WO2025006810A1

WO2025006810A1 - Intermittent dosing methods for treating a condition associated with increased 15-pgdh

Info

Publication number: WO2025006810A1
Application number: PCT/US2024/035916
Authority: WO
Inventors: Annie M. CLARK; Didier Bagnol; Micah WEBSTER; Alexander CASDIN; Bruce Fahr
Original assignee: Epirium Bio Inc
Current assignee: Epirium Bio Inc
Priority date: 2023-06-28
Filing date: 2024-06-27
Publication date: 2025-01-02
Anticipated expiration: 2025-12-28

Abstract

Provided are intermittent dosing methods for treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject with a 15-PGDH inhibitor to reduce toxicity. Further, provided herein are methods of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject by administering a 15-PGDH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject falls below the EC50 of the 15-PGDH inhibitor, while maintaining therapeutic efficacy of the 15-PGDH inhibitor.

Description

INTERMITTENT DOSING METHODS FOR TREATING A CONDITION ASSOCIATED WITH INCREASED 15-PGDH

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63/510,874, filed on June 28, 2023, and U.S. Provisional Application No. 63/588,989, filed on October 9, 2023, each of which is incorporated herein by reference in its entirety.

BACKGROUND

[0002] Prostaglandins are a group of physiologically active lipid compounds with diverse biological effects. Treatment of conditions, diseases, or disorders may require activation of prostaglandins, or inhibition of inactivation of prostaglandins. Hydroxyprostaglandin dehydrogenases, such as 15 -hydroxyprostaglandin dehydrogenase (15-PGDH) are involved in the inactivation of prostaglandins. As such, conditions, diseases, or disorders associated with prostaglandins can be prevented, treated and/or managed using inhibitors of hydroxyprostaglandin dehydrogenase, such as inhibitors of 15-PGDH.

[0003] However, therapeutic agents such as inhibitors can have drug toxicity, which can lead to adverse effects on a subject. In order for these therapeutic agents to be approved for clinical application, they are tested for toxicity. Several therapeutic agents entering clinical trials can fail because they are unsafe or ineffective due to toxicity.

INCORPORATION BY REFERENCE

[0004] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material. SUMMARY

[0005] There is an unmet need for methods and dosing regimens for reducing toxicity (e.g., neurotoxicity) associated with 15-PGDH inhibitor treatment. This disclosure meets this unmet need.

[0006] In one aspect, provided herein is a method of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject, the method comprising: administering a 15-PGDH inhibitor to the subject in an amount effective to inhibit 15-PGDH at a level sufficient to treat the condition, wherein the 15-PGDH inhibitor is administered to the subject at a dosing frequency that exhibits reduced toxicity to the subject as compared to a once every day dosing frequency of the 15-PGDH inhibitor at the same amount.

[0007] In some instances, the dosing frequency that exhibits reduced toxicity to the subject is less than once every day. In some instances, the dosing frequency that exhibits reduced toxicity to the subject is once every 2 days, once every 3 days, once every 4 days, once every 5 days, one every 6 days, or once every 7 days. In some instances, the dosing frequency that exhibits reduced toxicity to the subject is less than once every 2 days, less than once every 3 days, less than once every 4 days, less than once every 5 days, less than once every 6 days, or less than once every 7 days. In some instances, the administering comprises administering the 15-PGDH inhibitor when a plasma concentration of the 15-PGDH inhibitor in the subject is below the ECso of the 15-PGDH inhibitor.

[0008] In another aspect, the present disclosure provides a method of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject, the method comprising: administering a 15-PGDH inhibitor to the subject at an amount effective to increase a plasma concentration of the 15-PGDH inhibitor in the subject to a level above the ECso of the 15-PGDH inhibitor, where the subject has received at least one dose of the 15-PGDH inhibitor prior to the administering, and where the administering comprises administering the 15-PGDH inhibitor to the subject when the subject has a plasma concentration of the 15-PGDH inhibitor that is below the EC50 of the 15-PGDH inhibitor.

[0009] In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 48 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15- PGDH inhibitor greater than 72 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15 -PGDH inhibitor greater than 24 hours and less than 72 hours prior to the administering.

[0010] In some embodiments, the administering comprises administering the 15-PDGH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject is at least 2- fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000-fold, or greater than 1000-fold lower than the ECso of the 15-PGDH inhibitor.

[0011] In some instances, the method results in reduced toxicity to the subject as compared to administering the same amount of the 15-PGDH inhibitor to the subject when the plasma concentration of the 15-PGDH inhibitor in the subject is above the ECso of the 15-PGDH inhibitor. In some instances, the method results in reduced toxicity to the subject as compared to administering the same amount of the 15-PGDH inhibitor to the subject by once a day administration.

[0012] In some embodiments, the reduced toxicity is selected from the group consisting of: reduced neurological disorders, reduced muscle degeneration, reduced gastrointestinal and/or metabolic distress, reduced inflammation, or any combination thereof. In some embodiments, the reduced toxicity is measured by: safety pharmacology, genetic toxicology, acute and subchronic toxicology, absorption, distribution, metabolism, and excretion (ADME) studies, reproductive and developmental toxicity, an evaluation of carcinogenic potential, or any combination thereof. In some embodiments, the administering comprises administering the 15-PGDH inhibitor to the subject by oral administration.

[0013] In some embodiments, the 15-PGDH inhibitor is a small molecule.

[0014] In some embodiments, the 15-PGDH inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from -OCH₂- -C(O)NH-, -NHC(O)-, -C(O)NMe-, -NMeC(O)-, - SCH₂-, -S(O)CH₂-, -SO₂CH₂-; each Y is independently selected from N and CR¹¹; each R¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo or thio; each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; each R⁵ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl;

R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C₃-₁₀cycloalkyl; each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- ₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃. 1₀cycloalkyl; each R¹¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0015] In some embodiments, the compound is a compound of Formula la:

or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the compound is a compound of Formula lb:

or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the 15-PGDH inhibitor is a compound of Formula II:

Formula II or a pharmaceutically acceptable salt thereof, wherein:

T, U, W, X, and Y are independently selected from N and CR⁵;

S, V, and Z are independently selected from N and C;

R¹ is selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃-₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃-₁₀cycloalkyl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo or thio; each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; or two R⁴’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C₃-₁₀cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; each R⁵ is independently selected from H, halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃-₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C₃-₁₀cycloalkyl; each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3- ₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃- 1₀cycloalkyl; and n is 1, 2, 3, or 4; and m is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0018] In some embodiments, the compound is a compound of Formula Ila:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0019] In some embodiments, the compound is a compound of Formula lib :

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0020] In some embodiments, the compound is a compound of Formula lie:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5. [0021] In some embodiments, the compound is a compound of Formula lid:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0022] In some embodiments, the compound is a compound of Formula lie:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0023] In some embodiments, the compound is a compound of Formula Ilf:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0024] In some embodiments, the compound is a compound of Formula Ilg:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0025] In some embodiments, the compound is a compound of Formula Ilh:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0026] In some embodiments, the compound is a compound of Formula Ili :

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0027] In some embodiments, the compound is a compound of Formula Ilj :

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0028] In some embodiments, the compound is a compound of Formula Iln:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0029] In some embodiments, the compound is a compound of Formula lip:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0030] In some embodiments, the 15-PGDH inhibitor is a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR⁷;

Y is selected from O, S, SO₂, and C(R⁸)2;

R¹ is selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, - SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or R² and R³ are taken together to form oxo or thio;

R⁴ and R⁵ are independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, - SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 1₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; or

R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁶ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁶’S attached to the same carbon atom are taken together to form oxo, thio, or C₃- 1₀cycloalkyl, and any remaining R⁶’s are independently selected from halo, - NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², - SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, - NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁷ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁸ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁸’S can be taken together to form a C_3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, - C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1- ealkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁹ and R¹⁰ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; each R¹¹ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹² is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹³ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃- 1₀cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4.

[0031] In some embodiments, the compound is a compound of Formula Illa:

or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the compound is a compound of Formula Illb :

or a pharmaceutically acceptable salt thereof, wherein: each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0033] In some embodiments, the compound is a compound of Formula IIIc:

or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the compound is a compound of Formula Hid:

or a pharmaceutically acceptable salt thereof, wherein: each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C₃-₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0035] In some embodiments, the 15-PGDH inhibitor is a compound of Formula Ilk:

or a pharmaceutically acceptable salt thereof, wherein:

T, U, and Y are independently selected from N and CR⁶, provided that when U is N, at least one of T and Y is N;

R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, - SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, - NR¹¹SO₂R⁹, -NR¹¹SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 6cycloalkyl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo; each R⁴ is independently selected from H and halo;

R⁵ is selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, -SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, -NR¹¹ SO₂R⁹, - NR¹¹SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁶ is selected from H, halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, - SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, - NR¹¹SO₂R⁹, -NR¹¹ SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; R⁷ and R⁸ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C_3-6cycloalkyl; each R⁹ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹¹ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃- 6cycloalkyl; and p is 0, 1, or 2.

[0036] In some embodiments, the 15-PGDH inhibitor is a compound of Formula Ilm:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo; each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁴’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃-₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C₃-₁₀cycloalkyl; each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃. 1₀cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

[0037] In some embodiments, the 15-PGDH inhibitor is a compound of Formula Ilq:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃-₁₀cycloalkyl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or R² and R³ are taken together to form oxo; each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁴’ S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C₃-₁₀cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C₃-₁₀cycloalkyl; each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃-₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃. 1₀cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

[0038] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIIc:

Y is selected from O, S, SO₂, and C(R⁸)2;

R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, - SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 6cycloalkyl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo;

R⁴ and R⁵ are independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-6cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, - SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; or

R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁶ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁶’S attached to the same carbon atom are taken together to form oxo, and any remaining R⁶’s are independently selected from halo, -NR⁹R¹⁰, -OR¹¹, - C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1- ealkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁷ and R⁸ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁹ and R¹⁰ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C_3-6cycloalkyl; each R¹¹ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹² is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹³ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃- 6cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0039] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0040] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0041] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0042] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt thereof:

wherein, ring Q is phenyl or 5- to 10-membered heteroaryl;

Z is CR¹ or N;

Y is CR² or N;

R¹ is H, halogen, -CN, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -NR⁸R⁹, -C(O)NR⁸R⁹, - NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl; each R² is independently H, halogen, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -CN, -C(O)NR⁸R⁹, - NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl; each R³ is independently selected from H, halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, - C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10- membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, or -C(O)NR⁸R⁹;

R⁴ is substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₁-C₈ aminoalkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, substituted or unsubstituted C₁-C₈ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, each of which is substituted with one or more R⁶; wherein each R⁶ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₁-C₆ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8- membered heteroaryl; or two R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted C₃-C₈ heterocycloalkyl;

X^A is -NR⁵R⁵ or -OR⁵; wherein each R⁵ is independently H or C₁-C₆ alkyl;

R^5a is H or CH₃; or R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted C₃-C₆ heterocycloalkyl; each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is optionally substituted with one or more R^a; each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R^a; each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R^a; each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is optionally substituted with one or more R^a; each R^a is independently selected from halogen, -OH, -CH₃, -CF₃, -OCH₃, -NH₂, - NHCH₃, -N(CH₃)₂, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃; and p is 1, 2, 3, or 4.

[0043] In some embodiments, ring Q is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 N atoms. In some embodiments, ring Q is a phenyl, pyrimidinyl, or pyridinyl. In some embodiments, when Q is phenyl then one of R³ is not H.

[0044] In some embodiments

wherein,

X¹, X², X³ and X⁴ are each independently N or CR³; each R³ is independently selected from H, halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, - C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10- membered heteroaryl, each of which is substituted with one or more R¹³; each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, or -C(O)NR⁸R⁹; each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; and each R^a is independently selected from halogen, -OH, -CH₃, -CF₃, -OCH₃, -NH₂, - NHCH₃, -N(CH₃)₂, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃.

[0045] In some embodiments, X¹, X², X³ and X⁴ are each CR³. In some embodiments, X¹ is N; and X², X³, and X⁴ are each CR³. In some embodiments, X¹ and X² are each N; and X³ and X⁴ are each CR³. In some embodiments, X¹ and X³ are each N; and X² and X⁴ are each CR³. In some embodiments, X¹ and X⁴ are each N; and X² and X³ are each CR³. In some embodiments, X¹, X², and X³ are each N; and X⁴ is CR³. In some embodiments, X¹, X², and X⁴ are each N; and X³ is CR³. In some embodiments, each R³ is independently selected from H, halogen, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, each R³ is independently selected from H, halogen, -C(O)OR¹⁰, -C(O)NR⁸R⁹, and substituted or unsubstituted 5-membered heteroaryl. [0046] In some embodiments, the compound has the structure of Formula V, or a pharmaceutically acceptable salt thereof:

wherein,

Z is CR¹ or N;

X¹ is N or CR^3a;

Y is CR² or N;

R¹ is H, halogen, -CN, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -NR⁸R⁹, -C(O)NR⁸R⁹, - NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl; each R² is independently H, halogen, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -CN, -C(O)NR⁸R⁹, - NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl;

R^3a, R^3b, and R^3c are each independently selected from H, halogen, -CN, -NO₂, -NR⁸R⁹, - OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, - NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, or -C(O)NR⁸R⁹;

R⁴ is substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₁-C₈ aminoalkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, substituted or unsubstituted C₁-C₈ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₃-C₈ heterocycloalkyl, each of which is substituted with one or more R⁶; wherein each R⁶ is independently halogen, CN,-N02, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted C_1-C₆ haloalkyl, substituted or unsubstituted C₁-C₆ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted C₃-C₈ heterocycloalkyl;

X^A is NR⁵R⁵ or OR⁵; wherein each R⁵ is independently H or C₁-C₆ alkyl;

R^5a is H or CH₃; or R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl; each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; and each R^a is independently selected from halogen, -OH, -CH₃, -CF₃, -OCH₃, -NH₂, - NHCH₃, -N(CH₃)₂, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃.

[0047] In some embodiments, X^A is NR⁵R⁵. In some embodiments, X^A is OR⁵. In some embodiments, Yis CR². In some embodiments, Y is N.

[0048] In some embodiments, the compound of Formula V has the structure of Formula Via, or a pharmaceutically acceptable salt thereof:

[0049] In some embodiments, the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:

[0050] In some embodiments, Z is N. In some embodiments, Z is CR¹. In some embodiments, Z is CH.

