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

Attn Docket: FATH-023 / 02WO 351027-2511 HPD INHIBITOR COMPOSITIONS AND METHODS OF USE 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 metabolic 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 usingAttn Docket: FATH-023 / 02WO 351027-2511 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):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, X2, X3, Z1, Z2, n, Y1, Y2, Y3, Y4, and Y5are 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 R1a, R1a’, R2a, R2a’, R3a, R3a’, n, Y1, Y2, Y3, Y4, and Y5are 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:Attn Docket: FATH-023 / 02WO 351027-2511 wherein R1a, R1a’, R3a, R3a’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I), and R1a3, R2a3, R3a3, R4a3, and R5a3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[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 R1b, R2b, R2b’, R3b, R3b’, n, Y1, Y2, Y3, Y4, and Y5are 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:wherein R2b, R2b’, R3b, R3b’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I), and R1b3, R2b3, R3b3, R4b3, and R5b3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[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, R2b’, R3b, R3b’, n, Y1, Y2, Y3, Y4, and Y5are 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:Attn Docket: FATH-023 / 02WO 351027-2511wherein R1c, R1c’, R2c, R2c’, R3c, n, Y1, Y2, Y3, Y4, and Y5are 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 R1c, R1c’, R2c, R2c’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I), and R1c3,and R5c3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[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:wherein R1c, R1c’, R2c, R2c’, n, Y1, Y2, Y3, Y4, and Y5are 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:Attn Docket: FATH-023 / 02WO 351027-2511wherein R1d, R1d’, R3d, R3d’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I).

[0016] In some embodiments, the compound of Formula (I) is a compound of Formula (ID-S), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein R1d, R1d’, R3d, R3d’, n, Y1, Y2, Y3, Y4, and Y5are 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:wherein R1d, R1d’, R3d, R3d’, n, Y1, Y2, Y3, Y4, and Y5are 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 R1e, R1e’, R3e, R3e’, n, Y1, Y2, Y3, Y4, and Y5are 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:Attn Docket: FATH-023 / 02WO 351027-2511wherein R1f, R1f’, R2f, R2f’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I).

[0020] In some embodiments, the compound of Formula (I) is a compound of Formula (IG-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein R1g, R2g, R2g’, n, Y1, Y2, Y3, Y4, and Y5are 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 R2g, R2g’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I), and R1g3, R2g3, R3g3, R4g3, and R5g3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O- C1-6alkyl.

[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 R2g, R2g’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I).Attn Docket: FATH-023 / 02WO 351027-2511

[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 R1h, R1h’, R2h, n, Y1, Y2, Y3, Y4, and Y5are 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 R1h, R1h’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I), and R1h3, R2h3, R3h3, R4h3, and R5h3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O- C1-6alkyl.

[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:wherein R1h, R1h’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I).

[0026] In some embodiments, the compound of Formula (I) is a compound of Formula (Ii-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Attn Docket: FATH-023 / 02WO 351027-2511wherein R1i, R3i, R3i’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I).

[0027] In some embodiments, the compound of Formula (Ii-N) is a compound of Formula (Ii- N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein R3i, R3i’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I), and R1i3, R2i3, R3i3, R4i3, and R5i3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-

[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:wherein R1j, R2j, R3j, R3j’, n, Y1, Y2, Y3, Y4, and Y5are 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:Attn Docket: FATH-023 / 02WO 351027-2511 wherein R2j, R3j, R3j’, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I), and R1j3, R2j3, R3j3, R4j3, and R5j3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and - O-C1-6alkyl.

[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:wherein R1k, R2k, n, Y1, Y2, Y3, Y4, and Y5are 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 Y5are as described for Formula (I), and R1k3, R2k3, R3k3, R4k3, and R5k3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[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 R1l, R3l, n, Y1, Y2, Y3, Y4, and Y5are 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:Attn Docket: FATH-023 / 02WO 351027-2511wherein R3l, n, Y1, Y2, Y3, Y4, and Y5are as described for Formula (I), and R1l3, R2l3, R3l3, R4l3, and R5l3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[0034] In some embodiments, the compound of Formula (I) is a compound of Formula (IM), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:whereinare as described for Formula (I).

[0035] The present disclosure also provides a compound of 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, X2, X3, n, RII1, RII2, RII3, RII4, and RII5are 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:Attn Docket: FATH-023 / 02WO 351027-2511wherein R1, R2, RII1, RII2, RII3, RII4, and RII5are 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, RII1, RII2, RII3, RII4, and RII5are as described for Formula (II), and R1a, R1b, R1c, R1d, and R1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[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:wherein R1, R2, RII1, RII2, RII3, RII4, and RII5are 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:Attn Docket: FATH-023 / 02WO 351027-2511 wherein R2, RII1, RII2, RII3, RII4, and RII5are as described for Formula (II), and R1a, R1b, R1c, R1d, and R1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[0040] In some embodiments, the compound of Formula (II) is a compound of Formula (IIB), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein R2, RII1, RII2, RII3, RII4, and RII5are 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:wherein RII1, RII2, RII3, RII4, and RII5are as described for Formula (II), and R2a, R2b, R2c, R2d, and R2eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[0042] In some embodiments, the compound of Formula (II) is a compound of Formula (IIC), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein R1, RII1, RII2, RII3, RII4, and RII5are 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:Attn Docket: FATH-023 / 02WO 351027-2511wherein RII1, RII2, RII3, RII4, and RII5are as described for Formula (II), and R1a, R1b, R1c, R1d, and R1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[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, RII1, RII2, RII3, RII4, and RII5are as described for Formula (II).

[0045] The present disclosure also provides a compound of Formula (III):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1, RIII1, RIII2, RIII3, RIII4, and RIII5are as described herein.

[0046] The present disclosure also provides a compound of 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, RIV1, and RIV2are as described herein.Attn Docket: FATH-023 / 02WO 351027-2511

[0047] In some embodiments, the compound of Formula (IV) is a compound of Formula (IVA), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein R1, R3, RIV1, and RIV2are 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:wherein R1, R3, and RIV2are as described for Formula (IV), and RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[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:wherein R1, R3, RIV1, and RIV2are as described for Formula (IV).

[0050] In some embodiments, the compound of Formula (IVB-O) is a compound of Formula (IVB-O3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Attn Docket: FATH-023 / 02WO 351027-2511 wherein R1, R3, and RIV2are as described for Formula (IV), and RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[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:wherein R1, R3, RIV1, and RIV2are 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:wherein R1, R3, and RIV2are as described for Formula (IV), and RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[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:wherein R2, RIV1, and RIV2are as described for Formula (IV).

[0054] In some embodiments, the compound of Formula (IVC-S) is a compound of Formula (IVC-S3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Attn Docket: FATH-023 / 02WO 351027-2511wherein R2and RIV2are as described for Formula (IV), and RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[0055] In some embodiments, the compound of Formula (IV) is a compound of Formula (IVD), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein R2, R3, RIV1, and RIV2are 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:wherein R2, R3, and RIV2are as described for Formula (IV), and RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

[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):Attn Docket: FATH-023 / 02WO 351027-2511or 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, X2, X3, Z1, Z2, n, Y1, Y2, Y3, Y4, and Y5are 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:wherein R1e, R1e’, R3e, R3e’, n, Y1, Y2, Y3, Y4, and Y5are 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 administering a therapeutically effective amount of a compound of 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, X3, n, RVI1, RVI2, RVI3, RVI4, and RVI5are 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):Attn Docket: FATH-023 / 02WO 351027-2511or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1, RVII1, RVII2, RVII3, RVII4, and RVII5are 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):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, RVIII1, and RVIII2are 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 (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), (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), (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), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-O), (ID-S), (ID-SO2), (IE),Attn Docket: FATH-023 / 02WO 351027-2511 (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), (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), (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), (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), (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), (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-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), (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), (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), (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), (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), (IVD3), (V), (VE), (VI), (VII), (VIII) or a pharmaceutically acceptable salt,Attn Docket: FATH-023 / 02WO 351027-2511 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), (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), (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), (Ii-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-O3), (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), (Ii-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), (IM), (II), (IIA-Attn Docket: FATH-023 / 02WO 351027-2511 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) 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), (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), (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), (IVD3), (V), (VE), (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), (Ii-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-O3), (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.

[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), (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), (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), (IVD3), (V), (VE), (VI), (VII), (VIII) or aAttn Docket: FATH-023 / 02WO 351027-2511 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), (Ii-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- O3), (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), (IH-N3), (IH-O), (Ii-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-O3), (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 uniformly13C-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.Attn Docket: FATH-023 / 02WO 351027-2511

[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 triketones 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 wild- type 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 exemplary 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 particularAttn Docket: FATH-023 / 02WO 351027-2511 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 fumarylacetoacetate 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,Attn Docket: FATH-023 / 02WO 351027-2511 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 activity.

[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):Attn Docket: FATH-023 / 02WO 351027-2511or 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: X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’; X1is NR1bor O, X2is CR2bR2b’, and X3is CR3bR3b’; X1is CR1cR1c’, X2is CR2cR2c’, and X3is NR3cor O; X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’; X1is CR1eR1e’, X2is C(O), and X3is CR3eR3e’; X1is CR1fR1f’, X2is CR2fR2f’, and X3is a bond; X1is NR1gor O, X2is CR2gR2g’, and X3is a bond; X1is CR1hR1h’, X2is NR2hor O, and X3is a bond; X1is NR1ior O, X2is C(O), and X3is CR3iR3i’; X1is NR1jor O, X2is NR2jor O, and X3is CR3jR3j’; X1is NR1kor O, X2is NR2kor O, and X3is a bond; X1is NR1lor O, X2is C(O), and X3is NR3lor O; or X1is CR1mR1m’, X2is CR2mR2m’, and X3is CR3mR3m’-CR4mR4m’; Z1and Z2are each independently selected from C(O) and S(O2); R1aand R1a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; R2aand R2a’are each independently selected from H, C2-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; R3aand R3a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; If Z1and Z2are both C(O), then at least one of R1a, R1a’, R2a, R2a’, R3a, or R3a’is C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the aryl of R1a, R1a’, R2a, R2a’, R3a, or R3a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1a, R1a’, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1a, R1a’, R2a, R2a’, R3a, or R3a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1a, R1a’, R2a, R2a’, R3a, or R3a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R2b, R2b’, R3b, and R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1b, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1b, R2b, R2b’, R3b, or R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1b, R2b, R2b’, R3b, or R3b’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1c, R1c’, R2c, and R2c’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1c, R1c’, R2c, or R2c’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1d, R1d’, R3d, and R3d’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the aryl of R1d, R1d’, R3d, or R3d’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1e, R1e’, R3e, and R3e’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1e, R1e’, R3e, or R3e’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1e, R1e’, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1e, R1e’, R3e, or R3e’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1e, R1e’, R3e, or R3e’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1f, R1f’, R2f, and R2f’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1f, R1f’, R2f, or R2f’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1f, R1f’, R2f, and R2f’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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1f, R1f’, R2f, or R2f’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1f, R1f’, R2f, or R2f’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 R2gand R2g’are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R2gor R2g’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1hand R1h’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1hor R1h’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R3iand R3i’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R3ior R3i’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R3jand R3j’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R3jor R3j’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, and R4m’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the aryl of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1bis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1bis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; or two or more of R1b, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1b, R2b, R2b’, R3b, or R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1b, R2b, R2b’, R3b, or R3b’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3cis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1cis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1gis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1gis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2his unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1iis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1iis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy;Attn Docket: FATH-023 / 02WO 351027-2511 R1jand R2jare each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, and heteroaryl; wherein the C1-6alkyl,cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1jor R2jis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1kand R2kare each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1kor R2kis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1land R3lare each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1lor R3lis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; n is 0 or 1; wherein: if X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’, then:C(R5a2); wherein R1a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3a2is H, halo, C1-6haloalkyl, NO2, or CN; R4a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1a2combines with R2a2to 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 C1-6alkyl, and R3a2, R4a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2a2combines with R3a2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclicAttn Docket: FATH-023 / 02WO 351027-2511 ring may be unsubstituted or substituted with C1-6 alkyl, and R1a2, R4a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3a2combines with R4a2to 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 C1-6alkyl, and R1a2, R2a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4a2combines with R5a2to 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 C1-6alkyl, and R1a2, R2a2, and R3a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1bor O, X2is CR2bR2b’, and X3is CR3bR3b’, then: Y1is C(R1b2) or N; Y2is C(R2b2) or N; Y3is C(R3b2) or N; Y4is C(R4b2) or N; and Y5is C(R5b2) or N; or Y1is C(O); Y2is N(R2b2’); Y3is C(R3b2’); Y4is C(R4b2’); and Y5is N; wherein R1b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl;halo,6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1b2combines with R2b2to 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 C1-6alkyl or OH, and R3b2, R4b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; or R2b2combines with R3b2to 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 C1-6alkyl or OH, and R1b2, R4b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; or R3b2combines with R4b2to 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 C1-6alkyl or OH, and R1b2, R2b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 R4b2combines with R5b2to 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 C1-6alkyl or OH, and R1b2, R2b2, and R3b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; R2b2’is H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R3b2’is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4b2’is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; 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 C1-6alkyl or halo, and R4b2’is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R4b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, 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 C1-6alkyl or halo, and R2b2’is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; if X1is CR1cR1c’, X2is CR2cR2c’, and X3is O or NR3c; then Y1is C(R1c2) or N; Y2is C(R2c2) or N; Y3is C(R3c2) or N; Y4is C(R4c2) or N; and Y5is C(R5c2) or N; wherein R1c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; orAttn Docket: FATH-023 / 02WO 351027-2511 R1c2combines with R2c2to 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 C1-6alkyl, and R3c2, R4c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2c2combines with R3c2to 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 C1-6alkyl, and R1c2, R4c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3c2combines with R4c2to 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 C1-6alkyl, and R1c2, R2c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4c2combines with R5c2to 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 C1-6alkyl, and R1c2, R2c2, and R3c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’, then Y1is C(R1d2) or N; Y2isR3d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1d2combines with R2d2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3d2, R4d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2d2combines with R3d2to 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 C1-6alkyl, and R1d2, R4d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3d2combines with R4d2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring mayAttn Docket: FATH-023 / 02WO 351027-2511 be unsubstituted or substituted with C1-6 alkyl, and R1d2, R2d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4d2combines with R5d2to 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 C1-6alkyl, and R1d2, R2d2, and R3d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1eR1e’, X2is C(O), and X3is CR3eR3e’, then: Y1is C(R1e2); Y2is C(R2e2); Y3is C(R3e2); Y4is C(R4e2); and Y5is C(R5e2); or Y1is C(R1e2’) or N; Y2is C(R2e2’) or N; Y3is C(R3e2’) or N; Y4is C(R4e2’) or N; and Y5is C(R5e2’) or N, wherein at least one of Y1, Y2, Y3, Y4, and Y5is N; wherein R1e2is H, F, CN, or SO2-C1-6alkyl; R2e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1e2is Cl; R2e2is H; R3e2is C1-6haloalkyl, NO2, or SO2-C1-6alkyl; R4e2is H; and R5e2is H; or R1e2is NO2; R2e2is H; R3e2is C1-6haloalkyl; R4e2is H; and R5e2is H; or R1e2combines with R2e2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3e2, R4e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2e2combines with R3e2to 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 C1-6alkyl, and R1e2, R4e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3e2combines with R4e2to 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 C1-6alkyl, and R1e2, R2e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4e2combines with R5e2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclicAttn Docket: FATH-023 / 02WO 351027-2511 ring may be unsubstituted or substituted with C1-6 alkyl, and R1e2, R2e2, and R3e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R1e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R2e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl;is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R4e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R5e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; or R1e2’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 C1-6alkyl, and R3e2’, R4e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2e2’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 C1-6alkyl, and R1e2’, R4e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3e2’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 C1-6alkyl, and R1e2’, R2e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4e2’combines with R5e2’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 C1-6alkyl, and R1e2’, R2e2’, and R3e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1fR1f’, X2is CR2fR2f’, and X3is a bond; then Y1is C(R1f2) or N; Y2is C(R2f2) or N; Y3Y4is C(R4f2) or N; an5 5f2d Y is C(R ) or N; wherein R1f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1f2combines with R2f2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring mayAttn Docket: FATH-023 / 02WO 351027-2511 be unsubstituted or substituted with C1-6 alkyl, and R3f2, R4f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2f2combines with R3f2to 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 C1-6alkyl, and R1f2, R4f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3f2combines with R4f2to 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 C1-6alkyl, and R1f2, R2f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4f2combines with R5f2to 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 C1-6alkyl, and R1f2, R2f2, and R3f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1gor O, X2is CR2gR2g’, and X3is a bond; then Y1is C(R1g2) or N; Y2is C(R2g2) or N; Y3is C(R3g2) or N; Y4is C(R4g2) or N; and Y5is C(R5g2) or N; wherein R1g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1g2combines with R2g2to 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 C1-6alkyl, and R3g2, R4g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2g2combines with R3g2to 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 C1-6alkyl, and R1g2, R4g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3g2combines with R4g2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring mayAttn Docket: FATH-023 / 02WO 351027-2511 be unsubstituted or substituted with C1-6 alkyl, and R1g2, R2g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4g2combines with R5g2to 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 C1-6alkyl, and R1g2, R2g2, and R3g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1hR1h’, X2is NR2hor O, and X3is a bond; then Y1is C(R1h2) or N; Y2is C(R2h2) or N; Y3is C(R3h2) or N; Y4is C(R4h2) or N; and Y5is C(R5h2) or N; wherein R1h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1h2combines with R2h2to 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 C1-6alkyl, and R3h2, R4h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2h2combines with R3h2to 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 C1-6alkyl, and R1h2, R4h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3h2combines with R4h2to 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 C1-6alkyl, and R1h2, R2h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4h2combines with R5h2to 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 C1-6alkyl, and R1h2, R2h2, and R3h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1ior O, X2is C(O), and X3is CR3iR3i’; then Y1is C(R1i2) or N; Y2is C(R2i2) or N; Y3is C(R3i2) or N; Y4is C(R4i2) or N; and Y5is C(R5i2) or N; wherein R1i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 R2i2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R3i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1i2combines with R2i2to 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 C1-6alkyl, and R3i2, R4i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2i2combines with R3i2to 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 C1-6alkyl, and R1i2, R4i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3i2combines with R4i2to 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 C1-6alkyl, and R1i2, R2i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4i2combines with R5i2to 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 C1-6alkyl, and R1i2, R2i2, and R3i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1jor O, X2is NR2jor O, and X3is CR3jR3j’; then Y1is C(R1j2) or N; Y2is C(R2j2) or N; Y3is C(R3j2) or N; Y4is C(R4j2) or N; and Y5is C(R5j2) or N; wherein R1j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1j2combines with R2j2to 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 C1-6alkyl, and R3j2, R4j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 R2j2combines with R3j2to 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 C1-6alkyl, and R1j2, R4j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3j2combines with R4j2to 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 C1-6alkyl, and R1j2, R2j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4j2combines with R5j2to 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 C1-6alkyl, and R1j2, R2j2, and R3j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1kor O, X2is NR2kor O, and X3is a bond; then Y1is C(R1k2) or N; Y2is C(R2k2) or N; Y3is C(R3k2) or N; Y4is C(R4k2) or N; and Y5is C(R5k2) or N; wherein R1k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1k2combines with R2k2to 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 C1-6alkyl, and R3k2, R4k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2k2combines with R3k2to 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 C1-6alkyl, and R1k2, R4k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3k2combines with R4k2to 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 C1-6alkyl, and R1k2, R2k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 R4k2combines with R5k2to 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 C1-6alkyl, and R1k2, R2k2, and R3k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1lor O, X2is C(O), and X3is NR3lor O; then Y1is C(R1l2) or N; Y2is C(R2l2) or N; Y3is C(R3l2) or N; Y4is C(R4l2) or N; and Y5is C(R5l2) or N; wherein R1l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl;alkyl; or R1l2combines with R2l2to 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 C1-6alkyl, and R3l2, R4l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2l2combines with R3l2to 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 C1-6alkyl, and R1l2, R4l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3l2combines with R4l2to 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 C1-6alkyl, and R1l2, R2l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4l2combines with R5l2to 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 C1-6alkyl, and R1l2, R2l2, and R3l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or if X1is CR1mR1m’, X2is CR2mR2m’, and X3is CR3mR3m’-CR4mR4m’; then Y1is C(R1m2) or N; Y2is C(R2m2) or N; Y3is C(R3m2) or N; Y4is C(R4m2) or N; and Y5is C(R5m2) or N; wherein R1m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 R3m2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1m2combines with R2m2to 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 C1-6alkyl, and R3m2, R4m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orR3m2to 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 C1-6alkyl, and R1m2, R4m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3m2combines with R4m2to 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 C1-6alkyl, and R1m2, R2m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4m2combines with R5m2to 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 C1-6alkyl, and R1m2, R2m2, and R3m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN.

