NAPHTHYRIDONE COMPOUNDS FOR INHIBITION OF RAF KINASES CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Application No. 63/422,856 filed November 4, 2022, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION [0002] Provided herein are compounds and compositions for inhibition of RAF serine/threonine protein kinases, methods of preparing said compounds and compositions, and their use in the treatment of various cancers, such as melanoma, non-small cell lung cancer, and chronic myeloid leukemia (CML). BACKGROUND [0003] The RAF family of serine/threonine protein kinases operate as an essential signaling node within the Ras/Raf/MEK/ERK pathway. Also referred to as the mitogen activated kinase (MAPK) pathway, this signaling cascade is critically involved in the regulation of a diverse array of basic physiological processes. The MAPK pathway is responsive to a variety of stimuli mediated through the input of numerous intracellular second messengers and transmembrane receptors including the receptor tyrosine kinases (RTKs). In the case of the RTKs, upon ligand binding, they act on the MAPK pathway through the recruitment/activation of the RAS GTPases which then bind and activate RAF. RAF then phosphorylates MEK (mitogen activated kinase kinase 1 & 2) at serine residues located within their activation loops that in turn induce certain conformational changes leading to their activation. Activated MEK in turn phosphorylates and activates the ERK kinases (Extracellular Regulated Kinase 1 & 2 also known as MAPK1/2 or mitogen-activated protein kinases 1 & 2) via activation loop phosphorylation. Activated ERK then acts as a broad-based effector of the pathway, modulating the activity of a variety of proteins including other protein kinases, structural proteins, metabolic enzymes and transcription factors that in turn modulate the broad cellular response to these stimuli. Importantly, the primary output of the MAPK pathway is to drive cell growth and proliferation as well as to suppress apoptosis (regulated cell death). Given its central role in the regulation of these processes, it is not surprising that the majority of genetic alterations associated with cellular transformation act entirely or at least in part via the aberrant activation of the MAPK pathway. Therefore, as an essential node in the MAPK pathway, the RAF kinases represent an important therapeutic intervention point for the treatment of a variety of malignancies whose dysregulated growth and survival rely upon this pathway. [0004] Thus, there remains a need for new compounds and compositions for inhibition RAF kinases. SUMMARY OF THE INVENTION [0005] Provided herein are compounds and compositions that inhibit RAF kinases and that are useful for treating disorders mediated by RAF kinases. [0006] In one aspect, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R ⁰ is C ₁ -C ₃ alkyl or cyclopropyl, wherein the C ₁ -C ₃ alkyl or cyclopropyl are optionally substituted with 1 to 5 R ⁵ groups; R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a ) ^0-1 -(C(R ² )R ² ) ^0-1 -OR ² , - (X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0- 1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )- C(R ² )R ² -N(R ² )R ² S(O) ² R ² , or -(X ^a )-(C(R ² )R ² ) ^0-1 -C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aromatic portions of Ring A are optionally substituted with 1 to 5 R ⁴ groups, and wherein when Ring A is C ⁶ aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C2-C6 alkenyl- OH, -C(=N-OH)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0007] In some embodiments, Ring A is selected from the group consisting of:

[0008] In some embodiments, the compound of formula (I) is a compound of formula (I’), (I’) or a pharmaceutically acceptable salt thereof, wherein: R ⁰ is C ₁ -C ₃ alkyl or cyclopropyl, wherein the C ₁ -C ₃ alkyl or cyclopropyl are optionally substituted with 1 to 5 R ⁵ groups; R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , - (X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0- 1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )- C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl- OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0009] In some embodiments, the compound of formula (I’) is a compound of formula (I’-1), (I’-1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , - (X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0- 1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )- C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ¹ -C ⁶ alkyl, C ¹ -C ⁶ haloalkyl, C ¹ -C ⁶ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl- OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ² , -CF ³ , -CF ² Cl, -CHF ² , -CN, -NO ² , C ¹ -C ⁶ alkyl, C ¹ -C ⁶ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0010] In other embodiments, the compound of formula (I’) is a compound of formula (I’-2) or a pharmaceutically acceptable salt thereof, wherein R ⁰ is C ₁ -C ₃ alkyl optionally substituted by 1 to 5 R ⁵ groups, and wherein R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl- CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1- N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² - S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )-C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ¹ -C ⁶ alkylene, C ¹ -C ⁶ heteroalkylene, C ³ -C ⁷ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ¹ -C ⁶ alkyl, C ¹ -C ⁶ haloalkyl, C ¹ -C ⁶ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N ³ , -OCHF ² , -CF ³ , -CF ² Cl, -CHF ² , -CN, -NO ² , -C(=O)C ¹ -C ⁶ alkyl, C ¹ -C ⁶ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl- OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0011] In some embodiments of any of the foregoing, R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1- (C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )-C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C1- C6 alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6-membered heteroaryl, F, Cl, -OH, -NH ₂ , - NHMe, -NMe2, -SH, -SMe, -S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, - NO2, -CHF ₂ , -CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , - N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C3-C7 cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0012] In other embodiments, R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a ) 0-1-(C(R ² )R ² )0-1- OR ² , or -(X ^a ) 0-1-(C(R ² )R ² )0-1-N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C1- C6 alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C1- C6 dialkylamino, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6-membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SMe, -S(O)Me, -S(O) ₂ Me, or -CN; Ring A is C6 aryl or 5- to 6-membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and each R ⁴ is independently H, F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CHF ₂ , -CN, - NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0013] In some embodiments, R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-CN, or C ₁ -C ₆ heteroalkyl, wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6-membered heteroaryl, F, Cl, - OH, -NH ₂ , -NHMe, -NMe2, -SMe, -S(O)Me, -S(O) ₂ Me, or -CN; Ring A is C6 aryl or 5- to 6- membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C1- C6 alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and each R ⁴ is independently H, F, Cl, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -OCHF ₂ , - CF ₃ , -CHF ₂ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl; each R ⁵ is independently F, -OCF ₃ , -OR ⁶ , - N(R ⁶ )R ⁶ , -OCHF ₂ , -CF ₃ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ heteroalkyl, wherein the aliphatic portions of R5 are optionally substituted with 1 to 3 R3 groups; and each R6 is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl. [0014] In some embodiments, R ¹ is H or C ₁ -C ₆ alkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is -CH ₃ or -CH ₂ CH ₃ . [0015] In some embodiments, Ring A is 6-membered heteroaryl substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and optionally further substituted with 1 to 4 R ⁴ groups. In some embodiments, Ring A is pyridyl or pyrimidyl, wherein the pyridyl or pyrimidyl is substituted by C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 4 R ⁴ groups. [0016] In other embodiments, Ring A , wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 4 R ⁴ groups, each R ⁴ is independently F, C ₁ -C ₆ alkyl, -OR ⁶ , -CN, -CH ₂ CN, -CH ₂ CH ₂ CN, C ₁ -C ₆ alkyl-OH, or C ₁ -C ₆ haloalkyl-OH; and each R ⁶ is independently H or C ₁ -C ₆ alkyl. In some embodiments, Ring A is substituted by -C(=N-OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 4 R ⁴ groups. [0017] In certain embodiments, Ring A is [0018] In some embodiments, R ⁵ , if present, is F. [0020] Also provided herein is a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), or (I-h):

one R ⁴ is C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 2 R ⁴ groups. In some embodiments, R ¹ is H or –CH ₃ ; and at least one R ⁴ is -C(=N-OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , - CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . In some embodiments, R ¹ is -CH ₃ ; and at least one R ⁴ is -C(=N-OH)CH ₂ CH ₃ , -C(=N- OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . [0021] Provided herein is a compound which is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. [0022] Also provided herein is a compound which is selected from the group consisting :

or a pharmaceutically acceptable salt thereof. [0023] In another aspect, provided herein is a pharmaceutical composition comprising any compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [0024] In yet another aspect, the present disclosure provides a method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof. [0025] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof. [0026] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation. In some embodiments, the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in ARAF selected from the group consisting of S214C and S214F. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in BRAF selected from the group consisting of Class I, Class IIa, Class IIb, Class IIc, and Class III mutations. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in CRAF selected from the group consisting of P261A, P261L, E478K, R391W, R391S and T491I, or is associated with a CRAF fusion. In other embodiments, the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs). In some embodiments, the one or more genetic lesions is a point mutation, a fusion or any combination thereof. In some embodiments, the one or more receptor tyrosine kinase is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROS1. [0027] In some embodiments of the present aspect, the cancer is a refractory BRAF Class I mutant cancer. In some embodiments, the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R. In certain embodiments of the foregoing, the refractory cancer is associated with a genetic alteration in KRAS, NRAS, HRAS or BRAF that drives BRAF dimerization and confers resistance to approved Type 1.5 inhibitors (including vemurafenib, dabrafenib and encorafenib) both alone and in the context of MEK inhibitor (including cobimetinib, trametinib and binimetinib) combinations. In some embodiments, the refractory cancer is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the refractory cancer is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the refractory cancer is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the refractory cancer is associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. In some embodiments, the refractory cancer is associated with one or more Class II or Class III mutations in BRAF. In some embodiments, the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q. In some embodiments, the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10. In still further embodiments of the foregoing, the method further comprises administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation. [0028] In some embodiments of the present aspect, the cancer is a refractory cancer. In certain embodiments of the foregoing, the refractory cancer is associated with one or more genetic alterations in KRAS, NRAS, HRAS, BRAF, or one or more RTKs. In some embodiments, the refractory cancer is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the refractory cancer is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the refractory cancer is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the refractory cancer is associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. In some embodiments, the refractory cancer is associated with one or more Class II or Class III mutations in BRAF. In some embodiments, the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q. In some embodiments, the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10. In some embodiments wherein the refractory cancer is associated with one or more genetic alterations in one or more RTKs, the one or more RTKs is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROS1. [0029] In some embodiments, the cancer is a solid tumor or a hematological malignancy. In some embodiments, the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, colorectal carcincoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC). [0030] In still further embodiments of the foregoing, the method further comprises administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro- apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation. DETAILED DESCRIPTION [0031] The following description sets forth exemplary methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. I. Definitions [0032] As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art. [0033] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the present disclosure as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc. [0034] The terms “individual”, “subject” and “patient” refer to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human. [0035] As used herein, the term “mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. [0036] “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration. [0037] As used herein, the term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (e.g., C ₁ -C ₆ means one to six carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. In some embodiments, the term “alkyl” may encompass C ₁ -C ₆ alkyl, C2-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C1-C5 alkyl, C2-C5 alkyl, C3-C5 alkyl, C4-C5 alkyl, C1-C4 alkyl, C2-C4 alkyl, C3-C4 alkyl, C ₁ -C ₃ alkyl, C2-C3 alkyl, or C1-C2 alkyl. [0038] As used herein, the term “alkenyl” refers to an unsaturated branched or straight- chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1- yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl). In some embodiments, the alkenyl group may be attached to the rest of the molecule by a carbon atom in the carbon-carbon double bond. In other embodiments, the “alkenyl” may be attached to the rest of the molecule by a saturated carbon atom, and the carbon-carbon double bond is located elsewhere along the branched or straight-chain alkyl group. [0039] The term “cycloalkyl,” “carbocyclic,” or “carbocycle” refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices. As used herein, “cycloalkyl,” “carbocyclic,” or “carbocycle” is also meant to refer to bicyclic, polycyclic and spirocyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norborene, spirocyclic C5-12 alkane, etc. In some embodiments, “cycloalkyl” encompasses C ₃ -C ₇ cycloalkyl, C4-C7 cycloalkyl, C5-C7 cycloalkyl, C5-C7 cycloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, C5-C6 cycloalkyl, C3-C5 cycloalkyl, C4-C5 cycloalkyl, or C3-C4 cycloalkyl. [0040] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain hydrocarbon radical, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group. The heteroatom Si can be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. A “heteroalkyl” can contain up to three units of unsaturation, and also include mono- and poly-halogenated variants, or combinations thereof. Examples include -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -O-CF ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ - CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O -CH ₃ , - Si(CH ₃ )3, -CH2-CH=N-OCH ₃ , and -CH=CH=N(CH ₃ )-CH ₃ . Up to two heteroatoms can be consecutive, such as, for example, -CH ₂ -NH-OCH ₃ and -CH ₂ -O-Si(CH ₃ )3. [0041] The term “heterocycloalkyl,” “heterocyclic,” or “heterocycle” refers to a cycloalkyl radical group having the indicated number of ring atoms (e.g., 5-6 membered heterocycloalkyl) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, nitrogen atom(s) are optionally quaternized, as ring atoms. Unless otherwise stated, a “heterocycloalkyl,” “heterocyclic,” or “heterocycle” ring can be a monocyclic, a bicyclic, spirocyclic or a polycylic ring system. Non-limiting examples of “heterocycloalkyl,” “heterocyclic,” or “heterocycle” rings include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine, tropane and the like. A “heterocycloalkyl,” “heterocyclic,” or “heterocycle” group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms. In some embodiments, “heterocycloalkyl” encompasses 4- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkyl, 6- to 8-membered heterocycloalkyl, 7- to 8-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 6- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl, or 4- to 5-membered heterocycloalkyl. [0042] The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH ₂ CH ₂ CH ₂ CH ₂ -. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms. In some embodiments, an alkyl (or alkylene) group will have 10 or fewer carbon atoms. [0043] The term “heteroalkylene” by itself or as part of another substituent means a divalent radical, saturated or unsaturated or polyunsaturated, derived from heteroalkyl, as exemplified by -CH ₂ -CH ₂ -S-CH ₂ CH ₂ -, -CH ₂ -S-CH ₂ -CH ₂ -NH-CH ₂ -, -O-CH ₂ -CH=CH-, - CH ₂ -CH=C(H)CH ₂ -O-CH ₂ - and -S-CH ₂ -&Ł&-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). [0044] The term “heterocycloalkylene” by itself or as part of another substituent means a divalent radical, saturated or unsaturated or polyunsaturated, derived from heterocycloalkyl. For heterocycloalkylene groups, heteroatoms can also occupy either or both of the chain termini. [0045] The terms “alkoxy” and “alkylamino” are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom or an amino group, respectively. [0046] The term “heterocycloalkoxy” refers to a heterocycloalkyl-O- group in which the heterocycloalkyl group is as previously described herein. [0047] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-C4 haloalkyl” is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like. [0048] The term “haloalkyl-OH” refers to a haloalkyl group as described above which is also substituted by one or more hydroxyl groups. The term “haloalkyl-OH” is meant to include haloalkyl substituted by one hydroxyl group, as well as haloalkyl substituted by multiple hydroxyl groups. The term “haloalkyl-OH” also encompasses haloalkyl groups substituted by one or more hydroxyl groups on any carbon of the haloalkyl group. For example, the term “haloalkyl-OH” includes -CH(F)OH, -CH ² CFHCH ² OH, -CH(OH)CF ³ , and the like. [0049] The term “alkyl-OH” or “alkylene-OH” refers to an alkyl or alkylene substituted by one or more hydroxyl groups. The term “alkyl-OH” is meant to include alkyl substituted by one hydroxyl group, as well as alkyl substituted by multiple hydroxyl groups. The term “alkylene-OH” is meant to include alkylene substituted by one hydroxyl group, as well as alkylene substituted by multiple hydroxyl groups. The terms “alkyl-OH” and “alkylene-OH” also encompass alkyl groups and alkylene groups, respectively, that are substituted by one or more hydroxyl groups on any carbon of the alkyl or alkylene group, as valency permits. For example, the term “alkyl-OH” includes -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, and the like. [0050] The term “alkyl-OR ⁶ ” refers to an alkyl substituted by one or more –OR ⁶ groups. The term “alkyl-OR ⁶ ” is meant to include alkyl substituted by one -OR ⁶ group, as well as alkyl substituted by multiple -OR ⁶ groups. The term “alkyl-OR ⁶ ” also encompasses alkyl groups substituted by one or more OR ⁶ groups on any carbon of the alkyl, as valency permits. [0051] The term “alkyl-CN” refers to an alkyl substituted by one or more cyano groups. The term “alkyl-CN” is meant to include alkyl substituted by one cyano group, as well as alkyl substituted by multiple cyano groups. The term “alkyl-CN” also encompasses alkyl groups substituted by one or more cyano groups on any carbon of the alkyl group. For example, the term “alkyl-CN” includes -CH ₂ CN, -CH ₂ CH ₂ CN, -CH(CN)CH ₃ , and the like. [0052] The term “aryl” means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group, which can be a single ring or multiple rings (up to three rings) which are fused together. In some embodiments, “aryl” encompasses C6-C14 aryl, C8-C14 aryl, C10-C14 aryl, C12-C14 aryl, C6-C12 aryl, C8-C12 aryl, C10-C12 aryl, C6-C10 aryl, C8-C10 aryl, or C6-C8 aryl. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non- limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. In some embodiments, the term “heteroaryl” encompasses 5- to 10-membered heteroaryl, 6- to 10-membered heteroaryl, 7- to 10-membered heteroaryl, 8- to 10-membered heteroaryl, 9- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 6- to 9-membered heteroaryl, 7- to 9- membered heteroaryl, 8- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 6- to 8- membered heteroaryl, 7- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, 6- to 7- membered heteroaryl, or 5- to 6-membered heteroaryl. [0053] The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. [0054] As used herein, the term “heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). [0055] As used herein, the term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. [0056] As used herein, the term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. [0057] As used herein, a wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule. [0058] As used herein, the representation of a group (e.g., X ^a ) in parenthesis followed by a subscript integer range (e.g., (X ^a )0-1) means that the group can have the number of occurrences as designated by the integer range. For example, (X ^a )0-1 means the group X ^a can be absent or can occur one time. [0059] “Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography. [0060] “Enantiomers” refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.

[0061] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the present disclosure can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present disclosure. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0062] As used herein, the term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0063] As used herein, the term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water. Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. [0064] The term “co-crystal” as used herein refers to a solid that is a crystalline single phase material composed of two or more different molecular or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. A co-crystal consists of two or more components that form a unique crystalline structure having unique properties. Co- crystals are typically characterized by a crystalline structure, which is generally held together by freely reversible, non-covalent interactions. As used herein, a co-crystal refers to a compound of the present disclosure and at least one other component in a defined stoichiometric ratio that form a crystalline structure. [0065] As used herein, the term “protecting group” refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4 ^th edition, Wiley-Interscience, New York, 2006. [0066] As used herein, the term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, 1^1ƍ- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. [0067] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure. [0068] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure. [0069] The compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present disclosure and include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as ² H (“D”), ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I. Certain isotopically labeled compounds of the present disclosure (e.g., those labeled with ³ H or ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated ( ³ H) and carbon-14 ( ¹⁴ C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [0070] “Treating” or “treatment” of a disease in a patient refers to inhibiting the disease or arresting its development; or ameliorating or causing regression of the disease. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the present disclosure contemplate any one or more of these aspects of treatment. [0071] “Preventing”, “prevention”, or “prophylaxis” of a disease in a patient refers to preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease. [0072] The phrase “therapeutically effective amount” means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. [0073] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. [0074] It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. II. Compounds [0075] In one aspect, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: R ⁰ is C ₁ -C ₃ alkyl or cyclopropyl, wherein the C ₁ -C ₃ alkyl or cyclopropyl are optionally substituted with 1 to 5 R ⁵ groups; R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , - (X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0- 1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )- C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aromatic portions of Ring A are optionally substituted with 1 to 5 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C2-C6 alkenyl- OH, -C(=N-OH)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ¹ -C ⁶ alkylene(-OH)-C ¹ -C ³ alkoxy, C ¹ -C ⁶ alkyl-CN, C ¹ -C ⁶ heteroalkyl, C ³ -C ⁷ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0076] In some embodiments, the compound of formula (I) is a compound of formula (I’), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: R ⁰ is C ₁ -C ₃ alkyl or cyclopropyl, wherein the C ₁ -C ₃ alkyl or cyclopropyl are optionally substituted with 1 to 5 R ⁵ groups; R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , - (X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0- 1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )- C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl- OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0077] In some embodiments, the compound of formula (I’) is a compound of formula (I’-1) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , - (X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0- 1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )- C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl- OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0078] In other embodiments, the compound of formula (I’) is a compound of formula (I’-2): or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R ⁰ is C ₁ -C ₃ alkyl optionally substituted by 1 to 5 R ⁵ groups, and wherein R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl- CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1- N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² - S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )-C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl- OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0079] In some embodiments, the compound of formula (I’) is a compound of formula

