claim 46, wherein R4 is selected from, , and.

48. The compound or salt of claim 42, wherein R4 is selected from, , ,.

49. The compound or salt of any one of claims 27 to 48, wherein one of X1 is N.

50. The compound or salt of any one of claims 27 to 48, wherein each of X1 is C(R10).

51. The compound or salt of claim 50, wherein R10 is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, =NR11, and -CN.

52. The compound or salt of claim 51, wherein R10 is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -NO2, -CN; and C1-3alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -NO2, =O, =S, and - CN.

53. The compound or salt of claim 52, wherein R10 is selected from hydrogen, fluoro, andmethyl. -260-Attorney Docket No.60185-70660154. The compound or salt of claim 53, wherein R10 is selected from hydrogen, fluoro, methyl,chloro, -CHF2, -CN, -OCH3, and -CF3.

55. The compound or salt of any one of claims 27 to 54, wherein R1 is selected fromhydrogen, halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, - NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -NO2, =O, =S, =NR12, and -CN.

56. The compound or salt of claim 55, wherein R1 is selected from hydrogen, halogen, -OR12,-SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -NO2, and -CN; and each R12is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

57. The compound or salt of claim 56, wherein R1 is selected from hydrogen, halogen, -OR12,-SR12, and -N(R12)2; and each R12is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl.

58. The compound or salt of claim 57, wherein R1 is -N(R12)2; and each R12 is selected fromhydrogen, C1-6 alkyl, and C1-6 haloalkyl.

59. The compound or salt of claim 58, wherein R1 is selected from, , and.

60. The compound or salt of any one of claims 27 to 50, wherein R1 and R10 may cometogether with the atom to which they are attached, to form a C3-6carbocycle or a 3- to 6- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

61. The compound or salt of claim 60, wherein R1 and R10 may come together with the atomto which they are attached to form a C3-6 carbocycle optionally substituted with one or more substituents independently selected from: -261-Attorney Docket No.60185-706601 halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

62. The compound or salt of claims 60, wherein R1 and R10 may come together with the atomto which they are attached to form a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

63. The compound or salt of claim 62, wherein R1 and R10 may come together with the atomto which they are attached to form a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -NO2, =O, =S, and -CN.

64. The compound or salt of claim 63, wherein R1 and R10 may come together with the atomto which they are attached to form a 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -C(O)OR13, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -NO2, =O, =S, and -CN.

65. The compound or salt of claim 63, wherein R1 and R10 may come together with the atomto which they are attached, to form:-262-Attorney Docket No.60185-70660166. The compound or salt of claim 64, wherein R1 and R10 may come together with the atomto which they are attached, to form:,67. The compound or salt of any one of claims 27 to 66, wherein R3 is independently selectedat each occurrence from (i), (ii), and (iii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15,-C(O)OR15, -OC(O)R15, -NO2, and -CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted withone or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN, C3-6 carbocycle and 3- to 6- membered heterocycle, the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - NO2, =O, =S, and -CN; and (iii) C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - NO2, =O, =S, and -CN.

68. The compound or salt of claim 67, wherein R3 is independently selected at eachoccurrence from (i) and (ii): (i) hydrogen, halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15,-C(O)OR15, -OC(O)R15, -NO2, and -CN; and -263-Attorney Docket No.60185-706601 (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted withone or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN, C3-6 carbocycle and 3- to 6- membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, - NO2, =O, =S, and -CN.

69. The compound or salt of claim 68, wherein R3 is independently selected at eachoccurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C3-6carbocycle; the C1-6alkyl, C2-6alkenyl, and C3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, - N(R15)2, -NO2, =O, -CN; and C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -NO2, =O, and -CN.

70. The compound or salt of claim 69, wherein R3 is independently selected at eachoccurrence from hydrogen, C1-6alkyl, and C2-6alkenyl, the C1-6alkyl, and C2-6alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN, and C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - C(O)OR15, -OC(O)R15, -NO2, =O, =S, -CN, C1-6 alkyl, and C1-6 haloalkyl.

71. The compound or salt of claim 70, wherein R3 is independently selected at eachoccurrence from hydrogen, C1-6 alkyl, and C2-6 alkenyl, the C1-6 alkyl, and C2-6 alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, and C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. -264-Attorney Docket No.60185-70660172. The compound or salt of claim 71, wherein R3 is independently selected at eachoccurrence from hydrogen,, , , , , ,73. The compound or salt of claim 70, wherein R3 is independently selected at eachoccurrence from hydrogen, C1-6alkyl, and C2-6alkenyl, the C1-6alkyl, and C2-6alkenyl are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, and C3-6 carbocycle optionally substituted with C1-6 alkyl, and C1-6haloalkyl.

74. The compound or salt of claim 73, wherein R3 is independently selected at eachoccurrence from hydrogen,.

75. The compound or salt of claim 70, wherein R3 is independently selected at eachoccurrence from hydrogen and C3-6carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -NO2, -CN, C1-6alkyl, and C1-6 haloalkyl.

76. The compound or salt of claim 75, wherein R3 is independently selected at eachoccurrence from hydrogen and.

77. The compound or salt of any one of claims 27 to 76, wherein R3 is independently selectedat each occurrence from hydrogen,.

78. The compound or salt of any one of claims 27 to 77, wherein R3 is independently selectedat each occurrence from hydrogen,, , , , , , ,-265-Attorney Docket No.60185-70660179. The compound or salt of any one of claims 27 to 66, wherein two R3 may come togetherwith the atom to which they are attached, to form a C3-6 carbocycle or a 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, - C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN.

80. The compound or salt of claim 79, wherein two R3 may come together with the atom towhich they are attached, to form a C3-6 carbocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, - C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN; andC1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN.

81. The compound or salt of claim 80, wherein two R3 may come together with the atom towhich they are attached, to form a saturated C3-6carbocycle, optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, - C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -C(O)OR16, -OC(O)R16, -NO2, =O, =S, =NR16, and -CN.

82. The compound or salt of claim 81, wherein two R3 may come together with the atom towhich they are attached, to form.

83. The compound or salt of any one of claims 27 to 82, wherein when one R3 is n-butyl, R4is methyl, and R1is NH2; then R10is selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -266-Attorney Docket No.60185-706601 -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =O, =S, and -CN.

84. The compound or salt of claim 1, wherein the compound of Formula (I-A), (I-B), (I-C),(I-D), or (I-E) is selected from a compound of Table 1, or a pharmaceutically acceptable salt thereof.

85. A pharmaceutical composition comprising a compound or salt of any one of claims 1 to84, and a pharmaceutical acceptable excipient.

86. A method of killing a cancer cell or inhibiting cell proliferation, comprising contacting acell with a compound or salt of any one of claims 1 to 84, or a pharmaceutical composition of claim 85.

87. The method of claim 86, wherein the cancer cell is a Cal 27 cell or a HeLa cell.

88. The method of claims 86 or 87, wherein the cancer cell is a squamous cell carcinoma or ahepatocellular carcinoma cell.

89. A method of treating a carcinoma comprising, administering to a subject in need thereof acompound or salt of any one of claims 1 to 84, or a pharmaceutical composition of claim 85.

90. The method of claim 89, wherein the carcinoma is a squamous cell carcinoma or ahepatocellular carcinoma cell. -267-

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