HPD inhibitor compositions and methods of use

Abstract

Disclosed herein are inhibitors of 4-hydroxyphenylpyruvate dioxygenase (HPD or HPPD) that have decreased inhibitory activity against sepiapterin reductase (SPR). Disclosed herein are methods of administering an HPD inhibitor alone or in combination with a diet low in tyrosine and / or phenylalanine, with or without dihydrobiopterin (BH2) and / or tetrahydrobiopterin (BH4) supplementation and / or monoamine salvage therapy. The compounds of the present disclosure can be used to treat conditions responsive to modulation or inhibition of HPD, such as inborn errors of metabolism, including tyrosinemia. The compounds of the present disclosure can also be used as herbicides to control weeds.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Greek Patent Application No. 20240100223 filed March 27, 2024, the content of which is incorporated herein by reference in its entirety for all purposes. FIELD OF DISCLOSURE

[0002] The present disclosure relates to compounds for modulating or inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPD) that have decreased inhibitory activity against sepiapterin reductase (SPR), their use in therapeutic methods of treating conditions and disorders, and their use in method for controlling weeds. BACKGROUND

[0003] Tyrosinemia type I can be characterized by the lack of activity of the enzyme fumarylacetoacetate hydrolase (FAH), resulting in impaired tyrosine metabolism and the accumulation of tyrosine and metaboli c byproducts. The 4-hydroxyphenylpyruvate dioxygenase (commonly abbreviated to HPD or HPPD) inhibitor nitisinone is the standard-of-care for the inborn error of tyrosinemia type I. It has been reported that subjects with tyrosinemia type I develop progressive neurocognitive decline, the causation of which is unknown, but which may be attributable to treatment with nitisinone. Thus, there is a need for compounds and methods of treatment for modulating or inhibiting HPD that do not contribute to neurocognitive decline.

[0004] In addition, various HPD inhibitors have herbicidal properties. Considering these triketone herbicides are routinely used on commercial crops for human consumption and enter the human food chain, there is a need for compounds, herbicidal compositions, and methods of treating weeds associated with modulating or inhibiting HPD activity that do not have off-target effects which may be toxic to humans and other mammals. SUMMARY

[0005] The present disclosure provides compounds that inhibit HPD with no or minimal inhibition of SPR. The present disclosure also provides methods of treatment, methods of using compounds, pharmaceutical formulations, and medicaments for treating inborn errors of metabolism (e.g., conditions responsive to modulation or inhibition of HPD, such as tyrosinemia) in a subject in need thereof by inhibition of HPD with no or minimal inhibition of SPR.

[0006] The present disclosure provides a compound of Formula (I): Formula (Q or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each ™ independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, or all =-- together form an and ring or heteroaryl ring, wherein X1, X2, XJ, Z!, Z2, ri, Y1, Y2, Y3, Y4, and Y3 are as described herein.

[0007] In some embodiments, the compound of Formula (I) is a compound of Formula (IA), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein Rla, Rla, R2a, R2a, R / '“, R3a , n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0008] In some embodiments, the compound of Formula (IA) is a compound of Formula (IA3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: O O Y'-”' Y3 wherein R!a, Rla’, R3a, R5a’, n, Y1, Y2, Y3, Y4, and Y3 are as described for Formula (I), and Rla3, R2a3, R3a3, R4aJ, and R3a3 are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

[0009] In some embodiments, the compound of Formula (I) is a compound of Formula (IB-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein Rlb, R2”, R2b, R3b, R3b’, n, Y1, Y2, Y3, Y4, and Y3 are as described for Formula (I).

[0010] In some embodiments, the compound of Formula (IB-N) is a compound of Formula (IB-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: R2b3 wherein R2”, R2b , R3b, R3b’, n, Y1, Y2, Y3, Y4, and Y3 are as described for Formula (I), and Rlb3, R2b3, R3b5, R4b3, and R5b3 are each independently selected from H, halo, Ci-6 alkyl, Cue haloalkyl, and -O-Ci-6 alkyl.

[0011] In some embodiments, the compound of Formula (I) is a compound of Formula (IB-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R2b, R2”’, R3b, R3b , n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0012] In some embodiments, the compound of Formula (I) is a compound of Formula (IC-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: ^Y2 O O Y1 "'"Y3 R3c wherein Rlc, Rlc, R2c, R2c, R3c, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0013] In some embodiments, the compound of Formula (IC-N) is a compound of Formula (IC-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R!c, Ric, R20, R2c’, n, Y1, Y2, Y3, Y4, and Y3 are as described for Formula (I), and Rlc3, R2c3, R3c3, R4c3, and R5c3 are each independently selected from H, halo, Cj-6 alkyl, Cj-6 haloalkyl, and -O-Cn6 alkyl.

[0014] In some embodiments, the compound of Formula (I) is a compound of Formula (IC-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: y2 O O          Y3 wherein Rlc, Rlc, R2c, R2c, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0015] In some embodiments, the compound of Formula (I) is a compound of Formula (ID-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein Rld, Rld, R3d, R3d, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0016] hi some embodiments, the compound of Formula (I) is a compound of Formula (ID-S), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: O O Y1^ Y3 wherein Rld, Rld, R3d, R3d, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0017] In some embodiments, the compound of Formula (I) is a compound of Formula (ID-SO2), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: y2 O O Yr> XY3 wherein Rid, Rld’, R3d, R3d’, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0018] In some embodiments, the compound of Formula (I) is a compound of Formula (IE), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R!®, Rle’, R3®, R3®’, n, Y1, Y2, Y3, Y4, and Y3 are as described for Formula (I).

[0019] In some embodiments, the compound of Formula (I) is a compound of Formula (IF), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R’lf, Rlf, R2f, R2f, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0020] hi some embodiments, the compound of Formula (I) is a compound of Formula (IGA), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R1®, R2g, R2®’, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0021] In some embodiments, the compound of Formula (IG-N) is a compound of Formula (IG-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R2®, R2g, n, Y!, Y2, Y3, Y4, and Y5 are as described for Formula (I), and Rlg3, R2®5, R3g3, R4g3, and R3g3 are each independently selected from H, halo, Ci-6 alkyl, CA haloalkyl, and -O-Ci-6 alkyl.

[0022] In some embodiments, the compound of Formula (I) is a compound of Formula (IG-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein Rzg, R2®’, ri, Y1, Y2, Y3, Y4, and Y3 are as described for Formula (I).

[0023] In some embodiments, the compound of Formula (I) is a compound of Formula (IH-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein Rlh, Rln’, R2h, n, Yl, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0024] In some embodiments, the compound of Formula (IH-N) is a compound of Formula (IH-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. wherein Rlh, Rln’, n, Y1, Y2, Y3, Y4, and Y' are as described for Formula (I), and RUiJ, R2h3, R3n3, R4hj, and R5nj are each independently selected from H, halo, Ci-6 alkyl, Ci^ haloalkyl, and -O-Cj-6 alkyl.

[0025] In some embodiments, the compound of Formula (I) is a compound of Formula (IH-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Formula (IH-O) wherein Ri!!, Rlh, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0026] In some embodiments, the compound of Formula (I) is a compound of Formula (li-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: ^Y2 O 0 Y1 Y3 wherein Ri!, R3', R3', n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0027] In some embodiments, the compound of Formula (li-N) is a compound of Formula (li-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: R23 wherein R31, R31’, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I), and Rb3, R2'3, R313, R413, and R5'3 are each independently selected from H, halo, Cur, alkyl, Ci-6 haloalkyl, and -O-Cn

[0028] In some embodiments, the compound of Formula (I) is a compound of Formula (IJ-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: / Y2 O O Y1^ Y3 wherein R1’, R2-', R\ R3', n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0029] In some embodiments, the compound of Formula (IJ-N) is a compound of Formula (IJ-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: R2^ wherein R?J, R3j, R3', n, Y1, Y2, Y\ Y4, and Y3 are as described for Formula (I), and R!k\ R2^, R3j3, R4j3, and R5-’3 are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

[0030] In some embodiments, the compound of Formula (I) is a compound of Formula (IK-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: q O Y1^ Y3 R1( AAA-A R ~N [ / O Formula (IK-N) wherein R!k, R2k, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0031] In some embodiments, the compound of Formula (IK-N) is a compound of Formula (IK-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof wherein R2k, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I ), and Rlk3, R2k3, R3k3, R4k3, and R5kj are each independently selected from H, halo, Ci-6 alkyl, Ci-e haloalkyl, and -O-Ci-6 alkyl.

[0032] In some embodiments, the compound of Formula (I) is a compound of Formula (IL-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein Rn, R3i, n, Y1, Y2, YJ, Y4, and Y5 are as described for Formula (I).

[0033] In some embodiments, the compound of Formula (IL-N) is a compound of Formula (IL-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: R2I3 I            Formula (IL-N3) R3' wherein R31, n, Y1, Y2, Y’, Y4, and Y5 are as described for Formula (I), and R113, R213, R313, R4ij, and R'b are each independently selected from H, halo, Cj-e alkyl, Ci-s haloalkyl, and -0-0.-6 alkyl.

[0034] In some embodiments, the compound of Formula (I) is a compound of Formula (IM), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein Rim, Rlm’, R2m, R2m’, R3m, R3m’, R4m, R4"1’, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (I).

[0035] The present disclosure also provides a compound of Formula (II): Ria Formula (I!) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each — independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein X1, X2, XJ, n, Rin, R112, RI!3, Rn4, and RI!5 are as described herein.

[0036] In some embodiments, the compound of Formula (II) is a compound of Formula (IIA-C), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R1, R2, R111, Rl!2, R113, R114, and Rl!5 are as described for Formula (II).

[0037] In some embodiments, the compound of Formula (IIA-C) is a compound of Formula (IIA-C3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R2, Rm, R112, R113, Rn4, and R115 are as described for Formula (II), and Rla, Rlb, Rlc, Rld, and Rle are each independently selected from H, halo, Cue alkyl, Cj.g haloalky!, and -O-Ci-s alkyl.

[0038] In some embodiments, the compound of Formula (II) is a compound of Formula (IIA-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (!IA-N) wherein R\ R2, Rm, R112, R113, R114, and R115 are as described for Formula (II).

[0039] In some embodiments, the compound of Formula (IIA-N) is a compound of Formula (IIA-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R2, R113, Rn2, Rn3, R114, and Rn5 are as described for Formula (II), and Rla, Rlb, R3c, Rld, and R!e are each independently selected from H, halo, Ct-6 alkyl, Ci-6 haloalkyl, and -O-Cn6 alkyl.

[0040] In some embodiments, the compound of Formula (II) is a compound of Formula (IIB), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (HB) wherein R2, R111, R112, RU3, R114, and R11’ are as described for Formula (II).

[0041] In some embodiments, the compound of Formula (IIB) is a compound of Formula (IIB3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IIB3} K wherein R133, R112, R113, R1’14, and R115 are as described for Formula (II), and R2a, R2b, R2c, R2d, and R2e are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

[0042] In some embodiments, the compound of Formula (II) is a compound of Formula (IIC), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IIC) wherein R1, R111, R112, RU3, R114, and R11’ are as described for Formula (II).

[0043] In some embodiments, the compound of Formula (IIC) is a compound of Formula (IIC3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (!!C3) wherein Rm, RU2, Rlb, R114, and Ru’ are as described for Formula (II), and Rla, Rlb, Rlc, Rid, and Rje are each independently selected from H, halo, Ci-6 alkyl, Ci-e haloalkyl, and -O-Ci-6 alkyl.

[0044] In some embodiments, the compound of Formula (II) is a compound of Formula (IID), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R3, R111, R112, RU3, R114, and R11’ are as described for Formula (II).

[0045] The present disclosure also provides a compound of Formula (III): RIII4 Formula (III) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1, Rlin, R!I12, R1113, R1114, and Rll!5 are as described herein.

[0046] The present disclosure also provides a compound of Formula (IV): O O Formula (IV) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein Y1, Y2, Y3, Rm, and RW2 are as described herein.

[0047] In some embodiments, the compound of Formula (IV) is a compound of Formula (IVA), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVA) wherein R1, R3, R13 ’, and R™2 are as described for Formula (IV).

[0048] In some embodiments, the compound of Formula (IVA) is a compound of Formula (IVA3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVA3) wherein R1, R3, and 2 are as described for Formula (IV), and RIvla, R1Vlb, RIV’1C, R!vld, and Riwe are independently selected from H, halo, Ci-s alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

[0049] In some embodiments, the compound of Formula (IV) is a compound of Formula (IVB-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVB-O) wherein R\ R3, RW1, and R1^ are as described for Formula (IV).

[0050] In some embodiments, the compound of Formula (IVB-O) is a compound of Formula (FVB-O3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVB-O3) wherein R1, R3, and RIV2 are as described for Formula (IV), and RIvla, RA ,b, RIVic, RIvld, and R{vle are each independently selected from H, halo, Q..6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

[0051] In some embodiments, the compound of Formula (IV) is a compound of Formula (IVB-S), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formate (!VB-S) wherein R1, R3, RiV1, and RIVz are as described for Formula (IV).

[0052] In some embodiments, the compound of Formula (IVB-S) is a compound of Formula (IVB-S3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: R3 Formuia (IVB-S3) wherein R\ R3, and 2 are as described for Formula (IV), and RIvla, R1Vlb, RIV’1C, R!vld, and Riwe are independently selected from H, halo, Ci-s alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

[0053] In some embodiments, the compound of Formula (IV) is a compound of Formula (IVC-S), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVC-S) wherein R2, RIV], and R!v2 are as described for Formula (IV).

[0054] In some embodiments, the compound of Formula (IVC-S) is a compound of Formula (FVC-S3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVC-S3) wherein R2 and R1V2 are as described for Formula (IV), and RIV3a, R’^115, RIV1C, Rn ,d, and Rlv l are each independently selected from H, halo, Cue alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

[0055] In some embodiments, the compound of Formula (IV) is a compound of Formula (IVD), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: R3 Formula (IVD) wherein R2, R3, R^1, and R^2 are as described for Formula (IV).

[0056] In some embodiments, the compound of Formula (IVD) is a compound of Formula (IVD3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVD3) wherein R2, R3, and Rn2 are as described for Formula (IV), and RIvla, R1V lb, RIV’1C, R!vld, and R!Vle are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

[0057] The present disclosure also provides methods of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (V): Formula (V) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each =-=-= independently represents a single bond or a double bond, subject to the satisfaction of valencyrequirements, or all = together form an aryl ring or heteroaryl ring, wherein X!, X2, X3, Z1, Z2, n, Y1, Y2, Y3, Y4, and Y5 are as described herein.

[0058] In some embodiments, the compound of Formula (V) is a compound of Formula (VE), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: o' 0 R3e ^3e’ Formula (VE) wherein Rle, Rle, R3e, R3e, n, Y1, Y2, Y3, Y4, and Y5 are as described for Formula (II).

[0059] The present disclosure also provides methods of treating a condition in a subject in need thereof, the method comprising admini stering a therapeutically effective amount of a compound of Formula (VI): RV!2 RVIS Formula (VI) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each = independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein X1, X2, XJ, n, Rvn, RU2, RV!3, RVI4, and RVI5 are as described herein.

[0060] The present disclosure also provides methods of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VII): O O Rvii1 RVii4 Formula (VII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R\ RV1Ii, RV112, RViI3, Rvip1, and RVlb are as described herein.

[0061] The present disclosure also provides methods of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VIII): Formula (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each — independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein Y1, Y2, Y3, Rvhn, and R' ll!2 are as described herein.

[0062] The present disclosure also provides methods of treating a condition in a subject in need thereof (e.g., a condition that is responsive to modulation or inhibition of HPD), the method comprising administering a therapeutically effective amount of a compound of Formulae (1), (IA), (IA3), (IBA). (IB A3). (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID - S), (ID-SO2), (IE), (IF), (IG-N), (IGA3), (IG-O), (IHA), (Ui A3), (IH-O), (li-N), (Ii-N3), (IJA), (IJ-N3), (IKA), (IKA3), (ILA), (U.A3). (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (HAA3), (IIB), (IIB3), (IIC), (IIC3), (HD), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0063] The present disclosure also provides for use of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising: administering to the subject an effective amount of the compound of Formulae (I), (IA), (IA3), (IBA), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), UGA3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (H-N3), (UA), (LiA3), (IKA), (IK A3). (ILA), (ILA3), (IM), (II), (IIA-C), (HA-C3), (IIAA), (IIAA3), (IIB), (IIB3), (IIC), (HC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing,

[0064] The present disclosure also provides for use of a compound of Formulae (I), (IA), (IA3), (IBA), (IBA3), (IB-O). (ICA), (IC A3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IGA), (KiA3), (KM)), (IH-N), (IH-N3), (IH-O), (liA), (HA3). (IJ-N), (IJA3), (IK-N), (IK-N3), (ILA), (IL A3), (IM), (II), (IIA-C), (IIA-C3), (HAA). (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3 ), (V), (VE), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising: administering to the subject an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof

[0065] The present disclosure also provides for use of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, wherein the medicament comprises an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and the compound is of Formulae (I), (IA), (IA3), (IB A), (IB A3), (IB-O), (IC A), (IC-N3), (IC-O), (ID-O), (ID-S), (1D-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (liA3), (UA), (IJ-N3), (IKA), (IKA3), (ILA), (ILA3), (IM), (II), (IIA-C), (IIA-C3), (IIAA), (IIA-N3), (IIB), (HB3), (IIC), (IIC3), (HD), (HI), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

[0066] The present disclosure also provides for use of a compound of Formulae (I), (IA), (IA3), (IBA), (IBAS), (IB-O), (IC-N), (ICA3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (H I A3). (IH-O), (li-N), (li-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (ILA), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (HB3), (IIC), (HC3), (HD), (Hl), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (XT), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, wherein the medicament comprises an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0067] The present disclosure also provides for a compound for use in a method of treating a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising: administering an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to the subject, wherein the compound is of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (Ii-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (HA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (DC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (HD), (IVD3), (V), (VE), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

[0068] The present disclosure also provides for the compound of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (h-\), (I1-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (11B3), (IIC), (IIC 3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, for use in a method of treating a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising: administering an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to the subject.

[0069] The present disclosure also provides for a pharmaceutical formulation for use in a method of treating a condition that is responsive to modulation or inhibition of HPD, the formulation comprising an effective amount of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, wherein: the method comprises administering the pharmaceutical formulation to a subject having the condition, and the compound is of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (li-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA- C), (IIA-C3), (IIA-N), (IIA-X3), (HB), (IIB3), (IIC), (IIC3), (III)), (HI), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

[0070] The present disclosure also provides for a pharmaceutical formulation for use in a method of treating a condition that is responsive to modulation or inhibition of HPD, the formulation comprising an effective amount of a compound of Formulae (I), (IA), (IA3), (IB-N), (IBA3). (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (H-X), (H-X3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (HA-C), (IIA-C3), (IIA-N), (IIA-X3). (11B), (IIB3), (HC), (IIC3), (IID), (III), (IV), (IVA), (IV A3 ), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VTi), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, wherein: the method comprises administering the pharmaceutical formulation to a subject having the condition.

[0071] The present disclosure also provides for a medicament for treating a condition that is responsive to modulation or inhibition of HPD, the medicament comprising an effective amount of a compound, or a pharmaceutically acceptable salt., stereoisomer, or tautomer thereof, wherein: the treatment comprises administering the medicament to a subject having the condition, and the compound is of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (H-X3). (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (HA-X3), (IIB), (IIB3), (IIC), (HC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (AT), (VI), (ATI), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

[0072] The present disclosure also provides for a medicament for treating a condition that is responsive to modulation or inhibition of HPD, the medicament comprising an effective amount of the compound of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (H ), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (HC3). (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: the treatment comprises administering the medicament to a subject having the condition.

[0073] The present disclosure also provides for an herbicidal composition comprising the compound of any one of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (H-N3), (IJ-N), (U-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (H VC3). (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (DC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), or (VIII), or an agriculturally acceptable salt thereof.

[0074] The present disclosure also provides for a method of controlling a weed, comprising administering the herbicidal composition comprising the compound of any one of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (1H-M), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), or (VIII), or an agriculturally acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] FIG, 1 shows the growth of DLD1 cells expressing phenylalanine hydroxylase (PAH) and lacking PAH in tyrosine-free and complete media treated with nitisinone and other triketones.

[0076] FIG. 2 shows the effect of nitisinone on PAH-dependent tyrosine synthesis in DLD1 -EV or DLD1-PAH cells were cultured in media with uniformly 13C-labelled phenylalanine (m+9).

[0077] FIG. 3 shows the effect of nitisinone treatment on A549-PAH cells in the presence and absence of tyrosine with tetrahydrobiopterin (BH4) supplementation.

[0078] FIG. 4 shows the effect of nitisinone on DLD1-PAH cells in tyrosine-free media in the presence and absence of BH4 or dihydrobiopterin (BH2).

[0079] FIG. 5 shows the effect of nitisinone on BH4 - and BH2 levels in DLD1-EV and DLD1-PAH cells.

[0080] FIG, 6 shows the effect of nitisinone on BH2 levels in Kelly and SKNBE(2) cells.

[0081] FIG. 7 shows the effect of nitisinone on biopterin levels in DLD1-EV / PAH, Kelly and SKNBE(2) cells.

[0082] FIG. 8 shows the effect of nitisinone on sepiapterin levels in DLD1-EV / PAH, Kelly and SKNBE(2) cells.

[0083] FIG. 9A~9L show in vitro activity of SPR and the effects of SPR inhibitors and tri ketones on SPR. activity.

[0084] FIG. 10 shows the effect of nitisinone and other HPD-targeting inhibitors on recombinant mouse SPR.

[0085] FIG. 11 shows the effect of nitisinone on plasma and brain sepiapterin levels in wildtype Balb / c mice.

[0086] FIG. 12 shows the effect of nitisinone on the ability of mice to learn, as assessed via a Morris Water Maze.

[0087] FIG. 13 shows the effect of nitisinone on the behavior of mice in an open field test. DETAILED DESCRIPTION

[0088] The following description sets forth numerous exemplary' compounds, methods, uses, 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 exempt ary embodiments.

[0089] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0090] The articles “a” and “an,” as used herein, refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” refers to one element or more than one element.

[0091] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary' skill in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently. Inborn Errors of Metabolism

[0092] Inborn errors of metabolism are a heterologous group of disorders characterized by the failure of metabolic pathways involved in metabolism of nutrients, including, but not limited to: carbohydrates, fatty acids, proteins, and amino acids. Inborn errors of metabolism arise from congenital defects in enzymatic or transport protein activity resulting in metabolic deviations that can comprise accumulation of toxic substrates or defects in energy production. Inborn errors of metabolism usually present in the neonatal period or infancy, but can present even in adulthood.

[0093] In humans, tyrosine is synthesized from the essential amino acid phenylalanine. Tyrosine or phenylalanine may be derived from food or derived from drugs, e.g, parenteral nutrition products. The conversion of phenylalanine to tyrosine is catalyzed by the enzyme phenylalanine hydroxylase (PAH), a monooxygenase. As a proteinogenic amino acid, tyrosine is required for protein synthesis. Furthermore, tyrosine is a key constituent of proteins that are part of signal transduction processes and functions as a receiver of phosphate groups that are transferred by way of protein kinases. Tyrosine bioavailability is governed by multiple factors, including dietary availability of tyrosine and phenylalanine, the uptake and transport of these amino acids from the GI tract, the biosynthesis of tyrosine from phenylalanine (via PAH), protein breakdown and recycling (e.g., via autophagy) and the rate of tyrosine utilization in anabolic pathways such as protein synthesis. Within cells, tyrosine metabolism is carefully regulated through the activities of multiple enzymes. Tyrosine is synthesized from the amino acid phenylalanine through the activity of phenylalanine hydroxylase (PAH), requiring tetrahydrobiopterin (BH4) as a cofactor. Additional enzymes in the tyrosine metabolism included tyrosine aminotransferase (TAT), 4-hydroxyphenylpyruvate dioxygenase (HPD), homogentisate 1,2-dioxygenase (HGD), glutathione S-transferase zeta 1 (GSTZ1), and fumaryl acetoacetate hydrolase (FAH). The concerted activity of these enzymes results in the production of fumarate that is utilized by cells as a substrate for energy production.

[0094] Sepiapterin reductase (SPR) is an enzyme involved in BH4 de novo biosynthesis and BH4 salvaging, ensuring that cells have adequate levels of BH4 necessary’ for cellular functions, including tyrosine synthesis. In BH4 de novo biosynthesis, SPR catalyzes the NADPH-dependent reduction of 6-pyruvolytetrahydropterin to BH4. Furthermore, in BH4 salvaging, following uptake of sepiapterin, SPR catalyzes the NAPDH-dependent reduction of sepiapterin into 7,8-BH2, which can then be utilized as a source for BH4.

[0095] At any point in the tyrosine metabolic pathway, deficits in enzymatic activity can result in metabolic defects. Multiple inborn errors of metabolism are a result of these deficits. Phenylketonuria results from loss of PAH function, tyrosinemia type II results from loss of TAT function, tyrosinemia type III results from loss of HPD function, alkaptonuria results from loss of HGD function, and tyrosinemia type I results from loss of FAH activity7.

[0096] Tyrosinemia type I occurs in individuals lacking FAH function and presents in either acute or chronic form. Acute tyrosinemia type I presents at birth or during the first months of life with individuals presenting with failure to gain weight and a failure to thrive that can later progress to developmental delays, liver failure, and blood-clotting abnormalities that can lead to death. Prior to the discovery of the small molecule HPD inhibitor nitisinone, tyrosinemia type I was fatal in childhood without a liver transplant. Nitisinone is the standard of care for tyrosinemia type I and is effective at managing the disease across the life of an individual. However, chronic administration of nitisinone is associated with neurocognitive decline in individuals due to a hereto unknown mechanism. Applicant has made the surprising discovery that, nitisinone can inhibit SPR., which can result, in BH4 cofactor deficiency, which in turn can result in neurocognitive decline, an unintended effect of nitisinone and other HPD inhibitors. Embodiments of the present disclosure are directed to practical applications of that surprising result (e.g., SPR-sparing HPD inhibitors, and methods of treating conditions and disorders associated responsive to modulation or inhibition of HPD with SPR-sparing HPD inhibitors.) SPR-sparing HPD specific inhibitors

[0097] In some embodiments, the disclosure provides compositions comprising compounds that inhibit HPD, but have no or minimal inhibitory activity for SPR, and methods of using such compositions, thereby reducing or eliminating side effects in subjects caused by currently available standard-of-care for treating inborn errors of metabolism.