or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , - (X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0- 1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )- C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C2-C6 alkenyl- OH, -C(=N-OH)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0080] In other embodiments, the compound of formula (I’) is a compound of formula (I’’-2) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R ⁰ is C ₁ -C ₃ alkyl optionally substituted by 1 to 5 R ⁵ groups, and wherein R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl- CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1- N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² - S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )-C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ¹ -C ⁶ alkylene, C ¹ -C ⁶ heteroalkylene, C ³ -C ⁷ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C2-C6 alkenyl- OH, -C(=N-OH)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. [0081] In some embodiments, R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a ) 0-1-(C(R ² )R ² )0-1- OR ² , or -(X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-CN, or C ₁ -C ₆ heteroalkyl, wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is H or C ₁ -C ₆ alkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is -CH ₃ . [0082] In some embodiments, R ¹ is H. [0083] In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is unsubstituted C ₁ -C ₆ alkyl. In some embodiments, R ¹ is C ¹ -C ⁶ alkyl substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is C ¹ -C ³ alkyl optionally substituted with 1 to 3 R ³ groups. In some embodiments, R ¹ is methyl, ethyl, n- propyl, or isopropyl. In some embodiments, R ¹ is -CH ₃ or -CH ₂ CH ₃ .. In some embodiments, R ¹ is -CH ₃ . In some embodiments, R ¹ is -CH ₂ CH ₃ . [0084] In some embodiments, R ¹ is C ₁ -C ₆ haloalkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is C ₁ -C ₆ haloalkyl which is not substituted by any R ³ groups. In some embodiments, R ¹ is C ₁ -C ₆ haloalkyl substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is C ₁ -C ₆ haloalkyl containing 1-13 halogen atoms. In some embodiments, R ¹ is C ₁ -C ₃ haloalkyl. In some embodiments, R ¹ is C ₁ -C ₃ haloalkyl containing 1-7 halogen atoms. In some embodiments, R ¹ is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R ¹ is -CF ₃ , -CCl3, -CF2Cl, -CFCl2, -CHF ₂ , - CH ₂ F, -CHCl2, -CH ₂ F, or -CHFCl. In some embodiments, R ¹ is -CF ₃ . [0085] In some embodiments, R ¹ is C ₁ -C ₆ alkyl-CN. In some embodiments, R ¹ is C ₁ -C ₆ alkyl-CN containing 1-6 cyano groups. In some embodiments, R ¹ is C ₁ -C ₆ alkyl-CN containing 1 cyano group. In some embodiments, R ¹ is C ₁ -C ₆ alkyl-CN containing 2 cyano groups. In some embodiments, R ¹ is C ₁ -C ₆ alkyl-CN containing 3 cyano groups. In some embodiments, R ¹ is C ₁ -C ₃ alkyl-CN. In some embodiments, R ¹ is C ₁ -C ₃ alkyl-CN containing 1-3 cyano groups. In some embodiments, R ¹ is C ₁ -C ₃ alkyl-CN containing 1 cyano group. In some embodiments, R ¹ is -CH ₂ CN, -CH ₂ CH ₂ CN, -CH(CN)CH ₃ , -CH ₂ CH ₂ CH ₂ CN, - CH(CN)CH ₂ CH ₃ , or -CH ₂ CH(CN)CH ₃ . In some embodiments, R ¹ is -CH ₂ CN or - CH ₂ CH ₂ CN. In some embodiments, R ¹ is -CH ₂ CN. In some embodiments, R ¹ is - CH ₂ CH ₂ CN. [0086] In some embodiments, R ¹ is C ₁ -C ₆ heteroalkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is C ₁ -C ₆ heteroalkyl which is not substituted by any R ³ groups. In some embodiments, R ¹ is C ₁ -C ₆ heteroalkyl substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is C ₁ -C ₆ heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R ¹ is C ₁ -C ₆ heteroalkyl containing 1 nitrogen atom. In some embodiments, R ¹ is C ₁ -C ₆ heteroalkyl containing 1 oxygen atom. In some embodiments, R ¹ is C ₁ -C ₃ heteroalkyl optionally substituted with 1 to 3 R ³ groups. In some embodiments, R ¹ is -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , or -CH ₂ -NH- CH ₃ . [0087] In some embodiments, R ¹ is C ₃ -C ₇ cycloalkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is C ₃ -C ₇ cycloalkyl which is not substituted by any R ³ groups. In some embodiments, R ¹ is C3-C6 cycloalkyl substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is cyclopropyl. In some embodiments, R ¹ is -CH ₂ -cyclopropyl. [0088] In some embodiments, R ¹ is 4- to 7-membered heterocycloalkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is 4- to 7-membered heterocycloalkyl which is not substituted by any R ³ groups. In some embodiments, R ¹ is 4- to 7-membered heterocycloalkyl substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is 4- to 6-membered heterocycloalkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R ¹ is 4- to 7-membered heterocycloalkyl containing 1 nitrogen atom. In some embodiments, R ¹ is 4- to 7-membered heterocycloalkyl containing 1 oxygen atom. In some embodiments, R ¹ is pyrrolidinyl or piperidinyl. [0089] In some embodiments, R ¹ is -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1- N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1- S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² - S(O)R ² , -(X ^a )-C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is -(X ^a )0-1-(C(R ² )R ² )0-1-OR ² , -(X ^a ) 0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1- (C(R ² )R ² )0-1-OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )- (C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )- C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ¹ is -(X ^a ) 0-1- (C(R ² )R ² )0-1-OR ² or -(X ^a ) 0-1-(C(R ² )R ² )0-1-N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups. [0090] In some embodiments, X ^a is C ₁ -C ₆ alkylene optionally substituted with 1 to 5 R ³ groups. In some embodiments, X ^a is C ₁ -C ₆ alkylene which is not substituted with any R ³ groups. In some embodiments, X ^a is C ₁ -C ₆ alkylene substituted with 1 to 5 R ³ groups. In some embodiments, X ^a is C ₁ -C ₃ alkylene optionally substituted with 1 to 3 R ³ groups. In some embodiments, X ^a is -CH ₂ -, -CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ -. [0091] In some embodiments, X ^a is C ₁ -C ₆ heteroalkylene optionally substituted with 1 to 5 R ³ groups. In some embodiments, X ^a is C ₁ -C ₆ heteroalkylene which is not substituted with any R ³ groups. In some embodiments, X ^a is C ₁ -C ₆ heteroalkylene substituted with 1 to 5 R ³ groups. In some embodiments, X ^a is C ₁ -C ₆ heteroalkylene containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, X ^a is C ₁ -C ₆ heteroalkylene containing 1 nitrogen atom. In some embodiments, X ^a is C ₁ -C ₆ heteroalkylene containing 1 oxygen atom. In some embodiments, X ^a is C ₁ -C ₃ heteroalkylene optionally substituted with 1 to 3 R ³ groups. In some embodiments, X ^a is -CH ₂ -NH-CH ₂ -, -CH ₂ CH ₂ - NH-CH ₂ -, or -CH ₂ -NH-CH ₂ CH ₂ -. [0092] In some embodiments, X ^a is C ₃ -C ₇ cycloalkylene optionally substituted with 1 to 5 R ³ groups. In some embodiments, X ^a is C ₃ -C ₇ cycloalkylene which is not substituted with any R ³ groups. In some embodiments, X ^a is C ₃ -C ₇ cycloalkylene substituted with 1 to 5 R ³ groups. In some embodiments, X ^a is C3-C6 cycloalkylene optionally substituted with 1 to 3 R ³ groups. In some embodiments, X ^a is cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene. [0093] In some embodiments, X ^a is C ₃ -C ₇ heterocycloalkylene optionally substituted with 1 to 5 R ³ groups. In some embodiments, X ^a is C ₃ -C ₇ heterocycloalkylene which is not substituted with any R ³ groups. In some embodiments, X ^a is C ₃ -C ₇ heterocycloalkylene substituted with 1 to 5 R ³ groups. In some embodiments, X ^a is C3-C6 heterocycloalkylene optionally substituted with 1 to 3 R ³ groups. In some embodiments, X ^a is pyrrolidinylene or piperidinylene. [0094] In some embodiments, each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6- membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups. [0095] In some embodiments, R ² is H. [0096] In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ² is unsubstituted C ₁ -C ₆ alkyl. In some embodiments, R ² is C ₁ -C ₆ alkyl substituted with 1 to 5 R ³ groups. In some embodiments, R ² is C ₁ -C ₃ alkyl optionally substituted with 1 to 3 R ³ groups. In some embodiments, R ² is methyl, ethyl, n- propyl, or isopropyl. In some embodiments, R ² is -CH ₃ . [0097] In some embodiments, R ² is C ₁ -C ₆ haloalkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ² is C ₁ -C ₆ haloalkyl which is not substituted by any R ³ groups. In some embodiments, R ² is C ₁ -C ₆ haloalkyl substituted with 1 to 5 R ³ groups. In some embodiments, R ² is C ₁ -C ₆ haloalkyl containing 1-13 halogen atoms. In some embodiments, R ² is C ₁ -C ₃ haloalkyl. In some embodiments, R ² is C ₁ -C ₃ haloalkyl containing 1-7 halogen atoms. In some embodiments, R ² is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R ² is -CF ₃ , -CCl3, -CF2Cl, -CFCl2, -CHF ₂ , - CH ₂ F, -CHCl2, -CH ₂ F, or -CHFCl. In some embodiments, R ² is -CF ₃ . [0098] In some embodiments, R ² is C ₁ -C ₆ heteroalkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ² is C ₁ -C ₆ heteroalkyl which is not substituted by any R ³ groups. In some embodiments, R ² is C ₁ -C ₆ heteroalkyl substituted with 1 to 5 R ³ groups. In some embodiments, R ² is C ₁ -C ₆ heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R ² is C ₁ -C ₆ heteroalkyl containing 1 nitrogen atom. In some embodiments, R ² is C ₁ -C ₆ heteroalkyl containing 1 oxygen atom. In some embodiments, R ² is C ₁ -C ₃ heteroalkyl optionally substituted with 1 to 3 R ³ groups. In some embodiments, R ² is -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , or -CH ₂ -NH- CH ₃ . [0099] In some embodiments, R ² is C ₃ -C ₇ cycloalkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ² is C ₃ -C ₇ cycloalkyl which is not substituted by any R ³ groups. In some embodiments, R ² is C3-C6 cycloalkyl substituted with 1 to 5 R ³ groups. In some embodiments, R ² is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ² is cyclopropyl. [0100] In some embodiments, R ² is 4- to 7-membered heterocycloalkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ² is 4- to 7-membered heterocycloalkyl which is not substituted by any R ³ groups. In some embodiments, R ² is 4- to 7-membered heterocycloalkyl substituted with 1 to 5 R ³ groups. In some embodiments, R ² is 4- to 6-membered heterocycloalkyl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ² is 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R ² is 4- to 7-membered heterocycloalkyl containing 1 nitrogen atom. In some embodiments, R ² is 4- to 7-membered heterocycloalkyl containing 1 oxygen atom. In some embodiments, R ² is pyrrolidinyl or piperidinyl. [0101] In some embodiments, R ² is 5- to 6-membered heteroaryl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ² is unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R ² is 5- to 6-membered heteroaryl substituted with 1 to 5 R ³ groups. In some embodiments, R ² is 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, R ² is a 5-membered heteroaryl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ² is a 6-membered heteroaryl optionally substituted with 1 to 5 R ³ groups. In some embodiments, R ² is pyridyl, pyridazinyl, pyrimindinyl, or pyrazolyl. [0102] In some embodiments, two R ² groups attached to the same nitrogen are taken together to form a 4- to 7-membered heterocyclic ring optionally substituted with 1 to 5 R ³ groups. In some embodiments, two R ² groups attached to the same nitrogen are taken together to form a 5- to 6-membered heterocyclic ring optionally substituted with 1 to 5 R ³ groups. In some embodiments, two R ² groups attached to the same carbon atom are taken together to form a 3- to 6-membered carbocyclic ring optionally substituted with 1 to 5 R ³ groups. In some embodiments, two R ² groups attached to the same carbon atom are taken together to form a 3- to 5-membered carbocyclic ring optionally substituted with 1 to 5 R ³ groups. In some embodiments, two R ² groups attached to the same carbon atom are taken together to form a 4- to 6-membered heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and optionally substituted with 1 to 5 R ³ groups. In some embodiments, two R ² groups attached to the same carbon atom are taken together to form a 5- to 6-membered heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, and optionally substituted with 1 to 5 R ³ groups. [0103] In some embodiments, each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6-membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SMe, -S(O)Me, -S(O) ₂ Me, or -CN. [0104] In some embodiments, R ³ is C ₁ -C ₆ alkyl. In some embodiments, R ³ is C ₁ -C ₃ alkyl. In some embodiments, R ³ is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R ³ is -CH ₃ . [0105] In some embodiments, R ³ is C ₁ -C ₆ alkoxy. In some embodiments, R ³ is C ₁ -C ₃ alkoxy. In some embodiments, R ³ is -OCH ₃ , -CH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , or -OCH(CH ₃ ) ₂ . In some embodiments, R ³ is -OCH ₃ . [0106] In some embodiments, R ³ is C ₃ -C ₇ cycloalkyl. In some embodiments, R ³ is C3-C6 cycloalkyl. In some embodiments, R ³ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0107] In some embodiments, R ³ is C ₃ -C ₇ cycloalkoxy. In some embodiments, R ³ is C3- C6 cycloalkoxy. In some embodiments, R ³ is -O(cyclopropyl), -O(cyclobutyl), - O(cyclopentyl), or -O(cyclohexyl). [0108] In some embodiments, R ³ is C ₁ -C ₆ haloalkyl. In some embodiments, R ³ is C ₁ -C ₆ haloalkyl containing 1-13 halogen atoms. In some embodiments, R ³ is C ₁ -C ₃ haloalkyl. In some embodiments, R ³ is C ₁ -C ₃ haloalkyl containing 1-7 halogen atoms. In some embodiments, R ³ is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R ³ is -CF ₃ , -CCl3, -CF2Cl, -CFCl2, -CHF ₂ , -CH ₂ F, -CHCl2, -CH ₂ F, or -CHFCl. In some embodiments, R ³ is -CF ³ . [0109] In some embodiments, R ³ is C ₁ -C ₆ alkylamino. In some embodiments, R ³ is C ₁ -C ₃ alkylamino. In some embodiments, R ³ is C1-C2 alkylamino. In some embodiments, R ³ is -NH(CH ₃ ) or -NH(CH ₂ CH ₃ ). [0110] In some embodiments, R ³ is C ₁ -C ₆ dialkylamino. In some embodiments, R ³ is C1- C6 dialkylamino wherein the two C ₁ -C ₆ alkyl groups are the same. In some embodiments, R ³ is C ₁ -C ₆ dialkylamino wherein the two C ₁ -C ₆ alkyl groups are different. In some embodiments, R ³ is C ₁ -C ₃ dialkylamino. In some embodiments, R ³ is -N(CH ₃ ) ₂ , - N(CH ₂ CH ₃ ) ₂ , or -N(CH ₃ )(CH ₂ CH ₃ ). [0111] In some embodiments, R ³ is 4- to 7-membered heterocycloalkyl. In some embodiments, R ³ is 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R ³ is 4- to 7-membered heterocycloalkyl containing 1-2 nitrogen atoms. In some embodiments, R ³ is 4- to 7- membered heterocycloalkyl containing 1-2 oxygen atoms. In some embodiments, R ³ is 4- to 7-membered heterocycloalkyl containing 1 oxygen atom and 1 nitrogen atom. In some embodiments, R ³ is 4- to 6-membered heterocycloalkyl. In some embodiments, R ³ is pyrrolidinyl or piperidinyl. [0112] In some embodiments, R ³ is 4- to 7-membered heterocycloalkoxy. In some embodiments, R ³ is 4- to 7-membered heterocycloalkoxy containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R ³ is 4- to 7-membered heterocycloalkoxy containing 1-2 nitrogen atoms. In some embodiments, R ³ is 4- to 7- membered heterocycloalkoxy containing 1-2 oxygen atoms. In some embodiments, R ³ is 4- to 7-membered heterocycloalkoxy containing 1 oxygen atom and 1 nitrogen atom. In some embodiments, R ³ is 4- to 6-membered heterocycloalkoxy. In some embodiments, R ³ is -O(pyrrolidinyl) or -O(piperidinyl). [0113] In some embodiments, R ³ is 5- to 6-membered heteroaryl. In some embodiments, R ³ is 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, R ³ is 5- to 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of O and N. In some embodiments, R ³ is 5- to 6-membered heteroaryl containing 1-2 nitrogen atoms. In some embodiments, R ³ is 5- to 6-membered heteroaryl containing 1 nitrogen atom. In some embodiments, R ³ is 5- to 6-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, R ³ is 5- to 6-membered heteroaryl containing 1 oxygen atom. In some embodiments, R ³ is 5- to 6-membered heteroaryl containing 1 sulfur atom. In some embodiments, R ³ is a 5-membered heteroaryl. In some embodiments, R ³ is a 6-membered heteroaryl. In some embodiments, R ³ is pyridyl, pyridazinyl, pyrimindinyl, or pyrazolyl. [0114] In some embodiments, R ³ is F. In some embodiments, R ³ is Cl. In some embodiments, R ³ is -OH. In some embodiments, R ³ is -NH ₂ . In some embodiments, R ³ is -NHMe. In some embodiments, R ³ is -NMe2. In some embodiments, R ³ is -SMe. In some embodiments, R ³ is -S(O)Me. In some embodiments, R ³ is -S(O) ₂ Me. In some embodiments, R ³ is -S(O)(=NH)Me. In some embodiments, R ³ is -S(O)(=NMe)Me. In some embodiments, R ³ is -CN. In some embodiments, R ³ is -NO2. In some embodiments, R ³ is -CHF ₂ . In some embodiments, R ³ is -CF ₃ . In some embodiments, R ³ is -CF2Cl. In some embodiments, R ³ is -OCF ₃ . In some embodiments, R ³ is -OCHF ₂ . In some embodiments, R ³ is -SCF ₃ . In some embodiments, R ³ is -SCHF ₂ . In some embodiments, R ³ is -SF5. In some embodiments, R ³ is -P(O)(Me) ₂ . In some embodiments, R ³ is -N3. [0115] In some embodiments, ring A is C6-C10 aryl optionally substituted with 1 to 5 R ⁴ groups, wherein when Ring A is C6 aryl, then any two substituents attached to adjacent atoms of said aryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups. In some embodiments, ring A is C6 aryl optionally substituted with 1 to 5 R ⁴ groups. In some embodiments, Ring A is C6 aryl and two substituents attached to adjacent atoms of said aryl are taken together to form a 4- to 6- membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups. In some embodiments, the resulting 4- to 6-membered heterocyclic ring contains 1-2 heteroatoms selected from the group consisting of N and O. In some embodiments, the resulting 4- to 6-membered heterocyclic ring contains 1 nitrogen atom. In some embodiments, the resulting 4- to 6- membered heterocyclic ring contains 1 oxygen atom. In some embodiments, the resulting 4- to 6-membered heterocyclic ring contains 1 nitrogen atom and 1 oxygen atom. [0116] In some embodiments, Ring A is 5- to 10-membered heteroaryl optionally substituted with 1 to 5 R ⁴ groups, and wherein when Ring A is 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups. In some embodiments, ring A is 5- to 10-membered heteroaryl optionally substituted with 1 to 5 R ⁴ groups. In some embodiments, ring A is 5- to 6-membered heteroaryl wherein two substituents attached to adjacent atoms of said heteroaryl are taken together to form a 4- to 6- membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups. In some embodiments, the resulting 4- to 6-membered heterocyclic ring contains 1-2 heteroatoms selected from the group consisting of N and O. In some embodiments, the resulting 4- to 6-membered heterocyclic ring contains 1 nitrogen atom. In some embodiments, the resulting 4- to 6- membered heterocyclic ring contains 1 oxygen atom. In some embodiments, the resulting 4- to 6-membered heterocyclic ring contains 1 nitrogen atom and 1 oxygen atom. [0117] In some embodiments, Ring A is C6 aryl or 5- to 6-membered heteroaryl, each of which is optionally substituted with 1 to 5 R ⁴ groups. In some embodiments, Ring A is C6 aryl or 5- to 6-membered heteroaryl, each of which is substituted with 1 to 5 R ⁴ groups. In some embodiments, Ring A is unsubstituted C6 aryl or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, Ring A is unsubstituted phenyl or phenyl substituted with 1 to 5 R ⁴ groups. In some embodiments, Ring A is 5-membered heteroaryl optionally substituted with 1 to 4 R ⁴ groups. In some embodiments, Ring A is unsubstituted 5- membered heteroaryl. In some embodiments, Ring A is 6-membered heteroaryl optionally substituted with 1 to 4 R ⁴ groups. In some embodiments, Ring A is unsubstituted 6- membered heteroaryl. In some embodiments, Ring A is 6-membered heteroaryl substituted with 1 to 4 R ⁴ groups. In some embodiments, Ring A is 6-membered heteroaryl substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and optionally further substituted with 1 to 4 R ⁴ groups. In some embodiments, Ring A is pyridyl or pyrimidyl, wherein the pyridyl or pyrimidyl is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 4 R ⁴ groups. In some embodiments, Ring A is pyridyl optionally substituted with 1 to 4 R ⁴ groups. In some embodiments, Ring . some embodiments, Ring A is pyrimidyl 4 (R )0-4 N 4 N optionally substituted with 1 to 4 R groups. In some embodiments, Ring A is N N N . In other embodiments, Ring A is or , wherein Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 4 R ⁴ groups, each R ⁴ is independently F, C ₁ -C ₆ alkyl, -OR ⁶ , -CN, -CH ₂ CN, -CH ₂ CH ₂ CN, C ₁ -C ₆ alkyl-OH, or C ₁ -C ₆ haloalkyl-OH; and each R ⁶ is independently H or C ₁ -C ₆ alkyl. In some embodiments, Ring A is substituted by -C(=N-OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 4 R ⁴ groups. [0118] In some embodiments, Ring A is selected from the group consisting of:

some embodiments, Ring A is selected from the group consisting of: from the group consisting of:

some embodiments, Ring A is selected from the group consisting of: some embodiments, Ring A is selected from the group consisting of: . [0119] In some embodiments, Ring A is selected from the group consisting of: embodiments, Ring A is [0120] In some embodiments, each R ⁴ is independently H, F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , - SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C2-C6 alkenyl-OH, -C(=N-OH)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl. In some embodiments, each R ⁴ is independently H, F, Cl, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -OCHF ₂ , -CF ₃ , -CHF ₂ , -CN, C ₁ -C ₆ alkyl, C1- C6 haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ alkyl-OH, C2-C6 alkenyl-OH, - C(=N-OH)C ¹ -C ⁶ alkyl, C ¹ -C ⁶ heteroalkyl, or C ³ -C ⁷ cycloalkyl. In some embodiments, each R ⁴ is independently F, C ₁ -C ₆ alkyl, -OR ⁶ , -CN, -CH ₂ CN, -CH ₂ CH ₂ CN, C ₁ -C ₆ alkyl-OH, C2- C6 alkenyl-OH, -C(=N-OH)C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl-OH, and each R ⁶ is independently H or C ₁ -C ₆ alkyl. In some embodiments, each R ⁴ is independently C2-C6 alkenyl-OH or - C(=N-OH)C ₁ -C ₆ alkyl. In some embodiments, Ring A is substituted by C2-C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ as defined herein. [0121] In some embodiments, each R ⁴ is independently F, -CH ₃ , -OCH ₃ , -OH, -CN, - CH ₂ OH, -CH(OH)CH ₃ , -CH(OH)CH ₂ CH ₃ , -CH(OH)CF2CH ₃ , -CH(OH)CH ₂ CH ₂ CH ₃ , - CD(OH)CH ₂ CH ₂ CH ₃ , -C(=O)CH ₂ CH ₃ , -C(=O)CH ₂ CH ₂ CH ₃ , -CH(OH)CH ₂ OCH ₃ , - C(CH ₃ ) ₂ OH, -C(=N-OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , - CH(OH)CH ₂ CH=CH ₂ , -CD(OH)CH=CHCH ₃ , or -CH(OH)CF ₃ . In some embodiments, each R ⁴ is independently F, -CH ₃ , -OCH ₃ , -OH, -CN, -CH ₂ OH, -CH(OH)CH ₃ , -CH(OH)CH ₂ CH ₃ , - C(CH ₃ ) ₂ OH, -C(=N-OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , - CH(OH)CH ₂ CH=CH ₂ , -CD(OH)CH=CHCH ₃ , or -CH(OH)CF ₃ . In some embodiments, each R ⁴ is independently -C(=N-OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , - CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ [0122] In some embodiments, R ⁴ is H. In some embodiments, R ⁴ is F. In some embodiments, R ⁴ is Cl. In some embodiments, R ⁴ is Br. In some embodiments, R ⁴ is I. In some embodiments, R ⁴ is -SCF ₃ . In some embodiments, R ⁴ is -SCHF ₂ . In some embodiments, R ⁴ is -SF5. In some embodiments, R ⁴ is -OCF ₃ . In some embodiments, R ⁴ is - N3. In some embodiments, R ⁴ is -OCHF ₂ . In some embodiments, R ⁴ is -CF ₃ . In some embodiments, R ⁴ is -CHF ₂ . In some embodiments, R ⁴ is -CN. In some embodiments, R ⁴ is - NO2. [0123] In some embodiments, R ⁴ is C ₁ -C ₆ alkyl. In some embodiments, R ⁴ is C ₁ -C ₃ alkyl. In some embodiments, R ⁴ is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R ⁴ is methyl. [0124] In some embodiments, R ⁴ is C ₁ -C ₆ haloalkyl. In some embodiments, R ⁴ is C ₁ -C ₆ haloalkyl containing 1-13 halogen atoms. In some embodiments, R ⁴ is C ₁ -C ₃ haloalkyl. In some embodiments, R ⁴ is C ₁ -C ₃ haloalkyl containing 1-7 halogen atoms. In some embodiments, R ⁴ is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R ⁴ is -CF ₃ , -CCl3, -CF2Cl, -CFCl2, -CHF ₂ , -CH ₂ F, -CHCl2, -CH ₂ F, or -CHFCl. In some embodiments, R ⁴ is -CF ₃ . [0125] In some embodiments, R ⁴ is C ₁ -C ₆ haloalkyl-OH. In some embodiments, R ⁴ is C1- C6 haloalkyl-OH containing 1-12 halogen atoms and one hydroxyl group. In some embodiments, R ⁴ is C ₁ -C ₆ haloalkyl-OH containing 1-12 halogen atoms and one hydroxyl group. In some embodiments, R ⁴ is C ₁ -C ₆ haloalkyl-OH containing 1-11 halogen atoms and two hydroxyl groups. In some embodiments, R ⁴ is C ₁ -C ₆ haloalkyl-OH containing 1-10 halogen atoms and three hydroxyl groups. In some embodiments, R ⁴ is C ₁ -C ₆ haloalkyl-OH containing 1-9 halogen atoms and 4 hydroxyl groups. In some embodiments, R ⁴ is C ₁ -C ₃ haloalkyl-OH. In some embodiments, R ⁴ is C ₁ -C ₃ haloalkyl-OH containing 1-6 halogen atoms and one hydroxyl group. In some embodiments, R ⁴ is C ₁ -C ₃ haloalkyl-OH containing 1-5 halogen atoms and two hydroxyl groups. In some embodiments, R ⁴ is C ₁ -C ₃ haloalkyl- OH containing 1-4 halogen atoms and three hydroxyl groups. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R ⁴ is -CH(OH)CF ₃ , -CHF(OH)CH ₃ , -CF2(OH)CH ₃ , or -CF2(OH)CF ₃ . In some embodiments, R ⁴ is -CH(OH)CF ₃ . [0126] In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-OH. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-OH containing 1-6 hydroxyl groups. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-OH containing 1 hydroxyl group. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-OH containing 2 hydroxyl groups. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-OH containing 3 hydroxyl groups. In some embodiments, R ⁴ is C ₁ -C ₃ alkyl-OH. In some embodiments, R ⁴ is C ₁ -C ₃ alkyl-OH containing 1-3 hydroxyl groups. In some embodiments, R ⁴ is C ₁ -C ₃ alkyl-OH containing 1 hydroxyl group. In some embodiments, R ⁴ is -CH ₂ OH, -CH ₂ CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CH ₂ CH ₂ OH, -CH(OH)CH ₂ CH ₃ , -CH(OH)CH ₂ CH ₂ CH ₃ , -CH ₂ CH(OH)CH ₃ , or - C(CH ₃ ) ₂ OH. In some embodiments, R ⁴ is -CH ₂ OH, -CH(OH)CH ₃ , -CH(OH)CH ₂ CH ₃ , or - C(CH ₃ ) ₂ OH. [0127] In some embodiments R ⁴ is C ₁ -C ₆ alkenyl-OH. In some embodiments, R ⁴ is -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ .In some embodiments, R ⁴ is -CD(OH)CH ₂ CH=CH ₂ . In some embodiments, R ⁴ is -CH(OH)CH ₂ CH=CH ₂ . In some embodiments, R ⁴ is -CD(OH)CH=CHCH ₃ . [0128] In some embodiments, R ⁴ is -C(=N-OH)C ₁ -C ₆ alkyl. In some embodiments, R ⁴ is -C(=N-OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , In some embodiments, R ⁴ is -C(=N- OH)CH ₂ CH ₃ . In some embodiments, R ⁴ is -C(=N-OH)CH ₂ CH ₂ CH ₃ . [0129] In some embodiments of Formula (I), at least one R ⁴ is C ₁ -C ₆ alkenyl-OH or - C(=N-OH)C ¹ -C ⁶ alkyl. In soe embodiments, at least one R ⁴ is C ¹ -C ⁶ alkenyl-OH or -C(=N- OH)C ₁ -C ₆ alkyl. [0130] In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-OR ⁶ . In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-OR ⁶ containing 1-6 -OR ⁶ groups. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-OR ⁶ containing 1 -OR ⁶ group. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-OR ⁶ containing 2 -OR ⁶ groups. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-OR ⁶ containing 3 -OR ⁶ groups. In some embodiments, R ⁴ is C ₁ -C ₃ alkyl-OR ⁶ . In some embodiments, R ⁴ is C ₁ -C ₃ alkyl-OR ⁶ containing 1-3 -OR ⁶ groups. In some embodiments, R ⁴ is C ₁ -C ₃ alkyl-OR ⁶ containing 1 -OR ⁶ group. In some embodiments, R ⁴ is -CH ₂ -OR ⁶ , -CH ₂ CH ₂ -OR ⁶ , -CH(-OR ⁶ )CH ₃ , - CH ₂ CH ₂ CH ₂ -OR ⁶ , -CH(-OR ⁶ )CH ₂ CH ₃ , -CH ₂ CH(-OR ⁶ )CH ₃ , or -C(CH ₃ ) ₂ -OR ⁶ . In some embodiments, R ⁴ is -CH ₂ -OR ⁶ , -CH(-OR ⁶ )CH ₃ , -CH(-OR ⁶ )CH ₂ CH ₃ , or -C(CH ₃ ) ₂ -OR ⁶ . [0131] In some embodiments, R ⁴ is C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy. In some embodiments, R ⁴ is C ₁ -C ₃ alkylene-C ₁ -C ₃ alkoxy. In some embodiments, R ⁴ is –CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , –CH ₂ OCH ₂ CH ₃ , or -CH ₂ CH ₂ OCH ₂ CH ₃ . [0132] In some embodiments, R ⁴ is C ₁ -C ₆ alkylene(OH)-C ₁ -C ₃ alkoxy. In some embodiments, R ⁴ is C ₁ -C ₃ alkylene(OH)-C ₁ -C ₃ alkoxy. In some embodiments, R ⁴ is – CH(OH)CH ₂ OCH ₃ , -CH ₂ CH(OH)OCH ₃ , –CH(OH)CH ₂ OCH ₂ CH ₃ , or - CH ₂ CH(OH)OCH ₂ CH ₃ . [0133] In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-CN. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-CN containing 1-6 cyano groups. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-CN containing 1 cyano group. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-CN containing 2 cyano groups. In some embodiments, R ⁴ is C ₁ -C ₆ alkyl-CN containing 3 cyano groups. In some embodiments, R ⁴ is C ₁ -C ₃ alkyl-CN. In some embodiments, R ⁴ is C ₁ -C ₃ alkyl-CN containing 1-3 cyano groups. In some embodiments, R ⁴ is C ₁ -C ₃ alkyl-CN containing 1 cyano group. In some embodiments, R ⁴ is -CH ₂ CN, -CH ₂ CH ₂ CN, -CH(CN)CH ₃ , -CH ₂ CH ₂ CH ₂ CN, - CH(CN)CH ₂ CH ₃ , or -CH ₂ CH(CN)CH ₃ . In some embodiments, R ⁴ is -CH ₂ CN or - CH ₂ CH ₂ CN. In some embodiments, R ⁴ is -CH ₂ CN. In some embodiments, R ⁴ is - CH ₂ CH ₂ CN. [0134] In some embodiments, R ⁴ is C ₁ -C ₆ heteroalkyl. In some embodiments, R ⁴ is C ₁ -C ₆ heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R ⁴ is C ₁ -C ₆ heteroalkyl containing 1 nitrogen atom. In some embodiments, R ⁴ is C ¹ -C ⁶ heteroalkyl containing 1 oxygen atom. In some embodiments, R ⁴ is C ₁ -C ₃ heteroalkyl. In some embodiments, R ⁴ is -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ - NH-CH ₃ , or -CH ₂ -NH-CH ₃ . [0135] In some embodiments, R ⁴ is C ₃ -C ₇ cycloalkyl. In some embodiments, R ⁴ is C3-C6 cycloalkyl. In some embodiments, R ⁴ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0136] In some embodiments, R ⁴ is C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl. In some embodiments, R ⁴ is C ₁ -C ₃ alkylene-C3-C6 cycloalkyl. In some embodiments, R ⁴ is –CH ₂ - cyclopropyl, –CH ₂ CH ₂ -cyclopropyl, –CH ₂ -cyclobutyl, –CH ₂ CH ₂ -cyclobutyl, –CH ₂ - cyclopentyl, –CH ₂ CH ₂ -cyclopentyl, –CH ₂ -cyclohexyl, or –CH ₂ CH ₂ -cyclohexyl. [0137] In some embodiments, R ⁴ is C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl. In some embodiments, R ⁴ is C ₁ -C ₃ alkylene(-OH)-C3-C6 cycloalkyl. In some embodiments, R ⁴ is – CH(OH)-cyclopropyl, –CH(OH)CH ₂ -cyclopropyl, – CH(OH)-cyclobutyl, –CH ₂ CH ₂ - cyclobutyl, – CH(OH)-cyclopentyl, – CH(OH)CH ₂ -cyclopentyl, – CH(OH)-cyclohexyl, or – CH(OH)CH ₂ -cyclohexyl. [0138] In some embodiments, R ⁴ is -OR ⁶ . In some embodiments, R ⁴ is -OR ⁶ , and R ⁶ is H or C ₁ -C ₆ alkyl. In some embodiments, R ⁴ is -OR ⁶ , and R ⁶ is H or C ₁ -C ₃ alkyl. In some embodiments, R ⁴ is -OR ⁶ , and R ⁶ is H or methyl. In some embodiments, R ⁴ is -OH. In some embodiments, R ⁴ is -O(C ₁ -C ₆ alkyl). In some embodiments, R ⁴ is -OCH ₃ . [0139] In some embodiments, R ⁴ is -N(R ⁶ )R ⁶ . In some embodiments where R ⁴ is - N(R ⁶ )R ⁶ , each R ⁶ is the same. In other embodiments where R ⁴ is -N(R ⁶ )R ⁶ , each R ⁶ is different. [0140] In any of the embodiments described herein, R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. In some embodiments, R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl. [0141] In some embodiments, R ⁶ is H. [0142] In some embodiments, R ⁶ is C ₁ -C ₆ alkyl. In some embodiments, R ⁶ is C ₁ -C ₃ alkyl. In some embodiments, R ⁶ is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R ⁶ is methyl. [0143] In some embodiments, R ⁶ is C ₁ -C ₆ haloalkyl. In some embodiments, R ⁶ is C ₁ -C ₆ ^{haloalkyl containing 1-13 halogen atoms. In some embodiments, R6 is C1-C3 haloalkyl. In} some embodiments, R ⁶ is C ₁ -C ₃ haloalkyl containing 1-7 halogen atoms. In some embodiments, R ⁶ is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R ⁶ is -CF ₃ , -CCl3, -CF2Cl, -CFCl2, -CHF ₂ , -CH ₂ F, -CHCl2, -CH ₂ F, or -CHFCl. In some embodiments, R ⁶ is -CF ₃ . [0144] In some embodiments, R ⁶ is C ₁ -C ₆ heteroalkyl. In some embodiments, R ⁶ is C ₁ -C ₆ heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R ⁶ is C ₁ -C ₆ heteroalkyl containing 1 nitrogen atom. In some embodiments, R ⁶ is C ₁ -C ₆ heteroalkyl containing 1 oxygen atom. In some embodiments, R ⁶ is C ₁ -C ₃ heteroalkyl. In some embodiments, R ⁶ is -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ - NH-CH ₃ , or -CH ₂ -NH-CH ₃ . [0145] In some embodiments, R ⁶ is C ₃ -C ₇ cycloalkyl. In some embodiments, R ⁶ is C3-C6 cycloalkyl. In some embodiments, R ⁶ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0146] In some embodiments, R ⁶ is C6 aryl. In some embodiments, R ⁶ is phenyl. [0147] In some embodiments, R ⁶ is 5- to 10-membered heteroaryl. In some embodiments, R ⁶ is 5- to 10-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, R ⁶ is 5- to 10-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of O and N. In some embodiments, R ⁶ is 5- to 10-membered heteroaryl containing 1 nitrogen atom. In some embodiments, R ⁶ is 5- to 10-membered heteroaryl containing 1 oxygen atom. In some embodiments, R ⁶ is 5- to 10-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, R ⁶ is 5- to 10-membered heteroaryl containing 1nitrogen atom and 1 oxygen atom. In some embodiments, R ⁶ is 8- to 10-membered heteroaryl. In some embodiments, R ⁶ is 8-membered heteroaryl. In some embodiments, R ⁶ is 10-membered heteroaryl. In some embodiments, R ⁶ is 5- to 6-membered heteroaryl. In some embodiments, R ⁶ is 5-membered heteroaryl. In some embodiments, R ⁶ is 6-membered heteroaryl. In some embodiments, R ⁶ is pyridyl, pyridazinyl, pyrimindinyl, or pyrazolyl. [0148] In some embodiments, R ⁶ is 4- to 7-membered heterocycloalkyl. In some embodiments, R ⁶ is 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R ⁶ is 4- to 7-membered heterocycloalkyl containing 1-2 nitrogen atoms. In some embodiments, R ⁶ is 4- to 7- membered heterocycloalkyl containing 1-2 oxygen atoms. In some embodiments, R ⁶ is 4- to 7-membered heterocycloalkyl containing 1 oxygen atom and 1 nitrogen atom. In some embodiments, R ⁶ is 4- to 7-membered heterocycloalkyl containing 1 nitrogen atom. In some embodiments, R ⁶ is 4- to 7-membered heterocycloalkyl containing 1 oxygen atom. In some embodiments, R ⁶ is 4- to 7-membered heterocycloalkyl containing 2 nitrogen atoms. In some embodiments, R ⁶ is 4- to 6-membered heterocycloalkyl. In some embodiments, R ⁶ is 5- to 6- membered heterocycloalkyl. In some embodiments, R ⁶ is pyrrolidinyl or piperidinyl. [0149] In some embodiments, each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, - OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl, -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl. In some embodiments, each R ⁵ is independently F, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -OCHF ₂ , -CF ₃ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ heteroalkyl. In some embodiments, each R ⁵ is F. [0150] In some embodiments, R ⁵ is F. In some embodiments, R ⁵ is Cl. In some embodiments, R ⁵ is -SCF ₃ . In some embodiments, R ⁵ is -SCHF ₂ . In some embodiments, R ⁵ is -SF5. In some embodiments, R ⁵ is -OCF ₃ . In some embodiments, R ⁵ is -N3. In some embodiments, R ⁵ is -OCHF ₂ . In some embodiments, R ⁵ is -CF ₃ . In some embodiments, R ⁵ is -CF2Cl. In some embodiments, R ⁵ is -CHF ₂ . In some embodiments, R ⁵ is -CN. In some embodiments, R ⁵ is -NO2. [0151] In some embodiments, R ⁵ is -OR ⁶ . In some embodiments, R ⁵ is -OR ⁶ , and R ⁶ is H or C ₁ -C ₆ alkyl. In some embodiments, R ⁵ is -OR ⁶ , and R ⁶ is H or C ₁ -C ₃ alkyl. In some embodiments, R ⁵ is -OR ⁶ , and R ⁶ is H or methyl. In some embodiments, R ⁵ is -OH. In some embodiments, R ⁵ is -O(C ₁ -C ₆ alkyl). In some embodiments, R ⁵ is -OCH ₃ . [0152] In some embodiments, R ⁵ is -N(R ⁶ )R ⁶ . In some embodiments where R ⁵ is - N(R ⁶ )R ⁶ , each R ⁶ is the same. In other embodiments where R ⁵ is -N(R ⁶ )R ⁶ , each R ⁶ is different. [0153] In some embodiments, R ⁵ is C ₁ -C ₆ alkyl. In some embodiments, R ⁵ is C ₁ -C ₃ alkyl. In some embodiments, R ⁵ is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R ⁵ is methyl. [0154] In some embodiments, R ⁵ is C ₁ -C ₆ haloalkyl. In some embodiments, R ⁵ is C ₁ -C ₆ haloalkyl containing 1-13 halogen atoms. In some embodiments, R ⁵ is C ₁ -C ₃ haloalkyl. In some embodiments, R ⁵ is C ₁ -C ₃ haloalkyl containing 1-7 halogen atoms. In some embodiments, R ⁵ is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R ⁵ is -CF ₃ , -CCl3, -CF2Cl, -CFCl2, -CHF ₂ , -CH ₂ F, -CHCl2, -CH ₂ F, or -CHFCl. In some embodiments, R ⁵ is -CF ₃ . [0155] In some embodiments, R ⁵ is C ₁ -C ₆ heteroalkyl. In some embodiments, R ⁵ is C ₁ -C ₆ heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R ⁵ is C ₁ -C ₆ heteroalkyl containing 1 nitrogen atom. In some embodiments, R ⁵ is C ₁ -C ₆ heteroalkyl containing 1 oxygen atom. In some embodiments, R ⁵ is C ₁ -C ₃ heteroalkyl. In some embodiments, R ⁵ is -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -OH, -CH ₂ -O- CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ ) ₂ , -CH ₂ -N(CH ₃ ) ₂ , or -CH ₂ -NH-CH ₃ . [0156] In some embodiments, R ⁵ is C ₃ -C ₇ cycloalkyl. In some embodiments, R ⁵ is C3-C6 cycloalkyl. In some embodiments, R ⁵ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0157] In some embodiments, the moiety of formula (I) is other variations, 1-5 R ⁵ groups are present. In some embodiments, 1 or 2 R ⁵ groups are present. [0158] In some embodiments, the compound of formula (I) is of formula (IA), (IB), (IC), (ID), (IE), (IF), or (IG):

, wherein Ring A and R ¹ are as defined for formula (I). In some embodiments, the compound is of formula (IA). In some embodiments, the compound is of formula (IB). In some embodiments, the compound is of formula (IC). In some embodiments, the compound is of formula (ID). In some embodiments, the compound is of formula (IE). In some embodiments, the compound is of formula (IF). In some embodiments, the compound is of formula (IG). In any variation of formula (IA), (IB), (IC), (ID), (IE), (IF), or (IG), R ¹ is H, C ₁ -C ₆ alkyl, or C1- C6 alkyl-CN; and Ring A is 5- to 10-membered heteroaryl optionally substituted with 1 to 5 R ⁴ groups. In some embodiments, R ¹ is H, methyl, ethyl, or -CH ₂ -cyclopropyl. In some embodiments, R ¹ is methyl. In some embodiments, Ring A is 6-membered heteroaryl optionally substituted with 1 to 4 R ⁴ groups. In some embodiments, Ring A is pyridyl optionally substituted with 1 to 4 R ⁴ groups. In some embodiments, Ring A is pyrimidyl optionally substituted with 1 to 4 R ⁴ groups. In some embodiments, each R ⁴ is independently F, C ₁ -C ₆ alkyl, -OR ⁶ , -CN, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkenyl-OH, -C(=N-OH)C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl-OH; and each R ⁶ is independently H or C ₁ -C ₆ alkyl. In some embodiments, each R ⁴ is independently C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl; and each R ⁶ is independently H or C ₁ -C ₆ alkyl. In some embodiments, each R ⁴ is independently F, -CH ₃ , - OCH ₃ , -OH, -CN, -CH ₂ OH, -CH(OH)CH ₃ , -CH(OH)CH ₂ CH ₃ , -C(CH ₃ ) ₂ OH, -CH ₂ CN, - CH ₂ CH ₂ CN, -C(=N-OH)CH ₂ CH ₃ , -C(=N- OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , -CD(OH)CH=CHCH ₃ , or -CH(OH)CF ₃ . In some embodiments, each R ⁴ is independently -C(=N-OH)CH ₂ CH ₃ , -C(=N- OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . [0159] In some embodiments, the compound of formula (I) is of formula (IA), (IB), (IC), (ID), (IE), (IF), or (IG): , , , wherein Ring A and R ¹ are as defined for formula (I)., and wherein Ring A is ssubstitued C1- C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and optionally further substituted with 1 to 4 R ⁴ groups. [0160] In some embodiments, the compound of formula (I) is of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), or (I-h) , , (I-g) , or (I-h) , wherein R ¹ and R ⁴ are as described for formula (I). In some embodiments, the compound is of formula (I-a). In some embodiments, the compound is of formula (I-b). In some embodiments, the compound is of formula (I-c). In some embodiments, the compound is of formula (I-d). In some embodiments, the compound is of formula (I-e). In some embodiments, the compound is of formula (I-f). In some embodiments, the compound is of formula (I-g). In some embodiments, the compound is of formula (I-h).In any variation of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), or (I-h), R ¹ is H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl- CN; each R ⁴ is independently F, -OR ⁶ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkenyl-OH, -C(=N-OH)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-CN, or C ₁ -C ₆ haloalkyl-OH; and each R ⁶ is independently H or C ¹ -C ⁶ alkyl. In some embodiments, R ¹ is H or –CH ³ ; and each R ⁴ is independently H, F, -CH(OH)CH ₃ , -CH(OH)CH ₂ CH ₃ , -CH(OH)CH ₂ CH ₂ CH ₃ , - CD(OH)CH ₂ CH ₂ CH ₃ , -C(CH ₃ ) ₂ OH, -C(=N-OH)CH ₂ CH ₃ , -C(=N- OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , -CD(OH)CH=CHCH ₃ , or -CH(OH)CF ₃ . In some embodiments, R ¹ is H or –CH ₃ ; and each R ⁴ is independently -C(=N- OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . In some embodiments, R ¹ is -CH ₃ ; and each R ⁴ is independently F, -CH ₃ , -OCH ₃ , -OH, -CN, -CH ₂ OH, -CH(OH)CH ₃ , -CH(OH)CH ₂ CH ₃ , -C(CH ₃ ) ₂ OH, -CH ₂ CN, -CH ₂ CH ₂ CN, -C(=N-OH)CH ₂ CH ₃ , -C(=N- OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , -CD(OH)CH=CHCH ₃ , or -CH(OH)CF ₃ . In some embodiments, R ¹ is -CH ₃ ; and each R ⁴ is independently -C(=N- OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . [0161] In some embodiments, provided herein is a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), or (I-h):

one R ⁴ is C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 2 R ⁴ groups. In some embodiments, R ¹ is H or –CH ₃ ; and at least one R ⁴ is -C(=N-OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , - CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . In some embodiments, R ¹ is -CH ₃ ; and at least one R ⁴ is -C(=N-OH)CH ₂ CH ₃ , -C(=N- OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . [0162] In some embodiments, provided is a compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Table 1.