[0051] In some embodiments, the compound of Formula V has the structure of Formula Vila, or a pharmaceutically acceptable salt thereof:

[0052] In some embodiments, the compound of Formula V has the structure of Formula Vllb, or a pharmaceutically acceptable salt thereof:

[0053] In some embodiments, the compound of Formula V has the structure of Formula Vile, or a pharmaceutically acceptable salt thereof:

[0054] In some embodiments, the compound of Formula V has the structure of Formula Vlld, or a pharmaceutically acceptable salt thereof:

[0055] In some embodiments, X¹ is N. In some embodiments, R^3b is H; and R^3c is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, - SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, - NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or -C(O)NR⁸R⁹. In some embodiments, R^3b is H; and R^3c is selected from halogen, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R^3c is H; and R^3b is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or - C(O)NR⁸R⁹. In some embodiments, R^3c is H; and R^3b is selected from halogen, -NR⁸R⁹, - OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, X¹ is CR^3a. In some embodiments, R^3a and R^3b are independently H or halogen; and R^3c is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, - SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, - NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or - C(O)NR⁸R⁹. In some embodiments, R^3c is selected from H, halogen, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted Ci-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R^3c is -C(O)OR¹⁰, - C(O)NR⁸R⁹, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R^3a and R^3b are each H. In some embodiments, R^3a and R^3c are independently H or halogen; and R^3b is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, - NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, - SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or -C(O)NR⁸R⁹. In some embodiments, R^3b is selected from H, halogen, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R^3b is -C(O)OR¹⁰, -C(O)NR⁸R⁹, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R^3a and R^3c are each H. In some embodiments, R^3b and R^3C are each H or halogen; and R^3a is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, - SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or - C(O)NR⁸R⁹. In some embodiments, R^3a is selected from H, halogen, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted Ci-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R^3a is -C(O)OR¹⁰, - C(O)NR⁸R⁹, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R^3b and R^3c are each H. In some embodiments, each R² is H. In some embodiments, R^5a and one of R⁶ combine together with the atom(s) to which they are attached to form a C₃-C₆ cycloalkyl. In some embodiments, R^5a is H. In some embodiments, R⁵ is H. In some embodiments, R⁴ is substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted Ci- Cs aminoalkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, substituted or unsubstituted C_1- C 8 hydroxy alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₃-C₈ heterocycloalkyl, each of which is substituted with one or more R⁶. In some embodiments, R⁴ is substituted or unsubstituted C₁-C₈ alkyl or substituted or unsubstituted C₁-C₈ heteroalkyl, each of which is substituted with one or more R⁶. In some embodiments, R⁴ is substituted or unsubstituted C₃-C₈ cycloalkyl or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R⁶. In some embodiments, R⁴ is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl. In some embodiments, each R⁶ is independently halogen, -NR⁸R⁹, -OR¹⁰, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1- C₆haloalkyl, substituted or unsubstituted C₁-C₆ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₃-C₈ heterocycloalkyl. In some embodiments, each R⁶ is independently halogen, -OR¹⁰, C₁-C₆ alkyl, C_1-C₆ haloalkyl, or C₃-C₈ cycloalkyl. In some embodiments, each R⁶ is independently -F, -CH₃ , -CF₃ , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the compound is selected from Table 4, or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the condition is a muscle condition. In some embodiments, the muscle condition is muscle atrophy, muscle damage, a muscle disorder, or muscle injury. In some embodiments, the condition is selected from the group consisting of: Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), an inherited myopathy, myotonic muscular dystrophy (MDD), oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery -Dreifuss muscular dystrophy, myotonia congenita, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, stress induced urinary incontinence, urethral sphincter deficiency, sarcopenia, and any combination thereof.

[0057] In some embodiments, the condition is spinal muscular atrophy (SMA). In some instances, the condition is facioscapulohumeral muscular dystrophy (FSHD). In some embodiments, the condition is hair loss. In some embodiments, the condition is skin inflammation and/or damage. In some embodiments, the condition is vascular insufficiency. In some embodiments, the condition is congestive heart failure or cardiomyopathy. In some embodiments, the condition is a gastrointestinal disease. In some embodiments, the condition is renal dysfunction. In some embodiments, the condition is a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder. In some embodiments, the condition is a fibrotic or adhesion disease, disorder, or condition. In some embodiments, the condition is scar formation. In some embodiments, the condition is fibrosis. In some embodiments, the condition is idiopathic pulmonary fibrosis. In some embodiments, the condition is kidney fibrosis. In some embodiments, the condition is acute kidney injury. In some embodiments, the condition is sarcopenia. In some embodiments, the condition is a neuromuscular disease.

BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0059] Fig. 1 shows an overview of the effects of MF-300 on PGE2 signaling.

[0060] Figs. 2A-2C show the mechanism of action and pharmacokinetic profile of MF-300. Fig. 2A shows the effects of MF-300 on NADH production in a biochemical 15-PGDH inhibition assay. Fig. 2B shows the effects of MF-300 on PGE2 stability in A549 cells. Fig. 2C shows the plasma levels of varying doses of MF-300 twenty-four hours after administration in mice.

[0061] Figs. 3A-3G show the effects of intraperitoneally administered MF-300 in SMNA7 mice. Fig. 3A shows an experimental overview for assessing the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice. Fig. 3B shows the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice on isometric plantar flexor force. Fig. 3C shows the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice on isometric plantar flexor maximum force. Fig. 3D shows the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice on isometric plantar flexor maximum force as a percentage relative to the average maximum force of vehicle-treated animals. Fig. 3E shows the level of HPGD expression in gastrocnemius muscles from SMNA7 mice. Fig. 3F shows a principal component analysis of the effects of repeated SMN-C3 and MF-300 administration in gastrocnemius muscles of SMNA7 mice. Fig. 3G shows the effects of repeated SMN-C3 and MF-300 administration in SMNA7 mice on the probability of righting within 30 seconds. [0062] Figs. 4A-4J show the effects of orally administered MF-300 in SMN1^C/C mice. Fig. 4A shows an experimental overview for assessing the effects of repeated MF-300 administration in SMN1^C/C mice. Fig. 4B shows the effects of repeated MF-300 administration in SMN1^C/C mice on isometric plantar flexor force and percent increase in maximum force relative to vehicle-administered mice. Fig. 4C shows the effects of repeated MF-300 administration in SMN1^C/C mice on isometric plantar flexor force and percent increase in maximum force relative to vehicle-administered mice normalized to muscle mass. Fig. 4D shows an overview and rationale for experiments in which mice were treated with MF-300 and nerve and direct muscle-stimulated contractions measured to localize the effects of MF-300. Fig. 4E shows the effects of MF-300 treatment on maximal force associated with sciatic nerve stimulation. Fig. 4F shows the effects of MF-300 treatment on maximal force associated with sciatic nerve stimulation and normalized to muscle weight. Fig. 4G shows the effects of MF-300 treatment on maximal force associated with direct muscle stimulation. Fig- 411 shows the effects of MF-300 treatment on maximal force associated with direct muscle stimulation and normalized to muscle weight. Fig. 41 shows the effects of MF-300 treatment on maximal force associated with normalized muscle stimulation to nerve stimulation. Fig- 4 J shows the effects of MF-300 treatment on maximal force associated with normalized muscle stimulation to nerve stimulation and represented as fold difference.

[0063] Figs. 5A-5H show the effects of orally administered MF-300 in a sciatic nerve crush mouse model. Fig. 5A shows an overview of the experimental timeline for assessing effects of MF-300 in a sciatic nerve crush mouse model on isometric plantar flexor force. Fig. 5B shows the maximum force at baseline for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle. Fig. 5C shows the maximum force on day 14 for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle. Fig. 5D shows the maximum force on day 21 for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle. Fig. 5E shows the maximum force on day 28 for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle. Fig. 5F shows the maximum force on day 35 for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle. Fig. 5G shows the maximum force normalized by muscle weight on day 35 for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle. Fig. 5H shows muscle mass at the end of testing for surgery sham mice administered vehicle and sciatic nerve crush mice administered MF-300 or vehicle.

[0064] Figs. 6A-6F show the effects of intermittently dosed, orally administered MF-300 in SMN1^C/C mice. Fig. 6A shows an overview of the experimental timeline for assessing the effects of intermittently dosed MF-300 on isometric plantar flexor force in SMN1^C/C mice. Fig. 6B shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 60 mg/kg MF-300 administration every day. Fig. 6C shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 60 mg/kg MF-300 administration every 2 days. Fig. 6D shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 60 mg/kg MF-300 administration every 3 days. Fig. 6E shows the effect of intermittent doses of MF-300 treatment on maximum isometric plantar flexor force and percent increase in maximum force relative to vehicle-administered cohorts. Fig. 6F shows the effect of intermittent doses of MF-300 treatment on maximum isometric plantar flexor force and percent increase in maximum force relative to vehicle-administered cohorts normalized to muscle weight.

[0065] Figs. 7A-7H show the effects of intermittently administered MF-300 in SMNA7 mice. Fig. 7A shows an experimental overview for assessing the effects of SMN-C3 and intermittent MF-300 administration in SMNA7 mice. Fig. 7B shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 30 mg/kg MF-300 administration every day. Fig. 7C shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 30 mg/kg MF-300 administration every two days. Fig. 7D shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 30 mg/kg MF-300 administration every three days. Fig. 7E shows the predicted plasma concentrations of MF- 300 in cohorts of mice that received 10 mg/kg or 30 mg/kg MF-300 administration every day. Fig. 7F shows the predicted plasma concentrations of MF-300 in cohorts of mice that received 10 mg/kg or 30 mg/kg MF-300 administration every two days. Fig. 7G shows the effect of intermittent doses of MF-300 treatment on maximum isometric plantar flexor force in SMNA7 mice. Fig. 7H shows the effect of intermittent doses of MF-300 treatment on percent increase in maximum force from vehicle in SMNA7 mice.

DETAILED DESCRIPTION

[0066] Determination of a dosage regimen requires a fine balance between drug effectiveness and safety, aiming to reduce toxicity and side effects while maintaining the dose at a therapeutic level. Half maximal effective concentration or EC50 refers to the concentration of a drug that induces an effect or a response halfway between the baseline and the maximum possible effect after a certain exposure time. In order to maintain effectiveness, some drugs require maintaining the concentration above the EC50 throughout the dosing interval, which may increase incidents associated with unwanted drug toxicity and side effects. In one aspect, the present disclosure provides methods for administering a 15-PGDH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject falls below the EC50 of the 15-PGDH inhibitor, while maintaining therapeutic efficacy of the 15-PGDH inhibitor. In some instances, the methods described herein reduce or avoid the toxicity associated with more frequent dosing of the 15-PGDH inhibitor.

[0067] Provided herein are methods for treating a condition associated with increased 15- hydroxyprostaglandin dehydrogenase (15-PGDH) activity and/or expression levels in a subject. The methods may involve the administration of a 15-PGDH inhibitor to a subject at a dosing frequency that is less than a once a day (QD) dosing frequency and/or at a frequency that reduces toxicity as compared to a once a day (QD) dosing frequency. For example, the methods may involve administering to a subject (e.g., by oral administration) a 15-PGDH inhibitor at a once every 2 days (Q2D) dosing frequency, a once every 3 days (Q3D) dosing frequency, or less than a once every 3 days dosing frequency.

[0068] In some cases, the methods may involve administering a 15-PGDH inhibitor to a subject when a plasma concentration of the 15-PGDH inhibitor in the subject is less than the EC50 of the 15-PGDH inhibitor. For example, a subject may receive or may have received at least one dose of a 15-PGDH inhibitor at an amount such that a plasma concentration of the 15-PGDH inhibitor in the subject is above the EC50 of the 15-PGDH inhibitor at some time point after the 15-PGDH inhibitor is administered. The methods may involve administering the subsequent dose of the 15-PGDH inhibitor to the subject when the plasma concentration of the 15-PGDH inhibitor drops below the EC50 of the 15-PGDH inhibitor (e.g., at some time point after administering the previous dose (e.g., greater than 24 hours after administering the previous dose)). The methods provided herein are based on the discovery that 15-PGDH inhibitors may be administered at a less frequent dosing regimen such that the plasma concentration of the 15-PGDH inhibitor can drop below the EC50 prior to the subsequent dose, while maintaining efficacy of the 15-PGDH inhibitor (e.g., to treat the condition) and with less risk of toxic side effects to the subject.

[0069] Provided herein are methods of treating a condition associated with increased 15- hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject. In some cases, the method comprises administering a 15-PGDH inhibitor to the subject in an amount effective to inhibit 15-PGDH at a level sufficient to treat the condition. In some cases, the 15-PGDH inhibitor is administered to the subject at a dosing frequency that exhibits reduced toxicity to the subject as compared to a once every day dosing frequency of the 15-PGDH inhibitor at the same amount.

[0070] Further provided herein are methods of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject. In some cases, the method comprises administering a 15-PGDH inhibitor to the subject at an amount effective to increase a plasma concentration of the 15-PGDH inhibitor in the subject to a level above the EC50 of the 15-PGDH inhibitor. In some cases, the subject has received at least one dose of the 15-PGDH inhibitor prior to the administering. In some cases, the administering comprises administering the 15-PGDH inhibitor to the subject when the subject has a plasma concentration of the 15-PGDH inhibitor that is below the EC50 of the 15-PGDH inhibitor.

[0071] In some embodiments, the dosing frequency refers to the frequency that therapeutic agents, such as medicines, drugs, compounds, or inhibitors, are administered to the subject or are taken by the subject. In some embodiments, the dosing frequency that exhibits reduced toxicity to the subject is once every day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, or once every 10 days.

[0072] In some embodiments, the dosing frequency that exhibits reduced toxicity to the subject is less than once every day. In some embodiments, the dosing frequency that exhibits reduced toxicity to the subject is less than once every 2 days, less than once every 3 days, less than once every 4 days, less than once every 5 days, less than once every 6 days, or less than once every 7 days. [0073] In some embodiments, the dosing frequency that exhibits reduced toxicity to the subject is less than once every day to once every 10 days, less than once every day to once every 9 days, less than once every day to once every 8 days, less than once every day to once every 7 days, less than once every day to once every 6 days, less than once every day to once every 5 days, less than once every day to once every 4 days, less than once every day to once every 3 days, or less than once every day to once every 2 days.

[0074] In some embodiments, the dosing frequency that exhibits reduced toxicity to the subject is less than once every day to less than once every 10 days, less than once every day to less than once every 9 days, less than once every day to less than once every 8 days, less than once every day to less than once every 7 days, less than once every day to less than once every 6 days, less than once every day to less than once every 5 days, less than once every day to less than once every 4 days, less than once every day to less than once every 3 days, or less than once every day to less than once every 2 days.

[0075] In some instances, the ECso is determined using biochemical assays and/or cell-based assays that measure 15-PGDH activity and/or levels of 15-PGDH substrate, such as prostaglandin E2. In some instances, the administering comprises administering the 15- PGDH inhibitor when a plasma concentration of the 15-PGDH inhibitor in the subject is below the ECso of the 15-PGDH inhibitor.

[0076] In some instances, the administering comprises administering the 15-PGDH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject is at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000- fold, or greater than 1000-fold lower than the ECso of the 15-PGDH inhibitor.

[0077] In some embodiments, the administering comprises administering the 15-PGDH inhibitor when the a plasma concentration of the 15-PGDH inhibitor in the subject is below the ECso of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by at least 2-fold, by at least 5-fold, by at least 10-fold, by at least 50-fold, by at least 100-fold, by at least 500-fold, by at least 1000-fold, or greater than 1000-fold.

[0078] In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 2-fold to about 10-fold than the EC50 of the 15- PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 2-fold to about 100-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15- PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 10-fold to about 100-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 2-fold to about 1000-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 10-fold to about 1000-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 100-fold to about 1000-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 2-fold to about lOOOOO-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 10-fold to about 1 OOOOO-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 100-fold to about 1 OOOOO-fold than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor falls below the EC50 of the 15-PGDH inhibitor by about 1000-fold to about 1 OOOOO-fold than the EC50 of the 15- PGDH inhibitor.

[0079] In some embodiments, the administering comprises administering the 15-PGDH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject is at least 2- fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000-fold, or greater than 1000-fold lower than the EC50 of the 15-PGDH inhibitor. [0080] In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 2-fold to about 10-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 2-fold to about 100-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 10- fold to about 100-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 2-fold to about 1000-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 10-fold to about 1000-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 100-fold to about 1000-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 2-fold to about 100000-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 10-fold to about 100000-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 100-fold to about 100000-fold lower than the EC50 of the 15-PGDH inhibitor. In some embodiments, the plasma concentration of the 15-PGDH inhibitor in the subject is about 1000-fold to about 100000- fold lower than the EC50 of the 15-PGDH inhibitor.

[0081] In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours, greater than 48 hours, greater than 72 hours, or greater than 96 hours, prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 48 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 72 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours and less than 96 hours prior to the administering. In some instances, the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours and less than 72 hours prior to the administering.

[0082] In some instances, the method described herein results in reduced toxicity to the subject as compared to administering the same amount of the 15-PGDH inhibitor to the subject when the plasma concentration of the 15-PGDH inhibitor in the subject is above the EC50 of the 15-PGDH inhibitor. In some instances, the method described herein results in reduced toxicity to the subject as compared to administering the same amount of the 15- PGDH inhibitor to the subject by once a day administration.

