Substituted heterocyclic modulators for the treatment of disease

Abstract

The disclosure herein provides compounds and pharmaceutical compositions for killing a cancer cell or inhibiting cancer cell proliferation. Further, the compound and pharmaceutical compositions disclosed herein, are useful in methods for the inhibition of cancer cell proliferation.

Description

SUBSTITUTED HETEROCYCLIC MODULATORS FOR THE TREATMENT OF DISEASE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 655,288 filed on June 3, 2024, and U.S. Provisional Application No.63 / 708,643 filed on October 17, 2024, the entirety of each 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. This number is expected to increase to 30.2 million by 2040. In 2022, there will be an estimated 1.9 million new cancer cases diagnosed and 609,360 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 structure of Formula (I): (I); or a pharmaceutically acceptable salt thereof, wherein: Y1 is selected from N and C(R3); X1 is selected at each occurrence from N and C(R3), wherein one occurrence of X1 is N and two occurrences of X1 are C(R3); R1 is selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =NR11, and -CN; andC3-12carbocycle and 3- to 12-membered heterocycle, 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, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, - N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -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, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, - N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =NR11, and -CN; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -OC(O)R12, -N(R12)C(O)R12, -N(R12)S(O)2R12, -S(O)R12, -S(O)2R12, -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, -C(O)N(R12)2, -OC(O)R12, -N(R12)C(O)R12, -N(R12)S(O)2R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =NR12, and -CN; or two occurrences of R2 come together with the adjacent carbon atoms to which they are each bound to form a C3-6 cycloalkyl; each R3 is independently selected at each occurrence from: hydrogen, halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, - OC(O)R13, -N(R13)C(O)R13, -N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, - OC(O)R13, -N(R13)C(O)R13, -N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =NR13, and -CN; and C3-12carbocycle and 3- to 12-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, -C(O)N(R13)2, -OC(O)R13, -N(R13)C(O)R13, - N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -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, -C(O)N(R13)2, -OC(O)R13, -N(R13)C(O)R13, - N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =NR13, and -CN; Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from:halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, - OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN; each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; each R15is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle; wherein the C3-10carbocycle is optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; and m is selected from 0, 1, 2, 3, 4, and 5.

[0004] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt of any one thereof:Formula (Ia); Formula (Ib); or Formula (Ic); wherein Ring A, R1, R2, R3, and m are each defined as for a compound or salt of Formula (I).

[0005] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Id), Formula (Ie), or Formula (If), or a pharmaceutically acceptable salt of any one thereof:Formula (Id); Formula (Ie); or Formula (If); wherein Ring A, R1, R2, R3, and m are each defined as for a compound or salt of Formula (I).

[0006] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ia-ii), Formula (Ib-ii), or Formula (Ic-ii), or a pharmaceutically acceptable salt of any one thereof:Formula (Ia-ii); Formula (Ib-ii); or Formula (Ic-ii); wherein Ring A and R1 are each defined as for a compound or salt of Formula (I).

[0007] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), or a pharmaceutically acceptable salt of any one thereof:Formula (Id-ii); Formula (Ie-ii); or Formula (If-ii); wherein Ring A and R1 are each defined as for a compound or salt of Formula (I).

[0008] In some aspects, the present disclosure provides a compound represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: Y2 is selected from N and C(R22); R21 is selected from: hydrogen, halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, - C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, - S(O)2R121, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, - C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, - S(O)2R121, -NO2, =O, =S, =NR121, and -CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, -OC(O)R121, - N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, =O, =S, =NR121, and -CN. Each R22 is independently selected from at each occurrence from: hydrogen, halogen, -OR122,, -SR122,, -N(R122,)2, -C(O)R122,, -C(O)OR122,, -C(O)N(R122,)2, - OC(O)R122,, -N(R122,)C(O)R122, -N(R122),S(O)2R122,, -S(O)R122,, -S(O)2R122,, -NO2, -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR122,, -SR122,, -N(R122,)2, -C(O)R122,, -C(O)OR122,, -C(O)N(R122,)2, - OC(O)R122,, -N(R122,)C(O)R122,, -N(R122,)S(O)2R122,, -S(O)R122,, -S(O)2R122,, -NO2, =O, =S, =NR122,, and -CN;Ring B is selected from phenyl and pyridinyl, wherein the phenyl is substituted with one or more R23 and the pyridinyl is optionally substituted with one or more R24; wherein each R23 is independently selected at each occurrence from: halogen, -OR125, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, -C(O)N(R123)2, - OC(O)R123, -N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR123, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, -C(O)N(R123)2, -OC(O)R123, -N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, -NO2, =O, =S, =NR123, and -CN; and each R24 is independently selected from at each occurrence from: fluoro, bromo, iodo, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, - C(O)N(R124)2, -OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, - NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, -C(O)N(R124)2, -OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, -NO2, =O, =S, =NR124, and -CN; each R121, R122,, R123and R124are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionallysubstituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; and each R125 is independently selected at each occurrence from: hydrogen; C2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN.

[0009] In some embodiments, for the compound or salt of Formula (II), the compound is represented by the structure of Formula (IIa), or Formula (IIb), or a pharmaceutically acceptable salt of any one thereof:Formula (IIa); or Formula (IIb). wherein Ring B, R21, and R22 are each defined as for a compound or salt of Formula (II).

[0010] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of the Formulas provided herein and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (II) and at least one pharmaceutically acceptable excipient.

[0011] In some aspects, the present disclosure provides a method for killing a cancer cell or inhibiting cancer cell proliferation comprising contacting the cancer cell to a compound or salt of Formula (I). In some aspects, the present disclosure provides a method for killing a cancer cell or inhibiting cancer cell proliferation comprising contacting the cancer cell to a compound or salt of Formula (II).

[0012] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound or salt of Formula (I). In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound or salt of Formula (II). In some embodiments, the cancer is ovarian cancer or melanoma. INCORPORATION BY REFERENCE

[0013] All publications, patents, and patent applications mentioned in this specification are herein 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

[0014] While preferred embodiments of the present disclosure have been shown and described herein, 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 disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. Definitions

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference.

[0016] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0017] "Alkyl" refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12alkyl). 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-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4alkyl). 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., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15alkyl). 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-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5alkyl). 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.

[0018] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8alkenyl). 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.

[0019] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkynyl). 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-C6alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0020] "Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C10alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5alkylene).

[0021] "Alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (i.e., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene).

[0022] "Alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10 alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene).

[0023] 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. The term -Cx-y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example, -C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0024] The terms “Cx-y alkenyl” and “Cx-y alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx-y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, - C2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C2-6 alkynylene- may be selected from ethynylene, propynylene,butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0025] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which 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 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 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.

[0026] "Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical 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., C3-12cycloalkyl). 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., C5-7 cycloalkyl). 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.

[0027] "Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon 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., C3-10cycloalkenyl). 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.

[0028] The term “carbocyclene” refers to a divalent ring, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen atoms. The carbocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the carbocyclene are to the rest of the molecule and to the radical group are through any two carbons respectively. Carbocyclene includes arylene and cycloalkylene. The term therefore distinguishes carbocyclene from heterocyclene in which the divalent ring comprises at least one atom that is different from a carbon atom. The heterocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the heterocyclene are to the rest of the molecule and to the radical group through any two atoms respectively, valency permitting. Heterocyclene includes heteroarylene and heterocycloalkylene. Carbocyclene and heterocyclene may each be optionally substituted by one or more substituents such as those substituents described herein.

[0029] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon 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.

[0030] A “Cx-y carbocycle” is meant to include groups that contain from x to y carbons in a ring. For example, the term “C3-6 carbocycle” 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.

[0031] The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, 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 oneheteroatom 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 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.

[0032] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical that comprises 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, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0033] The term “heteroaryl” refers to a radical derived from a 5- to 12-membered aromatic ring radical 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.

[0034] 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.

[0035] An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0036] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.

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

[0038] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, 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.

[0039] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or 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.

[0040] In some embodiments, substituents may include any substituents described herein, for example: 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) a b a tR (where t is 1 or 2), -R -S(O)tR (where t is 1 or 2), -Rb-S(O) a tOR (where t is 1 or 2), and -Rb-S(O) a tN(R )2(where t is 1 or 2); and alkyl, alkenyl, 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) a tR (where t is 1 or 2), -Rb-S(O)Ra (where t is 1 or 2), -Rb-S( a b a t O)tOR (where t is 1 or 2) and -R -S(O)tN(R )2(where t is 1 or 2); wherein each Ra is 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) a b a tR (where t is 1 or 2), -R -S(O)tR (where t is 1 or 2), -Rb-S(O) a b a tOR (where t is 1 or 2) and -R -S(O)tN(R )2(where t is 1 or 2); and wherein each Rb is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rc is 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.

[0041] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety 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.

[0042] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical 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.

[0043] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” 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 must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0044] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the 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.

[0045] As used herein, the phrase "a subject in need thereof" refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0046] The terms “administer”, “administered”, “administers” and “administering” are defined as providing 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 certain embodiments, 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 disclosure or a prodrug of a compound of the disclosure to the individual in need.

[0047] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired 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 somelevel 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.

[0048] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder 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.

[0049] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / 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. Compounds Compounds of Formula (I)

[0050] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: Y1 is selected from N and C(R3); X1 is selected at each occurrence from N and C(R3), wherein one occurrence of X1 is N and two occurrences of X1 are C(R3); R1 is selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2,C3-12carbocycle and 3- to 12-membered heterocycle, 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, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, - N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -OC(O)R12, -N(R12)C(O)R12, -N(R12)S(O)2R12, -S(O)R12, -S(O)2R12, -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, -C(O)N(R12)2, - OC(O)R12, -N(R12)C(O)R12, -N(R12)S(O)2R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =NR12, and -CN; or two occurrences of R2 come together with the adjacent carbon atoms to which they are each bound to form a C3-6 cycloalkyl; each R3 is independently selected at each occurrence from: hydrogen, halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, - OC(O)R13, -N(R13)C(O)R13, -N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, - OC(O)R13, -N(R13)C(O)R13, -N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =NR13, and -CN; and C3-12carbocycle and 3- to 12-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, -C(O)N(R13)2, -OC(O)R13, -N(R13)C(O)R13, - N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -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, -C(O)N(R13)2, -OC(O)R13, -N(R13)C(O)R13, - N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =NR13, and -CN; Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from:halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, - OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN; each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; each R15is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle; wherein the C3-10carbocycle is optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; and m is selected from 0, 1, 2, 3, 4, and 5.

[0051] In some embodiments, for the compound or salt of Formula (I), Y is selected from N and C(R3). In some embodiments, Y is N. In some embodiments, Y is C(R3). In some embodiments, Y is C(R3), wherein R3 is hydrogen. In some embodiments, Y is C(H).

[0052] In some embodiments, for the compound or salt of Formula (I), X1 is selected at each occurrence from N and C(R3), wherein one occurrence of X1 is N and two occurrences of X1 are C(R3). In some embodiments, X1 is selected at each occurrence from N and C(H), wherein one occurrence of X1 is N and two occurrences of X1 are C(H).

[0053] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt of any one thereof:Formula (Ia); Formula (Ib); or Formula (Ic); wherein Ring A, R1, R2, R3, and m are each defined as for a compound or salt of Formula (I).

[0054] In some aspects, the compound or salt of Formula (I) is represented by the structure of Formula (Ia), Formula (Ib), or Formula (Ic):Formula (Ia); Formula (Ib); or Formula (Ic); or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2,C3-12carbocycle and 3- to 12-membered heterocycle, 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, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, - N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -OC(O)R12, -N(R12)C(O)R12, -N(R12)S(O)2R12, -S(O)R12, -S(O)2R12, -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)OR12, -C(O)N(R12)2, - OC(O)R12, -N(R12)C(O)R12, -N(R12)S(O)2R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =NR12, and -CN; or two occurrences of R2 come together with the adjacent carbon atoms to which they are each bound to form a C3-6 cycloalkyl; each R3 is independently selected at each occurrence from: hydrogen, halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, - OC(O)R13, -N(R13)C(O)R13, -N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, - OC(O)R13, -N(R13)C(O)R13, -N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =NR13, and -CN; and C3-12carbocycle and 3- to 12-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, -C(O)N(R13)2, -OC(O)R13, -N(R13)C(O)R13, - N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -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, -C(O)N(R13)2, -OC(O)R13, -N(R13)C(O)R13, - N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =NR13, and -CN; Ring A is selected from phenyl, pyrazolyl, and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from:halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -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)OR14, -C(O)N(R14)2, - OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN; each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; each R15is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle; wherein the C3-10carbocycle is optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; and m is selected from 0, 1, and 2.

[0055] In some aspects, the compound or salt of Formula (I) is represented by the structure of Formula (Ia):Formula (Ia); or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: hydrogen, halogen, -OR11, -N(R11)2, -C(O)R11, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -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 from: halogen, -OR11, - N(R11)2, -C(O)R11, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl; each R2 is independently selected at each occurrence from halogen, -OR12, -N(R12)2, -C(O)R12, - NO2, -CN, C1-6alkyl, and C1-6haloalkyl; or two occurrences of R2 come together with the adjacent carbon atoms to which they are each bound to form a C3-6 cycloalkyl; each R3 is independently selected at each occurrence from: hydrogen, halogen, -OR13, -N(R13)2, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -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 from halogen, -OR13, - N(R13)2, -C(O)R13, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl; Ring A is selected from phenyl, pyrazolyl, and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R14)2, - C(O)R14, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl; each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; andC3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; each R15is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle; wherein the C3-10carbocycle is optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; and m is selected from 0, 1, and 2.

[0056] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ia), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ic), or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Id), Formula (Ie), or Formula (If), or a pharmaceutically acceptable salt of any one thereof:Formula (Id); Formula (Ie); or Formula (If); wherein Ring A, R1, R2, R3, and m are each defined as for a compound or salt of Formula (I).

[0058] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Id), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ie), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (If), or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ia-ii), Formula (Ib-ii), or Formula (Ic-ii), or a pharmaceutically acceptable salt of any one thereof:Formula (Ia-ii); Formula (Ib-ii); or Formula (Ic-ii); wherein Ring A and R1 are each defined as for a compound or salt of Formula (I).

[0060] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ia-ii), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ib-ii), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ic-ii), or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), or a pharmaceutically acceptable salt of any one thereof:Formula (Id-ii); Formula (Ie-ii); or Formula (If-ii); wherein Ring A and R1 are each defined as for a compound or salt of Formula (I).

[0062] In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Id-ii), or a pharmaceutically acceptable salt thereof. Insome embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (Ie-ii), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound or salt of Formula (I), the compound is represented by the structure of Formula (If-ii), or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), or Formula (If), m is selected from 0, 1, 2, 3, 4, and 5. In some embodiments, m is selected from 0, 1, 2, 3, and 4. In some embodiments, m is selected from 0, 1, 2, and 3. In some embodiments, m is selected from 0, 1, and 2. In some embodiments, m is selected from 0 and 1. In some embodiments, m is selected from 1, 2, 3, 4, and 5. In some embodiments, m is selected from 1, 2, 3, and 4. In some embodiments, m is selected from 1, 2, and 3. In some embodiments, m is selected from 1 and 2. In some embodiments, m is selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0 or 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0064] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), or Formula (If), m is 2. In some embodiments, two occurrences of R2 come together with the adjacent carbon atoms to which they are each bound to form a C3 cycloalkyl.

[0065] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), or Formula (If), each R3 is independently selected at each occurrence from: hydrogen, halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, - OC(O)R13, -N(R13)C(O)R13, -N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -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, -C(O)N(R13)2, -OC(O)R13, -N(R13)C(O)R13, -N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =NR13, and -CN.

[0066] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), or Formula (If), each R3 is independently selected at each occurrence from: hydrogen, halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, -OC(O)R13, - N(R13)C(O)R13, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, -OC(O)R13, -N(R13)C(O)R13, -NO2, =O, and -CN.

[0067] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), or Formula (If), each R3 is independently selected at each occurrence from: hydrogen, halogen, -OR13, -N(R13)2, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -NO2, =O, and -CN. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, -OR13, -N(R13)2, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, - NO2, =O, and -CN; and m is 0. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, -OR13, -N(R13)2, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, - NO2, =O, and -CN; and 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -NO2, -CN, and C1-6alkyl.

[0068] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), or Formula (If), each R3 is independently selected at each occurrence from: hydrogen, halogen, C1-6haloalkyl, C1-6hydroxyalkyl, and C1-6alkyl. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, C1-6haloalkyl, C1-6hydroxyalkyl, and C1-6alkyl. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, C1-6fluoroalkyl, C1-6alkyl, and 5- to 6-membered heterocycle optionally substituted with one or more C1-6alkyl. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, C1- 6 fluoroalkyl, C1-6alkyl, and 5- to 6-membered heterocycle optionally substituted with one or more C1-6alkyl; and m is 0 or 2. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, C1-6fluoroalkyl, C1-6alkyl, and 5- to 6-membered heterocycle optionally substituted with one or more C1-6alkyl; and m is 0. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, C1-6fluoroalkyl, C1-6alkyl, and 5-membered heterocycle optionally substituted with one or more C1-6alkyl. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, C1-6fluoroalkyl, C1-6alkyl, and pyrazolyl optionally substituted with one or more C1-6alkyl. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, C1-6fluoroalkyl, C1-6alkyl, and . In some embodiments, each R3 isindependently selected at each occurrence from hydrogen, methyl, and . In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, C1- 6 fluoroalkyl, and C1-6alkyl. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, and C1-6alkyl. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen and C1-6alkyl. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen and C1-6fluoroalkyl. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen and halogen. In some embodiments, each R3 is hydrogen. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, C1-6fluoroalkyl, and C1-6alkyl; and m is 0. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen, halogen, and C1-6alkyl; and m is 0. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen and C1-6alkyl; and m is 0. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen and C1-6fluoroalkyl; and m is 0. In some embodiments, each R3 is independently selected at each occurrence from: hydrogen and halogen; and m is 0. In some embodiments, each R3 is hydrogen; and m is 0.

[0069] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), or Formula (If), R1 is selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -S(O)R11, -S(O) 11 2R , -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =NR11, and - CN; and C3-12carbocycle and 3- to 12-membered heterocycle, 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, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -S(O)R11, - S(O)2R11, -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, - C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =NR11, and -CN.

[0070] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), or Formula (If), R1 is selected from: hydrogen, halogen, -OR11, -N(R11) 11 11 11 2, -C(O)R , -C(O)OR , -C(O)N(R )2, -OC(O)R11, -N(R11)C(O)R11, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -NO2, =O, and -CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -NO2, =O, and -CN.

[0071] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), or Formula (If), R1 is selected from: hydrogen, halogen, -OR11, -N(R11)2, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, =O, and -CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, =O, and -CN.

[0072] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), R1 is selected from: hydrogen, halogen, -OR11, -N(R11)2, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, =O, and -CN; and C3-8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(R11)2, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -NO2, =O, and -CN.

[0073] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), R1 is selected from:hydrogen, halogen, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11-OC(O)R11, -N(R11-CN; and C3-12carbocycle and 3- to 12-membered heterocycle, 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, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, - S(O)R11, -S(O)2R11, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -

[0074] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), R1 is selected from: hydrogen, halogen, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen and -OR11; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, and C1-6alkyl. In some embodiments, R1 is selected from: hydrogen, halogen, - CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen and -OR11; and C3-6 cycloalkyl and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR11, and C1-6alkyl. In some embodiments, R1 is selected from: hydrogen, halogen, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen and -OH; and C3-6 cycloalkyl and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, and C1-6alkyl. In some embodiments, R1 is selected from: hydrogen, halogen, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen and -OH; and C3-6 cycloalkyl optionally substituted with one or more substituents independently selected from: halogen, -OH, and C1-6alkyl. In some embodiments, R1 is selected from: hydrogen, halogen, - CN; methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen and -OH; and cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, and pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, and C1-6alkyl. In some embodiments, R1 is selected from: hydrogen, halogen, -CN; methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen and -OH; and cyclopropyl optionally substituted with one or more substituents independently selected from: halogen, -OH, and C1-6alkyl. In some embodiments, R1 is selected from: tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, and pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, and C1-6alkyl. In some embodiments, R1 is selected from: hydrogen, chloro, bromo, -CN, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-selected from: hydrogen, chloro, bromo, -CN, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl,, , . In some embodiments, R1 is selected from hydrogen and methyl. In some embodiments, R1 is methyl. In some embodiments, R1 is hydrogen.

[0076] In some embodiments, for the compound or salt of Formula (selected from:.

[0077] In some embodiments, for the compound or salt of Formulaselected from:

[0078] In some embodiments, for the compound or salt of Formula (selected from:

[0079] In some embodiments, for the compound or salt of Formula (.

[0080] In some embodiments, for the compound or salt of Formula (from:

[0081] In some embodiments, for the compound or salt of Formula (Ia-ii)selected from:

[0082] In some embodiments, for the compound or salt of Formula (Ib-ii)from:

[0083] In some embodiments, for the compound or salt of Formula (Ic-ii).

[0084] In some embodiments, for the compound or salt of Formula (Ie-ii)selected from:

[0085] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, - C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, - NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN.

[0086] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is selected from C6-10 aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, - N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN.

[0087] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is selected from phenyl and 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, - C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, - NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independentlyselected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN.

[0088] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is selected from phenyl and 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, - C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, - NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN; and each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN, C1-6alkyl, and C1-6haloalkyl; each R15is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN, C1-6alkyl, and C1-6haloalkyl.

[0089] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is selected from phenyl and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, - C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected fromhalogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, - N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN.

[0090] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is pyrazolyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, - N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, - S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN. In some embodiments, Ring A is pyrazolyl optionally substituted with one or more substituents independently selected from C1-6alkyl and C1-6haloalkyl. In some embodiments, Ring A is pyrazolyl substituted with one or more C1-6haloalkyl groups. In some embodiments, Ring A is pyrazolyl substituted with one trifluoromethyl group.

[0091] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is selected from phenyl and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, - C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, - N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN; and each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN, C1-6alkyl, and C1-6haloalkyl; each R15is independently selected at each occurrence from: hydrogen;C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN, C1-6alkyl, and C1-6haloalkyl.

[0092] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is selected from:.

[0093] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is C3-12carbocycle optionally substituted with one or more substituents independently selected from: halogen, - OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, - NO2, =O, =S, =NR14, and -CN. In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, - C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, - S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN. In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, and -CN. In some embodiments, each R14is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6fluoroalkyl; and each R15is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6fluoroalkyl. In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, and -CN; wherein each R14is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6fluoroalkyl; and each R15is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6fluoroalkyl.

[0094] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is selected from:

[0095] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is selected from:.

[0096] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii),Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is 3- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, - N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN. In some embodiments, Ring A is pyridinyl optionally substituted with one or more substituents independently selected from: halogen, - OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, - NO2, =O, =S, =NR14, and -CN. In some embodiments, Ring A is pyridinyl optionally substituted with one or more substituents independently selected from: halogen, and -OR15. In some embodiments, Ring A is pyridinyl optionally substituted with one or more substituents independently selected from: halogen, and -OR15; wherein each R15is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is pyridinyl optionally substituted with one or more substituents independently selected from: halogen and -OR15; wherein each R15is independently selected at each occurrence from C1-6alkyl and C1-6haloalkyl.

[0097] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is 5- to 9-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, - N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN. In some embodiments, Ring A is 5- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN. In some embodiments, Ring A is pyridinyl optionally substituted with one or more substituents independently selected from: halogen, - OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, - NO2, =O, =S, =NR14, and -CN. In some embodiments, Ring A is pyridinyl optionally substituted with one or more substituents independently selected from: halogen, and -OR15. In some embodiments, Ring A is pyridinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, - C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, - NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN. In some embodiments, Ring A is pyridinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, and C1-6haloalkyl. In some embodiments, each R15is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is pyridinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR15, and C1-6haloalkyl; wherein each R15is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is pyridinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, and C1-6haloalkyl; wherein each R15is independently selected at each occurrence from C1-3 alkyl and C1-3 haloalkyl. In some embodiments, Ring A is pyridinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, and C1-6haloalkyl; wherein each R15is independently selected at each occurrence from methyl, ethyl,. In some embodiments, Ring A is pyrazolyl optionally substituted with halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is pyrazolyl optionally substituted with C1-6haloalkyl. In some embodiments, Ring A is pyrazolyl optionally substituted with CF3. In some embodiments, Ring A is.In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii),Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii), Ring A is selected from:.In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii): each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN, C1-6alkyl, and C1-6haloalkyl; each R15is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN, C1-6alkyl, and C1-6haloalkyl.

[0098] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii): each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle; andC3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN, C1-6alkyl, and C1-6haloalkyl; each R15is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN, C1-6alkyl, and C1-6haloalkyl.

[0099] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii): each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and each R15is independently selected at each occurrence from: hydrogen; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle; wherein the C3-10carbocycle is optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN.

[0100] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii): each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen;C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and each R15is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle.

[0101] In some embodiments, for the compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii): each R11, R12, R13, R14, and R15and are independently selected at each occurrence from: hydrogen; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, and -CN. In some embodiments, each R11, R12, R13, R14, and R15and are independently selected at each occurrence from: hydrogen, C1-6alkyl and C1- 6 haloalkyl.

[0102] In some embodiments, the compound or salt of Formula (I) is selected from:pharmaceutically acceptable salt of any one thereof.

[0103] In some embodiments, the compound or salt of Formula (I) is selected from:,,,pharmaceutically acceptable salt of any one thereof. Compounds of Formula (II).

[0104] In some aspects, the present disclosure provides a compound represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: Y2 is selected from N and C(R22); R21 is selected from: hydrogen, halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, - C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, - S(O)2R121, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, - C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, - S(O)2R121, -NO2, =O, =S, =NR121, and -CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, =O, =S, =NR121, and -CN. each R22 is independently selected from at each occurrence from: hydrogen, halogen, -OR122,, -SR122,, -N(R122,)2, -C(O)R122,, -C(O)OR122,, -C(O)N(R122,)2, - OC(O)R122,, -N(R122,)C(O)R122,, -N(R122,)S(O)2R122,, -S(O)R122,, -S(O)2R122,, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR122,, -SR122,, -N(R122,)2, -C(O)R122,, -C(O)OR122,, -C(O)N(R122,)2, - OC(O)R122,, -N(R122,)C(O)R122,, -N(R122,)S(O)2R122,, -S(O)R122,, -S(O)2R122,, -NO2, =O, =S, =NR122,, and -CN;Ring B is selected from phenyl and pyridinyl, wherein the phenyl is substituted with one or more R23 and the pyridinyl is optionally substituted with one or more R24; wherein each R23 is independently selected at each occurrence from: halogen, -OR125, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, -C(O)N(R123)2, - OC(O)R123, -N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR123, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, -C(O)N(R123)2, -OC(O)R123, -N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, -NO2, =O, =S, =NR123, and -CN; and each R24 is independently selected from at each occurrence from: fluoro, bromo, iodo, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, - C(O)N(R124)2, -OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, - NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, -C(O)N(R124)2, -OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, -NO2, =O, =S, =NR124, and -CN; each R121, R122,, R123and R124are independently selected at each occurrence from: hydrogen;C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; and each R125 is independently selected at each occurrence from: hydrogen; C2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN.

[0105] In some embodiments, for the compound or salt of Formula (II), Y2 is selected from N and C(R22). In some embodiments, for the compound or salt of Formula (II), Y2 is selected from N and C(H). In some embodiments, Y2 is N. In some embodiments, Y2 is C(R22). In some embodiments, Y2 is C(H).

[0106] In some embodiments, for the compound or salt of Formula (II), the compound is represented by the structure of Formula (IIa), or Formula (IIb), or a pharmaceutically acceptable salt of any one thereof:Formula (IIa); or Formula (IIb). wherein Ring B, R21, and R22 are each defined as for a compound or salt of Formula (II).

[0107] In some embodiments, for the compound or salt of Formula (II), the compound is represented by the structure of Formula (IIa), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound or salt of Formula (II), the compound is represented by the structure of Formula (IIb), or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), each R22 is independently selected from at each occurrence from: hydrogen, halogen, -OR122,, -SR122,, -N(R122,)2, -C(O)R122,, -C(O)OR122,, -C(O)N(R122,)2, - OC(O)R122,, -N(R122,)C(O)R122,, -N(R122,)S(O)2R122,, -S(O)R122,, -S(O)2R122,, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR122,, -SR122,, -N(R122,)2, -C(O)R122,, -C(O)OR122,, -C(O)N(R122,)2, -OC(O)R122,, - N(R122,)C(O)R122,, -N(R122,)S(O)2R122,, -S(O)R122,, -S(O)2R122,, -NO2, =O, =S, =NR122,, and -CN.

[0109] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), each R22 is independently selected from at each occurrence from: hydrogen, halogen, -OR122,, -N(R122,)2, -C(O)R122,, -C(O)OR122,, -C(O)N(R122,)2, - OC(O)R122,, -N(R122,)C(O)R122,, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR122,, -N(R122,)2, -C(O)R122,, -C(O)OR122,, -C(O)N(R122,)2, -OC(O)R122,, - N(R122,)C(O)R122,, -NO2, =O, and -CN.

[0110] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), each R22 is independently selected from at each occurrence from: hydrogen, halogen, -OR122,, -N(R122,)2, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR122,, -N(R122,)2, -NO2, =O, and -CN. In some embodiments, each R22 is independently selected at occurrence from hydrogen, halogen, and C1-6alkyl. In some embodiments, each R22 is independently selected at occurrence from hydrogen and halogen. In some embodiments, each R22 is independently selected at occurrence from hydrogen, fluoro, and bromo. In some embodiments, each R22 is hydrogen.