[0163] Although certain compounds described in Table 1 are presented as specific stereoisomers and/or in a non-stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of Table 1 are herein described. In some embodiments, the compound described herein is selected from Compound No. 1-30. [0164] This disclosure also includes all salts, such as pharmaceutically acceptable salts, of compounds referred to herein. This disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms, such as N-oxides, solvates, hydrates, or isotopomers, of the compounds described. The present disclosure also includes co-crystals of the compounds described herein. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced. [0165] In the descriptions herein, it is understood that every description, variation, embodiment, or aspect of a moiety can be combined with every description, variation, embodiment, or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment, or aspect provided herein with respect to R ¹ of formula (I) may be combined with every description, variation, embodiment, or aspect of X ^a , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and/or Ring A, the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments, or aspects of formula (I), where applicable, apply equally to any of formulae (I), (I’), (I’-1), (I’-2), (I’’-1), (I’’-2), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (I-a), (I-a-1), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), and (I-h) detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. III. General Synthetic Methods [0166] The compounds of the present disclosure may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein. [0167] The intermediates described in the following preparations may contain a number of nitrogen, hydroxy, and acid protecting groups such as esters. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature. See e.g., Greene and Wuts, Protective Groups in Organic Synthesis, (T. Greene and P. Wuts, eds., 2d ed.1991). [0168] Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See e.g., J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). [0169] The compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be prepared by a variety of procedures known in the art, some of which are illustrated in the Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the present disclosure, or salts thereof. The products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry which are analogous to the syntheses of known structurally-similar compounds and the procedures described in the Examples which follow including any novel procedures. [0170] Compounds of formula (I) can be prepared according to Scheme A, Scheme B, Scheme C, or Scheme D, wherein the Ring A moiety, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X ^a are as defined for formulae (I), (I’), (I’-1), (I’-2), (I’’-1), (I’’-2), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (I-a), (I-a-1), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), and (I-h). or any applicable variation thereof as detailed herein. [0171] Compounds of formula (I) may be prepared according to the general synthetic scheme shown in Scheme A. In Scheme A, acylation of nicotinaldehydes of general formula A-a with Ring A-substituted esters of formula A-b yields the corresponding coupled amides which then undergo cyclization to yield naphthyridinones of general formula A-c. The naphthyridinones of general formula A-c can be reacted with optionally R ⁵ -substituted cyclopropylamides of general formula Intermediate D to give compounds of formula (I). Alternatively, naphthyridinones of general formula A-c may be aminated to compounds of general formula A-d, and subsequently reacted with optionally R ⁵ -substituted cyclopropyl carboxylic acids (X is OH) or cyclopropyl acid chlorides (X is Cl) of general formula A-e to yield compounds of formula (I). Scheme A. [0172] Compounds of formula (I) may also be prepared according to the general synthetic scheme shown in Scheme B. In Scheme B, intermediate B-a is coupled with compound B-b to afford compound B-c, which is subsequently converted to compound B-d. Compound B-d is then brominated with N-bromosuccinimide to afford compound B-e. Compound B-e can be deprotonated with sodium hydride to allow further substitution of the annular nitrogen (e.g., alkylation with an R ^1’ substrate having a suitable leaving group X, such as methyl iodide) to afford Intermediate B-f, wherein R ^1’ is equivalent to R ¹ except that R ^1’ does not include hydrogen. Either compound B-e or compound B-f is used as Intermediate B in subsequent reactions to be coupled with a suitable Ring A-substituted boronic acid derivative B-g, wherein R ^A and R ^B are independently selected from the group consisting of halogen, OH, and O-(C ₁ -C ₆ alkyl), or R ^A and R ^B are taken together with the boron atom to which they are attached to form a 5-10 membered heterocycle, to afford Intermediate C. Intermediate C can then be reacted with Intermediate D to give compounds of formula (I). [0173] Compounds of formula (I) may also be prepared according to the general synthetic scheme shown in Scheme C. In Scheme C, intermediate B can be coupled with a suitable Ring A’-substituted boronic acid derivative B-g’, wherein Ring A’ is a precursor to Ring A, and wherein R ^A and R ^B are independently selected from the group consisting of halogen, OH, and O-(C ₁ -C ₆ alkyl), or R ^A and R ^B are taken together with the boron atom to which they are attached to form a 5-10 membered heterocycle, to afford Intermediate C’. Intermediate C’ can be reduced or deprotected to yield Intermediate C, which can then be reacted with Intermediate D to give compounds of formula (I). [0174] Compounds of formula (I) may also be prepared according to the general synthetic scheme shown in Scheme D. In Scheme D, intermediate B can be coupled with a suitable Ring A’-substituted boronic acid derivative B-g’, wherein Ring A’ is a precursor to Ring A, and wherein R ^A and R ^B are independently selected from the group consisting of halogen, OH, and O-(C ₁ -C ₆ alkyl), or R ^A and R ^B are taken together with the boron atom to which they are attached to form a 5-10 membered heterocycle, to afford Intermediate C’. Intermediate C’ can be reacted with Intermediate D yield Intermediate E, which can then be reduced or deprotected to give compounds of formula (I). [0175] It should be recognized that the present disclosure also provides for any intermediates of the compounds and methods for synthesizing the compounds as described herein. In another aspect, provided herein are general intermediates as described in any one of Schemes A through D above, or compound-specific intermediates as described in the examples below. It should be further recognized that the present disclosure also provides for synthetic methods comprising any individual step or combination of individual process steps, or compositions of synthetic intermediates and/or reaction products as described herein. IV. Pharmaceutical Compositions and Formulations [0176] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition. [0177] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. [0178] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein is in substantially pure form. In one variation, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. For example, a composition of a substantially pure compound selected from a compound of Table 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound of Table 1. In one variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 5% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 3% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 1% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 0.5% impurity. In yet other variations, a composition of substantially pure compound means that the composition contains no more than 15%, no more than 10%, no more than 5%, no more than 3%, or no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, and without limitation, a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound. [0179] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein. In some embodiments, the compounds and compositions as provided herein are sterile. Methods for sterilization known in the art may be suitable for any compounds or form thereof and compositions thereof as detailed herein. [0180] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs. [0181] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, with a pharmaceutically acceptable carrier. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference. [0182] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. [0183] Any of the compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated as a 10 mg tablet. [0184] Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, provided herein are also described. In one variation, the composition comprises a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. I n another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein. [0185] Compositions formulated for co-administration of a compound provided herein and one or more additional pharmaceutical agents are also described. The co-administration can be simultaneous or sequential in any order. A compound provided herein may be formulated for co-administration with the one or more additional pharmaceutical agents in the same dosage form (e.g., single tablet or single i.v.) or separate dosage forms (e.g., two separate tablets, two separate i.v., or one tablet and one i.v.). Furthermore, co-administration can be, for example, 1) concurrent delivery, through the same route of delivery (e.g., tablet or i.v.), 2) sequential delivery on the same day, through the same route or different routes of delivery, or 3) delivery on different days, through the same route or different routes of delivery. V. Methods of Use [0186] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of formula (I) or any variation thereof provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays. [0187] In one aspect, provided herein are methods of a method of treating a cancer or neoplastic disease in a human in need thereof. In some embodiments, provided herein are methods of treating a disease or disorder mediated by a RAF kinase. RAF Kinase Inhibition [0188] In one aspect, provided herein is a method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. [0189] The compounds and compositions described herein may be used in a method of treating a disease or disorder mediated by ARAF, BRAF, or CRAF kinase activity. In some embodiments, the compound or composition is administered according to a dosage described herein. [0190] In some embodiments, provided herein is a method for treating a disease or disorder mediated by RAF kinase activity comprising administering to an individual in need of treatment an effective amount of a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. In some embodiments, the disease or disorder is a cancer or neoplastic disease. [0191] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. RAF Kinase Family [0192] In vertebrates, RAF is comprised of a family of three genetically distinct serine/threonine protein kinases designated ARAF, BRAF and CRAF (sometimes referred to as RAF-1). These family members are highly conserved at the primary sequence level (75% amino acid identity across their entire protein sequence and >87% identity within their respective kinase domains) and exhibit the same overall domain architecture. ARAF, BRAF and CRAF are ubiquitously and differentially expressed across all cell and tissue types. As such, they collectively serve as an essential signaling node of the Ras/Raf/MEK/ERK (MAPK) pathway. Importantly, a substantial proportion of all cancers are driven by genetic alterations in either the RTKs or a particular member of the MAPK pathway especially HRAS, KRAS, NRAS and the RAF isoforms. that then drive aberrant activation of the pathway. Therefore, as an essential node in the MAPK pathway, the RAF kinases represent an important therapeutic intervention point for the treatment of a variety of malignancies whose dysregulated growth and survival rely upon MAPK signaling. Accordingly, multiple RAF kinase inhibitors have been approved for specific indications including melanoma and NSCLC and numerous additional inhibitors are currently undergoing clinical investigation for a variety of other malignancies. RAF function [0193] Upon ligand binding, RTKs homo- or hetero oligomerize with other receptors and auto-phosphorylate key tyrosine residues in trans. These phosphorylated residues then serve as docking sites for downstream effectors, especially adapter proteins involved in the recruitment and activation of RAS (H-, K- and N-RAS) such as Grb2 and SOS, respectively. Activated GTP-bound RAS now binds and recruits RAF thereby inducing conformational changes in the latter to induce its dimerization and concomitant activation. RAF then binds and phosphorylates /activates MEK which then phosphorylates/activates ERK. Activated ERK then redistributes to the cytoplasm, the cytoskeleton and the nucleus to control cell growth/division, differentiation and survival. RAF Structure and Regulation [0194] Grossly, the primary structure of RAF can be divided into two domains; an N- terminal regulatory domain and a C-terminal kinase domain (KD) connected by a linker region. The regulatory domain contains multiple elements including a RAS-binding domain (RBD) followed immediately downstream by a Cysteine-Rich Domain (CRD). A key phosphorylation site resides within the linker region and another at the extreme C-terminus downstream of the KD. In its inactive conformation, RAF is located in the cytoplasm in a monomeric, dual-phosphorylated, autoinhibited state. This autoinhibition is mediated via two cooperative mechanisms: (1) direct interaction between the RBD and the KD and (2) 14-3-3 protein dimers that simultaneously interact with the two phosphorylated residues flanking the KD. The combination of these interactions effectively binds up the KD into the inactive conformation. Upon RAS engagement via interactions with both the RBD and CRD, the RBD-KD interaction is effectively disrupted exposing the phosphorylation site within the linker region to phosphatase action via the MRAS/SHOC2/PP1 complex. Subsequent dephosphorylation of this residue abrogates intramolecular 14-3-3 binding thereby fully relieving autoinhibition and exposing residues critical for interaction with the plasma membrane. RAS-bound hemi-phosphorylated RAF can now dimerize with another RAF protein (homo- or heterodimerization) via intermolecular interactions between their respective KDs as well as 14-3-3 cross-linking between the two adjacent phosphorylated residues at the C-terminus of each protomer. Importantly, this fully active RAF complex functions as an obligate dimer to both bind to and activate MEK, ultimately driving ERK activation to complete the signaling cascade. RAF Mutations and Cancer [0195] Given their critical involvement in the RTK/RAS/RAF/MEK/ERK pathway, it should be no surprise each of the RAF isoforms are bona fide proto-oncogenes. Accordingly, a variety of mutations have been identified in ARAF, BRAF and CRAF that have been functionally linked to tumor formation. Importantly, these mutations fall into distinct classes with discrete mechanisms of kinase activation. [0196] BRAF is the most commonly mutated RAF isoform with alterations reported in approximately 8% of all solid tumors. Melanomas harbor the greatest proportion of BRAF mutations with 40-50% prevalence followed by thyroid, colorectal (CRC) and non-small cell lung cancers (NSCLC). These mutations can be divided into three distinct functional classes based upon how they elicit aberrant activation of RAF kinase activity. Class I mutations render the kinase constitutively active and independent of the requirement for RAS binding or dimerization with another RAF isoform. These mutations are unique to BRAF and are associated with highly specific alterations within the 600 ^th codon leading to the conversion of a valine residue to an aspartate, glutamate, lysine or arginine (V600D/E/K/R). Class II mutations drive aberrant kinase activation by conferring constitutive RAS-independent RAF- dimerization without adversely impacting the intrinsic kinase activity of the mutant. These mutations can be further subdivided into 3 subclasses according to which region within the kinase domain the alteration occurs (designated as Class IIa and IIb) or the formation of a kinase fusion arising from a chromosome translocation event (designated Class IIc) whereby the negative regulatory RBD and CRD domains are removed by deletion and replaced with the fusion partner. The class II mutations include the following: G464V, G469A, G469V, G469R, E586K, K601E, K601N, L597R, L597S, L597Q) These mutations are most common in NSCLC and CRC. Finally, Class III mutants confer enhanced RAS-dependent RAF dimerization to drive pathway activation. These mutations substantially attenuate the intrinsic kinase activity of the mutant such that transactivation of the wildtype RAF dimerization partner is key to aberrant pathway activation. Accordingly, other genetic alterations leading to RAS activation are often found co-occurring with these Class III mutations to facilitate dimerization. The class III mutations include the following: G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R. [0197] Compared to BRAF, the prevalence of oncogenic mutations within CRAF are relatively rare and found sporadically across a wide array of cancers including melanoma, NSCLC, pancreatic carcinoma, glioma, colorectal and hematological malignancies. There are two distinct mutation types that have been reported for CRAF. The first mutation type consists of point mutations that reside within the linker region effectively disrupting 14-3-3 binding to the linker domain phosphorylation site and conferring a more open confirmation that is now accessible to phosphatase action and subsequent dimerization/activation. These mutations include P261L and P261A. The second CRAF mutation type is analogous to the Class II mutations in BRAF. Specifically, there are reports of point mutations found in regions of the kinase domain analogous to the Class IIa and IIb BRAF mutants in CRAF across multiple cancer types, especially melanomas. These mutations include E478K, R391W, R391S and T491I as well as certain mutations that are also found in a subset of RASopathies; a cluster of diverse genetic diseases whose underlying etiology appears to derive from chronic MAPK pathway activation. There are also multiple reports of Class IIc mutations in RAF (CRAF fusions), which, like the BRAF fusions, possess fusion partners that effectively replace the RBD and CRD domains to relieve autoinhibition and drive dimerization and activation. [0198] To date, only one oncogenic mutation at codon 214 in ARAF has been reported. This mutation results in either a cysteine or phenylalanine for serine substitution (S214C/F) and has been identified in multiple NSCLC patients with an approximate prevalence of 0.5%. Given that no additional oncogenic mutations were identified in these tumors, it is likely that the ARAF mutants are the oncogenic drivers in these cancers. Accordingly, in vitro characterization of cell lines engineered to express an S214F ARAF mutant revealed that the mutant induces MAPK pathway activation and markedly enhances colony formation (a hallmark activity of an oncogene) in a kinase-dependent manner. Given that S214 is the linker region phosphorylation site critical for 14-3-3 binding, it is likely conferring constitutive activation in a manner very similar to the CRAF point mutants described above. RAF Kinase Inhibitors [0199] Given the strong link between genetic alterations in components of the MAPK pathway and the development of cancer in a wide array of tumor types, this pathway represents a key opportunity for the development of targeted therapies to control these proliferative diseases. In particular, inhibitors directed against the RAF family should offer an important treatment option for patients harboring RAF kinase activating mutations found in a number of cancer types including those of the skin, thyroid and lung. Accordingly, over the last 2 decades, numerous small molecule RAF inhibitors have been discovered and several of these have advanced into the clinic and gone on to full regulatory approval. The vast majority of these compounds are ATP-competitive small molecule inhibitors and bind in the kinase active site. They are divided into three types, dependent upon the specific structural conformation they induce within the kinase upon binding. These inhibitor types are designated type 1 inhibitors, type 1.5 inhibitors and type 2 inhibitors. Type 1 Inhibitors [0200] Type 1 inhibitors bind in the active or ‘closed’ form of the kinase domain which is largely defined by the relative inward orientation of the C-helix and the ‘DFG’ loop which both comprise key structural and functional elements of the active site. This binding mode is designated C-helix-in/DFG-in. These compounds make key interactions with what is known as the hinge (the flexible linker between the amino and carboxyl terminal lobes of the kinase domain) as well as the pocket that normally accommodates the adenine ring of ATP. SB590885 and GDC-0879 are two literature examples of type I RAF inhibitors. Both were demonstrated to be almost exclusively active in BRAF Class 1 mutant cell contexts both in vitro and in vivo. Despite this promising activity, to date, no type I inhibitors have entered clinical development. Type 2 inhibitors [0201] Type 2 inhibitors bind to the kinase domain in an open conformation in which the DFG-loop is oriented in an outward or inactive position. This conformation exposes an allosteric, hydrophobic pocket adjacent to the ATP binding site that can be exploited to gain further enhancements in potency and selectivity via hydrogen bonding, Van der Waals and hydrophobic interactions. Accordingly, Type 2 inhibitors consist of functionalities that interact with both the hinge region as well as the allosteric pocket leaving the C-helix in an inward undisturbed orientation. Accordingly, this conformation is denoted as C-helix- in/DFG-out. In the literature, there exist a number of examples of Type 2 RAF inhibitors including several that have undergone clinical evaluation. Unlike the Type 1 inhibitor examples, these molecules as a class are more broadly active, exhibiting activity across a range of mutant contexts including RAS (KRAS, NRAS, HRAS), BRAF (Class 1, II and III) and CRAF. To date, multiple Type 2 inhibitors have entered into clinical development for patients harboring genetic alterations in the MAPK pathway. Importantly, several of these agents have demonstrated clinical activity in both Class I mutant BRAF and RAS mutant contexts. However, the activity has been limited and no Type 2 RAF inhibitor is currently approved for any indication. Type 1.5 Inhibitors [0202] Type 1.5 inhibitors bind to both the hinge region as well as the space typically occupied by the adenine moiety of ATP in much the same way as the Type 1 RAF inhibitors. What distinguishes the Type 1.5 inhibitors is that they take advantage of additional interactions at the back of the ATP binding pocket made accessible by the relatively small threonine gatekeeper residue found in all RAF isoforms (T382 in ARAF, T529 in BRAF and T421 in CRAF). Importantly, these back-pocket interactions alter the conformation of the C- helix, forcing it into an outward conformation while the DFG loop is oriented in its active or ‘in’ conformation. This conformation is denoted as C-helix-out/DFG-in. This conformation exerts a significant impact on the affinity of inhibitor for the second protomer of the RAF dimer rendering it markedly less able to bind inhibitor. Consequently, Type 1.5 inhibitors are highly active against BRAF Class I mutants that signal as monomers versus other MAPK pathway mutant contexts and the wildtype state where RAF signals as an obligate dimer. To date, 3 Type 1.5 inhibitors have been approved for the treatment of malignant melanomas harboring Class 1 BRAF mutations: vemurafenib, dabrafenib and encorafenib. Paradoxical activation [0203] As described above, ARAF, BRAF and CRAF are primarily regulated at the structural level in which various intra- and inter-molecular protein-protein interactions define both their localization and activity state. Accordingly, the structural changes induced with inhibitor binding exert biological effects beyond simple inhibition of kinase activity and these effects can differ depending upon the genetic context of the cells or tissues being exposed to inhibitor. In addition, dependent upon the inhibitor type, these effects are distinct, having important implications regarding safety as well as sensitivity and resistance to inhibitor treatment. [0204] In normal cells and tissues in which the RAF isoforms are unmutated, inhibitor binding actually enhances signaling flux through the MAPK pathway in what is known as paradoxical activation. This effect derives from one or more of four distinct yet interdependent mechanisms; (1) attenuation of inhibitory auto-phosphorylation in the linker region, (2) interruption of kinase domain interactions, (3) enhancement of binding to GTP- bound RAS at the plasma membrane and (4) transactivation of the second protomer of the RAF dimer. The first 3 of these mechanisms collectively drive enhanced RAF protomer dimerization and therefore enhance downstream signaling. The fourth mechanism involves inhibitor binding to the first protomer of the RAF dimer to induce a C-helix out conformation that effectively locks the conformation of the active site of the second protomer to the active C-helix-in conformation thereby inducing both its activation and markedly reducing its affinity for inhibitor (negative allostery). The extent and magnitude of activation is dependent upon which of these mechanisms are induced by inhibitor binding and this is ultimately dictated by the binding mode of the inhibitor. Accordingly, Type 1, 2 and 1.5 inhibitors all engage the first 3 mechanisms to induce paradoxical activation. Only the Type 1.5 inhibitors engage the fourth mechanism to further enhance paradoxical activation. Therapeutic Resistance [0205] Clinical resistance to Type 1.5 and Type 2 inhibitors has been observed, but with distinct mechanisms of action. Patients with BRAF Class I mutant melanoma that become refractory to or relapse on Type 1.5 inhibitor therapies often exhibit mutations that drive RAF dimerization. These alterations typically involve RAF amplification/overexpression or RAS mutations but can also include aberrant alternative splicing events that remove the RBD and CRD and effectively remove the blockade to dimerization. When the Class I mutant BRAF protomer acts in the context of a dimer rather than its typical monomeric state, it is much less sensitive to Type 1.5 inhibitor treatment. This is due largely to the inhibitor’s impact on the C-helix which, as mentioned in the previous section not only results in transactivation of the unoccupied protomer but it also renders this protomer markedly less able to bind inhibitor such that super-clinical concentrations of inhibitor are required to significantly attenuate MAPK pathway signaling in the resistant tumor. Given the relatively limited clinical data available for the Type 2 RAF inhibitors, only one mechanism of therapeutic resistance has been reported thus far. In the case of belvarafenib, multiple patients that relapsed on therapy exhibited alterations in ARAF. These mutations reside within the kinase domain active site and rendered the kinase resistant not only to belvarafenib but a panel of Type 2 inhibitors. Mutant coverage [0206] Because the type 1.5 inhibitors are not effective at inhibiting RAF activity in the context of a dimer, they are only effective at inhibiting Class I BRAF mutants that signal as monomers. Because Type 2 inhibitors can inhibit both monomeric and dimeric RAF, they are able to inhibit Class II and III BRAF mutants that signal as obligate dimers in addition to the Class I mutants. Clinical Safety [0207] Paradoxical activation is known to adversely impact the tolerability of these inhibitors in patients, thereby limiting their clinical utility. As mentioned previously, Type 1.5 inhibitors markedly induce paradoxical activation in normal tissues by binding RAF dimers and transactivating the second unbound protomer. Accordingly, in the clinic, Type 1.5 inhibitor treatment is associated with multiple adverse events associated with aberrant MAPK pathway activation particularly involving the skin such as palmoplantar erythrodysaesthesia syndrome and proliferative skin lesions including keratoacanthomas and cutaneous squamous cell carcinomas. MEK inhibitors have been successfully deployed in combination with Type 1.5 RAF inhibitors to effectively manage these toxicities. Specifically, vemurafenib, dabrafenib and encorafenib have been approved in combination with cobimetinib, trametinib and binimetinib, respectively, for patients with BRAF Class I mutant metastatic melanoma. Not only have these combinations improved tolerability by attenuating paradoxical activation in normal tissues but they have also improved therapeutic benefit both in terms of overall response rate and long term survival. [0208] In contrast, Type 2 inhibitors can bind and inhibit both protomers equally thereby significantly attenuating paradoxical activation and driving full MAPK inhibition, even in normal unmutated tissues. Consequently, the toxicities associated with Type 2 inhibitors are more in keeping with those elicited by MEK inhibitors. [0209] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation. In some embodiments, the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in ARAF selected from the group consisting of S214C and S214F. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in BRAF selected from the group consisting of Class I, Class IIa, Class IIb, Class IIc, and Class III mutations. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in CRAF selected from the group consisting of P261A, P261L, E478K, R391W, R391S and T491I, or is associated with a CRAF fusion. In other embodiments, the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs). In some embodiments, the one or more genetic lesions is a point mutation, a fusion or any combination thereof. In some embodiments, the one or more receptor tyrosine kinase is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROS1. [0210] The compounds and compositions of the present disclosure may be suitable for treatment of certain subtypes of cancer or neoplastic diseases, which may also be associated with mutations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer is is a solid tumor or a hematological malignancy. In some embodiments, the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, colorectal carcincoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In one aspect, provided herein is a method of treating a solid tumor or a hematological malignancy, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing. In some embodiments, the solid tumor or hematological malignancy is melanoma, lung cancer, pancreatic carcinoma, glioma, colorectal carcincoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC). [0211] In some embodiments of the present aspect, the cancer is a refractory cancer. In certain embodiments of the foregoing, the refractory cancer is associated with a genetic alteration or alterations in KRAS (including mutants G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E), NRAS (including mutants G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, G61L), HRAS (including mutants G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, Q61H), BRAF (including gene amplification, class II and III mutants [including G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, L597Q], BRAF fusions or alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10), RTKs (including ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1). In still further embodiments of the foregoing, the refractory cancer may be combined with any preceding embodiments of the present aspect, the method further comprises administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation. [0212] In some embodiments of the present aspect, the cancer is a refractory BRAF Class I mutant cancer. In some embodiments, the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R. In certain embodiments of the foregoing, the refractory cancer is associated with a genetic alteration in KRAS, NRAS, HRAS or BRAF that drives BRAF dimerization and confers resistance to approved Type 1.5 inhibitors (including vemurafenib, dabrafenib and encorafenib) both alone and in the context of MEK inhibitor (including cobimetinib, trametinib and binimetinib) combinations. In some embodiments, the refractory cancer is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the refractory cancer is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the refractory cancer is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the refractory cancer is associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. In some embodiments, the refractory cancer is associated with one or more Class II or Class III mutations in BRAF. In some embodiments, the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q. In some embodiments, the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10. In still further embodiments of the foregoing, the method further comprises administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation. [0213] In some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old. [0214] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents. In some embodiments, the method further comprises administering radiation. In some embodiments, the method further comprises administering one or more additional pharmaceutical agents, including anti-microtubular therapies (e.g. paclitaxel, vincristine), topoisomerase inhibitors (e.g. adriamycin), alylating agents (e.g. busulfan, cyclophosphamide), nucleotide synthesis inhibitors (hyroxyurea), DNA synthesis inhibtiors (e.g. cytarabine), protein synthesis inhibitors (e.g. omacetaxine), developmental signaling pathway inhibitors (e.g. sonidegib, Hedgehog pathway), pro-apoptotic agents (e.g. venetoclax), Abl myristoyl-pocket binding inhibitors (e.g. asciminib), MEK1/2 inhibitors (e.g. trametinib, binimetinib), AKT inhibitors (e.g. ipatasertib), PI3K inhibitors (e.g. apelisib)and radiation. VI. Dosing and Method of Administration [0215] The dose of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular cancer, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is a therapeutically effective amount. [0216] The compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal. [0217] The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight. An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily. [0218] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable excipient. [0219] A compound or composition provided herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein. VII. Articles of Manufacture and Kits [0220] The present disclosure further provides articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, a composition described herein, or one or more unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed. [0221] The present disclosure further provides kits for carrying out the methods of the present disclosure, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer or neoplastic disease, such as those associated with or mediated by RAF kinase activity. [0222] In some embodiments, the kit contains instructions for the treatment of a disease or disorder mediated by or associated with RAF kinase activity. In some embodiments, the disease or disorder is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. [0223] The kits optionally further comprise a container comprising one or more additional pharmaceutical agents and which kits further comprise instructions on or in the package insert for treating the subject with an effective amount of the one or more additional pharmaceutical agents. [0224] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf-life permit. [0225] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies). [0226] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual. ENUMBERATED EMBODIMENTS [0227] The following enumerated embodiments are representative of some aspects of the invention. Embodiment 1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: R ⁰ is C ₁ -C ₃ alkyl or cyclopropyl, wherein the C ₁ -C ₃ alkyl or cyclopropyl are optionally substituted with 1 to 5 R ⁵ groups; R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1- OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )-C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the aromatic portions of Ring A are optionally substituted with 1 to 5 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl , -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkenyl-OH, -C(=N-OH)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ³ , -SCHF ² , -SF ⁵ , -OCF ³ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N ³ , -OCHF ₂ , -CF ₃ , -CF2Cl , -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. Embodiment 2. The compound of embodiment 1, wherein Ring A is selected from the group consisting of:

Embodiment 3. The compound of embodiment 1 or embodiment 2, wherein Ring A is . Embodiment 4. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (I’), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: R ⁰ is C ₁ -C ₃ alkyl or cyclopropyl, wherein the C ₁ -C ₃ alkyl or cyclopropyl are optionally substituted with 1 to 5 R ⁵ groups; R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1- OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )-C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6-membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, -S(O)Me, - S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , -CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl , -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl- OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ³ , -SCHF ² , -SF ⁵ , -OCF ³ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N ³ , -OCHF ₂ , -CF ₃ , -CF2Cl , -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. Embodiment 5. The compound of embodiment 1 or embodiment 4, wherein the compound of formula (I) is a compound of formula (I’-1): or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1- OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )-C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; ^{each R4 is independently F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, -N(R6)R6,} -N3, -OCHF ₂ , -CF ₃ , -CF2Cl , -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl- OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl , -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. Embodiment 6. The compound of embodiment 1 or embodiment 4, wherein the compound is a compound of formula (I-2): or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R ⁰ is C ₁ -C ₃ alkyl optionally substituted by 1 to 5 R ⁵ groups, and wherein R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1- OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )-C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² )0-1-C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl , -CHF ₂ , -CN, -NO2, -C(=O)C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl- OR ⁶ , C ₁ -C ₆ alkylene-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkylene(-OH)-C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene-C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkylene(-OH)-C ₃ -C ₇ cycloalkyl, or 5- to 6-membered heteroaryl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl , -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. Embodiment 7. The compound of any one of embodiments 1 and 4 to 6, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a )0-1-(C(R ² )R ² )0-1- OR ² , -(X ^a )0-1-(C(R ² )R ² )0-1-N(R ² )R ² , -(X ^a )0-1-(C(R ² )R ² )0-1-S(O) ₂ R ² , -(X ^a )-(C(R ² )R ² )0-1-S(O)(=NR ² )R ² , -(X ^a )-C(R ² )R ² -S(O) ₂ N(R ² )R ² , -(X ^a )-C(R ² )R ² -S(O)R ² , -(X ^a )-C(R ² )R ² -N(R ² )R ² S(O) ₂ R ² , or -(X ^a )-(C(R ² )R ² ) ^0-1 -C(O)N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups, and wherein any two R ² groups attached to the same nitrogen are optionally taken together to form a 4- to 7-membered heterocyclic ring, or any two R ² groups attached to the same carbon atom are optionally taken together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SH, -SMe, - S(O)Me, -S(O) ₂ Me, -S(O)(=NH)Me, -S(O)(=NMe)Me, -CN, -NO2, -CHF ₂ , - CF ₃ , -CF2Cl, -OCF ₃ , -OCHF ₂ , -SCF ₃ , -SCHF ₂ , -SF5, -P(O)(Me) ₂ , or -N3; Ring A is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein Ring A is substituted by C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and wherein when Ring A is C6 aryl or 5- to 6-membered heteroaryl, then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6- membered heterocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, wherein each carbocyclic or heterocyclic ring is optionally substituted with 1 to 5 R ⁴ groups; each R ⁴ is independently F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl , -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CF2Cl , -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. Embodiment 8. The compound of any one of embodiments 1 and 4 to 7, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkyl-CN, 4- to 7-membered heterocycloalkyl, -(X ^a ) 0-1-(C(R ² )R ² )0-1- OR ² , or -(X ^a ) 0-1-(C(R ² )R ² )0-1-N(R ² )R ² , wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; X ^a is C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₃ -C ₇ cycloalkylene, or C4-C7 heterocycloalkylene, each of which is optionally substituted with 1 to 5 R ³ groups; each R ² is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the aliphatic and aromatic portions of R ² are optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SMe, -S(O)Me, - S(O) ₂ Me, or -CN; Ring A is C6 aryl or 5- to 6-membered heteroaryl, wherein Ring A is substituted by C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and each R ⁴ is independently H, F, Cl, Br, I, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl; each R ⁵ is independently F, Cl, -SCF ₃ , -SCHF ₂ , -SF5, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -N3, -OCHF ₂ , -CF ₃ , -CHF ₂ , -CN, -NO2, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl. Embodiment 9. The compound of any one of embodiments 1 and 4 to 8, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: R ¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-CN, or C ₁ -C ₆ heteroalkyl, wherein the aliphatic portions of R ¹ are optionally substituted with 1 to 5 R ³ groups; each R ³ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, 4- to 7- membered heterocycloalkyl, 4- to 7-membered heterocycloalkoxy, 5- to 6- membered heteroaryl, F, Cl, -OH, -NH ₂ , -NHMe, -NMe2, -SMe, -S(O)Me, - S(O) ₂ Me, or -CN; Ring A is C6 aryl or 5- to 6-membered heteroaryl, wherein Ring A is substituted by C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, wherein the remaining aromatic portions of Ring A are optionally substituted with 1 to 4 R ⁴ groups, and each R ⁴ is independently H, F, Cl, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -OCHF ₂ , -CF ₃ , -CHF ₂ , - CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkyl-OH, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl; each R ⁵ is independently F, -OCF ₃ , -OR ⁶ , -N(R ⁶ )R ⁶ , -OCHF ₂ , -CF ₃ , -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ heteroalkyl, wherein the aliphatic portions of R ⁵ are optionally substituted with 1 to 3 R ³ groups; and each R ⁶ is independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, or C ₃ -C ₇ cycloalkyl. Embodiment 10. The compound of any one of embodiments 1 to 9, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R ¹ is H or C ₁ -C ₆ alkyl optionally substituted with 1 to 5 R ³ groups. Embodiment 11. The compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R ¹ is -CH ₃ or -CH ₂ CH ₃ . Embodiment 12. The compound of any one of embodiments 1 and 4 to 11, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is 6-membered heteroaryl substituted by C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C1- C6 alkyl, and optionally further substituted with 1 to 4 R ⁴ groups. Embodiment 13. The compound of any one of embodiments 1 and 4 to 12, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is pyridyl or pyrimidyl, wherein the pyridyl or pyrimidyl is substituted by C1- C6 alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 4 R ⁴ groups. Embodiment 14. The compound of any one of embodiments 1 and 4 to 13, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: N Ring A is or , wherein Ring A is substituted by C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 4 R ⁴ groups, each R ⁴ is independently F, C ₁ -C ₆ alkyl, -OR ⁶ , -CN, -CH ₂ CN, -CH ₂ CH ₂ CN, C ₁ -C ₆ alkyl-OH, or C ₁ -C ₆ haloalkyl-OH; and each R ⁶ is independently H or C ₁ -C ₆ alkyl. Embodiment 15. The compound of any one of embodiments 1 and 4 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is substituted by -C(=N-OH)CH ₂ CH ₃ , -C(=N- OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 4 R ⁴ groups. Embodiment 16. The compound of any one of embodiments 1 to 2 and 4 to 15, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Embodiment 17. The compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: R ⁵ , if present, is F. Embodiment 18. The compound of any one of embodiments 1 to 5 and 7 to 17, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the compound of formula (I) is a compound of formula (I’-I) and the . Embodiment 19. The compound of embodiments 1, 4 to 5, and 7 to 15, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, which is of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), or (I-h): , wherein at least one R ⁴ is C ₁ -C ₆ alkenyl-OH or -C(=N-OH)C ₁ -C ₆ alkyl, and wherein the pyridyl or pyrimidyl is independently optionally further substituted with 1 to 2 R ⁴ groups. Embodiment 20. The compound of embodiment 20, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R ¹ is H or –CH ₃ ; and at least one R ⁴ is -C(=N-OH)CH ₂ CH ₃ , -C(=N- OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . Embodiment 21. The compound of embodiment 21 or 22, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: R ¹ is -CH ₃ ; and at least one R ⁴ is -C(=N-OH)CH ₂ CH ₃ , -C(=N-OH)CH ₂ CH ₂ CH ₃ , -CD(OH)CH ₂ CH=CH ₂ , -CH(OH)CH ₂ CH=CH ₂ , or -CD(OH)CH=CHCH ₃ . Embodiment 22. A compound, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, which is selected from the group consisting of:

Embodiment 23. A compound, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, which is selected from the group