[0098] In some embodiments, the disclosure provides a compound, of Formula (I): Formula (!) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each = independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, or all together form an aryl ring or heteroaryl ring, wherein: X! is CRHVx X2 is CR2aR2a\ and X3 is CR3aR3a; X1 is NRlb or O, X2 is CR2bR2b’, and X3 is CR3bR3b’, X1 is CRlcRlc’, X2 is CR^R20’, and X3 is NR3c or O; X1 is CRldRld', X2 is O, S, or S(02), and X3 is CR3dR3d’; X; is CRh;Rb;, X2 is C(0), and X3 is CRNCN X’1 is CRlfRlf, X2 is CR:iR2r; and X3 is a bond; X1 is NRlg or 0, X2 is CR2gR28 , and X3 is a bond; X1 is CR]hRib , X2 is NR2h or 0, and X3 is a bond; X1 is NR1’ or 0, X2 is C(0), and X3 is CR3iR3k; X! is NRh or 0, X2 is NR2j or 0, and X ’ is CR3jR3i; X1 is NRlk or 0, X2 is NR2k or 0, and X3 is a bond, Xs is NRn or 0, X2 is C(0), and X3 is NR3f or 0, or X1 is CRlmRlm’, X2 is CR2mR2m’, and X3 is CR3mR3m’-CR4mR4ra’; Z! and Z2 are each independently selected from C(0) and 8(()2), Rla and Rla are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -C0(0)-Ci-6 alkyl, and aryl; R2a and R2a are each independently selected from H, C2-6 alkyl, Ci-6 haloalkyl, Cs-6 cycloalkyl, -C0(0)~Ci-6 alkyl, and aryl; R3a and R3a are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -C0(0)-Ci-6 alkyl, and aryl; If Z1 and Z2 are both C(0), then at least one of R13, R,a’, R2a, R2a’, R3a, or R3a is Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -C0(0)-Ci-6 alkyl, or aryl; wherein the aryl of Rla, Rla’, R2a, R23’, R3a, or R3a is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; or two or more of Rta, Rla, R2a, R2a, R~’a, and R 'a combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined Rla, Rla’, R2a, R2a’, Rja, or Rja are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;       wherein the aryl of Rka, Rla’, R2a, R2a, R3a, or R3a is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; R2b, R2b , R3b, and R3b are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of R2b, R2b , R3b, or R3b is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-6 alkyl, Cws haloalkyl, and -CO(O)-Ci-6 alkyl; or two or more of R1D, R2b, Rzb , R3b, and R3b combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined Rib, R2b, R2b , Rjb, or R3b are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rlb, R2b, R2b’, Rjb, or R3b’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ck, alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; Rlc, Rlc’, R2c, and R2c’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyd, and aryl; wherein the aryl of Rlc, Rlc’, R2c, or R2c is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-s alkyl, Cws haloalkyl, and -CO(O)-Ci-6 alkyl; Rld, Rld’, R3c!, and R3d’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, ”CO(O)-Ci-6 alkyd, and aryl; wherein the aryl of Rld, R,d, R3d, or R3d is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-e alkyl, Ci-e haloalkyl, and -CO(O)-Ci-6 alkyl; R'\ Rle, R3e, and Rk' are each independently selected from H, Cue alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rle, Rle’, R3s, or R3e is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C0(0)-Cj-6 alkyl; or two or more of Rie, Rle, R3e, and RJS combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1..6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined Rie, Rle, R3e, or R3e’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -C0(0)-Cj-6 alkyl, and aryl; wherein the aryl of Rle, Rle’, R3s, or R3e is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; Rlf, Ri3 , R2f, and R21 are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rlf, Rlf, R2f, or R2f is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; or two or more of R11, Ru , R21, and R2r combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1..6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined R11, R1P, R21, or Rzf are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, Cs-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rlf, Rlf, R2f, or R2t is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C0(0)-Ck6 alkyl; R2® and R2g' are each independently selected from H, Ci-s alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -C0(0)-Ci-6 alkyd, and aryl; wherein the aryl of R2® or R2®’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; Rlh and Rlb are each independently selected from H, Ci-s alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyd, and aryl; wherein the aryl of R,h or Rllf is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; R’1 and R3' are each independently selected from H, Cue alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyd, and aryl; wherein the aryl of R31 or R11 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C (}(())-<'i alkyd; RJ-i and R3i are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rjj or R ’1 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyd; Rlra, Rim Rm, Rm, Rm, Rm’, Rm, anj Rm’ are eacj1 independently selected from H, Ci-6 alkyd, Cue, haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of R1®, R1®’, R2m, R2m', R3m, R3®’, R4®, or R4®’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyd; or two or more of Rlm, Rlm’, R2®, R2®’, R3m, R3®’, R4m, and R4®’ combine to form a cycloalkyd ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-e alkyl, Cj-e haloalkyl, and -CO(O)-Cn6 alkyl, and any uncombined Rlm, Rlm , R2®, Rm’, Rm, Rm, Rm, or Rm’ are independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyd, -CO(O)-Cn6 alkyl, and aryl; wherein the aryl of Rlm, R1En, R2m, R2m, R3’", R3m’, R4m, or R4m is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C;-6 alkyl, Oi-6 haloalkyl, and -00f0)~0i-6 alkyl; Rlb is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-e alkyl-aryl, or heteroaryl; wherein the C1-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlb is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, and alkoxy; or two or more of Rlb, R20, R2b , R3b, and R3b combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, C1-6 haloalkyl, and -CO(O)-Ci~6 alkyl, and any uncombined Rib, R2b, R2b , Rjb, or R3b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rlb, R2b, R2b’, Rjb, or R3b’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Cue haloalkyl, and -CO(O)-Ci-6 alkyl; R3c is H, C1-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl; wherein the Ci-6 alkyl, €3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of Rlc is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; Rlg is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl; wherein the Cj.g alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rls is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj.g alkyl, and alkoxy; R2h is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cn6 alkyl-aryl, or heteroaryl; wherein the Ci-g alkyl, C w, cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of R2h is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-g alkyl, and alkoxy, Rh is H, Ci-g alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-g alkyl-aryl, or heteroaryl of Rh is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; R1-' and R2j are each independently selected from H, 0.-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl; wherein the Ci-6 alkyl, (’ -.-s cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlj or R2j is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, 0-6 alkyl, and alkoxy; Rlk and R2k are each independently selected from H, 0-6 alkyl, C3-6 cycloalkyl, aryl, 0.-6 alkyl-aryl, and heteroaryl; wherein the 0-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlk or R2k is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, 0-6 alkyl, and alkoxy; R11 and R3i are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-e alkyl-aryl, and heteroaryl; wherein the 0-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlf or R31 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, 0-6 alkyl, and alkoxy; n is 0 or 1; wherein: if X1 is CR1aRla’, -X2 is CR2aR2a, and X3 is CR3aR3a, then: Y1 is C(H); Y2 is C(H) orN; Y3 is C(CO). Y4 is C(H) or N; and Y5 is C(H); or Y] is C(R!a2) or N; Y2 is C(R2 :2): Y3 is C(R3a2) or N; Y4 is C(R4a2); and Y5 is C(R5a2); wherein Rla2 is H, halo, 0-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R2a2 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl; R3a2 is H, halo, Cue haloalkyl, NO?, or CN, R4a2 is H, halo, Cn6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R5a2 is H, halo, 0-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rla2 combines with R2a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3a2, R4a2, and R5a2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R?< combines with R3a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rla2, R4a2, and R5a2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or r3s2 cotnbjnes with R4a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rla2, R2a2, and R5a2 are each independently selected from H, halo, Cm haloalky], NO2, and CN; or R4a2 combines with R5a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rla2, R2a2, and Rjaz are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; if X! is NR!b or O, X2 is CR2bR2b‘, and X3 is CR3bR3b’, then: Y1 is C(Rlb2) or N; Y2 is C(R2b2) orN; Y3 is C(R3b2) orN; Y4 is C(R4b2) orN; and Y5 is C(R'°2) or N; or Y1 is C(O); Y2 is N(R2b2’); Y3 is C(R3b2’); Y4 is C(R4b2’); and Y5 is N; wherein Rlb2 is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl; R2b2 is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl; R3b2 is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl, R4b2 is H, halo, C1.6 haloalkyl, NO2, CN, or S02-Cm alkyl; R5b2 is H, halo, Cm haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rlb2 combines with R2h / to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl or OH, and R3b2, R4b2, and R,b2 are each independently selected from H, Cm alkyl, halo, Cm haloalkyl, NO2, and CN; or R2b2 combines with R3b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl or OH, and Rlb2, R4b2, and R5b2 are each independently selected from H, Cm alkyl, halo, Cm haloalkyl, NO2, and CN; or R3b2 combines with R4b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl or OH, and Rlb2, R2b2, and R3b2 are each independently selected from H, Cm alkyl, halo, Cm, haloalkyl, NO?, and CN; or R4b2 combines with R,b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci^ alkyl or OH, and Rlb2, R2b2, and R3b2 are each independently selected from H, Cue alkyl, halo, Cue haloalkyl, NO2, and CN; R2b2’ is H, Cue alkyl, ( --:. cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl; wherein the Cue alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of R2”2’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cur, alkyl, and alkoxy; Rjb2’ is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R4b2’ is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or R2b2 combines with R~’b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci^ alkyl or halo, and R4b2’ is selected from H, Cue alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, and heteroaiyl; wherein the Cue alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of R4d2’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, and alkoxy; or Rjb2 combines with R4b2 to form an aryl ring, heteroaiyl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl or halo, and R2b2 is selected from H, Ci-6 alkyl, C3-6 cycloalkyl, and, Ci-6 alkyl-aryl, and heteroaryl; wherein the Cw alkyl, C3.6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of R2b2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, and alkoxy; if X! is CRlcRlc, X2 is CR2cR2c, and XJ is O orNRJc; then Y1 is C(Rlc2) orN; Y2 is C(R2c2) or N; Y3 is C(R3c2) or N, Y4 is C(R4c2) or N; and Y5 is C(R5c2) or N; wherein Ric2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R2c2 is H, halo, Cu6 haloalkyl, NO?„ CN, or SO2-C1-6 alkyl; R3c2 is H, halo, Cue haloalkyl, NO2, CN, or SO?-Cu6 alkyl; R4c2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R5c2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rlc2 coinbjnes with r2c2 t0 form an ary] ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be tin substituted or substituted with Ci-6 alkyl, and R3c2, R4c2, and R5c2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R2c2 combines with R3c2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with C1-6 alkyl, and RIc2, R4c2, and R5c2 are each independently selected from H, halo, Cue, haloalkyl, NO?, and CN, or R3c2 combines with R4e2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and Ric2, R2c2, and R5c2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R4c2 combines with R5c2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cn6 alkyl, and Rlc2, R2c2, and R3c2 are each independently-selected from H, halo, Ci-6 haloalkyl, NO2, and CN; if X1 is CRldRld’, X2 is O, S, or S(02), and X3 is CR3dR3d’, then Y1 is C(Rld2) or N; Y2 is C(R2d2); YJ is C(R 'd2) orN; Y4 is C(R4a2) orN; and Y5 is C(R5d2) or N; wherein Rld2 is H, halo, Cue haloalkyl, N02, CN, or SO2-C1-6 alkyl; R2a2 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl; R3d2 is H, halo, Ci-6 haloalkyl, N02, CN, or SO2-C1-6 alkyl; R4d2 is H, halo, Cue haloalkyl, NO2, CN, or SOs-Cne alkyl; R3d2 is H, halo, Cue haloalkyl, N02, CN, or SO2-C1-6 alkyl; or Ru2 combines with R2d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3d2, R4d2, and R5d2 are each independently selected from H, halo, Cue haloalkyl, N02, and CN; or R2d2 combines with R3d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cn6 alkyl, and Rld2, R4d2, and R’d2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R3d2 combines with R4d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rld2, R2d2, and R’d2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R4e’2 combines with R5d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R!d2, R2d2, and R3d2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; if X1 is CRleRle’, X2 is C(O), and X3 is CR3eR3®’, then: Y1 is C(Rie2); Y2 is C(R2e2); Y3 is C(R3®2); Y4 is C(R4e2), and Y5 is C(R5e2); or Y1 is C(Rle2’) or N; Y2 is C(R2e2’) orN; Y3 is C(R3e2’) orN; Y4 is C(R4e2’) orN; and Y5 is C(R5®2’) or N, wherein at least one of Y1, Y2, YJ, Y4, and Y5 is N; wherein Rls2 is H, F, CN, or SOs-Cm alkyl; R2e2 is H, halo, Ci-6 haloalkyl, NO2, CN, or S02-Cm alkyl; R3s2 is H, halo, Ci-s haloalkyl, NO2, CN, or S0?-Cm alkyl; R4e2 is H, halo, Ci-6 haloalkyl, NO2, CN, or S02-Cm alkyl; R5e2 is H, halo, Ci-6 haloalkyl, NO?, CN, or SOj-Cm alkyl; or Rle2 is Cl; R2e2 is H; R3e2 is Ci-6 haloalkyl, NO2, or SO-Cm alkyl; R4e2 is H; and R5®2 is N or Rie2 js n02- pj. q 6 haloalkyl; R4e2 is H; and R5s2 is H; or Rle2 combines with R2ez to form an aryl ring, heteroaryd ring, cycloalkyl ring, or heterocyclic ring and R3s2, R4e2, and R3e2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or R2®2 combines with R3®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rle2, R4®2, and R5e2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or R3®2 combines with R4®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rle2, R2e2, and R5e2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or R4e2 combines with R5e2 to form an aryl ring, heteroaryd ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryd ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rle2, R2®2, and R3®2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or R1®2’ is H, halo, Cm haloalkyl, NO2, CN, and SO2-C1-6 alkyl, R2s2 is H, halo, Cm haloalkyl, NO2, CN, and SO2-CM alkyl; R- ' is H, halo, Cm haloalkyl, NO2, CN, and SOs-Cm alkyl; R4®2 is H, halo, Cm haloalkyl, NO2, CN, and SO2-CM alkyl; R5®2 is H, halo, Cm haloalkyl, NO2, CN, and SO2-CM alkyl; or R3®2’ combines with R2®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and R3®2, R4®2’, and R5®2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or R2®2 combines with R3®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and R1®2, R4®2’, and R5®2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or R3®2 combines with R4®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and R!e2 , R2e2 , and R3®2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or R4®2 combines with R3e2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and R1®2, R2®2, and R3®2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; if X1 is CRlfR]t, X2 is CR2fR2t, and X3 is a bond; then Y1 is C(Rlf2) orN, Y2 is C(R2f2) or N; YJ is C(R'12) or N; Y4 is C(R4f2) or N; and Y5 is C(R3f2) or N; wherein Rlf2 is H, halo, Cm haloalkyl, NO2, CN, or SOi-Cm alkyl; R'22 is H, halo, Cm haloalkyl, NO?, CN, or SO2-CM alkyl; R332 is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl, R412 is H, halo, Cm haloalkyl, NO2, CN, or SO2-CM alkyl, R?” is H, halo, Cm haloalkyl, NO2, CN, or SO2-CM alkyl; or Rlf2 combines with R212 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3f2, R4f2, and R5f2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R2f2 combines with R312 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R!f2, R4f2, and R5f2 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; or R3” combines with R4*2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rm, R2f2, and RM2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R412 combines with R532 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cj-e alkyl, and Ril2, R212, and R3f2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; if X1 is NR!g or O, X2 is CR2gR2g, and X3 is a bond; then Y1 is C(Rlg2) or N, Y2 is C(R2g2) orN; Y3 is C(R3g2) orN; Y4 is C(R4g2) orN; and Y5 is C(R5g2) orN; wherein Rlg2 is H, halo, Cn6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2g2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R3g2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4g2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R5g2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rlgi combines with R^82 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3g2, R4®2, and R’g2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R2g2 combines with R3g2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyd, and Rlg2, R4g2, and R5g2 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; or R3g2 combines with R4g2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlg2, R2^, and R’®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R4g2 combines with R5g2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R!g2, R2g2, and R3g2 are each independently selected from H, halo, Cj.g haloalkyl, NO2, and CN; if X1 is CRlhRlh, X2 is NR2!1 or O, and X3 is a bond; then Yl is C(Rlh2) or N; Y2 is C(R2h2) or N; Y3 is C(R3h2) orN; Y4 is C(R4b2) orN; and Y5 is C(R5h2) or N; wherein Rlh2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R2h2 is H, halo, Cn6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R3h2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4h2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R5h2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rlh2 combines with R2h2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3h2, R4n2, and R5h2 are each independently selected from H, halo, Ci-6 haloalkyl, NO?, and CN, or R2h2 combines with R3b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rth2, R4”2, and R5h2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R3tu combines with R^2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cur, alkyl, and Rlh2, R2m2, and R’h2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R4h2 combines with R5n2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R!h2, R3"\ and R3h2 are each independently selected from H, halo, Cj.g haloalkyl, NO2, and CN; if X1 is NRh or O, X2 is C(0), and X3 is CR3'R3i’; then Y1 is C(R112) orN; Y2 is C(R212) or N; Y3 is C(R3i2) orN; Y4 is C(R4'2) orN; and Y5 is C(R512) or N; wherein Rli2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R2’2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R3’2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R412 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R5s2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl; or Rh2 combines with R212 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3'2, R412, and R^2 are each independently selected from H, halo, Cur, haloalkyl, NO?, and CN, or R2i2 combines with R3'2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and R1’2, R4’2, and R5i2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R312 combines with R4'2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cur, alkyl, and R112, R212, and R512 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R412 combines with R512 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R!12, R212, and R312 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; if X1 is XR:: or O, X2 is NR2j or O, and X3 is CR3jR3j’; then Y1 is C(Rlj2) or N; Y2 is C(R2'2) or N; Y3 is C(R3’2) or N; Y4 is C(R4j2) or N; and Y5 is C(R5j2) or N; wherein Rlj2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2j2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R3j2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4^2 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl; R5j2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl; or Rlj2 combines with R2'2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3’2, R4]2, and Rf*2 are each independently selected from H, halo, Cue, haloalkyl, NO?, and CN, or R2j2 combines with RA'2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rk? R4’2, and R3j2 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; or R3j2 combines with R4'2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with C1-6 alkyl, and RIj2, R2j2, and RR*2 are each independently selected from H, halo, Cue, haloalkyl, NO?, and CN, or R4j2 combines with R5-'2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and Rij2, R2’2, and R ’j2 are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; if X1 is NRlk or O, X2 is NR2k or O, and X3 is a bond; then Y1 is C(Rlk2) or N; Y2 is C(R2k2) or N; Y3 is C(R3k2) or N; Y4 is CYri orN; and Y5 is C(R5k2) or N; wherein Rlk2 is H, halo, Ci-s haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R2k2 is H, halo, C1-6 haloalkyl, N02, CN, or SO2-C1-6 alkyl; R3k2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4k2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R5k2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rlk2 combines with R2k2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and R3k2, R4k2, and R5k2 are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R2k2 combines with R^2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with C1-6 alkyl, and Rik2, R4k2, and R5k2 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; or R3k2 combines with R4k2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlk2, R2k2, and R5k2 are each independently selected from H, halo, Cue, haloalkyl, NO?, and CN, or R4k2 combines with R’K2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroasyi ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rik2, R2k2, and R3k2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; if X1 is NR!1 or O, X2 is C(O), and X3 is NR31 or O; then Y1 is C(R112) or N; Y2 is C(R2i2) or N; Y3 is C(R312) or N; Y4 is C(R4i2) or N; and Y5 is C(R5!2) or N; wherein Rli2 is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R2!2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R3!2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R412 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R312 js                       NCh, CN, or SO2-C1-6 alkyl; or Rli2 combines with R212 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R312, R412, and R512 are each independently selected from H, halo, Cj.g haloalkyl, NO2, and CN; or R212 combines with Rjl2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rn2, Rn2, and R5i2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R3’2 combines with R412 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rii2, R212, and R512 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R4'2 combines with R312 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rii2, R212, and R312 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or if X1 is CRlmRhn’, X2 is CR2mR2m’, and X3 is CR3raR3m’-CR4mR4“’; then Y1 is C(Rhn2) or N; Y2 is C(R2m2) or N; Y3 is C(R3m2) or N; Y4 is C(R4m2) or N; and Y5 is C(R5m2) or N; wherein Rlm2 is H, halo, Cur, haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2ra2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R3”’2           q_6 haioa]kyl, NO2, CN, or SO2-C1.6 alkyl; R4m2 is H, halo, C1.6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R5m2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rjm2 comb{nes wjth jC1”210 form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cn6 alkyl, and R3m2, R4’"2, and R5m2 are each independently-selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R2m2 combines R3m2t0 forni an aryf ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R!m2, R4m2, and R5m2 are each independently-selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R3m2 combines with R4ro2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R !”2, R2m2, and R5™2 are each independently-selected from H, halo, Cue haloalkyl, NO2, and CN; or R4m2 combines with R2”"2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with C1.6 alkyl, and Rbu2, R2m2, and R3™2 are each independently-selected from H, halo, Ci-6 haloalkyl, NO2, and CN, ^0099^ In some embodiments of the compounds of Formula (I): X1 is CRlaRia’, X2 is CR2aR2a', and X3 is CR3aR3a’; X! is NRlb, X2 is CH2, and X3 is CR3bR3b’; X’1 is CRlcRlc', X2 is CR^R20’, and X3 is O; X1 is CR,dRld', X2 is O, S, or S(O2), and X3 is CR3dR3d’; Xs is CRleR‘e’, X2 is C(O), and X3 is CR3eR3e’; X1 is NR18, X2 is CH2, and X3 is a bond; or X! is NRn, X2 is C(O), and X3 is NR31; Z1 and Z2 are each independently selected from C(O) and S(O:): Rla and Rla’ are each independently selected from H, Cur, alkyl, and -CO(O)-Ci-6 alkyl; R2a and R2a’ are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, -CO(O)-Cu6 alkyl, and aryl; R3a and R3a are each independently selected from H and Ci-6 alkyl; If Z1 and Z2 are both C(O), then at ieast one of Ria, R,a’, R2a, R2a’, R3a, or R3a is Ci-6 alkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl; wherein the and of R2a or R2a is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; or Rla and Rla combine to form a cycloalky] ring or heterocyclic ring, and R2a, R2a’, R3a, and R3a are each H; orR2a and R2a’ combine to form a cycloalkyl ring or heterocyclic ring, and Rla, Rla’, R3a, and R3a are each H; or Rla and R3a combine to form a cycloalkyl ring, wherein the cycloalkyl ring may be unsubstituted or substituted with one or more Ci-6 alkyl, and Rla, R2a, R2a, and R3a are each independently selected from the group consisting of H and Ci-6 alkyl; R3b is Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aiyl, or heteroaryl; wherein the Cj-s alkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of R,b is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-6 alkyl, and alkoxy; Rjb and R3b are each independently selected from H and Ci-6 alkyl; Rlc, Rlc’, R2c, and R2®’ are each independently selected from H and Ci-6 alkyl; Rld, Rld, Rto, and RJd are each independently selected from H and Ci-6 alkyl; Rle, Rle, R3e, and R3e are each independently selected from H and Ci-6 alkyl, Rlg is aryl; wherein the and of Rlg is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-6 alkyl, and alkoxy; R1! and Rjl are each independently selected from H, Ci-6 alkyl, and aryl; wherein the aryl of Rlf or R31 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; wherein: if X1 is CR1aRla’, X2 is CR2aR2a, and X3 is CR3aR3a, then: Y1 is C(H); Y2 is C(H) orN; Y3 is C(CF3), Y4 is C(H) or N; and Y5 is C(H); or Y’ is C(R!a2); Y2 is C(R2a2); Y3 is C(R3a2); Y4 is C(R4a2); and Y5 is C(R5a2); wherein Rla2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO2; R2a2 is H, halo, Ci-6 haloalkyl, SO2C1-6 alkyl, or NO2; R3a2 is H, halo, Ci-6 haloaikyl, SO2-C1-6 alkyl, or NO2; R4a2 is H, halo, C1-6 haloaikyl, SO2-C1.6 alkyl, or NO2; R5a2 is H, halo, Ci-6 haloaikyl, SO2-C1-6 alkyl, or NO2; if X1 is NRib, X2 is CH2, and X3 is CRjbR3b; then Yj is C(Rlb2); Y2 is C(R2”2); YJ is C(R3b2); Y4 is C(R4b2); and Y5 is C(R5b2); wherein Rlb2 is H, halo, Ci-s haloaikyl, SO2-C1-6 alkyl, or NO?; R2b2 is H, halo, Ci-6 haloaikyl, SO2-C1-6 alkyl, orNCh; R3b2 is H, halo, Ci-6 haloaikyl, SO2-C1-6 alkyl, or NO2; R4b2 is H, halo, Ci-6 haloaikyl, SO2-C1.6 alkyl, or NO2; R5b2 is H, halo, Ci-6 haloaikyl, SO2-C1-6 alkyl, or NO?; if X! is CRlcRlc, X2 is CR2cR2c, and XJ is O; then Y1 is C(R!c2); Y2 is C(R2c2); Y3 is C(R3c2); Y4 is C(R4c2); and Y5 is C(R5c2); wherein Rlc2 is H, halo, Cj-e haloaikyl, or NO2, R2c2 is H, halo, Ci-6 haloaikyl, or NO2; R3c2 is H, halo, Ci-6 haloaikyl, or NO2; R4c2 is H, halo, Ci-6 haloaikyl, or NO2; R5c2 is H, halo, Ci-6 haloaikyl, or NO2; if X1 is CRldRid , X2 is O, S, or 8(()2), and X3 is CRjdR3d, then Y1 is C(Rla2); Y2 is C(R2d2); Y3 is C(R3d2); Y4 is C(R4d2); and Y5 is C(R5d2); wherein Rla2 is H, halo, Ci-e haloaikyl, or NO?; R2a2 is H, halo, Ci-6 haloaikyl, or NO?; R3d2 is H, halo, Ci-6 haloaikyl, or NO2; R4d2 is H, halo, Ci-6 haloaikyl, or NO2; R’a2 is H, halo, Ci-s haloaikyl, or NO?; if X! is CRlsRls, X2 is C(0), and XJ is CR3eR3e; then Yj is C(R!s2); Y2 is C(Rze2); Y3 is C(R3e2); Y4 is C(R4e2); and Y5 is C(R5e2); wherein Rie2 is H, F, CN, or SO2-C1-6 alkyl; R2e2 is H, halo, Ci-6 haloaikyl, CN, SO2-C1-6 alkyl, or NO2; R3e2 is H, halo, Ci-6 haloaikyl, CN, SO2-C1-6 alkyl, or NO2; R4e2 is H, halo, Ci-6 haloaikyl, CN, SO2-C1-6 alkyl, or NO2; R5e2 is H, halo, Cj-e haloaikyl, CN, SO2-C1-6 alkyl, or NO2; or Rle2 conibines with R2e2 to form a heteroaryl ring, and R3e2, R4s2, and R'e2 are each H; if X1 is NRig, X2 is CH2, and X3 is a bond, then Y1 is C(Rlg2); Y2 is C(R2g2); Y3 is C(R3g2); y4 is C(R4g2); and Y5 is C(R5g2); wherein Rlg2 is H, halo, Ci-6 haloalkyl, or NO2; R2g2 is H, halo, Ci-s haloalkyl, or NO2; R3g2 is H, halo, Ci-6 haloalkyl, or NCh; R4g2 is H, halo, Ci-6 haloalkyl, or NO2; R2g2 is H, halo, Cn6 haloalkyl, or NO2; or if X! is NRb, X2 is C(O), and XJ is NR31; then Y1 is C(R1!2); Y2 is C(R2i2); Y3 is C(R3i2); Y4 is C(R412); and Y?' is C(R512); wherein R112 is H, Ci-6 haloalkyl, or NO2; R2!2 is H, Ci-6 haloalkyl, or NO2; R3'2 is H, Cj-6 haloalkyl, or NO2; R432 is H, Ci-6 haloalkyl, or NO2; R532 is H, Ci-6 haloalkyl, or NO2.

[0100] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IA), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: y2 0    0    Y1^ XY3

[0101] In some embodiments of the compounds of Formulae (I) and (IA), or the pharmaceutically acceptable salts or tautomers thereof, R3a and R3a are each Ci-6 alkyl. In some embodiments, Rja and R3a’ are each Ci-6 alkyl, and Rla, Ria’, R2a, and R2a are each H. In some embodiments, R2® and R2a are C3-5 cycloalkyl and H respectively. In some embodiments, R2a and R2a’ are C3.6 cycloalkyl and H respectively, and R!a, Ria’, R ’a, and RJa are each H. In some embodiments, Rla and Rla are -CO(O)-Ci-6 alkyl and H respectively. In some embodiments, Ria and R!a are -CO(O)-Ci-6 alkyl and H respectively, and R2a, R2a, R3a, and R3a are each H. In some embodiments, R2a and R2a’ are -C0(0)-Ci-6 alkyl and H respectively. In some embodiments, R2a and R2a are -C0(0)-Ci-6 alkyl and H respectively, and Rla, R?a, R3a, and R3a are each H. In some embodiments, two or more of Ria, Rla’, R2a, R2a’, Rja, and R3a combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-s alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl. In some embodiments, Rla and Ria’, R2a and R2a, or R3a and R3a combine to form a cycloalkyl ring or heterocyclic ring. In some embodiments, Rla and R2a, R2a and R3a, or Rla and R3a combine to form a cycloalkyl ring or heterocyclic ring.

[0102] In some embodiments, Rla and R2a, R2a and R3a, or Rla and R3a combine to form a Ci-6 cycloalkyl ring. In some embodiments, Ria and R2a, R2a and R3a, or Ria and R3a combine to form a Ci-s cycloalkyl ring. In some embodiments, Rla and R2a, R2a and R3a, or R’ia and Rja combine to form a heterocyclic ring comprising 4 to 8 atoms carbon atoms and 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, Rla and R2a, R2a and R3a, or Ria and

[0103] In some embodiments, the compound of Formula (LA), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IA3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0104] In some embodiments, the compound of Formula (I) or (IA) is a compound of Formula (IA3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Rla3, R2a3, R3a3, R4aJ, and R’a3 are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl. In some embodiments, Rla3, R2®3, R3ad, R4a3, and R5a3 are each H. In some embodiments, R4aJ is -O-Cne alkyl. In some embodiments, R4a3 is -O-Cw alkyl, and R,a3, R2a3, R3a3, and RA’ are each H.

[0105] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IB-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0106] In some embodiments of the compounds of Formulae (I) and (IB-N), or the pharmaceutically acceptable salts or tautomers thereof, Rib is cycloalkyl, aryl, or heteroaryl. In

[0107] In some embodiments, the compound of Formula (IB-N) is some embodiments, the compound of Formula (IB-N) is embodiments, the compound of Formula (IB-N) is p F

[0108] In some embodiments, the compound of Formula (IB-N), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IB-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (SB-N3)

[0109] hi some embodiments, the compound of Formula (I) or (IB-N) is a compound of Formula (IB-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Rlb3, R2b3, R3b3, R4”3, and R5b3 are each independently selected from H, halo, Cj-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl. In some embodiments, one of Rlb3, R2b3, R3b3, R4b3, or R5b3 is F, and the others are each H. In some embodiments, R3b3 is F, and Rlb3, R2dj, R4b3, and R5b3 are each H. In some embodiments, R]b3, R2b3, R3b3, R4b3, and R?03 are each H.

[0110] In some embodiments, the compound of Formula (IB-N3) is

[0111] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IB-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0112] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IC-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: y2 O 0    Y1^ ^Y3 R3c

[0113] hi some embodiments, the compound of Formula (IC-N), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IC-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: y2 O O       ^Y3 R3c3

[0114] In some embodiments, the compound of Formula (I) or (IC-N) is a compound of Formula (IC-N3), or s pharmaceutically acceptable salt., stereoisomer, or tautomer thereof, and R!c3, pM, g4c3, anj are independently selected from H, halo, Cue alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl. In some embodiments, Rlc3, R2c3, R3c3, R4c3, and R5c3 are each H.

[0115] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IC-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: y2 O O Y1> ^Y3

[0116] In some embodiments of the compounds of Formulae (I) and (IC-O), or the pharmaceutically acceptable salts or tautomers thereof, R2c and R2c’ are Ci-6 alkyl and H respectively. In some embodiments, R2c and R2c are Ci-s alkyl and H respectively, and R!c and Rlc are each H. In some embodiments, Rlc, Rlc, R2c, and R2c are each Cue alkyl. In some embodiments, the compound of Formula (IC-O) is

[0117] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (ID-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0118] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (ID-S), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0119] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (ID-SO2), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0120] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IE), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0121] In some embodiments, R!e, Rls’, and R'e are each Ci-6 alkyl. In some embodiments, the compound of Formula (IE) is

[0122] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IF), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0123] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IG-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0124] In some embodiments, the compound of Formula (IG-N), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IG-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In some embodiments, R's is Ci-6 alkyl-aryl, wherein the Ci-6 alkyl-aryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy. In some embodiments, the Ci-6 alkyl-aryl is substituted with alkoxy (e.g, -O-CIE). In some embodiments, R18 is -CHs-aryl, wherein the -CH2-aiyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy. In some embodiments, the -CHs-aryl is substituted with alkoxy (e.g., -O-CH3). In some embodiments, R18 is -CHa-Cearyl, wherein the -CEh-Cearyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy. In some embodiments, the -CEh-Cearyl is substituted with alkoxy (e.g., -O-CH3). In some embodiments, Rig is -CHa-methoxybenzyl.

[0125] In some embodiments, the compound of Formula (I) or (IG-N) is a compound of Formula (IG-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Rlg3, Rzg3, R3g3, R4gJ, and R5g3 are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl. In some embodiments, R!gJ, R2g3, R3gJ, R4g3, and R5g3 are each H.

[0126] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IG-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: O O Y1 Y3 R2s\ r29' Formula (IG-O)

[0127] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IH-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: / Y* 0 O Y''x Y3 I / O r2!i               Formula (IH-N)

[0128] In some embodiments, the compound of Formula (IH-N), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IH-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0129] In some embodiments, the compound of Formula (I) or (IH-N) is a compound of Formula (IH-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Rih3, R2hj, R3h3, R4iu, and R5h3 are each independently selected from H, halo, Ci-6 alkyl, Ci^ haloalkyl, and -O-Ci-6 alkyl. In some embodiments, Rih3, R2h3, R3h3, R4hj, and R5nj are each H.

[0130] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IH-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (SH-O) [0131 [ In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (E-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0132] In some embodiments, the compound of Formula (E-N), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (Ii-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: R2i3

[0133] In some embodiments, the compound of Formula (I) or (li-N) is a compound of Formula (Ii-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Rh3, R2u pM, £413, anc| £513 are eack independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl. In some embodiments, R113, Rzo, R313, R413, and R5B are each H.

[0134] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IJ-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0135] In some embodiments, the compound of Formula (IJ-N), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IJ-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0136] In some embodiments, the compound of Formula (I) or (IJ-N) is a compound of Formula (IJ-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and r2jj, £3j3, £4j3, ancj £5,3 are eack independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Cne alkyl. In some embodiments, R^, R2j3, R^3, R4-*3, and R3p are each H.

[0137] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IK-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0138] In some embodiments, the compound of Formula (IK-N), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IK-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0139] In some embodiments, the compound of Formula (I) or (IK-N) is a compound of Formula (IK-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Rlkj, R2k3, R3kj, R4k3, and R5k3 are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Cu6 alkyl. In some embodiments, Rlk3, R2k3, R3k3, R4kJ, and R’K3 are each FI

[0140] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IL-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: I            Formula (SL-N) R3'

[0141] In some embodiments, the compound of Formula (IL-N), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IL-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0142] In some embodiments, the compound of Formula (I) or (IL-N) is a compound of Formula (IL-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Rn3, R2b, R313, R4U, and R5B are each independently selected from H, halo, Ci-6 alkyl, Cn6 haloalkyl, and -O-Ci-6 alkyl. In some embodiments, R113, RZ1J, R313, R413, and R513 are each H.

[0143] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IM), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0144] In some embodiments, Rla and Rla, R2a and R2a, R3a and R3a’, R20 and R2b, R3b and R3b’, R18 and R18’, R38 and R38’, Rlf and Rlf, R2f and R2f, Rlm and Rlm’, R2™ and R2m’, R3m and R3,n’, or R4m and R4m, when combined to form a cycloalkyl ring or heterocyclic ring, form

[0145] In some embodiments, Rla and Rla, R2a and R2a, R3a and R3a, R2” and R2b, R3b and R3b , R!c and Rtc, R2c and R2c, R!a and Rid, R~’d and R3d , Rls and R!e, R3e and R3e, Rjt and R!t, R2f and R2r, R2g and R2g', Rlh and Rlh’, R31 and R3i’, R3j and R3j’, Rlm and Rlm’, R2m and R2m’, R3m and R3m , or R4m and R4m’, when combined to form a cycloalkyl ring or heterocyclic ring, form

[0146] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IHA3X (IH-O), (Si-N), (HAS), (U A), CM AS), (IKA), MK AS), (ILA), (ILA3), and (IM), or the pharmaceutically acceptable salts or tautomers thereof, n is 0. In some embodiments, n is 1.

[0147] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IBA), (IBAS), (IB-O), (IC-N), (ICA3), (IC-O), (ID-O), (ID-S), (ID-S02), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IHA3), (IH-O), (li-N), (HA3), (IJ-N), (IJA3), (IK-N), (IK A3 ), (ILA), (IL-N3), and (IM), or the pharmaceutically acceptable salts or tautomers thereof Y1 is CIMh).

[0148] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IBA), (IB A3), (IB-O), (IC-N), (ICA3), (IC-O), (ID-O), (ID-S), (ID-S02), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (H I A3). (IH-O), (li-N), (H A3), (IJ AI (M A3), (IK-N), (IK A3 ), (ILA), (IL-N3), and (IM), or the pharmaceutically acceptable salts or tautomers thereof, Y1 is C(C1).

[0149] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IBA), (IB-N3), (IB-O), (IC-N), (ICA3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IHA3), (IH-O), (liA), (IiA3), (U-N), (IJ-N3), (IK-N), (IKA3), (ILA), (IL-N3), and (IM), or the pharmaceutically acceptable salts or tautomers thereof, Y1 is C(F).

[0150] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IBA), (IB-N3), (IB-O), (IC-N), (ICA3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (liA), (Ii-N3), (MX). (IJ-N3), (IK-N), (IKA3), (IL-N), (IL-N3), and (IM), or the pharmaceutically acceptable salts or tautomers thereof, Y3 is C(CFs).

[0151] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IH-N), (IH-N3), and (IH-O), or the pharmaceutically acceptable salts or tautomers thereof, Rla and Rla’, Rlc and Rlc’, Rld and RkV, Rle and Rle, Rlf and R11, or RIi3 and R’lh are each CH3. In some embodiments, Rla and Rka, Rlc and Ric’, Rld and Rld’, Rie and R,e’, Rb and Rlf, or Rlh and R1M’ are each H.

[0152] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (ICA3), (IC-O), (IF), (IGA), (IG A3), and (IG-O), or the pharmaceutically acceptable salts or tautomers thereof, R2a and R2a, R2b and R2b, R2c and R2c, R2t and R2f, or R2g and R2g’ are each CH3. In some embodiments, R2a and R2a’, R2b and R2b , R2c and R2c’, R21 and R2t, or R2® and R2g’ are each H.

[0153] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IBA), (IB-N3), (IB-O), (IC-N), (ICA3), (IC-O), (IF), (IG-N), (IG A3), and (IG-O), or the pharmaceutically acceptable salts or tautomers thereof R2a and R2a’ are CH3 and H respectively, R2b and R2b are CH3 and H respectively, R2c and R2c’ are CH3 and H respectively, R2f and R2t are ( 1 h and H respectively, or R2g and R2g’ are CH3 and H respectively.

[0154] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (UFO). (ID-O), (ID-S), (ID-SO2), (IE), (li-N), (Ii-N3), (IJ-N), and (IJ-N3), or the pharmaceutically acceptable salts or tautomers thereof, R3a and Rja, R3b and R3b’, Rjd and R3d, R3e and R3e, R31 and R3’’, or R3j and R1-1 are each CH3. In some embodiments, R3a and R3a’, R3b and R3b’, R3d and R3d’, R3e and R3e’, R3i and R3i’, or R3j and R3j’ are each H.

[0155] In some embodiments, the disclosure provides a compound of Formula (II): R"2 RIIS Formula (II) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each — independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein: X1 is NR1, X2 is CR2, and X3 is N or CH; X1 is O, X2 is CR2, and X3 is N; Xs is N, X2 is NR1, and X3 is N; or X1 is NR3, X2 is N, and X3 is N; n is 0 or 1; R1 is selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, and, Ci-6 alkyl-aryl, or heteroaryl of R1 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; R2 is selected from H, halo, Ci-6 haloalkyl, NO2, CN, SO2-C1-6 alkyl, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; R1 is selected from C4-6 alky], cycloalkyl, aryl substituted with one or more substituents selected from the group consisting of halo and methyl, benzyl substituted with one or more F, and heteroaryl; R111, RIU, RU3, R114, and R115 are each independently selected from H, halo, Cn6 haloalkyl, NO2, CN, and SOz-Cne alkyl.

[0156] In some embodiments, X1 is NR1, X2 is CR2, and X3 is N or CH. In some embodiments, X1 is O, X2 is CR2, and X’ is N. In some embodiments, X1 is N, X2 is NR1, and X3 is N. In some embodiments, X1 is NR3, X2 is N, and X3 is N.