[0111] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), R21 is selected from: hydrogen, halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, - OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, -OC(O)R121, - N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, =O, =S, =NR121, and -CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR121, -SR121, - N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, - N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR121, -SR121, -N(R121)2, - C(O)R121, -C(O)OR121, -C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, - S(O)R121, -S(O)2R121, -NO2, =O, =S, =NR121, and -CN.

[0112] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), R21 is selected from: hydrogen, halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, - OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, -OC(O)R121, - N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, =O, =S, =NR121, and -CN.

[0113] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), R21 is selected from: hydrogen, halogen, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR121, and -CN. In some embodiments, R21 is selected from: hydrogen, halogen, C1-6haloalkyl, and C1-6alkyl. In some embodiments, R21 is selected from: hydrogen and C1-6alkyl. In some embodiments, R21 is selected from: hydrogen and methyl. In some embodiments, R21 is hydrogen. In some embodiments, R21 is methyl.

[0114] In some embodiments, for the compound or salt of Formula

[0115] In some embodiments, for the compound or salt of Formula (selected from:

[0116] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), Ring B is selected from phenyl and pyridinyl, wherein the phenyl is substituted with one or more R23 and the pyridinyl is optionally substituted with one or more R24; wherein each R23 is independently selected at each occurrence from: halogen, -OR125, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, -C(O)N(R123)2, -OC(O)R123, - N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR123, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, -C(O)N(R123)2, -OC(O)R123, - N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, -NO2, =O, =S, =NR123, and -CN; and each R24 is independently selected from at each occurrence from: fluoro, bromo, iodo, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, -C(O)N(R124)2, - OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, -NO2, -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, -C(O)N(R124)2, -OC(O)R124, - N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, -NO2, =O, =S, =NR124, and -CN.

[0117] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), Ring B is phenyl or pyridinyl, wherein the phenyl is substituted with one or more R23 and the pyridinyl is optionally substituted with one or more R24; wherein each R23 is independently selected at each occurrence from: halogen , -OR125, C1-6alkyl and -CN; and each R23 is independently selected at each occurrence from: halogen , -OR124C1-6alkyl and -CN. In some embodiments, Ring B is phenyl or pyridinyl, wherein the phenyl is substituted with one or more R23 and the pyridinyl is optionally substituted with one or more R24; wherein each R23 is independently selected at each occurrence from: halogen , -OR125, C1-6alkyl and -CN; and each R23 is independently selected at each occurrence from: halogen , -OR124C1-6alkyl and -CN; and each R121, R122,, R123and R124are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN C1-6alkyl, and C1-6haloalkyl; and each R125 is independently selected at each occurrence from: hydrogen; C2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN, C1-6alkyl, and C1-6haloalkyl.

[0118] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), Ring B is selected from:

[0119] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), Ring B is selected from:.

[0120] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), Ring B is phenyl substituted with one or more R23; wherein each R23 is independently selected at each occurrence from: hydrogen, halogen, -OR125, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, -C(O)N(R123)2, - OC(O)R123, -N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR123, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, -C(O)N(R123)2, -OC(O)R123, - N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, -NO2, =O, =S, =NR123, and -CN.

[0121] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), Ring B is phenyl substituted with one or more R23; wherein each R23 is independently selected at each occurrence from: halogen and -CN. In some embodiments, Ring B

[0122] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), Ring B is pyridinyl optionally substituted with one or more R24; wherein each R24 is independently selected at each occurrence from: fluoro, bromo, iodo, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, -C(O)N(R124)2, -OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, - S(O)R124, -S(O)2R124, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR124, -SR124, -N(R124)2, -C(O)R124, - C(O)OR124, -C(O)N(R124)2, -OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, -NO2, =O, =S, =NR124, and -CN. In some embodiments, Ring B is pyridinyl optionally substituted with one or more R24; wherein each R24 is independently selected at each occurrence from: -OR124and C1-6alkyl. In some embodiments, Ring B is selected from.

[0123] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb): each R121, R122,, R123and R124are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN C1-6alkyl, and C1-6haloalkyl; and each R125 is independently selected at each occurrence from: hydrogen; C2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN, C1-6alkyl, and C1-6haloalkyl.

[0124] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb): each R121, R122,, R123and R124are independently selected at each occurrence from: hydrogen; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and each R125 is independently selected at each occurrence from: hydrogen; and C2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN.

[0125] In some embodiments, for the compound or salt of Formula (II), Formula (IIa), or Formula (IIb), each R121, R122,, R123and R124are independently selected at each occurrence from: hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R125 is independently selected at each occurrence from hydrogen, C2-6 alkyl, and C2-6 haloalkyl.

[0126] In some embodiments, the compound or salt of Formula (II) is selected from:pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the compound or salt of Formula (II) is selected from:pharmaceutically acceptable salt thereof.

[0128] In some aspects, the present disclosure provides a compound selected from:or a pharmaceutically acceptable salt thereof.

[0129] In some aspects, the present disclosure provides a compound selected from:thereof. Methods of Treatment

[0130] The compounds described herein can be used in the preparation of medicaments for the prevention 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.

[0131] The compositions containing the compound(s) described herein can be administered for prophylactic 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 this use will depend on the severity and course of the disease or condition, previous therapy, thepatient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0132] In prophylactic applications, compositions containing the compounds described herein are administered 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.

[0133] In some aspects, the present disclosure provides methods of treating a cancer, comprising administering a compound or salt of the present disclosure to the cancer. In some embodiments, the cancer is a melanoma. In some embodiments, the cancer is ovarian cancer.

[0134] In some aspects, the present disclosure provides methods of inhibiting a A2058 cell, comprising administering a compound or salt of the present disclosure.

[0135] In some aspects, the present disclosure provides methods of inhibiting a PA1 cell, comprising administering a compound or salt of the present disclosure.

[0136] In some aspects, the present disclosure provides a method for killing a cancer cell or inhibiting cancer cell proliferation. In some embodiments, the cancer cell is a melanoma cell. In some embodiments, the cancer cell is an ovarian cancer cell. In some embodiments, inhibiting cancer cell proliferation comprises inhibiting proliferation of a melanoma cell. In some embodiments, inhibiting cancer cell proliferation comprises inhibiting proliferation of an ovarian cancer cell.

[0137] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound or salt of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ia-ii), Formula (Ib-ii), Formula (Ic-ii), Formula (Id-ii), Formula (Ie-ii), or Formula (If-ii). In some embodiments, the cancer is ovarian cancer or melanoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is ovarian cancer.

[0138] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound or salt of Formula (II), Formula (IIa), or Formula (IIb). In some embodiments, the cancer is ovarian cancer or melanoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is ovarian cancer.

[0139] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound or salt selected from Table 26. In some embodiments, the cancer is ovarian cancer or melanoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is ovarian cancer.

[0140] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I). In some embodiments, the cancer is ovarian cancer or melanoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is ovarian cancer.

[0141] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (II). In some embodiments, the cancer is ovarian cancer or melanoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is ovarian cancer.

[0142] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound or salt selected from:pharmaceutically acceptable salt thereof. In some embodiments, the cancer is ovarian cancer or melanoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is ovarian cancer.

[0143] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound orpharmaceutically acceptable salt thereof. In some embodiments, the cancer is ovarian cancer or melanoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is ovarian cancer.

[0144] While preferred embodiments of the present disclosure have been shown and described herein, 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 disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0145] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist 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.

[0146] “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 bedesignated (+) 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 can 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.

[0147] The compounds or salts for the Formulas provided herein, herein may in some cases exist as diastereomers, 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.

[0148] In certain embodiments, compounds or salts for the Formulas provided herein, may comprise two 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 andisolated 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 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.

[0149] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. 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:

[0150] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and / or 14C. 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.

[0151] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H 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.

[0152] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [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.

[0153] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0154] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure.

[0155] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, and 125I are all contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0156] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the 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.

[0157] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds 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 and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Pharmaceutical Formulations

[0158] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of the Formulas provided herein and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (II) and at least one pharmaceutically acceptable excipient.

[0159] 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.

[0160] 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). EXAMPLES

[0161] The disclosure now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration ofcertain aspects and embodiments of the present disclosure, and are not intended to limit the disclosure in any way.

[0162] The following synthetic schemes and / or procedures are provided for purposes of illustration, not limitation. The following 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 available 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. General Experimental

[0163] All solvents and commercial reagents were used as received. Where products were purified by chromatography, silica refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure of nitrogen up to 10 psi accelerated column elution or use of the CombiFlash® Companion purification system or use of the Biotage SP1 purification system. Where products were purified by preparative HPLC purification this was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution UV directed system. Specific columns, mobile phases, modifiers and gradients are listed with the data. Where products were purified by SFC purification this was performed using a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with Stacked InJection Module). Specific columns, mobile phases, modifiers, flow rates, pressures and temperatures are listed with the data. For both preparative HPLC and SFC a Waters 2767 liquid handler acted as both auto-sampler and fraction collector. The purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm and triggered a threshold collection value at 260 nm and, when using the Fractionlynx, the presence of target molecular ion as observed under API conditions. Collected fractions were analysed either by LCMS for preparative HPLC (Waters Acquity systems with Waters SQD) or by SFC (Waters / Thar SFC systems with Waters SQD).

[0164] The purity of the example compounds was assessed by UPLC. The methods used are listed below and the relevant method is listed with the data. All compounds showed ≥ 95% purity. All methods use the gradient program below for the listed mobile phase.

[0165] Analytical Method A: UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS instrument fitted with an Acquity UPLC BEH C181.7 µm 100 x 2.1 mm column plus guard cartridge maintained at 40 °C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid); Flow rate: 0.4 mL / min. Wavelength: 210-400 nm DAD.

[0166] Analytical Method B: UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC- MS instrument fitted with an Acquity UPLC HSS C181.8 µm 100 x 2.1 mm column plus guard cartridge maintained at 40 °C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid); Flow rate: 0.4 mL / min; Wavelength: 210-400 nm DAD.

[0167] Analytical Method C: UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC- MS instrument fitted with an Acquity UPLC BEH C181.7 µm 100 x 2.1 mm column plus guard cartridge maintained at 40 °C. Mobile phase: MeCN (0.1% ammonium hydroxide) in water (0.1% ammonium hydroxide); Flow rate: 0.4 mL / min. Wavelength: 210-400 nm DAD.

[0168] Analytical Method D: UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC- MS instrument fitted with an Acquity UPLC BEH C181.7 µm 100 x 2.1 mm column plus guard cartridge maintained at 40 °C. Mobile phase: MeCN in water + 10 mM ammonium bicarbonate; Flow rate: 0.4 mL / min. Wavelength: 210-400 nm DAD.

[0169] NMR spectra were yield on a Varian Unity Inova 400 spectrometer with a 5mm inverse detection triple resonance probe operating at 400 MHz or on a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detection triple resonance TXI probe operating at 400 MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5mm dual frequency probe operating at 300 MHz. Where DMSO is listed as an NMR solvent, this refers to DMSO-d6. Shifts are given in ppm relative to tetramethylsilane (δ = 0 ppm) or residual solvent (CHCl3 = 7.27 ppm, DMSO = 2.52 ppm). J values are given in Hz throughout. NMR spectra were assigned using DataChord Spectrum Analyst Version 4.0.b21 or SpinWorks version 3. All spectra were in accordance with the assigned structures.Abbreviations

[0170] aq. = aqueous; BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene; Boc = tert- butoxycarbonyl; br = broad; d = doublet; CPME = cyclopentyl methyl ether; dd = double doublet; ddd = doublet of doublet of doublet; DAD = diode array detector; DavePhos Pd G3 = methanesulfonato 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2′-amino-1,1′- biphenyl-2-yl) palladium(II); DCM = dichloromethane; DEA = diethylamine; DIPEA = N,N- diisopropylethylamine; DMF = N,N’-dimethylformamide; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; equiv = eqivalents; HATU = (1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC = high pressure liquid chromatography; hr = hour or hours; IMS = Industrial methylated spirits; IPA = isopropyl alcohol; LCMS = liquid chromatography / mass spectrometry; MeCN = acetonitrile; MeOH = methanol; min = minutes; m / z = mass / charge; NMR = nuclear magnetic resonance; q = quartet; rt = room temperature; RT = retention time; s = singlet; sat. = saturated; RuPhos Pd G3 = (2- dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate; RuPhos Pd G4 = [dicyclohexyl(2′,6′-diisopropoxy-2- biphenylyl)phosphine-κP](methanesulfonatato-κO)[2′-(methylamino-κN)-2-biphenylyl- κC2]palladium; SCX-2 = strong cation exchange chromatography; SFC = supercritical fluid chromatography; t = triplet; T3P = 1-propanephosphonic anhydride solution; TCFH = chloro- N,N,N',N'-tetramethylformamidinium hexafluorophosphate; td = triplet of doublets; TFA = trifluoroacetic acid; THF = tetrahydrofuran; UPLC = ultra performance liquid chromatography; Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; Xantphos Pd G3 = [(4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate. Example 1: Synthesis of Intermediates Intermediate 1: Synthesis of 3-fluoro-5-(piperazin-1-yl)benzonitrile

[0171] Step 1: Synthesis of tert-butyl 4-(3-cyano-5-fluorophenyl)piperazine-1-carboxylate. To a solution of 1-Boc-piperazine (1.00 g, 5.37 mmol, 1.0 equiv.) in toluene (15 mL) in a vial was added 3-bromo-5-fluoro-benzonitrile (1.07 g, 5.37 mmol, 1.0 equiv.), sodium tert-butoxide(0.77 g, 8.05 mmol, 1.5 equiv.), racemic BINAP (0.33 g, 0.537 mmol, 0.1 equiv.) and tris(dibenzylideneacetone)dipalladium(0) (0.49 g, 0.537 mmol, 0.1 equiv.) and the vial was sealed. The mixture was thoroughly degassed with nitrogen after repeated evacuation and refill with nitrogen. This method was repeated to give 4 vials of the same reaction scale. These vials were then stirred at 100°C for 4 hr, then allowed to cool to rt and stood for 16 hr. The four vials were combined and diluted with EtOAc. The organics were washed with water, then brine and dried with sodium sulfate. The mixture was filtered, the filtrate collected, and the solvent was removed. The material was purified by column chromatography on silica (40 g cartridge.15 µm, 0-50% EtOAc / cyclohexane). The appropriate fractions were combined, and the solvent was removed to yield the title compound (5.15 g, 78%) as a pale-yellow solid. ¹H NMR (400 MHz, CDCl3) δ 6.89 (s, 1H), 6.82 – 6.72 (m, 2H), 3.58 (t, J = 5.1 Hz, 4H), 3.20 (t, J = 5.1 Hz, 4H), 1.49 (s, 9H).

[0172] Step 2: Synthesis of 3-fluoro-5-(piperazin-1-yl)benzonitrile. To a solution of tert-butyl 4-(3-cyano-5-fluoro-phenyl)piperazine-1-carboxylate (5.30 g, 17.4 mmol, 1.0 equiv.) in DCM (60 mL) was added TFA (30 mL, 0.392 mol, 22.6 equiv.) and the mixture was stirred at rt for 2 hr. The solvent was removed, the material re-dissolved in DCM then loaded onto an SCX-2 cartridge (50 g, pre-washed with DCM). The cartridge was washed with DCM, then methanol and eluted with 2M NH3 in methanol. The appropriate fractions were combined, and the solvent was removed to yield the title compound (3.19 g, 89%) as an orange oil which crystallised on standing to a yellow solid. ¹H NMR (400 MHz, CDCl3) δ 6.89 (s, 1H), 6.93 – 6.72 (m, 2H), 3.19 (t, J = 5.1 Hz, 4H), 3.02 (t, J = 5.1 Hz, 4H), 1.66 (s, 1H). Intermediate 2: Synthesis of 3-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride

[0173] 3,5-Difluorobenzonitrile (3000 mg, 21.6 mmol, 1.0 equiv.), piperazine (3716 mg, 43.1 mmol, 2.0 equiv.), and potassium carbonate (4471 mg, 32.4 mmol, 1.5 equiv.) were suspended in DMSO (30 mL). The mixture was sparged with nitrogen for 5 min then stirred at 80°C for 2 hr. The mixture was diluted with EtOAc and washed three times with water, then once with brine. The organic layer was separated and dried over Na2SO4, then filtered. The filtrate was stirred and 2 M hydrogen chloride in diethyl ether (34 mL, 67.1 mmol, 3.1 equiv.) was added slowly, resulting in the formation of a white precipitate. The resulting mixture was stirred at rt for30 min, then filtered and the solid was collected and washed with EtOAc then dried in a vacuum desiccator at 45°C for 18 hr to yield the title compound (4940 mg, 93%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 9.48 (br s, 1H), 7.32 - 7.30 (m, 1H), 7.21 (td, J = 2.4, 12.7 Hz, 1H), 7.17 - 7.14 (m, 1H), 3.56 (t, J = 5.3 Hz, 4H), 3.17 (t, J = 5.1 Hz, 4H). Intermediate 3: Synthesis of 3-chloro-5-(piperazin-1-yl)benzonitrile

[0174] Step 1: Synthesis of tert-butyl 4-(3-chloro-5-cyanophenyl)piperazine-1-carboxylate. To a solution of 1-Boc-piperazine (850 mg, 4.56 mmol, 1.0 equiv.) in CPME (15 mL) in a vial was added 3-bromo-5-chloro-benzonitrile (1185 mg, 5.48 mmol, 1.2 equiv.), sodium tert- butoxide (789 mg, 8.21 mmol, 1.8 equiv.) and RuPhos Pd G3 (286 mg, 0.342 mmol, 0.075 equiv.) and the vial was sealed. The mixture in each was thoroughly degassed with nitrogen after repeated evacuation and refill with nitrogen. This method was repeated to give 4 vials of the same reaction scale. These vials were then stirred at 100°C for 5 hr, then allowed to cool to rt and stood for 16 hr. The four vials were combined and diluted with EtOAc. The organics were washed with water, then brine and dried with sodium sulfate. The mixture was filtered, the filtrate collected, and the solvent was removed. The material was purified by column chromatography on silica (40 g cartridge, 50 µm, 0-40% EtOAc / cyclohexane). The appropriate fractions were combined, and the solvent was removed to yield a pale-yellow oil which crystallised on cooling. The material was triturated with hexane, filtered, and dried to yield the title compound (3.17 g, 54%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 7.04 (s, 1H), 6.99 (s, 1H), 3.58 (t, J = 4.5 Hz, 4H), 3.20 (t, J = 4.5 Hz, 4H), 1.49 (s, 9H).

[0175] Step 2: Synthesis of 3-chloro-5-(piperazin-1-yl)benzonitrile. To a solution of tert-butyl 4-(3-chloro-5-cyano-phenyl)piperazine-1-carboxylate (2200 mg, 6.84 mmol, 1.0 equiv.) in DCM (30 mL) was added TFA (15 mL, 0.196 mol, 29 equiv.) and the mixture was stirred for 1.5 hr. The solvent was removed, and the material was re-dissolved in DCM and washed with sat. aq. NaHCO3, then water and brine. The solution was dried with sodium sulfate, filtered, the filtrate collected, and the solvent was removed. The material was purified by column chromatography on silica (40 g cartridge, 15 µm, 0-5% (5% 2M NH3 in MeOH / DCM) / DCM). The appropriate fractions were combined, and the solvent was removed to yield the title compound (1343 mg,89%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.03 (s, 2H), 6.99 (s, 1H), 3.19 (t, J = 5.3 Hz, 4 H), 3.02 (t, J = 5.3 Hz, 4H). NH not observed. Intermediate 4: Synthesis of 3-chloro-5-(piperazin-1-yl)benzonitrile hydrochloride

[0176] 3-Chloro-5-fluorobenzonitrile (12.00 g, 77.1 mmol, 1.0 equiv.), piperazine (19935 mg, 0.231 mol, 3.0 equiv.) and potassium carbonate (15991 mg, 0.116 mol, 1.5 equiv.) were suspended in DMSO (120 mL). The mixture was sparged with nitrogen for 5 minutes, then stirred at 80 °C for 2 hr and allowed to rt. The mixture was diluted with EtOAc and washed three times with water, then once with brine. The organic layer was separated and dried over Na2SO4, then filtered. The filtrate was stirred and 2 M hydrogen chloride in diethyl ether (120 mL, 0.240 mol, 3.1 equiv.) was added slowly, resulting in the formation of a white precipitate. The resulting mixture was stirred at rt for 30 min, then filtered and the solid was collected and washed with EtOAc then dried in a vacuum desiccator at 45°C for 18 hr to yield the title compound (18.25 g, 91%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 9.38 (br s, 2H), 7.43 (dd, J = 1.3, 2.3 Hz, 1H), 7.39 (t, J = 2.3 Hz, 1H), 7.35 (t, J = 1.3 Hz, 1H), 3.55 (t, J = 5.3 Hz, 4H), 3.20-3.13 (m, 4H). Intermediate 5: Synthesis of 3-methoxy-5-(piperazin-1-yl)benzonitrile

[0177] Step 1: Synthesis of tert-butyl 4-(3-cyano-5-methoxy-phenyl)piperazine-1- carboxylate. To a solution of 1-Boc-piperazine (900 mg, 4.83 mmol, 1.0 equiv.) in CPME (15 mL) was added 3-bromo-5-methoxy-benzonitrile (1210 mg, 5.71 mmol, 1.18 equiv.), sodium tert-butoxide (836 mg, 8.70 mmol, 1.8 equiv.) and RuPhos Pd G4 (205 mg, 0.242 mmol, 0.05 equiv.) in a 25 mL vial. This was repeated in three further 25 mL vials. The mixture in each vial was thoroughly degassed with nitrogen by repeated evacuation and refill, then heated at 100°C for 2 hr, then allowed to rt. The mixture was partitioned between EtOAc and water and the phases were separated. The organic layer was washed with water, then with brine and dried with sodium sulfate. The mixture was filtered, the filtrate collected the solvent was removed. Thematerial was purified by column chromatography on silica gel (40 g cartridge, 0-50% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (4.80 g, 76%) as a pale-yellow solid. ¹H NMR (400 MHz, CDCl3) δ 6.76 (dd, J = 1.3, 2.3 Hz, 1H), 6.64 (dd, J = 1.2, 2.5 Hz, 1H), 6.60 (t, J = 2.3 Hz, 1H), 3.80 (s, 3H), 3.59 - 3.55 (m, 4H), 3.18 - 3.14 (m, 4H), 1.48 (s, 9H).

[0178] Step 2: Synthesis of 3-methoxy-5-(piperazin-1-yl)benzonitrile. To a solution of tert- butyl 4-(3-cyano-5-methoxy-phenyl)piperazine-1-carboxylate (4.80 g, 15.1 mmol, 1.0 equiv.) in DCM (40 mL) was added TFA (20 mL, 0.261 mol, 17.3 equiv.) and the mixture was stirred at rt for 1 hr. The solvent was removed and the material was dissolved in DCM and washed with sat. aq. NaHCO3 solution, then dried with sodium sulfate. The mixture was filtered and the solvent was removed. The material was purified by column chromatography on silica gel (40 g cartridge, 15 µM, 0-5% MeOH / DCM) and the appropriate fractions were combined and the solvent was removed to yield the title compound (3000 mg, 91%) as a colourless oil. ¹H NMR (400 MHz, CDCl3) δ 6.77 (t, J = 1.8 Hz, 1H), 6.61 - 6.60 (m, 2H), 3.80 (s, 3H), 3.18 - 3.14 (m, 4H), 3.03 - 3.00 (m, 4H), 1.66 (br s, 1H). Intermediate 6: Synthesis of 3-bromo-5-(difluoromethoxy)benzonitrile

[0179] 3-Bromo-5-hydroxy-benzonitrile (2.0 g, 10.1 mmol, 1.0 equiv.), potassium carbonate (3472 mg, 25.1 mmol, 2.5 equiv.) and (2-bromo-2,2-difluoro-acetyl)oxysodium (2982 mg, 15.1 mmol, 1.5 equiv.) were suspended in a mixture of DMF (18 mL) and water (2 mL). The mixture was stirred at 100°C for 2 hr, then cooled to rt. The mixture was diluted with water and then extracted with diethyl ether. The organics were washed with water and brine, then dried with sodium sulfate, filtered, the filtrate collected, and the solvent was removed. The material was purified by column chromatography on silica gel (25 g cartridge, 50 µm, 0-25% EtOAc / cyclohexane). The appropriate fractions were combined, and the solvent was removed to yield the title compound (1.62 g, 65%) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.56 (s, 1H), 7.39 (s, 1H), 6.55 (t, J = 71.8 Hz, 1H).Intermediate 7: Synthesis of 3-(difluoromethoxy)-5-(piperazin-1-yl)benzonitrile

[0180] Step 1: Synthesis of tert-butyl 4-(3-cyano-5-(difluoromethoxy)phenyl)piperazine-1- carboxylate. To a solution of 1-Boc-piperazine (750 mg, 4.03 mmol, 1.0 equiv.) in CPME (15 mL) was added 3-bromo-5-(difluoromethoxy)benzonitrile (1099 mg, 4.43 mmol, 1.1 equiv.), sodium tert-butoxide (697 mg, 7.25 mmol, 1.8 equiv.) and RuPhos Pd G4 (171 mg, 0.201 mmol, 0.05 equiv.). The mixture was thoroughly degassed with nitrogen by repeated evacuation and refill, then heated at 100°C for 2 hr then allowed to cool to rt. The mixture was diluted with EtOAc and washed with water, then brine and dried with sodium sulfate. The mixture was filtered, the filtrate collected, and the solvent was removed. The material was purified by column chromatography on silica (40 g cartridge, 50 µm, 0-50% EtOAc / cyclohexane). The appropriate fractions were combined, and the solvent was removed to yield the title compound (744 mg, 52%) as a pale-yellow oil. ¹H NMR (400 MHz, CDCl3) δ 6.92 (dd, J = 1.2, 2.3 Hz, 1H), 6.92-6.84 (m, 1H), 6.81 (t, J = 2.3 Hz, 1H), 6.50 (t, J = 72.9 Hz, 1H), 3.59 (t, J = 5.2 Hz, 4H), 3.21 (t, J = 5.2 Hz, 4H), 1.49 (s, 9H).

[0181] Step 2: Synthesis of 3-(difluoromethoxy)-5-(piperazin-1-yl)benzonitrile. To a solution of tert-butyl 4-[3-cyano-5-(difluoromethoxy)phenyl]piperazine-1-carboxylate (744 mg, 2.11 mmol, 1.0 equiv.) in DCM (10 mL) was added TFA (5.0 mL, 65.3 mmol, 31 equiv.) and the mixture was stirred at rt for 2 hr. The solvent was removed, and the material was re-dissolved in DCM and washed with sat. aq. NaHCO3, then water and brine. The solution was dried with sodium sulfate, filtered, the filtrate collected, and the solvent was removed. The material was purified by column chromatography on silica (12 g cartridge, 15 µm, 0-5% methanol / DCM). The appropriate fractions were combined, and the solvent was removed to yield the title compound (340 mg, 64%) as a pale-yellow oil. ¹H NMR (400 MHz, CDCl3) δ 6.96 (dd, J = 1.4, 2.3 Hz, 1H), 6.83-6.79 (m, 1H), 6.50 (t, J = 73.0 Hz, 1H), 3.31-3.17 (m, 4H), 3.11-3.01 (m, 4H), 1.75 (s, 1H).Intermediate 8: Synthesis of 3-(difluoromethoxy)-5-(piperazin-1-yl)benzonitrile hydrochloride

[0182] Step 1: Synthesis of 3-(difluoromethoxy)-5-fluorobenzonitrile.3-Fluoro-5-hydroxy- benzonitrile (4.0 g, 29.2 mmol, 1.0 equiv.), potassium carbonate (10.0 g, 72.6 mmol, 2.5 equiv.) and (2-bromo-2,2-difluoro-acetyl)oxysodium (8.62 g, 43.7 mmol, 1.5 equiv.) were suspended in a mixture of DMF (18 mL) and water (2 mL). The mixture was stirred at 100°C for 2 hr, then cooled to rt. The mixture was diluted with water and then extracted with diethyl ether. The organics were washed with water and brine, then dried with sodium sulfate, filtered, the filtrate collected, and the solvent was removed. The material was purified by column chromatography on silica (80 g cartridge, 50 µm, 0-25% EtOAc / cyclohexane). The appropriate fractions were combined, and the solvent was removed to yield the title compound (2.85 g, 52%) as a colourless oil. ¹H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.56 (s, 1H), 7.39 (s, 1H), 6.55 (t, J = 71.8 Hz, 1H).