[0083] In some embodiments, the reduced toxicity comprises reduced neurotoxicity (e.g., reduced neurological disorders). In some embodiments, the reduced toxicity comprises reduced muscle degeneration. In some embodiments, the reduced toxicity comprises reduced gastrointestinal and/or metabolic distress. In some embodiments, the reduced toxicity comprises reduced inflammation. In some embodiments, reduced toxicity is measured by safety pharmacology, genetic toxicology, acute and subchronic toxicology, absorption, distribution, metabolism, and excretion (ADME) studies, reproductive and developmental toxicity, an evaluation of carcinogenic potential, or any combination thereof.

[0084] In some embodiments, the administering comprises administering the 15-PGDH inhibitor to the subject by various methods. For example, oral administration, intramuscular administration, intradermal administration, subcutaneous administration, intrathecal administration, intravenous administration, intraperitoneal administration, topical (transdermal), instillation, and implantation (for example, of a slow-release device such as polymeric implant or miniosmotic pump) can all be appropriate routes of administration. In some embodiments, the administering comprises administering the 15-PGDH inhibitor to the subject by oral administration. In some embodiments, the administering comprises administering the 15-PGDH inhibitor to the subject by intramuscular administration. In some embodiments, the administering comprises administering the 15-PGDH inhibitor to the subject by intraperitoneal injection.

[0085] In some embodiments, the 15-PGDH inhibitor is a small molecule. In some embodiments, the 15-PGDH inhibitor is an orally bioavailable small molecule.

[0086] In some embodiments, the 15-PGDH inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from -OCH₂- -C(O)NH- -NHC(O)-, -C(O)NMe- -NMeC(O)-, - SCH₂-, -S(O)CH₂- -SO₂CH₂-; each Y is independently selected from N and CR¹¹; each R¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C₃-₁₀cycloalkyl; each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃-₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃. 1₀cycloalkyl; each R¹¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; provided that said compound of Formula I is not

[0087] In some embodiments, X is selected from -OCH₂-, -C(O)NH- -NHC(O)-, - C(O)NMe-, -NMeC(O)-, -SCH₂-, -S(O)CH₂- and -SO₂CH₂-. In some embodiments, X is -OCH₂-. In some embodiments, X is -C(O)NH- In some embodiments, X is -NHC(O)-. In some embodiments, X is -C(O)NMe- In some embodiments, X is -NMeC(O)-. In some embodiments, X is -SCH₂-. In some embodiments, X is -S(O)CH₂- In some embodiments, X is -SO₂CH₂-.

[0088] In some embodiments, each Y is independently selected from N and CR¹¹. In some embodiments, each Y is N. In some embodiments, each Y is CR¹¹. In some embodiments, one Y is N and the other Y is CR¹¹.

[0089] In some embodiments, each R¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, - C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and - NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R¹ is independently selected from halo, - NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷,-NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, - NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, and -C(O)OR⁸.

[0090] In some embodiments, R² is H and R³ is -CF₃. In some embodiments, R² and R³ are taken together to form oxo. In some embodiments, R² and R³ are taken together to form thio. [0091] In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, - C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, - OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷,- NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷ In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, and -C(O)OR⁸.

[0092] In some embodiments, each R⁵ is independently selected from halo, -NR⁶R⁷, -OR⁸, - C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁵ is independently selected from halo, -NR⁶R⁷, - OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R⁵ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷,- NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R⁵ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, and -C(O)OR⁸.

[0093] In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl. In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H, and C_1-6alkyl.

[0094] In some embodiments, each R⁸ is independently selected from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, and C_3-10cycloalkyl. In some embodiments, each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁸ is independently selected from H, and C_1-6alkyl.

[0095] In some embodiments, each R⁹ is independently selected from C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, and C_3-10cycloalkyl. In some embodiments, each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁹ is independently selected from C_1-6alkyl.

[0096] In some embodiments, each R¹⁰ is independently selected from H, C_1-6alkyl, C_1- ₆haloalkyl, and C_3-10cycloalkyl. In some embodiments, each R¹⁰ is independently selected from H, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments, each R¹⁰ is independently selected from H and C_1-6alkyl.

[0097] In some embodiments, each R¹¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹¹ is independently selected from halo, -NR⁶R⁷, - OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R¹¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷,- NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷ In some embodiments, each R¹¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, and -C(O)OR⁸.

[0098] In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0099] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0100] In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9 . In some embodiments, p is 10.

[0101] In some embodiments, the compound is a compound of Formula la:

[0102]

[0103] or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound is a compound of Formula lb:

[0105] or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the 15-PGDH inhibitor is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

T, U, W, X, and Y are independently selected from N and CR⁵;

S, V, and Z are independently selected from N and C;

R¹ is selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, - C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo or thio; each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁴’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, - SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁵ is independently selected from H, halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; and n is 1, 2, 3, or 4; and m is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0107] In some embodiments, T, U, W, X, and Y are independently selected from N and CR⁵. In some embodiments, at least one of T, U, W, X, and Y is N and the rest are CR⁵. In some embodiments, at least two of T, U, W, X, and Y are N and the rest are CR⁵. In some embodiments, at least three of T, U, W, X, and Y are N and the rest are CR⁵. In some embodiments, at least four of T, U, W, X, and Y are N and the rest are CR⁵. In some embodiments, T, U, W, X, and Y are CR⁵. In some embodiments, T, U, W, X, and Y are N. [0108] In some embodiments, S, V, and Z are independently selected from N and C. In some embodiments, at least one of S, V, and Z is N and the rest are C. In some embodiments, at least two of S, V, and Z are N and the rest are C. In some embodiments, S, V, and Z are N. In some embodiments, S, V, and Z are C.

[0109] In some embodiments, R¹ is selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R¹ is selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, and - C(O)NR⁶R⁷.

[0110] In some embodiments, R² is H and R³ is -CF₃. In some embodiments, R² and R³ are taken together to form oxo. In some embodiments, R² and R³ are taken together to form thio. [0111] In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, - C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, - OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1- ₆haloalkyl. In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, - OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, and -C(O)NR⁶R⁷. In some embodiments, each R⁴ is halo. In some embodiments, each R⁴ is fluoro. [0112] In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’S are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R⁴’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, - NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, - C(O)OR⁸, and -C(O)NR⁶R⁷. In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo. In some embodiments, two R⁴’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are fluoro.

[0113] In some embodiments, each R⁵ is independently selected from H, halo, -NR⁶R⁷, - OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁵ is independently selected from H, halo, -NR⁶R⁷, - OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1- ₆haloalkyl. In some embodiments, each R⁵ is independently selected from H, halo, -NR⁶R⁷, - OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R⁵ is independently selected from H, halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, and -C(O)NR⁶R⁷. In some embodiments, each R⁵ is independently selected from H and halo.

[0114] In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl. In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H and C_1-6alkyl.

[0115] In some embodiments, each R⁸ is independently selected from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, and C_3-10cycloalkyl. In some embodiments, each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁸ is independently selected from H and C_1-6alkyl.

[0116] In some embodiments, each R⁹ is independently selected from C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, and C_3-10cycloalkyl. In some embodiments, each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁹ is independently selected from C_1-6alkyl.

[0117] In some embodiments, each R¹⁰ is independently selected from H, C_1-6alkyl, C_1- ₆haloalkyl, and C_3-10cycloalkyl. In some embodiments, each R¹⁰ is independently selected from H, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments, each R¹⁰ is independently selected from H and C_1-6alkyl.

[0118] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0119] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9 . In some embodiments, m is 10.

[0120] In some embodiments, the compound is a compound of Formula Ila:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0121] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0122] In some embodiments, the compound is a compound of Formula lib :

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0123] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0124] In some embodiments, the compound is a compound of Formula lie:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.

[0125] In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0126] In some embodiments, compound is a compound of Formula lid:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0127] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0128] In some embodiments, the compound is a compound of Formula lie:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0129] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0130] In some embodiments, the compound is a compound of Formula Ilf:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0131] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. [0132] In some embodiments, the compound is a compound of Formula Ilg:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

[0133] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0134] In some embodiments, the compound is a compound of Formula Ilh:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0135] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0136] In some embodiments, the compound is a compound of Formula Ili:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4. [0137] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0138] In some embodiments, the compound is a compound of Formula Ilj :

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0139] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0140] In some embodiments, the compound is a compound of Formula Iln:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

[0141] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0142] In some embodiments, the compound is a compound of Formula lip:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4. [0143] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0144] In some embodiments, the 15-PGDH inhibitor is a compound of Formula III:

Y is selected from O, S, SO₂, and C(R⁸)2;

R¹ is selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, - C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo or thio;

R⁴ and R⁵ are independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C₃- ₁₀cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; or

R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, - SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, - NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁶ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁶’ S attached to the same carbon atom are taken together to form oxo, thio, or C₃- ₁₀cycloalkyl, and any remaining R⁶’s are independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁷ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁸ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁸’ S can be taken together to form a C_3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁹ and R¹⁰ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; each R¹¹ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- ₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹² is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- ₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹³ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; m is 1 or 2; and n is 0, 1, 2, 3, or 4. [0145] In some embodiments, each X is independently selected from N and CR⁷. In some embodiments, at least one X is N and the rest are CR⁷. In some embodiments, at least two X are N and the rest are CR⁷. In some embodiments, each X is N. In some embodiments, each X is CR⁷.

[0146] In some embodiments, Y is selected from O, S, SO₂, and C(R⁸)2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO₂. In some embodiments, Y is C(R⁸)2.

[0147] In some embodiments, R¹ is selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², - SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C 1 -ehaloalky 1, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R¹ is selected from C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C₆- waryl, and 5- to 10-membered heteroaryl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1- ₆haloalkyl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, - SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and - NR¹³SO₂NR⁹R¹⁰. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and - C(O)NR⁹R¹⁰.

[0148] In some embodiments, R² is H and R³ is -CF₃. In some embodiments, R² and R³ are taken together to form oxo. In some embodiments, R² and R³ are taken together to form thio. [0149] In some embodiments, R⁴ and R⁵ are independently selected from C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², - SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁴ and R⁵ are independently selected from C_3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, R⁴ and R⁵ are independently selected from C₃- ₁₀cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁴ and R⁵ are independently selected from C_3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², - SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and - NR¹³SO₂NR⁹R¹⁰. In some embodiments, R⁴ and R⁵ are independently selected from C₃- ₁₀cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and - C(O)NR⁹R¹⁰.

[0150] In some embodiments, R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², - SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3 - to 10- membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², - SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and - NR¹³SO₂NR⁹R¹⁰. In some embodiments, R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and -C(O)NR⁹R¹⁰.

[0151] In some embodiments, each R⁶ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁶ is independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1- ₆haloalkyl. In some embodiments, each R⁶ is independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and -NR¹³SO₂NR⁹R¹⁰. In some embodiments, each R⁶ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and - C(O)NR⁹R¹⁰.

[0152] In some embodiments, two R⁶’s attached to the same carbon atom are taken together to form oxo, thio, or C_3-10cycloalkyl, and any remaining R⁶’s are independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², - SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C 1 -ehaloalky 1, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆- loaryl, and 5- to 10-membered heteroaryl. In some embodiments, two R⁶’s attached to the same carbon atom are taken together to form oxo, thio, or C_3-10cycloalkyl, and any remaining R⁶’S are independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, two R⁶’s attached to the same carbon atom are taken together to form oxo, thio, or C_3-10cycloalkyl, and any remaining R⁶’s are independently selected from halo, - NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(0)OR", -C(0)NR⁹R^{I O}, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and -NR¹³SO₂NR⁹R¹⁰. In some embodiments, two R⁶’s attached to the same carbon atom are taken together to form oxo, thio, or C_3-10cycloalkyl, and any remaining R⁶’s are independently selected from halo, - NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and -C(O)NR⁹R¹⁰.

[0153] In some embodiments, each R⁷ is independently selected from H, halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(0)OR", -C(0)NR⁹R^{I O}, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, each R⁷ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁷ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR", -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², - SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and -NR¹³SO₂NR⁹R¹⁰. In some embodiments, each R⁷ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, - C(O)R¹¹, -C(O)OR¹¹, and -C(O)NR⁹R¹⁰.

[0154] In some embodiments, each R⁸ is independently selected from H, halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(0)OR", -C(0)NR⁹R^{I O}, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, each R⁸ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁸ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR", -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -

-n- SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and -NR¹³SO₂NR⁹R¹⁰. In some embodiments, each R⁸ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, - C(O)R¹¹, -C(O)OR¹¹, and -C(O)NR⁹R¹⁰.

[0155] In some embodiments, two R⁸’s can be taken together to form a C_3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, two R⁸’s can be taken together to form a C₃- ₁₀cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, and C_1-6haloalkyl. In some embodiments, two R⁸’s can be taken together to form a C_3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², - SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and -NR¹³SO₂NR⁹R¹⁰. In some embodiments, two R⁸’s can be taken together to form a C_3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, - C(O)R¹¹, -C(O)OR¹¹, and -C(O)NR⁹R¹⁰.

[0156] In some embodiments, R⁹ and R¹⁰ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl. In some embodiments, R⁹ and R¹⁰ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁹ and R¹⁰ are independently selected at each occurrence from H and C_1-6alkyl.

[0157] In some embodiments, each R¹¹ is independently selected from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹¹ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R¹¹ is independently selected from H and C_1- ealkyl.

[0158] In some embodiments, each R¹² is independently selected from C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹² is independently selected from C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R¹² is independently selected from C_1-6alkyl. [0159] In some embodiments, each R¹³ is independently selected from H, C_1-6alkyl, C_1- ₆haloalkyl, and C_3-10cycloalkyl. In some embodiments, each R¹³ is independently selected from H, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments, each R¹³ is independently selected from H and C_1-6alkyl.

[0160] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0161] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0162] In some embodiments, the compound is a compound of Formula Illa:

or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the compound is a compound of Formula Illb :

or a pharmaceutically acceptable salt thereof, wherein: each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C₆- waryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3.

[0164] In some embodiments, each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, - NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, and -NR¹³SO₂NR⁹R¹⁰. In some embodiments, each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and -C(O)NR⁹R¹⁰. In some embodiments, each R¹⁴ is independently halo. In some embodiments, each R¹⁴ is independently fluoro.

[0165] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0166] In some embodiments, the compound is a compound of Formula IIIc:

or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the compound is a compound of Formula Hid:

or a pharmaceutically acceptable salt thereof, wherein: each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C₆- waryl, and 5- to 10-membered heteroaryl; and p is 0, 1, 2, or 3. [0168] In some embodiments, each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, - NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, and -NR¹³SO₂NR⁹R¹⁰. In some embodiments, each R¹⁴ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and -C(O)NR⁹R¹⁰. In some embodiments, each R¹⁴ is independently halo. In some embodiments, each R¹⁴ is independently fluoro.

[0169] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0170] In some embodiments, the 15-PGDH inhibitor is a compound of Formula Ilk:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, -SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, - NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, -NR¹¹ SO₂R⁹, -NR¹¹ SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or R² and R³ are taken together to form oxo; each R⁴ is independently selected from H and halo;

R⁵ is selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, -SOR¹⁰, - SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, -NR¹¹SO₂R⁹, -NR¹¹SO₂NR⁷R⁸, C_1- ealkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁶ is selected from H, halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, -SOR¹⁰, - SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, -NR¹¹SO₂R⁹, -NR¹¹SO₂NR⁷R⁸, C_1- ealkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁷ and R⁸ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-6cycloalkyl; each R⁹ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- ₆cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- ₆cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹¹ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C_3-6cycloalkyl; and p is 0, 1, or 2.

[0171] In some embodiments, T, U, and Y are independently selected from N and CR⁶, provided that when U is N, at least one of T and Y is N. In some embodiments, one of T, U, and Y is N and the rest are CR⁶. In some embodiments, two of T, U, and Y are N and the rest are CR⁶. In some embodiments, one of T, U, and Y is CR⁶ and the rest are N. In some embodiments, two of T, U, and Y are CR⁶ and the rest are N. In some embodiments, T, U, and Y are N. In some embodiments, T, U, and Y are CR⁶.