[0157] In some embodiments, the compound of Formula (II), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IIA-C), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0158] In some embodiments, the compound of Formula (IIA-C), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IIA-C3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0159] In some embodiments, the compound of Formula (II) or (IIA-C) is a compound of Formula (IIA-C3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Rla, Rlb, Rlc, Rld, and Rle are each independently selected from H, halo, C1.6 alkyl, C1.6 haloalkyl, and -O-C1-6 alkyl. In some embodiments, Rla, Rlb, Rlc, Rld, and R18 are each H. In some embodiments, the compound of Formula (HA-C3) is

[0160] In some embodiments, the compound of Formula (II), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IIA-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0161] In some embodiments, the compound of Formula (IIA-N), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IIA-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0162] In some embodiments, the compound of Formula (II) or (IIA-N) is a compound of Formula (IIA-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Rla, Rlb, Rlc, Rld, and Rle are each independently selected from H, halo, Cue alkyl, Cue haloalkyl, and -O-Ci-6 alkyl. In some embodiments, Rla, R1D, RIC, Rld, and Rle are each H.

[0163] In some embodiments, the compound of Formula (II), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IIB), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formuia (MB)

[0164] In some embodiments, the compound of Formula (IIB), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (HB3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (HB3)

[0165] In some embodiments, the compound of Formula (II) or (IIB) is a compound of Formula (IIB3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and R2a, R2b, R2c, R2d, and R2e are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl. In some embodiments, R2a, R20, R2c, R2d, and R2e are each H.

[0166] In some embodiments, the compound of Formula (II), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (DC), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (HC)

[0167] In some embodiments, the compound of Formula (HC), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IIC3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (HC3)

[0168] In some embodiments, the compound of Formula (II) or (IIC) is a compound of Formula (IIC3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Ria, Rib, Ric, Ria, anj Rie are eac|1 independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl. In some embodiments, Rla, Rlb, Rlc, Rld, and Rle are each H. In some embodiments, one of Rla, Ri0, Rlc, Rld, and Rle is halo, and each of the others is H. In some embodiments, RIC is F, and Rka, Rlb, Rld, and Rle are each H.

[0169] In some embodiments, the compound of Formula (II), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IID), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0170] In some embodiments, the compound of Formula (II) is a compound of Formula (IID), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and R3 is C4-6 alkyl or phenyl substituted with one or more halo. In some embodiments, R3 is phenyl substituted with F. In some embodiments, RJ is phenyl substituted with one instance of F. In some embodiments, RJ is C4 alkyl. In some embodiments, R3 is tert-butyl. ?               . In some

[0171] In some embodiments, the compound of Formula (IID) is embodiments, the compound of Formula (IID) is

[0172] In some embodiments of the compounds of Formulae (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (HB3), (IIC), (IIC3), and (IID), or the pharmaceutically acceptable salts or tautomers thereof, RU1 is H or NO2. In some embodiments, Rin is H. In some embodiments, RI1! isNO2.

[0173] In some embodiments of the compounds of Formulae (II), (IIA-C), (HA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), and (IID), or the pharmaceutically acceptable salts or tautomers thereof, Rlb is H or CF3. In some embodiments, R1B is H. In some embodiments, R113 is CF3.

[0174] In some embodiments, the disclosure provides a compound of Formula (III): O O R!!!1 Formula (III) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from the group consisting of C3-6 cycloalkyl, Ci alkyl-C3-6 cycloalkyl, aryl. Ci alkyl-aryl, heteroaryl, and Ci alkyl-heteroaryl; wherein the C3-6 cycloalkyl, Ci alkyl-C3-6 cycloalkyl, aryl, Ci alkyl-aryl, heteroaryl, or Ci alkyl-heteroaryl of R1 is unsubstituted or substituted with halo; R111’, Rm2, Rm3, Rm4, and R1U' are each independently selected from H, halo, Ci-6 haloalkyl, NO2, CN, and SO2-C1.6 alkyl.

[0175] In some embodiments of the compounds of Formula (III), or the pharmaceutically acceptable salts or tautomers thereof, R! is aryl or Ci alkyl-aryl, wherein the aryl or Ci alkyl-aryl may be unsubstituted or substituted with one or more halo. In some embodiments, R1 is cycloalkyl or Ci alkyl-cycloalkyl, wherein the cycloalkyl or Ci alkyl-cycloalkyl may be unsubstituted or substituted with one or more halo. In some embodiments, R1 is phenyl substituted with one or more F. In some embodiments, R1 is benzyl substituted with one or more F. In some embodiments, Rl is benzyl substituted with one or more Cl. In some embodiments,

[0176] In some embodiments of the compounds of Formula (III), or the pharmaceutically acceptable salts or tautomers thereof, Rmi is H or NO2. In some embodiments, R11U is H. In some embodiments, Rnn is NO2.

[0177] In some embodiments of the compounds of Formula (III), or the pharmaceutically acceptable salts or tautomers thereof, R1112 is H, halo, or SO2-C1-6 alkyl. In some embodiments, R!l12 is H. In some embodiments, R1112 is halo. In some embodiments, is SO2-C1-6 alkyl.

[0178] In some embodiments of the compounds of Formula (III), or the pharmaceutically acceptable salts or tautomers thereof, R1113 is H or CF3. In some embodiments, R1113 is H. In some embodiments, Rm3 is CF3.

[0179] In some embodiments, the disclosure provides a compound of Formula (IV): Formula (IV) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each — independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein: Y1 is CR1, Y2 is N, and Y! is NR3, Y1 is CR1, Y2 is O or S, and Y3 is CR3; Y1 is N, Y2 is CR2, and Y3 is O or S; or Y1 is 0 or S, Y2 is CR2, and Y3 is CR3, R1 and R2 are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or and of R1 or R2 is un substituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-e alkyl, Ci-6 haloalkyl, and -CO(O)-Ci~6 alkyl; RJ is H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl; wherein the Cj.g alkyl, Cj.g haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl of R3 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-s alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; or R’ combines with RIV2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; R1Vl is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-e alkyl-aryl, or heteroaryl of R13'1 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; R1V2 is H, halo, Ci-6 haloalkyl, NO2, CN, and SO2-C1-6 alkyl, or R132 combines with r3 form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl.

[0180] In some embodiments, R3 and RIV2 combine to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring. In some embodiments, RJ and RIV2 combine to form a Cs-io aryl ring. In some embodiments, R3 and R13,2 combine to form a heteroaryl ring comprising 4 to 8 carbon atoms and 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, RJ and RIV2 combine to form a C3-6 cycloalkyl ring. In some embodiments, R3 and R1V2 combine to form a Cs-g cycloalkyl ring. In some embodiments, R3 and RIV2 combine to form a heterocyclic ring comprising 3 to 8 carbon atoms and 1 or 2 heteroatoms selected from oxygen, V-—N nitrogen, and sulfur. In some embodiments, R3 and RiV2 combine to form \.

[0181] In some embodiments, the compound of Formula (IV), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IVA), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVA)

[0182] In some embodiments, the compound of Formula (IVA), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IV A3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVA3)

[0183] In some embodiments, the compound of Formula (IV) or (IVA) is a compound of Formula (IVA3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and Ri'-'Ja, Rivw rivr anj Rivie are each independently selected from H, halo, Cn6 alkyl, Cue haloalkyl, and -0-0.-6 alkyl. In some embodiments, RIV1C is F, and RIvla, Rlvlb, RA ,d, and RIvle are each H. In some embodiments, RIV!a, RIVtb, Rmc, Rn ]d, and RIVie are each H.

[0184] In some embodiments, the compound of Formula (IV), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IVB-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVB-O)

[0185] In some embodiments, the compound of Formula (IVB-O), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IVB-O3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formuia (IVB-O3)

[0186] In some embodiments, the compound of Formula (IV) or (IVB-O) is a compound of Formula (IVB-O3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and R!Vla, RIvib, R1^10, RIvla, and R1Ms are each independently selected from H, halo, Ci-6 alkyl, Ci-e haloalkyl, and -O-Ci-6 alkyl. In some embodiments, R1Vlc is F, and R1Vla RIvlb, RIvld, and R1Vle are each H. In some embodiments, Rma, RIV!o, RIV!c, RIVid, and R1^6 are each H.

[0187] In some embodiments, the compound of Formula (IV), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IVB-S), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: O O R1 Formula (IVB-S)

[0188] In some embodiments, the compound of Formula (IVB-S), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IVB-S3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: RIV1b Formula (M3-S3)

[0189] In some embodiments, the compound of Formula (IV) or (IVB-S) is a compound of Formula (IVB-S3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and R!Vla, RIvlb, RIV1C, Rlvld, and RIvle are each independently selected from H, halo, Ci-6 alkyl, Cw haloalkyl, and -O-Ci-6 alkyl. In some embodiments, R1Vla, RIvlb, Rlvlc, Rp''!d, and Rlvle are each H.

[0190] In some embodiments, the compound of Formula (IV), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IVC-S), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVC-S)

[0191] In some embodiments, the compound of Formula (IVC-S), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IVC-S3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: RIV1b Formula (IVC-S3)

[0192] In some embodiments, the compound of Formula (IV) or (IVC-S) is a compound of Formula (IVC-S3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and R1Vla RIvlb, RIV1C, Rlvld, and RIvle are each independently selected from H, halo, Ci-6 alkyl, Cw haloalkyl, and -O-Ci-6 alkyl. In some embodiments, R1VJc is F, and R1VJa, RIvlb, Rlvld, and R1VJe are each H. In some embodiments, RIv la, RWlb, RIV1C, RIvld, and RIV!e are each H.

[0193] In some embodiments, the compound of Formula (IV), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IVD), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: R3 Formula (IVD)

[0194] In some embodiments, the compound of Formula (I VD ), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IVD3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Formula (IVD3)

[0195] In some embodiments, the compound of Formula (IV) or (IVD) is a compound of Formula (IVD3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and R1Vla, RIvlb, RIV1C, RiVld, and RIvle are each independently selected from H, halo, Ci-6 alkyl, Cw haloalkyl, and -O-Ci-6 alkyl. In some embodiments, R1Vla RI, / lb, RIV1C, Rn ,d, and Rlvle are each

[0196] In some embodiments of the compounds of Formulae (IV), (IVA), (IV A3), (IVB-O), (IVB-03), (IVB-S), and (IVB-S3), or the pharmaceutically acceptable salts or tautomers thereof, R1 is H or CF3. In some embodiments, R! is H. In some embodiments, R1 is CF3.

[0197] In some embodiments of the compounds of Formulae (TV), (IVC-S), (IVC-S3), (IVD), and (IVD3), or the pharmaceutically acceptable salts or tautomers thereof, R2 is H or CF3. In some embodiments, Rz is H. In some embodiments, R2 is CF3.

[0198] In some embodiments of the compounds of Formulae (IV), (IVA), (IVAS), (IVB-O), (IVB-O3), (IVB-S), (IVB-S3), (IVD), and (IVD3), or the pharmaceutically acceptable salts or tautomers thereof, R3 is H or Cue, alkyl. In some embodiments, R3 is H. In some embodiments, R3 is Ci-6 alkyl.

[0199] In some embodiments, the compound, or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is selected from the group consisting of the following Table 1 compounds: Compound Nos. I, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 110, 111, 112, 113, 114, 116, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, and pharmaceutically acceptable salt and tautomers of any of the foregoing. acceptable salt or tautomer of any of the foregoing. In some embodiments, the compound is O O Cl , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof In some embodiments, the compound is                          F , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0201] The present disclosure also provides a pharmaceutical composition comprising a compound of Formulae (I), (LA), (I.A3), (IB-N), (1BA3), (IB-O), (IC-N), (IC-N3), (IC-O), (IDO), (ID-S), (ID-S02), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (11 L \3). (IH-O), (li-N), (li-N3),        (IJ-N3),         (IK-N3), (IL-N), (IL-N3), (IM), (II), (HA-C), (IIA-C3), (IIA-N), (HA-X3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (TVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), or (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing, and a pharmaceutically acceptable carrier.

[0202] Unless otherwise stated, structures depicted herein are also meant to include pharmaceutically acceptable salts, tautomers, and stereoisomers thereof. Accordingly, embodiments of the present disclosure are directed to compounds and methods of using compounds of Formulae (I), (I A), (I A3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (IDO), (ID-S), (ID-S02), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (li-N3), (IJ-N), (IJ-N3) HK-\), (IK-N3), (IL-N), (IL-N3), (IM), (II), (HA-C), (IIA-C3), (IIA-N), (HA-X3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII) and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof. Moreover, reference to compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (IDO), (ID-S), (ID-S02), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (li-N3), (IJ-N), (1J-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (HA-N), (IIA-N3), (IIB), (HB3). (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-Sr (IVB-S3), (IVC-S), HVC-S3). (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII) and pharmaceutically acceptable salts and tautomers thereof is considered to include reference to stereoisomers of any thereof.

[0203] In some embodiments, the compound is a stereoisomer of a compound of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (HB3k (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), or (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0204] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically-enriched atoms. For example, compounds having the present structure except for the replacement of a hydrogen atom by deuterium or tritium, the replacement of a carbon atom by 13C or 14C, the replacement of a nitrogen atom by {5N, or the replacement of an oxygen atom by : '0 or {8O are within the scope of the present disclosure. Such isotopically-labeled compounds are useful as research or diagnostic tools.

[0205] “Alkyl,” as used herein, refers to an unbranched or branched saturated hydrocarbon chain. In some embodiments, alkyl as used herein has 1 to 6 carbon atoms (Cue alkyl.) In some embodiments, Ci-6 alkyl refers to a group with 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, alkyl as used herein has 2 to 6 carbon atoms (Cs-ealkyl). in some embodiments, Ca-galkyl refers to a group with 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pemJ. isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methyl pentyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed. Thus, for example, “butyl” can include n-butyl, sec-butyl, isobutyl and t-butyl, and “propyl” can include n-propyl and isopropyl. In some embodiments, an alkyl (e.g., Ci-6 alkyl) is bound to another atom to form an ether (e.g., -O-Cw alkyl), an ester (e.g, -C0(0)-Cj-6 alkyl), an aryl attached via the alkyl (e.g., -Cue alkyl-aryl), an aryl substituted with an alkyl (e.g., -aryl-Cu6 alkyl), a heteroaryl attached via the alkyl (e.g, -Ci-6 alkyl-heteroaryl), a heteroaryl substituted with an alkyl (e.g., -heteroaryl-Ci-6 alkyl).

[0206] “Alkoxy,” as used herein, refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). In some embodiments, alkyl as used herein has 1 to 6 carbon atoms (-O-Ci-6 alkyl.) In some embodiments, -O-Ci-6 alkyl refers to a group with 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0207] “Cycloalkyl” or “cycloalkyl ring,” as used herein, refers to a saturated or partially saturated, monocyclic, fused or spiro polycyclic, carbocycle having from 3 to 18 carbon atoms per ring. In some embodiments, the cycloalkyl is a saturated, monocyclic carbocycle. In some embodiments, the cycloalkyl has 3 to 6 carbon atoms (C3-6 cycloalkyl.) In some embodiments, C3-6 cycloalkyl refers to a group with 3, 4, 5, or 6 carbon atoms. In some embodiments, the €3-6 cycloalkyl is a saturated, monocyclic carbocycle having 3 to 6 (i.e., 3, 4, 5, or 6) carbon atoms. In some embodiments, the cycloalkyl is a saturated, monocyclic carbocycle. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, and cyclooctanyl. In some embodiments, C3.6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0208] “Aryl” or “aryl ring,” as used herein, refers to a monocyclic or polycyclic group having at least one hydrocarbon aromatic ring wherein all of the ring atoms of the at least one hydrocarbon aromatic ring are carbon. Aryl may include groups with a single aromatic ring (e.g., phenyl) and multiple fused aromatic rings (e.g, naphthyl, anthryl). Aryl may further include groups with one or more aromatic hydrocarbon rings fused to one or more non-aromatic hydrocarbon rings (e.g., fluorenyl; 2,3-dihydro-lH-indene; 1,2,3,4-tetrahydronaphthalene). In some embodiments, aryl as used herein has from 6 to 14 (6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms ((C6-Cu)aryl), or 6 to 10 (6, 7, 8, 9, or 10) carbon atoms ((C6-Cio)atyl). Where the atyl includes fused rings, the aryl may connect to one or more substituents or moieties of the Formulae described herein through any atom of the fused ring for which valency permits. In some embodiments, the aryl has 6 carbon atoms (Cgaryl). In some embodiments, the aryl is a phenyl.

[0209] “Heteroaryl” or “heteroaryl ring,” as used herein, refers to a monocyclic or polycyclic group comprising at least one aromatic ring, wherein the aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S. The heteroaryl group may comprise 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, where ring atoms refer to the sum of carbon and heteroatoms in the one or more rings (e.g., be a 5-membered, 6-membered, 7membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered heteroaryl). In some embodiments, heteroaryl includes groups with an aromatic ring that comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S, (e.g., pyridinyl, pyrazinyl, furanyl, thiophenyl). In certain embodiments, heteroaryl includes polycyclic groups with an aromatic ring comprising at least one ring heteroatom, fused to a non-aromatic hydrocarbon ring (e.g., 5,6,7,8-tetrahydroquinolinyl; 4,5,6,7-tetrahydroisobenzofuranyl). In some embodiments, heteroaryl includes polycyclic groups with an aromatic ring comprising at least one ring heteroatom fused to an aromatic hydrocarbon ring (e.g., quinolinyl, quinoxalinyl, benzothiazolyl). In still further embodiments, heteroaryl includes polycyclic groups with two fused aromatic rings, wherein each ring comprises at least one ring heteroatom (e.g., naphthyridinyl). Heteroaryl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each ring heteroatom is independently selected from the group consisting of N, O, and S. In one example, a heteroaryl has 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from N, O, and S. Examples of heteroaryl groups include, without limitations, pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, and pyrazolyl.

[0210] “Heterocycle” or “heterocyclic ring,” as used herein, refers to a saturated or partially unsaturated and non-aromatic monocyclic or fused or spiro polycyclic ring structure of 4 to 18 atoms containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur wherein there is not delocalized rr-electrons (aromaticity) shared among the ring carbon or heteroatoms. Examples of heterocyclic rings include, but are not limited to, imidazolidin-2-one, oxadiazole (e.g., 1,2,5-oxadiazole), oxetane, azetidine, tetrahydrofuran, pyrrolidine, oxazoline, oxazolidine, thiazoline, thi azoli di ne, pyran, thiopyran, tetrahydropyran, dioxane, piperidine, morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, piperazine, azepine, oxepine, diazepine, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, 2,5-dihydro-IH-pyrrole, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, l,3-dioxolan-2-one, isothiazolidine-1,1-dioxide, 4,5-dihydro-lH-imidazo1e, 4,5-dihydrooxazo1e, oxirane, pyrazolidine, 4H-l,4-thiazine, thiomorpholine, 1,2,3,4-tetrahydropyridine, 1,2,3,4-tetrahydropyrazine, l,3-oxazinan-2-one, tetrahydro-2H-thiopyran 1,1-dioxide, 7-oxabicyclo[2.2. l]heptane, 1,2-thi azepane-1,1 -dioxide, octahydro-2H-quinoHzinyl, 1,3-diazabicyclo[2.2.2]octane, 2,3-dihydrobenzo[b][l,4]dioxine, 3-azabicyclo[3.2.IJoctane, 8-azaspiro[4.5]decane, 8-oxa-3-azabicyclo[3.2.IJoctane, 2-azabicydo[2,2.IJheptane, 2,8-diazaspiro[5.5Jundecane, 2-azaspiro[5.5]undecane, 3-azaspiro[5.5]undecane, decahydroisoquinoline, l-oxa-8-azaspiro[4.5Jdecane, 8-azabicyclo[3.2. IJoctane, 1,4’-bipiperidine, azepane, 8-oxa-3-azabicyclo[3.2.IJoctane, 3,4-dibydro-2H-benzo[b][l,4]oxazine, 5,6,7,8-tetrahydroimidazo[l,2-aJpyridine, 1,4-di azepane, phenoxathiine, benzo[d][l,3]dioxole, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][l,4]dioxine, 4-(piperidin-4-yl)morpholinyl, 3-azaspiro[5.5]undecane, decahydroquinoline, piperazin-2-one, l-(pyrrolidin-2-ylmethyl)pyiTolidine, 1,3’-bi pyrrolidine, and 6,7,8,9-tetrahydro~lH,5H-pyrazolo[1,2-a][l,2]diazepine. In some embodiments, the heterocyclic ring is imidazolidin-2-one. In some embodiments, the heterocyclic ring is oxadiazole (e.g., 1,2,5-oxadiazole). [0211J As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0212] As used herein, the term “unsubstituted” means that the specified group bears no substituents,

[0213] “Halo,” as used herein, refers to fluoro, chloro, bromo, or iodo radicals.

[0214] “Haloalkyl,” as used herein, refers to an alkyl group (e.g, Ci-6 alkyl) substituted with one more halogen (e.g., fluoro, chloro, bromo, or iodo radicals.)

[0215] In some embodiments, haloalkyl has 1 to 6 carbon atoms (Ci-6 haloalkyl) substituted with one more halogen (e.g., fluoro, chloro, bromo, or iodo radicals.) In some embodiments, Cue haloalkyl refers to a group with 1, 2, 3, 4, 5, or 6 carbon atoms substituted with 1, 2, 3, or more halogen (e.g., fluoro, chloro, bromo, or iodo radicals.) In some embodiments, the halogen is fluoro. In some embodiments, the halogen is chloro. In some embodiments, the halogen is bromo. Examples of Ci-6 haloalkyl include, but are not limited to, tri fluoromethyl (CF3).

[0216] It should be understood that when a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6 alkyl” (which may also be referred to as C1-C6 alkyl, CnCe alkyl, or Cue, alkyl) is intended to encompass Ci, C2, C3, C4, C5, C6, C1.6, C1.5, Cm, Ci-3, C1-2, C2-6, C2-5, C2.4, C2.3, C3.6, C3-5, C3.4, C4-6, C4-5, and C5-6 alkyl.

[0217] It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0218] It should be understood that all geometric isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans- configuration.

[0219] The compounds of the various Formulae may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that, all stereoisomeric forms of the compounds of the various Formulae as well as mixtures thereof, including racemic mixtures, form part, of the present disclosure. In addition, the present disclosure embraces all geometric isomers. For example, if a compound of the various Formulae incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the present disclosure. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[0220] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically-active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the various Formulae may be atropisomers (e.g., substituted biaryls) and are considered as part of the present disclosure. Enantiomers can also be separated by use of a chiral HPLC column.

[0221] In some embodiments, the compounds of Formulae (I), (IA), (IA3), (IB-N), (TB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (DBA), (IIC), (IIC3), (HD). CH). (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), (VIII) and pharmaceutically acceptable salts or tautomers of any of the foregoing are enantiomers. In some embodiments, the compounds or pharmaceutically acceptable salts or tautomers thereof are the (S)-enantiomer. In other embodiments the compounds or pharmaceutically acceptable salts or tautomers thereof are the (A)-enantiomer. In some embodiments, the compounds or pharmaceutically acceptable salts or tautomers thereof are the (+) enantiomer or (-) enantiomer.

[0222] Some embodiments are directed to isotopically-labelled compounds 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 an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H (or D), 3H, 13C, 14C, l5N, 18O, i7O,3iP, 32P, 35S, iSF, and 36C1, respectively.

[0223] Certain isotopically-labelled compounds of the various Formulae (e.g., those labeled with 3H and 14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) 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. Isotopically-labelled compounds of the various Formulae can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below by substituting an appropriate isotopically-labelled reagent for a nonisotopically-labelled reagent.

[0224] The compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (K'-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (H-X), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-X3I (IM), (II), (uA-C), (IIA-C3), (HA-N), (IIA-N3), (HB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), (VIII), and pharmaceutically acceptable salts or tautomers of any of the foregoing may form salts which are also within the scope of the present disclosure. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

[0225] The present disclosure is directed to compounds as described herein and pharmaceutically acceptable salts or tautomers thereof. The present disclosure is also directed to pharmaceutical compositions comprising one or more compounds as described herein or pharmaceutically acceptable salts or tautomers thereof.

[0226] “Pharmaceutically acceptable,” as used herein, refers to that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use. For example, provided herein is a pharmaceutical composition comprising a compound of Formulae (I), (IA), (I A3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (IDO), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), HK-X3), (IL-N), (IL-N3), (IM), (II), (U A-C). (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-0), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing, and a pharmaceutically acceptable excipient.

[0227] “Pharmaceutically acceptable salt,” as used herein, refers to a salt which is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use.

[0228] In some embodiments, a compound of the disclosure inhibits HPD. In some embodiments, a compound of the disclosure comprises no or minimal inhibitory activity for SPR (e.g:, selectively inhibits HPD over SPR). Methods of Synthesizing the Compounds

[0229] The compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (HA-C), (UA-C3), (IIA-N), (HA-N3). (IIB), (IIB3), (IIC), (IIC3), (HD), (III), (IV), (IVA), (IVA3), (IVB-0), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII) and pharmaceutically acceptable salts or tautomers thereof may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic scheme and in light of the teaching provided herein. In the scheme described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessaryin accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, which is hereby incorporated by reference in its entirety). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of the disclosed compounds (e.g., Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-0), (ID-S), (ID-S02), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (HA-C), (IIA-C3), (HA-X), (IIA-N3), (IIB), (HB3). (IIC), (HC3y (IID), (III), (IV), (IVA), (IVA3), (IVB-0), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII) and pharmaceutically acceptable salt, stereoisomer, or tautomer thereof).

[0230] The compounds described in this patent were synthesized using the following general scheme shown on compound 1 as an example. This synthetic approach was described in detail before for nitisinone (WO2015101794Al, which is hereby incorporated by reference in its entirety). Briefly, the compounds were synthesized by a two-step reaction in which an appropriate benzoic acid (or analogue as required) was used to prepare its acyl chloride. In the second step, the acyl chloride was reacted with the appropriate 1,3-diketone in alcohol-free chloroform. In step 2 of the reaction, 1,3-diketone reacts with acyl chloride in the presence of triethylamine to give an unstable O-alkyl intermediate, which converts into the final product using a catalytic amount of trimethyl silylcyanide. The final product was obtained using an acidbase extraction and further purified by HPLC. The general reaction scheme is given using compound 1 as an example. Any changes to the procedure used for specific products as well as synthesis of precursors where they were not available are described in detailed examples below. Scheme 1: General Synthetic Scheme DCM, (COCI)z (1.05 eq), DMF RT. 24 h CHCfa, NEt3 (3 eq), TMSCN (0.05 eq) RT. 24 h Those skilled in the art will recognize if a stereocenter exists in the disclosed compounds (e.g., Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (H-X). (h-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (HA-X). (HA-X3), (IIB), (IIB3), (IIC), (IIC3), (HD), (III), (IV), (IVA), (IVAS), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII) and pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994), which is hereby incorporated by reference in its entirety.

[0231] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0232] Compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (H-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK X3), (IL-N), (IL-N3), (IM), (II), (HA-C), (IIA-C3), (IIA-N), (HA-X3), (IIB), (UB3), (IIC), (IIC3), (HD), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII) and pharmaceutically acceptable salts or tautomers thereof can be prepared according to procedures outlined in Schemes and Examples herein. In the Examples section, compounds of the present disclosure are further exemplified by specific examples. Unless otherwise specified, all temperatures \vere expressed in °C and all reactions are conducted at room temperature. Pharmaceutical Compositions

[0233] The compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (HA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-O3), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), (VIII), and pharmaceutically acceptable salts or tautomers of the foregoing may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the disclosed compound or pharmaceutically acceptable salts or tautomers thereof is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs”, M. E. Aulton, Churchil l Livingstone, 1988, which is hereby incorporated by reference in its entirety.

[0234] The term “pharmaceutically acceptable carrier,” as used herein, encompasses one or more carriers, excipients, and diluents and refers to a material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body, of a subject. Excipients should be selected on the basis of compatibility and the release profile properties of the desired dosage form. Exemplary pharmaceutically acceptable carriers include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, and the like.

[0235] The present disclosure provides a pharmaceutical composition comprising a compound of Formulae (I), (IA), (IA3), (1B-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (H-X), (Ii-N3), (IJ-N), (U-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (BC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), or (V H1), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing, and a pharmaceutically acceptable carrier.

[0236] The present disclosure also provides a compound of Formulae (I), (IA), (IA3), (EB-N), (IB A3). (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IGA), (IG-N3), (IG-Oh (H IA), (IH-N3), (IH-O), (hA), (E-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIAA3), (11B), (IIB3} (HC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-0), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing, for use in medicine.

[0237] The present disclosure also provides a pharmaceutical composition comprising a compound of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (IDO), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (li-N3), (IJ-N), (IJ-N3), (IKA). (IK-N3), (IL-N), (1L-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (DC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-0), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0238] The present disclosure further provides a process for the preparation of a pharmaceutical composition of the present disclosure which comprises mixing a compound of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC A3). (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (HA-N3), (IIB), (IIB3), (IIC), (HC3), (IID), (III), (IV), (IVA), (IVAS), (IVB-0), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing, with a pharmaceutically acceptable adjuvant, diluent or carrier.

[0239] Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 to about 99 %w (per cent by weight), more particularly from about 0.05 to about 80 %w, still more particularly from about 0.10 to about 70 %w, and even more particularly from about 0.10 to about 50 %w, of active ingredient, all percentages by weight being based on total composition.

[0240] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are liquids in vials or ampoules. Aqueous suspension compositions can be packaged in singledose non-reciosable containers. Multipie-dose reclosable containers can be used, for example, in combination with a preservative. Formulations for parenteral injection can be presented in unit dosage form, for exampie, in ampoules, or in multi-dose containers with a preservative. Methods of Treatment

[0241] In some embodiments, disclosed herein is a method of treating a condition (e.g., a condition that is responsive to modulation or inhibition of HPD, for example, tyrosinemia), the method comprising administering to a subject in need thereof a therapeutically effective amount of an HPD inhibitor with no or minimal off-target inhibitory activity for SPR. In some embodiments, the HPD inhibitor is a selective HPD inhibitor.

[0242] The terms “treat,” "treating,” or “treatment,” as used herein, refer to any indicia of success in the amelioration of a disorder (such as injury, disease pathology, or condition), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disorder more tolerable to the subject; slowing or stopping the rate of degeneration, decline, or development; slowing the progression of disorder; making the final point of degeneration less debilitating; improving a subject’s physical or mental well-being; or relieving or causing regression of the disorder. The treatment of symptoms, including the amelioration of symptoms, can be based on objective or subjective parameters, which may include the results of a physical examination, a neuropsychiatric exam, and / or a psychiatric evaluation.

[0243] The terms “administered,” “administration,” or “administering,” as used herein, refer to either directly administering a disclosed compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of the disclosed compound or a composition to a subject, including an animal, in need of treatment by bringing such individual in contact with, or otherwise exposing such individual to, such compound.

[0244] As used herein, the term “subject” encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the present disclosure, the mammal is a human.