Embodiment 24. A pharmaceutical composition comprising the compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable excipients. Embodiment 25. A method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition according to embodiment 24. Embodiment 26. A method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of any one of embodiments 1- 23, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition according to embodiment 24. Embodiment 27. The method of embodiment 26, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation. Embodiment 28. The method of embodiment 26 or 27, wherein the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. Embodiment 29. The method of any one of embodiments 26-28, wherein the cancer or neoplastic disease is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E; or one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L; or one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H; or one or more mutations in ARAF selected from the group consisting of S214C and S214F; or one or more mutations in BRAF selected from the group consisting of Class I, Class IIa, Class IIb, Class IIc, and Class III mutations; or one or more mutations in CRAF selected from the group consisting of P261A, P261L, E478K, R391W, R391S and T491I, or a CRAF fusion. Embodiment 30. The method of any one of embodiments 26-29, wherein the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs). Embodiment 31. The method of embodiment 30, wherein the one or more genetic lesions is a point mutation, a fusion or any combination thereof. Embodiment 32. The method of embodiment 30 or 31, wherin the one or more receptor tyrosine kinase is selected from the group consistion of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROS1. Embodiment 33. The method of any one of embodiments 26-32, wherein the cancer is a refractory cancer. Embodiment 34. The method of any one of embodiments 26-33, the refractory cancer is associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. Embodiment 35. The method of any one of embodiments 26-34, the cancer is a refractory BRAF Class I mutant cancer. Embodiment 36. The method of embodiment 35, wherein the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R. Embodiment 37. The method of any one of embodiments 26-34, wherein the refractory cancer is associated with one or more Class II or Class III mutations in BRAF. Embodiment 38. The method of embodiment 37, wherein the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q. Embodiment 39. The method of embodiment 37, wherein the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10. Embodiment 40. The method of any one of embodiments 26-39, wherein the cancer is a solid tumor or a hematological malignancy. Embodiment 41. The method of embodiment 40, wherein the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, colorectal carcincoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). Embodiment 42. The method of embodiment 41, wherein the lung cancer is non-small cell lung cancer (NSCLC). Embodiment 43. The method of any one of embodiments 26-42, further comprising administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro- apoptotic agents, RTK inhibitors, RAF inhibitors representing alternative binding modes, MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors, PI3K inhibitors and/or radiation. EXAMPLES [0228] It is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of present disclosure. Synthetic Examples [0229] The chemical reactions in the Examples described can be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds of this disclosure are deemed to be within the scope of this disclosure. For example, the synthesis of non-exemplified compounds according to the present disclosure can be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure. [0230] Abbreviations used in the Examples include the following: ACN: acetonitrile; Brettphos: 2-(dicyclohexylphosphino)3,6-dimethoxy-2’,4’,6’-triiso propyl-1,1’-biphenyl; dppf: 1,1’-ferrocenediyl-bis(diphenylphosphine); DCM: dichloromethane; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate; EtOH: ethanol or ethyl alcohol; ¹ H NMR: proton nuclear magnetic resonance; LCMS: liquid chromatography– mass spectrometry; LiHMDS: lithium hexamethyldisilazide; MeOH: methanol or methyl alcohol; NBS: N-bromosuccinimide; OAc: acetate; Py: pyridine; THF: tetrahydrofuran; and TLC: thin-layer chromatography. Example 1. Synthesis of (1R)-2,2-difluoro-N-[3-(5-fluoro-4-methylpyridin-3-yl)-1-met hyl- 2-oxo-1,6-naphthyridin-7-yl]cyclopropane-1-carboxamide (Compound 1) Step 1. Synthesis of 7-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-1-methyl-1,6- naphthyridin-2-one dioxane, H ₂ O [0231] To a mixture of 7-chloro-1-methyl-2-oxo-1,6-naphthyridin-3-ylboronic acid (1806.9 mg, 7.58 mmol) in dioxane/H ² O (30.0 mL/6.0 mL) was added 3-bromo-5-fluoro-4- methylpyridine (1200.0 mg, 6.32 mmol), K2CO3 (2618.4 mg, 18.95 mmol) and Pd(dppf)Cl2 (462.1 mg, 0.63 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (35/65, v/v) to afford 7-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-1- methyl-1,6-naphthyridin-2-one (720.0 mg, 37%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 304.1. Step 2. Synthesis of tert-butyl N-[3-(5-fluoro-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,6- naphthyridin-7-yl]carbamate [0232] To a mixture of 7-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-1-methyl-1,6- naphthyridin-2-one (680.0 mg, 2.24 mmol) in dioxane (15.0 mL) was added tert-butyl carbamate (524.57 mg, 4.478 mmol), Cs2CO3 (2188.4 mg, 6.72 mmol), XPhos (213.5 mg, 0.45 mmol) and Pd(OAc) ₂ (50.3 mg, 0.22 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (3/7, v/v) to afford tert-butyl N-[3-(5- fluoro-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,6-naphthyridin -7-yl]carbamate (500.0 mg, 58%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 385.2. Step 3. Synthesis of 7-amino-3-(5-fluoro-4-methylpyridin-3-yl)-1-methyl-1,6- [0233] To a solution of tert-butyl N-[3-(5-fluoro-4-methylpyridin-3-yl)-1-methyl-2-oxo- 1,6-naphthyridin-7-yl]carbamate (500.0 mg, 1.30 mmol) in CH ₂ Cl2 (5.0 mL) was added TFA (2.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was basified to pH=8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH ₂ Cl2. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 7-amino-3-(5-fluoro-4-methylpyridin-3- yl)-1-methyl-1,6-naphthyridin-2-one (330.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 285.1. Step 4. Synthesis of (1R)-2,2-difluoro-N-[3-(5-fluoro-4-methylpyridin-3-yl)-1-met hyl-2- oxo-1,6-naphthyridin-7-yl]cyclopropane-1-carboxamide (Compound 1) [0234] To a mixture of 7-amino-3-(5-fluoro-4-methylpyridin-3-yl)-1-methyl-1,6- naphthyridin-2-one (100.0 mg, crude) in pyridine (10.0 mL) was added (1R)-2,2- difluorocyclopropane-1-carboxylic acid (85.9 mg, 0.70 mmol) at room temperature. Then EDCI (123.0 mg, 0.64 mmol) was added to the mixture at 0 °C. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (10/1, v/v) and then purified by Prep-HPLC with the following FRQGLWLRQV^^^&ROXPQ^^;%ULGJH^3UHS^2%'^&^^^&ROXPQ ^^^^[^^^^PP^^^^^P^^0RELOH^ Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 36% B in 8 min; Wave Length: 220 nm) to afford (1R)-2,2-difluoro-N- [3-(5-fluoro-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,6-naphth yridin-7-yl]cyclopropane-1- carboxamide (Compound 1) (20.1 mg, 14%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 389.0. ¹ H NMR (400 MHz, DMSO-d6): ¥ 11.43 (s, 1H), 8.76 (s, 1H), 8.54 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 3.62 (s, 3H), 3.11 - 3.03 (m, 1H), 2.13 (s, 3H), 2.12 - 2.05 (m, 2H). Example 2. Synthesis of (R)-N-(1-ethyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2 -oxo- 1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamide (Compound 2) and (S)-N-(1- ethyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2-oxo-1,2- dihydro-1,6-naphthyridin-7- yl)cyclopropanecarboxamide (Compound 3) Step 1. Synthesis of 3-(6-butyryl-4-methylpyridin-3-yl)-7-chloro-1-ethyl-1,6- naphthyridin-2(1H)-one [0235] To a solution of 3-bromo-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (830.0 mg, 2.89 mmol) in 1,4 - dioxane/H2O (20.0 mL/4.0 mL) was added (6-butyryl-4-methylpyridin-3- yl)boronic acid (896.5 mg, 4.33 mmol), K2CO3 (1.2 g, 8.66 mmol) and Pd(PPh3)4 (667.1 mg, 0.58 mmol) at room temperature under N2. The resulting mixture was stirred DW^^^^^^IRU^^^K^ under N2. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (76/24, v/v) to afford 3-(6-butyryl-4-methylpyridin-3-yl)-7-chloro-1-ethyl-1,6-naph thyridin- 2(1H)-one (600.0 mg, 56%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 370.1. Step 2. Synthesis of N-(3-(6-butyryl-4-methylpyridin-3-yl)-1-ethyl-2-oxo-1,2-dihy dro- 1,6-naphthyridin-7-yl)cyclopropanecarboxamide [0236] To a solution of 3-(6-butyryl-4-methylpyridin-3-yl)-7-chloro-1-ethyl-1,6- naphthyridin-2(1H)-one (103.6 mg, 1.22 mmol) in dioxane (10.0 mL) was added cyclopropanecarboxamide (103.6 mg, 1.22 mmol), Cs2CO3 (792.8 mg, 2.43 mmol), XPhos (232.0 mg, 0.49 mmol) and Pd2(dba)3 (139.9 mg, 0.24 mmol) at room temperature under N2. The resulting mixture was stirred DW^^^^^^^IRU^^^K^^After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (44/56, v/v) to afford N-(3-(6-butyryl-4- methylpyridin-3-yl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyrid in-7- yl)cyclopropanecarboxamide (170.0 mg, 50%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 419.2. Step 3. Synthesis of N-(1-ethyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2-oxo -1,2- dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamide [0237] To a solution of N-(3-(6-butyryl-4-methylpyridin-3-yl)-1-ethyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamide (148.0 mg, 0.35 mmol) in THF/MeOH ((4.0 mL/0.8 mL) was added NaBH4 (26.8 mg, 0.71 mmol) at 0 ^o C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with acetonitrile/water (28/72, v/v) to afford N-(1-ethyl-3-(6-(1- hydroxybutyl)-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,6-na phthyridin-7- yl)cyclopropanecarboxamide (78.0 mg, 52%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 421.2. Step 4. Chiral Separation of (R)-N-(1-ethyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3- yl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanecarb oxamide (Compound 2) and (S)-N-(1-ethyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2 -oxo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropanecarboxamide (Compound 3) 2 3 [0238] The racemic product of N-(1-ethyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)- 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxam ide (78.0 mg, 0.18 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-6&^^^[^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^^ 0^1+3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 60% B to 60% B in 12 min; Wave Length: 220\254 nm; RT1(min): 7.79; RT2(min): 9.68) to afford N-(1-ethyl-3-(6- (1-hydroxybutyl)-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,6 -naphthyridin-7- yl)cyclopropanecarboxamide Enantiomer A (17.9 mg, 46%) as a white solid and N-(1-ethyl- 3-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2-oxo-1,2-dihydr o-1,6-naphthyridin-7- yl)cyclopropanecarboxamide Enantiomer B (21.9 mg, 56%) as a white solid. The absolute stereochemistry of Enantiomer A and Enantiomer B was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixtures as described above are shown as Compounds 2 and 3 in Table 1. [0239] Enantiomer A: RT2(min): 7.79; LCMS (ESI, m/z): [M+H] ⁺ =421.2. ¹ H NMR (300 MHz, DMSO-d6^^^į^^^^^^ (s, 1H), 8.72 (s, 1H), 8.30 - 8.28 (m, 2H), 8.01 (s, 1H), 7.40 (s, 1H), 5.31 (d, J = 3.9 Hz, 1H), 4.60 - 4.58 (m, 1H), 4.25 - 4.18 (m, 2H), 2.20 (s, 3H), 2.13 - 2.05 (m, 1H), 1.78 - 1.57 (m, 2H), 1.47 - 1.32 (m, 2H), 1.28 - 1.24 (m, 3H), 0.93 - 0.83 (m, 7H). [0240] Enantiomer B: RT2(min): 9.68; LCMS (ESI, m/z): [M+H] ⁺ = 421.3. ¹ H NMR (300 MHz, DMSO-d6^^^į^^^^^^ (s, 1H), 8.73 (s, 1H), 8.30 - 8.28 (m, 2H), 8.01 (s, 1H), 7.40 (s, 1H), 5.31 (d, J = 4.8 Hz, 1H), 4.60 - 4.57 (m, 1H), 4.25 - 4.17 (m, 2H), 2.20 (s, 3H), 2.09 - 2.01 (m, 1H), 1.85 - 1.56 (m, 2H), 1.47 - 1.32 (m, 2H), 1.28 - 1.24 (m, 3H), 0.93 - 0.86 (m, 7H). Example 3. Synthesis of (R)-N-(1-cyclopropyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3 -yl)- 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxam ide (Compound 4) and (S)-N-(1-cyclopropyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3 -yl)-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropanecarboxamide (Compound 5) Step 1. Synthesis of 3-bromo-7-chloro-1-cyclopropyl-1,6-naphthyridin-2(1H)-one [0241] To a solution of 3-bromo-7-chloro-1,6-naphthyridin-2(1H)-one (1.5 g, 5.78 mmol) in DME (15.0 mL) was added bipyridyl (993.15 mg, 6.36 mmol), cyclopropylboronic acid (1.24 g, 14.43 mmol), Cu(OAc) ₂ (404.1 mg, 6.36 mmol) and Na2CO3 (1.5 g, 14.43 mmol) at room temperature under O2. The resulting mixture was stirred at 70 ^o C for 16 h under O2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (43/57, v/v) to afford 3-bromo-7-chloro-1-cyclopropyl-1,6-naphthyridin-2(1H)-one (450.0 mg, 26%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 299.0. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^^V^^ 1H), 8.60 (s, 1H), 7.75 (s, 1H), 3.20 - 2.98 (m, 1H), 1.35- 1.25 (m, 2H), 0.90 - 0.75 (m, 2H). Step 2. Synthesis of 3-(6-butyryl-4-methylpyridin-3-yl)-7-chloro-1-cyclopropyl-1, 6- naphthyridin-2(1H)-one [0242] To a solution of 3-bromo-7-chloro-1-cyclopropyl-1,6-naphthyridin-2(1H)-one (350.0 mg, 1.17 mmol) in dioxane/H2O (10.0 mL/2.0 mL) was added (6-butyryl-4- methylpyridin-3-yl)boronic acid (241.9 mg, 1.17 mmol), K2CO3 (484.4 mg, 3.50 mmol) and Pd(PPh3)4 (135.0 mg, 0.12 mmol) at room temperature under N2. The resulting mixture was stirred at 80 ^o C for 16 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford 3-(6-butyryl-4-methylpyridin-3-yl)-7-chloro-1- cyclopropyl-1,6-naphthyridin-2(1H)-one (310.0 mg, 67%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 382.1. Step 3. Synthesis of N-(3-(6-butyryl-4-methylpyridin-3-yl)-1-cyclopropyl-2-oxo-1, 2- dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamide [0243] To a solution of 3-(6-butyryl-4-methylpyridin-3-yl)-7-chloro-1-cyclopropyl-1, 6- naphthyridin-2(1H)-one (310.0 mg, 0.81 mmol) in dioxane (5.0 mL) was added cyclopropanecarboxamide (82.9 mg, 0.97 mmol), Cs2CO3 (793.5 mg, 2.44 mmol), Pd2(dba)3 (74.3 mg, 0.08 mmol) and Xphos (77.4 mg, 0.16 mmol) at room temperature under N2. The resulting mixture was stirred at 100 ^o C for 2 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (46/54, v/v) to afford N-(3-(6-butyryl-4- methylpyridin-3-yl)-1-cyclopropyl-2-oxo-1,2-dihydro-1,6-naph thyridin-7- yl)cyclopropanecarboxamide (140.0 mg, 40%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 431.2. Step 4. Synthesis of N-(1-cyclopropyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl) -2- oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamid e [0244] To a solution of N-(3-(6-butyryl-4-methylpyridin-3-yl)-1-cyclopropyl-2-oxo-1, 2- dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamide (130.0 mg, 0.30 mmol) in THF/MeOH (2.0 mL/2.0 mL) was added NaBH4 (13.7 mg, 0.36 mmol) at 0 ^o C under N2. The resulting mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (95/5, v/v) to afford N-(1-cyclopropyl-3-(6- (1-hydroxybutyl)-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,6 -naphthyridin-7- yl)cyclopropanecarboxamide (80.0 mg, 61%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 433.2. Step 5. Chiral Separation of (R)-N-(1-cyclopropyl-3-(6-(1-hydroxybutyl)-4- methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl) cyclopropanecarboxamide (Compound 4) and (S)-N-(1-cyclopropyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3 -yl)-2- oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamid e (Compound 5) OH OH OH [0245] The product of N-(1-cyclopropyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl) -2- oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamid e (70.0 mg, 0.16 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-6%^^^[^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^0^1+^ -MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 24.2 min; Wave Length: 254/220 nm; RT1(min): 17.98; RT2(min): 22.26) to afford N-(1- cyclopropyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl)-2-ox o-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropanecarboxamide Enantiomer A (15.6 mg, 45%) as a white solid and N-(1-cyclopropyl-3-(6-(1-hydroxybutyl)-4-methylpyridin-3-yl) -2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropanecarboxamide Enantiomer B (12.4 mg, 35%) as a white solid. The absolute stereochemistry of Enantiomer A and Enantiomer B was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixtures as described above are shown as Compounds 4 and 5 in Table 1. [0246] Enantiomer A: RT1(min): 17.98; LCMS (ESI, m/z): [M+H] ⁺ = 433.2. ¹ H NMR (400 MHz, DMSO-d6^^^į 11.10 (s, 1H), 8.66 - 8.64 (m, 2H), 8.26 (s, 1H), 7.94 (s, 1H), 7.38 (s, 1H), 5.28 (d, J = 5.2 Hz, 1H), 4.60 - 4.56 (m, 1H), 3.00 - 2.96 (m, 1H), 2.18 (s, 3H), 2.11 - 2.07 (m, 1H), 1.75 - 1.68 (m, 1H), 1.65 - 1.57 (m, 1H), 1.42 - 1.35 (m, 2H), 1.29 - 1.24 (m, 2H), 0.94 - 0.78 (m, 9H). [0247] Enantiomer B: RT2(min): 22.26; LCMS (ESI, m/z): [M+H] ⁺ = 433.2. ¹ H NMR (400 MHz, DMSO-d6^^^į 11.08 (s, 1H), 8.66 - 8.64 (m, 2H), 8.26 (s, 1H), 7.94 (s, 1H), 7.38 (s, 1H), 5.29 (d, J = 4.8 Hz, 1H), 4.60 - 4.56 (m, 1H), 3.00 - 2.96 (m, 1H), 2.31 (s, 3H), 2.18 - 2.10 (m, 1H), 1.75 - 1.70 (m, 1H), 1.65 - 1.59 (m, 1H), 1.45 - 1.35 (m, 2H), 1.32 - 1.28 (m, 2H), 0.98 - 0.90 (m, 7H), 0.88 - 0.74 (m, 2H). Example 4. Synthesis of (1R,2R)-2-fluoro-N-(3-{6-[(1S)-4-fluoro-1-hydroxybutyl]-4- methylpyridin-3-yl}-1-methyl-2-oxo-1,6-naphthyridin-7-yl)cyc lopropane-1-carboxamide (Compound 6) and (1R,2R)-2-fluoro-N-(3-{6-[(1R)-4-fluoro-1-hydroxybutyl]-4- methylpyridin-3-yl}-1-methyl-2-oxo-1,6-naphthyridin-7-yl)cyc lopropane-1-carboxamide (Compound 7) Step 1. Synthesis of methyl 4-[methoxy(methyl)carbamoyl]butanoate [0248] To a solution of glutaric acid monomethyl ester (5.0 g, 34.21 mmol) in DMF (150.0 mL) was added N,O-dimethylhydroxylamine hydrochloride (6.7 g, 68.43 mmol), DIEA (22.1 g, 171.07 mmol) and HATU (26.0 mg, 68.43 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (91/9, v/v) to afford methyl 4- [methoxy(methyl)carbamoyl]butanoate (2.9 g, 44%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 190.1. Step 2. Synthesis of methyl 5-(5-bromo-4-methylpyridin-2-yl)-5-oxopentanoate [0249] To a solution of 2,5-dibromo-4-methylpyridine (3.7 g, 14.80 mmol) in toluene (40.0 mL) was added i-PrMgCl (14.0 ml, 2.0 mol/L) at 0 ^o C under N2. The resulting mixture was stirred at 0 ^o C for 2 h under N2. Then methyl 4-[methoxy(methyl)carbamoyl]butanoate (2.8 g, 14.80 mmol) was added to the mixture at 0 ^o C under N2. The resulting mixture was stirred at 0 ^o C for additional 2 h under N2. After the reaction was completed, the reaction mixture was quenched with aq.NH4Cl and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (7/3, v/v) to afford methyl 5-(5-bromo-4- methylpyridin-2-yl)-5-oxopentanoate (2.0 g, 45%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 300.0. 1H NMR (400 MHz, DMSO-d6^^^į^^^^^^^V^^^+^^ 7.94 (s, 1H), 3.59 (s, 3H), 3.30 - 3.20 (m, 2H), 2.51 (s, 3H), 2.49 - 2.38 (m, 2H), 1.91 - 1.83 (m, 2H). Step 3. Synthesis of 5-(5-bromo-4-methylpyridin-2-yl)-5-oxopentanoic acid [0250] To a solution of methyl 5-(5-bromo-4-methylpyridin-2-yl)-5-oxopentanoate (2.0 g, 6.69 mmol) in THF/H2O (10.0 mL/10.0 mL) was added LiOH (319.2 mg, 13.32 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate The pH value of the aqueous layer was adjusted to 5 with HCl (2 mol/L). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 5-(5-bromo-4-methylpyridin-2-yl)-5-oxopentanoic acid (1.5 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 286.0. Step 4. Synthesis of 1-(5-bromo-4-methylpyridin-2-yl)-4-fluorobutan-1-one [0251] To a solution of 5-(5-bromo-4-methylpyridin-2-yl)-5-oxopentanoic acid (1.5 g, crude) in ACN/H2O (20.0 mL/20.0 mL) was added Selectfluor (5.6 g, 15.73 mmol), Na2HPO4 (1.5 g, 10.48 mmol) and IR[DF(CF ₃ )PPY]2(DTBPY)PF6 (588.2 mg, 0.52 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 10 min under N2 and then irradiated with 34 W blue LEDs (at 4 cm from the light source) for 20 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (85/15, v/v) to afford 1-(5-bromo-4-methylpyridin-2-yl)-4-fluorobutan-1-one (350.0 mg, 25%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 260.0. Step 5. Synthesis of 7-chloro-3-[6-(4-fluorobutanoyl)-4-methylpyridin-3-yl]-1-met hyl- 1,6-naphthyridin-2-one [0252] To a solution of 1-(5-bromo-4-methylpyridin-2-yl)-4-fluorobutan-1-one (330.0 mg, 1.27 mmol) in dioxane/H2O (5.0 mL/0.5 mL) were added 7-chloro-1-methyl-2-oxo-1,6- naphthyridin-3-ylboronic acid (605.0 mg, 2.54 mmol), K2CO3 (526.0 mg, 3.81 mmol) and Pd(dppf)Cl2 CH ₂ Cl2 (103.4 mg, 0.13 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (60/40, v/v) to afford 7-chloro-3-[6-(4- fluorobutanoyl)-4-methylpyridin-3-yl]-1-methyl-1,6-naphthyri din-2-one (230.0 mg, 48%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 374.1. Step 6. Synthesis of (1R,2R)-2-fluoro-N-{3-[6-(4-fluorobutanoyl)-4-methylpyridin- 3-yl]- 1-methyl-2-oxo-1,6-naphthyridin-7-yl}cyclopropane-1-carboxam ide [0253] To a solution of 7-chloro-3-[6-(4-fluorobutanoyl)-4-methylpyridin-3-yl]-1- methyl-1,6-naphthyridin-2-one (300.0 mg, 0.80 mmol) in dioxane (15.0 mL) was added (1R,2R)-2-fluorocyclopropane-1-carboxamide (248.2 mg, 2.41 mmol), K2CO3 (332.8 mg, 2.41 mmol), Brettphos (86.1 mg, 0.16 mmol) and Brettphos Pd G3 (72.8 mg, 0.08 mmol) at room temperature under N2. The resulting mixture was stirred at 80 ^o C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (20/80, v/v) to afford (1R,2R)-2-fluoro-N-{3-[6-(4-fluorobutanoyl)-4-methylpyridin- 3-yl]-1-methyl-2-oxo- 1,6-naphthyridin-7-yl}cyclopropane-1-carboxamide (240.0 mg, 67%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 441.2. Step 7. Synthesis of (1R,2R)-2-fluoro-N-{3-[6-(4-fluoro-1-hydroxybutyl)-4- methylpyridin-3-yl]-1-methyl-2-oxo-1,6-naphthyridin-7-yl}cyc lopropane-1-carboxamide [0254] To a solution of (1R,2R)-2-fluoro-N-{3-[6-(4-fluorobutanoyl)-4-methylpyridin- 3- yl]-1-methyl-2-oxo-1,6-naphthyridin-7-yl}cyclopropane-1-carb oxamide (200.0 mg, 0.45 mmol) in THF/MeOH (10.0 mL/10.0 mL) was added NaBH4 (17.2 mg, 0.45 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction mixture was quenched by the addition of water at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/CH ₃ OH (94/6, v/v) to afford (1R,2R)- 2-fluoro-N-{3-[6-(4-fluoro-1-hydroxybutyl)-4-methylpyridin-3 -yl]-1-methyl-2-oxo-1,6- naphthyridin-7-yl}cyclopropane-1-carboxamide (100.0 mg, 49%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 443.2. Step 8. Chiral Separation of (1R,2R)-2-fluoro-N-(3-{6-[(1S)-4-fluoro-1-hydroxybutyl]-4- methylpyridin-3-yl}-1-methyl-2-oxo-1,6-naphthyridin-7-yl)cyc lopropane-1-carboxamide (Compound 6) and (1R,2R)-2-fluoro-N-(3-{6-[(1R)-4-fluoro-1-hydroxybutyl]-4- methylpyridin-3-yl}-1-methyl-2-oxo-1,6-naphthyridin-7-yl)cyc lopropane-1-carboxamide (Compound 7) [0255] The product of (1R,2R)-2-fluoro-N-{3-[6-(4-fluoro-1-hydroxybutyl)-4- methylpyridin-3-yl]-1-methyl-2-oxo-1,6-naphthyridin-7-yl}cyc lopropane-1-carboxamide (100.0 mg 0.23 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2h^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^^0^1+3-MeOH)- -HPLC, Mobile Phase B: IPA: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 21 min; Wave Length: 254/220 nm; RT1(min): 13.58; RT2(min): 17.58) to afford (1R,2R)-2-fluoro-N-{3-[6-(4-fluoro-1-hydroxybutyl)-4-methylp yridin-3-yl]-1-methyl- 2-oxo-1,6-naphthyridin-7-yl}cyclopropane-1-carboxamide Isomer A (4.4 mg, 9%) as a white solid and (1R,2R)-2-fluoro-N-{3-[6-(4-fluoro-1-hydroxybutyl)-4-methylp yridin-3-yl]-1- methyl-2-oxo-1,6-naphthyridin-7-yl}cyclopropane-1-carboxamid e Isomer B (8.0 mg, 16%) as a white solid. The absolute stereochemistry of Isomer A and Isomer B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixtures as described above are shown as Compounds 6 and 7 in Table 1. [0256] Isomer A: RT1(min): 13.58; LCMS (ESI, m/z): [M+H] ⁺ = 443.2. ¹ H NMR (400 MHz, DMSO-d6^^^į 11.20 (s, 1H), 8.72 (s, 1H), 8.28 - 8.24 (m, 2H), 8.01 (s, 1H), 7.42 (s, 1H), 5.47 (d, J = 4.4 Hz, 1H), 5.11 - 4.91 (m, 1H), 4.53 - 4.42 (m, 3H), 3.61 (s, 3H), 2.30 - 2.23 (m, 1H), 2.21 (s, 3H), 1.90 - 1.82 (m, 1H), 1.80 - 1.60 (m, 4H), 1.27 - 1.19 (m, 1H). [0257] Isomer B: RT2 (min): 17.58; LCMS (ESI, m/z): [M+H] ⁺ = 443.1. ¹ H NMR (400 MHz, DMSO-d6^^^į 11.20 (s, 1H), 8.72 (s, 1H), 8.28 - 8.25 (m, 2H), 8.02 (s, 1H), 7.42 (s, 1H), 5.44 (s, 1H), 5.07 - 4.81 (m, 1H), 4.63 - 4.42 (m, 3H), 3.62 (s, 3H), 2.30 - 2.23 (m, 1H), 2.21 (s, 3H), 1.92 - 1.82 (m, 1H), 1.80 - 1.62 (m, 4H), 1.26 - 1.21 (m, 1H). Example 5. Synthesis of (S)-N-(3-(6-(1-hydroxybutyl-1-d)-4-methylpyridin-3-yl)-1-met hyl- 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (Compound 8) and (R)-N-(3-(6-(1- hydroxybutyl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-d ihydro-1,6-naphthyridin-7- yl)acetamide (Compound 9) Step 1. Synthesis of N-(3-(6-(1-hydroxybutyl-1-d)-4-methylpyridin-3-yl)-1-methyl- 2-oxo- 1,2-dihydro-1,6-naphthyridin-7-yl)acetamide [0258] To a solution of N-[3-(6-butanoyl-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,6- naphthyridin-7-yl]acetamide (180.0 mg, 0.47 mmol) in THF (5.0 mL) and CD3OD (1.0 mL ) was added NaBD4 (99.5 mg, 2.38 mmol ) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (93/7, v/v) to afford N-(3-(6-(1-hydroxybutyl-1-d)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)acetamide (80.4 mg, 44%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ =382.1. Step 2. Chiral Separation of (S)-N-(3-(6-(1-hydroxybutyl-1-d)-4-methylpyridin-3-yl)-1- methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (Compound 8) and (R)-N- (3-(6-(1-hydroxybutyl-1-d)-4-methylpyridin-3-yl)-1-methyl-2- oxo-1,2-dihydro-1,6- naphthyridin-7-yl)acetamide (Compound 9) [0259] The racemic product of N-(3-(6-(1-hydroxybutyl-1-d)-4-methylpyridin-3-yl)-1- methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (80.4 mg, 0.21 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: Lux 5um Cellulose- 2, 2.12x^^^FP^^^^^P^^0RELOH^3KDVH^A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 18.5 min; Wave Length: 254/220 nm; RT1(min): 12.62; RT2(min): 15.49) to afford N-(3-(6-(1- hydroxybutyl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-d ihydro-1,6-naphthyridin-7- yl)acetamide Enantiomer A (24.4 mg, 60%) as a white solid and N-(3-(6-(1-hydroxybutyl-1- d)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naph thyridin-7-yl)acetamide Enantiomer B (26.2 mg, 64%) as a white solid. The absolute stereochemistry of Enantiomer A and Enantiomer B was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixtures as described above are shown as Compounds 8 and 9 in Table 1. [0260] Enantiomer A: RT1(min): 12.62 LCMS (ESI, m/z): [M ⁺ H] ⁺ = 382.2. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^- 8.23 (m, 2H), 7.99 (s, 1H), 7.40 (s, 1H), 5.26 (s, 1H), 3.61(s, 3H), 2.20 - 2.17 (m, 6H), 1.78 - 1.69 (m, 1H), 1.66 - 1.58 (m, 1H), 1.44 - 1.33 (m, 2H), 0.92 - 0.88 (m, 3H). [0261] Enantiomer B: RT2(min): 15.49 LCMS (ESI, m/z): [M ⁺ H] ⁺ = 382.2. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^- 8.24 (m, 2H), 8.00 (s, 1H), 7.40 (s, 1H), 5.25 (s, 1H), 3.61 (s, 3H), 2.20 - 2.17 (m, 6H), 1.74 - 1.62 (m, 2H), 1.42 - 1.37 (m, 2H), 0.93 - 0.89 (m, 3H). Example 6. Synthesis of (S)-N-(3-(2-(1-hydroxybutyl)-4-methylpyrimidin-5-yl)-1-methy l-2- oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamid e (Compound 10) and (R)- N-(3-(2-(1-hydroxybutyl)-4-methylpyrimidin-5-yl)-1-methyl-2- oxo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropanecarboxamide (Compound 11) Step 1. Synthesis of (7-chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)b oronic acid _pp ^{, c, o a e} [0262] To a solution of 3-bromo-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (1.0 g, 3.65 mmol) in 1,4-dioxane (10.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (1.3 g, 5.48 mmol), KOAc (1.0 g, 10.96 mmol) and Pd(dppf)Cl2 (0.2 g, 0.36 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford (7-chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)b oronic acid (800.0 mg, 91%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 239.0. Step 2. Synthesis of 3-(2-butyryl-4-methylpyrimidin-5-yl)-7-chloro-1-methyl-1,6- naphthyridin-2(1H)-one [0263] To a mixture of (7-chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3- yl)boronic acid (400.0 mg, 1.67 mmol) in 1,4-dioxane/H2O (10.0 mL/2.0 mL) was added 1- (5-bromo-4-methylpyrimidin-2-yl)butan-1-one (489.4 mg, 2.01 mmol), KOAc (493.9 mg, 5.03 mmol) and Pd(dppf)Cl2 (122.7 mg, 0.16 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (10/1, v/v) to afford 3-(2-butyryl-4-methylpyrimidin-5- yl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (500.0 mg, 83%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 357.1 Step 3. Synthesis of N-(3-(2-butyryl-4-methylpyrimidin-5-yl)-1-methyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamide [0264] To a mixture of 3-(2-butyryl-4-methylpyrimidin-5-yl)-7-chloro-1-methyl-1,6- naphthyridin-2(1H)-one (500.0 mg, 1.40 mmol) in 1,4-dioxane (10.0 mL) was added cyclopropanecarboxamide (357.7 mg, 4.20 mmol), Cs2CO3 (1.3 g, 4.20 mmol), Brettphos (150.4 mg, 0.28 mmol) and Brettphos Pd G3 (127.0 mg, 0.14 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (10/1, v/v) to afford N-(3-(2-butyryl-4- methylpyrimidin-5-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthy ridin-7- yl)cyclopropanecarboxamide (420.0 mg, 73%) as a brown solid. LCMS (ESI, m/z): [M+H] ⁺ = 406.2. Step 4. Synthesis of N-(3-(2-(1-hydroxybutyl)-4-methylpyrimidin-5-yl)-1-methyl-2- oxo- 1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamide [0265] To a solution of N-(3-(2-butyryl-4-methylpyrimidin-5-yl)-1-methyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamide (400.0 mg, 0.98 mmol) in THF/MeOH (10.0 mL/2.0 mL) was added NaBH4 (74.6 mg, 1.97 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (10/1, v/v) to afford N-(3-(2-(1- hydroxybutyl)-4-methylpyrimidin-5-yl)-1-methyl-2-oxo-1,2-dih ydro-1,6-naphthyridin-7- yl)cyclopropanecarboxamide (65.0 mg, 16%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 408.2. Step 3. Chiral Separation of (S)-N-(3-(2-(1-hydroxybutyl)-4-methylpyrimidin-5-yl)-1- methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanec arboxamide (Compound 10) and (R)-N-(3-(2-(1-hydroxybutyl)-4-methylpyrimidin-5-yl)-1-methy l-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)cyclopropanecarboxamide (Compound 11) OH OH OH 1 ₀ ¹¹ [0266] The racemic product of N-(3-(2-(1-hydroxybutyl)-4-methylpyrimidin-5-yl)-1- methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropanec arboxamide (65.0 mg, 0.16 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-6%^^^î^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^^0^1 +3-MeOH)- -HPLC, Mobile Phase B: IPA: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 60% B to 60% B in 16 min; Wave Length: 254/220 nm; RT1(min): 8.75; RT2(min): 12.12) to afford N-(3-(2-(1-hydroxybutyl)-4-methylpyrimidin-5-yl)-1-methyl-2- oxo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropanecarboxamide Enantiomer A (23.7 mg, 72%) as a white solid and N-(3-(2-(1-hydroxybutyl)-4-methylpyrimidin-5-yl)-1-methyl-2- oxo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropanecarboxamide Enantiomer B (22.9 mg, 70%) as a white solid. The absolute stereochemistry of Enantiomer A and Enantiomer B was not assigned. The two enantiomeric structures that could be obtained from chiral separation of the enantiomeric mixtures as described above are shown as Compounds 10 and 11 in Table 1. [0267] Enantiomer A: RT1(min): 8.75; LCMS (ESI, m/z): [M+H] ⁺ = 408.2. ¹ H NMR (400 MHz, DMSO-d6): ¥ 11.18 (s, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 5.12 (d, J = 6.0 Hz, 1H), 4.65 - 4.60 (m, 1H), 3.60 (s, 3H), 2.39 (s, 3H), 2.13- 2.06 (m, 1H), 1.85 - 1.69 (m, 2H), 1.46 - 1.24 (m, 2H), 0.93 - 0.89 (m, 7H). [0268] Enantiomer B: RT2(min): 12.12; LCMS (ESI, m/z): [M+H] ⁺ = 408.2. ¹ H NMR (400 MHz, DMSO-d6^^^į 11.18 (s, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 5.12 (d, J = 6.0 Hz, 1H), 4.65 - 4.60 (m, 1H), 3.60 (s, 3H), 2.39 (s, 3H), 2.13 - 2.07 (m, 1H), 1.85 - 1.68 (m, 2H), 1.44 - 1.24 (m, 2H), 0.93 - 0.87 (m, 7H). Example 7. Synthesis of (R,E)-2,2-difluoro-N-(3-(5-fluoro-6-(1-(hydroxyimino)propyl) -4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 12) Step 1. Synthesis of tert-butyl (3-(5-fluoro-4-methyl-6-propionylpyridin-3-yl)-1-methyl- 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate [0269] To a solution of 7-chloro-3-(5-fluoro-4-methyl-6-propionylpyridin-3-yl)-1- methyl-1,6-naphthyridin-2(1H)-one (800.0 mg, 2.22 mmol) in dioxane (15.0 mL) was added tert-butyl carbamate (777.7 mg, 6.71 mmol), Pd(OAc) ₂ (190.4 mg, 0.23 mmol), XPhos (206.3 mg, 0.46 mmol) and Cs2CO3 (1.5 g, 4.47 mmol) at room temperature under N2. The reaction mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (25/75, v/v) to afford tert-butyl (3-(5- fluoro-4-methyl-6-propionylpyridin-3-yl)-1-methyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7- yl)carbamate (445.0 mg, 45%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 441.3. Step 2. Synthesis of 7-amino-3-(5-fluoro-4-methyl-6-propionylpyridin-3-yl)-1-meth yl- 1,6-naphthyridin-2(1H)-one [0270] To a solution of tert-butyl (3-(5-fluoro-4-methyl-6-propionylpyridin-3-yl)-1- methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate (450.0 mg, 2.31 mmol) in CH ₂ Cl2 (10.0 mL) was added TFA (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The pH value of the residue was adjusted to 8.0 with sat. NaHCO3. The mixture was extracted with CH ₂ Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford 7-amino-3-(5-fluoro-4-methyl-6-propionylpyridin-3-yl)-1-meth yl- 1,6-naphthyridin-2(1H)-one (400.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 341.3. Step 3. Synthesis of (R)-2,2-difluoro-N-(3-(5-fluoro-4-methyl-6-propionylpyridin- 3-yl)- 1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropan e-1-carboxamide [0271] To a solution of 7-amino-3-(5-fluoro-4-methyl-6-propionylpyridin-3-yl)-1- methyl-1,6-naphthyridin-2(1H)-one (200.0 mg, crude) in pyridine (5.0 mL) was added (1R)- 2,2-difluorocyclopropane-1-carboxylic acid (71.7 mg, 0.59 mmol) and EDCI (411.7 mg, 2.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (95/5, v/v) to afford (R)- 2,2-difluoro-N-(3-(5-fluoro-4-methyl-6-propionylpyridin-3-yl )-1-methyl-2-oxo-1,2-dihydro- 1,6-naphthyridin-7-yl)cyclopropane-1-carboxamide (150.0 mg, 57%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 445.3. Step 4. Synthesis of (R,E)-2,2-difluoro-N-(3-(5-fluoro-6-(1-(hydroxyimino)propyl) -4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 12) [0272] To a solution of (R)-2,2-difluoro-N-(3-(5-fluoro-4-methyl-6-propionylpyridin- 3- yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopr opane-1-carboxamide (200.0 mg, 0.47 mmol) in EtOH (10.0 mL) was added pyridine (110.3 mg, 1.41 mmol) and hydroxylamine hydrochloride (34.2 mg, 0.49 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: YMC-$FWXV^7ULDUW^&^^^([56^^^^[^^^^PP^^^^^P^^ Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B in 10 min; Wave Length: 254 nm) to afford (R,E)-2,2- difluoro-N-(3-(5-fluoro-6-(1-(hydroxyimino)propyl)-4-methylp yridin-3-yl)-1-methyl-2-oxo- 1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropane-1-carboxamide (Compound 12) (16.4 mg, 5%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 460.2. ¹ H NMR (400 MHz, CD32'^^^į^ 8.72 (s, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 3.77 (s, 3H), 2.99 - 2.87 (m, 3H), 2.34 (s, 3H), 2.24 - 2.15 (m, 1H), 1.96 - 1.87 (m, 1H), 1.17 - 1.13 (m, 3H). [0273] To a stirred mixture of (1S,2S)-2-fluoro-N-[1-methyl-3-(4-methyl-6- propanoylpyridin-3-yl)-2-oxo-1,6-naphthyridin-7-yl]cycloprop ane-1-carboxamide (100.0 mg, 0.25 mmol) and hydroxylamine hydrochloride (25.5 mg, 0.37 mmol) in EtOH (6.0 mL) was added pyridine (58.1 mg, 0.74 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2 / MeOH (10/1, v/v) and then purified by Prep-HPLC with the following conditions (Column: Xselect &6+^&^^^2%'^&ROXPQ^^^[^^^^PP^^^^^P^^0RELOH^3KDVH ^$^^:DWHU^^^^^^^ FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 60% B in 10 min; Wave Length: 254 nm) to afford (1S,2S)-2-fluoro-N-(3-{6-[(1Z)-1-(hydroxyimino)propyl]-4- methylpyridin-3-yl}-1-methyl-2-oxo-1,6-naphthyridin-7-yl)cyc lopropane-1-carboxamide (Compound 13) (17.1 mg, 16%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 424.1. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^^^s, 1H), 11.24 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 8.26 (s, 1H), 8.06 (d, J = 6.4 Hz, 1H), 7.76 (s, 1H), 5.08 - 4.88 (m, 1H), 3.62 (s, 3H), 2.91 - 2.84 (m, 2H), 2.33 - 2.26 (m, 1H), 2.22 (s, 3H), 1.74 - 1.66 (m, 1H), 1.26 - 1.21 (m, 1H), 1.09 - 1.03 (m, 3H). Example 9. Synthesis of (1R,2R)-2-fluoro-N-(3-{6-[(1Z)-1-(hydroxyimino)propyl]-4- methylpyridin-3-yl}-1-methyl-2-oxo-1,6-naphthyridin-7-yl)cyc lopropane-1-carboxamide (Compound 14) Step 1. Synthesis of (1R,2R)-2-fluoro-N-[1-methyl-3-(4-methyl-6-propanoylpyridin- 3- [0274] To a stirred mixture of 7-chloro-1-methyl-3-(4-methyl-6-propanoylpyridin-3-yl)- 1,6-naphthyridin-2-one (500.0 mg, 1.46 mmol) and (1R,2R)-2-fluorocyclopropane-1- carboxamide (181.0 mg, 1.76 mmol) in dioxane (10.0 mL) were added Pd(OAc) ₂ (65.7 mg, 0.29 mmol), XPhos (69.7 mg, 0.15 mmol) and Cs2CO3 (1429.9 mg, 4.39 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford (1R,2R)- 2-fluoro-N-[1-methyl-3-(4-methyl-6-propanoylpyridin-3-yl)-2- oxo-1,6-naphthyridin-7- yl]cyclopropane-1-carboxamide (140.0 mg, 23%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 409.1. Step 2. Synthesis of (1R,2R)-2-fluoro-N-(3-{6-[(1Z)-1-(hydroxyimino)propyl]-4- methylpyridin-3-yl}-1-methyl-2-oxo-1,6-naphthyridin-7-yl)cyc lopropane-1-carboxamide (Compound 14) [0275] To a stirred mixture of (1R,2R)-2-fluoro-N-[1-methyl-3-(4-methyl-6- propanoylpyridin-3-yl)-2-oxo-1,6-naphthyridin-7-yl]cycloprop ane-1-carboxamide (100.0 mg, 0.25 mmol) and NH ₂ OH ^. HCl (25.5 mg, 0.37 mmol) in EtOH (6.0 mL) was added Pyridine (58.1 mg, 0.74 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (10/1, v/v) and then purified by Prep-HPLC with the following conditions (Column: Xselect &6+^&^^^2%'^&ROXPQ^^^[^^^^PP^^^^^P^^0RELOH^3KDVH ^$^^:DWHU^^^^^^^)$^^^0RELOH^ Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 28% B in 10 min; Wave Length: 254/220 nm) to afford (1R,2R)-2-fluoro-N-(3-{6-[(1Z)-1-(hydroxyimino)propyl]-4- methylpyridin-3-yl}-1-methyl-2-oxo-1,6-naphthyridin-7-yl)cyc lopropane-1-carboxamide (Compound 14) (17.8 mg, 17%) as an off-white solid. LCMS (ESI, m/z): [M+H] ⁺ = 424.2. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^^^V^^^+^^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^ ^^^V^^^+^^^ 8.26 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 5.07 - 4.89 (m, 1H), 3.62 (s, 3H), 2.89 - 2.84 (m, 2H), 2.31 - 2.27 (m, 1H), 2.22 (s, 3H), 1.73 - 1.66 (m, 1H), 1.26 - 1.20 (m, 1H), 1.09 - 1.05 (m, 3H). [0276] To a solution of (R)-2,2-difluoro-N-(1-methyl-3-(4-methyl-6-propionylpyridin- 3- yl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropane-1-c arboxamide (153.0 mg, 0.36 mmol) in EtOH (10.0 mL) was added hydroxylamine hydrochloride (37.4 mg, 0.54 mmol) and pyridine (85.1 mg, 1.08 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (9/1, v/v) and then purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30×^^^^PP^^^^^P^^0RELOH^3KDVH^$^^:DWHU^^^^^PPRO^/^1+4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 40% B in 10 min; Wave Length: 254 nm) to afford (R,Z)-2,2-difluoro-N-(3-(6-(1-(hydroxyimino)propyl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 15) (65.4 mg, 41%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 442.1. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^^^V^^^+^^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^ ^^^V^^ 1H), 8.22 (s, 1H), 8.07 (s, 1H), 7.76 (s, 1H), 3.62 (s, 3H), 3.11 - 3.03 (m, 1H), 2.89 - 2.84 (m, 2H), 2.22 (s, 3H), 2.12 - 2.05 (m, 2H), 1.09 - 1.03 (m, 3H). Example 11. Synthesis of (1R,2R)-2-fluoro-N-(3-(6-((R)-1-hydroxybut-3-en-1-yl-1-d)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 16) and (1R,2R)-2-fluoro-N-(3-(6-((S)-1-hydroxybut-3-en-1-yl-1- d)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naph thyridin-7-yl)cyclopropane- 1-carboxamide (Compound 17) Step 1. Synthesis of (5-bromo-4-methylpyridin-2-yl)methan-d2-ol [0277] To a stirred solution of methyl 5-bromo-4-methylpyridine-2-carboxylate (5.0 g, 21.73 mmol) in CD3OH (2.6 mL) and THF (26.0 mL) was added NaBD4 (1.6 g, 43.47 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h under N2. After the reaction was completed, the reaction mixture was quenched with water at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford (5-bromo-4-methylpyridin-2-yl)methan-d2-ol (3.2 g, 72%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 204.0 Step 2. Synthesis of (5-bromo-4-methylpyridin-2-yl)formaldehyde-d1 [0278] To a stirred mixture of (5-bromo-4-methylpyridin-2-yl)methan-d2-ol (3.0 g, 14.70 mmol) in EtOAc (30.0 mL) was added IBX (8.2 g, 29.40 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford (5-bromo-4-methylpyridin-2-yl)formaldehyde-d1 (2.4 g, 81%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 201.0 Step 3. Synthesis of 1-(5-bromo-4-methylpyridin-2-yl)but-3-en-1-d-1-ol [0279] To a stirred mixture of (5-bromo-4-methylpyridin-2-yl)formaldehyde-d1 (1.5 g, 2.49 mmol) in tetrahydrofuran (20.0 mL) was added dropwise allylmagnesium bromide (9.0 mL, 1 mol/L in THF) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h under N2. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (3/1, v/v) to afford 1-(5-bromo-4-methylpyridin-2-yl)but-3-en-1-d-1-ol (750.0 mg, 41%) as a light yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 243.0 Step 4. Synthesis of 7-chloro-3-(6-(1-hydroxybut-3-en-1-yl-1-d)-4-methylpyridin-3 -yl)-1- methyl-1,6-naphthyridin-2(1H)-one [0280] To a stirred mixture of 1-(5-bromo-4-methylpyridin-2-yl)but-3-en-1-d-1-ol (750.0 mg, 3.09 mmol) and 7-chloro-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,6- naphthyridin-2-one (1.2 g, 3.70 mmol) in dioxane (10.0 mL) and H2O (2.0 mL) were added Pd(dppf)Cl2 (451.5 mg, 0.62 mmol) and KOAc (908.3 mg, 9.26 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (10/1, v/v) to afford 7-chloro-3-(6-(1- hydroxybut-3-en-1-yl-1-d)-4-methylpyridin-3-yl)-1-methyl-1,6 -naphthyridin-2(1H)-one (350.0 mg, 31%) as a red solid. LCMS (ESI, m/z): [M+H] ⁺ = 357.0. Step 5. Synthesis of (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl-1-d)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- [0281] To a stirred mixture of 7-chloro-3-(6-(1-hydroxybut-3-en-1-yl-1-d)-4- methylpyridin-3-yl)-1-methyl-1,6-naphthyridin-2(1H)-one (350.0 mg, 0.98 mmol) and (1R,2R)-2-fluorocyclopropane-1-carboxamide (303.4 mg, 2.94 mmol) in dioxane (10.0 mL) were added Brettphos Pd G3 (88.9 mg, 0.10 mmol), Brettphos (105.3 mg, 0.19 mmol) and Cs2CO3 (958.8 mg, 2.94 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (5/1, v/v) to afford (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl-1-d)-4-meth ylpyridin- 3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclo propane-1-carboxamide (80.0 mg, 19%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 424.1. Step 6. Chiral Separation of (1R,2R)-2-fluoro-N-(3-(6-((R)-1-hydroxybut-3-en-1-yl-1-d)- 4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthy ridin-7-yl)cyclopropane- 1-carboxamide (Compound 16) and (1R,2R)-2-fluoro-N-(3-(6-((S)-1-hydroxybut-3-en-1- yl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-7- yl)cyclopropane-1-carboxamide (Compound 17) 16 17 [0282] The product of (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl-1-d)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (80.0 mg, 0.19mmol) was separated by Prep-Chiral-HPLC with the following conditions ^&ROXPQ^^&+,5$/3$.^,+^^^[^^^FP^^^^^P^^0RELOH^3KDVH^$ ^^+H[^^^^^^^^0^ NH3-MeOH)--HPLC, Mobile Phase B: IPA: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 22 min; Wave Length: 254/220 nm; RT1(min): 12.39; RT2(min): 18.64) to afford (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl-1-d)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide Isomer A (7.8 mg, 19%) as a white solid and (1R,2R)-2-fluoro-N-(3-(6-(1- hydroxybut-3-en-1-yl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-o xo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropane-1-carboxamide Isomer B (9.1 mg, 22%) as a white solid. The absolute stereochemistry of Isomer A and Isomer B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixtures as described above are shown as Compounds 16 and 17 in Table 1. [0283] Isomer A: RT1(min): 12.39, LCMS (ESI, m/z): [M+H] ⁺ = 424.1. ¹ H NMR (400 MHz, DMSO-d6): ¥ 11.22 (s, 1H), 8.72 (s, 1H), 8.28 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.41 (s, 1H), 5.91 - 5.80 (m, 1H), 5.46 (s, 1H), 5.09 - 4.87 (m, 3H), 3.61 (s, 3H), 2.61 - 2.55 (m, 1H), 2.44 - 2.39 (m, 1H), 2.33 - 2.25 (m, 1H), 2.21 (s, 3H), 1.74 - 1.64 (m, 1H), 1.26 - 1.19 (m, 1H). [0284] Isomer B: RT2(min): 18.64, LCMS (ESI, m/z): [M+H] ⁺ = 424.1. ¹ H NMR (400 MHz, DMSO-d6^^^į 11.22 (s, 1H), 8.72 (s, 1H), 8.28 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.42 (s, 1H), 5.91 - 5.80 (m, 1H), 5.46 (s, 1H), 5.08 - 4.87 (m, 3H), 3.61 (s, 3H), 2.60 - 2.55 (m, 1H), 2.44 - 2.38 (m, 1H), 2.32 - 2.25 (m, 1H), 2.21 (s, 3H), 1.74 - 1.63 (m, 1H), 1.27 - 1.19 (m, 1H). 18 [0285] To a solution of (1R,2R)-N-(3-(6-butyryl-4-methylpyridin-3-yl)-1-methyl-2-oxo - 1,2-dihydro-1,6-naphthyridin-7-yl)-2-fluorocyclopropane-1-ca rboxamide (100.0 mg, 0.24 mmol) in EtOH (10.0 mL) was added pyridine (56.2 mg, 0.71 mmol) and hydroxylamine hydrochloride (11.7 mg, 0.35 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: ;%ULGJH^3UHS^2%'^&^^^&ROXPQ^^^^[^^^^PP^^^^^P^^0RELOH ^3KDVH^$^^:DWHU^^^^^PPRO^/^ NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 43% B in 8 min; Wave Length: 220 nm) to afford (1R,2R)-2-fluoro-N-(3-(6-((E)-1- (hydroxyimino)butyl)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1, 2-dihydro-1,6-naphthyridin- 7-yl)cyclopropane-1-carboxamide (Compound 18) (32.4 mg, 31%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 438.2. ¹ H NMR (400 MHz, DMSO-d6^^^į^11.41 (s, 1H), 11.21 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 8.26 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 5.08 - 4.88 (m, 1H), 3.62 (s, 3H), 2.88 - 2.84 (m, 2H), 2.33 - 2.26 (m, 1H), 2.22 (s, 3H), 1.76 - 1.71 (m, 1H), 1.69 - 1.55 (m, 2H), 1.28 - 1.15 (m, 1H), 0.93 - 0.88 (m, 3H). Example 13. Synthesis of (1R,2R)-2-fluoro-N-(3-(5-fluoro-6-((E)-1-(hydroxyimino)propy l)- 4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthy ridin-7-yl)cyclopropane-1- carboxamide (Compound 19) Step 1. Synthesis of (1R,2R)-2-fluoro-N-(3-(5-fluoro-4-methyl-6-propionylpyridin- 3-yl)- 1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropan e-1-carboxamide [0286] To a solution of 7-chloro-3-(5-fluoro-4-methyl-6-propionylpyridin-3-yl)-1- methyl-1,6-naphthyridin-2(1H)-one (300.0 mg, 0.92 mmol) in 1,4-dioxane (12.0 mL) was added (1R,2R)-2-fluorocyclopropane-1-carboxamide (142.5 mg, 1.82 mmol), Pd(OAc) ₂ (84.2 mg, 0.10 mmol), Xphos (105.4 mg, 0.20 mmol) and Cs2CO3 (840.0 mg, 2.21 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (10/90, v/v) to afford (1R,2R)-2-fluoro-N-(3-(5-fluoro-4- methyl-6-propionylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7- yl)cyclopropane-1-carboxamide (184.0 mg, 50%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 427.1. Step 2. Synthesis of (1R,2R)-2-fluoro-N-(3-(5-fluoro-6-((E)-1-(hydroxyimino)propy l)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide formate (Compound 19) [0287] To a solution of (1R,2R)-2-fluoro-N-(3-(5-fluoro-4-methyl-6-propionylpyridin- 3- yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopr opane-1-carboxamide (200.0 mg, 0.47 mmol) in EtOH (10.0 mL) was added pyridine (110.3 mg, 1.41 mmol) and hydroxylamine hydrochloride (34.2 mg, 0.49 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with ACN/H2O (0.5% FA) (87/13, v/v) to afford (1R,2R)-2-fluoro-N- (3-(5-fluoro-6-((E)-1-(hydroxyimino)propyl)-4-methylpyridin- 3-yl)-1-methyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)cyclopropane-1-carboxamide formate (Compound 19) (11.5 mg, 4%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 442.2. ¹ H NMR (400 MHz, DMSO- d6^^^į^11.43 (s, 1H), 11.21 (s, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 5.08 - 4.88 (m, 1H), 3.62 (s, 3H), 2.88 - 2.83 (m, 2H), 2.31 - 2.28 (m, 1H), 2.22 (s, 3H), 1.76 - 1.66 (m, 1H), 1.28 - 1.22 (m, 1H), 1.10 - 1.02 (m, 3H). Example 14. Synthesis of (1S,2S)-2-fluoro-N-(3-(5-fluoro-6-((E)-1-(hydroxyimino)propy l)- 4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthy ridin-7-yl)cyclopropane-1- carboxamide formate (Compound 20) Step 1. Synthesis of 2-bromo-5-chloro-3-fluoro-4-methylpyridine [0288] The solution of 2-bromo-5-chloro-3-fluoropyridine (10.0 g, 39.23 mmol) in THF (500.0 mL) was dropwise added LDA (29.4 mL, 2.0 mol/L) at - 65 °C under N2. The resulting mixture was stirred at -65 °C for 0.5 h under N2. Then CH ₃ I (6.7 g, 47.08 mmol) was added to the mixture at -65 °C under N2. The resulting mixture was stirred at - 65 °C for additional 1 h. After the reaction was completed, the reaction mixture was quenched with sat. NH4Cl (aq.) at -65 °C and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (60/40, v/v) to afford 2-bromo-5-chloro- 3-fluoro-4-methylpyridine (6.5 g, 62%) as a light brown solid. LCMS (ESI, m/z): [M+H] ⁺ =224.1. Step 2. Synthesis of 1-(5-chloro-3-fluoro-4-methylpyridin-2-yl)propan-1-one [0289] To a solution of 2-bromo-5-chloro-3-fluoro-4-methylpyridine (1.0 g, 3.72 mmol) in THF (15.0 mL) was dropwise added n-BuLi (1.5 mL, 2.5 mol/L) at - 65 °C under N2. The resulting mixture was stirred at - 65 °C for 0.5 h. Then N-methoxy-N-methylpropionamide (647.9 mg, 11.16 mmol) was added to the mixture at -65 °C under N2. The resulting mixture was stirred at -65 °C for additional 0.5 h under N2. After the reaction was completed, the reaction mixture was quenched with sat. NH4Cl (aq.) at -65 °C and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (70/30, v/v) to afford 1-(5-chloro-3-fluoro-4-methylpyridin-2-yl)propan-1-one (350.0 mg, 37%) as a colorless oil. LCMS (ESI, m/z): [M+H] ⁺ =202.0. Step 3. Synthesis of 7-chloro-3-(5-fluoro-4-methyl-6-propionylpyridin-3-yl)-1-met hyl- 1,6-naphthyridin-2(1H)-one dioxane, H _{2O, K3} PO ₄ [0290] To a solution of 7-chloro-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2- yl)-1,6-naphthyridin-2(1H)-one (500.0 mg, 1.56 mmol) in 1,4-dioxane (15.0 mL) and H2O (3.0 mL) was added 1-(5-chloro-3-fluoro-4-methylpyridin-2-yl)propan-1-one (313.5 mg, 1.56 mmol), K3PO4 (992.2 mg, 4.68 mmol), XPhos (143.3 mg, 0.30 mmol) and XPhos Pd G3 (126.3 mg, 0.15 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford 7-chloro-3-(5- fluoro-4-methyl-6-propionylpyridin-3-yl)-1-methyl-1,6-naphth yridin-2(1H)-one (275.0 mg, 49%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ =360.2. Step 4. Synthesis of (1S,2S)-2-fluoro-N-(3-(5-fluoro-4-methyl-6-propionylpyridin- 3-yl)- 1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropan e-1-carboxamide [0291] To a solution of 7-chloro-3-(5-fluoro-4-methyl-6-propionylpyridin-3-yl)-1- methyl-1,6-naphthyridin-2(1H)-one (150.0 mg, 0.45 mmol) in 1,4-dioxane (8.0 mL) was added (1S,2S)-2-fluorocyclopropane-1-carboxamide (77.5 mg, 0.91 mmol), Pd(OAc) ₂ (42.0 mg, 0.05 mmol), Xphos (52.7 mg, 0.10 mmol) and Cs2CO3 (420.0 mg, 1.10 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (15/85, v/v) to afford (1S,2S)-2-fluoro-N-(3-(5-fluoro-4- methyl-6-propionylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7- yl)cyclopropane-1-carboxamide (79.0 mg, 49%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 427.1. Step 5. Synthesis of (1S,2S)-2-fluoro-N-(3-(5-fluoro-6-((E)-1-(hydroxyimino)propy l)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide formate (Compound 20) [0292] To a solution of (1S,2S)-2-fluoro-N-(3-(5-fluoro-4-methyl-6-propionylpyridin- 3- yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopr opane-1-carboxamide (200.0 mg, 0.47 mmol) in EtOH (10.0 mL) was added pyridine (110.3 mg, 1.41 mmol) and hydroxylamine hydrochloride (34.2 mg, 0.49 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with ACN/H2O (0.5% FA) (85/15, v/v) to afford (1S,2S)-2-fluoro-N- (3-(5-fluoro-6-((E)-1-(hydroxyimino)propyl)-4-methylpyridin- 3-yl)-1-methyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)cyclopropane-1-carboxamide formate (Compound 20) (14.3 mg, 4%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 442.1. ¹ H NMR (400 MHz, DMSO- d6^^^į^11.43 (s, 1H), 11.21 (s, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 5.08 - 4.88 (m, 1H), 3.62 (s, 3H), 2.88 - 2.85 (m, 2H), 2.31 - 2.26 (m, 1H), 2.22 (s, 3H), 1.75 - 1.66 (m, 1H), 1.28 - 1.21 (m, 1H), 1.09 - 1.06 (m, 3H). Example 15. Synthesis of (1R,2R)-2-fluoro-N-(3-(6-((S,E)-1-hydroxybut-2-en-1-yl-1-d)- 4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 21), (1R,2R)-2-fluoro-N-(3-(6-((R,E)-1-hydroxybut-2-en-1-yl-1- d)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naph thyridin-7-yl)cyclopropane- 1-carboxamide (Compound 22), and (1R,2R)-2-fluoro-N-(3-(6-((S,Z)-1-hydroxybut-2-en-1- yl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-7- yl)cyclopropane-1-carboxamide (Compound 23), and (1R,2R)-2-fluoro-N-(3-(6-((R,Z)-1- hydroxybut-2-en-1-yl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-o xo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropane-1-carboxamide (Compound 24) Step 1. Synthesis of 1-(5-bromo-4-methylpyridin-2-yl)but-2-en-1-d-1-ol [0293] To a stirred mixture of 5-bromo-4-methylpyridin-2-yl)(2H)formaldehyde (2.0 g, 9.94 mmol) in tetrahydrofuran (20.0 mL) was added dropwise bromo((1E)-prop-1-en-1- yl)magnesium (24.0 mL, 0.5 mol/L in THF) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h under N2. After the reaction was completed, the reaction mixture was quenched with water at 0 °C and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (5/5, v/v) to afford 1-(5-bromo-4- methylpyridin-2-yl)but-2-en-1-d-1-ol (1.8 g, 74%) as a yellow oil. LCMS (ESI, m/z): [M+H] ⁺ = 243.1. Step 2. Synthesis of 5-bromo-2-(1-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl-1-d )-4- methylpyridine [0294] To a stirred mixture of 1-(5-bromo-4-methylpyridin-2-yl)but-2-en-1-d-1-ol (1.6 g, 6.42 mmol) and t-butyldimethylchlorosilane (1.9 g, 12.85 mmol) in DCM (20.0 mL) was added imidazole (1.7 g, 25.7 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (7/3, v/v) to afford 5-bromo-2-(1-((tert- butyldimethylsilyl)oxy)but-2-en-1-yl-1-d)-4-methylpyridine (2.0 g, 85%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 357.1. Step 3. Synthesis of 3-(6-(1-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl-1-d)-4- methylpyridin-3-yl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H) -one dioxane, H ₂ O [0295] To a stirred mixture of 5-bromo-2-(1-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl- 1-d)-4-methylpyridine (1.0 g, 2.80 mmol) and 7-chloro-1-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,6-naphthyridin-2(1H)-one (1.3 g, 4.20 mmol) in 1,4-dioxane (20.0 mL) and H2O (4.0 mL) was added KOAc (1.1 g, 8.38 mmol) and Pd(dppf)Cl2 (455.8 mg, 0.56 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (6/4, v/v) to afford 3-(6-(1-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl-1-d)-4-m ethylpyridin-3-yl)-7- chloro-1-methyl-1,6-naphthyridin-2(1H)-one (400.0 mg, 30%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 471.2. Step 4. Synthesis of (1R,2R)-N-(3-(6-(1-((tert-butyldimethylsilyl)oxy)but-2-en-1- yl-1-d)- 4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthy ridin-7-yl)-2- fluorocyclopropane-1-carboxamide [0296] To a stirred mixture of 3-(6-(1-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl-1-d)-4- methylpyridin-3-yl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H) -one (340.0 mg, 0.64 mmol) and (1R,2R)-2-fluorocyclopropane-1-carboxamide (328.3 mg, 3.18 mmol) in 1,4-dioxane (10.0 mL) was added Cs2CO3 (622.5 mg, 1.91 mmol), XPhos (121.4 mg, 0.25 mmol) and Pd2(dba)3 (116.6 mg, 0.13 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5/5, v/v) to afford (1R,2R)-N-(3-(6-(1-((tert-butyldimethylsilyl)oxy)but-2-en-1- yl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-7-yl)-2- fluorocyclopropane-1-carboxamide (300.0 mg, 77%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 538.3. Step 5. Synthesis of (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-2-en-1-yl-1-d)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide [0297] To a stirred mixture of (1R,2R)-N-(3-(6-(1-((tert-butyldimethylsilyl)oxy)but-2-en- 1-yl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7-yl)-2- fluorocyclopropane-1-carboxamide (200.0 mg, 0.37 mmol) in THF (6.0 mL) was added TBAF (195.4 mg, 0.75 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 4 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (10/1, v/v) to afford (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-2-en-1-yl-1-d)-4-meth ylpyridin-3-yl)-1- methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropane- 1-carboxamide (Compounds 23, 24, 25, and 26) (140.0 mg, 88%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 424.2 Step 6. Chiral Separation of (1R,2R)-2-fluoro-N-(3-(6-((S,E)-1-hydroxybut-2-en-1-yl-1- d)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naph thyridin-7- yl)cyclopropane-1-carboxamide (Compound 21), (1R,2R)-2-fluoro-N-(3-(6-((R,E)-1- hydroxybut-2-en-1-yl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-o xo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropane-1-carboxamide (Compound 22), and (1R,2R)-2-fluoro- N-(3-(6-((S,Z)-1-hydroxybut-2-en-1-yl-1-d)-4-methylpyridin-3 -yl)-1-methyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)cyclopropane-1-carboxamide (Compound 23), and (1R,2R)-2-fluoro-N-(3-(6-((R,Z)-1-hydroxybut-2-en-1-yl-1-d)- 4-methylpyridin-3-yl)-1- methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropane- 1-carboxamide (Com [0298] The product of (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-2-en-1-yl-1-d)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (140.0 mg, 0.33 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: Lux 5um Cellulose-^^^^^^^[^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^ 2M NH3-MeOH)--HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 85% B to 85% B in 19 min; Wave Length: 254 nm; RT1(min): 22.19; RT2(min): 24.31, RT3(min): 26.00, RT4(min): 30.96) to afford (1R,2R)-2-fluoro-N-(3-(6-(1- hydroxybut-2-en-1-yl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-o xo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropane-1-carboxamide Isomer A (7.4 mg, 10%) as a white solid, (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-2-en-1-yl-1-d)-4-meth ylpyridin-3-yl)-1-methyl-2- oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopropane-1-carboxa mide Isomer B (7.2 mg, 10%) as a white solid, (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-2-en-1-yl-1-d)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide Isomer C (43.5 mg, 62%) as a white solid and (1R,2R)-2-fluoro-N-(3-(6-(1- hydroxybut-2-en-1-yl-1-d)-4-methylpyridin-3-yl)-1-methyl-2-o xo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropane-1-carboxamide Isomer D (43.2 mg, 62%) as a white solid. The absolute stereochemistry of Isomers A-D was not assigned. The four isomeric structures that could be obtained from chiral separation of the isomeric mixtures as described above are shown as Compounds 21, 22, 23, and 24 in Table 1. [0299] Isomer A: RT2 (min): 24.31; LCMS (ESI, m/z): [M+H] ⁺ = 424.1. ¹ H NMR (400 MHz, DMSO-d6^^^į 8.69 (s, 1H), 8.19 - 8.16 (m, 2H), 7.94 (s, 1H), 7.37 (s, 1H), 5.74 - 5.69 (m, 1H), 5.62 - 5.58 (m, 1H), 5.03 - 4.83 (m, 1H), 3.58 (s, 3H), 2.24 - 2.15 (m, 4H), 1.74 - 1.61 (m, 4H), 1.27 - 1.18 (m, 1H). [0300] Isomer B: RT4 (min): 30.96; LCMS (ESI, m/z): [M+H] ⁺ = 424.1. ¹ H NMR (400 MHz, DMSO-d6^^^į 11.20 (s, 1H), 8.72 (s, 1H), 8.26 - 8.25 (m, 2H), 8.00 (s, 1H), 7.38 (s, 1H), 5.76 - 5.63 (m, 2H), 5.53 (s, 1H), 5.09 - 4.87 (m, 1H), 3.62 (s, 3H), 2.34 - 2.25 (m, 1H), 2.20 (s, 3H), 1.78 - 1.65 (m, 4H), 1.28 - 1.19 (m, 1H). [0301] Isomer C: RT1 (min): 22.19; LCMS (ESI, m/z): [M+H] ⁺ = 424.1. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^ (s, 1H), 8.24 - 8.22 (m, 2H), 7.98 (s, 1H), 7.39 (s, 1H), 5.58 - 5.49 (m, 2H), 5.07 - 4.85 (m, 1H), 3.61 (s, 3H), 2.31 - 2.23 (m, 1H), 2.20 (s, 3H), 1.79 - 1.64 (m, 4H), 1.27 - 1.20 (m, 1H). [0302] Isomer D: RT3 (min): 26.00; LCMS (ESI, m/z): [M+H] ⁺ = 424.1. ¹ H NMR (400 MHz, DMSO-d6^^^į 11.20 (s, 1H), 8.72 (s, 1H), 8.26 - 8.25 (m, 2H), 8.01 (s, 1H), 7.40 (s, 1H), 5.58 - 5.48 (m, 3H), 5.09 - 4.87 (m, 1H), 3.61 (s, 3H), 2.34 - 2.27 (m, 1H), 2.20 (s, 3H), 1.81 - 1.65 (m, 4H), 1.28 - 1.19 (m, 1H). Example 16. Synthesis of (1R,2R)-2-fluoro-N-(3-(6-((S)-1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 25) and (1R,2R)-2-fluoro-N-(3-(6-((R)-1-hydroxybut-3-en-1-yl)- 4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthy ridin-7-yl)cyclopropane-1- carboxamide (Compound 26) Step 1. Synthesis of 1-(5-bromo-4-methylpyridin-2-yl)but-3-en-1-ol [0303] To a stirred solution of 5-bromo-4-methylpyridine-2-carbaldehyde (9.0 g, 45.00 mmol) in ACN (500.0 mL) was added tributyl(prop-2-en-1-yl)stannane (14.9 g, 45.00 mmol) and SnCl2 (12.9 g, 67.49 mmol) at 0 ^o C under N2. The resulting mixture was stirred at room temperature for 15 min. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (1/1, v/v) to afford 1-(5-bromo-4-methylpyridin-2-yl)but-3-en-1-ol (8.3 g, 76%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 242.0. Step 2. Synthesis of 5-bromo-2-{1-[(tert-butyldimethylsilyl)oxy]but-3-en-1-yl}-4- methylpyridine [0304] To a stirred solution of 1-(5-bromo-4-methylpyridin-2-yl)but-3-en-1-ol (8.3 g, 34.28 mmol) in DCM (100.0 mL) was added t-butyldimethylchlorosilane (15.5 g, 102.84 mmol) and 1H-imidazole (11.7 g, 171.41 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford 5-bromo-2-{1-[(tert- butyldimethylsilyl)oxy]but-3-en-1-yl}-4-methylpyridine (10.0 g, 81%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 356.1. Step 3. Synthesis of 3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-4-methy lpyridin- 3-yl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one [0305] To a solution of 5-bromo-2-{1-[(tert-butyldimethylsilyl)oxy]but-3-en-1-yl}-4- methylpyridine (2.0 g, 5.61 mmol) in dioxane (15.0 mL) and H ² O (3.0 mL) was added 7- chloro-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,6-naphthyridin-2-one (2.7 g, 8.42 mmol), Pd(dppf)Cl2 (0.8 g, 1.12 mmol) and KOAc (1.7 g, 16.84 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (1/1, v/v) to afford 3-(6-{1-[(tert-butyldimethylsilyl)oxy]but-3-en-1-yl}-4-methy lpyridin-3-yl)-7-chloro- 1-methyl-1,6-naphthyridin-2-one (850.0 mg, 32% ) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 470.2. Step 4. Synthesis of (1R,2R)-N-[3-(6-{1-[(tert-butyldimethylsilyl)oxy]but-3-en-1- yl}-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,6-naphthyridin-7-yl]-2- fluorocyclopropane-1- carboxamide [0306] To a solution of 3-(6-{1-[(tert-butyldimethylsilyl)oxy]but-3-en-1-yl}-4- methylpyridin-3-yl)-7-chloro-1-methyl-1,6-naphthyridin-2-one (500.0 mg, 1.06 mmol) in dioxane (10.0 mL) was added (1R,2R)-2-fluorocyclopropane-1-carboxamide (329.0 mg, 3.19 mmol), Pd2(dba)3 (194.8 mg, 0.21 mmol), Cs2CO3 (1039.7 mg, 3.19 mmol) and XPhos (202.8 mg, 0.43 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate/petroleum ether (1/1, v/v) to afford (1R,2R)-N-[3-(6-{1-[(tert- butyldimethylsilyl)oxy]but-3-en-1-yl}-4-methylpyridin-3-yl)- 1-methyl-2-oxo-1,6- naphthyridin-7-yl]-2-fluorocyclopropane-1-carboxamide (150.0 mg, 26%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 537.3. Step 5. Synthesis of (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpy ridin- 3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclo propane-1-carboxamide [0307] To a stirred mixture of (1R,2R)-N-[3-(6-{1-[(tert-butyldimethylsilyl)oxy]but-3- en-1-yl}-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,6-naphthyrid in-7-yl]-2- fluorocyclopropane-1-carboxamide (130.0 mg, 0.24 mmol) in THF (8.0 mL) was added TBAF (126.7 mg, 0.48 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH ₂ Cl2/MeOH (9/1, v/v) to afford (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpy ridin-3- yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopr opane-1-carboxamide (70.0 mg, 68%) as a yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 423.2. Step 6. Chiral Separation of (1R,2R)-2-fluoro-N-(3-(6-((S)-1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 25) and (1R,2R)-2-fluoro-N-(3-(6-((R)-1-hydroxybut-3-en-1- yl)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-nap hthyridin-7- yl)cyclopropane-1-carboxamide (Compound 26) [0308] The product of (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (70.0 mg, 0.17 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: Lux 5um Cellulose-^^^^^^^î^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^ 2M NH3-MeOH)--HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 18 min; Wave Length: 254/220 nm; RT1(min): 14.74; RT2(min): 17.28) to afford (1R,2R)-2-fluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide Isomer A (15.6 mg, 44%) as a white solid and (1R,2R)-2-fluoro-N-(3-(6-(1- hydroxybut-3-en-1-yl)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1 ,2-dihydro-1,6-naphthyridin- 7-yl)cyclopropane-1-carboxamide Isomer B (18.4 mg, 52%) as a white solid. The absolute stereochemistry of Isomer A and Isomer B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixtures as described above are shown as Compounds 25 and 26 in Table 1. [0309] Isomer A: RT1(min): 14.74; LCMS (ESI, m/z): [M+H] ⁺ = 423.2. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^- 8.26 (m, 2H), 8.02 (s, 1H), 7.41 (s, 1H), 5.92 - 5.81 (m, 1H), 5.46 (d, J = 4.8 Hz, 1H), 5.09 - 4.90 (m, 3H), 4.67 - 4.63 (m, 1H), 3.62 (s, 3H), 2.62 - 2.57 (m, 1H), 2.46 - 2.39 (m, 1H), 2.31 - 2.28 (m, 1H), 2.21 (s, 3H), 1.74 - 1.67 (m, 1H), 1.31 - 1.19 (m, 1H). [0310] Isomer B: RT2(min): 17.28; LCMS (ESI, m/z): [M+H] ⁺ = 423.2. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^- 8.26 (m, 2H), 8.02 (s, 1H), 7.41 (s, 1H), 5.92 - 5.81 (m, 1H), 5.46 (d, J = 4.8 Hz, 1H), 5.09 - 4.88 (m, 3H), 4.68 - 4.63 (m, 1H), 3.62 (s, 3H), 2.63 - 2.56 (m, 1H), 2.46 - 2.39 (m, 1H), 2.33 - 2.28 (m, 1H), 2.21 (s, 3H), 1.76 - 1.66 (m, 1H), 1.28 - 1.19 (m, 1H). Example 17. Synthesis of (S)-2,2-difluoro-N-(3-(6-((R)-1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 27), (R)-2,2-difluoro-N-(3-(6-((R)-1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 28), (S)-2,2-difluoro-N-(3-(6-((S)-1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide(Compound 29), and (R)-2,2-difluoro-N-(3-(6-((S)-1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 30) Step 1. Synthesis of tert-butyl (3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)carbamate [0311] To a solution of 3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-4- methylpyridin-3-yl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H) -one (1.3 g, 2.76 mmol) in dioxane (13.0 mL) was added tert-butyl carbamate (0.9 g, 8.29 mmol), K2CO3 (1.1 g, 8.29 mmol), XPhos (0.3 g, 0.5 mmol, 0.2 equiv) and Pd(OAc) ₂ (0.25 g, 1.106 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 12 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (3/1, v/v) to afford tert-butyl (3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-4-meth ylpyridin-3-yl)- 1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate (900.0 mg, 59%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 551.3. Step 2. Synthesis of 7-amino-3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl) -4- methylpyridin-3-yl)-1-methyl-1,6-naphthyridin-2(1H)-one [0312] To a solution of tert-butyl (3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)carbamate (900.0 mg, 1.63 mmol) in DCM (8.0 mL) was added TFA (4.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the resulting mixture was neutralized to pH = 8 with saturated NaHCO3 (aq). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (10/1, v/v) to afford 7-amino-3-(6-(1-((tert- butyldimethylsilyl)oxy)but-3-en-1-yl)-4-methylpyridin-3-yl)- 1-methyl-1,6-naphthyridin- 2(1H)-one (700.0 mg, 95%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 451.2. Step 3. Synthesis of N-(3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)-2,2- difluorocyclopropane-1-carboxamide [0313] To a solution of 7-amino-3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl) -4- methylpyridin-3-yl)-1-methyl-1,6-naphthyridin-2(1H)-one (300.0 mg, 0.66 mmol) in pyridine (4.0 mL) was added (R)-2,2-difluorocyclopropane-1-carboxylic acid (162.5 mg, 1.33 mmol) and POCl3 (0.75 mL, 8.05 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The mixture was purified by flash column chromatography with petroleum ether/ethyl acetate (1/1, v/v) to afford N-(3-(6-(1-((tert-butyldimethylsilyl)oxy)but- 3-en-1-yl)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro- 1,6-naphthyridin-7-yl)-2,2- difluorocyclopropane-1-carboxamide (150.0 mg, 40%) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ = 555.3. Step 4. Synthesis of 2,2-difluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpyridi n-3- yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopr opane-1-carboxamide [0314] To a solution of N-(3-(6-(1-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)-2,2- difluorocyclopropane-1-carboxamide (150.0 mg, 0.27 mmol) in THF (4.0 mL) was added TBAF (141.4 mg, 0.54 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane/methanol (10/1, v/v) to afford 2,2-difluoro-N-(3-(6-(1-hydroxybut-3-en-1- yl)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-nap hthyridin-7-yl)cyclopropane- 1-carboxamide (100.0 mg, 83%) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ = 441.1. Step 5. Chiral Separation of (S)-2,2-difluoro-N-(3-(6-((R)-1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 27), (R)-2,2-difluoro-N-(3-(6-((R)-1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide (Compound 28), (S)-2,2-difluoro-N-(3-(6-((S)-1-hydroxybut-3-en-1-yl)-4- methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyri din-7-yl)cyclopropane-1- carboxamide(Compound 29), and (R)-2,2-difluoro-N-(3-(6-((S)-1-hydroxybut-3-en-1-yl)- 4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthy ridin-7-yl)cyclopropane- 1-c [0315] The product of 2,2-difluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpyridi n-3- yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)cyclopr opane-1-carboxamide (110.0 mg, 0.12 mmol) was separated by Prep-Chiral-HPLC with the following conditions (Column: Lux 5um Cellulose-2, 2.12x^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^0^1+3-MeOH)-- HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20 mL/min˅ Gradient: 70% B to 70% B in 22 min; Wave Length: 220/254 nm; RT1(min): 6.92; RT2(min): 7.71; RT3(min): 14.52; RT4(min): 18.23) to afford 2,2-difluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)- 4-methylpyridin-3-yl)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthy ridin-7-yl)cyclopropane-1- carboxamide Isomer A (17.0 mg, 68%) as a white solid and 2,2-difluoro-N-(3-(6-(1- hydroxybut-3-en-1-yl)-4-methylpyridin-3-yl)-1-methyl-2-oxo-1 ,2-dihydro-1,6-naphthyridin- 7-yl)cyclopropane-1-carboxamide Isomer B (9.3 mg, 37%) as a white solid and 2,2-difluoro- N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpyridin-3-yl)-1-met hyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)cyclopropane-1-carboxamide Isomer C (9.7 mg, 38%) as a white solid and 2,2-difluoro-N-(3-(6-(1-hydroxybut-3-en-1-yl)-4-methylpyridi n-3-yl)-1-methyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)cyclopropane-1-carboxamide Isomer D (20.8 mg, 83%) as a white solid. The absolute stereochemistry of Isomers A-D was not assigned. The four isomeric structures that could be obtained from chiral separation of the isomeric mixtures as described above are shown as Compounds 27, 28, 29, and 30 in Table 1. [0316] Isomer A: RT1(min): 6.92; LCMS (ESI, m/z): [M+H] ⁺ = 441.1. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^ (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.41 (s, 1H), 5.91 - 5.80 (m, 1H), 5.45 (d, J = 5.2 Hz, 1H), 5.09 - 4.99 (m, 2H), 4.67 - 4.62 (m, 1H), 3.61 (s, 3H), 3.10 - 3.03 (m, 1H), 2.62 - 2.56 (m, 1H), 2.45 - 2.37 (m, 1H), 2.20 (s, 3H), 2.11 - 2.04 (m, 2H). [0317] Isomer B: RT2(min): 7.71; LCMS (ESI, m/z): [M+H] ⁺ = 441.1. ¹ H NMR (400 MHz, DMSO- d6^^^į^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^V^^ ^+^^^^^^^^^V^^^+^^^^^^^^ (s, 1H), 5.91 - 5.82 (m, 1H), 5.42 (d, J = 6.8 Hz, 1H), 5.10 - 4.99 (m, 2H), 4.68 - 4.62 (m, 1H), 3.61 (s, 3H), 3.10 - 3.05 (m, 1H), 2.62 - 2.56 (m, 1H), 2.46 - 2.40 (m, 1H), 2.21 (s, 3H), 2.11 - 2.04 (m, 2H). [0318] Isomer C: RT3(min): 14.52; LCMS (ESI, m/z): [M+H] ⁺ = 441.1. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^ (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.41 (s, 1H), 5.91 - 5.80 (m, 1H), 5.43 (d, J = 6.4 Hz, 1H), 5.10 - 4.99 (m, 2H), 4.68 - 4.63 (m, 1H), 3.62 (s, 3H), 3.10 - 3.02 (m, 1H), 2.63 - 2.56 (m, 1H), 2.46 - 2.40 (m, 1H), 2.21 (s, 3H), 2.13 - 2.03 (m, 2H). [0319] Isomer D: RT2(min): 18.23; LCMS (ESI, m/z): [M+H] ⁺ = 441.1. ¹ H NMR (400 MHz, DMSO-d6^^^į^^^^^^ (s, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.41 (s, 1H), 5.91 - 5.80 (m, 1H), 5.43 (d, J = 6.8 Hz, 1H), 5.10 - 4.99 (m, 2H), 4.67 - 4.62 (m, 1H), 3.61 (s, 3H), 3.11 - 3.03 (m, 1H), 2.62 - 2.56 (m, 1H), 2.45 - 2.38 (m, 1H), 2.21 (s, 3H), 2.11 - 2.04 (m, 2H).