[0172] In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, - SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, -NR¹¹ SO₂R⁹, - NR¹¹SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, - C(O)NR⁷R⁸, -SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, -NR¹¹ SO₂R⁹, -NR¹¹SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁷R⁸, - OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, -SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, - NR¹¹C(O)NR⁷R⁸, -NR¹¹ SO₂R⁹, and -NR¹¹ SO₂NR⁷R⁸. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁷R⁸, -OR⁹, - C(O)R⁹, -C(O)OR⁹, and-C(O)NR⁷R⁸.

[0173] In some embodiments, R² is H and R³ is -CF₃. In some embodiments, R² and R³ are taken together to form oxo.

[0174] In some embodiments, each R⁴ is independently selected from H and halo. In some embodiments, each R⁴ is independently selected from H and fluoro. In some embodiments, each R⁴ is H. In some embodiments, each R⁴ is fluoro. In some embodiments, one R⁴ is H and one R⁴ is fluoro.

[0175] In some embodiments, R⁵ is selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, -SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, - NR¹¹SO₂R⁹, -NR¹¹ SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁵ is selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, - SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, -NR¹¹ SO₂R⁹, - NR¹¹SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁵ is selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, -SOR¹⁰, -SO₂R¹⁰, - SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, -NR¹¹SO₂R⁹, and -NR¹¹SO₂NR⁷R⁸. In some embodiments, R⁵ is selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, and - C(O)NR⁷R⁸.

[0176] In some embodiments, R⁶ is selected from H, halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, - C(O)OR⁹, -C(O)NR⁷R⁸, -SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, - NR¹¹SO₂R⁹, -NR¹¹ SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁶ is selected from H, halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, - C(O)NR⁷R⁸, -SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, -NR¹¹ SO₂R⁹, -NR¹¹ SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁶ is selected from H, halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, -SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, -NR¹¹ SO₂R⁹, and -NR¹¹SO₂NR⁷R⁸. In some embodiments, R⁶ is selected from H, halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, and- C(O)NR⁷R⁸.

[0177] In some embodiments, R⁷ and R⁸ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-6cycloalkyl. In some embodiments, R⁷ and R⁸ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1- ₆haloalkyl. In some embodiments, R⁷ and R⁸ are independently selected at each occurrence from H and C_1-6alkyl.

[0178] In some embodiments, each R⁹ is independently selected from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁹ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁹ is independently selected from H and C_1-6alkyl. [0179] In some embodiments, each R¹⁰ is independently selected from C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹⁰ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R¹⁰ is independently selected from C_1-6alkyl. [0180] In some embodiments, each R¹¹ is independently selected from H, C_1-6alkyl, C_1- ₆haloalkyl, and C_3-6cycloalkyl. In some embodiments, each R¹¹ is independently selected from H, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments, each R¹¹ is independently selected from H and C_1-6alkyl.

[0181] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0182] In some embodiments, the 15-PGDH inhibitor is a compound of Formula Ilm:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, - NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo; each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁴’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, - SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C 1 -ehaloalky 1, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆- waryl, and 5- to 10-membered heteroaryl;

R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- ₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- ₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

[0183] In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10- membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, - OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, - C(O)R⁸, -C(O)OR⁸, and-C(O)NR⁶R⁷.

[0184] In some embodiments, R² is H and R³ is -CF₃. In some embodiments, R² and R³ are taken together to form oxo.

[0185] In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, - C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and - NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R⁴ is independently selected from halo, - NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, and -C(O)NR⁶R⁷. In some embodiments, each R⁴ is independently selected from halo. In some embodiments, each R⁴ is fluoro.

[0186] In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’S are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, - C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, - NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and - NR¹⁰SO₂NR⁶R⁷. In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, and -C(O)NR⁶R⁷.

[0187] In some embodiments, R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10- membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, - SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷ In some embodiments, R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, and - C(O)NR⁶R⁷

[0188] In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl. In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl. In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H and C_1-6alkyl.

[0189] In some embodiments, each R⁸ is independently selected from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁸ is independently selected from H and C_1-6alkyl. [0190] In some embodiments, each R⁹ is independently selected from C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl. In some embodiments, each R⁹ is independently selected from C_1-6alkyl.

[0191] In some embodiments, each R¹⁰ is independently selected from H, C_1-6alkyl, C_1- ₆haloalkyl, and C_3-10cycloalkyl. In some embodiments, each R¹⁰ is independently selected from H, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments, each R¹⁰ is independently selected from H and C_1-6alkyl.

[0192] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0193] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0194] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0195] In some embodiments, the 15-PGDH inhibitor is a compound of Formula Ilq:

or a pharmaceutically acceptable salt thereof, wherein:

R² is H and R³ is -CF₃; or

R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C i -ehaloalky 1, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C₆- waryl, and 5- to 10-membered heteroaryl;

[0196] In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10- membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, - OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁶R⁷, -OR⁸, - C(O)R⁸, -C(O)OR⁸, and-C(O)NR⁶R⁷.

[0197] In some embodiments, R² is H and R³ is -CF₃. In some embodiments, R² and R³ are taken together to form oxo.

[0198] In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, - C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and - NR¹⁰SO₂NR⁶R⁷. In some embodiments, each R⁴ is independently selected from halo, - NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, and -C(O)NR⁶R⁷. In some embodiments, each R⁴ is independently selected from halo. In some embodiments, each R⁴ is fluoro.

[0199] In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’S are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, - C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, - NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and - NR¹⁰SO₂NR⁶R⁷. In some embodiments, two R⁴’s are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C_3-10cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, and -C(O)NR⁶R⁷.

[0200] In some embodiments, R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10- membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, - SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, - NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, - SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, and -NR¹⁰SO₂NR⁶R⁷ In some embodiments, R⁵ is selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, and - C(O)NR⁶R⁷

[0201] In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl. In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl. In some embodiments, R⁶ and R⁷ are independently selected at each occurrence from H and C_1-6alkyl.

[0202] In some embodiments, each R⁸ is independently selected from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁸ is independently selected from H and C_1-6alkyl. [0203] In some embodiments, each R⁹ is independently selected from C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl. In some embodiments, each R⁹ is independently selected from C_1-6alkyl.

[0204] In some embodiments, each R¹⁰ is independently selected from H, C_1-6alkyl, C_1- ₆haloalkyl, and C_3-10cycloalkyl. In some embodiments, each R¹⁰ is independently selected from H, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments, each R¹⁰ is independently selected from H and C_1-6alkyl. [0205] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0206] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0207] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0208] In some embodiments, the 15-PGDH inhibitor is a compound of Formula IIIc:

Y is selected from O, S, SO₂, and C(R⁸)2;

R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo;

R⁴ and R⁵ are independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C₃- ₆cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; or R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, - SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, - NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁶ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁶’ S attached to the same carbon atom are taken together to form oxo, and any remaining R⁶’S are independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁷ and R⁸ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁹ and R¹⁰ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-6cycloalkyl; each R¹¹ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- ₆cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹² is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- ₆cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹³ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C_3-6cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0209] In some embodiments, each X is independently selected from N and CR⁷. In some embodiments, at least one X is N and the rest are CR⁷. In some embodiments, at least two X are N and the rest are CR⁷. In some embodiments, each X is N. In some embodiments, each X is CR⁷. [0210] In some embodiments, Y is selected from O, S, SO₂, and C(R⁸)2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO₂. In some embodiments, Y is C(R⁸)2.

[0211] In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, - SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, - NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, and 5- to 10- membered heteroaryl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10- membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², - SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and -NR¹³SO₂NR⁹R¹⁰. In some embodiments, R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and-C(O)NR⁹R¹⁰.

[0212] In some embodiments, R² is H and R³ is -CF₃. In some embodiments, R² and R³ are taken together to form oxo.

[0213] In some embodiments, R⁴ and R⁵ are independently selected from C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², - SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁴ and R⁵ are independently selected from C_3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1- ₆haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl. In some embodiments, R⁴ and R⁵ are independently selected from C₃- ₁₀cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, - C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁴ and R⁵ are independently selected from C_3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², - SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and - NR¹³SO₂NR⁹R¹⁰. In some embodiments, R⁴ and R⁵ are independently selected from C₃- ₁₀cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and - C(O)NR⁹R¹⁰.

[0214] In some embodiments, R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², - SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3 - to 10- membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², - SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and - NR¹³SO₂NR⁹R¹⁰. In some embodiments, R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and -C(O)NR⁹R¹⁰. [0215] In some embodiments, each R⁶ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁶ is independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1- ₆haloalkyl. In some embodiments, each R⁶ is independently selected from halo, -NR⁹R¹⁰, - OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and -NR¹³SO₂NR⁹R¹⁰. In some embodiments, each R⁶ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and - C(O)NR⁹R¹⁰.

[0216] In some embodiments, two R⁶’s attached to the same carbon atom are taken together to form oxo, and any remaining R⁶’s are independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R⁶’s attached to the same carbon atom are taken together to form oxo, and any remaining R⁶’s are independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, and C_1-6haloalkyl. In some embodiments, two R⁶’s attached to the same carbon atom are taken together to form oxo, and any remaining R⁶’s are independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², - SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and -NR¹³SO₂NR⁹R¹⁰. In some embodiments, two R⁶’s attached to the same carbon atom are taken together to form oxo, and any remaining R⁶’s are independently selected from halo, -NR⁹R¹⁰, -OR¹¹, - C(O)R¹¹, -C(O)OR¹¹, and -C(O)NR⁹R¹⁰.

[0217] In some embodiments, each R⁷ and R⁸ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R⁷ and R⁸ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², - SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R⁷ and R⁸ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, - SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, and - NR¹³SO₂NR⁹R¹⁰. In some embodiments, each R⁷ and R⁸ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, and-C(O)NR⁹R¹⁰.

[0218] In some embodiments, R⁹ and R¹⁰ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl. In some embodiments, R⁹ and R¹⁰ are independently selected at each occurrence from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, R⁹ and R¹⁰ are independently selected at each occurrence from H and C_1-6alkyl.

[0219] In some embodiments, each R¹¹ is independently selected from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹¹ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R¹¹ is independently selected from H and C_1- ealkyl.

[0220] In some embodiments, each R¹² is independently selected from C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹² is independently selected from C_1-6alkyl, C_1-6heteroalkyl, and C_1-6haloalkyl. In some embodiments, each R¹² is independently selected from C_1-6alkyl. [0221] In some embodiments, each R¹³ is independently selected from H, C_1-6alkyl, C_1- ₆haloalkyl, and C_3-10cycloalkyl. In some embodiments, each R¹³ is independently selected from H, C_1-6alkyl, and C_1-6haloalkyl. In some embodiments, each R¹³ is independently selected from H and C_1-6alkyl.

[0222] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0223] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0224] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

-801-

[0225] In some embodiments, the 15-PGDH inhibitor is a compound selected from the group consisting of:

[0226] In some cases, the solubility and hPGDH ICso of the inhibitors are characterized as shown in Tables 1 and 2.

-Ill-



Table 2: Characteristics of PGDH Inhibitors with a phenyl core.

[0227] Provided in Table 3 are analytical data for some of the inhibitors described herein.

Table 3: Analytical data for select inhibitors

[0228] In some embodiments, the 15-PGDH inhibitor is a compound of having the structure of Formula IV, or a pharmaceutically acceptable salt thereof:

wherein, ring Q is phenyl or 5- to 10-membered heteroaryl;

Z is CR¹ or N;

Y is CR² or N;

R¹ is H, halogen, -CN, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -NR⁸R⁹, -C(O)NR⁸R⁹, -NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl; each R² is independently H, halogen, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -CN, -C(O)NR⁸R⁹, - NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃- Cs cycloalkyl; each R³ is independently selected from H, halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, - C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, or -C(O)NR⁸R⁹;

R⁴ is substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₁-C₈ aminoalkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, substituted or unsubstituted C_1- Q hydroxy alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₃-C₈ heterocycloalkyl, each of which is substituted with one or more R⁶; wherein each R⁶ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₁-C₆ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted C₃-C₈ heterocycloalkyl;

R^5a is H or CH₃; or R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted C₃-C₆ heterocycloalkyl; each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; each R^a is independently selected from halogen, -OH, -CH₃, -CF₃, -OCH₃, -NH₂, -NHCH₃, - N(CH₃)₂, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, - NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃; and p is 1, 2, 3, or 4.

[0229] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula IV, or a pharmaceutically acceptable salt thereof:

wherein, ring Q is phenyl or 5- to 10-membered heteroaryl;

Z is CR¹ or N;

Y is CR² of N;

R¹ is H, halogen, -CN, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -NR⁸R⁹, -C(O)NR⁸R⁹, -NR⁸C(O)R⁹ substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl;

R² is H, halogen, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -CN, -C(O)NR⁸R⁹, -NR⁸C(O)R⁹, or substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl; each R³ is independently selected from H, halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -C(O)R¹⁰, - C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl;

R⁴ is substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₁-C₈ heteroalkyl, substituted or unsubstituted C₁-C₈ hydroxyalkyl; substituted or unsubstituted C₃-C₈ cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R⁶; wherein each R⁶ is independently H, halogen, CN,-N02, -NR⁸R⁹, -OH, -OR¹⁰, -SR⁸, - C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -NR⁸C(O)R⁹, Ci-C₆ alkyl, C_1-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, phenyl, or 5- to 8- membered heteroaryl; or two R⁶ combine together with the atom(s) to which they are attached to form a C₃- C₆ cycloalkyl ring;

R^5a is H or CH₃; or R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a C₃- C₆ cycloalkyl ring; each R⁸ and R⁹ is independently selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C_1-C₆ heteroalkyl, C_1-C₆ haloalkyl, C₃-C₁₀ cycloalkyl, and C4-C₁₀ heterocycloalkyl; each R¹⁰ is independently selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ heteroalkyl, C_1- C₆ haloalkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl; each R¹¹ is independently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl; each R¹² is independently selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, and C₃-C₈ cycloalkyl; and p is 1, 2, 3, or 4.

[0230] In some embodiments, In some embodiments, ring Q is 5- to 10-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is 5- to 8-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, ring Q is 5- to 8-membered heteroaryl, comprising 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is a monocyclic, bicyclic, or polycyclic heteroaryl. In some embodiments, ring Q is a bicyclic heteroaryl comprising 1, 2, 3, or 4 heteroatoms selected from N and O. In some embodiments, ring Q is indole, benzimidazole, benzotri azole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyridine, or tetrazolo pyridine. In some embodiments, ring Q is [l,2,4]triazolo[l,5-a]pyridine.

[0231] In some embodiments, ring Q is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 N atoms. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is a phenyl, pyrimidine, or pyridine In some embodiments, ring Q is phenyl. In some embodiments, ring Q is pyrimidine In some embodiments, ring Q is pyridine.

[0232] In some embodiments, ring Q is phenyl, pyridine, or triazolopyridine.

[0233] In some embodiments,

wherein,

X¹, X², X³ and X⁴ are each independently N or CR³; each R³ is independently selected from H, halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, - C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or -C(O)NR⁸R⁹; each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; and each R^a is independently selected from halogen, -OH, -CH₃, -CF₃, -OCH₃, -NH₂, -NHCH₃, - N(CH₃)₂, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, - NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃.

[0234] In some embodiments, X¹, X², X³ and X⁴ are each CR³.

[0235] In some embodiments, X¹ is N; and X², X³, and X⁴ are each CR³.

[0236] In some embodiments, X¹ and X² are each N; and X³ and X⁴ are each CR³. [0237] In some embodiments, X¹ and X³ are each N; and X² and X⁴ are each CR³. [0238] In some embodiments, X¹ and X⁴ are each N; and X² and X³ are each CR³. [0239] In some embodiments, X¹, X², and X³ are each N; and X⁴ is CR³.

[0240] In some embodiments, X¹, X², and X⁴ are each N; and X³ is CR³.

[0241] In some embodiments, each R³ is independently selected from H, halogen, -CN, - NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, - SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, - NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each R³ is independently selected from H, halogen, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, each R³ is independently selected from H, halogen, -C(O)R¹⁰, -C(O)OR¹⁰, - C(O)NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, each R³ is independently selected from H, halogen, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl.