[0099] In some embodiments of the compounds of Formula (I): X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’; X1is NR1b, X2is CH2, and X3is CR3bR3b’; X1is CR1cR1c’, X2is CR2cR2c’, and X3is O; X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’; X1is CR1eR1e’, X2is C(O), and X3is CR3eR3e’; X1is NR1g, X2is CH2, and X3is a bond; or X1is NR1l, X2is C(O), and X3is NR3l; Z1and Z2are each independently selected from C(O) and S(O2); R1aand R1a’are each independently selected from H, C1-6alkyl, and -CO(O)-C1-6alkyl; R2aand R2a’are each independently selected from H, C1-6alkyl, C3-6cycloalkyl, -CO(O)- C1-6alkyl, and aryl; R3aand R3a’are each independently selected from H and C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 If Z1and Z2are both C(O), then at least one of R1a, R1a’, R2a, R2a’, R3a, or R3a’is C1-6 alkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl; wherein the aryl of R2aor R2a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; or R1aand R1a’combine to form a cycloalkyl ring or heterocyclic ring, and R2a, R2a’, R3a, and R3a’are each H; orR2aand R2a’combine to form a cycloalkyl ring or heterocyclic ring, and R1a, R1a’, R3a, and R3a’are each H; or R1aand R3acombine to form a cycloalkyl ring, wherein the cycloalkyl ring may be unsubstituted or substituted with one or more C1-6alkyl, and R1a’, R2a, R2a’, and R3a’are each independently selected from the group consisting of H and C1-6alkyl; R1bis C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1bis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R3band R3b’are each independently selected from H and C1-6alkyl; R1c, R1c’, R2c, and R2c’are each independently selected from H and C1-6alkyl; R1d, R1d’, R3d, and R3d’are each independently selected from H and C1-6alkyl; R1e, R1e’, R3e, and R3e’are each independently selected from H and C1-6alkyl; R1gis aryl; wherein the aryl of R1gis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1land R3lare each independently selected from H, C1-6alkyl, and aryl; wherein the aryl of R1lor R3lis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; wherein: if X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’, then: Y1is C(H); Y2is C(H) or N; Y3is C(CF3); Y4is C(H) or N; and Y5is C(H); or Y1is C(R1a2); Y2is C(R2a2); Y3is C(R3a2); Y4is C(R4a2); and Y5is C(R5a2); wherein R1a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R2a2is H, halo, C1-6haloalkyl, alkyl, or NO2;Attn Docket: FATH-023 / 02WO 351027-2511 R3a2is H, halo, C1-6 haloalkyl, SO2-C1-6 alkyl, or NO2; R4a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R5a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; if X1is NR1b, X2is CH2, and X3is CR3bR3b’; then Y1is C(R1b2); Y2is C(R2b2); Y3is C(R3b2); Y4is C(R4b2); and Y5is C(R5b2); wherein R1b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R2b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R3b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R4b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R5b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; if X1is CR1cR1c’, X2is CR2cR2c’, and X3is O; then Y1is C(R1c2); Y2is C(R2c2); Y3is C(R3c2); Y4is C(R4c2); and Y5is C(R5c2); wherein R1c2is H, halo, C1-6haloalkyl, or NO2; R2c2is H, halo, C1-6haloalkyl, or NO2; R3c2is H, halo, C1-6haloalkyl, or NO2; R4c2is H, halo, C1-6haloalkyl, or NO2; R5c2is H, halo, C1-6haloalkyl, or NO2; if X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’, then Y1is C(R1d2); Y2is C(R2d2); Y3is C(R3d2); Y4is C(R4d2); and Y5is C(R5d2); wherein R1d2is H, halo, C1-6haloalkyl, or NO2; R2d2is H, halo, C1-6haloalkyl, or NO2; R3d2is H, halo, C1-6haloalkyl, or NO2; R4d2is H, halo, C1-6haloalkyl, or NO2; R5d2is H, halo, C1-6haloalkyl, or NO2; then Y1is C(R1e2); Y2is C(R2e2); Y3isR2e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R3e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R4e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R5e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; orAttn Docket: FATH-023 / 02WO 351027-2511 R1e2combines with R2e2to form a heteroaryl ring, and R3e2, R4e2, and R5e2are each H; if X1is NR1g, X2is CH2, and X3is a bond; then Y1is C(R1g2); Y2is C(R2g2); Y3is C(R3g2); Y4is C(R4g2); and Y5is C(R5g2); wherein R1g2is H, halo, C1-6haloalkyl, or NO2; R2g2is H, halo, C1-6haloalkyl, or NO2; halo, C1-6haloalkyl, or NO2; R4g2is H, halo, C1-6haloalkyl, or NO2; R5g2is H, halo, C1-6haloalkyl, or NO2; or if X1is NR1l, X2is C(O), and X3is NR3l; then Y1is C(R1l2); Y2is C(R2l2); Y3is C(R3l2); Y4is C(R4l2); and Y5is C(R5l2); wherein R1l2is H, C1-6haloalkyl, or NO2; R2l2is H, C1-6haloalkyl, or NO2; R3l2is H, C1-6haloalkyl, or NO2; R4l2is H, C1-6haloalkyl, or NO2; R5l2is H, C1-6haloalkyl, 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:.

[0101] In some embodiments of the compounds of Formulae (I) and (IA), or the pharmaceutically acceptable salts or tautomers thereof, R3aand R3a’are each C1-6alkyl. In some embodiments, R3aand R3a’are each C1-6alkyl, and R1a, R1a’, R2a, and R2a’are each H. In some embodiments, R2aand R2a’are C3-6cycloalkyl and H respectively. In some embodiments, R2aand R2a’are C3-6cycloalkyl and H respectively, and R1a, R1a’, R3a, and R3a’are each H. In some embodiments, R1aand R1a’are -CO(O)-C1-6alkyl and H respectively. In some embodiments, R1aand R1a’are -CO(O)-C1-6alkyl and H respectively, and R2a, R2a’, R3a, and R3a’are each H. InAttn Docket: FATH-023 / 02WO 351027-2511 some embodiments, R2aand R2a’are -CO(O)-C1-6 alkyl and H respectively. In some embodiments, R2aand R2a’are -CO(O)-C1-6alkyl and H respectively, and R1a, R1a’, R3a, and R3a’are each H. In some embodiments, two or more of R1a, R1a’, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl. In some embodiments, R1aand R1a’, R2aand R2a’, or R3aand R3a’combine to form a cycloalkyl ring or heterocyclic ring. In some embodiments, R1aand R2a, R2aand R3a, or R1aand R3acombine to form a cycloalkyl ring or heterocyclic ring.

[0102] In some embodiments, R1aand R2a, R2aand R3a, or R1aand R3acombine to form a C1-6cycloalkyl ring. In some embodiments, R1aand R2a, R2aand R3a, or R1aand R3acombine to form a C1-8cycloalkyl ring. In some embodiments, R1aand R2a, R2aand R3a, or R1aand R3acombine 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, R1aand R2a, R2aand R3a, or R1aand

[0103] In some embodiments, the compound of Formula (IA), 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 R1a3, R2a3, R3a3, R4a3, and R5a3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and - O-C1-6alkyl. In some embodiments, R1a3, R2a3, R3a3, R4a3, and R5a3are each H. In some embodiments, R4a3is -O-C1-6alkyl. In some embodiments, R4a3is -O-C1-6alkyl, and R1a3, R2a3, R3a3, and R5a3are each H.Attn Docket: FATH-023 / 02WO 351027-2511

[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, R1bis cycloalkyl, aryl, or heteroaryl. In

[0107] In some embodiments, the compound of Formulasome embodiments, the compound of Formulaembodiments, the compound of Formula.

[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:Attn Docket: FATH-023 / 02WO 351027-2511.

[0109] In 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 R1b3, R2b3, R3b3, R4b3, and R5b3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, one of R1b3, R2b3, R3b3, R4b3, or R5b3is F, and the others are each H. In some embodiments, R3b3is F, and R1b3, R2b3, R4b3, and R5b3are each H. In some embodiments, R1b3, R2b3, R3b3, R4b3, and R5b3are 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:Attn Docket: FATH-023 / 02WO 351027-2511.

[0113] In 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:.

[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 R1c3, R2c3, R3c3, R4c3, and R5c3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, R1c3, R2c3, R3c3, R4c3, and R5c3are 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:.

[0116] In some embodiments of the compounds of Formulae (I) and (IC-O), or the pharmaceutically acceptable salts or tautomers thereof, R2cand R2c’are C1-6alkyl and H respectively. In some embodiments, R2cand R2c’are C1-6alkyl and H respectively, and R1candAttn Docket: FATH-023 / 02WO 351027-2511 R1c’are each H. In some embodiments, R1c, R1c’, R2c, and R2c’are each C1-6 alkyl. In some embodiments, the compound of Formula

[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:Attn Docket: FATH-023 / 02WO 351027-2511.

[0121] In some embodiments, R1e, R1e’, R3e, and R3e’are each C1-6alkyl. In some embodiments, the compound of Formula.

[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, R1gis C1-6alkyl-aryl, wherein the C1-6alkyl-aryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy. In some embodiments, the C1-6alkyl-aryl is substituted with alkoxy (e.g., -O-CH3). In some embodiments, R1gis -CH2-aryl, wherein the -CH2-aryl is unsubstituted or substituted with one orAttn Docket: FATH-023 / 02WO 351027-2511 more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, and alkoxy. In some embodiments, the -CH2-aryl is substituted with alkoxy (e.g., -O-CH3). In some embodiments, R1gis -CH2-C6aryl, wherein the -CH2-C6aryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy. In some embodiments, the -CH2-C6aryl is substituted with alkoxy (e.g., -O-CH3). In some embodiments, R1gis -CH2-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 R1g3, R2g3, R3g3, R4g3, and R5g3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, R1g3, R2g3, R3g3, R4g3, and R5g3are 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:.

[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:.Attn Docket: FATH-023 / 02WO 351027-2511

[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 R1h3, R2h3, R3h3, R4h3, and R5h3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, R1h3, R2h3, R3h3, R4h3, and R5h3are 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:.

[0131] In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (Ii-N), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:.

[0132] In some embodiments, the compound of Formula (Ii-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:Attn Docket: FATH-023 / 02WO 351027-2511.