Biological Examples Example B1. Cell Viability Assays [0320] Cell viability was measured in the following MAPK pathway mutant cancer cell lines: A375 (BRAF V600E), HepG2 (NRAS Q61L), SK-MEL-30 (NRAS Q61K), OCI- AML-2 (MBNL1-CRAF fusion), and K562. [0321] A375, HepG2, SK-MEL-30, OCI-AML-2 and K562 cells were grown in the appropriate growth medium as described in Table 2 below, and harvested at 50-80% confluence. Cells were counted and seeded at their appropriate density (see Table 2) in a 384- well plate (Corning 3570). A375, HepG2 and SK-MEL-30 were allowed to adhere overnight prior to treatment and the OCI-AML-2 were treated immediately for the indicated drug treatment times (Table 2). Table 2 provides the growth media, number of cells seeded per well and drug treatment times for each cell line. Table 2. [0322] Compounds were dissolved in DMSO and serially diluted. Serially-diluted compound or a DMSO only control (high control, “HC”) was added to the plated cells in each well. Compounds were tested at concentrations of about 10 µM to 0.51 nM, using three- fold dilutions. The final proportion of DMSO never exceeded 0.1%. [0323] 3ODWHV^ZHUH^SODFHG^LQ^D^^^^^^^^^&22 incubator for the indicated treatment times (Table B1). Plates were then removed from the incubator and equilibrated for 15 minutes at room temperature. 40 µl of CellTiter Glo reagent (Promega) was added to measure the relative level of metabolically active cells by quantifying intracellular ATP concentrations. Plates were incubated for 30 minutes at room temperature, and luminescence was measured. Percent viability was normalized to a vehicle control only using the following formula: % viability = 100 x (LumSample – LumLC) / (LumHC – LumLC). IC50 values were calculated using XLFit software or Prism (GraphPad Software), as shown in Table 3, below. Graphical curves were fitted using a nonlinear regression model with a sigmoidal dose response. Table 3.