[0242] In some embodiments, each R³ is independently selected from H or halogen. In some embodiments, each R³ is independently substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, each R³ is independently a substituted or unsubstituted 5-membered heteroaryl.

[0243] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula V, or a pharmaceutically acceptable salt thereof:

wherein,

Z is CR¹ or N;

X¹ is N or CR^3a;

Y is CR² or N;

R¹ is H, halogen, -CN, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -NR⁸R⁹, -C(O)NR⁸R⁹, -NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl; each R² is independently H, halogen, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -CN, -C(O)NR⁸R⁹, - NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃- Cs cycloalkyl;

R⁴ is substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₁-C₈ aminoalkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, substituted or unsubstituted C_1-Q hydroxy alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₃-C₈ heterocycloalkyl, each of which is substituted with one or more R⁶; wherein each R⁶ is independently halogen, CN,-N02, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₁-C₆ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8-membered heteroaryl; or two R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted C₃-C₈ heterocycloalkyl;

R^5a is H or CH₃; or R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl; each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; and each R^a is independently selected from halogen, -OH, -CH₃, -CF₃, -OCH₃, -NH₂, -NHCH₃, - N(CH₃)₂, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, - NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃

[0244] In some embodiments, the 15-PGDH inhibitor is a compound having the structure of Formula V, or a pharmaceutically acceptable salt thereof:

wherein,

Z is CR¹ or N;

X¹ is N or CR^3a;

Y is CR² or N;

R¹ is H; each R² is independently H or C₁-C₆ alkyl;

R^3a, R^3b, and R^3c are each independently selected from H, halogen, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, or -C(O)NR⁸R⁹;

R⁴ is substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, substituted or unsubstituted C₁-C₈ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₃-C₈ heterocycloalkyl, each of which is substituted with one or more R⁶; wherein each R⁶ is independently halogen, CN,-N02, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₁-C₆ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₃-C₈ heterocycloalkyl; or two R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted C₃-C₈ heterocycloalkyl;

X^A is -OR⁵; wherein each R⁵ is independently H or C₁-C₆ alkyl;

R^5a is H or CH₃; or R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl; each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; and each R^a is independently selected from halogen, -OH, -CH₃, -CF₃, -OCH₃, -NH₂, -NHCH₃, - N(CH₃)₂, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, - NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃.

[0245] In some embodiments, X^A is NR⁵R⁵. In some embodiments, X^A is OR⁵.

[0246] In some embodiments, Y is N. In some embodiments, Y is CR².

[0247] In some embodiments, the compound of Formula V has the structure of Formula Via, or a pharmaceutically acceptable salt thereof:

[0248] In some embodiments, the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:

[0249] In some embodiments, Z is N. In some embodiments, Z is CR¹. In some embodiments, Z is CH.

[0250] In some embodiments, the compound of Formula V has the structure of Formula Vila, or a pharmaceutically acceptable salt thereof:

[0251] In some embodiments, the compound of Formula V has the structure of Formula Vllb, or a pharmaceutically acceptable salt thereof:

[0252] In some embodiments, the compound of Formula V has the structure of Formula Vile, or a pharmaceutically acceptable salt thereof:

[0253] In some embodiments, the compound of Formula V has the structure of Formula Vlld, or a pharmaceutically acceptable salt thereof:

[0254] In some embodiments, R¹ is H, halogen, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, or substituted or unsubstituted C₁-C₆ alkyl. In some embodiments, R¹ is H.

[0255] In some embodiments, each R² is independently H, halogen, -OR¹⁰, -C(O)R¹⁰, - C(O)OR¹⁰, or substituted or unsubstituted C₁-C₆ alkyl. In some embodiments, each R² is independently H or C₁-C₆ alkyl.

[0256] In some embodiments, each R² is H.

[0257] In some embodiments, X¹ is CR^3a. In some embodiments, X¹ is N.

[0258] In some embodiments, R^3a, R^3b, and R^3c are each independently selected from H, halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -S⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, - SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, - NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R^3a, R^3b, and R^3c are each independently selected from H, halogen, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10- membered heteroaryl. In some embodiments, R^3a, R^3b, and R^3c are each independently selected from H, halogen, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6- membered heteroaryl. In some embodiments, R^3a, R^3b, and R^3c are each independently selected from H, halogen, -C(O)R¹⁰, -C(O)NR⁸R⁹, and substituted or unsubstituted 5- membered heteroaryl. In some embodiments, R^3a, R^3b, and R^3c are each independently selected from H, halogen, -OR¹⁰, -S⁸,-C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹,- NR¹²C(O)R¹⁰, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R^3a, R^3b, and R^3c are each independently selected from H, halogen, substituted or unsubstituted C₁-C₆ alkyl, -C(O)R¹⁰, -C(O)NR⁸R⁹, C₃-C₆ heterocycloalkyl, and 5- membered heteroaryl.

[0259] In some embodiments, R^3a, R^3b, and R^3c are each independently selected from H, halogen, -C(O)OH, -C(O)NH₂, -C(O)NH(CH₃), -C(O)N(CH₃)₂, triazole, tetrazole, pyrrolidine, morpholine, or C₁-C₆ alkyl substituted with -C(O)OH. [0260] In some embodiments, R^3a and R^3b are each H or halogen; and R^3c is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, - SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, - NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R^3a and R^3b are each H or halogen; and R^3c is selected from halogen, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R^3a and R^3b are each H or halogen; and R^3c is selected from halogen, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, - NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R^3a and R^3b are each H or halogen; and R^3c is selected from -NR¹²C(O)OR¹⁰, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R^3a and R^3b are each H or halogen; and R^3c is selected from substituted or unsubstituted C₁-C₆ alkyl, - C(O)R¹⁰, -C(O)NR⁸R⁹, C₃-C₆ heterocycloalkyl, and 5- membered heteroaryl. In some embodiments, R^3a and R^3b are each H or halogen; and R^3c is a substituted or unsubstituted 5- membered heteroaryl.

[0261] In some embodiments, R^3a is halogen and R^3b is H. In some embodiments, R^3a is -Cl or -F; and R^3b is H. In some embodiments, R^3b is halogen and R^3a is H. In some embodiments, R^3b is -Cl or -F; and R^3a is H.

[0262] In some embodiments, R^3a and R^3b are each H.

[0263] In some embodiments, R^3a and R^3c are independently H or halogen; and R^3b is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, - SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, - NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R^3a and R^3c are each H; and R^3b is selected from halogen, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R^3a and R^3c are each H; and R^3b is selected from halogen, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6- membered heteroaryl. In some embodiments, R^3a and R^3c are each H; and R^3b is selected from -C(O)R¹⁰, -C(O)OR¹⁰, -NR¹²C(O)OR¹⁰, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, R^3a and R^3c are each H or halogen; and R^3b is selected from substituted or unsubstituted C₁-C₆ alkyl, -C(O)R¹⁰, - C(O)NR⁸R⁹, C₃-C₆ heterocycloalkyl, and 5- membered heteroaryl.

[0264] In some embodiments, R^3a and R^3c are each H or halogen; and R^3b is selected from - C(O)R¹⁰, -C(O)OR¹⁰ and substituted or unsubstituted 5-membered heteroaryl.

[0265] In some embodiments, R^3a is halogen and R^3c is H. In some embodiments, R^3a is H and R^3b is halogen. In some embodiments, R^3a is -Cl or -F; and R^3c is H. In some embodiments, R^3c is -Cl or -F; and R^3a is H.

[0266] In some embodiments, R^3a and R^3c are each H.

[0267] In some embodiments, each R³, R^3a, R^3b, and R^3c are each independently a 5- membered heteroaryl selected from pyrrole, triazole, tetrazole, oxazole, diazole, oxadiazole, thiadiazole, and furanyl. In some embodiments, each R³, R^3a, R^3b, and R^3c are each independently a 5-membered heteroaryl selected from pyrrole, triazole, and tetrazole. In some embodiments, each R³, R^3a, R^3b, and R^3c are each independently a 5-membered heteroaryl selected from triazole and tetrazole.

[0268] In some embodiments, each R³, R^3a, R^3b, or R^3c is independently selected from the

[0269] In some embodiments, each R³, R^3a, R^3b, or R^3c is independently selected from the

In some embodiments, each R³, R^3a, R^3b, or R^3c is independently selected from the group consisting

[0270] In some embodiments, R⁴ is substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₁-C₈ aminoalkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, substituted or unsubstituted C_1-Q hydroxy alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R⁶. In some embodiment, R⁴ is substituted or unsubstituted Ci- C₈ alkyl, substituted or unsubstituted C₁-C₈ aminoalkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, or substituted or unsubstituted C₁-C₈ hydroxy alkyl. In some embodiments, R⁴ is substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, or substituted or unsubstituted C₁-C₈ hydroxy alkyl.

[0271] In some embodiment, R⁴ is substituted or unsubstituted C₁-C₈ alkyl or substituted or unsubstituted C₁-C₈ heteroalkyl. In some embodiment, R⁴ is substituted or unsubstituted Ci- Cs alkyl. In some embodiments, the alkyl is a straight chain or branched alkyl. In some embodiment, R⁴ is substituted or unsubstituted C₁-C₈ heteroalkyl. In some embodiments, the heteroalkyl is an alkyl chain wherein one or more of the carbon atoms is replaced with an O or N atom. In some embodiment, R⁴ is substituted or unsubstituted -CH₂CH₂-O-(C₁-C₄ alkyl), -CH₂-O-(CI-C₄ alkyl), substituted or unsubstituted -CH₂CH₂-O-(C₁-C₄ haloalkyl), -CH₂-O- (C1-C4 haloalkyl), -CH₂CH₂-O-(C₃-C₆ cycloalkyl), -CH₂-O-(C₃-C₆ cycloalkyl), -CH₂CH₂-O- (C₃-C₆ heterocycloalkyl), or -CH₂-O-(C₃-C₆ heterocycloalkyl). In some embodiment, R⁴ is substituted or unsubstituted -CH₂CH₂-O-(C₁-C₄ alkyl), -CH₂-O-(C₁-C₄ alkyl), substituted or unsubstituted -CH₂CH₂-O-(C₁-C₄ haloalkyl), or -CH₂-O-(C₁-C₄ haloalkyl). In some embodiments, R⁴ is -CH₂CH₂-O-(C₃-C₆ cycloalkyl), -CH₂-O-(C₃-C₆ cycloalkyl), -CH₂CH₂- O-(C₃-C₆ heterocycloalkyl), or -CH₂-O-(C₃-C₆ heterocycloalkyl). In some embodiments, R⁴ is -CH₂CH₂-O-(C₃-C₆ cycloalkyl). In some embodiments, R⁴ is -CH₂-O-(C₃-C₆ cycloalkyl). In some embodiments, R⁴ is -CH₂CH₂-O-(C₃-C₆ heterocycloalkyl). In some embodiments, R⁴ is -CH₂-O-(C₃-C₆ heterocycloalkyl).

[0272] In some embodiments, R⁴ is substituted or unsubstituted C₁-C₈ alkyl, which is substituted with one or more halogen, -OR¹⁰, C₁-C₈ alkyl, or C₃-C₆ cycloalkyl.

[0273] In some embodiments, R⁴ is substituted or unsubstituted C₃-C₈ cycloalkyl or substituted or unsubstituted C₃-C₈ heterocycloalkyl, each of which is substituted with one or more R⁶. In some embodiments, R⁴ is C₃-C₈ cycloalkyl. In some embodiments, R⁴ is monocyclic, polycyclic, spirocyclic, or bridged cycloalkyl. In some embodiments, R⁴ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R⁴ is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R⁴ is cyclopropyl. In some embodiments, R⁴ is cyclobutyl. In some embodiments, R⁴ is cyclopentyl. In some embodiments, R⁴ is cyclohexyl. In some embodiments, R⁴ is

[0274] In some embodiments, R⁴ is substituted or unsubstituted C₃-C₈ heterocycloalkyl, each of which is substituted with one or more R⁶. In some embodiments, R⁴ is monocyclic, polycyclic, spirocyclic, or bridged heterocycloalkyl. In some embodiments, R⁴ is a 4- membered heterocycloalkyl. In some embodiments, R⁴ is a 5-membered heterocycloalkyl. In some embodiments, R⁴ is a 6-membered cycloalkyl. In some embodiments, R⁴ is a 7- membered cycloalkyl. In some embodiments, R⁴ is tetrahydrofuran, pyrrolidine, tetrahydropyran, or piperidine. In some embodiments, R⁴ is tetrahydrofuran or tetrahydropyran.

[0275] In some embodiments, each R⁶ is independently halogen, -CN,-NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -NR⁸C(O)R⁹, Ci-C₆ alkyl, C_1- C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocycloalkyl, phenyl, or 5- to 8-membered heteroaryl. In some embodiments, each R⁶ is independently halogen, -NR⁸R⁹, - OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -NR⁸C(O)R⁹, CI-C₆ alkyl, Ci-C₆ haloalky 1, Ci-C₆ hydroxyalkyl, or C₃-C₈ cycloalkyl. In some embodiments, each R⁶ is independently halogen, -NR⁸R⁹, -OR¹⁰,-C(O)OR¹⁰, -C(O)NR⁸R⁹, CI-C₆ alkyl, or C₃-C₈ cycloalkyl. In some embodiments, each R⁶ is independently halogen, -NR⁸R⁹, -OR¹⁰, or C₃-C₈ cycloalkyl. In some embodiments, each R⁶ is independently -NR⁸R⁹ or -OR¹⁰. In some embodiments, each R⁶ is independently C₃-C₈ cycloalkyl. In some embodiments, the cycloalkyl is monocyclic, spirocyclic or bridged cycloalkyl. In some embodiments, each R⁶ is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R⁶ is independently halogen. In some embodiments, each R⁶ is independently H, Cl, F, or Br. In some embodiments, each R⁶ is independently F. In some embodiments, each R⁶ is independently F, -OH, -CH₃, -CF₃, -N(CH₃)₂, -NH(CH₃), -NH(CH₃CH₃), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, piperidine, piperazine, oxetane, tetrahydrofuran, or tetrahydropyran. In some embodiments, each R⁶ is independently F, -OH, -CH₃, -CF₃, -N(CH₃)₂, -NH(CH₃), -NH(CH₂CH₃), cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R⁶ is independently F, -OH, -CH₃, or -CF₃. In some embodiments, each R⁶ is independently F. In some embodiments, each R⁶ is independently -OH. In some embodiments, each R⁶ is independently -CF₃. In some embodiments, each R⁶ is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R⁶ is independently cyclopropyl. In some embodiments, each R⁶ is cyclobutyl.

[0276] In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted C₃-C₆ heterocycloalkyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a cyclopropyl or cyclobutyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a cyclobutyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a cyclopropyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a C₃-C₆ heterocycloalkyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a 4 membered heterocycloalkyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a 5 membered heterocycloalkyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a 6-membered heterocycloalkyl. In some embodiments, two R⁶ combine together with the atom(s) to which they are attached to form a pyran, piperazine, piperidine, or morpholine.

[0277] In some embodiments, R⁴ is -CH₃, -CH₂CH₃, -CH₂CH₃CH₃, -CH₂(CH₂)₂CH₃, - CH₂(CH₂)₃CH₃, -CH₂(CH₂)₄CH₃, -CH₂CH₂CH(CH₃)₂, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substitute or unsubstituted oxetane, substituted or

[0278] In some embodiments, each R⁵ is independently C₁-C₆ alkyl. In some embodiments, each R⁵ is independently -CH₂CH₃ or -CH₃. In some embodiments, each R⁵ is independently -CH₂CH₃. In some embodiments, each R⁵ is independently -CH₃. In some embodiments, each R⁵ is independently H.

[0279] In some embodiments, R^5a is CH₃. In some embodiments, R^5a is H.

[0280] In some embodiments, R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a C₃-C₆ cycloalkyl. In some embodiments, R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a cyclopentyl or cyclohexyl. In some embodiments, R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a cyclohexyl. In some embodiments, R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a cyclopentyl.