[0133] In some embodiments, the compound of Formula (I) or (Ii-N) is a compound of Formula (Ii-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and R1i3, R2i3, R3i3, R4i3, and R5i3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, R1i3, R2i3, R3i3, R4i3, and R5i3are 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 R1j3, R2j3, R3j3, R4j3, and R5j3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, R1j3, R2j3, R3j3, R4j3, and R5j3are each H.Attn Docket: FATH-023 / 02WO 351027-2511

[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 R1k3, R2k3, R3k3, R4k3, and R5k3are each independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, and -O-C1-6alkyl. In some embodiments, R1k3, R2k3, R3k3, R4k3, and R5k3are each H.

[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:.

[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:Attn Docket: FATH-023 / 02WO 351027-2511.

[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 R1l3, R2l3, R3l3, R4l3, and R5l3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, R1l3, R2l3, R3l3, R4l3, and R5l3are 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, R1aand R1a’, R2aand R2a’, R3aand R3a’, R2band R2b’, R3band R3b’, R1eand R1e’, R3eand R3e’, R1fand R1f’, R2fand R2f’, R1mand R1m’, R2mand R2m’, R3mand R3m’, or R4mand R4m’, when combined to form a cycloalkyl ring or heterocyclic ring, form

[0145] In some embodiments, R1aand R1a’, R2aand R2a’, R3aand R3a’, R2band R2b’, R3band R3b’, R1cand R1c’, R2cand R2c’, R1dand R1d’, R3dand R3d’, R1eand R1e’, R3eand R3e’, R1fand R1f’, R2fand R2f’, R2gand R2g’, R1hand R1h’, R3iand R3i’, R3jand R3j’, R1mand R1m’, R2mand R2m’, R3mand R3m’, or R4mand 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),Attn Docket: FATH-023 / 02WO 351027-2511 (IH-N), (IH-N3), (IH-O), (Ii-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), 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), (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), and (IM), or the pharmaceutically acceptable salts or tautomers thereof, Y1is C(NO2).

[0148] 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), (IH-N3), (IH-O), (Ii-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), and (IM), or the pharmaceutically acceptable salts or tautomers thereof, Y1is C(Cl).

[0149] 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), (IH-N3), (IH-O), (Ii-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), and (IM), or the pharmaceutically acceptable salts or tautomers thereof, Y1is C(F).

[0150] 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), (IH-N3), (IH-O), (Ii-N), (Ii-N3), (IJ-N), (IJ-N3), (IK-N), (IK-N3), (IL-N), (IL-N3), and (IM), or the pharmaceutically acceptable salts or tautomers thereof, Y3is C(CF3).

[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, R1aand R1a’, R1cand R1c’, R1dand R1d’, R1eand R1e’, R1fand R1f’, or R1hand R1h’are each CH3. In some embodiments, R1aand R1a’, R1cand R1c’, R1dand R1d’, R1eand R1e’, R1fand R1f’, or R1hand R1h’are each H.

[0152] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (IF), (IG-N), (IG-N3), and (IG-O), or the pharmaceutically acceptable salts or tautomers thereof, R2aand R2a’, R2band R2b’, R2cand R2c’, R2fand R2f’, or R2gand R2g’are each CH3. In some embodiments, R2aand R2a’, R2band R2b’, R2cand R2c’, R2fand R2f’, or R2gand R2g’are each H.

[0153] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (IF), (IG-N), (IG-N3), and (IG-O), or the pharmaceutically acceptable salts or tautomers thereof, R2aand R2a’are CH3and H respectively, R2band R2b’areAttn Docket: FATH-023 / 02WO 351027-2511 CH3 and H respectively, R2cand R2c’are CH3 and H respectively, R2fand R2f’are CH3 and H respectively, or R2gand R2g’are CH3and H respectively.

[0154] In some embodiments of the compounds of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (ID-O), (ID-S), (ID-SO2), (IE), (Ii-N), (Ii-N3), (IJ-N), and (IJ-N3), or the pharmaceutically acceptable salts or tautomers thereof, R3aand R3a’, R3band R3b’, R3dand R3d’, R3eand R3e’, R3iand R3i’, or R3jand R3j’are each CH3. In some embodiments, R3aand R3a’, R3band R3b’, R3dand R3d’, R3eand R3e’, R3iand R3i’, or R3jand R3j’are each H.

[0155] In some embodiments, the disclosure provides a compound of 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: X1is NR1, X2is CR2, and X3is N or CH; X1is O, X2is CR2, and X3is N; X1is N, X2is NR1, and X3is N; or X1is NR3, X2is N, and X3is N; n is 0 or 1; R1is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R2is selected from H, halo, C1-6haloalkyl, NO2, CN, SO2-C1-6alkyl, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 R3is selected from C4-6 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; RII1, RII2, RII3, RII4, and RII5are each independently selected from H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl.

[0156] In some embodiments, X1is NR1, X2is CR2, and X3is N or CH. In some embodiments, X1is O, X2is CR2, and X3is N. In some embodiments, X1is N, X2is NR1, and X3is N. In some embodiments, X1is NR3, X2is N, and X3is 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 R1a, R1b, R1c, R1d, and R1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, R1a, R1b, R1c, R1d, and R1eare each H. In some embodiments, the compound of FormulaAttn Docket: FATH-023 / 02WO 351027-2511

[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 R1a, R1b, R1c, R1d, and R1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, R1a, R1b, R1c, R1d, and R1eare 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:.

[0164] In some embodiments, the compound of Formula (IIB), or the pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (IIB3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Attn Docket: FATH-023 / 02WO 351027-2511.

[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 R2eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, R2a, R2b, R2c, R2d, and R2eare 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 (IIC), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:.

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

[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 R1a, R1b, R1c, R1d, and R1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, R1a, R1b, R1c, R1d, and R1eare each H. In some embodiments, one of R1a, R1b, R1c, R1d, and R1eis halo, and each of the others is H. In some embodiments, R1cis F, and R1a, R1b, R1d, and R1eare each H.Attn Docket: FATH-023 / 02WO 351027-2511

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

[0170] In some embodiments, the compound of Formula (II) is a compound of Formula (IID), orthe pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and R3 is C4-6 alkyl orphenyl substituted with one or more halo. In some embodiments, R3 is phenyl substituted with F.In some embodiments, R3is phenyl substituted with one instance of F. In some embodiments, R3is C4 alkyl. In some embodiments, R3 is tert-butyl.

[0171] In some embodiments, the compound of Formula. In someembodiments, 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), (IIB3), (IIC), (IIC3), and (IID), or the pharmaceutically acceptable salts ortautomers thereof, RII1 is H or NO2. In some embodiments, RII1 is H. In some embodiments, RII1is NO2.

[0173] In some embodiments of the compounds of Formulae (II), (IIA-C), (IIA-C3), (IIA-N),(IIA-N3), (IIB), (IIB3), (IIC), (IIC3), and (IID), or the pharmaceutically acceptable salts ortautomers thereof, RII3 is H or CF3. In some embodiments, RII3 is H. In some embodiments, RII3is CF3.

[0174] In some embodiments, the disclosure provides a compound of Formula (III):Attn Docket: FATH-023 / 02WO 351027-2511or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1is selected from the group consisting of C3-6cycloalkyl, C1alkyl-C3-6cycloalkyl, aryl, C1alkyl-aryl, heteroaryl, and C1alkyl-heteroaryl; wherein the C3-6cycloalkyl, C1alkyl-C3-6cycloalkyl, aryl, C1alkyl-aryl, heteroaryl, or C1alkyl-heteroaryl of R1is unsubstituted or substituted with halo; RIII1, RIII2, RIII3, RIII4, and RIII5are each independently selected from H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl.

[0175] In some embodiments of the compounds of Formula (III), or the pharmaceutically acceptable salts or tautomers thereof, R1is aryl or C1alkyl-aryl, wherein the aryl or C1alkyl-aryl may be unsubstituted or substituted with one or more halo. In some embodiments, R1is cycloalkyl or C1alkyl-cycloalkyl, wherein the cycloalkyl or C1alkyl-cycloalkyl may be unsubstituted or substituted with one or more halo. In some embodiments, R1is phenyl substituted with one or more F. In some embodiments, R1is benzyl substituted with one or more F. In some embodiments, R1is 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, RIII1is H or NO2. In some embodiments, RIII1is H. In some embodiments, RIII1is NO2.

[0177] In some embodiments of the compounds of Formula (III), or the pharmaceutically acceptable salts or tautomers thereof, RIII2is H, halo, or SO2-C1-6alkyl. In some embodiments, RIII2is H. In some embodiments, RIII2is halo. In some embodiments, RIII2is SO2-C1-6alkyl.

[0178] In some embodiments of the compounds of Formula (III), or the pharmaceutically acceptable salts or tautomers thereof, RIII3is H or CF3. In some embodiments, RIII3is H. In some embodiments, RIII3is CF3.

[0179] In some embodiments, the disclosure provides a compound of Formula (IV):Attn Docket: FATH-023 / 02WO 351027-2511or 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: Y1is CR1, Y2is N, and Y3is NR3; Y1is CR1, Y2is O or S, and Y3is CR3; Y1is N, Y2is CR2, and Y3is O or S; or Y1is O or S, Y2is CR2, and Y3is CR3; R1and R2are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl of R1or R2is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3is H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-C1-6 alkyl, or aryl; wherein the C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl of R3is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or R3combines with RIV2to 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; RIV1is H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of RIV1is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; RIV2is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; or RIV2combines with R3to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one or moreAttn Docket: FATH-023 / 02WO 351027-2511 substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, C1-6 haloalkyl, and - CO(O)-C1-6alkyl.

[0180] In some embodiments, R3and RIV2combine to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring. In some embodiments, R3and RIV2combine to form a C6-10aryl ring. In some embodiments, R3and RIV2combine 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, R3and RIV2combine to form a C3-6cycloalkyl ring. In some embodiments, R3and RIV2combine to form a C3-8cycloalkyl ring. In some embodiments, R3and RIV2combine to form a heterocyclic ring comprising 3 to 8 carbon atoms and 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, R3and RIV2combine 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:.

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

[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 RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare independently selected from H, halo, C1-6alkyl, C1-6Attn Docket: FATH-023 / 02WO 351027-2511 haloalkyl, and -O-C1-6 alkyl. In some embodiments, RIV1cis F, and RIV1a, RIV1b, RIV1d, and RIV1eare each H. In some embodiments, RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare 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:.

[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:.

[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 RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, RIV1cis F, and RIV1a, RIV1b, RIV1d, and RIV1eare each H. In some embodiments, RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare 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:.Attn Docket: FATH-023 / 02WO 351027-2511

[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:.

[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 RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare 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:.

[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:.Attn Docket: FATH-023 / 02WO 351027-2511

[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 RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, RIV1cis F, and RIV1a, RIV1b, RIV1d, and RIV1eare each H. In some embodiments, RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare 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:.

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

[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 RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl. In some embodiments, RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each H.

[0196] In some embodiments of the compounds of Formulae (IV), (IVA), (IVA3), (IVB-O), (IVB-O3), (IVB-S), and (IVB-S3), or the pharmaceutically acceptable salts or tautomers thereof, R1is H or CF3. In some embodiments, R1is H. In some embodiments, R1is CF3.Attn Docket: FATH-023 / 02WO 351027-2511

[0197] In some embodiments of the compounds of Formulae (IV), (IVC-S), (IVC-S3), (IVD), and (IVD3), or the pharmaceutically acceptable salts or tautomers thereof, R2is H or CF3. In some embodiments, R2is H. In some embodiments, R2is CF3.

[0198] In some embodiments of the compounds of Formulae (IV), (IVA), (IVA3), (IVB-O), (IVB-O3), (IVB-S), (IVB-S3), (IVD), and (IVD3), or the pharmaceutically acceptable salts or tautomers thereof, R3is H or C1-6alkyl. In some embodiments, R3is H. In some embodiments, R3is C1-6alkyl.

[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.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.Attn Docket: FATH-023 / 02WO 351027-2511acceptable salt or tautomer of any of the foregoing. In some embodiments, the compound is

[0201] The present disclosure also provides a pharmaceutical composition comprising acompound 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), (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), (IVD3), (V), (VE), (VI), (VII), or (VIII) or apharmaceutically acceptable salt, stereoisomer, or tautomer of any of the foregoing, and apharmaceutically acceptable carrier.

[0202] Unless otherwise stated, structures depicted herein are also meant to includepharmaceutically acceptable salts, tautomers, and stereoisomers thereof. Accordingly,embodiments of the present disclosure are directed to compounds and methods of usingAttn Docket: FATH-023 / 02WO 351027-2511 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), (Ii-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-O3), (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), (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), (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), (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), (Ii-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-O3), (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 by13C or14C, the replacement of a nitrogen atom by15N, or the replacement of an oxygen atom by17O or18O 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 (C1-6alkyl.) In some embodiments, C1-6alkyl 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 (C2-6alkyl). In some embodiments, C2-6alkyl refers to a group with 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl groups includeAttn Docket: FATH-023 / 02WO 351027-2511 methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 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., C1-6alkyl) is bound to another atom to form an ether (e.g., -O-C1-6alkyl), an ester (e.g., -CO(O)-C1-6alkyl), an aryl attached via the alkyl (e.g., -C1-6alkyl-aryl), an aryl substituted with an alkyl (e.g., -aryl-C1-6alkyl), a heteroaryl attached via the alkyl (e.g., -C1-6alkyl-heteroaryl), a heteroaryl substituted with an alkyl (e.g., -heteroaryl-C1-6alkyl).

[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-C1-6alkyl.) In some embodiments, -O-C1-6alkyl 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 (C3-6cycloalkyl.) In some embodiments, C3-6cycloalkyl refers to a group with 3, 4, 5, or 6 carbon atoms. In some embodiments, the C3-6cycloalkyl 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, C3-6cycloalkyl 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-1H-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) carbonAttn Docket: FATH-023 / 02WO 351027-2511 atoms ((C6-C14)aryl), or 6 to 10 (6, 7, 8, 9, or 10) carbon atoms ((C6-C10)aryl). Where the aryl 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 (C6aryl). 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, 7- membered, 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 π-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,Attn Docket: FATH-023 / 02WO 351027-2511 thiazoline, thiazolidine, 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- 1H-pyrrole, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2-one, isothiazolidine-1,1-dioxide, 4,5-dihydro-1H-imidazole, 4,5-dihydrooxazole, oxirane, pyrazolidine, 4H-1,4-thiazine, thiomorpholine, 1,2,3,4-tetrahydropyridine, 1,2,3,4- tetrahydropyrazine, 1,3-oxazinan-2-one, tetrahydro-2H-thiopyran 1,1-dioxide, 7- oxabicyclo[2.2.1]heptane, 1,2-thiazepane-1,1-dioxide, octahydro-2H-quinolizinyl, 1,3- diazabicyclo[2.2.2]octane, 2,3-dihydrobenzo[b][1,4]dioxine, 3-azabicyclo[3.2.1]octane, 8- azaspiro[4.5]decane, 8-oxa-3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.1]heptane, 2,8- diazaspiro[5.5]undecane, 2-azaspiro[5.5]undecane, 3-azaspiro[5.5]undecane, decahydroisoquinoline, 1-oxa-8-azaspiro[4.5]decane, 8-azabicyclo[3.2.1]octane, 1,4’- bipiperidine, azepane, 8-oxa-3-azabicyclo[3.2.1]octane, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine, 1,4-diazepane, phenoxathiine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxine, 4-(piperidin-4-yl)morpholinyl, 3- azaspiro[5.5]undecane, decahydroquinoline, piperazin-2-one, 1-(pyrrolidin-2- ylmethyl)pyrrolidine, 1,3’-bipyrrolidine, and 6,7,8,9-tetrahydro-1H,5H-pyrazolo[1,2- a][1,2]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).

[0211] 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., C1-6alkyl) substituted with one more halogen (e.g., fluoro, chloro, bromo, or iodo radicals.)