[0245] In some embodiments, the disclosure provides a compound of Formula (V). In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (V): O Y1' 'Y3 yl U Ik ,Jy4 X2 ..z2 'X3 Formula (V) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, or all together form an aryl ring or heteroaryl ring, wherein: X1 is CRlaRia’, X2 is CR2aR2a', and X3 is CR3aR3a’; X1 is NRlb or O, X2 is CR2bR2b’, and X3 is CR3bR3b’; X’1 is CRlcRlc', X2 is CR^R20’, and X3 is NR3c or O; X1 is CRldRid\ X2 is O, S, or S(O2), and X3 is CR3dR3d’; Xs is CRleR‘e’, X2 is C(O), and X3 is CR3eR3e’; X! is CRnRlf, X2 is CR21^, and X3 is a bond; X! is NRlg or O, X2 is CR2gR2g, and X3 is a bond; X’1 is CRlbRlh, X2 is NR2h or 0, and X3 is a bond; X1 is XRb or 0, X2 is C(0), and X3 is CRbRd: X1 is NR1-’ or 0, X2 is NR2j or 0, and X3 is CR-R3^; X1 is NR1K or 0, X2 is NR2k or 0, and X3 is a bond; X! is NR11 or 0, X2 is C(0), and X’ is NR~’! or O; or X1 is CRlmRlm’, X2 is CR2mR2m’, and X3 is CR3mR3m’-CR4mR4m’; Z1 and Z2 are each independently selected from C(0) and S(02); Rla and Rla’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -C0(0)-Ci-6 alkyd, and aryk R2a and R2a’ are each independently selected from H, C2-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyd, and aryl; R3a and R3a are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; If Z! and Z2 are both C(O), then at least one of Rla, Rla’, R2a, R2a’, R3a, or R3a’ is C1-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl; wherein the aryl of Rla, Rla’, R2a, R2a’, Rja, or Rja is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, C1-6 haloalkyl, and -C0(0)-Ct-6 alkyl; or two or more of Rka, Rla, R2a, R2a, R3a, and R3a combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, C1-6 haloalkyl, and -CO(O)-Cu6 alkyl, and any uncombined Rla, Rla, R2a, R2a, R3a, or R3a’ are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of R!a, Rla , R2a, R2a’, R3a, or R3a is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; R2b, , ^3b, anj ^3b are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of R2b, R2b’, R3b, or R3b’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; or two or more of R!o, R2b, R3b, and R3b’ combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined Rlb, R2b, R2b , R3b, or R3b are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and and; wherein the aryl of Rlb, R2b, R2b’, R3b, or R3b’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1..6 alkyl, Cn6 haloalkyl, and -CO(O)-Ci-6 alkyl; Rlc, R!c , R2c, and R2c are each independently selected from H, Cn6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rlc, Rlc’, R2c, or R2® is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C0(0)-Cj-6 alkyl; Rld, Rld’, R3a, and R3d are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rld, R!d’, R'd, or R3d is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C0(0)-Cj-6 alkyl; Rle, Rle, R3e, and R3s are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3.6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rle, Rle, R3e, or R3e is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; or two or more of Rie, Rle’, R3e, and RJS combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C0(0)-Cj-6 alkyl, and any uncombined Rie, Rle, R3®, or R3® are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rle, Rls’, R3s, or R3e is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; R11, Ru , R21, and R2f are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rlf, R11, R2f, or R2f is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and ”CO(O)“Ci-6 alkyl; or two or more of R!t, Rlf, R21, and R2t combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined R!f, Rlf, R2f, or R2t are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rlf, R11, R2f, or R2f is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cur, alkyl, Cue, haloalkyl, and -CO(O)-Ci-6 alkyl; R2g and R2g’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyd, and aryl; wherein the and of R2g or R2g is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, Cj-e haloalkyl, and -CO(O)”Ci-6 alkyl; Rlh and Rlb are each independently selected from H, Ci-s alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyd, and aryl; wherein the and of Rlh or Ri!!’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; R'1 and R3' are each independently selected from H, C1.6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyd, and and; wherein the aryl of R31 or R51’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C (alkyd; Rd and Rd are each independently selected from H, Cue alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rjj or Rd' is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C (alkyd; Rlra, Rim ^2m_               anj ^4m’ are eacj1 independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Cn6 alkyl, and aryl; wherein the aryl of Rlm, R1En, R2m, R2m, R3m, R3m’, R4m, or R4m is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C>i-6 alkyl, Oi-6 haloalkyl, and -00f0)~0i-6 alkyd; or two or more of Rtm, Rw, R2m, R2m’, R3m, R3m , R4ra, and R4m combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined Rlm, Rlra , R2,n, R2“ , R3m, R3m, R4m, or R4m are each independently selected from H, Cj-s alkyl, Cj^ haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rlrn, Rlm’, R2m, R2m’, R3m, R3m’, R4rn, or R4m’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, C1-6 haloalkyl, and -CO(O)-Ci-6 alkyl; Rlb is H, Ci-6 alkyl, C3-6 cycloalkyl, ary], C1-6 alkyl-ary 1, or heteroaryl; wherein the C1-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, or heteroaryl of Rlb is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, and alkoxy; or two or more of R1D, R2b, Rzb , R3b, and R3b combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, C1-6 haloalkyl, and -CO(O)-Ci~6 alkyl, and any uncombined Rib, R2b, R2b , Rjb, or R3b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; w'herein the aryl of Rlb, R2b, R2b’, Rjb, or R3b’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Cue haloalkyl, and -CO(O)-Ci-6 alkyl; R3c is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl; wherein the Ci-6 alkyl, €3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of Rlc is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-e alkyl, and alkoxy; Rlg is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of R’8 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; R2h is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Ra is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; R1' is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cj-s alkyl-aryl, or heteroaryl; wherein the Ci-6 alkyl, €3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of R11 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; R3j and R^ are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlj or R2-’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; Rlk and R2k are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlk or R2k is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; R11 and R3! are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rn or R31 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; n is 0 or 1; wherein: if X1 is CRlaRla\ X2 is CR2aR2a’, and X3 is CR3aR3a’, then: Y1 is C(H); Y2 is C(H) or N; Y3 is C(CF3); Y4 is C(H) or N; and Y5 is C(H); or Y1 is C(Rla2) or N; Y2 is C(R2a2); Y3 is C(R3a2) or N; Y4 is C(R4a2); and Y5 is C(R5a2); wherein Rla2 is H, halo, Ci-6 haloaikyl, NO?, CN, or SO2-C1-6 alkyl; R2a2 is H, halo, Ci-6 haloaikyl, NO2, CN, or SO2-C1.6 alkyl; R3a2 is H, halo, Ci-6 haloaikyl, NO2, or CN; R4a2 js halo, 6 haloaikyl, NO2, CN, or SO?-Cu6 alkyl; R5a2 is H, halo, Ci-6 haloaikyl, NO?, CN, or SO2-C1-6 alkyl; or Rla2 combines with R2a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci^ alkyl, and R3a2, R4a2, and R3a2 are each independently selected from H, halo, Ci-6 haloaikyl, NO2, and CN; or R2a2 combines with R3az to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rla2, R*a2, and R5a2 are each independently selected from H, halo, Cue, haloaikyl, NO?, and CN, or Rja2 combines with R4a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rla2, R2a2, and R5a2 are each independently selected from H, halo, Cur, haloaikyl, NO?, and CN, or R4a2 combines with R5a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Ria2, R2a2, and R3a2 are each independently selected from H, halo, Ci-6 haloaikyl, NO2, and CN; if X1 is 'NRib or O, X2 is CR2bR2b’, and X3 is CR3bR3b’, then: Y1 is C(Rib2) orN; Y2 is C(R2b2) orN; Y3 is C(R3b2) orN; Y4 is C(R4b2) orN; and Y5 is C(R5b2) or N; or Y! is C(O); Y2 is N(R2b2); Y3 is C(R3h' K Y4 is C(R4b2); and Y5 is N; wherein Rlb2 is H, halo, Cue haloaikyl, NO2, CN, or SO2-C1-6 alkyl, R2b2 is H, halo, Ci-6 haloaikyl, NO2, CN, or SO2-C1-6 alkyl; R3b2 is H, halo, Ci-6 haloaikyl, NO?, CN, or SO2-C1-6 alkyl; R4b2 is H, halo, Ci-6 haloaikyl, NO?, CN, or SO2-C1-6 alkyl; R5b2 is H, halo, Ci-6 haloaikyl, NO?, CN, or SO2-C1-6 alkyl; or Rib? combjnes wjth &2b210 form an aJ.y| heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cw alkyl or OH, and R3b2, R4b2, and R5b2 are each independently selected from H, Ci-6 alkyl, halo, Ci-6 haloalkyl, NO2, and CN; or R2b2 combines with R3bz to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl or OH, and Rlb2, R4b2, and R5b2 are each independently selected from H, Cj-e alkyl, halo, Cj.g haloalkyl, NO2, and CN; or R3b2 combines with R4b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl or OH, and Rlb2, R2bz, and R5b2 are each independently selected from H, Ci-6 alkyl, halo, Ci-6 haloalkyl, NO2, and CN; or R4b2 combines with R3b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci^ alkyl or OH, and Rlb2, R2b2, and R3b2 are each independently selected from H, Ci-6 alkyl, halo, Ci-6 haloalkyl, NO2, and CN; R2b2’ is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of R2b2’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; R3b2’ is H, halo, Cn6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4b2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or R2b2 combines with Rjb2’ to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl or halo, and R4b2 is selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cj-e alkyl-aryl, and heteroaryl; wherein the Ci-6 alkyl, €3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of R4b2’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; or R3b2’ combines with R4b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl or halo, and R2b2 is selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl; wherein the Cue alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of R2®2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, and alkoxy; if X1 is CR^1®’, X2 is CR2cR2®, and X3 is O or NR3®; then Y1 is C(Ric2) or N; Y2 is C(R2®2) or N; Y3 is C(R3®2) orN; Y4 is C(R4®2) or N; and Y5 is C(R5®2) or N, wherein R1®2 is H, halo, Cue haloalkyl, NO?, CN, or SO?-Cu6 alkyl; R2®2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R3®2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4®2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R5®2 is H, halo, Cue haloalkyl, NO?, CN, or SO2-C1-6 alkyl; or R1®2 combines with R2®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and R3®2, R4®2, and R3®2 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; or R2®2 combines with R3®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R!c2, R4®2, and R5®2 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; or R3®2 combines with R4®2 to form an aryl ring, heteroaryl ring, cycloalkyd ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and R1®2, R2®2, and R5®2 are each independently selected from H, halo, Cue, haloalkyl, NO?, and CN, or R4®2 combines with R3®2 to form an aryl ring, heteroaryl ring, cycloalkyd ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and R1®2, R2®2, and R3®2 are each independently selected from H, halo, Cur, haloalkyl, NO?, and CN, if X1 is CRldRid , X2 is O, S, or 8(()2), and X3 is CRjdR3d, then Y1 is C(R!a2) or N; Y2 is C(R2d2); Y3 is C(R3d2) or N, Y4 is C(R4d2) or N; and Y5 is C(R5d2) or N; wherein Ru2 is H, halo, Cue haloalkyl, NO2, CN, or SO?-Cue alkyl; R2d2 is H, halo, Cue haloalkyl, N02, CN, or SO2-C1-6 alkyl; R3d2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4d2 is H, halo, Cue haloalkyl, NO2, CN, or SOz-Cue alkyl; R5a2 is H, halo, Ci-s haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rld2 combines with R2d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3d2, R4d2, and R5d2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R2d2 cotnbjnes with R^2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and RId2, R4d2, and R5d2 are each independently selected from H, halo, Cue, haloalkyl, NO?, and CN, or R3d2 combines with R4d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and Rid2, R2d2, and R5d2 are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R4d2 combines with R5d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cn6 alkyl, and Rld2, R2d2, and Rdd2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; if X1 is CRkRk, X2 is C(O), and X3 is CR3eR3e’, then: Y1 is C(Rie2); Y2 is C(R2®2); YJ is C(RJez); Y4 is C(R4e2); and Y5 is C(R3e2); or Y1 is C(R!®2’) or N; Y2 is C(R2e2’) orN; Y3 is C(R3e2’) orN; Y4 is C(R4e2’) orN; and Y5 is C(R5s2) or N, wherein at least one of Y], Y2, Y3, Y4, and Y5 is N; wherein Rle2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R2e2 is H, halo, Ci-s haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R3e2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4®2 is H, halo, Cue haloalkyl, NO?, CN, or SO2-C1-6 alkyl; R5®2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl; or R1®2 is Cl; R2®2 is H, R3®2 is Ci^ haloalkyl, NO2, or SO2-C1-6 alkyl; R4®2 is H; and R5®2 is H; or R1®2 is NO2; R2®2 is H; R3®2 is Ci-6 haloalkyl, R4®2 is H; and R5®2 is H; or R1®2 combjnes with R2s2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3®2, R4®2, and R5®2 are each independently selected from H, halo, Cn6 haloalkyl, NO2, and CN, or R2®2 combines with R3®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rle2, R4®2, and R5®2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or R3®2 combines with R4ez to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rie2, R2e2, and R5®2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN, or R4e2 combines with R5ez to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and R3®2, R2®2, and R3®2 are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R3®2’ is H, halo, Ci-6 haloalkyl, NO2, CN, and SO2-C1-6 alkyl; R2®2’ is H, halo, Ci-6 haloalkyl, NO2, CN, and SO2-C1 .6 alkyl; R3®2 is H, halo, Cm haloalkyl, NO2, CN, and S0?-Cm alkyl; R4®2 is H, halo, Cm haloalkyl, NO2, CN, and SO2-C1-6 alkyl; R5®2’ is H, halo, Ci-6 haloalkyl, NO2, CN, and SO2-C1-6 alkyl, or R1®2 combines with R2e2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and R3e2, R4®2’, and R5e2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R2®2 combines with R3e2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rle2’, R4®2’, and R5e2’ are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or R3e2’ combines with R4e2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and R1®2, IV®2, and R5®2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; or R4e2 combines with R5®2 to form an aryl ring, heteroaiyl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rle2’, R2®2’, and R3e2’ are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; if X1 is CRnRir, X2 is CR2fR2f, and X3 is a bond, then Y1 is C(R!12) orN; Y2 is C(R212) or N; Y3 is C(R3f2) or N; Y4 is or N; and Y5 is C(R5f2) or N; wherein Rn2 is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl, R212 is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl, R3” is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl; R432 is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl; R3”2 is H, halo, Cm haloalkyl, NO?, CN, or S02-Cm alkyl; or R112 combines with R2f2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and R312, R412, and R5f2 are each independently-selected from H, halo, Cm, haloalkyl, NO?, and CN, or R232 combines with R3” to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring maybe unsubstituted or substituted with Cm alkyl, and R112, R412, and R5f2 are each independently-selected from H, halo, Cm haloalkyl, NO?, and CN, or R332 combines with R412 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rtf2, R232, and R5f2 are each independently-selected from H, halo, Cm haloalkyl, NO2, and CN; or R4Q combines with R312 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and Rlf2, R2f2, and R3f2 are each independently selected from H, halo, Cm haloalkyl, NO2, and CN; if X1 is NRlg or O, X2 is CR2gR2g’, and X3 is a bond; then Y1 is C(Rlg2) orN; Y2 is C(R2g2) or N; YJ is C(RJg2) orN; Y4 is C(R4g2) orN; and Y5 is C(R5g2) or N; wherein Rlg2 is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl; R2g2 is H, halo, Cm haloalkyl, NO2, CN, or S0?-Cm alkyl; R3g2 is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl; R4g2 is H, halo, Cm haloalkyl, NO2, CN, or S02-Cm alkyl; R?g2 is H, halo, Cm haloalkyl, NO2, CN, or SOz-Cne alkyl; or Rlg2 combines with R2®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaiyi ring, cycloalkyl ring, or heterocyclic ring may be tin substituted or substituted with Ci-6 alkyl, and R3g2, R4g2, and R5g2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R2g2 combines with R3g2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and RIg2, R4g2, and R5g2 are each independently selected from H, halo, Cw haloalkyl, NO?, and CN, or R3g2 combines with R4g2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rig2, R2g2, and R5®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R4g2 combines with R5g2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rsg2, R2®2, and R3®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; if X1 is CRlhRlh, X2 is NR2h or O, and X3 is a bond; then Y1 is C(Rlh2) or N; Y2 is C(R2h2) or N; YJ is C(RJh2) orN; Y4 is C(R4h2) orN; and Y5 is C(R5h2) or N; wherein Rlh2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2h2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R3h2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4h2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R3h2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or RUi2 combines with R2i’2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3h2, R4h2, and R5h2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R2h2 combines with R3n2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlh2, R4n2, and R5h2 are each independently selected from H, halo, Cw haloalkyl, NO?, and CN, or R3h2 combines with R4i’2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaiyi ring, cycloalkyl ring, or heterocyclic ring may be tin substituted or substituted with Ci-6 alkyl, and Rih2, R2h2, and R5h2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R4h2 combines with R5n2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlh2, R2n2, and Rjh2 are each independently selected from H, halo, Cur, haloalkyl, NO?, and CN, if X1 is NR11 or O, X2 is C(O), and X3 is CR31R3‘; then Y1 is C(Rb2) or N; Y2 is C(R2i2) or N; Y3 is C(R312) or N; Y4 is C(R412) or N; and Y3 is C(R312) or N; wherein Rb2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2'2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R312 is H, halo, Cur, haloalkyl, NO?, CN, or SO2-C1-6 alkyl; R4i2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R3'2 is H, halo, Cj-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rb2 combines with R212 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3’2, R4’2, and R5'2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R2’2 combines with R312 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rb2, R412, and R5'2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R3'2 combines with R412 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rb2, R212, and R312 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R4“ combines with R312 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and RC2, R212, and R312 are each independently selected from H, halo, Cur, haloalkyl, NO?, and CN, if X1 is NR1J or O, X2 is NR2j or O, and X3 is . then Y1 is C(Rlj2) or N; Y2 is C(R2j2) orN; Y3 is C(R3j2) orN; Y4 is C(R4i2) orN; and Y5 is C(R3j2) orN; wherein R1'2 is H, halo, Ci-6 haloalkyl, N02, CN, or SO2-C1-6 alkyl; R2j2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R3j2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4j2 is H, halo, Cj-s haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R5j2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or R1’2 combines with R2!2 to form an aryl ring, heteroaryl ring, cycloalky] ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3’2, R4’2, and R5'2 are each independently-selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R2j2 combines with R!|2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R^2, R4-’2, and R5j2 are each independently-selected from H, halo, Cj-6 haloalkyl, NO2, and CN; or R3j2 combines with R4'2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with C1.6 alkyl, and Rk2, R2'2, and R5!2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R4j2 combines with R5-'2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring maybe unsubstituted or substituted with Ci-6 alkyl, and R2-’2, R2'2, and R3!2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; if X1 is NR!k or 0, X2 is NR2k or 0, and X3 is a bond; then Y1 is C(Rlk2) or N; Y2 is C(R2k2) orN; Y3 is C(R3k2) orN; Y4 is C(R4k2) or N; and Y3 is C(R5k2) orN; wherein Rlk2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2k2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R3k2 is H, halo, Ci-6 haloalkyl, N02, CN, or SO2-C1-6 alkyl; R4k2 is H, halo, Ci-s haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R5k2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rlk2 combines with R2k2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cw, alkyl, and R3k2, R4k2, and R3k2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R2k2 combines with R3k2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R!k2, R4k2, and R5k2 are each independently selected from H, halo, Cj.g haloalkyl, NO2, and CN; or R3k2 combines with R4k2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R’lk2, R2k2, and R5k2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R4k2 combines with R5k2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R!k2, R2k2, and R3k2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; if X1 is NR11 or O, X2 is C(O), and X3 is NR3i or O; then Y1 is C(Rn2) or N; Y2 is C(R212) orN; Y3 is C(R312) orN; Y4 is C(R412) orN; and Y5 is C(R512) orN; wherein R1!2 is H, halo, Ci-6 haloalkyl, NO? CN, or SO2-C1-6 alkyl; R2’2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R312 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyd; R4’2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R512 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rhi combines with R / J2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cw, alkyl, and R312, R412, and R5i2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R212 combines with R312 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyd, and R!12, R412, and R512 are each independently selected from H, halo, Cj.g haloalkyl, NO2, and CN; or R312 combines with R412 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cu6 alkyl, and R112, R212, and R5i2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; or R412 combines with R512 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cu6 alkyl, and R!12, R212, and R312 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; or if X1 is CRbnRlm’, X2 is CR2mR2m’, and X3 is CJl3mR3rakCR^Vm’; then Y1 is C(Rlm2) or N; Y2 is C(R2m2) or N; Y3 is C0^3m2) or N; Y4 is C(R4m2) or N; and Y5 is C(R5m2) or N; wherein Rlm2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2m2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R3m2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R4m2 is H, halo, Cu6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; R5®2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or Rbn2 combines with R2m2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3"’\ R4m2, and R3m2 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; or R2m2 corabines Wj^ R3m2 form an ary| rjng, heteroaryd ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rim2, R4m2, and R5m2 are each independently selected from H, halo, Cue, haloalkyl, NO2, and CN, or R3ra2 combines with R4m2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and R{m2, R2my and R5m2 are each independently selected from H, halo, Cur, haloalkyl, NO?., and CN, or R4m2 comhines whh R5m2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cu6 alkyl, and R1En2, R2m2, and R3m2 are each independently-selected from H, halo, Ci-6 haloalkyl, NO2, and CN.

[0246] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X! is CRlaRla\ X2 is CR^R23’, and X3 is CR3aR3a’; X! is NRlb, X2 is Cl h and X3 is CR3bR3b’; X1 is CRkRk\ X2 is CR2'and X3 is 0. X1 is CR'dRld', X2 is O, S, or S(()2), and X3 is CR3dR3d’; X! is CR1SR1S’, X2 is C(0), and X3 is CR3'- R k : X1 is NR18, X2 is CH2, and X3 is a bond; or X’1 is NRX2 is C(O), and X3 is NR31; Z1 and Z2 are each independently selected from C(0) and S(02); Rla and Ria are each independently selected from H, Ci-6 alkyl, and -C0(0)-Ci-6 alkyl; R2a and R2a’ are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, -C0(0)-Ci-6 alkyl, and aryl; R3a and R3a are each independently selected from H and Ci-6 alkyl; If Z1 and Z2 are both C(0), then at least one of Ria, R,a’, R2a, R2a’, R3a, or R3a is Ci-6 alkyl, C3-6 cycloalkyl, -C0(0)-Ci-6 alkyl, or aryl; wherein the aiyl of R2a or R2a is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; or Rla and Ria combine to form a cycloalkyl ring or heterocyclic ring, and R2a, R2a’, R3a, and R3a are each H; orR2a and R2a’ combine to form a cycloalkyl ring or heterocyclic ring, and Rla, Rla’, R3a, and R3a are each H; or Rla and R3a combine to form a cycloalkyl ring, wherein the cycloalkyl ring may be unsubstituted or substituted with one or more Ci-6 alkyl, and Rla, R2a, R2a, and R3a are each independently selected from the group consisting of H and Ci-6 alkyl;R,D is Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl; wherein the Ci-6 alkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of R!b is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-6 alkyl, and alkoxy; Rjb and R3b are each independently selected from H and Ci-6 alkyl; Rlc, Rlc, R2c, and R2c are each independently selected from H and Ci-6 alkyl; Rld, Rld’, R3a, and R3d are each independently selected from H and Ci-6 alkyl; Rls, Rle’, R3e, and R3e are each independently selected from H and Ci-s alkyl; Rlg is aryl; wherein the aiyl of R18 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; R11 and R31 are each independently selected from H, Ci-6 alkyl, and aiyl; wherein the aryl of Rlf or R31 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; wherein: if X1 is CRlaRla’, X2 is CR2aR2a’, and X3 is CR3aR3a’, then: Y1 is C(H); Y2 is C(H) or N; Y3 is C(CF3), Y4 is C(H) or N; and Y5 is C(H); or Y] is C(R!a2); Y2 is C(R2a2); Y3 is C(R3a2); Y4 is C(R4a2); and Y5 is C(R5a2); wherein Rla2 is H, halo, Ci-s haloalkyl, SO2-C1-6 alkyl, or NO?; R2a2 is H, halo, Ci-6 haloalkyl, SO?alkyl, or NO?; R3a2 is H, halo, Cue haloalkyl, SO2-C1-6 alkyl, or NO2; R'a2 is H, halo, Ci-6 haloalkyl, SO2-Ci-6 alkyl, orNO2; R5a2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO2; if X1 is NRib, X2 is CH2, and X3 is CRjbR3b; then Y4 is C(Rlb2); Y2 is C(R2”2); YJ is C(R3b2); Y4 is C(R4b2); and Y5 is C(R5b2); wherein Rlb2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO?; R2b2 is H, halo, Ci-6 haloalkyl, SO2-Ci-6 alkyl, orNO2; R3b2 is H, halo, Cue haloalkyl, SO2-C1-6 alkyl, or NO2; R4b2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, orNO2; R5b2 is H, halo, Ci-s haloalkyl, SO2-C1-6 alkyl, or NO?; if X! is CRlcRlc, X2 is CR2cR2c, and X3 is O; then Y1 is C(R!c2); Y2 is C(R2c2); Y3 is C(R3c2); Y4 is C(R4c2); and Y5 is C(R5c2); wherein Ric2 is H, halo, Ci-6 haloalkyl, or NO2; R2c2 is H, halo, Ci-6 haloalkyl, or XO?: R3c2 is H, halo, Ci-6 haloalkyl, or NO?; R4c2 is H, halo, Ci-6 haloalkyl, or NO2; R5c2 is H, halo, Cue haloalkyl, or NO2, if X1 is CR / dR'd, X2 is O, S, or S(O2), and X3 is CR3dR3d’, then Y1 is C(Rld2); Y2 is C(R2d2); Y3 is C(R3d2); Y4 is C(R4d2); and Y5 is C(R5d2); wherein Rla2 is H, haio, Ci-6 haloalkyl, or NO2; R2d2 is H, halo, Ci-6 haloalkyl, or NO2; R342 is H, halo, Ci-6 haloalkyl, or NO2; R4a2 is H, halo, Ci-s haloalkyl, or N02; R5a2 is H, halo, Ci-6 haloalkyl, or NO?; if X1 is CR3®R’®’, X2 is C(O), and X3 is CR3eR3®’; then Yl is C(Rle2), Y2 is C(R2®2); Y3 is C(R4®2); Y4 is C(R4e2); and Y3 is C(R5®2); wherein Rle2 is H, halo, Ci-6 haloalkyl, CN, SO2-C1-6 alkyl, or NO2; R2e2 is H, halo, C1-6 haloalkyl, CN, SO2-C1-6 alkyl, or NO2; R3e2 is H, halo, Ci-6 haloalkyl, CN, SO2-C1-6 alkyl, or NO2; R4e2 is H, halo, Cj-e haloalkyl, CN, SO2-C1-6 alkyl, or NO2; R3e2 is H, halo, C1-6 haloalkyl, CN, SO2-C1-6 alkyl, or NO2; or Rie2 conibines with R2®2 to form a heteroaryl ring, and R3®2, R4®2, and R’®2 are each H; if X1 is NRig, X2 is CH?, and X3 is a bond, then Y1 is C(Rlg2); Y2 is C(R2g2); Y3 is C(lCg2y Y4 is C(R4g2); and Y5 is C(R5g2); wherein Rlg2 is H, halo, Ci-6 haloalkyl, or NO2; R2g2 is H, halo, Ci-e haloalkyl, or NO?; R3g2 is H, halo, Ci-6 haloalkyl, or NO?; R4g2 is H, halo, Ci-6 haloalkyl, or NO2; R3g2 is H, halo, Ci-6 haloalkyl, or NO2; or if X! is NRb, X2 is C(0), and XJ is NR31; then Y1 is C(R1!2); Y2 is C(R2i2); Y3 is C(R312); Y4 is C(R d?): and Y5 is C(R512); wherein Rn2 is H, Ci-6 haloalkyl, or NO2; R212 is H, Ci-6 haloalkyl, or NO2, R312 is H, Cj-6 haloalkyl, or NO2; R |;2 is H, Ci-6 haloalkyl, or NO2; R512 is H, Ci-6 haloalkyl, or NO2.

[0247] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VE), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

[0248] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formulae (V) or (VE), or the pharmaceutically acceptable salts or tautomers thereof, wherein n is 0.

[0249] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formulae (V) or (VE), or the pharmaceutically acceptable salts or tautomers thereof, wherein Y] is QNCh).

[0250] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formulae (V) or (VE), or the pharmaceutically acceptable salts or tautomers thereof, wherein Y3 is C(CF3).

[0251] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formulae (V) or (VE), or the pharmaceutically acceptable salts or tautomers thereof, wherein Rla and Rla’, Rlc and R1C’, Rld and Rld , Rie and Rle, Ri! and Rlf’, or Rln and Rlh are each CH3.

[0252] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formulae (V) or (VE), or the pharmaceutically acceptable salts or tautomers thereof, wherein R3a and R3a’, R3b and R3b , R3d and R3d’, or R3e and R3e, R31 and R31’, or R3j and R3j are each CH3.

[0253] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formulae (V) or (VE), or the pharmaceutically acceptable salts or tautomers thereof, wherein Rlb is cycloalkyl or heteroaryl.

[0254] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VI): Formate (VI) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each =^= independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein: X1 is NR1, X2 is CR2, and X3 is N or CH; X1 is O, X2 is CR2, and X3 is N; X! is N, X2 is NR1, and X3 is N; or X! is NR3, X2 is N, and X3 is N; n is 0 or I; R1 is selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, and heteroaryl; wherein the Cj.g alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of R1 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-e alkyl, Cj-e haloalkyl, and -CO(O)-Ci-6 alkyl, R2 is selected from H, halo, Cn6 haloalkyl, NO2, CN, SO2-C1.6 alkyl, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-6 alkyl, Cj-e haloalkyl, and -CO(O)-Ci-6 alkyl, RJ is selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl; wherein the Ci-6 alkyl, C3.6 cycloalkyl, aryl, C1-6 alkyl-aryl, or heteroaryl of R3 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; Rvn, RV12, Rw, R™, and Rw are each independently selected from H, halo, Civ haloalkyl, NO2, CN, and SO2-C1-6 alkyl.

[0255] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VI), or the pharmaceutically acceptable salts or tautomers thereof, wherein R3 is C4-6 alkyl or phenyl substituted with one or more halo.

[0256] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VI), or the pharmaceutically acceptable salts or tautomers thereof, wherein Rvn is H or NO2. In some embodiments, Rvn is H. In some embodiments, Rv” is NO2.

[0257] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount, of a compound of Formula (VI), or the pharmaceutically acceptable salts or tautomers thereof, wherein RVI3 is H or CF3. In some embodiments, RVI3 is H. In some embodiments, RVI3 is CF3.

[0258] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VII): O O RVii1 N              I RVII4 Formula (Vi!) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from the group consisting of Csv cycloalkyl, Ci alkyl-C3-6 cycloalkyl, aryl, Ci alkyl-aryl, heteroaryl, and Ci alkyl-heteroaryl; wherein the C3-6 cycloalkyl, Ci alkyl-C3-6 cycloalkyl, aryl, Ci alkyl-aryl, heteroaryl, or Ci alkyl-heteroaryl of R1 is unsubstituted or substituted with halo; rviu, Rvm, rvlu, anj are independently selected from H, halo, Ci-s haloalkyl, NO2, CN, and SO2-C1-6 alkyl.

[0259] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VII), or the pharmaceutically acceptable salts or tautomers thereof, wherein R* is aryl or Ci alkyl-aryl, wherein the aryl or Ci alkyl-aryl may be unsubstituted or substituted with one or more halo.

[0260] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VII), or the pharmaceutically acceptable salts or tautomers thereof, wherein Rvin is H or NO2. In some embodiments, Rvm is H. In some embodiments, Rvm is NO2.

[0261] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VII), or the pharmaceutically acceptable salts or tautomers thereof, wherein R'1’2 is H, halo, or SO2-C1-6 alkyl. In some embodiments, Rvl12 is H. In some embodiments, RVU2 is halo. In some embodiments, R^112 is SOs-Cns alkyl.

[0262] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VII), or the pharmaceutically acceptable salts or tautomers thereof, wherein R2 Ib is H or CF3. In some embodiments, Rvi!3 is H. In some embodiments, RV!l3 is CF3.

[0263] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VIII): Formula (VIII) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof wherein each — independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wh erein: Y; is CR!, Y2 is N, and Y3 is NR3; Y2 is CR1, Y2 is O or S, and Y3 is CR3; Y! is N, Y2 is CR2, and Y3 is O or S; or Y1 is O or S, Y2 is CR2, and Y3 is CR3; R1 and R2 are each independently selected from H, Cue alkyl, Cue haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl of R1 or R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Cu6 alkyl; RJ is H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl; wherein the Cj.g alkyl, Cj.g haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl of R3 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; or R’ combines with Rvni2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; RWiJ q_6 c3 6 cycloalkyl, aryl, Cue, alkyl-aryl, or heteroaryl; wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci^ alkyl-aryl, or heteroaryl of Rv 1111 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, and alkoxy; R'1112 is H, halo, Ci-6 haloalkyl, NO2, CN, and SO2-C1-6 alkyl; or R31112 combines with RJ to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Cue haloalkyl, and -CO(O)-Ci-6 alkyl.

[0264] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VIII), or the pharmaceutically acceptable salts or tautomers thereof, wherein R{ is H or CF3. In some embodiments, R1 is H. In some embodiments, R1 is CF3.

[0265] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VIII), or the pharmaceutically acceptable salts or tautomers thereof, wherein R2 is H or CF3. In some embodiments, R2 is H. In some embodiments, R2 is CF3.

[0266] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VIII), or the pharmaceutically acceptable salts or tautomers thereof, wherein R3 is H or Ci-6 alkyl. In some embodiments, RJ is H. In some embodiments, R3 is Ci-6 alkyl.

[0267] The present disclosure also provides compounds of Formulae (V), (VE), (VI), (VII), and (VIII), as described herein

[0268] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound, wherein the compound is or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0269] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of the compound of any one of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (Hi-Oh (li-N), (Ii-N3), (U-X}, (IJ-N3 X (IK-N), (IK-N3), (H.-X), (IL-N3), (IM), (II), (IIA-C), (HA-C3), (IIA-N), (HA-X3 h (IIB), (IIB3), (IIC), (I IC3), (HD), (III), (IV), (IVA), (IV A3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

[0270] In some embodiments, the disclosure provides a use of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (H-X3), (U-X), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (HA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB- 03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

[0271] In some embodiments, the disclosure provides a use of the compound of any one of Formulae (I), (IA), (IA3), (1B-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (H-X). (h-N3), (IJ-N), (LLN3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (HA-C3), (H A-X). (UA-X3), (IIB), (IIB3), (DC), (DC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-0), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising administering to the subject an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0272] In some embodiments, the disclosure provides a use of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, wherein the medicament comprises an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and the compound is of any one of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

[0273] In some embodiments, the disclosure provides a use of the compound of any one of Formulae (I), (IA), (IA3), (IB-N), 0B-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (li-N3), (IJ-N), (U-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IK23), (IID), (III), (IV), (IVA), (IVA3), (1VB-0), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, wherein the medicament comprises an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0274] In some embodiments, the disclosure provides a compound for use in a method of treating a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising administering an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to the subject, wherein the compound is of any one of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), HGA3). (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IKA), (IK-N3), (ILA). (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (H A A), (IIA-N3), (IIB), (UB3), (IIC), (IIC3), (UD), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

[0275] In some embodiments, the disclosure provides a compound of any one of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (1GA3), (IG-O), (IHA), (IH-N3), (IH-O), (h A). (Ii-N3), (IJ-N), (II-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, for use in a method of treating a condition that, is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising administering an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to the subject.

[0276] In some embodiments, the disclosure provides a pharmaceutical formulation for use in a method of treating a condition that is responsive to modulation or inhibition of HPD, the formulation comprising an effective amount of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable earner, wherein the method comprises administering the pharmaceutical formulation to a subject having the condition, and the compound is any one of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (II l-Ny (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (WB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (AT), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

[0277] In some embodiments, the disclosure provides a pharmaceutical formulation for use in a method of treating a condition that is responsive to modulation or inhibition of HPD, the formulation comprising an effective amount of the compound of any one of Formulae (I), (IA), (IA3), (IB-N), (1B-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (HA-C3), (IIA-N), (IIA-N3), (IIB), (HB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, wherein the method comprises administering the pharmaceutical formulation to a subject having the condition.