[0281] In some embodiments, each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a. In some embodiments, each R⁸ and R⁹ is independently selected at each occurrence from H, Ci- C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, C_1-C₆ haloalkyl, and C₃-C₁₀ cycloalkyl. In some embodiments, each R⁸ and R⁹ is independently selected at each occurrence from H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₃-C₁₀ cycloalkyl, and C₃-C₁₀ heterocycloalkyl. In some embodiments, each R⁸ and R⁹ is independently selected at each occurrence from C₃-C₁₀ cycloalkyl and C₃-C₁₀ heterocycloalkyl.

[0282] In some embodiments, each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a. In some embodiments, each R¹⁰ is independently selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹⁰ is independently selected from H, C₁-C₆ alkyl, C₃- C₁₀ cycloalkyl, and C₃-C₁₀ heterocycloalkyl. In some embodiments, each R¹⁰ is independently selected from H and C₁-C₆ alkyl. In some embodiments, each R¹⁰ is independently selected from C₃-C₁₀ cycloalkyl and C₃-C₁₀ heterocycloalkyl.

[0283] In some embodiments, each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a. In some embodiments, each R¹¹ is independently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R¹¹ is independently selected from C₁-C₆ alkyl, C₁-C₆ heteroalkyl, and C_1-C₆ haloalkyl. In some embodiments, each R¹¹ is independently selected from C₃-C₁₀ cycloalkyl and C₃-C₁₀ heterocycloalkyl.

[0284] In some embodiments, each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a. In some embodiments, each R¹² is independently selected from H, straight or branched chain C_1-C₆ alkyl, C₂-C₆ alkenyl, C_1-C₆haloalkyl, C₃-C₁₀ cycloalkyl, and C₃-C₁₀ heterocycloalkyl. In some embodiments, each R¹² is independently selected from H, straight or branched chain C_1-C₆ alkyl. In some embodiments, each R¹² is independently selected from C₃-C₁₀ cycloalkyl and C₃-C₁₀ heterocycloalkyl.

[0285] In some embodiments, each R^a is independently selected from halogen, -OH, -CH₃, - CF₃, -0CH₃, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃. In some embodiments, each R^a is independently selected from -F, -Cl, -Br, -OH, -CH₃, -CF₃, -OCH₃, -C(O)OH, -C(O)NH₂, and -NHC(O)CH₃. In some embodiments, each R^a is independently selected from -F, -OH, -CH₃, -CF₃, or - C(O)OH.

[0286] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. 1 some embodiments, p is 3. In some embodiments, p is 5. In some embodiments, p is 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.

[0287] In some embodiments, the PDGH inhibitor is a compound described in Table 4, or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the condition is a muscle condition. In some embodiments, the condition is spinal muscular atrophy (SMA). In some embodiments, the condition is a disease. In some embodiments, the disease is a muscle disease. In some embodiments, the muscle condition is muscle atrophy, muscle damage, muscle disorder, or muscle injury. In some embodiments, the muscle disease is associated with muscle atrophy, muscle damage, or muscle injury.

[0289] In some embodiments, the condition associated with muscle damage, injury, or atrophy is selected from the group consisting of acute muscle injury or trauma, soft tissue hand injury, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), inherited myopathies, myotonic muscular dystrophy (MDD), mitochondrial myopathies, myotubular myopathy (MM), myasthenia gravis (MG), congestive heart failure, periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, cardiac cachexia, stress induced urinary incontinence, and sarcopenia.

[0290] In some embodiments, the muscle damage can be any muscle of the body, including but is not limited to, musculi pectoralis complex, latissimus dorsi, teres major and subscapularis, brachioradialis, biceps, brachialis, pronator quadratus, pronator teres, flexor carpi radialis, flexor carpi ulnaris, flexor digitorum superficialis, flexor digitorum profundus, flexor pollicis brevis, opponens pollicis, adductor pollicis, flexor pollicis brevis, iliopsoas, psoas, rectus abdominis, rectus femoris, gluteus maximus, gluteus medius, medial hamstrings, gastrocnemius, lateral hamstring, quadriceps mechanism, adductor longus, adductor brevis, adductor magnus, gastrocnemius medial, gastrocnemius lateral, soleus, tibialis posterior, tibialis anterior, flexor digitorum longus, flexor digitorum brevis, flexor hallucis longus, extensor hallucis longus, hand muscles, arm muscles, foot muscles, leg muscles, chest muscles, stomach muscles, back muscles, buttock muscles, shoulder muscles, head and neck muscles, facial muscles, oculopharyngeal muscles, and the like.

[0291] In some embodiments, the muscle condition comprises musculoskeletal injuries (e.g., fractures, strains, sprains, acute injuries, overuse injuries, and the like), post-trauma damages to limbs or face, athletic injuries, post-fractures in the aged, soft tissue hand injuries, muscle atrophy (e.g., loss of muscle mass), Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, myotonia congenita, myotonic dystrophy, other muscular dystrophies, muscle wasting disease, such as cachexia due to cancer, end stage renal disease (ESRD), acquired immune deficiency syndrome (AIDS), or chronic obstructive pulmonary disease (COPD), post-surgical muscle weakness, post-traumatic muscle weakness, sarcopenia, inactivity (e.g., muscle disuse or immobility), urethral sphincter deficiency, urethral sphincter deficiency, neuromuscular disease, and the like.

[0292] In some embodiments, the muscle condition comprises a neuromuscular disease. In some embodiments, the neuromuscular diseases include, but are not limited to, acid maltase deficiency, amyotrophic lateral sclerosis, Andersen-Tawil syndrome, Becker muscular dystrophy, Becker myotonia congenita, Bethlem myopathy, bulbospinal muscular atrophy, carnitine deficiency, carnitine palmityl transferase deficiency, central core disease, centronuclear myopathy, Charcot-Marie-Tooth disease, congenital muscular dystrophy, congenital myasthenic syndromes, congenital myotonic dystrophy, Cori disease, Debrancher enzyme deficiency, Dejerine-Sottas disease, dermatomyositis, distal muscular dystrophy, Duchenne muscular dystrophy, dystrophia myotonica, Emery-Dreifuss muscular dystrophy, endocrine myopathies, Eulenberg disease, facioscapulohumeral muscular dystrophy, tibial distal myopathy, Friedreich's ataxia, Fukuyuma congenital muscular dystrophy, glycogenosis type 10, glycogenosis type 11, glycogenosis type 2, glycogenosis type 3, glycogenosis type 5, glycogenosis type 7, glycogenosis type 9, Gowers-Laing distal myopathy, hereditary inclusion-body myositis, hyperthyroid myopathy, hypothyroid myopathy, inclusion-body myositis, inherited myopathies, integrin-deficient congenital muscular dystrophy, spinal- bulbar muscular atrophy, spinal muscular atrophy, lactate dehydrogenase deficiency, Lambert-Eaton myasthenic syndrome, McArdel disease, merosin-deficient congenital muscular dystrophy, metabolic diseases of muscle, mitochondrial myopathy, Miyoshi distal myopathy, motor neuron disease, muscle-eye-brain disease, myasthenia gravis, myoadenylate deaminase deficiency, myofibrillar myopathy, myophosphorylase deficiency, myotonia congenital, myotonic muscular dystrophy, myotubular myopathy, nemaline myopathy, Nonaka distal myopathy, oculopharyngeal muscular dystrophy, paramyotonia congenital, Pearson syndrome, periodic paralysis, phosphofructokinase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, phosphorylase deficiency, polymyositis, Pompe disease, progressive external ophthalmoplegia, spinal muscular atrophy, Ullrich congenital muscular dystrophy, Welander distal myopathy, ZASP-related myopathy, and the like.

[0293] In some embodiments, Muscle atrophy (e.g., muscle wasting) can be caused by or associated with, for example, normal aging (e.g., sarcopenia), genetic abnormalities (e.g., mutations or single nucleotide polymorphisms), poor nourishment, poor circulation, loss of hormonal support, disuse of the muscle due to lack of exercise (e.g., bedrest, immobilization of a limb in a cast, etc.), aging, damage to the nerve innervating the muscle, poliomyelitis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), heart failure, liver disease, diabetes, obesity, metabolic syndrome, demyelinating diseases (e.g., multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, and Guillian-Barre syndrome), denervation, fatigue, exercise-induced muscle fatigue, frailty, neuromuscular disease, weakness, chronic pain, and the like.

[0294] In some embodiments, the condition is hair loss. In some embodiments, the condition is skin inflammation and/or damage. In some embodiments, the condition is vascular insufficiency. In some embodiments, the condition is congestive heart failure or cardiomyopathy. In some embodiments, the condition is a gastrointestinal disease. In some embodiments, the condition is renal dysfunction. In some embodiments, the condition is a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder. In some embodiments, the condition is a fibrotic or adhesion disease, disorder, or condition. In some embodiments, the condition is scar formation. In some embodiments, the condition is fibrosis. In some embodiments, the condition is idiopathic pulmonary fibrosis. In some embodiments, the condition is kidney fibrosis. In some embodiments, the condition is acute kidney injury. In some embodiments, the condition is sarcopenia. In some embodiments, the condition is a neuromuscular disease.

EXAMPLES

[0295] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.

Example 1: Effects of 15-PGDH inhibitor (e.g., MF-300) administration on PGE2 signaling.

[0296] Administration of a 15-PGDH inhibitor (e.g., MF-300) blocks binding of PGE2 to 15- PGDH, which within skeletal muscle results in increased stem cell proliferation, increased muscle force, and improved mitochondrial function. An overview of the effects of a 15- PGDH inhibitor (e.g., MF-300) on the PGE2 signaling pathway is shown in Fig. 1.

Example 2: Mechanism of action and pharmacokinetic profile of MF-300.

[0297] The mechanism of action and pharmacokinetic profile of a 15-PGDH inhibitor, MF- 300, was assessed using biochemical assays, cell-based assays utilizing A549 cells, and single-dose, 24-hour plasma pharmacokinetic analysis in mice. The effect of administration of various doses of MF-300 on NADH production in a 15-PGDH inhibition biochemical assay is shown in Fig. 2A. The effect of administration of various doses of MF-300 on PGE2 stability in A549 cells in a cell -based assay is shown in Fig. 2B. The effect of administration of 10 mg/kg, 30 mg/kg, and 60 mg/kg doses of MF-300 over 24-hours in circulating plasma of mice is shown in Fig. 2C.

Example 3: Effects of intraperitoneal MF-300 administration in SMNA7 mice.

[0298] SMNA7 mice are used as a model for severe spinal muscle atrophy (SMA). The SMNA7 mouse genome contains a deletion in the endogenous SMN gene locus and two transgenes, the human SMN2 gene coding region and the murine SMN gene deleted for exon 7 (i.e., SMNA7). This combination of genetic alterations leads to severe skeletal muscle denervation and weakness that can be mitigated pharmacologically by the SMN splice modulator, SMN-C3, an analogue of Risdiplam. The effect of intraperitoneal injections of MF-300 at various doses within cohorts of male and female SMNA7 mice was assessed. Briefly, beginning the day after birth, SMNA7 mice received daily intraperitoneal injections of the SMN splice enhancer SMN-C3 (3 mg/kg) for 21 days, and then received an additional 28 days of daily intraperitoneal injections of either SMN-C3 (3 mg/kg) alone or SMN-C3 (3mg /kg) in combination with MF-300 (3 mg/kg, 10 mg/kg, or 30 mg/kg; N = 10-13 per group). Wildtype mice (WT) received no injections. Mice were then tested for isometric plantar flexor force, after which gastrocnemius muscles were harvested (N = 6 per group) for RNA-seq analysis. RNA-seq analysis was performed using Poly A selection with paired end reads and a read depth of approximately 30 x 10⁶ per sample. An additional cohort of SMNA7 med/med model mice (SMN-C3 1 mg/kg) received daily intraperitoneal injections of SMN-C3 and SMN-C3 combined with MF-300 (3 mg/kg or 10 mg/kg) beginning on postnatal day 3 and then assessed for their time-to-right on postnatal day 12, during which they were given 30 seconds to right.

[0299] An overview of the experimental timeline for assessing the effects of SMN-C3 and varying doses of MF-300 on isometric plantar flexor force in SMNA7 mice is shown in Fig. 3A. The effects of repeated treatment with either SMN-C3 only (vehicle), or SMN-C3 with varying doses of MF-300 (3 mg/kg [3MPK], 10 mg/kg [10MPK], or 30 mg/kg [30MPK]) on isometric plantar flexor force of SMNA7 mice is shown in Fig. 3B. Wildtype mice (WT) received no treatment. The effects of repeated treatment of SMNA7 mice with either SMN- C3 only (vehicle), or SMN-C3 with varying doses of MF-300 (3 mg/kg [3MPK], 10 mg/kg [10MPK], or 30 mg/kg [30MPK]) on isometric plantar flexor maximum force of SMNA7 mice is shown in Fig. 3C. Wildtype mice (WT) received no treatment. The effects of repeated treatment with SMN-C3 and varying doses of MF-300 (3 mg/kg [3MPK], 10 mg/kg [10MPK], or 30 mg/kg [30MPK]) on maximum force of SMNA7 mice shown as a percentage relative to the average maximum force of the vehicle-treated cohorts (SMN-C3 only) is shown in Fig. 3D

[0300] 15-PGDH is encoded by Hpgd gene. The levels of HPGD expression in gastrocnemius muscles (represented as transcripts per million) between wildtype (WT) and SMNA7 mice (57 SMNC3) were investigated, and result is shown in Fig. 3E. A principal component analysis comparing gene expression in mice exposed to repeated treatment with either SMN-C3 only (vehicle; SMNA7 mice without 15-PGDH inhibitor; Delta 7 Veh;), no injections (WT mice), or the combined doses of SMN-C3 with MF-300 (SMNA7 mice with 15-PGDH inhibitor; Delta7 MF-300) is shown in Fig. 3F. [0301] The effect of repeated treatment in SMNA7 mice with either SMN-C3 only (1 mg/kg) (SMN-C3 Impk (Veh)), or SMN-C3 with varying doses of MF-300 (3 mg/kg or 10 mg/kg) (SMN-C3 + MF-300 3mpk; or SMN-C3 + MF-300 lOmpk), respectively on the probability of time-to-right within 30 seconds is shown in Fig. 3G. WT mice were included for comparison and did not receive treatment. This result suggests that SMNA7 mice administered with 15-PGDH inhibitor, e.g., MF-300, were able to better regain an upright posture (righting behavior) compared to SMNA7 mice without administration of 15-PGDH inhibitor.

[0302] Overall, these results show that, in SMNA7 mice, administration of 15-PGDH inhibitor, e.g., MF-300, significantly increased force when compared to SMNA7 mice without 15-PGDH inhibitor treatment.

Example 4: Effects of orally-administered MF-300 in SMN1^C/C mice.

[0303] The effect of orally administered MF-300 at various doses was assessed in the SMN1^C/C model of SMA. The SMNl^c/c genome contains a hybrid mouse SMN gene/human SMN2 gene as well as a transgenic human SMN2 gene. These animals have a mild atrophy phenotype and are not treated with SMN-C3. Briefly, 6-8 week old male SMN1^C/C mice received either daily oral vehicle administration (Veh) or daily oral MF-300 administration (10 mg/kg [10MPK], 30 mg/kg [30MPK], or 60 mg/kg [60MPK]) for four weeks, and then tested for isometric plantar flexor force. An additional experiment was performed using mice treated with either vehicle or MF-300 (60 mg/kg) incorporating measurements of nerve and direct muscle-stimulated contractions to localize the effects of MF-300. An overview of the experimental timeline for assessing the effects of the SMN1^C/C genotype and varying doses of MF-300 on isometric plantar flexor force in SMN1^C/C mice is shown in Fig. 4A.