[0215] In some embodiments, haloalkyl has 1 to 6 carbon atoms (C1-6haloalkyl) substituted with one more halogen (e.g., fluoro, chloro, bromo, or iodo radicals.) In some embodiments, C1-6haloalkyl refers to a group with 1, 2, 3, 4, 5, or 6 carbon atoms substituted with 1, 2, 3, or moreAttn Docket: FATH-023 / 02WO 351027-2511 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 C1-6haloalkyl include, but are not limited to, trifluoromethyl (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, “C1-6alkyl” (which may also be referred to as C1-C6 alkyl, C1-C6alkyl, or C1-6alkyl) is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[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) theAttn Docket: FATH-023 / 02WO 351027-2511 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), (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), (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), (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 (R)-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 as2H (or D),3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively.

[0223] Certain isotopically-labelled compounds of the various Formulae (e.g., those labeled with3H and14C) 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.Attn Docket: FATH-023 / 02WO 351027-2511

[0224] 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), (Ii-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-O3), (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), (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), (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), (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),Attn Docket: FATH-023 / 02WO 351027-2511 (IH-O), (Ii-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-O3), (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 necessary in 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-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), (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), (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 (WO2015101794A1, 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 trimethylsilylcyanide. The final product was obtained using an acid- base 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.Attn Docket: FATH-023 / 02WO 351027-2511 Scheme 1: General Synthetic SchemeThose 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), (Ii-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-O3), (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), (Ii-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- O3), (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 ofAttn Docket: FATH-023 / 02WO 351027-2511 the present disclosure are further exemplified by specific examples. Unless otherwise specified, all temperatures were 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), (Ii-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-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, Churchill 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), (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), (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), (IVD3), (V), (VE), (VI), (VII), or (VIII), or aAttn Docket: FATH-023 / 02WO 351027-2511 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), (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), (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), (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), (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), (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), (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-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), (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), (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.Attn Docket: FATH-023 / 02WO 351027-2511

[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 single- dose non-reclosable containers. Multiple-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 example, 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:Attn Docket: FATH-023 / 02WO 351027-2511 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):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: X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’; X1is NR1bor O, X2is CR2bR2b’, and X3is CR3bR3b’; X1is CR1cR1c’, X2is CR2cR2c’, and X3is NR3cor O; X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’; X1is CR1eR1e’, X2is C(O), and X3is CR3eR3e’; X1is CR1fR1f’, X2is CR2fR2f’, and X3is a bond; X1is NR1gor O, X2is CR2gR2g’, and X3is a bond; X1is CR1hR1h’, X2is NR2hor O, and X3is a bond; X1is NR1ior O, X2is C(O), and X3is CR3iR3i’; X1is NR1jor O, X2is NR2jor O, and X3is CR3jR3j’; X1is NR1kor O, X2is NR2kor O, and X3is a bond;Z1and Z2are each independently selected from C(O) and S(O2);Attn Docket: FATH-023 / 02WO 351027-2511 R1aand R1a’are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-C1-6alkyl, and aryl; R2aand R2a’are each independently selected from H, C2-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; R3aand R3a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; If Z1and Z2are both C(O), then at least one of R1a, R1a’, R2a, R2a’, R3a, or R3a’is C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl; wherein the aryl of R1a, R1a’, R2a, R2a’, R3a, or R3a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1a, R1a’, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1a, R1a’, R2a, R2a’, R3a, or R3a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1a, R1a’, R2a, R2a’, R3a, or R3a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R2b, R2b’, R3b, and R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1b, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1b, R2b, R2b’, R3b, or R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the aryl of R1b, R2b, R2b’, R3b, or R3b’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl;and R2c’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1c, R1c’, R2c, or R2c’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1d, R1d’, R3d, and R3d’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1d, R1d’, R3d, or R3d’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1e, R1e’, R3e, and R3e’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1e, R1e’, R3e, or R3e’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1e, R1e’, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1e, R1e’, R3e, or R3e’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1e, R1e’, R3e, or R3e’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1f, R1f’, R2f, and R2f’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1f, R1f’, R2f, or R2f’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; orAttn Docket: FATH-023 / 02WO 351027-2511 two or more of R1f, R1f’, R2f, and R2f’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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1f, R1f’, R2f, or R2f’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1f, R1f’, R2f, or R2f’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R2gand R2g’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R2gor R2g’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1hand R1h’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1hor R1h’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R3iand R3i’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R3ior R3i’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R3jand R3j’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R3jor R3j’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, and R4m’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the aryl of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1bis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1bis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; or two or more of R1b, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1b, R2b, R2b’, R3b, or R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1b, R2b, R2b’, R3b, or R3b’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3cis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1cis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1gis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the C1-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, or heteroaryl of R1gis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R2his H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2his unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1iis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1iis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1jand R2jare each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1jor R2jis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1kand R2kare each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1kor R2kis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1land R3lare each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1lor R3lis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; n is 0 or 1; wherein: if X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’, then:C(R5a2); whereinAttn Docket: FATH-023 / 02WO 351027-2511 R1a2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3a2is H, halo, C1-6haloalkyl, NO2, or CN;haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1a2combines with R2a2to 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 C1-6alkyl, and R3a2, R4a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2a2combines with R3a2to 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 C1-6alkyl, and R1a2, R4a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3a2combines with R4a2to 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 C1-6alkyl, and R1a2, R2a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4a2combines with R5a2to 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 C1-6alkyl, and R1a2, R2a2, and R3a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1bor O, X2is CR2bR2b’, and X3is CR3bR3b’, then: Y1is C(R1b2) or N; Y2is C(R2b2) or N; Y3is C(R3b2) or N; Y4is C(R4b2) or N; and Y5is C(R5b2) or N; orwherein R1b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1b2combines with R2b2to form an arylheteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclicAttn Docket: FATH-023 / 02WO 351027-2511 ring may be unsubstituted or substituted with C1-6 alkyl or OH, and R3b2, R4b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; or R2b2combines with R3b2to 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 C1-6alkyl or OH, and R1b2, R4b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; or R3b2combines with R4b2to 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 C1-6alkyl or OH, and R1b2, R2b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; or R4b2combines with R5b2to 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 C1-6alkyl or OH, and R1b2, R2b2, and R3b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; R2b2’is H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R3b2’is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4b2’is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; 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 C1-6alkyl or halo, and R4b2’is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R4b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, 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 C1-6alkyl or halo, and R2b2’is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the C1-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, or heteroaryl of R2b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; if X1is CR1cR1c’, X2is CR2cR2c’, and X3is O or NR3c; then Y1is C(R1c2) or N; Y2is C(R2c2) or N; Y3is C(R3c2) or N; Y4is C(R4c2) or N; and Y5is C(R5c2) or N; wherein R1c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1c2combines with R2c2to 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 C1-6alkyl, and R3c2, R4c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2c2combines with R3c2to 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 C1-6alkyl, and R1c2, R4c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3c2combines with R4c2to 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 C1-6alkyl, and R1c2, R2c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4c2combines with R5c2to 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 C1-6alkyl, and R1c2, R2c2, and R3c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’, then Y1is C(R1d2) or N; Y2is C(R2d2); Y3is C(R3d2) or N; Y4is C(R4d2) or N; and Y5is C(R5d2) or N; wherein R1d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 R5d2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or R1d2combines with R2d2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3d2, R4d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2d2combines with R3d2to 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 C1-6alkyl, and R1d2, R4d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3d2combines with R4d2to 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 C1-6alkyl, and R1d2, R2d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4d2combines with R5d2to 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 C1-6alkyl, and R1d2, R2d2, and R3d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1eR1e’, X2is C(O), and X3is CR3eR3e’, then: ; orN; and Y5is C(R5e2’) or N, wherein at least one of Y1, Y2, Y3, Y4, and Y5is N; wherein R1e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1e2is Cl; R2e2is H; R3e2is C1-6haloalkyl, NO2, or SO2-C1-6alkyl; R4e2is H; and R5e2is H; or R1e2is NO2; R2e2is H; R3e2is C1-6haloalkyl; R4e2is H; and R5e2is H; or R1e2combines with R2e2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3e2, R4e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 R2e2combines with R3e2to 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 C1-6alkyl, and R1e2, R4e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3e2combines with R4e2to 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 C1-6alkyl, and R1e2, R2e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4e2combines with R5e2to 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 C1-6alkyl, and R1e2, R2e2, and R3e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R1e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R2e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R3e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R4e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R5e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; or R1e2’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 C1-6alkyl, and R3e2’, R4e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2e2’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 C1-6alkyl, and R1e2’, R4e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3e2’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 C1-6alkyl, and R1e2’, R2e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4e2’combines with R5e2’to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclicAttn Docket: FATH-023 / 02WO 351027-2511 ring may be unsubstituted or substituted with C1-6 alkyl, and R1e2’, R2e2’, and R3e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1fR1f’, X2is CR2fR2f’, and X3is a bond; then Y1is C(R1f2) or N; Y2is C(R2f2) or N; Y3is C(R3f2) or N; Y4is C(R4f2) or N; and Y5is C(R5f2) or N; wherein R1f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1f2combines with R2f2to 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 C1-6alkyl, and R3f2, R4f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2f2combines with R3f2to 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 C1-6alkyl, and R1f2, R4f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3f2combines with R4f2to 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 C1-6alkyl, and R1f2, R2f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4f2combines with R5f2to 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 C1-6alkyl, and R1f2, R2f2, and R3f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1gor O, X2is CR2gR2g’, and X3is a bond; then Y1is C(R1g2) or N; Y2is C(R2g2) or N; Y3is C(R3g2) or N; Y4is C(R4g2) or N; and Y5is C(R5g2) or N; wherein R1g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; orAttn Docket: FATH-023 / 02WO 351027-2511 R1g2combines with R2g2to 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 C1-6alkyl, and R3g2, R4g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2g2combines with R3g2to 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 C1-6alkyl, and R1g2, R4g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3g2combines with R4g2to 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 C1-6alkyl, and R1g2, R2g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4g2combines with R5g2to 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 C1-6alkyl, and R1g2, R2g2, and R3g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1hR1h’, X2is NR2hor O, and X3is a bond; then Y1is C(R1h2) or N; Y2is C(R2h2) or N; Y3is C(R3h2) or N; Y4is C(R4h2) or N; and Y5is C(R5h2) or N; wherein R1h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1h2combines with R2h2to 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 C1-6alkyl, and R3h2, R4h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2h2combines with R3h2to 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 C1-6alkyl, and R1h2, R4h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 R3h2combines with R4h2to 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 C1-6alkyl, and R1h2, R2h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4h2combines with R5h2to 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 C1-6alkyl, and R1h2, R2h2, and R3h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1ior O, X2is C(O), and X3is CR3iR3i’; then Y1is C(R1i2) or N; Y2is C(R2i2) or N; Y3is C(R3i2) or N; Y4is C(R4i2) or N; and Y5is C(R5i2) or N; whereinC1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1i2combines with R2i2to 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 C1-6alkyl, and R3i2, R4i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2i2combines with R3i2to 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 C1-6alkyl, and R1i2, R4i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3i2combines with R4i2to 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 C1-6alkyl, and R1i2, R2i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4i2combines with R5i2to 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 C1-6alkyl, and R1i2, R2i2, and R3i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN;Attn Docket: FATH-023 / 02WO 351027-2511 if X1is NR1jor O, X2is NR2jor O, and X3is CR3jR3j’; then Y1is C(R1j2) or N; Y2is C(R2j2) or N; Y3is C(R3j2) or N; Y4is C(R4j2) or N; and Y5is C(R5j2) or N; wherein R1j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1j2combines with R2j2to 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 C1-6alkyl, and R3j2, R4j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2j2combines with R3j2to 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 C1-6alkyl, and R1j2, R4j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3j2combines with R4j2to 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 C1-6alkyl, and R1j2, R2j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4j2combines with R5j2to 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 C1-6alkyl, and R1j2, R2j2, and R3j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1kor O, X2is NR2kor O, and X3is a bond; then Y1is C(R1k2) or N; Y2is C(R2k2) or N; Y3is C(R3k2) or N; Y4is C(R4k2) or N; and Y5is C(R5k2) or N; wherein R1k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1k2combines with R2k2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring mayAttn Docket: FATH-023 / 02WO 351027-2511 be unsubstituted or substituted with C1-6 alkyl, and R3k2, R4k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2k2combines with R3k2to 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 C1-6alkyl, and R1k2, R4k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3k2combines with R4k2to 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 C1-6alkyl, and R1k2, R2k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4k2combines with R5k2to 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 C1-6alkyl, and R1k2, R2k2, and R3k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; then Y1is C(R1l2) or N; Y2is C(R2l2)or N; wherein R1l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1l2combines with R2l2to 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 C1-6alkyl, and R3l2, R4l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2l2combines with R3l2to 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 C1-6alkyl, and R1l2, R4l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3l2combines with R4l2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring mayAttn Docket: FATH-023 / 02WO 351027-2511 be unsubstituted or substituted with C1-6 alkyl, and R1l2, R2l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4l2combines with R5l2to 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 C1-6alkyl, and R1l2, R2l2, and R3l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or then Y1 1m2is C(R ) or N; Y2is C(R2m2) or N; Y3is C(R3m2) or N; Y4is C(R4m2) or N; and Y5is C(R5m2) or N; wherein R1m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1m2combines with R2m2to 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 C1-6alkyl, and R3m2, R4m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2m2combines with R3m2to 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 C1-6alkyl, and R1m2, R4m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3m2combines with R4m2to 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 C1-6alkyl, and R1m2, R2m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4m2combines with R5m2to 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 C1-6alkyl, and R1m2, R2m2, and R3m2are each independently selected from H, halo, C1-6haloalkyl, 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 amountAttn Docket: FATH-023 / 02WO 351027-2511 of a compound of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’; X1is NR1b, X2is CH2, and X3is CR3bR3b’; X1is CR1cR1c’, X2is CR2cR2c’, and X3is O; X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’; is CR3eR3e’;bond; or X1is NR1l, X2is C(O), and X3is NR3l; Z1and Z2are each independently selected from C(O) and S(O2); R1aand R1a’are each independently selected from H, C1-6alkyl, and -CO(O)-C1-6alkyl; R2aand R2a’are each independently selected from H, C1-6alkyl, C3-6cycloalkyl, -CO(O)- C1-6alkyl, and aryl; R3aand R3a’are each independently selected from H and C1-6alkyl; If Z1and Z2are both C(O), then at least one of R1a, R1a’, R2a, R2a’, R3a, or R3a’is C1-6alkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl; wherein the aryl of R2aor R2a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; or R1aand R1a’combine to form a cycloalkyl ring or heterocyclic ring, and R2a, R2a’, R3a, and R3a’are each H; orR2aand R2a’combine to form a cycloalkyl ring or heterocyclic ring, and R1a, R1a’, R3a, and R3a’are each H; or R1aand R3acombine to form a cycloalkyl ring, wherein the cycloalkyl ring may be unsubstituted or substituted with one or more C1-6alkyl, and R1a’, R2a, R2a’, and R3a’are each independently selected from the group consisting of H and C1-6alkyl;R1bis C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1bis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R3band R3b’are each independently selected from H and C1-6alkyl; R1c, R1c’, R2c, and R2c’are each independently selected from H and C1-6alkyl; R1d, R1d’, R3d, and R3d’are each independently selected from H and C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 R1e, R1e’, R3e, and R3e’are each independently selected from H and C1-6 alkyl; R1gis aryl; wherein the aryl of R1gis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1land R3lare each independently selected from H, C1-6alkyl, and aryl; wherein the aryl of R1lor R3lis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; wherein: if X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’, then:wherein R1a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R2a2is H, halo, C1-6haloalkyl,alkyl, or NO2; R3a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R4a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R5a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; if X1is NR1b, X2is CH2, and X3is CR3bR3b’; then Y1is C(R1b2); Y2is C(R2b2); Y3is C(R3b2); Y4is C(R4b2); and Y5is C(R5b2); wherein R1b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R2b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R3b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R4b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R5b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; if X1is CR1cR1c’, X2is CR2cR2c’, and X3is O; then Y1is C(R1c2); Y2is C(R2c2); Y3isand Y5is C(R5c2); wherein R1c2is H, halo, C1-6haloalkyl, or NO2; R2c2is H, halo, C1-6haloalkyl, or NO2; R3c2is H, halo, C1-6haloalkyl, or NO2; R4c2is H, halo, C1-6haloalkyl, or NO2; R5c2is H, halo, C1-6haloalkyl, or NO2;Attn Docket: FATH-023 / 02WO 351027-2511 if X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’, then Y1is C(R1d2); Y2is C(R2d2); Y3is C(R3d2); Y4is C(R4d2); and Y5is C(R5d2); wherein R1d2is H, halo, C1-6haloalkyl, or NO2; R2d2is H, halo, C1-6haloalkyl, or NO2; R3d2is H, halo, C1-6haloalkyl, or NO2; R4d2is H, halo, C1-6haloalkyl, or NO2; R5d2is H, halo, C1-6haloalkyl, or NO2; if X1is CR1eR1e’, X2is C(O), and X3is CR3eR3e’; then Y1is C(R1e2); Y2is C(R2e2); Y3is C(R3e2); Y4is C(R4e2); and Y5is C(R5e2); wherein R1e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R2e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R3e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R4e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R5e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; or R1e2combines with R2e2to form a heteroaryl ring, and R3e2, R4e2, and R5e2are each H; if X1is NR1g, X2is CH2, and X3is a bond; then Y1is C(R1g2); Y2is C(R2g2); Y3is C(R3g2); Y4is C(R4g2); and Y5is C(R5g2); wherein R1g2is H, halo, C1-6haloalkyl, or NO2; R2g2is H, halo, C1-6haloalkyl, or NO2; R3g2is H, halo, C1-6haloalkyl, or NO2; R4g2is H, halo, C1-6haloalkyl, or NO2; R5g2is H, halo, C1-6haloalkyl, or NO2; or if X1is NR1l, X2is C(O), and X3is NR3l; then Y1is C(R1l2); Y2is C(R2l2); Y3is C(R3l2); Y4is C(R4l2); and Y5is C(R5l2); wherein R1l2is H, C1-6haloalkyl, or NO2; R2l2is H, C1-6haloalkyl, or NO2; R3l2is H, C1-6haloalkyl, or NO2; R4l2is H, C1-6haloalkyl, or NO2; R5l2is H, C1-6haloalkyl, or NO2.Attn Docket: FATH-023 / 02WO 351027-2511