[0278] In some embodiments, the disclosure provides a medicament for treating a condition that is responsive to modulation or inhibition of HPD, the medicament comprising an effective amount of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the treatment comprises administering the medicament to a subject having the condition, and the compound is of any one of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (H-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

[0279] In some embodiments, the disclosure provides a medicament for treating a condition that is responsive to modulation or inhibition of HPD, the medicament comprising an effective amount of the compound of any one of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (BINS), (IH-O), (li-N), (li-N3), (IJ-N), (LL\3). (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof wherein the treatment comprises administering the medicament to a subject having the condition.

[0280] In some embodiments, administration of a compound of the disclosure inhibits SPR less than nitisinone. In some embodiments, the compound has inhibitory' activity for SPR that is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% less than nitisinone. Inhibitory activity for HPD and for SPR. can be measured by any known means, for example, in vitro biochemical assays and in vivo cell-base characterization assays such as those described in Biological Examples 3, 5, and 6.

[0281] The term “inhibitor,” as used herein, refers to a molecule such as a compound, a drug, enzyme, or a hormone that blocks or otherwise interferes with a particular biologic activity. For example, “HPD inhibitor,” as used herein, refers to a molecule that interferes with HPD. Interference of an inhibitor for with a particular biologic activity can be measured by any known means, for example, in vitro biochemical assays and in vivo cell-base characterization assays such as those described in Biological Examples 3, 5, and 6.

[0282] In some embodiments, a compound of the disclosure is a selective HPD inhibitor. The term “selective inhibitor,” as used herein, refers to an inhibitor that specifically targets and inhibits the activity of a particular biological molecule, pathway, or process while exhibiting minimal or no effect inhibition on other molecules or pathways. Selective inhibitors may modulate specific cellular functions or biochemical reactions associated with the target without causing significant off-target effects. A selective inhibitor may have an ICso value for the target that is lower than an IC50 value for other off-target molecules. For example, “selective HPD inhibitor,” as used herein, refers to a molecule that interferes with HPD with no or minimal off-target activity on other molecules {e.g.. SPR, enzymes in the tyrosine catabolism pathway, enzymes homologous to HPD, etc.) Comparative inhibitory' activity for particular biologic activity compared with off-target molecules can be measured by any known means, for example, in vitro biochemical assays and in vivo cell-base characterization assays such as those described in Biological Examples 3, 5, and 6.

[0283] The term “IC50,” as used herein, refers to concentrations at which a measurable activity, phenoty pe or response, for example growth or proliferation of cells such as tumor cells, is inhibited by 50%. IC50 values can be estimated from an appropriate dose-response curve, for example, by eye or by using appropriate curve fitting or statistical software. More accurately, IC50 values may be determined using non-linear regression analysis. IC50 values can be measured by any known means, for example, in vitro biochemical assays and in vivo cell-base characterization assays such as those described in Biological Examples 3, 5, and 6.

[0284] In some embodiments, a compound of the disclosure inhibits HPD more than SPR. Inhibitory activity for HPD and for SPR can be measured by any known means, for example, in vitro biochemical assays and in vivo cell-base characterization assays such as those described in Biological Examples 3, 5, and 6. In some embodiments the ICso of the compound for HPD is less than the IC50 for SPR. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least. 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45, at least 46, at least 47, at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, at least 60, at least 61, at least 62, at least 63, at least 64, at least 65, at least 66, at least 67, at least 68, at least 69, at least 70, at least 71, at least 72, at least 73, at least 74, at least 75, at least 76, at least 77, at least 78, at least 79, at least 80, at least 81, at least 82, at least 83, at least 84, at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, at least 100, at least 500, at least 1000, at least 10000 or at least 100000. The SPR:HPD IC50 ratio of the compound may be referred to as the “selectivity” of the compound for SPR and HPD.

[0285] In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 1. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 2. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 5. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 10. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 30. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 30. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 40. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 50. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 60. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 70. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 80. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 90. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 100. In some embodiments, the SPR:HPD ICso ratio of the compound is at least 500. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 1000. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 10000. In some embodiments, the SPR:HPD IC50 ratio of the compound is at least 100000.

[0286] In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 600 nM, greater than 650 nM, greater than 700 nM, greater than 750 nM, greater than 800 nM, greater than 850 nM, greater than 900 nM, greater than 950 nM, greater than 1000 nM, greater than 1050 nM, greater than 1100 nM , greater than 1150 nM, greater than 1200 nM, greater than 1250 nM, greater than 1300 nM, greater than 1350 nM, greater than 1400 nM, greater than 1450 nM, greater than 1500 nM, greater than 1550 nM, greater than 1600 nM, greater than 1650 nM, greater than 1700 nM, greater than 1750 nM, greater than 1800 nM, greater than 1850 nM, greater than 1900 nM, greater than 1950 nM, greater than 2000 nM, greater than 2050 nM, greater than 2100 nM, greater than 2150 nM, greater than 2200 nM, greater than 2250 nM, greater than 2300 nM, greater than 2350 nM, greater than 2400 nM, greater than 2450 nM, greater than 2500 nM, greater than 2550 nM, greater than 2600 nM, greater than 2650 nM, greater than 2700 nM, greater than 2750 nM, greater than 2800 nM, greater than 2850 nM, greater than 2900 nM, greater than 2950 nM, greater than 3000 nM n, greater than 5000 nM, greater than 10000 nM, greater than 100 pM, greater than 500 pM, greater than 1 mM, greater than 10 mM, or greater than 100 mM.

[0287] In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 600 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 700 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 800 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 900 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 1000 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 1100 nM. In some embodiments, a compound of the disclosure inhibits SPR. with an in vitro IC50 greater than 1200 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 1300 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 1400 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 1500 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 1600 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 1700 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 1800 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 1900 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC 50 greater than 2000 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 2100 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 2200 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 2300 nM. In some embodiments, a compound of the disclosure inhibits SPR. with an in vitro IC50 greater than 2400 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 2500 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 2600 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 2700 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 2800 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 2900 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 3000 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 5000 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 10000 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 100 pM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 500 pM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 1 mM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 10 mM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50 greater than 100 mM.

[0288] In some embodiments, a compound of the disclosure inhibits HPD more than nitisinone. For example, in some embodiments, the IC50 of the compound for HPD (HPDCOmpound IC50) is less than the IC50 of nitisinone for HPD (HPDnitisinone IC50). In some embodiments, the HPDnitisinone: HPDcompound IC50 ratio is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45, at least 46, at least 47, at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, at least 60, at least 61, at least 62, at least 63, at least 64, at least 65, at least 66, at least 67, at least 68, at least 69, at least 70, at least 71, at least 72, at least 73, at least 74, at least 75, at least 76, at least 77, at least 78, at least 79, at least 80, at least 81, at least 82, at least 83, at least 84, at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, at least 100, at least 500, at least 1000, at least 10000 or at least 100000.

[0289] In some embodiments, the HPDnitisinone: HPDcompound ICso ratio is at least 1. In some embodiments, the HPDnitisinone: HPDcompound IC50 ratio is at least 2. In some embodiments, the HP Dnitisinone • HP Dcompound IC50 ratio is at least 5. In some embodiments, the HP Dnitisinone -HPDcompound IC50 ratio is at least 10. In some embodiments, the HPDnitisinone: HPDcompound ICso ratio is at least 30. In some embodiments, the HPDmtisinone: HPDcompound IC50 ratio is at least 30. In some embodiments, the HPDnitisinone: HPDcompound IC50 ratio is at least 40. In some embodiments, the HPDnitisinone: HPDcompound IC50 ratio is at least 50. In some embodiments, the HPDnitisinone. HPDcompound IC50 ratio is at least 60. In some embodiments, the HPDnitisinone: HPDcompound IC50 ratio is at least 70. In some embodiments, the HPDnitisinone: HPDcompound IC50 ratio is at least 80. In some embodiments, the HPDnitisinone: HPDcompound IC50 ratio is at least 90. In some embodiments, the HPDnitisinone: HPDcompound ICso ratio is at least 100. In some embodiments, the HPDnitisinone: HPDcompound IC50 ratio is at least 500. In some embodiments, the HP Dnitisinone • HP Dcompound IC50 ratio is at least 1000. In some embodiments, the HPDnitisinone: HP Dcompound IC50 ratio is at least 10000. In some embodiments, the HPDnitisinone- HPDcompound ICsO ratio is at least 100000.

[0290] In some embodiments, a compound of the disclosure inhibits SPR less than nitisinone. For example, in some embodiments, the IC50 of the compound for SPR (SPRcompound IC50) is greater than the IC50 of nitisinone for SPR (SPRnitisinone IC50). In some embodiments, the S PRcompound- SPRnitisinone IC50 ratio is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45, at least 46, at least 47, at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, at least 60, at least 61, at least 62, at least 63, at least 64, at least 65, at least 66, at least 67, at least 68, at least 69, at least 70, at least 71, at least 72, at least 73, at least 74, at least 75, at least 76, at least 77, at least 78, at least 79, at least 80, at least 81, at least 82, at least-83, at least 84, at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, at least 100, at least 500, at least 1000, at least 10000 or at least 100000.

[0291] In some embodiments, the SPRcompound: S P Rnitisinone ICso ratio is at least 1. In some embodiments, the SPRcompound.’SPRnitisinone ICso ratio is at least 2. In some embodiments, the SPRcompound-SPRnitisinone IC-50 ratlO IS at least 5, III SOme embodiments, the SPRcompound-SPRnitisinone IC50 ratio is at least 10. In some embodiments, the SPRcompound:SPRnitisinone IC50 ratio is at least 30. In some embodiments, the SPRcompound: SPRnitisinone IC50 ratio is at least 30. In some embodiments, the SPRcompound: SPRnitisinone IC50 ratio is at least 40. In some embodiments, the SPRcompound:SPRnitisinone IC50 ratio is at least 50. In some embodiments, the SPRcompound: SPRnitisinone IC50 ratio is at least 60. In some embodiments, the SPRcompound:SPRnitismone IC50 ratio is at least 70. In some embodiments, the SPRcompound:SPRnitisinone ICso ratio is at least 80. In some embodiments, the S PRcompound- SPRnitisinone IC50 ratio is at least 90. In some embodiments, the SPRcompound:SPRnitismone IC50 ratio is at least 100. In some embodiments, the SPRcompound: SPRnitisinone IC50 ratio is at least 500. In some embodiments, the SPRCOmPound: SPRnitismone IC50 ratio is at least 1000. In some embodiments, the SPRcompound:SPRnitisinone IC50 ratio is at least 10000. In some embodiments, the SPRcompound. SPRnitisinone ICso ratio is at least 100000.

[0292] In some embodiments, disclosed herein is a method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the compound is a selective HPD inhibitor.

[0293] In some embodiments, disclosed herein is a method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the compound inhibits HPD in the subject, wherein the compound results in a lower inhibition of SPR than HPD.

[0294] In some embodiments, disclosed herein is a method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the di sclosure, wherein the compound inhibits HPD in the subject, wherein the compound results in a lower inhibition of SPR than in a subject treated with nitisinone.

[0295] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the compound does not inhibit SPR.

[0296] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the compound results in a lower inhibition of SPR than HPD.

[0297] In some embodiments, administration of a compound of the disclosure to a subject lowers dihydrobiopterin (BH2) levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 2-fold, a 3-fold, a 4-fold, a 5-fold, a 6-fold, a 7-fold, an 8~fold, a 9-fold, a 10fold, an 11-fold, a 12-fold, a 13-fold, a 14-fold, a 15-fold, a 16-fold, a 17-fold, an 18-fold, a 19fold, a 20-fold, a 21 -fold, a 22-fold, a 23-fold, a 24-fold, a 25-fold, a 26-fold, a 27-fold, a 28fold, a 29-fold, a 30-fold, a 40-fold, a 50-fold, a 60-fold, a 70-fold, a 80-fold, a 90-fold, a 100fold, a 500-fold, a 1000-fold, a 5000-fold, or a 10000-foldlower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 2-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 3-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 4-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 5-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 6-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 7-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in an 8-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 9-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 10-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 15-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 20-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 25-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 30-fold lower reduction of BH2 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject does not result in BH2 deficiency in the subject. In some embodiments, administration of a compound of the disclosure to a subject results in a lower reduction of tetrahydrobiopterin (BH4) levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 2-fold, a 3-fold, a 4-fold, a 5-fold, a 6-fold, a 7-fold, an 8-fold, a 9-fold, a 10-fold, an 11-fold, a 12-fold, a 13-fold, a 14-fold, a 15-fold, a 16-fold, a 17-fold, an 18-fold, a 19-fold, a 20-fold, a 21-fold, a 22-fold, a 23-fold, a 24-fold, a 25-fold, a 26-fold, a 27fold, a 28-fold, a 29-fold, a 30-fold, a 40-fold, a 50-fold, a 60-fold, a 70-fold, an 80-fold, a 90fold, a 100-fold, a 500-fold, a 1000-fold, a 5000-fold, or a 10000-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 2-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 3-fold lower reduction of BH levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 4-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 5-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 6-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 7-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in an 8-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 9-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 10-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 15-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 20-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 25-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject results in a 30-fold lower reduction of BH4 levels in the subject compared to a comparable subject treated with nitisinone. In some embodiments, administration of a compound of the disclosure to a subject does not result in BH4 deficiency in the subject.

[0298] BH2 and BH4 levels in a subject may be measured by any known means, for example derivatization with benzoyl chloride coupled with liquid chromatography-tandem mass spectrometry analysis (see, for example, Yuan TF et al, A novel and reliable method for tetrahydrobiopterin quantification: Benzoyl chloride derivatization coupled with liquid chromatography-tan dem mass spectrometry analysis. Free Radic Biol Med. 2018 Apr;118:119-125, which is hereby incorporated by reference in its entirety.) BH2 and BH4 levels can also be determined by indirect chemical oxidation using iodine oxidation treatment and two corresponding liquid chromatography fluorometric runs (see, for example, T. Fukushima, J.C. Nixon, Analysis of reduced forms of biopterin in biological tis- sues and fluids, Anal. Biochem. 102 (1980) 176-188), which is hereby incorporated by reference in its entirety.)

[0299] In some embodiments, disclosed herein is a method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the compound inhibits HPD in the subject, wherein the administering results in a lower reduction in BH4 levels in the subject compared to a subject treated with nitisinone.

[0300] In some embodiments, disclosed herein is a method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the compound inhibits HPD in the subject, wherein the administering results in a lower reduction in BH2 levels in the subject compared to a subject treated with nitisinone.

[0301] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the compound results in a lower reduction in BH4 levels in the subject compared to a subject treated with nitisinone.

[0302] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the compound results in a lower reduction in BH2 levels in the subject compared to a subject treated with nitisinone.

[0303] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the treatment provides improved neurocognitive function in the subject compared to a subject treated with nitisinone.

[0304] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure to replace nitisinone, or other non-selective HPD inhibitors, wherein the subject has neurocognitive symptoms, wherein the method stabilizes neurocogni ti ve functi on.

[0305] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure to replace nitisinone, or other non-selective HPD inhibitors, wherein the subject is having neurocognitive decline, wherein the method stabilizes n eurocogniti v e fun ction.

[0306] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure to replace nitisinone, or other non-selective HPD inhibitors, wherein the subject has neurocognitive symptoms, wherein the method improves n eurocogniti v e fun cti on.

[0307] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure to replace nitisinone, or other non-selective HPD inhibitors, wherein the subject has neurocognitive decline, wherein the method improves n eurocogniti v e fun cti on.

[0308] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the subject is currently taking a non-selective HPD inhibitor, such as nitisinone, and wherein the subject stops taking the non-selective HPD inhibitor.

[0309] In some embodiments, disclosed herein is a method of inhibiting HPD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, wherein the subject has taken a non-selective HPD inhibitor, such as nitisinone.

[0310] As described herein, the compounds may be used to treat a condition in a subject. In some embodiments, the condition is an inborn error of metabolism, myalgic encephalomyelitis (also known as chronic fatigue syndrome), Parkinson’s disease, Lewy Body dementia, mood disorders, autoimmune disorders, inflammatory / disorders, neuropathic pain, refractory hypertension, low sex drive, attention-deficit / hyperactivity disorder (ADHD), sleep disorders, restless leg syndrome, obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), substance abuse disorder, chronic constipation, tremor disorders, CoQ10 deficiency, and oculocutaneous albinism. In some embodiments, the condition is an inborn error of metabolism. In some embodiments, the condition is Parkinson’s disease. In some embodiments, the condition is Lew Body dementia. In some embodiments, the condition is an autoimmune disorder. In some embodiments, the condition is an inflammatory' disorder. In some embodiments, the condition is neuropathic pain. In some embodiments, the condition is refractory hypertension. In some embodiments, the condition is low sex drive. In some embodiments, the condition is attendon-deficit / hyperactivity disorders (ADHD). In some embodiments, the condition is sleep disorders. In some embodiments, the condition is restless leg syndrome. In some embodiments, the condition is obsessive-compulsive disorder (OCD). In some embodiments, the condition is panic disorders. In some embodiments, the condition is post-traumatic stress disorder (PTSD). In some embodiments, the condition is substance abuse disorder. In some embodiments, the condition is chronic constipation. In some embodiments, the condition is a tremor disorder. In some embodiments, the condition is CoQlO deficiency. In some embodiments, the condition is oculocutaneous albinism.

[0311] In some embodiments, the condition is a mood disorder. In some embodiments, the mood disorder is depression.

[0312] In some embodiments, the inborn error of metabolism is an inborn error of tyrosine metabolism. In some embodiments, the inborn error of tyrosine metabolism is tyrosinemia type I, tyrosinemia type II, tyrosinemia type III, alkaptonuria, or hawkinsinuria. In some embodiments, the condition is tyrosinemia type I. In some embodiments, the condition is tyrosinemia type II. In some embodiments, the condition is tyrosinemia type III. In some embodiments, the condition is alkaptonuria. In some embodiments, the condition is hawkinsinuria. In some embodiments, an inborn error of metabolism can comprise an inborn error of phenylalanine metabolism. In some embodiments, the condition is phenylketonuria.

[0313] In some embodiments, the methods increase overall survival of a subject. In some embodiments, the methods increase overall survival of a subject by at least about 5%, at least about. 10%, at least about 15%, at least about 20%, at least, about 25%, at least, about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about. 80%, at least about 85%, at least about 90%, or at least about 95%. In some embodiments, the methods increase overall survival of a subject by at least about 10%. In some embodiments, the methods increase overall survival of a subject by at least about 20%. In some embodiments, the methods increase overall survival of a subject by at least about 10%.

[0314] In some embodiments, the methods further comprise utilizing metabolites to direct therapy. In some embodiments, methods of the disclosure can further comprise utilizing phenylalanine levels to direct therapy (e.g., with respect to increasing / decreasing dose amounts or dose frequency in a subject.) In some embodiments, methods of the disclosure can further comprise utilizing tyrosine levels to direct therapy. In some embodiments, methods of the disclosure can further comprise utilizing BH4 levels to direct therapy. In some embodiments, methods of the disclosure can further comprise utilizing BH2 levels to direct therapy. In some embodiments, methods of the disclosure can further comprise utilizing metabolites to monitor subject response. In some embodiments, methods of the disclosure can further comprise utilizing metabolites to titrate dosing. In some embodiments, methods of the disclosure can further comprise utilizing sepiapterin levels to direct therapy. In some embodiments, methods of the disclosure can further comprise utilizing biopterin levels to direct therapy. In some embodiments, methods of the disclosure can further comprise utilizing succinylacetone levels to direct therapy.

[0315] In some embodiments, the compositions and the methods further comprise administering BH4, BH2. levodopa, carbidopa and / or serotonin supplementation.

[0316] In some embodiments, the compositions and methods of the disclosure comprise administering BH4 and / or BH2 in combination with an HPD inhibitor for treating a condition.

[0317] In some embodiments, the compositions and methods of the disclosure comprise administering sepiapterin in combination with an HPD inhibitor for treating a condition.

[0318] In some embodiments, the compositions and methods of the disclosure comprise administering BH4 and / or BH2 in combination with nitisinone for the treatment of an inborn error of metabolism. In some embodiments, the compositions and methods of the disclosure comprise administering BH4 and BH2 supplementation in combination with nitisinone for the treatment of tyrosinemia type I. In some embodiments, the compositions and methods of the disclosure comprise administering BH4 and BH2 supplementation in combination with nitisinone for the treatment of alkaptonuria. In some embodiments, the compositions and methods of the disclosure comprise administering BH4 and BH2 supplementation in combination with nitisinone for the treatment of hawkinsinuria.

[0319] In some embodiments, the compositions and methods of the disclosure comprise administering a dopamine precursor therapy in combination with an HPD inhibitor for treating a condition.

[0320] In some embodiments, the compositions and methods of the disclosure comprise administering a dopamine precursor therapy in combination with nitisinone for the treatment of an inborn error of metabolism.

[0321] In some embodiments, the compositions and methods of the disclosure comprise administering levodopa and / or an inhibitor of peripheral DOPA decarboxylase such as carbidopa in combination with an HPD inhibitor for treating a condition.

[0322] In some embodiments, the compositions and methods of the disclosure comprise administering levodopa and / or an inhibitor of peripheral DOPA decarboxylase such as carbidopa and serotonin supplementation in combination with an HPD inhibitor for treating a condition.

[0323] In some embodiments, the compositions and methods of the disclosure comprise administering serotonin supplementation in combination with an HPD inhibitor for treating a condition.

[0324] In some embodiments, the compositions and methods of the disclosure comprise administering levodopa and / or an inhibitor of peripheral DOPA decarboxylase such as carbidopa in combination with nitisinone for the treatment of inborn errors of metabolism. In some embodiments, the compositions and methods of the disclosure comprise administering levodopa and / or an inhibitor of peripheral DOPA decarboxylase such as carbidopa in combination with nitisinone for the treatment of tyrosinemia type I. In some embodiments, the compositions and methods of the disclosure comprise administering levodopa and / or an inhibitor of peripheral DOPA decarboxylase such as carbidopa in combination with nitisinone for the treatment of alkaptonuria. In some embodiments, the compositions and methods of the disclosure comprise administering levodopa and / or an inhibitor of peripheral DOPA decarboxylase such as carbidopa in combination with nitisinone for the treatment of hawkinsinuria.

[0325] In some embodiments, the compositions and methods of the disclosure comprise administering serotonin supplementation in combination with nitisinone for the treatment of inborn errors of metabolism. In some embodiments, the compositions and methods of the disclosure comprise administering serotonin supplementation in combination with nitisinone for the treatment of tyrosinemia type 1. In some embodiments, the compositions and methods of the disclosure comprise administering serotonin supplementation in combination with nitisinone for the treatment of alkaptonuria. In some embodiments, the compositions and methods of the disclosure comprise administering serotonin supplementation in combination with nitisinone for the treatment of hawkinsinuria.

[0326] In some embodiments, the compositions and methods of the disclosure comprise administering levodopa and / or an inhibitor of peripheral DOPA decarboxylase such as carbidopa and serotonin supplementation in combination with nitisinone for the treatment of inborn errors of metabolism. In some embodiments, the compositions and methods of the disclosure comprise administering levodopa and / or an inhibitor of peripheral DOPA decarboxylase such as carbidopa and serotonin supplementation in combination with nitisinone for the treatment of tyrosinemia type I. In some embodiments, the compositions and methods of the disclosure comprise administering levodopa and / or an inhibitor of peripheral DOPA decarboxylase such as carbidopa and serotonin supplementation in combination with nitisinone for the treatment of alkaptonuria. In some embodiments, the compositions and methods of the disclosure comprise administering levodopa and / or an inhibitor of peripheral DOPA decarboxylase such as carbidopa and serotonin supplementation in combination with nitisinone for the treatment of hawkinsinuria.

[0327] The terms “effective amount” or “'therapeutically effective amount,” when used in connection with a compound, refer to a sufficient amount of the compound to provide the desired biological result. That result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic use is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease. An appropriate “effective amount” in any individual case may be determined by one of ordinary skill in the art using routine experimentation. Thus, the expression “effective amount” generally refers to the quantity for which the active substance has therapeutic effects. In the present disclosure the active substance is an inhibitor of HPD.

[0328] The term “disorder,” as used herein, refers to and is used interchangeably with the terms disease, condition, or illness, unless otherwise indicated. Amino acid (AA) modulation therapy

[0329] In some embodiments, compositions and the methods further comprise administering an AA modulation therapy to lower an average plasma level of an amino acid in a subject. In some embodiments, compositions of the disclosure are administered to a subject in combination with an AA modulation therapy that delivers less than a recommended dietary requirement of one or more amino acids (e.g., tyrosine, phenylalanine, or both) to a subject. In some embodiments, the AA modulation therapy comprises a diet (e.g., a food-based diet.) In some embodiments, the AA modulation therapy comprises a dietary product (e.g., a plurality of amino acids, such as in powder form.) In some embodiments, the AA modulation therapy comprises a diet (e.g, a food-based diet) and a dietary product (e.g, a plurality of amino acids, such as in powder form.)

[0330] Daily recommended dietary requirement, as used herein, refers to the daily dietary intake level (e.g, of protein, carbohydrates, fat, and amino acids) that suffices to meet the nutrient requirements (e.g., protein, carbohydrate, fat, and amino acid requirements) of nearly all (e.g, 95% or more) healthy person of a specific sex and age. For example, recommended dietary intake levels may be recommended dietary allowance (RD A) as determined by the Food and Nutriti on Board of the Institute of Medicine. Also for example, recommended dietary intake levels may be daily median intake as recommended by the National Health and Nutrition Examination Survey (NHANES).

[0331] Average plasma levels of a biomarker (e.g., an amino acid level, such as a tyrosine level or a phenylalanine level), as used herein, refers to levels of a biomarker (e.g., an amino acid) as measured from a blood panel. For example, in some embodiments, blood is collected for amino acid panel(s) approximately 2 hours (+ / - 60 min) after a meal. Also for example, in some embodiments, for baseline average plasma levels of a biomarker (e.g, of an amino acid such as tyrosine or phenylalanine), two blood collections on different days occur before treatment (e.g., during screening.) In some embodiments, average plasma levels of a biomarker (e.g, of an amino acid such as tyrosine or phenylalanine) after treatment with an AA modulation therapy involve blood collection 1-5 days (i.e., 1, 2, 3, 4, or 5 days) after treatment with AA modulation therapy.

[0332] In some embodiments, the AA modulation therapy decreases an amino acid level in a subject. In some embodiments, the amino acid level is decreased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about. 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about. 90%. In some embodiments, the amino acid level is decreased by at least about 10%. In some embodiments, the amino acid level is decreased by at least about 20%. In some embodiments, the amino acid level is decreased by at least about 50%.

[0333] In some embodiments, the AA modulation therapy provides less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, or less than 0.1% of a recommended dietary requirement of tyrosine for the subject’s age group, as determined by the Food and Nutrition Board of the Institute of Medicine.

[0334] Recommended dietary requirements may vary based on factors including subjects age, sex, and physical activity. For example, recommended dietary requirements for tyrosine may vary as shown: Tyrosine (mg / kg / day) Infants (0.3 to 1 year) 29.9 Children (1 to 3 years) 29.3 Adult -- low physical activity 26.6 Adult - moderate physical activity 34.6 Adult - intense physical activity 42.6 These reference values are adapted from: Wu G. Dietary protein intake and human health. Food & Function. 2016;7(3): 1251-1265. doi: 10.I039 / c5fo01530h, which is hereby incorporated by reference in its entirety. Also for example, recommended dietary requirements for combined intake of phenylalanine and tyrosine may vary as shown: Phenylalanine + Tyrosine (mg / kg / day) Infants (0-6 months) 135 Infants (6-12 months) 84 Children (1-3 years) 54 Children (4-8 years) 41 Children (9-13 years) 41 (boys), 38 (girls) Adolescents (14-18) 38 (boys), 35 (girls) Adults 33 These reference values are adapted from: Institute of Medicine. 2006. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington, DC: The National Academies Press. https: / / doi.org / 10.17226Zl 1537, which is hereby incorporated by reference in its entirety.

[0335] In some embodiments, the AA modulation therapy provides iess than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, or less than 0,1% of a recommended dietary allowance (RD A) of tyrosine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0336] In some embodiments, the AA modulation therapy provides less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, or less than 0.1% of an RDA of phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0337] In some embodiments, the AA modulation therapy provides less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, or less than 0.1% of an RDA of tyrosine and phenylalanine combined, for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine. In some embodiments, the recommended dietary allowance of tyrosine and phenylalanine is 33 mg / kg / day.

[0338] In some embodiments, the AA modulation therapy provides less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, or less than 0.1% of average recommended dietary intake of tyrosine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine. In some embodiments, the AA modulation therapy provides less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, or less than 0.1% of average recommended dietary' intake of phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0339] In some embodiments, the AA modulation therapy provides less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, or less than 0.1% average recommended dietary intake of each of tyrosine and phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0340] In some embodiments, the AA modulation therapy provides less than the daily median intake of tyrosine. In some embodiments, the AA modulation therapy provides less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, or less than 0.1% of the daily median intake amount of tyrosine as determined by the National Health and Nutrition Examination Survey (NHANES). In some embodiments, the daily median intake of tyrosine is 3.9 g / day.

[0341] In some embodiments, the AA modulation therapy provides less than the daily median intake of pheny lalanine. In some embodiments, a dietary product provides less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, less than 0.5%, or less than 0.1% of the daily median intake amount of phenylalanine as determined by the National Health and Nutrition Examination Survey (NHANES). In some embodiments, the median intake of phenylalanine is 4,8 g / day.

[0342] In some embodiments, the AA modulation therapy comprises a diet (e.g, a food-based diet) that has less than a recommended dietary' requirement of one or more amino acids. In some embodiments, the diet is devoid of one or more amino acid. In some embodiments, after detecting an absence or a decreased level of a biomarker of an amino acid metabolism pathway in a subject, the subject is administered an AA modulation therapy that removes the amino acid from the subject’s diet. In some embodiments, the diet is administered via tube feeding.

[0343] “Devoid of’, as used herein, is used interchangeably with “does not comprise” or “lacks”.

[0344] Diet, as used herein, refers to the nutritional intake consumed by the subject from meals, snacks, and drinks throughout the day. For example, the diet may be a food-based diet that comprises the subject’s food and beverages over the course of a day. The diet may also comprise meal replacement products, medical food, or parenteral nutritional intake.

[0345] In some embodiments, the diet accounts for almost all food consumed by the subject. For example, in some embodiments, the diet accounts for at least 80%, at least 90%, at least 95%, or at least 95% of calories from food consumed by the subject. In some embodiments, the diet accounts for all food consumed by the subject. For example, in some embodiments, the diet, accounts for 100% of calories from food consumed by the subject.

[0346] In some embodiments, the diet is a low-protein diet. In some embodiments, the low-protein diet comprises less than about 2 g / day, about 1.75 g / day, about 1.5 g / day, about 1.25 g / day, about 1 g / day, about 0.75 g / day, or about 0.5 g / day of protein. In some embodiments, a composition of the disclosure is administered to a subject that is on a low-protein diet comprising less than about 500 mg / day, about 450 mg / day, about 400 mg / day, about 350 mg / day, about 300 mg / day, about 250 mg / day, about 200 mg / day, about 150 mg / day, about 100 mg / day, or about 50 mg / day of protein.

[0347] In some embodiments, the diet comprises meals with modified types of proteins, amino acids, or peptides that contain low levels of specific amino acids. In some embodiments, the diet comprises meals with modified levels of one amino acid. In some embodiments, the amino acid is tyrosine. In some embodiments, the amino acid is phenylalanine. In some embodiments, two amino acid levels are lowered in a subject by administering to the subject meals with modified levels of the amino acids or by modifying amino acid levels for the subject’s daily food intake. In some embodiments, the two amino acids are tyrosine and phenylalanine.

[0348] In some embodiments, the diet comprises less than about 75%, less than about. 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of a recommended dietary' requirement of tyrosine for the subject’s age group, as determined by the Food and Nutrition Board of the Institute of Medicine.

[0349] In some embodiments, the diet comprises less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about. 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of a recommended dietary- allowance (RDA) of tyrosine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0350] In some embodiments, the diet comprises less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about. 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of the daily median intake amount of tyrosine as determined by the National Health and Nutrition Examination Survey (NHANES). In some embodiments, the daily median intake of tyrosine is 3.9 g / day.

[0351] In some embodiments, the diet comprises less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about. 1%, less than about 0,5%, or less than about 0.1% of an RDA of phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0352] In some embodiments, the diet comprises less than about 75%, less than about. 70%, less than about. 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about. 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0353] In some embodiments, the diet comprises less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about. 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, less than about. 0.5%, or less than about 0.1% of the daily median intake amount of phenylalanine as determined by the National Health and Nutrition Examination Survey (NHANES). In some embodiments, the median intake of phenylalanine is 4.8 g / day.

[0354] In some embodiments, the diet comprises less than about 75%, less than about 70%, less than about 65%, less than about. 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about. 0.1% of an average recommended dietary'’ intake of tyrosine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine and less than about 75%, less than about. 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about. 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of average recommended dietary'- intake of phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0355] In some embodiments, the diet comprises less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about. 1%, less than about 0.5%, or less than about 0.1% of an average recommended dietary intake of each of tyrosine and phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0356] In some embodiments, the diet comprises less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of a combined RDA of tyrosine and phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine. In some embodiments, the combined RDA of tyrosine and phenylalanine is 33 mg / kg / day. Dietary Product

[0357] In some embodiments, the AA modulation therapy comprises a dietary product. In some embodiments, treatments comprise administering to a subject a therapeutically effective amount of an inhibitor of HPD and a dietary' product, wherein the dietary' product comprises less than a recommended dietary requirement of one or more amino acids (e.g., tyrosine, phenylalanine, or tyrosine and phenylalanine.) In some embodiments, the dietary product is administered with food (e.g., with food from a low-protein food-based diet.) In some embodiments, the dietary product is a sole source of protein for the subject. In some embodiments, the dietary product is a sole source of amino acids for the subject. In some embodiments, the dietary product is a sole source of calories for the subject.