[0304] The effects of repeated treatment with vehicle or varying doses of MF-300 (10 mg/kg, 30 mg/kg, or 60 mg/kg) on isometric plantar flexor force and percent increase in maximum force from vehicle at 150 Hz is shown in Fig. 4B. The effects of repeated treatment with vehicle or varying doses of MF-300 (10 mg/kg, 30 mg/kg, or 60 mg/kg) on isometric plantar flexor force and percent increase in maximum force from vehicle at 150 Hz normalized to muscle mass is shown in Fig. 4C.

[0305] An overview of the design and rationale for the experiments wherein mice were treated with either vehicle or MF-300 (60 mg/kg) and incorporating measurements of nerve and direct muscle-stimulated contractions to localize the effects of MF-300 is shown in Fig.

4D

[0306] The effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force associated with nerve stimulation is shown in Fig. 4E. The effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force normalized to muscle weight (MW) and associated with nerve stimulation is shown in Fig. 4F. The effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force associated with muscle stimulation is shown in Fig. 4G. The effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force normalized to muscle weight (MW) and associated with muscle stimulation is shown in Fig. 4H. The effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force associated with normalized muscle stimulation to nerve stimulation is shown in Fig. 41. The effects of vehicle and MF-300 treatment (60 mg/kg) (MF300 60MPK) on maximal force associated with normalized muscle stimulation to nerve stimulation and represented as fold difference is shown in Fig. 4J.

[0307] Overall, SMN1^C/C mice administered with 15-PGDH inhibitor, e.g., MF-300, showed better isometric plantar flexor force compared to SMN1^C/C mice in the vehicle group.

Example 5: Effects of orally administered MF-300 in a sciatic nerve crush mouse model. [0308] The effect of orally administered vehicle or MF-300 within cohorts of male mice (C57B1/6, 10-12 weeks old) exposed to sciatic nerve crush or sham surgery controls was assessed. The nerve crush cohorts were exposed to 30 seconds of nerve crush while the surgery sham cohorts were not exposed to the nerve crush. Sham surgery control mice received daily oral administration of vehicle for 35 days. Nerve crush cohorts received daily oral administration of vehicle or MF-300 (60 mg/kg) for 35 days. Isometric plantar flexor force was measured for each cohort at baseline, and then on days 14, 21, 28, and 35 post treatment-onset.

[0309] An overview of the experimental timeline for assessing the effects of MF-300 on isometric plantar flexor force in a sciatic nerve crush mouse model is shown in Fig. 5A. The maximum force at baseline for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5B. The maximum force on day 14 for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5C. The maximum force on day 21 for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5D. The maximum force on day 28 for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5E. The maximum force on day 35 for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5F. The maximum force normalized by muscle weight on day 35 for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5G. The muscle mass at the end of testing for the surgery sham control mice orally administered vehicle (Sham), the sciatic nerve crush mice orally administered vehicle (Crush - Vehicle), and the sciatic nerve crush mice orally administered MF-300 (60 mg/kg) (Crush - MF300 60mpk QD) is shown in Fig. 5H.

[0310] Overall, in a sciatic nerve crush model, mice that received 15-PGDH inhibitor, e.g., MF-300, showed improvement on isometric plantar flexor force when compared to mice without 15-PGDH inhibitor treatment.

Example 6: Effects of orally-administered MF-300 in a sciatic nerve crush mouse model. [0311] The effect of intermittently dosed, orally administered MF-300, a 15-PGDH inhibitor, at 60 mg/kg within cohorts of male SMN1^C/Cmice was assessed. Briefly, 6-8-week-old male SMN1^C/C mice received either daily oral vehicle administration (Veh) or intermittent doses of oral MF-300 administration (60 mg/kg, given either daily, every 2 days, or every 3 days) for four weeks and were then tested for isometric plantar flexor force. A simulation was also performed to predict plasma concentrations of varying doses of MF-300 based upon the plasma concentration of MF-300 24 hours after a single 60 mg/kg administration in mice. An overview of the experimental timeline for assessing the effects of intermittent dosing of MF- 300 in the SMN1^C/C mice on isometric plantar flexor force is shown in Fig. 6A. The predicted plasma concentrations of MF-300 for the daily MF-300 administration cohort (60 mg/kg) across 8 days is shown in Fig. 6B. The predicted plasma concentrations of MF-300 for the cohort given MF-300 administration every 2 days (60 mg/kg) across 8 days is shown in Fig. 6C. The predicted plasma concentrations of MF-300 for the cohort given MF-300 administration every 3 days (60 mg/kg) across 8 days is shown in Fig. 6D. The data in Figs. 6B-6D demonstrate that the plasma concentration of MF-300 remains above the ECso prior to administration of the subsequent dose with once a day dosing (QD) at 60 mg/kg, whereas with once every 2 days (Q2D) and once every 3 days (Q3D) dosing at 60 mg/kg, the plasma concentration of MF-300 is above the ECso after dosing and then drops below the ECso before administration of the subsequent dose.

[0312] The effects of treatment with vehicle or intermittent doses of MF-300 (60 mg/kg, given either daily, every 2 days, or every 3 days) on maximum isometric plantar flexor force and percent increase in maximum force from vehicle at 150 Hz is shown in Fig. 6E. The effects of treatment with vehicle or intermittent doses of MF-300 (60 mg/kg, given either daily, every 2 days, or every 3 days) on maximum isometric plantar flexor force and percent increase in maximum force from vehicle at 150 Hz normalized to muscle weight is shown in Fig. 6F. The data in Figs. 6E and 6F demonstrate that Q2D dosing of the 15-PGDH inhibitor at 60 mg/kg increases maximum isometric plantar flexor force and maximum force relative to vehicle to a level that is similar to QD dosing. The data in Figs. 6E and 6F further demonstrate that Q3D dosing of the 15-PGDH inhibitor at 60 mg/kg also increases maximum isometric plantar flexor force and maximum force relative to vehicle. This data demonstrates that less than once a day dosing (e.g., Q2D, Q3D) in which the plasma concentration of the 15-PGDH inhibitor is initially above the ECso and then falls below the ECso prior to administration of the subsequent dose, may be sufficient to improve muscle function (e.g., muscle force, e.g., in a subject, e.g., having a muscle condition).

Example 7: Effects of intermittently administered MF-300 in SMNA7 mice

[0313] The effect of intermittently administered intraperitoneal injections of the 15-PGDH inhibitor, MF-300, to SMNA7 mice was assessed. Briefly, beginning the day after birth mice received daily intraperitoneal injections of the SMN splice enhancer SMN-C3 (3 mg/kg) for 21 days, and then received an additional 28 days of intraperitoneal injections of either SMN- C3 (3 mg/kg) alone or SMN-C3 (3mg /kg) in combination with MF-300 (30 mg/kg) administered either daily, every two days, or every three days. SMNA7 mice were compared to wildtype (WT) mice that did not receive injections. Mice were then tested for isometric plantar flexor force. An overview of the experimental timeline for assessing the effects of SMN-C3 and intermittent doses of MF-300 on isometric plantar flexor force in SMNA7 mice is shown in Fig. 7A. The predicted plasma concentrations of MF-300 for the daily MF-300 administration cohort (30 mg/kg) is shown in Fig. 7B. The predicted plasma concentrations of MF-300 for the every two days MF-300 administration cohort (30 mg/kg) is shown in Fig. 7C. The predicted plasma concentrations of MF-300 for the every three days MF-300 administration cohort (30 mg/kg) is shown in Fig. 7D. The predicted plasma concentrations of MF-300 for the daily MF-300 administration cohort (10 mg/kg overlaid with 30 mg/kg) is shown in Fig. 7E. The predicted plasma concentrations of MF-300 for the two days MF-300 administration cohorts (10 mg/kg overlaid with 30 mg/kg) is shown in Fig. 7F. The data in Figs. 7B-7D demonstrate that the plasma concentration of MF-300 remains above the ECso prior to administration of the subsequent dose with once a day dosing (QD) at 30 mg/kg, whereas with once every 2 days (Q2D) and once every 3 days (Q3D) dosing at 30 mg/kg, the plasma concentration of MF-300 is above the ECso after dosing and then drops below the ECso before administration of the subsequent dose. The data in Figs. 7E and 7F show that the plasma concentration of MF-300 is predicted to remain above the EC50 prior to administration of the subsequent dose with once a day dosing (QD) at 10 mg/kg, whereas with once every other day dosing (QOD) at 10 mg/kg, the plasma concentration of MF-300 is predicted to be above the EC50 after dosing and then predicted to drop below the EC50 prior to administration of the subsequent dose.

[0314] The effects of treatment with SMN-C3 alone or SMN-C3 in combination with intermittent doses of MF-300 (30 mg/kg) on maximal isometric plantar flexor force is shown in Fig. 7G The effects of treatment with SMN-C3 alone or SMN-C3 in combination with intermittent doses of MF-300 (30 mg/kg) on and percent increase in maximum force from vehicle at 150 Hz is shown in Fig. 7H. The data in Figs. 7G and 7H demonstrate that Q2D dosing of the 15-PGDH inhibitor at 30 mg/kg increases maximum isometric plantar flexor force relative to vehicle to a level that is similar to QD dosing. The data in Figs. 7G and 7H further demonstrate that Q3D dosing of the 15-PGDH inhibitor at 30 mg/kg also increases maximum isometric plantar flexor force relative to vehicle. This data demonstrates that less than once a day dosing (e.g., Q2D, Q3D), in which the plasma concentration of the 15-PGDH inhibitor is initially above the EC50 and then falls below the EC50 prior to administration of the subsequent dose, may be sufficient to improve muscle function (e.g., muscle force, e.g., in a subject, e.g., having a muscle condition).

[0315] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments described herein may be employed. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS What is claimed is:

1. A method of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject, the method comprising: administering a 15-PGDH inhibitor to the subject in an amount effective to inhibit 15- PGDH at a level sufficient to treat the condition, wherein the 15-PGDH inhibitor is administered to the subject at a dosing frequency that exhibits reduced toxicity to the subject as compared to a once every day dosing frequency of the 15-PGDH inhibitor at the same amount.

2. The method of claim 1, wherein the dosing frequency that exhibits reduced toxicity to the subject is less than once every day.

3. The method of claim 1, wherein the dosing frequency that exhibits reduced toxicity to the subject is once every 2 days, once every 3 days, once every 4 days, once every 5 days, one every 6 days, or once every 7 days.

4. The method of claim 1, wherein the dosing frequency that exhibits reduced toxicity to the subject is less than once every 2 days, less than once every 3 days, less than once every 4 days, less than once every 5 days, less than once every 6 days, or less than once every 7 days.

5. The method of any one of claims 1-4, wherein the administering comprises administering the 15-PGDH inhibitor when a plasma concentration of the 15-PGDH inhibitor in the subject is below the ECso of the 15-PGDH inhibitor. .

6. A method of treating a condition associated with increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity or expression levels in a subject, the method comprising: administering a 15-PGDH inhibitor to the subject at an amount effective to increase a plasma concentration of the 15-PGDH inhibitor in the subject to a level above the ECso of the 15-PGDH inhibitor, wherein the subject has received at least one dose of the 15-PGDH inhibitor prior to the administering, and wherein the administering comprises administering the 15-PGDH inhibitor to the subject when the subject has a plasma concentration of the 15-PGDH inhibitor that is below the ECso of the 15-PGDH inhibitor.

7. The method of claim 6, wherein the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours prior to the administering.

8. The method of claim 6 or 7, wherein the subject has received the at least one dose of the 15-PGDH inhibitor greater than 48 hours prior to the administering.

9. The method of any one of claims 6-8, wherein the subject has received the at least one dose of the 15-PGDH inhibitor greater than 72 hours prior to the administering.

10. The method of any one of claims 6-9, wherein the subject has received the at least one dose of the 15-PGDH inhibitor greater than 24 hours and less than 72 hours prior to the administering.

11. The method of any one of claims 5-10, wherein the administering comprises administering the 15-PGDH inhibitor when the plasma concentration of the 15-PGDH inhibitor in the subject is at least 2-fold, at least 5-fold, at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000-fold, or greater than 1000-fold lower than the ECso of the 15-PGDH inhibitor.

12. The method of any one of claims 5-11, wherein the method results in reduced toxicity to the subject as compared to administering the same amount of the 15-PGDH inhibitor to the subject when the plasma concentration of the 15-PGDH inhibitor in the subject is above the EC50 of the 15-PGDH inhibitor.

13. The method of any one of claims 5-12, wherein the method results in reduced toxicity to the subject as compared to administering the same amount of the 15-PGDH inhibitor to the subject by once a day administration.

14. The method of any one of claims 1-13, wherein the reduced toxicity is selected from the group consisting of: reduced neurological disorders, reduced muscle degeneration, reduced gastrointestinal and/or metabolic distress, reduced inflammation, or any combination thereof.

15. The method of any one of claims 1-14, wherein the reduced toxicity is measured by: safety pharmacology, genetic toxicology, acute and subchronic toxicology, absorption, distribution, metabolism, and excretion (ADME) studies, reproductive and developmental toxicity, an evaluation of carcinogenic potential, or any combination thereof.

16. The method of any one of claims 1-15, wherein the administering comprises administering the 15-PGDH inhibitor to the subject by oral administration.

17. The method of any one of claims 1-16, wherein the 15-PGDH inhibitor is a small molecule.

18. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from -OCH₂- -C(O)NH- -NHC(O)-, -C(O)NMe- -NMeC(O)-, - SCH₂-, -S(O)CH₂- -SO₂CH₂-; each Y is independently selected from N and CR¹¹; each R¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C₃-₁₀cycloalkyl; each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃-₁₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃. 1₀cycloalkyl; each R¹¹ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 1₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

19. The method of claim 18, wherein the compound is a compound of Formula la:

or a pharmaceutically acceptable salt thereof.

20. The method of claim 18, wherein the compound is a compound of Formula lb:

or a pharmaceutically acceptable salt thereof.

21. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

T, U, W, X, and Y are independently selected from N and CR⁵;

S, V, and Z are independently selected from N and C;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo or thio; each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; or two R⁴’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C₃-₁₀cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; each R⁵ is independently selected from H, halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, -C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, - NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C_3-10cycloalkyl; each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃- 1₀cycloalkyl; and n is 1, 2, 3, or 4; and m is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; provided that the compound of Formula II is not

22. The method of claim 21, wherein the compound is a compound of Formula Ila:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

23. The method of claim 21, wherein the compound is a compound of Formula lib :

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

24. The method of claim 21, wherein the compound is a compound of Formula lie:

25. The method of claim 21, wherein the compound is a compound of Formula lid:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

26. The method of claim 21, wherein the compound is a compound of Formula lie:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

27. The method of claim 21, wherein the compound is a compound of Formula Ilf:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

28. The method of claim 21, wherein the compound is a compound of Formula Ilg:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

29. The method of claim 21, wherein the compound is a compound of Formula Ilh:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

30. The method of claim 21, wherein the compound is a compound of Formula Ili :

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

31. The method of claim 21 , wherein the compound is a compound of Formula Ilj :

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

32. The method of claim 21, wherein the compound is a compound of Formula Iln:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.

33. The method of claim 21, wherein the compound is a compound of Formula lip:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.

34. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound of Formula III:

Formula III or a pharmaceutically acceptable salt thereof, wherein: each X is independently selected from N and CR⁷;

Y is selected from O, S, SO₂, and C(R⁸)2;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo or thio;

R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁶ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁶’S attached to the same carbon atom are taken together to form oxo, thio, or C₃- 1₀cycloalkyl, and any remaining R⁶’s are independently selected from halo, - NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², - SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, - NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁷ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁸ is independently selected from H, halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁸’S can be taken together to form a C_3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, - C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, CI. ealkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

35. The method of claim 34, wherein the compound is a compound of Formula Illa:

or a pharmaceutically acceptable salt thereof.

36. The method of claim 34, wherein the compound is a compound of Formula Illb :

37. The method of claim 34, wherein the compound is a compound of Formula IIIc:

or a pharmaceutically acceptable salt thereof.