[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 Y1is C(NO2).

[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 Y3is 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 R1aand R1a’, R1cand R1c’, R1dand R1d’, R1eand R1e’, R1fand R1f’, or R1hand R1h’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 R3aand R3a’, R3band R3b’, R3dand R3d’, or R3eand R3e’, R3iand R3i’, or R3jand R3j’are each CH3.Attn Docket: FATH-023 / 02WO 351027-2511

[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 R1bis 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):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: X1is NR1, X2is CR2, and X3is N or CH; X1is O, X2is CR2, and X3is N; X1is N, X2is NR1, and X3is N; or X1is NR3, X2is N, and X3is N; n is 0 or 1; R1is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R2is selected from H, halo, C1-6haloalkyl, NO2, CN, SO2-C1-6alkyl, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the C1-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, or heteroaryl of R3is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; RVI1, RVI2, RVI3, RVI4, and RVI5are each independently selected from H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl.

[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 R3is C4-6alkyl 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 RVI1is H or NO2. In some embodiments, RVI1is H. In some embodiments, RVI1is 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 RVI3is H or CF3. In some embodiments, RVI3is H. In some embodiments, RVI3is 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):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1is selected from the group consisting of C3-6cycloalkyl, C1alkyl-C3-6cycloalkyl, aryl, C1alkyl-aryl, heteroaryl, and C1alkyl-heteroaryl; wherein the C3-6cycloalkyl, C1alkyl-C3-6cycloalkyl, aryl, C1alkyl-aryl, heteroaryl, or C1alkyl-heteroaryl of R1is unsubstituted or substituted with halo;independently selected from H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl.Attn Docket: FATH-023 / 02WO 351027-2511

[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 R1is aryl or C1alkyl-aryl, wherein the aryl or C1alkyl-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 RVII1is H or NO2. In some embodiments, RVII1is H. In some embodiments, RVII1is 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 RVII2is H, halo, or SO2-C1-6alkyl. In some embodiments, RVII2is H. In some embodiments, RVII2is halo. In some embodiments, RVII2is SO2-C1-6alkyl.

[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 RVII3is H or CF3. In some embodiments, RVII3is H. In some embodiments, RVII3is 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):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: Y1is CR1, Y2is N, and Y3is NR3; Y1is CR1, Y2is O or S, and Y3is CR3; Y1is N, Y2is CR2, and Y3is O or S; orAttn Docket: FATH-023 / 02WO 351027-2511 Y1is O or S, Y2is CR2, and Y3is CR3; R1and R2are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl of R1or R2is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3is H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl; wherein the C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl of R3is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or R3combines with RVIII2to 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; RVIII1is H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of RVIII1is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; RVIII2is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; or RVIII2combines with R3to 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, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl.

[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 R1is H or CF3. In some embodiments, R1is H. In some embodiments, R1is 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 R2is H or CF3. In some embodiments, R2is H. In some embodiments, R2is CF3.Attn Docket: FATH-023 / 02WO 351027-2511

[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 R3is H or C1-6alkyl. In some embodiments, R3is H. In some embodiments, R3is C1-6alkyl.

[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 compoundacceptable 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), (IH-O), (Ii-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-O3), (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), (Ii-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-Attn Docket: FATH-023 / 02WO 351027-2511 O3), (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), (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), (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), (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), (Ii-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-O3), (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), (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), (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), (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 ofAttn Docket: FATH-023 / 02WO 351027-2511 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), (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), (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), (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), (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), (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), (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 carrier, 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), (IH-N), (IH-N3), (IH-O), (Ii-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-O3), (IVB-S), (IVB-S3), (IVC-S), (IVC-S3), (IVD), (IVD3), (V), (VE),Attn Docket: FATH-023 / 02WO 351027-2511 (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), (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), (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), (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), (Ii-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-O3), (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), (IH- N3), (IH-O), (Ii-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-O3), (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,Attn Docket: FATH-023 / 02WO 351027-2511 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 IC50value for the target that is lower than an IC50value 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, phenotype or response, for example growth or proliferation of cells such as tumor cells, is inhibited by 50%. IC50values can be estimated from an appropriate dose-response curve, for example, by eye or by using appropriate curve fitting or statistical software. More accurately, IC50values may be determined using non-linear regression analysis. IC50values can beAttn Docket: FATH-023 / 02WO 351027-2511 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 IC50of the compound for HPD is less than the IC50for SPR. In some embodiments, the SPR:HPD IC50ratio 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 IC50ratio of the compound may be referred to as the “selectivity” of the compound for SPR and HPD.

[0285] In some embodiments, the SPR:HPD IC50ratio of the compound is at least 1. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 2. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 5. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 10. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 30. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 30. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 40. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 50. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 60. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 70. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 80. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 90. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 100. InAttn Docket: FATH-023 / 02WO 351027-2511 some embodiments, the SPR:HPD IC50 ratio of the compound is at least 500. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 1000. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 10000. In some embodiments, the SPR:HPD IC50ratio of the compound is at least 100000.

[0286] In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater 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 μM, greater than 500 μM, 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 IC50greater than 600 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 700 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 800 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 900 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 1000 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 1100 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 1200 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 1300 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 1400 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 1500 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 1600 nM. In someAttn Docket: FATH-023 / 02WO 351027-2511 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 IC50greater than 1800 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 1900 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 2000 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 2100 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 2200 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 2300 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 2400 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 2500 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 2600 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 2700 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 2800 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 2900 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 3000 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 5000 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 10000 nM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 100 μM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 500 μM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 1 mM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 10 mM. In some embodiments, a compound of the disclosure inhibits SPR with an in vitro IC50greater than 100 mM.

[0288] In some embodiments, a compound of the disclosure inhibits HPD more than nitisinone. For example, in some embodiments, the IC50of the compound for HPD (HPDcompoundIC50) is less than the IC50of nitisinone for HPD (HPDnitisinoneIC50). In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio 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 leastAttn Docket: FATH-023 / 02WO 351027-2511 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: HPDcompoundIC50ratio is at least 1. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 2. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 5. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 10. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 30. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 30. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 40. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 50. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 60. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 70. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 80. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 90. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 100. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 500. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 1000. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 10000. In some embodiments, the HPDnitisinone: HPDcompoundIC50ratio is at least 100000.

[0290] In some embodiments, a compound of the disclosure inhibits SPR less than nitisinone. For example, in some embodiments, the IC50of the compound for SPR (SPRcompoundIC50) is greater than the IC50of nitisinone for SPR (SPRnitisinoneIC50). In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio 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, atAttn Docket: FATH-023 / 02WO 351027-2511 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:SPRnitisinoneIC50ratio is at least 1. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 2. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 5. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 10. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 30. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 30. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 40. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 50. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 60. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 70. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 80. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 90. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 100. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 500. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 1000. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio is at least 10000. In some embodiments, the SPRcompound:SPRnitisinoneIC50ratio 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.Attn Docket: FATH-023 / 02WO 351027-2511

[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 disclosure, 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 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 27-fold, a 28- fold, 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 100- fold, 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,Attn Docket: FATH-023 / 02WO 351027-2511 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 27- fold, 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 90- fold, 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 subjectAttn Docket: FATH-023 / 02WO 351027-2511 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-tandem 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 beAttn Docket: FATH-023 / 02WO 351027-2511 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 neurocognitive function.Attn Docket: FATH-023 / 02WO 351027-2511

[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 neurocognitive function.

[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 neurocognitive function.

[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 neurocognitive function.

[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 errorAttn Docket: FATH-023 / 02WO 351027-2511 of metabolism. In some embodiments, the condition is Parkinson’s disease. In some embodiments, the condition is Lewy 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 attention-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 CoQ10 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%.Attn Docket: FATH-023 / 02WO 351027-2511

[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.Attn Docket: FATH-023 / 02WO 351027-2511

[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 I. 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.Attn Docket: FATH-023 / 02WO 351027-2511

[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 someAttn Docket: FATH-023 / 02WO 351027-2511 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 (RDA) as determined by the Food and Nutrition 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%,Attn Docket: FATH-023 / 02WO 351027-2511 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:These reference values are adapted from: Wu G. Dietary protein intake and human health. Food & Function.2016;7(3):1251-1265. doi:10.1039 / 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: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 / 10.17226 / 11537, which is hereby incorporated by reference in its entirety.Attn Docket: FATH-023 / 02WO 351027-2511

[0335] 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 allowance (RDA) 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%,Attn Docket: FATH-023 / 02WO 351027-2511 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 phenylalanine. 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 350Attn Docket: FATH-023 / 02WO 351027-2511 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 thanAttn Docket: FATH-023 / 02WO 351027-2511 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 thanAttn Docket: FATH-023 / 02WO 351027-2511 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.Attn Docket: FATH-023 / 02WO 351027-2511

[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 ofAttn Docket: FATH-023 / 02WO 351027-2511 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 dietaryAttn Docket: FATH-023 / 02WO 351027-2511 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 / day, 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 acidsAttn Docket: FATH-023 / 02WO 351027-2511 or a salt thereof. In 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 non- essential 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 non- essential 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 someAttn Docket: FATH-023 / 02WO 351027-2511 embodiments, the dietary product comprises 9 essential amino acids or salts thereof and 9 non- essential 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-phenylalanine, 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 β-Attn Docket: FATH-023 / 02WO 351027-2511 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.Attn Docket: FATH-023 / 02WO 351027-2511 Herbicidal Compositions

[0388] In some embodiments, the disclosure provides an herbicidal composition comprising a compound of Formulae (I), (IA), (IA3), (IB-N), (IB-N3), (IB-O), (IC-N), (IC-N3), (IC-O), (ID-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), (IVD3), (V), (VE), (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), (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), (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 comprises fluroxypyr-meptyl.

[0396] In some embodiments, the herbicidal composition further comprising a second herbicide. In some embodiments, the second herbicide does not inhibit HPD. In some embodiments, the second herbicide shows synergistic effects with the herbicidal composition.Attn Docket: FATH-023 / 02WO 351027-2511

[0397] In some embodiments, 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 acetyl-coenzyme 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. Methods of Treating Weeds

[0398] In some embodiments, the disclosure provides a method of controlling a weed, the method comprising contacting a weed with an herbi...

Claims

Attn Docket: FATH-023 / 02WO 351027-2511 CLAIMS WHAT IS CLAIMED IS:

1. A compound of 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, or all together form an aryl ring or heteroaryl ring, wherein: X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’; X1is NR1bor O, X2is CR2bR2b’, and X3is CR3bR3b’; X1is CR1cR1c’, X2is CR2cR2c’, and X3is NR3cor O;Z1and Z2are each independently selected from C(O) and S(O2); R1aand R1a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl;Attn Docket: FATH-023 / 02WO 351027-2511 R2aand R2a’are each independently selected from H, C2-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; R3aand R3a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; If Z1and Z2are both C(O), then at least one of R1a, R1a’, R2a, R2a’, R3a, or R3a’is C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl; wherein the aryl of R1a, R1a’, R2a, R2a’, R3a, or R3a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1a, R1a’, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1a, R1a’, R2a, R2a’, R3a, or R3a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1a, R1a’, R2a, R2a’, R3a, or R3a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R2b, R2b’, R3b, and R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, 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, C1-6 alkyl, C1-6 haloalkyl, and - CO(O)-C1-6alkyl; or two or more of R1b, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1b, R2b, R2b’, R3b, or R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1b, R2b, R2b’, R3b, or R3b’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 R1c, R1c’, R2c, and R2c’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1c, R1c’, R2c, or R2c’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1d, R1d’, R3d, and R3d’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1d, R1d’, R3d, or R3d’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1e, R1e’, R3e, and R3e’are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1e, R1e’, R3e, or R3e’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; or two or more of R1e, R1e’, 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, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl, and any uncombined R1e, R1e’, R3e, or R3e’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1e, R1e’, R3e, or R3e’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1f, R1f’, R2f, and R2f’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1f, R1f’, R2f, or R2f’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; or two or more of R1f, R1f’, R2f, and R2f’combine to form a cycloalkyl ring or heterocyclic ring, wherein the cycloalkyl ring or heterocyclic ring may be unsubstituted or substituted with one orAttn Docket: FATH-023 / 02WO 351027-2511 more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl, and any uncombined R1f, R1f’, R2f, or R2f’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1f, R1f’, R2f, or R2f’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R2gand R2g’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R2gor R2g’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6 alkyl; R1hand R1h’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1hor R1h’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R3iand R3i’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R3ior R3i’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6 alkyl; R3jand R3j’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R3jor R3j’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, and R4m’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the aryl of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1m, R1m’, 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, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1bis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1bis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; or two or more of R1b, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1b, R2b, R2b’, R3b, or R3b’are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -CO(O)-C1-6 alkyl, and aryl; wherein the aryl of R1b, R2b, R2b’, R3b, or R3b’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3cis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1cis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1gis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1gis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R2his H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2his unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1iis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1iis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, and alkoxy; R1jand R2jare each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1jor R2jis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1kand R2kare each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1kor R2kis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, and alkoxy; R1land R3lare each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1lor R3lis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; n is 0 or 1; wherein: if X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’, then: Y1is C(H); Y2is C(H) or N; Y3is C(CF3); Y4is C(H) or N; and Y5is C(H); orAttn Docket: FATH-023 / 02WO 351027-2511 Y1is C(R1a2) or N; Y2is C(R2a2); Y3is C(R3a2) or N; Y4is C(R4a2); and Y5is C(R5a2); wherein R1a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3a2is H, halo, C1-6haloalkyl, NO2, or CN; R4a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1a2combines with R2a2to 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 C1-6alkyl, and R3a2, R4a2, and R5a2are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R2a2combines with R3a2to 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 C1-6alkyl, and R1a2, R4a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3a2combines with R4a2to 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 C1-6alkyl, and R1a2, R2a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4a2combines with R5a2to 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 C1-6alkyl, and R1a2, R2a2, and R3a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1bor O, X2is CR2bR2b’, and X3is CR3bR3b’, then: Y1is C(R1b2) or N; Y2is C(R2b2) or N; Y3is C(R3b2) or N; Y4is C(R4b2) or N; and Y5is C(R5b2) or N; or Y1is C(O); Y2is N(R2b2’); Y3is C(R3b2’); Y4is C(R4b2’); and Y5is N; wherein R1b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 R4b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1b2combines with R2b2to 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 C1-6alkyl or OH, and R3b2, R4b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; or R2b2combines with R3b2to 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 C1-6alkyl or OH, and R1b2, R4b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; orto 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 C1-6alkyl or OH, and R1b2, R2b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; or R4b2combines with R5b2to 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 C1-6alkyl or OH, and R1b2, R2b2, and R3b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; R2b2’is H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R3b2’is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4b2’is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; 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 C1-6alkyl or halo, and R4b2’is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R4b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, 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 C1-6alkyl or halo, and R2b2’is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; if X1is CR1cR1c’, X2is CR2cR2c’, and X3is O or NR3c; then Y1is C(R1c2) or N; Y2is C(R2c2) or N; Y3is C(R3c2) or N; Y4is C(R4c2) or N; and Y5is C(R5c2) or N; wherein R1c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1c2combines with R2c2to 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 C1-6alkyl, and R3c2, R4c2, and R5c2are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R2c2combines with R3c2to 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 C1-6alkyl, and R1c2, R4c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3c2combines with R4c2to 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 C1-6alkyl, and R1c2, R2c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 R4c2combines with R5c2to 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 C1-6alkyl, and R1c2, R2c2, and R3c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’, then Y1is C(R1d2) or N; Y2is C(R2d2); Y3is C(R3d2) or N; Y4is C(R4d2) or N; and Y5is C(R5d2) or N; wherein R1d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5d2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or R1d2combines with R2d2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3d2, R4d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2d2combines with R3d2to 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 C1-6alkyl, and R1d2, R4d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3d2combines with R4d2to 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 R1d2, R2d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4d2combines with R5d2to 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 C1-6alkyl, and R1d2, R2d2, and R3d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; then: ; Y4is C4e2 5 5e2(R ); and Y is C(R ); or Y1is C(R1e2’) or N; Y2is C(R2e2’) or N; Y3is C(R3e2’) or N; Y4is C(R4e2’) or N; and Y5is C(R5e2’) or N, wherein at least one of Y1, Y2, Y3, Y4, and Y5is N; whereinAttn Docket: FATH-023 / 02WO 351027-2511 R1e2is H, F, CN, or SO2-C1-6alkyl; R2e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1e2is Cl; R2e2is H; R3e2is C1-6haloalkyl, NO2, or SO2-C1-6alkyl; R4e2is H; and R5e2is H; or R1e2is NO2; R2e2is H; R3e2is C1-6haloalkyl; R4e2is H; and R5e2is H; or R1e2combines with R2e2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3e2, R4e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2e2combines with R3e2to 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 C1-6alkyl, and R1e2, R4e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3e2combines with R4e2to 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 C1-6alkyl, and R1e2, R2e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4e2combines with R5e2to 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 C1-6alkyl, and R1e2, R2e2, and R3e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R1e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R2e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R3e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R4e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R5e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; or R1e2’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 ringAttn Docket: FATH-023 / 02WO 351027-2511 may be unsubstituted or substituted with C1-6alkyl, and R3e2’, R4e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2e2’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 C1-6alkyl, and R1e2’, R4e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3e2’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 C1-6alkyl, and R1e2’, R2e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4e2’combines with R5e2’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 C1-6alkyl, and R1e2’, R2e2’, and R3e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1fR1f’, X2is CR2fR2f’, and X3is a bond; then Y1is C(R1f2) or N; Y2is C(R2f2) or N; Y3is C(R3f2) or N; Y4is C(R4f2) or N; and Y5is C(R5f2) or N; wherein R1f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5f2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or R1f2combines with R2f2to 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 C1-6alkyl, and R3f2, R4f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2f2combines with R3f2to 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 C1-6alkyl, and R1f2, R4f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 R3f2combines with R4f2to 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 C1-6alkyl, and R1f2, R2f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4f2combines with R5f2to 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 C1-6alkyl, and R1f2, R2f2, and R3f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1gor O, X2is CR2gR2g’, and X3is a bond; then Y1is C(R1g2) or N; Y2is C(R2g2) or N; Y3is C(R3g2) or N; Y4is C(R4g2) or N; and Y5is C(R5g2) or N; wherein R1g2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1g2combines with R2g2to 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 C1-6alkyl, and R3g2, R4g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2g2combines with R3g2to 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 C1-6alkyl, and R1g2, R4g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3g2combines with R4g2to 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 C1-6alkyl, and R1g2, R2g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4g2combines with R5g2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beAttn Docket: FATH-023 / 02WO 351027-2511 unsubstituted or substituted with C1-6alkyl, and R1g2, R2g2, and R3g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1hR1h’, X2is NR2hor O, and X3is a bond; then Y1is C(R1h2) or N; Y2is C(R2h2) or N; Y3is C(R3h2) or N; Y4is C(R4h2) or N; and Y5is C(R5h2) or N; wherein R1h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1h2combines with R2h2to 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 C1-6alkyl, and R3h2, R4h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2h2combines with R3h2to 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 C1-6alkyl, and R1h2, R4h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3h2combines with R4h2to 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 C1-6alkyl, and R1h2, R2h2, and R5h2are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R4h2combines with R5h2to 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 C1-6alkyl, and R1h2, R2h2, and R3h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1ior O, X2is C(O), and X3is CR3iR3i’; then Y1is C(R1i2) or N; Y2is C(R2i2) or N; Y3or N; Y4is C(R4i2) or N; and Y5is C(R5i2) or N; wherein R1i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 R4i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1i2combines with R2i2to 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 C1-6alkyl, and R3i2, R4i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2i2combines with R3i2to 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 C1-6alkyl, and R1i2, R4i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3i2combines with R4i2to 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 C1-6alkyl, and R1i2, R2i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4i2combines with R5i2to 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 C1-6alkyl, and R1i2, R2i2, and R3i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1jor O, X2is NR2jor O, and X3is CR3jR3j’; then Y1is C(R1j2) or N; Y2is C(R2j2) or N; Y3is C(R3j2) or N; Y4is C(R4j2) or N; and Y5is C(R5j2) or N; wherein R1j2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1j2combines with R2j2to 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 C1-6alkyl, and R3j2, R4j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 R2j2combines with R3j2to 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 C1-6alkyl, and R1j2, R4j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3j2combines with R4j2to 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 C1-6alkyl, and R1j2, R2j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4j2combines with R5j2to 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 R1j2, R2j2, and R3j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1kor O, X2is NR2kor O, and X3is a bond; then Y1is C(R1k2) or N; Y2is Cor N; Y3is C(R3k2) or N; Y4is C(R4k2) or N; and Y5is C(R5k2) or N; wherein R1k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1k2combines with R2k2to 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 C1-6alkyl, and R3k2, R4k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2k2combines with R3k2to 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 C1-6alkyl, and R1k2, R4k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3k2combines with R4k2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beAttn Docket: FATH-023 / 02WO 351027-2511 unsubstituted or substituted with C1-6alkyl, and R1k2, R2k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4k2combines with R5k2to 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 C1-6alkyl, and R1k2, R2k2, and R3k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; then Y1is C(R1l2) or N; Y2is C(R2l2) oror N; wherein R1l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3l2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1l2combines with R2l2to 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 C1-6alkyl, and R3l2, R4l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2l2combines with R3l2to 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 C1-6alkyl, and R1l2, R4l2, and R5l2are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R3l2combines with R4l2to 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 C1-6alkyl, and R1l2, R2l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4l2combines with R5l2to 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 C1-6alkyl, and R1l2, R2l2, and R3l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 if X1is CR1mR1m’, X2is CR2mR2m’, and X3is CR3mR3m’-CR4mR4m’; then Y1is C(R1m2) or N; Y2is C(R2m2) or N; Y3is C(R3m2) or N; Y4is C(R4m2) or N; and Y5is C(R5m2) or N; wherein R1m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1m2combines with R2m2to 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 C1-6alkyl, and R3m2, R4m2, and R5m2are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R2m2combines with R3m2to 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 C1-6alkyl, and R1m2, R4m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3m2combines with R4m2to 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 C1-6alkyl, and R1m2, R2m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4m2combines with R5m2to 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 C1-6alkyl, and R1m2, R2m2, and R3m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’; X1is NR1b, X2is CH2, and X3is CR3bR3b’; X1is CR1cR1c’, X2is CR2cR2c’, and X3is O; X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’;Attn Docket: FATH-023 / 02WO 351027-2511X1is NR1g, X2is CH2, and X3is a bond; or X1is NR1l, X2is C(O), and X3is NR3l; Z1and Z2are each independently selected from C(O) and S(O2); R1aand R1a’are each independently selected from H, C1-6alkyl, and -CO(O)-C1-6alkyl; R2aand R2a’are each independently selected from H, C1-6alkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; R3aand R3a’are each independently selected from H and C1-6alkyl; If Z1and Z2are both C(O), then at least one of R1a, R1a’, R2a, R2a’, R3a, or R3a’is C1-6alkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl; wherein the aryl of R2aor R2a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; or R1aand R1a’combine to form a cycloalkyl ring or heterocyclic ring, and R2a, R2a’, R3a, and R3a’are each H; orR2aand R2a’combine to form a cycloalkyl ring or heterocyclic ring, and R1a, R1a’, R3a, and R3a’are each H; or R1aand R3acombine to form a cycloalkyl ring, wherein the cycloalkyl ring may be unsubstituted or substituted with one or more C1-6alkyl, and R1a’, R2a, R2a’, and R3a’are each independently selected from the group consisting of H and C1-6alkyl; R1bis C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6 alkyl, aryl, C1-6 alkyl-aryl, or heteroaryl of R1bis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R3band R3b’are each independently selected from H and C1-6alkyl;selected from H and C1-6alkyl; R1d, R1d’, R3d, and R3d’are each independently selected from H and C1-6alkyl; R1e, R1e’, R3e, and R3e’are each independently selected from H and C1-6alkyl; R1gis aryl; wherein the aryl of R1gis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy;Attn Docket: FATH-023 / 02WO 351027-2511 R1land R3lare each independently selected from H, C1-6alkyl, and aryl; wherein the aryl of R1lor R3lis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; wherein: if X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’, then: Y1is C(H); Y2is C(H) or N; Y3is C(CF3); Y4is C(H) or N; and Y5is C(H); or Y1is C(R1a2); Y2is C(R2a2); Y3is C(R3a2); Y4is C(R4a2); and Y5is C(R5a2); wherein R1a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R2a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R3a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R4a2is H, halo, C1-6 haloalkyl, SO2-C1-6 alkyl, or NO2; R5a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; if X1is NR1b, X2is CH2, and X3is CR3bR3b’; then Y1is C(R1b2); Y2is C(R2b2); Y3is C(R3b2); Y4is C(R4b2); and Y5is C(R5b2); wherein R1b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R2b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R3b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R4b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R5b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; if X1is CR1cR1c’, X2is CR2cR2c’, and X3is O; then Y1is C(R1c2); Y2is C(R2c2); Y3is C(R3c2); Y4is C(R4c2); and Y5is C(R5c2); wherein R1c2is H, halo, C1-6haloalkyl, or NO2; R2c2is H, halo, C1-6haloalkyl, or NO2; R3c2is H, halo, C1-6haloalkyl, or NO2; R4c2is H, halo, C1-6haloalkyl, or NO2; R5c2is H, halo, C1-6haloalkyl, or NO2; if X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’, then Y1is C(R1d2); Y2is C(R2d2); Y3is C(R3d2); Y4is C(R4d2); and Y5is C(R5d2); wherein R1d2is H, halo, C1-6haloalkyl, or NO2; R2d2is H, halo, C1-6haloalkyl, or NO2;Attn Docket: FATH-023 / 02WO 351027-2511 R3d2is H, halo, C1-6haloalkyl, or NO2; R4d2is H, halo, C1-6haloalkyl, or NO2; R5d2is H, halo, C1-6haloalkyl, or NO2; if X1is CR1eR1e’, X2is C(O), and X3is CR3eR3e’; then Y1is C(R1e2); Y2is C(R2e2); Y3is C(R3e2); Y4is C(R4e2); and Y5is C(R5e2); wherein R1e2is H, F, CN, or SO2-C1-6alkyl; R2e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R3e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R4e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R5e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; or R1e2combines with R2e2to form a heteroaryl ring, and R3e2, R4e2, and R5e2are each H; if X1is NR1g, X2is CH2, and X3is a bond; then Y1is C(R1g2); Y2is C(R2g2); Y3is C(R3g2); Y4is C(R4g2); and Y5is C(R5g2); wherein R1g2is H, halo, C1-6haloalkyl, or NO2; R2g2is H, halo, C1-6haloalkyl, or NO2; R3g2is H, halo, C1-6haloalkyl, or NO2; R4g2is H, halo, C1-6haloalkyl, or NO2; R5g2is H, halo, C1-6haloalkyl, or NO2; or if X1is NR1l, X2is C(O), and X3is NR3l; then Y1is C(R1l2); Y2is C(R2l2); Y3is C(R3l2); Y4is C(R4l2); and Y5is C(R5l2); wherein R1l2is H, C1-6haloalkyl, or NO2; R2l2is H, C1-6haloalkyl, or NO2; R3l2is H, C1-6haloalkyl, or NO2; R4l2is H, C1-6haloalkyl, or NO2; R5l2is H, C1-6haloalkyl, or NO2.Attn Docket: FATH-023 / 02WO 351027-2511 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 R1a3, R2a3, R3a3, R4a3, and R5a3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

5. The compound of claim 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1a3, R2a3, R3a3, R4a3, and R5a3are 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:Attn Docket: FATH-023 / 02WO 351027-2511.

7. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IB-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein R1b3, R2b3, R3b3, R4b3, and R5b3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1b3, R2b3, R3b3, R4b3, and R5b3are 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:.Attn Docket: FATH-023 / 02WO 351027-2511 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 R1c3, R2c3, R3c3, R4c3, and R5c3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1c3, R2c3, R3c3, R4c3, and R5c3are 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:Attn Docket: FATH-023 / 02WO 351027-2511.

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 (ID-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:Attn Docket: FATH-023 / 02WO 351027-2511.

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 tautomer thereof, 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:Attn Docket: FATH-023 / 02WO 351027-2511.

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 R1g3, R2g3, R3g3, R4g3, and R5g3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1g3, R2g3, R3g3, R4g3, and R5g3are 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:.Attn Docket: FATH-023 / 02WO 351027-2511 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 R1h3, R2h3, R3h3, R4h3, and R5h3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1h3, R2h3, R3h3, R4h3, and R5h3are each H.

26. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IH-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Attn Docket: FATH-023 / 02WO 351027-2511.

27. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (Ii-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 (Ii-N3), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:wherein R1i3, R2i3, R3i3, R4i3, and R5i3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1i3, R2i3, R3i3, R4i3, and R5i3are each H.Attn Docket: FATH-023 / 02WO 351027-2511 30. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IJ-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:wherein R1j3, R2j3, R3j3, R4j3, and R5j3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

32. The compound of claim 31, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1j3, R2j3, R3j3, R4j3, and R5j3are 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:Attn Docket: FATH-023 / 02WO 351027-2511.

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 R1k3, R2k3, R3k3, R4k3, and R5k3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

35. The compound of claim 34, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1k3, R2k3, R3k3, R4k3, and R5k3are 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:.Attn Docket: FATH-023 / 02WO 351027-2511 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:wherein R1l3, R2l3, R3l3, R4l3, and R5l3are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

38. The compound of claim 37, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1l3, R2l3, R3l3, R4l3, and R5l3are 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:.

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 1.Attn Docket: FATH-023 / 02WO 351027-2511 42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Y1is C(NO2).

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Y3is C(CF3).

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 R1aand R1a’, R1cand R1c’, R1dand R1d’, R1eand R1e’, R1fand R1f’, or R1hand R1h’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 R1aand R1a’, R1cand R1c’, R1dand R1d’, R1eand R1e’, R1fand R1f’, or R1hand R1h’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 R2aand R2a’, R2band R2b’, R2cand R2c’, R2fand R2f’, or R2gand R2g’are each CH3.

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 R2aand R2a’are CH3and H respectively, R2band R2b’are CH3 and H respectively, R2cand R2c’are CH3 and H respectively, R2fand R2f’are CH3and H respectively, or R2gand R2g’are CH3and 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 R2aand R2a’, R2band R2b’, R2cand R2c’, R2fand R2f’, or R2gand 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 R3aand R3a’, R3band R3b’, R3dand R3d’, R3eand R3e’, R3iand R3i’, or R3jand R3j’are each CH3.Attn Docket: FATH-023 / 02WO 351027-2511 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 R3aand R3a’, R3band R3b’, R3dand R3d’, R3eand R3e’, R3iand R3i’, or R3jand R3j’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 R1bis cycloalkyl or heteroaryl.

52. A compound of 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: X1is NR1, X2is CR2, and X3is N or CH; X1is O, X2is CR2, and X3is N; X1is N, X2is NR1, and X3is N; or X1is NR3, X2is N, and X3is N; n is 0 or 1; R1is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R2is selected from H, halo, C1-6haloalkyl, NO2, CN, SO2-C1-6alkyl, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3is selected from C4-6alkyl, 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; RII1, RII2, RII3, RII4, and RII5are each independently selected from H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl.

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 R1a, R1b, R1c, R1d, and R1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.Attn Docket: FATH-023 / 02WO 351027-2511 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:.

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 R1a, R1b, R1c, R1d, and R1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

57. The compound of claim 52, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IIB), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:.Attn Docket: FATH-023 / 02WO 351027-2511 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:wherein R2a, R2b, R2c, R2d, and R2eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

59. The compound of claim 58, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2a, R2b, R2c, R2d, and R2eare each H.

60. The compound of claim 52, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IIC), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:.

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:Attn Docket: FATH-023 / 02WO 351027-2511wherein R1a, R1b, R1c, R1d, and R1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

62. The compound of any one of claims 54, 56, and 61, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1a, R1b, R1c, R1d, and R1eare 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:.

64. The compound of claim 63, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R3is C4-6alkyl 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 RII1is NO2.

66. The compound of any one of claims 52-65, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RII3is CF3.

67. A compound of Formula (III):Attn Docket: FATH-023 / 02WO 351027-2511or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1is selected from the group consisting of C3-6cycloalkyl, C1alkyl-C3-6cycloalkyl, aryl, C1alkyl-aryl, heteroaryl, and C1alkyl-heteroaryl; wherein the C3-6cycloalkyl, C1alkyl-C3-6cycloalkyl, aryl, C1alkyl-aryl, heteroaryl, or C1alkyl-heteroaryl of R1is unsubstituted or substituted with halo; RIII1, RIII2, RIII3, RIII4, and RIII5are each independently selected from H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl.

68. The compound of claim 67, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1is aryl or C1alkyl-aryl, wherein the aryl or C1alkyl-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 RIII1is H or NO2.

70. The compound of any one of claims 67-69, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RIII2is H, halo, or SO2-C1-6alkyl.

71. The compound of any one of claims 67-70, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RIII3is CF3.

72. A compound of Formula (IV):Attn Docket: FATH-023 / 02WO 351027-2511or 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: Y1is CR1, Y2is N, and Y3is NR3; Y1is CR1, Y2is O or S, and Y3is CR3; Y1is N, Y2is CR2, and Y3is O or S; or Y1is O or S, Y2is CR2, and Y3is CR3; R1and R2are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl of R1or R2is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3is H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl; wherein the C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl of R3is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or R3combines with RIV2to 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; RIV1is H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of RIV1is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; RIV2is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; orAttn Docket: FATH-023 / 02WO 351027-2511 RIV2combines with R3to 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl.

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:.

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:wherein RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

75. The compound of claim 72, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of Formula (IVB-O), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Attn Docket: FATH-023 / 02WO 351027-2511.

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:wherein RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

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:.

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:Attn Docket: FATH-023 / 02WO 351027-2511whereinRIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

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:.

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:wherein RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.Attn Docket: FATH-023 / 02WO 351027-2511 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:.

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:wherein RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl, and -O-C1-6alkyl.

83. The compound of any one of claims 74, 76, 78, 80, or 82, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RIV1a, RIV1b, RIV1c, RIV1d, and RIV1eare each H.

84. The compound of any one of claims 72-78 and 83, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1is CF3.

85. The compound of any one of claims 72 and 79-84, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2is CF3.Attn Docket: FATH-023 / 02WO 351027-2511 86. The compound of any one of claims 72-78 and 81-85, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R3is C1-6alkyl.

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. ,Attn Docket: FATH-023 / 02WO 351027-251189.pharmaceutically acceptable salt,stereoisomer, or tautomer thereof.

90. A compound of the structure, or a pharmaceuticallyacceptable salt, stereoisomer, or tautomer thereof.Attn Docket: FATH-023 / 02WO 351027-2511 91. 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):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: X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’; X1is NR1bor O, X2is CR2bR2b’, and X3is CR3bR3b’; X1is CR1cR1c’, X2is CR2cR2c’, and X3is NR3cor O; X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’;bond; X1is NR1gor O, X2is CR2gR2g’, and X3is a bond; X1is CR1hR1h’, X2is NR2hor O, and X3is a bond; X1is NR1ior O, X2is C(O), and X3is CR3iR3i’; X1is NR1jor O, X2is NR2jor O, and X3is CR3jR3j’; X1is NR1kor O, X2is NR2kor O, and X3is a bond; X1is NR1lor O, X2is C(O), and X3is NR3lor O; or X1is CR1mR1m’, X2is CR2mR2m’, and X3is CR3mR3m’-CR4mR4m’; Z1and Z2are each independently selected from C(O) and S(O2);Attn Docket: FATH-023 / 02WO 351027-2511 R1aand R1a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; R2aand R2a’are each independently selected from H, C2-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; R3aand R3a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; If Z1and Z2are both C(O), then at least one of R1a, R1a’, R2a, R2a’, R3a, or R3a’is C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl; wherein the aryl of R1a, R1a’, R2a, R2a’, R3a, or R3a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6 alkyl; or two or more of R1a, R1a’, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1a, R1a’, R2a, R2a’, R3a, or R3a’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1a, R1a’, R2a, R2a’, R3a, or R3a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R2b, R2b’, R3b, and R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6 cycloalkyl, -CO(O)-C1-6 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, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; or two or more of R1b, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1b, R2b, R2b’, R3b, or R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the aryl of R1b, R2b, R2b’, R3b, or R3b’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1c, R1c’, R2c, and R2c’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1c, R1c’, R2c, or R2c’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - alkyl; R1d, R1d’, R3d, and R3d’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1d, R1d’, R3d, or R3d’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - alkyl; R1e, R1e’, R3e, and R3e’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1e, R1e’, R3e, or R3e’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; or two or more of R1e, R1e’, 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, C1-6 alkyl, C1-6 haloalkyl, and - CO(O)-C1-6alkyl, and any uncombined R1e, R1e’, R3e, or R3e’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1e, R1e’, R3e, or R3e’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1f, R1f’, R2f, and R2f’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the aryl of R1f, R1f’, R2f, or R2f’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; or two or more of R1f, R1f’, R2f, and R2f’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, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl, and any uncombined R1f, R1f’, R2f, or R2f’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1f, R1f’, R2f, or R2f’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6 alkyl; R2gand R2g’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R2gor R2g’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1hand R1h’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1hor R1h’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6 alkyl; R3iand R3i’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R3ior R3i’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R3jand R3j’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the aryl of R3jor R3j’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, and R4m’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or two or more of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, 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, C1-6 alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1m, R1m’, R2m, R2m’, R3m, R3m’, R4m, or R4m’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R1bis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1bis 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 R1b, 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl, and any uncombined R1b, R2b, R2b’, R3b, or R3b’are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; wherein the aryl of R1b, R2b, R2b’, R3b, or R3b’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3cis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1cis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1gis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1gis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R2his H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2his unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, and alkoxy; R1iis H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1iis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1jand R2jare each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1jor R2jis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1kand R2kare each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, aryl, C1-6 alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1kor R2kis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1land R3lare each independently selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1lor R3lis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy;Attn Docket: FATH-023 / 02WO 351027-2511 n is 0 or 1; wherein: if X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’, then: Y1is C(H); Y2is C(H) or N; Y3is C(CF3); Y4is C(H) or N; and Y5is C(H); or Y1is C(R1a2) or N; Y2is C(R2a2); Y3is C(R3a2) or N; Y4is C(R4a2); and Y5is C(R5a2); wherein R1a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3a2is H, halo, C1-6haloalkyl, NO2, or CN; R4a2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5a2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or R1a2combines with R2a2to 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 C1-6alkyl, and R3a2, R4a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2a2combines with R3a2to 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 C1-6alkyl, and R1a2, R4a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3a2combines with R4a2to 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 C1-6alkyl, and R1a2, R2a2, and R5a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4a2combines with R5a2to 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 C1-6alkyl, and R1a2, R2a2, and R3a2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1bor O, X2is CR2bR2b’, and X3is CR3bR3b’, then: Y1is C(R1b2) or N; Y2is C(R2b2) or N; Y3is C(R3b2) or N; Y4is C(R4b2) or N; and Y5is C(R5b2) or N; orAttn Docket: FATH-023 / 02WO 351027-2511 Y1is C(O); Y2is N(R2b2’); Y3is C(R3b2’); Y4is C(R4b2’); and Y5is N; wherein R1b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5b2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1b2combines with R2b2to 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 C1-6alkyl or OH, and R3b2, R4b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; or R2b2combines with R3b2to 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 C1-6alkyl or OH, and R1b2, R4b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; or R3b2combines with R4b2to 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 C1-6alkyl or OH, and R1b2, R2b2, and R5b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; or R4b2combines with R5b2to 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 or OH, and R1b2, R2b2, and R3b2are each independently selected from H, C1-6alkyl, halo, C1-6haloalkyl, NO2, and CN; R2b2’is H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R3b2’is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4b2’is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; 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 ringAttn Docket: FATH-023 / 02WO 351027-2511 may be unsubstituted or substituted with C1-6alkyl or halo, and R4b2’is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R4b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, 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 C1-6alkyl or halo, and R2b2’is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2b2’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; if X1is CR1cR1c’, X2is CR2cR2c’, and X3is O or NR3c; then Y1is C(R1c2) or N; Y2is C(R2c2) or N; Y3is C(R3c2) or N; Y4is C(R4c2) or N; and Y5is C(R5c2) or N; wherein R1c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5c2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1c2combines with R2c2to 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 C1-6alkyl, and R3c2, R4c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2c2combines with R3c2to 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 C1-6alkyl, and R1c2, R4c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3c2combines with R4c2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beAttn Docket: FATH-023 / 02WO 351027-2511 unsubstituted or substituted with C1-6alkyl, and R1c2, R2c2, and R5c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4c2combines with R5c2to 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 C1-6alkyl, and R1c2, R2c2, and R3c2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’, then Y1is C(R1d2) or N; Y2is wherein R1d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3d2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5d2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1d2combines with R2d2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3d2, R4d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2d2combines with R3d2to 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 C1-6alkyl, and R1d2, R4d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3d2combines with R4d2to 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 C1-6alkyl, and R1d2, R2d2, and R5d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4d2combines with R5d2to 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 C1-6alkyl, and R1d2, R2d2, and R3d2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1eR1e’, X2is C(O), and X3is CR3eR3e’, then: Y1is C(R1e2); Y2is C(R2e2); Y3is C(R3e2); Y4is C(R4e2); and Y5is C(R5e2); orAttn Docket: FATH-023 / 02WO 351027-2511or N; and Y5is C(R5e2’) or N, wherein at least one of Y1, Y2, Y3, Y4, and Y5is N; wherein R1e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5e2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1e2is Cl; R2e2is H; R3e2is C1-6haloalkyl, NO2, or SO2-C1-6alkyl; R4e2is H; and R5e2is H; or R1e2is NO2; R2e2is H; R3e2is C1-6haloalkyl; R4e2is H; and R5e2is H; or R1e2combines with R2e2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring and R3e2, R4e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2e2combines with R3e2to 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 C1-6alkyl, and R1e2, R4e2, and R5e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3e2combines with R4e2to 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 C1-6alkyl, and R1e2, R2e2, and R5e2are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R4e2combines with R5e2to 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 C1-6alkyl, and R1e2, R2e2, and R3e2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R1e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R2e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R3e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R4e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; R5e2’is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; orAttn Docket: FATH-023 / 02WO 351027-2511 R1e2’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 C1-6alkyl, and R3e2’, R4e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2e2’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 C1-6alkyl, and R1e2’, R4e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3e2’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 C1-6 alkyl, and R1e2’, R2e2’, and R5e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4e2’combines with R5e2’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 C1-6alkyl, and R1e2’, R2e2’, and R3e2’are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1fR1f’, X2is CR2fR2f’, and X3is a bond; then Y1is C(R1f2) or N; Y2is C(R2f2) or N; Y3is C(R3f2) or N; Y4is C(R4f2) or N; and Y5is C(R5f2) or N; wherein R1f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3f2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R4f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5f2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1f2combines with R2f2to 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 C1-6alkyl, and R3f2, R4f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2f2combines with R3f2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beAttn Docket: FATH-023 / 02WO 351027-2511 unsubstituted or substituted with C1-6alkyl, and R1f2, R4f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3f2combines with R4f2to 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 C1-6alkyl, and R1f2, R2f2, and R5f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4f2combines with R5f2to 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 C1-6alkyl, and R1f2, R2f2, and R3f2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1gor O, X2is CR2gR2g’, and X3is a bond; then Y1is C(R1g2) or N; Y2is C(R2g2) or N; Y3is C(R3g2) or N; Y4is C(R4g2) or N; and Y5is C(R5g2) or N; wherein R1g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5g2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1g2combines with R2g2to 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 C1-6alkyl, and R3g2, R4g2, and R5g2are each independently selected from H, halo, C1-6 haloalkyl, NO2, and CN; or R2g2combines with R3g2to 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 C1-6alkyl, and R1g2, R4g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3g2combines with R4g2to 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 C1-6alkyl, and R1g2, R2g2, and R5g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 R4g2combines with R5g2to 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 C1-6alkyl, and R1g2, R2g2, and R3g2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is CR1hR1h’, X2is NR2hor O, and X3is a bond; then Y1is C(R1h2) or N; Y2is C(R2h2) or N; Y3is C(R3h2) or N; Y4is C(R4h2) or N; and Y5is C(R5h2) or N; wherein R1h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl;alkyl; R4h2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5h2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or R1h2combines with R2h2to 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 C1-6alkyl, and R3h2, R4h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2h2combines with R3h2to 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 C1-6alkyl, and R1h2, R4h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3h2combines with R4h2to 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 C1-6alkyl, and R1h2, R2h2, and R5h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4h2combines with R5h2to 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 C1-6alkyl, and R1h2, R2h2, and R3h2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1ior O, X2is C(O), and X3is CR3iR3i’; then Y1is C(R1i2) or N; Y2is C(R2i2) or N; Y3is C(R3i2) or N; Y4is C(R4i2) or N; and Y5is C(R5i2) or N; wherein R1i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl;Attn Docket: FATH-023 / 02WO 351027-2511 R2i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5i2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1i2combines with R2i2to 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 C1-6alkyl, and R3i2, R4i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2i2combines with R3i2to 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 R1i2, R4i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3i2combines with R4i2to 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 C1-6alkyl, and R1i2, R2i2, and R5i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4i2combines with R5i2to 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 C1-6alkyl, and R1i2, R2i2, and R3i2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1jor O, X2is NR2jor O, and X3is CR3jR3j’; then Y1is C(R1j2) or N; Y2is C(R2j2) or N; Y3is C(R3j2) or N; Y4is C(R4j2) or N; and Y5is C(R5j2) or N; wherein R1j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5j2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1j2combines with R2j2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beAttn Docket: FATH-023 / 02WO 351027-2511 unsubstituted or substituted with C1-6alkyl, and R3j2, R4j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2j2combines with R3j2to 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 C1-6alkyl, and R1j2, R4j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3j2combines with R4j2to 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 C1-6alkyl, and R1j2, R2j2, and R5j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4j2combines with R5j2to 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 C1-6alkyl, and R1j2, R2j2, and R3j2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1kor O, X2is NR2kor O, and X3is a bond; then Y1is C(R1k2) or N; Y2is C(R2k2) or N; Y3is C(R3k2) or N; Y4is C(R4k2) or N; and Y5is C(R5k2) or N; wherein R1k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4k2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5k2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; or R1k2R2k2to 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 C1-6alkyl, and R3k2, R4k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2k2R3k2to 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 C1-6alkyl, and R1k2, R4k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; orAttn Docket: FATH-023 / 02WO 351027-2511 R3k2combines with R4k2to 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 C1-6alkyl, and R1k2, R2k2, and R5k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4k2combines with R5k2to 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 C1-6alkyl, and R1k2, R2k2, and R3k2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; if X1is NR1lor O, X2is C(O), and X3is NR3lor O; thenN; Y3is C(R3l2) or N; Y4is C(R4l2) or N; and Y5is C(R5l2) or N; wherein R1l2is H, halo, C1-6 haloalkyl, NO2, CN, or SO2-C1-6 alkyl; R2l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5l2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1l2combines with R2l2to 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 C1-6alkyl, and R3l2, R4l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2l2combines with R3l2to 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 C1-6alkyl, and R1l2, R4l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3l2combines with R4l2to 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 C1-6alkyl, and R1l2, R2l2, and R5l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4l2combines with R5l2to form an aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring, wherein the aryl ring, heteroaryl ring, cycloalkyl ring, or heterocyclic ring may beAttn Docket: FATH-023 / 02WO 351027-2511 unsubstituted or substituted with C1-6alkyl, and R1l2, R2l2, and R3l2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or if X1is CR1mR1m’, X2is CR2mR2m’, and X3is CR3mR3m’-CR4mR4m’; then Y1is C(R1m2) or N; Y2is C(R2m2) or N; Y3is C(R3m2) or N; Y4is C(R4m2) or N; and Y5is C(R5m2) or N; wherein R1m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R2m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R3m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R4m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; R5m2is H, halo, C1-6haloalkyl, NO2, CN, or SO2-C1-6alkyl; or R1m2combines with R2m2to 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 C1-6alkyl, and R3m2, R4m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R2m2combines with R3m2to 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 C1-6alkyl, and R1m2, R4m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R3m2combines with R4m2to 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 R1m2, R2m2, and R5m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN; or R4m2combines with R5m2to 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 C1-6alkyl, and R1m2, R2m2, and R3m2are each independently selected from H, halo, C1-6haloalkyl, NO2, and CN.