[0358] In some embodiments, the dietary product, provides at. least, about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about. 99% of the amino acids consumed by the subject. In some embodiments, the dietary product provides about 100% of the amino acids consumed by the subject. In some embodiments, the dietary product is substantially a sole source of protein for the subject. In some embodiments, the dietary product is substantially a sole source of amino acids for the subject. In some embodiments, the dietary' product is substantially a sole source of calories for the subject.

[0359] The term “source”, such as in the phrase “substantially a sole source,” as used herein, refers to a provider of nutrition such as a diet, a dietary regimen, or a dietary product as used herein. The phrase “substantially a sole source,” as used herein, refers to said source providing almost all if not all of the indicated nutritional component. For example, the phrase “a dietary regimen is substantially a sole source of calories for a subject” indicates the dietary regimen provides almost all, if not all calories (including calories from carbohydrates, protein, and fat) taken in by a subject. Also for example, the phrase “a dietary' regimen is substantially a sole source of amino acids for a subject” indicates the dietary regimen provides almost all, if not all of the amino acids taken in by a subject. For example, substantially a sole source may refer to at least 90% of the stated daily intake of the nutritional item originating from the stated source.

[0360] In some embodiments, the dietary product accounts for almost all calories consumed by the subject (e.g, in some embodiments, the AA modulation therapy consists of a dietary' product without a food-based diet.) For example, in some embodiments, the dietary product account for at least 80%, at least 90%, at least 95%, or at least 95% of calories consumed by the subject. In some embodiments, the dietary / accounts all calories consumed by the subject. For example, in some embodiments, the diet accounts for 100% of calories consumed by the subject.

[0361] In some embodiments, the dietary product comprises less than about. 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about. 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of a recommended dietary' requirement of tyrosine for the subject’s age group, as determined by the Food and Nutrition Board of the Institute of Medicine.

[0362] In some embodiments, the dietary' product comprises less than about 50%, less than about 45%, less than about. 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about. 1%, less than about 0.5%, or less than about 0.1% of a recommended dietary allowance (RDA) of tyrosine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0363] In some embodiments, the dietary product, comprises less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about. 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of the daily median intake amount of tyrosine as determined by the National Health and Nutrition Examination Survey (NHANES). In some embodiments, the daily median intake of tyrosine is 3.9 g / day.

[0364] In some embodiments, the dietary product comprises less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about. 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of an RDA of phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0365] In some embodiments, the dietary product comprises less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about. 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0366] In some embodiments, the dietary' product comprises less than about. 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about. 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of the daily median intake amount of phenylalanine as determined by the National Health and Nutrition Examination Survey (NHANES). In some embodiments, the median intake of phenylalanine is 4.8 g / day.

[0367] In some embodiments, the dietary product comprises less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about. 0.1% of an average recommended dietary / intake of tyrosine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine and less than about 50%, less than about. 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about. 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of average recommended dietary' intake of phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0368] In some embodiments, the dietary product, comprises less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about. 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of an average recommended dietary' intake of each of tyrosine and phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine.

[0369] In some embodiments, the dietary product comprises less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about. 15%, less than about 10%, less than about 5%, less than about 1%, less than about 0.5%, or less than about 0.1% of a combined RDA of tyrosine and phenylalanine for the subject’s age group as determined by the Food and Nutrition Board of the Institute of Medicine. In some embodiments, the combined RDA of tyrosine and phenylalanine is 33 mg / kg / day.

[0370] In some embodiments, the dietary product is devoid of at least 1, 2, 3, 4, 5, 6, 7, or 8 amino acids. In some embodiments, the dietary product is devoid of at least 1 amino acid. In some embodiments, the dietary product is devoid of at least 2 amino acids. In some embodiments, the dietary product is devoid of at least 3 amino acids. In some embodiments, the dietary product is devoid of at least 4 amino acids. In some embodiments, the dietary product is devoid of at least 5 amino acids.

[0371] In some embodiments, the dietary product is devoid of at least tyrosine. In some embodiments, the dietary / product is devoid of at least phenylalanine. In some embodiments, the dietary product is devoid of tyrosine and phenylalanine.

[0372] In some embodiments, the dietary product is devoid of tyrosine and contains less than about 100 mg / kg / day, about 95 mg / kg / day, about 90 mg / kg / day, about 85 mg / kg / day, about 80 mg / kg / day, about 75 mg / kg / day, about 70 mg / kg / day, about 65 mg / kg / day, about 60 mg / kg / day, about 55 mg / kg / dav, about 50 mg / kg / day, about 45 mg / kg / day, about 40 mg / kg / day, about 35 mg / kg / day, about 30 mg / kg / day, about 25 mg / kg / day, about 20 mg / kg / day, about 15 mg / kg / day, about 10 mg / kg / day, or about 5 mg / kg / day of phenylalanine. In some embodiments, the dietary product is devoid of tyrosine and contain less than about 30 mg / kg / day of phenylalanine. In some embodiments, the dietary product is devoid of at least, tyrosine and contain less than about 25 mg / kg / day of phenylalanine. In some embodiments, the dietary product is devoid of at least tyrosine and contain less than about. 20 mg / kg / day of phenylalanine. In some embodiments, the dietary product is devoid of at least tyrosine and contain less than about 15 mg / kg / day of phenylalanine.

[0373] The dietary product comprises at least ten amino acids or salts thereof. In some embodiments, the dietary' product comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acids or a salt thereof, hi some embodiments, the dietary product comprises 10 amino acids or a salt thereof. In some embodiments, the dietary product comprises 14 amino acids or a salt thereof. In some embodiments, the dietary product comprises 18 amino acids or a salt thereof.

[0374] In some embodiments, the dietary product comprises 1, 2, 3, 4, 5, 6, 7, 8, or 9 essential amino acids or salts thereof. In some embodiments, the dietary- product comprises 7, 8, or 9 essential amino acids or salts thereof. In some embodiments, the dietary-’ product comprises 8 essential amino acids or salts thereof. In some embodiments, the dietary' product comprises 9 essential amino acids or salts thereof.

[0375] Essential amino acids, as used herein, refers to histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine . [0376[ In some embodiments, the dietary product comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 non-essential amino acids or salts thereof. In some embodiments, the dietary- product comprises 7, 8, 9, 10, or 11 non-essential amino acids or salts thereof. In some embodiments, the dietary product comprises 7 non-essential amino acids or salts thereof. In some embodiments, the dietary product comprises 8 non-essential amino acids or salts thereof. In some embodiments, the dietary product comprises 9 non-essential amino acids or salts thereof.

[0377] Non-essential amino acids, as used herein, refers to alanine, asparagine, aspartic acid, glutamic acid, arginine, cysteine, glutamine, tyrosine, glycine, proline, and serine. Some nonessential amino acids are conditionally essential amino acids. Conditionally essential amino acids, as used herein, refers to asparagine, arginine, cysteine, glutamine, tyrosine, glycine, proline, and serine.

[0378] In some embodiments, the dietary' product comprises essential amino acids or salts thereof and non-essential amino acids or salts thereof. In some embodiments, the dietary' product comprises 1, 2, 3, 4, 5, 6, 7, 8, or 9 essential amino acids or salts thereof and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 non-essential amino acids or salts thereof. In some embodiments, the dietary product comprises 7, 8, or 9 essential amino acids or salts thereof and 6, 7, 8, or 9 non-essential amino acids or salts thereof. In some embodiments, the dietary' product comprises 8 or 9 essential amino acids or salts thereof and 8 or 9 non-essential amino acids or salts thereof. In some embodiments, the dietary product comprises 9 essential amino acids or salts thereof and 7 nonessential amino acids or salts thereof. In some embodiments, the dietary' product comprises 9 essential amino acids or salts thereof and 8 non-essential amino acids or salts thereof. In some embodiments, the dietary product comprises 9 essential amino acids or salts thereof and 9 nonessential amino acids or salts thereof.

[0379] In some embodiments, the dietary product comprises histidine, isoleucine, leucine, lysine, methionine, cysteine, phenylalanine, tyrosine, threonine, tryptophan, valine, arginine, glutamine, alanine, aspartic acid, asparagine, glutamic acid or proline. In some embodiments, the dietary product comprises L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-cysteine, L-phenylalanine, L-tyrosine, L-threonine, L-tryptophan, L-valine, L-arginine, L-glutamine, L-alanine, L-aspartic acid, L-asparagine, L-glutamic acid, or L-proline.

[0380] In some embodiments, a composition comprises histidine or a salt thereof, such as L-histidine or L-histidine hydrochloride. In some embodiments, the dietary' product comprises isoleucine or a salt thereof such as L-isoleucine, L-isoleucine methyl ester hydrochloride, or L-isoleucine ethyl ester hydrochloride. In some embodiments, the dietary' product comprises leucine or a salt thereof, such as L-leucine, L-leucine methyl ester hydrochloride, or L-leucine ethyl ester hydrochloride. In some embodiments, the dietary product comprises lysine or a salt thereof, such as L-lysine, L-lysine hydrochloride, or L-lysine dihydrochloride. In some embodiments, the dietary / product comprises methionine or a salt thereof, such as L-methionine, L-methionine methyl ester hydrochloride, or L-methionine hydrochloride.

[0381] In some embodiments, the dietary product comprises cysteine or a salt thereof, such as L-cysteine, L-cysteine hydrochloride, L-cysteine methyl ester hydrochloride, or L-cysteine ethyl ester hydrochloride. In some embodiments, a composition discloses cystine or a salt thereof, such as L-cystine. In some embodiments, the dietary' product comprises phenylalanine or a salt thereof, such as L-phenylalanine, DL-phenyl alanine, or L-phenylalanine methyl ester hydrochloride. In some embodiments, the dietary' product comprises tyrosine or a salt thereof, such as L-tyrosine or L-tyrosine hydrochloride. In some embodiments, the dietary / product comprises threonine or a salt thereof, such as L-threonine or L-threonine methyl ester hydrochloride. In some embodiments, the dietary product comprises L-tryptophan. In some embodiments, the dietary product comprises valine or a salt thereof, such as L-valine, L-valine methyl ester hydrochloride, or L-valine ethyl ester hydrochloride.

[0382] In some embodiments, the dietary product comprises arginine or a salt thereof, such as L-arginine or L-arginine hydrochloride. In some embodiments, the dietary' product comprises glutamine or a salt thereof, such as L-glutamine or L-glutamine hydrochloride. In some embodiments, the dietary' product comprises alanine or a salt thereof, such as L-alanine or 0- alanine. In some embodiments, the dietary product comprises aspartic acid or a salt thereof, such as L-aspartic acid, D-aspartic acid, L- or D-aspartic acid potassium salt, L- or D-aspartic acid hydrochloride salt; L- or D-aspartic acid magnesium salt, or L- or D-aspartic acid calcium salt. In some embodiments, the dietary product comprises L-asparagine. In some embodiments, the dietary product comprises glutamic acid or a salt thereof, such as L-glutamic acid or L-glutamic acid hydrochloride. In some embodiments, the dietary' product comprises proline or a salt thereof, such as L-proline, L-proline hydrochloride, L-proline methyl ester hydrochloride, or L-proline ethyl ester hydrochloride.

[0383] In some embodiments, the dietary' product is administered orally. In some embodiments, the dietary product is formulated as a solid (e.g, a powder). In some embodiments, the dietary product is formulated as a beverage. In some embodiments, the dietary product is formulated as a solid (e.g., a powder) that is reconstituted in water.

[0384] In some embodiments, the dietary' product is administered via tube. In some embodiments, the dietary' product is administered via nasogastric tube. In some embodiments, the dietary product is administered intravenously or parenterally.

[0385] In some embodiments, the subject is administered a therapeutically effective amount of the dietary product. In some embodiments, the therapeutically effective amount of the dietary product is from about 0.5 g / kg / day to about 1 g / kg / day. In some embodiments, the therapeutically effective amount of the dietary product, is about 0.5 g / kg / day, about. 0.6 g / kg / day, about 0.7 g / kg / day, about 0.8 g / kg / day, about 0.9 g / kg / day, or about 1.0 g / kg / day. In some embodiments, the therapeutically effective amount of the dietary’ product is about 0.8 g / kg / day.

[0386] In some embodiments, the dietary' product is administered 3 to 5 times a day. In some embodiments, the dietary product is administered 3 times a day. In some embodiments, the dietary product is administered about 5 times a day.

[0387] A salt of an amino acid disclosed herein can be a pharmaceutically acceptable salt. A salt of an amino acid disclosed herein can be a nutritionally acceptable salt. In some embodiments, a nutritionally acceptable salt meets the requirements of its applicable FCC monograph. In some embodiments, a nutritionally acceptable salt meets the requirements of its applicable Joint FAO, / WHO Expert Committee on Food Additives (JECFA) reports, monographs, or specifications. In some embodiments, a nutritionally acceptable salt meets the FDA requirements at 21 CFR 172.320. Herbicidal Compositions

[0388] In some embodiments, the disclosure provides an herbicidal composition comprising a compound of Formulae (I), (IA), (I A3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (IDO),        (ID-S02), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (h-\). (II- N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (U A-C). (IIA-C3), (HA-N), (IIA-N3), (IIB), ClB3f (HC), (IIC3), (HD), (H). (IV), (IVA), (IVA3), (IVB-O), (IVB-03), (WB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (AT), (VI), (VII), or (VIII) or an agriculturally acceptable salt thereof.

[0389] In some embodiments, the disclosure provides an herbicidal composition comprising a compound of Formulae (I), (LA), (1A3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (IDO), (ID-S), (ID-SO2), (IE), (IF), (IG-N), (IG-N3), (IG-O), (IH-N), (IH-N3), (IH-O), (li-N), (li-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-C), (IIA-C3), (IIA-N), (IIA-N3), (IIB), (IIB3), (IIC), (IIC3), (IID), (III), (IV), (IVA), (IVA3), (IVB-O), (IVB-O3), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), or (IVD3), or an agriculturally acceptable salt thereof.

[0390] “Agriculturally acceptable salt,” as used herein, refers to a salt that is generally safe non-toxic, and is otherwise not undesirable to mammals, birds, crops, and other animals or plants that are not being targeted for control, and which confers suitable properties (e.g., solubility) for agricultural use.

[0391] In some embodiments, the herbicidal composition further comprises an herbicidal safener, wherein the safener increases a metabolic rate of the herbicidal composition in a crop.

[0392] In some embodiments, the safener increases expression of a gene that encodes an enzyme responsible for xenobiotic degradation of the herbicidal composition in the crop. In some embodiments, the gene encodes Cytochrome P450, glutathione-S-transferase, or an ATP-binding cassette transporter.

[0393] In some embodiments, the safener is identified in a biological screen.

[0394] In some embodiments, the herbicidal composition and the safener are present in a ratio of at least 4:1 by weight (compound: safener).

[0395] In some embodiments, the safener ...

Claims

1. A compound of Formula (I):Formula (!)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, or all together form an aryl ring or heteroaryl ring, wherein:X1 is CRiaRia, X2 is CR2aR2a", and X3 is CR3aR3a’;X1 is NRlb or O, X2 is CR2bR2b’, and X3 is CR3bR3b’;X1 is CRlcR!c’, X2 is CR2cR2c’, and X3 is NR3c or O;X1 is CRldRld’, X2 is O, S, or S(02), and X3 is CR3dR3d’;X1 is CRMV' . X2 is C(0), and X3 is CR3sR3e';X1 is CRi!Rir, X2 is CR2fR2f, and X3 is a bond;X1 is NR’8 or 0, X2 is CR2gR2g’, and X3 is a bond,X1 is CR!hR!h’, X2 is NR2h or 0, and X3 is a bond;X1 is NRn or 0, X2 is C(0), and X3 is CR3,R.X1 is NRlj or 0, X2 is NR2j or 0, and X3 is CR5 IC :X1 is NRlk or 0, X2 is NR2k or 0, and X3 is a bond;X1 is NRn or 0, X2 is C(0), and X3 is NR3! or O; orX1 is CRlmRim', X2 is CR2mR2m’, and X3 is CR3mR3ra’-CR4mR4m’;Z’! and Z2 are each independently selected from C(0) and S(0?);Rla and Rla’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -C0(0)-Cu6 alkyl, and aryl;R2a and R23’ are each independently selected from H, C2-6 alkyl, Cj-s haloalkyl, C3-6 cycloalkyl, -C0(0)-Ci-6 alkyl, and aryl;R3a and R3a are each independently selected from H, Ci-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;If Z1 and Z2 are both C(O), then at least one of Rla, Rla’, R2a, R2a, R3a, or R38’ is Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Cu6 alkyl, or aryl;wherein the aryl of Ria, Rla, R2a, R2a’, Rja, or Rja is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Cur, haloalkyl, and -CO(O)-Ci-6 alkyl; ortwo or more of Rla, Ria’, R2a, R2a, R3a, and R38’ combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Cj-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined Rla, Rla, R2a, R2a, R3a, or R3a’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Rla, Rla, R2a, R2a, R3a, or R3a’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl,R2b, R2b, R3b, and R3b are each independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of R2b, R2b’, R3b, or R3” is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C0(0)-0.-6 alkyl; ortwo or more of Rlb, R2b, R2b , R30, and R3d combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C0(0)-Ci-6 alkyl, and any uncombined Rlb, R2b, R2b , R3”, or R3b are each independently-selected from H, Cn6 alkyl, Ci-6 haloalkyl, €3-6 cycloalkyl, -C0(0)-Ci-6 alkyl, and aryl;wherein the aryl of R!D, R2b, R2b , R3b, or R3” is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C0(0)-Ci-6 alkyl;Rlc, Rlc’, R20, and R2c are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3. 6 cycloalkyl, -C0(0)-Ci-6 alkyl, and aryl;wherein the aryl of Rlc’, R2c, or R2c’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;Rld, R,d , R5d, and R3d’ are each independently selected from H, Cue alkyl, Cue haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of Rid, Rld, R3d, or R3d is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;Rle, RJe, R3e, and R3e’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, Ch-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of Rie, R,e, R3e, or R3e is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; ortwo or more of Rle, Rle, R3e, and R3e’ combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)~Ci-6 alkyl, and any uncombined R!e, Rle’, R3e, or R3e’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, Cs-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of Rie, Rle, R3e, or R3e’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Cm haloalkyl, and -CO(O)-Ci-6 alkyl;R11, Rlf, R2f, and Ra are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci~6 alkyl, and aryl;wherein the aryl of R:!, R1P, R21, or Rzf is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; ortwo or more of Rlf, R.lf, R2f, and R21 combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one ormore substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined R!f, R!i , R2f, or R2f are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the and of R!f, Rlf, R2f, or R2f is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R2g and R2g’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-C]-6 alkyl, and aryl;wherein the and of R2g or R2g is unsubstituted or substituted with one or more substituents sel ected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;Rlh and Rlh’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -C0(0)-Cj-6 alkyl, and aryl;wherein the and of Rln or Rlh is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R31 and R3f are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the and of R31 or R31 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R3’ and R3j’ are each independently selected from H, Ci-6 alkyl, Cj-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the and of R3j or R3' is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cn6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;Rim, pym',         ,               an^ ^4m are eac^ independently selected from H, Ci-ealkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of R‘“, Rhn, R2m, R2m’, R3m, R3m, R4m, or R4m’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Cj-6 haloalkyl, and -CO(O)-Ci-6 alkyl; ortwo or more of Rlm, Rlm, R2m, R2m , R3m, RJm , R4™, and R4m combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined Rlm, Rlm’, R2m, R2m’, R3m, R3m’, R4m, or R4m’ are each independently selected from H, Cue alkyl, Ci-6 haloalkyl, C3-5 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of R!m, Rlm , R2m, R2m’, R3m, R3m, R4m, or R4m’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;Rlb is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cur, alkyl-aryl, or heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rib is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; ortwo or more of Rlb, R2b, R2b , R3”, and R3”’ combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cw alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined Rlb, R2b, R2b, R3b, or R3b are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Cu6 alkyl, and aryl;wherein the aryl of Ri0, R2b, R2b’, R3b, or R30’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Cu6 alkyl,R3c is H, Cue alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl;wherein the Cue alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl of Rlc is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, and alkoxy;Rlg is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl;wherein the Cj-e alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlg is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, and alkoxy,R21’ is H, Cn6 alkyl, Cs-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl;wherein the C1-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of R2h is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;R11 is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl;wherein the Cue alkyl, C3-6 cycloalkyl, aryl, Ci-e alkyl-aryl, or heteroaryl of Rb is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-e alkyl, and alkoxy;Rlj and R2j are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlj or R2i is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;Rlk and R2k are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlk or R2k is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;R1! and R31 are each independently selected from H, Ci-s alkyl, C3-6 cycloalkyl, and, Ch-6 alkyl-aryl, and heteroaryl;wherein the Cue alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of R': or R3! is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy,n is 0 or 1;wherein:if X1 is CRlaRla’, X2 is CR2aR2a’, and X3 is CR3aR3a’, then:Yl is C(H); Y2 is C(H) or N; Y3 is C(CF3); Y4 is C(H) or N; and Y5 is C(H); orY1 is C(Rla2) or N; Y2 is C(R2a2); Y3 is C(R3a2) or N, Y4 is C(R4a2); and Y5 is C(R5a2); whereinRla2 is H, halo, Ci-6 haloalkyl, NO?„ CN, or SO2-C1-6 alkyl;R2a2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R3a2 is H, halo, Cue haloalkyl, NO2, or CN;R4a2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R5a2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1,. alkyl; orRia2 com|jines ^th R2a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cw alkyl, and R3a2, R4a2, and R5a2 are each independently selected from H, halo, Cue haloalkyl, NO?, and CN; orR2a2 combines with Rja2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-e alkyl, and Rla2, R4a2, and R5a2 are each independently selected from H, halo, Cue haloalkyl, NO?, and CN; orR3a2 combines with R4a2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and Rla2, R2a2, and R5a2 are each independently selected from H, halo, Ci-6 haloalkyl, NO?, and CN; orR4a2 combines with R5a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and Rla2, R2a2, and R3a2 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN;if X1 is NRlb or O, X2 is CR2oR2b , and X3 is CR3bR3b’, then:Y1 is C(Rlb2) or N; Y2 is C(R2b2) or N; Y3 is C(R3b2) or N; Y4 is C(R4b2) or N; and Y5 is C(R5b2) or N, orY3 is C(O); Y2 is N(R2b2 ); Y3 is C(R3b2 ); Y4 is C(R4b2 ); and Y5 is N; whereinRlb2 is H, halo, Cw haloalkyl, NO?., CN, or SOi-Ci-e alkyl,R2b2 is H, halo, Cue haloalkyl, NO?, CN, or SO2-CU6 alkyl, R3b2 is H, halo, Cue haloalkyl, NO2, CN, or SOu-C ue alkyl;R4b2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-CJ-6 alkyl,R5b2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orRlb2 combines with R2”2 to form an aiyl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cw alkyl or OH, and R3b2, R4”2, and R5”2 are each independently selected from H, Ci-s alkyl, halo, Ci-6 haloalkyl, NO2, and CN, orR2b2 combines with R3b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl or OH, and R!b2, R4b2, and R5b2 are each independently selected from H, Ci-6 alkyl, halo, Ci-6 haloalkyl, NO2, and CN, orR3b2 combines with R4b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring maybe unsubstituted or substituted with Ci-6 alkyl or OH, and Rlb2, R2b2, and R5b2 are each independently selected from H, Ci-6 alkyl, halo, Ci-6 haloalkyl, NO2, and CN; orR4b2 combines with R5b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring maybe unsubstituted or substituted with Ci-6 alkyl or OH, and Rlb2, R2b2, and R3b2 are each independently selected from H, Cn6 alkyl, halo, Ci-6 haloalkyl, NO2, and CN;R2b2 is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-e alkyl-aryl, or heteroaryl of R2b2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, and alkoxy;R3bz is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R4b2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; orR2b2 combines with R3b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl or halo, and R4b2 is selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl;wherein the Ci-6 alky I, C3-6 cycloaikyi, aryl, Cj-s alkyl-ary!, or heteroaryl of R4b2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy, orR3b2’ combines with R4b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl or halo, and R2b2 is selected from H, Cue alkyl, C3-6 cycloalkyl, and, Ci-6 alkyl-aryl, and heteroaryl;wherein the Cue alkyl, C3-6 cycloaikyi, aryl, Ci-6 alkyl-aryl, or heteroaryl of R2b2’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;if X1 is CR^R10', X2 is CR2cR2c’, and X3 is O or NR3c; then Y1 is C(Rlc2) or N; Y2 is C(R2C2) orN; Y3 is C(R3c2) orN; Y4 is C(R4c2) or N; and Y5 is (W';2) orN; whereinRlc2 is H, halo, Ci-s haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R2c2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R3c2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SOz-Cns alkyl,R4c2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R5c2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orRlc2 combines with R2C2 to form an aryl ring, heteroaryl ring, cycloaikyi ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloaikyi ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3'2. R4c2, and R5c2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2c2 combines with R3c2 to form an aryl ring, heteroaryl ring, cycloaikyi ring, or heterocyclic ring, wherein the aiyl ring, heteroaryl ring, cycloaikyi ring, or heterocyclic ring may be unsubstituted or substituted with Ci-s alkyl, and Rlc2, R4c2, and R5c2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3c2 combines with Rfc2 to form an aryl ring, heteroaryl ring, cycloaikyi ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloaikyi ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlc2, R2c2, and R3c2 are each independently selected from H, halo, Cj-s haloalkyl, NO2, and CN; orR4c2 combines with R5c2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rk'2, R2c2, and R3c2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN;if X1 is CRldRld’, X2 is O, S, or S(02), and X3 is CR3dR3d’, then Y1 is C(R!d2) or N; Y2 is C(R2d2); Y3 is C(R3d2) or N; Y4 is C(R4d2) or N; and Y5 is C(R5d2) or N; whereinRld2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R2d2 is H, halo, Cng haloalkyl, N02, CN, or SO2-C1.6 alkyl;Rjd2 is H, halo, Ci-6 haloalkyl, N02, CN, or SO2-C1-6 alkyl;R4d2 is H, halo, (Yr haloalkyl, N02, CN, or SO2-Ci-6 alkyl;R5d2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-Ci-6 alkyl; orRld2 combines with R2d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3a2, R4d2, and R5d2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2d2 combines with R3d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rld2, R4d2, and R5d2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3d2 combines with R4d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rld2, R2d2, and R5d2 are each independently selected from H, halo, Cur, haloalkyl, NO2, and CN, orR4d2 combines with R5d2 to form an aiyl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-e alkyl, and Rld2, R2d2, and R~’d2 are each independently selected from H, halo, Ci-6 haloalkyl, NO?, and CN, if X! is CRleRle, X2 is C(O), and XJ is CRJeR3e, then:Y1 is C(Rle2); Y2 is C(R2e2); Y3 is C(R3e2); Y4 is C(R4e2); and Y5 is C(R5e2); orY1 is C(Rle2) or N; Y2 is C(R2 2 ) or N; Y3 is C(R<2) or N, Y4 is ( (R k2) or N, and Y?1 is C(R5s2 ) or N, wherein at least one of Y1, Y2, Y3, Y4, and Y5 is N; whereinRle2 is H, F, CN, or SO2-C1-6 alkyl;R2e2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R3e2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R4e2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R5e2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orRle2 is Cl; R2®2 is H; R3e2 is Ci-6 haloalkyl, NO2, or SO2-C1-6 alkyl; R4e2 is H; and R5e2 is H; orRle2 is NO2; R2e2 is H; R3e2 is Ci-6 haloalkyl; R4®2 is H; and R5e2 is H; orR!e2 combines with R2e2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3e2, R4e2, and R5e2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2e2 combines with RJs2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rle2, R4e2, and R5e2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3e2 combines with R4s2 to form an and ring, heteroaryl ring, cycloalkyl ring,or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rls2, R2e2, and R5e2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR4e2 combines with R5s2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wdierein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring maybe unsubstituted or substituted with Ci-6 alkyl, and Rle2, R2e2, and R3e2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orRle2’ is H, halo, Cw haloalkyl, NO2, CN, and SO2-C1-6 alkyl,R2er is H, halo, Ci-6 haloalkyl, NO2, CN, and SO2-C1-6 alkyl;R3e2’ is H, halo, Ci-6 haloalkyl, NO2, CN, and SO2-C1-6 alkyl;R4e2 is H, halo, Ci-6 haloalkyl, NO2, CN, and SO2-C1-6 alkyl;R5e2’ is H, halo, Ci-6 haloalkyl, NO2, CN, and SO2-C1-6 alkyl, orRle2’ combines with R2s2 to form an aryl ring, heteroaryl ring, cycloalky]ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ringmay be unsubstituted or substituted with Ci-6 alkyl, and R3e2’, R4®2’, and R5e2’ are each independently-selected from H, halo, Ci-6 haloalkyl, NO?, and CN; orR2®2’ combines with R3®2’ to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R1®2 , R4®2’, and R5®2 are each independently-selected from H, halo, Ci-6 haloalkyl, NO?, and CN; orR3e2’ combines with R4®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R!e2, R2e2, and R3®2 are each independently-selected from H, halo, Ci-6 haloalkyl, NO?, and CN; orR4-2 combines with R ■' to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cj-e alkyl, and R1®2, R2®2, and R3®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO?, and CN;if X1 is CR^R11’, X2 is CR2tR2f, and X3 is a bond; then Y1 is C(Rn2) or N; Y2 is C(R2£2) or N;Y3 is C(R3Q) orN; Y4 is C(R412) orN; and Y5 is C(R512) orN; whereinR112 is H, halo, Ci-6 haloalkyl, NO?, CN, or S0?-Cj-6 alkyl;R2t2 is H, halo, Cn6 haloalkyl, NO?, CN, or S0?-Ci-6 alkyl;R312 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO?-Ci-6 alkyl;R4f2 is H, halo, Ci-6 haloalkyl, NO?, CN, or S0?-Ci-6 alkyl;R5f2 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl; orRn2 combines with R2f2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-s alkyl, and R3f2, R4f2, and R312 are each independently selected from H, halo, Ci-6 haloalkyl, NO?, and CN; orR212 combines with R312 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlf2; R4f2, and R512 are each independently selected from H, halo, Cns haloalkyl, NO?, and CN; orR3f2 combines with R4G to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R112, R212, and R5f2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR '12 combines with R51z to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R112, R212, and R3” are each independently selected from H, halo, Cur, haloalkyl, NO2, and CN,if X! is NRJg or O, X2 is CR2gR2g, and X3 is a bond; then Y! is C(Rlg2) or N; Y2 is C(R2g2) or N; Y3 is C(R3g2) or N; Y4 is C(R4g2) or N; and Y5 is C(R5g2) or N; whereinRlg2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R2g2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R‘ '? is H, halo, Cng haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R4g2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO: •(11,. alkyl;R5g2 is H, halo, Cw haloalkyl, NO2, CN, or SO2-C1.6 alkyl; orRlg2 combines with R2g2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and RJg2, R4g2, and R5g2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2g2 combines with R3gz to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and Rlg2, R4g2, and R5g2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3g2 combines with R4g2 to form an aryl ring, heteroaryl ring, cycloalky] ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlg2, R2g2, and R5g2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR4g2 combines with R5g2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beunsubstituted or substituted with Cue alkyl, and Rlg2, R2®2, and R3®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN;if X! is CRlhRlh’, X2 is NR2h or 0, and X3 is a bond, then Y1 is C(Rlh2) or N; Y2 is C(R2h2) or N; Y3 is C(R3b2) orN; Y4 is C(R41’2) or N; and Y3 is C(R5b2) orN; whereinRlh2 is H, halo, C:-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl;R2h2 is H, halo, Cw haloalkyl, NO?, CN, or SO2-C1.6 alkyl;R3h2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R4112 is H, halo, Cj-s haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R5”2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orR.ln2 combines with R2112 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3h2, R4112, and R3h2 are each independently selected from H, halo, Cue, haloalkyl, NO?, and CN, orR2n2 combines with Rjh2 to form an aiyl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlh2, R41*2, and R3h2 are each independently selected from H, halo, Ci-6 haloalkyl, NO?, and CN, orR ’"2 combines with R41’2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with C1.6 alkyl, and Rlb2, R2h2, and R51’2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR4i’2 combines with R5h2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aiyl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlb2, R2h2, and R3h2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN;if X! is NR11 or O, X2 is C(0), and X3 is CR3iR3i’; then Y1 is C(Rii2) or N; Y2 is C(R2i2) or N;Y3 is C(R3'2) orN; Y4 is C(R4'2) orN; and Y5 is C(R312) orN; whereinR112 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl;R2'2 is H, halo, Ci-6 haloalkyl, NO?, CN, or S0?-Cn6 alkyl;R3'2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R4'2 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl;R5'2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orR112 combines with R212 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R312, R412, and R512 are each independently selected from H, halo, Cj-s haloalkyl, NO2, and CN; orR2'2 combines with R312 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and R1’2, R4'2, and R312 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3'2 combines with R4’2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with C1-6 alkyl, and R312, R2'2, and R”2 are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; orR4'2 combines with R”2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with C1-6 alkyl, and R112, R212, and R3i2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN;if X1 is NR1’ or O, X2 is NR2’ or O, and X3 is CR-R3j’; then Y1 is C(Rlj2) or N, Y2 is C(R2’2) or N; Y3 is C(R3’2) or N; Y4 is CfR4’2) or N; and Y5 is C(R5-'2) or N; whereinR1-'2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R2'2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl;RJ’2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R4’2 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl;R5’2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl; orR1’2 combines with R2’2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3’2, R4'2, and R5’2 are each independently selected from H, halo, Cns haloalkyl, NO2, and CN; orR2!2 combines with R3j2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R1-’2, R4j2, and R5j2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3’2 combines with R4j2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlj2, R2j2, and R^2 are each independently selected from H, halo, Cur, haloalkyl, NO?, and CN, orR4-'2 combines with R5j2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with C1.6 alkyl, and Rlj2, R2-'2, and R3j2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN;if X1 is NRlk or O, X2 is NR2k or O, and X3 is a bond; then Y1 is C(R,k2) or N; Y2 is C(R2k2) orN; Y3 is C(R3k2) orN; Y4 is C(R4k2) or N; and Y5 is C(R5k2) orN; whereinRlk2 is H, halo, Cw haloalkyl, NO?, CN, or SO2-C1.6 alkyl;R2k2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R4 2 is H, halo, Ci-6 haloalkyl, N02, CN, or SO2-C1-6 alkyl;R4k2 is H, halo, Ci-6 haloalkyl, N02, CN, or SO2-C1-6 alkyl;R5k2 is H, halo, Cm haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orRlk2 combines with R2k2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and RAK2, R4k2, and R5k2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2k2 combines with R3k2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R;: \ R4k2, and R3k2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3k2 combines with R4k2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beunsubstituted or substituted with Ci-6 alkyl, and Rlk2, R2k2, and R5k2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orcom5jnes R5kz |0 form an aryj ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlk2, R2k2, and R3k2 are each independently selected from H, halo, Cj.g haloalkyl, NO2, and CN;if X! is NR1! or O, X2 is C(0), and X3 is NR3i or O; then Y1 is C(Rli2) or N; Y2 is C(R2i2) or N; Y3 is C(R3!2) or N; Y4 is C(R4!2) or N; and Y' is CfR312) or N; whereinR112 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R212 is H, halo, Ci-6 haloalkyl, N0?„ CN, or SO2-C1-6 alkyl;R312 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R4i2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R’12 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orR112 combines with R2!2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R312, R412, and R3!2 are each independently selected from H, halo, Ci-6 haloalkyl, NO?., and CN, orR212 combines with R3’2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-e alkyl, and R112, R412, and R5'12 are each independently selected from H, halo, Ci-6 haloalkyl, NO?, and CN; orR312 combines with R442 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aiyl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R1!2, R212, and R5!2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR412 combines with R512 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R112, R2’2, and R3!2 are each independently selected from H, halo, Cns haloalkyl, NO2, and CN;orif X1 is CRlmRlm’, X2 is CR2,nR2m’, and X3 is CR3mR3“’-CR4mR4m’; then Y1 is C(Rlm2) or N;Y2 is C(R2™2) or N; Y3 is C(R;im2) or N; Y4 is C(R4™2) or N; and Y5 is C(R5m2) or N; whereinRlm2 is H, halo, Cn6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl,R2’"2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R.3m2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R4m2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R5m2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orRlm2 combines with R2m2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3m2, R4m2, and R5m2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2m2 combines with R3m2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlm2, R4m2, and R51"2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3m2 combines with R4m2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R1™2, R2m25 and R5’"2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR4m2 combines with R3m2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlm2, R2m2, and R3m2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:X1 is CRiaRia, X2 is CR2aR2a’, and X3 is CR3aR3a’;X1 is NRlb, X2 is CH2, and X3 is CR3bR3b2X1 is CRlcRic’, X2 is CR2 R2' , and X3 is O;X1 is CRldRld’, X2 is O, S, or S(O2), and X3 is CR3dR3d’;X1 is CRleRie’, X2 is C(O), and X3 is CR3sR3e’;X1 is NR!g, X2 is CH2, and X3 is a bond; orX1 is NR11, X2 is C(O), and X3 is NR3i;Z! and Z2 are each independently selected from C(O) and S(02);Rla and Rla’ are each independently selected from H, C1-6 alkyl, and -C0(0)-Ci-6 alkyl;R2a and R2a’ are each independently selected from H, Cj-e alkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;R3a and R3a are each independently selected from H and Ci-6 alkyl;If Z1 and Z2 are both C(0), then at least one of Rla, Ria\ R2a, R2a, R3a, or R3a is Cn6 alkyd, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl;wherein the aryl of R2a or R2a is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, C1-6 haloalkyl, and -C0(0)-0.-6 alkyl; orRla and Rla’ combine to form a cycloalkyl ring or heterocyclic ring, and R2a, R2a, R3a, and R3a’ are each H; orR?a and R2a combine to form a cycloalkyl ring or heterocyclic ring, and R!a, Rla , Rja, and R3a are each H; orRla and R3a combine to form a cycloalkyl ring, wherein the cycloalkyl ring may be unsubstituted or substituted with one or more Ci-6 alkyl, and Rla, R2a, R2a, and R3a are each independently selected from the group consisting of H and Ci-6 alkyl,R!b is Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl;wherein the Ci-6 alkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlb is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;R3b and R3b are each independently selected from H and Ck, alkyl;Ric, r1c , r2c, anj Rie’ are injepenc|ently selected from H and Ci-6 alkyl;Rld, Rld’, R3d, and Rjd’ are each independently selected from H and Ci-6 alkyl,Rje, Rle’, R~’s, and R3e are each independently selected from H and Ci-6 alkyl;Rlg is aryl;wherein the aryl of Rlg is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;R11 and R3! are each independently selected from H, Ci-6 alkyl, and aryl;wherein the aryl of Rd or R~’! is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;wherein:if X1 is CRlaRla', X2 is CR2aR2a’, and X3 is CR3aR3a’> then:Y1 is C(H); Y2 is C(H) or N; Y3 is 0(0): Y4 is C(H) or N; and Y5 is C(H); orYl is C(Rla2); Y2 is C(R2a2); Y3 is C(R3a2); Y4 is C(R4a2); and Y5 is C(R5a2); whereinRla2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO?;R2a2 is H, halo, C1-6 haloalkyl, SO2-C1-6 alkyl, or NO2;R3a2 is H, halo, C1-6 haloalkyl, SO2-C1-6 alkyl, or NO2,R4a2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO2;R3a2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO2;if X1 is NRlb, X2 is CH2, and X3 is CR3bR3b’; then Y1 is C(Rlb2); Y2 is C(R2b2); Y3 is C(R3b2);Y4 is C(R4b2); and Y5 is C(R5b2); whereinRlb2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO2;R2b2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, orNCh;R3b2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, orNO2;R4”2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, orNO2;R5b2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO?;if X1 is CR!cRi c, X2 is CR2oR2c’, and X3 is O; then Yl is C(Ric2); Y2 is C(R2c2); Y3 isC(R3c2); Y4 is C(R4c2); and Y5 is C(R5c2); whereinRlc2 is H, halo, Ci-s haloalkyl, or NO?;R2c2 is H, halo, Ci-6 haloalkyl, or NO?;R3c2 is H, halo, Cue haloalkyl, or NO2;R4c2 is H, halo, Ci-6 haloalkyl, or NO2;R5c2 is H, halo, Ci-6 haloalkyl, or NO?.;if X! is CRldRld, X2 is O, S, or S(02), and X3 is CR3aRjdthen Y1 is C(Rid2); Y2 is C(R2d2);Y3 is C(R3d2); Y4 is C(R4d2); and Y5 is C(R5d2); whereinRld2 is H, halo, Ci-6 haloalkyl, or NO2;R2d2 is H, halo, Ci-6 haloalkyl, or NO?;R3d2 is H, halo, Cw haloalkyl, or NO2;R4d2 is H, halo, Cne haloalkyl, or NO2;R5d2 is H, halo, C1-6 haloalkyl, or NO2,if X! is CRleRle, X2 is C(O), and XJ is CR^R58’; then Y1 is C(Rie2); Y2 is C(R2e2); Y3 is C(R3e2); Y4 is C(R4e2); and Y5 is C(R5e2); whereinRk2 is H, F, CN, or SO2-Ck6 alkyl;R2e2 is H, halo, Ci-6 haloalkyl, CN, SO2-Ci-6 alkyl, or NO2;R3®2 is H, halo, Ci-s haloalkyl, CN, SO2-C1.6 alkyl, or NO?;R4s2 is H, halo, Ci-e haloalkyl, CN, SO2-C1-6 alkyl, or NO2;R5e2 is H, halo, C1-6 haloalkyl, CN, SO2-Cj-6 alkyl, or NO2; orRls2 combines with R2e2 to form a heteroaryl ring, and R3e2, R4e2, and R5s2 are each H;if X! is NR18, X2 is CH2, and X3 is a bond; then Y1 is C(Rlg2); Y2 is C(R2g2), Y3 is C(R3g2);Y4 is C(R4g2); and Y5 is C(R5g2); whereinRlg2 is H, halo, Cw haloalkyl, or NO2;R2g2 is H, halo, C1-6 haloalkyl, or NO2;R382 is H, halo, Ci-6 haloalkyl, or NO2,R4g2 is H, halo, Ci-6 haloalkyl, or NO2;R5g2 is H, halo, Ci-6 haloalkyl, or NO2;orif X1 is NR11, X2 is C(O), and X3 is NR3’; then Y1 is C(R112); Y2 is C(R212); Y3 is C(R312); Y4 is C(R412); and Y5 is C(R312); whereinR112 is H, Ci-6 haloalkyl, or NO2;R212 is H, Ci-6 haloalkyl, or NO?;R312 is H, Ci-6 haloalkyl, or NO2;R4’2 is H, Ci-6 haloalkyl, or NO2,R512 is H, Ci-6 haloalkyl, or NO2.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IA), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