[0183] Step 2: Synthesis of 3-(difluoromethoxy)-5-(piperazin-1-yl)benzonitrile hydrochloride. To two reaction vials was added 3-(difluoromethoxy)-5-fluoro-benzonitrile (2.35 g, 12.6 mmol, 1.0 equiv.), piperazine (4327 mg, 50.2 mmol, 4.0 equiv.), potassium carbonate (2603 mg, 18.8 mmol, 1.5 equiv.) and DMSO (30 mL). The mixture was sparged with nitrogen for 5 min, then stirred at 80°C for 2 hr, then allowed to rt. The reaction mixtures were combined and diluted with EtOAc and washed three times with water, then once with brine. The organic layer was separated and dried with sodium sulfate, then filtered. The filtrate was collected and 2 M hydrogen chloride in diethyl ether (20 mL, 39.1 mmol, 3.11 equiv.) was added slowly with stirring, resulting in a white precipitate forming. The mixture was stirred at rt for 30 min, then filtered, washing with EtOAc. The solid was collected and dried in a vacuum desiccator at 45°C for 18 hr to yield the title compound (2910 mg, 80%) as an off-white solid. ¹H NMR (400 MHz, DMSO) δ 9.20 (br s, 1H), 7.35 (t, J = 1.9 Hz, 1H), 7.34 (t, J = 73.6 Hz, 1H), 7.11 - 7.09 (m, 2H), 3.53 (t, J = 5.2 Hz, 4H), 3.19 (t, J = 5.2 Hz, 4H).Intermediate 9: Synthesis of 1-bromo-3-(difluoromethoxy)-5-fluorobenzene

[0184] 3-Bromo-5-fluorophenol (2.0 g, 10.5 mmol, 1.0 equiv.), potassium carbonate (3.6 g, 26.0 mmol, 2.5 equiv.) and (2-bromo-2,2-difluoro-acetyl)oxysodium (3.1 g, 15.7 mmol, 1.5 equiv.) were suspended in a mixture of DMF (18 mL) and water (2 mL). The mixture was stirred at 100°C for 2 hr. The mixture was diluted with water and then extracted with diethyl ether. The organics were washed with water and brine, then dried with sodium sulfate, filtered, the filtrate collected, and the solvent was removed. The material was purified by column chromatography on silica (25 g cartridge, 15 µm, 0-25% EtOAc / cyclohexane). The appropriate fractions were combined, and the solvent was removed to yield the title compound (2.33 g, 92%) as a colourless oil. ¹H NMR (400 MHz, CDCl3) δ 7.15-7.10 (m, 2H), 6.84 (d, J = 9.9 Hz, 1H), 6.50 (t, J = 73.2 Hz, 1H). Intermediate 10: Synthesis of 1-[3-(difluoromethoxy)-5-fluoro-phenyl]piperazine

[0185] Step 1: Synthesis of tert-butyl 4-[3-(difluoromethoxy)-5-fluoro-phenyl]piperazine-1- carboxylate. To a solution of 1-Boc-piperazine (703 mg, 3.77 mmol, 1.0 equiv.) in CPME (15 mL) was added 1-bromo-3-(difluoromethoxy)-5-fluoro-benzene (1.0 g, 4.15 mmol, 1.1 equiv.), sodium tert-butoxide (652 mg, 6.79 mmol, 1.5 equiv.) and RuPhos Pd G4 (160 mg, 0.189 mmol, 0.05 equiv.). The mixture was thoroughly degassed with nitrogen by repeated evacuation and refill, then stirred at 100°C for 3 hr. The mixture was cooled to rt then partitioned between EtOAc and water and the phases separated. The organics were washed with water, then brine and dried with sodium sulfate. The mixture was filtered, the filtrate collected, and the solvent was removed. The material was purified by column chromatography on silica (40 g cartridge, 50 µm, 0-50% EtOAc / cyclohexane). The appropriate fractions were combined, and the solvent was removed to yield the title compound (530 mg, 37%) as a pale-yellow oil. ¹H NMR (400 MHz, CDCl3) δ 6.47 (t, J = 73.6 Hz, 1H), 6.44 (t, J = 2.3 Hz, 1H), 6.42-6.38 (m, 1H), 6.32 (t, J = 2.3 Hz, 1H), 3.56 (t, J = 5.0 Hz, 4H), 3.16 (t, J = 5.0 Hz, 4H), 1.48 (br s, 9H).

[0186] Step 2: Synthesis of 1-[3-(difluoromethoxy)-5-fluoro-phenyl]piperazine. To a solution of tert-butyl 4-[3-(difluoromethoxy)-5-fluoro-phenyl]piperazine-1-carboxylate (530 mg, 1.53 mmol, 1.0 equiv.) in DCM (10 mL) was added TFA (5.0 mL, 65.3 mmol, 43 equiv.) and the mixture was stirred at rt for 2 hr. The solvent was removed, and the material re-dissolved in methanol then loaded onto an SCX-2 cartridge (10 g, pre-washed with DCM). The cartridge was washed with methanol and eluted with 2M NH3 in methanol. The appropriate fractions were combined, and the solvent was removed to yield the title compound (300 mg, 80%) as a pale- yellow gum. NMR (400 MHz, CDCl3) δ 6.48 (t, J = 74.3 Hz, 1H), 6.44 (t, J = 2.3 Hz, 1H), 6.42-6.38 (m, 1H), 6.31 (t, J = 2.3 Hz, 1H), 3.16 (t, J = 5.0 Hz, 4H), 3.01 (t, J = 5.0 Hz, 4H), 1.86 (br s, 1H). Intermediate 11: Synthesis of 1-(5-methylpyridin-3-yl)piperazine

[0187] Step 1: Synthesis of tert-butyl 4-(5-methyl-3-pyridyl)piperazine-1-carboxylate.1- Boc-piperazine (1440 mg, 7.73 mmol, 1.2 equiv.), 3-bromo-5-methylpyridine (0.75 mL, 6.44 mmol, 1.0 equiv.), DavePhos Pd G3 (246 mg, 0.322 mmol, 0.05 equiv.) and sodium tert-butoxide (928 mg, 9.66 mmol, 1.5 equiv.) were suspended in CPME (24 mL) in two vials. The vials were sealed, evacuated and flushed with nitrogen twice. The solutions were stirred at 110°C for 4 hr, then allowed to cool to rt. The mixture was partitioned between EtOAc and water and the phases were separated. The organics were washed with brine, dried with sodium sulfate, filtered, the filtrate collected and the solvent was removed. The material was purified by column chromatography on silica gel (40 g cartridge, 15 µM, 10-100% EtOAc / cyclohexane). The appropriate fractions were combined and the solvent was removed to yield the title compound (1370 mg, 75%) as a white solid. ¹H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 2.8 Hz, 1H), 7.99 - 7.97 (m, 1H), 7.00 (t, J = 2.0 Hz, 1H), 3.59 (t, J = 5.3 Hz, 4H), 3.15 (t, J = 5.2 Hz, 4H), 2.30 (s, 3H), 1.49 (s, 9H).

[0188] Step 2: Synthesis of 1-(5-methylpyridin-3-yl)piperazine. To a solution of tert-butyl 4- (5-methyl-3-pyridyl)piperazine-1-carboxylate (1370 mg, 4.94 mmol, 1.0 equiv.) in DCM (16 mL) was added TFA (8.0 mL, 0.104 mol, 21 equiv.). The mixture was stirred at rt for 3 hr, then the solvent was removed. The material was dissolved in MeOH then loaded onto an SCX-2cartridge (25 g, pre-washed with DCM). The cartridge was washed with methanol and eluted with 2M NH3 in methanol. The appropriate fractions were combined, and the solvent was removed to yield the title compound (860 mg, 96%) as yield a brown oil. ¹H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 2.7 Hz, 1H), 7.95 (s, 1H), 6.99 (s, 1H), 3.18 - 3.14 (m, 4H), 3.06 - 3.02 (m, 4H), 2.29 (s, 3H), 1.65 (br s, 1H). Intermediate 12: Synthesis of 1-(4-methoxypyridin-3-yl)piperazine

[0189] Step 1: Synthesis of benzyl 4-(4-methoxy-3-pyridyl)piperazine-1-carboxylate.3- Bromo-4-methoxy-pyridine (10.00 g, 53.2 mmol, 1.0 equiv.), 1-Z-Piperazine (16 mL, 84.0 mmol, 1.58 equiv.), racemic BINAP (3.31 g, 5.32 mmol, 0.1 equiv.), palladium(II) acetate (597 mg, 2.66 mmol, 0.05 equiv.) and caesium carbonate (35 g, 0.11 mol, 2.0 equiv.) were suspended in anhydrous CPME (200 mL) and the mixture was sparged with nitrogen for 10 min, then stirred at 100°C under an atmosphere of nitrogen for 7 hr. The mixture was allowed to cool to rt, filtered and the solid washed with EtOAc. The filtrate was washed with water (200 mL), the phases separated and the aqueous phase was extracted with EtOAc (2x100 mL). The combined organic phases were then washed with brine (150 mL), dried with sodium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (330 g cartridge, 0-50% acetone / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (9.72 g, 56%) as a colourless crystalline solid. ¹H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 5.5 Hz, 1H), 8.10 (s, 1H), 7.40 - 7.36 (m, 4H), 7.36 - 7.31 (m, 1H), 6.79 (d, J = 5.6 Hz, 1H), 5.17 (s, 2H), 3.92 (s, 3H), 3.71 - 3.67 (m, 4H), 3.11 - 3.04 (m, 4H).

[0190] Step 2: Synthesis of 1-(4-methoxypyridin-3-yl)piperazine. To 10% palladium on carbon (1.07 g, 1.0 mmol, 0.033 equiv.) under a nitrogen atmosphere was added a solution of benzyl 4-(4-methoxy-3-pyridyl)piperazine-1-carboxylate (10.68 g, 31.0 mmol, 1.0 equiv.) in IMS (160 mL). The vessel was evacuated and purged successively with nitrogen (three times) and hydrogen (three times) and the mixture was stirred under an atmosphere of hydrogen at rt for 3 hr. The vessel was evacuated and purged with nitrogen three times and the mixture was filtered through a bed of celite, washing with IMS. The filtrate was collected and the solvent was removed to yield the title compound (5.30 g, 88%) as a colourless oil. ¹H NMR (400 MHz,DMSO) δ 8.11 (d, J = 5.9 Hz, 1H), 7.99 (s, 1H), 6.95 (d, J = 5.4 Hz, 1H), 3.84 (s, 3H), 2.92 (t, J = 5.6 Hz, 4H), 2.81 (t, J = 5.6 Hz, 4H). Intermediate 13: Synthesis of methyl 3-hydroxy-2-iodoisonicotinate

[0191] Step 1: Synthesis of methyl 3-hydroxyisonicotinate hydrochloride. In a 3 L three-neck flask, 3-hydroxypyridine-4-carboxylic acid (75 g, 0.539 mol, 1.0 equiv.) was dissolved in MeOH (1.2 L). Thionyl chloride (90 mL, 1.23 mol, 2.3 equiv.) was added dropwise over 30 min and the mixture was stirred at 70°C for 16 hr. The solvent was removed to give the title compound (95.6 g, 94%) as a brown solid.1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J = 5.5 Hz, 1H), 7.93 (d, J = 5.6 Hz, 1H), 3.90 (s, 3H).

[0192] Step 2: Synthesis of methyl 3-hydroxy-2-iodoisonicotinate. To a suspension of methyl 3-hydroxypyridine-4-carboxylate hydrochloride (40.0 g, 0.211 mol, 1.0 equiv.) in water (0.65 L) was added sodium carbonate (44.7 g, 0.422 mol, 2.0 equiv.) and the mixture was stirred until inorganic base is dissolved. N-Iodosuccinimide (42.7 g, 0.190 mol, 0.9 equiv.) was added in one portion to give a solution after 10 min of stirring. The mixture was stirred at rt for 5 hr and left to stand for 16 hr. The mixture was acidified to ca. pH 2 with 37% HCl aq. The resulting brown precipitate was filtered, the solid collected and dried. The material was partitioned between water (3.75 L) and EtOAc (3.75 L). The phases were separated and the aqueous extracted with EtOAc (3.75 L). The combined organics were washed with brine, dried with sodium sulfate, filtered and the solvent removed. The material was purified by column chromatography on silica gel (330 g, 0-1% MeOH / DCM) and the appropriate fractions were combined and the solvent was removed to yield the title compound (12.06 g, 20%) as an off-white solid.1H NMR (400MHz, CDCl3) δ 11.13 (s, 1H), 8.84 (d, J = 5.0 Hz, 1H), 7.57 (d, J = 5.0 Hz, 1H), 4.03 (s, 3H). Intermediate 14: Synthesis of 4-bromo-2-iodopyridin-3-ol

[0193] 4-bromopyridin-3-ol (4.50 g, 25.9 mmol, 1.0 equiv.) was dissolved in a solution of NaHCO3 (6.67 g, 77.6 mmol, 3.0 equiv.) in water (125.0 mL). Iodine (6.56 g, 25.9 mmol, 1.0equiv.) was added and the mixture was stirred at rt for 3 hr. The mixture was diluted with water (50 mL), and the mixture was acidified to ca. pH 4 with 10% citric acid solution. The solution was extracted with EtOAc (3 x 100 mL) and the combined organics were washed with water, then brine, dried with sodium sulfate, filtered and the solvent removed. The resulting solid was triturated with EtOAc, the mixture was filtered and the solid collected to yield the title compound (5.79 g, 71%) as a pale-yellow solid. ¹H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 5.1 Hz, 1H), 7.39 (d, J = 5.1 Hz, 1H), 5.96 (brs, 1H). Intermediate 15: Synthesis of methyl 4-hydroxy-5-iodonicotinate

[0194] Step 1: Synthesis of methyl 4-hydroxynicotinate. To a stirred suspension of 4- hydroxypyridine-3-carboxylic acid (10.0 g, 71.9 mmol, 1.0 equiv.) in MeCN (250 mL) was added triethylamine (11 mL, 78.9 mmol, 1.1 equiv.). The mixture was stirred and sonicated until a yellow solution formed, then CDI (12.8 g, 79.1 mmol, 1.1 equiv.) was added portion wise, resulting in mild gas evolution. Upon complete addition the mixture was stirred at rt for 4 hr. A further portion of CDI (4.66 g, 28.8 mmol, 0.4 equiv.) was added, resulting in mild gas evolution and the mixture was stirred at rt for 16 hr. To the mixture was added MeOH (150 mL) slowly over approximately 5 min and the mixture was stirred at rt for 30 min. The mixture was concentrated to ca.100 mL and the suspension was filtered. The solid was collected, washed with MeCN then dried under vacuum for 1 hr to yield the title compound (9.35 g, 85%) as an off- white solid. ¹H NMR (400 MHz, DMSO) δ 11.70 (br s, 1H), 8.21 (s, 1H), 7.63 (d, J = 5.3 Hz, 1H), 6.20 (d, J = 6.4 Hz, 1H), 3.70 (s, 3H).

[0195] Step 2: Synthesis of methyl 4-hydroxy-5-iodonicotinate. To a suspension of methyl 4- hydroxypyridine-3-carboxylate (5.0 g, 32.6 mmol, 1.0 equiv.) in MeCN (50 mL) and acetic acid (25 mL) was added N-Iodosuccinimide (8.08 g, 35.9 mmol, 1.1 equiv.). The mixture was stirred at 60°C for 2 hr. The solvent was removed and the residue was taken up in acetone and filtered. The filtered solid was washed with acetone then dried under vacuum for 1 hr to yield the title compound (8.4 g, 92%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 11.92 (d, J=0.5 Hz, 1H), 8.87 (s, 1H), 8.86 (d, J=0.3 Hz, 1H), 4.03 (s, 3H). Intermediate 16: Synthesis of 3-bromo-5-iodopyridin-4-ol

[0196] To a suspension of 3-bromopyridin-4-ol (2.70 g, 15.5 mmol, 1.0 equiv.) in MeCN (60 mL) was added N-Iodosuccinimide (4.20 g, 18.6 mmol, 1.2 equiv.) and the mixture was stirred at 80°C for 2.5 hr. The mixture was filtered, the solid was collected and washed with acetone, then dried at 40°C for 16 hr to yield the title compound (4.45 g, 96%) as a yellow solid. ¹H NMR (400 MHz, DMSO) δ 12.12 (br s, 1H), 8.29 (d, J = 1.5 Hz, 1H), 8.24 (d, J = 1.5 Hz, 1H). Intermediate 17: Synthesis of 3-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-5-chlorobenzonitrile hydrochloride

[0197] Step 1: Synthesis of tert-butyl 5-(3-chloro-5-cyano-phenyl)-2,5- diazabicyclo[4.1.0]heptane-2-carboxylate. A vial was charged with 3-bromo-5-chloro- benzonitrile (92 mg, 0.425 mmol, 1.0 equiv.), tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2- carboxylate (101 mg, 0.510 mmol, 1.2 equiv.), BINAP (27 mg, 0.043 mmol, 0.1 equiv), tris(dibenzylideneacetone)dipalladium(0) (39 mg, 0.043 mmol, 0.1 equiv.) and sodium tert-butoxide (61 mg, 0.638 mmol, 1.5 equiv.). The vial was sealed and flushed with argon. Toluene (2 mL) was added, and the mixture was sparged with nitrogen for 5 min, then stirred at 100°C for 4 hr. The mixture was allowed to rt, then filtered through celite, eluting with DCM. The filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (10% acetone / cyclohexane) to yield the title compound (86 mg, 61%) as an orange oil.

[0198] Step 2: Synthesis of 3-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-5-chlorobenzonitrile hydrochloride. To a solution of tert-butyl 5-(3-chloro-5-cyano-phenyl)-2,5- diazabicyclo[4.1.0]heptane-2-carboxylate (86 mg, 0.258 mmol, 1.0 equiv.) in DCM (0.86 mL) was added 3 M hydrogen chloride in CPMΕ (0.86 mL, 2.58 mmol, 10 equiv.) and the mixture was heated at 50°C for 19 hr. Further 3 M hydrogen chloride in CPMΕ (0.86 mL, 2.58 mmol, 10 equiv.) was added, the flask was sealed and the mixture was heated at 60°C for 5 hr. The mixturewas allowed to rt and the solvent was removed to yield the title compound (65 mg, 93%) as a pale yellow solid. The material was used directly in the next step without further purification. Intermediate 18: Synthesis of 1-(5-methoxypyridin-3-yl)piperazine

[0199] Step 1: Synthesis of tert-butyl 4-(5-methoxy-3-pyridyl)piperazine-1-carboxylate.1- Boc-piperazine (1.32 g, 7.07 mmol, 1.2 equiv.), 3-bromo-5-methoxypyridine (0.75 mL, 5.89 mmol, 1.0 equiv.), DavePhos Pd G3 (225 mg, 0.295 mmol, 0.05 equiv.) and sodium tert-butoxide (849 mg, 8.84 mmol, 1.50 equiv.) were suspended in CPME (24 mL) in two vials. The vials were sealed, evacuated, and flushed with nitrogen twice, then stirred at 110°C for 4 hr and allowed to cool to rt.

[0200] The mixture was partitioned between EtOAc and water, and the phases were separated. The organics were washed with water, then brine, dried with magnesium sulfate, filtered, the filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica (40 g cartridge, 15 µM, 10-60% EtOAc / cyclohexane) and the appropriate fractions were combined, and the solvent was removed to yield the title compound (812 mg, 46%) as a white solid. ¹H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1 H), 6.70 (t, J = 2.3 Hz, 1H), 3.85 (s, 3H), 3.59 (t, J = 5.0 Hz, 4H), 3.17 (t, J = 5.0 Hz, 4H), 1.49 (s, 9H).

[0201] Step 2: Synthesis of 1-(5-methoxypyridin-3-yl)piperazine. To a solution of tert-butyl 4-(5-methoxy-3-pyridyl)piperazine-1-carboxylate (812 mg, 2.77 mmol, 1.0 equiv.) in DCM (10 mL) was added TFA (5.0 mL, 65.3 mmol, 24 equiv.) and the mixture was stirred for 2 hr. The solvent was removed, and the material was dissolved in methanol, then loaded onto an SCX-2 cartridge (10 g) and the cartridge was washed thoroughly with methanol, then eluted with 2 M ammonia in methanol. The filtrate was collected, and the solvent was removed to yield the title compound (420 mg, 77%) as a dark brown oil. ¹H NMR (400 MHz, CDCl3) 8.12 (d, J = 2.6 Hz, 1H), 7.95 (s, 1H), 6.99 (s, 1H), 3.18-3.14 (m ,4H), 3.06-3.01 (m, 4H), 2.29 (s, 3H). Intermediate 19: Synthesis of 1-(1-(trifluoromethyl)-1H-pyrazol-4-yl)piperazine

[0202] Step 1: Synthesis of benzyl 4-[1-(trifluoromethyl)pyrazol-4-yl]piperazine-1- carboxylate. A vial was charged with 4-bromo-1-(trifluoromethyl)pyrazole (50 mg, 0.233 mmol, 1.0 equiv.), 1-Z-piperazine (0.058 mL, 0.302 mmol, 1.3 equiv.), tBuXPhos Pd G3 (14 mg, 0.0174 mmol, 0.075 equiv.) and sodium trimethylsilanolate (27 mg, 0.244 mmol, 1.05 equiv.). CPME (0.58 mL) was added and the mixture was sparged with nitrogen for 5 min, and stirred under an argon atmosphere at 50°C for 6 hr. The mixture was filtered, the filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (0-10% acetone / cyclohexane) to yield the title compound (38 mg, 43%) as a colourless oil.

[0203] Step 2: Synthesis of 1-(1-(trifluoromethyl)-1H-pyrazol-4-yl)piperazine. A solution of benzyl 4-[1-(trifluoromethyl)pyrazol-4-yl]piperazine-1-carboxylate (38 mg, 0.107 mmol, 1.0 equiv.) was dissolved in IMS (1.2 mL) under Ar.10% Pd / C (8.0 mg, 7.51 μmol, 0.07 equiv.) was added and the mixture was purged with hydrogen gas three times and stirred at rt under an atmosphere of hydrogen (1 atm) for 3 hr. The mixture was filtered through Celite, eluting with IMS. The filtrate was collected, and the solvent was removed to yield the title compound (23 mg, 97%) as a colourless oil that solidified into a pale-yellow solid over 72 h. The material was used directly in the next step without further purification. Intermediate 20: Synthesis of 1-(5-fluoro-4-methoxypyridin-3-yl)piperazine

[0204] Step 1: Synthesis of tert-butyl 4-(5-fluoro-4-methoxy-3-pyridyl)piperazine-1- carboxylate. A vial was charged with 3-bromo-5-fluoro-4-methoxy-pyridine (114 mg, 0.553 mmol, 1.0 equiv.), 1-Z-piperazine (0.19 mL, 0.989 mmol, 1.5 equiv.), palladium(II) acetate (7.4 mg, 0.033 mmol, 0.05 equiv.), BINAP (41 mg, 0.066 mmol, 0.1 equiv.) and cesium carbonate (430 mg, 1.32 mmol, 2.0 equiv.). CPME (4.5 mL) was added and the vial was sealed, sparged with nitrogen for 5 min, and stirred at 100°C for 18 hr. The mixture was filtered through Celite, eluting with DCM. The filtrate was collected, and the solvent was removed. Thematerial was purified by column chromatography on silica gel (10% acetone / cyclohexane) to yield the title compound (141 mg, 82%) as a colourless oil.

[0205] Step 2: Synthesis of 1-(5-fluoro-4-methoxypyridin-3-yl)piperazine. To a solution of tert-butyl 4-(5-fluoro-4-methoxy-3-pyridyl)piperazine-1-carboxylate (141 mg, 0.453 mmol, 1.0 equiv.) in DCM (3 mL) was added TFA (0.35 mL, 4.53 mmol, 10 equiv.) dropwise. The mixture was stirred at rt for 3 hr and the solvent was removed. The material was re-dissolved in DCM (3 mL) and washed with a sat. aq. NaHCO3 (2 x 2 mL). The phases were separated, and the aqueous layer was extracted with DCM (2 x 3 mL) and 3:1 CHCl3 / IPA (3 mL). The combined organics were filtered through a hydrophobic frit, the filtrate was collected, and the solvent was removed. The material was dissolved in DCM and loaded onto an SCX-2 cartridge and the cartridge was washed successively with DCM and methanol, then eluted with 2 M ammonia in methanol. The eluent was collected, and the solvent was removed to yield the title compound (75 mg, 78%) as a pale brown oil.1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 2.7 Hz, 1H), 7.98 (s, 1H), 4.08 (d, J = 3.2 Hz, 3H), 3.14-3.03 (m, 8H). NH not observed. Intermediate 21: Synthesis of 3-bromo-4-ethoxypyridine

[0206] To a solution of 3-bromo-4-chloro-pyridine (100 mg, 0.520 mmol, 1.0 equiv.) in THF (4.3 mL) and was added sodium ethoxide (21% in ethanol, 580 µL, 1.56 mmol, 3.0 equiv.) dropwise and the mixture was stirred at 55°C for 18 hr. The solvent was removed, and the material was partitioned between EtOAc (3 mL) and water (3 mL). The phases were separated, and the aqueous was extracted further with EtOAc (3 mL), DCM (2 x 3 mL) and 3:1 CHCl3 / IPA (3 mL). The combined organic phases were filtered through a hydrophobic frit, the filtrate was collected, and the solvent was removed to yield the title compound (59 mg, 56%) as an orange oil.1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.37 (d, J = 5.6 Hz, 1H), 6.79 (d, J = 5.6 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H). Intermediate 22: Synthesis of 3-bromo-4-(2,2-difluoroethoxy)pyridine

[0207] To an oven-dried three-neck 25-ml flask was added THF (3 mL) under an argon atmosphere, followed by 2,2-difluoroethanol (40 µL, 0.632 mmol, 1.2 equiv.) and the mixture was stirred at 0°C for 5 min. Sodium hydride (60% in mineral oil, 27 mg, 0.675 mmol, 1.3 equiv.) was added portion wise. The mixture was stirred at 0°C for 30 min, then 3-bromo-4- chloro-pyridine (100 mg, 0.520 mmol, 1.0 equiv.) was added in one portion. The mixture was allowed to rt and stirred at 50°C for 18 hours. The mixture was filtered through a hydrophobic filter, the solids were washed with EtOAc (2 x 5 mL), the filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (4 g cartridge, 0-10% MeOH / DCM) to yield the title compound (78 mg, 49%) as a colourless oil.1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 6.81 (d, J = 5.6 Hz, 1H), 6.18 (tt, J = 4.1, 54.1 Hz, 1H), 4.31 (td, J = 4.1, 12.6 Hz, 2H). Intermediate 23: Synthesis of 3-bromo-4-(fluoromethoxy)pyridine

[0208] To a solution of 3-bromopyridin-4-ol (80 mg, 0.460 mmol, 1.0 equiv.) in DMF (1.8 mL) under an argon atmosphere was added fluoromethyl 4-methylbenzenesulfonate (0.12 mL, 0.598 mmol, 1.3 equiv.) and potassium carbonate (95 mg, 0.690 mmol, 1.5 equiv.) and the mixture was stirred at at 90°C for 4 hr. DCM (17 mL) and water (6 mL) were added and the phases were separated. The organics were extracted with DCM (10mL) and 3:1 CHCl3 / IPA (2 x 7 mL). The combined organics were filtered through a hydrophobic frit. The filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (0- 100% acetone / cyclohexane) to yield the title compound (31 mg, 33%) as a colourless oil.1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.07 (dd, J = 1.6, 5.6 Hz, 1H), 5.90 s, 1H), 5.77 (s, 1H).Example 2: Synthesis of 3-(4-(benzofuran-7-carbonyl)piperazin-1-yl)benzonitrile (Compound 105)

[0209] To a solution of benzofuran-7-carboxylic acid (50 mg, 0.308 mmol, 1.0 equiv.) and 3- piperazin-1-ylbenzonitrile (58 mg, 0.308 mmol, 1.0 equiv.) in EtOAc (2 mL) was added triethylamine (0.13 mL, 0.925 mmol, 3.0 equiv.) and the mixture was stirred at rt for 5 min, then T3P (50% in EtOAc, 0.28 mL, 0.463 mmol, 1.5 equiv.) was added and the mixture was stirred at rt for 3 hr. The mixture was partitioned between EtOAc and water, the phases were separated, the organics collected and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 0.1% formic acid, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (63 mg, 61%) as an off-white solid. LCMS: AcHSSC18, m / z = 332.3 (M + H)⁺, RT = 4.59 min. ¹H NMR (400 MHz, DMSO) δ 8.08 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 2.7, 6.3 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.38 - 7.34 (m, 3H), 7.34 - 7.28 (m, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.06 (d, J = 2.7 Hz, 1H), 3.87 (s, 2H), 3.38 (s, 4H), 3.23 (s, 2H). Example 3: Synthesis of 3-(4-(5-fluorobenzofuran-7-carbonyl)piperazin-1-yl)benzonitrile (Compound 104)

[0210] To a suspension of 5-fluorobenzofuran-7-carboxylic acid (75 mg, 0.416 mmol, 1.0 equiv.) and 3-piperazin-1-ylbenzonitrile (82 mg, 0.437 mmol, 1.05 equiv.) in EtOAc (2 mL) was added triethylamine (0.23 mL, 1.67 mmol, 4.0 equiv.) followed by T3P (50% in EtOAc, 0.37 mL, 0.620 mmol, 1.5 equiv.) and the mixture was stirred at rt for 18 hr. The mixture was partitioned between DCM and sat. aq. sodium bicarbonate and the phases separated. The organics were collected and the solvent removed. The material was purified by SFC (WATERS VIRIDIS2-EP 20 x 250 mm, 5 µm, 5-15% MeOH + 0.1% NH4OH / CO2, 100 mL / min, 120 bar, 40°C, DAD 250 nm) and the appropriate fractions were combined and lyophilized to yield the title compound (58 mg, 40%) as an off-white solid. LCMS: AcHSSC18, m / z = 350.3 (M + H)⁺, RT = 4.73 min. ¹H NMR (400 MHz, DMSO) δ 8.15 (d, J = 2.1 Hz, 1H), 7.62 (dd, J = 2.6, 8.6 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.38 - 7.37 (m, 1H), 7.29 (dt, J = 2.4, 10.1 Hz, 2H), 7.22 - 7.19 (m, 1H), 7.06 (d, J = 2.1 Hz, 1H), 3.84 (t, J = 5.4 Hz, 2H), 3.39 - 3.38 (m, 4H), 3.24 (s, 2H). Example 4: Synthesis of 3-(4-(furo[3,2-c]pyridine-7-carbonyl)piperazin-1-yl)benzonitrile (Compound 1)

[0211] To a solution of 3-piperazin-1-ylbenzonitrile (207 mg, 1.10 mmol, 1.2 equiv.) in EtOAc (15 mL) was added furo[3,2-c]pyridine-7-carboxylic acid (150 mg, 0.920 mmol, 1.0 equiv.) and triethylamine (0.51 mL, 3.68 mmol, 4.0 equiv.) followed by T3P in EtOAc (50%, 1.0 mL, 1.75 mmol, 1.9 equiv.) and the mixture was stirred at rt for 20 hr. The mixture was diluted with EtOAc, washed with sat. aq. NaHCO3 solution and dried with sodium sulfate. The mixture was filtered and the solvent was removed. The material was purified by column chromatography on silica gel (12 g cartridge, 15 µM, 0-100% EtOAc / cyclohexane) the further purified by column chromatography on silica gel (24 g cartridge, 15 µM, 0-100% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (169 mg, 55%) as a white solid. LCMS: AcHSSC18, m / z = 333.4 (M + H)⁺, RT = 3.78 min. ¹H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.62 (s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.19 - 7.12 (m, 3H), 6.96 (d, J = 2.3 Hz, 1H), 4.05 - 4.01 (m, 2H), 3.60 - 3.51 (m, 2H), 3.38 - 3.34 (m, 2H), 3.27 - 3.22 (m, 2H).