Example B2. Detection of phosphorylated ERK (pERK) [0324] A375 cells were counted and seeded at 10,000 cells/well in 384 well plates (Corning 3764) and allowed to adhere overnight. [0325] Compounds were dissolved and serially diluted in DMSO. The compounds were then DGGHG^^PL[HG^^DQG^LQFXEDWHG^IRU^IRXU^KRXUV^DW^^^^^^^^^&2 2. Compounds were added using four-fold dilutions at final concentrations ranging from 10 µM to 0.01 nM. DMSO only and 10uM staurosporine were added as high and low controls. [0326] Following the four-hour incubation with compounds, cell lysates were prepared and AlphaLISA assay measuring phosphorylated ERK was performed. Media was removed using the Apricot Designs pipettor. Lysis buffer was made from 1X AlphaLISA SureFire Assay Kit (AlphaLISA SureFire Ultra pERK ½ (Thr202/Tyr204) ALSU-PERK-A50K) lysis buffer with protease and phosphatase inhibitors. Cells were lysed by adding 10uL to all the wells and mixed for 40 minutes on a plate shaker. 10uL cell lysate was transferred to a new Optiplate (PerkinElmer 6007290) and incubated with 5uL 1X acceptor mix for 2 hours in the dark. 5uL of 1X donor mix was added to all wells and mixed by shaking followed by overnight incubation in the dark. [0327] pERK AlphaLISA signal was read on the Envision using standard AlphaLISA settings. Percent inhibition of ERK phosphorylation was calculated by %Inhibition = 100 x (LumHC – LumSample) / (LumHC –LumLC). The low and high controls (LC/HC) are generated from lysate from wells with cells treated with DMSO or 10 mM Staurosporine (BioAustralis, cat # BIA-S1086), respectively. IC50 values were calculated by fitting the Curve using XLfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom)/(1 + 10^((LogIC50 - X)*HillSlope)). The IC50 values are shown in Table 4 below. Table 4. [0328] All publications, including patents, patent applications, and scientific articles, mentioned in this specification are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, including patent, patent application, or scientific article, were specifically and individually indicated to be incorporated by reference. [0329] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced in light of the above teaching. Therefore, the description and examples should not be construed as limiting the scope of the invention.