4. The compound of claim 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IA3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein RUJ, R2aj, R4a3, and R3^ are each independently selected from H, halo, Cuealkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

5. The compound of claim 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Ria3, R2a3, R3a3, R4a3, and R'a3 are each H.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IB-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

7. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, wherein the compound is of Formula (IB-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:R2b3wherein Rlb3, R2dj, R3b3, R4b3, and R5b3 are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-e alkyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rib3, R2b3, R3b3, R4b3, and R5b3 are each H.

9. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IB-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:10, The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IC-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

11. The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IC-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein Rlc3, R2c3, R303, R4c3, and R5c3 are each independently selected from H, halo, Ci-salkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rlc3, R2c3, R3c3, R4c3, and R5c3 are each H.

13. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IC-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

14. The compound of claim 1, or a pharmaceutically acceptable salt stereoisomer, or tautomer thereof, wherein the compound is of Formula (ID-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

15. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (1D-S), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

16. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (ID-SO2), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

17. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IE), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

18. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, wherein the compound is of Formula (IF), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

19. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IG-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

20. The compound of claim 19, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IG-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein Rlg3, R2gJ, R3g3, R4g3, and R5g3 are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-e alkyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rig3, R2g3, R; < R4g3, and R5g3 are H.

22. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IG-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

23. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IH-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

24. The compound of claim 23, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IH-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein Rlh3, R2*13, R3h3, R4h3, and R5h3 are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rlh3, R2h3, R3h3, R4h3, and R5h3 are each H.

26. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (1H-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

27. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (D-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

28. The compound of claim 27, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (li-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:py pp:' Formula (II-N3)wherein R113, R213, R313, R413, and R5'3 are each independently selected from H, halo, Ci-6 alkyl, Cj-6 haloalkyl, and -O-Ci-s alkyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1’3, R2i3, R3u, R4’3, and R5'3 are each H.30, The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (U-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

31. The compound of claim 30, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IJ-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:R3j p3i' Formula (IJ-N3)wherein RhJ, R2-'3, R’iy R4^, and R5j3 are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl,32. The compound of claim 31, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R^3, R2-!3, R3i3, and R5-'3 are each H.33, The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IK-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

34. The compound of claim 33, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IK-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein R!kj, R2k3, Rjk3, R4k3, and R5kJ are each independently selected from H, halo, Ct-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

35. The compound of claim 34, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RiK3, R2k3, R3k3, R4k3, and R5k3 are each H.

36. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IL-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

37. The compound of claim 36, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IL-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Formula (IL-N3)wherein RU3, R213, R3U, R4u, and R313 are each independently selected from H, halo, Cj-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

38. The compound of claim 37, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rii3, R213, R3!3, R4B, and R5B are each H.

39. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IM), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Formula (iM)40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is 0.

41. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein n is I.42, The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Y* is C(N02).

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Y3 is C(CF?,).

44. The compound of any one of claims 1-5, 10-18, 23-26, and 40-43, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rla and Rla, R,c and Rlc, Rld and Rld, Rls and R!e, Rif and R]f, or Rlh and Rlb are each CH3.

45. The compound of any one of claims 1-5, 10-18, 23-26, and 40-43, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rla and Rla, Rlc and Rlc, Rld and Rld’, Rle and Rle, Rlf and R]t, or Rlh and Rlb are each H.

46. The compound of any one of claims 1-3, 6-13, 18-22, and 40-45, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2a and R2a, R2b and R2b’, R2° and R2c’, R21 and R2f, or R2g and R2g’ are each CH?,.

47. The compound of any one of claims 1-3, 6-13, 18-22, and 40-45, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2a and R2a’ are CH? and H respectively, R20 and R2b are CH3 and H respectively, R2c and R2c’ are CH?, and H respectively, R2f and R2f are CH? and H respectively, or R2g and R2®’ are CH3 and H respectively.

48. The compound of any one of claims 1-3, 6-13, 18-22, and 40-45, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2a and R2a’, R2b and R2b’, R2c and R2c, R21 and R2f, or R2g and R2g’ are each H.

49. The compound of any one of claims 1-9, 14-17, 27-32, and 40-48, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R3a and R’’a , R3b and R3b, R3d and R3d, Rje and R3s’, R3' and R31, or Rjj and R3i are each CH?.

50. The compound of any one of claims 1-9, 14-17, 27-32, and 40-48, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R3a and R3a, R3b and Rjb’, R3d and R3d’, R3s and R3e, R3s and R3’, or R3! and RJf are each H.

51. The compound of any one of claims 1-2, 6, 40-43, and 46-50, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rlb is cycloalkyl or heteroaryl.

52. A compound of Formula (II):Formula (!l)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each — independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein:X1 is NR', X2 is CR2, and X3 is N or CH,X1 is O, X2 is CR2, and X3 is N;X1 is N, X2 is NR1, and X3 is N; orX1 is NR3, X2 is N, and X3 is N;n is 0 or 1;R1 is selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, and heteroaryl;wherein the C1-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, or heteroaryl of Rl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, C1-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R2 is selected from H, halo, Cj-g haloalkyl, NO2, CN, SO2-C1-6 alkyl, Ci-g alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, and heteroaryl;wherein the Cj-e alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, or heteroaryl of R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, C1-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R3 is selected from €4-6 alkyl, cycloalkyl, aryl substituted with one or more substituents selected from the group consisting of halo and methyl, benzyl substituted with one or more F, and heteroaryl;gm, gH3, gH4 anj g^iis are each independently selected from H, halo, Ci-6 haloalkyl, NO2, C'N, and SO2-Cf.6 alkyl.

53. The compound of claim 52, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IIA-C), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

54. The compound of claim 53, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IIA-C3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein Rla, Rlb, R,c, Rld, and Rle are each independently selected from H, halo, Cj-s alkyl,C1-6 haloalkyl, and -O-C1-6 alkyl.55, The compound of claim 52, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IIA-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Formate (HA-N)56. The compound of claim 55, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IIA-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein Ria, Rlb, R!c, Rid, and Rie are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

57. The compound of claim 52, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (HE), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:58, The compound of claim 57, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IIB3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Formula (HB3)wherein R2a, R2b, R2c, R2a, and R2e are each independently selected from H, halo, Cue, alkyl, Cue haloalkyl, and -O-Ci-6 alkyl.

59. The compound of claim 58, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2a, R2b, R2c, R2d, and R2e are each H.

60. The compound of claim 52, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (HC), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Formula (HC)61. The compound of claim 60, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IIC3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Formula (HC3)wherein R!a, R!b, Rlc, R!a, and R!e are each independently selected from H, halo, Ci-6 alkyl.Ci-6 haloalkyl, and -O-Ci-6 alkyl.

62. The compound of any one of claims 54, 56, and 61, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rla, Rlb, Rlc, Rld, and Rle are each H.

63. The compound of claim 52, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IID), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Formula (IID)64. The compound of claim 63, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R3 is C4-6 alkyl or phenyl substituted with one or more halo.

65. The compound of any one of claims 52-64, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rrn is NO2.

66. The compound of any one of claims 52-65, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R113 is CF3.

67. A compound of Formula (III):0      0 R!ii1N              IFormula (III)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:R1 is selected from the group consisting of C3-6 cycloalkyl, Ci alkyl-C?^ cycloalkyl, aryl, Ci alkyl-aryl, heteroaryl, and Ci alkyl-heteroaryl;wherein the C3-6 cycloalkyl, Ci alkyl-C3-6 cycloalkyl, aryl, Ci alkyl-aryl, heteroaryl, or Ci alkyl-heteroaryl of R1 is unsubstituted or substituted with halo;Rlin, R!I12, R1113, R1114, and RII!5 are each independently selected from H, halo, C1-6 haloalkyl, NO2, CN, and SCMV,. alkyl.

68. The compound of claim 67, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R{ is aryl or Ci alkyl-aryl, wherein the aryl or Ci alkyl-aryl may be unsubstituted or substituted with one or more halo.

69. The compound of claim 67 or 68, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Run is H or NO2.

70. The compound of any one of claims 67-69, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RIU2 is H, halo, or SO2-C1-6 alkyl.

71. The compound of any one of claims 67-70, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RIilJ is CF3.

72. A compound of Formula (IV):Formula (!V)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each — independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein:Y1 is CR1, Y2 is N, and Y3 is NR3;Y1 is CR1, Y2 is O or S, and Y3 is CR3;Y1 is N, Y2 is CR2, and Y3 is O or S; orY1 is O or S, Y2 is CR2, and Y3 is CRJ;Rl and R2 are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl of R5 or R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Cue haloalkyl, and -CO(O)-Ci-6 alkyl;R3 is H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl;wherein the Cue alkyl, Cue haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl of R3 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Cue, haloalkyl, and -CO(O)-Ci-6 alkyl; orR3 combines with R1V2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R1V1 is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, or heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl ofR^1 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, and alkoxy;R1V2 is H, halo, Cue haloalkyl, NO2, CN, and SO2-C1-6 alkyl; orR1V2 combines with R3 to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cj-6 alkyl, Cj-6 haloalkyl, and -CO(O)-Ci-6 alkyl.

73. The compound of claim 72, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVA), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:O O R1Formula (IVA)74. The compound of claim 73, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVA3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:RIV1bFormula (IVA3)wherein Rma, Rmb, R13'11', RiVld, and Rlvle are each independently selected from H, halo,Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

75. The compound of claim 72, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVB-0), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:O O R1Formula (iVB-O)76. The compound of claim 75, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVB-O3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:RIV1bFormula (IVB-03)wherein RIvla, Rn'lb, RIvlc, R1™, and RIvle are each independently selected from H, halo, Cue alkyl, Ci-6 haloalkyl, and -O-Cj-e alkyl.

77. The compound of claim 72, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVB-S), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:R3Formula (IVB-S)78. The compound of claim 77, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVB-S3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:pJVIbFormula (IVB-S3)wherein RIvla, R1Vib, Rmc, RIV!d, and Rme are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

79. The compound of claim 72, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVC-S), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Formula (IVC-S)80. The compound of claim 79, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVC-S3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Formula (IVOS3)wherein RIvla, RR lb, RIvic, RIV’ld, and RIvie are each independently selected from H, halo, Cue alkyl, Ci-6 haloalkyl, and -O-Cj-e alkyl.81, The compound of claim 72, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVD), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:O OFormula (IVD)82. The compound of claim 81, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVD3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Formula (IVD3)wherein RIvla, R1Vlb, Rlvlc, RIVid, and Rlvle are each independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, and -O-Ci-6 alkyl.

83. The compound of any one of claims 74, 76, 78, 80, or 82, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R™18, RR lb, RIvic, RIV’ld, and RIvie are each H.

84. The compound of any one of claims 72-78 and 83, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1 is CF3.

85. The compound of any one of claims 72 and 79-84, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2 is CF3.86, The compound of any one of claims 72-78 and 81-85, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rf is Cue alkyl.

87. A compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, selected from the group consisting of the following Table 1 compounds: Compound Nos. 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 110, 111, 112, 113, 114, 116, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165 and pharmaceutically acceptable salt and tautomers of any of the foregoing.Ay  ^^0 F ' 0. ,0                         ( o o 'N'           0 0C o» F 0   0   Ci 0     0 Ci                        || 11 । y   AX u F Q 0^0      AX 0 O °'N'C '1 A f          I A .H A A f y         - y y j " / A        :        F                = '     , or or tautomer of any of the foregoing. V    / -. o o%"° A A. ;ua a-AA   kA, AAxF js       0 A r                                F ? > o o ci       qo Ar° A AAA AAp ^Oc!^F AoA 9 V n-n o V X A,         N ii !i j t h 11 . xzF A XXA / H k A V      A Zj '' >< F ' F?                                                       F ? ? ? f'F F , or a pharmaceutically acceptable salt, stereoisomer.0 O Cl 89.    A compound of the structure stereoisomer, or tautomer thereof. o o Uy kA0 90. A compound of the structure acceptable salt, stereoisomer, or tautomer thereof. x^F kF F , or a pharmaceutically acceptable salt, °Y° X^A--F rF F , or a pharmaceutically91, A pharmaceutical composition comprising the compound of any one of claims 1-90, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

92. A method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (V):O Y1 Y3Formula (V)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each — independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, or all --= together form an and ring or heteroaryl ring, wherein:X1 is CRlaRla’, X2 is CR2aR2a’, and X3 is CR3aR3a’;X1 is NRlb or O, X2 is CR2bR2b’, and X3 is CR3bR3b’;X1 is CRlcR!c’, X2 is CR2cR2c\ and X3 is NR3c or O;X1 is CR!aR!d’, X2 is O, S, or S(02), and XJ is CR3dR3djX1 is CRleR’ie', X2 is C(0), and X3 is CR3eR3s’;X1 is CR’hV1, X2 is CR2fR2f, and X3 is a bond;X1 is NRlg or O, X2 is CR2sR2g’, and X3 is a bond;X1 is CRUiR,h, X2 is NR2h or 0, and X3 is a bond,X1 is NRn or 0, X2 is C(0), and X3 is CR31R31';X1 is NRlj or 0, X2 is NR2’ or 0, and X3 is CR3’R3j’;X1 is NRlk or 0, X2 is NR2k or 0, and X3 is a bond;X1 is NR11 or 0, X2 is C(0), and X3 is NRd or O; orX1 is CRlmRw, X2 is CR2mR2m’, and X3 is CR3mR3m’-CR4mR4m’;Z1 and Z2 are each independently selected from C(0) and SfOs);Rla and R13’ are each independently selected from H, Cue alkyl, Cj-s haloalkyl, C3-6 cycloalkyl, -C0(0)-Ci-6 alkyl, and aryl;R2a and R2a are each independently selected from H, C2-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;R3a and R33’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;If Z1 and Z2 are both C(0), then at least one of R13, Rla, R2a, R2a, R3a, or R3a is Ci-6 alkyd, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl;wherein the and of R!a, R!a, R2a, R23’, R3a, or R3a is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Cn6 alkyl; ortwo or more of R13, R’13, R2a, R2a, R3a, and Rja combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C0(0)-Cj-6 alkyl, and any uncombined Rla, R,a’, R2a, R2-3’, R3a, or R3a are each independently selected from H, Ci-6 alkyl, Cue haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl; wherein the aryl of Ria, Rla’, R2a, R23’, Rja, or Rja is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyd, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R2b, R2b’, Rjb, and R’b are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aiyd;wherein the aryl of R20, R2b , R3b, or R3b is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; ortwo or more of Rlb, R2b, R2b, R3b, and R3b combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-C]-6 alkyl, and any uncombined Rlb, R2b, R2b’, R3”, or Rjb’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3.6 cycloalkyl, -CO(O)-Cu6 alkyl, and aryl;wherein the aryl of Rlb, R2b, R2b , R3b, or R3b is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl'Ric, Rlc’, R2c, and R2c are each independently selected from H, Ci-6 alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of Rlc, Rlc, R2c, or R2c’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, C1-6 haloalkyl, and -C0(0)-Ck6 alkyl;Rid, Rld , R3d, and R3d are each independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of Rid, R!a’, R3d, or R3d is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, C1-6 haloalkyl, and -C0(0)-Ck6 alkyl;Rie, Rle’, Rje, and R3e are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-e cycloalkyl, -C0(0)~Cj-6 alkyl, and aryl;wherein the aryl of Rie, Rle, R3e, or R3e’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Cu6 alkyl; ortwo or more of Rle, Rie’, R3e, and R3e combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -C0(0)-Ck6 alkyl, and any uncombined Rle, Rle, R3e, or R3e are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of Rle, Rle, R3e, or R3e’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;Rid, Ru , R2f, and R2F are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the and of Rlf, R]t, R2f, or R21 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl; ortw?o or more of Rlf, R!f, R2t, and R2f combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be tin substituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined Rlf, Rlf, R2f, or R21 are each independently selected from H, Cj-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, ~CO(O)-Ci-6 alkyl, and aryl;wherein the and of R!f, Rlf, R2f, or R2f is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R2g and R2g’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -C0(0)-Cj-6 alkyl, and aryl;wherein the aryl of R2g or R2g is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;Rlh and Rlh’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of R!n or Rlh is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R31 and R3f are each independently selected from H, Cj-6 alkyl, Cj-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of R31 or R31 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R3j and R3j are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, €3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of R3j or R3' is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;Rjm, ghn,               an^ ^4m are eac^ independently selected from H, Ci-ealkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of R‘“, Rhn, R2m, R2m’, R3m, R3m, R4m, or R4m’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, Cj-6 haloalkyl, and -CO(O)-Ci-6 alkyl; ortw?o or more of Rlm, Rlm, R2m, R2m , R3m, RJm , R4™, and R4m combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cn6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl, and any uncombined Rlm, Rlm’, R2m, R2m’, R3m, R3m’, R4m, or R4m’ are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)~Ci-6 alkyl, and aryl;wherein the aryl of R‘“, Rhn, R2m, R2m’, R3m, R3m , R4m, or R4m’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;Rjb is H, Ci-6 alkyl, €3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlb is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; ortwo or more of R!b, R2b, R2b , R30, and R30’ combine to form a cycloalky] ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cw alkyl, Ci-6 haloalkyl, and "CO(O)-Ci-6 alkyl, and any uncombined Rlb, R2b, R2b, R3b, or R3b are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the aryl of R!D, R2b, R2b’, R3b, or Rj0 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cw alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl,R3c is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl;wherein the Cj-e alkyl, C3-6 cycloalkyl, aryl, Ci~6 alkyl-aryl, or heteroaryl of Rlc is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, and alkoxy,Rjg is H, Ci-6 alkyl, Cs-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl;wherein the C1-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlg is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;R2h is H, Cue alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-e alkyl-aryl, or heteroaryl of R21’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-e alkyl, and alkoxy;Rl! is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cj-6 alkyl-aryl, or heteroaryl of R11 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;Rlj and R2j are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-e alkyl-aryl, or heteroaryl of Rij or R2j is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-e alkyl, and alkoxy;Rlk and R2k are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlk or R2k is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;R1! and R31 are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, and heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl ofR11 orR3! is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;n is 0 or 1;wherein:if X! is CRlaRla’> X2 is CR2aR2a', and X3 is CR3aR3a’, then:Y1 is C(H); Y2 is C(H) or N; Y3 is C(CFs); Y4 is C(H) or N; and Y3 is C(H); orY1 is C(Rla2) or N; Y2 is C(R2a2); Y3 is C(R3a2) or N, Y4 is C(R4a2), and Y5 is C(R5a2); whereinRla2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1,. alkyl;R2a2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-Ci-6 alkyl;R3a2 is H, halo, Ci-6 haloalkyl, NO2, or CN;R4a2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R5a2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orRla2 combines with R2a2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3a2, R4a2, and R5a2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2a2 combines with Rja2 to form an and ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rla2, R4a2, and R5a2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3a2 combines with R4a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rla2, R2a2, and R5a2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR4a2 combines with R5a2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rla2, R2a2, and R3a2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN;if X1 is NRlb or O, X2 is CR2bR2b’, and X3 is CR3bR3b’, then:Y1 is C(Rlb2) orN, Y2 is C(R2b2) or N, Y3 is C(R3b2) or N; Y4 is C(R4b2) or N; and Y5 is C(R5b2) or N; orY1 is C(O); Y2 is N(R'b2 ). Y3 is C(R3b2'); Y4 is C(R4b2’); and Y5 is N, whereinRjb2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R2b2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R3b2 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl;R4b2 is H, halo, Cw haloalkyl, NO2, CN, or SOi-Ci-e alkyl,R5b2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-CJ-6 alkyl, orRlb2 combines with R2b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl or OH, and R3b2, R4b2, and R5b2 are each independently selected from H, Ci-6 alkyl, halo, Ci-6 haloalkyl, NO?., and CN, orR2b2 combines with R3b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alky] or OH, and Rlb2, R4b2, and R5b2 are each independently selected from H, Ci-6 alkyl, halo, Ci-6 haloalkyl, NO?, and CN; orR3b2 combines with R4b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring maybe unsubstituted or substituted with Ci-6 alkyl or OH, and Rlb2, R2b2, and R5b2 are each independently selected from H, C1..6 alkyl, halo, Ci-6 haloalkyl, NO2, and CN; orR4bz combines with R5d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring maybe unsubstituted or substituted with Ci-6 alkyl or OH, and Rlb2, R2”2, and RJ°2 are each independently selected from H, Cue alkyl, halo, Cue haloalkyl, NO2, and CN;R2b2 is H, Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl;w'herein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Cj-s alkyl-aryl, or heteroaryl of R2b2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy,R3b2’ is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R4b2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orR2b2 combines with R3b2’ to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ringmay be unsubstituted or substituted with Ci-6 alkyl or halo, and R4b2 is selected from H, Cue alkyl, C3-6 cycloalkyl, and, Ci-6 alkyl-aryl, and heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of R4b2’ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy; orR3b2 combines with R4b2’ to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl or halo, and R2b2’ is selected from H, Cu6 alkyl, C3..6 cycloalkyl, aryl, Cue alkyl-aryl, and heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aiyl, or heteroaryl of R2b2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;if X1 is CRlcRlc’, X2 is CR2 R? , and X3 is O orNR3c; then Y’ is C(R!®2) orN; Y2 is C(R2c2) orN; Y3 is C(R3c2) or X; Y4 is C(R4®2) orN; and Y5 is C(R5®2) orN; whereinRlc2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SCh-Cns alkyl,R2®2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R3®2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R4®2 js pj halo, 6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R5®2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SCb-Cne alkyl, orR1®2 combines with R2c2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3®2, R4®2, and R5®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2®2 combines with R3®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R1®2, R4®2, and R5®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3cz combines with R4cz to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beunsubstituted or substituted with Ci-s alky], and Rlc2, R2c2, and R5c2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR4c2 combines with R3c2 to form an aryl ring, heteroaryl ring, cycloalky! ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlc2, R2c2, and R3c2 are each independently selected from H, halo, Cj.g haloalkyl, NO2, and CN;if X1 is CRldRld', X2 is O, S, or S(02), and X3 is CR3dR3d', then Y1 is C(Rld2) or N; Y2 is C(R2d2); Y3 is C(R3d2) orN, Y4 is C(R4d2) orN; and Y3 is C(R’a2) orN; whereinRld2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R2d2 is H, halo, C:.6 haloalkyl, NCh, CN, or SO2-C1-6 alkyl;R3d2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-Ci-6 alkyl;R4d2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R3d2 is H, halo, Cng haloalkyl, N02, CN, or SO2-C1-6 alkyl; orRld2 combines with R2d2 to form an aiyl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3d2, R402, and R3d2 are each independently selected from H, halo, C1-5 haloalkyl, N02, and CN; orR2d2 combines with R3dz to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rld2, R4d2, and R5d2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3d2 combines with R4d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rld2, R2d2, and R5d2 are each independently selected from H, halo, Cj.g haloalkyl, N02, and CN; orR4d2 combines with R5d2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rld2, R2d2, and R3d2 are each independently selected from H, halo, Ci-6 haloalkyl, N02, and CN;if X1 is CRleRle’, X2 is C(O), and X3 is CR3eR3e, then:Yl is C(Rle2); Y2 is C(R2e2); Y3 is C(R3e2); Y4 is C(R4e2); and Y5 is C(R5e2); orY' is C(Rle2') or N; Y2 is C(R2s2') or N; Y3 is (7RA2) or N; Y4 is (7 R u ' ) or N; and Y5 is C(R5®2) or N, wherein at least one of Y!, Y2, Y3, Y4, and Y5 is N; whereinRle2 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl;R2e2 is H, halo, Cm haloalkyl, NO2, CN, or SO2-CM alkyl;R3e2 is H, halo, Cm haloalkyl, NO2, CN, or SO2-CM alkyl;R4e2 is H, halo, Cm haloalkyl, NO2, CN, or SO2-CM alkyl;R5e2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1,. alkyl; orRle2 is Cl; R2e2 is H; R3e2 is Cm haloalkyl, NO2, or SO2-CM alkyl, R4®2 is H; and R5®2 is H; orRle2 is NO2, R2®2 is H; R3e2 is Ci-6 haloalkyl; R4®2 is H; and R5®2 is H; orR3®2 combines with R2®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and RJ®2, R4®2, and R3®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2e2 combines with R3®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rle2, R4®2, and R3®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3e2 combines with R4e2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and R1®2, R2®2, and R5®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR4®2 combines with R5®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cm alkyl, and R3®2, R2®2, and R3®2 are each independently selected from H, halo, Cm haloalkyl, NO?, and CN; orR1®2’ is H, halo, Cm haloalkyl, NO?., CN, and SO2-C1-6 alkyl;R2e2 is H, halo, Cm haloalkyl, NO2, CN, and SO2-CM alkyl;R3e2’ is H, halo, Cm haloalkyl, NO?, CN, and SO2-CM alkyl,R4®2’ is H, halo, Cm, haloalkyl, NO?, CN, and SOz-Cm alkyl, R3®2 is H, halo, Cm haloalkyl, NO2, CN, and SO2-C1-6 alkyl; orR1®2’ combines with R2s2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3®2’, R4®2, and R3®2’ are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2®2 combines with R3e2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rle2’, R4®2 , and R^2’ are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3e2 combines with R4s2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rie2, R2®2’, and R5e2 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; orR4®2 combines with R''- to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R1®2’, R2®2’, and R3®2’ are each independently-selected from H, halo, Cue haloalkyl, NO2, and CN;if X! is CRnRlf, X2 is CR2fR2f, and X3 is a bond; then Y1 is C(Rlf2) or N; Y2 is C(R2f2) orN; Y3 is C(R3f2) or N; Y4 is C(R412) or N; and Y5 is C(R5f2) orN; whereinRn2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R2f2 is H, halo, Ci-e haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R3f2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R412 is H, halo, Ci-6 haloalkyl, NO2, CN, or SCh-Cne alkyl;R5f2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orRlf2 combines with R212 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R312, R412, and R5f2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR212 combines with R31z to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beunsubstituted or substituted with Ci-s alky], and Rlf2, R4f2, and R512 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR312 combines with R4i2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlf2; R2f2, and R512 are each independently selected from H, halo, Cj.g haloalkyl, NO2, and CN; orR4f2 combines with R5f2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and Rlf2, R2f2, and R3t2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN;if X1 is NRlg or O, X2 is CR2gR2g , and XJ is a bond; then Y1 is C(R!®2) or N; Y2 is C(R2®2) or N; Y3 is C(R3g2) or N; Y4 is C(R4®2) or N; and Y5 is C(R5g2) or N; whereinR1®2 is H, halo, Cng haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R2g2 is H, halo, C w. haloalkyl, NO2, CN, or SO:-C:,. alkyl;R3g2 is H, halo, C1.6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R4g2 is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R5®2 is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orRlg2 combines with R2g2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-e alkyl, and R3g2, R4g2, and R5®2 are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; orR2®2 combjnes vidth R3®2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aiyl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-s alkyl, and Rlg2, R4®2, and R5®2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3®2 combines with R4®z to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlg2, R2®2, and R5®2 are each independently selected from H, halo, Cj-s haloalkyl, NO2, and CN; orR4®2 combines with R5g2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlg2, R2g2, and R3g2 are each independently selected from H, halo, C1..6 haloalkyl, NO2, and CN;if X1 is CRlhRlh’, X2 is NR2h or O, and X3 is a bond; then Y1 is C(Rlh2) or N; Y2 is C(R:h?) or N; Y3 is C(R3m2) or N; Y4 is C(R4h2) or N; and Y5 is C(R5h2) or N; whereinRlh2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R2i’2 is H, halo, Cj-s haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R'"2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R2:2 is H, halo, C:.6 haloalkyl, NO2, CN, or SO2-Ci-6 alkyl;R5b2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl; orRlh2 combines with R2h2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rjn2, R4h2, and R5h2 are each independently selected from H, halo, Cj-g haloalkyl, NO2, and CN; orR2h2 combines with R3h2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R1”2, R4h2, and R5b2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR3b2 combines with R4b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rln2, R2h2, and R5b2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR4h2 combines with R5b2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R1B2, R2h2, and R3h2 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN;if X1 is NRn or O, X2 is C(0), and X3 is CR3,R3i’; then Y1 is C(R112) or N, Y2 is C(R212) or N; Y3 is C(R312) or N; Y4 is C(R4’2) or N; and Y5 is C(R512) or N, whereinR1'2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R2'2 is H, halo, Ci-6 haloalkyl, NO?, CN, or SO2-C1-6 alkyl;R3'2 is H, halo, Cne haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R412 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl,R512 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orR112 combines with R2“ to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R312, R4'2, and R3i2 are each independently selected from H, halo, Cue, haloalkyl, NO?, and CN, orR212 combines with R3’2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-e alkyl, and Rb2, R412, and R5s2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orr?i2 combjnes wjth r4i2 t0 form an gjyj ^ng, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R1'2, R2'2, and R512 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR412 combines with R512 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R112, R212, and R312 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN;if X1 is NRlj or O, X2 is NR2j or O, and X3 is CR3jR3r; then Y1 is C(Rij2) or N; Y2 is C(R2j2) or N; Y3 is C(R3'2) or N; Y4 is C(R4'2) or N; and Y5 is C(R5j2) or N, whereinR1-"2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R2j2 is H, halo, Cn6 haloalkyl, NO?, CN, or SCh-Cne alkyl;R3j2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R4'2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl,R5-'2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orR1’2 combines with R2j2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beunsubstituted or substituted with Ci-6 alkyl, and R3j2, R4'2, and R5-*2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2'2 combines with R3j2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R1’2, R4'2, and R5-*2 are each independently selected from H, halo, Cj-s haloalkyl, NO2, and CN; orR3'2 combines with R4j2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cn6 alkyl, and Rlj2, R2j2, and R3j2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR4j2 combines with R3j2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with C1-6 alkyl, and Rlj2, R2j2, and R3j2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN;if X1 is NRlk or O, X2 is NR2k or 0, and X3 is a bond; then Y1 is C(Rlk2) or N; Y2 is C(R2k2) or N; Y3 is C(R3k2) orN; Y4 is C(R4k2) orN; and Y5 is (< j or N; whereinRlk2 is H, halo, Ci-6 haloalkyl, N02, CN, or SO2-C1-6 alkyl;R2*2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R3k2 is H, halo, Cm haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R4k2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R5k2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orr1k?. combjnes wjth R2k2 to form an afyj rjng, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aiyl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3k2, R4k2, and R5k2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orr2k2 com5jnes          |0 form an aryj ring, heteroaryl ring, cycloalkyl ring, orheterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlk2, R4k2, and R5k2 are each independently selected from H, halo, Cns haloalkyl, NO2, and CN; orR3k2 combines with R4k2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlk2, R2k2, and R3k2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and C’N; orR4k2 combines with R3k2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlk2, R2k2, and Rjk2 are each independently selected from H, halo, Cue, haloalkyl, NO2, and CN,if X! is NR11 or O, X2 is C(O), and XJ is NR33 or O; then Y* is C(Rn2) or N; Y2 is C(R212) or N; Y3 is C(R312) or N; Y4 is C(R412) or N; and Y5 is C(R5!2) or N; whereinRli2 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1.6 alkyl;R2i2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R312 is H, halo, Cue haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R412 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1 -6 alkyl;R512 is H, halo, Cur, haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orRli2 combines with R212 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Cue alkyl, and R42, R412, and R312 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; orR212 combines with R3’2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R332, R412, and R3*2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR312 combines with R4'2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rli2, R212, and R'4 are each independently selected from H, halo, Cue haloalkyl, NO2, and CN; orR412 combines with R512 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beunsubstituted or substituted with Ci-6 alkyl, and R1!2, R212, and R3!2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN;orif X! is CRlmR!m', X2 is CR2mR2m’, and X3 is CR3mR3m’-CR4mR4m'; then Y1 is C(R!m2) or N;Y2 is C(R2m2) or N; Y3 is C(R3m2) or N; Y4 is C(R4m2) orN; and Y5 is C(R5m2) or N; whereinRlm2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R2m2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R3m2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R4’"2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl;R5m2 is H, halo, Ci-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; orRlm2 combines with R2m2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and R3m2, R4m2, and R”n2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR2m2 combines with R3m2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlm2, R4rn2, and R5m2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR.3m2 combines with R4m2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-6 alkyl, and Rlm2, R2ro2, and R5m2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN; orR41"2 combines with R3ra2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with Ci-e alkyl, and Rlm2, R2m2, and R3m2 are each independently selected from H, halo, Ci-6 haloalkyl, NO2, and CN.