[0212] The compounds in Table 1 were made according to the method described in Example 4, using an appropriate amine reagent:Table 1: Structure and Data for Compounds 5, 6, 22, 24, and 32.Example 5: Synthesis of 3-(4-(furo[3,2-b]pyridine-7-carbonyl)piperazin-1-yl)benzonitrile (Compound 2)

[0213] To a solution of furo[3,2-b]pyridine-7-carboxylic acid (50 mg, 0.307 mmol, 1.0 equiv.) and 3-piperazin-1-ylbenzonitrile (63 mg, 0.337 mmol, 1.1 equiv.) in EtOAc (2.00 mL) was added triethylamine (0.17 mL, 1.23 mmol, 4.0 equiv.) and the mixture was stirred at rt for 5 min, then T3P (50% in EtOAc, 0.27 mL, 0.460 mmol, 1.5 equiv.). The mixture was stirred at rt for 2 hr. The mixture was partitioned between EtOAc and water, the phases were separated, the organics collected and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 0.1% formic acid, 20 mL / min, rt) and the appropriate fractions were combined and lyophilized to yield the title compound (68 mg, 66%) as an off-white solid. LCMS: AcHSSC18, m / z = 333.5 (M + H)⁺, RT = 3.77 min. ¹H NMR (400 MHz, DMSO) δ 8.63 (d, J = 4.9 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.37 (s, 1H), 7.29 (dd, J = 2.3, 8.3 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 3.85 (t, J = 5.3 Hz, 2H), 3.42 - 3.34 (m, 4H), 3.23 (t, J = 5.1 Hz, 2H).

[0214] The compounds in Table 2 were made according to the method described in Example 5, using an appropriate amine reagent:Table 2: Structure and Data for Compounds 3, 4, 7, 9, 10, and 102.Example 6: Synthesis of 3-(4-(benzo[d]oxazole-7-carbonyl)piperazin-1-yl)benzonitrile (Compound 106)

[0215] To a solution of 1,3-benzoxazole-7-carboxylic acid (50 mg, 0.307 mmol, 1.0 equiv.) and 3-piperazin-1-ylbenzonitrile (57 mg, 0.307 mmol, 1.0 equiv.) in EtOAc (2 mL) was added triethylamine (0.17 mL, 1.23 mmol, 4.0 equiv.) and the mixture was stirred at rt for 5 min, then T3P (50% in EtOAc, 0.27 mL, 0.460 mmol, 1.5 equiv.). The reaction was stirred at rt for 2 hr and then the mixture was partitioned between EtOAc and water, the phases were separated, the organics collected and the solvent was removed. The material was purified by HPLC (Xbridge Phenyl 19 x 150 mm, 10 µm, 40-100% MeOH / water + 10 mM NH4CO3, 20 mL / min, rt) and the appropriate fractions were combined and lyophilized to yield the title compound (38.5 mg, 36%) as an off-white solid. LCMS: AcHSSC18, m / z = 333.3 (M + H)⁺, RT = 3.97 min. ¹H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 7.94 (dd, J = 2.2, 7.0 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.42 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.30 (dd, J = 2.6, 8.6 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 3.87 (br s, 2H), 3.40 (br s, 4H), 3.25 (br s, 2H).

[0216] The compounds in Table 3 were made according to the method described in Example 6, using an appropriate amine reagent:Table 3: Structure and Data for Compounds 108, 109, and 110.Example 7: Synthesis of 3-(4-(2-methyloxazolo[4,5-c]pyridine-7-carbonyl)piperazin-1- yl)benzonitrile (Compound 17)

[0217] Step 1: Synthesis of 7-bromo-2-methyloxazolo[4,5-c]pyridine. A vial was charged with 3-amino-5-bromopyridin-4-ol (189 mg, 1.00 mmol, 1.0 equiv.), trimethylorthoacetate (2.0 mL, 14.8 mmol, 14.8 equiv.), and acetic acid (1 mL). The mixture was stirred at 100°C in a microwave for 1 hr. Sat. aq. sodium bicarbonate was added and the mixture was stirred for 5 min, then DCM was added. The phases were separated, the organics were collected and dried withsodium sulfate. The mixture was filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (0-60% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (146 mg, 69%) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.61 (s, 1H), 2.73 (s, 3H).

[0218] Step 2: Synthesis of 3-(4-(2-methyloxazolo[4,5-c]pyridine-7-carbonyl)piperazin-1- yl)benzonitrile.7-Bromo-2-methyl-oxazolo[4,5-c]pyridine (75 mg, 0.352 mmol, 1.0 equiv.), 3- piperazin-1-ylbenzonitrile (81%, 87 mg, 0.378 mmol, 1.07 equiv.) and XantPhos Pd G4 (34 mg, 0.0352 mmol, 0.1 equiv.) were combined in a vial. The vial was sealed, evacuated and flushed with nitrogen. This process was repeated twice, then CPME (1.5 mL) and triethylamine (0.20 mL, 1.41 mmol, 4.0 equiv.) were added, then the vial was evacuated and flushed with nitrogen again. The vial was intensively stirred and purged with carbon monoxide for 15 min, then stirred at 50°C for 96 hr under an atmosphere of carbon monoxide (1 atm). The mixture was diluted with DCM (20 mL) and filtered through a celite pad, washing with DCM (2 x 20 mL). The filtrate was collected and the solvent was removed. The material was purified by HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 µm, 40-100% MeOH / water + 0.1% formic acid, 20 mL / min, rt) then further purified by SFC (WATERS TORUS 2-PIC 20 x 250 mm, 5 µm, 5-15% MeOH + 0.1% NH4OH) / CO2, 100 mL / min, 120 bar, 40°C, DAD 265 nm) and the appropriate fractions were combined and lyophilised to yield the title compound (62 mg, 50% yield) as an off-white solid. LCMS: AcHSSC18, m / z = 348.4 (M + H)⁺, RT = 3.54 min.1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.60 (s, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.37 (t, J = 2.1 Hz, 1H), 7.31 (dd, J = 7.7 and 2.1 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 3.84 (s, 2H), 3.47 (s, 2H), 3.40 (s, 2H), 3.27 (s, 1H), 2.69 (s, 3H).

[0219] The compounds in Table 4 were made according to the method described in Example 7, using an appropriate amine reagent: Table 4: Structure and Data for Compounds 18, 19, and 23.Example 8: Synthesis of 3-(4-(benzo[d]thiazole-7-carbonyl)piperazin-1-yl)benzonitrile (Compound 126)

[0220] To a solution of 1,3-benzothiazole-7-carboxylic acid (75 mg, 0.419 mmol, 1.0 equiv.) and 3-piperazin-1-ylbenzonitrile (86 mg, 0.460 mmol, 1.1 equiv.) in EtOAc (2 mL) was added triethylamine (0.23 mL, 1.67 mmol, 4.0 equiv.). The mixture was stirred at rt for 5 min then T3P (50% in EtOAc, 0.37 mL, 0.628 mmol, 1.5 equiv.) was added and the mixture was stirred at rt for 3 hr. The mixture was was partitioned between EtOAc and water, the phases were separated and the organic phase was collected and the solvent was removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 10 mM NH4CO3, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (17 mg, 12%) as an off-white solid. LCMS: AcHSSC18, m / z = 349.5 (M + H)⁺, RT = 4.18 min. ¹H NMR (400 MHz, DMSO) δ 9.49 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 3.69 (s, 4H), 3.36 (s, 4H). Example 9: Synthesis of 3-fluoro-5-(4-(2-methylthiazolo[4,5-c]pyridine-7- carbonyl)piperazin-1-yl)benzonitrile (Compound 125)

[0221] Step 1: Synthesis of N-(5-bromo-4-hydroxy-3-pyridyl)acetamide.3-Amino-5- bromopyridin-4-ol (431 mg, 2.28 mmol, 1.0 equiv.) was suspended in DCM (10 mL) and DIPEA (1.4 mL, 7.98 mmol, 3.5 equiv.) was added. A solution of acetyl chloride (0.18 mL, 2.51 mmol, 1.1 equiv.) in DCM (5 mL) was added dropwise at rt. The mixture was stirred at reflux for 5 hr, allowed to rt and the solvent was removed. The solid was triturated with acetone, filtered and the solid was collected to yield the title compound (400 mg, 70%) as a colourless solid. The material was used directly in the next step without further purification.

[0222] Step 2: Synthesis of 7-bromo-2-methyl-thiazolo[4,5-c]pyridine. N-(5-Bromo-4- hydroxy-3-pyridyl)acetamide (0.15 g, 0.49 mmol, 1.0 equiv.) and phosphorus pentasulfide (0.22 g, 0.98 mmol, 2.0 equiv.) were suspended in anhydrous pyridine (5 mL) and the mixture was refluxed for 4 hr. The solvent was removed and the material was dissolved in water (10 mL), sat. aq. sodium bicarbonate solution was added to adjust the pH to 8. EtOAc was added and the phases were separated. The organics were washed successively with sat. aq. sodium bicarbonate solution and brine, dried with sodium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (25 g cartridge, 0-40% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (69 mg, 46%) as a pale-yellow solid. ¹H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.57 (s, 1H), 2.89 (s, 3H).

[0223] Step 3: Synthesis of 3-fluoro-5-(4-(2-methylthiazolo[4,5-c]pyridine-7- carbonyl)piperazin-1-yl)benzonitrile. A vial charged with 7-bromo-2-methyl-thiazolo[4,5- c]pyridine (78 mg, 0.340 mmol, 1.0 equiv.), 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (107 mg, 0.443 mmol, 1.3 equiv.), XantPhos Pd G3 (32 mg, 0.034 mmol, 0.1 equiv.) and sealed. A degassed solution of triethylamine (0.22 mL, 1.55 mmol, 4.54 equiv.) in anhydrous CPME (1.5 mL) was added and the mixture was degassed and sparged with nitrogen for 10 min. The vial was then evacuated and purged with carbon monoxide three times. The mixture was stirred at 50°C under an atmosphere of carbon monoxide for 72 hr. The mixture was allowed to rt, diluted with DCM (10 mL) and filtered through a bed of celite. The filtrate was collected and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 0.1% formic acid, 20mL / min, rt) and the appropriatefractions were combined and lyophilised to yield the title compound (23 mg, 17%) as a brown solid. LCMS: AcBEHC18, m / z = 382.4 (M + H)⁺, RT = 3.95 min. ¹H NMR (400 MHz, DMSO) δ 9.26 (s, 1H), 8.65 (s, 1H), 7.26 (dd, J = 1.0, 2.1 Hz, 1H), 7.16 (td, J = 4.5, 8.9 Hz, 1H), 7.12 (qd, J = 2.0, 6.0 Hz, 1H), 3.71 (t, J = 4.9 Hz, 4H), 3.41 (t, J = 3.2 Hz, 4H), 2.88 (s, 3H). Example 10: Synthesis of 3-fluoro-5-(4-(2-methylthiazolo[5,4-c]pyridine-7- carbonyl)piperazin-1-yl)benzonitrile (Compound 124)

[0224] Step 1: Synthesis of 3-bromo-5-fluoro-pyridin-4-amine. To a stirred solution of 4- amino-3-fluoropyridine (300 mg, 2.68 mmol, 1.0 equiv.) in MeCN (10 mL) was added solution of N-bromosuccinimide (0.50 g, 2.84 mmol, 1.06 equiv.) in MeCN (10 mL) dropwise at rt and the mixture was stirred for 16 hr. The solvent was removed and the material was purified by column chromatography on silica gel (25 g cartridge, 50% EtOAc / petroleum ether) and the appropriate fractions were combined and the solvent was removed to yield the title compound (400 mg, 78%) as a yellow solid.

[0225] Step 2: Synthesis of N-(3-bromo-5-fluoro-4-pyridyl)acetamide.3-bromo-5-fluoro- pyridin-4-amine (150 mg, 0.785 mmol, 1.0 equiv.) was suspended in DCM (7 mL) and DIPEA (0.48 mL, 2.75 mmol, 3.5 equiv.) and acetyl chloride (0.061 mL, 0.864 mmol, 1.1 equiv.) in DCM (3 mL) was added dropwise at rt. The mixture was stirred at reflux for 12 hr, allowed to rt and the solvent was removed. The material was purified by column chromatography on silica gel (25 g cartridge, 0-100% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (120 mg, 66%) as a white solid.

[0226] Step 3: Synthesis of 7-bromo-2-methyl-thiazolo[5,4-c]pyridine. N-(3-bromo-5-fluoro- 4-pyridyl)acetamide (126 mg, 0.541 mmol, 1.0 equiv.) and phosphorus pentasulfide (120 mg, 0.541 mmol, 1.0 equiv.) were suspended in anhydrous pyridine (5 mL) and the mixture was refluxed for 4 hr and allowed to rt. The solvent was removed and the material was dissolved in water (10 mL), sat. aq. sodium bicarbonate solution was added to adjust the pH to 8. EtOAc was added and the phases were separated. The organics were washed successively with sat. aq. sodium bicarbonate solution and brine, dried with sodium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography onsilica gel (25 g cartridge, 0-40% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (30 mg, 24%) as a white solid.

[0227] Step 4: Synthesis of 3-fluoro-5-(4-(2-methylthiazolo[5,4-c]pyridine-7- carbonyl)piperazin-1-yl)benzonitrile. A vial was charged with 7-bromo-2-methyl-thiazolo[5,4- c]pyridine (30 mg, 0.131 mmol, 1.0 equiv.), 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (41 mg, 0.170 mmol, 1.3 equiv.) and XantPhos Pd G3 (12 mg, 0.0131 mmol, 0.1 equiv.) then sealed. The vial was evacuated and flushed with nitrogen. CPME (1.5 mL) was added followed by triethylamine (0.083 mL, 0.594 mmol, 4.54 equiv.) and the mixture was degassed and sparged with nitrogen for 10 min. The vial was then evacuated and purged with carbon monoxide three times. The mixture was stirred at 50°C under an atmosphere of carbon monoxide for 72 hr. The mixture was allowed to rt, diluted with DCM (10 mL) and filtered through a bed of celite. The filtrate was collected and the solvent was removed. The material was purified by HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 µm 40-100% MeOH / water + 0.1% formic acid, 20mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (3 mg, 6.5%) as an off-white solid. LCMS: AcBEHC18, m / z = 382.3 (M + H)⁺, RT = 3.77 min. ¹H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 8.58 (s, 1H), 7.25 (s, 1H), 7.12 (tdd, J = 2.0, 11.9, 11.9 Hz, 2H), 3.84 (t, J = 5.4 Hz, 2H), 3.46 (t, J = 5.7 Hz, 2H), 3.28 (s, 4H), 2.89 (s, 3H). Example 11: Synthesis of (4-(4-methoxypyridin-3-yl)piperazin-1-yl)(2-methylthieno[3,2- b]pyridin-7-yl)methanone (Compound 123)

[0228] A vial was charged with 7-chloro-2-methyl-thieno[3,2-b]pyridine (89%, 75 mg, 0.363 mmol, 1.0 equiv.), 1-(4-methoxy-3-pyridyl)piperazine (91 mg, 0.471 mmol, 1.3 equiv.), palladium(II) acetate (8.2 mg, 0.0363 mmol, 0.1 equiv.) and Xantphos (42 mg, 0.0727 mmol, 0.2 equiv.). The vial was sealed, evacuated and backfilled with nitrogen three times. Degassed CPME (2.5 mL) was added, followed by triethylamine (0.41 mL, 2.91 mmol, 8.0 equiv.). The resulting suspension was sonicated, then sparged with carbon monoxide for 1 minute, then stirred at 60°C under an atmosphere of carbon monoxide for 18 hours. The temperature was increased to 90°C and stirred at 90°C for a further 48 hours. The mixture was allowed to rt and the mixture was partitioned between DCM and water, the organic phase wascollected, dried with magnesium sulfate, filtered, the filtrate collected and the solvent was removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm, 5-60% MeCN / water + 10 mM NH4CO, 20mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (31 mg, 23%) as an off-white solid. LCMS: AcBEHC18, m / z = 369.3 (M + H)⁺, RT = 2.25 min. ¹H NMR (400 MHz, DMSO) δ 8.67 (d, J = 4.8 Hz, 1H), 8.16 (d, J = 5.4 Hz, 1H), 8.05 (s, 1H), 7.36 - 7.33 (m, 2H), 7.00 (d, J = 5.5 Hz, 1H), 3.86 - 3.85 (m, 5H), 3.44 - 3.44 (m, 2H), 3.13 - 3.11 (m, 2H), 3.02 - 3.00 (m, 2H), 2.64 (d, J = 1.3 Hz, 3H). Example 12: Synthesis of 3-fluoro-5-(4-(2-methylthieno[3,2-b]pyridine-7- carbonyl)piperazin-1-yl)benzonitrile (Compound 122)

[0229] A vial was charged with 7-chloro-2-methyl-thieno[3,2-b]pyridine (75 mg, 0.408 mmol, 1.0 equiv.), 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (148 mg, 0.613 mmol, 1.5 equiv.), palladium(II) acetate (10 mg, 0.0445 mmol, 0.11 equiv.) and Xantphos (48 mg, 0.083 mmol, 0.203 equiv.). The vial was sealed, evacuated and backfilled with nitrogen three times. Degassed CPME (2 mL) was added followed by triethylamine (0.46 mL, 3.30 mmol, 8.08 equiv.). Carbon monoxide was bubbled through the solution for 5 min and then the mixture was stirred at 60°C under an atmosphere of carbon monoxide 18 hr. The temperature was increased to 90°C and stirred at 90°C for a further 48 hours. The mixture was allowed to rt and partitioned between 10 mL of NaHCO3 and 10 mL of EtOAc. The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL) and dried with magnesium sulfate, filtered, the filtrate collected and the solvent was removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 10 mM NH4CO, 20mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (77 mg, 49%) as an off-white solid. LCMS: AcBEHC18, m / z = 381.3 (M + H)⁺, RT = 4.26 min.1H NMR (400MHz, DMSO): δ 8.68 (d, J = 4.8 Hz, 1H), 7.37 - 7.34 (m, 2H), 7.25 (d, J = 1.1 Hz, 1H), 7.18 - 7.11 (m, 2H), 3.84 - 3.79 (m, 2H), 3.46 - 3.40 (m, 2H), 2.64 (d, J = 1.1 Hz, 3H).4H obscured by water peak. Example 13: Synthesis of 3-(4-(4-fluorobenzofuran-7-carbonyl)piperazin-1-yl)benzonitrile (Compound 107)

[0230] To a solution of 3-piperazin-1-ylbenzonitrile (55 mg, 0.291 mmol, 1.1 equiv.) in EtOAc (2 mL) was added 4-fluorobenzofuran-7-carboxylic acid (50 mg, 0.278 mmol, 1.0 equiv.) and triethylamine (0.15 mL, 1.11 mmol, 4.0 equiv.) followed by T3P in EtOAc (50%, 0.25 mL, 0.416 mmol, 1.5 equiv.) and the mixture was stirred at rt for 2 hr. The mixture was diluted with EtOAc, washed with water, and dried with sodium sulfate. The mixture was filtered, and the solvent was removed. The material was purified by HPLC (Xbridge Phenyl 19 x 150 mm, 10 µm, 40-100% MeOH / water + 10 mM NH4CO3, 20mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (66mg, 66%) as an off-white solid. LCMS: Method B, m / z = 350.3 (M + H)⁺, RT = 4.74 min. ¹H NMR (400 MHz, DMSO) δ 8.14 (d, J = 2.3 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.38 - 7.34 (m, 1H), 7.29 (dd, J = 2.4, 8.4 Hz, 1H), 7.23 - 7.17 (m, 3H), 3.87 - 3.79 (m, 2H), 3.42 - 3.34 (m, 4H), 3.26 - 3.19 (m, 2H). Example 14: Synthesis of 3-(4-(2-methylbenzo[d]oxazole-7-carbonyl)piperazin-1- yl)benzonitrile (Compound 111)

[0231] To a solution of 3-piperazin-1-ylbenzonitrile (58 mg, 0.310 mmol, 1.1 equiv.) in EtOAc (2 mL) and DMF (50 uL) was added 2-methyl-1,3-benzoxazole-7-carboxylic acid (50 mg, 0.282 mmol, 1.0 equiv.) and triethylamine (0.16 mL, 1.13 mmol, 4.0 equiv.), followed by T3P in EtOAc (50% in EtOAc) (50%, 0.25 mL, 0.423 mmol, 1.5 equiv.) and the mixture was stirred at rt for 3 hr. The mixture was diluted with DCM, washed with sat. aq. NaHCO3 solution and dried with sodium sulfate. The mixture was filtered and the solvent was removed. The material was purified by HPLC (Xbridge Phenyl 19 x 150 mm, 10 µm, 40-100% MeOH / water + 10 mM NH4CO3, 20mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (43.8 mg, 44%) as an off-white solid. LCMS: Method B, m / z = 347.6 (M + H)⁺, RT = 4.09 min. ¹H NMR (400 MHz, DMSO) δ 7.79 - 7.75 (m, 1H), 7.44 - 7.39 (m, 3H), 7.38 -7.35 (m, 1H), 7.32 - 7.28 (m, 1H), 7.22 - 7.18 (m, 1H), 3.81 (br s, 2H), 3.44 - 3.36 (m, 4H), 3.27 - 3.21 (m, 2H), 2.63 (s, 3H). Example 15: Synthesis of 3-(4-(5-fluorobenzo[d]oxazole-7-carbonyl)piperazin-1- yl)benzonitrile (Compound 112)

[0232] Step 1: Synthesis of methyl 5-fluoro-1,3-benzoxazole-7-carboxylate. A vial was charged with methyl 3-amino-5-fluoro-2-hydroxy-benzoate (200 mg, 1.08 mmol, 1.0 equiv.), trimethyl orthoformate (2.4 mL, 21.6 mmol, 20.0 equiv.) and acetic acid (0.093 mL, 1.62 mmol, 1.5 equiv.). The mixture was stirred at 100°C in a microwave for 1 h. The mixture was diluted with EtOAc and washed with water. The organics were filtered and the solvent was removed to yield the title compound (211 mg, Quant.) as a pale brown solid.¹H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.79 (dd, J = 2.6, 9.4 Hz, 1H), 7.70 (dd, J = 2.6, 7.6 Hz, 1H), 4.04 (s, 3H).

[0233] Step 2: Synthesis of 5-fluoro-1,3-benzoxazole-7-carboxylic acid. To a solution of methyl 5-fluoro-1,3-benzoxazole-7-carboxylate (211 mg, 1.08 mmol, 1.0 equiv.) in THF (3 mL) and MeOH (3 mL) was added a solution of lithium hydroxide monohydrate (50 mg, 1.19 mmol, 1.1 equiv.) in water (1.5 mL) and the mixture was stirred at rt for 16 hr. Solvents were removed and the residue was partitioned between EtOAc and water. The phases were separated and the aqueous phase was treated with aqueous HCl 1M (1.19 mL). The resulting precipitate was collected by vacuum filtration, washed with water and dried to yield the title compound (153 mg, 78%) as a solid. ¹H NMR (400 MHz, DMSO) δ 13.78 (br s, 1H), 8.95 (s, 1H), 8.02 (dd, J = 2.6, 8.3 Hz, 1H), 7.71 (dd, J = 2.6, 9.8 Hz, 1H).

[0234] Step 3: Synthesis of 3-(4-(5-fluorobenzo[d]oxazole-7-carbonyl)piperazin-1- yl)benzonitrile. To a solution of 3-piperazin-1-ylbenzonitrile (65 mg, 0.348 mmol, 1.1 equiv.) in EtOAc (2 mL) was added 5-fluoro-1,3-benzoxazole-7-carboxylic acid (60 mg, 0.331 mmol, 1.0 equiv.) and triethylamine (0.18 mL, 1.33 mmol, 4.0 equiv.), followed by T3P in EtOAc (50%, 0.30 mL, 0.497 mmol, 1.5 eq) and the mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc, washed with sat. aq. NaHCO3 solution and dried with sodium sulfate. The mixture was filtered and the solvent was removed. The material was purified by HPLC (Xbridge C1819 x 150mm, 10 µm, 20-80% MeCN / water + 10mM NH4CO3, 20 mL / min, rt) and the appropriatefractions were combined and lyophilised to yield the title compound (59.1 mg, 50%) as an off- white solid. LCMS: Method B, m / z = 351.0 (M + H)⁺, RT = 4.22 min. ¹H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.37 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 3.86 - 3.78 (m, 2H), 3.45 - 3.36 (m, 4H), 3.24 - 3.24 (m, 2H).

[0235] The compounds in Table 5 were made according to the method described in Example 15, using an appropriate amine reagent in Step 3: Table 5: Structure and Data for Compounds 117 and 118.Example 16: Synthesis of 3-(4-(5-bromobenzo[d]oxazole-7-carbonyl)piperazin-1- yl)benzonitrile (Compound 113)

[0236] Step 1: Synthesis of methyl 5-bromo-1,3-benzoxazole-7-carboxylate. A vial was charged with methyl 3-amino-5-bromo-2-hydroxy-benzoate (200 mg, 0.813 mmol, 1.0 equiv.),trimethyl orthoformate (1.8 mL, 16.3 mmol, 20.0 equiv.) and acetic acid (0.070 mL, 1.22 mmol, 1.5 equiv.). The mixture was stirred at 100°C in a microwave for 1 hr. The mixture was diluted with EtOAc, washed with water and dried with sodium sulfate. The organics were filtered, the filtrate was collected and the solvent was removed to yield the title compound (195 mg, 92%) as a pale brown solid. The material was used directly in the next step without further purification.

[0237] Step 2: Synthesis of 5-bromo-1,3-benzoxazole-7-carboxylic acid. To a suspension of methyl 5-bromo-1,3-benzoxazole-7-carboxylate (98%, 178 mg, 0.681 mmol, 1.0 equiv.) in THF (2 mL) and MeOH (2 mL) was added a solution of lithium hydroxide monohydrate (30 mg, 0.715 mmol, 1.1 equiv.) in water (1 mL). and the mixture was stirred at rt for 30 hr. Solvents were removed and the residue was partitioned between EtOAc and water. The phases were separated and the aqueous phase was treated with aqueous HCl 1M (0.71 mL). The resulting precipitate was collected by vacuum filtration, washed with water and dried to yield the title compound (121 mg, 73%) as a brown solid. ¹H NMR (400 MHz, DMSO) δ 13.81 (br s, 1H), 8.94 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H).

[0238] Step 3: Synthesis of 3-(4-(5-bromobenzo[d]oxazole-7-carbonyl)piperazin-1- yl)benzonitrile. To a solution of 3-piperazin-1-ylbenzonitrile (49 mg, 0.260 mmol, 1.1 equiv.) in EtOAc (2 mL) was added 5-bromo-1,3-benzoxazole-7-carboxylic acid (60 mg, 0.248 mmol, 1.0 equiv.) and triethylamine (0.14 mL, 0.992 mmol, 4.0 equiv.), followed by T3P in EtOAc (50%, 0.22 mL, 0.372 mmol, 1.5 equiv.) and the mixture was stirred at rt for 4 hr. The mixture was diluted with EtOAc, washed with water, and dried with sodium sulfate. The mixture was filtered, and the solvent was removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 10 mM NH4CO3, 20mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (26.4 mg, 25%) as an off-white solid. LCMS: Method B, m / z = 411.2 (M + H)⁺, RT = 4.60 min. ¹H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.20 (s, 1H), 7.71 (s, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.36 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.20 (1H, d, J = 7.3 Hz), 3.87 – 3.79 (2H, m), 3.46 – 3.36 (4H, m), 3.24 – 3.24 (2H, m). Example 17: Synthesis of 3-(4-(5-fluoro-2-methylbenzo[d]oxazole-7-carbonyl)piperazin-1- yl)benzonitrile (Compound 115)

[0239] Step 1: Synthesis of methyl 5-fluoro-2-methyl-1,3-benzoxazole-7-carboxylate. A vial was charged with methyl 3-amino-5-fluoro-2-hydroxy-benzoate (250 mg, 1.35 mmol, 1.0 equiv.), trimethylorthoacetate (3.6 mL, 27.0 mmol, 20.0 equiv.), and acetic acid (0.12 mL, 2.03 mmol, 1.50 equiv.). The mixture was stirred at 100°C in a microwave for 1 hr. The mixture was diluted with EtOAc, washed with water and dried with sodium sulfate. The organics were filtered, the filtrate was collected and the solvent was removed to yield the title compound (290 mg, Quant.) as a pale brown solid. ¹H NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 2.6, 9.6 Hz, 1H), 7.54 (dd, J = 2.6, 7.8 Hz, 1H), 4.02 (s, 3H), 2.72 (s, 3H).