93. The method of claim 92, wherein: X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’; X1is NR1b, X2is CH2, and X3is CR3bR3b’;Attn Docket: FATH-023 / 02WO 351027-2511 X1is CR1cR1c’, X2is CR2cR2c’, and X3is O;X1is NR1g, X2is CH2, and X3is a bond; or X1is NR1l, X2is C(O), and X3is NR3l; Z1and Z2are each independently selected from C(O) and S(O2); R1aand R1a’are each independently selected from H, C1-6alkyl, and -CO(O)-C1-6alkyl; R2aand R2a’are each independently selected from H, C1-6alkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl; R3aand R3a’are each independently selected from H and C1-6alkyl; If Z1and Z2are both C(O), then at least one of R1a, R1a’, R2a, R2a’, R3a, or R3a’is C1-6 alkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl; wherein the aryl of R2aor R2a’is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl; or R1aand R1a’combine to form a cycloalkyl ring or heterocyclic ring, and R2a, R2a’, R3a, and R3a’are each H; orR2aand R2a’combine to form a cycloalkyl ring or heterocyclic ring, and R1a, R1a’, R3a, and R3a’are each H; or R1aand R3acombine to form a cycloalkyl ring, wherein the cycloalkyl ring may be unsubstituted or substituted with one or more C1-6alkyl, and R1a’, R2a, R2a’, and R3a’are each independently selected from the group consisting of H and C1-6 alkyl;R1bis C1-6 alkyl, C3-6 cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1bis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R3band R3b’are each independently selected from H and C1-6alkyl; R1c, R1c’, R2c, and R2c’are each independently selected from H and C1-6alkyl; R1d, R1d’, R3d, and R3d’are each independently selected from H and C1-6alkyl; R1e, R1e’, R3e, and R3e’are each independently selected from H and C1-6alkyl; R1gis aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the aryl of R1gis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; R1land R3lare each independently selected from H, C1-6alkyl, and aryl; wherein the aryl of R1lor R3lis unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, and alkoxy; wherein: if X1is CR1aR1a’, X2is CR2aR2a’, and X3is CR3aR3a’, then: Y1is C(H); Y2is C(H) or N; Y3is C(CF3); Y4is C(H) or N; and Y5is C(H); or Y1is C(R1a2); Y2is C(R2a2); Y3is C(R3a2); Y4is C(R4a2); and Y5is C(R5a2); wherein R1a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R2a2is H, halo, C1-6 haloalkyl, SO2-C1-6 alkyl, or NO2; R3a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R4a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R5a2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; if X1is NR1b, X2is CH2, and X3is CR3bR3b’; then Y1is C(R1b2); Y2is C(R2b2); Y3is C(R3b2); Y4is C(R4b2); and Y5is C(R5b2); wherein R1b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R2b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R3b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R4b2is H, halo, C1-6haloalkyl, SO2-C1-6alkyl, or NO2; R5b2is H, halo, C1-6 haloalkyl, SO2-C1-6 alkyl, or NO2; if X1is CR1cR1c’, X2is CR2cR2c’, and X3is O; then Y1is C(R1c2); Y2is C(R2c2); Y3is wherein R1c2is H, halo, C1-6haloalkyl, or NO2; R2c2is H, halo, C1-6haloalkyl, or NO2; R3c2is H, halo, C1-6haloalkyl, or NO2; R4c2is H, halo, C1-6haloalkyl, or NO2; R5c2is H, halo, C1-6haloalkyl, or NO2; if X1is CR1dR1d’, X2is O, S, or S(O2), and X3is CR3dR3d’, then Y1is C(R1d2); Y2is C(R2d2); Y3is C(R3d2); Y4is C(R4d2); and Y5is C(R5d2); whereinAttn Docket: FATH-023 / 02WO 351027-2511 R1d2is H, halo, C1-6haloalkyl, or NO2; R2d2is H, halo, C1-6haloalkyl, or NO2; R3d2is H, halo, C1-6haloalkyl, or NO2; R4d2is H, halo, C1-6haloalkyl, or NO2; R5d2is H, halo, C1-6haloalkyl, or NO2; if X1is CR1eR1e’, X2is C(O), and X3is CR3eR3e’; then Y1is C(R1e2); Y2is C(R2e2); Y3is C(R3e2); Y4is C(R4e2); and Y5is C(R5e2); wherein R1e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R2e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R3e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; R4e2is H, halo, C1-6 haloalkyl, CN, SO2-C1-6 alkyl, or NO2; R5e2is H, halo, C1-6haloalkyl, CN, SO2-C1-6alkyl, or NO2; or R1e2combines with R2e2to form a heteroaryl ring, and R3e2, R4e2, and R5e2are each H; if X1is NR1g, X2is CH2, and X3is a bond; then Y1is C(R1g2); Y2is C(R2g2); Y3is C(R3g2); Y4is C(R4g2); and Y5is C(R5g2); wherein R1g2is H, halo, C1-6haloalkyl, or NO2; R2g2is H, halo, C1-6haloalkyl, or NO2; R3g2is H, halo, C1-6haloalkyl, or NO2; R4g2is H, halo, C1-6haloalkyl, or NO2; R5g2is H, halo, C1-6 haloalkyl, or NO2; or if X1is NR1l, X2is C(O), and X3is NR3l; then Y1is C(R1l2); Y2is C(R2l2); Y3is C(R3l2); Y4is C(R4l2); and Y5is C(R5l2); wherein R1l2is H, C1-6haloalkyl, or NO2; R2l2is H, C1-6haloalkyl, or NO2; R3l2is H, C1-6haloalkyl, or NO2; R4l2is H, C1-6haloalkyl, or NO2; R5l2is H, C1-6haloalkyl, or NO2.Attn Docket: FATH-023 / 02WO 351027-2511 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 Y1is C(NO2).

97. The method of any one of claims 92-96, wherein Y3is C(CF3).

98. The method of any one of claims 92-97, wherein R1aand R1a’, R1cand R1c’, R1dand R1d’, R1eand R1e’, R1fand R1f’, or R1hand R1h’are each CH3.

99. The method of any one of claims 92-98, wherein R3aand R3a’, R3band R3b’, R3dand R3d’, R3eand R3e’, R3iand R3i’, or R3jand R3j’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 R1bis 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):Attn Docket: FATH-023 / 02WO 351027-2511or 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: X1is NR1, X2is CR2, and X3is N or CH; X1is O, X2is CR2, and X3is N; X1is N, X2is NR1, and X3is N; or X1is NR3, X2is N, and X3is N; n is 0 or 1; R1is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R1is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R2is selected from H, halo, C1-6haloalkyl, NO2, CN, SO2-C1-6alkyl, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R2is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3is selected from H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, and heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of R3is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; RVI1, RVI2, RVI3, RVI4, and RVI5are each independently selected from H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl.Attn Docket: FATH-023 / 02WO 351027-2511 102. The method of claim 101, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R3is C4-6alkyl 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 RVI1is NO2.

104. The method of any one of claims 101-103, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RVI3is 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):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1is selected from the group consisting of C3-6cycloalkyl, C1alkyl-C3-6cycloalkyl, aryl, C1alkyl-aryl, heteroaryl, and C1alkyl-heteroaryl; wherein the C3-6cycloalkyl, C1alkyl-C3-6cycloalkyl, aryl, C1alkyl-aryl, heteroaryl, or C1alkyl-heteroaryl of R1is unsubstituted or substituted with halo; RVII1, RVII2, RVII3, RVII4, and RVII5are each independently selected from H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl.

106. The method of claim 105, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1is aryl or C1alkyl-aryl, wherein the aryl or C1alkyl-aryl may be unsubstituted or substituted with one or more halo.Attn Docket: FATH-023 / 02WO 351027-2511 107. The method of claim 105 or 106, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RVII1is H or NO2.

108. The method of any one of claims 105-107, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RVII2is H, halo, or SO2-C1-6alkyl.

109. The method of any one of claims 105-108, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein RVII3is 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):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: Y1is CR1, Y2is N, and Y3is NR3; Y1is CR1, Y2is O or S, and Y3is CR3; Y1is N, Y2is CR2, and Y3is O or S; or Y1is O or S, Y2is CR2, and Y3is CR3; R1and R2are each independently selected from H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, and aryl;R1or R2is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; R3is H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CO(O)-C1-6alkyl, or aryl;Attn Docket: FATH-023 / 02WO 351027-2511 wherein the C1-6alkyl, C1-6haloalkyl,6cycloalkyl, -CO(O)-C1-6alkyl, or aryl of R3is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; or R3combines with RVIII2to 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, C1-6alkyl, C1-6haloalkyl, and -CO(O)-C1-6alkyl; RVIII1is H, C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl; wherein the C1-6alkyl, C3-6cycloalkyl, aryl, C1-6alkyl-aryl, or heteroaryl of RVIII1is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, alkoxy, C1-6 alkyl, and alkoxy; RVIII2is H, halo, C1-6haloalkyl, NO2, CN, and SO2-C1-6alkyl; orR3to 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, C1-6alkyl, C1-6haloalkyl, and - CO(O)-C1-6alkyl.

111. The method of claim 110, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1is CF3.

112. The method of claim 110 or 111, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2is CF3.

113. The method of any one of claims 110-112, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R3is C1-6alkyl.Attn Docket: FATH-023 / 02WO 351027-2511 114. 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 ispharmaceutically 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 (Ii-N), Formula (Ii-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 (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.Attn Docket: FATH-023 / 02WO 351027-2511 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, 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 (IH-N), Formula (IH-N3), Formula (IH-O), Formula (Ii-N), Formula (Ii-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 (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.Attn Docket: FATH-023 / 02WO 351027-2511 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-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 (Ii-N), Formula (Ii-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 (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.

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; andAttn Docket: FATH-023 / 02WO 351027-2511 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 (IH-N), Formula (IH-N3), Formula (IH-O), Formula (Ii-N), Formula (Ii- 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 (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.

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 (IH-N), Formula (IH-N3), Formula (IH-O), Formula (Ii-N), Formula (Ii- 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 (IIB3), Formula (IIC), Formula (IIC3), Formula (IID),Attn Docket: FATH-023 / 02WO 351027-2511 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.

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.Attn Docket: FATH-023 / 02WO 351027-2511 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, obsessive- compulsive disorder (OCD), panic disorders, post-traumatic stress disorder (PTSD), substance abuse disorders, chronic constipation, tremor disorders, CoQ10 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 RDA 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, wherein 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 averageAttn Docket: FATH-023 / 02WO 351027-2511 recommended 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.Attn Docket: FATH-023 / 02WO 351027-2511 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.Attn Docket: FATH-023 / 02WO 351027-2511 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.

156. 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.

159. 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.Attn Docket: FATH-023 / 02WO 351027-2511 162. An herbicidal composition comprising the compound of any one of claims 1-90, or an agriculturally acceptable salt thereof.

163. The herbicidal composition of claim 162, further comprising an herbicidal safener, wherein the herbicidal safener increases a metabolic rate of the herbicidal 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.Attn Docket: FATH-023 / 02WO 351027-2511 171. The herbicidal composition of claim 169 or 170, 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 acetyl- coenzyme 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 paraquat- resistant weed, an aminopyralid + 2,4-D-resistant weed, a picloram-resistant weed, a 2,4- dichlorophenoxyacetic acid-resistant weed, a propanil-resistant weed, a 3,4-dichloroaniline + 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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