93. The method of claim 92, wherein:X1 is CRlaRu’, X2 is CR2aR2a\ and X3 is OCIVNX1 is NRlb, X2 is CH2, and X3 is CR3bR3b';X1 is CRlcR!c’, X2 is CR2cR2c', and X3 is O;X1 is CR!aR!d’, X2 is O, S, or S(Ch), and XJ is CR3dR3d’;X1 is CRleRle, X2 is C(0), and X3 is CR3eR3e’;X1 is NRlg, X2 is CH2, and X3 is a bond; orX1 is NR11, X2 is C(O), and X3 is NR31,Z? and Z2 are each independently selected from C(0) and 8(62);Rla and Rla are each independently selected from H, C1-6 alkyl, and -C0(0)-Ci-6 alkyl;R2a and R2a are each independently selected from H, Ci-6 alkyl, C3-6 cycloalkyl, -CO(O)-Cu6 alkyl, and aryl;R3a and R3a’ are each independently selected from H and C1-6 alkyl;If ZJ and Z2 are both C(0), then at least one of Rla, Rla, R2a, R2a, R3a, or R3a is Ci .6 alkyl, C3-6 cycloalkyl, -C0(0)-Ci-6 alkyl, or aryl;wherein the aryl of R2a or R2a is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, C1-6 haloalkyl, and -CO(O)-Ci-6 alkyl; orRla and Rla combine to form a cycloalkyl ring or heterocyclic ring, and R2a, R2a, R3a, and R3a are each H; orR2a and R2a’ combine to form a cycloalkyl ring or heterocyclic ring, and R.!a, Rla’, R3a, and R3a are each H; orRla and R3a combine to form a cycloalkyl ring, wherein the cycloalkyl ring may be unsubstituted or substituted with one or more Ci-6 alkyl, and Ria, R2a, R2a’, and R3a are each independently selected from the group consisting of H and Ci-6 alkyl;Rlb is Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl;wherein the Ci-6 alkyl, aryl, Ci-6 alkyl-aryl, or heteroaryl of Rlb is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;R3b and R3b’ are each independently selected from H and Ci-6 alkyl;Ric, Rlc’, R2c, and R2c are each independently selected from H and Ci-6 alkyl;Rld, Rld , R3d, and R3d are each independently selected from H and Ci-6 alkyl;Rle, Rle’, R3s, and R3e are each independently selected from H and Ci-6 alkyl;Rlg is aryl;wherein the aryl of Rlg is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy;R11 and R31 are each independently selected from H, Ci-6 alkyl, and aryl;wherein the and of Rn or R3f is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, and alkoxy, wherein:if X1 is CRlaRia’, X2 is CR2aR2a’, and X3 is CR3aR3a’, then:Y1 is C(H); Y2 is C(H) or N; Y3 is C(CF3); Y4 is C(H) or N; and Y5 is C(H); orYj is C(R!a2); Y2 is C(R2a2); Y3 is C(R3a2); Y4 is C(R4a2); and Y3 is C(R5a2); whereinRla2 is H, halo, Ci-6 haloalkyl, SO2-Cn6 alkyl, or NO2,R2a2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or YOsR3a2 is H, halo, C1-6 haloalkyl, SO2-Ci-6 alkyl, or NO2;R4a2 is H, halo, Ci-6 haloalkyl, SO2-Cu6 alkyl, or NO2;R3a2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO2;if X1 is NRlb, X2 is CH2, and X3 is CR3bR3b’; then Y1 is C(R,b2); Y2 is C(R2b2); Y3 is C(R3b2);Y4 is C(R4b2); and Y5 is C(R5b2); whereinRlb2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, orNO2,R2”2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, orNO2;R3b2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO2;R4b2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, or NO2;R5b2 is H, halo, Ci-6 haloalkyl, SO2-C1-6 alkyl, orNO2;if X1 is CRlcRlc, X2 is CR2cR2c, and X3 is O; then Y] is C(Ric2); Y2 is C(R2c2); Y3 isC(R3c2); Y': is C(Rand Y5 is C(R5c2); whereinRlc2 is H, halo, Cue haloalkyl, or NO2;R2c2 is H, halo, Ci-6 haloalkyl, or NO2;R3c2 is H, halo, Ci-6 haloalkyl, or NO?;R4c2 is H, halo, Ci-e haloalkyl, or NO2;R5cz is H, halo, Ci-6 haloalkyl, or NO2;if X1 is CR,dRld’, X2 is O, S, or S(02), and X3 is CR^R33', then Y1 is C(Rid2); Y2 is C(R2d2);Y3 is C(R3d2); Y4 is C(R4d2); and Y5 is C(R5d2); whereinRld2 is H, halo, Cw haloalkyl, or NO2;R2d2 is H, halo, C1-6 haloalkyl, or NO2;R3d2 is H, halo, C1-6 haloalkyl, or NO2,R4d2 is H, halo, Ci-6 haloalkyl, or NO?;R5d2 is H, halo, Ci-6 haloalkyl, or NO?;if X1 is CRleRle’, X2 is C(O), and X3 is CR3eR3®’; then Y3 is C(R1®2); Y2 is C(R2s2); Y3 is C(R3e2); Y4 is C(R4e2); and Y5 is C(R5e2); whereinRls2 is H, halo, Ci-6 haloalkyl, CN, SO2-C1.6 alkyl, or NO?;R2®2 is H, halo, Ci-e haloalkyl, CN, SO2-C1-6 alkyl, or NO2;R3®2 is H, halo, Ci-6 haloalkyl, CN, SOi-Ci-e alkyl, or NO2;R4®2 is H, halo, Ci-6 haloalkyl, CN, SO2-C1.6 alkyl, or NO2;R5e2 is H, halo, Ci-6 haloalkyl, CN, SO2-C1-6 alkyl, or NO?; orR3®2 combines with R2®2 to form a heteroaryl ring, and R3®2, R4®2, and R’®2 are each H;if X1 is NRlg, X2 is CH2, and X3 is a bond; then Y3 is C(R3g2); Y2 is C(R2g2); Y3 is C(R3g2);Y4 is C(R4g2); and Y5 is C(R5g2); whereinRlg2 is H, halo, Ci-6 haloalkyl, or NO2,R2®2 is H, halo, Ci-6 haloalkyl, or NO?;R3g2 is H, halo, Ci-6 haloalkyl, or NO?;R4g2 is H, halo, Ci-6 haloalkyl, or NO2;R5g2 is H, halo, Ci-6 haloalkyl, or NO2;orif X3 is NR11, X2 is C(O), and X3 is NR31; then Yl is C(R112); Y2 is C(R2i2); Y3 is C(R3i2); Y4 is C(R4i2); and Y3 is C(R512); whereinRli2 is H, Ci-6 haloalkyl, or NO2;R2’2 is H, Ci-6 haloalkyl, or NO2,RJ12 is H, Ci-6 haloalkyl, or NO2;R412 is H, Ci-6 haloalkyl, or NO?;R512 is H, Ci-6 haloalkyl, or NO?.

94. The method of claim 92 or 93, wherein the compound is of Formula (VE), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

95. The method of any one of claims 92-94, wherein n is 0.

96. The method of any one of claims 92-95, wherein Y] is C(NO2).

97. The method of any one of claims 92-96, wherein Y3 is C(CF3).

98. The method of any one of claims 92-97, wherein Ria and Rla’, Rlc and Rlc’, Rld and Rld , Rieand Rls’, Rlf and Rlf, or Rtb and RL" are each CH3.

99. The method of any one of claims 92-98, wherein R3a and R3a, R3b and R3b, R3d and Rjd , RJe and R3e’, RJi and R3', or R3j and Rjj’ are each CH3.

100. The method of any one of claims 92-97 or 99, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rlb is cycloalkyl or heteroaryl.

101. A. method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VI):rV!2Formula (VI)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each — independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein:X1 is NR1, X2 is CR2, and X3 is N or CH,X1 is O, X2 is CR2, and X3 is N;X1 is N, X2 is NR1, and X3 is N; orX1 is NR3, X2 is N, and X3 is N;n is 0 or 1;R1 is selected from H, Cue alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, and heteroaryl;wherein the C1-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, or heteroaryl of R1 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, C1-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R2 is selected from H, halo, Ci-6 haloalkyl, NO2, CN, SO2-C1-6 alkyl, Ci-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, and heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-6 alkyl-aiyl, or heteroaryl of R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, C1-6 haloalkyl, and -CO(O)-Ci-6 alkyl;R3 is selected from H, Cue alkyl, C3-6 cycloalkyl, aryl, Cue alkyl-aryl, and heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, or heteroaryl of R3 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl;RV11, RV12, RV1J, R'14, and Rvi5 are each independently selected from H, halo, Cw haloalkyl, NO2, CN, and SO2-C1-6 alkyl.

102. The method of claim 101, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R3 is C4-6 alkyl or phenyl substituted with one or more halo.

103. The method of claim 101 or 102, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Rvn is NO2.

104. The method of any one of claims 101-103, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RVD is CF3.

105. A method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VII):O O RVihFormula (VH)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:R1 is selected from the group consisting of C3-6 cycloalkyl, Ci alkyl-C.^ cycloalkyl, aryl, Ci alkyl-aryl, heteroaryl, and Ci alkyl-heteroaiyl;wherein the C3-6 cycloalkyl, Ci alkyl-C3-6 cycloalkyl, aryl, Ci alkyl-aryl, heteroaiyl, or Ci alkyl-heteroaryl of R1 is unsubstituted or substituted with halo;RV1U, RV112, RV113, R?!i4, and RV1L5 are each independently selected from H, halo, Cue, haloalkyl, NO2, CN, and SO2-C1-6 alkyl.

106. The method of claim 105, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof wherein R! is aryl or Ci alkyl-aryl, wherein the aryl or Ci alkyl-aryl may be unsubstituted or substituted with one or more halo.

107. The method of claim 105 or 106, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RVU1 is H or NCh.

108. The method of any one of claims 105-107, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R'112 is H, halo, or SO2-C1-6 alkyl.

109. The method of any one of claims 105-108, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RV313 is CF3.

110. A method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (VIII):Formula (VIII)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each — independently represents a single bond or a double bond, subject to the satisfaction of valency requirements, wherein:Y1 is CR, Y2 is N, and Y3 is NR3,Y1 is CR1, Y2 is O or S, and Y3 is CR3;Y3 is N, Y"2 is CR2, and Y; is O or S; orY1 is O or S, Y2 is CR2, and Y"3 is CR3,R1 and R2 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, and aryl;wherein the Ci-6 alkyl, C1.6 haloalkyl, €3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl of R1 or R2 is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Ci-e haloalkyl, and -CO(O)-Ci-6 alkyl;R3 is H, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl;wherein the Cj-e alkyl, Cj-6 haloalkyl, C3-5 cycloalkyl, -CO(O)-Ci-6 alkyl, or aryl of R ' is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, Cj-6 haloalkyl, and -CO(O)-Ci-6 alkyl; orR3 combines with R'!H2 to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-6 alkyl, C1-6 haloalkyl, and -CO(O)-Ci-6 alkyl;Rvmi is H, Cue alkyl, C3-6 cycloalky], aryl, Ci-6 alkyl-aryl, or heteroaryl;wherein the Ci-6 alkyl, C3-6 cycloalkyl, aryl, Ci-e alkyl-aryl, or heteroaryl of Rwu is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Ci-e alkyl, and alkoxy;RV1112 js hal0, Ci-6 haloalkyl, NO2, CN, and SO2-C1-6 alkyl; orRwn combines R-’ form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, Cue alkyl, Ci-6 haloalkyl, and -CO(O)-Ci-6 alkyl.

111. The method of claim 110, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof wherein R! is CF3.

112. The method of claim 110 or 111, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2 is CF3.

113. The method of any one of claims 110-112, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R ‘ is Ci-6 alkyl.

114. A method of treating a condition in a subject in need thereof, the method comprisingadministering a therapeutically effective amount of a compound, wherein the compound is, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

115. A method of treating a condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of the compound of any one of claims 1-90, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

116. Use of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising:administering to the subject an effective amount of the compound of Formula (I), Formula (IA), Formula (IA3), Formula (IB-N), Formula (IB-N3), Formula (IB-O), Formula (IC-N), Formula (IC-N3), Formula (IC-O), Formula (ID-O), Formula (ID-S), Formula (ID-SO2), Formula (IE), Formula (IF), Formula (IG-N), Formula (IG-N3), Formula (IG-O), Formula (IH-N), Formula (IH-N3), Formula (IH-O), Formula (li-N), Formula (I1-N3), Formula (IJ-N), Formula (U-N3), Formula (IK-N), Formula (IK-N3), Formula (IL-N), Formula (IL-N3), Formula (IM), Formula (II), Formula (IIA-C), Formula (IIA-C3), Formula (IIA-N), Formula (IIA-N3), Formula (IIB), Formula (IIB3), Formula (IIC), Formula (IIC3), Formula (IID), Formula (III), Formula (IV), Formula (IVA), Formula (IVAS), Formula (IVB-O), Formula (IVB-03), Formula (IVB-S), Formula (IVB-S3), Formula (IVC-S), Formula (IVC-S3), Formula (IVD), Formula (IVD3), Formula (V), Formula (VE), Formula (VI), Formula (VII), Formula (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

117. Use of the compound of any one of claims 1-90, or a pharmaceutically acceptable salt,stereoisomer, or tautomer thereof, in the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising:administering to the subject an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

118. Use of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof,wherein the medicament comprises an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, andthe compound is of Formula (I), Formula (IA), Formula (IA3), Formula (IB-N), Formula (IB-N3), Formula (IB-O), Formula (IC-N), Formula (IC-N3), Formula (IC-O), Formula (ID-O), Formula (ID-S), Formula (ID-SO2), Formula (IE), Formula (IF), Formula (IG-N), Formula (IG-N3), Formula (IG-O), Formula (IH-N), Formula (IH-N3), Formula (IH-O), Formula (li-N), Formula (Ii-N3), Formula (U-N), Formula (U-N3), Formula (IK-N), Formula (IK-N3), Formula (IL-N), Formula (IL-N3), Formula (IM), Formula (II), Formula (IIA-C), Formula (IIA-C3), Formula (IIA-N), Formula (IIA-N3), Formula (IIB), Formula (IIB3), Formula (IIC), Formula (IIC3), Formula (IID), Formula (III), Formula (IV), Formula (IVA), Formula (IVA3), Formula (IVB-O), Formula (IVB-O3), Formula (IVB-S), Formula (IVB-S3), Formula (IVC-S), Formula (IVC-S3), Formula (IVD), Formula (IVD3), Formula (V), Formula (VE), Formula (VI), Formula (VII), Formula (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

119. Use of the compound of any one of claims 1-90, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, wherein the medicament comprises an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

120. A compound for use in a method of treating a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising:administering an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to the subject,wherein the compound is of Formula (I), Formula (IA), Formula (IA3), Formula (IB-N), Formula (IB-N3), Formula (IB-0), Formula (IC-N), Formula (IC-N3), Formula (IC-O), Formula (ID-O), Formula (ID-S), Formula (ID-SO2), Formula (IE), Formula (IF), Formula (IG-N), Formula (IG-N3), Formula (IG-O), Formula (IH-N), Formula (IH-N3), Formula (H CO). Formula (li-N), Formula (Ii-N3), Formula (U-N), Formula (IJ-N3), Formula (IK-N), Formula (IK-N3), Formula (IL-N), Formula (IL-N3), Formula (IM), Formula (II), Formula (IIA-C), Formula (IIA-C3), Formula (IIA-N), Formula (IIA-N3), Formula (IIB), Formula (IIB3), Formula (IIC), Formula (IIC3), Formula (HD), Formula (III), Formula (IV), Formula (IVA), Formula (IVA3), Formula (IVB-O), Formula (IVB-O3), Formula (IVB-S), Formula (IVB-S3), Formula (IVC-S), Formula (IVC-S3), Formula (IVD), Formula (IVD3), Formula (V), Formula (AT), Formula (VI), Formula (VII), Formula (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

121. The compound of any one of claims 1-90, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, for use in a method of treating a condition that is responsive to modulation or inhibition of HPD in a human subject in need thereof, the method comprising: administering an effective amount of the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, to the subject.

122. A pharmaceutical formulation for use in a method of treating a condition that is responsive to modulation or inhibition of HPD, the formulation comprising an effective amount of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier, wherein:the method comprises administering the pharmaceutical formulation to a subject having the condition; andthe compound is of Formula (I), Formula (IA), Formula (IA3), Formula (IB-N), Formula (IB-N3), Formula (IB-O), Formula (IC-N), Formula (IC-N3), Formula (IC-O), Formula (ID-O), Formula (ID-S), Formula (ID-S02), Formula (IE), Formula (IF), Formula (IG-N), Formula (IG-N3), Formula (IG-O), Formula (1H-N), Formula (IH-N3), Formula (IH-O), Formula (li-N), Formula (li-N3), Formula (IJ-N), Formula (IJ-N3), Formula (IK-N), Formula (IK.-N3), Formula (IL-N), Formula (IL-N3), Formula (IM), Formula (II), Formula (H. VC), Formula (H.VC3), Formula (IIA-N), Formula (IIA-N3), Formula (IIB), Formula (IIB3), Formula (IIC), Formula (IIC3), Formula (IID), Formula (III), Formula (IV), Formula (IVA), Formula (IVA3), Formula (IVB-O), Formula (IVB-03), Formula (IVB-S), Formula (IVB-S3), Formula (IVC-S), Formula (IVC-S3), Formula (IVD), Formula (IVD3), Formula (V), Formula (VE), Formula (VI), Formula (VII), Formula (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

123. A pharmaceutical formulation for use in a method of treating a condition that is responsive to modulation or inhibition of HPD, the formulation comprising an effective amount of the compound of any one of claims 1-90, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, wherein:the method comprises administering the pharmaceutical formulation to a subject having the condition.

124. A medicament for treating a condition that is responsive to modulation or inhibition of HPD, the medicament comprising an effective amount of a compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:the treatment comprises administering the medicament to a subject having the condition; and the compound is of Formula (I), Formula (IA), Formula (IA3), Formula (IB-N), Formula(IB-N3), Formula (IB-O), Formula (IC-N), Formula (IC-N3), Formula (IC-O), Formula (ID-O), Formula (ID-S), Formula (ID-SO2), Formula (IE), Formula (IF), Formula (IG-N), Formula (IG-N3), Formula (IG-O), Formula (1H-N), Formula (IH-N3), Formula (IH-O), Formula (li-N), Formula (li-N3), Formula (IJ-N), Formula (IJ-N3), Formula (IK-N), Formula (IK-N3), Formula (IL-N), Formula (IL-N3), Formula (IM), Formula (II), Formula (IIA-C), Formula (IIA-C3), Formula (IIA-N), Formula (IIA-N3), Formula (IIB), Formula (HB3), Formula (IIC), Formula (IIC3), Formula (IID),Formula (HI), Formula (IV), Formula (IVA), Formula (IVA3), Formula (IVB-O), Formula (IVB-03), Formula (TVB-S), Formula (IVB-S3), Formula (IVC-S), Formula (IVC-S3), Formula (IVD), Formula (IVD3), Formula (V), Formula (VE), Formula (VI), Formula (VII), Formula (VIII), or a pharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing.

125. A medicament for treating a condition that is responsive to modulation or inhibition of HPD, the medicament comprising an effective amount of the compound of any one of claims 1-90, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:the treatment comprises administering the medicament to a subject having the condition.

126. The method of any one of claims 92-115, wherein the condition is responsive to modulation or inhibition of HPD.

127. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 92-126, wherein the condition is an inborn error of metabolism.

128. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 127, wherein the inborn error of metabolism is an inborn error of tyrosine metabolism.

129. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 128, wherein the inborn error of tyrosine metabolism is tyrosinemia type I, tyrosinemia type II, tyrosinemia type III, alkaptonuria, or hawkinsinuria.

130. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 127, wherein the inborn error of metabolism is an inborn error of phenylalanine metabolism.

131. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 130, wherein the inborn error of phenylalanine metabolism is phenylketonuria.

132. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 92-126, wherein the condition is selected from the group consisting of myalgic encephalomyelitis, Parkinson’s disease, Lewy Body dementia, mood disorders, autoimmune disorders, inflammatory disorders, neuropathic pain, refractory hypertension, low sex drive, attention-deficit / hyperactivity disorder (ADHD), sleep disorders, restless leg syndrome, obsessivecompulsive disorder (OCD), panic disorders, post-traumatic stress disorder (PTSD), substance abuse disorders, chronic constipation, tremor disorders, CoQlO deficiency, and oculocutaneous albinism.

133. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 92-132, further comprising administering low-protein diet to the subject, wherein the low-protein diet comprises less than about 2 g / day of protein.

134. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 92-133, further comprising administering a dietary product to the subject.

135. The method, the use, the compound, the pharmaceutical formulation, or the medicament, of claim 134, wherein the dietary product comprises less than 25% of a recommended dietary allowance (RDA) of tyrosine for the subject’s age group, less than 25% of an RD A. of phenylalanine for the subject’s age group, or less than 25% of an RDA of tyrosine and phenylalanine for the subject’s age group.

136. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 135, w'herein the RDA for the subject’s age group is as determined by the Food and Nutrition Board of the Institute of Medicine.

137. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 134-136, wherein the dietary product comprises less than 25% of an average recommended dietary intake of tyrosine for the subject’s age group, less than 25% of an averagerecommended dietary intake of phenylalanine for the subject’s age group, or less than 25% of an average recommended dietary intake of tyrosine and phenylalanine for the subject’s age group.

138. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 137, wherein the average recommended dietary / intake is an RDA for the subject’s age group is determined by the Food and Nutrition Board of the Institute of Medicine.

139. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 134-138, wherein the dietary / product comprises less than a daily recommended amount of phenylalanine and tyrosine combined,140. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 139, wherein the daily recommended amount of phenylalanine and tyrosine is 33 mg / kg / day.

141. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 134-140, wherein the dietary’ product comprises less than 25% of a median dietary intake of tyrosine in a control or healthy subject of the same age group as the subject, less than 25% of a median dietary intake of phenylalanine in a control or healthy subject of the same age group as the subject or less than 25% of a median dietary intake of tyrosine and phenylalanine in a control or healthy subject of the same age group as the subject.

142. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 134, wherein the dietary product is devoid of tyrosine, devoid of phenylalanine, or devoid of tyrosine and devoid of phenylalanine.

143. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 134-142, wherein the dietary / product is administered orally.

144. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claims 134-143, wherein the dietary’ product is formulated as a solid or as a beverage.

145. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claims 134-144, wherein the dietary product is administered via tube.

146. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 145, wherein the dietary'’ product is administered via nasogastric tube.

147. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 134-146, wherein the dietary product is administered intravenously or parenterally.

148. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 134-147, wherein the subject is administered a therapeutically effective amount of the dietary’ product.

149. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 148, wherein the therapeutically effective amount of the dietary? product is from about 0.5 g / kg / day to about 1 g / kg / day.

150. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 148 or 149, wherein the therapeutically effective amount of the dietary product is about 0.8 g / kg / day.

151. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 134-150, wherein the dietary' product is administered with food.

152. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 134-151, wherein the dietary product is administered 3 times a day or 5 times a day.

153. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 134-152, wherein the dietary product is a sole source of amino acids for the subject.

154. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 134-153, wherein the dietary product is a sole source of calories for the subject.

155. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 92-154, wherein the administering is oral or via tube.I56. The method, the use, the compound, the pharmaceutical formulation, or the medicament of claim 155, wherein the administering is via nasogastric tube.

157. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 92-154, wherein the administering is intravenous.

158. The method, the use, the compound, the pharmaceutical formulation, or the medicament, of any one of claims 92-157, wherein the administering is once daily or twice daily.I59. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 92-158, wherein the administering is with food.

160. The method, the use, the compound, the pharmaceutical formulation, or the medicament of any one of claims 92-158, wherein the subject is in a fasted state.

161. The method, the use, the compound, the pharmaceutical formulation, or the medicament, of any one of claims 92-160, wherein the compound is administered in a pharmaceutical composition, wherein the pharmaceutical composition is in unit dosage form, the unit dosage form comprising a pharmaceutically acceptable excipient.

162. An herbicidal composition comprising the compound of any one of claims 1-90, or an agriculturally acceptable salt thereof163. The herbicidal composition of claim 162, further comprising an herbicidal safener, wherein the herbi cidal safener increases a metaboli c rate of the herbi cidal composition in a crop.

164. The herbicidal composition of claim 163, wherein the herbicidal safener increases expression of a gene that encodes an enzyme responsible for xenobiotic degradation of the herbicidal composition in the crop.

165. The herbicidal composition of claim 164, wherein the gene encodes Cytochrome P450, glutathione-S-transferase, or an ATP-binding cassette transporter.

166. The herbicidal composition of any one of claims 163-165, wherein the herbicidal safener is identified in a biological screen.

167. The herbicidal composition of any one of claims 163-166, wherein the herbicidal composition and the herbicidal safener are present in a ratio of at least 4:1 by weight (compound: safener).

168. The herbicidal composition of any one of claims 163-167, wherein the herbicidal safener comprises fluroxypyr-meptyl.

169. The herbicidal composition of any one of claims 162-168, further comprising a second herbicide.

170. The herbicidal composition of claim 169, wherein the second herbicide does not inhibit HPD.

171. The herbicidal composition of claim 169 or I / O, wherein the second herbicide shows synergistic effects with the herbicidal composition.

172. The herbicidal composition of any one of claims 169-171, wherein the second herbicide is a photosystem II inhibitor herbicide, an acetolactate synthase inhibitor, 5-enolpyruvlshikimate 3-phosphate synthase inhibitor, a very long-chain fatty acid biosynthesis inhibitor, an acetylcoenzyme A carboxylase inhibitor, a synthetic auxin, a protoporphyrinogen oxidase inhibitor, a microtubule inhibitor, a carotenoid biosynthesis inhibitor, a glutamine synthetase inhibitor, or a photosystem I electron driver.

173. A method of controlling a weed, comprising contacting the weed with the herbicidal composition of any one of claims 162-172.

174. The method of claim 173, comprising contacting the weed with an effective amount of the herbicidal composition.

175. The method of claim 173 or 174, wherein the weed is selected from the group consisting of a dicotyledonous weed and a monocotyledonous weed.

176. The method of any one of claims 173-175, wherein the weed has an acquired resistance to an herbicide.

177. The method of claim 176, wherein the weed, is an acetyl-coenzyme A carboxylase-resistant weed, an acetolactate synthase-resistant weed, a glyphosate-resistant weed, a paraquatresistant weed, an aminopyralid + 2,4-D-resistant weed, a picloram-resistant weed, a 2,4-di chlorophen oxy acetic acid-resistant weed, a propanil-resistant weed, a 3,4-dich1oroaniline + propionic acid-resistant weed, a dichloroaniline-resistant weed, a pendimethalin-resistant weed, or a weed with a combination of any of the foregoing resistances.

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