[0240] Step 2: Synthesis of 5-fluoro-2-methyl-1,3-benzoxazole-7-carboxylic acid. To a solution of methyl 5-fluoro-2-methyl-1,3-benzoxazole-7-carboxylate (140 mg, 0.669 mmol, 1.0 equiv.) in THF (1.5 mL) and MeOH (1.5 mL) was added a solution of lithium hydroxide monohydrate (29 mg, 0.703 mmol, 1.1 equiv.) in water (0.75 mL) and the mixture was stirred at rt for 16 hr. Solvents were removed and the residue was treated with aqueous 1 M HCl (0.7 mL), then partitioned between water and EtOAc. The phases were separated, the organic layer was filtered and solvent was removed to yield the title compound (112 mg, 86%) as a beige solid. ¹H NMR (400 MHz, DMSO) δ 13.71 (br s, 1H), 7.85 (dd, J = 2.7, 8.3 Hz, 1H), 7.59 (dd, J = 2.7, 9.9 Hz, 1H), 2.67 (s, 3H).

[0241] Step 3: Synthesis of 3-(4-(5-fluoro-2-methylbenzo[d]oxazole-7-carbonyl)piperazin-1- yl)benzonitrile. To a solution of 3-piperazin-1-ylbenzonitrile (48 mg, 0.256 mmol, 1.0 equiv.) in EtOAc (2 mL) was added 5-fluoro-2-methyl-1,3-benzoxazole-7-carboxylic acid (50 mg, 0.256 mmol, 1.0 equiv.) and triethylamine (0.14 mL, 1.02 mmol, 4.0 equiv.), followed by T3P (50% in EtOAc, 0.23 mL, 0.384 mmol, 1.5 equiv.) and the mixture was stirred at rt for 1 hr. The mixture was diluted with EtOAc, washed with water, and dried with sodium sulfate. The mixture was filtered, and the solvent was removed. The material was purified by HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 µm 40-100% MeOH / water + 0.1% formic acid, 20mL / min, rt) then further purified (Xbridge C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 10 mM NH4CO3, 20mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (52 mg, 40%) as an off-white solid. LCMS: Method B, m / z = 365.5 (M + H)⁺, RT = 4.34 min. ¹H NMR (400 MHz, DMSO) δ 7.70 (dd, J = 2.6, 8.6 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.38 - 7.28 (m, 3H), 7.21 (d, J = 7.5 Hz, 1H), 3.85 - 3.79 (m, 2H), 3.46 - 3.36 (m, 4H), 3.29 - 3.22 (m, 2H), 2.64 (s, 3H).

[0242] The compounds in Table 6 were made according to the method described in Example 17, using an appropriate amine reagent in Step 3: Table 6: Structure and Data for Compound 114.Example 18: Synthesis of 3-(4-(5-bromo-2-methylbenzo[d]oxazole-7-carbonyl)piperazin-1- yl)benzonitrile (Compound 116)

[0243] Step 1: Synthesis of methyl 5-bromo-2-methyl-1,3-benzoxazole-7-carboxylate. A vial was charged with methyl 3-amino-5-bromo-2-hydroxy-benzoate (155 mg, 0.630 mmol, 1.0 equiv.), trimethylorthoacetate (1.7 mL, 12.6 mmol, 20.0 equiv.), and acetic acid (0.054 mL, 0.945 mmol, 1.5 equiv.). The mixture was stirred at 100°C in a microwave for 1 hr. The mixture was diluted with EtOAc, washed with water and dried with sodium sulfate. The organics were filtered and the solvent was removed to yield the title compound (165 mg, 97%) as a pale brown solid. ¹H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 4.01 (s, 3H), 2.72 (s, 3H).

[0244] Step 2: Synthesis of 5-bromo-2-methyl-1,3-benzoxazole-7-carboxylic acid. To a solution of methyl 5-bromo-2-methyl-1,3-benzoxazole-7-carboxylate (70 mg, 0.259 mmol, 1.0 equiv.) in THF (2 mL) and MeOH (2 mL) was added a solution of lithium hydroxide monohydrate (11 mg, 0.272 mmol, 1.1 equiv.) in water (1 mL) and the mixture was stirred at rt for 16 hr. Solvents were removed and the residue was treated with 1 M aqueous HCl (0.27 mL), then partitioned between water and EtOAc. The phases were separated, the organic layer was filtered and solvent was removed to yield the title compound (64 mg, 96%) as a beige solid. ¹H NMR (400 MHz, DMSO) δ 13.71 (br s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 2.67 (s, 3H).

[0245] Step 3: Synthesis of 3-(4-(5-bromo-2-methylbenzo[d]oxazole-7-carbonyl)piperazin-1- yl)benzonitrile. To a solution of 3-piperazin-1-ylbenzonitrile (45 mg, 0.242 mmol, 1.0 equiv.) inEtOAc (2 mL) was added 5-bromo-2-methyl-1,3-benzoxazole-7-carboxylic acid (62 mg, 0.242 mmol, 1.0 equiv.) and triethylamine (0.13 mL, 0.969 mmol, 4.0 equiv.), followed by T3P (50% in EtOAc, 0.22 mL, 0.363 mmol, 1.5 equiv.) and the mixture was stirred at rt for 1 hr. The mixture was diluted with EtOAc, washed with water, and dried with sodium sulfate. The mixture was filtered, and the solvent was removed. The material was purified by HPLC (Luna Phenyl- Hexyl 21.2 x 150 mm, 10 µm, 40-100% MeOH / water + 0.1% formic acid, 20 mL / min, rt) then further purified (Xbridge C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 10 mM NH4CO3, 20mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (25.4 mg, 25%) as an off-white solid. LCMS: Method B, m / z = 425.2 (M + H)⁺, RT = 4.72 min. ¹H NMR (400 MHz, DMSO) δ 8.03 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.38 - 7.37 (m, 1H), 7.30 (dd, J = 2.1, 8.4 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 3.85 - 3.82 (m, 2H), 3.41- 3.39 (m, 4H), 3.27 - 3.22 (m, 2H), 2.65 (s, 3H). Example 19: Synthesis of (4-(3-(difluoromethoxy)-5-fluorophenyl)piperazin-1-yl)(furo[3,2- b]pyridin-7-yl)methanone (Compound 8)

[0246] Step 1: Synthesis of tert-butyl 4-(furo[3,2-b]pyridine-7-carbonyl)piperazine-1- carboxylate. To a suspension of furo[3,2-b]pyridine-7-carboxylic acid (504 mg, 3.09 mmol, 1.0 eq) in EtOAc (20.0 mL) was added triethylamine (1.7 mL, 12.2 mmol, 4.0 equiv.) followed by T3P (50% in EtOAc, 2.8 mL, 4.70 mmol, 1.5 equiv.). The mixture was stirred at rt for 10 min then 1-Boc-piperazine (575 mg, 3.09 mmol, 1.0 equiv.) was added and the mixture stirred at rt for 3 hr. The mixture was diluted with EtOAc, washed with sat. aq. NaHCO3 solution and dried with sodium sulfate. The mixture was filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (12 g cartridge, 0- 100% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (519 mg, 51%) as a light-green solid. ¹H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 4.9 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 4.9 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 3.87 - 3.82 (m, 2H), 3.62 - 3.57 (m, 2H), 3.47 - 3.42 (m, 2H), 3.33 - 3.29 (m, 2H), 1.48 (s, 9H).

[0247] Step 2: Synthesis of furo[3,2-b]pyridin-7-yl(piperazin-1-yl)methanone. To a stirred solution of tert-butyl 4-(furo[3,2-b]pyridine-7-carbonyl)piperazine-1-carboxylate (519 mg, 1.57mmol, 1.0 equiv.) in DCM (5 mL) was added TFA (2.4 mL, 31.3 mmol, 20.0 equiv.) and the mixture stirred at rt for 1 hr. The solvent was removed and the residue dissolved in MeOH and loaded onto an SCX-2 cartridge (20 g, pre-washed with MeOH). The cartridge was washed with MeOH and then eluted with 2M NH3 in MeOH. The eluent was collected and the solvent was removed to yield the title compound (380 mg, Quant.) as a beige solid. ¹H NMR (400 MHz, DMSO) δ 8.59 (d, J = 4.8 Hz, 1H), 8.38 (d, J = 2.3 Hz, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 3.66 - 3.62 (m, 2H), 3.15 - 3.11 (m, 2H), 2.82 - 2.77 (m, 2H), 2.66 - 2.61 (m, 2H). NH proton not observed.

[0248] Step 3: Synthesis of (4-(3-(difluoromethoxy)-5-fluorophenyl)piperazin-1-yl)(furo[3,2- b]pyridin-7-yl)methanone. Furo[3,2-b]pyridin-7-yl(piperazin-1-yl)methanone (50 mg, 0.216 mmol, 1.0 equiv.) and 1-bromo-3-(difluoromethoxy)-5-fluoro-benzene (63 mg, 0.261 mmol, 1.2 equiv.) were combined in a vial. CPME (1.2 mL) was added, followed by RuPhos Pd G3 (18 mg, 0.022 mmol, 0.1 equiv.). The suspension was sparged with argon under sonication for 10 min prior to addition of sodium tert-butoxide (42 mg, 0.437 mmol, 2.0 equiv.). The vial was sealed and the mixture stirred at 100°C for 2 hr. The mixture was diluted with water and extracted with EtOAc (x3). The combined organics were filtered and the solvent removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 10 mM NH4HCO3, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (13 mg, 15%) as a yellow solid. LCMS: Method B, m / z = 392.3 (M + H)⁺, RT = 4.46 min. ¹H NMR (400 MHz, DMSO) δ 8.63 (d, J = 4.9 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.26 (t, J = 74.0 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 6.68 (td, J = 2.1, 12.8 Hz, 1H), 6.56 (s, 1H), 6.47 (td, J = 1.9, 9.8 Hz, 1H), 3.85 - 3.82 (m, 2H), 3.25 - 3.22 (m, 2H).4H obscured by water peak. Example 20: Synthesis of 3-(4-(2-isopropylfuro[3,2-b]pyridine-7-carbonyl)piperazin-1- yl)benzonitrile (Compound 21)

[0249] Step 1: Synthesis of methyl 2-isopropylfuro[3,2-b]pyridine-7-carboxylate. A vial was charged with methyl 3-hydroxy-2-iodo-pyridine-4-carboxylate (50 mg, 0.179 mmol, 1.0 equiv.), 3-methyl-1-butyne (0.025 mL, 0.244 mmol, 1.4 equiv.), bis(triphenylphosphine)palladium(II)dichloride (8.8 mg, 0.013 mmol, 0.07 equiv.) and copper(I) iodide (4.8 mg, 0.025 mmol, 0.14 equiv.) and placed under a nitrogen atmosphere. CPME (1 mL) was added and the vial was cooled to 10oC in an ice-bath and stirred for 30 min. Triethylamine (0.07 mL, 0.502 mmol, 2.8 equiv.) was added dropwise then the mixture was stirred at 80°C for 4 hr. The mixture was filtered through Celite, the filtrate collected and the solvent removed. The material was purified by column chromatography on silica gel (4 g cartridge, 0-80% EtOAc / cyclohexane) and the appropriate fractions were combined and solvent was removed to yield the title compound (23 mg, 57%) as a yellow solid. ¹H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.04 Hz, 1H), 7.63 (d, J = 5.0 Hz, 1H), 6.66 (d, J = 1.1 Hz, 1H), 4.03 (s, 3H), 3.20 (septet of doublets, J = 1.0, 6.9 Hz, 1H), 1.41 (d, J = 6.9 Hz, 6H).

[0250] Step 2: Synthesis of lithium 2-isopropylfuro[3,2-b]pyridine-7-carboxylate. To a solution of methyl 2-isopropylfuro[3,2-b]pyridine-7-carboxylate (191 mg, 0.871 mmol, 1.0 equiv.) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (40 mg, 0.958 mmol, 1.1 equiv.) in water (2 mL). The mixture was stirred at rt for 16 hr. The solvent was removed and the residue suspended in toluene (2 mL) and the solvent removed and this process was repeated three times. The material was dried under high vacuum to yield the title compound (190 mg, 99%) as an orange solid. The material was used directly in the next step without further purification.

[0251] Step 3: Synthesis of (3-[4-(2-isopropylfuro[3,2-b]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile. To a solution of lithium 2-isopropylfuro[3,2-b]pyridine-7-carboxylate (50 mg, 0.237 mmol, 1.0 equiv.) and 3-piperazin-1-ylbenzonitrile (44 mg, 0.237 mmol, 1.0 equiv.) in DMF (2.0 mL) was added triethylamine (0.13 mL, 0.947 mmol, 4.0 equiv.), followed by T3P in EtOAc (50%, 0.21 mL, 0.355 mmol, 1.5 equiv.) and the mixture was stirred at rt for 16 hr. The mixture was diluted with EtOAc, washed with sat. aq. NaHCO3 solution and dried with sodium sulfate. The mixture was filtered and the solvent was removed. Material was purified by HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 µm, 40-100% MeOH / water + 0.1% formic acid, 20mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (40 mg, 45%) as an off-white solid. LCMS: Method B, m / z = 375.5 (M + H)⁺, RT = 4.46 min. ¹H NMR (400 MHz, DMSO) δ 8.53 (d, J = 5.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.38 - 7.35 (m, 1H), 7.31 - 7.28 (m, 2H), 7.20 (d, J = 7.4 Hz, 1H), 6.88 (s, 1H), 3.85 (t, J = 4.9 Hz, 2H), 3.19 - 3.11 (m, 1H), 1.31 (d, J = 6.9 Hz, 6H).6H obscured by water peak.

[0252] The compounds in Table 7 were made according to the method described in Example 20, using an appropriate amine reagent in Step 3: Table 7: Structure and Data for Compounds 11, 14, 26, and 31.Example 21: Synthesis of 3-(4-(2-(difluoromethyl)furo[3,2-c]pyridine-7-carbonyl)piperazin- 1-yl)benzonitrile (Compound 12)

[0253] Step 1: Synthesis of 2-(diethoxymethyl)-7-iodo-furo[3,2-c]pyridine. A flask was charged with 3,5-diiodopyridin-4-ol (1.50 g, 4.32 mmol, 1.0 equiv.) and copper(II) oxide (241 mg, 3.03 mmol, 0.7 equiv.). The flask was placed under argon then pyridine (11 mL) and 3,3- diethoxy-1-propyne (0.74 mL, 5.19 mmol, 1.2 equiv.) were added. The mixture and stirred at reflux for 12 hr then cooled to rt. The mixture was diluted with EtOAc and filtered. The solvent was removed and the residue dissolved in EtOAc and washed with sat. aq. NaHCO3, then water, then brine. The organics were dried over sodium sulfate, filtered and the solvent removed. The material was purified by column chromatography on silica gel (80 g cartridge, 0-70% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent removed to yield the title compound (157 mg, 16%) as a yellow solid. ¹H NMR (400 MHz, CDCl3) δ 9.04 - 8.91 (m, 2H), 7.01 (d, J = 0.9 Hz, 1H), 5.69 (d, J = 0.9 Hz, 1H), 3.72 - 3.66 (m, 4H), 1.28 (t, J = 7.1 Hz, 6H).

[0254] Step 2: Synthesis of 7-iodofuro[3,2-c]pyridine-2-carbaldehyde. To a suspension of 2- (diethoxymethyl)-7-iodo-furo[3,2-c]pyridine (152 mg, 0.438 mmol, 1.0 equiv.) in THF (0.9 mL) was added 3 M aq. HCl (2.7 mL, 8.10 mmol, 18.5 equiv.) dropwise and the reaction stirred at rt for 16 hr. The mixture was basified with sat. aq. NaHCO3, then diluted with EtOAc and stirred for 10 min. The phases were separated and the organics washed with water, then brine, then dried over sodium sulfate, filtered and the solvent removed. The residue was taken up in EtOAc and filtered. The solvent was removed from the filtrate to yield the title compound (84 mg, 70%) as a brown solid. ¹H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 9.01 (s, 1H), 8.93 (s, 1H), 7.71 (s, 1H).

[0255] Step 3: Synthesis of 2-(difluoromethyl)-7-iodo-furo[3,2-c]pyridine. To a suspension of 7-iodofuro[3,2-c]pyridine-2-carbaldehyde (80 mg, 0.293 mmol, 1.0 equiv.) in DCM (1 mL), cooled in an ice-water bath, was added DAST (78 µL, 0.589 mmol, 2.0 equiv.) dropwise and the reaction stirred and allowed to warm to rt for 16 hr. The mixture was quenched by slow addition of sat. aq. NaHCO3 and diluted with DCM. The phases were separated and the organics washed with water and brine, dried over sodium sulfate, filtered, the filtrate was collected and the solvent was removed to yield the title compound (63 mg, 73%) as a light brown solid. ¹H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.83 (s, 1H), 7.23 (dt, J = 0.6, 2.0 Hz, 1H), 6.81 (dt, J = 0.5, 53.8 Hz, 1H).

[0256] Step 4: Synthesis of 3-(4-(2-(difluoromethyl)furo[3,2-c]pyridine-7- carbonyl)piperazin-1-yl)benzonitrile. A vial was charged with 2-(difluoromethyl)-7-iodo- furo[3,2-c]pyridine (47 mg, 0.159 mmol, 1.0 equiv.), 3-piperazin-1-ylbenzonitrile (43 mg, 0.230 mmol, 1.4 equiv.), and XantPhos Pd G3 (15 mg, 0.016 mmol, 0.1 equiv.) and placed under an argon atmosphere. CPME (1.5 mL) was added, followed by triethylamine (0.08 mL, 0.574 mmol, 3.6 equiv.) and the mixture was sparged with CO then stirred at 50°C under a CO balloon for 16 hr. The mixture was diluted with EtOAc, filtered through Celite, the filtrate was collected and the solvent was removed. The material was purified by HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 µm, 20-80% MeOH / water + 0.1% formic acid, 20mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (26 mg, 41%) as an off-white solid. LCMS: Method B, m / z = 383.4 (M + H)⁺, RT = 4.03 min. ¹H NMR (400 MHz, DMSO) δ 9.17 (s, 1H), 8.67 (s, 1H), 7.67 - 7.63 (m, 1H), 7.52 - 7.19 (m, 5H), 3.89 - 3.83 (m, 2H), 3.46 - 3.37 (m, 4H), 3.29 - 3.24 (m, 2H). Example 22: Synthesis of 3-chloro-5-(4-(2-(difluoromethyl)furo[3,2-c]pyridine-7- carbonyl)piperazin-1-yl)benzonitrile (Compound 44)

[0257] Step 1: Synthesis of 7-bromo-2-(diethoxymethyl)furo[3,2-c]pyridine. A vial was charged with 3-bromo-5-iodo-pyridin-4-ol (1.0 g, 3.33 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (164 mg, 0.234 mmol, 0.07 equiv.), and copper(I) iodide (90 mg, 0.473 mmol, 0.14 equiv.) and placed under a nitrogen atmosphere. CPME (22 mL) was added followed by 3,3-diethoxy-1-propyne (0.48 mL, 3.35 mmol, 1.0 equiv.) and the mixture was cooled to 10°C prior to addition of triethylamine (1.4 mL, 10.0 mmol, 3.0 equiv.). The mixture was stirred at 80°C for 16 hr. The mixture was filtered through Celite, the filtrate collected and the solvent removed. The material was purified by column chromatography on silica gel (25 g cartridge, 0-100% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (265 mg, 26%) as a yellow solid. ¹H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.58 (s, 1H), 6.95 (d, J = 1.0 Hz, 1H), 5.69 (d, J = 1.0 Hz, 1H), 3.75 - 3.64 (m, 4H), 1.28 (t, J = 7.1 Hz, 6H).

[0258] Step 2: Synthesis of 7-bromofuro[3,2-c]pyridine-2-carbaldehyde. To a solution of 7- bromo-2-(diethoxymethyl)furo[3,2-c]pyridine (200 mg, 0.666 mmol, 1.0 equiv.) in THF (4.0mL) and water (0.8 mL) was added TFA (0.1 mL, 1.30 mmol, 2.0 equiv.) and the mixture stirred at 50°C for 16 hr. The reaction was quenched with sat. aq. NaHCO3 and diluted with EtOAc. The phases were separated and the organics were dried over sodium sulfate, filtered, the filtrate was collected and the solvent removed to yield the title compound (253 mg, 85%) as an orange-brown solid. ¹H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 9.03 (s, 1H), 8.77 (s, 1H), 7.68 (s, 1H).

[0259] Step 3: Synthesis of 7-bromo-2-(difluoromethyl)furo[3,2-c]pyridine. To a solution of 7-bromofuro[3,2-c]pyridine-2-carbaldehyde (150 mg, 0.664 mmol, 1.0 equiv.) in dry DCM (5 mL) at 0°C was added DAST (0.14 mL, 1.06 mmol, 1.6 equiv.) dropwise and the mixture was stirred at rt for 16 hr. The mixture was quenched with sat. aq. NaHCO3. The phases were separated, and the aqueous washed with DCM (2 x 10 mL). The combined organics were dried over sodium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica (4 g cartridge, 0-60% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (82 mg, 50%) as an off-white solid. The material was used directly in the next step without further purification.

[0260] Step 4: Synthesis of 3-chloro-5-(4-(2-(difluoromethyl)furo[3,2-c]pyridine-7- carbonyl)piperazin-1-yl)benzonitrile. A vial was charged with 3-chloro-5-piperazin-1-yl- benzonitrile hydrochloride (53 mg, 0.205 mmol, 1.3 equiv.), 7-bromo-2- (difluoromethyl)furo[3,2-c]pyridine (39 mg, 0.157 mmol, 1.0 equiv.), and XantPhos Pd G4 (15 mg, 0.016 mmol, 0.1 equiv.) and placed under an atmosphere of nitrogen. CPME (1 mL) was added, followed by triethylamine (0.092 mL, 0.663 mmol, 4.2 equiv.). The mixture was sparged with CO for 5 minutes, then heated at 50°C under a CO atmosphere for 40 hr. The mixture was filtered through Celite, the filtrate was collected and the solvent was removed. The material was purified by HPLC (Xbridge Phenyl 19 x 150 mm, 10 µm, 20-80% MeOH / water + 10 mM NH4CO3, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (32 mg, 48%) as an off-white solid. LCMS: Method D, m / z = 417.0 (M + H)⁺, RT = 4.45 min. ¹H NMR (400 MHz, DMSO) δ 9.17 (s, 1H), 8.66 (s, 1H), 7.65 (t, J = 2.2 Hz, 1H), 7.51 - 7.24 (m, 5H), 3.86 (s, 2H), 3.48 (s, 2H), 3.41 (s, 2H), 2.07 (s, 2H).2H obscured by water peak.

[0261] The compounds in Table 8 were made according to the method described in Example 22, using an appropriate amine reagent in Step 4: Table 8: Structure and Data for Compound 53.Example 23: Synthesis of 3-chloro-5-[4-[2-(difluoromethyl)furo[3,2-b]pyridine-7- carbonyl]piperazin-1-yl]benzonitrile (Compound 13)

[0262] Step 1: Synthesis of methyl 2-(diethoxymethyl)furo[3,2-b]pyridine-7-carboxylate. A vial was charged with methyl 3-hydroxy-2-iodo-pyridine-4-carboxylate (70 mg, 0.251 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium (II) dichloride (13 mg, 0.019 mmol, 0.07 equiv.) and copper(I) iodide (7.0 mg, 0.037 mmol, 0.15 equiv.). The vial was degassed and CPME (1.4 mL) was added, followed by 3,3-diethoxy-1-propyne (0.050 mL, 0.349 mmol, 1.4 equiv.). The mixture was stirred at rt for 30 min, cooled to 10°C and triethylamine (0.10 mL, 0.717 mmol, 2.86 equiv.) was added dropwise. The mixture was stirred at 80°C for 2.5 h and allowed to rt. The mixture was filtered through a Celite pad eluting with EtOAc. The filtrate was collected and washed with water. The aqueous phase was separated and further extracted with EtOAc. The organics were combined and washed with brine, dried with magnesium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (4 g cartridge, 0-80% EtOAc / cyclohexane) to yield the title compound (52 mg, 71%) as a brown oil.1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 3.8 Hz, 1H), 7.73 (d, J = 5.0 Hz, 1H), 7.09 (d, J = 0.8 Hz, 1H), 5.74 (d, J = 0.7 Hz, 1H), 4.04 (s, 3H), 3.79 - 3.69 (m, 1H), 1.30 (t, J = 7.1 Hz, 6H).

[0263] Step 2: Synthesis of methyl 2-formylfuro[3,2-b]pyridine-7-carboxylate. To a solution of methyl 2-(diethoxymethyl)furo[3,2-b]pyridine-7-carboxylate (51 mg, 0.183 mmol, 1.0 equiv.) in THF (1.2 mL) and water (0.3 mL) was added TFA (0.020 mL, 0.261 mmol, 1.4 equiv.). The mixture was stirred at rt for 3 hr, then at 50°C for 24 hr. The mixture was quenchedwith sat. aq. NaHCO3 and extracted with EtOAc. The organic phase was dried with magnesium sulfate, filtered, the filtrate was collected and the solvent was removed to yield the title compound (37 mg, 98%) as a brown solid.1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.85 (d, J = 4.8 Hz, 1H), 7.97 (d, J = 4.8 Hz, 1H), 7.81 (s, 1H), 4.10 (s, 1H).

[0264] Step 3: Synthesis of methyl 2-(difluoromethyl)furo[3,2-b]pyridine-7-carboxylate. To a solution of methyl 2-formylfuro[3,2-b]pyridine-7-carboxylate (304 mg, 1.47 mmol, 1.0 equiv.) in DCM (10 mL) at 0°C under a nitrogen atmosphere was added DAST (0.30 mL, 2.27 mmol, 1.6 equiv.). The mixture was allowed to warm to rt and stirred for 18 hr. The reaction was quenched with sat. aq. NaHCO3 and the phases were separated. The aqueous phase was further extracted with DCM. The organics were combined and washed with brine, dried with magnesium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (25 g cartridge, 0-100% EtOAc / cyclohexane) to yield the title compound (219 mg, 64%) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 5.0 Hz, 1H), 7.85 (d, J = 5.0 Hz, 1H), 7.33 (td, J = 2.0, 0.4 Hz, 1H), 6.86 (t, J = 53.8 Hz, 1H), 4.07 (s, 3H).

[0265] Step 4: Synthesis of lithium 2-(difluoromethyl)furo[3,2-b]pyridine-7-carboxylate. To a solution of methyl 2-(difluoromethyl)furo[3,2-b]pyridine-7-carboxylate (40 mg, 0.176 mmol, 1.0 equiv.) in THF (1.5 mL) was added a solution of lithium hydroxide monohydrate (8.1 mg, 0.194 mmol, 1.1 equiv.) in water (0.5 mL). The mixture was stirred at rt for 18 hr. The solvent was removed to yield the title compound (39 mg, 100%) as a pale-yellow solid. The material was used directly in the next step without further purification.

[0266] Step 5: Synthesis of 3-chloro-5-[4-[2-(difluoromethyl)furo[3,2-b]pyridine-7- carbonyl]piperazin-1-yl]benzonitrile. To a suspension of lithium 2-(difluoromethyl)furo[3,2- b]pyridine-7-carboxylate (39 mg, 0.178 mmol, 1.0 equiv.) and 3-chloro-5-piperazin-1-yl- benzonitrile hydrochloride (46 mg, 0.178 mmol, 1.0 equiv.) in DMF (1.5 mL) was added triethylamine (0.10 mL, 0.717 mmol, 4.0 equiv.) followed by T3P (50% in EtOAc, 0.080 mL, 0.269 mmol, 1.5 equiv.) and the mixture was stirred at rt for 3 days. The mixture was diluted with EtOAc and washed with sat. aq. NaHCO3 then brine. The organics were dried with magnesium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (4 g cartridge, 0-100% EtOAc / cyclohexane) the further purified by column chromatography on silica gel (24 g cartridge, 15 µm, 0-100% EtOAc / cyclohexane) to yield the title compound (169 mg, 55%) as a white solid. LCMS: Method A, m / z = 417.3 (M + H)⁺, RT = 4.60 min. ¹H NMR (400 MHz, DMSO) δ 8.74 (d, J = 4.8 Hz, 1H), 7.69 (t, J = 1.9 Hz, 1H), 7.56 (d, J = 4.8 Hz, 1H), 7.38 - 7.37 (m, 1H), 7.38 (t,J = 52.7 Hz, 1H), 7.32 - 7.31 (m, 2H), 3.84 (t, J = 4.6 Hz, 2H), 3.48 (t, J = 4.9 Hz, 2H).4H obscured by water peak.

[0267] The compounds in Table 9 were made according to the method described in Example 23, using an appropriate amine reagent in Step 5: Table 9: Structure and Data for Compounds 25, 27, 30 and 83.Example 24: Synthesis of (3-[4-(2-cyclopropylfuro[3,2-b]pyridine-7-carbonyl)piperazin-1- yl]-5-fluoro-benzonitrile (Compound 15)

[0268] Step 1: Synthesis of methyl 2-cyclopropylfuro[3,2-b]pyridine-7-carboxylate. To a vial were added bis(triphenylphosphine)palladium(II) dichloride (23 mg, 0.032 mmol, 0.07 equiv.), copper(I) iodide (12 mg, 0.065 mmol, 0.14 equiv.) and methyl 3-hydroxy-2-iodo-pyridine-4- carboxylate (128 mg, 0.459 mmol, 1.0 equiv.). The vial was sealed and purged with nitrogen before CPME (3.5 mL) and cyclopropylacetylene (0.060 mL, 0.709 mmol, 1.6 equiv.) were added. The mixture was cooled to 10°C, and triethylamine (0.18 mL, 1.31 mmol, 2.9 equiv.) was added. The mixture was slowly allowed to rt, then stirred at 80°C for 2 hr. The mixture was cooled to rt, filtered through a Celite pad, eluting with EtOAc. The filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (4 g cartridge, 0-100% EtOAc / cyclohexane) then further purified by column chromatography on silica gel (4 g cartridge, 0-100% EtOAc / cyclohexane) to yield the title compound (48 mg, 48%), as a yellow solid. ¹H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 5.1 Hz, 1H), 7.59 (d, J = 5.1 Hz, 1H), 6.60 (s, 1H), 4.03 (s, 3H), 2.19 - 2.12 (m, 1H), 1.14 - 1.08 (m, 4H).