38. The method of claim 34, wherein the compound is a compound of Formula Illd:

39. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound of Formula Ilk:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from C_6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, - SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, - NR¹¹SO₂R⁹, -NR¹¹ SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 6cycloalkyl, and 5- to 10-membered heteroaryl;

R² is H and R³ is -CF₃; or

R⁶ is selected from H, halo, -NR⁷R⁸, -OR⁹, -C(O)R⁹, -C(O)OR⁹, -C(O)NR⁷R⁸, - SOR¹⁰, -SO₂R¹⁰, -SO₂NR⁷R⁸, -NR¹¹C(O)R⁹, -NR¹¹C(O)NR⁷R⁸, - NR¹¹SO₂R⁹, -NR¹¹ SO₂NR⁷R⁸, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl;

R⁷ and R⁸ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C_3-6cycloalkyl; each R⁹ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹¹ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃- 6cycloalkyl; and p is 0, 1, or 2.

40. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound of Formula Ilm:

or a pharmaceutically acceptable salt thereof, wherein:

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo; each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁴’ S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C₃-₁₀cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

41. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound of Formula Ilq:

or a pharmaceutically acceptable salt thereof, wherein:

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo; each R⁴ is independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁴’S are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C₃-₁₀cycloalkyl, and any remaining R⁴’s are independently selected from halo, -NR⁶R⁷, -OR⁸, -C(O)R⁸, -C(O)OR⁸, - C(O)NR⁶R⁷, -SOR⁹, -SO₂R⁹, -SO₂NR⁶R⁷, -NR¹⁰C(O)R⁸, -NR¹⁰C(O)NR⁶R⁷, -NR¹⁰SO₂R⁸, -NR¹⁰SO₂NR⁶R⁷, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃. 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

R⁶ and R⁷ are independently selected at each occurrence from H, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, and C₃-₁₀cycloalkyl; each R⁸ is independently selected from H, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-10cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁹ is independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- 1₀cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R¹⁰ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, and C₃- 1₀cycloalkyl; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is 0, 1, 2, or 3.

42. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound of Formula IIIc:

Y is selected from O, S, SO₂, and C(R⁸)2;

R² is H and R³ is -CF₃; or

R² and R³ are taken together to form oxo;

R⁴ and R⁵ are independently selected from C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, and C_3-6cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, - SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, - NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C₃- ₆cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10- membered heteroaryl; or

R⁴ and R⁵ are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁶ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; or two R⁶’S attached to the same carbon atom are taken together to form oxo, and any remaining R⁶’s are independently selected from halo, -NR⁹R¹⁰, -OR¹¹, - C(O)R¹¹, -C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, - NR¹³C(O)R¹¹, -NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, CI. ealkyl, C_1-6heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl; each R⁷ and R⁸ is independently selected from halo, -NR⁹R¹⁰, -OR¹¹, -C(O)R¹¹, - C(O)OR¹¹, -C(O)NR⁹R¹⁰, -SOR¹², -SO₂R¹², -SO₂NR⁹R¹⁰, -NR¹³C(O)R¹¹, - NR¹³C(O)NR⁹R¹⁰, -NR¹³SO₂R¹¹, -NR¹³SO₂NR⁹R¹⁰, C_1-6alkyl, C_1- ₆heteroalkyl, C_1-6haloalkyl, C_3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

43. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound selected from the group consisting of:

44. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound selected from the group consisting of:

-893-

45. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound selected from the group consisting of:

46. The method of any one of claims 1-17, wherein the 15-PGDH inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt thereof:

wherein, ring Q is phenyl or 5- to 10-membered heteroaryl;

Z is CR¹ or N;

Y is CR² or N;

R¹ is H, halogen, -CN, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -NR⁸R⁹, -C(O)NR⁸R⁹, -

NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl; each R² is independently H, halogen, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -CN, -C(O)NR⁸R⁹, - NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl; each R³ is independently selected from H, halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, - C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10- membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, or -C(O)NR⁸R⁹;

R⁴ is substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₁-C₈ aminoalkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, substituted or unsubstituted C_1- Q hydroxy alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, each of which is substituted with one or more R⁶; wherein each R⁶ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₁-C₆ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 8- membered heteroaryl; or two R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted C₃-C₈ heterocycloalkyl;

R^5a is H or CH₃; or R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl or substituted or unsubstituted C₃-C₆ heterocycloalkyl; each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is optionally substituted with one or more R^a; each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C_1- C₆haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R^a; each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R^a; each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is optionally substituted with one or more R^a; each R^a is independently selected from halogen, -OH, -CH₃, -CF₃, -OCH₃, -NH₂, - NHCH₃, -N(CH₃)₂, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃; and p is 1, 2, 3, or 4.

47. The method of claim 46, wherein ring Q is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 N atoms.

48. The method of claim 46, wherein ring Q is a phenyl, pyrimidinyl, or pyridinyl.

49. The method of claim 46 or 48, wherein when Q is phenyl then one of R³ is not H.

50. The method of claim 46, wherein

wherein,

X¹, X², X³ and X⁴ are each independently N or CR³; each R³ is independently selected from H, halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, - C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, - NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10- membered heteroaryl, each of which is substituted with one or more R¹³; each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, or -C(O)NR⁸R⁹; each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; and each R^a is independently selected from halogen, -OH, -CH₃, -CF₃, -OCH₃, -NH₂, - NHCH₃, -N(CH₃)₂, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃.

51. The method of claim 50, wherein X¹, X², X³ and X⁴ are each CR³.

52. The method of claim 50, wherein X¹ is N; and X², X³, and X⁴ are each CR³.

53. The method of claim 50, wherein X¹ and X² are each N; and X³ and X⁴ are each CR³.

54. The method of claim 50, wherein X¹ and X³ are each N; and X² and X⁴ are each CR³.

55. The method of claim 50, wherein X¹ and X⁴ are each N; and X² and X³ are each CR³.

56. The method of claim 50, wherein X¹, X², and X³ are each N; and X⁴ is CR³.

57. The method of claim 50, wherein X¹, X², and X⁴ are each N; and X³ is CR³.

58. The method of any one of claims 46-57, wherein each R³ is independently selected from H, halogen, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, - SO₂R¹¹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

59. The method of claim 58, wherein each R³ is independently selected from H, halogen, -C(O)OR¹⁰, -C(O)NR⁸R⁹, and substituted or unsubstituted 5-membered heteroaryl.

60. The method of claim 46, wherein the compound has the structure of Formula V, or a pharmaceutically acceptable salt thereof:

wherein,

Z is CR¹ or N;

X¹ is N or CR^3a;

Y is CR² or N;

NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl; each R² is independently H, halogen, -OR¹⁰, -C(O)R¹⁰, -C(O)OR¹⁰, -CN, -C(O)NR⁸R⁹, - NR⁸C(O)R⁹, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl; R^3a R^3b and R^3C are each independently selected from H, halogen, -CN, -NO₂, -NR⁸R⁹, - OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, - NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, or -C(O)NR⁸R⁹;

R^5a is H or CH₃; or R^5a and one R⁶ combine together with the atom(s) to which they are attached to form a substituted or unsubstituted C₃-C₆ cycloalkyl; each R⁸ and R⁹ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; each R¹⁰ is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C_1- C₆haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹¹ is independently selected from substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ heteroalkyl substituted or unsubstituted, C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₁₀ cycloalkyl, substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R^a; each R¹² is independently selected from H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, and substituted or unsubstituted C₃-C₁₀ heterocycloalkyl, each of which is substituted with one or more R^a; and each R^a is independently selected from halogen, -OH, -CH₃, -CF₃, -OCH₃, -NH₂, - NHCH₃, -N(CH₃)₂, -C(O)OH, -C(O)OCH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -NHC(O)OH, -OC(O)NH₂, and -NHC(O)CH₃.

61. The method of any one of claims 46-60, wherein X^A is NR⁵R⁵.

62. The method of any one of claims 46-60, wherein X^A is OR⁵.

63. The method of any one of claims 46-62, wherein Y is CR².

64. The method of any one of claims 46-62, wherein Y is N.

65. The method of claim 60, wherein the compound of Formula V has the structure of Formula Via, or a pharmaceutically acceptable salt thereof:

66. The method of claim 60, wherein the compound of Formula V has the structure of Formula VIb, or a pharmaceutically acceptable salt thereof:

67. The method of any one of claims 46-66, wherein Z is N.

68. The method of any one of claims 46-66, wherein Z is CR¹.

69. The method of any one of claims 46-66, wherein Z is CH.

70. The method of claim 60, wherein the compound of Formula V has the structure of

Formula Vila, or a pharmaceutically acceptable salt thereof:

71. The method of claim 60, wherein the compound of Formula V has the structure of Formula VHb, or a pharmaceutically acceptable salt thereof:

72. The method of claim 60, wherein the compound of Formula V has the structure of Formula Vile, or a pharmaceutically acceptable salt thereof:

Formula Vile.

73. The method of claim 60, wherein the compound of Formula V has the structure of Formula Vlld, or a pharmaceutically acceptable salt thereof:

Formula Vlld.

74. The method of any one of claims 60-73, wherein X¹ is N.

75. The method of any one of claims 60-74, wherein R^3b is H; and R^3c is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, - SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, - NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or - C(O)NR⁸R⁹.

76. The method of claim 75, wherein R^3b is H; and R^3c is selected from halogen, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

77. The method of any one of claims 60-74, wherein R^3c is H; and R^3b is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, - SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, - NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or - C(O)NR⁸R⁹.

78. The method of claim 77, wherein R^3c is H; and R^3b is selected from halogen, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

79. The method of any one of claims 60-73, wherein X¹ is CR^3a.

80. The method of any one of claims 60-73 or 79, wherein R^3a and R^3b are independently H or halogen; and R^3c is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, - SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or -C(O)NR⁸R⁹.

81. The method of claim 80, wherein R^3c is selected from H, halogen, -NR⁸R⁹, -OR¹⁰, - SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted C_1- C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

82. The method of claim 81, wherein R^3c is -C(O)OR¹⁰, -C(O)NR⁸R⁹, or substituted or unsubstituted 5-membered heteroaryl.

83. The method of any one of claims 80-82, wherein R^3a and R^3b are each H.

84. The method of any one of claims 60-73 or 79, wherein R^3a and R^3c are independently H or halogen; and R^3b is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, -NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1- C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, - SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or -C(O)NR⁸R⁹.

85. The method of claim 84, wherein R^3b is selected from H, halogen, -NR⁸R⁹, -OR¹⁰, - SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted C_1- C₆ alkyl, substituted or unsubstituted C_1-C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

86. The method of claim 84, wherein R^3b is -C(O)OR¹⁰, -C(O)NR⁸R⁹, or substituted or unsubstituted 5-membered heteroaryl.

87. The method of any one of claims 84-86, wherein R^3a and R^3c are each H.

88. The method of any one of claims 60-73 or 79, wherein R^3b and R^3c are each H or halogen; and R^3a is selected from halogen, -CN, -NO₂, -NR⁸R⁹, -OR¹⁰, -SR⁸, -C(O)R¹⁰, - C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, -SO₂NR⁸R⁹, -NR¹²C(O)R¹⁰, -NR¹²C(O)OR¹⁰, - NR¹²C(O)NR⁸R⁹, -NR¹²SO₂R¹⁰, -NR¹²SO₂NR⁸R⁹, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C_1- C₆haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted 5- to 10-membered heteroaryl, each of which is substituted with one or more R¹³; wherein each R¹³ is independently halogen, CN, -NO₂, -NR⁸R⁹, -OR¹⁰, - SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, or -C(O)NR⁸R⁹.

89. The method of claim 88, wherein R^3a is selected from H, halogen, -NR⁸R⁹, -OR¹⁰, - SR⁸, -C(O)R¹⁰, -C(O)OR¹⁰, -C(O)NR⁸R⁹, -SOR¹¹, -SO₂R¹¹, substituted or unsubstituted C_1- C₆ alkyl, substituted or unsubstituted C_1-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C_3-C₈ heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

90. The method of claim 88, wherein R^3a is -C(O)OR¹⁰, -C(O)NR⁸R⁹, or substituted or unsubstituted 5-membered heteroaryl.

91. The method of any one of claims 88-90, wherein R^3b and R^3c are each H.

92. The method of any one of claims 46-91, wherein each R² is H.

93. The method of any one of claims 46-92, wherein R^5a and one of R⁶ combine together with the atom(s) to which they are attached to form a C₃-C₆ cycloalkyl.

94. The method of any one of claims 46-92, wherein R^5a is H.

95. The method of any one of claims 46-94, wherein R⁵ is H.

96. The method of any one of claims 46-95, wherein R⁴ is substituted or unsubstituted Ci-

Cs alkyl, substituted or unsubstituted C₁-C₈ aminoalkyl, substituted or unsubstituted C₁-C₈ heteroalkyl, substituted or unsubstituted C₁-C₈ hydroxy alkyl, substituted or unsubstituted C₃- Cs cycloalkyl, or substituted or unsubstituted C₃-C₈ heterocycloalkyl, each of which is substituted with one or more R⁶.

97. The method of claim 96, wherein R⁴ is substituted or unsubstituted C₁-C₈ alkyl or substituted or unsubstituted C₁-C₈ heteroalkyl, each of which is substituted with one or more R⁶.

98. The method of any one of claims 46-95, wherein R⁴ is substituted or unsubstituted C₃- C₈ cycloalkyl or 4- to 8-membered heterocycloalkyl, each of which is substituted with one or more R⁶.

99. The method of claim 98, wherein R⁴ is cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or tetrahydropyranyl.

100. The method of any one of claims 46-99, wherein each R⁶ is independently halogen, - NR⁸R⁹, -OR¹⁰, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₁-C₆ hydroxyalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted or unsubstituted C₃-C₈ heterocycloalkyl.

101. The method of claim 100, wherein each R⁶ is independently halogen, -OR¹⁰, C₁-C₆ alkyl, C_1-C₆ haloalkyl, or C₃-C₈ cycloalkyl.

102. The method of claim 100 or 101, wherein each R⁶ is independently -F, -CH₃ , -CF₃ , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

103. The method of any one of claims 46-102, wherein the compound is selected from Table 4, or a pharmaceutically acceptable salt thereof.

104. The method of any one of claims 1-103, wherein the condition is a muscle condition.

105. The method of claim 104, wherein the muscle condition is muscle atrophy, muscle damage, a muscle disorder, or muscle injury.

106. The method of any one of claims 1-105, wherein the condition is selected from the group consisting of: Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), an inherited myopathy, myotonic muscular dystrophy (MDD), oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery -Dreifuss muscular dystrophy, myotonia congenita, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, stress induced urinary incontinence, urethral sphincter deficiency, sarcopenia, and any combination thereof

107. The method of any one of claims 1-106, wherein the condition is spinal muscular atrophy (SMA).

108. The method of any one of claims 1-106, wherein the condition is facioscapulohumeral muscular dystrophy (FSHD).

109. The method of any one of claims 1-103, wherein the condition is hair loss.

110. The method of any one of claims 1-103, wherein the condition is skin inflammation and/or damage.

111. The method of any one of claims 1-103, wherein the condition is vascular insufficiency.

112. The method of any one of claims 1-103, wherein the condition is congestive heart failure or cardiomyopathy.

113. The method of any one of claims 1-103, wherein the condition is a gastrointestinal disease.

114. The method of any one of claims 1-103, wherein the condition is renal dysfunction.

115. The method of any one of claims 1-103, wherein the condition is a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder.

116. The method of any one of claims 1-103, wherein the condition is a fibrotic or adhesion disease, disorder, or condition.

117. The method of any one of claims 1-103, wherein the condition is scar formation.

118. The method of any one of claims 1-103, wherein the condition is fibrosis.

119. The method of any one of claims 1-103, wherein the condition is idiopathic pulmonary fibrosis.

120. The method of any one of claims 1-103, wherein the condition is kidney fibrosis.

121. The method of any one of claims 1-103, wherein the condition is acute kidney injury.

122. The method of any one of claims 1-103, wherein the condition is sarcopenia.

123. The method of any one of claims 1-103, wherein the condition is a neuromuscular disease.