[0269] Step 2: Synthesis of lithium 2-cyclopropylfuro[3,2-b]pyridine-7-carboxylate. To a solution of methyl 2-cyclopropylfuro[3,2-b]pyridine-7-carboxylate (48 mg, 0.222 mmol, 1.0 equiv.) in THF (1.1 mL) was added a solution of lithium hydroxide monohydrate (10 mg, 0.244 mmol, 1.1 equiv.) in water (1.1 mL). The mixture was stirred at rt for 2 hr and then at 50°C for 18 hours. The mixture was allowed to rt and the solvent was removed. The material was azeotroped with toluene to yield the title compound (47 mg, 100%), as a pale-yellow solid. The material was used directly in the next step without further purification.

[0270] Step 3: (3-[4-(2-cyclopropylfuro[3,2-b]pyridine-7-carbonyl)piperazin-1-yl]-5-fluoro- benzonitrile. To a solution of lithium 2-cyclopropylfuro[3,2-b]pyridine-7-carboxylate (47 mg, 0.224 mmol, 1.0 equiv.) and 3-fluoro-5-piperazin-1-yl-benzonitrile (46 mg, 0.224 mmol, 1.0 equiv.) in DMF (1.5 mL) was added triethylamine (0.13 mL, 0.933 mmol, 4.2 equiv.) and T3P (50% in EtOAc, 0.10 mL, 0.336 mmol, 1.5 equiv.). The mixture was stirred at rt for 48 hr then diluted with EtOAc. The mixture was washed with sat. aq. NaHCO3 then brine. The organics were dried with magnesium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 0.1% formic acid, 20 mL / min, rt) and the appropriate fractions were combinedand lyophilised to yield the title compound to yield the title compound (32 mg, 36%) as an off- white solid. LCMS: Method B, m / z = 391.6 (M + H)⁺, RT = 4.38 min. ¹H NMR (400 MHz, DMSO) δ 8.49 (1H, d, J = 4.9 Hz), 7.27 - 7.24 (2H, m), 7.18 - 7.10 (2H, m), 6.86 (1H, s), 3.82 (2H, t, J = 5.1 Hz), 3.46 (2H, t, J = 5.1 Hz), 3.32 (4H, m), 2.34 - 2.17 (1H, m), 1.12 - 1.06 (2H, m), 1.00 - 0.95 (2H, m).

[0271] The compounds in Table 10 were made according to the method described in Example 24, using an appropriate amine reagent in Step 3: Table 10: Structure and Data for Compounds 16, 33, and 47.Example 25: Synthesis of 3-[4-(2-cyclopropylfuro[3,2-c]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile (Compound 20)

[0272] Step 1: Synthesis of methyl 2-cyclopropylfuro[3,2-c]pyridine-7-carboxylate. To a vial were added bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.025 mmol, 0.07 equiv.), copper(I) iodide (10 mg, 0.051 mmol, 0.14 equiv.) and methyl 4-hydroxy-5-iodo- pyridine-3-carboxylate (100 mg, 0.358 mmol, 1.0 equiv.). The vial was sealed and flushed with nitrogen, then DMF (2.5 mL) was added. The mixture was stirred for 5 min, then cyclopropylacetylene (0.041 mL, 0.488 mmol, 1.4 equiv.) was added and stirred for a further 15 min, then the mixture was cooled to 10°C and triethylamine (0.14 mL, 1.02 mmol, 2.9 equiv.) was added. The mixture was allowed to rt then stirred at 80°C for 2 hr. The mixture was allowed to rt then filtered through a celite pad, eluting with EtOAc. The filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (4 g cartridge, 0-100% EtOAc / cyclohexane) to yield the title compound (22 mg, 29%) as a pale- yellow solid. ¹H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.89 (s, 1H), 6.44 (s, 1H), 4.02 (s, 3H), 2.16 - 2.09 (m, 1H), 1.13 - 1.02 (m, 4H).

[0273] Step 2: Synthesis of lithium 2-cyclopropylfuro[3,2-c]pyridine-7-carboxylate. To a solution of methyl 2-cyclopropylfuro[3,2-c]pyridine-7-carboxylate (26 mg, 0.121 mmol, 1.0 equiv.) in THF (0.8 mL) was added a solution of lithium hydroxide monohydrate (5.6 mg, 0.133 mmol, 1.1 equiv.) in water (0.4 mL). The mixture was stirred at 50°C for 3 hr and allowed to rt. The solvent was removed to yield the title compound (25 mg, 100%) as an off-white solid. The material was used directly in the next step without further purification.

[0274] Step 3: Synthesis of 3-[4-(2-cyclopropylfuro[3,2-c]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile. To a solution of lithium 2-cyclopropylfuro[3,2-c]pyridine-7-carboxylate (25 mg, 0.122 mmol, 1.0 equiv.) and 3-piperazin-1-ylbenzonitrile (23 mg, 0.122 mmol, 1.0 equiv.) in DMF (1 mL) was added triethylamine (0.07 mL, 0.502 mmol, 4.1 equiv.) followed by T3P (50% in EtOAc, 0.055 mL, 0.185 mmol, 1.5 equiv.) and the mixture was stirred at rt for 2.5 hr. The mixture was diluted with EtOAc and washed with sat. aq. NaHCO3 then brine. The organics were dried with magnesium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by HPLC (Xbridge Phenyl 19 x 150 mm, 10 µm, 40-100% MeOH / water + 10 mM NH4CO3, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (16 mg, 35%) as an off-white solid. LCMS: MethodB, m / z = 373.2 (M + H)⁺, RT = 3.57 min. ¹H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.41 (s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.38 - 7.36 (m, 1H), 7.30 (dd, J = 2.1, 8.4 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.81 (s, 1H), 3.88 - 3.81 (m, 2H), 2.24 - 2.16 (m, 1H), 1.09 - 1.03 (m, 2H), 0.96 - 0.90 (m, 2H).6H obscured by water peak.

[0275] The compounds in Table 11 were made according to the method described in Example 25, using an appropriate amine reagent in Step 3: Table 11: Structure and Data for Compounds 37, 45, and 48.Example 26: Synthesis of 3-[4-(2-isopropyloxazolo[4,5-c]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile (Compound 28)

[0276] Step 1: Synthesis of 7-bromo-2-isopropyl-oxazolo[4,5-c]pyridine. A vial was charged with 3-amino-5-bromopyridin-4-ol (150 mg, 0.794 mmol, 1.0 equiv.), acetic acid (0.14 mL, 2.38 mmol, 3.0 equiv.) and 1,1,1-trimethoxy-2-methyl-propane (2.6 mL, 15.9 mmol, 20 equiv.). The suspension was stirred at rt for 5 min then stirred at 100°C in a microwave for 1 hr. Sat. aq. NaHCO3 was added and the mixture was extracted with DCM (3 x 25 mL). The organics were combined, dried with sodium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (0-60% EtOAc / cyclohexane) to yield the title compound (152 mg, 77%) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.60 (s, 1H), 3.32 (septet, J = 6.9 Hz, 1H), 1.50 (d, J = 6.9 Hz, 6H).

[0277] Step 2 : Synthesis of 3-[4-(2-isopropyloxazolo[4,5-c]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile. To a vial was added 7-bromo-2-isopropyl-oxazolo[4,5-c]pyridine (75 mg, 0.311 mmol, 1.0 equiv.), 3-piperazin-1-ylbenzonitrile (77 mg, 0.334 mmol, 1.1 equiv.) and XantPhos Pd G4 (30 mg, 0.0311 mmol, 0.1 equiv.). The vial was sealed, evacuated, and flushed with nitrogen three times. CPME (1.5 mL) and triethylamine (0.17 mL, 1.24 mmol, 4.0 equiv.) were added and the vial was further flushed with nitrogen. The vial was intensively stirred and purged with carbon monoxide for 15 min, then stirred at 50°C for 16 hr under an atmosphere of carbon monoxide (1 atm). The vial was allowed to rt, then further XantPhos Pd G4 (30 mg, 0.0311 mmol, 0.1 equiv.) was added and the vial was sealed evacuated and flushed with nitrogen. The vial was intensively stirred and purged with carbon monoxide for 15 min, then stirred at 50°C for 16 hr under an atmosphere of carbon monoxide (1 atm). The mixture allowed to rt and diluted with DCM (20 mL), then filtered through a celite pad washing with DCM (2 x 10 mL). The filtrate was collected, and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm, 20-80% MeCN / water +0.1% formic acid, 20 mL / min, rt) the further purified by SFC (REPROSPHER PEI 10020 x 150 mm, 5 µm, 5-15% MeOH +0.1% NH4OH / CO2, 100 mL / min, 120 bar, 40°C, DAD 255 nm) and the appropriate fractions were combined and lyophilised to yield the title compound (24 mg, 20% yield) as an off-white solid. LCMS: Method B, m / z = 376.5 (M + H)⁺, RT = 4.11 min. ¹H NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 8.61 (s, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.37 (t, J = 2.8 Hz, 1H), 7.30 (dd, J = 2.8, 7.9 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H) 3.84 (br s, 2H), 3.47 (br s, 4H), 3.42 - 3.34 (m, 3H), 3.27 (br s, 2H), 1.39 (d, J = 7.18 Hz, 6H).

[0278] The compounds in Table 12 were made according to the method described in Example 26, using an appropriate amine reagent in Step 2: Table 12: Structure and Data for Compounds 34, 38, and 39.Example 27: Synthesis of 3-chloro-5-[4-(2-methylfuro[3,2-b]pyridine-7-carbonyl)piperazin- 1-yl]benzonitrile (Compound 50)

[0279] Step 1: Synthesis of methyl 2-methylfuro[3,2-b]pyridine-7-carboxylate. A reaction vial charged with 3-hydroxy-2-iodo-pyridine-4-carboxylate (124 mg, 0.444 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-yn-1-yl)-1,3,2-dioxaborolane (111 mg, 0.667 mmol, 1.5 equiv.), bis(triphenylphosphine)palladium(II) dichloride (16 mg, 0.022 mmol, 0.05 equiv.) and potassium carbonate (184 mg, 1.33 mmol, 3.0 equiv.) was evacuated and purged with nitrogen, DMF (1.5 mL) and water (0.07 mL) were added and the mixture was stirred at 50°C for 18 hr. The cooled mixture was diluted with EtOAc, filtered through celite and the filtrate was washed successively with 5% aq. LiCl and brine. The organic phase was dried with magnesium sulfate, filtered, the filtrate was collected, and the solvent was removed. The material was purified by columnchromatography on silica gel (0-50% EtOAc / cyclohexane) to yield the title compound (37 mg, 43%) as a yellow solid.1H NMR (400MHz, CDCl3) δ 8.57 (d, J = 5.0 Hz, 1H), 7.63 (d, J = 5.0 Hz, 1H), 6.68 (q, J = 1.0 Hz, 1H), 4.04 (s, 3H), 2.60 (d, J = 1.0 Hz, 3H).

[0280] Step 2: Synthesis of lithium 2-methylfuro[3,2-b]pyridine-7-carboxylate. To a solution of methyl 2-methylfuro[3,2-b]pyridine-7-carboxylate (36 mg, 0.19 mmol, 1.0 equiv.) in 1:1 THF:water (2 mL) was added lithium hydroxide monohydrate (8.7 mg, 0.21 mmol, 1.1 equiv.). The mixture was stirred at rt for 3 hr and the solvent was removed to yield the title compound (34 mg, 100%) as a yellow solid. The material was used directly in the next step without further purification.

[0281] Step 3: Synthesis of 3-chloro-5-[4-(2-methylfuro[3,2-b]pyridine-7- carbonyl)piperazin-1-yl]benzonitrile. To a solution of (2-methylfuro[3,2-b]pyridine-7- carbonyl)oxylithium (19 mg, 0.10 mmol, 1.0 equiv.) in DMF (0.5 mL) was added HATU (43 mg, 0.11 mmol, 1.1 equiv.). The mixture was stirred at rt for 10 min prior to slow addition of a solution of 3-chloro-5-piperazin-1-yl-benzonitrile hydrochloride (33 mg, 0.13 mmol, 1.2 equiv.) and DIPEA (55 µL, 0.32 mmol, 3.0 equiv.) in DMF (0.5 mL). The mixture was stirred at rt for 2 hr, diluted with EtOAc and washed with water. The phases were separated, and the organic phase was washed successively with sat. aq NaHCO3, 5% aq. LiCl, brine then dried with magnesium sulfate, filtered, the filtrate was collected, and the solvent was removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 10 mM NH4CO3, 20mL / min, rt) to yield the title compound (21 mg, 52%) as an off-white solid. LCMS: Method B, m / z = 381.2 (M + H)⁺, RT = 4.44 min. ¹H NMR (400 MHz, DMSO) δ 8.52 (d, J = 5.0 Hz, 1H), 7.39 - 7.36 (m, 1H), 7.34 - 7.29 (m, 2H), 7.27 (d, J = 5.1 Hz, 1H), 6.88 - 6.86 (m, 1H), 3.85 - 3.79 (m, 2H), 3.49 - 3.44 (m, 2H), 2.53 (d, J = 0.7 Hz, 3H).4H obscured by water peak.

[0282] The compounds in Table 13 were made according to the method described in Example 27, using an appropriate amine reagent in Step 3: Table 13: Structure and Data for Compounds 52, 67, 69, 75, 94, and 96.Example 28: Synthesis of (4-(4-ethoxypyridin-3-yl)piperazin-1-yl)(2-methylfuro[3,2- b]pyridin-7-yl)methanone (Compound 98)

[0283] Step 1: Synthesis of benzyl 4-(2-methylfuro[3,2-b]pyridine-7-carbonyl)piperazine-1- carboxylate. To a suspension of lithium 2-methylfuro[3,2-b]pyridine-7-carboxylate (221 mg, 1.18 mmol, 1.0 equiv.) in DMF (12 mL) was added 1-Z-piperazine (0.25 mL, 1.30 mmol, 1.1 equiv.) and triethylamine (0.66 mL, 4.73 mmol, 4.0 equiv.) followed by T3P (50% in EtOAc, 1.4 mL, 2.37 mmol, 2.0 equiv.). The mixture was stirred at rt for 3 hr, then partitioned between 5% aq. LiCl solution (4 mL) and EtOAc (4 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2 x 4 mL) and 3:1 CHCl3 / IPA (2 x 2 mL). The combined organic phases were filtered through a hydrophobic frit, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (0% to 60% acetone in cyclohexane) to yield the title compound (309 mg, 69%) as a pale-yellow oil.

[0284] Step 2: Synthesis of (2-methylfuro[3,2-b]pyridin-7-yl)(piperazin-1-yl)methanone. A solution of benzyl 4-(2-methylfuro[3,2-b]pyridine-7-carbonyl)piperazine-1-carboxylate (309 mg, 0.814 mmol, 1.0 equiv.) in IMS (6.8 mL) was added to 10% palladium on carbon (61 mg, 0.057 mmol, 0.07 equiv.) The mixture was purged three times with hydrogen and stirred at rt under an atmosphere of hydrogen (1 atm) for 5.5 hr. The suspension was filtered through celite, eluting with IMS, the filtrate was collected and the solvent was removed to yield the title compound (187 mg, 94%) as a colourless oil that solidified upon standing. The material was used directly in the next step without further purification.

[0285] Step 3: Synthesis of (4-(4-ethoxypyridin-3-yl)piperazin-1-yl)(2-methylfuro[3,2- b]pyridin-7-yl)methanone. To a vial was added (2-methylfuro[3,2-b]pyridin-7-yl)-piperazin-1- yl-methanone (53 mg, 0.216 mmol, 1.0 equiv.), caesium carbonate (226 mg, 0.694 mmol, 3.2 equiv.), palladium diacetate (6 mg, 0.027 mmol, 0.13 equiv.) and BINAP (20 mg, 0.0324 mmol, 0.15 equiv.). The vial was sealed, evacuated and flushed with nitrogen three times. A solutionof 3-bromo-4-ethoxy-pyridine (59 mg, 0.292 mmol, 1.35 equiv.) in CPME (2 mL) was added and the mixture was stirred at 100°C for 22 hr. The mixture was allowed to rt and partitioned between DCM and water. The phases were separated, and the aqueous was extracted with DCM twice. The combined organic phases were dried with magnesium sulfate, filtered, the filtrate was collected, and the solvent was removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm, 5-60% MeCN / water + 10 mM NH4CO3, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (28 mg, 36%) as an off- white solid. LCMS: Method A, m / z = 367.3 (M + H)⁺, RT = 2.25 min. ¹H NMR (400 MHz, DMSO) δ 8.51 (d, J = 5.0 Hz, 1H), 8.12 (d, J = 5.5 Hz, 1H), 8.05 (s, 1H), 7.27 (d, J = 4.9 Hz, 1H), 6.97 (d, J = 5.5 Hz, 1H), 6.86 (d, J = 1.1 Hz, 1H), 4.11 (q, J = 7.0 Hz, 2H), 3.85 (t, J = 4.9 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H), 3.16 (t, J = 4.9 Hz, 2H), 3.03 (t, J = 4.8 Hz, 2H), 2.53 (d, J = 1.6 Hz, 3H), 1.36 (t, J = 6.9 Hz, 3H).

[0286] The compounds in Table 14 were made according to the method described in Example 28, using an appropriate aryl halide reagent in Step 3: Table 14: Structure and Data for Compounds 99, 103, 127.Example 29: Synthesis of 3-[4-(2-cyclopropyloxazolo[4,5-c]pyridine-7-carbonyl)piperazin- 1-yl]benzonitrile (Compound 43)

[0287] Step 1: Synthesis of 7-bromo-2-cyclopropyl-oxazolo[4,5-c]pyridine. To a stirred suspension of 3-amino-5-bromopyridin-4-ol (241 mg, 1.28 mmol, 1.0 equiv.) in MeCN \l(2.5 mL) was added cyclopropanecarboxylic acid (0.12 mL, 1.5 mmol, 1.2 equiv.). The mixture wasstirred at rt for 5 min prior to the portion wise addition of phosphorus pentachloride (990 mg, 4.75 mmol, 3.7 equiv.). The mixture was then stirred at 80°C for 16 hr. The solvent was removed, the residue quenched with sat. aq. NaHCO3 and the resultant mixture was extracted with DCM three times. The combined organic phases were dried with magnesium sulfate, filtered, the filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (0-100% EtOAc / cyclohexane) to yield the title compound (70 mg, 19%) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.56 (s, 1H), 2.31- 2.22 (m, 1H), 1.39-1.24 (m, 4H).

[0288] Step 2: Synthesis of 3-[4-(2-cyclopropyloxazolo[4,5-c]pyridine-7-carbonyl)piperazin- 1-yl]benzonitrile. A vial charged with 7-bromo-2-cyclopropyl-oxazolo[4,5-c]pyridine (85 mg, 0.36 mmol, 1.0 equiv.), 3-piperazin-1-ylbenzonitrile (71 mg, 0.38 mmol, 1.1 equiv.) and XantPhos Pd G4 (34 mg, 0.036 mmol, 0.1 equiv.) was evacuated and purged with nitrogen prior to addition of CPME (1.5 mL) and triethylamine (0.20 mL, 1.4 mmol, 4.0 equiv.). The suspension was sparged with CO for 10 min and then the mixture was stirred at 50°C, under an atmosphere of CO, for 96 hr. The cooled mixture was filtered through celite, the filtrate was collected, and the solvent was removed. The material was purified by SFC (REPROSPHER PEI 10020 x 150 mm, 5 µm, 5-15% MeOH + 0.1% NH4OH / CO2, 100 mL / min, 120 bar, 40°C, DAD 260 nm) to yield the title compound (19 mg, 14%) as an off-white solid. LCMS: Method B, m / z = 374.5 (M + H)⁺, RT = 3.87 min. ¹H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.56 (s, 1H), 7.42 (t, J = 8.4 Hz,1H), 7.37 (t, J = 1.5 Hz, 1H), 7.30 (dd, J = 1.5, 8.4 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 3.83 (br s, 2H), 3.47 (br s, 4H), 3.27 (br s, 2H), 2.41-2.34 (m, 1H), 1.31-1.16 (m, 4H).

[0289] The compounds in Table 15 were made according to the method described in Example 29, using an appropriate amine reagent in Step 2: Table 15: Structure and Data for Compounds 46, 49, and 41.Example 30: Synthesis of 3-fluoro-5-[4-(5-methylfuro[3,2-b]pyridine-7-carbonyl)piperazin- 1-yl]benzonitrile (Compound 29)

[0290] Step 1: Synthesis of 4-bromo-2-iodo-6-methyl-pyridin-3-ol. To a vial was added 4- bromo-6-methyl-pyridin-3-ol (982 mg, 5.22 mmol, 1.0 equiv.) and N-iodosuccinimide (1.29 g, 5.75 mmol, 1.1 equiv.) followed by MeCN (18 mL) and AcOH (12 mL) and the mixture was stirred at rt for 40 min. The solvent was removed and the residue quenched with sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc and the phases were separated. The organic phase was washed successively with 2 M aq. Na2S2O3, brine, dried with magnesium sulfate, filtered, the filtrate was collected, and the solvent was removed to yield the title compound (1.48 g, 90%) as a yellow solid. ¹H NMR (400 MHz, DMSO) δ 10.25 (br s, 1H), 7.46 (s, 1H), 2.33 (s, 3H).

[0291] Step 2: Synthesis of (7-bromo-5-methyl-furo[3,2-b]pyridin-2-yl)-trimethyl-silane. A reaction vial charged with 4-bromo-2-iodo-6-methyl-pyridin-3-ol (500 mg, 1.59 mmol, 1.0 equiv.), copper(I) iodide (30 mg, 0.16 mmol, 0.1 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (56 mg, 0.080 mmol, 0.05 equiv.) was evacuatedand purged with argon three times, then degassed MeCN (7.5 mL) was added, followed by triethylamine (0.45 mL, 3.2 mmol, 2.0 equiv.). Ethynyltrimethylsilane (0.23 mL, 1.6 mmol, 1.0 equiv.) was added dropwise, and the mixture was stirred at rt for 18 hr. The solvent was removed, the residue was suspended in DCM and the resultant suspension filtered through celite. The filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (0-10% EtOAc / cyclohexane) to yield the title compound (328 mg, 72%) as an orange oil. ¹H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.10 (s, 1H), 2.62 (s, 3H), 0.39 (s, 9H).

[0292] Step 3: Synthesis of 3-fluoro-5-[4-(5-methylfuro[3,2-b]pyridine-7- carbonyl)piperazin-1-yl]benzonitrile. A reaction vial charged with (7-bromo-5-methyl- furo[3,2-b]pyridin-2-yl)-trimethyl-silane (106 mg, 0.373 mmol, 1.0 equiv.), 3-fluoro-5-piperazin- 1-yl-benzonitrile (115 mg, 0.559 mmol, 1.5 equiv.) and XantPhos Pd G3 (35 mg, 0.037 mmol, 0.1 equiv.) was evacuated and purged with argon three times then degassed CPME (2 mL) was added, followed by triethylamine (0.24 mL, 1.7 mmol, 4.6 equiv.). The vial was evacuated and purged with CO, then the mixture was stirred at 50°C, under an atmosphere of CO, for 72 hr. The mixture was diluted with EtOAc, filtered through celite, the filtrate was collected, and the solvent was removed. The residue was dissolved in THF (2 mL), TBAF (1 M solution in THF) (0.41 mL, 0.41 mmol, 1.1 equiv.) was added and the mixture was stirred at rt for 2 hr. The solvent was removed, the residue was taken up in EtOAc and the resultant solution was washed with successively with sat. aq. NH4Cl, water and brine. The organic phase was dried with magnesium sulfate, filtered, the filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (0-70% EtOAc / cyclohexane) to yield the title compound (39 mg, 28%) as an off-white solid. LCMS: Method A, m / z = 365.3 (M + H)⁺, RT = 3.93 min. ¹H NMR (400 MHz, DMSO) δ 8.32 (d, J = 2.4 Hz, 1H), 7.26 - 7.25 (m, 2H), 7.18 - 7.09 (m, 3H), 3.83 (t, J = 5.2 Hz, 2H), 3.45 (t, J = 5.3 Hz, 2H), 2.60 (s, 3H).4H obscured by water peak.

[0293] The compounds in Table 16 were made according to the method described in Example 30, using an appropriate amine reagent: Table 16: Structure and Data for Compound 101.Example 31: Synthesis of 3-[4-(2-isopropylfuro[3,2-c]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile (Compound 35)

[0294] Step 1: Synthesis of 7-bromo-2-isopropyl-furo[3,2-c]pyridine. A vial charged with 3- bromo-5-iodo-pyridin-4-ol (500 mg, 1.67 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (82 mg, 0.12 mmol, 0.07 equiv.), and copper(I) iodide (45 mg, 0.24 mmol, 0.14 equiv.) was degassed, CPME (11 mL) was added followed by 3- methyl-1-butyne (0.17 mL, 1.7 mmol, 1.0 equiv.). Triethylamine (0.70 mL, 5.0 mmol, 3.0 equiv.) was added at 10°C before the mixture was heated to 80°C and stirred for 18 hr. The cooled mixture was diluted with EtOAc, filtered through celite, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (0-100% EtOAc / cyclohexane) to yield the title compound (276 mg, 34%) as a yellow oil.1H NMR (400MHz, CDCl3) δ 8.70 (s, 1H), 8.50 (s, 1H), 6.49 (d, J = 1.1 Hz, 1H), 3.15 (septet of doublets, J = 1.1, 6.9 Hz, 1H), 1.38 (d, J = 6.9 Hz, 6H).

[0295] Step 2: Synthesis of 3-[4-(2-isopropylfuro[3,2-c]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile. A vial charged with 7-bromo-2-isopropyl-furo[3,2-c]pyridine (50 mg, 0.21 mmol, 1.0 equiv.), 3-piperazin-1-ylbenzonitrile (42 mg, 0.22 mmol, 1.1 equiv.) and XantPhos Pd G3 (20 mg, 0.02 mmol, 0.1 equiv.) was placed under argon atmosphere prior to addition of CPME (2.5 mL) and triethylamine (0.087 mL, 0.63 mmol, 3.0 equiv.). The suspension was degassed, sparged with CO and the mixture was stirred at 55°C, under an atmosphere of CO, for 3 days. The mixture was diluted with water and extracted with EtOAc three times. The combined organic phases were dried with magnesium sulfate, filtered, the filtrate was collected, and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm,20-80% MeCN / water 0.1% formic acid, 20mL / min, rt) to yield the title compound (3.5 mg, 4%) as an off-white solid. LCMS: Method B, m / z = 375.5 (M + H)⁺, RT = 3.82 min. ¹H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.44 (s, 1H), 7.44 - 7.36 (m, 2H), 7.29 (dd, J = 2.1, 8.4 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 6.82 (s, 1H), 3.89 - 3.83 (m, 2H), 3.44 - 3.37 (m, 4H), 3.28 - 3.23 (m, 2H), 3.18 - 3.11 (m, 1H), 1.31 (d, J = 6.9 Hz, 6H).

[0296] The compounds in Table 17 were made according to the method described in Example 31, using an appropriate amine reagent in Step 2: Table 17: Structure and Data for Compounds 40, 42, and 51.Example 32: Synthesis of 3-(4-(2-methylfuro[3,2-c]pyridine-7-carbonyl)piperazin-1- yl)benzonitrile (Compound 36)

[0297] Step 1: Synthesis of methyl 2-methylfuro[3,2-c]pyridine-7-carboxylate. A reaction vial charged with methyl 4-hydroxy-5-iodo-pyridine-3-carboxylate (60 mg, 0.22 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-yn-1-yl)-1,3,2-dioxaborolane (54 mg, 0.32 mmol, 1.5 equiv.), bis(triphenylphosphine)palladium(II) dichloride (7.6 mg, 0.011 mmol, 0.05 equiv.) and potassium carbonate (89 mg, 0.65 mmol, 3.0 equiv.) was placed under nitrogen atmosphere prior to addition of DMF (1 mL) and water (0.05 mL). The mixture was stirred at 50°C for 18 hr before the cooled mixture was diluted with EtOAc and filtered through celite. The filtrate was collected and washed with 5% aq. LiCl, brine, then dried with magnesium sulfate, filtered, the filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (0-25% acetone / cyclohexane) to yield the title compound (20 mg, 49%) as a yellow solid. ¹H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.91 (s, 1H), 6.52 (s, 1H), 4.03 (s, 3H), 2.57 (s, 3H).

[0298] Step 2: Synthesis of lithium 2-methylfuro[3,2-c]pyridine-7-carboxylate. To a stirred solution of methyl 2-methylfuro[3,2-c]pyridine-7-carboxylate (19 mg, 0.10 mmol, 1.0 equiv.) in THF (0.5 mL) was added a solution of lithium hydroxide monohydrate (4.6 mg, 0.11 mmol, 1.1 equiv.) in water (0.5 mL). The mixture was stirred at rt for 1 hr, the solvent was removed, and the material was used directly in the next step without further purification.

[0299] Step 3: Synthesis of 3-[4-(2-methylfuro[3,2-c]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile. To a stirred solution of (2-methylfuro[3,2-c]pyridine-7-carbonyl)oxylithium (19 mg, 0.10 mmol, 1.0 equiv.) in DMF (0.5 mL) was added HATU (43 mg, 0.11 mmol, 1.1 equiv.). The mixture was stirred at rt for 10 min before a solution of 3-piperazin-1-ylbenzonitrile (24 mg, 0.13 mmol, 1.2 equiv.) and DIPEA (55 µL, 0.32 mmol, 3.0 equiv.) in DMF (0.5 mL) was added. The mixture was stirred at rt for 10 min, diluted with EtOAc and washed successively with sat. aq. NaHCO3, 5% aq. LiCl and brine. The organic phase was separated, dried with magnesium sulfate, filtered, the filtrate was collected, and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm, 5-60% MeCN / water + 0.1% formic acid, 20mL / min, rt) to yield the title compound (8.3 mg, 22%) as an off-white solid. LCMS: Method B, m / z = 347.4 (M + H)⁺, RT = 3.25 min. ¹H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.43 (s, 1H), 7.44 - 7.39 (m, 1H), 7.38 - 7.35 (m, 1H), 7.32 - 7.27 (m, 1H), 7.22 - 7.18 (m, 1H), 6.82 (d, J= 1.3 Hz, 1H), 3.87 - 3.82 (m, 2H), 3.43 - 3.37 (m, 4H).2H obscured by water peak and 3H obscured by DMSO peak.

[0300] The compounds in Table 18 were made according to the method described in Example 32, using an appropriate amine reagent in Step 3: Table 18: Structure and Data for Compounds 56, 58, 59, and 82.Example 33: Synthesis of 3-chloro-5-[4-[2-(1-hydroxy-1-methyl-ethyl)furo[3,2-b]pyridine-7- carbonyl]piperazin-1-yl]benzonitrile (Compound 55)

[0301] Step 1: Synthesis of 2-(7-bromofuro[3,2-b]pyridin-2-yl)propan-2-ol.4-Bromo-2-iodo- pyridin-3-ol (508 mg, 1.70 mmol, 1.0 equiv.), 2-methyl-3-butyn-2-ol (0.16 mL, 1.65 mmol, 0.98 equiv.), bis(triphenylphosphine)palladium(II) dichloride (84 mg, 0.12 mmol, 0.07 equiv.) and copper(I) iodide (46 mg, 0.24 mmol, 0.14 equiv.) were combined in a vial. The vial was sealed, evacuated, and flushed with nitrogen. CPME (12.5 mL) and triethylamine (0.70 mL, 5.00 mmol, 3.0 equiv.) were added and the mixture stirred at 0°C for 2 hr. The mixture was filtered through celite, washing with EtOAc. The filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (12 g cartridge, 0- 50% EtOAc / cyclohexane) and the appropriate fractions combined and solvent removed to yield the title compound (141 mg, 32%) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 5.3 Hz, 1H), 7.38 (d, J = 5.3 Hz, 1H), 6.86 (s, 1H), 1.72 (s, 6H).

[0302] Step 2: Synthesis of 3-chloro-5-[4-[2-(1-hydroxy-1-methyl-ethyl)furo[3,2-b]pyridine- 7-carbonyl]piperazin-1-yl]benzonitrile.3-Chloro-5-piperazin-1-yl-benzonitrile (58 mg, 0.260 mmol, 1.3 equiv.), 2-(7-bromofuro[3,2-b]pyridin-2-yl)propan-2-ol (50 mg, 0.195 mmol, 1.0 equiv.) and XantPhos Pd G3 (19 mg, 0.012 mmol, 0.1 equiv.) were combined in a vial. The vial was sealed, evacuated, and flushed with nitrogen. This process was repeated twice, then CPME (1.5 mL) and triethylamine (0.11 mL, 0.797 mmol, 4.0 equiv.) were added and the vial was evacuated and flushed with nitrogen again. The vial was intensively stirred and purged with carbon monoxide for 1 minute, then stirred at 50°C for 72 hr under an atmosphere of carbon monoxide (1 atm). The mixture was diluted with EtOAc and water. The phases were separated, the organics collected and dried with sodium sulfate. The mixture was filtered, the filtrate collected, and the solvent was removed. The material was purified by HPLC (Xbridge Phenyl 19 x 150 mm, 10 µm, 40-100% MeOH / water + 10 mM NH4CO3, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (41 mg, 49% yield) as an off white solid. LCMS: Method A, m / z = 409.6 (M + H)⁺, RT = 3.82 min. ¹H NMR (400 MHz, DMSO) δ 8.55 (d, J = 4.9 Hz, 1H), 7.38 - 7.36 (m, 1H), 7.33 - 7.30 (m, 3H), 6.94 (s, 1H), 5.59 (s, 1H), 3.83 (t, J = 5.1 Hz, 2H), 3.47 (t, J = 4.9 Hz, 2H), 1.53 (s, 6H).4H obscured by water peak.

[0303] The compounds in Table 19 were made according to the method described in Example 33, using an appropriate amine reagent in Step 2:Table 19: Structure and Data for Compounds 54, 61, and 62.Example 34: Synthesis of 3-fluoro-5-[4-(furo[2,3-c]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile (Compound 57)

[0304] To a suspension of furo[2,3-c]pyridine-7-carboxylic acid (50 mg, 0.307 mmol, 1.0 equiv.) and 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (89 mg, 0.368 mmol, 1.2 equiv.) in EtOAc (3 mL) and triethylamine (0.17 µL, 1.23 mmol, 4.0 equiv.) was added T3P (50% in EtOAc, 0.274 µL, 0.460 mmol, 1.5 equiv.) and the mixture was stirred at rt for 5 hr. The mixture was diluted with EtOAc, washed with sat. aq. NaHCO3 solution and dried with sodium sulfate. The mixture was filtered, and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 0.1% formic acid, 20mL / min, rt) andthe appropriate fractions were combined and lyophilised to yield the title compound (24 mg, 23% yield) as an off-white solid. LCMS: Method A, m / z = 351.4 (M + H)⁺, RT = 4.02 min. ¹H NMR (400 MHz, DMSO) δ 8.41 (d, J = 5.1 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 5.3 Hz, 1H), 7.26 - 7.25 (m, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.15 - 7.10 (m, 2H), 3.87 - 3.82 (m, 2H), 3.49 - 3.42 (m, 4H). Example 35: Synthesis of 3-fluoro-5-[4-[2-(1-methylpyrazol-4-yl)furo[3,2-b]pyridine-7- carbonyl]piperazin-1-yl]benzonitrile (Compound 60)

[0305] Step 1: Synthesis of methyl 2-(1-methylpyrazol-4-yl)furo[3,2-b]pyridine-7- carboxylate. A vial was charged with 3-bromo-5-iodo-pyridin-4-ol (500 mg, 1.67 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (82 mg, 0.117 mmol, 0.07 equiv.), and copper(I) iodide (45 mg, 0.236 mmol, 0.14 equiv.). The vial was sealed, evacuated, and flushed with nitrogen. CPME (11 mL), 4-ethynyl-1-methyl-1H-pyrazole (40 mg, 0.377 mmol, 1.1 equiv.) and triethylamine (0.70 mL, 5.02 mmol, 3.0 equiv.) was added and the vial was evacuated and flushed with nitrogen. The mixture was stirred at 60°C for 1 hr. The reaction mixture was filtered and the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (0-10% MeOH / DCM) and the appropriate fractions were combined, and the solvent was removed to yield the title compound (31 mg, 34%) as orange oil.1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 5.0 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.63 (d, J = 5.0 Hz, 1H), 6.92 (s, 1H), 4.06 (s, 3H), 4.00 (s, 3H).

[0306] Step 2: Synthesis of 2-(1-methylpyrazol-4-yl)furo[3,2-b]pyridine-7- carbonyl]oxylithium. To a solution of methyl 2-(1-methylpyrazol-4-yl)furo[3,2-b]pyridine-7- carboxylate (34 mg, 0.132 mmol, 1.0 equiv.) in THF (1 mL) was added a solution of lithium hydroxide monohydrate (5.8 mg, 0.139 mmol, 1.1 equiv.) in water (0.25 mL). The mixture was stirred at 40°C for 16 hr. The solvent was removed and azeotroped with toluene (3 x 2 mL) to yield the title compound (32 mg, 100%). The material was used directly in the next step without further purification.

[0307] Step 3: Synthesis of 3-fluoro-5-[4-[2-(1-methylpyrazol-4-yl)furo[3,2-b]pyridine-7- carbonyl]piperazin-1-yl]benzonitrile. To a solution of 3-fluoro-5-piperazin-1-yl-benzonitrilehydrochloride (35 mg, 0.145 mmol, 1.1 equiv.), [2-(1-methylpyrazol-4-yl)furo[3,2-b]pyridine-7- carbonyl]oxylithium (33 mg, 0.132 mmol, 1.0 equiv.) in DMF (1 mL) was added T3P (50% in EtOAc, 0.12 mL, 0.202 mmol, 1.5 equiv.) and triethylamine (0.09 mL, 0.646 mmol, 4.9 equiv.). The mixture was stirred at rt for 2 hr. The mixture was diluted with EtOAc, washed with sat. aq. NaHCO3 solution and dried with magnesium sulfate. The mixture was filtered, the filtrate was collected and the solvent was removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm, 40-100% MeCN / water + 10mM NH4CO3, 20 mL / min, rt) and the appropriate fractions were combined and lyophilized to yield the title compound (27 mg, 60%) as an off- white solid. LCMS: Method A, m / z = 431.5 (M + H)⁺, RT = 3.86 min. ¹H NMR (400 MHz, DMSO) δ 8.53 (d, J = 4.9 Hz, 1H), 8.37 (s, 1H), 8.04 (s, 1H), 7.29 - 7.25 (m, 3H), 7.18 - 7.10 (m, 2H), 3.91 (s, 3H), 3.86 (t, J = 5.0 Hz, 2H), 3.52 (d, J = 5.9 Hz, 2H).4H obscured by water peak. Example 36: Synthesis of 3-fluoro-5-[4-(2-tetrahydrofuran-2-ylfuro[3,2-b]pyridine-7- carbonyl)piperazin-1-yl]benzonitrile (Compound 63)

[0308] Step 1: Synthesis of 7-bromo-2-tetrahydrofuran-2-yl-furo[3,2-b]pyridine. A vial was charged with 4-bromo-2-iodo-pyridin-3-ol (200 mg, 0.667 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (33 mg, 0.047 mmol, 0.07 equiv.), and copper(I) iodide (18 mg, 0.095 mmol, 0.14 equiv.) then sealed, evacuated, and flushed with nitrogen. CPME (4.0 mL), 2-ethynyltetrahydrofuran (0.096 mL, 0.665 mmol, 1.0 equiv.) and triethylamine (0.70 mL, 5.02 mmol, 3.0 equiv.) were added. The mixture was stirred at 0°C for 4.5 hr. The reaction mixture was filtered through a celite pad, washing with DCM. The filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (12 g cartridge, 0-50% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (113 mg, 63%) as a dark orange oil.1H NMR (400 MHz, CDCl3) δ 8.31 (bd, J = 4.2 Hz, 1H), 7.37 (d, J = 5.2 Hz, 1H), 6.90 (s, 1H), 5.14 (dd, J = 1.8 Hz, 13.2 Hz, 1H), 4.12 - 4.07 (m, 1H), 4.00 - 3.94 (m, 1H), 2.41 - 2.32 (m, 1H), 2.26 - 2.01 (m, 3H).

[0309] Step 2: Synthesis of 3-fluoro-5-[4-(2-tetrahydrofuran-2-ylfuro[3,2-b]pyridine-7- carbonyl)piperazin-1-yl]benzonitrile. A vial was charged with 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (100 mg, 0.414 mmol, 1.3 equiv.), 7-bromo-2-tetrahydrofuran-2-yl- furo[3,2-b]pyridine (88 mg, 0.322 mmol, 1.0 equiv.), and XantPhos Pd G3 (32 mg, 0.0337 mmol, 0.1 equiv.). The vial was sealed, evacuated, and flushed with nitrogen. This process was repeated twice, then CPME (2.5 mL) and triethylamine (0.19 mL, 1.36 mmol, 4.2 equiv.) were added and the vial was evacuated and flushed with nitrogen again. The vial was intensively stirred and purged with carbon monoxide for 1 min, then stirred at 50°C for 72 hr under an atmosphere of carbon monoxide (1 atm). The reaction mixture was filtered through a celite pad, washing with DCM (20 mL). The filtrate was collected, and the solvent removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm 40-100% MeCN / water + 10mM NH4CO3, 20 ml / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (76 mg, 56% yield) as an off white solid. LCMS: Method A, m / z = 421.5 (M + H)⁺, RT = 4.18 min. ¹H NMR (400 MHz, DMSO) δ 8.58 (d, J = 4.9 Hz, 1H), 7.35 (d, J = 5.0 Hz, 1H), 7.26 - 7.26 (m, 1H), 7.17 - 7.10 (m, 3H), 5.10 (dd, J = 6.1, 7.3 Hz, 1H), 3.93 - 3.77 (m, 4H), 3.47 (t, J = 4.3 Hz, 2H), 2.33 - 2.24 (m, 1H), 2.15 - 1.94 (m, 3H).4H obscured by water peak. Example 37: Synthesis of 3-fluoro-5-[4-(2-tetrahydrofuran-3-ylfuro[3,2-b]pyridine-7- carbonyl)piperazin-1-yl]benzonitrile (Compound 64)

[0310] Step 1: Synthesis of 7-bromo-2-tetrahydrofuran-3-yl-furo[3,2-b]pyridine. A vial charged with 4-bromo-2-iodo-pyridin-3-ol (200 mg, 0.667 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (33 mg, 0.047 mmol, 0.07 equiv.) , and copper(I) iodide (18 mg, 0.095 mmol, 0.14 equiv.) was sealed, evacuated, and flushed with nitrogen. CPME (22 mL), 3-ethynyltetrahydrofuran (0.096 mL, 0.665 mmol, 1.0 equiv.) and triethylamine (0.28 mL, 2.01 mmol, 3.0 equiv.) were added. The mixture was stirred at rt for 16 hr and the mixture was filtered through a celite pad, washing with DCM. The filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (12 g cartridge, 0-50% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (66 mg, 37%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 5.3 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 6.76 (d, J = 0.8Hz, 1H), 4.20 (dd, J = 7.6 Hz, 8.5 Hz, 1H), 4.08 - 3.94 (m, 3H), 3.69 (p, J = 7.6 Hz, 1H), 2.46 - 2.38 (m, 1H), 2.30 - 2.20 (m, 1H).

[0311] Step 2: Synthesis of 3-fluoro-5-[4-(2-tetrahydrofuran-3-ylfuro[3,2-b]pyridine-7- carbonyl)piperazin-1-yl]benzonitrile.3-Fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (56 mg, 0.232 mmol, 1.3 equiv.), 7-bromo-2-tetrahydrofuran-3-yl-furo[3,2-b]pyridine (49 mg, 0.179 mmol, 1.0 equiv.) and XantPhos Pd G3 (18 mg, 0.019 mmol, 0.11 equiv.) were combined in a vial. The vial was sealed, evacuated, and flushed with nitrogen. This process was repeated twice, then CPME (1.4 mL) and triethylamine (0.11 mL, 0.789 mmol, 4.4 equiv.) were added, then the vial was evacuated and flushed with nitrogen again. The vial was intensively stirred and purged with carbon monoxide for 15 min, then stirred at 50°C for 72 hr under an atmosphere of carbon monoxide (1 atm). The mixture was diluted with DCM (20 mL) and filtered through a celite pad, washing with DCM (20 mL). The filtrate was collected, and the solvent was removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm, 40-100% MeCN / water + 10 mM NH4CO3, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (34 mg, 45% yield) as an off white solid. LCMS: Method A, m / z = 421.5 (M + H)⁺, RT = 4.18 min. ¹H NMR (400 MHz, DMSO) δ 8.54 (d, J = 4.9 Hz, 1H), 7.31 (d, J = 4.9 Hz, 1H), 7.25 (s, 1H), 7.18 - 7.10 (m, 2H), 7.04 (d, J = 0.9 Hz, 1H), 4.04 (dd, J = 8.0, 8.0 Hz, 1H), 3.90 - 3.70 (m, 6H), 3.47 (t, J = 4.6 Hz, 2H), 2.38 - 2.29 (m, 1H), 2.19 - 2.10 (m, 1H). 4H obscured by water peak. Example 38: Synthesis of 3-fluoro-5-[4-[2-(3-pyridyl)furo[3,2-b]pyridine-7- carbonyl]piperazin-1-yl]benzonitrile (Compound 65)

[0312] Step 1: Synthesis of methyl 2-(3-pyridyl)furo[3,2-b]pyridine-7-carboxylate. A vial was charged with methyl 3-hydroxy-2-iodo-pyridine-4-carboxylate (100 mg, 0.358 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.0256 mmol, 0.07 equiv.), copper(I) iodide (10 mg, 0.0525 mmol, 0.15 equiv.) and 3-ethynylpyridine (45 mg, 0.436 mmol, 1.2 equiv.). The vial was sealed, evacuated, and flushed with nitrogen. CPME (2.3 mL) and triethylamine (0.7 mL, 5.02 mmol, 3.0 equiv.) were added. The mixture was stirred at 60°C for 1 hr, allowed to rt, filtered and the filtrate was collected, and the solvent was removed. Thematerial was purified by column chromatography on silica gel (12 g cartridge, 0-100% EtOAc / cyclohexane) with the appropriate fractions combined and the solvent was removed to yield the title compound (39 mg, 43%) as an off white solid.1H NMR (400 MHz, CDCl3) δ 9.22 (dd, J = 1.5 Hz, 3.0 Hz, 1H), 8.69 - 8.67 (m, 2H), 8.23 (dq, J = 0.5 Hz, 3.9 Hz, 8.0 Hz, 1H), 7.75 (d, J = 5.0 Hz, 1H), 7.45 (ddd, J = 0.8 Hz, 4.8 Hz, 8.0 Hz, 1H), 7.38 (s, 1H).

[0313] Step 2: Synthesis of [2-(3-pyridyl)furo[3,2-b]pyridine-7-carbonyl]oxylithium. To a solution of methyl 2-(3-pyridyl)furo[3,2-b]pyridine-7-carboxylate (31 mg, 0.12 mmol, 1.0 equiv.) in THF (1.0 mL) was added a solution of lithium hydroxide monohydrate (5.4 mg, 0.128 mmol, 1.1 equiv.) in water (0.25 mL). The mixture was stirred at 40°C for 16 hr and allowed to rt. The solvent was removed to yield the title compound (31 mg, 100%) as a white solid. The material was used directly in the next step without further purification.

[0314] Step 3: Synthesis of 3-fluoro-5-[4-[2-(3-pyridyl)furo[3,2-b]pyridine-7- carbonyl]piperazin-1-yl]benzonitrile. To a solution of 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (29 mg, 0.120 mmol, 1.1 equiv.) and [2-(3-pyridyl)furo[3,2-b]pyridine-7- carbonyl]oxylithium (27 mg, 0.110 mmol, 1.0 equiv.) in DMF (1 mL) was added triethylamine (0.07 mL, 0.502 mmol, 4.6 equiv.) and T3P (50% in EtOAc, 0.10 mL, 0.168 mmol, 1.5 equiv.). The mixture was stirred at rt for 4 hr, then diluted with EtOAc, washed with sat. aq. NaHCO3 solution and dried with magnesium sulfate. The mixture was filtered, the filtrate was collected and the solvent was removed. The material was dissolved in 9:1 DMSO:water (1.5 mL) and a precipitate formed, which was filtered and the solid was collected and dried to yield the title compound (15 mg, 33%) as an off-white solid. LCMS: Method A, m / z = 428.4 (M + H)⁺, RT = 3.84 min. ¹H NMR (400 MHz, DMSO) δ 9.23 (d, J = 1.6 Hz, 1H), 8.68 - 8.64 (m, 2H), 8.39 - 8.35 (m, 1H), 7.95 (s, 1H), 7.57 (ddd, J = 0.7, 4.8, 8.1 Hz, 1H), 7.43 (d, J = 4.9 Hz, 1H), 7.25 (s, 1H), 7.17 - 7.09 (m, 2H), 3.89 (t, J = 4.5 Hz, 2H), 3.53 (t, J = 5.0 Hz, 2H), 3.45 (t, J = 4.0 Hz, 2H).2H obscured by water peak. Example 39: Synthesis of 3-fluoro-5-[4-(2-tetrahydropyran-4-ylfuro[3,2-b]pyridine-7- carbonyl)piperazin-1-yl]benzonitrile (Compound 66)

[0315] Step 1: Synthesis of methyl 2-tetrahydropyran-4-ylfuro[3,2-b]pyridine-7- carboxylate. A vial was charged with 3-bromo-5-iodo-pyridin-4-ol (500 mg, 1.67 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (82 mg, 0.117 mmol, 0.07 equiv.), and copper(I) iodide (45 mg, 0.236 mmol, 0.14 equiv.). The vial was sealed, evacuated, and flushed with nitrogen. CPME (2.3 mL), 4-ethynyltetrahydropyran (48 mg, 0.436 mmol, 1.2 equiv.) and triethylamine (0.70 mL, 5.02 mmol, 3.0 equiv.) were added. The mixture was stirred at rt for 1 hr. The mixture was filtered, the filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (12 g cartridge, 0-100% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (67 mg, 67%) as a light yellow solid. The material was used directly in the next step without further purification.

[0316] Step 2: Synthesis of (2-tetrahydropyran-4-ylfuro[3,2-b]pyridine-7- carbonyl)oxylithium. To a solution of methyl 2-tetrahydropyran-4-ylfuro[3,2-b]pyridine-7- carboxylate (67 mg, 0.241 mmol, 1.0 equiv.) in THF (1.8 mL) was added a solution of lithium hydroxide monohydrate (11 mg, 0.253 mmol, 1.05 equiv.) in water (0.8 mL). The mixture was stirred at 40°C for 16 hr and the solvent was removed, azeotroping with toluene (3 x 2 ml) to yield the title compound (62 mg, 95%). The material was used directly in the next step without further purification.

[0317] Step 3: Synthesis of 3-fluoro-5-[4-(2-tetrahydropyran-4-ylfuro[3,2-b]pyridine-7- carbonyl)piperazin-1-yl]benzonitrile. To a solution of (2-tetrahydropyran-4-ylfuro[3,2- b]pyridine-7-carbonyl)oxylithium (62 mg, 0.245 mmol, 1.0 equiv.) and 3-fluoro-5-piperazin-1- yl-benzonitrile hydrochloride (65 mg, 0.269 mmol, 1.1 equiv.) in DMF (1.8 mL) was added triethylamine (0.16 mL, 1.15 mmol, 4.7 equiv.) and T3P (50% in EtOAc, 0.22 mL, 0.370 mmol, 1.51 equiv.). The mixture was stirred at rt for 2 hr, then diluted with EtOAc, washed with sat. aq. NaHCO3 solution and dried with magnesium sulfate. The mixture was filtered, and the solvent was removed. The material was purified by HPLC (Luna Phenyl-Hexyl 21.2 x 150 mm, 10 µm, 40-100% MeOH / water + 0.1% formic acid, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (25 mg, 23% yield) as an off white solid. LCMS: Method A, m / z = 435.5 (M + H)⁺, RT = 4.08 min. ¹H NMR (400 MHz, DMSO) δ 8.54 (d, J = 4.9 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 7.25 (s, 1H), 7.17 - 7.10 (m, 2H), 6.93 (d, J = 1.0 Hz, 1H), 3.94 - 3.90 (m, 2H), 3.82 (t, J = 5.1 Hz, 2H), 3.21 - 3.12 (m, 2H), 1.97 (dd, J = 1.8, 12.7 Hz, 2H), 1.78 - 1.67 (m, 2H).7H obscured by water peak. Example 40: Synthesis of 3-fluoro-5-[4-[2-(1-hydroxycyclopropyl)furo[3,2-b]pyridine-7- carbonyl]piperazin-1-yl]benzonitrile (Compound 68)

[0318] Step 1: Synthesis of 1-(7-bromofuro[3,2-b]pyridin-2-yl)cyclopropanol. A vial was charged with 4-bromo-2-iodo-pyridin-3-ol (100 mg, 0.333 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (17 mg, 0.0235 mmol, 0.07 equiv.) and copper(I) iodide (9.0 mg, 0.0473 mmol, 0.14 equiv.). The vial was sealed, evacuated, and flushed with nitrogen. CPME (2.0 mL), 1-ethynylcyclopropanol (0.039 mL, 0.413 mmol, 1.2 equiv.) and triethylamine (0.41 mL, 2.91 mmol, 2.9 equiv.) were added. The mixture was stirred at 0°C and allowed to come to rt over 16 hr. The mixture was filtered through celite, washing with DCM (3 x 5 mL). The filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (4 g cartridge, 0-50% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (35 mg, 40%) as a yellow oil.1H NMR (400MHz, CDCl3) δ 8.22 (d, J = 5.0 Hz, 1H), 7.31 - 7.29 (m, 1H), 7.01 (s, 1H), 1.38 - 1.37 (m, 4H).

[0319] Step 2: Synthesis of 3-fluoro-5-[4-[2-(1-hydroxycyclopropyl)furo[3,2-b]pyridine-7- carbonyl]piperazin-1-yl]benzonitrile.1-(7-Bromofuro[3,2-b]pyridin-2-yl)cyclopropanol (35 mg, 0.135 mmol, 1.0 equiv.), 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (42 mg, 0.174 mmol, 1.3 equiv.), XantPhos Pd G3 (13 mg, 0.0137 mmol, 0.1 equiv.) were combined in a vial. The vial was sealed, evacuated, and flushed with nitrogen. This process was repeated twice, then CPME (1.1 mL) and triethylamine (0.08 mL, 0.574 mmol, 4.25 eq) were added and the vial was evacuated and flushed with nitrogen again. The vial was intensively stirred and purged with carbon monoxide for 15 min, then stirred at 50°C for 96 hr under an atmosphere of carbon monoxide (1 atm). The mixture was allowed to rt and then filtered through a celite pad, washing with DCM (20 mL). The filtrate was collected, and the solvent was removed. The material was purified by HPLC (Xbridge Phenyl 19 x 150 mm, 10 µm, 40-100% MeOH / water + 10 mM NH4CO3, 20 mL / min, rt) then further purified by SFC (WATERS VIRIDIS 2-EP 20 x 250 mm, 5 µm, 5-15% MeOH + 0.1% NH4OH / CO2, 100 mL / min, 120 bar, 40°C, DAD 230 nm) and the appropriate fractions were combined and lyophilised to yield the title compound (3.3 mg, 6% yield) as an off white solid. LCMS: Method A, m / z = 407.5 (M + H)⁺, RT = 3.79 min. ¹H NMR (400 MHz, DMSO) δ 8.52 (d, J = 4.9 Hz, 1H), 7.27 (d, J = 4.7 Hz, 1H), 7.26 - 7.24 (m, 1H), 7.17 - 7.10 (m, 2H), 6.95 (s, 1H), 6.63 (s, 1H), 3.81 (t, J = 4.9 Hz, 2H), 3.45 (t, J = 5.1 Hz, 2H), 1.20 - 1.16 (m, 4H).4H obscured by water peak.Example 41: Synthesis of 3-[4-(2-ethyloxazolo[4,5-c]pyridine-7-carbonyl)piperazin-1-yl]-5- fluoro-benzonitrile (Compound 70)

[0320] Step 1: Synthesis of 7-bromo-2-ethyl-oxazolo[4,5-c]pyridine. A vial was charged with 3-amino-5-bromopyridin-4-ol (150 mg, 0.794 mmol, 1.0 equiv.), triethyl orthopropionate (3.2 mL, 15.9 mmol, 20 equiv.) and acetic acid (0.14 mL, 2.38 mmol, 3.0 equiv.). The mixture was stirred at 100°C in a microwave for 1 hr. Sat. aq. NaHCO3 was added and the mixture was stirred for 5 min, then DCM was added. The phases were separated, the organics were collected and dried with sodium sulfate. The mixture was filtered, the filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (0-60% EtOAc / cyclohexane) and the appropriate fractions were combined and the solvent was removed to yield the title compound (110 mg, 59%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.60 (s, 1H), 3.05 (q, J = 7.6 Hz, 2H), 1.49 (t, J = 7.3 Hz, 3H).

[0321] Step 2: Synthesis of 3-[4-(2-ethyloxazolo[4,5-c]pyridine-7-carbonyl)piperazin-1-yl]- 5-fluoro-benzonitrile.7-Bromo-2-ethyl-oxazolo[4,5-c]pyridine (50 mg, 0.220 mmol, 1.0 equiv.), 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (69 mg, 0.286 mmol, 1.3 equiv.), CPME (2.5 mL) and triethylamine (0.12 mL, 0.881 mmol, 4.0 equiv.) was added followed by XantPhos Pd G3 (21 mg, 0.022 mmol, 0.10 equiv.). The vial was sealed, evacuated, and flushed with argon. The vial was intensively stirred and purged with carbon monoxide for 15 min, then stirred at 50°C for 72 hr under an atmosphere of carbon monoxide (1 atm). The mixture was allowed to rt, then partitioned between water (10 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine (15 mL), dried with sodium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by HPLC (Xbridge C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 10 mM NH4CO3, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (39 mg, 46%) as an off-white solid. LCMS: Method A, m / z = 380.3 (M + H)⁺, RT = 4.01 min. ¹H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 8.60 (s, 1H), 7.26 - 7.26 (m, 1H), 7.19 - 7.11 (m, 2H), 3.82 - 3.82 (m, 2H), 3.46 - 3.46 (m, 6H), 3.04 (q, J = 7.5 Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H).Example 42: Synthesis of 3-[4-(2-chlorofuro[3,2-c]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile (Compound 71)

[0322] Step 1: Synthesis of methyl 2-trimethylsilylfuro[3,2-c]pyridine-7-carboxylate. A flask charged with methyl 4-hydroxy-5-iodo-pyridine-3-carboxylate (3.0 g, 10.8 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (540 mg, 0.769 mmol, 0.07 equiv.), and copper(I) iodide (300 mg, 1.58 mmol, 0.15 equiv.) was evacuated and flushed with nitrogen. DMF (45 mL), ethynyl(trimethyl)silane (1.8 mL, 13.0 mmol, 1.2 equiv.) and triethylamine (4.2 mL, 30.1 mmol, 2.8 equiv.) was added. The mixture was stirred at 80°C for 1.5 hr then allowed to rt. The solvent was removed and the material was purified by column chromatography on silica gel (120 g cartridge, 0-50% EtOAc / cyclohexane). The appropriate fractions were combined and the solvent was removed to yield the title compound (1464 mg, 52%) as a yellow-orange waxy solid. ¹H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 9.03 (s, 1H), 7.07 (s, 1H), 4.03 (s, 3H), 0.40 (s, 9H).

[0323] Step 2: Synthesis of methyl 2-chlorofuro[3,2-c]pyridine-7-carboxylate. To a solution of methyl 2-trimethylsilylfuro[3,2-c]pyridine-7-carboxylate (700 mg, 2.81 mmol, 1.0 equiv.) in MeCN (24 mL) was added N-chlorosuccinimide (1.50 g, 11.2 mmol, 4.0 equiv.). The mixture was stirred at 80°C for 4 hr then allowed to rt. The solvent was removed and the mixture was suspended in EtOAc. The mixture was filtered, the solid collected and dried to yield the title compound (230 mg, 39%) as a pale yellow-orange solid. ¹H NMR (400 MHz, MeOD) δ 9.44 (s, 1H), 9.26 (s, 1H), 7.48 (s, 1H), 4.13 (s, 3H).

[0324] Step 3: Synthesis of lithium 2-chlorofuro[3,2-c]pyridine-7-carboxylate. To a solution of methyl 2-chlorofuro[3,2-c]pyridine-7-carboxylate (40 mg, 0.189 mmol, 1.0 equiv.) in THF (0.8 mL) and water (0.8 mL) was added 1 M lithium hydroxide solution (0.28 mL, 0.284 mmol, 1.5 equiv.). The mixture was stirred at 50°C for 2 hr and the solvent was removed to yield the title compound (38 mg, 100%) as a pale brown solid. The material was used directly in the next step without further purification.

[0325] Step 4: Synthesis of 3-[4-(2-chlorofuro[3,2-c]pyridine-7-carbonyl)piperazin-1- yl]benzonitrile. To a solution of lithium 2-chlorofuro[3,2-c]pyridine-7-carboxylate (9.0 mg, 0.044 mmol, 1.0 equiv.) and 3-piperazin-1-ylbenzonitrile (8.4 mg, 0.044 mmol, 1.0 equiv.)in DMF (0.5 mL) was added triethylamine (25 µL, 0.177 mmol, 4.0 equiv.) and T3P (50% in EtOAc, 40 µL, 0.068 mmol, 1.5 equiv.). The mixture was stirred at rt for 72 h. The mixture was diluted with EtOAc, washed with sat. aq. NaHCO3 solution and brine. The phases were separated, the organics were collected and dried with sodium sulfate. The mixture was filtered, the filtrate was collected, and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 0.1% formic acid, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (3.7 mg, 22% yield) as an off white solid. LCMS: Method A, m / z = 367.3 (M + H)⁺, RT = 3.95 min. ¹H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.56 (s, 1H), 7.44 - 7.39 (m, 1H), 7.38 - 7.36 (m, 1H), 7.32 - 7.30 (m, 2H), 7.22 - 7.19 (m, 1H), 3.84 (s, 2H). 6H obscured by water peak.

[0326] The compounds in Table 20 were made according to the method described in Example 42, using an appropriate amine reagent in Step 4: Table 20: Structure and Data for Compounds 72 and 73.Example 43: Synthesis of 3-[4-(2-chlorofuro[3,2-b]pyridine-7-carbonyl)piperazin-1-yl]-5- fluoro-benzonitrile (Compound 74)

[0327] Step 1: Synthesis of methyl 2-trimethylsilylfuro[3,2-b]pyridine-7-carboxylate. A vial was charged with methyl 3-hydroxy-2-iodo-pyridine-4-carboxylate (1.50 g, 5.38 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (270 mg, 0.385 mmol, 0.07 equiv.), and copper(I) iodide (150 mg, 0.788 mmol, 0.15 equiv.). The vial was sealed, evacuated, and flushed with argon. CPME (35 mL), ethynyltrimethylsilane (0.90 mL, 6.51 mmol, 1.2 equiv.) and triethylamine (2.1 mL, 15.1 mmol, 2.8 equiv.) were added. The mixture was stirred at rt for 16 hr. The solvent was removed and the material was purified by column chromatography on silica gel (0-100% EtOAc / cyclohexane). The appropriate fractions were combined, and the solvent was removed to yield the title compound (695 mg, 51%) as a yellow-orange waxy solid. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 4.9 Hz, 1H), 7.69 (d, J = 4.9 Hz, 1H), 7.21 (s, 1H), 4.04 (s, 3H).

[0328] Step 2: Synthesis of methyl 2-chlorofuro[3,2-b]pyridine-7-carboxylate. To a solution of methyl 2-trimethylsilylfuro[3,2-b]pyridine-7-carboxylate (311 mg, 1.25 mmol, 1.0 equiv.) in MeCN (12 mL) was added N-chlorosuccinimide (668 mg, 5.00 mmol, 4.0 equiv.). The mixture was stirred at 80°C for 6 hr and allowed to rt. The solvent was removed and the mixture was triturated with EtOAc. The mixture was filtered, the filtrate was collected, and the solvent was removed. The material was purified by column chromatography on silica gel (0-5% MeOH / DCM) and the appropriate fractions were combined and the solvent was removed to yield the title compound (81 mg, 31%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 5.1 Hz, 1H), 7.77 (d, J = 5.1 Hz, 1H), 7.00 (s, 1H), 4.06 (s, 3H).

[0329] Step 3: Synthesis of (2-chlorofuro[3,2-b]pyridine-7-carbonyl)oxylithium. To a solution of methyl 2-chlorofuro[3,2-b]pyridine-7-carboxylate (12 mg, 0.057 mmol, 1.0 equiv.) in THF (0.5 mL) was added 1 M lithium hydroxide solution (0.10 mL, 0.100 mmol, 1.8 equiv.). The mixture was stirred at 50°C for 16 hr then allowed to rt. The solvent was removed to yield the title compound (12 mg, 94%). The material was used directly in the next step without further purification.

[0330] Step 4: Synthesis of 3-[4-(2-chlorofuro[3,2-b]pyridine-7-carbonyl)piperazin-1-yl]-5- fluoro-benzonitrile. To a solution of 2-chlorofuro[3,2-b]pyridine-7-carbonyl)oxylithium (41 mg, 0.200 mmol, 1.0 equiv.) and 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (68 mg, 0.281 mmol, 1.4 equiv.) in DMF (1.1 mL) was added triethylamine (0.15 mL, 1.08 mmol, 5.4 equiv.) and T3P (50% in EtOAc, 0.23 mL, 0.386 mmol, 1.9 equiv.). The mixture was stirred at rt for 16 hr. The mixture was diluted with EtOAc (10 ml), washed with sat. aq. NaHCO3 (3 x 5 ml) and dried with magnesium sulfate. The mixture was filtered, the filtrate was collected, and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm, 20-80%MeCN / water + 0.1% formic acid, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (7.6 mg, 10%) as an off-white solid. LCMS: Method A, m / z = 385.3 (M + H)⁺, RT = 4.39 min. ¹H NMR (400 MHz, DMSO) δ 8.62 (d, J = 5.0 Hz, 1H), 7.43 (d, J = 4.9 Hz, 1H), 7.40 (s, 1H), 7.26 - 7.25 (m, 1H), 7.18 - 7.11 (m, 2H), 3.82 (t, J = 4.5 Hz, 2H), 3.46 (t, J = 5.56 Hz, 2H), 3.40 - 3.38 (m, 2H).2H obscured by water peak.

[0331] The compounds in Table 21 were made according to the method described in Example 43, using an appropriate amine reagent in Step 4: Table 21: Structure and Data for Compounds 76 and 77.Example 44: Synthesis of 3-[4-(2-bromofuro[3,2-c]pyridine-7-carbonyl)piperazin-1-yl]-5- fluoro-benzonitrile (Compound 78)

[0332] Step 1: Synthesis of methyl 2-bromofuro[3,2-c]pyridine-7-carboxylate. To a solution of methyl 2-trimethylsilylfuro[3,2-c]pyridine-7-carboxylate (100 mg, 0.401 mmol, 1.0 equiv.) in MeCN (3.5 mL) was added N-bromosuccinimide (107 mg, 0.602 mmol, 1.5 equiv.) and the solution was stirred at 50°C for 3 hr, then allowed to rt. The solvent was removed, and the mixture was suspended in EtOAc and filtered. The filtrate was collected, and the solvent was removed. The material was used directly in the next step without further purification.

[0333] Step 2: Synthesis of lithium 2-bromofuro[3,2-c]pyridine-7-carboxylate. To a solution of methyl 2-bromofuro[3,2-c]pyridine-7-carboxylate (80 mg, 0.253 mmol, 1.0 equiv.) in THF (1 mL) and water (1 mL) was added lithium hydroxide (9.1 mg, 0.380 mmol, 1.5 equiv.). The mixture was stirred at 50°C for 24 hr and the solvent was removed, azeotroping with toluene (3 x 1 ml) to yield the title compound (71 mg, 74%) as a brown solid. The material was used directly in the next step without further purification.

[0334] Step 3: Synthesis of 3-[4-(2-bromofuro[3,2-c]pyridine-7-carbonyl)piperazin-1-yl]-5- fluoro-benzonitrile. To a solution of lithium 2-bromofuro[3,2-c]pyridine-7-carboxylate (81%, 27 mg, 0.088 mmol, 1.0 equiv.) and 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (32 mg, 0.133 mmol, 1.5 equiv.) in DMF (0.8 mL) was added triethylamine (49 µL, 0.353 mmol, 4.0 equiv.) and T3P (50% in EtOAc, 81 µL, 0.136 mmol, 1.5 equiv.). The reaction mixture was stirred at rt for 24 hr, then diluted with EtOAc, and washed with sat. aq. NaHCO3 solution (2 mL) and brine (2mL). The organics were dried with sodium sulfate, filtered, the filtrate was collected, and the solvent was removed. The material was purified by HPLC (Sunfire C1819 x 150 mm, 10 µm, 20-80% MeCN / water + 0.1% formic acid, 20 mL / min, rt) and the appropriate fractions were combined and lyophilised to yield the title compound (2.3 mg, 6% yield) as an off white solid. LCMS: Method A, m / z = 429.2 (M + H)⁺, RT = 4.21 min. ¹H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.53 (s, 1H), 7.40 (s, 1H), 7.26 (m, 1H), 7.18 - 7.10 (m, 2H), 3.83 (s, 2H).6H obscured by water peak.

[0335] The compounds in Table 22 were made according to the method described in Example 44, using an appropriate amine reagent in Step 3: Table 22: Structure and Data for Compound 81.Example 45: Synthesis of 7-(4-(3-cyano-5-fluorophenyl)piperazine-1-carbonyl)furo[3,2- c]pyridine-2-carbonitrile (Compound 79)

[0336] Step 1: Synthesis of 7-bromo-2-(diethoxymethyl)furo[3,2-c]pyridine. A vial was charged with 3-bromo-5-iodo-pyridin-4-ol (500 mg, 1.67 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (82 mg, 0.117 mmol, 0.07 equiv.) and copper(I) iodide (46 mg, 0.239 mmol, 0.14 equiv.) then placed under an atmosphere of nitrogen. DMF (12 mL) was added followed by 3,3-diethoxy-1-propyne (0.25 mL, 1.75 mmol, 1.1 equiv.) and the mixture was cooled to 0°C prior to addition of triethylamine (0.65 mL, 4.67 mmol, 2.8 equiv.). The mixture was stirred at 50°C for 6 hr, allowed to cool to rt and the solvent was removed. The material was purified by column chromatography on silica gel (0-50% EtOAc / cyclohexane) to yield the title compound (393 mg, 74%) as a yellow oil. ¹H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.58 (s, 1H), 6.95 (d, J = 0.9 Hz, 1H), 5.69 (d, J = 0.9 Hz, 1H), 3.74 - 3.66 (m, 4H), 1.28 (t, J = 7.1 Hz, 6H)

[0337] Step 2: Synthesis of 7-bromofuro[3,2-c]pyridine-2-carbaldehyde. To a solution of 7- bromo-2-(diethoxymethyl)furo[3,2-c]pyridine (385 mg, 1.28 mmol, 1.0 equiv.) in THF (7 mL) and water (2.8 mL) was added TFA (0.20 mL, 2.57 mmol, 2.0 equiv.). The resultant mixture was stirred at 50°C for 20 hr. The solvent was removed, the residue was basified with sat. aq. NaHCO3 and extracted with EtOAc three times. The combined organic phases were washed with brine, dried over magnesium sulfate and the solvent was removed to yield the title compound (252 mg, 84%) as an orange-brown solid. The material was used directly in the next step without further purification. ¹H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 9.03 (s, 1H), 8.77 (s, 1H), 7.68 (s, 1H).

[0338] Step 3: Synthesis of 7-bromofuro[3,2-c]pyridine-2-carbonitrile. A solution of 7- bromofuro[3,2-c]pyridine-2-carbaldehyde (250 mg, 1.11 mmol, 1.0 equiv.) and hydroxylamine hydrochloride (85 mg, 1.21 mmol, 1.1 equiv.) in DMSO (10 mL) was heated at 90°C for 18 hr. The solvent was removed, and the material was purified by column chromatography on silica gel (0-100% EtOAc / cyclohexane) to yield the title compound (95 mg, 38%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.78 (s, 1H), 7.62 (s, 1H).

[0339] Step 4: Synthesis of 7-[4-(3-cyano-5-fluoro-phenyl)piperazine-1-carbonyl]furo[3,2- c]pyridine-2-carbonitrile. A vial was charged with 3-fluoro-5-piperazin-1-yl-benzonitrile hydrochloride (37 mg, 0.153 mmol, 1.1 equiv.), palladium(II) acetate (3.1 mg, 0.014 mmol, 0.1equiv.) and Xantphos (16 mg, 0.030 mmol, 0.2 equiv.). A solution of 7-bromofuro[3,2- c]pyridine-2-carbonitrile (31 mg, 0.14 mmol, 1.0 equiv.) in CPME (1 mL) and DMF (0.1 mL) was added under an atmosphere of nitrogen, followed by triethylamine (0.15 mL, 1.11 mmol, 8.00 equiv.). The mixture was sparged with CO for 1 minute, and stirred at 50°C under an atmosphere of CO (1 atm) for 72 hr. The mixture was partitioned between EtOAc and water, the phases were separated, and the organic layer was dried with magnesium sulfate, filtered, the filtrate was collected and the solvent was removed.. The the material was purified by HPLC (Xbridge Phenyl 19 x 150 mm, 10 µm, 20-80% MeCN / water + 10 mM NH4CO3, 20 mL / min, rt) to yield the title compound (5 mg, 9%) and the appropriate fractions were combined and lyophilised to yield the title compound as an off-white solid. LCMS: Method A, m / z = 376.2 (M + H)⁺, RT = 4.14 min. ¹H NMR (400 MHz, DMSO) δ 9.25 (s, 1H), 8.76 (s, 1H), 8.35 (s, 1H), 7.26 (s, 1H), 7.19 - 7.09 (m, 2H), 3.82 (s, 2H), 3.52 - 3.44 (m, 4H).2H obscured by water peak.

[0340] The compounds in Table 23 were made according to the method described in Example 45, using an appropriate amine reagent in Step 4: Table 23: Structure and Data for Compound 80.Example 46: Synthesis of 3-(4-(2-(1-fluorocyclopropyl)furo[3,2-b]pyridine-7- carbonyl)piperazin-1-yl)benzonitrile (Compound 84)

[0341] Step 1: Synthesis of methyl 2-(1-hydroxycyclopropyl)furo[3,2-b]pyridine-7- carboxylate. To a solution of methyl 3-hydroxy-2-iodo-pyridine-4-carboxylate (500 mg, 1.79 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) dichloride (92 mg, 0.13 mmol, 0.07 equiv.), and copper(I) iodide (50 mg, 0.26 mmol, 0.15 equiv.) in CPME (14 mL) was added 1-ethynylcyclopropanol (0.22 mL, 2.31 mmol, 1.3 equiv.). The mixture was cooled to 0°C, triethylamine (0.41 mL, 2.91 mmol, 3.0 equiv.) was added, and the mixture was stirred at rt for 18 hr. The mixture was filtered through Celite, the filtrate was collected, and the solvent was removed. The material was purified by hot filtration from EtOAc, the filtrate was collected, allowed to cool and the filtered to yield the title compound (331 mg, 78%) as a brown solid. The material was used directly in the next step without further purification.

[0342] Step 2: Synthesis of methyl 2-(1-fluorocyclopropyl)furo[3,2-b]pyridine-7- carboxylate. To a suspension of methyl 2-(1-hydroxycyclopropyl)furo[3,2-b]pyridine-7- carboxylate (200 mg, 0.858 mmol, 1.0 equiv.) in dry DCM (8 mL) was added DAST (0.17 mL, 1.29 mmol, 1.5 equiv.) at 0°C. The mixture was stirred at 0°C for 2 hr, allowed to warm to rt and stirred for 18 hr. The mixture was quenched with sat. aq. NaHCO3 and extracted with EtOAc three times. The combined organic phases were washed with brine, dried with magnesium sulfate, filtered, the filtrate was collected and the solvent was removed. The material was purified by column chromatography on silica gel (0-5% MeOH / DCM) to yield the title compound (81 mg, 2...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound represented by the structure of Formula (I): (I); or a pharmaceutically acceptable salt thereof, wherein: Y1 is selected from N and C(R3); X1 is selected at each occurrence from N and C(R3), wherein one occurrence of X1 is N and two occurrences of X1 are C(R3); R1 is selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =NR11, and -CN; and C3-12carbocycle and 3- to 12-membered heterocycle, 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, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, - N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -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, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, - N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =NR11, and -CN; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -OC(O)R12, -N(R12)C(O)R12, -N(R12)S(O)2R12, -S(O)R12, -S(O)2R12, -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, -C(O)N(R12)2, -OC(O)R12, -N(R12)C(O)R12, -N(R12)S(O)2R12, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =NR12, and -CN;or two occurrences of R2 come together with the adjacent carbon atoms to which they are each bound to form a C3-6 cycloalkyl; each R3 is independently selected at each occurrence from: hydrogen, halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, - OC(O)R13, -N(R13)C(O)R13, -N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -C(O)N(R13)2, - OC(O)R13, -N(R13)C(O)R13, -N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =NR13, and -CN; and C3-12carbocycle and 3- to 12-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, -C(O)N(R13)2, -OC(O)R13, -N(R13)C(O)R13, - N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -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, -C(O)N(R13)2, -OC(O)R13, -N(R13)C(O)R13, - N(R13)S(O)2R13, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =NR13, and -CN; Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, - OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN; each R11, R12, R13, and R14are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; andC3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; each R15is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, and C3-10carbocycle; wherein the C3-10carbocycle is optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; and m is selected from 0, 1, 2, 3, 4, and 5.

2. The compound or salt of claim 1, wherein the compound is represented by the structure of Formula (Ia), Formula (Ib), or Formula (Ic), or a pharmaceutically acceptable salt of any one thereof:.

3. The compound or salt of claim 1, wherein the compound is represented by the structure of Formula (Id), Formula (Ie), or Formula (If), or a pharmaceutically acceptable salt of any one thereof:.

4. The compound or salt of any one of claims 1 to 3, wherein m is selected from 0, 1, and 2.

5. The compound or salt of claim 4, wherein m is 0 or 2.

6. The compound or salt of claim 5, wherein m is 2.

7. The compound or salt of claim 6, wherein two occurrences of R2 come together with the adjacent carbon atoms to which they are each bound to form a C3 cycloalkyl.

8. The compound or salt of claim 5, wherein m is 0.

9. The compound or salt of any one of claims 1 to 8, wherein each R3 is independently selected at each occurrence from hydrogen, halogen, C1-6haloalkyl, C1-6alkyl, and 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from C1-6alkyl.

10. The compound or salt of claim 9, wherein each R3 is hydrogen.

11. The compound or salt of claim 9, wherein each R3 is independently selected at each occurrence from hydrogen, methyl,.

12. The compound or salt of any one of claims 1 to 11, wherein R1 is selected from:hydrogen, halogen, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)OR11, -C(O)N(R11)2,C3-12carbocycle and 3- to 12-membered heterocycle, 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, -C(O)N(R11)2, -OC(O)R11, -N(R11)C(O)R11, - N(R11)S(O)2R11, -S(O)R11, -S(O)2R11, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - , -alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycle.

13. The compound or salt of claim 12, wherein R1 is selected from: hydrogen, halogen, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen and -OR11; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, and C1-6alkyl.

14. The compound or salt of claim 13, wherein R1 is selected from: hydrogen, halogen, -CN; methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen and -OH; and cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, and pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, and C1-6alkyl.

15. The compound or salt of claim 14, wherein R1 is selected from: hydrogen, halogen, -CN; methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen and -OH; andcyclopropyl optionally substituted with one or more substituents independently selected from: halogen, -OH, and C1-6alkyl.

16. The compound or salt of claim 14, wherein R1 is selected from: tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, and pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, and C1-6alkyl.

17. The compound or salt of claim 14, wherein R1 is selected from: hydrogen, chloro, bromo, -CN, methyl, ethyl,, , , , ,.

18. The compound or salt of claim 17, wherein R1 is selected from hydrogen and methyl.

19. The compound or salt of claim 1, whereinselected from:,20. The compound or salt of claim 1, wherein is selected from:,.

21. The compound or salt of any one of claims 1 to 20, wherein: Ring A is C3-12carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, - C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, - NO2, -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)OR14, - C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, - NO2, =O, =S, =NR14, and -CN.

22. The compound or salt of claim 21, wherein: Ring A is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, - C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, - 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)OR14, -C(O)N(R14)2, - OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN.

23. The compound or salt of claim 22, wherein: Ring A is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, and -CN.24.

25. The compound or salt of claim 23, wherein Ring A is selected from: ,.

26. The compound or salt of any one of claims 1 to 20, wherein: Ring A is 3- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, - C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, - S(O)2R14, -NO2, -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)OR14, - C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, - NO2, =O, =S, =NR14, and -CN.

27. The compound or salt of claim 26, wherein: Ring A is pyridinyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, - C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, - 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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =NR14, and -CN.

28. The compound or salt of claim 27, wherein: Ring A is pyridinyl optionally substituted with one or more substituents independently selected from: halogen, and -OR15.

29. The compound or salt of claim 26, wherein: Ring A is pyridinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR14, -N(R14)2, - C(O)R14, -C(O)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, - S(O)R14, -S(O)2R14, -NO2, -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)OR14, -C(O)N(R14)2, -OC(O)R14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -S(O)R14, - S(O)2R14, -NO2, =O, =S, =NR14, and -CN.

30. The compound or salt of claim 29, wherein: Ring A is pyridinyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR15, and C1-6haloalkyl.

31. The compound or salt of claim 30, wherein Ring A is selected from:,acceptable salt of any one thereof., , ,,,pharmaceutically acceptable salt of any one thereof.

34. A compound represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: Y2 is selected from N and C(R22); R21 is selected from: hydrogen, halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, - C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, - S(O)2R121, -NO2, -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, - C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, - S(O)2R121, -NO2, =O, =S, =NR121, and -CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, -OC(O)R121, - N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, -CN, and C1-6alkyl optionally substituted with one or more substituents independently selected fromhalogen, -OR121, -SR121, -N(R121)2, -C(O)R121, -C(O)OR121, -C(O)N(R121)2, -OC(O)R121, -N(R121)C(O)R121, -N(R121)S(O)2R121, -S(O)R121, -S(O)2R121, -NO2, =O, =S, =NR121, and -CN; each R22 is independently selected from at each occurrence from: hydrogen, halogen, -OR122,, -SR122,, -N(R122,)2, -C(O)R122,, -C(O)OR122,, -C(O)N(R122,)2, - OC(O)R122,, -N(R122,)C(O)R122,, -N(R122,)S(O)2R122,, -S(O)R122,, -S(O)2R122,, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR122,, -SR122,, -N(R122,)2, -C(O)R122,, -C(O)OR122,, -C(O)N(R122,)2, - OC(O)R122,, -N(R122,)C(O)R122,, -N(R122,)S(O)2R122,, -S(O)R122,, -S(O)2R122,, -NO2, =O, =S, =NR122,, and -CN; Ring B is selected from phenyl and pyridinyl, wherein the phenyl is substituted with one or more R23 and the pyridinyl is optionally substituted with one or more R24; wherein each R23 is independently selected at each occurrence from: halogen, -OR125, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, -C(O)N(R123)2, - OC(O)R123, -N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR123, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, -C(O)N(R123)2, -OC(O)R123, -N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, -NO2, =O, =S, =NR123, and -CN; and each R24 is independently selected from at each occurrence from: fluoro, bromo, iodo, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, - C(O)N(R124)2, -OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, - NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, -C(O)N(R124)2, -OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, -NO2, =O, =S, =NR124, and -CN; each R121, R122,, R123and R124are independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituentsselected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN; and each R125 is independently selected at each occurrence from: hydrogen; C2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and CN; and C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -NH2, -NO2, =O, and -CN.

35. The compound or salt of claim 34, wherein the compound is represented by the structure of Formula (IIa) or a pharmaceutically acceptable salt thereof:Formula (IIa) .

36. The compound or salt of claim 34, wherein the compound is represented by the structure of Formula (IIb), or a pharmaceutically acceptable salt thereof:Formula (IIb).

37. The compound or salt of any one of claims 34 to 36, wherein each R22 is independently selected at each occurrence from hydrogen, halogen, and C1-6alkyl.

38. The compound or salt of claim 37, wherein each R22 is hydrogen.

39. The compound or salt of claim 37, wherein each R22 is hydrogen and halogen.

40. The compound or salt of any one of claims 34 to 39, wherein R21 is selected from hydrogen, halogen, C1-6haloalkyl, and C1-6alkyl.

41. The compound or salt of claim 40, wherein R21 is hydrogen or methyl.

42. The compound or salt of claim 34, whereinselected from:,43. The compound or salt of claim 34, whereinselected from:,44. The compound or salt of any one of claims 34 to 43, wherein: Ring B is phenyl substituted with one or more R23; wherein each R23 is independently selected at each occurrence from: hydrogen, halogen, -OR125, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, - C(O)N(R123)2, -OC(O)R123, -N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, - NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR123, -SR123, -N(R123)2, -C(O)R123, -C(O)OR123, - C(O)N(R123)2, -OC(O)R123, -N(R123)C(O)R123, -N(R123)S(O)2R123, -S(O)R123, -S(O)2R123, - NO2, =O, =S, =NR123, and -CN.

45. The compound or salt of claim 44, wherein: Ring B is phenyl substituted with one or more R23; wherein each R23 is independently selected at each occurrence from: halogen and -CN.

46. The compound or salt of claim 45, wherein Ring B is selected fromand.

47. The compound or salt of claim 45, wherein Ring B is selected from:

48. The compound or salt of any one of claims 34 to 43, wherein: Ring B is pyridinyl optionally substituted with one or more R24; wherein each R24 is independently selected at each occurrence from: fluoro, bromo, iodo, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, - C(O)N(R124)2, -OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, - NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR124, -SR124, -N(R124)2, -C(O)R124, -C(O)OR124, -C(O)N(R124)2, -OC(O)R124, -N(R124)C(O)R124, -N(R124)S(O)2R124, -S(O)R124, -S(O)2R124, -NO2, =O, =S, =NR124, and -CN.

49. The compound or salt of claim 48, wherein: Ring B is pyridinyl optionally substituted with one or more R24; wherein each R24 is independently selected at each occurrence from: -OR124and C1-6alkyl.

50. The compound or salt of claim 49, wherein Ring B is selected from:.

51. The compound or salt of claim 49, wherein Ring B is selected from:

52. The compound or salt of claim 34, selected from:,acceptable salt of any one thereof.

53. The compound or salt of claim 34, selected from:,pharmaceutically acceptable salt of any one thereof.

54. A compound selected from:, ,pharmaceutically acceptable salt of any one thereof.or a pharmaceutically acceptable salt of any one thereof.

56. Use of a compound or salt of any one of claims 1 to 55 as a medicine.

57. A pharmaceutical composition comprising: (i) a compound or salt of any one of claims 1 to 55, and (ii) a pharmaceutically acceptable excipient.

58. A method of killing a cancer cell, comprising contacting the cancer cell to a compound or salt of any one of claims 1 to 55, or a pharmaceutical composition of claim 57.

59. The method of claim 58, wherein the cancer cell is selected from a melanoma cell and an ovarian cancer cell.

60. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound or salt of any one of claims 1 to 55, or a pharmaceutical composition of claim 57.

61. The method of claim 60, wherein the cancer is selected from melanoma and ovarian cancer.

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